Advances in Physical Organic Chemistry, Volume 43

ADVISORY BOARD B. Feringa University of Groningen, The Netherlands E. Fukuzumi Osaka University, Japan E. Juaristi CINVESTAV-IPN, Mexico J. Klinman University of California, Berkeley C. Perrin University of California, San Diego Z. Rappoport The Hebrew University of Jerusalem, Israel H. Schwarz Technical University, Berlin, Germany C. Wentrup University of Queensland, Australia

Advances in Physical Organic Chemistry Volume 43

Editor J. P. RICHARD Department of Chemistry University at Buffalo, SUNY Buffalo, NY 14260-3000, USA

Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo Academic Press is an imprint of Elsevier

Academic Press is an imprint of Elsevier Linacre House, Jordan Hill, Oxford OX2 8DP, UK 32, Jamestown Road, London, NWI 7BY, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA First edition 2009 Copyright  2009 Elsevier Ltd. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (þ44) (0) 1865 843830; fax (þ44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://www.elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made ISBN: 978-0-12-374749-5 ISSN: 0065-3160 For information on all Academic Press publications visit our website at elsevierdirect.com Printed and bound in Great Britain 09 10 11 12 10 9 8 7 6 5 4 3 2 1

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Editor’s Preface

The editor is grateful to the contributing authors for their efforts in preparing the six chapters in Volume 43 of Advances in Physical Organic Chemistry. Each chapter focuses on a significant topic in organic chemistry and includes themes from chemical biology, environmental and computational chemistry. The landmark studies by Grunwald and Winstein of solvent effects on organic reactions are part of the fabric of modern physical organic chemistry. Water has many advantages as a solvent for organic reactions and the significant disadvantage that organic reagents show a low solubility in this medium. This solubility problem can be ameliorated by the use of surfactants that contain a hydrophobic part that interacts favorably with organic molecules and a hydrophilic part that interacts favorably with the aqueous medium. Niklaas Buurma describes the results of recent approaches to model the kinetics of organic reactions at such surfactants in water. Light triggers rapid photochemical reactions, in processes that are readily adapted in the design of molecular systems known as photoswitches. A recurring element in the design of photoswitches is the use photoenolization to trigger rapid removal of a protecting group in order to expose short-lived reactive organic functionality to interesting chemical and biochemical environments. The chapter by Sankaranarayanan, Muthukrishnan, and Gudmunsdottir provides a compelling discussion of the application of the results of fundamental studies on the mechanism of photoenolization to the design of photoswitches. Two chapters in this volume describe the mechanism for the formation of radicals and the impact of their reactions in strikingly different milieu. Combustion processes that convert chemical energy into heat and mechanical energy play many important roles in modern society. The chemistry of combustion is dominated by the formation and reaction of a variety of reactive radical intermediates. These include alkyl radicals, alkoxy radicals, and peroxyradicals. The gap between the complex and poorly defined chemistry that occurs during the rapid combustion of organic material and the rigorous experiments required for the systematic study of these reactions has been nicely bridged by Hayes, Merle, and Hadad. Their chapter focuses on the importance of reactive oxygen species in these combustion processes. A fundamental hypothesis of chemical carcinogenesis is that damage to DNA represents the first step in the initiation of tumor formation. The addition of the hydroxyl radical, the nitrogen dioxide radical, the phenoxide radical, and other radical species to DNA nucleobases lie on the pathways to DNA damage, and these reactions are therefore ix

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EDITOR’S PREFACE

strongly associated with carcinogenesis. The chapter by Manderville highlights recent advances in our understanding of the mechanism for direct radical addition to DNA nucleobases that have resulted from detailed characterization of the reaction products Two chapters in this volume describe the generation of carbocations and the characterization of their structure and reactivity in strikingly different milieu. The study of the reactions in water of persistent carbocations generated from aromatic and heteroaromatic compounds has long provided useful models for the reactions of DNA with reactive electrophiles. The chapter by Laali and Borosky on the formation of stable carbocations and onium ions in water describes correlations between structure–reactivity relationships, obtained from wholly chemical studies on these carbocations, and the carcinogenic potency of these carbocations. The landmark studies to characterize ‘‘reactive’’ carbocations under stable superacidic conditions led to the award of the 1994 Nobel Prize in Chemistry to George Olah. The chapter by Reddy and Prakash describes the creative extension of this earlier work to the study of extremely unstable carbodications under conditions where they show long lifetimes. The chapter provides a lucid description of modern experimental methods to characterize these unusual reactive intermediates and of ab initio calculations to model the results of experimental work. John P. Richard University at Buffalo

Contributors to Volume 43 Gabriela L. Borosky Unidad de Matema´tica y Fı´ sica, INFIQC, Facultad de Ciencias Quı´ micas, Universidad Nacional de Co´rdoba, Ciudad Universitaria, Co´rdoba 5000, Argentina Niklaas J. Buurma Physical Organic Chemistry Centre, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom Anna D. Gudmundsdottir Cincinnati, OH 45221, USA

Department of Chemistry, University of Cincinnati,

Christopher M. Hadad Department of Chemistry, The Ohio State University, 100 W. 18th Ave., Columbus, OH 43210, USA and Department of Chemistry, Winston-Salem State University, 601 Martin Luther King Jr. Dr., Winston-Salem, NC 27110, USA Carrigan J. Hayes Department of Chemistry, The Ohio State University, 100 W. 18th Ave., Columbus, OH 43210, USA Kenneth K. Laali Department of Chemistry, Kent State University, Kent, OH 44242, USA Richard A. Manderville Departments of Chemistry and Toxicology, University of Guelph, Guelph, Ontario N1G 2W1, Canada John K. Merle Department of Chemistry, Winston-Salem State University, 601 Martin Luther King Jr. Dr., Winston-Salem, NC 27110, USA Siva Muthukrishnan Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA G. K. Surya Prakash Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, USA V. Prakash Reddy Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA Jagadis Sankaranarayanan Cincinnati, OH 45221, USA

Department of Chemistry, University of Cincinnati,

xi

Kinetic medium effects on organic reactions in aqueous colloidal solutions NIKLAAS J. BUURMA Physical Organic Chemistry Centre, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK 1 2

Introduction 1 Self-aggregating amphiphiles 3 Hydrotropes 3 Micelle-forming surfactants 4 Vesicle-forming surfactants 7 3 Reactivity effects in aqueous colloidal solutions 8 An inventory of factors affecting reactivity 8 Binding location and substrate positioning 9 4 Kinetic models 10 (Pseudo) unimolecular reactions 11 Bimolecular reactions 13 The pseudophase ion exchange model 13 The pseudophase model for bimolecular reactions 13 Data analysis 14 5 Hydrotropes and organic reactivity 15 6 Micelles and organic reactivity 17 Micellar medium effects as experienced by (reactive) probes 17 Arenediazonium salts as probes of the Stern region 17 Arenediazonium salts and cationic surfactants 18 Arenediazonium salts and anionic, zwitterionic, and nonionic micelles Solvatochromic probes 20 Pseudounimolecular reactions 21 Reactions involving counterions 25 Bimolecular reactions involving neutral reactants 27 7 Vesicles and organic reactivity 28 8 Conclusions and future directions 30 Acknowledgments 30 References 31

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19

Introduction

Interest in organic reactivity in aqueous solutions has been growing steadily over the last decades and water is increasingly regarded as a viable alternative for more traditional organic solvents.1–4 Water as a solvent has many advantages: it is (generally) readily available and cheap; it is environmental friendly,5 nontoxic, and nonflammable; and it can have significant beneficial effects on organic reactions (see, e.g., Otto and Engberts,6 Hailes,7 and Rideout and Breslow8). These advantages are not recent discoveries, of course, and therefore cannot explain the increased interest 1 ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 43 ISSN: 0065-3160 DOI: 10.1016/S0065-3160(08)00001-4

 2009 Elsevier Ltd. All rights reserved

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in water as a solvent for organic chemistry. In fact, despite the advantages, water and aqueous solutions have historically been avoided by organic chemists because of two relatively straightforward reasons: (1) the low solubility of typical organic compounds in water and (2) the reactivity of water. One could therefore state that the recent change in attitude toward water in essence stems from a re-evaluation of these two factors. The issue of water’s reactivity will, to some extent, obviously remain; butyllithium and water are simply not compatible. However, the increase in subtlety of organic chemistry and improved control of reactivity leads to processes that are increasingly compatible with an aqueous environment. For example, while C—C bond formation through traditional procedures involving lithiation or Grignard reactions is preferably (though for the case of Grignard reactions no longer necessarily9,10) done under the exclusion of water, palladium-catalyzed C—C bond-forming reactions are far more tolerant of water. The Suzuki–Miyaura cross-coupling reaction frequently even benefits from aqueous reaction conditions.1 This leaves us with the issue of solubility of organic reactants in aqueous solutions. This is actually a rather intriguing issue. Arguably, the low solubility of typical organic compounds in water would render water an impractical solvent for organic reactions; reactant concentrations are limited. However, it should be kept in mind that the chemical potential  of a solute in equilibrium with its liquid/solid phase is equal to the chemical potential in the neat compound. In addition, the remarkable rate enhancements observed for ‘‘on water chemistry’’11,12 illustrate that limited solubility is not necessarily a problem.13 Hydrophobic interactions, while also resulting in the low solubility of reactants, can drive reactants together (enforced hydrophobic interactions)14 resulting in reaction rate accelerations. Driving reactants together – for example, through favorable pairwise interactions, that is, stabilized encounter complex formation15 en route to the transition state – is not necessarily beneficial, however, if reactant and/or catalyst orientations cannot be carefully controlled. In this respect, hydrophobic interactions may currently seem less convenient for the design of highly selective recognition patterns compared to traditional hydrogen bonding strategies as used in organic solvents. Nevertheless, the effects of pairwise interactions, both between reactants and between reactants and cosolutes, on rates of reaction in aqueous solutions have been studied in detail (the reader is referred to Otto and Engberts14 and references therein for further information). Further work on such aqueous systems in combination with an improved understanding of intermolecular interactions will certainly result in increasingly successful use of the ‘‘molecular recognition toolbox’’16 in aqueous solutions – with Nature providing (at least) occasional inspiration! While pairwise hydrophobic interactions can be favorably employed for the acceleration of organic reactions, one can alternatively overcome the lower solubility of many organic reactants using solubilizers. Typically, solubilizers are amphiphiles containing both a hydrophobic and a hydrophilic moiety, and as a result, they are able to effectively bridge between a hydrophobic solute and solvent water. For sufficiently hydrophobic solubilizers and at higher concentrations, interactions higher than pairwise become increasingly important. In fact, a range of different self-aggregation states

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exists for amphiphilic molecules with the exact structure and stability of the aggregates depending on factors such as shape and hydrophobicity of the amphiphile in question. When organic reactants undergo reactions while bound to amphiphile aggregates, the aggregates can cause a variety of effects depending on, among others, size, precise structure, and the potential presence of catalytic functionality within these aggregates. While remarkable successes in enhancing reaction rates have been achieved by the introduction of catalytic moieties in micellar and vesicular solutions, we limit our discussion here to medium effects on organic reactions as they occur in solutions of unfunctionalized amphiphiles. Admittedly, the distinction between medium effects and surfactants equipped with catalytic moieties may occasionally be rather artificial, as for example in the case of micelles with catalytic counterions (see, e.g., Otto et al.17) or counteranions that act as bases (vide infra). In addition, despite (and because of) the wealth in available literature on some of the topics discussed here, this chapter focuses on relatively recent developments.

2

Self-aggregating amphiphiles

Self-aggregating amphiphiles can broadly be divided into hydrotropes and surfactants. The main difference between hydrotropes and surfactants lies in the fact that hydrotropes are typically not sufficiently hydrophobic to cooperatively self-aggregate and form organized structures, whereas surfactants form distinct aggregates such as micelles and vesicles above their critical aggregation concentrations.

HYDROTROPES

The most elusive of self-aggregation processes is presented by the so-called hydrotropes;18,19 amphiphilic compounds with the hydrophobic moiety being typically too small to induce micelle formation.20 Examples of hydrotropes are butylmonoglycosulfate (BMGS), p-toluenesulfonate (PTS), and cumenesulfonate (CS) (Scheme 1).

Scheme 1

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N.J. BUURMA

Hydrotrope action is characterized by a steep increase in aqueous solubilities of otherwise sparingly soluble hydrophobic compounds at a certain threshold concentration (typically 0.1–1.0 M) called the minimum hydrotrope concentration (MHC). This solubilizing power of hydrotropes was recognized as early as 1916 by Neuberg.21 The steep increase in solubility of the solubilizate around the MHC has been attributed to a cooperative self-aggregation process since the threshold concentration for solubilization appears to be rather solubilizate insensitive.22 This cooperativity is disputed,22–24 however, as is the exact mechanism of solubilization by hydrotropes.24 It should be noted in this respect that solubilization by hydrotropes differs from that of typical salting-in compounds and cosolvents in that the increase in solubility is typically sigmoidally dependent on hydrotrope concentration. Salting-in cosolutes and cosolvents usually cause a monotonic increase in solubility without a levelling off at higher concentrations.22 A recent study, however, found no fundamental differences between hydrotropes and cosolvents and attributed the higher solubilizing power of hydrotropes simply to a larger hydrophobic moiety.25 Compared to micelle-forming surfactants, hydrotropes are often more effective in solubilizing organic solutes and can be more selective.20,22,26,27 Phase diagrams of their respective aqueous solutions reveal a crucial difference between micelle-forming surfactants and hydrotropes. Aqueous solutions of hydrotropes lack the lamellar liquid crystal region found for solutions of micelle-forming surfactants. Instead, phase diagrams for aqueous solutions of hydrotropes show a single continuous isotropic liquid phase.28,29

MICELLE-FORMING SURFACTANTS

Contrary to hydrotropes, micelle-forming surfactants spontaneously self-aggregate cooperatively above the critical micelle concentration (cmc) even in the absence of solubilizate. Typical examples of micelle-forming surfactants include sodium dodecylsulfate (SDS), dodecyltrimethylammonium bromide (DTAB), cetyltrimethylammonium bromide (CTAB), and heptaoxyethylene dodecyl ether (C12E7) (Scheme 2). Depending on the shape of the surfactant, different highly dynamic aggregates can be formed. The morphologies of different micelles (and vesicles – vide infra) are

Scheme 2

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conveniently predicted from the shape of the constituent surfactants as described using the dimensionless packing parameter P [Equation (1)] as developed by Ninham and Israelachvili.30 P¼

V ao lc

ð1Þ

Here, V is the volume of the hydrocarbon chain(s) of the surfactant, ao the mean cross-sectional (effective) headgroup surface area, and lc is the length of the hydrocarbon tail in the all-trans configuration. Surfactants with P < 1/3 are cone-shaped and form spherical micelles. For 1/3 < P < 1/2, surfactants are truncated-cone-shaped, resulting in wormlike micelles (the term ‘‘wormlike’’ is preferred over ‘‘rodlike’’ to highlight the highly dynamic nature of these micelles). For spherical micelles, one of the more commonly accepted models for the micellar structure is that proposed by Gruen (Fig. 1).31 This model features a rather sharp interface between a dry hydrophobic hydrocarbon core and a region filled with surfactant headgroups, part of the counterions (for ionic surfactants), backfolding surfactant tails, and water, namely, the Stern region. In the remainder of this chapter, intramicelle volumes with specific features such as the Stern region and the hydrophobic core will be referred to as ‘‘zones.’’ Typical radii for spherical micelles (related to the length of a typical surfactant tail) are around 5 nm. Aggregation numbers N (surfactant monomers per micelle) are typically 40–100.32 The fractional counterion binding of micelles  generally lies

1 nm

Fig. 1 Gruen’s standard picture of ionic micelles, reproduced from Gruen31, with kind permission of Springer Science and business Media.

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N.J. BUURMA

between 0.7 and 0.9 (not to be confused with the degree of ionization , which simply is 1 – ). The incomplete counterion binding results in an electrostatically non-neutral local environment for ionic surfactants. It has been estimated33–35 that the concentration of headgroups in the Stern region lies in the range of 3–5 mol dm3 though lower values have been suggested based on chemical trapping experiments.36,37 The concentration of counterions is obviously slightly less than the concentration of headgroups due to incomplete counterion binding as mentioned above. Nevertheless, local concentrations of both headgroups and counterions are sufficiently high for ion pair formation to play a role.38 The headgroup concentration in the Stern region can be estimated from known micellar and molecular dimensions,39 together with the aggregation number N and counterion binding .32 If one assumes a simple model for spherical micelles involving two concentric spheres, where one sphere represents the hydrophobic core (with a radius equal to the length of the hydrophic tail, lc) and the other sphere representing the total micelle (with a radius equal to the total length of a surfactant molecule, lc þ dStern), then the volume difference between these two spheres corresponds to the volume of the micellar Stern region. All surfactant headgroups and part of the counterions reside in this volume leading to calculated ‘‘salt concentrations’’ in the micellar Stern region between 2 and 6 mol dm3 for ionic surfactants and even higher ‘‘ethylene glycol concentrations’’ (expressed in ethylene glycol monomers) for typical nonionic surfactants (Table 1). This calculation is for spherical micelles, but a similar calculation could be used to obtain estimates of salt concentrations for ionic wormlike micelles. Such ‘‘salt concentrations’’ for wormlike micelles are expected to be increased in comparison to spherical micelles. In fact, the addition of counterions or a sufficient increase in surfactant concentration often leads to a transition from spherical micelles to wormlike micelles. As the free counterion concentration in solution increases, so does the counterion binding. As a result, electrostatic repulsion between the charged headgroups is increasingly shielded and the mean cross-sectional (effective) headgroup Table 1 Calculated salt concentrations in the micellar Stern region of selected surfactants Surfactant SDS CTAB DTAB C12E7

[Headgroup]/mol dm3 2.7–5.4 2.9–5.7 2.6–5.3 7–10a or 15–18b

The following parameters were used in the estimation of headgroup concentrations in the Stern region – SDS: lc = 16.7 A˚, dStern = 3.7–6.5 A˚, N = 64,  = 0.65; CTAB: l = 21.7 A˚, dStern = 4.0–6.6 A˚, N = 110,  = 0.8; DTAB: lc = 16.7 A˚, dStern = 4.0–6.6 A˚, N = 60,  = 0.75; C12E7: lc = 16.7 A˚, dStern = 3.6 A˚, N = 64–100. See Van Os et al.32 a Monomer concentration assuming completely stretched ethylene glycol chain. b Monomer concentration assuming backfolded ethylene glycol chain.

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surface area ao decreases accordingly. This eventually leads to the formation of wormlike micelles. Computational studies such as that by Gruen31 are now increasingly complemented by detailed experimental studies involving a combination of techniques including time-resolved fluorescence quenching and electron paramagnetic resonance. Such studies are now producing detailed information on aggregation numbers, counterion binding, hydration, and microviscosity as a function of surfactant concentration, concentration of added salts and temperature for cationic,40,41 anionic,41–49 and mixed50,51 micelles. Finally, it is stressed that all of the abovementioned micellar properties represent averages over a continuous range of highly dynamic structures. For example, the typical lifetime of a micelle is 103–102 s while individual surfactants exchange on a 106–105 s time scale.52 In addition, many features of micelles are the result of rather delicate balances between opposing forces53 (e.g., hydrophobic interactions between surfactant tails vs. electrostatic repulsion between surfactant headgroups) rendering them sensitive to temperature and concentrations of additives, and so on. Both the dynamic nature of micelles and the delicate balance of the interactions holding micelles together and shaping them strongly affect our understanding of the micellar pseudophase as a (reaction) medium; aggregation numbers, shapes, and sizes of different zones, the extent of water penetration in the hydrophobic core, and microviscosities, to name a few, are all potentially changing averages over highly dynamic aggregates.

VESICLE-FORMING SURFACTANTS54

Surfactants for which the packing parameter P lies between 1/2 and 1 are roughly cylinder-shaped, resulting in the formation of vesicles or flat bilayers for P = 1. Vesicles consist of a surfactant bilayer encompassing a volume of water and as a result can be used for encapsulation.55,56 In addition, both unilamellar and multilamellar vesicles can be formed. Often, vesicle-forming surfactants are double-tailed amphiphiles such as dioctadecyldimethylammonium bromide (DODAB) and dipalmitoylphosphatidylcholine (DPPC) (Scheme 3). Vesicle size, bilayer fluidity, membrane permeability, microviscosity, ability to bind small molecules, susceptibility to pore formation, flip-flop rates, extent of water penetration, lateral amphiphile diffusion, vesicle fusion, and kinetic medium effects (some of which will be discussed briefly below) all depend on the packing of

Scheme 3

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N.J. BUURMA

the surfactants in the bilayer. This packing itself depends on various factors including the length of the hydrophobic tails, the presence of double bonds in the hydrophobic tails, the presence or absence of cholesterol57 or other additives,58 and counterion concentration and type59,60 as well as pH.60,61 In extreme cases, pH-dependent packing parameters can even result in a vesicle to micelle transition.62,63 In addition, while micelles are highly dynamic aggregates, the dynamics of vesicles are temperature dependent and vesicles typically go through a gel to liquid-crystalline phase transition at a temperature where the vesicle bilayer fluidity and lateral diffusion of individual surfactant molecules increases considerably.64 This phase transition temperature again depends on surfactant packing and hence on the factors already mentioned above. Vesicle formation is frequently not spontaneous; in fact, vesicles are typically relatively long-lived (metastable) structures rather than stable equilibrium structures.65 As a consequence, uniform vesicles can often not be produced by simple dissolution of surfactants in aqueous solutions, and the preparation of vesicular solutions typically involves a series of manipulations in order to try to reproducibly generate uniform unilamellar vesicles.66 As a corollary, vesicular properties depend on the method of preparation,54 and once vesicles have been formed, solutions can be diluted below their critical aggregation concentrations without the vesicles falling apart.67 As is the case for micelles, the vesicular bilayer can be subdivided into a hydrophobic core and two Stern regions (in the direction orthogonal to the bilayer), again featuring incomplete counterion binding resulting in an electrostatically non-neutral environment. For a vesicle, the two Stern regions are not identical, however, as one distinguishes the inner from the outer leaflet. That this is not just an arbitrary distinction is nicely illustrated by a ganglioside that preferably resides in the outer leaflet of DPPC vesicles.68 Transfer of amphiphiles from the inner to the outer leaflet and vice versa (‘‘flip-flop’’) is generally a slow process occurring on a timescale of several hours.69 Related to the flip-flop process, vesicular bilayers are of varying permeability toward small molecules. Bilayer permeability for small nonionic organic molecules is typically good, but for ionic compounds including hydroxide, bilayer permeability appears to be a complicated function of vesicle structure and charge and may even depend on the bilayer permeability of charge-balancing ions flowing in the opposite direction.56,70–83 In addition to the inner and outer bilayer leaflet being different, ‘‘raft’’ formation has been found. Raft formation is caused by different surfactants mixing nonideally along the bilayer surface resulting in patches or rafts enriched in one of the component surfactants.84–87 For example, phospholipids with hydrophobic tails of markedly dissimilar length (>4 carbons longer) are thought to segregate into domains.88,89 Intriguingly, it has recently been found that even nonionic surfactants accumulate OH at the vesicular surface,62,63,90,91 an effect that has been attributed to the molecular orientation of water molecules in the first two hydration layers of hydrophobic surfaces.92,93 Finally, as for micelle-forming surfactants, increasingly detailed experimental information on aggregation numbers, counterion binding, hydration, and

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microviscosity are becoming available from combined time-resolved fluorescence quenching and electron paramagnetic resonance experiments.94,95

3

Reactivity effects in aqueous colloidal solutions

AN INVENTORY OF FACTORS AFFECTING REACTIVITY

From the perspective of the overall solution, both hydrotropes and surfactants can be used to solubilize reactants in aqueous solutions in order to increase overall reactant concentrations with the aim of increasing reaction rates. In addition to such an overall increase in reactant concentration, local reactant concentrations in surfactant aggregates can be increased even more provided that the reactants bind to micelles or vesicles reasonably strongly. Whereas this probably is true to some extent for hydrotropes as well, no clear examples of increased local concentrations appear to have been reported (vide infra). This may be a result of the more open, less defined aggregate structures in hydrotrope solutions. Ideally, interactions with surfactant aggregates bring together all reactants and a catalyst required for reaction. Whether this results in an increased rate of reaction depends on a series of factors. If reactants and catalyst share the same binding site (vide infra), high reaction rates are in principle achievable. However, local reaction rate constants may then be higher or lower than those in bulk water. If local rate constants are lower, this counteracts increased concentrations. The final result then is a fine balance between increased local concentrations and reduced local reaction rate constants. Whether local rate constants are in fact higher or lower depends on the local reaction medium. Key features of the local reaction medium in micelles and vesicles in comparison with bulk water are (1) the lower local water concentration, (2) the reduced polarity, (3) the high ionic strength in the Stern region, and (4) the local charge in the Stern region. All of these factors can affect reaction rate constants. If reactants and catalyst do not share the same binding site, local concentrations may still be significant but only partially overlapping, reducing reaction rates, unless of course local reaction rate constants are considerably higher than those in bulk aqueous solution. As a result, micelles and vesicles can both accelerate reactions and slow them down and it may not be immediately apparent why reaction rates vary. In order to understand these different contributions to micellar and vesicular rate effects, medium and concentration effects have to be separated first, after which the medium effects are interpreted further.

BINDING LOCATION AND SUBSTRATE POSITIONING

To understand the effects of micelles and vesicles on (organic) reactions, it is important to know where reactants are located in the micellar and vesicular pseudophase and what this region looks like in terms of a reaction medium. As mentioned above, micelles (but similar arguments are valid for vesicles) can be thought of as offering

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several binding sites in different zones. These binding sites include sites in the hydrophobic core and binding sites located in the Stern region. The Stern region is particularly flexible in binding molecules as it contains highly hydrophilic surfactant headgroups and hydrophobic domains due to backfolding of the surfactant tails31,96,97 as well as water molecules. Various techniques are suitable for the study of binding locations of organic solubilizates in micelles and vesicles. Typically, these methods have included changes in NMR chemical shifts as a result of aromatic ring current effects,98–100 paramagnetic relaxation enhancement experiments,101–103 fluorescence probing experiments,104 fluorescence lifetime experiments,105 and combined time-resolved fluorescence quenching and electron paramagnetic resonance experiments.106–108 Despite difficulties in the interpretation of the results of such studies, it is now commonly assumed that most solubilized molecules preferably bind to micelles in the Stern region99,106,108–119 and the same appears to be true for vesicles.120 However, as an illustration of the difficulty in predicting binding locations, for benzene the binding depends on surfactant structure with the preference for binding in the Stern region being higher for trimethylammonium headgroups (DTAB and CTAB) than for sulfate headgroups (SDS).121 This highlights one of the additional problems in assigning binding sites to solubilized compounds; instead of residing in only one clearly defined zone such as the Stern region, there is no reason why a solubilizate cannot be distributed over a series of different binding zones. In fact, one could subdivide the micellar pseudophase into as many zones as required and devise equilibrium constants or partition coefficients for the distribution of a solubilizate over all of these zones. This could be done, for example, to represent gradual variations in local environment along the axis of a spherical micelle such as local water concentration. However, there currently do not appear to be situations where subdividing the micellar pseudophase into more than two zones is required and it is not immediately obvious where the interface between such zones would be. Rather, some authors have chosen to describe the different distributions of reactants using simple descriptive distribution functions. For example, in the case of a micellar Diels–Alder reaction, different micellar binding sites for diene (hydrophobic core) and dienophile (Stern region) were thought to be behind the observed low micellar rate constant.17 Further studies designed to probe this possible mismatch in binding sites through kinetic studies involving dienes of markedly different polarity and paramagnetic relaxation enhancement experiments did not confirm the initial suspicion.122 However, it was noted that the relaxation enhancement experiments only provide an average binding site, without any indication of the width of the distribution in binding sites. If the distribution of one of the reactants over the micelle is rather broad, then the local concentration of this reactant in the overlap region may still not be high, even if the centers of the distributions of the two reactants over the micelle coincide. In a different study involving a combination of time-resolved fluorescence quenching and electron spin resonance, indications of slightly mismatched binding zones of pyrene and quenchers dimethylbenzophenone and 5-doxyl stearic acid methyl ester were in fact found.108,123 To worsen matters further, as a result of changing size and shape of micellar structures (vide supra), the description of the different zones may change with surfactant and counterion concentrations or temperature as well. This may lead

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to the solubilizate sensing a changing environment, the solubilizate itself may redistribute itself over different zones, or both of these occur. For example, with increasing SDS concentration, solubilized pyrene on average is found progressively in the Stern region.106 Once again, the dynamic and changing nature of colloidal structures in aqueous solutions renders one single unified description of micelles and vesicles difficult and maybe even unrealistic. Finally, reactant orientation in the micelle might conceivably influence reactivity as well, but opinions differ on this topic.124–129

4

Kinetic models

Despite the abovementioned difficulties, kinetic models reproducing typical micellar kinetics have found widespread use and typically reproduce micellar reactivity well. Whereas these models are described here in terms of micellar kinetics, they can equally be adopted for the analysis of most vesicular rate effects, as long as bilayer permeation is either slow or fast compared to the rate of reaction. The issue of bilayer permeation-dependent rates of reaction has been addressed in detail by Moss et al.55,56,74 and will not be discussed here. A brief overview of the basic kinetic models typically employed for the analysis of micellar catalysis and inhibition is presented here, but for a more detailed discussion and an overview of additional kinetic models for micelle-catalyzed reactions, the reader is referred to Khan52 and Romsted.130

(PSEUDO) UNIMOLECULAR REACTIONS

The most straightforward of the various models describing micellar kinetics is the Menger–Portnoy model for (pseudo) unimolecular reactions.131 The Menger–Portnoy model assumes rapid equilibration of the reactant of interest over bulk water and the micellar pseudophase with equilibrium constant Km. The reaction then proceeds in both pseudophases with rate constants kw and km in bulk water and the micellar pseudophase, respectively (Scheme 4).

Scheme 4

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N.J. BUURMA

This model leads to Equation (2) describing the observed rate constant kobs as a function of surfactant concentration [S], cmc, and aggregation number N; ([S]-cmc)/N corresponds to the concentration of micelles. kobs ¼

kw þ km Km  ð½S  cmcÞ=N 1 þ Km  ð½S  cmcÞ=N

ð2Þ

Traditionally, the Menger–Portnoy equation was frequently used in its linearized form [Equation (3)]. ðkw  kobs Þ 1 ¼ ðkw  kmic Þ 1 þ ðkw  kmic Þ 1 

N  ð½S  cmcÞ 1 Km

ð3Þ

It should be noted, however, that the linearization process introduces significantly nonconstant error margins, both on the y-axis value (kw – kobs)1 and on the x-axis value ([S]-cmc)1. As a result, unless datafits are carefully weighted, results from the nonlinearized model should be considered more reliable. The Menger–Portnoy model is closely related to the Berezin model employing partition coefficients instead of equilibrium constants.132 For the case where only two pseudophases (bulk water and micelle) are considered, the partitioning of the reactant is given by the partition coefficient Pm. This leads to Equation (4) describing observed rate constants as a function of surfactant concentration.
kw  1  ½Sm Vm;S þ km Pm  ½Sm Vm;S kobs ¼ ð4Þ 1 þ Pm  ½Sm Vm;S Here, kobs, kw, and km are defined as before, [S]m is the concentration of micellized surfactant and Vm,S is the molar volume of the surfactant. Both the model based on equilibrium constants and the model based on partition constant will result in micellar rate constants and micellar binding or partitioning constants. For neutral reactants, these micellar binding (or partitioning) constants are often thought to be governed to a significant extent by hydrophobic interactions.133 In terms of transition state theory, the micellar rate constant represents the activation Gibbs energy change for the reaction occurring within the micelle. In combination with the micellar binding constant, this can be used to calculate a micellar binding constant for the transition state Km,TS.134–137 The binding constant for the transition state can then be interpreted in terms of stabilizing and destabilizing interactions of the activated complex with the micelle. While for certain reactions, this may be a valuable approach, it should be kept in mind that the transition state in the micellar Stern region may be different from that in the bulk aqueous pseudophase (cf. enzyme catalysis, see Carpenter138). In addition, this approach begins to lose its appeal if the process is pseudounimolecular rather than truly unimolecular. For example, in the case of water-catalyzed hydrolysis reactions involving two water molecules in the activated complex (vide infra), the water concentration in the Stern region [H2O]m will be different from the concentration of water in the bulk [H2O]w and this should ideally be factored in (and it may even be better to use water activities instead of

COLLOIDAL MEDIUM EFFECTS ON ORGANIC REACTIONS

13

concentrations139). The resulting expression for Km,TS [Equation (5)] becomes somewhat unwieldy.140 00

Km;TS ¼

km Km k  ½H2 O2m Km ¼ m 00 kw kw  ½H2 O2w

ð5Þ 00

00

Here, variables are as defined before and kw and km are the third-order rate constants for hydrolysis. Both the Menger–Portnoy model and the model by Berezin were effectively derived on the assumption that micellar solutions contain two pseudophases, namely the micellar pseudophase and bulk water. However, both models can be expanded to take more than one micellar pseudophase into account. For example, this could be done when the micellar pseudophase is seen to consist of two separate pseudophases (zones) itself, namely a pseudophase corresponding to the hydrophobic core and a pseudophase corresponding to the micellar Stern region.140–142 If one then assumes a reaction to occur with a rate constant kS in the Stern region while the reaction does not occur in the micellar core, the expression for km includes the distribution of the reactant over different zones [Equation (6)].140   VStern PwS km ¼ kS  ð6Þ Vmic Pm Here, ks is the rate constant for hydrolysis in the Stern region, VStern and Vmic are the volumes of the Stern region and of the micelle, respectively, PwS and Pm are the water-to-Stern region and water-to-micelle partition coefficients, respectively. Equation (6) shows that, for the assumptions described above, the micellar rate constant is given by the rate constant for the reaction in the Stern region, multiplied by a factor representing the distribution of the reactant within the micelle. Further subdivision of the micellar pseudophase is (mathematically) possible143,144 but may not be warranted. BIMOLECULAR REACTIONS

If reactions are not (pseudo) unimolecular but bimolecular, data analysis becomes considerably more complicated (higher order reactions will not be discussed here, but kinetic schemes can be derived following similar approaches). Two limiting cases can be discerned: (1) the second reactant is a counterion to the surfactant or (2) the second reactant is a neutral molecule. THE PSEUDOPHASE ION EXCHANGE MODEL

For the first case, one can use the so-called pseudophase ion exchange (PIE) model.145–147 The PIE model is based on the Menger–Portnoy model but additionally allows for ion exchange to occur in the micellar Stern region where a reactive counterion competes with nonreactive counterions (Scheme 5).

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Scheme 5

The additional assumptions underlying the PIE model compared to the Menger–Portnoy model are that the degree of counterion binding  remains constant, that is, counterion exchange occurs strictly 1:1 and the micellar Stern region effectively behaves as an ion exchange resin.33,52 Based on these assumptions, one can calculate local concentrations of the reactive counterion if the equilibrium constant for counterion exchange is known. This local counterion concentration is then used in conjunction with the pseudophase model to yield second-order rate constants for the bimolecular reaction of interest. Typically, counterion competition reflects, among others, the hydration energies of the counterions, with better hydrated counterions binding most weakly. For organic counterions, hydrophobic interactions (which in essence are also related to hydration energies of course) may play a role as well. Although the assumption that counterion exchange occurs strictly 1:1 (i.e., total counterion binding remains constant) is known to break down for a variety of systems,148,149 the PIE model remains popular for the analysis of bimolecular kinetics involving reactive counterions.

THE PSEUDOPHASE MODEL FOR BIMOLECULAR REACTIONS

The second case of a bimolecular reaction occurring between two uncharged reactants A and B requires further extensions of the pseudophase model. The simplest of the possible expansions involves bimolecular reactions not involving reactions crossing the interface between the pseudophases, in other words, reactant A in the aqueous pseudophase reacts only with reactant B in the aqueous pseudophase while reactant A in the micellar pseudophase reacts only with reactant B in the micellar pseudophase (Scheme 6). To what extent the reaction occurring in each of the two separate pseudophases contributes to the overall observed reaction depends on the local reaction rate constants and local concentrations. Typically, plots representing the rate of reaction or the (related) observed second-order rate constant kobs,2 as a function of surfactant concentration go through a maximum. This maximum is related to the lowest surfactant concentration where both reactants are fully bound in the micellar pseudophase, that is, local concentrations in the micellar pseudophase are highest.

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15

Scheme 6

Addition of further surfactant then dilutes the reactants by increasing the volume of the micellar pseudophase and the observed reaction rate (or reaction rate constant) decreases. This kinetic scheme results in Equation (7) describing the observed secondorder rate constant kobs,2 as a function of micellized surfactant concentration [S]m.
kw;2  1  ½Sm Vm;S þ km;2 Pm;A Pm;B  ½Sm Vm;S



kobs;2 ¼ ð7Þ 1 þ Pm;A  1  ½SVm;S  1 þ Pm;B  1  ½SVm;S Here variables are defined as before, kw,2 and km,2 are the (second order) rate constants in water and in the micellar pseudophase, respectively, Pm,A and Pm,B are the partition coefficients for reactants A and B, respectively.

DATA ANALYSIS

For (pseudo) unimolecular reactions, the Menger–Portnoy and Berezin approaches both typically result in reasonably well-defined optimized (fitted) parameters. This is not the case for the models describing bimolecular reactions. As a result of the number of optimizable parameters in combination with their relative appearances (as products or ratios) in the rate equations, several of the kinetic parameters typically show strong covariance. This is most easily demonstrated for the PIE model, where the reaction rate within the micelle is related to the product of the local counterion concentration and the local rate constant. As a result, one can reproduce (fit) kinetic data equally well for a range of values of the counterion binding and second-order rate constant, as long as the product of these two variables remains virtually the same. This parameter correlation was found by several authors149–153 and discussed in some detail154,155 (though it is noted that the procedure described in Fig. 2 of Klijn and Engberts154 is applicable only for the reduced w2 and not for w2,156 the conclusions of Klijn and Engberts154 still stand). Similar arguments are applicable to the description of micellar kinetics involving secondorder reactions between two uncharged reaction partners. As a result, several of the parameters used in these models to reproduce kinetic data are therefore ideally determined independently. An additional issue with the models describing

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bimolecular kinetics is the definition of the micellar volume and the related problem that the reaction does not necessarily take place in the whole aggregate volume.157 Finally, these kinetic models typically require experiments at varying surfactant concentrations while assuming that the surfactant pseudophase remains the same. While this assumption is not strictly correct (vide supra), for most studies effects resulting from changing aggregate morphology appear not to be significant. The exception to this involves systems undergoing radical changes in aggregate morphology, such as sphere-to-wormlike micelle transitions.

5

Hydrotropes and organic reactivity

Compared to surfactants, reports on the effects of hydrotropes on organic reactivity are sparse. Nevertheless, the fact that hydrotropes affect organic reactivity in aqueous solutions is beyond doubt. The aqueous condensation reaction of benzaldehydes with ammonia and acetoacetic esters leading to 4-aryl-1,4-dihydropyridines was accelerated by aliphatic hydrotropes.158 This procedure was subsequently improved by condensing methyl a-aminocrotonate, methyl and ethyl acetoacetate, and substituted aromatic and alkylated aldehydes in the presence of the hydrotrope butylmonoglycosulfate under batch microwave conditions.159 In a more recent report, the same reaction was also performed under continuous microwave conditions using p-toluenesulfonate as the selected hydrotrope.160 In these cases, aqueous hydrotrope solutions were chosen over organic solvents for their ‘‘green’’ credentials. The Claisen–Schmidt condensation of benzaldehydes and acetophenones similarly benefited from the addition of a range of different hydrotropes.161 The Maillard reaction between amino acids and reducing sugars was found to be accelerated greatly by hydrotropes even below the MHC and the results were interpreted in terms of mixed aggregate formation between the reactants and the hydrotrope.162 Similarly, mixed aggregate formation between amino acids and hydrotropic sodium benzoate has been proposed as the cause for the observed enhancement in the rate of the reaction between ninhydrin and a series of amino acids.163 The alkaline hydrolysis of benzylchloride was accelerated significantly, but also rendered more selective for the formation of dibenzyl ether, by the addition of sodium cumenesulfonate. Both the increased rate and the increased selectivity were principally attributed to the increased solubility of the reactant.164 A number of hydrotropes was found to similarly enhance (up to 17-fold) the rates of reaction of the biphasic (solid–liquid) hydrolysis of phenyl benzoate, ethyl p-nitrobenzoate, and 2,4-dichlorophenyl benzoate. It was noted that the products of some of these hydrolysis reactions were hydrotropes themselves, further enhancing reaction rates.165 Such ‘‘autocatalysis’’ was also found for the biphasic alkaline hydrolysis of aromatic esters.166 In summary, reaction rates can be increased through the use of hydrotropes. However, for the currently known examples, the increased solubility of organic reactants appears to be the main reason for the observed rate enhancements. In an attempt to understand the processes involved in organic reactions in hydrotrope solutions, the group of Engberts167,168 studied a series of hydrotropes using

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17

NMR and through their effects on the pH-independent water-catalyzed hydrolysis of the hydrolytic probe 1-benzoyl-3-phenyl-1,2,4-triazole (vide infra). In particular for the least hydrophobic hydrotropes, concentration-dependent NMR studies suggest self-aggregation without the occurrence of critical concentrations. More hydrophobic compounds eventually showed a critical self-aggregation concentration, possibly indicating the transition from hydrotropes to surfactants. The effect on the hydrolysis of the hydrolytic probe again showed little evidence for the self-aggregation of the hydrotropes. Interactions between individual hydrotropes and the hydrolytic probe turned out to be relatively weak (with equilibrium constants up to 3 kg mol1 – the molality scale was used) but still appeared stronger than interactions between the hydrotrope molecules themselves. It was suggested that electrostatic repulsion between the ionic moieties of the hydrotropes can typically not be overcome by the hydrophobic interactions between the relatively small hydrophobic moieties of the hydrotropes, unless these hydrophobic interactions are further strengthened or bridged by interactions with an uncharged hydrophobic solubilizate such as 1-benzoyl-3-phenyl-1,2,4-triazole. This suggestion was subsequently confirmed by others.169,170 In this respect, a tentative link between hydrotropy, premicellar aggregation, and solubilizate-induced premicellar aggregation could be made. Furthermore, this suggestion offers an attractively simple explanation for the high solubilizing power of hydrotropes as being the result of the high availability of hydrophobic binding sites. As hydrotropes do not self-aggregate without the solubilizate, the solubilizate does not have to compete for the hydrophobic binding sites with hydrotrope molecules.

6

Micelles and organic reactivity

MICELLAR MEDIUM EFFECTS AS EXPERIENCED BY (REACTIVE) PROBES

Contrary to the situation for hydrotropes, the literature on the use of micelles in organic reactions is truly vast (for overviews see, e.g., Khan,52 Tas¸ ciog˘lu,171 and Dwars et al.172). Here, we focus on studies of the reaction medium as offered by micelles using (reactive) probe molecules. Understanding the local reaction medium offered by micelles is crucial for the selection of appropriate surfactants for micellar catalysis. A nice recent example of surfactant selection based on predicted medium effects is provided by Mubofu and Engberts.173 In addition, in particular for bimolecular reactions, the analysis of reaction data is sufficiently nontrivial (vide supra) to warrant a search for alternative procedures leading to estimates of reaction rate constants in the micellar pseudophase. Such estimates would preferably result from a thorough understanding of the reaction medium offered by the micellar Stern region and ideally from kinetic experiments using model solutions accurately mimicking the micellar Stern regions of different micelles. Because the majority of reactants appears to bind to micelles in the micellar Stern region (vide supra), we will focus on this zone. A number of approaches has been

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employed to study the local environment offered by the micellar Stern region (several of these are equally valid for reactions in vesicular solutions which we discuss below). Here, we discuss some of the more recently used methods.

ARENEDIAZONIUM SALTS AS PROBES OF THE STERN REGION

A particularly successful approach in probing the micellar Stern region was developed by the group of Romsted, who realized that the dediazoniation of substituted arenediazonium ions results in the rate-determining production of highly reactive (and rather unselective) aryl cations which will react at a diffusion controlled rate37 even with weak nucleophiles such as chloride anions and urea174 (Scheme 7). As a result, the aryl cation will react with any nucleophile in its vicinity, thereby effectively sampling its environment. In fact, the product distribution of the dediazoniation reaction represents the equilibrium distribution of the diazonium cation–anion and diazonium cation–molecule intimate pairs.37 For cetyltrimethylammonium halides, the arenediazonium moiety of a long-tailed arenediazonium salt was found to reside in the micellar Stern region based on its fluorescence quenching of Ru(bpy)3 2þ.175 With the aryl cation in the micellar Stern region, the product distribution provides a snapshot of all the nucleophiles present in that zone. This effect was first observed when comparing reaction products from a micelle-forming diazonium salt with those of a diazonium salt that does not form micelles, both with bromide counterions; the micellar dediazoniation resulted in only the corresponding bromide, whereas the nonmicellar dediazoniation resulted in only the corresponding phenol.176 This approach has subsequently been used to study a variety of systems and some of the results are summarized here.

Scheme 7

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19

ARENEDIAZONIUM SALTS AND CATIONIC SURFACTANTS

The concentrations of interfacial water, counterions, and even some additives in the micellar Stern region of examples of cationic, anionic, zwitterionic, and nonionic micelles have all been sampled using the arenediazonium trapping method. For cetyltrimethylammonium-based surfactants, the counterion concentration in the Stern region was found to increase with added NaCl and NaBr. The same study found the counterion exchange between Cl and Br to be relatively insensitive to ionic strength and surfactant concentration.177 In an extension of this work,37 a second water-soluble diazonium salt was used as a reference probe for use in model aqueous solutions. The selectivity of the micelle-bound probe for the different nucleophiles was assumed to be the same as that of the water-soluble probe – this water-soluble reference arenediazonium salt was used in all further studies employing this approach. Counterion binding  was found to be 0.75 for CTABr and 0.71 for CTACl, while the equilibrium constant for ion exchange KBr/Cl was found to be 2.6  0.4. For cationic cetyltrialkylammonium halides at 40 C and a bulk counterion concentration of 0.1 mol dm3, increasing surfactant headgroup size (and hydrophobicity) was found to result in a decreasing counterion concentration in the Stern region whereas interfacial water concentration remained more or less the same.178 Counterion binding and related headgroup hydration further vary with surfactant concentration and counterion concentration and type.178 An increase in counterion concentration in the bulk aqueous phase [X]w universally leads to an increase in the counterion concentration in the Stern region [X]m (i.e., counterion binding  increases). An increase in [X]m is also found with increasing surfactant concentration together with the concomitant decrease in Stern region water concentration. For the surfactants with the largest headgroups and at sufficiently high added salt concentrations, [X]m eventually increases linearly with [X]w suggesting that added counterions, presumably as ion pairs, freely move between the bulk aqueous phase and the micellar Stern region. Reminiscent of this increase in [X]m with increasing [X]w as a result of freely diffusing ion pairs is the behavior of added urea in solutions of cetyltrimethylammonium halide; Stern region urea concentrations are only slightly lower than bulk urea concentrations,174 and the micelle-destabilizing effect of added urea was attributed to the destabilization of the headgroup–counterion pairs in the micellar Stern region. For the cetyltrialkylammonium surfactants with smaller headgroup size, however, added counterion leads to a sphere-towormlike transition. At this sphere-to-wormlike transition, [X]m increases significantly while [H2O]m shows the corresponding decrease.53,178 In this model, the sphere-to-wormlike transition is attributed to the formation of tight ion pairs between the surfactant headgroups and the counterions, resulting in partial dehydration and compaction of the micellar Stern region. This compaction effectively corresponds to a change in packing parameter (vide supra). Importantly, it is noted that the increase in [X]m with increasing [X]w is at odds with the assumption of the PIE model that the total counterion binding remains constant.179 The sphere-to-wormlike transition of micelles of gemini surfactants was also probed through the determination of ion-pair formation of the component bolaform diammonium cations with

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counterions,38 together with arenediazonium trapping experiments on the gemini surfactants themselves.180 As for simple cetyltrimethylammonium halides, the sphere-to-wormlike transition of gemini surfactants is associated with the formation of tight ion pairs, the formation of which leads to a loss of hydration water molecules for the Stern region. Added 3,5-dichlorobenzoate counterions similarly induce a sphere-to-wormlike transition where the concentration of 3,5-dichlorobenzoate increases significantly through the transition. On the contrary, added 2,6dichlorobenzoate does not induce a sudden increase in local counterion concentration, highlighting the subtlety of the interactions resulting in micellar morphology changes.181 Combining these results suggests that the sphere-to-wormlike transition results from a delicate balance of intermolecular forces, with hydrophobic interactions driving the formation of headgroup–counterion pairs if headgroup size, counterion type, and concentration are all suitable.53,180 The effective surface area then decreases as a result of this ion-pair formation together with the concomitant release of hydration water. Within the packing parameter description, this is equivalent to an increase in P, or a surfactant shape change from cone to truncated cone, and hence a change in micellar shape from spherical to wormlike.

ARENEDIAZONIUM SALTS AND ANIONIC, ZWITTERIONIC, AND NONIONIC MICELLES

The arenediazonium probe has similarly been used to study a range of anionic, zwitterionic, and nonionic micelles. The concentrations of Cl and Br (as co-ions to the counterion Naþ) in the Stern region of sodium dodecylsulfate compared favorably with their concentrations as predicted by the Poisson–Boltzmann equation.182 Hydration numbers and local concentrations of terminal OH-groups were determined for nonionic C12E6.183 Hydration numbers were found to decrease both with increasing surfactant concentration and with increasing temperature. Hydration numbers in mixed nonionic micelles (C10E4/C12E6, C10E4/C16E8, C10E5/C16E8, C12E6/C16E8, and C10E5/C12E5 – cf. Scheme 2) were found to be around three at room temperature while the distribution of the terminal OH was found to follow a simple radial one-dimensional random walk pattern.179,184 For zwitterionic micelles of 3-(N-hexadecyl-N,N-dimethylammonio)propanesulfonate and hexadecylphosphorylcholine, the effects of added salts of Cl and Br were investigated. Interfacial Br concentrations were found to be consistently higher than interfacial Cl concentrations, but these interfacial concentrations themselves depend on the added cations.185

SOLVATOCHROMIC PROBES

Solvatochromic probes report on the polarity of the local medium through changes in their UV vis absorption spectra. Perhaps the most famous example of these solvatochromic probes is provided by the ET30 probe developed by Reichardt186 (Scheme 8).

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Scheme 8

As reporters of local medium properties, polarity in particular, solvatochromic dyes have found obvious use in the study of micellar pseudophases187 and are often used in combination with kinetic studies (see, e.g., Rodrı´ guez et al.188). For such combined studies, it should be noted, however, that the binding site of a reactant or reactants may differ significantly from the binding site of the solvatochromic probe. Hence, one has to be careful with direct comparisons. Typically, solvatochromic probes report the micellar pseudophase to be less polar than water. As an example, the ET30 value for water is 63.1,186 whereas the ET30 values for SDS, CTAB, and C12E20 are 57.5, 53.4, and 52.8,189 respectively. In principle, different solvatochromic probes can show different sensitivities to certain aspects of the micellar pseudophase such as local water concentration, suggesting that the use of a variety of probes may be beneficial. The drawback to the use of several probes is that these, a priori, do not necessarily bind in the same zone. The group of El Seoud190192 in particular has used series of solvatochromic dyes to study the medium offered by the micellar pseudophase. Using a series of solvatochromic dyes in conjunction with a series of cationic surfactants of different headgroup size, it was found that the reported polarity depends on both solvatochromic probe structure and headgroup size. This result was interpreted in terms of different binding sites of the different solvatochromic probes as caused by their different polarities. Water concentrations at the average binding locations of typical solvatochromic dyes (as determined through comparison with model aqueous solutions typically containing 1-propanol or dioxane) for cationic surfactants all lie roughly in the 35–45 mol dm3 range. The interfacial water concentration of anionic micelles (SDS) was similarly found to be in the 35–40 mol dm3 range using two ET30-related probes as well as a merocyanine dye.187,193 An increasing surfactant headgroup size was found to gradually ‘‘dehydrate’’ the Stern region.190 Similar to kinetic probes for the micellar pseudophase (vide infra), ET30 values at a range of surfactant concentrations are determined. The observed concentration-dependent ET30 values are analyzed to provide micellar ET30 values.192 Related to this, it was suggested that ET30 values

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of surfactant solutions should be used and interpreted with care as experiments using gemini surfactant at a low concentration suggested the possible existence of probesurfactant mixed aggregates.194 Finally, recent reports suggest that anionic organic counterions can displace certain betaine dyes from cationic surfactants,195,196 suggesting that solvatochromic dyes can provide further information on surfactant solutions, provided they are used with care.

PSEUDOUNIMOLECULAR REACTIONS

As mentioned in Section 4, the analysis of rate data resulting from unimolecular reactions is considerably easier than the analysis of such data for bimolecular reactions, and the same is true for pseudounimolecular reactions. Kinetic probes currently used to study the micellar pseudophase showing first-order reaction kinetics are almost exclusively compounds undergoing hydrolysis reactions showing in fact pseudofirst-order kinetics. In these cases, water is the second reactant and it is therefore anticipated that these kinetic probes report at least the reduced water concentration (or better water activity139) in the micellar pseudophase. As for solvatochromic probes, the sensitivity to different aspects of the micellar pseudophase can be different for different hydrolytic probes and as a result, different probes may report different characteristics. Hence, as for solvatochromic probes, the use of a series of hydrolytic probes may provide additional insight. Most of the pseudounimolecular hydrolytic probe reactions involve watercatalyzed pH-independent hydrolysis of activated esters, amides, or acid chlorides140,188,197–204 (Scheme 9). The hydrolysis of these probes occurs via a dipolar

Scheme 9

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Scheme 10

activated complex in which two water molecules, one acting as a nucleophile and the other as a general base, are involved with three protons in flight. Scheme 10 illustrates this mechanism for 1-benzoyl-1,2,4-triazole.205–207 The fact that most hydrolytic probes currently in use for the study of micellar pseudophases react according to the same general mechanism provides an excellent opportunity for comparisons of micellar rate effects beyond the single hydrolytic probe level. Based on the mechanism of these hydrolysis reactions, one expects the following properties of the micellar pseudophase to play a role in the increase or decrease of rate constants: (1) the lower local water concentration in the micellar Stern region, (2) the polarity of the micellar Stern region, (3) the high ionic strength in the micellar Stern region, and (4) the local charge in the micellar Stern region resulting from incomplete counterion binding. All of these properties have indeed been used to explain observed micellar rate effects. In addition, when comparing different kinetic probes, one could add (5) the average micellar solubilization site of the probe as becoming a factor as well. With respect to the reduced water concentration (1), it seems as if all but one of the hydrolysis reactions following the mechanism shown in Scheme 10 are retarded in micellar solutions (the exception being the hydrolysis of 4-nitrophenyl chloroformate 1a in cationic micelles197) and the lower water concentration in the micellar Stern region (estimated to be 45 mol dm3 for CTAB36,37 and 33 mol dm3 for SDS208) will surely play a role in this. This suggestion is further corroborated by the observation that increasing headgroup bulk and counterion binding affinity, as well as the addition of perchlorate counterions (all of which decrease the water content of the micellar Stern region), increase the micellar rate retarding effect.200 The decreased local water concentration alone is seldom sufficient, however, to explain the full rateretarding effect caused by micelles and other factors will play a role.

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The lower polarity of the micellar Stern region (2) is also widely thought to make a significant contribution to the rate retarding effects of micelles; in fact, the transition state of the type of hydrolysis reactions commonly used to probe the micellar pseudophase is thought to be more polar than the reactants, indicating that a more polar medium would be favorable for reaction to occur.197,201,209 The effects of the high ionic strength (3) appear to depend rather much on the details of the hydrolytic probe. For example, aqueous rate constants for 4-nitrophenyl 2,2-dichloropropionate 2 decrease as a function of added electrolyte (as typically happens), but the origin of this rate decrease by added electrolytes was interpreted to be different from the rate-retarding effect exerted by micelles based on activation parameter considerations.198 For another hydrolytic probe, phenyl chloroformate 1b, increasing electrolyte concentrations also decrease the rate of reaction, but this effect is negligible in comparison to the micellar rate effects.201 The effect of the local non-neutral environment (4) should be considered together with the detailed reaction mechanism of the hydrolysis reaction and together with the charge development in the activation process in particular. The electrostatically non-neutral environment offered by ionic micelles is generally thought to be the reason for the observation that rate-retarding effects exerted by anionic surfactants on this type of hydrolysis reaction are typically stronger than those by other surfactants.140,197,200,201 This stronger rate retardation by SDS was explained in terms of the development of a partial negative charge on the activated complex.201 The generation of such a partial negative charge in the activated complex is considerably less favorable in a negatively charged local environment than in any other environment. The potential impact of the local charge in the micellar Stern region is further illustrated by the rate enhancement of hydrolysis of 4-nitrophenyl chloroformate 1a in cationic surfactants, with other surfactants having decreasing rates.197 However, the exact impact of the micellar charge is rather sensitive to the detailed reaction mechanism as shown by Bunton’s observation that, for a series of differently substituted hydrolytic probes, kCTACl/kSDS increases with increasing electron withdrawing ability of the substituent.210 In subsequent work involving a series of different kinetic probes reacting by different mechanisms, Bunton et al.199,211 found a marked relation between the mechanism of the reaction and the charge of the micellar Stern region. Reactions involving rate-determining bond breaking (SN1 hydrolyses) were least decelerated by anionic surfactants, whereas reactions involving ratedetermining bond making were least decelerated by cationic surfactants. The results were interpreted in terms of partial charge formation in the activated complex and such partial charges were determined for the hydrolysis of substituted acid chlorides 3.211 If the kinetic probe itself is charged, however, the micellar excess charge may stabilize the reactant more than the transition state, resulting in a rate decrease.212 Finally, changes in the average binding location (5) of kinetic probes could in principle always be invoked to explain differences in micellar rate constants. NMR experiments have suggested, however, that for several of these hydrolytic probes, the binding site in the micellar Stern region does not change significantly with surfactant charge or length of the hydrophobic tail.197 Nevertheless, comparison of the rates of hydrolysis of 4-nitrophenyl chloroformate 1a and 4-nitrophenyl 2,2-dichloropropionate 2 shows a

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marked difference in the rate effects exerted by different surfactants. Whereas the hydrolysis of 4-nitrophenyl chloroformate 1a was accelerated by cationic micelles and most strongly decelerated by anionic micelles, the micellar rate constants for hydrolysis of 4-nitrophenyl 2,2-dichloropropionate 2 were far more similar. This difference was attributed to an ‘‘average nearness to the micellar Stern region’’ with the data suggesting that the more hydrophobic 4-nitrophenyl 2,2-dichloropropionate 2 binds more deeply within the micelle. Considering the number of factors influencing micellar rate constants, it is no wonder that not even the order of reactivity in micellar aggregates can be reliably predicted,202,203 and a separation of the micellar medium effect into its component parts would be advantageous. Not surprisingly, it is rather difficult to separate the different contributions of the different interactions as they occur in the micellar Stern region. In an attempt to solve this problem, the group of Engberts used a series of hydrolysis reactions of activated esters and amides to probe the reaction environment offered by micelles. The reactions initially involved the water-catalyzed pH-independent hydrolysis reactions of p-methoxyphenyl dichloroacetate 4 and 1-benzoyl-3-phenyl-1,2,4-triazole 5, as extensive information on the rate retarding effects of added cosolutes on this reaction was available.213–225 It was initially140 found that the rate-retarding effects of DTAB, CTAB, SDS, and C12E7 micelles could be reproduced using aqueous mimicking solutions containing only headgroup mimics tetramethylammonium bromide (for DTAB and CTAB), sodium methylsulfate (for SDS), and tetraethyleneglycol (for C12E7). This observation led to the conclusion that the micellar retardation of the hydrolysis of 4 and 5 is dominated by a salt effect. In this description, the salt effect includes the effect of the hydrophobic groups forming part of the surfactant headgroup such as the methyls of the trimethylammonium headgroup of CTAB. For nonionic C12E7 micelles, the term ‘‘salt effect’’ denotes the effect of the oligoethyleneoxide moieties in the C12E7 headgroup even though these are not ionic. The Stern region was therefore regarded as a separate phase with a high surfactant headgroup and counterion concentration. However, it was noted that the discrepancy between the micellar rate constant and the rate constant in the model compound solution was largest for 4, which was known to be more sensitive toward hydrophobic interactions than 5. In addition, the solvatochromic ET30 probe indicated a much more hydrophobic environment and other authors similarly found systems for which a model solution only mimicking the surfactant headgroups was insufficient to reproduce properties of the micellar pseudophase.201 The Hammett -value for hydrolysis of substituted 1-benzoyl-1,2,4-triazoles 6a–f could similarly not be reproduced using a model solution mimicking ionic interactions only.204 These observations were taken as an indication that further interactions needed to be included in a subsequent study.204 The most obvious candidate was the interaction with the hydrophobic micellar tails, and the model solution originally containing only ionic headgroup mimics was extended with a mimic for the hydrophobic tail, namely 1-propanol (as the longest unbranched single-tail alcohol miscible with water in all ratios). It was found that the sensitivity of the hydrolysis of substituted 1-benzoyl1,2,4-triazoles 6a–f to added 1-propanol and tetramethylammonium bromide varied

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Table 2 Molalities m and concentrations c of 1-propanol and tetramethylammonium bromide (TMAB) in solutions mimicking the Stern regions of DTAB and CTAB micelles DTAB 1

1-Propanol TMAB Water

CTAB 3

1

m (mol kg )

c (mol dm )

m (mol kg )

c (mol dm3)

ma (mol kg1)

9.3 1.5

5.1 0.8 30

5.0 4.9

2.6 2.6 29

7.7 5.7

Concentrations were determined using the experimentally determined densities of the solutions. a Make-up of the ‘‘second-order solution.’’

in a way that allowed hydrophobic effects of surfactant tails (mimicked by 1propanol) and ionic effects of surfactant heagroups (mimicked by tetramethylammonium bromide) to be separated using singular value decomposition. This approach resulted in a quantitative separation of the hydrophobic and ionic effects exerted by DTAB and CTAB micelles (Table 2). To correct for nonideal behavior of the 1-propanol and tetramethylammonium at these high concentrations, a further optimization of the mimicking solution was required. A ‘‘second-order solution’’ for CTAB was elaborated using the ‘‘first-order solution’’ as a starting point. This second-order solution was found to reproduce not only the micellar rate constants for the hydrolysis of the substituted 1-benzoyl-1,2,4-triazoles 6a–f but the hydrolysis rate constant for 5 and the ET30 value with good accuracy as well.204

REACTIONS INVOLVING COUNTERIONS

Literature on reactions involving micellar counterions is particularly rich and for good reasons. The local concentration of counterions in the micellar Stern region is extremely high compared to typical aqueous solutions. As a result, bimolecular reactions involving bases such as hydroxide and acetate or oxidants such as perchlorate can be accelerated significantly by using these as a counterion for cationic surfactants. Discussion here will be restricted to a selected number of relatively recent examples of particular interest. This should not, however, distract from the merit of many of the other publications in this field. The kinetic profile of reactions involving the micelle’s counterions is frequently analyzed in terms of the PIE model. Despite the known shortcomings of this model, it nevertheless typically reproduces kinetic data rather well – though one should remain conscious of the potential problems related to parameter covariance (vide supra). Despite the sometimes impressive reaction rate enhancements, second-order rate constants for most bimolecular reactions involving counterions actually decrease,126,127,209,212,226–232 with just a few remaining virtually constant233 or increasing.232,234–238 As discussed (vide supra), micellar rate constants for (pseudo) unimolecular reactions are frequently lower than rate constants in water. Many of the

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arguments for rate constant decreases for (pseudo) unimolecular reactions are valid for reactions involving reactive counterions as well. For example, stabilization of a developing partial charge is a factor in reactions involving reactive counterions as well238 and can even lead to interesting differentiation between reaction pathways.227 Similarly, the micellar Stern region has been found to be less polar as reported by an increased Hammett  for micellar reactions compared to reactions in bulk water.126,129,212,239 As the reasons for rate retardations have been discussed for pseudounimolecular probe reactions already, we focus on the reported increased bimolecular rate constants. Two main reasons for increases in bimolecular rate constants come to the fore: (1) dehydration of the reactive counterions and (2) charge delocalization during the activation process leading to the transition state. An intriguing third reason (although, admittedly, not strictly equating to an increased bimolecular rate constant) is (3) the increase in local counterion concentration as a result of comoving counterions. We will discuss these three effects in order. In virtually all cases, bimolecular reactions involving reactive counterions involve cationic surfactants and anionic (basic and/or nucleophilic) counterions. Typical water concentrations in the Stern region are lower than in bulk water and local counterion concentrations are high. As a result, the counterions are partially dehydrated. This partial dehydration renders these counterions more reactive. Such effects have been found, for example, for the SN2 reactions of alkyl naphthalene-2-sulfonates with Br and OH, where increasing headgroup hydrophobicity resulted in an increase in the second-order rate constant for the reaction with Br (but not for the more strongly hydrated OH).232 In one example, F which is normally strongly hydrated was found to catalyze the dephosphorylation of p-nitrophenyldiphenyl phosphate even in competition with the a-effect nucleophile isonitroacetylacetone.228 The effect of charge delocalization en route to the activated complex is the result of the relatively nonpolar micellar environment; compared to bulk water, charges in the micellar pseudophase are less stabilized by interactions with their environment (cf. stabilization of developing charges by the electrostatically non-neutral environment for (pseudo) unimolecular reactions). This effect was found for the dehydrobromination reaction of 2-(p-nitrophenyl) ethyl bromide234,235 and the dehydrochlorination of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane.235 Finally, as an example of the effect of ion-pairing of surfactant counterions with co-moving ions, the reaction of methyl 4-nitrobenzenesulfonate with Br was accelerated when the concentration of Br in the Stern region was increased through the appropriate choice of cation.237

BIMOLECULAR REACTIONS INVOLVING NEUTRAL REACTANTS

Compared to micellar bimolecular reactions involving reactive surfactant counterions, considerably less work has been done on micellar bimolecular reactions involving two neutral reactants. We will discuss here micellar effects on cycloaddition reactions though this is by no means the only system for which micellar catalysis has been investigated (see, e.g., Bonollo et al.240).

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Diels–Alder reactions provide one of the prime examples of beneficial effects of aqueous solvents. Following extensive research of the aqueous acceleration of Diels–Alder reactions,6 it is now thought that the two main reasons for this acceleration are enforced hydrophobic interactions and hydrogen bonding. Given the beneficial effects of water on the Diels–Alder reaction, additional micellar acceleration was envisaged. However, it turned out that micellar catalysis of the Diels–Alder reaction using unfunctionalized surfactants was less successful than hoped241 (with one notable exception17). Attempts at catalysis of Diels–Alder reactions using chiral surfactants resulted in low e.e.,242 and for cycloaddition reactions in general, only modest rate enhancements were found,122,157,243–245 which typically result from increased local reactant concentrations counteracted by decreased local second-order rate constants. In some cases, no rate effect or even rate retardation was found.17,246 Reduced hydrogen bonding to the transition state was found to be a key contribution to the rate-retarding effect through a simultaneous study of a Diels–Alder reaction and its retro Diels–Alder reaction.245 Both the micellar rate constant for the Diels–Alder reaction and for the retro Diels–Alder reaction were found to be decreased compared to bulk water. This decreased micellar rate constant was compensated by increased local reactant concentrations for the Diels–Alder reaction, resulting in a higher reaction rate, a concentration effect not ‘‘available to’’ the unimolecular retro Diels–Alder reaction. A further study17 resulted in a combination of initially confusing findings. Whereas the second-order micellar rate constant for a series of Diels–Alder reactions was found to be exceptionally low compared to bulk water, endo/exo ratios, and Hammett -values still very much resembled those for aqueous solutions. In combination with paramagnetic relaxation enhancement studies, the low micellar rate constant was attributed to different micellar binding sites of diene and dienophile. This conclusion was partially refuted, however, by a subsequent study122 involving reactants designed to bind in different micellar zones. This study showed that the main factor in decreasing rate constants for Diels–Alder reactions is the local water concentration, which was estimated to be rather low, namely 10–15 mol dm3, at the micellar reaction site. This local water concentration was similarly found to provide a good model for the micellar reaction site for 1,3-dipolar cycloadditions.157 These 1,3-dipolar cycloadditions are catalyzed rather considerably by micellar solutions, however, because they are less sensitive to solvent effects. As a result, micellar rate constants are decreased less compared to bulk water, but local concentration effects remain operative. Finally, part of the decreased hydrogen bonding effects of the micellar pseudophase (compared to bulk water) were reinstated in a study employing a carefully designed combination of specific acid catalysis, surfactants with hydrogen bonding capacity and Lewis acid counterions.173

7

Vesicles and organic reactivity247

Micelles offer a variety of highly dynamic binding sites, which makes their description as a reaction medium an intricate affair. Whereas vesicular dynamics are slower than micellar dynamics, this by no means results in more straightforward descriptions of the

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vesicular pseudophase as a reaction medium. To an important extent, this is caused by the fact that vesicles are not equilibrium structures. As a result, it can be difficult to compare vesicular effects on organic reactions even if the same surfactant is used, as the properties of the vesicular solutions themselves may depend on the method of preparation. In addition, reactivity could be affected by membrane fluidity differences (below and above Tm) and membrane permeability of one or more of the reactants. Such membrane permeability effects have been discussed in detail by Moss et al.55,56,73,75,248 and will not be discussed here. Most of the characteristics invoked to explain rate accelerations and rate retardations by micelles are valid for vesicles as well. For example, the alkaline hydrolysis of N-methyl-N-nitroso-p-toluenesulfonamide is accelerated by cationic vesicles (dioctadecyldimethylammonium chloride). This rate acceleration is the result of a higher local OH concentration which more than compensates for the decreased polarity of the vesicular pseudophase (compared to both water and micelles) resulting in a lower local second-order rate constant.70 Similar to effects found for micelles, the partial dehydration of OH and the lower local polarity are considered to contribute significantly to the catalysis of the Kemp elimination249–251 by DODAB vesicles.252 Even the different sensitivities of reactions following associative and dissociative reaction mechanisms, as found for micellar systems,199,253 were found for vesicles as well.254 As discussed above, the packing parameter for vesicle-forming surfactants differs from that for micelle-forming surfactants. One would expect this to have an effect on the properties of the Stern region as a reaction medium. The high vesicular counterion binding  (compared to micelles) of 0.87 for small vesicles and 0.96 for large vesicles appears to confirm such a difference.255 Nevertheless, arenediazonium trapping experiments for DODAB255 suggest Br concentrations of 1.2 mol dm3 for small vesicles and 1.6 mol dm3 for large vesicles, not dissimilar from typical values for micellar solutions without added salt.178 Vesicle size was found to affect reaction kinetics for the alkaline hydrolysis and thiolysis of p-nitrophenyl octanoate, with small vesicles being more effective as catalysts, and it was concluded that this size dependence itself was brought about by differences in ion dissociation, substrate binding constants, and intrinsic reactivities.256 Similarly, the decarboxylation of 6-nitrobenzisoxazole (6-NBIC)249,257,258 was found to be faster in incomplete surfactant assemblies than in fully formed vesicles.259 Contradicting results were found, however, for vesicle-catalyzed Diels–Alder reactions, where the reaction rate in the absence of catalytic Cu2þ does not appear to be size dependent260 but in the presence of Cu2þ it is.261 Similarly, vesicular reactivity is dependent on bilayer fluidity and Arrhenius (or Eyring) plots for the decarboxylation of 6-NBIC show a break around Tm.262–264 For the Kemp elimination in different bilayers, it was found that the bilayer for which kinetic data had been gathered below its Tm was least effective as a catalyst.252 Ester hydrolysis has also been found to be faster above Tm.265 For the decarboxylation of 6-NBIC, the increase in catalytic efficiency was attributed to different aggregate surface dynamics based on the observation that vesicles above Tm showed intermediate activation parameters between vesicles below Tm and micelles.263 One could, of course, discuss causality here considering the fact that many of the bilayer

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properties change significantly at Tm and improved substrate solubilization has also been used as an explanation for the superior catalytic properties of vesicles above their Tm.256 There may even be a link between the enhanced rate effects of small vesicles and vesicles above their Tm, as Tm is lower for small (more curved) vesicles.266 The effect of additives betrays the intricacy of the balance of rate effects even more. The addition of cholesterol to catalytic bilayers has been found to be beneficial for the Kemp eleminiation252 but to inhibit the decarboxylation of 6-NBIC.264 In general, the effects of additives on the decarboxylation of 6-NBIC appear to subtly depend on the structure of the hydrophobic tail and hydrophilic headgroup of additives.264 Similarly subtle effects were found for the Kemp elimination and nucleophilic attack by Br and water on aromatic alkylsulfonates; depending on the choice of additive, hydrogen bonding effects, reactivity of partially dehydrated OH, and local water concentrations all played a role and vesicular catalysis could be increased or decreased.116,267

8

Conclusions and future directions

The highly dynamic colloidal structures described in this chapter result in considerable complexity in behaviors. This complexity has resulted in relatively slow improvement in our understanding of colloidal systems despite the fact that the structure of micelles was in essence described almost a century ago already.268 Results from a series of relatively recent approaches to describe colloidal aggregates are now beginning to coalesce into a model of colloidal structures incorporating the dynamic and nonhomogeneous structures of these aggregates. Further work on mapping out binding locations and local reaction media offered by aqueous colloidal structures will benefit from continuous effort using all of the approaches described in this chapter. It is anticipated that combining the results from such detailed studies will eventually result in meaningful predictions of binding sites and local medium properties. Such predictions in turn can then be used to carefully select or design amphiphiles to assist organic reactivity in aqueous solutions. Based on currently available work, this situation would be achievable first for micellar systems with vesicular systems following suit. The extremely dynamic structure, if one can even speak of a structure, of the aggregates formed by hydrotropes may well continue to escape accurate description for some time to come. A situation that is only worsened by an apparent lack in interest in, or fear of, these systems in academia. It is tempting to speculate about the reasons for the observation that surfactant aggregates often do not appear to be as effective as hoped. In the author’s opinion, the reasons for this could well be (1) the choice of reactions and (2) the way in which reaction rates are compared. Starting with the first point, it appears as if micellar and vesicular catalysis is often studied for reactions for which water is intrinsically a good solvent, that is, a better solvent than less polar organic solvents. By using the less polar pseudophase formed by surfactant aggregates as a ‘‘base’’ for catalysis, part of

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the beneficial effects of water as a solvent will be lost. In that respect, micelles and vesicles may be viewed in a far better light if micellar or vesicular catalysis of reactions for which water is not a good solvent were to be studied. Regarding the second point, many studies (correctly) report relative rate enhancements or compare first- or second-order rate constants. When comparing micelle- or vesicle-catalyzed reactions with reactions in bulk water, however, it should not be forgotten that reactant concentrations can also be increased as a result of the solubilizing effects of surfactants. The increased reactant concentrations should then result in higher overall reaction rates as long as the added reactants do not disrupt aggregate formation.

Acknowledgments The EPSRC is thanked for support [grant number EP/D001641/1]. Prof. Dr. Jan B. F. N. Engberts, Prof. Radha Ranganathan, and Dr. Lavinia C. Onel are thanked for fruitful discussions. JBFNE and LCO are further thanked for constructive criticism on the manuscript.

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Photoremovable protecting groups based on photoenolization JAGADIS SANKARANARAYANAN, SIVA MUTHUKRISHNAN and ANNA D. GUDMUNDSDOTTIR Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA 1 2

Introduction 39 Photoenolization 41 Photoenolization of o-alkyl arylketones 41 Photoenolization of 2-nitrotoluene 45 3 Photorelease via photoenolization 47 Photoelimination from b-substituted o-alkyl arylketones 48 Photoelimination from a-substituted o-alkyl acetophenone derivatives 54 Photorelease via photoenolization followed by intramolecular lactonization 57 Photorelease from nitrotoluene derivatives 66 4 Conclusion 72 Acknowledgments 72 References 72

1

Introduction

In the past decade, a series of useful molecular systems known as phototriggers, photoswitches, photocaging groups, or photoremovable protecting groups have been used in a wide variety of applications. Their utility has spanned a wide variety of areas, including the release of fragrances from household goods (Fig. 1), aiding in multistep syntheses, and drug and gene delivery.1–11 Photoremovable protecting groups also allow biochemists to release bioactive compounds in living tissue with both high temporal and spatial accuracy, thus making it possible to study physiological events such as enzyme activity, ion channel permeability, protein folding, and muscle contraction by ATP hydrolysis. For example, nitric oxide has only recently been shown to be involved in various bioregulatory processes, such as blood clotting, blood pressure control, and neurotransmission.12–16 Additionally, it has just been determined that macrophages, blood cells that ingest foreign substances, kill cancerous cells and intracellular parasites by releasing large amounts of nitric oxide. However, since nitric oxide is a reactive molecule, with a half-life of only a few seconds in physiological settings, it is convenient for researchers to use photoremovable protecting groups to liberate in a controlled manner nitric oxide in biological systems and investigate the resulting physiological responses.17 In the same way, photoremovable protecting groups are being developed to release nitric oxide for photodynamic therapy applications.18 39 ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 43 ISSN: 0065-3160 DOI: 10.1016/S0065-3160(08)00002-6

 2009 Elsevier Ltd. All rights reserved

40

J. SANKARANARAYANAN ET AL. (a)

(b)

Fig. 1 Caging fragrance molecules to a photoremovable protecting group (a) and releasing the fragrance molecules by exposure to sunlight (b).

Photorelease mechanisms can be divided into two main categories: those in which directly cleave from a reactive excited state of the photoremovable protecting group and those in which the cleavage can take place from the ground state of a high-energy photoproduct that has a low-energy barrier for releasing the protected molecule. Photocleavages from excited states can result in very rapid photorelease although the formation of highly reactive radical intermediates may lead to undesirable by-products. In comparison, the efficiency of cleavage from ground state photoproducts will depend on both the structure of the molecule being released and the protecting group; this efficiency is therefore expected to be different for dissimilar groups. Detailed knowledge of the photorelease mechanism makes it easier to determine the possible shortcomings of the photoremovable protecting groups for each application. For example, knowledge of the actual release rate in physiological conditions is a prerequisite for using photoremovable protecting groups to study any time-dependent biological responses because the rate of the photorelease must exceed that of the biological response being investigated. The ideal conditions for fragrance delivery in detergents are a slow release with low quantum yields so that the scent will linger.5,19,20 In contrast, investigation of protein folding requires photoremovable protecting groups with release rates shorter than a submillisecond.21–27 At the same time, both of these applications need photoremovable protecting groups that are not quenched by molecular oxygen. The above examples represent only fractions of the photoremovable protecting groups that are being developed and used for applications; thus, it is clear that the choice of photoremovable protecting group is critical, depends on the system under investigation, and must be tailored to each application.

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

41

Moreover, there is a need for new photoremovable protecting groups that can satisfy the requirements of diverse applications. Understanding mechanistic details makes it easier to select the most suitable photoremovable protecting group for each specific application and to design new photoremovable protecting groups that can be tailored to specific applications. This chapter focuses mainly on photoremovable protecting groups that rely on photoinduced intramolecular H-atom abstraction to form photoenols that then release their protected or caged molecules. However, we will also compare these photoremovable protecting groups to others that release their protected molecule by different mechanisms. The most widely used photoremovable protecting groups are o-nitrotoluene derivatives, but since this group has been reviewed recently,2,11,28–30 we will focus more on others that also rely on photoenolization to release their protected molecules. The examples in this chapter do not offer a comprehensive review of the literature but rather illustrate the mechanisms of photorelease from several photoremovable protecting groups, making it easier to determine their ability and limitations in distinct applications.

2

Photoenolization

PHOTOENOLIZATION OF o-ALKYL ARYLKETONES

Intramolecular g-hydrogen abstraction in o-alkyl phenyl ketones or o-nitrotoluenes results in the formation of photoenols, which will regenerate their starting materials and can therefore be described as a photochromic system (Scheme 1).31–36 Several photoremovable protecting groups have been designed that, on exposure to light, undergo photoenolization followed by the elimination of the caged substrate. Reketonization of the photoenols competes with the elimination of the protected substrate. Thus, for better understanding of the release mechanism from these photoremovable protecting groups, we will describe the mechanisms of photoenolization for o-alkyl arylketones and o-nitrotoluene. Several researchers have investigated the photoenolization of various o-methyl acetophenone and o-methyl benzophenone derivatives.37–41 The mechanism of photoenolization of o-methyl benzophenone, 1, has been studied with laser flash photolysis and can be described as follows (Scheme 2): Irradiating 1 forms its first H

O R

O

hν

R R

O

+

H

hν ′ or Δ Z-photoenol

Scheme 1 Photoenolization of o-alkyl arylketones.

E-photoenol

42

J. SANKARANARAYANAN ET AL.

O

O

*

O

H

hν

1

2

T1K of 1

ISC 1,5-Hydrogen shift H O O H Z-3

E-3

Scheme 2 Photoenolization of o-methyl benzophenone 1.

singlet excited state, which undergoes efficient intersystem crossing to the first excited triplet ketone (T1K) of 1.37,42–48 The lifetime of T1K of 1 has been estimated to be around 2 ns. Intramolecular H-atom abstraction quenches T1K of 1 effectively and yields biradical 2, which has a maximum absorption of around 520 nm and a lifetime of 30 ns. Biradical 2 decays by intersystem crossing to form photoenols Z-3 and E-3. In ethanol, photoenols 3 have maximum absorption at 420 nm, and E-3 and Z-3 are formed in the approximate ratio of 1:4. The ratio of the Z and E photoenols is affected somewhat by the solvent; however, the Z-photoenol is always the major product. Photoenol Z-3 decays back to 1 through a sigmatropic 1,5-H-atom shift. The lifetime of Z-3 in ethanol is between 3 and 4 ms, whereas E-3 has a much longer lifetime that has been measured to be between 3 and 7 ms in ethanol.46,47 Enol E-3 reketonizes via the aid of the solvent, and the reketonization can be facilitated with acids or bases.49 Furthermore, photolysis of 1 in CH3OD or CH3OT leads to the incorporation of deuterium or tritium atoms on the methyl group of 1 (Scheme 3), thus verifying that reketonization of E-3 is solvent-assisted.50 Enol E-3 undergoes electrocyclic ring closure to form cyclobutanol 4; however, since 4 can revert back thermally, its yields are most likely underreported.51–56 Yang and Rivas reported the first successful trapping of photoenols by using dienophiles to form Diels–Alder adducts, 5.57 The rate of trapping E-3 with dienophiles such as acetylenedicarboyxlates has been reported to be in the order of 102 M 1 s 1.39 Sammes et al. demonstrated that only the E-photoenol formed from o-methyl benzaldehyde is trapped in Diels–Alder reactions, presumably since the Z-photoenol is too short-lived to be intercepted.58 Currently, photoenols have been shown to be indispensible in organic synthesis and have been intercepted in Diels–Alder reactions to make various antitumor agents, antiretroviral agents, and natural products.59–64

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

43

R R

R

R OH

Ph O

Diels–Alder

Electrocyclic ring closure

O

H

H E-3

5

4

CH3OD

CH2D O

1-d

Scheme 3 Interception of photoenol E-3.

H O

Z-7 Cyclohexane Benzene Methanol Dimethyl sulfoxide

50 ns 30 ns 2600 ns 35,000 ns

Scheme 4 Solvent dependency of the lifetime of photoenol Z-7.

Wagner and coworkers have shown that the lifetime of Z-7, formed from 2,4dimethyl benzophenone (6), is solvent-dependent (Scheme 4).37 Solvents with the ability to form H-bonding stabilize Z-7 and retard the 1,5-H-atom shift to reform 6. For example, the lifetime of Z-7 is 50 and 30 ns in cyclohexene and benzene, respectively. Conversely, the lifetime of Z-7 in methanol and dimethyl sulfoxide is increased to 2.6 and 35 ms, respectively. In comparison, Hamanoue et al. demonstrated that the lifetime of E-3 is also significantly longer in benzene and acetonitrile, at 840 and 990 ms, respectively, than in ethanol, where the lifetime of E-3 was measured to be only 3 ms.46 The authors suggested that methanol could facilitate reketonization of E-3 via double H-atom transfer through an ethanol bridge, as shown in Scheme 5.

44

J. SANKARANARAYANAN ET AL. O H

O

O H 1

E-3

Scheme 5 Proposed double H-atom transfer of E-3 in ethanol.

Photolysis of 1 in oxygen-saturated solutions yields the products displayed in Scheme 6.65 T1K of 1 is too short-lived to be quenched by the diffusion of oxygen in solution, but presumably, biradical 2 is intercepted with molecular oxygen to yield these products. It is also possible that singlet oxygen can add to E-3 to form the products in Scheme 6. However, oxygen trapping of 2 can be expected to be close to diffusion rates, whereas the trapping of E-3 is expected to be much slower and to depend on the concentration of singlet oxygen. Formation of 8 presumably comes from secondary reaction of E-3. In the same way, photolysis of 9 in oxygen-saturated solutions yields peroxide 10 (Scheme 7).58,66 The photoreactivity of o-methyl acetophenone 11 has been studied extensively;37,67–77 it is somewhat different from 1 because the singlet excited ketone (S1K) in 11 intersystem crosses to its triplet state in less than quantitative yields, as observed for 1 (Scheme 8). Thus, S1K in 11 decays by both intramolecular H-atom abstraction to form exclusively photoenol Z-13 and intersystem crossing to T1K of 11. Haag et al. estimated that T1K of 11 has a lifetime of 10 ns in benzene and decays by intramolecular H-atom abstraction to form biradical 12.37 The maximum

O

O

O

hν

O

OH O

O

O

O

O2 O

1

Scheme 6

8

Photo-oxidization of o-methyl benzophenone 1.

O

O

O

hν O2

9

Scheme 7 Photo-oxidization of 9.

10

OH

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION O*

O*

O

O

hν

11

Singlet excited ketone

45

H

12

Triplet ketone

ISC

1,5-Sigmatropic hydrogen shift

H

O H

O

O

H

Z-13

E-13

14

Scheme 8 Photoenolization of o-methyl acetophenone 11.

absorption of biradical 12 is 330 nm. Like biradical 2, 12 intersystem crosses to form photoenols Z-13 and E-13, which have maximum absorbance at 385 nm. In cyclohexane, Z-13 has a lifetime of 20 ns; it is longer-lived in methanol ( = 730 ns). As expected, E-13 is considerably longer-lived and has a lifetime in the order of 1 s in cyclohexane and 8 s in 2-propanol.78,79 In benzene, Z-13 and E-13 are formed in the ratio of 9:1. The major difference between the photoenolization of 1 and 11 is that, in solvents capable of H-bonding, such as methanol, 11 yields only Z-13, from its S1K. Since S1K of 11 is short-lived, presumably only a few picoseconds, it cannot undergo internal rotation to form E-13 and, thus, yields exclusively Z-13. Wirz et al. proposed that the intermolecular H-atom bonding between methanol and 11 reduces the intersystem crossing rate for S1K of 11. Thus, biradical 12 is not formed, and consequently, E-13 is not formed either.69 Wessig et al. used density functional theory to calculate the transition state for the sigmatropic 1,5-H-shift of Z-13 to reform 11; they found that this transition state is only 2 kcal/mol above the energy of Z-13,80 which explains the efficient reketonization of Z-13. In comparison, the calculated transition state for E-13 undergoing electrocyclic ring closure to form butanol 1481 is located 20 kcal/mol above E-1380 and is reflected in E-13 having a much longer lifetime than Z-13. As with photoenol E-3, the reketonization of E-13 is facilitated by acids and bases,49 and E-13 can be trapped in Diels–Alder reactions.58,82–85 For example, photoenols formed from derivatives of 11 have been used to functionalize fullerenes.86

PHOTOENOLIZATION OF 2-NITROTOLUENE

The most extensively used photoremovable protecting groups are based on o-nitrotoluene derivatives, which, on exposure to light, undergo intramolecular H-atom abstraction to form photoenols (Scheme 9), followed by the elimination of their protected or caged substrate.28,30,36,42,43,87–97

46

J. SANKARANARAYANAN ET AL. O– NO2

N

hν

15

OH

+

N

OH

E-16

+ –

O

Z-16

Scheme 9 Photoenolization of o-nitrotoluene 15.

The mechanism of photoenolization of o-nitrotoluene derivatives, studied extensively in the past, is different from the photoenolization of o-alky arylketones.98–114 For example, irradiation of 15 gives rise to a singlet excited state of 15, which has a weak absorption between 300 and 600 nm and a lifetime in the order of 10 ps.115–117 Most of the singlet excited state of 15 decays by internal conversion to the ground state of 15, and presumably, a small fraction yields photoenols 16 (Scheme 9), which have maximum absorption of around 400 nm.118 In organic solvents, this absorption decays at a biexponential rate due to different isomers of 16. For example, in dried hexane, the fast component decays with a rate constant of 1  105 s 1, and the slower one decays with a rate constant of 18 s 1. The short-lived component was designated as Z-16, which reformed 15 by a sigmatropic 1,5-H-atom shift. The ratio of Z-16 to E-16 was estimated to be between 0.4 and 1, depending on the reaction medium. Interestingly, the lifetime of Z-16 decreased in H-bonding solvents, behavior opposite to that observed for Z-photoenols formed from o-alkyl arylketones. Presumably, in polar solvents, deprotonation of Z-16 yields nitronic acid 17, which can be reprotonated to form E-16 (Scheme 10). Thus, isomerization of Z-16 into E-16 competes with its 1,5-H-atom shift to reform 15. Calculations demonstrate that Z-16 is approximately 4 kcal/mol higher in energy than E-16; thus, formation of E-16 should be favored.119 In aqueous solutions, irradiation of 15 results in the formation of a transient absorption due to 16, with max at 390 nm.98,119 This absorption band is shifted to 405 nm, indicating ionization of 16 to form 17. The rate constant for forming 17 was measured to be 2  107 s 1, whereas 17 decayed with a rate constant of 1.67 s 1. In addition, photolysis of 15 in D2O leads to deuterium incorporation at the benzylic position, thus verifying the mechanism of solvent-assisted reformation of 15 from 16.120

O– N

E-16

–

O

+

+

+

–H OH

N

H+

–

O

17

Scheme 10 Isomerization of E-16 into Z-16 via anion 17.

H+ –H+

OH N

Z-16

+

O

–

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

47

The transient absorption formed from laser flash photolysis of 15 was not quenched in oxygen-saturated solutions, presumably because the photoenolization to form 16 takes place from a singlet excited state of 15. Furthermore, Schworer and Wirz did not observe any transient absorption that can be attributed to the formation of the triplet excited state of 15 from direct irradiation. In contrast, Hurley and Testa used energy transfer to estimate that the triplet excited state of 15 is formed in 67% yield,121 whereas Takezaki et al. have measured the yields for forming the triplet excited state of 15 to be slightly higher or above 80%.122 They estimated the lifetime of the lowest triplet excited state of 15 to be 350 ps in ethanol.

3

Photorelease via photoenolization

Photoremovable protecting groups that use photoenolization of o-alkyl arylketones to release their protected group or caged substrate can be categorized into two major groups. First, there are arylketones that have a good leaving group on either the o-alkyl substituent or the a-position next to the aryl ketone (Scheme 11). The leaving L

L O

O

hν R

H

O

–HL

R

R

L hν

O

–HL

L

O

O H

O O

O

L

H hν

O

O

R = Alkyl or aryl L = Leaving group

Scheme 11 Photorelease from o-alkyl arylketones.

L

O –HL

48

J. SANKARANARAYANAN ET AL.

L

O L

O

hν

NO2

H

O N

O

+

O

–L

–

NO

Scheme 12 Photorelease from o-nitrobenzyl compounds.

groups have to be stable enough on the o-alkyl arylketones that they do not cleave in the absence of light yet also good enough leaving groups on the photoenols to be liberated faster than the photoenols reketonisize to reform the starting materials. Presumably, the driving force for the elimination from the photoenols is rearomatization. The second category of photoremovable protecting groups achieves the release of the caged compound by intramolecular lactonization of the photoenol alcohol moiety with an ester group. The intramolecular lactonization also needs to be able to compete with the reketonization of the photoenols. The quantum yields for the photorelease of these systems will depend mainly on whether both the Z and the E photoenols contribute to the photorelease. The mechanism of photorelease from o-nitrotoluene derivatives is different from and more complicated than the release mechanism of the photoenols from o-alkyl arylketones (Scheme 12). The photorelease mechanism from o-nitrotoluene derivatives is strongly affected by the reaction medium and its pH value.

PHOTOELIMINATION FROM b-SUBSTITUTED o-ALKYL ARYLKETONES

Tseng and Ullman demonstrated in 1976 that substituting the b-alkyl position of the o-alkyl benzophenone with good leaving groups leads to the elimination of the b-substituent on irradiation, presumably via formation of photoenols (Scheme 13).123

L

Ph

O OH

Ph

18

L

L

hν

E-19

L = a) –OH, b) (C6H3)3CO– c) p-CH3C6H4SO3– d) p-C2H5OCOC6H4NHCO2– e) p-O2NC6H4CO2– f) N

Scheme 13 Photoelimination from 18.

+

OH

O

Ph

Z-19

Ph

20

+ LH

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

49

Table 1 Quantum yields for photoelimination from 18 Reactant 18c 18d 18e 18f a

Fa 0.47 0.22 0.16 0.25

Irradiation in methanol with 254 nm light.

According to the authors, the driving force for the elimination was the rearomatization of the photoenols; thus, b-substituents that were unreactive in the benzophenone precursor could be eliminated. Tseng and Ullman studied leaving groups such as tosyl, trityl, piperidyl, and substituted carboxylic acids. They found that the quantum yields for the elimination from 18 correlated directly with leaving ability of the b-substituent from the ground state (Table 1). The authors proposed that the elimination came from photoenols 19 based on several observations. Irradiation of 18e and 1 in ether–ethanol solution at 150 K resulted in transients with maximum absorption at 400 nm, comparable to the transient absorption observed for photoenols E-3 and Z-3. The investigators noted that the transient absorbance for 19e decayed faster than that for 3. In similar experiments at room temperature, irradiation of o-ethyl benzophenone yielded a transient absorption with a maximum at 400 nm, which took minutes to decay, while irradiating 18e under identical conditions did not yield any transient absorption. Based on these findings, Tseng and Ullman concluded that the E-19 undergoes solvent-assisted reketonization but that this process is sufficiently slow to compete with b-elimination. The authors theorized that the increased quantum yield for product formation from 18 was simply due to the better leaving groups being able to eliminate from E-19 more efficiently than it reketonized or due to elimination also taking place from Z-19. In 2003, Banerjee et al. designed an efficient photoremovable protecting group for the release of carboxylic acids based on similar b-elimination from photoenols (Scheme 14).124 They showed that o-alkyl acetophenone derivatives with various ester groups in the b-position release their ester moiety in high chemical yields. The authors proposed that the photorelease took place as shown in Scheme 14 but did not support the mechanism with transient spectroscopy. Formation of 21, which is expected to be the major product in the reaction, was not confirmed, and thus, the authors speculated that 21 undergoes polymerization to yield oligomers. Sobczak and Wagner showed that o-acetylphenyl and o-benzoylphenyl acetic acids in benzene also undergo efficient decarboxylation on exposure to light (Scheme 15).125 However, the corresponding ester and amide derivatives of 22 were photostable. Furthermore, since the corresponding meta- and para-derivatives of 22 did not undergo photodecarboxylation, the authors concluded that the photorelease

50

J. SANKARANARAYANAN ET AL. OCOR′

OCOR′ O

R

OCOR′ O 3*

R

•

R

OH

hν

•

20

Triplet ketone

Biradical ISC

OCOR′

OCOR′ OH

R 1,5-H-atom shift

R +

OH

Z-Enol

E-Enol

O

R

+ R′COOH

21

Scheme 14 Photoelimination from 20.

R

R O

22

O

hν

O

+

CO2

OH

R = CH3 R = Ph

Scheme 15 Photodecarboxylation of 22.

from 22 takes place not by electron transfer but by photoenolization. The authors speculated that ester and amide derivatives of 22 are unreactive because the corresponding photoenols will be reketonized by trace impurities of carboxylic acid since decarboxylation is not possible.

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

51

In comparison, photodecarboxylation of various other carboxylic acids has been studied extensively.126 For example, photodecarboxylation of 23 in water presumably involves electron transfer from the carboxylate anion to the phenyl ring (Scheme 16).126–130 The electron transfer is followed by decarboxylation to form the anion 24, which is protonated by the solvent. As shown in Scheme 16, in less polar aprotic solvents, homolytic cleavage leads to decarboxylation subsequent to charge transfer in 23. Interestingly, nonsteroidal anti-inflammatory drugs, such as ketoprofen 25 (Scheme 17), which are used to treat a wide range of ailments, such as inflammation, pain, and fever, also undergo photodecarboxylation.131–136 Unfortunately, many of these drugs have been shown to have cutaneous side effects, which are caused by their photodecomposition. Various research groups have demonstrated that irradiation of ketoprofen 25 yields 26 under anaerobic conditions, whereas in oxygen-saturated solutions, the compounds shown in Scheme 18 are formed in addition to 26.137,138 hν Water O

O

–

–

23

24

hν

•

+ •

Methanol O

O

OH

OH

23

Scheme 16 Photodecarboxylation of 23. O

O

O O –

hν

–

+

H

–CO2

O 25

26A

26

Scheme 17 Photodecarboxylation of 25.

O O

–

hν O2

25

Scheme 18 Photo-oxidation of 25.

O

O

O

O

OH

OOH

O

52

J. SANKARANARAYANAN ET AL.

Scaiano et al. used laser flash photolysis to show that irradiation of 25 forms anion 26A, which has a maximum absorption at 600 nm.139,140 Anion 26A is considered stable in anhydrous solvents but is efficiently quenched by water. Furthermore, molecular modeling done by Eriksson et al. shows that the initial excitation of 25 leads to its first excited singlet state, which intersystem crosses to a triplet excited state.141,142 Decarboxylation is presumably spontaneous from the triplet state of carboxylate anion 26A. However, several low-lying singlet excited states of 25 were also identified as being capable of undergoing decarboxylation with an activation barrier between 3 and 5 kcal/mol. The mechanism for the addition of oxygen to anion 26A to give the corresponding peroxyl radical has also been investigated.141,142 Scaiano and coworkers designed the two new photoremovable protecting groups 27 and 28, based on ketoprofen 25.139,143 Photolysis of 27 in aqueous solutions releases ibuprofen in quantum yields of 0.75 (Scheme 19). Furthermore, the rate constant for the release of ibuprofen from 27 was measured to be 5  106 s 1. Thus, 27 can release ibuprofen both rapidly and in high quantum yields. In the same way, irradiation of 28 in aqueous solutions led to efficient decarboxylation with a quantum yield of 0.67 (Scheme 20). Recently, Falvey and coworkers have designed photoremovable protecting group 29 for carboxylic acids.144–146 Irradiation of 29 releases, in quantitative chemical yields, its carboxylic acid moiety (Scheme 21). Furthermore, N-protected amino acids and phosphates can also be released from 28. Falvey et al. studied the mechanism of the photorelease from 28, which is initiated by photoinduced electron transfer.

O

COOH

O

hν

O O

O

O

HOOC

27

Ibuprofen

Scheme 19 Photoremovable protecting group (27) for ibuprofen.

O

O COO– O 28

Scheme 20 Photodecarboxylation of 28.

hν –CO2

O

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION O

53

O Photoinduced R

O N + ClO4–

+ Sensitizer

O

•

Electron transfer

R

•

+ Sensitizer

+

N ••

29

• O R

O

–

N +

Scheme 21 Photorelease of carboxylic acid derivatives from 29.

Kamdzhilov and Wirz reported a new photoremovable protecting group (30) that uses photoenolization for photorelease (Scheme 22).147 Since 30 is both watersoluble and absorbs light out to 400 nm, it could have potential use in biological applications. The authors measured the quantum yields for the release of bromine and diethyl phosphate anion to be 0.47 and 0.67, respectively. The mechanism of the photorelease from 30 was studied using time-resolved UV and IR spectroscopy. Laser flash photolysis of 30 in acetonitrile yields a transient absorption with max at 550 nm. The authors assigned this transient absorption to 31. Furthermore, since this transient absorption was not quenched with molecular oxygen or triplet quenchers such as piperlyne or naphthalene, Kamdzhilov and Wirz proposed that the singlet excited state of 30 underwent H-atom abstraction to form photoenol 31. The decay of photoenol 31 was biexponential, which indicates that two isomers, E-31 and Z-31, are formed. The rate constants of release from the two isomers of 31a in water were 2.13  107 and 1.57  106 s 1, respectively. Conversely, the release rate constants for 31b were somewhat lower at 3.3  104 and 1  104 s 1. As expected, both the rate of release and the quantum yields of photorelease from 30 are dependent on the structure of the leaving group.

hν L

O

O

O

O

+ L– + H+

+ L

OH

OH L

30

O

E-31

30a: L = Br 30b: L = OPO(OEt)2

Scheme 22 Photorelease from 30.

Z-31

O

54

J. SANKARANARAYANAN ET AL. H H O

C5H11

O Pr

OH

• O

Pr

C5H11

O Pr

hν

OH O H

O2 O

32

H

O

O

O •

O C5H11 OH

Scheme 23 Photorelease from 32.

Jones et al. have designed photoremovable protecting group 32 for aldehydes that is based on a somewhat similar structure to 30.148,149 The authors proposed that the photorelease from 32 was initiated by intermolecular -H-atom abstraction (Scheme 23).

PHOTOELIMINATION FROM a-SUBSTITUTED o-ALKYL ACETOPHENONE DERIVATIVES

In 1978, Bergmark determined that photorelease can also take place when the a-position of an o-methyl acetophenone has a good leaving group, such as a chlorine atom.150 He showed that photolysis of 33 in benzene resulted in the formation of 36, whereas in methanol, both 36 and 37 were formed (Scheme 24). In 1985, Bergmark followed up his earlier work with a more detailed study and showed that the elimination of a chorine atom from 33 took place in high quantum yields, especially in methanol.150 Thus, Bergmark concluded that both E-34 and Z-34 released their chlorine atoms. Additionally, he theorized that the release from Z-34 took place via solvolysis to from carbocation 35. Bergmark theorized that photosolvolysis of Z-34 in methanol resulted in the release of the chlorine atom and the formation of 35 but that release from E-34 took place in a concerted reaction to form a chlorine atom and 36. This claim was further supported by the photoreactivity of 38 (Scheme 25). Photolysis of 38 in methanol resulted in products 39, 40, 41, and 42, and Bergmark suggested that the formation of 42 came from a ‘‘photo-Favorksii’’ rearrangement, which supports the notion that products 39–42 were formed via a carbocation intermediate. Scaiano and Netto-Ferreira studied the photorelease mechanism of 33 with transient spectroscopy,151 and more recently, Wirz et al. reinvestigated the mechanism.69 It was determined that the main photoreactivity of 33 is photoenolization and that the major reactivity of 33 in methanol was not from the triplet ketone but, rather, from the singlet excited state of the ketone. Laser flash photolysis of 33 produces a transient absorption, which has a maximum around 385 nm and a lifetime of 22.5 ms. Since this transient absorption was not quenched in oxygen-saturated solutions or by the addition of a triplet quencher such as piperylene, the authors assigned it as Z-34 and proposed that it was formed directly from the singlet excited state of the ketone chromophore. The long lifetime of Z-34 was attributed to the hydrogen bonding

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION O

O Cl

R

hν

O

Cl

ISC

R Singlet excited ketone

33 R = H, Ch3

•

O Cl

55

Cl

•

R Triplet excited ketone

R Biradical ISC

Cl

OH Cl

1,5-H-atom shift

OH

R

R

Z-34

E-34

–Cl–

–HCl

OH O

+

O

R

O

R

36 MeOH +

OH

R

37 Cation 35 R

Scheme 24 Photoelimination from 33.

O

O

Cl

O

O

O

O O

hν Methanol

38

Scheme 25

39

40

41

42

Photolysis of 38 in methanol.

between Z-34 and the methanol solvent, which retarded the sigmatropic 1,5-H-atom shift to reform 33. The authors proposed that preassociation of methanol with the ground state of 33 through hydrogen bonding reduced the intersystem crossing rate

56

J. SANKARANARAYANAN ET AL.

constant from the singlet excited ketone in 33. Additionally, since E-34 is not formed in significant amounts in methanol and the quantum yield for forming 37 and 36 from 33 is 0.76, the photorelease must come from Z-34.150,152 In comparison, irradiation of 33 in benzene resulted in a transient spectra with max = 390 nm. The decay of transient absorption was resolved into a slow and a fast component ( = 10 ms and 225 ns), which were assigned to E-34 and Z-34, respectively. Enol Z-34 is short-lived in benzene because it reketonizes efficiently via sigmatropic 1,5-H atom shift, which is not retarded with H-atom bonding, as occurs in methanol. Addition of triplet quenchers in benzene solutions did not completely quench the formation of Z-34; thus, the authors concluded that both triplet and singlet pathways were prevalent in benzene. However, the low quantum yield, 0.11,150,152 for product formation from 33 in benzene suggests that only E-34 eliminates the chlorine atom. Klan and coworkers have studied in further detail the photorelease from 33 and compared that with photorelease from 43 and 44 (Scheme 26).153–157 Klan et al. determined that sulfonate esters and phosphonate esters are released in high quantum yields when 43 is irradiated in methanol (Table 2).69,154,156,158 In comparison, photolysis of 43 in benzene released the sulfonate and phosphonate esters in poor quantum yield. Thus, the authors proposed that the mechanism of photorelease from 43 is similar to that observed for 33.69 Klan and coworkers also measured the quantum yield for the photorelease of acids, alcohols, amines, and amino acids from 44, finding that they were released in moderate to low quantum yields in protic and aprotic solvents such as methanol, O L

32: L = Cl 43: L = Sulfonate esters or phosphonate esters 44: L = Carbonates and carbamates

Scheme 26 Photoremovable protecting groups 33, 43, and 44.

Table 2

Quantum yields for product formation from 33 and 43

Compound (L) Cl OPO2 OTS OSO2C8H17

Methanol

Benzene

0.76 0.71 0.68 0.68

0.11 0.09 0.19 0.16

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION Table 3

57

Quantum yields for photorelease from 44

Compound (L) OCOPh OCOCH2Ph OCOMe OCOOEt OCOOPh OCOOBn OCOODecyl OCOOGalactopyranosyl OCONHPh OCOpiperdyl

Methanol

Benzene

Cyclohexane

0.09 0.11 0.14 0.13 0.20 0.14 0.09 0.16 0.027 0.056

0.23 0.18 0.25 – – – – – – –

– – – 0.51 0.5 0.48 0.36 0.4 0.054 0.087

benzene, or cyclohexene (Table 3). The authors demonstrated that the release took place mainly via the triplet ketone in 44 and elimination from the E-photoenols of 44. The Z-photoenols formed from 44 undergo solvolysis, presumably too slowly to compete with sigmatropic 1,5-H atom shifts to reform 44. Klan et al. proposed that both alcohols and amines are initially released as carbonates and carbamates from 44; these undergo thermal decarboxylation to release CO2 and form their respective alcohols and amines.153 Furthermore, the chemical yields of the protected amine were reduced since they were involved in electron transfer reactions that decomposed 44.

PHOTORELEASE VIA LACTONIZATION

PHOTOENOLIZATION

FOLLOWED

BY

INTRAMOLECULAR

We have designed photoremovable protection groups 45, 46, and 47, which release alcohols on irradiation (Scheme 27).159–161 Ester 45 releases its alcohol independent of the reaction medium. For example, photorelease of geraniol from 45 takes place in solvents such as benzene, chloroform, toluene, and methanol (Fig. 2). Furthermore, the photorelease also takes place when thin films of ester 45 are deposited inside flasks sealed under ambient air and exposed to daylight. In oxygen- and air-saturated solutions, 45 released its alcohol moiety and formed products 49 and 48, respectively (Scheme 28). The quantum yields for forming 49 and 48 were 0.17 and 0.14, respectively.159

O

O

45

OR

O

O

OR

46

Scheme 27 Photoremovable protecting groups 45, 46, and 47.

O

O

47

OMe

58

J. SANKARANARAYANAN ET AL. 100 Toluene 2-Propanol Benzene Chloroform

% Conversion of 45

80 60 40 20 0 0

2

4 Irradiation time (hours)

6

8

Fig. 2 Photorelease from 45 in various solvents.

O

OO

O

O

hν

O

OR

O

O

hν

Argon –ROH

Oxygen –ROH 49

45

48

Scheme 28 Photorelease from 45 in oxygen- and argon-saturated solutions.

In a similar way, 46 released its alcohol moiety and formed 50 in argon-saturated solvents (Scheme 29).160 In comparison, 47 was unreactive in solvents that do not have easily abstractable H-atoms, such as benzene and chloroform. However, photolysis of 47 in solvents such as methanol, ethanol, and toluene, which have H-atoms that can easily be abstracted, released the alcohol moiety of 47 and yielded lactone 51 (Scheme 30). The quantum yield for forming 51 was 0.02 in 2-propanol. Lactone 51 must come from intermolecular H-atom abstraction of 47 from the solvent rather than intramolecular H-atom abstraction to form photoenols. O O O

O

OR hν

Argon –ROH 46

Scheme 29 Photorelease from 46 in argon-saturated solutions.

50

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

O No reaction

O

OR

O

hν

hν

Argon benzene

Argon methanol –ROH 47

59

O

51

Scheme 30 Photorelease from 47 in argon-saturated benzene and methanol.

The reaction mechanism of photorelease from esters 45, 46, and 47 was determined using transient spectroscopy. The lifetime of T1K of 45 was estimated to be less than a nanosecond. T1K of 45 presumably decays by H-atom abstraction to form biradical 55 (Scheme 31), which intersystem crosses to yield Z-56 and E-56. Photoenols 56 have max at 390 nm, and their transient absorption is quenched with isoprene, verifying that they come from the T1K of 45. Enol Z-56 has a lifetime of 1300 ns in chloroform and, as expected, it is shorter-lived than E-56, which has a lifetime in the order of seconds. However, in nonhydrogen bonding solvents, Z-56 is considerably longer-lived than Z-3, presumably because it is stabilized by intramolecular H-bonding that is not possible for Z-3. This theory is further supported by the fact that the lifetime of Z-56 in solvents like methanol and 2-propanol is only increased to about 3000 ns. The ratio of E-56 and Z-56 is in the order of 1:4, and it was not affected strongly by the solvent. Since the quantum yield in the photorelease is low, or around 0.14, we concluded that only E-56 is long-lived enough to undergo intramolecular lactonization to release the alcohol moiety. Laser flash photolysis of 46 showed results similar to those obtained for 45. The lifetimes and yields of Z and E photoenols from 46 are comparable to those obtained for 56. Similarly, laser flash photolysis of 47 reveals that the major reactivity pattern of 47 is intramolecular H-atom abstraction to form Z-58 and E-58 even though no products were observed that can be attributed to the formation of photoenol 58. Laser flash photolysis of 47 in methanol showed formation of biradical 57 (max  330 nm,  = 22 ns), which was efficiently quenched with oxygen (Scheme 32). Biradical 57 intersystem crosses to form Z-58 and E-58, which have maximum absorption at 400 nm. Enols Z-58 to E-58 were formed in the approximate ratio of 1:4. Enol Z-58 had a lifetime of 6.5 ms in methanol, but its lifetime in dichloromethane was only 110 ns. The measured lifetime of E-58 in methanol was 162 ms, while it was 44 ms in 2-propanol. Thus, E-58 is considerably shorter-lived than E-56. Furthermore, E-58 is also shorter-lived than the analogous E-59 (Scheme 33), which cannot decay by intramolecular lactonization and has a lifetime of 3.6 ms in methanol. Thus, we proposed that E-58 undergoes solvent-assisted reketonization that is facilitated by the intramolecular H-atom bonding, as shown in Scheme 34. Photolysis of 47 in oxygen-saturated solution yielded 60 as the major product, whereas at low conversion, 61 and 62 were the major products (Scheme 35).161 Therefore, we proposed that, in oxygen-saturated solutions, biradical 57 was trapped with oxygen to form 63, which can undergo intramolecular lactonization

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J. SANKARANARAYANAN ET AL.

R

OR

O

O

45 hν

O

O

*

OR

1,5-H-atom shift R

Triplet excited ketone (0.08–0.8 ns)

⋅•

OR O O H

H

H O

O

OR

⋅•

ISC

O

O

OR

ISC R

R R E-56

Biradical 55 Fast O2 trapping –ROH

–ROH

O

Z-56

O OO O

O

R R 48

49

Scheme 31 Proposed mechanisms for photorelease from 45.

to release the alcohol moiety and form 61. In competition with lactonization, 63 must also undergo dehydration to form 62. Secondary photolysis of 62 results in the formation of 60, presumably via formation of ketene 64. Thus, the photooxidation of 47 is similar to that reported for 2-benzoyl-benzaldehyde and 2-methyl benzophenone.65,162 The photo-oxidization of 47 further verifies that the main

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

O

O

O

*O

O

• H O O

O

hν

46

•

O Intersystem crossing

+

Intermolecular H-atom abstraction O OH

O

Z-58

57

Triplet excited state

O OH

61

O O OH

O

E-58

•

59

51

Scheme 32 Photolysis of 46.

O

O

OH

E-59

Scheme 33 Photoenol E-59.

O O

47

O H

E-58

Scheme 34 Reketonization of E-58.

reactivity of 47 is photoenolization that does not lead to any products in the absence of molecular oxygen. Furthermore, we concluded that the intramolecular lactonization of E-56 and E-58 must be a slow process and that only photoenols that are long-lived can undergo intramolecular lactonization to release their alcohol moiety faster than they reketonize.

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J. SANKARANARAYANAN ET AL.

O

O

H

OMe

O hν

O

O

OMe

O

O

O OH

hν

O2

OMe

–H2O

OH

47

O

OMe

O

63

62

64

–MeOH O

OO

O

O

O

61

O

OMe

60

Scheme 35 Proposed mechanism for photo-oxidization of 47.

Porter et al. studied the photorelease of various alcohols from ester 65, which release their alcohol moiety and form lactones 67 and 68 in solvents with abstractable H-atoms (Scheme 36).163 They also reported that the photorelease from 65 could be initiated by electron transfer from amines. We used transient spectroscopy to elucidate the photorelease mechanisms of 65 in 2-propanol. Laser flash photolysis of 65 resulted in the formation of the triplet excited state of 65, which has a max at 330 and 530 nm. The triplet excited state of 65 decayed with a rate constant of 3  108 s 1 in 2-propanol to form radical 66. The quantum yield for photorelease from 65 was determined to be 0.62 in 2-propanol. In comparison, photoremovable protecting groups such as 69 also release their protected molecule via intramolecular lactonization, but the photorelease is initiated by cis–trans isomerization. Cis–trans isomerization has been extensively used to turn molecular switches off and on,164 but there are a few examples where cis–trans isomerization has been used to activate photorelease. Initially, Stoermer showed that photoinduced cis–trans isomerization of trans-69 yields 71, presumably via intramolecular lactonization of cis-70 (Scheme 37).165,166 In a similar way,

O

O

OR

O

O

OR

*

hν

H

O

O

OR

O Ph

–ROH

•

2-Propanol

65

Triplet excited ketone

66

O –ROH toluene

O

68

Scheme 36 Photorelease form 65.

Ph

O

O

67

O

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

63

H O

O H

H O O

O

O

O

hν

H

O –H2O

cis-70

trans-69

71

Scheme 37 Photoisomerization of trans-69 and intramolecular lactonization.

O

X

O

H

X 72: X = Cl or MeO

Scheme 38

Photoremovable protecting group 72.

NH2HCl O

NH

O

Protein-OH

O O

O

H

O H

Protein hν OO H

74

–Protein–OH O Protein

O

O

75

NH2HCl

73

NH HO

Scheme 39 Photorelease from 73.

Arad-Yellin et al. and Morrison et al. demonstrated that the photolysis of trans-72 also yields 71 (Scheme 38).167,168 However, Morrison et al. reported that the quantum yield for forming lactone from trans-72 was low or less than 0.04.168 Porter et al. developed photoremovable protecting group 73, based on 69, and used it to inhibit several serine proteases such as thrombim and trypsin (Scheme 39).169 Trans-esterification between 73 and a hydroxyl group in the proteases render these enzymes inactive. However, irradiation liberated the enzymes from their protecting group and restored the enzymatic activity. Porter et al. subsequently designed other photoremovable protecting groups to inhibit serine proteases.169–171 There are several examples in the literature where similar cis–trans isomerizations of o-hydroxy cinnamic acid derivatives have been used to deliver fragrances.5 For example, ester 76, which was absorbed into cloth and exposed to sunlight, released its fragrant alcohol moiety, whereas samples that were stored in the dark did not

64

J. SANKARANARAYANAN ET AL.

(Scheme 40). Various derivatives of 76 have been used to deliver fragrances on exposure to light.172–174 Flachsmann and Bachmann designed photoremovable protecting group 77, which has to undergo hydrolysis before its fragrant alcohol moiety can be released by exposure to light (Scheme 41).173 The protection of the phenol group as a carbonate was incorporated into the photoremovable protecting group to avoid discoloration of the substrates into which 77 was absorbed on. More recently, Porter et al. investigated the photorelease of 78 absorbed on CdSe nanocrystals (Scheme 42).175 Irradiation of 78 at 374 nm under aerobic conditions released 79 and degraded the nanocrystals. Irradiating 78 on CdSe nanocrystals with visual light (78 does not absorb it, but the nanocrystals do) resulted in photorelease.

O OH

O

O

hν

O

+

HO

76

Scheme 40 Photorelease from 76.

O O

O

O

O

77 H2O OH

–CO2

O OH +

O

hν

O

O HO

Scheme 41 Hydrolysis and photolysis of 77.

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

65

O S

O

n

n

CdSe-nanocrystals hν

+ N

O

N

78

O

R

HO

O

S n

n

CdSe-nanocrystals

79

R = H, Me, 4-I-PhCH2

Scheme 42 Photorelease from 78 on CdSe nanocrystals.

Thus, the authors theorized that the photorelease was initiated by electron transfer from the CdSe nanocrystal surface to 78 to form the anion of 78, which undergoes cis–trans isomerization, followed by lactonization to release 79. The authors suggested that photorelease from CdSe nanocrystals may have potential use in the areas of drug delivery and imaging. Photorelease in the solid state also has potential applications, such as surface modification and solvent-free synthesis. Thus, we have included an example of photorelease from molecular crystals. Photolysis of 80 in solution releases hydrazoic acid (Scheme 43).176 The high volatility of hydrazoic acid and its small size make it possible to use solid-state irradiation of 80 to release hydrazoic acid. The reaction mechanism has been proposed to be as follows: Irradiation of azide 80 with light above 300 nm populates the first excited state of the triplet ketone (n,*), which results in cleavage of the C—N bond. The formation of radical 81 was confirmed by laser flash photolysis in toluene, which showed formation of a transient with max at 310 nm. To verify that the azido radical formed by irradiating azide 80 abstracts an H-atom to form hydrazoic acid, crystals of 80 were placed in a Pyrex segment inserted into an argon deposition line. The glass segment of the line was irradiated while argon flowed over the crystals. The flowing argon was condensed on the matrix cold window at 14 K and monitored by IR spectroscopy. IR bands were observed at 2135 and 1146 cm 1, which match the two most intense bands reported for hydrazoic acid in argon matrices.177 1H-NMR spectra of the remaining yellow solid in the glass tube showed formation of mainly trans-82. The X-ray structure of 80 showed that it crystallizes in a conformer with the carbonyl and azido groups in a pseudosyn alignment (Fig. 3). Additionally, the crystal structure revealed that the distances from N1 to H-atoms Ha and Hb are only 2.64 and 3.35 A˚, respectively (Fig. 3). Thus, we proposed that solid-state irradiation of 80 breaks the C—N bond to form 81 and an azido radical, which abstracts a nearby H-atom on C8 and forms hydrazoic acid and trans-82.

N3

O

Ph

Ph

80

O

hν Crystals

O •

Ph

Ph

+ •N3

81

Scheme 43 Photorelease of hydrazoic acid from 80.

–HN3 Ph

Ph

82

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J. SANKARANARAYANAN ET AL.

C5 C4

C6 C12 Hα

C3

C7

C1

C8

C2

Hβ

C13

C11

C14 C9

C10

C15

N1 01 N2

N3

Fig. 3 X-ray structure of 80.

The calculated bond dissociation energy for 80 to form 81 and the azido radical is 55 kcal/mol. Since the bond dissociation energy for breaking the C—N bond in 80 is considerably lower than the energy of its triplet ketone (74 kcal/mol), it is feasible to break the C—N bond photochemically to form an azido radical and 82. The photorelease from 80 is an example of a photorelease from an excited state and thus it is fast enough to take place in crystals.

PHOTORELEASE FROM NITROTOLUENE DERIVATIVES

Even though most commonly used photoremovable protecting groups in applications are based on o-nitrobenzyl derivatives, the mechanistic details of photorelease from nitrobenzyl derivatives were not known. Recently, Wirz et al. and Corrie et al. investigated the mechanism.178–182 The mechanism of photorelease from the photoenols formed by irradiating 2-nitrobenzoyl compounds is more complex than for o-alkyl arylketones. Wirz et al. showed that irradiating 83 yields the singlet excited state of 83, which decays by intramolecular H-atom abstraction to form 84 (Scheme 44).178,179 In acetonitrile, tautomers 84 have a broad absorption with max at 425 nm. There are four different isomers possible for 84, and density functional theory calculations predict that the E,E and E,Z isomers are the more stable ones. The initial H-atom transfer in 83 will presumably lead to the formation of Z,E-84 and Z,Z-84 where the N—OH moiety is in close proximity to the o-alkyl group. However, these isomers are several kcal/mol higher in energy than E,E-84 and E,Z-84. Photoenols 84 decay by

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION O

RO

R NO2

hν

O–

OR – O

+

+

N

83a: R = H 83b: R = CH3

N

OH

E,E-84

RO

OR OH

OH +

N

OH

E,Z-84

67

+

N

–

O

Z,E-84

–

O

Z,Z-84

Scheme 44 Photoenolization of 83.

HO

HO

H

R

R NO2

O

OH

–

R

+

N

hν

83

N

OH

84

R

O

OH OH

OH

NO

87

88 –H2O

a: R = H b: R = CH3

O

R

R OH N

OH

NO

–H2O

85

Scheme 45

O

86

Proposed mechanism for photoelimination of water from 83.

two competing mechanisms, leading to the formation of 85 and 87 (Scheme 45). The yields of 84 and 87 depend mainly on the reaction medium. In aprotic solvents such as hexane, 84 decays mainly to 85, which has been characterized with time-resolved IR spectroscopy. The decay of 84a obeyed a second-order rate law (k  (1–2)  1010 M 1s 1) rather than biexponential decay. Thus, Wirz et al. proposed that irradiation of 84a results mainly in Z,Z-84a, which undergoes proton transfer with the aid of another Z,Z-84a molecule to form E,Z-84a. The resulting E,Z-84a consequently undergoes rapid intramolecular proton transfer to yield 85. In comparison, the decay of 84b followed a first-order rate law, but the observed rate constant increased linearly with the concentration of its precursor 83b, presumably because the H-atom shift to convert Z,Z-84b to E,Z-84b is accelerated by the precursor. Finally, 85 dehydrated to form 86. The rate constant for the dehydration of 85 is slow in hexane and was estimated to be in the order of k  1 s 1.

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J. SANKARANARAYANAN ET AL.

In comparison, photolysis of 83 in protic solvents such as methanol, ethanol, and water yields 84 as expected, but 84 forms mainly 87 rather than 85. Furthermore, in these solvents, the transient absorption (max  425 nm) due to 84 decays not with a second-order rate law but by biexponential decay. For example, the decay of transient absorption of 84 (max  420 nm) in water at pH 7 had rate constants of 2  107 and 3  104 s 1. Subsequent to the decay of 84, a transient absorption was formed with max 330 nm and a weak absorption band at 740 nm. However, this transient was formed much slower than 84 decayed. The absorption at 330 nm was described as a biexponential growth with rate constants of 584 and 21 s 1. The authors assigned this absorption to 88. Since 84 and 88 do not form and decay at the same rate, the authors theorized that 84 decays into 87, which then furnishes 88. Even though intermediate 87 does not absorb in the near UV, the authors characterized it with time-resolved IR spectroscopy. The authors demonstrated that, in hexane and a strongly acidic or basic aqueous solution, the photorelease from 83 goes through the formation of 87, whereas in near neutral aqueous solution, formation of 85 predominates. The authors concluded that the dehydration of intermediates 85 and 88 to form 86 is the rate-determining step for the release from 83 and that the release rate is affected by the reaction medium. Wirz and coworkers also studied photorelease from o-nitrotoluene derivative 89 (Scheme 46). The authors proposed a mechanism of photorelease from these compounds that is similar to that proposed for 83. The authors demonstrated that the reaction medium, including solvent, pH, and buffer concentration, affects the rate of release (Scheme 45). For example, in methanol (pH up to 8), the rate of release from 89 is limited by the decay of 94, whereas under acid-catalyzed conditions, the reaction goes through intermediate 93. At a pH above 10, the release of methanol took place in a single step from 92. Thus, the authors concluded that the decay of 91 is not a good indicator for the rate of release of 89 since intermediates 93, 94, and 95 may be longer-lived, depending on the reaction medium. Wirz and coworkers also studied the photorelease of ATP from 89 and found that it correlated with the decay rate of 91 at pH > 6, as previously reported by Walker et al.183 However, for pH < 6, the decay of 91 exceeded the rate of formation of 86, and Wirz et al. concluded that the release of ATP went through intermediate 94. Wirz et al. also studied photorelease of glycolic acid from 96 (Scheme 47). They used spectroscopy to reinforce that the mechanism of photorelease from 96 is similar to that observed for 89. They found that the hydrolysis from 101 limits the release rate from 96 in aqueous solutions at pH  7. Additionally, they also observed that the release from 98 can be retarded by buffers. As an example, they showed that 98, in aqueous solution, was trapped intramolecularly to form 100, which had lifetimes in the order of minutes. Corrie et al. studied the photorelease of a caged sulfate from 102 and demonstrated that the mechanism of release of sulfate is, in principle, similar to that observed for 96 (Scheme 48).182 Steiner et al. designed photoremovable protecting group 103 for photolithographic in situ DNA-chip synthesis (Scheme 49).184,185 These protecting groups have a

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

69

R O NO2

89 hν

R

R O

N

R

O

OH

OH

–H+

+

OH

+

N

H+

–

O

–H+

O

O– +

N

H+

O–

91

90

92 Nu = OH or base R

R O

Nu

O

O

OH N

N OH

OH

94

93

H+

–H2O

R O

OH

O

NO

R = CH3 R = ATP

95

–ROH

NO

86

Scheme 46 Proposed mechanism of photorelease from 89.

built-in triplet sensitizer, thioxanthone, that is covalently bonded to o-nitrotoluene derivatives. The thioxanthone chromophore was incorporated into the photoremovable protecting group to ensure better light sensitivity during the photorelease. Thus, irradiating 103 where the thioxanthone moiety absorbs yields its first

70

J. SANKARANARAYANAN ET AL. CO2H O

O N

– +

OH

96 hν CO2–

CO2H O

O

–

O–

O

–H+

N

OH

N

OH

H+ 98

97

O CO2H O

O O

O

–

O N

N

OH

OH 100

99 H2O

CO2H O

OH NO

101

O

OH

–H2O

NO

HO

CO2H

86

Scheme 47 Proposed mechanism for photorelease of glycolic acid from 96.

excited state, which has a (,*) configuration. The first excited state of the thioxanthone intersystem crosses to the second excited triplet state, which has a (n,*) configuration. The authors theorized that when the linker between the thioxanthone and the o-nitrotoluene is flexible and short, the energy transfer between the

PHOTOREMOVABLE PROTECTING GROUPS BASED ON PHOTOENOLIZATION

71

O

OSO3– hν

NO2

NO

+

H+

SO4–2

+

102

Scheme 48 Photorelease of sulfate from 102. O

O

NH

O N O

103

NO2

N

O O

O

S

OH

O

O

O

hν

O

O

S

NH

O*

OH

O

NO2

O

Triplet ketone Energy transfer

NH

O N

O

O O

O

S

*

OH

O

NO2

Triplet nitrotoluene

H-atom abstraction ISC

O O

NH

NH

O N

N O

O

S

+

HO

–CO2

OH

105

O

O

+

104

O

O

S

NO2

O

N

O

–

O

OH

OH

Scheme 49

Photorelease from 103.

thioxanthone and the o-nitrotoluene takes place from the triplet (n,*) of the thioxanthone. In comparison, when the linker in 103 is long or inflexible, internal conversion of the (n,*) state to the first triplet excited state of thioxanthone, which has a (,*) configuration, takes place before energy transfer to the nitrotoluene moiety. The authors theorized that the triplet state of the nitrotoluene moiety of 103 undergoes intramolecular H-atom abstraction to yield enol 104, which then cleaves to release 105. Robles and Bochet showed that nitrotoluene derivatives 106 (Scheme 50) can be used as a photoremovable protecting group for aldehydes.186 Irradiation of 106 released aldehydes in good yields, and the authors demonstrated that aldehydes such as phenylacetalaldehyde and citronellal, which are important for flavor and fragrances, are released efficiently from 106.

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J. SANKARANARAYANAN ET AL. OAc MeO

O

R

O

hν H

MeO

R

NO2 106

Scheme 50 Photorelease of aldehydes form 106.

4

Conclusion

From the examples described in this chapter, it can be seen that the mechanisms of photoenolization has been determined for various o-alkyl arylketone and o-nitrotoluene derivatives. However, the mechanism of the release from photoenols is more complicated and has been elucidated for only some of the systems. Photoremovable protecting groups that rely on photoenolization for release all have in common low quantum yields, unless all the isomers of the photoenols release faster than they reform the starting material. Thus, there is a need to control the stereochemistry of the photoenols to favor the longer-lived E-isomers. Furthermore, it might also be possible to prevent the sigmatropic 1,5-H-atom shift from the Z-photoenols and, thus, to make them long-lived enough to release. Even though the quantum yields can be low for release from photoenols, it is an added benefit that the photoenols decay back to the starting material rather than form undesired by-products. The rate constants of release for the photoenols depend on the structure of the leaving group as well as the photoenols; these rate constants have been measured to be anywhere from a few ms 1 to a s 1. The rate of the release is also affected by the reaction medium, such as the solvent, pH value of the solvent, and the presence of oxygen. However, there is still immense opportunity to design new photoremovable protecting groups, especially those where the rate of release from photoenols can be effectively controlled.

Acknowledgments We thank our collaborators, Professor Cornelia Bohne, and Tamara Pace at the University of Victoria, and Dr. Jana Pika at Firmenich for valuable discussions while preparing this manuscript. We also express our gratitude to Dr. Kristinn Kristinsson for his technical and pedagogical support that made it possible to prepare this chapter. We also thank ACS-PRF for their support.

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4. Ellis-Davies GCR. Nat Methods 2007;4:619–28. 5. Herrmann A. Angew Chem Int Ed 2007;46:5836–63. 6. Pincock JA. CRC handbook of organic photochemistry and photobiology. 2nd ed. 2004; pp. 66/1–17. 7. Conrad PG, II, Chavli RV, Givens RS. Methods Mol Biol 2007;356:253–65. 8. Bochet CG. Pure Appl Chem 2006;78:241–7. 9. Bochet CG. Adv Org Synth 2005;1:3–23. 10. Young DD, Deiters A. Org Biomol Chem 2007;5:999–1005. 11. Bochet CG. J Chem Soc Perkin Trans 1 2002;125–42. 12. Pavlos CM, Xu H, Toscano JP. In: Goeldner M, Givens R, editors. Dynamic studies in biology. Weinheim: Wiley-VCH; 2005. pp. 178–205. 13. Miranda KM, Nagasawa HT, Toscano JP. Curr Top Med Chem 2005;5:649–64. 14. Furchgott RF. Angew Chem Int Ed 1999;38:1870–80. 15. Ignarro LJ. Angew Chem Int Ed 1999;38:1882–92. 16. Murad F. Angew Chem Int Ed 1999;38:1856–68. 17. Thomas DD, Liu X, Kantrow SP, Lancaster JR, Jr. Proc Natl Acad Sci USA 2001;98:355–60. 18. Hofseth LJ, Hussain SP, Wogan GN, Harris CC. Free Radical Biol Med 2003;34:955–68. 19. Pika J, Herrmann A, Vial C. (Firmenich S.A., Switz.). WO, 1999. p. 75. 20. Levrand B, Herrmann, A. Flavour Fragrance J 2006;21:400–9. 21. Zhu Y, Wang T, Gai F. In: Goeldner M, Givens R, editors. Dynamic studies in biology. Weinheim: Wiley-VCH; 2005. pp. 461–78. 22. Hansen KC, Rock RS, Larsen RW, Chan SI. J Am Chem Soc 2000;122:11567–8. 23. Huang C-Y, Klemke JW, Getahun Z, DeGrado WF, Gai F.J Am Chem Soc 2001;123:9235–8. 24. Jones CM, Henry ER, Hu Y, Chan CK, Luck SD, Bhuyan A et al. Proc Natl Acad Sci USA 1993;90:11860–4. 25. Volk M, Kholodenko Y, Lu HSM, Gooding EA, DeGrado WF, Hochstrasser RM. J Phys Chem B 1997;101:8607–16. 26. Wittung-Stafshede P, Lee JC, Winkler JR, Gray HB. Proc Natl Acad Sci USA 1999;96:6587–90. 27. Kumita JR, Smart OS, Woolley GA. Proc Natl Acad Sci USA 2000;97:3803–8. 28. Corrie, JET. In: Goeldner M, Givens R, editors. Dynamic studies in biology. Weinheim: Wiley-VCH; 2005; pp. 1–28. 29. Givens RS, Yousef AL. In: Goeldner M, Givens R, editors. Dynamic studies in biology. Weinheim: Wiley-VCH; 2005. pp. 55–75. 30. Givens RS, Kotala MB, Lee J-I. In: Goeldner M, Givens R, editors. Dynamic studies in biology. Weinheim: Wiley-VCH; 2005. pp. 95–129. 31. Sammes PG. Tetrahedron 1976;32:405–22. 32. Wagner P, Park BS. Org Photochem 1991;11:227–366. 33. Collie JN. J Chem Soc Trans 1904;85:971–80. 34. Huffman KR, Loy M, Ullman EF. J Am Chem Soc 1965;5417–23. 35. Wettermark G. Nature 1962;194:677. 36. Margerum JD. J Am Chem Soc 1965:87:3772–3. 37. Haag R, Wirz J, Wagner P. J Helv Chim Acta 1977;60:2595–607. 38. Scaiano JC. Acc Chem Res 1982;15:252–8. 39. Porter G, Tchir MF. J Chem Soc A 1971;23:3772–7. 40. Porter G, Tchir MF. J Chem Soc D 1970;20:1372–3. 41. Takahashi Y, Miyamoto K, Sakai K, Ikeda H, Miyashi T, Ito Y, et al. Tetrahedron Lett 1996;37:5547–50. 42. Ujiie K, Kikuchi K, Kokubun H. Chem Lett 1977;5:499–502. 43. Ujiie K, Kikuchi K, Kokubun H. J Photochem 1979;10:145–57.

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The chemistry of reactive radical intermediates in combustion and the atmosphere CARRIGAN J. HAYES,a JOHN K. MERLEb and CHRISTOPHER M. HADADa a

Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA Department of Chemistry, Winston-Salem State University, Winston-Salem, NC 27110, USA

b

1 2

Introduction 79 Basic concepts of combustion chemistry 80 Free radicals 80 Combustion at different temperatures 81 Methods for studying reactive combustion species 87 3 Reactive radical intermediates in combustion chemistry 91 Aliphatic systems 91 Aromatic systems 98 4 Future challenges in combustion chemistry 121 Fuel additives 122 Biodiesel 123 5 Conclusions 125 Acknowledgments 126 References 126

1

Introduction

Combustion processes convert chemical energy into heat and work, playing several important roles in today’s society. Oxidation processes provide power to beneficiaries ranging from automobiles to electrical generators; atmospheric oxidation reactions impact a wide range of environmental phenomena (i.e., ozone formation, photochemical smog, and acid rain). To fully understand combustion chemistry, it is necessary to understand the properties of the common reactive intermediates that participate in these reactions. Alkyl radicals (R•), alkoxy radicals (RO•), and peroxy radicals (ROO•) constitute the main classes of reactive radical intermediates involved in combustion. The occurrence and stability of the intermediates is governed by the temperature and pressure at which combustion (or oxidation) class takes place. Understanding these complex and dynamic relationships presents challenges for experimentalists and also for theorists. This review will first examine the fundamental chemistry that occurs during combustion of a fuel and then move into an exploration of some key classes of reactive intermediates. In particular, we will focus on the importance of reactive oxygen species (ROS) to combustion processes, highlighting our work on the unimolecular dissociative pathways available to the peroxy radicals of alkyl, aromatic, and heteroaromatic compounds. 79 ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 43 ISSN: 0065-3160 DOI: 10.1016/S0065-3160(08)00003-8

 2009 Elsevier Ltd. All rights reserved

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Basic concepts of combustion chemistry

FREE RADICALS

Any type of combustion chemistry is essentially dictated by the radical intermediates present. Before discussing how this occurs, it is first instructive to review some key aspects of radical chemistry. Most simply, free radicals are molecules with unpaired electrons. The lifetimes of these species vary widely given molecular composition and reaction environment, but the alkyl radicals of interest in combustion chemistry are highly reactive and thus short-lived. Radicals can vary in their hybridization (sp3, sp2, or sp), as well as the nature of the orbital in which their unpaired electron is placed (one dominated by s or p character); these orbital characteristics dictate the geometry around the radical center. Substituents (or functional groups) play a large role in stabilizing or destabilizing radicals. A free radical is stabilized by alkyl substituents on the radical center; tertiary radicals are more stable than secondary radicals, which are correspondingly more stable than primary radicals. Resonance stabilization (electron delocalization) also plays a role in radical stability: a radical adjacent to a p network (i.e., an allylic or benzylic system, or a carbonyl functionality) can delocalize the unpaired electron through this system and gain stability. Finally, inductive effects caused by an electronegative atom such as chlorine or a functionalized alkyl chain can affect radical stability. A radical is an odd-electron molecule, due to an unpaired electron, which can be oriented either spin-up (") or spin-down (#), leading to two degenerate electronic states as a doublet. The unpaired electron enables reactions that are different from those of closed-shell molecules. The basic steps of a radical chain reaction are familiar from undergraduate organic chemistry: initiation, whereby a reactive radical species forms; propagation, the processes by which the newly-formed radicals react with other molecular species to generate other radicals; and termination, via the collision of any two radical species to form one closed-shell molecule, thereby removing radicals from the system. Initiation can occur either thermolytically (when heat homolytically breaks a molecule’s bond) or photolytically (when high-energy light homolytically breaks a molecule’s bond). Once a radical forms, it can undergo a variety of propagation reactions, including hydrogen atom transfers, eliminations, additions, and unimolecular fragmentations; any reaction step that begins with a radical reactant and yields a radical product is classified as a chain-propagating step. Often, in flame chemistry, a reactive hydroxyl (HO•) radical is first formed, which then reacts with the fuel molecule via an initiation step (R—H þ HO• ! R• þ H2O). The ensuing variety of propagation possibilities constitute much of the chemistry of interest in combustion processes; this topic will be revisited shortly. Bond dissociation enthalpies (BDEs) aid in predicting relative reactivities for different organic (fuel) molecules. BDEs correspond to the enthalpy change for the homolytic cleavage of a chemical bond. The more stable the resulting radical is, relative to the reactant, the more favorable it is for the bond to break. General explanations for radical stability include alkyl substitution and resonance effects (as noted above). Additionally, Gronert has recently summarized work leading to an alternative explanation, that the

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potential for release of 1,3 repulsive energy (strain) has the greatest effect on these quantities: that is, a tertiary radical is more stable than a primary radical not because of the larger number of alkyl substituents attached to the radical center, but because of the greater magnitude of the geminal interactions in the parent (more congested) hydrocarbons that are relieved upon C—H bond cleavage to form the radical.1 Regardless of the origin of the effect, these BDE quantities are useful in rationalizing initiation steps for given fuels. Free radicals are involved in a wide variety of reactions, due to their reactivity and versatility; understanding their behavior as it relates to combustion is a goal of many experimentalists and theoreticians. Two specific classes of radicals of interest to combustion processes are peroxy (ROO•) radicals and oxy (RO•) radicals; along with hydroxyl (HO•) radical, many of these radicals are important members in the general class referred to as reactive oxygen species (ROS).2

COMBUSTION AT DIFFERENT TEMPERATURES

The concept behind combustion is straightforward – when a hydrocarbon fuel reacts with oxygen, the organic component is eventually converted to carbon dioxide and water – but the reality is more complicated. For instance, the combustion of methane (Reaction 1) is often used to teach students how to balance reaction equations: CH4 þ 2O2 ! CO2 þ 2H2O

ð1Þ

However, the combustion process for methane requires no fewer than 325 individual mechanistic steps (elementary reactions) to be accurately described, rather than the one-step route shown above.3 As such, incomplete combustion is a common occurrence and ROS are pervasive byproducts of that phenomenon, affecting an engine’s fuel efficiency and producing atmospherically detrimental emissions. Moreover, combustion varies with system temperature, as different oxidative pathways become accessible, as well as fuel/oxidizer ratio (equivalence ratio). By examining the representative cases of methane oxidation at high and low temperatures, this phenomenon becomes clearer. High-temperature combustion At high temperatures (as a general rule, T >1000 K), methane oxidation4 is initiated via hydrogen atom abstraction by hydroxyl radical, oxygen atom, or hydrogen atom (all of which are species generated in flames, oxygen to the smallest extent). Subsequently, in the most direct oxidative route (Fig. 1), methyl radical is oxidized to formaldehyde, which then loses a hydrogen atom to form formyl (HCO•) radical. Formyl radical can subsequently lose a hydrogen atom via collisional dissociation or reaction with molecular oxygen, thereby forming carbon monoxide (CO). A final oxidation step via the reaction of CO with hydroxyl radical yields the fully oxidized carbon dioxide as a final product. To more completely characterize the overall methane combustion mechanism,

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Fig. 1 High-temperature methane combustion. Adapted from Reference 7.

additional reactions such as methyl radical recombination and hydrocarbon eliminations, as well as ethene and acetylene oxidations, must also be considered. In this basic scenario, methyl, methoxy, and formyl radicals are intermediates of great interest; extending beyond this most straightforward case, the reactions of alkyl, alkenyl, alkynyl, alkoxy, and aldehydic radicals are all reactive intermediates of interest in high-temperature fuel combustion. Low-temperature combustion The low-temperature oxidation of methane (as a general rule, T < 1000 K) requires a more complex reaction scheme (Fig. 2). In reality, low-temperature oxidation of methane is unlikely to proceed readily, due to its substantial C—H bond strength; nevertheless, these pathways are shown below chiefly to illustrate common hydrocarbon oxidation pathways at low temperatures. The reaction scheme for oxidation of methane can be rationalized as proceeding in two phases.4 Since reactive flame species such as O(3P), H•, and HO• are not observed at low temperatures, the formation of the methyl radical must be achieved instead via an endothermic reaction with molecular oxygen.5 Once methyl radical is formed, it reacts with another oxygen molecule to form methylperoxy radical (CH3OO•), which abstracts a hydrogen atom from methane to form methyl hydroperoxide (CH3OOH) and methyl radical. Methyl hydroperoxide can unimolecularly dissociate to produce methoxy (CH3O•) and hydroxyl (HO•) radical. These last two steps are crucial, as they build up a reactive radical pool. Once a sufficient amount of methyl, methoxy, and hydroxyl radicals has formed, these species appropriate the initial duty of abstracting H atoms from methane, driving the reaction rate forward rapidly. Methyl radical is now formed at an appreciable rate and can undergo oxidation and recombination steps. More generally, low-temperature combustion relies heavily on the tendency of radical propagation to yield chain-branching reactions, a phenomenon first explored

THE CHEMISTRY OF REACTIVE RADICAL INTERMEDIATES O2

O2

•

•

CH3

CH4 •

•

CH4

83 •

CH3OOH + CH3

CH3O2

•

R = CH3, OH, CH3O • •

R•

CH4

CH3O + OH

•

CH3 + RH

•

•

CH3O2 •

O2

CH3OH + HCO

CH3OH •

CH3O + CH3O

•

CH3OH

CH3O2 •

CH3O2

•

CH2OH + CH3OH

CH2O

•

R

•

CH3OH + CH2O + O2

CH3OOH + HCO

O2 •

CH2O + HO2•

CH2OH + RH

• •

2CH3O + OH •

H + CO

•

HCO + RH

CH3OH + CH2O

Fig. 2 Low-temperature methane oxidation. Adapted from Reference 4.

by Semenov.6 Semenov’s reaction scheme is most relevant for species with two or more carbons and can be written as R• þ O2 ! alkene þ HO2•

ð2Þ

R• þ O2 þ M ! RO2• þ M •

ð3Þ

RO2 þ R—H ! RO2H þ R •

•

ð4Þ

•

ð5Þ

HO2• þ R—H ! H2O2 þ R•

ð6Þ

0

00

RO2 ! R CH(TO) þ R O

RO2H ! RO• þ •OH

ð7Þ •

R0 CH(TO) þ O2 ! R0 C (TO) þ HO2

•

ð8Þ

Using this scheme, we can track the original alkyl radical through the most likely mechanisms for oxidation at low temperatures that lead to chain-branching. Once formed from the parent molecule (R—H), an alkyl radical (R•) can react with molecular oxygen to form an alkene and hydroperoxyl (HO2•) radical [Equation (2)], via

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1,4-H-atom abstraction from the peroxy radical adduct. Alternatively, alkylperoxy radicals can be stabilized by collisionally transferring some excess energy, obtained during formation, to other molecules or atoms (M). The branching ratio between Reactions 2 and 3 is therefore highly pressure-dependent (i.e., it depends on the concentration of M). Once formed, the peroxy radical can abstract a hydrogen atom from an alkane to form a new radical [Equation (4)] or dissociate unimolecularly, yielding an aldehyde and alkoxy radical [Equation (5)]; both of these reactions produce a molecule that can participate in a chain-branching reaction. Since HO2• is unreactive at lower temperatures, Reaction 6 is less likely than the self-reaction of HO2• resulting in H2O2 and O2. Reactions 7 and 8 are chain-branching steps, which figure heavily in the exponential increase in radical concentration necessary to achieve ignition for the combustion of a given fuel (R—H). As shown, peroxy radical chemistry plays a substantial role in low-temperature combustion as opposed to the alkoxy radical chemistry of high-temperature combustion. Thus, the peroxy radicals constitute an important class of reactive intermediates with significant implications for low temperature combustion and atmospheric reactions. Negative temperature coefficient phenomenon In terms of temperature regions, low-temperature combustion occurs over the range 298–550 K, whereas high-temperature combustion mechanisms dominate at temperatures over 1000 K. Intermediate temperatures, from 550 to 700 K, demonstrate an unusual phenomenon called the negative temperature coefficient (NTC), which is observed for methane and larger hydrocarbon fuels.7 As shown in Fig. 3, when the correct alkylperoxy radical chemistry is included in a fuel’s combustion mechanism, a NTC range exists (Fig. 3, plot C) where an increase in temperature causes a decrease

Ignition delay

(a) (a) High T chemistry only (b, c) Peroxy radical chemistry included

(c)

(b)

Initial temperature

Fig. 3 Typical ignition delay of an alkane fuel as a function of the initial mixture’s temperature. Three different kinetic models are shown: (a) High temperature chemistry only; that is, no peroxy radical chemistry. (b) Same as (a), but the ‘‘Q•OOH’’ chain-branching channel of the peroxy radicals has been considered. (c) Same as (b), but the concerted elimination of RO2• to olefin þ HO2• has been considered (courtesy of Dr. Timothy Barckholtz, ExxonMobil Research and Engineering).8

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in reaction rate (i.e., a longer time to ignition).8 A simplified view9 of this phenomenon can be rationalized via an examination of the low-temperature combustion mechanism. Again, a crucial step in achieving the combustion of hydrocarbon fuels involves the unimolecular dissociation of an alkyl hydroperoxide (ROOH) into alkoxy (RO•) and hydroxyl (HO•) radicals, that is, chain-branching. The alkylperoxy radical leading to an alkyl hydroperoxide [Equation (4)] is in equilibrium with the reactants: alkyl radical and molecular oxygen (O2) [reverse of Equation (3)]. As the temperature increases, entropy favors the reactants, so that the alkylperoxy radical concentration will be minimized, and therefore, so will the alkyl hydroperoxide concentration. Thus, the chain-branching step cannot drive the oxidation forward, and the ignition time will increase. Moreover, for a hydrocarbon with two or more carbons, molecular oxygen can instead abstract a hydrogen atom from the alkyl radical, yielding an alkene and (notoriously unreactive) hydroperoxyl (HO2•) radical [Equation (2)]. It is also important to note the pressure-dependence of the competition between Equations (2) and (3); to persist, peroxy radicals must be stabilized after formation via collisions with other species. The NTC regime will remain in effect until the temperature increases sufficiently to allow for high-temperature, chain-branching pathways. At high temperatures, NTC is no longer relevant and the ignition rate increases with increasing temperature once again. Atmospheric oxidation The chemistry of the troposphere (the layer of the atmosphere closest to earth’s surface) overlaps with low-temperature combustion, as one would expect for an oxidative environment. Consequently, the concerns of atmospheric chemistry overlap with those of combustion chemistry. Monks recently published a tutorial review of radical chemistry in the troposphere.10 Atkinson and Arey have compiled a thorough database of atmospheric degradation reactions of volatile organic compounds (VOCs),11 while Atkinson et al. have generated a database of reactions for several reactive species with atmospheric implications.12 Also, Sandler et al. have contributed to the Jet Propulsion Laboratory’s extensive database of chemical kinetic and photochemical data.13 These reviews address reactions with atmospheric implications in far greater detail than is possible for the scope of this review. For our purposes, we can extend the low-temperature combustion reactions [Equations (4) and (5)], whereby peroxy radicals would have the capacity to react with prevalent atmospheric radicals, such as HO2•, NO•, NO2•, and NO3• (the latter three of which are collectively known as NOy): RCH2O2• þ NO• ! RCH2O• þ NO2• •

•

ð9Þ

RCH2O2 þ NO þ M ! RCH2ONO2 þ M

ð9aÞ

RCH2O2• þ NO2• þ M ! RCH2OONO2 þ M

ð10Þ

RCH2O2• þ HO2• ! RCH2OOH+O2

ð11Þ

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RCH2O2• þ HO2• ! RCHO þ H2O þ O2

ð11aÞ

RCH2O2• þ RCH2O2• ! RCH2O• þ RCH2O• þ O2

ð12Þ

RCH2O2• þ RCH2O2• ! RCHO þ RCH2OH þ O2

ð12aÞ

RCH2O2 þ NO3• ! RC(¼O)H þ HOx þ NOx

ð13Þ

Oxidation in the atmosphere begins photolytically with radiation from the sun rather than thermolytically; thus, atmospheric chemistry differs between day and night. In the daytime, the most common initiation step for VOC degradation involves photolysis of ozone by the sun’s ultraviolet light, leading to hydroxyl (HO•) radical generation: O3 þ h ! O(1D) þ O2 1

O( D) þ H2O ! 2HO

ð14Þ

•

ð15Þ

Once formed, the peroxy radicals have longer tropospheric lifetimes than HO• and can maintain larger concentrations. Common reactions of peroxy radicals include self-reactions to yield two carbonyl functionalized molecules and O2 [Equations (12) and (12a)]; reactions with HO2• to yield alkylhydroperoxides, aldehydes, H2O, and O2 [Equations (11) and (11a)]; and reactions with NOx species [NOx = NO• and NO2•] to yield alkoxy, alkylnitrate, and alkylperoxynitrate species [Equations (9), (9a) and (10)]. NOx reactions are of significant interest because alkylnitrate and alkylperoxynitrate molecules are stable enough to act as reservoirs, traveling long distances from VOC emission sources before decomposing, thus affecting distant air quality. For example, alkylnitrates can decompose to yield RO• and NO2•, and alkoxy radicals readily react with O2 to yield aldehydes. After H-atom transfer, the weak aldehydic CH bond is readily abstracted to yield an acyl radical, which can react with O2 and NO2• in succession to form peroxyacylnitrates (RC(¼O)OONO2 or PANs). PANs have various detrimental effects; in addition to the reservoir behavior described above, they are lachrymators and demonstrate mutagenic effects.14 Reactions of alkylperoxy radicals with NO3• can serve as an alternative nighttime source for HO• via a complicated series of reactions approximated by Equation (13). At night, when the sun’s radiation is minimal, the dominant VOC oxidant is nitrate radical (NO3•). The chemistry initiated by NO3• differs from that initiated by HO• radical in that NO3• prefers to react with unsaturated compounds via addition to one of the carbons of the p-system, rather than by hydrogen atom abstraction: NO2• þ O3 ! NO3• þ O2

ð16Þ

NO3• þ CH3CHTCH2 ! CH3•CHCH2ONO2 •

•

CH3 CHCH2ONO2 þ O2 ! CH3CH(OO )CH2ONO2

ð17Þ ð18Þ

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As shown, NO3• radical leads to different chemistry than does HO• radical; the peroxy radical can decompose to yield several products, including acetaldehyde, formaldehyde, 1,2-propanediol dinitrate (PDDN), nitroxyperoxypropyl nitrate (NPPN), and a-nitrooxyacetone. The reactions of the peroxy radicals with NOx species can lead to highly functionalized (and oxidized) organic compounds. The interplay of HO•, peroxy radicals, VOCs, and NOx species has substantial implications for tropospheric air quality. For instance, VOCs, NOx, and sunlight result in poor visibility from ozone and aerosol formation, together denoted as photochemical smog, which can lead to adverse health effects in sensitive individuals. Normally, we think of minimizing either class of compounds as beneficial to the atmosphere. However, minimizing VOC emissions only impacts ozone concentration in high-NOx areas. Moreover, in VOC-sensitive areas, reductions in NOx may lead to the overproduction of ozone. We can examine a simplified scheme15 for ozone production: NO2• þ h ! NO• þ O(3P)

ð19Þ

O(3P) þ O2 þ M ! O3 þ M

ð20Þ

In an ideal troposphere, O3 would react with NO• yielding NO2• and ultimately regenerating O3 [Equations (19) and (20)], thus no over-production of ozone could occur. However, in the presence of VOCs, the resultant peroxy radicals formed can compete with O3 by also reacting with NO• to form excess NO2•, thus resulting in the formation of excess ozone. This is just one example of the complexity of atmospheric chemistry; peroxy radicals and NOx have substantial implications for reaction with climate gases, acid rain formation, and other aspects of air quality. Saunders et al.16 and Jenkin et al.17 have provided a wealth of information on the tropospheric degradation of aliphatic and aromatic VOCs. Additionally, the interested reader may wish to consult References 10–17 for further discussion of these important topics. An additional concern in the commercial applications of combustion chemistry involves understanding and minimizing the production of harmful emissions [such as CO, carbon dioxide, and the oxides of sulfur (SOx), in addition to NOx] in combustion processes. Carbon dioxide increases the amount of greenhouse gas in the atmosphere and contributes to global warming, while NOx and SOx (oxidized derivatives of nitrogen and sulfur) can be transformed in water aerosols resulting in acid rain (via HNO3 and H2SO4, respectively). Another concern involves the formation of soot particles that can have severe respiratory effects. Many studies in combustion chemistry seek to reduce the production of these harmful byproducts.18

METHODS FOR STUDYING REACTIVE COMBUSTION SPECIES

Experimental methods Experiments performed in the 1960s and 1970s used a variety of approaches to detect molecular species and determine rate coefficients for the elementary steps that

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comprised hydrocarbon combustion. Many of these experimental methods are still widely used in combustion studies today. We will briefly discuss these methods as well as surveying some of the more sophisticated methods developed in recent decades. In combustion experiments, there are two key considerations: first, generating a flame and second, detecting the species of interest. Gaseous flows in a flame can be classified as laminar (streamlined layers) or turbulent. While these flames can be analyzed directly, it is less confounding to study flame chemistry through controlled generation of reactive species in one of a wide variety of experimental apparata. One such device is the shock tube.19 This cylindrical apparatus has both a highpressure region filled with an inert gas and a low-pressure region that contains the reactants of interest – fuel only if pyrolytic (thermal decomposition) processes are being examined, fuel and oxidizer if combustion processes are being examined – separated by a thin membrane. After the membrane is ruptured, a high-pressure shock wave travels down the low-pressure region and is reflected back on a microsecond time scale. The system temperature increases rapidly enough to yield hightemperature chemistry and is rapidly quenched for clean analysis. Other techniques simulate postignition flame processes. In the flow reactor, reactants of interest enter the reactor at one end and travel through a constant temperature region.7 Ideally, all concentrations and temperatures are consistent across the cross section of the reactor, so that all movement is in one direction and wall reactions are minimized. A similar approach involves the use of crossed molecular beams,20 wherein two molecular beams are directed into one another; the area of collisional intersection demonstrates chemistry that can occur in flames. Additionally, specific flame species of interest can be directly generated. Radicals can be generated photolytically (via light), thermolytically (via heat), chemically, or via microwaves. Laser-based methods are used to photolytically generate radicals. However, not every radical of interest can be generated from a convenient precursor; moreover, radicals generated via photolytic methods have excess internal energy, which increases the potential of their side reactions. Likewise, pyrolytic sources can be used with a wider range of species, but often necessitate a long residence time (ms) for radicals in the heating zone, giving high probabilities for radical–radical reactions and radical–wall reactions. These drawbacks have been circumvented via novel instrumentation in certain cases. For instance, Chen et al. developed a hyperthermal pyrolytic nozzle21 that works on a shorter time scale (ms) and generates thermally cold radicals via a jet expansion; this nozzle has been coupled with several targets and techniques by various researchers.22 In terms of coupling flame generation and detection methods, several combinations are common. Generally, shock tubes are coupled with IR and UV absorption and gas chromatography (GC) detectors, while flow reactors are used in tandem with GC, electron spin resonance, and resonance fluorescence detection. More advanced techniques are also available. For instance, mass spectrometry (MS) can be used by converting neutral radicals to ions, via chemical ionization and electron impact; these ions are then separated and detected according to their massto-charge ratios (m/z). The primary drawback of this method is that it cannot directly

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discern between isomers; structural isomers have identical m/z ratios but may behave in chemically unique fashions. Moreover, when MS is coupled with a flamegenerating system, the probe location must be chosen carefully, as the species population can vary greatly given the distance from the flame. Instrumental methods have become more sophisticated to face these challenges.23 In particular, Westmoreland and Cool have developed a flame-sampling mass spectrometer that has provided several revelations in terms of relevant molecular intermediates in combustion.24 Their setup couples a laminar flat-flame burner to a mass spectrometer. This burner can be moved along the axis of the molecular beam to obtain spatial and temporal profiles of common flame intermediates. By using a highly tunable synchrotron radiation source, isomeric information on selected mass peaks can be obtained. This experiment represents a huge step forward in the utility of MS in combustion studies: lack of isomer characterization had previously prevented a full accounting of the reaction species and pathways. When paired with an appropriate radical target, laser-based methods can serve either diagnostically, to discern which intermediates are present in a flame, or analytically, to explore the kinetics and dynamics of elementary steps of interest. Laser-induced fluorescence (LIF) and Raman spectroscopy (RS) are two typical diagnostic techniques; the former explores electronic transitions of a radical of interest, while the latter explores structural aspects of a species via observation of changes in its polarizability. Laser flash photolysis (LFP) is a common kinetic technique, in which a radical precursor is generated via a laser pulse, and the resultant radicals react with a target of interest; the rate of this reaction can be thus extrapolated by monitoring decreasing radical concentration over time. Many laser techniques are currently available and can provide a wealth of information on the structural, vibrational, and electronic properties of reactive radical intermediates. Several reviews of the use of lasers in combustion chemistry have been compiled, including those by Wolfrum,25 Crosley,26 and Eckbreth.27 Computational methods Computational and experimental methods clearly benefit from a symbiotic relationship in combustion studies.28 Theoretical calculations can propose important pathways to yield empirically observed intermediates by providing reaction energies and rate coefficients of elementary reactions, thereby guiding experiments. Moreover, theoretical calculations can potentially fill some gaps caused by limitations in experimental approaches: the vast majority of analytical techniques fail to distinguish between structural isomers and to identify short-lived intermediate species, both of which are important objectives in delineating overall combustion behavior. Finally, modeling can identify species to look for experimentally. Quantum chemical calculations are the most accurate theoretical methods available for studying the structures, energies, and elementary reactions of molecules. It is possible to determine the structure, energy, and geometrical parameters (i.e., vibrational frequencies, electronic states, and rotational constants) for reactants, transition states, and products of a chemical reaction. With this information,

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reaction thermodynamics [enthalpy (H), entropy (S), and free energy (G)] at specified temperatures can be estimated and reaction barriers and energies predicted. Furthermore, since reaction barriers can be calculated, absolute rate coefficients can be determined according to transition state theory (TST).29

k ðT Þ TST ¼ GðTÞ

kB T ðD G6¼ = kBT Þ 0 e h

ð21Þ

In Equation 21, T is the absolute temperature, h is Planck’s constant, kB is Boltzmann constant, and DG6¼ 0 is the free energy barrier height relative to infinitely-separated reactants. The temperature-dependent factor (T) represents quantum mechanical tunneling and the Wigner approximation30 to tunneling through an inverted parabolic barrier:   1 h i 2 ð22Þ GðTÞ ¼ 1 þ 24 kB T where  i is the imaginary vibrational frequency representing the curvature of the transition state barrier. Transition state theory yields rate coefficients at the high-pressure limit (i.e., statistical equilibrium). For reactions that are pressure-dependent, more sophisticated methods such as RRKM31 rate calculations coupled with master equation32 calculations (to estimate collisional energy transfer) allow for estimation of lowpressure rates. Rate coefficients obtained over a range of temperatures can be used to obtain two- and three-parameter Arrhenius expressions: Ea kðTÞ ¼ Aeð RT Þ

ð23Þ

Eo kðTÞ ¼ AT m eð RT Þ

ð24Þ

Common quantum mechanical methods for exploring the energetics of elementary reaction steps include ab initio33 and density functional theory (DFT).34 As computational speeds have increased, use of higher levels of theory have allowed for more accurate prediction of properties and reactions for reactive radical intermediates, further advancing our understanding of combustion chemistry. Using these methods, the elementary reaction steps that define a fuel’s overall combustion can be compiled, generating an overall combustion mechanism. Combustion simulation software, like CHEMKIN,35 takes as input a fuel’s combustion mechanism and other system parameters, along with a reactor model, and simulates a complex combustion environment (Fig. 4). For instance, one of CHEMKIN’s applications can simulate the behavior of a flame in a given fuel, providing a wealth of information about flame speed, key intermediates, and dominant reactions. Computational fluid dynamics7 can be combined with detailed chemical kinetic models to also be able to simulate turbulent flames and macroscopic combustion environments.

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Kinetic mechanism

Thermodynamic data

Reactor model

Results

Transport data

Fig. 4

Flow chart for a typical combustion simulation method. Adapted from Reference 35.

While theoretical calculations generally have been used to supplement experimental findings, they also hold enormous promise for fully discerning the potential energy surfaces of relevant combustion pathways, as well as identifying and exploring the chemistry of relevant reactive intermediates.

3

Reactive radical intermediate chemistry in combustion

ALIPHATIC SYSTEMS

Methane combustion The simplest hydrocarbon, methane, has posed a wealth of challenges to experimentalists and theoreticians seeking to discern its combustion mechanism. Methane’s reactions have been explored in a wide variety of contexts over the past several decades. We have discussed these briefly; the interested reader is referred to the reviews cited in our previous discussion for further details. Due to the scope of this review, we are primarily interested in these reactions insofar as they provide useful benchmarks for the reactions of larger alkylperoxy (RO2•) and alkoxy (RO•) systems. With respect to the reactive intermediates present in methane combustion and their implications for larger systems, Lightfoot has published a review on the atmospheric role of these species,36 while Wallington et al. have provided multiple overviews of gas-phase peroxy radical chemistry.37 Lesclaux has provided multiple reviews of developments in peroxy radical chemistry.38 Batt published a review of the gas-phase decomposition reactions available to the alkoxy radicals.39 Notably, the Gas Research Institute’s mechanism (GRI-MECH) for methane combustion3 is well-established, drawing on research from several groups over several decades to define and calibrate kinetic and thermodynamic data for each elementary reaction step. Additional mechanisms40 for methane oxidation are also available and updated periodically to include the most recent data. Methoxy (CH3O•) and methylperoxy (CH3O2•) radicals have been subjected to substantial study. Zaslonko et al. have reviewed several reactions involving the

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methoxy radical.41 More specifically, several experimental methods have been employed in studying this species. As early as 50 years ago, methoxy radical was an experimental target in mass spectrometric studies by Lossing.42 Burcat and Kudchadker used IR vibrational spectra of methanol at varying temperatures to extrapolate the ideal gas properties of methoxy radical.43 Ruscic and Berkowitz used photoionization MS44 to determine the ionization potential (IP) and heat of formation (DfH0) of methoxy radical. Martinez et al. used LIF to determine the temperature and pressure dependence of the rate coefficients for CH3O• þ NO2• over the 250–390 K temperature and 50–600 Torr pressure ranges.45 Wollenhaupt et al. examined the same reaction using pulsed laser photolysis (PLP).46 Computationally, Carter and Cook completed an extensive assessment of theoretical approaches for methoxy radical,47 while Page explored the kinetics of its unimolecular decomposition.48 Subsequent studies have focused on methoxy radical’s reactivity with a variety of molecules: Pan et al.49 and Sun et al.,50 with NO2•; Pang et al.,51 with NO•. Gomez et al.52 have modeled the addition and H-atom abstraction reactions of methoxy radical with various hydrocarbons. In early studies of methylperoxy radical, Simonaitis and Heicklin53 observed its reaction with NO• and NO2•, while Cox and Tyndall54 used molecular modulation spectroscopy to supplement these findings, and Kan and Calvert studied the water vapor dependence of the CH3O• self-reaction.55 More recently, Wallington et al. obtained absorption spectra of methylperoxy and other alkylperoxy radicals, over the 200–400 nm range.56 Tyndall et al. explored the self-reaction of methylperoxy radical via Fourier Transform Infrared (FTIR) spectroscopy, while Ghigo et al. have modeled the reaction energy surface computationally.57 Their findings complemented an earlier FP study by Lightfoot et al.58 Lesar et al. completed a quantum mechanical investigation of the reaction of CH3O2• with NO•.59 Biggs et al. explored the reaction of methylperoxy radical with NO3•60 as a possible source of nighttime HO• radical. Atkinson and Spillman have explored the kinetics of CH3O2• using cavity ring-down spectroscopy (CRDS), confirming previous findings by Hunziker61 and Pushkarsky.62 Enami et al. explored the kinetics of the reaction between bromine monoxide (BrO•) and methylperoxy radical.63 Together, these experimental and computational investigations provided mechanistic insights, rate constants, pressure dependences, branching ratios, and so on for the creation and validation of the 325step GRI-MECH for methane combustion. Ethyl radical þ O2 Intramolecular reactions become increasingly important as the size of the alkyl chain increases, for a given radical. Ethylperoxy (CH3CH2O2•) radical is a target of significant interest because it can undergo intramolecular rearrangement via a low-strain, fivemembered ring transition state structure. Historically, ethyl radical has been implicated as a discrete intermediate in many reactions. While early experimental studies of ethyl radical suggested that this species reacts bimolecularly with O2 to yield ethene (H2CTCH2, or C2H4) and hydroperoxyl (HO2•) radical,64 subsequent observation of other products such as acetaldehyde and oxirane imply a more complex mechanism. In

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1975, Hickel65 affirmed that this initial view of ethyl radical oxidation was incomplete, with support by Dechaux and Delfosse66 in 1979. Rather, it was deemed likely that ethyl radical oxidation proceeded through a Semenov-type mechanism [Equation (3)], in which ethylperoxy radical is an intermediate, formed by collisional cooling, which could transfer a hydrogen atom intramolecularly and decompose via multiple pathways. Subsequent experimental work bolstered the likelihood that ethylperoxy radical was an ethane oxidation intermediate. Baldwin postulated in 1986 that molecular oxygen adds to ethyl radical to form ethylperoxy radical, which then undergoes concerted H-atom transfer and elimination to yield ethene and hydroperoxyl radical.67 These and other experimental findings have been summarized in several reviews, including those of Fish,68 Walker,69 and Pilling et al.70 The small size of the CH3CH2• þ O2 system makes high-level computational exploration of its reaction energy surface tractable. Rienstra-Kiracofe et al. have provided an excellent review of the advances made in ab initio modeling of the CH3CH2• þ O2 potential energy surface over the past several years.71 These authors also summarized their own high-level calculations, noting the five most plausible pathways for the ethyl radical þ O2 reaction, four of which involve the unimolecular decomposition/rearrangement of ethylperoxy radical. C2H5• þ O2 ! C2H4 þ HO2•

ð25Þ

• • • C2H5• þ O2 !  CH3CH2OO !  CH2CH2OOH !  c-CH2CH2O+HO

ð26Þ

• • • C2H5• þ O2 !  CH3CH2OO !  CH3 CHOOH !  CH3CHO þ HO

ð27Þ

• • • C2H5• þ O2 !  CH3CH2OO !  CH2CH2OOH !  C2H4 þ HO2

ð28Þ

•

C2H5 þ O2 !  CH3CH2OO

•

• !  C2H4 þ HO2

ð29Þ

Equation (25) accounts for the NTC range observed for the ignition of ethane. Essentially, these reactions are refinements of the Semenov mechanism, since unimolecular reactions are important pathways in the oxidation of ethane. Due to its importance to hydrocarbon combustion as a model alkylperoxy radical, ethylperoxy radical continues to be the subject of experimental studies. Xing et al. used time-resolved, negative-ion MS to explore the reaction of ethylperoxy radical and nitric oxide.72 In separate works, Maricq and Szente explored the kinetics of ethylperoxy’s reaction with acetylperoxy radical73 and NO74 using transient diode laser absorption and time-resolved ultraviolet (TR-UV) spectroscopy. Atkinson and Hudgens have used ultraviolet cavity-ringdown spectroscopy (CRDS) to perform kinetic studies on the ethylperoxy radical self-reaction,75 while Rupper et al. used CRDS to explore the A˜ X˜ electronic transition of CH3CH2O2•.76 Hasson et al. used FT-IR and high-performance liquid chromatography (HPLC) with fluorescence detection to study the reaction of CH3CH2O2• with HO2•,77 while Mah et al. produced a mid-IR spectrum of this species.78 Ethoxy radical (CH3CH2O•) has enjoyed considerable interest as well. Choi et al. explored its photodissociation dynamics via photofragment translational

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spectroscopy,79 while Faulhaber et al. pursued the same goal using photofragment coincidence imaging.80 Computationally, Matus et al. performed CCSD(T) calculations81 to generate quantities of interest for this radical, including computing a heat of formation (–2.7  0.8 kcal/mol) via atomization energies. The development of an ethane combustion mechanism provides a historical context for understanding some overall trends of alkyl radical combustion. An understanding of the likely pathways for this small system is useful in modeling chemistry of larger systems, as can be observed from an examination of some other reactive radical intermediates. n-Propylperoxy radical (CH3 CH2 CH2 O2 ) In longer chain hydrocarbon radicals, isomerization reactions become more important; these pathways compete with bimolecular oxidation reactions and can impact ignition rates at low temperatures. For instance, n-propylperoxy radical can undergo several unimolecular dissociations/rearrangements:82 CH3CH2CH2OO• ! CH3CH2CH•2 þ O2

ð30Þ

CH3CH2CH2OO• ! CH3CHTCH2 þ HO•2

ð31Þ

CH3CH2CH2OO• ! CH3CH2CH•OOH

ð32Þ

CH3CH2CH2OO• ! CH3CH•CH2OOH

ð33Þ

CH3CH2CH2OO• ! •CH2CH2CH2OOH

ð34Þ

Reversion to reactants [Equation (30)] is straightforward; similarly, the concerted H-atom transfer and elimination pathway [Equation (31)] observed for ethylperoxy radical can also occur for CH3CH2CH2O2•. However, multiple isomerization pathways [Equations (32–34)] are now possible because the length of the alkyl chain has increased. In particular, the 1,5-H-atom transfer occurs via a six-membered ring transition state, thereby minimizing ring strain. Rearrangement reactions lead to a more complex mixture of products. Extrapolating from our knowledge of the ethylperoxy radical pathways, these isomerization products can decompose into propene, propanal, and other oxidation products. The preferences of n-propylperoxy radical will impact overall propane combustion. Because n-propylperoxy radical is small and can undergo low-barrier rearrangements, it is important to understand its possible rearrangement products; these findings have implications for larger hydrocarbons. DeSain et al. studied the production of hydroperoxyl radical via the reaction of n-propyl radical with O2 and proposed an activation barrier of 26.0 kcal/mol for Reaction 31;83 moreover, they have also observed sizable amounts of HO• radical, likely following one of the unimolecular H-atom transfer steps.84 Zalyubovsky et al. examined the A˜ X˜ • transition of CH3CH2CH2O2 (using CRDS) and detected several of its rotational isomers at 298 K.85b Chow et al. explored the kinetics of CH3CH2CH2O2• þ NO• via

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high-pressure chemical ionization mass spectrometry (CIMS).86 Kaiser explored the production of propene from the CH3CH2CH2• þ O2 reaction as a function of temperature and pressure and posited that chemically activated CH3CH2CH2O2• was an intermediate, resulting from the addition reaction’s exothermicity.87 Computationally, DeSain et al.88 performed QCISD(T) studies to explore the 1,4- and 1,5H-atom transfer reactions for several RO2• systems (including CH3CH2CH2O2•), generating RRKM/master equation rates to model HO2• and HO• production. Naik et al.89 performed a similar study using quantum RRK rates to yield rates for hydroperoxyl radical production in the n-propyl radical þ O2 system. Chen and Bozzelli have completed ab initio and DFT studies on the thermochemical and kinetic parameters of the n-propyl radical þ O2 reaction; they hypothesized that low-temperature ignition for this system results from intramolecular H-transfer reactions of CH3CH2CH2O2• followed by the addition of a second oxygen molecule making it capable of forming products that undergo chain-branching.90 Our group has examined the conformations of CH3CH2CH2O2•, as well as its possible unimolecular decomposition pathways.91 n-Propylperoxy radical conformations are described by two torsion angles: CC—CO in an anti orientation [here called trans (t)] or gauche (g) orientation and CC—OO in an anti orientation [trans (T)] or gauche (G) orientation. Energy profiles for these torsions were generated computationally, minima were obtained, enantiomers were noted, and five unique conformers were identified (Fig. 5). These conformers could rapidly interconvert, as the highest torsional barrier was predicted to be less than þ5.0 kcal/mol. Using the CBS-QB3 theoretical method,92 the 298 K distribution of rotamers was calculated to be 28.1, 26.4, 19.6, 14.0, and 11.9% for the gG, tG, gT, gG0 , and tT conformers, respectively. Therefore, all five conformers will be present as seen experimentally by Zalyubovsky et al.85b The unimolecular reactions of CH3CH2CH2O2• were studied in detail (Fig. 6); complete potential energy surfaces were generated using both DFT [B3LYP/ 6–31þG(d,p) and mPW1K/6–31þG(d,p)]34,93 and CBS-QB392 methods. As expected, 1,5-H transfer [Equation (34)] occurs with the lowest barrier, followed by simultaneous 1,4-H transfer and HO2• expulsion [Equation (31)]. The overall decompositions of each H-atom transfer product (i.e., each QOOH radical) were modeled. It

tG

gT

tT

gG′

gG

Fig. 5 Conformers of n-propylperoxy radical, named according to the conformational preferences around the central C—C bond, then around the C—O bond. [courtesy of John Merle (J Phys Chem A 2005;109:3637–3646). Reprinted with permission of J Phys Chem A.]

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1,3-H transfer TS

‡ •

CH3CH2CH2 + O2 31.4 31.3 36.1

1,4-H transfer TS

Concerted 1,4-H transfer/elimination ‡

32.4 35.7 31.7 ‡

23.8 26.7 23.2

27.5 37.0 30.8

1,5-H transfer TS

ΔH(298 K), kcal/mol, relative to n-propylperoxy 0.0 B3LYP/6–31+G** 0.0 mPW1K/6–31+G** 0.0 CBS-QB3

Fig. 6 Initial reaction barriers for unimolecular reactions of n-propylperoxy radical. [courtesy of John Merle (J Phys Chem A 2005;109:3637–3646). Reprinted with permission of J Phys Chem A.]

was shown that, although the 1,5-H-transfer reaction has the lowest barrier, the resultant •CH2CH2CH2OOH cannot easily undergo further unimolecular rearrangements. Rather, the 1,4-H atom transfer routes [Equations (31) and (33)] encounter lower barriers in subsequent steps. This pathway for n-propylperoxy radical parallels a likely pathway involved in the decomposition of ethylperoxy radical.71 The CBS-QB3 potential energy surface accounts for the various experimentally observed products, including hydroperoxyl radical, propene, HO•, propanal, and oxirane (c-C3H6O). The activation barrier for simultaneous 1,4-H transfer and HO2• expulsion, obtained via calculations, compares well to the experimentally observed barrier (26.0 kcal/mol) of DeSain et al.83,84 This work provides some ramifications for larger alkylperoxy radicals: multiple conformers of long alkylperoxy radicals are likely to play a role in the overall oxidation chemistry and dictate consideration for correct treatment of thermochemistry; at lower temperatures (T < 500 K), unimolecular reactions dictate peroxy radical chemistry. n-Butoxy radical (CH3CH2CH2CH2O•) Just as n-propylperoxy radical is the smallest peroxy radical that can undergo the 1,5H-atom transfer, n-butoxy radical is the smallest alkoxy radical that can do so, while

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pentyl radical is the smallest alkyl radical with this potential. Similarly, these species are often used as models to understand the chemistry of larger alkoxy radical and alkyl radical systems. n-Butoxy radical exists in multiple conformer forms and can undergo a facile 1,5H-atom transfer. Vereecken and Peters94 exhaustively examined this possibility, via DFT calculations and TST rate coefficients, to recommend a rate coefficient of 1.4  105 s1, which agreed well with the experimental rates of both Atkinson95 and Hein et al.96 Vereecken and Peters used multiple approaches for deriving their multirotamer transition state theory expressions and demonstrated consistency through all of these. Ferenac et al. examined this unimolecular isomerization (1,5H shift) for n-butoxy radical and its functionalized derivatives, noting substantial substituent effects (more dependent on substitution patterns than on the functional groups themselves).97 Lendvay and Viskolcz examined unimolecular reactions available to n-butoxy radical via ab initio and RRKM calculations and noted that, while 1,5-isomerization was the fastest route, fragmentation reactions would compete at combustion temperatures.98 This finding was corroborated by exhaustive quantum chemical/RRKM dynamics calculations by Somnitz and Zellner.99 Jungkamp et al. generated an exhaustive atmospheric mechanism for n-butane via DFT and ab initio methods, proposing that n-butoxy radical will react primarily via 1,5-H transfers to ultimately form 4-hydroxy-1-butanal, while 2-butoxy radical will tend to decompose via b-scission to ethyl radical and acetaldehyde.100 Cassanelli et al. completed relative rate studies of 1-butoxy radical using FT-IR spectroscopy, noting that reaction with oxygen competed with isomerization.101 1-Pentyl radical (CH3 CH2 CH2 CH2 CH2 ) For pentyl radical, internal H-atom transfers can occur regardless of whether further oxidation occurs. These unimolecular reactions can directly compete with oxidation steps and so have implications for low-temperature combustion. For instance, n-pentyl radical can quickly isomerize to iso-pentyl radical via 1,4-H atom transfer; each of these radicals can undergo b-scission reactions to yield a new alkyl radical + alkene: C3 H7 þH2 C¼CH2

  n-pentyl !  iso-pentyl ! H2 C¼CHCH3 þC2 H5

ð35Þ

Several experimental studies, over the past several decades, have modeled the overall combustion of this system.102 Jitariu et al. have calculated unimolecular rates for reactions of pentyl radical (i.e., intramolecular H-atom transfer, b-scission, and elimination) noting that isomerizations have lower barriers than b-scissions.103 Larger aliphatic species In general, the trends predicted by n-propylperoxy radical, 1-butoxy radical, and n-pentyl radical provide good benchmarks for understanding the oxidation chemistry of longer chain radicals.104,105 For instance, 1,5-H-atom transfer and

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1,4-H-atom transfer concurrent with elimination provide two important routes with implications for both low- and high-temperature combustion. These possibilities constitute an important subclass of the reactions included in comprehensive mechanisms106 for the corresponding parent compound (i.e., propane,107 butane,108 and pentane). Also, developing larger mechanisms by substituting reaction data for similar, smaller species is a common practice in mechanism development (referred to as lumping109); thus, the reactions of these model compounds have parallels in the chemistry of larger fuels (in particular, n-heptane110 and iso-octane,111 which together constitute the primary reference fuels used to model gasoline combustion,112 as well as n-hexadecane, which shows promise for understanding diesel oxidation113). Chemistry taking place through five- and six-membered ring transition states is consistently favored kinetically over larger and smaller transition states. Gasoline and diesel fuels are two largely aliphatic hydrocarbon fuels that merit further discussion.114 These fuels are primarily used in different types of combustion environments: gasoline, in a spark-ignition (SI) engine, and diesel, in an autoignition engine. A SI engine relies on a four-stroke internal combustion process, involving the reciprocating piston, the intake valve, the exhaust valve, and a spark plug. In terms of the mechanism of combustion, a spark plug ignites the compressed fuel–air mixture, and the resultant flame ideally propagates smoothly across the engine cylinder. The speed at which the flame propagates is dependent on the fuel used. In a diesel engine, ignition relies on compression of the fuel until the autoignition temperature can be reached; no spark ignition is used, and no flame propagation occurs, and thus fewer emissions are involved. Similarly, autoignition temperature varies between given fuels. Even from this general overview, it is clear that the efficiency at which either type of engine operates depends heavily on fuel identity. Common metrics for understanding the ignitability of gasoline and diesel fuels are referred to as the octane number and the cetane number, respectively. Essentially, octane number refers to the volume percent of iso-octane in a given gasoline sample; cetane number refers to the volume percent of cetane (n-hexadecane) in a given diesel sample. In practice, the octane and cetane numbers refer to the practical efficiency of a given fuel to that of iso-octane and n-hexadecane, respectively. Wallington et al. have recently provided an excellent tutorial review of these and other related topics involving chemistry’s many roles in automotive fuels and engines.114

AROMATIC SYSTEMS

Soot formation Before we examine the oxidation pathways available to aromatic systems, it is first instructive to review the most notorious role of these compounds in combustion chemistry: their propensity to lead to soot formation. Soot is a byproduct of fuel-rich combustion, and soot particles can affect respiration and general health in humans.115 Soot production is a result of polycyclic aromatic hydrocarbon (PAH) formation in flames: as reactive hydrocarbon radical intermediates combine to grow

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and propagate, they can also cyclize into rings, which ultimately yield large networks of aromatic rings.116 To work toward minimizing harmful soot emissions, it is important to understand the mechanisms by which soot forms. Generally, the first cyclization step, whereby a benzene ring is formed from acyclic radical species, has been postulated to occur by one of two steps based on acetylene (C2H2) experiments: (1) the reaction of acetylene with either 1,3-butadien-1-yl radical (H2CTCH—CHTCH•) or buta-1-en-3-yn-1-yl radical (HCUC—CHTCH•) and (2) propargyl radicals (HCUC—CH2•) self-reaction, followed by H-atom transfers. More recently, cyclopentadiene has also been implicated as a likely precursor to benzene formation.117 Once the initial benzene ring has cyclized, it can undergo sequences of H-atom abstraction followed by acetylene addition, to yield PAHs. This is known as the H-abstraction-C2H2-addition (HACA) process, proposed by Frenklach and Wang.118 As an aromatic species aggregates to a size over 500 amu, it adopts a particulate form and can coalesce with other PAHs to further increase in size. When many of these particles agglomerate, they form soot.119 Efforts to minimize soot production are widespread. Notably, decreasing the carbon content relative to oxidizer concentration in a fuel/oxidizer mixture decreases the amount of soot formed.

Benzene and toluene In addition to their roles in soot formation, aromatic compounds undergo oxidation processes unique from acyclic saturated hydrocarbons. Aromatic species comprise 10–40% of gasoline and 5–30% of diesel; they reduce undesirable autoignition events (engine knock), thereby increasing a fuel’s octane rating. Therefore, aromatic oxidative decompositions have implications for combustion and atmospheric chemistry. The C—C and C—H bonds present in aromatic hydrocarbons are substantially stronger than those of alkanes, due to their sp2-hybridized carbons. When we consider the combustion reaction of a simple unsaturated species such as benzene or toluene, a new initiation step is possible. A reactive radical (for instance, HO•) may either abstract a hydrogen atom or add directly to the ring’s p-system, generating an allylic-type radical system: these multiple pathways compete (Fig. 7). Both pathways contribute to the combustion chemistry of aromatic species; HO• addition to the aromatic ring is the more prevalent at 298 K.120 In a monoalkyl-substituted aromatic species, such as toluene, abstraction of a hydrogen atom from the side chain can compete with HO• addition at positions ipso, ortho, meta, or para to the side chain. Thus, the possibilities for oxidative initiation and subsequent peroxy radical reactions increase.

Benzene oxidation Of the aromatic hydrocarbons, the oxidative pathways of benzene have been studied most exhaustively. Fujii et al.121 proposed a global mechanism in the early 1970s, in which the C—H bond of benzene is broken to form the phenyl (C6H5•) radical that

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Fig. 7 Reactions of toluene with HO• radical. HO• can abstract a benzylic hydrogen atom (a) or add to the aromatic ring at the ipso (b), ortho (c), meta (d), and para (e) positions relative to the methyl group. Each resultant radical can decompose by various pathways, depending on temperature and pressure.

subsequently reacts with molecular oxygen to form the phenylperoxy (C6H5OO•) radical: C6H5• þ O2 ! C6H5OO• ! 2CO þ C2H2 þ C2H3•

ð36Þ

Although greatly simplified, this model demonstrates the importance of phenylperoxy radical (C6H5OO•) as a reactive intermediate and accounts for some of the major combustion products. However, several other mechanistic intermediates (C3, C4, and C5 hydrocarbons) were also observed. Subsequently, Glassman’s mechanism for benzene combustion accounted for several more products, proposing that phenoxy (C6H5O•) radical was the chief reactive intermediate driving the combustion of benzene. The stepwise mechanism for benzene combustion122 began with H-atom loss to form a phenyl radical (C6H5•), then proceeded through reaction with O2, and then CO expulsion to form cyclopentadienyl (c-C5H5•) radical, which could react with O2 and expel CO again to form smaller hydrocarbon species (Fig. 8). However, this model still over-predicted the formation of phenyl, phenoxy, and cyclopentadienyl radicals; moreover, it failed to account for additional experimentally observed products (i.e., furan, pyranyl radical, and oxobutadiene).123 The tendency of the benzene combustion mechanism to substantially overestimate the formation of phenoxy radical suggested either flaws in the kinetic data involving C6H5O• or incompleteness of the combustion mechanism. Subsequent work verified the kinetics and energetics used in modeling C6H5O• decomposition. In separate studies, Liu et al.124 and Olivella et al.125 used ab initio and DFT models, along

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Fig. 8 High-temperature oxidation pathways of benzene, as proposed by Glassman in Reference 122.

with RRKM rate coefficients, to confirm the data for these pathways. (More recently, these data were also borne out in a quantum mechanical/RRKM study by Hodgson et al.126) Consequently, the benzene oxidation mechanism was further developed by considering additional decomposition and oxidation steps. Sethuraman et al. proposed that phenyl radical decomposition can occur by either of two key pathways:127 b-scission of phenyl radical or by breakdown of the phenylperoxy radical formed by the oxidation of phenyl radical (Fig. 9). Using PM3 calculations,128 which were ultimately verified by DFT studies,129 Carpenter predicted that another species, 2-oxepinoxy radical (3 in Fig. 9b), is an important intermediate due to its relative stability, formed via a spirodioxiranyl intermediate (2 in Fig. 9b) from phenylperoxy radical. Pathway A in Fig. 9b is the thermodynamically preferred pathway at temperatures increasing up to 432 K, while pathway B has an entropic benefit at higher temperatures. While pathway B essentially matched the traditional view of benzene combustion, pathway A introduced a new route for phenylperoxy radical, which could resolve discrepancies observed using previous models. This supposition was validated by experimental studies that demonstrated the prevalence of different ROS at different temperatures. Using CRDS, Yu and Lin studied the reaction of phenyl radical and oxygen, noting that phenylperoxy radical was the only adduct formed at temperatures ranging up to 473 K;130 Venkat et al. completed flow reactor studies of benzene combustion at 1200 K and identified phenoxy radical as a key intermediate.122 Our group has completed several studies of key reactions for some relevant reactive intermediates in benzene oxidation. Barckholtz et al. examined the oxidation pathways of several aromatic species, using benzene as a benchmark.129a General

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(a)

a b

– O

(b)

A

1

O•

B

O O

O• + O(3P)

• 2

6

O •

• O

O 7

3 –CO O

• O 4

• –CO2 5

Fig. 9 (a) Enthalpies (kcal/mol) leading to 2-oxepinoxy radical formation via unimolecular rearrangement of phenylperoxy radical. PM3/UHF = DfH and DFT (B3LYP/6–311 þ G(d,p)// B3LYP/6–31G(d)) = DH298. (b) Potential decomposition pathways for phenylperoxy radical A involving 2-oxepinoxy radical and B involving oxygen atom loss. [courtesy of Steven Kroner (J Am Chem Soc 2005;127:7466–7473). Reprinted with permission of J. Am. Chem. Soc.]

models were proposed for aromatic hydrocarbon and heterocycle oxidation (namely, benzene, pyridine, furan, and thiophene) in preparation for more specific studies of each relevant species. Carbon-centered radicals at each relevant position underwent exoergic oxidation, and the resulting peroxy radical unimolecular decomposition pathways were delineated. It was proposed that these peroxy radicals could undergo rearrangements that make them of significant atmospheric interest. A subsequent study examined phenylperoxy radical in greater detail. Fadden et al.129b identified five possible unimolecular decomposition pathways for phenylperoxy radical (Fig. 10): via oxygen atom loss to form phenoxy radical (Fig. 10, route A), via a dioxiranyl radical species (Fig. 10, route B), via a dioxetanyl radical

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Fig. 10 Potential unimolecular reaction pathways for phenylperoxy radical. Adapted from Reference 129b.

intermediate (Fig. 10, route C), via a 1,3-peroxy radical species (Fig. 10, route D), and via a p-phenylquinone radical intermediate (Fig. 10, route E). These routes were examined using DFT (B3LYP/6–31G(d)) and ab initio (CASSCF) structures, with high-level CAS-MP2, and UCCSD(T) single-point energies. Formation of the dioxetanyl species was predicted to be most favorable based on DG298 energies. This radical could unimolecularly decompose to produce smaller species, including cyclopentadienyl and pyranyl radicals, as well as acyclic oxygenated species, that are experimentally observed. At higher temperatures (T > 500 K), the entropic benefit afforded via oxygen atom loss becomes a contributing factor, and pathway A is the major decomposition route. Moreover, route B leads directly to 2-oxepinoxy radical (3 in Fig. 9b), which is potentially an important intermediate in low-temperature benzene oxidation. The stability of 2-oxepinoxy radical qualified it as a target for further theoretical and experimental study. The calculations of Barckholtz et al.129a allowed the refinement of a feasible energetic pathway toward 2-oxepinoxy radical; these DFT calculations supplemented the semiempirical work of Carpenter and also proposed a triradical intermediate between the dioxiranyl and oxepinoxy species (Fig. 9a). Consequently, the unimolecular decomposition of 2-oxepinoxy radical (3 in Fig. 9b) was thoroughly modeled by Fadden et al. using DFT (B3LYP) methods.131 Gibbs free energy profiles (T = 298–1250 K) were generated. A wide range of decomposition pathways were examined, which could account for typical experimentally observed products (Fig. 11). Notably, the delineated decomposition pathway did not require the generation of cyclopentadienyl radical. Cyclopentadienone is a commonly observed product in benzene combustion, and most mechanisms presume that cyclopentadienyl radical is its most likely precursor. However, it was shown that

O

40.8 + 2CO

H + CO 15 +30.3

16 +20.2

18 +54.2

13 +27.9

17 +26.2

49.0

+ CO H 19 –11.7

12.0

O CH2 C

H

O

3.4

6 +0.1

O

36.7

+ CO

12 +4.3

7 + 14.1

8 +36.6

H

O

C 6.8 36.3 O

+ HCO

C 22 +46.7

O C

O C

C

21 +25.0

+ CO 9 +39.0

O 30.5

C

H

2.7

6 +0.1

O

O

7.6

O + CO

O + CO

5 +28.9 C

H + CO

0.3

O

O

35.5

O

+ CO2 4 –28.1

3 +17.3

CO

23.4

7.7 H

2 +10.0

10.0

+ CO C 14 +3.3 O

–0.7

8.6

CH2

+ 2CO

CO2

39.4

43.8

29.4 4.6

O

8.8

+ 2CO

C2H3 + C2H2 + 2CO

104

O

O CO

O C

O C 26.6

34.7

13.3

2.8 H O

O + C2H2 + CO

40.2

11 +65.7

41.3 O

O H 30 +22.9

27.6

O O

C 29 +6.1

C 19.5

28 +7.3

40.6 C

26 +22.4

O

25 +42.3

O C

8.6

+ C2HO

C + C2H2O 27 +47.5

O 34.7

CO O 5 +28.9

0.3

O + CO 6 +0.1

Fig. 11 Unimolecular decomposition pathways of 2-oxepinoxy radical (1). The relative free energies (298 K, kcal/mol) at the B3LYP/ 6–311 þ G(d,p)//B3LYP/6–31G(d) level are shown for each intermediate relative to 1, and each free energy of activation is relative to the reactant for that specific step. [courtesy of Michael Fadden (J Phys Chem A 2000;104:8121–8130) Reprinted with permission of J Phys Chem A.]

C.J. HAYES ET AL.

+ C2HO 31 +34.2

22.8

O

23 +7.7

50.3 O

10 +38.8

O C O

20 +10.9 H + CO

C 24 +24.6 O

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2-cyclopenten-1-yl radical (19 in Fig. 11), a feasible source of cyclopentadienone, could be formed from the 2-oxepinoxy radical. These computed pathways supported the experimental results of Pfefferle and coworkers,140b in their work on the lowtemperature combustion of benzene, in which C2, C3, and C4 hydrocarbons were observed without formation of C5 constituents. 2-Oxepinoxy radical is highly stabilized by its unique structure; Mebel et al. determined, via PUMP3/6–31G(d)//UHF/6–31G(d) calculations, that it would have a relative enthalpy of DH0 = –91.8 kcal/mol as compared to phenylperoxy (C6H5O2•) radical.132 The stability of this species suggests that it will be fairly longlived and thus could undergo reactions of atmospheric interest, such as the addition of molecular oxygen. Merle and Hadad studied the oxygen-initiated decomposition of 2-oxepinoxy radical using both DFT and CBS-QB3 calculations.133 Calculations predicted that from T = 298–750 K, O2 addition routes compete with unimolecular decomposition (Fig. 12); for T > 750 K, however, the entropic penalty associated with the O2 addition step causes the unimolecular decomposition of 2-oxepinoxy radical to be more favored. The most stable O2 addition adduct below T = 1250 K is 6-peroxyoxepinone (route A in Fig. 12), which can cyclize to form a 1,4-peroxy intermediate which subsequently releases CO2 to form a 5-oxopentanalyl radical. This species can cyclize and fragment, yielding formyl radical, furan, and carbon dioxide. Above T = 1250 K, the

Fig. 12 Most favorable oxidative decomposition pathways for 2-oxepinoxy radical, at 298 K (path A) and 1250 K (path B). Adapted from Reference 131.

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dissociative pathway (route B in Fig. 12) afforded by 2-peroxyoxepinone’s loss of oxygen atom becomes more favorable. Even though 2-oxepinoxy radical (3 in Fig. 9b) may be an important intermediate in benzene oxidation, no confirmatory experimental evidence exists. Recently, Kroner et al. published an experimental study of the gas-phase acidity of 2(3H)oxepinone (C6H6O2), obtained via flowing-afterglow MS.134 They postulated that this quantity could be used along with a thermodynamic cycle to determine the heat of formation of 2-oxepinoxy radical: C6H6O2 ! C6H5O2 þ H þ

DHacid

ð37Þ

C6H5O2 ! C6H5O2• þ e

EA(C6H5O2)

ð38Þ

Hþ þ e ! H•

 IP(H)

C6H6O2 ! C6H5O2• þ H•

ð39Þ BDE=DHacid þ EA  IP

DHf(2-oxepinoxy radical, C6H5O2•)=BDE þ DHf(H•)  DHf(C6H6O2)

ð40Þ ð41Þ

A value of DHacid = 352  2 kcal/mol was determined for Equation (37). This experimental evidence could ultimately be valuable in conclusively identifying 2-oxepinoxy radical as a reactive species of interest. The overall pathways of benzene oxidation and the decompositions of possible intermediates have been well characterized via theoretical methods. Thus far, we have discussed these species mainly in the context of their oxidation mechanisms, but phenylperoxy and phenoxy radicals have also been investigated as individual experimental targets. The chemistry of phenoxy (C6H5O•) radical has been of interest for several decades. Benson et al. proposed the first rate coefficient for its unimolecular decomposition,135 while Lin and Lin provided information on the Arrhenius parameters for the reaction.136 Experimental and theoretical studies have examined phenoxy radical’s electronic states,137 molecular vibrational frequencies,138 and spin density, as well as its thermal and oxidative decomposition.139 Benzene combustion mechanisms rely heavily on the inclusion of phenoxy radical data;121,122,140 additionally, phenoxy radical decomposition reactions are necessary in the mechanisms for combustion of several other species, including propane,141 butane,142 and anisole.143 More notoriously, phenoxy radical has recently been implicated in routes to dioxin and polychlorinated naphthalenes; several theoretical studies have been completed on these potential reactions.144 Finally, the roles of phenoxy radical in flame chemistry,145 emissions,146 and other aspects of combustion147 have been compiled in several reviews. Phenylperoxy radical has similarly been a topic of experimental and theoretical interest. Tokmakov et al.148 calculated a potential energy surface for phenyl radical and O2 using ab initio G2(MP2) calculations. Weisman and Head-Gordon used timedependent density functional theory (TD-DFT) calculations to examine the effect of substituents on the phenylperoxy radical’s UV-vis absorption spectrum.149 Lin and Mebel used ab initio methods to study the phenoxy radical þ O-atom reaction.150

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Just et al. have examined the A˜ X˜ electronic transition of phenylperoxy using CRDS.151 Tonokura et al.152 used CRDS to study the visible absorption spectrum of the phenyl radical, as well as the kinetics of its reaction with O2. Krauss and Osman examined the UV absorption spectra of vinylperoxy radical (H2CTCHO2•) and phenylperoxy radicals.153 Phenylperoxy radical, originally assumed to be a factor in low-temperature combustion only, has actually been shown to play a substantial role in dictating the overall combustion trends of benzene. Just as the isomerizations and eliminations of the alkylperoxy radicals significantly affected their overall combustion pathways, rearrangements and other intramolecular pathways available to phenylperoxy radical similarly impact the overall progress of benzene combustion. This knowledge can be extrapolated to more complex aromatic species. Alkylated aromatics Like benzene, toluene (C6H5CH3) is a common constituent of gasoline. Much of the literature concerning toluene’s oxidation focuses on a global mechanism for understanding its combustion. Emdee et al.154 proposed that toluene’s combustion mechanism is most sensitive to its reaction with O2 to form benzyl radical (C6H5—CH2•) and HO2•. Dagaut et al. proposed that toluene oxidation is initiated by benzylic H-atom abstraction by O2 to form the benzyl radical, which can unimolecularly decompose to acetylene and cyclopentadienyl or react with an additional O2 and unimolecularly decompose to phenyl and formyl radicals (via benzaldehyde, (C6H5—C(TO)H).155 Pitz et al. generated a comprehensive mechanism for toluene combustion in varying settings, due to its widespread use as a fuel additive.156 El Bakali et al. noted an overall similarity between the chemistry of benzene and the chemistry of toluene, based on their oxidation mechanisms.157 Ethylbenzene has also been the subject of mechanistic studies,158 most recently by Ergut et al.159 As mentioned previously, the low-temperature oxidation of toluene is proposed to begin with either of two steps; if hydroxyl radical is present, HO• can abstract a benzylic hydrogen atom or add directly to the aromatic ring. Once a radical is generated on the aromatic ring or side chain of toluene, rapid oxidation can occur. The resulting peroxy radical has several viable pathways available. Atkinson compiled data on low-temperature atmospheric reactions for both the benzyl radical and the C6H5—CH3/HO• adduct.11 Andino et al. modeled the atmospheric oxidation of toluene and disubstituted xylenes, noting that several cyclized peroxy radical rearrangement products were energetically stable.160 Additionally, studies have focused on benzylperoxy radical (C6H5CH2O2•), although this is a less common target than phenylperoxy radical, because HO• addition to the aromatic ring is more dominant than H-atom abstraction from the benzylic C—H bond, in toluene combustion.120 Elmaimouni et al. studied the equilibrium for benzylperoxy radical and benzyl radical þ O2 over the temperature range 393–433 K, extrapolating the addition reaction enthalpy to be –20.1 kcal/mol at 298 K, and the free energy to be 11.4 kcal/mol.161 Fenter et al. performed a kinetic study162 using the same equilibrium at 760 torr with a temperature range of 298–398 K, proposing a

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rate expression kf(T) = (7.6  2.4)  1013 exp[(190  160)/T(K)] cm3/molecule-s, equilibrium Kp = 6.3  0.2  104 atm1, and reaction enthalpy DH298 = –21.8 kcal/mol. Buth et al. used a flow reactor coupled to mass spectrometric detection in a comparable study,163 determining kf = (4.44  1.3)  1011 cm3/molecule-s and Kp = 57,200 bar1 at 298 K. Noziere et al. monitored the reaction of benzylperoxy radical with hydroperoxyl radical using LFP/UV absorption and continuous photolysis/FTIR.164 El Dib et al. performed a LFP kinetics study of the self-reaction of benzylperoxy radical.165 It was again observed that rearrangement pathways comprise a substantial portion of the oxidation routes for alkylated aromatics.11,160 Since this phenomenon is mainly due to peroxy radical reactivity rather than to identity of the parent compound, it is clear that comparable rearrangements would be factors for PAHs, as well as for nitrogen-, oxygen-, and sulfur-containing heteroaromatic rings and their alkylated derivatives. Heteroaromatic combustion Considering additional functionalities in an aromatic ring allows for conclusions with implications for coal chemistry. Coal is a vital fossil fuel; about 50% of the United States is dependent on coal for electric power generation, and its use accounts for 90% of Ohio’s electrical power. Current clean-coal engineering efforts are underway to maximize coal’s energy potential while minimizing harmful environmental emissions (i.e., Hg, SOx, NOx, and CO2).166 Unlike hydrocarbon-based fuels like methane and gasoline, coal has never been subjected to a comprehensive mechanistic analysis, due to the complexity of its molecular structure. However, coal’s complex structure consists of various monocyclic units that can be explored: aromatic hydrocarbons and heteroaromatic rings are recurring units in coal’s structure, even while the overall structure varies geographically. Understanding low- and high-temperature oxidation reactions for these subunits and their reactive radical intermediates will facilitate a better understanding of their chemistry in combustion. Heteroaromatic compounds (Fig. 13) have been used as models for understanding coal chemistry in several pyrolytic studies. The azabenzenes (N-containing

Fig. 13 Heteroaromatic compounds of interest in coal combustion.

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heteroaromatics) have historically been most often studied; their pyrolysis has been shown to proceed through reactive radical intermediates although the identity of these intermediates can vary with reaction conditions.167 Using a shock tube, Mackie et al. observed the pyrolytic decomposition of pyridine,168 noting that three initial radicals derived from C—H bond scission: o-pyridinyl, m-pyridinyl, and p-pyridinyl. Of these, o-pyridinyl radical was dominant and was observed to yield cyanoacetylene (NUC—CUCH) through a ring-opening process, while m- and p-pyridinyl radicals formed HCN as a major product, via a less discernable pathway. Similarly, Kiefer et al. studied the pyrolysis of pyrazine, pyrimidine, and pyridine;169 all were observed to undergo ring-scission to yield 2-cyanovinyl radical (•CHTCH—CUN), which accounts for several combustion products upon decomposition, including HCN, NUC—CUCH, and acetylene. 2-Cyanovinyl radical has been identified in several pyrolytic studies of the azabenzenes, originally via the shock-tube study of Doughty et al.167f,g These authors proposed that the relative position of the nitrogen atoms in the ring substantially impacts the reactivity of a ring toward pyrolysis: for example, pyrazine dissociates more quickly than pyrimidine. Overall, the azabenzenes demonstrate increased reactivity relative to benzene; their C—H BDEs range from 93 to 98 kcal/mol, compared to benzene’s C—H BDE of 112 kcal/mol.170 The smallest C—H BDEs occur at positions ortho to nitrogen [although being a C—H bond that is twice ortho to N (as in pyrimidine) does not render a further lowering of the BDE].167 Kikuchi et al,171 Mackie et al.,172 and Jones et al.173 have attributed the lower BDE to the nitrogen atom’s in-plane lone pair electrons interacting with the unpaired electron on the carbon center of the radical, thereby reducing the strength of the C—H bond via radical product stabilization. The oxidative decomposition of the azabenzenes has not been studied in such great detail. Tabares et al. studied the reaction of pyridine with O-atom, noting a decrease in reactivity relative to benzene.174 Alfassi et al. studied the formation and reactivity of pyridylperoxy radicals in solution.175 Eisele postulated that the presence of ions derived from pyridine and picoline in the troposphere implicates these species as atmospherically significant.176 Yeung and Elrod explored this claim via chemical ionization MS to study the reactions of HO• with pyridine, the picolines, the lutidines, and the ethylpyridines and postulated that pyridinated compounds could indeed have substantial implications on tropospheric ion content.177 As with toluene, the reaction of HO• with pyridine and alkylated pyridines is likely to proceed either via HO• addition to the aromatic ring or hydrogen atom abstraction from a C—H bond. The new radicals can unimolecularly decompose or undergo reaction with O2. These reactions have been modeled for toluene and the hydrocarbon analogues by Andino et al.160 Heteroaromatic compounds have the potential to add O2 at the ring nitrogen and thus form NOx species,178 potentially leading to excess tropospheric ozone and acid rain.179 The five-membered heteroaromatic (furan, oxazole, pyrrole, and thiophene) are of additional interest. Besides their role in coal combustion, these have been implicated as emissions of biomass burning,180 residential fires,181 waste tire burning,182 cigarette smoking,183 and motor vehicles.184 Bruinsma et al. examined the pyrolysis of heteroaromatic rings most commonly found in coal volatiles,185 determining a rank of increasing pyrolytic reactivity: thiophene < benzene < pyridine < pyrrole < cyclopentadiene < furan; they also noted that an additional, fused aromatic ring

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has a stabilizing effect, especially for pyridine and furan. Cullis and Norris also studied the pyrolytic processes of the heteroaromatics, yielding methane and benzene as major products, via hydrocarbon radical intermediates. Qualitative product analysis revealed that these heteroaromatics decomposed by similar mechanisms regardless of identity; the heteroatoms were generally not present as major combustion products; they were lost as water, hydrogen sulfide, or hydrogen cyanide.186 Braslavsky and Heicklen extensively reviewed the thermal and photochemical decomposition of heteroaromatic compounds.187 Klein et al. studied variations in heteroaromatic C—H BDEs for substituted aromatic compounds.188 In particular, furan and pyrrole, as well as their methylated derivatives, have been common targets of pyrolytic studies. The pyrolysis reactions of furan and its methylated derivatives have been shown to lead to various products, including CO, acetylene, acetaldehyde, propyne, and allene. Grela et al. observed that methylated furan is likely to undergo C—O bond scission, yielding either benzene and water, via the biradical •C(CH3)TCH—CHTC(CH3)O•, or to isomerize prior to decomposition to produce CO and C5H8.189 Organ and Mackie also suggested that the biradical intermediate was the most likely intermediate.190 The mechanism has since been re-evaluated. Fulle et al. noted that the major decomposition products of unsubstituted furan were formed via one of two pathways,191 one which resulted in C2H2 and ketene (H2CTCTO) and one which led to propyne and CO; Sendt et al. confirmed these pathways and proposed that they were achieved via 1,2-H transfer in the original furan molecule, which led to cyclic carbene intermediates.192 The pyrolysis of pyrrole produces a variety of products: hydrogen cyanide, propyne, allene, acetylene, cis-crotonitrile, and allyl cyanide, among them. Lifshitz et al. hypothesized that pyrrole undergoes 1,2-bond (N—C) cleavage, then an internal H-atom transfer, to yield a radical intermediate that can isomerize to either cis-crotonitrile or allyl cyanide, or dissociate to HCN and propyne.193 Bacskay et al. completed quantum chemical comparisons of the isoelectronic pyrrolyl and cyclopentadienyl radicals; they hypothesized that pyrrolyl radical is formed via C—H bond scission in the intermediate pyrrolenine (2H-pyrrole) rather than directly via N—H bond cleavage (Fig. 14).194 Mackie et al. explained a similar finding, postulating that it was the formation of pyrrolenine that dictated the rate at which pyrrole pyrolysis occurred.195 While most studies have focused on the pyrolytic unimolecular decomposition of these monoheteroaromatic compounds, our group has explored their oxidative decomposition. As with benzene, where phenylperoxy radical plays a major role in dictating oxidation pathways, we hypothesize that the peroxy radicals derived from heteroaromatic rings are reactive species of considerable interest for combustion and atmospheric reactions.

Fig. 14 Likely pyrolysis pathway of pyrrole, via intermediate pyrrolenine. Adapted from Reference 194.

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Barckholtz et al. surveyed a variety of computational methods and basis sets to select an appropriate theoretical model for study of these molecules, finding that DFT provided a good balance of accuracy and computational economy.196 This study also validated the use of heteroaromatic monocyclic rings as constructive models for their polycyclic analogues (by extension, this finding could also confirm the similarities between the chemistry of coal and these smaller model compounds). BDEs were compiled for a variety of polyheteroaromatic rings; the resulting values were compared to the corresponding monoheteroaromatics. For example, for benzofuran, the C—H BDE at the 2-position of the furan ring is 117.8 kcal/mol, which is 0.6 kcal/mol less than the corresponding BDE in furan itself. These calculations showed that increasing the number of rings in the compound did not have a substantial effect on BDE, except in the case of a C—H bond adjacent to a bridgehead junction when an electronegative heteroatom was present on the other side of the bridgehead. Even in such cases, the deviation between the monocyclic analogue and the polycyclic derivative was only 2 kcal/mol. In separate DFT studies, Fadden et al. examined the rearrangement pathways (Fig. 15) of peroxy radicals from azabenzenes197 and five-membered heteroaromatic rings.198 It was observed that each azaphenylperoxy radical can lose molecular oxygen (2 ! 1), rearrange to a dioxiranyl species (2 ! 3) or a dioxetanyl species (2 ! 4), or lose atomic oxygen (2 ! 5). Other unimolecular decomposition pathways afforded to alkylperoxy radicals (i.e., H-atom transfer and b-scission) are not possible for their aromatic analogs. From the calculated energies, several main conclusions were drawn. Loss of O2 is less endoergic at 298 K than loss of O-atom for most heteroaromatic peroxy radicals; two exceptions are 3-pyridinylperoxy radical, which mimics phenylperoxy radical in this aspect of its reactivity as well as many

Fig. 15 Unimolecular pathways available to heteroaromatic peroxy radicals; example shown for 2-pyridinylperoxy radical. Adapted from Reference 198.

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others, and 3-pyridazinylperoxy radical, in which the oxy radical is a -radical (2A0 ) and maintains aromaticity not observed in the peroxy radical. Dioxiranyl formation is generally less endoergic than O2 and O-atom loss at 298 K; however, at temperatures greater than 500 K, the entropic contributions reverse the stabilities. Dioxetanyl intermediates are more strained and, therefore, unstable intermediates; a few exceptions are observed for compounds in which an alkyl chain is adjacent to a ring nitrogen and cyclization can form stable nitrosyl radicals (as for Pathway 4b for 2-pyridinylperoxy radical), but these reactions still incur high reaction barriers. Similar routes are available to peroxy radicals of O-, S-, N-, and O,N-containing five-membered ring heteroaromatics. The kinetic and thermodynamic parameters for the viable arylperoxy radical unimolecular dissociation steps were calculated for the furanylperoxy radicals; the effect of a second heteroatom was examined by a comparable approach for the oxazolylperoxy radicals. Thermodynamic parameters for these reactions were compared to those of the pyrrolylperoxy and thiophenylperoxy radicals. For smaller heteroaromatic peroxy radicals, loss of O-atom to form the corresponding aryloxy radical is preferred at 298 K to other decomposition routes. Dioxiranyl formation (Fig. 15, pathway 3) competes thermodynamically with oxygen atom loss (Fig. 15, pathway 5) in some cases and is universally more favorable than O2 loss (Fig. 15, pathway 1). The dioxetanyl route (Fig. 15, pathway 4) is disfavored for five-membered ring heteroaromatic peroxy radicals, often due to formation of an anti-Bredt double bond in the ring system. As with the azabenzenes, the dissociative pathways become more favorable than rearrangements at high temperatures. Overall, reactivity of the heteroaromatic peroxy radicals was shown to depend heavily on ring size. For azabenzylperoxy radicals, losing an oxygen atom is substantially unfavorable, and reversion to reactants (aryl radical þ O2) is a more likely dissociation pathway; the peroxy radical of the five-membered ring heteroaromatics can lose oxygen atom at a lower cost. For both sets of arylperoxy radicals, isomerization pathways are important at low temperatures. Additionally, intramolecular cyclizations compete with O-atom loss, and some cyclizations lead to nitroso radicals, creating implications via possible NOx formation. As with phenylperoxy radical, the azabenzylperoxy radicals have lower barriers for rearrangement than for loss of oxygen atom, and consequent products will influence overall combustion pathways. Alkylated heteroaromatics Substantially fewer studies have been published for the reactions of alkyl-substituted heteroaromatics, although these compounds also have implications for coal combustion. Several references discussed in the previous section contain information on methylated heteroaromatic rings. Mackie and coworkers completed experimental199,200 and theoretical201 studies of the pyrolytic decomposition of 2-picoline (2-methylpyridine). They concluded that decomposition proceeded mainly through o-pyridinyl and 2-picolinyl radicals. The former tended to decompose predominantly to yield cyanoacetylene, while the latter favored decomposition to a cyano-functionalized cyclopentadiene (Fig. 16).

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Fig. 16 Cyanocyclopentadiene.

Despite the authors’ assertion that alkylated heteroaromatic compounds provide a better model for fuel-bound nitrogen than do the unsubstituted heterocycles, their pyrolytic study remains the most comprehensive look at substituted heteroaromatic chemistry, even several years later.196–202 Kinetic studies are more common in the literature: Frerichs et al. examined the reaction of the picolines with oxygen atom,202 while Yeung and Elrod studied reactions of HO• with pyridine and its methyl- and ethyl-substituted derivatives.177 Both groups noted that the presence of nitrogen did not demonstrably affect the species’ chemistry; generally, reactivity is comparable to toluene. The oxidation pathways for alkylated heteroaromatics start with the formation of a radical species, via hydrogen atom loss or alkyl group homolytic bond cleavage. We calculated these BDEs for methyl- and ethyl-substituted derivatives of several key heteroaromatics (Tables 1–3).203 Few of these experimental values exist;204 therefore, Table 1 Thermodynamic and spin density information for methyl hydrogen atom loss reactions of methyl-substituted heteroaromatic rings. Enthalpies and energies in kcal/mol, obtained at the B3LYP/6–311þG**//B3LYP/6–31G* (designated as B3LYP) and CBS-QB3 (designated as CBS) levels

DH298

Toluene Pyrrole Furan Thiophene Oxazole Pyridine Pyridazine

DG298

( – )

Methyl

B3LYP

CBS

Experimental BDE

B3LYP

CBS

1 2 3 2 3 2 3 2 4 5 2 3 4 3 4

86.7 83.1 86.8 83.1 87.4 85.2 87.0 86.4 88.1 84.5 88.2 87.0 87.9 88.9 87.6

90.6 86.1 90.1 86.3 90.5 86.5 89.9 89.9 91.1 87.9 92.0 91.0 91.6 93.3 91.7

88.0–90.3a

79.4 75.3 78.9 75.3 79.5 84.2 88.1 78.7 80.2 76.6 80.5 79.6 80.6 81.3 80.5

83.8 78.9 82.4 78.6 82.7 79.1 82.2 82.3 83.3 80.1 84.7 83.7 84.6 85.8 84.6

96.0b

0.72 0.63 0.74 0.60 0.73 0.60 0.71 0.64 0.63 0.72 0.73 0.72 0.74 0.76 0.75

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Table 1 (continued ) DH298

Pyrimidine Pyrazine

Methyl

B3LYP

CBS

2 4 5 2

89.5 89.3 87.5 88.0

93.1 92.7 91.4 92.3

DG298 Experimental BDE

( – )

B3LYP

CBS

82.4 81.9 80.7 80.5

86.7 85.5 84.7 85.0

0.73 0.75 0.72 0.72

See Fig. 13 for structures and numbering. a Reference 158. b Reference 173.

Table 2 Thermodynamic and spin density information for ethyl (or methylene) hydrogen atom loss reactions of ethyl-substituted heteroaromatic rings; enthalpies and energies in kcal/ mol, obtained at the B3LYP/6–311þG**//B3LYP/6–31G* (designated as B3LYP) and CBSQB3 (designated as CBS) levels

DH298

Ethylbenzene Pyrrole Furan Thiophene Oxazole Pyridine Pyridazine Pyrimidine Pyrazine a

Reference 118.

DG298

( – )

Ethyl

B3LYP

CBS

Experimental BDE

B3LYP

CBS

1 2 3 2 3 2 3 2 4 5 2 3 4 3 4 2 4 5 2

83.9 80.8 83.8 80.1 84.2 79.8 83.5 82.4 84.5 81.5 84.2 82.9 83.7 84.7 83.7 84.2 83.9 84.3 83.8

88.1 84.6 87.7 83.9 87.9 83.8 87.1 86.5 88.3 85.6 88.1 85.6 87.2 90.1 88.7 89.0 88.5 89.1 90.2

85.4–86.9a

75.2 72.2 75.3 71.6 75.4 71.1 74.4 74.1 76.0 73.0 75.2 74.8 74.5 77.6 75.1 76.1 75.7 74.9 75.1

79.7 75.9 78.9 75.5 79.1 75.2 78.1 78.4 79.9 77.1 80.0 77.2 78.7 83.1 79.7 80.9 80.4 80.5 81.4

0.68 0.61 0.71 0.57 0.69 0.55 0.67 0.61 0.68 0.60 0.67 0.69 0.69 0.68 0.68 0.69 0.70 0.66 0.68

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Table 3 Thermodynamic information (kcal/mol, 298 K, B3LYP/6–311þG**//B3LYP/ 6–31G*) for alkyl group loss reactions of methyl- and ethyl-substituted heteroaromatic rings

Pyrrole Furan Thiophene Oxazole Pyridine Pyridazine Pyrimidine Pyrazine

Methyl

DH298

DG298

Ethyl

DH298

DG298

2 3 2 3 2 3 2 4 5 2 3 4 3 4 2 4 5 2

106.1 104.3 108.8 105.7 103.9 100.9 109.8 106.9 110.8 94.1 98.3 97.6 96.2 97.1 97.4 90.3 99.7 94.9

89.3 87.7 92.1 89.1 87.3 84.2 93.3 90.3 94.1 77.9 82.1 81.7 79.7 81.2 81.5 74.1 84.1 78.5

2 3 2 3 2 3 2 4 5 2 3 4 3 4 2 4 5 2

101.1 99.1 103.9 100.6 99.1 95.6 104.9 102.1 105.9 89.3 93.4 92.7 91.4 92.2 92.5 89.7 94.9 87.1

87.1 85.6 89.9 86.8 85.3 81.6 91.1 88.3 92.1 75.5 79.4 78.9 77.7 78.6 78.8 75.9 81.1 72.3

we also briefly examined the chemistry of benzylperoxy radical, because it is a hydrocarbon analog for methylated heteroaromatics and a more common experimental target. Calculations at the CBS-QB3 level closely replicated toluene’s experimentally determined geometry, spectroscopic information, and BDE; additionally, DFT (B3LYP) calculations replicated the qualitative trends predicted by the CBSQB3 calculations. Quantitatively, the DFT calculations consistently underpredicted the BDEs and reaction energies relative to CBS-QB3. The reactivity of methyl- and ethyl-substituted azabenzenes was explored by calculation of the homolytic BDEs and free energies for alkyl C—H hydrogen atom and alkyl side-chain loss. These values were analyzed as a function of heteroatom, ring size, side chain length, spin density, and temperature. Furthermore, the impact on the thermodynamic values derived from the harmonic oscillator approximation was analyzed, by treating side-chain torsions as hindered rotors. At 298 K, loss of hydrogen atom to form a benzylic-like radical is roughly 10 kcal/mol more favorable than loss of the alkyl group, due to the electron delocalization possible for the benzylic-like radical, regardless of ring size or heteroatom; this trend is consistently exhibited over a wide temperature range (T = 298–2000 K) although both reactions become increasingly favorable with increasing temperature, due to entropic effects on the free energy (Fig. 17). Spin densities for heteroaromatic radicals correlate well with the BDE values: the more diffuse the spin density, the lower the corresponding BDE. This is most dramatically evident for the five-membered ring heteroaromatics. Both the harmonic oscillator and hindered rotor treatments give comparable values for reaction enthalpies and free energies. The ethyl derivatives have lower reaction enthalpies and free energies than methyl derivatives.

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90

80

20

20

10

10

0

0

13

10

70

50

30

30

00 15 00 18 00 20 00

30

0

30

00

40

0

40

0

50

0 70 0 10 00 13 00 15 00 18 00 20 00

50

0

60

ΔG rxn (kcal/mol)

70

60

50

ΔG rxn (kcal/mol)

70

80

(b)

(a)

Temperature (K)

Fig. 17 Variation of reaction free energy (kcal/mol) with temperature (K) for alkyl C—H hydrogen atom loss in (a) five-membered ring methyl-substituted heteroaromatic rings and (b) six-membered ring methyl-substituted heteroaromatic rings.

With respect to predicting the chemistry of larger heteroaromatic systems (such as those in coal), these calculations suggest that both hydrogen atom and alkyl group loss can contribute to the combustion of coal in initiation reactions; the subsequent oxidation pathways of both the aromatic peroxy radicals (previously explored197,198) and the alkylated aromatic peroxy radicals are of interest. Reactivity will likely increase with increasing alkylation of a subunit, and the azabenzene units are more likely to react than the five-membered heteroaromatic rings. The initial steps of radical formation are expected to become more favorable at higher temperatures, primarily due to entropic considerations. Oxidative decomposition of alkylated heteroaromatics When alkylated heteroaromatic radicals are formed, these species can rapidly react with O2 to form various peroxy radicals. Again, it seems likely that these resultant reactive species will have an impact on overall combustion processes. Benzylperoxy radical was initially explored computationally to obtain a qualitative picture of peroxy radical decomposition for species containing both alkyl and aromatic components; these findings were then extended to peroxy radicals of methyl- and ethylsubstituted azabenzylperoxy radicals.205 The alkyl chains of these species are large enough than conformeric considerations are a concern. We performed calculations to analyze rotational profiles for alkyl group torsions to isolate the most stable conformation. In all cases, rotation of and alkyl dihedral angle occurred with a

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Fig. 18 Unimolecular pathways for 2-picolinylperoxy radical, a representative peroxy radical for alkylated azabenzenes.

barrier less than 5 kcal/mol. As shown in Fig. 18, alkylated heteroaromatic peroxy radicals (2) can revert to reactants (1) or cyclize via attack of the side chain’s terminal O at a position ipso (3) or ortho (4) to the alkylperoxy chain. Oxygen atom loss can occur (5). Given the presence of the exocyclic methylene group, isomerization via H-atom transfer (6) can occur from a methylene carbon to the terminal peroxy oxygen; this cannot occur in the nonalkylated parent compounds. Additionally, entire side chain loss (as dioxirane in the case of methyl-substituted aromatics) is possible (7). Calculated kinetic and thermodynamic values for unimolecular decomposition of benzylperoxy radical and 2-picolinylperoxy radical (2-methylpyridinylperoxy radical) at 298 K are presented in Table 4 (representative structures shown in Fig. 18). The energies for decomposition of these two compounds are similar: bicyclic ring formation at the carbon ortho to the alkyl group (pathway 4) occurs with a barrier of 30 kcal/mol; cyclization at the carbon ipso to the alkyl group (pathway 3) occurs with a barrier of 35–40 kcal/mol; internal H-atom transfer (pathway 6) occurs with a barrier of 40 kcal/ mol. The added functionality afforded by the nitrogen atom in 2-picolinylperoxy radical allows a cyclization resulting in a stable N—O radical after O—O bond scission (pathway 4b), which has potential for yielding precursors to NOx chemistry; however, this process has a substantially high barrier (50 kcal/mol) and is unlikely to be a factor at atmospheric temperatures. While the qualitative trends were replicated between benzylperoxy radical and 2-picolinylperoxy radical, the latter has slightly higher reaction barriers and energies in nearly every case, which can be attributed to the relative stabilization of the allylic systems in the cyclized derivatives. CBS-QB3 calculations helped demonstrate that the DFT (B3LYP) approach provides good qualitative predictions for the energetic trends. The trends for 2-picolinylperoxy radical were similar for other picolinylperoxy radicals, as well as peroxy radicals of alkylated diazabenzenes (i.e., pyridazine, pyrimidine, and pyrazine). It was observed that the presence of a second ring nitrogen has little effect on either the identity or energetics of the preferred pathways. Likewise, the ethyl

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Table 4 Comparison of reaction pathway energetics (kcal/mol) for benzylperoxy radical and 2-picolinylperoxy radical at 298 K, via B3LYP/6–311þG**//B3LYP/6–31G*. Numbers refer to pathways depicted in Fig. 18. All enthalpies and free energies are relative to the peroxy radical (2); when preceded by TS, the relative data are the enthalpy and free energies of activation Benzylperoxy radical B3LYP 

2!1 TS(2–3) 2!3 TS(2–4a) 2 ! 4a TS(2–6) 2!5 2!6 2!7

CBS-QB3 

DH

DG

–16 35.7 33.2 33.5 35.6 37.9 56.5 –33.9 53.7

–5.5 37.2 34.2 35.6 23.7 38.9 47.3 –35.4 42.9

DH



Experiment

DG



–22.7 30.1 25.8 29.7 14.6 38.4 61.9

–12.2 31.7 26.9 31.8 15.1 39.2 52.5

55.8

45.3

a

DH

DG

–20.1b, –21.8c

–12.2

a

2-Picolinylperoxy radical B3LYP

2!1 TS(2–3) 2!3 TS(2–4a) 2 ! 4a TS(2–4b) 2 ! 4b 2!5 TS(2–6) 2!6 2!7

CBS-QB3

DH

DG

DH

DG

16.3 37.1 34.2 30.4 20.6 47.1 –5.8 61.6 38.0 –24.7 49.2

6.5 39.4 35.7 33.2 23.2 49.8 –4.1 53.0 39.4 –33.6 38.7

22.7 31.0 26.1 25.6 13.2

13.2 33.4 27.9 28.7 16.0

37.6 –23.7

39.2 –32.4

Where applicable, 4a refers to cyclization at a ring carbon and 4b refers to cyclization at nitrogen. a Geometry could not be optimized. b Reference 161. c Reference 162.

analogs favored similar reaction pathways, with energies of activation and reaction varying by only 2 kcal/mol between the methyl and the ethyl analogs. When present, the disparities in the reaction energetics were rationalized via consideration of the inductive effects caused by the nitrogen atom(s) and varying amounts of geometric strain introduced in the rearrangement pathways. Fig. 19 shows that with increasing temperature, formation of 1, 5, and 7 benefit entropically and become substantially exoergic reactions. Formation of 3 and 4a exhibit little entropic benefit. As shown in Fig. 20, the reaction barriers similarly

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80 60

ΔGreaction (kcal/mol)

40 20 0 –20

0

1000

500

1500

2000

2500

×

–40

× ×

–60

×

–80

× ×

–100

×

–120

×

–140

T (K)

Fig. 19 DGrxn versus temperature for the unimolecular pathways of 2-picolinylperoxy radical. 2 ! 3 denoted by open diamond; 2 ! 4a denoted by solid square; 2 ! 4b denoted by open triangle; 2 ! 5 denoted by dash; 2 ! 6 denoted by symbol ; 2 ! 7 denoted by solid diamond. All energies calculated at the B3LYP/6–311þG(d,p)//B3LYP/6–31G(d) level of theory.

50 45 40 ΔGactivation (kcal/mol)

× ×

35

×

30

×

25

× ×

20

×

15

×

10 5 0

500

1000

1500

2000

2500

T (K)

Fig. 20 DGactivation versus temperature for unimolecular pathways for 2-picolinylperoxy radical. Activation energy for 2 ! 3 denoted by open diamond; activation energy for 2 ! 4a denoted by solid square; activation energy for 2 ! 4b denoted by open triangle; activation energy for 2 ! 6 denoted by symbol  . All energies calculated at the B3LYP/ 6–311þG(d,p)//B3LYP/6–31G(d) level of theory.

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demonstrate minimal entropic effects. Formation of 4b has a similarly small entropic benefit but maintains a high reaction barrier, such that any NOx formation via this process is expected to be minimal except at extremely high temperatures. Formation of 6 exhibits a precipitous drop in its barrier and is the dominant processes at T  1250 K. This last reaction is of considerable interest given its relevance to both lowand high-temperature combustion, since it essentially constitutes a dissociative rearrangement pathway. Both the direct and the indirect decomposition intermediates (1, 5, 6, and 7) will play a substantial role in combustion as temperatures rise above 298 K, as peroxy radicals, themselves ROS, demonstrate the potential to generate reactive O-atom and hydroxyl radical. The overall chemistry of alkylated azabenzylperoxy radicals was consistent regardless of alkyl substitution or number of nitrogen atoms. The picolinylperoxy radicals provide excellent models for the chemistry exhibited by this larger class of species. Moreover, aromatic hydrocarbons can themselves predict several aspects of this chemistry, the exception being those processes involving oxidation or rearrangement with ring nitrogens. When this approach is extended to alkylated derivatives of the five-membered heteroaromatic rings,206 the energetic trends can be considered in light of ring size and heteroatom effects. In general, the same six pathways are available, such that rearrangements and dissociations are observed to contribute to the chemistry of these species. Many trends are consistent between both sets of alkylated heteroaromatics: increasing alkyl substitution leads to small stabilization of reaction barriers and energies. Increasing temperature leads to a shift in preference for the dissociation pathways. However, a difference was observed for smaller rings: while cyclizations are favored pathways at 298 K regardless of parent ring size, alkyl-substituted heteroaromatic peroxy radicals of the five-membered rings cyclize in such a manner as to generate an allylic radical system (cyclizing at a position either ipso or ortho to the side chain). On the other hand, alkyl-heteroaromatic peroxy radicals of the sixmembered rings preferred to form five-membered rings via ortho cyclization, due to their increased stability over spirodioxetane structures (which would result from ipso cyclization). This general trend is represented in Fig. 21.

Fig. 21 Qualitative depiction of favorable cyclization pathways for representative peroxy radicals of methyl heteroaromatics (top, pyridine and bottom, furan). Cyclization for the alkylated six-membered heteroaromatics is driven by the thermodynamic stability of the resulting ring, while cyclization for the alkylated five-membered heteroaromatics is dictated by which pathway allows the generation of a stable allylic radical system.

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Heteroatom identity also has an impact on the reactions of interest. Oxygen, nitrogen, and sulfur atoms affected heteroaromatic chemistry to slightly different quantitative extents (though qualitative trends were consistent), and the effect of multiple heteroatoms (as in oxazole) led to small differences in reaction energetics. Notably, the pyrrole, oxazole, and thiophene analogs reacted to form various species wherein their heteroatoms are oxidized, and these effects were unique to each heterocycle. Thus, data for aromatic hydrocarbon species are useful in estimating the energetics of these species but cannot completely predict their chemistry, due to the propensity of increasing functionalization to lead to different products and pathways. Relative to nonalkylated heteroaromatic peroxy radicals,197,198 we observed that alkylated species demonstrated a greater affinity for intramolecular reactions, due to the length and flexibility of their side chains. Dissociative reactions were less favorable for alkylated derivatives, due to a reduction of aromatic character. Our studies have provided important details regarding the oxidative decomposition of alkyl-substituted heteroaromatic rings: in particular, pathways originating with peroxy radicals derived from the heteroaromatic rings and temperature effects on these pathways. We have shown that the alkylated five-membered heteroaromatics demonstrate certain unique tendencies in their reactivity. Given the differences in reactivity between the five- and the six-membered heteroaromatics, as well as between the alkylated and the nonalkylated heteroaromatics, it seems likely that the chemical behavior of coal could vary somewhat depending on the abundance and nature of the cyclic subunits present in its structure. However, these discrepancies are mainly limited to the variety of products formed via combustion rather than the overall kinetics and thermodynamics of the relevant processes.

4

Future challenges in combustion chemistry

In closing this review, it seems logical to highlight some of the most recent progress in combustion chemistry. Alternate forms of energy and methods of combustion are continually being developed, thereby continuously invoking new challenges for experimentalists and theoreticians. Some alternatives involve new combustion processes, as in the case of homogenous-charge compression-ignition (HCCI)207 chemistry, which depends on autoignition (low temperature) chemistry within a homogenous gas mixture (unlike a SI engine). This new combustion method has the potential to increase fuel efficiency and decrease harmful emissions.208,209 One significant issue with HCCI is adequately controlling fuel ignition during the compression stroke of the engine; this is essentially a kinetics problem, requiring understanding of the reaction rates and mechanisms of the radical species generated by the fuel. Thus, reactions normally associated with low-temperature combustion and often treated cursorily in oxidative mechanisms can have a greater impact on combustibility. In this review, we are most interested in the implications of the changing energy landscape for the reactive pathways involved. As the nature of the fuels used in everyday life change, the reactive radical intermediates formed in their combustion will also change. We will examine the context of two classes of relevant fuel developments.

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FUEL ADDITIVES

Oxygenated molecules have long been used to augment gasoline formulations. For instance, since the elimination of tetraethyl lead (Pb(C2H5)4) as an additive. oxygenates have been used as gasoline additives to reduce harmful CO emissions and increase a fuel’s octane rating. The most prominent oxygenate has been methyl tert-butyl ether (MTBE); however, this additive has since been flagged as a potential carcinogen and odorous component that can taint water supplies.210 Moreover, MTBE necessitates the use of the industrial byproduct, isobutene, for its generation, further competing with crude oil supplies for a value-added product. As the downsides to MTBE use have become more apparent, ethanol has emerged as an attractive alternative oxygenate. Ethanol does not demonstrate the negative health effects of MTBE, and moreover, it can be produced from renewable (biomass) materials.211 Compared to MTBE, ethanol has a higher oxygen-to-carbon ratio. Ethanol has been used primarily as a gasoline additive; in fact in the years since the Energy Policy Act of 1992,212 a shift has occurred, such that current manufacturers are building cars with the capacity to run on fuel blends of 85 and 95% ethanol, along with a small amount of gasoline – these fuels are often referred to as E85 or E95, respectively. (However, some engine modifications are necessary for vehicles to run effectively on blended fuels with greater than 20% ethanol.) This advance has been hampered by the general lack of availability of ethanol at fueling stations, a shortage that is being gradually remedied. Currently, the cost benefits of using ethanol over gasoline are substantial, but the availability of the former is still limited.213 Ethanol itself demonstrates several drawbacks as an alternative fuel, despite its increasing availability. Most notably, ethanol absorbs water. Thus, it cannot travel through existing gasoline pipelines, as the water could subsequently separate and freeze during colder temperatures, possibly bursting the pipelines; moreover, ethanol is also corrosive.214 Thus, ethanol has to be transported via other means (a fact which, ironically, generally necessitates the use of gasoline, diesel, or other fuel and results in a higher cost that negates one monetary benefit of using ethanol as a fuel). Moreover, ethanol evaporates relatively quickly, and so in warmer temperatures, it must be blended carefully.215 Butanol possesses the chemical benefits of ethanol while avoiding its drawbacks. Its use is considerably less temperature-sensitive: it is six times less evaporative than ethanol, and it is not corrosive, so can be shipped via existing fuel pipelines.216 In terms of fuel benefits, due to its higher number of carbons, it has higher energy content (110,000 Btu/gallon) than ethanol (84,000 Btu/gallon) and is comparable to gasoline (115,000 Btu/gallon); it can also be generated more easily from biomass than can ethanol.217 Unlike ethanol, it can be used as a direct replacement for gasoline rather than as an additive therein, since butanol’s air/fuel ratio is comparable to that of gasoline.218 Finally, butanol’s primary combustion byproduct is carbon dioxide; it avoids formation of the pollutants NOx, SOx, and CO.219 Thus, butanol is a potential fuel of substantial interest. Studies have been completed specifically on combustion processes of ethanol and butanol, and several of the peroxy and oxy radical species have been examined.95–108

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Marinov proposed an exhaustive mechanism for ethanol’s combustion.220 Cavalli et al. examined the initial reaction of HO• radical with 1-butanol by FTIR spectroscopy,221 and Chen et al. studied the anodic oxidation of this species.222 Recent experiments by McEnally and Pfefferle led them to propose that butanol combustion primarily occurs via a complex fission reaction rather than H-atom abstraction.223 While we have discussed the historical background of the main gasoline oxygenates, it is worthwhile to note that several other species have been discussed in this context as well. Notably, it has been shown that simply adding oxygen to a given combustion environment does not in itself achieve soot reduction; the role of the oxygen within the structure of the oxygenate plays a major part. For instance, Westbrook et al. completed a modeling study on the effect of various oxygenated hydrocarbons on soot production.224 They saw a significant reduction in the number of alkynyl radicals serving as soot precursors in a diesel flame via the inclusion of alcohol (ROH) and ether (ROR0 ) additives, but noted a lesser effect when esters (RCO2R0 ) were included. This is due to the fact that esters can readily fragment to generate CO2, so that their oxygen atoms are not involved in the processes that can affect soot reduction. Similarly, Sinha and Thomson225 studied three C3 oxygenated hydrocarbons – isopropyl alcohol, dimethoxy methane (DMM), and dimethyl carbonate (DMC) – all in comparison to propane, noting different effects for each. DMM and DMC lack C—C bonds. Thus, the concentration of the alkenyl and alkynyl radicals necessary to form benzene and larger aromatic hydrocarbons is correspondingly smaller in these species and soot production drops. Nag et al.226 have postulated that the identity of a given oxygenate contributes to the resultant balance of CO and CO2 in the emission pool; CO has a greater propensity for PAH reduction than does CO2. The implications for power output and efficiency are important as well, since a significant amount (33%) of the eventual heat is generated by the conversion of CO to CO2 in the combustion environment (usually mediated by HO• radical). The structure of an oxygenate has notable implications for both its reactivity and its propensity for the formation of emissions.

BIODIESEL

Having alluded briefly to biomass compounds in the previous section, as sources for ethanol and butanol, we turn now to the potential of these species as fundamental alternatives to fossil fuels. In 1912, Rudolf Diesel presciently stated,227 ‘‘The use of vegetable oils for engine fuels may seem insignificant today. But such oils may in the course of time become as important as petroleum and the coal tar products of the present time.’’ Biodiesel can be produced from a variety of sources,228 including animal fats (on small scales), algae, and vegetable oils: the fuel itself is produced via esterification of these lipids with methanol or ethanol. In terms of the overall benefits and sources of fuels, several reviews are currently available. As early as 1987, Schwab et al. reported on the potential of vegetable oils for forming diesel fuels.229 More recently, Graboski and McCormick,230 Srivastava and Prasad,231 and Lin et al.232 have reviewed the fuel properties (emissions, engine performance, etc.) of

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these species. Ma and Hanna have compiled a review of the general benefits of biodiesel chemistry.233 The emergence of biofuels as potential energy sources demands a mechanistic approach comparable to those currently in use for hydrocarbon compounds. Biofuels are commonly esters (RCO2R0 ) of large long-chain fatty acids, so their reactivity will depend on more factors than these extant mechanisms. Kulkarni and Dalai have summarized mechanistic aspects of biodiesel chemistry, with respect to waste cooking oil.234 Thermolytic decomposition can yield alkanes, alkenes, ketones, esters, and small acids. Oxidative decomposition leads to highly functionalized peroxy radicals, which then can add a hydrogen atom to form hydroperoxides, ultimately decomposing to aldehydes, hydrocarbons, and acids; additionally, these peroxy radicals might dimerize or oligomerize if excess oxygen is present. Hydrolytic reactions comprise an additional possibility: triglycerides readily decompose to glycerol, monoglycerides, diglycerides, and free fatty acids (FFA), in the presence of water. Zhenyi et al. have completed thermodynamic calculations on the pyrolysis of vegetable oils, postulating that, for a given ester, the key initiation step proceeds via breaking of the alkyl (sp3) C—O bond.235 We can summarize the different possible initiation routes for a given triglyceride, familiar from our previous discussions (Fig. 22). Even from this basic view, it is clear that several classes of reactive radical intermediates will play a role in biofuel combustion: alkyl (sp3) and alkenyl (sp2) radicals are readily formed, as well as peroxy radicals and functionalized derivatives of each of these original species.

Fig. 22 Initial reaction steps for fatty acid ester decomposition, represented by ethyl butanoate, which can decompose via thermolysis (pyrolysis), oxidation, or hydrolysis.

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Mechanism development traditionally depends on the inclusion of data for relevant, smaller compounds; that philosophy will apply in this case, where the reactions of both small hydrocarbons and small esters are of interest. Mechanisms for methyl butanoate (CH3CH2CH2CO2CH3) have been developed by Gail et al.236 and Curran et al.;237 the latter notes the NTC range demonstrated by this species, suggesting that future work may benefit by exploring comparisons to hydrocarbon chemistry. Good and Francisco have modeled the tropospheric oxidation mechanism of methyl formate (HCO2CH3).238 Metcalfe et al. explored unimolecular decomposition pathways and derived combustion mechanisms for methyl butanoate and ethyl propanoate, using shock-tube experiments and CBS-QB3 calculations.239 Recent studies by Glaude et al.,240 Schwartz et al.,241 and Sarathy et al.242 have provided experimental information on larger esters, in an effort to model further reactions with implications for biofuel combustion. This area is of significant interest, and it is expected that the next few years will provide a more thorough understanding of the important species and relevant mechanisms involved in biofuel combustion.

5

Conclusions

Throughout this review, we have provided a historical context for understanding combustion chemistry as it applies to some of the most fundamental hydrocarbon compounds. We have explored the implications of these processes for larger and increasingly functionalized molecules. These species can be used to model the chemistry of petroleum and coal, in addition to smaller hydrocarbon fuels. Combustion is a complex topic, such that both theoretical and experimental methods are useful in exploring chemistry with implications for high-temperature oxidation and lowtemperature atmospheric reactions. In particular, the master equation methods developed over the past few decades can consider the collective chemistry of thousands of elementary steps to predict the overall oxidation of a given fuel; the kinetics and thermodynamics of each of these elementary steps can be generated via experiment or computational modeling. ROS and other radical intermediates dictate the oxidative decomposition of fuels. We have noted that peroxy radical intermediates provide an enormous amount of flexibility in the combustion of a given compound, specifically in the unimolecular steps available to that compound. In an instructive display of the interaction of experimental and theoretical techniques, rearrangement pathways of the peroxy radicals have been modeled computationally and provide justification for several unexpected products. At the start of the twenty-first century, efforts are underway to decrease society’s dependence on fossil fuels. It is clear that alternate energy forms will bring with them their own sets of reactive radical intermediates and revisit the important intermediates seen from smaller model compounds, as we consider future challenges in combustion chemistry. We expect that advances in experimental techniques and computational approaches will correspondingly be developed in the years ahead.

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Acknowledgments We are grateful to Dr. Timothy Barckholtz (ExxonMobil Research and Engineering) for helpful discussions and for providing Fig. 3. We extend sincere thanks to Dr. Donald Burgess, Jr. (NIST) for his help in the editing of this review.

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Stable carbocations and onium ions from polycondensed aromatic and heteroaromatic compounds as models for biological electrophiles and DNA-transalkylating agents KENNETH K. LAALIa and GABRIELA L. BOROSKYb a

Department of Chemistry, Kent State University, Kent, OH 44242, USA Unidad de Matema´tica y Fı´sica, INFIQC, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Ciudad Universitaria, Co´rdoba 5000, Argentina

b

1 Introduction 135 2 Protocols 138 3 Pyrenium ions 139 4 Phenanthrenium ions 147 5 Benzanthracenium ions 152 6 Chyrsenium and benzo[c]phenanthrenium ions 156 7 Carbenium ions and onium cations from hetero-PAHs 160 8 Carbenium ions derived from nonalternant PAHs 166 9 Miscellaneous systems 173 10 Concluding remarks 174 Acknowledgement 174 References 175

1

Introduction

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants well known as mutagenic/carcinogenic agents.1 They exert their biological activity principally through metabolic formation of their diol epoxides (DEs) and generation of carbocations by DE ring opening.2 Bay-region DEs (Fig. 1) exhibit increased mutagenic and carcinogenic properties,3 and these observations led to the development of the so-called bay-region theory.4 Metabolic formation of bay-region DEs involves oxidation of a terminal, angular benzo ring of the hydrocarbon to form an arene oxide, hydration of the arene oxide to form a trans-dihydrodiol, and subsequent epoxidation of the bay-region double bond of the dihydrodiol. Benzylic carbocations, generated from these electrophilic DEs by opening of the O-protonated epoxide, are capable of forming covalent adducts with the nucleic acids.2 Adduct formation by reaction with the nucleophilic sites in DNA and RNA has been recognized as an important event in the mechanism of chemical carcinogenesis by PAHs (Fig. 2).2 For PAHs with lower ionization potentials, direct biological single-electron oxidation to the radical cations (RCs) could intervene, with the resulting PAHþ• undergoing nucleophilic attack by DNA nucleotides to form PAH–DNA adducts (Fig. 2).5 135 ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 43 ISSN: 0065-3160 DOI: 10.1016/S0065-3160(08)00004-X

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Fig. 1 Different types of DEs or epoxide derivatives from model PAHs.

With the methylated PAHs, another bioactivation pathway leading to benzylic carbocations becomes available through side chain oxidation to form a benzylic alcohol, followed by esterification and solvolysis.5 Thus, benzylic sulfate ester formation (via initial formation of benzyl alcohol) constitutes an additional route that could contribute to metabolic activation (Fig. 2).5 Nitration opens up another pathway to metabolic activation. Nitro-PAHs are wide-spread environmental pollutants that are mutagenic and carcinogenic. Metabolism of nitro-PAHs could occur via nitro-activation (reduction to hydroxylamine, eventually leading to nitrenes that can bind to nucleotides) and/or by ring oxidation and formation of DEs.6 Generation and NMR studies of the carbocations from various classes of PAHs under stable ion conditions, in combination with computational studies, provide a powerful means to model their biological electrophiles. These approaches allow the determination of their structures, relative stabilities, charge delocalization modes, and substituent effects, as a way to understand structure/reactivity relationships. Theoretical calculations complement and enhance the experimental NMR studies, by providing charge delocalization maps via changes in computed charges (Dq) and through computed Dd 13C values from gauge-independent atomic orbitals (GIAO)NMR (Section 2), for comparison with the charge delocalization maps derived from experimental Dd 13C values. Computed relative arenium ion energies establish comparative links with the experimentally observed site(s) of protonation, while the density functional theory (DFT)-optimized structures give insight into the geometries and steric factors. Substituent effects on charge delocalization and relative

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Fig. 2 Various metabolic activation pathways for PAHs.

carbocation stabilities/reactivities provide a bridge to structure/activity relationships that are determined by biological tests, namely by relative DNA-binding studies and/ or comparative mutagenicity assay. A long-term goal is to evaluate the correspondence between carbocation-derived structure/reactivity relationships and those derived from biological assays. Such comparisons could prove valuable toward predictability of cancer induction in various environmentally relevant classes of PAHs and hetero-PAHs. Earlier progress in these studies has been summarized in reviews published in the last decade, emphasizing carbocations and oxidation dications,7–9 RCs,7 as well as reactive intermediates from the nitro- and nitroso-derivatives.9,10 The review article published in 1996 emphasized groundwork studies on protonation as well as oxidation (both RCs and stable dications) of polycyclic arenes and explored possible relationships between charge distribution and carcinogenicity, in concert with its

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modulation via strategically positioned substituents.7 These topics were updated in a 2004 review, where related theoretical calculations were also discussed.8 Furthermore, Laali and Okazaki9 summarized stable ion studies involving the nitro- and nitrosopyrenes in various superacid media. Under appropriate combustion conditions, incorporation of nitrogen into the aromatic ring system leads to the formation of aza-PAHs.11 Substantial evidence has been obtained, suggesting that the aza-analogs are also metabolically activated to DEs according to the bay-region theory.12 Experimental data have revealed that the position of the nitrogen heteroatom in the aza-PAHs could have a significant effect on the carcinogenic potencies of their dihydrodiol and bay-region DE metabolites. Recently, model computational studies aimed at understanding structure/reactivity relationships and substituent effects on carbocation stability for aza-PAHs derivatives were performed for several families of compounds, and comparisons were made with the biological activity data when available.13 The goal of this chapter is to highlight the more recent studies on several classes of PAHs and hetero-PAHs from our laboratory, with stronger emphasis being placed on quantum-chemical calculations and their relationships with the biological activity data.

2

Protocols

PAH arenium ions are typically generated in low concentrations at low temperatures in FSO3H/SO2ClF. Diprotonation can be effected with FSO3HSbF5 (4:1)/SO2ClF. The use of higher acidity, more oxidizing, FSO3HSbF5 (1:1)/SO2ClF could lead to competing oxidation and/or polymerization. The resulting carbocation(s) are examined directly by high-field NMR (whereas earlier studies were performed on a 300-MHz instrument, working with a 500-MHz instrument became essential in later studies involving more complex systems) to assign their structure and to deduce charge delocalization modes from Dd 13C values. Specific assignments of the ring carbons including the ring junction carbons are accomplished via HMQC and HMBC experiments. Assignments are assisted by NOED experiments that also provide conformational information in relevant cases. The NMR studies are complemented with theoretical work. Given the size of the systems, AM114 minimizations and single-point calculations were performed in earlier studies. Relative arenium ion energies are typically computed for all possible carbocations derived from a given PAH, for comparison with experiment (this method proved to work quite well). Subsequently, DFT methods (B3LYP functional15) were employed to compute (1) natural charges from which changes in charges are mapped out for comparison with the NMR-based conclusions, (2) GIAO-NMR16 to predict the chemical shifts for comparison with the experimental results, and (3) nuclear-independent chemical shift (NICS)17 in order to evaluate relative aromaticity in different rings. Finally, solvent effects were estimated by the polarized continuum model (PCM).18 In selected cases, parallel DNA-binding studies (with MCF-7 human mammary

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carcinoma cells) were performed, starting with the covalent precursors of model benzylic carbocations (typically alcohols and chlorides) for comparative purposes. Comparative mutagenicity assay (Ames test) were performed on the nitroderivatives.

3

Pyrenium ions

It was shown in earlier studies19 that dihydropyrene 1 and its 2,7-di-tBu derivative 3 were both monoprotonated with FSO3H/SO2ClF at C-3. Diprotonation of 3 gave the 3,6-diprotonated cation selectively, that of 1 produced primarily the 3,6diprotonated dication. When lHþ was heated, it was oxidized to 2Hþ (Fig. 3). This process was explained by equilibrium deprotonation at higher temperature and stepwise oxidation. Protonation of a mixture of 2 plus 1 led to NMR detection of 2Hþ only (Fig. 3). This was rationalized by a facile H abstraction from lHþ by 2þ, which was formed from 2 in the superacid. Formation of lþ was inferred from Electron Spin Resonance (ESR). Protonation of a mixture of 4 and 1, on the other hand, produced lHþ and 4þ. This was consistent with the NMR spectrum showing no signals for the chlorochrysene (Fig. 3). Heating of this sample led to NMR detection of 2Hþ. A series of regioisomeric tertiary and secondary methylcarbenium ions bearing 1-pyrenyl, 4-pyrenyl, and 2-pyrenyl substitutents were generated from their carbinol precursors.20 Charge delocalization into the pyrene moiety was evaluated on the basis of the magnitude of the Dd13Cs and the chemical shift of the cation center. For both tertiary and secondary 1-pyrenylmethylcarbenium ions, the positive charge was effectively delocalized. The pyrenium ion character of the resulting benzylic carbocations decreased in the order 1-pyrenyl > 4-pyrenyl > 2-pyrenyl. As a guiding tool and for comparison with the solution NMR studies, AM1 energies and charges were calculated for a set of tertiary and secondary a-pyrenyl carbocations. The AM1 relative stability order was in accord with the NMR-based stability trends for the regioisomeric secondary pyrenyl(methyl)methylcarbenium ions. For the regioisomeric tertiary pyrenyldimethylcarbenium ions, peri interactions raised the energy. Thus, from the model carbocations generated in this study, the carcinogenic activity in benzo[a]pyrene (BaP) was related to the enhanced stability and the highly delocalized nature of 5aþ as compared to 5bþ (Fig. 4), while the lack of carcinogenicity in benzo[e]pyrene (BeP) could stem from lower relative stability of 6þ. A series of regioisomeric PyCþ(CF3)R (R = Me, Ph) (Py = pyrene) and (9-Phe)Cþ(CF3)Me (Phe = phenanthrene) carbocations, having a CF3 group a to the cation center, were generated from their carbinols in order to examine the influence of carbocation destabilization (increasing electron demand) on the magnitude of p-participation by an a-pyrene (or a-phenanthrene) moiety.21 Multinuclear (13C, 19F, and 1H), NOED, and 2D NMR (H/H COSY and C/H HETCOR) were used to deduce the mode and magnitude of charge delocalization and the extent of Ar—Cþ double-bond character in the carbocations. AM1 calculations were used to examine their energies, charges, and conformations for comparison with NMR.

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Fig. 3 Mono- and diprotonation of pyrene derivatives.

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Fig. 4 Simplified carbocations generated as model for carbocations from the BaP and BeP skeletons.

Since charge delocalization into the 1-Py-, 4-Py-, and 9-Phe-substituents was quite effective, the presence of a-CF3 greatly increased p-participation and the arenium ion character. On the other hand, diminished charge delocalization into a 2-Py-substituent, coupled with destabilization by a-CF3, provoked ring protonation. Representative 13C NMR data for these carbocations are shown in Fig. 5. Furthermore, the crowded carbenium ions, (1-pyrenyl)diphenylmethylcarbenium ion and the 1,6- and 1,8-bis(diphenylmethylenium)pyrene dications, were generated along with their brominated analogs (Fig. 6).22 By use of semiempirical MO and force field calculations, the minimum energy conformations of the trityl cation and the preferred ring rotations were evaluated and compared with experiments. Subsequently, the conformations and the charge distribution patterns in the more crowded (1-pyrenyl)diphenylmethyl cations and their related dications were probed along with dynamic NMR (DNMR) studies of the persistent ions. Since there is no degeneracy in these carbenium ions, flipping of the rings could be followed by DNMR; the cation showed a conventional two-ring flip (ph,ph), whereas the disubstituted pyrene dications showed one-ring flips (py) and two-ring flips (ph,ph) with a higher rotational barrier in agreement with AM1 calculations. The AM1 method gave the transitionstate energies in best agreement with experiment. The charge at the Cþ carbon was most extensively delocalized in the cation, whereas in the species with two Cþ groups, the pyrene moieties were less effective in charge delocalization.

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Fig. 5 13C NMR data for the carbocations. Dd 13C values: cation minus carbinol. a, b, c, and d denote interchangeable assignments within a cation; n.o. means not observed.

Fig. 6 Generated (1-pyrenyl)diphenylmethylcarbenium ion, 1,6- and 1,8-bis(diphenylmethylenium)pyrene dications, and the brominated analogs.

Low-temperature protonation of 1-nitropyrene and its 15N-labeled isotopomer with FSO3HSbF5 (1:1) (‘‘magic acid’’)/SO2ClF (or SO2) or with FSO3HSbF5 (4:1)/SO2ClF generated either the dihydroxyiminium–pyrenium dication (NO2 diprotonation) or the hydroxyiminium–pyrenium dication as the principle NMR-observable persistent species (Fig. 7).23 The latter was independently generated by diprotonation of

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Fig. 7 Mono- and dications generated from nitropyrenes.

authentic 1-nitrosopyrene. Variable formation of dihydroxyiminium–pyrenium and hydroxyiminium–pyrenium dications was also observed in the protonation of sterically crowded 1-nitro-2,7-di-tert-butylpyrene, which gave the corresponding dihydroxyiminium–pyrenium dication in FSO3HSbF5 (1:1)/SO2ClF (or SO2) and the hydroxyiminium–pyrenium dication by low-temperature reaction with FSO3H/SO2ClF or CF3SO3H/SO2. Protonation of the buttressed 1-nitro-2,4,6,8,10-pentaisopropylpyrene

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and its 15N-labeled isotopomer produced the dihydroxyiminium–pyrenium dication that underwent a facile cyclization to the oxazoline-fused pyrenium cation. Diprotonation and subsequent cyclization of the singly 15N-labeled 1,3-dinitro-2,4,6,8,10pentaisopropylpyrene were also studied. PM3 semiempirical calculations were used as a complementary tool to examine the geometries and energies of the resulting dications. Regioisomeric monoacyl- and monobenzoyl-substituted pyrenes are diprotonated in FSO3HSbF5(4:1)/SO2ClF to give persistent carboxonium–pyrenium dications, whereas diacetyl- and dibenzoylpyrenes were diprotonated to give dicarboxonium dications.24 The resulting dications were studied by lowtemperature NMR. Conformational aspects of the carboxonium group in various regioisomers were addressed by a combination of NOED spectra and 2D NMR and AM1 calculations. Charge delocalization pathways were gauged and compared on the basis of the magnitude of Dd13C values. Some representative examples are shown in Fig. 8. It was concluded that the carboxonium group is a robust electron-withdrawing substituent whose electronic response is sensitive to steric factors. In this way, it could be used to modulate charge delocalization into PAHs and their carbocations, as a function of substitution position. In stable ion studies of BaP derivatives, 7,8-dihydro-BaP gave a bay-region benzylic carbocation with extensive charge delocalization into the pyrene moiety.25 In contrast, a persistent carbocation could not be generated from 9,10-dihydro-BaP; introduction of bulky substituents at C-6 prevented side reactions, and the initially formed carbocation underwent rearrangement to the corresponding bay-region carbocation. Introduction of methoxy substituents into the 1- or 3- positions of 9,10dihydro-BaP-7(8H)-one increased its electrophilic reactivity to the extent that stable carboxonium–arenium dications were produced in FSO3H/SO2ClF (Fig. 9). Energies for various possible arenium ions and regioisomeric benzylic cations were computed at the DFT B3LYP/6-31G(d) level or by AM1 for comparison with the experimental results. These findings provided further evidence in support of the stability sequence: 1-pyrenyl > 4-pyrenyl > 2-pyrenyl in a-pyrene-substituted carbocations as models for the intermediates arising from BaP-epoxide ring opening (Fig. 10). In an effort to bridge the reactivity trend emerged from the stable ion studies, a series of a-pyrenylcarbinols were subjected to a DNA-binding study using human MCF-7 cells.25 DNA-binding data were compatible with the relative stability orders deduced from direct studies of regioisomeric a-pyrene-substituted carbocations, and the importance of steric contribution to DNA binding was emphasized. A systematic carbocation concentration dependency study on NMR chemical shifts was performed for the C-1-protonated 4H-cyclopenta[def]phenanthrenium cation 7Hþ and the C-1-protonated pyrenium cation 2Hþ (Fig. 11).26 Shielding of the PAH arenium ion protons and carbons was observed with decreasing FSO3H : PAH ratios without noticeable line-broadening. This was attributed to cation–anion interactions in the low FSO3H : PAH domain and possible formation of contact ion

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Fig. 8 13C NMR data for the carbocations and Dd 13C values in parenthesis (a and b denote interchangeable assignments within a cation; * means one of the two or both D values were derived from chemical shifts that were interchangeable; n.o. means not observed).

pairs. Lowering the ratio gave separate sets of resonances for the unprotonated PAH, indicative of the presence of the equilibrium: þ  PAH þ FSO3H !  PAHH þ FSO3

Variations in the absolute concentration of the carbocation solutions and temperature had minor effects on chemical shifts. The counter ion effect and the equilibrium could be minimized by going to higher superacidity systems with lower nucleophilicity counter ions. Resonances due to the PAH itself were considerably shielded. Solvation by FSO3H and the formation of ion pair-molecule clusters were suggested as possible reasons.

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Fig. 9 Mono- and dications generated from BaP derivatives.

Fig. 10 a-BaP-substituted carbenium ions as simplified models for BaP-epoxide ring opening.

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Fig. 11 Protonation of 7 and 2 with FSO3H/SO2ClF.

4

Phenanthrenium ions

Superacid protonation studies on 2-methyl-, 3-methyl-, 3,6-dimethyl-phenanthrene, and 4H-cyclopenta[def]phenanthrene (7) resulted in the generation of phenanthrenium mono- and dications.27 Their charge delocalization paths were examined by 13C and 2D-NMR studies. AM1 energies and charges were calculated for all conceivable mono- and diprotonated phenanthrenes, for comparison with experiments, in order to compare their relative stabilities and charge delocalization modes. Persistent monocations were generated from four compounds. The monomethylated structures were partially diprotonated, while the dimethylated analog gave a symmetrical dication (Fig. 12). The observed mono- and dications were in most cases those predicted by AM1 to be the most stable. A parallel was drawn between stable ion and AM1 studies of methylphenanthrenes and solvolytic studies of K-region and non-K-region phenanthrene oxides.28 The carbocation formed by opening of the 1,2-epoxide closely resembled the 2-methylphenanthrene cation (and 7Hþ), and the regiochemistry of phenol formation (1-phenanthrol) could be understood. Similarly, phenanthrenium cations derived from the 3-methyl and dimethylated compounds served as models for carbocations formed by solvolysis of phenanthrene-3,4-epoxide (formation of 4-phenanthrol following hydride shift). Subsequently, a series of regioisomeric a-phenanthrene-substituted carbocations were generated from their alcohols by ionization with FSO3H/SO2ClF.29 Model carboxonium ions were also generated by O-protonation of the isomeric acetyl- and

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Fig. 12 13C NMR data for the carbocations and Dd 13C values in parenthesis (a and b denote interchangeable assignments within a cation; * means one of the two or both D values were derived from chemical shifts that were interchangeable).

benzoylphenanthrenes. The charge delocalization paths and the arenium ion character in the resulting carbocations and carboxonium ions were evaluated via lowtemperature NMR studies and by AM1 calculations (Fig. 13). Conformational aspects in the carboxonium ions were also analyzed. The carbocations and carboxonium ions studied may be viewed as simplified models of DE ring opening in several classes of PAHs. The magnitude of charge delocalization into the phenanthrene system was much larger in the carbocations than in the carboxonium ions. In all cases, the protonated ketones showed the same delocalization path as the carbocations, but the arenium ion character was significantly lower. Charge delocalization into the phenanthrene system in the model arenium ions and carboxonium ions was most effective from the meso position. The phenyl group reduced phenanthrenium ion character, whereby additional stabilization was gained by delocalization into the phenyl group, as compared to the methyl groups.

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Fig. 13 13C NMR data for a-phenanthrene-substituted carbocations and carboxonium ions and Dd 13C values in parenthesis.

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In a later study, persistent carbocations were generated from five A-ring monoand disubstituted phenanthrenes [3-OMe, 4-OMe, 1,3-bis(OMe), 2,4-bis(OMe), and 1,3-bis(Me)].30 In all cases, protonation occurred in the A-ring, ortho/para relative to methoxy or methyl substituent(s). Mild nitration (with 20–50% aqueous HNO3 at – 10C or at room temp.) and bromination (NBS/MeCN/room temp.) of these substrates resulted in the synthesis of several novel mononitro-/dinitro-derivatives as well as monobromo/dibromo-derivatives, including those with the nitro- or bromosubstituent in the bay region. There was very good overall correspondence between the low-temperature protonation study and the regioselectivity observed in mild aqueous nitration. In most reactions, two nitro-products were obtained, one of them arising from a common type of carbocation intermediate as in protonation and the other likely arising from a higher energy regioisomeric carbocation or by further nitration of the initial product. In 2,4-bis(OMe), identical regioselectivity was observed in protonation and nitration. With bromination, steric control of regioselectivity was much more significant, but nevertheless bay-region bromination reflected the highly favorable carbocation stabilizing effects of the 1,3-dimethoxy substituents. A comparative DNA-binding study with MCF cells on three of the synthesized mononitro- and one dinitro-derivative showed that 1,3-dimethyl-9-nitro- (nitro at the meso position), 3-methoxy-4-nitro- (nitro in bay-region), and 1,3-dimethoxy-4,9dinitrophenanthrenes (nitro in both meso and bay regions) formed DNA adducts.30 The X-ray structures of 2,4-dimethoxy-1-nitro- and 1,3-dimethyl-4-nitro-Phe indicated that in both cases the nitro-group was severely buttressed. In line with previous observations that nitro-Phes with nitro-group forced out of coplanarity exhibited low or no activity (presumably because they were unable to intercalate into DNA),31 2,4dimethoxy-1-nitro-Phe did not exhibit DNA-binding activity. Moreover, HOMO/ LUMO energies for the nitro-compounds were calculated at the B3LYP/6-31G(d) level. Although only a limited set of compounds was studied for DNA binding, it appeared that the methoxy and methyl substituents increased bioactivity in the nitroderivatives, and consideration of HOMO/LUMO energies suggested that the tendency for nitro-reduction as a main metabolic pathway had diminished in the case of 1,3-dimethoxy-4,9-dinitro- and 3-methoxy-4-nitro-Phe relative to their unsubstituted nitro-derivatives. Protonation studies were carried out for a series of cyclopenta[a]phenanthrenes in superacid media (Fig. 14).32 Charge delocalization modes in the resulting mono- and dications (deduced primarily based on magnitude of Dd13C) were discussed and compared. In an effort to further enhance the NMR assignments, and for comparison, monoarenium ions 8Hþ, 11Hþ, 13Hþ, 14Hþ, and their neutral precursors were calculated at the B3LYP/6-31G(d,p) level of theory, their 1H and 13C NMR chemical shifts were computed by the GIAO method, and their overall charge delocalization paths were deduced via differences in the natural population analysis (NPA) charges (cation minus neutral). Hydrocarbons 8, 11, and 14 were ring-protonated in FSO3H/ SO2ClF to form monoarenium ions. The observed substituent dependency of the site of protonation in hydrocarbon carbocations 8Hþ, 11Hþ, and 14Hþ pointed to relative carbocation stability and relief of steric crowding at the bay region as

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Fig. 14 Structures of cyclopenta[a]phenanthrene derivatives and their carbocations and carboxonium ions.

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important factors in directing electrophilic attack under kinetic control. Despite predominant charge localization in the ring undergoing attack, the overall delocalization pattern in the monoarenium ions signified an extended charge alternation path within the Phe moiety, hence phenanthrenium ion character. The 16(17)-ene compounds 10 and 13 were protonated at the D-ring double-bond to form stable a-Phe-substituted carbocations.32 Although the ease of formation and stability of both carbocations 10Hþ and 13Hþ implicated their potency, compound 13 is a stronger tumorigen than 10, which led to the suggestion of an additive effect. The 17-keto derivatives 9, 12, 15, 16, 21, and 22 were CO-protonated to form carboxonium ions.32 Low-temperature protonation of 15 and 16 with FSO3HSbF5 (4:1)/SO2ClF gave their corresponding carboxonium–arenium dications (protonation of 9 gave a mixture of mono- and dications), where ring protonation sites were controlled by the position of the methyl group and occurred in the A-ring for the Aring-methylated derivatives (15, 16). Whereas the 11-methoxy derivative (18) formed a carboxonium ion analogous to the 11-Me derivative (12), the 11-phenol derivative (17), the ethoxy (19), and propoxy (20) derivatives were more reactive, forming a mixture of mono- and dication (with 17 and 19) or gave mostly a carboxonium– arenium dication (with 20). Under thermodynamic control, carboxonium ions underwent fluorosulfonation in the biologically important A-ring. Moreover, a stable ion protonation and model nitration study of the methoxysubstituted hydrocarbon 23, its 15-ol 24, and the dimer 27 was performed in order to evaluate OMe substituent effects on directing electrophilic attack and on charge delocalization mode/conformational aspects in the resulting carbocations (Fig. 14).33 It was found that the C-11 methoxy group directed the electrophilic attack to C-12 and C-14. Thus, protonation of 23 with FSO3H/SO2ClF gave a 4:1 mixture of monoarenium ions 23Hþ/23aHþ. Prolonged reaction times and increased temperature induced fluorosulfonylation at C-14 (23þ-SO2F), whereas ambient  nitration with NOþ 2 BF4 occurred at C-12. These observations supported the notion that increased activity of 23 stems from attack by electrophilic oxygen at C-14/C-15 producing the biologically active 24 as a major metabolite. The 15-ol derivative 24 was cleanly ionized to 25þ, providing the first example of an a-Phe-substituted carbocation from Phe C-1 position. Contrasting behavior of the D-ring methylsubstituted 28 and the C-11 methoxy-substituted 27 dimers was remarkable in that unlike 28, which was readily cleaved to produce the monomeric arenium ion 26þ, protonation of 27 resulted in two skeletally intact diprotonated dications, with major species diprotonated at the two C-12 sites and the minor species protonated at C-12 and C-14.

5

Benzanthracenium ions

Low-temperature protonation of 9-isopropenylphenanthrene led to direct observation of 5,6-dihydrobenzanthracenium cation 29Hþ from which the corresponding benzo[de]anthracene was obtained in 92% yield upon quenching.34 Charge delocalization mapping in 29Hþ, as deduced from Dd 13C values, showed arene

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p-participation primarily via a naphthalenium ion (AB ring of phenanthrene moiety) and was in qualitative agreement with the overall mode of charge delocalization deduced based on the AM1-calculated carbon charges (Fig. 15). Parent benzo[a]anthracene (BA, a borderline carcinogen) was protonated at C-7/ C-12, and a 3:1 mixture was obtained, favoring C-7 protonation.35 Increasing steric crowding at the bay region by the introduction of a methyl at C-1 (1-MBA) changed the ratio of C-7/C-12 protonated arenium ions to 10:1. The highly potent 7,12-dimethylbenzo[a]anthracene (7,12-DMBA) gave a 1:1 mixture of the two ipso-protonated cations whose composition changed to 50:1 overtime, in favor of the ipso-attack at the bay region, showing it to be the thermodynamic carbocation. 3-Methylcholanthrene (3MC), another potent carcinogen, was exclusively protonated

Fig. 15 Structures of representative benzanthracene derivatives and their derived carbocations/carboxonium ions (and comparison with model anthracene cations).

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at C-6. Cation 30þ (a simplified model for bay-region epoxide ring opening, as in 30aHþ) was cleanly formed via its carbinol 30-OH with FSO3H/SO2ClF. Ketone 31 was O-protonated in TFAH and in TFAH/H2SO4 to give the bay-region carboxonium ion 31Hþ; its diprotonation in FSO3HSbF5 (4:1)/SO2ClF gave the first example of the oxonium–arenium dication 31H22þ. The a-BA-substituted secondary carbocation 32þ and the carboxonium ion 33Hþ were generated to probe charge delocalization into the a-BA moiety via C-7. To gauge the importance of the benzo[a] ring, and for comparison, the anthracene-substituted carbocations 34þ and carboxonium ion 35Hþ were generated and studied. Some key structures are shown in Fig. 15. Charge delocalization pathways were evaluated on the basis of Dd 13C values, and AM1 was used as a complementary tool for qualitative comparison with experiment. The resulting arenium ions and benzylic carbocations exhibited strong anthracenium ion character emphasizing the importance of an electron-deficient anthracene moiety. For carbocations derived from potent carcinogens and those that could be considered simple models for the potent bay-region and K-region epoxides as well as cholanthrene epoxide, the unifying pattern is one where positive charge resides at the C-4a/C-6/C-7/C-8/C-10/C-11a/C-12a positions. Structure/reactivity relationships and substituent effects on carbocation stability in the BA derivatives were also studied computationally at the B3LYP/6-31G* and MP2/6-31G** levels.36 Bay-region carbocations are formed by O-protonation of the 1,2-epoxides in barrierless processes (as in 30aHþ). This process was energetically more favored as compared to carbocation generation via zwitterion formation/ O-protonation, via single-electron oxidation to generate a RC, or via benzylic hydroxylation. Relative carbocation stabilities were determined in the gas phase and in water as solvent (PCM method). Although the solvent decreased the exothermicity of the epoxide ring opening reactions due to greater stabilization of the reactants, it provoked no changes in relative reactivities. Charge delocalization mode in the BA carbocation framework was deduced from NPA-derived changes in charges (carbocation minus neutral, Fig. 15), and substitution by methyl or fluorine was studied at different positions selected on the basis of carbocation charge density.36 A bay-region methyl group produced structural distortion with consequent deviation from planarity of the aromatic system, which destabilized the epoxide, favoring ring opening. Therefore, enhanced carcinogenic activity caused by methyl substitution at the bay region was explained by preferential opening of the epoxide ring due to higher energy of the more crowded epoxide. According to calculations, stability of the carbocations generated from the oxidized metabolites of BA correlated with the available data on their biological activity. Fluorine substitution at sites bearing significant positive charge led to carbocation stabilization by fluorine p-p back-bonding, and a fluorine atom at a ring position which presented negative charge density led to inductive destabilization. To model the crucial step of covalent adduct formation, adducts resulting from quenching of selected carbocations (derived from their corresponding epoxides) with guanine via the exocyclic amino group and via the N-7 were computed, and their geometrical features and relative energies were compared.36 The change in the preferred product of the addition reactions with guanine due to solvent effect was

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(a)

(b)

Fig. 16 Adducts formed between guanine and 7,12-DMBA-1,2-epoxide; (a) exocyclic N and (b) N-7 isomer.

noteworthy for 7,12-DMBA-1,2-epoxide (Fig. 16). Whereas the N-7 adduct was most stable in gas phase, in water as solvent the most stable adduct was the one formed by reaction with the exocyclic nitrogen of guanine, in accord with experimental observations, suggesting that DFT studies on the reactivity of this type of compounds could provide reasonable estimates when extrapolated to living organisms. A series of novel carbocations were generated from isomeric monoalkylated and dialkylated BAs by low-temperature protonation in FSO3H/SO2ClF (Fig. 17).37 With the monoalkyl derivatives (2-, 3-, 4-, 5-, 6-, 7-methyl, and 7-ethyl) as well as the D-ring-methylated analogs (9-, 10-, and 11-methyl), the C-7- or the C-12protonated carbocations were observed (as the sole or major carbocation) in all cases. Protonation of the 12-methyl derivative gave the C-7-protonated carbocation as the kinetic species and the ipso-protonated carbocation as the thermodynamic cation. With the 12-ethyl derivative, relief of steric strain in the bay region greatly favors ipso-protonation. With 3,9-dimethyl, C-7 protonation was strongly favored (with <10% protonation at C-12), and with 1,12-dimethyl the sole species observed is the C-7-protonated carbocation. For 7-methyl-12-ethyl, 7-ethyl-12-methyl, and

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Fig. 17 Protonation of 2-MBA as representative example.

7,12-diethyl derivatives, two ipso-protonated carbocations were initially formed (C-7/C-12), rearranging in time to give the C-12-protonated carbocations exclusively. Protonation outcomes were compared with relative energies computed by DFT.37 Charge delocalization paths in the resulting carbocations were deduced based on the magnitude of Dd13C values. For the thermodynamically more stable C-12-protonated carbocations, the charge delocalization path was analogous to those derived based on computed NPA charges for the benzylic carbocations formed by 1,2-epoxide (bay region) and 5,6-epoxide (K-region) ring opening. Nitration (and bromination) of the 4-methyl, 7-methyl, 7-ethyl, 3,9-dimethyl, and 1,12-dimethyl derivatives resulted in the isolation and characterization of several novel derivatives.37 Excellent agreement was found between low-temperature protonation selectivities and the regioselectivities observed in model substitution reactions.

6

Chyrsenium and benzo[c]phenanthrenium ions

The first series of persistent carbocations derived from mono- and disubstituted chrysenes (Ch, 36) (5-methyl, 2-methoxy, 2-methoxy-11-methyl, 2-methoxy-5-methyl, and 9-methyl-4H-cyclopenta[def]chrysene 37), monosubstituted benzo[c]phenanthrenes (BcPh, 38) (3-methoxy and 3-hydroxy), and monosubstituted benzo[g]chrysenes (BgCh, 39) (12-methoxy, 12-hydroxy) were generated in FSO3H/SO2ClF or FSO3HSbF5 (4:1)/ SO2ClF and studied by low-temperature NMR (Fig 18).38 Charge delocalization modes were probed based on the magnitude of Dd 13Cs, and conformational aspects were examined via NOED experiments. Complete NMR data were also reported for several benzoylation and nitration products. The methoxy and methyl substituents directed the protonation to their respective ortho positions.38 Whereas parent Ch was protonated at C-6/C-12, the 5-methyl derivative was protonated at C-6 and at C-12, with the latter being the thermodynamic cation. The 2-methoxy-Ch was protonated at C-1 to give two conformationally distinct carboxonium ions. In the disubstituted Ch derivatives, the 2-methoxy substituent was able to override the 5-methyl group, and the predominant carbocations formed were via attack at the position ortho to methoxy. For the methano derivative 37 (Me at C-9), a 3:1 mixture of 37aHþ/37bHþ was formed. For parent BcPh, nitration and benzoylation were directed to C-5.38 With 3-methoxy-BcPh, the site of protonation moved to C-4, thus producing two

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Fig. 18 Representative chrysenes, benzo[c]phenanthrenes, benzo[g]chrysene, and their carbocations and nitro-derivatives.

conformationally distinct carboxonium ions (3-OMe-38aHþ/3-OMe-38bHþ), whereas conventional nitration gave a 2:1 mixture of 3-OMe-38aNO2 and 3-OMe38bNO2. In 3-hydroxy-BcPh, the carboxonium ion was exclusively formed. For parent BgCh, protonation, nitration, and benzoylation were all directed to C-10, but the presence of OMe or OH substituent at C-12 changed the site of attack to C-11. Using GIAO-DFT (and NICS), the NMR chemical shifts (and aromaticity) in model carbocations A–D were evaluated. On the basis of GIAO calculations (Fig. 19), the hydroxy-chrysenium ion (B) resulting from 3,4-epoxide ring opening was more delocalized (A/B rings plus one conjugated carbon) than A formed via 1,2epoxide opening (the A-ring plus one conjugated carbon). This is in line with DNAbinding studies that identified C-4 as the binding site to form dG and dA adducts.39 Although the charge delocalization mode in protonated BcPh (not observed) could not be determined, theory predicted that positive charge in the hydroxy-arenium ion

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Fig. 19 GIAO-derived charge delocalization modes for hydroxy-substituted carbocations.

(C) formed by opening of its fjord-region epoxide resided heavily in the A/B rings (Fig. 19). This is a logical intermediate for covalent attachment to the exocyclic amino group of dG and dA. In good correspondence with experimental models, the theoretically predicted pattern for the hydroxy-arenium ion (D) formed via BgCh 13,14-epoxide ring opening was one where the positive charge resided in the D/E rings (Fig. 19). Carbocation (D) is, therefore, a logical intermediate to link to the N-6-amino group of dA or dG. Ch (36), 6-fluoro-Ch, 6-chloro-Ch, and 6-bromo-Ch were cleanly monoprotonated in FSO3HSbF5 (ca. 10:1)/SO2ClF at the C-12 position (Fig. 20).40 6-Acetyl-Ch was CO-protonated in FSO3H/SO2ClF with significant charge delocalization into the Ch framework and provided a model for a C-6-protonated chrysenium cation. 4H-Cyclopenta[def]chrysene was protonated at C-5 (site of bromination and acetylation). The observed chrysenium (or methanochrysenium) cations were those predicted by AM1 to have the lowest energies. The NMR characteristics of the resulting arenium ions were analyzed and the Dd13Cs were compared with AM1-calculated changes in charges [Dqc = qc(ion) – qc(neutral)]. The stable ion and AM1 studies demonstrated that in the absence of steric factors, C-12 (C-6) is the most favored site for electrophilic attack in Ch. Presence of halogen substituents at C-6 did not

Fig. 20 Protonation of Ch and its 6-halo derivatives.

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alter this preference nor the mode of charge delocalization in the resulting arenium ions. The presence of fluorine at C-6 lowered the energy for C-5 protonation, but the C-12-protonated cation still had the lowest energy. The positive charge in the chrysenium cation was located primarily at four carbon centers [ortho and para to the site attack and at C-12 (C-6)]. Thus, for 36Hþ and protonated 6-acetyl-Ch, C-5 and C-12 appeared to be the most plausible site(s) for subsequent nucleophilic trapping. However, metabolic studies did not support the notion that these sites are the preferred biological epoxidation sites. The metabolites of 5-methyl-Ch indicated epoxidations mainly at the 7,8-, 1,2-, and 9,10-positions.41 Thus, it appears that accessibility of the A and D ring to cytochrome P450 might be an important factor. The resulting epoxide(s) would then open in such a way to generate the most highly delocalized carbocation(s). In a more recent study, a series of novel carbocations were generated by lowtemperature protonation of substituted BcPhs, and their charge delocalization pathways were elucidated by NMR on the basis of the magnitude of Dd 13C values.42 In an effort to gain more insight into structure/reactivity relationships in the BcPh skeleton, this work focused on stable ion and electrophilic chemistry of a relatively large group of substituted derivatives, including those with substituents in the fjord region. Charge distribution modes in the regioisomeric-protonated carbocations formed via parent BcPh as well as in the benzylic carbocation formed via fjord-region epoxide ring opening were deduced by GIAO-DFT and from NPA-derived changes in charges over CHs. These patterns were compared with those derived from NMR experiments in the substituted derivatives. It was shown that the protonation regioselectivity was strongly controlled by methoxy and hydroxyl substituents, whose directive effects overwhelmed the methyl substitution effects.42 Regiocontrol by —OMe and —OH substituents, and its stronger influence relative to methyl groups, was also observed in the nitration and bromination reactions (Fig. 21). Regioselectivities observed in the nitration and bromination reactions in representative cases were the same as those via protonations.

Fig. 21 Some of the cations obtained from protonation of BcPh derivatives.

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In a recent collaborative investigation, the syntheses, 3D structures (by X-ray crystallographic analysis and computational studies), metabolism, and DNA-binding studies for 1,4-difluorobenzo[c]phenanthrene (1,4-DFBcPh) and some of its putative metabolites were described.43 In this way, 1,4-DFBcPh and its putative metabolites, the dihydrodiol and DEs, were synthesized and structurally characterized, and the extent of DNA binding by the metabolites was assessed. Interesting differences were noted in 1H NMR spectra of the series 1 (syn) DEs of BcPh and 1,4-DFBcPh. Specifically, the BcPh DE displayed a quasi-diequatorial orientation of the hydroxyl groups, but in the case of 1,4-DFBcPh, these were diaxially disposed. This difference probably stems from the presence of the fjord-region fluorine atom in 1,4-DFBcPh. A through-space, fjord-region H/F coupling was also observed for 1,4-DFBcPh and its derivatives. Comparative X-ray crystallographic analysis of BcPh and 1,4DFBcPh and their dihydrodiols showed that introduction of fluorine increased the molecular distortion by about 6–7. As a guide to estimating the molecular distortion and its effects and for comparison with the X-ray structures in known cases, optimized structures of BcPh, 1,4-DFBcPh, and 1,4-DMBcPh (the dimethyl analog) as well as their dihydrodiols and DEs were computed. Relative aromaticities of these compounds were also assessed by NICS calculations, and 13C NMR chemical shifts were computed by GIAO calculations. 1,4-DFBcPh and its dihydrodiol were subjected to metabolism, and the extent of DNA binding in human breast cancer MCF-7 cells was assessed.43 The extent of DNA binding was then compared with that for BcPh and its dihydrodiol and the potent carcinogen BaP. The 1,4-DFBcPh series 2 (anti) DE-derived DNA adducts were also compared with those arising from intracellular oxidation of the dihydrodiol with subsequent DNA binding. These experiments showed that increased molecular distortion decreased metabolic activation to the terminal metabolites but the DE metabolites formed were the DNA-damaging species.

7

Carbenium ions and onium cations from hetero-PAHs

Protonation of the epoxides, DEs, and dihydrodiols of benzo[h]quinoline (BhQ), benzo[f]quinoline (BfQ), Phe, benzo[c]phenanthridine (BcPhen), and Ch (Fig. 22) were studied by DFT at the B3LYP/6-31G* level and in selected cases were calculated with the 6-31þG* diffuse-function-augmented basis set for comparison purposes.44 Bay-region carbocations were formed from O-protonated epoxides via barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (PCM method). According to the calculations, nitrogen substitution did not significantly modify the charge density distribution, as determined by NPA-derived changes in charges and GIAO-NMR chemical shifts (based on Dd 13C values). Therefore, similar reactivity patterns are expected by both PAH and aza-PAH compounds. The computed relative ease of formation, that is, the stability of the carbocations, correlated with the mutagenic activities reported for tetrahydro epoxide and tetrahydro DE derivatives of Phe, BhQ, and BfQ.

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Fig. 22 Aza-PAH derivatives, their carbocyclic parent compounds, and model bay-region carbocations formed via DEs.

In all cases, a larger negative charge on N accounted for a greater stability of the carbocation. The presence of a heteroatom changed the regioselectivity of epoxide ring opening, in some cases favoring nonbay-region carbocations. The epoxide ring opening mode was also greatly influenced by N-protonation. The dications resulting from initial N-protonation followed by epoxide protonation were also studied by DFT. Relative aromaticity in different rings in the arenium ions was gauged by NICS and DNICS. In representative cases, the covalent adducts (syn and anti) formed by reaction of the benzylic carbocations derived from DEs and dihydrodiols with methoxide and methanethiolate anions were studied.44 The DEr and DGr values for reactions between the carbocations of Phe derivatives and those derived from aza-PAHs with nucleophiles did not correlate with the known relative experimental activities of these compounds. This fact reinforced the notion that the stability of the generated carbocation is the determining factor for its reactivity, by an SN1-like process (epoxide ring opening). Thus, the experimental activity order Phe > BhQ > BfQ could be explained by the relative stabilities of their derived carbocations. Aqueousphase computations modified the change in energy for the addition reactions due to greater stabilization of the reactants although inclusion of the solvent did not alter the relative reactivity trends.

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Furthermore, relative energies (in the gas phase and in water as solvent) and geometries of the adducts formed by quenching of the carbocations derived from BhQ and Phe epoxides with guanine via the exocyclic amino group and via the N-7 were also investigated computationally.44 The change in the preferred product of the addition reactions with guanine due to solvent effect was noteworthy. Whereas the N-7 adducts were most stable in the gas phase; in water as solvent the most stable adducts were those formed by reaction with the exocyclic nitrogen of guanine, in accordance with experimental observations from the literature. Subsequently, the epoxides, DEs, and dihydrodiols of dibenzo[a,h]acridine (DBahAcr) were studied at the B3LYP/6-31G* level.45 Both 8,9- and 1,2-epoxide analogs were considered in order to assess the effect of the relative position of the nitrogen heteroatom on the ease of formation of the respective carbocations (Fig. 22). Bayregion carbocations were formed via the O-protonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (PCM method). Charge delocalization modes in the resulting carbocations were deduced by GIAO-NMR (based on Dd 13C values) and via NPA-derived changes in charges. Although the solvent decreased the exothermicity of the epoxide ring-opening reactions due to the greater stabilization of the reactants, relative reactivity trends remained the same. The stability of the carbocations generated from oxidized metabolites of DBahAcr and dibenzo[a,h]anthracene (DBahA) correlated with the available data on the biological activities of their DEs.45 Thus, carbocations derived from DBahA were more stable than those from DBahAcr. Furthermore, in the DBahAcr system, carbocation formation at C-8 was preferred over the C-1 isomer. Relative stabilities of the derived aza-PAH carbocations did not correlate with the extent of delocalization of the positive charge but rather with the magnitude of the negative charge at N-7. Therefore, development of less negative charge at N resulted in the destabilization of the open carbocationic structures and was a determining factor in the relative stability order. A fluorine atom at a highly positively charged site stabilized the carbocations by p-p back-bonding, and development of fluoronium ion character overwhelmed the inductive electron withdrawal of F.45 Correlation between the stability of the generated carbocation and the loss in electron density at F corresponded with shortening of the C—F bond length. On the other hand, F substitution at a position bearing negative charge density decreased the exothermicity of the ring-opening reaction. Moreover, methylated compounds exhibited more exothermic DEr values than the nonmethylated analogs although very similar values were obtained for each methylated epoxide series. As NPA-derived charges did not reveal significant hyperconjugation effects, it was inferred that methyl substitution stabilized the carbocations mostly by donor inductive effect. The neutral epoxide presented deviation from planarity of the aromatic system with a methyl group placed at C-14. Therefore, enhanced carcinogenic activity caused by methyl substitution at the bay region was explained by preferential opening of the epoxide ring due to higher energy of the more crowded epoxide. A subsequent project focused on DFT study aimed at understanding structure/ reactivity relationships and fluorine substitution effects on carbocation stability in

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Fig. 23 Charge delocalization modes in model carbocations from BaP, BeP, and azaBaP.

BaP, BeP, and aza-benzo[a]pyrene (azaBaP) derivatives (Fig. 23).46 The relative energies of the resulting carbocations were examined and compared, taking into account the available biological activity data on these compounds. O-Protonation of the epoxides and DEs led to carbocation formation by barrierless processes. Charge delocalization modes in the resulting carbocations were deduced via NPA-derived changes in charges. The relative stabilities of the carbocations generated from oxidized metabolites of BaP, BeP, and azaBaPs correlated with the available literature data on the biological activities of their DEs. Hence, benzylic carbocations derived from BaP were more stable than those derived from BeP and azaBaPs. For the azaBaPs studied, the predicted reactivity order was 6-azaBaP > 4-azaBaP > 10-azaBaP, which was attributed to the degree of delocalization of the net positive charge throughout the aromatic system, as indicated by the development of negative charge density at the carbocationic center. Magnitude of the negative charge at nitrogen was also important for carbocation stability. On the other hand, protonation reactions for the azaBaP derivatives appeared to be governed by the HOMO of the neutral compounds. Fluorine substitution effects were analyzed on the basis of charge density at different carbocation positions.46 Thus, fluorination led to a decrease in carbocation stability. This decrease was less pronounced for fluorine substitution at the highly positively charged sites due to p-p back-bonding and development of fluoronium ion character. On the other hand, F-substitution at a position with negative charge density produced a greater reduction in the exothermicity of the ring opening reaction. This was a general trend observed in the absence of any other interactions, such as attractive F  H interactions and repulsive/steric interactions between F and an OH group. To model the crucial step of covalent adduct formation, adducts resulting from quenching of 10-azaBaP-4,5-epoxide with cytosine via the exocyclic amino group were computed, and their geometrical features and relative energies were compared (Fig. 24).46 The most stable stereoisomer was the one with the cytosine moiety trans to the hydroxyl, with both groups in pseudoequatorial conformation. Two structures

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(b)

(c)

Fig. 24 Lowest energy conformations of the adducts of 10-azaBaP-4,5-epoxide with cytosine. (a) Trans conformation, (b) cis conformation (OH pseudoequatorial), and (c) cis conformation (cytosine residue pseudoequatorial).

were characterized for the cis isomer, each presenting one group in pseudoequatorial conformation while the other group was pseudoaxial. The most stable cis isomer was the one with the cytosine in the pseudoaxial disposition (OH pseudoequatorial).

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However, according to the calculations of the cytosine adducts, both trans and cis isomers should form experimentally in nearly equal amounts. First examples of stable carbocations were reported from several classes of thiaPAHs with four fused rings, namely, benzo[b]naphtho[2,1-d]thiophene (40) and its 3-methoxy derivative (41), phenanthro[4,3-b]thiophene (42) and its 7-methoxy (43), 10-methoxy (44), and 9-methoxy (45) derivatives, phenanthro[3,4-b]thiophene (46) and its 7-methoxy (47) and 9-methoxy (48) derivatives, and 3-methoxybenzo[b]naphtha[1,2-d]thiophene (50) (Fig. 25).47 Regioselectivity issues and charge

Fig. 25 Studied thia-PAHs.

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delocalization modes as a function of epoxidation site and thia-PAH structure were addressed by NMR and by GIAO-DFT studies. A series of S-alkylated onium tetrafluoroborates, namely, 40Meþ, 40Etþ, 41Etþ, and 46Meþ (from 40, 41, and 46), 49Meþ and 49Etþ (from benzo[b]naphtha[1,2d]thiophene 49), 51Meþ and 51Etþ (from phenanthro[3,2-b][1]benzothiophene 51), 52Meþ (from 3-methoxyphenanthro[3,2-b]benzothiophene 52), 53Meþ (from phenanthro[4,3-b][1]benzothiophene 53), and 54Meþ (from 3-methoxyphenanthro[4,3b][1]benzothiophene 54), were synthesized.47 The PAH sulfonium salts 40Meþ, 40Etþ, 49Meþ, 49Etþ, 51Meþ, and 53Meþ proved to be efficient transalkylating agents toward model nitrogen nucleophile receptors (imidazole and azaindole). Facile transalkylation to model nucleophiles (including guanine) was also supported by favorable reaction energies computed by DFT. To gain insight into structure/ activity relationships, DFT was also used to model epoxide ring opening reactions with the thia analogs of Ch and BcPh. Ring opening energies in thia-PAH-epoxides from 40, 42, and 46 and charge delocalization modes in the resulting carbocations were evaluated. The four-ring-fused thia-PAHs 40, 41, 42, 43, 44, 46, 47, and 50 were effectively nitrated under extremely mild conditions.47 Nitration regioselectivity corresponded closely to protonation under stable ion conditions. Bromination of 43 and 45 was also reported. Comparative mutagenicity assays (Ames test) were performed on 40 versus 40NO2, 44 versus 44NO2, and 50 versus 50NO2. Compound 44NO2 (nitrated at C-9) was found to be a potent direct acting mutagen.

8

Carbenium ions derived from nonalternant PAHs

The first series of persistent arenium ions from large methylene-bridged PAHs (mostly 22 six-fused ring systems) were generated.48 Low-temperature protonation (FSO3H/SO2ClF) and model nitration (with HNO3/HOAC or NO2þBF4–) were used as mimic reactions for the formation of biological electrophiles. The site(s) of protonation (and nitration) were determined as a function of PAH structure and benzannelation mode. Charge delocalization mode in the resulting arenium ions of protonation was assessed based on detailed low-temperature NMR studies. Relative arenium ion energies for all possible protonation sites were computed by AM1, for comparison with experiment. Systems studied were 1-methylcyclopenta[def]phenanthrene 55, 11H-benz[bc]aceanthrylene 56, 5H-benzo[b]cyclopenta[def]chrysene 57, 13H-dibenzo-[bc,l]aceanthrylene 58, 13H-cyclopenta[rst]pentaphene 59, 4H-benzo[b]cyclopenta[mno]chrysene 60, 6H-cyclopenta[ghi]picene 61, 4H-cyclopenta[pqr]picene 62, and 4H-cyclopenta[def]dibenz[a,c]anthracene 63. For comparison, dibenzo[a,c]anthracene 64 and dibenzo[a,h]anthracene 65 were also included (Fig. 26). It was shown that the methano-bridge exerts a strong directive effect that diminishes as the bridge moves from the more central ‘‘inner’’ positions to more peripheral ‘‘outer’’ positions.48 Charge alternation paths in the resulting carbocations were discussed based on the magnitude of Dd13C values. It was apparent that both

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Fig. 26 Charge delocalization modes in the carbocations derived from methylene-bridged PAHs (and their analogs).

the benzannelation mode and the number of annelated benzene rings had a major impact on the charge delocalization mode in the derived carbocations (comparing 56Hþ, 57Hþ, 58Hþ, and 59Hþ). Competing oxidation (RC formation) with 62 and 63 was inferred from 1H NMR spectra (broad signals and paratropic proton shifts). Using these patterns, it was possible to speculate on the preferred epoxidation sites and possible ring opening modes, which could induce similar charge delocalization paths. In relation to metabolic epoxidation and subsequent DNA adduct formation, these patterns pointed to the possible importance of K-region and M-region epoxides for some of the methano-PAHs.

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Fig. 27 Fluoranthene-PAH carbocations.

In another study, the first examples of persistent carbocations were reported from parent fluoranthene (66, four fused rings), benzo[e]acephenanthrylene (benzo[b]fluoranthene, 67) (five fused rings), and its C-10 substituted derivatives (X = OMe, F), as well as indeno[1,2,3-cd]pyrene (68, six fused rings) by protonation with FSO3H/ SO2ClF (Fig. 27).49 NMR characteristics of the resulting carbocations, their charge delocalization mode, and tropicity were examined. Relative arenium ion energies for all possible protonation sites were calculated by AM1, for comparison with the NMR-based assignments. Relative aromaticity in various rings in the resulting PAH-arenium ions was gauged via NICS calculations. It was shown that the site of protonation and nitration in 10-methoxybenzo[e]acephenanthrylene was the same (C-9). Quenching of the superacid solutions of 66 and 10-methoxybenzo[e]acephenanthrylene produced the novel dimers 3,30 -bifluoranthenyl and 10,100 -dimethoxy-9,90 -biacephenanthrenyl as minor products (ca. 10% and 33%, respectively) in addition to the intact PAHs. It was also demonstrated that fluoranthene–PAHs and their derivatives could be easily protonated with NH4NO3 and observed in the gas phase via electrospray mass spectrometry (ES-MS). The predicted antiaromaticity in fluoranthene–PAH carbocations (NICS) could well be the origin of the observed paratropicity and proton shielding in these nonalternantPAH carbocations. The observed broadening in the proton spectra in several cases, the appearance of upfield-shifted broad humps, and the formation of insoluble precipitates (which upon quenching returned the intact PAH) were taken as evidence for the concomitant presence of the RC which could additionally contribute to proton shielding. In another project, protonation of parent azulene, homoazulene, representative isomeric benzazulenes, and benzohomoazulenes as well as the mono- and diprotonation of isomeric azulenoazulenes were studied by DFT at the B3LYP/6-31G(d) level (Fig. 28).50 The most likely carbocations were identified based on relative protonation energies. For comparison, complete experimental 13C NMR data were obtained for parent azulenium ion and guaiazulenium ion in TFA. The oxidation dications derived from benzazulenes, benzohomoazulenes, and azulenoazulenes were also investigated. For azulenoazulene dications, the singlet and triplet states were both minima, and in general, the triplet states were higher in energy. Structural/geometrical changes in the carbocations were examined. GIAO-NMR, NPA charges (and changes in charges), and NICS (and DNICS) were employed to compute the NMR chemical shifts (Dd 13C values) to derive charge delocalization maps and to gauge relative

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Fig. 28 Representative azulenes, parent homoazulene, isomeric benzazulenes and benzohomoazulenes, and isomeric azulenoazulenes substrates studied.

aromaticity/antiaromaticity in the energetically most favored carbocations and oxidation dications. Creation of tropylium or homotropylium entities in the carbocations (monoprotonated) and carbodications (diprotonated) was identified as an important driving force governing the protonation outcomes. Consideration of the AM1-derived DDHf values (and the DFT-derived DDG values) suggested that the two-electron oxidation of azulenoazulenes and benzazulenes should be experimentally feasible. In another study, the arenium ions of protonation and the two-electron oxidation dications derived from BaP and three of its nonalternant isomers, namely, azuleno[5,6,7-cd]phenalene 69 (a strong carcinogen reported to be as potent as BaP), azuleno[1,2,3-cd]phenalene 70 (a strong mutagen/weak carcinogen), and

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Fig. 29 Nonalternant analogs of benzo[a]pyrene and pyrene and other model structures studied.

azuleno[4,5,6-cd]phenalene 71 (a weak mutagen), were investigated at the B3LYP/631G(d) level (Fig. 29).51 The most favored sites for electrophilic attack were identified on the basis of relative protonation energies in the arenium ions. Computed NMR chemical shifts (GIAO-NMR), the NPA-derived charges (and changes in charges), as well as NICS (and DNICS) were employed to derive charge delocalization maps and to gauge relative aromaticity/antiaromaticity in the resulting carbocations and the oxidation dications. For the studied PAHs, formation of singlet dications was computed to be strongly favored, except in 71 for which the triplet was 5 kcal/mol lower than singlet. Quantitative correlations between the experimental (superacid) 13C NMR data and GIAO chemical shifts and between computed changes in charges and GIAO Dd 13C NMR values were explored for benzo[a]pyrenium ion and its singlet oxidation dication as representative cases. Good correlation was observed between the experimental NMR data in superacid media and GIAO-NMR, as well as reasonable correlations between the NPA-derived charges and GIAO chemical shifts. Furthermore, NICS data for the dications were consistent with the experimentally observed paratropicity in the dication. The mono- and diprotonated carbocations and the two-electron oxidation dications derived from parent pyrene and its nonalternant isomers ‘‘azupyrene’’ (dicyclopenta[ef,kl]heptalene) (DCPH) 72 and dicyclohepta[ed,gh]pentalene (DCHP) 73 were studied at the B3LYP/6-31G(d) level (Fig. 29).52 The most likely site(s) for monoand diprotonation were determined based on relative arenium ion energies and the structures of the energetically most favored carbocations were determined by

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geometry optimization. The NMR chemical shifts for the protonated mono- and dications and the oxidation dications were computed by GIAO-NMR, and their charge delocalization paths were deduced based on magnitude of the computed Dd 13C NMR values and the NPA-derived changes in charges. Relative aromaticity/ antiaromaticity in various rings in the energetically favored mono- and dications was estimated via NICS and DNICS. Calculated NMR chemical shift data for pyrenium cation and oxidation dication were compared with the available experimental NMR values. The GIAO-based charge delocalization paths agreed quite well with the stable ion NMR data. Paratropicity (antiaromaticity) in the singlet dication, previously deduced by NMR, was reaffirmed by NICS. Furthermore, NICS predicted that the less stable triplet dication should be aromatic (diatropic). The available data on chemical and physical properties of 72 and 73 are extremely limited and biological activity data are nonexistent. Thus, this study provided the first glance into their carbocations and oxidation dications, while augmenting and reinforcing the previous stable ion data on the pyrenium cations. The annulenium ions of protonation, the two-electron oxidation dications, and the two-electron reduction dianions derived from dihydro- and dimethyldihydro derivatives (cis and trans) of compounds 72 and 73 were also studied by DFT at B3LYP/6-31G(d), 6-31þG(d,p), or 6–31þþG(d,p) levels (Fig. 29).53 Charge delocalization modes in the energetically most favored annulenium ions, as well as in the singlet and triplet dications and dianions, were assessed based on GIAO Dd13C values and via changes in NPA charges. Relative aromaticity/antiaromaticity in the annulenes were gauged via NICS and DNICS. Annulenium ions of monoprotonation, the dications, and dianions derived from bismethano- and propanediylidene [14]annulenes 78 and 79 were also studied by DFT for comparison with the cis-dihydro isomers derived from 73. Computed GIAO-NMR chemical shifts were compared with the experimental data when available, and the optimized geometries were compared with the X-ray data if known.53 The lowest energy annulenium cation derived from 76 and 77 (both cis) was formed by protonation at C-1, and this was in concert with experimental observation of 76Hþ in superacid media.54 The resulting annulenium ions were less delocalized than those via 74 and 75. DFT and stable ion study were also in concert regarding the protonation of 78. The availability of X-ray structures and stable ion NMR data for the dications and dianions of 78 and 79 enabled comparison with the DFT-optimized structures and GIAO-NMR shifts. Very recently, a series of novel carbocations and carboxonium ions were generated from 7H-benzo[c]fluorene (80), 11H-benzo[b]fluorene (81), 11H-benzo[a]fluorene (82), 2-methoxy- (83), 7-methoxy- (84), and 9-methoxy-11H-benzo[a]fluorene (85), 7H-dibenzo[c,g]fluorene (86), 13H-dibenzo[a,g]fluorene (87), 2-methoxy-13H-dibenzo [a,g]fluorene (88), and 5,6-dihydro-13H-dibenzo[a,g]fluorene (89) (Fig. 30).55 Charge delocalization modes in the resulting carbocations were derived based on experimental and/or computed (GIAO-DFT) Dd13C NMR values and via the NPA-derived changes in charges (Dq). While protonation regioselectivity in the parent systems corresponded to the energetically most favored carbocations computed by DFT, selectivity in the OMe-substituted derivatives was strongly controlled by the methoxy group. Benzofluorenes 81, 83, 84, and 85, and dibenzofluorenes 86 and 88 were nitrated under very mild conditions. Nitration

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Fig. 30 Studied benzofluorene and dibenzofluorene derivatives.

selectivity in the parent systems 81 and 86 paralleled those in stable ion protonation, whereas regioselectivity in the MeO derivatives (84, 85, and 88) corresponded more closely to relative arenium ion energies in the parent unsubstituted systems. Comparative mutagenicity assays (Ames test) were performed on 81NO2, 83NO2, 85NO2, 86NO2, and 88NO2 relative to their precursors.55 Compounds 88NO2, 85NO2, and 86NO2 were found to be potent direct acting mutagens (with 88NO2, 86NO2 also capable of acting as potent indirect mutagens). The X-ray structures of 83NO2 and 86NO2 were determined. The angle between the plane of the nitro-group and the aromatic ring bearing NO2 group was 89.4 in 83NO2 and 32.4 in 86NO2. In this way, structure/activity relationships in the nitro-derivatives were studied by a combined comparative mutagenicity assay, X-ray analysis, and structure optimizations. Taken together, the results demonstrated the relationship between nitro-buttressing and bioactivity and reinforced the earlier findings in other classes of PAHs, that the highly mutagenic nitro-derivatives were those with planar nitro-groups, with the severely distorted analogs being inactive.56,31

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Miscellaneous systems

Low-temperature protonations of benzo[a]coronene 90 and benzo[ghi]perylene 91 were studied in FSO3H/SO2ClF and CF3SO3H/SO2ClF superacids (Fig. 31).57 For 90, rapid competing oxidation to the RC prevented the observation of 90Hþ by NMR spectroscopy; the RC was probed by ESR spectroscopy. For 91, competing oxidation was less problematic and a persistent arenium ion 91Hþ could be seen by NMR which was line-broadened due to the presence of the RC. Protonation of a mixture of 90 and 4,5-dihydropyrene 1 produced the C-3 protonated 1Hþ and 90Hþ. Addition of 1 to the superacid solution containing 91Hþ and 91þ led to the detection of the C-3 protonated 1Hþ and the disappearance of 91Hþ (by NMR). Arenium ion energies (DDH ion – neutral) and changes in carbon charges [Dq = qc (ion) – qc (neutral)] for protonation of 90 and 91 were probed by the AM1 method. The singlet oxidation dication of 90 was also calculated. The charge delocalization modes in the PAH arenium ions were discussed and compared. The AM1 studies indicated that benzo[a]coronene cations were less delocalized than benzo[ghi]perylene ions. Benzannelation (91 ! 92) severely limited the conjugation path in the carbocations despite the fact that coronene 92 was still planar. Further benzannelation (92 ! 90) had a minimal effect on the charge delocalization mode. Complexation of Ag(I) cation to a series of substituted anthracenes, phenanthrenes, pyrenes, and cyclopenta[a]phenanthrenes was studied in competitive experiments by allowing PAHs to react in pairs with AgOTf.58 The resulting complexes were examined by ES-MS to determine relative abundances of the corresponding monomeric and dimeric complexes. Based on this data, a sequence of complexation ability rankings was derived for each group. Among the substituents examined, a —COMe group when placed at the meso position in anthracene and Phe, or at the C-1 in Py, was most effective in Agþ complexation, whereas an –NO2 group was least efficient. Methyl groups at the meso positions were better than in the terminal rings. For the cyclopenta[a]phenanthrene series, bay-region substitution (methyl and alkoxy) had limited effect as did carbonyl substitution in the annelated ring. In the Py series, a —COPh or a —CH(Me)OH group at C-1 was as efficient as —COMe. Based on extensive potential energy searches, four types of complexation modes were identified by B3LYP/LANL2DZ calculations involving Agþ complexation to —NO2 oxygens, to —COMe or to —OH and a peri-carbon, to just one ring carbon, or by bridging two ring carbons.58 Among these modes, the first two were most favorable. The energetic preferences were rationalized with charge decomposition analysis (CDA).

Fig. 31 Miscellaneous large PAHs studied.

174

K.K. LAALI AND G.L. BOROSKY

Effect of Agþ complexation on relative aromaticity in various rings was examined by NICS in two representative cases. Structures and energies of the acetyl pyrene–Agþ– pyrene hetero-dimer and acetyl pyrene–Agþ–acetyl pyrene homo-dimer complexes were determined with the same model. Interestingly, only sandwich complexes were formed and no stable structures in which the silver ion was not sandwiched between two PAH units could be found. In a different study, anthracene, phenanthrene, perylene 93 (Fig. 31), and 2,7di-tert-butylpyrene underwent regioselective oxidative-substitution reactions with iodine(III) sulfonate reagents in dichloromethane to give the corresponding aryl sulfonate esters.59 The use of [hydroxy(tosyloxy)iodo]benzene, in conjunction with trimethylsilyl isothiocyanate, led to thiocyanation of the PAH nucleus.

10

Concluding remarks

Carbocations derived from PAHs represent models for their biological activation via oxidative pathways leading to PAH-epoxides, dihydrodiols, and DEs which undergo subsequent epoxide ring opening. In stable ion studies, protonation is used as a mimic reaction for the generation of electrophiles from the PAHs, allowing the site(s) of electrophilic attack to be determined, while Dd13C values provide insight into their charge delocalization modes, revealing potential sites for nucleophile attachment in the biologically significant step of covalent binding to DNA or RNA. Furthermore, the a-PAHsubstituted carbocations are considered as simple models of PAH-epoxide ring opening. This chapter has illustrated some of the progress achieved in the area of stable arenium ions from PAHs. A large number of persistent carbocations from several classes of PAHs ranging in activity from highly potent to inactive have been generated and studied. The sites of electrophilic attack and charge delocalization modes in the resulting carbocations and carboxonium ions have been determined, thus allowing the identification of the most probable sites for covalent attachment to nucleotides. Conformational aspects and substituent effects on charge delocalization and p-participation have also been probed as a function of structure. Computational data enabled charge delocalization modes, substituent effects, and in relevant cases conformational aspects to be addressed, and comparison with experiments were found to be fairly good. Moreover, the calculated relative stabilities of the carbocations correlated reasonably well with the available biological activities. Taken together, these studies represent the ground work for building up a carbocation-based structure/reactivity database. Additional comparison of these trends with the data obtained by comparative DNA-binding studies and by tumorigenicity and mutagenicity assays will be needed in an effort to draw a parallel.

Acknowledgement Support of our work at KSU in the area of reactive intermediates of carcinogenesis of PAHs over the past decade by the NCI of NIH (R15 CA063595-01A1, R15 CA078235-01A1 and 2R15 078235-02) is gratefully acknowledged. G.L.B gratefully

STABLE CARBOCATIONS AND ONIUM IONS

175

acknowledges financial support from CONICET and the Secretarı´ a de Ciencia y Tecnologı´ a de la Universidad Nacional de Co´rdoba (Secyt-UNC).

References 1. International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risks to humans, vol. 32: polycyclic aromatic compounds, part 1, chemical environmental and experimental data. Lyon: IARC; 1983. 2. (a) Harvey RG. Polycyclic aromatic hydrocarbons: chemistry and carcinogenicity. Cambridge (UK): Cambridge University Press; 1991. (b) Harvey RG. Polycyclic aromatic hydrocarbons. New York: Wiley-VCH; 1997. 3. Wood AW, Chang RL, Levin W, Ryan DE, Thomas PE, Croisy–Delcey M, et al. Cancer Res 1980;40:2876–83 and references therein. 4. (a) Jerina DM, Yagi H, Lehr RE, Thakker DR, Schafer-Ridder M, Karle JM. In: Gelboin HV, Tso POP, editors. Polycyclic hydrocarbons and cancer, vol. 1. New York: Academic Press; 1978. pp. 173–88. (b) Wood AW, Levin W, Chang RL, Yagi H, Thakker DR, Lehr RE, et al. In: Jones PW, Leber P, editors. Polycyclic aromatic hydrocarbons. Ann Harbor (MI): Ann Harbor Science Publishers, Inc.; 1979. pp. 531–51. 5. Xue W, Warshawsky D. Toxicol Appl Pharmacol 2005;206:73–93. 6. (a) Fu PP. Drug Metab Rev 1990;22(2–3):208–68. (b) Howard PC, Hecht SS, Beland FA, editors. Nitroarenes: the occurrence, metabolism and biological impact, vol. 40. New York: Plenum Press; 1990. (c) Beland FA, Kadlubar FF. In: Cooper CS, Grover PL, editors. Handbook of experimental pharmacology. Berlin: Springer-Verlag; 1990. pp. 267–325. (d) Beland FA, Marques MM. IARC Sci Publ 1994;125:229–44. 7. Laali KK. Chem Rev 1996;96:1873–906. 8. Laali KK. In: Olah GA, Prakash GKS, editors. Carbocation chemistry. Wiley: Hoboken, NJ; 2004. pp. 237–277. 9. Laali KK, Okazaki T. Annual Reports on NMR Spectroscopy, vol. 47. Academic Press: London, UK; 2002. pp. 149–214. 10. Laali KK. Coord Chem Rev 2000;210:47–71. 11. Committee on Biologic Effects of Atmospheric Pollutants, Particulate Polycyclic Organic Matter. Biological Effects of Atmospheric Pollutants. Washington, DC: National Academy of Sciences; 1972. 12. (a) Lehr RE, Wood AW, Levin W, Conney AH, Jerina DM. In: Yang SK, Silverman BD, editors. Polycyclic aromatic hydrocarbon carcinogenesis: structure-activity relationships. Boca Raton (FL): CRC Press; 1988. vol. 1. pp. 31–58 and references therein. (b) Lang RL, Wood A1W, Xie JG, Huang MT, Cui X, Kole PL, et al. Proc Am Assoc Cancer Res 1996;37:128. (c) Warshawsky DJ. Environ Sci Health 1992;C10:1–71. 13. Borosky GL, Laali KK. Recent developments in carbocation and onium ion chemistry (ACS Symposium Series 965). Washington, DC: ACS; 2007. pp. 329–63 [chapter 16]. 14. Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP. J Am Chem Soc 1985;107:3902–9. 15. (a) Becke AD. J Chem Phys 1993;98:5648–52. (b) Lee C, Yang W, Parr RG. Phys Rev B 1998;37:785–9. (c) Miehlich B, Savin A, Stoll H, Preuss H. Chem Phys Lett 1989;157: 200–206. 16. Wolinski K, Hinton JF, Pulay P. J Am Chem Soc 1990;112:8251–60. 17. Schleyer PvR, Maerker C, Dransfeld A, Jiao H, Hommes NJvE. J Am Chem Soc 1996;118:6317–8. 18. (a) Cance`s MT, Mennucci B, Tomasi J. J Chem Phys 1997;107:3032–41. (b) Mennucci B, Tomasi J. J Chem Phys 1997;106:5151–8. (c) Mennucci B, Cance`s E, Tomasi J. J Phys Chem B 1997;101:10506–17. (d) Tomasi J, Mennucci B, Cance`s E. J Mol Struct (Theochem) 1999;464:211–26. 19. Laali KK, Hansen PE. Res Chem Intermed 1996;22:737–51.

176 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.

57. 58. 59.

K.K. LAALI AND G.L. BOROSKY Laali KK, Hansen PE. J Org Chem 1997;62:5804–10. Laali KK, Tanaka M, Hollenstein S. J Org Chem 1997;62:7752–7. Hansen PE, Spanget-Larsen J, Laali KK. J Org Chem 1998;63:1827–35. Laali KK, Hansen PE. J Chem Soc Perkin Trans 1998;1167–72. Laali KK, Okazaki T, Hansen PE. J Org Chem 2000;65:3816–28. Laali KK, Okazaki T, Lakshman M, Zajc B, Kumar S, Baird WM, et al. Org Biomol Chem 2003;1:1509–16. Hollenstein S, Laali KK. J Chem Soc Perkin Trans 1999;895–900. Laali KK, Hollenstein S, Hansen PE. J Chem Soc Perkin Trans 1997;2207–13. (a) Bruice PY, Bruice TC, Yagi H, Jerina DM. J Am Chem Soc 1976;98:2973. (b) Bruice PY, Bruice TC, Dansette PM, Selander HG, Yagi H, Jerina DM. J Am Chem Soc 1976;98:2965. Laali KK, Hollenstein S. J Chem Soc Perkin Trans 1998;897–904. Brule C, Laali KK, Okazaki T, Musafia T,Baird WM. European J Org Chem 2007;3:487–97. (a) Sera N, Fukuhara K, Miyata N, Tokiwa H. Mutat Res 1996;349:p137–44. (b) Fukuhara K, Takei M, Kageyama H, Miyata N. Chem Res Toxicol 1995;8:47–54. Laali KK, Hollenstein S, Galembeck SE, Coombs M. J Chem Soc Perkin Trans 2000;211–20. Laali KK, Okazaki T, Coombs M. J Org Chem 2000;65:7399–405. Hollenstein S, Laali KK. Chem Commun 1997;2145–46. Laali KK, Tanaka M. J Org Chem 1998;63:7280–5. Borosky GL, Laali KK. Chem Res Toxicol 2006;19:899–907. Laali KK, Arrica MA, Okazaki T, Harvey RG. J Org Chem 2007;72:6768–75. Laali KK, Okazaki T, Kumar S, Galembeck SE. J Org Chem 2001;66:780–8. Szeliga J, Amin S, Zhang F-J, Harvey RG. Chem Res Toxicol 1999;12:347. Laali KK, Hollenstein S, Hansen PE, Harvey RJ. J Org Chem 1997;62:4023–8. Hecht SS, Mazzarese R, Amin S, LaVoie E, Hoffmann D. In: Jones PW, Leber P, editors. Polynuclear aromatic hydrocarbons. Ann Arbor (MI): Ann Arbor Science; 1979. pp. 733–52. Brule C, Laali KK, Okazaki T, Lakshman MK. J Org Chem 2007;72:3232–41. Bae S, Mah H, Chaturvedi S, Musafia TJ, Baird W, Katz AK, et al. J Org Chem 2007;72:7625–33. Borosky GL, Laali KK. Org Biomol Chem 2005;3:1180–8. Borosky GL, Laali KK. Chem Res Toxicol 2005;18:1876–86. Borosky GL, Laali KK. Org Biomol Chem 2007;5:2234–42. Laali KK, Chun J-H, Okazaki T, Kumar S, Borosky GL, Swartz C. J Org Chem 2007;72:8383–93. Laali KK, Okazaki T, Harvey RG. J Org Chem 2001;66:3977–83. Laali KK, Okazaki T, Galembeck SE. J Chem Soc Perkin Trans 2002;621–9. Okazaki T, Laali KK. Org Biomol Chem 2003;1:3078–93. Okazaki T, Laali KK. J Org Chem 2004;69:510–6. Okazaki T, Laali KK. Org Biomol Chem 2004;2:2214–9. Okazaki T, Laali KK. Org Biomol Chem 2005;3:286–94. Wallraff GM, Vogel E, Michl J. J Org Chem 1988;53:5807–12. Laali KK, Okazaki T, Sultana F, Bunge SD, Banik BK, Swartz C. Eur. J. Org. Chem. 2008;10:1740–1752. (a) Fu PP, Chou MW, Beland FA. In: Yang SK, Silverman BD, editors. Polycyclic aromatic hydrocarbon carcinogenesis: structure-activity relationships, vol. 2. Boca Raton (FL): CRC Press; 1988 [chapter 2]. (b) Fu PP, Ni Y-C, Zhang Y-M, Heflich RH, Wang Y-K, Lai J-S. Mutat Res 1989;225:121–5. (c) Lin S-T, Jih Y-F, Fu PP. J Org Chem 1996;61:5271–3. Laali KK, Houser JJ, Zander M. J Chem Soc Perkin Trans 1996;1265–9. Laali KK, Hupertz S, Temu AG, Galembeck SE. Org Biomol Chem 2005;3:2319–26. Koser GF, Telu S, Laali KK. Tetrahedron Lett 2006;47:7011–5.

Structural and biological impact of radical addition reactions with DNA nucleobases RICHARD A. MANDERVILLE Departments of Chemistry and Toxicology, University of Guelph, Guelph, ON N1G 2W1, Canada 1

Introduction 177 Direct radical addition reactions 177 C-8 adducts of arylamines and nitroaromatics 2 Hydroxyl and nitrogen dioxide radicals 181 Products and reaction pathways 181 Structural and biological impact 188 3 Alkyl radicals 192 Products and reaction pathways 192 Structural and biological impact 195 4 Aryl radicals 196 Products and reaction pathways 196 Structural and biological impact 205 5 Phenoxyl radicals 208 Products and reaction pathways 208 6 Summary 212 Acknowledgments 212 References 212

1

179

Introduction

DIRECT RADICAL ADDITION REACTIONS

The basic hypothesis of chemical carcinogenesis is that formation of a covalent bond between a chemical and DNA to form a DNA adduct represents the first essential step in the tumor initiation process.1,2 The nucleobases, especially 20 -deoxyguanosine (dG), are preferential targets of electrophilic attachment in which a single electrophile can react with all four DNA bases and at multiple sites. The electrophile can be derived from endogenous, such as oxygen or lipids, or exogenous sources from exposure to chemicals in the environment. Most genotoxic chemicals require metabolic activation to form the ultimate reactive (electrophilic) species that attaches covalently to the nucleophilic sites on the DNA nucleobases.2 In cases that the DNA adducts evade repair by DNA repair enzymes, mutations in the DNA sequence may occur upon DNA replication, which can induce cancer formation. 177 ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 43 ISSN: 0065-3160 DOI: 10.1016/S0065-3160(08)00005-1

 2009 Elsevier Ltd. All rights reserved

178

R.A. MANDERVILLE Alkylating agents Alkylating agents epoxides

O6 N-7

Hydroxyl radical Nitrogen dioxide radical Alkyl radicals Aryl radicals Phenoxyl radicals Arylamines Nitroaromatics

O N

C-8

8

7 9

N HO

5 4

6 3

1NH 2

N

N-1, N2

α,β-unsaturated carbonyls quinones

NH2 N2

O OH

N2,

N-3

Arylamines quinone methide epoxides

α,β-unsaturated carbonyls

Fig. 1 Electrophilic attachment to the nucleophilic sites of dG.

Shown in Fig. 1 are the sites on dG that are modified by electrophiles derived from chemical carcinogens. Alkylating agents, such as epoxides, diazonium ions, and carbocations, derived from aflatoxin, nitrosamines, mustards, and methyl methanesulfonate target the heteroatoms, especially the endocyclic N-7 and the exocyclic sites O6 and N2.3,4 Polycyclic aromatic hydrocarbons (PAHs) that can undergo bioactivation to generate dihydrodiol epoxides5 and other agents that transfer an araalkyl group tend to target the exocyclic N2 atom.4 Bis-electrophiles, such as a, b-unsaturated carbonyls that are derived from lipid peroxidation (4-hydroxy-2nonenal6) and quinones from the bioactivation of chlorophenols,7 also target N2. Due to the bifunctional electrophilicity of these chemicals, they also react with the endocyclic N-1 and N3 sites to form linear or angular etheno-type adducts.6,7 Reactivity at N-1 is typically favored, as the purine N3 atom is sterically hindered by the deoxyribose (dR) sugar and the N-1 proton is fairly acidic (N-1 pKa of dG is 9.258) making N-1 deprotonation favorable upon covalent bond formation. In fact, the N-1 pKa is in the range expected for a phenol, as delocalization of N-1 negative change into O6 yields a phenolate-like moiety, which provides a rationale for the preponderance of O6 alkylation.3 While it is to be expected that the heteroatoms of dG would be targeted by electrophiles, C-8 of dG is also a target site of many established carcinogens. This is an interesting aspect of C-8 reactivity because this site is not thought to be highly nucleophilic and does not react with most electrophilic species.3,4 However, it is the preferred site of certain radical addition reactions.9 This preference stems, in part, from the fact that dG has the lowest oxidation potential (1.3 V vs. NHE, pH 710) of all four nucleobases making it most susceptible to oxidation. As shown in Fig. 1, hydroxyl radical, nitrogen dioxide radical, alkyl radicals, aryl radicals and phenoxide radicals are all known to form covalent adducts at C-8 of dG. Direct radical addition reactions at the nucleobases of DNA were discussed in an excellent review by Burrows and Muller in 1998.11 This chapter highlights recent advances in this research topic that include the author’s contributions to phenoxide radical reactions.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

179

C-8 ADDUCTS OF ARYLAMINES AND NITROAROMATICS

The last two examples in Fig. 1 that form C-8 adducts with dG are arylamines12 and nitroaromatic13 carcinogens. This family of compounds represents an extremely important class of mutagens that are present in cigarette smoke and diesel exhaust.14–16 Heteroaromatic amines are also derived from the pyrolysis of amino acids and sugars and are found in cooked meets.17 Thus, an extensive body of literature is available on adducts derived from arylamines and nitroaromatics, and much of our understanding about the structural and biological impact of bulky C-8-adducts stems from work on these carcinogens. However, these chemicals do not form C-8-adducts by direct radical addition reactions. Both require a two-stage bioactivation before they can react with DNA, as outlined in Scheme 1. Arylamine activation involves an initial N-oxidation by a cytochrome P450 to form a hydroxylamine intermediate.12 For nitroaromatics, the hydroxylamine is generated through reduction of the nitro group primarily catalyzed by cytosolic nitroreductases.13 Esterification of the hydroxylamine by N-acetyltransferase or sulfotransferase followed by solvolysis of the hydroxylamine ester gives an aryl nitrenium ion,18,19 which is the DNA-modifying agent.12,13 That electrophilic aryl nitrenium ions form C-8-purine adducts is inconsistent with the reactivity of other electrophiles that prefer to react at the heteroatoms of DNA.3,4 The close proximity of the endocyclic N-7 atom, which is the most nucleophilic site within the heterocyclic bases of DNA,20 led to the proposal for initial attachment of aryl nitrenium ions to the nucleophilic N-7 atom of dG.21,22 As outlined in Scheme 2a, N—N bond formation at N-7 yields a cationic intermediate. The C-8 proton in ArNH2

[O]

OH NH

Ar

Ar

OR NH

Ar

[H]

ArNO2

+ – NH + OR

Aryl nitrenium ion

Scheme 1 Proposed pathways for the bioactivation of arylamines and nitroaromatics. (a) O

O N

HN H2N

N

(b)

O

H2N

N dR

N

HN H2 N

N

Ar HN N+ N dR

O –H+

HN H2N

N

Ar HN N+ – N dR

O N

HN

+ Ar–NH

N dR

•

R

H2N

•

N

N

HN H 2N

N

N dR

Ar N H

O N

HN

O

R

N H dR

–e–/–H+ or –H•

N

HN H 2N

R N

N dR

Scheme 2 Proposed pathways for C8-dG adduct formation by aryl nitrenium ions (a) and radical species (b).

180

R.A. MANDERVILLE

N-7-alkylguanines readily undergoes exchange with solvent protons, and mechanistic studies suggest that exchange of the C-8 proton takes place via a ylide intermediate.23,24 Thus, in analogy to N-7-alkylguanines, deprotonation of the C-8 proton from the cationic species would yield the ylide that undergoes rearrangement to form the stable C-8 arylamine adduct21,22 although other mechanisms including direct attachment of the nitrenium ion at C-8 are possible.25 This rearrangement is analogous to the Stevens 1,2-rearrangement of ylides26 and is contrasted by direct radical addition at C-8, which is outlined in Scheme 2B. In bacterial assays and mammalian systems, C-8-adducts induce mutations.13,27 Understanding conformational changes to C-8-adducted DNAs can provide insight into the biological impact of the DNA adduct. Although C-8-adducts can form Watson–Crick base pairs with cytosine, they show a syn glycosidic bond preference, as shown in Fig. 2 for a C-8-arylamine adduct. For a small C-8-adduct, such as 7,8-dihydro-8-oxo-guanine (8oxoG), the syn orientation permits a Hoogsteen-like base pair with adenine.28 The mutational consequence of this is that 8oxoG is read during replication as a thymidine.29 For a bulky C-8-arylamine adduct, the syn structure causes the attached aromatic group to intercalate into the helix30 with displacement of cytosine.31 It has been hypothesized that the structures of the adducted DNAs are relevant to the biochemical functioning of the adducts and determine their mutational properties in DNA polymerases.32,33 Thus, the structural change in the helix brought about by C-8-arylamine adducts is thought to provide a rationale for their tendency to be potent inducers of frameshift mutations.27,34 These studies provide a basis for understanding the structural and biological impact of C-8-adducts derived from direct radical addition reactions.

O

O N N HO

N

NH2

N

HN

NH

H2N HO

N O

O OH

OH O

Ar

N

N H HO O OH anti

N

N

O NH

N

NH2

H2N HO

Ar

N

HN

N N O OH syn

Fig. 2 Anti and syn conformations for dG and C8-arylamine-dG.

N

H

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

2

181

Hydroxyl and nitrogen dioxide radicals

In the 1980–1990s, a great deal of effort in the area of radical-mediated DNA damage was focused on defining dR sugar oxidation derived from initial hydrogen atom abstraction leading to strand breaks and oxidized abasic sites.35 Studies of Fe–EDTA systems,36,37 copper–phenanthroline complexes,38 and metalloporphyrins39 provided significant progress in defining radical-mediated dR-oxidative chemistry. Some of this effort was driven by the desire to understand the mechanisms of DNA singlestrand and double-strand cleavage by the chemotherapy molecules, bleomycin,40–42 and the enediyne antitumor agents.43,44 The descriptive chemistry of dR-oxidation has been well documented in reviews,45 texts,46 and an update has been provided by Dedon.47 Today studies of nucleobase oxidation by radical-mediated processes dominate the literature. This change in focus has been brought about, in part, by technological advances in mass spectrometry that have enabled researchers to detect DNA adducts in vivo with high sensitivity (1 adduct/1011 nucleotides).48–50 Oxidizing and nitrosating agents may play a critical role in the pathology of inflammation, cancer, and degenerative diseases,51,52 and oxidative DNA base damage is likely to be as important as dR-oxidation47 for cellular function and survival.53 Understanding the relationship between base damage and biological significance has been identified by the Health and Environmental Sciences Institute (HESI) as a key area for future research.54 Many reports over the last 10 years have detailed the formation and properties of oxidative DNA base damage. Following the review by Burrows & Muller in 1998,11 additional comprehensive reviews on this subject have been provided by Bjelland and Seeberg,53 Cadet and coworkers,55,56 Evans and collegues,57 and Neeley and Essigmann.58 A recent review of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) lesions by Tudek59 in also available. This chapter focuses only on the oxidative lesions of dG that are provided in Table 1 with emphasis on 8-oxoG and 8-nitroguanine (8-NO2-G) that have been detected in vivo.60,61 The principles for their mechanisms of formation, further oxidation reactions, structural and biological impact provides a starting point for understanding other DNA base damage derived from radical-mediated processes.

PRODUCTS AND REACTION PATHWAYS

The interaction of the hydroxyl radical with dG is shown in Scheme 3. Direct attachment to the C-8-position to form the hydroxyl adduct radical can be followed by an oxidative process to generate 8-oxo-dG. Alternatively, one-electron reduction of the hydroxyl adduct radical intermediate generates the ring-opened FapyG lesion.57 It has been estimated that levels of 8-oxoG in human cells are between 0.3 and 4 lesions/106 nucleotides.60 After oxidative stress, FapyG and FapyA lesions are formed at equal or higher levels than 8-oxoG.57,62

182

R.A. MANDERVILLE

Table 1

Abbreviations and full names of nucleobases and DNA adducts

Abbreviation

Full name

dG dA 8-oxoG FapyG Iz Z 8-NO2-G NI Sp Gh C8-IQ C8-Lys C8-Me C8-2-HE C8-1-HE 8-Ph-dG 8-p-PhOH-dG 8-o-PhOH-dG 8-BP-dG 8-3,4-EQ-dG 8-Ar-dG 8-p-OMePh-dG C8-OPCP C8-CPCP dG-OTA dG-OTHQ

20 -deoxyguanosine 20 -deoxyadenosine 8-oxo-7,8-dihydroguanine 2,6-diamino-4-hydroxy-5-formamidopyrimidine 2,5-diamino-imidazolone 2,2,4-triamino-2H-oxazol-5-one 8-nitroguanine 5-guanidino-4-nitroimidazole Spiroiminodihydantoin 5-guanidinohydantoin 8-(2-amino-3-methylimidazole[4,5-f]quinoline)-20 -deoxyguanosine 8-(Na-acetyllysine methyl ester)-20 -deoxyguanosine 8-methyl-20 -deoxyguanosine 8-(2-hydroxyethyl)-20 -deoxyguanosine 8-(1-hydroxyethyl)-20 -deoxyguanosine 8-phenyl-20 -deoxyguanosine 8-(400 -hydroxyphenyl)-20 -deoxyguanosine 8-(200 -hydroxyphenyl)-20 -deoxyguanosine 8-(benzo[a]pyrene)-20 -deoxyguanosine 8-(3,4-estronequinone)-20 -deoxyguanosine 8-aryl-20 -deoxyguanosine 8-(400 -methoxyphenyl)-20 -deoxyguanosine 8-(O-pentachlorophenol)-20 -deoxyguanosine 8-(C-pentachlorophenol)-20 -deoxyguanosine 8-(C-ochratoxin A)-20 -deoxyguanosine ochratoxin hydroquinone-20 -deoxyguanosine

• N

HN H2N

O2• –

O•

O –H+

N + N dR G• +

H2 N

O2• –

N N G(–H)• dR

+H+

O

H2N

N

[O]

O N

HN

O

[H] HN

[O]

N dR

HO•

HN H2 N

N

H 2N

H2N H2N

O N Z

O NH dR

H N O

N

N dR

N •

OH

N

H

dR

O +H2O

N Iz NH dR

+H+

N

N

N

H2N

8-oxoG [H]

O HN H 2N

N

H N CHO NH dR

FapyG

Scheme 3 Proposed pathways for formation of major dG products following exposure to the hydroxyl radical (HO•).

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

183

The hydroxyl radical can also abstract a single electron from dG to generate the base radical cation (G•þ). In duplex DNA, the G•þ will be stabilized by its delocalization into adjacent bases. Both calculations63 and kinetic measurements64 indicate that GG sequences have a lower oxidation potential than an ‘‘isolated’’ G. Nucleobases on the 30 -side of G determine the extent of G•þ formation,65,66 and here purines are more effective than pyrimidines at lowering the oxidation potential of G, which accounts for the GG effect67 and that GA sites are also reactive.68 Base radical cations are also more acidic than their uncharged forms and the N-1 pKa of G•þ is 3.9 at the nucleoside level69 (compared to an N-1 pKa of 9.25 for dG8). Thus, neutral pH deprotonation of G•þ generates the neutral radical G(—H)• that can react with O•– 2 to eventually yield 2,5-diamino-imidazolone (Iz) and its hydrolysis oxazolone derivative Z.70 In a competitive process, 8-oxoG can also be generated from G(—H)•.58 For oxidation of G in duplex DNA, Steenken concluded that the proton on N-1 of G•þ shifts spontaneously to N-3 of the cytosine in the normal Watson–Crick base pair to generate [Cþ(H)/G•].71 Consistent with this proposal, calculations indicate that charge transfer in oxidized DNA is coupled with proton transfer from G to C.72 Experiments carried out in D2O also reveal a kinetic isotope effect for G oxidation, implicating a concerted proton-coupled electron transfer mechanism.73 However, density functional theory (DFT) calculations in the gas phase predict that the structure with a proton on G N-1 [C/HG•þ] is more stable than [Cþ(H)/G•] by 1.4 kcal/mol.74 In an effort to address the issue of proton transfer from G•þ to C, the Schuster laboratory prepared a duplex oligomer containing 5-fluoro-Cs (5-F-C) in positions complementary to GG steps.75 Compared to dC, the N-3 pKa of 5-F-C shows a 50-fold decrease in basicity, and consequently, proton transfer from a G•þ to 5-F-C is thermodynamically unfavorable. Thus, the reduced basicity of 5-F-C was expected to inhibit radical cation hopping from one GG step to the next if the process is strongly coupled to proton transfer from G to C.75 To test this prediction, the 50 -end of the GGrich sequence was modified with an anthroquinone (AQ) label. Selective photoirradiation of the AQ label at 350 nm introduces a radical cation into the duplex that will migrate through the duplex until it reaches a GG site (deep trap) where the G•þ reacts with H2O or O• 2 to generate 8-oxoG or Iz/Z lesions. Subsequent treatment with FpyG enzyme results in strand scission at each GG step, as Fpg cleaves DNA at sites that contain either 8-oxoG or Iz/Z, and 5-F-C does not inhibit the enzymatic activity of Fpg. The experiments showed that substitution of the duplex with 5-F-C does not measurably affect the efficiency of hopping, suggesting that the N-1 proton remains primarily on G•þ,75 which is consistent with the DFT calculations.74 The generation of reactive nitrogen species (RNS) also leads to radical addition reactions. The reaction of nitric oxide (•NO) with O•– 2 at diffusion-limited rates generates peroxynitrite (ONOO–), which oxidizes and nitrates all major classes of biological molecules including nucleic acids.76 Spontaneous hydrolysis of ONOO– under physiological conditions generates nitrogen dioxide (•NO2) and hydroxyl radical (HO•).77 The reduction potential of •NO2 (Eo = 1.04 V vs. NHE)78 is not high enough to cause the oxidation of dG. However, in the presence of sodium

184

R.A. MANDERVILLE

bicarbonate [NaHCO3/carbon dioxide (CO2)] at physiological pH, the nitrosoperox
 ocarbonate ONOOCO adduct is formed, which decomposes to yield carbonate
792 . At pH 7, the reduction potential of CO• radical anion CO• 3 3 is 1.7 V versus 80 NHE, which is a strong enough oxidant to abstract an electron from dG (Eo = 1.29 V vs. NHE10) to yield G•þ. Following deprotonation of G•þ to yield the neutral radical G(—H)•, reaction with •NO2 produces 8-nitro-dG and the 5-guanidino-4nitroimidazole derivative (NI) following attachment of •NO2 at C-5 of G(—H)• (Scheme 4).81 The Shafirovich laboratory has studied the kinetics of radical combination for • NO2 and G(—H)• using laser flash photolysis.82 For these experiments, 2-aminopurine (2AP) was incorporated into oligonucleotides strands at sites separated by a TC dinucleotide step. Excitation of the strand at 308 nm induces a two-photon ionization of the 2AP bases to generate 2AP•þ and solvated electrons. The deoxygenated solutions contained NO 3 that scavenge the solvated electrons resulting in formation of •NO2. Time-resolved spectroscopic methods could then be used to monitor the disappearance of G(—H)• at 315 nm (" = 7.3  103/M/cm); the molar absorptivities of •NO2 do not exceed 200/M/cm in the spectral range 250–600 nm and thus could not be observed directly. The decay of the G(—H)• transient absorption at 315 nm was accompanied by an isosbestic point at 330 nm and an increase in absorbance at 385 nm for formation of the nitro products with relative yields of 70 and 30% for the NI-oligonucleotide and 8-NO2-dGoligonucleotide, respectively. Rate constants for the bimolecular radical–radical addition reaction were 4.3  108/M/s in both single- and double-stranded DNA.82 While NI is a stable lesion, 8-NO2-dG undergoes deglycosylation with a half-life of 1 h at 37oC (pH 7.2) at the nucleoside level.83 As outlined in Scheme 5, attachment of the electron-withdrawing NO2 group to C-8 of dG increases the leaving-group ability of the purine base. However, despite the instability of 8-NO2-dG, the adduct has been incorporated site-specifically into single-stranded DNA. Using the 11-mer 50 -d(CCATCGCTACC) the photochemical conversion of the lone G base into

O

O O• N H2N

N

•NO2

H2N

N

N

NO2

N

H

O

•NO2

N H2N

N

H2N

NO2 N

N 8-NO2-G

NO2 N

+H2O

N

–CO2

dR

N

HN

dR

N

N G(–H)• dR

N

O2N HN

N

N H

N

H2N

dR

dR NI

Scheme 4 Proposed pathways for the reaction of nitrogen dioxide radical neutral guanine radical.


NO•2 with the

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

HO

O +N O

N N

NH N

O

O

O –

185

NH2

HO

–O +N –O

N N+

NH N

deglycosylation

–O +N O

NH2

HO

••

O

O

O

+

NH

N H

N

NH2

OH

OH

OH 8-NO2-dG

N

Scheme 5 Proposed pathway for deglycosylation of 8-NO2-dG.

8-NO2-dG was achieved by the selective photodissociation of persulfate anions that generate CO3• and •NO2 by one-electron oxidation of bicarbonate and nitrite anions in solution.84 The CO3• site-selectively generates G(—H)• in the 11-mer that combines with •NO2 to yield the 8-NO2-dG-adducted strand in 3% following HPLC purification. The nitrated 11-mer was stable at 4oC for 4 days, but depurinated at room temperature at pH 7 with a half-life of 20 h.84 Heteroatom (O and N) attachment to the C8-site of dG to form 8-oxo-dG and C8-arylamine adducts lowers the oxidation potential relative to dG. The oxidation potential of 8-oxo-dG is 0.74 V versus NHE.85 Consequently, 8-oxo-dG can act as a deep radical cation trap within duplex DNA. Depending on the DNA sequence, an 8-oxo-dG lesion will be the preferential site of further oxidation and will protect isolated Gs and GG steps from oxidation;86 the oxidation of 8-oxo-dG by G(—H)• occurs with a rate of 4.6  108/M/s.85 Thus, there is speculation that GC-rich domains outside the coding regions of genes serve to protect the genome from mutagenesis by oxidation.58 Intermediates derived from the oxidation of 8-oxo-dG are outlined in Scheme 6. The one-electron oxidation of 8-oxoG forms the radical cation (8-oxoG•þ) that is

O HN

+ H N

N • N dR

H2N

O

H2O

O OH H N HN H2N

N • N dR O NO2 H N N

H2N

HN H2N

O

N

H N

[O] O

N

N dR

8-oxoG

HN H2N

O

H • N

N + N dR 8-oxoG•+

O

–H+

N H2N

O

–H+

H2N

N

O

N

dR 5-HO-8-oxoG – – NO2 +

H2O O

–H

N •

O

O OH H N N

–e–

dR NO2

H • N O

N

N

dR 8-oxoG(–H)•

Scheme 6 Proposed pathway for formation of 5-HO-8-oxoG from the oxidation of 8-oxoG.

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R.A. MANDERVILLE

characterized by a narrow absorption band near 325 nm.82 The pKa of 8-oxo-dG is 8.6,87 while the pKa of 8-oxoG•þ is 6.6.85,88 At pH 7.5, the deprotonation rate for 8-oxoG•þ is 2 ms for neutral radical (8-oxoG(—H)•) formation.82 For most experiments carried out at neutral pH, 8-oxoG•þ and 8-oxoG(—H)• are present in similar concentrations, and both species give similar transient absorption spectra making it impossible to unambiguously assign the absorption band at 325 nm as belonging to 8-oxoG•þ or 8-oxoG(—H)•.82 The reaction of 8-oxoG•þ with water followed by an oxidation step gives rise to 5-hydroxy-8-oxoG (5-HO-8-oxoG). This intermediate has been structurally characterized by the Foote laboratory using low-temperature NMR techniques.89 Originally, the NMR peaks of this intermediate were assigned as the corresponding 4HO-8-oxoG regioisomer.90 However, new HMBC experiments carried out at 40oC in acetone-d6 revealed a clear three-bond coupling from the anomeric proton (H-10 ) to C-8 at 155 pm and C-4 at 173 ppm, confirming that C-4 is sp2-hybridized, which is consistent with the 5-HO-8-oxoG assignment.89 Calculations carried out at the B3LYP/ 6-31G(d) level of theory also show that 5-HO-9-Me-8-oxoG is 13.2 kcal/mol more stable than the 4-HO-9-Me-8-oxoG regioisomer.89 The 5-HO-8-oxoG intermediate is also produced from radical coupling of •NO2 with 8-oxoG(—H)•, which occurs with a similar rate (4.3  108/M/s) to the bimolecular radical–radical addition of •NO2 with G(—H)•.82 Here it is proposed that the initially produced C-5 nitro adduct is unstable, 82 and its hydrolysis with release of the NO 2 anion generates 5-HO-8-oxoG. At room temperature, the alcohol 5-HO-8-oxoG undergoes rearrangement to spiroiminodihydantoin (Sp) that is 18.2 kcal/mol more stable than the alcohol precursor (Scheme 7).89 The quaternary spiro carbon of Sp is evident at 80 ppm, while the urea carbonyl is seen at 154 ppm; three-bond coupling between these carbons and the anomeric H-10 proton has been used to confirm the spiro structure assignment.89 A rate constant of 2.24  104 s1 for the conversion of 5-HO-8-oxoG into Sp has been determined in acetone at room temperature.89 The spiro adduct Sp is also the major product from treatment of 8-oxoG with Na2IrCl6 at room temperature91 or from treatment with peroxynitrite.92 A second major product generated from the decomposition of 5-HO-8-oxoG is guanidinohydantoin (Gh) (Scheme 7). A great deal of effort by Burrows93 and others H H H+

O O N H 2N

H

H2O

N

H dR 5-HO-8-oxoG

N

H2N

OH H N

Acyl

–

O N

N

HN

migration O

H N

N dR O Sp

O2C HN H2N

dR O

H N O

N

+

O O

NH2 N

N

OH H N O N dR HN

H2N

H N

Carboxylate HN O migration H2N

O

H N

N H

N

– CO2

N H

O N dR CO2–

O dR Gh

Scheme 7 Proposed pathways for production of Sp and Gh from 5-HO-8-oxoG.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

187

has been devoted to understanding the principles that dictate Sp versus Gh formation, and these studies have been summarized in the review by Neely and Essigmann.58 One determining factor appears to be the pH of the reaction solution, where Gh forms preferentially at pH below 5.8, while Sp is the dominant product above pH 5.8. This led to the proposal that the pKa of 5-HO-8-oxoG is 5.8 and that deprotonation of the alcohol favors Sp formation.58 C-8-arylamine adducts can also undergo oxidative rearrangement to give Sp and Gh products.94 The Rizzo laboratory has studied the electrochemical oxidation of a number of C-8-arylamine adducts and the C8-IQ adduct has a peak potential of 0.419 versus Ag/AgCl (0.619 vs. NHE), which is similar to the oxidation potential of 8-oxo-dG.95 Treatment of C8-IQ with Na2IrCl6 using conditions developed by Burrows91 generated a species with a mass of 493 Da, which was tentatively assigned to the 5-OCH3-derivative shown in Scheme 8. Upon warming the sample to room temperature, the initially formed adduct broke down to yield the 8-IQ-Sp derivative as the major product (observed as a near equal mixture of two diastereomers) and 8-IQ-Gh as the minor product.95 A similar pattern of reactivity has been observed by Burrows and coworkers for the reaction between Na-acetyllysine methyl ester (Lys) and dG.96 This reaction was studied in order to gain an understanding of structural aspects of DNA–protein cross-links (DPCs). These cross-links are regarded as a common lesion of oxidative damage to cells, but remain, from a chemical point, a poorly understood DNA lesion. As pointed out by Burrows, oxidation of protein–DNA complexes should occur preferentially at the primary amines since these sites have a lower oxidation potential (1.1 V vs. NHE, pH 10)97 than G.96 While protonation of the primary amine inhibits the oxidative process, transient deprotonation of a lysine residue would give rise to a lysine aminyl radical (or aminium radical cation). Using

N

N

H3C

NH

N N

H

H3C

O

N N

HO

N

IQ

Na2IrCl6 MeOH, 4°C

O

O

N

N

N N

H

NH2

N

NH2

dR

O

4°C – 25°C O

OH C8-IQ

N IQ

N

H N

N

O H dR 8-IQ-Sp

NH2 N

HN H2N

O

IQ

N N

N H

N dR

H

8-IQ-Gh

Scheme 8 Formation of Sp and Gh products derived from C8-IQ following oxidation with Na2IrCl6.

188

R.A. MANDERVILLE CO2CH3 AcHN

Lys O

O N

NH

N HO

N

H

N

N

[O] Lys

NH2

O

H N

N N N O H dR 8-Lys-Sp

N NH2

N Lys

H N

NH2

N N N O H dR 5,8-diLys-Sp

OH C8-Lys

Scheme 9 Oxidation of C8-Lys to generate 8-Lys-Sp and 5,8-diLys-Sp.

photochemical oxidation systems to generate singlet oxygen, it was found that oxidation centered on Lys led primarily to adduct formation at C-8 of dG (Scheme 9). Under the conditions of excess oxidant and Lys, the initially formed C8-Lys adduct was not observed and the isolated products were 8-Lys-Sp and the 5,8-diLys-Sp lesion. These results were contrasted by oxidation of the Lys/dG mixture with Na2IrCl6 or sulfate radicals in which both 5-Lys-Sp and 8-Lys-Sp products were detected.96

STRUCTURAL AND BIOLOGICAL IMPACT

The steps involved in understanding the structural and biological impact of adducted DNA has been outlined in reviews by Guengerich98 and Delaney and Essigmann99 and is summarized briefly here. The first step involves the synthesis of an oligonucleotide containing a single welldefined modification at an individual site.98 Four major approaches can be used to prepare the adducted DNA and include (1) synthesis of the modified phosphoramidite for solid-phase DNA synthesis; (2) postsynthetic modification of DNA bearing a convertible nucleoside; (3) postsynthetic modification of DNA by direct reaction with an electrophile; and (4) enzymatic incorporation of a derivatized dNTP into DNA.98,99 Following purification of the adducted oligonucleotides, Tm measurements using optical spectroscopies or differential scanning colorimetry are used to determine the thermodynamics of base pairing, while NMR and X-ray crystallography are used to determine the 3-dimensional structure of the adducted duplex DNA. The structural studies are most often done on 11- and 13-mers. Once the site-specifically modified oligonucleotide has been made and purified, the biological impact of the lesion may be assessed using in vitro polymerase assays and/ or in vivo site-specific mutagenesis assays. The in vitro polymerase assays require adducted templates of 40 base pairs, which are often generated by ligation of the shorter adducted strand to a nonadducted strand of the appropriate length. These assays provide information on lesion mutagenesis (misincorporation and extension), adduct repair (exonuclease activity), lesion bypass, and mechanistic details by

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

189

performing presteady-state kinetic experiments.98 These assays provide the most detailed understanding of the system98 because one knows exactly which polymerase or repair protein caused the observed effect.99 However, it may be difficult to know whether the results obtained from the in vitro assay are biologically relevant, since within a cell there are multiple DNA repair enzymes and bypass polymerases. In the in vivo site-specific mutagenesis assay, the adducted strand is incorporated into a plasmid (vector) and introduced into mammalian or bacterial cells by electroporation. A double-stranded vector provides information on nucleotide excision repair (NER) and base excision repair (BER), which require duplex DNA, but can lead to the reduction of mutation signal, since replication of the nonadducted strand may be strongly favored.99 A single-stranded vector is ideal for measuring lesion traversal and for studying lesion repair by a direct reversal mechanism.99 A significant advantage to the in vivo site-specific mutagenesis assay is that the biological effects of an adduct can be observed in a cellular environment. A disadvantage is that the experiment does not inherently provide any information about which proteins are involved.98 For the oxidative base lesions discussed in this section, the phosphoramidite of 8-oxo-dG is commercially available. For coupling on a DNA synthesizer, no changes are required from the standard method recommended by the synthesizer manufacturer. However, for deprotection and cleavage from the solid support with ammonium hydroxide, 0.25 M 2-mercaptoethanol is added to avoid oxidative degradation of the 8-oxo-dG site. The Greenberg laboratory has developed the synthesis of dinucleotide phosphoramidites containing Fapy-dA and Fapy-dG lesions.100–103 For solid-phase oligonucleotide synthesis using these phosphoramidites, modification of the standard protocol is required and include using trimethylacetic anhydride as capping agent, 4,5-dicyanoimidazole as activating agent, replacing I2 as oxidant with tert-butyl hydroperoxide (t-BOOH), and the use of double-coupling to improve yields.103 The instability of the Fapy nucleosides to acid was accounted for by their incorporation as dinucleotides.101 A postsynthetic strategy has been utilized by Burrows to prepare oligonucleotides containing Sp and Gh lesions.104 Here, three different template strands (40 base pairs) containing a single 8-oxoG lesion were treated with NaIr2Cl6 to oxidize 8-oxoG and convert it into Sp or Gh. At 65C, the Sp lesion was formed preferentially, while treatment of the template at 4C converted 8-oxo-dG into Gh and its isomer iminoallantoin.104 A postsynthetic strategy was also employed by the Shafirovich laboratory to prepare an oligonucleotide containing a single 8-NO2-G lesion.84 Using the 11-mer 50 -d(CCATCGCTACC), the photochemical conversion of the lone G base into 8-NO2-dG was achieved by the selective photodissociation of persulfate anions that generate CO3• and •NO2 by one-electron oxidation of bicarbonate and nitrite anions in solution,84 as discussed earlier. For 8-oxo-dG, it is generally believed that nonmutagenic pairing occurs between anti-8-oxo-dG with anti-dCTP, and mutagenic pairing occurs between syn-8-oxo-dG with anti-dATP.29 In the syn conformation, 1H NMR analysis shows that the imino and NH2 amino protons exhibit a significant upfield shift, indicating that they are not hydrogen bonded.28 In contrast, the H7 imino proton of 8-oxo-dG shifts

190

R.A. MANDERVILLE

downfield by 2.6 ppm and shows NOE contacts with imino and amino protons of adjacent base pairs, indicative of H-bonding to the dA residue. The X-ray crystal structure of the dodecamer d(CGCAAATTO8GGCG) confirms the NMR results and shows that O8G (8-oxoG) adopts the syn conformation and forms H-bonds to dA in the anti conformation.105 UV melting studies shows that the duplex containing two syn-8-oxo-dG-anti-dATP Hoogsteen base pairs is destabilized by only 6C compared to the native dodecamer duplex; a dodecamer containing two A : G mispairs exhibits a Tm that is depressed by more than 35C compared to the native dodecamer.105 The X-ray crystal structure of d(CCAO8GGCGCTGG) shows anti-8-oxo-dG-anti-dCTP Watson–Crick base pairs.106 Interestingly, both X-ray structures show that incorporation of 8-oxo-dG into the helix induces only subtle structural perturbations to the unmodified B-form DNA duplex regardless of its H-bonding partner. For Fapy-dG, NMR and X-ray crystallographic studies have yet to be carried out. However, the Greenberg laboratory performed UV-melting studies on a dodecamer 50 -TGCAGTYTCAGC, where Y = Fapy-dG, and found that replacement of dG in the native strand with Fapy-dG depressed the duplex Tm by a small amount (3C).101 Interestingly, placing dA opposite Fapy-dG generated a duplex with Tm similar to the duplex containing the Fapy-dG-dC base pair, and significantly (8.6oC) higher than the duplex containing dA opposite dG. In contrast, melting studies for duplexes containing Fapy-dA did not indicate a preference for base pairing to a base other than T.101 Polymerase assays in vitro using Klenow fragment from DNA polymerase I of Escherichia coli show that Fapy-dG is bypassed and that dA is misincorporated opposite it, while Fapy-dA induces misincorporation much more infrequently;107 these findings are consistent with the thermal melting studies101 and that 8-oxo-dG is much more mutagenic than 8-oxo-dA.108 Incorporation of Fapy-dG into a single-stranded vector for in vivo mutagenicity studies in simian kidney cells (COS-7) showed that Fapy-dG is mutagenic causing Fapy-dG ! T transversions.109 In a 50 -T(Fapy-dG)T sequence, the mutational frequency of Fapy-dG was 30%, which was 25–35% more mutagenic than 8-oxo-dG in the same sequence. Molecular mechanics calculations using the CHARMM 27 all-atom forcefield showed that in a T(syn-Fapy-dG)T sequence, with Fapy-dG base paired with dA, the Fapy-dG base is efficiently p-stacked with T on the 30 -side, which may provide insight into the misincorporation of dA opposite the Fapy-dG lesion.109 While 8-oxo-dG is mildly mutagenic, yielding <10% G ! T transversions,29 numerous studies show a wider range of mutations following treatment of cells to oxidants, suggesting that additional G-derived lesions are responsible for the observed mutagenesis.58 Since Sp is a known product from the oxidation of 8-oxo-dG,91 there has been much interest in understanding its biological impact given that it has been detected in vivo.110 UV-melting studies of duplex DNAs containing the Sp lesion has been carried out by the Burrows laboratory.111 These studies showed that the presence of the Sp lesion was detrimental to duplex stability and lowered Tm regardless of the opposite interacting base. Molecular dynamics

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

191

simulations using the AMBER 8.0 forcefield show that the diastereoisomers of Sp favor a major groove/syn conformation.112 The extent of H-bonding between Sp and partner base follows the order G>A&C>T. It was noted that the A-ring of Sp (bound to the sugar dR) acts as a T in its H-bonding properties. In the syn conformation, the A-ring of Sp is directed into the helix and will preferentially base pair with a purine ring.112 An issue that has yet to be resolved for Sp is assignment of the absolute configurations for the two 4R and 4S diasteriomers. Using a combination of experimentally measured optical rotatory dispersion (ORD) spectra in aqueous media and computed ORD-specific rotations using DFT, Geacintov and coworkers concluded that peak 1 (Sp1) in the HPLC chromatogram using a Hypercarb column has ()-S absolute configuration, while peak 2 (Sp2) has (þ)-R absolute configuration.113 However, Cadet and coworkers reached the opposite conclusion using two-dimensional NOESY measurements.114 Here a key NOE was observed between the B-ring (not attached to the sugar dR) imino NH proton with H20 ,H200 of dR for one of the diasteriomers, which is consistent with the syn-(S)-Sp structure.114 Currently, the origin of the observed discrepancies in the assignment of the stereochemistry for Sp is not clear. Polymerase assays in vitro using Klenow fragment show that a Sp-containing DNA template directed insertion of dAMP and dGMP (2:1 preference for dAMP) opposite the lesion.111 Incorporation of Sp into a single-stranded vector for in vivo mutagenicity studies in E. coli cells (AB1157) showed that the Sp lesion was a strong block to DNA polymerase bypass, with survival percentages of 9%.115 For the 8-oxo-dG control, the vector survival was 87%. While the mutation frequency of 8-oxo-dG was modest, providing 3% G ! T transversion, the mutation frequency of Sp was essentially 100% and caused 72% G ! C and 27% G ! T transversions for Sp1 and 57% G ! C and 41% G ! T transversions for Sp2.115 It has also been found by the Essigmann laboratory, that MutY, a base excision enzyme that diminishes the mutagenic potential of 8-oxo-dG, does not alleviate the potent mutagenicity of the Sp lesion.116 Taken together, these findings demonstrate that Sp is highly mutagenic in vivo,115 is not repaired by the MutY repair enzyme,116 and its formation may contribute to the observed G ! T and G ! C transversions upon replication of oxidized DNA in E. coli and mammalian cells.58 The in vitro miscoding potential of 8-NO2-dG has also been assessed.117 Primer extension reactions catalyzed by mammalian DNA polymerases (pol) showed that 8NO2-dG is a strong block to pol a and b; primer extension past the lesion was more efficient with the human Y-family error-prone pol Z or DC. These polymerases showed significant amounts of dAMP misincorporation, and thus 8-NO2-dG is expected to generate primarily G ! T transversions in cells.117 However, it is important to note that dAMP is also preferentially inserted opposite apurinic sites by E. coli DNA polymerase, a phenomenon referred to as the ‘‘A rule.’’118 The ‘‘A rule’’ also holds for translesion bypass of apurinic sites by pol Z.119 Thus, given the tendency of 8-NO2-dG to undergo deglycosylation,83 the observed mutagenicity may have resulted from extension past an abasic site.

192

3

R.A. MANDERVILLE

Alkyl radicals

PRODUCTS AND REACTION PATHWAYS

The methyl radical (•CH3) is generated from a variety of methyl hydrazines120–122 and hydroperoxides123,124 following oxidative metabolism.11 Direct attachment of • CH3 to the C8-position of dG generates 8-Me-dG (Fig. 3) from rats administered with 1,2-dimethylhydrazine (DMH)125 or from reaction of t-BOOH and Fe(II) with calf thymus DNA.126,127 Formation of 8-Me-dG provides in vivo evidence for DNA alkylation by •CH3.125 Because DMH induces colon cancer in rodents128 and 8-MedG has been detected in the liver and colon DNA of rats treated with DMH,125 it is speculated that 8-Me-dG formation may play a key role in tumor promotion by DMH129 and t-BOOH.130 Alcohol consumption may also lead to C8-dG adducts through ethanol metabolism to 1-hydroxyethyl (1-HE) and 2-HE radicals that attach to C-8 of dG to produce C8-1-HE-dG and C8-2-HE-dG, respectively (Fig. 3).131 The ethanol-derived alkyl radicals are generated by treatment of ethanol with hydrogen peroxide and Fe(II) and have been shown to induce immunologic responses through protein modification in patients with alcoholic cirrhosis.132 The C8-1-HE-G adduct has also been detected in liver DNA and RNA of rats treated with 5 g/kg ethanol for 12 h.133 However, the marginal increase of C8-1-HE-G in treated rats argued that this adduct is unlikely to play a major role in ethanol carcinogenesis.133 It is important to note that the metabolism of ethanol also generates acetaldehyde, which produces N2-ethyl-dG, a DNA adduct that has been detected in peripheral white blood cells of alcoholic abusers.134 Hydrogen atom abstraction from the 5-methyl group of T produces the 5-(20 -deoxyuridinyl)methyl radical (T(—H)•), which is one of the main reactive radiation-induced decomposition products of T.135,136 As outlined in Scheme 10, T(—H)• can also be formed in a two-step process involving radical cation formation produced by photosensitizers operating through a type I mechanism, followed by deprotonation. Cadet has also developed the photolabile phenyl sulfide precursor that upon irradiation at 254 nm generates T(—H)•.137 The corresponding phenyl selenide138 and methoxy-substituted sulfides139 were developed by the Greenberg

O N

NH

H3C N HO O OH C8-Me

N

O

O

NH2

H 2 H2 HO C C

N N

HO O OH C8-2-HE

Fig. 3 Structures of C8-alkl-dG adducts.

NH N

NH2

OH N H3C CH N HO O OH C8-1-HE

NH N

NH2

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

H3C

O

O

O

H abstraction

•H2C

NH N

NH

ArX

NH hν N

O

N

O

O

HO

HO

HO O

193

O

O

1. –e– 2. –H+

OH ArX = PhS; PhSe; 4-MeOPhS; 2,5-di-MeOPhS

OH

OH T

T(–H)•

Scheme 10 Generation of the 5-(20 -deoxyuridinyl)methyl radical (T(—H)•).

laboratory because they exhibit red-shifted absorption and will undergo photolysis to yield T(—H)• in a Rayonet photoreactor with lamps that emit maximally at 350 nm. Reactions involving T(—H)• in dinucleotides and single-stranded oligonucleotides led to the formation of tandem lesions in deaerated aqueous solution involving covalent bond formation between the 5-methyl and C-8 of dG.140–142 The d(G^T) and d(T^G) lesions shown in Fig. 4 were isolated by the Cadet laboratory through incorporation of the phenyl sulfide precursor into oligonucleotides using the solidphase phosphoramidite method followed by photoirradiation at 254 nm.143 The dinucleoside monophosphates were fully characterized by NMR and MS analysis and served as authentic standards for the detection of tandem lesions produced from treatment of isolated DNA with -radiation in oxygen-free aqueous solution. The dinucleotide monophosphates were released from -irradiated DNA by enzymatic hydrolysis and were quantified using HPLC-MS/MS. These studies showed that the d(G^T) and d(T^G) lesions were produced more efficiently than the corresponding A-T cross-links and that a higher yield is produced when the purine base is located on the 50 -end [d(G^T) >> d(T^G) > d(A^T) > d(T^A)].143 The Greenberg laboratory has studied the fate of T(—H)• within duplex DNA and have discovered that tandem lesions (intrastrand cross-links) are not produced and O

O HN H2N HO

N

O O P O–

O

N

O

CH2

HN

N O H2C

O

O

O N

NH N

O

HO

N

O

O O

P O–

OH d(G^T)

Fig. 4 Structures of thymine–guanine tandem lesions.

N

O O OH d(T^G)

NH N

NH2

194

R.A. MANDERVILLE

that interstrand cross-links (ISCs) between T(—H)• and the opposing dA base are the sole products under aerobic or anaerobic conditions.139,144 This result is the first example involving ISC formation by a DNA radical. Initially, the 16-mer 50 -d(AGATGGACXCAGGTAC), where X = phenyl selenide photolabile precursor of T(—H)•, was irradiated at 350 nm for 30 min and examined using denaturing polyacrylamide gel electrophoresis (PAGE).144 Cross-linked material (25% yield) was gel-purified and initially characterized by ESI-MS (molecular weight m/z 9760.1), which was consistent with reaction between T(—H)• and the opposing strand, followed by formal one-electron oxidation and deprotonation. Enzymatic digestion of the ISC material and characterization by NMR and ESI-MS showed that the isolated adduct was generated by covalent linkage between N6 of dA and the methylene carbon derived from T(—H)•. At this stage in the analysis,144 it was speculated that the N6 adduct may have been produced via Dimroth rearrangement of the originally formed N-1 adduct during the isolation procedure, as outlined in Fig. 5. Additional experiments by the Greenberg laboratory139 confirmed the above hypothesis and demonstrated that the product resulting from radical attachment at N-1 of dA is the primary product, but this adduct isomerizes to the thermodynamically more stable N6-dA adduct in solution (Fig. 5). Further experiments also predict that the N6-dA ISC derived from T(—H)• accounts for approximately one fourth of the ISCs produced in DNA by  radiolysis.145 Treatment of DNA with -radiolysis can also lead to the formation of 50 ,8-cyclonucleosides, which have an additional base-sugar linkage between the C50 position of the 20 -dR and the C-8 of the purine (Fig. 6).146–148 Oxygen inhibits this reaction due to its diffusion-controlled reaction with the sugar radical prior to cyclization. These lesions have two diastereoisomeric forms, the (50 S) and (50 R) isomers. Interestingly, the 50 R isomers of both purines are formed preferentially from -irradiation of aqueous solutions containing the nucleoside or single-stranded DNA,146 while the (50 S) isomer of 50 ,8-cyclo-dG is formed preferentially in duplex DNA.147,148 If the 20 -dR hydroxyl groups of dG are protected with t-BuMe2Si, then the (50 S) diastereomer is formed exclusively with a rate 106 s1 for the stereoselective cyclization process.149 This shows that the influence of supramolecular organization contributes to the stereochemical outcome.150

O NH N N

O O O

N

NH

N N

HN

O

N

O

Rearrangement O O

N

O

N

N

O

O

O N

O

O Initial ISC

NH

O O

Isolated ISC

Fig. 5 Structure of initial thymine–adenine ISC and its rearrangement to the isolated ISC product.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION O N N

HO

NH2 N

NH N

195

NH2

O OH 5′,8-Cyclo-dG

N

HO

N N

O OH 5′,8-Cyclo-dA

Fig. 6 Structures of 50 ,8-cyclo-purine lesions.

The 50 ,8-cyclonucleosides are now recognized as significant oxidative lesions that are chemically stable and form in mammalian DNA in vivo. In pig liver DNA, the levels of (50 S)-50 ,8-cyclo-dA (0.7 lesions/106 DNA bases) were approximately fourto seven-fold lower than the levels of 8-oxo-dG, but were approximately three-fold higher than levels of 8-oxo-dA.151 Elevated levels of (50 S)-50 ,8-cyclo-dA have also been observed in the breast connective tissue stroma of women between 33 and 46 years of age, which correlates with the known sharp increase in breast cancer incidence for women of this age group.152

STRUCTURAL AND BIOLOGICAL IMPACT

The phosphoramidite of 8-Me-dG has been prepared and used to site-specifically incorporate 8-Me-dG into oligonucleotides.129 In the 12-mer 50 -d(GCGCCXGCGGTG), where X = 8-Me-dG, the Tm of the duplex was 5.5C lower than the normal dG : dC base pair. However, the Tm of 8-Me-dG : dG was 2.5C higher than that of the mismatched dG : dC base pair and the DGo values of 8-Me-dG : dG and 8-Me-dG : dA were 2.3 and 2.0 kcal/mol lower that that of the dG mismatches. From this data, it was speculated that 8-Me-dG exists primarily in the anti conformation when paired with dC, while the syn conformation of 8-Me-dG may pair with dAMP or dGMP.129 The miscoding properties of 8-Me-dG have been assessed using in vitro primer extension analysis.129 Both Klenow fragment from E. coli and mammalian pol a incorporate predominately the correct base dCMP opposite 8-Me-dG. Only small amounts of dGMP (0.82–1.10%) and dAMP (0.38–0.41%) were incorporated opposite the lesion. These findings showed that the miscoding frequencies of 8-Me-dG are 25–50 times less than that of O6-Me-dG, that is also produced in rat DNA following treatment with 1,2-DMH. Overall, 8-Me-dG is regarded as a weakly mutagenic lesion capable of generating G ! C and G ! T transversions and deletion in cells.129 The Cadet laboratory has prepared phosphoramidites of stereoisomers for 50 ,8-cyclo-dA and 50 ,8-cyclo-dG for incorporation into oligonucleotides.153,154 Primer extension assays using the mammalian replicative enzyme pol d demonstrated that 50 ,8-cyclonucleosides block DNA replication in vitro and thus would be highly

196

R.A. MANDERVILLE

cytotoxic in the absence of DNA repair or efficient bypass polymerases.155 Incorporation of the adducted oligonucleotides into a 7059-bp plasmid showed that 50 ,8cyclonucleoside adducts are substrates for NER, and unlike 8-oxo-dG and other oxidative lesions cannot be repaired by BER mechanisms because the C50 —C8 covalent bond would remain intact following hydrolysis of the glycosidic bond. For NER, stereospecific differences were noted; the S isomer of 50 ,8-cyclo-dA is removed by NER less efficiently than the R isomer.155 Additional experiments showed that the S isomer is also a more effective block than the R isomer of the exonucleolytic activity of T4 DNA polymerase, which functions as a 30 to 50 exonuclease and mammalian DNase III.156 It was also found that human pol Z has the ability to perform translesion synthesis at a (50 R)-50 ,8-cyclo-dA adduct but has only weak activity on the (50 S) isomer. Taken together, these results show that 50 ,8cyclonucleoside adducts have a cytotoxic effect by inhibiting DNA replication and that the S diastereoisomer is likely to be a more cytotoxic lesion than the R isomer. These adducts are not repaired by the BER machinery but can be repaired by NER mechanisms, albeit inefficiently.155,156 The 50 ,8-cyclonucleoside adducts have also been implicated in human neurodegenerative diseases, such as Cockayne syndrome (CS),157 and in human breast cancer.158 For the other lesions derived from alkyl radicals discussed in this section, little is known of their structural and biological impact. However, given that a single ISC can be sufficient to kill a eukaryotic cell,159,160 the consequences of the ISCs derived from T(—H)• should be evaluated.145

4

Aryl radicals

PRODUCTS AND REACTION PATHWAYS

Similar to the activity of alkyl hydrazines that liberate alkyl radicals upon metabolic activation,120–122 several aryl hydrazines with various para substituents (X = H, CH3, CH2OH, COOH) are found in the mushroom Agaricus bisporus161 and are metabolized to arenediazonium ions162–164 and then to aryl radicals165 that form the 8-PhdG (X = H) adducts shown in Fig. 7.166 Aryl hydrazines are mutagenic in bacteria,167 produce tumors in mice,168,169 and the formation of 8-(4-X-Ph)-dG adducts correlates with the carcinogenicity of the parent hydrazine, suggesting a role for the 8-aryldG adducts.162 Structurally related adducts include the 8-phenol derivatives, 8-(400 hydroxyphenyl)-dG (8-p-PhOH-dG), and 8-(200 -hydroxyphenyl)-dG (8-o-PhOHdG) that are generated by reaction of phenol with excess nitrite.170 This reaction generates diazoquinones that break down into hydroxyphenyl radicals that attach covalently to C-8 of dG. Diazoquinones are mutagenic in the Ames test without metabolic activation,171 and it is expected that hydroxyphenyl radicals and the isomeric adducts, 8-p-PhOH-dG and 8-o-PhOH-dG, play a key role in the mutagenic activity of diazoquinones.170 Carcinogenic PAHs, such as benzo[a]pyrene (BP), also form C8-dG adducts (8-BP-dG, Fig. 7).172,173 While classical metabolic activation of

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION O 12 11

N

NH

X N HO

N

R

NH2

14

HO 4′

OH

O

N dR

8-BP-dG

1

θ N9

O

OH

N

NH

8

1′ 2′

4

χ

N

2

3

NH2

R = OH, R′ = H = 8-p-PhOH-dG R = H, R′ = OH = 8-o-PhOH-dG

O

N

5′

6

5

N

3′

X = H = 8-Ph-dG X = CH3 X = CH2OH X = COOH

H2N

7

13

O

HN

O

R′ 10 15

197

H2N

HO

OH

N

HN N

N dR

8-3,4-EQ-dG

O

Fig. 7 Structures of C8-aryl-dG adducts.

PAHs involves diol epoxide formation,5 or activation to quinone intermediates,174 PAHs also undergo one-electron oxidative processes in the presence of P450 peroxidase to form radical cations, in which the most electrophilic carbon is at C6 on BP.172 Radical cations of PAHs form purine N-7 adducts, N3 adducts with dA, and C-8 adducts with dG, that is, 8-BP-dG shown in Fig. 7. These adducts undergo depurination to generate abasic sites, and the Cavalieri laboratory has published evidence to suggest that depurinating adducts formed by radical cations play a major role in the initiation of tumors by PAHs.173 The estrogen 3,4-estronequinone (3,4EQ) also undergoes metabolic activation to form C8-dG adducts, such as 8-3,4-EQdG (Fig. 7);175 in this case the reactive intermediate is the 3,4-EQ radical anion.175 A common property of C8-aryl-purine adducts are their tendency to undergo depurination to form abasic sites. As outlined in Scheme 11, isolation of the C8-dG adduct is accompanied with formation of the corresponding C8-G adduct. For example, diazonium ion treatment of calf thymus DNA generated 30% 8-Ph-dG (X = CH3) and 70% 8-Ph-G (X = CH3), while for X = CH2OH the corresponding ratios were 7 and 93%, respectively.176 For 8-BP-dG formation, inspection of the supernatant showed that 50% had undergone depurination to form 8-BP-G,177 while 8-3,4-EQ-dG gave way to 8-3,4-EQ-G following 30 min incubation in 1:1 DMF : aqueous buffer.175 The latter result prompted Akanni and Abul-Hajj to propose that 8-3,4-EQ-dG is formed as an intermediate prior to the loss of the dR sugar.175

198

R.A. MANDERVILLE O HN

H2 N

N

O

O N

Ar •

N dR

• N

HN H2N

N

H

HN

N Ar dR

H2N

O N Ar

N dR 8-Ar-dG N

N

HN

+

H2N

Ar N

N H

8-Ar-G

Scheme 11 Aryl radical attachment to C-8 of dG.

Because the loss of the sugar from C-8 adducts cannot be easily explained, we determined rates of deglycosylation for a number of p-substituted 8-Ph-dG adducts in aqueous solution. First-order rate constants were determined spectrophotometrically by monitoring the formation of the deglycosylated product at its absorbance maximum. Figure 8 shows plots of half-lives (t1/2) versus Hammett þ values for the adducts in 0.1 N HCl (a) and citrate buffer at pH 4 (b). In 0.1 N HCl at 37oC, t1/2 (a)

1.6 OH

1.4

OCH3

CH3

1.2

t1/2 (min)

1 H 0.8 0.6 CHO CN

0.4 0.2 0 –1.5

–1

–0.5

σ

0

1

0.5

+

(b)

31 CN CHO

29

t1/2 (min)

27 H 25 CH3

OCH3

23 OH 21 R = 0.9678

19 –1.5

–1

–0.5

σ

0

0.5

1

+

Fig. 8 Plots of half-lives for deglycosylation rates of 8-p-X-Ph-dG adducts versus Hammett þ values in 0.1 N HCl at 37.2C (a) and 0.05 M citrate buffer (pH = 4.0),  = 0.31 M NaCl at 48.4C (b). The X-substituent of the phenyl ring is identified next to its data point.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

199

ranged from 0.4 min for the phenyl adducts bearing the electron-withdrawing CN and CHO substituents up to 1.45 min for 8-p-PhOH-dG. In pH 4 at 48.4oC, 8-p-PhOH-dG is the most reactive and undergoes hydrolysis with t1/2  22 min. Protonation of N-7 of dG (pKa for protonated dG is 2.348) is known to accelerate the rate of hydrolysis, as the positively charged purine ring becomes a good leaving group for a heteroatomassisted SN1-type hydrolysis reaction.24 Thus, in acid where N-7 is protonated, the purine rings bearing electron-withdrawing CN and CHO substituents are better leaving groups and increase the rate of hydrolysis, while in pH 4 where N-7 is not initially protonated, electron-withdrawing CN and CHO substituents lower N-7 basicity and decrease the rate of hydrolysis. For dG itself, the t1/2 is 17.7 min in 0.1 N HCl at 37oC and 2840 min in pH 4.1 at 48oC.178 Thus, 8-p-PhOH-dG undergoes deglycosylation 12 times faster than dG in 0.1 N HCl and 129 times faster at pH 4. The generation of pH rate profiles at 37oC allowed the determination of deglycosylation rates at pH 7, and for 8-p-PhOH-dG a rate constant of 3.82  105 s1 for t1/2  302 h (12.6 days) was determined. A rate for spontaneous loss of purines from duplex DNA at pH 7.4 at 37oC is 3  1011 s1 (t1/2 = 730 years).179 While 8-Ph-dG adducts are certainly more reactive than dG toward depurination, they are not as reactive as 8-NO2-dG (t1/2  1 h at 37oC, pH 7.283) and are reasonably stable at physiological pH. These results suggest that 8-Ph-dG adducts should be stable in duplex DNA where purines are more resistant to depurination.24 At present, our findings do not readily provide a rationale for the tendency of 8-Ph-dG adducts to undergo hydrolysis, as pointed out in the literature.175–177 As noted for heteroatom attachment in 8-oxo-dG91 and C8-arylamine adducts,95 attachment of the Ph moiety to the C-8 site of dG enhances the one-electron donor characteristics of the purine nucleoside.180 The redox properties of 8-p-X-Ph-dG (X = OH, OCH3, CH3, H, CN, CHO) adducts have been studied by cyclic voltammetry in anhydrous DMF.181 The C8-aryl adducts exhibited irreversible one-electron oxidation peaks with half-peak potentials (Ep/2) ranging from 0.85 V versus saturated calomel electrode (SCE) for 8-p-PhOH-dG (X = OH) up to 1.11 V/SCE for 8-p-CHO-Ph-dG. All adducts were oxidized more readily than dG, which gave Ep/2 = 1.14 V/SCE in DMF (Table 2). Table 2 X OH OCH3 CH3 H CN CHO dG

Electrochemical data for 8-p-X-Ph-dG in DMF181 Ep (V vs. SCE)

Ep/2 (V vs. SCE)

þ a

0.97 1.08 1.12 1.14 1.19 1.20 1.23

0.85 0.99 1.04 1.06 1.09 1.11 1.14

0.92 (2.3b) 0.78 0.31 0 0.66 0.73

Containing 0.1 M TBAF and 0.5 equivalent 9,10-anthraquinone as an internal standard. a Hammett substituent constants taken from Hansch et al.182 b Hammett þ value for O.

200

R.A. MANDERVILLE

Figure 9 shows plots of Hammett þ values versus Ep/2 for the 8-p-X-Ph-dG adducts. In Fig. 9A, the OH (0.92182) þ value was used and the regression deviated from linearity. However, Fig. 9B shows that the regression is improved to almost unity when the O– (2.30182) þ value is used. These results suggested that the oxidation of 8-p-PhOH-dG may be coupled with phenol deprotonation. As shown in Scheme 12, resonance structures for the radical cation of 8-p-PhOH-dG create a p-substituted phenol radical cation, which possess negative pKa values (pKa  2 for phenol radical cation183). Phenolic radical cations undergo deprotonation rapidly in 184 the presence of water (0.6–6  1) to yield neutral phenolic radicals. In the

anhydrous DMF solvent used for electrochemical measurements, an N-7 adduct atom or adventitious water in the solvent could serve as base to facilitate phenolic radical production.181

(a)

1.2

Ep/2 (V/SCE)

To identify oxidation products of 8-p-PhOH-dG, it was treated with Na2IrCl6 using conditions developed by Burrows91 for the oxidation of 8-oxoG. As shown in Fig. 10, oxidation of 8-p-PhOH-dG (starting material, SM) gave rise to three new products observable by HPLC that eluted after SM. Electrospray MS analysis using negative ionization (ESI–) showed that the peak labeled (SM)2 had [MH] = 715 for attachment of two 8-p-PhOH-dG (m/z 359) moieties with the loss of two protons.181

1.1

CN, CHO CH3

H

OCH3 1 0.9 OH 0.8 –1.5

–0.5

0.5

1.5

(b)

1.2

Ep/2 (V/SCE)

σp+

1.1

CN, CHO OCH3

1

CH3

H

O–

0.9 OH 0.8 –2.5

–1.5

–0.5

0.5

1.5

σp+ Fig. 9 Plots of Hammett þ values versus Ep/2 (volts vs. SCE) for 8-p-X-Ph-dG adducts using (a) þ value for OH (0.92) for 8-p-PhOH-dG; (b) þ value for O– (2.30) for 8-p-PhOH-dG. The X-substituent of the phenyl ring is identified next to its data point. See 181.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

201

O N +

NH

HO N • N

NH2

dR O

O –e 8-p-PhOH-dG

N +• N

–

HO

NH N

– H+

N

•

N

NH2

O N

NH2

Phenolic radical NH

•

N

N

dR

dR

+ HO

NH

O

N

NH2

dR

Scheme 12 Formation of the phenolic radical following oxidation of 8-p-PhOH-dG.

(a)

SM

(b)

SM

(SM)3 (SM)2 (SM)4

10

12

14 Time (min)

16

18

Fig. 10 HPLC traces of (a) 8-p-PhOH-dG adduct, starting material (SM); (b) the product mixture following oxidation of SM with Na2IrCl6 at pH 7, room temperature. See 181.

The major product (SM)3 had [MH] = 1072 for oxidative coupling of three 8-p-PhOH-dG moieties, while the broad peak labeled (SM)4 had [MH] = 1429 for coupling of four 8-p-PhOH-dG lesions. The structure of the trimer material (SM)3 was determined by NMR spectroscopy. Figure 11 shows the aromatic region of the 1 H NMR spectrum, which confirmed ortho–ortho C–C coupling of 8-p-PhOH-dG during the oxidation. These results show that 8-p-PhOH-dG undergoes oxidative coupling in the presence of Na2IrCl6 to form polyphenol materials through the intermediacy of the phenolic radical intermediate.181 In contrast to the behavior of 8-p-PhOH-dG, treatment of 8-p-OMe-Ph-dG with Na2IrCl6 gave rise to two peaks that eluted prior to SM, as shown in Fig. 12. Analysis of the products by ESIþ showed that the peak labeled (a) in Fig. 12 consisted of two

202

R.A. MANDERVILLE Ha

Ha

Hb

dG

dG

Hd Hc

Hb

7.7

Hb

OH HO OH

7.6

7.5

7.4

Hc

7.3

Hd dG (SM)3

Hd

7.2

Hc

7.1

Ha

7.0

ppm

1

Fig. 11 Aromatic region (6.9–7.7 ppm) of the 800 MHz H NMR spectrum of (SM)3 recorded at 33C. See 181.

(a)

p-OMe-Ph-dG

(b)

i ii 7

8

9

10

11 Time (min)

12

13

14

15

Fig. 12 HPLC traces of (a) 8-p-OMe-Ph-dG and (b) the product mixture following oxidation with Na2IrCl6 at pH 7, room temperature. See 181.

products with [M þ H]þ = 390 and [M þ H]þ = 408 that correspond to SM þ 16 and SM þ 34. The MS/MS spectra of these products were consistent with Sp formation.91 Oxidation of G gives an M þ 34 product due to hydrolytic opening of the initially formed spirocyclic adduct.185 Peak (b) in Fig. 12 had [M þ H]þ = 267 that was ascribed to the decomposition of the SM þ 34 product. These results are outlined in Scheme 13 and show that replacement of the phenolic OH in 8-p-PhOH-dG with OCH3 restores the well-established oxidative chemistry of the purine nucleoside.182

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION O

O N

NH

H3CO N

Na2IrCl6 H2O

N

dR 8-p-OMePh-dG

NH2

N

O

H N

N

NH2

H2O

M + 16

H N

H2N O

N

dR H3CO

NH2 N

N

dR O H3CO

203

O

M + 34

O

dR N H

H3CO

[M + H]+ = 267

Scheme 13 Proposed product formation from treatment of 8-p-OMePh-dG with Na2IrCl6.

Overall, these results show that attachment of the phenolic ring to dG expands the redox chemistry of the nucleoside to generate the phenolic radical instead of the purine radical cation that reacts with water. Given that the 5-(20 deoxyuridinyl)methyl radical (T(—H)•) generates ISCs,139,144 the fate of the phenoxyl radical of 8-p-PhOH-dG in duplex DNA should be examined. Because p-substituted phenols have been utilized historically to determine substituent ð Þ constants,186 the C8-PhOH-purine adducts can provide insight into the electronic properties of p-purine substituent by determining phenolic pKa values. For 8-p-PhOH-N1-Me-dG, a phenolic pKa of 8.90 was determined from basic pH titrations using the spectrophotometric procedure;180 a phenolic pKa for 8-p-PhOH-dG could not be determined due to overlap with N-1 deprotonation (N-1 pKa of dG is 9.258). The phenolic pKa of 8-p-PhOH-dA is 8.70.180 The dA adduct is a stronger acid than the dG adduct, which is consistent with the one-electron oxidation potentials (Eo) for purine nucleosides (1.42 V/NHE for A vs. 1.29 V/NHE for G10). Calculation of Hammett substituent constants using the equation pKa = 9.92 – 2.23 (), derived by Biggs and Robinson for substituted phenols187 afforded a  of 0.55 for dA and 0.46 for N1-Me-dG.188 These  values are comparable to those established182 for 2-pyridyl (0.55), CONH2 (0.61), N(CF3)2 (0.53), and C6F5 (0.43). Another interesting aspect of 8-PhOH-purine adducts is that, in contrast to dG and dA,188 they act as fluorophores (emission at 390 nm in aqueous buffer at pH 7), and the fluorescence is quenched upon addition of base (Table 3). For 8-oPhOH-dA and the deglycosylated analog 8-o-PhOH-A, the red-shifted emission at 447 nm is due to the phenolate, which is consistent with the drop in quantum yield. For the p-isomers, the protonation/deprotonation on/off fluorescence switching mechanism may be exploited for the development of nucleobase analogs with fluorescent pH-sensing properties.180 Figure 13 highlights the pHdependent fluorescence of 8-p-PhOH-dG and 8-p-PhOH-dA. The properties noted for 8-p-PhOH-dA prompted the synthesis of 8-p-(2-Cl-PhOH)-dA (Table 3) that has a phenolic pKa of 7.29. This derivative exhibits fluorescent pH-sensing in the physiological pH range.180

204 Table 3

R.A. MANDERVILLE Photophysical data for 8-PhOH-purine adducts

Adduct 8-p-PhOH-dG 8-p-PhOH-N1Me-dG 8-p-PhOH-dA 8-p-(2-Cl-PhOH)-dA 8-o-PhOH-dG 8-o-PhOH-N1Me-dG 8-o-PhOH-dA 8-p-PhOH-G 8-p-PhOH-A 8-o-PhOH-G 8-o-PhOH-A dG dA

max (nm), log ea

em (nm)

fla

278, 4.26 279, 4.27 282, 4.27 290, 4.21 276, 4.25 277, 4.25 270, 4.23 309, 4.30 302, 4.26 319, 4.28 317, 4.16 253c, 4.14 260c, 4.17

390 378 391 383 395 396 374,447 388 372 393 446 334c 307c

0.47 0.25 0.56 0.22 0.44 0.57 0.04 0.45 0.44 0.20 0.05 9.7.105 8.6.105

pKa (PhOH)b nd 8.90 8.70 7.29 nd 9.05 nd nd nd nd nd – –

a

10 mM MOPS buffer, pH 7.0,  = 0.1 M NaCl. Errors are  0.03 from UV-vis titrations done in triplicate. c Taken from Onidas et al.188 b

pH = 7

Fluorescence intensity

(a) 600 500 400

pH = 11

300 200 100 0 300

350

Fluorescence intensity

(b) 350

450 500 400 Wavelength (nm)

550

600

pH = 7

300 250 200 150 100 pH = 11

50 0 300

350

400 450 500 Wavelength (nm)

550

600

Fig. 13 Emission spectra of (a) 8-p-PhOH-dG and (b) 8-p-PhOH-dA in water at pH 7 and 11. Spectra were recorded with excitation at the absorbance maxima of the adducts at the different pH values (280 nm at pH 7, 292, or 310 nm at pH 11).

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

205

STRUCTURAL AND BIOLOGICAL IMPACT

The optical properties of the 8-o-PhOH-purine adducts have provided insight into their ground-state structures at the nucleoside level. These adducts have the ability to phototautomerize, through an excited-state intramolecular proton transfer (ESIPT) process, to generate the keto form. This tautomerization depends on the presence of a intramolecular hydrogen (H)-bond between the phenolic OH and the imine nitrogen (N-7).189 Figure 14 shows normalized absorption and emission spectra for 8-o-PhOH-dG and 8-o-PhOH-dA in aqueous buffered water and hexane. In water, 8-o-PhOH-dG shows only enol emission at 395 nm, while 8-o-PhOH-dA shows enol emission at 374 nm and phenolate emission at 447 nm. In hexane, both adducts show keto emission at 475 nm; 8-o-PhOH-dA also shows a small amount of enol emission and no phenolate emission. These results show that in water, the intramolecular H-bond

Normalized spectral intensity

Buffered water 1 0.8 0.6 0.4 0.2 0 240

Normalized spectral intensity

Hexane

290

340

390 440 Wavelength (nm)

490

540

Buffered water

1.00

Hexane 0.80 0.60 0.40 0.20 0.00 250

300

350

400 450 500 Wavelength (nm)

550

600

Fig. 14 Normalized absorption and emission spectra of 8-o-PhOH-dG (upper trace) and 8-oPhOH-dA in buffered water (10 mM MOPS, pH 7, 0.1 M NaCl) (black trace) and hexane (grey trace). Emission spectra recorded at 280 nm.

206

R.A. MANDERVILLE

Relative spectral intensity (AU)

required for ESIPT is disrupted, while the H-bond is present in the nonpolar hexane solvent. The absorption spectrum of 8-o-PhOH-dG in hexane also displayed a shoulder at 320 nm that was absent in water (Fig. 14). In CHCl3 and acetonitrile (MeCN), the absorbances at 320 and 280 nm are of almost equal intensity. Excitation-dependent emission spectra for 8-o-PhOH-dG in CHCl3 (Fig. 15) demonstrate that excitation at 280 nm gives rise to both enol (383 nm) and keto (481 nm) emission, while excitation at 340 nm gives the keto emission preferentially. These results provided insight into the conformational equilibria of 8-o-PhOH-purine adducts, which are summarized in Scheme 14 for 8-o-PhOH-dG.189 In water, these adducts exist in a

1 0.8 0.6 0.4 0.2 0 250

300

350

400 450 500 Wavelength (nm)

550

600

Fig. 15 Normalized absorption and emission spectra of 8-o-PhOH-dG in CHCl3 highlighting the dependence of the excitation wavelength on the emission spectra (excitation 280 nm, light grey emission; excitation 320 nm, dark grey emission; and excitation 340 nm, black emission).

S H

O

O N N

O

N

NH NH2

N

O

H

S

dR Twisted solvated

hν O

N N

NH2

N

dR Twisted H-bonded

S O H

NH

N

O NH

N

dR Planar H-bonded

NH2

hν

H N

O

N

N

dR Keto

Scheme 14 Proposed conformational equilibria of 8-o-PhOH-dG.

NH NH2

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

207

solvated (S) nonplanar ‘‘twisted’’ conformation that absorbs at 280 nm and cannot undergo ESIPT. Desolvation of this structure yields the twisted H-bonded structure that is prevalent in hexane and undergoes ESIPT. In CHCl3, the equilibrium shifts more in favor of the planar H-bonded species that absorbs at 320 nm and undergoes ESIPT. Support for the predicted conformations of 8-PhOH-purine adducts derived from optical data is provided by DFT calculations.190 The adducts adopt a syn conformation about the glycosidic bond due to the presence of an O50 –H  N3 hydrogen bond (see Fig. 7 for numbering), where the anti minima are 20–30 kJ/mol higher in energy.190 While the deglycosylated nucleobase adducts are planar, the presence of the dR sugar induces a twist about the C—C bond connecting the phenol and nucleobase rings. The 8-o-PhOH-purine adducts are less twisted (25o) than the corresponding 8-p-PhOH-purine adducts (40o) due to stabilization provided by an intramolecular O—H  N-7 bond. Solvation calculations demonstrate that the structural preference is solvent-dependent, where solvents with hydrogen-bonding abilities disrupt the intramolecular O—H  N-7 hydrogen bond such that a greater degree of twist is observed, and less polar solvents stabilize the planar structure.190 The phosphoramidite of 8-Ph-dG has been prepared and used to site-specifically incorporate it into oligonucleotides using solid-phase DNA synthesis.191–193 In the 12-mer 50 -d(GCGCCXGCGGTG), where X = 8-Ph-dG,191 the adduct behaved very similar to 8-Me-dG129 with Tm of the duplex being 5.6oC lower than the normal dG : dC base pair, while the Tm of 8-Ph-dG : dG was 2.1oC higher than that of the mismatched dG : dC base pair. This data suggested that, similar to 8-Me-dG,129 8-Ph-dG exists primarily in the anti conformation when paired with dC, while the syn conformation may pair with dGMP.191 NMR structural analysis combined with molecular dynamics calculations for the self-complementary duplex 50 -d(CGCGCXCGCG), where X = 8-Ph-dG, shows that the phenyl modification destabilizes the B-form DNA and stabilizes the Z-form duplex.192,193 In the B-form, the Ph ring lies in the major groove and is largely shielded from the water solvent. In the Z-form, the Ph group lies outside of the helix and is fully exposed to solvent. Because Z-form DNA have been identified in oncogenes, it is speculated that C8-aryl-dG adducts may activate these genes by stabilizing Z-form DNA.192 The miscoding properties of 8-Ph-dG have also been assessed using in vitro primer extension analysis.191 Similar to these studies with 8-Me-dG,129 Klenow fragment from E. coli incorporated predominately the correct base dCMP opposite 8-Ph-dG. Primer extension by mammalian pol a was strongly blocked opposite the lesion. Small amounts of dGMP and dAMP were incorporated opposite the lesion; two-base deletions were also observed. Similar to 8-Me-dG,129 8-Ph-dG is weakly mutagenic capable of generating G ! C and G ! T transversions and deletions in cells.191 It is important to note that the stability of the 8-Ph-dG-adducted oligonucleotides have not been addressed. The possibility of enhanced abasic site formation during manipulation of the adducted strand and during biochemical evaluation is a cause of concern since the stability of the glycosidic bond of 8-Ph-dG within DNA is uncertain.

208

5

R.A. MANDERVILLE

Phenoxyl radicals

Phenols are ubiquitous substances that possess a range of biological activities. Vitamin E and related phenols containing electron-donating groups possess antioxidant properties that are beneficial to human health.194 However, other phenols, such as chlorophenols, display deleterious pro-oxidant properties that are initiated through the one-electron oxidation of phenols into phenoxyl radical intermediates by enzymes with peroxidase activity.195 Phenoxyl radicals undergo a redox-cycling mechanism by H-atom abstraction of essential thiols, such as glutathione (GSH) and protein sulfhydryls, to yield thiyl radicals, which repeatedly generates the parent phenol as a substrate for peroxidase.196 The thiyl radicals react with GSH to generate a GSH disulfide anion radical that can reductively activate molecular O2, which in the presence of transition metal complexes, can yield ROS that cause oxidative DNA damage.197 Phenol-induced oxidative stress mediated by thiol oxidation, antioxidant depletion, and enhanced free radical production plays a key role in the deleterious activities of certain phenols.198 In this mode of DNA damage, the phenol does not interact with DNA directly and the observed genotoxicity is caused by an indirect mechanism of action induced by ROS. A direct mode of phenol-induced genotoxicity involves covalent DNA adduction derived from electrophilic species of phenols produced by metabolic activation. Oxidative metabolism of phenols can generate quinone intermediates that react covalently with N-1,N2 of dG to form benzethenotype adducts.199,200 Our laboratory has also recently shown that phenoxyl radicals can participate in direct radical addition reactions with C-8 of dG to form oxygen (O)-adducts.201,202 Because the metabolism of phenols can also generate C-adducts at C-8 of dG, a case can be made that phenoxyl radicals display ambident (O vs. C) electrophilicity in DNA adduction.203 The direct reaction of phenoxyl radicals with DNA bases to generate DNA adducts has been published in recent reviews by our laboratory,7,203,204 and the products and reactions pathways are summarized briefly here. Currently, the structural and biological impact of C8-dG adducts derived from phenoxyl radical intermediates has not been addressed and represents an area for future research. PRODUCTS AND REACTION PATHWAYS

Direct reactions of phenols with DNA and dG in vitro have been characterized for the chlorophenols shown in Fig. 16. The Environmental Protection Agency (EPA) lists pentachlorophenol (PCP), 2,4,6-trichlorophenol (TCP), 2,4,5-TCP, and 2,4dichlorophenol (DCP) as priority pollutants, and PCP and 2,4,6-TCP are classified as probable human carcinogens.7 Ochratoxin A (OTA: X = Cl) is a mycotoxin produced by several species of fungi of the genera Aspergillus and Penicillium fungi that is composed of a substituted dihydroisocoumarin moiety amide linked to L-phenylalanine.205 Dietary feeding of OTA induces renal adenomas and carcinomas in male rats.206 Consequently, its classification by the International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans207 has fostered much research on its risk to human health following ingestion of contaminated food.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION OH Cl

OH

Cl

OH

Cl

Cl

209 OH

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

PCP

2,4,6-TCP

2,4,5-TCP

2,4-DCP

O

OH

OH O

O

N H

O CH3 X

OTA: X = Cl OTHQ: X = OH OTB: X = H

Fig. 16 Structures of chlorophenols and metabolites of ochratoxin A (OTA) with an OH group [ochratoxin hydroquinone (OTHQ)] and a hydrogen atom [nonchlorinated OTA (OTB)].

Pathways for the genotoxicity PCP are outlined in Scheme 15. In the presence of cytochrome P450, PCP undergoes oxidative dechlorination to form tetrachlorobenzoquinone (TCBQ) that reacts with dG and other DNA bases to form benzethenotype adducts.202,208,209 Activation by enzymes with peroxidase activities furnishes the

OH Cl Cl

Cl5 Cl

DNA

N

HO

N

NH2

O

Fe3+

OH C8-CPCP

Reductive dehalogenation Fe

NH

HO

Cl

•

O N

2+

O O

OH Cl

Fe2+ O 2

Cl

Cl

GSSG

GS•

N

Cl DNA

N

HO

Cl

OH

Benzetheno adduct Peroxidase/H2O2 Cl

GSH

• O Cl

Cl

Cl

Cl

Cl

Cl Cl

Phenolic radical

DNA

Cl

Cl N

O

N

N

NH

O

HO

NH2

O OH C8-OPCP

Scheme 15 Proposed mechanisms for DNA adduct formation by PCP.

Cl

N H

O

Cl

N N

O

O TCBQ

Cl PCP GS– O2

Cl Cl

Cl

Fe3+ O2– •

CYP450

O

210

R.A. MANDERVILLE

PCP-phenolic radical that possesses an absorption spectrum in H2O at 440 nm and decays via second-order kinetics with kd = 9.1  108/M/s, as evidenced by pulse radiolytic studies.210 The PCP-phenolic radical can attach covalently to the C8-site of dG to generate the C8-OPCP adduct.201,202,209 In the presence of GSH, redox cycling of the phenoxyl radical with thiyl radical generation will yield a GSH disulfide anion radical
that can reductively activate O2 to generate the superoxide radical anion O2• that can generate free ferrous iron (Fe2þ).196 Free Fe2þ may also act directly on PCP to cause a reductive dehalogenation process and produce the carbon-centered radical that, if formed, would react with dG to yield the C8-CPCP adduct.204 Thus, bioactivation of PCP by peroxidase enzymes yields radical intermediates that cause oxidative DNA damage and covalent DNA adducts through attachment to the C8-site of dG. Electrophilic benzoquinone (TCBQ) intermediates are produced by cytochrome P450 activation, and TCBQ is known to form covalent adducts with DNA,209,211 which may contribute to PCP-mediated carcinogenesis. For OTA, it is generally accepted that it causes genotoxicity by an indirect mechanism that involves oxidative DNA damage.212,213 The oxidative stress observed in animal tissues from OTA treatment also suggests that OTA-derived electrophiles, such as the OTA phenoxyl radical and OTA quinone (OTQ), would be generated and expected to react covalently with DNA to yield covalent DNA adducts.204 Structure–activity relationships for the photoreactions of OTA analogs provide insight into their chemical reactivity. As outlined previously, the photoreaction of OTA generates the nonchlorinated OTB (Fig. 16), the hydroquinone OTHQ (Fig. 16), and the dG-OTA adduct shown in Fig. 17 that results from attachment of OTA to C-8 of dG with loss of HCl.214 While dG-OTA may stem from a phenoxyl radical intermediate,214 a carbon-centered radical is also possible from a reductive dehalogenation process.204 The nonchlorinated OTB analog does not react with dG and is resistant to photodegradation. The OTHQ analog, which is a known metabolite of OTA,215 reacts with dG to form an adduct with max = 376 nm and [M  H] = 631. The proposed structure for dG-OTHQ shown in Fig. 17 is consistent with its mass and the known tendency of benzoquinone electrophiles to form benzetheno-type adducts.199,200 These results demonstrate that OTA and OTHQ can react with dG, O

OH

OH

O

N H HO HO

OH O

O

O

OH O

N OH

O

O N

O

NH

N N

N

N

N

O

N NH

HO

O

H2N dG-OTA

OH

dG-OTHQ

Fig. 17 Chemical structure of dG-OTA and proposed structure for dG-OTHQ.

STRUCTURAL AND BIOLOGICAL IMPACT OF RADICAL ADDITION

211

which is consistent with the formation of radical and benzoquinone intermediates in DNA adduction, in analogy to the established chemistry of chlorinated phenols (Scheme 15). That OTB cannot react covalently with dG following photoirradiation stresses the importance of the C5 chlorine atom of OTA for covalent attachment and provides a rationale for the decreased toxicity of the OTB analog.204 Evidence for a direct mode of OTA-mediated genotoxicity involving covalent DNA adduction has been derived from the 32P-postlabeling method.216,217,218 These studies have shown that the dG-OTA adduct (Fig. 17) is the primary OTA– DNA adduct identifiable in DNA isolated from the kidney of rat and pig following OTA treatment. More recent 32P-postlabeling results also suggest that dG-OTHQ adducts may play a role in OTA-mediated genotoxicity.219 Figure 18 shows the adduct pattern for OTHQ by autoxidation (Fig. 18A) versus the adduct pattern generated by OTA following treatment with pig kidney microsomes/NADPH (Fig. 18B).218 With microsomal activation, OTA yields two clear adduct spots (indicated by the bold arrow) that possess the same migration properties as two of the adduct spots detected from the autoxidation of OTHQ. Like other hydroquinones, OTHQ undergoes autoxidation (t1/2 = 11 h at pH 7.4, 37oC) to generate the superoxide radical anion and the quinone electrophile OTQ.220 Thus, OTHQ is more reactive than OTA, which is not oxidized by O2 alone and does not generate DNA adducts in the absence of metabolic activation. The adduct spots detected in Fig. 18 do not comigrate with the dG-OTA adduct (Fig. 18C), which migrates faster on the TLC plate, suggesting that the OTHQ-mediated adducts are less polar. The results presented in Fig. 18 show a direct correlation between DNA adduction mediated by the autoxidation of OTHQ with DNA adduction by OTA following microsomal activation and suggest that the quinone electrophile OTQ is involved in covalent modification of DNA. Overall, these results highlight the role played by benzoquinone and radical electrophiles in DNA adduction by phenolic toxins.218

(a)

(b)

(c)

(d)

C8

OTHQ

OTA

dG-OTA

Fig. 18 32P-postlabeling analysis of salmon sperm DNA following incubation for 24 h at 37C in 20 mM tris–HCl pH 7.4, 0.1 M KCl with (a) OTHQ (1 mM) in the absence of added cofactors and (b) OTA (1 mM) in the presence of pig kidney microsomes and NADPH; (c) Autoradiogram of postlabeled C-C8 dG-OTA standard; (d) numbering of DNA adducts observed in (b) and (c); C8 corresponds to standard adduct. See 218.

212

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R.A. MANDERVILLE

Summary

Radical species are an important family of reactive intermediates that give rise to single- and double-strand DNA breaks and also lead to covalent modification of DNA bases including cross-link formation. The C-8 site of purines, especially dG, is most susceptible to radical attachment, as exemplified by the in vivo detection of 8oxo-dG that results from hydroxyl radical attack. Recent advances have uncovered the tendency of 8-oxo-dG to undergo further oxidation to afford Sp adducts (among others) that enhance the biological impact of 8-oxo-dG. Other C8-dG adducts, such as those with C-8 phenolic groups, can undergo oxidative polymerization reactions to afford new biomaterials through the intermediacy of phenoxyl radicals. Such modified bases are also expected to form covalent cross-links in duplex DNA, given the tendency of phenoxyl radicals to attach to C-8 of dG, and in analogy to DNAderived alkyl radicals formed from -radiolysis that form cytotoxic lesions derived from covalent cross-linked material. Covalent DNA adduction by carcinogenic PAHs is facilitated by radical cation formation that can form C-8 purine adducts. The fungal carcinogen, OTA, has also been shown by the 32P-postlabeling method to form a C8-dG adduct in vivo through the intermediacy of radical species. As in vivo LC/MS evidence for such DNA adducts becomes available, it is expected that efforts to understand their structural and biological impact will take on the intensity that is currently devoted to DNA adducts derived from direct radical addition reactions by the hydroxyl and nitrogen dioxide radical.

Acknowledgments The research in the author’s laboratory was supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canada Foundation for Innovation, the University of Guelph, and the Ontario Innovation Trust Fund. I also acknowledge with gratitude the contributions of my coworkers to these studies. Their names appear in the references; special thanks are due to Drs Jian Dai (Wake Forest University, Winston-Salem, North Carolina), Annie Pfohl-Leszkowicz (National High School of Agriculture, Toulouse, France), and Stacey D. Wetmore (University of Lethbridge, Alberta, Canada).

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Recent studies of persistent carbodications V. PRAKASH REDDYa and G.K. SURYA PRAKASHb a

Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA b Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, USA 1 2 3

Introduction 220 Gitonic methylium-based carbodi- and polycations 221 1,2-Carbodications 222 Tetrakis(dimethylamino)ethylene dication 224 Acetyl dication 224 1,2-Dicarboxonium ions 225 Protio-methyleniminium dications 225 4 1,3-Carbodications 226 Malonyl dicarboxonium ion 226 Cyclopropyl and phenyl group-stabilized 1,3-carbodications 226 1,3-Adamantanediyl dications 229 Trimethylenemethane dications (Y-conjugated carbodications) 229 5 1,4-Carbodications 231 2,5-Dimethylhexane-2,5-diyl dication 231 Bicyclo[2.2.2]octane-1,4-diyl dications 231 Cyclohexane-1,4-diyl dications 232 1,4-Diaryl-1,4-cycloalkylcarbodications 232 1,6-Diamantanediyl dication 233 anti-Tricyclo[4.2.1.1]-deca-3,7-diene-9,10-diyl dication 233 endo-3,10-Dimethyltricyclo[5.2.1.0]deca-4,8-dien-3,10-diyl dication 235 trans-Cyclopropane-1,2-diyl bis(cyclopropylmethylium) dication 235 6 1,5-Carbodications 236 1.3-Adamantanedimethylium dications 236 Bicyclo[3.3.3]undecane-1,5-diyl dication (manxyl dication) 238 A sulfur-stabilized carbodication 238 7 Benzyl dications 239 Benzene-derived dienyl, allylic dications 239 Fluorenyl dications 240 8 1,6-Carbodications 242 1,6-Dodecahedryl dication 242 Diamantane-4,9-diyl dication 243 3,30 -(1,10 -Biadamantyl) dication 243 Cubyl-1,4-dicarboxonium ion 244 9 m-Hydrido dications 245 10 Aromatic dications 247 Pagodane dications 247 Dehydroadamantanediyl dication 249 2,10-para[3,5]octahedranedimethyl dication 250 Bis(Tropylium) dications 251 1,2:3,4:5,6:7,8-Tetrakis(bicyclo(2.2.2)octyl)cyclooctatetraene dication 253 Tetrakis(Bicyclo[2.2.2]octanonaphthalene dication 254 219 ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 43 ISSN: 0065-3160 DOI: 10.1016/S0065-3160(08)00006-3

 2009 Elsevier Ltd. All rights reserved

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Trihydroxycyclopropenium ion and homologous ions 254 Hogeveen dication [C6(CH3)6]2þ 256 11 Oxygen-stabilized carbodications 257 References 258

1

Introduction

Persistent carbodications, bearing two positive charges in the same molecule, show unusual behavior in their reactivity and spectral characteristics.1 Carbodications show uniquely high reactivities in electrophilic substitution reactions,1,2 and thus superelectrophilic activation of carbomonocations in suitable cases have direct synthetic applications.3 Interestingly, the 13C NMR spectra of carbodications show relatively shielded absorptions for the cationic centers as compared to those of the corresponding carbomonocations, which is contrary to the normal expectation.1,2 The shielded absorptions are reflective of the greater charge delocalization in these species, as compared to those of their corresponding carbomonocations. Due to the electrostatic repulsion between the cationic centers, the stability of these carbodications and polycations depends on the number of intervening carbons between the cationic centers and is enhanced by the electron releasing groups directly attached to the cationic centers. Some of the carbodications owe their stabilization to aromaticity. A unique three-dimensional aromaticity was demonstrated in one case, the 1,3-dehydro-5,7-adamantanediyl dication (vide infra). The characterization of the carbodications has been achieved mostly by using 13C NMR spectroscopy, and therefore the present review emphasizes the 13C NMR spectra in their analysis. Onium di- and polycations involving heteroatoms have been reviewed earlier.4 Heteroatom-centered dications such as disulfonium and diselenonium dications have been recently reviewed, and no attempt is made to discuss these dications topic in this review.5 A review by Schleyer and coworkers addresses the detailed theoretical aspects of the 2þ carbodications.6 Among the simplest carbodications, CH2þ 2 and CH4 have been generated only in the gas phase and their structures probed by mass spectrometry and high-level theoretical calculations. Interestingly, the methane dication, CH2þ 4 , is an anti-Vant Hoff’s molecule, having a C2v symmetry with a planar trivalent, tetracoordinated sp2 hybridized carbon and a vacant p-orbital orthogonal to the plane
of the molecule. It is essentially resembles a complex of methylenedication CH2þ with a 2 hydrogen molecule.7,8 The current trend is that the structures of the stable carbocations are usually established by comparing the experimentally observed 13C NMR chemical shifts with those obtained by ab initio Individual Gauge for Localized Orbitals (IGLO) and more recently by ab initio Gauge-including Atomic Orbitals (GIAO) calculations for appropriately optimized structures. A text book example of its application is in the case of the truly bridged dehydroadamantanediyl dication, in which case, an excellent correlation of the experimental and theoretical chemical shifts was obtained for the three-dimensional bridged structure, but not for the charge-localized species. The

RECENT STUDIES OF PERSISTENT CARBODICATIONS

221

pentacoordinated CH3þ 5 trication is a planar D5h symmetric species at MP2/6-31G* and QCISD(T)/6-31G* caculations.9 Hexacoordinated methylium dication, CH2þ 6 , and heptacoordinated methylium trication, CH3þ , were shown to have minimum energy 7 structures (C2v and C3v, respectively).10,11 The isoelectronic boron analogs of these 2þ carbocations, BHþ 6 , and BH7 were also shown to be stable by the same methods, and the former monocation was even observed in the gas phase. The carbon-centered organometallic analogs of CH6þ 2 were also synthesized and characterized by singlecrystal X-ray crystallography (vide infra).

2

Gitonic methylium-based carbodi- and polycations

The prototypical pentacoordinated carbocation, the parent nonclassical carbocation, CHþ 5 , 1, has been extensively studied in the gas phase as well as by theoretical calculations.10,12,13 Among the higher coordinate carbocations, the hexacoordinated methylium dication, 2, and heptacoordinated trication, 3, were also shown to be energy minima by ab initio calculations. High-level ab initio calculations show that they have C2v and C3v structures, respectively.10 Their isoelectronic boron analogs were also studied. 2+

+ H H

H C

H H

H

H

H

H

H

C

H C

H

H

H

H

3+

H H

H

CH5+ (Cs)

CH62+ (C2v)

CH73+ (C3v)

1

2

3

Schmidbaur and coworkers have prepared the pentaaurylated carbomonocation (4), an isolobal analog of CHþ 5 , and hexaaurylated carbodication (5), the isolobal 14–17 analog of CH2þ . From X-ray crystallographic studies, it was shown that the 6 former is trigonal planar, while the latter is octahedral. The isolation and study of these hypercoordinated organometallic species greatly contributed to our knowledge of hypercoordinated carbocations.

+ AuPPh3 AuPPh3 Ph3PAu

2+ Ph3PAu

AuPPh3 AuPPh3 C

C Ph3PAu

AuPPh3

AuPPh3 AuPPh3

4

5

AuPPh3

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V.P. REDDY AND G.K.S. PRAKASH

þ The isoelectronic boron analog of the hexacoordinated CH2þ 6 dication, BH6 , 6, þ has been recently generated in the gas phase by the reaction of BH4 and H2 and characterized under fairly high-pressure conditions in flowing afterglow-selected ion flow tube (FA-SIFT) apparatus, by DePuy and coworkers.18,19 The ion can be considered as a complex formed by the reaction of BHþ 2 with two dihydrogen molecules. The BHþ , 6, is calculated (at MP2(fu)/6-311G(d,p)//MP2(fu)/66 311G(d,p) level) to have approximate tetrahedral geometry, with two corners of the tetrahedron being occupied by the dihydrogen species involving two-electron three center bonds.20 The observation of the ion in FA-SIFT, by itself, shows that its dissociation to BHþ 4 and H2 is unfavorable by at least 8–10 kcal/mol. Ab initio calculations indicate the latter bond energy ðBHþ 4 H2 Þ as 17.6 kcal/mol. Further protonation of the CH3þ , 3, would give CH4þ 7 8 , 7, which was computationally elusive species, that is, a minimum energy structure could not be located for this species at the highest theoretical levels used. The analogous diprotonation of 3þ þ BHþ 6 , however, gives BH8 , 8 (through BH7 ), which is an energy minimum, and 21 has a propellar shape (Td). It can be viewed as a tripositively charged boron B3þ, attached to four dihydrogens in a tetrahedral arrangement.

+ H

H H2

+

BH2

BH4

CH73+ + H+ 3

3

+

H2

H H

H 2 H+

B H

H H

H H B

H

H

H H

BH6+ (Td), 6

BH83+, 8

CH84+ 7 (Computationally elusive)

1,2-Carbodications

The elusive ethylene dication (C2H4)2þ has been observed in the gas phase, and its potential surface has been well characterized by ab initio theory at MP3/6-31G**/631G* level. The perpendicular conformer (D2d) has been shown to be lower in energy than the planar conformation (D2h) by an unusually large value, 28.1 kcal/mol.6,22 The other possible isomeric carbodications also have very low-activation barriers for the conversion into the perpendicular conformer.22 A range of substituted ethylene dications have also been calculated by ab initio 2þ 2þ 2þ methods. The dications C2 F2þ 4 , C2 ðOHÞ4 , C2 H2 ðNH2 Þ2 , and C2 ðOHÞ2 ðNH2 Þ2 2þ 2þ prefer the planar geometries, whereas C2 ðNH2 Þ4 and C2 ðSHÞ4 prefer the twisted (nearly perpendicular) geometries.22 The results can be explained in terms of the competing effects of steric repulsion between the substituent groups and the conjugative interactions of the lone pair of electrons with the vacant p-orbitals.

RECENT STUDIES OF PERSISTENT CARBODICATIONS

223

The tetraphenylethylene dication (10, R = H) and tetraanisylethylene dication (10, R = OCH3) were studied under superacidic conditions.23 The Magic Acid (SbF5/ FSO3H) solutions of these dications were obtained from the tetraarylethylenes (9) at low temperatures (<–80C). The charges in these dications are extensively delocalized into the aromatic rings, as shown by the deshielded 13C NMR absorptions of the ortho- and the para-carbons of the aromatic rings. At higher temperatures, they yield 9,10-diarylphenanthrene dications (11). The formation of the carbodication is also indicated by the fact that the difference in the sums of the 13C chemical shifts of all the carbons between the dication and the substrate is 319.9 ppm (i.e., d13C RH2þ –d 13C RH = 319.9), which is twice the expected shift difference for a carbomonocation. The carbodication 10 cannot be obtained from the ionization of the corresponding 1,2-diol or dichloride as it results in the formation of 9,10diphenylphenanthrene.

R

R

SbF5/FSO3H

R

R

R +

SO2ClF –78°C

R

R

9

R

R

R

2+

–40 to –20°C

+

R

R

10

11

Recently, Kochi and coworkers24 have isolated the tetraanisylethylene dication as a crystalline compound (10, R = OCH3) by electron exchange of tetraanisylethylene with aromatic cations, or antimony (V) oxidants, at low temperatures. Reaction of the olefin 9 with one mole equivalent of the 9,10-ethoxyanthracene radical cation gives the radical cation 10a, whereas reaction of 9 with two mol equivalents the aromatic radical cation gives the dication 10. The latter could be obtained as a crystalline solid at low temperature using the reaction of the olefin 9 with three mole equivalents of antimony pentachloride. The dication 10 is severely twisted as compared to that of the corresponding radical cation 10a, as shown by its singlecrystal X-ray diffraction. This twisting enhances the delocalization of the positive charge into the neighboring aromatic rings and thereby diminishes the electrostatic repulsion of the adjacent carbocationic centers. At the same time, the steric repulsion between the neighboring aryl groups is also diminished.

R 9

3 SbCl5

R

+

(SbCl5–)2

+ R

R 10

+

SbCl3

224

V.P. REDDY AND G.K.S. PRAKASH

OEt

•+

•+

R

•+

OEt

R

OEt

OEt

9

10 R

R 10a

TETRAKIS(DIMETHYLAMINO)ETHYLENE DICATION

The oxidation of the tetrakis(dimethylamino)ethylene (12) with I2 gives the 1,2-dication (13), which has been characterized by single-crystal X-ray structure determination.25 The X-ray structure shows that it is twisted around the central C—C single bond by 53, as compared to a twist angle of 19 in the precursor olefin. The charge is extensively delocalized among the four nitrogen atoms. Each of the four nitrogen atoms has þ0.45 units of charge, leaving only þ0.2 units of charge on the central C—C bond. The distortion from the plane caused by dication formation, termed as cyanine distortion,26 was also observed for other ethylene dications R2Cþ—þCR2 (R = NMe2) and 1,1,2,2tetrathiophenyl dication, 14. The Cþ—Cþ single bond length of 1.50 A0 also is in agreement with the dication formation. The olefin 12 has an ionization potential of only 6.13 eV, suggesting that it can even be ionized in pure water!27 R

R Me2N

NMe2

Me2N

NMe2 12

I2

Me2N + Me2N

NMe2 + NMe2 13

S

S +

+ S

S

R R R = H, CH3, SCH3 14

ACETYL DICATION

Acetylium hexafluoroantimonate reacts at enhanced rates with benzene and chlorobenzene in CF3SO3H as compared to CF3COOH. These results were explained by Shudo in terms of the intermediate protonated acetylium dication (15). The protonation of the already electron-deficient acetylium cation (protosolvation) makes it a superelectrophile in its reactions with arenes. Theoretical calculations by Olah and coworkers show that the C—H-protonated form (16) is 18.9 kcal/mol less stable than the O-protonated form (15). It was shown that the 13C NMR chemical shifts (at the GIAO-MP2 theoretical level) would be very similar for the mono- and dications. However, the mono- and the dications differ significantly in the 17O NMR chemical shifts (at the GIAO-MP2 and IGLO theories). The GIAO-MP2 calculated d17O for the monocation is 340.8, whereas it is 190.2 for the dication.28 The experimental 17O NMR data are lacking for this system, and hence a clear-cut distinction among the mono- and dications cannot be verified experimentally for this species.

RECENT STUDIES OF PERSISTENT CARBODICATIONS

H H

C

+ C

H

H H

O +

225

H + C

O C+

H

H 15

16

1,2-DICARBOXONIUM IONS

The dicarboxonium ions would be useful intermediates for the diacylation of aromatics. The 1,2-dicarboxonium ion (oxalyl dication, 17) has yet to be experimentally obtained. The ionization of the oxalyl fluoride in SbF5 presumably forms the donor–acceptor complex, 18, which spontaneously decomposes to CO and COF2.29,30 The expected oxalyl dication (OCCO)2þ, 17, was not observed although theoretical calculations at MP2/6-31G* level indicate 17 to be a minimum on the potential energy surface. O C F

F C

n SbF5/SO2ClF

FCOCO+ Sbn F5n+1–

O

CO + COF2

18

SbF5 /SO2ClF + + O C C O 17 PROTIO-METHYLENIMINIUM DICATIONS

The protonation of the methyleneiminium cation gives rise to the superelectrophilic methyleniminium dication, 19, which is a gitonic 1,2-dicationic species (carbenium ammonium species). Such a carbodication has been observed by charge stripping mass spectrometry by Schwarz and coworkers.31 Olah and coworkers have shown by theoretical calculations that the carbenium ammonium species, 19a, is 27.6 kcal/mol more stable than the three-center two-electron (3c-2e) bonded structure, 19b.32

+ H2C NH2

+ H3C

H+

+ NH2

19 H + + H C N H H H 19a

H C

H + H H 19b

+ H N H

226

V.P. REDDY AND G.K.S. PRAKASH

The electronic structures and energies of superelectrophilic dications derived from protonation of methyl and dimethylmethyleniminium ions were also calculated at the ab initio (MP2/6-311þG**) level.33 In each of these cases, the nitrogen-protonated form is the most stable structure. It is interesting to note that the N-protonated isopropyleniminium (Me2CHTNH2þ) is isoelectronic with the tert-butyl cation, 20. Whereas in the tert-butyl cation, 20, the carbocation center is stabilized by C—H hyperconjugation; the cationic center of the isopropylammonium dication, 21, is further destabilized by the adjacent ammonium group. The C—H-protonated tertbutyl cation, 22, is similarly destabilized prompting enhanced hyperconjugative interactions from the adjacent methyl groups in the latter two carbocations. The GIAO-derived d13C values for the carbocationic center are also very similar for the latter two cations in agreement with the expectation.

H3C

CH3 + CH3

+ H3N

20 δ13C

C+

H H+ H C H

CH3 + CH3 21

δ13C

358.5

C+

CH3 + CH3 22

δ13C

304.0

C+ 319.6

GIAO-MP2/tzp/dz/MP2/6-311+G** calculated δ13C values

4

1,3-Carbodications

MALONYL DICARBOXONIUM ION (23)

Malonyl fluoride forms the diacyl cation (24), which is in equilibrium with the donor– acceptor complex (23). The higher homologs of the dications are quite stable.29 δ– F5Sb

δ+ O F 23

C + O

SbF5 +O

C

C

– O + (SbF6 )2

24

CYCLOPROPYL AND PHENYL GROUP-STABILIZED 1,3-CARBODICATIONS

The attempted preparation of an acyclic 1,3-carbodication by ionization of 2,4-dichloro2,4-dimethylpentane in SbF5/SO2ClF or from 2,3,3,4-tetramethyl-2,4-pentanediol (25) using FSO3H-SbF5 was unsuccessful. The former reaction cleanly gave the tetramethylallyl cation while the latter reaction resulted in the disproportionation of the initially formed monocation (26), giving the equilibrating isopropyldimethylmethylium cation

RECENT STUDIES OF PERSISTENT CARBODICATIONS

227

(27) and O-protonated acetone (28) in the strong acid medium used.23 An earlier review describes these and other attempts of preparation of such 1,3-carbodications.33

H+

FSO3H/SbF5 SO2; –78°C

OH OH

+

25

+

+

+ OH +

OH

26

28

27

The more recent efforts of generating the 1,3-carbodications using cyclopropyl and phenyl groups as potential stabilizers mostly gave either the allyl cations (e.g., 31 from 29) or the disproportionated species (e.g., 33 and 34 from 32). However a 1,3-dication, 1,3-propanebis(dicyclopropyl)-1,3-diyl dication (36), was prepared by ionization of the corresponding diol (35) using Magic Acid at low temperatures. The dication, 36, shows a 13 C NMR chemical shift for the cationic center at d13C 262.9 and was stable at temperature below –90C.34 The latter absorption is shielded by 12 ppm as compared to the corresponding monocation, dicyclopropylethyl cation, indicating the increased delocalization of the charge into the neighboring cyclopropyl groups in the carbodication. Such charge delocalization is also revealed in the relatively deshielded d 13C for the cyclopropyl carbons, as compared to the related carbomonocation, 1,1dicyclorpopylethyl cation (Daverage = 13.8, 15.1 for cyclopropyl methine and methylene carbons, respectively). Even though substantial charge is delocalized into the neighboring cyclopropyl groups, this carbodication does not exist as nonclassical, s-charge delocalized species, which is confirmed by the theoretically calculated structure as well as by the chemical shift additivity criterion as proposed by Schleyer and coworkers.35 The difference in the summation of the 13C chemical shifts of the carbodication and the corresponding hydrocarbon is 901, which is 450 ppm per unit positive charge. Typically, nonclassical carbocation has this chemical shift difference of about 250 ppm or less.

Ph Ph

FSO3H/SbF5

Ph Ph OH OH

SO2ClF, –78°C

Ph

Ph Ph

29

HO

+ Ph

Ph +

31

30

OH

+

FSO3H/SbF5

OH

33 +

HO

OH

+

34 +

FSO3H/SbF5 SO2ClF, –78°C

35

+

SO2ClF, –78°C

32

36

Ph + Ph Ph

228

V.P. REDDY AND G.K.S. PRAKASH

An aromatically stabilized carbodication, 37, was prepared by Komatsu and coworkers in strongly acidic media.36 The ion undergoes deprotonation to give a conjugated monocation, 38, in less acidic media. The corresponding distonic carbodications with 1,4-phenylene, 1,5-naphthalene, and 1,8-naphthalene spacer groups (39, 40, and 41) have been prepared and well characterized.37–39a

Ph

+

Ph

+

Ph

Ph

+

Ph Ph

Ph

Ph 38

37

Ph

Ph + R

R +

+

R

R

Ph

+ 39; R = Ph, H

Ph

Ph

40

+

+

Ph

Ph

Ph

41

The p-phenylene-bis(diphenylcyclopropenium) dication, 39 (R = H), was found to have a pKRþ value of –1.1, that is, the dication is less stable than the triphenylcyclopropenium cation (pkRþ = 2.8) by 1.7 pK units, again owing to charge–charge repulsion in this dication.39b The oxygen-bridged carbodications analogous to 29, bis(dipropyl)dicyclopropenium ether, ditropylium ether, and dipyridylium ether ditriflates (42, 43, and 44), have been synthesized from the reaction of triflic anhydride with dipropylcyclopropenone, tropone, and N-methyl-2-pyridone, respectively.40 These carbodications, unlike 37, are quite stable for isolation and characterization. n-Pr

n-Pr

O

Tf2O

n-Pr

Pr-n O

+

+ 42

n-Pr O

Tf2O

+

O

43

Pr-n +

2 (OTf)–

RECENT STUDIES OF PERSISTENT CARBODICATIONS

+ O N CH3

Tf2O N O CH3

229

+ N CH3

2 (OTf)–

44

1,3-ADAMANTANEDIYL DICATIONS

The 1,3-adamantanediyl dication (47) could not be prepared from the ionization of the 1,3-difluoroadmantane (45) in a variety of superacids. Only the monocation monodonor–acceptor complex (46) was obtained. In 47, the two positive charges are separated by just one carbon, thus precluding its formation in the absence of extra neighboring group stabilization.41a

F +

+ SbF5/SO2ClF

F

or other superacids

45

δ+

δ–

F

SbF5

+

46

47

Attempted preparation of the other adamantane 1,3-diyl dications was also futile. Thus, ionization of 2-methyl-5-bromoadamantane in FSO3H-SbF5/SO2 gave only the monocation donor–acceptor complex (48). Even the ionization of the 5-bromo-2adamantanone gave the carboxonium donor–acceptor complex (49).41a

δ13C 314.3 + OH

+ CH 3 δ+ Br

+ Br

δ– SbF

δ13C 92.6 δ– SbF

5

5

48

49

TRIMETHYLENEMETHANE DICATIONS (Y-CONJUGATED CARBODICATIONS)

The trimethyl trihydroxy derivative of the trimethylenemethane dication (50) was observed under stable ion conditions.41b The dication 50 is the first Y-conjugated dication system experimentally observed. However, the question of the effect of the Y-conjugation

230

V.P. REDDY AND G.K.S. PRAKASH

on its stability cannot be answered by this example alone, as it owes extra stability due to charge delocalization into the adjacent hydroxyl groups on the cationic centers.41b Analogous sulfur-stabilized Y-shaped carbodications, such as 51, were also reported.41c

S

2+

OH

Me

S +

OH

HO

S

+ S

S

Me Me

S 51

50

Olah and coworkers have prepared the (hexaphenyltrimethylene)methane dication (53), a Y-conjugated dication, by the ionization of the precursor diol, 52, using FSO3H in SO2ClF.41d The dication is unusually crowded and stable up to at least –20C. The 1H and 13C NMR spectra [d13C 208.5 (s, C2), 145.5 (s, C1), 144.1 (d, ortho), 142.4 (d, ortho0 ), 141.5 (s, ipso), 137.5 (d, para), 131.21 (d, meta), 131.18 (d, meta0 )] show that both the ortho- and the meta-carbons of the phenyl ring are nonequivalent, indicating the high steric congestion in this dication. The 1H NMR also shows separate absorptions, three triplets (m-, m0 -, and p-H) and two doublets (o- and o0 H), between 6.4 and 7.6, for the five distinct phenyl hydrogens. The NMR spectra clearly show that all of the six phenyl groups are identical indicating the symmetrical charge distribution. The d 13C of the cationic center (208.5) of 53 is quite similar to that of the trityl cation (210.9). If the Y-aromaticity due to the 2p-electron Y-conjugated system plays a major role in the stabilization of the cation, a more shielded cationic center’s absorption would be expected. The hexa-CF3 derivative of the cation (55) was also prepared, and it was stable only at very low temperature (–90C). At higher temperatures, it rearranges to the indenyl cation (56).

Ph Ph HO

Ph

Ph

Ar HO

Ph Ph 53

Ar

Ar

Ar

Ar OH

2+

Ph

Ph

Ph OH Ph Ph 52

Ar

Ph

Ar

SO2ClF –120°C

F3C Ar

Ar

Ar = p-CF3-C6H4

2+

Ar

Ar

FSO3H

+

Ar

Ar

55

56

54 Cl

Cl 57

SbF5/SO2ClF –120°C

Ar Ar

2+ 58

Ar + Ar

RECENT STUDIES OF PERSISTENT CARBODICATIONS

231

The carbodication, 55, also displays similar 13C NMR spectrum as that of the (hexaphenyltrimethylene)methyl dication (53), which is quite unexpected based on the electron-withdrawing nature of CF3 groups [(d 13C 209.8 (s, C2), 146.7 (s, C1), 145.6 (d, ortho), 143.1 (s, ipso), 142.4 (q, para), 138.8 (d, ortho0 ), 128.4 (d, meta), 128.1 (d, meta0 ), and 121.4 (q, CF3)]. These results may suggest the involvement of aromatic Y-stabilization in the carbodications 53 and 55. However, Y-aromaticity was shown to be unimportant in these cations, as several attempts of preparation of analogous dications, with one or more phenyl groups replaced by H, CH3, or cyclopropyl groups, were not successful. They usually spontaneously rearranged to the allenyl cations, involving the Friedel–Crafts alkylation of the transiently formed allyl dication. Attempted preparation of unsubstituted trimethylenemethane dication, 58, by treatment of 2-(chloromethyl)-3-chloropropene (57) with SbF5 in SO2ClF at –120C was also unsuccessful, further showing that the Y-aromaticity is unimportant in this system.

5

1,4-Carbodications

2,5-DIMETHYLHEXANE-2,5-DIYL DICATION

The ionization of 2,5-dichloro-2,5-dimethylhexane (59) using SbF5/SO2ClF gave the symmetrical dication, 60 [d13C 331.3 (Cþ), 52.7 (CH2), and 47.1 (CH3)]. The cationic center of 60 is relatively shielded as compared with that of the analogous monocation, ethyldimethylmethylium cation (d 13C 333.8). An earlier review covers these and related dications.1b,42

Cl

+

SbF5 /SO2ClF +

–78°C

Cl 59

60

BICYCLO[2.2.2]OCTANE-1,4-DIYL DICATIONS

The bicyclo[2.2.2]octane-1,4-diyl dication, 61, and its tricyclopropane derivative, 62, could not be prepared under stable ion conditions even though they were attempted under various reaction conditions.43,44 The possible existence of these carbodications was supported by Modified Neglect of Differential Overlap (MNDO) calculations. +

+ +

+

61

62

232

V.P. REDDY AND G.K.S. PRAKASH

CYCLOHEXANE-1,4-DIYL DICATIONS

All attempts of preparing the parent secondary dication (63), anti-tricyclo(5.1.0.03,5) octa-2,6-diyl dication, were unsuccessful. The dication was originally anticipated to undergo the circumambulatory rearrangement, as in cyclopropylmethyl cation rearrangements.45a However, it spontaneously rearranged into the thermodynamically more stable homotropylium cation (64).

+ +

+ +

+

+

+

63

64

Several 1,4-disubstituted derivatives of the dication, 63, were successfully prepared. The 1,4-diphenyl,1,4-dimethyl,1,4-dicyclopropyl-substituted derivatives of carbodication 63 (65, 66, and 67) are exceptionally stable. The 1,4-dimethyl-1,4cyclohexyl dication, devoid of the adjacent cyclopropyl groups, could not be prepared. The carbocationic center in all these dications are somewhat shielded as compared to their monocations. The 13C NMR chemical shifts of the carbocationic centers for the dications 65, 66, and 67 are 235.4, 293.4, and 260.8 ppm, respectively. The diprotonated anti-tricyclo(5.1.0.03,5)octa-2,6-dione, 68, may be treated as a dicarboxonium ion, instead of dihydroxy dicarbenium ion, since the cabronyl carbon is shielded by only 25.2 ppm, much smaller than that observed for the protonated cyclohexanedione (34 ppm). The para carbons of the phenyl substituents in carbodication 65 are relatively shielded by about 5 ppm from that of the parent 1,4-diphenylcyclohexane-1,4-diyl dication showing relatively less delocalization of the charge into the aromatic rings.

+

+ +

65

CH3

+ CH3 66

+ OH

+ +

67

OH + 68

1,4-DIARYL-1,4-CYCLOALKYLCARBODICATIONS

The 1,4-diaryl-1,4-cyclohexanediyl dications (69) and 2,5-diaryl-2,5-norbornanediyl dications (70) are essentially classical, charge-localized species as evident by their

RECENT STUDIES OF PERSISTENT CARBODICATIONS

233

13

C NMR spectra.45b Thus, a plot of the dC1 versus dC3 showed an excellent linear fit with a wide variety of substituents indicating the regular carbenium ion nature to these species. In case of the corresponding carbomonocations, the 2-aryl-2-norbornyl cations, significant deviation from the linearity was observed due to the onset of nonclassical s-delocalization. Due to the charge–charge repulsion in the dications, the charges are extensively delocalized into the aromatic rings.

Ar + Ar + + Ar

+ Ar 69

70

1,6-DIAMANTANEDIYL DICATION

The ionization of 1,6-dihalodiamantane (71) in SbF5/SO2ClF or other superacids under various conditions gave only the monocation monodonor–acceptor complex (e.g., 72), and the 1,6-dication, 73, was not observed.45c

X SbF5/SO2CIF

X

X = Br, F 71

δ+ X δ– SbF

+

+ +

5

72

73

anti-TRICYCLO[4.2.1.12,5]DECA-3,7-DIENE-9,10-DIYL DICATION

The anti-tricyclo[4.2.1.12,5] deca-3,7-diene-9,10-diyl dication (75) is a bishomoaromatic system. The corresponding parent monocarbocation, the bishomocyclopropenium cation, 76 (1-cyclopent-3-ene cation), is not known experimentally despite extensive efforts.42,46 The carbodication system 75 once again illustrates the special stabilization involved in the carbodications. The carbodication 75 was prepared from the corresponding diol in SbF5/SO2ClF solution by Prakash and coworkers.45d The dication can be classified as a sandwiched bishomoaromatic dication or a 4p-electron bicyclo (polycyclo)aromatic dication. It can also be viewed as a longicyclic four ribbon 4p-electron [0,2,0,2] aromatic system based on the Goldstein and Hoffman’s criterion.45e However, the observed modestly shielded 13C NMR chemical shifts [(d 13C 52.9 (C9, C10), 131.7 (C3, C4, C7, C8), and 38.1 (C1, C2, C5, C6)] could not be interpreted as due to the longicyclic ribbon aromatic interactions.

234

V.P. REDDY AND G.K.S. PRAKASH

H

OH

δ13C 52.9

δ13C 38.1 +

+

SbF5/SO2ClF Low temp.

+

δ13C 131.7 H

HO 74

75

76

The structure of the sandwiched bishomoaromatic dication was confirmed by theoretical calculations at the HF/6-31G* level. The stabilization of the carbocation was shown to be mainly due to the bishomoaromatic interactions. The long-postulated longicyclic interactions do not contribute to the stability of the cation, as shown by the energies of the following isodesmic reactions:45f

Isodesmic reaction 1

+

+ 2

79 +

Isodesmic reaction 2

+

75

78

77

+ 80

Thus, the isodesmic reaction 1 is more exothermic than that of reaction 2 by 108 kcal/mol. If longicyclic interactions were of any importance, the isodesmic reaction 2 should be more exothermic.45ef The 13C NMR chemical shifts of the dication were temperature-independent ruling out the contribution of the possible equilibrating tricyclic structures (81 and 82). The donor–acceptor monocation (83) can also be rejected based on the symmetry arguments. δ– SbF5 δ+ OH + +

H

+ + + 81

82

83

RECENT STUDIES OF PERSISTENT CARBODICATIONS

235

endo-3,10-DIMETHYLTRICYCLO[5.2.1.02,6]DECA-4,8-DIEN-3,10-DIYL DICATION

The endo-3,10-dimethyltricyclo[5.2.1.02,6]deca-4,8-dien-3,10-diyl dication (85) having both the allylic and the bishomoaromatic cation framework was also generated from the corresponding diol (84) in superacidic media by Prakash and coworkers using FSO3H/SO2ClF at –120C.47 The dication rearranges to the bisallylic dication 86 involving antarafacial 1,3-sigmatropic rearrangements. Isomeric structure 87 could not be convincingly ruled out.

CH3

OH

H 3C

+ FSO3H/SbF5 –120°C HO

+ Warm to –80°C

85

CH3 84

H3C

CH3 +

+

H3C

+ CH3

86

+

+

H3C 87

trans-CYCLOPROPANE-1,2-DIYL BIS(CYCLOPROPYLMETHYLIUM) DICATION

The cyclopropane-stabilized 1,4-dication, 88, was prepared in order to see special effects of the stabilization by the cyclopropyl groups.48 Ionization of the corresponding diol using FSO3H-SbF5/SO2ClF gave the stable carbodication (88), which showed a d 13C for the cationic center at 264.1 ppm. The cationic center is 16 ppm shielded as compared to the analogous monocation, the tricyclopropylmethylium cation (d13C 280.1). The shielding in the dication is typical of most dications and indicates more effective charge delocalization into the cyclopropane rings. The Ca and Ca0 carbons show a single absorption (d 13C 39.3), even at –73C, indicating a very low rotational barrier around Cþ—C1 or Cþ—C2 bonds. The dication also shows reversible temperature-dependent behavior of its 13C NMR; at –50C, all four of the distinct cyclopropyl Cb-methylene carbons coalesced into a single broad peak at d13C 37.3. Upon re-cooling to –73C, the original multiline spectrum was obtained, based on which the barrier to Cþ—Ca (or Cþ—Ca0 ) can be estimated at about 10–12 kcal/mol. It was shown to be a classical carbodication with substantial charge delocalization into the cyclopropane rings. In the related dication with four phenyl ring substituents (89), it was shown to have similarly extensive charge delocalization into the phenyl rings, as well as the central cyclopropane ring.23

236

V.P. REDDY AND G.K.S. PRAKASH

3 +

1

2

+

α′ Ph

α

Ph

Ph

Ph

88

6

+

+

89

1,5-Carbodications

1.3-ADAMANTANEDIMETHYLIUM DICATIONS

The ,,0 0 -tetraphenyl- and ,,0 ,0 -tetramethyl-1,3-adamantanedimethyl dications (90 and 91) were prepared by ionizing their corresponding alcohols in 1:1 SbF5/ SO2ClF at –80C.49a The analogous tetracyclopropyl-derived carbodications, however, could not be prepared. The positive charges of the former dications are extensively delocalized into the substituents to minimize the charge–charge repulsion, since the cationic centers are separated by only three carbons. A comparison of the 13 C NMR chemical shifts of the dication 90 with that of the 2,6-diphenyl-2,6adamantanediyl dication (92) shows that the cationic center of the former is markedly shielded (d13C 245.6 for 90 vs. 252.3 for 92), showing that the cation is better stabilized by delocalization of the charge into the phenyl rings. The tetramethyl-derived carbodication, 91, shows a highly deshielded cationic center, d 13C 324.0, evidently reflecting more localized charge at the cationic center as compared to that of carbodication 90. It is worth noting that the 2,8dimethyladamantane-2,8-diyl dication (93) could not be prepared; the ionization of the corresponding diol gave only the monocation–monooxonium species, 94. The stability of the carbodication, 91, was explained as partly due to the extended hyperconjugation involving the bridgehead C—C bonds and due to the additional hyperconjugation involving the two methyl groups at each cationic center. Thus, the stable dication 93 could not be prepared, evidently due to the ineffective hyperconjugative interaction, involving only one methyl group on the cationic center.41a Prakash and coworkers49b have also prepared a tetracation 95 built around the adamantane skeleton.

R + R

+ R + R R

90; R = Ph (δ13C C+ = 245.6)

R

+

92; R = Ph (δ13C C+ = 252.3)

91; R = CH3 (δ13C C+ = 324.0) 93; R = CH3

+ CH3 + H2O CH3

94

RECENT STUDIES OF PERSISTENT CARBODICATIONS

237

Ph + Ph Ph

+ Ph Ph + Ph

Ph + Ph

95

Olah and coworkers49a also prepared the diacyl dications involving the adamantane framework. The ionization of the bis-1,3-adamantanedicarbonyl chloride, 96, in SbF5/ SO2ClF at –80C gave the corresponding 1,3-adamantanedicarbonyl dication, 97. The carbonyl carbons of the dication (d 13C 147.5) show shielded 13C NMR absorptions with respect to those of the precursor diacyl chloride (d 13C 178.0), implying that the dication exists mostly as dioxonium ion in which the positive charge is extensively localized on the oxygen atoms.

CO+

COCl SbF5/SO2ClF

CO+

COCl 97

96

The 2,6-dicyclopropyl-2,6-adamantanediyl dication, 98, was prepared by the ionization of the 2,6-dicyclopropyladamantane-2,6-diol in 1:1 FSO3H/SbF5/ SO2ClF.41a The secondary dication, 2,6-adamantanediyl dication, however, could not be obtained by this method, reflecting the necessity of stabilizing the positive charges by charge delocalization into cyclopropyl rings. The bridgehead carbons (C1 and C3) show distinct chemical shifts. The hindered rotation due to the cyclopropyl group participation and the distinct C1 and C3 absorptions could also be seen in the monocarbocation, the 2-cyclopropyl-2-adamantyl cation. The cation center in the monocation absorbs at d13C 294.3, while it is at d 13C 277.1 for the dication. The relatively shielded absorptions for the dication implies greater charge delocalization into the cyclopropyl ring.

1+ 3 +

98

238

V.P. REDDY AND G.K.S. PRAKASH

The dissolution of the adamanantane-2,6-dione in 1:4 SbF5 : FSO3H/SO2 gave the 2,6-dihydroxy-2,6-adamantanediyl dication (99). This dicarboxonium ion has more oxonium character than the carbenium character as shown by the much shielded absorption for the carbonyl carbon (d 13C 247.7), relative to the monocarboxonium ion, 100 (d 13C 267.1).41a + OH

+ OH

99

HO +

100

The shielded chemical shift is in turn due to the strong magnetic anisotropy of the sp2-hybridized carbons. All the above dications are definitively classical, nonbridged cations, as also shown by the chemical shift additivity criterion of Schleyer and coworkers.35

BICYCLO[3.3.3]UNDECANE-1,5-DIYL DICATION (MANXYL DICATION)

The manxyl dication (101), a 1,5-carbodication, in which the charge centers are separated by three carbons could be successfully prepared by the ionization of the 1,5dichloromanxane in SbF5/SO2ClF at –78C.50a The carbodication is stable below –50C. The 13C NMR spectrum at –85C shows the following absorptions: d13C 346.2 (s, Cþ), 58.7 (t, JCH = 137.2 Hz, Cb), and 23.5 (dd, JCH = 148.5, 148.7 Hz, Cg ). The doublet of doublets for Cg carbons indicate that the conformational equilibrium involving the flipping of the methylene groups is frozen out at –85C. The manxyl monocation shows a d 13C for Cþ at 356.3 ppm, which is about 10 ppm deshielded as compared to that of the dication, again showing more charge dispersal in the dication. The carbocationic center of the dication is highly deshielded (d13C 346.2). It is even more deshielded than that of the illustrative classical carbocations, tertbutyl cation (d13C 329) and 1-adamantyl cation (d 13C 299.8), further indicating its highly charge-localized nature. + + 101

A SULFUR-STABILIZED CARBODICATION

Miller and coworkers50b have recently prepared a sulfur-stabilized carbodication, 1,3,5,7-tetramethyl-2,4,6,8,9-pentathiabicyclo[3.3.1]nonane-3,7-diylium dication (103).

RECENT STUDIES OF PERSISTENT CARBODICATIONS

239

The carbodication, 103, has been obtained by desulfurative cleavage of 1,3,5,7-tetramethyl-2,4,6,8,9,10-hexathiatricyclo[3.3.1.13,7]decane (102) in triflic acid, fuming sulfuric acid, or magic acid. Quenching of the dication with water gives 1,3,5,7-tetramethyl-2-oxa-4,6,8,9,10-pentathiatricyclo[3.3.1.13,7]decane (104) in modest yields, which may be a synthetically useful intermediate. Me

Me S Me

S

S S

S Me

S

S

H+ Me

–H2S

S

S Me

S

S

H2O

+

S

Me

102

Me

+ Me

S Me

O S

103

Me

S

S Me 104

The formation of the dication involves protonation of one of the sulfur atoms forming the sulfonium ion and subsequent elimination of H2S.

7

Benzyl dications

BENZENE-DERIVED DIENYL, ALLYLIC DICATIONS

Even though the parent benzyl cation, C6H5CHþ 2 , evaded several attempts of its preparation, substituted primary benzyl carbodications have been prepared by Olah and coworkers.51 The 2,6-dimethylmesityldiyl dication (107) and 2,6-dimethyl-5methoxy-m-xylidyl dication (108) were prepared, and they were found to be stable even at –10C. Thus, the ionization of 2,6-bis-(chloromethyl)mesitylene (105) and 2,4-bis(chloromethyl)-3,5-dimethylanisole (90) using SbF5 in SO2ClF at –78C gave their respective dications. The structures of these dications were established as dienylic, allylic dicationic systems by 13C- and 1H NMR, and DFT calculations. The dienylic and the allylic portions of the dications were fully isolated from each other in accordance with their theoretically calculated structures.52 The chargelocalized canonical form is unimportant as shown by the theoretical calculations at the DFT B3LYP/6-31G* level. These charge-isolated systems are similar to those of the theoretically well characterized, but experimentally elusive, benzene diyl dication, whose allylic systems are essentially isolated from each other.5,53

CH3

CH3 ClH2C R

CH2Cl SbF5 /SO2ClF CH3 105; R = CH3 106; R = OCH3

–78°C

+H C 2

R

CH3 CH2+

H2C R

CH3 107; R = CH3 108; R = OCH3

+ +

CH2 CH3

240

V.P. REDDY AND G.K.S. PRAKASH

H3C H3C

CH2Cl CH3

SbF5 /SO2ClF –78°C

CH3 CH2Cl

H3C H3C

109

H3C

CH3 CH2Cl 110

CH2Cl

+

SbF5 /SO2ClF

CH3 CH2Cl 112

–78°C

CH2+ CH3

H3C

CH3 CH2+

H3C SbF5

111 CH3

CH3

CH3 ClH2C

CH2+ CH3

H2C

CH2+

H2C

H3C

CH3 CH2Cl SbF5

H3C

+ +

CH2

CH3 SbF5 CH2Cl

113

The dications display 13C NMR spectra, which are very similar to those of allylic carbocations. The terminal carbons of the dienylic and the allylic systems of the carbodications 107 and 108 show d13C between 192 and 198, characteristic of the typical allylic carbocations. The IGLO-calculated chemical shifts closely match with those of the experimentally observed values for these carbodications. The 1,4-dibenzylium dication (111) could not be formed in the superacidic media. The ionization of the 2,3,5,6-tetramethyl-1,4-bis(chloromethyl)benzene (109) in SbF5/SO2ClF at –78C gave only the monocation Lewis acid–base complex (110). Thus, the observed 13C NMR chemical shifts of the positively charged benzylic carbon C1 and the CH2Cl carbon are deshielded as expected for the monocation/ Lewis acid–base complex (d13C 170.2 and 82.9, respectively). It was also of interest to generate the related symmetric primary benzylic trication. However, the ionization of the 2,4,6-tris(chloromethyl)mesitylene (112) in excess SbF5/SO2ClF at –78C gave apparently only the dienylic allylic dication Lewis acid–base complex (113). The unionized chloromethyl carbon displayed a relatively deshielded 13C NMR absorption, d 13C 35.3, indicative of a weak Lewis acid–base interaction. The terminal methylene carbons of the dienylic system showed a d 13C of 197.7 and the terminal carbons of the allylic system displayed a d 13C of 194.8, quite similar to that of the previously described dienylic allylic dications, 107 and 108.

FLUORENYL DICATIONS

The 9-fluorenyl cation, being a 4n p-electron system, should be antiaromatic, as has been generally believed. However, Richard and coworkers provided experimental and theoretical data suggesting that this cation is not antiaromatic.54 Recent preparation of several fluorenyl dications, on the other hand, does prove that the fluorenyl system is antiaromatic in the dicationic systems. Mills and coworkers have generated the fluorenyl dications (115–120) by SbF5-oxidation of the tetrabenzofulvalene derivatives containing fluorenylidene and —five- and seven-membered rings.55,56 Molecular orbital calculations on these systems show that the fluorenyl

RECENT STUDIES OF PERSISTENT CARBODICATIONS

241

rings are perpendicular to the other substituents in these dications. This perpendicular orientation results in the s-electron donation from the opposite ring through cross-hyperconjugation (s-p donation). All the systems studied show paratropic ring current in the fluorenyl system. The paratropicity is reflected most noticeably in the 1 H NMR spectra for the He and Hf protons, and the 13C NMR chemical shifts for the Ca carbons (structures 115–120). The 1H NMR chemical shifts for the Hc and Hd are strongly influenced by the paratropicity or diatropicity of the opposite ring. It was observed that the Hf protons are largely shielded (d 1H 4.97–5.57) and so are the 13C NMR chemical shifts for C1 (189–211). The cationic centers of all the fluorenyl dications are, in general, shielded relative to those of the 9-substituted fluorenyl monocation (d 13C 226), indicating a decrease in positive charge of the cationic center. The decreased charge may result from the orthogonal arrangement of the two rings favoring s-p donation from the opposite rings.57 Thus, the shielding of the Ca and He or Hf are the hall marks of the antiaromaticity in the fluorenylic dications. Several 2,7-disubstituted tetrabenzo[5.5]fulvalene derivatives were oxidized with SbF5 to give the respective 2,7-disubstituted fluorenylic dications. Fluorine and CH3 substituents increase the antiaromaticity of the ring while chlorine decreases the antiaromaticity. Although the effects of the substituents on the paratropicity of the ring is not well understood, it is expected that, in general, electron donating groups, either through the p-polarization or resonance, would increase the electron density in the ring and hence enhance its paratropicity. f

e

+ b a c

SbF5–SO2ClF

d

+

114

115

+

+

+

+

+

+

116

+

+

CH3

H3C

117

118

+

Z

+

Z

O 119

Z = H, CH3, Cl, F, Br, OCH3 120

242

8

V.P. REDDY AND G.K.S. PRAKASH

1,6-Carbodications

1,16-DODECAHEDRYL DICATION

1,16-Dodecahedryl dication, (123), was generated from the dodecahedryl monocation (122), which was in turn obtained by ionizing dodecahedrane, hydroxydodecahedrane, or chlorododecahedrane (121) in SbF5/SO2ClF at –78C.58,59 The monocation, 122, was further oxidized to the dication, 123, upon warming the superacid solution to –50C over a period of 6–7 h. The carbodication is stable for several days even at 0C! The 1H NMR spectrum of the dication shows only two signals at d 1H 4.74 (br, 6-H) and 3.23 (br, 12-H) at –70C. The 13C NMR also shows only three signals at d 13C 379.2 (s), 78.8 (d), and 59.8 (d). These data clearly show that the observed carbocation is 1,16-dodecahedryl dication. The formation of the dication from the monocation obviously involves the protosolvation of the C16—H bond and the loss of H2. The intramolecular charge–charge repulsions in the carbodication forces the charged centers to be on the opposite sides of the sphere, that is, as far away from each other as possible. The ionization of any of the C—H bonds followed by rapid 1,2-H– shifts is, therefore, not excluded. In fact, when three regioisomers of dibromododecahdrane were ionized in SbF5, the only species formed was the 1,16-dodecahedryl dication showing the possibility of the rapid 1,2-hydrogen shifts in this dication. The positive charge in the dication 123 seems to be delocalized into the ring system analogous to the 1-adamantyl cation. Interestingly, such 1,2hydride shifts could not be observed in the dodecahedryl monocation, 122. Such 1,2hydride shifts were expected to have a relatively higher energy barrier. X +

+ SbF5/SO2ClF –78°C

121 (X = H, OH, Cl)

–50°C 6–7 h

122

CH3OH

+ 123

Br

OMe

Br2/25°C

OMe 124

OMe 125

The cationic centers of the dodecahedryl mono- and dications (d13C 363.9 and 379.2, respectively) are the most deshielded absorptions yet observed for any

RECENT STUDIES OF PERSISTENT CARBODICATIONS

243

carbocationic species. Among other carbocations that are similarly deshielded are 1-bicyclo[3.3.3]undecyl cation (d13C 356.3) and 1,5-bicyclo[3.3.3]undecyldiyl cation (d 13C 346.2) Further characterization of the dication was achieved by its quenching with methanol to give the 1,16-dimethoxydodecahedrane (124). The dimethyoxydodecahedrane when stirred in liquid bromine at room temperature was transformed consecutively into 1-bromo-16-methoxydodecahedrane (125) and then ultimately into 1,16-dibromo derivative. Thus, the regioselective functionalization of dodecahedrane is possible through the dodecahedryl cation.

DIAMANTANE-4,9-DIYL DICATION

The ionization of the 4,9-dichlorodiamantane in superacids gave the diamantane-4,9diyl dication, C14H2þ 20 (126), which due to the intramolecular charge–charge repulsion exhibits reduced C—C hyperconjugative effects as compared to the 1-adamantyl cation.49c It has similar NMR characteristics as that of the 1-adamantyl cation, except for its more charge-localized nature. The dication shows only three 13C absorptions d13C 337.3 (s Cþ), 78.8 (d, JCH = 147.5 Hz), and 58.3 (t, JCH = 147.5 Hz) in accordance with the high symmetry of the dication. The reduced hyperconjugation is obvious from the relatively less deshielded absorption for the Cg -carbons (78.8 vs. 85.8 ppm for 1-adamantyl cation). Thus, the charge–charge repulsion seems to diminish the C—C hyperconjugative interaction. In SO2 solution, the dication forms donor–acceptor complex (127) with two molecules of SO2, giving the more shielded absorption for the cationic centers (d 13C (Cþ) 230.9).

+

2+

S O

O O

O

+ 126

S

127

3,30 -(1,10 -BIADAMANTYL) DICATION

The 3,30 -(1,10 -biadamantyl) dication (112) was obtained by dissolving the 1,10 biadamantane in SbF5/SO2ClF. It was also obtained by the ionization of the 3,30 dibromo-1,10 -biadamantane under similar conditions; 13C NMR: d13C 99.3 (C1), 61.0 (C2), 300.9 (Cþ), 68.6 (C4, C10), 82.9 (C5, C7), and 34.8 (C6). Thus, it shows very similar spectral characteristics as the 1-adamantyl cation [d13C(Cþ) = 300]. The Cg bridgehead carbons (d13C 82.9 and 99.3) are more deshielded than the Cb-methylene carbons, reflecting the C—C hyperconjugative effect in the ring. The carbodication, interestingly, does not undergo protolytic cleavage to 1-adamantyl cation.49c

244

V.P. REDDY AND G.K.S. PRAKASH

+

+

128

CUBYL-1,4-DICARBOXONIUM ION

The cubyl-1,4-dicarboxonium ion (130) was prepared by treatment of cubane-1,4dicarboxylic acid (129) with FSO3H in either SO2 or SO2ClF.60 The dication, 130, was stable at –20C for at least 24 h, whereas the cubane monocarboxonium ion was transformed into the monoacylium ion upon warming to –30C. The cubane-1,4dicarboxonium ion (130) was stable under these conditions, showing that the cubane dicarboxonium ion is more stable than the cubane monocarboxonium ion, 133. The 13C NMR chemical shifts for the mono- and the dications are similar (d13C(Cþ) 190.6 and 189.2, respectively). The greater stability of the dication over the monocation may be due to the more extensive delocalization of the charge into the oxygens in the dication, due to the intramolecular charge–charge repulsion. In other words, the hyperconjugative interactions are less important in the dication compared to the monocation, as reflected in the C2-methine carbon chemical shifts (d13C 51.5, 49.0 for the mono- and the dications, respectively). Similarly, the cubane-1,4-diacylium ion (132) was also found to be stable even at –20C. The theoretical calculations also show that compared to the adamantane dicarboxonium ion, more of the charge is delocalized into the cubane framework in the cubane-1,4-dicarboxonium (130) and the cubane-1,4-diacylium ions (132). The strained cubane C—C bonds with high p-character are better suited for hyperconjugative stabilization, as shown below for the monocarboxonium ion, 133.

OH O

4

HO 3

+ OH

FSO3H

2 1

OH

SO5ClF, –80°C HO 130

O 129

SbF5/SO2 Cl

–45°C + O

O 131

132

+ OH

OH HO +

.

OH

+O

Cl O

HO

+

133

etc.

RECENT STUDIES OF PERSISTENT CARBODICATIONS

9

245

m-Hydrido dications

These carbodications are unique in that the hydrogen is dicoordinated in these systems. Sorensen and coworkers have generated many m-hydrido-bridged carbocations (e.g., 134) involving cyclic (mono-, bi-, and tricyclic) frameworks.61 The direct observation of the m-hydrido-bridged carbocations in superacidic media is in accord with the transannular hydrogen migrations in the solvolysis of the medium ring compounds. McMurry has reported an unusually stable m-hydrido-bridged cation, the [4.4.4]tetradecyl cation (135).62 Most of the other such carbocations are highly unstable and could be characterized at very low temperatures, typically around –120C.63

H

n

H m 134

135

The m-hydrido-bridged carbocations are intriguing cations in that the hydrido hydrogen typically shows a 1H NMR signal between –3.5 and –7.9 ppm, rather highly shielded absorptions. However, in related acyclic systems, no such m-Hbridged cation could be observed even though degenerate equilibrium (136) is established in these systems.64

+ +

+

H 137

136

Although the acyclic m-hydrido-bridged carbomonocations (e.g., 137) cannot be prepared, Sorensen has shown that the acyclic m-hydrido-bridged carbodications can be readily prepared. The following such carbodications have been prepared from their corresponding diols in FSO3H/SO2ClF: 2,6-dimethyl-4-isobutylheptane-2,6diyl dication (139), 4,6-trimethyl-4-isobutylheptane-2,6-diyl dication (140), and 4,4diisobutyl-2,6-dimethylheptane-2,6-diyl dication (141).

OH

OH

+

+

+

δ+

H δ+

138

139

246

V.P. REDDY AND G.K.S. PRAKASH

+

+

+

2+

δ+

H

H δ+

140

141

In carbocation 139, the m-H appears at d 1H –0.78 at 203 K and –1.34 at 159 K. The relatively low shielding and temperature dependence of the chemical shift indicates the involvement of the equilibrium between the bridged and the unbridged structures. The more shielded chemical shift at lower temperatures indicates that the equilibrium favors the bridged structure as the temperature is lowered, that is, the bridged structure is favored enthalpically while the unbridged structure is favored entropically. The dication 140, which differs from 139 in having 4-methyl group in place of the hydrogen, favors the bridged structure even more. It shows d1H for the m-H at –3.36 at 200 K and –4.73 at 153 K, favoring predominantly bridged structure at lower temperatures. The equilibrium constant (K) was estimated to range from 2.2 to –7.3 (200 to 153 K). Replacing the 4-H of the cation 139 with an isobutyl group makes it possible to form the m-H-bridged dicationic species, 143, whose m-H shows a 1H NMR signal at –4.53 ppm at 200 K to –5.10 ppm at 160 K. The temperature dependence of the chemical shifts indicates that there is equilibrium, possibly involving the exchange of the m-hydrido hydrogens.64

HO OH

H

2+

H

H H 142

143

Galasso has recently calculated the 1H and 13C chemical shifts for the m-Hbridged acyclic carbodications by using the continuous-set-of-gaugetransformations (CSGT) formalism on the B3LYP/6-31 þ G (2d,p)-optimized geometries for the bridged structures.65,66 The excellent agreement of the 1H and 13C chemical shifts with the experimentally obtained values further

RECENT STUDIES OF PERSISTENT CARBODICATIONS

247

substantiates the bridging nature of these acyclic carbodications. The theoretical calculations also rule out the alternate triply-m-hydrogen-bridged carbodication structure, 141, which was predicted to have extremely shielded m-H (d 1H = –9) and highly deshielded for the bridgehead carbon (d13C = 223). The existence of such four-centered-two-electron dications has not yet been demonstrated experimentally.

10

Aromatic dications

The aromatic dications typically show ring-current effects in their NMR spectra and usually follow the Huckel’s 4n þ 2 aromaticity rule. The aromatic nature of these carbocations may originate through the s- or the p-conjugation. The pagodane and their derived dications (vide supra) and the dehydroadamantanediyl dication (vide supra) fall under the former category while the ditropylium dication and their derivatives (vide infra) are in the latter category. The cyclopropenylium-derived dications may also be included in the same category.

PAGODANE DICATIONS

The D2h symmetrical [1.1.1.1]pagodane (C20H20), 144, is a structural isomer of the most symmetrical dodecahedrane (Ih). The attempted isomerization of pagodane to dodecahedrane in superacids was not successful. Instead, the pagodane was oxidized to the quite stable [1.1.1.1]pagodane dication (145, D2h symmetry) in superacids. The [1.1.1.1]pagodane dication (145) shows only four 13C NMR absorptions [d13C 251.0 (s), 65.3 (t), 57.2 (d), and 52.3 (d)] in accordance with the D2h symmetry for the carbodication, similar to that of the parent [1.1.1.1]pagodane molecule. A diatropic ring current, as expected for the 2p-aromatic system, is manifested in this dication. The methine protons directly above and below the cyclobutane framework show relatively shielded absorptions as compared to those in the parent pagodane molecule. Furthermore, the Ca absorption for the carbodication at d 13C 52.3 is also shielded by 7.3 ppm from that of the progenitor [1.1.1.1]pagodane [d 13C (Ca) 59.6]. Quenching of the dication with methanol gave the dimethoxy adduct (146) in support of the dicationic species. This dication can be considered to be a frozen two-electron Woodward–Hoffmann transition state for the cycloaddition of ethylene to ethylene dication. The same dication was also obtained by the ionization of the diene valence isomer of the [1.1.1.1]pagodane (147) and also from its Br2 adduct (148).67–69 The dication is uniquely stable for several hours even at ambient temperatures.

248

V.P. REDDY AND G.K.S. PRAKASH

Cα

Cα 2+

SbF5/SO2ClF

Cα 145

144

OMe OMe

MeOH

Cα

146

SbF5/SO2ClF

SbF5/SO2ClF

Br Br

147

148

2+

SbF5/SO2ClF –78°C to –20°C

–78°C 150

149

Electrochemical

+

+

151

2+

oxidation

152

153

The bishomologous [2.2.1.1]pagodane (149) upon ionization in SbF5 gave the [2.2.1.1]pagodane dication (150), which is analogous to that of [1.1.1.1]pagodane dication, 145. The carbons directly above and below the cyclobutane ring are shielded by 5.2 ppm relative to that of the neutral precursor. However, the dication is unstable and rearranges to the bisallylic (C2 symmetric) dication, 151, even at –78C, the latter being stable at temperatures as high as 0C. The formation of these dications proceeds through the initially formed radical cations, which were characterized by electrochemical and Electron Spin Resonance (ESR) studies.70,71 The [2.2.2.2]pagodane (152) was recently electrochemically oxidized reversibly to the presumably s-bishomoaromatic 4c-2e dication (153). The first oxidation potential at 1.33 V corresponds to the formation of the 4c/3e radical cation, which has a half-life of about 10–1 s. The second oxidation potential was observed at 1.49 V (vs. Ag/AgCl in CH2Cl2 at –50C), which corresponds to the dication. However, the dication could not be isolated for its NMR characterization. It should be noted that the second

RECENT STUDIES OF PERSISTENT CARBODICATIONS

249

oxidation potential for this species is reversible unlike that for [1.1.1.1]- and [2.2.1.1]pagodanes, where the second oxidation potential was irreversible. Thus, the [2.2.2.2]pagodane dication (153) should be even more stable than the former ions, 145 and 150, suggesting that under appropriate reaction conditions, the [2.2.2.2]pagodane dication (153) could be prepared as a stable species. Isomeric highly symmetric [1.1.1.1]isopagodane 154 and its bishomo analog [2.2.1.1]isopagodane 157 were also synthesized72 in order to explore the unusual cage radical cations and dications. Even though the interaction of ethylene and ethylene radical cation to form cyclobutane radical cation is symmetry forbidden, such a 4c/3e radical cation was found to be stabilized in the rigid [1.1.1.1]pagodane and [1.1.1.1]isopagodane skeletal frameworks.70 On the other hand, interaction of ethylene with ethylene dication is symmetry allowed based on Woodward–Hoffmann theory.73,74 Smooth two-electron oxidation of both [1.1.1.1]isopagodane 154 and [2.2.1.1]isopagodane 157 in SbF5/ SO2ClF solutions to their respective diamagnetic dications, 156 and 158, takes place at –78C through the intermediacy of respective monoradical cations. Their characterization was achieved by low-temperature 1H and 13C NMR spectroscopy.75

SbF5

+•

–e–

2+

SO2ClF –78°C 154

155

SbF5

156

2+

SO2ClF –78°C 157

158

The structures of the intriguing dications 156 and 158 were also computed by DFT calculations. The 13C NMR chemical shifts were also calculated using both GIAO and IGLO methods. Both dications 156 and 158 can also be characterized as 4c/2e s-bishomoaromatic rectangular cyclobutane dications as well as frozen Woodward– Hoffmann transition state analogs.

DEHYDROADAMANTANEDIYL DICATION

The 1,3-dehydro-5,7-adamantanediyl dication, 160, was obtained through the ionization of 1,3-dehydro-5,7-difluoroadamantane (159). This dication shows three-dimensional

250

V.P. REDDY AND G.K.S. PRAKASH

aromaticity, that is, the four p-orbitals on each of the bridgehead carbons overlap in a tetrahedral fashion. The d13C of the bridgehead carbons and the methylene carbons show 13C absorptions at d13C 6.6 and 35.6, respectively, which agree closely with the theoretically (IGLO) calculated chemical shifts (7.0 and 33.0) for the nonclassical dication.76 The difference in the sums of the chemical shifts (Dd) of the parent hydrocarbon, 1,3-dehydroadamantane (d = 454), and the dication (d = 240) was found to be –214 ppm, which by itself shows that the carbodication is a nonclassical species. For classical carbodications, the difference in the chemical shifts (D) would be expected to be in the order of þ400 per unit charge. For most nonclassical carbocation, the difference of the sums of the chemical shifts (D) was less than þ200 ppm. Only in certain exceptionally delocalized systems such as trishomocyclopropenyl cation (D = –48 ppm), negative values were found.

F 2+ F

+

SbF5/SO2ClF

+

+

+ 159

160

2,10-para[32,56]OCTAHEDRANEDIMETHYL DICATION

A bis s-bridged dication structure was proposed for the 2,10-para[32,56]octahedranedimethyl dication (162), generated by the ionization of the corresponding diol (161) with SbF5 in SO2ClF at –78C.77 The dication shows only five absorptions in its 13C NMR indicating its symmetric structure (d 13C 135.7, 118.9, 105.0, 66.4, and 53.3). The relative stability of the nonclassical structure over the static structure has not been calculated, but in the closely related monocation, 2-triaxanemethyl cation (163), the s-bridged structure is more stable than the static structure by only 0.6 kcal/ mol. The 13C NMR chemical shifts for the mono- and the dications, 162 and 163, are also similar. Essentially, the methylene and a-cyclopropyl carbons in the dication (d 13C 118.9 and 135.7 respectively) and the monocation (d 13C 47.3, 147.9) are highly shielded, relative to those of the static Sorensen’s nortricyclylmethyl cation,78 ruling out the static structures for these mono- and the dications.

CH2OH

+

CH2

+ CH2

SbF5/SO2ClF –78°C +

HOH2C

H2C 161

H2C 162

+

RECENT STUDIES OF PERSISTENT CARBODICATIONS

+

CH2

251

CH2 +

163

BIS(TROPYLIUM) DICATIONS

The bis(tropylium) dication was reported nearly two decades ago, and it was characterized by only 1H NMR spectroscopy.79,80 No unusual properties were reported for the dication. Its thermodynamic properties were also not studied. Recently, a derivative of the dication, bis[tris(bicyclo(2.2.2)octeno]tropyliumyl acetylene dication (165), was prepared by Komatsu and coworkers as a highly stable crystalline material.81a The individual aromatic tropylium units are also stabilized through conjugation with the p-electrons of the acetylene unit. The dication was obtained from the acetylene derivative (164) through stepwise hydride abstraction using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and trityl hexachloroantimonate sequentially. The attempted hydride abstraction using excess trityl hexachloroantimonate was not successful in obtaining the pure crystalline material of the carbodication. The carbodication was obtained as yellow needles and was stable in air.

H 1. DDQ(2 eq)/CH2Cl2 H

2. Ph3C+ SbCl6–(2 eq)/CH3CN

164

+

+

165

252

V.P. REDDY AND G.K.S. PRAKASH

H

+

H3C

+

+ H

166

167

168

A single-crystal X-ray diffraction of the dication showed that the two tropylium rings are twisted with each other by an angle of 44, and the tropylium rings are slightly bent into boat conformations. The dication was neutralized in aqueous acetonitrile in two steps to the neutral hydrocarbon, yielding a pKRþ of 7.0 for the dication and 11.5 for the half-neutralized species, the monocation. The dication is 5–6 pKRþ units destabilized with respect to the model monocations 166–168. The half-neutralized species, the monocation, 166, is comparable in stability with those of carbomonocations 167 and 168. The charge–charge repulsion is responsible for the decreased stability of the dication. Whereas the monocations 167 and 168 were irreversibly reduced in cyclic voltammetry, the dication showed two reversible one-electron reductions, first giving the radical cation and then the neutral hydrocarbon. The formation of the diradical was, however, not detectable by CV/ESR experiments. The 1,2:3,4:5,6-tris(bicyclo(2.2.2)octeno)tropylium units connected by p- and m-phenylene spacers result in the conjugated carbodications, 169 and 170, which were obtained as highly stable crystalline compounds.81bc Both of these dications were found to be quite stable colorless crystalline materials. It is interesting that in these cations, as well as the 9-phenyl derivative, 168, the phenyl ring is perpendicular to the plane of the tropylium rings, as shown by the 1H NMR chemical shifts of the bridgehead proton of the bicyclooctyl substituent, which is 0.3–0.4 ppm shielded as compared to the parent unsubstituted tris((2.2.2)bicycloocteno)tropylium cation. The shielded proton implies that the phenyl ring is perpendicular to the plane of the tropylium ring, and the proton is in the shielding zone of the phenyl ring. The conjugation of the tropylium ring with the phenyl ring is prohibited, which explains the lower pKRþ values of these dications as well as the 9-phenyl derivative, 168, as compared to the parent 9-Hderivative, 166. The still smaller pKRþ value for the dications 169 and 170 implies the intramolecular repulsion of the positive charges. The m-phenylene dication, 170, has only one pKRþ value, 11.5 as both the rings are neutralized concurrently, independently of each other. The p-phenylene dication, 169, on the other hand, shows two pKRþ values, 10.4 for the neutralization of the dication to the monocation and one at 12.2 for the further neutralization of the halfneutralized species. The cyclic voltammetry studies of these cations in

RECENT STUDIES OF PERSISTENT CARBODICATIONS

253

conjunction with electron spin resonance spectroscopy revealed that the 9-phenyl-substituted monocation, 168, gave a stable free-radical persisting in solution at room temperature. The m-phenylene dication, 170, gave two very closely spaced reduction waves, and the resulting fully reduced species was identified as a triplet diradical. The p-phenylene-derived dication, 169, did not give any radical species, instead it gave a closed shell hydrocarbon.

H

H

+

+ H

+ H

H

+

H H

169

170

1,2:3,4:5,6:7,8-TETRAKIS(BICYCLO(2.2.2)OCTYL)CYCLOOCTATETRAENE DICATION

Although the parent cyclo-octatetraene dication has not been well characterized in the superacid media, several substituted systems are well studied.1b Komatsu and coworkers have recently prepared the dication derivative, 171, using the bicyclo(2.2.2)octyl rings as the four substituents.82 Using the latter substituents, they were able to prepare several other dications in the crystalline form (vide supra). The radical cation of the tetrakis(bicyclo(2.2.2)octeno)cyclooctatetraene on oxidation with SbF5 gave the corresponding dication, 171, which was characterized by 13C NMR. The dication, 171, at room temperature shows d13C 177.9, 41.0, and 23.9. The 13 C NMR at –80C shows that the signal originally at d 13C 23.9 at room temperature was split into two signals: d13C 24.8 and 20.4. This temperature-dependent behavior was accounted for by proposing the equilibration of the two nonplanar tub-shaped conformers in which there are two sets of nonidentical methylene carbons. From the coalescence temperature (–35C  15C), the energy barrier for the interconversion was calculated to be 10.8  0.7 kcal/mol. The interconversion presumably proceeds through the planar conformation as the transition state. The precursor tetraene, on the other hand, was estimated to have at least 24 kcal/mol barrier for the conformational interconversion. Electrochemical oxidation of the tetra(bicycloocteno)cyclooctatetraene in CH2Cl2/CF3CO2H/(CF3CO)2O (2:1:1) exhibits two well-defined reversible oxidation waves at E1/2 þ0.39 and þ1.14 V versus Ag/Agþ, corresponding to the sequential formation of mono- and dications.

254

V.P. REDDY AND G.K.S. PRAKASH

2+

171

TETRAKIS(BICYCLO[2.2.2]OCTANONAPHTHALENE DICATION

Naphthalene annelated with four bicylo[2.2.2]octane frameworks (172) upon oxidation with SbF5 in CH2Cl2 at low temperatures gave the carbodication, tetrakis(bicyclo[2.2.2]octanonaphthalene dication (173), as a purple solution.83 The 13C NMR signals of the aromatic ring are all deshielded (d13C 210.8, 160.7, and 154.0), and the average 13C NMR chemical shift of all the sp2-hybridized carbons is 179.4 ppm, which is similar to that of the other arene dications (vide infra). The bridgehead protons of the bicyclooctano substituents are shielded (Dd 0.1 and 0.32) with respect to those of the neutral hydrocarbon (172) indicating the paratropicity of the dication. The hydrocarbon, 172, also showed two oxidation waves at E1/2 = þ0.33 V and þ1.17 V versus ferrocene/ferrocenium in cyclic voltammetry in 1,1,2,2tetrachloroethane at room temperature. Whereas the former oxidation wave is reversible, the latter wave is irreversible indicating the relative instability of the dication under these conditions.

2+

SbF5/CD2Cl2 –78°C

172

173

TRIHYDROXYCYCLOPROPENIUM ION AND HOMOLOGOUS IONS

The monoprotonated deltic acid, a trihydroxycyclopropenium ion (175), was prepared by the ionization of the di-tert-butoxydeltate (174) in FSO3H (H0 = –15).84 It was earlier shown by Hopkinson that the electron-donating OH groups on the cyclopropenium ion are less effective in the delocalization of the positive charge.85

RECENT STUDIES OF PERSISTENT CARBODICATIONS

255

The trihydroxyyclopropenium ion (175) shows a single absorption in its 13C NMR spectrum, d 13C 128.7, which can be ascribed to the monoprotonated deltic acid from the DFT/IGLO calculations. Interestingly, the cation does not form the diprotonated species (176) even in Magic Acid (H0 = –22).

+ OH2

OH

O FSO3H–SbF5

+ ButO

t

OBu

+

HO

HO

OH

175

176

OH 177

The four-, five-, and six-membered analogs (178, 180, and 182) were also obtained from the diprotonation of squaric acid (3,4-dihydroxy-3-cyclobutene-1,2-dione, 177), tri-O-protonation of croconic acid (4,5-dihydroxy-4-cyclopentene-1,2,3-trione, 179), and tetra-O-protonated rhodizonic acid (5,6-dihydroxy-5-cyclohexene-1,2,3,4tetraone, 181), respectively.86 These ions were prepared in either Magic Acid (1:1 FSO3H-SbF5) or fluorosulfuric acid at low temperature and characterized by 13C NMR. Ab initio/IGLO calculations showed that di-O-protonated squaric acid (178) is planar and aromatic, whereas the polyprotonated croconic and rhodizonic acids (180 and 182) have more carboxonium ion character, and no indication was obtained for any significant contributing homoaromatic structures.

HO

HO

O FSO3H/SbF5

HO 177 O

O

FSO3H/SbF5

HO

OH +

etc.

OH

3+

180

O

OH O O

FSO3H/SbF5

HO HO

OH

179

O

HO

HO

O

181

OH

OH

HO

HO

+ OH

178

HO

HO

HO

2+

HO

O

OH

HO

OH 4+

HO

OH OH 182

+ OH + OH etc. OH +

+ OH + HO OH + HO OH + OH

etc.

256

V.P. REDDY AND G.K.S. PRAKASH

HOGEVEEN DICATION [C6(CH3)6 2]2þ

The carbodications, due to coulombic repulsion of charges, are usually chargelocalized (classical). However, there are few dications in which the charges are delocalized efficiently involving either s- or the p-bonds. Although p-delocalized systems (aromatic) are well studied, Hogeveen’s pyramidal dication, 187, is illustrative of s-delocalization.87,88 The dication could be prepared from a variety of precursors (e.g., 183, 185, and 186) in superacidic media. The 13C NMR of the cation shows rather shielded chemical shifts for the ring carbons (22.5, apical C; 126.3, basal carbon), indicating the nonclassical structure to the ion. The ion was shown to have nonclassical structure by applying the technique isotopic perturbation of resonance developed by Saunders, that is, the substitution of a basal CH3 group by CD3 group, as in [C6(CH3)5CD3]2þ, resulted in insignificant isotopic perturbation on the 13C signals of the basal carbons (D = 0.41 ppm at –50C);89 the low-field signal (d 13C 126.3) for the basal carbons of the unlabeled ion is split into two different signals in the CD3-substituted dication, one of which is downfield of the unlabeled ion by 0.14 ppm and the other is upfield of the unlabeled ion by 0.27 ppm. If equilibrating classical carbodications (188a–188e) are involved, the splitting of the signals as high as 100 ppm would be expected.90 The parent [C6H6]2þ dication, however, was too unstable to be prepared. Hogeveen also prepared the ethyl and isopropyl analogs of the pyramidal dications.91 Further confirmation of the nonclassical structure to these cations was made by the correlation of their 13C NMR chemical shifts with those of the isoelectronic borane B6H6.

H3C

CH3 CH

H3C

O CH 3 CH3

H3C

CH3 CH

H 3C

CH3 CH3 186

3

3

185 FSO3H

H3C OH CH3 H3C OH H3C H3C CH 3

FSO3H, or SbF5/SO2, or FSO3H/SbF5

H3C H3C

+

CH3 CH3

1. Br2/CH2Cl2 2. FSO3H/SbF5

CH3 H3C

OH2 +

H3C

CH3

CH3 2+

H3C

CH3 CH3

183

184

187

RECENT STUDIES OF PERSISTENT CARBODICATIONS

257

CH3 H3 C +

H3C

H3C

CH3 +

+ CH3

Me

Me

+

+ Me

Me

+ CH3 188e

CH3 H3C

Me

CH3

Me 188d

CH3

CH3 H3C

CH3

CH3

188a H3C

CH3 +

H3C +

+ CH3 CH3

H 3C +

CH3

188c

CH3 188b

The fact that the apical carbon of the carbocation is so highly shielded (d 13C –2.0) indicates its hypercoordinated nature. Moreover, the 13C and 1H chemical shifts are unaltered up to –150C, and there was no significant line broadening, which indicates that there are no equilibrating structures (188a–188e). Thus, the five-fold symmetry of the cation can be readily explained through the involvement of the bridged structure.

11

Oxygen-stabilized carbodications

The ortho-, meta-, and para-phenylene bis(1,3-dioxolanium) dications (189–191) have been prepared by the ionization of the corresponding 2-methoxyethyl benzoates in FSO3H or CF3SO3H at 40C.92 These carbodications are exceptionally stable to over 100C.

O + O

O + O O +

O O + O 189

190

The charge delocalization in carbocations, 189–191, was probed by 13C NMR spectroscopy and substantiated by GIAO/DFT calculations. Extensive charge delocalization into neighboring oxygen atoms were observed. The rotational

258

V.P. REDDY AND G.K.S. PRAKASH

O + O O + O

O

O O

+

191

O

+

+

O

O 192

barriers around the Cþ—Ar bond for carbodications 189 and 190 were estimated to be 8–10 kcal/mol by dynamic 13C NMR spectroscopy. A related carbotrication, 192, has also been studied.92

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AUTHOR INDEX Barnes, C., 54, 56 Barth, A., 66 Bartoletti, A., 11, 27 Barzaghi, M., 222 Bashir-Heshemi, A., 244 Batt, L., 91, 92 Bau, R., 247, 249 Bauduin, P., 4 Bausch, J. W., 225 Beck, S. M., 106 Becke, A. D., 90, 138 Beland, F. A., 136, 172 Benak, H., 25 Benrraou, M., 7 Bent, D. V., 106 Bergmark, W. R., 54, 56 Berneth, H., 228 Bevington, P. R., 15 Bhuyan, A., 40 Biggs, P., 92 Bischof, P., 231 Bittker, D. A., 100 Bittner, J. D., 99 Bjelland, S., 181 Black, E. D., 46 Black, E., 46 Blagoeva, I. B., 26, 27 Blake, J. A., 52 Blanc, A., 45 Blandamer, M. J., 8, 13, 22, 25 Blokzijl, W., 12, 25 Bochet, C. G., 39, 41, 45, 71 Bock, H., 224 Bo¨cker, J., 10 Bollinger, J. M., 227, 233 Bonollo, S., 27 Borosky, G. L., 138, 154, 160–3 Borrmann, H., 224 Bosca, F., 51 Bosco Bharathy, J. R., 26 Bowman, F. M., 123 Bowman, J. M., 221 Braams, B. J., 221

Abbott, J. E., 46 Abbruzzetti, S., 66 Abuin, E., 8, 10 Aceves, S. M., 121 Alabugin, I. V., 232, 233 Albagi, A., 91 Alfassi, Z. B., 109 Al-Lohedan, H., 14, 15 Almgren, M., 10 Alves, M., 9 Amyes, T. L., 240 Anderson, D., 64 Andino, J. M., 107 Andrade, C. K. Z., 1 Angell, A. D., 23 Apperloo, J. J., 25 Arad-Yellin, R., 63 Arai, M., 228 Armona-Ribeiro, A. M., 7, 8 Arnold, B. J., 42, 44, 45 Arvanaghi, M., 229, 230, 235 Asaba, T., 99, 106 Atemnkeng, W. N., 49 Atkinson, D. B., 93 Atkinson, R., 85, 97, 99, 122 Ault, B. S., 65 Axworthy, A. E., 109 Babinec, P., 220, 239 Babushok, V. I., 106 Bachmann, J.-P., 64 Bacskay, G. B., 110 Bae, S., 109, 160 Baker, R. R., 92, 93, 109 Balasubramanian, D., 3, 4 Baldwin, R. R., 92, 93 Balenkova, E. S., 220, 232, 233 Bales, B. L., 7, 9, 10, 11 Bally, T., 44, 45 Banerjee, A., 49 Barckholtz, C. A., 101 Barckholtz, T. A., 85, 111, 113 Barker, J. R., 97, 122

261

262 Bramhall, J., 8 Braslavsky, S., 110 Breheret, E., 45 Bremer, M., 250 Brinchi, L., 22–4, 26, 27 Brinson, R. G., 54 Brown, R. E., 7 Broxton, T. J., 11, 15 Bruhnke, J. D., 63 Bruice, P. Y., 147 Bruinsma, O. S., 109 Brule, C., 150, 159 Buchholz, H. A., 250 Budac, D., 51 Bunting, B. G., 121 Bunton, C. A., 6, 10, 14, 22, 24, 29 Burcat, A., 92 Burns, E., 240 Burrichter, A., 224, 239 Burrows, C. J., 181, 186–91, 200 Buth, R., 108 Buurma, N. J., 2, 13, 16, 22, 24–6 Cabaleiro-Lago, C., 29 Cadet, J., 181, 192–6 Cambria, A., 51 Cance`s, M. T., 138 Cang, H., 10 Carey, F. A., 109 Carganico, G., 51 Carlsen, W., 122 Carmona-Ribeiro, A. M., 7, 8 Carpenter, B. K., 12 Carter, J. T., 92 Casanova, J., 235 Casavecchia, P., 88 Casey, M. L., 29 Cassanelli, P., 97 Castell, J. V., 51 Castle, K. J., 46 Cavalli, F., 123 Chai, Y., 105, 106 Chan, C. K., 40 Chan, S. I., 40 Chang, H. M., 106 Chang, M., 65 Chase, R., 122 Chaudhuri, A., 6, 18, 19, 23 Chavli, R. V., 39

AUTHOR INDEX Chen, C. P., 44 Chen, C.-C., 95 Chen, P. C., 45 Chen, P., 88 Chen, W.-S., 46 Chen, X., 16 Chen, Y. L., 123 Chiarini, M., 24, 26 Choi, H., 94 Chow, J. M., 95 Christe, K. O., 224 Ciccioli, P., 109 Clark, A., 46 Clark, J., 54, 56 Clark, W. D., 107, 114 Collie, J. N., 41 Colussi, A. J., 106 Condorelli, G., 51 Connors, R., 45 Conrad, P. G., 39 Continetti, R. E., 221 Cool, T., 89 Corrie, J. E. T., 41, 45, 46, 66 Costanzo, L. L., 51 Costas-Costas, U., 26 Cox, R. A., 92 Crosley, D. R., 89 Cuccovia, I. M., 18, 20 Cullis, C. F., 110 Curran, H. J., 98, 122 Da Rocha Pereira, R., 13 Da Silva, R. C., 4 Dagaut, P., 107 Dai, J., 210 Damrauer, R., 222 D’Anna, A., 99 Das, P. K., 44 Davico, G. E., 113 Davico, G., 222 Davidson, S. M. K., 8 Davies, D. M., 13 Davis, A. P., 46 De Guidi, G., 51 De Meijere, A., 231 Deamer, D. W., 8 Dearden, D. V., 97, 122 Deas, R. M., 46 Dechaux, J. C., 93

AUTHOR INDEX Dedon, P. C., 181 DeGrado, W. F., 40 Deiters, A., 39 Del Mar Graciani, M., 26, 27 DePuy, C. H., 113, 222 DeSain, J. D., 94, 95, 96 Dewar, M. J. S., 138 Diego-Castro, M. J., 28 Diehl, C. A., 46 Dietrich, C., 8 DiPardo, J., 122 Dogliotti, L., 46 Doughty, A., 109, 112, 113 Dunkin, I. R., 45 Durst, T., 42, 45 Dwars, T., 17 Ebert, K. H., 113 Eckbreth, A. C., 89 Edidin, M., 8 Eiben, K., 45 Eicher, T., 228 Eisele, F. L., 109 El Bakali, A., 107 El Dib, G., 108 Ellis, D. E., 221, 224 Ellis-Davies, G. C. R., 39 Ellison, G. B., 113 Elmaimouni, L., 107 El-Nahas, A. M., 125 Emdee, J. L., 107 Enami, S., 92 Encinas, M. V., 44 Encinas, S., 51 Endrenyi, L., 97, 122 Engbersen, J. F. J., 23 Engberts, J. B. F. N., 11, 25 Epling, G. A., 51 Ergut, A., 107 Eriksson, J. C., 10 Eriksson, L. A., 52 Erker, G., 220 Esparza, E., 240 Essigmann, J. M., 181, 187–8, 191 Fadden, M. J., 101, 103, 111, 113 Falvey, D. E., 52 Fama, M., 51

263 Farnia, M., 232, 233, 234 Faulhaber, A. E., 94 Fendler, J. H., 10, 30 Fenter, F. F., 107 Ferenac, M. A., 97, 122 Ferna´ndez, A., 26 Fessner, W. D., 242, 247, 248, 249 Fife, T. H., 23 Findlay, D. M., 45 Finlayson-Pitts, B. J., 87 Fish, A., 93 Fisher, E. M., 125 Fisk, T. E., 228 Flachsmann, F., 64 Flaim, T., 4 Forst, W., 90 Fournet, R., 98 Fox, K. K., 10 Frank, P., 106 Frater, G., 64 Frenking, G., 225 Frenklach, M., 99, 114 Frerichs, H., 113 Frey, H. M., 97, 122 Friberg, S. E., 3, 4 Friderichsen, A. V., 99 Friemel, C., 62 Fu, P. P., 136, 172 Fukuhara, K., 150, 172 Fukuyama, K., 228 Fulle, D., 110 Furchgott, R. F., 39 Gagnon, E., 52 Gai, F., 40 Gail, S., 125 Galasso, V., 247 Galetskaya, M., 68 Gallivan, J. P., 10 Gao, Z. S., 10 Gaplovsky, M., 66 Gareyev, R., 247 Garneau, F. X., 44 Gawienowski, M., 51 Geacintov, N. E., 191 Gebicki, J., 42, 44, 45 Geng, Y., 6, 19, 20 Georgallas, A., 8 George, H., 255

264 Germani, R., 15, 29 Gescheidt, G., 247, 248 Getahun, Z., 40 Ghaly, M. Y., 46 Ghigo, G., 92 Giasson, R., 46 Gibbs, J., 240 Gilbert, B. C., 46 Gilbert, R. G., 90 Gilbertson, R. D., 228 Giordano, C., 256 Givens, R. S., 39, 41, 45 Glassman, I., 81, 82 Glaude, P. A., 125 Glombitza, C., 45 Gnann, R., 224 Goelitz, P., 231 Goerling, A., 221 Gomez, N., 92 Gomez-Lechon, M. J., 51 Good, D. A., 125 Gooding, E. A., 40 Graboski, M. S., 123 Grant, J. L., 223 Gravel, D., 46 Gray, D. L. F., 42 Gray, D., 42 Gray, H. B., 40 Green, A., 240 Green, B. S., 63 Greenberg, M. M., 189, 192–4 Grela, M. A., 110 Grellmann, K. H., 44 Grieco, P. A., 1 Grieser, F., 21 Griffiths, P. C., 7 Grohmann, A., 221 Gronert, S., 81 Grossweiner, L. I., 51 Grotheer, H.-H., 106 Gruen, D. W. R., 5, 7, 10 Gudmundsdottir, A. D., 57, 58 Guengerich, F. P., 188 Haag, R., 41–4 Haeberlen, O. D., 221 Hailes, H. C., 1 Haley, M. M., 228 Hamanoue, K., 42, 43

AUTHOR INDEX Hankin, J., 222 Hannemann, K., 42 Hansen, K. C., 40 Hansen, P. E., 141 Harder, T., 8 Harris, C. C., 39 Harrison, A. G., 106 Hartel, G., 46 Harvey, R. G., 135 Haseneder, R., 46 Hasson, A. S., 93 Hattori, Y., 228 Hausmann, M., 106 Havlas, Z., 224 Hawrylak, B. E., 10 Hayes, C. J., 113, 116, 120 Head, N. A., 236 Head, N. J., 244 Heagy, M. D., 236 Hecht, S. S., 159 Heckel, A., 39, 62 Heger, D., 56 Hehre, W. J., 90 Hein, H., 97, 122 Heindel, N. D., 44, 60 Heineman, W. R., 42 Heinz, B., 68 Heinze, J., 236 Heldeweg, R. F., 256 Hellrung, B., 66 Henry, E. R., 40 Herges, R., 247, 249 Herrmann, A., 39, 40, 63 Herrmann, U., 8 Herve´s, P., 8, 29 Hickel, B., 93 Hidaka, T., 42 Himmel, H.-J., 65 Hinchliffe, A., 106 Hippler, H., 113 Hirai, M., 8 Hirota, N., 47 Hochstrasser, R. M., 40 Hodgdon, T. K., 3 Hodges, J., 240 Hodgson, D., 101 Hofseth, L. J., 39 Hogeveen, H., 256 Hol, P., 25

AUTHOR INDEX Hollenstein, S., 144, 152 Hoover, K. W., 51 Hopkinson, A. C., 254 Horner, L., 42 Horva´th-Szabo´, G., 4 Houser, T. J., 109 Howard, P. C., 136 Hu, Y., 40 Huang, C.-Y., 40 Huang, H., 98, 106 Huang, Y., 98 Hubbard, S. C., 54 Huber, B., 221 Huffman, K. R., 41 Hughes, J. L., 51 Hughes, K. J., 91 Hunter, C. A., 2 Hunziker, H. E., 92 Hurley, R., 47 Hussain, S. P., 39 Hutter, M. C., 66 Ichimura, T., 42 Ignarro, L. J., 39 Iida, K., 44 Ikeda, E., 112, 113 Ikeda, H., 41 Il’ichev, Y. V., 45, 46, 66 Ishida, A., 42 Israelachvili, J. N., 5 Ito, Y., 41 Jadhav, A. V., 65 Jafvert, C. T., 46 Jagannathan, N. R., 10 Janakiraman, B., 16 Jenkin, M. E., 87 Jerina, D. M., 135 Jitariu, L. C., 97, 122 Johnson, C. R., 106 Johnsson, M., 8 Johnston, L. J., 106 Jones, C. M., 40 Jones, J., 109, 114 Jones, P. B., 54, 62 Jongejan, M. G. M., 29, 30 Joschek, H. I., 51 Juan, C.-N., 46

265 Jungkamp, T. P. W., 97, 122 Junker, M., 65 Just, G. M. P., 107 Kabuto, C., 251 Kachel, K., 10 Kadlecek, D. E., 240, 241 Kagayama, A., 251 Kaiser, E. W., 95 Kaiser, S., 8 Kambo, N., 16 Kamdzhilov, Y., 53, 66 Kammari, L., 56, 57 Kan, C. S., 92 Kantrow, S. P., 39 Kaplan, M. L., 251 Karzijn, W., 23 Kassel, L. S., 90 Kates, M. R., 256 Katsube, Y., 228 Kausch, M., 250 Kavalek, J., 45 Kawamuro, M. K., 29, 30 Kee, R. J., 84, 88, 90, 91 Keiper, J., 19, 20 Kemp, D. S., 29 Kern, R. D., 109 Kerstholt, R. P. V., 25 Keyanian, S., 232, 233, 234 Khadilkar, B. M., 16 Khan, M. N., 7, 11, 14, 17 Kholodenko, Y., 40 Khrapkovskii, G. M., 45 Kiefer, J., 109 Kikuchi, K., 42, 45 Kikuchi, O., 109 Kim, D. H., 106 Kirchen, R. P., 245 Kirchhoff, J. R., 42 Kiszka, M., 45 Klan, P., 44, 45, 54, 56, 57 Klein, E., 110 Kleindienst, T. E., 46 Klemke, J. W., 40 Klijn, J. E., 2, 8, 15, 30 Klima, R. F., 65 Klumpp, D. A., 220, 232, 239 Knothe, L., 248 Knox, J. H., 92

266 Kobayashi, T., 242 Koch, W., 225 Kochevar, I. E., 51 Kochi, J. K., 223 Kohn, D. W., 88 Kokubun, H., 42, 45 Komatsu, K., 228, 251, 253, 254 Kombarova, S. V., 66 Kong, W., 46 Konnov, A. A., 91 Konosonoks, A., 57, 58, 59 Koparkar, Y. P., 4, 17 Kornberg, R. D., 8 Kos, A. J., 222 Koser, G. F., 174 Kosmidis, C., 46 Kotala, M. B., 41, 45 Kraus, G. A., 42 Krauss, M., 107 Kraut, J., 12 Krempp, M., 222 Krishnamurthy, V. V., 229, 230, 236, 237, 238, 243, 247, 249 Kroner, S. M., 106 Krueger, C., 221 Kuhn, H. J., 232, 233, 234 Kulhanek, P., 56 Kulkarni, M. G., 124 Kumar, A. S., 223 Kumar, S., 46 Kumita, J. R., 40 Kumli, F., 64 Kunitake, T., 29 Kurz, J. L., 12 Kwant, P. W., 256 Laali, K. K., 137–9, 142, 144, 147, 150, 152, 153, 155, 156, 158, 165, 166, 168, 171–4 Labanowski, J. W., 90 Laferriere, M., 52 Lage Robles, J., 71 Laidler, K. J., 90 Laimgruber, S., 68 Lajis, N. H., 15 Lami, A., 44 Lammertsma, K., 220, 222, 239 Lancaster, J. R., 39 Land, E. J., 106 Lang, R. L., 138

AUTHOR INDEX Langmuir, M. E., 46 Larsen, R. W., 40 Larson, R. A., 46 Laughlin, R. G., 8 Lebedeva, N., 7, 10, 11 Lectka, T., 245 Ledingham, K. W. D., 46 Lee, C., 90, 138 Lee, G., 235 Lee, J. C., 40 Lee, J.-I., 41, 45 Lee, Y. T., 46 Lehr, R. E., 138 Leidreiter, H. I., 109 Lemieux, P. M., 109 Lendvay, G., 97, 122 Lenoir, D., 227, 238 Leonhardt, J., 249 Lesar, A., 92 Lesclaux, R., 91 Leszczynski, J., 220 Levendis, Y. A., 109 Levrand, B., 40 Li, C. J., 1, 2 Li, H., 63 Liang, G., 227, 238, 243 Lichtenberg, D., 30 Lien, M. H., 254 Lifshitz, A., 110 Lightfoot, P. D., 91, 92 Lim, Y. Y., 8 Lin, C.-Y., 106, 123 Lin, M. C., 46, 106 Lin, M.-F., 46 Lin, S.-T., 172 Lindeman, S. V., 223 Lindqvist, L., 45 Lindstrom, U., 1 Literik, J., 56 Liu, R., 100 Liu, X., 39 Lopes, A., 51 Lossing, F. P., 92 Loughlin, J. A., 19 Louisiana, L. D., 49 Louw, R., 106 Lowery, J. A., 241 Loy, M., 41 Lu, H. S. M., 40

AUTHOR INDEX Luchetti, L., 22 Luck, S. D., 40 Lukeman, M., 52 Lutz, G., 248 Lutz, H., 45 Lycka, A., 45 Lynch, B. J., 95 Ma, F., 124 Maas, G., 228 Mac, M., 66 Machacek, V., 45 Mackay, A. C., 44 Mackie, J. C., 109, 110 Mah, D. A., 93 Mal, P., 42 Malandra, J. L., 240, 241 Malik, R., 42 Manabe, K., 28 Mandel, S. M., 57, 59 Manderville, R. A., 177–213 Mann, J. E., 221 Maquin, F., 225 Marcinek, A., 44, 45 Marconi, G., 51 Marcus, R. A., 90 Margerum, J. D., 41, 45 Maricq, M. M., 93 Marin, M. A. B., 24, 26, 27 Marin, M. L., 51 Marinov, N. M., 98, 106, 122, 123 Marley, K. A., 46 Marshall, A., 46 Martin, H. D., 247 Martinek, K., 12 Martinez, E., 92 Martins, C. T., 21 Marynowski, S., 54, 56 Masumoto, K., 228 Mateescu, G. D., 231, 243 Mathew, D. S., 16 Matsuura, A., 254 Matus, M. H., 94 Matxain, J. M., 52 Mauleon, D., 51 Mayer, G., 39, 62 Mayer, R., 46 McBain, J. W., 30 McCray, J. A., 68

267 McDonald, J. D., 109 McEnally, C. S., 123 McHedlov-Petrossyan, N. O., 22 McIver, C. D., 46 McMurry, J. E., 245 Mebel, A. M., 105 Meiggs, T. O., 51 Melius, C. F., 99 Mellows, S. M., 42, 44, 45 Menger, F. M., 6, 10, 11 Mennucci, B., 138 Mereau, R., 97, 122 Merle, J. K., 94, 95, 105 Metcalfe, W. K., 125 Michalak, J., 42, 44, 45 Miehlich, B., 138 Migdalof, B. H., 46 Miller, J. A., 90, 98, 99, 122 Miller, S. I., 51 Mills, N. S., 240 Minami, S., 45 Minero, C., 13 Miranda, K. M., 39 Miranda, M. A., 51 Mison, P., 227, 238 Mitra, A., 244 Miyamoto, K., 41 Miyashi, T., 41 Mohammad Niyaz, K., 15 Mohammad, T., 63 Molnar, J., 44, 60 Molto, J., 109 Monks, P. S., 85 Monobe, M., 224 Monti, S., 51 Moorthy, J. N., 42 Morera, I., 51 Morrison, H., 63 Mortensen, J., 248 Moss, R. A., 7, 8, 11, 18, 29 Mubofu, E. B., 17, 28 Mueller, G., 45 Mukerjee, P., 6, 10 Muller, J. G., 181 Muller-Markgraf, W., 107, 114 Munasinghe, V. R. N., 46, 66 Mun˜oz, M., 22, 24, 25 Murad, F., 39 Muralha, V., 113

268 Murray, R. K. Jr., 250 Murray, R. W., 251 Murty, B. A. R. C., 248 Musa, K. A. K., 52 Muszkat, K. A., 63 Nag, P., 123 Nagahara, T., 42, 43 Nagasawa, H. T., 39 Naik, C., 95 Najt, P. M., 121 Nakamura, Y., 45 Nakayama, T., 42, 43 Narayan, S., 2 Nascimento, D. B., 8 Navaratnam, S., 51 Nenajdenko, V. G., 220, 232, 239 Netto-Ferreira, J. C., 42, 45, 54, 60 Neuberg, C., 4 Ni, C.-K., 46 Nichols, J. W., 8 Nicolaou, K. C., 42 Nishimoto, K., 28 Nishimura, J., 45 Nishinaga, T., 251, 253, 254 Noguchi, M., 121 Noordman, W. H., 25 Novak, K., 57, 59 Novak, M., 39, 40, 42 Novaki, L. P., 21 Noziere, B., 108 Nwether, C., 224 Oberhammer, H., 224 Ochterski, J. W., 95 Ogawa, T., 45 Okamoto, K., 228 Okamoto, M., 42 O-Kawa, K., 45 Okazaki, T., 168, 170, 171 Olah, G. A., 222, 224, 225, 230, 237, 239 Olivella, S., 100 Omori, T., 42 Onishi, S., 121 Organ, P. P., 110 Otto, S., 1–3, 10, 28 Ouarti, N., 26, 27 Ozawa, T., 109

AUTHOR INDEX Pacansky, J., 97, 122 Page, M., 92 Pan, X. M., 92 Pandey, E., 16 Pang, X., 92 Paparian, S., 54, 56 Paquette, L. A., 242 Park, B. S., 41, 44, 45 Parker, W., 238 Parr, R. G., 90 Parsons, B. J., 51 Pate, C. T., 86 Patel, M. S., 29 Paul, A., 7 Pavanello, S., 98 Pavlos, C. M., 39 Pelliccioli, A. P., 39, 41, 44, 45, 54, 56 Peng, W., 46 Peng, X., 46 Pe´rez-Juste, J., 29, 30 Peric, M., 7, 9 Peters, E. M., 42 Peters, K., 42 Petersson, G. A., 95 Pfau, M., 44, 60 Pfleiderer, W., 68 Pfohl-Leszkowicz, A., 212 Phillips, G. O., 51 Pika, J., 40, 57, 58, 59 Pilling, M. J., 93 Pincock, J. A., 39 Pinkos, R., 249 Pirrung, M. C., 45 Pitz, W. J., 107 Pizzo, S. V., 63 Plistil, L., 56, 57 Pollastri, M. P., 62 Poochikian, G. K., 4 Pople, J. A., 90, 222 Porter, G., 41 Porter, N. A., 62, 63, 64 Pospisil, T., 56 Possidonio, S., 22, 23, 24 Prakash, G. K. S., 138 Prinzbach, H., 247, 248, 249 Pullin, D., 106 Pushkarsky, M. B., 92 Qin, Z., 98, 122 Quina, F. H., 13

AUTHOR INDEX Radom, L., 84, 88, 90 Raffaelli, A., 89 Ramey, D., 122 Rana, V. S., 45 Ranganathan, R., 10 Rasul, G., 220, 221, 222, 224, 227, 239, 244, 250, 254, 255, 258 Rathore, R., 223 Raudino, A., 8 Rawlins, W. T., 109 Reddy, R., 42 Reddy, V. P., 220, 227, 235, 257 Reichardt, C., 20, 21 Reid, G. P., 68 Relich, S., 56 Rice, O. K., 90 Richard, J. P., 240 Richter, H., 99 Rideout, D. C., 1 Rienstra-Kiracofe, J. C., 93, 96 Rispens, T., 10, 16, 28, 29 Rivas, C., 42 Rizzo, C. J., 187 Robinson, P. J., 90 Robinson, R. M., 57 Rock, R. S., 40 Rodrı´ guez, A., 21, 22, 25–7 Roebber, J. L., 106 Roesch, N., 221 Rogowski, J., 44, 45 Rohrs, H. W., 88 Romsted, L. S., 7, 11, 13, 18–20 Rosenthal, S. J., 64 Ross, A., 196 Ross, P. L., 97, 122 Rottger, D., 220 Rozakis, G., 63 Rupper, P., 93 Ruppert, K., 224 Ruscic, B., 92 Russell, J. C., 10 Sadvilkar, V. G., 16 Saito, M., 44 Sakai, K., 41 Sakimura, T., 224 Sammes, P. G., 41, 42, 44, 45 Sander, S. P., 85 Sanders, W. A., 106

269 Sanin-Leira, D., 45 Sankaranarayanan, J., 65 Sanrame, C. N., 52 Sarathy, S. M., 125 Saunders, M., 256 Saunders, S. M., 87 Savee, J. D., 221 Sawaryn, A., 225 Scaiano, J. C., 41, 42, 44, 45, 52, 54, 60 Scarpa, M. V., 29 Scarzello, M., 8 Schaffner, K., 232, 233, 234 Schallner, O., 231 Scherbaum, F., 221 Schindler, M., 249, 250 Schlegel, H. B. J., 82 Schleyer, P. V. R., 138 Schmidbaur, H., 221 Schmitz, L. R., 250 Schmoltner, A.-M., 106 Schnockel, H., 65 Schoebel, A., 105, 106 Schoetz, K., 250 Schuler, R. H., 106 Schuster, G. B., 183 Schwab, A. W., 123 Schwartz, W. R., 125 Schwarz, H., 220, 222, 225 Schwoerer, M. A., 66 Schworer, M., 46 Sebbar, N., 106 Seeberg, E., 181 Semenov, N. N., 83 Sendt, K., 110 Seoud, O. A. E. I., 22, 24 Sera, N., 150, 172 Serianz, A., 223 Sethuraman, S., 101 Shafirovich, V., 184 Shamma, T., 239 Shamov, A. G., 45 Shariq Vohra, M., 46 Sharma, D. K., 46 Shelley, J., 10 Shevchenko, N. E., 220 Shih, J. G., 243 Shiohara, H., 224 Shlyapochnikov, V. A., 45

270

AUTHOR INDEX

Sidhu, S., 109 Siebrand, W., 44 Simon, A., 224 Simonaitis, R., 92 Singh, J., 10 Singh, P. N. D., 57, 65 Singhal, N. V. P., 42 Singhal, R. P., 46 Sinha, A., 123 Sipos, G., 223, 226, 233 Small, R. D., 44 Smart, O. S., 40 Smirnova, J., 68 Smith, D. F., 46 Smith, G. P., 81, 91 Sobczak, M., 44, 49 Soldi, V., 19, 29 Sommer, J., 231 Somnitz, H., 97, 122 Sorensen, T. S., 245, 250 Sosnowski, J. J., 250 Sottini, S., 66 Spear, R. J., 223, 235 Srinivas, V., 3, 4 Srivastava, A., 123 Stahl, D., 225 Stang, P. J., 228 Steenken, S., 183 Steiner, U. E., 68 Stigter, D., 6 Stoermer, R., 62 Streefland, L., 25 Streit, G. E., 87, 109 Subrahmanyam, D., 45 Subramanian, P. V., 42 Sugita, N., 253 Sugiyama, K., 45 Sun, F., 245 Sun, Y., 92 Sundararajan, C., 52 Sussingham, R., 108 Suzuki, T., 42 Szeliga, J., 157

Takeuchi, K., 251 Takezaki, M., 47 Tanaka, K., 46 Tanaka, S., 224 Tang, W., 44, 45 Tarczay, G., 94 Tardy, D. C., 97, 122 Tascioglu, S., 17 Tauer, E., 44 Tcacenco, C. M., 7 Tchir, M. F., 41, 45 Tee, O. S., 12 Teranishi, H., 42 Terazima, M., 47 Terentis, A., 112, 113 Terrian, D. L., 63 Testa, A. C., 47 Teubner, J., 45 Thomas, D. D., 39 Thring, R. H., 121 Thuring, J. W., 63 Tidwell, T. T., 254 Tobita, S., 45 Tokmakov, I. V., 106 Tomasi, J., 138 Tonnies, K., 46 Tonokura, K., 107 Torii, Y., 42, 43 Toscano, J. P., 39 Trentham, D. R., 68 Tripathi, G. N. R., 106 Tripathy, S., 42 Tsang, W., 88, 97, 122 Tsao, M.-L., 57, 59 Tseng, S.-S., 48 Tsuno, T., 45 Turner, A. D., 63

Taberes, F. L., 109 Tada, E. B., 21, 26 Tae, J., 42 Takahashi, Y., 41 Takamuku, S., 42

Van De Langkruis, G. B., 11, 26, 27 van der Laarse, J. D., 109 Van der Wel, G. K., 28 Van Kruchten, E. M. G. A., 256 Van Os, N. M., 5, 6

Ujiie, K., 42 Ullman, E. F., 41, 48 Ulmius, J., 10 Unruh, K. E., 240

AUTHOR INDEX Vanos, C., 65 Vargas, F., 51 Venkat, C., 100, 101, 106 Venugopalan, P., 42 Vereecken, L., 97 Vial, C., 40 Viappiani, C., 66 Vitha, M. F., 10 Volk, M., 40 Vottero, B., 49 Vovelle, C., 106 Wagner, P. J., 41–5, 49 Wagstaff, K., 245 Walker, A. M., 245 Walker, J. W., 68 Walker, J., 113 Walker, R. W., 93 Wallace, T. W., 42, 44, 45 Wallington, T. J., 91, 92, 98 Wallraff, G. M., 171 Walsh, R., 97, 122 Wan, P., 51 Wang, H., 113 Wang, Q., 236 Wang, R. C., 121 Wang, T., 40 Wang, Z., 106 Ward, B., 106 Warnatz, J., 87, 91 Warshawsky, D. J., 138 Watkins, K. W., 97, 122 Watt, C. I. F., 238 Weakley, T. J. R., 228 Weber, K., 249 Weber, W., 231 Wei, K.-M., 46 Weickhardt, C., 46 Weisman, J. L., 106 Weller, H., 44 Wen, Y. X., 46 Wessig, P., 45 Westbrook, C. K., 89, 121, 123 Westmoreland, P. R., 99 Wetmore, S. D., 212 Wettermark, G., 41, 45, 46 White, A. M., 225 Whitwood, A. C., 46 Wiater-Protas, I., 106

271 Wigner, E. P. Z., 90 Wijnen, J. W., 28 Wijtmans, M., 64 Wildman, T. A., 44 Williams, A., 87, 109 Williams, J. A., 98 Williams, R. V., 233 Wilson, R. M., 42 Winkler, J. R., 40 Wintgens, V., 42, 45 Wirz, J., 39, 41–6, 54, 56, 57, 66 Witte, F. M., 11, 26 Wittung-Stafshede, P., 40 Woell, D., 68 Wogan, G. N., 39 Wolfrom, J., 89 Wolinski, K., 138 Wollenhaupt, M., 92 Wollenweber, M., 249 Wolszczak, M., 42 Wong, M. W., 220 Wood, A. W., 135 Woolley, G. A., 40 Wright, P. J., 57, 59 Wu, C. W., 45 Wu, S. H. W., 8 Xie, H., 109 Xie, Z., 221 Xing, J.-H., 93 Xu, H., 39 Xu, S., 46 Xue, W., 135, 136 Yamamoto, K., 42 Yamashita, Y., 224 Yamauchi, N., 97, 122 Yang, N. C., 42, 51 Yao, H., 26 Yates, P., 44 Yeung, L. Y., 109, 113 Yip, R. W., 46 Yong, P. K., 49 Yoshino, A., 10 Yoshioka, M., 44 Young, D. D., 39 Yousef, A. L., 41 Yu, T., 101 Yuan, H., 247, 250

272 Zabadal, M., 44, 45, 54, 56 Zachariasse, K. A., 21 Zalyubovsky, S. J., 94 Zangi, R., 8 Zaslonko, I. S., 92 Zerefos, C. S., 81 Zgierski, M. Z., 44 Zhang, H.-Y., 105, 106 Zhang, W. C., 2

AUTHOR INDEX Zhang, X., 88 Zhao, G., 42 Zhenyi, C., 124 Zhou, D., 88 Zhu, Y., 40 Zuidema, D. R., 54 Zwanenburg, B., 64 Zwicker, E. F., 51

Cumulative Index of Authors Abboud, J.-L.M., 37, 57 Ahlberg, P., 19, 223 Alabugin, I., 42, 1 Albery, W.J., 16, 87; 28, 139 Alden, J.A., 32, 1 Alkorta, I., 37, 57 Allinger, N.I., 13, 1 Amyes, T.L., 35, 67; 39, 1 Anbar, M., 7, 115 Antoniou, D., 41, 317 Arnett, E.M., 13, 83; 28, 45 Ballester, M., 25, 267 Bard, A.J., 13, 155 Basner, J., 41, 317 Baumgarten, M., 28, 1 Beer, P.D., 31, I Bell, R.P., 4, 1 Bennett, J.E., 8, 1 Bentley, T.W., 8, 151; 14, 1 Berg, U., 25, 1 Berger, S., 16, 239 Bernasconi, C.F., 27, 119; 37, 137 Berreau, L.M., 41, 81 Berti, P.J., 37, 239 Bethell, D., 7, 153; 10, 53 Blackburn, G.M., 31, 249 Blandamer, M.J., 14, 203 Bohne, C., 42, 167 Bond, A.M., 32, 1 Borosky, G. L., 43, 135 Bowden, K., 28, 171 Brand, J.C.D., 1, 365 Bra¨ndstro¨m, A., 15, 267 Braun-Sand, S., 40, 201 Breiner, B., 42, 1 Brinker, U.H., 40, 1 Brinkman, M.R., 10, 53 Brown, H.C., 1, 35 Brown, R.S., 42, 271 Buncel, E., 14, 133 Bunton, C.A., 21, 213 Buurma, N. J., 43, 1

Cabell-Whiting, P.W., 10, 129 Cacace, F., 8, 79 Capon, B., 21, 37 Carter, R.E., 10, 1 Chen, Z., 31, 1 Clennan, E.L., 42, 225 Collins, C.J., 2, 1 Compton, R.G., 32, 1 Cornelisse, J., 11, 225 Cox, R.A., 35, 1 Crampton, M.R., 7, 211 Datta, A., 31, 249 Da´valos, J.Z., 37, 57 Davidson, R.S., 19, 1; 20,191 de Gunst, G.P., 11, 225 de Jong, F., 7, 279 Denham, H., 31, 249 Desvergne, J.P., 15, 63 Detty, M.R., 39, 79 Dosunmu, M.I., 21, 37 Drechsler, U., 37, 315 Eberson, K., 12, 1; 18, 79; 31, 91 Eberson, U., 36, 59 Ekland, J.C., 32, 1 Eldik, R.V., 41, 1 Emsley, J., 26, 255 Engdahl, C., 19, 223 Farnum, D.G., 11, 123 Fendler, E.J., 8, 271 Fendler, J.H., 8, 271; 13, 279 Ferguson, G., 1, 203 Fields, E.K., 6, 1 Fife, T.H., 11, 1 Fleischmann, M., 10, 155 Frey, H.M., 4, 147 Fujio, M., 32, 267 Gale, P.A., 31, 1 Gao, J., 38, 161 Garcia-Viloca, M., 38, 161 Gilbert, B.C., 5, 53 Gillespie, R.J., 9, 1

273

Glover, S.A., 42, 35 Gold, V., 7, 259 Goodin, J.W., 20, 191 Gould, I.R., 20, 1 Greenwood, H.H., 4, 73 Gritsan, N.P., 36, 255 Gudmundsdottir, A. D., 43, 39 Hadad, C. M., 43, 79 Hamilton, T.D., 40, 109 Hammerich, O., 20, 55 Harvey, N.G., 28, 45 Hasegawa, M., 30, 117 Havjnga, E., 11, 225 Hayes, C. J., 43, 79 Henderson, R.A., 23, 1 Henderson, S., 23, 1 Hengge, A.C., 40, 49 Hibbert, F., 22, 113; 26, 255 Hine, J., 15, 1 Hogen-Esch, T.E., 15, 153 Hogeveen, H., 10, 29, 129 Horenstein, N.A., 41, 277 Hubbard, C.D., 41, 1 Huber, W., 28, 1 Ireland, J.F., 12, 131 Iwamura, H., 26, 179 Johnson, S.L., 5, 237 Johnstone, R.A.W., 8, 151 Jonsa¨ll, G., 19, 223 Jose´, S.M., 21, 197 Kemp, G., 20, 191 Kice, J.L., 17, 65 Kirby, A.J., 17, 183; 29, 87 Kitagawa, T., 30, 173 Kluger, R.H., 25, 99 Kochi, J.K., 29, 185; 35, 193 Kohnstam, G., 5, 121 Korolev, V.A., 30, 1 Korth, H.-G., 26, 131 Kramer, G.M., 11, 177 Kreevoy, M.M., 6, 63; 16, 87 Kunitake, T., 17, 435

274 Kurtz, H.A., 29, 273 Laali, K.K., 43, 135 Le Fe`vre, R.J.W., 3, 1 Ledwith, A., 13, 155 Lee, I., 27, 57 Lee, J.K., 38, 183 Liler, M., 11, 267 Lin, S.-S., 35, 67, 351 Lodder, G., 37, 1 Logan, M.E., 39, 79 Long, F.A., 1, 1 Lu¨ning, U., 30, 63 Maccoll, A., 3, 91 MacGillivray, L.R., 40, 109 McWeeny, R., 4, 73 Manderville, R.A., 43, 177 Mandolini, L., 22, 1 Manoharan, M., 42, 1 Maran, F., 36, 85 Matsson, O., 31, 143 Melander, L., 10, 1 Merle, J. K., 43, 79 Mile, B., 8, 1 Miller, S.I., 6, 185 Mo, Y., 38, 161 Modena, G., 9, 185 More O’Ferrall, R.A., 5, 331 Morsi, S.E., 15, 63 Mu¨llen, K., 28, 1 Mu¨ller, P., 37, 57 Muthukrishnan, S., 43, 39 Nefedov, O.M., 30, 1 Nelsen, S.F., 41, 185 Neta, P., 12, 223 Neverov, A.A., 42, 271 Nibbering, N.M.M., 24, 1 Norman, R.O.C., 5, 33 Novak, M., 36, 167 Nu´ne˜z, S., 41, 317 Nyberg, K., 12, 1 O’Donoghue, A.M.C., 35, 67 Okamoto, K., 30, 173 Okuyama, T., 37, 1 Olah, G.A., 4, 305 Olsson, M.H.M., 40, 201 Oxgaard, J., 38, 87 Paddon-Row, M.N., 38, 1 Page, M.I., 23, 165 Parker, A.J., 5, 173

CUMULATIVE INDEX OF AUTHORS Parker, V.D., 19, 131; 20, 55 Peel, T.E., 9, 1 Perkampus, H.H., 4, 195 Perkins, M.J., 17, 1 Pittman, C.U., Jr., 4, 305 Platz, M.S., 36, 255 Pletcher, D., 10, 155 Poulsen, T.D., 38, 161 Prakash, G.K.S., 43, 219 Pross, A., 14, 69; 21, 99 Quintanilla, E., 37, 57 Rajagopal, S., 36, 167 Rajca, A., 40, 153 Ramirez, F., 9, 25 Rappoport, Z., 7, 1; 27, 239 Rathore, R., 35, 193 Reddy, V. P., 43, 219 Reeves, L.W., 3, 187 Reinboudt, D.N., 17, 279 Richard, J.P., 35, 67; 39, 1 Ridd, J.H., 16, 1 Riveros, J.M., 21, 197 Robertson, J.M., 1, 203 Romesberg, F.E., 39, 27 Rose, P.L., 28, 45 Rosenberg, M.G., 40, 1 Rosenthal, S.N., 13, 279 Rotello, V.M., 37, 3l5 Ruasse, M.-F., 28, 207 Russell, G.A., 23, 271 Saettel, N.j., 38, 87 Samuel, D., 3, 123 Sanchez, M. de N. de M., 21, 37 Sandstro¨m, J., 25, 1 Sankaranarayanan, J., 43, 39 Save´ant, J.-M., 26, 1; 35, 117 Savelli, G., 22, 213 Schaleger, L.L., 1, 1 Scheraga, H.A., 6, 103 Schleyer, P., von R., 14, 1 Schmidt, S.P., 18, 187 Schowen, R.L., 39, 27 Schuster, G.B., 18, 187; 22, 311 Schwartz, S.D., 41, 317 Scorrano, G., 13, 83 Shatenshtein, A.I., 1, 156 Shine, H.J., 13, 155

Shinkai, S., 17, 435 Siehl, H.-U., 23, 63 Siehl, H-U., 42, 125 Silver, B.L., 3, 123 Simonyi, M., 9, 127 Sinnott, M.L., 24, 113 Speranza, M., 39, 147 Stock, L.M., 1, 35 Strassner, T., 38, 131 Sugawara, T., 32, 219 Sustmann, R., 26, 131 Symons, M.C.R., 1, 284 Takashima, K., 21, 197 Takasu, I., 32, 219 Takeuchi, K., 30, 173 Tamara, C.S. Pace, 42, 167 Tanaka, K.S.E., 37, 239 Tantillo, D.J., 38, 183 Ta-Shma, R., 27, 239 Tedder, J.M., 16, 51 Tee, O.S., 29, 1 Thatcher, G.R.J., 25, 99 Thomas, A., 8, 1 Thomas, J.M., 15, 63 Tidwell, T.T., 36, 1 Tonellato, U., 9, 185 Toteva, M.M., 35, 67; 39, 1 Toullec, J., 18, 1 Tsuji, Y., 35, 67; 39, 1 Tsuno, Y., 32, 267 Tu¨do¨s, F., 9, 127 Turner, D.W., 4, 31 Turro, N.J., 20, 1 Ugi, I., 9, 25 Walton, J.C., 16, 51 Ward, B., 8, 1 Warshel, A., 40, 201 Watt, C.I.F., 24, 57 Wayner, D.D.M., 36, 85 Wentworth, P., 31, 249 Westaway, K.C., 31, 143; 41, 219 Westheimer, F.H., 21, 1 Whalen, D.L., 40, 247 Whalley, E., 2, 93 Wiest, O., 38, 87 Williams, A., 27, 1 Williams, D.L.H., 19, 381

CUMULATIVE INDEX OF AUTHORS Williams, J.M., Jr., 6, 63 Williams, J.O., 16, 159 Williams, K.B., 35, 67 Williams, R.V., 29, 273 Williamson, D.G., 1, 365

Wilson, H., 14, 133 Wolf, A.P., 2, 201 Wolff, J.J., 32, 121 Workentin, M.S., 36, 85 Wortmaan, R., 32, 121

275 Wyatt, P.A.H., 12, 131 Zimmt, M.B., 20, 1 Zipse, H., 38, 111 Zollinger, H., 2, 163 Zuman, P., 5, 1

Cumulative Index of Titles

Abstraction, hydrogen atom, from O—H bonds, 9, 127 Acid–base behaviour macroeycles and other concave structures, 30, 63 Acid–base properties of electronically excited states of organic molecules, 12, 131 Acid solutions, strong, spectroscopic observation of alkylcarbonium ions in, 4, 305 Acids, reactions of aliphatic diazo compounds with, 5, 331 Acids, strong aqueous, protonation and solvation in, 13, 83 Acids and bases, oxygen and nitrogen in aqueous solution, mechanisms of proton transfer between, 22, 113 Activation, entropies of, and mechanisms of reactions in solution, 1, 1 Activation, heat capacities of, and their uses in mechanistic studies, 5, 121 Activation, volumes of, use for determining reaction mechanisms, 2, 93 Addition reactions, gas-phase radical directive effects in, 16, 51 Aliphatic diazo compounds, reactions with acids, 5, 331 Alkene oxidation reactions by metal-oxo compounds, 38, 131 Alkyl and analogous groups, static and dynamic stereochemistry of, 25, 1 Alkylcarbonium ions, spectroscopic observation in strong acid solutions, 4, 305 Ambident conjugated systems, alternative protonation sites in, 11, 267 Ammonia liquid, isotope exchange reactions of organic compounds in, 1, S56 Anions, organic, gas-phase reactions of, 24, 1 Antibiotics, b-lactam, the mechanisms of reactions of, 23, 165 Aqueous mixtures, kinetics of organic reactions in water and, 14, 203 Aromatic photosubstitution, nucleophilic, 11, 225 Aromatic substitution, a quantitative treatment of directive effects in, 1, 35 Aromatic substitution reactions, hydrogen isotope effects in, 2, 163 Aromatic systems, planar and non-planar, 1, 203 N-Arylnitrenium ions, 36, 167 Aryl halides and related compounds, photochemistry of, 20, 191 Arynes, mechanisms of formation and reactions at high temperatures, 6, 1 A-SE2 reactions, developments In the study of, 6, 63 Base catalysis, general, of ester hydrolysis and related reactions, 5, 237 Basicity of unsaturated compounds, 4, 195 Bimolecular substitution reactions in protic and dipolar aprotic solvents, 5, 173 Bond breaking, 35, 117 Bond formation, 35, 117 Bromination, electrophilic, of carbon–carbon double bonds: structure, solvent and mechanisms, 28, 207 I3C NMR spectroscopy in macromolecular systems of biochemical interest, 13, 279 Captodative effect, the, 26, 131 Carbanion reactions, ion-pairing effects in, 15, 153 Carbene chemistry, structure and mechanism in, 7, 163

277

278

CUMULATIVE INDEX OF TITLES

Carbenes generated within cyclodextrins and zeolites, 40, 1, 353 Carbenes having aryl substituents, structure and reactivity of, 22, 311 Carbocation rearrangements, degenerate, 19, 223 Carbocationic systems, the Yukawa–Tsuno relationship in, 32, 267 Carbocations, partitioning between addition of nucleophiles and deprotonation, 35, 67 Carbocations, thermodynamic stabilities of, 37, 57 Carbon atoms, energetic, reactions with organic compounds, 3, 201 Carbon monoxide, reactivity of carbonium ions towards, 10, 29 Carbonium ions, gaseous, from the decay of tritiated molecules, 8, 79 Carbonium ions, photochemistry of, 10, 129 Carbonium ions, reactivity towards carbon monoxide, 10, 29 Carbonium ions (alkyl), spectroscopic observation in strong acid solutions, 4, 305 Carbonyl compounds, reversible hydration of, 4, 1 Carbonyl compounds, simple, enolisation and related reactions of, 18, 1 Carboxylic acids, tetrahedral intermediates derived from, spectroscopic detection and investigation of their properties, 21, 37 Catalysis, by micelles, membranes and other aqueous aggregates as models of enzyme action, 17, 435 Catalysis, enzymatic, physical organic model systems and the problem of, 11, 1 Catalysis, general base and nucleophilic, of ester hydrolysis and related reactions, 5, 237 Catalysis, micellar, in organic reactions; kinetic and mechanistic implications, 8, 271 Catalysis, phase-transfer by quaternary ammonium salts, 15, 267 Catalytic antibodies, 31, 249 Cation radicals, in solution, formation, properties and reactions of, 13, 155 Cation radicals, organic, in solution, and mechanisms of reactions of, 20, 55 Cations, vinyl, 9, 135 Chain molecules, intramolecular reactions of, 22, 1 Chain processes, free radical, in aliphatic systems involving an electron transfer reaction, 23, 271 Charge density-NMR chemical shift correlation in organic ions, 11, 125 Charge distribution and charge separation in radical rearrangement reactions, 38, 111 Chemically induced dynamic nuclear spin polarization and its applications, 10, 53 Chemiluminesance of organic compounds, 18, 187 The chemistry of reactive radical intermediates in combustion and the atmosphere, 43, 79 Chiral clusters in the gas phase, 39, 147 Chirality and molecular recognition in monolayers at the air–water interface, 28, 45 CIDNP and its applications, 10, 53 Colloidal medium effects on organic reactions in aqueous colloidal solutions, 43, 1 Computer modeling of enzyme catalysis and its relationship to concepts in physical organic chemistry, 40, 201 Computational studies of alkene oxidation reactions by metal-oxo compounds, 38, 131 Computational studies on the mechanism of orotidine monophosphate decarboxylase, 38, 183 Conduction, electrical, in organic solids, 16, 159 Configuration mixing model: a general approach to organic reactivity, 21, 99 Conformations of polypeptides, calculations of, 6, 103 Conjugated molecules, reactivity indices, in, 4, 73 Cross-interaction constants and transition-state structure in solution, 27, 57 Crown-ether complexes, stability and reactivity of, 17, 279

CUMULATIVE INDEX OF TITLES

279

Crystalographic approaches to transition state structures, 29, 87 Cycloaromatization reactions: the testing ground for theory and experiment, 42, 1 Cyclodextrins and other catalysts, the stabilisation of transition states by, 29, 1 D2O—H2O mixtures, protolytic processes in, 7, 259 Degenerate carbocation rearrangements, 19, 223 Deuterium kinetic isotope effects, secondary, and transition state structure, 31, 143 Diazo compounds, aliphatic, reactions with acids, 5, 331 Diffusion control and pre-association in nitrosation, nitration, and halogenation, 16, 1 Dimethyl sulphoxide, physical organic chemistry of reactions, in, 14, 133 Diolefin crystals, photodimerization and photopolymerization of, 30, 117 Dipolar aptotic and protic solvents, rates of bimolecular substitution reactions in, 5, 173 Directive effects, in aromatic substitution, a quantitative treatment of, 1, 35 Directive effects, in gas-phase radical addition reactions, 16, 51 Discovery of mechanisms of enzyme action 1947–1963, 21, 1 Displacement reactions, gas-phase nucleophilic, 21, 197 Donor/acceptor organizations, 35, 193 Double bonds, carbon–carbon, electrophilic bromination of: structure, solvent and mechanism, 28, 171 Dynamics for the reactions of ion pair intermediates of solvolysis, 39, 1 Dynamics of guest binding to supramolecular systems: techniques and selected examples, 42, 167 Effect of enzyme dynamics on catalytic activity, 41, 317 Effective charge and transition-state structure in solution, 27, 1 Effective molarities of intramolecular reactions, 17, 183 Electrical conduction in organic solids, 16, 159 Electrochemical methods, study of reactive intermediates by, 19, 131 Electrochemical recognition of charged and neutral guest species by redox-active receptor molecules, 31, 1 Electrochemistry, organic, structure and mechanism in, 12, 1 Electrode processes, physical parameters for the control of, 10, 155 Electron donor–acceptor complexes, electron transfer in the thermal and photochemical activation of, in organic and organometallic reactions, 29, 185 Electron spin resonance, identification of organic free radicals, 1, 284 Electron spin resonance, studies of short-lived organic radicals, 5, 23 Electron storage and transfer in organic redox systems with multiple electrophores, 28, 1 Electron transfer, 35, 117 Electron transfer, in thermal and photochemical activation of electron donor-acceptor complexes in organic and organometallic reactions, 29, 185 Electron transfer, long range and orbital interactions, 38, 1 Electron transfer reactions within s- and p-bridged nitrogen-centered intervalence radical ions, 41, 185 Electron-transfer, single, and nucleophilic substitution, 26, 1 Electron-transfer, spin trapping and, 31, 91 Electron-transfer paradigm for organic reactivity, 35, 193 Electron-transfer reaction, free radical chain processes in aliphatic systems involving an, 23, 271

280

CUMULATIVE INDEX OF TITLES

Electron-transfer reactions, in organic chemistry, 18, 79 Electronically excited molecules, structure of, 1, 365 Electronically excited states of organic molecules, acid-base properties of, 12, 131 Energetic tritium and carbon atoms, reactions of, with organic compounds, 2, 201 Enolisation of simple carbonyl compounds and related reactions, 18, 1 Entropies of activation and mechanisms of reactions in solution, 1, 1 Enzymatic catalysis, physical organic model systems and the problem of, 11, 1 Enzyme action, catalysis of micelles, membranes and other aqueous aggregates as models of, 17, 435 Enzyme action, discovery of the mechanisms of, 1947–1963, 21, 1 Equilibrating systems, isotope effects in NMR spectra of, 23, 63 Equilibrium constants, NMR measurements of, as a function of temperature, 3, 187 Ester hydrolysis, general base and nucleophitic catalysis, 5, 237 Ester hydrolysis, neighbouring group participation by carbonyl groups in, 28, 171 Excess acidities, 35, 1 Exchange reactions, hydrogen isotope, of organic compounds in liquid ammonia, 1, 156 Exchange reactions, oxygen isotope, of organic compounds, 2, 123 Excited complexes, chemistry of, 19, 1 Excited molecular, structure of electronically, 3, 365 Finite molecular assemblies in the organic solid state: toward engineering properties of solids, 40, 109 Fischer carbene complexes, 37, 137 Force-field methods, calculation of molecular structure and energy by, 13, 1 Free radical chain processes in aliphatic systems involving an electron-transfer reaction, 23, 271 Free Radicals 1900–2000, The Gomberg Century, 36, 1 Free radicals, and their reactions at low temperature using a rotating cryostat, study of, 8, 1 Free radicals, identification by electron spin resonance, 1, 284 Gas-phase heterolysis, 3, 91 Gas-phase nucleophilic displacement reactions, 21, 197 Gas-phase pyrolysis of small-ring hydrocarbons, 4, 147 Gas-phase reactions of organic anions, 24, 1 Gaseous carbonium ions from the decay of tritiated molecules, 8, 79 General base and nucleophilic catalysis of ester hydrolysis and related reactions, 5, 237 The Gomberg Century: Free Radicals 1900–2000, 36, 1 Gomberg and the Nobel Prize, 36, 59 H2O—D2O mixtures, protolytic processes in, 7, 259 Halides, aryl, and related compounds, photochemistry of, 20, 191 Halogenation, nitrosation, and nitration, diffusion control and pre-association in, 16, 1 Heat capacities of activation and their uses in mechanistic studies, 5, 121 Heterolysis, gas-phase, 3, 91 High-spin organic molecules and spin alignment in organic molecular assemblies, 26, 179 Homoaromaticity, 29, 273 How does structure determine organic reactivity, 35, 67 Hydrated electrons, reactions of, with organic compounds, 7, 115

CUMULATIVE INDEX OF TITLES

281

Hydration, reversible, of carbonyl compounds, 4, 1 Hydride shifts and transfers, 24, 57 Hydrocarbon radical cations, structure and reactivity of, 38, 87 Hydrocarbons, small-ring, gas-phase pyrolysis of, 4, 147 Hydrogen atom abstraction from 0—H bonds, 9, 127 Hydrogen bonding and chemical reactivity, 26, 255 Hydrogen isotope effects in aromatic substitution reactions, 2, 163 Hydrogen isotope exchange reactions of organic compounds in liquid ammonia, 1, 156 Hydrolysis, ester, and related reactions, general base and nucleophilic catalysis of, 5, 237 Interface, the air-water, chirality and molecular recognition in monolayers at, 28, 45 Intermediates, reactive, study of, by electrochemical methods, 19, 131 Intermediates, tetrahedral, derived from carboxylic acids, spectroscopic detection and investigation of their properties, 21, 37 Intramolecular reactions, effective molarities for, 17, 183 Intramolecular reactions, of chain molecules, 22, 1 Ionic dissociation of carbon-carbon a-bonds in hydrocarbons and the formation of authentic hydrocarbon salts, 30, 173 Ionization potentials, 4, 31 Ion-pairing effects in carbanion reactions, 15, 153 Ions, organic, charge density-NMR chemical shift correlations, 11, 125 Isomerization, permutational, of pentavalent phosphorus compounds, 9, 25 Isotope effects and quantum tunneling in enzyme-catalyzed hydrogen transfer. Part I. The experimental basis, 39, 27 Isotope effects, hydrogen, in aromatic substitution reactions, 2, 163 Isotope effects, magnetic, magnetic field effects and, on the products of organic reactions, 20, 1 Isotope effects, on NMR spectra of equilibrating systems, 23, 63 Isotope effects, steric, experiments on the nature of, 10, 1 Isotope exchange reactions, hydrogen, of organic compounds in liquid ammonia, 1, 150 Isotope exchange reactions, oxygen, of organic compounds, 3, 123 Isotopes and organic reaction mechanisms, 2, 1 Kinetics, and mechanisms of reactions of organic cation radicals in solution, 20, 55 Kinetics and mechanism of the dissociative reduction of C—X and X—X bonds (X ¼ O, S), 36, 85 Kinetic and mechanistic studies of the reactivity Zn–Ohn (n=1 or 2) species in small molecule analogs of zinc-containing metalloenzymes, 41, 81 Kinetics and spectroscopy of substituted phenylnitrenes, 36, 255 Kinetics, of organic reactions in water and aqueous mixtures, 14, 203 Kinetics, reaction, polarography and, 5, 1 -Lactam antibiotics, mechanisms of reactions, 23, 165 Least nuclear motion, principle of, 15, 1 Macrocyles and other concave structures, acid-base behaviour in, 30, 63 Macromolecular systems of biochemical interest, 13C NMR spectroscopy in, 13, 279 Magnetic field and magnetic isotope effects on the products of organic reactions, 20, 1

282

CUMULATIVE INDEX OF TITLES

Mass spectrometry, mechanisms and structure in: a comparison with other chemical processes, 8, 152 Matrix infrared spectroscopy of intermediates with low coordinated carbon silicon and germanium atoms, 30, 1 Mechanism and reactivity in reactions of organic oxyacids of sulphur and their anhydrides, 17, 65 Mechanism and structure, in carbene chemistry, 7, 153 Mechanism and structure, in mass spectrometry: a comparison with other chemical processes, 8, 152 Mechanism and structure, in organic electrochemistry, 12, 1 Mechanism of the dissociative reduction of C—X and X—X bonds (X¼O, S), kinetics and, 36, 85 Mechanisms for nucleophilic aliphatic substitution at glycosides, 41, 277 Mechanisms of hydrolysis and rearrangements of epoxides, 40, 247 Mechanisms of oxygenations in zeolites, 42, 225 Mechanisms, nitrosation, 19, 381 Mechanisms, of proton transfer between oxygen and nitrogen acids and bases in aqueous solutions, 22, 113 Mechanisms, organic reaction, isotopes and, 2, 1 Mechanisms of reaction, in solution, entropies of activation and, 1, 1 Mechanisms of reaction, of -lactam antibiotics, 23, 165 Mechanisms of solvolytic reactions, medium effects on the rates and, 14, 10 Mechanistic analysis, perspectives in modern voltammeter: basic concepts and, 32, 1 Mechanistic applications of the reactivity–selectivity principle, 14, 69 Mechanistic studies, heat capacities of activation and their use, 5, 121 Mechanistic studies on enzyme-catalyzed phosphoryl transfer, 40, 49 Medium effects on the rates and mechanisms of solvolytic reactions, 14, 1 Meisenheimer complexes, 7, 211 Metal-catalyzed alcoholysis reactions of carboxylate and organophosphorus esters, 42, 271 Metal complexes, the nucleophilicity of towards organic molecules, 23, 1 Methyl transfer reactions, 16, 87 Micellar catalysis in organic reactions: kinetic and mechanistic implications, 8, 271 Micelles, aqueous, and similar assemblies, organic reactivity in, 22, 213 Micelles, membranes and other aqueous aggregates, catalysis by, as models of enzyme action, 17, 435 Molecular recognition, chirality and, in monolayers at the air-water interface, 28, 45 Molecular structure and energy, calculation of, by force-field methods, 13, 1 N-Acyloxy-N-alkoxyamides – structure, properties, reactivity and biological activity, 42, 35 N-Arylnitrinium ions, 36, 167 Neighbouring group participation by carbonyl groups in ester hydrolysis, 28, 171 Nitration, nitrosation, and halogenation, diffusion control and pre-association in, 16, 1 Nitrosation, mechanisms, 19, 381 Nitrosation, nitration, and halogenation, diffusion control and pre-association in, 16, 1 NMR chemical shift-charge density correlations, 11, 125 NMR measurements of reaction velocities and equilibrium constants as a function of temperature, 3, 187 NMR spectra of equilibriating systems, isotope effects on, 23, 63

CUMULATIVE INDEX OF TITLES

283

NMR spectroscopy, 13C, in macromolecular systems of biochemical interest, 13, 279 Nobel Prize, Gomberg and the, 36, 59 Non-linear optics, organic materials for second-order, 32, 121 Non-planar and planar aromatic systems, 1, 203 Norbornyl cation: reappraisal of structure, 11, 179 Nuclear magnetic relaxation, recent problems and progress, 16, 239 Nuclear magnetic resonance see NMR Nuclear motion, principle of least, 15, 1 Nuclear motion, the principle of least, and the theory of stereoelectronic control, 24, 113 Nucleophiles, partitioning of carbocations between addition and deprotonation, 35, 67 Nucleophili aromatic photolabstitution, 11, 225 Nucleophilic catalysis of ester hydrolysis and related reactions, 5, 237 Nucleophilic displacement reactions, gas-phase, 21, 197 Nucleophili substitution, in phosphate esters, mechanism and catalysis of, 25, 99 Nucleophilic substitution, single electron transfer and, 26, 1 Nucleophilic substitution reactions in aqueous solution, 38, 161 Nuckophilic vinylic substitution, 7, 1 Nucleophilic vinylic substitution and vinyl cation intermediates in the reactions of vinyl iodonium salts, 37, 1 Nucleophilicity of metal complexes towards organic molecules, 23, 1 O—H bonds, hydrogen atom abstraction from, 9, 127 One- and two-electron oxidations and reductions of organoselenium and organotellurium compounds, 39, 79 Orbital interactions and long-range electron transfer, 38, 1 Organic materials for second-order non-linear optics, 32, 121 Organic reactivity, electron-transfer paradigm for, 35, 193 Organic reactivity, structure determination of, 35, 67 Orotidine monophosphate decarboxylase, the mechanism of, 38, 183 Oxyacids of sulphur and their anhydrides, mechanisms and reactivity in reactions of organic, 17, 65 Oxygen isotope exchange reactions of organic compounds, 3, 123 Partitioning of carbocations between addition of nucleophiles and deprotonation, 35, 67 Perchloro-organic chemistry: structure, spectroscopy and reaction pathways, 25, 267 Permutations isomerization of pentavalent phosphorus compounds, 9, 25 Phase-transfer catalysis by quaternary ammonium salts, 15, 267 Phenylnitrenes, Kinetics and spectroscopy of substituted, 36, 255 Phosphate esters, mechanism and catalysis of nuclcophilic substitution in, 25, 99 Phosphorus compounds, pentavalent, turnstile rearrangement and pseudoration in permutational isomerization, 9, 25 Photochemistry, of aryl halides and related compounds, 20, 191 Photochemistry, of carbonium ions, 9, 129 Photodimerization and photopolymerization of diolefin crystals, 30, 117 Photoremovable protecting groups based on photoenolization, 43, 39 Photosubstitution, nucleophilic aromatic, 11, 225 Planar and non-planar aromatic systems, 1, 203 Polarizability, molecular refractivity and, 3, 1 Polarography and reaction kinetics, 5, 1

284

CUMULATIVE INDEX OF TITLES

Polypeptides, calculations of conformations of, 6, 103 Pre-association, diffusion control and, in nitrosation, nitration, and halogenation, 16, 1 Principle of non-perfect synchronization, 27, 119 Products of organic reactions, magnetic field and magnetic isotope effects on, 30, 1 Protic and dipolar aprotic solvents, rates of bimolecular substitution reactions in, 5, 173 Protolytic processes in H2O—D2O mixtures, 7, 259 Proton transfer between oxygen and nitrogen acids and bases in aqueous solution, mechanisms of, 22, 113 Protonation and solvation in strong aqueous acids, 13, 83 Protonation sites in ambident conjugated systems, 11, 267 Pseudorotation in isomerization of pentavalent phosphorus compounds, 9, 25 Pyrolysis, gas-phase, of small-ring hydrocarbons, 4, 147 Radiation techniques, application to the study of organic radicals, 12, 223 Radical addition reactions, gas-phase, directive effects in, 16, 51 Radical rearrangement reactions, charge distribution and charge separation in, 38, 111 Radicals, cation in solution, formation, properties and reactions of, 13, 155 Radicals, organic application of radiation techniques, 12, 223 Radicals, organic cation, in solution kinetics and mechanisms of reaction of, 20, 55 Radicals, organic free, identification by electron spin resonance, 1, 284 Radicals, short-lived organic, electron spin resonance studios of, 5, 53 Rates and mechanisms of solvolytic reactions, medium effects on, 14, 1 Reaction kinetics, polarography and, 5, 1 Reaction mechanisms, in solution, entropies of activation and, 1, 1 Reaction mechanisms, use of volumes of activation for determining, 2, 93 Reaction velocities and equilibrium constants, NMR measurements of, as a function of temperature, 3, 187 Reactions, in dimethyl sulphoxide, physical organic chemistry of, 14, 133 Reactions, of hydrated electrons with organic compounds, 7, 115 Reactive intermediates, study of, by electrochemical methods, 19, 131 Reactivity, organic, a general approach to; she configuration mixing model, 21, 99 Reactivity indices in conjugated molecules, 4, 73 Reactivity-selectivity principle and its mechanistic applications, 14, 69 Rearrangements, degenerate carbocation, 19, 223 Recent studies of persistent carbodications, 43, 219 Receptor molecules, redox-active, electrochemical recognition of charged and neutral guest species by, 31, 1 Redox and recognition processes, interplay between, 37, 315 Redox systems, organic, with multiple electrophores, electron storage and transfer in, 28, 1 Reduction of C—X and X—X bonds (X¼O, S), kinetics and mechanism of the dissociative, 36, 85 Refractivity, molecular, and polarizability, 3, 1 Relaxation, nuclear magnetic, recent problems and progress, 16, 239 Selectivity of solvolyses and aqueous alcohols and related mixtures, solvent-induced changes in, 27, 239 Short-lived organic radicals, electron spin resonance studies of, 5, 53 Small-ring hydrocarbons, gas-phase pyrolysis of, 4, 147

CUMULATIVE INDEX OF TITLES

285

Solid state, tautomerism in the, 32, 129 Solid-state chemistry, topochemical phenomena in, 15, 63 Solids, organic, electrical conduction in, 16, 159 Solutions, reactions in, entropies of activation and mechanisms, 1, 1 Solvation and protonation in strong aqueous acids, 13, 83 Solvent effects, reaction coordinates, and reorganization energies on nucleophilic substitution reactions in aqueous solution, 38, 161 Solvent, protic and dipolar aprotic, rates of bimolecular substitution-reactions in, 5, 173 Solvent-induced changes in the selectivity of solvolyses in aqueous alcohols and related mixtures, 27, 239 Solvolytic reactions, medium effects on the rates and mechanisms of, 14, 1 Spectroscopic detection of tetrahedral intermediates derived from carboxylic acids and the investigation of their properties, 21, 37 Spectroscopic observations ofalkylcarbonium ions in strong acid solutions, 4, 305 Spectroscopy, 13C NMR in macromolecular systems of biochemical interest, 13, 279 Spectroscopy of substituted phenylnitrenes, kinetics and, 36, 255 Spin alignment, in organic molecular assemblies, high-spin organic molecules and, 26, 179 Spin trapping, 17, 1 Spin trapping, and electron transfer, 31, 91 Stable carbocations and onium ions from polycondensed aromatic and heteroaromatic compounds as models for biological electrophiles and DNA-transalkylating agents, 43, 135 Stability and reactivity of crown-ether complexes, 17, 279 Stereochemistry, static and dynamic, of alkyl and analogous groups, 25, 1 Stereoelectronic control, the principle of least nuclear motion and the theory of, 24, 113 Stereoselection in elementary steps of organic reactions, 6, 185 Steric isotope effects, experiments on the nature of, 10, 1 Structural and biological impact of radical addition reactions with DNA nucleobases, 43, 177 Structure, determination of organic reactivity, 35, 67 Structure and mechanism, in curbene chemistry, 7, 153 Structure and mechanism, in organic electrochemistry, 12, 1 Structure and reactivity of carbencs having aryl substitutents, 22, 311 Structure and reactivity of hydrocarbon radical cations, 38, 87 Structure of electronically excited molecules, 1, 365 Substitution, aromatic, a quantitative treatment of directive effects in, 1, 35 Substitution, nueleophilic vinylic, 7, 1 Substitution reactions, aromatic, hydrogen isotope effects in, 2, 163 Substitution reactions, bimolecular, in protic and dipolar aprotic solvents, 5, 173 Sulphur, organic oxyacids of, and their anhydrides, mechanisms and reactivity in reactions of, 17, 65 Superacid systems, 9, 1 Tautomerism in the solid state, 32, 219 Temperature, NMR measurements of reaction velocities and equilibrium constants as a function of, 3, 187 Tetrahedral intermediates, derived from carboxylic acids, spectroscopic detection and the investigation of their properties, 21, 37 The interplay between experiment and theory: computational NMR spectroscopy of carbocations, 42, 125

286

CUMULATIVE INDEX OF TITLES

The interpretation and mechanistic significance of activation volumes for organometallic reactions, 41, 1 The physical organic chemistry of very high-spin polyradicals, 40, 153 Thermodynamic stabilities of carbocations, 37, 57 Topochemical phenomena in solid-slate chemistry, 15, 63 Transition state analysis using multiple kinetic isotope effects, 37, 239 Transition state structure, crystallographic approaches to, 29, 87 Transition state structure, in solution, effective charge and, 27, 1 Transition stale structure, secondary deuterium isotope effects and, 31, 143 Transition states, structure in solution, cross-interaction constants and, 27, 57 Transition states, the stabilization of by cyclodextrins and other catalysts, 29, 1 Transition states, theory revisited, 28, 139 Tritiated molecules, gaseous carbonium ions from the decay of, 8, 79 Tritium atoms, energetic reactions with organic compounds, 2, 201 Turnstile rearrangements in isomerization of pentavalent phosphorus compounds, 9, 25 Unsaturated compounds, basicity of, 4, 195 Using kinetic isotope effects to determine the structure of the transition states of SN2 reactions, 41, 219 Vinyl cation intermediates, 37, 1 Vinyl cations, 9, 185 Vinyl iodonium salts, 37, 1 Vinylic substitution, nuclephilic, 7, 1; 37, 1 Voltammetry, perspectives in modern: basic concepts and mechanistic analysis, 32, 1 Volumes of activation, use of, for determining reaction mechanisms, 2, 93 Water and aqueous mixtures, kinetics of organic reactions in, 14, 203 Yukawa–Tsuno relationship in carborationic systems, the, 32, 267

SUBJECT INDEX

Note: The locators with letter ‘f denote figures Benzophenone derivatives, 41–4, 48, 49, 60 Benzoylation, 156–7 1-Benzoyl-1,2,4-triazoles, 22–3, 25–6 Benzyl dications, 239 Benzylic carbocations, 135–6, 139, 154, 156, 161, 163 Benzylic trication, 240 Berezin model see Kinetic model Biadamantyl dication, 243 Bicyclo[2.2]octane-1,4-diyl dication, 231 Bicyclo[3.3]undecane-1,5-diyl dication, 238 1-Bicyclo[3.3]undecyl cation, 243 1,5-Bicyclo[3.3]undecyldiyl cation, 243 Bilayer permeation, 7–8, 11, 29 Bimolecular reactions (micellar), 13–16, 17, 26–8 Binding constant see Equilibrium constant Binding site, 9–11, 17, 21, 24–5, 28 mismatch in, 10 Biofuels, 124, 125 Biological activity, 135, 138, 152, 154, 163, 171–2 Biradical, 42, 44, 45, 50, 55, 59, 60 Bishomoaromatic dication, 234, 235 Bishomocyclopropenium cation, 233 Bis(tropylium) dications, 251 Bond dissociation energy (BDE), 66, 80, 81, 106, 109, 110, 111, 113, 114, 115 Bromination, 150, 156, 158–9, 166

Acetophenone derivatives, 41, 44, 45, 49, 54 Acetyl dication, 224 1,3-Adamantanedicarbonyl dication, 237 1,3-Adamantanediyl dication, 229 1,3-dehydro-5,7-adamantanediyl dication, 220 Adamantane dicarboxonium ion, 244 Adamantanedimethylium dications, 236 1-Adamantyl cation, 242 Aggregation number (micellar), 5–7 Amphiphiles, 3–9 Anion, 46, 51, 52, 53, 65 Application of photoremovable protecting groups, 39–41, 53, 65, 66 Aqueousphase computations, 161–2 Aqueous solution, 1–37 Arenediazonium salts, 18–20, 29 Aromatic dications, 247 Aromaticity, three dimensional, 220 Aromatic oxidation: alkylaromatics, 107–108 benzene, 99–107 toluene, 99, 100, 107, 109, 113, 115 Arrhenius expression, 90 Arylamines: bioactivation, 179 DNA adducts, 179–80, 187 mutations, 180 oxidation potential, 187 oxidation products, 187 Aryl hydrazines: bioactivation, 196 DNA adducts, 196–7 mutagenicity, 196, 207 2-Aryl-2-norbornyl cation, 233 Aza-PAHs, 138, 161–4

Carbocation, 54 Carbocations, m-hydrido-bridged, 245 Carbodications, 219 1,2-carbodications, 222 1,3-carbodications, 226 1,4-carbodications, 231 1,5-carbodications, 236 1,6-carbodications, 242 cyclopropyl and phenyl group-stabilized, 226 m-hydrido-bridged, 245 oxygen-stabilized, 257 sulfur stabilized, 238

Base excision repair (BER), 189, 196 Benzannelation mode, 166–7, 173 Benzanthracenium ions, 152 Benzo[a]pyrene (BP), 196–7

287

288 Carboxonium–pyrenium dications, 144 Carboxylic acid, 49–53 Catalysis: hydrotropic, 16 micellar, 3, 9, 11, 17, 27–8 vesicular, 3, 9, 29–30 Cavity ring-down spectroscopy (CRDS), 92, 93, 94, 101, 107 Charge delocalization, 136, 139, 141, 144, 148, 152–4, 158–9, 174 mode, 136, 138, 144, 147–8, 150, 152, 154, 156–9, 162–3, 166–8, 170–1, 173–4 Charge delocalization, 27 Chemkin, 90 Chlorophenols: bioactivation, 208–10 DNA adducts, 208–10 Cholesterol, 8, 30 Chrysenium ions, 157–9 Cis–trans isomerization, 62, 63, 65 Cmc see Critical micelle concentration Coal, 108, 109, 111, 112, 116, 121, 123, 125, 235, 253 Colloidal solution, 1–37 Combustion, 79–134, 138 Comparative mutagenicity assay, 137, 139, 166, 172 Complexation, 173–4 Computational methods: ab initio, 90, 103, 106 B3LYP, 95 CAS-MP2, 103 CASSCF, 103 CBS-QB3, 95, 96 CCSD(T), 94 density functional theory (DFT), 90, 106 MP2, 103, 106 mPW1K, 95, 96 PM3, 101, 102 Computational studies, 136, 138, 154, 160, 162, 174 Computed NPA charges, 150, 154, 156, 159–60, 162–3, 168, 170–1 Counterion binding (micellar), 5–6 estimate, 6 from kinetic studies, 26–7 and the PIE model, 13–15 from trapping, 19–20

SUBJECT INDEX Counterion binding (vesicular), 8, 29 Counter ion effect, 145 Counterions: reactions involving, 26–7 Covariance see Data analysis for micellar kinetics Critical micelle concentration, 4 Crossed molecular beam, 88 Cross-hyperconjugation, 241 Crowded carbenium ions, 141, 143, 154, 162 Crystals, 64–6 Cubane-1,4-diacylium ion, 244 Cubane-1,4-dicarboxonium, 244 Cubyl-1,4-dicarboxonium ion, 244 Cyclobutanol, 42 Cyclohexane-1,4-diyl dication, 232 Cyclooctatetraene dication, 253 Cyclooctatetraene, tetra(bicycloocteno), 253 Cyclopropane-1,2-diyl bis(cyclopropylmethylium) dication, 235 Cyclopropenium ion, trihydroxy, 254, 255 2-Cyclopropyl-2-adamantyl cation, 237 Data analysis for micellar kinetics, 15–16 DDQ, 251 Decarboxylation, 49–52, 57 Dediazoniation see Arenediazonium salts Deglycosylation, 198–9 Degree of ionization, 6 see also Counterion binding Dehydration of reactive counterions, 27, 29 Dehydroadamantanediyl dication, 249 Density functional theory (DFT), 136, 138, 144, 155–7, 159–62, 166, 168–9, 171 20 -deoxyguanosine (dG) reaction with alkyl radicals, 192–6 reaction with aryl radicals, 196–207 reaction with hydroxyl radical, 181–9 reaction with nitrogen dioxide radical, 181–9 reaction with phenoxyl radical, 208–11 sites of alkylation, 178 Depurination, 197–9 DFT, 249 Diamantane-4,9-diyl dication, 243 1,4-Diamantanediyl dication, 233

SUBJECT INDEX 1,4-Diaryl-1,4-cycloalkylcarbodications, 232 2,5-Diaryl-2,5-norbornanediyl dications, 232 Diatropicity, 241 Diazoquinones, 196 1,4-Dibenzylium dication, 240 Dicarboxonium ions, 1,2-, 225 Dications, (hexaphenyltrimethylene)methane, 230 1-Dicyclopropylethyl cation, 227 2,6-Dicyclopropyl-2,6-adamantanediyl dication, 237 Diels–Alder adducts, 42, 43, 45 Diels–Alder reaction: micellar, 10, 27–8 vesicular, 29 Dienyl, allylic dications, 239 1,4-Dimethyl-1,4-cyclohexyl dication, 232 2,5-Dimethylhexane-2,5-diyl dication, 231 2,6-Dimethyl-5-methoxy-m-xylidyl dication, 239 2,6-Dimethylmesityldiyl dication, 239 3,10-Dimethyltricyclo[5.2.1.02,6]deca-4,8dien-3,10-diyl dication, 235 Diol epoxides (DEs), 135–6, 138, 160–3, 174 1,3-Dipolar cycloaddition (micellar), 28 Diprotonated dications, 139, 144, 147, 152, 169–70 Distonic carbodications, 228 DNA: 32 P-postlabeling analysis, 211f cleavage, 181 DNA–protein cross-links (DPCs), 187 interstrand cross-links (ISCs), 194 Z-form geometry, 207 DNA-binding studies, 137–8, 144, 150, 157, 160 1,6-Dodecahedryl dication, 242 Dodecahedryl monocation, 242 Electrocyclic ring closure, 42, 45 Electron Spin Resonance (ESR), 10, 88, 139, 173, 248, 252, 253 Electron transfer, 51–3, 57, 62, 65 Encounter complex formation, 2 Endo/exo ratios see Diels–Alder reaction Enforced hydrophobic interactions, 2, 28 Equilibrium constant, 10–16, 17, 19, 29 for binding of transition state, 12 ET30 probe, 20–2, 25–6

289 ET30 values (examples), 21 Ethylene dication, 222 Excited-state intramolecular proton transfer (ESIPT), 205–207 Flip-flop, 8 Flow reactor, 88, 101, 108 Fluorenylic dications, 241 Fluorine substitution, 154, 159–60, 162–3 Fluoronium ion character, 162–3 Fragrances, 39, 40, 63, 64, 71 Gas chromatography (GC), 88, 185 Gasoline, 98, 99, 107, 108, 122, 123 GIAO, 220, 249 GIAO-NMR, 136–7, 150, 156–60, 162, 166–8, 170–1 Gitonic, 225 GRI-MECH, 91, 92 Guanidinohydantoin (Gh), 186–7, 189 Hammett substituent constants, 203 Hammett -value, 25, 27, 28 Headgroup concentration: from chemical trapping, 30 estimate of, 6 from kinetic studies, 26–7 Heteroaromatic oxidation: alkylheteroaromatics, 112–16 furan, 109–14 oxazole, 109, 113, 114 pyrazine, 109, 114 pyridazine, 113, 114 pyridine, 109, 110 pyrimidine, 109, 114 pyrrole, 109, 110, 113, 114 thiophene, 109, 113, 114 Hetero-PAHs, 137–8, 160–6 High-temperature combustion, 81–2, 84, 98, 120 Hogeveen dication, 256 HOMO, 150, 163 Huckel’s aromaticity rule, 247 Human MCF-7 cells, 138, 144, 150, 160 1,2-Hydride shifts, in dodecahedryl cation, 242 Hydrogen abstraction, 41 Hydrogen bonding, 55, 59 Hydrolytic probe see Pseudounimolecular reactions

290 1,5-Hydrogen shift, 42, 45, 46, 55 Hydrotropes, 3–4, 9, 30 organic reactivity in, 16–17 Hydroxyiminium–pyrenium dications, 142–4 Hyperthermal pyrolytic nozzle, 88 Ibuprofen, 52 IGLO, 249, 250 Infrared (IR), 53, 65, 67, 68, 88, 92, 93, 97 Intersystem crossing (ISC), 42, 44, 45, 50, 52, 55, 59–61, 70, 71 Ionic strength (micellar), 9, 23–4 Isodesmic reaction, 234 Isolobal analog, 221 Isopagodane, 249 Isopropyleniminium, 226 Kemp elimination (vesicular), 29–30 Kinetic control, 152, 155 Kinetic model: Berezin model, 12–13, 15 Menger–Portnoy model, 11–13, 15 pseudophase ion exchange model, 13–14, 15, 21, 27 pseudophase model for bimolecular reactions, 14–15 Klenow fragment, 190–1, 195, 207 Lactones, 58, 62, 63 Lactonization, 48, 57, 59, 60–3, 65 Laminar flame, 88, 89 Laser flash photolysis (LFP), 41, 47, 52, 53, 54, 59, 62, 65, 89, 108, 184 Laser-induced fluorescence (LIF), 89, 92 Leaving groups, 47–9, 53, 54, 72 Lifetime (micellar), 7 Local charge, 9, 23–4, 29 Local rate constant see Rate constant (local) Low-temperature combustion, 82–4, 85, 97, 107, 121 Magic acid, 223 Manxyl dication, 238 Mass spectrometry (MS) chemical ionization (CI), 88, 95, 109 electron impact (EI), 88 Master equation, 90, 95, 125

SUBJECT INDEX Membrane permeability see Bilayer permeation Menger–Portnoy model see Kinetic model Methane oxidation (combustion), 81, 83, 91 Methyleneiminium cation, 225 MHC see Minimum hydrotrope concentration Micellar rate constant see Rate constant (local) Micelle: organic reactivity in, 17–28 spherical, 5–6 wormlike, 5 Microwave, 16 Minimum hydrotrope concentration, 4 Model nucleophiles, 161, 166 Morphology see Packing parameter m-phenylene dication, 252, 253f Mutagenesis, 188 Mutagenic activities, 135–7, 160, 172 Napthalene dication, tetrakis(bicycle[2.2]octano, 254 6-NBIC see 6-Nitrobenzisoxazole Negative temperature coefficient (NTC), 84–5, 93, 125 NICS, 138, 157, 160–1, 168, 170–1, 174 Nitration, 136, 150, 152, 156–7, 159, 166, 168, 171 Nitroaromatics: bioactivation, 179 DNA adducts, 179–80 6-Nitrobenzisoxazole: decarboxylation of, 29–30 8-Nitroguanine (8-NO2-G), 182–4, 189 o-Nitrotoluene derivatives, 41, 45, 46, 48, 66, 68–72 Nonalternant PAHs, 166, 168–70 Non-neutral environment see Local charge NOx, 86, 87, 108, 109, 112, 117, 120, 122 NOy, 85 Nucleotide excision repair (NER), 189, 196 Ochratoxin A (OTA), 208–11 Octahedranedimethyl dication, 250 8-oxo-guanine (8oxoG), 180–91 Oxygenates, 103, 122, 123, 184

SUBJECT INDEX Oxygen quenching, 44, 51–4, 57–9, 61, 72 Ozone, 79, 86, 87, 109 Packing parameter, 5, 7–8, 19–20, 29 Pagodane, 247, 248 Pagodane dications, 247, 248 PAH–DNA adducts, 135, 150, 154–5, 157, 160–6, 167 Pairwise interactions, 2–3 Parameter correlation see Data analysis for micellar kinetics Paratropicity, 241 Paratropic ring current, 241 Partition coefficient see Equilibrium constant Pentachlorophenol, 208–10 Peroxide, 44 Peroxyl radical, 52 Persistent carbocations, 141–2, 144, 147, 150, 156, 166, 168, 174 Phase transition temperature (vesicular), 8, 29–30 Phenanthrenium ion, 144, 147–8, 152 Photochemical smog, 79, 87 Photoenols, 41, 42, 45, 46, 47, 49, 50, 57–9, 61, 66, 72 lifetimes, 42–5, 54, 55, 59 transient absorption, 42, 46, 47, 49, 54, 56, 59, 62 PIE model see Kinetic model Piroiminodihydantoin (Sp), 186–91 Polarity: micellar, 9, 21, 23–4 vesicular, 29 see also ET30 probe Polyaromatic hydrocarbons (PAH), 196 Polycations, 221 Polycyclic aromatic hydrocarbons (PAHs), 98, 99, 108, 123, 135–8, 144–5, 148, 160–2, 165–8, 170, 172–4, 178, 196, 197, 212 p-phenylene dication, 252, 253f Preparation of vesicular solutions, 8, 29 1,3-Propanebis(dicyclopropyl)-1,3-diyl dication, 227 Protio-methyleniminium dications, 225 protonated, 226 Pseudophase ion exchange model see Kinetic model

291 Pseudophase model for bimolecular reactions see Kinetic model Pseudounimolecular reactions, 12–13, 22–6 Pyramidal dication, 256 Pyrenium ions, 139, 144, 171 Pyrolytic, 88, 108, 109, 110, 112, 113 Quantum yield, 40, 48, 49, 52–4, 56–9, 62, 63, 72 Quencher, 40, 42, 44, 47, 52, 53, 54, 56, 59 Quenching, 152, 154, 162–3, 168 Radical, 40, 52, 65 Radical chain reaction: chain branching, 80, 82 initiation, 80 propagation, 80 termination, 80 Radicals (or Free radicals): alkoxy radicals, 81, 82 alkyl radicals, 80 ethylperoxy, 92–4 hydroxyl, 80–1 n-butoxy, 96–7 1-pentyl, 97 n-propylperoxy, 94–6 peroxy radicals, 82 Radius of spherical micelle see Micelle Raft formation, 8 Raman spectroscopy (RS), 89 Rate coefficients, 87, 89, 90, 92, 97, 101, 106 Rate constant (local), 9–16, 17, 23–30 Reactant orientation, 11 Reactive nitrogen species (RNS), 183 Reactive oxygen species (ROS), 79, 81, 101, 120, 125, 208 see also Radicals (or Free radicals) Regioselectivity, 161, 165–6 for protonation, 150, 159, 171–2 Relative aromaticity, 138, 157, 161, 168–71, 174 Relative carbocation stabilities, 136–9, 144, 147, 150, 152, 154, 160–3, 174 Resonance fluorescence, 88 Retro Diels–Alder reaction (micellar), 28 RRKM theory, 90, 95, 97, 101 RRK theory, 95

292 Semenov mechanism, 93 Sensitizer, 53, 69 Shock tube, 88, 109 Singlet excited states of ketones, 42, 44, 45, 52–6, 66 Singlet oxygen, 44 Solubility in aqueous solution, 2 Solvatochromic probes see ET30 probe Solvent, 42, 43, 45, 46, 49, 51, 52, 55–9, 62, 65, 67, 68, 72 Solvolysis, 54, 57 Soot, 87, 98–9, 123 Sphere-to-wormlike transition, 16, 19–20 Squaric acid, 255 Stable ion protonation, 136–8, 144, 147, 152, 158–9, 165–6, 171–2, 174 Stern region (micellar) definition of, 5 solutions mimicking, 17, 25–6 Structure/reactivity relationships, 136–8, 154, 159, 162 Surfactant: micelle-forming, 4–7, 17–28 vesicle-forming, 7–9, 28–30 Temperature, 49 Tert-butyl cation, 226 Tetraanisylethylene dication, 223 tetrakis(dimethylamino), 224 Tetramethyl-1,3-adamantanedimethyl dications, 236 Tetraphenylethylene dication, 223 Theoretical calculations, 45, 66 Tm see Phase transition temperature (vesicular) Transition state theory (TST), 12, 90, 97 2-Triaxanemethyl cation, 250 Tricyclo[4.2.1.12,5]deca-3,7-diene-9,10-diyl dication, 233 Trimethylenemethane dications, 229, 231

SUBJECT INDEX Triphenylcyclopropenium cation, 228 Triplet excited state of ketones, 42, 44, 45, 47, 50, 52, 54–7, 60–2, 65, 66, 69–71 Tris((2.2.2)bicycloocteno)tropylium, 252 Trityl hexachloroantimonate, 251 Tropone, 228 Tunneling: Wigner approximation, 90 Turbulent flame, 88, 90 Two-electron oxidation dications, 169–71 Ultraviolet (UV), 20, 53, 68, 86, 88, 93, 106, 107, 108, 190, 204 Urea (micelle-destabilizing effect of), 19 Vesicle, 7–9 organic reactivity in, 28–30 Vesicular rate constant see Rate constant (local) Volatile organic compounds (VOCs), 85, 87 ‘‘On water chemistry’’, 2 Water concentration (micellar Stern region), 9, 12, 23 from kinetic studies, 22–3, 26, 29 from solvatochromic probes, 20–2 from trapping, 19–20 Woodward–Hoffmann theory, 249 X-ray structures, 65, 66, 150, 160, 171–2 Y-aromaticity, 231 Y-conjugated carbodications, 229 Zones (micellar), 5, 7, 10–11, 13, 28