Photosensitizers in Medicine, Environment, and Security
Tebello Nyokong • Vefa Ahsen Editors
Photosensitizers in Medicine, Environment, and Security
Editors Tebello Nyokong Department of Chemistry Rhodes University Grahamstown South Africa
[email protected]
Vefa Ahsen Department of Chemistry Gebze Institute of Technology PO Box 141 41400 Gebze, Kocaeli Turkey
[email protected]
ISBN 978-90-481-3870-8 e-ISBN 978-90-481-3872-2 DOI 10.1007/978-90-481-3872-2 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011941751 © Springer Science+Business Media B.V. 2012 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Photosensitizers, in broad a meaning, included molecules interacting with light and having their properties modified under light irradiation. These properties proved to be useful in a wide range of applications, mainly in medical field but as well to solve some environmental problems, security issues, energy generation and modern synthetic methods. The book addresses the synthesis of the photosensitizers with a focus on tetrapyrrolic derivatives, their photochemistry and photophysics, and their use in environmental control, safety, solar energy and medicine. It discusses to common structure which are beneficial to these applications. In particular, tetrapyrrolic derivatives are currently being investigated as potential photosensitisers for applications to solve a wide variety of above cited real world problems. Metalloporphyrins and related metallophthalocyanines have a wide variety of applications due to their diverse chemical, structural, electronic and optical properties. As a result of their bright blue, green to violet colors and excellent fastness to light, traditional uses of metallophthalocynines are as dyes and pigments since nearly one century. In the last decades, their use in high technologic fields was developed as their properties have been found to be matching those required for several modernworld issues. This induced great developments in the design and synthetic method of these derivatives, possibly assisted by theoretical chemistry. Their photochemical and photophysical characterization have therefore a huge importance. High triplet state quantum yields, and long triplet lifetimes as well as high singlet oxygen quantum yields are required for efficient photosensitization, and these criteria may be fulfilled by the incorporation of diamagnetic metals such as zinc, aluminum or silicon into the macrocycle. For medical applications, and especially for treatment of cancer by photodynamic therapy, both metalloporphyrins and related metallophthalocyanines show promise as photosensitisers. PDT uses a combination of a photosensitizing drug and light in the presence of molecular oxygen to obtain a therapeutic effect based on selective cell destruction by the local generation of singlet oxygen, particular in aqueous media. Recently new type of materials – semiconductor quantum dots (QDs) – have became available for use in PDT, because of their considerably higher molar extinction v
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Preface
coefficients than that of any organic molecules. Unfortunately, QDs show very low singlet oxygen quantum yields. Based on this observation, QDs are now being combined with photosensitisers for possible application in PDT. This is the new way of treating cancer through “combination therapy”. In environmental applications, the photosensitisers are employed for water purification and treatment of waste. There is also an increasing demand for more sustainable processes for production of “fine” chemicals without the formation of undesirable toxic wastes, this is the so called “green” chemistry. The MPc complexes are being employed as catalysts for both formation of “fine” chemicals and for treatment of water. For use in photocatalysis (photosensitization), metalloporphyrins and metallophthalocyanines complexes containing non-transition metal ions are employed. For security applications photosensitisers are explored in the protection of lightsensitive elements such as optical sensors, human eyes and other light sensitive material from sudden and intense light sources. This application is based on a property referred to as optical limiting. When light interacts with light-sensitive material or elements, damage may occur if a protective devise is not available. This application has become of importance in warfare, where in many cases laser weapons are used as threats, especially for civil pilots on landing approach or in the army. In solar energy generation, new affordable photovoltaic solar cells that can be used to provide electricity independent from an installed grid is an attractive way of a sustainable supply with electricity. A word to thank the authors who participated and the referees who made a precious contribution to the quality of the book? Tebello Nyokong Vefa Ahsen
Contents
1
Design and Conception of Photosensitisers .......................................... Fabienne Dumoulin
2
Recent Developments of Synthetic Techniques for Porphyrins, Phthalocyanines and Related Systems ....................... Ayşe Gül Gürek and Catherine Hirel
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47
3
The Contribution of Theoretical Chemistry to the Drug Design in Photodynamic Therapy ..................................... 121 Angelo D. Quartarolo, Nino Russo, Emilia Sicilia, and Carlo Adamo
4
Photochemical and Photophysical Characterization ........................... 135 Mahmut Durmuş
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Sensitization of Singlet Oxygen Formation in Aqueous Media ................................................................................... 267 Nina Kuznetsova
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The Use of Phthalocyanines and Related Complexes in Photodynamic Therapy .................................................. 315 Rodica-Mariana Ion
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Combination Therapy: Complexing of QDs with Tetrapyrrols and Other Dyes......................................................... 351 Vladimir Maslov, Anna Orlova, and Alexander Baranov
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Exogenously Induced Endogenous Photosensitizers............................ 391 Gesine Heuck and Norbert Lange
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Photocatalytic Degradation of Pollutants with Emphasis on Phthalocyanines and Related Complexes ........................................ 433 Alexander B. Sorokin
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Photosensitisation and Photocatalysis for Synthetic Purposes ............................................................................ 469 Lucia Tonucci, Alessandro Cortese, Mario Bressan, Primiano D’Ambrosio, and Nicola d’Alessandro
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Photosensitizers in Solar Energy Conversion ....................................... 527 Katja Willinger and Mukundan Thelakkat
12
Chromophores for Optical Power Limiting.......................................... 619 Yann Bretonnière and Chantal Andraud
Index ................................................................................................................. 655
Contributors
Carlo Adamo Laboratoire d’Electrochimie, Chimie des Interfaces et Modélisation pour l’Energie, CNRS UMR 7575, Ecole Nationale Supérieure de Chimie de Paris – Chimie Paristech, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France,
[email protected] Chantal Andraud Laboratoire de Chimie de l’ENS Lyon, UMR 5182 CNRS-ENS Lyon, Université de Lyon, 46 allée d’Italie, 69364 Lyon, France,
[email protected] Alexander Baranov St. Petersburg State University of Information Technologies, Mechanics and Optics, Kronverksky pr. 49, St. Petersburg 197101, Russia,
[email protected] Mario Bressan Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Yann Bretonnière Laboratoire de Chimie de l’ENS Lyon, UMR 5182 CNRS-ENS Lyon, Université de Lyon, 46 allée d’Italie, 69364 Lyon, France,
[email protected] Alessandro Cortese Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Nicola d’Alessandro Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Primiano D’Ambrosio Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Fabienne Dumoulin Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] Mahmut Durmuş Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] Ayşe Gül Gürek Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] ix
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Contributors
Gesine Heuck School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, 30, Quai Ernest Ansermet, CH – 1211 Geneva 4, Switzerland,
[email protected] Catherine Hirel Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey,
[email protected] Rodica-Mariana Ion Analytical Department, National Institute of R&D for Chemistry and Petrochemistry – ICECHIM, 202 Splaiul Independentei, Bucharest 060021, Romania Faculty of Materials Engineering, Mecathronics and Robotics, Valahia University, 013200 Targoviste, Romania,
[email protected] Nina Kuznetsova Federal State Unitary Enterprise “State Scientific Centre “Organic Intermediates and Dyes Institute” (FSUE“SSC”NIOPIK)”, B. Sadovaya str., 1, block 4, Moscow 123995, Russia,
[email protected] Norbert Lange School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, 30, Quai Ernest, Ansermet, CH – 1211 Geneva 4, Switzerland,
[email protected] Vladimir Maslov Center of Information Optical Technologies, Saint-Petersburg State University of Information Technologies, Mechanics and Optics Saint-Petersburg, st. Petersburg 197101, Russia,
[email protected];
[email protected] Anna Orlova St. Petersburg State University of Information Technologies, Mechanics and Optics, Kronverksky pr. 49, St. Petersburg 197101, Russia,
[email protected] Angelo D. Quartarolo Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per Elaborazioni, Parallele e Distribuite-Centro d’Eccellenza MIUR, Universita’ della Calabria, I-87030 Arcavacata di Rende (CS), Italy,
[email protected] Nino Russo Dipartimento di Chimica, Università della Calabria, Via P. Bucci cubo 14c, I-87036 Rende, Italy,
[email protected] Emilia Sicilia Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per Elaborazioni, Parallele e Distribuite-Centro d’Eccellenza MIUR, Universita’ della Calabria, I-87030 Arcavacata di Rende (CS), Italy,
[email protected] Alexander B. Sorokin Institut de Recherches sur la Catalyse et l’Environement de Lyon – IRCELYON, UMR 5256, Université Lyon 1, 2, Avenue Albert Einstein, 69626 Villeurbanne Cedex, France,
[email protected] Mukundan Thelakkat Applied Functional Polymers, NW II, Room 363, University of Bayreuth, 95440 Bayreuth, Germany,
[email protected] Lucia Tonucci Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy,
[email protected] Katja Willinger Applied Functional Polymers, B6, Room 12, University of Bayreuth, 95440 Bayreuth, Germany,
[email protected]
Abbreviations
Abs ADMA ADPA AIP AIST AK ALA ALA 5-ALA ALAD ALAS Al-TSPc AOP AP ARN AT ATO ATR-FTIR AZO BAT BBB BCC BHDC [bmim]BF4 [bmim]PF6 BNCT BPD-MA CaspACE
CB
Absorber Antracene-9,10-bis-methylmalonate Anthracenedipropionic acid Acute intermittent porphyria Advanced industrial science and technology Actinic keratosis 5-aminolevulinic acid Aminolevulinic acid 5-amino levulinic acid ALA–dehydratase ALA-synthetase AlOH-tetrasulfophthalocyanine Advanced Oxidation Processes Apurinic/apyrimidinic sites in DNA on RNA Acid ribonucleic Adenine thiamine Antimony doped tin oxide Attenuated total reflectance - fourier transform infrared (spectroscopy) Aluminium doped zinc oxide Brain adjacent to tumour Blood brain barrier Basal cell carcinoma Benzyl-n-hexadecyldimethyl ammonium chloride 1-Butyl-3-methylimidazolium fluoride-boron trifluoride 1-Butyl-3-methylimidazolium fluoride-hexafluorophosphate Boron-neutron capture therapy Benzoporphyrin derivative monoacid In Situ Marker that provides fluorogenic substrates and inhibitors that allow quantitative measurement of Caspase-1 and Caspase-3 protease activities Conduction band xi
xii
CDCA CEL Chle6 CLSM 1-ClNP CNV COPO 2-CP 3-CP 4-CP CSF CTAC CuP d.r. DBU DCA DCA DCC DCP DCQ DDQ DFO DFT DMAE DME DMF DMF DMPO DMPO DMSO DNA DPA DPBF DSC DTPA DTPC e.e. EDOT EDTA EDTA EMIB(CN)4 [emim]AlCl4 EPR EPR
Abbreviations
Chenodeoxycholic acid Cremophore EL Chlorin e6 Confocal laser scanning microscopy 1-chloronaphthalene Choroidal neovascularization Coproporphyrinogen III oxidase 2-chlorophenol 3-chlorophenol 4-chlorophenol Blood-cerebrospinal fluid Cetyltrimethylammonium chloride Copper [5,10,15,20-tetra(4-tertbutylphenyl)]porphyrin Diastereoselectivity ratio 1,8-Diazabicyclo[5.4.0]undec-7-ene 9,10-Dicyanoanthracene Deoxycholic acid N,N’-dicyclohexylcarbodiimide 2,4-dichlorophenol 2,6-dichloro-1,4-benzoquinone 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Deferoxamine Density functional theory Dimethylamino ethanol Dimethyl ether N,N-Dimethylformamide N,N¢-dimethylformamide 5,5-dimethyl-1-pyrroline-1-oxide 5,5-dimethyl-1-pyrroline-N-oxide Dimethylsulfoxide Deoxyribonucleic acid 1-decylphosphonic acid 1,3-diphenylisobenzofuran Dye-sensitized solar cell Diethylenediaminepentaacetic acid Di-(N,N-trimethylammoniumpropylene)-3,4,9,10-perylenebiscarboximide Enantiomeric excess 3,4-ethylenedioxythiophene Ethylenediaminetetra-acetate Ethylenediaminetetraacetic acid 1-ethyl-3-methylimidazolium tetracyanoborate 1-Ethyl-3-methylimidazolium chloride-aluminium(III) chloride Electron paramagnetic resonance Enhanced permeability and retention
Abbreviations
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Er:YAG Et2S Et2SO EtAc EtOH FC FCS FDA FePcS FeTPPS FRET FTO GABA GC GC-MS GIT Gly GZO H2P H2Pc H2TCP H376 HDMA HMDS HOMO HONb HPD HpD HPPH HTM i-Pr2NEt IL ISC ITO LC LDH L-DSC LOX LSR-SF-SR LUMO MAL MB MBP MBR MC
Erbium:yttrium-aluminum-garnet Diethyl sulfide Diethyl sulfoxide Ethyl acetate Ethanol Ferrochelatase Fetal calf serum American Food and Drug Administration Iron tetrasulfophthalocyanine Iron tetrasulfophenylporphyrin Fluorescence (or Förster) resonance energy transfer Fluorinated tin oxide g -amino butyric acid Guanine cytosine Gas chromatography coupled with mass-spectrometry Gastro intestinal tract Glycine Gallium doped zinc oxide Metal free [5,10,15,20-tetra(4-tertbutylphenyl)]porphyrin Metal free phthalocyanine Tetracarboxyphenylporphyrin Oral squamous cell carcinoma-derived cells n-hexadecylmalonic acid Hexamethyldisilazane Highest Occupied Molecular Orbital N-hydroxy-5- norbornene-2,3-dicarboximide Hematoporphyrin Hematoporphyrin derivative (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) Hole transport material N,N-Diisopropylethylamine Ionic liquid Inter-system crossing Indium tin oxide Ligand centred Lactate dehydrogenase hydrogen Liquid-state dye-sensitized solar cell Human melanoma cells Transplantable sarcoma in rat induced by Rous sarcoma virus strain Lowest Unoccupied Molecular Orbital 5-ALA methylester Methylene blue Maltose binding protein Mitochondrial benzodiazepine receptor Metal entered
xiv
MC540 2-ME MEM MLA MLCT MPA MPc MPc MPcS MPcS4 MPcSn MSA MTCP mTHPC MTT MV MW nBCC [NBupy]AlCl4 NC-TPP NLS NMP 1 O2 3 O2 O/W OCPc OEP ORL P3HT P3TAA PACT PAH PAN PBG PBGD PBGS PBS Pc Pc4 PCNA PCP PD PDT PEDOT
Abbreviations
Merocyanine 540 2-mercaptoethanol Eagle’s minimal essential medium Methyl aminolevulinate Metal-to-ligand charge transfer 3-mercaptopropionic acid Metal phthalocyanine complex Metal phthalocyanine Metal tetrasulfophthalocyanine Tetrasulfonated metallophthalocyanines Metal sulfophthalocyanine obtained by sulfonation, n = 2,3 Methanesulfonic acid Meso-tetra(4-carboxyphenyl)porphine Meso-tetra-phenyl-chlorine Methylthiazol tetrazolium bromide Methylviologen Microwave Nodular basal cell carcinoma N-Butylpyridinium-aluminium(III) chloride N-Confused tetraphenylporphyrin Nuclear localization sequence 1-Methyl-2-pyrrolidinone Singlet oxygen Ground state oxygen Oil in water Octacarboxyphthalocyanine Octaethylporphyrin Oto-rhino-laryngology Poly(3-hexylthiophene) Poly(3-thiophenylacetic acid) Photodynamic antimicrobial chemotherapy Polycyclic aromatic hydrocarbon 1-(2-pyridylazo)-2-naphthol Porphobilinogen Porphobilinogen deaminase Porphobilinogen-synthase Phosphate buffer solution Phthalocyanine HOSiPcOSi(CH3)2(CH2)3N(CH3)2 – Si-phthalocyanine with long axial ligand applicable in PDT Proliferating Cell Nuclear Antigen Pentachlorophenol Fluorescence photodetection Photodynamic therapy Poly(3,4-ethylenedioxythiophene)
Abbreviations
PEG PET PGMEA PI PMII POM PPGIX PPIX PROTO PS PVP Py QD r.t. RB RB RCPV RhB ROS RPE SA SCC SCWO SDS S-DSC SMCC SnET2 spiro-OMeTAD SRB STV TAPc TAPP TBAB TBADT tBP TCO TCP TCPc TEMP TEMPO TEWL Tf TfR TGA
xv
Polyethylene glycol Photo-induced electron transfer Propylene glycol methyl ether acetate Propidium iodide 1-propyl-3-methylimidazolium iodide Polyoxometallated metal complexes Protoporphyrinogen IX Protoporphyrin IX Protoporphyrin IX oxidase Photosensitizer Poly(vinylpyridine) Pyridine Quantum Dot Room temperature Rose bengal dye Rose Bengal Research center for photovoltaics Rhodamine B Reactive oxygen species Retinal pigment epithelium Salicylic acid Squamous cell carcinoma Supercritical water oxidation Sodium dodecylsulfate Solid-state dye-sensitized solar cell Succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate Tin ethyl etiopurpurin 2,2¢,7,7¢-tetrakis(N,N-di-p-methoxyphenylamine)-9,9¢spirobifluorene Sulforhodamine B Streptavidin Tetraaminophthalocyanine Meso-tetra(p-trimethylaminophenyl)porphine Tetrabutylammonium bromide Tetrabutylammonium decatungstate 4-tert-butylpyridine Transparent conducting oxide 2,4,6-trichlorophenol Tetracarboxyphthalocyanine 2,2,6,6-tetramethyl-4-piperidone 2,2,6,6-tetramethyl-4-piperidone-N-oxyl Transepidermal water loss Transferrin Transferrin receptor Thioglycolic acid
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THF TMGT TOC TOF TON TOPO TPA TPA TPD TPP TPPA TPPS TSPc TSPP TX UP UROD UROS UV Vis WAO Zn-Tmtppa tF tT Fd FF FT FD
Abbreviations
Tetrahydrofuran 1,1,3,3- N,N,N¢,N¢-Tetramethyl-guanidinium trifluoroacetate Total organic carbon Turnover frequency Turnover number Trioctylphosphine oxide Two-photon absorption Thiopropionic acid Triphenyldiamine Tetraphenylporphyrin Tetrapyridinoporphyrazine 5,10,15,20-tetra-p-sulphonato-phenyl-porphyrin Tetrasulfophthalocyanine Meso-tetra(4-sulfonatophenyl)porphine Triton X-100 Human epidermal keratinocytes Uroporphyrinogen III decarboxylase Uroporphyrinogen III synthase Ultraviolet Visible Wet air oxidation Zn-tetramethyl-tetra-2,3-pyridinoporphyrazine Fluorescence lifetime Triplet lifetime Photodegradation quantum yield Fluorescence quantum yield Triplet quantum yield Singlet oxygen quantum yield
Chapter 1
Design and Conception of Photosensitisers Fabienne Dumoulin
Abstract This chapter resumes the general strategies and the last progresses in the design of photosensitisers, with chosen examples, many of them being extracted for the last 5 years literature.
1.1 1.1.1
Introduction Some Definitions
Let’s start with some definitions. This chapter deals with the design, the conception of photosensitisers. The design of a molecule consists in defining a molecular structure that will be synthesised. Designed molecules aim at exhibiting properties for specific utilisations in a more or less fundamental and/or applicative extend. The design of a molecule requires a minimum of knowledge about these targeted properties and/or applications, and a good dialogue with the concerned people. The design is thus a multidisciplinary process, at the interface of several fields [1, 2]. While designing molecular structures, eventual synthetic limitations should be kept in mind, as it is always easier to imagine, to draw a molecule on paper, than to make it. “Design”, “conception” are words implying a conscientious, volunteer demarche … but the contribution of random, serendipity shouldn’t be forgotten! Two roots are easily identified in the word “photosensitiser”: photo means in Greek light, and the Latin word “sensus” means perception, deals with what is likely
F. Dumoulin (*) Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey e-mail:
[email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_1, © Springer Science+Business Media B.V. 2012
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to feel, to detect, to be affected by external effects, with variable perception threshold of the intensity of these effects. The basic meaning of photosensitiser is “something affected by light”. This definition is in our case restricted to photodynamic events, to the cases in which the interaction between the photosensitiser and the light occurs in combination with a third partner: oxygen, converted into singlet oxygen. On a strictly photophysical point of view, a photosensitiser is a molecule which upon irradiation at appropriate wavelengths is converted into its excited singlet state. When turning back to its electronic ground state, energy can be transferred via an inter-system crossing to oxygen which is in turn excited into its singlet radical form: singlet oxygen (Type II photosensitisation). Other reactive oxygen species (ROS) can be generated as well by direct electronic transfer from the excited photosensitiser to the molecule (Type I photosensitisation). Most of the photosensitisation reactions are Type II processes, on which will be focus along this chapter. As the events of photodynamic processes are known at an electronic level, the help of theoretical chemistry may be invaluable while designing photosensitisers, see relevant chapter of this book [3, 4].
1.1.2
Different Types of Photodynamic Actions
The singlet oxygen generated during a Type II photodynamic process [5] can be used in different applications, not only in medical fields, but as well for environmental or synthetic purposes. Medical applications Besides the most-known use for cancer treatment, photodynamic therapy is used in the treatment of age-related macular degeneration. Internal Photodynamic Antimicrobial Chemotherapy (PACT) is successfully used to clean and heal infected wounds. At an external level it is used to disinfect surfaces requiring complete aseptisation, such as hospital working places, including surgery-devoted devices. A very large majority of the photosensitisers are for these medical applications. Antimicrobial comprises antibacterial, antiviral [6, 7] and antifungi effects, for blood sterilisation [8, 9]. The number of reviews dealing with the state-of-the-art of the development of photosensitisers at regular intervals highlights the last improvements of the technique [10–13]. Environmental applications Photodynamic processes can be used for water-remediation and pollutants remediations. In the first case it another antimicrobial use, when in pollutants remediation the singlet oxygen is used to oxidize pollutants into environmental safe derivatives. This later issue will be detail in another section of this book (see relevant chapter of this book).
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Design and Conception of Photosensitisers
3
Synthetic applications The oxidative effects of photodynamically generated singlet oxygen can be used for synthetic purposes in oxidation reactions, a topic described later on in the book (see relevant chapter of this book).
1.1.3
Required Properties of Photosensitisers
The required properties of photosensitisers are frequently listed in reviews devoted to this topic [14–17]. A good generation of singlet oxygen, quantified by its quantum yield and lifetime, is the first desired for Type II photosensitisation. The mechanisms from energy and transition point of view are detailed in another chapter. The second important issue is the localisation of the photosensitiser selectively at its action site, as the singlet oxygen is generated and active at the immediate surrounding of the photosensitiser. The targeted application may imply specific features for the photosensitiser: absorption in the biological therapeutic window (at wavelengths not absorbed by the biological molecules such as heme proteins), in the near infra-red region of the electromagnetic spectrum [18, 19], and/or appropriate amphiphilicity [17]. Water-solubility is required for uses in aqueous media, and more especially medical and biological applications, with different chemical possibilities depending on the nature of the photosensitiser [20]. Cationic structures are needed for antibacterial PDT (quaternized substituted porphyrins or phthalocyanines, phenothiazinium, poly-L-lysine/chlorin e6 conjugate [21, 22]).
1.2
1.2.1
Presentation of the Different Types and Generations of Photosensitisers The Different Types of Photosensitisers
Tetrapyrrole-based structures The most represented class of photosensitisers is based on a tetrapyrrolic structure, with a strong occurence of porphyrins (1) and phthalocyanines (2) [23, 24]. Chlorins (3), bacteriochlorins (4), and other related tetrapyrrolic derivatives as porphycenes (5), texaphyrins (6), are being used as well in a less important extend. Expanded structures are reported with still scarce investigations [25]. BODIPY (for boron-dipyrromethene) (7), firstly developed for its fluorescence [26, 27] and other optical properties, is now extremely promising as photosensitiser [28]. Its aza derivatives proved to have excellent tunable singlet oxygen generation properties [29].
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ALA The approved and widely used 5-Aminolevulinic acid (ALA) (8) is actually a precursor of the photosensitising molecule: protoporphyrin IX [30]. ALA is a precursor at the basic stage of the haem biosynthesis, protoporphyriIX being the last step between haem. The photosensitiser is then formed in situ using the cell-available enzymatic sources. Some modifications of its structure were designed to produce more efficient derivatives. Phenothiazinium (9) Methylene blue is historically the first member of this category of compounds. It was firstly used in malaria treatment in the nineteenth century. These intrinsically cationic derivatives are especially suitable for antibacterial treatment. Hypericin (10) This chromophore of naphthodianthrone type is extracted from St John’s wort, and remains only partially studied, either from its chemistry (derivatized structures are uncommon) or physiological effects. Besides its curative use as photosensitiser, it is employed as well as a fluorescence marquor for cancer cells, for which hypericin has a high affinity [31]. N N NH
N M
N
N
N
HN
N
2
N H
R
N
N H N
HN
N
3
N
H N
4
N
R N
N
CI – + H3N
N
O
R
R
6
F
7
N H N
5 OH O
OH
OH O
OH
HO HO
R OH
B
1.2.2
NH
R
R
NH
N HN
N
N
1
R
NH
N
N
O
F
8
S
+
9
10
The Different Generations of Photosensitisers
Another way to classify the photosensitisers has a more historical perspective. The first developed photosensitisers, hematoporphyrin derivatives (HpD) and its purified fraction Photofrin® exhibited several drawbacks that immediately induced a need for new molecules [32]. They are commonly designated as the first generation of photosensitisers. Following the development of new strategies, so-called second and third-generation of photosensitisers have been developed.
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Design and Conception of Photosensitisers
5
Second generation photosensitisers are mainly tetrapyrrolic derivatives based on porphyrins and phthalocyanines. They are well-defined and characterized. A major representative is the clinically used Verteporfin, known as well as Visudyne. The third generation defines photosensitisers targeting the tumours, as for example antibody-specific derivatives. If no new photosensitising structures are being developed as far as we know, needs lie more in the optimization of the existing ones’ properties. Several photosensitisers have been clinically approved in the last decades and are commercially available [13, 33].
1.3
Why New Photosensitisers?
It seems that interrogations about the need for new photosensitisers rise in the last years. The talk given by Professor David A. Russell (University of East Anglia, UK) during the 2008 edition of the International Symposium on Photodynamic Therapy and Photodiagnosis in clinical practice (Bressanone-Brixen, Italy, 7th edition, 7–11 October 2008) was entitled “Do we need any more new photosensitisers for PDT?” If chemists produce numerous new structures at a quite important rythme, the fact is that their biological evaluation doesn’t follow the same tempo, as the procedures are much more time-consuming. In addition, many researches at a biological and clinical stage are performed with already approved photosensitisers, in order to shorter the time of procedure approval if the case arise. This is another point that may the work of chemists maybe less performant. Each design of new structures doesn’t benefit form biological results of relevant structures, and anyway most of the new photosensitisers will never have their biological activity studied, due to a lack of suitable laboratories. The need for new structures was nevertheless obvious since the development of the first hematoporphyrin derivative [34]. This can lead us to one more definition: The efficacy of a photosensitiser, on an application point of view. There is a direct relationship, even if not always known, between the structure of a molecule, its properties and from these properties the use that can be made of this molecule, in a word, its applications (Fig. 1.1). Depending on the researcher/team/background, etc… the diagram goes one way or the other one in the process [35]. Two strategies are exploited, and can be developed following different ways for the design of new photosensitisers: – The photophysical and photochemical optimization of the singlet oxygen generation, the active species of photodynamic process – The selective accumulation of the photosensitiser in the targeted tissues or against the targeted pathogens (case of aPDT)
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Applications
Properties
Structure Fig. 1.1 Structure, properties and applications relationships
1.4
Strategies to Design Photosensitisers
1.4.1
Several Working Axes
The most commonly developed strategies to improve a photosensitiser’s efficacy are presented in Fig. 1.2. Some of these strategies can be combined.
1.4.2
Optimization of Photophysical and Photochemical Properties
Two orientations lead the optimization of the photophysical properties of a photosensitiser: a better generation of singlet oxygen, the active species in a photodynamic process, and the use of excitation wavelengths within the therapeutic window. 1.4.2.1
Optimization of the Singlet Oxygen Generation
The electronic events leading to the generation of singlet oxygen via an intersystem crossing between the photosensitiser and oxygen at its fundamental electronic state can be optimized thanks to several modifications. The quantification of the efficacy of the event is made by the measurement of the singlet oxygene quantum yield and lifetimes. In addition, other physical and biophysical parameters relieving of physics field [36], such as the optimization of light source for better light penetration for example must be cited but won’t be further detailed as they are outside the scope of this chapter devoted to the role of chemists. Incorporation of Heavy Atoms The basic properties of the photosensitising structures can be tailored mainly by the incorporation of heavy atoms [37, 38]. This positive effect [39] increasing the
1
Design and Conception of Photosensitisers
7
Fig. 1.2 Strategies to improve photosensitisers’ properties and efficacy
ISC has been demonstrated in vitro on a wide range of pyrrolic and non-pyrrolic photosensitisers [40]. The effect of the introduction of halogens atoms on photosensitisers such as 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin has been extensively studied [41] and widely utilized to optimize their photophysical and photochemical properties thanks to a more efficient intersystem crossing. A library of halogenated bacteriochlorins has been constituted for systematic investigation purposes [42]. Ng and coll. aimed at increasing the efficacy of silicon phthalocyanines by incorporating halogens atoms. Two octahalogenated silicon phthalocyanines bearing axial PEG [43, 44] were designed and prepared (11, 12), one octabrominated and the other one octachlorinated, whereas the analogous octaiodo derivative couldn’t be obtained. A second axially glucose-substituted with PEG spacer were prepared under their halogenated or non-halogenated form. In order to balance the aggregative effect of the chlorine atoms in aqueous media but to benefit from its heavy effect, only two chlorines were introduced on phthalocyanine (13). Following these results confirming the positive effect of the presence of chlorine atoms, the diaxially diisopropylidene galactose-substituted phthalocyanine (14) [45, 46], the corresponding chlorinated derivatives (15–17) were designed and prepared [47].
8
F. Dumoulin Me
Me O n
O n O
Cl
Br
Cl O
Cl
Br O
Br
Cl
N
O Cl
Br
n: 550 or 750
Me
O
O
O
Si
N
13
O
OO
O
OO
O
O
Cl
O N
N
N
N
Si
N
N
N
N
N
Si
N
O
O
O
O
N
15
Cl
Si
N
N
N
N N
Cl Cl
O
O
Cl Cl
O O
O OO
OO
14
N
O
O OO
N
O
O
O O
Cl
O N N
N
N
N
N
O
Cl Cl
N N
OO
O
O O
Cl
N N
O
OO
O
O
Cl
O
N
N
O
O
O O
N N
O
O O
n
12
O
O O
Me
11
O
O O
N
Br
On
O
Br
O
O
N
Si
N
O
Br
Cl
N
N N
N N
Cl
O
N
N
N
N N
Cl
Cl
N Si
N
N
Si N
O
O Cl
N
N
N
O Br
N
N
OO
16
17
Chemistry of BODIPY allows versatile modifications [48]. Similar attempts were conducted on BODIPY dyes [49], with the preparation of a rather complete series of BODIPY derivatives (18–22) bearing one, two or three iodine atoms at various positions, designed to investigate fine tuning of the expected properties.
I
I
I N
N
I
I N
N
B
B
18
19
NaO3S
N
N
SO3Na
B
20 COOH
I
I N
N B
21
I
I N
N B
22
Same effects were observed for the iodinated hypericin (23), designed with the same purpose to benefit of this heavy atom effect [50].
1
Design and Conception of Photosensitisers
9
OH
O
OH
OH
O
OH
I HO HO I
23 Heavy metals such as platin and palladium are introduced on photosensitisers to successfully enhance their photophysical properties. Two examples are currently at an advanced clinical trials stage: The palladium(II) complex of bacteriopheophorbide : TOOKAD (24) designed by Salomon and Scherz [51–53] and the tin complex of etiopurin (25). O
EtOOC
H N
N
H N Cl N Sn
Pd N
N
H
N Cl N H
HOOC
MeOOC H O
24
25
Following this strategy, platin and palladium were introduced on pyrrolidine-fused chlorins (26 and 27), with a significant increase of the singlet oxygen generation [54]. F
F
F
F
F
F
F
F N
F
N F
N
F
Pt F
N
F
F
F
F
F
F
F
F N
F N
F
F
F
F
N F
N
F
Pd F
N
F
F N F
F
F
F
F
F F
F
F
26
27
F
10
F. Dumoulin
In our case, we played with the central metal of phthalocyanines. Aware of the good water-solubilising effect of glycerol, we compare in a preliminary study the properties of two sets of solketal substitued phthalocyanines metalated by platinum and zinc (28–31, M: Zn or Pt) [55].
O
O
O
O
O O
O
O
O
N
M
N
N
N N O
O
O
28
N
N M
N
O O
O O
O
N
O
O
O
N
N N
O
N
O O
O O O O
29
O O O
N M
N O O
O N
O
N
N
O
O O
N
N
N
O O
N
N
N
O
O O
O
O O
N
O O N
M
N O
N
N
O
O
O
O O
N
O
O
O
O
O
O O
N N
O
O
O
O O O
O
30
O
O O
O O
31
More rare photosensitisers such as chalcogenapyrylium dyes [56] have been designed as well with similar approach.
Inhibition of Aggregation Aggregation quenches the electronic transferts required to generate the singlet oxygen and has therefore a negative effect on a photophysical point of view. This stacking tendency is particularly problematic with phthalocyanines, far more aggregating than other photosensitisers [57]. A common aggregation-lowering effect is provided by bulky substituents, which sterically prevent the stacking of the photosensitisers. This avoids or limits the undesirable quenching of the electronic events. The design of the octatbutylthio substituted Zn(II) phthalocyanine 32 compared with the analoguous substituted by thiooctyl chains proved to be pertinent towards this aim, with the expected benefits in terms of photophysical properties [58].
S
S S
S N N
N Zn
N N
N N
N S
S S
S
32
1
Design and Conception of Photosensitisers
11
Axial substitution of center metals or pseudo-metals has a similar effect: aluminium and silicon phthalocyanines are known to exhibit an enhanced efficacy due to a low aggregation. Non-peripherally substituted phthalocyanines are less aggregated than corresponding ones, due to the intercalating effect of the substituents between the macrocycles [59].
1.4.2.2
Shifting of the Absorption Toward the Therapeutic Window
Due to numerous biologic components absorbing at various wavelengths, ideal photosensitisers are excited by the small range wavelengths in the near-infra region of the visible spectrum, avoiding undesired interactions between the light and biological chromophores. Excitation at such wavelengths offers in addition the advantage to penetrate more deeply the tissues. This range of wavelengths is called the therapeutic irradiation window (Fig. 1.3). Some photosensitisers have this property directly from their structure, when others can be modified to have their maximum absorption wavelength suitably shifted. Usual methods are the extension of the electronic delocalisation via an extended conjugation, or the nature and eventually position of the substituents. One must keep in mind anyway that red-light excitation can yet have negative effects for some cancers (ORL and oesophageal for example) when there is a risk to damage fine organ’s wall. In this case, photosensitisers are excited by green light to avoid such undesirable effects.
Fig. 1.3 Reprinted from Ref. [19] with kind permission of John Wiley & Sons, Inc.
12
F. Dumoulin
Extension of Conjugation On BODIPY, variation of extended conjugation at the 4-pyrrolic position was investigated through a series (33–41) designed to combined fine-tuned conjugation extension combined with tailored amphiphilicity [49]. COOMe
SO3H
COOH
COOnBu
CHO N
N
N
N
B F F
B F F
33
34
B F
N
N B
F
F
38
N
N
B
F
F
35
N
B F
F
F
37 COOMe
N
MeOOC
N
N
BuOn OC
B
B F
N
36
COOMe
COOMe
MeOOC
N
N
N
F F
F
N
F
40
39
COOnBu N B F
41
The extension of the chromophoric system of chlorin by exocyclic substituted double bond induced a bathochromic shift up to 60 nm in the case of 42, and 20 nm for 43, depending on the extension of the electronic delocalisation [60].
N
N
N
N Ni
Ni N
N
N
42
N
43
BODIPY-porphyrin [61] fused conjugate 44 were thus designed with an astonishing combining effect of the two chromophores.
F
F B N NH N
N HN
44
N
1
Design and Conception of Photosensitisers
13
Three BODIPY derivatives (45–47) combining water-solubility and absorption in the therapeutic window thanks to extended conjugation were designed [62], all including bromine heavy atoms and PEG chains. O
O
O O
O O
O
O
O
O
O
O O O
O
O
O
O O
O
O
Me
Me
O O
Br
Br
N
O
N B F
Me
Me
F
Br
Br
N B
Br
Br
N F
45
O
O
F O
O
O
O Br
O
O
O
O
O
O
Me N F
O
O O
O
O
O
F
O
O
O O
N B
O
O O
Br
Br
O
O
O Me
O
O
O
O
O
O
O
O
O
O
46
O O O
O O
O
O
O
O
O
47
On tetrapyrrolic photosensitisors, the extension of the electronic delocalisation can be induced by the addition of a second fused macrocycle. The preparation of fused bi and trinuclear phthalocyanines 48 and 49 shifted their respective absorption to the near infra red as often desired [63, 64] and previously reported [65] (Fig. 1.4). RO
N RO
N H
RO N
RO
N
N
H N
N
N
N
RO
OR
RO
N
N OR
RO
HN
NH
N
N
OR
RO
OR
N
OR
N H
RO N
RO
N N
N OR
N
OR
H N
N
OR
48
RO
N
OR
N
N
N HN
NH N
RO
N
OR
RO
N
OR
N
N
RO
N OR R:
HN
NH N
OR N
OR
49
Modification of Substituents: Nature and Position The substitution pattern of porphyrins and phthalocyanines is easily tunable. In the case of phthalocyanines, the nature and number of substituents (axial and/or macrocyclic: tetra, octa, peripheral, non-peripheral) has a direct important effect on the photophysical properties of the molecule. These parameters are discussed in the relevant chapter of this book and numerous publications [66, 67].
14
F. Dumoulin
Fig. 1.4 Reprinted from Ref. [63] with kind permission of John Wiley & Sons, Inc.
The mono carboxy phthalocyanine 50 (X: CH) and azaphthalocyanine 51 (X: N) were designed with several of these parameters in mind, the design being very well detailed along the manuscript [68]. It combines as said above the aggregation inhibition effect of the bulky tBu groups, a red-shifting effect of the thioether link [69], and in addition further functionalization opportunities.
S
S X
S
X N
X N
N
N X S
N
Zn
N
N X
N X
S X
X
COOH
S
50 X: C 51 X: N
Still for phthalocyanines, same substituents positioned on the non-peripheral position instead of the peripheral ones induce the desired bathochromic shift of 20–50 nm [59].
1
Design and Conception of Photosensitisers
1.4.2.3
15
Photosensitisers for New Excitation Modes
Two-Photon Excitation Recently, the generation of singlet oxygen by a two-photon absorption (TPA) process raised interest, with potential advantages still under investigation [70], with a likely long-term medical use. The main expected advantage is the overcoming of the limited penetration of one photon absorption. The design of relevant photosensitisers depends on the TPA based on different mechanisms [71]. The concerned structures are thus very different. The structures combine cores known to have good TPA properties (52–56 among others) and bearing water-solubilizing groups [72]. –
CH3SO4
H3C(OH2CH2C)3O
Br
Br
O(CH2CH2O)3CH3
N
N
HO3S
Br
Br
O(CH2CH2O)3CH3
52
–
CH3SO4 S
S
SO3K
H3C(OH2CH2C)3O
OMe
+
N+
MeO
53
54
–
CH3SO4 N
+
Br
Br
–
CH3SO4
S
+
S Br
N I
N N
–
N
+
I
–
Br
N+
55
56
Ruthenium complexes proved to be excellent TPA agent and 1O2 generator. Thus the complex below was designed to offered several of the required properties: membrane crossing thanks to suitable ethylene glycol substitution, the photosensitising core being a tri 5-fluorene-1,10-phenanthroline Ru(II) complex (57) [73]. O O O
O O
O O O
N
2
N
N Ru
N O O O
O
N
2 PF6
O
N O O
O
O
O O
O O
O
O O
57
16
F. Dumoulin
1O 2
PUNP
Vis
IR laser
Tumor cell
Drug + SiO2 Antibody
Fig. 1.5 Reprinted from Ref. [76] with kind permission of The American Chemical Society
Mediated Excitation by Upconversion A promising development of nanotechnology in PDT is the use of upconverting nanoparticles, made of lanthanides [74, 75]. Based on the conversion of lowerenergy light to higher-energy light through excitation with multiple photons, they offer the enormous advantages to be excited by infrared wavelengths, a desired property as it fit the biological window and avoid light-interaction with biological absorbing components. PUNP (photon upconverting nanoparticles) have the other required facilities. Its design is explained in the figure taken out of the paper (Fig. 1.5) [76]. Such nanoparticles, by being excited with different wavelengths, solve partially the problem of the tissues-light low penetration [77, 78]. The range of the application of these nanosystems seems to be infinite. This is obviously due to their striking tailorability. Recently, the development of porphyrin-nanosensors made possible the following of intracellular reactive oxygen species [79]. Immobilization of porphyrins on carbon nanotubes has been very recently described [80]. This is one example among the tenth newly described every year.
X-Ray Excitation Since the description of the feasible luminescence generation by X-ray on porphyrins [81], together with singlet oxygen generation, excitation by low dose irradiations is being developed [82].
1
Design and Conception of Photosensitisers
1.4.3
17
Optimization of Biological Parameters
It is important to have the photosensitiser accumulated in a maximum extend on its action site, that is to say on the cancer or bacterial cells. This implies, at the organism level, the in vivo targeting of an injected photosensitiser to the concerned organ (when local topical application for some reasons are not possible or preferred). At a local level, it implies the recognition of the cells to destroy (cancer cells among healthy ones), then a good cell uptake, which means a good membrane crossing of the photosensitiser. An optimized intracellular localization improved the PDT efficacy and thus intracellular targeting may be envisageable. Different strategies have been developed to answer one or more of these issues. In addition, the stability of the photosensitiser inside the organism must be balanced: long enough to reach its target but not too long to avoid poisonuous accumulative issues [15].
1.4.3.1
Optimized Membrane Crossing
Cell membranes are self-assembled structures made of amphiphilic components. Their crossing is therefore easier for amphiphilic molecules. Amphiphilic structures are obtained by introducing two types of substituents on a same molecule, one type being hydrophilic, the other one hydrophobic. The amphiphilic balance of the molecule can be tailored by the nature and number of each of these substituents, and easily combined with other features. Three silicon (IV) phthalocyanines (58–60) having asymmetric axial substitution (one diisopropylidene galactose facing one alkyl chain of various lengths) have been designed to be compared with the symmetrically substituted by two galactose (15) [46]. The design of this series is based on two points: the presence of carbohydrates supposed to be attracted by the highly metabolically active tumour zone, and the amphiphilicity favouring the cell uptake.
OO O O O
O
O
N
N N
Si
N
N
Si
N
O O OO
N
N
O
15
Si
N
O OO
N
O
58
Si
N
N O
O O
N
N N
N
N
O O
N
N N
N
N
N
N N
N N
N
O
O
N
N
O OO
O O
59
O OO
O O
60
N
N
18
F. Dumoulin
In the case of ALA (9), it has been demonstrated that several esterified derivatives have a better cell uptake and thus required less administration. This lead to the design of a rather complete set of ALA esters in order to investigate the influence of the nature of the added part (61–69 ) [30, 83]
Cl H3N
O OH
9 Cl H3N
O
Cl H3N
O
61
O O
Cl H3N
O
O
O
Cl H3N
O
O
O
Cl H3N
O
O
O O
64
O O
O
67
Cl H3N
O
63
O
O
66
Cl H3N
O
62
O
O
65
Cl H3N
O
Cl H3N
O O
O
68
O
69
From mixtures of sulfophthalocyanines (70–74) in the 1980s to the powerful porphyrazine (76) in 2009. The design through several years of photosensitising sulfonated phthalocyanines by van Lier and co-workers is a very good illustration of the design process (Fig. 1.6). Since the PDT properties of zinc (II) sulfophthalocyanines are known [84], and more especially of the adjacent di derivative, it was thought to be possibly because of it amphiphilic nature [85]. A next step was the design of other amphiphilic sulfophthalocyanines, this time with three sulfo units facing one alkyl moiety of various lengths (75) [86]. The following step was the modification of the macrocyclic structure, with the introduction of an annulated benzene ring likely to improve its absorption window and modify the amphiphilic balance again of the molecule (76) [87].
1.4.3.2
Targeting Photosensitiser-Conjugates: The Two Levels of the Design Process
In addition to the required photophysical and solubility properties, the photosensitiser bears a functional group suitable for grafting to targeting moiety. Two designing processes occur in this case: the design of the photosensitiser-targeting agent conjugate, and the design of the photosensitiser under a “graftable” form, with the appropriate functionalisation. The third aspect consisting of the eventual design of the activated targeting moiety isn’t our purpose and won’t be much evokated here.
Design of the Conjugates: Choice of the Targeting Moieties [88] Cancers have characteristic features that are likely to be targeted, presented hereafter and detailed in specific paragraphs afterwards.
1
Design and Conception of Photosensitisers
19 SO3Na
SO3Na
Step 1 A first design: water soluble sulfophthalocyanines Preparation of the different sulfonated Zn(II) phthalocyanines
N
N N Zn
N
N
NaO3S
SO3Na
Di opposite
71
N
72 SO3Na
SO3Na N
NaO3S
N
N
N
Di adjacent
Zn
N N
N
N N
N
N
N Zn
N
N
N SO3Na
N
N
N
N N
N
N
N
N NaO3S
SO3Na
NaO3S
SO3Na
Tri
Tetra
73
74
R
NaO3S
Step 3 Design of more versatile structures with similar amphiphilicity: 4 sulfo and 1 alkyl chain
N Zn
N
N
N
70
N
N Zn
N
Mono
Step2 Determination of the best one Hypothesis: its suitable amphiphilicity
N
N
N
N N
N Zn
N N
Synthetic strategy: coupling of aklynes to the monoiodo
N N
N NaO3S
SO3Na
75
R NaO3S
Step 4 Design of molecule with a better activation window Addition of an annulated benzene ring
N N
N Zn
N N
N N
N NaO3S
76
SO3Na
Fig. 1.6 Multi steps design leading to the porphyrazine 76 with optimized properties and PDT results
20
F. Dumoulin
The rapid development of the continuously dividing cells required high energy, leading to highly active metabolism needing the development of hypervascularisation to bring the required energy and nutriments. Targeting this vasculature system is an exploited mean to eradicate tumour [89, 90]. These two points, the elevated needs in nutriments and energy and the development of neovasculature to carry them are related but will be treated in two different parts. The conjugation of photosensitisers with cancer cells specific antigenic determinant is called photoimmunotherapy, and considered as one of the way to explore to improve photodynamic treatments [91, 92]. This strategy was mainly developed on tetrapyrrolic photosensitiser the number of targeting units grafted on a photosensitiser is an important part of the design, as well as the choice of the other units in case of asymmetrical substitution.
Design of the Functionalised Photosensitiser: Molecular Design and Synthetic Strategies Chemical Derivatizations Several activated functions are commonly used to graft the photosensitiser to the targeting moieties: COOH [93], –N=C=S [94–96], triple bond [97], amine [97], SO3H [98]. These groups react easily with functions present on proteins (case of antibodies), carbohydrates, vitamines or any azido derivatives via a click reaction. Eventuel presence of a spacer to maximize interactions. The presence of a spacer is commonly supposed to be desirable to avoid steric hindrance between the photosensitiser core and the target. Efficacy related to the nature and length of the spacer are routinely investigated (see examples below). Photoimmunotherapy The antibody has generally several reactive functions that can be chemically used for the covalent coupling with the photosensitiser. It depends on its aminoacid composition and on the accessibility of the active residues.
1.4.3.3
The Different Cancer Targeting Strategies
As said above, the biological level of targeting can be various: at a macroscale, the tumour system is targeted. The targeting is based on the high metabolism of the tumour and can be directed against the elevated energy and nutriments (vitamins) required by prolifering cells, or the hyper vasculature developed by the tumour. At a more local scale, the cancer cells can be differentiated from the healthy ones thanks to receptors specifically expressed by the proliferating cells. Then at an intracellular level, uptake into specific organelle is likely to improve the efficacy of the treatment.
1
Design and Conception of Photosensitisers
21
Targeting of the High Metabolism of Tumour Folic acid (77), as a vitamin (B9), is highly demanded by prolifering cells. This is the reason why cancer cells generally overexpress folate receptors [99]. Photosensitiser covalently binded to folic acid is therefore a potentially efficient cancer targeting conjugate. The folate-porphyrin conjugate 79 was designed for this purpose [100, 101], with a short spacer. On a synthetic point of view, the design of the coupling intermediate 78 includes the presence of the spacer and of a activate function for the amide bond creation, the folic acid being activated as well by the DCC-HONb method.
OMe
HO
O
O
N H
O
NH OH
NH OH
N N
N
NH2
O
MeO N
N
HN
NH2
N
77 OMe
78 OMe
O NH
N O
MeO N
HO
HN
HO
H N
HN
O
O
N H
N N
N N
NH2
79 OMe
In the case of folate-porphyrin conjugates 80 and 81, the folic acid moiety is derivatized and grafted on a N-hydroxysuccinimide activated carboxyporphyrin. The design of the two conjugates includes, in addition to the targeting effect of the folate, an investigation of the nature of the spacer, more or less hydrophilic [102, 103].
22
F. Dumoulin
OH
H2N
O O
N
N N
OH
N H
HN
N
O
NH
NH
N
O
NH
NH
N
N H
O
N HN
80
OH
H2N
O O
N
N N
N H
N
OH HN
O
O
N H
O
N HN
81
Biotin, another vitamin known as well as the B8 or H vitamin, is readily uptaken by dividing cells. This lead to the design of the biotine-conjugated aluminum phthalocyanine 82, using a cadaverine spacer [104]. This photosensitiser benefits as well from the modification of its amphiphilicity compared to the corresponding trisulfonated one, used without modification for the grafting of the biotin moieties. O N H
HN S O O N OH N N N O HN H
NH H S H
H N
H HN
H NH O
SO3H N
Al
N
H S
N N H N S O O
O
82
Carbohydrates, as the first and quickest available energy resource of cells, can be used as a substituent of photosensitisers with the same aim: taking advantage of the high metabolism of the prolifering cells to have carbohydrate-photosensitiser
1
Design and Conception of Photosensitisers
23
conjugates internalised by energy demanding cells. The reasons enounced by authors to design and prepare carbohydrates-functionalized photosensitisers are numerous and therefore the object of an entire section of the chapter. Endocrine receptors are overexpressed in tumour. In a steroid-receptor based approach, estradiol-photosensitiser conjugates have been designed and prepared. van Lier et al. prepared a series of several Zn(II) phthalocyanine monoconjugates (83–86) with small structural variations likely to modify the efficacy of the conjugate, and three sulfonates groups for the water-solubility [105]. The syntheses based on a Pd catalyzed coupling of the estradiol moieties was prealably optimized on organosolubles derivatives [106]. The biological activities of both the water-soluble and lipopihilic derivatives were compared. OH
OH SO3Na
N NaO3S
N N
N Zn N
SO3Na
O
O
N
N
N
N
NaO3S
N
N
N Zn N
SO3Na
N N N
SO3Na
83
84 SO3Na
O N NaO3S
N
N
N
N
Zn
OH
N
N
N
SO3Na
85
SO3Na O
N NaO3S
N N
N Zn N
N
OH
N N
SO3Na
86
Other conjugates with a porphyrin photosensitiser core have been designed as well [107, 108].
24
F. Dumoulin
Targeting of the Cancer Neoangiogenic System Angiogenic systems exhibit marquors that are extremely concentrated in tumour growing neovasculature. In this case, photosensitiser can be conjugated to antiangiogenic antibody directed against marker of angiogenesis. A commonly used antibody for such purposes is the antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis. Bis(triethanolamine)Sn(IV) chlorin e6 has been conjugated to L19 (compound 87), via small modification of the photosensitiser [109]. H3C
COOH CH2COOH N
H3C N
Sn
CONH
2+
N
LP19 CH3
N CH2CH3
H 3C
87
With the same strategy, the antiangiogenic antibody L19, expressed in small immunoprotein (SIP) format, has been conjugated to different porphyrins (88–90), designed following different criteria: [110] – cationic substituents ensuring the water-solubility of the conjugate, – one SMCC (succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate) group, chosen as it reacts specifically with thiol functions and can advantageously used for covalent coupling with cysteine containing proteins, – spacer of different length. N N
O NH
O
N
NH
N
N N
N
HN
HN
O
HN
N
O
3I
N
O N H
N
N O
3I
N
89
88 N
O O NH
N
HN
HN
O
O
HN N
O
O
O
O
O
O
HN N O
3I
N
90
Neuropilin-1 is a receptor expressed by endothelial cells, thus very present in cancer neovasculature systems. It can be targeted by photosensitiser to enhance their accumulation in a tumour asphyxia strategy. This receptor is recognised by peptides
1
Design and Conception of Photosensitisers
25
exhibiting unfortunately an excessive degradation by peptidases [111]. A first neuropilin-targeted photosensitiser 91 was designed, made of a photosensitiser core: monocarboxylic tetraphenyl chlorin, covalently linked via an amide bond to a spacer bearing the targeting peptide.
N NH
HN N O
H N
ATWLPPR
O
91
A second step of this neuropilin tarteging strategy, aiming at overcoming the peptidase degradation, was the design of three pseudopeptides, more stable towards peptidases, and conjugated with the same photosensitiser [112]. It is interesting to note that for this series, the main point of the design process is the one of the targeting moiety which isn’t a “native” biomolecule, the photosensitiser itself remaining unmodified. Targeting of Cancer Receptors: Photoimmunotherapy Cancer cells may express specific receptors at their surface. Bombesine is a peptide recognised by a gastrin-releasing peptide receptor [98]. In the case of prostate cancer, this receptor is early expressed and its presence was correlated with elevated tumor aggressiveness, making its targeting judicious. This lead to the design of the photosensitiser 92 conjugating several features: good photopgysical and photochemical properties thanks to an aluminum phthalocyanine core, water-solubility provided by the presence of three sulfonates, a good intereaction with the receptor thanks to a spacer limiting steric hindrance from the phthalocyanine core. −O S 3 NH2
O
N −O S 3
N N
N OH Al N N
N
H N
O S N H O
O N H
O
N
SO3−
H N O
O N H NH
H N O
O N H
H N
O N H
O N
NH
H N
O NH2
O S
92
In order to target ovarian cancer, a photoimmunoconjugate was designed: chlorin e6 was conjugated with a poly Lys residue activated thereafter by a pyridyldithiopropionic acid N-hydroxysuccinimide ester and subsequently coupled with OC-125F (ab8)2, leading to the desired cationic conjugate [113–115]. Similar anionic derivatives with water-solubility provided by succinyl groups instead of the amino are reported.
26
F. Dumoulin
Other monoclonal antibodies have been used for photoimmunotherapy, conjugated to NCS functionalized porphyrins 93 and 94, which have different water-solubilizing patterns [116]. NCS
HO
NCS
OH
N
NH
CI
HN
N
N HN
N
OH
HO
OH
HO
N
NH N
CI
N
CI
93
94
Intracellular Targeting The intracellular repartition of the internalized photosensitiser has an effect as well of the overall PDT efficacy [117–120]. Maximum damaging of DNA is expected to considerably enhance PDT efficacy. It is therefore important in such strategy to concentrate the photosensitiser into the cell nuclei. As retinoic acid receptor are among the nuclear receptors, porphyrins retinamides conjugates (96–99) were designed, with two different retinoic acids (of cis and trans configuration), both grafted by an amide function on the mono aminoporphyrin 95 and the presence or not of a hydrophilic spacer [119].
N
N
HN
HN
NH N
95
N
H N
NH2 NH N
HN
H N
NH N
O
O
96
97 NH
N
N
HN
H O N
O O
98 NH N
N
H O N
O O
N H
HN
99
O
O
H N O
N H
O
O
H N O
1
Design and Conception of Photosensitisers
27
Selective DNA-binding properties of the polyamines derivatives lead to the design of spermine and spermidine conjugates to porphyrin and protoporphyrin IX, with an aliphatic spacer, see the structure of the spermidine-porphyrin 100 [120].
NH2
N
N
NH
O
NH2
N H O
HN
N
100
Targeting of nucleoporins, proteins controlling the nuclear pore-complex can be achieved by derivatization with nuclear localization sequence (NLS). Several constructs made of these peptidique sequence and chlorin e6 conjugated with polyLys residus have been designed for this purpose [118]. Mitochondria is another organelle that can be advantageously targeted. Porphyrins bearing mitochondria localization sequence have thus been designed (101) [121].
NH N
O
N N H
HN
O O
N H
O
MSVLTPLLLRGLTGSARRLPVPRAKIHSL
O 5
O
101
Besides the use of this labelled photosensitisers, derivatization with lipophilic cation is a mitochondria targeting means, due to the high potential of the mitochondria membrane [122], among which triphenylphosphine based cationic (102) [123], guanine (103) and biguanine (104) [121] porphyrins.
NH
N O
N
HN
P
NH N
102
NH2 NH2
N N H
HN
103
N
NH2
CI
NH N
NH2
N N H
HN
104
NH2
CI
28
F. Dumoulin
1.4.3.4
Case of Carbohydrates Substitution
The strong increase of carbohydrate substituted photosensitisers is quite recent and concerns the tetrapyrrolic ones. As far as we could find out, no carbohydrate-BODIPY derivative has been designed to be used as a photosensitiser, nor phenothiazinium derivatives. In addition to the use of carbohydrates as biocompatible water-solubilizing substituents, two targeting approaches cohabit that lead to the design of carbohydratesubstituted photosensitisers: The first one is once again based on the highly active metabolism of cancer cells. Carbohydrates being an available source of energy easily metabolisable, prolifering cells are likely to uptake any glycoconjugates, including carbohydrate-decorated photosensitisers. The carbohydrates have the role of a hook. The second approach is based on the expression by cancer cells of specific lectines recognised by the corresponding carbohydrates following an interaction highly specific, comparable to an antigen-antibody interaction. This approach aims at being more selective. In both cases, the uptake is enhanced by the carbohydrates transporters overexpressed by cancer cells [124]. For these reasons, several glycoconjugates of chlorins (see 105–107) [125, 126], porphyrins (see 108–111) [126–128] and phthalocyanines [119–137] are reported. Systematic variations of the number (105–107) [125], of the position [138] and of the nature (108–111) [127] of the carbohydrates have been studied. The introduction of a spacer between the macrocycle and the carbohydrates was envisaged to study its potential effect [128]. OH
OH HO HO
OH
OH HO HO
HO HO
O
O NH
OH
N
O
N
HO
HO HO
OH OH
HO HO
O NH
N
O NH
OH
N
HN
HN
N
OH HO HO
OH
105 Sugar
Sugar O :
OH
O OH
107
HO
O
O HO
HO
OH OH
N
O
HO
O OH
OH
108
HN
O
HN
OH HO HO
O
106
O
N
/
O
Sugar
O OH
OH
OH
OH HO HO
OH
OH
HO
OH HO HO
O
109
O NH
N
Sugar
O HO
O
O
O OH
HO
O OH
OH
OH
110
111
Sugar
Given the promising results of tetra non-peripherally substituted glycerol Zn phthalocyanines [139], we designed four monocarbohydrate functionalized derivatives
1
Design and Conception of Photosensitisers
29
(112–115). The design aims at still benefiting from the water-solubilizing effect of three glycerols, the fourth substituent being a clicked carbohydrate of different nature at the extremity of a spacer in order to maximize potential interaction with lectine without inhibition due to the steric hindrance of the phthalocyanine macrocycle [129]. OH HO
O
OH
O
O N
N N
N
O
O
O
O
N
N Zn N HO
N
N N O
N
HO
O
OH
HO
AcO
OAc
O O
:
AcO AcO
AcO
O
O OAc
AcO AcO
O OAc
AcO
112
1.4.3.5
OAc
O
113
OAc OAc O
114
AcO AcO
O
OAc
OAc
O
O
O AcO OAc
OAc
O
115
Antimicrobial Photosensitisers
The negative character of the bacterial membrane requires cationic photosensitisers. Their electrostatic interactions ensure of maximized damages by the singlet oxygen. Besides cationic charges, amphiphilic structures optimize the cell penetration. Antimicrobial photosensitisers are used for different applications: blood sterilisation, treatment of infected wounds [140], cleaning of surfaces and materials requiring to be aseptised, waste waters remediation [141]. Phenotiazinium and related derivatives, due to their intrinsic cationic nature, are widely used [142–144]. Since the methylene blue (116) and Nile blue (117) basic structures, the design of optimized photosensitisers followed the strategies enounced previously: – Introduction of heavy atoms: halogens, sulfur [145], – Introduction of hydrophobic chains to enhance the amphiphilicity of a basically highly hydrophilic molecule: DO15 (118) and series with chains variations [146] – conjugation with peptides [147] Me
Me N
N Me2N
S
NMe2
Et2N
O
Methylene blue
Nile blue
116
117
N NH2
Me Me
N Et
S
DO15
N Et
Me Me
118
Many cationic porphyrins and phthalocyanines have been designed and prepared. Several parameters have been studied in a more or less systematic way with the design of series, as for example the charge effect [148] and the nature of the central metal in phthalocyanines: Zn, Ga [149].
30
F. Dumoulin
Recently, cationic prophycene (119) [150] proved to be of potential use in antimicrobial PDT. Br
Br N
N
N H N
N H N
MeO
N
119
1.4.4
Br
Bi and Multicomponents Photosensitisers
This part deals with covalent combinations of two or more active molecules having at least one photosensitiser component. The combination of several properties leads to molecules exhibiting, in addition to the photosensitising ability itself, either other therapeutic effects or imaging properties. One could think that photosensitisers bearing targeting moiety may have taken place here instead of in the previous part. This would have been another way to consider these conjugates, reasonable as well. 1.4.4.1
Combination of Two Photosensitisers
Two ALA-phthalocyanine [151] conjugates were designed to hopefully benefit synergically from their respective effects. As the tetra symmetrically substituted 120 was aggregated in water, the asymmetric derivative 121 has been designed. The menthol substituents, thanks to their bulkiness successfully lowered the aggregation and are expected in addition to improve cell uptake, menthol being a known additive of formulations [152]. O
O
NH3+, CF3SO2−
O(CH2)2O
+H N 3
O(H2C)2O
CF3SOO 2
O
N
N Zn
N
N
O
N
NH3+, CF3SO2−
O(CH2)2O
O(H2C)2O
+H N 3
N N
N O
O NH3 CF3SO2
N Zn
N
N N
N
O
N
N N
CF3SO2−
O(CH2)2O
O
O
O
O O
120
121
Radachlorin is a patented mixture of two photosensitisers, chlorin e6 and purpurine. The effect of this combination is currently under investigation [153].
1
Design and Conception of Photosensitisers
1.4.4.2
31
Combination of Photosensitisers with Other Anticancer Agents
The conjugates of SiPc and cis-platin (122 and 123) [154] were designed following previous conclusions about the synergic effect of PDT and chemotherapy [114], aiming at a “win-win” cooperation, with a nucleus targeting effect thanks to the DNA binding of the cis-platin. H3N NH3 Pt N CI
2+
NH3 N Pt NH3 CI
O
O N
N
N N
2+
Si
N N
N
N
N
N
N
Si
N
N N
N
N O
CI H3N Pt N H3N
CI
N Pt H3N NH3
122
O
123
Conjugates of ruthenium complex and porphyrin were designed following similar idea, and are schematically represented Fig. 1.7 [155].
N N
O
HN
O N N
N H
NH
N
N NH
N
HN
NH
O : ruthenium-based metal fragment N
N
Fig. 1.7 Conjugates of porphyrin and ruthenium complex
N O
32
1.4.4.3
F. Dumoulin
Combination of Photosensitisers with Imaging Agents
This later is increasing exponentially since the last years [156, 157]. This has the following advantages: – Visualisation of the photosensitiser, usually possible thanks to its intrinsic fluorescence, – Follow and monitor the response to the photodynamic treatment The incorporation of radioactive atom to photosensitiser is used to couple imaging and PDT [158]. A covalent amphiphilic combination (124) of a two-photon tumour imaging (a ruthenium complex) and a photosensitiser agent (a porphyrin) was recently obtained [159].
2+ O N N
N
Ru N
NH
NH
N
O N
N
HN
N
124
1.4.4.4
Dual PDT and BNCT Agents
Boron-neutron capture therapy is a tumour treatment based on tumour irradiation with low energy neutrons, inducing the irradiation site production of two cytotoxic species: 4He 2+ and 7Li3+, causing irreversible damage to tissue via ionization processes [160]. The rapid development of the chemistry of carboranyl chemistry extended the range of BNCT agents [161]. The interest of combining this technique with PDT for complete tumour eradication is growing in the last years, leading to the design of several dual BNCT-photosensitiser molecules. Red absorbing photosensitisers are once again prefered during the design of such dual agents. Therefore the chosen photosensitiser core is chlorin, tetrabenzoporphyrin [162, 163] and phthalocyanine [164, 165]. When the exhibition of water-solubility enters the design process, these designed dual agents exhibit the required hydrophily thanks to partial deboronation into ionic derivatives. Reported phthalocyanines bear a various number of boronated units [166, 167]. Their design was based on the synthetic possibilities offered by suitable synthetic pathways and commercially available boronated derivatives. The aim being a dual
1
Design and Conception of Photosensitisers
33
agent, we can note that all the described boronated phthalocyanines are metalated by a Zn. In the case of chlorin derivatives, two molecules offer a good example of the choices made during the design. Tetra boronated derivatives (127–128) [168, 169] focus on a high boron charge when 129 takes advantage of the exceptional photophysical properties of chlorin e6 core but is substituted by only one boronated unit [170]. K
H K
F
S
F
N F
S
F F
F NH N
H
N
N
F F
NH
HN
NH
HN
F
HN
F
N
2
F
F F S
H
125
N
N
F F
F
S
K HH
MeOOC
MeOOC
O
NH N N N
O
O
K
126
127
Recently, it was evidenced that carboranyl including photosensitisers exhibit a higher PDT efficiency than comparable non-carboranyl photosensitisers. This was the case of chlorin [171] and porphyrins [172, 173].
1.4.5
Beyond the Molecular Level. Design of Nanosystems
The exponential interest for nanoparticles in biological [174] and medical fields [175] early reached the photodynamic therapy [176, 177]. We will explain here briefly the impact it has for the design of photosensitiser, as well as the two levels of design occuring during the conception of photosensitising nanoparticles: the design of the nanoobject itself, and the design of the photosensitiser intended to be included in the nanoobject. The purpose of this part isn’t to be exhaustive but to give the reader an idea of the new parameters to be taken in account during design processes. Nanoparticles can be made of very different materials: metal (quantum dots, upconverter, gold nanoparticles), lipids (liposomes, micelles), etc…. Not all of them are suitable for in vivo applications due to their intrinsic toxicity, as in the case of quantum dots that have an amazing photophysical properties enhancing effects [178–180] but are unfortunately made of toxic metals.
1.4.5.1
Photosensitiser-Delivering Nanosystems
Another purpose of nanosystems can be the optimized delivery of the photosensitiser. Emulsions such as the widely used Cremophor EL®, nanogels [181] and pre-mixing
34
F. Dumoulin
with lipids [182], despite their promising effect, are out of the scope of this chapter and won’t be mentioned. Liposomes are an important representant of this use [183, 184]. The encapsulated drug (the photosensitiser in the case of photodynamic therapy) has a better uptake due to optimized endocytose, enhanced by the fusion of the liposome bilayer with the cell membrane, and eventual optimized localization in the organelles [185]. Depending on their composition, liposomes are degraded by photodynamic effect itself [186]. Dendrimer structures such as glycodendrimeric phenylporphyrins associated with liposomes are a type of nanostructures that proved very efficient to enhance the cell uptake of the photosensitiser. They combine the liposome carrying effect with the carbohydrates conjugation [187]. Micelles are more fragile system, used as well for photosensitiser carrying. Depending on their composition, their pH-related stability takes advantage of the tumoral acidic pH for a targeted delivery of the photosensitiser [188]. Protein-based nanoparticles Albumine nanoparticles with hematoporphyrin and gamma-emitting nuclides (99mTc) is a bimodal nanoparticle, used for concomitant scintigraphic imaging and photodynamic therapy [158]. Human Serum Albumin nanoparticles have been used to encapsulate an approved photosensitiser: pheophorbide. The nanoparticles have been designed to take advantage of the Enhanced Permeability and Retention effect of the tumour vasculature, retaining high molecular weight molecules (more than 40 kDa) in a much greater extend than normal cells [189–191]. HSA was a chosen macromolecule for this photosensitiser loading as it has no anti-genic effect and is biodegradable. The delivery of the pheophorbide proved to be as expected very efficient, and the overall phototoxicity after optimum irradiation condition determination was superior to those of free pheophorbide, thanks to the sole apoptosis occurring without necrosis induced by the irradiation [192–194]. The use of other plasma proteins for photosensitisers vectorization such as lipoproteins proved as well efficient to enhanced liposomes (used here this study as a membrane-model) – internalization [195].
1.4.5.2
Photosensitising Nanosystems
Nanoparticles are routinely a way to prepare multimodal objects and can be used as targeting photosensitising objects [92]. A nanoparticle with photodynamic purposes must exhibit the properties previously listed (see part 3. required properties of the photosensitisers). These properties are likely to be affected by the nanoparticle, being either enhanced, lowered or unchanged. A molecular design implies the covalent linkage of several moieties, each having some properties gathered on the molecular construct. In the case of nanoparticles, each of these moieties will be grafted or integrated separately, covalently or not.
1
Design and Conception of Photosensitisers
35
A targeting photosensitising nanoparticle bears some photosensitisers and the targeting units that are now brought together via the nanoparticles. Same things for the solubilizing functions, knowing that emulsion are widely utilized. The design of the nanoparticle 128 by the authors is a good example of the conception of a photosensitising nanoobject, with the following criteria [196]. Choice of the nanoparticles: mesoporous silica nanoparticles have easily tunable size and surface properties. Double decoration pattern: the nanoparticle is covalently linked to a water-soluble photosensitiser. The suitable trisulfonated monoaminoporphyrin was designed to be covalently grafted. Introduction of mannose units likely to target the breast cancer cells is the last feature of this nanoobject.
OH HO HO
OH
O −
O
SO3
NH H N
O O
S MSN
HN
N
−
(CH2)3 HNOCHN
SO3 NH
128
N
−
SO3
Three-component gold nanoparticles were designed [197]: the core gold nanoparticle is covalently bound to highly hodrophobic phthalocyanine, and the addition of a phase transfer agent (tetraoctylammonium bromide) for solubility purposes. This nanoconstruct exhibit most of the PDT desired properties: very good singlet oxygen generation, probably thanks to a heavy atom effect from the PTC-bromide atom, appropriate absorption wavelength (695 nm) due to the non-peripheral substitution pattern of the phthalocyanine, and suitable solubility. Nanoparticles made of organic polymers emerged in the last decade, and have been utilized for brain cancer surgery [198]. One of the advantage is their better clearance by the mononuclear phagocyte system, [199] overcoming one of the biggest problem related to biomedical nanoparticles use. The photophysical properties of dyes loaded encapsulated in these particles has been proved to be unaffected [200]. One should expect therefore bright scope for these polymeric nanopayloads. Upconverter nanoparticles have been described in a previous part of the chapter as they represent a new mode of excitation, nevertheless one should remember that it is among the more promising development of the nanotechnologies for biological and medical photodynamic applications.
36
1.5
F. Dumoulin
Conclusion
This chapter, with a selection of chosen examples, aimed at explaining how photosensitisers are designed. As for all the biological applications, implied criteria are numerous, and it is interesting to highlight the choices made depending on the purpose of the work.
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F. Dumoulin potential bifunctional two-photon tumor-imaging and photodynamic therapeutic agent. J Inorg Biochem 104:62–70 Barth RF, Soloway AH, Fairchild RG, Brugger RM (1992) Boron neutron capture therapy for cancer. Realities and prospects. Cancer 70:2995–3007 Hawthorne MF (1993) The role of chemistry in the development of boron neuron-capture therapy of cancer. Angew Chem Int Ed 32:950–984 Gottumukkala V, Ongayi O, Baker DG, Lomax LG, Vicente MGH (2006) Synthesis, cellular uptake and animal toxicity of a tetra(carboranylphenyl)-tetrabenzoporphyrin. Bioorg Med Chem 14:1871–1879 Ongayi O, Gottumukkala V, Fronczek FR, Vicente MGH (2005) Synthesis and characterization of a carboranyl-tetrabenzoporphyrin. Bioorg Med Chem Lett 15:1665–1668 Li H, Fronczek FR, Vicente MGH (2008) Synthesis and properties of cobaltacarboranefunctionalized Zn(II)-phthalocyanines. Tetrahedron Lett 49:4828–4830 Li H, Fronczek FR, Vicente MGH (2009) Cobaltacarborane–phthalocyanine conjugates: syntheses and photophysical properties. J Organomet Chem 694:1607–1611 Fabris C, Jori G, Giuntini F, Roncucci G (2001) Photosensitizing properties of a boronated phthalocyanine: studies at the molecular and cellular level. J Photochem Photobiol B Biol 64:1–7 Friso E, Roncucci G, Dei D, Soncin M, Fabris C, Chiti G, Colautti P, Esposito J, De Nardo L, Rossi CR, Nitti D, Giuntini F, Borsettoa L, Jori G (2006) A novel 10B-enriched carboranylcontaining phthalocyanine as a radio- and photo-sensitising agent for boron neutron capture therapy and photodynamic therapy of tumours: in vitro and in vivo studies. Photochem Photobiol Sci 5:39–50 Luguya R, Jensen TJ, Smith KM, Vicente MGH (2006) Synthesis and cellular studies of a carboranylchlorin for the PDT and BNCT of tumors. Bioorg Med Chem 14:5890–5897 Hao E, Friso E, Miotto G, Jori G, Soncin M, Fabris C, Sibrian-Vazquez M, Vicente MGH (2008) Synthesis and biological investigations of tetrakis(p-carboranylthio-tetrafluorophenyl) chlorin (TPFC). Org Biomol Chem 6:3732–3740 Bregadze VI, Semioshkin AA, Las’kova JN, Berzina MY, Lobanova IA, Sivaev IB, Grin MA, Titeev RA, Brittal DI, Ulybina OV, Chestnova AV, Ignatova AA, Feofanov AV, Mironov AF (2009) Novel types of boronated chlorin e6 conjugates via ‘click chemistry’. Appl Organometal Chem 23:370–374 Ol’shevskaya VA, Nikitina RG, Savchenko AN, Malshakova MV, Vinogradov AM, Golovina GV, Belykh DV, Kutchin AV, Kaplan MA, Kalinin VN, Kuzmin VA, Shtil AA (2009) Novel boronated chlorin e6-based photosensitizers: synthesis, binding to albumin and antitumour efficacy. Bioorg Med Chem 17:1297–1306 Spiuirril PG, Hill JS, Kahl SB, Ghiggino KP (1996) Photophysics and intracellular distribution of a boronated porphyrin phototherapeutic agent. Photochem Photobiol 64:975–983 Ol’shevskaya VA, Nikitina RG, Zaitsev AV, Luzgina VN, Kononova EG, Morozova TG, Drozhzhina VV, Ivanov OG, Kaplan MA, Kalinin VN, Shtil AA (2006) Boronated protohaemins: synthesis and in vivo antitumour efficacy. Org Biomol Chem 4:3815–3821 De M, Partha PS, Rotello VM (2008) Applications of nanoparticles in biology. Adv Mater 20:4225–4241 http://cordis.europa.eu/nanotechnology/nanomedicine.htm Niamien Konan Y, Gurny R, Allémann E (2002) State of the art in the delivery of photosensitizers for photodynamic therapy. J Photochem Photobiol B Biol 66:89–106 Kumar Chatterjee D, Shan Fong L, Zhang Y (2008) Nanoparticles in photodynamic therapy: an emerging paradigm. Adv Drug Deliv Rev 60:1627–1637 Britton J, Antunes E, Nyokong T (2010) Fluorescence quenching and energy transfer in conjugates of quantum dots with zinc and indium tetraamino phthalocyanines. J Photochem Photobiol A Chem 210:1–7 Chidawanyika W, Litwinski C, Antunes E, Nyokong T (2010) Photophysical study of a covalently linked quantum dot–low symmetry phthalocyanine conjugate. J Photochem Photobiol A Chem 212:27–35
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Design and Conception of Photosensitisers
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180. Idowu M, Tebello Nyokong T (2009) Study of the photophysical behavior of tetrasulfonated metallophthalocyanines in the presence of CdTe quantum dots. Polyhedron 28:891–896 181. Li F, B-c B, Na K (2010) Acetylated hyaluronic acid/photosensitizer conjugate for the preparation of nanogels with controllable phototoxicity: synthesis, characterization, autophotoquenching properties, and in witro phototoxicity against HeLa cells. Bioconjug Chem 21:1312–1320 182. Kello M, Mikĕs J, Jendželovský R, Kovaĺ J, Fedoročko P (2010) PUFAs enhance oxidative stress and apoptosis in tumour cells exposed to hypericin-mediated PDT. Photochem Photobiol Sci 9:1244–1251 183. Sawant RR, Torchilin VP (2010) Liposomes as ‘smart’ pharmaceutical nanocarriers. Soft Matter 6:4026–4044 184. Deryckel ASL, de Witte PAM (2004) Liposomes for photodynamic therapy. Adv Drug Deliv Rev 56:17–30 185. Guelluy P-H, Fontaine-Aupart M-P, Grammenos A, Lécart S, Piette J, Hoebeke M (2010) Optimizing photodynamic therapy by liposomal formulation of thephotosensitizer pyropheophorbide-a methyl ester: in vitro and ex vivo comparative biophysical investigations in a colon carcinoma cell line. Photochem Photobiol Sci 9:1252–1260 186. Pashkovskaya A, Kotova E, Zorlu Y, Dumoulin F, Ahsen V, Agapov I, Antonenko Y (2010) Light-triggered liposomal release: membrane permeabilization by photodynamic action. Langmuir 26:5726–5733 187. Ballut S, Makky A, Loock B, Michel J-P, Maillard P, Rosilio V (2009) Chem Commun 2009:224–226 188. Koo H, Lee H, Lee S, Hyun Min K, Sang Kim M, Sung Lee D, Choi Y, Chan Kwon I, Kim K, Young Jeong S (2010) In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micelles. Chem Commun 46:5668–5670 189. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284 190. Matsamura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanisms of tumoritropic accumulation of protein and the antitumor agent SMANCS. Cancer Res 46:6387–6392 191. Tanaka T, Shiramoto S, Miyashita M, Fujishima Y, Kaneo Y (2004) Tumor targeting based on the effect of enhanced permeability and retention (EPR) and the mechanism of receptormediated endocytosis (RME). Int J Pharm 277:39–61 192. Preuß A, Chen K, Hackbarth S, Wacker M, Langer K, Röder B (2011) Photosensitizer loaded HSA nanoparticles II: in vitro investigations. Int J Pharm. 404:308–316 193. Chen K, Preuß A, Hackbarth S, Wacker M, Langer K, Röder B (2009) Novel photosensitizerprotein nanoparticles for photodynamic therapy: photophysical characterization and in vitro investigations. J Photochem Photobiol B Biol 96:66–74 194. Wacker M, Chen K, Preuss A, Possemeyer K, Roeder B, Langer K (2010) Photosensitizer loaded HSA nanoparticles. I: preparation and photophysical properties. Int J Pharm 393:253–262 195. Bonneau S, Morlière P, Brault D (2004) Dynamics of interactions of photosensitizers with lipoproteins and membrane-models: correlation with cellular incorporation and subcellular distribution. Biochem Pharmacol 68:1443–1452 196. Brevet D, Gary-Bobo M, Raehm L, Richeter S, Hocine O, Amro K, Loock B, Couleaud P, Frochot C, Morère A, Maillard P, Garcia M, Durand J-O (2009) Mannose-targeted mesoporous silica nanoparticles for photodynamic therapy. Chem Commun 1475–1477 197. Hone DC, Walker PI, Evans-Gowing R, Simon FitzGerald S, Beeby A, Chambrier I, Cook MJ, Russell DA (2002) Generation of cytotoxic singlet oxygen via phthalocyanine-stabilized gold nanoparticles: a potential delivery vehicle for photodynamic therapy. Langmuir 18:2985–2987 198. Lee Koo Y-E, Reddy GR, Bhojani M, Schneider R, Philbert MA, Rehemtulla A, Ross BD, Kopelman R (2006) Brain cancer diagnosis and therapy with nanoplatforms. Adv Drug Deliv Rev 58:1556–1577
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199. Gao D, Xu H, Philbert MA, Kopelman R (2008) Bioeliminable nanohydrogels for drug delivery. Nano Lett 8:3320–3324 200. Tang W, Xu H, Park EJ, Philbert MA, Kopelman R (2008) Encapsulation of methylene blue in polyacrylamide nanoparticles platforms protects its photodynamic effectiveness. Biochem Biophys Res Commun 369:579–583
Chapter 2
Recent Developments of Synthetic Techniques for Porphyrins, Phthalocyanines and Related Systems Ayşe Gül Gürek and Catherine Hirel
Abstract This chapter surveys two methods recently developed for the synthesis of porphyrins, phthalocyanines and related compounds: (i) microwave-assisted synthesis and (ii) the use of ionic liquids instead of conventional solvents. These two techniques, that can even be combined, offer several advantages such an increase in the yields and shorter reaction times when compared to the classical reaction conditions. Microwave-assisted reactions can be divided in two main categories, depending on the reaction medium (solid phase or solvent). As it will be discussed in Sect. 2.2 of this chapter, microwave irradiation affords higher yields and leads to noticeably cleaner reaction product. In addition to the green chemistry conditions, the use of an ionic liquid as the reaction solvent enhances the yields and eases the purification process in the synthesis of phthalocyanines and porphyrins, as will be discussed in Sect. 2.3.
2.1
Introduction
Generally, synthesis of phthalocyanines and porphyrins need long reaction times in high temperature boiling solvents that gives low to moderate yield reactions due to the formation of by-products and degradation of the reactants. To by-pass these problems, the development of convenient high-yield techniques is a prerequisite. Two techniques in the synthesis of porphyrins, phthalocyanines and related compounds have attracted a considerable amount of attention in recent years: the use of microwave irradiation instead of conventional thermal heating and utilization of ionic liquids instead of ordinary solvents. Before detailing the A.G. Gürek (*) • C. Hirel Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey e-mail:
[email protected];
[email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_2, © Springer Science+Business Media B.V. 2012
47
48
A.G. Gürek and C. Hirel
Table 2.1 Experimental Conditions for the most common methods in meso-substituted porphyrin synthesis R -6 H+/ 6e− -4H2O
O + 4
4 R
NH
N H
H
N R
R HN
N
R
Solvent
Rothemund Pyridine
Adler (i) Propionic acid (ii) Acetic acid
Lindsey Dichloromethane Chloroform
Temperature
220°C
(i) 141°C (ii) 120°C
25°C
Catalyst
–
Same as solvent
TFA BF3.OEt2 BF3.OEt2/ethanol
Oxidant
–
O2
DDQ or p-Chloranil
Reactant concentration
3.6 M
0.3–1.0 M
0.001–0.1 M
Time of reaction
48 h
0.5–1.0 h
1h
Procedure
One step
One step
Two step
Purification
Crystal separation
Filtration
Chromatography
Yield
<10%
~20%
Up to 40%
Method range
Restrict
Medium
Wide
Adapted from Ref. [1] with kindly permission of Academic Press
advantages of these two techniques, a brief summary of the synthetic pathway of meso-substituted porphyrins and phthalocyanines is presented hereafter. • Porphyrins [1] The most developed method to synthesize symmetric porphyrins is based on the heating of an equimolar mixture of pyrrole and aldehydes upon three different reaction conditions due to Rothemund, Adler and more recently Lindsey. Rothemund synthesis, achieved in boiling pyridine, was shown to be relatively general, but sensitive aldehydes could not be used as they suffer degradation during the harsh reaction conditions. Whereas Adler and Lindsey method are based on an acid-catalyzed condensation, the differences come from the acidic conditions; in the Adler method, the acidic medium is obtained by a high boiling point acid, generally acid propionic or acid acetic, while the Lindsey method uses milder conditions with a chlorinated solvent like such as dichloromethane and a Lewis acid such as boron trifluoride as a catalyst (see Table 2.1). However, the classical methods were not convenient in many cases to obtain asymmetric porphyrins. A strategy has been developed to give access to meso-porphyrins bearing up to four distinct meso-substituents, based on
2 Recent Developments of Synthetic Techniques for Porphyrins…
49
dipyrromethane, tripyrrane or bilane derivatives as building block. The different synthetic routes from dipyrromethanes, acyldipyrromethanes, and dipyrromethane-carbinols are summarized in Scheme 2.1. R2 NH HN R1
R3
HO
OH
R4 NH HN
R2 R2 NH HN R1
O R3
O
O
NH N
X
R2
R3
R1
+ X
+
N
N H
H
HO
OH R1
R3
NH HN
HN
NH HN R4
R4 R4 O
X= H, CO2H, CO2R R2 2
R1
H
R2
NH HN R1
NH HN O
R1=R3 R2=R4
R1=R3 R2=R4
Scheme 2.1 Synthesis of porphyrins from dipyrromethanes derivatives
• Phthalocyanines [2] The synthesis of phthalocyanines, may be accomplished in moderate yields by cyclotetramerization of different phthalocyanine precursors, for example phthalimide, diiminoisoindoline, phthalic anhydride or phthalonitrile in high boiling point solvent in the presence of a strong base like 8-diazabicyclo[5.4.0]undec-7-ene (DBU)(Scheme 2.2). Asymmetric phthalocyanines may be synthesized by statistical methods from the phthalocyanine precursors mentioned above affording mixtures of compounds that have to be isolated by chromatographic techniques. But also, selective methods may be applied depending on the type of product that one wishes to obtain (A3B and trans-A2B2) [3]. An effective method to obtain an A2B2 phthalocyanines results from the reductive condensation of 1,3,3-trichloroisoindolenine derivative with 1,3-diminoisoindoline (see Scheme 2.3). A3B phthalocyanines arise from the enlargement of subphthalocyanines. The approach involves a ring expansion reaction of a subphthalocyanine by treating it with a diiminoisoindoline derivative (Scheme 2.4).
50
A.G. Gürek and C. Hirel
NH
CN
NH3 NH
CN
MCl2, quinoline
PcH2
NH
MCl2, solvent
solvent M
N
N
N
N
M
N
N
N
N
MX2, solvent
PcLi
MX2, M formamide
(H2N)2CO solvent
O
MCl2, formamide O
O O
CN
NH
CONH2
O Scheme 2.2 General synthetic routes to MPcs
B
A N NH
Cl Cl A
N
NH +
N
B
Cl
N
N
N N
NH
HN N
B
A
Scheme 2.3 Selective synthesis of trans-ABAB-phthalocyanines via 1,3,3 trichloroisoindolenine
A
A
A N
Cl N
N N
B
NH +
B
N
N M
N
N
N N
N
NH
N A
N
MX 2
N
N
A B
A
Scheme 2.4 Selective synthesis of an unsymmetrically substituted phthalocyanines (A3B) via subphthalocyanines
2 Recent Developments of Synthetic Techniques for Porphyrins…
2.2 2.2.1
51
Microwave Irradiation General Introduction About Microwave
Microwave heating has become a common technique for chemical applications and it is a performing non-conventional heating source for chemical reactions. In practice, the microwave irradiation penetrates directly through the vessel and heats only the reactant and solvent not the vessel wall, while for conventional heating the temperature on the outside surface is greater than the internal temperature (Fig. 2.1). Microwave irradiation is rapid, with the whole material being heated simultaneously. In contrast, conventional heating is slow and is introduced into the sample from the surface. Microwave heating uses the ability of some compounds (liquid or solids) to transform electromagnetic energy into heat. Heating is produced by dielectric losses, which is in contrast to conduction and convection processes observed in conventional heating. The exact term that must be used is microwave dielectric heating. Consequently, the magnitude of microwave heating depends on the dielectric properties of the molecules that are represented by their dielectric constant and their loss tangent (tan d). A summary of tan d and dielectric loss of some common solvents are summarized in Table 2.13. The microwave dielectric heating is effected via two main mechanisms: (i) dipole rotation also known as dielectric heating and (ii) ionic conduction (Fig. 2.2). In the former mechanism, molecules with a permanent dipole moment submitted to an electric field become aligned. When the field alternates, the molecules reverse direction with each oscillation. Rotating molecules push, pull, and collide with other molecules, distributing the energy to adjacent molecules and atoms in the material causing an intense internal heating. During ionic conduction, ions dissolved in the sample, migrate under the influence of the microwave field; they collide with their neighbouring molecules or atoms. These collisions cause agitation or motion; generating heat [4].
Conventional heating
Microwave heating Vessel wall is transparent to microwave energy
Reactant-Solvent mixture absorb microwave energy
Temperature on the outside surface is greater than the internal temperature
Located superheating
Fig. 2.1 Conventional heating versus microwave heating
52
A.G. Gürek and C. Hirel
Fig. 2.2 Dipole rotation and ionic conduction mechanisms
Even some reactions that do not occur under conventional heating could be performed using microwave (MW), for example the synthesis of 2-substituted-5,6dicyanobenzimidazole compounds via the Rosenmund-Von Braun reaction (nitrilation of dibrominated benzenic derivatives) [5]. The change in reactivity and selectivity can not only be explained by the heating effect but also by a so-called “microwave effect”. In fact, the heat generated by the microwave irradiation is due to a combination of a thermal effect (overheating, hot spots and selective heating) and non thermal effect (molecular mobility, field stabilization) that is still a controversial matter [6, 7]. The synthesis of porphyrins, phthalocyanines and related compounds by MW dielectric heating can be divided into two major categories: Reactions performed (i) with solvent and (ii) without solvent. Reactions with solvent are limited by the use of domestic or modified domestic ovens due to safety risks. Especially, in such systems because of uncontrolled MW heating reaction temperature and pressure can not be kept under control. So, the first publications were focused on developing solvent free reaction conditions that can be performed safely in an open vessel system. Consequently results are not reliable due to the lack of reproducibility. Then, MW ovens dedicated to chemistry were developed, increasing the efficiency and accessibility of this technique, justifying the rapid growing number of publications. Within the category of solvent free reactions, two subdivisions can be encountered: (i) reactions between neat solid reactants and (ii) reactions in the presence of microwave active mineral oxides such as silica and alumina. Numerous examples of phthalocyanines, porphyrins [8] and related systems have been synthesized by microwave dielectric heating whether it be the formation of the macrocycle, its metal insertion or its functionalization.
2.2.2
“Neat Reaction” Syntheses
The advantages of neat reactions are that microwaves interact directly with the reactants without interferences of a solvent and, therefore, can more efficiently drive chemical reactions. Neat reactions were especially developed for the syntheses of
2 Recent Developments of Synthetic Techniques for Porphyrins…
53
phthalocyanines for which a large amount of references may be found. Neat reactions have not been a convenient method to synthesize porphyrins.
2.2.2.1
Porphyrins
Neat porphyrin forming reactions were not successful for porphyrins syntheses. The only reported example [9] does not mention the acidic conditions usually favoring the formation of the porphyrin macrocycle. The synthesis of the porphyrins results from the condensation of pyrrole (1) and aldehyde (2, 3) at 240 W for 5 min. Depending on the substituent of the aldehyde, the yield of the corresponding freebase porphyrins (4 or 5) were 44% (R=C(CH3)3) and 48% (R = OH) respectively (Scheme 2.5).
R
NH 1 N
HN
NH
N
R
+ MW (240 W, 5 min) R
R
CHO 2 or 3
2, 4: R= C(CH 3)3 3, 5: R= OH
4 or 5 R
Scheme 2.5 Synthesis of porphyrins under neat conditions
2.2.2.2
Phthalocyanines
Synthesis of Metallophthalocyanine Macrocycles Synthesis of MPcs in dry medium has been carried out from different precursors such as phthalonitrile, phthalimide, phthalic anhydride and phthalic acid (Scheme 2.6). The reactivity of these phthalocyanine precursors increase in the order: phthalic acid
54
A.G. Gürek and C. Hirel R1
O
R2 O R3 R4
O
R1
R2
R2
CN
R3
CN
R1
R4
R3
R3 R1
R4
O
R2
Metal
R4
N N
R1
R3
R1
N N
M
N
MW
NH R4
R2 N
N
R4
N
O
R2
R1 R2
COONH 4
R3
R3 R3
R4
R1
R2
COONH 4 R4
Scheme 2.6 General synthesis of metallophthalocyanines starting from different phthalocyanine precursors
From Phthalic Anhydride Among the various examples, the first synthesis of metallophthalocyanines under microwave irradiation by A. Shabaani in 1998 should be mentioned [11]. The synthesis of metallophthalocyanines was performed with a home made MW oven without any temperature control; starting from metal salt, urea and phthalic anhydride as metallophthalocyanines precursor. Depending on the metals, the yields were between 81% and 86% (see Table 2.2, entries 1–4). Comparing entries 6/7 and 9/11 in Table 2.1, it highlights the problems of reproducibility of domestic ovens [12]. The synthesis of compounds 8-Co and 8-Cu shows yields of reactions that are not in agreement. Entries 6/7 have yields between 86% and 93% whereas in entries 9/11 reactions do not happen. The reproducibility problems encountered with domestic ovens can be overcome by using ovens dedicated to chemistry.
From Phthalonitrile The higher reactivity of phthalonitrile compared to phthalic acid is confirmed when comparing the synthesis of compounds 6-Cu and 6-Co in oven dedicated to chemistry. Starting from phthalic anhydride (see Table 2.2, entries 28 and 29) the yields
MPc 6-Cu 6-Co 6-Ni 6-Fe
8-FeCl 8-Co 8-Cu
8-Fe 8-Co 8-Ni 8-Cu
10-Cu 10-Co 10-Mn
12-Ni 12-Cu 12-Co 12-Mn 12-Fe 12-Pd
Entry 1 2 3 4
5 6 7
8 9 10 11
12 13 14
15 16 17 18 19 20
R4
R1
O
R1=R3=R4=H; R2=NO2
13
R1=R2=R3=R4=F
11
R1=R2=R3=R4=Cl
9
NH
O
R1=R2=R3=R4=Cl
9
R1=R2=R3=R4=H
7
R3
R2
Ni Cu Co Mn Fe Pd
Cu Co Mn
Fe Co Ni Cu
FeCl Co Cu
Metal (M) Cu Co Ni Fe
Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
Catalyst Mo7O24(NH4)6·4H2O
Table 2.2 Metallophthalocyanines synthesized from phthalic anhydride and urea
900 + 630a
–
–
420 620 620
MW power (watt) 900a 900a 900a 630a
2+1 2+1 1+1 3+1 3+1 4+1
–
–
2 2 2
Time (min) 6 5 4.5 7
30 72 35 14 30 80
No Pc
0
86 92 93
[14]
[12]
[13]
[12]
Ref. [11]
(continued)
Yield (%) 86 81 86 85
2 Recent Developments of Synthetic Techniques for Porphyrins… 55
16-Co
16-Fe
6-Cu 6-Co
21 22 23 24 25
26
27
28 29
R4
R1
b
O
NH
O
7 R1=R2=R3=R4=H
R1=R3=R4=H; R2=COOH
17
R2=R3=R4=H; R1=NO2
15
R3
R2
Domestic oven-multimode Oven dedicated to chemistry-monomode
a
MPc
14-Fe 14-Co 14-Ni 14-Cu 14-Pd
Entry
Table 2.2 (continued)
Metal (M)
Cu Co
Fe
Co
Fe Co Ni Cu Pd
Catalyst
Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
200°Cb 180
10 5
7
3+1 1+1 2+1 2+1 4+1
Medium power
Time (min)
MW power (watt) 900 + 630a
80 52
90 81
30 14 30 72 80
Yield (%)
[16]
[15]
[13]
Ref.
56 A.G. Gürek and C. Hirel
MPc 6-Mg 6-Cu 6-Zn 6-Cd 6-TiCl 6-VO 6-MoO 6-Mn 6-Fe 6-FeCl 6-RuCl 6-Ni 6-Pd 6-Pt 6-Co 6-RhCl 6-Eu 6-Uo 6-La 6-Cr 6-CeCl
6-Pb
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
22
R4
R1
CN
CN
18 R1=R2=R3=R4=H
R1=R2=R3=R4=H
18
R3
R2
Pb
Metal Mg Cu Zn Cd TiCl VO MoO Mn Fe FeCl RuCl Ni Pd Pt Co RhCl Eu Uo La Cr CeCl HCO2NH4 (6 eq) HCO2NH4 (8 eq) HCO2NH4 (8 eq)
Catalyst
Table 2.3 Metallophthalocyanines synthesized from phthalonitrile
Time (min) 5 10 5 10 10 15 10 4 10 10 3 3 10 10 10 5 15 5 – – – 5+5
MW power (watt) 560a 560 490 630 630 560 630 560 630 490 630 560 630 560 560 490 630 630 – – – 720 + 54a 0
92
Yield (%) 89 92 87 88 86 81 83 90 87 79 91 78 65 78 91 87 77 91 87 92 90
(continued)
[15]
Ref. [12]
2 Recent Developments of Synthetic Techniques for Porphyrins… 57
Pb
Metal
Cu Cu Co Co
CN
CN
26 6-Cu 18 27 6-Cu 28 6-Co R1=R2=R3=R4=H 29 6-Co a Domestic oven-multimode b Oven dedicated to chemistry-monomode
6-Cu 6-Co
24 25
19 R1=R3=R4=H; R2=NO2
R4
R1
Cu Co
12-Pb
23
R3
R2
18 R1=R2=R3=R4=H
MPc
Entry
Table 2.3 (continued)
+ 3 drops of water + 3 drop of DMF + 3 drops of water + 3 drop of DMF
Catalyst
10 10 10 10
6
225°Cb 210–220°Cb 180–200°C 180°C
15
180°Cb
16
Time (min)
190–210°Cb
360
a
MW power (watt)
86 82 86 78
86
88
90
Yield (%)
[16]
[16]
[15]
Ref.
58 A.G. Gürek and C. Hirel
2 Recent Developments of Synthetic Techniques for Porphyrins…
59
Table 2.4 Comparison of different reaction conditions Heating method Conventional with solvent: o-dichlorobenzene Dimethylaminoethanol
Yield (%) 2–3 4–5
Fusion MW heating
6–8 4–6
Table 2.5 Metallophthalocyanines synthesized from phthalimide R1
O
R2 NH R3
MPc 12-Fe 20
R4
O
R1 = R3 = R4 = H; R2 = NO2
MW power Time Yield Metal (M) Catalyst (watt) (min) (%) Ref. Fe Mo7O24(NH4)6·4H2O High+medium 2+5 87 [18] power
are 80% and 52% for 6-Cu and 6-Co respectively whereas and from phthalonitrile (see Table 2.3, entries 24 and 25) the yields are 88% and 86% for 6-Cu and 6-Co. In order to improve the temperature homogeneity of the reaction [16], some drops of DMF or water are added. DMF and water are polar solvents with a large loss tangent, able to have a strong interaction with the microwave irradiation. The energy transfer between the polar molecules and the phtalonitrile is rapidly leading to higher heating rates for the whole mixture. Compounds 6-Cu and 6-Co (entries 26–29, Table 2.3) have been synthesized by this method. The yields obtained with the addition of water are better than with DMF, even if they are very similar to those without the addition of polar molecules (entries 24 and 25, Table 2.3). One publication is related with an asymmetric phthalocyanine synthesized by microwave irradiation without solvents. It is an AB3 phthalocyanine obtained by condensation of a mixture of two phthalonitriles [17]. Especially the yields obtained were compared for three different synthetic conditions: conventional method with solvent, conventional method without solvent (fusion) and microwave (see Table 2.4) showing that the best result was obtained by fusion.
From Phthalimide (Table 2.5) From Phthalic Acid Derivatives Phthalic acids were used as well as phthalocyanines precursors. Free-base, Mg, Cu and Zn complexes of tetrasulfonated phthalocyanines [19] were obtained in the presence of ammonium chloride, ammonium molybdate and antimony as catalysts. The syntheses were done by microwave irradiation at 560 W for 10 min with the yields of 72%, 84%, 75% and 77% for Free-base, Mg, Cu and Zn complexes respectively.
60
A.G. Gürek and C. Hirel Table 2.6 Equivalent employed during the microwave synthesis (1,000 W/5 min) HO3 S
COOH COOH
SnTSPc (22) SnTSTBC (23)
26
Urea
SnCl2
Equiv.
32.3 mmol 8.1 mmol
260 mmol 24.3 mmol
4.1 mmol 4.1 mmol
8:64:1 2:6:1
Surprisingly, it was demonstrated that during the synthesis by microwave irradiation of tetrasulfonated tin phthalocyanine (SnTSPc, 22); tetrasulfonated tin-a, b, gtetrabenzcorrole (SnTSTBC, 23) was also formed only by varying the ratio of the reagents [20] (see Table 2.6 and Scheme 2.7).
SO3Na
NaO3S N N
N Sn
N N
N N
N SO3Na
NaO3S HO3S
COOH
urea, SnCl2
COOH
1000W, 5 min
22 SnTSPc
NaOH
SO3Na
NaO3S N
21
N N
N Sn
N
N N SO3Na
NaO3S 23 SnTSBC
Scheme 2.7 Synthesis pathway for SnTSPc (22) and SnTSTBC (23)
In some cases, diammonium salts of phthalic acid were employed instead of phthalic acid to improve yields of the synthesis of phthalocyanine macrocycles [14] (see Table 2.7). Synthesis of Double Deckers Lanthanide complexes of phthalocyanines have been synthesized under neat conditions. The reactivity order of the precursors is: phthalic acid < phthalic
14-Fe
24-Fe
12
25 R1=R4=H; R2=R3=Cl
28 R2=R3=R4=H; R1=NO2 Fe
Fe Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
Mo7O24(NH4)6·4H2O
NH4Cl
11
R1=R3=R4=H; R2=SO3NH4
Ni Cu Co Pd Pt
26-Ni 26-Cu 26-Co 26-Pd 26-Pt
6 7 8 9 10
27
Metallophthalocyanines synthesized from phthalic acid diammonium salt MPc Compound/Substituent Metal (M) Catalyst 24-Fe 25 Fe Mo7O24(NH4)6·4H2O 24-Co Co 24-Ni R1=R4=H; R2=R3=Cl Ni 24-Cu Cu 24-Zn Zn
Table 2.7 Entry 1 2 3 4 5
High+medium
2+5
2+5
2+2 3+1 3+1 2+1 3+1
900+630a
High+medium
Time 7 2.5 8 10 7
MW power (watt) 900a
80
79
55 30 15 34 31
Yield (%) 35 33 57 39 0
[18]
[18]
[14]
Ref. [13]
2 Recent Developments of Synthetic Techniques for Porphyrins… 61
62
A.G. Gürek and C. Hirel Table 2.8 Synthesis of sandwich-type phthalocyaninato lanthanide double complexes from phthalonitrile derivatives MW power Time Conditions 29-Ln LnX3 (watt) (min) 300–450 W 29-Lu Lu(OAc)3 300 5 29-Lu Lu(acac)3 – –
decker
5–8 min
20 17
29-Eu 29-Eu
Eu(OAc)3 Eu(acac)3
450 –
8 –
Yield (%) 16 23
Table 2.9 Axial ligand substitution on titanyl phthalocyanines (H3C)3 C
C(CH3) 3 N N X N Ti
N
N
N
N N C(CH3) 3
(H3 C) 3C
X=
O
O
O
O
O
O
O
C(CH3 )3
O
CHO
O
CN
O
CN
Br O
Br
O
Br Br
Molecule Reaction time (min) Yield (%)
30-Ti-a 7
30-Ti-b 7
30-Ti-c 9
30-Ti-d 7
30-Ti-e 8
30-Ti-f 8
87
84
91
88
95
92
anhydride < phthalimide < phthalonitrile [10]. But only phthalonitrile derivatives give sandwich-type phthalocyaninato lanthanide double decker complexes, while the other phthalocyanine precursors give only mono-lanthanide phthalocanine complexes. With 4,5-dibutyldinitrile as the precursor [21], yields of the corresponding doubledecker (29-Lu, 29-Eu) are summarized in Table 2.8. Functionalization Axial ligation substitution [15] of catechols to tetra-tert-butyl titanyl phthalocyanines (OTiPc(t-But)4) was carried at 800 W power. Titanium will bind to both oxygen atoms in catecholic compounds to form a stable axially substituted molecule. Six different catechols were included in the study which is summed up in Table 2.9. The use of microwave irradiation increased the product yield of these compounds (84–95%) compared to the conventional heating (65–80%) in a solvent like chloroform or a similar solvent.
2 Recent Developments of Synthetic Techniques for Porphyrins…
63
Table 2.10 Solvent free syntheses of porphyrin on solid support MW power Time Yield by Entry Porphyrin Aldehyde Substrate (watt) (min) MW (%) Ref. 1 31 Zeolite Domestic oven 12 23.5 [24] CHO Al-MCM-41 32 2
33 MeO
CHO
Zeolite Domestic oven 12 Al-MCM-41
16
[24]
Zeolite Domestic oven 12 Al-MCM-41
40
[24]
Zeolite Domestic oven 12 HZSM-5(30)
28
[24]
Kieselgel 160 450
38
[25]
34 3
35
4
31
Me
CHO
36 CHO
32 5
37
O
12
CHO 200–500 mm H3 CO
38
2.2.3
Dry Medium Syntheses in Solid Phase: Silica/Alumina/Zeolite
Another way to perform a solvent-free reaction is to mix a solution of starting materials (reactants) in a volatile solvent with a solid support which is able to absorb microwave irradiation (silica, alumina, zeolite). The solvent is then removed via evaporation, and the dry mixture is irradiated by microwaves [22].
2.2.3.1
Porphyrins
Synthesis of Porphyrin Macrocycle The first and quick synthesis of porphyrins [23] in dry media conditions under microwave irradiation was reported in 1992. Heating pyrrole and benzaldehydes, absorbed on a solid acidic support, affords porphyrins within 10 min with less than 10% yield. Porphyrin formation was driven on the surface of inorganic support in which the yield was improved by the acidic nature of the catalyst [24]. The results, varying the aldehydes and the solid supports, are summarized in Table 2.10. One example of the synthesis of asymmetric porphyrin [25] was described in literature with a 13% yield (see Fig. 2.3).
64
A.G. Gürek and C. Hirel
OH
N
HN
NH
N
H 3COOC
COOCH 3
COOCH3 39
Fig. 2.3 Structure of 5- (3-hydroxyphenyl)-10, 15, 20–tris-(4-carboxymethylphenyl) – 21, 23-H porphyrin (39)
Functionalization A nice example of macrocycle functionalization is the formylation of the metalloporphyrins 40-M and 41-M (M=Ni and Cu) by the Duff reaction, Scheme 2.8 [26]. H
R
N R
R N
M N
R
R N
H + / Silica gel
R 40-M 41-M
N
Urotropine
O
40 and 42
41 and 43
R=
R=
N M
N
R N
R M: Ni or Cu
42-M 43-M
Scheme 2.8 Formylation of metalloporphyrin by the Duff reaction
In conventional heating, the standart Vilsmeier reaction is applied to introduce the formyl group on porphyrin. But the Vilsmeier reaction, over a silica gel support, failed with microwave heating and only the demetallation of the porphyrin was observed. This problem was bypassed by using the alternative Duff reaction. The Duff reaction requires strong acidic conditions whereas under such conditions metalloporphyrins undergo demetallation. To overcome this problem, acid was replaced by an acidified silica gel solid support. Depending on the substituent of the porphyrin and the metal (Cu or Ni), 42-M and 43-M were obtained with a yield between 50% and 54%.
2 Recent Developments of Synthetic Techniques for Porphyrins…
65
Table 2.11 Yields of corroles obtained with conventional heating at 120°C during 20 min (NH) and microwave heating during 2–20 min at 120–200°C (MW) Substituent NH Yield MW Yield Substituent NH Yield MW Yield (Ar) Corrole (%) (%) Ar Corrole (%) (%) 45 46 1–1.5 2.5 53 54 9.1 12 CF3 F
47
48
6.7
8.9
F
55
56
5.7–9.5
10.2–11.2
58
4.5
6.2
60
2
3.3
F3 C
F F
F3 C
49
50
F
10.5
14
57 Cl
F
N N F
Cl
F
51
52 F
8–11
13–15
59
F
N F F
F
2.2.3.2
Corroles
Collman and Decréau have developed a modified solvent-free approach for the preparation of a new free base corrole substituted by tris-aryl and tris-pyrimidyl (Table 2.11) using MW irradiation and activated basic alumina (Scheme 2.9). When compared with conventional heating, the MW technique afforded higher yields and led to noticeably cleaner reaction products [27].
Ar
NH
1. MW/solid support ArCHO
NH
+
2. DDQ 32
N
Ar
44 N
N
1 Ar
Scheme 2.9 Synthesis of corroles
66
A.G. Gürek and C. Hirel
Table 2.12 Phthalocyanines synthesis on alumina solid support Phthalocyanine precursors + Urea
COOH
O
CN
O
NO2
CN
NH
COOH
COOH
O
O
2.2.3.3
NO2
O
O
Yields with ammonium molybdate (%) Yields without ammonium molybdate (%)
O
COOH O
7
61
62
18
15
63
55
48
51
79
28
25
34
27
62
61
18
15
Phthalocyanines
The solvent-free syntheses of phthalocyanines have been carried from various phthalocyanines precursors (phthalic anhydrides, phthalic acids, phhalimide and phthalonitrile). Free-base phthalocyanines have been synthesized in 3 min at 700 W in the presence of basic alumina and urea. The influence of the ammonium molybdate as a catalyst [28] was studied in the framework of this reaction (See Table 2.12). Whichever phthalocyanine precursors were used, the presence of ammonium molybdate increased the yield of the reaction except when phthalimide was used.
2.2.4
Syntheses in the Presence of Solvent
The breakthrough of microwave reactor dedicated to chemistry allows the increase of the number of reactions performed with solvents [29]. The key point of the syntheses in the presence of solvent is the choice of an adequate solvent that will be able to interact with the microwave irradiation to produce heat. As mention previously in Sect. 2.1, heating is correlated to the dielectric properties of the molecules which are defined by two parameters (i) the dielectric loss and (ii) the loss tangent (tan d). The dielectric loss represents the polarity of the solvent and the more readily microwave irradiation is absorbed, and the loss tangent represented the capability to absorb microwave energy and to convert the absorbed energy into heat [4]. The ideal solvent should: – Solubilize the reagents – Possess a high loss tangent (tan d) for a good interaction with microwave and – Have a high chemical stability and inertness to minimize side reactions. Generally solvents can be classified as high (tan d > 0.5), medium (tand 0.1–0.5), and low microwave absorbing (tan d < 0.1). Solvent with a tan d > 0.1 are considered suitable for microwave heating [30].
2 Recent Developments of Synthetic Techniques for Porphyrins…
67
Table 2.13 tan d and dielectric loss of some common solvents Solvent tan d Solvent Dielectric loss Ethylene glycol 1.35 Ethylene glycol 49.95 Ethanol 0.941 Formic acid 42.2 DMSO 0.825 DMSO 37.125 Formic acid 0.722 Glycerin 28 Benzyl Alcohol 0.667 Ethanol 22.87 MeOH 0.659 Methanol 21.5 Glycerol 0.651 Nitrobenzene 20.497 Nitrobenzene 0.589 1-Propanol 15.2 1-Pentanol 0.427 Water 9.89 1-Hexanol 0.344 NMP 8.86 Benzaldehyde 0.337 DMF 6.07 NMP 0.275 Acetonitrile 2.325 Acid acetic 0.174 Nitromethane 2.304 H2O 0.123 Acetone 1.12 Chloroform 0.091 Acid acetic 1.08 Nitromethane 0.064 Chloroform 0.437 Acetonitrile 0.062 CH2Cl2 0.382 Ethyl acetate 0.059 Ethyl acetate 0.354 acetone 0.054 THF 0.348 THF 0.047 Toluene 0.096 Dichloromethane 0.042 Hexane 0.038
Microwave active solvents such as polar molecules (DMF, DMSO, etc.) with a high loss tangent and dielectric loss are preferred. However, nonpolar solvent can also be used provided that one of the reactants is polar to generate heat during the irradiation. A summary of tan d [31] and dielectric loss [32, 33] at 2.45 GHz of some common solvents are provided in Table 2.13.
2.2.4.1
Porphyrins
Synthesis of Porphyrin Macrocycles The microwave-assisted synthesis of porphyrins has been focused in the development of the Adler-Longo conditions (Table 2.1), giving symmetrical porphyrins. The experiments that are recapitulated in Table 2.14, were run in refluxing propionic acid at 155–160°C under normal atmosphere. The high concentration allowance for reactants at MW irradiation is an important advantage. The concentrations of reactants are allowed up to 2 M with MW heating. However, typical reactant concentrations are 0.1–0.3 mol and 0.001–0.1 mol for Adler-Longo and Lindsey porphyrin syntheses, respectively For the synthesis of tetraphenylporphyrin (31), Pineiro et al. [34]. obtained a 12% yield (Table 2.14, entry 12) that is really lower compared to the 41% yield
68
A.G. Gürek and C. Hirel
Table 2.14 Free-base porphyrins yields were obtained by Adler-Longo synthetic pathway under microwave irradiation Propionic acid NH + aldehyde
meso-substituted porphyrin MW
[C]a of the MW power Time Yield by solution (watt) (min) MW (%) (mol/l) Ref. – 3–5 41 2 [35]
Entry Porphyrin Aldehyde 1 31
CHO
32 2
64
OMe
–
3–5
43
2
[35]
–
3–5
15
2
[35]
–
3–5
25
2
[35]
–
3–5
28
2
[35]
–
3–5
19
2
[35]
–
3–5
4
2
[35]
–
3–5
7
2
[35]
560
5
56
1.85
[36]
650
5–10 15–18
0.2
[37]
CHO
65 3
33
4
66
MeO
CHO
34 NO2 CHO
67 5
68
6
70
O2 N
CHO
69 Me Me
CHO Me
71 7
72
Cl CHO
73 8
74
9
4
10
31
Cl
CHO
75 CHO
2 CHO
32 (continued)
2 Recent Developments of Synthetic Techniques for Porphyrins…
69
Table 2.14 (continued) Propionic acid NH + aldehyde
meso-substituted porphyrin MW
Entry Porphyrin Aldehyde
[C]a of the MW power Time Yield by solution (watt) (min) MW (%) (mol/l) Ref.
11
400
10
12
–
[38]
560
5
12
2
[34]
76 N
N
CHO
N
12
31
77
CHO
32 Concentration of the solution based on aldehyde
a
obtained by Chauhan and coworker (Table 2.14, entry 1). This divergence of results may be correlated to the use of domestic ovens that limit the reproducibility of the reactions. The same reaction achieved with a microwave dedicated to chemistry (Table 2.14, entry 10) provided a maximum yield of 18% yield. To increase the yield of the synthesis of porphyrins and especially to bypass the well known formation of chlorin as a by-product, nitrobenzene was added to the reaction mixture as an oxidant. Due to its dielectric constant and high boiling point, nitrobenzene (tan d = 0.589) has good features for MW irradiation [29]. The results obtained in presence of nitrobenzene were summarized in Table 2.15. To study the effect of solvent and pressure in the synthesis of porphyrin, it is preferable to consider the results obtained in microwave ovens dedicated to chemistry as mentioned in the publication of Cavaleiro et al. [37] The synthesis of the tetraphenylporphyrin (31) was accomplished in propionic acid and propionic acid/ nitrobenzene at atmospheric pressure and under pressure in a closed vessel in propionic acid/nitrobenzene. These results are summed up in Table 2.16. In the closed vessel, the temperature of the solution can go above boiling point, generating an internal pressure that can reach the maximum value of 3 bars. In these conditions, the yield of 35% has been obtained which is higher than the 20% yield obtained by conventional heating [39]. To explain the effect attributed to the MW irradiation, the thermodynamic factors of the reaction have been calculated. The activation energy (Ea) and the entropy (−TDS) are grouped in Table 2.17. Both of these values are smaller for microwave heating than in conventional heating. Under microwave irradiation, molecules align and realign themselves with the oscillating electromagnetic field. Therefore, the entropy of the system is smaller; the molecules are better organized with a better possibility to enter in contact and to react.
70
A.G. Gürek and C. Hirel
Table 2.15 Free-base porphyrins yields in presence of nitrobenzene
Entry 1
Porphyrin 31
Aldehyde CHO
[C] of the solution (mol/l) 2
Ref. [34]
8
2
[34]
5× 1 min
21
2
[34]
640
5× 1 min
4
2
[34]
640
5× 1 min
5.5
2
[34]
640
5× 1 min
12
2
[34]
640
5× 1 min
8
2
[34]
640
5× 1 min
15
2
[34]
640
5× 1 min
12
2
[34]
640
5× 1 min
20
2
[34]
640
5× 1 min
25
2
[34]
640
5× 1 min
2
[34]
MW power (watt) 640
Time 5× 1 min
640
5× 1 min
640
Yield by MW (%) 20
32 2
72
Cl CHO
73 3
74
4
78
Cl
CHO
75 Cl CHO Cl
79 5
80
Br CHO
81 6
82
Br
CHO
83 7
84
O2 N CHO
85 8
86
MeO CHO
87 9
88
HO CHO
89 10
33
MeO
CHO
34 11
2
12
70
CHO
4 Me Me
1.5
CHO Me
71 (continued)
2 Recent Developments of Synthetic Techniques for Porphyrins…
71
Table 2.15 (continued)
Entry
Porphyrin
13
90
Aldehyde OMe MeO
Time
Yield by MW (%)
[C] of the solution (mol/l)
Ref.
640
5× 1 min
13
2
[34]
650
5–10 min
20
0.2
[37]
MW power (watt)
CHO OMe
91 14
31
CHO
32
Table 2.16 Synthesis of porphyrin 31 from benzaldehyde without and with pressure MW power Yield by Concentration Method (watt) Time (min) Temp (°C) Pressure MW (%) (mol/l) Propionic acid 650 5–10 155–160 Atm 18 0.2 Propionic acid/ 650 5–10 155–160 Atm 20 0.2 nitrobenzene Propionic acid/ 650 5 200 3 bar 35 0.2 nitrobenzene –closed vessel
Table 2.17 Thermodynamic factors of the synthesis of porphyrin (31): Microwave versus normal heating
Conditions Oil-bath (longo condition [40]) MW (experimental result)
Ea(kj) 58.5
−TDS (kj) 4.18
14.9
3.93
Consequently, the energy value necessary to induce the reaction, represented by its activation energy, is divided by 4. The closed vessel conditions mention above, were adapted to the synthesis of resorcin[4]arene cavitant-capped porphyrin capsules [41] (Scheme 2.10). The best yield was obtained at 160°C for 5 min with a reaction concentration of 0.01 mol.dm3. A single example has been reported of one-pot microwave-promoted synthesis of metalloporphyrins (4-M) directly from pyrrole and 4-tert-butylbenzaldehyde [42]. See Scheme 2.11 and Table 2.18. In recent years, great efforts have been performed to improve and develop new and powerful versatile synthetic methods giving access to porphyrins with high yields and a variety of substituents. Among them, a one-pot microwave-assisted synthesis of porphyrin was described taking advantage of the mild Lewis-acidity of iodine and microwave activation to catalyze the condensation between pyrrole, aldehydes and dichloromethane, leading to a new porphyrin synthesis method (Scheme 2.12). The parameters of the
72
A.G. Gürek and C. Hirel R
R R
R
H O
O
Pyrrole
n O
n(H2C)
n(H2C)
O
O O
O
Propionic acid MW
O O
O
O
n(H2C)
O
O
(CH2)n
O
R
O N NH
4
92a-f
O
O
O
O
HN N
93a-f
93a 93b 93c 93d 93e 93f
R: C5H11 C5H11 C5H11 CH2CH2C6H5 CH2CH2C6H5 CH2CH2C6H5
n 4 3 2 4 3 2
Yield (%) 10 10 17 8 13 18
Scheme 2.10 Synthesis of resorcin[4]arene cavitant-capped porphyrin capsules 93a-f
CHO
H N
N
Propionic acid, DBU, Metal N
+ MW (560 Watt, 5 min)
2
1
M
N
N
4-M
Scheme 2.11 One pot microwave-promoted synthesis of metalloporphyrins
reaction, like the influence of the concentrations of pyrrole, benzaldehyde and I2, the temperature and the power of activation, were optimized. Based on the preferred conditions TPP (31) was obtained between 35% and 47% yield [43] (Table 2.18). The key advantages of this method includes short reaction times, opportunity of working at high reagent concentrations (compared
2 Recent Developments of Synthetic Techniques for Porphyrins… Table 2.18 Yields for the one-pot synthesis of 4 4-Mg 4-Cu 4-Tb M= Mg Cu Tb(OAc) Yield (%) 58 61 56
73
4-Lu Lu(OAc) 51
4-La La(OAc) 54
Ph O H N
I2 , CH2Cl2 + MW
N
Ph
HN
Ph
p-chloranil
NH
N
MW
Ph 1
N
HN
NH
N
Ph
Ph
Ph
Ph
32
31
Scheme 2.12 One-pot synthesis of TPP in presence of I2
Table 2.19 Yields in function of the different reaction conditions Reagent concentration Activation Activation time I2 (equiv) (mol/L) conditions (min)first/second 0.1 0.2
10−2 10−1
30°C–100 W 35°C–300 W
20/1 1/1
Isolated yield (%) 47 35
to Lindsey’s method), and possibility of using undistilled reagents and solvents (see Table 2.19). Lindsey et al. have promoted a microwave-assisted synthesis of porphyrins based on dipyrrolic (dipyrromethane) or tetrapyrolic (bilanes) precursors to allow the synthesis of porphyrins bearing four (A4, cis-A2B2, cis-ABC2, trans-A2B2) or fewer (A, cis-AB, cis-A2, trans-A2) meso substituents. The method entails condensation of two 1-acyldipyrromethanes in the presence of a metal salt (MgBr2, 3 mol equiv) and a noncoordinating base (DBU, 10 mol equiv) in toluene under microwave heating and exposure to air. The condensation of two identical 1-acyldipyrromethanes was used to synthesize selectively trans-A2B2 (Table 2.20) [44], whereas the synthesis of various 1–4 meso porphyrins was enabled by condensation of two nonidentical 1-acyldipyrromethanes [45] (Table 2.21) for which access is limited via other methods. The magnesium porphyrins undergo easily demetallation and may be efficiently isolated as a free-base species. The intramolecular cyclization of 1-bromo-19-acylbilane [46] in the same conditions as previously mentioned for 1-acyldipyrromethanes, giving access to a new route to porphyrins bearing four distinct meso substituents (Table 2.22).
74
A.G. Gürek and C. Hirel
Table 2.20 Synthesis of trans-A2B2-magnesium porphyrin directly from 1-acyldipyrromethanes [44] R2 R2
DBU, MgBr2 Toluene, air
H
NH HN R1
N R1
MW, 115 oC
N Mg
N
R1 N
O R2
Entry 1
Porphyrin 95a- Mg
1-acyldipyrromethanes Cmpd R1 F F 94a
R2
Yields (%) 1
Refs. [45]
F F
2
95b- Mg
94b
3
95c- Mg
94c
4
95d- Mg
94d
F
–H
95e- Mg
94e
6
95f- Mg
94f
[45]
19
[45]
61
[45]
47
[45]
21
[45]
4
[45]
13
[45]
37
[44]
N
N
5
0
N
N
N N
7
95 g- Mg
94 g
–H N
8
95 h- Mg
94 h
–H
O O
9
95i- Mg
94i
–H
–H
Metallation of Porphyrins The classical method to obtain metalloporphyrins is to metallate free-base porphyrins. The common metal insertion use an excess of metal salt in refluxing solvents like pyridine (bp = 115°C), DMF (bp = 153°C) or benzonitrile (bp = 191°C). This method has been directly adapted to microwave heating but also DBU or ionic liquid have been utilized; results are summarized in Table 2.23. The yield of the metallation of porphyrin is influenced by the counter-ion involved in the reaction. For example, in the case of Mn (see Table 2.23, entries 23 and 24) 83% and 70% yield have been obtained with MnCl2 and with Mn(OAc)2 respectively. Depending on the metal ion source, an order of reactivity may be deduced. In ionic solvent (Table 2.23, entries 23–28) the reactivity is as follow Fe~Co<Mn
2 Recent Developments of Synthetic Techniques for Porphyrins…
75
Table 2.21 Statistical cis-AB-porphyrin synthesis from two non-identical 1-acyldipyrromethanes [45] R2
H
NH HN R1
O
94 +
1) DBU, MgBr Toluene, air MW, 115 oC
R2
2
NH
2) Dem etallation
HN
N
N
4
94k
N
HN
HN
cis -AB- por phy rin
N
. Yield (%) 12
Porphine Yield (%) 15
trans 95 95j
Yield (%) 13
cis 97 97j
95d
28
97d
3
13
95e
27
97e
14
16
95k
9
97k
11
7
95f
14
97f
NI
NI
95l
0
97l
11
28
95g
32
97g
Trace
95m
21
97m
11
N
N
N
N
94f
Porphine
97
N
94d 94e
N
+
95
1-acyldipyrromethanes Cmpd R1 R2 94j
3
NH
N
R1
R2
N
5
+
trans-A B-porphyr in 96
2
NH R1
N
O
Entry 1
N
R1
NH HN H
R2
N N
6
94l
N
N
7
94g
–H
6
N
8
94m
–H
N
Trace
NI not isolated
The experiments performed in a closed vessel (entries 29–33) allow working at temperatures above the boiling point of the solvents giving a quantitative yield (entries 29, 31 and 33) in the optimized conditions. Faure et al. have demonstrated a strong kinetic effect of lithium ions on the metallation of porphyrin by lanthanides (erbium and gadolinium) in dimethylacetamide. The catalytic effect of lithium is concentration-dependent and was observed both with classical heating and microwave irradiation (Scheme 2.13). In the same conditions of temperature and pressure, it was established that microwave irradiation exerts a strong effect on the rate constant ka when compared to classical heating. The ka value of erbium (gadolinium) for microwave irradiation is 35-fold (14-fold) higher than for conventional heating (Table 2.24).
98g 98h
7 8
4
98e
98d
3
98f
98c
2
5
98b
Entry 1
6
Bilane Cmpd 98a
R1
R1
N
N
R2
N
N
O
N H R3 H
N H HN
R4
98
-H
R2
N
N
N
N
R= ar yl, pyr idyl, alkyl
NH
H
Table 2.22 Synthesis of ABCD porphyrins [46]
Br
H
R3
R4
2) D e m e ta l l a ti o n
N
N
N
N
1) DBU, MgBr2 Toluene 100 mM, air MW, 115o C R1
R4
M N
N
16 23 18 24
99f- 2H 99g- 2H 99h- 2H
25
17
8
99e- 2H
99d- 2H
99c- 2H
99b- Mg
Yields (%) 12
Porphyrin
.
R3
99a- Mg
99
M= Mg(II),or H 2
N
N
R2
Type
ABCD ABCD
trans-AB2C
cis-A2B2
ABCD
trans-AB2C
A3 B
trans-AB2C
76 A.G. Gürek and C. Hirel
Por 4-Lu 4-Mg
5-Mg
88-Zn 88-Cu 88-Ni 88-Mn
74-Zn 74-Cu 74-Ni 74-Co
74-Mn 74-Mn
Entry 1 2
3
4 5 6 7
8 9 10 11
12 13
Cl
HO
HO
Ar=
NH
N
Ar
N
HN
100–110°C 320 W; 5 mina
[Bmim][BF4]b
MnCl2..H20; 1.5 eq
MnCl
Zn Cu Ni Co Mn
480 W; 3 mina 480 W; 3 mina 480 W; 3 mina 480 W; 3 mina 480 W; 3 mina DMF DMF DMF DMF DMF
Zn Cu Ni Mn
480 W; 3 mina 480 W; 3 mina 480 W; 3 mina 480 W; 3 mina
Ar
Mg
N
N
240 W, 5 mina
Ar
M
M= Lu(OAc) Mg
N
N
Ar
Conditions 240 W, 5 mina 240 W, 5 mina
Ar
Zn(OAc)2. xH2O; 5 eq Cu(OAc)2. xH2O; 5 eq Ni(OAc)2. xH2O; 5 eq Co(OAc)2. xH2O; 5 eq Mn(OAc)2. xH2O; 5 eq
DBU
Solvent DBU DBU
MW
Metal salt Solvent
DMF DMF DMF DMF
Ar
Zn(OAc)2. xH2O; 5 eq Cu(OAc)2. xH2O; 5 eq Ni(OAc)2. xH2O; 5 eq Mn(OAc)2. xH2O; 5 eq
MgCl2; 1.5 eq
Metal salt Lu(OAc)2; 1 eq MgCl2; 1.5 eq
Ar
Ar
Table 2.23 Microwave-promoted metallation of porphyrins
76
96 89 78 78 90
95 92 92 91
68
Yield (%) 75 72
(continued)
[47]
[34]
[34]
[9 ]
Ref. [36] [9 ]
2 Recent Developments of Synthetic Techniques for Porphyrins… 77
Por
78-Mn
68-Mn
70-Mn
100-Mn
Entry
14
15
16
17
Table 2.23 (continued)
F
Me
F
F
O2 N
Ar=
Cl
Cl
F
F
Me
Me
N
N
MnCl2..H20; 1.5 eq
MnCl2..H20; 1.5 eq
MnCl2..H20; 1.5 eq
[Bmim][BF4]b
[Bmim][BF4]b
[Bmim][BF4]b
Ar
Ar
M
100–110°C 320 W; 10 mina
100–110°C 320 W; 6 mina 100–110°C 320 W; 5 mina
Conditions
Ar
100–110°C 320 W; 7 mina
MW
Metal salt Solvent
[Bmim][BF4]b
Ar
Solvent
Ar
N
HN
MnCl2..H20; 1.5 eq
NH
N
Metal salt
Ar
Ar
N
N
MnCl
MnCl
MnCl
MnCl
M=
Ar
71
72
74
71
Yield (%)
[47]
[47]
[47]
[47]
Ref.
78 A.G. Gürek and C. Hirel
31-Co 31-Ni
31-Ni
31-Pd
31-Pt
31-Pt
28 29
30
31
32
33
Pyridine
Ni(OAc)2. 4H2O; 1 eq
Pt(Acac)2; 3 eq
Pt(Acac)2; 3 eq
b
PhCN
PhCN
Pyridine
Bmim][BF4]b Bmim][BF4]b Bmim][BF4]b Bmim][BF4]b Bmim][BF4]b Pyridine
Mn (OAc)2; 1.5 eq FeCl2..2H20; 1.5 eq ZnCl2.; 1.5 eq CuCl2..2H20; 1.5 eq CoCl2.; 1.5 eq Ni(OAc)2. 4H2O; 3 eq
Pd(Acac)2; 3 eq
DMF DMF DMF DMF DMF [Bmim][BF4]b
Zn(OAc)2. xH2O; 5 eq Cu(OAc)2. xH2O; 5 eq Ni(OAc)2. xH2O; 5 eq Co(OAc)2. xH2O; 5 eq Mn(OAc)2. xH2O; 5 eq MnCl2..H20; 1.5 eq
Domestic microwave oven 1-butyl-3-methylimidazolium tetrafluoroborate c Microwave oven dedicated to chemistry- closed vessel
a
31-Zn 31-Cu 31-Ni 31-Co 31-Mn 31-Mn 31-Mn 31-Fe 31-Zn 31-Cu
18 19 20 21 22 23 24 25 26 27
180°C; 300 W; 15 minc 180°C; 300 W; 15 minc 180°C; 300 W; 15 minc 180°C; 300 W; 15 minc 250°C; 300 W; 15 minc
320 W; 5 mina
480 W; 3 mina 480 W; 3 mina 480 W; 3 mina 480 W; 3 mina 480 W; 3 mina 100–110°C
Pt
Pt
Pd
Ni
Ni
Zn Cu Ni Co Mn MnCl Mn(Oac) FeCl Zn Cu Co
100
75
100
60
100
95 83 74 73 88 83 70 74 96 98 75 [48]
[47]
[34]
2 Recent Developments of Synthetic Techniques for Porphyrins… 79
80
A.G. Gürek and C. Hirel
O O Ln Ln=Er, Gd NH
N
HO N
Ln(Acac)2
N
N
HO HN
N DMA LiCl
10 1
N
10 1- L n
Scheme 2.13 Metallation reaction of hydroxyl porphyrin by lanthanide acetyl acetonate
Table 2.24 Rate constant (ka) of porphyrin 101-Er and 101-Gd under classical and microwave heating Conditions (150°C) Oil-bath MW irradiation Erbiuma ka (s−1) 3.5 × 10−3 1.25 × 10−3 Gadoliniumb ka ( s−1) 8.8 × 10−4 1.2 × 10−2 a Lithium concentration = 2.7 mM b Lithium concentration = 5.4 mM
Functionalization A few examples of functionalization have been developed using microwave heating. • Diels-Alder Diels-Alder cycloaddition of tetrakis(pentafluorophenyl)porphyrin (100) with pentacene (102) and naphthacene (103) were carried under microwave irradiation giving the corresponding chlorins [49] 104 and 105 (Scheme 2.14). A microwave dedicated to chemistry with a closed vessel system was preferred to achieve the reaction in 1,2-dichlorobenzene (DCB), with 3 equivalents of pentacene or naphthacene added in 3 times. The yields are summed up in Table 2.25. When the chlorin was submitted to the same experimental procedure, a 7% mixture of bacteriochlorin and isobacteriochlorin were formed. • Substitution reaction Nucleophilic aromatic substitution of fluoro atoms by primary amines in N-methylpyrrolidone has yielded only the tetra-substituted porphyrin (106) (Scheme 2.15) under microwave irradiation. The reaction time was drastically reduced from 10 to 30 min compared to 1 or 2 days for conventional heating, but under similar conditions secondary amine exhibit no reactivity [50].
2 Recent Developments of Synthetic Techniques for Porphyrins… C6F5
C6F5
N H N
81
N H N
C6F5
C6F5 100
3
3 o
DCB, 200 C 3x10 min
102
C6F5
103
DCB, 180 oC 3x15 min C6F5
C 6 F5
C6F5
N H N
N H N
N
N
H N
H N
C6F5
C6F5
C6F5
C6F5 105
104
Scheme 2.14 Synthetic pathway for the barrelene-fused chlorines 104 and 105 Table 2.25 Yields of Diels-Alder cycloaddition Conditions 200°C; 3× 10 min 180°C; 3× 15 min
Pentacene (95) Naphthacene (96)
MW heating yield (%) 83 23
Conventional heating yield (%) 22 no reaction
F
F
NHR
F
F
F
F
F
F
F
F
F NH
N
F
F
F
F HN
F
F F F
F
F
NH
F
N
RHN
F N F
F
10 eq R-NH2 NMP, MW
NHR F
N
F
F
F
F
F
F
F 100
HN F
F F NHR 106
Scheme 2.15 Substitution reaction leading to porphyrin 106
• Wittig reaction The Wittig condensation of porphyrin 107 with an aldehyde under microwave irradiation in the presence of an excess of DBU was done with a trans stereoselectivity (Scheme 2.16). For that Wittig condensation, the trans stereoselectivity is an unusual observation. The porphyrin 108 which can not be obtained by conventional heating [51], was obtained in high yield (40%).
82
A.G. Gürek and C. Hirel Ph
NH
N
N
NH
Ph
Ph N
Ph
CH 3 CHO N
HN
N
Ph
Cl
Ph N
P(Ph)3
CH 3 N
HN
DBU,CHCL 3 MW:10 min 60Wattt
Ph
N
Ph
107
108
Scheme 2.16 Wittig condensation
• Hydrolysis Demethylation of the methyl ester group by basic hydrolysis under microwave irradiation of Hangman porphyrin [52] is much simplified and less-time consuming than conventional harsh acidic conditions (4 h instead of 7 day). Depending on substituent R1 (Scheme 2.17.) yields were between 75% and 97%. Ph
NH
N
N
NH
Ph
Ph N
Ph
CH3 CHO N
HN
N
Ph
Cl
Ph N
P(Ph)3
CH3 N
HN
DBU, CHCL 3 MW:10min 60Watt
Ph
N
Ph 108
107
Scheme 2.17 Ester hydrolysis of Hangman porphyrin under microwave irradiation
The same protocol was performed to afford the corresponding Hangman corroles [53] 112 featuring the carboxylic acid hanging group using microwave irradiation. The yields are between 70% and 82% (See Scheme 2.18).
CO2Me CO2H O
R1 N H N
1)6NNaOH/THF MW
O
R1
N N H
N N
2)20%HCl R1 R1 111
112
Scheme 2.18 Ester hydrolysis of Hangman corrole under microwave irradiation
N N
2 Recent Developments of Synthetic Techniques for Porphyrins…
2.2.4.2
83
Phthalocyanines
Synthesis of Phthalocyanine Macrocycles Numerous publications mention the synthesis of phthalocyanines using a range of solvents such as 1-chloronaphthalene [54], quinoline [54], o-DCB [55], DBU [56, 57], ethylene glycol [58], glycerin [59], n-pentanol [60, 61], hexanol [62], nitrobenzene [13, 14], propylene glycol methyl ether acetate (PGMEA) [19, 36] and DMAE [63–80]. Mostly reports inform us about the synthesis of Pc starting with phthalonitriles as phthalocyanine precursors, and only a few articles mention the use of diiminoisoindoline [54] and phtalic acid [63]. The results are recapitulated in Table 2.26 for phthalonitriles and in Table 2.28 for diiminoisoindolines. The synthesis of phthalocyanines like those for porphyrins is influenced not only by the metal ion but also by the counter-ions. Considering the synthesis of copper phthalocyanines (see Table 2.26 entries 8–11, 13–16 and 30–46) which demonstrates that the solvent and the counter-ion both play a role in the reactivity. For example, in Glycerin/DBU (see Table 2.26 entries 8–11, 13–16 and 41–46), the reactivity observed is as follows: CuSO4>CuCl2>Cu(OAc)2. But this order of reactivity is inverted when glycerin is replaced by ethylene glycol (see Table 2.26 entries 34–40). Another point to be noticed is that when working with DBU as solvent at high temperatures [59], it degrades in the presence of oxygen, so for maximum efficiency, it is necessary to work under inert atmosphere. DMAE was intensively used under microwave irradiation to synthesize polymeric phthalocyanines [65–71], metal-free and metallophthalocyanines [65, 72–82]. Some examples of phthalonitriles and the corresponding yields of metal-free phthalocyanines and metallophthalocyanines are shown in Tables 2.27 and 2.28.
Lanthanide Double Deckers Under microwave irradiation, the synthesis of homoleptic and heteroleptic lanthanide double-decker complexes has been carried out exclusively starting from free phthalocyanines. Heteroleptic phthalocyanine–porphyrin double-decker complexes have been synthesized with a 66% yield from a lutetium porphyrin (4-LuOAc) and the metalfree phthalocyanine 137-2H in DBU [36] under microwave irradiation during 10 min at 440 W (Scheme 2.19). The synthesis of homoleptic phthalocyanine double-decker complexes have been achieved under microwave irradiation starting with the metal-free phthalocyanine 137-2H in DBU (Scheme 2.20) [19]. The yields of 159-Tb, 159-Dy and 159-Lu were 63%, 61% and 75%, respectively.
CN
CN
117 R1=R4=H, R2=R3=–OC12H25
113 R1=R4=H, R2=R3=−OC4H9
115 R1=R4=H, R2=R3=−OC8H17
117 R1=R4=H, R2=R3=−OC12H25
113 R1=R4=H, R2=R3=–OC4H9
117
3
4
5
6
7
8 9 10 11 12
119 R1=R4=H, R2=R3=−O–C6H4–OCH2–C6H5
R1=R4=H, R2=R3=−OC12H25
115 R1=R4=H, R2=R3–OC8H17
113 R1=R4=H, R2=R3–OC4H9
R4
R1
2
Entry 1
R3
R2
118-Cu 118-Cu 118-Cu 118-2H 120
114-SnCl2
118-GeCl2
116-GeCl2
114-GeCl2
118-SiCl2
116-SiCl2
Pc 114-SiCl2
Table 2.26 Synthesis starting from various phthalonitriles
1-Pentanol/DBU
Glycerin/DBU
1-chloronaphthalene
Quinoline
Solvent Quinoline
Cu(OAc)2.H2O CuCl2 CuSO4 Without metal Pb(OAc)2
SnCl4
GeCl4
Metal SiCl4
220°C; 10 min 240°C; 10 min 240°C; 10 min 220°C; 10 min 1,000 W; 8 min
190°C, 15 mina
190°C, 15 mina
Conditions (Watt, min, T =°C) 190°C, 15 mina
28 42 44 22.4 46
88
73
78
80
56
60
Yield % 45
[60]
[59]
[54]
[54]
Ref. [54]
84 A.G. Gürek and C. Hirel
R1=R4=H, R2=R3=–OC12H25
15 16 17
125 R1=R3=R4=H R2=
19
O
123 R1=R3=R4=H R2=Me(OCH2CH2)2O–
18
121 R1=R3=R4=H R2=4-ButO–C6H4O–
117
13 14
126-Cu
124-Zn
122-Zn
118-2H
DBU
DBU/Glycerin
Zn(OAc)2 CuCl2
Zn(OAc)2
H2 Cu(OAc)2.H2O CuCl2 CuSO4
27 77
13
160°C; 3 min a
190°C; 5 min a 440 W; 10 min
22.4 28 42 44
220°C, 10 min, N2 220°C, 10 min, N2 240°C, 10 min, N2 240°C, 15 min, N2
(continued)
[64]
[56]
[59]
2 Recent Developments of Synthetic Techniques for Porphyrins… 85
23
22
tBu
O
Me
O
133 R1=−O-C6H4-OCH2-C6H5, R2=R3=R4=H
R2=R3=R4=H
131 R1=
R2=
129 R1=R3=R4=H
21
CN
CN
127 R1=R3=R4=H O R2=
R4
R1
20
Entry
R3
R2
Table 2.26 (continued)
134
132-Cu
130-2H
128-2 H
Pc
1-Pentanol/DBU
DBU
n-pentanol
Solvent
Pb(OAc)2
CuCl2
Li
Metal
1,000 W; 15 min
440 W; 10 min
440 W; 138°C; 10 min
a
Conditions (Watt, min, T =°C)
19
71
16
21
Yield %
[60]
[64]
[61]
Ref.
86 A.G. Gürek and C. Hirel
139 R1=R3=R4=H R2=
29
30 31 32 33 34 35 36 37
R2=tBu
28
R1=R2=R3=R4=H
17
R1=R2=R3=R4=H
18
tBu
R1=R3=R4=H
27
tBu
137
26
OH
137 R1=R3=R4=H R2=tBu
6-Cu 6-Cu 6-Cu 6-2H 6-2H 6-Cu 6-Cu 6-Cu
140-2H
138-Cu
138-Mg
138-2H
138-Cu
136-Zn 136-Co 136-Ni
R1=R2=R3=R4=
O
136-2H
135
25
24
Glycerin/DBU Ethylene glycol/DBU
DBU
Ethylene glycol
n-pentanol
DBU, PGMEA
DBU
1-hexanol / hydroquinone 1-hexanol/DBU 1-hexanol/DBU 1-hexanol/DBU
Cu(II)O Cu(I)2O CuSO4 H2 H2 Cu(OAc)2.H2O CuCl2 CuSO4
Li
CuCl2
MgCl2
H2
Zn(OAc)2 Co(OAc)2 Ni(OAc)2 CuCl2
H2
20 min reflux 10 min reflux 5 min reflux 20 min reflux 240°C, 15 min, N2 180°C, 10 min, N2 180°C, 15 min, N2 180°C, 5 min, N2
440 W; 138°C; 10 min a
440 W, 10 min
440 W, 10 min
350 W; 160°C; 10 min
59 86 69 16 15.3 84 80 53
6.5
74
75
71
18 19 74
24
9
(continued)
[59]
[58]
[61]
[19]
[64]
[62]
2 Recent Developments of Synthetic Techniques for Porphyrins… 87
R1=R4=H
R2=R3=SC12H25 41 143 42 43 R1=R4=H 44 45 R2=R3=SC8H17 46 a Laboratory scale microwave oven
40
141
CN
CN
39
R4
R1
38
Entry
R3
R2
Table 2.26 (continued)
CuSO4 H2 Cu(OAc)2.H2O Cu2O CuO CuCl2 CuSO4
Cu(I)2O
Cu(II)O
Metal
144-2H 144-Cu 144-Cu 144-Cu 144-Cu 144-Cu
Glycerin/DBU
Ethylene glycol
Solvent
142-Cu
142-Cu
142-Cu
Pc
240°C, 10 min, N2 220°C, 5 min, N2 240°C, 10 min, N2 240°C, 10 min, N2 240°C, 10 min, N2 240°C, 10 min, N2
10 min reflux
10 min reflux
10 min reflux
Conditions (Watt, min, T =°C)
71.2 59 45 52 54 64
–
6
12
Yield %
[59]
[58]
Ref.
88 A.G. Gürek and C. Hirel
2 Recent Developments of Synthetic Techniques for Porphyrins… Table 2.27 Some phthalocyanines synthesis in DMAE as solvent Entry Phthalonitriles Pc Conditions 1 146-Zn 350 W, 8 min 146-Cu O N
CN
O
CN
145
146-Co 146-Ni S
2
CN
148-Cu
89
Yields (%) 38 64
Ref. [65]
11 32 350 W, 8 min
64
[72]
CN
H3CO
OCH3
147
148-Zn
3
150-2H
147 Ts S
N
S
N
CN
350 W, 10 min
36
150-Zn
31
150-Cu 150-Co 150-Ni
28 34 26
4
CN
CH3
CN O S O
O
N
O
O
152-2H 152-Zn
350 W, 6 min
152-Cu 152-Co 152-Ni
5
CN S
S O
HO S
CN
154-2H 154-Zn
44 40 42 350 W, 8 min
154-Cu 154-Co 154-Ni N
156-2H 156-Zn
NH
S O
55 60
[80]
63 69 64 350 W, 4–15 min
54 55
CN O
[81]
S
153
6
37 51
CN
151
155
[75]
Ts
149
HO
66
N
156-Cu 156-Co 156-Ni
41 32 53
[79]
90
A.G. Gürek and C. Hirel
Table 2.28 Synthesis of Phthalocyanines starting from diiminoisoindoline HN R HN R
/R Pc Entry 1 157/ –OC4H9 114-SiCl2 2 158/ –OC8H17 116-SiCl2 3 159/ –OC12H25 118-SiCl2 4 157/ –OC4H9 114-GeCl2 5 158/ –OC8H17 116-GeCl2 6 159/ –OC12H25 118-GeCl2 7 157/ –OC4H9 114-SnCl2 8 158/ –OC8H17 116-SnCl2 a Laboratory scale microwave oven HN
Solvent Quinoline
Metal SiCl4
Quinoline
GeCl4
1-chloronaph- SnCl4 thalene
Conditions (Watt, min, T =°C) Yield % 190°C, 15 mina 78 70 75 190°C, 15 mina 86 81 92 190°C, 15 mina 95 90
Ref. [54]
[54]
[54]
AcO N N
Lu N
N N N
N
N
N N
+
4-LuOAc
N
N
DBU
440 W, 10 min Lu
N NH N N
N HN
N
N
HN
N
N
N
159 137-2H
Scheme 2.19 Synthesis of porphyrin-phthalocyanines heteroleptic lanthanide complexe 159
N N
N
N
N
N
N N
N Ln NH 2
N
DBU, Ln(OAc)3 N
N
N N
HN
240 Watt, 10 min N
N
137-2H
N
N
N
N
N N
Ln=Tb, Dy, Lu 160
Scheme 2.20 Synthesis of phthalocyanines-phthalocyanines homoleptic lanthanide complexes 160-Ln
2 Recent Developments of Synthetic Techniques for Porphyrins…
91
Functionalization • Reduction Lead tetraaminophthalocyanine 161 was prepared by reduction of the nitro derivative 12-Pb using sodium sulphide in water irradiated at 180 W for 10 min. A 90% yield was obtained that is similar to the 88% yield received by conventional heating (Scheme 2.21) [83]
O 2N
NH2
H2N
NO2
N
N N
N Pb
N
N Pb
N MW
N
N
N
NaS/ H2O N
N N
N N
N NO2
O2N
H2 N
NH2
1 2-P b
1 61
Scheme 2.21 Reduction of tetranitrophthalocyanine 12-Pb
• Axial substitution Trans-PcSn dichloride is transformed stereoselectively to cis-PcSn dicarboxylate using microwave heating method that accelerates the reaction at least 15 times (Scheme 2.22). Yields range from 54% to 78% and 49% to 90% for conventional and microwave heating respectively [84, 85].
O 2
O
CH3-(CH 2 )n
(CH 2)nCH 3
KO
162
O
O Sn
(CH 2)n-CH3 O
1) DMF, 2.5 h, N
Cl
2) 5 & 10 min, 300 & 600 W, 150oC
N N
N
Sn
N
N
N
N
N
N N
N N
N
2 K C l
N 6-Sn-cis
N Cl 6-SnCl2
Scheme 2.22 Stereoselective reaction pathway leading to the formation of PcSnIV(carboxylate)2 derivatives
92
A.G. Gürek and C. Hirel
The same reaction has been achieved on trans-SiPcCl2 to obtain trans-PcSi dicarboxylate (Scheme 2.23) [86]. This substitution was carried out by microwave irradiation in N,N-dimethylformamide for 10 min at 600 W and 145°C and produced yields between 42% and 67%.
2
O
O
(CH2)nCH3
KO
(CH2)nCH3
O 162 DMF, 10 min, MW, 600 W, 145o C
Cl
N N
N
Sn
N
N
N
N N
N N
N
Si
N
N
N
N N
H3Cn(H2C)
O O 6-Si-trans
Cl 6-SiCl2
Scheme 2.23 Synthetic route for the preparation of trans-PcSi dicarboxylate
2.3 2.3.1
Ionic Liquids (ILs) General Introduction About ILs
Ionic liquids are salts of organic cations with melting points generally below 100°C and are being widely investigated as replacements for volatile organic solvents in industrial and laboratory processes because they are thought to be “environmentally benign.” At least one ion has a delocalized charge and one component is organic, which prevents the formation of a stable crystal lattice. The major advantage of using ionic liquids (ILs) as solvents is their low pressure, which, coupled with the fact that they can often act as both catalyst and solvent, has sparked considerable interest [87, 88]. Ionic liquids have been described as “designer solvents” [89]. The properties such as solubility, density, refractive index and viscosity can be adjusted to suit requirements simply by making changes to the structure of either the anion or cation, or both [90, 91]. This degree of control can be of substantial benefit when carrying out solvent extractions or product separations, as the relative solubility of the ionic and extraction phases can be adjusted to assist with the separation [92]. Ionic liquids have been known for many years. In broad terms, they can be viewed like common liquid at low temperatures, this being due to poor packing of respective ions. In order to achieve this poor packing requirement, room temperature ionic liquids are generally made from relatively large, non coordinating,
2 Recent Developments of Synthetic Techniques for Porphyrins…
93
Table 2.29 Some common room temperature ionic liquids Structure Classification 163 1-ethyl-3-methylimidazolium chlorideN N aluminium(III) chloride([emim]AlCl4) Al( Cl)4
N
164
N-butylpyridinium-aluminium(III)chloride ([NBupy]AlCl4)
165-BF4
1-butyl-3-methylimidazolium-tetrafluoroborate ([bmim]BF4)
Al(Cl)4 N
N
B F4
N
N
N
N
165-PF6
1-butyl-3-methylimidazolium -hexafluoro-phosphate ([bmim]PF6)
165-Br
1-butyl-3-methylimidazolium -bromide ([bmim]Br)
PF 6
Br
Table 2.30 Some common ionic liquids solid at room temperature Structure Classification 166 1-Butyl-1-methyl piperidinium bromide N Br
167
1-Butyl-1-methyl piperidinium tetrafluoroborate
N BF4
168
1-Butyl-2-methyl pyridinium chloride
N
HO
169 N
Choline bis(trifluoromethylsulfonyl)imide
(CF3 SO2) 2N
asymmetric ions. Invariably at least one of these ions is organic in nature. Based on this criterion there are many thousands of possible ionic liquids. Some of the most common ones are shown in Tables 2.29 and 2.30. Newer ionic liquids containing ClO4− and NO3− anions, for example, which are less air and moisture sensitive, are now being more widely studied, but these are less catalytically active. Other than lack of vapor pressure and catalytic properties there are several other features common to most ionic liquids that make them attractive as reaction solvents. These include; – Tunability; by varying the cation/anion ratio, type and alkyl chain length properties such as acidity, basicity, melting temperature and viscosity can be varied to meet particular demands.
94
A.G. Gürek and C. Hirel
– Stability; many ionic liquids are stable at temperatures over 300°C, providing the opportunity to carry out high-temperature reactions at low pressure. – Ionic liquids that are not miscible with organic solvents or water may be used to aid product separation or used in liquid-liquid extraction processes. ILs have gained wide recognition as potential environmentally benign solvents for a variety of reactions [93–97]. In particular, functional imidazolium-, pyridiniumand ammonium-based ionic liquids are receiving a considerable upsurge of interest due to their applications in various reactions such as Knoevenagel condensation [98], aldol condensation [99], Heck reaction [100] and Diels–Alder reactions [101]. They are environmentally friendly solvents because they have negligible vapor pressure; are recyclable, nonexplosive, thermally stable, and easy to handle; and can be easily prepared from inexpensive starting materials. Recently ionic liquids or mixtures of ionic liquids and comparatively non polar solvents have been used as solvents in various reactions assisted by microwave irradiation [102–105]. The ability of ionic liquids to dissolve both organic as well as inorganic compounds efficiently prompted several teams to perform the metallation reactions of porphyrins and phthalocyanines in ionic liquid as reaction media. The advantages of using ionic liquid as the reaction medium are the high yield of the products obtained, coupled with the ease of their purification and separation. Further, the organic transformations carried out under microwave irradiation give enhanced reaction rates, high yields, and provide environmental friendly reaction conditions [106–109]. The use of ILs in the synthesis of phthalocyanines and porphyrins provides a new methodology for phthalocyanines and porphyrins preparation.
2.3.2
Porphyrin Synthesis in ILs
Tetraphenylporphyrin (TPP) offers attractive features in a wide variety of model studies [110]. The equimolar condensation of benzaldehyde with pyrrole followed by oxidation generally provides TPP in a one flask synthesis. Heated pyridine and refluxing propionic acid in open air system allowed Rothemund [111] and Adler et al. [112, 113], respectively, to have obtained TPP with less than 20% yield. Instead of using these high boiling point solvents, Lindsey et al. have preferred to use dichloromethane with an appropriate Lewis acid as reaction medium, having improved the yield up to around 40% [114]. Due to its mild conditions, good yield and convenience, the Lindsey method has come into widespread use for numerous preparations of porphyrins. By the method using dihloromethane, N-confused tetraphenylporphyrin (NC-TPP, 170) was firstly isolated in ca. 5% yield by Furuta et al. [115]. and LatosGrazynski et al. [116], and thereafter, Lindsey et al. again optimized the reaction condition to yield 170 in 39% [117–119]. In the Lindsey method, the halogenated solvent and harmful acids can be recognized to be prerequisite because of their superior solubility for porphyrins and the catalytic activity for the ring condensation.
2 Recent Developments of Synthetic Techniques for Porphyrins…
95
To keep using these materials because of their efficiency, however, is likely to become more undesirable than ever, particularly in green chemistry. To obtain 1.0 g of NC-TPP(170) (or 1.0 g TPP (31)), for instance, as much as 5 L (or 2 L) dichloromethane needs to be mounted in the reaction vessel under the optimal conditions when utilizing the Lindsey method, which employs methanesulfonic acid -MSA(171), as the acid catalyst [117]. The need for both reducing the use of the halogenated solvent and increasing the reusability of acid catalyst will increase rather than decrease. These two requirements become indispensable to develop a successful green chemistry for porphyrin.
2.3.2.1
Synthesis of Porphyrin in the Biphasic System
Room temperature ILs could be suitable and environmentally safer replacements for the volatile, toxic, and flammable organic solvents currently used in synthetic and catalytic reactions [96]. There are various reports, in fact, about using ILs as reaction media, for instance, nucleophilic [120] reactions, esterification [121] and epoxidation with a manganese(III) porphyrin as a catalyst [122]. If the green property born from IL could be applicable to the preparation of porphyrins, then it may be possible to undertake the Lindsey procedure without the need for the halogenated solvent. Ishikawa et al. have studied firstly the usage of IL as a new medium for porphyrin preparation aiming at being as green a reaction as possible throughout and prepared the Brønsted acidic IL, 3-butyl-1-(butyl-4-sulfonyl)imidazolium trifluoroethanesulfonate R–SO3H (172), with which the dichloromethane phase is in fact immiscible (Scheme 2.24) [123]. Ph
O H N
H +
1
Ar N H
N
+
N
IL CH2Cl2, r .t
32
Ar
Ph N H
1) aci d 2) DDQ
N
N
H N
H N
Ph
Ph
Ar
Ar
TPP
NC-TPP
31
170
------------- --------------- --------------- --------------- --------------- --------------- --------------- --------------- --------------- -------CF 3SO3 H3C
SO3H
C 4H 9
(MS A)
171 Scheme 2.24 Biphasic reaction of porphyrins
N
N
C 4H 9 S O3H
[C 4 -SA bim][ CF 3 SO 3 ]
172
96
A.G. Gürek and C. Hirel
Fig. 2.4 Photograph showing colour change due to condensation reaction at interface between CH2Cl2 and Brønsted acidic IL. Reproduced from Ref. [124] with kindly permission of Elsevier Table 2.31 Different type of ILs Class I
(CF 3 SO2 )2N
(CF 3SO2)2N
(CF3 SO 2)2 N H3 C
N
N
(CH 2) 2CH 3
Effect of cation skeleton
[C4mim] [TFSI] 173
Class II
H 3C
N
N
(CH2)3CH 3
(CF3 SO2)2N
N
(CH 2)3CH3
[C4p] [TFSI] 174
N H 3C
(CH 2)2CH3
[C4mppr] [TFSI] 175
n C6H 13)4 N
[(C6)4N] [TFSI] 176
[C4mim] [X]
X
Effect of Counter Anion Class III
177-X− X− : TFSI−, PF6−, BF4−, Br−, CF3CO2−, CF3SO3 H 3C
N
N
(CH2)n-1CH 3 (CF 3S O2 )2N
Effect of Alkyl Chain Length
[Cnmim] [TFSI] n: 2–10 178
Dichloromethane solution of pyrrole was placed on the acidic IL in a test tube, having formed the interface at room temperature. Adding neat benzaldehyde onto the upper solution immediately brought a color into the dichloromethane phase. The color stemming from precursors of the porphyrins heightened on standing, as shown in Fig. 2.4. As opposed to the dichloromethane solution, the IL phase was not colored at all, for the reaction period. It is obvious that the biphasic procedure is broadly comparable in yield to the Lindsey method apart from selectivity for the expected and N-confused porphyrins. In the other study, Ishikawa and co-workers chose a series of ILs ranging from class I to class III, as shown in Table 2.31 and they examined their behavior as a
2 Recent Developments of Synthetic Techniques for Porphyrins… Table 2.32 Porphyrin preparation in class I and class II ILs with various anions Yield % Viscosity of H2O content Solvent IL/cP of IL/wt.% 31 [C4mim][TFSI](173) 50.2 0.12 41 [C4p][TFSI] (174) 63.5 0.08 33 4.2 [C4mppr][TFSI] (175) 192 0.11 23 [(C6)4 N][TFSI] (176) 573.4 0.12 2 CH2Cl2 – – 8 [C4mim][PF6] (177- PF6) 289 0.22 11 [C4mim][BF4](177- BF4) 92.2 1.09 0.8 [C4mim][Br] (177-Br) 1,462 2.45 0.1 [C4mim][CF3CO2](177- CF3CO2) 71.2 2.10 0.5 [C4mim][CF3SO3](177- CF3SO3) 93.2 1.62 0.3
97
155 7
0 0 38 4 0.3 0 0 0.7
[Pyrrole]=[aldehyde]=[DDQ] = 10 mM, [MSA] = 7 mM, 22°C, reaction time 30 min, yields were determined by HPLC analysis. Adapted from Ref. [124] with kind permission of Elsevier
medium [124] in the synthesis of tetraphenylporphyrin (31) (Scheme 2.24). The viscosity and water content of the ILs are factors well-known [125, 126] to affect reactivity. Thus, these two factors in particular were carefully considered in the usage of IL as a single homogeneous medium. As a result, the hydrophobic and moderately fluid [C4mim] [TFSI] (173) was the most appropriate medium for the porphyrin formation (Table 2.31). However, reusing the IL as a homogeneous reaction medium was impractical due to the readily contamination of the produced by-product As a result, the hydrophobic and moderately fluid [C4mim] [TFSI] (173) was the most appropriate medium for the porphyrin formation (Table 2.32). However, reusing the IL as a homogeneous reaction medium was impractical due to the readily contamination of the produced by-product In place of the homogeneous system, a biphasic mode reaction was devised for the porphyrin formation. In the case of the acidic IL, [C4-SAbim][CF3SO3] (172- CF3SO3) in Scheme 2.24, its usage in the biphasic system together with dichloromethane was studied with a view to reduce the amount of halogenated solvent and reusing the acid IL. The porphyrin yield in the IL was comparable to that in the dichloromethane, as long as both the water content and the fluidity were conditioned to be in the optimum state. When acidic IL, [C4-SAbim] [CF3SO3] (172- CF3SO3) possessing a sulfonic acid moiety was used as the reaction medium, nothing but a black tarry by-product was obtained due to its strong acidity. However, using the acidic IL in a biphasic mode together with dichloromethane enabled porphyrins to form, even at a high reactant concentration. An acidic IL provides a new methodology for porphyrin preparation. The acidic IL phase separated with dichloromethane becomes quite instrumental for reducing the amount of the halogenated solvent used in porphyrin preparation. More important than the superior productivity in the high reactant concentration is the reusability of the acidic IL to catalyze the formation of porphyrinogens without deterioration
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A.G. Gürek and C. Hirel
of the activity. Furthermore, the phase-separated acidic IL was reusable at least ten times without any loss of catalytic activity [124].
2.3.2.2
Synthesis of Porphyrin in IL
A variety of synthetic methods have been developed for non-natural porphyrins, especially meso-tetra substituted porphyrins. meso-Substituted porphyrins were synthesized from pyrrole and aryl aldehydes cleanly and efficiently in a one step reactions at 100°C in 1-butyl-3 methyl imidazolium tetrafluorborate([bmim]BF4) (165-BF4) as IL and air as oxidant [127]. Chandramouli et al. have adopted Rothemund (aerobic) reaction conditions unlike Ishikawa and co-workers who used Lindsey (anaerobic) reaction conditions for the synthesis of porphyrin [127]. They have observed only porphyrin (31) and no NC-TPP (170) in this method unlike Ishikawa and co-workers [123, 124] who observed both porphyrin and NC-TPP under anaerobic conditions. This methodology has been extended to a variety of aryl and heteryl aldehydes and the results were presented in Table 2.33. Chandramouli et al. developed an alternative method for meso-substituted porphyrins by using ILs under aerobic reaction conditions and the yields are better than in the propionic acid method [128–130]. The major advantage of this method is that no chlorinated solvent, no acid catalyst and no oxidizing agent have been used unlike in other porphyrin synthetic methods. The IL used in this method acts as well as Lewis acid catalyst, providing a quick and efficient route for the synthesis of mesosubstituted porphyrins with higher yields compared with Rothemund method.
2.3.2.3
Metallation of Porphyrin in IL
Different solvents and reaction conditions have been used for the preparation of metalloporphyrins from free-base porphyrins and metal salts [131–133]. Metallation is usually carried out in a carefully chosen solvent that offers mutual solubility to both the metal salt and free-base porphyrin. However, these methods suffer from certain disadvantages, such as slow reaction rates and low yields. Especially the high boiling solvents that are required for certain metals cause the partial decomposition of the macrocycle, and troublesome purification workup. Further, chlorinated hydrocarbons, pyridine, and or dimethylformamide (DMF) have been used as solvents to metallate different free-base 5,10,15,20-tetrakisarylporphyrins. DMF as a solvent is known to decompose during reflux and results in the formation of dimethylamine during metallation, which acts as a nucleophile and gives side products in the metallation of porphyrins with electron-withdrawing groups, such as H2F20TPP (100) [134]. The use of pyridine as a solvent in metallation reactions is discouraged because it forms complexes with metals of high charge and consequently retards the metallation process [135]. The ability of ionic liquids to dissolve efficiently both organic as well as inorganic compounds prompted us to perform these metallation reactions of porphyrins
Table 2.33 meso-Substituted porphyrins by using ILs under aerobic reaction conditions
Ar
N
NH
[bmim]BF 4
+ A r-CHO
100 C 2-3 hrs
H
N Ar
Ar
o
N
HN
Ar
Entry
Aldeyhde
1
Yield % 26
CHO
32 2
H3 C
28
CHO
36 3
H3 CO
CHO
29
34 4
HO
33
CHO
H 3CO
178 5
23
H 3CO
CHO
179 6
H3 CO
CHO
N
18
Cl
180 7
CHO
H3 CO
N
17
Cl
181 8
24
Cl CHO
O
O
182 Cl
9 H3 C
24 CHO
O
O
183 10
26
nBu N NH CHO
184 11
nBu
28
N NH
Cl
CHO
185 12
nBu N Br
NH CHO
186
22
100
A.G. Gürek and C. Hirel
in ionic liquid as reaction medium. The advantages of using ionic liquid as reaction medium are the high yield of the products obtained, coupled with the ease of their purification and separation. Chauhan et al. [47]. reported firstly a simple, fast, and environmentally friendly synthesis of metalloporphyrins from free-base 5,10,15,20-tetrakisarylporphyrins and metal salts under microwave irradiation in 1,3-dialkylimidazolium ionic liquids (Scheme 2.25a).
(A ) MX2 / MW, 5-10 min [bmim][BF4] (165-B F 4)
Ar
N
N
N
NH
M
Ar
Ar
Ar
Ar N
Signh's method (B )
Ar
MX2 / r t [hmim][Br]
CH3 N
Ar M= Fe, Co, Cu, Mn, Zn
Br N 187
CH 3
F
Cl
F F
Cl
78
74
F
NO 2
Cl
Ar :
31
N
N
Chauhan method
HN
Ar
68
F
100-M
Scheme 2.25 The comparison of Chauhan’s (a) and Singh’s (b) methods for the synthesis of transition metal complexes of porphyrins from free-base 5,10,15,20-tetraaryl-porphyrins
A comparative study of the metallation reactions of 5,10,15,20-tetraarylporphyrins was done by taking two different ionic liquids, 1-butyl-3-methylimidazolium bromide [bmim][Br] (165-Br) and 1-butyl-3-methylimidazolium tetrafluoroborate [bmim][BF4] (165-BF4). The ionic liquid [bmim][BF4] (165-BF4) was found to be more suitable for metallation reactions than [bmim][Br] (165-Br), which decomposed slightly at extended reaction times. The ionic liquid was recovered by extracting the product with petroleum ether–ethyl acetate (20:80), followed by drying of ionic liquid under reduced pressure. Recycling experiments were carried out by adding a fresh lot of free-base porphyrin and metal salt to the recovered ionic liquid and irradiating it in microwave for an appropriate time [47]. As mentioned above, the room-temperature ionic liquids especially those based on the 1,3-dialkylimidazolium cation provide an ecofriendly reaction medium for a variety of chemical and biochemical transformations, as they lack significant vapor pressure, have ease of reuse, absence of flammability and tolerance for large temperature variations [125, 136–138]. Also, the synthesis of metal porphyrins from 5,10,15,20-tetraarylporphyrins have been synthesized with metal salts in the
2 Recent Developments of Synthetic Techniques for Porphyrins…
101
presence of reusable 1-hexyl-3-methylimidazolium bromide ([hmim][Br]) (187) as solvent at room temperature to afford the corresponding metalloporphyrins in 80–98% yields by Singh et al. using a different IL (Scheme 2.25b) [139].
2.3.3
Pc Synthesis in ILs
Phthalocyanines have found a wide range of application in the area of material science because of their distinct optical and electrical properties as well as their thermal stability [1, 140–143]. In view of these important applications, there is a need to develop efficient synthetic methods for differently substituted phthalocyanines, in particular those methods which are easy to operate and environmentally benign if one considers the large-scale preparation of these materials. Substituents on the peripheral positions are usually introduced through nucleophilic substitution of common phthalonitrile precursors such as 3- (or 4)-nitrophthalonitrile, 4,5-dichlorophthalonitrile, and 2,3-dicyanohydroquinone [144]. These reactions together with the subsequent cyclization are usually performed in organic solvents. Recently, ionic liquids have emerged as superior reaction media in organic synthesis because of their low vapor pressure, high thermal stability, high ionic conductivity, and ease of recovery.
2.3.3.1
Synthesis of Phthalonitrile Derivatives as Phthalocyanine Precursors in IL
Due to their ionic nature, ILs are particularly useful for reactions involving charged reactive species [96, 145–148]. For nucleophilic substitution reactions, they can enhance the reactivity of the nucleophiles, reducing the yield of the side products formed [104, 149]. On this basis, Ng. and his group firstly described the use of tetrabutylammonium bromide (188, TBAB) as a low-cost ionic liquid medium for the preparation of a series of substituted (alkylthio, alkoxy, and phenoxy) phthalonitriles and their corresponding metal-free and metallophthalocyanines [150]. The preparation was mainly based on nucleophilic aromatic substitution reactions of common nitro-, chloro-, and fluoro-phthalonitrile precursors. The results summarized in Tables 2.34 and 2.35 show that a wide range of substituted phthalonitriles can be prepared in molten tetrabutylammonium bromide (188, TBAB). It is worth noting that these nucleophilic substitution reactions are usually performed in dipolar aprotic solvents such as N,N-dimethylformamide and dimethyl sulfoxide [151–155]. The use of commercially available ionic liquid, which can be used as received, can greatly simplify the procedure including a prior solvent treatment and subsequent removal of the high-boiling solvents. The solvent-free condition and the recyclable property of the medium make these re- actions attractive as an environmentally benign method to prepare these useful phthalocyanine precursors.
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A.G. Gürek and C. Hirel
Table 2.34 Preparation of alkylthio phthalonitriles in tetrabutylammonium bromide (188, TBAB) Thiol Temp. Yield Entry Precursor Thiol (equ.) (°C) Product (%) CN CN 1 C8H17SH 1 90 29 O2N
2 3
CN
C 8H17S
19 19 19
C8H17SH C12H25SH
2 1
100 90
CN
189 189 CN
C 12 H 25S
4 5
19 19
C12H25SH C12H25SH C8H17SH
CN
6
1 2 2
100 100 100
51 79 91
CN
CN
NO2
7
CN
190 190 190
CN
77 30
SC 8H 17
191 191
192 C12H25SH
2
100
93
CN
CN SC 12 H 25
193 8
Cl
CN
Cl
CN
C8H17SH
5
100
194
CN
C 8H17S
CN
F
CN
F
CN
C8H17SH
8
SC 8 H 17
100 C 8H17S
2.3.3.2
55
CN
C 8H17S
F
195
50
143 F
9
C 8H17S
CN SC 8 H 17
196
Synthesis of Phthalocyanine from Phthalonitrile in IL
The treatment of various mono- and disubstituted phthalonitriles with (DBU) in molten tetrabutylammonium bromide (130°C) gives the corresponding metal-free and metallophthalocyanines, respectively. The yields are comparable with those obtained in classical organic solvent media (see Table 2.36) [151, 154, 156, 157]. Shaabani et al., used a very fast and easy procedure for the synthesis of metallophthalocyanine under classical heating conditions (130°C) without using any other reagents in 1,1,3,3-N,N,N’,N’-tetramethyl-guanidinium trifluoroacetate (210, TMGT) as ionic liquid (Scheme 2.26) [158].
2 Recent Developments of Synthetic Techniques for Porphyrins…
103
Table 2.35 Preparation of alkoxy and phenoxy phthalonitriles in tetrabutylammonium bromide (188, TBAB) Equiv of Alcohol/alkyl alcohol/alkyl Equiv of Entry Precursor halide Product Yield (%) halide K2CO3 1
C8H17OH
19
1.5
6
CN
C 8H17 O
19
CN
197
2
19
C8H17OH
4
8
3
190
C8H17OH
1.5
6
197
39
20
CN
CN OC 8H 17
4
190
C8H17OH
4
8
5
194
C6H5OH
3
15
198 198
72
C 6 H 5O
CN
C 6H5S
CN
39
199
6
C7H15Br
OH
3
8
OC 7H 15
CN
CN OH
200
86
CN
CN
OC 7H 15
201
The ionic liquids can be recovered conveniently and reused efficiently for these two methods. It should be noted that the nitrogen of TMGT has sufficient nucleophilcity toward –CN groups of phthalonitrile, when activated with a strong protic acid of conjugated acid of TMGT. These characteristic reactive features of TMGT lead to a novel, convenient synthesis method for peripherally phthalocyanines having various metals from phthalonitrile. Also, Shaabani et al. studied the possibility of synthesizing metal-free phthalocyanines by cyclotetramerization of phthalonitrile, in the presence of co-reactants
104
A.G. Gürek and C. Hirel Table 2.36 Preparation of phthalocyanine in tetrabutyl ammonium bromide (188, TBAB) R2
R3
R4
R1
R2
R3 N R1 R2
CN
MXn 2- 4 equ iv DBU
R3
CN
2 equiv nB u4NB r 130 oC
R4
N
R1
R4
N
M
N
R1
N
N
N
R4
N R3
R2 R3
R4
R1
R2
R1 R2
CN CN
R3
Entry 1 2 3 4 5 6 7
R4
189 R1=R3=R4=H, R2=SC8H17 190 R1=R3=R4=H, R2=SC12H25 191 R2=R3=R4=H, R1=SC8H17 205 R1=R4=H, R2=R3=SC4H9 143 R1=R4=H, R2=R3=SC8H17 197 R1=R3=R4=H, R2=OC8H17 208 R1= , R2=R3=R4=H
Pc 202-2H
Yield% 20
203-2H
20
204-2H
13
206-2H
50
144-2H
50
207-2H
20
209-2H
40
203-Zn
31
206-Zn
67
206-Co
33
144-Zn
20
144-Ni
50
O
8 9 10 11 12
190 R2=R3=R4=H, R1=SC12H25 205 R1=R4=H, R2=R3=SC4H9 205 R1=R4=H, R2=R3=SC4H9 143 R1=R4=H, R2=R3=SC8H17 143 R1=R4=H, R2=R3=SC8H17
2 Recent Developments of Synthetic Techniques for Porphyrins…
CN
CN
N
TMGT 130 oC 8- 100 min MX n
N
M: Cu+, Cu2+, Co2+, Ni2+ , Fe2+, Zn2+, Pd2+, Pt 4+, Ru3+
F 3C
N M
N
N
TM GT
O O
O
NH 2 N
N
210
N
N
18
105
N 6-M 25- 74 %
Scheme 2.26 The synthesis of metallophthalocyanines 6-M in TMGT as an ionic liquid
such as hexamethyldisilazane (211, HMDS), sodium sulfide or urea in TMGT as an ionic liquid, or TBAB as a phase transfer reagent (Scheme 2.27), under conventional or microwave heating [159]. HMDS , TMGT/TBAB, Δ /MW 5 -25 min, 7 0-80 % CN
Na2S.xH 2O, TMGT/TBAB, Δ /MW 3-25 mi n, 73-88 %
CN 18
N NH
H Si N Si
N N
N
211 N
Ur ea, TMG T/TBAB, Δ /MW 5-30 min, 45-6 0 %
HM D S
HN N 6-2H
Scheme 2.27 Various routes for the synthesis of H2Pc (6-2H) from phthalonitrile 18 (yields in MW conditions)
The reaction conditions for the syntheses of H2Pc were optimized for the coreactants of HMDS, Na2S.xH2O and urea. It was found that the molar ratio of the reactants influenced the conversion as well as the yields. The best results were obtained for a 1:2:0.1:1 mole ratio of phthalonitrile, HMDS, (NH4)2SO4 and TMGT or TBAB when HMDS is the co-reactant, a 1:0.075:1.5:0.25 mole ratio of phthalonitrile, Na2S.xH2O, 1,2-propylene glycol (PG) and TMGT or TBAB in the case of Na2S, and finally a 1:10:0.1:1 mole ratio of phthalonitrile, CO(NH2)2, (NH4)2SO4 and TMGT or TBAB in the case of urea [159]. A convenient, fast, efficient, and ecofriendly synthesis of metal-free phthalocyanines from various alkoxy-substituted phthalonitriles in different hydroxyalkylammonium ionic liquids (212-Br and 212-PF6) (Fig. 2.5) in the presence of (DBU) at 140°C is reported by Chauhan et al. in moderate yields (Scheme 2.28) [160]. The effect of the concentration of DBU and temperature on the synthesis of phthalocyanines in
106
A.G. Gürek and C. Hirel
Fig. 2.5 Structure of ILs 212
X
Bu H 3C
R3
N CH CH OH 2 2 CH 3
R3
R2 N
R4 R3
CN
R2
CN R1
R1
DB U
NH
IL
18 , 6-2H
R 1=R 3=R 4= R 2= H
19 7, 207-1H R1=R3=R4= H, R 2= O C8H 17
21 7, 218-2H R1=R3=R4= H, R 2= O C12H 25 R2
R2
−
R1
R3 R1
X= PF 6
21 5, 216-2H R1=R3=R4= H, R 2= O C5H 11
HN N
18, 1 97, 213, 2 15, 217, 219, 221
212-PF6
21 3, 214-2H R1=R3=R4= H, R 2= O CH 3
N N
R4
R4
N
N
X= Br −
R2
R1
R4
212-Br
R4
R3
21 9, 220-2H R1=R4= H, R 2=R 4= O C16H 33 22 1, 222-2H R1=R4= H, R 2=R 4= O C18H 37
6-2H , 20 7-2H , 214-2H , 216- 2H, 218-2 H ,22 0-2H , 222-2H
Scheme 2.28 Synthesis of metal-free phthalocyanines in ionic liquids
N-(2-hydroxyethyl)-N,N-dimethylbutylammonium bromide (212-Br) has been examined, and the ionic liquid has been recovered and reused conveniently. The presence of DBU is important for the synthesis of free-based phthalocyanines under the condition of the experiment, as no phthalocyanine formation was observed in the reaction of phthalonitrile 18 in ionic liquid 212-Br in the absence of DBU at 140°C (Table 2.37). Further, the concentration of DBU in the reaction of unsubstituted phthalonitrile (18) affected not only the rate of its cyclotetramerization but also the yield of corresponding phthalocyanine 6-2H. The rate of phthalocyanine formation 6-2H as well as the yield are enhanced increasing DBU concentration in ionic liquid 212-Br at 140°C (Table 2.37). A decrease in reaction temperature affected more the rate of phthalocyanine formation than the yield of 6-2H as the reaction of 18 in the presence of DBU (2 equiv) in 212-Br gave 6-2H in 45% yield at 120°C after 2 h. Similarly, the reaction of unsubstituted phthalonitrile (18) in the presence of DBU (2 equiv) in ionic liquid 212-PF6 gave 6-2H in 24% yields at 140°C. The lower yield of 6-2H in 212-PF6 than in ionic liquid 212Br could be attributed to decomposition of PF6 anion to hydrofluoric acid or fluoride in the presence of a base. For phthalocyanine 6-2H, recyclability of ionic liquid 212-Br was examined. The ionic liquid 212-Br was recovered from the reaction mixture by washing the crude product with distilled water. Water was evaporated at 70°C under reduced pressure, and the resulting ionic liquid was reused three times for phthalocyanine synthesis. In the second run, phthalocyanine 6-2H was obtained in 42% yield by cyclotetramerization of 18 in the presence of DBU in recovered ionic liquid 212-Br. The reactivity of ionic liquid reduced appreciably in the third run as 6-2H was isolated in 20% yield.
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Table 2.37 Synthesis of unsusbtituted phthalocyanine (6-2H) in different ILs (212-Br and 212PF6) from phthalonitrile 18 under different reaction conditions Isolated Entry Ionic liquid Conc. of DBU Temp (°C) Time yield (%) 1 212-Br 0 equ. 140 24 h 0 2 212-Br Catalytic amount 140 2h 11 3 212-Br 0.5 equ. 140 1h 17 4 212-Br 1 equ. 140 30 min 27 5 212-Br 2 equ. 140 10 min 47 6 212-Br 2 equ. 120 2h 45 7 212-PF6 2 equ. 140 1h 24
Chauhan et al. reported the synthesis of phthalocyanines from phthalonitrile precursors in the presence of (DBU) and metal salts in several imidazolium, pyridinium and ammonium ionic liquids, as well as the metallation of free-phthalocyanines in hydroxyalkylated ammonium ionic liquid to afford various transition-metal phthalocyanines (Scheme 2.29) [161]. R1
CN
R2
CN
IL / M DBU
[bhyeda][Br] DBU
R2
R1
R2
R1 R1
R2
R1
R2 N
N N N
N
N
NH
M 2+ N
M
N
197, 217, 219, 221, 223, 225, 226,
N
N [bhyeda][Br] N
N
HN N
N R2
R1 R2
R1=R2 = H R 1=H, R 2 = O Me R 1= H, R 2= OC5 H 11 207 R 1= H, R2 = OC 8 H 17 218 R 1= H, R2 = OC 12H25 220 R 1= R2 = OC 16H 33 222 R1 = R 2 = OC 18 H 37 224 R 1=H, R 2 = O CH 2C 6H4 -4-O Me 12-2 H R 1=H, R2= NO2 227 R 1= H, R2 = Me
18, 6H 213, 214 215, 216
R1
R1
R2
6-M , 214-M , 216- M 207-M , 218-M , 220-M , 222-M , 224- M, 12 -M, 2 27-M
M= Zn, Co, Cu, Fe, Pd, Ni
R2
R1
6-2 H, 2 14-2H , 216-2H 207-2H , 218-2H , 220-2 H, 2 22-2H , 224-2H , 12- 2H, 2 27-2H Structure of ILs
N
N
1 65-B r 1 65-B F4
X
X= Br X=B F4
R1 R2
N R3
R4
X
212-B r R1= R3=Me, R2=C2 H 4 OH, R4=nBu , X = B r. [b hyed a][Br] 212-C l R1= R3=Me, R2=C2H 4OH, R4 =nBu, X = Cl. [bhyeda][Cl]
Scheme 2.29 Synthesis of transition-metal phthalocyanines in functional ionic liquids. Reproduced from Ref. [161] with kind permission of Georg Thieme Verlag
The influence of ionic liquids on the course of metallophthalocyanines formation has emerged as being associated with the Coulombic interaction between the cations and anions in ionic liquids as well as the nucleophilicity of the anions [162].
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Table 2.38 Synthesis of various phthalocyanines in the presence of DBU in different ionic liquids at 140°Ca. Adapted from ref. [161] with kind permission of Georg Thieme Verlag Yield Entry Phthalonitrile Phthalocyanine IL Metal salt Time (%)b 1 18 (R1=R2=H) 6-2H 165-Br – 1h 31 2 18 (R1=R2=H) 6-2H 165-BF4 – 20 min 47 3 18 (R1=R2=H) 6-2H 188, TBAB – 1h 53c 1 2 4 217 (R =H R =OC12H25) 218-2H 165-BF4 – 3h 28 5 217 (R1=H R2=OC12H25) 218-2H 212-Br – 1h 65d 6 217 (R1=H R2=OC12H25) 218-2H 212-Br – 2h 39e 7 18 (R1=R2=H) 6-Cu 212-Br Cu(OAc)2 5 min 76 8 18 (R1=R2=H) 6-FeCl 212-Br FeCl3 5 min 58 9 213 (R1=H R2=OMe) 214-Zn 212-Br Zn(OAc)2.2H2O 3 h 58 10 215 (R1=H R2=OC5H11) 216-Zn 212-Br Zn(OAc)2.2H2O 2 h 72 11 197 (R1=H R2=OC8H17) 207-Zn 212-Br Zn(OAc)2.2H2O 1 h 74 12 217 (R1=H R2=OC12H25) 218-Co 212-Br Co(OAc)2 20 63 13 219(R1=H R2=OC16H33) 220-Zn 212-Br Zn(OAc)2.2H2O 16 h 62 14 223 (R1=H 224-Zn 212-Br Zn(OAc)2.2H2O 2 h 59 R2=OCH2C6H4-pOMe) 15 225(R1=H R2=NO2) 12-Zn 212-Br Zn(OAc)2.2H2O 10 min 40 16 225(R1=H R2=NO2) 12-Co 212-Br CoCl2 10 min 43 17 226(R1=H R2=Me) 227-Co 212-Br CoCl2 30 min 69 a Reaction conditions: phthalonitrile (1 mmol), DBU (2 equiv), metal salt (0.25 equiv), ionic liquid 212-Br (1.5 g for 250 mg of phthalonitriles) b Isolated yields c Product 18 was isolated in 4% yield when the reaction was carried out in the absence of DBU d Product 215-2H was isolated in 5% and 30% yields after 16 h and 1 h when the reaction was performed at 100°C and 120°C, respectively e Reaction was performed in presence of 1 equiv of DBU. Adapted from Ref. [161] with kind permission of Georg Thieme Verlag
The effect of the size of the anion on the Coulombic interaction with the cationic nucleus of ionic liquids is also remarkable [162]. Better yields obtained for the formation of metallophthalocyanines in ionic liquid 165-BF4 compared to 165-Br, or in ionic liquid 212-Br compared to 212-Cl could be attributed to the larger size of tetrafluoroborate than bromide or bromide than chloride ions, which results in weaker Coulombic interactions between the cationic and anionic parts of the ionic liquids, thereby improving the nucleophilicity of the anionic partner. The synthesis of metallophthalocyanines by the reaction of a range of phthalonitriles, in the presence of metal salts, in hydroxylated-ammonium-based ionic liquid 209-Br is simple and efficient. Moreover, hydroxylated ammonium ionic liquids are UV-Vis transparent, biodegradable, cost-effective and can be easily synthesized from bulk precursors. The presented method has been worked well with a range of transition- metal salts (M = Zn, Co, Ni, Fe, Cu, Pd) and different metallophthalocyanines with electron-donating as well as electron-withdrawing substituents; all were synthesized in good yields in ionic liquid 212-Br under mild conditions (Table 2.38). It was
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109
observed that the reaction time and the yields were affected by the nature and number of substituents on the phthalonitriles (Table 2.38).
2.3.3.3
Synthesis of Phthalocyanines from Phthalic Anhydrides in IL
As known, the metallophthalocyanines are usually prepared by cyclotetramerization of phthalonitrile or phthalic acid analogues such as phthalimide, phthalic anhydride and phthalic acid at high temperature (about 200°C) and reaction times of several hours are needed. A reaction in which metallophthalocyanines have been synthesized in a very short time, from phthalic anhydride using tetrabutylammonium bromide (188, TBAB) as an ionic liquid under classical heating conditions at 175–185°C, was reported by Shabani et al. (Scheme 2.30) [163]. The ionic liquid can be recycled for subsequent reactions without any appreciable loss of efficiency.
R3
R2
R4
R1
O
R2 O R3 R4
ur ea [NH4] 6Mo 7O 2 [( nB u4)N] +Br − M 2+
O
R1
R1
N
N
N
R3
R2 M
N R3 R4
R2
N
N
N
R 1=R 2=R 3 =R 4= H
9
R 1=R 2 =R 3=R 4= Cl
15 R 2=R 3 =R 4= H, R 1= NO2
R1
R4 R2
22 8 R1=R4 = H, R 2=R 3= Cl
M: Cu2+, Co2+, Ni2+ , Fe2+ , Zn2+, P d2+, Rh 3+
N
R1
7
R4
R3
6-M 229 -M 8-M 1 4-M
Scheme 2.30 Synthesis of metallophthalocyanines
2.3.3.4
Synthesis of Phthalocyanine from Phthalic Acid in IL
Phthalocyanines can be obtained from phthalic acid derivatives used as precursors. Gedanken et al. carried out a conventional cyclocondensation reaction in 1-butyl-3methylimidazolium tetrafluoroborate (165-BF4) as an ionic liquid solvent to prepare one-dimensional metal phthalocyanine with a high (Scheme 2.31) [164]. The yield of the prepared product was 35% by using the imidazolium ionic liquid 165-BF4 as the solvent. It is worth mentioning that the same reaction performed in N,N,N’,N’-tetramethyl-guanidinium trifluoroacetate but starting from phthalonitriles yielded 24–74% products with different transition metal salts [150, 158, 163].
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A.G. Gürek and C. Hirel
N O N
IL OH + Ni SO .6H O + Urea + NH Cl 4 2 4 OH O
Ni
N 175 +- 5 C
N
N
N N
N
Scheme 2.31 Schematic representation for the synthesis of nickel phthalocyanine
The formation of these 1-D structures is attributed to the unique properties of the ionic liquid used in the experiments. Because of the unique p-p stacking of the imidazol ring they induce a specific directed growth. This synthesis confirms the important role that ionic liquids play in the field of inorganic material synthesis, especially for the fabrication of 1-D nanomaterials. The product obtained contains no impurities or residue from the ionic liquid. A similar reaction with copper(II) nitrate has yielded copper phthalocyanine nanorods; however, the product obtained contains some impurities or residue from the ionic liquid.
2.3.3.5
Synthesis of Unsymmetrically Substituted Phthalocyanines in IL
Different methods are available for the preparation of noncentrosymmetric phthalocyanines [165, 166] and the most common one being the ring expansion reaction of boron(III) subphthalocyanines with various 1,3-diiminoisoindolines [167–171] or phthalonitriles [172]. Usually these ring expansion reactions are widely carried out at an elevated temperatures with high boiling solvents like dimethylsulfoxide (DMSO), DMSO/1-chloronaphthalene, DMSO/chlorobenzene, DMSO/o-dichlorobenzene and N,N-dimethylaminoethanol. In comparison to many of the organic solvents used in the synthesis of phthalocyanines, ionic liquids can be thought of as a greener alternative. Chauhan et al. report a simple and efficient method to synthesize unsymmetrically substituted metal-free and metallated phthalocyanines by the ring expansion reaction of corresponding boron(III) subphthalocyanines (230–233) with phthalonitriles (18, 197) or 3,4-dicyanopyridine 234 in two functional ammonium ionic liquids (tetrabutylammonium bromide; (188, TBAB=[Bu4N][Br]), and butyl(2-hydroxy-ethyl)dimethylammonium bromide [bhyeda][Br] (212-Br)) in the presence of DBU and zinc acetate under different reaction conditions (Scheme 2.32) [173]. It is believed that the alkoxide ion of ionic liquid [bhyeda][Br] (239), generated by proton abstraction with DBU [160, 161], attacks on phthalonitrile 18 leading to the formation of an imidoisoindoline type intermediate (240). The nucleophilic attack of 217 on highly strained imine core of subphthalocyanines (230–233) results in an open tetrameric intermediate (241), which on cyclization gives metal-free phthalocyanines. However, in the presence of metal ion 241 cyclizes rapidly and
2 Recent Developments of Synthetic Techniques for Porphyrins…
111 R
R CN N N
CN
R
N
N
234
N
N
M
Zn(OAc) 2
N
N N
Cl CN
BCl 3
N
N
N
18, 137 225 or 226
DBU
N
N
CN
235-Zn , R= H 236-Zn R=CH3 237-Z n R= C(CH3 )3 236-2 H R=CH3
(TBAB or 212-Br
B R
N
IL
N
R
R
CN
R
R
R N 230-233
R
R= H R=C(CH3 )3 R=NO2 R=CH3
18 , 23 0 137, 2 31 225 , 2 32 226, 2 33
CN N
18 R:H 19 7 R :OC 8 H17
N
N N
M
Zn(OAc)2
N
N N
R
Structure of ILs
R2
R 237-2H , R:= C(CH 3 )3 R = H, 238-Zn : R= NO2 , R'= OC8H 17
R1 N
R4
X TB A B R1=R2=R=3=R4= nBu, X= Br, [Bu4 N][Br ] 2 12-B r R1= R3=Me, R2=C2 H4 O H, R4=nBu, X = Br. [bhyeda][Br]
R3
Scheme 2.32 Ring expansion of boron(III) subphthalocyanines 230–233 in ionic liquids TBAB and 212-Br
efficiently to yield metallo-phthalocyanines, indicating the template effect of metal ion (Scheme 2.33). Consequently, selective ring opening of 230–233 by 240 in ionic liquid [bhyeda][Br] (239) could be accountable for the formation of desired unsymmetrically substituted phthalocyanines (242–245) in good yields. The mechanism is detailed in Scheme 2.33. Me
Me Bu
OH
N
Me
H-DBU
+ DBU
+
N
Me
Br
Br
Bu
O 239 N
212-B r R
R
R
R
N N N
N
NH N
M N
N
N O
N N
N
N R
N
HN
N
N
N O 2 42-245 242 243 244 245
HN
240
R
R
Cl 241
N
N
R= H R=C(CH 3)3 R=NO 2 R=CH3
N
230 231 232 233
B N
N
R= H R=C(CH 3)3 R=NO2 R=CH3
N R
R
Scheme 2.33 Proposed mechanism for expansion of subphthalocanines 230–233 in ionic liquid 203-Br
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The selective ring opening of 242–245 in ionic liquid [bhyeda][Br] 212-Br could be accountable for the formation of the desired unsymmetrically substituted phthalocyanines (242–245) in good yields about 50%. Ionic liquid [bhyeda][Br] (212-Br) can be used also in statistical condensation of two different phthalonitriles affording different unsymmetrically substituted phthalocyanines in good yields [173]. Furthermore, nucleophilicity [162], high moisture and thermal stability of ionic liquid ([bhyeda][Br]) (212-Br) [174, 175] offer an additional advantage and act as a promising promoter for the ring enlargement reaction of boron(III) subphthalocyanines. These results justify the versatility of ionic liquid ([bhyeda][Br]) (212-Br) in ring expansion reaction of different subphthalocyanines bearing electron withdrawing as well as electron donating groups with various phthalonitriles affording different unsymmetrically substituted metal-free and metallated phthalocyanines in good yields.
2.4
Conclusion
Synthetic methods for the synthesis of porphyrins, phthalocyanines and related compounds have been enriched in the last years by the contribution of microwave irradiation and the use of ionic liquids. Microwave irradiation is a very performing heating method for a range of reactions, including porphyrin and phthalocyanine syntheses. It is now considered that all the conventional heated reactions could be managed by this technique. The main advantages are an instantaneous heating without interaction with the vessel and drastic reduction of the reaction times, generally to a few minutes, limiting the formation of by-products compared to conventional heating conditions. More surprisingly, microwave heating allows to complete some reactions that otherwise would not occur under standard conditions. Recently, ionic liquids have emerged as superior reaction media in organic synthesis because of their low vapor pressure, high thermal stability, high ionic conductivity, and ease of recovery, making these conditions attractive as an environmentally benign method to prepare porphyrins, phthalocyanines and their precursors. Furthermore, the metallation of free phthalocyanines and porphyrins can be achieved in excellent yields in these ionic liquids under mild conditions. The method offers other advantages such as fewer side products, easy isolation, good to excellent yields and tolerance of a variety of substituents and metals, added to the recyclability of the ionic liquid.
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Chapter 3
The Contribution of Theoretical Chemistry to the Drug Design in Photodynamic Therapy Angelo D. Quartarolo, Nino Russo, Emilia Sicilia, and Carlo Adamo
Abstract The possibility to design new photosensitizers active in photodynamic therapy starting from computed chemical physics electronic and geometrical properties by using the density functional theory is presented. In particular, we were concerned with the porphyrin-like systems able to activate the singlet O2 excited state (Type II reactions). The investigated properties include the energy gap between ground and excited states with different spin multiplicities (Singlet-Triplet) and the electronic excitation energies (Q band of the UV-Vis spectra).
3.1
Introduction
The therapeutic use of light begins in 1900 when Raab reported that the combination of acridine orange and light could destroy living organisms. Nowadays, photodynamic therapy (PDT) does not account for only the therapy of a variety of cancer types but is currently being explored in the areas of cardiology, ophthalmology, dermatology,
A.D. Quartarolo • E. Sicilia Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per Elaborazioni, Parallele e Distribuite-Centro d’Eccellenza MIUR, Universita’ della Calabria, I-87030 Arcavacata di Rende (CS), Italy e-mail:
[email protected];
[email protected] N. Russo (*) Dipartimento di Chimica, Università della Calabria, Via P. Bucci cubo 14c, I-87036 Rende, Italy e-mail:
[email protected] C. Adamo Laboratoire d’Electrochimie, Chimie des Interfaces et Modélisation pour l’Energie, CNRS UMR 7575, Ecole Nationale Supérieure de Chimie de Paris – Chimie Paristech, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France e-mail:
[email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_3, © Springer Science+Business Media B.V. 2012
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immunology, gynaecology and urology [1–4]. In addition, PDT is becoming a potential alternative to the antimicrobial agent in the inactivation of many microbial infections [5]. For these reasons, in the last decades the interest in proposing new photosensitizers for PDT [6] is rapidly growing and different generations of new synthesized molecules have been proposed. Many of them are porphyrin-like systems [7, 8] but also new classes of nonporphyrin PDT agents based on tetrarylazadipyrromethenes [9], squaraine [10] and other groups have been synthesized, characterized and tested at biological and clinical levels. Today, for PDT there is a commercially available series of drugs including Levulan (D-5-aminolevulinic acid), Photofrin (Porfimer sodium), SnET2 (Sn-ethylporphyrin), MV9411, Lutrin (lutetium texaphyrin) and others are in an advanced stage of clinical test or already used in the treatment of various diseases (i.e. different solid tumors, macular degeneration) [11–14]. The main advantages of PDT over other therapies is its non-invasive nature and the use of drugs with very small toxicity. Nowadays PDT is currently used in oncology and ophthalmology in many countries (e. g. United States, Japan, Canada, France, Netherlands). An ideal PDT photosensitizer should be a substance of known composition, selective localization in the tumor cells, minimal toxicity in absence of light and cytotoxic at appropriate wavelength of visible light. Consequently metal containing complexes with high dark toxicity are not good candidates as PDT drugs. In this contribution we will show how the theoretical methods, and in particular the time dependent formulation of density functional theory, can contribute in the rational design of new PDT drugs starting from an “a priori” knowledge of their structural and spectroscopic properties. In particular, we will focus our attention on photosensitizers based on porphyrin-like systems as well as their metal containing complexes.
3.2
Photophysical and Photochemical Mechanisms of PDT
The photophysical mechanism of PDT can be summarized by well-know Jablonski diagram, depicted in Scheme 3.1. Type I reactions
Absorption PS
Fluorescence
So
T1
Phosphorescence
Intersystem spin crossing (ISC)
S1
PS
Free radicals Type II reactions 1
Δg
0.98 eV 3
Σg
O2
Scheme 3.1 Schematic picture of Jablonski diagram adapted for PDT
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Upon the absorption of light in the form of photons a photosensitizer (PS) is excited from its ground electronic state (S0) to a shorter-lived first excited state with the same electronic spin multiplicity (S1). The PS can decay to the S0 state by loosing its energy as emitting fluorescent light or as radiation-less internal conversion into heat. Alternatively, S1 can undergo to conversion into the first excited state with different electronic spin multiplicity (e.g. triplet, T1). This conversion should occur with a reasonable high quantum yield and it is due to the spin-orbit coupling between the two different states. From the T1 state the PS can return to the S0 one emitting phosphorescence through a non-radiative path. If this state has a sufficient long live and the process occurs in the presence of other molecules, like molecular oxygen or water, it can generate radical intermediate species or transfer energy to the oxygen producing highly reactive singlet oxygen. Of course, this last process requires that the energy of T1 is higher than that of the singlet O2 state. Throughout the population of the triplet state a series of reactions, defined as Type I chemical reactions, (see Scheme 3.1), can occur. Indeed, the PS can react directly with a substrate, such as the cell membrane or a molecule, and transfer a proton or an electron to form a radical anion or cation, respectively. These radicals may further react with oxygen to produce reactive oxygen species (ROS). When the energy of the excited triplet is transferred to the oxygen molecules the produced singlet oxygen induces on the surrounding biological tissue an oxidative cellular damage leading the apoptosis or necrosis of the cells (Type II chemical reactions). Type 1 and 2 reactions, both exploited in PDT, often occur simultaneously, and the ratio between these processes depends on the type of PS used, as well as the concentrations of substrate and oxygen [15]. In this contribution we concentrate our attention on photosensitizers that work by using Type 2 reactions, so that the cytotoxic agent is the singlet oxygen species and the entire physical and chemical process can be summarized as in the following cycle: S0 + hn → S1 (singlet ground state) (singlet excited state) S1 → S1* (vibrational relaxed S1 level) (relaxation of the photosensitizer) S1* → T1 (intersystem spin crossing) 3 1 T1 + O2 → S0 + O2 (energy transfer) The practical clinical cycle include the following steps: 1. a non toxic photosensitizer is introduced in the body of the appropriate target; 2. the target is irradiated with light of appropriate wavelength, ranging from 600 to 900 nm (the so-called therapeutic window), in order to excite the photosensitizer from its ground state (S0) to a shorter-lived first excited state (S1); 3. S1 can undergo conversion to the first excited triplet state (T1) by intersystem crossing. Then the T1 state of the sensitizer can release its energy to the surrounding biological tissue exciting the O2 from its triplet to the highly reactive singlet state
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that induces an oxidative cellular damage leading the apoptosis or necrosis of the cells; 4. finally, the photosensitizer returns to its ground state and the cycle can be repeated with a new light irradiation. At the end of the therapeutic cycle the sensitizer is eliminated from the body.
3.3
Method and Computational Details
Today computational methods are available for modelling the physical and chemical properties of complex molecular systems with reliable results that often are in very good agreement with the experimental counterparts. Among these tools, the density functional theory (DFT) based methods can give information about structures, properties and energetics with an accuracy comparable to the very expensive ab initio methods but with reduced computational efforts. For the prediction of the spectroscopic behaviour of the compounds active in PDT the time dependent version of DFT (hereafter called TDDFT) must be used [16]. A recent review on the performance of TDDFT in the prediction of UV- and visible spectra clearly shows as this tool gives results close to those obtained by high level post HF methods and with the experimental findings [17]. In all the computations presented here the Gaussian 03 [18] and Turbomole [19] codes were used. Geometry optimizations were performed without constrains with the exception of the systems with high symmetry topology for which the corresponding symmetry group were imposed. Different exchange-correlation functionals (B3LYP [20], PBE0 [21]) and double-zeta quality basis set (SVP [22], 6-31G(d) [23]) were utilized. Solvent effects were introduced as single point computations on the optimized gas phase structures, by using the conductor-like approach within the framework of the polarizable continuum model (SCRF-CPCM) [ 24– 28 ] , in which the cavity is created via a series of overlapping spheres. The proper dielectric constant values were chosen to take into account the medium in which the experimental electronic spectra were measured. With the aim to demonstrate the reliability of the employed protocol for the prediction of the UV-Vis and the energy gap between ground and excited states we present some benchmarks on these properties considering systems for which the experimental values are known. Table 3.1 compares our results for the ΔES0 −T1 energies for a series of aromatic systems. The agreement between computed and measured values is excellent, the largest difference being 0.1 eV in the case of anthracene. A large number of works exists in literature [29–33] concerning the DFT prediction of the optical spectra. In a recent review Jacquemin et al. [33] determined the absorption spectra for a large series of indigoid derivatives, including compounds with several heteroatoms, and various substitutions on the outer phenyl rings. The analysis of the results of this large set of aromatic systems, which covers the full width of the visible part of the electromagnetic spectrum, clearly shows
3 The Contribution of Theoretical Chemistry to the Drug Design… Table 3.1 Singlet-triplet energy gap, Δ ES0 −T1 (eV), for some aromatic hydrocarbons from TDDFT (PBE0) calculations in comparison with the experimental values
125 Δ ES0 −T1 (eV)
Molecule Benzene Naphthalene Anthracene Pyrene
PBE0 3.68 2.65 1.72 2.05
Experiment 3.69 2.65 1.82 2.08
that PBE0 exchange-correlation functional in conjunction with the Polarizable Continuum Model to take into account the solvent effect, give results in very good agreement with the experimental counterparts and can be used with confidence for the prediction of the optical spectra of new compounds.
3.4
Design of a Photosensitizer Active in PDT
A large number of photosensitizers have been tested in vivo and in vitro in PDT experiments, but very few have shown ideal properties and for this reason recent studies have focused on the development and efficacy of new photosensitizers [6]. The prerequisites for a rational design of new ideal sensitizers include the following intrinsic characteristics: – the core of the system, generally a ligand , should be represented by a moiety able to absorb in the therapeutic window (about 600–900 nm) and preferably should be red shifted. It is well known, indeed, that high absorbance values increase the penetration efficiency in the biological tissue (i.e. a 500 nm wavelength radiation penetrates into the tissue for about 3.5 mm while the depth of light penetration increases to about 8 mm at 700 nm); – the presence of a metal or a heavy atom generally increases the efficiency of the singlet-triplet intercrossing (the so-called heavy atom effect) due to the enhanced spin-orbit perturbations; – the energy gap between singlet and triplet states should be higher than the energy required to excite the oxygen molecule in its singlet state (about 1 eV) [34]. In addition, the triplet state should be generated with high quantum yield (j > 0.4) and have a long lifetime (> 1 ms); – the photosensitizer should have an high photo and thermodynamic stability. A good photosensitizer should be a single substance with constant composition and a high degree of chemical purity and sufficiently stable under physiological conditions; – the photosensitizer should have no toxicity in the dark; – the proposed drug must be soluble in the physiological solution. Many of these required properties can be easily solved by using the large experience of chemists on modern synthetic strategies (e.g. combinatorial). For example, the last
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requirement can be achieved by adding appropriate electrophylic substituents around the main ligand. Among all these factors determining the activity of a new PDT drug, the first two are the most important, while if we would like to promote Type II reactions the energy gap between the ground electronic state and the first excited one with different spin multiplicity (e.g. singlet-triplet) must have a value higher than that necessary to activate the first oxygen excited singlet. Since the most used drugs in PDT are porphyrin-like complexes, in this work we will examine a series of porphyrin-like systems with different numbers of p electrons, namely porphyrin (P), porphyrazin (Pz), chlorin (C), bacteriochlorin (BC), texaphyrin (Tex), phthalocyanine (Pc), naphthalocyanine (Nc) and anthracocyanine (Ac) and some of their complexes with transition metal cations. In order to design a new metal-porphyrin like PS we will investigate the properties of the ligands and the changes induced by the metalation process. Figure 3.1 shows
therapeutic window
850 800
λ max (nm)
750 700 650 600 550 500
1,4
Active in PDT (Type II reaction)
eV
1,2 1,0 0,8 0,6 0,4 BC
C
P
Pz
Tex
Pc
Nc
Ac
Molecule Fig. 3.1 Plot of the Qx band and DES−T values for the considered porphyrin-like systems
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127 H H H H
N
N
N
N
N
H H
H H
P
N H
H
H N
N
N H
H
N
H H
BC
H
N
H H
N
C
N
H
N
N
N
N
N
H N
N
N
H H N
+
N
OMe
N
OMe
N
Tex
Pz N N
N N
H
N N
N N
H N
N H
N
N
N
H N
N N
Pc
Nc
N N
N H
N
N
H N
N N
Ac Scheme 3.2 Structures of the examined porphyrin-like systems
the variation of the Q band absorption wavelength as a function of ligand species (Scheme 3.2). Considering that the optimal absorption wavelength for a PS active in PDT is in the range between 600 and 900 nm, the systems with absorption wavelength that can better penetrate into the tissue are BC, Tex, Pc, Nc and Ac. Thus, in principle,
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these five compounds can be considered as better candidates than C, P and Pz. As mentioned above, in order to induce the Type II reactions, the first excited triplet state should transfer its energy to the oxygen molecules and populate the reactive O2 singlet state. This means that the energy of the triplet state of the PS must have an energy higher than that of singlet oxygen (0.98 eV). In Fig. 3.1 the singlet-triplet energy gap (DES-T) is plotted against the considered porphyrin-like systems. As it is clear from this figure, Pc, Nc and Ac have DES-T lower than 0.98 eV. Using the data obtained for these two properties we can indicate only the BC and Tex compounds as reliable photosensitizers able to induce Type II reactions in PDT. What does happen if these ligands are metalated by transition metal ions? The presence of the metal can increase the stability of the system as well as induce an “heavy metal” effect and, consequently, increase the performance of the porphyrinlike systems as PS in PDT. In order to verify the effect of the metal atom on the properties of the bare porphyrin-like ligands, we have computed the maximum absorption Q band and the energy gap between the ground and first excited states, with different spin multiplicities, of the complexes formed by BC and the first-row transition metals. The results are collected in Fig. 3.2. From this figure it is clear that Q absorption band is not sensibly affected by the presence of the metal. In contrast, the energy gap, that in the free ligand is larger than 0.98 eV, is strongly reduced in the Iron complex. Also Nickel induces a reduction of the band gap of about 0.2 eV that remain essentially unaffected in the Co, Cu and Zn complexes. Finally it is worth to note the strong increase (about 0.4 eV) of the energy gap induced by the metalation of BC with the Mn ion. Analyzing the behaviour of these two reported properties it is evident that the “a priori” knowledge of the maximum absorption band and of the energy gap between states at different spin multiplicities (e.g. singlet-triplet) is very important before to start with the synthesis and experimental characterization of a new photosensitizer. In other words, the computed properties can address the design of new active drugs avoiding the experimental work expenses on the basis of the similarity of the new proposed molecules with others for which their biological activity is known, but which often do not give the expected results. Computational chemistry can give other important contributions not only in the interpretation of experimental data (e.g. the UV-Vis spectral assignments), but also in predicting electronic properties that often are difficult to measure (e.g. HOMO-LUMO gap) or that cannot be obtained experimentally (e. g. molecular orbital picture and composition, atomic charges). Furthermore, it provides powerful tools for rationalizing the experimental data and predict the behaviour of many important properties. Considering the porphyrin-like systems previously examined, their spectra can be roughly rationalized in terms of the four orbital Gouterman’s model (see Fig. 3.3), where the principal excitations involve the two highest occupied molecular orbitals (HOMO and next-HOMO) and the two lowest unoccupied molecular orbitals (LUMO and next-LUMO) [35]. The substitution or the modification of the porphyrin ring can affect these levels in different ways. In fact, the hydrogenation of outer
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850
therapeutic window
λ max (nm)
800
750
700
650
600 1,4
Active in PDT (Type II reaction)
1,2
eV
1,0 0,8 0,6 0,4 0,2
Mn-Bc
Fe-BC
Co-BC
Ni-BC
Cu-BC
Zn-BC
Molecule Fig. 3.2 Plot of the Qx band and DES−T values for first-row transition metal complexes of bacteriochlorin
carbon double bonds, resulting in BC and C (see Fig. 3.3), decreases the number of p electrons involved in the aromatic system (22 for P, 20 for BC, and 18 for C) inducing changes in the UV spectra. Qx bands are, indeed, red-shifted as one goes from P (532 nm) to BC (544 nm) and C (590 nm). Along this series, the Qx band is mainly composed of the HOMO- > LUMO transition and in a smaller amount of the next-HOMO - > next-LUMO. The Qy counterpart equally corresponds to next-HOMO - > LUMO
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L+1 L
E (eV)
−3 −4
H
−5
H-1
−6 −7 −8
BC
C
P
Pz
Tex
Pc
Nc
Ac
Fig. 3.3 Gouterman frontier molecular orbital energies for porphyrin-like free bases
and HOMO - > next-LUMO excitations (these orbitals are depicted in Fig. 3.4 and their energies are plotted in Fig. 3.3). An exception is represented by P, whose frontier orbitals are quasi-degenerate and the transition assignment can change from one calculation to another one. In fact, there is an inversion in Q band assignments between in vacuo and in aqueous solution assignment. Looking at the Fig. 3.3 we can observe that the reduction of pyrrole rings in BC and C results in an energy increases of the HOMO and next-LUMO orbitals, while next-HOMO and LUMO energies are quite constant for the three considered systems. The relaxation of degeneracy of HOMO and next-LUMO makes the HOMO/LUMO difference smaller, whereas the next-HOMO/next-LUMO gap is strengthened. Wavelengths of the Qx bands are, therefore, enhanced, and the corresponding oscillator strengths are also affected. In contrast, the symmetry variation in FBC and FBBC induces a partial cancellation of transition moments, and the oscillator strength is consequently raised [f(BC) = 0.098; f(C) = 0.243]. The same trend is observed for Qy bands but they are slightly blue-shifted from P (498 nm) to BC (491 nm) and C (483 nm). In the porphyrazine (Pz), the introduction of aza groups in the meso position significantly stabilizes, with respect to porphyrin (P), next-HOMO level, but also the other three Gouterman orbitals are slightly effected. The drastic modification of the porphyrin ring in the case of Tex corresponds to a strong stabilization of all the considered frontier orbitals. The Qx band is mainly composed by the HOMO-LUMO (71%) transition and the energy gap between these two levels becomes smaller. As a consequence, the excitation energy decreases and the transition is red shifted (634 nm) with respect to the P systems (526 nm). Analyzing the last three systems, starting from Pc, we underline that the annulations of further benzene rings at the Pc moiety increases the number of
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Fig. 3.4 Isodensity frontier molecular orbital plots (HOMO and LUMO) for Texaphyrin free base (Tex) and its manganese (II) complex
p electrons and the HOMO-LUMO gap decreases (2.35, 1.97 and 1.72 ev for Pc, Nc and Ac, respectively) and, consequently, the Q band sensibly shifts to longer wavelength (see Fig. 3.1). Also in these compounds, the main electronic transition is associated with the HOMO-LUMO levels (about 90%) and our computed gap indicate a decrease of the value in going from Pc to Nc (see Fig. 3.3). Due to its importance in the possible application of these compounds in the PDT it is worth to note that the value of the calculated oscillator strength for the Q band increases with the enlargement of the p system. The decrease in the HOMO-LUMO gap is almost determined by the destabilization of the HOMO as one goes from Pc (5.42 eV), to Nc (4.97 eV) and Ac (4.71 eV). The next-HOMO orbital follows the same behaviour, while the LUMO energy does not change considerably. The next-LUMO level is stabilized in going from Pc, to Nc and Ac. The Qy peak is mainly originated by a HOMO → next-LUMO transition (also in this case of about 90%) and to a smaller
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extend by the next-HOMO → LUMO one. For metal complexes, the contribution of d-metal orbital to HOMO and LUMO (and consequently upon electronic transitions) is pictorially shown in the case of Mn(II)-Tex complex (right part of Fig. 3.4). Finally, we underline that the calculated the transition energies well agree with the experimental data being the average error about 0.2 eV. So, the TDDFT simulation of the UV-Vis spectra of systems for which the experimental counterpart is not available or difficult to detect, can be considered reliable.
3.5
Conclusions
In this contribution we showed how the density functional theory, in its time-dependent formulation, is able to reproduce and rationalize spectroscopic parameters relevant for the photochemical processes. The agreement with the experimental results is quite good for both the electronic transitions and singlet-triplet energy gaps. On the basis of these results, we believe that this tool is useful in the design of new sensitizers active in the photodynamic therapy. Acknowledgements Financial support from the Università della Calabria and MIUR (PRIN 2008F5A3AF_005) is gratefully acknowledged.
References 1. MacDonald IJ, Dougherty TJ (2001) Basic principles of photodynamic therapy. J Porphyrins Phthalocyanines 5:105–129 2. Van Tenten Y, Schuitmaker HJ, De Wolf A, Willekens B, Vrensen GFJM, Tassignon MJ (2001) The effect of photodynamic therapy with bacteriochlorin a on lens epithelial cells in a capsular bag model. Exp Eye Res 72:41–48 3. Dolmans DEJGJ, Fukumura D, Jain RK (2003) Photodynamic therapy for cancer. Nat Rev Cancer 3:380–387 4. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q (1998) Photodynamic therapy. J Natl Cancer Inst 90:889–905 5. Hamblin MR, Hasan T (2004) Photodynamic therapy: a new antimicrobial approach to infectious disease? Photochem Photobiol Sci 3:436–450 6. O’Connor AE, William M, Gallagher WM, Byrne AT (2009) Porphyrin and nonporphyrin photosensitizers in oncology: preclinical and clinical advances in photodynamic therapy. Photochem Photobiol 85:1053–1074 7. Sternberg ED, Dolphin D, Bruckner C (1998) Porphyrin-based photosensitizers for use in photodynamic therapy. Tetrahedron 54:4151–4202 8. Nyman ES, Hynninen PH (2004) Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy. J Photochem Photobiol B Biol 73:1–28 9. Gorman A, Killoran J, O’Shea C (2004) In vitro demonstration of the heavy-atom effect for photodynamic therapy. J Am Chem Soc 126:10619–10631 10. Ramaiah D, Eckert I, Arun KT, Weidenfeller L, Epe B (2002) Squaraine dyes for photodynamic therapy: study of their cytotoxicity and genotoxicity in bacteria and mammalian cells. Photochem Photobiol 76:672–677
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30. Petit L, Quartarolo A, Adamo C, Russo N (2006) Spectroscopic properties of porphyrin-like photosensitizers: insights from theory. J Phys Chem B 110:2398–2404 31. Lanzo I, Russo N, Sicilia E (2008) First-principle time-dependent study of magnesiumcontaining porphyrin-like compounds potentially useful for their application in photodynamic therapy. J Phys Chem B 112:4123–4130 32. Quartarolo AD, Sicilia E, Russo N (2009) On the potential use of squaraine derivatives as photosensitizers in photodynamic therapy: a TDDFT and RICC2 survey. J Chem Theory Comput 5:1849–1857 33. Perpète EA, Jacquemin D (2009) J Mol Struct THEOCHEM 914:100–105 34. Herzberg G (1950) Spectra of diatomic molecules. Van Nostrand Reinhold, New York 35. Gouterman M, Wagnière G, Snyder L (1963) Spectra of porphyrins: part II. Four orbital model. J Mol Spectrosc 11:108–127
Chapter 4
Photochemical and Photophysical Characterization Mahmut Durmuş
Abstract This chapter highlights the photophysical and photochemical parameters of photosensitizers, with a focus on the different measuring and calculation methods. Singlet oxygen generation, photodegradation quantum yield, fluorescence quantum yield and lifetime and triple state quantum yield and lifetime of the photosensitizers are detailed and data regarding these parameters for photosensitizing phthalocyanines are summarized. The effects of number and position of substituents, nature of central metal and solvents on these parameters of phthalocyanine photosensitizers are also given in Table 4.1.
4.1
Introduction
Photodynamic therapy (PDT) is an emerging cancer treatment that takes advantage of the interaction between light and a photosensitizing agent to produce reactive oxygen in cells [1]. A major objective for cancer treatment is the selective destruction of malignant cells without damage to normal tissues and functions. The mode of operation in PDT is based on specific wavelength of light excitation of a tumour-localized photosensitizer. After excitation, energy is transferred from the photosensitizer (in its triplet excited state) to ground state oxygen (3O2), forming singlet oxygen (1O2) that can destroy tumor cells. This process is the dominating initial elementary step of PDT, and it is followed by oxidation of cellular targets by 1 O2; the so-called Type II mechanism (Fig. 4.1) [2].
M. Durmuş (*) Chemistry Department, Gebze Institute of Technology, PO Box 141, 41400 Gebze, Kocaeli, Turkey e-mail:
[email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_4, © Springer Science+Business Media B.V. 2012
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Fig. 4.1 The pathway of the photodynamic therapy for the cancer cells
The increasing popularity of this treatment method is largely due to its selectivity to destruction of tumor cells: only tissues that are simultaneously exposed to the photosensitizer and light, in the presence of oxygen, are subjected to the cytotoxic reactions during PDT. Thus, under ideal circumstances only diseased tissues are eradicated, leaving the surrounding healthy cells undamaged. Since the first demonstration of the photodynamic action in the early 1900s [3], great effort has been devoted towards the development of PDT agents, which have specific light absorption and tissue distribution properties. Many potential new PDT drugs have been investigated including porphyrins, chlorins, and phthalocyanines. The drug properties deemed favorable for PDT include synthetic purity, effectiveness at far-red and near infrared wavelength absorption, where tissues are more transparent, fast clearance from the body after PDT activity. Several of the new drugs have progressed to clinical trials. The first photosensitizer used was a hematoporphyrin derivative (HPD) known as Photofrin@ after purification [4]. The U.S. Food and Drug Administration (FDA) approval was obtained in Canada (1993), Japan (1994), USA (1995) and France (April 1996), promoted the synthesis and development of second generation photosensitizers [5]. Among the more promising secondgeneration photosensitizers that are currently being evaluated for PDT applications are the phthalocyanines (Pcs). Pc derivatives have favorable photophysical and photochemical properties, which include strong absorbance at long wavelengths and chemical tunability through substituent addition on the periphery of the macrocycle or on the axial position for certain central metals [6–8]. Photophysic is the study of interaction of light with molecules which results in net physical change. Photochemical reactions take place as a result of some chemical changes as a response to light absorption. Figure 4.2 shows a Jablonski diagram representing the photophysical processes following light illumination. Investigation of the photophysical and photochemical properties of the photosensitizers are very useful in applications involving PDT.
4
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Fig. 4.2 Jablonski diagram
4.2
Singlet Oxygen Quantum Yields (FD)
Molecular oxygen is one of the most important substances on the earth. Oxygen comprises 21% of the atmosphere, 89% of seawater by weight, and at least 47% of the Earth’s crust. Almost all living organisms utilize oxygen for energy generation and respiration. Molecular oxygen has two unpaired electrons in its lowest energy state. The existence of unpaired valence electrons in a stable molecule is very rare in nature and confers high chemical reactivity (Fig. 4.3). The production of singlet oxygen can be accomplished through the use of photosensitizers (PS). The absorption of light by these compounds leads to an excited singlet state (1PS*) of the sensitizer. Through a process of intersystem crossing, the excited singlet state can spin-flip into a lower energy triplet state (3PS*) that reacts in an energy transfer reaction with the ground triplet state of oxygen. The sensitizer returns to its singlet ground state while, bringing oxygen molecule to the excited singlet state. Energy transfer between the triplet state of photosensitizers and ground state molecular oxygen leads to its conversion into singlet oxygen (1O2) [9]. This transfer must be as efficient as possible to generate large amounts of singlet oxygen. This is quantified by the singlet oxygen quantum yield (FD), a parameter giving an indication of the potential of molecules to be used as photosensitizers in applications where singlet oxygen is required (such as Type II mechanism) [10]. The singlet oxygen quantum yield (FD) corresponds to the number of 1O2 molecules generated by one
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Fig. 4.3 Molecular orbital diagrams for the three electronic configurations of molecular oxygen
Fig. 4.4 Photochemical processes (Type I and Type II) mechanism of PDT
photon absorbed by a photosensitizer [11]. It is therefore a key parameter defining a photosensitizer. Two different types of mechanisms (Type I and Type II) are suggested during photosensitization (photocatalysis) process. In Type II mechanism (Fig. 4.4), the photosensitizer is first excited to the triplet state, then transfers its energy to ground state oxygen, O2(3Sg). The latter is converted in its excited state, O2(1Dg), which is the active cytotoxic species resulting cell death [12–20]. Singlet oxygen is generated thanks to the interaction of oxygen in its triplet basic state (3O2) with a photosensitizer
4
Photochemical and Photophysical Characterization
139
in its triplet excited state (3PS*). The PS in its excited triplet state is quenched by ground state oxygen, hence singlet oxygen quantum yields are expected to be comparable to PS’ triplet state quantum yields [14]. In Type I (Fig. 4.4), the interaction of the PS in its excited triplet state with either ground state molecular oxygen or substrate molecules, results in the generation of superoxide and hydroperoxyl radicals, which are the active cytotoxic species (Fig. 4.4) [12, 15]. Many factors associated with the sensitizers are responsible for the magnitude of the determined quantum yield of singlet oxygen, including: triplet excited state energy, ability of substituents and solvents to quench the singlet oxygen, the triplet excited state lifetime and the efficiency of the energy transfer between the triplet excited state of the sensitizer and the ground state of oxygen [21].
4.2.1
Detection and Measurement of Singlet Oxygen
Detection and measurement of singlet oxygen depend on the generating system. Optical spectroscopy is a method routinely used in laboratories as well as for the detection of 1O2 in planetary atmospheres. Condensed phases require different techniques and the development of new procedures is continuously ongoing [11]. The generation of singlet oxygen by PS can be quantified by mainly three methods. In the first one, called the direct method, is the measurement of the luminescence of singlet oxygen. In the second method, called the indirect method, the quenching of the absorption of a singlet oxygen by a quencher (usually 1,3-diphenylisobenzofuran (DPBF) in organic solvents or antracene-9,10-bis-methylmalonate (ADMA) in aqueous solution) is measured. The level of quenching is directly related to the quantity of singlet oxygen. The third method is based on electroparamagnetic measurements. 4.2.1.1
Singlet Oxygen Luminescence Method
Singlet oxygen luminescence method is based on the luminescence emitted in the radiative decay of 1O2 at 1270 nm which is a spin forbidden process (Fig. 4.5). The intensity of the emitted luminescence is quite weak and requires extremely sensitive detectors to be observed and quantified. Laser light sources have been employed for photosensitized systems. In the flash photolysis technique, the 1O2 generating system is irradiated with a strong light flash which induces a luminescence pulse (Fig. 4.6). The dynamic course of 1O2 concentration [1O2] can be clearly recorded using Eq. 4.1 as described theoretically in the literature [13]. tD éë 1 O2 ùû = A tT - t D
é êexp ë
æ -t ö çè t ÷ø - exp T
æ -t ö ù çè t ÷ø ú D û
(4.1)
where the tD is the lifetime of 1O2, tT is the lifetime of photosensitizer at its triplet state, t is time in seconds and A is a coefficient involved in sensitizer concentration
140
M. Durmuş
Fig. 4.5 Jablonski diagram showing the 1270 nm luminescence of singlet oxygen
Fig. 4.6 A schematic representation of the singlet oxygen detector system using the singlet oxygen luminescence at 1270 nm
4
Photochemical and Photophysical Characterization
141
Fig. 4.7 Schematic illustration of the set-up of an indirect detection of singlet oxygen
and singlet oxygen quantum yield. The singlet oxygen quantum yield may then be determined by the relative method using a standard (for example unsubstituted zinc phthalocyanine), Eq. 4.2: F D = F Std D
A A Std
(4.2)
std where F Std are the D is the singlet oxygen quantum yield for the standard, A and A coefficients of the sample and standard, respectively. The equipment uses a laser excitation source is shown in Fig. 4.6.
4.2.1.2
Chemical Method
Here the singlet oxygen quantum yield is determined by the measurement of the quenching of the absorption of a molecule sensitive to the presence of singlet oxygen. This is the most commonly used as it does not requires specific equipment, see the experimental set-up in Fig. 4.7 [22, 23]. The disappearance of the quencher absorption (417 nm for DPBF in DMSO or 380 nm for ADMA in aqueous media) is followed by UV-vis spectrophotometry (Fig. 4.8). Equation 4.3 is used to determine FD by the relative method, using standards. F D = F Std D
R . I Std abs R Std . Iabs
(4.3)
where F Std is the singlet oxygen quantum yield for the standard, R and RStd are the D quencher’s photobleaching rates in the presence of the respective photosensitizers Std and standards, respectively. Iabs and I abs are the rates of light absorption by the photosensitizers and standards, respectively. Solutions of photosensitizer containing
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M. Durmuş
a
1
Absorbance
0.8
0.6
0.4
0.2
0 300
400
500
600
700
800
700
800
Wavelength (nm)
b
1.2
Absorbance
1 0.8 0.6 0.4 0.2 0 300
400
500
600
Wavelength (nm)
Fig. 4.8 Change in absorption spectra of (a) DPBF for unsubstituted ZnPc in DMSO and (b) ADMA for ZnPcSmix in aqueous medium as singlet oxygen is produced by the photosensitizers
singlet oxygen quencher are prepared in the dark and irradiated with light using the setup shown in Fig. 4.7. DPBF or ADMA disappearances can be readily monitored by following the decrease in their absorption peaks at 417 and 380 nm, respectively (Fig. 4.8a for DPBF and Fig. 4.8b for ADMA). 4.2.1.3
Electron Paramagnetic Resonance Method
In recent times, electron paramagnetic resonance (EPR) is used for the detection of singlet oxygen. This method is not optical, but based on a highly sensitive detection of the energy transfer between the intrinsic magnetism of unpaired electrons and an external magnetic field, following this Eq. 4.4: DE = 2 μe B
(4.4)
4
Photochemical and Photophysical Characterization
143
me is magnetic moment of the electron (the Bohr magneton) and B is strength of the effective magnetic field. This is actually an indirect method: 1O2 itself is non-magnetic and cannot be detected directly by EPR. What is detected is the formation of a product oxidized by 1O2? As a condition, this oxidized product must have a long-lived free radical or a spin label that is identified by EPR. 2,2,6,6-Tetramethyl-4-piperidone (TEMP) is a routinely used spin label probe, due to its conversion into the free radical 2,2,6, 6-tetramethyl-4-piperidone-N-oxyl (TEMPO) when reacting with 1O2 (Scheme 4.1). The EPR spectrum of TEMPO in ethanol is characteristic, consisting of three equal intensity lines due to the nitroxide radical (I = 1 for the 14N7 atom).
O
O
+
1O 2
H+
N H
N O
.
Scheme 4.1 The generation of TEMPO detectable by EPR, resulting of the oxidation of 2,2,6, 6-tetramethyl-4-piperidone (TEMP) by 1O2
Other active oxygen species can be detected and identified with this spin label method, as in the case of superoxide forms which forms an unstable complex free radical (hydroxyl radical e.g.) with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). The corresponding EPR has four characteristic lines [11, 24–27].
4.3
Photodegradation Quantum Yields (Fd)
Degradation of the molecules under light irradiation can be used to study their stability and this is especially important for those molecules intended for use in photocatalysis such as photodynamic therapy applications. Photodegradation is the oxidative degradation of a photosensitizer under light illumination and this can be determined by the photodegradation quantum yield (Fd). Photodegradation of a molecule depends of course on the structure of the molecule but as well on its concentration, nature of the solvent and light intensity. Photodegradation is attributed to the in situ generation of singlet oxygen, an oxidative species which can oxidize the PS itself. A photosensitive photosensitizer illuminated by appropriate light generates singlet oxygen and is partially degradated via photooxydation reactions. Generally, phthalimide residue was found to be the photooxidation product following degradation of phthalocyanines (Scheme 4.2) [28]. This photodegradation results in a lowered intensity of the Q- and B-bands, without distortion of their neither shape nor formation of new bands (that would
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M. Durmuş
Scheme 4.2 Photodegradation of phthalocyanine by singlet oxygen (Modified from Ref. [28] © Elsevier)
0.6
Absorbance
0.5
0 sec 60 sec 120 sec 180 sec 240 sec 300 sec
0.4 0.3 0.2 0.1 0 300
400
500
600
700
800
Wavelength (nm)
Fig. 4.9 Photodegradation of the photosensitizers under light irradiation
evidence a phototransformation of the Pc concomitantly to the photodegradation) (Fig. 4.9). Generally, photodegradation quantum yield (Fd) determinations can be measured using the experimental set-up demonstrated in Fig. 4.7 [23, 29–31]. Photodegradation quantum yields may thus be determined using Eq. 4.5, Fd =
(Co - Ct ). V . N A Iabs . S . t
(4.5)
where C0 and Ct in mol dm−3 are the photosensitizers concentrations before and after light irradiation respectively, V is the reaction volume, NA is the Avogadro’s constant, S is the irradiated cell area and t is the irradiation time. Iabs is the overlap integral of the radiation source light intensity and the absorption of the samples and determined by Eq. 4.6. I abs =
a SI NA
(4.6)
4
Photochemical and Photophysical Characterization
145
Fluorescence Quantum Yields (FF) and Lifetimes (tF)
4.4
Fluorescence is the emission of light by a molecule that has absorbed light. In most cases, emitted light has a longer wavelength than the absorbed light (Fig. 4.10). Fluorescence occurs when an orbital electron of a photosensitizer relaxes to its ground state by emitting a photon of light after being excited to a higher quantum state (see Fig. 4.2). The fluorescence quantum yield (FF) gives the efficiency of the fluorescence process. It is defined as the ratio of the number of photons emitted to the number of photons absorbed. Fluorescence quantum yields are affected by several parameters: presence and nature of the aggregation, nature of solvent, pH, photoinduced electron transfer or electronic energy transfer. Fluorescence quantum yields are generally determined by a comparative method, using a known standard having a structure related to the analyzed photosensitizer, for example unsubstituted ZnPc in the case of photosensitive phthalocyanines. Equation 4.7 may be employed [19, 20, 32, 33], using a standard. F F = F F (Std)
F . A Std .n 2 2 FStd . A . n Std
(4.7)
where F and FStd are the areas under the fluorescence emission curves of the fluorophore and the standard, respectively. A and AStd are the respective absorbances of the fluorophore and standard at the excitation wavelengths, respectively. n and n Std are the refractive indices of solvents used for the fluorophore and standard, respectively. Fluorescence lifetime (tF) refers to the average time a molecule stays in its excited state before fluorescing, and its value is directly related to that of fluorescence quantum yield (FF); i.e. the longer the lifetime, the higher the quantum yield of fluorescence. Any factor that shortens the fluorescence lifetime of a fluorophore indirectly reduces the value of FF. Such factors include internal conversion and 1000
1.6
800
600 0.8 400
200
0 550
Absorption Emission
Excitation
Absorbance
Intensity a.u.
1.2
0.4
0 650
750
Wavelength (nm)
Fig. 4.10 An example of absorption, fluorescence emission and excitation spectra of phthalocyanine photosensitizers
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M. Durmuş
intersystem crossing. As a result, the nature and the environment of a fluorophore determine its fluorescence lifetime. Lifetimes of fluorescence (tF) may be calculated using the Strickler-Berg equation (Eq. 4.8) [34]. F (λ ) ò λ 2 .d (λ ) ε (λ ) 1 -9 2 = 2.88 ´ 10 .n ò λ .d (λ ) τ0 F λ λ .d λ ( ) ( ) ò
(4.8)
where t0 is the natural radiative lifetime, n is the refractive index of the solvent, F is fluorescence emission, l is wavelength, e is the extinction coefficient. The time correlated single photon counting (TCSPC) equipment is often used for time domain measurements.
4.5
Triplet State Quantum Yields (FT) and Lifetimes (tT)
The ability of a photosensitizer to generate the toxic singlet oxygen species is determined by its triplet properties. For PDT, the triplet excited state of the photosensitizer is responsible for the generation of the reactive singlet oxygen species since the excited molecules transfer their energy to ground state oxygen to produce singlet oxygen which is essential for Type II mechanism of PDT. However, the efficiency of the other processes that deactivate this state including its non-radiative decay and phosphorescence must be minimal or controlled to give good PDT results. The triplet state efficiency is expressed as triplet quantum yield (FT), which has been defined as the number of molecules that undergo intersystem crossing and laser flash photolysis is used to determine the change in absorbance in the triplet state, which is directly related to the triplet quantum yield. The equipment employed for laser flash photolysis is shown in Fig. 4.11. Laser flash photolysis gives information about the triplet-triplet absorption and lifetime of the excited species. The triplet quantum yield (FT) is based on absorption of light by the triplet state generated during laser flash photolysis studies. For phthalocyanine photosensitizers the triplet absorption is at approximately 500 nm, far from the ground singlet state absorption (Fig. 4.12). This provides measurements of the triplet absorption easily since there is no overlap. The change in absorbance (DA) in the triplet state is directly related to the quantum yield of the triplet state, FT. The triplet quantum yields (FT) may be determined using standard with known FT by the triplet absorption method by Eq. 4.9 [35, 36] or singlet depletion method by Eq. 4.10 [16, 36–39]. F Sample = F Std T T
DASample . ε Std T T Sample DAStd T .ε T
(4.9)
F Sample = F Std T T
DASample . ε SStd S Sample DAStd S .ε S
(4.10)
4
Photochemical and Photophysical Characterization
147
Fig. 4.11 The laser flash photolysis system for photophysical determinations
0 400
500
600
700
800
Wavelength (nm) -0.5
0.08
-1
ΔA
ΔA
0.06 0.04 0.02
-1.5
0 400
450
500
550
600
Wavelength (nm) -2
Fig. 4.12 Typical transient differential spectrum of phthalocyanine photosensitizer
Std where DA T and D A T are the changes in the triplet state absorbance of the photosensitizer and standard (such as unsubstituted ZnPc for phthalocyanines), respectively. DAs and D AStd S are the changes in the singlet state absorption of the photosensitizers and the standard, respectively. F STtd is the triplet state quantum yield for the standard. e T and ε TStd are the triplet state extinction coefficients for the photosensitizer and the standard, respectively. eS and ε SStd are the singlet state extinction coefficients for the photosensitizer and the standard, respectively.
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M. Durmuş 0.05
Delta A
0.04
0.03
0.02
0.01
0.00 0.000
0.001
0.002
0.003
0.004
Time (s)
Fig. 4.13 A typical triplet decay curve of phthalocyanine photosensitizer
The triplet state extinction coefficients (eT and ε Std ) are determined from the molar T extinction coefficients of photosensitizers’ respective singlet states (eS and ε Std S ), the changes in absorbances of the ground singlet states (DAs and D A Std ) and changes in S the triplet state absorptions (DAT and D A Std ), according to Eqs. 4.11 and 4.12 : T eT = e S
ε TStd = ε SStd
D AT D AS DATStd DASStd
(4.11)
(4.12)
The lifetimes of the transients may be determined from a software program such as OriginPro 7.5, used in fitting the triplet decay curve (Fig. 4.13).
4.6
Photophysical and Photochemical Data of Phthalocyanine Photosensitizers
Table 4.1 lists the photochemical and photophysical properties of phthalocyanines. The effects of the nature of substituents, substitution degree, position of the substituents, central metal atoms and nature of solvents on the photophysical and photochemical properties of phthalocyanine photosensitizers are discussed below.
4
Photochemical and Photophysical Characterization
4.6.1
149
Singlet Oxygen Quantum Yields (FD )
Energy transfer from triplet state of photosensitizers to ground state molecular oxygen leads to the production of singlet oxygen. Therefore singlet oxygen generation depends on the triplet state quantum yield and lifetime of a photosensitizer. Thus, the trend in variation of FD values within an array of photosensitizers should be parallel to the variations in their FT values. FD values of the phthalocyanine photosensitizers are lower in aqueous solutions than in organic solvents due to the aggregation behavior of phthalocyanine photosensitizers in aqueous solutions. The low singlet oxygen generation in water compared to other solvents such as deuterated water and DMSO is explained by the fact that singlet oxygen absorbs at 1270 nm, and water, which absorbs around this wavelength has a great effect on singlet oxygen lifetime, while DMSO which exhibits little absorption in this region has longer singlet oxygen lifetimes than water, resulting in large singlet oxygen generation in DMSO [16]. The values of FD are expected to increase on addition of detergents (e.g. Triton X-100) in aqueous solutions [175]. The same trend can be applied for the FT values of phthalocyanine photosensitizers. The singlet oxygen quantum yield (FD) values of the metal-free and metallo phthalocyanine photosensitizers in different solvents are given in Table 4.1. Mg, Ti, Zn, Cd, Hg, Al, Ga, In, Si, Ge and Sn are commonly used as central metals for FD measurements of phthalocyanine photosensitizers. Complexation of phthalocyanine compounds with transition metals gives photosensitizers with short triplet lifetimes [2]. Generally, closed shell or diamagnetic metal ions are selected as central metals because their phthalocyanine complexes give both high triplet yields and long lifetimes consequently they produce high singlet oxygen. The FD values of MPc complexes increase according to the atomic size of the metal ion due to heavy atom effect such as the FD values are 0.67 for ZnPc, 0.78 for CdPc and 0.82 for HgPc [107]. In general, MgPc complexes gave low FD values, most likely due to the large fluorescence expected for small central metals [42]. The number of sulfo groups is an influence on the generation of singlet oxygen. For a series of ZnPc(SO3)n(mix) (n = an average number of SO3 groups) complexes (Table 4.1), FD values are almost the same in DMSO, but an increase for FD values is observed with the increasing of value of n in PBS due to lowering aggregation. [42] The FD value is low for the more aggregated ZnPc(SO3)2.1(mix) (FD £ 0.01), but high for the mainly monomeric ZnPc(SO3)3.7(mix) (FD = 0.49) in PBS (Table 4.1) [42]. The FD values for tetrasulfonated MPc complexes increase as follows: ZnPc(SO3)4 (FD = 0.52) > ClGa(III) Pc(SO3)4 (FD = 0.41) > ClAl(III)Pc(SO3)4 (FD = 0.20) > H2Pc(SO3)4 (FD = 0.16) in DMF [30, 92]. MPc(COOH)8 (M = Zn, Al and Si) complexes have low FD values in aqueous solution. The FD values increase with the size of the central metal as follows: Zn (FD = 0.32) > Si (FD = 0.22) > Al (FD = 0.12) in aqueous solution [73, 74]. When considering the number of carboxyl groups on the phthalocyanine framework, the FD values obtained for ZnPc(COOH)8 (FD = 0.48) and ZnPc(COOH)4 (FD = 0.51) are similar in DMF (Table 4.1) [36, 62]. In general, the quaternization of the N atoms on the substituted groups cause a decrease of the FD values of phthalocyanine photosensitizers (Table 4.1).
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M. Durmuş
Table 4.1 Photophysical and photochemical parameters of phthalocyanine compounds R3
R2 R1
R4
R4 R3 R2 R1 X2
N
N
N
M
N
N
N
N
Compound
Metal
R1=R4=R2=R3=H R1=R2=R4=H, R3=SO3H
2H
R1=R2=R4=H, R3=CH2C(CH3)3 R1=R2=R4=H R3=O(CH2)2O(CH2)2OCH3 R1=R4=H R2=R3= O R1=R4=H R2=R3= O
O
R1=R4=H; R2=R3=SC5H11 R1=R4=H; R2=R3=SC8H17 R1=R4=H; R2=R3=SC12H25 R1=R2=R4=H H13C6O
R3=
OC6H13
O O H13C6O
R1=R2=R4=H
R3=
OC6H13
O
O O
R1=R2=R4=H OH
R3=
O
R2 R3 R4 R1
R3
H2Pc(SO3)2mix
R1
N
R4 R2
X1
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
CHCl3 H2O DMF PBS+TX DMSO CHCl3 Toluene
0.55 0.62 0.60
6.5
0.24
7.3
1-ClNP
0.21
1-ClNP
FT
tT (ms)
151
Fd (×10−5) FD
Reference
170
0.09 0.16 0.02 0.11
504
0.19
[40] [30, 41] [30] [42] [42] [40] [43]
0.40
55
0.05
[44]
0.25
0.47
50
0.01
[44]
1-ClNP 1-ClNP 1-ClNP DMSO
0.10 0.13 0.15 0.12
0.39 0.40 0.38
62 51 44
0.04 0.04 0.04
[44] [44] [44] [45]
DMSO
0.18
DMSO
0.10
0.22 0.24
[45]
0.54
310
[46]
(continued)
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M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=H
Metal
O O
O O
R4=
O O
R1=R2=R3=H
O O O
R4=
O O
O
R1=R4=H; R2=R3=O(CH2)3CH3 R2=R3=H; R1=R4=O(CH2)3CH3 R2=R3=H, R1=R4=C8H17 R2=R3=H, R1=R4=C10H21 R2=R3=H, R1=R4=C12H25 R2=R3=H, R1=R4=C14H29 COOH
R1=R2=R3=R4= O COOH
R1=R4=H R2=R3=
O S NH O
R1=R4=H H3C R2=R3=
H3C OR
RO
N
N
RO N
N
N
OR
N
N OR
HN
NH RO
N
RO
N
NH N
HN N
OR
N
H3C R= RO
OR
RO
OR
H3C
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
0.03 (CHCl3)
0.12
[47]
DMF
0.05 (CHCl3)
0.14
[47]
Toluene THF CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
0.96 0.19 0.10 0.07 0.06 0.05
FT
tT (ms)
153
[40] [40] [48] [48] [48] [48]
5.0 4.8 5.0 5.1
DMF
Reference
0.27
[49]
THF
0.33
1.23
[50]
DMSO
0.03
0.07
[50]
Toluene
0.33
6.2
0.10
[51]
Toluene
0.04
0.8
<0.02
[51]
(continued)
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M. Durmuş
Table 4.1 (continued) Compound
Metal
RO
N RO
N
N
N
N
N
N
OR
N
NH
HN
NH
RO
RO
OR
N
N HN
N
N
RO
N
OR
N
N
N OR
NH
HN N
OR H3C
N R=
RO
OR
RO
OR
RO
OR
H3C
OR OR N N
NH
O
N
N O
N
HN N
OR OR
R= 4-carboxyphenyl
R
N R
N
NH N
O
N
OH
HN N
N R=
N
O
F F F
R
R1=R4=R2=R3=H NPc R1=R4=R2=R3=H MgPc(SO3)2mix
Li Mg
R1=R2=R4=H
R3=
OH O
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
Toluene
<0.02
0.4
H2O
FT
tT (ms)
155
Fd (×10−5) FD <0.02
0.13
2.05
[52]
1.28 1.75 2.17 150
[52] [52] [52] [52] [53]
570
[54] [54] [18] [42] [42] [46]
CTAC MeOH DMSO CHCl3 DMSO
0.12 0.02 0.04 0.16 0.09
0.56 0.25 0.34
CH3CN Acetone 1-ClNP PBS+TX DMSO DMSO
0.50 0.50 0.6
0.60 0.60
0.62
0.13 0.19 0.57
Reference [51]
0.24
(continued)
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M. Durmuş
Table 4.1 (continued) Compound
Metal
R
R
O
N
N
N
N
Mg N
N
N
OH
N R=
O
N
F F F
R
R1=R2=R3=H O R4=
OTi(IV)
R1=R2=R4=H O R3= R1=R2=R3=H R4= R1=R2=R4=H R3=
O
O
R1=R2=R3=H S R4=
R1=R2=R4=H S R3=
R1=R2=R3=H R4= S
R1=R2=R4=H R3= S
R1=R2=R4=H O R3=
S
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
0.52
tF (ns)
FT
tT (ms)
0.49
275
157
Fd (×10−5) FD
Reference [53]
CH2Cl2
27
0.63
[55]
CH2Cl2
38
0.84
[55]
CH2Cl2
22
0.61
[55]
CH2Cl2
35
0.73
[55]
CH2Cl2
48
0.69
[55]
DMSO
0.05
0.31
150
CH2Cl2
DMSO CH2Cl2
0.11
DMSO
0.07
[56] 53
0.86
[55]
45
0.82 0.64
[56] [55]
210
0.50
150
CH2Cl2
[56] 50
200
0.77
[55]
DMSO
0.14
0.70
[56]
DMSO
0.13
0.78
29
4.3
0.79
[57]
DMF THF
0.10 0.20
0.69
12 3
42 2.0
0.63 0.51
[57] [57] (continued)
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Table 4.1 (continued) Compound
Metal
R1=R2=R4=H R3= S
O(CH2O)2CH2CH3 O(CH2O)2CH2CH3
R1=R4=H, R2=Cl R3= S
O(CH2O)2CH2CH3 O(CH2O)2CH2CH3
R1=R4=H R2=R3= O
O
R1=R4=H R2=R3= O R1=R4=H R2=R3= O R1=R2=R4=H O R3=
O O
R1=R2=R3=H O R4=
O O
R1=R4=H O R2=R3=
O O
R1=R4=H R2=R3= S R1=R2=R4=H R3= O X=Cl R1=R2=R4=H R3= O X=Cl
N
+ N
OTiPc(SO3)4 OTiPc(SO3)2mix
R1=R4=H; R2=R3=COOH
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
159
Fd (×10−5) FD
Reference
DMSO
0.16
1.39
0.78
150
1.31
0.72
[58]
DMSO
0.10
1.01
0.85
220
3.35
0.78
[58]
1-ClNP
0.19
0.81
0.45
60
[59]
1-ClNP
0.16
1.22
0.23
40
[59]
1-ClNP
0.17
0.64
0.56
100
[59]
DMSO
0.063
0.70
2.62
0.24
[60]
Toluene
0.58
12.11
6.35
0.19
[60]
DMSO
0.033
0.28
1.47
0.10
[60]
Toluene
0.45
5.27
7.84
0.22
[60]
DMSO
0.027
0.46
2.61
0.30
[60]
Toluene
0.50
11.80
3.55
0.11
[60]
1-ClNP
0.14
0.61
DMF
pH=11
pH=11+CEL pH=10 pH=10+CEL MeOH DMSO PBS pH=10
0.13
70
[59]
0.04
0.69
190
[61]
0.007
0.55
50
[61]
0.62 0.03 0.32
190 50 60
0.16 <0.01 0.012
0.01 0.09
0.18 0.42 0.03 0.07
3.51 6.17 0.75 1.59
0.20
70
0.49 0.61
1.98
0.03 0.13
0.24
[61] [62] [62] [63] [63] [63] [62] (continued)
160
M. Durmuş
Table 4.1 (continued) Compound
Metal ZrX1X2
R1=R2=R3=R4=H X1=X2=Cl R1=R2=R3=R4=H X1=X2=
O
O C10H20
O
N O
R1=R2=R3=R4=H X1=X2=
O OC6H13 O
R1=R2=R3=R4=H X1=X2=
O C7H15
O (Cl)3TaPc(SO3)2
mix
(Cl)3Ta(V)
R1=R4=R2=R3=H R1=R4=R2=R3=H R1=R4=R2=R3=H R1=R4=R2=R3=H R1=R4=R2=R3=H R1=R4=R2=R3=H R1=R4=H; R2=R3=COOH
Zn
R1=R2=R4=H; R3=COOH R1=R4=H R2=R3= O R1=R4=H R2=R3= O
O OH
R1=R2=R3=H R4= O
O OH
R1=R2=R4=H R3= O
O OH
4
Photochemical and Photophysical Characterization
Fd (×10−5) FD
Solvent
FF
tF (ns)
DMSO
0.006
14.17
[64]
DMSO
0.016
8.10
[64]
Toluene
0.009
8.21
[64]
DMSO
0.016
6.84
[64]
Toluene
0.009
6.91
[64]
DMSO
0.013
8.46
[64]
Toluene
0.009
9.08
[64]
MeOH DMSO PBS 1-ClNP Toluene Toluene/Py DMSO DMF Acetone Aqueous DMF/Py pH=10 DMF DMSO
0.22 0.18 0.15 0.3 0.07 0.30 0.20 0.17 0.17 0.23
3.81 4.72 2.91
3.3
0.58 0.40 0.67 0.58 0.17 0.32 0.48 0.52 0.51 0.52
[63] [63] [63] [41] [23] [65] [16, 66–68] [36, 69–71] [72] [73, 74] [36] [31] [62] [75]
0.24
0.23
[76]
0.90 3.90 1.22 1.03
FT
0.65 0.65 0.65 0.55–0.58 0.50
DMSO
tT (ms)
161
340 300 350 330 77 160
0.93 2.61 2.35 2.65
Reference
DMF
0.14
3.10
0.68
[77]
DMF
0.25
3.38
0.63
[77]
(continued)
162
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R3=H R4=
O OH
O
R1=R2=R4=H R3=
O OH
O
R1=R2=R3=H R4=
O
O
OH
R1=R2=R3=H R4=
O OH O
O
O
O
OH
R1=R2=R3=R4=
COOH O COOH
R1=R2=R4=H R3= O
N
R1=R2=R4=H R3= S
N
R1=R2=R4=H R3=
CF3
CF3
+ N CF3
S
R1=R2=R4=H O R3= N
R1=R2=R4=H O R3= N
+
4
Photochemical and Photophysical Characterization
Fd (×10−5) FD
Solvent
FF
tF (ns)
DMF
0.16
3.37
0.70
[77]
DMF
0.23
3.51
0.58
[77]
H2O/0.1M KOH
0.0015
2.3
[78]
H2O/0.1M KOH
0.006
2.3
[78]
FT
tT (ms)
163
DMF
Reference
0.40
[49]
DMSO
0.13
0.74
210
0.74
0.63
[79, 80]
DMSO
0.10
0.86
140
3.57
0.68
[79, 80]
DMSO
0.01
0.45
60
0.24
0.41
[79]
H2O+TX
0.02
0.32
12
7.05
0.24
[79]
DMSO
0.15
1.37
0.68
0.56
[81]
DMSO
0.02
0.13
0.54
0.13
[81]
3.64
0.07
[81]
PBS
(continued)
164
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H O R2=R3= N
R1=R4=H O R2=R3= N
R1=R2=R4=H
+
N
R3= O
N
R1=R2=R3=H
N
R4= O
N
S
N
S
N
R1=R2=R4=H R3= R1=R2=R4=H R3=
+
R1=R2=R4=H R3=
CH2(CF2)7CF3 S
O
R1=R2=R4=H
N S
R3=
N CF3
R1=R2=R4=H
N
CF3
R3= S
R1=R2=R4=H R3= O
R1=R4=H R2=R3= S C H2
S
4
Photochemical and Photophysical Characterization
Fd (×10−5) FD
Solvent
FF
tF (ns)
DMSO
0.17
1.64
1.75
0.69
[81]
DMSO
0.003
0.018
0.27
0.07
[81]
PBS DMSO
0.17
0.53
125
2.05 1.89
0.03 0.51
[81] [82]
DMF Toluene DMSO
0.14 0.06 0.13
0.51 0.55 0.62
4.2 5.1 160
1.73 0.98 2.35
0.47 0.49 0.57
[82] [82] [82]
DMF Toluene DMSO
0.10 0.03 0.10
0.57 0.71 0.79
7.8 7.0 171
1.04 0.71 3.98
0.51 0.55 0.56
[82] [82] [79]
DMSO
0.03
0.75
31
11
0.52
[79]
H2O+TX
0.08
0.80
110
18.7
0.34
[79]
Toluene
0.041
0.65
110
0.81
0.52
[83]
Toluene
0.035
0.69
90
0.14
0.60
[83]
Toluene
0.021
0.71
100
0.42
0.56
[83]
DMSO
0.14
0.80
260
2.4
0.72
[57]
DMF THF DMSO
0.12 0.16 0.13
0.74
18 9 630
20 0.3 0.03
0.60 0.46 0.43
[57] [57] [84]
FT
0.53
tT (ms)
165
Reference
(continued)
166
M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=H R4=
Metal
O O
O O
O O
R1=R2=R4=H R3=
O O
O O
O O
R1=R2=R3=H R4=
O O O O O
R1=R2=R4=H R3=
O
O O O O O
N
N
N
N
Zn
N
N
N
N
n=2, R=CH3 n=4, R=CH3 n=6, R=CH3 n=8, R=CH3 n~12, R=CH3
O
O
O
O n
nR
R
O
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
0.07 (CHCl3)
0.66
[47]
DMF
0.23 (CHCl3)
0.41
[47]
DMF
0.06 (CHCl3)
0.52
[47]
DMF
0.24 (CHCl3)
0.40
[47]
DMF
0.18
0.83
[85]
DMF DMF DMF DMF
0.18 0.18 0.18 0.19
0.83 0.83 0.82 0.81
[85] [85] [85] [85] (continued)
FT
tT (ms)
167
Reference
168
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R4=H R3=
O
O
O
O
O O
O
O O O
R1=R2=R4=H R3=
HO
O
O
O
HO O
O
O
OH OH O
N
N
N
N
Zn
N
N
N
N
N
N
N
N
Zn
N
N
N
N
O O
O
O
O
O O O O
R
O R
R=
O O
O
O
O
O O O O
N
N
N
N
Zn
N
N
N
N
R
HO R
R=
HO O
O
O
O
O O OH OH
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
0.33
0.49
[86]
DMF
0.23
0.58
[86]
DMF
0.32
0.43
[86]
DMF
0.15
0.86
[86]
DMF
0.18
0.78
[86]
FT
tT (ms)
169
Reference
(continued)
170
M. Durmuş
Table 4.1 (continued) Compound
N
N
N
N
Zn
N
N
N
N
Metal
R R
O O
O
R=
O
O
O
O O O O
OR OR N N
N
O O
N
Zn
N N
N N OR O
R=
OR
OH
R=
R= OR N N
N
O O
N
Zn
N N
N N OR
O R=
OH
OR N N
Zn
N O
N
N
O
N
N N O
R=
OH
OR
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
DMF
0.31
DMSO
0.17
THF CHCl3 DMF
0.10 0.20 0.20
DMSO
0.17
0.52
DMSO
0.16
DMSO
0.15
THF CHCl3 Benzene DMF
0.07 0.20 0.14 0.18
FT
tT (ms)
171
Fd (×10−5) FD
Reference
0.51
[86]
1.65
0.31
[36]
0.18 11.33 16.53
0.35 0.62 0.63
[36] [36] [36]
150
3.28
0.54
[36]
0.70
180
3.77
0.72
[36]
0.25
130
0.30
0.23
[36]
0.27 11.25 1.38 18.76
0.38 0.59 0.53 0.61
[36] [36] [36] [36] (continued)
0.27
90
0.86 1.55 0.93
0.93 1.49 0.90 0.89
172
M. Durmuş
Table 4.1 (continued) Compound
Metal
R=
R=
SO3Na
R=
N N
N
O O
O N
Zn
N N
O
N N
RO O
RO O
N N N
N
N Zn N
N
N
OR R=
O R= OH
ZnPc(SO3)mix
ZnPc(SO3)2 ZnPc(SO3)3
N
N N
OR
R=
N Zn N
N
N
R=
N
NO2
OR
OR
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
tF (ns)
173
Fd (×10−5) FD
FT
tT (ms)
0.20
0.45
120
0.93
0.47
[36, 87]
DMSO
0.22
0.62
90
2.3
0.58
[36, 87]
DMSO
0.26
0.88
0.37
[87]
DMSO
0.19
0.38
0.68
[36, 87]
DMSO
0.07
0.22
[88]
DMSO
0.06
0.06
[88]
DMSO
0.06
0.24
[88]
DMSO
0.08
0.14
[88]
PBS PBS+TX DMSO MeOH DMSO DMSO
0.16 0.21 0.14
0.45 0.54 0.72 0.52
[38] [38] [16, 38] [7, 89] [90] [90]
0.58
3.0 0.16 0.12
0.53 0.61 0.86 0.46 0.58 0.92
150
2.95 2.37 530 270 0.76 1.10
3.65 7.02 13.65
Reference
(continued)
174
M. Durmuş
Table 4.1 (continued) Compound
Metal
ZnPc(SO3)2.1 (mix)
ZnPc(SO3)2.9 (mix)
ZnPc(SO3)3.4(mix)
ZnPc(SO3)3.7(mix)
ZnPc(SO3)4
R1=R2=R3=H S R4= R1=R2=R3=H S R4=
N + N
R1=R2=R4=H S R3= R1=R2=R4=H S R3=
R1=R4=H R2=R3=
S
N + N
N
4
Photochemical and Photophysical Characterization
Solvent pH=7.4 pH=7.4+TX DMSO pH=7.4 pH=7.4+TX DMSO pH=7.4 pH=7.4+TX DMSO pH=7.4 pH=7.4+TX DMSO Aqueous pH=7.1 pH=7.4 pH=7.4+TX pH=10 pH=10+CEL DMSO DMSO DMF 0.1M CTAC/ H2O H2O/MeOH DMSO
PBS
PBS+CEL DMSO DMSO
PBS
PBS+CEL DMSO DMSO
FF
tF (ns)
FT
tT (ms)
175
Fd (×10−5) FD £0.01 0.65 0.74 0.10 0.70 0.70 0.10 0.69 0.69 0.49 0.67 0.70
0.32
<0.01 0.20 0.12 0.07 0.28
0.56
0.02 3.71
245 165 £0.01 0.30 0.03 0.12 0.68 0.46 0.52 0.31
Reference [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [41] [91] [42] [42] [62] [62] [42, 90] [16] [30, 92] [30]
0.56 0.65
190 270
0.94 1.42
0.88 0.56
470
4.03
0.14 0.07
0.56 0.66
180 190
66.2
0.64
[93] [94]
<0.01
0.15
20
9.3
0.10
[94]
0.03 0.09 0.13
0.17 0.63 0.71
90 200 180
12.2 18.1 66.1
0.12 0.51 0.68
[94] [94] [94]
<0.01
0.28
70
10.9
0.15
[94]
0.02 0.18 0.05
0.34 0.57 0.75
110 210 200
19.0 16.6 94
0.26 0.62 0.62
[94] [94] [94]
(continued)
176
M. Durmuş
Table 4.1 (continued) Compound R1=R4=H R2=R3=
Metal
+
S
N
R1=R2=R4=H
+ N O
R3=
N +
N
N
N
N
N
N
Zn
N
N
N
N
O
+ + N
N
O
N
N
N
N
Zn
N
N
N
N
N N
N
N O
N
Zn
N
N
N
N
N
4
Photochemical and Photophysical Characterization
Solvent
FF
PBS
<0.01
0.17
0.01 0.08
0.32 0.60
PBS+CEL DMSO H2O
tF (ns)
FT
tT (ms) 40
60 220 0.90
3.51
177
Fd (×10−5) FD
Reference
5.1
0.10
[94]
7.7 17.1 110
0.24 0.49 0.60
[94] [94] [95]
26
[95] [95] [96]
[96]
DMF PBS DMF
0.22
0.54 0.32 0.50
DMF
0.24
0.57
DMF
0.31
0.52
[96]
(continued)
178
M. Durmuş
Table 4.1 (continued) Compound
N
N
N
N
Zn
N
N
N
N
O
R1=R4=H R2=R3=
Metal
N
+ OH
CH2
R1=R4=H + R2=R3= H2C N
R1=R4=H R2=R3=OCH2CH2N(CH3)2 R1=R4=H R2=R3=OCH2CH2N+(CH3)3 R1=R4=H, R2=R3=SCH2CH2N(CH3)2 R1=R4=H R2=R3=SCH2CH2N+(CH3)3 R1=R4=H R2=R3=OCH2CON(CH3)2 R1=R4=H O R2=R3= OCH2CH2CH2N O
N + + N
4
Photochemical and Photophysical Characterization
Solvent
FF
DMF
0.26
tF (ns)
FT
tT (ms)
179
Fd (×10−5) FD
Reference
0.53
[96]
H2O
0.65
[97]
MeOH EtOH H2O
0.60 0.62 0.45
[97] [97] [97]
MeOH EtOH DMF
0.17 <0.05 0.30
[97] [97] [98]
DMF
0.30
[98]
DMF DMF THF DMF
0.26 0.13 0.26 0.15
DMF
0.30
THF
0.30
3.1
0.69
200
0.13 0.69 0.19
[98] [99] [98] [99] [98]
4.8
0.70
310
0.70
[98]
(continued)
180
M. Durmuş
Table 4.1 (continued) Compound
Metal
N
N
N
N
N
N
M
N
N
N
N
N
N
+ HC3
+
N CH3
N
N
N
N
N
M
N
N
N
N
N
+
CH3
+
N
N
N
N
N
N
M
N
N
N
N
N
N
CH3 N
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
181
Fd (×10−5) FD
Reference
DMSO
0.16
[22]
DMSO
0.06
[22]
0.56
[100]
DMF
0.35
(continued)
182
M. Durmuş
Table 4.1 (continued) Compound
Metal
R N+
R
+ N
N
N
N
N
M
N
N
N
N
N +
R
R = CH3 +N R
R=CH3 R=(CH2)4COOCH2CH3 R1=R2=R4=H
CH3 O N C7H15
R3=
R1=R2=R3=H R4=
O
O
O
O
R1=R2=R4=H R3= R1=R4=H R2=R3=
O
O
R1=R2=R3=H O R4=
OC12H25 OC12H25
OC12H25
R1=R2=R4=H R3=
O OC12H25
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
DMF
0.30
H2O (SDS) H2O (SDS) MeOH/Py Toluene
0.25 0.09 0.13 0.18
0.31 0.66
DMSO
0.18
0.81
Toluene DMSO
0.18 0.23
Toluene DMSO
0.19 0.08
Toluene DMF
0.18 0.17
1.7
0.78 0.65
Toluene DMF
0.15 0.18
1.6 1.7
Toluene
0.16
2.8
FT
tT (ms)
183
Fd (×10−5) FD
Reference
0.50
[100]
0.71 0.55 0.29 0.51
[101] [101] [101] [101]
0.50
0.76
[102]
0.81 0.60
6.70 0.33
0.77 0.52
[102] [102]
0.80 0.47
5.39 0.13
0.58 0.46
[102] [102]
76
2.87 139
0.58 0.62
[102] [103]
0.75 0.60
20 100
153 2.28
0.71 0.51
[103] [103]
0.81
40
790
0.77
[103]
139 133 71 57
(continued)
184
M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=H
Metal
t-Bu OH
O
R4=
t-Bu
R1=R4=H, t-Bu R2=R3=
OH
O
t-Bu
OH N
N
N
N
Zn
N
N
N
N
O O OH
R1=R2=R3=H R4=
O O OC4H9
R1=R2=R4=H R3=
O
O OC4H9
R1=R2=R3=H, R4=OCH2CF2CHF2 R1=R2=R4=H, R3=OCH2CF2CHF2 R1=R4=H, R2=Cl R3=OCH2CF2CHF2 R1=R4=H, R2=R3=OCH2CF2CHF2 R1=R2=R3=H, R4=OCH2CH2CH3 R1=R2=R4=H, R3=OCH2CH2CH3 R1=R4=H, R2=R3=OCH2CH2CH3 R1=R2=R3=H, R4=OCH2CH2CH2CH3 R1=R4=H, R2=R3=OCH2CH2CH2CH3
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMSO
0.003
0.69
[104]
DMSO
0.004
0.69
[104]
DMSO
0.20
0.20
[104]
DMF
0.24
2.74
[77]
DMF
0.31
3.43
[77]
DMSO
0.13
1.35
1.45
0.85
[105]
DMSO
0.31
2.50
1.46
0.53
[105]
DMSO
0.32
3.02
1.43
0.55
[105]
DMSO DMSO DMSO DMSO DMF DMF
0.20 0.10 0.26 0.27
2.77 0.95 2.00 2.71
1.53 2.78 2.74 3.16
0.79 0.88 0.68 0.71 0.58 0.58
[105] [105] [105] [105] [106] [106] (continued)
FT
tT (ms)
185
Reference
186
M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=R4=OCH2CH2CH2CH3 R1=R4=H, R2=R3=CN R1=R2=R4=H N R3= O + N
R1=R2=R4=H R3=
O
R1=R4=H R2=R3=
N+ O
R1=R2=R4=H R3= S
N
R1=R2=R4=H
+ N S
R3=
R1=R2=R3=H R4= S
N
R1=R2=R3=H
+ N S
R4=
R1=R4=H R2=R3= S
N
R1=R4=H
+ N
R2=R3=
S
Metal
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
187
Fd (×10−5) FD
Reference
DMF DMF DMF
0.17
1.09
0.68
DMSO Py/H2O (1:1)
0.077 0.17
1.22
0.80 0.78
DMSO
0.061
[71]
MeOH
0.039
[71]
Aqueous DMSO
0.003 0.17
DMF DMSO
0.19 0.02
Py/H2O (1:1) H2O DMSO
0.11 0.12
DMSO
7.3
350 30
0.63 0.47 0.40
[106] [106] [107]
0.46 0.66
[107] [108]
0.73
160
0.31
0.48
[71] [109, 110]
0.74
4
6.26 6.74
0.40 0.82
[110] [109, 110]
0.43
10
0.92
2.04 1.87
0.29 0.45 0.57
[108] [109, 110] [109]
0.01
0.19
2.64
0.45
[109]
H2O DMSO
0.11
1.10
2.30 2.19
0.19 0.51
[109] [109]
DMSO
0.03
0.17
10.58
0.63
[109]
3.61
0.10
[109]
H2O
0.20
(continued)
188
M. Durmuş
Table 4.1 (continued) Compound
Metal N
S
N
N
N
N
Zn N
N
N
N S
O
COOH
N
S N
N
N
N
N
Zn
N
N
N
N
O NH O
R
R
O
N
N
N
N
Zn N
N
N
OH
N
N R=
F F
O F
R
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
tF (ns)
189
Fd (×10−5) FD
FT
tT (ms)
0.16
0.82
230
0.11
0.64
[111]
Reference
DMF DMSO
0.25 0.097
0.68 0.82
8 180
6.93 0.066
0.63 0.59
[111] [111]
DMF Toluene DMSO
0.084 0.049 0.20
0.77 0.41 0.74
70 6 240
1.65 0.19
0.45 0.51
[111] [111] [53]
(continued)
190
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R4=H O R3=
O(CH2O)2CH2CH3
R1=R2=R4=H
O(CH2O)2CH2CH3
R3=
O O(CH2O)2CH2CH3
R1=R2=R4=H R3=
O(CH2O)2CH2CH3 O(CH2O)2CH2CH3 S O(CH2O)2CH2CH3
R1=R4=H, R2=Cl R3=
O(CH2O)2CH2CH3 O(CH2O)2CH2CH3 S O(CH2O)2CH2CH3
R1=R2=R4=H, R3=O(CH2)2O(CH2)2OCH3 R1=R2=R4=H R3=S(CH2O)3CH3
R1=R4=H R2=R3=S(CH2O)3CH3
R1=R4=H, R2=Cl R3=S(CH2O)3CH3 R1=R2=R4=H, R3=O(CH2CH2O)3CH2CH2OH
R1=R2=R3=H, R4=O(CH2CH2O)3CH2CH2OH
R1=R2=H, R3=R4=O(CH2CH2O)3CH2CH2OH
R1=R2=R4=H R3=SCH[(CH2O(CH2CH2O)2C2H5)2] R1=R4=H, R2=Cl R3=SCH[(CH2O(CH2CH2O)2C2H5)2]
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
0.14
DMF Toluene EtOH DMSO
0.13
0.10
DMSO
0.08
DMSO
0.10
tF (ns)
FT
tT (ms)
0.85
160
0.81
0.87
287 306 280
0.78
0.67
1.16
191
Fd (×10−5) FD 0.60
[16, 112]
9.41
0.22
0.42, 0.55 0.58 0.47 0.73
[30, 113] [43] [43] [67]
370
1.63
0.65
[67]
0.89
240
0.26
0.80
[67]
0.44 0.42 0.64
[43] [43] [114]
0.58 0.52 0.72
[69] [69] [114]
4.01
0.66 0.41 0.67
[69] [69] [69]
0.44 0.59 0.05 0.09 0.72 0.24 0.62 0.34 0.08 0.23 0.72
[69] [115] [115] [115] [115] [115] [115] [115] [115] [115] [21]
0.62
[21]
Toluene EtOH DMSO
0.20
0.77
263 381 230
DMF Toluene DMSO
0.15 0.04 0.13
0.64 0.67 0.85
210 180 280
DMF Toluene DMF
0.13 0.03 0.09
0.73 0.70 0.72
240 210 230
Toluene DMSO H2O H2O+TX DMSO H2O H2O+TX DMSO H2O H2O+TX DMSO
0.03 0.13
0.71
190
0.90
0.08 0.09 <0.01 0.10 0.11
3.78 1.18 0.02 2.46 1.04
0.04 0.22
3.11 1.34
0.73
220
1.88 4.30 2.62 3.48 7.40 1.44 0.78 0.58 1.07 0.26
0.10
0.83
0.71
210
0.19
DMSO
Reference
3.33
16.2 3.28 22 4.56
(continued)
192
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3=SCH[(CH2O(CH2CH2O)2C2H5)2] R1=R2=R4=H R3=
N O
R1=R2=R4=H O R3=
O O
R1=R2=R4=H O R3= R1=R2=R4=H R3=
O O
O O
O R1=R2=R4=H
O O
O
R3=
O
O C7H15
C7H15 R1=R2=R4=H
O O
R3=
O O
O
R1=R2=R4=H
N
R3=
N M
O N
N
4
Photochemical and Photophysical Characterization
193
Solvent
FF
tF (ns)
FT
tT (ms)
Fd (×10−5) FD
Reference
DMSO
0.15
1.57
0.75
300
1.94
0.60
[21]
0.59
[43]
EtOH
231
DCM
0.28
[116]
DCM
0.3
[116]
DCM
0.32
[116]
DCM
0.32
[116]
DCM
0.26
[116]
DMSO
0.03
0.71
0.12
230
[117]
(continued)
194
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R4=H OC6H13
H13C6O
R3=
O O H13C6O
R1=R2=R4=H
R3=
OC6H13
O
O O
R1=R2=R4=H OCH2 R3=
CF3
R1=R2=R4=H
N N N
R3=
N
N O
N F
F
R1=R2=R3=H R4=
O O
OC5H11
R1=R2=R4=H
O OC5H11 O
O
R3= O
OC5H11 O
R1=R2=R4=H, R3=NH2 R1=R2=R4=H, R3=NO2 R1=R2=R4=H, R3=C(CH3)3 R1=R2=R4=H, R3=OCH2C(CH3)3 R1=R2=R4=H, R3=OCH3
4
Photochemical and Photophysical Characterization
Solvent
FF
Toluene DMSO
0.02 0.11
DMSO
0.21
THF
0.25
tF (ns)
FT
tT (ms)
1.09
0.23
240
195
Fd (×10−5) FD
Reference [117] [45]
[45]
0.56
[118]
DMF/H2O
0.23
[119]
BHDC Micelles
0.30
[119]
THF
0.26
2.7
[78]
THF
0.30
2.8
[78]
DMSO DMSO EtOH CHCl3 THF
<0.01 0.022 0.26 0.25 0.26
3.4 3.9
0.58
200
0.11 0.11 0.54 0.56
[112] [112] [120] [40] [118] (continued)
196
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H
O
R2=R3=
O O
R1=R4=H R2=R3= O
R1=R4=H R2=R3= O R1=R4=H R2=R3= O R1=R4=H R2=R3=
O NH S O
R1=R4=H R2=R3= O
O H
R1=R4=H,
R2=R3=
O
O
R1=R4=H, O
R2=R3=
R1=R4=H, R2=R3= O
NO2
R1=R4=H, R2=R3= O
NH2
R1=R4=H, R2=R3=Cl
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
CHCl3
197
Fd (×10−5) FD
Reference
111
0.44
[76]
0.01
[76]
2.12
0.51
[16, 76]
2.53
0.60
[76]
0.53
[113] [50]
CHCl3
DMSO
0.24
0.63
370
DMSO DMF THF
0.17 0.25
1.44
12.1
DMSO DMSO
0.15
0.71
CHCl3
DMSO DMF Pyridine Benzene Toluene CHCl3
0.34
[50] [76]
275
0.64
[76]
275 6.61 6.15 1.89
0.43 0.60 0.64 0.51 0.54 0.44
[23] [23] [23] [23] [23] [76]
5.04
0.15 0.19 0.21 0.20 0.17
766
DMSO
1.41
0.36
[76]
DMSO
0.86
0.07
[76]
0.34
[16] (continued)
DMSO
0.02
370
198
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H, R2=R3= S
CH3
R1=R4=H, R2=R3=SC4H9 H13C6 C6H13
C6H13
C6H13 C6H13
N
N
N
N
M
N
N
N
N
H13C6
C6H13
C11H23SH
(PcSH+gold nanoparticles) R1=R4=H, R2=R3=SC8H17 R1=R4=H, R2=R3=C10H21 R1=R4=H, R2=R3=OC6H13 H21C10
C10H21
S
C10H21
N
N
N
N
M
N
N
N
N
S H21C10
C10H21
C10H21
H21C10
C10H21 S
S N
N
N
N
M
N
N
N
N S
S H21C10
C10H21
PcSH
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
199
Fd (×10−5) FD
Reference
DMF
6.3
0.54
[121]
DMF Toluene
5.2
0.61 0.45
[121] [122]
0.65 0.53 0.47 0.52
[122] [28] [123] [30]
DMF
0.85
[124]
DMF
0.92
[123]
EtOH DMF THF DMF
0.26
(continued)
200
M. Durmuş
Table 4.1 (continued) Compound
N
N
N
N
Zn
N
N
N
N
Metal
N S S
N
+
N
N
N
N
Zn
N
N
N
N
S S
+
N R N R
R= CH3
R=C5H11
N
N
N
N
Zn
N
N
N
N
S N
R2=R3=H, R1=R4=C10H21 R2=R3=H, R1=R4=C8H17 R2=R3=H, R1=R4=C10H21 R2=R3=H, R1=R4=C12H25 R2=R3=H, R1=R4=C14H29 R2=R3=R1=R4=F R1=R4=F, R2=R3=C(CF3)2F RO
RO RO
OR
N
N
N
N
Zn
N
N
OR N
OR N H3C R=
RO
OR
H 3C
4
Photochemical and Photophysical Characterization
FF
DMF
0.28
0.50
[99]
DMF
0.24
0.26
[99]
0.29
[99] [99]
0.24 0.01
THF Toluene DCM DCM DCM DCM DMF Acetone Acetone THF
0.26 0.28 0.13 0.17 0.16 0.13 0.04 0.39 0.28
FT
0.22
tT (ms)
Fd (×10−5) FD
Solvent
DMF DMF
tF (ns)
201
100 4
3.9 3.7 3.7 3.9 <1 131 3.05
0.58 0.13 0.21
Reference
[125] [125] [48] [48] [48] [48] [72] [72] [72] [126]
(continued)
202
M. Durmuş
Table 4.1 (continued) Compound OR
N
N
N
N
N
N
Zn N
N
Zn N
RO RO
Metal RO
OR
RO
N
N
N OR
N
N
N
OR
N
H3C R=
OR
RO
RO
OR
RO
RO
OR
H3C
OR
RO
OR
N
N
N
N
N
N
N
N
N
Zn N
N
Zn N
N
Zn N
RO RO
N
N
N
N
N
N
N OR
N
N
OR H3C
N R=
OR
RO
OR
RO
RO
RO
OR
RO
N
N
N
N
N
Zn N
N
Zn N
N
N
N
N
N
N
N
N
N
N
N
Zn N
N
N
RO
OR
OR
RO
H3C
H3C
OR
OR
RO
OR
OR
N
RO
RO
N
OR
R= H3C
RO
OR
N
N
N
N
Zn
N
N
N
N
R1=R2=R3=R4=H
Cd
R1=R2=R4=H R3= O
N
R1=R2=R3=H R4= O
N
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
203
Fd (×10−5) FD
Reference
THF
0.08
0.68
[126]
THF
<0.03
0.35
[126]
THF
<0.03
0.56
[126]
DMSO
0.07
0.37
DMF DMSO DMF
0.021 0.015 0.017
0.51 0.32 0.70
0.77 0.70 0.85
DMSO DMF
0.013 0.16
0.29
0.83 0.70
126
16.4
0.19
[16, 112, 113]
4.7 30 5.2
0.58 0.78 0.64
[107] [107] [107, 127]
30 10
0.74 0.60
[107, 127] [127] (continued)
204
M. Durmuş
Table 4.1 (continued) Compound
R1=R2=R4=H R3=
R1=R2=R3=H R4=
Metal
O
O
O
O
R1=R2=R4=H O R3=
R1=R2=R3=H O R4=
R1=R2=R4=H O R3=
R1=R2=R3=H O R4=
4
Photochemical and Photophysical Characterization
205
Fd (×10−5) FD
Reference
40
61.1
0.77
5
55.7 35.8
0.44 0.50 0.52 0.39
[127] [127] [127] [127]
0.10 0.14 0.21 0.25 0.19
0.36 0.82
30 30
0.53
7
16.3
0.23 0.042 0.025 0.015 0.41
[127] [127] [127] [127] [127]
DMSO Toluene CHCl3 THF
0.045 0.14 0.15 0.18
0.38 0.51
9 30
9.2 56.3 61.5 10.9
0.31 0.33 0.26 0.42
[127] [127] [127] [127]
DMF
0.29
0.40
3.55
0.39
[128]
DMSO Toluene THF CHCl3 DMF
0.20 0.13 0.29 0.27 0.31
0.61 0.87
0.42 0.98 2.72 4.40 3.89
0.41 0.32 0.31 0.19 0.42
[128] [128] [128] [128] [128]
DMSO Toluene THF CHCl3 DMF
0.063 0.054 0.47 0.39 0.32
0.66 0.73
2.86 2.53 4.01 2.20 2.47
0.80 0.58 0.43 0.31 0.26
[128] [128] [128] [128] [128]
DMSO Toluene THF CHCl3 DMF
0.21 0.14 0.27 0.27 0.53
0.54 0.76
0.56
0.41 0.92 0.069 3.84 2.13
0.35 0.33 0.27 0.19 0.56
[128] [128] [128] [128] [128]
DMSO Toluene
0.055 0.27
0.61 0.49
0.19 1.80
0.59 0.40
[128] [128] (continued)
Solvent
FF
tF (ns)
DMSO CHCl3 THF DMF
0.16 0.17 0.18 0.13
0.61
DMSO Toluene THF CHCl3 DMF
FT
0.49
0.41
tT (ms)
206
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R3=R4=H
Hg
R1=R2=R4=H R3= O
N
R1=R2=R3=R4=H; X=Cl R1=R2=R4=H R3=S(CH2)2O(CH2)2O(CH2)2OCH3 R1=R2=R3=H R4=S(CH2)2O(CH2)2O(CH2)2OCH3 R1=R4=H; R2=R3=COOH X=OH R1=R4=H; R2=R3=COOH X=OH ClAl(III)Pc(SO3)mix ClAl(III)Pc(SO3)2
ClAl(III)Pc(SO3)3
ClAl(III)Pc(SO3)4
Al(III)
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
THF CHCl3 DMF DMSO DMF
0.50 0.49 0.017 0.010 0.009
0.84 0.27 0.31
0.86 0.87 0.90
4.4 40 4
DMSO DMSO 1-ClNP DMSO
0.005 0.37 0.58 0.13
0.11 6.09 6.8 1.04
0.89
20
DMSO
0.26
2.04
Aqueous media pH=10
0.27
PBS DMSO PBS H2O D2O pH=7.4
0.44 0.39
5.34
0.44 0.52
0.40 0.54 0.40
5.0 6.8
0.17 0.23 0.17
MeOH CD3OD pH=7.4+TX DMSO CH3OD PBS D2O pH=7.4 PBS D2O pH=10 Aqueous pH=7.1 pH=7.4 DMF H2O/MeOH
0.56
6.2
FT
tT (ms)
207
Fd (×10−5) FD 1.67 3.30
[128] [128] [107] [107] [107]
321
0.78 0.24
341
0.27
[107] [129] [130] [129]
197
0.29
[129]
0.12
[73, 74]
0.12
[31]
0.42 0.48
[38, 39] [38] [131] [132, 133] [131, 133] [42, 89, 134, 135] [7, 89, 133] [131] [42] [42] [135] [131] [131] [131] [131] [131] [31] [41] [91] [136] [30, 92] [93]
0.4
0.32
0.24
450
2.93 800 520 500 1130 550 775 1440
0.26
0.40 5.79
0.01 0.27 0.15 0.39 0.30
490 1150 0.42 530 1140 0.18
0.13 0.56 0.18
6.04
0.36 0.28 0.36
500 440 470 0.20 560
Reference
0.44 0.49 0.57 0.82 0.56
(continued)
208
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4 H3C
R2=R3=
CH3 + N
OH
CH2
R1=R4 + R2=R3= H2C N
R1=R4 H3C
R2=R3=
CH3 + N
N CH3
CH2
R1=R4 R2=R3=
R1=R4 R2=R3=
OH
OH
C N H2
+ OH
CH3 + C N H2 CH3
R1=R2=R4=H O R3= X=Cl R1=R2=R4=H R3= O X=Cl
CH3 N CH3 CH3
N
+ N
R1=R2=R4=H OH
R3=
O
R1=R4=H R2=R3= S C
H2
R1=R2=R3=R4=H; X=Cl
Ga(III)
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
209
Fd (×10−5) FD
Reference
H2O
0.38
[97]
MeOH EtOH H2O
0.35 0.35 0.37
[97] [97] [97]
MeOH EtOH H2O
0.10 <0.05 0.35
[97] [97] [97]
MeOH EtOH H2O
0.33 0.20 < 0.05
[97] [97] [97]
MeOH EtOH H2O
< 0.05 0.05 0.35
[97] [97] [97]
0.27
MeOH DMF
0.12
0.65
70
[97] [61]
pH=11
0.12
0.56
70
[61]
pH=11+CEL DMSO
0.23 0.11
0.61 0.34
160 610
[61] [46]
DMSO
0.31
0.40
810
0.04
0.36
[84]
1-ClNP DMSO
0.31 0.30
0.7 0.69
200
0.93
0.41
[130] [137]
3.8 3.71
(continued)
210
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R4=H R3=S(CH2)2O(CH2)2O(CH2)2OCH3 R1=R2=R3=H R4=S(CH2)2O(CH2)2O(CH2)2OCH3 ClGa(III)Pc(SO3)2 ClGa(III)Pc(SO3)4 OHGa(III)Pc(SO3)4 (AcO)Ga(III)Pc(SO3)2mix
ClGa(III)Pc(SO3)1(C(CH3)3)3 ClGa(III)Pc(SO3)2(C(CH3)3)2 ClGa(III)Pc(SO3)3(C(CH3)3)1 R1=R4=H; R2=R3=COOH X=OH R1=R2=R3=H N R4= O X=Cl R1=R2=R3=H + N R4= O X=Cl
R1=R2=R4=H R3= O X=Cl R1=R2=R4=H R3= O X=Cl R1=R4=H R2=R3= O X=Cl R1=R4=H R2=R3= O X=Cl
N
+ N
N
+ N
-
R1=R4=H
SO3
+
R2=R3= X=Cl
N O
4
Photochemical and Photophysical Characterization
Fd (×10−5) FD
Reference
2.94
690
0.68
[129]
1.08
631
0.81
[129]
0.38 0.38 0.41
[7] [7] [30] [138] [138] [42] [42] [42] [7] [7] [7] [138]
Solvent
FF
tF (ns)
DMSO
0.30
DMSO
0.15
MeOH MeOH DMF pH=11 pH=11+CEL DMSO pH=7.4 pH=7.4+TX MeOH MeOH MeOH pH=11
211
4.2
0.09 0.15
FT
tT (ms)
0.36 0.36
390 420
0.52 0.63
60 80
4.13 4.24 3.90
0.36 0.36 0.36 0.67
440 360 300 80
0.21
0.37 0.16 0.38 0.38 0.38 0.38
DMSO
0.12
1.28
0.71
120
1.47
0.48
[139, 140]
DMSO
0.19
1.50
0.78
500
2.20
0.53
[139]
H2O
0.07
0.72
0.65
50
0.55
0.41
[139]
DMSO
0.19
2.05
0.57
160
1.44
0.59
[139]
DMSO
0.24
1.93
0.67
640
1.64
0.51
[139]
H2O DMSO
0.12 0.27
1.06 1.00
0.61
50
0.42 10.2
0.44 0.65
[139, 140] [141]
DMSO
0.12
0.83
22.3
0.54
[141]
PBS DMSO
0.28
1.94
19.4
0.35 0.58
[141] [141]
0.15
[141]
PBS
(continued)
212
M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=H R4= X=Cl R1=R2=R4=H R3= X=Cl R1=R2=R3=H R4= X=Cl R1=R2=R4=H R3= X=Cl R1=R4=H R2=R3= O X=Cl R1=R2=R4=H R3= X=Cl
Metal
O
O
O
O
N O
R1=R2=R4=H R3= O X=Cl R1=R2=R4=H R3= S
N
+
N
X=Cl R1=R2=R4=H R3= S X=Cl
+ N
R1=R2=R3=H R4= S X=Cl R1=R2=R3=H R4= S X=Cl
N
R1=R2=R3=H R4= O X=Cl R1=R2=R4=H R3= O X=Cl
+ N
O
O
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
213
Fd (×10−5) FD
Reference
DMSO
0.14
0.92
0.62
230
11.9
0.64
[142]
DMSO
0.19
1.29
0.61
270
28.2
0.64
[142]
DMSO
0.15
1.01
0.54
350
20.3
0.62
[142]
DMSO
0.20
1.19
0.45
340
23.2
0.58
[142]
0.52
[143]
DCM
0.93
DMSO
0.20
0.70
170
[138]
DMF pH=11
0.25 <0.01
0.59 0.55
120 60
[138] [138]
0.68 0.54
170 20
pH=11+CEL DMF
0.04 0.26
2.09
0.33
[138] [144]
DMSO
0.22
3.50
DMSO
0.12
1.57
144.4
0.79
[145]
386.1
0.75
[145]
H2O DMSO
0.074 0.20
1.41 3.41
1.0 2.7
0.26 0.67
[145] [145]
DMSO
0.11
0.78
419.1
0.52
[145]
H2O DMSO
0.021 0.15
0.38 1.39
0.77
280
4.1 0.27
0.29 0.69
[145] [137]
DMSO
0.23
1.90
0.75
210
1.92
0.62
[137]
(continued)
214
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3= O X=Cl
O
R1=R4=H R2=R3= O X=Cl
R1=R4=H R2=R3= O X=Cl
R1=R2=R4=H R3=t-Bu X=Cl X=
CF3 t-Bu
t-Bu N
N
t-Bu
X=O X=
O S O
O
CN
NC t-Bu
t-Bu
X N N N
Ga N N
t-Bu
X=Cl
t-Bu
t-Bu
O
X=
N
N N
N
N
N
M
N
N
t-Bu
N
N
N
N
M N
N
X
N
N N
t-Bu
t-Bu
t-Bu
4
Photochemical and Photophysical Characterization
215
Fd (×10−5) FD
Solvent
FF
tF (ns)
FT
tT (ms)
DMSO
0.13
0.70
0.74
200
0.5
0.51
[137]
DCM DMSO
0.19
2.3
0.66
370
0.31 1.23
0.56 0.53
[143] [146]
DMF Toluene THF CHCl3 DCM DMSO
0.19 0.14 0.19 0.12
1.3 1.5 1.5 1.0
0.79 0.65
0.22
2.1
0.67
290
0.42 2.91 1.49 5.89 0.14 1.77
0.66 0.68 0.41 0.41 0.63 0.56
[146] [146] [146] [146] [143] [146]
DMF Toluene THF CHCl3 Toluene
0.15 0.17 0.18 0.12
4.0 3.8 1.3 2.0 2.57
0.74 0.75
76 10 4.4 3.4 257
1.52 2.84 3.93 4.66
0.74 0.65 0.56 0.42
[146] [146] [146] [146] [147]
20 79 2.1 2.9
Reference
Toluene
2.48
200
[147]
Toluene
3.57
357
[147]
Toluene
3.46
667
[147]
Toluene
2.48
200
[147]
CHCl3
1.9
21.4
[148, 149]
(continued)
216
M. Durmuş
Table 4.1 (continued) Compound
Metal
X= CF3 t-Bu
t-Bu
N N N
N N
N N
Ga
t-Bu
O
N
N
t-Bu
N
N
N
N
N
Ga N N
t-Bu
t-Bu
t-Bu
t-Bu
R1=R2=R3=R4=H; X=Cl R1=R2=R3=R4=H; X=Cl R1=R2=R4=H R3=S(CH2)2O(CH2)2O(CH2)2OCH3 R1=R2=R3=H R4=S(CH2)2O(CH2)2O(CH2)2OCH3 R1=R2=R3=H R4= O X=Cl R1=R2=R3=H R4= O X=Cl
N
+ N
R1=R2=R4=H R3= O X=Cl R1=R2=R4=H R3= O X=Cl
R1=R4=H R2=R3= O X=Cl R1=R4=H R2=R3= O X=Cl
In(III)
N
+ N
N
+ N
-
R1=R4=H R2=R3= X=Cl
+ N O
SO3
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
217
Fd (×10−5) FD
Reference
CHCl3
1.79
18.2
[148, 149]
CHCl3
2.33
13.8
[148, 149]
1-ClNP DMSO DMSO
0.031 0.018 0.027
0.37 0.90 0.19
DMSO
0.013
011
DMSO
0.018
0.22
0.93
40
DMSO
0.020
0.35
0.94
50
H2O H2O+TX
0.002 0.008
0.08 0.19
0.73 0.82
7.2 20
DMSO
0.017
0.17
0.73
50
DMSO
0.082
1.61
0.81
70
H2O H2O+TX DMSO
0.017 0.048 0.02
0.59 1.43 0.41
0.66 0.67 0.66
8.2 20 80
DMSO
0.03
0.75
0.68
150
H2O+TX PBS DMSO
0.02
0.44
0.59
10
0.01
0.07
PBS
0.9 0.91
50
0.61 0.82
[130] [137] [129]
0.90
[129]
3.0
0.86
[150]
4.9
0.68
[150]
0.57 0.70
[150] [150]
2.4
0.65
[150]
5.0
0.44
[150]
71.2 87.9 3.41
0.56 0.56 0.63
[150] [150] [151]
40
0.66
[151]
1.20 18.4 9.0
0.56 0.15 0.76
[151] [141] [141]
7.0
0.23
[141]
3.43 34 137
68 103
(continued)
218
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R3=H O R4= X=Cl R1=R2=R4=H O R3= X=Cl R1=R4=H R2=R3= O X=Cl
R1=R2=R4=H R3= S X=Cl
N
R1=R2=R4=H R3= S X=Cl
+ N
R1=R2=R3=H R4= S X=Cl
N
R1=R2=R3=H R4= S X=Cl
+ N
R1=R4=H R2=R3= O
N
X=Cl R1=R4=H R2=R3= O X=Cl
R1=R2=R3=H O R4= X=Cl R1=R2=R4=H O R3= X=Cl
+ N
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMSO
0.048
0.51
0.78
40
9.2
0.88
[142]
DMSO
0.032
0.37
0.69
50
24.4
0.87
[142]
DMSO
0.025
0.84
60
1.39
0.79
[152]
DMF Toluene DCM DMF
0.018 0.023
0.76 0.55
20 20
5.64 2.75 9.08
0.03
0.26
0.89
50
0.60 0.31 0.84 0.53
[152] [152] [143] [144]
DMSO DMSO
0.029 0.021
0.26 0.36
212.3 224.2
0.85 0.79
[145] [145]
H2O DMSO
0.0008 0.017
<0.1 0.17
12.9 3.6
0.40 0.75
[145] [145]
DMSO
0.0028
0.024
6.8
0.57
[145]
H2O DMSO
0.02
0.41
0.66
80
37.3 3.41
0.80 0.63
[145] [151]
DMSO
0.03
0.75
0.68
150
40
0.66
[151]
H2O+TX PBS DMSO
0.02
0.44
0.59
10
0.015
0.14
0.59
40
1.20 18.4 13.9
0.56 0.15 0.92
[151] [145] [142]
DMSO
0.019
0.20
0.60
50
21.4
0.88
[142]
FT
tT (ms)
219
Reference
(continued)
220
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3= O X=Cl
R1=R2=R3=H R4= O X=Cl
O
R1=R2=R4=H R3= O X=Cl R1=R4=H R2=R3= O X=Cl
O
O
R1=R2=R4=H R3=t-Bu X=Cl X= CF3 t-Bu
t-Bu N
N
M
N N
N
N N
N t-Bu
X=O X=
N
N
N
M N
N
X
N
N N
t-Bu
t-Bu
t-Bu
t-Bu
F
F
F
F
t-Bu
X= CN
NC
R1=R2=R3=R4=H X1=X2=OH R1=R4=H + R2=R3= N O
X1=X2=OSi(CH2CH2CH3)3
Si
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
tF (ns)
221
Fd (×10−5) FD
FT
tT (ms)
0.020
0.70
50
2.35
0.72
[152]
Reference
DMF Toluene DCM DMSO
0.022 0.021
0.61 0.41
9.5 10
0.013
0.12
0.97
40
4.83 3.19 4.12 0.30
0.50 0.30 0.62 0.94
[152] [152] [143] [137]
DMSO
0.017
0.16
0.91
50
0.97
0.87
[137]
DMSO
0.017
0.09
0.89
70
0.27
0.78
[137]
1.64
0.66
DCM Toluene
0.47
46
[143] [147]
Toluene
0.28
22
[147]
Toluene
0.64
42
[147]
Toluene
0.35
35
[147]
Toluene
0.47
38
[147]
DMSO
0.28
[22]
DMSO
0.0518
[71]
MeOH pH=7
0.0958 0.0732
[71] [71] (continued)
222
M. Durmuş
Table 4.1 (continued) Compound R1=R4=H R2=R3=
Metal
+ N O
X1=X2=OSi(CH2(CH3)2)3
R1=R4=H R2=R3=
+ N O
X1=X2=OSi(C6H5)2C(CH3)3 + N
R1=R4=H R2=R3=
O
O
O
O
X1=X2=OSi(C6H5)2C(CH3)3
R1=R2=R3=R4=H X1=OH Si X2=
N
N
O
R1=R2=R3=R4=H X1=X2=
N
Si
O
R1=R2=R3=R4=H X1=OH Si X2= O R1=R2=R3=R4=H X1=X2=
N
N
N
Si
O R1=R2=R3=R4=H X1=X2=
O
R1=R2=R3=R4=H O X1=X2= R1=R2=R3=R4=H X1=X2=
H N N H
H N
O
R1=R2=R3=R4=H O X1=X2=
N H
N H
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMSO
0.0763
[71]
MeOH pH=7 DMSO
0.1146 0.0455 0.0361
[71] [71] [71]
MeOH pH=7 DMSO
0.0748 0.0566 0.0670
[71] [71] [71]
MeOH pH=7
0.0987 0.0594
[71] [71]
FT
tT (ms)
223
Reference
CH3CN
139
0.50
[153]
CH3CN
188
0.20
[153]
CH3CN
113
0.43
[153]
CH3CN
160
0.32
[153]
DMF
0.03
0.06
[154]
DMF
0.05
0.13
[154]
DMF
0.07
0.15
[154]
DMF
0.06
0.09
[154] (continued)
224
M. Durmuş
Table 4.1 (continued) Compound R1=R2=R3=R4=H X1=X2=
Metal
N H
O
R1=R2=R3=R4=H X1=X2=
H N
N
O R1=R2=R3=R4=H O X1=X2= R1=R2=R3=R4=H X1=X2=
N
R1=R2=R3=R4=H O X1=X2=
N
R1=R2=R3=R4=H X1=X2=
N
O R1=R2=R3=R4=H X1=X2=
R1=R2=R3=R4=H X1=X2=
N
O R1=R2=R3=R4=H X1=X2=
N O N
N N
N N
H N
N H
N
+
N
O
R1=R2=R3=R4=H X1=OCH2CH3 X2= O
N H
N
O
R1=R2=R3=R4=H X1=OCH3 X2= O
H N
N
+
+ N
N H
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
0.04
0.13
[154]
DMF
0.07
0.14
[154]
DMF
0.08
0.13
[154]
DMF
0.04
0.06
[154]
DMF
0.03
0.03
[154]
H2O
0.05
[155]
H2O
0.03
[155]
H2O
0.21
[155]
DMF
0.02
0.25
[156]
DMF
0.08
0.26
[156]
DMF
0.06
0.35
[157]
FT
tT (ms)
225
Reference
(continued)
226
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R3=R4=H X1=O(CH2)5CH3 X2= O
N N
R1=R2=R3=R4=H + X1=OCH3 N X2= O
+
N
R1=R2=R3=R4=H X1=X2=
+
N
O
+
N
R1=R2=R3=R4=H X1=X2= O
O
O O O
O
O O O O
R1=R2=R3=R4=H O X1=X2= R1=R2=R3=R4=H X1=X2= R1=R2=R3=R4=H X1=X2=
O O O
N
N
+ O
R1=R2=R3=R4=H O X1=X2=
O
N
N
O OMe
R1=R2=R3=R4=H X1=X2=
O
N F B N F
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
0.09
0.39
[156]
DMF
0.48
0.81
[156]
DMF
0.64
0.26
[156]
DMF
0.34
0.32
[157]
DCM
0.62
DMF
0.02
0.15
[157]
H2O DMF
0.01 0.22
0.49
[159] [159]
H2O Toluene
0.28 0.60
5.07
[159] [160, 161]
DMF Toluene
0.47 0.60
5.35 5.20
[161] [160, 161]
DMF
0.016
0.40
[161] (continued)
FT
tT (ms)
227
6.7
Reference
[158]
228
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R2=R3=R4=H X1=X2=
N F B N F
O
OMe OMe OMe
R1=R2=R3=R4=H X1=X2=
O
O
O O O
R1=R2=R3=R4=H X1=OC2H5 X2=
O
O
O O O
R1=R2=R3=R4=H X1=OC5H11
O
O
O O
X2= O
R1=R2=R3=R4=H X1=OC8H17
O
O
O O
X2= O
R1=R4=H R2=R3= O X1=X2=Cl R1=R4=H R2=R3= O X1=X2=OH R1=R4=H R2=R3= O X1=X2=O3SCH3
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
Toluene
0.003
0,015
DMF DMF
0.012 0.39
0.54
DMF
FT
tT (ms)
229
Fd (×10−5) FD
Reference [160, 161]
0.94
[161] [162]
0.45
0.79
[162]
DMF
0.47
0.82
[162]
DMF
0.42
0.88
[162]
DMSO
0.21
2.4
0.31
194
0.14
[19, 163]
DMSO
0.18
1.9
0.30
179
0.07
[19]
0.16
[163]
DMSO
1.0
1500
(continued)
230
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3= O
X1=X2=
O Si
R1=R4=H O R2=R3=
O Si
X1=X2=
R1=R4=H R2=R3= O X1=X2= O
R1=R4=H R2=R3= O X1=X2= O
NH2
R1=R4=H R2=R3= O X1=X2= O
CHO
R1=R4=H R2=R3= O X1=X2= O
R1=R4=H R2=R3= O X1=X2= O
NO2
4
Photochemical and Photophysical Characterization
231
Solvent
FF
tF (ns)
FT
tT (ms)
Fd (×10−5) FD
Reference
DMSO
0.29
3.6
0.40
311
4.1
0.41
[19, 163]
DMSO
0.34
4.0
0.41
356
3.0
0.20
[19, 163]
DMSO
0.02
1.8
0.29
260
170
0.20
[19, 163]
DMSO
0.03
3.5
0.43
271
0.03
[19, 163]
3.3
DMSO
200
0.21
[163]
DMSO
100
0.19
[163]
DMSO
160
0.21
[163]
(continued)
232
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3= O X1=X2= OH
O
R1=R4=H R2=R3= O X1=X2=
OH O
N OH
R1=R4=H R2=R3= O X1=X2=
O
NH2
R1=R4=H R2=R3= O X1=X2= OOC
COOH
R1=R4=H R2=R3= O X1=X2= OOC
N
R1=R4=H R2=R3= O X1=X2= O3S
R1=R4=H R2=R3= O X1=X2=
COOH
OOC R1=R4=H R2=R3= O X1=X2= O
R1=R2=R3=R4=H X1=X2= O
O n
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
tF (ns)
FT
tT (ms)
233
Fd (×10−5) FD
Reference
400
0.18
[163]
DMSO
1.9
0.11
[163]
DMSO
1.7
0.14
[163]
DMSO
1.8
0.21
[163]
DMSO
7.0
0.14
[163]
0.15
[163]
0.17
[163]
0.21
[163]
0.16
[164]
DMSO
800
DMSO
1.4
DMSO
DMF
170
0.82
(continued)
234
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H;R2=R3=Cl X1=X2= O O
n
R1=R4=H;R2=R3=Br X1=X2= O O
n
R1=R4=R2=R3=Cl X1=X2= O
O n
R1=R4=R2=R3=Br X1=X2= O
O
R1=R2=R4=H R3= O X=Cl
n
N
R1=R2=R4=H R3=
+ N
X=Cl
O
R1=R4=R2=H S R3= X1=X2=Cl
N
R1=R2=R4=H R3= OH O
R1=R4=R2=H; R3=SO3Na X1=X2=Cl
(OH)2Si(IV)Pc(SO3)mix R1=R4=R2=H, R3=SO3Na X1=X2=OH
R1=R4=H; R2=R3=COOH X1=X2=OH
Si(IV)
4
Photochemical and Photophysical Characterization
Solvent
FF
Toluene DMF
0.73
DMF
0.34
tF (ns)
FT
tT (ms)
235
Fd (×10−5) FD
Reference
4.6
0.27 0.38
[165] [164, 165]
3.3
0.52
[164]
DMF
0.42
[165]
DMF
0.55
[165]
DMF
0.10
0.77
pH=11
0.009
0.51
110
pH=11+CEL DMSO
0.10 0.20
0.73 0.80
220 130
DMF DMSO
0.20 0.17
0.62 0.35
80 3,460
PBS
0.01
0.49
200
PBS+CEL DMSO PBS DMSO H2O/MeOH
0.03 0.05 0.34 0.29 0.10
0.57 0.67 0.45 0.58 0.56
pH=10 pH=10+CEL Aqueous
0.04 0.05 0.24
0.28 0.30
pH=10 DMSO
0.06 0.27
0.54
13.2
11.82
4.55
40
[61]
[61]
0.62
[61] [144]
0.47
[144] [46]
4.48
0.50
[166]
270 310 2.9 439 280
5.82 8.62 0.71 7.35
0.55 0.68 0.49 0.52
[166] [166] [38] [38] [93]
0.53 0.58 0.34
40 60 90
0.11 0.15 86.3
0.20 0.52 0.22
[62] [62] [73, 74]
0.30 0.48
70 760
0.54
0.33 0.33
[106] [167] (continued)
236
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=R2=H; R3=COOH X1=X2=OH N OH
N
N
N
N
N
Si
N
N
N
N
N
OH N
+ H3C N
OH N
N
N
N +N N CH3 OH
Si
N
N
N
+
CH3 N
N CH3 +
R1=R2=R3=R4=H R1=R2=R3=R4=H R1=R2=R3=R4=H
R1=R2=R3=R4=H X1=X2=OH (OH)2Ge(IV)Pc(SO3)mix (OH)2Ge(IV)Pc(SO3)4 R1=R4=R2=H; R3=SO3Na X1=X2=Cl
R1=R4=H; R2=R3=COOH X1=X2=OH R1=R4=R2=H; R3=COOH X1=X2=OH R1=R4=H R2=R3= O X1=X2=Cl
Si(IV)Pc-O-Si(IV)Pc Si(IV)Pc-O-Si(IV) Pc-O-Si(IV)Pc Si(IV)Pc-O-Si(IV) Pc-O-Si(IV) Pc-O-Si(IV)Pc Ge(IV)
4
Photochemical and Photophysical Characterization
Solvent
FF
DMSO
0.14
tF (ns)
FT
tT (ms)
0.66
210
237
Fd (×10−5) FD
Reference
0.17
[167]
DMSO
0.21
[22]
DMSO
0.01
[22]
Toluene Toluene
0.22 0.114
116 51
[168] [168]
Toluene
0.094
37
[168]
DMSO DMF PBS DMSO H2O/MeOH PBS
0.30 0.21 0.12 0.05
PBS+CEL DMSO Aqueous
0.25
[22]
0.67 0.79 0.81 0.61
2.76 760 250 180
0.45 9.74
0.34 0.68 0.78
3.66
0.64
[22] [38] [38] [93] [166]
0.09 0.12 0.13
0.70 0.84 0.62
240 640 240
5.54 8.57 2.12
0.68 0.31 0.31
[166] [166] [73, 74]
DMSO DMSO
0.19 0.17
0.79 0.82
480 260
0.63 0.73
[167] [167]
DMSO
0.12
0.30
340
0.18
[20]
4.32
0.3
(continued)
238
M. Durmuş
Table 4.1 (continued) Compound R1=R4=H R2=R3=
Metal O
O
X1=X2=Cl R1=R4=H R2=R3= O X1=X2=Cl N OH
N
N
N
N
N
Ge N
N
N
N
N
OH N
+ H3C N OH N N +N N CH3 OH
N
N
+
CH3 N
Ge N N
N N 3CH +
R1=R2=R3=R4=H X1=X2=OH R1=R2=R3=R4=H X1=X2=Cl (OH)2Sn(IV)Pc(SO3)mix
R1=R2=R3=R4=H X1=X2=
Sn(IV)
O
O
4
Photochemical and Photophysical Characterization
239
Fd (×10−5) FD
Solvent
FF
tF (ns)
FT
tT (ms)
DMSO
0.21
5.1
0.20
205
0.18
[20]
Reference
DMSO
0.31
4.0
0.50
168
0.24
[20]
DMSO
0.17
[22]
DMF DMSO
0.22 <0.01
[22] [22]
DMSO
0.26
[22]
DMSO PBS PBS/TX DMSO DMSO
[20] 0.05 0.19 0.13 0.02
2.03
2.2
0.59 0.68 0.87 0.08
2.52 2.32 120 18
1.59 4.13 14.01
0.42 0.52 0.65 0.22
[38] [38] [38] [20]
(continued)
240
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3= O X1=X2=Cl R1=R4=H R2=R3=
O
X1=X2=Cl O R1=R4=H R2=R3= O X1=X2=Cl R1=R2=R3=H O R4= X1=X2=Cl R1=R2=R3=H O R4= X1=X2=Cl R1=R2=R3=H R4= O X1=X2=Cl
O
R1=R2=R4=H O R3= X1=X2=Cl R1=R2=R4=H O R3= X1=X2=Cl R1=R2=R4=H R3= O X1=X2=Cl
O
R1=R4=H S C R2=R3= H2 X1=X2=Cl R2=R3=H; R1=R4=C6H13 X1=X2=Cl
4
Photochemical and Photophysical Characterization
Fd (×10−5) FD
Solvent
FF
tF (ns)
FT
DMSO
0.04
0.3
0.19
30
0.22
[20]
DMSO
0.01
0.2
0.15
10
0.23
[20]
DMSO
0.06
0.4
0.45
32
0.34
[20]
DMSO
0.008
0.79
50
41.0
0.58
[169]
DMSO
0.007
0.76
40
43.1
0.74
[169]
DMSO
0.008
0.69
30
61.7
0.75
[169]
DMSO
0.014
0.89
40
27.9
0.73
[169]
DMSO
0.010
0.75
40
17.9
0.65
[169]
DMSO
0.011
0.71
30
42.9
0.73
[169]
DMSO
0.15
0.47
610
0.33
0.35
[84]
THF
0.23
Toluene
0.19
0.78
tT (ms)
241
Reference
100
[125]
30
[125] (continued)
242
M. Durmuş
Table 4.1 (continued) Compound
Metal
N OH
N
N
N
N
N
Sn N
N
N
N
N
OH N + H3C N OH
+
N
N
N
N
Sn N
N CH3 N OH
N
+
CH3 N
N N CH3 +
R1=R2=R4=H S R3=
N
Sn(II)
R1=R2=R3=H O R4=
Pb
R1=R2=R3=H O R4=
R1=R2=R4=H O R3=
R1=R2=R4=H O R3=
R1=R2=R4=H R3= O
O
4
Photochemical and Photophysical Characterization
Solvent
FF
tF (ns)
FT
tT (ms)
243
Fd (×10−5) FD
Reference
DMSO
0.15
[22]
DMSO
0.02
[22]
DMSO
0.012
0.49
0.88
40
0.59
[144]
DMF DMF
0.04 0.03
2.96
0.75 0.72
30 10
0.57
[144] [170]
DMSO Toluene DMF
<0.01 0.01 0.02
0.78 0.82 0.82
40 8 9
[170] [170] [170]
DMSO Toluene DMF
<0.01 0.05 <0.01
0.80 0.70 0.75
30 7 9
[170] [170] [170]
DMSO Toluene DMF
<0.01 0.02 <0.01
0.76 0.77 0.78
20 8 9
[170] [170] [170]
DMSO Toluene DMF
<0.01 0.04 <0.01
0.72 0.78 0.80
30 9 5
[170] [170] [171]
DMSO Toluene
<0.01 0.03
0.82 0.83
40 6
[171] [171] (continued)
244
M. Durmuş
Table 4.1 (continued) Compound
Metal
R1=R4=H R2=R3= O
R1=R4=H R2=R3= O
R1=R4=H R2=R3= O
O
R1=R2=R3=R4=H
Sb(III)+3I−
R1=R4=H R2=R3= O
R1=R4=H R2=R3= O
R1=R2=R3=R4=H X1=X2=Cl R1=R4=H, R2=R3=C(CH3)3 X1=X2=Cl R1=R4=H, R2=R3=C(CH3)3 X1=X2=Br R1=R2=R3=R4=H X1=X2=OH R1=R2=R3=R4=H X1=X2=
Sb(V)
P
FF= fluorescence quantum yield; tF= fluorescence lifetime; FT= triplet quantum yield; tT= triplet lifetime; Fd= photodegradation quantum yield; FD = singlet oxygen quantum yield
4
Photochemical and Photophysical Characterization
tF (ns)
Fd (×10−5) FD
Solvent
FF
DMF
<0.01
0.78
5
[170]
DMSO Toluene DMF
0.01 0.01 <0.01
0.76 0.85 0.74
20 7 5
[170] [170] [170]
DMSO Toluene DMF
<0.01 <0.01 <0.01
0.88 0.74 0.83
50 6 6
[170] [170] [171]
DMSO Toluene DMSO DMF DMSO
<0.01 0.01
0.84 0.86 0.75 0.76 0.79
30 7 30 7 20
0.31 0.52 0.42
[171] [171] [172] [172] [172]
DMF Toluene DMSO
0.78 0.77 0.80
5 7 30
0.61 0.57 0.48
[172] [172] [172]
DMF Toluene DCM
0.82 0.78
5 6
0.53 0.81
0.01
[172] [172] [173]
DCM
0.01
[173]
DCM
0.001
[173]
DMSO
0.13
2.02
0.52
113
[174]
DMSO
0.08
0.96
0.27
456
[174]
FT
tT (ms)
245
Reference
246
M. Durmuş
For example, the FD values of 2-diethylaminoethanethiol substituted ZnPc complexes decrease from 0.64 to 0.51 for non-peripherally tetra-substituted, from 0.68 to 0.62 for peripherally tetra-substituted and from 0.62 to 0.49 for peripherally octa substituted complexes in DMSO [94]. The lower singlet oxygen production of quaternized phthalocyanine photosensitizers in water compared to organic solvents such as DMSO is ascribed to the quenching of singlet oxygen by water as discussed above. The FD values of quaternized 6-oxyquinoline substituted ZnPc complexes decrease from 0.13 to 0.07 for tetra- and from 0.07 to 0.03 for octa-substitution in DMSO and PBS, respectively [81]. The FD values of quaternized 2-diethylaminoethanethiol substituted ZnPc complexes decrease from 0.51 to 0.10 for non-peripherally tetra-, from 0.62 to 0.15 for peripherally tetra- and from 0.49 to 0.10 for peripherally octa-substituted complexes in DMSO and PBS, respectively. The addition of CEL to PBS solutions of these complexes cause an increase in FD values (FD = 0.12 for non-peripherally tetra-, FD = 0.26 for peripherally tetra- and FD = 0.24 for peripherally octa-substituted complexes) [94]. The FD values of quaternized 2-mercaptopyridine substituted ZnPc complexes also have lower FD values in water than in DMSO (FD = 0.82 in DMSO and FD = 0.45 in water for peripherally tetra-, FD = 0.45 in DMSO and FD = 0.19 in water for non-peripherally tetra- and FD = 0.63 in DMSO and FD = 0.10 in water for peripherally octa-substituted complexes) [109]. The same decrease for the FD values of other quaternized MPc complexes is observed, depending on whether aqueous solution or organic media are employed (Table 4.1). The FD values of peripherally octa-substituted zwitterionic 3-hydroxypyridine substituted gallium and indium phthalocyanine complexes (FD = 0.58 for Ga(III)Pc and FD = 0.76 for In(III)Pc) are higher than respective quaternized cationic derivatives (FD = 0.54 for Ga(III)Pc and FD = 0.66 for In(III)Pc) in DMSO [141]. In the case of ClGa(III)Pc substituted with (benzyloxy)phenoxy groups, the trend of singlet oxygen quantum yields is as follows: non-peripherally tetrasubstituted (FD = 0.69) > peripherally tetrasubstituted (FD = 0.62) > peripherally octasubstituted (FD = 0.51) in DMSO [137]. The same trend applies for ClIn(III)Pc derivatives substituted with (benzyloxy)phenoxy groups (FD = 0.94 for non-peripherally tetra-, FD = 0.87 for peripherally tetra- and FD = 0.78 for peripherally octa-substituted complexes) [137]. As expected, due to the heavy atom effect ClIn(III)Pc complexes show larger singlet oxygen quantum yields in general (Table 4.1).
4.6.2
Photodegradation Quantum Yields (Fd)
The aryloxy and arylthio substituted OTi(IV) phthalocyanines exhibit the same photostability in CH2Cl2 [55]. Branched polyoxy thio substituted analogues have lower Fd values in DMSO (Table 4.1) [58]. Unsubstituted ZnPc is stable towards degradation in DMSO compared to some ring substituted derivatives (Table 4.1). This was explained in terms of intramolecular vibrations of some substituents on the phthalocyanine framework which quenches singlet oxygen as soon as it is formed [16]. The stability of unsubstituted ZnPc is
4
Photochemical and Photophysical Characterization
247
similar in DMSO (Fd = 2.61 × 10−5) [16] and DMF (Fd = 2.35 × 10−5) [69], but less stable in toluene (Fd = 0.93 × 10−5) [69]. Compared to stability of the ZnPc complexes according to linkage heteroatom (O or S), ZnPcs substituted through O heteroatom as linkage atom are more stable than substituted through S heteroatom as linkage atom. For example, 2-hydroxy-5-(trifluoromethyl) pyridine substituted ZnPc complex (Fd = 0.74 × 10−5) is more stable than respective 5-(trifluoromethyl)-2-thiopyridine substituted thio analogue (Fd = 3.57 × 10−5) in DMSO [79]. In general, for sulfonated ZnPc derivatives, Fd values are of the order of 10−5 (Table 4.1). For a series of MPc(SO3)mix complexes, photodegradation quantum yield values tend to follow singlet oxygen trends (Table 4.1) [38, 175]. Photodegradation quantum yields are found to be high for ZnPc complexes containing the 2-diethylaminoethanethiol group (Fd = 66.2 × 10−5 for non-peripherally tetra-, Fd = 66.1 × 10−5 for peripherally tetra- and Fd = 94.0 × 10−5 for peripherally octa-substituted ZnPcs) compared to their quaternized counterparts containing the quaternized 2-diethylaminoethanethiol group as substituents (Fd = 18.1 × 10−5 for non-peripherally tetra-, Fd = 16.6 × 10−5 for peripherally tetra- and (Fd = 17.1 × 10−5 for peripherally octa-substituted ZnPcs) in DMSO [94]. The lowest values of photodegradation are exhibited in PBS solution for the quaternized 2-diethylaminoethanethiol substituent on ZnPc (Table 4.1) [94], where Fd values are also low in PBS. This confirms that photodegradation is dependent on singlet oxygen. The Fd values of ZnPcs substituted with the more electron-withdrawing substituents such as (benzyloxy)phenoxy groups, the trend of photodegradation quantum yields is as follows: non-peripherally tetrasubstituted (Fd = 0.50 × 10−5) > peripherally tetrasubstituted (Fd = 0.33 × 10−5) > peripherally octasubstituted ( F d = 0.13 × 10−5) in DMSO [102 ] . The quaternization of the 2-mercaptopyridine groups on the ZnPc decrease the stability of these complexes in DMSO. For example, while the Fd is 2.19 × 10−5 for non-quaternized octa-2-mercaptopyridine substituted ZnPc complex, Fd is 10.58 × 10−5 for quaternized derivative Table 4.1) [109]. The phototransformation is ascribed to some distortion of the pyridyloxy substituted phthalocyanine macrocycle upon exposure to intense light [127]. The peripherally tetra-benzyloxyphenoxy substituted CdPc complex do not show phototransformation or photodegradation in some solvents (toluene, CHCl3, THF and DCM), since no decrease in absorption intensity was observed. The stability of this complex was ascribed to partial oxidation in these solvents (Table 4.1) [127]. Coordinating solvents such as DMSO are capable of protecting the molecule against oxidative attack, while non-coordinating solvents such as chloroform leave the molecule prone to oxidative attack, giving rise to a high Fd yields. The ClGa(III)Pc and ClIn(III)Pc complexes show about the same stability, with Fd of the order of 10−5 to 10−4 (Table 4.1) [152]. These complexes are however, generally less stable than the corresponding ZnPc derivatives. In general, the stability of XAlPc complexes (X = Cl or OH) is lower than other metallophthalocyanine complexes in DMSO (Fd = 321 × 10−5 for ClAlPc, Fd = 0.93 × 10−5 for ClGaPc, Fd = 3.43 × 10−5 for ClInPc, Fd = 2.61 × 10−5 for ZnPc) [129]. The substituted ClGa(III)Pc and ClIn(III)Pc complexes exhibit similar stability. The Fd value of ClAl(III)Pc(SO3)mix complex is lower in aqueous solution than in DMSO [38, 39].
248
M. Durmuş
The substitution of triethyleneoxythia groups on the ClGa(III)Pc and ClIn(III)Pc complexes cause decreasing of the stability of complexes according to increasing of Fd values [129]. The quaternization of the substituents (pyridiyloxy or pyridylthio) of the ClGa(III)Pc and ClIn(III)Pc complexes results in increase in the Fd values and decease in the stability of complexes in DMSO [138–141, 145, 150, 151]. The results of the photostability of Si(IV)Pc complexes under light irradiation are very limited in the literature. The photodegradation of some Si(IV)Pc complexes which are axially substituted with different organic substituents are described (Table 4.1) [163]. Photolysis of the less aggregated (OH)2Si(IV) or (OH)2Sn(IV) tetrapyridinoporphyrazine complexes resulted in degradation accompanied by reduction of the ring in DMSO. Thus these complexes showed a strong tendency towards reductive quenching of the excited states [22]. The stability of some sulfonated X2Ge(IV)Pc complexes (X = Cl or OH) were investigated in DMSO and aqueous solution (Table 4.1). These complexes are more stable in aqueous solution than in DMSO. The addition of CEL to PBS solution increase the Fd value of tetrasulfonated Cl2Ge(IV)Pc from 3.66 × 10−5 to 5.54 × 10−5. The lowering of the stability of this complex due to addition of CEL can be explained by changes in aggregation behavior of this complex in PBS or PBS+CEL solution [166]. The Fd value of (OH)2Sn(IV)Pc(SO3)mix complex is also lower in aqueous solution than in DMSO. The addition of Triton X-100 decreases the stability of this complex (Fd = 14.01 × 10−5 in DMSO, Fd = 1.59 × 10−5 in PBS and Fd = 4.13 × 10−5 in PBS + TX) [38]. The substitution of some organic groups such as phenoxy derivatives on the peripheral or non-peripheral position of (Cl)2Sn(IV)Pc complexes decrease the Fd values of these complexes [169]. Unsubstituted and substituted Sb(III) phthalocyanine complexes show about the same stability, with Fd of the order of 10−4 in DMSO and DMF (Table 4.1) [172].
4.6.3
Fluorescence Quantum Yields (FF) and Lifetimes (tF)
Unmetalated Pc complexes (H2Pc) are generally less soluble compared to their metalated analogues. Introduction of substituents onto the Pc skeleton as well as metalation enhances the solubility of these complexes. Thus, as Table 4.1 shows, there are fewer studies available about the photophysical and photochemical properties of unmetalated phthalocyanines. Unsubstituted H2Pc exhibits a higher FF value (FF = 0.55) when compared to the complex peripherally tetrasubstituted with OCH2C(CH3)3 group (FF = 0.24) in CHCl3 (Table 4.1) [40, 176]. On the contrary, the latter complex shows higher tF value (tF = 7.3 ns) than unsubstituted H2Pc (tF = 6.5 ns) in CHCl3. The FF values of non-peripherally octa-long chain substituted unmetalated phthalocyanines range from 0.05 to 0.10 in DCM. The fluorescence lifetime (tF) values of these complexes range from 4.8 ns to 5.1 ns in DCM [48]. On insertion of the Zn as central metal to these complexes, the FF values increased, ranging from
4
Photochemical and Photophysical Characterization
249
0.13 to 0.17 and tF values decreased, ranging from 3.7 to 3.9 ns (Table 4.1) [48]. The FF value of tetrasulfophathalocyanine is similar in DMF (FF = 0.60) and water (FF = 0.62) [30, 41]. The FF values of octa-peripherally SR substituted complexes (R=C5H11, C8H17, C12H25) increase from 0.10 to 0.15 in 1-ClNP according to increase in carbon chain length on the Pc molecule [44]. The FF values of monomeric, dimeric and trimeric H2Pc derivatives are 0.33, 0.04 and <0.02 in toluene, respectively [51]. There are only a few studies on the fluorescence properties of MgPc derivatives [18, 42, 46, 53]. The FF values of MgPc complexes are higher than other MPc complexes. Unsubstituted MgPc was found to give a FF value of 0.6 in 1-ClNP (Table 4.1) [18]. OTi(IV)Pc complexes containing the thiophenol and benzylthio substituents at the peripheral and non-peripheral positions have been studied in DMSO [56]. FF values for non-peripherally tetrasubstituted OTi(IV)Pcs are generally lower than that for the corresponding peripherally tetrasubstituted derivatives (Table 4.1). FF and tF values of octa-peripherally phexoxy, tert-butylphenoxy and benzyloxyphenoxy substituted OTi(IV)Pc complexes in 1-ClNP are similar (Table 4.1). OTi(IV)Pc complexes non-peripherally tetra, peripherally tetra and peripherally octa-substituted with 3,4-(methylendioxy)-phenoxy groups gave FF values which ranged from 0.027 to 0.063 in DMSO and from 0.45 to 0.58 in toluene (Table 4.1) [60]. There are a few FF and tF values of axially substituted Zr(IV)Pc complexes are given in Table 4.1. The FF values are very low ranging from 0.006 to 0.016, but tF values are high ranging from 6.84 to 9.08 ns (Table 4.1) [64]. Only sulfonated tantalum phthalocyanine complex has been studied for photophysical and photochemical properties in the literature. For (Cl)3Ta(V)Pc(SO3)mix complex, the FF values are 0.15 in PBS, 0.18 in DMSO and 0.22 in MeOH are not as low as would be expected for the complex containing the heavy Ta central metal. The tF values are 2.91 ns in PBS, 4.72 ns in DMSO and 3.81 ns in MeOH (Table 4.1). The fluorescence quantum yield and lifetime values of substituted ZnPc derivatives in different solvents are given in Table 4.1. ZnPc derivatives substituted with different substituents are the most intensively studied of all MPc complexes photochemically and photophysically [16, 66, 67, 72, 87, 103, 114, 116, 153, 177, 178]. Fluorescence quantum yield (FF) for unsubstituted ZnPc is 0.20 in DMSO [16] and this value is often employed as the reference for FF determinations of other MPc complexes. FF values for unsubstituted ZnPc range from 0.07 to 0.30 in different solvents. The tF values for unsubstituted ZnPc range from 0.90 to 3.90 ns in various solvents (Table 4.1). The values are influenced by the viscosity of the solvent, where lower values are obtained in less viscous solvents [23]. Halogenation of ZnPc derivatives with fluorine groups resulted in a decrease in fluorescence quantum yields as expected, due to the heavy atom effect. A decrease in the FF value was observed from ZnPc (FF = 0.17) to ZnPcF16, (FF = 0.04) followed by an increase for the ZnPc(C(CF3)2F)8F8 complex (FF = 0.39) in acetone (Table 4.1) [72]. This observation is consistent with the notion that aromatic fluorine groups in
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ZnPcF16 are part of the phthalocyanine p system and thus enhance the intersystem crossing. Aliphatic fluorine groups in ZnPc(C(CF3)2F)8F8 are not conjugated with the phthalocyanine p system, resulting in increased fluorescence lifetimes [72]. In general, the fluorescence quantum yields obtained for tetra- or octa-substituted ZnPcs with different organic substituents such as alkyl, alkoxy, fluoro alkoxy, benzyloxy phenoxy, branched alkoxy, polyoxy or polyoxythia are typical of MPc complexes (Table 4.1) [21, 48, 69, 102, 105]. Low FF value was also obtained for Zn naphthalocyanine (ZnNPc) complex and this was explained in terms of the fast degradation of this complex upon photolysis [16, 112]. The binuclear ZnPc complexes containing catechol bridges exhibit low FF values in DMSO (Table 4.1), and this is attributed to a self-quenching process in the binuclear phthalocyanine complexes [88]. Annulated dinuclear and trinuclear ZnPc phthalocyanine complexes gave much lower FF values (FF = 0.08 for dinuclear and FF = 0.03 for trinuclear complexes) compared to the monomeric complex (FF = 0.28) in THF, which is in agreement with the reduction in fluorescence lifetime [126]. FF values decrease as the number of sulfonate groups increase for ZnPc(SO3)2 (FF = 0.16), ZnPc(SO3)3 (FF = 0.12), ZnPc(SO3)4 (FF = 0.07) in DMSO [16, 90]. The low FF value for ZnPc(SO3)4 could be the result of some aggregation even in organic solvents such as DMSO. The FF values of tetra- and octa-2-mercaptopyridine substituted ZnPc complexes are ranged from 0.11 to 0.17 in DMSO. The peripherally tetra-substituted complex exhibits highest FF and peripherally octa-substituted complex shows lowest FF value in DMSO (Table 4.1) [109]. The quaternization of nitrogen atoms on the pyridine groups decreased FF values in DMSO (FF = 0.02 for peripherally tetra-substituted complex, FF = 0.01 for non-peripherally tetra-substituted complex and FF = 0.03 for peripherally octa-substituted complex). The quaternized ZnPc complexes do not fluorescence in water, this could be due to aggregation of these complexes in water. The tF values of 2-mercaptopyridine substituted ZnPc complexes ranged from 0.92 to 1.20 in DMSO (Table 4.1) [109]. For ZnPc complexes containing the 2-diethylaminoethanethiol substituent, there was a lack of agreement between absorption and emission spectra due to aggregation [94]. For these complexes, the band at around 640 nm in aqueous solution associated with the dimer, is not seen in the fluorescence excitation spectra since only the monomer fluorescence. In DMSO, the absorption and fluorescence excitation spectra of the complexes are similar and are mirror images of the emission spectrum. Monomerization of the 2-diethylaminoethanethiol substituted ZnPc leads to enhanced fluorescence and this is noticed in the FF value of this complex in the presence of CEL and in DMSO compared to the value in aqueous media alone. The FF values followed the trend DMSO > PBS+CEL > PBS solution for all ZnPc complexes substituted with 2-diethylaminoethanethiol groups at non-peripheral tetra-, peripheral tetra- and peripheral octa-positions [94]. Also in DMSO, FF values for quaternized ionic ZnPc complexes are slightly lower than for the non-ionic ZnPc complexes (Table 4.1) [94].
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The FF values of the carboxylated ZnPc complexes in DMF are given in Table 4.1. ZnPc complexes containing 4-carboxylphenoxy or 4-(2-carboxyl-ethyl)phenoxy substituents gave typical values of FF [76, 77]. For MPc(SO3)mix complexes, which are a mixture of sulfonated MPc complexes, the determined photophysical and photochemical parameters are an average for each mixture. It is important to report these parameters for the mixtures since such mixtures are already in use in PDT for example. For the aggregated ZnPc(SO3)mix complexes [42], it was only the monomer that fluorescence. The ZnPc(SO3)mix complex showed lower FF value in PBS (FF = 0.16) and the FF value increased when a surfactant such as Triton X-100 (FF = 0.21) was added (Table 4.1) [38]. The FF values are generally lower for the sulfonated ZnPc complexes in DMSO than in water (with or without surfactant) and this was attributed to the presence of the relatively heavier atoms in DMSO, which may tend to favor intersystem crossing rather than fluorescence. However, in general DMSO gives larger FF values compared to water in Table 4.1, since there is less aggregation in DMSO. The quaternization of the inner nitrogen atoms on the porphyrazine framework decreased the FF values from 0.35 to 0.30 in DMF (Table 4.1) [100]. All studied CdPc complexes by Nyokong and co-workers for photophysical and photochemical properties are those tetra-substituted with substituents phenoxy, tert-butylphenoxy, benzyloxyphenoxy and 2-pyridyloxy at the peripheral and non-peripheral positions [107, 127, 128]. In general, CdPc complexes do not exhibit aggregation, the absorption spectra are similar to the excitation spectra, and both are mirror images of the emission spectra. The fluorescence excitation and emission spectra of the 2-hydroxypyridine substituted CdPc complexes are typical of phthalocyanine complexes; with the fluorescence excitation spectrum is similar to the absorption spectrum and it being a mirror image of the emission spectrum [107]. Hence, no demetalation for this complex upon excitation occurred. However, the excitation spectra for peripherally tetra-benzyloxyphenoxy substituted CdPc show a split in the Q-band in toluene, CHCl3 and THF due to the demetalation of the heavier Cd atom. For this complex, the excitation spectrum was similar to the absorption spectrum of an unmetalated derivative, suggesting that the loss of symmetry is due to demetalation upon excitation [127]. The fluorescence quantum yields of CdPc derivatives tetrasubstituted with phenoxy and tert-butylphenoxy groups at the non-peripheral positions are generally high in THF and chloroform, compared to MPc complexes in general (Table 4.1 ) [ 128 ] . Unsubstituted CdPc shows low FF and high FT, as expected for complexes with heavy atoms (Table 4.1). The tF values of the unsubstituted CdPc are also low in DMSO (tF = 0.32 ns) and DMF (tF = 0.51 ns) [107]. Only one paper published about photophysical and photochemical properties of HgPc complexes in the literature [107]. Nyokong and co-workers studied unsubstituted and peripherally tetra-2-pyridyloxy substituted HgPc complexes [107]. For HgPc complexes containing 2-pyridyloxy substituent at the peripheral position, the fluorescence emission spectrum is broad compared to the absorption spectrum. This suggests the loss of symmetry for the fluorescing molecule, which is most likely due to demetalation as observed for the CdPc complexes.
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Peripherally tetra-2-pyridyloxy substituted HgPc complex gave the lowest FF value when compared to the corresponding CdPc and ZnPc derivatives [107]. In general, the effect of introducing 2-pyridyloxy substituents to peripheral positions on the HgPc framework is a reduction in FF values in both DMF and DMSO (FF = 0.010 for unsubstituted HgPc complex and FF = 0.005 for 2-pyridyloxy HgPc complex in DMSO) when considering the same solvent [107]. The FF value of unsubstituted ClAl(III)Pc complex (FF = 0.37) is higher than ClGa(III)Pc (FF = 0.30) and ClIn(III)Pc (FF = 0.018) complexes in DMSO due to small size of Al metal as central atom. tF value of ClAl(III)Pc is also higher than for MPcs containing heavier group 3A metals in DMSO (tF = 6.09 ns for ClAl(III)Pc, 3.71 ns for ClGa(III)Pc and 0.90 ns for ClIn(III)Pc) (Table 4.1) [129]. ClAl(III) Pc(SO3)2 complex exhibits relatively high FF and tF values in different solvents (FF = 0.40 and tF = 5.0 ns in H2O, FF = 0.54 and tF = 6.8 ns in D2O and FF = 0.56 and tF = 6.2 ns in MeOH) (Table 4.1) [89, 131–133]. The addition of CEL to pH = 11 solution of quaternized 2-hydroxypyridine substituted Al(III)Pc complex increased the FF value from 0.12 to 0.23 [61]. With a few exceptions, the shapes of the excitation spectra are similar to absorption spectra and both are mirror images of the fluorescence spectra for ClGa(III)Pc complexes. Table 4.1 shows that the FF and tF values of ClGa(III)Pc complexes are in general typical of MPc complexes. These values are slightly higher for peripherally substituted derivatives compared to the non-peripherally substituted complexes, suggesting less quenching of the excited singlet state by peripheral tetra-substitution compared to non-peripheral tetra-substitution. The water soluble tetra-substituted ClGa(III)Pc complexes containing 3-hydroxypyridine substituents are not aggregated and, as such, the excitation spectra are similar to absorption spectra and both were mirror images of the fluorescence spectra. The proximity of the wavelength of the Q-band absorption and excitation spectral maxima, suggest that the nuclear configurations of the ground and excited states are similar and are not affected by excitation [139, 140]. The fluorescence quantum yields and lifetimes of ClGa(III)Pc derivatives peripherally or non-peripherally substituted with 3-hydroxypyridine are typical of MPc complexes (Table 4.1). The peripherally substituted complexes showed marginally higher F F values in comparison to the non-peripherally substituted ClGa(III)Pc suggesting less quenching of the excited singlet state by non-peripheral substitution compared to the peripheral substitution [139]. The quaternization of nitrogen atoms on the 3-hydroxypyridine groups of tetra-substituted ClGa(III)Pcs caused increasing of the FF values in DMSO [139]. The octa-zwitterionic 3-hydroxypyridine substituted complex showed higher both FF and tF values in DMSO [141]. In general, for the ClIn(III)Pc complexes, the shape of the excitation spectra was different to the absorption spectra in that the Q-band of the former showed splitting, unlike the narrow Q-band observed for the latter. This suggests that there are changes in the molecule following excitation, most likely due to loss of symmetry. However, this was not observed for the corresponding ClGa(III)Pc complexes. The difference in the behavior of ClGa(III)Pc and ClIn(III)Pc upon excitation was explained in terms of the larger indium metal that is more displaced from the core of the phthalocyanine ring. The displacement becomes more pronounced upon excitation, causing
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loss of symmetry. For the ClIn(III)Pc complexes in general, the FF and tF values are very low due to an enhancement in intersystem crossing caused by the presence of the heavier indium atom [137, 142, 152]. Generally, the photophyical and photochemical properties of axially substituted Si(IV) phthalocyanine complexes are studied in the literature. Different groups are used for axially substituents [158, 163–165, 168, 179]. X2Si(IV)Pc complexes containing 4-tert-butylbenzoic acid as the axial ligand, giving a rigid conformation, gave a high FF and tF values in DCM (FF = 0.62 and tF = 6.7 ns) [158]. Peripherallyocta-unsubstituted, chlorinated and brominated Si(IV)Pc complexes containing two poly(ethylene glycol) axial ligands show a large FF value in DMF. The FF values for these complexes increase as follows: unsubstituted (FF = 0.82) > octa-chlorinated (FF = 0.73) > octa-brominated (FF = 0.34) since bromine encourages intersystem crossing more than hydrogen and chlorine (Table 4.1), being larger in size [164, 165]. The axially boron dipyrromethenes (BODIPY) substituted Si(IV)Pc complex exhibits high FF value (0.60) in toluene than in DMF (0.016). The axially bis(monostyryl BODIPY)-substituted silicon (IV) phthalocyanine showed very low FF value (0.003) in toluene [160, 161]. The FF and tF values for octa-subsubstituted X2Ge(IV)Pc (X = Cl or OH) derivatives are typical of MPc complexes in Table 4.1 [20, 38, 73, 74, 93, 166, 167]. For Cl2Sn(IV)Pc complexes, FF values are low for tetra-substituted derivatives due to the size of the Sn central metal ion, but these values increase on octa-substitution (Table 4.1). [20, 38, 169] The FF values of lead phthalocyanine complexes in both DMSO and toluene, and antimony (V) phthalocyanine in DCM are very low due to the bigger size of the central metal atoms [170, 171, 173].
4.6.4
Triplet State Quantum Yields (FT) and Lifetimes (tT)
In general, triplet quantum yields (FT) and lifetimes (tT) of unmetallated Pc complexes are lower compared to metallated phthalocyanine derivatives (Table 4.1). The FT value of tetra-sulfonated H2Pc complex is slightly lower in water (FT = 0.22) than in DMF (FT = 0.24) [30, 41]. The substitution of some organic groups such as phenoxy or benzyloxyphenoxy on the phthalocyanine ring increase FT values. The increase in alkyl chain length on the alkylthia substituted H2Pc slightly increased the FT values, but no significant change observed for tT values of these complexes [44]. Unsubstituted Li2Pc and Li2NPc complexes showed the same FT values in CH3CN and acetone [54]. Studies on the triplet state properties of OTi(IV)Pc derivatives are few. However, the FT values of these complexes range from moderate to high, where the highest value of FT =0.85 was obtained for branched poly(oxyethylene) OTi(IV)Pc derivative in DMSO. This complex showed the highest tT (220 ms) value in DMSO as well [58]. The triplet lifetimes are highly dependent on the solvent and substituents present, and the lowest values were obtained for OTi(IV)Pc tetra-substituted with
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4-(thiophen-3yl)-phenoxy groups in DMSO (tT = 29 ms), DMF (tT = 12 ms) and THF (tT = 3 ms) [57]. There have not been any studies about triplet quantum yields and lifetimes properties of zirconium and tantalum phthalocyanines. Unsubstituted ZnPc complex is used as a standard for triplet quantum yield measurements of phthalocyanine complexes. The FT values of unsubstituted ZnPc complex range from 0.55 to 0.65 in different solvents [16, 23, 36, 65–67, 69–71, 180]. The triplet lifetimes of unsubstituted ZnPc in DMSO are relatively long at around 300–350 ms in different solvents (Table 4.1). [16, 23, 36, 65–67, 69–71, 180] The FT and tT values of octa-carboxylated ZnPc complex are 0.50 and 160 ms in aqueous solution, respectively [73]. When compared to effects of linkage heteroatom (O or S), thia-substituted ZnPc complexes exhibit higher FT and longer tT values than oxy-substituted ZnPc complexes. For example, the FT values of peripherally tetra-2-mercaptopyridine (FT = 0.73) and 5-(trifluoromethyl)-2-thiopyridine (FT = 0.86) substituted ZnPc complexes are higher than respective peripherally tetra-2-hydoxypyrinine (FT = 0.68) and 2-hydroxy-5-(trifluoromethyl) pyridine (FT = 0.74) substituted ZnPc complexes [79, 80, 107, 109, 110]. The quaternization of the substituents on the phthalocyanine ring decreased both FT and tT values of ZnPc complexes. The FT values of 2-diethylaminoethanethiol substituted ZnPc complexes decreased from FT = 0.66 to FT = 0.63 (for nonperipherally tetra-substituted), from FT = 0.71 to FT = 0.57 (for peripherally tetrasubstituted) and from FT = 0.75 to FT = 0.60 (for peripherally octa-substituted) ZnPc complexes. On the contrary, tT values of these complexes increased due to quaternization of the nitrogen atoms on the 2-diethylaminoethanethiol group (Table 4.1) [94]. As expected, the presence of CEL gave increased FT values for ZnPc complexes containing the 2-diethylaminoethanethiol groups as substituent compared to the phosphate buffer solution (PBS) alone [94]. An increase in both triplet quantum yields (FT) and triplet lifetimes (tT) in the order, PBS < PBS + CEL < DMSO were observed with these ZnPc complexes. The lowest tT values exhibited in PBS solution are likely due to the fact that the triplet state of MPcs can be quenched by water, in addition to aggregation. The slight increase of tT values in the presence of CEL may be due to less exposure of the Pc to the aqueous medium as well as a decrease in aggregation [94]. It is important to note that the triplet states of MPc complexes are quenched by oxygen, hence deoxygenation is important for the accurate determination of triplet lifetimes [43]. Values of tT for ZnPc(SO3)mix complexes in general are very low in PBS solution compared to in DMSO [16, 38]. This was explained in terms of the near IR spectra of the solvents. The near IR absorption spectra of DMSO and H2O, and how these affect the triplet and singlet oxygen lifetimes in solution [16], has been described as stated above. The triplet state energy of ZnPc and many of its derivatives in solution is ~1.12 eV [12], which corresponds to an absorption wavelength of ~1108 nm. The intensity and broadness of the solvent absorption in this wavelength region should have a considerable effect on the triplet lifetime. H2O shows a very broad absorption band near 1108 nm, which implies that non-radiative decay and quenching
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of the sensitizer’s triplet state would be more rapid in H2O than in DMSO where absorption at 1108 nm is minimal. The triplet lifetimes are generally very low and triplet quantum yield values are high for the CdPc derivatives due to the heavy atom effect (Table 4.1). The substitution of the CdPc complexes with different substituents such as phenoxy, tertbutylphenoxy or benzyoxyphenoxy groups decreased the FT values in DMSO, except for 2-hydroxypyridine substitution (Table 4.1) [40, 107, 127]. The substituted HgPc complex with 2-hydroxypyridine groups (FT = 0.90 in DMF, FT = 0.89 in DMSO) at peripheral tetra-positions on the Pc ring showed slightly higher FT values than unsubstituted HgPc complex (FT = 0.86 in DMF, FT = 0.87 in DMSO) in both DMF and DMSO [107]. As expected, the HgPc complex containing 2-hydroxypyridine substituents at peripheral tetra-positions has the lowest triplet lifetime when compared to the corresponding ZnPc and CdPc complexes. The order of triplet lifetimes with respect to the central metal ions is Zn(II) (tT=350 ms) >Cd(II) (tT=30 ms) >Hg(II) (tT=20 ms) in DMSO (Table 4.1). There was little effect of the degree of sulfonation on triplet lifetimes [91, 131], when considering the same solvent [tT=520 ms for ClAl(III)Pc(SO3)2, tT=490 ms for ClAl(III)Pc(SO3)3 and tT=530 ms for ClAl(III)Pc(SO3)4 in PBS or tT=1130 ms, 1150 ms and 1140 ms, respectively in D2O)], in Table 4.1. A large tT value was obtained for ClAl(III)Pc(SO3)2 in CD3OD (tT=1440 ms) [131] compared to tT =550 ms in pH 7.4 buffer or 775 ms in methanol [7, 89, 134, 135]. For both ClGa(III)Pc and ClIn(III)Pc derivatives substituted with phenoxy, tertbutylphenoxy [142] and benzyloxyphenoxy groups [137], there was a change in absorption spectra following laser irradiation. The spectral changes involved a decrease in the Q band and an increase in absorption near 590 nm. However, upon exposure of the solution to air, the Q-band increased in intensity and the band around 590 nm decreased suggesting that this band was due to reduction products of the complexes. The first ring reduction in MPc complexes was characterized by a decrease in the Q-band and the formation of weak bands around 500–600 nm [181]. Thus during laser irradiation, these ClGa(III)Pc and ClIn(III)Pc derivatives were partly transformed into an anion (Pc−3) species. The suggested mechanism for the formation of Pc−3 in the presence of H donors is shown by Eqs. 4.13–4.15:
3
MPc + hν ®3 MPc *
(4.13)
MPc * + S - H ® MPc• - + S - H• +
(4.14)
MPc • - + O2 ® MPc + O2 • S = solvent
(4.15)
For a series of indium and gallium phthalocyanine complexes, the ClIn(III)Pc complexes (FT = 0.91 for unsubstituted ClIn(III)Pc complex in DMSO as an example) were found to have higher triplet quantum yields compared to the corresponding ClGa(III)Pc complexes (FT = 0.69 for unsubstituted ClGa(III)Pc complex in DMSO as an example), due to the heavy atom effect of In. On the contrary, the
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triplet lifetimes of ClIn(III)Pc complexes (tT = 50 ms for unsubstituted ClIn(III)Pc complex in DMSO as an example) much lower than corresponding ClGa(III)Pc complexes (tT = 200 ms for unsubstituted ClGa(III)Pc complex in DMSO as an example) (Table 4.1) [130, 137, 142]. The FT values of unsubstituted ClAl(III)Pc, ClGa(III)Pc and ClIn(III)Pc complexes increased with the size of the central metal as follows: ClAl(III) (FT =0.4)
ClGa(III) (FF =0.31) >ClIn(III) (FF =0.031) in 1-chloronaphthalene due to the heavy atom effect [130]. Peripherally or non-peripherally tetra-3-hydroxypyridine substituted ClIn(III)Pc and their quaternized complexes gave shorter lifetimes and correspondingly larger triplet quantum yields (FT) when compared to corresponding ClGa(III)Pc derivatives in DMSO (Table 4.1), due to the enhanced intersystem crossing induced by the larger In central metal. The FT value for the quaternized ClIn(III)Pc complexes tetrasubstituted with 3-hydroxypyridine substituents at peripheral positions (FT =0.94) was very high in DMSO [139, 140, 150]. In DMSO, FT value for the quaternized octasubstituted ClIn(III)Pc containing 3-hydroxypyridine as substituent, (FT =0.68) is larger than that in water with Triton X-100 (FT =0.59), which is attributed to increased intermolecular interaction in water compared to that in DMSO [151]. Even in the presence of Triton X-100, some level of aggregation still exists for ClIn(III)Pc complexes containing the 3-hydroxypyridine substituent in water. The triplet lifetime values for the ClIn(III)Pc complexes substituted with 3-hydroxypyridine were lower in water when compared to DMSO due to the aggregation in water, and this was also due to absorption by water at the same wavelength as triplet state of MPc complexes [150, 151]. tT values for the peripherally or non-peripherally tetra3-hydroxypyridine substituted ClIn(III)Pc complexes were similar to those of the corresponding quaternized derivatives in DMSO. Addition of Triton X-100 increased the tT values in water for these ClIn(III)Pc complexes. [150, 151] Triplet state lifetimes of the peripherally octa-phenoxy substituted axially ligated X2Si(IV)Pc complexes (X = Cl, OH, methylsulphonic acid, trihexylsilanol, triphenylsilanol, 1-naphtol, 4-aminophenol) vary according to the degree of aggregation, with the aggregated complex (containing OH as axially ligands) showing a shorter lifetime compared to the rest of the complexes in the series (ranging from 179 to 356 ms in DMSO) in Table 4.1. The FT values for these Si(IV)Pc complexes were low, ranging from 0.29 to 0.43 (Table 4.1) [163]. The sulfonated germanium(IV) phthalocyanine complexes showed relatively high FT (ranging from 0.84 to 0.61) and long tT values (ranging from tT = 180 ms to 760 ms), except for tT value of (OH)2Ge(IV)Pc(SO3)mix in PBS solution (tT = 2.76 ms) [38, 93, 166]. The octa-substituted (such as phenoxy, 2-methylphenoxy or estrone) (Cl)2Ge(IV)Pc complexes also showed high FT values and long tT values in DMSO (Table 4.1) [20]. In general, the FT values of tin(IV) phthalocyanine complexes are high, but the tT values are low in DMSO, PBS or PBS+TX solutions (Table 4.1) due to heavy atom effect of tin metal. Tin(IV)Pc complex containing estrone group as an axial ligand showed very short triplet lifetimes (tT = 18 ms), and uncharacteristically low triplet quantum yields (FT =0.08) [20, 38, 169].
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The F T and t T values of non-peripherally tetra-, peripherally tetra-, and octa-phenoxy, tert-butylphenoxy and benzyloxyphenoxy substituted lead phthalocyanines in DMSO, DMF and toluene are studied in the literature [170, 171]. Generally, these complexes have high FT values (ranging from 0.70 to 0.88), but low tT values (ranging from 5 to 50 ms) due to effect of the heavier lead atom as central metal. Unsubstituted and substituted antimony(III) phthalocyanine complexes showed high FT values and low tT values like other phthalocyanine complexes contain heavier central atoms such as tin or lead [172]. There have only one study about photophysical and photochemical properties of phosphorus phthalocyanine complexes in the literature. PPc complexes exhibit FF values which are typical of MPc complexes in general, but also show low FT values (Table 4.1). The axial substitution with phenoxy group decreased FT value, but increased tT value of PPc complex in DMSO [174].
4.7
Conclusion
The importance of photochemical and photophysical parameters of photosensitizers has been evidenced through this chapter. Their determination by different methods as well as the required equipments has been presented and the electronic events implied in each parameter are explained. Representative data for phthalocyanines are reviewed in a Table 4.1. This made hopeful this chapter useful to both students and experts in the field.
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10. Zorlu Y, Dumoulin F, Durmuş M, Ahsen V (2010) Comparative studies of photophysical and photochemical properties of solketal substituted platinum(II) and zinc(II) phthalocyanine sets. Tetrahedron 66:3248–3258 11. Grossweiner LI, Jones LR, Grossweiner JB, Rogers BHG (2005) The science of phototherapy: an introduction. Springer, Dordrecht 12. Bonnett R (2000) Chemical aspects of photodynamic therapy. Gordon and Breach Science, Amsteldijk, pp 199–222 13. Patterson MS, Madsen SJ, Wilson R (1990) Experimental tests of the feasibility of singlet oxygen luminescence monitoring in vivo during photodynamic therapy. J Photochem Photobiol B Biol 5:69–84 14. Foley S, Jones G, Liuzzi R, McGarvey DJ, Perry HM, Truscott TG (1997) The synthesis and photophysical properties of polyether substituted phthalocyanines of potential use in photodynamic therapy. J Chem Soc Perkin Trans 29:1725–1730 15. Rosenthal I, Ben-Hur E (1995) Role of oxygen in the phototoxicity of phthalocyanines. Int J Radiat Biol 67:85–91 16. Ogunsipe A, Chen JY, Nyokong T (2004) Photophysical and photochemical studies of zinc(II) phthalocyanine derivatives—effects of substituents and solvents. New J Chem 28:822–827 17. Kuznetsova NA, Gretsova NS, Derkacheva VM, Mikhalenko SA, Solov’eva LI, Yuzhakova OA, Kaliya OL, Luk’yanets EA (2002) Generation of singlet oxygen with anionic aluminum phthalocyanines in water. Russ J Gen Chem 72:300–306 18. Shen T, Yuan ZL, Xu HY (1989) Fluorescent properties of phthalocyanines. Dyes Pigm 11:77–80 19. Maree D, Nyokong T, Suhling K, Phillips D (2002) Effects of axial ligands on the photophysical properties of silicon octaphenoxyphthalocyanine. J Porphyrins Phthalocyanines 6:373–376 20. Maree S, Phillips D, Nyokong T (2002) Synthesis, photophysical and photochemical studies of germanium and tin phthalocyanine complexes. J Porphyrins Phthalocyanines 6:17–25 21. Atilla D, Durmuş M, Gürek AG, Ahsen V, Nyokong T (2007) Synthesis, photophysical and photochemical properties of poly(oxyethylene)-substituted zinc phthalocyanines. Dalton Trans 2007:1235–1243 22. Seotsanyana-Mokhosi I, Kuznetsova N, Nyokong T (2001) Photochemical studies of tetra-2, 3-pyridinoporphyrazines. J Photochem Photobiol A Chem 140:215–222 23. Ogunsipe A, Maree D, Nyokong T (2003) Solvent effects on the photochemical and fluorescence properties of zinc phthalocyanine derivatives. J Mol Struct 650:131–140 24. Fernandez JM, Bilgin MD, Grossweiner LI (1997) Singlet oxygen generation by photodynamic agents. J Photochem Photobiol B Biol 37:131–140 25. Grossweiner LI (1995) Photodynamic therapy. J Laser Appl 7:51–57 26. Moan J, Wold E (1979) Detection of singlet oxygen production by ESR. Nature 279:450–451 27. Lavi R, Sinyakov M, Samuni A, Shatz S, Friedmann H, Shainberg A, Breitbart H, Lubart R (2004) ESR detection of 1O2 reveals enhanced redox activity in illuminated cell cultures. Free Radic Res 38:893–902 28. Schnurpfeil G, Sobbi AK, Spiller W, Kliesch H, Wöhrle D (1997) Photo-oxidative stability and its correlation with semi-empirical MO calculations of various tetraazaporphyrin derivatives in solution. J Porphyrins Phthalocyanines 1:159–167 29. Ozoemena K, Kutznetsova N, Nyokong T (2001) Comparative photosensitised transformation of polychlorophenols with different sulphonated metallophthalocyanine complexes in aqueous medium. J Mol Catal A Chem 176:29–40 30. Spiller W, Kliesch H, Wöhrle D, Hackbarth S, Roder B, Schnurpfeil G (1998) Singlet oxygen quantum yields of different photosensitizers in polar solvents and micellar solutions. J Porphyrins Phthalocyanines 2:145–158 31. Ozoemena K, Kutznetsova N, Nyokong T (2001) Photosensitized transformation of 4-chlorophenol in the presence of aggregated and non-aggregated metallophthalocyanines. J Photochem Photobiol A Chem 139:217–224
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153. Li YS, Zaidi SIA, Rodgers MAJ, Mukhtar H, Kenney ME, Oleinick NL, He J, Hedy E, Larkin HE, Rihter BD (1997) The synthesis, photophysical and photobiological properties and in vitro structure-activity relationships of a set of silicon phthalocyanine pdt photosensitizers. Photochem Photobiol 65:581–586 154. Jiang XJ, Yeung SL, Lo PC, Fong WP, Ng DKP (2011) Phthalocyanine-polyamine conjugates as highly efficient photosensitizers for photodynamic therapy. J Med Chem 54:320–330 155. Jiang XJ, Lo PC, Yeung SL, Fong WP, Ng DKP (2010) A pH-responsive fluorescence probe and photosensitiser based on a tetraamino silicon(IV) phthalocyanine. Chem Commun 46:3188–3190 156. Lo PC, Huang JD, Cheng DYY, Chan EYM, Fong WP, Ko WH, Ng DKP (2004) New amphiphilic silicon(iv) phthalocyanines as efficient photosensitizers for photodynamic therapy: synthesis, photophysical properties, and in vitro photodynamic activities. Chem Eur J 10:4831–4838 157. Lo PC, Chan CMH, Liu JY, Fong WP, Ng DKP (2007) Highly photocytotoxic glucosylated silicon(IV) phthalocyanines. Effects of peripheral chloro substitution on the photophysical and photodynamic properties. J Med Chem 50:2100–2107 158. Farren C, FitzGerald S, Bryce MR, Beeby A, Batsanov AS (2002) Synthesis, structure and optical characterisation of silicon phthalocyanine bis-esters. J Chem Soc Perkin Trans 2:59–66 159. Jiang XJ, Huang JD, Zhu YJ, Tang FX, Ng DKP, Sun JC (2006) Preparation and in vitro photodynamic activities of novel axially substituted silicon (IV) phthalocyanines and their bovine serum albumin conjugates. Bioorg Med Chem Lett 16:2450–2453 160. Liu JY, Ermilov EA, Röder B, Ng DKP (2009) Switching the photo-induced energy and electrontransfer processes in BODIPY–phthalocyanine conjugates. Chem Commun 1517–1519 161. Ermilov EA, Liu JY, Ng DKP, Röder B (2009) Spectroscopic study of electron and energy transfer in novel silicon phthalocyanine—boron dipyrromethene triads. Phys Chem Chem Phys 11:6430–6440 162. Lee PPS, Lo PC, Chan EYM, Fong WP, Ko WH, Ng DKP (2005) Synthesis and in vitro photodynamic activity of novel galactose-containing phthalocyanines. Tetrahedron Lett 46:1551–1554 163. Maree DM, Kuznetsova N, Nyokong T (2001) Silicon octaphenoxyphthalocyanines: photostability and singlet oxygen quantum yields. J Photochem Photobiol A Chem 140:117–125 164. Huang JD, Wang S, Lo PC, Fong WP, Ko WH, Ng DKP (2004) Halogenated silicon(IV) phthalocyanines with axial poly(ethylene glycol) chains. Synthesis, spectroscopic properties, complexation with bovine serum albumin and in vitro photodynamic activities. New J Chem 28:348–354 165. Lo PC, Wang S, Zeug A, Meyer M, Roder B, Ng DKP (2003) Preparation and photophysical properties of halogenated silicon(IV) phthalocyanines substituted axially with poly(ethylene glycol) chains. Tetrahedron Lett 44:1967–1970 166. Idowu M, Nyokong T (2008) Photophysical and photochemical properties of tetrasulfonated silicon and germanium phthalocyanine in aqueous and non-aqueous media. J Photochem Photobiol A Chem 197:273–280 167. Idowu M, Nyokong T (2009) Photophysicochemical and fluorescence quenching studies of tetra- and octa-carboxy substituted silicon and germanium phthalocyanines. J Photochem Photobiol A Chem 204:63–68 168. Gunaratne T, Kennedy VO, Kenney ME, Rodgers MAJ (2004) Photophysics of octabutoxy phthalocyaninato-Ni(II) in toluene: ultrafast experiments and DFT/TDDFT studies. J Phys Chem A 108:2576–2582 169. Idowu M, Nyokong T (2008) Synthesis, photophysics and photochemistry of tin(IV) phthalocyanine derivatives. J Photochem Photobiol A Chem 199:282–290 170. Modibane D, Nyokong T (2008) Synthesis and photophysical properties of lead phthalocyanines. Polyhedron 27:1102–1110 171. Modibane KD, Nyokong T (2009) Synthesis, photophysical and nonlinear optical properties of microwave synthesized 4-tetra and octa-substituted lead phthalocyanines. Polyhedron 28:1475–1480
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172. Modibane D, Nyokong T (2009) Synthesis, photophysical and photochemical properties of octa-substituted antimony phthalocyanines. Polyhedron 28:479–484 173. Isago H, Miura K, Oyama Y (2008) Synthesis and properties of a highly soluble dihydoxo(tetra-tert-butylphthalocyaninato)antimony(V) complex as a precursor toward water-soluble phthalocyanines. J Inorg Biochem 102:380–387 174. Antunes E, Nyokong T (2009) Synthesis and photophysical behavior of axially substituted phthalocyanine, tetrabenzotriazaporphyrin, and triazatetrabenzcorrole phosphorous complexes. J Porphyrins Phthalocyanines 13:153–160 175. Gerhardt SA, Lewis JW, Zhang JZ, Bonnett R, McManus KA (2003) Photophysical behaviour of an opp-dibenzoporphyrin (2, 12-diethyl-3,13-dimethyldibenzo[g, q]porphyrin) in micelles and organic solvents. Photochem Photobiol Sci 2:934–938 176. Nyokong T (2007) Effects of substituents on the photochemical and photophysical properties of main group metal phthalocyanines. Coord Chem Rev 251:1707–1722 177. Stuzhin PA (1999) Azaporphyrins and phthalocyanines as multicentre conjugated ampholites. J Porphyrins Phthalocyanines 3:500–513 178. Lukyanets EA (1999) Phthalocyanines as photosensitizers in the photodynamic therapy of cancer. J Porphyrins Phthalocyanines 3:424–432 179. Daziano JP, Steenken S, Chabannon C, Mannoni P, Chanon M, Julliard M (1996) Photophysical and redox properties of a series of phthalocyanines: relation with their photodynamic activities on TF-1 and Daudi leukemic cells. Photochem Photobiol 64:712–719 180. Tran Thi TH, Desforge C, Thiec C, Gaspard S (1989) Singlet-singlet and triplet-triplet intramolecular transfer processes in a covalently linked porphyrin-phthalocyanine heterodimer. J Phys Chem 93:1226–1233 181. Mack J, Stillman MJ (2003) Electronic structures of metal phthalocyanine and porphyrin complexes from analysis of the UV-Visible absorption and magnetic circular dichroism spectra and molecular orbital calculations. In: Kadish KM, Smith KM, Guilard R (eds) The porphyrin handbook, vol 16. Academic Press, New York, pp 43–113
Chapter 5
Sensitization of Singlet Oxygen Formation in Aqueous Media Nina Kuznetsova
Abstract Photosensitized oxidation, mediated by singlet molecular oxygen (1O2) in aqueous or biological media, is of great importance for number of environmental and medical applications. However, sensitization of 1O2 formation and its reactivity in aqueous media have certain limitations, first of all owing to the extremely low 1O2 lifetime and intermolecular interactions of different nature. Methodologies for the quantification of 1O2 production and sensitizers, applicable for aqueous media, are considered with particular focus on factors, affecting photosensitizer ability in aqueous and biological environment.
5.1
Introduction
Many processes involving excited singlet oxygen, 1O2 (1Dg), occur in aqueous solution. Thus, 1O2 plays a leading role in degradation of pollutants and natural compounds under sunlight in natural surface waters. Formation of 1O2 in surface waters results from the photochemical excitation of natural substances, such as fulvic or humic acids and riboflavines ([1, 2] and refs. therein). Sensitization of singlet oxygen formation was suggested for wastewater treatment [3–5] and laundry bleaching [6]. In the last two decades, the applications of singlet oxygen sensitizers have expanded to biological systems for photodynamic therapy of cancer [7] and antimicrobial therapy [8, 9], as well as blood sterilization [10]. In biological systems the photodynamic processes occur in predominantly aqueous environment and also require water solubility of the sensitizers.
N. Kuznetsova (*) Federal State Unitary Enterprise “State Scientific Centre “Organic Intermediates and Dyes Institute” (FSUE“SSC”NIOPIK)”, B. Sadovaya str., 1, block 4, Moscow 123995, Russia e-mail: [email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_5, © Springer Science+Business Media B.V. 2012
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It was established that photodynamic action in biological systems proceeds in one or two ways known as Type I and Type II mechanisms. A Type I mechanism involves hydrogen-atom abstraction or electron-transfer between the excited sensitizer and a substrate, forming free radicals. These radicals can then react with ground-state oxygen to form an active species such as the superoxide radical anion. In a Type II mechanism, singlet oxygen is generated via an energy transfer from the sensitizer in excited triplet state to the ground-state (triplet) oxygen. Although both mechanisms can occur, the singlet oxygen is known to play a key role in photodynamic processes in biological systems. However, sensitization of 1O2 formation and its reactivity in aqueous media have certain limitations, first of all owing to the extremely low 1O2 lifetime and intermolecular interactions of different nature. Accordingly, it is of immense importance to know factors, influencing application of sensitizers in aqueous and biological media. A large body of literature now exists concerning the singlet oxygen generating abilities of a variety of compounds that can be photoactivated in the UV and visible regions of the spectrum. Reviews [11, 12] give a compilation of singlet oxygen yields up to 1999. A review by DeRosa and Crutchley [13] provides the photophysical properties of singlet oxygen and of the photosensitizers used in its generation. A recent review provides singlet oxygen quantum yields of metallophthalocyanine complexes containing main group metals and some unmetallated phthalocyanines [14]. Wohrle et al. [3] surveyed the works of author’s group on the photooxidation of toxic mercaptans and phenols in water under sensitization with low molecular weight and heterogenized phthalocyanines. However not much data one can find there on the singlet oxygen quantum yields (FD) in aqueous media owing to sensitizer aggregation and difficulties, which exist in determining FD in aqueous solution. Due to these reasons the FD values for water-soluble sensitizers often are evaluated in nonaqueous solutions [15, 16]. The present review focuses on the generation of singlet oxygen by water-soluble sensitizers in aqueous media. It will begin with a survey of mechanisms and methods for singlet oxygen quantification, followed by the overview of sensitizers, applicable for water solutions. Finally, the factors affecting singlet oxygen photogeneration in aqueous media will be discussed. The section on applications will explore the literature regarding the use of singlet oxygen in aqueous and biological systems.
5.2
Mechanisms of Singlet Oxygen Photosensitization
Photosensitization is a simple method for the production of singlet oxygen, when 1 O2 is produced upon illumination of sensitizer (as a rule, dye) in aerobic conditions. The comprehensive overview of current knowledge about mechanisms of singlet oxygen sensitization recently was given by Schmidt [17]. In a historical account by A. A. Krasnovsky Jr. [18] it is noted that Terenin (in 1943) indicated that the spin conservation rule (the Wigner rule) allows two mechanisms of 1O2 generation by photoexcited dye molecules.
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The first mechanism (Eq. 5.1) consists in 1O2 formation in process of energy transfer to oxygen from the sensitizer in excited singlet state. The first mechanism can only operate for relatively small group of photosensitizers, for which the energy gap between 1Sens* and 3Sens (DEST) is larger than energies of the singlet states of oxygen. Sensitization by excited singlet state is the dominant way of 1O2 formation for strongly fluorescing compounds with low triplet quantum yields. It is of interest that this mechanism suggests that two molecules of singlet oxygen can be generated by one sensitizer molecule and maximum value of FD can be 2. 1
( )
( )
( )
( )
(5.1)
( )
( )
( )
( )
(5.2)
Sens * ↑↓ + 3 O2 ↑↑ →3 Sens ↑↑ +1 O 2 ↑↓ 3
Sens ↑↑ + 3 O 2 ↓↓ →1 Sens ↑↓ +1 O 2 ↑↓
where 1Sens, 1Sens* and 3Sens are molecules of photosensitizers in the ground and excited singlet and triplet states. The second mechanism (sensitization by excited triplet states, Eq. 5.2) is the major process of singlet oxygen generation for most compounds, whose triplet levels are higher than the singlet levels of oxygen. Since 1O2(1Dg) lies 0.98 eV (94 kJ/mol) above the triplet ground state, the energy difference between 3S* and S0 of the sensitizer should be above this value to allow the generation of singlet oxygen. This prerequisite holds for most sensitizers. It has recently been demonstrated that singlet oxygen can also be produced upon nonlinear two-photon excitation of a sensitizer [19]. In this case, an upper excited state Sm is produced by the simultaneous absorption of two lower-energy photons. Irrespective of whether the excitation is mono- or biphotonic, fast relaxation of Sm to the lowest excited S1 and T1 states will take place. Because the processes leading to singlet oxygen sensitization originate from S1 and T1, the principal difference between mono- and two-photon sensitizers is the kind of excitation. The NIR-induced two-photon sensitization of singlet oxygen was suggested for photodynamic therapy (PDT) [17]. At present a few research groups are concentrated on the development of water-soluble sensitizers with enhanced two-photon absorption in the so-called body therapeutic window (700–900 nm) [19, 20]. It has been ascertained that, in a given sensitizer or sensitizer-oxygen complex, significant charge-transfer character can adversely affect singlet oxygen yields by providing an independent pathway for the deactivation of the sensitizer excited states by charge-transfer that competes with energy transfer to oxygen. The extent to which this charge-transfer character is manifested is greater in the more polar solvent. Thus, in comparison to quantum yields measured in other solvents, the data obtained in water may be smaller. One should bear in mind also that molecules of water-soluble photosensitizers generally have a reasonable amount of charge transfer due to presence of charged functional groups, and as such, these molecules unfortunately do not generate singlet oxygen in high yield.
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Methods for Quantification of Singlet Oxygen in Aqueous Media
The important photophysical parameter that determines the photosensitizing ability of a compound is the singlet oxygen quantum yield (FD). The FD is the probability that a photosensitizer, after absorbing a quantum of light, converts to the T1-state and then transfers its energy to 3O2, thus causing the formation of 1O2. The magnitude of FD is defined as a ratio between the number of generated singlet oxygen molecules, NSO (per time unit) and the number of photons absorbed by sensitizer, Nhn(abs), (per time unit): dN so
ΦΔ =
dt dN hv ( abs ) dt
(5.3)
In order to determine FD different methods have been applied which can be separated into photophysical and photochemical measurements [21]. The most applied photophysical method is the direct measurement of the singlet oxygen phosphorescence around 1,270 nm. The photophysical techniques which follow non-radiative relaxation of excited species such as laser-induced optoacoustic calorimetry and the photothermal method of time-resolved thermal lensing are less common. Difficulties exist, however, in determining FD values by all these methods in aqueous solution, primarily because of problems arising from the physical-chemical properties of 1O2 in water. Thus, the short lifetime of 1O2 in water (3.09 ± 0.06 ms [22], 1–2 orders of magnitude shorter than in other solvents) severely complicates detection of 1O2 in aqueous solutions using measurement of infrared phosphorescence at 1,270 nm corresponding to transition of oxygen molecules from the singlet to the ground (triplet) state. The laser-induced optoacoustic calorimetry and the photothermal method of time-resolved thermal lensing have reduced sensitivity in water due to unfavorable physical properties of this solvent (e.g. high specific heat capacity, low thermal expansion coefficient and low change in refractive index with temperature) [23]. Thus, watersoluble sensitizers have been largely investigated by indirect chemical methods using photoinduced bleaching of substrates which show selectivity for 1O2. The photochemical methods do not require expensive equipment and can be carried out easily. A most common methods employed for the singlet oxygen quantum yields estimation are characterized below. ESR spectroscopy. The heterocyclic amine 2,2,6,6-tetramethyl-4-piperidone (4-oxo-TEMP) can react with 1O2 to yield a nitroxide, i.e. 2,2,6,6-tetramethyl-4piperidone-N-oxyl radical (4-oxo-TEMPO, Scheme 5.1), which can be detected by ESR spectroscopy. In aqueous solution only neutral 4-oxo-TEMP molecules react with 1O2. Since 4-oxo-TEMP has a pK value of 7.6, it may be used in neutral solutions. However when using this method to monitor singlet oxygen yields in different aqueous solutions, pH should be carefully controlled [24]. It was shown that although O2•¯ or •OH react with 4-oxo-TEMP, these radicals do not convert 4-oxo-TEMP to 4-oxo-TEMPO, which suggests a high specificity of this method for 1O2 [25].
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Scheme 5.1
271
O
O +
1
O2
N
N
H
O
4-oxo-TEMP
4-oxo-TEMPO
Chemical trapping methods are based on the reaction of 1O2 with a singlet oxygen sensitive compound. The trap must be highly reactive towards 1O2, specific, soluble in water and transparent in the spectral range of the incident light. The 1O2 formation can be seen from consumption of the trap, accumulation of specific oxygenation products or from oxygen depletion in trap-containing systems. From the viewpoint of experimental convenience, it is desirable to use a singlet oxygen monitor, whose decay can be followed spectroscopically. Common traps of singlet oxygen in nonaqueous solvents (1,3-diphenylisobenzofuran and 9,10-dimethylanthracene) meet this requirement, however are virtually insoluble in water. A short review of 1O2 traps, suggested for aqueous solutions, was given by Nardello et al. [26]. Kraljic and Mohsni [27] described a simple spectrophotometric method to detect 1 O2, based upon the bleaching of N,N-dimethyl-4-nitrosoaniline at 440 nm by the transannular peroxide intermediate, formed by the reaction between the photogenerated singlet oxygen and imidazole or histidine. This method gives acceptable results in neutral aqueous solutions and was used in early studies [28, 29]. The series of anthracene derivatives [30–32] were suggested for aqueous solutions. Kuznetsova et al. [32] proposed for this purpose the use of water-soluble anthracene with four carboxy groups – tetrasodium anthracene-9,10-bis-methylmalonate (ADMA). The disappearance of ADMA, as the corresponding endoperoxide forms after reaction with singlet oxygen, can be easily followed by its absorption decay at 380 nm. This compound was applied for FD determination in number of studies [33–35].
COONa
Cl
N(CH3)3
Cl
N(CH3)3
COONa
NaOOC NaOOC ADMA
BPAA
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Most of the water-soluble traps described in the literature bear anionic functions (COO− and SO3−) and can not be used with cationic sensitizers because of the formation of ion pair complexes. Typical anionic traps such as ADMA interact with cationic sensitizer modifying the absorption spectrum and, hence, its efficiency as photosensitizer. Several cationic polycyclic aromatic compounds bearing watersolubilizing quaternary ammonium groups have been studied as singlet oxygen traps for singlet oxygen, generated by cationic sensitizers [36, 37]. The appropriate cationic water-soluble trap, bis 9,10-anthracene(4-trimethylphenylammonium) dichloride (BPAA), was suggested by Nardello and Aubry [38]. The presence of two phenyl groups in the 9,10 positions enhances its reactivity towards 1 O2. The high water solubility (>10−2 M) was obtained by grafting two quaternary ammonium functions which do not interfere with 1O2. BPAA is readily detectable by UV/visible spectroscopy in the spectral range 320–420 nm by three bands characteristic for its anthracenic core. The processes of trap reactivity with 1O2 can be represented by a scheme generally accepted for sensitized photooxidation of acceptor A with singlet oxygen: 3
S* + 3 O2 → 1S0 + 1O2 3
(5.4)
kd O2 ⎯⎯ → O2
(5.5)
kr A + 1O2 ⎯⎯ → AO 2
(5.6)
kq A + 1O2 ⎯⎯ → A + 3 O2
(5.7)
1
When 1O2 is generated in an aqueous solution of trap A (Eq. 5.4), it can disappear according to three main pathways (Eqs. 5.5–5.7). The process (5.5) is the deactivation of 1O2 by solvent (kd = 1/tD = 3.24 × 105 s−1 in H2O [22]). The two others are the chemical (Eq. 5.6) and the physical (Eq. 5.7) quenching of 1O2 with trap A. For the above scheme, under pseudo-stationary conditions (d[1O2]/dt = 0) the following relation is valid: ΦAO 2 = ΦΔ
kr [ A] kd + kr [ A] + kq [ A]
(5.8)
Here ΦAO 2 is the quantum efficiency of acceptor A photooxidation; FD is the singlet oxygen quantum yield for sensitizer S. Equation 5.8 admits two simplifications. If kr >> kq (holds for singlet oxygen traps) and kr[A] >> kd + kq[A] (all the singlet oxygen formed is trapped by acceptor) the reaction is zero-order with respect to A, and ΦAO 2 = FD. Such a situation may occur when the reaction takes place in D2O in which the lifetime of 1O2 is relatively long (68 ms [39]). Since in ordinary water, the kd of 1O2 is rather high (3.24 × 105 s−1), conditions with kr[A] >> kd + kq[A] are inaccessible. Then one should use low concentrations of A, meeting kr[A] + kq[A] << kd prerequisite. Under such conditions, the disappearance of A follows an exponential law, and Eq. 5.8 transforms into formula (5.9),
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Fig. 5.1 Typical set-up for singlet oxygen quantification by the photochemical trapping method: (A) lamp, (B) light rectifier, (C) circulating water chamber — absorbs IR radiation, (D) shutter, (E) monochromatic light filter, (F) reaction cell, (G) pH probe and (H) magnetic stirrer (Reproduced from Ref. [40] with kind permission of Elsevier)
from which relation (5.10) is obtained for determination of FD by the relative procedure. Any water-soluble sensitizer S with known singlet oxygen quantum yield may be used as reference. ΦΔ = ΦAO 2 ΦΔ = ΦΔref
ΦAO 2 ref ΦAO 2
kd kr [ A]
= ΦΔref
w × I ref wref × I
(5.9)
(5.10)
where w and wref are the rates of consumption of the 1O2 acceptor in the presence of the compound being tested and reference, respectively; I and Iref are the numbers of light quanta taken up in unit time by the sensitizer being tested and reference, respectively. This method is less accurate (±15%) than the previous one, as it is limited by the ΦΔref precision. The relative method for singlet oxygen quantum yield determination has the advantage of consuming a small amount of trap and avoiding the problems of oxygen depletion during irradiation. It was successfully applied for number of both anionic and cationic sensitizers in aqueous media. Chemical trapping methods are simple and highly sensitive. However, their reliability in some cases is limited by the fact that chemical traps interact, besides 1O2, with free radicals, peroxides and excited molecules of photosensitizers. Figure 5.1 shows the typical set-up for singlet oxygen quantification by the photochemical trapping method, the main parts of which are the visible light source and monochromatic light filter. The photosensitized phosphorescence of 1O2 (1Dg,). The quantum yields of singlet oxygen photogeneration by dye molecules are determined from comparison of intensities of the overall singlet oxygen phosphorescence at 1,270 nm in solutions of the tested dyes and the reference. In 1982–1983 set-ups appeared, which allowed microsecond time-resolution and reliable detection of the decays of photosensitized 1O2 phosphorescence after laser shots in organic solvents and deuterium oxide [41]. However, the use
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Fig. 5.2 Functional layout of the laser phosphorescence spectrometer with nanosecond resolution (Reproduced from Ref. [42] with kind permission of Pleiades Publishing)
of this equipment for investigation of singlet oxygen in aqueous sensitizer solutions was not quite successful. Later (after 1988), this equipment has been additionally improved by using better laser generators and electronic registration systems for nanosecond time-resolved measurements of 1O2 phosphorescence in aqueous solutions [22]. Figure 5.2 shows the functional layout of the nanosecond laser set-up, developed by A. A. Krasnovsky Jr. in the A. N. Bach Institute of Biochemistry, Russian Academy of Sciences. This set-up allows detailed analysis of the singlet oxygen phosphorescence kinetic curves after short laser shots in air-saturated water [41]. Since 1997, Hamamatsu Photonics Company started to manufacture similar set-ups, they are presently employed in many laboratories. At present, measurements of photosensitized 1O2 phosphorescence in water are widely used for photochemistry and photobiology research.
5.4
Types of Water-Soluble Sensitizers and Their Efficacy in Singlet Oxygen Production
For aqueous media homogeneous and heterogeneous sensitizers will be considered. Homogeneous photosensitizers are water-soluble, UV-/vis absorbing molecules that have shown singlet oxygen generating ability. The heterogeneous sensitizers of two
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types (immobilized on an insoluble support and on water-soluble nanoparticles) will also be mentioned. Owing to the extensive literature existing in this field, only the most representative examples of main groups of sensitizers will be considered.
5.4.1
Homogeneous Photosensitizers
Homogeneous photosensitizers should exhibit the following properties: (1) high water solubility; (2) high absorption of the excitation light; (3) energy of the excited triplet state above 94 kJ/mol (level of singlet oxygen); (4) high quantum yield of the triplet state (FT > 0.4); long triplet state lifetimes (tT > 1 ms); (5) high singlet oxygen quantum yields (FD > 0.3). As a rule, the skeletons of photosensitizers are hydrophobic. In order to obtain water solubility, various polar hydrophilic substituents are introduced in photosensitizers. Most common are sulfonic and carboxy acid groups, resulting in anionic photosensitizers; quaternary amino or pyridino groups lead to cationic ones. The presence of polyoxoethylene, hydroxyl or carbohydrate groups can result in neutral water-soluble photosensitizers. During the past few decades, different kinds of water-soluble photosensitizers have been synthesized and studied. Water-soluble aromatic hydrocarbons (napthalenes, anthracenes, biphenyls, quinones) have photosensitizer ability [13], however these compounds have low absorption in the visible spectral range, and their water-soluble derivatives have no significance as sensitizes for aqueous media. Interest has been paid to the small group of natural perylenequinones, of which the sulfonated derivatives, for example, 5-sulfonated hypocrellin [43] and hypericin tetrasulfonate [44], are water-soluble. The production of 1O2 on their photoexcitation have been confirmed, however FD values for aqueous solutions were not reported. OH
OH
O OCH3
HO3S CH3O
CH 3
CH3O
COCH3 OCH3 OH
O
Hypocrellin 5-sulfonate
O
OH
HO3 S
SO3H
H3C
OH
H3 C
OH SO3 H
HO3 S OH
O
OH
Hypericin tetrasulfonate
The groups of photosensitizers, most important for aqueous solutions, are the xanthene and phenothiazinium dyes, the porphyrins, phthalocyanines, and related macrocycles. The xanthene and phenothiazinium dyes such as Rose Bengal, Eosin, methylene blue are widely known water-soluble photosensitizers.
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N. Kuznetsova N (CH3)2N
Cl
S
N(CH3)2
Methylene Blue
Cationic photosensitizer methylene blue is a phenothiazinium dye with a strong absorbance in the range of 550–700 nm, and a significant singlet oxygen quantum yield (FD = 0.50–0.52 in alcohols and 0.47–0.49 in aqueous solutions [12]). Halogen substituted xanthene dyes are among the most important sensitizers. It is known that xanthene dyes as such have low quantum yield of the triplet states and, consequently, singlet oxygen quantum yields. Increasing the number and atomic mass of halogen substituents on the xanthene skeleton increases the yield of intersystem crossing to the triplet state of the dye. Halogen substituted derivatives of fluorescein and rhodamine are very effective in aqueous solutions. Anionic halogenated fluoresceins exhibit absorption band in the green area of the visible spectrum (480–550 nm). The FD values for Eosin (tetrabromofluorescein), Erythrosin (tetraiodofluorescein), and Rose bengal (tetrachlorotetraiodofluorescein) are well known and equal in H2O to 0.52, 0.63 and 0.75, respectively [13]. I
I Na
O
Br
O
O
I
I Cl
COO
Cl
Cl Cl
Na
H2N
Br O
NH2
X
COOCH3
Dibromorhodamine 123
Rose Bengal
Search for water-soluble photosensitizers of cationic nature with absorbance in the range of 500–600 nm was focused on Rhodamines. Rhodamine dyes are typically characterized by high quantum yields of fluorescence (FF ³ 0.9), low yields of the triplet state (FT < 0.1), and near-zero yields of singlet oxygen (FD £ 0.01) [45]. The introduction of heavy atoms (bromine or iodine) into the rhodamine molecule results in a decrease in the fluorescence intensity and in a significant increase in FT and FD. Thus, it has been shown that bromination of rhodamine 123 gives the FD increase for aqueous solutions from £0.02 for unsubstituted one to about 0.3 and 0.4 for mono- and dibromorhodamines 123, respectively. However, the introduction of bromine atoms into the rhodamine 123 molecule substantially decreases its solubility in water [46].
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The porphyrins are widely used as photosensitizers in PDT. The Soret band in the blue and the Q band in the red are major bands of their absorption spectra; however these bands have low extinction coefficients in the visible spectral region. The long-lived triplet states and high triplet quantum yields of many porphyrins allow for high singlet oxygen quantum yields, and substituents on the macrocycle, metal ions coordinated at its centre and ligands attached at axial position to the metal ion allow for tuning of the porphyrin properties. A well-studied porphyrin used in the photosensitized production of singlet oxygen is haematoporphyrin. Haematoporphyrin derivative, and its commercial analogues, such as Photofrin and Photoheme, are the first generation of photosensitizers for PDT. It was with these compounds that the first results and use in clinic for tumor treatment were obtained.
R N NH
CO2H
HN
R1
(1) R=R1= CH(OH)Me (2) R=R1= CH(OAc)Me
N
CO2H
Haematoporphyrin (HP, 1) is soluble in basic aqueous solutions due to ionization of two carboxylic groups. In neutral aqueous solution, HP can exist as monomeric species only up to a concentration of about 2 mM [47]. The haematoporphyrin derivative (HpD) was prepared in order to solubilize HP in neutral aqueous solution [13]. For this purpose HP is treated with mixture of sulfuric and acetic acid resulting in mixture with major component HP diacetate (2). This mixture is heated with sodium acetate to give HpD and Photofrin is prepared by removing the monomer fractions of HpD. In water at pH 7.4 HpD consists of a complex mixture of non-aggregated and self- and cross-aggregated monoporphyrinic and oligomeric species with FD of 0.64 and 0.11, respectively, for monomers and dimers [48]. Traditional approaches for imparting water solubility to synthetic porphyrins have relied on sulfonation of meso-aryl substituents or quaternization of mesopyridyl groups. Generally, these compounds, both free or metallated, tend to remain monomeric in solution [13, 49]. Photophysical properties of meso-substituted water-soluble porphyrins have been widely studied. For example, the quantum yield FD for meso-substituted tetrakis (4-sulfonatophenyl)porphyrin (TSPP), one of the most important water-soluble photosensitizers in current usage, in phosphate buffer (pH 7.4) at concentration ranging from 8 × 10−5 to 20 × 10−5 M is as
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N. Kuznetsova
high as 0.51 [ 50 ] . Cationic N-methylpyridyl-substituted porphyrin, TMPyP, is also an efficient water-soluble singlet oxygen sensitizer. This molecule produces singlet oxygen with a high quantum efficiency (FD = 0.77 [51]). TMPyP also has been shown to possess significant two-photon cross section and sensitize singlet oxygen in two-photon process [19]. Photophysical properties including FD values in methanol for a series of water-soluble asymmetric porphyrins with varying substituents, such as 4-hydroxyphenyl and N-methyl-4-pyridyl were established by Peng et al. [16].
SO3H
CH3 N
N
HO3 S
HN
NH
N
SO3H
TSPP
SO3H
N H3C
HN
N NH
N
N CH3
N CH3
TMPyP
In general, the quantum yields of 1O2 production by monomeric molecules of water- soluble metal-free porphyrins were shown to be equal to 0.65–0.77 independent of the side substituents. The high FD values of 60–100% are inherent to monomeric molecules of Zn-, Mg-, Al-, Sn-, Pd-porphyrin complexes, while Co-, Ni-, Mn-, and Fe-porphyrins are virtually inactive [52]. Chlorins and bacteriochlorins are the porphyrinic compounds that absorb strongly in the red and near-infrared regions, respectively. The singlet oxygen yield has been shown to be considerably high for this class of compounds [53]. A number of naturally occurring chlorins and bacteriochlorins have polar side chains. Chlorin e6 is a readily accessible derivative of chlorophyll a. The presence of three carboxylic acid groups along with substituents at nearly all the other peripheral positions of the macrocycle allow synthetic modification, so a number of water-soluble analogues have been prepared [54–57]. Chlorins e6 and p6 with ionizable –COOH groups exist as monomers at physiological pH, and this is important prerequisite for high efficacy in singlet oxygen photosensitization [58]. In oxygen-saturated phosphate buffer solution, Chlorin e6 has FD value 0.64 [59].
5
Sensitization of Singlet Oxygen Formation in Aqueous Media
NH
279
NH
N
N
N
HN
CO2H CO2H
HO2C
N HN
CO2H
HO2C
CO2H
Chlorin p6
Chlorin e6
Synthetic chlorins, exemplified by water-soluble chlorin 3 [60], typically have up to four meso-aryl groups. Access to such chlorines is based on reduction of the corresponding porphyrins. CO2 H O
HO 2C
O
N NH
HN N
O
CO2 H
O HO2C
3
Phthalocyanines are tetrabenzo[5, 10, 15, 20]tetraazaporphyrins, their hydrophilic derivatives are among the most important photosensitizers for aqueous media. Phthalocyanines have intense absorption band in the visible region near maximum of the solar radiation, which is important for many applications. The incorporation of non-transition elements such as aluminum, silicon, zinc and germanium in the centre of the phthalocyanine (Pc) ring results in complexes with high triplet state quantum yields and long triplet lifetimes, which are required for efficient singlet oxygen generation [14]. To date, a number of phthalocyanines bearing hydrophilic moieties, such as carboxylates [35], sulfonates [33, 35], carbohydrates [61, 62], phosphonates [34, 63], polyoxyethylene [64] and quaternized amino [65, 66] groups, have been reported.
280
N. Kuznetsova Table 5.1 Quantum yields FD for water-soluble phthalocyanines in aqueous mediaa Phthalocyanine FD Medium Refs. ZnPcS3.7mix ZnPcS3.7mix ZnPcS3.7mix ZnPcS4 ZnPcS4 ZnPcS4 ZnPc(COOH)4 ZnPc(COOH)8 ZnPcChol8b ZnNcS4c AlPcSnmix SiPcSnmix SiPcS4 GePcSnmix SnPcSnmix
0.49 0.67 0.70 £0.01 0.30 0.68 0.7 0.57 0.65 0.25 0.38 0.49 0.52 0.68 0.42
PBS (pH 7.4) PBS (pH 7.4) + D DMSO PBS (pH 7.4) PBS (pH 7.4) + D DMSO H2O + D PBS (pH 7.4) H 2O D2O, PBS (pH 7.4) + D PBS (pH 7.4) PBS (pH 7.4) PBS (pH 10) + D PBS (pH 7.4) PBS (pH 7.4)
[33] [33] [33] [33] [33] [33] [69] [34] [66] [70] [59] [71] [35] [71] [71]
a
S sulfogroup, D detergent Zinc octakis[N-(2-hydroxyethyl)-N,N-dimethylammoniomethyl] phthalocyanine (ZnPc7, Fig. 5.3) c Zinc naphthalocyanine tetrasulfonate b
From the water-soluble phthalocyanines, the sulfonated derivatives have received the most attention as sensitizers due to their accessibility. The sulfonated ZnPcs in particular are well known for their photosensitizing abilities; however aggregation, which reduces photosensitizing efficiency, is a very common phenomenon in this family of compounds [33, 67, 68]. From this point of view it is interesting to compare behavior of two Zn sulfophthalocyanines with close sulfonation degree, namely zinc tetra-4(5)-sulfophthalocyanine (ZnPcS4) and sulfonated zinc complex containing around four sulfogroups (ZnPcS3.7mix) but, unlike ZnPcS4, representing a mixture of complexes with different positions of substituents in the benzene rings. Compound ZnPcS4 has considerably lower FD values in buffer both in presence and absence of detergent as compared to ZnPcS3.7mix (Table 5.1). A reason lies in less aggregation of ZnPcS3.7mix due to steric hindrances from out of macrocycle plane sulfogroups in positions 3 or 6 [33]. Both ZnPcS4 and ZnPcS3.7mix are monomeric in DMSO solutions, where their FD values are high and almost the same (0.68–0.70, Table 5.1). The FD values for other water-soluble derivatives of ZnPc in comparison with that of zinc naphthalocyanine tetrasulfonate (ZnNcS4) are represented in the Table 5.1 as well. The quantum yield of singlet oxygen generation by ZnNcS4 is 0.25 in phosphate buffer in the presence of detergent. It may be observed that FD values for monomeric Zn sulfophthalocyanines (ZnPcS4 and ZnPcS3.7mix in DMSO, ZnPcS3.7mix in PBS + detergent) are close to what is reported in literature for other monomeric ZnPcs, particularly for ZnPc(COOH)4, ZnPc(COOH)8, ZnPcChol8 (Table 5.1). These FD range from 0.6 to 0.7. Consequently, no noticeable effect of the nature, number and position of the substituents was observed under conditions
5
Sensitization of Singlet Oxygen Formation in Aqueous Media
281
where the ZnPc-derived sensitizer exists as monomer. The same conclusion may be done for phthalocyanine complexes with other diamagnetic metals. The nature of the central metal ion affects FD, which is expected to increase along with the size of the central metal due to the heavy atom effect on the triplet quantum yield of the photosensitizer. It was found that in solutions in DMSO, where sulfonated phthalocyanines exist as monomers, FD values for MPcS2mix are equal to 0.11, 0.19, 0.37 for metal-free compound, Mg and Gd complexes, correspondingly. Lower singlet oxygen quantum yields were observed in aqueous solutions in the absence of detergents [33]. Yields FD for sulfophthalocyanine complexes with diamagnetic Al, Si, Ge and Sn in aqueous media under conditions, where they are expected to be monomeric, are presented in Table 5.1 also. The photosensitizing properties of sulfonated MPcs were comprehensively reviewed by Nyokong [14]. Carboxylated phthalocyanines are negatively charged in the 5.5–10 pH range. Their tetracarboxy-substituted derivatives, particularly Zn complexes, are dimerized at these conditions. Singlet oxygen yields for monomer and dimer in the micelles were shown to be 0.7 and 0.1, respectively [69]. From phthalocyanines with carboxy solubilizing groups the octacarboxysubstituted derivatives are most interesting. Octacarboxy phthalocyanine complexes (MPc(COOH)8) are water-soluble and are known to be monomeric at pH > 6 [72]. Complexes ZnPc(COOH)8, (OH)2SiPc(COOH)8 and (OH)2GePc(COOH)8 sensitize a singlet oxygen formation in aqueous media with quantum yields of 0.57 [34], 0.33 [35] and 0.31 [73], accordingly. For (OH)AlPc(COOH)8, FD at same conditions was found to be 0.15 ± 0.03, which is appreciably lower as compared to monomeric aluminum phthalocyanines (0.3–0.4 depending on the structure and solvent). Low sensitizing activity of aluminum complex was explained by formation in its solutions of associates and participation of axial hydroxy groups in associate formation [34]. The highly water soluble at pH > 7 ZnPc4, bearing 16 sodium carboxylate groups, has been synthesized [74]. The carboxylate groups in ZnPc4 lead to an increased distance between two neighboring macrocycles, which significantly lowers its tendency to form stacked aggregates and increases its solubility. Furthermore, the nonplanarity of the adjacent carboxyphenyl groups probably also contributes to decreased aggregation. Upon addition of HCl to an aqueous solution of ZnPc4 until pH 2, a green precipitate of this compound acid form was obtained. UV-vis and 1H NMR studies indicate that ZnPc4 dissolved in water or D2O exists mainly as two species with deprotonated one or two carboxylic acid groups from each phenoxy substituent. The ratio of these two main components is pH-dependent. No singlet oxygen yield data was reported however decreased aggregation suggests high sensitizing ability of this compound. Water-soluble phthalocyanines containing residues of phosphonic acids or their esters have been reported [34, 63]. Of particular interest are their aggregation and sensitizing properties. Thus, with respect to the quantum yields of the 1O2 generation, the series of aluminum phthalocyanines AlPc5, bearing eight free or esterified phosphonic acid residues, can be subdivided in two groups [34]. Full esters in aqueous buffer solutions are appreciably disaggregated and rather efficiently sensitize 1 O2 formation, with FD 0.25. Derivatives with free hydroxy groups in phosphonate
282
N. Kuznetsova CO2Na CO2Na
ZnPc4 NaO2C
O
CO2Na
O
CO2Na NaO2C
O
NaO2C
O
CO2Na N
N
N
N Zn
N
N
N
N
O
CO2Na
O
CO2Na
CO2Na
CO2Na O
NaO2C
O
CO2Na
CO2Na CO2Na
AlPc5
RO
O P
OR
RO
O P
OR OR P O
RO O
P
N
RO
N Al
N N RO O
OR N
N
OH
N OR
N
P
P
RO RO
P O
OR
RO
P O
O OR
OR
substituents (none or partially esterified) have about three times lower efficiency of singlet oxygen production, suggesting formation of associates. Recently series of phthalocyanine–carbohydrate conjugates have been synthesized by several research groups ([62] and refs. therein). Neutral Pcs, octasubstituted with D-galactose or glucopyranose residues, are highly water soluble and have great potential in PDT.
5
Sensitization of Singlet Oxygen Formation in Aqueous Media
R
R
N N
R
N
R
MPc6 : R = CH2
R
N
M N
N
R
N N
283
N
Cl
_ MPc7 : R = CH2 N
_ MPc8 : R = CH2 N
OH Cl Cl N
R
R
Cl _ MPc9 : R = CH2 N
Cl
I N OH
_
MPc10 : R = CH2 N
OH OH
Fig. 5.3 Octacationic metallophthalocyanines
There is a growing interest for PDT in silicon phthalocyanines with bulky hydrophilic axial ligands. SiPcs usually show reduced aggregation, good solubility in aqueous and biological media, and high photodynamic efficacy. Recently, SiPc with two axial glucose moieties linked to the silicon center through the tetraethylene glycol chain has been prepared. These axial groups greatly enhance the hydrophilicity of the phthalocyanine core, and resulting compound was shown to have substantial solubility in water (at least 50 mM) and high phototoxicity toward human carcinoma cells. The FD value for this axially substituted SiPc was found to be 0.32 in N,Ndimethylformamide [75]. To endow SiPcs with higher water-solubility additionally ionizable groups are grafted on phthalocyanine core. Li et al. [76] have combined, in a single macrocycle, peripheral cationic pyridyloxy groups and two bulky axial ligands on centrally chelated Si(IV) ions. These compounds exist mainly as monomers in aqueous media, were readily taken up by human carcinoma HEp2 cells and were found to be highly phototoxic. The complexes of hydroxyphthalocyanines are water-soluble but, all the same, aggregated in aqueous media [77, 78]. Very interesting water-soluble, non-aggregating Pc compounds which are viscous oils at room temperature have been prepared by the introduction of 16 polyoxyethylene groups at the Pc periphery [79]. Of particular interest are positively charged Pcs. Cationic dyes can penetrate the nucleus and produce photoinduced damage in DNA. During the past two decades few research groups have reported positively charged phthalocyanines [65, 66, 80, 81]. These studies show that phthalocyanines with 2–4 cationic substituents usually are aggregated in aqueous media. Makarov et al. [66] have studied several Zn(II) and Al(III) phthalocyanines (MPc6 – MPc10, Fig. 5.3) bearing eight peripheral positively charged substituents
284
N. Kuznetsova
Table 5.2 Spectral characteristics and singlet oxygen quantum yields for octacationic metallophthalocyanines in water [66, 82] Compound lmax, nm emax FD AlPc6 AlPc7 AlPc8 AlPc9 AlPc10 ZnPc6 ZnPc7 ZnPc8 ZnPc9 ZnPc10 TiOPc6 TiOPc7
678 684 680 680 685 677 680 677 679 638 697 697
190,000 190,000 170,000 170,000 100,000 180,000 190,000 175,000 195,000 66,000 80,000 70,000
0.37 0.38 0.35 0.35 <0.05 0.45 0.65 0.63 0.65 <0.05 0.40 0.51
of different hydrophilicity. These compounds are highly charged and are therefore readily soluble in water. With the exception of MPc10, phthalocyanines are monomeric in aqueous solution and show high activity in the light-induced generation of 1O2 (Table 5.2) [66]. The activity of AlPc10 was negligible due to aggregation. The photosensitizing properties in aqueous media of two octacationic oxotitanium phthalocyanines, bearing pyridiniomethyl- (TiOPc6) or cholinyl- (TiOPc7) substituents from ref. [82] are included in the Table 5.2 as well. In water, both compounds were monomeric with the high quantum yields of singlet oxygen formation (FΔ = 0.4 and 0.5). Obtained results evidenced that under illumination octacationic TiOPcs in aqueous solutions also produced hydroxyl radicals, which probably appeared owing to photocleavage of water molecules. The quantum yield of OH• formation was (3–5) × 10−5 after argon purging and twice as much in the presence of air [82]. The preparation of water-soluble quaternized 3-hydroxypyridine tetrasubstituted indium(III) phthalocyanine was described by Durmus and Nyokong [83]. This compound shows excellent solubility in water and very high efficiency in 1O2 generation (FD = 0.56 in H2O). The high versatility of phthalocyanines allows the substitution of some of their four-isoindole units by other heterocyclic moieties. Tetrapyridinoporphyrazine complexes are phthalocyanines in which the outer benzene rings are replaced with pyridine rings. Their quaternized forms are tetracationic and water-soluble [84, 85]. However these compounds mainly remain as aggregates in aqueous solutions. Recently the synthesis of water-soluble positively charged subphthalocyanines (SubPc) was described for the first time [86]. Unique cone-shaped geometry of SubPc provides them with high solubility and low tendency to aggregate. The SubPc derivatives containing alkylated pyridinium substituents located either at the peripheral
5
Sensitization of Singlet Oxygen Formation in Aqueous Media
285
R
R= N
N N
B
N
OPh N
I CH3
N
N R
R N
I
CH3
Fig. 5.4 Positively charged subphthalocyanines
or at the axial positions of the macrocycle (Fig. 5.4) were shown to be fairly water soluble, which suggests their high photosensitizing ability. Cationic photosensitizers, based on complexes of ruthenium (II), have excellent solubility in water and absorption in the UV-/vis regions of the spectrum. Tris(2,2¢-bipyridyl)ruthenium(II) [Ru(bpy)32+], one of the most important watersoluble photosensitizers, according to [50] in water (pH 7.4) generates singlet oxygen with quantum yield 0.41. Garcia-Fresnadillo et al. [87] for this complex reported lower FD (0.22 in D2O). The photosensitizing ability of a series of complexes RuL32+ where L is 2,2¢-bipyridine, 1,10-phenanthroline, 2,2¢-bipyrazine, 4,7-diphenyl-1,10-phenanthroline and diphenyl-1,10-phenanthroline-4,7-disulfonate was examined [87]. In this series of complexes, FD ranged from 0.19 to 0.43 in air-equilibrated D2O. The fullerenes constitute a class of spherically-shaped molecules made exclusively of carbon atoms. Fullerenes absorb strongly in the UV and moderately in the visible region. The efficiency of 1O2 formation for C60 (0.96 ± 0.04 at 532 nm [88]) is the highest among all photosensitizers investigated to date. Fullerenes are practically insoluble in aqueous media. A large number of fullerene derivatives have been synthesized, and most of the research aims at enhancing their water solubility. The most common way is to covalently attach hydrophilic groups on the surface of the fullerenes. The tris-dicarboxylate derivatives (C60[C(COOH)2]3) are highly soluble in water. However, the singlet oxygen quantum yield decreases with the increasing number of substituents due to the increased perturbation of the fullerene p-system. Prat et al. [89] studied a series of C60-methano adducts with increasing numbers of substituents and found that the quantum yield of singlet oxygen production decreases as the area of the conjugated fullerene core decreases. There have been several reports of improving the solubility of fullerenes by grafting a dendrimer. The fullerodendrimer, synthesized by grafting a poly(amidoamine) dendrimer to C60, is water-soluble and acts as a photosensitizer to generate singlet oxygen in water. The quantum yield FD in D2O was estimated to be 0.45, which is much lower than that for ‘naked’ C60 [90].
286
5.4.2
N. Kuznetsova
Immobilized Photosensitizers
For use in water purification the immobilization of singlet oxygen photosensitizers onto the various materials such as a polymer, metal, silica and glass is a desirable approach since the photosensitizer is easily separated from the reaction medium and reused. In 1973 the synthesis of the first example of a heterogeneous sensitizer for singlet oxygen formation was reported [91]. This polymer-immobilized reagent, P-Rose Bengal, consists of a photosensitizing dye, Rose Bengal, covalently bound to an insoluble poly(styrene-divinylbenzene) matrix. However P-Rose Bengal was found to be a poor photosensitizer in aqueous systems. The reason for this limited effectiveness was related to the observations that the hydrophobic polymer is not wetted by water and does not swell in water. Then Rose Bengal was immobilized on a water-compatible hydrophilic co-polymer of chloromethylstyrene and methacrylate ester of ethylene glycol [92]. The resulting hydrophilic polymer-bound sensitizer, HP-Rose Bengal, has shown good photooxygenations in aqueous media. Since then various types of sensitizers, covalently or noncovalently bound to a support, have been studied as singlet-oxygen solid sensitizers in H2O suspensions [93–95]. A fundamental requirement for a photosensitizer carrier is that it should not significantly quench singlet oxygen. It should be mentioned that not only hydrophilic, but hydrophobic sensitizers may be entrapped or adsorbed, or covalently attached on the surface of the carrier. It is important for photosensitizer to be embedded predominantly in the monomeric form, since aggregation promotes the non-radiative internal conversion, causing a shortening of the triplet lifetime and a drastic reduction in the overall efficiency of 1O2 production. The methods, used for singlet oxygen quantum yields determination in homogeneous aqueous solutions, cannot be used to directly determine the quantum yield of 1 O2 in a heterogeneous system, because the part of light absorbed by the sensitizer bound to support cannot be determined. However, the evidence of singlet oxygen production and comparison of the sensitizer’s efficiencies can be obtained from the production of 1O2 in heterogeneous systems under identical conditions. Photosensitizers, adsorbed on porous materials (silica, zeolites), usually are encapsulated within matrix and most of them show reduced yield of singlet oxygen due in part to the need for oxygen to diffuse into the support in order to be sensitized and then out of the support into surrounding medium. Examples of such systems are nonsubstituted and tetracarboxysubstituted Zn phthalocyanines on zeolite [96]. The water-soluble charged sensitizers often are immobilized by using ionic bound on ion-exchanging zeolites and resins. Phthalocyanines and porphyrins substituted with carboxy or sulfonato groups were attached to Amberlite [97]. Porphyrins and phthalocyanines bound to exchange resins were reported to behave as homogeneous compounds. Gerdes et al. [98] studied the photooxidation of phenol, cyclopentadiene, and citronellol by ionically bound anionic photosensitizers such as Rose Bengal, and Zn, AlOH, GaOH, and Si(OH)2 complexes of tetrasulfophthalocyanines onto Amberlite IRA 400. The immobilized photosensitizers showed comparable activities to those of the homogenous analogues. In a recent paper [99] cationic sensitizer
5
Sensitization of Singlet Oxygen Formation in Aqueous Media
287
TMPyP has been adsorbed onto anionic surface of the porous Vycor glass (PVG). It was demonstrated that TMPyP-impregnated PVG provides a heterogeneous system for use in water. Instead of being confined to the core, photosensitizers can be covalently bound to the surface of the support. The singlet oxygen is more available when generated from the surface, since it is able to diffuse into the solution more easily. Thus, commercially available Rose Bengal, covalently bound to a chloromethylated styrenedivinylbenzene copolymer (Sensitox) [100], sensitizes singlet oxygen with quantum yield 0.22–0.25 [11]. The quantum yield of singlet oxygen formation by Rose Bengal, covalently attached to poly(sodium styrenesulfonate-co-vinylbenzyl chloride), was found to be 0.73, which is close to that for free Rose Bengal [101]. The polymer has been shown to photosensitize oxidation reactions in aqueous solution. Metallated porphyrins or phthalocyanines were linked to organic polymers. Recent example is polydivinylbenzene-supported zinc phthalocyanine, which was found to be effective for removing and mineralizing the toxic 2,4-dichlorophenol in aqueous solution. The removal yield amounted to 98% after 4 h of irradiation [102]. Molecules may be chemically bonded to modified silica. Aminopropyl silica is commercially available and widely used for this purpose. Examples are the heterogeneous photosensitizers, obtained by grafting of phthalocyanines and porphyrins substituted with carboxyl or sulfonato groups to aminopropyl silica [97, 103] and many more. Also a silane derivative of the sensitizer can react with the silica surface to yield the silica bound photocatalyst. Obtained in this way heterogeneous material is a promising photocatalyst because of monomeric properties of attached silicon phthalocyanine, i.e., the sharp Q band and ability to generate singlet oxygen [104]. In recent years, an increasing number of researchers have considered the nanomaterials as carriers for singlet oxygen photosensitizers in biological media for photodynamic therapy (PDT). For this application nanoparticles could be made hydrophilic. Among them, colloidal particles of different structures and watersoluble ceramic-based nanoparticles recently gained great interest [105]. Efficiency of sensitizers, immobilized on nanomaterials, may be comparable with that of homogeneous ones due to enormous surface of nanocarries. Example of such systems is silica-based nanoparticles entrapped with the hydrophobic photosensitizer 2-divinyl-2-(1-hexyloxyethyl) pyropheophorbide via a controlled hydrolysis of triethoxyvinylsilane [106]. Mesoporous silica nanoparticles functionalized with protoporphyrin IX have been prepared [103]. It was established that singlet oxygen is efficiently produced upon irradiating this system. Owing to the porosity of the silica, the produced singlet oxygen can easily penetrate from the photosensitizer entrapped in the support into surrounding aqueous or physiological environment. Protoporphyrin IX, chemically attached to silica nanoparticles, have an efficiency of singlet oxygen generation 0.9 (in acetonitrile), that is higher than the quantum yield of free porphyrin. This high efficiency of singlet oxygen generation was attributed to changes on the monomer-dimer equilibrium after photosensitizer immobilization [107]. Light-harvesting complex of water-soluble anionic polymer with cationic porphyrin was prepared to enhance 1O2 generation by fluorescence resonance energy transfer (FRET) from polymer to porphyrin [108].
288
5.5
N. Kuznetsova
Factors, Affecting Singlet Oxygen Formation
5.5.1
Aggregation
It is well known that aggregation of photosensitizer decreases the efficiency of 1O2 photogeneration. Dyes in water are able to form dimers and higher order aggregates. This phenomenon is most easily recognized by broadening of the absorption bands in their optical spectra. The sensitizers of phthalocyanine group due to stronger p–p interaction and the flatness of the aromatic cores are more prone to aggregation in solution than the TPPs. The presence of meso-phenyl groups prevents a close packing of the TPP rings. The TPPs form J- or head-to-tail type of aggregates, while Pcs tend to organize into H- or cofacially stacked aggregates [64]. Since phthalocyanines are more inclined to aggregation than sensitizers of other classes, their aggregation is most considered. Various studies show an inverse correlation between the formation of photosensitizer noncovalent aggregates in aqueous solution on the one hand and singlet oxygen yield on the other [33, 50]. Thus, such relationship was found for a series of differently sulfonated phthalocyanines of Zn (ZnPcSnmix, were n varied from 2 to 4) in phosphate buffer at pH 7.4. Aggregation of these complexes is easily characterized by UV-vis spectroscopy via blue shifted band around 630 nm. Figure 5.5 shows that increase of ZnPcSnmix sulfonation degree shifts the equilibrium from dimers to monomers (maxima at about
1.6
4 5
1.4
Absorbance
1.2
3 2
1.0
1
0.8 0.6 0.4 0.2 0.0 500
550
600
650
700
750
800
Wavelength (nm)
Fig. 5.5 The concentration normalized absorption spectra of ZnPcS2.1mix – (1), ZnPcS2.9mix – (2), ZnPcS3.4mix – (3), ZnPcS3.7mix – (4) and ZnPcS4 – (5) in phosphate buffer at pH 7.4 and ionic strength 0.18 M (Courtesy of the author)
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Sensitization of Singlet Oxygen Formation in Aqueous Media
289
0.8
6 0.6
ΦΔ
4 0.4
5 0.2
2
3
1 0.0 0.0
0.2
0.4
α
0.6
0.8
1.0
Fig. 5.6 Effect of aggregation degree a on the yield of 1O2 produced by a series of ZnPcSnmix in phosphate buffer solution with (•) and without (o) addition of Triton X-100: ZnPcS2.1mix – (1), ZnPcS2.9mix – (2), ZnPcS3.4mix – (3), ZnPcS3.7mix – (4), ZnPcS4 – (5), average FD for ZnPcSnmix – (6) (Courtesy of the author)
630 and 675 nm, respectively). Since dimers and aggregates are photochemically inactive, FD of ZnPcSnmix samples in PBS increases linearly along with sulfonation degree up to rather high values of 0.5 for ZnPcS3.7mix and 0.68 in the presence of surfactant Triton X-100 (Fig. 5.6). Such dependence indicates that only the monomer fraction of the sensitizer is responsible for 1O2 production. The results demonstrated that a monomeric state of the photosensitizer in solution is crucial to its activity in singlet oxygen photogeneration. To reduce the extent of sensitizer aggregation, several methods have been employed [109]. These methods include using of electrostatic repulsive force between likely charged molecules, using hydrophilic groups as axial ligands coordinated to a central metal such as Si, using surfactants or other substances which can create a micro-heterogeneous environment such as micelle or liposome and use of bulky peripheral and dendrimer substituents on the phthalocyanine macrocycle, which sterically inhibit molecular aggregation and enhance solubility. All the above methods can to some extent improve efficiency of singlet oxygen generation by phthalocyanines in aqueous environment. One must distinguish noncovalent dimers from their covalently linked counterparts. For example, the latter is present in the mixture of monoporphyrinic and oligomeric species of HpD [48]. Behavior of covalently bound dimers depends on arrangement of dye units and structure of spacer. Thus, the spectroscopic features of linked via hydrocarbon chains -(CH2)n- linear-type porphyrin dimers show that for n > 4 the dimer behaves as two independent rings [110]. The singlet oxygen quantum yields for such dimers should be equal to those for monomers.
290
5.5.2
N. Kuznetsova
Coordination Interaction
Well known photosensitizers of zinc porphyrin or phthalocyanine family can coordinate neutral molecules with electron pairs that they can donate to the metal atom. Of the many such compounds, pyridine, 4,4¢-bipyridine, imidazole, 1,4diaza[2, 2, 2]bicyclooctane (DABCO) are among the most used to coordinate with zinc porphyrins and phthalocyanines [111]. Coordination interaction is a recognition factor in supramolecular chemistry. Water-soluble zinc porphyrins or phthalocyanines show coordination attractions for amino acids and peptides. The amino acids bind to the sensitizer through the coordination of the N atom with the central zinc ion. Molecules, coordinated in axial position to a central metal of porphyrin or phthalocyanine, impede the p-p interactions between the macrocycles and increase solubility, particularly in water. One of the reported examples is enhancement of Zn phthalocyanines monomerization in the presence of quinoline due to axial coordination of the base to the central metal atom in the complexes [112]. The coordination attraction for biomolecules results in photosensitizer disaggregation in biological environment [113, 114], and along with sensitizer monomerization the increase of singlet oxygen quantum yield is expected. Usually, coordinate bonds are not adequately strong in aqueous solution due to the competitive coordination of water. The coordination ability of the N atoms of amines is weak, thus, the binding constants of aminoethanol to water-soluble porphyrins are about 10 mol/l [115]. However binding of amino acids to cationic porphyrins is one or two orders of magnitude stronger due to the additively cooperated Coulomb interaction between the cation substituents of porphyrins and the carboxylate anion of amino acids [115].
5.5.3
Electrostatic Interactions
Charged sensitizers exhibit better solubility in aqueous media. For this reason, many researchers are engaged in studying these compounds [66, 116, 117]. Coulomb interaction between charged photosensitizer molecules, influencing dye aggregation, can both increase and decrease singlet oxygen generation. Although the Coulomb interaction decreases with the dielectric constant of solvents and thereby becomes weaker in aqueous solution than in nonpolar organic solvents, it is still very important. Electrostatic repulsion force between likely charged molecules is one of the methods to reduce the aggregation of photosensitizers in aqueous media. The introduction of eight anion [34, 118] or eight cation [66, 80] substituents resulted in complete monomerization of liable to aggregation zinc phthalocyanines in water. At the same time, four charged substituents [117–119] suppressed aggregation only partially. In the paper [120] the influence of the number of positively charged groups in the macrocycle of zinc and aluminum phthalocyanines on the state of these complexes
5
Sensitization of Singlet Oxygen Formation in Aqueous Media
291
Fig. 5.7 Phthalocyanine structures and designations
Table 5.3 Spectral characteristics, degree of dimerization (a), and the FD values for polycationic zinc and aluminum phthalocyanines in water (c = 5 × 10−6 M) Compound
lmax, nm
emax
a
l fl max , nm
Ffl
FD
ZnPcPym4 ZnPcPym5 ZnPcPym5.5 ZnPcPym6.5 ZnPcPym8 ZnPcChol4 ZnPcChol5 ZnPcChol5.5 ZnPcChol7 ZnPcChol8 ClAlPcChol3 ClAlPcChol4.5 ClAlPcChol6.5 ClAlPcChol8
677 677 677 677 677 677 680 680 680 680 680 681 682 684
70,000 90,000 110,000 170,000 180,000 90,000 130,000 140,000 190,000 190,000 80,000 150,000 185,000 190,000
0.76 0.66 0.47 0.13 0 0.60 0.35 0.27 0 0 0.70 0.20 0 0
688 688 689 690 692 690 690 692 693 694 688 689 691 692
0.05 0.07 0.09 0.12 0.12 0.08 0.08 0.09 0.10 0.11 0.17 0.12 0.17 0.18
0.10 0.13 0.19 0.38 0.45 0.25 0.38 0.46 0.60 0.65 0.15 0.23 0.29 0.38
Chol N-(2-hydroxyethyl)-N,N-dimethylammoniomethyl, Pym pyridiniomethyl (Fig. 5.7)
in aqueous solution, their efficiency of singlet oxygen generation, and photoinduced antimicrobial activity was studied thoroughly. For this purpose, several cationic phthalocyanines, which were mixtures of complexes with different number of pyridiniomethyl (ZnPcPymn) or cholinyl (ZnPcCholn, ClAlPcCholn) substituents and had the average degree of substitution n from 3 to 8 (Fig. 5.7), have been synthesized. Table 5.3 lists the characteristics for aqueous solutions of the compounds.
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The data of Table 5.3 indicate that as the number of charged substituents in the photosensitizer molecule increase, its aggregation ability in aqueous solutions decreases, leading to increase of singlet oxygen generation. In fact, the repulsion between likely charged molecules increases with the number of possible Coulomb interactions. Inversed situation is observed in mixtures of oppositely charged sensitizers. Coulomb interactions between the –COO− groups of the anionic octacarboxysubstituted and the –CH2Py+ groups of the cationic octapyridiniomethylsubstituted phthalocyanines yield in water remarkably stable neutral complexes. It was found, that such heteroaggregation totally suppresses singlet oxygen formation [121].
5.5.4
Hydrogen Bonding
Photosensitizers containing non-ionic water-solubilising substituents, such as hydroxy, polyoxyethylene, carbohydrate (glycerol, galactose, glucose) groups, as a rule are aggregated in aqueous solutions [61, 64, 116, 122]. Hydroxy substituents in such compounds form readily network both via direct intermolecular hydrogen bonding, or by bridging water species, incorporated into the hydrogen-bonding patterns (O–H…O–H) [123].
OH
OH N
OH N
N OH
N
N N
OH
N
N N
N
N
OH
OH
OH N
MPc7
N
N
N
OH OH
N
N
OH OH
OH
OH
M
OH
N
N
OH
N
N OH
N
N
OH N
OH
N
M
OH
OH
N
N
N
OH
OH
OH N
OH
OH N
N
N OH
OH OH
OH
OH
OH
MPc10
Phthalocyanines MPc7 and MPc10 (Table 5.2, [66]) demonstrate an impressive example of hydrogen bonding influence on the photosensitizer singlet oxygen quantum yield in aqueous solution. Both compounds have eight positively charged groups. The only difference between MPc7 and MPc10 is in the number of hydroxyethyl substituents – MPc7 contains one and MPc10 has three such groups at each
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quaternary nitrogen atoms. The MPc10 would seem to be less aggregated than MPc7 due to higher steric hindrances. However in fact aluminum and zinc phthalocyanines with one hydroxyethyl substituent at quaternary nitrogen in aqueous solution are monomeric and sensitize singlet oxygen formation with high quantum yields, 0.38 and 0.65, correspondingly, whereas their derivatives MPc10 in aqueous media exist almost completely in the aggregated form and have negligible activity in 1O2 production (Table 5.2). This tendency of complexes with structure MPc10 to form aggregates may be explained only by taking into account the multitude of hydroxy groups at the periphery, and their participation in intermolecular hydrogen bonding between adjacent molecules. Obviously, in aqueous media, intermolecular hydrogen bonds induced by the presence of eight hydroxyethyl groups in eight cationic substituents in MPc7 does not prevail over their electrostatic repulsion, but their threefold increase overcomes repulsion of substituents partially or completely and drastically changes the state of photosensitizers in solution. For aluminum phthalocyanines in aqueous solution the influence of the dye structure on the quantum yield of generation of singlet oxygen suggests participation of axial hydroxy groups in associate formation [34]. Thus, anionic aluminum phthalocyanines with a negative charge of the macroring from −4 to −16 (octacarboxy- or bearing more than 4 free phosphonate groups) have low FD as compared to monomeric aluminum phthalocyanines, suggesting formation of associates. For these compounds the hydrogen bonding of two adjacent Al(OH)Pcs via axial hydroxy groups owing to the high basicity of the axial oxygen atom was proposed [34]. In contrast to common co-facial dimers, this association gives no new bands in the electronic spectrum and is evidenced only by low singlet oxygen quantum yields.
5.5.5
Effect of pH on the Photosensitized Production of Singlet Oxygen
Changes in pH influence the sensitizer chromophore, which is revealed by changes in the absorption and fluorescence spectra of the sensitizer. Protonation/deprotonation of a sensitizer may have effect on the photophysics of the chromophore and, consequently, on yield of singlet oxygen. According to the information that is available, the influence of pH on the photosensitized production of singlet oxygen seems to be molecule specific with little evidence of systematic trends. Thus, the adverse effects of protonation on the yield of singlet oxygen, sensitized by amino-substituted phenylene vinylenes, methylene blue, phthalocyanine and chlorine derivatives have been observed ([124] and refs. therein). In other works, it has been found that protonation/deprotonation of the nitrogen in the macrocycle of water-soluble mesotetraphenylporphyrin and meso-tetrapyridylporphyrin derivatives does not appreciably affect the triplet state quantum yield and ability of porphyrin to generate singlet oxygen [125, 126]. Protonation-dependent changes in the yield of photosensitized singlet oxygen production may be ascribed to the following reasons: change in the quantum yield of the sensitizer triplet state; possible changes in the triplet
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Fig. 5.8 The pH dependence of the relative AlPcS2 singlet oxygen quantum yield (Reproduced from Ref. [127] with kind permission of John Wiley & Sons, Inc.)
state energy; protonation-dependent changes in sensitizer aggregation; effect of pH on nonradiative deactivation, enhanced as a consequence of the reversible protonation/deprotonation of the chromophore; protonation-dependent changes in the amount of charge-transfer character in the sensitizer-oxygen complex [124]. For phthalocyanines that are inclined to aggregation, the pH-dependent selfassociation (aggregation) is the reason for changes in the singlet oxygen quantum yield in the majority of cases. Thus, octacarboxyphthalocyanines at pH > 5.5 exist only in monomeric forms, in pH < 5.5 aggregates are present [72]. Consequences of such behaviour for singlet oxygen generation are foreseeable. Change in sensitizer aggregation in water with pH was observed for Zn phthalocyanine tetraphosphonate [63]. In 0.1 N NaOH (pH > 12) this complex judging from its UV-visible spectrum is monomeric, meanwhile in pH 5 buffer, Zn phthalocyanine tetraphosphonate is highly aggregated. At higher pH, it is completely ionized, leading to a large amount of negative charge on the Pc periphery which would prevent aggregation. Singlet oxygen quantum yield was not determined; however it is obvious that FD also changes with pH from high value, typical for monomeric Zn phthalocyanines, at high pH, to a complete disappearance of the singlet oxygen generation by aggregates at low pH. The effect of pH on the FD of di-sulfonated aluminum phthalocyanines (Fig. 5.8) was interpreted in terms of the pH dependence of the nature of the axial ligands at Al central atom, and was associated with equilibrium between a dimerizing AlPc(OH)(OH2) and nondimerizing [AlPc(OH)2]− species [127]. It should be mentioned, however, that tri-sulfonated aluminum phthalocyanine (AlPcS3mix, Photosens) does not hold to dependence in Fig. 5.8 (Kuznetsova unpublished results).
5.5.6
Electrolytes
Ionic photosensitizers exhibit higher tendency towards association in the presence of salts than in distilled water. Increasing the ionic strength by addition of simple
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salts such as NaCl to aqueous solution of charged sensitizer results in a substantial aggregation and reduction of singlet oxygen quantum yield. The added salt shields electrostatic repulsion between sensitizer molecules, promoting aggregation. The effect of ionic strength on the self-association of charged sensitizers is related to the ionic strength dependence of ion activity that can be expressed in terms of the Debye-Huckel model, which was used quite successfully in the case of porphyrin dimerization, although it constitutes a rough approximation [128]. Complexation of some ions with metal ligands of phthalocyanines may have a profound effect on their photodynamic activity. Thus, fluoride F− was shown to inhibit photohemolysis induced by chloroaluminum phthalocyanine tetrasulfonate (AlPcS4) [129]. The strong F−/sensitizer complex has a reduced affinity to a variety of proteins and probably has a reduced binding to critical cellular targets. As a result, the F− complexed AlPc is less effective in generating photodynamic damage to a vital cellular target. Primary photophysical processes of sensitizer and ability to generate singlet oxygen most probably are not affected by fluoride anion.
5.5.7
Photoinduced Electron Transfer
Singlet oxygen generation rate could be modulated by change in photoinduced electron transfer (PET) efficiency. Excited-state molecules can relax through a number of different pathways including two competing processes, intersystem crossing and PET. Blocking of PET process shuts down one channel of deactivation, and thus enhances intersystem crossing efficiency and the rate of singlet oxygen generation. Photoinduced electron transfer can be manipulated by a large variety of modulators; pH, cations and anions among others [130]. For example, it has been shown that blocking of PET process by protonation of the amine electron donor leads to increase of singlet oxygen yield [131]. The extent of PET processes is greater in the more polar solvent. Thus, in comparison to singlet oxygen quantum yields measured in other solvents, the data obtained in water may be smaller [50, 87].
5.6
Photostability of Photosensitizers
Stability of photosensitizers under illumination is important for their applications. As a rule, high photostability of sensitizer is needed in applications, where large number of photocatalitic cycles is required. However in some cases, in particular for medical use, the fast bleaching of photosensitizer might be important, because it reduces unwanted aftereffects of dye presence in the treated systems (such as skin photosensitivity, the major side effect of PDT treatment). Excited states of aggregated photosensitizers show rapid deactivation, hence they are resistant to bleaching. Presented below data were selected from studies, where sensitizer expected to be monomeric.
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Table 5.4 Photobleaching quantum yields (Fp) for porphyrins and their analogs in aqueous media Photobleaching quantum yield Fp(×105) Compound Medium Refs. TiOPcChol8 10 H2O [82] AlPcSnmix 0.17 H2O [133] SiPcSnmix 0.71 PBS (pH 7.4) [71] GePcSnmix 0.45 PBS (pH 7.4) [71] SnPcSnmix 1.49 PBS (pH 7.4) [71] ZnPcS4 1.7 D2O, PBS (pH 7.4) + D [70] ZnNcS4 420 D2O, PBS (pH 7.4) + D [70] Haematoporphyrin 4.7 PBS (pH 7) 0.22 mM O2 [134] Photofrin 5.4 PBS (pH 7) 0.22 mM O2 [134] TSPP 0.98 PBS (pH 7) 0.22 mM O2 [134] Chlorin e6 190 PBS (pH 7) 0.22 mM O2 [135] Chol N-(2-hydroxyethyl)-N,N-dimethylammoniomethyl, TSPP (4-sulfonatophenyl)porphyrin, Nc naphthalocyanine
Light induced modification of photosensitizer produces considerable change in its spectral characteristics as well as in photosensitizing efficacy. The dye phototransformation may be revealed spectroscopically as photobleaching (decrease in the intensity of the visible absorption band due to destruction of the chromophore) or as shift in maxima or formation of new bands due to modification of substituents. The phototransformation of substituents is of minor significance because products usually do not interfere with sensitization. There have been extensive studies on the photobleaching of photosensitizers, particularly used in photodynamic therapy (for a review see ref. [132]). However the photoprocesses in air-saturated aqueous solutions have been reported in a limited number of cases. The data on photostability of some photosensitizers in aqueous media are presented in the Table 5.4. The mechanisms for photobleaching of photosensitizers are far from simple and depend on both structure of sensitizer and nature of environment. In air-saturated aqueous or biological media photodegradation of sensitizer can result from oxidative reactions of Type I or Type II, and hydrolysis. This review does not intend to give an exhaustive coverage of the topic, but main principles of photosensitizer’s photodegradation in aqueous solutions. As was mentioned above, phenothiazinium, xanthene, phthalocyanine dyes as well as porphyrin derivatives are among most interesting photosensitizers. They markedly differ from one another in structure of aromatic scaffold, to which the solubilizing groups are attached. Concerning photobleaching, it is generally accepted that singlet oxygen may be involved in this process since 1O2 can oxidize unsaturated double bonds of dye (sensitizer) chromophoric system. However it was shown that electrophilic singlet oxygen is inactive with large group of dyes, which are
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positively charged in water [136]. With regards to anionic and neutral sensitizers, some results support singlet oxygen-mediated photodegradation of the chromophor [132], and some imply that photodegradation is probably not initiated by singlet oxygen alone [70, 71]. The Type I radical bleaching of photosensitizer in many cases competes successfully with self–sensitized photooxidation by singlet oxygen. The dyes under illumination in aerated aqueous solution and, especially, in biological media, besides singlet oxygen, sensitize formation of different radical oxidizing agents, such as OH•, O2•− (HO2•), RO2• radicals. The rate constants of hydroxyl radicals and dyes interaction are near to diffusion controlled limit (about 1010 M−1 s−1). Superoxide O2•− (HO2•) and RO2• contribution in dyes photodestruction as a rule is marginal, since respective rate constants are low (about 102 M−1 s−1) [136]. Involvement of hydroxyl radicals in photobleaching of sensitizer in aqueous solution was suggested for cationic oxotitanium phthalocyanines [82]. In aqueous solutions, these compounds were found under illumination besides singlet oxygen to produce hydroxyl radicals, which might be formed as a result of photocleavage of water molecules. The quantum yields of dye photodegradation in water were found to be about 1 × 10−4 (Table 5.4). The data indicate that singlet oxygen is weakly or not involved in oxotitanium phthalocyanines photodegradation, which likely occurs owing to the reactivity of hydroxyl radicals [82]. The photobleaching of photosensitizers in biological media most likely is initiated by photoinduced electron transfer processes, which are common for photosensitizers of different structure [137, 138], however typically photoreactions in biological systems are complex, following several pathways [132]. The nature of the photoproducts in majority of cases has not been determined, and in water there are no examples at all. On the ground of oxidative character of photobleaching, the products of 2p+2p cycloadditions or of 2p+4p cycloadditions of singlet oxygen to porphiryns and chlorins, and phthalimides production from phthalocyanines [132] may be considered for aqueous media also.
5.7
Applications
5.7.1
Water-Soluble Sensitizers in Biological Systems and Their Medical Applications
5.7.1.1
Photodynamic Inactivation of Microorganisms
The emergence of antibiotic resistance amongst pathogenic bacteria has led to a research effort to find alternative methods for inactivation of microorganisms. Example of these is the killing of bacteria by the photodynamic inactivation (PDI) [139]. This method is based on damage to bacterial cells by reactive oxygen species, mainly singlet oxygen, generated by exo- or endogenous sensitizers in
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Table 5.5 The photosensitizing properties of dyes [141]
Charge Singlet oxygen Sensitizer of sensitizer quantum yield, FD Rose Bengal Negative 0.75 Eozine Negative 0.52 AlPcS3mix Negative 0.38 AlPcPym8 Positive 0.37 ZnPcPym8 Positive 0.45 Methylene Blue Positive 0.52 Proflavine Positive <0.05 Pym pyridiniomethyl a Contact time of incubation: 1 h, irradiation time: 0.5 h
Photoinactivation of total coliform bacteria in natural watera Count in initial Count after water, CFU per photodisinfection, 0.1 dm3 CFU per 0.1 dm3 1,200 6 2,200 460 1,200 18 1,600 0 1,600 0 1,100 0 2,700 0
photoexcited states. The PDI is a promising approach for the treatment of localized infections [8, 9], surface water microbial contamination [140] and for drinking water disinfection [141]. It has been known that certain microorganisms, namely Gram-positive bacteria, are very sensitive to the photosensitizing action of a variety of photosensitizers, whereas Gram-negative bacteria display a resistance to photosensitization [139]. In Table 5.5, data on the photoinactivation of coliform bacteria along with FD yields for series of common photosensitizing dyes are presented. With exception of Proflavine, all tested dyes have high quantum yields for generation of cytotoxic singlet oxygen. However, from the data in Table 5.5 there is no relationship between FD values and photodynamic efficiency of dyes against Gram-negative coliform bacteria in water samples. Thus, Rose Bengal and Eozine, which have the highest values of FD among the tested dyes, possess low efficiency in coliform bacteria photoinactivation. Data in Table 5.5 show that substantial amount of coliform bacteria survive after photodynamic treatment with Rose Bengal and Eozine. Considering the charge of sensitizers we can infer that high photodisinfection activity occurs for positively charged sensitizers in aqueous media. Positive charge endows sensitizer molecule high affinity to negatively charged outer membrane of cell, inducing damage that enhances the penetration of the photosensitizer. Photosensitizers that are positively charged at physiological pH values are efficient in photoinactivation of both Gram-negative and Gram-positive bacteria [139]. Uncharged lipophilic dyes are not able to overcome the permeability barrier of Gram-negative cells – negatively charged outer cell membrane – and therefore they do not exhibit high activity towards this bacterial group. Anionic dyes also are inefficient in photosensitization of Gram-negative bacteria, which may be due to their electrostatic repulsion from the negatively charged surface of the outer membrane. Hence, the efficient interaction of photosensitizer with outer cell membrane is very important for bacteria photodynamic inactivation. It may occur through several
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Table 5.6 Contents of the total coliform bacteria (TCB, CFU/100 ml) in sewage before and after photodynamic treatment with polycationic zinc and aluminum phthalocyanines, differing in number of substituents [120] Contents of the total coliform bacteria in sewage (TCB, CFU/100 ml) Compound Before photodynamic treatment After photodynamic treatment ZnPcPym4 625 8 ZnPcPym5 625 10 ZnPcPym5.5 625 3 ZnPcPym6.5 625 0 ZnPcPym8 625 0 ZnPcChol4 725 28 ZnPcChol5 725 15 ZnPcChol5.5 725 0 ZnPcChol7 725 0 ZnPcChol8 725 0 ClAlPcChol3 1,500 40 ClAlPcChol4.5 1,500 18 ClAlPcChol6.5 1,500 0 Chol N-(2-hydroxyethyl)-N,N-dimethylammoniomethyl, Pym pyridiniomethyl
types of forces including electrostatic, hydrophobic and coordination. As will be demonstrated below, among them the electrostatic interactions are most important. The nature and number of cationic substituents generally have a limited influence on the photophysical properties of the parent compound however they appreciably affect extent of binding with microbial cells and their photodynamic inactivation. It was found that increasing the number of positively charged substituents enhances the extent of sensitizer (phthalocyanine) binding to Escherichia coli cells [142]. This, along with the high quantum yield of singlet oxygen generation due to sensitizer monomeric behavior, determines efficient photodynamic inactivation of Gram-negative bacteria by zinc and aluminum octacationic phthalocyanines (Table 5.6). Tetra-substituted cationic Zn phthalocyanines with high photodynamic activity toward microorganisms in aqueous media also were reported [143, 144]. It was shown that tetrakis-3(methylpyridyloxy)-phthalocyanine zinc(II), notwithstanding its monomer/dimer equilibrium, completely inactivated S. aureus and C. albicans, and with 4log10 P. aeruginosa at mild experimental conditions, such as drug dose of 1.5 mM and fluence of 50 mW cm−2 for 10 min irradiation time [143]. Cationic photosensitizers have affinity with double stranded DNA as well as the ability to cleave DNA ([145] and refs. therein). This property enhances the photobactericidal action of positively charged sensitizers. The activity of neutral or anionic photosensitizers may be increased by chelating compounds such as ethylenediaminetetraacetic acid (EDTA), which are known to alter and disorganize the outer membrane [146], enhancing the penetration of photosensitizers to inner cell compartments. The total negative charge on the outer membrane in Gram-negative bacteria originates mainly from lipopolysaccharides.
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Fig. 5.9 Salt effects on photodynamic quenching of bioluminescence B of genetically engineered E. coli strain pXen7. Salts were added to the bacterial suspension 5 min prior to addition of 0.5 mM ZnPcChol8. After incubation with sensitizer for 10 min, the suspension was irradiated by white light at a dose of 6 J/ cm2: (1) NaCl; (2) MgCl2; (3) CaCl2 (Courtesy of the author)
To prevent mutual repulsion of negatively charged lipopolysaccharide macromolecules and stabilize the outer leaflet of the outer membrane, lipopolysaccharides are bound via ionic bridges of Mg2+ and Ca2+. The addition of the metal chelator EDTA was found to cause the displacement and, respectively, the removal of the Mg2+ and the Ca2+ ions which neutralize the superficial negative charges. On the other hand a charge-dependent interaction between the photosensitizer and bacterium is influenced by the presence of ions in the suspending medium. As was mentioned above, the bacterium outer membrane has a strong negative charge, which attracts cations: the cationic photosensitizers or other cations present in the suspending medium, such as Mg2+, Ca2+, H+ and Na+. Attracted cations shield the negative charge on the membrane, thereby reducing the surface potential. This reduces the attraction and binding of cationic photosensitizers to the outer membrane. It was found that addition of cations strongly decreased the sensitivity of bacteria to photoinactivation [142, 147], and that the dications protected bacteria against PDI more efficiently than monocations. Thus, during preliminary incubation of cells with MgCl2 and CaCl2, but not with NaCl (in the range of 0.1–10 mM concentrations), photoinactivation of genetically engineered E. coli strain pXen7 with octacationic ZnPc decreased 3–4-fold (Fig. 5.9) compared to that in distilled water. Similar protective effects of NaCl were revealed at significantly higher concentrations [142]. It was observed also that increasing the acidity of the medium decreased the efficiency of photodynamic inactivation of E. coli pXen7 with cationic sensitizer ZnPcChol8 (Fig. 5.10). This effect is probably mediated by decreasing the number of negatively charged groups on the surface of bacterial cells due to their protonation, and as a result decreasing the photosensitizer binding and efficiency of photobactericidal action [142].
Sensitization of Singlet Oxygen Formation in Aqueous Media
Fig. 5.10 Effect of pH on efficiency of photodynamic inactivation of genetically engineered E. coli strain pXen7 bioluminescence (B0/B) in the presence of 1 mM ZnPcChol8. Irradiation by white light at a dose of 6 J/cm2 (Courtesy of the author)
301
8
6
B0/B, relative units
5
4
2
0 5,0
5,5
6,0
6,5
7,0
7,5
8,0
pH
The wide range of microorganisms was studied under photodynamic treatment with cationic photosensitizing dyes. For example, it was found that octapyridiniomethyl substituted phthalocyanine of zinc inactivated with 100% efficiency Gram-negative and Gram-positive microorganisms – coliform bacteria, pseudomonas, enterococcus [141]. Tetra alkyl-substituted cationic phthalocyanines with hydrocarbon chaines attached to the pyridyloxy group were shown to photoinactivate efficiently the Gram-positive Staphylococcus aureus, the Gram-negative Pseudomonas aeruginosa [143] and Aeromonas hydrophila [144]. Studies have revealed the difference in photodynamic action towards different groups of microorganisms. Lower sensitivity of Proteus mirabilis to photodynamic inactivation, compared to that of E. coli and Salmonella enteritidis, due to low affinity of the cationic dye to the cells of this species was reported [142]. Obviously the difference in photodynamic action towards different groups of microorganisms is connected with diversity in bacteria morphology, particularly density of negative charges on the surface of cells, influencing sensitizer interaction with bacteria and consequently efficiency of PDI. With few exceptions, only sensitizers incorporated into cell lead to photoinactivation, presumably because the 1O2 generated outside the membrane is quenched by the solvent before diffusion into the membrane can occur [47]. Thus one of the major parameters governing the photosensitizing efficiency of photosensitizers is their ability, after localizing in the plasma membrane, to cross it and reach at intracellular targets. Anionic sensitizers such as TSPP have been shown to accumulate preferentially either in the cytoplasmic membranes (the more lipophylic TS1PP) or in the lysosomes (the more hydrophilic forms) [148]. Cationic sensitizers could target nucleic acids and cause effective DNA photodamage [149]. Cationic phenothiazines, porphyrins, and phthalocyanines have been shown to efficiently photosensitize the inactivation of yeasts and fungi [9, 143]. With regard to spores, these of sulfite-reducing Clostridium are resistant to photoinactivation
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[141], however several types of Bacillus spores can be inactivated by red light irradiation in the presence of phenothiazinium dyes [150]. Viral pathogens are also inactivated effectively in water by cationic sensitizers [151]. Examples from recent works are photoinactivation of avian influenza [152], sewage bacteriophage [153], herpes simplex viruses [154]. Inactivation of viruses by anionic and neutral photosensitizers has been also observed but this requires higher irradiation periods than for cationic ones [155]. Protein capsid, nucleic acids and lipid envelopes are potential targets for photosensitizer binding to viruses, but no generalization can be made as to the primary target. It has been shown that enveloped viruses are significantly more sensitive to photodynamic destruction than nonenveloped viruses. It is likely that positively charged photosensitizers cause nucleic acid damage, whereas anionic photosensitizers act against the viral envelope [151]. The major use of photosensitizers for viral inactivation is in the disinfection of blood and blood products. The human immune-deficiency virus, hepatitis viruses B and C can spread through blood transfusion. Some in vitro studies showed that water-soluble sensitizers could inhibit replication of these viruses. Methylene Blue has, in fact, been widely used by several European transfusion services in the photodecontamination of blood plasma [151]. In conclusion, two groups of factors influence sensitizer interactions in aqueous media with microorganisms and consequently their photodynamic inactivation. On one side, these are the sign of the charge and the number of ionic substituents in sensitizer molecules, and on the other side, these are factors that define the charge of the microorganism surface (composition and charge of shell, content of bivalent ions Mg2+ and Ca2+ in the medium, pH) [142].
5.7.1.2
Photodynamic Therapy of Cancer
During the past two decades, research activity in the PDT field has expanded enormously. The greater number of potential photosensitizers for PDT have been synthesized and described in numerous reviews [54, 156, 157]. The photosensitizers used in clinical trials differ in hydrophilicity in wide range. The aim of this chapter is trying to show the role of sensitizer hydrophilicity in PDT. Water solubility of photosensitizer for PDT is required for injection and for easy administration into the blood stream. Additionally, the drug will have to traverse lipid membranes – consequently, it should also be lipophilic. Hydrophobic waterinsoluble sensitizers also have been successfully applied to PDT in a micellar composition or a liposomal formulation. The correlation between cellular uptake and hydrophobicity was not found [158]. However it is commonly accepted that the best photosensitizers in PDT are often amphiphilic, having both hydrophilic and hydrophobic regions [54]. The photosensitizer molecules often move in the circulation attached to plasma proteins, such as albumin and lipoproteins. Table 5.7 describes the distribution of photosensitizers with different hydrophilicity in various structural components of
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Table 5.7 The distribution of photosensitizers into different structures of blood and tumor (Reproduced from Ref. [54] with kind permission of Elsevier) Photosensitizer Transport in blood Target Aggregated Unbound, micelle-like structure Macrophages, endothelial and cancer cells Hydrophobic Bound to the lipid moiety of lipoproteins Cancer cells Hydrophilic Loosely bound to albumin, globulins, and Vascular stroma apolipoproteins
blood and tumor. Hydrophilic photosensitizers are less prone to self-aggregation in plasma than hydrophobic ones. Though the photosensitizer aggregates cannot normally penetrate the cell’s plasma membrane, the cancer cells can ingest smaller aggregates by endocytosis and the macrophages in the tumor tissue can ingest the larger ones ([54] and refs. therein). The most common water-soluble photosensitizers for PDT are the sulfonated MPcs. It was found that lower gallium phthalocyanine sulfonation favored liver and spleen uptake whereas higher dye sulfonation resulted in greater kidney uptake and preferential excretion via the urine [159]. Accumulation of anionic AlPcS in tumor increased with degree of sulfonation [160]. Studies on a cancer cell cultures have shown that photosensitizers can be ordered according to the relative uptake and cell killing efficacy as follows: cationic > neutral > anionic compounds [161]. As mentioned above, cationic photosensitizers possess good membrane binding due to the negative membrane potential. Phototoxicity was shown to increase proportionally with membrane binding efficiency, which allows more efficient membrane photooxidation. However photosensitizers of different charge have shown good therapeutic effects on tumors [157]. Hence, additional factors, besides photosensitizer charge, play an important role in PDT of cancer. Nevertheless, cationic photosensitizers are considered to be especially promising clinical agents because they can accumulate in mitochondria, an effect that is driven by the transmembrane potential of the inner mitochondrial membrane. Photosensitizers that accumulate in mitochondria have been found to trigger apoptosis efficiently [54]. At the cellular and subcellular level the lipophilic sensitizers are photoactive against hydrophobic or membrane-associated components, and hydrophilic ones are most effective on water-soluble components, including cytoplasmic enzymes [47]. Photosensitization can induce cell death via direct damage to the cell membrane resulting in cell membrane rupture (necrosis) or by triggering the DNA fragmentation process leading to apoptosis [162]. It seems that there is no connection of the mode of cell death with hydrophilicity of the photosensitizer. The mode of cell death is dependent on the doses of light and sensitizer. The low doses result in apoptosis, high – in necrosis [163].
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Tumor-specific accumulation of photosensitizers is extremely important for PDT. To utilize advantage of the enhanced uptake of glucose by malignant cells, much effort has been devoted to the development of photosensitizers incorporating biologically active sugar moieties [62, 164]. Carbohydrate residues improve the water-solubility and enhance sensitizer uptake by tumor cells. Owing to this the highly water-soluble neutral conjugates of carbohydrates and porphyrins or phthalocyanines are considered as photosensitizers with great potential in PDT. At the end of this section, other characteristics, which in addition to high singlet oxygen quantum yield the good photosensitizer for PDT of cancer must meet, are also reported [54]. Due to specific character of living organisms a good photosensitizer is not toxic in the absence of light. It should be enriched in the tumor as selectively as possible, and be eliminated from the body sufficiently quickly. It should not self-aggregate much in the body, because the aggregation decreases FD. It should also absorb light of sufficiently long wavelengths, where the transparency of biological tissue is higher. Unlike aqueous media, high hydrophilicity of photosensitizer is desirable, but not obligatory for PDT of cancer. To date the best photosensitizers in PDT are often amphiphilic, having both hydrophilic and hydrophobic regions. Currently, the cationic photosensitizers are considered to be especially promising clinical agents.
5.7.2
Wastewater Treatment
The use of solar energy in the photosensitized detoxification and treatment of industrial and urban wastewaters could be an economical solution to a difficult environmental problem. Singlet oxygen, being an electrophilic agent, oxidizes unsaturated double bonds, sulfide, phenolic, amino groups, and other electron-donor groups in organic compounds. A great deal of work has been done on the use of photosensitized singlet oxygen to remove the environmentally hazardous phenols, which are found in the wastewater of paper and dye manufacturing industries, as well as oil refineries [3–5, 165]. The results demonstrated that a monomeric state of the photosensitizer in solution is crucial to its activity in photoreactions. The addition of oppositely charged detergents to reduce aggregation improved phenol oxidation. The oxidation of sulfide salts in aqueous solution is also important in wastewater treatment, due to its occurrence as a byproduct of industrial processes such as petroleum refining, tanning, coking, natural gas purification, food processing, and this process was examined in number of studies [166, 167]. To take advantage of heterogeneous photocatalysts to be easily separated from the reaction medium and reused, the immobilization of singlet oxygen sensitizers onto the various materials was developed (see Sect. 5.4.2). However, full mineralization of organic contaminants with such moderate oxidant, as singlet oxygen, can not be achieved. Seemingly, for this reason singlet oxygen photosensitizers have not gained wide use for water detoxification by now.
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Conclusions
Generation of singlet oxygen in aqueous environment is important for number of applications including medical, namely photodynamic therapy of cancer and antimicrobial therapy. However water is unfavorable solvent for processes involving singlet oxygen and its quantification due to low lifetime of these species in aqueous solutions. A short tutorial coverage of different mechanisms for singlet oxygen formation and methods for the quantitative determination of singlet oxygen in aqueous media gives hope that this review will be a handy reference for those involved in study and application of sensitizers in aqueous and biological environment. It was demonstrated that major advances have been made in the synthesis of water-soluble photosensitizers and study of their activity. The main groups of photosensitizers for singlet oxygen formation in aqueous environment were considered. These comprise xanthene and phenothiazinium dyes, porphyrin derivatives, phthalocyanines (including carbohydrate conjugates and differently charged ones), subphthalocyanines, Ru-complexes, water-soluble fullerenes. Immobilized sensitizers are also very important for singlet oxygen applications in aqueous media not only for use in water purification, but for photodynamic therapy (on nanocarriers). This approach is very promising and requires further study. The understanding of factors affecting photosensitizer abilities in aqueous environment is also developed. Those include aggregation of photosensitizer, coordination and electrostatic interactions, hydrogen binding, influence of electrolytes, pH, photoinduced electron transfer. The problem of aggregation of photosensitizers has main detrimental effects to their use. The foregoing pages have illustrated strategies to improve the sensitizer ability in aqueous environment. The study of photosensitizer photobleaching is of immense importance for application. The currently known data on the photostability of photosensitizers with overview of possible photodegradation mechanisms in aqueous environment have been presented and discussed. Water-soluble photosensitizers are of interest for medicine, microbiology, environmental science. PDT seems to be the most important their application. Although major advances have been made in this field, the search of new photosensitizers still is needed. Thus, the selectivity of photosensitizer remains a major issue in PDT, as photosensitivity of the patient after PDT treatment is a serious problem. In microbiology the antibiotic resistance of pathogenic bacteria is a major concern nowadays. The possibility to eradicate bacteria, especially Gram-negative species, by light-activated sensitizers seems to have immediate potential for the treatment of localized infections, surface water microbial contamination and for drinking water disinfection. It was demonstrated that electrostatic interaction between charged dye and bacterial cell wall is the most important factor affecting bacteria photodynamic inactivation. This finding constitutes the background for design of new feasible and efficient sensitizers for this purpose. The use of solar energy and photosensitizer in the detoxification of chemicals, such as sulfides and phenols, in water is very attractive. Full mineralization of
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organic contaminants with such moderate oxidant, as singlet oxygen, can not be achieved; however in combination with other methods of wastewater purification, for example biological treatment, photosensitized oxidation may be helpful. Singlet oxygen reactions are highly selective and represent efficient synthetic route to a broad variety of products. However an aqueous solution is unfavorable medium for synthesis of fine chemicals due to extremely low lifetime of singlet oxygen in this solvent. Therefore this important application in review was omitted. At this point it is necessary to remark that described peculiarities of the sensitizer’s behavior and singlet oxygen generation in aqueous and biological media determine the efficacy of oxidation processes on discussed applications. Acknowledgments The author is grateful to Prof. O. L. Kaliya for encouragement and fruitful discussion. Financial support by the Moscow City Government is also deeply acknowledged.
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128. Dairou J, Vever-Bizet C, Brault D (2002) Self-association of disulfonated deuteroporphyrin and its esters in aqueous solution and photosensitized production of singlet oxygen by the dimers. Photochem Photobiol 75:229–236 129. Ben-Hur E, Dubbelman TM, Van Steveninck J (1992) Effect of fluoride on inhibition of plasma membrane functions in Chinese hamster ovary cells photosensitized by aluminum phthalocyanine. Radiat Res 131:47–52 130. De Silva AP, Gunaratne HQN, Gunnlaugsson T et al (1997) Signaling recognition events with fluorescent sensors and switchers. Chem Rev 97:1515–1566 131. Ozlem S, Akkaya EU (2009) Thinking outside the silicon box: molecular and logic as an additional layer of selectivity in singlet oxygen generation for photodynamic therapy. J Am Chem Soc 131:48–49 132. Bonnett R, Martinez G (2001) Photobleaching of sensitizers, used in photodynamic therapy. Tetrahedron 57:9513–9547 133. McCubbin I, Phillips D (1986) The photophysics and photostability of zinc(II) and aluminium(III) sulphonated naphthalocyanines. J Photochem 34:187–195 134. Spikes JD (1992) Quantum yields and kinetics of the photobleaching of hematoporphyrin, Photofrin II, tetra(4-sulfonatophenyl)-porphine and uroporphyrin. Photochem Photobiol 55:797–808 135. Spikes JD, Bommer JS (1993) Photobleaching of mono-L-aspartyl chlorine e6 (NPc6): a candidate sensitizer for the photodynamic therapy of tumors. Photochem Photobiol 58:346–350 136. Kuznetsova N, Kaliya O, Lukyanets E (1995) Photochemistry of laser dyes for visible region. “Atomic and molecular pulsed lasers”. Proc SPIE 2619:161–165 137. Darwent J, McCubbin I, Phillips D (1982) Exited singlet and triplet state electron-transfer reactions of aluminium(III) sulphonated phthalocyanine. J Chem Soc Faraday Trans 2(78):347–357 138. Linden SM, Neckers DC (1988) Type I and type II sensitizers based on rose Bengal onium salts. Photochem Photobiol 47:543–550 139. Jori G, Brown SB (2004) Photosensitized inactivation of microorganisms. Photochem Photobiol Sci 3:403–405 140. Kuznetsova N, Kaliya O, Vorozhtsov G (2006) Solar photodynamic oxidative disinfection of ponds. European conference “Environmental applications of advanced oxidation processes”, Chania, Book of Abstracts 141. Kuznetsova NA, Kaliya OL, Vorozhtsov GN (2007) Photosensitized oxidation by dioxygen as the base for drinking water disinfection. J Haz Mater 146:487–491 142. Strakhovskaya MG, Antonenko YN, Pashkovskaya AA et al (2009) Electrostatic binding of substituted metal phthalocyanines to enterobacterial cells: it’s role in photodynamic inactivation. Biochem (Moscow) 74:1305–1314 143. Mantareva V, Kussovski V, Angelov I et al (2007) Photodynamic activity of water-soluble phthalocyanine zinc(II) complexes against pathogenic microorganisms. Bioorg Med Chem 15:4829–4835 144. Kussovski V, Mantareva V, Angelov I et al (2009) Photodynamic inactivation of aeromonas hydrophila by cationic phthalocyanines with different hydrophobicity. FEMS Microbiol Lett 294:133–140 145. Ikawa Y, Moriyama S, Harada H, Furuta H (2008) Acid-base properties and DNA-binding of water-soluble N-confused porphyrins with cationic side-armes. Org Biomol Chem 6:4157–4166 146. Da Silva A, Jr TO (2003) Effects of the antimicrobial peptide PGLa on live Escherichia coli. Biochim Biophys Acta 1643:95–103 147. Lambrechts S, Aalders M, Langeveld-Klerks D et al (2004) Effect of monovalent and divalent cations on the photoinactivation of bacteria with meso-substituted cationic porphyrins. Photochem Photobiol 79:297–302
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148. Wessels JM, Strauss W, Seidlitz HK et al (1992) Intracellular localization of meso tetraphenylporphyrin tetrasulphonate probed by time-resolved and microscopic fluorescence spectroscopy. J Photochem Photobiol B Biol 12:275–284 149. Villanueva A (1993) The cationic meso-substituted porphyrins: an interesting group of photosensitizers. J Photochem Photobiol B Biol 18:295–298 150. Demidova TN, Hamblin MR (2005) Photodynamic inactivation of Bacillus spores mediated by phenothiazinium dyes. Appl Environ Microbiol 71:6918–6925 151. Wainwright M (2004) Photoinactivation of viruses. Photochem Photobiol Sci 3:406–411 152. Kuznetsova N, Kaliya O, Strakhovskaya M, Zubairov M (2009) Photodynamic inactivation of avian influenza virus in aqueous media. First international workshop on application of Redox technologies in the environment, Istambul, pp 145–147 153. Costa L, Alves E, Carvalho C et al (2008) Sewage bacteriophage photoinactivation by cationic porphyrins: a study of charge effect. Photochem Photobiol Sci 7:415–422 154. Silva EMP, Giuntini F, Faustino MAF et al (2005) Synthesis of cationic beta-vinyl substituted mesotetraphenylporphyrins and their in vitro activity against herpes simplex virus type 1. Bioorg Med Chem Lett 15:3333–3337 155. Casteel MJ, Jayaraj K, Gold A et al (2004) Photoinactivation of hepatitis a virus by synthetic porphyrins. Photochem Photobiol 80:294–300 156. Bonnett R (1995) Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem Soc Rev 24:19–33 157. Lukyanets EA (1999) Phthalocyanines as photosensitizers in the photodynamic therapy of cancer. J Porphyrins Phthalocyanines 3:424–432 158. Ben-Dror S, Bronshtein I, Wiehe A et al (2006) On the correlation between hydrophobicity, liposome binding and cellular uptake of porphyrin sensitizers. Photochem Photobiol 82:695–701 159. Rousseau J, Langlois R, Ali H, van Lier JE (1990) Biological activities of phthalocyanines. XII: synthesis, tumor uptake and biodistribution of 14C-labled disulfonated and trisulfonated gallium phthalocyanine in C3H mice. J Photochem Photobiol B 6:121–132 160. Chan W, Marshall J, Svensen R et al (1990) Effect of sulfonation on the cell and tissue distribution of the photosensirizer aluminum phthalocyanine. Cancer Res 50:4533–4538 161. Wood SR, Holroyd JA, Brawn SB (1997) The subcellular localization of Zn(II) phthalocyanines and their redistribution on exposure to light. Photochem Photobiol 65:397–402 162. Agarwal ML, Clay ME, Harvey EJ et al (1991) Photodynamic therapy induces rapid cell death by apoptosis in L5178Y mouse lymphoma cells. Cancer Res 51:5993–5996 163. Villanueva A, Dominguez V, Polo S et al (1999) Photokilling mechanisms induced by zinc(II)-phthalocyanine on cultured tumor cells. Oncol Res 11:447–453 164. Hirohara S, Obata M, Alitomo H et al (2009) Synthesis and photocytotoxicity of S-glucosylated 5,10,15,20-tetrakis(tetrafluorophenyl)porphyrin metal complexes as efficient 1O2-generating glycoconjugates. Bioconjug Chem 20:944–952 165. Cai J-H, Huang J-W, Zhao P et al (2008) Photodegradation of 1,5-dihydroxynaphthalene catalyzed by meso-tetra(4-sulfonatophenyl)porphyrin in aerated aqueous solution. J Mol Catal A Chem 292:49–53 166. Iliev V, Prahov L, Bilyarska L et al (2000) Oxidation and photooxidation of sulfide and thiosulfate ions catalyzed by transition metal chalcogenides and phthalocyanine complexes. J Mol Catal A Chem 151:161–169 167. Spiller W, Wohrle D, Schulz-Ekloff G et al (1996) Photo-oxidation of sodium sulfide by sulfonated phthalocyanines in oxygen-saturated aqueous solutions containing detergents or latexes. J Photochem Photobiol A Chem 95:161–173
Chapter 6
The Use of Phthalocyanines and Related Complexes in Photodynamic Therapy Rodica-Mariana Ion
Abstract The phthalocyanines and porphyrins are the most used compounds, called photosensitizers (PS) into photodynamic therapy, due to their NIR absorbing wavelenghts, non-toxicity and high photochemical efficiency. The aim of this chapter is to achieve a better understanding of the phthalocyanines and related compounds, like free bases and metallo-complexes and their sensitizer properties, especially. The photophysical properties (absorption, triplet state, singlet oxygen, photobleaching, and fluorescence quantum yields, and triplet lifetimes so on) are discussed well correlated with their photodynamic activity. Their photodynamic tests in vitro on different cells lines, is discussed properly, taking into account the huge number of existing publications. Some clinical results obtained by using phthalocyanines, porphyrins and related compounds are discussed, too, in order to provide initial data on how currently used PS differ regarding basic PDT-related properties.
6.1
Introduction
Photodynamic therapy (PDT) is a relatively new cytotoxic treatment, predominantly used in anticancer approaches, that depends on the retention of photosensitizers (PS) in tumour cells and their activation within the tumour through irradiation with light of the appropriate wavelength [1]. Photoactivated PS generate reactive oxygen species (singlet oxygen, 1O2, and free radicals, such as ·OH, HO2 and·O2–) which are able to damage cellular structures, meaning that PDT is particularly attractive as an alternative means to kill drug- and radioresistant tumour cells. Normal cells, R.-M. Ion (*) Analytical Department, National Institute of R&D for Chemistry and Petrochemistry – ICECHIM, 202 Splaiul Independentei, Bucharest 060021, Romania Faculty of Materials Engineering, Mecathronics and Robotics, Valahia University, 013200 Targoviste, Romania e-mail: [email protected]
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however, are also able to accumulate PS and be damaged by them, so that prolonged skin photosensitization, light-sensitivity of the eye and other side-effects have proved to be severe limitations of PDT [2, 3]. When photoactivated, PS involves damage on many types of biomolecules without any specificity, their action being mediated via the reactive oxygen species mentioned, none of which travel more than several tens of nanometers before reacting with a biomolecule. Keeping in mind that cell dimensions are of micrometers or tens of micrometers, it is clear that the intracellular action of PS is restricted to the site of their subcellular location and the surrounding radius of not more than 40 nm [4]. In order to reduce the dose of PS administered to patients and hence to minimize the harmful side-effects of PDT, new approaches on PDT have been focused during last years on different directions, some of them being presented in this review. Ideally, a sensitizer should be red or near infrared light absorbing; non-toxic, with low skin photosensitizing potency; selectively retained in tumours relative to normal adjacent tissue; an efficient generator of cytotoxic species, usually singlet oxygen; fluorescent, for visualization; of defined chemical composition, and preferably water soluble, although with the use of liposome delivery systems, the last is not essential [5, 6]. Photosensitizers used in PDT differ from the following point of view: 1. chemical characteristics (molecular weight, hydrophilicity, electric charge); 2. photochemical and photophysical properties such as absorption maximum and quantum efficiency for formation of reactive oxygen species (ROS) and singlet oxygen, especially; 3. biological properties such as the cellular uptake mechanism, tumor selectivity, and intracellular localization [7–9]. Thus, it is of importance to find out which photosensitizer meets the necessary requirements to achieve the best clinical outcome. Allison et al. [5] proposed three broad chemical families that are clinically relevant PS: 1. porphyrins (e.g. hematoporphyrin derivative (HpD), and the endogenously produced protoporphyrin IX (PPIX), formed in most cell types from its precursor 5-aminolevulinic acid (ALA)); 2. chlorophyll derivatives (e.g. meso-tetrahydroxyphenylchlorin (mTHPC), bacteriochlorins); 3. dye substances (e.g. phthalocyanines and naphthalocyanine) [4]. The phthalocyanines and porphyrins are the most used compounds in this area, due to their NIR absorbing wavelenghts, non-toxicity and high photochemical efficiency [10–13].
6.2
Phthalocyanines and Porphyrins – Molecular Structure and Photophysical Properties
The relationships between the chemical structure and the tumor localizing activity of photosensitizers leads to the conclusion that the optimal tumor localizing efficiency is imparted to be phthalocyanine- and porphyrin-type macrocycle [14, 15].
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Fig. 6.1 The phthalocyanine structure
Fig. 6.2 The porphyrin structure
The present work is focussed on the principles of photodynamic therapy (PDT), emphasing the photochemical mechanisms of reactive oxygen species formation and the consequent biochemical processes generated by the action of reactive oxygen species on various biological macromolecules and organelles. This paper also presents some of the most used photosensitizers, including Photofrin, and the new types of photosensitizers – porphyrins and phthalocyanines – analyzing their physicochemical and spectroscopic properties [15]. Phthalocyanine molecules (Pc) are composed of four indole units – pyrrole rings linked by nitrogen atoms conjugated with benzene rings (Fig. 6.1) whereas the porphyrins (P) (Fig. 6.2) constitute a class of the molecules which contain four pyrrole rings linked by the methane carbon bridges. Phthalocyanines as expected from the extensively conjugated aromatic chromophore, exhibit UV-VIS absorption spectra with intense p−p* transitions [15]. Usually they referred to Q bands in the range 660–700 nm (e > 105 M−1 cm−1) with associated higher energy vibrational components in the range 600–660 nm.
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The relatively straightforward synthetic routes to the phthalocyanines furnish a wide range of compounds in terms of the central metal/semi-metalic atom and side chain functionality. A primary role of the ring substitution is to render the dye soluble in water. The presence of some substituents with high charge density (OH, COOH, and SO3H) on the periphery of the macrocycle make them to be soluble in polar media [16, 17]. The spatial spreading of the molecules after substitution might therefore be energetically favorable in view of their PDT activity. A higher number of p-electrons and their delocalization lead to the improvement of PDT effect. For PDT applications, the sulfonation reduces the efficiency of the interaction with oxygen, due to the short lifetime of the lowest-lying triplet state [18]. Although the phthalocyanines may be considered porphyrin derivatives, greatly increased aromatic character explains the more intense near infrared absorption of these compounds compared to that of the parent porphyrin nucleus. The metal free phthalocyanines show poor PDT activity as do phthalocyanines containing paramagnetic metals. In contrast, those with diamagnetic metals are active as a result of a long lifetime of the triplet states [19]. As a rule for predicting the ability of a photosensitizer to generate singlet oxygen on the basis of its O–O band an energy gap between the lowest excited singlet and triplet states of around 15 kcal/mol is required [20, 21]. As photosensitizers, phthalocyanines give high yields of singlet oxygen-greater than that of standard photosensitizers, such as methylene blue. Metalation, which reduces the electron density at the inner nitrogen atoms, produces a hypsochromic shift which depends on the electronegativity of the metal. Phthalocyanines become good sensitizers when they have short singlet and long triplet state lifetimes [22]. Typical fluorescence spectra of Pc complexes occur at around 700 nm and they are dependent on the central atoms [23]. When the central atoms belong to the first or second row elements (H2, Mg, Al and Si) the fluorescence quantum yield is high (0.57–0.85) [24]. This fluorescence quantum yield dramatically decreases in the case of third and fourth raw elements. Triplet lifetimes are high for metallo-complexes, especially for those with diamagnetic metals, while paramagnetic metals such as Cu, Ni – complexes show very short triplet lifetimes. Metallo-phthalocyanines (MPc) have triplet-state lifetimes of up to hundreds of ms, less than metallo-porphyrins. The fluorescence behavior of the phthalocyanines is in good agreement with the generally accepted idea concerning the effects of different metals on the excited states of the molecules. Some moderate fluorescence bands could be observed for Mg, Cd, Zn complexes, but with strong hypsochromic shifts. The small values of the lifetimes of the singlet states of the d10 or d0 metallo-porphyrins or metallo-phthalocyanines and the very short triplet state lifetimes are due to the rapid non-radiant excitation or the p−p* states (generated via a d-d or ring-metal charge transfer excited state). Long lived triplet state causes the efficient photosensitization, therefore phthalocyanines with diamagnetic metal such as Zn, seems to be better suited for PDT than those with paramagnetic metals. p-electrons of phthalocyanine ring rather than metal are involved in the charge separation process and thus they contribute to the
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dye activity. The metals are able to induce some changes in the electron cloud distribution. Not only metals can enhance PDT effect but also the peripheral groups attached to the main molecular core which can have photoresponse. Such a delocalization can weaken electrons bonding with the maternal molecules followed by the enhancement of their activity. When Pc is chelated with metals such as aluminium (diamagnetic metal) their photoxicity is enhanced. Aluminium appears to have a high potential for photodynamic activity of the Pc macrocycle compared with Zn and sulphonation progressively increase PDT activity. AlPcS2 and AlPcS4 are more effective than non-sulphonated AlPc in PDT, in contrast with the trend found in other work [25]. Triplet state, singlet oxygen, photobleaching and fluorescence quantum yields, and triplet lifetimes of MPc complexes are largely affected by the nature of substituents and by aggregation behaviour of the complexes. These paramenters are affected by addition of bovine serum albumin (BSA), or human serum albumin (HSA) surfactants, and deutederation. New nano-drug delivery system based on BSA nanospheres incorporating surface-functionalized magnetic nanoparticles and a sensitizer, as silicon-phthalocyanine, have been studied [25]. These systems present spherical shape with hydrodynamic average diameter values ranging from 170 to 450 nm. Their time-dependent fluorescence measurements revealed a bi-exponential decay for samples, in the time window ranging from 1.7 to 5.2 ns. Generally, the triplet quantum yields increase for the heavier central metals due to the heavy atom effect, which inevitably shortens the triplet lifetimes. There has been considerable literature on the Zn and Al phthalocyanine complexes with less attention to the other non-transition metal (e.g. Ge, Si, Sn, Ga and In) [26]. For a good sensitizer activity, a relationship between fluorescence-singlet state and substituents is necessary. In aqueous solutions, also in organic solvents, the free-base porphyrins and their Mg, Zn, Cd derivatives, show distinct fluorescence with one or two bands of moderate intensity in the 550–750 nm range and exhibit high quantum yields and long triplet excited state lifetimes. The transition metallo-porphyrins of groups VIII and IB show low fluorescence quantum yields associated with the filling of the eg(dp) orbitals. The stability of metal phthalocyanines is due to formation of four equivalent N→metal bonds involving filling of vacant ns, np, and (n − 1)d or nd orbitals of the cation with p electrons of the central nitrogen atoms. The nature of the central metal influences photophysical properties of phthalocyanines, among them the quantum yield of the formation of the triplet state and its lifetime. Pcs with open shell or paramagnetic metal ions such as Cu2+, Co2+, Fe2+, Ni2+, V2+, Cr3+ and Pd2+ exhibit short triplet lifetimes (submicrosecond range) due to increased intersystem crossing back to the ground state, which renders the dye photoinactive [27]. Pcs containing closed d shell or diamagnetic metal ions, such as Zn2+, Al3+ and Ga3+, are dyes exhibiting high triplet yields (dT > 0.4) with long triplet lifetimes in the micro- and millisecond range (tT > 200 ms) [28]. The energies of triplets, exceeding 1.14 eV (110 kJ mol−1) [29], are sufficient to generate singlet oxygen (E1O2 » 94 kJ mol−1, i.e., »0.97 eV).
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For PDT action, it is necessary that the drug be easy to administer via injection into the blood stream. Water solubility is also essential for use of MPc complexes. The most common water-soluble complexes are the sulfonated MPcs [30, 31]. Sulphonation [32] by the reaction of MPc complexes with fuming sulfuric acid (containing SO3) gives a variable mixture of differently sulphonated metallophthalocyanine complexes (MPc(SO3−)n where M = metal ion, n is a mixture of 1, 2, 3, or 4 sulfo groups, which will be represented as MPcSmix in this review), each containing a variety of positional isomers. Tetrasulphonated derivatives are generally synthesized by the method of Weber and Busch [33]. The sulphonation of the molecule significantly increases its solubility in polar solvents. For example, ZnPcS4 is highly water-soluble and allows its intravenous administration without the need for alternative delivery vehicles. The presence of zinc as the central metal ion confers some interesting characteristics to ZnPcS4: (a) short triplet lifetime; (b) high triplet quantum yields; (c) high singlet oxygen quantum yields, which increase its photoactivity [34–36]. AlPcS4 is released slightly faster into the medium supernatant as compared to mTHPC, hypericin, and Photofrin and the uptake is characterized by a rapid increase within the first hour and a lower but continuous rise up to 30 h post incubation, respectively. One of the advantages of AlPcS4 is its absorbance wavelength at 673 nm implicating the use of excitation wavelengths that efficiently penetrate into tissue. AlPcS4 represents a hydrophilic, anionic PS allowing for direct application in aqueous solution. A ring substitution of the phthalocyanines with sulphonated groups will render them water soluble and affect the cellular uptake. Taking into account a total of properties of the compounds under examination (solubility in water and physiological solutions, quantum yield of fluorescence, dimer formation, etc.), only Al(OH)PcS1 appears unsuitable. Less sulphonated compounds, which are more lipophilic, show the best membrane – penetrating properties and highest biological activity [37]. UV–Vis absorption spectra point to the dimerization of Al(OH)PcS2 and Al(OH) PcS3 in acidic solutions. Major spectral features of the compounds are weakly affected by the number of sulphonated groups. The fluorescence quantum yields are high (up to 0.74), depending on the number of sulfonate groups. The singlet state lifetimes are of the order of a few nanoseconds which may be considered typical values, the triplet lifetimes, however, appear quite short in comparison with the values reported in the literature [38, 39]. All these phthalocyanines have specific absorption spectra, as it is shown in Fig. 6.3. Except for zinc phthalocyanines, in photodynamic therapy, a number of other MPcSmix complexes (where M = Ge(IV), Zn(II), Si(IV), Sn(IV), Al(III), TiO), has been used in photodynamic therapy. GePcSmix in particular, showed very large triplet quantum yield (FT = 0.67) and triplet life time (tT = 780 ms) in dimethyl sulfoxide (DMSO) [40]. The latter value compares well with the value for AlPcSmix of 800 ms, but the FT value for the GePcSmix complex was even larger than FT = 0.52 for the AlPcSmix complex. GePcSmix also gave a relatively large singlet oxygen quantum yield (FD = 0.68).
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Fig. 6.3 The absorption spectra of symmetrical and asymmetrical phthalocyanines
The phthalocyanines showed high singlet oxygen quantum yields ranging from 0.76 to 0.85 because of their large triplet quantum yields and sufficient long triplet lifetime (80 and 69 ms). The Pcs still maintain long fluorescence lifetime and good fluorescence quantum yields. Together with their strong absorption in the red region around 700 nm, all these properties give an indication of the potential of the complexes as photosensitizers in applications where singlet oxygen is required (Type II mechanism), in particular as Type II photosensitizers for PDT, but also good for fluorescent imaging of tumors and the biodistribution detection of the sensitizers themselves [41].
6.3
PDT Mechanism
Photodynamic therapy (PDT) can be considered a very promising approach for anticancer research. It consists of the selectively uptake of a photosensitizing dye, often a porphyrin, by a tumor tissue and subsequent irradiation of the tumor with a light flux of an appropriate wavelength matched to the absorption spectrum of the photosensitizing dye. In PDT a chemical reaction activated by light is used to selectively destroy tissue. The reaction requires three basic elements: photosensitizing compound (porphyrins, porphyrin precursors, phthalocyanines, chlorines and others); light; oxygen (1O2) and other free radicals. Depending on the power density, light and laser light in particular induces different effects in biological tissues like photochemical reactions, coagulation, photo- and thermal ablation, plasma formation and photodisruption. The photochemical interaction occurs at very small power densities (0.01 − 50 W/cm2) and plays significant role during the PDT. To perform this therapy, spectrally adapted chromophores are injected into the body, the most used being porphyrins and related compounds. Irradiation with a suitable wavelength may trigger selective photochemical reactions, resulting in desirable biological transformations. The photodynamic reactions involve electronic excited states of the sensitizer’s molecules: the singlet state, the first transient after excitation and the triplet state which is the second intermediate.
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Firstly, the sensitizer is excited from its ground singlet state into an excited electronic triplet state (lifetime 10−3–10 s) via a short-lived excited singlet state, after the light absorption. It can react directly either with substrate or solvent by hydrogen atom or electron-transfer to form radicals and radical-ions which can produce oxygenated products after interaction with oxygen, or it can transfer its energy directly to oxygen to form singlet oxygen (lifetimes = 4 × 10−6 s in water, 50–100 × 10−6 s in lipids, 0.6 × 10−6 s in cellular environment), a highly reactive oxidative species [42]. The energy of the first excited triplet state leads to unfavorable Franck-Condon factors, which prevent efficient coupling of the initial sensitizer-oxygen encounter complex to product states, thereby inhibiting the generation of 1Dg O2 and/or highly excited 3Sg+ O2 molecules (excitation energy, approximately 13,200 cm−1) [43, 44]. The energy transfer from the S1 state of the sensitizer to molecular oxygen, with the subsequent generation of 1D g O2, may occur if the S1 --> T1 energy gap is greater than 7,900 cm−1 and the sensitizer has a singlet state lifetime long enough (tS > 500 ns), to allow ample bimolecular collisions with oxygen molecules. Compounds with a triplet state energy below 7,900 cm−1 possess a high triplet state quantum yield and a high absorbance in the red or near IR region (800–900 cm−1) and may still be good candidates for type I sensitizers if they possess long-lived excited singlet and/or triplet states (500 ns or longer) with a tendency to promote electron transfer reactions. The oxygen concentration in oxygen-saturated solutions is [O2] = 10−3–10−2 mol/l. The reaction between 3Sens* and oxygen is diffusion controlled type reaction, so that it is very rapid (kO2 = 109–1010 l/(mol. s)). A type I photooxidation reaction occurs only if kA[A] has a value of 106–107 s−1. If kA or [A] have small values, then type II reaction occurs (if oxygen is present in small concentration). If kA has a great value, then type III reaction occurs (the oxygen is completely absent in the system). These specie initiates the damaging effect of PDT which is realised via several pathways: 1. Cell necrosis and apoptosis: The relation between the mode of cell death (apoptosis or necrosis) may be dependent mainly on the cell line and the photosensitizer used. For example, AlPcS4 as hydrophilic sensitizer is located in endosomes and lysosomes due to its uptake cell death. This photoactivation would lead to a necrotic cell death [44]. By comparison, aluminium phthalocyanine chloride induced necrosis on the neoplastic cell line. This may be related to the fact that lesions to the lysosomes membrane are followed by enzyme leakage in the cytoplasm. The activation of these enzymes causes enzymatic digestion of cellular components evidenced by nuclear alterations. Lipid peroxidation and protein crosslinking affect cell membrane enzymes and transmembranous transport. This induces further accumulation of sensitizer and cell ballooning, while alteration of mitochondrial membranes and related enzymes blocks cell respiration [43]. Mitochondria and lysosomes have been identified as key components for apoptosis [43].
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2. Microcirculation arrest: Damage of endothelial cells promotes thrombus formation and vascular stasis which also contributes to tumour ablation [45]. 3. Inflammation in the exposed tissue: Accumulation of macrophages and myeloid cells follows the direct damage to cells and impaired circulation. 4. Induction of host immune response: Release of tumour antigens resulting from inflammation stimulates host immune response even to poorly immunogenic processes. From biological point of view, there are three main mechanisms by which tumors are destroyed during PDT: • direct cell destruction [46, 47] • damage to the vascular stroma [48] • immune elimination [49, 50]. The precise mechanism of cytotoxicity is a relative one. It is dependent on the sensitizer, light sources and cellular lines used for experiments. For example, for AlPcS4 it is suggested an initial process of intrinsic death pathway, while for ZnPc, a prostanoid-mediated activation of death machinery is suggested [50]. However, it is known that the reactive oxygen species, including 1O2, react with and oxidase many cellular constituents, including proteins, lipids and nucleic acids, producing an oxidative stress that is lethal to cells. PDT has been shown to induce apoptosis in many cultured cells and in most animal model tumors [51–54]. DNA has been determined to be a major target of the photodynamic damage. Loss of viscosity, single stranded breaks, apurination, dimerization, and loss to function as a template for DNA polymerase, is the main evidences of DNA damages in vitro, induced by different dyes [8, 55]. DNA damage may include not only single- and double- stranded breaks, but also, the production of damaged bases, such as thymine dimers or guanine residues that have been depurinated or hydroxylated, resulting in alkali-labile phosphodiester bonds. Kinds of DNA damage that happens under the influence of light include altered or missing bases, single-strand breaks, and cross-linking. Apurinic/apyrimidinic (AP) sites are generated spontaneously and by treatment with acid or as a result of chemical alkylation of deoxyguanosine, which weakens the N-glycosidic bond that attaches the base to the sugar-phosphate backbone of the DNA [56]. Instead of this aspect, the main effect of photodynamic therapy action upon DNA by different porphyrins is the degradation of the purine bases resulting in the biological activity lost and, under more drastic conditions chain breakage. The photodynamic action of porphyrins on DNA leads to a variety of changes in their properties including a decrease in the melting point temperature or in viscosity due to chain breaks. These alterations are caused by the selectively photooxidation of the guanine residues [57]. From the interaction with DNA point of view, the classification of porphyrins and metalloporphyrins into three groups is the following: Group I porphyrins which induce changes characteristic of intercalation in DNA samples, increasing the DNA viscosity, an intrecalative binding strongest in GC regions, the AT regions appearing to be only outside binding.
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Group II porphyrins are believed to be outside binders but have additional self-stacking features that induce DNA aggregation, produce small viscosimetric changes of DNA with greater than 40% GC content. Group III porphyrins do not cause any significant increase in the solution viscosity for any of the linear or superhelical DNA samples and they may bind with a preferential orientation [58, 59]. It is presumed that the interactions between the anionic porphyrins and DNA consist in three interaction modes: intercalation; outside self-stacking; outside random binding [60, 61]. The porphyrins are externally bound when their planar structure fit into the major/minor groove and interact with DNA electrostatically. It has been found that the stabilization of DNA against thermal denaturation of the cationic complexes is a consequence of a non-specific electrostatic interaction between the dye cations and the negatively charged phosphate groups and the specific interaction between DNA and the dye molecules. Both stabilization effects can be accounted by the dye molecule of one cationic dye bound more weakly on the surface of DNA double-helix. During the laser irradiation the relative viscosity increases due to some shortness of the double helix chains, generated by the double-stranded breaks and the helix destruction. The degradation process is achived by singlet oxygen effect due to the bonds breakage between the structural forms of DNA. DNA can be broken into small double helix when the electronic conjugation is not possible [62]. Porphyrins are generally prone to aggregate in solution. In aqueous solutions, at neutral pH, the electronic absorption spectrum of TPPS4 is typical of free base porphyrins and is characterized by an intense Soret band around 420 nm and other four Q-bands in the region 500–700 nm. In aqueous solutions, at neutral pH, the electronic absorption spectrum of TPPS4 is typical of free base porphyrins (D2h symmetry) and is characterized by an intense Soret band at about 412 nm and four Q bands in the 500–700 nm range (the aetio-type spectrum). With the increase of the medium acidity, complicated changes of the absorption spectrum occur for the TPPS4 aqueous solutions. The Soret band shows a significant batochromic shift from 412 to 433 nm, while the first Q bands become less intensive. Simultaneous formation of new absorption bands (at 644 and 707 nm) takes place. Also, a new band appears at 490 nm, arising from the J-aggregate (edge-to-edge interaction) of porphyrin molecule [9, 63]. In PDT mechanism should be take into account the correlation between the photostability and photodynamic efficacy for different photosensitizers. It should be noted that the photobleaching does not describe a “simple” photodegradation of the photosensitizer. It includes a chemical modification of the porphyrin, i.e. formation of photoproducts. The main factors influencing the photodegradation rate are: the meso-substituents; the central metal; the axial ligand attached to the central metal; the aggregation processes; the medium temperature; the solvent or binary mixture of solvents [63]. In this area, an important rule has been established by Ferreira [63]. For a PDT sensitizer is important to avoid the ketones and peroxides generation during the photobleaching (photodegradation) reaction [64]. The photosensitizer
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with the highest phototransformation rate, shows the lowest inhibitory concentration (IC50) and the thereshold dose (Dth), but shows more efficacy in cell killing and tissue necrosis during PDT applications. Chemists and clinicians have different opinions about the ideal sensitizers and their clinical applications. Chemists point to the absorption bands, high quantum yield of singlet oxygen generation, whereas the clinicians emphasize on low toxicity and high selectivity. Although some photosensitizers satisfy all of some of the above mention criteria, there are only few sensitizers which received official approval for clinical applications: • Photofrin® (Porfimer sodium; Axcan Pharma, Inc.); • Foscan® (temoporfin, meta-tetrahydroxyphenylchlorin, mTHPC; Biolitec AG); • Visudyne® (verteporfin, benzoporphyrin derivative monoacid ring A, BPD-MA; Novartis Pharmaceuticals); • Levulan® (5-aminolevulinic acid, ALA; DUSA Pharmaceuticals, Inc.); • Metvix® (methyl aminolevulinate, MLA or M-ALA; PhotoCure ASA.). Several promising photosensitizers are currently under clinical trials. These include HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a, Photochlor; Rosewell Park Cancer Institute), motexafin lutetium (MLu, lutetium(III) texaphyrin, Lu-Tex, Antrin; Pharmacyclics Inc.), NPe6 (mono-L-aspartyl chlorin e6, taporfin sodium, talaporfin, LS11; Light Science Corporation), SnET2 (tin ethyl etiopurpurin, Sn etiopurpurin, rostaporfin, Photrex; Miravant Medical Technologies) [64]. Some clinical results obtained with phthalocyanines and related compounds as sensitizers, are shown in the following section.
6.4 6.4.1
Clinical Results Ophthalmology Applications
Among non-cancer applications, PDT shows promise as a treatment for macular degeneration. Macular degeneration of the retina occurs as an age-related phenomenon when new vessels under the retina proliferate and leak, which causes distortion and scarring and leads to reduction of visual acuity. This disease, which affects large numbers of elderly people, is caused by the rapid growth of new blood vessels in the macular, the central portion of the retina opposite the lens. This causes people to lose the ability to look straight ahead; in time, the disease causes blurred vision and eventually blindness. With PDT, singlet oxygen attacks the proliferating red blood cells and causes thrombosis or formation of a blood clot which dries up the membrane. The blood vessels shrink and then the retina sits again on the membrane. Early trial results show significant improvement in the vision of affected patients and for most patients, the improvement was sustained for 3 months. The selectivity of PDT is defined by the nature of the sensitizer used [64].
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Nowaday, Verteporfin is used as photosensitizer; it is followed by a series of three to six treatments over 1–2 years, which results in a decrease of loss of vision relative to untreated controls, and, in some instances, an improvement of vision. This was approved by the US Food and Drug Administration in 2000 and has been used in more than one million applications [65]. In 1999, the treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group reported 1-year results from 2 randomized clinical trials of photodynamic therapy with Verteporfin (Visudyne; CIBA Vision Corp, Duluth, Ga) conducted among patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD). A visual acuity benefit through 1 year of follow-up was demonstrated for the entire study group assigned to verteporfin therapy. The mechanism of action is induction of apoptosis in the endothelial cells in the proliferating vessels, which is specific and leaves the rest of the retina intact [66]. Starting from the structure similarity between porphyrins and vitamin B12, was compared the singlet oxygen rate generation by such porphyrins with others and was extended the studies to vitamin B12. By comparison with vitamin B12 (a porphyrin derivative) with a strong capacity of electron transfer and a low capacity of singlet oxygen singlet, for vitamin B12 was observed a high quantum yield for singlet oxygen, so was performed PDT experiments by coupling of PDT with B2, as a very promising in this area [67, 68]. Recently, ZnPcS4 has been shown to efficiently occlude experimental choroidal neovascularization (CNV) and its application in the treatment of macular degeneration and other human diseases manifesting as CNV has been suggested [69]. ZnPcS4 selectively localizes to the choriocapillaris and CNV in rats, resulting in the occlusion of laser-induced CNV with minimal damage to the retina tissues. Additionally, the safety of ZnPcS4 was evaluated in pet dogs with naturally occurring tumors; it was shown to be well tolerated by all dogs and to induce tumor remission at low doses [34]. Compared to the most common PSs currently used, ZnPcS4 has some advantages: (a) it is a chemically pure compound rather than an inhomogeneous mixture; (b) can be activated by longer wavelength which allows increased tissue penetration; (c) have minimal systemic toxicity and (d) causes minimal skin photosensitization due to a faster systemic excretion. Also, the effects of phototoxicity on retinal pigment epithelial (RPE) cells after zinc tetrasulphonated phthalocyanine bound bovine serum albumin (ZnPcS4-BSA) based photodynamic therapy (PDT) as a new clinical perspectives in future choroidal neovascularization (CNV) therapy were investigated. Intracellular ROS formation may play an important role in mediating the apoptotic processes of RPE cells induced by ZnPcS4-BSA based PDT [70]. Mixed-sulphonated aluminium phthalocyanine (AlPcSmix) commercially known as Photosens® has been developed as a PDT drug with a fair measure of success [71, 72]. Neovascularisation occurs in many major ocular diseases such as diabetes, age-related macular degeneration, and sickle cell disease. The iris vessels of the albino rat were chosen because the treatment could be assessed unequivocally and
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followed with time. Aluminium phthalocyanine tetrasulphonate was encapsulated in heat sensitive liposomes and administered systemically. The iris vessels were irradiated with a yellow laser to raise their temperature to 41°C, cause a phase transition in the liposomes and thereby locally release the photosensitizer. The laser was also used to excite the released photosensitizer and cause occlusion. The effect was monitored immediately and for 8 months thereafter. Controls for the effect of the laser and the unencapsulated drug were conducted. The results demonstrated that occlusion can be achieved and sustained for the period of follow up. The controls showed that the effect was not due to heat or to the activation of the low dose of free drug. Photodynamic therapy using chloroaluminum sulphonated phthalocyanine (ClAlPcS4) effectively closed experimental iris neovascularization induced in six eyes of cynomolgus monkeys by argon laser retinal vein occlusion. Neovascularization was followed by iris photography, fluorescein angiography, and histopathologic examination by light and electron microscopy. Intravenous injection of ClAlPcS4 followed by irradiation with 675 nm light damaged endothelial cells and pericytes, leading to exposure of the basal lamina and thrombotic occlusion of the blood vessels. Surrounding tissue appeared preserved without evidence of thermal damage. Resorption of occluded vessels by macrophages began 2–3 days after photodynamic therapy. Neovascularization reappeared 7 days after photodynamic therapy, probably representing growth of new vessels. Photodynamic therapy with ClAlPcS4 may be a useful adjunct in the treatment of iris neovascularization. The model is useful in elucidating the ultrastructural changes observed after photodynamic therapy using phthalocyanines [73]. ClAlPcS4 is a photoactive dye capable of generating photochemical reactions when excited with 675 nm light. It has been used to produce photochemical closure of retinal medullary ray vessels and choroidal vessels in normal rabbits. Irradiation prior to injection produced no photographic, angiographic, or histologic lesions in any eyes. Identical irradiation of medullary ray and choroidal vessels after ClAlPcS4 injection produced complete vessel closure in all eyes. Histopathologic examination showed marked thrombosis of medullary ray and choroidal vessels, with minimal damage to contiguous tissues including the neurosensory retina. So, ClAlPcS4 can produce profound closure of normal retinal and choroidal vessels with minimal deleterious effect on surrounding tissues [74, 75].
6.4.2
Human Brain
Photodynamic therapy of cancer exposes adjacent arteries to the risk of injury and the possibility of haemorrhage and thrombosis. The nature of photodynamic injury to normal arteries has not been satisfactorily defined, and the ability of arteries to recover with time is unclear. To clarify these issues, we have investigated the effects of PDT on rat femoral arteries, using a second-generation photosensitizer, disulphonated aluminium phthalocyanine, and a new method of photosensitization, using
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endogenous synthesis of protoporphyrin IX following systemic administration of 5-aminolaevulinic acid (ALA). Pharmacokinetic studies of sensitiser fluorescence were carried out to determine peak levels of sensitiser. Subsequently photodynamic therapy at times corresponding to maximal fluorescence was performed using two light doses, 100 and 250 J cm−2. The nature of injury sustained and recovery over a 6 month period was investigated. Three days following PDT, all vessels treated showed complete loss of endothelium, with death of all medial smooth muscle cells, leaving an acellular flaccid artery wall. No vascular occlusion, haemorrhage or thrombosis was found. A striking feature was the lack of inflammatory response in the vessel wall at any time studied. Re-endothelialisation occurred in all vessels by 2 weeks. The phthalocyanine group showed repopulation of the media with smooth muscle cells to be almost complete by 3 months. However, the ALA group failed to redevelop a muscular wall and remained dilated at 6 months. Luminal cross-sectional area of the ALA-treated group was significantly greater than both control and phthalocyanine groups at 6 months. All vessels remained patent. This study indicates that arteries exposed to PDT are not at risk of catastrophic haemorrhage or occlusion, a finding that is of significance for both the local treatment of tumours and the use of PDT as an intraoperative adjunct to surgery for the ablation of microscopic residual malignant disease [76]. Some studies about photodynamic therapy have also reported transient or permanent worsening of neurological function following PDT, with neurological impairment or neurocognitive deficit in a few patients [77]. Muller and Wilson [78] also reported increased intracranial pressure post-operatively, attributed to PDT-induced oedema in the exposed normal brain. In a previous pre-clinical study in a rabbit model bearing intracranially-implanted VX2 carcinoma [79], the investigations of necrosis of normal brain and tumour to PDT mediated by 4 different photosensitizers: Photofrin, ALA (5-aminolaevulinic acid: a precursor in haem biosynthesis which results in the photosensitizer protoporphyrin IX, PpIX), ClAlPc (non-sulphonated chloroaluminium phthalocyanine) and SnET2 (tin ethyl etiopurpurin) were investigated. All four drugs produced significant gross haemorrhagic necrosis in both tumour and normal brain tissue. The zones of necrosis were very sharply delineated, consistent with a ‘threshold’ model of PDT in which a minimum concentration of 1O2 is required to produce necrosis [80, 81]. Clinical benefit depends on having higher drug concentration in tumour and accurate targeting of the treatment light. The exception was with ALA-PDT in white matter, where no necrotic damage was observed, probably due to lack of PpIX synthesis. In addition to these gross necrotic effects on normal brain and brain adjacent to tumour (BAT), Yoshida et al. have reported histopathologic evidence of lethal injury to neurons, extending beyond the zone of coagulative necrosis and developing over a period of 18 h after Photofrin-PDT in a rat model [82]. The apoptosis is certainly a possible mechanism of cell death following injury to normal brain. While PDT-induced necrosis usually results from direct photochemical injury to the cells or from destruction of tissue vasculature with subsequent ischaemic hypoxia, apoptosis is considered a deliberate response to specific, but often indirect stimuli [83, 84].
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Confocal laser scanning microscopy (CLSM) was used to quantify the local incidence of apoptosis and determine its spatial distribution throughout the brain. At 24 h post PDT, ClAlPc did not cause any detectable apoptosis, while the other photosensitizers produced varying numbers of apoptotic cells near the region of coagulative necrosis. The apoptotic response (visible by internucleosomal DNA cleavage in apoptotic cells) did not appear to be related to photosensitizer dose. A minimal and fairly localized apoptotic effect is produced in brain tissues, the extent of which depends largely on the particular photosensitizer. For ALA-PDT no necrotic damage was observed, probably due to lack of PpIX synthesis. Also, a significant proportion of patients develop late complications, including demyelination of nerve fibres and white matter necrosis [85–87], and animal model studies [88] have confirmed radiation-induced apoptosis in normal brain tissues. Hence, apoptosis is certainly a possible mechanism of cell death following injury to normal brain. The response characteristics may, therefore, be very different. The total apopotic counts and the volumes of PDT-induced necrosis are positive and different for Photofrin, ALA and SnET2, respectively. By contrast, ClAlPc does not appear to produce any significant level of apoptosis at 24 h post treatment, even although significant necrosis was seen (~65 mm3). Chan et al. [89] and Margaron et al. [90] have shown that phthalocyanines localize differently in cells in vitro than either Photofrin or ALA-PpIX. Since 1O2, which is generated by all these photosensitizers, is very short-lived and thus acts within <~0.1 mm of its site of generation [90], the intracellular sites of PDT damage will be different for ClAlPc and so might not activate the apoptotic pathways. This lack of consistent correlation between necrosis and apoptosis suggests that the latter is not simply a secondary response to the presence of necrotic tissue [91]. PDT has been used in the treatment of malignant brain tumors for the last two decades [92–95]. It is based on the interaction of a photosensitizer and light of an appropriate wavelength, with generation of oxygen species, mainly singlet oxygen. Brain is particularly susceptible to oxidative stress; therefore the study of PDT effects on cerebral mitochondria might provide mechanistic insights into the action of the therapy, contributing to its optimization. The mitochondrial toxicity of the second generation PS, zinc phthalocyanine tetrasulphonated (ZnPcS4), on rat brain isolated mitochondria was investigated through both intrinsic toxicity and photodynamic action. Coupled with 600 or 1,800 mJ/cm2 laser irradiation, ZnPcS4 (5 mM/mg proteins) caused more intense effects on state 3, RCR and ADP/O. The low intrinsic toxicity and the high photodynamic effect on rat brain mitochondria induced by ZnPcS4, allied to its improved photophysical properties, might indicate its potential for the treatment of malignant brain tumors [96–99]. The application of ZnPcS4-PDT as adjuvant in the treatment of brain tumors has not been suggested yet. ZnPcS4 improved properties associated with its low dark toxicity and intense photodynamic effects on brain mitochondria, here demonstrated, might indicate its usefulness in the treatment of the infiltrative malignant brain tumors Mitochondria have been considered as an important target for anticancer therapy due to their crucial role in photodynamic cell death [94]. An in vitro study of the
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genotoxic potential of ZnPcS4-PDT showed that the cell killing mechanism did not occur at the chromosome level, and suggested it might occur at a different cellular level, including mitochondria. The effects of ZnPcS4-PDT on brain mitochondria and the mechanisms involved in the induction of brain mitochondrial toxicity have been studied. The mitochondrial effects induced by irradiated ZnPcS4 can be attributed to its photodynamic action. The effects of ZnPcS4 on the mitochondrial respiration suggest that only at high concentrations, ZnPcS4 (alone) interfered with the electron transport and oxidative phosphorylation; however, it did not damage the mitochondrial inner membrane. The integrity of the inner membrane may explain why the membrane electrochemical potential was practically not affected. ZnPcS4 did not induce mechanisms related to cell death. On the other hand, the photodynamic effects of ZnPcS4 on the mitochondrial respiration, including the uncoupling effect on state-4 respiration, suggest that besides impairing electron transport, irradiated ZnPcS4 (600 or 1,800 mJ/cm2) damaged the mitochondrial inner membrane. As a consequence, differently from the intrinsic effect, when coupled with irradiation, ZnPcS4 intensely decreased the membrane potential. These three events were induced by ZnPcS4 irradiated with 600 and 1,800 mJ/cm2 light, but not by ZnPcS4 itself. The cytochrome c release induced by ZnPcS4 + 600 and ZnPcS4 + 1,800 mJ/cm2 is consistent with the involvement of protein tyrosime phosphatase (PTP) opening in the phototoxicity of ZnPcS4 and moreover, might indicate the activation of the intrinsic apoptotic pathway (mediated by mitochondria), since into the cytosol, cytochrome c activates caspases and causes apoptotic cell death [100]. ZnPcS4 presents: (a) low intrinsic (dark) toxicity on brain mitochondria, as the effects were mild and occurred only at high concentrations and (b) high phototoxicity on brain mitochondria, as intense effects were observed [96, 97]. For the in vitro experiments, some samples of brain tumoral tissues were prelevated from human patients and impregnated with different metallo-porphyrins solutions. Photosensitizers preferentially accumulate in malignant tissue whether via increased uptake due to an accelerated cellular proliferation rate, decreased intratumoral pH favouring photosensitizer retention, increased phagocytosis capabilities, leaky vasculature, and decreased lymph drainage tumour-associated macrophage engulfing photosensitizers or specific uptake via receptors. Gross edema and erythema is always the first sign of a PDT response. Cerebral microvasculature, particularly the endothelium is the primary target for PDT. A cytotoxic effect on the vascular network that results in cession of blood circulation and subsequent necrosis of the tissue could be observed. In experimental tumor systems, clumps of aggregated platelets in the brain parenchyma vessels and focal thrombosis in pial vessels of tumor tissue, may be observed in the microvasculature after light exposure, followed by transient vasoconstriction, vasodilatation and eventual complete blood stasis and haemorrhage, and all these are more pronounced for diamagnetic metallo-porphyrins, because the diamagnetic metal enhance the drug phototoxicity. The blood vessels become dilated and filled with a dense mass of red cells. In vitro irradiation experiments of tumoral human brain tissues obtained from different types of cerebral tumors prelevated from ten patients on whom there were made previously surgical interventions. The samples were obtained by cutting pieces from tumor tissues. An aseptically excised brain
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tissue was cut on a sterile paraffin plate into pieces about 1 mm of diameter. These fragments were washed in MEM (Eagle’s minimal essential medium) and then were places into wells. MEM with 10% fetal calf serum (FCS) in total volume of 0.15 ml was added into each well. The sample was irradiated by laser after 24–48 h incubation time. The dye impregnation was done immediately after operation [98, 99, 101]. In vitro samples of brain tumoral tissues were prelevated from human patients and impregnated with different metallo-porphyrin solutions. Photosensitizers preferentially accumulate in malignant tissue whether via increased uptake due to an accelerated cellular proliferation rate, decreased intratumoral pH favoring photosensitizer retention, increased phagocytosis capabilities, leaky vasculature, and decreased lymph drainage tumor- associated macrophage engulfing photosensitizers or specific uptake via receptors [70, 100, 102–107]. Three consecutive processes occur during the PDT treatment: • initial consumption of oxygen through the photodynamic process; • athophysiologic alterations in regional blood supply (hypoxia); • total vascular occlusion (ischemia). Gross edema and erythema is always the first sign of a PDT response. Cerebral microvasculature, particularly the endothelium is the primary target for PDT. A cytotoxic effect on the vascular network that results in cession of blood circulation and subsequent necrosis of the tissue could be observed. In experimental tumor systems, clumps of aggregated platelets in the brain parenchyma vessels and focal thrombosis in pial vessels of tumor tissue, may be observed in the microvasculature after light exposure, followed by transient vasoconstriction, vasodilatation and eventual complete blood stasis and hemorrhage, and all these are more pronounced for diamagnetic metallo-porphyrins, because the diamagnetic metal enhance the drug phototoxicity. The blood vessels become dilated and filled with a dense mass of red cells. The radiation of the nitrogen pulsed laser is emitted at 337.1 nm with a power density ranging from 1 to 3.5 mW/cm2, which correspond to a frequency range 3–10 pulses/s. The advantage of exciting the photosensitizers in UV is that the available sources in that range are more powerful than those with emission in red and we could obtain a more efficient effect for PDT. One has been outlined that the use of UV radiation for PDT experiments is recommended for the tumor bed treatment following the surgical extraction of the tumor tissue.
6.4.3
Dermatology
6.4.3.1
Oral Carcinoma
The use of photodynamic therapy for the treatment of skin and oral cancer has been the subject of several clinical studies but there has been little scientific evaluation of its mechanism of action. Oral carcinoma cells were used to evaluate chloroaluminumphthalocyanine encapsulated in liposomes as the photosensitizer agent in support of
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photodynamic therapy [108]. The genotoxicity and cytotoxicity behavior of the encapsulated photosensitizer in both dark and under irradiation using the 670-nm laser were investigated with the classical trypan blue cell viability test, the acridine orange/ethidium bromide staining organelles test, micronucleus formation frequency, DNA fragmentation, and cell morphology. The cell morphology investigation was carried out using light and electronic microscopes. After PDT, a reduction in cell viability (95%) associated with morphologic alterations, have been observed. The neoplastic cell destruction was predominantly started by a necrotic process, according to the assay with acridine orange and ethidium bromide, and this was confirmed by electronic microscopy analysis. Neither the PDT agent nor laser irradiation alone showed cytotoxicity, genotoxicity, or even morphologic alterations. Our results reinforce the efficiency of light-irradiated chloroaluminum-phthalocyanine in inducing a positive effect of PDT [109]. To investigate the mechanism of epithelial cell death following PDT, two cell lines, human epidermal keratinocytes (UP) and oral squamous cell carcinoma-derived cells (H376) were subjected to PDT with aluminium disulphonated phthalocyanine (AlPcS2) as the photosensitizer and red laser light at 675 nm [109]. The effects of PDT were assessed using an MTS cell-proliferation assay (significant reduction in viability for PDT-treated cells compared to controls), apoptosis (increased numbers of apoptotic cells). Apoptosis, confirmed by ultrastructural analysis and by in situ end-labelling of DNA fragments, show that PDT using AlPcS2 as a photosensitizer promotes apoptotic cell death in UP and H376 cells in vitro and suggest that direct killing of epithelial cells may contribute to tumour necrosis in vivo. The photosensitizing drug Foscan® has been developed to maximize the efficiency and selectivity of photosensitizing drugs, whilst also having a high absorption peak deep into the red light spectrum, maximizing the penetration of activating light through tissue, hence maximizing the clinical effect [109].
6.4.3.2
Melanoma
A comparison of time-dependent localization patterns between lower, asymmetrical aluminium phthalocyanine with two sulphonated groups on adjacent phenyl rings (AlPcS2a) and higher, symmetrical aluminium phthalocyanine with four sulfonate groups on phenyl rings (AlPcS4) in human malignant melanoma LOX transplanted to athymic nude mice from 1 to 120 h after intravenous administration (i.v.) was followed by means of laser scanning fluorescence microscopy [110]. The lipophilic AIPCS2a was distributed mainly in tumor cells, while the hydrophilic AlPcS4, localized only in the vascular stroma of the tumor tissue. Concomitantly, comparative observations on the killing mechanism of photodynamic effects after treatment with a much lower i. v. dose of AlPCS2a and AlPcS4 plus laser light on the human tumor LOX were also made by morphological studies. Light and electron microscopy showed that there was a direct, extensive, photo-damaging action on all organelles and nuclear structure in the tumor cells after PDT with AlPcS2a; whereas
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the photo-induced injury to the tumor tissue after treatment with AlPcS4 and light was largely the consequence of initial functional vasogenic response and ultimate damage to vascular structure. These findings correlate well with the different localization patterns of the two dyes observed in human tumor tissues [108]. Zinc phthalocyanine substituted with four hydroxyl groups attached to the macrocycle, either directly or via spacer chains of three or six carbonatoms, were tested for their photodynamic ability to inactivate Chinese hamster lung fibroblasts in vitro, and to induce regression of EMT-6 tumors grown subcutaneously in Balb/c mice. Both of the tetraalkylhydroxy substituted zinc phthalocyanines are effective photodynamic sensitizers in vivo with the tetrapropylhydroxy compound exhibiting about twice the activity of the tetrahexylhydroxy analogue. Tumor response with the active compounds was preceded by vascular stasis immediately following irradiation which suggests that tumor regression involves an indirect response to the photodynamic action rather than direct cell killing. This lack of activity of the tetrahydroxy Pc is in strong contrast with the high photodynamic activities of tetrahydroxyphenyl porphyrins and chlorins [111].
6.4.3.3
Actinic Keratosis
Photodynamic therapy (PDT) can be considered a very promising approach for anticancer research. It consists of the selectively uptake of a photosensitizing dye, often a porphyrin, by a tumor tissue and subsequent irradiation of the tumor with a light flux of an appropriate wavelength matched to the absorption spectrum of the photosensitizing dye. PDT produces cytotoxic effects through photodamage of cellular organelles and biomolecules. Actinic keratosis is the most common skin lesion with malignant potential, with a prevalence ranging from 11% to 25% in the Northern Hemisphere and from 40% to 50% in Australia [112]. Actinic keratosis is the most common skin lesion with malignant potential. The main factors responsible for these lesions are UV light, ionizing radiations, radiant warm and exposure to carbon processing products. The most affected persons are those with Fitzpatrick I and II phototype, men being more susceptible than women; this are considered in situ squamous cell carcinoma (SCC). In time, these lesions could remain unchanged, could spontaneously regress or could progress to SCC and further developing on the support of pre-existing actinic keratosis. The common therapy could be surgical (cryotherapy, removing with or without cauterization or laser therapy) or medication based on topic drugs like 5-flourouracyl, imiquimod, diclofenac gel or PDT. PDT works as a selective targeted treatment with high cure rates. The advantage of porphyrins-PDT is no general cutaneous photosensibility. On the left side of the scalp and face was applied 20% ALA and on the right side TPPS4 dissolved in an oil-in-water cream, both for 2 h incubation time under occlusion. Identical irradiation protocol was used: one session of irradiation 130 J/cm2 fluence at 635 nm wavelengths. Pain during treatment was quantified by the patient
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on a 0–10 analog scale. The tested TPPS4 showed an effective in vivo destructive effect on keratinocytes in the patient with actinic keratosis doubled by a good clinical response. The adverse events to PDT (pain, erythema) were slightly lower in the TPPS4 treated area [112]. The properties of some photosensitizers, namely Foscan, Fospeg, hypericin, aluminum (III) phthalocyanine tetrasulphonate chloride (AlPcS4), 5-aminolevulinic acid (ALA), and Photofrin in terms of: (1) cytotoxicity without illumination, (2) phototoxicity, (3) cellular uptake and release, and (4) apoptosis induction in A431 human epidermoid carcinoma cells using comparable illumination regimens. It was shown that meso-tetrahydroxyphenylchlorin (mTHPC, Foscan) is a very effective photosensitizer inducing high phototoxicity at very low concentrations. Also, in vitro characteristics and phototoxicity were observed for Fospeg, the water-soluble formulation of mTHPC. Hypericin, a photosensitizer extracted from plants of the Hypericum genus, is very effective in inducing apoptosis over a wide range of light fluences. AlPcS4 absorbs light of 674 nm wavelength providing a higher penetration depth in tissue. Its hydrophilic character allows for application as aqueous solution. ALA can be administered at very high concentrations without producing cytotoxic effects in the dark. The intracellular concentration of protoporphyrin IX rapidly decreases after withdrawal of ALA, thus minimizing the period of light sensitivity post PDT. Hypericin is characterized by high quantum yields, low photobleaching [113, 114] and has already successfully been used in photodiagnosis, especially for urinary bladder cancer.
6.5
Cellular Tests of Phthalocyanines and Related Compounds
Although the situation in the clinical application of a PS is more complicated and additional aspects have to be considered (e.g. the pharmacokinetics of the PS substance, clearance from target tissue, etc.), in vitro studies provide preliminary informations on basic PDT properties of a photoactive compound. Furthermore, direct comparisons between photosensitizers investigated in different PDT studies are generally complicated due to the use of different light sources with different spectral characteristics [115]. Based on these considerations, a comparative data on how currently used PS differ regarding basic PDT-related properties were investigated. The cell lines employed into the tests were: K562 lymphoblastic human cell line, LSR-SF-SR – transplantable sarcoma in rat induced by Rous sarcoma virus strain Schmidt-Ruppin, LSCC-SF-Mc29 – transplantable chicken hepatoma induced by the myelocytomatosis virus Mc29, 8-MG-BA – human glioblastoma, recognized as the most aggressive from the variety of gliomas and up to now there is no satisfactory treatment for these infiltrative neoplasms, MCF-7 – human breast adenocarcinoma, derived from a patient with metastatic breast cancer in 1970. G361 melanoma cells; U937 – hystocytic lymphoma from malignant cells from a patient with pleural
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ephusia, Jurkat – human line of lymphoblast leukemia T generator of IL-2, Splenocytes and EL-4 tumor cells were isolated from C57Black mice bearing EL-4 ascitis, Walker tumor cells and Hep G2 cells [116].
6.5.1
Cellular Parameters
The effect of the photosensitizer on viability of tumor cells was evaluated using a neutral red uptake cytotoxicity test. Cell viability and proliferation capacity were investigated in vitro in the presence of various concentrations of sensitizer. Cell viability vas assessed as LDH release measurement [117]. The proliferation capacity of cells was assessed by 3H-thymidine incorporation radioactive method, by using CellTiter 96 Aqueous One Solution Cell Proliferation kit. The incorporation of tritiated uridine, which are testing ARN synthesis [118]. The apoptotic process is analyzed with the system Annexin V-FITC Apoptosis Detection kit I. The apoptotyoc process is characterized by some morphological parameters: loosing of plasmatic membrane, condensing of cytoplasm with the nucleus, internucleozomal cleavage of DNA [119]. Cells percentage from a population which enters into apoptotic process were determined using CaspACE Assay System Colorimetric (Promega) [120], as cellular percent (%) from the total population, as Ann-/PI-cells (live cells), Ann+/ PI- (apoptotic cells), Ann+/PI+ and An-/PI+ (dead cells) [121, 122].
6.5.2
Photodynamic Results on Different Cell Types
Di-sulphonated and tetrasulphonated phthalocyanines were used for loading Walker and EL-4 tumor cells, subsequently irradiated 40 min. with laser radiation (He–Ne − 632 nm, 30 mW). For the in vitro experimental model, EL-4 tumor cells loaded with 20 mM ZnPcS2 or ZnPcS4 and irradiated presented a low proliferating capacity, while the non-irradiated cells loaded with any type of phthalocyanine exhibit a high proliferation rate. In the in vivo experimental model we obtained a significant higher rate of survival in the animals inoculated with phthalocyanine loaded/irradiated Walker tumor cells. Wistar R rats bearing Walker tumor and C57Black mice bearing EL-4 ascitis were used [123]. It was studied the survival rate, tumor growth and histopathological aspects of tumors, proliferating index = Proliferating Cell Nuclear Antigen (PCNA). The rate of survival correlates with the tumor volume, metastatic processes and the PCNA index. The best rate of survival was obtained in vivo with ZnPcS4 compound. The PCNA index was reduced to 50% comparative with the animals bearing untreated Walker tumor – 85%. Splenocytes isolated from tumor bearing animals treated in vitro with ZnPcS2 or ZnPcS4 display high proliferation rates, proving that these compounds do not alter the cellular immune response of the tumor bearer.
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The proliferation index for EL-4 cells loaded 24 h with ZnPcS2 (20 mM) or ZnPcS4 (20 mM) is different for laser and lamp irradiation. Photodynamic inactivation of cells containing phthalocyanines is strongly dependent upon the intracellular localization of the dye. Several cellular organelles can be postulated as the target for PDT with different photosensitizers such as plasmatic membrane, nucleus, mitochondria, endoplasmatic reticulum, Golgi complex, and others. The mitochondrion is the main target in PDT because it is the main organelle involved in apoptosis. One of the main agents is cytochrome c, a proapoptotic factor that preferentially links itself to the mitochondrial cardiolipin. PDT with AlPcS4 leads to significant alterations in mitochondria (mitochondrial migration to the perinuclear region), causing membrane potential loss, alteration in cardiolipin distribution and cell death [124]. In the case of AlPcS3 and AlPcS4, the damage of the lysosomes may contribute to the mechanism of PDT in cell killing. The fluorescence yield increases when cells are lysed. AlPcS3 and AlPcS2 show occasionally some fluorescence in the nuclear area of some cells. Also, they are distributed diffusely in the cytoplasm of the cells. A small fraction of AlPcS4 dyes was transferred into the nuclei and might be located close to the nuclear membrane, yielding the damage of DNA. Nevertheless, these drugs exhibit very good cytotoxic activity in the case of LSR-SF-SR and MCF-7 whereas for the LSCC-SF-Mc29 the tested concentration requires rather high radiant exposures. For example, 8-MG-BA the values of P50 for the ZnPcS4 were 5–8 J/cm2 at 10 mg/ml and 24 J/cm2 at 1 mg/ml. The irradiation has been performed with a laser diode emitting at 672 nm in a wide range of radiant exposures (2–100 J/cm2) and irradiance of 120 mW/cm2. It is interesting to compare the obtained values of P50% with the results of treatment of human tumor cell lines between 5 and 10 J/cm2 and P50% (5 mg/ml) about 14–15 J/cm2 for both ZnPcS3 and ZnPcS4 when being applied to 8 MG BA (glioblastoma multiforme) and MCF-7 (breast adenocarcinoma). The induction of apoptosis was determined by acridine orange dye staining. The cell observation was performed by fluorescent microscope. The obtained results confirm the general observation that the photodynamic effect produced by a certain PS can strongly vary with the cell line [124]. The fluorescent microscopic observation of the PS/light treated tumor cells after acridine orange staining revealed some typical apoptosis changes such as cell shrinkage, cytoplasmic condensation, pyknotic nuclear chromatine and membrane blebbing, in good agreement with literature [125]. A new water-soluble phthalocyanine derivative, 2,3,9,10,16,17, 23,24-octakis (3-aminopropyloxy) phthalocyaninato zinc II (PoII) was studied as a photosensitizer for photodynamic therapy (PDT) in MCF-7c3 cells. Caspase-independent apoptosis, in human MCF-7c3 breast cancer cells, following photodynamic therapy, is observed for this novel water-soluble phthalocyanine [126]. Photodynamic therapy has been approved as proper and effective kind of treatment for certain types of cancer and non-malignant diseases. Photodynamic effects on G361 human melanoma cells sensitized by zinc-5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrine (ZnTPPS4), chloraluminium phtalocyanine disulphonated (ClAlPcS2)
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and 5-aminolevulinic acid (ALA) were investigated. In particular the PDT efficiency was examined depending on applied light dose (0.8; 1.7; 3.3; 6.6; 13.2; 26.4 J cm2) [126]. The DNA gel electrophoresis, methylthiazol tetrazolium bromide (MTT) viability test, fluorescent microscopy using calcein AM and propidium iodide (PI) staining, and rhodamine 123 mitochondrial membrane potential assay were performed to detect and evaluate the cell death process. We also measured the time course of reactive oxygen species production and its dependence on sensitizer concentration within continuously irradiated sensitized cells. For G361 cells, the most significant phototoxic effect is for ClAlPcS2 by comparison with ZnTPPS4 which show a significantly high ROS production. On the other hand, ALA has a minimal photoeffect and induces negligible ROS formation in G361 cells [127]. The cytotoxic activity of the TPPS4 was considerably different for the animal and human tumor cell lines. At 10 mg/ml, the effect on the cell line LSCC-SF-Mc29 is comparable for ZnPcS2, ZnPcS3, ZnPcS4, whereas the TPPS4 action on the LSR-SF-SR is weaker in comparison with the ZnPcS3 and ZnPcS4 [128]. The cytotoxic effect of TPPS4 is most distinguished for this tumor line. The other important issue that should be addressed is to evaluate the TPPS4 influence on nonmalignantly transformed cell lines (normal mouse and bovine cell lines). The bovine cell line is more vulnerable than the mouse line, especially at 511 nm. The 2–4 times higher viability of the normal cell lines in comparison with the tumor line both at low and high PS’s concentration at 578 nm indicates that this wavelength could be more appropriate when using TPPS4 in photodynamic therapy [128]. For all the Zn phthalocyanines and TPPS4, K562 shows the best proliferation index for ZnPcS2. For the cellular samples loaded 24 h with variable concentrations of TPPS4 from the fluorescence resulted from flow cytometry could be observed a stronger fluorescence for K562 by comparison with Jurkat cells. From all cellular lines, Jurkat cells show the smallest cells number loaded with TPPS4, comparative with K562 cells, meanwhile U937 cells show biggest cells number loaded with TPPS4 [129, 130]. In order to detect some apoptotic phenomena in Jurkat line loaded with TPPS4 50 mg/ml these cell have been marked with propidium iodine and annexine V [7]. TPPS4 will activate both apoptosis and necrosis. A difference will be observed for U937, where the necrosis will be insignificant, while the early apoptosis are increased instead the control line. DNA topoisomerases are enzymes that control and modify the topological states of DNA in cells. Some chemotherapy drugs work by interfering with topoisomerases in cancer cells: type 1 is inhibited by irinotecan and topotecan and type 2 is inhibited by etoposide (VP-16), teniposide and HU-331 [131]. Topoisomerase I solve the problem caused by tension generated by winding/ unwinding of DNA. Type I topoisomerase cuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed. Type II topoisomerase cuts both strands of one DNA double helix, passes another unbroken DNA helix through it, and then reanneals the cut strand. A similar effect of TPPS4 is registered for Topo II (Topoisomerase II) Drug Screening kit (TopoGEN. Inc.) [132, 133] (Fig. 6.5, bands 2 and 3 from left to right).
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Fig. 6.4 Topoizomerase I with TPPS4 (unpublished results). Reaction with enzyme, no drug and solvent (E); Reaction with solvent, but without enzyme (S); Reaction with enzyme and solvent (ES); ADN marker – DNA relaxed with DNA open circular and DNA supercoiled; Reaction with Topo I and camptothecin (CPT)
Fig. 6.5 Topoizomerase I with TPPS4 (unpublished results). Reaction with enzyme, no drug and solvent (E); Reaction with solvent, but without enzyme (S); Reaction with enzyme and solvent (ES); DNA marker – linear DNA as reference marker; Reaction with Topo II and etoposide inhibitor (VP-16) (not published results)
This system allows the detection of cleavage products of DNA as: circular DNA or linear DNA [134]. An elocvent example could be obtained for the action of TPPS4 on K562 cells, Figs. 6.4 and 6.5. The efficacy of photodynamic therapy (PDT) mediated by aluminium phthalocyanine (AlPc) and its mono- and disulphonated derivatives (AlPcS1 and AlPcS2, respectively) on murine EMT-6 tumour were compared in vivo. PDT with AlPcS1 and AlPcS2 will produce tumour cures in 75% and 86% of mice, respectively. Immediately after PDT, tumour cells were found to be viable as determined by in vitro clonogenicity, but progressive cell death occurred thereafter. In contrast, AlPcS1 and AlPcS2
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produced substantial cell death (approximately 35% and 70%, respectively, of entire tumour) immediately after phototherapy, and yet further loss of tumour cell viability continued after PDT. The blood flow in tumours fell to approximately 25% of the control level by 24 h after AlPcS1. With AlPcS2, there was only an approximate 50% fall in tumour blood flow by 24 h [110, 135–144]. Among the sulphonated Pc derivatives, the mono and disulphonated GaOH-, AlOH- and Zn-PcS efficiently inactivate V-79 cells in vitro and induce tumor resorption in vivo [145–148]. In vitro, such amphiphilic dyes pass readily through the membrane explaining their high phototoxicity. The di- and trisulfonated GaOHPcS2 and GaOH-PcS3 respectively showed high tumor uptake with peak concentrations exceeding those of most non-neoplasmic tissues [149]. The biodistribution and tumor uptake of the sulphonated and non-sulphonated dye was investigated in mice bearing the RIF tumor. The singlet molecular oxygen are implicated in the photodynamic action of metallo-phthalocyanines [150], the quantum yield of singlet oxygen for the unsulphonated chlorogallium complex being around 0.5 and also, for all sulphonated chlorogallium complex. The biodistribution studies suggest that the amphiphilic galium phthalocyanine dyes, as compared to the highly lipophilic complexes, exhibit better tumor uptake and a more favorable tissue distribution pattern for a possible application in tumor therapy [151]. The PDT efficiency, and also modality of induced cell death, depends on the sensitizer distribution within the cell and on the energy transfer mechanism between excited molecule of sensitizer in triplet state and other interacting molecules. Mitochondria is the preferential subcellular localization of aluminium phtalocyanine [152] and silicon phthalocyanine 4 (Pc4) [104, 153–159] while plasma membrane, lysosomes and cytosol are preferred by some porphyrin based sensitizers [160–166]. It is generally accepted that the localization of sensitizer coincides with the primary site of photodamage because of very short lifetimes and very limited diffusion of ROS in biological systems [167]. The differing susceptibility of subcellular organelles to oxidative stress, affects the PDT efficiency in defining the extent of photodamage that is necessary to trigger the cell death program. The molecular nature of the photo-oxidised targets also influences the signaling pathways and mode of cell death initiated following PDT. Generally, photoactive agents targeting mitochondria, or the endoplasmatic reticulum (ER), promote apoptosis, while PDT with plasma membrane or lysosomes localized sensitizers can either delay or seven block the apoptotic program, predisposing the cell to necrosis [9, 168]. ClAlPcS2 shows a predominantly mitochondria-mediated apoptotic pathway, suggesting mitochondria targeted ClAlPcS2 subcellular localization [169–171]. For sure, the above mentioned examples, are only few from the huge number of such tests, in order to optimize the PDT process and to find the best and the cheapest sensitizer for cancer eradicating. Except these complexes, a water-soluble sodium salt of sulphonated phthalocyanines (MPc(SO3Na)4) and organo-soluble tetrakis(2,9,16,23-tert-butyl) dysprosium bisphthalocyanines (Dy(TBPc)2) have been tested as photosensitizers on different culture cells: E. Coli, B. cereus and Aurebacterium sp. [172]. Also, another
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photosensitizer – ZnPcBr(8)- has been photodynamically tested on L929 cells, by low-power semiconductor laser (AsGaAl), proofing that this phthalocyanine at 1 mM was the most effective concentration for PDT, with a decrease of 63% after 1 h, 99% after 12 h, and 100% after 24 h in relation to the control group. Also, is important to mention that this Pc was localized in the perinuclear region when analyzed 1 h after incubation, and a nuclear fragmentation occurred 24 h after PDT, cytoplasm retraction at 1, 12, and 24 h after PDT, and vacuoles along the cytoplasm at 12 and 24 h after PDT [172].
6.6
Conclusions
Photodynamic therapy is a potentially effective treatment approach for superficial human cancers and selected benign conditions. The technique can be used as an adjuvant therapy with surgery, radiation or chemotherapy. Newer generation photosensitizers are being tested which may produce less photosensitivity. The main benefit of PDT is that patients don’t have to go through surgery. Also, in contrast, PDT patients usually don’t even need to check into the hospital. Another advantage is that PDT can be repeated a number of times, unlike radiation and chemotherapy. This feature allows physicians to repeatedly treat tumours and control their growth in cases where cure is not possible. The major side effect of PDT is photosensitivity, or sensitivity to light. Most people find this inconvenient, but not intolerable. The photosensitizing drug currently used for PDT stays in the skin for 24 h up to 4–6 weeks (depends on photosensitizer). Pain is another side effect of PDT. As the diseased tissue breaks, down, it causes inflammation which can cause pain. Fortunately, the pain of PDT is usually mild to moderate and is easily controlled with a prescription painkiller. It is believed that PDT will develop further in the future and has a great potential for the treatment of malignant neoplasms. This will require efforts from physicists, biologists, chemists, pharmacologists and engineers to develop better photosensitizer dosimeters, light delivery devices and treatment planning.
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168. Kessel D, Luo Y, Deng Y, Chang CK (1997) The role of subcellular localization in initiation of apoptosis by photodynamic therapy. Photochem Photobiol 65:422–426 169. Xue LY, Chiu SM, Fiebig A et al (2003) Photodamage to multiple Bcl-xL isoforms by photodynamic therapy with the phthalocyanine photosensitizer Pc 4. Oncogene 22:9197–9204 170. Yslas EI, Prucca C, Romanini S et al (2009) Biodistribution and phototherapeutic properties of Zinc (II) 2, 9, 16, 23-tetrakis (methoxy) phtalocyanine in vivo. Photodiagn Photodyn Ther 6(1):62–70 171. Krestyn E, Kolarova H, Bajgar R et al (2010) Photodynamic properties of ZnTPPS4, ClAlPcS2 and ALA in human melanoma G361 cells. Toxicol In Vitro 24:286–291 172. (a) Liu MO, Tai CH, Sain MZ et al (2004) Photodynamic applications of phthalocyanines. J Photochem Photobiol A: Chem 165:131–136; (b) Machado AH, Braga FM, Soares CP et al (2007) Photodynamic therapy a new photosensitizing agent. Photomed Laser Surg 25(3):220–228
Chapter 7
Combination Therapy: Complexing of QDs with Tetrapyrrols and Other Dyes Vladimir Maslov, Anna Orlova, and Alexander Baranov
Abstract Analysis of recent works on investigation of photophysical properties of the complexes formed by the colloidal semiconductor quantum dots (QDs) and tetrapyrrol substances in liquid solution as well as the mechanisms of the complex formation was performed with the aim of utilization of the complexes in the cancer photodynamic therapy as a new approach in the combination therapy. It is demonstrated that the use of QDs as the energy donor allows to substantially extend spectral range of the complexes absorption and, therefore, to widen the set of the appropriate light sources for activation of sensitizer molecule in the complex. Besides the efficient energy transfer from QD to the tetrapyrrol molecule, it was shown that the molecule retains the capability of singlet oxygen generating with high quantum yield. Two solutions of the problem of delivery of the exciting radiation to the cancer cells due to strong absorption of the visible light by biological tissues are considered: (1) Two-photon activation of the QD/ photosensitizer complex by using light in the 700–1,200 nm spectral range where the biological tissues have a minimal absorption. (2) X-ray activation of the QD/photosensitizer complex. The results of the analysis of existing works demonstrate that the QD/tetrapyrrol complexes have a large potential for application in PDT.
V. Maslov (*) Center of Information Optical Technologies, Saint-Petersburg State University of Information Technologies, Mechanics and Optics Saint-Petersburg, St. Petersburg 197101, Russia e-mail: [email protected]; [email protected] A. Orlova • A. Baranov St. Petersburg State University of Information Technologies, Mechanics and Optics, Kronverksky pr. 49, St. Petersburg 197101, Russia e-mail: [email protected]; [email protected]
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Introduction
Photodynamic therapy (PDT) is a treatment that uses a photosensitizer and is based on two effects: (i) preferential accumulation of photosensitizer in target tissues and (ii), therapeutic effect, e.g. destruction of tumors caused by exposure of sensitized pathological tissues to visible light. Singlet oxygen is now recognized as a main intermediate in the photosensitized cell killing. Tetrapyrrol substances are the most used as the photosensitizers, since they have high molar extinction coefficients, high quantum yield of singlet oxygen generation, and show oncotropic properties. Recently new type of materials – semiconductor quantum dots (QDs) – became available for wide use in PDT, because of their considerably higher molar extinction coefficients than that of any organic molecules. Unfortunately, it turned out, that QDs are not able to generate singlet oxygen with efficiency suitable for practical applications. Taking this into account, the idea to combine anyway the high molar extinction coefficient of QDs and high quantum yield of singlet oxygen generation by tetrapyrrols seems attractive. The term “combination therapy” in its wide sense is utilized when two or more substances are applied for curing one disease. In this chapter, however, we will restrict our consideration to cases of medical application of complexes formed by semiconductor quantum dots and tetrapyrrol molecules where the complexes have better therapeutic properties than their components taken separately. It is assumed that the main sphere of application of such complexes would be the photodynamic cancer therapy or some analogues approaches. In this chapter, in particular, bonding mechanisms, spectral and photophysical properties of the complexes of QDs with tetrapyrrol substances are considered. The special attention is paid to the physical properties and processes playing a key role in potential applications of the complexes in PDT.
7.1.1
Quantum Dots (QDs). Spectral and Photophysical Properties
Quantum Dots and their role. The unique properties of QDs are caused by quantum size confinement that was first reported in 1982 in the pioneering work of Ekimov and Onushchenko on the example of CuCl nanocrystals in glass matrix [1]. The next very important achievement was the elaboration of procedures of synthesis of CdSe QDs soluble in organic solvents by Murray with coauthors [2]. The energies of optical transitions of QDs can be precisely tuned from the UV to the infrared region by changing their size and composition. The extinction coefficients of QDs are extremely high over a wide wavelength range, they are very photostable compared to organic dyes or luminescent proteins, and QDs with well passivated surface (e.g. CdSe QDs with ZnS surface) display narrow emission bands with high fluorescence quantum yields (up to 85%). The emission properties of QDs result from
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quantum-confinement effects and can be tuned to emit into the near-IR region as opposed to the visible emission of most conventional photosensitizers. Since there is minimal light scattering and absorption in the near-IR region of the spectrum, light of low intensity can be used to penetrate into tissue to depths of several centimeters, thereby allowing access to deep-seated tumors. On the other hand, as a very efficient accumulator of the incident light energy with extremely low inner losses QD can transfer this energy to molecules that possess very efficient ability to generate singlet oxygen. The efficient fluorescence resonance energy transfer (FRET) from QD-donor to molecule-sensitizer can be reached since optimal value of the overlap integral between QD luminescence band and acceptor absorption band can be easily realized by an appropriate choice of the QD size. Taken together these properties make QDs ideal agents for PDT applications. The biological applications of QDs became possible after the elaboration of procedures of preparation of water soluble QDs [3, 4]. After that, extensive efforts were undertaken in order to develop application of QDs for biodetection and bioimaging. The success of such attempts was caused in particular by compatibility of QDs with biomolecules due to their size similarity and relative easiness of QD surface modification. The latter could be achieved by coating QDs by special polymers or by linking of QD with certain ligands [5, 6]. In such a way QD were linked to various types of molecules, for instance, small proteins and peptides [6–8], nucleic acids [9], carbohydrates [10, 11], and some other types of molecules [12]. More detailed information devoted to biomedical applications of QDs can be found in reviews [13, 14]. Keeping in mind the QD applications in PDT, in this chapter we will analyze complexing of QDs with tetrapyrrols and other dyes that may be considered as the agents for the singlet oxygen generation. Energetic levels of QDs. In case of bulk semiconductor, the energy gap between the valence and conduction bands is a material-dependent constant. If the size of crystal is less than Bohr radius, which is a characteristic of material [15] and is in the range of 2–20 nm, quantum confinement effects, leading to size dependence of state energies, arise. The materials in which such effects take place in three dimensions are called as quantum dots, QDs [16]. If QD is modeled as spherically symmetric well with infinite potential barrier, the solution of the Schrodinger equation gives the reciprocal dependence of energy gap on the QD square radius R2. The energy levels can be labeled by the principal quantum number n = 1, 2, 3, etc. and angular momentum l = 0(S), 1(P), 2(D), etc.: En ,l (QD) = Eg ,0 +
h 2a n ,l 8p 2 meh R 2
(7.1)
where Eg,0 is the energy gap of corresponding bulk semiconductor, anl – nth root of the equation jl(an,l) = 0, where jl(x) is the spherical Bessel functions of l-th order (a10 = p, a11 = 4.49, a12 = 5.76, a20 = 2p, etc.), meh = me·mh/(me + mh) is the effective mass of an exciton (electron-hole pair), me and mh are the effective masses of an electron (e) and a hole (h), respectively. The lowest excited state usually called as first exciton state [17] is attributed as the transition 1S(e)→1S(h). If the QD size
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Fig. 7.1 Scheme of the electron energy structure of CdSe quantum dots, QDs. The allowed one-photon optical transitions are shown. Eg (QD) is the energy gap of the QD, allowed transitions are shown by arrows. The energy levels of electron (e) and hole (h) with different quantum numbers are denoted
decreases, its energetic gap increases, that leads the blue shift of both absorption and emission spectra. The electronic energy level structure of the CdSe QDs is shown in Fig. 7.1 schematically. In analogy with the well known Jablonski scheme describing the energy levels of the organic molecules [18, 19], including three levels: ground state, excited singlet state and excited triplet state, a three-level model is also valid for QDs. The QD analog of triplet state is called as “dark” or “trap” state and is populated non-radiatively from the singlet excited state [20]. In case of QDs, however this state is energetically very close to the corresponding singlet state and is depopulated at room temperature, in contrast to molecules, mainly by a thermal excitation to the singlet excited state. The triplet nature of QD “dark” state has been evidenced by the dependence of luminescent properties of QDs on external magnetic field [21]. Owing to their triplet nature this “dark” states should be capable of generating singlet oxygen [22] under QD photoexcitation. This opens a possibility to use QDs themselves as photosensitizers for the photodynamic cancer therapy, PDT. For generating the singlet oxygen, the sensitizer has to be in contact with the ground-state oxygen, because triplet energy transfer is short-distance process [23, 24]. In principle, the main requirements to the PDT sensitizers are as follows: (1) constant composition; (2) simplicity of synthesis; (3) non-toxicity in dark; (4) target specificity (capability to accumulate specifically in cancer tissues); (5) triplet state energy higher than 0.97 eV (the energy of singlet oxygen); (6) photostability; (7) high triplet state quantum yield; (8) quick clearing from body; (9) minimal self-aggregation. QDs satisfy six of these requirements [25]. At first glance, an ability of QDs to generate the singlet oxygen along with their optical properties makes them very attractive for use as the photosensitizers for PDT. However, there are few contradictory experimental data about an ability of
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the quantum dots to generate the singlet oxygen. For the first time the singlet oxygen generation by hydrophobic CdSe quantum dots was demonstrated by Burda et al. [22]. The singlet oxygen quantum yield of these QDs in toluene was found to be about 5%. It is much lower than that of conventional organic photosensitizers (usually about 30–50%). Since these QDs were insoluble in water, a principal possibility to generate the singlet oxygen by QDs was only shown in this work. A few unsuccessful attempts to generate the singlet oxygen by water-soluble QDs were reported in Refs. [26, 27]. Replacement of water by D2O allowed Nyokong and co-workers [28] to detect the singlet oxygen generation by QDs with quantum yield about 1% for the first time. Such low quantum yield of the singlet oxygen generation by water-soluble QDs makes them unsuitable in the practical application as the photosensitizers for PDT. The problem of low quantum yield of singlet oxygen of water-soluble QDs can be solved by using a QD/molecule complex as photosensitizers for PDT. In these complexes, quantum dots absorb light energy, and then after transfer of excitation energy from QD to molecule the conventional organic photosensitizer generates the singlet oxygen. In the case of QD/molecule complexes, an efficiency of generation of singlet oxygen can be significantly enhanced as compared with molecular photosensitizers due to high extinction coefficient of QDs in a broad spectral range. Enhancement of generation of singlet oxygen should decrease a therapeutic dose of photosensitizers, and thus the total body intoxication (side effect of PDT) should be also decreased. Below the main requirements for QDs, necessary for medical applications, in particular when bound in complexes with tetrapyrrols, are discussed. The requirements to tetrapyrrol substances used as components of the QD/tetrapyrrol complexes, necessary for their real application in medical sphere are also considered.
7.1.2
Main Requirements of QDs for the Formation of QD/Tetrapyrrol Complexes
Requirement of Functionalization. The main synthetic procedures used for production of QDs use organic solvents and produce QDs soluble in organic solvents. In order to be used in biology they should be biofunctionalized in order to satisfy the following requirements [18, 29]: (1) long-time stability in water, (2) presence of appropriate functional groups for bioconjugation if the latter is supposed to be used, (3) biocompatibility, the absence of immunogenicity, (4) retention of the useful QD properties. Solubilization. There are several methods of QD solubilization in the water. The most popular method consists in change of surface ligands with appropriate substances with thiol groups, such as mercapto-acetic acid [3] or polysilanes [4]. Another approach uses a hydrophobic interaction of trioctylphosphine oxide (TOPO) with an amphiphilic polymer. Encapsulation of QDs into phospholipid micellas is also used for this reason.
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It is worth noting that direct methods for synthesis of water-soluble CdSe and CdTe QDs with the luminescence quantum yields up to 30–40% have been proposed [30–32]. These methods allow to prepare the neutral and charged (positively or negatively) QDs with different surface ligands such as TGA, 3-mercapto-1,2propanediol, N-(2-mercaptopropionyl)-glycine, glutathione, N-acetil-L-cysteine and cysteamine. Toxicity of “traditional” quantum dots. CdSe or CdTe QDs are considered as potentially hazardous because of their colloidal instability due to slow realize of Cd2+ ions. The latter can lead to generation of radicals [33] and abnormal functioning of the cellular organelles [34]. Some recent results on cytotoxisity of QDs are reviewed in papers [3, 7, 29, 31, 35, 36]. Stabilization of QDs could be achieved by use of shells not containing cadmium atoms. It was demonstrated that core shell CdSe/ZnS QDs are nontoxic [37]. However, in conditions of longtime circulation in body this approach can be not very effective [6]. It was also shown that the toxicity of CdTe QDs can be significantly decreased by removing the free Cd2+ ions [38]. However, real toxicity of CdSe or CdTe QDs is not yet systematically investigated and is disputable up to now [39]. In all cases, the use of CdSe and CdTe QDs in in-vitro experiments (including the experiments with cells) is very useful because they give information on behavior of QD systems in dark and under irradiation.
7.1.3
Requirements of Tetrapyrrol Molecules in the QD/Tetrapyrrol Complexes
If the sensitizer molecule is used in complex with QD possessing the FRET effect, the requirements to its properties somewhat change in comparison with situation when this molecule is used separately. In this case, there are no strict requirements to the absorption spectrum of the tetrapyrrol molecule because optimal overlapping integral value needed for efficient FRET from QD to molecule can be easily achieved by selection of the proper QD size. The tetrapyrrol molecules bound in complex with QDs should be able to generate the singlet oxygen, to accumulate in the disease tissues, to be nontoxic in dark and to be easily removable from body after completing the therapeutic procedure. In addition to this, these molecules should be capable of binding to QDs. Below (see Sect. 7.2) the main possible mechanisms of binding of QDs with organic molecules such as electrostatic interaction, coordination bonding, covalent bonding and bioconjugation will be considered in detail.
7.1.4
Requirements to the QD/Tetrapyrrol Complexes
Two main conditions for efficient FRET between QD and tetrapyrrol molecules should be satisfied in the QD/molecule complexes. (1) The distance between QD
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and molecule should not exceed 10 nm. This requirement is usually met in the complexes considered. (2) The absorption spectrum of the tetrapyrrol molecule should overlap strongly with the luminescence spectrum of QD. As we stated above, this condition can be fulfilled in most cases by appropriate choice of the QD materials and core diameter. For application in PDT the complexes should be water soluble, capable of accumulating in cancer tissues and capable of penetrating into tissues. It is also necessary that after bonding with QD the molecule would retain capability of generating the singlet oxygen. The ease of clearing from body is also one of the main requirements for sensitizers for PDT. If the QD/tetrapyrrol complex is used as sensitizer, not only the clearing of the complex as whole is possible but also the dissociation of complex with subsequent removal of its components.
7.2
Modes of Bonding in the QD/Tetrapyrrol Complexes
In this section, the physical mechanisms of bonding of QD with tetrapyrrol moiety are considered. On the one hand, the bonding mechanism defines the laboriousness of the complex formation process and the variety of molecules capable of forming complexes. On the other hand, the bonding mechanism determines the physico-chemical conditions of stability of the complexes. On certain extent, the type of bonding affects the photophysical properties of the complexes considered in the next section. For the QD/tetrapyrrol complexes, three main bonding mechanisms can be considered, namely: covalent bonding, bonding due to electrostatic interaction between QD and molecule and coordination bonding of one or another type. It is reasonable to consider separately the complexes obtained by bioconjugation, because they have some peculiarities. In principle, some other types of bonding exist, e.g. hydrogen bonding, but for the moment, we do not know any works in which the QD/tetrapyrrol complexes of such type would be described. Below the complexes of all these types of bonding are considered together with their peculiarities of synthesis and stability. Their spectral properties are analyzed to such a degree that is necessary for identification of the complexes.
7.2.1
Complexes with Covalent Type of Bonding
Complexes with covalent bonding type are the strongest ones but also the most difficult in synthesis. One of the first examples of the covalent bonding at the QD/tetrapyrrol complex formation has been described in Ref. [40]. In this work CdTe QDs capped with thiopropionic acid (TPA) or thioglycolic acid (TGA) were covalently linked to zinc or indium derivatives of tetraaminophthalocyanine (TAPc) with N-ethyl-N(3-dimethylaminopropyl) carbodiimide and N-hydroxy succinimide as the coupling agents. It was marked that the covalent bonding leads to negligible
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a
c
H2N
Zn N H
CdSe QD
O H2 H2 C C C
S
N H
NH2 N
N N H
N
N
CdSe/ZnS QD
H N
N
N H N
Zn
N
N
NH2
b
d
+
N (CH3)3
-
CdSe QD
S
O H2 C C
NH
-
O
N
+
+
N (CH3)3
(H3C)3 N
N
HN
CdSe QD
S
SO3
O3S
O H2 C C
N O
N
Al N
-
-
N
-
O3S
SO3
+
N (CH3)3
Fig. 7.2 Schemes of different types of bonding in the QD/tetrapyrrol complexes: (a) covalent bonding of the TPA capped CdTe QD with TAPc; (b) electrostatic bonding of negatively charged CdSe QD capped by thioglycolic acid (TGA) with positively charged meso-tetra(p-trimethylaminophenyl)porphine; (c) coordination bonding with coordinating tetrapyrrol to the QD surface metal atom in complex of CdSe/ZnS QD with meso-tetrapyridineporphine; (d) coordination bonding with coordinating the QD capping molecule to the tetrapyrrol central metal atom in complex of the TGA capped CdSe QD with AlOH-tetrasulfophthalocyanine
shift of the phthalocyanine absorption spectrum (about 2 nm). It seems likely that this fact is a common peculiarity of this bonding type and is caused by a presence of long length linker chain between QD and phthalocyanine chromophore. Schematically this bonding type is shown in Fig. 7.2a by an example of covalent bonding of the TPA capped CdTe QD with TAPc. In reference [41] the CdSe/CdS/
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ZnS QDs capped by peptides had been also covalently bound with chlorin e6 (Chle6) or with the Rose Bengal (RB) dye via the peptide molecules. Obvious advantages of this mode of bonding are the very high stability, the absence of any dissociation processes at standard conditions and the fixed distance from QD to the tetrapyrrol molecule. The disadvantages are the rather complicated protocol of the synthesis, some limitations on the substituents used (e.g. presence of the amino group on the one component and carboxy group on the other one), and the relatively long distances between QD and molecule that limits the efficiency of all types of interaction between them including the energy transfer.
7.2.2
Electrostatic Interaction Between QD and Tetrapyrrol Molecule
Electrostatic interaction as the bonding mechanism will take place if QD and tetrapyrrol molecule are oppositely charged. This type of complexing can be relatively simply obtained. It is enough to prepare solutions of QDs and tetrapyrrol substances of appropriate concentrations and to fuse them. The possibility of formation of stable complexes between oppositely charged QDs of different sizes and between oppositely charged QDs and Au nanocrystals due to electrostatic interaction has been demonstrated in Ref. [42]. In Ref. [43] the complex formation between CdTe QDs with the surface modified by cysteamin-hydrochloride (positively charged) and molecules of AlOHtetrasulphophthalocyanine (Al-TSPc, negatively charged) has been reported. The results of spectral and luminescent studies showed irreversible bonding of QD with Al-TSPc during the formation of the complex. It has been found that complexes with different content of the components QDq·(Al-TSPc)n, where q £ 4 and n ³ 1, can be formed including the complexes containing one phthalocyanine molecule coupled with several QDs. In this work the quenching of luminescence of several QDs by single phthalocyanine molecule was demonstrated. Significant changes in the phthalocyanine absorption spectra caused by complexing were observed. In particular, a broadening of the Q-band in the absorption spectrum of the molecule and certain redistribution of intensities in its vibrational structure have been observed as it is demonstrated in Fig. 7.3. The analogues processes were described in reference [44] where complex formation induced by the electrostatic interaction between QDs CdTe/TGA (negatively charged) and metal free meso-tetra(p-trimethylaminophenyl)porphine (TAPP, positively charged) was demonstrated. Schematically the bonding mechanism for this case is shown in Fig. 7.2b. The complex formation was analyzed by the absorption/ luminescence techniques. Up to four different forms of TAPP in complexes with QDs distinguished by their luminescence, absorption or luminescence excitation spectra were revealed supporting creation of complexes of the type: QDq·(TAPP)n. The changes in the absorption spectra of TAPP in presence of QDs of different sizes are illustrated in Fig. 7.4 where inset shows the system of the Q bands of TAPP in details. Upon interaction with QDs, the maximum of the B band of TAPP
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Fig. 7.3 Absorption spectra of aqueous solutions of CdTe QDs, Al-TSPc, and their mixture: (1) the absorption spectrum of the initial QD solution, (2) the absorption spectrum of the mixture of QD and Al-TSPc solutions, and (3) the absorption spectrum of free Al-TSPc (Reproduced from Ref. [43] with kind permission of © Pleiades Publishing, Ltd. 2008. All Rights Reserved.)
0.05
0.04
optical density, D
3 1
0.03
2
0.02
0.01
0.00 500
600
700
800
wavelength, nm
3
2 1.75
0.12
1 optical density, D
1.50 1.25
2 0.08
B-band 3
1.00
0.04
1
0.75 0.00
0.50
500
600
700
0.25 0.00 300
400
500
600
700
wavelength, nm
Fig. 7.4 Absorption spectra of (1) free TAPP, (2) TAPP in the presence in a solution of CdTe QDs with diameter of 2.75 nm, and (3) TAPP in the presence of CdTe QDs with diameter of 3.0 nm. The inset shows the system of the Q bands of TAPP (Reproduced from Ref. [44] with kind permission of © Pleiades Publishing, Ltd. 2008. All Rights Reserved.)
is always red shifted from 412 to 425 nm. In some cases, the absorption spectrum of the porphyrin molecules bound with QDs exhibits the second B band with a maximum of 445 nm (Fig. 7.4, curve 3). The amplitude ratio of the bands at 425 and 445 nm varies with varying concentration of the molecules in the solution. This indicates that these bands belong to different forms of TAPP in complexes with QDs. This is also supported by changes in the positions and relative intensities of the Q bands of porphyrin associated with QDs as compared with the aqueous solution of porphyrin molecules.
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An additional example of the QD/porphyrin complex formation via electrostatic interaction is presented in reference [26], where optical properties of complex of meso-tetra(4-sulfonatophenyl)porphine (TSPP) with water-soluble CdTe QDs capped with 2-aminoethanethiol as a surface stabilizer were analyzed. A slight blue shift of the UV-vis absorption spectra of QD/TSPP complexes as compared with spectrum of free TSPP has been observed. It was remarked that the absorption peak of the CdTe QD/TSPP complexes increased in intensity with concentration of TSPP, while no obvious changes of the absorption peak of the QDs after combination with TSPP was found. The complexes of positively charged zinc tetramethyl-tetra-2,3-pyridinoporphyrazine (Zn-Tmtppa) with negatively charged water-soluble CdTe/TGA QDs described in Ref. [45] possibly belong to the same bonding type. The peculiarity of this system is that the complex formation is accompanied by strong changes in the Zn-Tmtppa absorption spectrum, consisting in significant decreasing the Q-band intensity and the appearance of a new absorption band in the region of 400–500 nm. These spectral changes as well as a synchronous quenching of the luminescence of both QD and Zn-Tmtppa were explained by the chemical reduction of Zn-Tmtppa to its radical anion. The study of concentration dependence of QD luminescence quenching allowed concluding that one QD could bind with up to two Zn-Tmtppa molecules.
7.2.3
Coordination Bonding
A coordination bonding is probably the most widespread type of bonding at the QD/ tetrapyrrol complex formation. It is reasonable to distinguish two cases of the coordination bonding differing from each other by the bonding mechanisms and the properties of formed complexes: (i) a ligand from tetrapyrrol is coordinated to the QD surface metal atom and (ii) a ligand from the organic QD shell is coordinated to the central metal atom of tetrapyrrol ring. These two possibilities are considered in details below.
7.2.3.1
Coordination of Non-tetrapyrrol Organic Ligands on the QD Surface Metal Atom
Let us first present some data on coordination of non-tetrapyrrol organic ligands on the QD surface metal atom. This type of bonding has been studied in a number of references [46–48]. The Zn and Cd atoms are served as the surface metal atoms for the core-shell CdSe/ZnS and CdSe (CdTe) QDs, respectively. Any molecule having active electron lone pairs can serve as a ligand. The liganding molecules can either substitute the stabilizer molecules (e.g. TOPO) bound to the QD surface or bind to the free surface metal atoms not occupied with TOPO.
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In one of the first works where this type of bonding was described [46], the binding of CdSe QDs and CdSe/ZnS QDs with the bidentate 1,12-diazaperylene ligand was studied by the analysis of the absorption and luminescence spectra of QD and dye solutions and their mixtures. The formation of the complex was expected since diazaperylene can readily substitute TOPO on the CdSe QD surface. Indeed, it was found that after addition of the dye to the QD solution at room temperature, the QD/dye complexes were immediately formed resulting in evident changes in the absorption and luminescence spectra of the mixture as compared with those of the QDs or dye solutions. In particular, one of the evidences of the QD – dye interaction within this system was the appearance of new absorption band at 474 nm, which was attributed by the authors to the red shifted lowest absorption diazaperylene band of 442 nm. In the same way, the evidences of complexing of CdSe/ZnS/TOPO QDs with o-phenanthroline in the mixture of their hexane solutions have been observed [47]. In this work the widening of the lowest o-phenanthroline band and its bathochromic shift from 264 to 273 nm were found in the absorption spectrum of the mixture with respect to that of the solution of the molecules. The process of binding takes rather long time (up to 26 h) that was explained by the necessity of substitution of surface TOPO molecules by the bidentate o-phenanthroline ligand. The complexing of CdSe/ZnS/TOPO QDs with 1-(2pyridylazo)-2-naphthol (PAN) has been described in Ref. [48]. This azo-dye is a tridentate ligand capable of binding with various metal ions. It was shown that this dye in various hydrophobic solvents forms complexes with QDs, which can be characterized by the absorption band at 560 nm absent in free PAN spectrum. At the same time, it is well known that this band is the characteristic one for complexes of PAN with Zn2+ ions. On this basis, the authors assumed that as the result of interaction of QD with PAN the complexes were formed in which the surface Zn atom coordinates one oxygen and two nitrogen atoms of PAN molecule. The rate of formation of the QD/PAN complexes depends on the absolute QD and PAN concentrations in the solution and their molar ratios. Particularly, upon mixing the toluene solutions of QDs with the concentration ~2 × 10−7 M and those of PAN with the concentration ~2 × 10−6 M, the complete bonding of QDs in the complex with the azo-dye was observed 5 h after the addition of PAN to the QD solution.
7.2.3.2
Coordination of Tetrapyrrols on the QD Surface Atoms
Formation of complexes between hydrophobic CdSe/ZnS QDs and metal free mesopyridine-substituted porphyrins has been reported in Refs. [49–51]. The conclusion about complex formation in these works was made mainly on the basis of QD luminescence lifetime measurements under interaction with the porphyrin molecules. There were no marked changes in the absorption spectra of the QD and molecule mixtures due to the complexing [50] but only a small bandshift of about 2 nm in the luminescence spectrum of the porphyrin. Based on systematic researches using appropriately varying porphyrin structures, the orthogonal porphyrin orientation against the QD surface was assumed where the binding is possible either in one or
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in two points. It was also shown that the number of porphyrin binding sites on the QD surface is limited. In reference [52] the complexes of CdSe/ZnS/TOPO QDs with meso-tetra(4-pyridyl)porphyrin have been studied. In this work the formation of complexes was illustrated by Raman and Attenuated Total Reflectance–Fourier Transfer Infrared (ATR–FT-IR) spectra in which the frequency shifts and intensity changes of characteristic TOPO vibration modes under complexing with QD was observed. Analogues complexes were also obtained for tetrapyridinetetrahydropophine [50]. Schematically this type of bonding is shown in Fig. 7.2c. In the reference [53] the complex formation of metal free tetrapyridinoporphyrazine (TPPA) with hydrophobic CdSe/ZnS QDs in chloroform has been reported. The authors demonstrated an appearance of new features in the absorption spectra of the QD/TPPA mixture significantly different from the spectrum of free TPPA. Three bands of comparable intensity in the region of Q-transitions were observed and attributed to the TPPA complexed with QD.
7.2.3.3
Coordination of QD Shell Component to the Tetrapyrrol Metal Central Atom
The capability of tetrapyrrol metal derivatives to add axial ligands can also be used as one of mechanisms of QD/tetrapyrrol complex formation by the coordination bonding. This idea was realized for the first time in the works of T. Nyokong and co-authors [28, 54]. Formation of the complex between Al-TSPc and CdTe QDs capped with TGA, 3-mercaptopropionic acid (MPA) or L-cysteine were described in Refs. [54] and [28]. Schematically this type of bonding is shown in Fig. 7.2d. The interaction of Al-TSPc with CdTe/TGA QDs was also studied in reference [55], though in conditions differing in the pH value (pH = 12) from references [28, 54]. It was marked that the complexing does not result in pronounced changes of the absorption spectra although the 2 nm shift of Al-TSPc absorption band was reported in Ref. [55]. At the same time, the complex formation was evidenced based on photophysical properties of this system that will be discussed below in Sect. 7.3. It is noteworthy that the complex formation in this case takes place in spite of similar (negative) charge of both components: QD and Al-TSPc.
7.2.4
Bioconjugation
There are certain pairs of molecules, as a rule they are biomolecules, which have very high selective affinity to each other. This property provides a strong non-covalent coupling between these molecules independent of parameters of surrounding media (pH, presence of another molecules, proteins, etc.). In this section the term ‘bioconjugation’ is used in narrow sense, namely as a formation of complex between two particles, which have a high affinity to each other or their surfaces are capped by molecules of high affinity.
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The pairs of avidin (protein isolated from eggs) with biotin (vitamin B7) and streptavidin (STV, protein isolated from the bacterium Streptomyces avidinii) with biotin are widely used for specific coupling. This pairs have very low dissociation constant: kD ~ 10−15 M. Now some corporations (for example, Quantum Dot Corporation and Invitrogen Corporation) produce quantum dots passivated by avidin or biotin for biological applications. Passivation of hydrophobic quantum dots by biomolecules provides them water solubility and reduces a probability of body intoxication with heavy metal ions (Cd2+ in the case of CdSe and CdTe QDs). Due to specific coupling of biomolecules the passivation can simplify the procedure of specific binding of QDs with DNA, proteins etc. for application in a fluorescent analysis of immunoassays. Biopassivation of quantum dots can lead to an enhancement of QD fluorescent quantum yield by 1.5–2.5 times, up to 24% [56] and to strong increasing their fluorescent lifetime up to several tens nanosecond (for CdTe QDs) [57]. Unfortunately, an appearance of the additional layer of biomolecules on the QD surface leads to significant increase of the size of quantum dots. For example, in Ref. [58] a passivation of ~5.3 nm CdSe/ZnS QDs by STV molecules results in increasing size of the nanoparticles up to ~17.2 nm. This is a disadvantage, since the increase of the QDs size can prevent the penetration of quantum dots inside cells. In the case of QD/molecule complex, this leads to increase in the distance between QD and molecules and thus to reduction of efficiency of intracomplex energy transfer. The energy transfer from terbium complex TbL, where L is the composite organic ligand with 2,2¢-bipyridine groups, used as a luminescent marker for STV, to biotin capped CdSe/ZnS QDs has been analyzed in Ref. [59]. In this case the distance between QD and TbL complex was equal to ~85 Ǻ. Use of TbL as an energy donor and QD as an acceptor allowed for the creation donor/acceptor pair with efficiency of energy transfer as much as 70%. It should be noticed, that in the case of such long donor-acceptor distances (up to 100 Ǻ), an efficient energy transfer can be observed only if the acceptor absorption spectrum and the donor fluorescent spectrum overlap completely and the acceptor has very high extinction coefficient. For such systems quantum dot should be preferably used as the acceptor of energy and organic molecule should be used as the donor of energy. If the organic molecules are used as the acceptor of energy, for efficient intracomplex energy transfer the donor-acceptor distance, as a rule, should not exceed 20 Ǻ. Therefore if the coupling of QDs with tetrapyrrols is performed via bioconjugation the efficiency of intracomplex energy transfers, and, consequently, of the generation of singlet oxygen, is expected will be sufficiently lower than in case of the other binding types.
7.2.5
Other Mechanisms of Bonding
In some works, the mechanism of complexing between QD and tetrapyrrol molecule had not been discussed. Sometimes, an assumed type of interaction does not correspond to any of described above types. For example, in Ref. [60]
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an interaction of CdTe QDs capped by TGA or 2-mercaptoethanol (2-ME) with the Zn and In derivatives of tetrasulphophthalocyanine (TSPc), tetracarboxyphthalocyanine (TCPc) and octacarboxyphthalocyanine (OCPc) has been studied. Similarly, in Ref. [61] an interaction of CdTe QDs capped by TGA with TSPP, meso -tetra(4-carboxyphenyl)porphyrin (MTCP), meso(4-N-methylpyridyl)porphyrin and meso -tetraphenylporphyrin was studied. The described photophysical properties evidenced for complex formation between QDs and tetrapyrrol molecules. However, the mechanisms of complexing in these cases were not clarified. An interaction between hydrophobic CdSe QDs capped by TOPO or tributylphosphine oxide and silicon phthalocyanine with long axial ligand HOSiPcOSi(CH3)2(CH2)nN(CH3)2 has been studied in references [62, 63]. It could be expected that in this case the formation of the complex will be caused by hydrophobic interaction between long alkyl substituents of QD stabilizer and phthalocyanine axial ligand. However, in one of subsequent works [64] the authors pointed out that the absence of the substituted amino group on the end of axial ligand leads to the impossibility of complexing. The authors concluded that the bonding in this case is mainly caused by interaction between the substituted amino group of the axial ligand and the QD surface.
7.3
Photophysical Processes in QD/Molecule Complexes
Formation of the QD/organic molecule complexes may lead to certain changes in spectral and photophysical properties of both QD and the molecule bound with each other. In particular, certain changes in absorption and/or luminescence spectra of molecule and/or QD can occur. In most cases, more or less efficient QD luminescence quenching takes place. Changes in QD optical properties induced by an interaction with organic molecules were tried to be explained by several physical mechanisms such as energy transfer between QD and the molecule, photoinduced electron transfer from QD to the molecule, formation of QD luminescence deactivation centers at the place of bonding of molecule to QD, etc. In is noteworthy that the physical mechanism of the QD luminescence quenching may be insignificant in case of the applications different from PDT, e.g. in luminescent sensors. However, these mechanisms are of great importance if the applications of QD/organic molecule complexes in PDT are considered. In this case, it is necessary that nonradiative photoexcitation energy transfer would take place between QD and the molecule within the complex, and its efficiency would be as high as possible. If other QD deactivation mechanisms dominate, this complex becomes useless for PDT. In this section, the results of investigation of photophysical processes occurring in QD/tetrapyrrol molecule complexes and the discussed in literature mechanisms of these processes are considered.
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Influence of Complexing on Absorption and Luminescence Spectra of QDs and Tetrapyrrol Molecules
The formation of complexes of QD with tetrapyrrol molecules is often accompanied by the changes in absorption spectra of molecules and sometimes of QDs. These changes, though often being rather small, are of great importance, because they allow one to determine the concentration of complexes in the mixture and thereby to yield information on dynamics of complexing. In previous section, some peculiarities of tetrapyrrol moiety absorption spectra changes at different types of bonding have already been described. Here some concluding remarks will be made. The significant changes in the tetrapyrrol absorption spectra take place only if a perturbation of the molecule electronic structure induced by the complexing is strong enough. Probably since the immediate contact between tetrapyrrol chromophore and the QD surface is absent for the most part of the considered bonding types, only relatively small shift (~2 nm) of the tetrapyrrol absorption bands is usually observed. It seems surprising that similar values of the shift were observed in the case of complexes of CdSe/ZnS QDs with meso-pyridine-substituted porphine derivatives [49–51], where immediate coordination of pyridine substituent nitrogen atoms onto QD surface Zn atom occurs. Probably the reason of such a small influence comes from the fact that only partial conjugation of pyridine meso-substituents with porphyrin chromophore takes place. Indeed, pronounced porphyrin absorption spectrum changes were observed in reference [53] at formation of complexes of TPPA with similar type of QDs and with the same type of bonding. Contrary to complexes described in Refs. [49–51], in this case the nitrogen atoms coordinating onto QD surface Zn atoms are completely involved into the tetrapyrrol ring conjugation system. It is necessary to note that in cases of electrostatic type of bonding much more pronounced changes in the tetrapyrrol component absorption spectra are usually observable than for other bonding types. The possible reason of the essential spectral changes comes most likely from a mutual neutralization of some charges that inevitably leads to significant change of symmetry and spatial distribution of electric field affecting the tetrapyrrol chromophore. In contrast to the changes of absorption spectra of the tetrapyrrol moieties, the changes in the QD absorption peak positions do not usually exceed 2 nm or are even unobservable for several types of bonding. These changes are certainly taking place for coordination bonding type when tetrapyrrol molecules substitute some of TOPO molecules [49–51]. Analogous effects were remarked in case of complex formation of QDs with o-phenanthroline [47]. As a rule, such spectral shifts in QD absorption spectra are accompanied by nearly equal in terms of shifts in QD luminescence spectra in the same direction.
7.3.2
QD Luminescence Quenching in Complex
A static quenching of the QD luminescence caused by their bonding with tetrapyrrol or analogues molecules is one of the most characteristic manifestations of the
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complex formation. In case of complexing of QDs with tetrapyrrol molecules, more or less pronounced QD luminescence quenching takes place practically always. 7.3.2.1
Concentration Dependence and Models of the QD Luminescence Quenching
One of the first characteristics of interest when studying the process of the QD luminescence quenching, is the quenching dependence on the quencher concentration (or so called “quenching curve”). This characteristic was studied practically in all works in which the complex formation of QDs with tetrapyrrol molecules was investigated. It is reasonable to distinguish between two cases of QD luminescence quenching in the complex: (i) the case when binding even one molecule leads to complete quenching of QD luminescence and (ii) the case when such binding leads to incomplete quenching. The first case is simpler in consideration, because all the observable QD luminescence belongs to the free QDs not bound into the complex. However, even here some complicated cases can take place caused by complicated complex stoichiometry and/or by the existence of equilibrium between complexes and free QDs and molecules. Indeed, in case of interaction of CdTe QDs capped by cysteamine with Al-TSPc molecules [43] the QD quenching curve in wide range of concentration of added phthalocyanine molecules is described by exponential decay function: F = e − nx , F0
(7.2)
where F and F0 are the QD luminescence intensities in presence and absence of phthalocyanine molecules, respectively, x = Cp/CQD, where CP and CQD are the concentrations of phthalocyanine molecules and QDs, respectively. The value of parameter n depended on the type of QDs used in experiments and varied from 2 to 4. It means that at low values of x one phthalocyanine molecule can quench luminescence of up to 4 QDs. The authors of the referred work assumed that the quenching of the QD luminescence is accompanied by the QD clasterization with formation of conglomerates consisting of 2–4 QDs. The exponential dependence was explained by the possibility of binding the phthalocyanine molecules to either free QDs or QD bound in complex. It was shown that, if the probability of binding of phthalocyanine molecule to QD does not depend on whether this QD is free or it is already bound into the complex, the F/F0 dependence on x should be strictly exponential. Similar dependence of the QD luminescence quenching on the concentration of added molecules has been observed in reference [44] in which the complex formation of CdTe/TGA QDs with TAPP has been studied. The values of parameter n in this case varied from 3.3 to 4. The exponential dependence of F/F0 on x was also observed in reference [55] where the complex formation of Al-TSPc with CdTe/TGA QDs was studied in aqueous solution. Although in this system at lower Al-TSPc concentrations some features of dynamic equilibrium were found, the measured quenching curve especially at higher x values demonstrates clear exponential decay dependence. The latter indicates that formation of complexes containing more than one phthalocyanine
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molecules per one QD is possible and that the numbers of such phthalocyanine molecules per one QD approximately obeys a Poisson distribution. The exponential dependence of QD luminescence intensity on quencher concentration was also observed in reference [65] where the interaction of CdSe QDs with TSPP was studied. In the cases when equilibrium of the complex formation is not completely shifted towards the complexes it is possible to determine the binding constant and the number of molecules capable of binding with one QD from the dependence of QD quenching degree on the concentration [Q] of quencher Q from the following equation (see, [45] and references therein): log
( F0 − F ) = log kb + n log[Q ] , F − F∞
(7.3)
where F0 and F are the QD luminescence intensities in the absence and presence of the quencher, respectively; F∞ is the intensity of QD luminescence saturated with [Q]; kb is the binding constant; n is the number of binding sites on one QD. Plots of ( F − F ) against log[Q] provided the values of n (from slope) and k (from the log 0 b F − F∞ intercept). When the QD luminescence quenching obeys the formal Stern–Volmer dependence: F0 = 1 + K[Q], F
(7.4)
the quenching constant K can be determined. Examples of utilization of the Eqs. 7.3 and 7.4 for determination of the parameters of complexing and quenching can be seen in a number of references [45, 50, 54]. The complexes of QDs CdTe of different sizes (from 3 to 4 nm) capped by TGA or 2-ME with Zn-Tmtppa have been studied in reference [45] where the value n = 2 was obtained in all cases. The values of binding constant in the case of CdTe/TGA varied from 2.7·1010 M−2 to 2.5·1013 M−2 demonstrating the evident tendency of increasing with the QD size. In case of the 2-ME coating the constants were found to be considerably smaller and the maximal kb value was equal to 5.2·109 M−2 for QDs of all sizes. The formation of the complex of Al-TSPc with CdTe QD capped by different molecules has been considered in the Ref. [54]. The value n = 1 was obtained for all cases while the kb values depended on the QD capping agents and varied in the range of (0.61–11.6) × 105 M−1 at the highest value for MPA. Analogously the complexing equilibrium constant has been also determined in reference [50] where the complex formation of CdSe/ZnS/TOPO QDs with meso-pyridine-substituted porphyrin derivatives has been studied. It has been found that the value of the constant varies from 1.4 × 105 M−1 to 4.8 × 105 M−1 depending on the number and location of pyridine substituents and that the value of constant is considerably higher for two substituents than for one. The case of incomplete QD luminescence quenching in the QD/porphyrin complex has been analyzed in details in references [49–51] where the complexing of
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CdSe and CdSe/ZnS QDs with meso-substituted porphyrins has been studied. The authors of reference [51] have measured in detail the QD quenching curve and showed that if the x values do not exceed the certain value n » 5 the Stern–Volmer dependence (Eq. 7.4) takes place. This dependence has been explained as follows. Since the QD is able to bind more than one molecules, it is reasonable to assume that the QD quenching rate constant in the complex is proportional to the number of bound porphyrin molecules (see also Ref. [56]). With the assumption that the equilibrium of the complexing is completely shifted towards the complexes, the latter is determined by the ratio of concentrations x. It is clearly seen, that if all these conditions are fulfilled and the value of x does not exceed the maximum number of the porphyrin molecules capable of binding to one QD, the Stern–Volmer dependence should really take place. Analogous results have been obtained in the references [56, 57] where the properties of complexes QD/organic dye molecule obtained by the bioconjugation method (see Sect. 7.2.4) were studied. In the systems described in the referred works each QD could bind up to ten (or even more) fluorophor molecules, and each of them could not quench completely the QD luminescence itself. The dependencies of QD quenching efficiency on the fluorophor concentrations or on the number of bound molecules are in qualitative agreement with the dependence described above, although its exact agreement with the Stern – Volmer equation was not discussed.
7.3.2.2
Mechanisms of the QD Luminescence Quenching
In this section the main mechanisms of the QD luminescence quenching due to complexing of QDs with organic molecules are considered. FRET. Energy transfer efficiency. Main evidences of energy transfer: sensitized luminescence, singlet oxygen generation. Fluorescence Resonance Energy Transfer, FRET is a process in which the radiationless energy transfer occurs from a photoexcited donor molecule (in our case QD) to an acceptor molecule located in vicinity of the donor molecule. The excited acceptor molecule can then return to its ground state either with emission of photon or via radiationless transitions. In the simplest approach, FRET is caused by dipole-dipole interaction between donor and acceptor and its efficiency strongly depends on the distance between them as well as on the value of the overlap integral between the donor emission spectrum and the acceptor absorption spectrum (see, for instance, Ref. [18]). The main experimental evidences of FRET are quenching the donor luminescence and increasing the intensity of the acceptor luminescence. Measuring of these parameters allows the determination of FRET efficiency. In accordance with Förster theory the FRET rate constant is determined by the following equation: kDA =
1 R06 , 6 t D0 RDA
(7.5)
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where tD0 is the lifetime of the donor excited state, RDA is the distance between donor and acceptor and R0 is the critical radius, i.e. the donor–acceptor distance at which the energy transfer probability has the same value as the probability of spontaneous donor de-excitation. R0 is determined by the following relation: R06 =
9000· ln10· Φ 2 · q0 D H −4 ∫ I D (v)· e A (v)· v · dv. 128· π 5 · n 4 · N
(7.6)
Here, q0D is the donor luminescence quantum yield in the absence of the quencher; F2 is the orientation factor; IHD(n) is the quantum spectral density of the donor luminescence, normalized to unity ( ∫ I DH (n )dn = 1 ), eA(n) is the acceptor molar extinction coefficient; n is the wavenumber; n is the refractive index of the medium; and N is Avogadro number. A high efficiency of FRET from QD to molecule and, therefore, dominant FRET contribution to the QD luminescence quenching is the key factor that determines possibility of application of the QD/tetrapyrrol complexes in PDT. As a measure of the energy transfer efficiency, the parameter E = kDA/(kf + kr + kDA) is commonly utilized. Here, kf and kr are the rate constants of the radiative and nonradiative energy deactivation of the donor excited state involved in the energy transfer process, respectively. This parameter has a physical sense of a quantum yield of the energy transfer. One of the ways of theoretical estimation of the energy transfer efficiency is based on using the Förster formula (7.5) that gives the following relation: E.theor . =
1 ⎛R ⎞ 1 + ⎜ DA ⎟ ⎝ R ⎠
6
, (7.7)
0
This expression is utilized for estimation of the energy transfer efficiency practically in all the works in which the photophysics of the QD/tetrapyrrol molecule complexes is investigated. It is necessary to remark, however, that this estimation is not enough reliable, at least because the distance R between donor and acceptor in the most cases cannot be determined exactly. The simplest way for estimation of the FRET efficiency from the experimental data on the QD luminescence quenching consists in using the following formula (see, for instance [56]): E = 1−
F , F0
(7.8)
where F and F0 are the QD luminescence intensities in presence and in absence of the energy acceptor, respectively. It is necessary to remark that the use of the formula (7.8) assumes that no new energy deactivation channels of the donor appear due to presence of the acceptor. It is evident that in case of tight contact between donor and acceptor in the complex it may not be so. In this case application of the formula (7.8) becomes groundless. However, when the immediate contact between
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QD and chromophore of acceptor molecule is absent, for instance in case of complex formation by mechanism of bioconjugation (see Sect. 7.2.4), the use of formula (7.8) is fully justified. Instead of the formula (7.8), the FRET efficiency can be also estimated by expression E = 1−
t , t0
(7.9)
where the QD luminescence decay times appear instead of the luminescence intensities. Here, t and t0 are the luminescence decay times in presence and in absence of the energy acceptor, respectively. The mentioned above limitation on the usage of formula (7.8) is also valid for formula (7.9). In experimental measurements of the energy transfer efficiency in highly concentrated solutions, it is necessary to take into account the reabsorption effects. For example, in Ref. [65] the increasing of the molecule concentration in mixture with QDs (at fixed QD concentration) leads to both quenching of the QD luminescence and shortening the QD luminescence lifetime. A degree of the luminescence quenching, however, appreciably exceeded the degree of the lifetime shortening, i.e. the appreciable difference between values obtained by using formula (7.8) and (7.9) took place. In particular, after addition of 1.5 × 10−4 M TSPP to the QD solution, the QD luminescence lifetime was shortened by ~5% whereas the luminescence intensity decreases by ~39%. Increasing the porphyrin concentration to 3 × 10−4 M leads to the 56% luminescence lifetime shortening and to the ~83% intensity decreasing. According to the authors’ point of view, the reason of this difference is that, besides the radiationless energy transfer leading to both decreasing the QD luminescence intensity and shortening its lifetime, the radiation energy transfer takes place, namely, reabsorption of the light emitted by QDs by the TSPP molecules. The latter process does not influence on QD lifetimes but leads to the QD luminescence intensity decrease. In Refs. [62–64] as the measure of FRET efficiency the authors used the Eq. 7.9 in which the QD excited state relaxation times instead of the luminescence decay times were substituted for t and t0. The excited state relaxation times were obtained from the time resolved absorption spectra after 130 fs light impulse. It is evident that the indicated above limitations on usage of the formula (7.8) are also valid in this case. If the tetrapyrrol molecule bound in complex retains the capability of luminescence, it may be possible to estimate the FRET efficiency by the formula: E=
j DA , jA
(7.10)
where jDA is the quantum yield of the sensitized by QD tetrapyrrol moiety luminescence, jA is the luminescence quantum yield of the same moiety under its direct excitation. Certain difficulty here may arise from incorrect determining the value of jDA, because any contribution of direct excitation of tetrapyrrol moiety should be
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taken into account. Equation (7.10) is more frequently used in somewhat another form (see for instance [49, 56]): E=
e A ( lex ) FAD , e D (lex ) FA ·n
(7.11)
where FAD is the acceptor luminescence intensity upon interacting with a donor, corrected for direct excitation, FA is the acceptor luminescence intensity in the absence of the QD donor at the same concentration as in the former case and the same experimental conditions, eA(lex) and eD(lex) are the extinction coefficients of the acceptor and donor at the excitation wavelength lex, respectively, and n corresponds to the number of acceptor (A) molecules per one donor (D). The utilization of expressions (7.10) and (7.11) for estimation of the FRET efficiency is more correct than (7.8) or (7.9) because they are completely applicable in cases when the complex formation leads to appearance of the supplementary radiationless transitions in donor (QD), and also when the acceptor luminescence quantum yield in complex is not the same as in the case of free acceptor. Both the experimental and theoretical estimations of the energy transfer efficiencies show that if the tetrapyrrol moiety in the complex is close enough to the QD surface, then the relatively high efficiencies of the energy transfer from QD to tetrapyrrol can be achieved. Indeed, for complex CdSe QD with TPPA [53] where intensities of the sensitized TPPA luminescence was compared with the directly excited TPPA luminescence the contribution of FRET to overall QD quenching in the complex has been estimated as high as 60%. It is not surprising since the immediate contact of TPPA with the QD surface was assumed in this system. As it will be discussed below in Sect. 7.3.4 in more detail, the close location of the tetrapyrrol moiety to the QD surface may in turn lead to the efficient tetrapyrrol luminescence quenching, that makes very difficult the observation of the sensitized luminescence of the tetrapyrrol molecules. In reference [44] where the luminescence of TAPP in the complexes with CdSe/TGA QDs has been detected, the QD absorption features have been revealed in the TAPP luminescence excitation spectra. This is a direct evidence of the energy transfer from QD to the molecules. Unfortunately, the substantial weakening of the sensitized luminescence in comparison with that of free TAPP and the existence of several forms of TAPP with different spectra did not allow for quantitative estimations of the energy transfer efficiency. The theoretical estimations by using the Förster formula gave the FRET efficiency value of 0.97–0.98 that can be considered only as the upper limit of this efficiency. In references [49–51] the mechanism of the luminescence quenching of the CdSe/ZnS and CdSe QDs in the complexes with meso-pyridinesubstituted porphyrins has been studied. Although in these complexes the immediate contact of the porphyrin molecule with the QD surface was assumed too, the sensitized luminescence of the porphyrin was reliably observed. From its intensity, the FRET efficiencies were estimated to be equal to 1–2%. Based on set of experimental data, the authors concluded that the FRET mechanism cannot explain completely the QD luminescence quenching in the complexes studied and the FRET contribution to the observed quenching is small. This implies the existence of other mechanisms.
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On the other hand, in complexes of Al-TSPc with CdSe/TGA QDs studied in references [28, 54, 55], the immediate contact of the molecule with the QD surface was not anticipated. Therefore, the luminescent properties of phthalocyanine in the complex were expected to be retained. Really, the Al-TSPc luminescence sensitized by QD phthalocyanine was successfully observed in all these works. The sensitized acceptor luminescence has been also observed in reference [56] where the complexes of CdTe QDs capped by TGA or 2-ME with Zn-and In- derivatives of TSPc, TCPc and OCPc in alkaline alcohol solutions have most likely the similar type of the bonding. It is noteworthy, that though in references [54, 56] the sensitized luminescence of the phthalocyanine has been observed, it was not used for the estimations of the energy transfer efficiency. The latter was determined from data on the QD luminescence quenching. Because of this, the FRET efficiency values obtained in these works can be considered only as the upper limits. In reference [55] for complexes of Al-TSPc with CdTe/TGA QDs in alkaline aqueous medium the FRET efficiency derived from the quantum yield of the sensitized phthalocyanine luminescence amounted to 0.4. Taking into account that in this work the complexing led to complete QD luminescence quenching, the sum of radiationless losses may amount to ~0.6. In case of these complexes the estimation of the FRET efficiency through the sensitized luminescence yield is facilitated by the fact that there is a spectral region where the intrinsic phthalocyanine absorption is very low but the QD absorption is high and the sensitized luminescence can be excited alone. Physical peculiarities of the energy transfer in complexes of QDs with organic molecules have been studied in several works. In reference [56] the dependence of the FRET efficiency on the overlap integral value between the lowest energy luminescence band of QD and the absorption spectrum of the energy acceptor was analyzed on example of bioconjugated system of QD with the modified maltosebinding protein (MBP) covalently linked with cyanine dye Cy3. The FRET efficiencies were determined for three types of QDs with different spectral positions of the luminescence bands. As a result, an evident correlation of the FRET efficiency with the overlap integral value in the range of its two-fold variation was found. This problem has been investigated in details in reference [64] where the energy transfer in the complexes of the phthalocyanine Pc4 with the CdSe/TOPO and CdSe/ZnS/ TOPO QDs having different spectral positions of the luminescence bands. Although the expected increase in FRET efficiency with the overlap integral was found in this work, two significant deviations from linearity were marked. First, at low overlap integral values the FRET efficiency was found to be higher than the assumed one. Second, the FRET efficiency demonstrated saturation with growth of the overlap integral and even a slight decrease of the efficiency was observed at the further increasing of the overlapping. The first of these deviations the authors explained by the participation in the energy transfer of some local states with the energies inside the QD energy gap. Such states, when the fundamental QD exciton transition is substantially higher in energy than that of the acceptor, can be in resonance with the acceptor transition and can increase thereby the energy transfer efficiency. In the referred work authors’ opinion, this assumption is indirectly supported by the fact that the FRET efficiency in the Pc4 complexes with CdSe/TOPO QDs was higher
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than in the Pc4 complexes with CdSe/ZnS/TOPO since the latter have a considerably lesser number of local states within the energy gap. The FRET efficiency in the complexes of CdSe QDs capped by TOPO or tributylphosphine oxide with HOSiPcOSi(CH3)2(CH2)nN(CH3)2 – a silicon phthalocyanine with a long axial ligand has been studied in references [57, 58]. Here, the n value varied from 1 to 6. It was supposed that in such a way the dependence of the FRET efficiency on the donor to acceptor distance can be obtained. The result, however, showed that this dependence was in evident disagreement with that expected from the Förster law (Eq. 7.7). The FRET efficiency increased with the distance for the TOPO capped QDs while for QDs capped by the tributylphosphine oxide it had a maximum at n = 4. The reason of the disagreement could be that this type of bonding (see Sect. 7.2.5) does not always strictly fix the distance between the energy donor and acceptor, which in discussed case can be determined not only by the number n but also by other factors. It is necessary to note that in these works, the energy transfer in the QD/phthalocyanine complexes is convincingly proved. Here not only the sensitized luminescence of the phthalocyanine was demonstrated but also the results of time resolved absorption spectra measurements at 130 fs laser pulse excitation are presented. According to these results, immediately after the excitation pulse a bleaching of the QD lowest absorption band takes place. In parallel with the decreasing of this bleaching, the bleaching in the lowest phthalocyanine absorption band was developed. Thereby the main scheme of the energy transfer from QD to the phthalocyanine molecule is demonstrated without noticeable contribution of any other intermediate states that could make any appreciable contribution to the absorption spectrum. It is necessary to keep in mind that the unambiguous evidence of the energy transfer in the QD/tetrapyrrol complexes is a generation of the singlet oxygen by these complexes. Such experiments were described in references [20, 28, 41]. In the first of these works where the complex of water-soluble QDs with TSPP was studied, the photosensitized by QDs singlet oxygen generation with the quantum yield achieving 0.43 was reported. In reference [41] the bioconjugated complexes of QDs with Chle6 and with RB have been studied. In aqueous media the singlet oxygen generation quantum yield was equal to 0.1–0.3. In the reference [28] it was demonstrated that the complexes of CdTe/MPA QDs with Al-TSPc are capable of generating the singlet oxygen with the quantum yield of up to 15%. Electron transfer, tunneling Electron transfer is one of possible mechanisms of the QD luminescence quenching in the QD complexes with organic molecules. In contrast to FRET, this is a shortrange process, because its efficiency drops exponentially with the electron donor to acceptor distance. This process operates independently of FRET. Moreover, the electron transfer can occur in systems in which FRET is impossible because of absence of the overlap between the donor luminescence spectrum and the acceptor absorption spectrum. One of such cases has been described in reference [46] where the complex formation between CdSe/ZnS/TOPO or CdSe/TOPO QDs and 1,12-diazaperylene has been studied. Since the absorption spectrum of
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diazaperylene is far blue-shifted from the lowest energy absorption and luminescence QD spectra, FRET from QD to diazaperylene is impossible. However, the authors reported a very efficient QD luminescence quenching after formation of the QD/ diazaperylene complexes. The authors had formulated the main features of physical picture of the luminescence quenching due to the electron transfer mechanism in application to this case. The main requirement to the quencher molecule in this case is that either both LUMO and HOMO or one of these orbitals should be located energetically within the energy gap of the CdSe core of QD. If the ZnS shell is present, the quenching process can be considered as follows. Either an excited QD electron tunnels from the core through the shell and localizes at the LUMO of the quenching molecule or the hole, formed in the QD core because of photoexcitation, tunnels through the ZnS shell and localizes at the HOMO of the molecule. Subsequent radiationless recombination is caused by tunneling of the hole or electron the other way through the same barrier. Since the experimental data showed that the QD luminescence quenching effect does not depend on presence or absence of the ZnS shell, the authors conclude that the barrier is easily penetrable. This mechanism is frequently referred to in the cases when the FRET is either impossible or possible but its efficiency is insufficient for explanation of the observed QD luminescence quenching. Formation of recombination centers because of tetrapyrrol molecule attachment In reference [46], besides the mechanisms considered above, it has been pointed to the principal possibility of another QD luminescence quenching mechanism. The quenching in this case is a result of appearance of certain new local states on the surface of QD itself induced by the binding of the acceptor molecule to QD. This idea has been developed in details in reference [66] where the QD luminescence quenching in complexes of CdSe/ZnS QDs with meso-pyridine-substituted porphyrin derivatives was studied. According to the authors’ point of view, this mechanism can operate in the cases when an immediate contact of the molecule with the QD surface takes place (e.g. via coordination onto the surface Zn atoms) at two points but not at one point. The nature of the local states appearing at these conditions was not considered in this work but it was marked that these states were localized on the QD surface (or on its shell if it is present) and they were energetically located within the QD core energy gap. If the QD has a shell, then this mechanism implies the electron and hole tunneling through it. The authors have studied the efficiency of the quenching process in the presence of these states theoretically. It was established that a very pronounced size dependence of the electron transfer efficiency with participation of such states should take place and should decrease with QD size increasing. The physical reasons of such dependence originate in electron wave function normalization condition. Comparison of the experimental results with the theoretical calculations showed that such dependence does really exist and agrees fairly with theoretically expected one. It is noteworthy, however, that the physical reasons of the considered size dependence are of such a fundamental nature, that they are not necessarily associated with this concrete mechanism of formation of the local states.
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V. Maslov et al.
QD Luminescence Decay Time and Quantum Yield
In contrast to the most organic substances, the colloid solutions of QD at room temperature are usually characterized by the multiexponential luminescence decay. It is caused in the most cases by an existence of the QD energy state that is analog of molecular triplet level. As it was marked in Sect. 7.1.1, this state is energetically very close to the lowest energy singlet state and thermally induced nonradiative transitions from this state to the singlet state can take place thus forming the longerlived luminescence component. Besides this, in many works the possibility of the radiative transitions with participation of QD surface local states is discussed. In the most works where the kinetics of the QD luminescence decay in solution is studied under interaction with organic molecules, the decay curves are reasonably approximated by the biexponential decay function. In is noteworthy that the physical origin of the slow and fast components of the QD luminescence decay is not quite clear. In the most cases the short-lived component with the characteristic time less than 10 ns is attributed to the fundamental exciton transition of QDs, and the long-lived component with the characteristic time of the order of 15–20 ns is associated with the radiative transition from a lower energy level, so-called “trapping” luminescence (see, for instance reference [65]). However, another interpretation of the multiexponential QD luminescence decay does also exist. Indeed, in the work of Zenkevich with coauthors (see, for instance, [67]), an experimental decay curve was approximated by a three-exponential function. The short-lived (t ~ 1.75 ns) and medium-lived (t ~ 10.0 ns) components were attributed to the radiative transitions from the surface QD states, whereas the long-lived (t ~ 18.5 ns) component to the fundamental exciton transition. As it was remarked above, for complexes of QDs with organic molecules where the energy transfer can take place, two situations are possible: (i) binding of at least one molecule to QD leads to complete quenching of the QD luminescence and (ii) the degree of the QD luminescence quenching depends upon the number of the molecules bound to QD. Experimentally it is difficult to distinguish between these two types of systems in any other way than through the measurements of the luminescence decay kinetics. The classical systems with a static quenching type belong to the first case. The luminescence of free QDs not bound with molecules is only observable in this case and its decay time coincides with that of free QDs. The examples of such complexes with the tetrapyrrol substances are considered in references [43, 44]. In the case of incomplete QD quenching in the complex, the analysis of the QD luminescence kinetics allows not only for the study of the dependence of the decay time shortening on the number of molecules bound with QD, but also an estimation (by using formula (7.3)) of an efficiency of the intracomplex radiationless energy transfer. The key moment in creation of the QD/tetrapyrrol molecule complexes applicable in PDT is the efficiency of the intracomplex energy transfer from QD to the molecule. Because of this, the kinetic analysis of the QD luminescence gives ones an additional way for independent experimental estimation of the intracomplex
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energy transfer efficiency. It is necessary to mark that there is no unified approach to analysis of the QD luminescence kinetics in the complexes of QDs with the organic molecules. In several works, the shortening the luminescence decay times of QDs bound into a complex with molecules is considered as supplementary evidence for the formation of the complexes as well as for an existence of dependence of the QD luminescence quenching on the number of bound molecules. For instance, in references [41] the complexes of CdSe/CdS/ZnS QDs of different sizes passivated by peptides with bound Chle6 and RB have been studied. The authors stressed that the experimental luminescence decay curve for these QDs can be approximated only by the three-exponential function with the characteristic times of t1 ~ 4 ns, t2 ~17 ns, t3 ~ 73 ns and t1 ~ 1 nc, t2 ~12 nc, t3 ~ 49 nc for QDs smaller (QD538) and larger (QD620) diameters, respectively. Binding of QD538 with the RB molecules led to shortening of all three components and to redistribution of their contributions into total QD luminescence decay. As in the most other works, the short-lived component shortened to a larger degree from 4.3 to 1 ns, and its contribution increased from 58% to 90%. The authors report an abnormal change of the QD luminescence decay time on formation of the complexes of QD620/Chle6 with 26 chlorine molecules per one QD. The decay time of the short-lived component increased twice and that of the long-lived component increased almost three times (from 50 to 145 ns). The shortening of the middle-lived component from ~12 to ~8 ns was only observed. This fact allowed the authors to associate the shortening of just this component with the intracomplex energy transfer. It is noteworthy that in this work the passivation of the CdSe/CdS/ZnS QDs by peptide leads to the appearance of the long-lived (³50 ns) component (as is usually observed for such type of passivation), but with the retaining of the short-lived component (<10 ns) that is not typical for QDs with surface passivated by proteins or peptides. The works where an analysis of the kinetics of the QD luminescence in the complexes with molecules is used for estimation of the FRET efficiency can be considered as another kind of works. Indeed, in reference [56] the luminescence kinetics of bioconjugated complexes of QDs with the cyanine dye Cy3 has been studied as a function of the number of molecules in the complex. For this purpose QDs of three different diameters solubilized by dihydrolipoic acid molecules were passivated by a maltose binding protein (MBP) in the complex with Cy3. The QD luminescence decay was approximated by biexponential function. The authors took into account only the short-lived component (t ~ 3 ns), because its contribution in luminescence was dominated. For all QDs investigated in this reference, increasing the number of dye molecules in the complex led to decreasing the QD luminescence intensity. In case of complexes of ten Cy3 molecules per one QD the luminescence decay times were shortened in 2.5–4 times depending the QD sizes. The FRET efficiency estimated in this reference from the decay time shortening data agreed well with the efficiency calculated from data on the QD luminescence quenching and on the sensitized molecule luminescence enhancement. The authors remarked that the passivation of QDs by MBP leads to increasing the QD luminescence quantum yield by 1.5–2.5 times, up to 24%. It is noteworthy that in contrast to the most other
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references where the QDs passivated by peptides and proteins are used, a passivation of the QD surface by the MBP molecules does not lead to substantial changes in characteristic luminescence decay times. In reference [65] the luminescence kinetics of CdTe/TGA QDs interacting with TSPP has been studied. The QD luminescence was approximated by the biexponential function and contribution of each component was analyzed as a function of the number of the TSPP molecules bound to the complex. The FRET efficiency was estimated from an average QD luminescence decay time: 〈t 〉 =
∑A ⋅ τ i
2 i
∑A ⋅ τ i
,
(7.12)
i
where Ai and ti are the amplitudes and decay times of the i-th component. It was found that the increase of the molecule concentration in the solution leads to decrease of the average luminescence decay time by more than 50% from ~22 ns to ~9.7 ns and to increase of the short-lived component contribution into total luminescence intensity from 28% to 70%. In reference [68] an efficiency of the energy transfer from CdSe/ZnS/TOPO QDs to the merocyanine 540 (MC540) molecules has been also estimated from the average QD luminescence decay time. Binding of the MC540 molecules to QD led to significant shortening the QD luminescence decay time from ~12 ns to ~0.6 ns. It is the only work where the analysis of both the QD luminescence decay kinetics and the kinetics of the sensitized luminescence of molecules bound to QDs was performed. A time-resolved anisotropy of the QD polarized luminescence was also analyzed. It was observed that in toluene the average decay time of the luminescence anisotropy of free QDs is equal to ~8 ns. This value agrees well with the QD rotational correlation time (tr) of ~9.5 ns estimated by using the Stokes-Einstein-Debye model. After the QD/MC540 complex formation, a fast component of ~130 ps appeared in the QD luminescence anisotropy decay and dominated the total decay curve. The appearance of such fast component was explained by the migration of the exciton from QDs to the proximal molecules and thus it may be an additional evidence for the existence of FRET in these complexes. In reference [57] the QD luminescence decay was approximated by biexponential function too. A passivation of the CdTe QD surface by STV led to considerable increase in the decay time of both the short-lived (~30 ns) and long-lived (~100 ns) components. The authors associated the fast component of the luminescence decay with the radiative transition from the QD surface states and the slow component with the fundamental exciton transition. Increasing of the number of molecules of DY731 dye covalently bound with biotin (DY731-Bio) in the complex with QD led to shortening of both decay components. The authors analyzed the FRET efficiency for each component separately. Increasing the number of DY731-Bio molecules to 20 per one QD in the complex led to 50% shortening of the short-lived component, whereas the characteristic decay time of the long-lived component decreased only by 25%. The authors explain the stronger shortening of the short-lived component by the fact that the energy transfer is more efficient from the QD surface states due to shorter distance to the molecule as compared with the exciton delocalized inside QD.
Combination Therapy: Complexing of QDs with Tetrapyrrols and Other Dyes 1.2
1.2
relative intensity, I/I0
1.0 0.8
2
1.0 0.8
1 x5
0.6
0.6
0.4
0.4
0.2
0.2
0.0 0.0
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0.5
1.0
1.5
2.0
relative intensity, IP/IP0
7
0.0 2.5
CP/CQD
Fig. 7.5 Dependences of the relative luminescence intensity of CdTe QDs (CQD = 1·10−7 M) and Al-TSPc on the relative Al-TSPc concentration in a mixed solution. (1) Relative intensity of the QD luminescence: (symbols) experimental data and (solid line) approximation by the function exp(−4.7·Cp/CQD). (2) Relative luminescence intensity of the added Al-TSPc: (symbols) experimental data and (dashed line) approximation by the linear function y = 0.091CP/CQD – 0.03. The errors in measuring the Al-TSPc luminescence intensity are indicated (Reproduced from Ref. [43] with kind permission of © Pleiades Publishing, Ltd. 2008. All Rights Reserved.)
7.3.4
Tetrapyrrol Luminescence Quenching in Complexes with QDs
The application of the QD/tetrapyrrol complexes in PDT presupposes the retaining the photophysical properties of the tetrapyrrol moiety within the complex, and fist of all its capability of the singlet oxygen generating under the photoexcitation. Binding of the molecule into the complex with QD does not guarantee the lack of change in its photophysical properties. For example, pronounced changes of the absorption spectra of the tetrapyrrol component after complexing were discussed in Sect. 7.2. In this section, we will consider the influence of the complexing on the luminescence parameters of the tetrapyrrol component. In most of experimental works on investigation of the QD/tetrapyrrol complexes the significant changes in the luminescent properties of the tetrapyrrol component after the complex formation were not marked. Exception is the more or less pronounced quenching of the tetrapyrrol luminescence after its complexing with QDs observed in some works. In reference [53] it has been marked that TPPA in the complex had the luminescence quantum yield about 3·10−4 that means the considerable quenching in comparison with the value 0.6 obtained in the same work for free TPPA. The well pronounced Al-TSPc luminescence quenching after its complexing with CdTe QDs capped by cysteamine has been observed in reference [43]. It is demonstrated in Fig. 7.5, where the QD luminescence intensity changes with increasing the Al-TSPc concentration in the mixture of QDs with Al-TSPc is shown (curve 1).
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The dependence of the relative intensity IP/IP0 of the molecule luminescence on x is shown in Fig. 7.5 (curve 2). Here, x = Cp/CQD, CP and CQD are the concentrations of molecules and QDs, respectively, IP is the measured Al-TSPc luminescence intensity and IP0 is the Al-TSPc luminescence intensity in the absence of QDs at CP = CQD. It can be seen, that the Al-TSPc luminescence intensity in the mixed solution is much lower than in the solution without QDs; therefore, it was detected only at the sufficiently high relative concentration of the phthalocyanine molecules. Then, the Al-TSPc luminescence intensity increases almost linearly with increase of the Al-TSPc relative concentration. This dependence is well approximated by a linear function of 0.091x-0.03. The authors noted the difference of the coefficient proportionality value from 1, expected for the free molecules. This indicates that the observed luminescence belongs to the molecules forming complexes where the Al-TSPc luminescence is strongly quenched. Just the same dependence was observed in case of complexes of CdSe/TGA QDs with TAPP described in reference [44]. According to the model developed in references [43, 44], the dependence of the relative intensity of the tetrapyrrol component luminescence on the ratio of its concentration to the concentration of QDs should be described by the following relation: I P / I P 0 = η(1 − r ) x ,
(7.13)
where h is the ratio of the luminescence quantum yield of the associated molecules to that of free molecules, and r is the fraction of molecules in the complexes with QDs that precipitated. Importantly, all the cases listed here are just the cases for which in Sect. 7.2 the changes of the absorption spectra of the molecules at complexing with QDs were significant. It is obvious that both the luminescence quenching and the absorption spectra changes are the consequences of the same reason – a significant perturbation of the molecule under complexing with QD. In many cases [50, 54] any noticeable influence of the complexing on the molecule luminescence quantum yield was not observed. Although the complete quenching of the molecule luminescence has been reported in reference [45] for the Zn-Tmtppa molecules in complexes with CdTe and ZnS QDs in aqueous solution, the quenching as well as the synchronous decreasing the Q-band in the absorption spectrum of the molecules was explained by the chemical reduction of the tetrapyrrol on the QD surface. In reference [55], 25% increase of the Al-TSPc luminescence quantum yield in the QD/Al-TSPc complexes has been reported. In references [54, 56] the influence of the complexing on photophysical parameters of the molecule triplet state and, in particular, on the triplet state quantum yield and its lifetime has been studied. Only a small decrease in the triplet state quantum yield and a clear increase in the triplet state lifetime were reported for the complexes of the Zn-derivatives TCPc, OCPc and TSPc with CdTe/TGA or CdTe/2-ME QDs [56]. For complexes of Al-TSPc with CdTe QDs capped by different substances [54] a certain (also small) increase in the triplet state quantum yield was observed at complexing.
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Mechanisms of the tetrapyrrol component luminescence quenching under complexing with QDs have not been studied in details. However, practically in all cases described above the FRET mechanism is excluded since the luminescence spectra of molecules are located far from the QD absorption region. As a result, in reference [43] an assumption has been made that this quenching could be caused by an electron transfer between the molecule and QD.
7.4 7.4.1
New Variants of Combination Therapy PDT Under Two-Photon Excitation
It is known that for deep penetration of the exciting radiation into biological tissues it is necessary to use the light in the spectral range of 700–1,200 nm. At the same time, most of the tetrapyrrol substances do not have the absorption bands longer than 700 nm. That is why the cancer PDT at the single-photon excitation is only efficient if an illumination can be performed immediately at the place of the photosensitizer location. The same limitation is valid in the case of using the QD/ molecule complexes. One of the solutions of the problem of penetration of exciting radiation into the biological tissues is the use of two-photon excitation of sensitizers or QD/sensitizer complexes. Most of organic substances have the two-photon absorption cross-section about several units of GM. It makes inefficient the use of the two-photon excitation of sensitizers for the singlet oxygen generation. At the same time, QDs have much higher two-photon absorption cross-sections about 102–103 GM [69] a value of which is determined by the QD size. That is why it seems possible to use the twophoton excitation of the QD/tetrapyrrol molecule complexes in PDT. The luminescent properties of the complexes of CdSe QDs of averaged core diameter of 5 nm with Pc4 molecules in toluene at two photon excitation has been studied in reference [70]. It has been found that at two-photon excitation of QDs by the light with the wavelength of 1,100 nm the FRET from QDs to Pc4 took place that was accompanied by the QD luminescence quenching and an enhancement of the sensitized Pc4 luminescence. The energy transfer efficiency from QD to Pc4 reached 38%. Unfortunately, an efficiency of the singlet oxygen generation by Pc4 was not studied in this work. The two-photon excitation of the TSPP molecules bound in complex with the water-soluble QDs CdTe/TGA with 130 fs pulsed laser radiation at the wavelength of 800 nm has been performed in reference [65]. The intensive sensitized luminescence of the TSPP molecule has been observed. Although the singlet oxygen generation was not examined in this work, the absence of noticeable changes in the photophysical properties of TSPP after binding in the complex with QDs, allows ones to assume that such a system in principle can be used for the cancer PDT.
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X-Ray-Induced Photodynamic Therapy
Although the use of the two-photon excitation of QDs in the range of 700–1,200 nm for activation of the organic photosensitizers increases the penetration depth of the excitation radiation by 1–3 cm, it is obvious that even in this case PDT cannot be efficiently used for internal or vast malignant tumors. On the other hand, a conventional radiotherapy is based on generation of the free radicals such as hydroxyl OH·, hydrogen H·, water H2O·+, super oxide O2·−, HOO· and others as a result of interaction of x-rays or gamma rays with water or tissues. In such method of influence on the cancer cells the restriction on the penetration depth of the radiation into biological tissues does not take place. One of the fundamental drawbacks of the radiotherapy of cancer is difficulty to obtain highly collimated beam of x-ray radiation for minimization of radiation dose affected neighboring healthy cells. Therefore, the high radiation doses are necessary for obtaining a positive therapeutic effect and this implies the damage of healthy cells too. Now a search of the particles that can efficiently generate reactive oxygen species (ROS) under x-rays or gamma rays is very active. A probability of absorption of the x-ray radiation by matter increases as the 3–5th power of the atomic numbers of the elements the matter consists of. Therefore, the nanoparticles like semiconductor quantum dots containing the heavy metal atoms and having the large surface-to-volume ratio are the best candidates for use in the cancer radiotherapy. The nano-sized biocompatible quantum dots can penetrate inside cells. If these nanoparticles are therewith oncotropic, the total radiation dose needed for the radiotherapy can be significantly reduced. An ability of the ROS generation by TiO2, ZnS:Ag, CeF3 particles and CdTe quantum dots in water under the x-ray radiation with energy of 20–170 keV was investigated in Ref. [71]. Concentrations of the TiO2, ZnS:Ag, CeF3 particles were varied in the range of 0.3–30 mg/ml. Since the surface-to-volume ratio of the CdTe quantum dots was about 103 times higher than that of the other particles investigated in this work, their concentration was low enough and varied from 0.001 to 1 ng/ml. For detection of ROS generated upon interaction of the x-ray radiation with the particle surface dihydroethidium was used. Dihydroethidium is a reagent which is converted to ethidium on reaction with O2·−, HOO· or OH·. Quantitatively the ROS values were determined by the intensity of the ethidium luminescence at 585 nm under the 465 nm light excitation. Increasing the power of the x-ray radiation led to the increase in the ROS generation for all types of the particles. It was found that TiO2 particles and CdTe quantum dots generate ROS better than other particles. In this work it was also shown that CdTe QDs solubilized with SVD inhibit the growth of the HeLa cells after the x-ray exposure. The greatest difference between the HeLa cells with CdTe QDs and the HeLa cells alone was observed under radiation dose of 2–3 Gy. The mechanism of the internal conversion of the absorbed x-ray irradiation into ROS is not known at present for all studied particles. Therefore, it is impossible to predict and control the efficiency of the conversion, i.e. to determine which fraction of the absorbed x-ray energy was spent on generation of ROS and which one
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produced the photoluminescence of the particles (e.g. CdTe QDs). Nevertheless, all these facts allow for the conclusion that the semiconductor QDs can be used as an efficient ROS generator. It is interesting to note that introduction of the metal nanoparticles into tumor cells results also in an increase in the effect of x-ray irradiation [72, 73]. Combination of the radiotherapy with PDT is the novel approach to the cancer treatment. In this case a scintillator/photosensitizer complex can be used. A scintillator absorbs the x-ray or gamma-ray radiation and transfers this energy (as a rule by FRET) to a photosensitizer which generates the singlet oxygen. Combination of the radiotherapy and PDT should allow for the reduction of time and dose of the x-ray radiation. Central to this combination consists of removal of the limitations of the PDT application related to the penetration depth of the excitation light into the biological tissues. The semiconductor QDs and the porphyrin (phthalocyanine) molecules can be considered as partners in the scintillator/photosensitizer complexes. In the porphyrin molecules utilized in PDT the Soret band at 400 nm is the most intensive band in the absorption spectrum. Some researches showed that the singlet oxygen generation under an excitation in the Soret band can be an order of value more efficient than under excitation in the region of the lowest energy absorption band of 600–700 nm. It means that for maximal efficiency of the singlet oxygen generation in complexes with sensitizers of porphyrin type complexes, it is reasonable to use as energy donors the QDs with luminescence spectrum located in region about 400 nm. It should be noted that for phthalocyanine molecules where the Q-band at 650–590 nm usually dominates in the absorption spectra, the requirement to luminescence spectrum of the energy donor will change. In Ref. [74] the sensitized fluorescence of porphyrins at the x-ray excitation was observed in complexes of the water soluble CdS QDs covered by L-cysteine with tretrakis(o−aminophenyl)porphyrin molecules. Nanoparticles of LaF3:Ce3+, LuF3:Ce3+, CaF2:Mn2+, CaF2:Eu2+, BaFBr:Eu2+, BaFBr:Mn2+, and CaPO4:Mn2+ were also investigated as the scintillators in this work. These particles have fluorescence spectrum in the spectral range of 350–500 nm that match well the spectral range of the absorption of most photosensitizers used in PDT. The authors also synthesized scintillators with afterglow or persistent luminescence with decay time varied from several minutes to several hours. For example, the afterglow luminescence of the BaFBr:Eu2+ and BaFBr:Mn2+ scintillator particles with decay time up to 8 min was demonstrated. It is very attractive, since the utilization of the scintillators with afterglow luminescence as an excitation sources for the photosensitizers in PDT should significantly reduce the x-ray irradiation time. Estimation of the quantum yield of the singlet oxygen generation by porphyrins in complexes with nanoparticles under x-ray irradiation was not carried out in this work. Complexes of the LaF3:Tb3+ scintillator particles with MTCP molecules were investigated in Ref. [72, 75]75. The intracomplex energy transfer by FRET mechanism from the scintillator particles excited by x-rays with energy of ~250 keV to the porphyrin molecules was demonstrated. It should be noticed that in classical radiotherapy significantly higher energies of the x-ray radiation (of order of several MeV) are usually used. Efficiency of the energy transfer was evaluated from degree of the
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luminescence quenching of the LaF3:Tb3+ scintillator particle in the complexes with porphyrin. The luminescence quenching of the bands at 487, 542, 582, and 620 nm assigned to the 5D4 → 7Fi (j = 6–3) transitions of Tb3+ varied from 50% to 68%. However, the luminescence decay time of Tb3+ in the complexes with porphyrins reduced only by 12%. It was also demonstrated that generation of the singlet oxygen by porphyrins at the x-ray irradiation is the result of the intracomplex energy transfer from LaF3:Tb3+ scintillator particles. The detection of the singlet oxygen was performed by the measuring of the quenching of the anthracenedipropionic acid (ADPA) luminescence. It was found that under x-ray irradiation the generation of the singlet oxygen by the MTCP molecules in the complex with LaF3:Tb3+ is much more effective than by free MTCP molecules. Indeed, after 30 min of the x-ray irradiation (dose is about 13.2 Gy) the ADPA luminescence was totally quenched in the mixture with LaF3:Tb3+- MTCP complexes. At the same time in the mixture with free MTCP molecules the quenching of the ADPA luminescence was only 50%. It was also demonstrated that an attachment of folic acid, which has high affinity to folate receptor in the cells, to the LaF3:Tb3+/MTCP complexes did not reduce the quantum yield of the singlet oxygen generated by MTCP. The last results clearly show that use of x-ray irradiation for generation of the singlet oxygen by photosensitizers in the complexes with scintillators is one of the most prospective directions of development of cancer treatment. Such combination of conventional therapeutic treatments of cancer should increase treatment efficiency and reduce negative side effects in treatment of oncological diseases.
7.5
Conclusions
In conclusion, the analysis of recent works on investigation of photophysical properties of the complexes formed from the colloidal semiconductor quantum dots and tetrapyrrol substances in liquid solution as well as the mechanisms of the complex formation was performed on the aim of utilization of the complexes in the cancer photodynamic therapy as a new approach in the combination therapy. The main goal of these studies is to increase an efficiency of the singlet oxygen generation by the traditional molecular photosensitizers by using the nonradiative energy transfer from a high efficient absorber of the radiation energy to the photosensitizer-acceptor. It was demonstrated that the extremely high absorbance in wide spectral range and the high luminescence quantum yield in combination with good photostability make QDs practically ideal energy donor in complexes with tetrapyrrol substances. Moreover, since the QD luminescence spectrum is determined by the nanocrystal core size and can be easily turned for matching the molecule absorption, the efficient intracomplex energy transfer from QD to the photosensitizer can be reached by the selection of the QD size and by the choice of bonding type.
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At present, the possibility of obtaining the stable water-soluble QD/tetrapyrrol molecule complexes with the high efficiency (up to 70%) energy transfer from QD to the molecule is demonstrated. The use of QDs as the energy donor allows ones to substantially extend spectral range of the complexes absorption and, therefore, to widen the set of the appropriate light sources for activation of sensitizer molecule in the complex. It is important that, besides the efficient energy transfer from QD to the tetrapyrrol molecule, it was shown that the molecule retains the capability of singlet oxygen generating with high quantum yield. The collection of these facts demonstrates that the QD/tetrapyrrol complexes have a large potential for application in PDT since it allows for a decrease in therapeutic dose of photosensitizer and time of irradiation of body. The existence of potential hazard of intoxication of the organism due to instability of colloidal QDs in conditions of long circulation in organism can be substantially decreased by covering QD surface by the shell not containing heavy atoms and also by supplementary covering, e.g., by peptides. On the other hand, the tetrapyrrol substances used now in PDT in therapeutic doses themselves lead to strong organism intoxication. As far as we know, there are no data on comparison of intoxication of organism by QDs and the tetrapyrroles. It is obvious that such investigations would be necessary in order to determine whether CdTe and CdSe QDs will be retained only in vitro objects in the combination PDT or complexes with them will in future be used in vivo in therapy of oncological diseases. PDT is one of the softest and at the same time efficient modern therapeutic approaches in cure of the cancer diseases. However, due to strong absorption of the visible light by biological tissues the problem of delivery of the exciting radiation to the cancer cells localization exists in the classical cancer PDT. Because of this, now PDT is used either for therapy of skin forms of the cancer or in the cases when the delivery of photoexcitation is possible near the cancer cells, for instance through optical fiber. We discuss the of solution of the problem of delivery of exciting radiation into the biological tissues using two most prominent approaches which also utilize the semiconductor QD properties: (1) Two-photon activation of the QD/photosensitizer complex by using light in the 700–1,200 nm spectral range where the biological tissues have a minimal absorption. This allows for penetrating the exciting light onto depth of up to 3 cm. The performed researches demonstrate that an efficient intracomplex energy transfer from QD to molecule takes place at two-photon excitation of QDs. (2) Any limitations of exciting radiation penetration depth can be removed in case of the use of the x-ray radiation for activation of photosensitizer in the complexes with QDs. Indeed, it was demonstrated that CdTe and CdSe QDs effectively absorb x-ray radiation and are capable of transferring the absorbed energy to the photosensitizer molecules generating the singlet oxygen. An analysis of works in this field clearly shows that the use of the QD/photosensitizer complexes in combination with traditional x-ray therapy and PDT is now one of the most prospective ways of development and widening of sphere of applicability of photosensitizers for cure of oncological diseases.
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68. Narayanan SS, Sinha SS, Pal SK (2008) Sensitized emission from a chemotherapeutic drug conjugated to CdSe/ZnS QDs. J Phys Chem C 112:12716–12720 69. Yingli Qu, Wei J (2009) Two-photon absorption of quantum dots in the regime of very strong confinement: size and wavelength dependence. J Opt Soc Am B 26:1897–1904 70. Dayal S, Burda C (2008) Semiconductor quantum dots as two-photon sensitizers. J Am Chem Soc 130:2890–2891 71. Takahashi J, Misawa M (2007) Analysis of potential radiosensitizing materials for x-rayinduced photodynamic therapy. Nanobiotechnology. doi:10.1007/s12030-008-9009-x 72. Liu C-J, Wang C-H, Chien C-C et al (2008) Enhanced x-ray irradiation-induced cancer cell damage by gold nanoparticles treated by a new synthesis method of polyethylene glycol modification. Nanotechnology. doi:10.1088/0957-4484/19/29/295104 73. Jeong SY, Park SJ, Yoon SM et al (2009) Systemic delivery and preclinical evaluation of Au nanoparticle containing b-lapachone for radiosensitization. J Control Release 139:239–245 74. Chen W, Zhang J (2006) Using nanoparticles to enable simultaneous radiation and photodynamic therapies for cancer treatment. J Nanosci Nanotechnol 6:1159–1166 75. Liu Y, Chen W, Wang Sh, Joly AG (2008) Investigation of water-soluble x-ray luminescence nanoparticles for photodynamic activation. Appl Phys Lett 92:0439
Chapter 8
Exogenously Induced Endogenous Photosensitizers Gesine Heuck and Norbert Lange
Abstract The photosensitizing properties of endogenous porphyrins have been discovered about 100 years ago. Since then they have become an attractive means to detect and treat neoplastic tissue by fluorescence photodetection (PD) and photodynamic therapy (PDT). The probably most important endogenous photosensitizer is protoporphyrin IX (PPIX), the direct precursor of heme. It accumulates preferentially in neoplastic cells upon administration of 5-aminolevulinic acid (5-ALA). 5-ALA is an early precursor of heme. When applied exogenously it takes up the function of a prodrug, which is converted into PPIX by the enzymes of the heme biosynthetic pathway. Numerous approaches have been undertaken to improve the pharmacodynamics and pharmacokinetics of 5-ALA PDT with respect to tissue selectivity and biocompatibility. This chapter shall give an overview of the methods used to optimize 5-ALA PDT and PD.
8.1
Introduction
Life on our planet as it exists today would probably not be possible without porphyrins. The wide distribution of these tetrapyrrol structures in fossil sediments attests their existence dating back as far as the first appearance of oxygen in the earth’s atmosphere. The benefit of porphyrins for medical purposes was discovered only in the second half of the twentieth century, although their pathological manifestation was already noticed in ancient Greece by Celsus, Galen and Hippocrates. The latter described a patient having peculiar symptoms: “fears and much rambling, depression and light
G. Heuck (*) • N. Lange School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, 30, Quai Ernest Ansermet, CH – 1211 Geneva 4, Switzerland e-mail: [email protected]; [email protected]
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Fig. 8.1 Photo showing a patient with congenital erythropoietic porphyria featuring severe mutilations as well as hypertrychosis. Reprinted from Ref. [7] with kind permission of © the Royal Society of Medicine Press. ALL RIGHTS RESERVED
feverishness. Early in the morning frequent convulsion, whenever these frequent convulsions intermitted, she wandered and uttered obscenities; many pains, severe and continuous.” Towards the end of the episode, her urine turned black [1]. The statement appears to be the first record of a group of diseases which much later, in the nineteenth century, will be known as porphyrias [2–4]. The characteristic symptoms of some of these disorders, notably the purple/red coloured stool and urine (porphurous = greek for purple) in combination with psychotic attacks led scientists and historians to retrospective diagnoses in various subjects, going as far as making porphyrias responsible for political turnovers. An example is the case of King George III, who was known for his “madness” [5]. The probability, that George III’s attacks originated from porphyria is supported by the fact that two living descendants of the king suffer from variegate porphyria [6]. Symptoms of the extremely rarely occurring congenital erythropoietic porphyria, notably the pale, yellow skin, red teeth, skin aberrations, protruding teeth, avoidance of sunlight and blood thirst often accompanied by psychotic attacks and sometimes hypertrichosis (see Fig. 8.1), has even led scientists to explain the occurrence of werewolves and vampires [7, 8]. Admittedly, the resemblance between the disease and descriptions in historical reports, together with the independent appearance of these creatures in different areas on the globe give an attractive basis for such a hypothesis. Nevertheless, porphyria as possible explanation for the occurrence of legendary creatures is a step too daring.
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Fig. 8.2 Photo of Friedrich Meyer-Betz featuring lesions on face and hands after self-injection of 200 mg hematoporphyrin and exposure to sunlight Source Ref. [11]
Scherer was the first to describe the chemistry of endogenous porphyrins in 1841 [9]. He treated a dried blood sample with sulfuric acid, removed the free iron, and dissolved the water-insoluble product in ethanol. He obtained a substance of blood-red colour, which he called “iron-free hematin”. Hoppe-Seyler later gave the compound the name “hematoporphyrin” [10]. In 1913, the German physician Meyer-Betz used hematoporphyrin in a self-experiment and injected himself 200 mg of the substance. When exposing parts of his skin to sunlight, he obtained lesions that remained for several weeks (Fig. 8.2). Meyer-Betz’ experiment provided evidence for the close relationship between the red pigments in the urine of patients with certain forms of porphyria and their sensitivity to light [11]. In 1924 Policard observed that tumor tissue intrinsically exhibited more fluorescence than normal tissue [12]. The underlying cause, namely the preferential accumulation of porphyrins in neoplastic tissue, was identified by Auler and Banzer [13]. They also observed that injection of exogenous hematoporphyrin increased tumor fluorescence. The findings were confirmed by several studies until the mid 1950s [14–16]. However, the application of hematoporphyrin for the cancer detection by fluorescence came along with a pronounced phototoxic effect. This inconvenience was due to the need of high drug doses, in order to obtain a satisfying fluorescence signal. Schwartz et al. compared purified with raw hematoporphyrin material. To their surprise they observed stronger tumor fluorescence and higher response to x-ray radiation using the impure compound, rather than with the purified hematoporphyrin [17]. Although Schwartz did not identify the exact nature of the impurity fraction, it can be assumed that it consisted of a complex mixture of porphyrin monomers and oligomers.
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Lipson et al. treated crude hematoporphyrin with glacial acetic acid and sulfuric acid and obtained hematoporphyrin derivative (HpD). Detection and treatment of cancer with HpD was superior to treatment with crude hematoporphyrin [18, 19]. Also, lower doses of HpD could be applied [18]. In 1972 Diamond et al. observed an increase of tumor cell death in vitro and in vivo upon pre-treatment with HpD and after irradiation with cool light [20]. Three years later Dougherty et al. succeeded in the complete tumor removal in mice after application of HpD and subsequent exposure to red light [21]. Dougherty further optimized the HpD formulation by removing the monomers in the mixture, which were attributed the part for phototoxicity due to their high water solubility. The final compound, now called Porfimer sodium, obtained marketing authorization as Photofrin®. It is probably still the most widely used photosensitizer in medical care. Nevertheless, a major drawback remains the low selectivity of the substance, leading to skin photosensitization of subjects treated with this drug. The gravity of this adverse effect becomes even more important, when considering that cancer therapy is most often of palliative rather than curative nature. The necessity to prevent the exposure of patients to light annihilates the primary aim of palliative cancer treatment, which is the improvement of quality of life. Realizing this problem, research focused on more selective ways of treatment in the field of photodynamic therapy (PDT) and fluorescence photodetection (PD). A breakthrough was achieved by Kennedy et al. who exogenously applied the heme precursor 5-aminolevulinic acid (5-ALA) [22]. He hypothesized that PPIX, the penultimate precursor of heme with photosensitizing properties, would accumulate in the cell, if the negative feedback of heme on the first building block, 5-ALA, is by-passed. If the production of protoporphyrin IX (PPIX) is faster than its transformation into heme, then PPIX will accumulate. Effectively, Kennedy found a particularly high accumulation of PPIX in tumor tissue after administration of 5-ALA [22]. The pharmacokinetics of 5-ALA together with the particular physiology of tumor cells provide the heme precursor with the attribute to accumulate preferentially in neoplastic tissue and to be cleared within hours instead of days or weeks. This in turn reduces skin photosensitization and gives 5-ALA a major advantage over preformed photosensitizers. Today, six products containing 5-ALA and two of its derivatives are authorized on the market for the visualization or treatment of malignant tissue (see Table 8.1).
8.2
The Heme Biosynthetic Pathway and Pathological Implications
Heme is essential for many processes in living organisms. Apart from its role as oxygen binding unit in red blood cells in mammals and invertebrates, it is an important metabolic co-factor in cytochrome associated enzymes. The pivotal function of heme in a living organism explains why it was found to be one of the earliest
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Table 8.1 Commercialized products containing 5-ALA or derivatives Name Levulan® Kerastick® (Dusa) Metvix® (Photocure)
Compound 5-ALA
Formulation Alcoholic solution with application stick 5-ALA methyl Cream ester
Indication Treatment of actinic keratosis
Effala®/Alacare® 5-ALA (Intendis)
Treatment of precancerous and skin cancer lesions, e.g. actinic keratosis Powder for Detection of bladder solution cancer Powder for oral Fluorescence guided solution resection of malignant glioma Medicated plaster Treatment of actinic keratosis
Cysview® (Photocure)
Powder for solution
Hexvix® (Photocure) Gliolan® (Photonamic)
5-ALA hexyl ester 5-ALA
5-ALA hexyl ester
Detection of bladder cancer
Country of licence USA
A, AUS, B, D, DK, E, F, I, N, NZ, USA, S A, D, E, F, N, S D
A, D, DK, E, F, FIN, IRL, I, N, PL, P, S USA
biomolecules. Palaeo-chemical investigations led to the conclusion that living organisms produced heme already four billion years ago. Its formation takes place in virtually all nucleated cells and particularly in tissues with high metabolic turnover, such as bone marrow and the liver. In eukaryotes the biosynthesis of heme includes eight consecutive steps, each one involving a different enzyme (see Fig. 8.3). Four enzymes are located in the mitochondria, while the other four enzymes operate in the cytoplasm. They are kept under strict feedback control to prevent the overproduction of intermediate products during heme biosynthesis. Genetic mutation, and/or enzyme malfunction may disturb the equilibrium, which may result in the accumulation of cytotoxic byproducts, notably porphyrins. This is why diseases involving a malfunction of the heme cycle have been grouped as porphyrias. Depending on the type of mutation and the involved enzyme, different forms of porphyria may develop. The biochemistry of the heme biosynthesis has been reviewed in detail elsewhere [23–25]. Therefore the following intercept shall only shortly recall the respective steps to provide a better understanding of the pharmacodynamics of 5-ALA. The basis of all biologically produced tetrapyrrols, be it in bacteria, mammals or plants, is the onset of 5-ALA and its subsequent transformation into uroporphyrinogen III [26]. While most bacteria and plants biosynthesize 5-ALA from glutamic acid in a two-step reaction, eukaryotes form 5-ALA by condensation of glycine with succinyl-CoA. The reaction takes place in mitochondria and is catalyzed by ALA-synthase (ALAS) [27]. There are two isoforms of ALAS: ALAS I, the housekeeping enzyme, is expressed throughout the body, whereas the erythropoietic
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Fig. 8.3 The heme biosynthesis. The first step, catalyzed by ALA-synthase (ALAS), consists of the mitochondrial synthesis of 5-aminolevulinic acid (5-ALA) from glycine and succinyl CoA. In the cytosol eight 5-ALA molecules are condensed in four consecutive steps to coproporphyrinogen III (COPIII). Each reaction is catalyzed by the corresponding enzyme. The formation of uroporphyrinogen III (UROIII) involves the asymmetric condensation of 4 porphobilinogen molecules (PBG). Non-enzymatic, symmetric condensation leads to biologically inactive uroporphyrin I (UROI). COPIII is translocated into mitochondria, where its structure is transformed to protoporphyrin IX (PPIX). Subsequently, ferrochelatase (FC) mediates the complexation of Fe2+ by this tetrapyrrol skeleton, resulting in the formation of heme. Heme regulates the synthesis of 5-ALA through a negative feedback mechanism. ALAD ALA dehydratase, PBGD porphobilinogen deaminase, UROS uropophorphyrinogen III synthase, UROD uroporphyrinogen III decarboxylase, MBR mitochondrial benzodiazepine receptor, COPO coproporphyrinogen III oxidase, PPGIX protoporphyrinogen IX, PROTO protoporphyrinogen IX oxidase
ALAS II only occurs in bone marrow. Mutation of the ALAS II encoding gene, which is located on the X-chromosome, leads to x-linked sideroblastic anaemia [23]. After its formation, 5-ALA is translocated into the cytoplasm, where it is transformed into uroporphyrinogen III. The reaction is the same in all porphyrin producing organisms and implies three steps: First, two 5-ALA molecules are asymmetrically condensed to yield the pyrrol structure of porphobilinogen (PBG). This reaction is catalyzed by ALA–dehydratase (ALAD), a zinc containing enzyme, which is synonymous to porphobilinogen-synthase (PBGS). Patients with a deficiency of ALAD accumulate 5-ALA. The similarity of 5-ALA to the neurotransmitter g-amino butyric
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acid (GABA) allows it to bind to GABA-ergic receptors [28]. As a consequence the patients suffer from neuropathies, typically characterized by abdominal pain, dysfunction in the extremities and, sometimes, psychotic attacks. In lead (Pb)poisoning the central Zn atom in ALAD is replaced by Pb resulting in an inactivation of the enzyme. The symptoms of Pb-poisoning are the same as in the disease developing from a mutation of the enzyme. Therefore ALAD-associated porphyria is also called plumboporphyria (plumbum = latin: lead). The following two steps in the formation of uroporphyrinogen III are catalyzed by two closely associated enzymes [29]: Porphobilinogen deaminase (PBGD) condenses four PBG molecules to pre-uroporphyrinogen, a linear tetrapyrrol. This molecule may cyclize spontaneously to uroporphyrin I, which has a symmetric tetracyclic structure and is biologically inactive. The active isomer uroporphyrinogen III, in contrast, necessitates the action of uroporphyrinogen III synthase (UROS). UROS catalyzes the inversion of one of the four pyrrols (the D-ring) in the porphyrin skeleton. The transformation results in the final asymmetric structure of uroporphyrinogen III [30]. A deficiency of PBGD leads to acute intermittent porphyria (AIP). With 300 mutations the disorder is the most frequent form of porphyria. It may be triggered by enzyme-inducing drugs, such as barbiturates and sulphonamides, which enhance the expression of ALAS. The symptoms of AIP are of neurovisceral nature and treatment is well elaborated [31]. A defect in UROS causes congenital erythropoietic porphyria. In this rare but severe form of porphyria the accumulation of tetrapyrrols such as uroporphyrin I and its de-carboxylized form coproporphyrin I lead to discoloring of urine, hypertrichosis and skin photosensitization with subsequent mutilation [32]. Since photosensitization is caused by the reaction of tetrapyrrols during UV-radiation, the symptom is typically found in porphyrias accumulating porphyrins in the blood. Porphyrias accumulating porphyrin precursors, i.e. featuring a deficiency at the beginning of the heme cycle, are limited to neurovisceral symptoms. After the synthesis of uroporphyrinogen III the side chains of the tetrapyrrol skeleton are modified. The first step implies the decarboxylation of uroporphyrinogen III to coproporphyrinogen III through the action of uroporphyrinogen III decarboxylase (UROD). Coproporphyrinogen III is translocated to the mitochondria in an ATP dependent step. It involves the mediation of the mitochondrial benzodiazepine receptor (MBR) [33, 34], a small protein of 18kD anchored in the outer mitochondrial membrane [35, 36]. The MBR can be over-expressed in neoplastic tissues, such as breast [37], endometrium [38], ovary [39], liver [40], brain [41] and colon [42] cancer. It is therefore conceived to hold a key role for the tumor selectivity of 5-ALA mediated PPIX generation. In the mitochondrial inter-membrane space, two of the four remaining carboxylate groups of the porphyrin are reduced to vinyl-residues, resulting in the water insoluble protoporphyrinogen IX. The reaction is catalyzed by coproporphyrinogen III oxidase (COPO), which is located at the outer surface of the mitochondrial membrane [43]. Protoporphyrinogen IX (PPGIX) is then aromatized to PPIX by the inner mitochondrial membrane-bound protoporphyrin IX oxidase (PROTO) [44]. Mutation of PROTO causes variegate porphyria, a disease with a particularly high
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incidence in South Africans. The disorder spread from descendants of an immigrant in the seventeenth century. For this reason it is sometimes referred to as South African genetic porphyria [45]. The synthesis of heme is completed with the incorporation of ferrous iron into the PPIX skeleton through the enzymatic action of ferrochelatase (FC), which is also located on the inner mitochondrial membrane [46]. According to Grandchamp et al. [43], the close mitochondrial location of the enzymes for the distal steps of heme biosynthesis, COPO, PROTO and FC, removes the obstacle of translocating water-insoluble porphyrins through an aqueous environment. The acquirement of lipophilicity, in turn, seems to be necessary for the porphyrin to cross the mitochondrial membrane for the final transformation into heme. Heme acts as regulator of its own biosynthesis through a direct negative feedback on ALAS in the mitochondrial matrix [46, 47]. 5-ALA is an endogenous molecule. The major reason for administering an endogenous molecule as drug to a patient is to compensate a deficiency, e.g. insulin in diabetes, or to increase its physiological activity, e.g. prostaglandins as contracting agents for the uterus. Rather than compassing the replacement or increasing the physiological function of the endogenous molecule the exogenous administration of 5-ALA aims at the induction of an extrinsic effect, i.e. the controlled accumulation of the photosensitizing porphyrin PPIX. As the direct precursor of heme, the physiological relevance of PPIX as well as that of other porphyrins is restricted to its role as intermediate of the heme biosynthetic pathway. In a normal functioning organism PPIX concentrations are kept to a minimum. The phototoxic effect becomes clinically relevant only in the case of intracellular accumulation as in the case of porphyrias or the targeted induction by 5-ALA. In the context of PDT and PD, 5-ALA takes up the function of a prodrug for PPIX. Prodrugs are defined as inactive precursors of a drug, which are enzymatically or non-enzymatically transformed by the organism into the active compound. The derivation into a prodrug is generally used to obtain an increased bioavailability and/or to decrease adverse side effects. Levodopa, for example, the prodrug of dopamine, is used for the therapy of Parkinson’s disease. In contrast to dopamine, Levodopa is able to cross the blood brain barrier. In the brain, it is subsequently decarboxylated to the active compound dopamine. In the case of 5-ALA, the transformation into PPIX is carried out by the enzymes of the heme cycle.
8.3
8.3.1
Alteration in Neoplastic Tissue – Implications for Preferential PPIX Induction by 5-ALA Enzymes of the Heme Biosynthetic Pathway
While intracellular porphyrin concentrations are strictly controlled by heme biosynthetic enzymes in physiologically healthy tissue, this is not necessarily the case in neoplastic tissue, where levels of PPIX are sometimes elevated [2]. An explanation
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for the observed phenomenon is a dysfunction of tumor proteins. Effectively, tumors may over-express PPIX preceding enzymes and/or feature down-regulation of ferrochelatase. In an early study, Kondo et al. investigated the enzyme activities of ALAD, PBGD and UROD, as well as FC in five normal epithelial cell lines of rat liver and five cell lines derived from hepatoma. The study revealed an increased activity of PBGD in all cancer cell lines [48]. Navone et al. compared ALAD, PBGD and UROD activity in cells derived from human breast cancer tissue to normal mammary tissue and noticed an up-regulation of PBGD and UROD. When undertaking the same investigations in vivo on mice, however, they did not observe any significant changes in enzyme activity [49]. Gibson et al. examined the enzymatic activity of ALAD, PBGD and FC in a tumor rat model and four tumor cell lines with the addition of exogenous 5-ALA. They could report an increase in PBGD activity for their in vitro and in vivo experiments [50]. Levels furthermore correlated with the mitochondrial content of the cells [51]. To study the key-role of PBGD in more detail Hilf et al. successfully transfected a mammary carcinoma cell line and a mesothelioma cell line with a PBGD encoding plasmid. Incubation with 5-ALA triggered the expression of PBGD by up to three times, but against all expectations, no increase in PPIX production was observed in PBGD transfected cells [52]. From Hilf’s observations Gibson et al. concluded that PBGD was lacking its substrate PBG and that ALAD, the enzyme immediately preceding PBGD and synthesizing PBG, must account for a rate limiting step in the production of PPIX. They tested their hypothesis in three breast cancer cell lines, as well as a human mesothelioma cell line [53]. To prevent any accumulation of PBG and thus a negative feedback on the expression of ALAD, they over-expressed PBGD in all cell lines. Upon addition of excessive amounts of 5-ALA, however, ALAD levels remained unchanged. The observation supported the hypothesis that ALAD is a possible rate-limiting factor in the production of PPIX. In agreement with other studies [54, 55] Krieg et al. found that PBGD activity is dependent on the proliferation stage of cells. It was significantly higher in cancerous cell lines than in the corresponding stromal cell line. However, PBGD activity of poorly differentiated colon carcinoma cells (SW480) was higher during the plateau phase rather than during exponential growth. The opposite observation was made in moderately well differentiated HT29 cells and in normal fibroblasts (CCD18). In well differentiated CaCo2 cells PBGD activity did not seem to be affected by the growth stage [56]. It was not so for human bladder carcinoma cells when compared to urothelial cells [57]. In fact, the main responsible factor for higher PPIX accumulation in bladder carcinoma cells seemed to be a down-regulation of the “post-PPIX”enzyme FC. Bartosova et al. found similar results using leukemic cells [58]. Hinnen et al. concluded that PPIX accumulates as a result of an imbalance between PBGD and FC expression. They introduced a so-called power index, which represents the activity ratio of PBGD to FC. The purpose of the index was to predict porphyrin concentrations in tissues after administration of 5-ALA and hence to evaluate the susceptibility of the tissue to photosensitization. Results, however, could only partially confirm this hypothesis [59]. This may be due to the fact that they were not aware of the role of ALAD.
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Alteration of the Iron Pool
FC requires two substrates to form heme: one is PPIX; the other one is ferrous iron (Fe2+). The cellular uptake of iron for the biosynthesis of heme has been extensively studied by Morgan et al. [60, 61]. Iron reaches the cell bound to its carrier protein, transferrin (Tf). This relatively small glycoprotein of 80 kDa binds two Fe3+ ions with high affinity (Kd = 10−23) at pH 7.4 [62]. The binding of ferric iron, in turn, raises the affinity to a transferrin receptor (TfR) at the cell surface. TfR is made up of two subunits of 94 kDa. Each subunit can bind one transferrin molecule. The Tfiron -TfR complex is internalized by endocytosis. In the endosome, a proton influx provokes the dissociation of iron from the receptor-protein-complex. Tf and its receptor are recycled to the cell surface, while Fe3+ may be transferred to sites of gene regulation in the nucleus or heme synthesis in mitochondria. Mitochondrial iron is bound to FC. It is therefore likely that FC acquires the metal ion directly from the mitochondrial membrane or is even involved in the iron transfer. However, further studies need to be undertaken to confirm this hypothesis. In case of excess, iron may also be incorporated into ferritin, a storage protein composed of 24 subunits, with a molecular weight of 430–460 kDa and a capacity to store 4,500 iron atoms. The expression TfR seems to be a characteristic feature of proliferating cells. In normal tissue, it is particularly abundant in hemoglobin synthesizing tissues and cells, such as erythroblasts and reticulocytes. During erythropoiesis the FC-mediated insertion of iron into PPIX to form heme occurs in the erythroblast stage. The need for iron explains why erythroblasts express abundant concentrations of TfR at their cell surface. After formation of heme, TfR is no more required. Therefore erythroblasts release TfR into the blood plasma (soluble TfR). The surface-bound concentration of TfR is lower in reticulocytes, and erythrocytes virtually have no TfR. The measurement of the soluble TfR concentration is used as estimate for erythropoiesis. Kearsley et al. observed in human squamous head and neck cancers that TfR was highly expressed in the invading margin, which mainly consists of proliferating cells [63]. TfR was not expressed inside the tumor, where cells were mostly well differentiated. In accordance with these findings, Parodi et al. reported, that TfR expression correlated negatively with the differentiation status of erythroleukemia cells K562 after treatment with the chemical differentiation inducer cis-platin [64]. Prutki et al., however, observed the contrary in tissues obtained from colon carcinoma patients, where the TfR expression was high in differentiated cells, but low or absent in poorly differentiated cells [65]. As shown by Page et al. [66], rat hepatocytes and some neoplastic tissues exploit additional mechanisms to internalize iron-transferrin through non-specific endocytosis. Small lung cancer cells on the other hand can express their own Tf and human melanoma cells express a cell membrane based Tf homologue [67]. The high metabolic turnover and the increased expression of receptors such as TfR make it conceivable that certain neoplastic tissues feature increased iron
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acquisition [68]. Nevertheless, other factors may explain why the availability of Fe2+ for heme biosynthesis may be restricted in the same neoplastic tissue. Considering that iron binding to Tf is pH dependent, the typically lower pH of tumor tissue may account for a pre-mature release of iron from Tf into the interstitium. Another factor can be explained by the hosts’ own protection mechanisms against neoplastic growth. During inflammation the human body reduces its total plasma iron through a self-generated iron-scavenging mechanism in addition to a reduction of iron mobilization: On one hand Tf expression from the liver is reduced. On the other hand the increased production of cytokines during inflammatory processes and tumor growth augments the expression of macrophageal ferritin in liver and spleen. One function of these macrophages is to phagocytose and digest aged erythrocytes. Iron from hemoglobin decomposition is then usually recycled, e.g. by re-introduction into the heme cycle. High ferritin levels in the macrophages, however, create a virtual iron sink and prevent the release of iron into the blood plasma. Another macrophage-associated mechanism for the withdrawal of iron from tumor cells was proposed by Hibbs et al. who demonstrated that tumor cells released iron upon co-cultivation with activated macrophages [69]. Macrophages release unstable compounds that generate reactive nitrogen oxide (NO) intermediates. It was proposed that this may trigger the release of iron from the cells. Finally, it is tempting to speculate that the characteristically big size of the nucleus of tumor cells and the small cytosolic volume may abet transport of iron into the nucleus for gene regulation, to the disadvantage of the iron level in mitochondria. In conclusion, iron does not necessarily reach FC for the final step of heme biosynthesis in mitochondria despite the effort of tumor tissue to take up high concentrations of iron, thus leading to a higher accumulation of PPIX in these cells upon administration of 5-ALA.
8.3.3
Transporter Systems for 5-ALA
Exogenous 5-ALA enhances PPIX formation in neoplastic tissue. As summarized above, a reason for this may lie in the altered kinetics of the heme biosynthesis in neoplastic cells. However, it does not explain the preferential uptake of exogenous 5-ALA by cancer cells. Cancer cells cover their high demand for metabolites through an increased expression of nutrient transporters in tumors, such as amino acid transporters and/ or their isoforms. The similarity to a-amino acids makes 5-ALA (a d-amino acid) a candidate for competitive transport. For instance, neutral a-amino acids, and the structurally related amino acids, in particular b-alanine, taurine and GABA, inhibit the uptake of 5-ALA into WiDr tumor cells [70]. The three amino acids are substrates for the system BETA, an Na+/Cl− dependent transporter of broad specificity in epithelial cells of the intestine [71]. The fact that 5-ALA is translocated into the
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cytosol by this transporter is in accordance with the finding that cellular 5-ALA accumulation correlates with extracellular Na+ and Cl− concentration [70, 72]. Brennan et al. showed that 5-ALA is a substrate for the neuronal GABA transporter [73], which may account for the GABA-like systemic adverse effects, such as bradykardia and decrease of blood pressure. The competitive uptake of 5-ALA instead of the neurotransmitter by GABA transporters in peripheral nerves may explain the greater sensation of pain in patients treated with 5-ALA compared to patients treated with 5-ALA esters. Esters of 5-ALA do not interact with the GABA transporters [70, 74–76]. The competitive interaction of 5-ALA with compounds that are not substrates for the system BETA provides evidence that 5-ALA can also bind to other receptors. Döring et al., for example, showed that 5-ALA is translocated by the proton dependent intestinal PEPT1 and renal PEPT2 transporter [77]. This explains the efficient intestinal uptake and the renal re-absorption of 5-ALA from the proximal tubule. Di- and tri-peptides such as Gly-Gly and Gly-Gly-Gly, but not GABA and the other structurally related amino acids glutamate, glycine (Gly), or lysine inhibit 5-ALA uptake in both transporter systems. 5-ALA interacts with the glutamergic system in brain synaptosomes and glycine has been shown to induce renal 5-ALA excretion in patients with acute porphyria [78, 79] and to inhibit 5-ALA uptake into amelanotic melanoma cells [80]. This observation points to a further transport system for 5-ALA. Two research groups recently proposed the amino acid transporter SLC36A1 (PAT1) as carrier for 5-ALA [81, 82]. SLC36A1 is expressed in the gastrointestinal tract and mainly in the small intestine. It is an H+-dependent carrier for small amino acids, such as GABA, glycine, proline and alanine, but also for numerous drugs [83, 84]. 5-ALA uptake of the physiological substrates into frog oocytes and CaCo2 cells decreased upon coincubation with 5-ALA. Inversely, 5-ALA uptake into SLC36A1 transfected COS-7 cells was inhibited by glycine, proline and GABA. The choroid plexus represents an exceptional part of the blood-cerebrospinal fluid (CSF) barrier, lining the blood capillaries with normal (fenestrated) endothelium on one side (basolateral side) and the CSF containing brain ventricles with fenestrated ependyme on the other (apical side). It allows small molecules such as vitamins and nucleotides to penetrate into the brain, but also represents the “weak point” for the influx of drugs. PEPT2 seems to play a role in 5-ALA transport in the choroid plexus. It seems to function as an efflux pump rather than an uptake mechanism, to keep 5-ALA concentrations low in the CSF [85–87]. It is difficult to tell, whether accumulation of 5-ALA in brain tumors is a consequence of selective interaction of 5-ALA with cell transporters or if the passage into tumor invaded areas is facilitated after disruption of the blood brain barrier (BBB). In an in vitro experiment, Correa Garcia et al. did not see any uptake of 14C-5-ALA into epithelial cells of isolated capillaries of the BBB [88]. Similar results were obtained by Terr et al., who analyzed the uptake of radio-labelled 5-ALA by various parts of the brain after systemic application. They found exogenous 5-ALA only in structures lacking the BBB, notably the choroid plexus, whereas other areas did not feature any 5-ALA uptake [89]. Most probably, the intact BBB is impermeable for
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5-ALA. In agreement with other studies [90–92] Hebeda et al. failed to detect PPIX in brains of healthy rats after systemic 5-ALA administration, but observed elevated PPIX in experimentally induced brain tumors of rats. Interestingly, the animals had higher PPIX concentrations in intact brain tissue than the control group. The decrease of fluorescence correlated with the distance from the tumor. No PPIX fluorescence was observed in the plexus region. It is likely that the brain tumors impaired the protective function of the BBB and thereby enhanced the permeation of 5-ALA into the diseased tissue [93].
8.3.4
Altered Morphology of Tumors
The vascular system of tumors exhibits alterations in the morphology of endothelial tissue, which favours the retention of large molecules in the neoplasm. This feature is referred to as the enhanced permeability and retention (EPR) effect [94, 95]. In tumors oxygen pressure is reduced and gene expression is switched to adapt to the hypoxic environment, notably through anaerobic glycolysis. The prevailing anaerobic conditions favor lactic acid formation with concomitant pH decrease in the interstitial fluid. Recent findings suggest that low extracellular pH in neoplastic tissue is also mediated by the over-expression of tumoral carboanhydrases. These enzymes catalyze the reaction of a physiologic buffering system by generating bicarbonate and protons from CO2 and water. Formed bicarbonate is shovelled into the cell to ensure neutral pH for enzyme functioning, thus leading to elevated extracellular proton concentrations [96]. The pH in tumors is about 0.2–0.4 units lower than in normal tissue. The change of pH has been considered to have an effect on the supply of iron for FC (see Sect. 8.2), but also on the selectivity of 5-ALA uptake in cancer cells. 5-ALA-mediated PPIX production is decreased at extracellular pH below 6.0 and above 7.0 [97–101]. According to Bech et al. this may be explained by an activity decrease of enzymes of the heme cycle such as PBGD [100]. This explanation stands in contrast to the elevated PBGD levels observed in tumor cells as described under Sect. 8.1. Despite apparently lower PPIX levels at decreased pH, it was observed that the susceptibility of 5-ALA treated cells to PDT was higher. This phenomenon was mainly attributed to the impairment of cellular repair enzymes which in turn raises the cells susceptibility to PDT [98, 100]. It should be mentioned at this point that the stability of 5-ALA as well as the fluorescence of PPIX change with pH [101–103]. The requirement for nutrients and oxygenation from blood circulation prompts tumors to express angiogenic growth factors (e.g. vascular endothelial growth factor, platelet derived growth factor). However, the poor coordination of the growth leads to a network of incomplete, fenestrated vascular structures. Depending on the tumor, the gaps in neoplastic vascular endothelium may attain several hundred nanometers, making it an adequate target for large molecular 5-ALA derivatives and modern formulations such as liposomes and nanoparticles (see Sect. 8.4.2). In addition, the typically underdeveloped lymphatic system in neoplasms prevents the evacuation
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of same said molecules and particles. The high density of microvessels associated with inflammation responsive signals furthermore leads to elevated temperature in tumor tissue [104, 105]. Moan et al. investigated the influence of temperature on the PPIX production in vitro. After incubation of WiDr cells with 5-ALA at 37°C for 20 min they monitored the PPIX accumulation over several hours, PPIX induced fluorescence increased with incubation temperature up to 37°C, but did not seem to influence 5-ALA penetration into the cell [106]. The results were in accordance with observations on 5-ALA treated skin of three volunteers and two other studies on the temperature dependent PPIX production on mouse skin after topical 5-ALA application. In the first study, temperature was changed before and after a 10 min application of a 5-ALA containing cream. In the second study, temperature was varied during the application period. Temperature did not seem to have any effect on the penetration of 5-ALA into the skin. However, PPIX formation from 5-ALA as well as its esters correlated with temperature increase [107, 108]. The authors hypothesized that a temperature increase may have a positive influence on the activation of the bottleneck-enzyme PBGD, where the activation energy changes from 21.7 kcal/mol for temperatures lower than 35°C to 12.7kcl/mol°C for temperatures between 35°C and 46°C [107, 109]. The result of the first study should be considered with caution. Since 5-ALA application times were short, it is conceivable that the diffusion process through the stratum corneum was not completed when the skin was heated or cooled after cream application. Van den Akker et al. observed that PPIX induction on the back skin of healthy volunteers depended on the skin temperature during 15 min application of 5-ALA using a hydrogel [110]. A non-negligible aspect is the temperature-dependent release of 5-ALA from its application form. Unfortunately, none of the studies on temperature dependent PPIX induction provide data on in vitro release kinetics for direct comparison. As already mentioned for the BBB, the invasive character of neoplastic tissue affects the architecture of surrounding tissue, notably of epithelial cell linings. Epithelia delineate organs and tissues in the organism and have a protective barrier function. Drugs of small size may diffuse passively through small gaps between epithelial cells into the underlying tissue. The limiting factor for this mode of entrance is constituted of intercellular tight junctions. Alternatively, the drug may interact with cellular receptors and transporters or feature adequate physico-chemical properties in order to penetrate the cell membrane. Disruption of the epithelial cell layers, for example by tumor invasion, facilitates the accessibility of underlying tissue. The defect is advantageous for the drug delivery via the topical route. The epithelium of the skin represents a particular structure to maintain its protective function against influences from the environment. It consists of five layers. During their life cycle of approximately 21 days, epidermal cells progressively move from the stratum basale at the bottom into the overlying stratum spinosum, stratum granulosum and stratum lucidum until reaching the stratum corneum, the outermost layer, as fully differentiated corneocytes. These cells are characterized by a cornified cell envelope consisting of proteins and lipids and the lack of a nucleus. They are embedded into a lipid layer containing approximately 41% ceramids, 39% cholesterol and
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cholesterol derivatives and 9% free fatty acids, which form a lipophilic film at the surface of the skin. Eventually the corneocytes scale off through the contact with the outer world. The lipophilic nature of the stratum corneum, which – one should note – is only a few microns thick, prevents the dehydration of the body from excessive evaporation, and represents the main protective barrier from external influences. In combination with the underlying cell layers (the dermis containing lymph vessels, sebaceous glands and small blood vessels and the subcutis hosting large blood vessels, nerve endings and hair follicles), the skin represents an organ with alternating hydrophilic and lipophilic layers. This feature makes drug delivery through the skin particularly challenging. But it also leaves way for the targeted delivery of drugs to parts where the penetration barrier is damaged, e.g. by skin diseases. The trespassing of a compound through the intact epidermis is controlled by its diffusivity within the cell layers [111]. Removal of the lipophilic stratum corneum may augment the permeation capacity of the compound. Several studies recorded a higher amount of PPIX accumulation in healthy skin after topical application of 5-ALA with prior tape stripping or micro-dermabration than in skin without pretreatment [107, 112–116]. In a permeation study on mouse skin Tsai et al. modified the permeability of the skin with acetone, and showed ex vivo that transdermal flux of 5-ALA corresponded to the level of transepidermal water loss (TEWL), an indicator for the degree of corneal disruption. According to an Emax model, the flux correlated with the in vivo PPIX fluorescence at the respective TEWL levels using the same concentration for each 5-ALA formulation [117]. In agreement with Tsai’s findings, a group at the Radboud University Medical Center in Nijmegen stated that the extent of PPIX formation in psoriatic skin is dependent on the thickness of overlying stratum corneum rather than on patho-physiological characteristics of the epidermal cells [118, 119]. In other hyperkeratotic diseases the variation of fluorescence after topical 5-ALA administration could be also ascribed to the poor penetration of 5-ALA through the overlying stratum corneum.
8.4
Means to Improve PPIX Formation
Various techniques have been explored to improve 5-ALA delivery to its site of action with the principal aim of increasing PPIX generation at the target. As it is beyond the scope of this chapter to review all the studies relating this topic, the reader is referred to several excellent reviews treating this matter [120–124]. The following sections shall nevertheless give some insight into the approaches that have been evaluated so far. One can distinguish between physical, chemical and galenic means to direct a drug to its target. Physical methods describe the application of a treatment prior to or in combination with the drug that physically alters the tissue or creates a physical driving force for the molecule to reach its target. Chemical means imply the derivatization of the 5-ALA molecule, into a compound with more advantageous properties with respect to bioavailability. The term “galenics”, finally, stands for the science of
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preparing and optimizing the drug dosage form, i.e. the drug vehicle in order to obtain the required delivery profile. This involves the right choice of the drug carrier and possible adjuvants.
8.4.1
Physical Means
8.4.1.1
Surface Ablation
In certain skin diseases, such as actinic keratosis, psoriasis, basal- and squamous cell carcinoma, the presence of a hyper-keratotic layer impedes the penetration of the photosensitizer and also the penetration of light. Curettage or debulking of the tissue may overcome this constraint. In many clinical protocols for topical PDT gentle curettage or debulking prior to photosensitizer administration is applied as standard procedure [125, 126]. Unfortunately, many trials lack control groups that did not undergo mechanical tissue removal, so that the true impact of this method is difficult to evaluate. Moseley et al. examined the effect of the removal of the outermost layer of the lesions by gentle abrasion prior to exposure to 5-ALA on 16 lesions in 15 patients with superficial non-melanoma skin cancer. Comparing the fluorescence of curetted parts with untreated parts of the same lesion, they could not find any difference between treatment and control group. They concluded that pre-treating lesions by gentle curettage does not influence 5-ALA penetration into the tissue [127]. On the other hand, Soler et al. treated patients with basal cell carcinoma (BCC) of at least 2 mm thickness with 5-ALA in combination with dimethyl sulfoxide (DMSO). In the test group, BCCs were debulked using a curette, the control group did not get any pre-treatment. After an average follow-up of 17 months 95% of curetted lesions showed complete response versus 50% in the control group [128]. A follow-up study with a similar treatment modality reported complete response for 81% of the treated lesions after 6 years [129]. The study, however, does not mention the response of the control group. Itoh et al. used an electro-curettage technique to remove melanin in 16 patients with pigmented BCC prior to 5-ALA administration. This form of BCC is usually not prone to standard PDT due to light absorption by melanin in the lesion. In this study, however, 14 out of 16 patients showed complete response to the treatment [130]. Shen et al. chose an erbium:yttrium-aluminum-garnet (Er:YAG) laser for tissue ablation on mice bearing skin cancer lesions [131]. In this technique, the instant evaporation of water through absorption of the laser beam causes a micro-explosion ejecting desiccated skin from the surface until a depth of 10–15 mm [132]. Lasertreated BCCs prior to topical 5-ALA application, accumulated PPIX faster and in significantly higher amounts than non-pre-treated lesions [131]. In agreement with this finding, although less pronounced, a clinical study on patients with recurrent and nodular BCC had a better outcome in the case of PDT using the combination of
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Er:YAG laser and 5-ALA methyl ester on human skin than when using Er:YAG laser or PDT alone (final efficacy of 98.97%, 91.75% and 94.85%, respectively) [133]. Other lasers, for example a CO2 laser, have been used for the same purpose [134]. Pretreatment of the target surface with penetration enhancers (see Sect. 8.4.1) and/or keratolytics, such as salicylic acid and urea, may facilitate the ablation of the stratum corneum [118, 135, 136]. In an attempt to remove plantar warts by 5-ALA PDT, Fabbrocini et al. combined the keratolytic treatment with 5-ALA PDT. They applied an ointment containing 10% urea and 10% salicylic acid onto plantar warts for 7 days before removing the surface by gentle curettage. Three weeks after PDT surface of plantar warts was reduced by 70% in patients treated with 5-ALA versus 30% in patients with placebo PDT [135].
8.4.1.2
Skin Perforation
Recently, micro-needle perforation techniques [137] and needle-free jet injection [138] have been explored to optimize 5-ALA delivery through the skin. Microneedle arrays consist of a multitude of small perforators of defined form and size attached to a small platform. The platform functions as support for the perforators; it also controls their penetration depth into the skin and prevents the stimulation of nociceptive nerve endings in deeper lying tissue. After gentle pressure to the skin, the micro-needles leave small pores, which facilitate the permeation for water-soluble compounds, such as 5-ALA. In jet injection, the drug is delivered subcutaneously, intradermally or intramuscularly by a high velocity liquid jet. Penetration depth depends on pressure and speed of the jet and the mechanical resistance of the skin. Ex vivo studies on porcine skin revealed a positive effect on the penetration capacity of 5-ALA. For micro-perforated murine skin in vivo, a faster induction of PPIX accumulation was visible. Higher PPIX amounts were detected when low concentrations of 5-ALA were applied. Delivery of 5-ALA methyl ester (MAL) to nodular BCCs by means of oxygen pressure injection showed better results in PPIX induction than application of MAL alone [139].
8.4.1.3
Ultrasound and Iontophoresis
Iontophoresis takes advantage of the ability of molecules to migrate in an electric field. In the context of drug delivery, the procedure involves the application of two electrode compartments on the surface of the skin. The electrodes are connected to a power source. Charged compounds are loaded into the electrode compartment bearing the same charge. Application of a low electric potential between the two electrodes establishes a current flow and consequently sways the ions to migrate through the skin. The two driving forces dictating this phenomenon are electromigration and electro-osmosis. In the former, the movement of ions is driven by the electric field force. The delivered drug dose usually correlates directly with the
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charge of the drug and the magnitude of the applied current. Electro-osmosis, in contrast, implies the passive transport of molecules with the liquid flow caused by electric current [140]. Several in vivo and ex vivo studies have shown that 5-ALA penetration through healthy skin in combination with iontophoresis reduces the application time to observe a fluorescence signal [141]. PPIX fluorescence correlated with the applied iontophoretic charge [142–144]. Mizutani et al. performed PDT supported by directcurrent pulsed iontophoresis in five patients with thin to moderate aktinic keratosis. Differing from the usual lag time of 4–5 h, they detected PPIX within 1 h [145]. Lopez et al. and Merclin et al. reported that the efficacy of 5-ALA iontophoresis is dependent on the ionic strength and type of 5-ALA formulation [141, 146]. Decrease from pH 7.4 to pH 4 does not affect 5-ALA electromobility. This is surprising, since one would expect that the driving force of electophoretic transport at neutral pH is electro-osmosis. Below pH 4.5 electro-migration should synergistically augment the transport with decreasing pH. However, low pH also impedes the electro-osmotic flow. The authors, therefore, concluded that electro-migration compensates the effect of the electro-osmotic flow rather than enhancing it [143]. In parallel to the beginnings of 5-ALA iontophoresis, Ma et al. examined the influence of ultrasound (1 MHz) on PPIX induction in subcutaneous tumors in BALB/c nude mice. Fluorescence intensity was the same after 1 h with 5-ALA and ultrasound compared to 3 h incubation with 5-ALA alone [147]. Charoenbanpachon et al. used ultrasound in combination with 5-ALA formulated in Eucerin® on dysplastic and healthy oral mucosa of hamsters. 5-ALA induced PPIX fluorescence increased significantly after 20 min when ultrasound was applied. The same PPIX fluorescence intensity appeared after 180 min when applying a 5-ALA in Eucerin® and a penetration enhancer containing formulation (Pluronic® Lecithin Organogel) without ultrasound, respectively. PPIX fluorescence was higher in dysplastic tissue than in normal tissue. It also increased when ultrasound of higher frequency was applied, suggesting that higher amounts of 5-ALA levels reached the target tissue with this method [148].
8.4.2
Chemical Means
8.4.2.1
5-ALA Esters
The likeliness of a molecule to diffuse through the cell membrane is dictated by certain physical-chemical characteristics, which have been resumed by Lipinski’s “rule of five”. According to this rule the cell permeation of a molecule is promoted, when its octanol-water partition coefficient (expressed as logP) is smaller than 5, the molecular weight is under 500 and the molecule contains less than 5 hydrogen bond donors and no more than 10 hydrogen bond acceptors [149]. The partition coefficient is crucial for the ability of a drug to passively penetrate biological barriers. A molecule with a negative logP, hence with good solubility in water, is not likely to trespass the
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lipophilic cell membrane. This may be improved by raising the lipophilicity of the molecule. However, if the logP is too high, partition into the intracellular aqueous environment is low, i.e. the molecule remains “trapped” in the membrane. With a negative logP (−1.5) [150] and a zwitterionic structure at physiological pH, 5-ALA represents a highly water-soluble molecule. The only possible way into the cytosol is therefore restricted to active transport systems, such amino acid and peptide transporters (see Sect. 8.3). For the topical application this brings the drawback of inhomogenous distribution in the target tissue. Instability in aqueous media and its susceptibility to the first pass effect make 5-ALA less suitable for oral and intravenous application. High doses are necessary to obtain a pharmacologically satisfying response thereby increasing the risk of neurological side effects. Knowing that lipophilicity of a drug may have a positive impact on the bioavailability, Kloek et al. [151] and Peng et al. [152] were the first to 5-ALA with lipophilic residues. When applied topically, ester induced fluorescence remained confined to the area of application. In contrast, the fluorescence induced by free 5-ALA was detected in collateral sites of the application site and persisted for a longer time [113, 153–156]. Uehlinger et al. esterified 5-ALA at the carboxyl end with a homologous series of aliphatic alcohols to investigate the controlled change of lipophilicity in a simple manner [150, 151]. The esterification of the carboxyl group turns the previously zwitterionic amino acid into a cation, which facilitates the interaction with the negatively charged cell surface [157]. All 5-ALA esters induced PPIX formation in J82 and T24 bladder carcinoma cells, an A459 human lung carcinoma cell line, and in BEAS-2B immortalized normal human bronchial epithelial cells. The extent depended on the type and the concentration of the ester. 5-ALA hexyl ester induced the highest amount of PPIX at a concentration about ten times lower than free 5-ALA [150]. De Rosa et al. observed that short alkyl esters with a chain length of up to six carbons induce PPIX fluorescence at low concentrations. Longer esters failed to do so [158]. According to the influence of the logP on the penetration capacity of a small molecule, one may conclude, that contrarily to free 5-ALA, 5-ALA alkyl esters diffuse through skin or the cell membrane [159]. Chen et al. found that esterification of 5-ALA also has positive influence on the chemical stability. He observed that in aqueous solution 5-ALA hexyl ester forms less dimers than free 5-ALA [160]. The vast possibilities derivatizing the 5-ALA molecule have been extensively explored and the reader is referred to a review written by Fotinos et al. [123] for a more detailed description of the methodology. Table 8.2 provides an overview of some chemical strategies to improve 5-ALA mediated PPIX accumulation in the target tissue. So far the most promising derivatives have proven to be 5-ALA alkyl esters. In fact, the new findings on 5-ALA derivatives represented a breakthrough for their introduction into the market. Today, the 5-ALA products Levulan® Kerastick® (for treatment of actinic keratosis) and Gliolan® (detection of malignant glioma during surgery), as well as two 5-ALA esters, 5-ALA methyl ester (Metvix®) and 5-ALA hexyl ester (Hexvix®), have obtained marketing authorization (see Table 8.1).
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Table 8.2 Approaches for chemical modification of 5-ALA
Class
R1
R2
Data
In vitro, in vivoa In vivoa Ex vivob In vitro In vitro Ex vivob,c In vitro In vitro Acyloxyalkyl H In vitro Peptide H Amino acid In vitro Alkyl, ethylene oxide Di-, tripeptide In vitro H Oligopeptide In vitro Dendrimer Dendrimer H In vitro In vitro In vitro In vitro Vitamine Tocopherol H In vitro (only synthesis) Cholecalciferol H Biotin H Glucoside Monosacharide H In vitro Nucleoside Adenosine H In vitro Ester
Alkyl
H
Reference Kloek et al. [151] Peng et al. [152] De Rosa et al. [158, 159] Uehlinger et al. [150] Rud et al. [70] Casas et al. [155] Moan et al. [154, 156] Chen et al. [160] Berkovitch et al. [161] Bourré et al. [162] Berger et al. [163] Dixon et al. [164] Battah et al. [165–167] Brunner et al. [168] Di Venosa et al. [169] Casas et al. [170] Vallinayagam et al. [171]
Vallinayagam et al. [172] Gurba et al. [173]
a
mouse mouse skin c human skin b
Metvix is approved for the treatment of precancerous and cancerous skin lesions in Europe, Australia and USA. Hexvix® is commercialized in Europe for the detection of recurrent bladder cancer and recently gained marketing authorization in the USA under the name Cysview® (see Fig. 8.4). A novel approach was tempted by Berkovitch et al., who attached an acyl oxy alkyl component to the carboxyl end of 5-ALA. Metabolization of the prodrug leads to the release of formaldehyde and butyric acid [161]. They favor the formation of ROS and apoptosis and thus may increase the effect of PDT.
8.4.2.2
5-ALA Peptides
The possible translocation of 5-ALA by the dipeptide transporter on one hand, and the targeting of tumoral aminopeptidases on the other, led to the synthesis of 5-ALA
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Fig. 8.4 Endoscopic image of human bladder carcinoma in situ visualized under white (a) and blue (b) light after instillation with 5-ALA hexyl ester. Under blue light the carcinoma appears with a red fluorescence due to preferential accumulation of PPIX mediated by 5-ALA hexyl ester (b). The same carcinoma is not distinguishable under white light (a). Unpublished work
derivatives with peptidic structure. Casas et al. [155] and Berger et al. [174] found that some, but not all amino acid- and short peptide derivatives induce PPIX formation in vitro and in vivo. An advantage of amino acid derivatives is their increased stability in aqueous solutions at physiological pH, provided that the amino terminal group is protected or longer peptides are used for the conjugation [163, 174, 175]. Berger et al. discussed that the occupation of the amino functional group prevents the cyclization of the molecule by a Schiff base reaction between the amine and the g-carbonyl moiety of 5-ALA [163]. However, activation of these compounds necessitates the presence of peptidases. In this context, the conjugated amino acid as well as the N-terminal group determines the compounds’ susceptibility to the respective amino peptidase. As an example, 5-ALA methyl ester conjugated with neutral amino acids such as L- phenyl–alanine induces porphyrin formation in A549 human lung carcinoma cells. This cell line expresses the aminopeptidase N/M, which has a high affinity to neutral amino acids. 5-ALA methyl ester conjugated N-acetylated L-phenyl alanine failed to induce PPIX formation [163, 176] in A549 cells. Incubation of the spontaneously transformed murine keratinocyte cell line PAM212 with the same conjugate resulted in three times higher PPIX accumulation than with free 5-ALA [175, 176]. PPIX accumulation was drastically decreased when silencing the acylpeptide hydrolase gene, which encodes for a peptidase detaching acylated amino acid residues from oligopeptides [162]. Dixon et al. synthesized the first 5-ALA conjugated oligopeptide, comprising eight amino acids. Unlike short amino-acid compounds, which are taken up by the cell transporters or via diffusion, oligo peptides self-trigger their internalization by endocytosis. They can carry multiple payloads, which makes them an interesting alternative for the intracellular drug delivery. The 5-ALA oligopeptide was successfully internalized by endocytosis. However, PPIX induction was only half compared to porphyrin induction with equimolar amounts of free 5-ALA. Therefore, further improvement of this approach is required [164].
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5-ALA Conjugates with Macromolecules
Lately, several groups conjugated 5-ALA and its esters with macromolecules. Such structures may be loaded with multiple 5-ALA units and improve tumor penetration by enhanced permeability and retention (see Sect. 8.4) due to their large size. Attachment of residues interacting with tumor receptors may favor tumor uptake. A high payload may especially be achieved with dendrimers. These highly branched polymers (dendron = greek: tree) consist of a core molecule, from which arise linker chains in a star shape. A functional group at the end of the linker allows the attachment of active moieties or functional groups, such as hydrophilic residues to improve solubility. During screening assays of various 5-ALA esters to improve prophyrin induction, Battah et al. [165] and Brunner et al. [168] found that certain 5-ALA dendrimers were able to induce PPIX formation in tumor cells. Further research revealed that the type and length of the linker influenced the bioavailability of 5-ALA. Functional groups that make the ester bonds more sensitive to cleavage, increased 5-ALA discharge, while dendrimers with sterically hindered ester bonds delivered 5-ALA less efficiently [167]. Logically, the susceptibility of ester bonds to cleavage together with the number of 5-ALA molecules bound to the dendrimer determines the kinetics of PPIX generation. A second generation dendrimer conjugated with 18 5-ALA molecules induced sustained PPIX formation over a period of 48 h in vitro [167] and in vivo [170], while PPIX levels were significantly lower already after 24 h when free 5-ALA was applied. While small dendrimers seem to follow an internalisation mechanism similar to that of free 5-ALA or its derivatives [166, 169], large dendrimers reach the cytosol by endocytosis [167]. The synthesis of 5-ALA conjugates with vitamins, monosaccharides and nucleosides has also been reported [171–173].
8.4.3
Galenic Approaches
To achieve the wanted effect with a treatment it is not sufficient to use a drug with satisfying pharmacodynamics. It is equally important to deliver the drug to the targeted sight of action, at the right time and in concentrations that correspond to the therapeutic window. An alternative way to and physical methods for penetration enhancement and chemical derivatization of the active compound is to optimize the vehicle from which the drug is delivered. The release of 5-ALA and its derivatives from topical formulations such as creams, gels and solutions has been extensively studied [117, 154, 177–181]. However, the expansion of possible target sites for 5-ALA PDT, e.g. its use for topically inaccessible tumors, demands more adequate vehicles. During the development of a drug formulation several factors must be taken into consideration: First, the formulation may considerably influence the chemical stability of the contained drug. Under alkaline conditions, for example, 5-ALA forms
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biologically inactive dimers of pyrazine and pyrrol structure [182–184]. Following an Arrhenius plot, Elffson et al. predicted a shelf life (time after which 10% of the product are degraded) of only 10 min for a 10% aqueous solution of 5-ALA at pH 7.5. Stability can be improved by decreasing pH, concentration and temperature of the aqueous solution [185]. In a further aspect, the excipients of the formulation have a strong impact on the pharmacokinetics of the drug. On one hand, the affinity of a drug with high logP to its carrier increases with the lipophilicity of the vehicle. As a consequence, release of the drug from the vehicle may be slower than from a more hydrophilic formulation. Collaud et al. reported that release of 5-ALA hexyl ester was more complete from thermosetting hydrogels than from a cold cream and a lipophilic base (Unguentum M®) [177]. The findings are in agreement with studies, in which 5-ALA hexyl ester formulations in lipophilic ointments did not efficiently induce PPIX production [186, 187]. On the other hand, a pronounced hydrophilicity of the vehicle can be disadvantgeous for the solubilization of a lipophilic compound and thus be inadequate for its delivery.
8.4.3.1
Topical Formulations
Casas et al. performed extensive research on the release of 5-ALA and its esters from topical formulations. 5-ALA hexyl ester induced twice as much PPIX when applied in an oil in water (O/W) cream than when applied from an aqueous solution [188]. For 5-ALA the best results were observed for hydrophilic saline solution (preferably containing additional penetration enhancers) and hydrophilic lotions [153, 178]. In a clinical trial, Hürlimann et al. applied a nanocolloid gel containing 10% 5-ALA to patients with BCC prior to irradiation with white light. They reported complete response in 84% during a follow-up of at least 6 months. Unfortunately the exact formulation parameters have not been reported [189]. Aiming at stabilizing 5-ALA and derivatives by liposomal encapsulation, Batlle et al. recently showed, that the loading capacity of liposomes drastically increases for more lipophilic 5-ALA esters [190–194]. The use of negatively charged lipids further improved the loading. Thus, 5-ALA loading of conventional phosphatidyl choline liposomes increased from 5% to 87% when using 5-ALA undecanoyl ester and 20% phosphatidyl glycerol, which is anionic at pH of the skin. Encapsulated 5-ALA esters remained stable up to 1 week [193]. However, compared to the free compound, undecanoyl ester liposomes failed to induce the formation of higher intracellular amounts of porphyrins [195]. Similar results were obtained when using free versus liposomal 5-ALA or 5-ALA hexyl ester [190]. Han et al. prepared DMPC-DMPG-CH-DOTAP (Dimyristol phosphatidyl choline- dimyristol phosphatidyl glycerol – cholesterol – dioleyl trimethyl ammonium propane; 7/1/2/1) liposomes and observed elevated PPIX production in pilosebaceous glands on dorsal rat skin [196]. The selective targeting of pilosebaceous glands may be of interest for PDT aided hair removal.
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A new approach is the incorporation of 5-ALA into solid lipid microparticles. Al-Kassas et al. proposed Witepsol H 15 as topical drug vehicle. Witepsol H15 is an established suppository base consisting of saturated mono-, di- and triglycerides with a melting point close to body temperature. The rationale behind the use of such a base is to physically impede 5-ALA dimerisation at room temperature by entrapment into a solid. Melting of the base at contact with the body surface allows instant drug release. Indeed, microparticle entrapped 5-ALA remained stable for at least 9 months. The microparticles further improved transdermal 5-ALA flux in an ex vivo skin permeation model [197]. Their application in practice, however, is more complicated, since bulk particles only adhere poorly to the skin. Therefore incorporation into bio-adhesive systems is required. The formulation into bioadhesive semi-solid carriers was investigated. The most appropriate vehicle was a propylene glycol based gel. PPIX production with this formulation was comparable to a cream containing the same amount of 5-ALA [198]. The topical delivery of a drug is especially challenging for mucosa and moist ondulated parts of the skin. These areas are often exposed to frictional stress (e.g. digestive contractions in gastro intestinal tract (GIT) or movement of the patient), which complicates the exposure of the targeted area to 5-ALA or derivatives during the incubation period. Thermosetting gels have been shown to be advantageous for the drug delivery to surfaces such as mucosa of oesophagus, stomach or cervix. The liquid state below room temperature facilitates the incorporation of water-soluble drugs. It also allows the application of the formulation in a liquid state, which is particularly advantageous for targeting the inner cavities. With increasing temperature (i.e. in contact with the body) the gel reaches the visco-elastic state. When targeting the oesophageal mucosa, for example, the patient may drink the formulation. The gel solidifies on the oesophageal mucosa, thus securing the contact of 5-ALA with its target site. Removal of the gel is possible by washing it away with a cold liquid, which puts it back into the sol state. One challenge in the formulation of drug delivery systems with changing physical properties is the coordination of formulation parameters. The type and concentration of the gelling agent, as well as of the incorporated drug influence the thermosetting temperature of the gel. Thus, 5-ALA increased the thermosetting temperature of a simple poloxamer gel containing the polymer and water [199]. The effect was the opposite in a gel using the same gelling agent, this time in combination with isopropanol, dimethyl isosorbide, medium chain triglycerides and water [200]. 5-ALA concentration had no effect on the setting temperature of a gel containing the same polymer with additional sorbic acid (0.15%) in citrate phosphate buffer pH 4.0 [177]. Sites exposed to high frictional stress, such as rectum or vulva or crease areas of the skin, require even more stable and rigid dosage forms than semi solids. Donnelly et al. developed of a bioadhesive patch in order to address this problem. The patch consists of a bioadhesive water soluble poly (methylvinylether/maleic anhydride) (PVME/MA) layer, which contains 5-ALA, and a backing poly vinyl chloride (PVC) layer [201–205]. In 2009, the patch was tested on 23 patients with vulval intraepithelial neoplasia. It showed adequate adhesion; however, photodynamic
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treatment of the lesions after patch application did not improve response with respect to conventional treatment [204]. Another dermatological patch was invented by Lee et al. [206] and recently gained marketing authorisation in Europe under the name Alacare® and Effala® for the treatment of mild actinic keratosis on hairless areas of skin and scalp (see Table 8.1) [207]. The drug is incorporated in its crystalline state into a poly acrylate methacrylate (Eudragit®) matrix, which is backed by a poly ethylene aluminium poly ester film. The system can be advantageously applied to the lesion without previous curettage or occlusion. In two randomized controlled trials including 449 patients with mild to moderate actinic keratosis, single dose PDT in combination with the patch showed a statistically significant better result than cryosurgery and placebo PDT. After a 12 week follow-up complete response was observed in 82% (patch PDT) versus 19% (placebo PDT) in the first trial and 89% versus 29% second trial, respectively. The response rate was favorable in comparison to treatment with the commercially available alcoholic 5-ALA solution (Levulan® Kerastick®, 66% complete response after single treatment) and 5-ALA methyl ester containing cream (Metvix®, 86.9% after single treatment) [208]. Seventy five percent of the patch-treated patients still showed complete response after 12 months [209]. As mentioned above, the access of 5-ALA from the skin to underlying tissues is limited by poor permeation. Penetration enhancers have therefore been considered for a pre-treatment or as additives for dermatologic 5-ALA formulations. Typically, penetration enhancers alter the highly organized structure of the stratum corneum by interacting with intracellular proteins and lipid structures through lysis and/or hydration of keratinocytes. They may also function as solubilizers for the drug in the stratum corneum. The best established penetration enhancer is DMSO. In fact, it is the sole chemical penetration enhancer mentioned in the Guidelines of the British Photodermatology Group [210]. Many studies reported the positive effect of DMSO as adjuvant or in combination with other targeting strategies for enhanced 5-ALA delivery [128, 129, 141]. The mechanism, by which this substance acts as penetration enhancer in the skin is not completely elucidated. It is assumed to denaturate intracellular proteins and to enhance the fluidity of the lipid bilayer by dissolving lipid structures [211]. DMSO is further known to trigger cell differentiation in neoplastic cells. An explanation for this may be the induction of certain enzymes of the heme cycle [212]. Synergistically to their effect on alteration of heme biosynthesis, chelating agents have been considered as modulators of tumor cell proliferation and immune response following PDT. This argument is well conceivable since iron acts also as regulator in transcriptional processes in the nucleus [213]. The relevance of iron disposability for the accumulation of PPIX becomes most obvious through the use of chelating agents. Chelators intervene in the heme cycle by depriving FC from its substrate ferrous iron. This leads to an accumulation of PPIX in normal tissue [214]. Since exogenous 5-ALA induces PPIX formation, it may be assumed that the combined application of the PPIX precursor with an iron chelator has a synergistic effect [213, 215]. Taking further into account that 5-ALA has preferential affinity for dysplastic
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tissue, the synergistic effect is even more pronounced in tumors [216, 217]. An iron chelator may therefore allow to down-size 5-ALA concentrations and hence reduce cytotoxic side effects, while maintaining a high free porphyrin concentration in the cells. Ethylenediaminetetra-acetate (EDTA) is a well-established metal ion chelator. Experiments with EDTA support the concept of enhanced porphyrin accumulation through the chelation of iron [218, 219]. Low specificity and poor penetration of EDTA through the cell membrane reduce its potential for clinical use. Deferoxamine (DFO) permeation of the cell membrane exceeds that of EDTA. The chelator was originally discovered as bacterial siderophore [220]. Today, it is used for the therapy of iron overload diseases such as thalassemia. However, the response to topically applied DFO varies greatly and is not well reproducible. It should be used together with other penetration enhancers. Another molecule that gained growing interest during the last decade is CP94, a benzopyrridinone. It was originally developed to improve iron binding in the treatment of hemochromatosis. CP94 permeates the skin and reaches the intracellular cell pool faster than EDTA and DFO. These properties can be attributed to its low molecular weight and higher lipophilicity, which also render it suitable for oral application. In a study on subcutaneously implanted C26 colon carcinoma in mice, Malik et al. compared the PPIX induction capacity of a formulation containing 20% 5-ALA alone, 5-ALA + 2% DMSO and 5-ALA + 2% DMSO + 2% EDTA, respectively. In agreement with a similar study conducted by Casas et al. [153] the DMSO containing formulation induced faster and overall higher PPIX accumulation in tumors than the plain 5-ALA cream. The effect was even more pronounced in the skin overlying the tumor [221]. Addition of the iron chelator increased PPIX fluorescence. In a clinical trial on patients with nodular BCC (nBCC), Peng et al. applied a cream with 20% ALA alone, 20% ALA + 20% DMSO + 4% EDTA, respectively, onto the lesions and monitored the PPIX fluorescence. Part of the nBCCs was also pre-treated with 99% DMSO for 15 min. They observed four times higher fluorescence in lesions treated with DMSO prior to 5-ALA application than in lesions that were treated with topical 5-ALA alone. DMSO containing cream also induced higher PPIX fluorescence than the control. The best penetration into the lesions was achieved upon DMSO pre-treatment. nBCCs treated with DMSO containing cream showed a twofold higher fluorescence and an improved penetration depth [222]. In another study DMSO enhanced 5-ALA penetration and PPIX accumulation on healthy murine skin in vivo and ex vivo. The increase of PPIX fluorescence was significant when using formulations containing 1.5% 5-ALA + 20% DMSO and 5% 5-ALA + 10% DMSO, respectively. DMSO neither had an effect on the partition coefficient neither in isopropylmyristate/water, nor in stratum corneum/phosphate buffer saline pH 5.0. One may therefore speculate that the action of DMSO on 5-ALA diffusion into the skin occurs through restructuring the skin rather than solubility mediation. The addition of 3% EDTA to the formulation did not have a significant effect on the PPIX accumulation in skin [223]. Based on the positive effect of the combination 5-ALA/DMSO/EDTA, Ziolkowski et al. made an attempt to improve PPIX accumulation in dysplastic skin diseases by adding glycolic acid.
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This a-hydroxy acid increases the penetration of hydrophilic drugs [224] possibly due to hydration of the stratum corneum [225]. In the squamous cell carcinoma cell line A431 and skin fibroblasts glycolic acid led to a twofold increase of PPIX concentration. In adenocarcinoma bearing BALBc mice PPIX accumulated faster when glycolic acid was added to the formulation (4 h versus 6 h without glycolic acid). In patients with squamous cell carcinoma (SCC) complete response was obtained for all lesions (size 2–9 mm) after PDT using the glycolic acid formulation. When using the formulation without glycolic acid the same result could only be obtained for SCCs smaller than 3 mm [226]. Other penetration enhancers have been assessed as alternatives for DMSO. Oleic acid impedes the barrier function of the skin by interacting with lipid structures in the stratum corneum and propylene glycol typically increases the drug solubility in the stratum corneum [227]. It was observed that PPIX amounts in murine skin were significantly higher when 5-ALA was formulated with a combination of propylene glycol and oleic acid than with propylene glycol alone (approximately twice as much) [228]. The replacement of oleic acid by glycerol mono oleate showed similar results [229]. Glycerol mono oleate is a well established biodegradable penetration promoter. In the GIT it is generated endogenously during fat digestion. Next to its surfactant properties it functions as gelling agent in aqueous dispersion. At adequate concentrations it will form a so-called cubic phase. A cubic phase is characterized by a continuous, three dimensional lipid bilayer network of gel like texture. The amphiphilic nature of the formulation allows the dissolution of hydrophilic, as well as hydrophobic compounds. In 2003, Turchiello et al. investigated the stability of 5-ALA and its esters in such a system and concluded that it is an adequate vehicle for the delivery of the PPIX precursor [230]. In murine skin, 5-ALA methyl esterinduced fluorescence from cubic phase gels was up to two times higher compared to an ethanolic solution and up to five times higher than after application of 5-ALA methyl ester in Unguentum M and an aqueous solution, respectively [231]. Similar to oleic acid, azone modifies the lipid structure of the stratum corneum [232]. Pre-treatment with this pyrrolidone derivative enhances the response of plantar warts to 5-ALA PDT. In patients bearing two types of plantar warts, myrmecia and mosaic warts, pre-treatment with a 3% azone formulation achieved 100% and 66.7% response, whereas the response was 37.5% and 70%, for warts without pre-treatment, respectively [233]. The commercially available 5-ALA formulation Levulan® Kerastick® is a hydrophilic alcohol mixture. PPIX fluorescence induction in porcine skin from this formulation was faster and more effective than from a hydrophilic gel containing 40% DMSO and the same 5-ALA concentration [234].
8.4.3.2
Formulations for Systemic Application
Since its introduction on the market, 5-ALA has become an established pro-drug for fluorescence guided resection and PDT of topical tumors. Current research tries to exploit this treatment/detection modality for other neoplastic (ocular applications,
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solid tumors, interstitial cancers such as mammary carcinoma, cervical cancer and prostate cancer) and non-neoplastic diseases (mycosis, oral leukoplakia, anti-bacterial therapy) as well as for cosmetic purposes (skin rejuvenation, hair removal). In some of these cases the target site is not or only difficult to access for topical administration. Therefore, parenteral formulations are needed to deliver appropriate amounts of 5-ALA or its derivatives to the site of interest. Nevertheless, intravenous formulations are rare. This can be attributed to drawbacks such as instability of free 5-ALA at physiological pH. Intravenous application necessitates high drug doses, which cause neurovisceral side effects. Free 5-ALA esters, in turn, have shown high acute toxicity in mice [235]. A way to overcome such problems is by encapsulation of the drug into nanoparticles [236]. The size of these midget delivery devices is below 1 mm [237]. They are small enough to freely circulate in the blood. They may be extravasated through the typically fenestrated neoplastic blood vessels into tumors, where they are trapped due to the enhanced permeability and retention. However, they are too big to trespass the intact epithelia, which prevents their accumulation in healthy tissue. Many organic and inorganic materials can be converted into nanosize particles. 5-ALA has previously been adsorbed onto inorganic nanoparticles made of superparamagnetic iron oxide [238] and gold [239]. However, these materials are inconvenient for intravenous application, because they are not biodegradable. In fact, only three biocompatible polymers (poly lactic acid, poly (lactic co-glycolic acid) and poly ε-caprolactone), are approved by the American Food and Drug Administration (FDA) for systemic drug delivery. Their formulation into nanoparticles involves the use of an organic solvent and an aqueous or gaseous dispersion phase. The hydrophilic to amphiphilic nature of 5-ALA and its esters make the compounds challenging candidates for nano-encapsulation, since the molecules have the tendency to stay in aqueous phase or adsorb to the surface of the particle.
8.5
Conclusions
Literature search reveals that 5-ALA mediated PDT and PD have gained considerable interest over the past 20 years, especially in the therapy of neoplastic diseases. For PDT, this may be attributed to the advantage of the drug to induce less severe side effects than traditional chemotherapeutic agents. Furthermore, the different mechanism of action, low interference with other chemotherapeutics and the possibility of repeated application in a short time, make it suitable for the combination with other therapeutic agents and therapies. PD serves as a powerful tool to visualize neoplasms. It may be carried out by the surgeon in situ during tumour resection. As alternative to long lasting procedures of tumor margin determination by biopsy, it may considerably speed up the surgical process. The use of 5-ALA for PDT and PD is particularly interesting: being an endogenous molecule itself, exogenous 5-ALA serves as prodrug for PPIX, the direct precursor of heme. PPIX, in turn, takes up the function of a photosensitizer.
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Approaches to optimize 5-ALA mediated PDT and PD involve physical and chemical methods as well as the modification of the drug carrier. The chemical derivatization into more lipophilic esters has proven to be of great value, as it could drastically increase bioavailability of the compound. Nevertheless, the use of 5-ALA and its derivatives is still limited to topical application. Therefore, the trend goes towards the development of systems, which can be administered systemically. These systems include the synthesis of 5-ALA conjugates with macromolecules, such as dendrimers, or the formulation of lipophilic 5-ALA derivatives into injectable polymeric nanoparticles. When looking at the biosynthesis of heme, the generation of PPIX is theoretically possible through another way than the conversion of 5-ALA. 5-ALA transformation follows the heme pathway in its physiological way. The other way, implies the generation of PPIX from heme and thus goes against the direction of the heme cycle. The retrieval of iron from heme was until now known to occur via cleavage of the tetrapyrrol skeleton into biliverdin by heme oxygenases or homologues. Recently, Letoffé et al. proposed two proteins in Escherichia coli, YfeX and EfeB, to retrieve iron from heme without breaking the tetrapyrrol structure. Since this mechanism rewinds the action of the enzyme FC, this newly found activity was referred to as deferrochelatase activity [240]. Taking into consideration that YfeX and EfeB are highly spread in gram negative and gram positive bacteria, alternative ways of PPIX formation, e.g. by using heme as precursor, may become of interest in future research.
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194. Casas A, Batlle A (2006) Aminolevulinic acid derivatives and liposome delivery as strategies for improving 5-aminolevulinic acid-mediated photodynamic therapy. Curr Med Chem 13:1157–1168 195. Di Venosa G, Hermida L, Fukuda H, Defain MV, Rodriguez L, Mamone L, MacRobert A, Casas A, Batlle A (2009) Comparation of liposomal formulations of ALA Undecanoyl ester for its use in photodynamic therapy. J Photochem Photobiol B 96:152–158 196. Han I, Jun MS, Kim SK, Kim M, Kim JC (2005) Expression pattern and intensity of protoporphyrin IX induced by liposomal 5-aminolevulinic acid in rat pilosebaceous unit throughout hair cycle. Arch Dermatol Res 297:210–217 197. Al Kassas R, Donnelly RF, McCarron PA (2009) Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy. J Pharm Pharmacol 61:1125–1135 198. Donnelly RF, McCarron PA, Al Kassas R, Juzeniene A, Juzenas P, Iani V, Woolfson AD, Moan J (2009) Influence of formulation factors on PpIX production and photodynamic action of novel ALA-loaded microparticles. Biopharm Drug Dispos 30:55–70 199. Bourre L, Thibaut S, Briffaud A, Lajat Y, Patrice T (2002) Potential efficacy of a delta 5-aminolevulinic acid thermosetting gel formulation for use in photodynamic therapy of lesions of the gastrointestinal tract. Pharmacol Res 45:159–165 200. Gruning N, Muller-Goymann CC (2008) Physicochemical characterisation of a novel thermogelling formulation for percutaneous penetration of 5-aminolevulinic acid. J Pharm Sci 97:2311–2323 201. McCarron PA, Donnelly RF, Zawislak A, Woolfson AD, Price JH, McClelland R (2005) Evaluation of a water-soluble bioadhesive patch for photodynamic therapy of vulval lesions. Int J Pharm 293:11–23 202. McCarron PA, Donnelly RF, Andrews GP, Woolfson AD (2005) Stability of 5-aminolevulinic acid in novel non-aqueous gel and patch-type systems intended for topical application. J Pharm Sci 94:1756–1771 203. McCarron PA, Donnelly RF, Zawislak A, Woolfson AD (2006) Design and evaluation of a water-soluble bioadhesive patch formulation for cutaneous delivery of 5-aminolevulinic acid to superficial neoplastic lesions. Eur J Pharm Sci 27:268–279 204. Zawislak A, Donnelly RF, McCluggage WG, Price JH, McClelland HR, Woolfson AD, Dobbs S, Maxwell P, McCarron PA (2009) Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patchtype system loaded with 5-aminolevulinic acid. Photodiagnosis Photodyn Ther 6:28–40 205. Donnelly RF, Ma LW, Juzenas P, Iani V, McCarron PA, Woolfson AD, Moan J (2006) Topical bioadhesive patch systems enhance selectivity of protoporphyrin IX accumulation. Photochem Photobiol 82:670–675 206. Lee G, Szeimies RM (2005) Dermal for aminolaevulinic acid. 10/332547[PCT/EP01/08131]. United states. 13-7-2001. Ref Type: Patent 207. Public Assessment Report, Decentralised Procedure, Alacare 8 mg Medicated Plaster. UK/H/1533/001/DC. 2009. Medicines and Healthcare Products Regulatory Agency. Ref Type: Report 208. Hauschild A, Stockfleth E, Popp G, Borrosch F, Bruning H, Dominicus R, Mensing H, Reinhold U, Reich K, Moor ACE, Stocker M, Ortland C, Brunnert M, Szeimies RM (2009) Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies. Br J Dermatol 160:1066–1074 209. Szeimies RM, Stockfleth E, Popp G, Borrosch F, Bruning H, Dominicus R, Mensing H, Reinhold U, Reich K, Moor ACE, Stocker M, Ortland C, Brunnert M, Hauschild A (2010) Long-term follow-up of photodynamic therapy with a self-adhesive 5-aminolaevulinic acid patch: 12 months data. Br J Dermatol 162:410–414 210. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, Langmack K, McKenna K, Moseley H, Pearse AD, Stringer M, Taylor DK, Wong G, Rhodes LE (2002) Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 146:552–567
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211. Walker RB, Smith EW (1996) The role of percutaneous penetration enhancers. Adv Drug Deliv Rev 18:295–301 212. Conder LH, Woodard SI, Dailey HA (1991) Multiple mechanisms for the regulation of hemesynthesis during erythroid cell-differentiation – possible role for coproporphyrinogen oxidase. Biochem J 275:321–326 213. Chang SC, McRobert AJ, Porter JB, Bown SG (1997) The efficacy of an iron chelator (CP94) in increasing cellular protoporphyrin IX following intravesical 5-aminolaevulinic acid administration: an in vivo study. J Photochem Photobiol B 38:114–122 214. Juzeniene A, Juzenas P, Iani V, Moan J (2007) Topical applications of iron chelators in photosensitization. Photochem Photobiol Sci 6:1268–1274 215. Curnow A, McIlroy BW, Postle-Hacon MJ, Porter JB, MacRobert AJ, Bown SG (1998) Enhancement of 5-aminolaevulinic acid-induced photodynamic therapy in normal rat colon using hydroxypyridinone iron-chelating agents. Br J Cancer 78:1278–1282 216. Bech O, Phillips D, Moan J, McRobert AJ (1997) A hydroxypyridinone (CP94) enhances protoporphyrin IX formation in 5-aminolaevulinic acid treated cells. J Photochem Photobiol B 41:136–144 217. Pye A, Campbell S, Curnow A (2008) Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical doseescalating safety study for the treatment of nodular basal cell carcinoma. J Cancer Res Clin 134:841–849 218. Hanania J, Malik Z (1992) The effect of EDTA and serum on endogenous porphyrin accumulation and photodynamic sensitization of human K562 leukemic-cells. Cancer Lett 65:127–131 219. Harth Y, Hirshowitz B, Kaplan B (1998) Modified topical photodynamic therapy of superficial skin tumors, utilizing aminolevulinic acid, penetration enhancers, red light, and hyperthermia. Dermatol Surg 24:723–726 220. Miller MJ (1989) Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogues. Chem Rev 89:1563–1579 221. Malik Z, Kostenich G, Roitman L, Ehrenberg B, Orenstein A (1995) Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice. J Photochem Photobiol B 28:213–218 222. Peng Q, Warloe T, Moan J, Heyerdahl H, Steen HB, Nesland JM, Giercksky KE (1995) Distribution of 5-aminolevulinic acid-induced porphyrins in noduloulcerative basal cell carcinoma. Photochem Photobiol 62:906–913 223. De Rosa FS, Marchetti JM, Thomazini JA, Tedesco AC, Bentley MV (2000) A vehicle for photodynamic therapy of skin cancer: influence of dimethylsulphoxide on 5-aminolevulinic acid in vitro cutaneous permeation and in vivo protoporphyrin IX accumulation determined by confocal microscopy. J Control Release 65:359–366 224. Copovi A, Diez-Sales O, Herraez-Dominguez JV, Herraez-Dominguez M (2006) Enhancing effect of alpha-hydroxyacids on “in vitro” permeation across the human skin of compounds with different lipophilicity. Int J Pharm 314:31–36 225. Kraeling MEK, Bronaugh RL (1997) In vitro percutaneous absorption of alpha hydroxy acids in human skin. J Soc Cosmet Chem 48:187–197 226. Ziolkowski P, Osiecka BJ, Oremeck G, Siewinski M, Symonowicz K, Saleh Y, Bronowicz A (2004) Enhancement of photodynamic therapy by use of aminolevulinic acid/glycolic acid drug mixture. J Exp Ther Oncol 4:121–129 227. Moser K, Kriwet K, Naik A, Kalia YN, Guy RH (2001) Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm 52:103–112 228. Pierre MBR, Ricci E, Tedesco AC, Bentley MVLB (2006) Oleic acid as optimizer of the skin delivery of 5-aminolevulinic acid in photodynamic therapy. Pharm Res §23:360–366 229. Steluti R, De Rosa FS, Collett J, Tedesco AC, Bentley MVLB (2005) Topical glycerol monooleate/propylene glycol formulations enhance 5-aminolevulinic acid in vitro skin delivery and in vivo protophorphyrin IX accumulation in hairless mouse skin. Eur J Pharm Biopharm 60:439–444
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230. Turchiello RF, Vena FC, Maillard P, Souza CS, Bentley MV, Tedesco AC (2003) Cubic phase gel as a drug delivery system for topical application of 5-ALA, its ester derivatives and m-THPC in photodynamic therapy (PDT). J Photochem Photobiol B 70:1–6 231. Bender J, Ericson MB, Merclin N, Iani V, Rosen A, Engstrom S, Moan J (2005) Lipid cubic phases for improved topical drug delivery in photodynamic therapy. J Control Release 106:350–360 232. Hadgraft J, Peck J, Williams DG, Pugh WJ, Allan G (1996) Mechanisms of action of skin penetration enhancers retarders: azone and analogues. Int J Pharm 141:17–25 233. Ziolkowski P, Osiecka BJ, Siewinski M, Bronowicz A, Ziolkowska J, Gerber-Leszczyszyn H (2006) Pretreatment of plantar warts with azone enhances the effect of 5-aminolevulinic acid photodynamic therapy. J Environ Pathol Toxicol 25:403–409 234. Maisch T, Worlicek C, Babilas P, Landthaler M, Szeimies RM (2008) A HCl/alcohol formulation increased 5-aminolevulinic acid skin distribution using an ex vivo full thickness porcine skin model. Exp Dermatol 17:813–820 235. Perotti C, Casas A, Fukuda H, Sacca P, Batlle AM (2002) ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice. Br J Cancer 87:790–795 236. Konan YN, Gurny R, Allemann E (2002) State of the art in the delivery of photosensitizers for photodynamic therapy. J Photochem Photobiol B 66:89–106 237. Allemann E, Gurny R, Doelker E (1993) Drug-loaded nanoparticles – preparation methods and drug targeting issues. Eur J Pharm Biopharm 39:173–191 238. Park SI, Lim JH, Kim JH, Yun HI, Kim CO (2005) In vivo and in vitro investigation of photosensitizer-adsorbed superparamagnetic nanoparticles for photodynamic therapy. IEEE Trans Magn 41:4111–4113 239. Oo MKK, Yang X, Du H, Wang H (2008) 5-aminolevulinic acid-conjugated gold nanoparticles for photodynamic therapy of cancer. Nanomedicine 3:777–786 240. Letoffe S, Heuck G, Delepelaire P, Lange N, Wandersman C (2009) Bacteria capture iron from heme by keeping tetrapyrrol skeleton intact. PNAS 106:11719–11724
Chapter 9
Photocatalytic Degradation of Pollutants with Emphasis on Phthalocyanines and Related Complexes Alexander B. Sorokin
Abstract Safe disposal of different harmful substances considered as pollutants is a key problem in the environmental context. Principal approaches for decontamination are briefly overviewed. The main focus is then placed on different photochemical methods used for degradation of pollutants. Application of phthalocyanine complexes for degradation of chlorinated phenols, dyes, etc. is discussed in more details. Three principal approaches involving these readily accessible catalysts are formulated: (i) chemical systems including a catalyst and an oxidant; (ii) photochemical systems based on photosensitizers absorbing UV and visible light for generation of reducing and oxidizing sites which react directly with molecules of pollutants and with molecular oxygen to form strong oxidants like hydroxyl radical; (iii) combined photo-assisted oxidation processes when external oxidant like hydrogen peroxide and light are used together to boost the oxidative degradation. Mechanistic aspects of different approaches are discussed to illustrate the essential features of different processes to provide some background for the choice of optimal system for new developments.
9.1
Introduction
There is an increasing demand for more sustainable chemical and technological processes for production of chemicals avoiding the formation of undesirable toxic wastes. This approach, now widely known as “green chemistry”, has been becoming
A.B. Sorokin (*) Institut de Recherches sur la Catalyse et l’Environnement de Lyon – IRCELYON, UMR 5256, Université Lyon 1, 2, Avenue Albert Einstein, 69626 Villeurbanne Cedex, France e-mail: [email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_9, © Springer Science+Business Media B.V. 2012
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the major driving force for research and industry in moving to the clean and environmentally friendly production. However, the zero-waste level is not yet reached and many important processes contributing for the current standards of living inevitably produce by-products which are often considered as pollutants. A pollutant is a waste material that pollutes air, water or soil. Principal pollutant types are phenols and halogenated phenols, surfactants, herbicides, pesticides, dyes, etc. The contamination of environment results not only from industrial, but also from urban and agricultural activities. It is often challenging to completely eliminate the contamination because many of pollutants are recalcitrant to conventional wastewater treatment methods. In particular, contamination of the environment by chlorinated aromatic compounds is a severe problem, despite their useful applications as biocides, lubricants and solvents. Accumulation of chloroaromatics in the environment is a result of their slow bio-transformation to less toxic and more biodegradable compounds. Currently about 80 dyes can be found in process wastes from textile industry. All these compounds should be destroyed and removed from environment. Several approaches can be used for environment remediation. Photocatalytic approach is among the most promising advanced oxidation technologies for depollution as can be seen from numerous excellent reviews [1–4]. Although a great attention has been devoted to photocatalytic applications of TiO2 for degradation of different types of organic pollutants, there is a considerable interest in developing novel catalysts with improved activity. In this chapter we give a brief overview of different existing methods used for degradation of pollutants. The main focus will be on the different photochemical approaches. Application of phthalocyanine complexes for chemical and photochemical depollution including mechanistic issues will be discussed in details. Following principal approaches used for remediation can be listed: 1. Biological degradation of pollutants Many microorganisms are able to grow using different chemicals as sources of carbon. This natural and green method for remediation is largely used although it is often difficult to achieve a complete detoxification. For instance, the treatment of persistent chlorinated organic compounds, especially in high concentration, is problematic. 2. Incineration Incineration is a widely used technique for the destruction of concentrated pollutants which, however is energy consuming. Despite the very high temperatures developed in incineration (>800°C), the emission of highly toxic dioxins, polychlorinated dioxins and furans can occur. Insufficient temperatures and dioxygen amounts favour the formation of these dangerous pollutants. Although incineration is still considered as the principal depollution method, some critical recent reports are available [5]. 3. Supercritical water oxidation (SCWO) Supercritical water is a unique medium where O2 and organics have a high solubility. Free radical mechanisms operating in SCWO provide quasi-complete
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oxidation of most organic molecules. In the case of recalcitrant pollutants catalysts can be added to boost SCWO systems. Although this method requires high temperatures (400–500°C) and high pressures (240–300 atm) and suffers from severe corrosion problems, several pilot scale SCWO systems are operating [6]. Wet air oxidation (WAO) To decrease energy consumption the process can be performed at temperatures and pressures lower than the critical temperature and pressure of water. WAO process is typically performed at 200°C and 100 bars with longer residence time in the reactor. The use of catalysts is especially useful in this case [7]. Photochemical treatment of wastes Several approaches discussed in details below have been developed. Several excellent and comprehensive reviews on the different photochemical methods are available [1–3]. Chemical and electrochemical reductions Along with electrochemical systems a number of reductants and catalysts have been proposed to perform mainly hydrodehalogenation of chlorinated compounds. Scope and limitations of this approach were discussed [5]. Fenton-like oxidation These processes based on the generation of hydroxyl radicals are probably mostly applied for the treatment of industrial streams [8, 9]. This approach will be discussed in more details in the section devoted to photo-Fenton chemistry.
Obviously, a high efficiency of pollutant destruction is the main objective of all these processes. However, some other considerations should also be taken into account. No toxic or hazardous products should be released to the environment after the treatment. All reagents used in the process should be environmentally friendly, cheap and available in the large scale. Technologies operating at ambient pressure and temperatures are preferred since in this case there is no need for heavy equipment and high energy consumption. The use of sun light is especially attractive because of evident reasons. Three principal photocatalytic approaches can be formulated as: 1. Heterogeneous photocatalysis using semiconductor materials 2. Photo-Fenton processes 3. Photosensitized transformations Photochemical approach can also be used for the synthetic purposes as an alternative green route [10, 11]. While applications of semiconductors, especially TiO2, and photo-Fenton systems for abatement of harmful pollutants have widely been summarized in numerous reviews [1–3, 12], to the best of our knowledge, the use of phthalocyanine and related complexes for different depollution processes have never been reviewed.
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9.2.1
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Heterogeneous Photocatalysis Using Semiconductor Materials Titanium Oxide Based Photocatalysis
Upon illumination of a semiconductor with photons whose energy is equal to or higher than an energy of the band gap, the formation of the bulk electron – hole pairs occurs after absorption of photons. An injection of electrons in the conduction band while holes are situated in valence band leads to the separation of charges (Fig. 9.1). Electrons and holes can react with molecules absorbed on the surface provided that their redox potentials are sufficient for the reactions could take place. Acceptor molecules, typically O2, are reduced by electrons from conduction band. In turn, positively charged holes, which can be considered as strong oxidants, oxidize donor molecules:
(
hv + semiconductor → semiconductor e − + P +
)
A ads + e − → A ads − Dads + P + → Dads + These fundamental reactions are the initial steps of photochemical activation of the whole catalytic process. The photocatalytic efficiency can be reduced by electron-hole recombination. To limit this phenomenon the rate of interfacial electron transfer should be high. A variety of semiconductor materials have been evaluated as photocatalysts: TiO2, ZnO, WO3, CeO2, Fe2O3, NiO, CdS, ZnS, etc. Most of the UV-irradiation λ<400 nm Electron Energy
Conduction Band
e–
Adsorption (O2) Reduction (O2–)
Recombinaison of charges
POLLUTANT P Oxidation (P°+)
3.2 eV h+
E
Valence Band Semiconductor (TiO2)
Oxidation (H+ +OH°) Adsorption (H2O) Adsorption (POLLUTANT P)
D E G R A D A T I O N
Fig. 9.1 Energy band diagram and chemical reactions related to the oxidation of pollutants initiated by electrons and holes (Reproduced from Ref. [12] with kind permission of Springer Science and Business Media, Inc.)
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studies have focused on TiO2 which exhibits a high long-term stability and reactivity. Anatase is the most active titania allotropic form which needs illumination with light wavelength less than 387 nm exceeding the band gap of 3.2 eV for photoactivation. Among semiconductors, TiO2 provides the best photocatalytic efficiencies and highest quantum yields. In addition, TiO2 is cheap, non-toxic, chemically and photochemically stable. The most frequently used material is non-porous Degussa TiO2 P-25 consisting of 70:30 anatase/rutile mixture with a specific surface of ~50 m2/g. In laboratory, different lamps can be used as source of UV/ visible light. Several types of photoreactors have been built for large scale applications [2, 12]. A solar photoreactor was constructed at Plataforma Solar de Almeria (PSA) in Spain [2]. Interestingly, a typical solar UV flux of 20–30 W/m2 corresponds to 0.2–0.3 mol photons/m2 h in the 300–400 nm region [2]. Photocatalytic systems do not require heating and can operate at room temperature. The fundamentals, the scope of applications and limitations of photocatalytic processes involving TiO2 are presented in details in the recent comprehensive reviews [1, 2, 12]. A large variety of organic pollutants can be degraded to remove their toxicity and persistence. The main objective is to mineralize organic compounds by converting them to CO2 and inorganic compounds (Cl−, NO3−, NH4+, etc). The absence of total mineralization has been observed only for s-triazine herbicides. In this case the final product was non-toxic cyanuric acid [2]. Chlorinated pollutants undergo dechlorination relatively readily and treated wastes become more amenable to the biological treatment. The formation of inorganic anions like Cl−, SO4−, PO4− in significant concentrations (>1 mM) can reduce the degradation rate owing to the competitive adsorption at the surface of the photocatalyst [2]. Decontamination of industrial effluents is probably one of the most promising fields of application of solar TiO2 photocatalysis. Special attention has been devoted to “emerging pollutants”: pharmaceuticals, antibiotics, analgesics, steroids, hormones, cyanotoxins, methyl tert-butyl ether and products of their transformation [2]. These unregulated compounds may be under future regulation depending on the their toxicological and occurrence data. However, each particular problem should be treated on a case-by-case basis in terms of catalytic setup, reaction conditions and analytical approaches. A review on the photocatalytic degradation of organic dyes in the presence of TiO2 is available [13]. The important limitation in TiO2 photocatalytic applications is the recombination of electrons and holes leading to waste of energy and limiting a quantum yield. When dissolved molecular oxygen serves as the only electron acceptor generating O2−· species, efficiency of mineralization is often low. A useful strategy to decrease the rate of electron-hole recombination is to add to the reaction mixture an electron acceptor. Hydrogen peroxide is particularly suitable for this purpose due to the generation of hydroxyl radicals not only via reaction with photoelectrons but also in several other reactions. Higher concentration of these powerful oxidizing species results in improved photodegradation efficiency. A recommended H2O2/pollutant molar ratio should not exceed 10–100 to avoid inhibition of degradation owing to H2O2 absorption and detrimental reactions [2]. Peroxodisulfate, peroxymonosulfate and ozone are even more efficient oxidative additives than H2O2 in the TiO2 photodegradation of pentachlorophenol [14].
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Doped TiO2 Materials
Another strategy for development of semiconductor photocatalysts is directed to lower the band gap and to shift its optical response to the visible region by doping TiO2. Several approaches have been proposed: (i) doping transition metals to TiO2, (ii) doping anionic species, and (iii) preparation of TiOx reduced photocatalysts. Deposition of Ag, Pt, Ni, Cu, Rh and Pd onto TiO2 surface was claimed to enhance the photocatalytic properties due to more efficient charge separation. Since the Fermi levels of the metals are lower than the level of conduction band of TiO2 photo-excited electrons can be transferred from conduction band to deposited metal particles that reduces the rate of electron-hole recombination [2]. Doping to TiO2 surface with appropriate amounts of Fe, Rh, Mo, V, Ru, Os, and rare earth metal ions can also improve a photocatalytic activity [4]. However, since metal ions can also be a recombination centres this approach should be applied with caution. Incorporation of boron atoms in TiO2 extended the spectral response to the visible region (l = 532 nm), but photocatalytic activity was still limited. The further modification of the material with Ni2O3 facilitated the excited electron transfer and suppressed the recombination of photo-produced electron – hole pair [15]. A generation of OH· radicals was evidenced using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) spin trap. A reduction of 70% of total organic carbon (TOC) and 80% conversion of total chloride content into Cl− was achieved after 4 h illumination of 2,4,6-trichlorophenol (TCP) solution. Nitrogen-doped TiO2 showed increased activity using visible light with l < 500 nm in photodegradation of methylene blue and acetaldehyde [16]. Another approach is to combine two semiconductors. Conduction band electrons can be injected from the small band gap semiconductor to the large band gap semiconductor (e.g. TiO2) to create an efficient separation of charges. Similarly, the excitation of dye photosensitizers by visible light can lead to injection of electrons to the conduction band of semiconductor thus initiating photochemical processes. The latter approach will be discussed in more details below. The state of the art, perspectives and limitations of doped TiO2 materials have been considered in the recent comprehensive review by Malato et al. [2].
9.3
Fenton and Photo-Fenton Chemistry
Fenton chemistry is associated with generation of OH· radicals from H2O2 in the presence of Fe2+ salts: Fe 2 + + H 2 O2 → Fe 3+ + OH − + OH •
k = 53 − 76M −1 s−1
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Fe2+ is further regenerated in acidic conditions (pH 2.7–2.8) making this process catalytic [17]: Fe 3 + + H 2 O2 FeOOH 2 + + H + FeOOH 2 + → HO•2 + Fe 2 + Fe3 + + HO•2 → Fe 2 + + O2 + H +
k = 3.1 × 10 −3 k = 1 − 2 × 10 −2 M −1s −1 k = 0.33 − 2.1 × 106 M −1s −1
Rate and equilibrium constants of many reactions involved in Fenton chemistry have been published [18]. Hydroxy radical is extremely reactive species reacting with organic compounds by abstraction of hydrogen atom with high reaction constants (106–109 M−1 s−1), by electrophilic addition to double bonds and aromatic rings or by electron transfer: OH• + RH → R • + H 2 O R • + O2 → RO•2 → further oxidation RCH = CH 2 + OH • → RCH • CH 2 OH OH • + RX → RX • + + OH − Thus formed organic radicals react with molecular oxygen to form peroxy radicals which initiate radical chain reactions of oxidative degradation resulting in the formation of CO2, H2O and inorganic salts. The initial step of the oxidation of aromatic compounds is usually addition of hydroxyl radicals leading to phenol, hydroquinone and quinone intermediate products before the cleavage of the aromatic cycle. Hydroquinones can regenerate Fe2+ ions by reduction of Fe3+ ions. Fe2+ ions can be regenerated more rapidly according to the following reactions: Fe3 + + HO•2 → Fe 2 + + O2 + H + Fe 3 + + R • → Fe 2 + + R + Fe 3 + + O•2− → Fe 2 + + O 2
k = 0.33 − 2.1 × 106 M −1s −1 k = 0.05 − 1.9 × 10 9 M −1s −1
However, several reactions consuming OH· are detrimental for oxidation activity [19]: Fe 2 + + OH• → Fe3 + + HO − H 2 O2 + OH • → HO•2 + H 2 O HO•2 + OH • → H 2 O + O2 OH • + OH • → H 2 O 2
k = 3.2 × 108 M −1s−1 k = 2.7 × 107 M −1s −1 k = 5.2 × 10 9 M −1s −1
Complex reaction kinetics of the Fenton system including about 30 reactions of chain initiation, propagation and termination strongly depends on the reaction conditions [2, 18]. The most important of them are pH, temperature, concentrations of Fe salt, H2O2, O2 and substrate(s).
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The Fenton system exhibits a very large substrate scope including refractory contaminants. Since iron is very abundant non-toxic metal and H2O2 is clean, available in a large scale at low price and easy-to-handle oxidant, this system is very suitable for the treatment of wastewaters. Other advantages of the Fenton process are simple and flexible operations which can be easily implemented in plants and no energy need. The drawbacks of this approach are the cost of H2O2 and safety problems related to its transportation and storage. Large amounts of acids and bases should be used for adjusting effluents to pH 2.0–4.0 and for neutralizing treated solutions before disposal. Significant loss of the generated active species occurs before the reacting with pollutants molecules. This situation occurs during the treatment of wastes with low pollutants concentrations. The formation of iron complexes with carboxylic acids formed during treatment often prevents a complete mineralization [18]. Inorganic ions formed in the process can strongly influence the efficiency of the oxidation. The formation of phosphate ions results in the precipitation of iron and in quenching of hydroxyl radical. Sulphate and halogen anions form iron complexes thus changing the catalytic activity and leading to less reactive radicals. To avoid the loss of homogeneous iron catalyst and to facilitate regeneration of the catalyst after the process heterogeneous Fe-based catalysts can be used. The efficiency of oxidative degradation depends on the rate of the generation of radical intermediates and on the concentration of dissolved O2. The former can be improved in electro-Fenton process [18], photo-Fenton method (UV light) and solar photo-Fenton method (sunlight) [6, 7]. Accumulated during Fenton process [Fe(OH)]2+ species plays a key role under UV irradiation [20] regenerating Fe2+ and producing OH·: hv [Fe(OH)]2 + ⎯⎯ → Fe 2 + + OH •
The quantum efficiency of this reaction increases with decrease of UV wavelength being of 0.14–0.19 at l = 313 nm [18]. UV irradiation induces the photodegradation of some oxidation products and their terminal Fe3+ carboxylate complexes to form catalytic Fe2+ ions: hv Fe(RCO2 )2 + ⎯⎯ → Fe 2 + + CO2 + R •
The influence of the different reaction parameters such as pH; temperature; iron concentration and iron source; irradiation wavelength, light penetration and irradiation intensity; substrate concentrations and chemical characteristics; salinity; oxidant concentration as well as engineering aspects relevant to photo-Fenton processes have been discussed by Malato et al. in great details [2]. Photo-Fenton type processes have been applied for degradation of pesticides [21], chlorophenols [22], natural phenolic contaminants (vanillin, protocatechuic acid, syringic acid, p-coumaric acid, gallic acid, L-tyrosine) [23], pharmaceuticals and dyes [19]. However, some compounds are refractory to Fenton process, for example acetic acid, oxalic acid, maleic acid, malonic acid, acetone, CCl4, CH2Cl2, trichloroethane, n-paraffins, etc [19, 24]. Nevertheless, Fenton and photo-Fenton methods have been shown as feasible technologies for the large-scale treatment of a wide diversity of industrial wastewaters [19].
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Phthalocyanines as Photosensitizers
Chlorophylls are the most important photosensitizers in Nature playing a key role in the fundamental for life photosynthesis processes. Obviously, porphyrin-like compounds have widely been employed in photochemical studies and applications [4], including remediation methods [25–31]. On the other hand, porphyrin complexes often constitute active sites of enzymes responsible for biodegradation of pollutants. Inspired by the ability of heme containing enzymes (ligninases, cytochromes P-450, etc.) to perform degradation of aromatic and chloroaromatic compounds chemists have been developing bio-inspired chemical model systems capable of oxidizing these recalcitrant pollutants under mild conditions. Accessibility of the catalysts in terms of their price and availability at a large scale plays an important role for economical viability of the processes. In this context, available and cheap phthalocyanine metal complexes (MPc) are more attractive than porphyrin complexes. Three principal approaches involving porphyrin-like macrocyclic complexes can be formulated. 1. Purely chemical systems including a catalyst and an oxidant. For evident reason, the oxidant should be cheap, available and clean. The best option is to use dioxygen, but application of hydrogen peroxide is also possible. 2. Photochemical systems based on photosensitizers absorbing UV and visible light for generation of reducing and oxidizing sites which reacts directly with molecules of pollutants and with O2 to form strong oxidizing species, like O2·−, OH·. 3. Both approaches can be combined in photo-assisted oxidation processes when external oxidant like H2O2 and light are used together to boost the oxidative degradation. Reaction mechanisms and active species involved in chemical, photochemical and photo-assisted chemical processes are often different. The most important features of these approaches and mechanistic aspects will be considered below.
9.4.1
Phthalocyanines in Combination with Chemical Oxidants
Chlorinated phenols are extremely persistent in the environment because of their slow degradation by reductive or oxidative enzymatic pathways. 2,4,6-trichlorophenol (TCP) is a benchmark for research on the degradation of recalcitrant pollutants. Meunier et al. used water-soluble Fe and Mn sulfonated porphyrins in combination with H2O2 or KHSO5 for the oxidation of TCP to corresponding quinone [25]. These porphyrin catalysts were especially active with KHSO5 (0.1–0.3 mol% loading, turnover frequency (TOF) = 10–20 s−1). However, a low catalytic activity with cleaner and more available H2O2 oxidant, the cost of porphyrins and the lack of deep oxidation of pollutants are the limits of this system. In the search for accessible, cheap and efficient catalysts able to use H2O2, the clean oxidant producing only water as co-product during oxidation, we turned to
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Fig. 9.2 Schematic representation of the key steps of the degradation of TCP
OH Cl
Cl
_
_
Cl
Cl Cl
dechlorination to inorganic Cl – cleavage of the aromatic cycle
Cl H Cl
Cl
COOH
Cl
O
Cl
O
Cl
Cl OH
Cl
Cl
Cl
O
HO
O
Cl Cl
Cl
Cl
O
Cl
Cl
Cl
O
O
OH
Fig. 9.3 Identified coupling products formed in the course of the oxidation of TCP by FePcS – H2O2 system
phthalocyanine complexes which are large scale industrial products. The important requirements for degradation of chlorinated aromatics are to cleave aromatic cycle and to transform organic chlorine substituents into inorganic Cl− without formation of more dangerous products like chlorinated dibenzodioxins and dibenzofurans (Fig. 9.2). In the middle of 1990s we have tested different phthalocyanine complexes in combination with H2O2 or KHSO5 for oxidation of TCP. Iron 2,9(10),16(17),23(24)tetrasulfophthalocyanine (FePcS) was especially active in the catalytic oxidation of TCP by H2O2 [26–29]. Using only 5 equiv of H2O2 with respect to substrate in pH 7 buffered water/MeCN mixture (3/1, v/v), TCP was quantitatively converted at room temperature within several minutes. 2,6-Dichloro-1,4-benzoquinone (DCQ), the initial oxidation product was detected only in the beginning of the reaction. The transient formation of DCQ and the release of two Cl− ions per consumed TCP molecule implied the desired deep degradation of TCP. The final products identified and quantified by GC-MS analyses fell in two categories [27]: 1. five products corresponding to aromatic ring cleavage 2. four products resulting from oxidative coupling of TCP (Fig. 9.3). The total yield of identified products achieved 70% after 60 min reaction at 25°C. Chloromaleic acid was the principal TCP cleavage product with 24% yield.
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Photocatalytic Degradation of Pollutants with Emphasis on Phthalocyanines… CO + CO2
14 %
H
OH Cl
Cl
Cl
HOOC
COOH
COOH
H
HOOC
H
COOH
H
+
13 %
H
+
+
69 %
HOOC
Cl
HOOC
H Cl
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HOOC COOH
COOH
Dimeric coupling products
Fig. 9.4 Product distribution of TCP oxidation by H2O2 catalyzed by FePcS Table 9.1 Release of Cl− in the oxidation of 2,4,6-trichlorophenol or pentachlorophenol in the presence of 0.37 mM FePcS and 50 mM H2O2. Reaction time – 1 h Run H2O2 as oxidant 1 2 3 4 KHSO5 as oxidant 5 6
[Substrate], mM
Cl−/converted TCP
Cl−/converted PCP
2.5 5.0 7.5 10
2.12 1.96 1.73 1.74
1.43 0.97 0.59 0.34
5.0 10
1.06 0.20
Other C4 diacids, such as chlorofumaric, maleic and fumaric acids were formed in minor amounts. Oxalic acid was also obtained as expected partner for C4-acids as signature of the oxidative TCP ring cleavage. Coupling products identified by GC-MS were formed via the radical coupling of the intermediates generated in the course of TCP oxidation. The product distribution profiles were dependent on the initial concentration of TCP and on the substrate/catalyst ratio. The complete analysis of the reaction products was performed using completely 14 C labelled radioactive substrate (U-14C)-TCP [28]. After 90 min reaction at room temperature 11% and 3% of the initial radioactivity was recovered as CO2 and CO. Water soluble acid products of deep degradation of aromatic ring accounted for 69%. Only 13% of the TCP radioactivity was recovered as hydrophobic organic products resulting from oxidative coupling reactions, suggesting that these dimers also underwent oxidative destruction. The study with radiolabeled TCP gave a complete overview of the oxidative degradation of TCP (Fig. 9.4) [28]. Determination of the amount of Cl− formed also indicated the efficient degradation of TCP. About 2 Cl− per TCP molecule were released (Table 9.1). When KHSO5 was used as the oxidant, dechlorination of TCP was less efficient: only 1 Cl− per TCP molecule. Pentachlorophenol (PCP), another highly recalcitrant substrate to
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aerobic biodegradation was rapidly converted within 5 min with 1 mol% catalyst (96% conversion). Dechlorination of PCP ranged from 0.34 to 1.43 Cl− per PCP depending on initial PCP concentration [27]. This lower level of dechlorination in PCP oxidation was mainly due to the presence of dimeric coupling products which can be easily recovered by filtration due to the low solubility. Dichloromaleic anhydride was the only identified product resulting from the oxidative cleavage of PCP. Importantly, that chlorodibenzodioxins and chlorodibenzofurans were not detected in the oxidations of PCP and TCP. Peroxidasemediated formation of these harmful pollutants has been published for TCP biological oxidations. The mechanism of TCP oxidation by FePcS – H2O2 was thoroughly investigated using kinetic studies, identification and analysis of intermediate and final products, 18 O labelling data [27, 29]. To examine a possible involvement of OH· radicals the oxidation was carried out in the presence of EtOH, which is a better trap for OH·· than MeCN. The oxidation of TCP in the presence of 25 vol.% EtOH was even slightly more efficient indicating that OH· was not the key active species in this catalytic oxidation of TCP. The catalytic performance of the system was the same under inert atmosphere and in the presence of air [27]. The absence of the influence of O2 and OH· traps on TCP oxidation indicates alternative oxidative pathways, other than auto oxidation or oxidation involving hydroxyl radicals. Labeling experiments using 18O2 and H218O showed that oxygen atom sources in diacids derived from TCP ring cleavage were, in decreasing order, H2O2, H2O and O2. Iron-centered active species generated from FePcS and H2O2 were proposed to be responsible for this remarkable reactivity [27, 29]. In aqueous solution FePcS exists mainly in the m-oxo dimeric form. Coordination of dissociating solvent or strong anionic ligand like TCP phenolate (pK 6.2) favours a cleavage of m-oxo dimer to monomer (Scheme 9.1) which in the presence of H2O2 forms a hydroperoxo complexes (L) PcSFeIII–OOH [27]:
FeIII
FeIII
O FeIII
TCP-
FeIII
+
OH
H2O2
OOH FeIII
OOH
+
FeIII
TCP-
TCPScheme 9.1 Initial step of the process: formation of hydroperoxo complexes
Remarkable catalytic properties of FePcS – H2O2 system in deep degradation of chlorinated phenols can be explained by the presence of several types of iron based active species [27–29]. The degradation of TCP includes several reaction steps: different oxidations, dechlorination, cleavage of the aromatic cycle, formation of CO and CO2. It is reasonable to propose that in order to perform all these different reactions several active species should be involved. In addition to hydroperoxo complexes with nucleophilic properties, powerful oxidizing species should also be formed.
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Iron(III) hydroperoxo complexes can undergo a homolytic or heterolytic cleavage of the peroxide O–O bond to form LFeIV=O or L+·FeIV=O strong oxidants, respectively [27]. The heterolytic cleavage of O–O bond with OH− release should be facilitated in the hydroperoxo complex having TCP− ligand (Scheme 9.2):
_ OH O
O
FeIII
FeIV . +
O Cl
Cl Cl
intramolecular 1e oxidation
Cl
Cl
+
O Cl
coupling products
Cl
Cl
.
+
Cl
Cl
O
O TCP
OH FeIII
+ H+
O Cl
Cl
intramolecular 1e oxidation
FeIV
O
- OH-
O
Cl
Cl
Cl
Cl
. Cl
DCQ O
Scheme 9.2 Formation of the putative iron oxo complex leading to intra-molecular oxidation of TCP
Iron oxo complex having two redox equivalents above Fe(III) state, formally PcSFeV=O which can be in (PcS+·)FeIV=O form, should be a very strong oxidant. The first step is the oxidation of TCP to DCQ. Intramolecular 1e− oxidation of coordinated TCP− gives rise to TCP cation radical. After dissociation this TCP radical can be further oxidized to DCQ or to react with an excess of TCP to afford coupling products. Their formation should be more pronounced at higher TCP concentration in solution that was confirmed in the experiments. The second intramolecular 1e− oxidation leads to the cationic TCP which is dechlorinated and oxidized to DCQ in further steps. Thus, FePcS is regenerated for the next catalytic cycle. In turn, PcSFeIV=O formed after the first intramolecular 1e− transfer can also participate in the different oxidation steps. DCQ formation results from the 1e− oxidation of phenolate form of TCP. Then the phenoxy radical might be trapped by O2 or oxidized to an aromatic carbocation which reacts with water to give rise to DCQ with the release of one Cl−. Cationic or radical TCP species can also react with an excess of TCP leading to dimeric coupling products [27–29]. Another key step of the process is the relatively fast epoxidation of DCQ which initiate the aromatic cycle cleavage [27]. This step can be performed by PcSFeIII– OOH acting as a nucleophilic oxidant (Scheme 9.3).
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A.B. Sorokin O OH
Cl - HCl O Cl
Cl
O
O PcSFeOOH
Cl
Cl
O
O
+ H2O
Cl
O
OH H OH
O
O
OH
Cl
A
O Cl
Cl
- H2O OH B
O
Scheme 9.3 Nucleophilic epoxidation of DCQ
Hydrolysis of the epoxide to diol followed by HCl or H2O elimination leads to violet quinones A and B, respectively (Scheme 9.3). These two quinones were isolated after 4 min. of the reaction and were fully characterized [27]. Second epoxidation step by PcSFeIII–OOH provides D via C (Scheme 9.4).
O Cl
O Cl
PcSFeOOH
Cl
Cl
O
OH O
Cl
COOH COOH
O
[O]
Cl
O
C
H O
O
O
HO
H
Cl
O Cl O
O
OH
HO
COOH O
-COx
FePcS
PcSFeOOO OH Cl Cl
O
D
O
Cl
HO
O
O
H2O Cl
O
O
-CO2 O
O
H
F
O O
Cl E
Scheme 9.4 Proposed mechanism of the cleavage of the aromatic cycle of TCP
The key C–C bond cleavage step leading to breaking up the aromatic cycle might be due to the nucleophilic attack of PcSFeIII–OOH on one quinone carbonyl group of D leading to E via Grob fragmentation. CO2 might be formed as a result of decarboxylation of different intermediates after the cleavage of the aromatic cycle. After decarbonylation and O2 incorporation, intermediate F would lead to chloromaleic acid, the principal C4-diacid identified in the reaction mixture. The key steps of the deep oxidation of chlorinated quinones involve hydroperoxo species, PcSFeIII–OOH or PcSFeIII–OO−, which can be considered as a significant feature of this mechanism. First, the epoxidation of the double bonds of electron-deficient chlorinated quinones by nucleophilic hydroperoxo complex to provide after hydrolysis
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derivatives with a hydroxyl group adjacent to a carbonyl position. Second, the same nucleophilic PcSFeIII–OO− complex can attack the carbonyl group of the different quinone intermediates leading to the C–C bond cleavage of the aromatic cycle [27–29]. The FePcS – H2O2 system was also investigated for degradation of dichloroanilines and related anilides [30]. Efficient oxidation of catehols, in particular tetrachlorocatechol to dichloromaleic acid was reported [31]. One of the principal sources of chlorinated phenols is the traditional chlorinebased bleaching process used in the paper industry. The pulp industry has been reducing chlorine consumption in recent years by replacing these processes by the cleaner processes involving H2O2 and O3 oxidants. However, the shift to chlorinefree processes leads to increasing consumption of chelating agents, like ethylenediaminetetraacetic acid (EDTA) and diethylenediaminepentaacetic acid (DTPA). In the absence of chelating agents, transition metal ions naturally occurring in wood catalyze the degradation of H2O2 and O3 reducing the efficiency of the bleaching process and the quality of the final product. The addition of chelating agents is essential to prevent this undesired catalase activity. Metal plating, water softening and using of detergents are other sources of pollution by chelating agents. Their resistance in biological wastewater treatment processes make them difficult to remove. According to estimations, EDTA concentration perhaps is the highest of all organic chemicals in European lakes and rivers [32]. Consequently, more advanced methods of degradation of chelates are needed. Catalytic oxidation by H2O2 of various chelating agents including EDTA, DTPA, diethylenetriaminepentakis-(methylphosphonic) acid, nitrilotriacetic acid and b-alaninediacetic acid was studied in aqueous solutions using MPcS (M=Fe, Mn, Cr, Co, Ni) [33]. The impact of pH, temperature, catalyst/substrate ratio was investigated. FePcS operating at neutral conditions at 40–60°C was the most efficient catalyst. Over 90% of EDTA was destroyed using a FePcS:substrate:H2O2 ratio of 4:100:2,000 within 3 h. The metal speciation of the chelates had a significant effect on their degradability. Fe, Mn and Na complexes were most degradable, while Zn, Cu and Ca complexes were more difficult to be oxidized. Photochemical degradation of EDTA in the UV/ H2O2 process was studied in the absence and presence of iron [32].
9.4.2
Heterogeneous Systems for Chemical Degradation of Pollutants
The fixation of the active catalysts onto appropriate supports is highly desirable to provide a high catalyst stability as well as a facile recovery and recycling. From practical point of view, heterogeneous catalysts are more useful for industrial applications. Sulfonated phthalocyanines and porphyrins are particularly suitable for supporting onto ion-exchange resins [34, 35]. Amberlite IRA 900 derived from poly(vinylbenzene) contains quaternary ammonium residues which provide a strong electrostatic interaction with negatively charged sulfonate groups of MPcS (Fig. 9.5).
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_O S 3 + CH3 H3C N CH3 (CH2)n
SO3 +
M
_
CH3 H3C N CH 3 R R
NaO3S
M
N
N N
N
(CH2)n
SO3Na
PVP Amberlite IRA 900 _O S 3
M
+ CH3 N
CH3 N +
CH3 N+
PVPMe+
SO3 CH3 N +
_
_O S 3
M
+ CH3 N
CH3 N +
N
_ SO3 CH3 N +
PVPMe+
Fig. 9.5 Schematic representation of the fixation of sulfonated metal complexes of phthalocyanines and porphyrins onto cationic ion-exchange resins
Poly(vinylpyridine) support (PVP) can provide fixation via the coordination of metal ion with pyridine residue. This can change a reactivity of the catalyst especially in the case of Mn complexes [25]. An additional treatment with acid or methylating agent creates the pyridinium groups which reinforces the complex-polymer interaction by additional electrostatic interactions. Due to the strong fixation, no phthalocyanine complexes can be removed from the impregnated Amberlite or PVP-based resins by washing them with different solvents (water, methanol, or acetone) [34, 35]. Importantly, FePcS-Amberlite IRA 900 catalyst was more efficient compared to homogeneous catalyst. Almost full TCP conversion was achieved with 1 mol% catalyst at pH 7 after 1 h [35]. Furthermore, FePcS-Amberlite IRA 900 can be recycled and re-used. High conversions of TCP were observed in three successive TCP oxidation with H2O2: 93%, 92% and 90%, respectively [35]. The FePcS-Amberlite IRA 900 catalyst is cheap and can readily be accessible in a large scale. The FePcS – H2O2 system which don’t need sophisticated equipment can especially be useful for oxidative degradation of large amounts of concentrated pollutants in process wastes still containing organic solvents, in conditions making difficult an efficient use of microbiological approach. Covalent fixation of MPcS (M=Fe, Co) onto the acrylic copolymers MetExpansin-NH2 and Met-Expansin-Piperazine was developed by Meunier and coworkers (Fig. 9.6) [36]. These heterogeneous catalysts were capable of efficiently degrading TCP. The influence of the spacer and the reaction medium on catalytic properties was investigated. The advantage of these catalysts was their ability to degrade TCP by H2O2 in pure aqueous solutions. The recycling capacity of the catalysts was shown in the oxidative degradation of 3,5-di-tert-butylcatechol.
Photocatalytic Degradation of Pollutants with Emphasis on Phthalocyanines…
or
NH2
C NH (CH2)2 O 3
NH C CH2 O
=
=
C NH (CH2)2 O 2
=
9
N
449
NH
+ ClO2S
SO2Cl
N
SO2Cl
N M N N
N
N
= =
=
O NH S O
9: M = Fe (20.0 µmol/g)
SO2Cl
1a: M = FeIII(OH) 1b: M = CoII
SO2Cl Pyridine
SO2Cl
C NH (CH2)2 O
M
SO2X M SO2X
O
SO2X
C NH (CH2)2 O
NH C CH2 N O
= =
ClO2S
ClO2S
=
N
=
N
N S
O
SO2X M
SO2X
SO2X
10a: M = Fe (26.5 µmol/g) 10b: M = Co (42.0 µmol/g)
Fig. 9.6 Covalent anchoring of sulfonated phthalocyanines onto amino containing polymers (Reproduced from Ref. [36] with kind permission of Wiley-VCH Verlag GmbH & Co)
9.4.3
Photo-Assisted Oxidations in the Presence of MPc and H2O2
The FePcS – H2O2 system was further developed by Zhao and co-workers for degradation of dyes by applying photochemical approach [37–39]. In the presence of visible light the degradation of organic pollutants was accelerated. Using a 500 W halogen lamp with a cutoff filter to ensure irradiation with l > 470 nm, salicylic acid, p-hydroxybenzoic acid, Rhodamine B (RhB), Sulfo-Rhodamine B, Crystal Violet, Acridine Orange and Orange II (Fig. 9.7) were rapidly degraded while dark reactions were slow. After 160 min the conversions of RhB (10 mM aqueous solution) in the presence of 40 mM FePcS and 1 mM H2O2 were 20% and 95% in dark and photoassisted oxidation, respectively (Fig. 9.8). It should be noted that while absorption band intensity of RhB at 555 nm decreased, the 639 nm band of FePcS was almost unchanged indicating a good stability of the complex (Fig. 9.8). This stability allows performing several oxidation cycles. Degradation of RdB was also observed using monochromatic light source (l = 640 nm, Dl1/2 = 10 nm) where RhB showed no absorption. The quantum yield was 0.0038. The degradation of salicylic acid was also accelerated under visible light irradiation although this substrate doesn’t absorb in the visible range. The dependence of concentration of FePcS, H2O2 and salicylic acid versus irradiation time is shown in Fig. 9.9.
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+ NEt2 Cl
SO3Na _ SO3
COOH
Et2N
+ Cl NEt2
O
_ Et2N
Rhodamine B
+ NEt2
O
Et2N
Sulforhodamine B
NaO3S
NEt2
N
NEt2 Crystal Violet
HO Et2N
_
COOH OH
N N
Acridine Orange
Orange II
COOH
Salicylic acid OH p-Hydroxybenzoic acid
1.0
1
Absorbance
0.8
2 3
0.6
Concentration of RhB/10–5 M
Fig. 9.7 Structure of dyes and aromatic substrates
1.0 0.8 0.6 0.4 0.2 0.0
4 0.4
dark
hv 0 20 40 60 80 100 120 140
Irradiation time/min
5 6
0.2
7 0.0 450
8 500
550
600
650
700
Wavelength/nm
Fig. 9.8 UV/Vis spectral changes of RhB as a function of irradiation time in aqueous FePcS/H2O2 solutions under visible light irradiation. The initial concentrations of the reaction system: RhB (1 × 10−5 M), FePcS (1.7 × 10−5 M), and H2O2 (1 × 10−3 M). pH 3. Spectra 1, 2, 3, 4, 5, 6, 7, and 8 denote irradiation for 0, 20, 40, 60, 80, 100, 120, and 140 min, respectively. Inset shows concentration changes of RhB both in the dark and under visible irradiation (Reproduced from Ref. [38] with kind permission of Wiley-VCH Verlag GmbH & Co)
FePcS was also stable during photoassisted oxidation of salicylic acid despite the formation of OH· radical detected using spin trap EPR. EPR experiments in the presence of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) radical trap showed the formation of DMPO-OH· adduct with a typical 1:2:2:1 quartet EPR signal pattern under irradiation conditions. Importantly, the DMPO-OH· adduct was not detected in the dark reaction with FePcS and H2O2. The further evidence for the involvement of OH· radical in photo-assisted reaction was obtained in the oxidation in the presence
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[Fe(PcS)]
1.0
C/C0
0.8
0.6
SA 0.4
0.2
0.0
H2O2
0
100
200
300
400
500
Irradiation time/min
Fig. 9.9 The plot of concentrations of SA, FePcS, and H2O2 versus irradiation time during the photodegradation of salicylic acid (SA, 1 × 10−4 M) in the presence of FePcS (1.7 × 10−5 M) and H2O2 (1 × 10−3 M) at pH 3 (Reproduced from Ref. [38] with kind permission of Wiley-VCH Verlag GmbH & Co) H2O2 hv [HOOFeIII-(PcS)]
[HOFeIII-(PcS)]
[HOOFeIII-(PcS)]*
[O=FeIV-(PcS)]
.
.
[HOOFeII-(PcS )]
.
[ O-FeIII-(PcS)] + OH
Degraded products
RH (substrate or H2O2)
Fig. 9.10 Proposed photodegradation mechanism of organic pollutants in the aqueous FePcS/ H2O2 system under visible light irradiation (Adapted from Ref. [38] with kind permission of Wiley-VCH Verlag GmbH & Co)
of 50 or 100 equiv of EtOH. A strong inhibition of RhB or Orange II oxidation rate in the presence of EtOH confirms participation of OH· radicals in the photoassisted oxidation. The possible mechanism of photoassisted oxidation of dyes by FePcS – H2O2 system is proposed in Fig. 9.10.
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Upon addition of H2O2 the formation of hydroperoxo complex HOO–FeIIIPcS occurs by substitution of hydroxo ligand. Interestingly, the addition of increasing amounts of KF to the reaction mixture progressively inhibited the photooxidation of RhB [38]. Fluoride ions being good ligands for FePcS block axial positions of the complex thus preventing coordination of HOO− and further catalytic activity. HOO– FeIIIPcS can be excited by irradiation to form transient [HOOFeIII-(PcS)]* or metalligand charge transfer complex [HOOFeII-(PcS·)]. Homolytic cleavage of O–O peroxide bond generates OH· radical and putative oxo complex O=FeIVPcS. Although an oxidative degradation of the dyes should mainly be associated with highly reactive OH· radical, O=FeIVPcS species might also be involved, at least in some steps of further degradation of intermediate oxidation products. Thus, the key step of this photoassisted oxidation of dyes was proposed to be photogeneration of OH· radicals from hydroperoxo complex HOO-FeIIIPcS [38]. A beneficial effect of visible irradiation (l > 450 nm) was also observed in the heterogeneous oxidation of Orange II using FePcS supported onto Amberlite IRA 900 resin [39]. FePcS is strongly fixed onto this resin due to electrostatic interaction between four sulfonato groups of the complex and ammonium groups of Amberlite IRA 900. While in the presence of FePcS-resin and H2O2 no significant degradation of Orange II was observed in the dark after 60 min., a brown Orange II solution became colourless after 50 min exposure to visible light [39]. It should be noted that small decrease of Orange II concentration (about 15%) was detected in control dark experiments due to absorption of the dye by resin. Further 20 min. irradiation changed the colour of the supported catalyst from brown (due to absorbed Orange II) to blue (due to FePcS). The significant advantage of heterogeneous catalysts is the easy recovery from the reaction mixture after reaction. The FePcS-resin catalyst was shown to retain the catalytic activity in three consecutive oxidations [39]. Turnover number of 14 was obtained. Several products of Orange II degradation including phthalic, oxalic and formic acids were detected by GC-MS [39]. Atrazine and other s-triazines widely used in agriculture are pollutants recalcitrant to bio-remediation and advanced oxidation methods [40]. Iron porphyrin and iron phthalocyanine were supported onto Amberlite IRA 910 ion-exchange resin. The photocatalytic activity of these materials (4.6% of complexes vs substrate) was tested in the degradation of atrazine (10 mg/L) under irradiation with a medium pressure Hg lamp doped with thallium iodide (TQ 150 Z2 nu, HERAEUS) and compared with those of TiO2 (5 mg/L). Although supported iron complexes did catalyze photodegradation of atrazine, TiO2 showed a superior catalytic activity. Atrazine half-live was 2,914 (no catalyst), 640 (Fe porphyrin), 217 (Fe phthalocyanine) and 137 min (TiO2). Cyanuric acid was the ultimate by-product in all cases, but supported iron complexes were able to cleave triazine cycle in some extent with formation of formamide [40].
9.4.4
Photochemical Systems Involving Homogeneous MPc
Although phthalocyanine complexes of metals with open d-electron configuration (FeII, FeIII, CoII) show good catalytic properties, they are poor photosensitizers
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because of too short life time of the excited triplet state. The complexes of metals with closed d-configuration (Zn, AlIII(OH), SiIV(OH)2) exhibit a good combination of sufficiently long triplet life times and high quantum yields of the excited triplet state [41]. Due to high photostability and visible light absorption ability, phthalocyanine complexes have widely been used in purely photocatalytic depollution [41, 42]. Upon absorption of light MPc is excited to the singlet state. Then the excited photosensitizer in the singlet state (1MPc*) undergoes transformation to the triplet state via intersystem crossing. 3MPc* interacts with the ground state oxygen via triplettriplet energy transfer process to form the singlet oxygen 1O2 followed by its reactions with substrates [42]. This Type II mechanism is the dominating initial elementary process: hv isc MPc ⎯⎯ → 1 MPc* ⎯⎯ → 3 MPc*
MPc* + 3O 2 → MPc + 1O 2
3
O2 + S → SOX
1
Alternatively, photo-induced electron transfer process gives rise to oxygencentered radicals (Type I mechanism) [42]: MPc* + 3 O2 → MPc • + + O•2− MPc• + + S → MPc + S• + O•2− + H + → HO•2 HO•2 + SH → H 2 O2 + S• cat S• + + HO•2 + H 2 O2 ⎯⎯ → Sox
3
cat S• + HO•2 + H 2 O2 ⎯⎯ → Sox
High triplet state quantum yields and long triplet lifetimes are required for efficient photosensitization. Phthalocyanines with diamagnetic metals (zinc, aluminium, silicon, etc.) are more suitable for Type II mechanism. Singlet oxygen quantum yield can be comparable to triplet state yield if quenching of the 3MPc* by 3O2 is efficient. This parameter is important for the choice of photosensitizer and can be determined using singlet oxygen quencher (e.g. 1,3-diphenylisobenzofuran) or using singlet oxygen luminescence method (SOLM) [41]. The generation of radical ions, superoxide, hydroperoxide radicals and hydrogen peroxide in Type I mechanism also contributes to the oxidative degradation of substrates, especially in the presence of the catalyst able to activate these active oxygen species. Photostability of MPcs is an essential parameter for their use in photocatalytic processes. MPcs can be attacked by 1O2 generated by them leading to the decrease in the intensity of UV-vis spectrum without shifting of Q and B bands or formation of new bands. Since the introduction of peripheral substituents in phthalocyanine molecules strongly influences on their properties [43], the appropriate modification of phthalocyanine moiety might improve their photostability. Indeed, fluorinated MPcs were more stable toward photodegradation and showed high 1O2 quantum
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yields demonstrating their potential as Type II photosensitizers [44]. Other factors such as temperature, pH, irradiation time and light intensity influence on the photostability of MPc. Photobleaching quantum yields were determined for many phthalocyanine complexes. Essential photochemical and photophysical data (triplet states, singlet oxygen, photobleaching, and fluorescence quantum yields and triplet lifetimes of MPc) for main group metal phthalocyanines can be found in the recent review [41]. Due to electronic interaction between phthalocyanine rings, MPc can form in solutions dimeric and oligomeric structures. Aggregation reduces the lifetime of the excited state owing to radiationless dissipation thus leading to lower photosensitization efficiency. The tendency to aggregation depends on the nature of metal and substitution pattern of the phthalocyanine moiety. The degree of aggregation in water is higher for more hydrophobic phthalocyanine ligands. T. Nyokong’s team has explored the influence of the structure of phthalocyanine sensitizers on the photocatalytic properties. The efficiency of photodegradation of polychlorophenols depends on 1O2 quantum yield of sensitizer and on its photostability. Among Zn, Al, Si and Sn mixed sulfonated phthalocyanines (MPcSn) Sn complex showed the highest 1O2 quantum yield but a low efficiency in degradation of chlorinated phenols because of its low photostability [42]. AlPcSn was the most efficient in the oxidation of TCP and PCP to corresponding quinones. Based on the experiments in the presence of NaN3, the 1O2 quencher, it was concluded that oxidation of chlorinated phenols occurred mainly via Type II pathway. The contribution of Type I mechanism was more significant in the oxidation of easier-to-oxidize 4-chlorophenol (4-CP) with ZnPcSn and AlPcSn, which were the most efficient photocatalysts [45]. In general, the rates of 4-chlorophenol oxidation follow the efficiency of 1O2 photosensitization at l = 670 nm. 1O2 quantum yields were 0.48 and 0.38 for ZnPcSn and AlPcSn, respectively. The relative contribution of both mechanisms depended on the substrate concentration. At [4-CP] < 10−4 M photooxidation by 1O2 was dominating mechanism, while at [4-CP] > 10−3 M the role of Type I mechanism increased. The influence of phthalocyanine structure in the range of zinc water soluble complexes was investigated in the photocatalytic oxidation of 4-nitrophenol at pH 8.2 and l > 600 nm [46]. The products of photodegradation were hydroquinone and 4-nitrocatechol. ZnPc(COOH)8 was more efficient than ZnPcSn and ZnPcS providing a 22% conversion. D. Wöhrle and co-workers have studied phthalocyanine based sensitizers in various applications [47]. They developed together with proSysTM GmbH (Bremen) a loop reactor (~250 cm high and ~50 cm in diameter) for waste water cleaning under irradiation with quartz halogen lamps or solar light. Comparative photooxidation of phenol, 2-CP, 3-CP and 4-CP using visible light (halogen lamp, 180 mW/cm2) in the presence of AlPcS, ZnPcS, GaPcS as well as metal-free tetracarboxyphenylporphyrin (H2TCP), di-(N,N-trimethylammoniumpropylene)-3,4,9,10-perylenebis-carboximide (DTPC), rose bengale (RB) and methylene blue (MB) in aqueous solutions at pH 13 was investigated [48]. The efficiency of photooxidation was estimated by the measurement of O2 consumption (Table 9.2).
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Table 9.2 Photooxidation of phenol (7.16 mM) in aqueous solution at pH 13 using different photosensitizers (5 mM) Reaction time – 12,000 s 1 Consumed O2, mol/ Reaction rate, Degradation of O2 quantum Sensitizer [PhOH]init , mol mmol min−1 sensitizer, % yield AlPcS 3.7 41 ZnPcS 2.0 4.7 GaPcS 3.3 23 H2TCP 3.4 35 DTPC 0.3 0.84 RB 3.4 17 MB 0.9 2.9 Adapted from Ref. [48] with kind permission of Elsevier
0 33.3 100 84 66.7 100 100
0.20 0.52 0.41 0.47 0.23 0.64 0.37
Table 9.3 Photooxidation of 2-CP, 3-CP and 4-CP (7.16 mM) in aqueous solution at pH 13 in the presence of AlPcS and Rose Bengal (5 mM) Reaction time – 8,000 s Consumed O2, mol/ Reaction rate, Degradation of Sensitizer Substrate [PhOH]init , mol mmol min−1 sensitizer, % AlPcS 2-CP 3.3 AlPcS 3-CP 3.2 AlPcS 4-CP 2.9 Rose bengal 2-CP 3.3 Rose bengal 3-CP 3.3 Rose bengal 4-CP 2.9 Adapted from Ref. [48] with kind permission of Elsevier
36 36 36 22 22 23
0 0 0 100 100 100
The different activities observed for the photooxidation of phenol in terms of initial reaction rates calculated from the linear slopes of the oxygen consumption over time and the overall oxygen consumption, are determined mainly by (i) 1O2 quantum yield, (ii) photostability of the photosensitizer, (iii) the aggregation of the photosensitizer. Aggregation leads to the dissipation of the energy of the excite state. The aggregation tendency of ZnPcS and DTPC in aqueous solution was proposed to be the main reason for their low activity. Methylene blue (MB) is typical example of very unstable photosensitizer. Having a high initial reaction rate, MB was completely degraded after 33 min. that resulted in a loss of activity. Although 1 O2 quantum yield of AlPcS is rather moderate, due to the high stability and the absence of the aggregation this sensitizer exhibited the best photodegradation activity. Noteworthy, the consumption of O2 was about 4 mol per mole of phenol suggesting efficient oxidation of phenol. The detection of maleic and fumaric acids and the formation of CO2 (0.9 mol per mole of phenol) supported this conclusion. The involvement of 1O2 was evidenced by the increase of the initial reaction rate and in oxygen consumption in D2O where 1O2 lifetime is longer than in H2O. In turn, NaN3 (1O2 trap) slowed down the oxidation of phenol. No dependence of the structure of monochlorinated phenols on the degradation efficiency was observed in the presence of AlPcS and Rose Bengal sensitizers (Table 9.3).
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Again, AlPcS exhibited a high reaction rate and a high photostability. In the course of the oxidation of phenols benzoquinone was detected as intermediate product. It was shown [48] that phenol reacts with 1O2 via a [2 + 4] cycloaddition to form 4-hydroperoxycyclohexadienone followed by its transformation to benzoquinone:
OH
O
OH
O COOH HOOC
+
1O
2
O
+
O H
OOH
COOH
+
CO2
COOH
O
The formation of this peroxide by photoinduced electron transfer involving phenol cation radical and superoxide anion can not be excluded. Further oxidation of benzoquinone consumes dioxygen and gives rise to maleic/fumaric acids and CO2. This photooxidation of phenols includes several reactions steps showing a complex kinetics. A notable retardation of the kinetics in the advanced stages of the photooxidation was observed which might be owing to an inhibition of photosensitizer by intermediates or products. Interaction of metal with phthalocyanine p-system greatly influences on the spectroscopic and photochemical properties of the complexes. In this context, lanthanide double-Decker phthalocyanines are quite particular in coupling of two macrocyclic p-systems via metal ion. Photocatalytic dechlorination of PCP in the presence of lanthanide diphthalocyanine has been studied [49]. Using a visible light diphthalocyanine complexes of neodymium(III), dysprosium(III) and lutetium(III) were one-electron oxidized to corresponding diphthalocyanine cation-radicals and PCP was reductively dechlorinated to tetra- and trichlorophenols with quantum yields of the order 10−4. Photocatalytic oxidation of 4-chlorophenol in the presence of solid neodymium diphthalocyanine and oxygen using UV and visible radiation resulted in the formation of 4-chlorocatechol as the main product as well as phenol, hydroquinone and benzoquinone [50].
9.4.5
Heterogenized Phthalocyanine Photosensitizers
To evaluate the feasibility of the practical applications of phthalocyanine based photosensitizers it is of much importance to prepare heterogeneous materials and to test them in the photodegradation of pollutants. The essential point for photoactivity of heterogeneous catalysts is a monomolecular distribution of photosensitizer on the support surface in order to get a high quantum yield of 1O2. To fulfil this criteria the MPc loading should not be very high. To determine optimal photosensitizer loading, a specific surface of the support should be taken into account. In general, loadings of <0.1 mmol/g are used for the supports with specific surface of 200–300 m2/g. However, in each particular case the optimal amount of the photosensitizer fixed
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onto particular support should be determined experimentally. Photoactivity of supported catalysts should be studied for several MPc loadings. The state of the supported MPc can be evaluated by UV-vis spectroscopy. For MPcS (M = Mg(II), Zn(II), Al(III)X, Si(IV)X2) the presence of an additional absorption near 630 nm is indicative of aggregation [41]. Heterogeneous phthalocyanine complexes were prepared by impregnation onto SiO2, Al2O3, TiO2 and charcoal, by covalent grafting to SiO2, organic polymers or by electrostatic interaction onto ion-exchange resin [47]. The experiments were performed using laboratory thermostated reactor with oxygen consumption measurement with irradiation under visible light with an intensity of 180 mW cm−2 (quartz halogen lamp), under solar irradiation (1,000 mW cm−2) or in a large scale reactor. Amberlite IRA 400 ion-exchange resin containing quaternary ammonium groups was especially suitable for supporting of MPcS in monomeric form due to electrostatic interaction between – NR3+ groups of support and SO3− functions of MPcS. At pH 10 dioxygen consumption was 3–3.5 mol O2 per mole of phenol. The order of the activity of different supported tetrasulfophthalocyanines and traditional photosensitizers in the photooxidation of phenol was determined to be: Si (OH )2 PcS > Ge (OH )2 PcS > Rose Bengal > Ga (OH )PcS > ZnPcS > Al (OH )PcS > Methylene Blue
In turn, the order of the stability of photosensitizers was following: Si (OH )2 PcS > Al (OH )PcS > ZnPcS > Rose Bengale > Methylene Blue The degradation of MPcS was evaluated by the decrease of the Q band at 680 nm in the UV-vis spectrum. Si(OH)2PcS-Amberlite IRA 400 catalyst showed particularly high activity and stability. This catalyst was re-used in five successive oxidations of phenol without notable loss of activity [47]. The influence of the phthalocyanine structure was studied in the photooxidation of 4-CP, 2,4-dichlorophenol, 2,4,5-trichlorophenol and PCP under visible light [51]. Octacarboxyphthalocyanine Zn and Al complexes (ZnPc(COOH)8, AlPc(COOH)8) as well as ZnPcS, AlPcS, ZnPcSn, AlPcSn, GePcSn, SiPcSn and SnPcSn were supported onto Amberlite IRA 900 with loading of 5 mmol/g. Amberlite IRA 900 ion exchange resin is a strongly basic, macro-reticular resin of moderately high porosity with benzyltrialkylammonium groups. These MPc photosensitizers were chosen because of their different photochemical and photophysical characteristics which might influence on the photoactivity towards the degradation of pollutants. The efficiency of singlet oxygen generation by photosensitizers in aqueous solution follows the trend: SiPcSn > ZnPc(COOH)8 > GePcSn = SnPcSn > ZnPcSn > ZnPcS > AlPcSn > AlPc(COOH)8 > AlPcS
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With all supported photosensitizers, photodegradation was more difficult for more chlorinated phenols (4-CP > DCP > TCP > PCP) and resulted mainly in the formation of chlorinated benzoquinones. The photocatalytic properties of the supported MPc were compared in oxidation of PCP at pH 10 using 1:99 catalyst/substrate ratio [51]. The order of photoactivity was following (conversion of PCP after 5 min, %): ZnPc(COOH)8 > SiPcSn > SnPcSn > ZnPcSn > GePcSn > ZnPcS > AlPcSn > AlPc(COOH)8 > AlPcS 29.8 26.0 24.4 21.1 16.5 12.8 10.7 10.7 6.2
The supported catalysts showed a superior catalytic activity compared to homogeneous counterparts and could be re-used [51]. Another approach for TCP degradation was realized using PdIIPcS as sensitizer, supported onto bentonite treated with surfactants which is widely used as a sorbent for uptake of organic pollutants from water [52]. PdPcS possesses a high quantum yield of 1O2 generation and a high photostability. This complex is aggregated in aqueous solution as evidenced by the 612 nm band in the UV-vis spectrum. The change of the maximum to 646 nm upon absorption at organoclay indicated PdPcS was supported mainly in monomer form. At pH 12, 0.3 mM TCP solution was completely degraded in the presence of 1 g/L PdPcS-organoclay material within 25 min reaching almost complete dechlorination after 300 min irradiation with l > 450 nm. This photocatalyst exhibited a good stability and recyclability. Bentonite can also be modified with AlPcS, but AlPcS-organoclay material was less active than Pd catalyst in the TCP photodegradation under the same conditions. This was in agreement with the 1 O2 quantum yield determined for PdPcS and AlPcS in homogeneous conditions.
9.4.6
Porphyrins as Photosensitizers
Iron porphyrins also exhibit photocatalytic activity in the oxidation of pollutants [53]. Iron tetrasulfophenylporphyrin (FeTPPS) supported onto Amberlite IRA 900 activated H2O2 in water under irradiation with l > 450 nm. The irradiation accelerated the degradation of Sulforhodamine B (SRB) and 2,4-dichlorophenol (DCP) with mineralization of 56% and 68% at a catalyst/substrate ratio 1:33 and 1:535, respectively. The release of inorganic SO4− from SRB and Cl− from DCP was 65% (160 min irradiation) and 70% (380 min irradiation), respectively. Several intermediate products (2-hydroxybenzoic acid, 4-(ethylamino)benzoic acid and 1,3-isobenzofurandione) were identified. However, cationic compounds like RhB and Malachite Green were not degraded, probably because of difficult approach to the catalyst embedded into cationic resin. The first order constants of photodegradation of 3 compounds by FeTPPS/AmberliteIRA900 – H2O2 system were determined: Sulforhodamine B
k1 = 1.3 × 10 −2 min −1
Orange II Salicylic acid
k1 = 1.2 × 10 −2 min −1 k1 = 6.2 × 10 −3 min −1
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The supported FeTPPS catalyst was stable enough to allow re-uses in five photocatalytic experiments without significant loss of activity. EPR spin trap experiments with DMPO showed the involvement of OH· radicals. Similarly to phthalocyanine analogue, hydroperoxo HOOFeIIITPPS complex was proposed to undergo a homolytic cleavage of O–O bond to form OH· responsible for degradation of pollutants. Impregnation of metal-free or copper tetra(4-tert-butylphenyl)porphyrin onto TiO2 surface improved the photocatalytic activity of the bare TiO2 in the degradation of 4-nitrophenol [54].
9.5
Combined TiO2 – MPc Systems
Owing to a wide 3.2 eV band gap of TiO2 only UV light accounting only for 4–5% of solar light can be used. In addition, the quantum yields for organic oxidation are low, e.g. 0.14 (l = 365 nm) for phenol oxidation using Degussa P25 TiO2 in water at pH 3 [55]. In order to use visible light TiO2 can be modified by supporting photosensitizers. The idea of modification of semiconductor surface by metal complexes as electron relays was introduced by Grätzel and co-workers [56]. Cobaltocenium dicarboxylate supported on colloidal TiO2 efficiently reduced methylviologen (MV2+) to the radical cation MV+· during laser flash photolysis. The attachment of sensitizer molecules in order to extend the photocatalytic activity of the catalyst into the visible part of the spectrum was demonstrated for the first time in 1980s [57, 58]. At the same time, thin films of MPc (M=Mg, Zn, Co, AlCl, Fe, TiO) were deposited onto semiconductor electrodes by Bard et al. [59]. This topic has mainly been devoted to the development of dyes-sensitized solar cells [60] and will not be covered in this chapter. Applications of phthalocyanine and porphyrins for molecular photovoltaics are discussed in details in recent review [61]. Stability of these composite catalysts is an important issue. Organic ligand of the adsorbed complex can be oxidized by generated active species. In this context, MPcs seem to be suitable photosensitizers. A high chemical and thermal stability of phthalocyanines coupled with their strong absorption in the visible region (Q band between 600 and 700 nm) make them interesting candidates for doping semiconductors [61]. In addition, the quantum yield of the redox process can be increased when a sensitizer absorbed onto semiconductor surface is excited by visible light followed by inter-phase transfer of electron from the sensitizer to semiconductor. In other words, a charge recombination can be diminished in this case. Moreover, by appropriate design of the dye it is possible to slow down interfacial electron transfer recombination dynamics and to favour the formation of O2−·. Indeed, a modification of the structure of porphyrin sensitizer grafted onto TiO2 surface showed a significant change in the rate of charge recombination between injected electrons in the TiO2 and the oxidized porphyrin [62]. The slower recombination rate was observed for the porphyrin with bulkier substituents most probably due to a larger physical separation of the porphyrin cation-radical from the semiconductor surface. The control of the electron transfer step allows improving the efficiency of such combined MPcTiO2 systems.
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This approach can be used for development of hybrid MPc-TiO2 materials for photodegradation of pollutants. After absorption of visible light MPc photosensitizer injects electrons in the conduction band of TiO2: hV MPc ⎯⎯ → MPc*
(
MPc* + TiO2 → MPc • + + TiO2 e − CB
)
Generation of oxygen active species and oxidation of the substrate by MPc+. initiate the degradation process: MPc* + O 2 → MPc +1 O 2
(
)
TiO2 e − CB + O2 → TiO2 + O•2− MPc • + + S → MPc + S• + The benefit of TiO2 support with respect to Al2O3 was shown in the photosensitized by supported H2Pc oxidation of phenol and benzoquinone [63]. H2Pc was supported onto TiO2 (Riedel de Haen, 100% anatase, 4 m2/g) and Al2O3 (Merck, 60 m2/g) with loadings of 24 mmol/g. Under irradiation by a halogen lamp (l > 450 nm, 38 mW/cm2) phenol was converted to maleic and fumaric acid accompanying by CO2 formation with 0.95 and 1.5 mol CO2/mole of phenol for H2PcAl2O3 and H2Pc-TiO2, respectively. Total O2 consumption was also higher for H2Pc-TiO2: 6.9 vs 4.2 mol/mol of phenol. The higher photocatalytic activity of H2Pc-TiO2 can be explained by an electron transfer from excited H2Pc to the conduction band of TiO2 and generation of superoxide radicals leading to the increase of the quantum yield and a higher mineralization of phenol. Cooperative action of TiO2 and supported phthalocyanine or porphyrin sensitizers (CuPc, H2Pc, CuP, H2P) was observed in photodegradation of 4-nitrophenol (125 W medium pressure Hg lamp, 300 K) [64]. Significantly, CuP-TiO2 and H2P-TiO2, stable after irradiation during 5–7 h in the absence of the substrate, exhibited a higher photoactivity than TiO2 itself. Three series of experiments were performed: (i) without filter, (ii) with 370 nm interference filter and (iii) with 420 nm cutoff filter. Initial reaction rates of 4-nitrophenol oxidation mediated by combined catalysts normalized on the rate in the presence of TiO2 follow the trend: (i) no filter : CuP − TiO 2 > CuPc − TiO 2 > H 2 P − TiO 2 > H 2 Pc − TiO 2 > TiO 2 1.57 1.32 1.2 1.07 1 (ii) 370 nm interference filter : CuP − TiO2 > CuPc − TiO2 > TiO2 > H 2 P − TiO2 > H 2 Pc − TiO2 1.63 1.54 1 0.83 0.54
In the case (ii) the initial rates values were lower by 3–4 times compared to rates obtained under conditions (i). Almost no photoactivity was observed for all materials when 420 nm cutoff filter was used showing the essential role of TiO2 photoexcitation.
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Superior photooxidation activity of CuP-TiO2 and CuPc-TiO2 compared with that of TiO2 suggests a cooperative mechanism involving both TiO2 and dye sensitizer (PS). Palmisano and co-workers proposed detailed set of reactions operating in this system (Adapted from ref. [64] with permission from Elsevier, Copyright 2003): Reaction involving TiO2:
(
hv
)
< 394 nm TiO2 @ PS ⎯⎯⎯⎯ → TiO2 e − CB + h + VB @ PS
Reactions involving e−CB: 3
O2 + e − CB → O•2−
1
O2 + e − CB → O•2−
H 2 O 2 + e − CB → OH • + OH − TiO2@PSCu II + e − CB → TiO2@PSCu I Reactions involving holes: OH − + h + VB → OH • H 2 O + h + VB → OH • + H + H 2 O 2 + h + VB → HO•2 + H + HO•2 + h + VB → O2 + H + TiO2@PS + h + VB → TiO2@PS+ Reactions involving sensitizer: 1
3
hv isc PS ⎯⎯ → PS* ⎯⎯ → PS* 3
3
PS* + 3O2 → PS + 1O2
PS* + 3O2 → PS+ + O•2−
TiO2@PS* → TiO2@PS+ + e − CB TiO2@PS+ + OH − → TiO2@PS + OH • TiO2@PS+ + 4NP → TiO2@PS + oxidationproducts
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Reactions involving radical species in aqueous phase: O•2 − + H 2 O → HO2• + OH − O•2− + H + → HO•2 2OH • → H 2 O 2 2HO•2 → H 2 O2 + O2 H 2 O 2 + O•2− → OH • + OH − + O 2 2HO•2 + O•2− → OH • + OH − + 2O2 Reactions involving metal of sensitizer: TiO2@PSCu I + 3 O2 → TiO2@PSCu II + O•2− TiO2@PSCu I +1 O2 → TiO2@PSCu II + O•2− TiO2@PSCu I + H 2 O2 → TiO2@PSCu II + OH • + OH − Oxidation reactions in aqueous phase: 1
O2 + 4NP → oxidationproducts
OH • + 4NP → oxidationproducts HO•2 + 4NP → oxidationproducts CuPc(COOH)4 – TiO2 showed a photocatalytic activity in degradation of Methyl Orange under irradiation with l > 550 nm [65]. The participation of CuPc(COOH)4 cation-radical was demonstrated in control experiments. AlPc(COOH)4 impregnated on several TiO2 samples was shown to be a good sensitizer for degradation of 4-CP in water under irradiation with l > 450 nm [55]. Among several parameters, such as AlPc(COOH)4 loading, the substrate concentration, pH and the amount of O2, the latter determined the efficiency of degradation. The optimum loading was about 1 wt.% providing a necessary balance between amounts of absorbed photons and absorbed O2 to achieve an optimal efficiency of oxidation. TiO2 functioned as electron mediator and AlPc(COOH)4 as sensitizer. The involvement of [AlPc(COOH)4]+, O2−· and OH− radicals was shown using EPR and trapping experiments. This catalyst was also used for oxidative degradation of phenol, 2,4-DCP, TCP, catechol, hydroquinone, salicylic acid and 4-sulfosalicylic acid. The stability of AlPc(COOH)4 –TiO2 was assessed in the oxidation of 4-CP. The rate of 4-CP degradation gradually decreased in successive runs because of slow decomposition of [AlPc(COOH)4]+. photogenerated on the TiO2 surface [55].
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The photocatalytic activity of TiO2 impregnated with lanthanide double Decker phthalocyanines LnPc2–TiO2 (Ln=Ce, Pr, Nd, Sm, Ho, Gd) was studied in degradation of 4-NP under irradiation with 125 W medium pressure Hg lamp (15.5 mW/ cm2) [66]. It is generally accepted that dimerization of regular phthalocyanine sensitizers leads to the loss of the photocatalytic activity because of the radiationless energy dissipation. However, all LnPc2–TiO2 materials showed a good photoactivity. Ho, Sm and Nd based catalysts were even slightly more active compared to anatase TiO2. A plausible explanation of this activity is that the presence of two macrocycles connected via lanthanide ion probably provides a better delocalization of the positive charge developed during photocatalytic process.
9.6
Conclusion
This chapter overviews principal photochemical methods used for degradation of pollutants. Although several photochemical approaches can be successfully used, the field is largely dominated by investigations dealing with applications of TiO2based photocatalysts. The state of the art and perspectives of the development of TiO2 materials for remediation have been covered in numerous recent comprehensive reviews [1, 2, 12]. For this reason, this area was only briefly discussed in this chapter. A major challenge that remains is an increase of photocatalytic efficiency of TiO2-based catalysts in terms of more effective use of visible light. To achieve this goal, several doping strategies have been developed and application of phthalocyanine sensitizers is one of them. Vast experimental results obtained in chemical and light-driven pollutant degradations with phthalocyanine complexes have never comparatively been reviewed. Moreover, researchers working with phthalocyanines in different fields of environmental applications are not obligatory aware of the related works in other areas. Mechanistic considerations have been discussed in as much detail as seems necessary to illustrate the essential features of different processes and to provide some background for the choice of optimal system for novel developments. However, the lack of sufficient quantitative data in original publications often makes difficult the direct comparison of the efficiency of different systems. While photosystems involving phthalocyanine sensitizers operate mainly via Type II pathway and generation of 1O2, photo-assisted processes in the presence of H2O2 include the formation of very active OH· radicals. In turn, a high activity of chemical systems consisting of iron phthalocyanines and H2O2 is associated with iron-centered active species, like oxo and peroxo complexes. Consequently, the search for better photosensitizers should not be restricted to diamagnetic MPc. The results obtained in FePc mediated photo-assisted oxidative degradation illustrate a usefulness of combined approaches. Recent discovery of remarkable catalytic properties of N-bridged diiron phthalocyanines capable of oxidizing methane, benzene, alkylaromatic compounds at very mild conditions [67–70] make these emerging catalysts very interesting to apply also in environmental remediation.
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Mechanistic studies are the subject of great interest which have played an important role in advancing fundamental knowledge in this field. The efforts in this direction should result in improving of existing photocatalysts and in development of new catalytic systems which might be a basis for future industrial applications.
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20. Zepp RG, Faust BC, Hoigné J (1992) Hydroxyl radical formation in aqueous reactions (pH 3–8) of iron(II) with hydrogen peroxide: the photo-Fenton reaction. Environ Sci Technol 26:313–319 21. Ikehata K, El-Din MG (2006) Aqueous pesticide degradation by hydrogen peroxide/ultraviolet irradiation and Fenton-type advanced oxidation processes: a review. J Environ Eng Sci 5:81–135 22. Pera-Titus M, Garcia-Molina V, Baos MA et al (2004) Degradation of chlorophenols by means of advanced oxidation processes: a general review. Appl Catal B 47:219–256 23. Cernjak W, Krutzler T, Glaser A et al (2003) PhotoFenton treatment of water containing natural phenolic pollutants. Chemosphere 50:71–78 24. Bigda RJ (1995) Consider Fenton’s chemistry for wastewater treatment. Chem Eng Prog 91:62–66 25. Labat G, Séris J-L, Meunier B (1990) Oxidative degradation of aromatic pollutants by chemical models of ligninase based on porphyrin complexes. Angew Chem Int Ed Engl 29:1471–1473 26. Sorokin A, Séris J-L, Meunier B (1995) Efficient oxidative dechlorination and aromatic ring cleavage of chlorinated phenols catalyzed by iron phthalocyanines. Science 268:1163–1166 27. Sorokin A, Meunier B (1996) Oxidative degradation of polychlorinated phenols catalyzed by metallophthalocyanines. Chem Eur J 2:1308–1317 28. Sorokin A, De Suzzoni-Dezard S, Poullain D et al (1996) CO2 as the ultimate degradation product in the H2O2 oxidation of 2,4,6-trichlorophenol catalyzed by iron tetrasulfophthalocyanine. J Am Chem Soc 118:7410–7411 29. Meunier B, Sorokin A (1997) Oxidation of pollutants catalyzed by metallophthalocyanines. Acc Chem Res 30:470–476 30. Hadasch A, Meunier B (1999) Oxidation of dichloroanilines and related anilides catalyzed by iron(III) tetrasulfonatophthalocyanine. Eur J Inorg Chem 2319–2325 31. Sorokin A, Fraisse L, Rabion A, Meunier B (1997) Metallophthalocyanine-catalyzed oxidation of catechols by H2O2 and its surrogates. J Mol Catal A 117:103–114 32. Sörensen M, Zurell S, Frimmel FH (1998) Degradation pathway of the photochemical oxidation of ethylenediaminetetraacetate (EDTA) in the UV/H2O2 process. Acta Hydrochim Hydrobiol 26:109–115 33. Pirkanniemi K, Sillanpää M, Sorokin A (2003) Degradative hydrogen peroxide oxidation of chelates catalysed by metallophthalocyanines. Sci Total Environ 307:11–18 34. Hadasch A, Sorokin A, Rabion A et al (1997) Oxidation of 2,4,6-trichlorophenol (TCP) catalyzed by iron tetrasulfophthalocyanine (FePcS) supported on a cationic ion-exchange resin. Bull Soc Chim Fr 134:1025–1032 35. Sorokin A, Meunier B (1994) Efficient H2O2 oxidation of chlorinated phenols catalyzed by supported iron phthalocyanines. J Chem Soc Chem Commun 1799–1800 36. Sanchez M, Chap N, Cazaux JP, Meunier B (2001) Metallophthalocyanines linked to organic copolymers as efficient oxidative supported catalysts. Eur J Inorg Chem 1775–1783 37. Tao X, Ma W, Zhang T, Zhao J (2001) Efficient photooxidative degradation of organic compounds in the presence of iron tetrasulfophthalocyanine under visible light irradiation. Angew Chem Int Ed 40:3014–3016 38. Tao X, Ma W, Zhang T, Zhao J (2002) A novel approach for the oxidative degradation of organic pollutants in aqueous solutions mediated by iron tetrasulfophthalocyanine under visible light radiation. Chem Eur J 8:1321–1326 39. Tao X, Ma W, Li J (2003) Efficient degradation of organic pollutants mediated by immobilized iron tetrasulfophthalocyanine under visible light irradiation. Chem Commun 80–81 40. Héquet V, Le Cloirec P, Gonzalez C, Meunier B (2000) Photocatalytic degradation of atrazine by porphyrin and phthalocyanine complexes. Chemosphere 41:379–386 41. Nyokong T (2007) Effects of substituents on the photochemical and photophysical properties of main group metal phthalocyanines. Coord Chem Rev 251:1707–1722 42. Ozoemena K, Kuznetsova N, Nyokong T (2001) Comparative photosensitised transformation of polychlorophenols with different sulfonated metallophthalocyanine complexes in aqueous medium. J Mol Catal A 176:29–40
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43. Lukyanets EA, Nemykin VN (2010) The key role of peripheral substituents in the chemistry of phthalocyanines and their analogs. J Porphyrins Phthalocyanines 14:1–40 44. Gürol I, Durmus M, Ahsen V (2010) Photophysical and photochemical properties of fluorinated and nonfluorinated n-propanol-substituted zinc phthalocyanines. Eur J Inorg Chem 1220–1230 45. Ozoemena K, Kuznetsova N, Nyokong T (2001) Photosensitized transformation of 4-chlorophenol in the presence of aggregated and non-aggregated metallophthalocyanines. J Photochem Photobiol A 139:217–224 46. Marais E, Klei R, Antunes E, Nyokong T (2007) Photocatalysis of 4-nitrophenol using zinc phthalocyanine complexes. J Mol Catal A 261:36–42 47. Wöhrle D, Suvorova O, Gerdes R et al (2004) Efficient oxidations and photooxidations with molecular oxygen using metal phthalocyanines as catalysts and photocatalysts. J Porphyrins Phthalocyanines 8:1020–1041 48. Gerdes R, Wöhrle D, Spiller W et al (1997) Photo-oxidation of phenol and monochlorophenols in oxygen-saturated aqueous solutions by different photosensitizers. J Photochem Photobiol A 111:65–74 49. Nensala N, Nyokong T (1997) Photosensitization reactions of neodymium, dysprosium and lutetium diphthalocyanine. Polyhedron 16:2971–2976 50. Nensala N, Nyokong T (2000) Photocatalytic properties of neodymium diphthalocyanine towards the transformation of 4-chlorophenol. J Mol Catal A 164:69–76 51. Agboola B, Ozoemena KI, Nyokong T (2006) Comparative efficiency of immobilized nontransition metal phthalocyanine photosensitizers for the visible light transformation of chlorophenols. J Mol Catal A 248:84–92 52. Xiong Z et al (2005) Enhanced photodegradation of 2,4,6-trichlorophenol over palladium phthalocyaninesulfonate modified organobentonite. Langmuir 21:10602–10607 53. Huang Y, Li J, Ma W et al (2004) Efficient H2O2 oxidation of organic pollutants catalyzed by supported iron sulfophenylporphyrin under visible light irradiation. J Phys Chem B 108:7263–7270 54. Mele G, Del Sole R, Vasapollo G et al (2005) TRMC, XPS, and EPR characterizations of polycrystalline TiO2 porphyrin impregnated powders and their catalytic activity for 4-nitrophenol photodegradation in aqueous suspension. J Phys Chem B 109:12347–12352 55. Sun Q, Xu Y (2009) Sensitization of TiO2 with Aluminium Phthalocyanine: factors influencing the efficiency for chlorophenol degradation in water under visible light. J Phys Chem C 113:12387–12394 56. Kölle U, Moser J, Grätzel M (1985) Dynamics of interfacial charge-transfer reactions in semiconductor dispersions. Reduction of cobaltoceniumdicarboxylate in colloidal titania. Inorg Chem 24:2253–2258 57. Anderson S, Constable EC, Dare-Edwards MP et al (1979) Chemical modification of a titanium (IV) oxide electrode to give stable dye sensitisation without a supersensitiser. Nature Lond 280:571–573 58. Ghosh PK, Spiro TG (1980) Photoelectrochemistry of tris(bipyridyl)ruthenium(II) covalently attached to n-type tin(IV) oxide. J Am Chem Soc 102:5543–5549 59. Giraudeau A, Fan FF, Bard A (1980) Semiconductor electrodes. 30. Spectral sensitization of the semiconductors titanium oxide (n-TiO2) and tungsten oxide (n-WO3) with metal phthalocyanines. J Am Chem Soc 102:5137–5142 60. Special issue on dye sensitized solar cells (2004) Coord Chem Rev 248(issues 13–14) 61. Martinez-Diaz MV, de la Torre G, Torres T (2010) Lighting porphyrins and phthalocyanines for molecular photovoltaics. Chem Commun 46:7090–7108 62. Clifford JN, Yahioglu G, Milgrom LR et al (2002) Molecular control of recombination dynamics in dye sensitised nanocrystalline TiO2 films. Chem Commun 1260–1261 63. Iliev V (2002) Phthalocyanine-modified titania – catalyst for photooxidation of phenols by irradiation with visible light. J Photochem Photobiol A 151:195–199
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64. Mele G, Del Sole R, Vasapollo G et al (2003) Photocatalytic degradation of 4-nitrophenol in aqueous suspension by using polycrystalline TiO2 impregnated with functionalized Cu(II)porphyrin or Cu(II)-phthalocyanine. J Catal 217:334–342 65. Chen F, Deng Z, Li X et al (2005) Visible light detoxification by 2,9,16,23-tetracarboxyl phthalocyanine copper modified amorphous titania. Chem Phys Lett 415:85–88 66. Mele G, Garcia-Lopez E, Palmisano L et al (2007) Photocatalytic degradation od 4-nitrophenol in aqueous suspension by using polycrystalline TiO2 impregnated with lanthanide doubleDecker phthalocyanine complexes. J Phys Chem C 111:6581–6588 67. Sorokin AB, Kudrik EV, Bouchu D (2008) Bio-inspired oxidation of methane in water catalyzed by N-bridged diiron phthalocyanine complex. Chem Commun 2562–2564 68. Sorokin AB, Kudrik EV (2008) N-Bridged diiron phthalocyanine catalyzes oxidation of benzene by H2O2 via benzene oxide with NIH Shift evidenced using benzene-1,3,5-d3 as a probe. Chem Eur J 14:7123–7126 69. Isci U, Afanasiev P, Millet JM et al (2009) Preparation and characterization of m-nitrido diiron phthalocyanines with electron-withdrawing substituents: application for catalytic aromatic oxidation. Dalton Trans 7410–7420 70. Afanasiev P, Bouchu D, Kudrik EV et al (2009) Stable N-bridged diiron (IV) phthalocyanine cation-radical complexes: synthesis and properties. Dalton Trans 9828–9836
Chapter 10
Photosensitisation and Photocatalysis for Synthetic Purposes Lucia Tonucci, Alessandro Cortese, Mario Bressan, Primiano D’Ambrosio, and Nicola d’Alessandro
Abstract The synthetic potential of photocatalytic and photosensitised routes is far from fully realised, even if the new concepts of green chemistry now have a central role. Photocatalysis, such as by means of semiconductors, represents a good tool to obtain industrially attractive chemicals, including conversion of alcohols to aldehydes, oxygenation of hydrocarbons, and reduction of nitrocompounds to amines. The more selective photosensitised reactions, which include photooxidation by singlet oxygen, are useful for obtaining oxygenated derivatives starting from unsaturated hydrocarbons; the reaction products are hydroperoxides, alcohols and carbonyl derivatives, with the main reactions being cycloadditions (4+2 and 2+2) and ene reactions (Schenck reaction). There are also the novel families of sensitisers, like fullerenes and metal macrocycles, which can provide promising alternatives to traditional organic photosensitisers.
10.1
Introduction
The pharmaceutical and food industries and many other industrial processes require various amounts of organic materials. If a derivative is not “natural” the only way to obtain it might be through chemical transformation of a natural raw material. Another problem is sustainability: renewable derivatives must be taken into consideration as a priority, compared to feedstock that comes from fossil fuels. Of course, the world of organic synthesis is huge, so our aim in the present chapter is to explore that part of it that refers to transformations that occur only in the presence of light. In other words, we will exclude all thermal reactions.
L. Tonucci • A. Cortese • M. Bressan • P. D’Ambrosio • N. d’Alessandro (*) Department of Science, University “G.D’Annunzio” of Chieti and Pescara, Viale Pindaro, 42, Pescara, Italy e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_10, © Springer Science+Business Media B.V. 2012
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hν
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Abs Fig. 10.1 Photochemical transformation scheme in which the reagent (R) is not involved in any interaction with the light
We start by introducing the field of photochemistry, which studies the interactions of light with matter that induce chemical transformations. As illustrated in Fig. 10.1, chemical reactions occur due to the energy that photons (hn) provide to a light absorber (Abs), which than makes this energy available for reactions. However, photochemistry embraces all photochemical transformations, where reagents can also absorb light. Our aim is to cover only the field of phototransformations where the reagents are transparent. Remaining within this last limitation, we can introduce two kinds of photochemical reactions that use substances that can absorb light, but that remain unchanged at the end of the reaction. After the photon absorption step, the excited substrate can evolve either by transferring this energy to other species or by reacting with a reagent in its ground state (Fig. 10.1, R), through electron or atom transfer. In both cases, a chemical reaction can occur. The great advantage of such transformations is the potential for high specificity and efficiency, and also the “mode” that is used to obtain the energy input that is sometimes necessary to allow a reaction to occur. This “mode” is particularly intriguing, since it is certainly much more “green” than the classical operations used in thermal chemistry, i.e. those where the heat is supplied by combustion or electricity, by the use of organic solvents, or of toxic metals, and so on. This use of light energy as a green energy source is not new, as even in the early 1900s, Giacomo Ciamician deplored the use of aggressive reagents and high temperatures in organic syntheses, and he believed in the possibility of carrying out photochemical reactions without depletion of the fossil resources [1, 2].
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Fig. 10.2 Photosynthesis, with the production of carbohydrates and oxygen from water and carbon dioxide
Today, the use of energy from light is specifically emphasized for industrial processes because “green chemistry” has become an indispensable concept for chemists and engineers in their thinking, designing and development of any synthetic reaction. The term “green chemistry” was coined by Paul Anastas in the early 1990s, when he was working for the U.S. Environmental Protection Agency. It was defined as “the design of new products and processes that reduce or eliminate the use and generation of hazardous substances” [3]. To meet the principles of green chemistry, the use of renewable feedstocks is fundamental, along with the use of clean solvents (water, supercritical carbon dioxide, ionic liquids, etc.), selective catalysts, non-toxic oxidants (hydrogen peroxide, molecular oxygen), and mild conditions of pressure and temperature. Over the last 20 years, many studies have been published in many and various fields that have followed the concepts expressed by some 12 green chemistry principles. For examples, oxidative catalytic reactions can be carried out in water rather than in organic solvents [4], or by using molecular oxygen as an oxidant, which is always of great interest as the only by-product here is water [5]. The main photochemical process that leads to organic derivatives is photosynthesis (Fig. 10.2). Above all, this is the most important natural event, and this is devoted
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Fig. 10.3 The principal applications of TiO2 as photocatalyst during the last 40 years
to the obtaining of organics starting from the very simple molecules of carbon dioxide and water. The role of photosynthesis is to store the energy of the sun through its transformation into a chemical form, i.e. carbohydrates. A consequence of this is that the water molecule is split, with production of molecular oxygen, while the other reagent, CO2, is fixed into the sugar. This natural event of photosynthesis has inspired a lot of research in the search for synthetic pathways that can be used to furnish a similar crucial result. At the end of the 1960s, Fujishima discovered an interesting phenomenon: when titanium dioxide electrode in an aqueous solution was exposed to a strong light, it produced a gas that bubbled off the surface of the electrode that disappeared when the light was switched off. That gas was shown to be oxygen, and hydrogen was also generated at the counter electrode, which was made of platinum. Thus, the result was a very interesting water-splitting reaction that produced hydrogen and oxygen, which can than be used as fuel. 2H 2 O + 4hv → O 2 + 2H 2
(10.1)
This phenomena is now known as the “Honda-Fujishima effect” [6]. Indeed, Fujishima discovered a system that mimics photosynthesis by using a very simple derivative, TiO2, which thus replaces the chlorophyll [7]. The main difference is obviously that TiO2 only absorbs in the UV region, and not in the Vis one, even if it has a higher stability than chlorophyll. From about 1975–1980, other studies used TiO2 as a redox system, as a photocatalyst in both oxidation (many examples) and reduction (a few examples) modes, thus opening the door for a new field called photocatalysis. The main applications developed over the last 30 years have been, above all, in environmental chemistry, such as for water and air purification, with phenomena that have been classified as advanced oxidation processes (AOP) [8]. More recently, the new concept of autopurification has been introduced into bio-architecture: again, with TiO2, but now in a nanosize form, which can be added to building materials with the goal of the photocatalysis of the degradation of environmental pollutants, such as organic derivatives, nitrogen oxides, to name but a few (Fig. 10.3) [9].
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Fig. 10.4 The most common polymorphic forms of TiO2: rutile (a), anatase (b) and brookite (c) (Source: http://ruby.colorado.edu/~smyth/Home.html)
A large part of the research that has been carried out in the past regarding photocatalysis has favoured the water-splitting reaction and the environmental applications towards the degradation of pollutants. In this last case, the goal is completely reversed, since the selectivity of these processes is not important, and, on the contrary, unselective reactions are required. On the other hand, when the photocatalysis acts as a tool in synthetic chemistry, the selectivity should be as high as possible, to provide reasonable yields of target products. The question now is: how can a photocatalytic system be designed to achieve this goal? The answer is not simple, nor immediate. Although the type of reactor is an important issue for the efficiency and selectivity of any photocatalytic reaction [10], we prefer here to leave aside this aspect, and instead to focus our attention on solvents and catalysts. The solvent certainly has an important role in the evaluation of the whole process, with the first limitation being the concentration of the solute: dilute solutions are used because light must penetrate into the reaction medium to a significant depth to provide efficient absorption from the catalyst. Furthermore, the solvent must be reasonably inactive and transparent to the wavelength range requested. Acetonitrile has been widely used because of both its low absorption in the UV-Vis range and its rare participation in a variety of potential chemical transformations [11]. However, acetonitrile is not a suitable choice if we are to consider our environment [12], and instead, where possible, water is indeed the best candidate to replace it. The advantage of the use of water is its total absence of toxicity and its particularly economic convenience. The most diffuse photocatalyst, remains TiO2, which exists in three polymorphic forms: rutile, anatase and brookite (Fig. 10.4). Historically, anatase and rutile were preferentially used, with anatase showing a higher photocatalytic activity [13]. However, the most used catalyst in environmental applications has been the P-25 TiO2 produced by Degussa (now part of Evonik Industries), in a mixture of anatase/rutile at about a 3:1 ratio. Interestingly, Ohno et al. [14] found that the photocatalytic oxidation of naphthalene is inefficient when
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rutile or anatase are used alone, whereas even a simple mixture of them definitely enhances the reaction. Their conclusion was that the particles of the two polymorphic forms must be in contact, thus leading to a synergistic effect [14]. A comparative study related to the selectivity of obtaining p-methoxybenzaldehyde starting from p-methoxybenzyl alcohol was reported by Augugliaro et al. [15], where three samples of home-made titania (rutile, anatase and brookite) were irradiated in water suspension. Rutile gave the best result in terms of selectivity. Particle size and crystallinity also have important roles: it has been reported that the selectivity in cyclohexane photooxidation is strictly dependent upon the particle size, as the yield of cyclohexanol increases with an increase in the diameter of the particles, whereas the productivity and the cyclohexanone yields both decrease [16]. Alternatively the performance of the photocatalyst can be modified by some metal deposition, which appears to lead to changes in the semiconductor surface properties. The added metal can enhance either the yield of particular products or the rate of the photocatalytic reaction [17]. This effect was first observed in the water-splitting photoreaction, where a photocatalyst of platinum deposited on TiO2, enhanced the production of hydrogen and oxygen [18]. Generally, noble metals deposited on TiO2 enhance the performance of the catalyst, and above all when a gas (namely hydrogen) is a reaction product. However, the metal does not always act in favour of the desired product: for example, gold deposited on anatase negatively affects the activity of the catalyst in the selective photooxidation of cyclohexane, which probably occurs because there is significant modification of the surface OH-population of the catalyst induced by the added metal [19]. Another example, which was reported by Ohthani and his group, deals with the effect of noble-metal-modified titania on the photocatalytic transformation of lysine to pipecolinic acid, where a small effect of the noble metal load on the catalytic activity of TiO2 was seen [20]. Modification of the catalyst surface can also be achieved by non-metal derivatives. In this case, it was recently reported that fluorination of the titania surface can enhance the selectivity for obtaining 1,3-dihydroxyacetone and glyceraldehyde in the photooxidation of glycerol [21]. In conclusion, although several studies have been carried out with the aim of optimization of selectivity, the choice of the catalytic system must still be considered case by case. As showed in Fig. 10.1, there is an alternative pathway by which the light absorber can transfer the energy to the reagent. Among photosensitized processes, the activation of oxygen is by far the most common for synthetic purposes, and this is the reason that from here on we focus our attention on this field. A number of reviews have been published on the chemistry of singlet oxygen [22–26]. However, we retain that a brief overview is necessary to introduce its synthetic potentiality. The existence of singlet oxygen was proposed in 1931 by Kautsky, on the basis of a study previously carried out by Mulliken, in 1928 [27, 28], when molecular orbital theory was applied to the oxygen molecule [29]. The first experimental evidence of the existence of singlet oxygen was published by Foote in 1964, where a solution of sodium hypochlorite and hydrogen peroxide was able to oxygenate olefins [30, 31]. In 1968, luminescence of singlet oxygen was reported
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for the first time, at 1,268 nm in benzene vapour, and it was demonstrated that the emission was due to the energy transfer from the excited state of benzene to oxygen [32]. It then took 8 years to directly measure luminescence in an air-saturated solution [33]. Meanwhile the word luminescence was replaced by phosphorescence, since singlet oxygen gives a forbidden intersystem transition to the final stable triplet state. For the synthetic use of singlet oxygen, as well as the early works by Schenck (see, for example, reference [34]), who investigated the formation of hydroperoxides from olefins for the first time, by the end of 1970s, diffuse applications in organic synthesis had been developed by several authors. We can cite the efforts of Gollnick, who irradiated a methanolic solution of Rose Bengal containing 2,3-dimethyl-2-butene [35], and the pioneering examples of synthetic singlet oxygen chemistry by the Italian group of Forzatti, where they oxidised alkenes to allyl hydroperoxides by methylene blue, in homogeneous solution or using the sensitiser supported on silica [36]. The diastereoselective oxyfunctionalisation of organic derivatives by the ene reaction is also worth noting. While its regioselectivity had been extensively studied previously, only after the 1990s was attention focused on stereocontrol [37]. This breakthrough substantially enhanced the utility of singlet oxygen in diastereoselective synthesis. At present, singlet oxygen is particularly evoked in important photoreactions that deal with the study of its biological effects. Triplet molecular oxygen is relatively stable and diffuses rapidly through most biological media, including cell membranes, which normally act as barriers for many substrates. On the contrary, singlet oxygen reacts quickly with a lot of biological substances, such as fatty acids and proteins, which restricts its ability to diffuse around the media. Thus, the degenerative action of singlet oxygen occurs only at short distances from the photosensitiser that generated it. This phenomena represents the conceptual basis of photodynamic therapies against cancers: molecules selectively attached in a region close to a tumor site can photosensitise the formation of singlet oxygen, which quickly reacts with its closest “neighbours” (for reviews, see references [38–41]). A photosensitiser is a light-absorbing substance that initiates a photochemical or photophysical reaction in another substance (molecule), and is not itself consumed in the reaction. As illustrated in Fig. 10.5, the photosensitiser (S0) must have a high absorption coefficient in the correct spectral region. Through photon absorption, S0 can be excited to S1* in its singlet state. After an intersystem crossing to the triplet state (T1*), the excited sensitiser can excite by a physical step, such as the energy transfer, whereby this second molecule can than react with an organic substrate (Fig. 10.5) [42]. In summarising there above concepts, we can conclude that our aim is to explore the literature to extrapolate all of the applications that are devoted to synthetic purposes that have made use of photocatalysis (atom or electron transfer) and photosensitisation (energy transfer).
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Energy S1* Intersystem Crossing
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S0 Ground state (Abs)
Photosensitiser
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Fig. 10.5 Singlet oxygen formation by a photosensitised process
10.2
Photocatalysis
As defined by Albini and co-workers, a photocatalyst is an active compound in its excited state that increases the reactivity of a substrate through a chemical step (i.e. electron or atom transfer) [42]. Here we have concerned ourselves, above all, with reactions that deal with synthetic purposes, leaving out all of the applications in environmental depollution, water-splitting, hydrogen formation and reduction of gases like CO2. Recently, many interesting reviews have been published about the concept of photocatalysis (see, for example, references [42–44]). The main photocatalysts we are dealing with here are semiconductors, polyoxometallated metal complexes (POM), and some other organic compounds. The chemical reactions mainly occurring by photocatalysis are: – – – –
Oxidation; Reduction; Alkylation; Other reactions, like activation of C–H and C–N bond, etc.
10.2.1
Oxidation Reactions
10.2.1.1
Alcohols
Alcohol oxidation still represents a big challenge for organic synthesis, as the more classical stoichiometric methods use unfriendly environmental reagents (e.g. high valent metals) and conditions that are no longer in agreement with the modern principles of green chemistry [3]. Metal catalysts have contributed to a reduce in the
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OH
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Fig. 10.6 Oxidation of a 1-phenethyl alcohol to acetophenone by anatase TiO2
use of toxic reagents [45–47]; however, there remains the need to develop new methodologies that can contribute to reductions in the use of both materials and energy, as well illustrated by the new concept of the E-factor introduced by Sheldon [48]. Photocatalysis (with UV or visible light) can provide efficient methodologies to oxidise an alcohol functional group to a carbonyl/carboxyl group under green conditions. Many studies have been published in recent years that have dealt with the photocatalysis of benzyl or cyclic alcohols, to obtain their carbonyl derivatives. The oxidation of benzyl alcohols in dry acetonitrile in the presence of TiO2 (anatase) and neat oxygen (P = 1 atm) and irradiated with medium pressure Hg lamps was reported by Mohamed [49]. Figure 10.6 illustrates the oxidation of a secondary aromatic alcohol to acetophenone (with 94% yield). The by-product is benzoic acid, although it does not appear in concentrations higher than 2%. The TiO2 behaves as a classical semiconductor, for the ejecting of an electron (eCB−): *
hv + TiO2 ⎯⎯ → TiO2 → e −CB + hVB
(10.2)
Initially, the oxygen is reduced by the electron to a superoxide radical anion (O2·−), while the alcohol substrate, which is adsorbed on the titanium dioxide, entraps the positive hole and is transformed into a radical cation, which is easily oxidisable by O2·−. The benzyl alcohol oxidation reaction has been examined also in other studies. p-Methoxybenzyl and benzyl alcohols were oxidised by bubbling oxygen through a water solution irradiated by 366 nm light at 300 K in the presence of TiO2 from both home-made and purchased origins (Degussa and Merck) [50]. All semiconductors are active, but with some differences: the commercial oxides speed up the reactions, although the acid and hydroxylated derivatives were also formed; in the presence of the home-made TiO2, only benzaldehyde (28% selectivity) or methoxybenzaldehyde (41% selectivity) and CO2 were produced. By adding small amounts of simple alcohols to the reaction mixture, like methanol, ethanol or isopropanol, the reaction rate was slowed down, while the aldehyde selectivity increased. The authors explained this behaviour as competition between the simple alcohol and the benzyl alcohol in the mineralisation pathway.
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Fig. 10.7 The proposed mechanism for the activity of Nb2O5 as a photocatalyst
An interesting green oxidation of primary or secondary benzyl and aliphatic alcohols was reported by Shishido [51]. The neat substrates are irradiated by UV light (500 W, Hg ultra pressure lamps) at 323 K in an oxygen atmosphere (P = 1 atm) in the presence of Nb2O5 as photocatalyst (which can be recovered at the end of the reaction and reused, without loss of photocatalytic activity). The conversions were very high, although long times of irradiation were necessary (up to 10 days). The products were aldehydes/ketones, carboxylic acids and CO2. Some alcohols were also oxidised in the absence of oxides, but the yields and selectivities were different. Although Nb2O5 does not absorb in the visible region, the reactions can also occur at wavelengths around 400 nm, with good reactivity up to 480 nm. The reaction mechanism with Nb2O5 appears to be slightly different from that commonly reported for other semiconductors. Indeed, although a typical oxide like TiO2 can be active for the oxidation of alcohols, it shows a lower selectivity than Nb2O5. Furthermore, the reaction also occurs in the presence of visible light, which is a region where TiO2 (and also Nb2O5) does not absorb. Starting from the experimental data, this study concluded that the alcohol is adsorbed onto the surface oxide; this alcoholate of Nb5+ absorbs a visible photon, which allows the electron transfer process that reduces Nb5+ to Nb4+. The radical-alcoholate intermediate evolves to a carbonyl derivative, which is desorbed from the surface. Molecular oxygen provides the re-oxidising of Nb4+ to Nb5+ (Fig. 10.7). The alternative mechanism involving the superoxide radical anion appears not to be operative. The primary and secondary benzyl alcohols are effectively oxidised in the presence of some polyoxometalates (POMs). In particular, when the reaction was conducted on 4-methyl benzyl alcohol, in acetonitrile, with an oxygen atmosphere, at 293 K, irradiation of the solution with near UV and in the presence of H3PW12O40 encapsulated on silica, lead to the formation of the 4-methyl benzaldehyde at a 92% yield [52]. When encapsulated, this POM catalyst is more active than in a homogeneous
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Photosensitisation and Photocatalysis for Synthetic Purposes
POM
479
OH
OH
hν POM *
+
POMred + Ar
Ar
R
R
+ O2 O
POM
+ Ar
R
Fig. 10.8 The proposed mechanism for the activity of H3PW12O40 as a photocatalyst
phase, and the significantly higher activity of H3PW12O40/SiO2, as compared with that of pure H3PW12O40, has been attributed to the much greater specific surface area of the composite derivative [53]. Benzyl and alkyl alcohols have been selectively oxidised to carbonyl compounds in 2–3 h without overoxidation products, while low oxidation yields have been obtained in the case of aliphatic and aromatic non-benzyl alcohols. In the proposed mechanism (Fig. 10.8), the excited POM extracts one (or two) electron(s) from the alcohol substrate. The POM catalyst is reoxidised by oxygen and can be reused without any loss of activity. Oxidation of benzyl alcohol to benzaldehyde was reported by Rüther [54]. In spite of the use of acetonitrile as solvent, the methodology can still be considered green since the oxidation was performed by exposure to solar light and under aerobic conditions at room temperature, using the quaternary ammonium salt of S2M18O624− as photocatalyst (known as the Wells-Dawson anion; M = Mo and W). With 88% aldehyde selectivity obtained after 25 days of irradiation, there was 12% benzoic acid as a by-product. To prepare p-anisaldehyde, which is an important derivative in the synthetic chemical industry and is also used as a scent, it is possible to irradiate the p-methoxybenzyl alcohol in the presence of brookite TiO2 (prepared in the laboratory). Photocatalytic oxidation at room temperature leads to the aldehyde in a water mixture exposed to sunlight. The reported yield was 42% (at 65% conversion). After long times of irradiation, CO2 and traces of acids and open-chain derivatives were also detected [55]. Under similar conditions, but with neat benzyl alcohol, Ohkubo and co-workers [56] obtained benzaldehyde with the 9-phenyl-10-methylacridinium cation as photocatalyst. The reaction was conducted with visible light, and the only by-product detected was hydrogen peroxide. A summary of the photocatalysed oxidation of benzyl alcohols is reported in Table 10.1.
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Table 10.1 The photocatalytic oxidations of benzyl alcohols Product (yield, Substrate selectivity) Photocatalyst Solvent; reaction conditions 9-Phenyl-10No solvent; air (1 atm), 15 h, methylacridium r.t. ion O
OH
H
Reference [56]
(n.d.) O
OH
H
H3PW12O40/SiO2
CH3CN; O2 (1 atm), 1 h, r.t.
[52]
S2W18O624−
CH3CN; air (1 atm), 600 h, solar light
[54]
TiO2 (anatase)
CH3CN (dry); O2 (1 atm), 6 h, [49] r.t.
Nb2O5
No solvent; O2 (1 atm), 240 h, [51] 323 K
TiO2 (brookite, home made)
H2O; O2 (1 atm), 8 h, 300 K
TiO2 (home made)
H2O; methanol (small [50] amount), O2 (1 atm), 17 h, 300 K
(92%, n.d.) O
OH
H
(26%, 88%) H3C
OH
H3C
O
H3C
OH
H3C
O
(94%, 99%)
(95%, 96%) OH
O H
OCH3
OCH3
OH
(42%, 65%)
O H
OCH3
OCH3
[55]
(40%, 62%)
Cyclohexanol dehydrogenation to cyclohexanone can be obtained by irradiating either in the B or the Q band of the rhodium (III) Cl(tetraphenylporphyrinate) complex [57]. Geraniol, and in general primary and allyl alcohols (citronellol, trans-2-penten-1-ol, 1-pentanol) can be selectively photooxidised in the presence of P25-TiO2, at l >320 nm, in acetonitrile at 293 K and 1 atm oxygen [58]. In 1–2 h, citral was obtained with 60% selectivity, at 75% conversion of alcohol. Over-oxidation products and CO2 were not observed. Alkoxy radicals were revealed by electron spin resonance during the reaction, while OH· radicals were formed only by a marginal pathway, and consequently in very tiny amounts. The substrate was adsorbed on titania, and after the oxidation step, aldehyde was quantitatively released into solution.
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Photosensitisation and Photocatalysis for Synthetic Purposes
481
OH O
HO
OH
O
O
O
glyceraldehyde OH
HO
OH
dihydroxyacetone
OH
tartronic acid OH
HO
OH
O O
O
OH
O
hydroxyethanoic acid OH
OH
O
HO
OH
mesoxalic acid
formic acid OH
OH
HO
OH
O
HO
OH
O
glyceric acid
O
O
HO O
oxalic acid
hydroxypyruvic acid
Fig. 10.9 The most common products coming from selective oxidation of glycerol
The alcohol conversion was enhanced with the addition of increasing amounts of water, although the selectivity was reduced because CO2 began to be produced. The presence of water diminishes the amount of adsorbed geraniol, and at the same time, it increases the formation of OH·: the result is a loss of selectivity. This behaviour is analogous to the case of allyl alcohols (i.e. pentenyl alcohol), although in the last case, also in the dry mixture reaction, small amounts of CO2 are formed and OH· is seen. Irradiation (l <300 nm) of an acetonitrile solution of 1-aryl-1-alkanols in the presence of 9,10-dicyanoanthracene (DCA) and oxygen gives the corresponding carbonyl derivative with good yields and high selectivities. However, when the starting material was replaced by 2-aryl-1-alkanols, the relative yield of the 2-aryl aldehydes was noticeably lowered (<10%), although the selectivity remained extremely high (>99%). In general, the conversion of 1-aryl-1-alkanols rises if the para position is substituted by an electron-donating group; on the contrary, the presence of an electron-withdrawing group (e.g. –CF3) slows down or totally inhibits the oxidation of the alcohol [59]. Selective transformation of glycerol remains a dream of chemists, but we are still far from obtaining efficient and selective processes when operating, if possible, under green conditions. Taking into consideration exclusively the oxidation reaction, Fig. 10.9 illustrates the main products that can be obtainable by selective transformation of glycerol.
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L. Tonucci et al.
A recent overview of the potential applications of photocatalysis to the synthesis of glycerol derivatives was reported by the Minero research group [21]. The kinetics and mechanisms of transformation of glycerol were explored as a function of several experimental parameters, like catalyst, pH, starting concentration of glycerol, etc. The authors demonstrated that a useful tuning of the catalyst surface properties (i.e. by fluorination of P25-TiO2) greatly influences the selectivity of the whole process. Another recent example of the selective transformation of glycerol was reported by Augugliaro and co-workers [60]: they performed the photocatalytic transformation of glycerol in oxygen-saturated water solution under non-buffered conditions. The mixture was irradiated by 366 nm light at 300–320 K in the presence of TiO2. The products were 1,3-dihydroxyacetone, glyceraldehyde, formic acid, CO2, and two derivatives at higher molecular mass. The best results were obtained with Degussa and Aldrich TiO2; in contrast, with home-made TiO2, low conversions and worse selectivities were obtained, and a large quantity of CO2 was observed.
10.2.1.2
Hydrocarbons
Selective oxygenation of hydrocarbons is a fundamental industrial technology. Catalysis and organometallic chemistry now allow activation of the C–H bond, but the field still requires a lot of work [61]. Photocatalysis can also contribute to the solving of the problem of C–H activation, and some interesting reactions have been discovered recently, although it is necessary to increase efforts to solve the big problem of selectivity. Alkyl aromatic hydrocarbons can be efficiently photooxidised (with visible light) when neat and in the presence of oxygen (1 atm), using diiron(III) bisporphyrin as photocatalyst. The products, are illustrated in Fig. 10.10, and they were obtained with 100% selectivity [62]. In summary, the diiron(III)-m-oxo-bisporphyrin absorbs a photon that allows for the generation of a highly oxidizing ferryl (FeIV O porphyrin) intermediate that can oxygenate a number of hydrocarbons, with the concomitant formation of reduced Fe(II) porhyrin. The molecular oxygen re-forms the diiron(III)-m-oxo-bisporphyrin, closing the photocatalytic cycle (Fig. 10.11). Again, the porphyrins have been used to photocatalyse the oxidation of unsaturated hydrocarbons to epoxides or carbonyl derivatives by oxygen. Maldotti and co-workers reported the irradiation (light, l >350 nm) of cyclohexene and cyclooctene at room temperature and 1 atm oxygen pressure, using iron(III) mesotetrakis(2,6-dichlorophenyl)porphyrin in the presence of a surfactant in aqueous media [63]. Surprisingly, from cyclooctene, the main reaction product was the epoxide, with a selectivity >90%, while from cyclohexene, the main reaction product was the a,b-unsaturated ketone. The regiochemistry of the photocatalysed oxidation of unsaturated hydrocarbons was recently investigated [64]. The visible-light photooxidation of cyclohexene
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Photosensitisation and Photocatalysis for Synthetic Purposes
483 H
O
h , O2
O
h , O2 O
h , O2
Fig. 10.10 Aromatic hydrocarbons photooxidised by diiron(III) bisporphyrin, with 100% selectivity
(room temperature, 1 atm O2) using commercial 5,10,15,20-tetrakis(pentafluorophe nyl)porphyrin-iron(III) chloride in dichloromethane and in the presence of several solid bases, led to the epoxide. The presence of the solid base was extremely important, as without this, the reaction went through porphyrin-photosensitised oxidation of the alkene (by singlet oxygen), which gave the expected allyl alcohol as the reaction product. Mg-Al hydrotalcite showed the best selectivity versus the epoxide. Porphyrins supported on cyclodextrines or Nafion in 2-propanol can photocatalyse the oxidation of cyclohexene to cyclohexenol and cyclohexenone. Of note, there is a difference in the turnover number (TON) and porpyhrin stability when the complex was used in a homogeneous or heterogeneous phase: cyclodextrine- and Nafion-supported catalysis showed an increased TON with a noticeably better chemical stability of the photocatalyst [65, 66]. Also, P25-TiO2 by Degussa has been used [67] to photocatalyse the oxidation of hydrocarbons, like ethylbenzene, toluene, cyclohexane and methylcyclohexane, to, respectively, acetophenone (selectivity, 100%), benzaldehyde (selectivity, 90%), a cyclohexanol/cyclohexanone mixture, and in the case of methyl cyclohexane, a mixture of several oxygenated products. The reactions were performed with a water suspension of TiO2 irradiated for 2 h. H2O2 (30%) was also added in the case of cyclohexane. The advantage of this reaction is that neither CO2 nor open-chain products were detected. Simple alkenes can be photooxidised efficiently in presence of semiconductors (e.g. TiO2, MoO3, WO3, CdS, CuMoO4). Propylene in a water mixture and in the presence of titania and oxygen was irradiated by a 500 W Hg lamp. Acetaldehyde was obtained here with a 78% yield, while small amounts of epoxide, alcohol and
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L. Tonucci et al. C6F5 N
III
Fe
N
N
C6F5
N
hνvis O
O
C6F5
C6F5 III N
N
Fe N
C6F5
N C6F5
C6F5
N
II
Fe
N
O
N
C6F5
N
C6F5
C6F5 O N IV N
1/2 O2
N
C6F5
N
II
N
N
O
C6F5
N
C6F5
C6F5
Fe
Fe
N
C6F5
RH
C6F5
N
II
N
Fe N
N
C6F5
ROH
C6F5
Fig. 10.11 Photocatalytic cycle for the oxidation of hydrocarbons in presence of diiron(III)-moxo-bisporphyrin
higher molecular weight aldehydes were also formed [68]. The photooxidation of cyclohexane was investigated by Boarini under similar experimental conditions [69]. They studied the distribution of the products relative to the solvent used. By increasing the content of CH2Cl2 in the solvent mixture formed by cyclohexane itself and methylene chloride, the rate of formation of mono-oxygenated products was enhanced, and the production of CO2 was decreased. At the same time, the alcohol:ketone ratio was increased.
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Photosensitisation and Photocatalysis for Synthetic Purposes
485
SO3H
N
N SO3H
Fe(III)
HO3S
N
N
SO3H
Fig. 10.12 Iron (III) meso-tetrakis(sulphonatophenyl)porphyrin
Titania doped with 0.5% Fe3+ in an oxygen atmosphere can photocatalyse the near UV (365 nm) oxidation of toluene to benzaldehyde. Benzyl alcohol and carboxylic acid were detected only after long irradiation times [70]. The yield and selectivity of this doped TiO2 were higher than when the oxide was used alone. However, the doped catalyst tended to lose the iron, and hence the catalyst cannot be re-used [71]. An iron sulphonated porphyrin (Fig. 10.12) that is covalently bound to TiO2 can photocatalyse (365 nm, in pure oxygen) the oxidation of cyclohexane and cyclohexene within 3–4 h. Comparing the behaviour of the heterogeneous composite catalyst with both TiO2 and porphyrin used alone, in the first case, there was a greater selectivity for the formation of cyclohexanol, and generally versus the monooxygenate derivatives of cyclohexene (e.g. alcohol, ketone, epoxide). In addition, the turnover number was increased from 120 to 12,000 [72], while the formation of CO2 was negligible. Cyclohexane and cyclohexene can be oxidised, respectively, to cyclohexanol/ cyclohexanone and cyclohexenyl hydroperoxide/cyclohexenone under the following reaction conditions: l = 254 nm, 280 nm or 300 nm, 1 atm O2, 293 K, in the presence of the POM W10O324− supported on silica [73]. The cyclohexane oxidation
486
L. Tonucci et al. OH
OH
OH OH
+ OH
.
+
+
OH
Fig. 10.13 Oxidation of benzene by a hydroxyl radical
occurred in the absence of solvent or in dichloromethane. The ketone:alcohol ratio was 2.3:1, and the yield of CO2 was <0.5% (with only TiO2: 3–5%), and that of the hydroperoxides was <5% [74]. When the cyclohexene photooxidation was conducted under similar conditions (325 nm, 1 atm oxygen, 294 K) but in the presence of W10O324− mixed with some iron porphyrine derivatives, low amounts of hydroperoxides and high amounts of alcohol/ketone (40% selectivity) were obtained; the ketone:alcohol ratio in this case was about 1:1, and neither CO2 nor H2O were observed [75]. The functionalisation of benzene has been obtained in H2O/CH3CN as solvent and with a suspension of TiO2 as photocatalyst. Phenol (12% yield), catechol and hydroquinone were obtained as the final products (Fig. 10.13). This study further investigated several modifications to the TiO2 photocatalyst, i.e. doped by Fe3+, H2O2, [Fe3+ + H2O2], Pt nanoparticles or fluorinated TiO2. In all cases, the yield and selectivity in phenol was increased, the best results in this sense were obtained with a TiO2 suspension in the presence of POM (PW12O403−) [76]. From the synthetic point of view, a methodology that improves selectivity is the use of semiconductor oxides highly dispersed onto silica (e.g. V2O5/SiO2, TiO2/ SiO2, ZnO/SiO2). Generally, these can be prepared by impregnation or sol-gel methods, and they show novel interesting behaviours: the excited state of the metal oxides reduces the oxygen, allowing easy contact between the oxygen radical anion and the substrate [77]. The result is a different product distribution, compared to the semiconductors alone. For example, in the case of propylene, propylene oxide was obtained with a variety of the above binary systems: in the presence of TiO2/SiO2, with a conversion of 10% and selectivity of 58% [78], whereas in the presence of ZnO/SiO2, there was conversion of 9% and selectivity of 33% [79]. The same reaction was conducted also with saturated hydrocarbons. In the presence of V2O5/ SiO2, propane was oxidised to carbonyl products with only traces of carbon oxides [80], while alumina-supported vanadium oxide showed a specific photocatalytic performance for the oxidation of cyclohexane, to produce cyclohexanone [81]. The mechanism of this reaction was studied in detail [82], suggesting as the ratedetermining step the elimination of a proton from the adsorbed hydrocarbon under photo-irradiation.
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Photosensitisation and Photocatalysis for Synthetic Purposes
487
TiO2 O2 r.t. 1 atm hν (365 nm) O O
Fig. 10.14 One-pot photosynthesis of 6H-benzo[C]chromen-6-one, a coumarin derivative
Oxygenated polycyclic aromatic hydrocarbons can be obtained by irradiating the polycyclic aromatic hydrocarbon (PAH) in dry acetonitrile with visible light, in the presence of oxygen and the 9-mesityl-10-methylacridinium ion, which acts as an electron-transfer photocatalyst. The reaction proceeds via O2−., which provides radical coupling with the radical cation of the PAH, and forms epidioxy-PAH. The reaction also works in the presence of alkenes, giving the oxetanes as the final products [83]. Coumarins are important chemicals that are used in the pharmaceutical industry as precursors in the synthesis of a number of anticoagulants. Various methods are available to obtain coumarins, generally starting from compounds like o-cresol, phenol and salicylaldehyde, which cannot be defined as green. This is the reason for the importance of the one-pot coumarin synthesis published by Higashida [84]. In acetonitrile and water, the hydrocarbon was irradiated by 365 nm light at room temperature and pressure, in presence of TiO2. The yield for the coumarin derivative was 45% (Fig. 10.14). Naphthalene has shown interesting photoreactivity in the presence of TiO2, depending strictly on the nature of the solvent; namely, aqueous or organic. In water media, the reaction products were cis and trans-2-formylcinnamaldehydes and 1,4-naphthoquinone (Fig. 10.15a), while in acetonitrile, phthalic anhydride was formed, together with 1,4-naphthoquinone (Fig. 10.15b) [85]. Of note, Ti-pillared montmorillonite can behave as photocatalyst in the oxidising of neat aromatic hydrocarbons (toluene and xylenes) to aldehydes at 1 atm oxygen with near UV light [86]. At the end of this reaction, CO2 is present in very low amounts, and the overoxidation of the reaction products is extremely low for the optimised reaction time (3–4 h). This study also compared the results obtained under analogous conditions: in the presence of P25-TiO2 from Degussa, with the selectivity in the aldehyde derivatives noticeably higher for the Ti-montmorillonite photocatalyst, and the production of CO2 lower.
10.2.2
Reduction Reactions
Compared with the number of reports in the field of oxidation photocatalysis, the photocatalytic reduction reactions have been shown to be of lesser interest, as there
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L. Tonucci et al.
a
O
H
O
+
O H
H2 O
O H
+ hν, TiO2
O O
H
b
O
O
CH3CN
O
+
hν, TiO2 O O
Fig. 10.15 Photooxygenation of naphthalene with TiO2 in water (a) and organic (b) solvents NO2
NH2
hν, TiO2 (anatase) EtOH
O
O OMe
O
O
O
O
OMe
Fig. 10.16 Photocatalytic reduction of a nitroaromatic derivative in the presence of TiO2
are very few references in the literature. An intriguing example is the reduction of aliphatic and aromatic nitrocompounds to amines in the presence of TiO2. This reaction is depicted in Fig. 10.16, and it was conducted in ethanol under a N2 atmosphere; in the reported example, the product yield was 85%, whereas for other nitroaromatic derivatives, the yields reported have never exceeded 75% [87]. In alcoholic solvents, 4-nitrophenol can be reduced to 4-aminophenol in the presence of TiO2 under UV light, with a selectivity close to 100% [88]. In particular,
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Photosensitisation and Photocatalysis for Synthetic Purposes
489
NH2
+
N
O-
N NH
N
N
Fig. 10.17 Aromatic products obtained from photocatalytic UV light reaction of nitrobenzene in the presence of cyclohexene
by changing the solvent from methanol to ethanol, (normal and iso) propanols, and finally (normal, iso) butanols, it was possible to note a stabilising effect of the solvent (due to its polarity/polarisability) on the charged intermediate species. The reduction of nitrobenzene, nitrotoluene (both, 3- and 4-) and nitrobenzonitrile in deoxygenated solution with TiO2 in the presence of a simple alcohol as a sacrificial electron donor, like methanol or isopropanol, leads to the formation of amines. Some differences have been observed: nitrobenzene lead to the formation of anilines in high yields and selectivities, while when 4-nitrobenzonitrile was the reagent, 4-aminobenzonitrile was formed with low selectivity. The proposed explanation was that the electron-withdrawing nature of the substituent increased the acidity of the hydroxylamine hydrogen, the proposed intermediate, which increased the electron density on the nitrogen, and made the reduction less favorable [89, 90]. When nitrobenzene was irradiated by UV light in the presence of cyclohexene and semiconductors like TiO2, WO3 and CdS, at room temperature and 1 atm air pressure, new interesting functionalities were obtained (Fig. 10.17) [91]. While in the absence of semiconductors, a random distribution of the four products was obtained, with yields ranging from 15% (aniline) to 32% (both, cyclohexenyl aniline and N-oxide of azobenzene), in the presence of photocatalysts, better selectivity was observed, depending on the nature of the semiconductor: TiO2 enhanced the formation of azobenzene, CdS of aniline, and WO3 of both azobenzene N-oxide and azobenzene. Another interesting reaction is the reduction of arylazides to amines, photocatalysed by CdS or CdSe nanoparticles in water solution (neutral pH) at room temperature and pressure. Here, the amines were produced with high yields and about 100% selectivity. In this system, sodium formate acts as a sacrificial electron-donor (Fig. 10.18) [92].
490
L. Tonucci et al. NH2
N3
hν CdS or CdSe nanoparticles R
R
HCOONa
CO2
Fig. 10.18 Photocatalytic formation of aniline catalysed by CdS and CdSe nanoparticles O
hν
+
POM acetonitrile O
Fig. 10.19 Photoalkylation of butenone by cycloheptane in the presence of TBADT
10.2.3
Inter and Intramolecular C–C Bond Formation
It is known that alkanes do not absorb in the visible or near UV regions, although this problem can be solved by the use of photocatalysts, such as POMs. Tetrabutylammonium decatungstate (TBADT) is an emerging photocatalyst because it absorbs in the UV-A region, which makes it suitable for sun-light-driven photoreactions. TBADT has been used as the photocatalyst in the alkylation of electrophilic alkenes under mild conditions, which avoided the synthetic steps that involve alkyl and acyl halides. The photoreaction proceeded in de-aerated acetonitrile, with a 56% yield (Fig. 10.19) [93]. tert-Butylcyclohexane and methylcyclohexane can react efficiently with electrophilic olefins (e.g. isopropylidenmalononitrile, cyclohexylidenmalononitrile) at 310 K under a N2 atmosphere in acetonitrile, in the presence of the decatungstate anion. Only two products were formed in the reaction mixture, and the reaction was guided by the steric hindrance of the substituent. The 1,3-substituted product was formed mainly in the cis orientation, with the 1,4-substituted product in the transorientation; to support the steric effects, 1,2-substituted products were not detected (Fig. 10.20) [94]. The same photocatalyst can be also used in an acylation reaction between heptanal and the cis-malonic acid dimethyl ester with UV light (310 nm) (Fig. 10.21) [95]. Indeed, the same research group obtained a better yield of the ketone product shown in Fig. 10.21 simply by exposing the reaction mixture for 16 h to the summer sunlight on the laboratory window ledge [96].
10
Photosensitisation and Photocatalysis for Synthetic Purposes
491 Me
NC tBu
Me
H
CN
h
+ Me
tBu
CN
acetonitrile 48 hours
Me NC Me
51% cis +
NC
H NC
tBu
Me
19% trans
Fig. 10.20 Photocatalysed reaction between cycloalkanes and olefins in the presence of the decatungstate anion O
O
+ n-C6H13
MeO2C
CO2Me
H
h
acetonitrile
n-C6H13
CO2Me CO2Me
Fig. 10.21 Acylation of cis-malonic acid dimethyl ester photocatalysed in the presence of TBADT
F
F
+
NC
H N-Bz
N-Bz CN
Fig. 10.22 Alkylation reaction photocatalysed in the presence of CdS or ZnS
Semiconductors like CdS and ZnS can also photocatalyse photoalkylation reactions to a double bond. Figure 10.22 illustrates the reaction between cyclopentene and an electrophilic alkene that occurs in acetonitrile, with a product yield of 81% [97]. A series of bicyclic, tricyclic and tetracyclic derivatives has been synthesised by oxidative photo-induced electron transfer (PET) reactions using various cyclic
492
L. Tonucci et al.
OSiMe3 H
h acetonitrile DCA
O
H
Fig. 10.23 Example of the PET synthetic reaction reported in reference [98]
H COOEt O COOEt
COOEt
hν DCA benzene
O COOEt
Fig. 10.24 Cyclisation of diethylmalonate derivatives in benzene in the presence of DCA
cyclopropyl(vinyl) silyl ethers with an olefinic or acetylenic side chain. The reaction was carried out in the presence of DCA in de-aerated dry acetonitrile at 273.15 K (Fig. 10.23) [98]. The Diels-Alder reaction of furans represents an intriguing method for the preparation of polycyclic molecules with high regio-selectivity and stereo-selectivity, although they often need hard experimental conditions. Arai and co-workers [99] reported an interesting intramolecular cyclisation of furans in the presence of DCA. Diethylmalonate derivatives irradiated by a high pressure Hg lamp at 293 K in several solvents were transformed selectively into diasteromerically pure forms of the corresponding polycyclic compounds. Among the solvents investigated (benzene, toluene, EtAc, THF, CH3OH, CH3CN, DME and 1,4-dioxane), the apolar ones gave better results in terms of conversions and selectivities; furthermore, benzene showed an almost quantitative conversion (selectivity of about 85%) after 84 h of irradiation (Fig. 10.24). On the other hand, when a phenyl substituent was present on the furane ring, the reaction pathway changed, and both a spyro and a tricyclic derivative were formed (Fig. 10.25). It is important to note that in this last case, the reaction also occurred in polar solvents (acetonitrile and methanol), avoiding the use of the toxic benzene. The well known Ru(bpy)32+ can be used as photocatalyst for [2+2] cycloaddition reactions. The advantage here is that it can be excited by visible light (450 nm), and its excited state has a relative long lifetime (about 600 ns). Ru*(bpy)32+ can be quenched either by a reductant or an oxidant. For the former, a secondary electronrich amine (i.e. i-Pr2NEt) reduces the complex to Ru(bpy)3+, which transfers the
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Photosensitisation and Photocatalysis for Synthetic Purposes
493
COOEt
Ph
Ph
COOEt
methanol
O
COOEt
O
+
COOEt DCA, 12 h O
Ph
Fig. 10.25 Cyclisation of diethylmalonate derivatives in polar solvent in the presence of DCA
O
O
CH3CN, vis. light, 50'
O
O
H
H
Fig. 10.26 The [2+2] cycloaddition of a bis(enone) photocatalysed by Ru(bpy)32+ MeO MeO
CH3NO2, vis. light H O
H
3.5 hours O
Fig. 10.27 The [2+2] cycloaddition of an electron-poor olefin photocatalysed by Ru(bpy)32+
electron to the substrate (electrophilic olefins, such as aryl enones), to transform it into a radical anion that is ready to provide cycloaddition. However, this mechanism required an electron-poor olefin for efficient reduction by Ru(bpy)32+. Figure 10.26 illustrates the cyclo-adduct that can be obtained with an 89% yield and high diasteroselectivity (>10:1 d.r.). To increase the Ru(bpy)32+ solubility, the addition of LiBF4 is necessary. This reaction can be conducted under fully green conditions; indeed, the reaction proceeds with comparable yields also in presence of ambient sunlight (inside the laboratory, near the window) [100]. When the olefin is electron-rich, it is necessary to change the reaction system: it is important to have an oxidant quencher, like methylviologen (MV2+), which extracts an electron from Ru*(bpy)32+; the complex can then oxidise the substrate, which is transformed into a radical cation. The reaction in Fig. 10.27 occurs in dry nitromethane in 3.5 h [101]. The yield and the diastereoselectivity are comparable to the previous example, and this reaction can also be carried out with ambient sunlight. An intermolecular [2+2] cycloaddition in the presence of Ru(bpy)32+ has been obtained by irradiating two acyclic enones in acetonitrile with visible light. The presence of at least one aryl enone is necessary, to facilitate the start of the reaction (Fig. 10.28) [102].
494
L. Tonucci et al. O
O
O
O
CH3CN,
+
vis. light, 4 h
Me
Fig. 10.28 The [2+2] intermolecular cycloaddition of acyclic enones photocatalysed by Ru(bpy)32+
N
+ Alkene (R) CO2Me
hν methanol CdS/SiO2
HN
HN
+ R
CO2Me
H
CO2Me
Fig. 10.29 Synthesis of a-aminoesters photocatalysed by CdS/SiO2
A further synthetic route that can reach the goal of C–C formation is the photocatalysed reaction between aromatic imines and olefins, to give the saturated amino derivatives. The reaction has been performed in methanol with a suspension of CdS as photocatalyst, and light >400 nm [103]. The same reaction can be performed with silica-supported CdS, resulting in the production of small amounts of an imino reduction derivative, the yields of which depended on the nature of the alkene (Fig. 10.29) [104]. A detailed mechanistic study of C–C bond formation through semiconductor photocatalysis that mainly used ZnS was published by Horner [105]. They also investigated the role of substrate adsorption and the nature of photoreactive surface sites in the photodehydrodimerization of 2,5-dihydrofuran. The experimental data indicated that the organic substrate was adsorbed onto the semiconductor surface at all of the available zinc sites. They suggested a concerted dissociative mechanism, whereby electron transfer (from substrate to the hole) and deprotonation occur simultaneously. Alternatively, both the step-wise oxidation mechanisms and the involvement of the sulphur radical (already observed on the surface of the semiconductor) in the hydrogen abstraction step appear to be excluded since previous experiments conducted by other researchers did not show any reactivity between THF and the methyl sulphur radical [106].
10.2.4
C–N Bond Formation
Pipecolinic acid serves as a substrate of some non-ribosomal peptides and polyketide synthetases, which results in the formation of secondary meta bolites with interesting pharmacological activities, e.g., the immunosuppressor rapamycin [107].
10
Photosensitisation and Photocatalysis for Synthetic Purposes H H2N
495 COOH
COOH
hν NH2
Pt or PtO2
NH
CdS or TiO2
Fig. 10.30 Photosynthesis of pipecolinic acid from l-lysine in the presence of CdS H3C CH
hν acetonitrile
CH2
+
NH
HO
CH2 CH2
ZnO, TiO2, CdS/zeolite
H N
H N
N H
N H
a
b
H2 N
Fig. 10.31 Products obtained from irradiation of N-(b-hydroxypropyl)ethylenediamine in the presence of semiconductors/zeolite
Pipecolinic acid can be synthesised using a photocatalyst that is obtained by loading Pt or PtO2 onto CdS or TiO2 particles. The photoreaction is conducted in de-aerated water solution, and the reaction can evolve in two different directions: the formation of pipecolinic acid, and the racemisation of the reagent, i.e. l-lysine. Only the correct amounts of the platinum derivatives (0.3% Pt or PtO2) can enhance the yield of pipecolinic acid (Fig. 10.30) [108–110]. Of note, under some particular conditions, the deaminocyclisation reaction occurs, which preserves the configuration of the pre-existing chiral carbon, allowing acceptable enantiomeric excess to be obtained. Substituted piperazines are very important in medicinal chemistry. As an example, the 2-methylpiperazines are commonly used as intermediates in the synthesis of an important class of quinolone-type antibacterial derivatives: i.e. lomefloxacin [111]. With this concept in mind, the most important amine dehydrogenation reactions that deserves to be cited is the UV irradiation of the N-b-hydroxyalkylethylendiamines in acetonitrile under continuous oxygen bubbling in the presence of a composite material formed by loading semiconductors, like TiO2, CdS and ZnO, on zeolites [112]. Higher reaction yields of piperazine (Fig. 10.31b) and alkylpiperazine (Fig. 10.31a), the two products of the reaction, were obtained when the binary TiO2/zeolite system was used as photocatalyst. The semiconductors alone did not catalyse this reaction. Again, when the TiO2/zeolite binary system was irradiated by UV light in acetonitrile and in the presence of ethylenediamine, propylene glycol and oxygen, dihydropyrazine was formed, which is an important intermediate for pyrazine synthesis. Depending on the nature of the zeolite used (HY, HZSM-5, Hb and HM), different yields in dihydropyrazine can be obtained (best value, 20%, with Hbzeolite) [113].
496
L. Tonucci et al. CH3
CH3
hν ethanol TiO2 r.t., 1 atm of air N
NO2
CO2Et
H
Fig. 10.32 Photocarbonylation reaction catalysed by TiO2 Ph
Ph
AgF
+
Ph
C Ph
H
Ph
C
F
Ph
Fig. 10.33 The synthesis of triphenylfluoromethane photocatalysed by TiO2
It is possible to carry out the carbonylation reactions avoiding the use of phosgene [114]. Figure 10.32 illustrates the transformation of p-nitrotoluene to the corresponding carbamate in ethanol with TiO2 at room temperature and pressure, with a selectivity of 85% and a conversion of 26% [115].
10.2.5
Miscellaneous
Diaryl and alkylaryl sulphides in dry acetonitrile can be photooxidised to sulphoxides using 2,4,6,-triphenyl(thia)pyrylium salt encapsulated in zeolite or adsorbed on silica, to prevent the facile photodegradation. As an example, when irradiated with visible light in the presence of this catalyst, thioanisole has been oxidised to sulphoxide with a yield of 85% [116]. The synthesis of fluorinated compounds often uses toxic and dangerous reagents that require particular attention. Organic fluorine derivatives can be synthesised safely by a photocatalytic method, with TiO2 as photocatalyst [117]. Triphenylmethane in acetonitrile can react with AgF in an argon atmosphere under irradiation, and in the presence of the photocatalyst, leading to triphenylfluoromethane as the main reaction product (yield, 57%; Fig. 10.33). The irradiation of aniline in ethanol under mild conditions using sunlight and CdS as photocatalyst leads to the production of azobenzene. Under continuous oxygen bubbling, the substrate is adsorbed onto the CdS, which acts as a semiconductor,
10
Photosensitisation and Photocatalysis for Synthetic Purposes
497
NH2
hν
2
N
N
sunlight ethanol, O2
Fig. 10.34 Photocatalytic transformation of aniline to azobenzene by sunlight
I −O
I O
O
I
Br
−O
−
O
O
I
O
Br O
O
O2N
COO−
NO2
COO−
COO−
Cl
Rose Bengal
Fluorescein I
−
O
Eosin Blue
I O
O S
(H3C)2N I
N+(CH3)2
I N
COO−
Methylene Blue Erytrhosin B
Fig. 10.35 Common photosensitisers used in organic synthesis
by transferring an electron from aniline to molecular oxygen. Then the superoxide radical anion oxidises an aniline moiety to nitrosobenzene, which attacks another aniline molecule, to produce azobenzene (Fig. 10.34) [118].
10.3
Photosensitisation
Initially, the most popular photosensitisers used for organic synthesis purposes were Rose Bengal (RB), fluorescein, eosin blue, erytrhosin B, methylene blue (see Fig. 10.35) and fullerene. However, attention has more recently turned to the porphyrins and their analogues because of their presence in natural systems, which makes them ideal candidates for singlet oxygen generation. The most studied for this purpose are haematoporphyrin and two of its synthetic analogues: octaethylporphyrin (OEP) and tetraphenylporphyrin (TPP) (Fig. 10.36).
498
L. Tonucci et al. Ph
NH
N
NH
N
N
NH
Ph
Ph N
HN
N
HN
HN
N
Ph
Ph = Phenyl haematoporphyrin
octaethylporphyrin OEP
tetraphenylporphyrin TPP
Fig. 10.36 The most commonly used haematoporphyrins as photosensitisers
Fig. 10.37 Molecular formula of the phthalocyanine macrocycle N
N N
HN
NH
N N
N
Water-soluble porphyrins, whether metal-free or not, can be obtained through sulphonation, carboxylation or alkylation with N-pyridyl substituted compounds of the corresponding apolar derivatives. Generally, these polar molecules remain monomeric in aqueous solution, which leads to satisfactory absorption of solar light, in terms of both intensity and wavelength (e.g. TPP can absorb up to 46% visible light) [119]. The most common porphyrin analogues are the phthalocyanines (Fig. 10.37). These are an important class of macrocycles that are intensely coloured and differ from the porphyrins as they have four nitrogen atoms that link the pyrrolic units. Due to the presence of four benzene rings at the periphery of the macrocycle, the extended conjugation shifts absorption wavelengths to >600 nm [120].
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Photosensitisation and Photocatalysis for Synthetic Purposes
499
Longer lifetimes of the triplet state and higher singlet oxygen quantum yields are typical properties of a good photosensitiser; these are also the characteristics of the metal phthalocyanines with diamagnetic ions like Al3+ and Zn2+. Recently it was also demonstrated that the tetrasulphophthalocyanines of Pt and Pd were able to generate singlet oxygen which can be used for synthetic purpose in ene reaction [121]. However, in general, the water-soluble derivatives, such as the tetrasulphonated phthalocyanines and the tetracarboxylated phthalocyanines have the tendency to form dimeric species and large aggregates in aqueous media, a phenomenon that decrease remarkably the 1O2 quantum yields [24].
10.3.1
Photooxygenation Reactions
It is known that the singlet oxygen reactivity versus nucleophilic reagents is highly selective. This makes the photooxygenation route extremely advantageous, compared to the more common thermal chemical methods. As an example, in the early 1970s, the photoreaction for synthesis of a perfume component was reported, namely cis- and trans-ocimene, starting from a-pinene [122]. Again, in the same field, there have been several other examples, such as the oxidation of terpenes and terpenols [123–126], and the oxidation of citronellol [127, 128], to obtain several important fragrances, among which there is rose oxide [129]. However, to better understand the role of photosensitisers in organic synthesis, it is necessary to schematise the reactivity of singlet oxygen versus electron-rich species (Fig. 10.38), as follows: – [4+2] cycloaddition to conjugated dienes, anthracene and substituted anthracene, with the formation of endoperoxide intermediates (Fig. 10.38a); – [2+2] cycloaddition to enol-ethers, enamines and electron-rich olefins without allylic hydrogens, for the formation of 1,2-dioxetanes (Fig. 10.38b); – ene reaction (Schenck reaction) of double bonds, with the formation of allyl hydroperoxydes (Fig. 10.38c); – reactions involving lone-pair-heteroatom derivatives (S, N, P).
10.3.1.1
[4+2] Cycloaddition
The endoperoxide derivatives formed in [4+2] cycloaddition are important building blocks in organic synthesis, as they allow oxygen insertion into large and variegated kinds of organic substrates. These reactions have also been conducted on pentatomic heterocycles, such as furans, tiophenes, pyrroles, oxazoles, imidazoles, indoles, pyridines, pyrazines and pyrimidines [26]. The reaction of singlet oxygen with furfuryl alcohol in water in the presence of Rose Bengal as photosensitiser leads to the formation of different products, all of which have endoperoxide as the common intermediate (Fig. 10.39) [131].
500
L. Tonucci et al. a
1O2 Ph
Ph
Ph
[4+2]
Ph O
O
b O
O
1O2 [2+2]
c
OOH 1O2 ene
Fig. 10.38 Typical reactions involving singlet oxygen [130]
O
HO
O
O
O
O O
CH2OH
OH
OH O
O
CH2OH
O HO O
Fig. 10.39 Reaction scheme of singlet oxygen with the furfuryl alcohol
Another example is the synthesis of endoperoxide in the presence of zinc secoporphyrazine as the singlet oxygen sensitiser [132]. Furfural has also been usefully photooxidised in methanol solution, with the formation of the same endoperoxide mentioned above for furfuryl alcohol (Fig. 10.40). This reaction led to the formation of hydroxyfuranone (yield >90%), which was successively acetylated with l-menthol, to form (5R)- and (5S)-5-l-menthyloxyfuran2[5H]-one, both of which are of considerable interest as chiral synthons for organic synthesis [133].
10
Photosensitisation and Photocatalysis for Synthetic Purposes
501
O O C O
O2, hν, sens
- HCO2Me
O
MeOH
O
H
91%
O
HO
O
O
Fig. 10.40 Photooxidation of furfural O
O2, hν Rose Bengal
O
CH2Cl2 i-Pr2NH 88%
HO H
O
OH
HO
H
Fig. 10.41 Photooxygenation of sesquiterpenes
RO H
HO
O
O
1) CH2=CH-G / R4N+
O
2) Rose Bengal / 1O2
HO
O
O
G = electron-withdrawing group
Fig. 10.42 Baylis-Hillman reaction followed by [4+2] cycloaddition for the synthesis of a-substituted-g-hydroxybutenolide
5-Hydroxyfuranone derivatives are of particular interest because they are found in the natural environment as pheromones, flavour compounds and secondary metabolites. Furthermore, they are involved in the production of antibiotics, exoenzymes and virulence factors, and in biofilm formation [134]. The photooxygenation of these compounds in the presence of Rose Bengal as sensitiser forms dysidiolide (Fig. 10.41) [135], an important molecule with good anticancerogenic activity, as it is an inhibitor of protein phosphatase Cdc25A [136]. The [4+2] cycloaddition to furan derivatives is important in the synthesis of the butenolides, an important class of lactones with a four-carbon heterocyclic ring structure [123]. For example, synthesis of the a-substituted-g-hydroxybutenolides can be performed through the Baylis-Hillman reaction, followed by singlet oxygen oxidation (Fig. 10.42). It has been reported that the regiochemistry is strongly dependent on the nature of the quaternary ammonium salt used, and that the best selectivity was obtained in the presence of tetrabutylammonium fluoride [137].
502
L. Tonucci et al.
OAc
OAc
CO2Me O TMS
O
O2, RB, hν, CH2Cl2, 0°C
O
O
Fig. 10.43 Synthesis of the zoanthamine alkaloids
BnO
O
O
BnO
R
O O
1) 1O2, CH2Cl2, -20°C 2) Δ
BnO OBn
O R
BnO
O
OBn
Fig. 10.44 Photooxygenation of a furan derivative, and formation of the dicarbonylic compound
Another interesting photooxygenation of the furan derivatives represents a key step in the synthesis of the zoanthamine alkaloids, molecules with strong antiinflammatory actions. In this case, the photosensitised addition of singlet oxygen (Rose Bengal as sensitiser) led to the endoperoxide that subsequently forms the a,bunsaturated ketone, because of the ring opening (Fig. 10.43) [138]. The treatment of the furan endoperoxides with reducing agents, such as triphenylphosphine or dialkylsulphide, leads almost quantitatively to enediones [139], molecules that are of great interest in organic synthesis because of their versatility. Oxygenation in methanol of a furanon-phosphonate derivative, followed by reduction with alkylsulphide, gives enediones in high yields [140]. The functionalisation of the furan derivatives with d-arabinose or d-ribose has been used for the synthesis of new pyridazine C-nucleosides. In this process, the first step was photooxygenation (methylene blue as sensitiser), with the formation of an unstable endoperoxide, which decomposed to a dicarbonylic compound (Fig. 10.44) [141, 142]. The photosensitised reaction of the cyclopentadiene with singlet oxygen has been well described in the literature. Depending on the reaction conditions, the endoperoxide can be converted into 4,5-epoxy-2-penten-1-one, 1,3-dihydroxy-2cyclopentene, or alternatively into the 3-hydroxy-2-cyclopentenone, using sulphophthalocyanines of zinc, aluminum, germanium and silicium, supported on amberlite, as photosensitisers [143]. The last two derivatives are of great interest because they are precursors for the synthesis of prostaglandins [144]. Also Ru(II) complexes linked to poly(1-vinylimidazolium) have been used as singlet oxygen photosensitisers, for the oxidation of cyclopentadiene [145].
10
Photosensitisation and Photocatalysis for Synthetic Purposes
503
Fig. 10.45 Artemisinin
H3C
O
O O
CH3 O H
H
O H CH3
hν TPP, O2
O O
Fig. 10.46 Photosensitised synthesis of ascaridole endoperoxide
After the discovery of the antimalarial drug artemisinin (Fig. 10.45), peroxy derivatives promoted great interest due to their range of biological activities. These drugs are molecules that contain an endoperoxide moiety that usually interacts with the high iron content of the parasites, generating free radicals and leading to damage of the parasite. By the same mechanism, artemisinin becomes toxic to cancer cells, which are known to sequester relatively large amounts of iron compared to normal, healthy human cells. However, the whole mechanism of action is very complicated and still requires further in-depth studies. One of the main reasons is that artemisinin does not directly exert its lethal effects on the malaria parasite through the whole intact molecule, but rather, through some transient species that is generated after cleavage of the peroxy bond [146, 147]. As an example of artemisinin analogues, trioxaquine derivatives have shown antimalarial properties, and they can be obtained by [4+2] cycloaddition of a cyclohexadiene, in the presence of TPP as photosensitiser [148]. In particular, the key step in the synthesis is the reaction between the a-terpinene and 1O2, which leads to the formation of the ascaridole endoperoxide (Fig. 10.46). As an alternative photosensitiser, it is possible to use the hydroazafullerene C59HN and the bisazafullerene (C59N)2 [149, 150]. Photooxygenation of the cyclohexadiene and its derivatives is also possible in a heterogeneous phase linking the fullerene C60 to amino-functionalised silica [151]. Again in the antimalarial field, 4a-hydroxy-1b,7b-peroxy-10bH-guaia-5-ene has been obtained by photooxygenation of (+)-dihydrocarvone in the presence of methylene blue as photosensitiser [152].
504
L. Tonucci et al. R2 COOR3
N R2
R2 N R1
O2 , sens OR3
O
hν
R1
N R1
O
non nucleophilic solvent O
O
OR3 R1
O O
OMe
N
nucleophilic solvent
O
R2 R3O
OOH
Fig. 10.47 Photooxygenation of 5-methoxyoxazoles sensitised by tetrastyrilporphyrin and protoporphyrin-IX
b
a COOH NH
N
N
HN
NH
N
N
HN
COOH
Fig. 10.48 Protoporphyrin-IX (a) and tetrastyrilporphyrin (b)
Another interesting reaction that is carried out in the absence of solvent and under heterogeneous conditions is the photosensitised oxidation of 5-methoxyoxazoles (Fig. 10.47) using polystyrene nanocontainers doped by tetrastyrylporphyrin and protoporphyrin-IX (Fig. 10.48) [153]. These heterocyclics are versatile starting materials for the synthesis of a variety of compounds [154]. The a,b-unsaturated lactams can be obtained by photooxygenation of the pyrrole derivatives in CH2Cl2, sensitised by TPP (Fig. 10.49) [155]. Hydroxylactams are important synthons in organic synthesis, above all for the preparation of biologically active molecules, such as mitomycin. They can be obtained through the easy decomposition of the hydroperoxide from the photooxygenation of pyrrole analogues [156].
10
Photosensitisation and Photocatalysis for Synthetic Purposes
O2, hv TPP
N Ph
OH
Ph
505
OH
Ph
O
O
N
+
O
N O-
O
CH2Cl2
O
+
O
N
OH
O
N
Ph
Ph
6:1
Fig. 10.49 Photooxygenation of the pyrrole derivatives
1O
2
O
O
MPc
Fig. 10.50 Singlet oxygen addition on dimethylanthracene
a
R S
Me
R
Me
R
R S
Me
O
b O
R
Me −O
1O 2
R
Me
Me SH+
O
+ R
R
Me
Me O
O
Fig. 10.51 Formation of cis-sulphines (a) and enediones (b) in photooxygenation of substituted thiophenes
Sulphophthalocyanines of Al3+, Si4+ and Zn2+ (MPc) have also been used for [4+2] cyclo-addition, on dimethylanthracene to give the endoperoxide (Fig. 10.50) [157]. Oxygenation of substituted thiophenes leads to the formation of the endoperoxides, which decompose easily, which form cis-sulphines (Fig. 10.51a) or enediones (Fig. 10.51b) when sulphur elimination occurs [158].
506
L. Tonucci et al.
R
R N
R
O
R
O R
O
O
R
ROC
R
O
R O
COR
N
N
ROC
O
R
R N
1O 2
COR
O
O
N
R
Fig. 10.52 Photooxygenation of oxazole to give triamide
H3C H 3C
S
X
1O 2
CH3
O
O
O
H3C
SPhX CH3 CH3
PhX H3C
S
+ Acetone
Fig. 10.53 [2+2] cycloaddition on a vinyl sulphide to give a thioester
The Adam group reported the synthesis of thiirane compounds through thermal transformation of thiophene hydroperoxides, which can be obtained by singlet oxygen oxidation of thiophene [159, 160]. The key step of the thermal reaction was an unusual but efficient sulphur atom transfer that only occurred when the reactions were conducted in the presence of several strained cycloalkenes. The mechanism is a concerted process and does not involve open dipolar and/or diradical intermediates. Kinetic investigations showed that the thiophene endoperoxide is not the sulphurtransferring species; instead, it is thermally transformed to an intermediate which can then make the sulphur transfer. Singlet oxygen addition on oxazoles occurs in the 1,4 positions, with the formation of particularly unstable species, which rearrange to triamide derivatives (Fig. 10.52) [161].
10.3.1.2
[2+2] Cycloaddition
The [2+2] cycloaddition between a double bond and a singlet oxygen leads to 1,2-dioxethanes, compounds that are generally unstable and that decompose to form their carbonyl derivatives [162]. Photooxygenation of vinyl sulphides, allyl sulphides, allyl sulphoxides and allyl sulphones for the synthesis of the dioxethanes, in CDCl3 (Fig. 10.53), is an example of [2+2] cycloaddition in the presence of TPP as sensitiser [163]. The photooxygenation of the chiral enecarbamates under different experimental conditions (varying solvent and temperature) can give their dioxethane derivatives, which rearrange to methyldesoxybenzoin (Fig. 10.54) [164–166]. The photooxygenation of dihydropyran gives [2+2] cycloaddition, with the formation of the dicarbonyl compound (Fig. 10.55). Small rings and electron-donor substituents appear to favour the [2+2] reaction mechanism over the competing ene mechanism, which leads to the allyl hydroperoxide [167].
10
Photosensitisation and Photocatalysis for Synthetic Purposes O
O
O
H Ph
N
1O
O
2
O
O
O Ph
N
507
O
O H
N
Ph
+ O
CH(Me)Ph
CH(Me)Ph
Ph
E/Z
Fig. 10.54 [2+2] photooxygenation of chiral enecarbamates to give methyldesoxybenzoin
O O
1O 2
[2+2] O
O O
O
O
Fig. 10.55 Photooxygenation of dihydropyran
n
n
R1
R1
O
O
1O 2
S
n
R1 R2
O
Photosensitizer
S
R2
S
R2
O
n = 0, 1
Fig. 10.56 The photooxygenation of dihydrothiophene
X
Ph
Y
Ph
X
−78 °C
Ph
X
O Ph
O
1O 2
O Y
Ph
Ph Y O
Fig. 10.57 [2+2] cycloaddition to heterocyclics with two different heteroatoms
If photooxygenations are conducted on five-membered and six-membered ring derivatives where sulphur has been replaced by oxygen, namely substituted dihydrothiophenes (Fig. 10.56) and 3,4-dihydro-2H-thiopirans, the [2+2] cycloaddition mechanism becomes the dominant mechanism, with yields of >90% of the dicarbonyl derivatives. The relative thermal stability of dioxethane also appears to be linked to the type of heteroatom present in the ring. Sulphur derivatives are less rigid, as compared to the oxygenated analogues, due to the larger atomic radius of sulphur [168]. This makes the oxethane from the sulphur derivatives less stable. Similarly, photooxygenation of heterocyclics with two different heteroatoms (Fig. 10.57), in CH2Cl2 and at low temperature, results in the formation of dioxethane, which then decomposes to the dicarbonyl derivative [167].
508
L. Tonucci et al.
Ar 1O 2
CF3
Ar
N H
CF3
Ar O O Ar
NH2
F3C
H
HCl
Ar
CF3
N
NH2
O
N
F3C
O
CF3 N
F3C
CF3 NH2
Ar
N
Ar
H
O
H
Ar
Fig. 10.58 Synthesis of 4,4-bis(trifluoromethyl)imidazolines
S
S
R
O 1O
S
2
CDCl3, CFCl3, −70°C Me
Δ
S
Me
S Me O
O R
Et2S
O
a
+
R
Me R O
b
c
−70°C
Et2SO
+ −
+ − + − S O
S
S
S
O
R
S
O
S
+
R
Me Me
O
S
O
R
Me O
O
d
e'
e"
Fig. 10.59 Photooxygenation on 2,3-disubstitued dithiins
HO
Ar
O
tBu
HO 1O 2
N
N ROC
O tBu
Ar
ROC
Fig. 10.60 Photooxidation on the dihydropyrrole
The formation of the dicarbonyl compound, followed by dehydrocyclisation catalysed by acids, is a key step in the synthesis of 4,4-bis(trifluoromethyl)imidazolines (Fig. 10.58), which have shown inhibitory activities in cholesterol biosynthesis [169]. Photooxygenation carried out on 2,3-disubstituted dithiins leads to the dioxethane intermediate (Fig. 10.59a), which can evolve in two ways: decomposition to dithioesters (Fig. 10.59b) and dicarbonyl compounds (Fig. 10.59c), or at low temperatures, transformation into an epoxide (Fig. 10.59d), which rearranges to form a ketone (Fig. 10.59e¢, e″) [170]. Hydroxyaryl-substituted dioxethanes can be selectively synthesised by singlet oxygen addition to their corresponding dihydropyrroles (Fig. 10.60). An oxysubstituted dioxetane bearing a hydroxyaryl group provides one of the most versatile skeletons for the design and synthesis of high-performance chemiluminescence compounds. These N-acylamino-substituted bicyclic dioxethanes are relatively stable thermally [171]. When the dioxethanes are treated with tetrabutylammonium fluoride in DMSO, they undergo charge-transfer-induced decomposition, and emit yellow-orange light.
10
Photosensitisation and Photocatalysis for Synthetic Purposes
509
H H3C
CH3
H CH3
H
C59HN or (C59N)2 H3C
H
C6D6, hν > 400nm, O2
H3C
+ H3C
H
HOO H3C
OOH
H
Fig. 10.61 Formation of the hydroperoxide intermediates by photooxygenation on olefins
C60 /SiO2 (or Al2O3)
+
HOO
OOH
Fig. 10.62 Photooxygenation of the 2-methyl-2-heptene OH
OH
hν, sens, O2
OH
OH
O
OH
O
+
75 : 25
Fig. 10.63 Photooxygenation of hydroxyolefin
10.3.1.3
Ene Reaction
The ene reaction is a photooxygenation process that yields two hydroperoxide intermediates, which can subsequently be reduced to the corresponding alcohols. Over the last few years, the ene reaction has been applied to some of the steps in the synthesis of analogues of the antimalarial artemisinin [172]. Fullerene, bisfullerene and their aza-derivatives are sensitisers that are particularly used in the framework of photooxygenation reactions on olefins (Fig. 10.61), in both homogeneous [149, 150] and heterogeneous [151] phases. The fullerene C60 can be used in photooxygenation of 2-methyl-2-heptene (Fig. 10.62) in heterogeneous phase, either supported on silica [173, 174] or on g-alumina [175]. Another important ene reaction is photooxygenation of some hydroxyolefins, to form allylhydroperoxides in good yields (Fig. 10.63) [176]; this reaction can also be conducted in the absence of solvent (under very green conditions) [177]. The photosensitiser used was a tetraarylporphyrin loaded on polystyrene beads [178]. The ene reaction of chiral allylic alcohols in the presence of porphyrins on polystyrene beads yields diastereoselectively unsaturated b-hydroperoxy alcohols under
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OOHa
O
O
CH2Hb Ha
Hb
COO−
CH2Hb COO−
H H 2C
H
COO−
O
CH2
O
OOHb Hb
Ha
H COO−
H aH 2C
H aH 2C
COO−
Fig. 10.64 Photooxygenation of tiglic acid
a H3 C
H3C
S
X
1O 2
CH 3
b HOO
S-PhX
H3 C H3 C
H 3C
S-PhX
H 2C
CH3
+ CH2
OOH
Fig. 10.65 Photooxidation of arylsulphides
solvent-free conditions. The products have been used for the synthesis of monocyclic and spirobicyclic 1,2,4-trioxanes, molecules that have shown moderate-to-high antimalarial properties [179], and 3-b-naphthyl-substituted 1,2,4-trioxanes [180]. Porphyrin-functionalised pyrimidine dendrimers can also photosensitise the selective formation of allylhydroperoxides, in this case, in CHCl3 [181]. A very selective ene reaction in aqueous solution was studied by Stensaas and colleagues, who photooxidised a variety of a,b-unsaturated carboxylic acids (Fig. 10.64) (angelic, tiglic, 2,3-dimethyl-2-butenoic, 3-ethoxycarbonyl-5,6dihydro-2-methyl-4H-pyranoic, cis- and trans-3-hexenoic) using photosensitisers, such as methylene blue, Rose Bengal, tetraphenylporphine and aluminum tetrasulphophthalocyanine, in deuterated water [182, 183]. Furthermore, photooxidation of arylsulphides, arylsulphoxides, vinylsulphoxides and sulphones results in the formation of two hydroperoxide regioisomers (Fig. 10.65a, b). The regiochemistry strongly depends on the solvent character (protic or aprotic) and on the type of substituent on the aromatic ring (electronwithdrawing, such as −NO2; or electron-donor, such as −CH3) [163]. The use of the zinc phthalocyanine has also been reported as a photosensitiser in the oxygenation of cyclohexene to cyclohexene hydroperoxide and transcyclohexanediol (Fig. 10.66) [184]; however, other products are formed through the radical attack of the oxygen species on the substrate.
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Fig. 10.66 Photooxygenation of cyclohexene
1
511
O2
OOH
b
a 1O
TPP, CH 2 Cl 2
2
O O OOH
OOH
Fig. 10.67 Photooxidation of the 1,4-cyclohexadiene
H HN
O
COOH
L-Alanine DMSO, r.t., TPP
N
O
COO OOH
93%
OH
56% e.e.
Fig. 10.68 Synthesis of the a-hydroxyketone
Similarly, photooxidation of cyclohexene in the presence of palladium, zinc and aluminum tetrasulphophthalocyanines results in the formation of the corresponding hydroperoxide, together with two minor products, 2-cyclohexen-1-one and 2-cyclohexen-1-ol. Nevertheless, it is possible to obtain 99% selectivity for the hydroperoxide with palladium tetrasulphophthalocyanine, using a solvent mixture CH3CN/H2O 85:15 [185]. The photooxygenation of 1,4-cyclohexadiene derivatives has been conducted in CH2Cl2, using tetraphenylporphyrin as sensitiser (Fig. 10.67) [186]. The conjugated a,b-unsaturated hydroperoxide (Fig. 10.67a) is then easily trapped by a second mole of singlet oxygen, to give a stable endoperoxyl hydroperoxide (Fig. 10.67b). Photooxygenation has also been applied for asymmetric synthesis of a-hydroxyketones and diols from ketones and aldehydes as starting materials [187], using TPP as sensitiser. To induce enantioselectivity of the OH insertion on the ring (Fig. 10.68), a chiral amino acid (alanine) was added, and the enamine obtained reacts with singlet oxygen to form the hydroperoxide. Under these conditions, the intermediate is reduced to hydroxyketone in high yields (93%) and with good enantiomeric excess (56%). The electron-rich derivative of the indole can be selectively oxidised by the ene reaction. The tryptophan derivative has been oxidised to 3-hydroxypyrroleindole
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CO2Me
HOO
hν, O2 sens
NHBoc
NBoc
NBoc
+ N
N
N
Cl
Cl
Cl
CO2Me
HOO
30%
28%
Fig. 10.69 The ene reaction of the indole derivative Pr
Pr
Pr = n-propyl N
N N
Pr Zn
N
CONMe 2
N
CONMe
Pr
N
N
N
Pr
Polymer
Pr
O
Fig. 10.70 Zinc secoporphyrazine linked to a polymer
O
O
O
H CH 3
N
R
E/Z
CH2
1
O2
O
N Ph
Ph Y
OH
Y R
Fig. 10.71 Photooxidation of carbamates
using zinc secoporphyrazine as sensitiser (Fig. 10.69) [188]. Successively, the hydroperoxide intermediate is reduced to the corresponding alcohol using dimethylsulphides in situ. Linking the porphyrazine to polymers has also improved its re-use (Fig. 10.70) [189]. The photooxygenation of chiral enecarbamates (enamine derivatives) results in the ene reaction at room temperature (Fig. 10.71) [164–166]. Photooxygenation of non-aromatic heterocycles, such as dihydropyran under determined experimental conditions can result in the formation of both the hydroperoxide and the dihydropirone, by dehydration of the former (Fig. 10.72) [167]. The photooxygenation of dihydropyrrole results in an ene reaction with the formation of the pyrrole type (Fig. 10.73). In this case, the reaction can proceed either without or with the sensitiser (TPP), as it is the dihydropyrrole itself that produces the singlet oxygen [190].
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− H2O
1
O2 OOH O
O
O
O
H
Fig. 10.72 Photooxidation of the dihydropyran
CO2Et
N
Me
H2O2
CO2Et
hν, O2
CO2Et
Me
with or without TPP
N
N
OOH
Ar
Ar
Me
Ar
Fig. 10.73 Photooxidation of the dihydropyrrole
HOO
hν, 1O2 RB/polymer
N
N H
Na2SO3
HO
O
H2SO4 N
N
H
Fig. 10.74 Synthesis of the spiro derivatives
Another reaction that has an ene reaction as a key step is photooxygenation of indole derivatives in alkaloid synthesis. For example, the key step in the synthesis of spiro derivatives (used as starting material for synthesis of spiro analogues of ergot alkaloids) is the photooxygenation of 1,2,3,4-tetrahydrocarbazole. This reaction gives the corresponding hydroperoxide, which after reduction in aqueous solution with sodium sulphite and subsequent treatment with mineral acid, forms the final product in high yields (Fig. 10.74) [191]. Amati and co-workers have reported the use of the ethyl-3-phenylisothiazole4-carboxylate as a photosensitiser in the ene reaction of trans-a,a¢dimethylstilbene [192].
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S
hν, O2 sens. 1 mol %
S
CHCl3 / CH3OH 353.15 K
O
Fig. 10.75 Photooxidation of dobenzyl sulphide in the presence of oxygen and fullerodendrimer
Photooxygenation of norbornene derivatives in the presence of H2O2 and TPP has been used for synthesis of the 1,2,5,6-tetraoxacycloalkanes, a class of molecules with important antimalarial properties [193].
10.3.1.4
Reactions Involving Lone-Pair-Heteroatom Derivatives
A detailed study of the photooxygenation of benzyl alkyl sulphides by visible light via singlet oxygen was conducted using Rose Bengal as photosensitiser in apolar, polar and protic solvents [194]. In protic solvents, the sulphoxide is the main product, via a hydrogen-bonded persulphoxide. In apolar solvents, intramolecular a-H abstraction leads to oxidative carbon-sulphur bond cleavage. The behaviour of S derivatives has also been compared to that of alkenes and N-derivatives [195]. The only products of the reactions of the p-substituted aryl phosphines with tetraphenylporphyrin or C70 photogenerated singlet oxygen, are the corresponding phosphine oxides, while substituted o-aryl phosphines (with electron donating groups) lead to phosphinates, formed by intramolecular insertion and phosphine oxides [196]. The innovative fullerodendrimer photosensitiser has been used to photogenerate singlet oxygen in the presence of several substrates; among these, dibenzyl sulphide can be selectively photooxidised to its corresponding sulphoxide through visible light irradiation at 353.15 K in a chloroform/methanol solvent mixture (Fig. 10.75). A heterogeneous singlet oxygen photooxidation of sulphide to sulphoxide can be obtained with a methanofullerene derivative linked to polysiloxane-based beads (Deloxan®1 DAP). Di(n-octyl), dibenzyl, and benzyl methyl sulphides gave almost quantitative yields of transformation without formation of any by-products. The authors associated the reactivity to the nucleophilicity of sulphur combined with the steric hindrance. Indeed the diphenylsulphide was inert to the photooxidation, and both the di-isopropyl and methyl phenyl sulphides (note the different steric hindrance) showed transformation yields respectively of 27% and 28%, always with a selectivity of 100% of in the sulphoxide derivative [197].
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10.4
515
Conclusions and Perspectives
The potential of photocatalytic and photosensitised routes for the production of chemical agents has yet to be fully realised. The high yields and selectivities that can be obtained in several photooxidation reactions, as described above, make photocatalysed reactions useful to obtain chemicals by green procedures, such as, for example, the conversion of alcohols to aldehydes, and hydrocarbons to oxygenated derivatives. Reduction reactions have been less been studied, but in some cases they can reach satisfactory values of both selectivity and yield, as with the reduction of nitrocompounds to amines. The photosensitised reactions by singlet oxygen are traditionally selective and clean. Here, the new concept of green chemistry has added value to this photosensitised reaction in water media. Also worth mention, there are the new sensitisers, like the fullerenes and the metal macrocycles, which appear as useful choice to traditional photosensitiser of organic nature. The main handicaps linked to the industrial applications of some photochemical processes are the relatively high investment costs (e.g. production plant, efficient lamps, separation of the photosensitizer or photocatalyst). In addition, the maintenance is also not particularly cheap, since these plants require supplementary operations, such as cooling apparatus maintenance and lamp replacement. However, at present, the translation of these previously reported processes from the laboratory scale to industrial applications can occur more quickly than we would have imagined, which is also being helped by the forceful entry of nanotechnologies into our lives. Another important finding to be considered is the potential use of solar energy, which can make an entire process more convenient and particularly green, at least when visible light is needed. Examples of replacing artificial light with solar light, at the moment, are non common, at least when in the presence of industrial synthetic photosensitised or photocatalytic processes. Indeed, a first step has been achieved for a classical photochemical transformation that can be used as a pivotal example. The Japanese Toray Industries has bypassed the need for cyclohexanone or oximation steps by commercialising a photochemical process to convert cyclohexane into cyclohexanone oxime in the presence of nitrosyl chloride and hydrogen chloride [198]. The disadvantage is the cost of the energy that is required, which is high. However, it was demonstrated recently that it is indeed possible to replace the artificial light with solar light without losing the advantages of the entire process, which can thus now avoid the high consumption of fossil-fuel energy [199–201]. We believe that in both basic research and industrial applications, the most important goal must be to create new and alternative synthetic routes that are more respectful towards our environment (and so are more “green”), which will thus provide great advantages for the generations to come.
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Chapter 11
Photosensitizers in Solar Energy Conversion Katja Willinger and Mukundan Thelakkat
Abstract Today’s energy problems arise from the predicted exhaustion of fossil energy resources and the negative aspects of climate change. Additionally, the increasing energy needs and the improved environmental awareness of people all over the world necessitate the utilization of environmental friendly energy sources. The most abundant energy source is the sun. The solar energy is largely available, surpassing our annual energy demand by the factor of 10,000. Each second the sun produces enough energy to cover the energy demand for the whole humanity for 1,000,000 years. The dye-sensitized solar cell (DSC) concept is an interesting alternative to conventional silicon based solar cells due to its advantages of easy and fast fabrication, low production costs, short energy payback time and high photoelectric conversion efficiencies. In the following pages an overview shall be given of the operation principle of DSCs and the dyes used as sensitizers for solar energy conversion. The aim is to give an outline of the evolution of the DSC concept, the advantages and drawbacks of dye-sensitized systems and the different dyes (metalorganic and organic) applied in liquid and solid-state DSCs. Furthermore, the state of the art performance of the different types of dyes will be given.
K. Willinger Applied Functional Polymers, B6, Room 12, University of Bayreuth, 95440 Bayreuth, Germany e-mail: [email protected] M. Thelakkat (*) Applied Functional Polymers. NW II, Room 363, University of Bayreuth, 95440 Bayreuth, Germany e-mail: [email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_11, © Springer Science+Business Media B.V. 2012
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Historical Background of Dye-Sensitization
The photoelectric effect was first reported by A. E. Becquerel in 1839 [1]. He used an electrolyte solution surrounding two platinum electrodes with one additionally covered with a thin layer of silver chloride. As a consequence of illumination of the silver chloride plate, an electric current resulted. Becquerel supposed that the current arose from a chemical reaction but the mechanism was not clarified until H. Hertz and W. Hallwachs accomplished systematic investigations in 1886 [2]. They explained that charge carriers can be emitted from mater (metals, solids, liquids or gases) upon absorption of high energetic (short wavelength) irradiation, such as visible or ultraviolet light. These results were confirmed by P. Lenard in 1900 who verified that the emitted charge carriers were electrons. Furthermore, he discovered that the maximum kinetic energy of the emitted photoelectrons depends on the frequency of the absorbed wavelength, but not on its intensity which defines the number of ejected electrons. Besides these developments, the photoelectric effect had to wait until 1905 for an exact explanation by A. Einstein [3]. “For his service to Theoretical Physics, and especially for his discovery of the law of the photoelectric effect” Einstein was awarded the Nobel Prize in Physics of the year 1921 [4]. This was also the basis for the invention of the p-n junction silicon solar cell in 1954 by D. Chapin, C. Fuller, G. Pearson [5] which culminated in the first application in 1958 as energy source in the Vanguard 1 satellite [6]. Although the information flow with this satellite is broken since 1964, the solar cells still work and hence Vanguard 1 is the world’s oldest satellite still in orbit. As it is known, the energy conversion by semiconducting silicon solar cells on the basis of the inner photoelectric effect is currently one of the most promising renewable energy technologies. Built in 2008, the Olmedilla Photovoltaic Park in Spain is today the largest photovoltaic plant using silicon solar cells with a peak production of 60 MW. Unfortunately, the widespread use of silicon solar cells is somewhat hindered by the requirement of high-purity silicon, skilled manufacturing techniques and therefore high production costs. In view of this, it is a serendipity that J. Moser opened up a second way for photocurrent generation in 1887, also partly using the inner photoelectric effect but with an inventive add-on. On the base of Becquerel’s electrodes, Moser imbrued his halogenated silver plates in an erythrosine solution [7]. In this way, he was able to enhance the photocurrent caused by the photoelectric effect significantly. Whereas Becquerel’s silver chloride covered platinum electrode could just use the high energetic part of the incident light, Moser’s dye covered electrodes could also use a large part of the visible light thanks to the absorption of the dye. Later, metal electrodes were replaced by semiconductors to reduce recombination effects. In the following years, the theoretical understanding on the spectral sensitization of semiconductors by metal-organic/organic dyes steadily improved. Tributsch and co-workers, for example, investigated the sensitization effects occurring at the contact interface between the n-type semiconductor ZnO and a dye (fluorescein) [8]. They measured current/voltage characteristics for the sensitized single-crystal electrode with and without illumination by applying an increasing
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counter voltage. The same type of measurement is still used to characterize the performance of DSCs (cf. Sect. 11.2.3). In 1970 H. Tributsch and M. Calvin studied the electrochemical reactions of excited molecules (chlorophyll) at a wide-band gap semiconductor surface (ZnO) in contact with an electrolyte in detail, measured anodic photocurrents and investigated the role of the regenerating electrolyte [9]. With increasing understanding of the processes occurring in dye-sensitized systems, an application for the dye-sensitized photoelectrochemical cells drew scientists’ attention, viz. the photoelectrolysis of water. A. Fujishima and K. Honda discussed an electrochemical photocell based on an n-type TiO2 electrode in contact with an aqueous electrolyte and a platinum plate as counter electrode [10]. With this novel type of cell it was possible to decompose water into oxygen and hydrogen without application of any external voltage. Until this work of Fujishima and Honda, only a little attention had been paid to the idea of an application for the dye-sensitized concept. The photoelectrochemical cells were rather used for mechanistic interpretations of processes and reactions occurring at semiconductor/dye interfaces. Inspired by water splitting, H. Gerischer discussed the application of this type of cell for the conversion of light into electricity in 1975 [11]. After that, the field of light energy conversion in dye-sensitized photoelectrochemical cells began to flourish. Scientists like Tributsch, Gerischer and Grätzel exerted effort on the improvement of the visible light response of wide band gap semiconductors, such as ZnO and TiO2 by dye-sensitization at flat semiconductor electrolyte interfaces [12]. During this time, the understanding of photoinduced effects at dye-coated semiconductor surfaces which are in contact to a liquid electrolyte steadily increased, not only due to the interest in light-harvesting systems for energy conversion, but also due to the importance of dye-sensitization in photography. In 1988 K. Tennakone et al. invented a novel type of dye-sensitized solar cell [13]. Besides the known liquid-state dye-sensitized solar cells (L-DCS) comprising of a wide band gap semiconductor (e.g. TiO2), a dye (commonly natural dyes) and a liquid electrolyte, they used a solid hole transport material (p-CuCNS). Their aim was to overcome a major problem of L-DSCs, viz. the degradation of dye molecules. According to Tennakone, degradation takes place because the electron transfer and the excitation of the dye molecule occur in an environment containing reactive ions and molecules. Hence, the problem of dye degradation does not arise in DSCs where electrolytes are not employed. To realize their concept of solid-state dye-sensitized solar cells (S-DCS) they used thiocyanates of Rhodamine B and Methyl Violet as dyes to extend the spectral response of a semiconductor to visible light. The dye monolayer was sandwiched between two inorganic wide band gap semiconductors, the one of which exhibited a p-type while the other one exhibited an n-type conduction mechanism. After the excitation of the dye (D + hn → D*), charge separation happened at a semiconductor/dye/semiconductor interface (D* → D + h+ + e−). Whereupon hole transfer from the dye to the valence band of p-CuCNS and electron transfer to the conduction band of SnO2 took place. The efficiency of DSCs using a solid inorganic hole transport material in this early stage of research was in the order of 10−7–10−8 under monochromatic light [13].
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Despite great achievements in the field of dye-sensitized photoelectrochemical cell for solar energy conversion in the 1980s, the light harvesting efficiency of such devices remained low and the concept was far away from any efficient device application. The milestone in the development of efficient DSC was made by B. O’Regan and M. Grätzel in 1991 [14]. They designed an L-DSC from low-to medium-purity materials through low cost processes which exhibited a commercially realistic energy conversion efficiency of 7.9% (at 8.3 mW/cm²) and 7.12% (at 75 mW/cm²) measured under simulated solar light. These results exceeded all existing L-DSC because of two main innovations: (i) Instead of a flat semiconductor surface, they used a 10-mm-thick mesoporous TiO2 layer comprising of nanometer-sized TiO2 particles. Sintered porous TiO2 nanoparticles provide a 100-fold increased internal surface as compared to a compact and flat TiO2 layer [15]. This enhanced the light harvesting capability of the cell because a rough and porous TiO2-surface provides more space for dye molecules. Consequently, the dye surface concentration could be increased so that a lager quantity of dye molecules could absorb light and was simultaneously in contact with the electrolyte. (ii) Stability problems were partly overcome by newly developed charge-transfer dyes [16, 17]. These CN-bridged trinuclear ruthenium complexes carrying “COOH-anchoring groups” could chemisorb on TiO2 to give a proper connection between the dye and the electron conducting TiO2 for efficient charge injection. Upon absorption of electromagnetic irradiation from the visible region of light, the ruthenium dye acts as an electron pump to convey an electron from the HOMO (highest occupied molecular orbital) to the LUMO (lowest unoccupied molecular orbital). Afterwards the excited dye injects an electron into the wide band gap semiconductor titanium dioxide from where it reaches the photoanode. At the same time, the oxidized dye is regenerated by a hole transport material (an iodide/triiodide redox electrolyte) which transfers the holes to the cathode. Now the dye is ready for the next cycle and the charges are separated at the electrodes of the photoelectrochemical cell and can be used by a consumer load. After a turn over number of 5 × 106 cycles, which equals to 2 month under load, the change in photocurrent of O’Regan’s and Grätzel’s L-DSC was less than 10%, showing the high stability of the novel ruthenium dyes [14]. The effective concept of high surface porous TiO2 was also transferred to S-DSCs. In 1995 K. Tennakone et al. used a nanoporous TiO2 layer (thickness about 3 mm) deposited on conducting glass, sensitized it with a monolayer of the pigment cyanidine and filled the intercrystallite pores with p-type CuI (thickness about 6 mm) [18]. The use of thicker layers than a monolayer of dyes/pigments tends to result in electrical insulation and also cuts off light that should be incident to the dye molecules that are adsorbed directly at the semiconductor surface. With this assembly of an S-DSC, an impressive short-circuit photocurrent of 2.5 mA/cm² and an opencircuit voltage of 375 mV (at 80 mW/cm² in direct sunlight) could be reached. When two semiconductors (a p-type and an n-type) form an interpenetrating network on the nanometer-scale, there are several problems to be addressed. For example, the crystal lattice mismatch of the different semiconductors will prevent a good contact at the interface. Additionally, the processability of inorganic hole transport materials is a serious issue. In contrast to that, low molecular weight
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compounds offer the advantages of easy processability in combination with a high variety of the chemical structure and hence an almost unlimited diversity. Furthermore, low-molecular weight materials like triphenyldiamines (TPDs) provide a good hole transport mobility and their amorphous structure can easily adapt to the n-type semiconductor surface. Hagen et al. used these advantages to assemble an S-DSC employing a low molecular weigh hole transport material for the first time [19]. Unfortunately, the device displayed a low efficiency (0.2%) because (i) the cells were prepared by evaporation of the TPD transport layer. Therefore, the pores were not entirely filled and an efficient regeneration of the oxidized dye was not possible. (ii) The high thickness of the overstanding hole transport layer caused higher recombination losses due to longer trajectories between the inner surface and the counter electrode. Grätzel and co-workers improved Hagen’s concept by using the amorphous organic hole transport material 2,2¢,7,7¢-tetrakis(N,N-di-p-methoxyphenylamine)9,9¢-spirobifluorene (spiro-OMeTAD) (Fig. 11.1, 1) [20]. The spiro-center improved the glass-forming properties and prevented crystallization, which would otherwise lead to a bad contact between the mesoporous surface of TiO2 and the hole conductor. Spiro-OMeTAD in combination with different dopants such as Li[(CF3SO2)2N], N(PhBr)3SbCl6 [20, 21] and 4-tert-butylpyridine [21] (in the following denote as tBP) is even today a popular and efficient hole transport material. Parallel to the evolution of the concept of using low molecular weight semiconductors to overcome some of the typical drawbacks of L-DSCs, such as dye desorption/ degradation, solvent evaporation and sealing issues, Cao and co-workers [22] reported about the application of a viscous polymer gel electrolyte and Yanagida and co-workers [23] were the first to utilize a polymer (in situ polymerized pyrrole) as hole transport material. The efficiency of the devices suffered from the strong absorption of the polymer in the visible region, hence impairing the light harvesting at the dye monolayer. As expected, the handling of such S-DSCs was more favourable, but the efficiency of the S-DSCs was lower than that of L-DSCs (cf. Sect. 11.2.1.5).
O
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Fig. 11.1 2,2¢,7,7¢-tetrakis(N,N-di-p-methoxyphenylamine)-9,9¢-spiro-bifluorene (spiro-OMeTAD)
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In the last decade research was mainly focused on the development of more stable and high efficient dyes for L-DSCs according to Grätzel’s example from 1991 and S-DSC on the basis of spiro-OMeTAD, in which the main concepts of L-DSC and S-DSC were not changed drastically. Accordingly, an introduction on the operation principle of DSCs (including materials and mechanisms) will follow. Moreover, special focus will be put on different sensitizes (metal-organic and organic) for the application in DSCs as an attractive and promising concept for solar energy conversion.
11.2
Dye-Sensitized Solar Cells
The following section will give a short overview on the assembly of L-DSCs as well as S-DSCs and the different materials used for the manufacture. Furthermore, the processes and mechanisms that entail high performances and the ones which reduce the efficiency of DSCs will be outlined and the characterisation methods will be presented. A detailed overview of DSCs regarding materials, characterisation and modules is also published recently [24].
11.2.1
Assembly and Materials
As shown in Fig. 11.2, typical DSCs consist of an assembly of different functional layers. With regard to the slightly different demands of L-DSCs and S-DSCs, the materials, types of layers and their thicknesses vary somewhat. For both L- and S-DSCs a substrate (glass, a thin metal foil [25, 26] or a flexible polymer [27–29]) covered by a transparent conducting oxide (TCO) is forming an electrode contact (anode). The next layer, which is indispensable for S-DSCs, is a thin and flat compact blocking layer. It prevents the holes travelling through the hole transport material (HTM) from recombination with electrons collected in the TCO layer.
Fig. 11.2 Schematic representation of the assembly of typical DSCs
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In contrast to that, this layer is optional for L-DSCs because the energetic conditions of the contact formed between a solid HTM and a TCO are completely different from the ones between a liquid electrolyte and a TCO. The latter causes only less recombination (cf. Sect. 11.2.1.2). The adjacent layer – the wide band gap semiconductor layer – is the thickest layer in both types of DSCs (~10 mm for L-DSCs, ~2 mm for S-DSCs). It provides an extremely high surface due to its mesoporous nature and high electron conductivity due to its interconnected nanocrystalline structure. Typically, in L-DSCs, an additional mesoporous semiconductor layer is applied, the so called scattering layer. It consists of the same wide band gap semiconductor as used for the mesoporous layer but the single particles are larger (~400 nm). The function of this layer is the scattering of incident photons to improve the light harvesting efficiency. Under ideal conditions, the whole semiconductor surface is covered by the most variable component of DSCs, the sensitizer (metalorganic, organic or inorganic quantum dots [30–35]). It covers the surface in form of a monolayer and causes the light induced formation of an excited state, which results in charge separation at the semiconductor/dye interface, i.e. electron injection into the conduction band of the semiconductor and subsequent regeneration of the oxidized sensitizer by the HTM happen. The nature of the hole transport material characterises the most serious difference between liquid and solid-state DSCs. Regarding L-DSCs, generally an iodide/triiodide redox electrolyte dissolved in a non-protic solvent is used. It mediates the holes between the oxidized sensitizer and the counter electrode. In S-DSCs, the HTM is, as the name suggests, a solid material, viz. a p-type semiconductor (organic, inorganic or polymeric). However, the boundary between both DSC concepts is merging. The quasi-solidification is one approach to combine the advantages of liquid electrolytes and solid HTMs by adding a gelator to a liquid hole conductor. The last part to complete a DSC is the counter electrode. Its task is the reduction of the respective HTM. Under illumination, both assemblies (L- and S-DSC) can convert solar energy to electric energy which can be used to run a consumer. The single layers of typical DSCs and their functions will be explained in detail in the next sections.
11.2.1.1
Transparent Conducting Oxides
The most commonly used substrate for DSCs is glass coated with TCOs [36, 37], such as FTO (fluorinated tin oxide, Sn2O:F) [37, 38] or ITO (indium tin oxide, In2O3:SnO2) [37]; rarely also used are ATO (SnO2:Sb) [39] or AZO (ZnO:Al) [40] and GZO (ZnO:Ga) [37]. For highly efficient solar cells, the TCO has to meet some fundamental requirements, such as a high electrical conductivity, so that the efficiency of the cell is not diminished by the sheet resistance. This can be achieved by employing doped metal oxides. Furthermore, the positions of the energy levels of the TCO and the semiconductor layer in contact have to ensure that preferably all electrons are injected from the semiconductor layer into the TCO (i.e. the Fermi level of the TCO has to be lower than that of the semiconductor). Moreover, the
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TCO has to be transparent, so that as much light as possible reaches the dye monolayer. Additionally, the sheet resistance should be independent from the temperature, because the covering semiconductor layer is commonly sintered at temperatures as high as 500°C. ITO indeed shows the highest transparency (about 90% [41]) and conductivity, but at higher temperatures its resistance increases significantly and the stability decreases. Hence, FTO is usually the material of choice for DSCs mainly owing to its capability to fulfil above requirements and especially due to its temperature stability. As substrate, glass has the advantages of long-time stability, planarity and transparency (maximum transmission 92% which can be further enhanced [27]). But its main drawback is its inflexibility. Especially for a commercial application of DSCs, flexible cells are advantageous due to inexpensive high throughput roll-to-roll processes, easy handling and installation. At the present stage of performance of DSCs, indoor applications in watches and calculators or outdoor DSC panels [42] and photovoltaic clothes [43] are interesting perspectives. For this purpose, polymer substrates covered with TCOs in particular are promising because such polymers (e.g. ITO-coated polyethylene terephthalate, PET) [44] can be used as flexible, thin and lightweight conducting electrodes. However, polymer substrates suffer from thermal instability, photo oxidation, fatigue, insufficient barrier properties (due to permeability of moisture and oxygen) or the leaching out of plasticizers and stabilizers. Characteristically, the efficiencies of DSCs using a polymer substrate are lower than those using glass. The main reason for this can be the reduced sintering temperatures applied for the preparation of the mesoporous TiO2 layer in order to avoid melting of the substrate. At moderate temperatures (about 150°C) the organic additives in the semiconductor paste are not properly burned out [45]. Nevertheless, plastic-substrate DSCs have already reached an efficiency of 7.6% by using a TiO2water paste and a non-thermal press method [29]. The results were validated by the RCPV, AIST in Japan under standard conditions (100 mW/cm², 25°C) employing a ruthenium standard dye (N719, cf. Fig. 11.7) and a liquid iodide/triiodide electrolyte. Some reports regarding flexible metal foils as substrates (e.g. Ti) have also appeared in recent years [25, 26]. But they usually require a backside illumination due to the opaque nature of such films.
11.2.1.2
Compact Blocking Layer
As mentioned before, the compact electron conducting hole blocking layer is indispensable for S-DSCs but can also cause a slight improvement in the performance of L-DSCs. Each contact between the solid HTM and the TCO anode results in recombination and loss of photocurrent. The reduction of the generated photocurrent (and voltage) leads to an extreme loss in the performance and can culminate in short-circuit of the cell. Therefore, the introduction of a compact blocking layer was put forward by Grätzel and Kavan [46]. They could enhance the current output by three to four orders of magnitude via suppressing this recombination in S-DSCs. For the preparation of a blocking layer, different methods can be used, such as
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electron beam evaporation [47], chemical vapour deposition from precursors [48–50] or spray pyrolysis of an aerosol [46, 51]. The latter method was automated and investigated in detail by our group using an aerosol prepared from the common TiO2-precursor titanium diisopropoxide bis(acetylacetonate) (TAA) in ethanol (0.2 M solution) [51]. The optimal thickness and morphology as well as the rectifying properties of this layer were scrutinized by ellipsometry, scanning electron microscopy and current/voltage measurements (cf. Sect. 11.2.3). With increasing blocking layer thickness, the rectifying behaviour increased and hence recombination could be efficiently suppressed. The best overall performance was reached by a layer thickness of about 120–200 nm. In contrast to S-DSCs, it is generally assumed that a blocking layer is not necessary for L-DSCs because the recombination at the TCO/redox electrolyte interface is negligible. This can be ascribed to the similarity between the Fermi level of the FTO and the redox Fermi level of the iodide/triiodide redox electrolyte [52]. For this reason, there is no driving forces for recombination under short-circuit conditions (i.e. no electric resistance encountered, voltage is zero). The situation changes under open-circuit conditions (i.e. infinite resistance encountered, current is zero). Typically, the Fermi level of FTO strongly rises under these conditions (by up to 0.7 eV, marginally beyond the conduction band level of TiO2), so that a driving force for recombination at the electrolyte/FTO interface is established [52]. Therefore, the introduction of a blocking layer can theoretically prevent this recombination and thus enhance the suppression of leakage currents. The validity of this theory is being intensively discussed [52, 53], but an improvement of the open-circuit voltage was found in many cases [54–57].
11.2.1.3
Mesoporous Metal Oxide Semiconductors
Among the diverse wide bad gap semiconductors [58–60] such as SnO2 [61, 62], Nb2O5 [60], In2O3 [60], SrTiO3 [63] and NiO [64, 65] or combinations of these [62], titanium dioxide (TiO2) and zinc oxide (ZnO) are the most commonly used and most intensively studied materials. Both show a good chemical stability under visible irradiation, are non-toxic as well as inexpensive, largely abundant and easy to process. The essential requirements that an efficient mesoporous semiconductor has to fulfil are (i) a suitable conduction band energy level which facilitates the injection of electrons by a sensitizer, (ii) an interconnected nanocrystalline network of the semiconductor with efficient electron conduction, (iii) an optimum porosity for efficient pore-filling by the hole conductor and (iv) a high surface area for a high dye-uptake. Concerning nanocrystalline-TiO2 the formation of a pure anatase phase is significant. It is reported that anatase-TiO2 shows a higher efficiency compared to closely packed rutile-TiO2 due to a higher surface area and faster electron transport [66–68]. The mesoporous nanocrystalline semiconductor layer is commonly prepared by screen printing, doctor blading or spin coating of a suitable TiO2-paste and a subsequent sintering step (up to 500°C). For this purpose, nanocrystalline TiO2-colloids
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are dispersed in water or alcohol, or in a-terpineol [69]. The former method can lead to aggregation, whereas the latter gives more stable and reproducible colloidal pasts. However, optimised semiconductor pastes are also commercially available. The optimum thickness of the mesoporous layer for S-DSCs is approximately 2 mm [70], depending on the dye and the hole conductor used. This is less than the optical depth of the composite, which would be about 10 mm for 90% absorption over a wide spectral region employing a standard ruthenium complex as sensitizer [71]. Thus, a dye-coated 2 mm thick layer does not absorb all the incident light, a thicker layer would be favourable, but it is not possible to fill thicker layers efficiently by a solid hole transport material [71–73]. It was reported that for thicker layers both, pore infiltration and short electron diffusion length cause the limit of about 2 mm [72–74]. However, studies showed that the electron diffusion length is about 20 mm [71]. Consequently, the pore infiltration causes the limit and the efficiency of S-DSCs could be significantly enhanced if an efficient pore filling method for thicker films can be found. Regarding L-DSCs, pore filling is not a critical issue because the liquid redox electrolyte penetrates into even thicker mesoporous films and small pores. Thus, 10-20 mm thick films can be used. Taking the roughness factor (>1,000) into account, a mesoporous semiconductor film of 1 cm² (thickness about 10 mm) provides a surface area of 1,000 cm² for dye-sensitization [75]. This causes a light harvesting efficiency of about 100% at the peak absorption wavelength of a standard ruthenium dye. To increase the light harvesting efficiency over a broader range of the visible region of the spectrum, an additional layer is introduced in L-DSCs, viz. the scattering layer. It contains larger particles (400 nm), which cause a (back-) scattering of not absorbed light to enhance the absorption and thus the performance of the cell. Instead of the conventional mesoporous metal oxides, also specific nanostructured semiconductor vertical arrays (usually as well consisting of TiO2 or ZnO) can be used as electrodes for DSCs [58, 76, 77]. Transition metal oxide nanostructure assemblies, such as nanotubes, nanowires and nanorods, which do not only feature a large surface, but also an aligned nature are supposed to direct charge transfer along the length of the vertically oriented tubes/rods/wires etc. straight to the conducting substrate [78]. This can be beneficial for the charge-collection efficiency [79]. 11.2.1.4
Sensitizer – Requirements and Strategies
The sensitizer is an essential component of DSCs; it is continually excited by the incident light, injects an excited electron into the conduction band of a semiconductor and is subsequently regenerated by the hole transport material. Thus, it acts like an electron pump for the conversion of solar energy to electricity. Ideal sensitizers for DSCs should carry appropriate anchoring groups [68] (prevalently carboxylic acids, less frequently phosphonic acid [80], acetylacetonate [81], catechol [82], silanol [83, 84] or silyl [85] groups) to chemisorb on the semiconductor’s surface
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and thus guarantee an excellent connection between dye and semiconductor. For sensitizers employed in L-DSC, desorption from the semiconductor surface is always a problem, thus sensitizers should additionally show a high stability towards water-induced desorption [86]. Ideal sensitizer must show excellent light harvesting properties including high extinction coefficients and a broad absorption area. This is especially important for S-DSCs because the cells are thinner (~2 mm compared to ~10 mm for L-DSCs) and so an increase in the absorption coefficient or absorption cross section results in improved light harvesting which improves the performance of devices significantly. The molecular design of sensitizers should be so chosen that aggregation of dye molecules is suppressed, and consequently minimizing the loss through the associated deactivation of excited states. The LUMO level has to be sufficiently high enough for charge injection into the conduction band of the semiconductor and the HOMO level has to be sufficiently low enough for efficient regeneration of the oxidized dye by a liquid electrolyte or a solid hole transport material. By using the latter, the charge transfer rate of the dye regeneration depends strongly on the HOMO energy offset between the dye and the solid HTM. For instance, on the basis of the Marcus theory, an optimum energy offset at an energy gap of 0.79 eV was reported for a particular set of dyes and a series of hole conductors [66]. Further, it was reported [87], that interfacial charge transfer process like this one are not kinetically controlled but thermodynamically and that the band gap must be at least 0.2 eV for a charge transfer yield of 85%. Additionally, a polarity match between the dye and the solid HTM is favourable to facilitate a good electronic communication between both. Another requirement for sensitizers in both types of DSCs refers the electron injection into the conduction band of the semiconductor which has to be faster than the decay of excited state. Otherwise the absorbed photons are lost without current generation. Moreover, sensitizers should be stable for about 108 turnover cycles corresponding to 20 years under load [88]. Finally, the periphery of the dye should be hydrophobic to minimize direct contact between the electrolyte and the semiconductor surface, to prevent water-induced desorption and to increase the wettability with the solid HTM [86, 89]. Different strategies were developed to obtain new, efficient and stable sensitizers. Both metal-organic and organic dyes with suitable photophysical and electrochemical properties as well as a directed orientation and arrangement of the chemisorbed dye molecules were investigated and also summarized in elaborated reviews [89–91]. In the following, the diverse synthetic strategies for a suitable dye design will be briefly summarized. A detailed discussion of each class of dyes will be given in Sects. 11.3 and 11.4. Variation of ligands in ruthenium dyes: Already, at the beginning of the search for suitable sensitizers for the development of dye-sensitized semiconductor electrodes in the 1980s, ruthenium complexes attracted scientist’s attention. The prototype used at this time was tris(2,2¢-bipyridyl-4,4¢-dicarboxylic acid)ruthenium(II) [92]. The class of tris(bipyridyl)Ru(II) complexes remained attractive due to a unique combination of chemical stability, metal-to-ligand charge transfer (MLCT), suitable redox properties and long excited state lifetimes [93]. Thus, these dyes were further investigated for the use as sensitizer in DSCs, but they suffer from low extinction
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coefficients in the visible range (if no additional donor group is attached) and possess a less broad absorption range [94]. Therefore, one bipyridyl ligand was replaced by two NCS groups to shift the MLCT absorption band to longer wavelength regions [15]. Additionally, the geometry of the two ligands is an important factor which has to be taken into account because trans-complexes typically show a broader absorption up to higher wavelengths (lower energies) [95]. Also the use of terpyridyl ligands instead of bipyridyl can enhance the performance L-DSCs dramatically by the broadening of the absorption area (cf. “black dye”, Fig. 11.7 yielding over 10% power conversion efficiency) [96]. Introduction of hydrophobic chains: The attachment of hydrophobic chains to a bipyridyl ligand in ruthenium(II)bis(bipyridyl)(NCS)2 complexes can improve the performance and stability of L-DSCs. The hydrophobic layer that can be formed between the semiconductor surface and the liquid hole transport material created by the long hydrophobic chains of the dye is attributed to minimize recombination between electrons from the semiconductor and holes from the electrolyte [97]. Besides, the hydrophobic layer may enhance the stability towards water-induced desorption, hence increasing the long term stability [86]. Regarding S-DSCs, ruthenium dyes carrying hydrophobic chains yielded very high efficiencies of ~4% [70]. Here, the long hydrophobic chains were expected to improve interfacial properties, viz. the wetting of the dye covered semiconductor and the solid HTM due to a polarity matching. This can accelerate the regeneration of oxidized dye molecules [89, 98]. (For further information on amphiphilic dyes employed as sensitizers in DSCs cf. Sect. 11.3.1.2) Incorporation of donor-antenna groups: In a nutshell, the goal of the donor-antenna dye concept is the enhancement of the absorbance of ruthenium(II)bis(bipyridyl) (NCS)2 by covalently connecting electron-rich donor moieties (e.g. triphenylamine groups) to a bipyridyl ligand. In comparison, extremely high molar extinction coefficients can be reached due to the extended p-electron delocalized system. This improves the light harvesting efficiency and thus the performance of DSCs. Furthermore, the push pull system created by the donor and the acceptor/anchor parts of the dye results in a longer distance between the HOMO (located on the donor) and LUMO (located on the anchoring group), is assumed to slow down recombination [99–101]. Additionally, the donor groups can improve the wetting with the solid hole conductor spiro-OMeTAD via a polarity matching. (This concept will be discussed in detail and the dyes which meet the demands of the concept will be presented in Sect. 11.3.1.3.) Introduction of ion-coordinating groups: The concept of incorporating ioncoordinating moieties in ruthenium(II)bis(bipyridyl)(NCS)2 complexes is a design strategy which was developed for DSCs using the “magic salt” (Lithium bis(trifluoromethanesulfonyl)imide, LiN(SO2CF3)2) or other Li+-salts as additives in the HTM. This sophisticated approach is based on the interaction of ioncoordinating functionalities and Li+ ions. Its aim is to fix the Li+-ions at the dye/ TiO2 interface, thus preventing them from reaching the TiO2 surface and avoiding
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an unfavourable lowering of the TiO2 conduction band edge (which equals a lowering of the open-circuit voltage) while enhancing the photocurrent output. (The different effects on DSCs will be discussed in Sect. 11.3.1.5) Donor-pBridge-Acceptor structure for organic dyes: In the last years it was shown that organic dyes can act as efficient sensitizers and their absorbance and absorption range can be tuned by varying the chemical structure [89, 91]. Donor-pbridge-acceptor sensitizers incorporate an electron-rich donor moiety as well as an electron-deficient acceptor group covalently connected by a p-conjugate bridge. After excitation of these dyes intermolecular charge transfer happens in such a way that electrons are efficiently transferred from the donor unit to the anchoring acceptor moiety from where the electrons can be easily injected into the semiconductor. This causes a large distance between holes (delocalized mainly over the donor unit) and injected electrons and thus recombination can be reduced. In addition, the energy gap and consequently the maximum absorption wavelength can be easily tuned by changing the electrondonating and electron-accepting abilities, viz. changing the donor and acceptor groups. Regrettably, donor-pbridge-acceptor sensitizers frequently suffer from aggregation which reduces the performance of DSCs. (The different organic dyes on the basis of this concept will be presented in Sect. 11.4) Suppression of aggregation: Aggregation on the semiconductor surface is in all classes of sensitizers (metal-organic and organic) a critical issue. If aggregation occurs, excited states can be deactivated by intermolecular energy transfer between the dyes. Thus the performance of the solar cell can decrease. Furthermore, aggregation can induce a shift in the energy level of the dye, which can be seen in a shift of the absorption. The changed electronic properties can affect electron injection efficiency and thus the energy conversion efficiency of the cell. To solve these problems, bulky groups (e.g. tert-butyl groups) can be attached to the dye molecules to prevent aggregation, or coadsorbents can be used which also reduces the interaction between dye molecules. Influence of the dipole moment: Organic dyes are capable of yielding higher voltages in DSCs than ruthenium complexes if their dipole moment on the semiconductor surface is suitably directed. A fluorene containing dye (82, Fig. 11.37) for example reached an impressing voltage of 1 V in an S-DSC assembly [102]. This can be ascribed to the dipole moment of the dye which improves the rectifying behaviour if the dipole points away from the TiO2 surface [98]. Investigations on benzoic acids having different dipole moments showed, that a suitable dipole moment has a positive effect on the work function of TiO2 and the energy across the TiO2/dye/HTM interface [103].
11.2.1.5
Hole Transport Materials
The tasks to be fulfilled by of the HTM are (i) efficient and fast dye regeneration, (ii) transport of holes to the counter electrode and (iii) charge extraction at the cathode.
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HTMs for dye-sensitized solar cells can be roughly divided into two classes; viz. redox couple based HTMs (for L-DSCs) and solid HTMs (for S-DSCs). The electrolyte medium for L-DSCs in which the redox couple is dissolved can be a volatile polar solvent (e.g. acetonitrile/valeronitrile) or low volatile one (e.g. 3-methoxypropionitrile), an ionic liquid [104] or a gel [105]. The most frequently used electrolyte for L-DSCs consists of an organic solvent, a redox couple and additives. Commonly, the organic solvent electrolytes are nitriles such as acetonitrile, valeronitrile, 3-methoxypropionitrile or esters such as ethylene carbonate, propylene carbonate and g-butyrolactone. These are highly polar, dissolve the redox couple and facilitate fast charge charier transport by the redox couple [106]. The major redox couple is the iodide/triiodide couple. Its performance is unsurpassed by other redox couples such as Br−/Br3− [106, 107], SCN−/(SCN)2 [108, 109], SeCN−/ (SeCN)2 [108, 109], or Ni(III)/(IV) bis(dicarbollide) [110]. The counter ions used for the redox couple also influence the performance of solar cells because of their different ion conductivities in the electrolyte and because of the fact that these ions can adsorb on the semiconductor surface. This can induce a shift of the conduction band and hence a change in the open-circuit voltage. Alkyl imidazolium cations for example can adsorb on the TiO2 surface, charge it positively and can form an additional blocking layer which prevents triiodide ions from reaching the TiO2 surface and recombining there [111]. For a further improvement of the cell performance, additives can be used such as 4-tert-butylpyridine (tBP) [112], guanidinium-derivatives [113] and chenodeoxycholic acid (CDCA) [114] which can cause an increase in the opencircuit voltage, reduce recombination, enhance the long term stability, or suppress dye aggregation. Thus the compositions as well as the mass fractions of the liquid electrolyte ensemble have to be optimized for each sensitizer to reach high efficiencies. Since the diffusion of ions determines the charge transport in redox electrolytes, usually less dense viscous solvents are used to promote the ionic transport. Thus organic solvents employed in the electrolyte cell often are volatile and therefore the long term stability of L-DSCs is essentially inhibited because of the drying up of the solvents. Ionic liquids can replace organic solvent electrolytes. This implicates advantages which arise from the negligible vapour pressure of ionic liquids, their high electric conductivity supplemented by low-flammability and a very wide electrochemical stability window. Regrettably, the viscosity of ionic liquids is much higher compared to standard organic solvents which reduces the short-circuit current drastically due to the limited mass transport. Recently, it was reported that it is possible to reach competitive efficiencies (about 7.6% [115, 116] and 8.5% [117]) by ionic liquids with an optimized composition. Hence it seems to be possible to overcome the characteristic drawbacks of L-DSCs such as solvent leakage and evaporation of the solvent by the use of an appropriate ionic liquid electrolyte while preserving high efficiencies. But still corrosion caused by the aggressive nature of the iodide/triiodide redox couple can limit the long term stability of L-DSCs [118]. Sealing is procedure which is applied for L-DSCs on the basis of volatile/low volatile electrolyte to prevent leakage of the electrolyte and evaporation of the solvent.
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This is still the most critical issue of L-DSCs which constrains the commercialization because of less long term stability. For L-DSCs prepared in laboratory scale, the dye-sensitized semiconductor electrode and the counter electrode were assembled into a sealed sandwich-type cell by heating a Surlyn® (DuPontTM) film which simultaneously acts as a spacer between the electrodes. Surlyn® is a commercial thermoplastic ionomer resin consisting of the random copolymer poly(ethylene-comethacrylic acid). After the introduction of the electrolyte through a drilled hole in the counter electrode, the latter is sealed using a Bynel® film (DuPontTM) and a thin cover glass [75]. It is advantageous to replace liquid electrolytes by non-corrosive solid electronic transport materials, such as low molecular weight organic hole conductors, organic polymers and inorganic p-conductors. In contrast to liquid transport materials, where the infiltration of the mesoporous structure of the semiconductor is easily achieved, pore filling is a critical issue for S-DSCs. An ideal solid hole conductor has to fulfil the following key requirements: (i) excellent pore filling properties, (ii) capability of getting deposited at temperatures <100°C to avoid degradation the dye, (iii) absence of the tendency to be highly crystalline, (iv) good film forming capacity, (v) high hole transport mobility to guarantee fast dye regeneration and to suppress recombination, (vi) transparency in the region of the visible light to guarantee that the incident light reaches the sensitizer, (vii) photochemical stability and (viii) the HOMO energy level should be higher than the HOMO level of the respective dye for an efficient hole transfer [66, 87]. Among the solid hole transport materials, the most established one viz. spiro-OMeTAD (Fig. 11.1) (plus additives like tBP and LiN(SO2CF3)2) [20, 72, 119], belongs to the class of low molecular weight triphenylamine hole conductors. It shows moderate charge carrier mobility in the order of 10−4 cm²/Vs for spiro-OMeTAD [72] which can be enhanced by adding the “magic-salt” LiN(SO2CF3)2 [71]. Its good infiltration property has been shown to lead to a higher filling fraction of the pores of the semiconductor than with other hole transport materials [72]. So far, S-DSCs employing this material led to impressive efficiencies of 4.5% [120, 121], 4.6% [122], 4.7% [123] and 5.0% [124] (measured at 100 mW/cm²). However, this is just nearly half of the record efficiency of L-DSCs (11.5% [123], 100 mW/cm²). The intrinsically lower efficiency of S-DSCs compared to L-DSCs can be ascribed to (i) the lower hole transport mobility of organic semiconductors, (ii) high recombination between TiO2 and the HTM, (iii) a bad electrochemical contact between dye and HTM and (vi) less efficient pore filling and hence the use of thinner mesoporous layers which causes less light harvesting [66]. Polymers have a very high potential for the use as HTM in S-DSCs due to their good film forming properties and amorphous or partially crystalline nature [125– 128]. But for the pore filling, novel concepts and strategies should be developed. From a technological standpoint, a polymer semiconductor nanocomposite solar cell prepared at low temperatures on a flexible substrate has all the potentials to compete with other flexible types of solar cells.
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Counter Electrodes
At the counter electrode (cathode), the hole transport material is reduced. To do so, usually platinum coated glass is employed in L-DSCs. However, corrosion is the one main problem in L-DSCs [118]. Metals such as platinum, copper, aluminium, or zinc which show enough electro catalytic activity to mediate the electron exchange suffer from corrosion. This influences the long term stability negatively. Therefore, novel approaches were developed to facilitate electron exchange and simultaneously corrosion stability. Recently, graphite [129] and carbon materials (carbon black [130], activated carbon [129] and carbon nanotubes [131]) were reported. These materials are favourable due to low costs of the starting material, the possibility of roll-to-roll processing and their stability towards corrosion. The top-contact of S-DSCs typically composes of gold due to its large work function. However, also silver is reported to be employed as counter electrode. In a direct comparison to gold contacts, silver can enhanced the photocurrent without changing the other cell parameters. The reason for this observation is the reflection capability. The reflectivity for Au is 56% whereas that for Ag is 96% (at 510 nm). Thus, less light is dissipated into the metal and more is guided back to the sensitizer enhancing the optical path length of the cell [120].
11.2.2
Mechanisms
The following section will focus on the key processes of charge generation and transport in liquid and solid-state dye-sensitized solar cells as well as on the recombination process and the associated mechanisms. 11.2.2.1
Key Processes
The light induced processes as well as the energetic conditions of DSCs are depicted in Fig. 11.3. Under the influence of electromagnetic irradiation, the chemisorbed dye is excited (D + hn → D*) and forms an electron-hole pair. At the interface between dye and semiconductor, the excited electron is injected from the LUMO of the dye into the conduction band of the semiconductor. This process is extremely fast, it occurs in the femtoto picosecond time scale for both DSC types [71, 88, 134]. Although, the mechanism for electron transport of injected charge carriers in mesoporous semiconductors is still under discussion, there is almost consensus that the electron lifetime in the mesoporous semiconductor network is limited [71]. It can be calculated by the following equation: LD = De ·t e LD electron diffusion length De electron diffusion coefficient te electron lifetime
(11.1)
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-1.5
-3.0
LUMO
-1.0
-3.5
-0.5
-4.0
(1)
(2)
hν
Voc Voc (I-/l3-) (organic
(6)
-5.0
hole conductor)
(5) (4)
(7) (3) HOMO
E [V] vs. NHE
E [eV] vs. vacuum
TCO
TiO2
DYE
redox level of I-/l3HOMO of an organic hole conductor
Cathode
0.5
(2)
-4.5
anode
0
CB
HTM
Fig. 11.3 Schematic energy diagram for DSCs including the electronic processes that support the current and voltage generation (solid arrows) as well as the ones which reduce the solar cell performance (dashed arrows). (1) Excitation of the dye by absorption, (2) electron injection and conduction to the anode, (3) regeneration of the oxidized dye by the dissolved I−/I3− redox couple or a solid hole transport material whereas the energy level of the solid HTM is supposed to be lower, (4) hole transport to the cathode by diffusion controlled ionic conduction or polaron hopping for liquid and solid HTMs, respectively. (5) Recombination between electrons in the TiO2 and the oxidized dye, (6) recombination between electrons in the TiO2 and holes of the HTM (liquid/ solid), (7) recombination between electrons in the TCO and holes of the HTM (liquid/solid). Note that the plotted energy levels are no absolute values. For instance, the energy level of the TiO2 conduction band can shift appreciably with the media and additives [132, 133]. (+cf. Sect. 11.3.1.5) Furthermore, the I−/I3− system shows not just one redox level rather different unstable radicals associated with a variety of different redox levels [118]. Moreover, the Fermi level of the FTO coated substrate can shift (by about 0.7 eV) upon illumination under open-circuit conditions [52]
Under consideration that the electron lifetime as well as the electron diffusion coefficient depend on the light intensity, the electron diffusion length is in the range of 10–20 mm [88]. This limits the thickness of the mesoporous layer. After the electron transfer from the dye to TiO2, the dye has to be regenerated as fast as possible by a liquid electrolyte or by a solid HTM. This process takes place within nanoseconds [71, 88]. For liquid electrolyte DSCs, iodide regenerates the oxidized dye (D+) by reduction. In doing so, it is oxidized to triiodide (i.e. 2 D+ + 3 I−→ 2 D + I3−). In comparison to that, a solid hole transport material regenerates the oxidized dye by injecting an electron from its HOMO level to the vacancy in the HOMO of the dye. Therefore, as it was explained before, it is important that the HOMO level of the HTM lies higher than the one of the dye to create an energetic drifting force for the regeneration [66, 87].
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Depending on the type of HTM (liquid or solid), the transport of holes proceeds according to different mechanisms. In L-DSCs, the hole transport occurs via diffusion controlled ionic conduction whereas it occurs via a polaron hopping [71] process for solid HTMs like spiro-OMeTAD. Ionic conductance in general is determined by speed and medium dependent friction. The rate of diffusion is dependent on the solvent, the radius of the ion, the field intensity, the pressure and the temperature [135]. Ion diffusion in L-DSCs is a fast and efficient way of charge transport. The charge transport in S-DSCs employing spiro-OMeTAD via polaron hopping depends on the hole transport mobility. The latter is quite low in pristine spiroOMeTAD (~10−4 cm² V−1 s−1) [136], but can be enhanced by adding LiN(SO2CF3)2 (to ~10−3 cm² V−1 s−1) [71]. It was reported, that the hole mobility after addition of the Li-salt even exceeded the mobility of TiO2 [137]. Consequently, the hole transport is not limiting the efficiency of S-DSC, but the poor pore infiltration by the HTM and recombination processes.
11.2.2.2
Recombination Processes
The possible channels of recombination in DSCs are (i) between electrons in the TiO2 and the oxidized dye, (ii) between electrons in the TiO2 and holes in the HTM, (iii) between electrons in the TCO and holes of the HTM (shown as processes 5, 6, 7 in Fig. 11.3). Recombination between electrons in the TiO2 and the oxidized dye is a more important loss mechanism for L-DSCs than for S-DSCs. Under standard conditions, about 10–15% of the oxidized dyes are lost by recombination before regeneration by the liquid electrolyte [138]. The regeneration of the oxidized dye by the HTM is characteristically faster in S-DSCs than in L-DSCs (regeneration rate for L-DSCs in microsecond time scale, for S-DSCs in nanosecond range) [71]. Hence, the recombination with the oxidized dye is slow in S-DSCs [138]. Recombination between electrons in the TiO2 and holes in the HTM is less significant in L-DSCs. In general, if the oxidized dye is regenerated, the recombination is slow for L-DSCs. The reason for that is the formation of intermediate radical species I2−·, which can not recombine directly with injected electrons. It has to find an additional I2−· to generate I3− and I− to facilitate recombination [139]. In contrast to that, this kind of recombination is a one-step process in S-DSCs which can occur much more easily. Hence the recombination rate is higher. It was reported that this recombination can be greatly reduced with a suitable dye design, viz. ion-coordinating ruthenium dyes [138]. Recombination between electrons in the TCO and holes of the HTM is negligible for L-DSCs under short-circuit conditions, but becomes relevant under open-circuit condition [52]. In contrast to that, for S-DSCs this is the most significant recombination channel which can completely annihilate the current generation of the solar cell. Fortunately, it is quite easy to prevent this recombination absolutely by the incorporation of an electron conducting hole blocking layer (cf. Sect. 11.2.1.2).
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545
Characterization by Current/Voltage-Curves
The most significant characteristic of solar cells is the current/voltage curve (I/V curve). The dependence of I vs. V under illumination as well as under dark conditions are measured. While doing so, an increasing variable counter bias is applied to the cell and the respective current is detected to plot the current density against the applied voltage (Fig. 11.4): Under dark conditions the photocurrent should be zero, thus no current should be measured until the applied counter bias is larger than a threshold voltage, which is equal to the photovoltage generated by the solar cell under illumination. Then the applied electron pressure overcomes the energetic barrier of the cell and starts to inject heavily (the current rises extremely at further forward bias). Under illumination and short-circuit conditions (viz. no electric resistance encountered, voltage is zero) the maximum generated photocurrent flows and the short-circuit current ISC can be measured. Taking the cell area into account, the short-circuit current density JSC can be determined. The photocurrent stays constant with increasing applied bias until the photogenerated current is balanced to zero by the counter voltage. Under these open-circuit conditions (viz. infinite resistance encountered, current flow is zero) the open-circuit voltage VOC can be read off. From the shape of the I/V-curve under illumination, the maximum power point (MPP), the point at which the product of current and voltage is maximal, can be determined as well as the associated current density (JMPP) and voltage (VMPP). With these specifications the solar energy-to-electricity conversion efficiency of a solar cell can be calculated.
JSC short-circuit current density VOC open-circuit voltage MPP maximum power point JMPP current density at the MPP VMPP voltage at the MPP
Fig. 11.4 Typical I/V-curve under dark conditions and illumination including the characteristic parameters. JSC short-circuit current density, VOC open-circuit voltage, MPP maximum power point, JMPP current density at the MPP, VMPP voltage at the MPP
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h=
PMPP J sc ·VOC ·FF = Pin Pin
(11.2)
h solar energy-to-electricity conversion efficiency (expressed as percentage) PMPP power density at the maximum power point [W/cm²] Pin incident light power density [W/cm²] JSC short-circuit current density [mA/cm²] (ISC short-circuit current [mA]) VOC open-circuit voltage [V] FF =
J MPP ·VMPP ·100 J SC ·VOC
(11.3)
FF fill factor (expressed as percentage) JMPP current density at the maximum power point [mA/cm²] VMPP voltage at the maximum power point [V] To improve the accuracy, validity, reliability and reproducibility of reported power conversion efficiencies for solar cells, a universal specification standard was set [140]. According to that, solar cell testing has to be accomplished under an Air Mass 1.5 Global (AM1.5G [141]) solar spectrum for which the spectral intensity distribution equals that of the sun on the earth’s surface at an incident angle of 48.2° including both direct and diffuse irradiation. The power of the lamp should be 100 mW/cm² (1 sun). Furthermore, a suitable mask has to be used during the measurement to ensure that light incidents only on the reported area [140, 142].
11.2.4
Characterization by IPCE Measurements
The incident photon-to-current conversion efficiency (IPCE) is defined as the number of electrons delivered to the external circuit divided by the number of incident photons. It can be calculated for each wavelength by the following equation: IPCE =
h·c J l · ·100 e l ·Pl
= 1240.
Jl .100 l ·Pl
(11.4)
IPCE incident photon-to-current conversion efficiency (expressed as percentage) h Planck constant [C V s] c light velocity [nm/s] Jl short-circuit current density at l [A/cm²] e elementary charge [C]
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l wavelength [nm] Pl power density of monochromatic light at l [W/cm²] 1240 condensed coefficient [V nm] When a photon is absorbed by the sensitizer, an electron-hole pair is generated, which can either contribute to the photocurrent produced by the cell, or can be annihilated through recombination. In the latter case, the absorbed photon is lost without contributing to the current production. The IPCE curve, i.e. the wavelengthdependent spectral response of the photocurrent, illustrates how efficient photons are converted into current by the sensitizer at each wavelength. Thus, it is not surprising that the IPCE curve (also called action spectrum) and the absorption of the sensitizer chemisorbed on the semiconductor fit together very well if the absorbed photons contribute towards photocurrent. If the optical depth of the solar cell is high enough (caused by high molar extinction of the sensitizer or by a large thickness of the cell) and the data are corrected for reflection and absorption loss by the substrate, the IPCE can be close to 100% over a broad range of the absorption area of the dye.
11.3
Metal-Organic Sensitizers in Dye-Sensitized Solar Cells
In the following, focus will be on metal-organic dyes used as sensitizers in DSCs. The sensitizers, which serve as solar energy absorbers and electron pumps, decide the light harvesting properties as well as the overall performance of DSCs significantly. Thus, a lot of research effort has been done on the design, synthesis and characterisation of novel sensitizers. For example, systematic studies on the effect of different metals, suitable ligands and different substituent groups have been carried out. These efforts resulted in the development of various mononuclear and polynuclear dyes based on transition metals, such as RuII [90], OsII [143, 144], PtII [145, 146], ReI [90], IrIII [147], CuI [148], ZnII [91, 149, 150] and FeII [151]. Transition metal ions are used as central atoms in dyes such as polypyridyl ruthenium complexes, porphyrins and phthalocyanines. These three classes are the most promising and most intensively investigated ones among the metal-organic sensitizers. Hereafter, they will be discussed in detail, viz. their general properties, design concepts and strategies as well as selected examples, proving the capability of such dyes in their function as sensitizers in DSCs will be given.
11.3.1
Ruthenium Dyes
Most of the ruthenium complex sensitizers have the general structure RuLL¢(X)2. Here, L stands for the anchoring ligand (typically 2,2¢-bipyridyl-4,4¢-dicarboxylic acid)
548 Fig. 11.5 General structure of polypyridyl Ru(II) sensitizers
K. Willinger and M. Thelakkat A A
R
N N
N Ru SCN
A = anchoring group (e.g. carboxylic acid or phosphonic acid)
N NCS
R
R = carboxylic acid, hydrophobic chain, donor-antenna group, ion-coordinating moiety, or combinations of these
and L¢ for the ancillary ligand (which commonly is a bipyridyl ligand substituted by simple carboxylic acid, amphiphilic, donor or ion-coordinating groups or combinations of these). X represents a monodentate ligand (halogen or pseudohalogen, most frequently isothiocyanate) (Fig. 11.5) [15]. The ruthenium(II) transition metal center ion is in principle capable of forming numerous homo- or heteroleptic complexes with various ligands such as bipyridinederivatives, 2,2¢:6¢,2″-terpyridines, NCS−, NH3, CO, CN−, H2O etc., leading to a variety of different mono- or polynuclear [152–154] complexes. Generally, ruthenium in the oxidation state +2 (d6) is octahedrally surrounded by ligands and the 6 complexes are diamagnetic due to the low-spin configuration t2 g . Influenced by the Coulomb-repulsion in the presence of a symmetrical octahedral ligand field, the five d-orbitals of ruthenium are split into three energetically lower (t2g) and two higher (eg) orbitals. (In deformed octahedrons an additional splitting occurs, cf. Jahn-Teller effect.) The energetic distance between the t2g- and eg-orbitals is determined by the crystal field strength DO (Fig. 11.6). When a transition metal like ruthenium(II) has 4–7 electrons in the d-orbitals and tends to form octahedral complexes, two different electron distributions can be generated. If weak ligands, which cause only a weak splitting (small DO), are coordinated to the transition metal center, the high-spin configuration occurs. Here, according to Hund’s rules, the distribution with the highest number of unpaired electrons is generated. In contrast to that, the low-spin configuration (where the number of unpaired electrons is minimal) is generated, if a strong ligand, which causes a large splitting (large DO), is coordinated to the center ion. The strength of the respective ligand can be derived from the so called spectrochemical series. Roughly said, p-acceptors (e.g. bipyridines) cause a large splitting and p-donors (e.g. I−, Br−, SCN−) cause a weak splitting. Consequently, for typical Ru(II) complexes incorporating bipyridines, the electrons of Ru(II) are filled into the low energetic t2g orbitals resulting in low-spin complexes. Due to the fact that the eg-orbitals, which are antibonding regarding the metal-ligand bonds, are not filled, the bond between ligands and central ion is very strong. Hence, these complexes are chemically very stable and the ligands do not show any tendency towards dissociation even at elevated temperatures. Besides the crystal field splitting arising from Coulomb-repulsion, there is another contribution influencing the orbitals in complexes, viz. the hybridization
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Fig. 11.6 Schematic representation of the energetically degenerate d-orbitals of a free Ru2+ ion and the splitting of the energy levels due to the perturbation by a symmetrical octahedral ligand 6 field. (DO: crystal field strength) Here, the low-spin configuration of Ru2+ ( t 2g ) is depicted, which is created by the influence of strong ligands such as bipyridines
between orbitals of the transition metal ion and the orbitals of the ligand. Polypyridine ligands posses s-donor orbitals localized on the nitrogen atom as well as p-donor and p*-acceptor orbitals more or less delocalized on the aromatic rings [93]. By hybridization, a mixing of the metal associated and ligand associated orbitals occurs and the metal orbitals are split further. Then, the promotion of an electron from a pMetal-orbital (which is mainly localized on the metal) to the p*Ligand-orbital (which is mainly located on the ligand) gives rise to metal-to-ligand charge transfer (MLCT) excited states, whereas promotion of an electron from pMetal to s*Metal gives rise to metal entered (MC) excited state. Ligand centred (LC) excited states can be obtained by promoting an electron from pLigand to p*Ligand [93]. Due to the MLCT absorption in the longer wavelength range in combination with MC and LC absorption bands, these complexes are capable to absorb over a wide range of the visible spectrum, but suffer usually from low extinction coefficients. Moreover, if the complexes are applied as sensitizers in DSCs, they facilitate fast injection because of the fact that the absorption of photons places the excited electron on the anchoring ligand(s). The positive charge (hole) is thereby distributed over the metal and also to some extent over the NCS group causing a spatial separation between injected electrons and holes, thus retarding the rate of recombination [155, 156]. Furthermore, ruthenium(II) complexes show favourable photochemical, photophysical and electrochemical properties [93].
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The best photovoltaic performances in terms of conversion yield and long-term stability for L-DSCs and S-DSCs on the basis of spiro-OMeTAD have so far been achieved with polypyridyl ruthenium(II) complexes, although organic dyes started to catch up especially for S-DSCs. Due to the overwhelming number of efficient ruthenium sensitizers, they are in the following classified according to their functional groups attached to the ancillary ligand. The design concepts and selected examples are presented and the performances of the different complexes in DSCs are summarized in tables at the end of each section.
11.3.1.1
Unfunctionalized Ruthenium Dyes
The class of unfunctionalized ruthenium dyes is limited to different protonation degrees of Ru(2,2¢-bipyridyl-4,4¢-dicarboxylic acid)2(NCS)2 denoted as N3 and Ru(4,4¢,4″-tricarboxy-2,2¢:6¢,2″-terpyridine)(NCS)3 denoted as black dye (Fig. 11.7 structures 2–5). These sensitizers do not carry any functional groups, but just carboxylic acid/carboxylate groups attached to each pyridine moiety. Nevertheless, the long-term stability of such unfunctionalized sensitizers is reasonable [157] and the attainable efficiencies are high especially for L-DSCs. For example polypyridyl ruthenium(II) complex 2 (Fig. 11.7) was reported to deliver a short-circuit current density of more than 18 mA/cm² and an open-circuit voltage higher than 700 mV leading to a solar-to-electricity energy conversion efficiency of 10% (see Table 11.1) [15]. The high overall efficiency is a consequence of optimization, suitable additives, and the outstanding properties of the redox sensitizer, viz. the absorption of a sufficient fraction of the incident light in combination with long excited-state lifetimes. Since this first report of an L-DSC reaching 10% in 1993, only slight improvements in the solar cell performance could be achieved. In 2001, the so called black dye (Fig. 11.7, 5) surpassed the performance of 2 marginally with an efficiency of 10.4% [160]. In 2006, even 11.1% could be reached with this dye [161]. The improvement in the performance of 5 compared to 2 is attributed to the strong spectral response in the red and near-IR region. The IPCE started to rise at 940 nm, more than 100 nm further shifted into the IR-region than 2 resulting in higher short-circuit photocurrents, even though the surface coverage and the extinction coefficient of 5 are significantly lower than 2. In 2005 it was reported that N719 (Fig. 11.7, 4) and the mono salt (Fig. 11.7, 3) exhibited power conversion efficiencies
COOH HOOC
N
−
OOC
Bu4N+
N
N
COOH
N
−
OOC
Bu4N+
N
N
Ru SCN
COOH
COOH COOH
N
N
Ru
2 (N3)
N
SCN COOH
NCS
3
SCN COOH
OOC
Bu4N+ NCS
N
N
N
Ru
NCS
−
COOH
N
HOOC N
NCS
4 (N719)
Bu4N+ COO −
Ru N
NCS NCS
Bu4N+ −
OOC
5 (black dye)
Fig. 11.7 Molecular structures of unfunctionalized ruthenium(II) sensitizers (2–5) carrying protonated or deprotonated carboxylic acid groups on each pyridine moiety
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Table 11.1 Overview of the performances of unfunctionalized sensitizers tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMa [mA/cm²] [V] [%] [%] Ref. 2 3 4 4 4 5 5
L-DSC L-DCS L-DSC S-DSC S-DSC L-DSC L-DSC
Volatile Volatile Volatile Spiro-OMeTAD Spiro-OMeTAD Volatile Volatile
18.2 17.7 17.6 5.1 4.6 20.5 20.9
0.720 0.846 0.800 0.910 0.931 0.720 0.736
73 75 73 55 71 70 72
10.0 11.18 10.26 2.56 3.2 10.4 11.1
[ 15] [158] [158] [ 21] [159] [160] [161]
a
Volatile solvents for L-DSCs are on the basis of acetonitrile/valeronitrile
of 10.26% and 11.18%, respectively [158]. In the case of sensitizers that do contain deprotonated carboxylic groups, the open-circuit voltage is observed to be higher while the short-circuit current is lower. In the case of sensitizers which contain free carboxylic acid anchoring groups, most of the protons may be transferred to the TiO2 surface. This can cause a positive charging of the surface and shifts the Fermi level which can result in a decrease in the open-circuit voltage. Furthermore, a surface dipole is generated by the protons resulting in an electric field that enhances the adsorption and assists the electron injection which equals an increase in the shortcircuit current. Hence, the appropriated degree of deprotonation is a crucial issue for high efficiencies [158, 160]. Today only a few new functional dyes exceeded the best performance of the above dyes. For example, the ruthenium sensitizers C106 [162] (Fig. 11.17, 34) and CYC-B11 [123] (Fig. 11.18, 36) carrying extinction enhancing groups in combination with hydrophobic chains exhibit high short-circuit current densities and high efficiencies above 11.2% (Table 11.4). It was reported, that, taking into account electrical and optical losses in the dye-sensitized system, the maximum power conversion efficiency attainable as a function of the optical band gap of the sensitizer and the “loss-in-potential” from the optical band gap to the open-circuit voltage is estimated to be 13.4% for currently used sensitizers [172]. Accordingly, the upper limit of L-DSCs is almost reached and higher efficiencies can only be achieved by sensitizers that offer an absorption onset in the near-IR region or by reducing the loss-in-potential. Due to the lack of functional groups that enhance the absorption or reduce recombination, the unfunctionalized polypyridyl ruthenium(II) dyes are less attractive for S-DSCs considering the fact that S-DSCs have an optimum thickness of ~2 mm. In the early stage of S-DSCs development, these sensitizers were mainly used for device optimization. For instance, the performance of S-DSCs based on N719 and spiro-OMeTAD could be considerably improved by controlling charge recombination losses across the interface and enhancing the hole transport mobility of the spiro-OMeTAD [21]. To reach these goals, additives like tBP and Lithium bis(trifluoromethanesulfonyl)imide (LiN(SO2CF3)2) were added to the hole transport
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material. The cooperative effect of both additives was investigated and a 100% improvement in the open-circuit voltage and a considerable increase in the short-circuit current density was reached leading to an overall efficiency of 2.56%. The additive tBP has a beneficial effect on the homogeneity of the hole conductor film and promotes the dissolution process of the Li-salt in the hole transporters matrix. Furthermore, it reduces recombination and so does the Li-salt [21]. With increasing salt concentration the recombination was further slowed down. These results were confirmed by the National Renewable Energy Laboratories [21]. A further improvement was reached by adding silver ions (silver nitrate) to the dye solution which was used to cover the surface of the mesoporous semiconductor [159]. The silver ions are assumed to bind to the isothiocyanate group via the sulphur which has been described in terms of the hard-soft acid-base concept. The formation of such silver complexes is suggested to result in a higher packing density increasing the surface concentration of dyes. This treatment increased the open-circuit voltage and the short-circuit current density leading to an efficiency of 3.2% for a N719 sensitized solar cell (compared to 2.1% for an untreated cell). To cause a further improvement in the performance while maintaining the general device concept, two approaches were developed, which are complementary to each other. The first is the optimization of additives and device engineering and the second is the optimization of the sensitizer including novel strategies and concepts by variation of the functional ligands coordinated to the ruthenium(II) core. The latter topic is the subject matter of the following sections.
11.3.1.2
Amphiphilic Ruthenium Dyes
One design strategy to improve the properties of standard sensitizers such as N3 (Fig. 11.7, 2) and its double-deprotonated analogue N719 (Fig. 11.7, 4) is the introduction of hydrophobic alkyl substituents to obtain amphiphilic ruthenium complexes. These amphiphilic dyes are supposed to offer several advantages which favour their use as sensitizers in DSCs: (i) The hydrophobic spacer provides an insulating barrier between the sensitized semiconductor and the hole transport material to avoid charge carrier recombination between injected electrons and the positive charges of the HTM [97], (ii) the presence of the hydrophobic barrier increases the stability of solar cells towards water induced desorption of sensitizer molecules from the semiconductor surface [86], (iii) the ground state pKa value of the anchoring 2,2¢-bipyridyl-4,4¢-dicarboxylic acid is higher for amphiphilic complexes compared to standard sensitizers, this enhances the binding capability of the sensitizer onto the semiconductor surface [173], (iv) amphiphilic sensitizers show an increase in dye loading due to the decreased charge density on the sensitizer which attenuates the electrostatic repulsion [158] and (v) it is assumed, that the interaction between the dye and an organic HTM (e.g. hole conducting polymers) can be improved by hydrophobic chains which are capable to enhance the wettability and thus the electronic communication between dye and HTM [90].
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Table 11.2 Overview of the performances of amphiphilic sensitizers tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMb [mA/cm²] [V] [%] [%] Ref. 6a 6 6 7 7a 7 8 8 8 8 8 8 9 9a 9 9 10a 10 11 12 13 13 14
L-DSC L-DSC S-DSC L-DSC L-DSC S-DCS L-DSC L-DSC L-DSC L-DSC S-DSC S-DSC L-DSC L-DSC L-DSC S-DCS L-DSC S-DCS L-DSC L-DSC L-DSC L-DSC L-DSC
Volatile Volatile Spiro-OMeTAD Volatile Volatile Spiro-OMeTAD Volatile Low volatile Low volatile Polymer gel Spiro-OMeTAD Spiro-OMeTAD Volatile Volatile Volatile Spiro-OMeTAD Volatile Spiro-OMeTAD Volatile Volatile Volatile Volatile Volatile
14.6 6.2 5.4 15.5 6.4 5.8 16.0 15.2 14.6 12.5 6.3 8.3 16.2 7.0 16.8 6.3 3.5 5.8 12.62 16.37 15.16 16.5 15.73
0.700 0.660 0.714 0.700 0.690 0.712 0.750 0.764 0.722 0.730 0.738 0.752 0.740 0.750 0.778 0.744 0.670 0.718 0.630 0.707 0.693 0.666 0.707
66 56 60 68 58 61 70 68 69 67 61 64 72 62 73 66 56 55 62 69 66 71 67
6.7 2.4 2.3 7.4 2.6 2.5 8.4 7.8 7.3 6.1 2.8 4.0 8.6 3.2 9.57 3.1 1.3 2.3 5.68 8.0 6.92 7.81 7.45
[173] [97] [174] [173] [97] [174] [173] [175] [176] [177] [174] [70] [173] [97] [158] [174] [97] [174] [178] [80] [179] [180] [179]
a
Note that in order to enable transient absorption measurements, transparent mesoporous TiO2 films with a thickness of only 4 mm were applied. This reduces the amount of absorbed light, resulting in reduced JSC values b Volatile solvents for the electrolyte are on the basis of acetonitrile/valeronitrile and low volatile ones mainly rest upon 3-methoxypropionitrile
The number of amphiphilic dyes in the strict sense is quite low, because the possibilities of variation are limited to the modification of the length of the hydrophobic chains, their degree of branching and the anchoring group. Here, some examples of amphiphilic ruthenium complexes will be presented. The characteristic solar cell parameters can be found in Table 11.2. To gain more insight into the effects of the different chain lengths, complexes 6–10 carrying C1, C6, C9, C13 and C18 chains (Fig. 11.8) were systematically tested in devices [97, 173, 174]. It could be demonstrated, that in L-DSCs the short-circuit current density as well as the open-circuit voltage and thus the efficiency increased with an increase in chain length from C1 to C13. (Or rather, the current rose from 14.6 to 16.2 mA/cm² and the voltage from 700 to 740 mV resulting in an efficiency increase from 6.7% to 8.6%, from C1 to C13) [173]. Furthermore, it was reported that the series of amphiphilic ruthenium dyes with varying hydrocarbon chain length were able to act as an insulting barrier for recombination in L-DSCs as well as in
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HOOC
R
N N
R = C6
N
R = C9
N
R = C13
Ru SCN
R = C1 CH3
NCS
R
R = C18
6 7 8 (Z907) 9 (N621) 10
Fig. 11.8 Structures of a series of amphiphilic sensitizers (6–10)
S-DSCs [97]. It is assumed, that the chains stretch out creating a aliphatic network (especially in the presence of a solid hole transporter) and increasing the distance between semiconductor and HTM [174]. Moreover, it was suggested that sensitizers with long alkyl chains are being oriented normal to the semiconductor surface [97]. By time-resolved emission spectroscopy (monitoring the dynamics of electron injection) and transient optical absorption spectroscopy (monitoring the charge recombination and regeneration), it was observed, that the increasing alkyl chain length resulted in slower recombination dynamics for both, the recombination of injected electrons with dye cation and that one with the hole transport material (solid and liquid) [97]. Hence, the performance of DSCs improved with increasing alkyl chain length. An exception was the L-DSC on the basis of 10 carrying the longest alkyl chain (C18). Here, the dye cation recombination dynamics exceed the dye regeneration speed resulting in a reduced performance. The same reduced performance was observed for the S-DSCs employing this sensitizer. The low S-DSC performance of the amphiphilic dye carrying the longest chain was ascribed to the collapse of too long chains reducing the effective distance and the blocking behaviour between into the semiconductor injected electrons and the holes in the HTM [174]. Among the amphiphilic ruthenium sensitizers, the most prominent representative is compound 8, denoted as Z907. This amphiphilic heteroleptic sensitizer carrying two hydrophobic chains (–C9H19) was applied in DSCs using liquid electrolytes [173, 175, 176], a polymer gel electrolyte [177], and solid organic HTMs [70, 174]. The L-DSC performance of Z907 was improved by co-adsorbing amphiphilic molecules such as n-hexadecylmalonic acid (HDMA) [175] or 1-decylphosphonic acid (DPA) [176]. The co-adsorption is supposed to result in a more tightly packed mixed monolayer on the semiconductor surface providing a more effective insulating barrier and passivating the non dye adsorbed surface. The mixed monolayer seems to impair the recombination between injected electrons and the HTM very effectively, so that the losses due to decreased light harvesting caused by minor dye loading appear to be overridden. Compared to a device without coadsorbent, the efficiency could be enhanced from 7.2–7.8% to 6.8–7.3% for HDMA and DPA, respectively. Additionally these devices were also very stable under thermal stress and light soaking. In solid state devices, Z907 reached an efficiency of 4.0% under optimized conditions [70]. The addition of silver ions [159] caused no further enhancement. Although the voltage was increased by 106 mV under the influence of silver ions,
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Fig. 11.9 Structure of the amphiphilic, branched dye 11
COOH C6H13
HOOC
C6H13
N N
N Ru
N
SCN NCS
11
C6H13 C6H13
the current decrease significantly because of an unfavourable blue-shift of the absorption [70]. It is known, that chemisorbed sensitizers are susceptible to desorption from the surface under the influence of trace amounts of water, having serious consequences for the long term stability of the cells [86]. It is assumed, that amphiphilic dyes can cause an enhanced stability towards desorption. A quasi-solid-state DSC employing Z907 and a polymer gel electrolyte consisting of a photochemically stable fluorine polymer (poly(vinylidenefluoride-co-hexafluoropropylene), (PVDF-HFP)) which was used to solidify a 3-methoxypropionitrile based liquid electrolyte performed under both thermal stress and soaking with light equivalent to a DSC using a liquid electrolyte on the basis of 3-methoxypropionitrile [177]. This indicates that the gelation has no adverse effect on the conversion efficiency. The efficiency of ~6% which was archived for both systems is much below the highest efficiencies reported for DSCs using for example N719. However, the quasi-solid device showed an excellent stability with a little drop of 5% in efficiency under light soaking at 55°C for 1,000 h under a solar simulator (100 mW/cm² equipped with an ultraviolet filter). Even under heating for 1,000 h at 80°C the efficiency decreased just by 6%. Actually, within the first week the efficiency was moderately enhanced. (For comparison, in the case of N719 the efficiency decreased almost 35% during the first week at 80°C.) Beside amphiphilic sensitizers carrying linear hydrophobic chains, also the branched derivatives like 11 (cf. Fig. 11.9) were synthesized and the photovoltaic performance as well as the stability under special conditions were investigated [86, 178]. However, while maintaining the comparable good stability, the branching did not result in any advantage over the linear amphiphilic sensitizers [86]. Furthermore, amphiphilic sensitizers carrying the same functional aliphatic chains as Z907 but different anchoring groups were used as sensitizers. In compound 12 (cf. Fig. 11.10), denoted as Z955, for example the two carboxylic acid groups are replaced by phosphonic acid anchoring groups while maintaining the hydrophobic C9-chains of Z907 [80]. The H2PO3 anchoring groups caused an increase in stability by a stronger binding onto TiO2 compared to carboxylic acid groups, but the overall conversion efficiency decreased from 6.8% for Z907 compared to 6.4% for 12. The new H2PO3 groups also caused an unfavourable blue-shift of the absorption and a disadvantage in the electron injection capability because the
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Fig. 11.10 Molecular structure of 12
PO3H2 H2O3P
N N
N Ru SCN
12 (Z955) N
NCS
COOH
COOH HOOC
HOOC
C9H19
N N
N
N
N
Ru SCN
C9H19
N Ru
N NCS
SCN C9H19
13 (K9)
N NCS
C9H19
14 (K23)
Fig. 11.11 Structures of the amphiphilic sensitizer 13 and 14
groups are not in conjugation to the polypyridyl plane due to their non-plane structure [106]. Furthermore, a decrease in the open-circuit voltage was observed for 12 [80]. Further examples of amphiphilic dyes are 13 [179, 180] and 14 [179] (cf. Fig. 11.11). 13 incorporates carboxyvinyl acid anchoring moieties, whereas 14 contains 4-vinylbenzoic acid groups. Both are assumed to enhance the long wavelength spectral response and the extinction coefficients due to the increased delocalized system. The performances of the 13, 14 and Z907 sensitizers chemisorbed on a thin mesoporous TiO2 layer (2.5 mm + 5 mm scattering layer) were investigated in L-DSCs. The measured photocurrents are 15.16, 15.73 and 15.09 mA/cm² respectively, showing just a little impact of the increased delocalized system. Nevertheless, the concept of increasing the delocalized p-system to improve the light harvesting efficiency is a promising approach (especially for thin S-DSCs) if the extended delocalization is realize in the ancillary ligand. This will be explained in the next section.
11.3.1.3
Donor-Antenna Ruthenium Dyes
The term donor-antenna ruthenium dyes stands for ruthenium sensitizers incorporating an extended delocalized p-system. The main intention of this concept is the
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N
N COOH HOOC −
N
2 PF6
N HOOC
N HOOC
N N Ru 2+ N N
−
N
2 PF6
N HOOC
HOOC
N N Ru 2+ N N
N COOH
COOH
COOH N
2 PF6−
N N
HOOC
N N Ru 2+ N N
n
n
N COOH
COOH
16
17
N
15
N
Fig. 11.12 Structures of the Ru(II)tris(bipyridine) sensitizers 15, 16 and 17 carrying donor-antenna groups
improvement of the light harvesting efficiency by increasing the molar extinction coefficient. This is addressed by the covalent connection of electron-rich donor groups to one bipyridyl ligand. Especially in S-DSCs, where the optimum thickness of the mesoporous semiconductor layer is a compromise between light absorption and charge transport/recombination, it is extremely favourable to use sensitizers providing a good light harvesting ability. The donor-antenna sensitizers offer an excellent opportunity to enhance the optical depth of sensitized mesoporous thin-films. Hence, an extremely strong absorbing sensitizer provides the possibility to prepare thinner DSCs, while enhancing or maintaining the optimum light harvesting efficiency. A reduction of the thickness of the mesoporous layer saves material and can considerably reduce charge transport losses in both DSC types. A further benefit of this concept is based on the spatial separation of the dye cation from the metal oxide surface. Charge recombination dynamics (in particular the recombination between photoinjected electrons and the oxidized sensitizer) is significantly influenced by the dye cation to TiO2 distance which seems to be increased by donor-antenna ancillary ligands. More specifically, a linear correlation between the logarithm of the reciprocal charge recombination half-time (t50%) and the spatial separation r has been found [181]. Furthermore, an advantage of donor-antenna ruthenium dyes is the achievement of compatibility between donor-antenna groups and solid HTM which promotes an intimate electronic contact between sensitizer and HTM leading to higher regeneration rates. In the following, a selection of sensitizers based on the donor-antenna dye concept will be presented. The Ru(II)tris(bipyridine) complexes 15, 16, and 17 are examples for ruthenium donor-antenna dyes providing high extinction coefficients, a large spatial separation (between dye cation and the semiconductor surface) in addition to a polarity match between donor-antenna groups and spiro-OMeTAD. Each of these dyes bears two identical bipyridyl anchoring ligands and one triphenylamine-based electron-rich bipyridyl donor-antenna ligand (Fig. 11.12) [66, 94, 99, 182].
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Transient absorption spectroscopy of dye sensitized TiO2 films was employed to monitor charge recombination dynamics by observing the decay of the photoinduced cation absorption of dye/TiO2 films. Recombination half-times (t50%) of 350 ms, 5 ms, and 4 s were measured for 15, 16, and 17, respectively [99]. Compared to that, about 200 ms were measured for Z907 (Fig. 11.8, 7) [177, 183, 184]. The decelerated charge recombination behaviour was attributed to an increased physical separation of dye cations from the semiconductor surface as a result of the suitable location of the HOMOs and a translation of the holes away from the ruthenium core to the donor functionalities [99]. Density functional theory (DFT) ab initio calculations, accompanied by cyclic voltammetry measurements, were performed to support this hypothesis. The HOMO of the reference compound [RuII(2,2¢-bipyridyl-4,4¢dicarboxylic acid)3] which does no carry any donor-antenna groups was found to be centred on the ruthenium core. However, the HOMO of 15 is additionally delocalized over the triphenylamine donor-antenna ligand. For 16 and 17, the HOMO is exclusively located on the phenylamine moieties [99]. The spatial separations r of the dye cation from the TiO2 surface derived from DFT calculations were 10.8, 15.6 and 16.7 Å for 15, 16 and 17, respectively [99]. As expected [181], by plotting the logarithm of the reciprocal charge recombination half-time log(1/t50%) against the calculated spatial separation r a linear correlation was found [99]. Furthermore, the cyclic voltammetry measurements showed that these donor-antenna ruthenium sensitizers indeed provide the possibility of creating a charge transfer cascade [94]. If the HOMO level of the donor group is energetically located between the HOMO level of the Ru-core and the HOMO or redox level of the HTM, a charge transfer cascade can be envisaged. This is the case for complexes 15, 16 and 17. Here, after light absorption, an excited electron is shifted to the LUMO (delocalized over the anchoring group) whereas the hole is shifted to the HOMO which is mainly delocalised over the donor groups. This creates a large distance between (excited and injected) electrons and holes causing a lower recombination. The relationship between the spatial distance and the recombination rate is not only valid for polypyridyl ruthenium dyes; it is also true for phthalocyanines and porphyrins [181, 185]. However, there are some factors that have to be taken into account when discussing the distance dependency of the recombination dynamics. For instance, the DFT method to calculate the distribution of orbitals over a molecule is a technique that does not consider the real conditions of chemisorbed sensitizers generating a dense monolayer on a semiconductor surface. Additionally, the positioning of the sensitizer relative to the surface should not be disregarded, since the spatial separation between dye cation and semiconductor surface changes significantly when the relative orientation and conformation of the sensitizer change. Nevertheless, these calculations are used to estimate the distance between dye cation and semiconductor. Furthermore, the transient absorption spectroscopy measurements to determine the recombination half-times depend on experimental conditions, such as the intensity of the used light and the degree of dye adsorption [183, 184]. Despite the favourable long recombination half-times measured for 15, 16 and 17, the performance of such sensitizers in S-DSCs is rather low (cf. Table 11.3, 15) due
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Table 11.3 Overview of the performances of donor-antenna sensitizers tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMf [mA/cm²] [V] [%] [%] Ref. 15 18a 18 18 18 19 20b,c 20b,d 21 22 23 25 25 26 26 27 27 27 27e 27 28 29 30
S-DSC L-DSC L-DSC S-DSC S-DSC S-DSC L-DSC L-DSC S-DSC S-DCS S-DCS L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC
Spiro-OMeTAD Low volatile Volatile Spiro-OMeTAD Spiro-OMeTAD Spiro-OMeTAD Volatile Volatile Spiro-OMeTAD Spiro-OMeTAD Spiro-OMeTAD Low volatile Ionic liquid Low volatile Ionic liquid Low volatile Low volatile Ionic liquid Ionic liquid Volatile Volatile Volatile Volatile
2.5 13.44 16.75 4.4 7.6 9.6 17.6 19.2 1.06 2.15 3.42 16.98 10.90 15.00 10.50 15.40 17.5 7.95 15.1 19.2 17.2 18.84 17.47
0.718 0.723 0.727 0.767 0.790 0.757 0.801 0.748 0.625 0.635 0.685 0.500 0.590 0.470 0.600 0.500 0.737 0.565 0.702 0.780 0.777 0.783 0.697
34 63 72 34 53 35 73 72 46 42 42 66 78 69 78 67 79 78 71 73 76 73 71
0.8 6.1 8.70 1.5 3.2 3.4 10.3 10.3 0.31 0.58 0.99 5.77 4.93 4.87 4.91 5.16 9.0 3.50 7.6 10.5 10.2 10.82 8.65
[94] [186] [187] [66, 94] [184] [66, 94] [188] [188] [189] [189] [189] [155] [155] [155] [155] [155] [190] [155] [115] [190] [191] [192] [193]
Solvents for L-DSCs can be volatile such as acetonitrile/valeronitrile, low volatile such as 3-methoxypropio-nitrile or ionic liquids a The solar cell was prepared using an array of 14.4 mm long TiO2 nanotubes on a Ti foil subjected to illumination in the backside geometry b CDCA was used as coadsorbent c The volatile electrolyte involved a high concentration tBP and guanidinium thiocyanate and no LiI d The volatile electrolyte contained LiI but less tBP and guanidinium thiocyanate e 3-Phenylpropionic acid was used as coadsorbent f Volatile solvents for the electrolyte are on the basis of acetonitrile/valeronitrile and low volatile ones mainly rest upon 3-methoxypropionitrile
to the lack of absorption in the longer wavelength region. The replacement of one bipyridine anchoring ligand by two NCS-ligands leading to Ru(II)bis(bipyridine) (NCS)2 complexes increases the light harvesting efficiency expressed by an additional MLCT absorption band around 550 nm [66, 94]. The Ru(II)bis(bipyridine) (NCS)2 counterparts to 15 and 16 are the complexes 18 and 19 (cf. Fig. 11.13) which show a dramatic increase in absorption and solar cell performance [66, 94, 183, 184, 194]. The molar extinction coefficients of the additional MLCT band at 526 and 540 nm are 2.45·104 and 2.67·104 M−1 cm−1 for 18 and 19, respectively [194]. Thus, for 18 an overall conversion efficiency of 3.2% was measured for an
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N
R
COOH
COOH N HOOC
N R
N N
N
HOOC
N Ru
Ru SCN
N
N
N
SCN R
NCS
N NCS N
N
R=H
18
R = CH3
20
19 R
N
Fig. 11.13 Molecular structure of the high extinction coefficient donor-antenna dyes 18, 19 and 20
S-DSC [184]. Dye 18 was also employed as sensitizer in vertically oriented TiO2 nanotube arrays in conjugation with a liquid low volatile electrolyte [186]. By using 18 in combination with 14 mm long TiO2 nanotubes instead of a mesoporous electrode, an efficiency of 6.1% could be reached (with a volatile electrolyte and a mesoporous TiO2 electrode, 18 reached 8.7% [187]). An extremely similar sensitizer compared to 18, viz. complex 20 (cf. Fig. 11.13) was applied in standard L-DSCs using mesoporous TiO2 (thickness: 13 mm composed of 20 nm anatase TiO2 particles, plus 4 mm composed of 400 nm light scattering anatase particles) [188]. CDCA was added to the sensitizer solution meanwhile the dye-coating process to reduce aggregation of dye molecules and thus leading to higher efficiencies. Additionally, also the composition of the volatile electrolyte was optimized to cause either a higher photocurrent density by employing LiI or a higher voltage by adding more tBP and guanidinium thiocyanate. However, both electrolytes led to a power conversion efficiency of 10.3%. The sensitizers 21 , 22 , and 23 (Fig. 11.14a ) belong to a whole series of high extinction coefficient donor-antenna dyes [189]. They were characterized concerning their electrochemical, spectral and photovoltaic properties. In cyclic voltammetry measurements, it was found that the first reduction occurred at about −1.6 eV vs. ferrocene for all sensitizers resulting in LUMO levels of about −3.2 eV. Taking into account, that the LUMO level of the standard dye N719 occurred at the same value and that this orbital is known to be distributed over the
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a R=
S
COOH HOOC
R
N
R=
S
21
S
N
22
N
N Ru SCN
R=
N NCS
23
R
b R=
O
O
24 (N845)
N
O
Fig. 11.14 Structures of donor-antenna in which the donor is attached via (a) a vinyl spacer (21, 22 and 23) or (b) a methylene group (24)
2,2¢-bipyridyl-4,4¢-dicarboxylic acid ligands [158, 192], it is assumed that the LUMO of 21, 22 and 23 is also distributed over the anchoring ligand. Concerning the spectral properties, it was found, that 21 and 23 showed extremely high extinction coefficients compared to the standard dye N719. For example, at about 370 nm, the molar extinction coefficient of 23 is almost seven times as high as that of N719. For the weakest p-electron delocalisation donor-antenna group, viz. the dimethylamino moiety (cf. complex 22), the absorption behaviour is comparable to N719 and so is the photovoltaic performance. Under non optimized conditions, both sensitizers achieved comparable photocurrent densities, open-circuit voltages and fill factors resulting in equal efficiencies. Although the light harvesting efficiency and the position of the orbitals of 21 were found to be suitable for efficient solar cells, an S-DSC employing this sensitizer performed only less efficient. This shows clearly, that absorption and suitable energy level are not the only aspects affecting the solar cell performance. Nevertheless, the high extinction coefficient sensitizer 23 performed almost twice as good as N719 in these preliminary tests [189]. The donor-antenna ruthenium sensitizer 24 (Fig. 11.14b) is a further example for the control of charge-transfer dynamics [101]. Here, two N,N-(di-p-anisylamino) phenoxymethyl donor units are connected to a ruthenium complex via -CH2–O– groups. Transient absorption spectroscopy monitoring the rate of recombination between electrons from the conduction band of the TiO2 nanoparticles with the oxidized form of the ruthenium sensitizers showed a 1,000-fold retardation of the recombination compared to a dye without donor-antenna groups (t50% = 0.71 s and 0.85 ms for 24 and N719, respectively). This is also assumed to be caused by the increase in the spatial separation of the HOMO orbital from the TiO2 surface, which
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COOH HOOC
25 (HRD-1)
R=
26 (HRD-2)
R
N
O
27 (K-77)
R=
N
N
R=
Ru SCN
N NCS
R
R=
O
28 (Z910)
O
29 (N945)
R= O
R=
N
30 (HRS-2)
Fig. 11.15 Donor-antenna sensitizers 25–30 carrying different alkyl-, alkoxy- or alkylamino-substituted styryl moieties to enhance the light harvesting efficiency
was supported by semiempirical calculations. Despite the outstanding recombination behaviour and suitable position of the energy levels, until now no efficient DSC was reported using 24 as sensitizer. This may be due to the low absorption of 24. Although a strong donor is attached to the bipyridyl ligand, the link is not conjugated to enable p-electron delocalization and hence the extinction coefficient stays low (to be precise, the absorption of 24 is even lower than that of N719 except for the LC transition at about 300 nm). In the next group of sensitizers (Fig. 11.15, 25–30), alkyl-, alkoxy- or alkylamino-substituted styryl moieties were used as donor-antenna groups to increase the molar extinction coefficient. DFT calculations of 25 and 26 illustrated that the HOMO orbitals of each dye are delocalized over the ruthenium metal and the NCS ligands. The LUMO is localized on the carboxylic acid anchoring ligands [155]. The dyes 25, 26 and 27 were used as sensitizers in L-DSC employing durable redox electrolytes, both, a low volatile and an ionic liquid one [115, 155, 190]. As in the case of 20, the high LiI concentration of the low volatile electrolyte decreases the open-circuit voltage, but increases the electron transport properties, whereas the electrolyte on the basis of ionic liquids benefits from employing guanidinium thiocyanates which improves the open-circuit voltage by reducing the dark current [195]. Additionally, the long term performance of L-DSCs using the low volatile electrolyte was high under light soaking and thermal stress. The devices on the basis
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of 25 and 26 maintained about 90% of their initial photovoltaic performance in both stability tests. For 27, in combination with the co-adsorbent 3-phenylpropionic acid, the volume ration of a solvent-free binary ionic liquid electrolyte on the basis of 1-propyl-3-methylimidazolium iodide (PMII) and 1-ethyl-3-methylimidazolium tetracyanoborate (EMIB(CN)4) was optimized leading to a high efficiency of 7.6% as well as a high stability. By electrochemical impedance spectroscopy, it was shown, that the I3− transport in the electrolyte and the charge transfer to the counter became more slowly with increasing PMII concentration due to the increase in viscosity [115]. By using a low volatile electrolyte based on 3-methoxypropionitrile, 27 reached an efficiency of 9.0% and by using a volatile electrolyte based on acetonitrile/valeronitrile, 27 achieved 10.5% [190]. Comparable results were also accomplished by dye 28 using a volatile solvent for the electrolyte (h = 10.2%) [191]. For stability test, a low volatile ionic liquid electrolyte was used reaching an efficiency of about 7% which, is higher than the value reached for Z907 while the stability was similar [191]. In comparison to the unfunctionalized dye N719, 30 carrying the ancillary ligand 4,4¢-bis[p-(diethylamino)-a-styryl]-2,2¢-bipyridine showed a 400% increase in the absorption at about 400 nm and a 100% increase at about 540 nm (e of 30 is 5.93·104 and 2.81·104 M−1 cm−1 at 431 and 542 nm, respectively). Preliminary tests of this sensitizer in L-DSC resulted in an efficiency of 8.65% although no blocking layer and no antireflection layer was introduced [193]. The enhancement of the molar extinction coefficient by suitable donor-antenna groups opens up the possibility to create thinner DSCs and thus construct more efficient DSCs because of reduced transport losses. In order to investigate the impact of high molar extinction coefficients on the photovoltaic parameters, L-DSCs employing 29 using transparent mesoporous TiO2 films of various thicknesses were fabricated [192]. By increasing the thickness from 2, 5, 7 to 9 mm the efficiency rose from 5.72%, 7.31%, 8.04%, to 8.31%, respectively. With increasing thickness the photocurrent density increased drastically reaching a plateau value of almost 19 mA/ cm² at 14 mm with an efficiency of 10.82%. On the contrary, the open-circuit voltage decreased with increasing thickness. The investigations demonstrate further, that the difference in performance between 29 and N719 is strongly pronounced for thinner mesoporous layers (D ISC = 30%) consistent with the higher molar extinction coefficient. However, for thicker TiO2 layers, the disparity in efficiency between the two sensitizers decreases from 30% to less than 7%. Hence, for thicker TiO2 layers an upper limit is reached beyond which the influence of the high molar extinction coefficient is buffered.
11.3.1.4
Donor-Antenna Ruthenium Dyes Bearing Hydrophobic Chains
In order to create sensitizer which provide an increased optical cross section and simultaneously facilitate long-term stability, the concepts of donor-antenna dyes and amphiphilic sensitizers were combined. This approach is currently addressed by novel ruthenium(II) sensitizers carrying ancillary bipyridyl ligands which are
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Table 11.4 Overview of the performances of donor-antenna sensitizers bearing hydrophobic chains tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMb [mA/cm²] [V] [%] [%] Ref. 31 32 32 32 32 33 34 34 35 36 36 37 38 39 39 40 40 40 41 41a 42 43
L-DSC S-DSC L-DSC L-DSC L-DSC L-DSC L-DSC S-DSC L-DSC L-DSC S-DSC L-DSC L-DSC L-DSC S-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC
Low volatile Spiro-OMeTAD Volatile Low volatile Ionic liquid Low volatile Volatile Spiro-OMeTAD Volatile Volatile Spiro-OMeTAD Volatile Volatile Volatile Spiro-OMeTAD Volatile Low volatile Ionic liquid Volatile Volatile Volatile Volatile
14.61 8.193 17.94 17.98 14.77 17.80 19.2 8.27 19.5 20.05 9.22 16.50 18.32 17.87 8.386 18.35 17.51 15.93 21.6 12.69 19.18 18.74
0.711 0.800 0.778 0.746 0.681 0.730 0.776 0.848 0.669 0.743 0.825 0.710 0.680 0.760 0.814 0.760 0.771 0.710 0.669 0.741 0.739 0.754
67 69 79 74 74 73 76 71 66 77 63 65 72 78 69 75 71 75 63 74 75 75
7.0 4.5 11.0 9.7 7.41 9.5 11.29 5.0 8.55 11.5 4.7 7.66 9.03 10.53 4.6 10.4 9.6 8.5 9.02 6.31 10.7 10.61
[163] [121] [164] [164] [164] [164] [162] [124] [165] [123] [123] [166] [166] [167] [122] [168] [117] [117] [169] [170] [168] [171]
a
41 was used as sensitizers for a plastic DSC constructed by a low-temperature electrode preparation method using binder-free TiO2 paste on an ITO-polyethylene naphthalate substrate b Volatile solvents for the electrolyte are on the basis of acetonitrile/valeronitrile and low volatile ones mainly rest upon 3-methoxypropionitrile
covalently connected to donor-antenna groups (such as phenyl, thiophene, or thieno[3,2-b]thiophene derivatives) that additionally carry hydrophobic chains. This does not only increases the molar extinction coefficient of the dye via the extended p-delocalized system, but also augments its hydrophobicity by the alkyl chains. Hence, recombination losses can be minimized by allowing the preparation of thinner TiO2 films. Simultaneously, desorption of sensitizer molecules by water may be prevented stabilizing the device performance under long-term light soaking and thermal stress. In summary, donor-antenna ruthenium dyes bearing hydrophobic chains can provide the following key advantages: (i) high molar extinction coefficients, (ii) large spatial separation of the dye cation from the metal oxide surface, (iii) polarity match between the sensitizer and the solid standard hole transport material spiro-OMeTAD and (iv) the possibility to form an insulating barrier between the sensitized semiconductor and the HTM to diminish recombination losses and to prevent water induced desorption. (For a more detailed explanation of the single advantages of each concept cf. Sects. 11.3.1.2 and 11.3.1.3)
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Fig. 11.16 Structure of the amphiphilic high extinction coefficient sensitizer 31
565 COOH O
HOOC
C6H13
N N
N Ru SCN
N NCS
31 (K-19)
O
C6H13
The heteroleptic ruthenium(II) donor-antenna dyes bearing hydrophobic chains meets all the key demands of sensitizers for the application in high efficient DSCs. However, the synthetic procedure is very demanding because the ancillary ligands have to be prepared in multi-step synthesis. Nevertheless, the effort is worthwhile, since very high efficiencies were reached with such sensitizers [121, 122, 124, 162, 164]. The donor-antenna dye 31 (cf. Fig. 11.16) bearing hexyl chains shows a molar extinction coefficient of 1.82·104 M−1 cm−1 at the low energy MLCT absorption band at 543 nm which is significantly higher than that of the standard dyes N719 (1.40·104 M−1 cm−1) and Z907 (1.22·104 M−1 cm−1) [163]. The same order is represented by the photovoltaic measurements where 31, N719 and Z907 reached a efficiencies of 7.0%, 6.7% and 6.0%, respectively. During thermal ageing tests for 1,000 h at 80°C, N719 showed only a poor stability which is probably caused by desorption. In contrast, the amphiphilic sensitizers Z907 and 31 retained over 92% of their initial performance. Furthermore, a device containing 31 and a coadsorbent (3-phenylpropionic acid) kept 93% of its initial performance after the 1,000 h light soaking test [196]. Currently, remarkably high solar cell performances are reached with amphiphilic sensitizers incorporating thiophene moieties attached to the bipyridyl ligand without any spacer. A ruthenium(II) complex bearing a hexylthiophene-conjugated bipyridine as ancillary ligand is presented for the use in S-DSCs [121]. Complex 32, denoted as C101 (cf. Fig. 11.17a), is distinguished by its high absorption due to the p-conjugated system and the high hydrophobicity of stained TiO2 films (determined by water-contact angle measurements). 32 is capable to reduce the recombination of injected electrons with holes from the HTM compared to its thiophene-free counterpart Z907 and it can shift the band edge of TiO2 by its high dipole moment leading to a higher open-circuit voltage. The entirety of the mentioned advantages of 32 leads to an outstanding performance of this dye, reflected by an efficiency of 4.5% in an S-DSC device. Furthermore, 32 was employed as sensitizer in L-DSCs using a acetonitrile-based volatile redox electrolyte, a low volatile electrolyte and a solvent-free ionic liquid leading to efficiencies of 11.0%, 9.7% and 7.4%, respectively [164]. The lower efficiency of the solvent-free ionic liquid device can be explained
566 Fig. 11.17 Chemical structures of amphiphilic donor-antenna dyes carrying (a) hexyl thiophene/furan groups (32, 33) or (b) (hexylthio)-thiophene moieties (34)
K. Willinger and M. Thelakkat
a
COONa HOOC
C6H13
X
N N
N Ru
N
SCN
NCS
X C6H13
32 (C101) 33 (C102)
X=S X=O
b
COONa HOOC
N
S
S C6H13
S
C6H13 S
N
N Ru SCN
N NCS
34 (C106)
with the much shorter effective electron diffusion length due to the lower electron diffusion coefficient and shorter electron lifetimes in mesoporous TiO2 which limit the photocurrent. However, the stability of DSCs on the basis of ionic liquids and low volatile electrolytes is enhanced, both retaining over 95% of their initial performance after 1,000 h full sunlight soaking at 60°C. Hence, the low volatile electrolyte device represents the compromise between efficiency and stability. Considering the similar configuration, molecular size and anchoring mode of 33 compared to 32, the photovoltaic performance should be similar, but actually it is lower. It was found that a lower surface coverage is responsible for this. The molecular structure of the sensitizer 34 (Fig. 11.17b), denoted as C106, is very similar to 32, with the difference, that a sulphur atom is inserted between the n-hexyl chain and the thiophene [162]. This increases the absorption of a stained TiO2 film. Hence, the performance of an L-DSC employing this sensitizer is slightly improved compared to 32 leading to a remarkably high overall efficiency of 11.29% (and 11.4% at 30°C). By employing this high molar extinction coefficient ruthenium dye in an S-DCS using spiro-OMeTAD as organic hole transport material, a certificated electric power conversion efficiency of 5% could be reached (measured at the National Renewable Energy Laboratory, USA) [124]. To the best of our knowledge, this is currently the highest reported efficiency for a solid-state DSC using spiro-OMeTAD as HTM.
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Fig. 11.18 Structures of the octyl bithiophene and the (hexylthio)-thiophene substituted sensitizers 35 and 36
567 COOH
HOOC
S
R
S
R
S
N N
N Ru SCN
N NCS
S
R = C8
35 (CYC-B1)
R = S-C6 S
36 (CYC-B11)
The ruthenium photosensitizer 35 (CYC-B1, Fig. 11.18) bears an ancillary ligand in which one bipyridine is substituted with alkyl bithiophene groups. Here, the oligothiophene moiety can be regarded as a cis-oligoacetylene chain bridged with sulphur atoms. It was reported, that the bridging sulphur atoms can provide aromatic stability compared to oligoacetylene while preserving high charge transport properties [197, 198]. Furthermore, sulphur offers a greater radial extension in its bonding than for example carbon. Hence, thiophene is more electron-rich causing a high extinction coefficients and a red-shift of the absorption (e of 35 is 4.64·104 and 2.12·104 M−1 cm−1 at 400 and 553 nm, respectively) [198]. The photo-to-current conversion efficiency of L-DSCs sensitized with 35 is in the region of 8.5% [165, 198]. Following the development of 35, a (hexylthio)bithiophene containing sensitizers was reported [123]. This complex, referred to as CYC-B11, showed an absorption improvement of about 14% compared to is predecessor 35. It is supposed, that this is directly related to the influence of the additional sulphur atom. Inserting a sulphur atom between bithiophene and the alkyl chain can augment the electronic transition dipole momentum and hence the extinction coefficient of the MLCT band. A careful optimization of the device engineering facilitated the preparation of high efficient L- and S-DSCs yielding impressive efficiencies of 11.5% and 4.7%, respectively under AM 1.5 G simulated sunlight [123]. So far, 11.5% efficiency is the highest reported value for L-DSCs based either on metal-organic or organic sensitizers. Instead of simple 2,2¢-bipyridines, also 2,2¢-bipyridylamine ligands (cf. 37 and 38, Fig. 11.19) can be used as ligands to coordinate to the ruthenium center ion [166]. The alkyl-substituted bipyridylamines form six membered rings with less p-acceptor character on chelation than a five-membered ring of bipyridines. It is assumed, that the HOMO level of the corresponding complex is lifted due to more s-donating power of the amine, resulting in a red-shifted MLCT band. Additionally, the well established alkyl-thiophene (37) or alkyl-thienothiophene (38) moieties are attached for a better light harvesting efficiency. The analysis of the spectral properties of sensitizers 37 and 38 compared to N719 showed that the low-energy MLCT band is just marginally red-shifted and extinction coefficients are only slightly
568
K. Willinger and M. Thelakkat COOH
HOOC
N N
S N
Ru SCN
COOH C6H13
N NCS
37 (JK-85)
HOOC
N N
N C6H13 SCN
C6H13
S
COOH
HOOC
N
Ru
S
S
N Ru
SCN
N NCS
S
C6H13
38 (JK-86)
39 (C104) S
C8H17
S
N N
N C6H13
N NCS
S
C6H13
S S
C8H17
Fig. 11.19 Structures of sensitizers 37, 38 and 39, carrying different bipyridyl ligands substituted by alkyl-thiophene or alkyl-thieno[3,2-b]thiophene
increased or even lower. To be precise, the MLCT band of 37, 38 and N719 arises at 527, 525 and 521 nm, respectively corresponding to molar extinction coefficients of 1.02·104, 1.56·104 and 1.40·104 M−1 cm−1. The same order is kept regarding the photovoltaic performance of L-DSC resulting in 7.66%, 9.03% and 8.88% overall efficiency for 37 and 38 and N719, respectively. Although, the L-DSCs of 37 and 38 using a electrolyte on the basis of the low volatile solvent 3-methoxypropionitrile showed outstanding long-term stability under thermal stress and light soaking, the novel coordination ligand itself did not cause any improvement. However, the combination of a standard 2,2¢-bipyridine coordinating ligand with an 5-octylthieno[3,2-b]thiophene-2-yl moiety (dye 39) was more favourable sine it resulted in a red-shifted absorption, a high extinction coefficient (e of 2.05·104 M−1 cm−1 at 553 nm) and high power conversion efficiency of 10.53%. This sensitizer also reached a conversion efficiency of 4.6% in an S-DSC device using spiro-OMeTAD as HTM [122]. Sensitizers 40–42 (Fig. 11.20) featuring one or two electron-rich 3,4-ethylenedioxythiophene units, known as EDOT, in combination with long hydrophobic chains in their ancillary ligand facilitate high light harvesting capacity and good solubility. The low energy MLCT bands of 40, 41 and 42 are centred at 550, 546, and 559 nm corresponding to extinction coefficients of about 1.88·104, 1.87·104 and 2.74·104 M−1 cm−1, respectively [117, 168]. The HOMO of each dye is distributed among the metal center and the NCS ligands, whereas the LUMO concentrates on the anchoring ligand. The insertion of EDOT units depresses the LUMO and evidently lifts the HOMO [168, 169]. The sensitizers achieved efficiencies about 10% in L-DSCs; with the highest absorbing dye 42 a maximum solar-to-electricity conversion efficiency of 10.7% was reached employing a volatile redox electrolyte. Complex 41 was further examined as a sensitizer for plastic DSCs constructed at low temperatures. The effect of a compact blocking TiO2 layer was investigated as well as the electrolyte composition and co-adsorbents. Under optimized conditions, 41 worked very well (h = 6.31%), while the flexible plastic device was more stable than one incorporating N719 [170]. (Note that EDOT groups may interact with Li+ ions, as found for ion-coordinating sensitizers; cf. Sect. 11.3.1.5). The complexes 32 and 34–42 demonstrated the high potential of ruthenium dyes carrying thiophene based ancillary ligands. The DSCs showed excellent photovoltaic performances. Motivated by this and the lower band gap and broader photocurrent
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Fig. 11.20 Molecular structures of sensitizers 40 and 41 carrying alkyl-3,4ethylenedioxythiophene groups and structure of dye 42, carrying 5-octyl-2,2¢bis(3,4-ethylenedioxythiophene moieties)
569 COOH
O
O
R
NaOOC
S
N N
N Ru
N
SCN
S
NCS
R O
O
R = C6
40 (C103)
R = C8
41 (SJW-E1) COOH
O
O NaOOC
S S
N
O
N
N
C8H17 O
Ru SCN
N
O S
NCS
S
O
O C8H17
O
42 (C107) Fig. 11.21 Selenophene based high molar extinction coefficient dye 43
COONa HOOC
Se
N
C6H13
N
N Ru SCN
N NCS
Se C6H13
43 (C105)
response of poly(3-hexylselenophene) [199, 200] compared to poly(3-hexylthiophene), a hexylselenophene complex (43, coded as C105, Fig. 11.21) was synthesised for the use in L-DSC [171]. The molar extinction coefficient of 43 was higher than these of the thiophene and furan analogues (32 and 33). The molar extinction coefficient increased in the order 33 (furan) < 32 (thiophene) < 43 (selenophene) corresponding to extinction coefficients of 1.68·104, 1.75·104 and 1.84·104 M−1 cm−1 at 547, 547 and 550 nm. This order is also consistent with the electropositivity trend and the size of the heteroatom (O < S < Se). Sensitizer 43 reached an efficiency of 10.6% in an L-DSC device using a volatile electrolyte [171].
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11.3.1.5
Ion-Coordinating Ruthenium Dyes
The approach of integrating the so-called ion-coordinating functionalities (e.g. oligo ethylene oxide moieties) in ruthenium(II) sensitizers either directly connected to a bipyridyl ligand (Fig. 11.22a) or to a p-delocalized donor-antenna bipyridyl ligand (Fig. 11.22b) is an innovative concept to augment the performance of DSCs. In order to understand the benefit of ion-coordinating groups as parts of the sensitizer, it is important to figure out the mode of action of lithium ions in L- and S-DSCs influencing the characteristic parameters of DSCs devices (JSC, VOC and FF). However, the presence of Li+-ions causes diverse effects which can act contrary to one another affecting the solar cell performance. Until now, not all impacts of incorporating lithium salt in the HTM of DSCs are understood. Nevertheless, the two main effects will be explained briefly in the following. TiO2 band gap effect: Lithium ions are known to adsorb onto the TiO2 surface or even intercalate into the same [138, 201–203]. While Li+ insertion in rutile-TiO2 is negligible at room temperature; anatase-based electrodes tend to intercalate Li-ions [202]. This can be ascribed to the different connectivity modes of TiO6 octahedra.
COOH R1
R2
N N
N Ru
N
SCN
NCS
R2
a
R1 = COONa R2 =
O
R1 = COONa
O
R2 =
b
O
O
O
O
R2 =
R1 = COOH
R2 =
44 (K51)
O
45 (K68)
O
O
R1 = COOH
O
O
O
46 (K60)
N
47 O
O
O
O
Fig. 11.22 Structures of ion-coordinating complexes (a) without any donor groups (44, 45) and (b) with additional p-delocalized donor groups (46, 47)
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Anatase consists of edge sharing TiO6 octahedra, providing sufficient space for Li intercalation. Upon Li+-insertion serious structural changes occur, viz. the original tetragonal anatase host is disordered orthorhombically [202]. Depending on the intercalation/adsorption ratio a band edge shift away from the vacuum level occurs, hence the energetic distance between the redox or HOMO level of the hole transport material and the quasi-Fermi level of electrons in TiO2 decreases, resulting in an undesired decrease in the open-circuit voltage [204–206]. This does not only affect the open-circuit voltage, it also affects the electron injection, charge transport time constants and recombination lifetime of electrons [207, 208]. For instance, various studies have shown, that improvements of the photocurrent output arise partly from an increase in the efficiency of electron injection from the excited sensitizer after a downward shift of the conduction band [207, 209–212]. This can be understood as due to the increase in the thermodynamic driving force for injection as a consequence of lowering the TiO2 band edge relative to the excited state energy level of the sensitizer [207]. Furthermore, it was verified that a shift of the band edge or quasi-Fermi level away from the vacuum level slows down the recombination of electrons owing to a decrease in trapped electron density [213]. In contrast to the downward shift caused by lithium-ions, other ions like Mg2+ can shift the Fermi level in the opposite direction, causing higher open-circuit voltages of about 1 V [214]. Moreover, amines (e.g. tBP) can shift the band edge causing an increase in the open-circuit voltage. The nitrogen containing compounds charge the TiO2 surface negatively by deprotonating it [213] or they bring about a dipole moment normal to the TiO2 surface plane [132]. Bulk-effect: Lithium-ions incorporated in the bulk-phase of the hole transport material (liquid or solid) are known to increase the photocurrent output [21, 66, 155, 188, 215, 216]. In L-DSCs most frequently LiI is integrated in the “bulk” phase of a redox electrolyte delivering Li+ and simultaneously I−. Typically, an increase in the LiI concentration leads to an increase in the photocurrent density partly due to an increase in conductivity [217]. At higher concentrations (>0.3 M), the photocurrent density decreases again due to an increase in the viscosity of the solution which decreases the ion mobility in the solution. The open-circuit voltage decreases as well with an increasing LiI concentration in L-DSCs due to band gap effects and the enhanced production of I3− (by addition of I− the equilibrium I + I 2 U I 3 is shifted − towards I3 ) which favours back electron transfer [217]. With regard to S-DSCs, it was reported that the mobility of pristine spiro-OMeTAD can be increased by an order of magnitude due to ionic additives like LiN(SO2CF3)2. Furthermore, a 100fold increase in conductivity through spiro-OMeTAD within a TiO2 mesoporous network was observed due to the ionic additive [218]. It is assumed, that the Li-salt does not appear to p-dope the spiro-OMeTAD, it rather increases the conductivity by a more complicated mechanism whereby the potential landscape and the polarizability of the medium is altered by the ionic additives [71, 218]. By increasing the conductivity, the internal series resistance is decreased resulting in higher FF values. This effect can be seen either by using standard spiro-OMeTAD [21, 66] or in particular by using lithium ion binding hole transport materials [66, 219, 220].
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Taking all these facts into account, it becomes obvious, that fine-tuning and optimization of the concentration and also the combination of additives is a critical parameter for obtaining efficient DSCs. However, this is additionally complicated by the variety of sensitizers, with different HOMO/LUMO values and by the lack of knowledge of the precise functions of Li+ ions. Especially the latter leads to a lot of assumptions requiring further investigations. The main goal by using ion-coordinating sensitizers is to fix the Li+-ions at the dye/TiO2 interface, thus preventing them from reaching the TiO2 surface and avoiding an unfavourable lowering of the TiO2 conduction band edge (which equals a lowering of the open-circuit voltage) while enhancing the photocurrent output. Sensitizers based on this concept are rare; anyway, some representatives are depicted in Fig. 11.22. Complex 44 (coded as K51) is the analogue of Z907 in which the hydrophobic chains have been replaced with ion-coordinating triethylene glycol monomethyl ether groups [120, 138, 221, 222]. The light absorption of 44 and Z907 is almost identical, both in solution and as adsorbed on TiO2 films [221]. Due to the fact, that 44 was not stable during accelerated ageing test because of dye desorption, 45 (K68) additionally benefiting from the integration of hydrophobic chain ends was designed and synthesised in the hope that the attached alkyl chains imply the advantages of amphiphilic dyes (cf. 11.3.1.2) and prevent dye desorption [120, 222]. The main drawbacks of 44 and 45, viz. the low molecular extinction coefficient and the high solubility in organic solvents which favours dye desorption, were overcome by sensitizers 46 (K60) [223] and 47 [224]. Both carry an extended p-conjugated system in combination with ion-coordinating chains. It is assumed, that all these sensitizers are able to tether Li+ ions by the lewisbasic heteroatoms of the ion-coordinating chains. ATR-FTIR spectroscopy is known to be a suitable method to reveal structural information of metal complexes adsorbed on TiO2 surfaces. To prove the coordination of Li-ions to the chains, the sensitizers (44, 45, and 46) were adsorbed on a TiO2 surface and afterwards exposed to a solution of LiI in acetonitrile [138, 222, 223]. The ATR-FTIR spectra before and after the exposure were monitored. It was observed, that the initial n(C–O) stretch peak was partly shifted to lower energies due to the coordination (C–O…Li+). Additionally, the initial n(C–O) peak was diminished by about 50% after the exposure, leading to an estimated average of one Li+ per adsorbed dye molecule. After the films were rinsed with pure acetonitrile, the original spectra were retained. A hint towards coordination even by using a solid HTM was gained by current density measurements in the dark. Plotting the dark current density versus the applied bias, the current density through a Li-doped Z907 device was approximately three times that of the Li-doped 44 device, although the initial ionic concentration in both devices was identical. The only difference between the Z907 and 44 based devices is the ioncoordinating side chain. Consequently, the lower current directly indicates that a large portion of the ions are extracted from the bulk phase and immobilized on the surface by the ion-coordinating dye monolayer [221]. Apart from mechanistic considerations arising from Li+ and ion-coordinating functionalities, measurements on the recombination dynamics clearly show that ion-coordinating sensitizers are able to reduce recombination times. For instance, measurements of the transient decay of the open-circuit voltage were used to
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573
determine the overall charge lifetime of 44 and Z907 based solid-state devices. The charge separation lifetime for a Li-free Z907 sensitized device was determined to be 30 ms whereas an increase to 320 ms was observed by the addition of Li+-ions. By tethering the Li-ions to the 44 dye, the charge separation lifetime increased even further to 430 ms [221]. Transient absorption measurements on the dynamics of recombination of injected electrons with the oxidized dye were accomplished to estimate the half-reaction times of 44 and Z907 to be 200 ms and 180 ms, respectively. In the presence of a Li-free redox electrolyte, the decay of the oxidized dye was accelerated. The half-times due to regeneration were measured to be 10 ms and 30 ms for 44 and Z907, respectively. Thus, for 44 about 5% of the initial oxidized species recombine with conduction band electrons whereas the loss is 10–15% for Z907 [138]. The charge recombination rate constant (kred) was estimated from perturbation open-circuit voltage decay measurements. Here, for a better comparability, a reference dye carrying just methoxy groups (cf. Fig. 11.22, R 2 would be –O–Me) instead of ion-coordinating moieties. The kred decreases in the order reference dye > 44 > 45 indicating reduced recombination behaviour. Additionally, by the measurement of the open-circuit voltage perturbation, the relative position of the energy levels in the TiO2 with respect to those in the spiro-OMeTAD was estimated to increase in the order reference dye < 44 < 45. The photocurrent and the voltage also increased in this order [120]. Regarding 46, the lifetime of the excited state was determined to be 13.2 ns. Due to the fact that electron injection typically takes place within the femtosecond to picosecond time frame, the natural decay cannot compete kinetically with the interfacial charge transport. By nanosecond laser transient absorbance the regeneration of the oxidized dye (46) in the presence of a liquid redox electrolyte was estimated to be 10 ms, whereas the recombination of injected electrons with the oxidized dye was determined to be 200 ms (the same was measured for 44) [223]. In conclusion, all measured ion-coordinating sensitizers show slower recombination times and faster regeneration compared to reference dyes without ion-coordinating functionalities. How can these reduced recombination times be rationalized? If Li+-ions are really prevented from reaching the surface by ion-coordinating functionalities, there is no reason for a shift of the TiO2 band edge. However, this not only influences the opencircuit voltage positively, as mentioned before it also affects the electron injection [207], charge transport time constants and recombination lifetime of electrons [208]. As further noted, a shift of the band edge or quasi-Fermi level away from the vacuum level would slow down the recombination of electrons [213] and increase electron injection [207, 209–212]. But this does not seem to be case for ioncoordinating sensitizers. Here it is assumed, that the tethering of Li+-ions to the ion-coordinating functionalities near the interface does not only prevent a decrease of the open-circuit voltage, it is likely to “coulombically” retard recombination by “screening” the electrons in the TiO2 from the holes in the HTM, thus increasing the activation energy for recombination [120, 138, 221]. The lithium salt is known to have the ability to screen the electrostatic interactions deriving from Coulomb interactions between photogenerated charges and interface dipoles resulting in an increased charge injecting and reduced recombination, and hence an increase in DSC performance [73, 225].
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A further contribution to the increased performance of DSCs is expected to arise from the dipole moment [138]. Permanently adsorbed charge species in combination with the ion-coordinating dye molecule may acts as a dipole at the surface and causes a downward shift in the HOMO level of a solid HTM (e.g. spiro-OMeTAD) with respect to the Fermi level of TiO2 thereby increasing the quasi energy gap and thus the open-circuit voltage [221]. An evidence for this hypothesis was reported [103]. The introduction of a suitable oriented surface dipole in TiO2 solar cells has shown to increase the voltage by changing in the band bending at the TiO2 spiroOMeTAD interfaces. Furthermore, under illumination of S-DSCs, it is assumed, that a net positive space charge is formed in the HTM. This induces the generation of a local field that impairs current flow. The lithium salt is assumed to screen this field, thereby eliminating the space-charge control of the photocurrent [20]. Additionally, the globally positive charge on the surface is assumed to increase the local concentration of iodide and hence increases the dye regeneration rate [138]. Both factors can enhance the photocurrent output. There are two studies focusing on the influence of varying lithium salt concentrations in a redox electrolyte on the performance of L-DSCs [138, 222]. Without lithium salt, a higher efficiency was reached for the Li+-coordinating dye 44 (7.80%) compared to the amphiphilic dye Z907 (6.60%). This was assumed to be due to faster dye regeneration; half-life times of the dye regeneration in the same electrolyte were found to be 10 and 30 ms for 44 and Z907, respectively. By adding Li-salt and successively increasing the Li-concentration of the redox electrolyte, the current density increased for 44 and Z907. However, for Z907 the increase in current density was counterbalanced by a decrease in voltage resulting in almost the same overall efficiency as without salt. Regarding 44, the voltage also decreased but less leading to higher efficiency (8.10%). This might be ascribed to the ion-coordinating ability of 44 preventing a fraction of the Li+ ions from contacting the surface. High Li+ concentrations further reduce the voltage of Z907 and 44 based devices whereas the voltage of 44 sensitized cells always remained higher [138]. A similar behaviour was observed for 45. Here, the current density slightly increased with increasing Li+concentration in the redox electrolyte but decreased again at higher Li+ concentrations. Further, it was observed, that the open-circuit voltage successively decreased [222]. In S-DSCs it was observed, that the open-circuit voltage of 44 based DSCs increased constantly with increasing Li+ concentration [138]. However, for Z907 the open-circuit voltage was somewhat fluctuating but always remained lower than that of 44 based devices. The authors assumed that in solid-state devices the ioncoordinating sensitizers can hold a high concentration of Li+ ions. This prevents the Li+-ions from reaching the TiO2 surface and causes a strong charge screening effect. The latter is believed to reduce recombination and increase the voltage. The highest reported efficiency for S-DSCs sensitized with 44, 45, and 47 are 3.8% [221], 4.51% [120] and 3.30% [224] (the associated characteristic values are listed in Table 11.5). When compared to a reference dye carrying methoxy croups instead of ion-coordinating moieties, the efficiency of the sensitizers bearing oligo ethylene oxide substituents was enhanced by up to 83% [120].
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Table 11.5 Overview of the performances of ion-coordinating ruthenium sensitizers tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMf [mA/cm²] [V] [%] [%] Ref. 44 44a 44b 44c 44 44 44 45 45a 45c 45 46d 46e 47 47 47
L-DSC L-DSC L-DSC L-DSC L-DSC S-DSC S-DSC L-DSC L-DSC L-DSC S-DSC L-DSC L-DSC L-DSC S-DSC S-DSC
Low volatile Low volatile Low volatile Low volatile Low volatile Spiro-OMeTAD Spiro-OMeTAD Low volatile Low volatile Low volatile Spiro-OMeTAD Low volatile Low volatile Volatile Spiro-OMeTAD Spiro-OMeTAD
15.40 16.60 16.86 17.71 14.8 7.1 6.8 14.4 14.88 15.64 7.6 16.28 16.85 18.30 4.03 6.75
0.738 0.715 0.699 0.681 0.730 0.810 0.875 0.762 0.737 0.689 0.930 0.720 0.730 0.682 0.735 0.864
69 68 68 66 72 63 65 69 72 69 64 68 67 72 46 57
7.80 8.10 7.95 7.75 7.7 3.6 3.8 7.6 7.89 7.44 4.51 8.02 8.44 9.02 1.37 3.30
[138] [138] [138] [138] [222] [120] [221] [222] [222] [222] [120] [223] [223] [224] [189] [224]
The electrolyte contained additionally a50 mM, b125 mM, or c250 mM of LiClO4 d Device without any coadsorbent e Device with the coadsorbent DPA, the improvement in the performance is ascribed to the formation of a mixed monolayer of 46 and DPA f Volatile solvents for the electrolyte are on the basis of acetonitrile/valeronitrile and low volatile ones mainly rest upon 3-methoxypropionitrile
Tests regarding the long term stability of 45 based devices using a low volatile organic solvent electrolyte showed that over 94% of the initial value was retained after 1 month at 80°C in the dark. However, 44 based DSCs were not stable under similar high temperature accelerated ageing conditions [222]. 46 sensitized L-DSCs using also a low volatile electrolyte maintained 94% of their initial value during 1,000 h of ageing at 80°C [223] and 47 sensitized L-DSCs using an ionic liquid electrolyte remained 95% of their initial efficiency under long term accelerated ageing under light soaking conditions (100 mW/cm², 60°C) [224]. Note, that the presence of Li+-ions as additive to spiro-OMeTAD is indispensable for S-DSCs; without lithium salt the photocurrent density as well as the open-circuit voltage are extremely low [20, 66, 219]. Concerning L-DSCs, efficient solar cells can be obtained without Li-salt.
11.3.2
Phthalocyanine and Porphyrin Dyes
Due to the fact that only very recently a few reviews [91, 149, 150, 226, 227] about the application of phthalocyanines and porphyrins in DSCs were published, we just highlight here some highly efficient dyes of both classes.
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a
b
2
24 25
meso-position
1 3
23 26
N
28
β-position 3
4
22
N
N
21
5
N
N
19
α-position
7 8
N
8
N21 22 N M 24 N 23 N
1 20
18 14
19
12 9
17 15
11
10
9 10 11 12
18 16
16
7 6
2
N
M
N
5 4
17
14 15
13
Fig. 11.23 Core structures of (a) metallo-phthalocyanines and (b) metallo-porphyrins including the atom numbering. M represents the center metal
Although, it is well known that polypyridyl ruthenium complexes are currently the best performing dyes among all sensitizer classes (h = 11.5% [123] in L-DSCs), there are some disadvantages. Ruthenium is a rare and expensive metal; its complexes can cause undesirable environmental impacts and most importantly they suffer from the lack of absorption in the red/IR-region (e low above ~600 nm). However, phthalocyanines and porphyrins are distinguished by their intense absorption in the red/IR-region (Q band). Additionally, mainly abundant and inexpensive metals (e.g. Cu and Zn) are used as central metals. Furthermore, the optical, photophysical and electrochemical properties can be systematically tailored by modifying the peripheral substituents, changing the symmetry of the macrocycles and/or the inner metal center [228]. Moreover, phthalocyanines and porphyrins are known for their excellent chemical, light and thermal stability [226, 229]. The core structures of metallo-phthalocyanines and -porphyrins are shown in Fig. 11.23. In L-DSCs, efficiencies of 3–4% were reached with phthalocyanines, whereas porphyrins performed more efficient with about 11% efficiency. Phthalocyanines do not only exhibit an intense absorption in the red/NIR region (at about 700 nm) due to the Q band, they also show strong absorption in the UV/ blue region (at about 300 nm) due to the Soret band. Thus they are transparent over a large region of the visible spectrum. This provides the possibility to use them as sensitizers for “photovoltaic windows” [230, 231]. The use of red/IR absorbing solar cells instead of simple windows makes it possible to harvest the incident energy of the red/IR region for energy conversion meanwhile the solar heating of buildings is reduced as well as the demand for air-conditioning [232]. Furthermore, these dyes can be combined with blue/green absorbing dyes in tandem cells or energy transfer systems. Despite favourable absorption properties and suitable energy levels, the reported efficiencies of different metal phthalocyanine sensitized DSC were only about 1% for a long time [233–237]. This was mainly attributed to aggregation [236, 238–240], low solubility and the lack of directionality in the
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Photosensitizers in Solar Energy Conversion
577 COOH
C H2 N N
R= N
N N
48 (PCH001)
COOH
N
Zn
CH
N
R=
49 (TT1)
COOH
N R
COOH
R=
50 (TT5)
Fig. 11.24 Structures of the phthalocyanine sensitizers 48, 49 and 50 carrying different anchoring groups
Table 11.6 Overview of the performances of phthalocyanine sensitizers tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMd [mA/cm²] [V] [%] [%] Ref. 48a L-DSC Volatile 6.5 0.635 74 3.05 [232] 48b S-DSC Spiro-OMeTAD 2.1 0.72 52 0.87 [232] 49a L-DSC Volatile 7.60 0.617 75 3.52 [241] 49a L-DSC Volatile 7.78 0.611 75 3.56 [242] 49c L-DSC Volatile 16.20 0.666 72 7.74 [241] 50a L-DSC Volatile 6.80 0.613 74 3.10 [253] 51 L-DSC Volatile 10.4 0.630 70 4.6 [254] a
CDCA was used as coadsorbent to reduce aggregation Measured at 90 mW/cm² c Co-sensitized with 82 (Fig. 11.37) d Volatile solvents for the electrolyte are on the basis of acetonitrile/valeronitrile b
excited state [232] which influences an efficient electron transfer from the excited dye to the semiconductor. In order to address the latter issues, unsymmetrically substituted “push-pull” phthalocyanines were developed. The zinc phthalocyanine sensitizer 48 (Fig. 11.24, coded as PCH001) is a predecessor of this concept. It was synthesised as an unsymmetrical complex with three bulky tert-butyl groups to act as electron-donors. Simultaneously, these groups enhance the solubility, tune the LUMO level and minimize aggregation. But the two electron withdrawing carboxylic acid anchoring groups of 48 are not directly connected to the macrocycle. By using sensitizer 48 in S-DSCs, an efficiency of 0.87% (AM 1.5, 90 mW/cm²) was reached, whereas in L-DSCs using chenodeoxycholic acid (CDCA) as additive and a volatile electrolyte an efficiency of 3.05% could be achieved [232]. This was a breakthrough in the design and development of phthalocyanine-based DSCs (cf. Table 11.6). Later, unsymmetrical push-pull phthalocyanines sensitizers (49–51) having conjugated connection between donor, core-complex and acceptor were successfully
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applied in DSCs. The asymmetry and the created push-pull system generate directionality. This is important to provide an efficient electron transfer pathway from the excited sensitizer to the conduction band of the semiconductor by electronic coupling between the LUMO of the sensitizer and the Ti 3d orbitals [229, 232, 241]. Sensitizer 49, incorporated in an L-DSC with a volatile electrolyte achieved an efficiency of 3.5% [241, 242]. Here, the concentration of CDCA used as a coadsorbent on TiO2 was optimized [242]. It was found, that CDCA not only reduced the adsorption causing a negative influence on the photocurrent output, but it also increased the open-circuit voltage due to a shift of the TiO2 conduction band (measured by photovoltage decay) and a small increase in electron lifetime at high CDCA concentrations in the dye-coating solution (60 mM). The peak performance was found at 10 mM CDCA. A second promising approach which was already successfully applied for DSC on the basis of different dye classes, viz. the combination of two or more dyes by co-sensitization[89, 243–247] or multilayer co-sensitization [248–250], was also used for phthalocyanine based DSCs. For this purpose two dyes with complementary absorption were combined; 49 and an the organic dye 82 [102, 251, 252] denoted as JK2 (cf. Fig. 11.37) [241]. The mesoporous TiO2 film was sensitized for 1 and 3 h with solutions of the organic dye and 49, respectively. The overall device efficiency increased from 3.52%, for a pure 49 sensitized cell to 7.74% for the co-sensitized L-DSC. But compared to an L-DSC based solely on the organic dye 82 which showed an efficiency of 7.08% (under optimized conditions even 8.01% could be reached [251]) the improvement using co-sensitization is negligible. The intrinsic disadvantage of this concept is the limited surface. Always, the available surface area for a second dye is limited by the adsorbed first dye. Hence, the absorptions of the two dyes are counterbalanced by each other so that almost no improvement can be reached. In contrast to that, multilayer co-sensitization seams to have better prospects (cf. dye 66) [248]. In the course of a study about the structure-function relationship in Zn-phthalocyanines, sensitizer 50 (Fig. 11.24) turned out to be the most efficient one (beside 49) [253]. The spacer group between the chromophore and the TiO2 surface was found to be essential for the performance because it influences the electron injection as well as recombination [233]. By time-correlated singlephoton-counting measurements, the yield of electron injection for this dye (and also for others carrying different spacers, including 49) was determined to be higher than 90% with electron injection times in the range of 173–277 ps [253]. Furthermore, transient absorption spectroscopy was used to investigate the electron recombination kinetics [253]. For 50 an impressive recombination half-time t50% of 3.9 ms was found (cf. about 200 ms were measured for Z907 [177, 183, 184]). Although, another zinc-phthalocyanine sensitizer with a non conjugated spacer showed in this study a t50% value of even 11.7 ms, its solar cell performance was very poor (h = 0.4%). Therefore it is difficult to pinpoint the reason for the good performance of dye 50. Currently, the highest efficiency among the phthalocyanines (4.6%) was reached with sensitizers 51 (coded as PcS6, Fig. 11.25) [254]. All phthalocyanines sensitizers
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Photosensitizers in Solar Energy Conversion
579
Fig. 11.25 High efficient phthalocyanine sensitizer 51 Ph Ph
Ph
Ph
O
O
Ph Ph O
O
N
Ph
N
N
N
Ph
N
Zn
N
Ph
N
N O Ph Ph
51
O
COOH
Ph
(PcS6)
presented before were substituted by tert-butyl groups, but the fact, that for efficient DSC still a coadsorbent (e.g. CDCA) was needed to prevent aggregation arising from p-p stacking shows, that the bulkiness of these groups is not sufficient. Hence, bulkier groups like 2,6-diphenylphenoxy moieties were used to create highly sterically hindered Zn-phthalocyanines [255]. The three dimensional enlargement of the molecular structure prevents aggregation almost completely without wasting surface space for coadsorbents. This was proven by UV/vis spectroscopy. The absorption of 51 in solution as well as adsorbed on TiO2 showed just a weak blue-shifted shoulder peak of the Q band around 630 nm which can be assigned to H-aggregate species [254]. Similar to phthalocyanines, porphyrins possess an intense Soret band at about 400 nm and a moderate Q band at about 600 nm. The porphyrin skeletal structure is symmetrical (D4h symmetry) and the p-electrons are, in the ground state as well as in the excited state, delocalized over the whole structure [150]. In the beginning of using porphyrins as sensitizers in DSC, the efficiencies were quite low [150, 256–258]. But it was known, that zinc improves the solubility and shifts the LUMO as well as HOMO to higher energy levels [150]. Additionally, symmetrical porphyrins exhibit long-lived (>1 ns) p* singlet excited states, only weak singlet/triplet mixing and appropriate HOMO/LUMO levels for electron injection and dye regeneration [259]. Further it was known, that meso-phenyl groups extend the p-system and can act as spacer between anchoring group and chromophore to reduce the rate of recombination. Surprisingly, it was found that the rate of recombination as well as the rate of injection of symmetrical free base and zinc porphyrins are very similar to that of ruthenium complexes (N3, Fig. 11.7) although the delocalization of the cation is very different and the redox potentials are not equal [260]. It was revealed, that the lower efficiencies of porphyrins is a result of the increased probability of excitation annihilation due to the strong transition dipole of porphyrin single excited state which allows rapid migration of the excited state between neighbouring dyes at a
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Fig. 11.26 High efficient porphyrin sensitizer 52
N
N Zn N
N
HOOC
COOH
52
high dye coverage [260]. The poor performance was also assigned to the insufficient light harvesting capability of porphyrins and the effect of electronic coupling between the porphyrin and the TiO2 surface as well as the formation of molecular aggregates [91]. It was suggested, that low-symmetric structures are important for efficient charge separation. The loss of symmetry, not only creates directionality, but also caused a broadening as well as a red-shift of the absorption and an increase in the Q band relative to the Soret band. Today, unsymmetrical metal porphyrin sensitizers reach peak overall efficiencies of about 6–7% [261–267]. However, only lately a porphyrin with an impressive efficiency of 11% was published [268]. Until recently the best performance for porphyrin sensitized DSCs was reached with sensitizer 52 (cf. Fig. 11.26). The dye gave an efficiency of 7.1% with a liquid volatile redox electrolyte and 3.6% by using spiro-OMeTAD as solid HTM [261] (cf. Table 11.7). 52 emerged from a whole series of porphyrins with different aromatic (donor) substituents (e.g. 4-ethyl phenyl, 4-(n-butyl)phenyl and 4-(n-octyl) phenyl, or the here shown 4-methylphenyl group) attached to the meso-position while keeping the conjugated malonic acid anchoring group in one b-position. All dyes show a red-shift of the absorption compared to a non substituted porphyrin. The exact identity of the alkyl-phenyl group virtually influences neither the band position nor the molar extinction coefficient. Additionally negligible variations were observed for the HOMO (~−5.16 eV) and LUMO (~−3.08 eV) levels relative to the vacuum level. Nevertheless, the efficiency decreased from 7.1% to 5.8% by replacing the methyl groups of 52 with ethyl groups. Possibly, it is influenced by device preparation parameters as shown for sensitizers 53–55 [266]. In a study concerning dyes 53–55 (Fig. 11.27) and also in other studies, it was demonstrated, that the efficiency strongly depends on the immersing time for dyecoating [266, 269, 270]. For 54 it became obvious, that the efficiency at first increases rapidly with increasing immersion time and then decreased gradually (the peak value was reached below 1 h immersing time) [266]. This is not due to the surface concentration G, because G increases very rapidly and remains constant. Hence, the decline of the efficiency seems to be due to a change in orientation at longer
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Photosensitizers in Solar Energy Conversion
581
53
R=
S HOOC
CN
C6H13 N
N R
Zn N
R=
N
54
S HOOC O
O R=
CN
55
S HOOC
CN
Fig. 11.27 Structures of a series of thiophene-linked porphyrin sensitizers (53–55)
immersing times. The highest efficiencies for 53–55 were reached by immersing the TiO2 electrode for 15 min. (Note that dye-coating with Ru-dyes usually takes place over night or at least some hours.) These sensitizers also follow the donorpbridge-acceptor/push-pull concept, where the meso-tris(4-methylphenyl) porphyrin acts as donor, the cyanoacrylic acid as acceptor and the different thiophene derivatives as p-bridge. The thiophene derivatives were introduced to enhance light absorption and affect electron injection, whereas EDOT features a small torsion angle with the adjoining phenyl fragment. Again, for compounds 53–55 a broadening of the absorption accompanied by a red-shift was observed. The solar cell performance of these three dyes shows, that they differ just in the short-circuit current densities (JSC = 12.83, 13.71 and 15.59 mA/cm² for 53, 54 and 55 respectively). The poor performance of the 3-n-hexylthiophene derivative 54 was ascribed to the lowest G value in this series (1.8·10−8, 0.23.10−8 and 1.3·10−8 mol/cm² for 53, 54 and 55 respectively). Despite the high G value of 53, the photocurrent output is still low. For 55, carrying the EDOT groups, G showed a moderate value, but the highest current value was measured [266 ]. The degree of aggregation of these dyes under the applied condition of dye-coating is to be studied to quantify the performance differences. Sensitizers 56–61 (Fig. 11.28) emerged as the most efficient dyes of comprehensive studies about asymmetrically meso-substituted zinc donor-pbridge-acceptor porphyrins published by Yeh, Diau and co-workers [262, 264, 265]. All these porphyrin sensitizers carry different alkyl-functionalized donor groups (cf. amphiphilic ruthenium-dyes) and one anchoring group at the meso-positions. For 56–58 the only difference is the p-bridge between chromophore and anchoring moiety [262]. By replacing the phenyl p-bridge of 56 with naphthalene (57) and anthracene (58), an increasing broadening of the absorption spectra accompanied by a red-shift occurs, which reflects the increasing extension of the p-system. Additionally, the HOMO/ LUMO levels of all sensitizers were found to be comparable. Nevertheless, the
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R1 = C8H17
R2 =
COOH
56 (YD11)
R1 = C8H17
R2 =
COOH
57 (YD12)
R1 = C8H17
R2 =
COOH
58
R1 = C6H13
R2 =
COOH
59 (YD2)
R1 N
N R2
Zn
N
N
N R1
(YD13)
OCH3 C8H17
C8H17 N N
C8H17 N
N COOH
Zn
N
N
N N
N COOH
Zn
N
N
C8H17 C8H17
C8H17
OCH3
60
61
(YD14)
(YD17)
Fig. 11.28 Selection of efficient donor-pbridge-acceptor porphyrins (56–61) belonging to the YD-series
photovoltaic performance of 58 was far below that of 56 and 57, whereas 56 and 57 performed very similar. The reason for that behaviour was revealed by femtosecond fluorescence decay measurements. The determined quantum yields for electron injection were found to be 83, 83 and 62% for 56, 57 and 58 respectively. The low electron injection caused low photocurrents and hence a low overall efficiency in 58 sensitized L-DSCs. There are two possible explanations for the reduced electron injection ability of 58: Anthracene can either (a) induce rapid intramolecular relaxation due to effective vibronic coupling and/or (b) cause intermolecular relaxation due to aggregation. Time correlated single photon counting was used to determine the lifetime of the excited states of 56–58, which were found to be equal, thus eliminating the possibility (a). To verify the possibility (b), photovoltaic measurements of the sensitizers coadsorbed with a large amount of CDCA were performed. It was
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Photosensitizers in Solar Energy Conversion
583
Table 11.7 Overview of the performances of porphyrin sensitizers tested in L-DSCs as well as S-DSCs (measured under AM1.5, 100 mW/cm²) Solar cell JSC UOC FF h Complex type Type of HTMb [mA/cm²] [V] [%] [%] Ref. 52 52 53 54 55 56a 57a 58a 59a 59a 59a 60 61
L-DSC S-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC
Volatile Spiro-OMeTAD Low volatile Low volatile Low volatile Volatile Volatile Volatile Volatile Volatile Volatile Volatile Volatile
14.0 7.4 12.83 13.71 15.59 14.01 14.23 4.12 13.40 14.80 18.6 14.27 13.99
0.680 0.780 0.640 0.630 0.640 0.716 0.717 0.630 0.710 0.714 0.770 0.712 0.722
74 62 68 67 65 68 68 72 69 67 76 67 69
7.1 3.6 5.55 5.80 6.47 6.79 6.91 1.86 6.56 7.1 10.9 6.8 7.0
[261] [261] [266] [266] [266] [262] [262] [262] [265] [264] [268] [264] [264]
a
CDCA was used as coadsorbent to reduce aggregation Volatile solvents for the electrolyte are typically on the basis of acetonitrile/valeronitrile and low volatile ones mainly rest upon 3-methoxypropionitrile b
found, that for 56 and 57 the photocurrent output decreased (due to a lower dye uptake) whereas a significant increase was observed for 58 (due to reduced aggregation) [262]. Sensitizer 59, also belonging to the YD-series, shows an almost negligible structural difference compared to 56, viz. the length of the alkyl chain was changed from C8 to C6. This was also reflected by the comparable efficiency of about 7% [262, 264, 265]. But optimized by Grätzel and co-workers, 59 reached an impressive efficiency of about 11% [268]. To the best of our knowledge, this is the highest reported value for a porphyrin sensitized L-DSC. In extension of the YD-series, different phenyl, diarylamino and/or triphenylamino moieties were induced at the meso-positions to create a push-pull framework for high efficient L-DSCs [264]. Among these, 60 and 61 showed the best overall performance with an efficiency of ~7%.
11.4
Organic Sensitizers in Dye-Sensitized Solar Cells
Recently, comprehensive reviews on organic dyes for DSCs were published by Ooyama and Harima [91] and by Bäuerle and co-workers [89]. We just concentrate here on the general properties of organic sensitizers and emphasise the high efficient dyes of the most promising classes of organic sensitizers in a compact from. Organic dyes in general are very promising for the use as sensitizers for DSCs because (i) they can be synthesised and purified very easily at low costs, (ii) they do
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not contain rare and expensive metal, (iii) they have in particular extremely high extinction coefficients which facilitate a high light harvesting ability and hence reduce the optical depth so that organic dyes are suitable for thinner semiconductor electrodes, and (iv) a variety of possible functional groups and their facile modification provide the opportunity to tune the spectral, photophysical, photochemical and electrochemical properties very well considering structure-property relationships [89, 91, 271]. However, the performance of organic dyes for L-DSCs is currently still inferior compared to that of metal-organic dyes (which achieve h values about 11% [123, 158, 161, 162, 262]). Generally, S-DSCs follow this order except for S-DSCs using an indoline dye in combination with PEDOT as HTM [126]. This can be ascribed to some of the typical disadvantages of organic dyes such as (i) their narrow absorption bands in the visible region of the electromagnetic spectrum, which limits the light harvesting ability, (ii) their tendency towards p-p-stacking (aggregation), which reduces the electron injection rate by intermolecular energy transfer and excited state quenching, (iii) their lower stability, which may arise from the formation of excited triplet states and unstable radicals under illumination [272, 273], (iv) their short emission lifetimes of excited states, which are often shorter than those of metal complexes [90, 274, 275]. The latter aggravates charge separation because the electron injection has to be faster than the dye’s emission lifetime to achieve efficient charge separation [274, 276]. A large electronic coupling between dye and semiconductor can facilitates fast injection [277]. To match the general requirements of sensitizers (cf. Sect. 11.2.1.4) and to overcome or minimize the disadvantages, an appropriate design concept for organic sensitizers is needed. Commonly, organic dyes follow the donor-pbridge-acceptor concept. On the basis of the data obtained from literature, it was stated that electronrich aryl amines like aminocoumarins, (difluorenyl)phenylamines, triphenylamines and indolines are ideally suitable as donor groups, whereas cyanoacrylic acids and rhodanine-3-acetic acids are perfect acceptor and anchoring groups [89]. Additionally, it was found that the p-bridges are frequently based on thiophenes (e.g. oligothiophenes, thienylenevinylenes, or dithienothiophenes) or phenylenevinylenes due to their excellent charge transport properties [89]. At present, a large variety of different sensitizer classes are successfully applied in DSC such as BODIPYs (h = 1.66% [278] for L-DSC, volatile; h = 0.68% [279] for S-DSC, spiro-OMeTAD), polymer sensitizers (h = 2.4% [280] for L-DSC, volatile; h = 0.9% [127] for S-DSC, spiro-OMeTAD), squaraines (h = 5.40% [281] for L-DSC, volatile; h = 3.8% [282] for S-DSC, P3HT), hemicyanines (h = 6.3% [283] for L-DSC, low volatile), perylenes (h = 6.8% [284] for L-DSC, volatile; 3.2% [285] for S-DSC, spiro-OMeTAD), cyanines (h = 7.6% [286] for L-DSC, volatile), coumarins (h = 8.2% [287] for L-DSC, volatile), indolines (h = 9.5% [288] for L-DSC, volatile; h = 4.1 [289]/4.2% [290] for S-DSC, spiro-OMeTAD; h = 6.1% [126] for S-DSC, PEDOT) and oligothiophene bridged arylamine donor dyes (h = 10.1% [116] for L-DSC, volatile; ~4.8% [291, 292] for S-DSC, spiro-OMeTAD). (see Table 11.8) Note that this is only a selection of promising and efficient organic dye classes, a lot more were successfully tested in DSCs [89, 91, 299–301].
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Photosensitizers in Solar Energy Conversion
11.4.1
585
BODIPY Dyes
BODIPY dyes (4,4-difluoro-4-bora-3a,4a-diaza-s-indacens)[302–304] were prepared for the first time in 1968 by Treibs and Kreuzer [305]. Later, they were employed as laser dyes [306] and reagents for biological labeling [307]. Only very recently scientists started to regard them as interesting candidates for DSC [278, 279, 308–310] and bulk heterojunction solar cells [311–313]. Since these dyes are getting applied in DSCs the efficiency values reported did not yet exceed 2%. However, the BODIPY complexes are promising due to their outstanding properties such as their excellent thermal and photochemical stability, chemical robustness, good solubility, absence of toxicity [309], suitable redox levels, inherent directionality [278], high fluorescence quantum yield, modest stokes shift, negligible triplet formation, long excited state lifetimes [314] and their intense absorption profile [302]. The latter can be easily influenced by substituents which can shift the absorption up to red/near IR region while keeping very high molar extinction coefficients. This emphasizes BODIPY derivatives as potential aspirants not only for L- but also for S-DSCs. For L-DSCs, the highest reported efficiency (1.66%) was reached by the BODIPY sensitizer 62 depicted in Fig. 11.29 [278]. This sensitizer carries triphenylamine electron-donating groups and a 2-cyano-3-phenylacrylic acid electronwithdrawing unit at the meso-position (lmax at about 700 nm, e at peak value about 6.9·104 M−1 cm−1). It was found that an inherent asymmetry in charge redistribution occurs upon excitation (S0–S1 transition) which increases the charge density on the meso-position while decreasing it in most other positions. Hence, the meso-carbon (C–8) seams to be the preferable position for attaching an anchoring group. Furthermore, the HOMO/LUMO levels were determined to be −5.09 and −3.52 eV, respectively and thus they are suitable for electron injection and dye regeneration. In a recent report, the same dye (62) was successfully applied as red absorbing sensitizer in an S-DSC device (h = 0.68%). These preliminary results of this emerging dye class are encouraging.
CN COOH meso
N
N B F F
Fig. 11.29 BODIPY dye 62 carrying two triphenylamine donor groups
N
62
N
586
11.4.2
K. Willinger and M. Thelakkat
Polymer Sensitizers
Recently, polymeric sensitizers started to gain interest as an attractive alternative to commonly used low molecular weight dyes [127, 280, 297, 315–320]. Although, the performance of these sensitizers is quite low at the moment, conjugated polymers feature low costs, high absorption coefficients in the visible part of the spectrum, simple synthesis, capability for mass production and high charge carrier mobilities [297]. In combination with polymeric hole conductors, polymer sensitized DSCs offer a possibility for all-polymer and flexible S-DSCs. Yanagida and colleagues reported polymer sensitized L-DSCs on the basis of poly(3-thiophenylacetic acid) (P3TAA, 63, Fig. 11.30) chemisorbed on TiO2 or SnO2–ZnO electrodes [280]. P3TAA is a carboxylic acid functionalized derivative of one of the best known conjugated polymers poly(3-hexylthiophene) (P3HT); it posses an appropriate band matching with many inorganic semiconductors used in DSCs [321]. The best performance for a polymeric sensitizers (h ~2.4% [280]) was reported for 63 sensitized TiO2 DSCs employing a volatile liquid electrolyte additionally containing an ionic liquid [297, 298]. Although, the current density was quite high (JSC = 9.76 mA/cm²), the open-circuit voltage was very low (~400 mV). This was assumed to be due to the protonation of the surface by the polymer [280]. Poly(3-thiophenemalonic acid) carrying two carboxylic acid groups per monomer delivered an even lower open-circuit voltage (365 mV) [297]. Until now, there is only one report about a polymer sensitizer applied in a classical S-DSC on the basis of TiO2 and spiro-OMeTAD [127]. Highly regioregular P3HT (64, Fig. 11.30) with carboxylic acid end groups was synthesized in our group and tested as sensitizer (h = 0.9%). P3HT in general is known for its strong absorption between 450 and 600 nm and its high charge carrier mobility of up to 0.1 cmV−1 s−1 [322]. Additionally, it carries alkyl side chains which facilitate its solubility and it can self-assemble on surfaces [319]. The low efficiency of polymer sensitizers may be ascribed to a lack of optimization, the fact that polymers suffer from their small absorption overlap with the solar spectrum and that the polymer chains can cause a clogging of the pores of the mesoporous TiO2 electrode which can slow down regeneration [319].
HOOC
HOOC S S
Fig. 11.30 Structures of P3TAA (63) and regioregular, carboxylic acid end group functionalized P3HT (64) used as sensitizers for L- and S-DSCs, respectively
n
63
S
COOH C6H13
C6H 13 HOOC
64
S S
S n C6H13
COOH
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11.4.3
587
Squaraine Dyes
Squaraines are a well investigated class of organic dyes which was first reported by Treibs and Jacob in 1965 [323]. Squaraines suitable for a broad range of applications such as nonlinear optics, imaging, photodynamic therapy, ion sensing and photovoltaics [324]. Typically, squaraine sensitizers contain an electron deficient central four membered ring (derived from the squaric acid) and two electron donating groups, resulting in a resonance stabilized planar zwitterionic structure. The strong absorption (e > 105 M−1 cm−1) in the visible to near-IR region and the photostability favours these molecules to be used as sensitizers. On the basis of theoretical calculations it was proposed, that, the ground state and the excited singlet state of squaraines involve intramolecular charge transfer. Hence, the S0–S1 excitation is a charge transfer transition. Combining this consideration with an extended p-donor framework gives an explanation for the featured absorption behaviour [324]. Squaraines achieve moderate photovoltaic performances in both, L- and S-DSCs, whereas the best performing squaraines are very similar to each other (cf. Fig. 11.31) [281, 282, 325]. In general, unsymmetrical squaraines perform better than symmetrical ones [326]. The unsymmetrical dye 65, which reached an efficiency of 5.4% in an L-DSC, shows a strong absorption in the far red region (lmax = 662, e = 3.2·105 M−1 cm−1), suitable HOMO/LUMO levels (−5.31 and −3.72 eV, respectively) but suffers from aggregation which can be partly suppressed by CDCA [281]. 66 shows a slightly diminished absorption in the far red region due to a less delocalized p-system (lmax = 647, e = 2.9·105 M−1 cm−1), but also suitable HOMO/LUMO levels (−5.33 and −3.73 eV, respectively) [281]. 66 was successfully employed in an S-DSC device where TiO2 nanotube arrays and regioregular P3HT were used as electron transport material and HTM, respectively [282]. It was assumed, that the high efficiency (h = 3.8%) arose from the combination of an organic dye and P3HT. Here, the normal process of excitation of the organic dye, electron injection and subsequent regeneration by the HTM (P3HT) is thought to be complemented by exciton generation in the P3HT phase, diffusion of the excitons to the P3HT/dye interface, dissociation of the excitons at the interface in electrons and holes whereas the electrons travel through the dye to the TiO2 surface. Hence, both the
HOOC
N C8H17 HOOC
Fig. 11.31 Molecular structures of the squaraine sensitizers 65 and 66
N
O
65 (SQ2) O
N
O
66 (SQ1) N C8H17
O
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complementary absorbing sensitizers contribute to the photocurrent generation. This was proven by IPCE measurements [282]. Besides this, squaraines were also applied in co-sensitized DSC with the complementary absorbing low molecular weight dye 82 depicted in Fig. 11.37 [246–248]. Here, efficiencies of up to 8.65% were reached by a novel way of co-sensitization where a primary monolayer of dye is spatially separated from a second monolayer of another dye using Al2O3 (resulting architecture: TiO2/Dye1/Al2O3/Dye2) [248].
11.4.4
Perylene Dyes
Perylenes are distinguished for their outstanding chemical, thermal and photochemical stability [284], non-toxicity, high stability and broad absorption spectra [285]. However, the power conversion efficiency of perylene derivatives used as sensitizers in DSCs remained low (h <2%) [327–329] due to aggregation and energy-level matching issues [284, 330, 331]. The low electron-donating ability of perylenes imides (i.e. the LUMO is energetically very close to conduction band of TiO2) impedes efficient electron injection [330]. Substituents at the bay positions are known to tune the HOMO/LUMO levels and thereby the absorption behaviour. Hence, strongly electron donating perylenes with electron-rich substituents at the perylene core (bay-positions) were synthesised and applied in DSCs [284, 330, 331]. The most well performing perylene dye reported in L-DSCs is 67 (cf. Fig. 11.32) [284]. It shows an efficiency of 6.8% due to (i) a broad absorption (400–750 nm) with intramolecular charge transfer character, (ii) the high molar extinction coefficients (1.37·104 and 2.27·104 M−1 cm−1 at 462 and 620 nm, respectively) (iii) reduced aggregation as a consequence of the bulky side groups and (iv) the appropriate HOMO/LUMO location and levels for a more efficient electron injection and dye
HOOC O
O
O
O
S
N
O
S
N
N
67
68
Fig. 11.32 Chemical structures of the best performing perylene sensitizers 67 and 68 for L- and S-DSCs, respectively
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regeneration [284]. It is known, that upon adsorption on TiO2, perylene anhydrides like 67 show a blue-shift of the absorption. This is attributed to a ring opening of the anhydride group to form two carboxylates which indeed facilitate a strong coupling between the dye and TiO2, but concomitantly cause a further negative shift of the energy levels [284]. Nevertheless, the energy levels of 67 bearing two thiophenol groups in the 1 and 6 positions are even after the ring opening suitable for efficient electron injection and regeneration by a liquid electrolyte. With regard to S-DSC applications, 68 (cf. Fig. 11.32) was found to be an efficient sensitizer [285]. To prevent the energetically negative effects caused by the adsorption of perylene anhydrides, the anhydride anchor was replaced by a carboxylic acid anchor attached to a perylene monoimide. By cyclic voltammetry in solution, it was found that the LUMO is about 0.14 eV more positive than the conduction band level which should provide an appropriate driving force for electron injection. Efficient DSCs could only be manufactured if the standard additive tBP was omitted because it is known to shift the conduction band to more positive potentials which can cause an increase in the open-circuit voltage but also causes a hindering of the electron injection into TiO2 in perylene-sensitized DSCs [112, 132, 213]. In fact, the dye worked well in tBP free S-DSCs (h = 3.2%) but not in L-DSCs. The observation suggests a different injection mechanism for L- and S-DSCs, which were discussed but not yet completely understood [285, 290, 332, 333].
11.4.5
Cyanine Dyes
By definition, cyanines comprise of an electron withdrawing quaternary ammonium group and a ternary electron donating amino group which are connected by methine (–CH═CH–) or other conjugated units. Depending on whether the nitrogen atoms are parts of heterocyclic rings or carry aliphatic groups, the cyanines are classified as open chain cyanines, the so called streptocyanines (R2N+=CH[–CH═CH]n–NR2), hemicyanines (Aryl═N+═CH[–CH═CH]n–NR2) and closed chain cyanines which are seen as the classical cyanines (Aryl═N+═CH[–CH═CH]n–N═Aryl). Attractive for DSCs are only the last two types. These cationic donor-pbridge-acceptor molecules feature high extinction coefficient absorption bands in the visible region (~450–600 nm, emax ~105 M−1 cm−1) which are of charge transfer character and their absorption will undergo a red-shift upon increasing the electron donating and withdrawing ability of the donor and acceptor groups, respectively [334]. Additionally, they are characterised by their tendency for aggregation in solution as well as at the solid-liquid interface [333, 335]. A head-to-tail arrangement results in a formation of red-shifted J-aggregates, a plane-to-plane stacking causes blue-shifted H-aggregates and the formation of Herring-bone aggregates induces both a higher and lower wavelength band [335]. In various studies, the influence of aggregation of cyanines on the photosensitization was investigated [243, 333, 335, 336]. It was found that besides the monomer from also the aggregated forms can contribute to photoinduced electron injection in TiO2, but how effective the aggregate based
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Fig. 11.33 Molecular structure of the hemicyanine sensitizer 69
N
S N
−O S 3
HO
69
electron injection is, depends on the respective dye. Furthermore, it is known, that, cyanines can suffer from cis-trans photoisomerisation inducing a decay of excited states [275]. Characteristically, the donor part of hemicyanines comprises of p-dialkylaminophenyls and for the cationic acceptor part often benzo- and naphthothiazolium, pyridinium and indolium salts are employed. Methine units (–CH═CH–) are used to connect both parts [91]. As anchoring units sulfonate, carboxyl and hydroxy groups were found to be suitable. The efficiency of the DSC devices strongly depended on the anchoring groups. It decreased in the order: carboxyl + hydroxyl > carboxyl > sulfonate + hydroxyl [334]. The best performing representatives of this class is 69 (cf. Fig. 11.33), it exhibited a high overall efficiency of 6.3% (at 80 mW/cm², white light from a Xe lamp) by using a liquid electrolyte based on propylene carbonate [283]. The major structural difference to other less performing hemicyanines is the presence of the hydroxy group in 69. Considering the anchoring capability of this group along with the sulfonate anchoring group, the contact area between the dye and the TiO2 nanoparticles should be increased resulting in a decreased dye loading (which was confirmed by absorption measurements of the desorbed dye) and maybe an enhanced electron injection [283]. Regarding to cyanines it was found, that unsymmetrical derivatives perform superior compared to their symmetrical counterparts due to directionality which facilitates electron flow from the donor to the acceptor moiety carrying the anchoring group [326]. As a reminder, the same was found for phthalocyanines, porphyrins and squaraines. Additionally, by systematic investigations it was found that (i) the absorption maxima of cyanines shifts (by about 100 nm) to longer wavelength with each increase of one methine unit (ii) the IPCE decreases with increasing number of methine units because the LUMO level shifts to more negative values (i.e. energetically closer to the conduction band level of TiO2) with increasing number of methine units, (iii) the IPCE increases with decreasing distance between the cyanine skeleton and the TiO2 surface due to a more stable charge transfer state and (vi) the photocurrent output of cyanine sensitized electrodes increased with a shift of the conduction band in the order NB2O5 < TiO2 < ZnO < SnO2 [337]. Regarding L-DSCs, the best performing cyanine dye 70 (cf. Fig. 11.34) was reported by Tian and co-workers [286]. It contains a carboxylic acid acceptor/ anchoring group, a triphenylamine donor group and a bridging low-band-gap benzothiadiazole connecting the donor and the cyanine skeleton. The HOMO/LUMO values were determined to be −5.73 and −3.82 eV, respectively and Herring-bone
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N
S
591
N
N
N
70
N +
I−
COOH
Fig. 11.34 Structure of the efficient cyanine sensitizer 70
aggregates were assumed to broaden the absorption spectrum benefiting the photoelectrical conversion. The efficiency was found to be 7.62% (measured under irradiation with a Xe lamp at 75 W/cm²) with an photocurrent output of 22.10 mA/cm² (Under the same conditions, the efficiency of the Ru(II) dye N719 was found to be 9.5%; JSC = 27.25 mA/cm², VOC = 0.640 V, FF = 41%) Regarding S-DSCs cyanines are in their infancies and the reported efficiencies are still low [338].
11.4.6
Coumarin Dyes
Coumarins are known for their good photoresponse in the visible region, the tunability of the absorption [294], good long-term stability [339] and suitable HOMO LUMO levels/locations [340]. They are based on the donor-pbridge-acceptor concept using the coumarin derivative 1,1,6,6,-tetramethyl-10-oxo-2,3,5,6-tetrahydro1H,4H,10H-11-oxa-3a-aza-benzo[de]anthracene-9-yl as donor and (cyano)acrylic acid as acceptor connected by different p-conjugated bridges (cf. Fig. 11.35). A cyanoacrylic acid anchoring group was found to be more beneficial than a simple acrylic acid group, because the cyano units are known to shift the LUMO level more positively due to their strong electron accepting ability. Furthermore, they decrease the HOMO/LUMO band gap resulting in an increased efficiency in L-DSCs. For example, the h value for the acrylic acid anchoring coumarin 72 is 3.4% [274], whereas the cyanoacrylic acid anchoring coumarin 73 delivers 4.1% [274]. Furthermore, it was found that the bridge significantly influences the absorption, photovoltaic performance and the stability [287, 294]. By increasing the number of bridging methine units (that is an increase in the conjugation length), the absorption can be step-wise red-shifted causing an increase in the efficiency. Regrettably, this increases also the instability and reduces the efficiency for dyes incorporating long methine bridges owing to the possibility of isomer formation [294]. Thus the h values 73, 74 and 75 are 4.1% [274], 6.0% [293] and 3.5% [274]. Further, p-conjugated rings (thiophenes) were introduced to enhance the stability, absorption and concomitantly the efficiency. Thus, the efficiencies increase in the order 74, 76, 77, 71 with h values of 6.0% [294], 7.2% [294], 7.7% [294] and 8.2% [287], respectively.
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donor
S S N
O
denotation
η [%]
71 (NKX-2700)
8.2
COOH
72 (NKX-2398)
3.4
COOH
73 (NKX-2388)
4.1
74 (NKX-2311)
6.0
75 (NKX-2586)
3.5
76 (NKX-2593)
7.2
77 (NKX-2677)
7.7
78 (NKX-2697)
5.3
acceptor COOH CN
O
" "
CN
"
COOH CN
"
COOH CN
"
S
COOH CN
S
"
S
COOH CN
S
" S
S
COOH CN
Fig. 11.35 Selection of different coumarin donor-pbridge-acceptor sensitizers 71–78. Note that the values for the L-DSC efficiencies are taken from different references
But note that with increasing number of thiophenes the intermolecular p-p stacking interactions increase and hence the efficiency decreases again (cf. oligothiophenes). For instance, the trithiophene dye 78 delivers a lower efficiency of 5.3% [295]. In a detailed investigation about the interfacial electron transfer kinetics in DSC of coumarin dyes compared to a standard Ru dye (N719), Durrant and co-workers found: (i) a shorter lifetime of the electron injecting state for the coumarin dye compared to the Ru dye (resulting in a relative fast electron injection halftime of 60 ps for the coumarin dye compared to ~350 ps for the Ru dye), (ii) a faster rate constant for recombination between injected electrons and the electrolyte for the coumarin dye (lowering the photocurrent output) and (iii) a greater tendency for the coumarin dye to aggregate (reducing the electron injection efficiency) [341]. To reach such a high efficiency as the best performing coumarin dye 71, high amounts of deoxycholic acid (DCA) in the dye solution to reduce aggregation and high concentrations of tBP in the redox electrolyte to reduce charge recombination and to raise the conduction band are indispensable [287].
11.4.7
Indoline Dyes
The class of indoline sensitizers was established by Horiuchi and Uchida and is today dominated by three high extinction coefficient indoline based sensitizers
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593 O N
R= S
C8H17
79 (D205)
S
R= S
80 (D102)
N S
N
R=
N O
O
R
S COOH
C2H5
81 (D149) S
Fig. 11.36 Molecular structure of the efficient indoline dyes 81–83
(79, 80, and 81 denoted as D205, D102 and D149 respectively (cf. Fig. 11.36)) reaching impressive power conversion efficiencies in L-DSCs as well as in S-DSCs. All these dyes have push-pull systems with an indoline derivative as donor and rhodanine units carrying anchor groups as acceptor. Sensitizer 79 carries an octyl group, whereas 81 has an ethyl moiety on the terminal rhodanine unit. The dye 81 has a second rhodanine unit compared to 80 to extend its p-conjugated system. 80 was the first indoline dye reported as sensitizers in DSCs by Horiuchi, Miura and Uchida in 2003 [342, 343]. By comparing the absorption of 79 (in THF: lmax = 532 nm, e = 5.3·104 M−1 cm−1), 81 (in tert-butanol: lmax = 526 nm, e = 6.9·104 M−1 cm−1) and 80 (in THF: lmax = 494 nm, e = 6.1·104 M−1 cm−1) a red-shift upon incorporation of an additional rhodanine unit was observed, whereas the exchange of the alkyl chain changes the absorption only marginally [296]. By electrochemical impedance spectroscopy, the electron lifetimes of L-DSC were found to increase in the order: 80 (6.4 ms) <81 (10.9 ms) <79 (23.0 ms) indicating a more effective suppression of recombination between injected electrons and the redox electrolyte for 79 [296]. This may be an explanation for the high efficiencies reached by 79 in an L-DSC. Using a volatile electrolytes and CDCA to reduce aggregation, L-DSCs sensitized with 79 achieved an efficiency of 9.52% (whereas the h value of 81 was 8.85%) [288]. Even in L-DSCs using ionic liquid electrolytes, 79 led to a record efficiency of 7.18% (compared to 6.38% and 4.86% for 81 and 80, respectively) [296]. Dyes 80 and 81 were found to perform very well in S-DSCs using spiro-OMeTAD as HTM. h values of 4.1 [289] and 4.2% [290] were reached for 80 and 81, respectively and even 6.1% were achieved by 81 at 10 W/cm². The photovoltaic performance of 81 with poly(3,4-ethylenedioxythiophene) (PEDOT) as HTM is also very impressive [126]. Here, due to the common critical issues of HTMs in penetrating and filling into the pores intensified by the large size of polymers, in situ polymerization of pre-penetrated monomers was performed [126, 344]. Ramakrishna and co-workers manufactured in this way a solid-state DSC employing 81 as sensitizer yielding an unprecedented efficiency of 6.1%. (Z907 reached under the same conditions an efficiency of just 1.7%. But note that the sensitizer plays an important role
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for in situ polymerized HTM-based S-DSCs, viz. it influences the polymerisation process which can greatly affect interface properties and the penetration depth [126].) The high S-DSC performance of 81 in combination with a polymer HTM is unmatched by any other sensitizer neither organic nor metal-organic. A comparison between the polymer-HTM based 81 or Z907 sensitized DSCs shows an excellent light response owing to the broad absorption, low photoelectron recombination and good polymer penetration for the 81 based cell [126]. This indicates the great potential of polymers as hole transport materials on the way up to efficient solid-state dye-sensitized solar cells.
11.4.8
Oligothiophene Bridged Arylamine Donor Dyes
Sensitizers incorporating (alkyl-substituted) thiophene bridges between donor (i.e. phenylamine, fluorenylamine, carbazoles and triphenylamine) and acceptor perform very well in L-DSCs [273, 345–349] and S-DSCs [291, 292]. In contrast to that, pure oligothiophenes without any donor groups gave h values of less than 4% in L-DSCs due to strong intermolecular p-p interactions that impede high photocurrents [91, 350, 351]. This tendency towards strong p-p interactions with increasing thiophene number leading to dye aggregation is the main disadvantages of oligothiophenes [348, 349]. However, this impact is offset by the advantages of electronrich p-conjugated oligothiophene spacers. The use of such spacers facilitates high stability [352], high polarizability [89], high molar extinction coefficients and also the suppression of dark currents especially, if the thiophenes bear alkyl chains [353]. They are assumed to increase the electron lifetimes by preventing acceptors (i.e. dye cations or I3− ions) from reaching the TiO2 surface and/or by reducing the reorganization energy of the dye which is believed to increase the rate of dye cation regeneration [346, 354]. The effects of the alkyl chain number/position and the thiophene number on aggregation, the photophysical, photochemical and electrochemical properties of the sensitizers, the solar-cell performance and the kinetics of electron injection and charge recombination were investigated in detail by Hara and co-workers [348]. They showed that the electron lifetime in TiO2 can indeed be increased by the existence of alkyl side chains which causes a retardation of the charge recombination rate. Furthermore, it is suggested that the aggregation of oligothiophenes can be suppressed by the steric hindrance of the long alkyl chains [273, 354]. Additionally to the benefits of oligothiophene bridges, arylamines and especially triphenylamine derivatives have been identified as highly efficient donors for L- and S-DSC applications [116, 291, 292, 301, 355–360]. Among the oligothiophene bridged arylamine sensitizers, dyes 82, 83 and 84 (cf. Fig. 11.37) have turned out to belong to the best performing ones for L-DSCs applications (h = 8.01[251], 8.60 [273] and 10.1% [116], respectively). It was found that in donor-pbridge-acceptor dyes of this type the HOMO is delocalized over the donor groups and partly on the thiophene bridge, and the LUMO is determined to be
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595
82 (JK2)
N S
S COOH NC
N
83 (JK-46) S
S
S
S
COOH NC
O
Si
N
S O
NC
S O
S
COOH
84 (C219)
O
Fig. 11.37 Oligothiophene bridged arylamine donor dyes 82–84 for efficient L-DSCs
mainly delocalized over the cyanoacrylic anchoring group facilitating directionality and hence an efficient electron transfer to TiO2 [273, 349, 361]. This was also found for 82 [251] and 83 [273]. The dyes 82 and 83 consist of dimethylfluorenyl-amino donors which possesses a dipolar character that facilitates the formation of stable cation (and anion) radicals, a conducting thiophene bridge with or without n-hexyl chains and a cyanoacrylic acid acceptor/anchor. Although the absorption of 82 is slightly red-shifted compared to 83 (lmax = 452 and 430 nm for 82 and 83, respectively) and the molar extinction coefficient of 82 is higher (emax = 3.9·104 and 2.9·104 M−1 cm−1 for 82 and 83, respectively), the overall efficiency for 83 is higher
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NC COOH
S N
85 (C201)
S
NC
S S
F
86 (A2-F)
N C6H13
COOH
C6H13
Fig. 11.38 Oligothiophene bridged arylamine donor dyes 85 and 86 for efficient S-DSCs
using a volatile electrolyte (h = 8.01 and 8.60% for 82 and 83, respectively) [251, 362] By using a stable, solvent- free ionic-liquid electrolyte the measured efficiency for 83 was 6.82% which even increased slightly during a long term stability test (1,000 h, visible light soaking under AM1.5 G and 100 W/cm² at 60°C) to 7.03% [273]. A comparable stable device was manufactured on the basis of a similar dye but employing a fused dithienothiophene bridge which shows a low free energy of solution in the high polar standard electrolytes [347]. Bäuerle and co-workers compared linear and branched oligothiophenes [361]. It was found that the branched dye, even though it bore two donor groups compared to one for the unbranched derivative, performed inferior in L- and S-DSCs because of a lower dye loading on the surface facilitating higher recombination rates. Nevertheless, the stability of the branched dye was superior. Currently the highest efficiency among all organic dyes was reached by the unbranched dye 84 [116]. It reached an efficiency of 10.1% using a volatile electrolyte and 7.6% by using an ionic liquid. The sensitizers 85 and 86 (cf. Fig. 11.38) belong to the highest efficient organic dyes for S-DSC applications reaching efficiencies of 4.8 [291] and 4.86% [292], respectively. They carry a triphenylamine derivative as donor, a thiophene based bridge combined with and cyanoacrylic anchoring group creating a high molar extinction coefficient push-pull system. In these dye systems, a spatial separation between the HOMO (mainly located on the donor) and LUMO (mainly located on the anchor) was reached while maintaining an overlap to enhance electronic transition [116, 291]. The spatial separation is assumed to facilitate ultra fast electron injection and slow down recombination between injected electrons and the oxidized dye [181].
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Table 11.8 Overview of the L- and S- DSC performances of efficient organic sensitizers of different dye classes (BODIPY: 62; polymer sensitizers: 63 and 64; squaraines: 65 and 66; perylenes: 67 and 68; hemicyanine: 69; cyanine: 70; coumarins: 71–78; indolines: 79–81 and oligothiophene bridged arylamine donor dyes: 82–87) Solar cell JSC UOC FF h Complex type Type of HTMk [mA/cm²] [V] [%] [%] Ref. 62 62 63a 64 65b 66c 66d 67 67 68 68e 69f 70g 71h 72 73 74h 75 76h 77h 78 79i 79 80 81 81j 82b 82 83 84 84 85i 86
L-DSC S-DSC L-DSC S-DSC L-DSC L-DSC S-DSC L-DSC S-DSC L-DSC S-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC L-DSC S-DSC S-DSC S-DSC L-DSC S-DSC L-DSC L-DSC L-DSC S-DSC S-DSC
Volatile Spiro-OMeTAD Volatile Spiro-OMeTAD Volatile Volatile P3HT Volatile Spiro-OMeTAD Low volatile Spiro-OMeTAD Low volatile Volatile Volatile Volatile Volatile Volatile Volatile Volatile Volatile Volatile Volatile Ionic liquid Spiro-OMeTAD Spiro-OMeTAD PEDOT Volatile Spiro-OMeTAD Volatile Volatile Ionic liquid Spiro-OMeTAD Spiro-OMeTAD
4.03 2.27 9.76 3.7 11.3 17.6 10.75 12.60 2.83 4.2 8.7 15.6 22.10 15.9 11.1 12.9 14.0 15.1 14.7 14.3 11.6 18.56 13.73 7.7 6.6 9.3 14.0 3.85 17.45 17.94 14.96 9.06 7.52
0.562 0.80 0.400 0.540 0.667 0.696 0.550 0.740 0.838 0.440 0.640 0.512 0.540 0.690 0.510 0.500 0.600 0.470 0.670 0.730 0.680 0.717 0.728 0.866 0.885 0.860 0.753 1.088 0.664 0.770 0.693 0.860 0.910
74 37 61 46 72 70 55 74 75 66 57 63 48 75 60 64 71 50 73 74 67 72 72 61 72 75 77 68 74 73 74 61 71
1.66 0.68 2.4 0.9 5.4 8.65 3.2 6.8 1.78 1.2 3.2 6.3 7.62 8.2 3.4 4.1 6.0 3.5 7.2 7.7 5.3 9.52 7.18 4.1 4.2 6.1 8.01 3.17 8.60 10.1 7.6 4.8 4.86
[278] [279] [280] [127] [281] [248] [282] [284] [284] [285] [285] [283] [286] [287] [274] [274] [293] [274] [294] [294] [295] [288] [296] [289] [290] [126] [251] [102] [273] [116] [116] [291] [292]
Measured under AM1.5, 100 mW/cm² (except otherwise mentioned) a The volatile electrolyte additionally contained an ionic liquid (1-methyl-3-n-hexylimidazolium iodide) Formally, it was reported, that the adsorption of cationic species like ionic liquids enhances the diffusion coefficient of the TiO2 electrodes [297, 298]. Additionally, it was assumed that the ionic liquid reduces recombination at the polymer/electrolyte interface and an increase in surface contacts between them [280] b CDCA was used to reduce aggregation c Co-sensitized L-DSC (66 + 82, Fig. 11.37) based on a novel film architecture (TiO2/Dye1/Al2O3/ Dye2) (continued)
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Table 11.8 (continued) d
Average performance of nanotube L-DSCs measured under 90 mW/cm² (the champion cell reached about 3.8%) e The spiro-OMeTAD HTM did not contain any tBP f The L-DSC on the basis of propylene carbonate was measured under 80 mW/cm² g Measured at 75 mW/cm² under Xe lamp irradiation h DCA was used as coadsorbent to reduce aggregation; the efficiency without DCA was 5.0% for 71 i CDCA was used as coadsorbent j The optimized thickness of the mesoporous TiO2 layer was found to be 5.8 mm k Volatile solvents for the electrolyte are typically on the basis of acetonitrile/valeronitrile/ methoxyacetonitrile and low volatile ones mainly rest upon 3-methoxypropionitrile
11.5
Conclusions
To conclude, an overview of the operation principle of liquid- and solid-state dye-sensitized solar cells and the different types of metal-organic and organic sensitizers are given. Furthermore, the concepts behind the dye designs were presented and the state of the art performances of the diverse types of sensitizers were listed in tables. The main difference between L- and S-DSCs is the hole transport material and the associated thickness of the mesoporous semiconductor layer (~10–20 mm for L-DSCs, ~2 mm for S-DSCs). Regarding L-DSCs typically, the I−/I3− redox couple is used to mediate the electron/hole transport between cathode and sensitizer. Commonly, it is dissolved in a volatile solvent (on the basis of acetonitrile and/or valeronitrile), a low volatile solvent (mostly 3-methoxypropionitrile) or an ionic liquid which can penetrate the porous semiconductor network entirely leading to high solar energy to electricity conversion efficiencies. In contrast to that, S-DSCs show an intrinsically lower efficiency due to the solid standard hole conductor spiroOMeTAD (Fig. 11.1). This can be ascribed to the lower hole transport mobility of the organic semiconductor, the high recombination between TiO2 and the HTM, the poor wetting/bad contact between dye and HTM, the less efficient pore filling and hence the use of thinner mesoporous layers which causes less light harvesting and thus a lower photocurrent output. Nevertheless, it is possible to overcome the typical disadvantages of L-DSC such as solvent leakage/evaporation, corrosion (due to the aggressive nature of the redox couple) by using a solid HTM. The sensitizers for solar energy conversion can be divided into two classes, viz. metal-organic and organic sensitizers. The former comprises of ruthenium dyes, phthalocyanines and porphyrins. Ruthenium dyes feature MLCT absorption in the longer wavelength range in combination with MC and LC absorption bands which makes them capable of absorbing over a wide range of the visible spectrum. Furthermore, they facilitate fast injection because of the fact, that the absorption of photons places the excited electron on the anchoring ligand. The positive charge
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(hole) is thereby distributed over the metal and also to some extend over the NCS group causing a spatial separation between injected electrons and holes thus retarding the rate of recombination. Moreover, ruthenium(II) complexes show favourable photochemical, photophysical, electrochemical properties. However, ruthenium is a rare/expensive metal and the ruthenium complexes can cause undesirable environmental impacts and the lack absorption in the red/IR-region. Nevertheless, ruthenium complexes bearing donor groups belong to the most efficient sensitizers for DSC applications. In contrast to that, phthalocyanines and porphyrins feature an intense absorption in the red/IR-region (Q band) and on in the blue region (Soret band). Additionally, only large abundant and inexpensive metals (e.g. Cu and Zn) are used as central metals. Furthermore, the optical, photophysical and electrochemical properties can be systematically tailored by modifying the peripheral substituents, changing the symmetry of the macrocycles and/or the inner metal center. Moreover, phthalocyanines and porphyrins are known for their excellent chemical, light and thermal stability. But they are transparent over a large region of the visible spectrum. Organic sensitizers follow the donor-pbridge-acceptor concept to reach a high light harvesting efficiency and to create directionality. Typical donor groups are electron-rich aryl amines like aminocoumarins, (difluorenyl)phenylamines, triphenylamines and indolines. Cyanoacrylic acid groups are perfect acceptors/anchors and the p-bridges of the most efficient organic sensitizers are often based on thiophenes (e.g. oligothiophenes, thienylenevinylenes, dithienothiophenes or dithienolsilole) due to their excellent charge transport properties. Organic dyes in general are very promising for the use as sensitizers for DSCs because they can be synthesised and purified very easily at low costs, they do not contain rare and expensive metal and have high extinction coefficients which facilitate a high light harvesting ability and hence reduce the optical depth so that organic dyes are suitable for thinner semiconductor electrodes. Additionally, the variety of possible functional groups and the facile modifiability provide the opportunity to tune the spectral, photophysical, photochemical and electrochemical properties very well. In contrast to that, they suffer from their narrow absorption bands in the visible region of the electromagnetic spectrum and their tendency towards p-p-stacking (aggregation). Furthermore, the DSC performance is limited by their lower stability, which may arise from the formation of excited triplet states and unstable radicals under illumination. In conclusion, the general design strategy for any dye follows the donor-acceptor concept. However, each dye class as well as both DSC show advantages and disadvantages. We believe, that in order to manufacture solar cells capable of reaching higher efficiency not only optimization of the dye design and fine tuning of the devices is the key, but rather novel device concepts have to be established such as multilayer co-sensitization, tandem cells or the fluorescence energy transfer approach in order to exploit the complete solar spectrum more efficiently. Here, the basic ideas of light harvesting and photon management as practiced by the nature on photosynthesis have to be better understood and adapted in a bio-inspired nature.
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345. Mishra A, Ma C-Q, Bäuerle P (2009) Functional oligothiophenes: molecular design for multidimensional nanoarchitectures and their applications. Chem Rev 109(3):1141–1276 346. Justin Thomas KR, Hsu Y-C, Lin JT, Lee K-M, Ho K-C, Lai C-H, Cheng Y-M, Chou P-T (2008) 2,3-Disubstituted thiophene-based organic dyes for solar cells. Chem Mater 20(5):1830–1840 347. Qin H, Wenger S, Xu M, Gao F, Jing X, Wang P, Zakeeruddin SM, Grätzel M (2008) An organic sensitizer with a fused dithienothiophene unit for efficient and stable dye-sensitized solar cells. J Am Chem Soc 130(29):9202–9203 348. Wang Z-S, Koumura N, Cui Y, Takahashi M, Sekiguchi H, Mori A, Kubo T, Furube A, Hara K (2008) Hexylthiophene-functionalized carbazole dyes for efficient molecular photovoltaics: tuning of solar-cell performance by structural modification. Chem Mater 20(12):3993–4003 349. Kim S, Kim D, Choi H, Kang M-S, Song K, Kang SO, Ko J (2008) Enhanced photovoltaic performance and long-term stability of quasi-solid-state dye-sensitized solar cells via molecular engineering. Chem Commun 40:4951–4953 350. Tanaka K, Takimiya K, Otsubo T, Kawabuchi K, Kajihara S, Harima Y (2006) Development and photovoltaic performance of oligothiophene-sensitized TiO2 solar cells. Chem Lett 35(6):592–593 351. Tan S, Zhai J, Fang H, Jiu T, Ge J, Li Y, Jiang L, Zhu D (2005) Novel carboxylated oligothiophenes as sensitizers in photoelectric conversion systems. Chem Eur J 11(21):6272–6276 352. Katoh R, Furube A, Mori S, Miyashita M, Sunahara K, Koumura N, Hara K (2009) Highly stable sensitizer dyes for dye-sensitized solar cells: role of the oligothiophene moiety. Energy Environ Sci 2(5):542–546 353. Yang H-Y, Yen Y-S, Hsu Y-C, Chou H-H, Lin JT (2010) Organic dyes incorporating the dithieno[3,2-b:2¢,3¢-d]thiophene moiety for efficient dye-sensitized solar cells. Org Lett 12(1):16–19 354. Koumura N, Wang Z-S, Mori S, Miyashita M, Suzuki E, Hara K (2006) Alkyl-functionalized organic dyes for efficient molecular photovoltaics. J Am Chem Soc 128(44):14256–14257 355. Liang Y, Peng B, Chen J (2010) Correlating dye adsorption behavior with the open-circuit voltage of triphenylamine-based dye-sensitized solar cells. J Phys Chem C 114(24):10992–10998 356. Teng C, Yang X, Yang C, Li S, Cheng M, Hagfeldt A, Sun L (2010) Molecular design of anthracene-bridged metal-free organic dyes for efficient dye-sensitized solar cells. J Phys Chem C 114(19):9101–9110 357. Shen P, Liu Y, Huang X, Zhao B, Xiang N, Fei J, Liu L, Wang X, Huang H, Tan S (2009) Efficient triphenylamine dyes for solar cells: effects of alkyl-substituents and p-conjugated thiophene unit. Dyes Pigm 83(2):187–197 358. Choi H, Kang SO, Ko J, Gao G, Kang HS, Kang M-S, Nazeeruddin MK, Grätzel M (2009) An efficient dye-sensitized solar cell with an organic sensitizer encapsulated in a cyclodextrin cavity. Angew Chem Int Ed 48(32):5938–5941 359. Im H, Kim S, Park C, Jang S-H, Kim C-J, Kim K, Park N-G, Kim C (2010) High performance organic photosensitizers for dye-sensitized solar cells. Chem Commun 46(8):1335–1337 360. Moon S-J, Yum J-H, Humphry-Baker R, Karlsson KM, Hagberg DP, Marinado T, Hagfeldt A, Sun L, Grätzel M, Nazeeruddin MK (2009) Highly efficient organic sensitizers for solidstate dye-sensitized solar cells. J Phys Chem C 113(38):16816–16820 361. Fischer MKR, Wenger S, Wang M, Mishra A, Zakeeruddin SM, Grätzel M, Bäuerle P (2010) D-p-a sensitizers for dye-sensitized solar cells: linear vs. branched oligothiophenes. Chem Mater 22(5):1836–1845 362. Choi H, Baik C, Kang S, Ko J, Kang M-S, Nazeeruddin M, Grätzel M (2008) Highly efficient and thermally stable organic sensitizers for solvent-free dye-sensitized solar cells. Angew Chem 120(2):333–336
Chapter 12
Chromophores for Optical Power Limiting Yann Bretonnière and Chantal Andraud
Abstract Optical power limiting (OPL), which reduces the transmittance of high power incident lights, allows protecting sensors (human eyes as well detectors) against laser aggressions. This chapter describes the different kinds of processes generating OPL and the chemical systems designed for each of them. Among them, multiphotonic absorption and reverse saturable absorption (RSA) are widely used and are shown to present a great interest with broad band activity. Two-photon absorption (2PA) moities are conjugated charge transfer (CT) with an OPL range in relation with the strength of the CT molecular systems. Excited state absorption with a strong spectral overlap with 2PA allows improving OPL efficiency. For this purpose, heavy atoms systems with intersystem crossing (ISC) effect promote this effect. For RSA effect, ISC molecules with efficient ESA and high ratio between excited and ground states absorption cross-sections, such as phtalocyanines or porphyrines derivatives, are shown to present improved OPL properties. Furthermore, the combination with other effects, such as nonlinear scattering or photo-induced electron transfer by interaction with carbon-based systems, is shown to enhance OPL. Optical quality glasses with strong nonlinear absorption can lead to similar OPL properties than in solution for real applications.
12.1
Introduction
An optical power limiter is a device that significantly reduces the transmittance of high power incident lights [1, 2]. The behaviour of an “ideal” optical power limiter is displayed in Fig. 12.1. It behaves as a transparent medium for incident fluences lower
Y. Bretonnière • C. Andraud () Laboratoire de Chimie de l’ENS Lyon , UMR 5182 CNRS-ENS Lyon, Université de Lyon, 46 allée d’Italie, 69364 Lyon, France e-mail: [email protected]; [email protected]
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2_12, © Springer Science+Business Media B.V. 2012
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Fig. 12.1 Optical power limiting principle
than I th (called threshold of optical limiting) and limits the transmitted intensity to a value acceptable for the target I max (Fig. 12.1); efficient optical limiters will present I max lower than the intensity corresponding to the damage threshold of the sensor. The main characteristics of the device are: (1) a high linear transmittance at low power laser input, so that the detection range of the optical system is not significantly reduced; (2) a low activation threshold; (3) a large dynamic range, defined as the ratio between the linear transmittance and the transmittance at highest possible input, leading to a protection over a broad range of laser incident energy; (4) a response time shorter than the pulse duration of the laser threat to counter; (5) a broadband spectral response. Different phenomena can induce optical power limiting (OPL). In this Chapter, we limit us mainly to the description of OPL data based on NLO processes, such as two-photon absorption (2PA) and reverse saturable absorption (RSA).
12.2
Nonlinear Refraction and Nonlinear Scattering
OPL using nonlinear refraction arises from the defocusing of the beam: the total energy remains unchanged, while the intensity on the detector is decreased. Self-focusing has also been studied in photorefractive crystal both in pulse and continuous wave (CW) regime [3]. Recently chloroaluminium [4] and iron phtalocyanines [5] were shown to present respectively low power optical limiting due to self defocusing and self phase modulation effects. Although nonlinear refraction could be very interesting for OPL, since no energy is stored in the material, this nonlinearity is usually regarded as insufficient to make an efficient OPL alone. Therefore this process has mainly been used in combination with other nonlinear effects such as nonlinear absorption, as observed in colloidal CdSe/ZnS quantum dots for which nonlinear transmission was interpreted in terms of 2PA and self-defocusing effects [6]. OPL of pulsed lasers by carbon black suspensions (CBS) or single-wall carbon nanotubes (SWNT) suspensions is ascribed to the scattering of light by vapour bubble generated after the absorption of incident light by particles [7–9]: heating of the
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particles results in evaporation of the surrounding solvent and even in the sublimation of the particles themselves. For higher incident energy, a micro-plasma is formed that also contributes to the nonlinear response of CBS. Broadband optical limiting efficiency has been demonstrated on the whole visible-near IR spectral range. Recently, 2PA molecules have been mixed with or grafted on carbon nanotubes to increase the dynamic range [10]. The OPL efficiency of SWNT, dispersed in different nitrogen containing solvents, was shown to be strongly concentration dependent [11]. Higher effects in N,Ndimethylformamide dispersion due to larger average bundle size combined to lower boiling point and surface tension of this solvent were observed [12]. OPL performances of multi-walled carbon nanotubes have been studied in water, underlining the relevant role of hydrogen bonds interactions between nanotubes and water on nonlinear scattering [13].
12.3
Nonlinear Absorption: Two-Photon Absorption and Reverse Saturable Absorption
12.3.1
Nonlinear Absorption
When a medium is submitted to the external electric fields, its polarization can be expanded in a power series of the fields E: (2) (3) (4) DPi = K1 c ij(1) E j + K 2 c ijk E j Ek + K 3 c ijkl E j Ek El + K 4 c ijklm E j Ek El Em + ... (12.1)
where K’s are coefficients depending on systems of units, degeneracy of optical (n) processes and definition of the Fourier transform of electric field [14]; χ are n+1 rank 3D tensors describing the linear ( n = 1 ) or nonlinear ( n > 1 ) processes. Equation 12.1 can be written according to expression (12.2) in order to introduce the intensity dependent index of refraction: DPi = K1 c ij (1) Ej
(12.2)
(1) where the susceptibility c ij depends on the forcing fields Ek, El, Em… and (n) (1) on susceptibilities c ij (n = 1, 2, 3, …). c ij can be expressed according to expression (12.3), with n the index of refraction:
c ij (1) = n 2 - 1
(12.3)
n is given by Eq. 12.4, where I is the intensity of the propagating beam, n0 and n2 are respectively the linear and the nonlinear index of refraction. n = n0 + n2 I
(12.4)
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The absorption of the propagating beam will occur via multiphotonic process. The lowest multiphoton absorption process, in terms of intensity variations, is a 2PA process, described by c (3) ( -w ; w , -w , w ). In that case, the nonlinear index of refraction n2 is expressed according to Eq. 12.5: n2 ( I ) =
3 c (3) ( -w ; w - w , w ) 4e 0 cn02
(12.5)
n2 is complex as linear and cubic susceptibilities and is expressed according to the expression (12.6): n2 = n2r + ik 2
(12.6)
The intensity variation of the beam, propagating in the medium in z direction, is given by Eq. 12.7: dI ( z ) = -a (1) I - a (2) I 2 dz
(12.7)
where a (1) and a (2) are, respectively, linear and 2PA coefficients. The 2PA coefficient depends is given by the expression (12.8): a (2) =
4pk 2 l
(12.8)
where the nonlinear extinction coefficient k 2 is given by (12.9), according to Eq. 12.5 provided that Im(n0) = 0 k 2 (I ) =
3Im( c (3) ( -w ; w - w , w )) 4e 0 cn02
(12.9)
Another relevant parameter is the 2PA cross-section; it is expressed according to (12.10), in which N is the number of molecules. s 2PA =
wa (2) N
(12.10)
The Eq. 12.7 can be generalized by expression (12.11) for higher-order nonlinear absorption processes: dI ( z ) = -a (1) I - a (2) I 2 - a (3) I 3 - a (4) I 4 - .... dz
(12.11)
in which a(3) is the absorption coefficient describing simultaneous absorption of three photons and is proportional to c (5) ( -w ; w , w , w , -w , -w ), while a(4) represents (7) the four-photon absorption proportional to c ( -w; w , w , w , -w , -w ), etc… As a general point of view, nonlinear dissipative processes, such as multiphotonic absorption will be described by odd-order susceptibilities.
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The expression (12.11), which represents the beam attenuation in a NLO medium, depending on the nonlinear absorption coefficients a(2), a(3), a(5) … will describe the OPL effect.
12.3.2
Two-Photon Absorption
2PA based materials present great interest for OPL, since their high linear transmittance allows using thick filters to increase the dynamic range [15]. An ideal 2PA based optical limiter can fulfill all requirements stated previously, since it allows high transmission at low laser incident fluences. 2PA has been observed early in different semiconductors (Si, GaAs, CdS, CdSe, GaP…) [16], or in binary glass such as TeO2-PbO [17]. Since 2PA is a third-order NLO process, there are no restrictions on molecular symmetry for its observation. The optimization of 2PA properties of organic molecules is related to the optimization of the second hyperpolarizability (Eq. 12.10), following the Orr and Ward sum-over states (SOS) relationship [18]. It has been largely shown that, for almost organic systems, the three-level model can describe this hyperpolarizability. In this model, the lowest excited state 1 and the two-photon excited state 2 are considered to be the most significant contributor states to the hyperpolarizability value (Fig. 12.2) [19]. Different parameters, such as excited-state energies E0i and dipole moments
Fig. 12.2 Three-level model describing 2PA process for: (a) dipolar and (b) quadrupolar molecules
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Fig. 12.3 Example of a three-photon absorption process for OPL: 2PA followed by ESA from a triplet excited state
( m 01, m12 the transition dipole moments between 0 and 1 and between 1 and 2 respectively, and Dm 01 the static dipole moment difference between 0 and 1 ) must be tuned to optimise 2PA cross-sections. Molecules generally used for 2PA effects are linear and consist in a conjugated delocalised electrons bridge, bearing at each end donor (D) and/or acceptor (A) groups (Fig. 12.2) [20, 21]. It has been largely shown that the longest is the bridge and/or the highest is the strength of donor or acceptor, the largest will be the value of s 2 PA [22]. In the case of OPL against nanosecond pulsed lasers, the optimisation of 2PA induced OPL effect requires not only the optimization of 2PA properties of chromophores, but also that of excited states absorption (ESA) properties (Fig. 12.3) [23]; in this configuration, OPL process will consist in a 3 (2+1)-photon absorption process: 2PA immediately followed directly by ESA from the lowest excited singlet state S1 towards higher singlet states Sn, or after inter-system crossing (ISC) between excited triplet states (Fig. 12.3). The main challenge for molecular engineering will be to obtain the best spectral overlap between both 2PA and ESA phenomena. According to the Eq. 12.7, this three-photon induced OPL process is described according to Eq. 12.12, with a (2) I 2 << a '(3) I 3 under high laser intensity. dI ( z ) = -a (1) I - a (2) I 2 - a ' (3) I 3 dz
(12.12)
When the lifetime t 01 of the lowest excited state is shorter than the pulse duration, the three-photon coefficient a ' (3) can be written by the following Eq. 12.13: a '(3) =
N s 2 PA s ESAt 01 V 2(w )2
(12.13)
where s ESA is the ESA cross-section, while N/V is the concentration and w the laser frequency. The three-photon coefficient a '(3) is obtained from nonlinear transmission measurements by using Eq. 12.14, in which L is the sample thickness:
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TE = òò
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(12.14)
1 + 2a ' LI (r, t )
The optimization of a '(3) requires the simultaneous optimization of all parameters involved in Eq. 12.14, with a major difficulty in terms of molecular engineering, corresponding in the obtaining of the best spectral overlap between 2PA and ESA processes. Molecular engineering depends strongly on the spectral range for protection. We will distinguish two main ranges: (1) visible and near infra-red (NIR) between respectively 450–700 nm and 700–1,000 nm, (2) IR (including telecommunications wavelengths) between 1,100 and 1,600 nm. A lot of molecules have been designed for the different spectral ranges for protection, particularly in the visible or NIR. Next, we report 2PA molecules developed in our group in Lyon in this wavelength range, whereas, since only a few molecules were developed for telecommunications wavelengths in the view of OPL applications, we will give in this case a more detailed review of literature.
12.3.2.1
Visible Range and Near Infra-Red
A molecular engineering around weakly conjugated triphenyl amines derivatives 1–6 was performed in our group for OPL between 450 and 650 nm (Fig. 12.4) [24]. For this purpose, two different approaches were considered to optimize the two-step three-photon absorption coefficient a' (3) (Eq. 12.13): (1) optimization of the conjugation in molecules 1–6 for enhancement of s 2 PA , (2) minimization of nonradiative processes by hindering donor groups in molecules 4–6 for optimization of t 01 and then s ESA . For this first approach, molecule 2 was shown to be the most efficient with s 2 PA and a' (3) values up to 100 GM and 7,950 cm3·GW−2 respectively between 500 and 550 nm. For the second approach, molecule 4 gave rise to the best efficiency with a' (3) reaching 9,000 cm3·GW−2 at 535 nm. Similar a' (3) values for molecules 4 and 9 have different origins. Molecule 4 displays a weak s 2 PA value of 35 GM. In that case, it does not originate from 2PA, which is considered only to induce the process, but from a longer lifetime t 01 (420 against 320 ps for respectively 4 and 2) and a more efficient ESA process with an significant enhancement of s ESA (3.8 against 1.4·10−16 cm2 for respectively 4 and 2), as well as a better spectral overlap between 2PA and ESA phenomena (shown in Fig. 12.4). The optimization of s 2 PA in the visible range is a real challenge, due to the difficulty of optimization of the transparency/nonlinearity trade-off, since the increase of the charge transfer within molecules results in a red shift of linear and nonlinear absorption bands. For this purpose, the oligomer strategy was developed in our group. In contrast with classical approach using charge transfer molecules substituted by donor and/ or acceptor groups, this oligomer approach does not involve any charger transfer
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Fig. 12.5 Linear oligofluorenes and their linear absorption
functionalization, and opens the way for an alternative strategy for 2PA in the visible. We designed linear oligofluorenes (Ln in Fig. 12.5); these molecules are transparent in the visible with a cut-off wavelength below 420 nm and absorption energies E01 (n) varying according to the expression (12.15), in which A represents the linear absorption of fluorene and M the interaction matrix (Fig. 12.5) [25]: E01 ( n) = A - 2 M cos
p n +1
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Combined with a red shift of 2PA bands, a large enhancement of s 2 PA values as a function of the oligomer length n was observed with values up to 20,000 GM for L60 (Fig. 12.6a) [26]. The relevant parameter to compare the different oligomers is the intrinsic nonlinear efficiency per fluorenyl subunit calculated by the ratio s 2 PA /n. Although this ratio presents saturation for the longest molecules (Fig. 12.6b), a gain of at least one order of magnitude in terms of 2PA efficiency could be obtained using this strategy with respect to charge transfer molecule such as triphenylamine derivative 4 optimized for this wavelength range. As shown on Fig. 12.6, s 2 PA presents quadratic variations with n up to n = 10. This 2PA exaltation was explained on the basis of dipolar excitonic interactions between first neighbour monomers and was corroborated by theoretical calculations from perturbations theory [27]. Broadband OPL properties of Ln oligomers are displayed in Fig. 12.7: for L2 at c = 400 g·L−1, no OPL was observed above 600 nm, while for shorter wavelengths, the output energy is lower than 10 mJ for an input energy up to 200 mJ (Fig. 12.7a);
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Fig. 12.6 2PA properties of Ln oligomers
Fig. 12.7 OPL properties of oligomers: (a) L2, (b) L16 in chloroform and (c) 2PA and ESA spectral overlap in L2
for L16, at lower concentration (c = 100 g·L−1), the transmitted energy is clamped at a value below 10 mJ on the whole visible range, with an output energy limited at 2 mJ in the blue part of the visible spectrum for an incident energy up to 350 mJ (Fig. 12.7b). These results demonstrated the higher OPL efficiency of L16 with respect to that L2 in spite of a lower fluorene sub-unit concentration [28].
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Fig. 12.8 Branched oligofluorenes
These OPL properties were shown to be enhanced by ESA; the spectral overlap between 2PA and ESA properties is displayed in Fig. 12.7c [29]. The oligomers present similar OPL properties than those of the benchmark derivative stilbene 3 for the visible, for which the optical limiting was shown to occur in the overall visible spectrum with the best efficiency at l = 600 nm, where the clamping energy is about 4.5 mJ [30]. In order to induce higher-order dimension interactions, branched oligofluorenes were designed (Fig. 12.8): V-shape derivatives featuring C2v symmetry (Vn) and threefold dendrimers of generation N (DnGN). These spatially assemblies of nonsubstituted p-electron systems were also shown to be coupled by dipole-dipole interactions [31]. Enhancement of 2PA properties by 2D arrangements of monomers was shown, with lower 2PA properties per monomers for linear oligomers but with a better linear transparency (Fig. 12.9) [32]. These molecules were shown to present nonlinear absorption properties (Fig. 12.9b). Measurements were performed in chloroform between 450 and 650 nm for nanosecond time duration pulses. The two-steps three-photon (2+1) absorption coefficient a' (3) presents at resonance high values ( a' (3) >10,000 cm3/GW2 for D2G1 and D2G2 at a concentration of 50 g·L−1) [33]. These values are strongly enhanced with respect to those obtained in the same conditions for analog linear oligofluorenes
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− −
Fig. 12.10 Tris(bifluorene-funtionnalised-phenanthroline) Ru (II) complexes
and for other organic molecules symmetrically substituted such as Stilbene 3, which exhibits values weaker than 10,000 cm3·GW−2 at c = 200 g·L−1 (in the same conditions, a ' (3) values are nearly 40,000 cm3·GW−2 for D2G1 and D2G2) [34]. The role of ESA on OPL efficiency was highlighted recently in tris(bifluorenefuntionalized-phenanthroline) Ru (II) complexes displayed in Fig. 12.10 [35]. These complexes present broadband OPL properties in the near-IR between 730 and 990 nm (Fig. 12.11); the origin of this phenomenon depends strongly on the complex as reported below. The OPL efficiency of these complexes is illustrated in Fig. 12.12a by spectral variations of OPL threshold. This parameter is significantly weaker for the most conjugated complex 8, which can be considered as a better limiter. Two regions in
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threshold variations can be considered: 750–850 nm, for which OPL efficiency can be related to 2PA efficiency of complexes for both compounds 7 and 8 and 850–950 nm, for which a significant increase of OPL threshold was observed for compound 7, while this feature remains weak for complex 8. This trend could be ascribed to an excellent 2PA-ESA spectral overlap for compound 8 (Fig. 12.12c), which allows efficient OPL even in weak 2PA wavelength range such as 850–950 nm, while the weak 2PA-ESA spectral overlap for complex 7 (Fig. 12.12b) leads to an OPL decrease in this wavelength range.
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Fig. 12.13 Fluorene derivatives for 3PA based OPL in the IR
12.3.2.2
Infra-Red and Telecommunications Wavelengths
This wavelength range (1,100–1,600 nm) was recently investigated for 2PA related applications. Only a few papers describing 2PA engineering have been published since 2002; most of them have been summarized in a recent review [36]. We will detail only results related to OPL applications; several mechanisms were used for this purpose in this wavelength range. OPL properties of fullerenes doped polyimides induced by nonlinear refraction at 1,315 nm were described [37]. In nanosecond regime, a threshold of 0.1 J·cm−2 with a transmission of 35% was obtained for an incident intensity of 0.25 J·cm−2. The group of Prasad developed fluorene based chromophores for OPL applications induced by simultaneous 3PA. With the same approach, ferrocene derivatives 9–15 (Fig. 12.13) show broadband 3PA spectra [38]. 3PA coefficient values a ' (3) were assessed to 9 and 7.2 × 10−6 cm3 GW−2 for complexes 9 and 10 respectively.
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Fig. 12.14 3PA based OPL properties of molecules 11–13
Cooperative effects were shown in multibranched chromophores 11–13, with 3PA cross-sections of 2.9, 13.0 and 30.0 × 10−25 cm6·GW−2 respectively and improved OPL properties for branched molecules (Fig. 12.14) [39]; this led to 3PA coefficient values a ' (3) of respectively 2.5, 3.7 and 4.3 × 10−6 cm3 GW−2. Other branched molecules with a 3PA weaker efficiency were designed [40]. The same group designed also multipolar chromophores 14–15 [41]. With a broad-band 3PA effect between 1,217 and 1,445 nm and 3PA cross-sections varying between 171 and 47 × 10−25 cm6 GW−2 for complex 14 and 221 and 73 × 10−25 cm6 GW−2 for compound 15, these chromophores present OPL properties at 1,300 nm. The first OPL experiments in the telecommunications spectral range using 2PA based absorbers were described by our group using dipolar and symmetrical heptamethine cyanines 16–19 (Fig. 12.15) [42]. These chromophores present a strong linear absorption in the near infra-red spectral range (700–900 nm, Fig. 12.16), and a significant 2PA absorption in the 1,300–1,500 nm range. The 2PA spectrum of molecules 16–17 is blue shifted with respect to the wavelength doubled scale main transition of the 1PA spectrum, and seems to match the weakest band (Fig. 12.17a for compound 17), while the 2PA spectrum of the non centrosymmetric dipolar compound 18 matches the 1PA spectrum (Fig. 12.17b). All compounds present maximal 2PA wavelength between 1,430 and 1,500 nm, with maximum s 2 PA comprised between 450 and 800 GM. Typical variations of the nonlinear transmittance vs. the incident laser energy are displayed in Fig. 12.17c at 1,500 nm. The symmetric system 17 presents an OPL threshold at 1,500 nm of 0.4 J·cm−2 and a transmission of 70% for an incident intensity of 2.5 J·cm−2 in ns regime. These curves were interpreted on the basis of the 3 (2+1) PA model represented in Fig. 12.3: a 2PA process followed by an ESA phenomenon between 1,400 and 1,600 nm. The three photon coefficients a'(3) were assessed at 1,500 nm to 150, 200 and 330 cm3·GW−2 respectively for molecules 16, 17 and 18 using equations (12.12–12.14).
Fig. 12.15 Heptamethine cyanines for 2PA based OPL in the IR
400000
17 350000
ε (L Mol-1 cm-1)
300000
16
250000
200000
150000
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18 500000
0 500
550
600
650
700
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wavelength (nm)
Fig. 12.16 Absorption properties of heptamethine cynanines 16–18
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Experimental data (ns regime) Simulation incl. TPA and ESA - α(3)=330 cm3 GW-2 TPA contribution in the TPA+ESA simulation - α(2)=3.71 cm GW-1
100
101
Fig. 12.17 2PA spectra of heptamethine cyanines 17 (a) and 18 (b); (c) nonlinear transmittance for 18 (experimental data points and theoretical simulations using complete model including 2PA and ESA (green), including only the 2PA contribution within this latter hypothesis (blue))
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Fig. 12.18 Spectral variations of a '
Y. Bretonnière and C. Andraud
(3)
(gray circle) and of a
(2)
coefficient (open triangle)
The spectral distributions of the three and of the two-photon absorption coefficients a ' (3) and a (2 ) for molecule 18 are compared between 1,300 and 1,600 nm in Fig. 12.18. The shift in spectral distributions of these coefficients allowed to confirm the existence of a significant ESA process between 1,400 and 1,600 nm, and to deduce that the best spectral overlap between 2PA and ESA processes, required for an optimized OPL, is not reached and should be improved. This new class of compounds was shown to present many relevant advantages for practical applications (i) an easy two steps synthesis in a gram scale; (ii) a high solubility in organic solvents (the influence of concentration for OPL efficiency is illustrated in Fig. 12.19); and (iii) a good thermal stability. Furthermore, the existence of several sites allowing functionalization for a grafting in sol-gel or polymer matrices should allow the investigation of solid state OPL. As shown above, the optimization of OPL efficiency requires extremely high concentrations. The “site isolation” approach for minimizing aggregation and chromophore interactions consists in the functionalization of the chromophores by bulky dendrons. This strategy was validated in the case of the dendron decorated chromophore 19 (Fig. 12.15), which present similar absorption and optical limiting properties as the parent dyes. Furthermore these dendrons substituted NLO-active chromophores open interesting perspectives for the design of materials for solid state OPL purpose [43]. Azaboron-dipyrromethane dyes (aza-BODIPY) 20–21 (Fig. 12.20) functionalized by donor-p-conjugated systems, were designed and their 2PA and nonlinear transmittance properties in the 1,200–1,600 mm spectral range studied [44].
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Fig. 12.19 Nonlinear transmittance of compound 16 at 1,500 nm in dichloromethane solutions of different concentrations: C1 = 223.4 g L−1 (gray triangle); C2 = 281.6 g L−1 (open square); C3 = 320.4 g L−1 (black circle) Fig. 12.20 aza-BODIPY for 2PA based OPL in the IR
Whereas molecule 20 featuring a weak alkoxy donor end-group presents a rather small 2PA activity, the molecule 21 substituted with stronger amino donating moiety shows significant s 2PA values (around 1,070 GM at 1,220 nm) over the broad 1,300–1,450 nm spectral range, in the same order of magnitude than those observed for the above-mentioned cyanines dyes. Nonlinear transmittance experiments in the telecommunications spectral range have been performed on 21. These molecules were shown to present a typical optical limiter behavior: a good transmission was
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Fig. 12.21 Lasers pulses stabilization by BODIPY 22 at 1,310 nm
observed at low energy (T > 0.9), whereas beyond the nonlinear transmission threshold observed for a fluence of 0.7 J·cm−2, the laser beam intensity was strongly attenuated up to 60% at a fluence of 7 J·cm−2. As for cyanines discussed above, the simulation of the experimental curves based only on a 2PA process failed and a higher order effect related to a (2+1)-photon absorption had been taken into account, leading to a two-fold increase of the a' (3) coefficient of 620 cm3 GW−2 at 1,350 nm for molecule 21. This enhancement, which could not be interpreted by a stronger TPA efficiency, could be explained by a strong ESA contribution. Meanwhile, OPL properties of BODIPY 22 (Fig. 12.21) were studied. The authors demonstrated the efficiency of this chromophore at 1,310 nm, using it for the lasers pulses stabilization [45]. Finally a very innovating work recently performed on the lead bis(ethynyl)porphyrin polymer 23 (Fig. 12.22a) led to OPL properties over about 500 nm in the IR (1,050–1,600 nm) and for laser pulses widths spanning from 75 fs to 40 ns [46]. Nonlinear spectroscopic studies revealed that this exceptional spectral and temporal extending range could arise from the high as well broad and overlapping 2PA (14,000, 1,200 and 650 GM at 1,064, 1,450 and 1,550 nm respectively) and ESA (with for instance S2-S4 cross-sections of 1.3, 5.1 and 3.8 10−20 m2 at 1,064, 1,450 and 1,550 nm respectively) bands (Fig. 12.22b); these data were rationalized from excited singlet and triplet state dynamics (Fig. 12.22c). The optical limiting efficiency of this polymer was evaluated using fs- and ns-pulsed excitation at three different wavelengths effectively of IR spectral region. With high linear transmittances (larger than 89% for all wavelengths) and attenuation from nonlinear absorption beginning at low input energies (nearly 50 nJ for fs pulses, and 1 J for ns pulses), this system exhibits very promising OPL properties. It is worth noting that introduction of the material in a waveguide device geometry results in a strong OPL response (Fig. 12.22d). The use of OPL systems in real applications requires that chromophores can be introduced in solid optical host matrices. Organic materials have been a strategy for
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a
Chromophores for Optical Power Limiting R
b
R
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0.05 0 ps 0.12 ps 3 ps 3000 ps
0.04
N
ΔOD
Reduced 2x
N
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Pb N
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N
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n
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23 R
d
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T2 7.5 ps T1
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1
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233 ns 1E-7 0.0
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1064 nm 1300 nm
S2 S1
1200 1300 1400 Probe Wavelength (nm)
R
S4
Transmittance
c
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0.01 1E-10
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5.0x10-5
1E-8
1.0x10-4
1E-7
1.5x10-4
1E-6
1E-5
1E-4
Input Energy (J)
Fig. 12.22 (a) Lead bis(ethynyl)porphyrin polymer R=CON(CH2CHEtBu)2; (b) transient spectra at various probe delays; (c) energy level diagram and decay lifetimes; (d) optical limiting in microcapillary waveguides with ns pulsed, inset shows output energy versus input energy
OPL applications [47–53]. In the view of introducing covalently chomophores within the host material that enables polishing and other post-processing, hybrid sol-gel approach constitutes an interesting route for optical applications [54]. In this context, for example, the method developed by Ibanez and co-workers based on the growth of organic TPA nanocrystals in a sol-gel matrix was efficient [55–57]. Stilbene 3 was used as the nonlinear absorbing material. Results obtained in solid were similar to those in solution, with a TPA spectrum of stilbene 3 nanocrystals featuring a resonance at 620 nm and a TPA cross-section of 3.3 × 10−48 cm4 s/photon molecule (Fig. 12.23a). The three-photon absorption spectrum showed a main absorption band centred at 610 nm with a maximum amplitude of 9,500 cm3·GW−2 and a second resonance of 3,000 cm3·GW−2 at 520 nm (Fig. 12.23b). The optical limiting curves obtained from a f/5 configuration show properties in the visible range with a higher efficiency at 600 nm (Fig. 12.23c). Platinum based complexes were introduced in sol-gel matrices for OPL applications. It was shown that a simple dispersion of the chromophores does not provide sufficient concentration in the material to get important nonlinear absorption.
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Fig. 12.23 (a) two-photon excitation, (b) three-photon absorption spectra and (c) OPL curves of a silica based xerogel doped with stilbene 3 nanocrystals
The functionalization of chromophores with silane groups was used in order to improve the compatibility between the organic and the inorganic parts [58–61].
12.3.3
Reverse Saturable Absorbers
The reverse saturable absorption (RSA) corresponds to a three-photon absorption (5) (3PA) mechanism described by c susceptibility. Chromophores exhibiting RSA present an excited state absorption much higher than their linear (or ground state) absorption. Thus, the optical nonlinearity of such molecules comes from the increase of the excited state population during the incident pulse [62]. Both triplet-triplet and singlet-singlet absorption can play a significant role in the description of the nonlinear absorption. Thus, the optimization of nonlinear absorption requires to fulfill the following criteria: (1) a large ratio between excited state absorption cross-sections and ground state cross-section over a large spectral domain; (2) an intersystem crossing rate typically in the range of pulse duration to counter; (3) a triplet excited state lifetime larger than the pulse duration.
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641
S2 T2 τ2 # 0
σ12
σT τST
S1 σ01
τT2 # 0 T1
τ1 τT
S0 Fig. 12.24 Five-level system describing RSA
The widely-used kinetic model for RSA is based on a five-level system (with both singlet and triplet manifold) described by simple rate equation (Fig. 12.24) [47]. Metals clusters (such as cubane-like clusters [63]), CdS quantum dots from freecarrier absorption [64, 65], PbS nanocrystals in polymer solutions due to exciton bleaching in the presence of surface defects [66], stilbenic polyacetylenes [67], fullerenes [68], binuclear platinum (II) complexes [69] have been shown to be promising optical limiting chromophores exhibiting RSA at 532 nm. Recently the absorption of both triplet and intramolecular charge transfer states was shown to contribute strongly to the enhancement of OPL properties of RSA organometallic polyynes with a significant influence of the metal in the order Pt>Au>Hg>Pd (Fig. 12.25); these highly transparent systems present an excellent compromise nonlinear absorption/transparency with low optical limiting thresholds up to 0.07 J cm−2 with 92% of linear transmittance [70, 71]. Phthalocyanines [72–79] and naphthalocyanines [80, 81] derivatives have been widely studied for RSA based OPL effects; porphyrins represents also an interesting class of molecules for nonlinear absorption [82–85]. Typical the ratio k between excited state absorption cross-section and ground state absorption cross-section is 25–30. Different strategies can be considered in the view of improved OPL efficiency in these molecules. In this context, significant improvements in the nonlinear response have been obtained in phthalocyanines and naphthalocyanines organo-metallic complexes, using the heavy-atom effect to increase the triplet state effect by intersystem crossing, with an attenuation of ns pulsed laser of a factor of 540 at 532 [86, 87].
12.3.3.1
Effect of the Substituent
The role of electron withdrawing substituent such as Fluor is studied using the openaperture Z-scan technique, which measures the transmittance of the sample translated through the focal point of a focused beam. When the sample reach the focal point, the beam intensity is increased leading to an enhancement of the nonlinear absorption and therefore to the decrease of the transmittance due to RSA in the present case.
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1.0
0.8
0.8
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Transmittance
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0.6 0.4 0.2 0.0
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1
0.01 0.1 Input fluence/Jcm-2
Transmittance
1.0 0.8 0.6 0.4
Pt-D Pt-T Pt-P
0.2
0.01 0.1 Input fluence/Jcm-2 PEt3 Ph Pt PEt3 C H 8 17
C8H17
PBu3
PEt3
Pt
Pt Ph
PBu3 C H 8 13 Pt-T
PBu3 Pt
C8H13
n
1 PEt3
PEt3 Pt Ph
Ph Pt PEt3
PEt3
C8H17
C8H17
PEt3
Pt-D
MeHg
HgMe
PBu3 C H C8H17 8 17 Ph2P PPh2 Pt-P Pt
C8H17 C8H17 Hg-D Hg
C8H17 C H 8 17 cis-Pt-P
a C8H17
a
C8H17
Hg-P Hg
MeHg C8H17
C8H17
Hg-T
HgMe C8H17
C8H17
Fig. 12.25 Top: optical limiting curves (nonlinear transmittance with linear transmittance of 92%) of selected metal polyynes structures (Bottom)
Figure 12.26 displays the increase of the nonlinear transmission in perfluorinated compound 24 with respect to that observed in differently substituted systems 25–26. This trend is ascribed to the enhancement of the transition dipole moment associated with transition involved in OPL in the case of molecule 24 [88]. As in the case of phthalocyanines, an enhancement of the nonlinear absorption can be obtained by a fine modification on the para-position of the meso-phenyl rings in [TPP(4-CCTMS)_H2] and in its complexes with respect to standard analogues and the benchmark C60 (Fig. 12.27) [89]. This is ascribed to the strong influence of
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F F F
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F
24: MX = TiO 24
T / T0
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24 25 26
0,6
−200
−100
0
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z / 10-4 m
Fig. 12.26 Z-scan profiles of molecules 24–25 at 532 nm
substituent groups on the excited state absorption without any change in ground state absorption, and is illustrated by a larger change in transmission with increasing energy than in C60 or than in reference porphyrines. A similar effect has been observed in lanthanide porphyrins substituted by electron-rich moieties. [90]
12.3.3.2
Oligomerization
The oligomerization of phthalocyanines or porphyrins has been shown to lead to a significantly reduced saturation intensity of RSA with respect to the parent monomer [91–93]. The ratio between the excited state cross-section and that of the ground state is 50% weaker for the m-oxo bridged dimer of Fig. 12.28 with respect to that of the monomer; furthermore the monomer presents a higher nonlinear absorption coefficient at small laser intensities than that measured in the case of the dimer, while an inverse effect is observed at higher intensities [72]. Furthermore, Fig. 12.28
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R
R= N R
Si
N R
M N
N
R
M = 2H
TPP(4-CCTMS)_H2
M = ZH
TPP(4-CCTMS)_Zn
M = Ni
TPP(4-CCTMS)_Ni
M = GaCl
TPP(4-CCTMS)_GaCl
M = InCl
TPP(4-CCTMS)_InCl
M = SnCI2 TPP(4-CCTMS)_SnCI2
Transmittance
100
TPP_Zn_DCM TPP_Zn_DCM TPP(4-CCTMS)_Zn_DCM
10 10
100 1000 Input Peak Fluence (mJ/cm2)
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100
TPP(4-CCTMS)_Zn TPP(4-CCTMS)_N TPP(4-CCTMS)_GaCI TPP(4-CCTMS)_InCI TPP(4-CCTMS)_SnCI2 C60_Toluene TPP(4-CCTMS)_H2 Pc(I-Bu)InCI_DCM
10 10
100 1000 Input Peak Fluence (mJ/cm2)
10000
Fig. 12.27 Nonlinear optical transmission at 532 nm of standard and modified porphyrins
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Fig. 12.28 Normalized transmission with the incident pulse energy density for the monomer (circles) and the dimer (squares)
shows clearly that the m-oxo bridged dimer saturates at an energy density nearly 3.2 times weaker than that of the monomer. This type of behavior opens the way to the design of a two-layered performant device, with a first monomer layer followed by a dimer layer; this could lead to a decrease in transmission of nearly 80%. Fused porphyrin dimers revealed RSA in the NIR, which decays in a few hundred nanoseconds (Fig. 12.29a), while the comparison of the triplet excited state and ground state absorption spectra confirms this trend in the range 600–930 nm (Fig. 12.29b). In particular, this ESA is comparable to that of the ground state with peaks at 460, 625 and 870 nm with a ratio k = s ex / s gr = 6.9 [94].
12.3.3.3
Interactions with Carbone-Based Molecules
Graphene is a structure with remarkable electronic properties. The combination with porphyrins should give rise to materials with interesting properties. The hybrid material in Fig. 12.30 is based on a strong interaction between the excited state of the porphyrin, which presents a strong donor character, and the acceptor graphene
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N
Ar
N
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N Zn
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N Ar
785 nm probe
3
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0.9
2 630 nm probe 1
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b
40
60 t/ns
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σ0x
σ0
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0 20
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X = Br
4.0 σ/10-16 cm2
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1.0
X N
Ar
pulse intensity (arb units)
a normalised transmittance
N
Zn
X
400
120
600
800 λ / nm
1000
1200
Fig. 12.29 Nonlinear absorption of fused prorphyrins. (a) RSA at different wavelengths with a pump at 532 nm; (b) comparison of ground state (S0–S1) and excited state (T1–Tn) absorption spectra
1.2 NH N
HN N N HH N N
N HN NH N
N HN
C O
Tin=75%
HN O C Donor-Acceptor
HO O N C H O
OH O
ET O C
C O
NH
NH
PET N NH HN N
N NH HN N
fluorescence
Normalized transmittance
excitation
1.0
0.8
0.6
0.4 −20
TPP-NHCO-SPFGraphene TPP-NH2 graphene oxide the controlled sample C60
−10
0 z/mm
10
20
Fig. 12.30 Open-aperture Z-scan data (right) of graphene hybrid material (left) compared to those of C60, porphyrine and graphene oxide
moiety [95]. This is reflected by a fluorescence quenching due to several competitive processes such as photoinduced electron transfer (PET), energy transfer, as in the case of carbon nanotubes. The strong enhancement obtained in OPL efficiency of the hybrid system with respect to response of the parent moieties (graphene and porphyrin) is assumed to arise from the existence of these photo-induced processes (Fig. 12.30); it is worth noting that it leads to a more OPL efficient system than C60, the benchmark material in this field. This trend seems to be general to this type of graphene based material [96].
Chromophores for Optical Power Limiting
Output Fluence (J/cm2)
40 30 20
1 C60 SWNTs SWNT+TPP TPP Sn(OH)2DPP I II III
b
a
75%
10 0 0
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0.1
0.01
C60 SWNTs SWNT+TPP TPP Sn(OH)2DPP I II III
0.1 1 10 Input Fluence (J/cm2)
100
hv O NH N N HN
n
C
O N H
NHN NHN
n
C
O
NN Sn O N N
n
e− SWNT-TPP (I)
SWNT-NH-TPP (II)
SWNT-SnDPP (III)
Fig. 12.31 Top: optical limiting curves ((a) output fluence, (b) nonlinear transmittance) of C60, SWNT, parent 5,10,15,20-tetraphenylporphyrin TPP and trans-dihydroxo [5,15-bis-(3,5-dioctyloxyphyenyl)porphyrin]Tin(IV) (Sn(OH)2 DPP), SWNT+TPP, and porphyrin functionalised SWNT’s I, II, III (displayed in bottom)
Similarly, functionalized SWNT with RSA porphyrins have been shown to present a significant enhancement of OPL efficiency, with higher performances than those of the reference C60 and of the parent carbon nanotubes or porphyrin due to the combination of nonlinear scattering and RSA mechanisms, and to energy or PET between both moieties (Fig. 12.31) [97]. A similar trend is observed in the case of multiwall nanotubes covalently functionalized with conjugated metal free phthalocyanines [98].
12.3.3.4
Solid-State Results
The introduction of RSA systems in polymer host matrices is a good strategy to improve OPL efficiency with respect to the response observed in solution of the parent system [78, 99]. We will report the case of a supramolecular Zn-phthalocyanine in thin film (Fig. 12.32) [100]. Normalized transmission curves are compared in solution and in PPMA polymer (Fig. 12.32a): the drop observed around the focal point is higher in solid state (curve b) than in solution (curve a), suggesting a higher nonlinear absorption in PMMA. These curves allowed to determine relevant parameters characterizing OPL effect, such as the ratio k between the excited and ground state absorption cross-sections, the energy density output at saturation Fsat , and the nonlinear absorption coefficient b . The efficiency of the OPL process is related to high values of k and b and to a weak value of Fsat ; k and b are larger in solid state than in solution:
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Fig. 12.32 Comparison of nonlinear properties of the system in chloroform (a) or in polymer (b). (a) Open aperture Z-scan transmission; (b) OPL study
k = 18.6 and 16.2 respectively, while b presents a four order of magnitude higher value in solid than in solution (5.2 × 10−4 and 1.4 × 10−8 cm·W−1 respectively). Fsat is significantly weaker in PPMA than in chloroform (3.3 against 10.1 J·cm−1 respectively). All these results allow concluding to a better OPL efficiency in solid state, in good agreement with OPL curves displayed in Fig. 12.32b. The highest value of k in solid state could be related to weak intermolecular interactions in the polymer.
12.4
Conclusion
OPL has been widely used for ocular and sensors protection against lasers aggressions. Among different processes inducing OPL, multiphotonic absorption and reverse saturable absorption were shown to present interesting advantages with respect to other phenomena. Very low activation thresholds (as low as a few mJ·cm−2 in the ns regime) and strong laser attenuation can be obtained from the subpicosecond to the microsecond pulse regime by RSA, but only on a relatively narrow spectral band. Moreover, RSA behavior is initiated by one-photon absorption of the ground state, which means that RSA materials exhibit strong coloration. However, broadband OPL efficiency and acceptable color neutrality can be achieved by mixing several molecules, but only with a reduction of linear transmittance [101]. Such complexes have been successfully mixed in solid hosts (such as polymers and sol-gels) to obtain a neutral colorimetric aspect of the OPL [102]. On the contrary, the facts that 2PA is an instantaneous phenomena allows the use of transparent molecules and does not lead to saturation effect are of great interest for OPL applications.
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Different engineering approaches were considered, involving purely organic or metallic containing molecules. Generally for 2PA these consist in linear, 2D, dendritic or macrocyclic charge transfer systems; the charge transfer strength depends on the spectral range required for applications. A lot of molecules have been designed for the visible, NIR and IR such as telecommunications wavelengths. In addition to the optimization of 2PA efficiency in the targeted spectral range, it has been widely shown that OPL can be further enhanced by inducing ESA process, following 2PA in the same wavelength range. Heavy-metal atom that provides spin-orbit coupling enhances intersystem crossing (ISC) from an excited singlet state to a triplet state, leading to an enhancement of the OPL effect. This is described by a (2+1) PA phenomenon. For RSA, ISC molecules with efficient ESA with high ratio between excited and ground states absorption cross-sections, such as phthalocyanines or porphyrines derivatives, were shown to present improved OPL properties. The combination with other nonlinear effects, such as nonlinear scattering, or photo-induced electron transfer by interaction with carbon-based systems was shown to enhance OPL. Solid OPL materials allow post-processing and polishing. It is generally found that properties observed for the chromophore in the solid matrix are comparable to those in solution. Optical quality glasses with strong nonlinear absorption were obtained.
References 1. Hollins RC (2001) Goals, architecture, and materials for broadband eye protection. Nonlinear Opt 27:1–11 2. Van Stryland EW, Hagan DJ, Xia T, Said AA (1997) Application of nonlinear optics to passive optical limiting. In: Singh Nalwa H, Miyata S (eds) Nonlinear optics of organic molecules and polymers. CRC Press, Boca Raton 3. Wolfersberger D, Fressengeas N, Maufoy J, Kugel G (1999) Experimental evidence of laser beam self-focusing in photorefractive media from the nanosecond time-scale to steady-state. Nonlinear Opt 21:525–534 4. Sathiyamoorthy K, Vijayan C, Kothiyal MP (2008) Low power optical limiting in ClAlPhthalocyanine due to self defocusing and self phase modulation effects. Opt Mater 31:79–86 5. He C, Duan W, Shi G, Wu Y, Ouyang Q, Song Y (2009) Strong nonlinear optical refractive effect of self-assembled multilayer films containing tetrasulfonated iron phthalocyanine. App Surf Sci 255:4696–4701 6. Dneprovskii V, Kabanin D, Lyaskovskii V, Santalov A, Wumaier T, Dang TG, Zhukov E (2008) Nonlinear absorption and refraction of CdSe/ZnS quantum dots at two-photon resonant excitation of excitons. Phys Status Solid C 5:2507–2510 7. Vivien L, Riehl D, Delouis JF, Delaire JA, Hache F, Anglaret E (2002) Picosecond and nanosecond polychromatic pump–probe studies of bubble growth in carbon-nanotube suspensions. J Opt Soc Am B 19:208–214 8. Chung CK, Gohel A, Elim HI, Chen W, Ji W, Lee CG, Haur SC, Wee ATS (2006) Modified carbon nanotubes as broadband optical limiting nanomaterials. J Mater Res 21:2758–2766 9. Sun X, Xiong Y, Chen P, Lin J, Ji W, Hong LJ, Yang SS, Hagan DJ, Van Stryland EW (2000) Investigation of optical limiting mechanisms in multi-walled carbon nanotubes. Appl Opt 39:1998–2001
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Index
A Acellular flaccid artery, 328 N-Acetil-L-cysteine, 356 N-Acetylated L-phenyl alanine, 411 Acridine orange, 121, 332, 336, 449, 450 Actinic keratosis, 333–334, 395, 406, 409, 415 ADMA. See Antracene-9,10-bismethylmalonate Age-related macular degeneration (AMD), 2, 326 5-ALA. See 5-Aminolevulinic acid Alacare®, 395, 415 ALAS II encoding gene, 396 AMD. See Age-related macular degeneration 5-Aminolevulinic acid (5-ALA) amine, 20, 80, 270, 295, 411, 492, 495, 567 g-carbonyl, 411, 446 conjugates, 412, 419 dehydratase, 396 dimerisation, 414 discharge, 412 esters, 18, 402, 408–410, 412, 413, 418 free, 409, 411, 412, 418 hexyl ester, 395, 409, 411, 413 loading, 413 methyl ester, 395, 407, 409, 411, 415, 417 oligopeptide, 411 penetration, 404, 406, 408, 416 peptides, 410–411 synthetase, 494 undecanoyl, 413 Angiographic, 327 Annexin V-FITC apoptosis, 335, 337 Antracene-9,10-bis-methylmalonate (ADMA), 139, 141, 142, 271, 272
Antrin, 325 Apical, 402 Apoptosis, 34, 123, 124, 303, 322, 323, 326, 328, 329, 332, 334–337, 339, 410 Apoptotyoc, 335 Apurinic, 323 Apyrimidinic, 323 Athophysiologic alterations, 331 Athymic nude mice, 332 Attenuated total reflectance–Fourier transfer infrared (ATR–FT-IR), 363 Aurebacterium, 339 Axcan Pharma, 325 Azo-dye, 362
B Bacterial, 17, 29, 297, 298, 300, 305, 416 Bacterial siderophore, 416 Bacteriochlorins, 3, 7, 278, 316 BaFBr:Eu2+, 383 BaFBr:Mn2+, 383 Basolateral, 402 B.cereus, 339 Benzopyrridinon, 416 Benzyl-n-hexadecyldimethyl ammonium chloride ( BHDC), 195 Bioconjugation, 355–357, 363–364, 369, 371 Biodetection, 353 Biodistribution, 321, 339 Biofunctionalized, 355 Bioimaging, 353 Biolitec AG, 325 Biopassivation, 364
T. Nyokong and V. Ahsen (eds.), Photosensitizers in Medicine, Environment, and Security, DOI 10.1007/978-90-481-3872-2, © Springer Science+Business Media B.V. 2012
655
656 Biosynthesis, 4, 328, 395, 396, 398, 400, 401, 415, 419, 508 2, 2’–Bipyridine, 285, 290, 364, 563, 568, Bovine serum albumin (BSA), 319, 326 Butyric acid, 410
C Cadmium selenide (CdSe), 352, 354–356, 358, 361–366, 368, 369, 372–375, 377, 378, 380, 381, 385, 489, 490, 620, 623 CaF2:Eu2+, 383 CaF2:Mn2+, 383 Camptothecin, 338 Cancers cervical, 418 interstitial, 418 CaPO4:Mn2+, 383 Carbodiimide, 357 Carcinoma basal cell, 406, 407, 413, 416 bladder, 399, 409, 411 mammary, 399, 418 squamous cell carcinoma, 332, 333, 406, 417 Carboanhydrases, 403 CaspACE, 335 Caspase, 330, 336 Cauterization, 333 Ce3+, 383 Ceramids, 404 Cerebral microvasculature, 330, 331 Cerebrospinal fluid, 402 Cetyltrimethylammonium chloride (CTAC), 155, 175 Characterization, 128, 135–257, 545–547 Chinese hamster, 333 Chloraluminium phtalocyanine, 336 Chlorin e6 (Chle6), 3, 25, 27, 30, 278, 279, 296, 325, 359 Cholesterol, 404, 405, 413, 508 Choriocapillaris, 326 Choroidal neovascularization (CNV), 326 Choroid plexus, 402 Chromophores, 11, 12, 321, 619–649 Citrate phosphate buffer, 414 Clinical trials, 9, 136, 302, 325, 326 Clonogenicity, 338 CLSM. See Confocal laser scanning microscopy CNV. See Choroidal neovascularization Colorimetric, 335 Combination therapy, 351–385
Index Confocal laser scanning microscopy (CLSM), 329 Coordination, 290, 299, 305, 356–358, 361–363, 366, 375, 403, 414, 444, 448, 452, 568, 572 COPO. See Coproporphyrinogen III oxidase Coproporphyrin III oxidase, 396–398 Coproporphyrinogen III, 396, 397 Coproporphyrinogen III oxidase (COPO), 396, 397 Corneocytes, 404, 405 Cremophore EL (CEL), 159, 175, 177, 209, 211, 213, 235, 237, 246, 248, 250, 252, 254 Cryosurgery, 415 Cryotherapy, 333 CTAC. See Cetyltrimethylammonium chloride Cysteamine, 356, 367, 379 Cysteamin-hydrochloride, 359 L-Cysteine, 356, 363, 383 Cysview®, 395, 410 Cytochrome c, 330, 336, 394 Cytoplasm, 322, 335, 336, 340, 395, 396 Cytosol, 330, 336, 396, 402, 409, 412 Cytotoxic, 32, 122, 123, 136, 138, 139, 298, 315, 316, 330, 331, 333, 334, 336, 337, 395, 416
D Dark states, 354 Decay time, 376–379, 383, 384 Deferoxamine (DFO), 416 Dermatological patch, 415 Design, 1–36, 121–132, 291, 305, 459, 471, 473, 508, 530, 537, 538, 544, 547, 550, 552, 572, 577, 584, 598, 599, 625, 627, 629, 633, 636, 645, 649 DFO. See Deferoxamine Diazaperylene, 362, 374, 375 Dihydroethidium, 382 Dimethyl isosorbide, 414 5,5-Dimethyl-1-pyrroline-1-oxide (DMPO), 143, 459 Dimethyl sulfoxide (DMSO), 101, 320, 406 Dimyristol phosphatidyl choline, 93, 413 glycerol, 10, 28, 292, 413, 417, 474, 481, 482 Dioleyl trimethyl ammonium propane, 413 Dipeptide, 410 1,3-Diphenylisobenzofuran (DPBF), 139, 271, 453 Dipole-dipole interaction, 369
Index Disulphonate, 327 DMPO. See 5,5-Dimethyl-1-pyrroline-1-oxide DMSO. See Dimethyl sulfoxide DNA cleavage, 335, 338 damages, 29, 323 double helix, 324, 337 internucleozomal cleavage, 335 open circular, 338 polymerase, 323 relaxed, 338 superhelical, 324 topoisomerases, 337 unwinding, 337 viscosity, 323, 324 winding, 337 DUSA Pharmaceuticals, 325 Dyes sensitized solar cells, 459, 532–598 Dysprosium, 339, 456
E Eagle’s minimal essential medium (MEM), 331 E.Coli, 299–301, 339, 419 EDTA. See Ethylenediaminetetra-acetate Effala®, 395, 415 Electro-curettage, 406 Electro-migration, 407, 408 Electron microscopy, 327, 332, 535 Electron paramagnetic resonance (EPR), 142–143 Electron transfer, 322, 326, 374, 375, 381, 439, 453, 456, 459, 460, 470, 475, 478, 487, 494, 529, 571, 577, 578, 592, 595, 649 Electro-osmosis, 407, 408 Electrophoresis, 337 Endogenous, 297, 328, 391–419 Endoplasmatic reticulum (ER), 336, 339 Endothelial, 24, 303, 323, 326, 327, 403 Endothelialisation, 328 Endothelium, 328, 330, 331, 402, 403 Energy transfer, 59, 123, 137, 139, 142, 145, 149, 268, 269, 322, 339, 353, 359, 364, 365, 369–374, 376–378, 381, 383–385, 453, 470, 475, 539, 576, 584, 599, 646 Enhanced permeability and retention (EPR), 34, 403, 412, 418, 450, 459, 462 Epithelia delineate, 404 Epithelial, 326, 332, 399, 401, 402, 404, 409
657 EPR. See Electron paramagnetic resonance; Enhanced permeability and retention ER. See Endoplasmatic reticulum Erbium:yttrium-aluminum-garnet (Er:YAG) laser, 406 Erythema, 330, 331, 334 Erythroblasts, 400 Erythropoietic porphyria, 392, 397 Ethidium bromide, 332 Ethylenediaminetetra-acetate (EDTA), 300, 416, 447 Ethyl etiopurpurin, 325, 328 N-Ethyl-N(3-dimethylaminopropyl), 357 Etoposide inhibitor, 338 Eucerin®, 408 Eudragit®, 415 Eukaryotes, 395 Exogenous, 393, 398, 399, 401, 402, 415, 418 Exponential, 33, 272, 319, 367, 368, 376, 377, 399 Extinction coefficient, 146, 352, 355, 364, 370, 550, 557, 560–569, 572, 580, 589, 592, 595, 596, 622
F Fatty acids, 405, 475 FC. See Ferrochelatase Fenestrated, 402, 403, 418 Ferritin, 400, 401 Ferrochelatase (FC), 396, 398, 399 Fetal calf serum, 331 Fibroblasts, 333, 399, 417 Fitzpatrick, 333 Flow cytometry, 337 Fluorescein angiography, 327 Fluorescence lifetime, 145 quantum yield, 145–146, 248–253 Fluorescent microscopy, 332, 337 Fluorophor, 476 Folate, 21, 384 Food and Drug Administration (FDA), 136, 326, 418 Formaldehyde, 410 Förster, 369, 370, 372, 374 Foscan®, 325, 332, 334 Fospeg, 334 Fossil, 391, 469, 470, 515 Franck-Condon factors, 322 Functionalization, 14, 52, 62, 64, 80, 91, 355, 627, 636, 640
658 G GABA-ergic receptors, 397 Galenic, 405, 412–418 g-amino butyric acid (GABA), 396, 401, 402 Gamma rays, 382 Gastro intestinal tract, 402, 414, 417 Genotoxicity, 332 Genotoxic potential, 330 GIy. See Glycine Gliolan®, 395, 409 Glutamic acid, 395 Glutathione, 356 Glycerol mono oleate, 417 Glycine (GIy), 356, 395, 396, 402 Glycolic acid, 416–418 N-Glycosidic, 323 Golgi, 336 Gross edema, 330, 331 erythema, 330, 331, 334
H Haemorrhage, 327, 328, 330 Hematoporphyrin (HPD), 4, 5, 34, 136, 316, 393, 394 Hexvix®, 395, 409, 410 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), 287, 325 Histopathologic, 327, 328, 335 HPD. See Hematoporphyrin HPPH. See 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a Human breast adenocarcinoma, 334, 336 bronchial epithelial cells, 409 epidermal keratinocyte, 332 glioblastoma, 334, 336 lung carcinoma, 409, 411 squamous head, 400 transferrin receptor, 400 Human serum albumin, 34, 319 Hydrodynamic, 319 Hydrogels, 413 Hydrophilic, 17, 21, 26, 29, 275, 279, 283–287, 289, 301–304, 316, 320, 322, 332, 334, 405, 412, 413, 417, 418 N-Hydroxy succinimide, 25, 357 Hypericin, 4, 8, 275, 320, 334 Hyperkeratotic, 405, 406 Hypsochromic, 318 Hypsochromic shift, 318 Hystocytic lymphoma, 334
Index I Immune, 302, 323, 335, 415 Immunoassay, 364 Immunogenic, 323, 355 Inflammatory, 328, 401, 502 Intercalation, 323, 324, 571 Internucleosomal, 329 Intersystem crossing (ISC), 2, 6, 7, 123, 137, 146, 250, 251, 253, 276, 295, 319, 453, 475, 476, 624, 640, 641, 649 Intracellular, 16, 17, 20, 26, 301, 316, 326, 329, 334, 336, 398, 409, 411, 413, 415, 416 Intradermal, 407 Intramuscular, 407 Intraoperative adjunct, 328 Intravenous, 320, 327, 332, 409, 418 Iontophoresis, 407–408 ISC. See Intersystem crossing Ischemia, 331 Isopropano, 414, 477, 489
J Jablonski, 122, 136, 137, 140, 354 Jurkat cells, 337
K Kerastick®, 395, 409, 415, 417 Keratinocyte, 332, 334, 411, 415 Keratolytic, 407 Keratosis, 333–334, 395, 406, 408, 409, 415 Ketones, 324, 478, 511 Kinetics, 376–378, 401, 404, 412, 439, 456, 482, 578, 592, 594
L LaF3:Ce3+, 383 LaF3:Tb3+, 384 Laser therapy, 333 Lecithin Organogel, 408 Levodopa, 398 Levulan®, 122, 325, 395, 409, 415, 417 Lifetimes, 6, 145–149, 248–257, 275, 279, 318–320, 322, 339, 371, 453, 454, 499, 537, 550, 566, 584, 585, 593, 594, 639 Light microscopy, 327, 332 Light Science Corporation, 325 Lipophilic layer, 405 stratum, 405 LuF3, 383
Index Luminescence, 16, 139–141, 300, 301, 353, 356, 357, 359, 361, 362, 365–384, 453, 474, 475, 508 Luminescence anisotropy decay, 378 Luminescent, 352, 354, 359, 364, 365, 373, 379, 381 Lung, 333, 400, 409, 411 Lutetium(III), 325, 456 Lu-Tex, 325 Lymph, 330, 405 Lymphoblastic, 334 Lymphoblast leukemia, 335 Lysosomes, 301, 322, 336, 339
M Macrophage, 303, 323, 327, 330, 331, 401 Macular degeneration, 2, 122, 325, 326 Malignant, 135, 304, 328–334, 336, 337, 340, 382, 394, 395, 409 Maltose, 373, 377 MB. See Methylene blue Melanoma, 332–334, 336, 400, 402, 406 MEM. See Eagle’s minimal essential medium Membrane blebbing, 336 Mercaptoacetic acid, 355 Mercaptoethanol, 365 3-Mercapto-1,2-propanediol, 356 Mercaptopropionic, 363 N-(2-Mercaptopropionyl)-glycine, 356 Merocyanine 540, 378 Meso(4-N-methylpyridyl)porphyrin, 365 Meso-tetrahydroxyphenylchlorin (mTHPC), 316, 334 Meso-tetraphenylporphyrin, 293, 365 Meso-tetra(4-sulfonatophenyl)porphine, 361 Meso-tetra(4-carboxyphenyl)porphyrin (MTCP), 365 Mesothelioma, 399 Metal free meso-tetra(ptrimethylaminophenyl)porphine, 359 Metastatic, 334, 335 Meta-tetrahydroxyphenylchlorin, 325 Methyl aminolevulinate (MLA), 325 Methylene blue (MB), 4, 29, 275, 276, 293, 298, 302, 318, 438, 454, 455, 457, 475, 497, 502, 503, 510 Methylvinylether/maleic anhydride, 414 Metvix®, 325, 395, 409, 410, 415 Meyer-Betz’, 393 Miravant, 325 Mitochondria benzodiazepine, 396, 397 cardiolipin, 336
659 Mono-L-aspartyl chlorin e6, 325 Monosaccharides, 412 Mosaic warts, 417 Motexafin lutetium, 325 Murine, 338, 407, 411, 416, 417 keratinocyte cell, 411 Mycosis, 418 Myelocytomatosis virus, 334 Myeloid, 323 Myrmecia wats, 417
N Nanocrystals, 352, 359, 639–641 gold, 418 Nanoparticles, 16, 33–35, 199, 275, 287, 319, 364, 382, 383, 403, 418, 419, 486, 489, 490, 530, 561, 590 Necrosis, 34, 123, 124, 303, 322, 325, 328–331, 337, 339 Neoplasmic tissues, 339 Neoplasms, 334, 340, 403, 418 Neoplastic, 322, 332, 393, 394, 397–405, 415, 417, 418 Neovascularisation, 326 Neurocognitive, 328 Neurological, 328, 409 Neuropathies, 397 Nociceptive nerve, 407 Non-neoplastic, 418 Non-radiatively, 354 Novartis Pharmaceuticals, 325 Nuclear Antigen, 335 Nucleosides, 412, 502
O Occlusion, 327, 328, 331, 333, 415 Octacarboxyphthalocyanine (OCPc), 294, 365, 457 Octakis(3-aminopropyloxy) phthalocyaninato, 336 Ocular, 326, 417, 648 Oesophageal mucosa, 414 Oesophagus, 414 Oleic acid, 417 Oligopeptide, 410, 411 Optical limiting, 620, 621, 629, 636, 638, 639, 641, 642, 647 Oral leukoplakia, 418 Organelles, 34, 317, 332, 333, 336, 339, 356 Oxygen ground state, 135, 138, 139, 146, 268, 354, 453
660 P PAN. See (2-Pyridylazo)-2-naphthol Paramagnetic, 318, 319 Parkinson’s disease, 398 Passivation, 364, 377, 378 PBG. See Porphobilinogen PBGD. See Porphobilinogen deaminase Peptides, 24, 29, 290, 353, 359, 377, 378, 385, 402, 410–411, 494 Pericytes, 327 Peroxides, 273, 324 Phagocytosis, 330, 331 Pharmacodynamics, 395, 412 Pharmacokinetic, 328, 334, 394, 413 Pharmacyclics Inc, 325 o-Phenanthroline, 362, 366 Phenyl–alanine, 411 Phosphatidyl glycerol, 413 Phospholipid micellas, 355 Photocatalysis, 143, 435–438, 469–515 Photochemistry, 274, 470 Photochlor, 325 PhotoCure, 325, 395 Photodegradation, 143–144, 246–248, 296, 297, 305, 324, 437, 438, 440, 451–456, 458, 460, 496 Photodisruption, 321 Photodynamic damage, 295, 323 therapy, 2, 5, 33, 34, 121–132, 135, 136, 143, 267, 269, 287, 296, 302–305, 315–340, 352, 382–384, 394, 587 Photoexcitation, 275, 354, 365, 375, 379, 385, 460 Photofrin®, 4, 122, 136, 277, 296, 317, 320, 325, 328, 329, 334, 394 Photography, 327, 529 Photophysics, 293, 370 Photosensitiser, 1–36, 475, 476, 497–499, 502, 503, 509, 510, 513–515 Phototype, 333 Photoxicity, 319 Photrex, 325 Phthalocyanine aluminum, 22, 25, 281, 290, 291, 293, 294, 299, 331, 332 indium, 246, 284 silicon, 7, 11, 283, 287, 319, 339, 365, 374 zinc, 141, 287, 290, 293, 299, 320, 329, 333, 510, 577, 578 Placebo, 407, 415 Plantar warts, 407, 417 Plumboporphyria, 397
Index Pluronic®, 408 Pollutants, 2, 267, 433–464, 472, 473 Poloxamer, 414 Poly (lactic co-glycolid acid), 418 Poly acrylate methacrylate, 415 Poly caprolactone, 418 Poly lactic acid, 418 Polysilanes, 355 Porfimer, 122, 325, 394 Porphobilinogen (PBG), 396, 397 Porphobilinogen deaminase (PBGD), 396, 397, 399, 403, 404 Porphyrias, 392, 395, 397, 398 Porphyrin, 23, 27, 31, 32, 48, 53, 63, 64, 67, 69–76, 80–83, 90, 94–101, 122, 126–130, 277, 287, 289, 290, 293, 295, 296, 305, 316–318, 321, 324, 326, 333, 339, 360, 362, 363, 365, 366, 369, 371, 375, 383, 384, 393, 396–399, 411, 416, 441, 459, 460, 482, 483, 498, 504, 510, 575–583, 638, 639, 645–647 Pre-uroporphyrinogen, 397 Proapoptotic factor, 336 Prodrugs, 398 Proliferation, 330–332, 335–337, 399, 415 Promega, 335 Propidium iodide (PI), 337 Propylene glycol, 83, 105, 414, 417, 495 Prostanoid, 323 Prostate, 25, 418 Protoporphyrin IX oxidase, 397 Protoporphyrinogen IX oxidase, 396, 397 Psoriasis, 406 Pyknotic nuclear chromatine, 336 (2-Pyridylazo)-2-naphthol (PAN), 362
Q Q bands, 317, 324, 359, 360 Quantum dots (QDs), 33, 352–356, 364, 382, 384, 533, 620, 641 Quantum size confinement, 35 Quantum yield, 3, 6, 123, 125, 137, 139, 141, 143–147, 149, 244, 247, 249, 254, 255, 270, 272, 273, 275–281, 284–287, 290, 292–296, 298, 299, 304, 318–320, 322, 325, 326, 339, 352, 354, 355, 364, 370–374, 376–380, 383–385, 437, 449, 453–456, 458–460, 585 Quencher, 139, 141, 142, 367, 368, 370, 375, 453, 454, 493
Index R Radioresistant, 315 Radiotherapy, 382, 383 Raman, 363 RB. See Rose Bengal Reactive oxygen species (ROS), 2, 16, 123, 297, 315–317, 323, 337, 382 Rose Bengal (RB), 275, 276, 286, 287, 298, 359, 455, 457, 475, 497, 499, 501, 502, 510, 514 Rosewell Park Cancer Institute, 325 Rostaporfin, 325 Rotational correlation time, 378
S Sarcoma, 334 SCC. See Squamous cell carcinoma Schmidt-Ruppin, 334 Schrodinger equation, 353 Scintillator, 383, 384 SDS. See Sodium dodecylsulfate Sebaceous glands, 405, 413 Semiconductor, 340, 352, 353, 382–385, 435–438, 459, 474, 476–478, 483, 486, 489, 491, 494–496, 528 531, 533–542, 547, 554, 557, 558, 564, 577, 578, 584, 586, 598, 599, 623 Singlet oxygen quantum yield, 137–143, 149–246, 268, 270, 272, 273, 275–277, 281, 284, 285, 289, 290, 292–295, 298, 304, 320, 321, 355, 453, 499 Sodium dodecylsulfate (SDS), 183 Solar energy, 304, 515, 527–599 Soret band, 277, 324, 383, 576, 579, 580, 599 Squamous cell carcinoma (SCC), 332, 333, 406, 417 Stern–Volmer, 368, 369 Stokes-Einstein-Debye model basale, 404 corneum, 404, 405, 407, 415–417 granulosum, 404 lucidum, 404 spinosum, 404 stratum, 404, 405, 407, 415–417 Stratum corneum, 404, 405, 407, 415–417 Streptomyces avidinii, 364 Subcutaneously, 333, 407, 416 Subcutis, 405 Subfoveal choroidal neovascularization, 326 Synergistic effect, 415, 416, 474 Synthesis, 1, 47, 128, 136, 284, 328, 352, 395, 469, 547, 636
661 T Talaporfin, 325 TAPc. See Tetraaminophthalocyanine Taporfin sodium, 325 Temoporfin, 325 TEMP. See 2,6,6-Tetramethyl-4-piperidone TEMPO. See 2,2,6,6-Tetramethyl-4piperidone-N-oxyl Tetraalkylhydroxy substituted zinc phthalocyanines, 333 Tetraaminophthalocyanine (TAPc), 91, 357, 358 Tetracarboxyphthalocyanine, 365 Tetrahexylhydroxy, 333 Tetrakis(2,9,16,23-tert-butyl) bisphthalocyanines, 339 Tetrakis(4-sulphonatophenyl) porphyrine, 336 2,6,6-Tetramethyl-4-piperidone (TEMP), 143 2,2,6,6-Tetramethyl-4-piperidone-N-oxyl (TEMPO), 143, 270 Tetramethyl-tetra-2,3-pyridinoporphyrazine, 361 Tetra(4-pyridyl)porphyrin, 363 Tetrapropylhydroxy, 333 Tetrapyridinetetrahydropophine, 363 Tetrapyrrol, 3, 5, 13, 20, 28, 351–385, 391, 395–397, 419 Tetrasulphophthalocyanine aluminum, 499, 510, 511 indium, 253 zinc, 365, 499, 511 Texaphyrin, 3, 122, 126, 131, 325 TGA. See Thioglycolic acid Theoretical chemistry, 2, 121–132 Thioglycolic acid (TGA), 357–359, 361, 363, 365, 367, 368, 372 373, 378, 380, 381 Thiopropionic acid (TPA), 357 Thrombosis, 325, 327, 328, 330, 331 Thymidine, 335 Time-resolved anisotropy, 378 Tin etiopurpurin, 328 TOPO. See Trioctylphosphine oxide TopoGEN, 337 Topo II, 337, 338 Topoisomerase II, 337 Toxicity, 33, 122, 125, 316, 325, 326, 329, 330, 354, 356, 418, 437, 473, 585, 588 TPA. See Thiopropionic acid Transferrin (Tf), 400 Transmembranous, 322 Transplantable Rous sarcoma, 334 Trapping, 271, 273, 376, 462 Tretrakis(o–aminophenyl)porphyrin, 383 Tributylphosphine, 365, 374 Tributylphosphine oxide, 365, 374 Triglycerides, 414
662 Trioctylphosphine oxide (TOPO), 337, 338, 355, 361–363, 365, 366, 368, 373, 374, 378 Tripeptides, 402 Triplet lifetime, 244, 254–256, 286, 320, 321 quantum yield, 146, 244, 254, 255, 281, 320 Tumour ablation, 323 antigens, 323 Tunneling, 374, 375 Two-photon excitation, 15–16, 269, 381, 382, 385, 640 Type III reaction, 322
U Unguentum, 413, 417 Uropophorphyrinogen III synthetase, 396 Uroporphyrin I, 396, 397 Uroporphyrinogen I, 397 Uroporphyrinogen III decarboxylase, 396, 397 synthase, 396, 397 US Food and Drug Administration, 136, 326, 418
V Vascular occlusion, 328, 331 stasis, 323, 333 stroma, 303, 323, 332
Index Vasoconstriction, 330, 331 Vasodilatation, 330, 331 Verteporfin therapy, 326 Viability, 332, 335, 337, 339, 441 Visco-elastic, 414 Viscosimetric, 324 Visudyne®, 5, 325, 326 Vitamin B12, 326 Vitamins, 20, 402, 412 Vulval intraepithelial neoplasia, 414
W Walker, 335 Witepsol H 15, 414
X X-chromosome, 396 X-linked sideroblastic anaemia, 396 X-ray-induced photodynamic therapy, 382–384 X-ray radiation, 382, 383, 385, 393
Z Zinc sulphide, 14, 19, 200, 352, 356, 358, 359, 361–363, 366, 368, 369, 372–375, 377, 378, 380, 382, 436, 491, 494, 620 Zwitterionic amino, 409
