ADVANCES IN THEORETICALLY INTERESTING MOLECULES
Volume4
9 1998
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ADVANCES IN THEORETICALLY INTERESTING MOLECULES
Volume4
9 1998
This Page Intentionally Left Blank
ADVANCES IN THEORETICALLY INTERESTING MOLECULES Editon R A N D O L P H P. T H U M M E L Department of Chemistry University of Houston
VOLUME4
9 1998
~~'~ JAI PRESSINC. Stamford, Connecticut
London, England
Copyright 91998 by JAI PRESSINC. 1O0 Prospect Street Stamford, Connecticut 06904 JAI PRESSLTD. 38 Tavbtock Street Covent Garden London WC2E 7PB England All rights reserved. No part of this publication may be reproduced, stored on a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, filming, recording or otherwise without prior permission in writing from the publisher. ISBN: 0-7623-0070-1 ISSN: 1046-5766 Manufactured in the United States of America
CONTENTS
LIST OF CONTRIBUTORS PREFACE
Randolph P. Thummel
o~
VII
ix
ASPECTS OF THE CHEMISTRY OF ISOBENZOFURANS: BRIDGING THE GAP BETWEEN THEORETICALLY INTERESTING MOLECULES AND NATURAL PRODUCTS
Dieter Wege
FASCINATING STOPS ON THE WAY TO CYCLACENES AND CYCIACENE QUINONES" A TOUR GUIDE TO SYNTHETIC PROGRESS TO DATE
Robert M. Con/and Cameron L. A4cPhail
BENZOANNELATED FENESTRANES
Dietmar Kuck
SEMIBU LLVALENES--HOMOAROMATIC BOVINES?
Richard Vaughan Williams
CYCLOPENTYNES: ENIGMATIC INTERMEDIATES
John C. Gilbert and Steven Kirschner
53 81 157 203
OVERCROWDED POLYCYCLIC AROMATIC ENES
P. Ulrich Biedermann, John I. Stezowski, and Israel Agranat
245
AUTHOR INDEX
323
SUBJECT INDEX
341
This Page Intentionally Left Blank
LIST OF CONTRIBUTORS
Israel Agranat
Department of Organic Chemistry The Hebrew University of Jerusalem Jerusalem, Israel
P. Ulrich Biedermann
Department of Organic Chemistry The Hebrew University of Jerusalem Jerusalem, Israel
Robert M. Cory
Department of Chemistry University of Western Ontario London, Ontario, Canada
John C. Gilbert
Department of Chemistry The University of Texas at Austin Austin, Texas
Steven Kirschner
Department of Chemistry Austin Community College Austin, Texas
Dietmar Kuck
Department of Chemistry University of Bielefeld Bielefeld, Germany
Cameron L. McPhail
Department of Chemistry University of Western Ontario London, Ontario, Canada
John J. Stezowski
Department of Chemistry University of Nebraska-Lincoln Lincoln, Nebraska vii
viii
LIST OF CONTRIBUTORS
Richard V. Williams
Department of Chemistry University of Idaho Moscow, Idaho
Dieter Wege
Department of Chemistry University of Western Australia Nedlands, Western Australia, Australia
PREFACE
The contributions to Volume 4 continue in the tradition of the earlier volumes, operating at the interface of theory and experiment as applied to a wide variety of fascinating organic molecules. In the first chapter, Dieter Wege continues the saga of isobenzofurans begun by Bruce Rickborn in Volume 1. We are treated to difurans and trifurans, aryne-isobenzofurans, small ring-fused and heterocyclic isobenzofurans, as well as a wide variety of quinone and dione derivatives, leading ultimately to natural products such as lignan and dynemicin A. In Chapter 2, Robert Cory and Cameron McPhail give us a progress report on their approaches to the very challenging family of cyclacenes. These systems represent a maximum compromise on the planarity of so-called aromatic structures. Having prepared cyclophanes and cyclophane quinone precursors to the cyclacenes, these workers are coming temptingly close to the ultimate realization of an "aromatic wheel." Chapter 3 shows us that fenestranes are Dietmar Kuck's window on the world of theoretically interesting molecules. The central carbon of such species, common to four fused rings, stretches the concept of sp3 hybridization to the limit, tending towards planar carbon. Kuck has used benzoannelation, particularly on [5.5.5.5]fenestrane, to help stabilize both the reactive precursors as well as the fenestranes themselves.
x
PREFACE
In Chapter 4, Richard Williams revives the question of neutral homoaromaticity and suggests that semibullvalenes might be the ideal candidates for detecting this elusive effect. Although theoretical predictions are encouraging, the experimental evidence is still not convincing, which only makes the challenge of detecting homoaromaticity more appealing to physical organic chemists. Can an alkyne be incorporated into a five-membered ring? In Chapter 5 Jack Gilbert and Steve Kirschner have set out to convince us that it can, devising a variety of experiments aimed at the characterization of cyclopentyne. Pericyclic and cycloaddition chemistry argue for the discrete existence of this molecule, and with a deeper theoretical and chemical understanding of this species, its physical characterization should not be far away. Finally, Israel Agranat, Ulrich Biedermann, and John J. Stezowski give us a fascinating and in-depth molecular-modeling analysis of overcrowded polycyclic aromatic alkenes. The highly congested fjord region of these bridged derivatives of tetraphenylethylene causes them to distort in ways that offer a tantalizing challenge to the computational chemist and will likely provide a new family of "molecular switches." In closing, I would like to take this opportunity to inform our readers of a change in the leadership, but not the direction, of our series. A closely related and very successful title Advances in Strain in Organic Chemistry has been running parallel to our own, edited by Brian Halton. Due to the considerable overlap of our two series (nearly all the systems discussed in this volume involve strain), Brian and I have decided to combine our series; henceforth, this combined effort will be known as Advances in Strained and Theoretically Interesting Molecules and Brian will take over as editor. For me this editorship has been an exciting and rewarding experience and has allowed me to interact with some of the finest physical organic chemists in the world. I warmly thank the contributors to Volume 4 for their participation, and encourage you, the reader, to suggest or volunteer future contributions. Randolph P. Thummel Series Editor
ASPECTS OF THE CHEMISTRY OF ISOBENZOFURANS: BRIDGING THE GAP BETWEEN THEORETICALLY INTERESTING MOLECULES AND NATURAL PRODUCTS
Dieter Wege
1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . lsobenzofuran Chemistry at the University of Western Australia . . . . . . . . . 2.1 The Beginning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Digression: Other Cycloreversion Routes to Isobenzofuran . . . . . . . . 2.3 Properties of Isobenzofuran . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Stabilization of the Isobenzofuran Ring System . . . . . . . . . . . . . . 2.5 Trifuran and Difuran Derivatives Related to Isobenzofuran . . . . . . . . 2.6 Deoxygenation of Aryne-Furan and Aryne-Isobenzofuran Adducts . . . . 2.7 Small-Ring-Fused Isobenzofurans: A Kinetic Probe for the Mills-Nixon Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8 Heterocyclic Analogs of Isobenzofuran . . . . . . . . . . . . . . . . . . .
Advances in Theoretically Interesting Molecules, Volume 4, pages 1-52. Copyright 9 1998 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0070-1
17 21 22 25
2
DIETER WEGE
2.9 3-Trimethylsilyloxyisobenzofuran-l-carbonitrile as a Synthon for Substituted Naphthalene- 1,4-diones . . . . . . . . . . . . . . . . . . . . 2.10 Isobenzofurandiones and Related Compounds . . . . . . . . . . . . . . 2.11 4,7-Dihydroisobenzofuran and Its Role in Resolving a Structural Conundrum . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Recent Applications of Isobenzofuran Chemistry to the Synthesis of Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Lignan Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Intramolecular Trapping of Isobenzofurans and Thieno[2,3-c]furans . . 3.3 4,7-Dimethoxyisobenzofuran and Its Role in Dynemicin A Chemistry.. 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28 33 42 44 44 47 47 48 48
1. INTRODUCTION The study of theoretically interesting molecules is a worthy objective in its own right and has a long history in organic chemistry. For example, the pioneering work of Perkin on small ring compounds, 1 and Willstatter's classic synthesis of cyclooctatetraene 2 can be cited as early studies designed to test concepts of structure and reactivity as understood in modem terms. The availability of powerful computational techniques and the vast array of synthetic methods at the disposal of the modern organic chemist has led to a productive interplay between theoretical and preparative studies in more recent times. A further important outcome of the study of theoretically interesting organic molecules is the application of the results to other important areas of the discipline. In modern organic chemistry the distinction between areas such as theory, mechanism, structure, synthesis, and natural products has become blurred, and a healthy degree of symbiosis exits. Isobenzofuran (IBF, 1) is a theoretically interesting molecule that has been the subject of several detailed reviews. 36 It is not the purpose of this chapter to duplicate the material in these reviews, or to attempt to be comprehensive; rather, the aims are as follows. The first is to trace the evolution and development of our interest in the chemistry of isobenzofurans. The second is to illustrate how this chemistry is relevant to other areas, particularly the synthesis of natural products. Finally, we would like to update the progress on aspects of isobenzofuran chemistry since the last comprehensive review. 6
7
5
1
4
3 1
The Chemistryof Isobenzofurans 0
ISOBENZOFURAN CHEMISTRY AT THE UNIVERSITY OF WESTERN AUSTRALIA 2.1 The Beginning
Our efforts began in the early 1970s, when we had shown that substituted norbornenones such as 2 and 6 suffer from steric compression due to the proximity of H s of the methano bridge to the n-cloud of the etheno bridge. 7's This compression manifests itself in a pronounced deshielding of H s relative to H a in the 1H nuclear magnetic resonance (NMR) spectra of these compounds as well as an approximately 4000-fold increase in the rate of thermal decarbonylation relative to that of norborn-2-en-7-one. Thus 2 loses CO at temperatures as low as 60 ~ to give
Ha~ H= ~,/
90" 2
4
3
\o 6
0
Q
(~~
"~~OMe
1. Na,t-BuOI 2. H3O+
5
1,5[H] =
(~~
7
MeO OMe
10
12
OMe
13 110~
~)/C02Me
MeO~C/
w
~ C02Me. 0
-0 |
C02Me 14
15
Scheme 1.
4
DIETER WEGE
cyclopentadiene and benzene; these products arise from a retro-Diels-Alder reaction of 3, which was confirmed by an independent synthesis and reactivity study of 3. 9 In a similar fashion, ketone 6 affords 7, but this material does not undergo cycloreversion as readily as 3, and temperatures in excess of 150 ~ are required since it is necessary to interrupt the aromaticity of the benzenoid ring to generate isoindene 8 and benzene in a concerted cycloreversion process (Scheme 1). The above observations prompted us to prepare the epoxy-bridged ketone 13 to determine whether the smaller steric requirement of the epoxy bridge relative to that of the methano bridge in 6 would result in reduced steric compression. This was indeed observed, as ketone 13 underwent decarbonylation at an appreciable rate only at temperatures in excess of 110 ~ However the product of decarbonylation, the diene 14, could not be isolated at this temperature, but underwent cycloreversion to give benzene and IBF 1 as evidenced by the formation of adduct 15 in the presence of added dimethyl fumarate. 7 An interesting dichotomy thus is observed in the behavior of ketones 6 and 13. The former decarbonylates at lower temperatures due to greater steric compression, and the product of decarbonylation, the diene 7, undergoes cycloreversion only at higher temperatures. On the other hand, the epoxy-bridged ketone 13 decarbonylates at higher temperatures, but the cycloreversion of the presumed product 14 occurs much more readily than that of 7. Although both dienes 7 and 14 must suffer disruption of aromatic character of the left hand benzenoid ring in the transition state for cycloreversion, there is compensation for this in the case of 14 since the formation of IBF leads to a peripheral 10n aromatic system, whereas 7 leads to isoindene 8, a bridged o-xylylene (o-quinodimethane) possessing no additional stabilizing features. Our entry into the area of IBF chemistry was thus somewhat serendipitous and initially arose as an extension of our interest in the carbocyclic systems 2, 3, 6, and 7. The apparent facile cycloreversion of the presumed epoxy-bridged diene intermediate 14 suggested that this reaction might be worth further scrutiny and potentially could permit characterization of IBF 1, particularly in view of the fact that the by-product benzene is inert and should cause minimal interference. At this stage an examination of the literature revealed two publications pertinent to the generation of IBF under cycloreversion conditions. In their pioneering paper on the trapping of benzyne with furan to give 1,4-dihydro-l,4-epoxynaphthalene
0
0
l o
10
16
17
Scheme 2.
N
+ ~N
18
~
NH 19
The Chemistry of Isobenzofurans
10, Wittig and Pohmer l~ reported that thermolysis of the adduct 16, derived from 10 and diazomethane, gave pyrazole 19 and a pot residue formulated as the polymer 17 (Scheme 2). An important publication by Fieser and Haddadin 11established that 10 behaves as a dienophile towards tetracyclone 20 and o~-pyrone24 to give adducts 21 and 25, respectively. Thermolysis of these products in solution in the presence of 10 gave adducts 26 and 27, clearly implicating the intermediacy of IBF (Scheme 3). Since lactone 25 and ketone 13 both generate diene 14 on thermolysis, we focused on these compounds as potential candidates for the further characterization or possible isolation of IBE Preliminary experiments involving thermolysis of 13 or 25 in solution in the absence of trapping agents gave no characterizable material after evaporation of the solvent. Accordingly, simple vapor-phase reactions were attempted. When the ketone 13 was adsorbed onto Celite (which acts as a diluent), and then sublimed at
0 p.,
o
p..
~1~
165~
-
Ph
-CO
10
21
-
22
-
Ph 1650 _ ~~[~Phph ~0
o
"
Ph
o
24
23
165~
-C02
_ -Q
0 25
14
oC 26
27
Scheme 3.
[~0
6
DIETER WEGE
0 25
-002
in solution 14
Scheme 4.
10-2 mm Hg through a tube heated to 130 ~ it passed through largely unchanged. However, when lactone 25 was subjected to these conditions, the diene 14 (6%) condensed just outside the hot zone and IBF (30%) collected in the cold trap as a colorless solid that melted on warming to room temperature and then polymerized. 12 Decarboxylation of 25 is thus more facile than decarbonylation of 13. The IBF was characterized by its IH NMR spectrum and by conversion into adduct 15 by addition of dimethyl fumarate. 12 The cycloreversion of diene 14 to give IBF and benzene was followed spectroscopically in dilute solution in cyclohexane by measuring the appearance of IBF at 343 nm. Excellent first-order kinetics were observed over the range 46.8 to 66.9 ~ and extrapolating the Arrhenius plot to 170 ~ the only temperature at which an approximate rate constant for the cycloreversion of the methano-bridged diene 7 is known, s indicated that at this temperature 14 undergoes a retro-Diels-Alder reaction approximately 105 times faster than 7. This substantial reactivity difference reflects the fact that while both reactions give benzene as a product, the transition state for cycloreversion of 14 possesses some of the aromatic character of IBE
2.2 Digression: Other Cycloreversion Routes to Isobenzofuran At about the time that the above studies were being carded out, Warrener, on the other side of the Australian continent, independently developed the tandem DielsAlder/retro-Diels-Alder approach to IBF summarized in Scheme 5.13 The starting material is again 1,4-dihydro-1,4-epoxynaphthalene (10); this reacts at room temperature with the electron-deficient diene 3,6-di(pyridin-2'-yl)-s-tetrazine (28), a bright purple compound, to give adduct 29, which suffers spontaneous loss of dinitrogen. The resulting diazadiene 30 undergoes cycloreversion on gentle warming to deliver IBF and 3,6-di(pyridin-2'-yl)diazine (31). The cycloreversions of 14 (Schemes 1, 3, and 4), 22 (Scheme 3), and 30 (Scheme 5) all involve the formation oflBF and an aromatic component; hence they all occur at a convenient rate in the temperature range 40 to 60 ~ Strictly speaking, the minimum temperature required for onset of cycloreversion of the tetraphenyl-substituted diene 22 has not been established because of the high temperature (110 to 130 ~ required to effect decarbonylation of ketone 21. However, the reactivity of 22 can reasonably be assumed to be similar to that of 14 and 30.
The Chemistry of Isobenzofurans Py
NJ'-N I
It
N~.r..N
-
Q
N
-
60 ~
28
py 10
Q
N
29
N
3O
6o~
1
31
Scheme 5.
An alternative cycloreversion approach that is both conceptually elegant and experimentally convenient, and which involves expulsion of ethylene in the cycloreversion, is that of Wiersum and Mijs. 14These workers found that flash vacuum pyrolysis (FVP) of 1,2,3,4-tetrahydro-l,4-epoxynaphthalene (32) gives IBF in essentially quantitative yield (Scheme 6). The high temperature is needed because the 2n-component, ethylene, expelled in the cycloreversion is not aromatic, and the contact time in the hot zone in the FVP experiment is very short. This reaction permits collection of IBF uncontaminated by side products in a cold trap at liquid-nitrogen temperatures, and its subsequent use, for example, in trapping experiments, by dissolution in the appropriate reaction medium. In our experience, the three cycloreversion routes to IBF are complementary. Although the t~-pyrone adduct 25 played an important role in delivering the diene 14 for kinetic studies, ~2 its preparation is not particularly convenient. The tetracyclone adduct 21 (Scheme 3) is prepared more readily, and can be used if IBF is to O
10
H,,PO-C
O .
o ~
32
Scheme 6.
.
§
1
II..
8
DIETER WEGE
be generated at higher temperatures (approximately 110 ~ refluxing toluene) and trapped in situ. The byproduct 1,2,3,4-tetraphenylbenzene usually does not cause any complications as it is readily separated from desired product by chromatography. The dipyridyl-s-tetrazine route (Scheme 5) is useful if IBF is to be generated at or near room temperature, and if subsequent chromatographic or extractive separation of 3,6-di(pyridin-2'-yl)-l,2-diazine (31) is not problematic. The FVP method (Scheme 6) gives relatively large quantities of pure IBF, which can then be used for reactions at low temperatures. Examples of the application of all three variants of the cycloreversion route to IBF and its substituted derivatives will be given later.
2.3 Properties of Isobenzofuran When prepared by the FVP route, IBF is obtained as a colorless crystalline solid that melts at approximately 20 ~ under nitrogen and then forms a glassy polymer.14 Dilute (10 .-4 M) solutions in cyclohexane are stable up to 70 ~ as indicated by stable infinity absorbance values observed during the kinetic study of the generation of I from diene 14, but polymerization occurs in more concentrated solution. 12 Although IBF possesses a peripheral 10n-electron system that formally should endow it with aromatic properties, it is highly reactive and behaves like a bridged o-xylylene (o-quinodimethane). Hence, IBF and its derivatives find considerable use as diene components in Diels-Alder additions. 3~ Rickborn 4 has referred to IBF as holding the title of"the most reactive isolated diene for cycloaddition purposes" and evidence from our work to support this statement will be given. References to spectroscopic and other properties of IBF can be found in previous reviews. 3-~
2.4 Stabilization of the Isobenzofuran Ring System 2.4.1 StericStabilization The introduction of bulky substituents at the 1,3-positions of IBF should hinder the approach of reagents to those positions and result in overall stabilization of the system. We found that while 1,4-di-t-butyl- 1,4-dihydro- 1,4-epoxynaphthalene (33) fails to react with 5,5-dimethoxy-l,2,3,4-tetrachlorocyclopentadiene (11), ct-pyrone (24), and 3,6-di(pyridin-2'-yl)-s-tetrazine (28) because the environment around the alkene n-bond is screened by the bulky t-butyl groups, catalytic hydrogenation to give 34 is straightforward. 15 FVP of 34 then affords 1,3-di-tbutylisobenzofuran (35) as a crystalline solid, m.p. 43--44 ~ which is stable at room temperature for prolonged periods. 15An alternative synthesis of 35, involving cyclization of dione 39, has been published. 16 Despite the steric stabilization due to the t-butyl groups, 35 undergoes Diels-Alder reactions with dimethyl fumarate and dimethyl acetylenedicarboxylate to give adducts 3615 and 41,16 respectively, and with singlet oxygen affords the cyclic peroxide 40 (Scheme 7). 16
The Chemistry of Isobenzofurans
H2,Pd-C
I ~
b
t-Bu
9
t-Bu t ' B u t~
450 ~ 0.1 mm Hg -C=H4
.
33
34
NEt2
E
.NEt20 Bu-t Bu-t
,
O
0
38
39
t-Bu
,
t-Bu 35
0
37
E
t-Bu
E
36
E
t-B
t-B
OO O t-Bu
-
E
40
41
Scheme 7.
The tri-t-butyl substituted isobenzofurans 42 and 43, prepared by dehydration of the appropriately substituted hydroxy phthalides, are also stable at room temperature. 17'is Although unsubstituted in the 1,3-positions, these IBFs presumably owe their stability to the out-of-plane deformations induced by the bulky o-t-butyl groups. This interrupts the n-conjugation, which leads to a reduction of the o-xylylenoid character of the system. Irradiation of 4,5,6-tri-t-butylisobenzofuran (43) yields the valence isomer 44,18 in which the non-bonded interactions between the adjacent t-butyl groups are reduced (Scheme 8). 2.4.2 Electronic Stabilization
2.4.2.1 1,3-Diarylisobenzofurans. 1,3-Diphenylisobenzofuran (47) 19 and other 1,3-diarylisobenzofurans 2~have been known for many years as relatively t-Bu
t-Bu
t-Bu
.
42
43
Scheme &
44
10
DIETER WEGE
stable compounds; 47 is available commercially, or can be prepared from o-dibenzoylbenzene as shown in Scheme 9,19'21 and has found considerable use as a reactive diene in Diels-Alder trapping reactions. Although steric factors probably contribute to the stability of 47, conjugation of the phenyl substituents with the isobenzofuran moiety also is important.
2.4.2.2 BenzannulatedIsobenzofurans. Since the high reactivity of the parent IBF 1 must derive to a substantial extent from the resonance energy gained in going from a bridged o-xylylene structure to a benzenoid ring system, we felt that it should be possible to tune the reactivity of the system by benzannulation. Our first endeavor in this area involved the synthesis of phenanthro[9,10-c]furan (53), 15'22which may be viewed as dibenz[e,g]isobenzofuran (Scheme 10). 1,4-Dihydro- 1,4-epoxybiphenylene (51) had been prepared earlier by Wittig and co-workers by trapping 9,10-didehydrophenanthrene (49), generated from 9-fluorophenanthrene (48), with furan. 23 Since the synthesis of 48 requires reaction of 9-bromophenanthrene (50) with sodium amide in liquid ammonia to give 9-phenanthrylamine, via the aryne 49, followed by diazotization and thermolysis of the derived tetrafluoroborate salt, we decided to shorten the sequence. Thus, treatment of 9-bromophenanthrene (50) with a suspension of sodium amide in refluxing anhydrous tetrahydrofuran containing an excess of furan directly gave the adduct 51 in a gratifying yield of 62%. This reaction presumably works because sodium amide has only limited solubility in tetrahydrofuran (unlike liquid ammonia) and hence interception of 49 by amide ion to give 9-phenanthrylamine does not compete to a significant extent with trapping by furan. We subsequently used this dehydrobromination-trapping sequence to prepare a number of other arynefuran adducts (see later). Caub~re and co-workers have also generated arynes by dehydrobromination of bromo arenes in tetrahydrofuran with a "complex base" consisting of sodium t-butoxide and sodium amide, although trapping of the arynes has usually been with enolate anions. 24'25 In our experience, sodium amide alone generally is only effective in refluxing tetrahydrofuran, while the more reactive potassium amide or Caub~re's complex base system generates arynes at room temperature. In all of the trapping experiments with furans, monitoring of the Ph
O
NaBI'-14
H+ ,
O
Ph 45
=
H 46
Scheme 9.
Ph 47
The Chemistry of Isobenzofurans
F
11
BuLi |
I
.
THF, -50 ~
48
Br
NaNHa tl
THF, 66 ~
50
49
H2, Pd-C,
450 ~
|
0.1 turn Hg
51
52
53a
53
54
Scheme 10. reaction by thin layer chromatography (TLC) is essential, as prolonged reaction times can lead to degradation of the adducts. Hydrogenation of adduct 51 gave 1,2,3,4-tetrahydro-l,4-epoxytriphenylene (52), which on FVP afforded phenanthro[9,10-c]furan (53) as a stable crystalline product in essentially quantitative yield. ]5'22 In simple structural terms, this derivative of IBF can be viewed as 53a by analogy with triphenylene 54, with both assemblies containing the maximum number of isolated 6n-electron systems. 2628 The furanoid ring of 53 thus should possess little of the o-xylylenoid character of IBF itself, and this should be reflected in reduced reactivity. In order to probe this question further, we also prepared the benzannulated isobenzofurans 55--60 shown in Table 1 by treating the appropriate dihydroepoxyarene (obtained by dehydrobrominating the requisite bromo arene in the presence of furan) with 3,6-di-(pyridin-2'-yl)-s-tetrazine in chloroform at 50 to 60 ~ 22 Second-order rate constants for the addition of maleic anhydride to IBF 1 and the benzannulated derivatives 53 and 55--60 in benzene were measured spectrophotometrically (Table 1). In each of these cycloadditions there is a gain in resonance energy in going from a reactant with some of the character of an o-xylylene to a product containing a new benzenoid system (shown for IBF in
12
DIETERWEGE Table 1. Second-Order Rate constants for the Addition of Maleic
Anhydride to Benzannulated Isobenzofurans and Structure Counts for the Reactants and Products k 2 (I. mol -I sec-I)
Isobenzofuran
SCr
SCp
75.8
I
2
38.2
3
6
9.81
3
5
1.93
2
3
58 ~
0.43
3
4
53 ~ o
0.28
4
5
57 ~
0.22
5
6
1 [~~
56
59 ~
o
,~
55 ~ r-o
o
_
o
_ $
o
'o + o
1
61
o
62 Scheme 11.
o
63
The Chemistry of Isobenzofurans
13
Scheme 11). Some of this gain in resonance energy should be felt in the transition state 62, and hence be reflected in the numerical value of the second-order rate constant. If we assume that the transition states for the cycloaddition of each of the isobenzofuran derivatives lie on identical points of the reaction coordinate (i.e., bond-making is advanced to the same extent for each reaction), and that steric effects are negligible, then the observed rate constants should provide a measure of the difference in resonance energy between the isobenzofuran reactant and the product. Hemdon 29'3~has devised a semi-empirical structure count (SC) theory that has been used to correlate the reactivity of polycyclic aromatic hydrocarbons towards maleic anhydride (second-order rate constant k2) with differences in resonance energy between reactants and transition states. 31'32This energy difference is defined in terms of In[(SCp + SCr)/SCr], where SCp and SCc are the numbers of classical Kekul6 structures that can be drawn for product and reactant respectively. A plot of log k2 versus log SCraao is found to be linear. 29"32 Application of this procedure to the addition of maleic anhydride to the benzannulated isobenzofurans produces the plot shown in Figure 1.22,33This confirms that the reactivity of the isobenzofuran ring system in Diels-Alder reactions is related to the gain in resonance energy in going from reactants to products, and that an important component of the driving force for the cycloaddition is the conversion of the o-xylylenoid moiety of the IBF to a benzenoid ring in the adduct. The overall reactivity span of the IBFs investigated is 350, and the parent IBF is the most reactive member. It is clear that angular benzannulation, as in 53 and 55--60 (Table 1), reduces the reactivity of the IBF system, whereas linear benzannulation should increase the reactivity. This effect can be illustrated for naphtho[2,3-c]furan (65); the structure count ratio for the addition of maleic anhydride is 4, and extrapolation from Figure 1 leads to a value for k2 of 1.07 x 104 1 9mol-ls -l. This is 141 times faster than IBF itself, and such a rapid reaction would need to be followed by stopped-flow techniques. OR
-
-
.
OH .
.
CI..~OH 64
65
66
OMe
~
0
67
.
~
H* ' .
.
6g
68
Scheme 12.
14
DIETER WEGE
l+iog k2
2.5 -
o
2 -
1.5 ---
1 -
O.S
-
0 0.342
I
I
t
t
I
i
0.362
0.382
0.402
0.422
0.442
0.462
log SC,~.
Figure 1.
The Chemistry of Isobenzofurans
15
Although naphtho[2,3-c]furan 65 may well be too reactive to permit isolation under conventional reaction conditions, it has been generated and trapped in situ starting with either acetal 6434 or hemiacetal 6635 (Scheme 12). More recently, Dibble and co-workers have generated and trapped the more reactive anthra[2,3c]furan 69. 36
2.4.2.3 Annulation of an Antiaromatic System. In contrast to the situation discussed above, linear annulation of an antiaromatic ring system should stabilize IBF, while angular annulation should result in destabilization. Thus the propensity of cyclobut[f]isobenzofuran (70) (Scheme 13) to undergo Diels-Alder addition should be attenuated since the formation of adduct would generate an antiaromatic benzocyclobutadiene system, whereas the angularly fused isomer cyclobut[e]isobenzofuran (73) possesses a cyclobutadiene as well as an IBF system, and is predicted to be exceedingly reactive. Neither 70 nor 73 are known, although the highly substituted derivatives 71 and 72 have been prepared as stable crystalline materials. 37,38 We have prepared biphenyleno[2,3-c]furan (80), the benzoannulated derivative of 70, by the route shown in Scheme 14. 39'40 Dehydrobromination of 2-bromobiphenylene (74) with potassium amide in refluxing tetrahydrofuran in the presence of furan gave the adducts 77 and 78 in a ratio of 10:1 and in 44% yield. This ratio of 77:78 presumably reflects the relative rates of formation of the arynes 76 and 75. The preferential formation of 1,2-didehydrobiphenylene 76 may be a consequence of the enhanced kinetic acidity of H1 over H3 in the reactant 2-bromobiphenylene (74), a phenomenon well-known in biphenylene itself. 41 Hydrogenation of 78 followed by FVP gave biphenyleno[2,3-c]furan (80) as relatively stable, pale-yellow crystals, mp 178 to 180 ~ (dec) in 96% yield. The 90 MHz 1H NMR spectrum of 80 is very simple in that the aryl protons H5-H8 accidentally have the same chemical shift and are observed as a singlet at ~i 7.05 instead of the expected AA'BB' pattern, and the (x-furyl protons appear as a singlet at 8 7.56. H4 and H9 resonate at ~i 6.67, considerably upfield from the corresponding H4 and H9 signal at 8 7.3842 in the parent IBE which may be a consequence of a paratropic ring current effect43 operating in the four-membered ring of 80. Whatever the origin of the chemical shifts observed for 80 may be, there is enhanced chemical stability relative to IBF itself.
70
R
Ph
R
Ph
71 R=H 72 R=Bu-t
Scheme 13.
73
16
DIETER WEGE
~
Br
74
75
8 6.67
76
77
-
8 7.56 H
H
-
0.01 mm Hg
3
4
80
79
78
Scheme 14. We have also briefly attempted to gauge the effect of annulating a cyclobutadienetricarbonyliron moiety onto the IBF system (Scheme 15).~ Thus, treatment of tetrahalobenzocyclobutene 81 with Fe2(CO)9 gave the bcnzocyclobutadienetricarbonyliron complex 82 (22%), which on reaction with BuLi in the presence of furan .
X
Br
Fe2(CO)e D
y-
v
~
BuLl, -78 D
"Br
Fe(CO)3
81 X,Y=Br or I
Br
.
Fe(CO)a.
82
83
w
0
FVP
I
Fe(CO)a
H2, Pd-C
Fe(CO)=
Fe(CO)a
O@
85
86
~~o FeCO) a
Fe(CO)3
86a
87
Scheme 15.
0
84
The Chemistry of Isobenzofurans
17
afforded adduct 84 as a mixture of two stereoisomers in a 6:4 ratio (18%). Attempts to generate (cyclobuta[f]isobenzofuran)tricarbonyliron (86) by the addition of 3,6-di(pyridin-2'-yl)-s-tetrazine (28), both in the presence and absence of dimethyl fumarate, failed to give any recognizable product. Catalytic hydrogenation of 84 gave 85, but FVP of this material only gave a carbonaceous deposit in the hot zone of the pyrolysis tube, with no volatile material passing through into the cold trap. ~ While the outcome of these experiments is not completely clear-cut, it does suggest that 86 may be highly reactive and that it behaves like an IBF possessing a linearly annulated aromatic ring system. Indeed, if the cyclobutadienetricarbonyliron moiety is represented as in 86a to emphasize the need for the donation of 47t electrons to iron in order to fulfill the 18 electron rule, then a classical valence bond structure cannot be drawn for (cyclobuta[J]isobenzofuran)tricarbonyliron. Conversely, the angularly fused isomer 87 should behave as an angularly aromatic ring-fused IBF, and probably is a more realistic synthetic target. However, any projected synthetic route to 87 is not as straightforward as that shown for 86 in Scheme 15.
2.5 Trifuran and Difuran Derivatives Related to Isobenzofuran The finding that aromatic annulated IBFs were readily accessible through a route involving as a key step the dehydrobromination of aryl bromides in the presence of furan (Schemes 10, 14, and Table 1), prompted the question of whether this approach could be used to construct novel ring systems containing two or more c-fused furan rings. In particular, would 1,3,5-tribromobenzene (88) function as the trisbenzyne equivalent 89 and allow the construction of a six-membered ring possessing three c-fused furan rings, viz benzo[ 1,2-c:3,4-c':5,6-c"] trifuran (105, see later discussion)? This question seemed appropriate since at about that time Hart and Sasaoka reported the synthesis of the sulfur analog benzo[ 1,2-c:3,4-c':5,6c"]trithiophene (91) by dehydrogenation of the cyclic trisulfide 90 (Scheme 16).45 Treatment of 1,3,5-tribromobenzene 88 with an excess of sodium amide and furan in refluxing tetrahydrofuran gave the mono-adduct 93 (30%) together with two bis-adducts (44%) that could be separated by chromatography. Adduct 93 could also be prepared in 29% yield by generating 3,5-dibromobenzyne 92 from 3,5-dibromoanthranilic acid 95. The 13C NMR spectrum of each isomer of the bis-adduct displayed eight resonances, indicating that the products were the syn and anti isomers of 9-bromo-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene, 97 and 98, respectively, arising from trapping of the aryne 94. 39 The same two products were also obtained when mono-adduct 93 was subjected to the action of potassium amide in tetrahydrofuran in the presence of furan. The most acidic aryl proton in mono-adduct 93 should be H6 because it is flanked by two electron-withdrawing bromo substituents. Hence its abstraction by amide ion should be favored, but subsequent loss of bromide ion occurs predominantly from C7 to generate aryne 94; formation of the desired angular aryne 96 does not
18
DIETER WEGE S
1"
I s
DDQ
S
S
Br 88
89
91
90
NaNH2 THF
1
furan| _
Br
KNH2, THF I
.
Br
92
Br
93
~
1. NaNO2, HCI 2. heat I
Br-,,~CO2H T -NH2 Br 95
.
94
98
ran
Br
Br
97
98
Scheme 16.
ar
Br
1. NaNO2,HCl
NH=
Br
2. furan, heat
1
4*
NaNH2,THF
Br
99
11111
i=
~mn
Br 101 KNI-12,THF
fumn l,
I
'~"O~- -~~' X
O
550 ~ ' 0.01 mm Hg
H2, Pd-C a
Scheme 17.
+
The Chemistryof Isobenzofurans
19
occur to a detectable extent. This observation therefore necessitated the approach summarized in Scheme 17. Thermal decomposition of the diazonium hydrochloride derived from 3,6-dibromoanthranilic acid (99) in the presence of furan gave the symmetrical adduct 100, which by the usual dehydrobromination and trapping sequence gave first 101 (as a mixture of syn and anti isomers) and then 102 and 103. 39'4~More recently, Stoddard and co-workers have prepared these adducts by a route using hexabromobenzene as a trisbenzyne equivalent, and have used the C3v isomer 102 as a dienophile for the construction of an interesting cage compound. 46'47For our purposes, separation of the stereoisomers was not necessary and catalytic hydrogenation of the mixture of 102 and 103 gave 104, which on FVP afforded benzo[ 1,2-c:3,4-c':5,6-c"]trifuran (105) in essentially quantitative yield. Application of same cycloaddition-cycloreversion methodology, using 1,4-dibromonaphthalene (106) and 1,3-dibromobenzene (108) as bisbenzyne equivalents, afforded naphtho[ 1,2-c:3,4-c']difuran (107) and benzo[1,2-c:3,4-c']difuran (109), respectively (Scheme 18). 39'40 Compared to IBE the trifuran 105 and the difurans 107 and 109 are all relatively stable compounds.
2.5.1 Digression:Construction of Extended Aromatic Assemblies Using Difuran and Trifuran Systems In principle, use of the diene properties of the furan moieties of difurans such as 107 and 109, and of trifuran 105, offers the potential to build up extended angularly fused ring systems. One such reaction sequence involving 7,8-dimethylbenzo[ 1,2c:3,4-c']difuran (110) has been reported recently (Scheme 19).48 1,2,4,5-Tetrabromobenzene (115) functions as a bisbenzyne equivalent and affords 1,4,5,8-tetrahydro-l,4:5,8-diepoxyanthracene (116) on reaction with butyllithium in the presence of furan. 49'5~Reaction of 116 with tetracyclone yields 117, which on thermolysis in the presence of dienophiles behaves as a synthetic equivalent of benzo[1,2-c:4,5-c']difuran (118) and affords a variety of adducts, illustrated by the formation of 120 in the presence of 1,4-naphthoquinone (Scheme 20). 51 Although the mass spectra of Diels-Alder bis-adducts of 116 and of the tetrahydro derivative of 116 all show a base peak at m/e 158, corresponding to the radical cation of 118,51 it is probable that the cheletropic expulsion of carbon monoxide from 117 followed by the retro-Diels-Alder loss of tetraphenylbenzene occurs in a stepwise manner via two isobenzofuran intermediates that are trapped Br
~f 0
Br 106
0
Br 107
Scheme 18.
108
10g
20
DIETER WEGE CI CI Me
C
KOBu-t
Me
Me
CI
Me
CI CI
/
111
112
Me-
110
~~~,,~
E E
I E= CO2Me I
1.H=, Pd-C
Me
2. H+ Me
E
Me
E
E 114
113
Scheme 19.
O Br~Br Br
Ph:.P h , - ~ ~ - - P h ,
BuLi Br
furan syn or anti
117
116
115
O O
190-200 ~ -2CO - 2 CeHzPh4
O 119 O
O
O 120
118
Scheme 20.
E
Me
The Chemistry of Isobenzofurans
21
sequentially by the added dienophile. The linear benzodifuran, unlike the angular isomer 109 (Scheme 18), can only be represented by a diyl structure such as 118, and preliminary calculations indicate that 118 lies approximately 30 kcal/mol above 109. 51 Irrespective of the mechanistic and structural details, the difuran equivalent 118 serves as a convenient synthon for the construction of linear polycyclic assemblies. 51-53
2.6 Deoxygenationof Aryne-Furan and Aryne-lsobenzofuranAdducts Serendipity plays an important role in the advancement of an experimental science such as chemistry. 54 In connection with studies on the reaction of iron carbonyls with benzonorbornadiene and related compoundsY '56 we observed that the complex 121 decomposed in solution to give a brown precipitate (presumably FeO) and naphthalene 124, readily rationalized as occurring through either pathway a or b (Scheme 21).55 Although at that time this reaction proved to be of nuisance value only, we later wished to effect this sort of deoxygenation in other synthetic studies. 57 Accordingly, in order to assess the synthetic potential of this reaction, we treated a number of aryne-furan and aryne-isobenzofuran adducts 125 with Fe2(CO)9 in refluxing benzene and established that smooth deoxygenation occurred with formation of the appropriately substituted arene 126 in good yield (Scheme 22): 8 In the case of aryne-isobenzofuran adducts (125, R 2, R 3 = benzo) pathway b, involving direct coordination to the epoxy bridge, is the more likely mechanistic route. Other reagents that have been used to deoxygenate adducts of general structure 125 include 59 low-valent species produced by mixing transition-metal halides (Fe, W, Ti) with butyllithium at low temperatures, 6~TiCI4-LiAIH4, 61 NaBH 4 and acid, 62 and Me3SiI. 63 The Fe2(CO)9-mediated reaction is the mildest in that substrates ,.O-Fe(CO)3
o
Fe2(CO)9 ~ F e ( C O ) 4
a . - CO
10
121
122 - FeO -3C0
b o,,Fe(CO)4 -4C0 123
Scheme 21.
124
22
DIETER WEGE RI
1:12
R1
Fe2(CO)9
PhH, 80~
F~ 125
J R2, R3 = H, substituent, or benzol
R3
126
Scheme 22.
containing potentially reducible groups such as esters and halides, as well as acid-sensitive functionality such as acetals, can be used. 58
2.7 Small-Ring-Fused Isobenzofurans: A Kinetic Probe for the Mills-Nixon Effect In 1930 Mills and Nixon suggested that the difference in orientation effects observed in the electrophilic substitution of indane 128 compared to tetralin 127 were due to ring strain imposed on the benzenoid system by the five-membered ring of 128. 64 This strain was believed to result in bond fixation in the direction indicated by canonical structure 128a and this phenomenon became known as the Mills-Nixon effect. 65 With the availability in more recent years of more strained ring systems such as benzocyclobutene 129, benzocyclopropene 130, as well as systems containing two or more strained tings fused to a benzene ring, considerable effort has been expended in trying to demonstrate the presence or absence of the Mills-Nixon effect. 6672 Siegel has discussed some historical perspectives of this matter, 73'74 as well as the recent crystallographic and computational work 75"77 that indicates that deformations in such systems are a consequence of bent bonds around the positions of small ring-fusion. Bond alternation as required by the Mills-Nixon postulate is not observed. Nevertheless, in other systems, Mills-Nixon-type bond alternation is claimed to be present despite the existence of bent bonds. 7s The majority of probes into the Mills-Nixon effect have involved computational, crystallographic, or spectroscopic studies. 66-7g Consequently, we felt it would be of interest to view this problem from a different perspective and examine the reactivity of the cyclopropafused isobenzofuran 131 in Diels-Alder additions. In going from reactants to product, the dimethylidenecyclopropane moiety of 131 is converted into the cycloproparene system79 of 133 with an accompanying increase in n-bond order across the methylene-bridged C5--C6 bond (Scheme 23). A comparison of the reactivity of 131 with that of other 5,6-disubstituted isobenzofurans may give an indication of whether cyclopropa-fusion in 131 leads to a reluctance in accepting increased it-bond order across the C5-C6 bond. 5H-Cyclopropa[f] isobenzofuran (131), one of the first examples of a heterocyclic cycloproparene, was prepared as summarized in Scheme 24, and qualitatively
The Chemistryof Isobenzofurans
23
n 4 3
127a 128a 129a 130a
+
127b 128b
2 1
~CO=Me
129b 130b
,,~COzMe
.
=~ C 0 2 M e
~
131
132
133
Scheme 23.
possesses stability similar to that of the parent IBE 8~ For reactivity comparisons, 5,6-dimethylisobenzofuran (139), 5,6-dihydrocyclobut[/]isobenzofuran (140), 4,5dihydrocyclobut[ e] isobenzofuran (141), and 5,6-dibromoisobenzofuran (142) also were prepared from the appropriate dihydroepoxyarene precursor using the dipyridyl-s-tetrazine route. Second-order rate constants for the addition of dimethyl fumarate to these IBFs in cyclohexane were measured and are given in Table 2. 8tr82 The IBF derivatives show a reactivity span of only one order of magnitude. According to the concept of n-bond fixation or bond alternation (the Mills-Nixon effect), 5H-cyclopropa[f]isobenzofuran 131 should be less reactive than IBF 1 because of the reluctance of 131 to accept an increase in double-bond character
Br
MeaSi
/ ~Br
134
Ii,
ir
THF,-78 o
Br
ur
135
137
D~
'••O
I
KOBu-t,THF
Br
-78 ~
131
Scheme 24.
138
24
DIETERWEGE Table 2.
Compound
139 ~
5.03
3.0
140 ~ ~ ~ 0
2.s7
1.s
141 ~ 0
1.83
1.1
1 ~0
1.69
1.0
0.843
0.5
0.427
0.25
142 ~
131
0
Second-OrderRateConstants for the Addition of Dimethyl Fumarate to IBFs (25 ~ cyclohexane) k2 (I. mo1-1 s -1) krel
0
<••o
across C5-C6 in going from reactant to transition state 132 (Scheme 23). The cyclopropa-fused derivative 131 is indeed less reactive than the parent 1, but only by a factor of 4, corresponding to a difference in free energy of activation AAG. of 0.82 kcal/mol at 25 ~ The linearly cyclobuta-fused IBF 140 should also be less reactive than 1 if the Mills-Nixon effect operates; experimentally it is observed to be more reactive by a factor of 1.5. The angularly cyclobuta-fused isomer 141, which loses n-bond order across the bridged bond in going from reactants to transition state, should be more reactive than 1, but is observed to have about the same reactivity. It also is slightly less reactive than the linearly fused isomer 140, although the operation of the Mills-Nixon effect would demand it to be more reactive. Finally, the presence of the electron-donating methyl groups at C5 and C6 leads to a three-fold rate enhancement over IBF, while dibromo substitution as in 142 leads to a two-fold rate reduction. It is clear that the absence of substantial rate differences for the addition of dimethyl fumarate to the IBFs listed in Table 2 indicates that there is no significant destabilization of transition state 132 and the analogous transition state for the
The Chemistry of Isobenzofurans
25
addition to 140 due to annulation of a three or four-membered ring to thefbond of IBF. Although it could be argued that the cycloadditions all involve early transition states that are very much reactant-like and hence would not reflect much of the consequence of bond fixation effects, this seems unlikely given the substantial rate effects observed in the cycloadditions of benzannulated IBFs (Section 2.4.2.2); each transition state must reflect at least part of the character of the product. On the basis of these results we conclude that n-bond fixation in the direction indicated by structures 131a and 129a is not significant for adduct 133 and the adduct derived from 140, and that this kinetic probe rules against the operation of a Mills-Nixon effect in these systems.
2.8 Heterocyclic Analogs of Isobenzofuran Furo[3,4-c]pyridine 144, a simple heterocyclic analog of IBE was prepared by Wiersum and co-workers using their elegant FVP technique (Scheme 25). 83 This compound possesses reactivity similar to that of IBF itself; it polymerizes at room temperature and acts as a reactive diene in Diels-Alder reactions. We were intrigued by the possibility of preparing furo[3,4-b]furan 145 and thieno[2,3-c]furan 146 as heterocyclic analogs of IBF (Scheme 26); these compounds could, in principle, be less reactive than IBF or the analog 144 towards cycloaddition since only a furan or thiophene (rather than a benzene) ring is generated on cycloaddition across the diene system of 145 and 146, respectively. However, it must be borne in mind that 145 and 146 also may be regarded as oxygen-bridged derivatives of the dimethylidene systems 147 and 148; these species, like o-xylylene, are not isolable and behave as reactive intermediates. 84 Introduction of the oxygen-bridge also may introduce some angle deformation in going from 147 and 148 to 145 and 146 respectively, which may counteract any potential electronic stabilization. Our approach to the ring systems of 145 and that of the related thieno[3,4-b]furan 149 is shown in Scheme 27, and uses a tandem intramolecular Diels-Alder/reverse Diels-Alder reaction sequence, s5 A solution of the ester 151 was heated under reflux in toluene to give, after rapid chromatography, the intramolecular Diels-Alder adduct 153 in good yield. Addition of the electron-deficient diene 3,6-di(pyridin2'-yl)-s-tetrazine (28) to a solution of 153 in chloroform, followed by brief warming and chromatography, gave the substituted furan 159 via the usual Diels-Alder addition/cycloreversion sequence (see also Scheme 5). The intramolecular addition
650 ~ 0.1 mm Hg | - C2H4 143
N~~~ 144
Scheme 25.
0
26
DIETERWEGE
145
146
147 x = o 148 x = s
149
Scheme 26.
and cycloreversion steps could also be carded out in a one-pot reaction by heating the acetylenic ester 151 with one equivalent of the s-tetrazine 28 in toluene, since 28 reacts preferentially with the electron-rich alkene bond of 153 rather than the conjugated alkene bond, or the conjugated alkyne system of the reactant 151. The
N.fN II
C02Me o
II
0 .
I
co~M,,
,
--
0 .
XI
_
150 X=O 151 X=S
_
152 X--'O 153 X=S
154 X--O 155 X--S
- N2
MeO2C~..~.,3~m
OOO
MeO2 X
160
I
1.hydroids
~.
"
DDQ
PY
CO2Me
N'~
158 X---O 159 X=S
2. decarboxylation
156 X--O 157 X--S
"~
" IVle02C
149
N
Py
. hydrolysis decarboxylation 9
"N
,o 161
Scheme 27.
162
CHO .CliO
163
The Chemistry of Isobenzofurans
27
overall conversion of 151 into 159 illustrates the power and efficiency of tandem pericyclic reaction sequences in synthesis. 86 Brief treatment of 159 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) gave methyl thieno[3,4-b]furan-3-carboxylate (160) in good yield. Hydrolysis of 160 to the corresponding carboxylic acid, followed by decarboxylation, afforded thieno[3,4-b]furan (149), a heterocyclic analog of benzo[c]thiophene. Although thiophene and furan are both n-excessive five-membered heterocycles, an appropriate maxim is that, because the former resembles benzene more closely, its chemistry and that of its derivatives often has been developed earlier and in a different fashion. For example, the characterization of benzo[c]thiophene 87 predates that of IBF,~2'13 and the trithiophene derivative 91 could be obtained by dehydrogenation of the hexahydro derivative 90 (Scheme 16), a reaction not applicable to the preparation of the trifuran 105. The differences in thiophene and furan chemistry again became apparent in our approach to furo[3,4-b]furan (145). When the oxygen-linked acetylenic ester 150 was refluxed in toluene, the adduct 152 was not obtained, presumably because in this case the equilibrium for the intramolecular Diels-Alder reaction at that temperature lies on the side of the reactant 150, possibly as a consequence of additional ring strain arising in adduct 152 relative to 153 due to the presence of the smaller oxygen atom. However, when
'~O
Ph
o~S
RO
MeC(S)N, H2
RO2C~O . ~ S
Br 164
R 165
Ph
R
166
Ph
167
~CHO OAc
CF3CO2 H '
Ar 168
CO2R
9 RO2c
170
169
CN
FVP
172
==~CN
173
Scheme 28.
~ O Ar 171
28
DIETER WEGE
150 was heated under reflux in toluene in the presence of 3,6-di(pyridin-2'-yl)-stetrazine (28), adduct 152 was trapped in situ and delivered the desired substituted furan 158 in good yield by the expected pathway (Scheme 27). Unfortunately, attempts to dehydrogenate the dihydrofuran 158 under a variety of conditions were unsuccessful. This may be a consequence of the fact that the conversion of 158 into 161 would involve the loss of one furan ring (stabilized by a methoxycarbonyl group) and the gain of another. The associated lack of thermodynamic driving force for such a process could well result in a high activation energy for reaction, unlike in the case of the thia analog 159, in which a furan ring is lost and a thiophene ring is gained. Hydrolysis of 158 followed by decarboxylation afforded the somewhat unstable furan derivative 162. Attempts to introduce the final degree of unsaturation to deliver furo[3,4-b]furan (145) have been unsuccessful, although the formation in some of these reactions of dialdehyde 163, the product of hydration of 145, points to the intermediacy of 145. 88 Although the above route did not yield the parent furo[3,4-b]furan (145) and thieno[2,3-c]furan (149), several substituted derivatives of these ring systems have been prepared by other workers using a variety of non-cycloaddition approaches (Scheme 28). 89--93It should be noted that all of these compounds bear at least one substituent in each furan ring, which contributes to their relative stability. 4,6Diphenylthieno[2,3-c]furan (169) was characterized crystallographically; the phenyl tings and the heterocyclic moiety were found to be coplanar in the solid state, and the reactivity of 169 in Diels-Alder and other reactions was found to be similar to that of 1,3-diphenylisobenzofuran. 91
2.9 3-Trimethylsilyloxyisobenzofuran-l-carbonitrile as a Synthon for Substituted Naphthalene-l,4-diones In addition to the deoxygenation of aryne-furan and aryne-isobenzofuran adducts discussed in Section 2.6, the acid-catalyzed ring-opening of compounds such as 174 to afford phenols 175 also constitutes a useful synthetic procedure. 94Placement of an oxygen functionality at C1 provides the opportunity to generate 1,4-dioxygenated derivatives (naphthalene numbering) in the ring-opening step. Early exampies of this process include the preparation of naphthalene derivatives such as 180 via 1-alkoxyisobenzofurans 178, as shown in Scheme 29. 95 An elegant extension of this concept involved the use of the cyanophthalide 181 to generate the 3trimethylsilyloxyisobenzofuran-l-carbonitrile (182); this was trapped with the dienophile 183 to provide, after hydrolysis, the highly functionalized naphthalene derivative 185, a model compound related to fredericamycin A (Scheme 30). %
2. 9.1 Generation of Cyclopropa-fused p.Quinones Recently we have found that 3-trimethylsilyloxyisobenzofuran-l-carbonitrile (187) can be intercepted with 1-bromo-2-trimethylsilylcyclopropene (188) to give, after hydrolysis and chromatography, the cyclopropa-fused 1,4-naphthalenedione
The Chemistry of Isobenzofurans
29
R
Ra
R
174
R3(R2)
175
I R2, R3 = H, substituent,or benzo] E
OEt I-I*
-H*
E
_
17.
177
E
_
178
17,
OH
1~
Scheme 29.
derivative 190 (Scheme 31).97 Bromo desilylation of 190 with tetrabutylammonium fluoride at low temperature generated 1H-cyclopropa[b]naphthalene-2,7-dione (191), which could not be isolated but was trapped with furan to give adducts 192 and 193. In the absence of added trapping agent, 191 was intercepted by fluoride ion from the tetrabutylammonium fluoride to afford the fluoro-dione 194 in low yield. 97 We also have generated the parent bicyclo[4.1.0]hepta-l(6),3-diene-2,4-dione (benzocyclopropene-p-quinone, 199) by a related procedure (Scheme 32). In this case the use of 2-methoxyfuran in the cycloaddition necessitates the use of an oxidation step (197 --~ 198) to generate the requisite dione system; the push-pull IBF 187 possesses the advantage of having a built-in latent dione functionality. The cyclopropa-fused quinones 191 and 199 are theoretically interesting molecules
MeO M e O ' ~ MeO
O 0 CN
1. t-BuLi, THF, -78, ~ : . . . I I qD 2. Me3SiCI M e O ~ MeO CN
181
Scheme 30.
O
,, MeO" ~ MeO
"T" ~ OH O
30
O 1.
LDA,
[~~~0
Br;~
OSiMe3
THF,-780C
2. Me3SiCI CN
Me3Si 188
DIETER WEGE Me3SiO
|
CN
186
189
187
0
0
0
F"
II
e3
CN
Bu4NF
|
THF, -78 ~ 0
0
194
191
iMea
O
-
190
0
~ 0 192
193
Scheme 31.
OMe
_~o
B~
H§
Me3Si 188 9 SiMe3
HO H
196
195
~r 0
MeO
iMe3
197
PCC w
O
O
-
O
|
1
200
0
"
Bu4NF THF, -78~
0
O
201
199
Scheme 32.
0
iMe3
The Chemistry of Isobenzofurans
31
related to the cycloproparenes. However, they still possess the high reactivity observed for bicyclo[4.1.0]hepta- 1(6),3-diene. 98 2.9.2 The Total Synthesis of Favelanone (+)-Favelanone (202), a novel tetracyclic dione having in vivo activity against P-388 murine leukemia, was isolated from the Brazilian plant Favela, Cnidoscolus phyllacanthus (Mart.) Pax et K. Hoffm. (Euphorbiaceae). 99']~176 Favelanone incorporates the previously unknown 1,2,3,4,4a,4b-hexahydrobenzo[1,3]cyclopropa[ 1,2-b]naphthalene skeleton 203, and we wondered whether the cycloaddition sequence leading to the cyclopropa-fused naphthalene-l,4-dione 191 shown in Scheme 31 could be extended to the synthesis of this new ring system. Retrosynthetic analysis suggests that Diels-Alder addition between the electron-rich pushpull IBF 205 and the polarized cyclopropene 206 should occur in the sense shown in Scheme 33; liberation of the naphthalene-l,4-dione functionality from 204, followed by debromination, should then deliver favelanone 202. l~ 1,7,7-Tribromo-5,5-dimethylbicyclo[4.1.0]heptane (210), the precursor to the cyclopropene 206, was prepared from 6-bromo-2,2-dimethylcyclohexanone (207) as shown in Scheme 34. Treatment of the tribromide 210 with butyllithium at-100 ~ generated the reactive 1,3-bridged cyclopropene 206, as evidenced by the isolation of a single adduct 211 after addition of IBF 1. To determine the stereochemical outcome of this cycloaddition, 211 was debrominated with Bu3SnH to give 212; the observed lack of coupling between H4b and bridgehead H5 establishes that H4b has an endo orientation within the 7-oxabicyclo[2.2.1]heptyl system. The highly substituted cyclopropene 206 thus follows the same stereo0
6
202
M~e MeO CN
2
203
OSiMe3
OSiMe3
Me~A~..Br
5
,
Me*
~
J
MeO
204
Br\t~./Me
CN
205
Scheme 33.
+
3
206
32
DIETER WEGE
o OH Br~,,~ e er~ ~,,J~jMe L , ~ -Me NaBH4. T "~ Me
er,~.Me
(CF3SO2)20 . CH2CI2, py, DMAP
207
M* Me CHBr3 NaOH B~ r j-Me ar
"
208
209
210
BuLi -100~
,•j
~ 0 Hz .~ = 3.2 Hz v"
8 1.82
H
o~
_
~,
Br\ @
AIBN,Phil 212
211
Scheme 34.
Me~Br
~
O
1. n BuLi CO2 2 I"130+
o
|
OH
O
1. HCN
o
2. (COCIk" DMF,py
CN
214
213
BriM
215
1. LDA
2. Me3SX;~
e ,=
~)SiMe3 M e ~ , = / ~ , , ~Br M
OSiMe3 Meo~e
206
CN
--
CN
204
1-130+ 6
O Bu3SnH,AIBN PhH
i
Me~ ~ M
e
O i
~
O
~ H
~ O 202
21S
favelanone
Scheme 35.
e
The Chemistry of Isobenzofurans
33
chemical trend as observed in the addition of simpler cyclopropenes to furans and IBFs. 1~ The specifically substituted cyano phthalide 215 was prepared from the bromo acetal 213 using standard functional group manipulations (Scheme 35). Deprotonation followed by quenching with Me3SiCI gave an orange solution of the IBF 205, which was then treated at low temperature with a solution of the cyclopropene 206. Warming up to room temperature, followed by hydrolysis and chromatography afforded the key bromo dione 216, whose regiochemistry was established by NMR spectroscopy. The aryl protons H6 (5 7.85) and H9 05 7.39) could be assigned on the basis of nuclear Overhauser effects observed with the aromatic methyl and methoxy groups respectively, while three-bond correlations were established between H6 and C5 05 187.9) and H9 and C10 (5 192.9), respectively, using heteronuclear shift correlations via multiple bond connectivities (HMBC). The regiochemistry shown follows from the observation that H1 equatorial 05 3.29) shows a three-bond correlation with C 10. (+)-Favelanone 202, spectroscopically identical with the optically active natural product, was obtained by debromination of 216 with Bu3SnH. The above convergent synthesis illustrates the utility of 3-silyloxyisobenzofuran- 1-carbonitriles such as 205 in the construction of relatively complex substituted naphthalene-1,4-diones; the highly polarized nature of 205 results in a high degree of regiocontrol in the cycloaddition with the unsymmetrical cyclopropene 206. ~~
2.10 Isobenzofurandionesand Related Compounds Five isomeric isobenzofurandione structures 217-221 containing the maximum number of noncumulative double bonds are possible (Scheme 36). Although ChemicalAbstracts indexes phthalic anhydride 217 under 1,3-isobenzofurandione, this is for purposes of nomenclature rather than for reasons of chemical logic.
0
0
0
0
0
217
218
0
219
0 02 1
0 0
220
Scheme 36.
221
34
DIETER WEGE
Structures 218 and 219 are lactones also possessing an o- and p-quinonemethide moiety respectively; they are unknown and again are not germane to a discussion of the chemistry of IBFs. However, compounds 220 and 221 are significant in that they may be regarded as quinonoid derivatives of IBF and are interesting members of a growing family of heterocyclic quinones. 1~ Furthermore, a number of natural products containing the ring systems of 220 and 221 have been described recently. This section summarizes aspects of the chemistry of these compounds, as well as some of our synthetic efforts in the area.
2.10.1
Isobenzofuran-4,5-diones
Our attention was drawn to this ring system by the characterization of albidin 222, a red fungistatic and antibiotic metabolite produced by the fungus Penicillium albidum Sopp. Although the isolation of this compound was reported in 1947,1~ structural elucidation by NMR spectroscopy and X-ray crystallography was carried out more recently. 1~ Structurally, albidin 224 is related to (-)-curvulol 223, produced by the fungus Clavularia siddiqui, 1~ and we have carried out a concise synthesis of both metabolites as shown in Scheme 37.1~ The aryl bromide 225, prepared from 2-bromo-3,4-dihydroxy-5-methoxybenzaldehyde (224) by standard transformations, was treated with tributylstannane and AIBN in refluxing benzene to give the 226 and 227 in a ratio of 7:3 via cyclization
0
HO
Me
Me
222
MeO' ~
"CHO
"MeOA~,..'u',,,~ O AIBN,Phil MeO
224
225
MeO
226
227
w
0
O
~
HO HO~o
Me
0
DDO
MeO
Scheme 37.
228
Me
0 Me chlorantil 0 ~ ~ / 0 MeO" ~i 229
The Chemistryof Isobenzofurans
35
of the intermediate aryl radical. Hydrolysis of 226 afforded (+)-curvulo1228, which on oxidation with chloranil afforded the quinone 229. More vigorous dehydrogenation of 228 with DDQ in refluxing dioxane gave albidin 222, identical in all respects to an authentic sample. ~~ Access to the isobenzofuran-4,5-dione system 220 should, in principle, also be possible through the use of cycloaddition/cycloreversion methodology. So far we have been unable to prepare the parent compound 220, but we have obtained 7-t-butylisobenzofuran-4,5-dione (240) using this approach (Scheme 38). 1~ Treatment of the readily available bromoarene 230 with Caub&e's base in the presence of furan gave adduct 233 in 15% yield. A considerable improvement in yield (93%) was obtained using the less accessible bromide 231, in which the methoxy group activates the o-hydrogen towards metalation and subsequent elimination. The ether 233 was demethylated using NaSEt in DMF under carefully controlled conditions to afford the phenol 234, which on attempted oxidation to the corresponding o-quinone using Fremy's salt gave only complex mixtures. This may be a consequence of the presence of the homoconjugated double bond in 234, which could
~
MeO Br
or
Br
230
0
MeO
NaNH2,THF
i=
231
232
HO
HO
NaSEt ~ DMF/ 6
233
H
O
Ph== 236
;;-Ph4
234
235
238 "ON(SO3K)2
1 5 o~
o_2 O ~ \ .Bu-t
O
O
110~
~Ph4
- CO,- CeH2Ph4 0
237
240
Scheme 38.
239
36
DIETER WEGE
lead to abnormal reactions of the intermediate phenoxy radical, since the dihydro derivative 235 readily afforded 236 under these conditions. Flash vacuum pyrolytic extrusion of ethylene from 236 should deliver the target quinone 240. However, when 236 was heated to 150 ~ under vacuum in order to effect sublimation into the pyrolysis tube, a color change from red to yellow was observed, but no material volatilized into the tube. Chromatographic purification of the residue afforded a dimer of 236 as a single stereoisomer; this is tentatively formulated as 237, and arises from a reaction in which one molecule of 236 functions as a diene while a second acts as a dienophile. The poor volatility of 236 prompted a return to solution chemistry in order to effect cycloreversion. Treatment of phenol 234 with tetracyclone gave adduct 238, which was oxidized to quinone 239 using Fremy's salt. Thermolysis of 239 in refluxing toluene followed by rapid chromatography gave 7-t-butylisobenzofuran4,5-dione (240) as a yellow crystalline solid in 44% yield. 1~ To date, 240 and albidin 222 are the only reported isobenzofuran-4,5-diones, and the chemistry of this interesting ring system, in particular its behavior in cycloaddition reactions, remains to be explored.
2.10.2 Isobenzofuran.4,7-diones Isobenzofuran-4,7-dione (221) has been prepared using the cycloaddition/cycloreversion sequence shown in Scheme 39.1~ A key step involved the oxidative demethylation of the dimethyl ether 242 using silver (II) oxide in the presence of 6 M nitric acid. The acid-sensitive epoxy bridge survived, although the yield of quinone 243 was only 33%. Both the enedione and furan moieties of 221 offer the potential for further cycloaddition reactions, which remains to be realized.
2.10.3 Naphtho[2,3-cffuran-4,9-diones 2.10.3.1 Naphtho[2,3-c]furan-4,9-dione. In view of the fact that the naphtho[2,3-c]furan-4,9-dione ring system occurs in a number of natural products (see below), we have prepared the parent compound 246 by a procedure analogous to that used above for 221. The final cycloreversion step was effected by the FVP
NaNH2,THF MeO 241
0~]
AgO HNO3
Me<:) 242
py O
O 243
Scheme 39.
221
The Chemistry of Isobenzofurans
37
Ns II
0
MeO
N
I
N
0
AgO HN03 O
MeO
or H2, Pd-C then FVP
O 246
245
244
Scheme 40.
of the dihydro derivative of 245, as well as the dipyridyl-s-tetrazine-mediated route (Scheme 40). 11~Interestingly, the yellow epoxy-bridged quinone 245 undergoes an unusual photochemical rearrangement to afford the dark red methylenecyclopropane derivative 250 as the only significant product (Scheme 41). ill Substituted naphtho[2,3-c]furan-4,9-diones can be prepared by the double Friedel-Crafts acylation of benzene derivatives 251 with furan-3,4-dicarbonyl chlorides 252. ll2-115 Methoxy groups that end up ortho to a carbonyl group in the acylation product suffer demethylation under the reaction conditions. For example, acylation of 1,4-dimethoxybenzene (254) with furan-3,4-dicarbonyl chloride (255) affords 5,8-dihydroxynaphtho[2,3-c]furan-4,9-dione (256). 114 2.10.3.2 Natural Products Incorporating the Naphtho[2,3-c]furan-4,9dione Ring System. Nectriafurone 259, isolated from the fungus Nectria haematococca, 116 has been synthesized in racemic form as shown in Scheme 43. lIT Acylation of the hydroquinone 257 with furan-3,4-dicarbonyl chloride (255) under
0
hu, 350 nm )
c~c~
0 245
0
0
247
248
.H,
/ 0
0
249
250
Scheme 41.
H
0
38
b
c, o O
t-
R
DIETER WEGE
R
251
R
O
R
)
CI
O
O
R
252
253
MeO
0
HO
0
MeO
0
HO
0
254
255
256
Scheme 42.
rather drastic conditions, followed by remethylation gave 258 in low yield (18%), which on treatment with a large excess of LDA and acetaldehyde gave 259 (43%), in addition to smaller amounts of product derived by substitution at the other furyl position, as well as disubstituted material. The ventilones A-E 260--264 (Scheme 44) are five structurally related "isofuranonaphthoquinones" isolated from the root bark of Ventilago maderaspatana (Rhamnaceae), lIB while ventilone F 265 has been obtained from Ventilago goughii, 119 and ventilone G 266 from Ventilago vitensis. 12~ No synthetic work relating to these compounds has been reported, and we have investigated several approaches to the simplest member, ventilone A 260.121 Although this compound should in principle be accessible through a double acylation of the arene 267 with 2-methylfuran-3,4-dicarbonyl chloride 268, no trace of the desired product could be detected under a variety of reaction conditions. ~22 The highly activated arene 267 undergoes oxidative decomposition in the presence of Lewis acids, and accordingly we have examined cycloaddition chemistry to try to generate the desired ring system of 260.
-o.0 c, o, HO
0
+
HO 2~
CI
HO
0
9
2.CH2N=
O
o.-o
HO
CH:~HO HO
2~
O 2M
Scheme 43.
Lll y
HO
0
Me ,"OH
.L~,, o
~
~"
O 2~
The Chemistry of Isobenzofurans O HO
0
RO
O
Me ~
39
0 R10 ~ / O0
(
o-yy R20
A 260 R=H B 261 R=Me
Me
O
HO
O
HO
O
C 262 R~=H,R2=Me D 263 R~=Me,R2=H E 264 R~=R2=H
Me
HO
O
Me
HO
O
OMe
F 265
G 266
Scheme 44. Ventilones
The aryne generated from dibromide 269 by the action of n-butyllithium was trapped with furan to give adduct 270. Treatment of 270 with dipyridyl-s-tetrazine 28 in the presence of two molar equivalents of the acetylenic dienophile 272 did not yield the expected adduct 273 (which possesses functionality suitable for further
MeO <:~
~. ~Vle + OC '~C~ . - -
MeO
Lewis acid~
HO O < : ~ O
9
O
267
HO
2U
N'N
Br2
MeO
( O ' ~
Br
BuLl
O~y~Br MeO
II
MeO
I
O
260
MeO
N,,~N
MeO
MeO
271
270
269
Me
MemO . MeO o O.
-.
MeO"
I COMe
CO2Me Me
271
MeO
CO2Me
_
274
Scheme 45.
2Me 273
40
DIETER WEGE
co~ EtO
H§
II
C02Me,
[ ~ 0
275
o
N ~
C02Me 276
C02Me
1
277
C02Me C02~
C02~ 278
Scheme 46.
elaboration into ventilone A), but gave instead in 14% yield the double adduct 274, derived by reaction 273 with the IBF 271 (Scheme 45). This observation implies that the ethylenic moiety of mono-adduct 273 is a better dienophile than the acetylenic substrate 272. Rickborn and Mirsadeghi have observed analogous behavior in the trapping of IBF 1 with dimethyl acetylenedicarboxylate (Scheme 46). 4'123Although the yield of mono-adduct 276 could be raised to 72% by carrying out the acid-catalyzed generation of IBF from 1-ethoxyphthalan 275 at 140 ~ in chlorobenzene in the presence of three molar equivalents of dimethyl acetylenedicarboxylate, the double adducts 277 and 278 were also formed in a ratio of 4:1. Although the desired mono-adduct 273 (Scheme 45) may well be accessible through variation of reaction conditions and use of a larger excess of the acetylenic dienophile 272, we adopted instead the approach shown in Scheme 47.121Debromination of 269 in the presence of 1,3-dihydrofuro[3,4-c]furan (279), followed by conventional work-up failed to deliver the expected adduct 280, but gave instead the derived epoxide 281 (13%) and the butylated ring-opened product 282 (9%). The latter arises from addition of residual n-butyllithium (used to generate the intermediate aryne from dibromide 269) to the double bond of 280, followed by fragmentation. The former apparently results from oxidation of 280 by atmospheric oxygen, a reaction that has precedence in a number of structurally related systems. 124The formation of these abnormal products suggests that the adduct 280 is highly reactive, possibly as a consequence of pyramidalization of the alkene linkage. ]25 When the aryne trapping reaction was repeated and the crude product immediately subjected to the action of acid in the absence of oxygen, the desired
The Chemistry of Isobenzofurans
O ~
Br
O ' ~ M ~ " Br
41
n-BuLi ,
~,~....o
M ' ~~ -
0 ~ 0 279
269
MeO O\ O
02
MeO
L....(~ 281
280
OH
M~ o
MeO 282
283
ON(SO3K)2 9 w
MeO
MeO
O
O
NBS
MeO
O 285
284
Scheme 47. naphtho1283 was isolated in acceptable yield (56%). Oxidation with ceric ammonium nitrate gave the quinone 284 (86%), which on treatment with N-bromosuccinimide afforded 285 (79%), a structure closely related to that of ventilone A 260. The steps needed to prepare the natural product, viz introduction of the methyl group
~ M o e
OH O
O 286
Me
OH O
287
OH
OH
Me
288
OH
O
OH 289
290
Scheme 48.
Me
Me
42
DIETER WEGE
~
"
h
....~D
OH
R
H
Ph
R
O
Ph
Ac,ZO,heatNaOAc
h 291
R
-
Ph
292
R -
Ph 293
R = H or OMe
Scheme 49.
into the furan ring, and demethylation of the methyl ethers, remain to be carried out. Four other natural products related to naphtho[2,3-c]furan-4,9-dione have been reported recently. Dione 286 and ketones 287 and 288 were isolated from the Cape aloe (AloeferoxMiller) (Scheme 48). 126Ketones 287 and 288 are interesting in that they are tautomers of 8,9-dihydroxy- 1-methylnaphtho[2,3-c]furan (289); the latter, by analogy with the parent naphtho[2,3-c]furan (65) (Section 2.4.2.2), is predicted to be highly reactive. Similar considerations apply to MS-444 290, an inhibitor of myosin light chain kinase isolated from the culture broth of Microspora sp KY7123.127 Will a species such as 289, if generated by a suitable procedure, rearrange spontaneously to 287 or 288? Work is in progress to answer this question, but it may be noted that the formation of ketone 293 by dehydration of diol 291113 apparently proceeds through an analogous intermediate 292 (Scheme 49). 2.11
4,7-Dihydroisobenzofuran and Its Role in Resolving a Structural Conundrum
4,7-Dihydroisobenzofuran (297) has previously been obtained by thermolysis of 294128 and reduction and cyclization of 300 (Scheme 50). 129 A more convenient procedure involves oxidation of diol 302, available from 301, the adduct of butadiene and dimethyl acetylenedicarboxylate. 44 We recently have used 297 to contribute to the solution of a structural problem in natural products chemistry. ~3~ The metabolite SCH 58450, which inhibits farnesyl protein transferase, was isolated from a Streptomycessp, and assigned structure 304 on the basis of NMR experiments. The benz[a]anthracene ring skeleton and ring A and D substitution pattern of structure 304 is that observed for many members of the angucycline antibiotics, ~32 but the proposed diepoxy structural feature, incorporating a locked arene oxide as well as a 7-oxabicyclo[2.2.1]heptyl moiety, is unprecedented. We therefore prepared a number of compounds to provide model spectroscopic data for the suggested novel diepoxy structure. Addition of benzyne, generated from diazotized anthranilic acid, to 4,7-dihydroisobenzofuran 297 gave adduct 308 (Scheme 51). The more substituted double
TM
The Chemistry of Isobenzofurans
43 -
[ ~
0
. o~i,:,,~
150 ~ Phil
294
O 295
-
CH(OEt)2
~§ II
296
H(OEt)2
1. NaBH4 ~ O
I
9
v
"CHO
2. H§
CHO 298
300
299
297 J
~
CO2Me
LiAIH4
,
~CH2OH v
CO2Me
301
PCC ,
-CH20H
"
OH
~ O
"
.
302
303
Scheme 50.
Me
Me
MeO
.
"
0' R
.
MeO HO 305
7 304
9
"
'
~ R
"
306 R=H 307 R=OMe
m'CI'C6H4CO3H,
297
R 308 R=H 309 R=OMe
,
KOBu-t
~
B
r
THF 313
Br 312
Scheme 51.
310 R=H 311 R=OMe
BrJ
44
DIETERWEGE
bond was epoxidized selectively with m-chloroperoxybenzoic acid to give 310, which was converted into the arene oxide 313 by addition of bromine followed by dehydrobromination. In order to simulate more closely the ring D substitution pattern of the metabolite, the sequence was also carried through to diepoxide 311, using 3-methoxybenzyne 307 generated by the dehydrobromination ofm-bromoanisole. It was observed that in all of the compounds 310--313 the bridgehead carbons C9 and C 10 resonate within the narrow range of 77.3 to 79.6 ppm. In the natural product, the corresponding carbons C12 and C7 were observed at 69.1 and 63.6 ppm, respectively, which suggested that structure 304, incorporating the diepoxy feature of the model compounds, was unlikely to be the metabolite. 13~ This information led to a revision of the structure. Careful examination of the mass spectrum of SCH 58450 indicated the molecular formula to be C20H2006,133 and not C20H1805 as previously supposed. TM The metabolite is therefore now formulated as the diol 305 (stereochemistry still unknown), and the material appears to be identical with the compound labeled EI-1507-2 recently described by other workers. 13a
3. RECENTAPPLICATIONS OF ISOBENZOFURAN CHEMISTRY TO THE SYNTHESIS OF NATURAL PRODUCTS Rodrigo has discussed the use of IBFs in the synthesis of natural products and polycyclic aromatic hydrocarbons and has covered the literature up to 1988. 5 Several more recent applications of such chemistry that are germane to the general themes of Section 2 are detailed below.
3.1 Lignan Synthesis Rodrigo and co-workers have published full details of their synthesis of eight diastereomeric Podophyllum lignans. 135The key step involved trapping of the IBF 316 (Scheme 52). 1-Ethylthioisobenzofurans, generated by the cyclization of ketosulfoxides such as 317, are useful intermediates. 136 Adduct 319 has been CO2Me HOAc Ar 314
OH
.
.
.
Ar.
II
9
315
I Ar= 3,4,5-tdmethoxyphenylI
Scheme 52.
0.~ ~
~,~
I
Ar
316
The Chemistry of Isobenzofurans
45 C02Me
m
O,~s,,Et
SEt
0
A~O
0
C02Me
<~ '
SEt ~
~- ~
317
318
~
C02Me
V
~r'r~2~Aew,,,
319
w
OH
0
Justicidin E
Taiwanin C 321
320
Taiwanin E 322
Scheme 53.
transformed into the lignans Justicidin C, Taiwanin C, and Taiwanin E (Scheme 53). Another route to 1-thio substituted IBFs involves deprotonation and S-alkylation of thiophthalides 323 (Scheme 54); adduct 325 was characterized by singlecrystal X-ray crystallography. 137 The adduct of 5,6-methylenedioxyisobenzofuran (327) and dimethyl acetylenedicarboxylate has been converted into diacetate 329, which on hydrolysis with porcine pancreatic lipase (PPL) afforded alcohol 330 in good chemical yield and
s
1. LiNR'2 D
S o"
i~.C02Me Me02C
2. MeX
, v
R 323 R = H, Me, Ph
MeS
R 324
Scheme 54.
T "C02Me Ph 325
46
DIETER W E G E
CO2Me OMe
II HOAc heat
CO2Me
B
326
O~~~Q~/CO2Me CO2Me
--
327
328 1. H2, Pd-C 2. LiAII-~ 3. Ac,~O w
O
PPL
OAc
-
~o~ oF3 '~',OMe
331
33O
Ph
329
Scheme 55. ~o,c o 1. L~(t-SuO)3H 2.14'
~o ~J~J-~ ~
Me
333
332
~~
334
o" o
Cu(acac-F6)i=
H CO2Me
CO.~Ae
337
338
335
CHO ~'
-~o
OH I
~v 340
Scheme 56.
341
The Chemistry of Isobenzofurans
47
95% e.e. (Scheme 55). 138This material is of potential use for chiral lignan synthesis; its absolute configuration was established by single-crystal X-ray analysis of the derived ester 331.
3.2 Intramolecular Trapping of Isobenzofurans and Thieno[2,3-c]furans Friedrichsen and co-workers have developed an interesting intramolecular IBF trapping protocol that is applicable to the construction of biomolecules and their analogs (Scheme 56). 139-'147 For example, 3-O-methyl-18-hydroxyestrone (335) has been prepared by a sequence involving as the key step the intramolecular Diels-Alder reaction of 333.14~The requisite intermediate IBF for such a process can also be generated by cyclization of appropriately substituted o-diazo aryl ketones such as 336.142 Intramolecular Diels-Alder reaction of the thieno[2,3c]furan 339 delivers Thiafarfugin A 341, a thiophene analog of the furan sesquiterpene Farfugin A (341 O instead of S). 145
3.3 4,7-Dimethoxyisobenzofuran and Its Role in Dynemicin A Chemistry 4,7-Dimethoxyisobenzofuran (342), generated from 5,8-dimethoxy-l,4-dihydro-1,4-epoxynaphthalene by the dipyridyl-s-tetrazine route, has been obtained as a relatively stable crystalline material and has been characterized crystal-
MeO
MeO
MeO
MeO
342
MeO
N'~d
MeO
344
Me(~C
346
M~
N*"~, Me
"
HO
0
N~%,
HO
0
OH
~"
MeO
347
348
Scheme 57.
N"~'~d
345
48
DIETER W E G E
MeO
I
MeO
342
N
,,
i o:~,
,,, OAc
'
"'OAc
0
~
,
~c~,
" OAc
MeO 349
~17617617
N".,.,~.,,YJ,.'.~"1....OAc
MeO
'
0 350 a-O 351 13-0
Scheme 58.
lographically, l~s The molecule is essentially planar and shows pronounced single/double bond alternation. Trapping of 342 with the dienophile 343 gave adducts 344 (major) and 345 (minor), while use of the acetylenic dienophile 346 delivered adduct 347; both series of adducts have been converted into 348, the quinone moiety of Dynemicin A (Scheme 57). 149 Addition of 4,7-dimethoxyisobenzofuran (342) to the quinone imine 349 affords the dynamicin analogs 350 and 351 (Scheme 58). 15~
4. CONCLUSION Since the characterization of the parent IBF in the early 1970s, the chemistry of this ring system has grown considerably, as evidenced by over 700 literature citations in Friedrichsen's recent review. 6 As well as being theoretically interesting molecules that have served as useful probes for mechanistic problems, IBFs are finding increasing use for the construction of complex ring assemblies, including those of biomolecules. This aspect of IBF chemistry undoubtedly will continue to develop in the future.
ACKNOWLEDGMENTS I would like to express my appreciation to the enthusiastic students whose names are given in the references. Portions of our work were supported by grants from the Australian Research Council.
REFERENCES A N D NOTES 1. Perkin,W. H., Jr, Bet. Dtsch. Chent Ges. 1983, 16, 1787. 2. Willstatter,R.; Waser,E. Ber. 1911,44, 54. 3. Friedrichsen,W.Adv. HeterocycL Chem. 1980, 26, 135.
The C h e m i s t r y o f I s o b e n z o f u r a n s
49
4. Rickborn, B. Isobenzofurans in: Advances in Theoretically Interesting Molecules, Vol. 1; Thummel, R. P., Ed., JAI Press, Greenwich, 1989, p. 1. 5. Rodrigo, R. Tetrahedron 1988, 44, 2093. 6. Friedrichsen, W. in: Houben-Weyl, Methoden der Organischen Chemie; Vol. E6b, Kreher, R. Ed., Thieme, Stuttgart, 1994, p. 163. 7. McCulloch, R.; Rye, A. R.; Wege, D. Tetrahedron Letr 1969, 5231. 8. McCulloch, R.; Rye, A. R.; Wege, D. Auzr J. Chem. 1974, 27, 1929. 9. Rye, A. R.; Wege, D. Aust. J. Chem. 1974, 27, 1943. 10. Wittig, G.; Pohmer, L. Ber. 1956, 89, 1334. 11. Fieser, L. F.; Haddadin, M. J. Can. J. Chem. 1965, 43, 1599. 12. Wege, D. Tetrahedron Letr 1971, 2337. 13. Warrener, R. N. J. Am. Chem. Soc. 1971, 93, 2346. 14. Wiersum, U. E.; Mijs, W. J. J. Chem. Soc., Chem Commun. 1972, 347. 15. McCulloch, R. K.; Wege, D., unpublished results; McCulloch, R. K. Ph.D. Thesis, University of Western Australia, 1976. 16. Saito, I.; Nakata, A.; Matsuura, T. Tetrahedron Letr 1981, 22, 1697. 17. Miki, S.; Yoshida, M.; Yoshida, Z. Tetrahedron Letr 1989, 30, 103. 18. Miki, S.; Yoshida, M.; Yoshida, Z. Bull. Chem. Soc. Jpn. 1992, 65, 932. 19. Guyot, A.; Catel. J. Bull. Soc. Chim. Paris 1906, 35, 1124. 20. Adams, R.; Gold, M. H. J. Am. Chem. Soc. 1940, 62, 2038. 21. Cava, M. P.; Mitchell, M. J.; Deana A. A. J. Org Chem. 1960, 25, 1481. 22. Moursounidis, J.; Wege, D. Ausr J. Chem. 1988, 41,235. 23. Wittig, G.; Uhlenbrock, W.; Weinhold, P. Chem. Ber. 1962, 95, 1692. 24. Caub~re, P.; Loubinoux, B. Bull. Soc. Chim. Fr. 1968, 3857. 25. Caub~re, P. Acc. Chem. Res. 1974, 7, 301. 26. Clar, E. The Aromatic Sextet; John Wiley, London, 1972. 27. Glidewell, C.; Lloyd, D. J. Chem. Educ. 1986, 63, 306. 28. Moyano, A.; Parriagua, J.-C. J. Org. Chem. 1991, 56, 1858, and references therein. 29. Herndon, W. C. J. Org. Chem. 1975, 40, 3583. 30. Herndon, W. C. J. Chem. Educ. 1981, 58, 371. 31. Breimann, D.; Schmidt, W. J. Am. Chem. Soc. 1980, 102, 3163. 32. Breimann, D.; Schmidt, W. J. Am. Chem. Soc. 1980, 102, 3173. 33. The deviation of the from linearity of the point for pyreno[ 1,2-c]furan 56 discussed in Ref. 22 is due to an incorrect structure count. The corrected plot is that shown in Figure 1; see corrigendum Moursounidis, J.; Wege, D. Ausr J. Chem. 1988, 41, 1624. 34. Mir-Mohamad-Sadeghy, B.; Rickborn, B. J. Org. Chem. 1983, 48, 2237. 35. Smith, J. G.; Dibble, P. W.; Sandborn, R. E. J. Org. Chem. 1986, 51, 3762. 36. Tu, N. P. W.; Yip., J. C.; Dibble, P. W. Synthesis 1996, 77. 37. Firouzabadi, H.; Maleki, N. Tetrahedron Lett. 1978, 19, 3153. 38. Toda, F.; Tanaka, K. Chem. Letr 1979, 1451. 39. Stringer, M. B.; Wege, D., unpublished results; Stringer, M. B. PhD. Thesis, University of Western Australia, 1976. 40. Stringer, M. B.; Wege, D. Tetrahedron Lett. 1980, 21, 3831. 41. Barton, J. W. in: Nonbenzenoid Aromatics, Vol. 1, Snyder, J. P., Ed., Academic Press, New York, 1969, p. 50. 42. Palmer, M. H.; Kennedy, S. M. F. J. Chem. Soc., Perkin Trans. 1 1976, 81. 43. Garratt, P. J.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1972, 94, 7087. 44. Anthony, I. J.; Wege, D., unpublished results; Anthony, I. J. PhD. Thesis, University of Western Australia, 1988. 45. Hart, H.; Sasaoka, M. J. Am. Chem. Soc. 1978, 100, 4326. 46. Raymo, E; Kohnke, F. H.; Carullo, F.; Girreser, U.; Stoddard, J. F. Tetrahedron 1992, 48, 6827.
50
DIETER WEGE
47. Ashton, P. R.; Girreser, U.; Giuffrida, D.; Kohnke, F. H.; Mathias, J. P.; Raymo, F. M.; Slawin, A. M. Z.; Stoddard, J. F.; Williams, D. J. J. Am. Chem. Soc. 1993, 115, 5422. 48. Giuffrida, D.; Kohnke, F. H.; Parisi, M.; Raymo, E M.; Stoddard, J. E Tetrahedron Lett. 1994, 35, 4839. 49. Hart, H.; Raju, N.; Meador, M. A.; Ward, D. L. J. Org. Chem. 1983, 48, 4357. 50. Hart, H.; Lai, C.-y.; Nwokogu, G. C.; Shamouilian, S. Tetrahedron 1987, 43, 5203. 51. Luo, J.; Hart, H. J. Org. Chem. 1988, 53, 1341. 52. Blatter, K.; SchlUter, A.-D. Chem. Ber. 1989, 122, 1351. 53. Schirmer, H.; SchlUter, A.-D.; Enkelmann, V. Chem. Ber. 1993, 126, 2543. 54. Roberts, R. M. Serendipity: Accidental Discoveries in Science; Wiley, New York, 1989. 55. Lombardo, L.; Wege, D.; Wilkinson, S. P. Aust. J. Chem. 1974, 27, 143. 56. Raston, C. L.; Wege, D.; White, A. H. Aust. J. Chem. 1977, 30, 2153. 57. Best, W. M.; Wege, D. Tetrahedron Lett. 1981, 22, 4877; Best, W. M.; Wege, D. Aust. J. Chem. 1986, 39, 647. 58. Best, W. M.; Collins, P. A.; McCulloch, R. K.; Wege, D. Aust. J. Chem. 1982, 35, 843. 59. Review: Wong, H. N. C.; Ng, T.-K.; Wong, T.-Y Heterocycles 1983, 20, 1815. 60. Hart, H.; Nwokogu, G. J. Org. Chem. 1981, 46, 1251. 61. Xing, Y. D.; Huang, N. Z. J. Org. Chem. 1982, 47, 140. 62. Gribble, G. W.; Kelly, W. J.; Sibi, M. P. Synthesis 1987, 143. 63. Jung, K.-y.; Koreeda, M. J. Org. Chem. 1989, 54, 5667. 64. Mills, W. H.; Nixon, I. G. J. Chem. Soc. 1930, 2510. 65. Badger, G. M. Quart. Rev. 1951, 5, 147. 66. Hiberty, P. C.; Ohanessian, G.; Delbecq, E J. Am. Chem. Soc. 1985, 107, 3095. 67. Apeloig, Y.; Arad, D. J. Am. Chem. Soc. 1986, 108, 3241. 68. Collins, M. J.; Gready, J. E.; Sternhell, S.; Tansey, C. W. Aust. J. Chem. 1990, 43, 1547. 69. Davies, A. G.; Ng, K. M. J. Chem. Soc., Perkin Trans. 2 1992, 1857. 70. Stanger, A. J. Am. Chem. Soc. 1991, 113, 8277. 71. Baldridge, K. K.; Siegel, J. S. J. Am. Chem. Soc. 1992, 114, 9583. 72. Mitchell, R. H.; Lau, D. Y. K. Tetrahedron Left. 1995, 26, 9281. 73. Siegel, J. S. Angew. Chem. Int. Ed. Engl. 1994, 33, 1721. 74. Frank, N. L.; Siegel, J. S. in: Advances in Theoretically Interesting Molecules, Vol. 3, Thummel, R. P., Ed., JAI Press, Greenwich, 1996, p. 209. 75. Neidlein, R.; Christen, D.; Poign6e, V.; Boese, R.; Blltser, D.; Gieren, A.; Ruiz-P6rez, C.; HUbner, T. Angew. Chem. Int. Ed. Engl. 1988, 27, 294. 76. Boese, R.; Blgser, D. Angew. Chem. Int. Ed. Engl. 1988, 27, 304. 77. Boese, R.; Bl~er, D.; Billups, W. E.; Haley, M. M.; Maulitz, A. H.; Mohler, D. L.; Vollhardt, K. P. C. Angew. Chem. Int. Ed. Engl. 1994, 33, 313. 78. M6, O.; Yfu~ez, M.; Eckert-Maksic, M.; Maksic, Z. B. J. Org. Chem. 1995, 60, 1638. 79. MUller, P. in: Advances in Theoretically Interesting Molecules, Vol. 3, Thummr R. E, Ed., JAI Press, Greenwich, 1996, p. 37 and references therein. 80. Anthony, I. J.; Wege, D. Tetrahedron Lett. 1987, 28, 4217. 81. Dimethyl fumarate was chosen as the dienophile because it yields each adduct (except in the case of 141) as a single stereoisomer. In the additions of annulated IBFs to maleic anhydride (Table 1 and Figure 1), k2 is the sum for endo and exo adduct formation. 82. Anthony, I. J.; Wege, D. Aust. J. Chem. 1996, 49, 1263. 83. Wiersum, U. E.; Eked, C. D.; Vrijhof, P.; van der Plas, H. C. Tetrahedron Lett. 1977, 1741. 84. e. 8., Chaloner, L. M.; Crew, A. P. A.; O'Neill, P. M.; Storr, R. C.; Yelland, M. Tetrahedron 1992, 48, 8101; MUnzel, N.; Schweig, A. Angew. Chem. Int. Ed. Engl. 1987, 26, 471; Trahanovsky, W. S.; Huang, Y.-c. J.; Leung, M.-k. J. Org. Chem. 1994, 59, 2594. 85. Moursounidis, J.; Wege, D. Tetrahedron Lett. 1986, 27, 3045; Buttery, J. H.; Moursounidis, J.; Wege, D. Aust. J. Chem. 1995, 48, 593.
The Chemistry of Isobenzofurans
51
86. For a compendium and discussion of tandem reactions in organic synthesis see Ho, T.-S. Tandem Organic Reactions, Wiley-lnterscience, New York, 1992. 87. Mayer, R.; Kleinert, H.; Richter, S.; Gewald, K. J. Prakt. Chem. 1963, 20, 244. 88. Wege, D., unpublished results. 89. Shafiee, A.; Sattari, S. J. HeterocycL Chem. 1982, 19, 227. 90. Banks, M. R.; Barker, J. M.; Huddleston, P. R. J. Chem. Soc., Perkin Trans. 1 1986, 2223. 91. Friedrichsen, W.; Sch0ning, A. Heterocycles 1986, 24, 307; SchOning, A.; Debaerdemaeker, T.; Zander, M; Friedrichsen, W. Chem. Bet 1989, 122, 1119. 92. Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Kondo, K.; lwasaki, T. J. Chem. Soc., Chem. Commun. 1991, 1635. 93. Eberbach, W.; Fritz, H.; Laber, N.Angew. Chem. Int. Ed. Engl. 1988, 27, 568; Eberbach, W.; Laber, N.; Bussenius, J.; Fritz, H.; Rills, G. Chem. Bet 1993, 126, 975. 94. For representative examples see: Wolthuis, E.; Bossenbroek, B.; DeWall, G.; Geels, E.; Leegwater, A. J. Org. Chem. 1963, 28, 148; Batt, D. G.; Jones, D. G.; La Greca, S. J. Org. Chem. 1991, 56, 6704; Baker, R. W.; Baker (n6e Nicoletti), T. M.; Birkbeck, A. A.; Giles, R. G. E; Sargent, M. V.; Skelton, B. W.; White, A. H. J. Chem. Soc., Perla'n Trans. 1 1991, 1589. 95. Contreras, L.; Slemon, C. E.; MacLean, D. B. Tetrahedron Lett. 1978, 4237; see also Makhlouf, M. A.; Rickborn, B. J. Org Chem. 1981, 46, 2734; Russell, R. A.; Marsden, D. E.; Stems, M.; Warrener, R. N. Aust. J. Chem. 1981, 34, 1223. 96. Evans, J. C.; Klix, R. C.; Bach, R. D. J. Org. Chem. 1988, 53, 5519. 97. Collis, G. E.; Jayatilaka, D.; Wege, D. Aust. J. Chem. 1997, 50, 505. 98. Billups, W. E.; Luo, W.; Lee, G.-A.; Chee, J.; Amey, B. E. Jr.; Wiberg, K. B.; Arfis, D. R. J. Org. Chem. 1996, 61,764. 99. Endo, Y.; Ohta, T.; Nozoe, S. Tetrahedron Lett. 1991, 32, 5555. 100. The absolute stereochemistry of (+)-favelanone is unknown; enantiomer 202 is depicted arbitrarily. 101. Ng, W.; Wege, D. Tetrahedron Lett. 1996, 37, 6797. 102. For example, Dent, B. R.; Halton, B.; Smith, A. M. E Aust. J. Chem. 1986, 39, 1621; MUller, P.; Bemadinelli, G.; Pfyffer, J.; Rodriguez, D.; Schaller, J.-P. Heir. Chin Acta 1988, 71,544. 103. Tisler, M. Adv. Heterocycl. Chem. 1989, 45, 37. 104. Curtis, P. J.; Grove, J. E Nature (London) 1947, 160, 574. 105. Grove, J. E; Hitchcock, P. B. J. Chem. Soc., Perkin Trans. 1 1986, 1145. 106. Qureshi, A. A..; Rickards, R. W.; Kamal, A. Tetrahedron 1967, 23, 3801. 107. Tennant, S.; Wege, D. J. Chem. Soc., Perkin Trans. 1 1989, 2089. 108. Sims, C. G.; Wege, D. Aust. J. Chem. 1992, 45, 1983. 109. Cragg, G. L.; Giles, R. G. E; Roos, G. H. P. J. Chem. Soc., Perkin Trans. 1 1975, 1339; see also Fumagalli, S. E.; Eugster, C. H. Helv. Chim. Acta 1971, 54, 959. 110. Karichiappan, K.; Wege, D. unpublished results; Karichiappan, K. Honours Thesis, University of Western Australia, 1995. 111. Tolmie, M.; Wege, D. unpublished results; Tolmie, M. Honours Thesis, University of Western Australia, 1996. 112. Nightingale, D. V.; Sukomick, B. J. Org. Chem. 1959, 24, 497. 113. Villessot, D.; Lepage, Y. J. Chem. Res. (M) 1979, 3501. 114. Harper, M. E; Morley, J. O.; Preston, P. N. J. Chem. Res. (M) 1985, 3533. 115. Sartori, G.; Casnati, G.; Bigi, F.; Foglio, E Gazz. Chim. Ital. 1990, 120, 13. 116. Parisot, D.; Devys, M.; F6r6zou, J.-P.; Barbier, M. Phytochemistry 1983, 22, 1301. 117. Devys, M.; Barbier, M.; Parisot, D. Heterocycles 1990, 31, 1485. 118. Hanumaiah, T.; Rao, G. S. R.; Rao, C. P.; Rao, K. V. J.; Cowe, H. J.; Cox, P. J.; Howie, R. A.; Marshall, D. S.; Thomson, R. H. Tetrahedron 1985, 41,635. 119. Jammula, S. R.; PepaUa, S. B.; Telikepalli, H.; Rao, K. V. J.; Thomson, R. H. Phytochemistry 1991, 30, 2427.
52 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136.
137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150.
DIETER WEGE Ali, S.; Read, R. W.; Sotheeswaran, S. Phytochemistry 1994, 35, 1029. Buttery, J. H.; Wege, D. Aust. J. Chem. 1998, 51,409. Buttery, J. H.; Sargent, M. V.; Sianipar, H.; van Bruchem, D.; Wege, D. unpublished observations. Mirsadeghi, S.; Rickborn, B. unpublished results. e. g., Bartlett, E D.; Banavali, R. J. Org. Chem. 1991, 56, 6043; Kobayashi, T.; Suda, H.; Takase, H.; Iriye, R.; Kato, H. Bull. Chem. Soc. Jpn. 1995, 68, 3269. Hagenbuch, J. E; Vogel, P.; Pinkerton, A. A.; Schwarzenbach, D. Helv. Chim. Acta 1981, 64, 1818. Koyama, J.; Ogura, T.; Tagahara, K. Phytochemistry 1994, 37, 1147. Nakanishi, S.; Chiba, S.; Yano, H.; Kawamoto, I.; Matsuda, Y. J. Antibiot. 1995, 48, 948; Aotani, Y.; Saitoh, Y. J. Anu'biot. 1995, 48, 952. Roth, W. R.; Humbert, H.; Wegener, G.; Erker, G.; Exner, H.-D. Chem. Ber. 1975, 108, 1655. Stephan, D.; Gorgues, A.; Le Cot], A. Tetrahedron Lett. 1986, 27, 4295. Wege, D. Aust. J. Chent 1996, 49, 669. Phife, D. W.; Patton, R. W.; Berrie, R. L.; Yarborough, R.; Puar, M. S.; Patel, M.; Bishop, W. R.; Coval, S. J. Tetrahedron Lett. 1995, 36, 6995. Rohr, J.; Thiericke, R. Nat. Prod Rep. 1992, 9, 103. Corrigendum: Phife, D. W.; Patton, R. W.; Berrie, R. L.; Yarborough, R.; Puar, M. S.; Patel, M.; Bishop, W. R.; Coral, S. J. Tetrahedron Lett. 1996, 37, 5227. Tsukuda, E.; Tanaka, T; Ochiai, K.; Kondo, H.; Yoshida, M.; Agatsuma, T.; Saito, Y.; Teshiba, S.; Matsuda, Y. J. Antibiot. 1996, 49, 333. Forsey, S. P.; Rajapaksa, D.; Taylor, N. J.; Rodrigo, R. J. Org. Chem. 1989, 54, 4280. Padwa, A.; Cochran, J. E.; Kappe, C. O. J. Org. Chem. 1996, 61, 3706; see also Cochran, J. E.; Padwa, A. Tetrahedron Lett. 1995, 36, 3495; Kappe, C. O.; Padwa, A. J. Org. Chem. 1996, 61, 6166. Bailey, J. H.; Coulter, C. V.; Pratt, A. J.; Robinson, W. T. J. Chem. Soc., Perkin Trans. 1 1995, 589. Berkowitz, D. B.; Maeng, J.-H. Tetrahedron Asymm. 1996, 7, 1577. Friedrichsen, W.; K6nig, B.-M.; Hildebrandt' K.; Debaerdemaeker, T. Heterocycles 1986, 24, 297. K6nig, B.-M.; Friedrichsen, W. Tetrahedron Lett. 1987, 28, 4279. SchOning, A.; Friedrichsen, W. Tetrahedron Lett. 1988, 29, 1137. Hildebrandt, K.; Debaerdemaeker, T.; Frie&ichsen, W. Tetrahedron Lett. 1988, 29, 2045. SchOning, A.; Friedrichsen, W. l.a'ebigs Ann. Chem. 1989, 405. Assmann, L.; Friedrichsen, W. Heterocycles 1989, 29, 1003. SchOning, A.; Friedrichsen, W. 7_ Naturforsch., B: Chent Sci. 1989, 44, 825. Nagel, J.; Friedrichsen, W. Z Naturforsch., B: Chem. Sci. 1993, 48, 213. Peters, O.; Friedrichsen, W. Tetrahedron Lett. 1995, 36, 8581. Lynch, V. M.; Fairhurst' R. A.; Magnus, E; Davis, B. E. Acta Crystallogr, Sect. C 1995, 51,780. Magnus, P.; Eisenbein, S. A.; Magnus, N. A. J. Chem. Soc., Cher~ Commun. 1994, 1545. Shair, M. D.; Yoon, T.; Chou, T.-C.; Danishefsky, S. J.Angew. Chem. Int. Ed. Engl. 1994, 33, 2477.
FASCINATING STOPS ON THE WAY TO CYCLACENES AND CYCLACENE QUINONES" A TOUR GUIDE TO SYNTHETIC PROGRESS TO DATE
Robert M. Cory and Cameron L. McPhail
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 The Fullerene Connection . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Theoreticians Propose the Cyclacenes . . . . . . . . . . . . . . . . . . . The Stoddart Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 A Close Encounter with [ 12]Cyclacene . . . . . . . . . . . . . . . . . . . 2.2 Toward [14]Cyclacene . . . . . . . . . . . . . . . . . . . . . . . . . . . The Road to Solubilized Cyclacenes . . . . . . . . . . . . . . . . . . . . . . . 3.1 Schltiter's Belt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Stops on the Road to a Tetrahexyl [8]Cyclacene . . . . . . . . . . . . . . 3.3 Beginnings of the Journey to a Tetrahexyl [9]Cyclacene . . . . . . . . . . 3.4 Off to a Tetrahexyl [10]Cyclacene . . . . . . . . . . . . . . . . . . . . . Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Advances in Theoretically Interesting Molecules, Volume 4, pages 53-80 Copyright 9 1998 by JAI Press Inc. All fights of reproduction in any form reserved. ISBN: 0-7623-0070-1 53
54 54 55 57 57 59 60 60 60 75 76 77 78
54
ROBERT M. CORY and CAMERON L. McPHAIL 1.
INTRODUCTION
1.1 The Fullerene Connection The exciting discovery I of buckminsterfullerene, C60,2'3 and its isolation as a crystalline allotrope of carbon, 4 created a new field of science, 5 recognized by the awarding of the 1996 Nobel Prize in Chemistry to Curl, Kroto, and Smalley. 6 One of the most important outcomes of these developments was that they called attention to the fact that olefinic and aromatic compounds are not limited to planar systems, and that, in particular, benzene rings can be bent out of planarity and still retain their aromatic stability. 7-ll Today, on the threshold of the 21st century, synthetic organic chemists are continuing to create new types of molecules that test the extent to which 7t-conjugation and aromatic stabilization can overcome the destabilizing effects of bending strain. The discovery of the fullerenes has given rise to a number of syntheses of molecules representing fullerene substructure motifs, including a wide variety of bowl-shaped polycyclic aromatic hydrocarbons. 12-15 As soon as the soccer-ball structure of the buckyball was announced, we began to think about potential pathways by which hoop-shaped molecules, representing the equatorial bands of the fullerenes, might be synthesized. Such structural moieties, while present in the fullerenes, are unknown as isolated structures. At least two members of the fullerene family have been found to contain a band consisting exclusively of "linearly fused" six-membered carbocyclic unsaturated rings. The C78 isomer having D 3 symmetry (1), looking for all the world like a Faberg6 Easter egg, contains an equatorial belt of this type consisting of nine
~ "~41p ~F
1
2
Figure 1. Equatorial belts of C78 and C84 (x-bonds omitted for clarity).
Cyclacenesand CyclaceneQuinones
_
_
..z
__
j--
Figure 2.
55
_
.. ~ _ . . . ~ _ . . . _ _
,_.,,--- %~
_
A zigzag carbon nanotube (x-bonds omitted for clarity).
constituent rings, and a C84 isomer having D 2 symmetry (2) contains a ten-ring equatorial belt (Figure 1).16-18Undoubtedly, more fullerenes having these equatorial bands will be discovered in the future as research in this area continues. When these fullerene structures are stretched out into tubes by intercalating additional bands into the middle of the cage, the nanoscale carbon fibers known as zigzag carbon nanotubes are obtained. 19 These carbon allotropes therefore consist almost entirely of a hollow tube of bands of linearly fused six-membered unsaturated carbocyclic tings, except for the fullerene caps on the ends. For example, in nanotube 3, shown in Figure 2, each band consists of ten tings in a superring.
1.2 TheoreticiansProposethe Cyclacenes In 1954, more than 30 years before the fullerenes were discovered, Heilbronner published a seminal paper on "Molecular Orbitals in Homologous Series of Polynuclear Aromatic Hydrocarbons," in which he described the use of the linear combination of atomic orbitals (LCAO) method to calculate the molecular orbital (MO) eigenvalues for these compounds. 2~ Among the more mundane examples studied was the astounding proposal that the two ends of an acene molecule could be joined in such a way as to form a symmetrical molecular hoop of several linearly fused unsaturated six-membered tings (4, e.g., 5). Couched in the arcane mathematical terminology of the day, this proposal attracted little attention. Nevertheless, 14 years later, Derflinger and Sofer, acknowledging Heilbronner's earlier study, calculated Htickel MO (HMO) coefficients for the linear polyacenes in closed form, naming them "double-crown" molecules, after the appearance of the carbon skeletons of these hypothetical species as two crown-shaped rings of carbon atoms one on top of the other and bonded together at every other carbon atom. 21 In 1974, using unconstrained Hartree-Fock (UCH~ theory on the basis of HMO and self-consistent field (SCF) calculations, Ege and Vogler predicted the proton nuclear magnetic resonance (NMR) chemical shifts for these molecules,
56
ROBERT M. CORY and CAMERON L. McPHAIL
k. /
~ f l)
9
"n-1
-
)
which they renamed "circumpolyacenes. ''22 Their calculations for a series of these hoop-shaped structures containing from 3 to 18 six-membered rings converged at a value of about 87.45 for the larger hoops, and they extrapolated to a value of 89.00 for very large ones. Interestingly, however, for the smaller hoops containing up to 16 six-membered rings, those having an odd number of tings were predicted to exhibit chemical shifts significantly upfield from those having an even number of rings. The following year, Aihara predicted that no cyclic polyacene would be aromatic, based on the fact that it is not possible to draw any aromatic Kekul6 sextet in any of the six-membered tings without having unpaired electrons in the other rings. 23 In contrast, five years later, in 1980, an international group of collaborators calculated a resonance energy per n-electron of 0.019 [3 units for the hoop having 6 s i x - m e m b e r e d rings, n a m i n g it s o m e w h a t a w k w a r d l y "corannulene[61,61,61,61,61,61]," and suggesting that it should be "nearly as aromatic as azulene. ''24 Speaking at the same conference on aromaticity, Balaban, asking the question "Is aromaticity outmoded?," challenged synthetic chemists to synthesize [12]cycloacene (5) and other [n]cycloacenes. 25 He also speculated that these compounds, having an internal cavity, could act as hosts for molecular guests and metal atoms, and that these guests "would perceive interesting steric and magnetic effects." Kivelson and Chapman subsequently predicted that polyacene, an "infinite" linear acene, would exhibit interesting and useful properties, including high-temperature superconductivity and ferromagnetism, and that the ideal polyacene would be a cyclic one. 26 Much later, in 1992, after efforts toward the synthesis of these types of compounds (now more commonly referred to as cyclacenes) were already in progress in several research groups throughout the world, Haase and Zoellner published the results of modified neglect of diatomic overlap (MNDO) calculations on cyclo-anthracene (6), the "simplest" cyclic polyacene, predicting that this highly strained molecule would not be stable relative to an alternative structure. 2~ For the record, this hypothetical compound, [3]cyclacene, is not the simplest possible cyclacene.
Cyclacenes and Cyclacene Quinones
6
57
7
Rather, that distinction applies to [2]cyclacene (7). 28'29More challenging synthetic targets can hardly be imagined! Most recently Aihara returned to his theory of cyclacenes, demonstrating by the use of the topological resonance energy method that a Htickel-like rule should govern the stability of the cyclacenes; those having an even number of six-membered rings being less aromatic than those having an odd number. 3~ The fact that all cyclacenes were predicted to be aromatic (though not superaromatic), however, led Aihara to declare that "it will be possible to work with cyclopolyacenes under suitable conditions." Furthermore, he boldly predicted that a large cyclacene such as [ 15]cyclacene "may possibly be prepared in the near future!" Past and current explorations in search of the first synthesis of a cyclacene are presented below. Although several research groups are involved in this endeavor, we limit our discussion here to the work of those who have succeeded in preparing macrocyclic precursors. Efforts resulting so far only in linear (ladder) structures will not be described. 32'33
2. THE STODDART APPROACH 2.1 A Close Encounter with [12]Cyclacene Stoddart and coworkers have utilized Diels-Alder chemistry to synthesize a variety of molecular belts consisting of linearly-fused carbocyclic six-membered rings, with the ultimate goal (as yet unrealized) of making cyclacenes and related compounds. This work has been exceedingly well reviewed, 3.-37 and only a brief summary will be presented here. At the risk of stating the obvious, the overriding principle governing any strategy for the synthesis of a cyclacene must be based on the recognition that an acene, being rigidly linear, cannot be cyclized to a cyclacene, no matter what functionality is present. At least partially saturated tings are necessary in order for macrocyclization to be even possible. Only after macrocyclization has been accomplished can any hope be engendered of converting all of the tings to fully unsaturated ones. The key building blocks in Stoddart's attempted synthesis of [ 12]cyclacene were bisdiene 8 and bisdienophile 9, both rigid structures (Scheme 1). 38'39 Bisdiene 8 was known to undergo Diels-Alder reaction with dienophiles much more quickly than its mono-addition product, which retards competing polymerization. Further-
58
ROBERT M. CORY and CAMERON L. McPHAIL
O~ I~ 'I
+
PhC"3
9 9
~
A
-"
9 I,.,.,, II
f
0 I~ 'l # O
10
f~r
.~ .
10 kbar
-
II~l 0
fl 0
Scheme 1. Stoddart's synthesis of kohnkene.
more, cycloadditions of curved bisdiene 8 to common dienophiles occur predominantly at the endo-face of the bisdiene, and cycloadditions of curved bisdienophile 9 to common dienes occur predominantly at the exo-face of 9. This selectivity allows the molecular belt to be built up from the precursors in a very controlled manner. Bisdiene 8 undergoes double Diels-Alder cycloaddition to bisdienophile 9 to give, via flexible adduct 10, flexible bisdiene 11 in 80% yield. Although bisdiene 11 is unreactive toward bisdienophile 9 under these conditions, when they were combined at high pressure cyclophane 12 (kohnkene) was obtained in 36% yield. The flexibility and curvature of molecular ribbon 11 are both crucial to the success of the macrocyclization of the intermediate adduct since the two reactants are obviously not of the same length. Once molecular belt 12 is formed, much of the flexibility of its ribbon precursor is lost, making it somewhat rigid. Treatment of cyclophane 12 with the low-valent titanium reagent prepared from TiCI4/LAH removed two oxygen atoms, giving rise to cyclophane 13, in 43% yield (Scheme 2). 38,4o Dehydration of 13 with acetic anhydride gave unsymmetrical dinaphthalene cyclophane 15, in 56% yield, rather than the expected product, symmetrical dianthracene cyclophane 14. Dinaphthalene cyclophane 15 was presumably generated by an acid-catalyzed isomerization of 14. Stoddart was unable to prepare [12]cyclacene (5) from cyclophane 15, partly due to the low solubility of the latter. In an attempt to generate [ 12]beltene (16), cyclophane 15 was subjected to Birch reduction, but the product was, surprisingly, [12]collarene (17) (Scheme 3).
59
Cyclacenes and Cyclacene Quinones O~ .. ~
.,~
,._
O../ m
,,9
,
o.,
,.,
II
i~~AH 12
3
,j'-- ,, 14
e.o
Ac2? HCi
~'-- ,,
_ .
I
15
Scheme 2. Stoddart's synthesis of octahydro[12]cyclacene 15.
2.2 Toward [14]Cyclacene In order to extend this strategy to the synthesis of a larger molecular belt, only slight modifications were necessary. By analogy to the synth6sis of cyclophane 12, cyclophanes 18 (R = H) and 19 (R = Me), potential precursors to [14]cyclacenes, were also prepared. 38
Li/NH3
16
i/
Et20 EtOH D -78 ~ to -28 ~
M Scheme 3. Stoddart's synthesis of [12]collarene (dodecahydro[12]cyclacene
17).
60
ROBERTM. CORY and CAMERON L. McPHAIL
o,
1,/ ,
3.
R
i
18/19 R
THE R O A D T O S O L U B I L I Z E D CYCLACENES
One of the most challenging difficulties with the Stoddart approach has been the sparing solubilities of the fairly rigid macrocyclic cyclophanes involved. The addition of suitable alkyl substituents to a rigid molecular ribbon or belt can significantly increase its solubility by not allowing the rigid core structures of adjacent molecules in the crystal lattice to make efficient van der Waals contact with each other. Hexyl groups confer a significant increase in solubility over unsubstituted rigid molecular ribbons (a factor of about 20), but changing the substituents from hexyl to dodecyl increases solubility only by a factor of about two or less. A higher density of alkyl substituents on the backbone further increases the solubility of rigid molecular ribbons. 41
3.1 Schliiter's Belt The use of conformationally mobile aliphatic substituents, in this case annulated hexamethylene chains, to solubilize a rigid belt-shaped molecule is illustrated by the synthesis of a potential substituted [6]cyclacene precursor. Schltlter and coworkers synthesized molecular belt 23 in 70% yield via dimerization of diene-quinone 21, which was generated in situ via ring-opening of cyclobutene 20 (Scheme 4). 42,43 The yield of the macrocyclic belt 23 decreased at the expense of polymer 22 as the concentration of the reactants was increased. The facile formation of molecular belt 23 was rationalized by postulating a high degree of face-to-face double endo overlap in the transition state (24).
3.2 Stops on the Road to a Tetrahexyl [8]Cyclacene After a few fruitless forays into the wilderness of cyclacene synthesis, which will not be described here, we learned our lessons both from our own ill-fated adventures and the developing knowledge being accumulated at the time by our competitors
61
Cyclacenes and Cyclacene Quinones
(CH2)6\ ,j~ "11
,
II
(CH2)6(~ 20
21
.,
"'~~1~ 24 (hexametbylene bridges omitted for clarity) w
(CH2)6 i
II
II
(CH2)6 22
(CH~6 lOp__
I (
)s 23
Scheme 4. 5chlOter'ssynthesis of molecular belt 23. in the area. In view of Stoddart's difficulties with insoluble cyclacene precursors and Schltiter's success in solubilizing sparingly soluble structures using unbranched alkyl groups, we decided that a synthetic program aimed at a parent cyclacene would not be prudent, at least at first, and that a more attainable target for the first synthesis of a cyclacene would be an alkyl-substituted cyclacene. For a number of reasons, partly based on retrosynthetic analysis, our targets eventually became the tetrahexyl [8]cyclacene 25, and, secondarily, its quinone derivatives, such as triquinone 26. Preliminary modeling indicated that the roughly cylindrical rigid cavities of cyclophanes 25 and 26 would allow them to act as molecular hosts to cylindrical molecular guests of the diameter of acetylene and to molecules that have cylindrical end groups such as terminal acetylenes and terminal conjugated diynes (Figure 3). Since molecular belts 25 and 26 are expected to be electronically complementary, electron-rich host 25 should preferentially complex electron-poor guests, such as dicyanoacetylene, while electron-poor host 26 should preferentially complex electron-rich guests such as terminal conjugated diynes and triynes. It was envisioned that [8]cyclacene 25 and derivatives such as triquinone 26 could be generated from a common intermediate, cyclophane 27 (Scheme 5), which would in turn be prepared by an efficient convergent synthesis. A four-fold disconnection of cyclophane 27 by a double Diels-Alder cycloaddition transform gives bisdiene 28 and diquinone 29 (Scheme 6). In order for these two building
62
ROBERT M. CORY and CAMERON L. McPHAIL
\.
/
\,
t
/
25
\.
/
\.
\
i
\
/
/ f
26
\
\
blocks to be used for this purpose, conditions would have to be found that favor macroannulation to give 27, rather than polymerization. Miller and coworkers had previously utilized a double Diels-Alder cycloaddition of rigid bisdiene equivalent 30 to bismaleimide 31 to synthesize cyclophane 32 (Scheme 7). 44 The rigidity of the precursors to cyclophane 32 dictates that the distances between the termini of their respective reactive functionalities must be roughly equal in order for the double-Diels-Alder macroannulation to have occurred, and that it must have proceexted via a concerted double addition. Examination of molecular models of bisdiene 28 and diquinone 29, however, indicated that the distances between their respective reactive termini are not equal, diquinone 29 being somewhat shorter than bisdiene 28. Therefore, if these precursors were both rigid like Miller's, the desired macroannulation reaction to give cyclophane 27 could not occur. However, by analogy with the Stoddart approach, a certain amount of flexibility has been deliberately incorporated into bisdiene 28, in the form of the two partially saturated six-membered rings. Diels-Alder cycloaddition of bisdiene 28 to diquinone 29 was expected 45'~ to occur via an endo transition state to give diene--quinone adduct 33 (Scheme 8). Macrocyclization of this flexible diene--quinone by an intramolecular Diels-Alder reaction would then give cyclophane 27. However, if the macrocyclization of diene--quinone 34 is difficult due to the requirement that this molecular ribbon must adopt a less favorable hairpin conformation before cyclization can be possible, macrocyclization may not be favored either at all or under certain conditions, in which case a polymer might be obtained instead. A recent elegant study by Pollmann and Mtlllen further demonstrated how flexibility can allow macrocyclization of a molecular ribbon to a molecular belt via
63
~ L_
>,,, x
..~ 0
o ~
"0 oJO ~
0 N
>.,, oO
u
64
ROBERT M. CORY and CAMERON L. McPHAIL
R,~
.,,~ __.
/,d"i
/R
"'i ~
-.
R ~)
~) R
> i !"
R .~~
I <
.
" 25
~ ~) _~ ,R
~i 8
27
26
Scheme 5. Cyclophane 27 as a precursor of cyclacene 25 and its triquinone, 26 (R = hexyl).
R
~
~)
R
R
27
28
29
Scheme 6. A double Diels-Alder retrosynthetic transform on cyclophane 27.
intramolecular Diels-Alder cycloaddition (Scheme 9). 47 Combination of difuran 34 with bisdienophile 35 at high pressure in dichloromethane at 50 ~ generated a 50:50 mixture of oligomer 36 and molecular belt 38. The latter compound is formed by double Diels-Alder cycloaddition of the bisdienophile to the bisdiene, presumably via initial addition followed by macrocyclization of molecular ribbon 37.
o o+ 30
31
32
Scheme 7. Miller's synthesis of cyclophane 32 (Ar = p-tert-butylphenyl).
65
Cyclacenes and Cyclacene Quinones
R
29
R
+
I~_
_
-
---~D
.
R tl
? |1
RXl I~ I
I~ II I p
I ~ II ~1 6t
,
-
I
9
N
27
33 28
Scheme 8.
Formation of cyclophane 27 via diene-quinone 33 (R = hexyl).
It was envisioned that cyclop~ane 27 could be converted to [8]cyclacene 25 by dehydrogenation to [8]cyclacene diquinone 39, followed by reductive aromatization (Scheme 10). Alternatively, the synthesis of [8]cyclacene 25 might be accomplished by initial reductive aromatization of cyclophane 27 to give anthracene-containing cyclophane 40, which could then be dehydrogenated to 25. Triquinone 26 might be synthesized by oxidation of cyclophane 27 to anthraquinone-containing cyclophane 41, followed by dehydrogenation (Scheme 11). Reductive aromatization of triquinone 26 could then give [8]cyclacene 25.
E
E E Ex,,,~ E .,~'~
34
, 0,~~,
E
35 \
E ~
q ,,I
.'~
, , ~ _..~ E 37
Scheme 9.
~ E~ ~ I I ~ E
E~K~.~_~E
q I,'I
E 38
MiJllen's synthesis of molecular belt 38 (E = C02Me).
66
ROBERT M. CORY and CAMERON L. McPHAIL
% ...4'
R 27
!
R,,~~ "~
II .,0~~ R
U
I~ II
'
S_b
R
%x/R ~
"'"
40 Scheme 10. Proposed syntheses of [8]cyclacene 25 via 39 and 40 (R = hexyl).
~?-~ ~?I" ~1~11 ,,
,~ " .....
U
,..
~'~
" 27
R
g
~
I
"v ~ P
~
R
41
R 25
""
g 26
Scheme 11. Proposed synthesis of [8]cyclacene 25 via its triquinone, 26 (R = hexyl).
Cyclacenesand Cyclacene Quinones R
I
-
67
R
X
/1 -4-
~11
X
>R._. I / i__ R R X~][~X R I i,,,. Ii I R >' ~ +
28
42
44
43
Scheme 12. Retrosynthetic analysis of bisdiene 28 (R = hexyl).
The first tasks before us were the construction of the bisdiene 28 and the preparation of the diquinone 29, 28 and 29 being the two building blocks required for the proposed double Diels-Alder cycloaddition synthesis of the key intermediate, macrocyclic belt-shaped cyclophane 27. A retrosynthetic analysis of bisdiene 28 is shown in Scheme 12. A double reductive cyclization transform leads back to tetrayne 42, which could be synthesized from tetrahalide 43 by four-fold coupling with acetylide 44. After a great deal of experimentation over a period of about a year and a half, tetrayne 42 was finally synthesized in 41% yield by treatment of 1-octynyllithium 45, with tetrabromide 43 (X = Br) in refluxing dioxane (Scheme 13). This yield, though modest, may be considered optimized in view of the exhaustive variation of conditions we have investigated. Using a method developed by Negishi and coworkers, 48 the synthesis of bisdiene 28 was then carried out via zirconium-mediated reductive double-cyclization of tetrayne 42, in which 42 was reacted with the zirconocene complex prepared by the action of butyllithium on zirconocene dichloride (Scheme 14).49 The synthesis of diquinone 29 had been previously reported, but the methods used were lengthy and cumbersome. 5~ As we began our investigation of possible improved routes to this compound, Olofson and coworkers reported a one-pot procedure for the preparation of anthracene 46 from aryl bromide 47. 51 In our hands this method proved to be somewhat capricious, but we were able to modify it to
l)BuLi R
--
45
R --"
H
2)
43
i
I'
R ---
j 1%1
~
R
~
R
42
Scheme 13. Synthesis of tetrayne 42 by four-fold coupling (R = hexyl).
68
ROBERT M. CORY and CAMERON L. McPHAIL
R
--
1) Cp2ZrCl2 BuLi, THF
~
-78 ~
!.. | R
---
to r.t. |
-
~
n
2) H3O+ 28
42
Scheme 14. Synthesis of bisdiene 28 via double reductive cyclization (R = hexyl).
Me
OLi
Br
NaN]B2 A 47
"
P
OMe
~
CAN D 9
CH3CN H20
46
29
Scheme 15. Synthesis of diquinone 29 via anthracene 46.
give reproducible yields of around 50% by using sodium amide as the base and preforming acetaldehyde enolate prior to reaction with 47 (Scheme 15).52The latter was accomplished by the reaction between butyllithium and THF developed by Jung and Blum. 53 Oxidation of anthracene 47 with ceric ammonium nitrate (CAN) then proceeded smoothly to give diquinone 29 in 55% yield. 49 The big question was answered when slow, simultaneous addition of chloroform solutions of bisdiene 28 and diquinone 29 to refluxing chloroform (high dilution using two dilution tridents) gave cyclophane 27 in 28% yield (Scheme 16). The
R
~)
~) R
28
0 II ,...I 61 R 27 29
Scheme 16. Synthesis of cyclophane 27 (R = hexyl).
Cyclacenes and Cyclacene Ouinones
ii'
DDQ
69
~11
ii
14
% , 14
27
49
48
Scheme 17. Synthesis of naphthalene-containing cyclophane 49.
remainder of the material appeared by NMR to be higher ribbonlike oligomers. Subsequent experiments showed that high dilution was not necessary (consistent with theory), 54 but that higher temperatures favor macrocycle formation over oligomeric molecular ribbon formation. Slow simultaneous addition of dilute dioxane solutions of the bisdiene and diquinone to refluxing dioxane in the presence of BHT (2,6-di-tert-butyl-4-methylphenol) as a radical inhibitor gave a 69% yield of the macrocyclic adduct 27. 55 In contrast, double Diels-Alder cycloaddition of diquinone 29 to bisdiene 28 in dioxane or chloroform at room temperature gave a mixture that was approximately 90% oligomer and only 10% cyclophane 27. The increase in proportion and yield of macrocyclic product with increasing temperature may be rationalized using transition state theory in the following way. Macrocyclization to molecular belt 27 is unimolecular, of the form A --->B, with a relatively small negative entropy of activation (AS~) due to a small loss of degrees of freedom (loss of flexibility). In contrast, oligomerization is bimolecular, of the form 2 A---> AA and A + B --->AB,
Rf? ~R R~ ~?R .~, ~ MCPBA , I.. II I CH2C12' "J I.. II I ,l o, =l 6f I-I o, =l R II
,
U
27
j
50
I~ II I/ MCPBA J I~ II I o U ,..! 6 f CH2C12 ~6 II ,...I 6 [4 49
R 51
Scheme 18. Epoxidation of cyclophanes 27 and 49.
70
ROBERT M. CORY and CAMERON L. McPHAIL
I. II
I
TsO"
R
I
H
50
I
., II
It
~
H
52
Scheme 19. Synthesis of bisdiene 52. with a relatively large negative entropy of activation due to a large loss of degrees of freedom (decrease in number of molecules by a factor of two). The bond energy changes for the two diverging routes are nearly identical, and solvation effects may be ignored in these relatively non-polar solvents. However, the macrocyclization transition state is relatively strained due to bending of the diene end and steric repulsion due to peri-hexyl-oxygeninteractions. Therefore, the enthalpy of activation (Zk/-/s) should be greater for macrocyclization than for oligomerization, and there is a crossover point in the variation of the Gibbs free energy of activation (AG ~ = zkH~ - T&S4) with temperature for the two reactions. At lower temperatures, oligomerization is kinetically favored by a lower AG ~, while at higher temperatures, macrocyclization is favored by a lower AG ~. It was hoped that belt-shaped cyclophane 27 could be converted to anthracene 48 by dehydrogenation. However, when 27 was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in benzene, only naphthalene cyclophane 49 was obtained in 95% yield (Scheme 17). 56 Apparently, the additional strain introduced into the macrocyclic system by the fourth aromatic ring in 48 is just greater enough
c Hll
55
Scheme 20. Dehydration of epoxide 51.
56
Cyclacenes and Cyclacene Quinones R
~)
~)
71
R
R
,,I
R
OH V ,,
14
27
57
II
II
OH V R
I1
>i
-R
R l#
'
""H
dr
J
/.
R 52
58
Scheme 21. Reduction of tetraketones 27 and 52 to tetraols 57 and 58.
than the strain in 49 so that at room temperature it is not possible to dehydrogenate 27 beyond the naphthalene point. Molecular models indicated that, while 27 is somewhat flexible, 49 is rigid, without much distortion, and 48 is highly distorted in that the aromatic tings are bent out of planarity. Forcing conditions gave some indication that anthracene 48 may have enjoyed a transient existence, but extensive decomposition made further experimentation along these lines of doubtful value. Accordingly, alternative routes to anthracene 48 were sought. Epoxidation of cyclophane 27 and naphthalene 49 gave diepoxide 5056 and epoxide 51, respectively (Scheme 18). Subsequent dehydration of these epoxides was envisioned to give anthracene 48. Surprisingly, however, when diepoxide 50 was treated with a catalytic amount of p-toluenesulfonic acid in benzene at room temperature, bisdiene cyclophane 52 was obtained in 62% yield, rather than the expected anthracene cyclophane 48 (Scheme 19).56 Although the bisdiene has the same degree of unsaturation as the anthracene, it must be less strained to such an extent that aromatization is avoided. When naphthalene epoxide 51 was subjected to the same conditions, a 9:1 mixture of dienes 53 (27%) and 54 (3%), and a 1:3 mixture of dienes 55 (4%) and 56 (12%) were obtained (Scheme 20). Evidently, the additional strain here not only prevents the formation of the anthracene system but also forces the structure into multiple means of escape, including shifts of double bonds to exocyclic positions. Attention was also directed toward the tetraketone side of macrocyclic belts 27 and 52. A two-step aromatizing deoxygenation of cyclophanes 27 and 52 could involve reduction to their tetraol derivatives, followed by dehydration, to give anthracene systems on the opposite side of the macrocycles. Treatment of cyclophane 27 and 52 with a large excess of lithium aluminum hydride gave tetraols 57 and 58 in good yield (Scheme 21). A variety of protocols are available for either
72
.
ROBERT M. CORY and CAMERON L. McPHAIL
I~
_2.
n
I
6 II
6
b
~,
LII
MeMgl
-
R
~,-
R
n
,
_~.
...r
I~
o.
I
-JR
,
THF R
R
R
27
R
R
59
60
Scheme 22. Grignard addition to tetraketone 27 to give diols 59 and 60.
direct or indirect dehydration of these tetraols, and it remains to be seen whether any of them will lead to the desired anthracenes. The tetraols are also of interest as potential metal-complexing agents. Similarly, treatment of cyclophane 27 with excess methylmagnesium iodide was also expected to give a tetraol, but in this case, an 8:2 mixture of two diols, 59 and 60, was obtained in 56% yield (Scheme 22). Apparently, further addition is prevented by steric hindrance. The route to [8]cyclacene via a quinone derivative was explored by chromium VI oxidation of the tetrahydroanthracene portion of the double Diels-Alder adduct, cyclophane 27. When cyclophane 27 was treated with pyridinium chlorochromate (PCC) on Celite | in refluxing benzene, anthraquinone cyclophane 61 was obtained in 35% yield (Scheme 23). 56 It is reasonable to infer from this result that cyclophane
'
\l
~
I-I
,
. PCC
i/
Celite
R
/
~
I~ II
\
R
27
~ ~~ Pcc ~",,
,,
:I
C,;/.
61
49
*Scheme 23. Oxidation of cyclophanes 27 and 49 to anthraquinone cyclophane 61.
Cyclacenes and Cyclacene Quinones
73
"
61
62
63
Scheme 24. Functionalization of cyclophane 61 to diethoxy cyclophanes 62 and 63. 27 was dehydrogenated under these conditions to anthracene 48, which was then oxidized to give anthraquinone 61. Consistently, when naphthalene 49 was subjected to the same reaction conditions, quinone 61 was obtained in 33% yield. In an attempt to convert anthraquinone-tetraketone 61 to a triquinone, 61 was exposed to a stream of oxygen in alcoholic potassium hydroxide. Instead of the expected triquinone 26, a 1:1 mixture of diethoxytetraketone-anthraquinones 62 and 63 was obtained in 47% yield (Scheme 24). 56 Dehydrogenation of cyclophane 61 under these conditions should initially give diquinone 64, which contains a pyramidalized quinone double bond that would be especially reactive toward nucleophiles. Conjugate addition of ethoxide to this double bond could then occur to give ethoxy ketone 65 (Scheme 25). Subsequent functionalization of a second position in the same way then would lead to the observed diethoxy cyclophanes 62 and 63. The probable intermediacy of quinone 64 in this reaction is encouraging, and offers the hope that this dehydrogenation can be accomplished without concomitant conjugate addition by using modified conditions. A more drastic solution to this dehydrogenation problem is to introduce eliminatable groups at the beginning of the synthesis. The presence of two sulfide groups as substituents on the diquinone bisdienophile in the double Diels-Alder macroan-
I
61
i
,
u
64
R
,
I"
65
Scheme 25. Proposed mechanism for ethoxy functionalization of cyclophane 61.
74
ROBERTM. CORYand CAMERON L. McPHAIL 9Me ~Me Ph$~~~Ph M~IMRr Me1) BuLi B
Meq P h
'B
9
66
OMe
OLi
OMe
68 + Me~~,, 6
D
NaNH 2 THF A
2) PhSSPh e
~/9
Ph
67 Ph
OMe
69 Scheme 26. Synthesis of anthracenes 68 and 69.
nulation would set the stage for subsequent double sulfoxide elimination, thus obviating the need for dehydrogenation at that point. With this plan in mind, substitution of a phenylthio group for a bromo substituent of 1,4-dibromo-2,5-dimethoxybenzene (66), followed by double condensation of the resulting diaryl sulfide 67 with preformed acetaldehyde enolate (using the modified procedure described above for anthracene 53) gave bis(phenylthio) tetramethoxy anthracenes 68 and 69 in 15% and 25% yields, respectively (Scheme 26). 52 Oxidation of anthracenes 68 and 69 to diquinones 70 and 71, respectively, was accomplished in 60% yield by treatment of each anthracene with ceric ammonium nitrate (CAN) (Scheme 27). Each diquinone was then reacted with diene 28 in
Ph
II
-~Ph
PhcAN , 61} ~Me
6Me
6Me
.~
..SPh
9
t
70
~Me
69
PhS, 28
72
-~Ph28
II
/ ' P.s".' 8
CH3CN H20
71
73
Scheme 27. Synthesis of cyclophanes 72 and 73 via diquinones 70 and 71.
Cyclacenes and Cyclacene Quinones
75
o
o
o
o
I.. II
74
+
Celite
II
75
II 0
II
76
Scheme 28. Synthesis of [9]cyclacene precursors 75 and 76 (R = hexyl).
refluxing dioxane to give each of the expected double Diels-Alder adducts, the macrocyclic belt-shaped cyclophanes 72 and 73, in 45% yield. 52 Conversion of these disulfides to the corresponding disulfoxides, followed by double sulfoxide elimination should lead to the desired macrocyclic diquinones. As we learn more about the properties of these systems, we become more and more confident that [8]cyclacene 25 and its triquinone 26, will be within our grasp in the near future. 3.3
Beginnings of the Journey to a Tetrahexyl [9]Cyclacene
Extension of these methods to the synthesis of higher cyclacenes is now being investigated. Double Diels-Alder cycloaddition of bisdiene 28 to naphthacene diquinone 7457 gave macrocyclic belt-shaped cyclophane 75 in good yield (Scheme 28). 58 PCC oxidation then gave anthraquinone cyclophane 76. Conversion of these
\
/ "-~. /'
__.J
"
/"
!.,11..."
,,7
--X -'X X_
\ .~ I~ I F e..
[
-
I
i
|
,
(C=C x-bonds omitted for clarity)
~
o
78
\
\
76
ROBERT M. CORY and CAMERON L. McPHAIL
1) BuLi FI ~ "
FI--mm
~
|
H FI - - -
~
FI
~
[1
80
1) Cp2ZrCI2
79
2) H3 O+
BuLi, T H F -78 *C to r.t.
81
Scheme 29. Synthesis of bisdiene 81 (R = hexyl).
compounds to [9]cyclacene 77 and its triquinone 78, may be easier than for the lower homologues because of reduced strain. 3.4 Off to a Tetrahexyl [lO]Cyclacene
By analogy with our synthesis of bisdiene 28 we have prepared the higher homologue, bisdiene 81, by the following route (Scheme 29). 59 Four-fold coupling of 1-octynyllithium with tetrabromide 7960 gave tetrayne 80, which underwent zirconium-mediated double-reductive cyclization to bisdiene 81. Subsequent double Diels-Alder cycloaddition of bisdiene 81 to diquinone 74 is expected to give macrocyclic belt-shaped cyclophane 82, which can serve as the key intermediate in a synthesis of [ 10]cyclacene 83 and its quinone derivatives. Compared with the syntheses of the [8]cyclacene and [9]cyclacene derivatives described above, these [ 10]cyclacene systems should be even less strained, which may make life easier at the later stages of the synthesis.
\
/ 83
/
\ (x-bonds omitted for clarity)
Cyclacenes and Cyclacene Quinones
77
4. CONCLUDING REMARKS The quest for cyclacenes, set in motion by the creative imagination of Edgar Heilbronner more than 40 years ago, is still in its early stages, but it is now all but certain that we are closing in on the synthesis of the first cyclacene. At present the primary impetus is the recent discovery of fullerenes having cyclacene equatorial belts, demonstrating that there is nothing inherently unstable about the structure. Indeed, incorporation of the cyclacene motif into a fullerene framework should introduce more strain than would be present in the free cyclophane itself. In an isolated cyclacene, strain should be relieved by splaying outward of the carbon atoms in between the angular ones, making the six-membered tings boat-shaped. In a fullerene, on the other hand, all six of the bonds to each six-membered ring are bent out of the plane of that ring, and each ring is constrained to be planar or roughly planar. Even in the smaller cyclacenes, such as [8]cyclacene, the strain should not be prohibitive, given that each individual ring, though boat-shaped, should not be more bent out of planarity than the benzene rings in perfectly stable cyclophanes such as [2.2]paracyclophane. Molecular modeling indicates that the diameter of [8]cyclacene is approximately the same as that of buckyball itself. Future prospects for the synthesis of cyclacenes therefore look better than ever. These favorable signs should encourage more research groups to tackle this problem from a variety of angles, and we are continuing our own efforts in this area as well. It appears highly unlikely that it will be possible to synthesize a cyclacene at first without the presence of solubilizing substituents. Nevertheless, the fact that the fullerenes (though sparingly soluble) are tractable points the way to the eventual synthesis of the parent cyclacenes themselves. Whatever approach is finally successful in this endeavor will have to be very ingenious in order to avoid making intermediates that are so insoluble as to be intractable. The winning strategy will undoubtedly be one that involves the use of solubilizing substituents right up to the last step, in which a parent cyclacene is formed by elimination of those groups. Hopefully, that product will be characterizable! Any cyclacene should be very sensitive to air oxidation, as are the higher acenes, so it is most probable that glove-box and/or Schlenk techniques will be necessary in order to make and handle them. In contrast, cyclacene quinones will be much more robust toward exposure to air, and cyclacene polyquinones should be air-stable, provided no acene units larger than naphthalene are present within the macrocyclic structure. For this reason we are concentrating our present efforts on the synthesis of cyclacene polyquinones, which should be much easier to make and study than the corresponding cyclacenes. Once this initial goal is achieved, the cyclacenes should be fair game, and the cyclacene polyquinones themselves may serve as suitable precursors. From the standpoint of scientific interest, these polyquinones are almost as worthwhile as targets as the cyclacenes. Like cyclacenes, they will have a rigid hoop of purely unsaturated carbon atoms, although more pronounced bending of the quinone rings should give them a shape which is
78
ROBERT M. CORY and CAMERON L. McPHAIL
less perfectly round. Like cyclacenes, they will be fully conjugated throughout the entire circumference of the macrocyclic structure, and their electronic properties, as well as those of their radical anions, for example, will be of great interest. The cyclacenes and the cyclacene quinones taken together as a family would represent a new kind of molecular host, in which a guest molecule would be surrounded by a rigid, roughly cylindrical surface of g-electrons. Because of the full conjugation of such a structure, the electronic properties of the host hoop and the host-guest complex should be substantially different from each other, making them easily distinguishable. Possible applications include selective sensing of strongly complexed guest molecules and metal ions. Further in the future, a rotaxane fashioned from a cyclacene or cyclacene quinone wheel and a guest molecular axle of sufficient length, bearing a different stopper group on each end of the axle, could serve as the basis for a molecular memory device, addressable by optical means. Since the higher acenes and the acene quinones are highly colored, the corresponding macrocyclic acenes (cyclacenes) and macrocyclic acene quinones (cyclacene quinones) will undoubtedly be strongly colored as well. This will give them a lot of appeal, at least visually, if not for practical applications. The Stoddart group has pioneered the synthesis of cyclacene precursor cyclophanes, and Stoddart and his coworkers have reached to within tantalizingly close proximity to the ultimate goal, which has so far remained just out of reach, partly because of insurmountable solubility problems. Our group has synthesized advanced belt-shaped cyclophane intermediates bearing solubilizing groups, on a road which we hope will be more successful in reaching a destination, whether it be a land of cyclacenes, cyclacene quinones, or both. ACKNOWLEDGMENTS
We are grateful to the Natural Sciences and Engineering Research Council of Canada for financial support of our research on the synthesis of cyclacenes and cyclacene quinones. We also greatly appreciate Professor Rolf Huisgen of the University of Munich and Dr. Dominic Chan of DuPont for helpful discussions.
REFERENCES 1. Kroto,H. W.; Heath, J. R.; O'Brien, S. C.; Curl, R. E; Smalley,R. E. Nature 1985, 318(6042), 162. 2. Koruga, D.; Hameroff, S.; Withers, J.; Louffy, R.; Sundareshan, M. Fullerene C60: History, Physics, Nanobiology, Nanotechnology, North-Holland,New York, 1993,p 12. 3. Osawa,E. Phil. Trans. Royal Soc. London Ser. A - Phys. Sci. Engin. 1993,343(1667), 1. 4. Kratschmer,W.; Lamb,L. D.; Fostiropoulos,K.; Huffman,D. R. Nature 1990,347(6291), 354. 5. Dresselhaus,M. S.; Dresselhaus,G.; Eklund,P. C. Science of FuUerenes and Carbon Nanotubes, Academic Press, Toronto, 1996. 6. Ball,P. Nature 1996, 383(6602), 661.
Cyclacenes a n d C y c l a c e n e Q u i n o n e s
79
7. Bodwell, G. J.; Bridson, J. N.; Houghton, T. J.; Kennedy, J. W. J.; Mannion, M. R. Angew. Chem. Int. Ed. Engl. 1996, 35(12), 1320. 8. Pascal, R. A. Pure Appl. Chem. 1993, 65(1), 105. 9. Herndon, W. C.; Nowak, E C. in: Advances in Theoretically Interesting Molecules; Vol. 2, Thummel, R. E, Ed., JAI Press, Greenwich, 1992, p 113. 10. Bickelhaupt, E Pure Appl. Chem. 1990, 62(3), 373. 11. Garratt, P. J.; Payne, D.; Tsotinis, A. Pure Appl. Chem. 1990, 62(3), 525. 12. Rabideau, E W.; Sygula, A. in: Advances in Theoretically Interesting Molecules; Vol. 3, Thummel, R. E, Ed., JAI Press, Greenwich, 1995, p 1. 13. Scott, L. T. Pure Appl. Chem. 1996, 68(2), 291. 14. Rabideau, E W.; Sygula, A. Acc. Chem. Res. 1996, 29(5), 235. 15. Clayton, M. D.; Rabideau, E W. Tetrahedron Lett. 1997, 38(5), 741. 16. Diederich, E; Whetten, R. L.; Thilgen, C.; Ettl, R.; Chao, I.; Alvarez, M. M. Science 1991, 254(5039), 1768. 17. Kikuchi, K.; Nakahara, N.; Wakabayashi, T.; Suzuki, S.; Shiromaru, H.; Miyake, Y.; Saito, K.; Ikemoto, I.; Kainosho, M.; Achiba, Y. Nature 1992, 357(6374), 142. 18. Fowler, P. W.; Manolopoulos, D. E. An Atlas of Fullerenes, Clarendon Press, Oxford, 1995. 19. Dresselhaus, M. S.; Dresselhaus, G.; Eklund, P. C. Science of Fullerenes and Carbon Nanotubes, Academic Press, Toronto, 1996, p 758. 20. Heilbronner, E. Helv. Chim. Acta 1954, 37(3), 921. 21. Derflinger, G.; Sofer, H. Monatsh. Chem. 1968, 99, 1866. 22. Ege, G.; Vogler, H. Theor. Chim. Acta 1974, 35(3), 189. 23. Aihara, J. Bull. Chem. Soc. Jpn. 1975, 48(12), 3637. 24. Agranat, I.; Hess, B. A., Jr.; Schaad, L. J. Pure Appl. Chem. 1980, 52(6), 1399. 25. Balaban, A. T. Pure Appl. Chem. 1980, 52, 1409. 26. Kivelson, S.; Chapman, O. L. Phys. Rev. B 1983, 28, 7236. 27. Haase, M. A.; Zoellner, R. W. J. Org. Chem. 1992, 57(3), 1031. 28. Hosoya, H.; Kumazaki, H.; Chida, K.; Ohuchi, M.; Gao, Y.-D. Pure Appl. Chem. 1990, 62(3), 445. 29. Hosoya, H.; Aida, M." Kumagai, R.; Watanabe, K. J. Comput. Chem. 1987, 8(4), 358. 30. Aihara, J. J. Chem. Soc., Perkin Trans. 2 1994, 971. 31. Aihara, J. J. Chem. Soc. Faraday. Trans. 1995, 91(2), 237. 32. Graham, R. J.; Paquette, L. A. J. Org. Chem. 1995, 60(18), 5770. 33. Alder, R. W.; Allen, P. R.; Edwards, L. S.; Fray, G. I.; Fuller, K. E.; Gore, P. M.; Hext, N. M.; Perry, M. H.; Thomas, A. R.; Turner, K. S.J. Chem. Soc., Perkin Trans. 1 1994(21), 3071. 34. Schrtxler, A.; Mekelburger, H. B.; V~gtle, F. Top. Curr. Chem. 1994, 172, 179. 35. Girreser, U.; Giuffrida, D.; Kohnke, E H.; Mathias, J. P.; Philp, D.; Stoddart, J. F. Pure Appl. Chem. 1993, 65(1), 119. 36. Kohnke, F. H.; Mathias, J. P.; Stoddart, J. E Top. Curr. Chem. 1993, 165, 1. 37. Ashton, P. R.; Girreser, U.; Giuffrida, D.; Kohnke, E H.; Mathias, J. P.; Raymo, F. M.; Slawin, A. M. Z.; Stoddart, J. E; Williams, D. J. J. Am. Chem. Soc. 1993, 115(13), 5422. 38. Ashton, P. R.; Brown, G. R.; Isaacs, N. S.; Giuffrida, D.; Kohnke, F. H.; Mathias, J. P.; Slawin, A. M. Z.; Smith, D. R.; Stoddart, J. E; Williams, D. J. J. Am. Chem. Soc. 1992, 114(16), 6330. 39. Kohnke, E H.; Slawin, A. M. Z.; Stoddart, J. E; Williams, D. J. Angew. Chem. Int. Ed. Engl. 1987, 26(9), 892. 40. Ashton, E R.; Kohnke, E H.; Isaacs, N. S.; Slawin, A. M. Z.; Stoddart, J. E; Williams, D. J.; Spencer, C. M. Angew. Chem. Int. Ed. Engl. 1988, 27(7), 966. 41. Blatter, K.; Godt, A.; Vogel, T.; SchlUter, A. D. Makromol. Chem. - Macromol. Symp. 1991, 44, 265. 42. Godt, A.; Enkelmann, V.; SchlUter, A. D. Angew. Chem. Int. Ed. Engl. 1989, 28(12), 1680. 43. Godt, A.; SchlUter, A. D. Adv. Mater. 1991, 3(10), 497. 44. Chiba, T.; Kenny, E W.; Miller, L. L. J. Org. Chem. 1987, 52(19), 4327.
80 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.
ROBERT M. CORY and CAMERON L. McPHAIL Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc. 1984, 106(21), 6422. Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J. Am. Chem. Soc. 1987, 109(9), 2788. Pollmann, M.; MUllen, K. J. Am. Chem. Soc. 1994, 116(6), 2318. Negishi, E.; Holmes, S. J.; Cederbaum, E E.; Takahashi, T; Swanson, D. R.; Tour, J. M.; Miller, J. A. J. Am. Chem. Soc. 1989, 111(9), 3336. Cory, R. M.; McPhail, C. L.; Dikmans, A. J. Tetrahedron Lett. 1993, 34(47), 7533. Almlof, J. E.; Feyereisen, M. W.; Jozefiak, T H.; Miller, L. L. J. Am. Chem. Soc. 1990, 112, 1206. Fitzgerald, J. J.; Drysdale, N. E.; Olofson, R. A. Synth. Commun. 1992, 22(12), 1807. Cory, R. M.; Dikmans, A. J., unpublished results. Jung, M. E.; Blum, R. B. Tetrahedron Lett. 1977, 3791. Fastrez, J. J. Phys. Chem. 1989, 93(6), 2635. Cory, R. M.; McPhail, C. L.; Dikmans, A. J.; Vittal, J. J. Tetrahedron Lett. 1996, 37(12), 1983. Cory, R. M.; McPhail, C. L. Tetrahedron Lett. 1996, 37(12), 1987. Jozefiak, T H.; Almlof, J. E.; Feyereisen, M. W.; Miller, L. L.J. Am. Chem. Soc. 1989, 111(11), 4105. Cory, R. M.; Carrozzella, D., unpublished results. Cory, R. M.; Scott, C. J., unpublished results. Otsubo, T; Aso, Y.; Ogura, E; Misumi, S.; Kawamoto, A.; Tanaka, J. Bull. Chem. Soc. Jpn. 1989, 62(1), 164.
BENZOANNELATED FENESTRANES
Dietmar Kuck
1. 2. 3.
4. 5.
6.
7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 The Insight: Benzoannelated Di- and Triquinanes . . . . . . . . . . . . . . . . 84 Benzoannelated [5.5.5.6]Fenestranes . . . . . . . . . . . . . . . . . . . . . . . 96 3.1. Synthesis of All-cis-Stereoisomers . . . . . . . . . . . . . . . . . . . . . 96 3.2. cis, cis, cis, trans-Stereoisomers: General Aspects . . . . . . . . . . . . . . 97 . . 9 102 3.3. Synthesis of Benzoannelated cis, cis, cis, trans-[5.5.5.6]Fenestranes Benzoannelated [5.5.5.5]Fenestranes . . . . . . . . . . . . . . . . . . . . . . 104 Miscellaneous Areno-Fused Fenestranes . . . . . . . . . . . . . . . . . . . . 106 5.1. Attempts to Generate Benzoannelated [5.6.5.6]Fenestranes . . . . . . . 106 5.2. Naphtho-Annelated [5.5.5.6]Fenestranes . . . . . . . . . . . . . . . . 109 5.3. Thieno-Annelated Benzo[5.5.5.6]Fenestranes . . . . . . . . . . . . . . 110 Fenestrindane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 6.1. Solid-State Molecular Structure of Fenestrindane . . . . . . . . . . . . 114 6.2. Conformation and Spectroscopy of Fenestrindane . . . . . . . . . . . . 117 Bridgehead-Substituted Benzofenestranes . . . . . . . . . . . . . . . . . . . 120 7.1. Synthesis of Fully Bridgehead-Substituted Benzofenestranes . . . . . . 120 7.2. Synthesis of Partially Bridgehead-Substituted Benzofenestranes . . . . 121 7.3. Conformational and Flattening Effects in Bridgehead-Substituted Fenestrindanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 7.4. Bridged Benzoannelated Fenestranes . . . . . . . . . . . . . . . . . . 135
Advances in Theoretically Interesting Molecules, Volume 4, pages 81-155 Copyright 9 1998 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0070-1 81
82
DIETMAR KUCK
8. The "Outlook"uThrough Fenestrindanes . . . . . . . . . . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.
148 151 151
INTRODUCTION
The fenestrane motif is a very particular one within polycyclic organic chemistry. It contains no less than four mutually fused rings arranged in an apparently two-dimensional way, so that we can easily "look through" it. Yet, in fact, we don't! We see the frames, but not the framework. It is only at second glance that we discover that fenestranes are not fiat, in contrast to fenestrae, and that there are different ways to bend them! In no other type of polycyclic arrangement do we find a single (carbon) atom being shared by so many rings. Fenestranes, such as [5.5.5.5]fenestrane 2, and their homologs (e.g., 1 and 3) contain just one quaternary, tetracoordinate carbon atom common to all of the tings. Given that the central carbon atom must be embedded in a tetrahedral surrounding, l this inevitably renders the framework of fenestranes three-dimensional, as shown for all-cis-[5.5.5.5]fenestrane in 2a. Propellanes, such as 4, contain two quaternary atoms but only three rings. It is amusing to note that this renders the three-dimensionality of their structure much more evident (Chart 1). Fenestranes are different. The parent framework contains only tertiary bridgehead atoms, all of which may participate in interesting chemical transformations again in contrast to the mostly inert quaternary bridgehead atoms of propellanes. However, this may reverse our first insight and offer a clear view on a particular,
I I
C
'
2a
Chart 1.
Benzoannelated Fenestranes
83
fenestrane-specific outlook: the planar configuration of the central tetracoordinate carbon locked in a flat fenestrane framework, after having appropriately adjusted the surrounding bridgehead positions! In fact, a fenestrane bearing a suitably tailored tetracyclic periphery could force the central atom into a planar geometry! Since the suggestion by Hoffmann, Alder, and Wilcox 2'3 of planar tetracoordinate carbon as an altemative to the tetraedral model of Van't Hoff and Le Bel, 1 a large number of papers and reviews ~11 have appeared discussing the synthesis, stability, and structure of various fenestranes. But notably, most of Hoffmann's ideas (e.g., planarity of the central C atom in fenestraheptaene 5) and the results obtained by many other theoreticians, including recent suggestions by Dodziuk 12 and Radom et al. ~3-~5 on flattening or planarization of tetracoordinate carbon within a truly three-dimensional molecular network, are still awaiting experimental verification. 16 Thus, without any doubt, fenestranes are theoretically interesting molecules. In order to verify or falsify the theories that have been developed around them, we need proper, viable experimental accesses to this class of polycyclic compounds. At the same time, with their unusually complex molecular architecture, fenestranes are not only theoretically interesting but also, quite simply, experimentally interesting molecules. Alicyclic fenestranes that have been synthesized in the course of the last two decades may be divided into several groups. First, a series of small-ring homocyclic fenestranes were prepared by Agosta et al. 17-19 and also by Dauben, 2~ Saltzman, 21 Crimmins, 22 Keese, 23'z4 and Grieco 25'26 and their associates, in most cases by employing [2 + 2] cycloaddition techniques as the key steps. The chemistry of small-ring 'fenestranes was furthered by Agosta and his group who synthesized a derivative of the [4.4.4.5] congener 17'18that contributed much to the "planar-carbon problem." Small-ring fenestrane chemistry also includes interesting stereoisomers that have the four rings fused in the strained cis,cis,cis,trans orientation, 23'25 unlike the usual all-cis-stereochemistry in congeners such as 2a. Another group of alicyclic fenestranes is represented by a large number of [5.5.5.5]fenestranes, which were synthesize~ and studied by various laboratories. 4"11 Interestingly, all of these "normal-ring" fenestranes have only been prepared as the usual all-cis-stereoisomers (cf. 2a27-3~ although there is theoretical background on the hypothetical stereoisomers. 8 This appears to be a paradox since the fusion of four five-membered rings should be the least strain-demanding, g'31 Among the normal-ring fenestranes, congeners with other than [5.5.5.5] ring fusion are very rare. 5'6'8 Attempts to synthesize alicyclic [5.5.5.6]- or [5.5.6.6]-fenestranes so far have failed, 32 but several [5.5.5.7] congeners related to the only known naturally occurring fenestrane, the diterpene lauren-1-ene, have been prepared. 33-37 Highly unsaturated fenestranes, which were suggested as theoretically interesting targets quite early 2'3 have also remained very scarce. Although a number of independent routes to [5.5.5.5]fenestranes and [5.5.5.5]fenestrenes have been developed by Cook et al. 38'39 and by Keese et al., 27-30''Itr-43 no fully unsaturated
84
DIETMAR KUCK
fenestrenes such as 5 are known. Clearly, experimental access to partially or fully bridgehead-unsaturated fenestranes is extremely difficult. In this chapter, we describe our approach and contributions to fenestrane chemistry. In contrast to alicyclic fenestranes, these developments are based on aromatic chemistry, that is, on the generation of the polycyclic frameworks of fenestranes starting from arylaliphatic substrates and using, inter alia, the synthetic tools of electrophilic aromatic substitution. The presence of aromatic rings dramatically increases the stability of reactive and synthetic intermediates, as well as of that of the target fenestranes. In this way, exploration of the chemistry of benzoannelated fenestranes has contributed substantially to the expansion of the general field of fenestranes. Moreover, making use of conventional techniques and principles, the manifold of fenestrane compounds has been expanded to derivatives that have not been accessible in the alicyclic series. We will first discuss the synthetic strategy leading to benzoannelated fenestranes, which had been long restricted to all-cis-[5.5.5.6] and all-cis-[5.5.5.5] congeners. We will then turn to some strained cis,cis,cis,trans-stereoisomers of the [5.5.5.6] series and to various derivatives bearing substituents on the aromatic tings and at the bridgehead positions in particular. Structural effects will be discussed, in particular for all-cis-fenestrindane 6, which may be regarded as the prototype of all benzoannelated fenestranes and their various bridgehead-substituted derivatives.
,HH > a11-cjs-Fenestr•
Chart 2. @
THE INSIGHT: BENZOANNELATED DI- A N D TRIQUINANES
Our"insight" into fenestrane chemistry has emerged from a broader program aimed at the development of a new family of benzoannelated centropolycyclic compounds, which we named the centropolyindanes. '~'~ Based on our knowledge of relatively simple benzoannelated diquinanes (diindanes), we developed an efficient synthetic access to higher polyquinanes bearing up to six cyclopentane rings at a common carbon atom (the centropolyquinanes 31'47) and, at the same time, the
Benzoannelated Fenestranes
85
corresponding number of annelated benzene tings. As will be shown in Section 7.4, this approach culminated in the synthesis of unprecedented fenestranes in which the central carbon atom is, in fact, shared by more than four rings! From the outset of our work, tetrabenzoannelated all-c/s-[5.5.5.5]fenestrindane 6 has been a key synthetic target. At the outset, we recognized that the chemistry of 2,2'-spirobiindanes had been developed in several laboratories ~-51 and that some work also had been reported on tetrahydroindeno[1,2-a]indenes. 52-55 The parent hydrocarbons of these diindanes, 2,2'-spirobiindane 7 55 and cis-[ 1,2-a]diindane 8 56 (the Cs-symmetrical diindane), respectively, are obvious subunits of fenestrindane 6. Formally, two spiranes 7 may be annelated in a crosswise manner to give 6, or two Cs-diindanes 8 may be mutually fused in a lateral orientation. From our very first efforts 46'57'58in this field it was evident that cyclodehydration of benzyl-substituted indanols opens a very efficient route to centrodi- and triindanes (Scheme 1). Thus, diindanes such as 8 are formed upon acid-catalyzed dehydration of 2-benzylindan- 1-ols (e.g., 10). 56 Triindane 9, comprising the frameworks of 7 and 8 and lying halfway to the target fenestrane 6, can be synthesized in high yield from 2,2'-dibenzylindane-1,3-diol 11 in a single step. 'u'59 In the same way, several tribenzotriquinacenes were obtained from the corresponding 2-benzhydrylindane- 1,3-diols, albeit with only moderate yields. 'u'56 Stepwise cyclodehydration routes furnished related and even higher centropolyindanes. 6~ By retrosynthesis, we developed several approaches using cyclodehydration as the key methodology 46 (Scheme 2): (i) Preparation of suitably hydroxylated
H- ../ H H
H
H,d~ H
Chart 3.
H/'~ H H
86
DIETMAR KUCK H
(H+) -
H20
:tO
oH ,,~
I~.,~
(H §
.
_ 2 H20"
l:t
~ 9
Scheme 1.
diphenyl-substituted 2,2'-spirobiindanes such as 12 and 13 followed by two-fold ring closure; (ii) introduction of a benzhydryl substituent at the "central" carbon atom (C-9a) of a suitably functionalized Cs-diindane such as 14, which could undergo two-fold cyclodehydration; and (iii) stepwise construction of a phenylsubstituted centrotriindane alcohol such as 15, which would give 6 by single cyclization. However, none of these approaches is really straightforward. Very little is known about 2,2'-spirobiindan-l,l'-diols except that they are prone to undergo Grob fragmentation. Whereas diol 12 or related difunctionalized spiranes are unknown and certainly difficult to prepare, an isomer of 12, the tertiary diol 17 has been described by Sch6nberg and Sidky 62 and shown to suffer single dehydration under mild conditions after heterolysis of one of the central spirane bonds to give 18 (Scheme 3). This conversion corresponds to our findings on related simple benzylic 1,3-diols, such as 2-(o~-hydroxybenzyl)-l-indanol, which readily cleaves into benzaldehyde and indene upon treatment with acid. 63'64 Spirodiol 17 was prepared from the long-known 2,2'-spirobiindan-l,l'-dione 16. 50 It is interesting that besides the corresponding isomer, 2,2'-spirobiindan-1,3dione 19, 65a the tri- or tetraketones, 20 and 21, have not been described in the literature. Despite the fact that the latter are certainly of both experimental and theoretical interest, their conversion to substrates that could subsequently be cyclized into benzoannelated fenestranes appears extremely difficult. Even 19, a potential precursor of 1,3-diaryl-substituted [2,2']spirodiindanes such as 13, is difficult to synthesize. In our own attempts, we obtained this diketone only as the minor isomer upon spiroannelation of 1,3-indanedione with t~,ct'-dihaloxylenes. 65b Conversion of 19 into diphenylspirodiol 13 would still be very cumbersome.
Benzoannelated Fenestranes
87
OH
HO
~
0
IP i1~ "-%o,,~ ....
OH
HO,
(a I l - c i s )
15
14
Scheme 2.
Further possibilities to construct 1,3-difunctionalized l',3'-diphenyl-2,2-spirobiindanes have been envisaged, but to date have not been successful. 66 A conceptually different approach to benzoannelated fenestranes is based on Cs-diindanes as key intermediates (Scheme 4). At first sight, diindanedione 24, which had been described previously, 52a was promising. In fact, the facile condensation of sterically hindered 1,3-indanediones with benzhydrol (such as 22 giving the highly congested diketone 23), 56'67 encouraged us to attach a benzhydryl group at the enolizable bridgehead position of 24. This would lead to the interesting intermediate 25, which could be reduced to diol 14 and subsequently be subjected to a two-fold cyclization, despite the fact that the second cyclization step of the cyclodehydration appears sterically unfavorable. However, a study exploring the use of dione 24 revealed that it does not provide an efficient route to benzoannelated fenestranes. 59'68 It is interesting to note that 24 can be converted in a multistep sequence into an isomer of fenestrindane 6, trifuso-centrotetraindane 27, and some related interesting triindanes. 61 However, the '~r route" by annelation of a second Cs-diindane unit to a given one, as in the conversion 14 ~ 6, so far has
88
DIETMAR KUCK
C6H5MgBr Et20, C6H6 ,
0
~ : H. ~ O ~ ~ ~~~,,.,,~]/~
~
0
CH3COC1 a - CH3C02H
H
-C1-
17
~.6
H
(H+)
18
_
Scheme 3.
remained unsuccessful. Notably, the corresponding (pentalenopentalene) annelation strategy has been successful in synthesizing alicyclic [5.5.5.5]fenestranes. 10,42,69,70 An approach, very similar to the latter one, would consist of a stepwise au.[bau strategy. Considering the framework of 9 as a "broken fenestrane," derivatives such as 28 and 29 could be envisaged to undergo the last ring closure. Again, some attempts in this direction have been undertaken; for example, a stepwise approach by oxidation of 9 has been achieved. 63'71 Introduction of the fourth arene ring (as
0
o
oo
0
O0
OO
~9
20
21
Chart 4.
Benzoannelated Fenestranes
0
89
(CsHs)2CHOH H+, CBHB, A
76% 22
23
(CBHs)2CHOH H+, CBHB, 4
//
or"
(CBH5) 2CHC I Nail, THF, A
24
25 -
CBHsCH2CI NaH. toluene. A
46%
several steps
26
27
Scheme 4.
~ ~.**mtm...."
28
29
Chart 5.
14
90
DIETMAR KUCK
in 29, which is obtained in low yield by the cyclodehydration route) 63 accompanied by suitable functionalization and completed by cyclization appears viable, but turned out to be extremely tedious and inefficient. Summarizing the potential synthetic approaches to benzoannelated fenestranes at this point, we have to recognize that both spiro- and fuso-diindanes (cf. 7 and 8) represent rather unsuitable key substrates from which to begin the synthesis of benzoannelated fenestranes. Some further unsuccessful, though inspiring, approaches have been outlined elsewhere. 66 Before turning to the synthesis of fenestrindane (6) and a series of related benzoannelated fenestranes, we should give some credit to previous independent efforts in this field. In the course of extended studies on spiro compounds by Wynberg and his group, Ten Hoeve tackled the planar-tetracoordinated carbon challenge by pursuing the synthesis of benzoannelated fenestranes by two-fold cyclization of suitably substituted spiranes. 72 Essentially, two approaches were pursued, which differ in the directness of ring closure strategies. 73~ One approach consisted of the construction of triindanes, which could be subjected to cyclization to build the fourth pane of the fenestrane. In this context, Ten Hoeve and Wynberg synthesized triindane 32, 73 a strikingly close constitutional isomer of 9, 'u'59 which bears the angular indane units oriented in such a way that cyclodehydrogenation between a pair of ortho positions appeared possible. Triindane 32 is accessible in good yields via the morpholinium salt of 2-indanone (30) and the dibenzyl derivatives 31a or, more favorably, 31b (Scheme 5). Unfortunately, all attempts to convert 32 to the related distilbene 35, so as to perform a subsequent C-C bond formation across the 1,1'-spirobiindene moiety and eventually generate tribenzo[5.5.5.5]fenestrane 38, failed. Treatment of the synthetic intermediates 33 and 34 under Friedel--Crafts conditions in benzene yielded the singly unsaturated and/or saturated diphenyl derivatives 36 and 37 but, again, further (cyclo)dehydrogenation was not achieved. 73 The first effort to utilize benzoannelation as the stabilization factor to generate a "fiat" (or "flattened") carbon atom within a [5.5.5.5]fenestrane proved to be in vain. Thus, this general route to [5.5.5.5]fenestranes appeared to be blocked. It should be noted that C--C coupling, such as in 35 --~ 38, is unfavorable for thermochemical reasons since tribenzo[5.5.5.5]fenestrane 38 or its phenyl-substituted derivatives would contain only one benzo nucleus fused in the "low-strain" 1,2-annelation, but would have two others in a peri, or 1,6-annelation, with benzopentalene units. It has been known for several decades that the benzo[1,6-cd]-pentalenes 39 are markedly strained. +'75'76 Nevertheless, some interesting derivatives have been described, the most remarkable among them being fluoradene 4077 (Chart 6). The strain is intuitively obvious by considering fluoradene as a derivative of Cs-diindane $ bearing the benzo ring fused at its bent diquinane nucleus, i.e., along positions 9, 9a, and 10. In fact, 40 has been found to be highly acidic. 77 Indirectly, the benzo[ 1,6-cd]pentalene motif has received new interest in the context of fullerene and fullerene-fragment chemistry since it represents a counterexample to systems
Benzoannelated Fenestranes (~.)
~
0
HN
91 0 PPA
(2) C6HsCH28r
30
Br
31a
X=O
31b
X = HN+
k__J HO
(1) Cr vl
NBS
(2)
32
0 Br-
LAH
9
b
Br
//
i
HO
33
35
34
Alcl~
Alcl~
benzene
benzene
q--
[-2.]
o
4--
38
36
37
(Cg)
(unknown)
Scheme 5.
obeying the "isolated pentagon rule. ''78-8~ In view of fenestrane chemistry, however, we would like to encourage the reader to pursue independent ways to fenestranes bearing benzo nuclei fused across the bridgehead positions. The distorted vespirenes 41 [X = (CH2) . with n = 5 or 6] studied by Prelog et al. 81'82 may be considered to be the first benzoannelated fenestranes. Theoretically interesting and experimentally challenging targets would be the "broken" tetrabenzo[5.5.5.5]fenestrane 43 and even the intact congener 44! The former hydrocarbon could be accessible via the unknown phenylfluoradene 42 and its derivatives. Even more strained than 43 would be fenestrane 44 that, while well-protected against C--C bond cleavage, may contain the central carbon atom in a close to planar, or rather pyrimidal, 4'6'~1'83 configuration. To the best of our knowledge, not even a computational approach to this exotic prototype has been undertaken (Section 7.3). The other approach studied by Ten Hoeve and Wynberg TMwas based on suitably substituted spirane precursors (Scheme 6). These workers synthesized several spiro[5.5]undecane and spiro[cyclohexane-l,2'-indane] derivatives bearing aro-
92
DIETMAR KUCK
x"-"~/~.
l
I
H! ~x,./ I ~,~I
39
~'~-",.,~ x 40
41
Fluoradene
Vespirenes
I
I
I
I
I
42
43 (ali
I 44
unknown)
Chart 6.
matic groups at positions C-2 and C-6 of the cyclohexane ring. 84 Related work had been published by Freimanis et al. 8587 In fact, the target fenestranes for the Dutch researchers were the parent (non-benzoannelated) fenestranes of the [5.6.5.6] and [6.6.6.6] series, as inspired by Hoffmann's ideas on planar tetracoordinate carbon. 2'3 The synthetic plan to obtain these fenestranes started from cyclic 1,3-diketones such as 1,3-cyclohexanediones (e.g., 45) or 1,3-indanedione 46, which were converted into various spirotriketones by two-fold Michael addition with the corresponding diarylideneacetones 47. Interestingly, most of these spirotriketones 48 and 49 can be prepared as the trans-1,3-diaryl derivatives (trans-48 and trans-49) by running the Michael addition under kinetic control, whereas the corresponding cis-l,3diaryl isomers (cis-48, cis-49) are obtained as the products of the thermodynamically controlled reaction. Accordingly, targeted trans --~ cis stereoisomerization can be carried out readily in this series of spiranes. Among the various spiranes studied, the difuryl derivatives such as trans-48a were of particular interest since they
Benzoannelated Fenestranes
93
0 Ar
i
Ar
+ 45
o
(i) HOAc
0
(ii)
Ar
46
o Ar trans-48a, -48b trans-49a. -49b
base
base
0 Ar
47
o Ar
45 X= C
cJs-48a. -48b cJs-49a, -49b
46 X= I ~
47a
47b
X= C
48a
4Bb
X= ~
49a
49b
,/~ = H3C'~
,6/',= Q
Scheme 6.
promised to provide access to [6.6.6.6]fenestranes (Scheme 7). In fact, the dimedone-derived spirodiketone 50 was converted in good yield into the oligoketone 51 by mild hydrolysis of the furan tings but, unfortunately, subsequent two-fold cyclization by aldol condensation to the desired [6.6.6.6]fenestranetetraone 52 failed. Instead, mixtures of even more complex polycyclic compounds were formed under various conditions. For example, the enol ether 53, bearing an additional transannular ether bridge (see below), was identified as a product. Similar attempts starting from indanedione-derived spirodiketones obtained from 49a were also unsuccessful. Thus, this approach to benzoannelated fenestranes along the "long and winding road" to planar carbon 73 appeared to be blocked as well. As a matter of fact, the two-fold Michael adducts 49b described by Wynberg and by Freimanis and their associates do represent useful intermediates for a highly efficient access to benzoannelated fenestranes. 88 The key idea was to simply apply our two-fold cyclodehydration of dibenzylindane-l,3-diols to the corresponding indanediols which could be prepared from the spirotriketones presented above. As
94
DIETMARKUCK o HaC'~,.,~, 0 H3c
~
HaC- ~_~,""X_._/
H3o+
50
9
HsC X_~" X,._../ 0
o
HCi/H20
H3C~"~ 0
0
HsC? 0 H3C'~
H3C~o
0
D
HsC~o 0 52
51
o 9
HsC~ HsC \ 53
CHa
CH3
Scheme 7.
mentioned above, the conversion of 2,2-dibenzyl-1,3-indanediol 11 was found to be very efficient, giving the broken fenestrane 9 in > 90% yield (Scheme 1). Particularly encouraging was our finding that even trans-2,2-di(benzhydryl)-1,3indanediol S4, prepared from diketone 23, undergoes two-fold cyclodehydration to give the highly crowded tribenzotriquinacene 55 (Scheme 8). Notably, isomeric broken fenestranes such as 56 were not found. 4a'56 Taking these findings into account, trans-diphenylspirodiols of the general type 57 appeared to be good candidates for constructing benzoannelated [5.5.5.6]fenestranes (Scheme 9). Conversion of trans-49b, for example, into 57 (Ar = C6H5) should be straightforward without disturbing the anticipated favorable trans stereochemistry of the 1,3-diphenylcyclohexane moiety, in spite of the thermodynamically preferred cis-diphenyl stereochemistry evidenced for the spirotriketones. In any case, the trans orientation of the aryl tings in 57 appeared not only favorable, but even crucial, to our plans to convert the spiranes into fenestranes. In fact, the two-fold cyclodehydration of trans-diphenylspirotriols 57 (Ar = Ph) to tribenzo[5.5.5.6]fenestranol 58 proved excellent. 46'59'88 Ironically, however, we have found a6'89 that cis-diaryl isomers in this series serve as a useful basis for the
Benzoannelated Fenestranes ,J~,
95
_
H+, Cell e. A 23%
"~0
/
54
55
56
Scheme 8.
OH Ar OH
H3P04 xylene/A
OH
OH Ar
trans-57
58
(Ar = CsH5)
~,~/s
OH Ar
OH
OH Ar 59
Scheme 9.
60
96
DIETMAR KUCK
synthesis of various benzoannelated [5.5.5.6]fenestranes as well! For example, the cis-di(2-thienyl)spirodio159 demonstrates the variability of the concept. Of course, limitations were also encountered. By no means did we achieve the transformation of non-benzoannelated spirodiols (e.g. 60) into fenestranes. The overall synthetic route from 1,3-indanedione 46 via trans-diphenylspiroindandiol 57 (Ar = C6H5) and also of the respective cis isomers to the corresponding tribenzoanneleated all-cis- and cis,cis,cis,trans-[5.5.5.6]fenestranes is discussed in the following sections.
3. BENZOANNELATED [5.5.5.6]FENESTRANES 3.1. Synthesisof AII.cis.Stereoisomers Two experimental variants of the fenestrane synthesis are possible. The first one represents our first fenestrane synthesis and started by reduction of the trans-spirotriketone trans-49b with lithium aluminum hydride in tetrahydrofuran to give a mixture of several spirotriols 57 (Scheme 9). Two triol diastereomers were isolated and characterized with partial assignment of their sterexx:hemistry. In any case, the relative orientation of the phenyl groups does not change. When the mixture of spirotriols 57 is subjected to dehydrating conditions, a two-fold cyclization takes place, generating two additional indane units in a single synthetic step (Scheme 9). Best results are obtained by using orthophosphoric acid in refluxing xylene, and yields of fenestranol 58 are excellent. The corresponding tribenzo[5.5.5.6]fenestrene 62 is formed from 58 as a very minor product (yield < 5%). The fact that the cyclohexanol functionality does not undergo 1,2-elimination of water under the relatively harsh reaction conditions is remarkable and points to an increase of strain if the number of sp 2 centers is increased in [5.5.5.6]fenestranes with all-cis stereochemistry. Even harsher conditions in hexamethylphosphorus triamide (HMPT, >220 ~ are required to eliminate water from 58 in a controlled way (Scheme 10). Subsequent catalytic hydrogenation of 62 gives the tribenzo[5.5.5.6]fenestrane 63. The persistence of the hydroxyl group in 58 is fortunate since it is easily oxidized to give the corresponding [5.5.5.6]fenestrane ketone 61, which itself represents an interesting synthetic intermediate, and not only for the preparation of fenestrane 63. The second variant of the fenestrane synthesis avoids the reduction/reoxidation of the cyclohexanone functionality. This variant (Scheme 11) bears some practical advantages and the yields are similar to those of the first variant. Spirotriketone trans-49b is converted into the protected dispirocyclic 1,3-indanedione trans-64, which is easily reduced to the corresponding 1,3-indanediol trans-65. In complete analogy to the triol 57, two-fold cyclodehydration of trans-65 with concomitant deketalization leads directly to the [5.5.5.6]fenestranone 61. In all cases, the original stereoorientation of the phenyl groups in trans-49b remains unaffected, giving rise to the [5.5.5.6]fenestrane framework with all-cis stereochemistry.
Benzoannelated Fenestranes
OH
97
CrO3/HaS04 acetone
0
97~
0
58
61
HMPT 53% a ,
Nail4" HaO 82% KOH, DEG .
H2, Pd/C EtOAc/THF
0
95~
62
63
Scheme 10. Thus, the two-fold cyclodehydration strategy 46 found to be so efficient for the synthesis of the centrotriindanes, including the broken fenestrane 9, has provided the breakthrough for the synthesis of benzoannelated fenestranes. In fact, this strategy proved successful starting with various related spiro[cyclohexane-1,2'-indane]-diols such as 59 to produce a number of substituted tribenzo[5.5.5.6]fenestranes bearing other fused aromatic nuclei, such as thieno or naphtho tings (Section 5). Moreover, a series of interesting phenylated derivatives have been synthesized, such as the tetraphenyl-substituted [5.5.5.6]fenestranols 66 and 67 and the related fenestranones 68 and 69, which are aimed at the construction of fenestranes with an extended periphery of mutually condensed aromatic tings (Chart 7). 90 3.2.
cis, cis, cis, trans-Stereoisomers: General Aspects
The benzoannelated fenestranes discussed in the previous sections have the four rings fused by all-cis annelation. This means that the four stereogenic centers at the bridgehead positions bear their tertiary hydrogen atoms in an alternant orientation relative to the two faces of the fenestrane framework. Thus, fenestrindane 6 is the
98
DIETMAR KUCK
[i) HOCH2CH20H (ii)
0
(iii)
LiAIH4
H3PO4
60~
61
trans-49b
(i)
0
(iii) v
G
92~
0"0
(ii) 9
oo trans-65
trans-64
Scheme f f .
/
66
68
~X~x
X = H, OH
X
"- 0
Chart 7.
67
X = H, OH
69
X = 0
Benzoannelated Fenestranes
99
70 'Fenestrindene'
6
7i
al2-cJs-
cJs, cJs. cds, t r B n s ( ' e p j "-} F e n e s t r i n d a n e
Fenestrindane
Chart 8.
4b~,8b13,12bt~, 16b13-tetrahydro derivative of the yet hypothetical, fully unsaturated parent polyene, which we call "fenestrindene" 70. 91 Pencil-and-paper chemistry allows us to epimerize the bridgehead centers of 6 arbitrarily, or re-add hydrogen atoms to the bridgehead positions of 70 at random, such that a series of strained stereoisomers of all-cis-fenestrindane 6 would be envisaged. The least strained of these, 71, would represent the 4b~,8bt~,12bo~, 16bl3-tetrahydro derivative of fenestrindene 70, and the cis,cis,cis,trans-isomer of 6, and may be referred to as "epi-fenestrindane." Of the six conceivable stereoisomers of 6, epi-fenestrindane 71 appears to be the only one that could be synthesized. This follows from extending the results reported of Luef and Keese, who used semiempirical molecular orbital (MO) calculations for the stereoisomers of mainly alicyclic [5.5.5.5]fenestranes (Chart 9), 8'92and from experimental results on small-ring cis, cis, cis, trans-fenestrane stereoisomers. 59 For example, using AM 18 (and MNDO 92) the cis, cis, cis, trans-isomer of all-cis-[5.5.5.5]fenestrane 2a, epi-[5.5.5.5]fenestrane 72, has been calculated to be 18 (22) kcal mo1-1 less stable than 2a, while the next more highly strained (cis, trans, cis, trans) stereoisomer is 57
1O0
DIETMAR KUCK H
H
H
H"
H
H
H 2a
72
~epi
&L.straln
H e
\
:I k c a I mo 1 - i
H
"-.-....---.--.J
73 wepi
Ig.
H
H
6~_strain
=
=
6.4
.
H
........../
H
H
H
74
75
76
k c a I mo 1 -i
=elat At--strain = 2 . 0
I
Chart 9.
epi (64) kcal mol-l less stable [Chart 9, AEs~n) - LV-If(cis,cis, cis, trans) - zXHf(all-cis)]. The origin of the strain in cis, cis, cis, trans-fenestranes is obvious. These stereoisomers contain one trans-bicyclo[3.3.0]octane unit (74) in place of the otherwise four cis-bicyclo[3.3.0]octane moieties (73). This pair of systems has been studied in detail and the strain difference was determined as AHf(74) - AHf(73) = 6.4 kcal mo1-1 in agreement with force-field calculations. 93-9~ The increase of strain energy for cis --> trans isomerization is clearly less pronounced in the corresponding bicyclo[4.3.0]nonanes (hydrindanes) 75 and 76. 9'1'95 Unsaturation has been calculated to increase the strain in the [5.5.5.5]fenestrane framework significantly [viz. by 18 (12) kcal mo1-1 comparing 23 and 72]. 8'92 Therefore, we may expect that "--'strain A b'?-epi for the 4ba,8ba,12ba,16bf5 epimer 71 is much greater than for 72 (> 25 kcal mol-1). However, very little computational data on the epimerized stereoisomers of unsaturated fenestranes have been reported. 1~ To assess the strain effects in benzoannelated [5.5.5.6]- and [5.5.5.5]fenestranes, force-field and semi-empirical calculations have been performed in this laboratory for the pairs of unsaturated all-cis- and epi-[5.5.5.5]fenestranes. In fact, our MM+/AM 197 calculations suggest drastic strain effects (Chart 10). 63
Benzoannelated Fenestranes
H
101
H
t
H
H
=.
H
H
H
H
.T
H
H'~ T/~"-,,,,~/~--~x--" ~H
H
H
H
H
77
78
79
80
~.ept AL-straln =
35.9
kCB I mo
~ept
1-1
AL.straln
=
I 1.5
kca I
mo
1-1
\H .-i \/ix,
63
81 ~.ep~ &t_stratn
=
:11.3
k:ca], t o o l -1
Chart 10.
As expected, the synthesis of cis, cis,cis,trans-[5.5.5.5]fenestratetraene 78 should be difficult (AE epi -- - 36 kcal mol-l). In contrast, the preparation of the related strain [5.5.5.6]fenestratrienes, such as 80, bearing a saturated cyclohexane in place of a cyclopentene ring seems feasible since calculations suggest a rather moderate increase of strain (~A$~t r a lenp i 9 = 11.5 kcal mol-l). In any case, however, access to the b e n z o a n n e l a t e d analogues in the cis,cis,cis,trans-[5.5.5.6] and possibly cis,cis,cis,trans-[5.5.5.5] series should be less painstaking owing to the stabilizing effect of the benzoannulation (e.g., towards polymerization). On the other hand, the benzoannelated [5.5.5.5]- and also [5.5.5.6]fenestranes bearing a trans-bicyclo[3.3.0]octane unit are expected to be more reactive at the epimerized bridgehead position due to the presence of the benzo rings. In accord with the non-benzoannelated parent fenestranes, MM+/AM1 calculations on the stereoisomeric tribenzofenestranes 63 and 81 predict a moderate increase of strain in the cis,cis,cis,trans epimer (' ,A- -Fs-t r a ei np i 11 93 kcal mol -~) and a quite substantial increase for the fenestrindanes 6 and 71 (xA- -F- .- es tpria i n -- - 35.5 kcal mo1-1) 63
102
DIETMAR KUCK
From the beginning of our work, a directed entry into the subfamily of benzoannelated cis,cis,cis,trans-fenestranes appeared impossible; the trans orientation of the two aryl groups in the spirotriketone trans-49b and the derived spirotriols 57 appeared crucial to formation of the fenestrane skeleton. However, as shown in the next section, the two-fold cyclodehydration strategy has allowed us to prepare some benzoannelated cis,cis,cis,trans-[5.5.5.6]fenestranes simply by subjecting the corresponding cis-diarylspirotriketone cis-49b to the same synthetic sequence as for trans-49b. First we will present mostly unpublished results on the synthesis and some properties of tribenzo-annelated cis,cis,cis,trans-[5.5.5.6]fenestranes.
3.3. Synthesis of Benzoannelated
cis, cis, cis, trans-[ 5.5.5.6 ] Fenest ranes Access to the benzoannelated cis,cis,cis,trans-[5.5.5.6]fenestranes is perplexingly facile. Two examples, given below, are based on the cyclodehydration of cis(instead of trans-) diaryl-substituted spiro[cyclohexane-l,2'-indane]-diol derivatives. Similar to its stereoisomer trans-49b, cis-diphenylspirotriketone cis-49b can be reduced to the mixture of corresponding cis-diphenylspirotriols cis-57b (Scheme 12). When we first subjected this triol to the standard cyclodehydration conditions, the reaction mixture turned black within a few hours. We supposed that the starting material would have decomposed by either Grob fragmentation and/or polymerization at the cyclohexene double bond, which, in this case, may form more readily than in the case of the trans stereoisomer (vide supra). Much to our surprise, however, we found that a product of two-fold dehydration had formed that lacked olefinic C-H resonances in the IH NMR spectrum and displayed two sets of resonances for the four bridgehead methine and methylene groups, all being distinct from those of fenestranol 58. When heating with H3PO 4 for only 1 hr, tribenzo[5.5.5.6]fenestranol 82 was isolated in good yield as a mixture of two diastereoisomers. In further analogy to the trans isomer, cis-diphenylspirotriketone cis-49b was converted to related dispiroketaldiols cis-65, which likewise underwent twofold cyclodehydration to the cis,cis,cis,trans-[5.5.5.6]fenestranone 83. Unlike the all-cis-[5.5.5.6]fenestranone 61, epimer 83 lacks molecular symmetry (point group C l instead of C2), as clearly reflected in the IH and 13C NMR spectra. As a derivative of epi-fenestrane 81, cis,cis,cis,trans-[5.5.5.6]fenestranone 83 should be considerably more strained than the all-cis isomer 61. In fact, preliminary results have shown that the cis,cis,cis,trans-[5.5.5.6]fenestrane skeleton readily undergoes epimerization to the more stable all-cis framework. For example, attempted Wolff-Kishner reduction of 83 to the cis,cis,cis,trans-[5.5.5.6]fenestrane 81 at 180 ~ in diethylene glycol instead furnished the all-cis isomer 63 in good yield (Scheme 13). The same result was obtained working under milder conditions 98 by treatment of the related hydrazone 84 at ambient temperatures with
Benzoannelated Fenestranes
OH
103
HaPO4/xY l e n e
9
72~
OH H
/
-\
0
cJs-57b
H
82
0
HaPO4/x y 1 e n e
0
87~
.
cjs-65
0
/
\
83
Scheme 12.
butyllithium in DMSO. 89a We are currently exploring more elaborate methods to prepare the elusive cis,cis,cis,trans-tribenzo[5.5.5.6]fenestrane 81. These findings represent the first qualitative experimental evidence on the lability of strained benzoannelated cis,cis,cis,trans-[5.5.5.6]fenestranes toward epimerization to the all-cis stereoisomers. Evidently, deprotonation/reprotonation at the "inverted" bridgehead of the fenestrane framework occurs even at ambient temperatures. In any case, the findings give a hint of the difficulties that must be faced in handling more highly strained stereoisomers in the [5.5.5.6]- and [5.5.5.5]fenestrane series, and of epi-fenestrindane 71, in particular. Once in hand, these benzoannelated fenestranes will offer the possibility of determining quantitative data on the effect of strain on the kinetic acidities and the homolytic bond (C-H) cleavage at the inverted bridgehead position of fenestranes.
104
DIETMAR KUCK
HOH
0
N2H4 H20 9 KOH, DEG 180 ~
H
0
BuLi/DMSO/ 25 ~ /
83
H
63
!
I?
l
HOH /
NNH2
D 0
D
H
H
84
HOH
P P
0
H
81
Scheme 13.
4. BENZOANNELATED [5.5.5.5]FENESTRANES Ring contraction of the all-cis-tribenzo[5.5.5.6]fenestrane skeleton represents a key step in the nine-step synthesis of fenestrindane 6 from 1,3-indanedione. 59'88 It has been achieved first by ~,~'-dibromination of fenestranone 61 and subsequent Favorskii rearrangement to give the tribenzo[5.5.5.5]fenestrene carboxylic acid g6 (Scheme 14). Single bromination was found to be very inefficient. Decarboxylation of 86 under drastic conditions leads to tribenzo[5.5.5.5]fenestrene 88, and subsequent completion of the missing benzo ring was achieved by employing tetrachlorothiophene S,S-dioxide 89 as a C 4 synthon, followed by Gassman reduction as the final step. Thus, fenestrindane a is accessible in nine steps from 1,3-indanedione in an overall yield of approximately 15%. The corresponding all-cis-tribenzo[5.5.5.5]fenestrane 87 was prepared by hydrogenation of g8 (Scheme 14).59 It is obvious that alternative methods of ring contraction must be used to achieve the synthesis of cis,cis,cis,trans-[5.5.5.5]fenestranes. Current efforts aimed at this
~
4J W~ ~
.r.4
.rt
.c
~
,b
"l-
I~)I 7
o
.el
4-t
I
9r t
I oJ o
~
I
~
I.n
--...,
105
~
I,
..,,-
,
t
106
DIETMAR KUCK
goal have referred to the successful ring contraction techniques used in the synthesis of small-ring ([4.4.5.5]- and [4.4.4.5]-) fenestranes by Agosta et al. ls'19 In those studies, photo-Wolff rearrangement of the respective diazoketones was the key step. To test this method with benzoannelated fenestranes, tribenzo[5.5.5.6]fenestranone 61 was recently converted in good yield into tribenzo[5.5.5.5]fenestrane carboxylic acid 85. 89a
5.
MISCELLANEOUS ARENO-FUSED FENESTRANES
Several further variants of the two-fold cyclodehydration strategy for constructing the framework of benzoannelated fenestranes have been under investigation. In this section we present the results of attempts to generate benzoannelated fenestranes bearing more than one six-membered ring in the tetracyclic core and discuss the status of our studies on fenestranes containing fused homo- and heteroaromatic rings.
5.1. Attempts to Generate Benzoannelated [5.6.5.6]Fenestranes As shown above, the spirotriketones obtained by two-fold Michael addition of dibenzylideneacetone to 1,3-indanedione represented a very useful basis for the synthesis of benzoannelated [5.5.5.6]fenestranes and certain [5.5.5.5] congeners. In fact, that basis should be much broader considering the reports by Freimanis et al. s'5"s7 and Ten Hoeve and Wynberg74's4 who treated, for example, 1,3-cyclohexanedione with several diaryldienones and obtained the corresponding spiro[5,5]undecanetriones such as 90. Therefore, it appeared interesting to subject spirotriketones of this type to reduction and subsequent cyclodehydration in order to construct the respective dibenzo[5.6.5.6]fenestrane derivatives. Unfortunately, all these attempts have remained unsuccessful. Reduction of spiro[5,5]undecanetrione 90, bearing the two phenyl rings in the favorable trans orientation, led to the corresponding spiro alcohol 91 as a mixture of stereoisomers. However, dehydration of these intermediates under various experimental conditions, including the standard ones (H3PO4/xylenes or toluene) used for the spiro[cyclohexane-l,2'-indane]-diols, resulted in complex product mixtures. A two-fold C--C bond formation to give the desired all-c/s-dibenzo[5.6.5.6]fenestranol 92 (or the derived fenestrene) was never achieved. The only clearcut result was obtained usingpara-toluenesulfonic acid as a catalyst (Scheme 15). In this case, transannular etherification gave rise to tricyclic product 93 that, under forcing conditions, led to single cyclodehydration to form 94 bearing only one of the desired new indane units. All attempts to subsequently open the ether bridge of 94 and perform another cyclization to generate fenestranol 92 failed. Selective removal of the cyclohexanone moiety of the trans-diphenylspirotriketone 90 (in analogy to the reduction of the cis isomer TM) gave the corresponding spirodiketone 95 (Scheme 16). Surprisingly, this compound turned out to be
107
Benzoannelated Fenestranes
0 ~/,~0
LiAIH4 O0 Et20'', ~ ~ ~ O H
/
(H§
II.
oo go
Oen ~ts~
/ ~ H/~~
o\
0
93
H
H
H
H
O
/g,
92
Q
H, po,
benzene,,,,
H
H
(3 94
Scheme 15.
extremely reluctant to undergo two-fold reduction, and only forcing conditions (LiAIH4/dioxane, 72 hr) eventually afforded the desired conversion to spirodio196. In this case, and at marked variance from all comparable cases studied in the spiro[cyclohexane-l,2'-indane]-diol series, dynamic 1H NMR spectrometry revealed extreme steric hindrance in the spirocyclic framework of 96, in agreement with the difficulties in the reduction step of the precursor 95.
O
0
95
diLiAIH4 oxane~ O0
96 Scheme 16.
(H+)
97
108
DIETMAR KUCK
Obviously, the two rigid, spiro-fused cyclohexane rings bearing substituents at each of the four (neopentane) or-carbon atoms constitute a sterically much more crowded arrangement than the correspondingly substituted spiro[cyclohexane- 1,2'indane] skeleton of 57. In view of these arguments, we may also assume that etherification of 91 to 93 is strongly favored for steric reasons in the spiro[5.5]undecanetriol isomers. Notwithstanding these findings, we tried to generate dibenzo[5.6.5.6]fenestrane 97 by subjecting spirodiol 96 to dehydration under a variety of conditions. Although two-fold dehydration had obviously occurred (as shown by mass and IH NMR spectrometry), a myriad of products were formed, none of which could be unambiguously identified. Spectroscopic analyses, inter alia, suggest that undesired elimination reactions, as well as rearrangement and fragmentation processes of the spiro[5.5]undecane framework, intervene upon the harsh reaction conditions employed, and the formation of dibenzofenestranes is suppressed. To summarize, we may refer to Ten Hoeve and Wynberg's findings in their attempts to generate [5.6.5.6]fenestranes. These authors isolated only several complex product mixtures after treatment of their diarylspiroketones with acid catalysts, as we did. In fact, these systems easily elude the two-fold cyclization reactions if the spirane backbone is completely alicyclic. At variance from the aromatic annellated spirodiols or -triols of the indane derivatives, lack of stabiliza-
0
[i)
PhCHeBr
(ii) LiAIH 4
HAP04
9
98
99
.%
j
~.00
+ 47b AcOH [i)
L:i A1H4
(i i) .
o
H3PO4 9
I0~
//
9
OH
~02
Scheme 17.
Benzoannelated Fenestranes
109
tion and enhanced steric hindrance prevent the two-fold cyclization to the fenestrane framework. Inspired by these findings, another effort to generate the [5.6.5.6]fenestrane framework was undertaken. 99 In this case, we started from 2,3-dihydrophenalene1,3-dione 98 (Scheme 17). In a test sequence involving the 2,2-dibenzyl derivative and the corresponding diol 99, we prepared the "broken fenestrane" 100 in good yield, in close analogy to the synthesis of 9 from 11 (Scheme 1). However, attempts to generate the corresponding spiro[5,5]undecane framework by two-fold Michael addition of 98 to dibenzylideneacetone 47b instead formed the cis-diphenyl isomer 101 almost exclusively. Despite the unfavorable stereo-orientation of the phenyl groups, we pursued this approach. Reduction of the triketones, followed by dehydration of the resulting triols, did not produce any detectable amounts of the desired dibenzo,naphtho[5.6.5.6]fenestranol 102 or a derived fenestrene. In view of our recent findings on the two-fold cyclodehydration of cis-diphenyl substituted spiro[cyclohexane-l,2'-indane]-l',3'-diols, we may again conclude that the construction of the [5.6.5.6]fenestrane framework bearing two six-membered rings is much more difficult than the synthesis of the [5.5.5.6]fenestranes. 32'99
5.2. Naphtho-Annelated [5.5.5.6]Fenestranes In contrast to the attempts to construct the peri-condensed naphtho-annelated [5.6.5.6.]fenestrane skeleton of 102, the two-fold cyclodehydration strategy proved to be successful with a number of fenestranes bearing ortho-condensed naphthalene rings fused to the five-membered rings. As analogs of diphenylspirotriol 57, trans-di(t~-naphthyl) and trans-di(~5-naphthyl)-substituted spirotriols were prepared and subjected to the standard dehydration conditions. 99 The di(t~naphthyl)spirotriols were converted into the all-cis-benzodi(naphtho-a)[5.5.5.6]-
~,H F
103 ~.05
x
X = H, OH X = 0
:104 1.06
Chart 11.
X = H, OH X = 0
110
DIETMAR KUCK
fenestranol 103, which was isolated in good yields (Chart 9). As expected, additional six-membered tings were not generated during cyclization; thus, electrophilic attack at the peri position of the (~-naphthyl groups was not productive. In the case of the di(ffnaphthyl)-substituted spirotriols, we obtained a mixture of constitutional isomers, among which fenestranol 104, the product of two-fold electrophilic attack at the electron-rich t~-positions, dominated. Oxidation of the fenestranols 103 and 104 gave the C2-symmetrical benzodinaphtho[5.5.5.6]fenestranones 105 and 106, which exhibit characteristic shielding and deshielding effects in their ~H NMR spectra owing to the opposite orientation of the naphtho rings at the periphery of the fenestrane skeleton.
5.3. Thieno-Annelated Benzo[5.5.5.6]Fenestranes Another variant of the overall synthetic strategy for constructing fenestranes bearing aromatic rings fused to the tetracyclic core consists in the modification of the aryl rings introduced by the dienone synthon. Again reminiscent of the work of Ten Hoeve and Wynberg, we recently studied the conversion of the bis(furyl)- and bis(thienyl)-substituted spirotriketones 107-110 to the corresponding areno-annelated [5.5.5.6]fenestranes. This work was intended primarily to explore the usefulness of electron-rich aryl groups in the fenestrane synthesis, and the possibility to subsequently modify or partially dismantle these arene rings. However, in fact, this work allowed us to learn some surprising details on the cyclization step. The furyl derivatives 10789 and 10874'~ were smoothly converted into the corresponding ketaldiols; however, acid-catalyzed cyclodehydration gave rise mostly to decomposition. Once again, the difurylspirane derivatives eluded the formation of the fenestrane framework. In contrast, both the trans and cis stereoR
0
~ 0
---S 0
R I07
R = H
lOB
R
=
CH 3
trans-I og cJs-iO9
Chart 12.
t r a n s - I I0 ClS-liO
Benzoannelated Fenestranes
111
isomers of the thienyl analogs 109 and 110 undergo the two-fold cyclodehydration process to give several new benzodithieno[5.5.5.6]fenestranes. In the ]3-thienyl series (Scheme 18), two-fold cyclization of trans-111 and cis-111 took place stereospecifically. The trans isomer gave a mixture of the three possible constitutional isomers with all-cis stcreochemistry, among which the fraction of 112, i.e., the product of two-fold electrophilic attack at C-2 of the thienyl rings, amounted to approximately 40%. The constitutionally mixed isomer (not shown in Scheme 18), being statistically favored over 112, was formed with slight excess only (48%). The isomeric diol cis-lll was converted stereospecifically into the cis, cis, cis, trans-[5.5.5.6]fenestrane 113. Unlike trans-111, the product of two-fold attack at C-2 of cis-lll was the major constitutional isomer (approximately 90%), isolated in 60% yield. In view of the cyclization of the diphenyl-substituted dispirodiols 65, the stereospecificity of the cyclodehydration reactions of 111 had been expected. However, the highly regioselectivc formation of the cis,cis,cis,
0
to
Hx/
HAP04
luene, A
.
-,.H /
H
t r a n s - t 1i
0
H
ll2
I all-cia and
OH
I
constitutional
HAP04
H
toluene, a 9
--
isomers
H 0
s
I cJs, cJs, cJs, trans I major
(90~)
Scheme 18.
constitutional
isomer
11 2
DIETMAR KUCK
trans-fenestranone 113 was surprising and may shed light on the interplay of stereo-orientation, strain, and electronic factors in the cyclization processes. The reaction of the two stereoisomers bearing t~-thienyl groups was surprising. Both cis- and trans-ll4 were converted to the all-cis-[5.5.5.6]fenestranone 115, but the cis,cis,cis,trans-isomer 116 was not formed, as revealed by spectroscopic analysis of the crude product mixture. This result represented the first case in which the stereo-orientation of the two aryl rings in a spiro[cyclohexane-l,2"-indane]l',3'-diol precursor does not translate into the stereochemistry of the [5.5.5.6]fenestrane framework. Obviously, the system avoids the formation of the strained cis, cis, cis,trans-fenestrane core in the two-fold cyclodehydration process. Our first explanation of this phenomenon assumed an acid-catalyzed epimerization of the cis, cis, cis, trans- to the all-c/s-fenestrane framework (116 ~ 115) under the reaction conditions. The increased basicity of the electron-rich thieno rings 1~176 could enable protonolytic ring opening at the strained junction, followed by ring closure to the all-cis configuration. To test this hypothesis (without having the
OH~/S 0
O~
H3P04 toluene, a
S '
, H"
trans-I 14
-=--I oa~--%/S
HAP04
0 H
I 15
toluene
al l - c . i s
S 0
,
//
cJs-ll4
.
o
116 CdSo cJs. cJs, trans
Scheme 19.
Benzoannelated Fenestranes
113
cis,cis,cis,trans isomer 116 at hand), we studied another electron-rich precursor, the di(p-anisyl)spirodiol cis-ll7 (Scheme 20). In fact, cyclodehydration of cis-ll7 gave an interesting, and an again unexpected, result. The two possible stereoisomeric fenestranones, 118 and 119, were formed in a 2:1 ratio that was found to be independent of the reaction time. Thus, the cis,cis,cis,trans-[5.5.5.6]fenestranone 118, obtained as the major product, is stable towards the acidic medium and the all-cis isomer 119 forms after a kinetically controlled epimerization during the cyclodehydration process. Very likely, this crucial step takes place after the first, energetically least-demanding cyclization (Scheme 20). Cyclization of the yet "incomplete" (rather than truly "broken") fenestrane intermediate ion 120 may lead to the strained cis,cis,cis,trans framework of 118 but, in competition with this irreversible ring closure, heterolysis of the weakened neopentane C-C bond in 120 gives rise to the electronically stable hydroxyallyl cation 121. This intermediate may actually exist as a short-lived x-complex and undergo a fast electrophilic H3CO
HaCO
(;
OH
H3PO4
H3CO
H
toluene, a
H 0
~co
HaCO
+
0
12.1 1 t18
cis-117
tt9
J cJs, cJs. cJs, tPans I
(H+) ]
9
- OHC2H40H
HaC%
HaCO
/
I
(H§
HaCO
el
1-cJs 4,
//
-9 H+
HsCO H
H
HaCO i20
9
OH
HaCO
H OH
9
HaCO
i2i
Scheme 20.
J
122
114
DIETMAR KUCK
attack l~176 at the strained C--C double bond of the diindene moiety to give 122 and then complete the [5.5.5.6]fenestrane core in the low-strain, all-cis configuration of ketone 119. This mechanism is in qualitative agreement with the finding that the electronic nature of the two aryl groups in the spirocyclic precursors governs the degree of stereospecificity. This stereospecificity decreases distinctly (phenyl - []-thienyl > p-anisyl > (x-thienyl) with decreasing electron density of the ortho positions of the aryl groups in the series cis-6$, cis-lll, cis-ll7 and cis-ll4. Conversely, increasing the stabilizing effect of these aryl groups on the benzylic cation intermediate (phenyl < p-anisyl < (x-thienyl) favors epimerization. Obviously, the ~-thienyl group in c/s-lll behaves like the electronically non-activated phenyl group in cis-6$ since it does not provide additional stabilization to form the allylic ion intermediate corresponding to 121.
6.
FENESTRINDANE
All-c/s-fenestrindane 6 may be regarded as the prototype compound for all benzoannelated fenestranes. With its four five-membered rings fused pairwise to the four neopentane C--C bonds (thus representing the tetra-fuso-centrotetraindane), fenestrindane has a very stable, low-strain molecular framework of high (formal Dza) symmetry. Unlike the alicyclic all-cis-[5.5.5.5]fenestrane 2a and the corresponding [5.5.5.5]fenestratetraene 77, the four equivalent bridgehead positions are very reactive toward functionalization by radicals and anionic agents without competing side reactions. In fact, all four benzhydrylic (diphenylmethane-type) methine groups in 6 are easily converted into C-Br or C--OH groups; this has opened a notably facile access to the first fenestranes bearing either hydrocarbon or heteroatomic substituents at all the four bridgehead positions. In this section, we first focus our attention on the characteristic structural and spectroscopic features of fenestrindane. In the following two sections, the synthesis and properties of bridgehead derivatives of 6 and of a particular subfamily, the singly or doubly bridged fenestrindanes, will be described.
6.1. Solid-State Molecular Structure of Fenestrindane Although many fenestranes have been calculated by force-field or semi-empirical MO methods, little information has been reported on experimentally determined structures. Studies on small-ring [4.5.5.5]-, [4.4.5.5]- and [4.4.4.5]fenestranes by Keese et al., ~~ Dauben et al., ~~ and by Agosta et al., 5'6 respectively, culminated in the determination of the strongly enlarged bond angles (ix = 128 ~ to 132 ~ atthe unbridged sides of the flattened neopentane core. The structure of the naturally occurring diterpene lauren-l-ene, a [5.5.5.7]fenestrene has been determined. 1~ Considerable interest has been focused on [5.5.5.5]fenestranes. In fact, the first reported X-ray crystal structure of a fenestrane was that of [5.5.5.5]fenestra-
Benzoannelated Fenestranes
0
115
0
z.H 0 >,,,
0
0
0 123
a
=
i17.5
a'
=
~15.~
o
H H
(E~)
o
~H H
---
H
~
H
2a
a
=
a'
=
116.2
o
(Z::~)
(?hart 13.
2,6,8,12-tetrone 123, determined by Weiss, Cook, and their colleagues. 69The X-ray structural analysis of fenestrindane 6, published by our group in 1986,88 provided the first experimental data on a fenestrane hydrocarbon in which the putative symmetry of the parent all-cis-[5.5.5.5]fenestra-tetraene 7738 should be preserved. Most recently, Keese, Hargittai, and coworkers 3~published the first experimentally determined structure of the parent all-cis-[5.5.5.5]fenestrane 2a, obtained by gasphase electron-diffraction structure analysis. The unbridged bond angles in 123, 6 and 2a were similar, all being within the range of 115" to 118~ and depend slightly on the different molecular symmetries (Chart 13 and Figure 1). Moreover, our synthetic work on 6 and its bridgehead derivates provided further insight into the conformational ground state(s) of the [5.5.5.5]fenestrane framework in the solid state and in solution. The cumbersome synthetic access to fenestrindane is more than compensated for by its interesting chemistry. The compound precipitates from ethanol/toluene solutions in beautiful small, colorless, triclinic crystals (m.p. 325 to 330 ~ dec.). The X-ray molecular structure of 6 is reproduced in Figure 1. The two perspectives clearly show the considerable distortion of the fenestrane framework from the formal D20 symmetrical arrangement. The top view reveals a regular torsion of the entire skeleton such that the two planes of symmetry in the D20 conformation vanish
116
0 "13 i0 im
W
L~ t-i'o i0
tO i'o
l-
z
"13 l--
~
o ~ I_
i-
I_
0
L_
i._
0
E L_
L_
Benzoannelated Fenestranes
117
and the remaining symmetry element is an S4 axis dissecting the two open (unbridged) neopentane C--C--C bond angles (cz = ~' = 116.5 ~ Table 1). 88 The S4 symmetry of solid-state fenestrindane leaves the four C-H bridgehead methine groups equivalent, but gives rise to two four-fold degenerate sets of nonequivalent C(CH)(CH) moieties in each of the four benzo rings. This characteristic feature recurs not only in the solid state but also in the NMR spectra of suitably substituted, sterically hindered, four-fold bridgehead derivatives of 6 (see below). The side view (Figure 1) along one of the neopentane C--C bonds gives another insight into the tetracyclic core of fenestrindane. One of the four (equivalent) diindane subunits clearly exhibits the torsion about one of the central, neopentane bonds. The torsion angles, e.g.: 1Ol = H-C4b"ccentr~ were found to be 20.3 ~ (+ 0.5), and the corresponding angles within the two five-membered tings of the diindane subunit, e.g. c4a--.c4b--ccentr~ 16b and cac--C4b--cce"tr~ are I~1 = 21.1 ~ (+ 1.0) and I~gl = 19.6 ~ (+ 0.9), respectively (Table 2). It is worth contrasting these data with those determined for comparable congeners within the family of parent centropolyindanes (Figure 2). The related torsion effect in solid-state Cs-diindane 8 l~ is clearly less pronounced than in 6. In this isolated subunit, the three torsion angles are, respectively, I~1- 17 .1~ (+ 0.9), IX;I- 16.5 ~ and I~gl - 14.8 ~ Interestingly, the opposite effect is found in the X-ray structure of the angular (difuso) triindane 9.1~ This broken fenestrindane exhibits four (a priori nonequivalent) C--C-C-C torsion angles in the range of 22.0 ~ to 24.5 ~ Similarly, triptindane 124, the C3-symmetrical, propellane-derived isomer of 9 having three a priori equivalent C-C-C--C torsion angles, is distorted by 23.8 ~ (+ 0.4). 109These results demonstrate that (i) the "concerted" action of one or two additional indane units on the conformation of a given one is additive if the mutual annelation is appropriate. For example, two indanes act synergetically on a given one in both 9 and 124. This interaction gives rise to an enhanced tendency of the diindane subunits to avoid the fully eclipsed orientation along the neopentane C--C bonds. However, (ii) this observation does not hold for the case of the four-fold congener, fenestrindane 6. Here, the torsion effect is less pronounced than in 9 although, intuitively, the molecular S4 symmetry suggests that a synergetic effect should occur as well. Probably, (iii) the full fenestrane-type fusion of the four diindane subunits in 6 gives rise to an intrinsic flattening of the whole framework that counteracts the torsion effect along the neopentane C--C bonds.
6.2. Conformation and Spectroscopy of Fenestrindane In contrast to the solid state, the conformation of fenestrindane 6 in solution is flexible enough to allow it to be dynamic, leading to an increase of the molecular symmetry from S4 to apparent D2d symmetry. For example, the IH NMR spectrum of 6 measured at ambient temperature exhibits two-fold degeneracy of the elements of each benzo nucleus, giving rise to a single, AA'BB' spectrum for 16 protons at (5 7.27 and 7.53 besides the unique singlet of the bridgehead protons at (5 4.89. 59
118
~J
D
~
Os ~- O
~
o
G c:
O
o
~
o ~
"O'1:3
~E
O
O
tO
O
O --'O
Gu o ,t-
6 . _~
r-
o'< tO
0
0
~E ~_
O ~
E ~
Benzoannelated Fenestranes
119
Correspondingly, the 13CNMR spectrum of this C29H20hydrocarbon consists of only five distinct carbon resonances. Thus, this parent of all-cis-tetrabenzo[5.5.5.5]fenestrane exists in a fast degenerate equilibrium between two S4 symmetrical conformers, as shown in Scheme 21. As will be discussed below, this feature is strongly affected by substitution of the bridgehead C-H bonds of 6. Fenestrindane is the highest centropolyindane that exists in more than one ground-state conformation. This is due to the fact that it consists of four diindane subunits that can preserve their own intrinsic flexibility in the framework of 6. The same holds for lower members of the centropolyindane family such as 7, 9, and 124, and is a common property of all centropolyindanes that do not contain a rigidifying bridge between the two indane moieties of a diindane subunit. In contrast, all centropolyindanes containing a triquinacene unit such as the tribenzotriquinacene 27 and 55 (Scheme 8) are conformationally rigid, existing in a single minimum-energy conformation, l l0 Interestingly, the UV/Vis spectrum of 6 exhibits exactly the same absorptions as do the other conformationally flexible centropolyindanes. The lowest-energy n-n* transition is at ~'max = 273.5 nm, identical to that of indane, the parent arene. It follows that there is apparently no stabilizing interaction between the four n-electron systems of the formally isolated benzo nuclei of 6. In line with this finding, the specific absorptien of 6 is about four times that of indane and twice that of diindane 8. At variance with 6, however, the UV/Vis spectra of centropolyindanes with a conformationally rigid molecular framework (e.g., 27 and 55) exhibit a slight but characteristic bathochromic shift (AX = + 3.0 nm). This holds also for the derivatives of fenestrindane 6 that bear at least one rigidifying bridge across the "open" C-C-C bond angles of the neopentane core, i.e., centropentaindane 165 and centrohexaindane 163 (see Section 7.4.2).
s
Cs4)
s Scheme 21.
Cs4')
120
DIETMAR KUCK
7. BRIDGEHEAD-SUBSTITUTED BENZOFENESTRANES Introduction of substituents at the bridgehead positions of alicyclic fenestranes is difficult. A number of bridgehead-substituted fenestranes have been reported in the series of non-benzoannelated fenestranes, 5-8 but targeted functionalization or derivatization of a given fenestrane is very cumbersome. In contrast, bridgehead substitution of benzoannelated fenestranes occurs very easily owing to the benzylic or benzhydrylic activation of the bridgehead C-H bonds. This holds, in particular, for fenestrindane 6 since the complete benzoannelation of the [5.5.5.5]fenestrane core also excludes elimination or rearrangement processes. Once functionalized, a large variety of new benzoannelated fenestranes becomes accessible, including even more complex polycyclic derivatives, and the field has been explored only in part. In this section, we will first describe the chemistry of benzoannelated fenestranes bearing substituents at all the four bridgeheads and then present some results on partially bridgehead-substituted fenestranes.
7.1. Synthesisof Fully Bridgehead-Substituted Benzofenestranes The most facile access to four-fold bridgehead functionalized benzofenestranes is achieved by radical-induced bromination of fenestrindane 6 (Scheme 22). Thus, irradiating a solution of the hydrocarbon in carbon tetrachloride furnishes the tetrabromide 125, which can be isolated in gram amounts in 93% yield after recrystallization. 66'11~ The compound forms air-stable, colorless crystals and has been the key intermediate for the preparation of other fully bridgehead-substituted fenestranes, ll2 Several heterofunctionalized analogs were synthesized by SNl-type reaction (i.e., by solvolysis, Lewis-acid-catalyzed or Ag(I)-ion-assisted substitution). Among others, tetraalcohol 126, tetrafluoride 127, tetraazide 128, ll2 tetraaminofenestrindane 129, ll3 and the four-fold thioether 130 ll2 deserve special notice. Only two derivatives of 6 bearing four carbon-bonded substituents have been synthesized. Tetramethylfenestrindane 131 ll2 was prepared from 125 by treatment with trimethylaluminum in n-heptane and the four-fold nitrile 132 ~2 was obtained in moderate yield, besides the mixed [Br,(CN)] 4 analogs, by SnCl4-catalyzed reaction of 125 with trimethylsilyl cyanide. 114 Homo- and heterocyclic bridgehead-bridged derivatives of 6 will be discussed below. Four-fold bridgehead bromination is not limited to the highly symmetrical fenestrindane 6. It has also been performed with the broken fenestrindane 9 and with tribenzo[5.5.5.5]fenestrane 87. In both cases, the crude reaction products contained predominantly the corresponding tetrabromides. However, in contrast to 125, these bromides are relatively labile and have to be used for further synthesis without purification, as shown below (Scheme 31). An independent access to four-fold bridgehead substituted fenestrindanes has been reported in the context of our studies of dioxiranes for oxyfunctionalization of alkylbenzenes and nonnatural hydrocarbons (Scheme 23). 71'115 Use of di-
Benzoannelated Fenestranes
121 CN
Br a. CC14 hv, A
,2,
...,.
9 F'-'\
f
,32
Br ~
125
i27
t31
C; 12B
CH3
,
129
?
130
Scheme 22.
methyldioxirane 133 at 0 ~ gave rise to a slow conversion producing a mixture of several fenestrindan alcohols containing predominantly the tetraalcohol 126. In contrast, methyl(trifluoromethyl)dioxirane 134 effected this conversion at-10 ~ within only 25 min, and acetylation of crude 126 produced the corresponding tetraacetate 136 in 55% yield. 71 Previously, tetrakis(trifluoroacetoxy)fenestrindane 135 had been synthesized via the tetrabromide 125. ll6
7.2. Synthesisof Partially Bridgehead-Substituted Benzofenestranes Partial-bridgehead functionalization of benzoannelated fenestranes is difficult due to the similar reactivity of their four benzylic and/or benzhydrylic C-H bonds. For example, partial bromination of the broken fenestrindane 9 affords the doubly 4b,8b-dibromide 137 in only 10% isolated yield (Scheme 24), and the corresponding conversion of the all-c/s-tribenzo[5.5.5.6]fenestrane 63 could not be achieved at all. However, the ring-contracted tribenzo[5.5.5.5]fenestrane 87 gave dibromide
122
DIETMAR KUCK HaC~CH3
~
0--0 133
OH
P
HaC~CF3 0--0
6
126
:134
125
t35
i36
Y =" C02CF a
Z = C02CH 3
Scheme 23.
138 in good yield, and careful hydrolysis of the latter compound led to the corresponding diol 139. In turn, solvolysis of 138 in methanol gave rise to decomposition and the dimethyl ether 140 had to be prepared by methylation of 139.114
Br
~
BP
/
/
/H
HaO+/THF
RO
H
RO
!37 I
Br2 10%
9 I
87 !38 I Br2 l 75%
Scheme 24.
Nail
--- 139
CH31 ---- 140
A = H R = CH 3
Benzoannelated Fenestranes
123
Two-fold bridgehead substitution of benzoannelated all-cis fenestranes leads preferably to the isomer bearing the two substituents in the anti-1,3 orientation (Scheme 25). This orientation is reasonable since the steric repulsion of two groups in the respective syn-l,3 isomer is quite substantial and may even exclude its formation. Thus, not surprisingly, two-fold bromination of 6, which has to be carried out with iodine bromide as the reagent to furnish acceptable yields (25 to 30%), generates the anti-dibromide 141, but virtually no syn isomer (142). 117 Force-field calculations performed for bridgehead-brominated [5.5.5.5]fenestranes corroborate our findings (see below). In contrast to bromination, partial functionalization of 6 with methyl(trifluoromethyl)dioxirane allowed us to perform targeted single or double hydroxylation. 118 Nevertheless, the regio- or facial selectivity of the reaction is the same (Scheme 25), such that 4b-fenestrindanol 143 and, in a separate step, anti-4b,8bfenestrindanediol 144 were prepared in good yields. Again, the second functionalization took place with anti-1,3 orientation and no syn-1,3-diol 145 was observed, in contrast to expectation. 119'~2~The facial selectivity' and also the kinetics of the second oxidation step shed some light on the mechanism of the oxygen insertion into saturated C-H bonds by dioxiranes, ll8
''~H HC~//
,
IBr
ca.
Br
//
' H
25%
H
/
H
C> 141
//
BP
6
Br
\ HsC~.CFs
77%
0-0
142
134 H
/
o-o
I/.
HO
144
143 Scheme 25.
.-.
145
124
DIETMARKUCK
TMS-SCH3 SnC14 48~ //
.,.._,
~
TMS-SC2H5 SnC14 BP \ / Br
0
5.25
75~ ii
H
//'-' o/
H
#
SC2H5 ~.30
~.46 Scheme 26.
Another interesting access to partially bridgehead functionalized fenestrindanes involves the tendency of the tetrabromide 125 to undergo partial or even complete reduction under conditions favoring SN1 reactions. For example, heating 125 in neat alkanethiols such as n-butylmercaptan leads to complete reduction to the parent hydrocarbon 6.117A striking example is the SnCl4-catalyzed reaction of 125 with ethyl trimethylsilyl sulfide at ambient temperature (Scheme 26). In this case, partial reduction takes place and 4b,8b-di(ethylthio)fenestrindane 146 was isolated in 75% yield. In contrast, the corresponding four-fold methyl thioether 130 was obtained in 48% yield without significant reduction using methyl trimethylsilyl sulfide. 114'117 Obviously, substitution competes with single-electron or hydride transfer steps and depends in a sensitive way on the particular reaction parameters. These results show that a large variety of bridgehead-substituted fenestrindanes and related benzoannelated fenestranes has become available. Steric interactions and, as evident from the reduction of 125, electronic factors govern the outcome of the various transformations. Many of these effects are not yet understood. The four-fold bridgehead substituted congeners represent a challenging group of fenestranes. They allow us access to a wide variety of complex organic polycycles based on the molecular framework of fenestranes and to pursue the problem of flattening a tetracoordinated carbon embedded in the tetracyclic framework of fenestranes.
Benzoannelated Fenestranes
125
7.3. Conformational and Flattening Effects in Bridgehead-Substituted Fenestrindanes The ease of introducing four bridgehead substituents into fenestranes was not obvious. At first glance, four-fold bromination of fenestrindane 6 appeared to be impossible due to the unfavorable, two-fold syn- 1,3 interactions between two large bromine atoms in 125. On the other hand, the significant D2d -4 S4 torsion of the fenestrane skeleton of 6 suggested that the interaction of the bridgehead substituents could be attenuated by further torsion. Luef and Keese, who studied conformational effects in fenestranes by computational methods (including AM1), predicted a severe increase in strain (AEst~ain= 45 kcal mo1-1) if the four methyl groups were introduced at the bridgehead positions of all-cis-[5.5.5.5]fenestrane (cf. 2a -4 147, Chart 14). 8'92 A report by Cook et al., 1~presented computational results on strain and conformational effects due to stepwise introduction of bromine into the bridgeheads of all-cis-[5.5.5.5]fenestra-2,5,8,11-tetraene 77. Of the dibromides 149 and 150, the former (anti) isomer was predicted to be slightly less strained than the latter (AEstrain = 3 kcal mo1-1, by force-field calculations), in qualitative agreement with our experimental findings on the partial functionalization of 6 (see above). Four-fold bromination of 77 to give 148 was estimated to have a considerably stronger effect (AEstrain = 24 kcal mol-l). Also, the conformational distortions predicted for 149 and 150 were quite dramatic (and certainly overestimated). Despite all the uncertainties in the force-field and semi-empirical calculations, the tendencies were evident. Introduction of four bridgehead substituents into all-cis[5.5.5.5]fenestranes and all-cis-[5.5.5.5]-fenestratetraenes should increase the torsion of the tetracyclic framework. The other important geometric parameter is the size of the unbridged C-C--C bond angles (o~, ct') at the central carbon atom, i.e., the flattening of the fenestrane framework. Computational approaches suggested a small, albeit sizeable, flattening effect in the model compounds 147-150. However, no experimental data were available as far as the bridgehead substituents are concerned. The first qualitative, indirect hint was our observation in 1988 that tetrabromofenestrindane 125 exists in solution in two apparently static, i.e., non-interconverting, conformations of S,) symmetry, as determined from its IH NMR spectrum at 130 ~ Meanwhile, we have collected some additional results on the conformational effects of four-fold bridgehead-substituted fenestrindanes in the solid-state and in solution.
7.3.1. Conformational Effects in Solution As mentioned above, the lH and 13C NMR spectra of fenestrindane 6 reflect an apparent D2d molecular symmetry as a result of the fast dynamic equilibrium between two equivalent S,) conformations (Scheme 21). When four relatively small substituents, such as OH and F, are introduced at the bridgeheads of fenestrindanes 126 and 127, respectively, the IH NMR spectra reflect four equivalent AA'BB' spin systems for the benzo protons, just as found for the parent hydrocarbon 6. In
126
DIETMAR KUCK
contrast, tetrabromofenestrindane 125 displays a characteristic ABCX spectrum for the benzo protons with four of the eight ortho protons resonating at distinctly low field (8 7.95) as compared to the other four ortho protons and the remaining peripheral ones (all at 8 7.46 to 7.50). Similar behavior has been found for the room-temperature spectra of tetrachloro- (151), tetraamino- (129), tetra(thiomethyl)- (130), tetramethyl- (131), tetracyano- (132), and tetrakis(trifluoroacetyl)fenestrindane (135). As a borderline case, the spectrum of the tetraazido derivative 128 is close to coalescence at 30 ~ The origin of the deshielding effect on four of the ortho protons in static fenestrindanes is evident from Figure 3, which displays the 1H NMR spectra of the tetraalcohol 126 and tetrachloride 151. In each of the S4-symmetrical conformers, either the protons at positions C-1, C-5, C-9 and C-13, or those at positions C-4, C-8, C- 12 and C- 16, lie almost exactly in the plane of the respective adjacent benzo ring, the magnetic anisotopy of which gives rise to the low-field shift. In contrast, each of the ortho protons within the complementary set is hardly affected since it is oriented in an inclined position relative to the adjacent benzo nucleus. In the case
H H
CH 3 H
H,
CH a
H
CH 3
2a
!47 45.3
kcal
(by AM~,
mol -I
re f.
77
!48
(by MM2PI,
H BP
Br"
Br
H
BP 14g
150 =
2.7
(by MM2PI,
kcal ref.
Chart T 4.
-Br" BP
AEstraln = 2 3 . 6
H H
Br"
H
8)
aEstrain
Br"
!
HaC-
H
aEstraln :
H
!
mol -i iO)
k c a I mo I -I ref.
~0}
r--I
G)
L_._
127
1
j
o I~
E
r~
n~
X
2
t-
-D >,, I--
!
..Q
m m
O
U
O
O
~-.c_
O t'~ v
~
O -O
r
u
..D n,,' ,,D
_Q
Z~ "1-"-. ,-.
128
DIETMAR KUCK
of the two equivalent interconverting S4 conformers of 126, the deshielding effect on the time-averaged ortho-H resonance is much less pronounced in the resulting AA'BB' spectrum. In the apparently static equilibrium of 151, a distinct four-proton doublet persists at 5 7.88, even at 130 ~ The barrier toward interconversion of the two S4 conformers of 151 and 125 has been estimated to be > 24 kcal tool -l. The case of tetraaminofenestrindane 129 deserves special attention since one would expect a behavior similar to that found for the tetraalcohol 126. Although the difference of the chemical shifts of the two sets of ortho protons is similar ( 0.50 ppm), the tetraamine shows an apparently static behavior, in contrast to the tetraalcohol. Whereas the 13C NMR spectrum of 126 is just as simple as that of fenestrindane 6 [five lines at t5 145.5 (s), 129.7 (t), 124.0 (t), 90.3 (s, C-OH), and 78.4 (CCe"t"~ the spectrum of 129 exhibits two sets of resonances for the benzo carbons, as illustrated in Figure 4. The peripheral carbons are almost isochronous CHCI 3
.,~Nin'N,.w",,. - . ~
I
150
9v
I
,Sv
..~, ~,,,,,~
I
I
I
110
I
I
I
I
70
(~ [ppm]
Figure 4. 13C NMR spectrum (7.5.4 MHz, 30 ~ 4b,8b, l 2b, l 6b-tetraaminofenestrindane 129.114
CDCI3) of all-c/s-
BenzoannelatedFenestranes
129
(8 128.60 and 128.55) and the neopentane carbon nuclei resonate at 81.8 (s, C cent'~ and 72.8 (s, C-NH2). If we speculate that hydrogen bridging affects the overall conformational flexibility in both compounds, the two pairs of syn-1,3 oriented amino groups cause some additional bonding across the fenestrane framework, possibly due to the bidentate character of the amino group. To verify this, the corresponding monodentate tetrakis(methylamino)fenestrindane, as well as the tetrakis(dimethylamino) analogue, are required. However, attempts to carry out a four-fold solvolysis of 125 in methyl amines and in ammonia (Scheme 22) have failed. In contrast to 126,127, and related fenestrindanes, the tetramethyl derivative 131 represents a borderline case. The 300 MHz 1H NMR spectrum suggests a coalescence temperature not far above 130 ~ The 13C NMR spectrum of 131 is similar to that of 129, with a slightly enhanced chemical shift difference for the peripheral protons (A~5 = 0.40 ppm). Temperature-dependent line broadening of these resonances was used to estimate the kinetic parameters of the interconversion $4-131 -~ $4-131, and gave AG~298= 16.5 (_ 2.5) kcal mo1-1, AH~t= 11.7 (_ 2.5) kcal mo1-1 and AS~ = -16.7 (_+2.5) cal mol-lK -1. The significantly negative activation entropy suggests that the activated complex for interconversion in tetramethylfenestrindane 131 may, in fact, be highly ordered and thus have DEd symmetry. A systematic study of the dynamic behavior of the various four-fold bridgehead-substituted fenestrindanes is being planned.
7.3.2. Consequencesof Conformation and Symmetry Controlling the conformational behavior of fenestranes is not only of theoretical interest, but also important in terms of identification of fenestranes bearing only two bridgehead substituents or a mix of substituents. As an illustration, two examples will be discussed. One example concerns the distinction of the anti-1,3substituted dibromide 141 and the corresponding diol 144 from the respective syn-1,3 isomers 142 and 145 (cf. Scheme 25). The other example deals with the unusual anti-dibromo-anti-dicyanofenestrindane 152 obtained upon the conversion of tetrabromide 125 into tetracyanofenestrindane 132 (Scheme 27). We will first discuss this latter case of static behavior. Given the unequivocal elemental composition of 152 as determined by mass spectrometry, the constitutional identification of this molecule can be determined by NMR spectrometry only (Figure 5). In case that symmetry arguments are not sufficient, information on the conformational behavior may be indispensable to differentiate between 152 and its syn,syn isomer 153. Assuming first the highly unprobable case that 152 and 153 may be conformationally flexible, we expect apparent C 2 symmetry for 152 and apparent C2v symmetry for 153, so that distinction by means of NMR should be possible. By contrast, static behavior of both isomers would reduce the symmetry to C 1 for 152 and to C 2 for 153. Thus, the spectra of dynamic 152 and static 153 would reflect the same effective symmetry! The IH NMR spectrum of the product contains four downfield doublets but is too
130
DIETMAR KUCK 125 TMS-CN A1C13 CHaC1a
\
//
23%
153
152
Scheme 27.
m.
I
150
I
I
I
I
I
100 [ppm]
I
Figure 5. 13C NMR spectrum (75.4 MHz, 30 ~ bromo-8b,12b-dicyanofenestrindane 152.114
I
I
I
60
CDCI3) of all-cis-4b,8b-di-
Benzoannelated Fenestranes
131
complex for unequivocal assignment. The 13CNMR spectrum, however, is decisive (Figure 5). For example, this spectrum exhibits eight lines for the eight quaternary carbon nuclei at the indane junctions, two distinct cyano resonances, and two pairs of signals for the bridgehead carbons. Thus, the spectrum reflects the apparent C l symmetry (i.e., a lack of degeneracy), and the product has been identified as the anti,anti isomer, i.e., all-cis-4b,8b-dibromo-12b,16b-dicyanofenestrindane 152. This result is in line with the finding that both the uniformly substituted congeners 125 and 132 show static behavior, and is also in agreement with the general observation that syn-l,3-dibromo substitution at the all-cis-[5.5.5.5]fenestrane backbone is particularly unfavorable. Hence, the Lewis-acid-catalyzed exchange of bromide for cyanide in 125 obeys thermochemical intuition: While tribromocyano- and bromotricyanofenestrindane were formed as well, 152 was the only observed product of two-fold SN1 reaction. The second example concerns the identification of the 4b,8b-dibromofenestrindane 141 and its hydrolysis product, anti-diol 144. As mentioned above, a dibromofenestrindane 141 was isolated in moderate yield by careful bromination of 6 with iodine bromide. In this example, we are uncertain a priori about the static behavior of the anti-dibromide 141 and its syn isomer 142 (cf. the close strain energies computed for 149 and 150,1~ Chart 14), although intuition based on the static behavior of tetrabromide 125 suggests static behavior and thus effective C 2 molecular symmetry for the syn dibromide 142. However, if 141 is assumed to be dynamic, its NMR spectrum should reflect apparent C 2 symmetry as well! In fact, the ~3C NMR spectrum exhibits four lines for the quaternary carbon atoms of the benzo nuclei and eight lines for the tertiary ones. From this result, the option of a dynamic syn-dibromide 142 and apparent C2~ symmetry can be ruled out. Likewise, anti-dibromide 141, existing in two equivalent static C l symmetrical conformers, can also be excluded. However, both dynamic 141 and static 142 remain as possible explanations of the experimental results. The solution to this problem (Scheme 28) was provided by hydrolysis of the dibromide under SN1 conditions (THF/H2SO 4 on silica gel, cf. 138 --~ 139, Scheme 24). The resulting diol was obtained in 52% yield and its 13C NMR spectrum reflected no increase of the apparent molecular symmetry as compared to that of the precursor dibromide. Again, four and eight lines, respectively, were found for the quaternary and tertiary arene-carbon nuclei. Since the corresponding tetraalcoho1126 is certainly conformationally flexible, both diols 144 and 145 should exhibit dynamic behavior in their NMR spectra as well. As a consequence, the spectra of the anti-diol 144 should exhibit apparent C2 symmetry and those of the syn-isomer 145 should exhibit C2v symmetry. This argument allows only one possible explanation. Partial bromination of 6 leads to the dynamic anti dibromide 141 of apparent C 2 molecular symmetry whose hydrolysis generates the related anti diol 144, likewise being dynamic and displaying apparent C2 molecular symmetry. The stringency of this argumentation has been a clue in unravelling the course of the
t ~'-
"
.
II
9 9
ro
.
E
~,
4J
9
9 9
Q.G
Qi
EE
E
. ~J
iV
<~
"Zx
m
\~"'
"0
l=l.
~ : ' : ~ ' ~1
m
LI
~-
nl ~9
>,
0
in
-r
m
I--
m
~
~"
-
<~
" ~'L'~
'-_2 9
\.
~ E
121.11i
.
ill
f..
~-
' "'
f~'
"'-_2 132
"~
.7."
Benzoannelated Fenestranes
133
oxyfunctionalization of fenestrindane 6 by oxygen insertion with methyl(trifluoromethyl)dioxirane 135 (Scheme 25). ll8
7.3.3. The Solid State: "Flattening" of the Central Carbon Atom The facile availability of bridgehead-substituted fenestrindanes has enabled us to study the molecular structure of some congeners by single crystal X-ray diffraction. Apart from the parent hydrocarbon 6, the solid-state conformation of which has been discussed above with particular attention to torsion effects, we will now present the molecular structures of the tetrabromo and the tetramethyl derivative, 125 and 131. TM These data give experimental insight into both the conformational distortion and the flattening effect caused by bridgehead substitution. The molecular structure of tetrabromofenestrindane 125 is reproduced in Figure 6. It clearly corroborates the expectation that bridgehead substitution, in particular at all four bridgehead positions, both increases the torsion of the fenestrane skeleton and the size of the unbridged C--C-C bond angles (cz, cz') at the neopentane core. Tetramethylfenestrindane 131 exhibits similar conformational features. The characteristic bond distances and bond angles for 6, 125 and 131 are collected in Table 1. The corresponding torsion angles (~, ~, ~t) and interatomic distances between the bridgehead substituents are given in Table 2.
Figure 6. X-ray molecular structure of all-cis-4b,8b,12b,16b-tetrabromofenestrindane 125121 (see Tables I and 2).
134
DIETMAR KUCK
Table 1. Selected Bond Distances and Bond Angles of Fenestrindanes 6,
125, and 131
Compound 6 (X = H)
Central bonds d lAP C(4b)-C(16d) 1.549 (+ 0.004)
125 (X = Br)
1.566(____.0.009)
131 (X = CH 3)
1.576 (_+ 0.003)
Note:
Lateral bonds d [,~]a C4a-C4b C4b-C4c
Unbridged bond angle (z [~ C4b-C16d-C12b
C4b-C16d-C8b
116.5 (+ 0.2)
106.1 (+ 0.2)
121.4 (_+0.5)
103.9 (_+0.5)
118.6 (_+ 0.2)
105.1 (_+ 0.2)
151.1 (+ 0.004) 151.9 150.7 152.3 151.7 152.2
(-+ 0.007) (__+0.014) (__+0.014) (_+ 0.004) (+ 0.005)
Bridged bond angle
~3 [~
aLimits of experimental error.
Introduction of four large substituents at the pairwise syn- 1,3 oriented bridgehead positions of 6 gives rise to both flattening and additional torsion of the fenestrane framework. First, a slight elongation of the neopentane C--C bonds (by approximately 2 pm) was found as compared to 6, which may be a direct consequence of the strong repulsion within the pairs of substituents. In fact, the experimental interatomic Br .... Br distance (3.47/~) in 125 is in good agreement with the value calculated for !48 by Cook et al. ~~and shows that the substituent atoms are closer than the van der Waals contact. This observation holds similarly for tetramethylfenestrindane 131. The increase of torsion of the fenestrane framework caused by the presence of four bromines or methyl groups is very pronounced, but much less than predicted. In both 125 and 131, the torsion angles ~ involving the substituents exceed those of 6 by approximately 15 ~ and the intra-ring torsion along the neopentane bonds (cf. X and ~) is increased by approximately 11 o in 125 and by approximately 8 ~ in
Table 2. Selected Torsion Angles and Interatomic Distances of
Fenestrindanes 6, 125, and 131
Compound 6 (X = H) 125 (X = Br) 131 (X = C H 3)
Torsion angles Torsionangles Torsionangles $ [~ Z [~ u176 e.g., C4b-C16d- e.g., C4b-C16d- e.g., C4b-C16bC12b-X C12b-C12a CI 2b-Cl 2c 20.3 (+ 0.5) a 34.4 b 35.6 b
21.1 (__.I.0)a 32.6 b 28.1 b
Notes: a Limits indicate variations between the four angles.
19.6 (+ 0.9) a
30.7 b 28.0 b
b No variation limits given due to symmetry transformation.
Interatomic distances d [A] X(4b)-X(8b) m 3.47 3.24
Benzoannelated Fenestranes
135
131. Figure 6 gives a view perpendicular to the S4 axis of 125 such that the enormous deviation of the C-Br bonds from the synperiplanar orientation at the fenestrane core is obvious. The unbridged C--C--C bond angles of 6 (a = a ' = 116.5 ~ are also significantly increased. Four-fold methyl substitution in 131 leads to a slight increase by 2 ~ to a = t~' = 118.6 ~ but four bromine atoms give rise to a considerable angle widening by 5 ~ to t~ = ct' = 121.4 ~ The calculated effect of four methyl groups in the saturated all-cis-[5.5.5.5]fenestranes (i.e., 2a ~ 147) was predicted to be significantly larger (about + 7.2~ 8 whereas that of four bromine atoms in the unsaturated [5.5.5.5]fenestratetraenes (i.e., 77 ~ 148) was similar (about + 4.5~ l~ to that determined for the fenestrindanes. In each case, however, the predicted absolute values were in marked disagreement with those determined for 6, 125, and 131, as verified by our molecular mechanics calculations. 122'123 The X-ray data on the two tetrasubstituted fenestrindanes 125 and 131 confirm the prediction that bridgehead substitution on the fenestrane skeleton by large atoms or groups induce some flattening of the geometry of the central tetracoordinate carbon atom. The data also confirm that the type of planoid distortion of the neopentane core in four-fold bridgehead substituted fenestranes, or in fenestra2,5,8,11-tetraenes, is purely compression deformation (Sza), and not at all twist deformation (S2b), as predicted by Luef and Keese's systematic analysis of the distortions of the six C - C - C bond angles at the central carbon atom. 8'92 In this context, we may refer to Keese's so-called "index of planarization" (Pc) as a measure of the flattening of tetracoordinated arrangements. ~24'~25 For the special case of a fenestrane having ideal S4 symmetry, this value is reducible to Pc = (ct 13)/90, with its limits at Pc = 0 for an ideal tetrahedral geometry and at Pc = 1 for a completely square planar one. The experimentally determined data in the series of fenestrindanes leads to Pc(6) = 0.115, Pc(125) = 0.194, and Pc(131) = 0.150. In these formal terms, four-fold methylation of the bridgehead positions of fenestrindane 6 increases the flattening of the fenestrane framework by approximately 4%. The total flattening of tetrabromofenestrindane 125 is approximately 20% of the hypothetically possible maximum for square-planar geometry.
7.4. Bridged Benzoannelated Fenestranes Insight into fenestrane chemistry may be as beautiful as if one had a three-dimensional view through a window. More interesting are windows that allow one to look into more dimensions at the same time. In fact, the development of fenestrindane and related benzoannelated fenestranes has led to polycyclic organic compounds bearing three mutually fused fenestranes within the same molecule. Several homo- and heterocyclic congeners of this family will be discussed in the following section.
136
DIETMAR KUCK
7. 4.1. Structural Peculiarities When one or both of the open angles of a fenestrane is bridged by C 2 o r any other diatomic chain, one or two additional five-membered rings are formed, giving a centropentacyclic or a centrohexacyclic molecular arrangement such as 154 or 155, respectively (Scheme 29). Prior to the development of benzoannelated fenestranes and related centropolyindanes, very few organic centropentacyclanes were known other than heterocyclic ones such as 156.126 In contrast, the parent hydrocarbon, centropentaquinane 157, is unknown. Only a single centrohexacyclane, the socalled Simmons-Paquette molecule 158, has been described. This molecule has served as a benchmark in the search for the elusive homocyclic prototype molecule, centrohexaquinane 160 and the corresponding hexaene, centrohexaquinacene
159.127,130
Centropentacyclic and centrohexacyclic molecules are interesting for several reasons. First, introduction of an additional bridge between the bridgehead positions has a decisive effect on the geometry of the central carbon atom and increases the rigidity of the fenestrane framework. As a consequence, the two remaining bridgehead positions in 154 are more strongly locked in syn- 1,3 orientation than in comparable fenestranes. As will be shown, rigidity is most enhanced by bridges that are conformationally rigid on their own. Further, spiro annelation of two additional rings to the core of a fenestrane generates new fenestrane units inter-
H' /
k
/
K
,
X--Y ~56
154
155
XY = C ( O ) - O '157 X = CHe-CH 2
x, > ~58
(,"i') i5g
Scheme 29.
160
Benzoannelated Fenestranes
137
woven with the original one. Thus, centrohexacyclanes may be considered to be polycyclic systems containing three spiranes, or even three fenestranes fused at right angles in the three-space. Another peculiarity of centropenta- and centrohexacyclic rings concerns their molecular topology. Whereas the molecular graph of centropentacyclane 154 can be projected onto a plane without crossing of any two edges between the vertices of the graph (or bonds of the molecule), this criterion does not hold for centrohexacyclanes 155. Thus, a molecule containing a centrohexacyclic atomic arrangement is said to be topologically nonplanar.131-133 A visualization of this mathematical facet of polycyclic chemistry is shown in Scheme 30, which also demonstrates that, in turn, centropentacyclanes and all simple fenestranes are topologically planar. The planar graph 161 corresponds to the ring connectivity of pentacyclanes, whereas the nonplanar graph 162 (the so-called Kuratowski graph K5)134'135reflects the ring connectivity in centrohexacyclanes. ~36 7.4.2. Synthesis
Benzoannelated fenestranes have provided an efficient access to centropentacyclic, and, in particular, centrohexacyclic organic compounds. 136 Here again, fenestrindane 6 has been the most versatile starting material, but the broken fenestrindane 9 and tribenzo[5.5.5.5]fenestrane 87 may be used as well. Conversion
A
\
o
i57
16i
160
~62
Scheme 30.
c
II
K5
II
138
DIETMAR KUCK
to the respective bridgehead tetrabromides such as 125, 164, and 166 allowed us to incorporate two additional benzo nuclei in one step by Lewis-acid-catalyzed reaction with benzene (Scheme 31). This condensation reaction is remarkably efficient. Apparently, no fragmentation occurs due to the intrinsic stability of the polycyclic framework of the fenestranes. Thus, centrohexaindane 16366'11 and centropentaindane 165123'137 were isolated in excellent yields. The yield of pentabenzocentrohexaquinane 167113'128 was only moderate, possibly due to side reactions of intermediates induced by 1,2-elimination of 166, which are excluded in 125 and 164. In turn, centropentaindane 165 undergoes two-fold bromination of the remaining two bridgehead positions giving the dibromide 168 (Scheme 32). 66'123'137 With regard to the increased steric repulsion between the two bromine atoms (see below), this conversion is surprising, and the sensitivity of 168 to air and moisture, unlike 125, has been traced to this structural peculiarity. Nevertheless, 168 was converted
AIBr a
benzene,
,,~
&
80% 125
//-'"\ ~
163
AIBr3 benzene, 25~ BP
" Br
C
~
~
88% from 7 165
164
benzene/A ib
44%
from 88
166
167
Scheme 31.
Benzoannelated Fenestranes
1 39
into centrohexaindane 163 by a Friedel-Crafts type condensation with benzene, in analogy to the two-fold condensations of 125 --~ 163, 164 - ) 165, and 166 --> 167. Furthermore, dibromide 168 was used as an intermediate to prepare the related dimethyl- and dihydroxycentropentaindanes 169 and 170, as well as the heterobridged centropentaindane endoperoxide 171, endodisulfide 172,123 and the corresponding lactone 173.113 Besides centrohexaindanes 163 and 171-173, several other homo- and heterocyclic topologically nonplanar "K5 molecules" were synthesized (Chart 15). 136 Tetrabromide 125 was also converted in good yield to the bis(endoperoxide) 174 and the analogous bis(endodisulfide) 175. liE Furthermore, 125 afforded access to several fenestrindanes containing heterocyclic rings larger than five-members. 113'114Thus, [5.6.5.6.5.5]centrohexacyclane 176 was obtained via tetraaminofenestrindane 131 (Scheme 22) upon attempted exhaustive N-methyl-ation. Subsequent reduction to the corresponding tetramine 177 re-established the original
165 8ra. CC14 hu.A
~
"
//
173
t68
169
:172
e
170
t71 Scheme 32.
140
DIETMAR KUCK
S4 molecular symmetry. Fenestrindane 178, containing two opposite seven-membered rings (and hence representing a [5.7.5.7.5.5]centrohexacyclane), was obtained in good yield from 125 by solvolysis in neat dimercaptoethane or by Lewis-acid-catalyzed reaction with bis(trimethylsilylthio)ethane. In line with the behavior of the nonbridged bridgehead derivatives of fenestrindane 6, some of these tetrabenzofenestranes were found to be conformationally dynamic (174), slowly interconverting (175), ll2 or static (178). 113'114 An independent access to benzoannelated fenestranes with a centrohexacyclic molecular framework should be mentioned here for the sake of completeness (Scheme 33). 66'139 In these cases, the synthesis has been based on tribenzo[3.3.3]propellanes derived from triptindane 124.14~ The key synthetic intermediate to construct the fenestrane skeleton is triptindanetrione 179,144 which is easily accessible in four steps from 1,3-indandione. Addition of three carbon nucleophiles to 179 with subsequent (either one-pot or stepwise) three-fold ring closure leads to various hetero- and homocyclic centrohexacyclanes. Thus, the last two steps of a very efficient, alternative synthesis of centrohexaindane 163 employ the addition of three equivalents of phenyllithium to 179, followed by three-fold cyclodehydration of the intermediate triol. 66'139 Also, appropriate acetylides undergo three-fold addition to triptindanetrione 179. This process is particularly striking since it can be elaborated into a one-pot procedure affording, by a series of subsequent intramolecular steps, the centrohexacyclic enolethers 180 and 182. Subsequent thermal
o
's'/__k
i74
i75
g
NR
176
IR =
C H a, IR'
177
F; =
Pl'
=
=
CHO
CH 3
Chart 15.
:178
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-~ ~
U
O
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m
~,o
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.
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rr
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142
DIETMAR KUCK
isomerization gives the homocyclic centrohexacyclanetriones 181 and 183 in good yields. Wolff-Kishner reduction of 181 furnished the first tribenzocentrohexaquinane 184.139 Owing to the initial propellane-type annelation of the three benzo rings, the centrohexaquinanes 181,183, and 184 represent rather unusual, purely carbocyclic, dibenzo-[5.5.5.5]fenestranes. In these cases, only two of the three benzo rings share the same [5.5.5.5]fenestrane core. Finally, several benzoannelated fenestranes were prepared by oxidative degradation of the benzo nuclei from some benzoannelated centrohexaquinanes (Chart 16). 138 Although this strategy is cumbersome and inefficient, it furnished some interesting benzoannelated fenestranes that otherwise would be inaccessible. Centrohexaindane 163 was converted into the corresponding 1,2-diketone 185, which exhibits particularly low-energy n ~ rt~transitions in the visible range, responsible for the beautiful deep-red color of the crystals (see below). Similar reaction of a benzo nucleus of 167 furnished mainly tribenzo[5.5.5.5]fenestranedione 186. Finally, we converted tribenzocentrohexaquinane 184 in four successive low-yield steps into dibenzo- and monobenzocentrohexaquinane, 187 and 188.134 Besides their special role as the least-benzoannelated derivatives of the still elusive parent, centrohexaquinane 160, its congeners 187 and 188 also represent the least-benzoannelated fenestranes known to date.
0
0
0
~85
\
:186
r m
187
0
i88
Chart 16.
BenzoannelatedFenestranes
143
7.4.3. Structure and Conformational Rigidity As mentioned above, the fenestrindane portion of the molecule loses its conformational flexibility by introduction of an additional C 2 bridge if that moiety is itself rigid. We expected the fifth ortho-phenylene unit in centropentaindane 165 to render the molecular framework rigid since it contains two mutually fused (tribenzo)triquinacene entities which exist in a single conformational minimum. 1~ The rigidifying effect should be even more pronounced in centrohexaindane 163, and related two-fold bridged fenestrindanes. In the following section, we will discuss the X-ray molecular structure of centropentaindane 165 and centrohexaindane 163, as well as of the bridged diketone 185 containing a rather flexible cis-t~,~3-dioxoethano bridge. Also, some remarks will be made concerning the absence of flattening effects. The X-ray structure of centropentaindane 165 (Figure 7) confirms the expectation. 123In Table 3 selected structural data on 165 are compared to the corresponding parameters of fenestrindane 688 and centrohexaindane 163.146 In contrast to 6, the framework of centropentaindane 165 is close to C2v symmetric, with a slight deviation to C 2. The nonequivalence of the unbridged and the bridged faces of the fenestrindane moiety gives rise to small differences in the pairs of neopentane bond distances and to pronounced differences in the central unbridged C--C-C bond angle (t~) and its opposite, bridged angle (og), the former being significantly
Figure 7. X-ray molecular structure of centropentaindane 165.123 Tilted view onto the unbridged face of the fenestrindane unit, symmetry is close to C2,, (see Table 3).
144
DIETMAR KUCK
Table 3. Selected Structural Parameters of Fenestrindane 6, Centropentaindane 165, and Centrohexaindane 163 Central bonds Compound
6
165
dfA]"
C(4b)-C(16d) 1.549 (+ 0.004)
1.563, 1.557 (+ 0.004)
1.552, 1.549 (+ 0.004)
163
1.536-1.555 b
(+ 0.004)
Central C-C-C bond angles
Central torsion angles X [o] unbridged angles o~ fenestrane angles 13
116.5 (+ 0.2)
/C-C-C-H
20.3 (+ 0.5) b
106.1 (+ 0.2)
/C-C-C-C
2 I. I (ae 1.0) b
ZC-C-C--C ZC-C-C-H
19.6 (+ 0.9) b -0.9, -4.5 (+ 2.0)
ZC-C-C-C
0.3, -I .5 (+ 0.3)
unbridged 118.0 (+ 0.2) angle a angle opposite 107.7 (+ 0.2) to a' fenestrane 107.7, 107.5 angles I~ (+ 0.2)
all bridged angles 13
108.2, 107.4 (+ 0.2) 109.2-109.7 b
(fenestrane) ZC-C-C-C (fifth indane) C-C-C-C
6.1,5.6 (+ 0.3)
[-1.3] to
[+1.3] a (+ 0.2)
Notes: a Limits of experimental error are given in parentheses. b Spread of individual bond lengths or angles determined.
increased as compared to 6 (ct = 118.0~ Single bridging by the fifth benzo nucleus diminishes all torsional effects close to zero along the neopentane bonds, with the exception of two orientations deviating slightly (by about 6") from synperiplanarity. With another additional benzo nucleus bridging the neopentane core of fenestrindane 6, any torsion vanishes, as do all facial differences. In spite of relatively low refinement, the resulting molecular framework of centrohexaindane 163 is almost perfectly Td symmetric. The average of the four neopentane bond distances in 163 is da~ = 1.542 /~, close to the ideal C(sp3)-C(sp 3) value. The average of the neopentane C-C-C bond angles is t~ = 109 ~ 26', close to the angle of a perfectly tetrahedrally coordinated center (109 ~ 28'). As molecular torsion and angle spreading are gradually reduced to zero in the series 6 --> 165 ~ 163, the index of planarization decreases as well: Pc(6) = 0.1150, Pc(165) = 0.0572 and Pc(163) = 0.0006 (= 0). With these three experimentally determined values at hand, it is amusing to note that the "nominal flattening" in fenestrane 6 is reduced to half by single bridging in 165 on way to the perfectly "three-dimensional" fenestrane 163. A similar, albeit not as perfect, dependence of Pc on bridging is evident from the semi-empirical calculations for the saturated,
Benzoannelated Fenestranes
145
non-benzoannelated hydrocarbons [Pc(2a) = 0.089, Pc(157) = 0.05 and Pc(160) = 0.0], reported by Luef and Keese. 92 The strict orthogonality, and thus perfect tetrahedral symmetry, of the molecular structure of centrohexaindane 163 is simply the consequence of counterbalancing forces. In contrast to 6, as well as to a suitably all-trans-perhydrogenated derivative of 163,136 the central C-C bonds have no way to rotate synergetically out of the fully eclipsed conformation. Early on, Ermer 147predicted the same effect by means of force-field calculations on the elusive parent centrohexaquinacene 159, and contrasted with the fully saturated centrohexaquinane 160. Whereas 159 was suggested to have perfect Td molecular symmetry, the latter should exist in two equivalent T symmetrical conformers. Figure 8 shows the molecular structure of centrohexaindane 163 as determined by single crystal X-ray analysis, l~ providing two views along one of the three spiro (C2v) axes and along one of the four propellane (C3v) axes. 66 The perfect mutual orientation of the various indane "wings," including the benzene rings, is clearly evident. For instance, their mean planes are strictly orthogonal within each of the 2,2'-spirobiindane subunits (cf. 7) 148 [dihedral angle P = 90.1~ (_+0.1)], and those within a Cs-diindane subunit (cf. 8) are oriented at the ideal angle [o = 120 ~ (_+0.4)]. Thus, all lower polyquinane or polyindane entities embedded in 163 are fixed in strictly eclipsed conformations, in contrast to the free congeners (cf. Figure 2). Finally, this also means that centrohexaindane 163 is the only fenestrane known having ideal molecular D20 symmetry in its conformational ground state. The counteraction of D2d- and S4-symmetrical orientation in the benzoannelated fenestranes deserves more discussion. In contrast to centrohexaindane 163, the two-fold bridging of fenestrindane 6 by the flexible O-O or S-S units in 174 and 175, respectively, allows the molecular framework to adopt the more favorable S4 symmetry. Like the unbridged four-fold bridgehead-substituted fenestrindanes, both 174 and 175 exist in two equivalent conformers that interconvert in solution. In line with the drastically different dynamic behavior of (OR) 4- and -(SR) 4substituted fenestrindanes (cf. 126 vs 130), bis(endodisulfide) 175 is clearly less flexible, and presumably more flattened, than bis(endoperoxide) 174, as suggested by DNMR spectrometry. 1~2'116It would be of interest to study the conformational behavior of the corresponding centropentaindane derivatives, endoperoxide 171 and endodisulfide 172. In fact, the tendency to increase the S4-symmetrical torsion of the fenestrane framework by bulky substituents is counterbalanced by the presence of a fifth, rigidifying ortho-phenylene bridge spanning the fenestrindane core in the centropentaindanes. As mentioned, the bridgehead dibromide 168 is a markedly more reactive than 125. According to force-field (MM+) calculations, the unbridged angle ct of centropentaindane 165 [C~exp = 118.0 ~ O~caJc= 113.8 ~ is predicted to increase by Act = + 10.7 ~ in 168. At the same time, the torsion angles including the substituents Z = / [ Br-CSb--C16d-C16b] are calculated to be increased by I A~122.5 ~. As an illustration, the space-filling model of 168 is depicted in Figure 9.
146
DIETMAR KUCK
~
4
"-.
~
!
Figure 8. X-ray molecular structure of centrohexaindane 1631~ (Td symmetry, top). The sketches illustrate views of 163 highlighting a C2v-symmetric 2,2'-spirobiindane and a D2d-symmetrical fenestrindane unit (bottom left) and a triptindane and a tribenzotriquinacene unit, both being C3v-symmetric (right, see also Table 3).
Dimethylcentropentaindane 169 was calculated to exhibit similar conformational effects. 123 1,2-diketone 185 represents still another case in which the rigidified centropentaindane backbone is bridged by an intrinsically flexible C 2 unit. 138Unlike the other diatomic bridges, however, sp 2 hydridization of the two carbonyl carbons, combined with mesomeric stabilization within the cz-diketo functionality, was expected to bring about a similar rigidifying effect as does the second bridging benzo nucleus in centrohexaindane 163. In fact, X-ray analysis of 185 revealed that all the central bond angles are close to 109.5 ~ the angle within the cyclopentanedione ring being widened only slightly (cz = 110.8~ Most significantly, however, the two carbonyl
Figure 9. Space-filling model generated by force-field calculation (MM+)of dibromocentropentaindane 168. View along the C2 axis with the bromines in front (left) and side view showing the single indane unit roofed by the dibromofenestrindane (right).
148
DIETMAR KUCK
groups exhibit an out-of-plane torsion of 7.7 ~ and the torsion about the two adjacent C-C bonds also indicate the half-chair conformation of the cyclopentanedione ring. Nevertheless, the indane unit fused to the opposite face of the fenestrindane moiety is strongly fixed, as reflected by the minute torsional effects in that part of the centrohexacyclic core. The centropentaindane backbone is sufficiently rigid to force the t~-diketone group in 185 into an almost cis-coplanar arrangement, but the intrinsic dipole-dipole repulsion in this orientation does not allow it to adopt the fully coplanar geometry. Notwithstanding this limitation, the 1,2-dicarbonyl chromophore of 185 exhibits one of the strongest bathochromic shifts within the family of alicyclic t~-diketones; its lowest energy n ~ n" transition was found at Imax = 512 and 531 nm, 138 giving rise to the illusion that fenestrane molecules bear deep red windowpanes. 8.
THE"OUTLOOK"--THROUGH
FENESTRINDANES
The chemistry of benzoannelated fenestranes has started from ideas about and insights into simple indane derivatives and the diversity of polyquinanes. In the past decade, these insights have been developed into a kaleidoscope of new aspects of fenestrane chemistry. What is the present outlook? These are many dimensions. Current interest still concentrates on the quest for organic molecules containing a planar-tetracoordinate carbon, in spite of obvious limits encountered in the small-ring fenestrane chemistry. Recently predicted planar geometries of saturated carbon within complex, truly three-dimensional organic polycycles 13-15 are, in this respect, related to the space-filling molecular networks of centropolycyclanes such as centrohexaindane 163. Beyond the aim of generating planar tetracoordinate carbon within purely organic molecules, ~6 there is a need to understand structural distortions and the chemical consequences of saturated carbon centers within a large, polycyclic molecular arrangement, such as in 189. Similar to the "evergreen" chemistry of strained olefins, ~49'15~strained organic compounds bearing a saturated carbon fenestrane
190 ~.89 Chart 17.
~.91
Benzoannelated Fenestranes X
149
X
x
X
X
X
H
x X
X
x X
:1.92
X ~93
Chart 18.
core could reveal interesting reactivity. With regard to the stabilizing effects of benzoannelation on synthetic products, as well as reactive intermediates, we claim that the potential chemistry of benzoannelated fenestranes has not yet been fully recognized. The aromatic nature of the benzoannelated fenestranes and the ease of bridgehead functionalization also opens a variety of possibilities for coupling two or several fenestrane units. Thus, the functionalization of the peripheral arene positions could lead to tentacula molecules such as 192 and 193, in which the "arms" are spread out into three-dimensional space from a multiply bent (i.e., neither planar nor globular) core (Figure 11). Long-chain substituents could be attached at the four bridgehead positions, such that fenestrindane 6 could represent the nucleus of novel three-dimensional organic networks with cavities tailored according to the lengths of the spacers between the fenestrane centers. These ideas may be extended to bridged fenestrindanes and centrohexaindane 163. The well-defined spatial orientation of fenestrindanes also offer the potential for studying proximity effects that may operate between the groups at adjacent syn1,3-oriented bridgeheads of 6. For example, why not dream of novel cyclobutadienes (195), or even tetrahedranes (196), being formed from suitably substituted fenestrindanes (194) or centropentaindanes? Why not remove the pendant bridgehead atoms or groups from appropriately substituted fenestrindanes, such as the tetrabromide 125 or the hypothetical bis(azo)-bridged derivative 197 or bis(lactone) 198, to generate fenestrindene 70 (Chart 8)? 2'3'151-153 Maybe we will eventually succeed in generating a flattened carbon atom embedded in a large polycyclic carbon network such as 199 (Chart 20). Should the restriction to two-dimensional molecules impose too much strain, we always may revert to three dimensions. There are still beautiful, low-strain molecules such as the benzoannelated fenestrane 200 waiting to be synthesized.
150
DIETMAR KUCK
/
<_
k .,.~Z \
&
R/C~C\ R 195
194
~ \ pJ',
\_/d
\
R*"C--9 C~:I 197
~.96
198
X-X = N=N X-X = C[O)-O
Chart 19.
199
200
Chart 20.
Benzoannelated Fenestranes
I 51
9. CONCLUSION Fenestranes belong to the never-fading family of theoretically interesting molecules. Benzoannelation makes them in some ways more practical. This article has summarized the origin, development, and diversity of the chemistry of benzoannelated fenestranes. It may be regarded as an intermediate report since, owing to the interplay of alicyclic and aromatic chemistry, a large part of the work remains to be done. As a final word to this conclusion, the author would be happy to learn if any reader, having reached this point, joins him in considering benzoannelated fenestranes as "interesting."
ACKNOWLEDGMENTS I would like to thank all my students who have contributed with their own enthusiasm, experimental skill, and inspiration to the development of the chemistry of benzoannelated fenestranes. In particular, Dr. Andreas Schuster, Dr. Monika Seifert, Dr. Ralph Krause, Dr. Detlef Gestmann, and Mr. Bj0rn BredenkOtter have dedicated a great part of their doctoral theses to the topic of this chapter. The collaboration with several colleagues who contributed the X-ray structure determinations of various benzoannelated fenestranes has been much appreciated, in particular the contributions by Dr. Hartmut BOgge (Bielefeld), Professor Siegfried Pohl* (Oldenburg), and Dr. Hans Pritzkow (Heidelberg). I am grateful to the Deutsche Forschungsgemeinschaft (DFG, Bonn) and the Fonds der Chemischen Industrie (FCI, Frankfurt a. M.) for generous financial support. Finally, I would like to thank Professor Randy Thummel for his kind, patient, and helpful editorial work.
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152
DIETMAR KUCK
15. McGrath, P.; Nobes, R.H.; Radom, L. Angew. Chem. Int. Eel. Engl. 1994, 33, 1667. 16. For a review on organometallic compounds containing planar tetracoordinated carbon: Rttttger, D.; Erker, G. Angew. Cheat Int. Ed. Engl. 1997, 36, 812, and literature cited therein. 17. Rao, V.B.; Wolff, S.; Agosta, W.C.J. Chem. Soc., Chem. Commun. 1984, 293. 18. Rao, V.B.; George, C.E; Wolff, S.; Agosta, W.C.J. Am. Chem. Soc. 1985, 107, 5732. 19. Wolff, S.; Venepalli, B.R.; George, C.E; Agosta, W.C.J. Am. Chem. Soc. 1988, 110, 6785. 20. Dauben, W.G.; Walker, D.M. Tetrahedron Lett. 1982, 23, 711. 21. Georgian, V.; Saltzman, M. Tetrahedron Lett. 1972, 4315. 22. Crimmins, M.T.; Mascarella, S.W.J. Am. Cheat Soc. 1986, 108, 3435. 23. Keese, R. Angew. Chem. Int. Ed. Engl. 1992, 31,344. 24. Gerber, E; Keese, R. Tetrahedron Lett. 1992, 33, 3987. 25. Grieco, EA.; Brandes, E.B.; McCann, S.; Clark, J.D.J. Org. Chem. 1989, 54, 5849. 26. Grieco, EA.; Clark, J.D.; Jagoe, C.T.J. Am. Cheat Soc. 1991, 113, 5488. 27. Keese, R.; Pfenninger, A.; Roesle, A. Helv. Chim. Acta 1979, 62, 326; Schori, H.; Patil, B.B.; Keese, R. Tetrahedron. 1981, 37, 4457. 28. Luyten, M.; Keese, R. Angew. Cheat Int. Ed. Engl. 1984, 23, 390. 29. Luyten, M.; Keese, R. Helv. Chim. Acta. 1984, 67, 2242. 30. Brunvoll, J.; Guidetti-Grept, R.; Hargittai, I.; Keese, R. Helv. Chim. Acta 1993, 76, 2838. 3 I. Gund, P.; Gund, T.M.J. Am. Chem. Soc. 1981, 103, 4458. 32. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A.K.; Cook, J. M. Tetrahedron 1993, 49, 1511. 33. Tsunoda, T.; Amaike, M.; Tambunan, U.S.E; Fujise, V.; It6, S. Tetrahedron Lett. 1987, 28, 2537. 34. Crimmins, M.T.; Gould, L.D.J. Am. Chem. Soc. 1987, 109, 6199. 35. Paquette, L.A.; Okazaki, M.E.; Caille, J.-C. J. Org. Cheat 1988, 53, 477. 36. Wender, EA.; yon Geldern, T.W.; Levine, B.H.J. Am. Chem. Soc. 1988, 110, 4858. 37. Mehta, G.; Rao, K.S.J. Org. Chem. 1988, 53, 425. 38. Desphande, M.N.; Jawdosiuk, M.; Kubiak, G.; Venkatachalam, M.; Weiss, U.; Cook, J.M.J. Am. Chem. Soc. 1985, 107, 4786. 39. Venkatachalam, M.; Desphande, M.N.; Jawdosiuk, M.; Kubiak, G.; Wehrli, S.; Cook, J.M.; Weiss, U. Tetrahedron 1986, 42, 1597. 40. Mani, J.; Keese, R. Tetrahedron 1985, 41, 5697. 41. Mani, J.; SchUttel, S.; Zhang, C.; Bigler, E; MUller,C.; Keese, R. Helv. Chim. Acta 1989, 72, 487. 42. Thommen, M.; Gerber, E; Keese, R. Chimia 1991, 45, 21. 43. van der Waals, A.; Keese, R. J. Chem. Soc., Chem. Commun. 1992, 570. 44. Kuck, D. Angew. Chem. Int. Ed. Engl. 1984, 23, 508. 45. Kuck, D. in: Hargittai, I., Ed., Quasicrystals, Networks, and Molecules of Fivefold Symmetry, VCH Publishers, New York, 1990, p 289. 46. Kuck, D. Synlett 1996, 949. 47. For previous reports on the field of polyquinanes, see: Trost, B.M. Chem. Soc. Rev. 1982, 11,141; Paquette, L.A. Top. Curr. Chem. 1979, 79, 41; Paquette, L.A. Top. Curt Chem. 1984, 119, l; Paquette, L.A.; Doherty, A.M. Polyquinane Chemistry, Synthesis and Reactions, Springer-Verlag, Berlin, 1987. 48. Leuchs, H.; Lock, L. Ber. Deutsch. Chem. Ges. 1915, 48, 1432. 49. Langer, E.; Lehner, H. Tetrahedron 1973, 29, 375. 50. Falk, H.; FrOstl, W.; Schl/Sgl, K. Monatsh. Chem. 1974, 105, 574. 51. Neudeck, H.K.; Schlt~gl, K. Chem. Bet. 1977, 110, 2624. 52. Baker, W.; McOmie, J.EW.; Parfitt, S.D.; Watkins, D.A.M.J. Chem. Soc. 1957, 4026; for a recent, most efficient synthesis of 8, see Ref. 56. 53. Laarhoven, W.H.; Lijten, EA.T.; Smits, J.M.M.J. Org. Chem. 1985, 50, 3208. 54. Mittal, R.S.D.; Sethi, S.C.; Dev, S. Tetrahedron 1973, 29, 1321.
Benzoannelated Fenestranes
153
55. Related diindanes such as [ 1,1]spirobiindanes and tetrahydroindeno[ 1,2-a]indenes (C2-diindanes) will not be considered here; see also: Kuck, D.; Eckrich, R.; TellenbrOker, J. J. Org. Chem. 1994, 59, 2511. 56. Kuck, D.; Lindenthal, T.; Schuster, A. Chem. Bet 1992, 125, 1449. 57. Kuck, D.; GrUtzmacher, H.-E Adv. Mass Spectrom. 1980, 8, 867. 58. Kuck, D. Z Naturforsch. B 1984, 39, 369. 59. Kuck, D. Chem. Bet 1994, 127, 409. 60. Kuck, D.; Neumann, E.; Schuster, A. Chem. Bet 1994, 127, 151. 61. Kuck, D.; Seifert, M. Chem. Bet 1992, 125, 1461. 62. SchOnberg, A.; Sidky, M.M. Chem. Bet 1974, 107, 2341. 63. Kuck, D., unpublished results. 64. For the Grob fragmentation of indandiols and diindandiols, see Refs. 46, 59, and 61. 65. Fecht, H. Ber. Deutsch. Chem. Ges. 1907, 40, 3883; Kuck, D., unpublished results suggesting that the identity of compound 19 in Ref. 65a is ambiguous. 66. Kuck, D.; Schuster, A.; Paisdor, B.; Gestmann, D. J. Chem. Soc., Perkin Trans. 1 1995, 721. 67. de Winter, M.L.; Nauta, W. Th. Fur J. Med. Chem., Chim. Thdr 1977, 12, 125. 68. Seifert, M. Neue Benzoannelierte Fenestrane und verwandte Polycyclen, Ph.D. dissertation, Universit~t Bielefeld, 1991. 69. Mitschka, R.; Oehldrich, J.; Takahashi, K.; Cook, J.M.; Weiss, U.; Silverton, J.V. Tetrahedron 1981, 37, 4521. 70. Keese, R.; Guidetti-Grept, R.; Herzog, B. Tetrahedron Lett. 1992, 33, 1207. 71. Kuck, D.; Schuster, A.; Fusco, C.; Fiorentino, M.; Curci, R. J. Am. Chem. Soc. 1994, 116, 2375. 72. Ten Hoeve, W. The Long and Winding Road to Planar Carbon, Proefschrift, Rijksuniversiteit te Groningen, 1979. 73. Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1980, 45, 2930. 74. Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1980, 45, 2925. 75. Rapoport, H.; Pasky, J.Z.J. Am. Chem. Soc. 1956, 78, 3788. 76. Lindner, H.J.; Eilbracht. P. Chem. Bet 1973, 106, 2268. 77. Dietrich, H.; Bladauski, D.; Grosse, M.; Roth, K.; Rewicki, D. Chem. Bet 1975, 108, 1807. 78. Schmalz, T.G.; Seitz, W.A.; Klein, D.J.; Hite, G.E. Chem. Phys. Lett. 1986, 130, 203. 79. Kroto, H.W. Nature 1987, 329, 529. 80. Hirsch, A. The Chemistry of the Fullerenes; Thieme, Stuttgart, 1994, p 25. 81. Haas, G.; Prelog, V. Helv. Chim. Acta 1969, 52, 1202. 82. Haas, G.; Hulbert, P.B.; Klyne, W.; Prelog, V.; Snatzke, G. Helv. Chim. Acta 1971, 54, 491. 83. Wiberg, K.B. Chem. Rev. 1989, 89, 975; Wiberg, K.B. Acc. Chem. Res. 1984, 17, 379. 84. Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1979, 44, 1508. 85. Shternberga, I. Ya.; Freimanis, Ya. E J. Org. Chem. USSR1968, 4, 1044. 86. Popelis, Yu. Yu.; Pestunovich, V.A.; Shternberga, I. Ya.; Freimanis, Ya. E J. Org. Chem. USSR 1972, 8, 1907. 87. Shternberga, I. Ya.; Freimanis, Ya. E Latv. PSR Zinat. Akad. Vestis, Kim. Set 1972, 207. 88. Kuck, D.; BOgge, H. J. Am. Chem. Soc. 1986, 108, 8107. 89. Kuck, D.; Barth, D.; BredenkOtter, B., to be published; see also: BredenkOtter, B.; Kuck, D. XVllth European Colloquium on Heterocyclic Chemistry, Regensburg, Germany, 1996, SH 62. 90. Seifert, M.; Kuck, D., to be published. 91. The IUPAC name of 70 is dibenzo[a,f]dibenzo[2,3:4,5]pentaleno[ 1,6-cd]pentalene. 92. Luef, W.; Keese, R. Helv. Chim. Acta 1987, 70, 543. 93. Barrett, J.W.; Linstead, R.P.J. Chem. Soc. 1936, 611. 94. Chang, S.-J.; McNally, D.; Shary-Tehrany, S.; Hickey, M.R., Sr.; Boyd, R.H.J. Am. Chem. Soc. 1970, 92, 3109. 95. Eliel, E.L.; Wilen, S.H. Stereochemistry of Organic Compounds, Wiley, New York, 1994, p 776. 96. Allinger, N.L.; Yuh, Y.H.; Lii, J.-H. J. Am. Chem. Soc. 1989, III, 8551.
154
DIETMAR KUCK
97. MM+ force-field and AM 1 calculations were performed using the software package HyperChem 4.0, Hypercube Inc., Waterloo, Ontario, 1994. 98. Cram, D.J.; Sahyun, M.R.V.; Knox, G.R.J. Am. Chem. Soc. 1962, 84, 1734. 99. Seifert, M.; Kuck, D. Tetrahedron 1996, 52, 13167. 100. Lias, S.G.; Bartmess, J.E.; Liebman, J.F.; Holmes, J.L.; Levin, R.D.; Mallard, W.G.Z Phys. Chem. Ref. Data 1988, 17, suppl. 1. 101. For related gas-phase cyclizations and rt-complexes, see: Kuck, D. Int. J. Mass Spectrom. Ion Processes 1992, 117, 441 and Refs. 97-99. 102. Kuck, D. Mass Spectrom. Rev. 1990, 9, 583. 103. Kuck, D.; Matthias, C. J. Am. Chem. Soc. 1992, 114, 1901; Matthias, C.; Kuck, D. Org. Mass Spectrom., 1993, 28, 1073; Matthias, C.; Weniger, K.; Kuck, D. Eur. Mass Spectrom. 1995,1,445. 104. Fornarini; S. Mass Spectrom. Rev. 1997, 15, 365. 105. Cited in ref. 8; see also: Hirschi, D.; Luef, W.; Gerber, P.; Keese, R. Helv. Chim. Acta 1992, 75, 1897. 106. Unpublished results cited in Refs. 5, 6, and 8. 107. Corbett, R.E.; Couldwell, C.M.; Lauren, D.R.; Weavers, R.T.J. Chem. Soc., Perkin Trans. I 1979, 1791. 108. Smits, J.M.M.; Noordijk, J.H.; Beurskens, P.T.; Laarhoven, W.H.; Lijten, EA.T.J. Cryst. Spectrosc. Res. 1986, 16, 23. 109. Kuck, D.; MUller, A.; B6gge, H., unpublished results. 110. See also: Ceccon, A.; Gambaro, A.; Manoli, E; Venzo, A.; Kuck, D.; Bitterwolf, T.E.; Ganis, P.; Valle, G. J. Chem. Soc., Perkin Trans. 2 1991, 233; Ceccon, A.; Gambaro, A.; Manoli, F.; Venzo, A.; Ganis, P.; Valle, G.; Kuck, D. Chem. Ber. 1993, 126, 2053; Bitterwolf, T. E.; Ceccon, A.; Gambaro, A.; Ganis, P.; Kuck, D.; Manoli, E; Rheingold, A.L.; Valle, G.; Venzo, A. J. Chem. Soc., Perh'n Trans. 2 199% 735. 111. Kuck, D.; Schuster, A. Angew. Chem. Int. Ed. Engl. 1988, 27, 1192. 112. Kuck, D.; Schuster, A.; Krause, R.A.J. Org. Chent 1991, 56, 3472. 113. Kuck, D.; Krause, R.A.; Gestmann, D.; Posteher, E; Schuster, A. Tetrahedron 1998, 54, in press. 114. Krause, R.A. Beitrage zurChemie der Centropolyindane, Ph.D. dissertation, Universi~t Bielefeld, 1992. 115. Kuck, D.; Schuster, A. Z Naturforsch., Teil B 1991, 46, 1223. 116. Schuster, A. Briickenkopfsubstituierte Centropolyindane, Ph.D. dissertation, UniversiOt Bielefeld, 1991. 117. Krause, R.A.; Barth, D.; Kuck, D., to be published. 118. Fusco, C.; Fiorentino, M.; Dinoi, A.; Curci, R.; Krause, R.A.; Kuck, D. J. Org. Chem. 1996, 61, 8681. 119. For evidence concerning OH group participation on epoxidation with dioxiranes, see, for example: Murray, R.W.; Singh, M.; Williams, B.L.; Moncrieff, H.M.J. Org. Chem. 1996, 61, 1830. 120. Adam, W.; Smerz, A. K. J. Org. Chem. 1996, 61, 3506. 121. Kuck, D.; Schuster, A.; Saak, W.; Pohl, S., to be published. 122. In most cases, calculated angles o~and og fell short of the values determined by experiment; see Ref. 123. 123. Kuck, D.; Schuster, A.; Gestrnann, D.; Posteher, E; Pritzkow, H. Chem. Eur. J. 199@ 2, 58. 124. The index of planarization at the central atom ofa fenestrane has been defined as Pc - (2o~+ 2og - [3-13'- 13"- 13"'), where oq denote the unbridged and 13ithe bridged C--C--C bond angles (cf. Table 1)[Ref. 125]. 125. Luef, W.; Keese, R.; BUrgi, H.-B. Helv. Chim. Acta 1987, 70, 534. 126. Keese, R.; Pfenninger, A.; Roesle, A. Helv. Chim. Acta 1979, 62, 326. 127. Simmons III, H.E.; Maggio, J.E. Tetrahedron Lett. 1981, 22,287; Simmons III, H. E. The Synthesis, Structure and Reactions of Some Theoretically Interesting Propellanes: The Synthesis of the First Topologically Non-planar Organic Molecule, Ph.D. dissertation, Harvard University, 1980.
Benzoannelated Fenestranes 128. 129. 130. 131. 132. 133. 134. 135.
136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148.
149. 150. 151. 152. 153.
155
Benner, S.A.; Maggio, J.E.; Simmons III, H.E.J. Am. Chem. Soc. 1981, 103, 1581. Paquette, L.A.; Vazeux, M. Tetrahedron Lett. 1981, 22, 291. Paquette, L.A.; Williams, R.V.; Vazeux, M.; Browne, A.R.J. Org. Chem. 1984, 49, 2194. Harary, E in: Chemical Applications of Graph Theory, Balaban, A.T. Ed., Academic Press, London, 1976, pp 5. Simon, J. in: Graph Theory and Topology in Chemistry, King, R.B.; Rouvray, D.H., Eds., Elsevier, Amsterdam, 1987, p 43. Mislow, K. Bull. Soc. Chim. Belg. 1977, 86, 595. Kuratowski, C. Fund. Math. 1930, 15, 271. For recent work on a topologically nonplanar compound corresponding to the graph/(3, 3 (and termed the Kuratowski cyclophane), see: Chen, C.-T.; Gantzel, E; Siegel, J.S.; Baldridge, K.K.; English, R. B.; Ho, D. M. Angew. Chem. Int. Ed. Engl. 1995, 34, 2657. For a recent review on centrohexacyclic (or/(5) compounds, see: Kuck, D. Liebigs Ann. 1997, I043. Kuck, D.; Schuster, A.; Gestmann, D. J. Chem. Soc., Chem. Commun. 1994, 609. Gestmann, D.; Pritzkow, H.; Kuck, D. Liebigs Ann. 1996, 1349. Kuck, D.; Paisdor, B.; Gestmann, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 1251. Thompson, H.W. Tetrahedron Lett. 1966, 6489. Thompson, H.W.J. Org. Chem. 1968, 33, 621. Kuck, D.; Paisdor, B.; GriJtzmacher, H.-E Chem. Ber. 1987, 120, 589. Paisdor, B.; Griltzmacher, H.-E; Kuck, D. Chem. Ber. 1988, 121, 1307. Paisdor, B.; Kuck, D. J. Org. Chem. 1991, 56, 4753. X-ray structural analysis of triquinacene: Stevens, E.D.; Kramer, J.D.; Paquette, L.A.J. Org. Chem. 1976, 41, 2266. Kuck, D.; B6gge, H.; Neumann, B.; Pritzkow, H., unpublished results. The X-ray analysis of 163 has not yet been refined to R < 0.07 due to the tendency of the crystals to include solvent molecules. Ermer, O.Aspekte von KraftfeMrechnungen, Wolfgang-Baur-Verlag, Mianchen, 198 l, pp 393-426. 2,2'-Spirobiindane 7 is known to be conformationally flexible and exists in four equivalent conformers of C l molecular symmetry. To the best of our knowledge, no X-ray structure analysis has been published of 7. For the X-ray structure of a dimethyl derivative of 7, see: Lemmen, E; Ugi, I. Chem. Scr 1987, 27, 297. Borden, W.T. Chem. Rev. 1989, 89, 1095. Borden, W.T. Synlett 1996, 711. Chadrasekhar, J.; Wilrthwein, E.U.; Schleyer, Ev.R. Tetrahedron 1981, 37, 921. WUrthwein, E.-U.; Chadrasekhar, J.; Jemmis, E.D.; Schleyer, Ev.R. Tetrahedron Lett. 1981, 22, 843. B6hm, M. C.; Gleiter, R.; Schang, E Tetrahedron Lett. 1979, 20, 2575
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SEMIBULLVALENES BOVINES?
HOMOAROMATIC
Richard Vaughan Williams 1.
Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Prologue
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.
Bovine Research
2.
The C o p e R e a r r a n g e m e n t
3.
Homoaromaticity
4.
5.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Aromaticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Homoaromaticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Neutral H o m o a r o m a t i c i t y : S o m e Recent A d v a n c e s . . . . . . . . . . . B o v i n e s II: S e m i b u l l v a l e n e s . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.
Theoretical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
General Synthetic M e t h o d o l o g i e s
. . . . . . . . . . . . . . . . . . . .
4.3. The Quest for H o m o a r o m a t i c S e m i b u l l v a l e n e s . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Advances in Theoretically Interesting Molecules, Volume 4, pages 157-201 Copyright 9 1998 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0070-1
157
158 158 160 160 163 163 164 165 168 169 173 179 195 195
158
RICHARD VAUGHAN WILLIAMS
1. INTRODUCTION 1.1. Prologue In response to the series editor's admonition: "Besides presenting your work in the larger context of organic chemistry, the article should address questions of relevance and interest; how did you get involved in this work?; why do you find it exciting?; and where do you envision it going in the future?," this chapter will be a somewhat personalized account of semibullvalene chemistry. It will not be a comprehensive review of this fascinating area, but rather a tour through the author's favorite terrain using his work as a thread to follow on this expedition. No insult is intended to authors of work that is omitted. Wherever possible, reference will be made to pertinent review articles. The author first became interested in this work while he was preparing research proposals as part of an application package for academic positions. One area of proposed research was the development of dienophilic equivalents for the DielsAlder reaction. These ideas ultimately resulted in the development of new ketene, 1 allene, 2 and acetylene 3 equivalents for the Diels-Alder reaction. The proposed acetylene equivalent was 1-benzenesulfonyl-2-trimethylsilylacetylene (1). At this time, a major emphasis of the Paquette group, where the author was a postdoctoral associate, was the synthesis of dodecahedrane, a A key step in this most ambitious endeavor was the "domino Diels-Alder reaction" (1).4 It was an obvious extension to consider 1 as an alternative dienophile in this domino Diels-Alder reaction to give the complex pentacyclic system 5. While 5 could perhaps be elaborated to the dodecahedrane nucleus in a similar fashion to 4, what immediately excited this author was the topology of 5 and its structural relationship to the semibullvalene 6. There was no thought of attempting to prepare 6 from 5, instead this doodling with theoretically interesting molecules provided the catalyst to become involved with semibullvalene chemistry.
C~Me (X~Me
C~Me
2
3
4
(1)
SiMe3
2
§
~.
s%w
S02~ 5
6
5emibullvalenes
159
Having addressed how the author became involved in semibullvalene chemistry, the more important question is why? This cannot be answered without reference to homoaromaticity 5 (vide infra), which is well-established only for cationic systems. Neutral homoaromaticity is an extremely controversial topic. Indeed, from a theoretical study of the trimerization of acetylene to give benzene, Houk et al. 6 concluded that "homoconjugative interactions between neutral closed-shell n systems are destabilizing!" and that "in the absence of skeletally imposed alkene distortions, 'homoaromatic' interactions are actually destabilizing." The degenerate Cope rearrangement (2) of semibullvalene (7) proceeds through a homoaromatic transition state 7c with an exceptionally low activation barrier. 7 It is generally accepted that the semibullvalene nucleus is the system most closely approaching the elusive goal of neutral homoaromaticity. 8
V
(2)
7a
7b
Much effort has been, and continues to be, expended in modifying 7 to arrive at a ground state neutral homoaromatic molecule. 5 With this in mind, 6 presented a most tantalizing target. Intuitively, 6 appeared to be an excellent candidate for neutral homoaromaticity. Considering the left-hand side of structure 6a, there is the very high-energy spirocyclic arrangement that also includes a four-membered ring fused to a three-membered ring. Matters are no better for the fight-hand side of 6a, in which there are two bridgehead double bonds (doubly anti-Bredt); whereas in the homoaromatic 6c these destabilizing interactions are ameliorated. These intuitive conclusions have subsequently been supported by semiempirical and ab initio calculations.
6r
6a
6b
160
RICHARD VAUGHAN WILLIAMS
1.2. Bovine Research The author's wife, who is a librarian, was attempting to explain to one of her elderly volunteers just what her husband did. She mentioned "semibullvalene," to which the volunteer responded that she did not realize that he worked with bovines! This is particularly appropriate as the University of Idaho is a Land Grant Institution and has a large College of Agriculture, replete with a University farm. The colorful nomenclature and, of course, conception of these highly strained bridged polycycles can be traced to the Doering group of the early 1960s. It is likely that most of those reading this review have heard at least one explanation for this seemingly agricultural nomenclature; 9 its official origins are enigmatically described by Doering. l~
2. THE COPE REARRANGEMENT The origins of semibullvalene systems lie in Doering's extensive studies of the Cope rearrangement, 11 which have been summarized in a nice overview by Doering. 12 His initial work, aimed at delineating the mechanism of this rearrangement, established the preference for a chair-like conformation for the reaction. 13 Later studies were directed towards lowering the activation barrier of the Cope rearrangement. Reasoning that release of ring strain in the 3,4-cyclopropyl fused 1,5-hexadiene should facilitate the Cope process, Vogel14and Doering 15demonstrated that the activation enthalpy fell dramatically in going from the parent diene (AH~ = 33.4 kcal/mol) to the cis-cyclopropyl fused diene (AH~ = 19.4 kcal/mol). Obviously, for the concerted rearrangement, a c/s-ring fusion is required and the rearrangement must proceed through the disfavored boat-like conformation. Progressing along this logical pathway, the conformational mobility of the olefinic termini was reduced by successive methylene bridging to yield the fluxional molecules homotropilidine (8) (AH~ = 12.0 kcal/mol) and barbaralane (9) (AH~ = 8.2 kcal/mol), l~ 15
AH'4:--19|4
8a
AH:~=I2.0
~...~
~-~.2
~
8b
9b
5emibullvalenes
161
Out of this work came the marvelous prediction that the hypothetical molecule bullvalene (10) would be fluxional and undergo a series of degenerate Cope rearrangements, which would result in the equivalence of all of the hydrogen (and carbon) atoms. 15 Shortly following Doering's most exciting prediction, bullvalene was prepared by Schr6der. 16The single resonance in the fast-exchange proton NMR spectrum of 10 confirmed Doering's prediction. After another surprisingly short time, calfene (for an immature bullvalene9), better known as semibullvalene (7), was born in the laboratory of Zimmerman. 17
10
11
It was a surprise, at the time, that the Cope rearrangement of barbaralone (11) was more rapid than that of bullvalene. 18 Later Doering demonstrated that barbaralane (9) and a selection of its derivatives underwent the Cope rearrangement at a similar rate to barbaralone and more rapidly than bullvalene, i~ The Cope rearrangement in semibullvalene is extremely facile and even more rapid than that in the barbaralanes (vide infra). 17 Progress in the investigation of these and related systems has been summarized in several review articles. 19 The Cope rearrangement remains of considerable interest today. Despite extensive experimental 2~ and theoretical 22 work, the detailed mechanism of this ubiquitous rearrangement is surrounded by controversy. Is the reaction truly concerted? Is the intermediate/transition state an aromatic (homoaromatic) species or is it radicaloid? There are three limiting mechanistic possibilities (Scheme 1): The rearrangement is not concerted and proceeds through two allyl radicals (path 1); the rearrangement is concerted and proceeds through an aromatic transition state (path 2); and the rearrangement is not concerted or is concerted asynchronous and
Path 1
// Scheme I.
162
RICHARD VAUGHAN WILLIAMS
proceeds through a biradicaloid intermediate/transition state (path 3). 12'13'20-29 The nature of the intermediate/transition state depends upon the distance (r) between the two allylic fragments. The two radicals, path 1, represented by a very long r and the biradicaloid; path 3, by a short r with the aromatic species; path 2, intermediate between the two extremes. The extreme difficulty of experimentally probing such a problem as this has led to somewhat inconclusive results. Extensive thermodynamic, kinetic (including isotope effects), and substituent-effect studies have been carded out and are nicely summarized by Gajewski 2~ and Doering et al. 21 Doering first raised the possibility of a stepwise mechanism with a diradical intermediate (path 3) based on thermodynamic arguments. 2s Dewar supported this mechanism with his experimental results on phenyl substituted 1,5-hexadienes 29 and his theoretical studies on the parent diene. 3~Later, when a more accurate value for the enthalpy of formation for the isopropyl radical became available, Doering revised his earlier suggestion and concluded that the parent 1,5-hexadiene undergoes the Cope rearrangement in a concerted fashion. El However, he deduced, in agreement with Dewar, 29 that the Cope rearrangement of 2,5-diphenyl-l,5-hexadiene follows a diradical mechanism. 21 Gajewski proposed a mechanistic continuum between the diradical and concerted pathways, with the exact route depending on the nature of the 1,5-diene undergoing the Cope process. 2~ Early semiempirical calculations predicted a stepwise mechanism going through a biradicaloid intermediate (path 3), 30 while ab initio studies, of slightly later vintage, supported a concerted process with an aromatic transition state (path 2). 31 More recent work, at the ab initio level of theory, predicted two possible pathways with very similar energy requirements. One, a concerted path with an aromatic transition state (path 2) and the other stepwise passing through a biradicaloid intermediate (path 3). 32 Initially, these results appeared to be in concert with those obtained by Dewar et al. using the AM 1 semi-empirical method. 33 However, upon reinvestigation of this system, again using the AM1 method, Dewar and Jie concluded that there was only a single biradicaloid pathway. 23c The current stateof-the-art large-basis set highly correlated ab initio calculations all agree that in the parent 1,5-hexadiene there is a single concerted mechanism with an aromatic transition state (path 2). 23a'b'24'25'27 Similarly, the results from calculations using density functional theory are in agreement with this conclusion. 25'26 Schleyer confirmed the aromatic character of the single transition state for the parent 1,5-hexadiene by means of magnetic susceptibility exaltation and anisotropy calculations. 25 In conclusion, it would appear that the Cope rearrangement follows the "allowed" (Woodward-Hoffmann 34) concerted process (path 2) unless there is significant perturbation of the rearranging 1,5-diene to stabilize a 2,5-biradicaloid intermediate/transition state. In cases where the 2,5-biradicaloid is strongly stabilized, the reaction path probably moves towards the diradical mechanism much as suggested by Gajewski. 2~
163
Semibullvalenes
3.
HOMOAROMATICITY
3.1. Aromaticity In this account only a brief overview of homoaromaticity and some recent advances in the area of neutral homoaromaticity will be presented as, in addition to many other in-depth reviews on this topic, 5 there is a recent review by this author on homoaromaticity. 5r The concept of homoaromaticity was advanced four decades ago 35 and continues to be a topic of intense interest: It is impossible to discuss homoaromaticity without first considering aromaticity. Although aromaticity is a well-known and a widely studied and recognized phenomenon, it defies a universally applicable or acceptable definition. 36'37 Classically, aromaticity is attributed to the complete cyclic delocalization of (4n + 2)r~-electrons. This view has recently been challenged by the suggestion that the a framework in benzene perhaps enforces the bond equalized hexagonal geometry. 38 Usually aromaticity is considered in terms of thermodynamics. An aromatic molecule possesses a "special stability" resulting from its aromaticity (cyclic delocalization of n-electrons), relative to an "appropriate model compound" (non-aromatic). This special stability is usually expressed as resonance energy. 5d'39'4~Unfortunately, no direct experimental determination of resonance energy is possible. In general, the different "appropriate model compounds" proposed are hypothetical molecules and their thermodynamic properties are estimated from group additivity relationships: d'39'4~ The perfect model compound for benzene (12) would be the hypothetical non-aromatic hexagonal 13 and the resonance energy would be the difference in energy between 12 and 13. However, 13 is not an appropriate model compound, as it is not feasible to estimate its energy. The models most commonly used for benzene are three ethylenes (Hticke141) and a hypothetical cyclic polyene consisting of three C = C double bonds, three C--C single bonds, and six C-H single bonds (Dewar42).5d'39''10'43 It is generally agreed that the use of the Dewar model, no matter what method is used to estimate the energies, leads to closer agreement with experimental scales of aromaticity. 5d'39,a~ Similarly, isodesmic and homodesmotic schemes have also been used to estimate the aromatic stabilization of a molecule.5a,5d,37,39 Despite the lack of a satisfactory definition of aromaticity, the experimental classification of a compound as aromatic is often straightforward. The most widely applied experimental criterion for aromaticity makes use of the magnetic properties
H Non-smmetic
12
13
HOckel
H Dewar
H
164
RICHARD VAUGHAN WILLIAMS
of the molecule. The large magnetic anisotropy and magnetic susceptibility exaltation of aromatics is explained by invoking an induced ring current. 5d'39'~ Garratt introduced the terminology "diatropic" and "paratropic" to clarify the classification of molecules that enjoy cyclic electron delocalization. 44 A molecule that sustains an induced diamagnetic ring current is termed diatropic and equates with a Htickel (4n + 2) "aromatic," while a molecule that sustains an induced paramagnetic ring current is paratropic and equates with a Htickel 4n "antiaromatic." Diatropicity and paratropicity are most easily detected by NMR spectroscopy, thus affording, in many cases, a simple means of deciding if a molecule is or is not aromatic. ~ Supporting the use of a molecule's magnetic properties in classifying it as aromatic, Haddon derived a relationship linking the induced ring current with resonance energy. 45a Bird 45b and Fowler and Steiner 45r have also correlated magnetic properties with aromaticity. Although NMR spectroscopy provides the most convenient experimental probe for a ring current, and hence aromaticity, the diamagnetic anisotropy and diamagnetic susceptibility exaltation can be determined and related to ring current. 4~ Schleyer rather forcefully states that"diamagnetic susceptibility exaltation is the only measurable property which is uniquely associated with aromaticity. ''37 Based on this premise, he proposed the following definition of aromaticity: "Compounds which exhibit significantly exalted diamagnetic susceptibility are aromatic. Cyclic electron delocalization also may result in bond length equalization, abnormal chemical shifts and magnetic anisotropies, as well as chemical and physical properties which reflect energetic stabilization. Those compounds with exalted paramagnetic susceptibility may be antiaromatic. ''37 Magnetic susceptibilities can be accurately calculated. These calculated results are used as predictors for, or verification of, aromaticity (homoaromaticity) in a wide variety of systems, including transition states. 25'37'47
3.2. Homoaromaticity As with aromaticity, laomoaromaticity is also predicated upon a "special stability." Homoaromaticity results if in an aromatic molecule the conjugation is interrupted in one or more places by the insertion of a saturated unit (often a sp3-hybridized carbon residue), and the resulting molecule displays the properties of aromaticity. This concept is most easily illustrated for benzene (12), the archetype aromatic molecule. Inserting a methylene group into one of benzene's conjugated linkages yields cycloheptatriene (14). Is 14 homoaromatic? If there is an energylowering through space interaction of the terminal n-bonds (14a), and if cycloheptriene displays the properties of aromaticity, then it is homoaromatic. However, if 14 does not demonstrate aromaticity (14b), then it is not homoaromatic. In fact, cycloheptatriene is a controversial candidate for homoaromaticity. Early studies were equivocal, 5r whereas more recent calculations by Williams et al. 48 do not favor homoaromaticity for 14, but those of Schleyer 49 and Cremer ~b suggest that 14 is weakly homoaromatic. In the terminology of Winstein, the homoaromatic 14a
Semibullvalenes
165
> 12
Or 14a
I 14b
15
would be named monohomobenzene as there is one interruption to the conjugation of benzene. 5j Further interruptions to the conjugation in appropriate aromatic systems would lead to a bis-, tris-, tetra-, and so on, homoaromatics, while the size and nature of the inserted saturated group (-CH2-, -CH2CH2-, -O-, etc.) is not considered in Winstein's nomenclature. 5j As already mentioned, aromaticity is a contentious field that lacks even a universally accepted definition of the phenomenon. One may, therefore, question the wisdom of trying to extend these ideas to the seemingly more tenuous concept of homoaromaticity. In justification of continued investigations in this direction, homoaromaticity is well-established in cationic systems, with numerous examples of cationic homoaromatics known. 5 The homotropylium cation (15) is probably the most widely studied of these systems. Extensive experimental (magnetic, geometric, and energetic) and theoretical investigations all strongly support the homoaromatic nature of 15. 5'5~ Anionic and (neutral) radical homoaromaticity is on less-firm ground, with no well-accepted examples of these types of compounds:
3.3. Neutral Homoaromaticity: Some Recent Advances Although neutral homoaromaticity is a hotly disputed area, it is here that this author believes lies the most excitement and potential for future development. As already discussed, Houk et al. proposed that homoconjugation in neutral systems is destabilizing, 6 and Paquette et al. suggest in an even more negative light: "Do these findings ring the death knell on the possibility of uncovering homoaromatic character in neutral systems? Our answer is decidedly in the affirmative. ''53 Despite these predictions of gloom and doom there has been tremendous recent interest and progress in the neutral homoaromaticity arena. It should be noted that recent calculations on the trimerization of acetylene, at a much higher level of theory than those of Houk et al., 6 argue for weak aromatic stabilization of the planar D3h transition state. 54 Semibullvalenes and related systems have enjoyed continuous study ever since Doering first proposed bullvalene as a unique Cope system. Frequently, one of the goals of these studies was to lower the activation barrier to
166
RICHARD VAUGHAN WILLIAMS
the Cope process, perhaps ultimately resulting in the first neutral homoaromatic. Semibullvalenes will be discussed in detail in Section 4. In 1988 Paquette et al. presented thermochemical evidence for neutral homoaromaticity in triquinacene (16). 55 Using similar techniques, Scott has suggested that permethyl [5]pericyclyne (17) is a neutral homoaromatic, 56 and Rogers asserts that 1,3,5-cycloheptatriene (14) is homoaromatic. 57 In another thermochemical study, Roth et al. support the homoaromaticity of a series of cycloheptatrienes and norcaradienes from heats of hydrogenation data and a comparison of experimental heats of formation with those calculated using force-field methods (MM2ERW). 58 Calculations by the author59 and others 47'6~do not support the claims that either triquinacene or [5]pericyclyne should be considered to be neutral homoaromatics. It is believed that the non-conjugated models and inappropriate force fields used to account for strain-energy differences in these thermochemical studies are inadequate for the reliable assignment of homoaromaticity. 5b'Sc'6~ The case of cycloheptatriene (14) is controversial (vide supra), with the body of evidence from most recent studies supporting homoaromaticity for 14. 5b Closely related to permethyl [5]pericyclyne are the [N]pericyclynes 18, [N] denoting both the number of comers and the number of sides in the particular pericyclyne, 62 the cyclic polyalkadiynes 19, 63 and the cyclic polyacetylenes 20. 64 The comers of these cyclic acetylenes are either Me2C units, as in permethyl [5]pericyclyne (17), or spirocyclopropyl systems as in the [5]pericyclyne 21. It is proposed that homoconjugation is of considerable importance in these compounds. 64'65 The cyclopropyl systems were chosen to maximize the potential for homoconjugative interactions. 5a'Sb'6406y~ The cyclopropyl group plays a pivotal role in homoaromaticity.5a'yD Similarly, the epoxide group is considered to participate in homoconjugation. The unusually slow rates of solvolysis of a series of arene oxides (e.g., 22), compared with the Me Me Me. ~
Me
\\
II
Me-
sn
Me
Me 17
19 Comers Me,C: n= I-4
cyclopropyl:
n = !-6, 8
20 Comers Me2C &
cyclopropyl
18 Comers Me2C: n = 3-6
21
Semibullvalenes
167
22
23
rates for the analogous aromatic hydrates (e.g., 23), have been rationalized by assuming considerable homoaromatic stabilization of the arene oxides. 67 The homoaromatic systems considered thus far are characterized by the interruption of cyclic conjugation by a saturated linkage. The homoaromaticity results from an energy-lowering, through-space, or through-bond (in the case of the cyclopropyl-type systems) interaction across this interruption. There is another type of homoaromaticity in which a cyclically conjugated system is perturbed by transannular homoconjugation. 5a-5c'68The bridged [ 10]annulenes 24 and 25 illustrate this second type of homoaromaticity. 68'69They are best considered as perturbed naphthalenes and perturbed azulenes, respectively, and are commonly referred to as homonaphthalene (24) and homoazulene (25). 68,69This second type of homoaromaticity has been proposed to be important in the cyclopropyl bridged fullerenes, the fulleroids, and their substituted derivatives. 69-71 Insertion of a methylene unit into the buckminsterfullerene (C60) nucleus results in a "closed" (cyclopropylbridged) system at a 6-6 ring junction (26) and an "open" (methano-bridged) system at a 6--5 ring junction (27). 7~ Comparing the results from the n-orbital axis vector (POAV) analysis 72 for the fulleroids 27a,b,c with the bridged [ 10]annulenes 24 and 25, Haddon suggests that there is considerable homoconjugation in the fulleroids and that perhaps, just like 24 and 25, they are homoaromatic. 69
7,4
25
26
28
29
27 a--CH2, b = O, c = N H
30
168
RICHARD VAUGHAN WILLIAMS
Structural, spectroscopic, and computational data indicate that there is extensive homoconjugation in the bissecododecahedradiene 28. 73 The diene 28 could certainly be considered as a prime candidate for bishomoantiaromaticity. Similarly, both the diene 28 and pagodane 29 are easily oxidized to the stable homoaromatic dication 30. 73
4.
BOVINES I1: SEMIBULLVALENES
The focus of interest in the bovines is their fluxional nature achieved through extremely facile Cope rearrangements. The activation energy required for the Cope rearrangement decreases from 1,5-hexadiene to homotropilidine to bullvalene (vide supra). This is a direct consequence of the strain-induced raising of the ground state energy and the locking of the molecule in a conformation anticipated to mimic that in the transition state. Pinching the methano bridges closer together (bullvalene barbaralane --> semibullvalene) must further increase the ring strain and intuitively lead to decreased activation barriers for the Cope .5c It is interesting to note that Dewar and Lo attribute the decrease in activation energy for the Cope along the series bullvalene ~ barbaralane ~ semibullvalene to increasing stabilization of the transition states and not increasing ring strain per se. 74 They reached this conclusion from MINDO/2 energy partitioning (into one-and two-center terms) studies. It was in the one-center terms that there was significant differences for this series. These homotropilidine analogs rearrange through a (homo)aromatic transition state with exceedingly low activation barriers. 7 Much effort continues to be expended in the search for bovines in which this activation barrier is reduced to the point where it disappears, effectively becoming negative, and resulting in a ground state neutral homoaromatic molecule. 5a~ The semibullvalene nucleus, a Cope system par excellence, has long been recognized as the most likely candidate for neutral homoaromaticity, s In a 1965 review on benzene valence isomers, Viehe briefly mentions the octavalenes, vinylogues of benzvalene, which include semibullvalene. 75 The first synthesis of semibullvalene (7), carried out by Zimmerman and Grunewald in 1966, used the acetone-sensitized photolysis of barrelene (31) to give 7.17'76 Semibullvalene was also prepared by the low-temperature acetone-sensitized photolysis of cyclooctatetraene (32), 77 and later in a "practical synthesis" by the vapor-phase photolysis of cyclooctatetraene. 78 The mechanisms of these reactions, the prototypes of the di-lt-methane rearrangement, have been thoroughly investigated. 76'77'79 As an interesting sidelight, the first synthesis of the semibullvalene nucleus probably dates to 1963. Criegee et al. investigated the thermolysis of the octamethyl-derivatives 33-35 and initially incorrectly identified the product as the bicycle 36. 80 Later they recognized that their product was actually octamethylsemibullvalene (37). 81 The NMR spectrum of semibullvalene at 60 MHz showed only three proton There was no resonances at all temperatures between -110 ~ to +117 ~
5emibullvalenes
169
31
9
,r
7
32 ~
o
Or
33
NaOF.//F.tOH 240C
r
34
37
35
7a
36
7b
change in chemical shift or integration over this temperature range. This led Zimmerman to speculate that semibullvalene might exist as the delocalized bishomobenzene 7c, with the localized species 7a and 7b as resonance contributors rather than valence tautomers linked by a Cope rearrangement. He discounted this most appealing idea on the basis of the similarity between the UV and NMR spectra of semibullvalene and the other bovines that were well-known to be fluxional systems. It was not until 1974 that Anet et al., using a 251 MHz (1H) NMR spectrometer, were able to "freeze out" the Cope process in 7 and obtain a slow-exchange-limit proton spectrum and a partially frozen 13C spectrum. 7 From these data, they determined the activation parameters for the Cope rearrangement of semibullvalene (AG ~ 5.5 kcal/mol, AH~ 4.8 kcal/mol).
4.1. Theoretical Studies Theory continues to be central to the development of semibullvalene chemistry. Soon after the first preparation of semibullvalene, Dewar and Schoeller 82 used semiempirical calculations to confirm that 7a/7b and not 7c were the ground states, and to predict the activation energy for the Cope process (Dewar and Schoeller, 2.3 kcal/mol; 82Dewar and Lo, 3.6 kcal/mol; 74 Iwamura et al., 0.6 and 18.8 kcal/mo183).
1 70
RICHARD VAUGHAN WILLIAMS
In this same paper Dewar suggests that suitable substituents might stabilize the transition state 7c relative to 7a/Tb, resulting in a bishomoaromatic ground state molecule. He also suggested that theory was the method of choice in the search for these substituents. Rapidly following this work, Dewar (using the MINDO/2 method) and Hoffmann (using extended Htickel calculations) independently predicted that substitution on the semibullvalene nucleus with electron-donating groups (D) at the 1 and 5 positions and electron-withdrawing groups (A) at the 2, 4, 6, and 8 positions would result in a decreased barrier for the Cope rearrangement and possibly even a bishomoaromatic ground state. 74'~ This prediction was eagerly embraced by synthetic chemists and has led to the synthesis of numerous "DewarHoffmann" semibullvalenes. To date, no example of a ground state homoaromatic Dewar-Hoffmann semibullvalene has been characterized. t~xt
s/~
The localized diazasemibullvalene 37a is not a minimum on the MINDO/2 potential-energy surface, g5 Instead, the delocalized homoaromatic 37b is predicted to be the ground state for this molecule. This and previous results 74's2 led Dewar to speculate that the diazasemibullvalene 38 and the dinitrile 39 might also have homoaromatic ground states, s5 In a MINDO/3 study, Dewar s6 et al. reported good agreement between their calculated structure and the gas-phase electron-diffraction geometry for 7. s7 Miller, Grohmann, and Dannenberg examined the series of semibullvalenes (7, 39--45) using the MNDO method. 88 With the availability of improved computational facilities and methods, they made the very important advance of incorporating (minimal) electron correlation in their calculations. They included a simple 2 x 2 configuration interaction (CI) involving the highest occupied (HOMO) and lowest unoccupied (LUMO) molecular orbitals for the symmetric homoaromatic species. Inclusion of the 2 x 2 CI resulted in excellent agreement between their calculated (AH* 5.7 kcal/mol) and the experimental (AH* 4.8 kcal/mol 7) activation energy for the Cope rearrangement of 7, whereas without CI the agreement was very poor. The dinitrile 39 and tetranitrile 40 were predicted to have a homoaromatic ground state with 39 0.2 kcal/mol and 40 4.7 kcal/mol more stable than the localized forms. The dinitriles 41 and 42 had localized ground states with activation barriers
37a
37b
38
39
Semibullvalenes
39
171
40
41
CN 42
43
44
45
to the Cope of 8.9 and 9.8 kcal/mol respectively. Similarly, the 1,5-diaza- 43 and 1,5-cyclopropyl annelated 44 semibullvalenes were calculated to be homoaromatic (12.4 and 9.1 kcal/mol lower in energy than the localized structures respectively) and the cyclobutyl homologue 45 to be a Cope system (AH~ 5.4 kcal/mol). Dewar and Jie used the AM1 method to reinvestigate bullvalene, barbaralane, and the semibullvalenes 7 and 37, and to study 40--42 and 46---55.89 They reported a systematic error of--15 kcal/mol in their calculated enthalpies of activation/reaction that were determined at the uncorrelated (SCF) level. This author has found that in a wide variety of situations the AM 1 method gives excellent agreement with experimental and high-order ab initio and density functional theory (DFT) geometries and energies. However, he has found that the inclusion of simple configuration interactions is absolutely essential in systems anticipated to possess extended conjugation. For example, at the SCF level the AM 1-calculated activation enthalpy for 7 is 19.7 kcal/mol, 89 whereas with 2 x 2 CI this barrier drops to 4.17 kcal/mol 9~ (experiment: 4.8 kcal/molT). Dewar and Jie reported "corrected" enthalpies of reaction, AH*, for the formation of the symmetrical species (corresponding with 7c) from the localized forms (corresponding with 7a/Tb) for the compounds above (AH* = AHcaJcu~atea- 14.9 kcal/mol). 89 Of particular interest are their predictions that a large number of these semibullvalenes will a have a negative AH*, indicating that these compounds should be homoaromatic. The apparent conclusions from this investigation are that not only n-acceptors, but also electronegative n-donors substituted at the 2,4,6,8 positions, stabilize the bishomoaromatic species and that both n-donors and acceptors at the 1,3,5,7 positions destabilize the symmetric form and retard the Cope. Dewar and Jie also considered the effect on the Cope equilibrium of monosubstitution at the 1(5) position of semibullvalene by a nitrile, methyl, or fluoro group. In each case, and in agreement with experiment for the known systems (CN, Me), they predicted a preference for substitution at the cyclopropyl (1) position. 89 Continued improvements in computer hardware and software have made it possible to carry out high-order ab initio calculations on relatively large systems such as semibullvalenes. The use of a large basis set and the inclusion of electron correlation in these calculations is imperative. 5a Correlated (MP2) calculations using a 6-31G ~ basis set and including zero-point energy (ZPE) corrections closely reproduced the experimental geometry and activation parameters for the parent semibullvalene (7) (AH Expt. ~ 4.8 kcal/mol, AH~lcd. 4.1 kcal/mol), and led Schleyer and Jiao to predict that coordination of 7 with Li § would result in a complex with
1 72
RICHARD VAUGHAN WILLIAMS
I
5
N ~ C N
3 AH*
7 4.8
37 0.1
40 -5.0
"~ N
~
F 46
47
48
-0.3
7.4
-5.9
N C " ~ ~ ' ~.,,C N N ~ C N 51 All* -2.5
~ ~
AH*
CN
41 -2.1
42
5.9
~ .J C F
"~ .~
r
N
~
F
F 49 -2.8
50 -3.3
\
M e Or " ~ " ~.to M e Me~OMe 53 -4.4 ,
52 6.6
M e O(. - ' ~ ~ ' ~s C N CN~OMe 54 -7.9
\
N ~ :.N N......,~N 55 11.0
a homoaromatic ground state. 91 Similar results using both MP2 (AH* 4.0 kcal/mol) and MP4 (AH* 6.5 kcal/mol) correlation were obtained for 7 by Cremer. 5b As well as investigating 7, Cremer also determined that 40, 52, 56, and 57 should be homoaromatic compounds. 5b In a comprehensive study, Williams, Borden, Schleyer et al. used high-order ab initio and density-functional theory to examine 7 and a range of annelated derivatives (vide infra). 92 Theory has been remarkably successful in reproducing experimental results for the known bovines. There is consequently a high degree of confidence and a long-standing synergism between theory and experiment in this area. Shortly following the first synthesis of semibullvalene and before the experimental determination of its activation parameters, theory was used to confirm the "Cope nature" of the ground state and to predict the activation energy required to reach the (homo)aromatic transition state. Of even greater importance, theory was used to predict appropriate substitutions to decrease the activation barrier to the Cope. The ultimate goal in this is to arrive at a "negative barrier," thus producing a molecule that is homoaromatic. Many semibullvalenes of the Dewar-Hoffmann type have been prepared and, in complete accord with theory, they undergo the Cope rear,O
H 2 ~ B H 2 56
57
5emibullvalenes
173
rangement with greater facility than 7. The main feature operating in the DewarHoffmann semibullvalenes is the stabilization of the homoaromatic transition state. Unfortunately, as yet no homoaromatic (ground state) semibullvalene has been characterized. Another approach to this holy grail, favored by this author, is to destabilize the localized forms to such an extent that the homoaromatic species becomes the ground state (see Section 4.3.5).
4.2. General Synthetic Methodologies There have been many methods devised for the synthesis of semibullvalenes. 93 In this section, only the most general syntheses that can be applied to a wide range of target molecules will be considered. Various thermolytic and photolytic methods for the production of the parent 7 from barrelene and cyclooctatetraene have already been discussed. 17'76-78'94 In addition, the photolysis or thermolysis of cyclooctatetraene or barrelene derivatives (e.g., 58 and 59) has led to a variety of substituted semibullvalenes. 17'76-81'93'95These routes suffer from several limitations, including the restricted availability of appropriately substituted barrelenes and cyclooctatetraenes, the often moderate yields, and the difficultly separated mixture of products. Paquette 96 and Askani 97 independently developed very similar and general syntheses of semibullvalene and its derivatives. 98 The bishomocubyl systems (diazabasketanes) 60 undergo silver-ion-catalyzed rearrangement to diazasnoutanes, which upon hydrolysis and mild oxidation yield diazasnoutenes 61. These compounds (61) are extremely labile and cannot be isolated. They lose nitrogen with great facility to give semibullvalenes. This general synthesis has been used to prepare a significant diversity of substituted semibullvalenes, including annelated systems. 8,99 Although an attractive range of specifically substituted semibullvalenes are available by this route, the laborious multistep syntheses of the diazabasketanes 60 somewhat detract from this scheme. 99 In many cases mixtures of regioisomers of diazabasketanes 60 are obtained and overall yields are only moderate. 1~176 Steric
~F3
CF3 A
~, CCF3 CF3 58
~
CN
F3 ZCF3 CF3 F3% ~ C +~ F3
F
NC
F3% + >~ Reg95e 1 : : 3 ~ ~CI::3 CF3 CF3 CN
174
RICHARD VAUGHAN WILLIAMS R'
R , ~ AgBF4 61
? ? R. R = -C- IN-C-, or R = -CO2Me, or R = -CO2Et Ph
factors may also result in the failure of the silver-ion-catalyzed rearrangement of 60. 99d There are two major schemes for the synthesis of semibullvalenes starting with the Weiss--Cook reaction. 1~ In the first of these, due to Askani, 1~ the bicyclic diketone 62 was converted to a series of substituted 1,5-dimethylsemibullvalenes 63 (Scheme 2). In later papers, Askani et al. extended the range of semibullvalenes available by this method to include the 1,5-tetramethylene-bridged compound 64,103 and in modifications, cyano-substituted semibullvalenes 65.104'105 Further developments of Askani's basic route by Paquette et al. has led to the preparation of 1(5), 3-dimethylsemibullvalene (66), 1~ various 1,5-annelated semibullvalenes 67,1~ and the bis(semibullvalene) 68.1~ Quast and his coworkers have prepared many novel semibullvalenes, such as 69,1~ 70,11~71,1~ 72, ill and 73,112 by this and modified routes. In an impressive study, they report the optimization of conditions for the Askani synthesis of using the known compounds 63a, 64 and the previously unknown 67 (n - 3) as illustrative examples. 113
1,5-dialkylsemibullvalenes
0
D
bu)
R
Ph O
O 60
0
|
-0
hu ,
~
O
o
§
a~
0
am
~ ~
:I N
175
II
II
Ig
II
II
II
II
1 76
RICHARD VAUGHAN WILLIAMS
M\
Me
Re,.~ ~ N , ~ R ~ ~ ~ ~ R 7
Rs
a, R 2 = R 6 = CN; R 4 = R 8 = H; R 3 = R 7 = OMe b, R 2 = R s = CN; R 4 = R 6 = H; R 3 = R 7 = OMe c, R 2 = R 6 = C N ; R 3 = R 4 = R 7 = R s = H
R2
R3 64
65
Me
Me 66
n=5, 6, 8, I0 67
68
In a modification of the basic route, Askani converted the diketone 62 to the rearranged dione 74 and then followed a similar procedure to that in Scheme 2 to produce the 2,6-disubstituted semibullvalene 65c. 1~ Quast et al. further developed this modified route introducing a direct synthesis 114of the dione 74 and producing
b, R 2 = R4 = Br; R 6 = R a = H c, R2 = R 6 = Br; R 4 = R a = n CN
69
NC-~ ~
C
N
70
a, R =~ah ~ , R ' = H b, R = Ph, R' = H c, R = P h , R' = Br SO2Ph
R
SO2Ph n = 3,4, 6, 10 72
73
71
5emibullvalenes
177
MeO" N
PhO2 ~'~"rLN
"OMr
a"
SO-2Ph a, R = H ; IX R= Me
CN 74
75
76
77
R a, R = P h b, R =Ph
--
78
many new 2,6-disubstituted semibullvalenes (e.g. 65e, ll5 75,116 76, lIT 77, ill and 78,112 ).
This general approach has proved to be very versatile,leading to a vast array of novel semibullvalenes. However, as described in detail by Quast, ll3 this is by no means a trivial synthesis. Several of the steps lead to mixtures, often resulting in low yields and difficulties in handling. The final isolation of the desired semibullvalene can also be problematical. The second general route to semibullvalenes, starting from the Weiss-Cook reaction, was developed by Grohmann et al. (Scheme 3). 118 They used this method to prepare a series of 1,5-substituted tetramethyl-2,4,6,8-semibullvalenetetracar-
boxylates 79.119 This route was used by Mtillen and DUll in their attempted synthesis of the bisannelated semibullvalene 80,12~and by Williams et al. in the preparation of 81.1El Williams et al. also reported some improvements to the yield and operational simplicity in the synthesis of 79a. TM Although this route is relatively short and facile, the range of substituents at the 2, 4, 6, and 8 positions is, so far, limited to carboxylic acids and their derivatives, and to alkyl substituents at the 1 and 5 positions. In another general semibullvalene synthesis proceeding through a diazasnoutene 82, Sauer and coworkers developed the ingenious one-pot sequence in Scheme 4.122 Many 1,3,5,7-substituted semibullvalenes 83 have been prepared by this route. 122-126 In addition to the general syntheses of semibullvalenes discussed above, there are several syntheses of specific target semibullvalenes. In spite of this impressive synthetic arsenal, it is still not a trivial matter to prepare a desired semibullvalene. There is a strong need to develop new alternative syntheses of these fascinating molecules.
E
79
b,n=3 r n=4 d,n=5 e, n=6
fvl
.
0
0
0
0 iI,11
~i,i,1
178
Semibullvalenes M
179 e
Me
R
~
80
81
R'
a, R = M e b, R = E t
O
Me Me
R'
~I +
~Me
|
'
I
R
I
R R 82
a, R = R' =CChMe; Ix R = R' = Ph; c, R = R ' = Me; fl, R = R ' = m - C i - ~ ; e, R' = R' = m - M e O - ~ ; g, R = R' = p-Me-C_.61-h; k R = R' = m-CF3-C61-h; l, R = Ph, R' = H
83
L R = R ' = p-MeO-Csl-h;
Scheme 4.
4.3. The Quest for Homoaromatic Semibullvalenes In this section selected properties of some non-annelated semibullvalenes will be discussed in relation to the nature of their ground states m delocalized homoaromatic or localized Cope systems. Other properties of semibullvalenes, including their chemical reactivity, 127 have been less extensively investigated, partially because of the difficulty in preparing bulk amounts of these compounds. 113 As already mentioned (Section 4), Zimmerman et al. were unable to freeze out the Cope rearrangement (2), which led them to postulate that semibullvalene (7) might be a ground state homoaromatic. 17'76However, they concluded from chemical shift and UV data that 7 was a rapidly equilibrating Cope system. It was not until eight years later that the Anet group, using a much higher-field-strength NMR spectrometer, were able to freeze out the Cope rearrangement (2) and determine the activation parameters for this process (AG ~ = 5.5 kcal/mol). 7 Before confirmation
\
CF3 37
84
85
86
87
180
RICHARD VAUGHAN WILLIAMS
of 7 as a Cope system, the substituted semibullvalenes 37 (AG * = 6.4 kcal/mol), 128 84 and 85 (synthesized by the sensitized photolysis of the corresponding barrelene), 129 86 (AG ~ = 12.0 kcal/mol), 13~ and 87 [AG ) = 8.9 (from the low energy were already established tautomer) and 8.5 (from the other tautomer) kcal/mol] as localized Cope compounds.
TM
4.3.1. Barbaralane Model Studies Following the predictions of Dewar 74 and Hoffmann 84 that substitution of the semibullvalene nucleus with electron-withdrawing groups at the 2, 4, 6, and 8 positions and electron-donating groups at the 1 and 5 positions would lead to a decrease in (or even disappearance of) the activation barrier for the Cope rearrangement, many such Dewar-Hoffmann systems have been prepared. The substituted barbaralanes serve as an excellent indicator for the effect of substituents on the Cope rearrangement of the corresponding semibullvalenes. The barbaralanes are particularly useful in this respect as their activation energy for the Cope rearrangement is significantly higher than that in the semibullvalenes. In some semibullvalenes the Cope rearrangement is so facile that the activation parameters cannot be measured (vide infra). In these cases the corresponding barbaralanes provide a qualitative ordering of semibullvalene activation energies. Validation of the Dewar-Hoffmann prediction was first achieved with the barbaralane nucleus. Quast et al. prepared 132athe 2,6-dinitrile 88 and later determined the activation energy for its Cope rearrangement (AG* = 5.78 kcal/mol cf. the parent barbaralane AG* = 7.55 kcal/mol). 132bIt should be noted that Krow and Ramey earlier provided support for the Dewar-Hoffmann hypothesis from equilibrium studies on unsymmetrical semibullvalenes. 133 Quast and his co-workers have additionally prepared a series of Dewar-Hoffmann type barbaralanes. 134 The determination of the activation parameters for these novel Cope compounds is currently underway. 135 It is interesting to note that in spite of the inductive withdrawal of the trifluoromethyl group, the activation energy for the Cope rearrangement of the barbaralane 89 is higher than that found in the parent 9.134 This result suggests that for an effective Dewar-Hoffmann system the electron withdrawal must be mediated by a rt-acceptor. Grohmann's group prepared the interesting Dewar-Hoffmann tetraester 90 and triester 91.136 They estimated the activation barrier for the Cope rearrangement of 90 to be AG* = 5.95 kcal/mol. In addition to the Dewar-Hoffmann compounds, Quast et al. also examined a range of other barbaralanes, including the 2,6-diphenyl substituted molecules 92137 and 93,138 3-mono- and 3,7-di-substituted systems 94,139 and the tetraphenyl
9
~CN
~CF3
88
89
5emibullvalenes
181
M~e" ~~"-CO~M ~ MeO2~cO2M 9O
e 91
derivative 95.14~The 3,7-disubstituted barbaralanes 94d and 94j were studied by Kessler and Ott, TM the compounds 94d, 94f, and 94g by GUnther et al., 142 and 96 by Hoffmann and Busch. 143Phenyl groups show only small inductive effects; their major influence is through conjugation and steric factors. The phenyl groups in 92 proved to be even more effective in lowering the Cope activation energy than the nitriles in 88 (for 92 AG: = 5.16 kcal/mol). 137aWhile appropriate substituents at the 2,4,6, and 8 positions tend to facilitate the Cope process, any substituent at the 3,7 positions appears to retard it. ~41'~42Table I presents a summary of the activation energies found in the barbaralane series. Several entries in Table 1 confirm the validity of the Dewar-Hoffmann prediction, and similarly demonstrate that the phenyl group is the most effective activator of the substituents studied. Assuming that the decrease in AG: between the parent and the substituted derivative is similar for the barbaralanes and the semibullvalenes, and that the effects are additive, it is unlikely that a homoaromatic semibullvalene will result from polysubstitution, in any combination, with the substituents in Table 1.
4.3.2. Semibullvalenes The Cope activation parameters have only been determined for a few of the rapidly rearranging semibullvalenes. The Cope rearrangement in semibullvalenes is always more facile than in the corresponding barbaralanes, which often results
a, R-- H,R' = CI
Ph"
Ph~
~Ph
N ~ P h
92
c, R=H, R' = Me d,R=R'=Me e, R= R' = Cl f,R=R'=Br
CN R 94
93
PIT"~
Ph
Ph'~'v~'~
K R= R'= CO2Me i, R= R'= SO2Ph J,R=R'=Ph
a,R=H Me b, R= OMe c, R = OSiMe_~
Me""~
Ph R
Cl 95
I,~-~'-CN
96
182
RICHARD VAUGHAN WILLIAMS Table 1. Free Enthalpy of Activation for the Barbaralanes A G~ kcal/mol (temperature, K)
Structure
9.54 (298)142
Me
Structure
~ C/q
A G~ kcal/mol (temperature, K)
7.9 (298)142 7.65 (200)137a
94g
Mr Me ~~LMc3 0
9.4 (192)143
9.3 (298)142 8.25 (200)137a
Ph
~,,~
Me(:~'~/~'~'~C~
MeOz~cOzMc
7.6 (298)142 7.53 (200)137a 7.48 (158)136
5.95 (158)136
90
94j
9.2 (298)142
/ ~"~"-~CN
5.78 (200)132b
131" 94f
Me"~
88
Me 8.6 (178) '43
~ " ' ~ ~""1~
5.16 (200) '37a
0 92
Me~~
Me
8.4 (175)143
CI 96a
in unattainable coalescence temperatures and slow-exchange-limit chemical shifts, even with modem high-field NMR spectrometers. These extremely rapidly rearranging molecules have all been demonstrated, by a variety of techniques (vide infra), to be Cope (localized) and not homoaromatic (delocalized) systems. As already mentioned, the barbaralanes serve as useful models for the semibullvalenes.
5emibullvalenes
183
The qualitative agreement between AG~Est.,the estimated AG~ for the substituted semibullvalene, and the experimentally determined AGr is reasonable. AG~Est.is determined by adding or subtracting a correction factor to AGs for the parent semibullvalene (7). The correction factor is the difference in free enthalpy of activation between barbaralane (9) and the corresponding substituted barbaralane. For 1,5-dimethyl-substituted semibullvalenes, an additional correction o f - 1 kcal/mol is applied in an effort to account for the methyl substitution. In 1970, octamethylsemibullvalene (37) was the first semibullvalene to have its activation parameters measured (AG~ = 6.4 kcal/mol at 132 K). A partial slow-exchange-limit proton NMR spectrum of 37 was obtained at 122 K and 100 MHz (IH).128 Just two years later Moriarty et al. obtained the activation parameters for 86.13~ Subsequently, Paquette et al. determined the activation energy for the unsymmetrical 2,8-bridged semibullvalene 87131 and in 1974 Anet et al. obtained the same data for semibullvalene itself (AG~ = 5.5 kcal/mol at 133 K). 7 Following the validation of the Dewar-Hoffmann hypothesis in the barbaralane series (vide supra), Quast et al. demonstrated, again in agreement with the Dewar-Hoffmann hypothesis, that the activation barrier in the semibullvalene dinitrile 65c is less than in the parent 7.1~ The only other Dewar-Hoffmann system for which an estimated activation energy is reported is Grohmann's tetraester 79a. 145 The mildly electron-releasing methyl groups in 1,5-dimethylsemibullvalene 63a activate this molecule to the Cope rearrangement. 146 The Cope activation energy for 63a (AG~ - 5.0 kcal/mol) is the lowest barrier to be measured by means of dynamic NMR. 1~i GUnther et al. also determined the activation parameters for dibromide 97 and reinvestigated, using 13C dynamic NMR, the parent compound 7.146 The increased temperature range over which 7 was studied, made possible by using 13C rather than IH NMR, led to many more data points and, hence, increased accuracy. The Cope process in the 3,7-substituted semibullvalenes 63d, 126 63t",126 69a, 126 69b, 144 and 69c l~ has also been studied. The trends apparent from Table 2 nicely parallel those seen in Table 1 for the barbaralanes. Once more, for the two compounds for which activation energies have been estimated, Dewar-Hoffmann substitution leads to a reduction in activation energy compared with the unsubstituted compound. Again 3,7-substitution results in a retarding of the Cope rearrangement. Bromine substituents at the 2, 4, 6, or 8 positions also retard the Cope, as do methoxyl substituents at the 2 and 4 positions.
7
37
65c
86
87
184
RICHARD V A U G H A N WILLIAMS
Table 2. Free Enthalpy of Activation for the Semibullvalenes Structure
~oo~ 86
AG'* kcal/mol (temperature, K) IAG~Est"kcal/mol]
12.0 (273) 13~
Structure ~," ~ ~,,,-" 7
10.3 (115)T M C~
.~~[~~'/ 63f
69b 9.9 (200) 117
C~I "/6
CN
69a
6.2 (298)146 5.8 (1 73) 146 5.5 (1 23) 7
6.1 (298) 126 [6.9]
6.0 (298) 126 5.7 (115) 144 [5.5]
5.5 (298)126
9.2 (115) 144 CN
AG'* kcal/mol (temperature, K) [A G~Est"kcal/mol]
63d
69C
5.0 (298)146 4.78(173) 146
8.9 {8.53[I (187.5) 87
63a <3.8 (113) 145 [2.97]
7.4 (298)146 7.45 (173) 146
97
79a
6.4 (132) 128 37
6sc
-3.59 (115) T M 3.11 (115) flsb [2.73]
Semibullvalenes
63a
185
Ph
Ph
CN
CN
63(1
63f
69a
69b
7911
CN 69(:
97
Many of the other prepared substituted semibullvalenes are classified as undergoing extremely rapid Cope rearrangement. It can be assumed that in most cases these compounds rearrange more rapidly than the parent hydrocarbon 7 and that they have been determined to be Cope systems and not homoaromatic (vide infra). Some examples of these compounds are, 70, ll~ 72,111 73,112 77, Ill 78, ll2 79, ll9 98,147 99,1')8 100,149 and 101.15~ The effect of the trifluoromethyl group is rather difficult to assess. Compounds 8 4 , 85,129 and 10395b do not rearrange, whereas 102129 and 10495b are fluxional, but no activation parameters are reported. It can be anticipated, by analogy with the barbaralane series, that the trifluoromethyl group will tend to retard the Cope when in the 2, 4, 6, or 8 positions.
(C
NC~"
aR=Ph - - , R ' = H bR=Ph, R'=H c R= Ph, R' = Br
CN
70
R'
R'
SO2Pt a R = I-I; b R = Me
S02~ n-- 3, 4, 6, 10 72
R
73
M e O 2 ~ C O 2 M e aR=Ph bR=Ph
77
b,n=3 c,n=4 d,n=5 e,n-6
MeO2C"
"~R OR R = A c or H
78
79
98
"CO2Me
186
RICHARD VAUGHAN WILLIAMS NN%.
M
CO2Me
MeO2C"
"~R
"CO2Me
a, R = PhCO, R' = Me b, R = PhCO, R'= Et c, R= Me, R' = Me d, R= Me, R' =Et
a,R=H b,R=Me
Me02
CO2Me
OR 100
99
CN
N~r,h 101
F3%
F3CN
/ c~3 F3CN
F3CN
F 3 C / ~ CF3 84
85
102
F3
CF3
CF3
CF3
103
104
4.3.3. Spectroscopic Studies The method of choice for the in-depth analysis of the Cope process in semibullvalenes is dynamic NMR. l~ However, even with modem high-field NMR spectrometers, it is not always possible to reach the coalescence temperature. In fact, with many semibullvalenes, little or no change is seen in the NMR spectrum down to the lowest temperature achievable with the most sophisticated of instruments. Therefore, other methods must be used to decide upon the nature of the ground state (localized Cope or delocalized homoaromatic) of a particular semibullvalene. 4.3.3.1. Other NMR Methods. The Saunders' Isotopic Perturbation Method: 151 The equilibria between degenerate molecules can be probed using solution phase NMR by making very small structural changes that only slightly perturb the relative energies of the equilibrating species (e.g., isotopic substitution of selected hydrogens by deuterium). Now that the species are no longer degenerate they will not be equally populated and the population distribution will vary with temperature. The observed chemical shift of nuclei that are rapidly exchanging environments is the population weighted average of the individual chemical shifts in the "frozen" structure. For degenerate systems, where the populations are equal, the observed fast-exchange chemical shifts are the direct averages of the chemical
187
Semibullvalenes
shifts of the exchanging nuclei. To use the Saunders' isotopic perturbation method, the degeneracy of the potential semibullvalene tautomers must be lifted and the NMR spectrum recorded at different temperatures. If the semibullvalene has a localized Cope ground state, then the population of the tautomers will vary with temperature and the average chemical shift for each exchange equivalent nucleus will track with the temperature variations. If the semibullvalene has a delocalized homoaromatic ground state, then there is a single minimum potential energy surface with only one, delocalized, structure and no change will be seen in the NMR spectrum as the temperature is varied. Askani et al. used this method to study the Cope equilibrium in the 1,5-dimethylsemibullvalenes 63a and 79a. 152 The deuterated analogs 105, 106, and 107 were prepared and their 13C NMR spectra were recorded using, as appropriate, 63a or 79a as internal standards to account for the inherent dependence of chemical shift on temperature. In each case there was an equilibrium driven variation of chemical shift with temperature demonstrating that 105,106, and 107 (and consequently 63a and 79a) are not homoaromatic. In a modification of the Saunders' isotopic perturbation method, Gompper and his group prepared the unsymmetrical semibullvalenes 99b and 99d. 148 They assumed, while replacing one methyl group in 99a and 99c with an ethyl group, that similarly to isotopic substitution, the degeneracy would be lifted with only mild perturbation to the overall system. In the variable-temperature NMR spectra of these compounds, the chemical shifts were shown to be temperature-dependent, reflecting population changes in the non-degenerate species. Variable Temperature 13C Solid State NMR Spectroscopy: In one solid form of semibullvalene (7) Yannoni et al. demonstrated, using variable temperature solids 13C CP-MAS (cross-polarization magic angle spinning) NMR spectroscopy, that in the solid state 7 still underwent a rapid Cope rearrangement. 153However, in this
63a
79a
105
Me\
106
:e
105a
no longer degenerate
107
e
105b
188
RICHARD VAUGHAN WILLIAMS
M~C"
"~R
~'C02Me
a, R = P t ~ O , R' = Me b, R = P t ~ O , R' = E t c, R = M e , R' = Me dl, R = Me, R' = Et
OR 99
Me
65c
case the rearrangement was no longer degenerate. The lifting of the degeneracy of 7a and 7b is entirely a result of the crystalline environment. Once again, as with the Saunders' technique, this lifting of the degeneracy leads to a tracking of chemical shift with temperature (along with other changes), and clearly indicates that 7 is not homoaromatic. The dinitrile 65c has a crystalline modification (the "ffform") that upon X-ray structure determination displays apparent C 2 symmetry. 154 The usual conclusion from this observation would be that 65c is homoaromatic! However, the variable-temperature solids 13C CP-MAS studies revealed that 65c is in dynamic equilibrium with its non-degenerate tautomer through the usual Cope rearrangement. At ambient temperature there is accidental degeneracy of the tautomers of 65c that results in the apparent C 2 symmetry at this temperature. Again, it is shown that the 13-form of 65c is not homoaromatic.
4.3.3.2. Infrared Spectroscopy. Due to the very different time-scales for the NMR and IR experiments, it is possible to distinguish between localized Cope and delocalized homoaromatic semibullvalenes for much more rapid processes using IR (rather than NMR). In many of their extremely rapidly rearranging semibullvalenes and barbaralanes, Quast et al. have used IR to designate the molecule as a Cope system even though dynamic NMR may show no changes in the spectra with temperature. For example, the dinitriles 65c, 115 70, ll~ 101,15~ and 108155 each display two nitrile bands in their IR spectra, one corresponding with a vinyl cyanide and the other a cyanide bonded directly to a cyclopropyl moiety. 4.3.3.3. Ultraviolet/Visible Spectroscopy. Several semibullvalenes that lack a classical chromophore are highly colored compounds. The yellow dinitrile 65c was the first of these types of compounds to be recognized. 115'156Not only is 65c yellow, but it is also thermochromic. 156 At ambient temperature it is intensely
Semibullvalenes
189
70
101
108
yellow and at 180 K it is colorless. The yellow color was initially interpreted as an indication of the presence of a delocalized homoaromatic isomer. 156More recently, Quast et al. suggested that the long wavelength absorption, which is responsible for the color, results from a transition between a vibrationally excited level of the electronic ground state and an excited electronic state. 14~ Only the most fluxional semibullvalenes (e.g. 65c, 79,100,101) and barbaralanes are colored compounds which exhibit reversible thermochroism. 15~ Quast has correlated this phenomenon with a very flat double-minimum potential-energy surface and an exceptionally low activation barrier to the Cope rearrangement. 140a, 150
4.3.4. X-RayStudies X-ray structure determination would appear to be the ideal means to resolve the question of whether a particular semibullvalene is a localized equilibrating Cope system or a delocalized homoaromatic species. The homoaromatic species should have high symmetry with an equalization of bond/interatomic distances that would be readily apparent from the crystal structure. However, as already mentioned, the 13-form of the symmetrical dinitrile 65c, which was shown to be a Cope system by 13C CP-MAS NMR studies, displays apparent C2 symmetry. 154 At ambient temperature there is accidental degeneracy of the equilibrating and otherwise non-degenerate tautomers that results in the apparent C 2 symmetry at this temperature. 154 These results nicely explain the perplexing structural changes observed by variable temperature X-ray crystallography, in 69a where the C(2,8) distance decreases and the C(4,6) distance increases with decreasing temperature. 124As the temperature is lowered, the population of the low-energy tautomer increases and the C(2,8) and C(4,6) distances reflect this change in population. Quast et al. summarized the X-ray data for 16 semibullvalenes and proposed that the anomalous interatomic distances observed in the X-ray structures of many semibullvalenes are explained by similar Cope rearrangements between non-degenerate tautomers, l~l Thus, in the X-ray analyses of equilibrating semibullvalenes, it is to be expected that the time-averaged bond/internuclear distances will vary with temperature and parallel the increasing population of the low-energy tautomer. However, for homoaromatic species, C 2 symmetry should be maintained at all temperatures. Of course, in systems displaying such fine energy balances, crystal-packing forces may be of importance in determining the nature of the ground states. It might be anticipated
190
RICHARD VAUGHAN WILLIAMS
CN
CN 69a
that the barrier to the solid-state Cope rearrangement will be higher than, or at the least equivalent to, that in the solution phase. 153 Therefore, if the Cope rearrangement can be frozen out in the solid state, then the molecule is not homoaromatic (in the solid) and most likely will not be so in the solution or gas phases (unless the energy difference between the localized and delocalized forms is extremely small and of the same order as the crystal packing forces). However, if the Cope rearrangement cannot be frozen out, it is virtually assured that the molecule is homoaromatic under all conditions. Quast considers the sum of the C(2,8) and C(4,6) internuclear distances in semibullvalenes to be a molecular property and an indicator of the magnitude of the activation barrier for the Cope process. Ill The sum of the C(2,8) and C(4,6) internuclear distances in the more rapidly rearranging semibullvalenes (3.97 to 3.99 tl,) is significantly higher than the corresponding sum (3.85 to 3.93 A) in the less fluxional semibullvalenes. Ill Quast et al. used the estimated limiting values (for a single tautomer) of the C(2,8) and C(4,6) distances to assess the tautomeric equilibrium constant for a variety of semibullvalenes. Ill
4.3.5. Annelated Semibullvalenes There have been many studies, both by experiment and theory, on annelated semibullvalenes. In particular the effects of monoannelation across the 1,5 or 2,8 (4,6) positions have been examined. Early extended HUckel investigations by Hoffmann and Stohrer suggested that the Cope rearrangement of the bisetheno-annelated semibullvalene 109 would be strongly inhibited and that the perturbed transition state would be the strained cyclodecapentaene 110. z4 Paquette and Chamot suggested that in the bisannelated semibullvalene 111 the "breathing motion" of the Cope process would be inhibited and this would perhaps lead to a homoaromatic molecule. 99dMiller, Grohmann, and Dannenberg, using MNDO CI2
44
4S
109
II0
Ul
Semibullvalenes
191
calculations, predicted that the 1,5-cyclopropyl system 44 would be homoaromatic and that the 1,5-cyclobutyl compound 45 would be a localized Cope molecule. 88 More recently Williams and Kurtz used the MNDO and AM1 methods to investigate the bisethano semibullvalene 6. 90 As discussed in Section 1.1, intuitively 6 is an ideal candidate for homoaromaticity. These calculations fully supported intuition, predicting that the ground state is the homoaromatic 6c. Using the MNDO CI2 method, minima were located for both a localized geometry 6aJ6b (AHf = 108.245 kcal/mol) and the homoaromatic structure 6c (AHe = 98.877 kcal/mol). However with the AM 1 SCF and CI2 methods only the delocalized species 6c was found; no stable localized structure could be identified. 9~ These results led to the development of a set of discriminators for the detection of homoaromatic interactions: Negative two-center energy partitioning terms between the terminal centers completing the homoaromatic interaction and a significant decrease in the calculated heat of formation between the SCF and CI2 levels indicate a homoaromatic molecule. These discriminators were validated in calculations on systems where the importance, or lack thereof, of through-space interactions was well-established. 48 Williams and Kurtz subsequently used the same methodology to study a series of monoannelated semibullvalenes 112 and 113.157 Again there was excellent agreement with experiment, in predicting the preferred tautomer 113 or 113', for the known semibullvallenes ll3a--c. Perhaps the most interesting result from this study is the prediction that the singly ethano-annelated compound 112 is homoaromatic. Supporting the designation of 6 as a homoaromatic species, Cremer and Szabo concluded from high-order ab initio calculations (MP2 and MP4) that the delocalized 6c is 6 kcal/mol more stable than the localized classical forms 6a/6b.15s A high-order ab initio and density functional theory reinvestigation of the annelated semibullvalenes 6, 44, and 112 fully concur with the earlier semiempirical calculations finding these molecules to be homoaromatic. 92 The classification of homoaromatic in this work is made not only from geometric and energetic considerations, but also from the calculated magnetic properties of these molecules. The parent semibullvalene (7), as well as the novel annelated compounds 114 and
a,n=l b,n=2 r 6r
112
113
114
llY
115
192
RICHARD VAUGHAN WILLIAMS
<:
;%( ~ p h ~ N C " n=3, 5, 6, 8, 10
64
Ixn=3 c, n= 4 d,n=5 e,n=6
CN
67
70
SO2Ph n=3, 4, 6, 10 72
79
115, are also examined by these same high-order techniques. Bismethano 114 is concluded to be homoaromatic, while 115 is partially homoaromatic and frozen in the 2,8-annelated form; the other valence tautomer is unstable. 92 Numerous monoannelated semibullvalenes have been prepared. Unfortunately the smallest 1,5-annelation is with a five-membered ring. Compounds 64, 67, 70, 79 are all Cope systems, their activation parameters seem to depend more upon the other substituents present rather than the size of the annelating ring. There was an initial report, based on X-ray structural data, indicating that 79e was symmetrical. 159 However, the symmetry probably results from accidental degeneracy of the Cope tautomers that are undergoing rapid rearrangement in the solid state at the temperature of the X-ray determination. Paquette and his group prepared a large number of medium ring 2,8(4,6)monoannelated semibullvalenes including 87, 116, 117 and some unsaturated analogs. 16~The substitution pattern of these compounds has a profound effect upon their properties. All of these compounds are classical Cope systems and in some cases (e.g., 87) the Cope rearrangement is considerably retarded. In many of these semibullvalenes there is significant imbalance in the Cope equilibrium. With the smaller annelating tings the "anti-Bredt" destabilization dominates and the closed form l18a is favored; whereas with the larger annelating tings the additional ring strain of the closed form becomes most important and the open form llSb is preferred. Elassovalene, a potentially annelated semibullvalene, adopts the tautomeric form 119. It displays considerable homoconjugation but, from theory and experiment, is probably not homoaromatic. 8'4s'161'162 Paquette et al. also prepared the benzannelated derivatives 120 and 121. 99c
X=CH2 X=(CI~ X=O x-s x = NCH2Ph 87
116
~
X 117
X=O X - NCI-12Ph X-S X=SO2 X = SO (syn) x = SO (ann')
Semibullvalenes
193
l18a
l18b
.
~
-
~
119
120
121
Following the calculations of Williams and Kurtz that predict that 6 is homoaromatic, 9~ the Mtillen group were the first to prepare a bisannelated semibullvalene (122). 163 They demonstrated that 122 is a Cope system with an extremely low-activation barrier to the rearrangement. It is perhaps not too surprising that 122 is not homoaromatic, as the chloro substituents at the 3,7 positions of the semibullvalene 122 doubtlessly retard the Cope rearrangement (vide supra). Earlier, Vogel et al. prepared the bridged [14]annulene 123, which is isomeric with the bisannelated semibullvalene 124 (not observed). 162aMtillen and Drill attempted to prepare the bisannelated semibullvalene 80.12~ Unfortunately, they report that 80 rearranges spontaneously upon formation and cannot be observed. Using the discriminators developed by Williams and Kurtz, 48'9~the bisanhydride 81a is predicted to be homoaromatic. 121 It is a remarkably stable yellow compound that can be purified by sublimation at ambient pressure. This observation is in contrast with many other semibullvalenes that thermally rearrange at low temperatures to the corresponding cyclooctatetraene and/or react with ambient oxygen under mild conditions. 99c'118'119'150'163 The solution phase variable temperature 1 3 C NMR spectra of 81a showed no change between 298 and 183 K at 125 MHz.
80
io ci 122
-
-CO~M~ 123
124
194
RICHARD VAUGHAN WILLIAMS
a,R=Me b, R=Et
Similarly there was no change in the variable temperature solid CP-MAS spectra of 81a between 293 and 223 K. X-ray structure determination was carried out at 293,243, 163,148, and 123 K. At the three higher temperatures a highly symmetric structure was obtained; however, at the lower temperatures symmetry was broken. The X-ray results provided the first indication that 81a was not homoaromatic. In keeping with Quast's proposal that colored thermochromic semibullvalenes lacking classical chromophores are Cope systems with exceptionally low activation barriers, the yellow bisanhydride 81a is thermochromic. Confirmation of the Cope nature of 81a in the solution phase was provided by the equilibrium-induced tracking of chemical shift with temperature of 81b in a modified Saunders' isotopic perturbation experiment. Thus, in the solution and solid states 81 is not homoaromatic. However, quantum mechanical calculations of proven reliability predict that 81 should be homoaromatic. Of course, these calculations apply to the isolated molecule in the gas phase. Perhaps intermolecular forces in the condensed phases account for this discrepancy. Further studies in this direction are currently underway.
4.3.6. Other Semibullvalenes In this section other approaches to the study of homoaromaticity in semibullvalenes will be briefly mentioned. Recently, some new avenues of exploration have been developed in the pursuit of neutral homoaromaticity. As already mentioned, Schleyer et al. consider that the coordination ofLi § with the semibullvalene nucleus will result in homoaromaticity. 91'92 Using laser pulses, it should be possible to populate the homoaromatic transition state for the nearly degenerate Cope rearrangement of unsymmetrical semibullvalenes. This experiment may allow the spectroscopic study of these homoaromatic species. 164 Semibullvalenes, in addition to their potential as neutral homoaromatics, provide an excellent framework for the investigation of possible homoaromatic radical cations. Roth and Abelt produced the barbaralane radical cation (125) by photoinduced electron transfer.164 They concluded, from CIDNP effects, that 125 was a bishomoaromatic species. Williams et al. radiolytically oxidized semibullvalene to produce a radical cation that, from ESR studies, they assigned as the bishomoaromatic 126c. 165 A computational and experimental (CIDNP) reinvestigation of this system led Roth and Lakkaraju to suggest that from the available data it was not possible to distinguish between localized exchanging classical radical cations
195
5emibullvalenes
125
120a
126b
120c
126a/126b and the homoaromatic 126c. 166 The question of the nature of 126 now appears to have been resolved in favor of the classical species 126a/126b. 167
5. C O N C L U S I O N The emphasis of this review was on the quest for neutral homoaromatic ground state molecules, with semibullvalenes presented as the ideal candidates. This author asserts that there is currently no well-accepted example of a neutral homoaromatic molecule in which the cyclic delocalization is completed by a homoaromatic linkage. There is overwhelming evidence for homoaromaticity in compounds such as the bridged annulenes, in which the transannular homoconjugation serves to perturb the macrocyclic delocalization. 6s'69 Childs, Cremer, and Elia believe that there are several examples of neutral molecules that have been shown to be homoaromatic. 5b They include as neutral homoaromatics cycloheptatriene 14, norcaradiene, and their annelated derivatives. Although most recent studies tend to support the homoaromaticity of these systems, their candidacy is certainly still controversial (vide supra) and further work is mandated. Another example of neutral homoaromatics, chosen by Childs, Cremer, and Elia, are the semibullvalenes. Several semibullvalenes are calculated to be homoaromatic using dependable methods. However, to date no semibullvalene has been experimentally demonstrated to be a neutral homoaromatic. This is not to say that some of the compounds prepared thus far are not homoaromatic under certain experimental conditions. It is simply that there is no experimental verification of their homoaromaticity under the conditions studied. This author believes that several of the compounds mentioned throughout the body of this review may be homoaromatic, but further study is required to completely establish their homoaromaticity. The additional investigations provide a wonderful opportunity to engage in a fascinating area of research.
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131. Russell, R.K.; Paquette, L.A.; Greifenstein, L.G.; Lambert, J.B. Tetrahedron Letr 1973, 2855. 132. (a) Quast, H.; G&lach, Y.; Stawitz, J. Angew. Chem. Int. Ed. Engl. 1981, 20, 93; (b) Jackman, L.M.; Ibar, G.; Freyer, A.J.; GOrlach, Y.; Quast, H. Chem. Ber. 1984, 117, 1671. 133. Krow, G.R.; Ramey, K.C. Tetrahedron Letr 1971, 3141. 134. Quast, H.; Becker, C.; Witzel, M.; Peters, E.-M.; Peters, K.; von Schnering, H.G. La'ebigs Ann. 1996, 985. 135. See footnote 12, in Ref. 134. 136. Win, W.W.; Grohmann, K.G.; Todaro, L. J. Org. Chem. 1994, 59, 2803. 137. (a) Qua.st, H.; Geissler, E.; Mayer, A.; Jackman, L.M.; Colson, K.L. Tetrahedron 1986, 42, 1805; (b) Quast, H.; Carlsen, J.; Janiak, R. Chem. Bet. 1993, 126, 1461. 138. Quast, H.; GeiBler, E.; Herkert, T.; Knoll, K.; Peters, E.-M.; Peters, K.; von Schnering, H.G. Chem. Ber. 1983, 126, 1465. 139. Quast, H.; Witzel, M.; Peters, E.-M.; Peters, K.; von Schnering, H.G. ~'ebigs Ann. 1995, 725. 140. (a) Quast, H.; Knoll, K.; Peters, E.-M.; Peters, K.; yon Schnering, H.G. Chem. Ber. 1993, 126, 1047; (b) Quast, H.; Becker, C.; Peters, E.-M.; Peters, K.; von Schnering, H.G.l.a'ebigs Ann. 1997, 685. 141. Kessler, H.; Ott, W. J. Am. Chem. Soc. 1976, 98, 5014. 142. GUnther, H.; Rtmsink, J.; Schmickler, H.; Schmitt, P. J. Org. Chem. 1985, 50, 289. 143. Busch, A.; Hoffmann, H.M.R. Tetrahedron Letr 1976, 2379. 144. Quast, H.; GOrlach, Y.; Christ, J.; Peters, E.-M.; Peters, K.; von Schnering, H.G.; Jackman, L.M., Ibar, G.; Freyer, A.J. Tetrahedron Letr 1983, 24, 5595. 145. See footnote 16, Ref. 136. 146. Moskau, D.; Aydin, R.; Leber, W.; GUnther, H.; Quast, H.; Martin, H.-D.; Hassettrtick, K.; Miller, L.S.; Grohmann, K. Chem. Ber. 1989, 122, 925. 147. Gompper, R.; Schwarzensteiner, M.-L. Angew. Chem. Int. Ed. Engl. 1982, 21,438. 148. Gompper, R.; Schwarzensteiner, M.-L.; Wagner, H.-U. Tetrahedron Letr 1985, 26, 611. 149. Quast, H.; Witzel, A.; Peters, E.-M.; Peters, K.; von Schnering, H.G. Chem. Ber. 1992,125, 2613. 150. Quast, K.; Herkert, T.; Witzel, A.; Peters, E.-M.; Peters, K.; von Sclmering, H.G. Chem. Ber. 1994, 127, 921. 151. Siehl, H.-U. Adv. Phys. Org. Chem. 1987, 23, 63. 152. (a) Askani, R.; Kalinowski, H.-O.; Weuste, B. Org. Mag. Res. 1982, 18, 176; (b) Askani, Kalinowski, H.-O.; Pelech, B.; Weuste, B. Tetrahedron Letr 1984, 25, 2321. 153. Macho, V.; Miller, R.D.; Yannoni, C.S.J. Am. Chem. Soc. 1983, 105, 3735. 154. Benesi, A.; Jackrnan, L.M.; Mayer, A.; Qua.st, H.; Peters, E.-M.; Peters, K.; von Schnering, H.G. J. Am. Chem. Soc. 1989, 111, 1512. 155. Qua.st, H.; Janiak, R.; Peters, E.-M.; Peters, K.; von Schnering, H.G. Chem. Ber. 1992, 125, 969. 156. Quast, H.; Christ, J. Angew. Chem. Int. Engl. 1984, 23, 631. 157. Williams, R.V.; Kurtz, H.A.J. Chem. Soc. Perkin Trans. 2 1994, 147. 158. Reported in Ref. 5b; see also footnote 258, Ref. 5b. 159. Grohmatm, K.; lyengar, R.; Miller, L.; Pifia, R.; van Engen, D.; Todaro, L.; Kauer, J.; Davidson, E; Whitney, J. Abstracts of Papers, 193ra National Meeting of the American Chemical Society, Washington, DC, 1987, Abstract 2. 160. For a brief survey of these systems see Paquette, L.A.; Burson, R.L. Tetrahedron, 1978, 34, 1307, and references cited therein. 161. (a) Paquette, L.A.; Wingard, R.E., Jr.; Russel, R.K.J. Am Chem. Soc. 1972, 94, 4739; (b) Wenkert, E.; Hagman, E.W.; Paquette, L.A.; Wingard, R.E., Jr.; Russel, R.K.J. Chem. Soc. Chem. Commun. 1973, 135; (c) Cessar, G.P.; Green, J.; Paquette, L.A.; Wingard, R.E., Jr. Tetrahedron Letr 1973, 1721. 162. (a) Vogel, E.; Brinker, U.H.; Nachtkamp, K., Wassen, J.; Mtlllen, K. Angew. Chem. Int. Ed. Engl. 1973, 12, 758; (b) GUnther, H.; Schmickler, H.; Brinker, U.H.; Nachtkamp, K.; Wassen, J.; Vogel, E. Angew. Chem. Int. Ed. Engl. 1973, 12, 761.
Semibullvalenes 163. 164. 165. 166. 167.
Kohnz, H.; DUll, B.; MUllen, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 1343. Roth, H.D.; Abelt, C.J.J. Am. Chem. Soc. 1986, 108, 2013. Dai, S.; Wang, J.T.; Williams, E J. Am. Chem. Soc. 1990, 112, 2835. Roth, H.D.; Lakkaraju, P.S.J. Phys. Chem. 1993, 97, 13403. Bally, T.; Truttmann, L.; Dai, S.; Williams, E J. Am. Chem. Soc. 1995, 117, 7916.
201
This Page Intentionally Left Blank
CYCLOPENTYNES:
ENIGMATIC INTERMEDIATES
John C. Gilbert and Steven Kirschner
1. 2. 3. 4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial Characterization of Cyclopentyne . . . . . . . . . . . . . . . . . . . . Matrix Isolation Studies of Cyclopentynes . . . . . . . . . . . . . . . . . . . Cyclopentyne from Cyclobutylidenecarbene . . . . . . . . . . . . . . . . . . 4.1. [2+2] Cycloaddition Reaction of Cyclopentyne . . . . . . . . . . . . . 4.2. Stereochemistry of the Reaction . . . . . . . . . . . . . . . . . . . . . Diazoethenes and the Evolution of Their Chemistry . . . . . . . . . . . . . . 5.1. Approaching Diazoethenes via Wittig-type Chemistry . . . . . . . . . 5.2. Cyclopentyne from Cyclobutanone . . . . . . . . . . . . . . . . . . . 5.3. [2+2] Cycloaddition: Symmetry of the Reactive Intermediate . . . . . 5.4. [2+2] Cycloaddition: Stereochemistry of the Reaction . . . . . . . . . 5.5. [2+2] Cycloaddition: Mechanistic Rationale . . . . . . . . . . . . . . . 5.6. [2+2] Cycloaddition: Theoretical Analysis . . . . . . . . . . . . . . . . Pericyclic Reactions of Cyclopentyne with 1,3-Dienes . . . . . . . . . . . . . 6.1. [2+4] Cycloaddition: Theoretical Analysis . . . . . . . . . . . . . . . . 6.2. Unveiling Competing [2+2] and [2+4] Cycloadditions . . . . . . . . . 6.3. Cyclopentyne-Lithium Bromide Complex . . . . . . . . . . . . . . . .
Advances in Theoretically Interesting Molecules, Volume 4, pages 203-244 Copyright 9 1998 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0070-1
203
204 205 206 207 209 210 212 214 218 219 220 225 226 230 230 232 236
204
JOHN C. GILBERT and STEVEN KIRSCHNER
6.4. Competitive [2+2] Cycloadditions . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
239 241 241
1. INTRODUCTION Chemists have long been fascinated by the consequences of distortions of molecules from their thermodynamically preferred geometries on physical and chemical properties. The extraordinary creativity of organic chemists has been brought to bear on this subject, as they have prepared cycloalkanes, cycloalkenes, and cycloalkynes in which molecular constraints enforce substantial deviations from normal molecular geometries. Some examples include cubane (1), 1homocubene (2), 2 and benzyne (3). 3 The latter two are transient under ambient conditions, although 3 has recently been generated in a molecular cage at 77 K, and its IH and 13C NMR spectra have been determined at -75 and -98 ~ respectively. 4 The present chapter focuses on our efforts and those of others to define the properties of a relative of 3, cyclopentyne (4). 5 Attempts to synthesize molecules incorporating a single triple bond within an otherwise saturated carbocyclic ring were initiated in the late 19th century. However, it was not until the 1930s that Ruzicka and co-workers succeeded in isolating such a cycloalkyne by preparing cyclopentadecyne and cycloheptadecyne (Sa and 5b, respectively). 6 It remained for the Blomquist group in the early 1950s to define the minimum size of the carbocyclic ring required for a cycloalkyne to be isolable at room temperature; the lower limit is found in cycloOctyne (5c), which is stable for days in an oxygen-free atmosphere. 7
~---i~ CH
1
2
5 an=13 bn=15 c n=6
O'
O,
3
4
205
Cyclopentynes: Enigmatic Intermediates
2.
INITIAL CHARACTERIZATION OF CYCLOPENTYNE
Undeterred by this arbitrary kinetic limit for characterizing cycloalkynes, the efforts to define the properties of yet more highly strained systems were extended to lower temperatures. Most relevant to our own research were the results reported by Wittig and co-workers during the 1960s. 8 They found that treating 1,2-dibromocyclopentene (6) with magnesium followed by heating in the presence of 2,5-diphenylisobenzofuran (8) or oxidizing the bis-hydrazone of 1,2-cyclopentanedione in the presence of 8 afforded the 1:2 Diels-Alder adduct 9, albeit in low yields (Scheme 1).8a'b'9 They subsequently showed that transmetallating 6 with n-butyllithium at -70 ~ to give 11, adding 8, and then warming the solution also produced the bis-adduct 9 (Scheme 1).8c They also noted in this paper that the half-life of 11 in ethereal media was strongly solvent-dependent, being about 8 hrs in diethyl ether and 2 hrs in diethyl ether-tetrahydrofuran (-4:1 v:v), respectively, at 21 ~ This result presumably reflects the superior complexing ability of THF toward cations, 11 thereby facilitating loss of lithium bromide. An additional observation was that decomposition of 7 generated the benzene derivative 12 in about 2% yield. 12 The final contribution of the Wittig group to cyclopentyne chemistry involved more detailed study of the vinyllithium 11 as a source of cyclopentyne. 8d They found that the rate of decomposition of 11 in diethyl ether was cleanly first-order and had an activation energy of 24 kcal/mol. Interestingly, the disappearance of 11 in TI-IF occurred at a rate two to three times faster than in diethyl ether, and a Ph ar
<~Br
( ~
Mg
NNH2
<•MgBr
Pb(OAc)4
NNH2
Ph
Ph
12 Br
H
ki
Br nBuLii 6
9
, @1
10
~
Ph
Br
13
11
Scheme 1.
CI
206
JOHN C. GILBERTand STEVENKIRSCHNER
first-order plot of the process was now found to be non-linear after about 50% reaction, indicating incursion of a second-order component in the process. Adding one equivalent of diene 8 afforded the same non-linear plot, showing that neither unimolecular nor bimolecular processes involving 11 were influenced by the presence of the diene. Moreover, the addition of the 8 decreased the yield of 12, the trimer previously obtained from 7, 8c from 2.4% to 1.6%. Finally, warming 11 in the presence of lithium chloride yielded 1-chlorocyclopentene (13). As shown in Scheme 1, the Wittig group interpreted their observations as involving unimolecular decomposition of 11 to cyclopentyne (4). They also noted that formation of 13 implied that the loss of lithium bromide from 11 must be reversible in ethereal media. Their reports also defined two important chemical properties of cyclopentyne: its susceptibility to nucleophilic attack, as exemplified by formation of 13,13 and its ability to undergo cycloaddition reactions, as reflected in the formation of Diels-Alder adduct 9, and possibly of 12 as well. 14
3.
MATRIX ISOLATION STUDIES OF CYCLOPENTYNES
Unfortunately, the success in characterizing some important chemical properties of cyclopentyne has not been matched for its physical properties, as efforts to do so have been to no avail as of this writing. The likelihood that this might be the case was foreshadowed by SchtJller's studies in the 1960s. 15 He used the Diels-Alder reaction of 2,5-diphenylisobenzofuran (8) with cyclohexyne and cycloheptyne (5, n = 3 and 4, respectively) to estimate their half-lives, Xlr2. The cycloalkynes were first generated by oxidation of the corresponding 1-amino- 1,2,3-triazoles 14 at -75 ~ 8 was added at various time intervals, and Xlr2 was then approximated by measuring the relative yields of the Diels-Alder adducts that were produced. The results showed a decrease in x~r2 from 3600 s to <3 s in going from cycloheptyne to cyclohexyne, and thus strongly implied that physical characterization of 4 under readily accessible reaction conditions was unlikely. This was later demonstrated to be the case through matrix isolation experiments reported by Chapman et al. 16 They found that photolyzing the bis-diazoketone 15 at 8 K in an argon matrix produced the cyclopropenone 16, but its further photochemical decarbonylation failed to provide direct IR spectroscopic evidence for the intermediacy of cyclopentyne (4); the allene 17 was the only characterizable CsH 6. Nonetheless, the result was taken as evidence for 4 by postulating that it was indeed formed from 16, but underwent facile photochemical isomerization to 17. NH 2
0
0 --C=CH2
14, n = 4 , 5
15
16
17
Cyclopentynes:Enigmatic Intermediates
0
0
18
19
207
0
0
20
21
22
Support for the proposed photolability ofcyclopentyne was found in their success in converting bis-diazoketone 18 to acenaphthyne (19) under matrix isolation conditions. In this case, the cycloalkyne cannot undergo a 1,3 shift to give the allene analogous to 19. Three chemical transformations of acenaphthyne were reported in this paper: reactions with oxygen and with water to afford acenaphthoquinone (20) and acenaphthenone (21), respectively, and thermally induced trimerization to produce 22.17 Formation of 21, which presumably arises from nucleophilic attack of water on 19, and trimer 22 has precedent in the isolation of 12 and 13, respectively, from cyclopentyne (4) itself. 8c'd The genesis of 20 may involve [2+2] cycloaddition of oxygen and 19 to afford a dioxetene 23, which could undergo retroelectrocyclization (Eq. 1). Such a process would mimic that postulated for the trimerization process. 14The spectroscopic identification of 19 is gratifying, yet the extreme reactivity of this cycloalkyne illustrates the incredible challenges facing those wishing to achieve physical characterization of the parent compound. 0--0
0
0
(I) 19
23
20
4. CYCLOPENTYNE FROM CYCLOBUTYLIDENECARBENE Wolinsky and Erickson made an important contribution to cyclopentyne chemistry by unveiling a new type of precursor for the cycloalkyne. Building on the knowledge that the Fritsch-Buttenberg-Wiechell rearrangement 18of c0-bromocamphene (24) appeared to afford camphyne (25) as a precursor to enol ethers 26 and 27 (Eq. 2), 19 they reasoned that bromomethylenecyclobutane (28) might afford cyclopentyne. As shown in Scheme 2, treatment of a mixture of 28 and 2,5-diphenylisobenzofuran (8) with potassium tert-butoxide in refluxing toluene did, in fact, afford
208
JOHN C. GILBERT and STEVEN KIRSCHNER Ph
+ [~Br
8 KOBut /
Ph
toluene~
28
Ph
9
?
Ph 29
KOBut~
245 ~
N
~
Br
+
29
[~OBut 30
Scheme 2.
a
9
'
*
CHBr
24
OBut
(2)
OBut
25
26
27
Wittig's 1:2 adduct 9 in 12% yield, l~ This observation provided strong evidence that cyclopentyne could be produced by the carbene or carbenoid derived by a-elimination of HBr from 28 (Eq. 3).
,
OI
(3)
28
Another major product of the reaction presumably was 1-bromocyclopentene (29), as Wolinsky et al. subsequently reported that 29 was produced by subjecting 28 to the reaction conditions that gave 9, although the yield was not specified (Scheme 2). 2~ 1-Bromocyclopentene was also formed, in over 50% yield, when 28 was exposed to solid potassium tert-butoxide at 245 ~ accompanied by some 3% of the tert-butyl enol ether 30. Control experiments showed that only a minor part of the enol ether could have been derived from a secondary transformation of 29, so it was concluded that the major route to the enol ether involved cyclopentyne. 2~ It seemed reasonable that 29 would also be produced from the cycloalkyne, but Erickson et al., in an elegant series of papers, demonstrated that rearrangements of 28 and its analogs to bromocyclopentenes do n o t proceed via cyclopentynes. 21
Cyclopentynes: Enigmatic Intermediates
209
4.1. [2+2] Cycloaddition Reaction of Cyclopentyne The ground-breaking work of the 1960s by the groups of Wittig and Wolinsky seemingly had defined the fundamental chemical properties of cyclopentyne, and it was not until the early 1980s that the next reports of its chemistry appeared as a result of the work of Fitjer's group and our own. Remarkably, we were unaware of each other's research efforts prior to our respective initial publications in the area, and came to the study of cyclopentyne for very different reasons, as discussed below. Fitjer had been developing synthetic approaches to [n]rotanes and [m.n]coronenes and clearly felt that such molecules might be accessed through addition of cyclobutylidenecarbene(oid) to appropriate cyclohexenes, zz However, they found 23athat transmetallating 1-(dibromomethylene)cyclobutane (31) with phenyllithium in the presence of cyclohexene afforded a modest yield of tricyclo[6.3.0.02'7]undec-l(8)-ene (33), rather than the methylenecyclopropane 35 expected 24 from addition of cyclobutylidenecarbene (34) to cyclohexene (Scheme 3). The same cycloadduct was obtained upon reaction of 1,2-dibromocyclopentene (6) with n-butyllithium, a method previously reported 8c to afford cyclopentyne (4), as discussed above. Given this result and those of Wolinsky and Erickson with 1-(bromomethylene)cyclobutane (Scheme 2), Fitjer et al. interpreted their results in terms of 4 as the key intermediate. The [2+2] cycloaddition by which it was proposed to afford 33 represented a heretofore unknown reaction channel for a cyclopentyne, unless one accepts that trimerization (Scheme 1) or oxidation to a quinone (Eq. 1) is initiated by such a process. In any case, isolation of 33 was the
PhLi CBr2 -40 ocj 31
~Br 6
.LiBr/~, ~ c=C: ~ Li 34 C~Br
~ 32
Br
-
Li
n-BuLl 12
~ C ~ 35
"
1o,1
-L~
Br Scheme 3.
4
33
210
JOHN C. GILBERT and STEVEN KIRSCHNER
first definitive example of a [2+2] cycloaddition for a cyclopentyne, although this type of reaction had previously been reported for benzyne. 25 Mechanistically, it was alleged that the vinyllithium 32 could not be producing 4 by way of 12 as the latter is relatively stable under the conditions by which 33 is generated from the dibromide 32. This conclusion, although reasonable, must be viewed as somewhat speculative because its premise appears to have been the reported stability of 12 in ethereal media 8c'd rather than the hydrocarbon solvents in which the reaction was performed. Nonetheless, accepting this assumption still left both 32 and 34 as two obvious precursors to 4, and there was no basis for choosing between them. Analogous [2+2] cycloadducts were obtained using 31 and a variety of other alkenes. A single competition experiment was reported and showed that dihydropyran reacted 2.9 times faster with 4 than did cyclohexene, based on the relative yields of 33 and 36 (Eq. 4). This selectivity, though modest, indicated that cyclopentyne, despite its high reactivity, does n o t undergo diffusion-controlled [2+2] cycloadditions with alkenes.
(4) 31
0 / ~
36
4.2. Stereochemistry of the Reaction The observation that cyclopentyne affords [2+2] cycloadducts is mechanistically intriguing in light of the prediction from principles of orbital symmetry that the process, if occurring thermally, must be stepwise. 26 The same prediction applies to the corresponding cycloaddition of benzyne (37), of course, and had been tested experimentally several times with this species. Thus, reaction of benzyne with (E)- 1-deuterio-3,3-dimethyl- 1-butene (38) produced a 75:25 ratio of 41:42, a result involving net retention of the configuration of the alkene and in accord with the intervention of rotationally non-equilibrated biradicals 39 and 40 (Eq. 5). 23a
I
§
"c
9
.
(5)
§
D .C "H R' 37
38 R = C(CH3)3
39
R 40
R
D 41
R
D
42
Fitjer and Modaressi executed an analogous experiment with cyclopentyne, using the 2-butenes as the stereochemically labeled substrate. 27Unexpectedly, they found
Cyclopentynes: Enigmatic Intermediates
211
.CH3
[O1
CH3
45
43
~ 31
CBr2 Phil
.~,,,
CH3 CH3
@14
] ~ CH3 [OJ 44
CH3
~ ~ 'CH3 + ~ 46
CH3
CH3 47
CH3
Scheme 4.
that the reaction occurred with complete retention of configuration, regardless of whether the cis- or trans-alkene functioned as the substrate (Scheme 4). Stereodifferentiation of the cycloadducts 43 and 44 themselves by spectroscopic methods proved difficult, but Fitjer and Modaressi cleverly accomplished unambiguous proof of the structures by converting the products to their respective epoxides, 43 providing only 45, 44 giving both 46 and 47, as expected. To say the least, the stereospecificity of the reaction was extremely provocative, as it called into the question the famous war cry of the theory of orbital symmetry: "Violations. There are none! -28 Fitjer and Modaressi, however, found a potential solution to the dilemma by proposing that the electronic ground state of cyclopentyne (4) might be anti-symmetrical, as symbolized in 48. A concerted [2ns+2ns] cycloaddition then becomes thermally allowed 26 and stereospecificity is expected. Precedent for this supposition was available in the form of 1,8-dehydronaphthyne (49), which has an antisymmetrical electronic ground state 29 and undergoes stereospecific [2ns+2ns] cycloadditions with the 2-butenes. 3~Thus, the observation that decomposing 31 in the presence of 1,3-butadiene gave the [2+2] rather than the [2+4] cycloadduct (50 and 51, respectively, Eq. 6) was also consistent with an anti-symmetrical electronic ground state for 48. For this species, the Diels-Alder reaction would be forbidden
48
49
212
JOHN C. GILBERT and STEVEN KIRSCHNER
~==CBr 2 31
50
51
according to the tenets of orbital symmetry, whereas the [2+2] process would be allowed. We shall return to the issue of the ground state symmetry of cyclopentyne and its Diels-Alder reaction later. Q
DIAZOETHENES AND THE EVOLUTION OF THEIR CHEMISTRY
Our own entry into cyclopentyne chemistry was as unintentional as that of the Fitjer group, as seen from the ensuing discussion. In the mid- 1970s we became interested in the possibility of generating a vinylidene 52 in its triplet electronic state. Our fascination with this species was largely associated with the theoretically predicted gap of some 50 kcal/mol between the SOand T 1 states of the parent molecule (52a), 31 and our belief that some interesting chemistry might attend reactions on H
CH3x /C=C: CH:3
~C=C: H 52a
52b
the triplet hypersurface. At the time, chemical evidence using a classic probe for carbene multiplicity, the stereochemistry of addition to an alkene, 32 had shown that the ground electronic state was inde~ singlet. For example, Stang and Mangum found that base-promoted or-elimination of the vinyl triflate 53, a reaction shown to afford free dimethylvinylidene (52b) rather than its carbenoid, 33 provided either 55 or 56, depending on whether the (E)- or (Z)-isomer of the substrate alkene 54 was used (Eq. 7). 34
CH3,
IOSO:~Z~F3
C =C, H 53
H
CH3 OCH3 CH3,c_c,/~,,,OC H3 + ell3 "C=C./~ -,','CH3 ~ - ~%~H ,. CH/
tOCH3 KOBu'
+ OH ~-C=C,,cH 3 54
SS
(7)
56
The approach we chose for potentially accessing the triplet manifold of vinylidenes was photosensitized decomposition of a diazoethene, 57. This decision
a1\
C :CN2 R2 57
Cyclopentynes: Enigmatic Intermediates
213
was largely based on the precedent existing in the literature that intermolecular sensitization of a diazocompound could afford triplet carbenes. For example, benzophenone-sensitized decomposition of diazomethane (58) in the presence of either cis- or trans-2-butene (59) afforded mixtures of cis- and trans- 1,2-dimethylcyclopropane (60a and 60b, respectively, Eq. 8). 35 In designing possible target
CH2N2
Ph2CO + CH3CH=CHCH3 hv ~
58
,CH3
~ H2C~
+ '~CH 3
59
60a
H2C
~"
,CH 3
(8)
"%CH3
60b
diazocompounds, we recognized that the parent molecule, 57, (R l = R 2 = H), or derivatives of it wherein one of the R groups was either H or aryl, would yield alkylidenecarbenes that readily isomerized to the corresponding alkyne (Eq. 9), 36'37 whereas this was not the case when the R groups were alkyl. 34 We also realized that the necessity of having substituents at C(2) of the diazocompound 57 opened up the possibility of intramolecular sensitization of the decomposition, for example, if R l of 57 were benzoyl, photoexcitation of this moiety, followed by intersytem crossing to the triplet excited state and loss of dinitrogen, could provide the desired triplet species. RI\ C =CN 2 R2 ,
J
RI\ C =CN 2 R2 ,
J
RI\ C=C: R2
R1--C mC-R 2
,
(9)
S7
Naturally, a key to the success of our planned approach was generating the desired diazoethenes, and here the literature was not very encouraging. Thus, in 1965 Curtin et al. attempted to produce these types of compounds by nitrosation of enamines. Their results are consistent with the intermediacy of a diazoethene 62, as illustrated by formation of 63 through nitrosation of 9-aminomethylidenefluorene (61, Eq. 10), but 62 was not isolable under their reaction conditions. 38 Exploring the utility of nitrosation under milder reaction conditions as a general entry to 57 was unappealing because the needed enamines themselves are not readily available. 24b The base-promoted decomposition of N-nitrosooxazolidones (64) was likewise not
(10) CHNH2
61
CsHllNO
J
CN 2
62
~ .
N2
C
63
214
JOHN C. GILBERT and STEVEN KIRSCHNER
.s R
EtO"
b
,C-R
NO
(11)
R 65
64
R
~C=C H N = N S O2C6H4C H3 R 66
pursued because of two considerations: the challenge they represented synthetically, 39 and the fact that the very negative p-value for forming methylenecyclopropanes 65 from these precursors (Eq. 11)4~was inconsistent with the intervention of a free alkylidenecarbene. 33 Finally, a method involving unimolecular decomposition of tosylazoalkenes 66 did not suit our purpose because the temperatures required for the process, although moderate, still exceeded those at which the desired diazocompounds were expected to survive. 41
5.1. Approaching Diazoethenes via Wittig-type Chemistry At a group research meeting in 1978, Weerasooriya and Gilbert were contemplating the challenge of developing a synthesis of diazoethenes that would both be general and viable at low temperatures, when it occurred to us that an approach modeled after the Wittig reaction 42 could be the solution. The reaction was known to occur at low temperatures (e.g., -78 ~ and could involve a wide range of ketones as substrates. The rest was conceptually simple to write out, in that we required a phosphorus-containing reagent capable of transferring a "CN2" moiety. Such a reagent is 67, a derivative of diazomethane, and its generalized reaction with a carbonyl-containing substrate is shown in Equation 12. The expense and anticipated technical problems attending the use of the triphenylphosphonium derivative 67a prompted us to search for a phosphonate analog that would effect the Wadsworth-Emmons modification of the Wittig reaction. Thus the idea of diethyl diazomethylphosphonate (DAMP, 43 67b) was born.
RCHN 2
+
a2c=0
Bas., R2C=CN2
(12)
67 a. R = (CsH5)3P+ b. R = (EIO)2P(O)
Believing we had just conceived of a new compound, Weera.sooriya retired to the library to figure out how to prepare it. He returned in short order with the news not only that the compound was known, 44 but also that it had been used in the way we intended, namely in a reaction with ketones. 45 Thus, Colvin and Hamill had
Cyclopentynes: Enigmatic Intermediates
215
discovered that treating certain aldehydes and ketones, 68, with 67b in the presence of base afforded alkynes 71, and they proposed that diazoethenes 69 were indeed involved (Eq. 13). Our disappointment that we had not invented a new reagent was somewhat assuaged by the fact that the desired transformation appeared to work. Any excitement we felt, however, was immediately tempered by the disheartening realization that these workers had found the reaction to be effective only with non-enolizable aryl ketones and "highly electrophilic" aryl aldehydes. If true, their observations meant our hoped-for general approach to 57 was doomed to failure, as simple dialkyl ketones would not be viable substrates. Moreover, their results reconfirmed that diazoethenes such as 69 do not survive at room temperature; rather they lose dinitrogen to give an alkylidenecarbene 70, which isomerizes to the alkyne 71. 1.
n-BuLl
KOBut
(EtO)2P(O)CHN 2 + ArCR 2. -78 RT ~ R=HorAr 67b 68
or
_
,
,C = C N 2 _ H _ 69
Ar~
_
_
,
_
Ar
'C = C : _ R _ 70
,
Ar--C - C - R
(13)
71
We believed there was a possibility that a simple experimental modification might simultaneously expand the scope of the reaction and increase the probability for isolating the desired diazoethenes 57. The Colvin/Hamill protocol for the reaction was to combine the reagents at-78 ~ and then immediately allow the reaction mixture to warm to room temperature. We reasoned that holding the reaction mixture at low temperatures for longer periods of time might overcome the structural limitations noted by these workers. The logic underlying this relied on two reports in the literature. First, side-reactions under Wadsworth Emmons conditions appeared to be suppressed at low temperatures. 46 Second, enolization involving deprotonation of the carbonyl compound by the anion of DAMP (Eq. 14) was likely to have a favorable equilibrium constant. This was based on evidence that DAMP may be deprotonated by amines, which are much weaker bases than enolates, as illustrated by formation of a diazoaldol 73 from p-nitrobenzaldehyde (72, Eq. 15).47 H O I
II
--C-C
(EtO)2P(O)CHN2
R.
(EtO)2P(O)CN 2.
I
67b +
/C-C -" O
(14)
67b
O2N--~~CHO
+ 67b
(cat.)El'N:,
/=~o.
O2N ~ - - ~ ~ C - C - P ( O ) ( O E ' H N2
72
73
2)
(15)
216
JOHN C. GILBERT and STEVEN KIRSCHNER
Our hopes that modifying the protocol for the reaction would broaden the range of substrate carbonyl compounds to which it could be applied were fully met. Thus, by allowing solutions of an aliphatic or aromatic aldehyde or aryl ketone, DAMP, and potassium tert-butoxide to remain a t - 7 8 ~ for about 16 hrs, Weerasooriya was able to prepare the corresponding alkynes in unoptimized yields ranging from 27 to 88%, regardless of whether an enolizable hydrogen was present (Eq. 16). 48
CsHsCH2CHO + 67b
1. KOBut -78"C 2. 12h RT/2h,
CeHsCH2C =CH 80%
(16)
yield
What he was not able to do in any instance, however, was isolate the elusive diazoethene presumed to be the precursor to the alkyne or even to obtain spectroscopic evidence for its existence. For example, he prepared the diazoaldol 73 in methanol-d 4 and studied its decomposition in the presence of sodium methoxide by 1H NMR spectroscopy. Over the range of--40 ~ to 0 ~ he was unable to detect a resonance assignable to the desired diazoethene 75, although resonances associated with the betaine 74 and sodium dimethyl phosphate 76 did appear (Scheme 5). 49 In fact, nitrogen evolution was observed with most carbonyl substrates immediately upon combining the reagents at -78 ~ an indication that as a class, diazoethenes 57 are unstable at this temperature. We reported some modest theoretical support for this lack of stability, 5~ although detailed theoretical calculations remain to be done. Attempts to perform the reaction at still lower temperatures failed, either because the DAMP anion is insufficiently nucleophilic to react or because the betaines that result from its addition to the carbonyl compound do not undergo elimination to produce 57. More direct evidence for the intervention of diazoethenes from the DAMP protocol became available from the work of Berson and Lahti. 51 As part of their
OH i Ar-C-C-P(O)(OEt2), , H N2
.
NaOCD~ CD3OO
O'Na* i Ar-C-C-P(O)(OEt2) H N2
O'Na+ p O--i/(OEt)2 Ar-C--CN2
73
H 74
Ar = p-nitrophenyl
ArC-~CH
,'N2
ArCH=CN2 + (EtO)2PO 2" 75
Scheme 5.
76
Cyclopentynes: Enigmatic Intermediates
217
77
studies directed toward generating 2-alkylidenecyclobutane-l,3-diyls 77, they found that the reaction of DAMP with acetone in the presence of 3,3-dimethylcyclopropene (79) produced the dihydropyridine 80. They rationalized its genesis as shown in Scheme 6, with formation of the diazoethene 78, followed by its wellprecedented 52 [2+4] cyclization with the strained alkene, being key steps in their proposed mechanism. It is difficult to account for their observations without postulating the intermediacy of 78. HaCz~CHa H3C, C= O , H3C
DAMP ~ KOBut
H3C C=CN 2 , H3C
H3C
79 i H3C
~
CH 3 N I
H
9 H3C
"N ~/~
H3C
H3C
78
CH3
80
Scheme 6. Our inability to isolate diazoethenes prompted us to focus on potential chemical applications of the alkylidenecarbenes 80 derived from them. A sampling of our results is summarized in Figure 1. In addition to the previously mentioned onecarbon homologation affording alkynes 81 (Eq. 9 and path a of Figure 1),48 two other types of transformations involving alkylidenecarbenes are of particular relevance for the present discussion. 53One is intermolecular cycloaddition between
R 82 m
R R
pathb51a II~ R RI--CBC-.R 2 81
path a ~ !
RlorFF.. H ua~/I
RI\ C=C: / R2 80
F~
Rt\ Hit -R3 ~=C, R2 H
pathcSlb J H R3_Het_R 4 Her-O, N R3- alk~,R4-- alkylor"
83
Figure 1. Some characteristic reactions of alkylidenecarbenes from dia-
zoethenes.
218
JOHN C. GILBERTand STEVEN KIRSCHNER
the carbene and an alkene to produce a methylenecyclopropane 82 (path b). The p-value and stereospecificity for the process were found to be consistent with an unencumbered carbene reacting through its singlet electronic state. 53a The second is intermolecular insertion of the carbene into heteroatom-hydrogen bonds to produce aldehydic enol ethers and enamines 83 (path c), a reaction that presumably involves nucleophilic attack of the heteroatom on the carbenic center. 53b
5.2. Cyclopentyne from Cyclobutanone It was while exploring the scope of the carbon-homologation of a dialkyl ketone to a protected aldehyde moiety by way of 80 (path c, Figure 1), that we elected to subject cyclobutanone (85) to the protocol for the reaction in hopes of obtaining 88 (Scheme 7). 5'ta The task was assigned to an undergraduate student, Mark Baze, who was in the group at the time. He performed the reaction using 1-butanol as the trap for the expected cyclobutylidenecarbene (87). Upon working up the reaction mixture, he isolated a product in 43% isolated yield that had the proper exact mass for a 1:1 adduct between 87 and the alcohol, and an SH NMR spectrum with the general characteristics expected for 88. There was a particularly disturbing feature in this spectrum, however, the appearance of the chemical shift for the vinylic proton at 5 4.28, some 1.5 ppm higher field than in analogous enol ethers, e.g., 90. 51b Knowing of Wolinsky and Erickson's results (Scheme 2), Baze proposed that the product was enol ether 89, a structure more consistent with the observed chemical shift for the vinylic proton. He quickly proved his case by converting the product to the known cyclopentanone-2,4-dinitrophenylhydrazone (91). 1~ This exciting result prompted us to postulate that cyclopentyne (4), formed by ring expansion of either the diazoethene 86 or the cyclobutylidenecarbene 87, was a possible intermediate.
=0
1. n-BuOH , KH/-78"C (EtO)2P(O)CHN
- ~ ~~CN
2
2
D
"~=
C:
n-R.("JHIp
~ _
85
2. RT
86
",,, / 4
Scheme 7.
87
~
,OC4H9
< ~ : : = C"H 88
89
Cyclopentynes: Enigmatic Intermediates
219
'OC2H5
[~NNHC6H3N204
90
91
5.3. [2+2] Cycloaddition: Symmetry of the Reactive Intermediate Fitjer's repotted observation of [2+2] cycloaddition products using 1-dibromomethylenecyclobutane (31, Scheme 3)23 prompted us to explore this type of reaction using our methodology. Using dihydrofuran (92) as our alkene trap, we were gratified to isolate the cycloadduct 93 in about 30% yield (Eq. 17), adding further credence to a mechanistic scenario involving 4.
0 + 85
~ 92
1.KH/-78~ (EtO)2P(O)CHN ~ 2.RT
~.~[
1t~
(17)
93
But there were other mechanistic scenarios that could account for our results and would n o t involve cyclopentyne as an intermediate. One such possibility for formation of 89 is illustrated in Scheme 8. By involving the zwitterion 94, formed by nucleophilic attack of 1-butanol on either the diazocompound 86 or cyclobutylidenecarbene (87), this mechanism bears analogy to Erickson's proposed mechanism for base-promoted rearrangements of 1-(bromomethylene)-cyclobutane to 1-bromocyclopentene (Scheme 2). 21 A related mechanism could be written for reaction of an alkene and thus could account not only for our results with 92 (Eq. 17), but for those in Fitjer's system as well. What sets the mechanism of Scheme 7 apart from others that we were able to envision is the molecular symmetry resulting from the intervention of cyclopen-
H+
H §
~176
94
86
~ C4H9 t
89
Scheme 8.
.H + +H+ H
220
JOHN C. GILBERT and STEVEN KIRSCHNER
tyne, with its chemically equivalent acetylenic carbon atoms. This equivalency provides the basis for validating the mechanism of Scheme 7. Thus, addition of an unsymmetrical reagent, A-B, to a cyclopentyne in which the triply bound carbon atoms are isotopically distinct should afford a cyclopentene derivative 95 in which the label is distributed statistically; that is, equal amounts of 95a and 95b would be formed (Eq. 18). In contrast, any process having a reactive intermediate trapped prior to symmetrization of its unsaturated carbon atoms would perforce have an unequal distribution of the isotopic label.
Cc
+
A-B
m
C = 13C
Cc-' II
C'B 95a
-'
+ 95b
(18)
B
The most expeditious way to execute the labeling experiment was to prepare phosphonate 67b with excess 13C in the diazomethyl moiety, which was accomplished via the usual sequence, ~ but starting with 13C-labeled formaldehyde. Performing the reaction of cyclobutanone with the labeled material in the presence of either 1-butanol or dihydrofuran afforded cyclopentene derivatives 89 and 93, respectively, and analysis by integration of the 13C NMR spectrum of each product showed a statistical distribution of the excess 13C originally present in 67b (Scheme 9). 54a The symmetrization of the label is extremely difficult to rationalize without invoking cyclopentyne as an intermediate, so the results constituted compelling evidence for its formation.
_I-Bu~I,~ ,==0 + (EtO)2P(O)CHN2 85
=-, OI
67b C = 4.3% excess 13C
~.....C. 0C4H9 +
/~
0C4H9
~ H
~C'H 89a
1:1
89b
93a
I 'I
93b
4
Scheme 9.
5.4. [2+2] Cycloaddition: Stereochemistry of the Reaction Having observed the formation of the [2+2] cycloadduct 93, we immediately turned to assessing the stereochemistry of the process. The c/s- and trans-2-butenes are an obvious choice for a diastereomeric pair of alkenes to use as a probe and, as noted earlier, these were selected by Fitjer and Modaressi for their study (Scheme 4). 27 We wished to use substrate alkenes that might have an increased potential,
Cyclopentynes: Enigmatic Intermediates
221
relative to the 2-butenes, for revealing any stereorandomization that could accompany a stepwise mechanism involving either a biradical or zwitterionic species, as shown in Scheme 10. The success of this type of test for stepwise behavior depends on interconversion of reactive intermediates 95 or 96, so substituents, R 2, that serve to stabilize these species should facilitate their necessary interconversion. An alkoxy group is more effective than an alkyl group for stabilizing either a radical or a positive charge ~ to it. Thus, the bond dissociation energy (BDE) for a C-H bond in ethane (97) is 98 kcal/mol, whereas it is 5 kcal/mol lower for the corresponding bond in methanol (95): 5 the decrease in BDE signaling the enhanced stabilizing effect on a radical of an alkoxy group as compared to a methyl group. With respect to carbocations, one measure of the stabilizing effect of alkoxy vs. methyl is seen in the relative rates of electrophilic aromatic chlorination of toluene Biradical pathway:
(~
R1
,
J
=C 'R2
4
,
C,\ ,H~R 2
~
.R 1 -R2
95a
a1
I
C,,H
.R1 "'R2
95b
Zwittefionic pathway:
a1
I
C,,H
.R 1 -R 2
4
96a
a1
I
C,,H \^~H
96b
Scheme 10.
222
JOHN C. GILBERT and STEVEN KIRSCHNER
H -CHaCH 3
H-CH2OH
97
98
CH 3
~
OCHa 100
98
HaC" OCH 3 C=C H H 101
H
OCH a C=C,, H3C H 102
(99) and anisole (100), in which 100 reacts over 104 times faster. 56 The stabilizing characteristics of alkoxy therefore prompted us to select the methyl propenyl ethers 101 and 102 as our alkene trap. 54b We first used (Z)-l-methoxypropene (101), which contained about 2% of the E-isomer 102, and found that the [2+2] cycloadduct 103 was formed in 22% yield and at least 98% stereoselectively, based on the relative percentages of the products having the proper mass for a l:l adduct of cyclopentyne and 101 (Eq. 19). As we shall shortly see, the diene 104 was derived by thermal isomerization of the trans analog of 101. The formation of the diene might have indicated the incursion of a stepwise pathway, but we considered it more likely to be a consequence of the contamination of 101 by 102. OCH 3 I O +
85
CH3 1. KW-78oC (EIO)2P(O)CHN 9 ~CH3 2. RT 101
+ H3 98% 103
"H .H
+
I~
unidentified
(19)
CH 3 1% 104
To test the remote possibility that the intermediates 95 and/or 96 (R ~ = CH 3, R 2 = OCH 3, Scheme 10) were not cyclizing exclusively via 95a or 96a, the cycloaddition was repeated with 100 (Scheme 11). Analyzing the results in this case was considerably more complicated because IH NMR analysis of the crude reaction mixture failed to reveal resonances that could be assigned to the expected cycloadduct 105. Nor was any 103 detectable spectroscopically. What was observable were resonances that were consistent with the presence of 104, an extremely labile species that we were unsuccessful in isolating in pure form.'This forced us to resort to an indirect method for confirming its structural assignment, namely trapping the diene as a Diels-Alder adduct 106 that was characterized through X-ray crystallographic techniques. The cis stereochemistry of methyl and methoxy groups in the cycloadduct imposed the requirement on 104 that it be either the E, E-isomer, as shown in Scheme 11, or the diastereomeric Z, Z-isomer 106. From consideration of the steric factors that might control the preferred conrotatory mode of ring-opening of the cyclobutene ring of 105, 26 we assigned the stereochemistry of the diene as that of 104. Two years later, Kirmse and coworkers utilized ab initio (STO-3G) calculations and analysis of HOMO/LUMO interactions to demonstrate clearly that electronic rather than steric factors account for the preference of a methoxy group at the
Cyclopentynes: Enigmatic Intermediates ~=O
85
+
CH30~ L
223
~
pOCH 3
1"KH/'78~ " (EtO)zP(O)CHN2 "CH3 2.RT
[
9 "CH3
1%
102
103
pOCH3+ '"CH3
_
1%
105
/
OH 0 OH O H CH3
9CH3 ON 0
unidentified
~
C.H not
C -N
(~
I
CNa 98% 104
106
Hi
C'ocH3 C"CH3 i
H 107
Scheme 11.
9CH3 ,.C,.H [~
~C .H
OCH3
i
N
i~nward ~
(20)
H i
.,H H
3-position of a cyclobutene to rotate outward rather than inward (Eq. 20). 57 Their argument is summarized in Figure 2, which contains representations of the transition states for outward (Figure 2a) and inward (Figure 2b) ring-opening of a 3-alkoxy-l-cyclobutene. 58 As seen in Figure 2a, outward rotation provides a transition state that is stabilized by interaction of a pair of non-bonded electrons on oxygen with C(3) of the distorted sp3-orbital that represents the LUMO. The corresponding transition state for inward rotation (Figure 2b) has similar stabilization with regard to C(3) of the LUMO, but there is now a destabilizing anti-bonding interaction of the non-bonding electrons with C(4). The result is greater net stabilization for the outward mode, thus accounting for the preference for this mode of conrotation. The greater thermal lability toward retroelectrocyclization of 104 as compared to 11)3 was explainable from known effects of substituents on the activation enthalpy, E a, for the process. The relevant data to do so were derivable from the kinetic data shown for cyclobutenes 108-112. Relative to cyclobutene (108)
224
( ~
JOHN C. GILBERT and STEVEN KIRSCHNER
C(4~ (3~ ,,~
LUMO (Oxygen) (o*). p
3~~
HOMO(0)* p (Oxygen)
C(3)~_
~4)
~ ' ~ 4 )
(a)
LUMO(0*)+ p (Oxygen)
HOMO(a) + p (Oxygenj
(b)
Figure 2. Orbital interactions at transition states for ring-opening: (a) outward rotation, (b)inward rotation.
itself, 6~ introducing an alkoxy or a methyl group at the 3-position as in 1096~ and 1106~ lowers E a by 9 kcal/mol and 0.9 kcal/mol, respectively. That these substituent effects are additive is suggested by the data for 111,57 in which steric effects are not a factor, since the product of ring-opening is (E, E)-2,4-hexadiene (112). Consequently, E a for converting 105 to 104 can reasonably be predicted to be on the order of 10 kcal/mol less than that for transforming cyclobutene to 1,3-butadiene. This is a minimum value, by the way, since the energy of the transition state for reaction of 104 presumably reflects the larger release of strain that should attend ring-opening of the bicyclic rather than the monocyclic molecule. Estimating a reliable value for the E a of 103 is more straightforward in view of the known E a for 113, 6~ an analog of the bicyclic system. The cis relationship of methyl and methoxy is seen to lower the activation barrier by 7 kcal/mol relative to cyclobutene, but still leaves it some 3 kcal/mol higher than that predicted for 104, a result in line with our experimental observations of the relative thermal stabilities of 103 and 104. Despite our inability to isolate 105 itself, the diene 104 was clearly its surrogate. Subsequent analysis of a crude reaction mixture by gas-liquid chromatography showed that 104 had been formed in about 20% yield and comprised 98% of the substances present that had the proper mass to be 1:1 adducts between cyclopentyne and 102. Once again, the [2+2] cycloaddition was at least highly stereoselective, if not stereospecific, a result entirely congruent with that of Fitjer and Modaressi. 27
[~OCH2CH3 [ ~ CH3
108
log A 13.08 Ea 32.5
109 110 12.68t'0.18 13.56 23.5"t0.3 31.6
#,CH3
(~H3 ~C" H
"cH~
9
111 14.01~-0.23 30.6t0.4
CH3 112
i ~ OCH3 cm
113 11.7lt0.35 25.5t'0.6
Cyclopentynes: Enigmatic Intermediates
225
5.5. [2+2] Cycloaddition: Mechanistic Rationale We originally offered two possible rationales for our stereochemical results. 54b The first was that the cycloaddition was concerted. In the context of the tenets of orbital symmetry,26 we then envisioned two scenarios. One was that the triple bond participated antarafacially, since the alkene must react in a suprafacial fashion to account for the retention of its stereochemistry (Figure 3); this proposal had analogy in the stereochemistry of the cycloadditions of ketenes. 61 The second was that the cyclopentyne reacts through a low-lying $1 state, a hypothesis somewhat analogous to that put forth by Fitjer. 27 However, geometrical considerations rendered the first option unlikely, and SCF-MO computational analyses by ourselves, 62 and later by Olivella et al., 63 which showed the HOMO of cyclopentyne to be symmetrical, made the second option untenable. The stereochemical results could also be rationalized through a stepwise mechanism in which the stereorandomization of a biradical or zwitterionic species 95a/96a via its partner 95b/96b was slow relative to ring-closure (Scheme 10). We deemed this possibility unlikely by drawing an analogy between the biradicals 95 and the corresponding intermediates involved in [2+2] cycloaddition of benzyne and alkenes (Eq. 5), wherein stereorandomization was observable. 25a This conclusion was soon to be challenged through theoretical calculations using the MNDO approximation that supported a stepwise reaction process involving biradicals for the [2+2] cycloaddition of cyclopentyne and ethylene. 63a However, earlier theoretical results obtained by Dewar and Kirschner using MINDO/3 semi-empirical 64 methods, and later sustained by high level ab initio analyses, 65 were in accord with our expectation that interconversion of 1,4-biradicals, and presumably a 1,4-zwitterion as well, would be competitive with ring closure. The stereochemical results observed by the Fitjer group and our own therefore presented something of an enigma mechanistically, as none of the options to explain them appeared to have compelling support. Nonetheless, in the end we favored a concerted pathway involving antarafacial participation, s4b largely because of the power of orbital symmetry to explain the stereochemistries of a wide range of pericyclic phenomena.
Figure 3. (X2a+X2s)Cycloaddition of cyclopentyne and alkene.
226
JOHN C. GILBERT and STEVEN KIRSCHNER
5.6. [2+2] Cycloaddition: Theoretical Analysis This was the status of the mechanistic analysis of the [2+2] cycloaddition of cyclopentyne for almost a decade. However, in the early 1990s a chance discussion between the co-authors of this chapter led to further theoretical analyses of the reaction. Kirschner had been intimately involved in the pioneering work during the 1970s that allowed Dewar and co-workers to use semi-empirical methods for calculating reaction paths for a variety of pericyclic processes. 66 These techniques, using the most modern AM 1 protocol, 67 were applied to both the ring expansion of cyclobutylidenecarbene (84) to cyclopentyne, as seen in Equation 21, 68 and to the [2+2] cycloaddition reaction of the cycloalkyne (Eq. 22). 69
87
114
2.400 A
HH
l~ H
:,
"-LH
- ~
HH 0
_
114
The results of these calculations were at once revealing and provocative. For example, the ring expansion was found to afford a cyclopentyne 114 having C s symmetry (Eq. 2 1) and a AHf some 26 kcal/mol above that of the C2vform 4. 68 Moreover, the [2+2] cycloaddition of 114 and ethylene (Eq. 22) was found to have the "one-valley" potential energy surface (Figure 4) known from earlier work 7~ to
|
R2
Figure 4. Generalized potential energy surface for an allowed reaction, A --> B. R1 and R2 are reaction coordinates.
Cyclopentynes: Enigmatic Intermediates
227
characterize a allowed reaction. Based on the later ab initio calculations of Johnson et al., it has been suggested that 114 is likely to be an artifact of the NDDO approximation used in the AM1 method. 71 In reality, this possibility is of little consequence because we have found in subsequent AM 1 calculations that the C2v form, 4, of cyclopentyne also undergoes the [2+2] cycloaddition with ethylene in an allowed and concerted fashion! 72 Thus, the hypersurface for the [2+2] cycloaddition reaction of 4 and ethylene (Eq. 23) H
I,
H
:c=c
H
,
"H
"~..--:-L-- C H 2
(23)
115
4
was initially explored using the geometrical constraint that the t w o a-bonds undergoing formation did so synchronously. The results clearly indicated a singlevalley potential-energy surface, where there was only one calculated minimum-energy structure for each value of the reaction coordinate R 2, which is indicative of an allowed reaction (Figure 4). The calculated energy barrier for this process was about 15 kcal/mol. However, force constant analyses on the calculated maximum resulted in two negative eigenvalues, establishing this species as a stationary point, not the true transition state. Repeating the reaction-path computation with no geometrical constraints again resulted in a single-valley potential-energy surface,
150 -
14o130 -
.
100
-
144.9 . . . . . 4+
H,
H
H
H
C----C
146.9 "~"-'~,,146.7
,, ',, ',
',
'
,
',
, i
90 -
AH ~ (kcal/mol) 8 0 -
i
' '.----,90.7 87.0'----" ' ' 95a ', , ,, i
z
=
50 -
"i~ ,--- 45.8
40-
H
30-
<
~
H
115
Reaction Coordinate
b
Figure 5. Potential energy diagram for [2+2] cycloaddition of 4 and ethylene.
228
JOHN C. GILBERT and STEVEN KIRSCHNER
but a true transition state could now be identified and characterized by force constant analyses. The transition state for the reaction was quite unsymmetrical in terms of the lengths of the two forming t~-bonds, the distances being 2.6/~ and 3.3 A. The calculated activation barrier for the cycloaddition decreased significantly to a value of 2.0 kcal/mol. Despite the asynchronicity in bond formation, this pathway remained concerted and thus would lead to retention of stereochemistry, as symbolized by the bold-faced hydrogens in Figure 5 and observed experimentally.27,5ab An additional reaction channel was identified that involved a stepwise process proceeding through a biradical intermediate 95a (Scheme 10). Remarkably, the activation barrier calculated for this process was only 1.8 kcal/mol (Figure 5), a value that predicts the stepwise reaction to be competitive with the asynchronous concerted process. Moreover, the potential energy surface contained just a single valley. Since no orbital crossings were involved, even this two-step reaction mechanism was consistent with the experimentally observed retention of stereochemistry? A summary of the pathway calculations is that cyclopentyne and ethylene were predicted to participate in a suprafacial fashion in the [2+2] cycloaddition, so the reaction may be classified as (n2s+~2s). The allowed four-electron process of this sort represented an apparent violation of the rules of orbital symmetry, 26 of course, and a theoretical framework for such a remarkable proposal had to be found. Fortunately, one of us had assisted in developing the theory of orbital isomerism, which is fundamentally a topological analysis for understanding pericyclic reactions. r162 It is not appropriate to discuss the details of this approach to understanding pericyclic phenomena here, but its consequences are as follows: 66a'r 9 Forbidden pericyclic reactions always involve an odd number of orbital crossings between occupied and unoccupied molecular orbitals. 9 Allowed pericyclic reactions always involve an even number of orbital crossings between occupied and unoccupied molecular orbitals. The fundamental concept underlying the theory is that isomers having filled (and unfilled) molecular orbitals of identical topologies may be interconverted without an orbital crossing. Isomers whose orbital topologies are not identical may be interconverted only if such a crossing occurs and consequently may be termed "orbital isomers. ''66a-r Thus, a generalization of the theory of orbital isomerism is: The interconversion of orbital isomers is forbidden. 73 How does this theory account for a concerted [2+2] cycloaddition of cyclopentyne and ethylene to produce bicyclo[3.2.0]hept- l(5)-ene (115)? It may do so only if 4 75 itself were not "classical" cyclopentyne but rather an orbital isomer of "classical" cyclopentyne. The latter, whose orbitals are taken as having the topologies and ordering of a normal alkyne, e.g., acetylene, would require, an orbital crossing in a (rf2s + n2s) cycloaddition with ethylene and thus would be forbidden.
Cyclopentynes: Enigmatic Intermediates
229
However orbital symmetry rules would become reversed if 4 were an orbital isomer of the "classical" cycloalkyne, and the [2+2] cycloaddition would then be an allowed reaction. The identity of 4 as such an orbital isomer would be established if 4 were found to contain two molecular orbitals, one occupied and one unoccupied, that were transposed from their expected orderings relative to a classical alkyne. In a sense, the orbital isomer would then already have embedded in its orbital array the orbital crossing normally required for a forbidden reaction to occur. Based upon the common ideas concerning pericyclic reactions, the obvious place to look for such a transpositioning of orbitals was in the HOMO and the LUMO of 4, which are the bonding and antibonding orbitals of the n-bond coplanar with the cyclopentyne ring. Examination of these orbitals, however, showed that they were entirely normal with respect to their expected symmetries and topologies. Thus, we were compelled to examine other, less obvious, orbitals for evidence of transpositioning. It was the sigma system that in the end provided the clues showing 4 to be an orbital isomer of "classical" cyclopentyne. In particular, the molecular orbitals making up the two cy-bonds (x to the triple bond define the unusual nature of cyclopentyne. These G-bonds would normally be expected to be formed from the linear combination of p-atomic orbitals, as shown in Figure 6, where ~1 and ~2 would normally be occupied and ~3 and ~4 unoccupied. Each of these orbitals was then located in 4. Although all four of them could be identified, only W1 was found to be an occupied bonding molecular orbital, with W2, W3, and W4 being unoccupied and antibonding (Figure 6). Since W2 would normally be expected to be an occupied bonding molecular orbital, this established 4 as an orbital isomer of "classical" cyclopentyne rather than as the classical molecule itself. A possible rationalization of this phenomenon involves the sizable overlap between the o-system of the five-membered ring and the n-bond that is
m
antibonding_. bonding
-J-r-
Figure 6. Linear combinations of in-plane p-atomic orbitals for C(1)-C(5) o-bonds of cyclopentyne.
230
JOHN C. GILBERTand STEVENKIRSCHNER
coplanar with the ring. Given that a- and n-systems are usually orthogonal, this is indeed an unusual situation that allows substantial mixing between the orbitals. Indeed, ~F2 has the necessary topology to serve as the r~*-antibonding molecular orbital for the aforementioned n-bond and must undergo an orbital crossing in order to function in this manner. In summary, it was the unusual overlap between orbitals defining the a- and n-systems that was responsible for 4 being an orbital isomer of the hypothetical "classical" species. The consequence of this is that cyclopentyne would be predicted to undergo pericyclic reactions via a mechanistic protocol precisely opposite to that predicted by the theory of orbital symmetry. Furthermore, the principle should be general; that is, any system that has a sizable overlap between its t~- and n-systems would also be expected to be an orbital isomer of the hypothetical "classical" molecule and react according to the precepts of the theory of orbital isomerism. This is indeed found to be the case, at least computationally: Cyclobutyne and cyclohexyne (5, n = 2 and 4, respectively) are found to undergo allowed [2+2] cycloadditions, whereas cycloheptyne (5, n = 5) and cyclo6ctyne (5c) are forbidden from doing so. 72
6.
PERICYCLIC REACTIONS OF CYCLOPENTYNE W I T H 1,3-DIENES
6.1. [2+4] Cycloaddition: Theoretical Analysis Theoretical confirmation of the unusual orbital array for cyclopentyne was seen in the calculation of the reaction path for its [2+4] cycloaddition with 1,3-butadiene to afford bicyclo[4.3.0]nona-l(6),3-diene (116) as seen in Equation 24. For this
4
116
transformation, the potential energy surface appeared as a two-valley profile (Figure 7), having two calculated minima for each value of the reaction coordinate R 2. Such a surface is diagnostic for a forbidden reaction. 7~ The activation barrier was 2.5 kcal/mol (Figure 8), a value slightly higher than that for the allowed [2+2] cycloaddition, as discussed in the following paragraph. In examining this potential energy surface it was seen that the actual orbital crossing did not coincide with the transition state, but rather occurred after the transition state had been reached. Analogy for such a phenomenon may be found in the study of various forbidden electrocyclic reactions, where the transition state and the required orbital crossings occur at different points on the potential energy surface. 74 Since it truly is the orbital crossing that differentiates allowed and forbidden reactions, it is perhaps not surprising that in the case of the reaction between cyclopentyne and 1,3-butadiene,
231
Cyclopentynes: Enigmatic Intermediates
R1
R2
Figure 7. Generalized potential energy surface for a forbidden reaction, A B. R~ and I12 are reaction coordinates.
the difference in activation barrier between the allowed and the forbidden reactions is not very large. The calculation of the reaction path for the [2+2] cycloaddition of cyclopentyne (4) and 1,3-butadiene provided a single-valley potential energy surface characteristic of an allowed reaction (Figure 4). As was the case for the [2+2] process involving 4 and ethylene, the transition state was unsymmetrical, the distances of the newly forming a-bonds being 2.3/~ and 3.2/~. Nonetheless, the reaction profile was that of a concerted reaction. The activation barrier for the cycloaddition was
165 155 -
~-?~6o.8 60.2
158.3. . . . . 4 +F
', ,, " "
~
145 -
'
',
tI
55 ~HO
(kcal/mol) 45-
~
~t
'"',,
[2+2] Cycloadduct
',
',,
5-
~
'~---3.5
~ -5-
@ [2+4] Reaction Coordinate
Cycloadduct
,
Figure 8. Potential energy diagram for [2+2] and [2+4] cycloaddition of 4 and 1,3-butadiene.
232
JOHN C. GILBERT and STEVEN KIRSCHNER
1.9 kcal/mol (Figure 8), a value only 0.6 kcal/mol below for the [2+4] reaction. In fact, because average errors in the AM1 method are slightly greater than this difference, it is possible to conclude that the computationally allowed [2+2] and forbidden [2+4] reaction channels involving 4 and 1,3-butadiene may well be kinetically competitive. We believe that the competitive nature of the two processes results from the aforementioned fact that the orbital crossing for the forbidden pathway is subsequent to the transition state and thus does not define the activation barrier for the reaction. As a consequence, the relative energies of the transition states for the two pericyclic reactions largely reflect initiation of o-bond formation between the cycloalkyne and the diene.
6.2. UnveilingCompeting [2+2] and [2+4] Cycloadditions The theoretical calculations involving cyclopentyne and 1,3-butadiene prompted us to undertake the study of cyclopentyne with 1,3-dienes. Thus, the plan was to design a system in which the cyclopentyne that was generated would have the choice of two distinct reaction channels, namely, [2+2] cycloaddition and [2+4] cycloaddition. If cyclopentyne were to exist as two orbital isomers having a significant kinetic barrier to their interconversion, the calculations suggested that differing ratios of the two types of cycloadducts should result. Even if the theoretical prediction of the existence of the Cs was a computational artifact, study of the reaction of cyclopentyne with a 1,3-diene would still be of interest because of the opportunity to compare competing pericyclic reactions, only one of which is thermally allowed. In view of Fitjer's observation that 1,3-butadiene gave only the [2+2] cycloadduct (Eq. 5), 23 our plan might appear to have been a futile undertaking, but at the time we thought it was not, using the following reasoning. Cyclopentyne is an extremely reactive intermediate, and although it appeared not to react by diffusion control, based on the competition experiment between cyclohexene and dihydropyran, 23 its selectivity for dihydropyran versus cyclohexene is quite modest (Eq. 3). Consequently, it seemed reasonable to assume that there would be relatively few unproductive collisions with a substrate. Assuming this phenomenon extended to its reaction with 1,3-dienes, we thought that conformational issues associated with the diene might be relevant since only the s-cis conformation is susceptible to the [2+4] cycloaddition. In this context, 1,3-butadiene is then seen as a poor choice for testing the competition between [2+2] and [2+4] modes ofcycloaddition because this diene favors the s-trans conformation by 2.5 to 3.1 kcal/mol, which corresponds to a preference of greater than 99:1 for this conformer (Eq. 25). 76 Locking the 1,3-diene in an s-cis conformation was an obvious solution to the problem, and we felt that such a substrate would provide a more valid probe for studying the issue of competing cycloaddition reaction channels.
Cyclopen~nes: Enigmatic Intermediates H
233
H
I
H
H.~oc.f.,
!
H .~ oc.~ oc. H H
I
H
(25)
H H,,C,H
s-cis <1
s-trans >99
McKinley undertook the initial study by examining the reaction between spiro[4.2]-hepta-1,3-diene and cyclopentyne, which was prepared according to the DAMP protocol (Scheme 7). He found that producing the cycloalkyne in the presence of 117 afforded an approximately 1:3 mixture of 118 and 119, the [2+2]and [2+4]-cycloadducts, respectively (Eq. 26). 77 The isomers were formed in only
4
117
118
119
low isolated yields (Table 1), but crude yields were substantially higher. Once the cycloadducts were shown to be stable to the reaction conditions, it was possible to conclude that the [2+4] cycloaddition was competitive with the [2+2] process. Thus cyclopentyne could be added as a member of the select group of molecules that contain a strained re-system and simultaneously undergo these two modes of cycloaddition. 78 The generation of 119 also represented the first example of an aliphatic 1,3-diene undergoing a [2+4] reaction with cyclopentyne and confirmed our concerns regarding the validity of using 1,3-butadiene as a test diene for the competition. McKinley determined the ratio of 118:119 as a function of reaction temperature and found that it was basically unchanged over the range from-50 to +25 ~ (Table
Table 1. Product Ratios from 1-Diazomethylenecyclobutane (86) as a Function of Temperature Run
T (~
Yield (%)a
Ratio 118:119 b
1
-40
5
1:2.9
2
-25
-
1:3.6
3
0
5
1:2.7
4
25
2
1:3.4
5
-40
1
1:2.5
Notes: alsolatedyield.
bAverage of two or more runs.
234
JOHN C. GILBERTand STEVEN KIRSCHNER Table 2.
Product Ratios from 1,2-Dibromocyclopentene (6) as a Function of Temperature Yield (%)~
T (~
Ratio 118:119 b 60:1 c
0 25
20:1
60
11:1
80
20
9.4:1
Notes: a Isolated yield.
Average of two or more runs. c Owing to the small amounts of 119 formed, this ratio is subject to considerable experimental error. b
1). Our interpretation of this result was that ZktU/~for the [2+2] and [2+4] processes must be close to zero, so that the product ratio was largely being defined by zk~S~. He then proceeded to examine the reaction of 117 with the cyclopentyne generated by vicinal elimination of bromine from 1,2-dibromocyclopentene (6) using n-butyllithium (Scheme 3). This route was expected to provide the C2v form 4 of the cycloalkyne. Once again, both 118 and 119 were produced and were stable to the reaction conditions, but now their ratio strongly favored the [2+2] cycloadduct 118 (Table 2). Moreover, the ratio of the two was dependent on temperature over the range of 0 to +80 ~ indicating that ~ ~ for the [2+2] and [2+4] processes was no longer close to zero. At first glance, the results given in Tables 1 and 2 clearly indicated that a common reactive intermediate was not involved. We first hypothesized that the presence of lithium ion in the preparation of cyclopentyne from 6 was the source of the difference, which we sought to demonstrate through a control experiment in which 4 was generated from cyclobutanone in the presence of added lithium bromide. This modification did not, in fact, affect that ratio of products (Run 5, Table 2), thereby indicating that the lithium ion was not responsible for the differing results presented in Tables 1 and 2. However, we were concerned about the validity of the experiment as the lithium bromide was only slightly soluble in the reaction medium, and thus we questioned whether exogenous salt truly duplicated the reaction conditions under which lithium bromide was being generated by elimination from 1-1ithio-2bromocyclopentene (12, Scheme 3). Although our concerns were well-founded, as discussed below, we next opted to consider an alternate cause for the differences between 6 and 86 as sources of cyclopentyne. One possibility was that the vinyllithium 12 did not eliminate bromide to form 4 (Scheme 3), but instead added to 117 to afford the allylic anion 120 (Scheme 12). Intramolecular transmetallation and subsequent SN2 and/or Sty2 reaction of the resulting species could afford 118 and 119. Because Wittig and Heyn previously had shown that the rate of disappearance of anion 12 in diethyl ether was independent of the concentration of 2,5-diphenylisobenzofuran (Scheme 1),sa
Cyclopentynes: Enigmatic Intermediates
235 Br
LI
12
117
120 SN2
SN2 w
118
119
Scheme 12.
one might wonder why we even considered the pathways of Scheme 12 a possibility. The honest answer is that a "Devil's advocate," who had heard a presentation of our results at a meeting, 79 posed this option and convinced us that the alternate mechanism had to be addressed experimentally in our particular system. Another motivating factor was that Wittig and Heyn had reported evidence of second-order processes involving 12 in THF solutions, sa so if the tendency of this vinyllithium to react via bimolecular pathways extended to our hydrocarbonlike media, the sequence of Scheme 12 is more plausible. Hou undertook the challenging task of measuring the rate of disappearance of 6 as a function of the concentration of 117 present in solution. He found that the rate increased by a factor of about 50% over a four-fold change in [117], but the plots remained strictly first-order. Although such a change may be the result of the minor incursion of Srq processes like those of Scheme 12, it was ascribed instead to changes in the oligomerization of 11 as a function of the medium in which the vinyllithium was produced. 77 A mechanistic scenario to account for this result and those of Tables 1 and 2 was developed on the presumption that the [2+2] and [2+4] cycloadditions are subject to the precepts of either orbital symmetry (OS) 26 or orbital isomerism (OI). 66a The latter was preferred because of the stereospecificity observed for the [2+2] process (Scheme 4 and Eq. 19), and permitted the portrayal given in Scheme 13. To rationalize the predominance of 119 in the reaction when the diazocompound 86 was used,/c2, for the stepwise reaction channel must be slightly greater than k2 for the concerted pathway. Because the near invariance with temperature of the ratio of 118:119 required that A&Hr be about 0 kcal/mol for the two processes, the partitioning between the stepwise and concerted pathways was proposed to be entropy-controlled. Moreover, it was noted that the constancy of the product ratio also placed constraints on the fate of biradicaloid 121: Were it to collapse to both cycloadducts, the activation enthalpies for the corresponding transition states would also have to be essentially identical, an unlikely possibility in terms of the
236
JOHN C. GILBERT and STEVEN KIRSCHNER (2+2111
118
117
86
[2+4],~J7~'
Li
119
1 21
117
Br
12
~,
4
[2+2]-~ 122
118
Scheme 13.
differing stereoelectronic factors involved. It was thus concluded that 121 led exclusively to the thermodynamically more stable [2+4]-cycloadduct 119. 77
6.3. Cyclopentyne-LithiumBromide Complex To accommodate the results when 11 was used, we proposed the complex 122 as a key intermediate that reacted with diene 117 to afford the cycloadducts via concerted and stepwise pathways (Scheme 13). Precedents exist for complexes between cycloalkynes and transition metals, 8~ including an unpublished report of the isolation of a platinum(0)-cyclopentyne complex. 81 In this scenario, AH ~ was no longer 0 kcal/mol, presumably because there was an activation barrier to decomplexation as the cycloaddition processes proceeded. The ratio of k2/k 2, was now greater than 1 for unknown reasons. We accounted for the failure of exogenous LiBr to elicit formation of 122 from 86 to the solubility problem noted earlier and to the short lifetime of 4. Thus when 12 eliminates lithium bromide, the salt is produced within the solvent shell along with the cycloalkyne, and may be intimately associated with it. This situation is very different from one in which a bimolecular interaction between the short-lived 4 and the salt is required. On the basis of our hypothesis, the classical route to cyclopentyne (4) from 1,2-dibromocyclopentene (6), as developed by Wittig et al. (Scheme 1), was producing a complexed, rather than a free, form of this species. Moreover, there was the implication that the DAMP protocol involving 86 was affording 4 in its unencumbered state. Confirmation of the hypothesis of complexation was sought in a series of experiments executed by Hou. 82 He extended the studies of the competition between [2+2] and [2+4] cycloadditions of cyclopentyne using four different sources of the reactive intermediate: 1,2-dibromocyclopentene (6), 1-dibromomethylenecyclobutane (31), 1-diazomethylenecyclobutane (86), and 1-(l'bromo-l'-trimethylsilyl)cyclobutane (123). The latter precursor was a novel potential source of cyclopentyne that Hou found could be converted to the cycloalkyne by the action of fluoride ion (Scheme 14). As the diene, he selected spiro[4.4]-
Cyclopentynes: Enigmatic Intermediates
237
8r
123
124
nona- 1,3-diene (124). He used this substrate to avoid any possible stereoelectronic complications associated with the presence of the three-membered ring in 117. For example, at one time it was believed that spiroconjugation was present in 117, 83a although this was subsequently discounted. 83b Hou found that the expected [2+2] and [2+4] cycloadducts 127 and 128 were formed from all four precursors, but by examining product ratios and their temperature dependence he was able to develop some significant new conclusions. The results on which these conclusions were based are compiled in Table 3. The data from using 6 and 86 as precursors to cyclopentyne were entirely analogous to those observed with 117 as the diene (see Tables 1 and 2). The data provided for 31, which was not used as a precursor of cyclopentyne with 117, showed that its overall behavior was similar to that of 6, suggesting that it too provided a complex between cyclopentyne and lithium bromide. The differences in ratios observed in runs 1 and 6 appeared to be experimentally significant and were interpreted as implying differing forms of oligomerization of the complexes that depended on their mode of generation. Because the temperatures for runs 4 and 5 with dibromide 31 were below those at which 6 produces cycloadducts in the lipophilic medium for the reactions, the results confirmed Fitjer's conjecture 23 that 31 does n o t afford the vinyllithium 12 (Scheme 3); rather, it presumably loses bromide ion and provides the complex 122 (Scheme 13). All the data remained in accord with the scenario presented in Scheme 13. Even more illuminating were the results with 123. As seen in entries 10 and 11 of Table 3, the selectivity and temperature dependence for [2+2] relative to [2+4] cycloaddition matched those seen with 86, indicating that these two precursors
B r ~ F -
~=cc~Si(CH3)3 123
)' 125
34
r ""'"
126
Scheme 14.
..'"
4
238
JOHN C. GILBERT and STEVEN KIRSCHNER
128
127
provided the same reactive intermediate, viz., free cyclopentyne (4). It was unclear whether the conversion of 123 to 4 involved isomerization of the anion 125 to 126, although the temperature of run 10 was below that for decomposition of the lithium-containing analog, 12, of 126. However, the counter-ion for the latter is a quaternary ammonium ion, which makes 126 more carbanion-like and thus more susceptible to elimination to 4. The results with 123 also confirmed our hypothesis that lithium ion was the key factor that sets 6 and 123 apart from 86 in cycloaddition reactions involving dienes 117 and 124. We might summarize our understanding of the enigmatic character of cyclopentyne at this stage by saying that the molecule was capable of concerted [2+2] cycloadditions owing to its unusual orbital array, and followed two different reaction channels when generated in the presence of a diene, undergoing such reactions both in free and complexed forms. But the molecule had yet another surprise in store for us, revealed by performing what some would characterize as "one experiment too many." The rationale we used for doing so is worth describing.
Table 3.
Ratios o f C y c l o a d d u c t s as a F u n c t i o n o f Precursor and Temperature
Source of cyclopentyne
Run
T (~
Weld (%)a
36:1 27:1 21 :I 54:1 27:1 12:1
I
6
0
2 3 4 5 6 7
6 6 31 31 31 86
25 60 -78 -40 0 -40
-
1:1.5
8
86
0
-
1:1.5
9
86
25
4
1:1.6
10
123
-40
-
1 : 1.5
11
123
25
5.2
1:1.6
Notes: aGLC yield.
bAverage of two or more trials.
-
Ratiob 127:128
15 14
Cyclopentynes: Enigmatic Intermediates
239
6.4. Competitive [2+2] Cycloadditions From exploring competition between intramolecular cycloaddition pathways with dienes, we had gathered compelling evidence that the cyclopentyne-precursors 1,2-dibromocyclopentene (6) and 1-dibromomethylenecyclobutane (31) generated a complexed form of the cycloalkyne. The cyclopentyne from 1-diazomethylenecyclobutane (86) and (bromocyclohexylidenemethyl)trimethylsilane (123), on the other hand, was free. We then asked the question of what might happen if an intermolecular competition involving [2+2] cycloaddition were conducted between two monoenes. Our expectation was that 6 and 31 would have a different selectivity between the alkenes than would 86 and 123. Indeed, as noted earlier, Fitjer et al. had already performed such an experiment with 31 and found that dihydropyran reacted about three times faster than cyclohexene (Eq. 3). 23 Given this reference point, Hou elected to use the same pair of cycloalkenes with 6 and 86. 84 The results obtained at 25 ~ are summarized in Table 4. Our expectations were certainly not fulfilled, as all three precursors appeared to generate the s a m e reactive intermediate, within the experimental error of our GLC measurements of product ratios! 85 Of course, the result might have meant that free and complexed cyclopentyne have the same selectivity toward the two cycloalkenes. We considered it more likely, however, that an equilibrium might exist between the two species and that it was the uncomplexed form that provided the [2+2] cycloadducts (Scheme 15). This forced a reevaluation of our explanation for the behavior of dienes toward cyclopentyne as a function of its precursor, a situation in which there clearly was a dependence on whether or not lithium bromide was present (Tables 1-3). Was there a special role that might be specific to the dienes, viz., their potential ability to interact with the lithium bromide-cyclopentyne complex? A possible scenario for this involves modification of Scheme 13, and is portrayed in Scheme 16. The basic concept is that complex 122 is in equilibrium with a complex, 129, between the substrate diene and lithium bromide. This new complex is within the same solvent shell as 122, and it is 129 rather than 122 that is the direct precursor of the cycloadducts. Although still highly speculative at the
Table 4. Ratios of [2+2] Competition as a Function of Precursor
Cyclopentyne precursor 6
Ratio 36:33 3.5
31
3.3 a
86
3.8
Note:
awe believe this value differs from that of Fitjer et aL23 because we
corrected the ratio for detector response, whereas it appears they did not.
240
JOHN C. GILBERT and STEVEN KIRSCHNER
Q
OI
Ol-LiBr 122
4 36
Scheme 15.
I'LiBr
[~R
R_
/
Oi
122
BrLi_O \ /
.
Cycloadducts
129
Scheme 16
time of this writing, the results shown in Table 5, obtained using mixtures of spirodiene 124 and cyclohexene as the substrates at 25 ~ may be interpreted as supporting this hypothesis. ~ Thus, the data using 86 indicate that free cyclopentyne reacts more rapidly with cyclohexene than with 124. The selectivity for monoene v s . diene is reversed with precursors 6 and 31, which was taken as possibly indicating that formation of complex 129 fostered enhanced cycloaddition reactions with the 124 relative to cyclohexene. Importantly, with all three precursors of cyclopentyne, the selectivity between the intramolecular reactions channels leading to 127 and 128 was found to be unchanged in these competition experiments (Table 5).
Table 5. Competition between Diene and Monoene as Function of Precursor Relative amounts
Ratios
Cyc/opentyne precursor
127
128
33
127:128
(127+128):33
6 31 86
35 10.4 0.6
1 -1
I
19 3.6 2.2
35:1 10.4:1 1:1.6
1.9:1 3.2:1 1"1.3
Cyclopentynes: Enigmatic Intermediates
241
7. CONCLUSIONS We do not pretend to say that cyclopentyne is no longer an enigmatic molecule.The detailed mechanisms of its pericyclic reactions with various n-systems are clearly precursor-dependent, apparently as a result of the intervention of complexes that attend organolithium-mediated routes to it. The definitive classification of these pericyclic processes as concerted or stepwise remains an open question, and answers await development of appropriate mechanistic probes. The stereochemistry of the [2+4] cycloaddition of cyclopentyne with dienes are yet to be explored, and though the results of such studies may shed light on the theoretical paradigm controlling its pericyclic transformations, they may also serve to deepen the mysteries associated with this aspect of its chemistry. Of course, the physical characterization of cyclopentyne remains as a challenge of the first m a g n i t u d e - one that will require highly ingenious experimental efforts to address successfully. Nonetheless, we now have a deeper theoretical and chemical understanding of this fascinating member of the family of strained n-systems than we did when we "stumbled" into this area of research nearly fifteen years ago.
ACKNOWLEDGMENTS We thank the Robert A. Welch Foundation (Grant F-815), the Texas Higher Education Coordinating Board (Grant ARP-455), and the National Institutes of Health (Grant GM 29972) for partial financial support of the work on which this chapter is based. A dedicated corps of co-workers has contributed its exceptional intellectual and practical talents to our research efforts in alkylidenecarbene and cycloalkyne chemistry. With the exceptions of Brent Blackburn and Darin Laird, their names are contained in the various references cited from our group.
REFERENCES 1. Eaton, P. E.; Cole, T. W., Jr. J. Am. Chem. Soc. 1964, 86, 3157; review of cubanes: Griffin, G. W.; Marchand, A. E Chem. Rev. 1989, 89, 997. 2. Chen, N.; Jones, M., Jr.; White, W. R.; Platz, M. S. J. Ant Chem. Soc. 1991, 113, 4981; review of distorted alkenes: Warner, E M. Chem. Rev. 1989, 89, 1067. 3. Chapman, O. L.; Mattes, K.; Mclntosh, C. L.; Pacansky, J.; Calder, G. V.; Orr, G.; J. Am. Chem. Soc. 1973, 95, 6134; reviews of arynes: Gilchrist, T. L. The Chemistry of Functional Groups, Supplement C, pt. 1, Patai, S., Rappoport, Z., eds., Wiley, New York, 1983, pp 383; Reinecke, M. Tetrahedron 1982, 38, 427. 4. Warmuth, R. Angew. Chem. Int. Ed. Engl. 1997, 36, 1347. 5. Recentmore general discussions of cycloalkynes are available: Meier, H. Adv. Strain Org. Chem. 1991, 1, 215; Gleiter, R.; Merger, R. in: Modern Acetylene Chemistry, Stang, E; Diederich, E, eds., VCH: Weinheim, 1995, p 285. 6. Ruzicka, L.; H~bin, M.; Boekenoogen,H. A. Helv. Chim. Acta 1933, 16, 498. 7. Blomquist, A. T.; Burge, R. E.; Suscy, A. C. J. Am. Chem. Soc. 1952, 74, 3636; Blomquist, A. T.; Liu, L. H.; Bohrer, J. C. J. Am. Chem. Soc. 1952, 74, 3643; Blomquist, A. T.; Liu, L. H. J. Am. Chem. Soc. 1953, 75, 2153.
242
JOHN C. GILBERT and STEVEN KIRSCHNER
8. (a) Krebs, A.; Wittig, G. Chem. Ber. 1961, 94, 3260; (b) Wittig, G.; Pohlke, R. Chem. Ber. 1961, 94, 3276; (c) Wittig, G.; Weinlich, J.; Wilson, E. R. Chem. Bet. 1965, 98, 458; (d) Wittig, G.; He)m, J. Lz'ebigsAnn. Chem. 1969, 726, 57. 9. An original formulation as a 1:1 adduct 8a proved to be in error: See footnote 7 of Ref. 10. 10. Wolinsky, J.; Erickson, K. J. Am. Chem. Soc. 1965, 87, 1143. ll. Bauer, W.; Winchester, W. R.; Schleyer, E v. R. Organometallics 1987, 6, 2371; Ktbrich, G.; Angew. Chem. Intl. Ed. Engl. 1967, 6, 41. 12. Cf Favorskii, A. E.,J. Gen. Chem. USSR 1936, 6, 720 [Chem.Abstr. 193@30, 6337(8)]; Favorskii, A. E. Bull. Soc. Chim. France 1936, 3, 1727. 13. Additional evidence that cyclopentyne is subject to nucleophilic attack is found in the reports describing the mechanism of formation of l-phenylcyclopentene from the reaction of phenyllithium with 1-chlorocyclopentene (13): Montomery, L. K.; Scardiglia, E; Roberts, J. D. J. Am. Chem. Soc. 1965, 87, 1917; Montgomery, L. K.; Applegate, L. E. J. Am. Chem. Soc. 1967, 89, 5305. 14. It has been speculated that the thermal trimerization of cyclohex)me might involve Diels-Alder reaction of the diene i, itself possibly derived from a [2+2] cycloaddition, and subsequent isomerization of the Dewar benzene fi, that results: Wittig, G.; Mayer, U. Chem. Ber. 1963, 96, 342; Wittig, G.; Weinlich, J. Chent Bet. 1965, 98, 471.
i
ii
15. SchUller, J., Ph.D. Dissertation, Universitat Heidelberg, 1966, as cited in Hoffmann, R. W. Dehydrobenzene and Cycloalkynes, Academic Press, New York, 1967, p 357. 16. Chapman, O. L.; Gano, J.; West, P. R.; Regitz, M.; Maas, G. J. A n Chem. Soc. 1981, 103, 7033. 17. Trimerization of acenaphthyne (20) has recently been proposed to account for the formation of 23 upon treating acenaphthoquinone (21) with Ti(0): Zimmermann, K; Haenel, M. W. Synlett 1997, 609. 18. Review: KObrich, G.; Buck, E in: Chemistry of Acetylenes, H. G. Viehe, ed., Marcel Dekker, New York, 1969, p 99. 19. Wolinsky, J. J. Org. Chem. 1961, 26, 704. 20. Erickson, K. L.; Vanderwaart, B. E.; Wolinsky, J. J. Che~ Soc., Che~ Commun. 1968, 1031. 21. Erickson, K. L.; Markstein, J.; Kim, K. J. Org. Chem. 1971, 36, 1024; Erickson, K. L. J. Org. Chem. 1971,36, 1031; Samuel, S. P.; Niu, T-q.; Erickson, K. L. J. An~ Chem. Soc. 1989,111, 1429. 22. Fitjer, L.; Wehle, D. Angew. Che~ Int. Ed. Engl. 1979, 18, 868; Fitjer, L. Chem. Ber. 1982, 115, 1047; Fitjer, L.; Wehle, D. Che~ Ber. 1982, 115, 1061. 23. (a) Fitjer, L.; Kliebisch, U.; Wehle, D.; Modaressi, S. Tetrahedron Left. 1982, 23, 1661; (b) the generation and some aspects of the chemistry of l-alkenyllithium reagents have recently been reviewed: Braun, M. Angew Che~ Intl. Ed. 1998, 37, 431. 24. Reviews: (a) Hartzler, H. D. in: Carbenes, vol. 2, Moss, R. A., Jones, M., Jr., eds., Wiley-Interscience, New York, 1975, p 43; (b) Stang, P. J. ChenL Rev. 1978, 78, 383; (c) Stang, P. J. Acc. Chem. Res. 1982, 15, 348. 25. (a) For example, see Bowne, A. T; Christopher, T. A.; Levin, R. H. Tetrahedron Lett. 1976, 17, 4111, and references cited therein; (b) particularly fascinating recent examples are the [2+2] cycloaddition of fullerenes and benz)me: Hoke II, S. H.; Molstad, J.; Dilettato, D.; Jay, M. J.;
Cyclopentynes: Enigmatic Intermediates
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. 60. 61.
243
Carlson, D.; Kahr, B.; Cooks, R. G. J. Org. Chem. 1992, 57, 5069, and Meier, M. S.; Wang, G.-W.; Haddon, R. C.; Brock, C. A.; Lloyd, M. A.; Selegue, J. P. J. Am. Chem. Soc. 1998, 120, 2337. Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry, Verlag Chemie, Weinheim, Germany, 1970. Fitjer, L.; Modaressi, S. Tetrahedron Lett. 1983, 24, 5495. Ref. 26, page 173. Hoffmann, R.; Imamura, A.; Hehre, W. J. J. Am. Chem. Soc. 1968, 90, 1499. Rees, C. W.; Storr, R. C. J. Chem. Soc., Chem. Commun. 1965, 193. Kenney, J. W.; Simons, J.; Purvis, G. D.; Bartlett, R. J. J. Am. Chem. Soc. 1978, 100, 6930. Skell, P. S.; Woodworth, R. C. J. Am. Chem. Soc. 1956, 78, 4496. Stang, P. J.; Mangum, M. G. J. Am. Chem. Soc. 1975, 97, 1459. Stang, P. J.; Mangum, M. G.; Fox, D. P.; Haak, P. J. Am. Chem. Soc. 1974, 96, 4562. Kopecky, K. R.; Hammond, G. S.; Leermakers, P. A. J. Am. Chem. Soc. 1961, 83, 2397; Kopecky, K. R.; Hammond, G. S.; Leerinakers, P. A. J. Am. Chem. Soc. 1962, 84, 1015; Duncan, E J.; Cvetanovic, R. J. J. Am. Chem. Soc. 1962, 84, 3593. Stang, P. J.; Fox, D. R; J. Org. Chem. 1978, 43, 364. We eventually showed that this occurs at temperatures as low as -78 oC: Weerasooriya, U. Ph.D. Dissertation, The University of Texas at Austin, 1980; see also, Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997. Curtin, D. Y.; Kampmeier, J. A.; O'Connor, B. O. J. Am. Chem. Soc. 1965, 87, 863. Newman, M. S.; Okorodudu, A. O. M. J. Am. Chem. Soc. 1968, 90, 4189. Newman, M. S.; Patrick, T. J. J. Am. Chem. Soc. 1969, 91,6461. Stang, P. J.; Fox, D. P.; J. Org. Chem. 1977, 42, 1667. Review: Maryanoff, B.; Reitz, M. Chem. Rev. 1989, 89, 863. This is the acronym we coined for diethyl diazomethylphosponate. Seyferth, D.; Marrnar, R. M.; Hilbert, P. H. J. Org. Chem. 1971, 36, 1379. Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973, 151; Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1, 1977, 869. Kluge, A. E Tetrahedron Lett. 1978, 19, 3629; Kluge, A. F.; Cloudsdale, I. S. J. Org. Chem. 1979, 44, 4847. Disteldorf, W.; Regitz, M. Chem. Ber. 1976, 109, 546. Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997; Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47, 1837. Weerasooriya, U. Ph. D. Dissertation, The University of Texas at Austin, 1980. Gilbert, J. C.; Weerasooriya, U.; Giamalva, D. H. Tetrahedron Lett. 1979, 19, 4619. Lahti, P. M.; Berson, J. A.J. Am. Chem. Soc. 1981, 103, 7011. Behr, L. C.; Fusco, R.; Jarboe, C. H. Chem. Heterocycl. Compd. 1967, 22, 1. (a) Gilbert, J. C.; Giamalva, D. H. J. Org. Chem. 1992, 57, 4185; (b) Gilbert, J. C.; Weerasooriya, U.; Tetrahedron Lett. 1980, 21, 2041; Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1983, 48, 448. (a) Gilbert, J. C.; Baze, M. E. J. Am. Chem. Soc. 1983, 105, 664; (b) Gilbert, J. C.; Baze, M. E. J. Am Chem. Soc. 1984, 106, 1885. Gordon, A. J.; Ford, R. A. The Chemists Companion, John Wiley, New York, 1972. Stock, L. M. Aromatic Substitution Reactions, Prentice-Hall, Inc., Englewood Cliffs, 1968. Kirmse, W.; Rondan, N.; Houk, K. N. J. Am. Chem. Soc. 1984, 106, 7989. See also, Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471, for a review of the theoretical aspects of substituent effects on retrocyclization of cyclobutenes. This figure is an adaptation of Figures 2 and 3 of Ref. 57 and 58, respectively. (a) Copper, W.; Waiters, W. D. J. Am. Chem. Soc. 1958, 80, 4220; (b) Frey, H. M. Trans. Faraday Soc. 1962, 58, 957; (c) Frey, H. M.; Marshall, D. C. Trans. Faraday Soc. 1965, 61, 1715. Montaigne, R.; Ghosez, L. Angew. Chem. Int. Ed. Engl. 1968, 7, 221.
244
JOHN C. GILBERTand STEVEN KIRSCHNER
62. Gilbert, J. C., unpublished results. 63. (a) Olivella, S.; PericM, M. A.; Riera, A.; Sole, A. J. Chem. Res. 1985, 328; (b) Olivella, S.; Peric~s, M. A.; Riera, A.; Sol~,, A. J. Am. Chem. Soc. 1986, 108, 6884. 4. Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Soc. 1974, 96, 5246. 65. Doubleday, C., Jr. J. Am. Chem. Soc. 1993, 115, 11968. 66. (a) Dewar, M. J. S.; Kirschner, S.; Kollmar, H. W. J. Am. Chem. Soc. 1974, 96, 5240; (b) Dewar, M. J. S.; Kirschner, S.; Kollmar, H. W.; Wade, L. E. J. Am. Chem. Soc. 1974, 96, 5242; (c) Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Sot'. 1974, 96, 5244; (d) Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Soc. 1971, 93, 4291; (e) Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Soc. 1971, 93, 4292. 67. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. E; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902. 68. Gilbert, J. C.; Kirschner, S. Tetrahedron Lett. 1993, 34, 603. 69. Gilbert, J. C.; Kirschner, S. Tetrahedron Lett. 1993, 34, 599. 70. Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Soc. 1971, 93, 4294. 71. Johnson, R. P.; Daoust, K. J. J. Am. Chem. Soc. 1995, 117, 362. 72. Kirschner, S. unpublished results. 73. Gilbert, J. C.; Kirschner, S. Tetrahedron 1996, 52, 2279. 74. (a) Dewar, M. J. S.; Kirschner, S. J. Chem. Soc. 1975, 461--463; (b) Dewar, M. J. S.; Kirschner, S. J. Chem. Soc. 1975, 463. 75. The ensuing discussion will be couched in terms of the C2v species 4. The same arguments would apply to 133, since the topologies of its bonding molecular orbitals topologies to those of 4. 76. Squillacote, M. E.; Sheridan, R. S.; Chapman, O. L.; Anet, E A. L. J. Am. Chem. Soc. 1979, I01, 3657. 77. Gilbert, J. C.; McKinley, E. G.; Hou, D.-R. Tetrahedron 1997, 53, 9891. 78. These include benzyne (Wittig, G.; DUff, H. Liebigs Ann. Chem. 1964, 672, 55; Crews, E; Beard, J. J. Org. Chem. 1973, 38, 522), 1,2-dehydro-o-carborane (Ghosh, T.; Gingrich, H. L.; Kam, C. K.; Mobraaten, E. C.; Jones Jr., M. J. J. Am. Chem. Soc. 1991, 113, 1313, and possibly 1,2,4-cyclohexatriene (Christi, M.; Braun, M.; MUller, G. Angew. Chem. Int. Ed. Engl. 1992, 31, 473). 79. Schechter, H., private communication, July 1995. 80. Bennett, M. A. Pure Appl. Chem. 1989, 61, 1695. 81. Warnock, G. E, unpublished work cited in Ref. 80. 82. Hou, D.-R., unpublished results. 83. (a) Clark, R. A.; Fiato, R. A. J. Am. Chem. Soc. 1970, 92, 4736; (b) van de Ven, L. J. M.; de Haan, J. W. J. Magn. Resonance 1975, 19, 31; SchoeUer, W. W.; Dahm, J. Tetrahedron 1973, 29, 3237; Chiang, J. E; Wilcox, Jr., C. E J. Am. Chem. Soc. 1973, 95, 2885. 84. Data are not yet available for 123. 85. Interestingly, had this result been obtained before those involving the dienes, the latter experiments might never have been undertaken.
OVERCROWDED POLYCYCLIC AROMATIC ENES
P. Ulrich Biedermann, John J. Stezowski, and Israel Agranat 1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Effects of Overcrowding . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Leading Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Measures for the Nonplanarity in PAEs . . . . . . . . . . . . . . . . . 1.4. Conformations, Symmetry, and Chirality . . . . . . . . . . . . . . . . 1.5. Thermochromism and Photochromism . . . . . . . . . . . . . . . . . . 1.6. Molecular Switches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7. Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Modeling of Overcrowded Bistricyclic Enes . . . . . . . . . . . . 2.1. Conformational Energies . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Strain Energies Derived from Isodesmic Reactions . . . . . . . . . . . 2.3. Conformational Parameters . . . . . . . . . . . . . . . . . . . . . . . 2.4. Double Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Pyramidalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. C9a-C9--C8aBond Angle . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Overcrowding in the Fjord Regions . . . . . . . . . . . . . . . . . . .
Advances in Theoretically Interesting Molecules, Volume 4, pages 245--322 Copyright 9 1998 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0070-1
245
246 247 248 250 251 253 255 257 257 264 269 279 287 290 292 294
246
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
2.8. Geometrical Parameters of the Bridges . . . . . . . . . . . . . . . . . . 2.9. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Comparison of Calculated and Crystal Structures . . . . . . . . . . . . . . . . 4. Dynamic Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
302 308 309 313 318 319
1. INTRODUCTION The bistricyclic enes (1) enigma I has fascinated chemists since the red hydrocarbon bifluorenylidene (2) was synthesized in 1875, 2 the yellow dixanthylene (3) was synthesized in 1895, 3 and thermochromism and piezochromism were revealed in bianthrone (4) in 1909. 4.5 The bistricyclic enes are representatives of the more general class of overcrowded polycyclic aromatic enes (PAEs). They may be perceived as bridged tetraarylethylenes or tetrabenzofulvalenes and can be classified into homomerous bistricyclic enes (1, X = Y) and heteromerous bistricyclic enes (1, X ~: y).6
2
~
I
7
Oord . . . . . . . . .1. . . . . . . . . . .
I
X = Y: homomerous
I 8
0ord
X ~ Y: heteromerous
I
These systems are attractive substrates for the study of the ground-state conformations and the dynamic behavior of overcrowded aromatic enes. 1,7,8 0
2
3
4
Derivatives of bianthrone (4) are topologically related to the natural product hypericin (5) (wide spread in St. John's Wort), an antidepressant 9 and a potent antiretroviral agent with potential anti-AIDS capabilities, l~ Lucigenin (6), a dicationic salt derived from N,N'-dimethylbiacridan (1, X,Y: NCH 3) was consid-
Overcrowded Polycyclic Aromatic Enes
247
ered to be the most powerful of all synthetic chemiluminescent substances. ~2'~3A dixanthylene double calix[6]arene has recently been described. 14
T
v
HO~CHa
y-o.,
OH O OH 5
/-
C1"13
NO3"
6
7
Thermochromic and photochromic bistricyclic enes also serve as candidates for potential molecular switches (vide infra). Bifluorenylidene (2) and bi-4H-cyclopenta[def]-phenanhren-4-ylidene (7), 15 with their central five-membered rings, are fullerene fragments and potential starting materials for the preparation of buckybowls. 16--21 The topic ofbistricyclic enes has previously been reviewed. I'8'22Special attention should be drawn to a very recent review on strained olefins, including bistricyclic enes, by Sandstr0m. 23 The term intramolecular overcrowding was first introduced by Bell and Waring to denote aromatic systems that adopt non-planar forms in order to accommodate certain hydrogen atoms [e.g., in dibenzo[c,g]phenanthrene ([5]helicene)]. 24 Intramolecular overcrowding is a steric effect shown by aromatic structures in which the (intramolecular) distance of the closest approach between non-bonded atoms, calculated on the basis of conventional bond lengths and bond angles, is smaller than the sum of the van der Waals radii of the involved atoms. 25 This definition can be extended to structures, that are not aromatic, e.g., the elusive tetra-t-butylethene. 23 Why are the bistricyclic enes overcrowded or congested? In bistricyclic enes (1), the intramolecular overcrowding requires out-of-plane deformations in order to accommodate the sterically demanding tricyclic moieties without prohibitively close contacts of non-bonded atoms in the fjord region on both sides of the central double bond (C 9--C 9"). A hypothetical coplanar bistricyclic ene would maintain very short non-bonded carbon--carbon, carbon-hydrogen, and hydrogen-hydrogen distances in positions 1, 1', 8, and 8', leading to a considerable overlap of the van der Waals radii. The associated repulsive interactions could be relieved by deviations from coplanarity and by various bond angle and bond length distortions. 1.1. Effects of Overcrowding The overcrowding in 1 leads to various types of deformations.
248
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
Deformations of the central ethylene group: 9 stretching of C9-'C 9, and/or C9---C8a, C9---C9a, C9,---C8a,, and C9r"C9a, 9 distortions of bond angles around C 9 and C 9, 9 twisting of the double bond 9 anti- or syn-pyramidalization of the C 9 and C 9, atoms. Deformations of the tricyclic moieties and of their central rings: 9 anti- or syn-folding about the C9...X and Cg,...Y axes and hence boat confor-
mation of the central rings. Note that the boat conformation will reduce the bond angles Csa--Cg--Cga and C4a-X--CIo a. 9 propeller twisting about an axis connecting the centers of the two peripheral tings, and twist conformation of the central ring. Evidently, the energetic cost of such distortions may vary considerably. The following points should be noted in the present context: Once the molecule adopts a non-planar conformation in the ground state, it does not mean that it necessarily ceases to be overcrowded. Such a bistricyclic ene may still be overcrowded, but in a permissible manner. Obviously, the degree of overcrowding would be smaller than in the planar conformation. Secondly, the molecule need not adopt just one mode of deviation from planarity to achieve the equilibrium conformation in the ground state. Although various modes should be considered concomitantly, in many cases it may be expected that no more than one of these modes would be predominant. Two principal modes of out-of-plane deformations are to be considered: twisting around the double bond and out-of-plane bending. 22'26 In 1, the bending is realized by folding of the tricyclic moieties at both ends of the central ene about the C 9 ...X and C 9, ...Y axes, resulting in boat conformations of the central tings. In addition, the atoms C 9 and C 9, may be pyramidalized. Four pure conformations of 1 are considered: the twisted (t), the anti-folded (a), the syn-folded (s), and the orthogonally twisted (t• conformation. These modes may also occur simultaneously, leading to mixed folded-twisted conformations. A schematic representation of some of the simplest overall molecular shapes of bistricyclic enes is shown in Figure 1. This figure demonstrates some of the possible molecular conformations that could result from the intramolecular overcrowding of bistricyclic enes. These schematic projections should not be confused with Newman Projections of the double bond.
1.2. Leading Examples A variety of conformations have been revealed in the homomerous bistricyclic enes series, l Red bifluorenylidene (2), with central five-membered tings, adopts a twisted conformation in the crystalline state and in solution. 6' 27-31 The nonplanarity
Overcrowded Polycyclic Aromatic Enes
-Oplanar
249
-C)orthogonal
anti-folded twisted
twisted
syn-folded twisted
anti-folded syn-folded
unequally folded
Figure 1. Schematic projection along C9=C9' of various types of conformations (lines represent the peripheral benzene rings of the moieties).
of bifluorenylidene has already been inferred in 1935 on the basis of the dipole moment of 2,2'-difluorobifluorenylidene. 32 Yellow dixanthylene (3) 6'33-35 and bianthrone (4), 6'36"35 with central six-membered tings, are anti-folded with boat-shaped central rings in the crystalline state and in solution. Colorless 5,5'-bis-5Hdibenzo[a,d]cycloheptenylidene (8), with central seven-membered rings may adopt both an anti-folded and a syn-folded conformation in the crystalline state and in solution. 39-~3 The molecular structures of twisted 2, anti-folded 3, anti-folded 8, and syn-folded 8, as determined by X-ray crystallography are given in Figure 2. *L
2 $
9
An extreme case of syn-folding is represented by 9,9',10,10'-tetrahydrodianthracene (9), in which the anthracene tings in bianthrylidene are bent backward to the extent of permitting double bonds between the 9,9' and 10,10' positions. 45 It is interesting to note that in many cases it was possible to qualitatively distinguish between the twisted conformation and the anti-folded conformation of bistricyclic enes in solution using 1H-NMR spectroscopy. 35 '38 '46 '47 In a twisted conformation, the protons in the fjord regions appear in the 1H-NMR spectrum at low aromatic field (e.g., at 8.41 ppm in 2), while in an anti-folded conformation these protons appear at high aromatic field (e.g., at 7.16 ppm in 3).
250
P.u. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
twisted 2
ant/-folded 3
anti-folded 8
syn-folded 8
Figure 2. Molecular structures of bifluorenylidene (2), dixanthylene (3), and 5,5"-bis-5H-dibenzo[a,d]cycIoheptenylidene (8) determined by X-ray crystal-
1.3. Measures for the Nonplanarity in PAEs The pure twist of the central ethylene group is defined as the average of the signed torsional angles C9a-C9-C9,-C9a, and Csa---C9-C9,---Csa,'1
0~wis t = 1/2 (1;(C9a-C9-C9,-C9a,) + 'l;(Cga-C9-C9,-Csa,)) In addition to the twist in the double bond, the carbon atoms C 9 and C 9, of the ethylene group may be pyramidalized. '~'54 This out-of-plane deformation results in a change of the pure sp2-hybridization (towards sp3),49'50'52 and improves the n-overlap across the adjacent formal single bonds: 3 Pyramidalization of C 9 and C 9, may lead to syn- and to anti-pyramidalization as shown in Figure 3. Various measures for pyramidalization have been used in the literature. 4953 In the present study, the angle 7,,(C9), defined as the improper torsional angle "l;(C9aC9-C9,-C8a ) minus 180 ~ will be used:
Overcrowded Polycyclic Aromatic Enes
251 ,**
syn
anti
Figure 3. Hybridization in syn- and anti-pyramidalized double bonds.
9'
X(Cg) = (17 (C9a-Cg-C9,-C8a) M O D 360 ~ -
z(C9) 91""Q
8a
180 ~
X(Cg) = (17 (C9a,-Cg-Cg,-C8a,) M O D 360 ~ - 180 ~
In syn-pyramidalized double bonds, the pyramidalization angles x(C 9) and x(C9,) have identical signs, whereas in anti-pyramidalized double bonds they have opposite signs. The degree of nonplanarity of the tricyclic moieties may be measured by the dihedral of the least-squares-planes of the peripheral benzene rings. We will refer to the definitions presented above and the schemes presented in Figure 1 later on in the discussion of the stereochemistry and deviation from planarity of overcrowded bistricyclic enes.
1.4. Conformations, Symmetry, and Chirality The nonplanarity of bistricyclic enes raises the issue of their intrinsic chirality. 6'55-59The various conformations of homomerous and heteromerous bistricyclic enes may be classified according to their symmetry and chirality. 6 The following conformations were considered: 9 the planar conformation, pi, 9 the orthogonally twisted conformation t.L, 9 the orthogonally twisted conformation f• with nonplanar (propeller-twisted) bistricyclic moieties, 9 the pure twisted conformation t, 9 the twisted conformation t' with a different geometry in the two bistricyclic moieties, 9 the pure anti-folded conformation a, 9 the anti-folded conformation a' with bistricyclic moieties not having mirror symmetry, 9 the pure syn-folded conformation s, 9 the syn-folded conformation s" with bistricyclic moieties not having mirror symmetry, 9 the anti-folded, twisted conformation at, 9 the syn-folded, twisted conformation st,
252
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
9 the unequally folded conformation f, 9 the folded-twisted conformation ft. Positive and negative helicity may be indicated by subscripts P and M. E- and Z-isomers may be distinguished by subscripts E and Z, where relevant. These conformations need not necessarily be ground-state conformations. The symmetry classification also applies to transition states and/or intermediates in the dynamic processes characteristic of bistricyclic enes, and to molecules distorted by vibrational modes or the crystal environment. Furthermore, it should be noted that a specific conformation (e.g., t) may turn out to be a ground-state conformation of a specific bistricyclic ene, and an intermediate conformation or transition state in a dynamic process of a different bistricyclic ene. The conformations, symmetries and chirality of the unsubstituted bistricyclic enes (1) are given in Table 1. An extended analysis of the conformations, point groups, and chirality of bistricyclic enes, including homomerous and heteromerous monosubstituted and disubstituted 1, has been reported. 6 Figure 4 illustrates PM3 calculated conformations of unsubstituted homomerous bistricyclic enes with twisted t, anti-folded a, syn-folded s, and orthogonally twisted ti conformations and their respective point group symmetries and chirality. It should be noted that the role of chirality in the overcrowded PAEs is reminiscent of the benzenoid polycyclic aromatic hydrocarbon (benzenoid PAH) series. The
C o n f o r m a t i o n s , S y m m e t r y , and C h i r a l i t y of U n s u b s t i t u t e d B i s t r i c y c l i c Enes 1
Table 1.
Heteromerous X r Y
Homomerous X=Y
pl
D2h
achiral
pl
Czv
achiral
tj. t'•
D2d S4
achiral achiral
tl
C2v
achiral
tp t M tp tM
D2 C2
chiral chiral
t~ I~
C2
chiral
a
C2h
a"
Ci
achiral achiral
~
Cs
$
C2v
s'
Cs
achiral achiral
~
Cs
alp ai M
C2
chiral
--
C1
$tp st M
C2
chiral
--
C1
f
Cs
achiral
f
Cs
achiral
ftp fl~
C1
chiral
ftp fl M
C1
chiral
253
Overcrowded Polycyclic Aromatic Enes
"4
C~
%
,a
tM chiral
a achiral
s achiral
t• achiral
Figure 4. Conformations and symmetry elements of homomerous twisted bifluorenyliclene (D2), and anti-folded (C2h), syn-folded (C2v), and orthogonally twisted (D2d) dixanthylene using optimized PM3 structures. overcrowding and nonplanarity motifs are responsible for the incursion of chirality into both the PAE and PAH series. 6~ Kuhn et al. separated (E)- and (Z)-2,2'-diamino-bifluorenylidene by column chromatography by 1953.61 Diastereomers and enantiomers of substituted bistricyclic enes, e.g., derivatives of dithioxanthylene (1, X,Y: S), have been successfully separated. 62-64
1.5. Thermochromism and Photochromism Thermochromism is the phenomenon of reversible change of color with change of temperature. The thermochromism of bianthrones, dixanthylenes, and several other bistricyclic enes in solution has been shown to result (in each case) from a
254
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
thermal equilibrium between two distinct and interconvertible conformers (A ~ B), where A is the ground state folded yellow conformer and B is the thermochromic green or blue twisted conformer, absorbing at 6(X)-730 nm. 23'27'65-69 It has been claimed that "in bifluorenylidene (2), which is intensely red, but loses its color when chilled to low temperatures, the same phenomenon as in the case of dixanthylene may be assumed to occur, but in a different temperature range". 7~A,B type conformers were detected (along with other conformers) also in the photochromic and piezochromic phenomena exhibited by bianthrones, dixanthylenes and other bistricyclic enes. Photochromism is a phenomenon of photoinduced coloration which reverts either thermally or by irradiation. Piezochromism is a phenomenon of reversible change of color with change of pressure. It is generally accepted that the thermochromic B conformer and the photochromic B conformer are identical. Syn-folded conformers of bistricyclic enes with central six-membered tings have been reported as metastable conformations in the cases of dithioxanthylene (1: X,Y = S), 10,10'-dimethylbiacridan (1: X,Y = NCH3), 10,10,10',10'-tetrahydrobianthrylidene (1: X,Y = CH2) and 10,10'-dihydro-10,10'-dihydroxybianthrylidene (1: X , Y = C H O H ) . 65'69'71'72 These "intermediates" were generated photochemically from the corresponding anti-folded ground state conformers and readily reverted thermally to the anti-folded forms. 71'72 Photochromism in bianthrones, dixanthylenes and related bistricyclic enes has been reviewed. 68'69 Piezochromism of bistricyclic enes has so far gained only little attention. 69'73 The standard heat of the thermochromic equilibrium A ~ B in bianthrones and dixanthylene was investigated. 67'74"76 The data indicated that there was no direct correlation in AH ~ values and possible steric interactions in the vicinity of the overcrowded ene bond. 67 The thermal decay of the colored B species of 2,2'-bis-trifluoromethyl-bianthrone was studied by laser flash photolysis (AH*a_.,A). The relationship between the thermochromic process and the fast thermal E,Z-isomerization found in the bianthrone series indicated that both thermal phenomena have a common highest transition state. 67 Thermochromism has also been revealed in the solid state. Two crystal forms of Dixanthylene have been analyzed by X-ray crystallography. The yellow 13-form and the thermochromic deep blue green cz-form were shown both to be anti-folded. 33'34On the other hand a correlation between the ethylenic twist and the color of various crystalline modifications was observed for the related overcrowded enes 10 77 and 11. 78
~ ~ 10
11
CN
Overcrowded Polycyclic Aromatic Enes
255
It should be noted that the A to B transformation can be triggered not only by heating, photoexcitation, and pressure, but also by electrochemical redox cycles. 79-88
1.6. Molecular Switches The thermochromic and photochromic behavior of leading bistricyclic enes and the A ~ B conformational process inherent in these phenomena formed a basis for the prediction that such molecules may serve as possible switch units in molecular electronic devices. 88-9~A promising candidate is the bianthrone (4) molecule, an electron acceptor, substituted with electron-donor molecules. The rational behind this strategy was to try to couple a charge-transfer process to a large conformational change of the molecule in order to delay the charge recombination. The synthesis of 1,4-dithiafulvenyl substituted bianthrones, e.g., (12), is a step in this direction, as
AL CH3
O 12
Feringa et al. took advantage of the inherent chirality of substituted bistricyclic enes and related overcrowded dissymmetric enes and devised chiral optical molecular switches based on these systems. 58'59'91'92The topic of molecular switches has recently been reviewed. 93 Overcrowded polycyclic aromatic enes (PAEs), including derivatives of bistricyclic enes, play a prominent role in this endeavor. The first chiroptical molecular switch based on the bistability of the helical cis- and trans-tetrahydrophenanthrenylidene-thioxanthylene is depicted in Figure 5. 59'91'92'94 These overcrowded enes interconvert stereospecifically M-cis ~ - P-trans and in the enantiomeric switch P-cis ~ M-trans; the cis-trans isomerization is accompanied by a reversal of helicity. A remarkable improvement in the selectivity of the chiroptical switches was found by introducing strong donor and acceptor substituents in the thioxanthenylidene half (Figure 6). 95 The enantiomers of the racemic photoresponsive 12-(9"H-thioxanthene-9'ylidene)- 12H-benzo[a]xanthene (13) represent two distinct states that can be modulated with irradiation at a single wavelength of the light. Dynamic control over molecular chirality was obtained by the interaction of the enantiomers of the helically shaped 13 with either left or right circular polarized light (Figure 7). 96
256
P.U. BIEDERMANN, }. I. STEZOWSKI, and I. AGRANAT
"~"F l"C?"
"'"
M-cis
"
""
'"
P-trans
.................. i ................... ---X--................... i~...................
C -:Cz P-cis
M-trans
Figure 5. Summary of the various isomerization pathways of an overcrowded polycyclic ene constructed from a tetrahydrophenanthrene and an anthracene-like moiety. A potential data storage system based on racemic 13 was envisioned. Irradiation of a racemate (MP) with circular polarized light, r-CPL or/-CPL, for the writing process generates P-enriched and M-enriched regions, respectively. Detection (readout) is achieved nondestructively through use of linearly polarized light (LPL) by measuring CD, or optical rotation in transmission or reflection mode using wavelengths outside the absorption band. Written information can be erased by LPL or unpolarized light at the original wavelength, regenerating MP-13. Photoresolution of the above bistable compound 13 as a dopant in a nematic liquid crystalline phase by CPL irradiation led to a chiral mesoscopic phase. The chiral information
365 nm
O~q,,,..~,,~-,~. ~ .,,~,~,,~.~(CH3)2
435 nm
O~,,,..~.,,dM(CH3)2
~ s ~ Figure 6. Chiroptical switch with strong donor and acceptor substituents.
257
Overcrowded Polycyclic Aromatic Enes
,,~...~..~ ~S ~
r-CPL
. ~............ ~ ""',t
P-13
M-13
Figure 7. Photochemical interconversion of P-13 and M-13 helices upon irradiation with r-CPL and/-CPL light.
inherent to circular polarized light was transmitted to the bistable molecule, followed by amplification and macroscopic expression of the chirality in the liquid crystal. 96
1.7. Scope Previously there have been only sporadic reports on semi-empirical calculations of a few bistricyclic enes, e.g., bifluorenylidene (2)97and bianthrone(4). 89'90'98 Earlier molecular mechanics studies of the homomerous bistricyclic enes bifluorenylidene (2), 99"1~ dixanthylene (3), bianthrone (4), dithioxanthylene (1, X,Y: S), N,N'-dimetylbiacridan (1, X,Y: NCH3), and 9-(9( 10H)-anthracenylidene)-9,10-dihydroanthracene (1, X,Y: CH2) may also be mentioned. 68 The present chapter focuses on molecular modeling of homomerous and heteromerous overcrowded bistricyclic enes, using the semi-empirical method PM31~ Special emphasis is given to conformational energies, strain energies, conformational parameters, the central double bond, pyramidalization, bond angles, overcrowding in the fjord regions, and geometrical parameters of the bridges. A comparison of calculated and crystal structures is presented. Synthesis and chemical reactions of bistricyclic enes are outside the scope of this chapter. A glimpse into the dynamic stereochemistry of overcrowded PAEs is included at the end of the chapter.
2.
MOLECULAR M O D E L I N G OF OVERCROWDED
BISTRICYCLIC ENES
A systematic theoretical survey of bistricyclic enes, a representative series of overcrowded polycylic aromatic enes (PAEs), has been carried out using the semi-empirical method PM3.1~ Semi-empirical calculations have the advantage that their application to a large series of molecules of this size is feasible. A priori, the PM3 method may have certain advantages vis-d-vis the competing AM1 method, especially with respect to hetero atoms. However, a comparative investi-
258
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
Table 2. Tricyclic Moieties and Their Abbreviations Name
Structure a
Bridge
Symbol
9 H-fl uoren-9-yl idene
~
~
F
9( I 0 H)-a nth racen yl idene
~
CH 2
M (methylene)
C(CH3)2
I (isopropyl idene)
I 0, I 0-d imethyl-9(10 H)-anthracenyl idene
o
I 0-oxo-9(I OH)-anthracenylidene
CO
A
I 0-methyl-9(10 H)-acrid i nyl idene
NCH 3
N
O
O
S
$
CH=CH
H
9 H-xa nthen-9-yl idene
9 H-th ioxa nthen-9-yl idene
[
~
~
6 H- benzo [cd] pyren-6-yl ideneb
5 H-d i benzo [a,d] cyclohepten-5-yl idene
Notes: "Thevertex symbolizing the carbon atom at position 9 refersto a carbon of the overcrowded ene.
~entacyclic moiety.
Overcrowded Polycyclic Aromatic Enes
259
Table 3. Point Groups of the Various Conformations for Homomerous and Heteromerous PAEs Conformation anti-folded
syn-folded twisteda orthogonally twisteda
Homomerous P A E s
C2h
C2v D2
D2d
Heteromerous PAEs
CS
Cs C2
C2v
Note: "The N-CH 3 group in the acridinylidenes does not conform to this symmetry; therefore, the symmetry
constraints were not applied to the CH 3 group.
gation of the PAE series between the two leading semi-empirical methods is warranted. The systematic names of the moieties considered, their chemical structure, the bridging group in the central ring, and the abbreviated symbols used in the present chapter are given in Table 2. This selection includes tricyclic moieties with a central five-membered ring (F), central six-membered rings with various bridge functions, and a central sevenmembered ring (H). Anthracenylidene (M) and dimethyl-anthracenylidene (I) allow a study of the steric effects of substituents at the 10 position. Here the cyclic conjugation of the central ring is interrupted by an sp3-carbon atom in the bridge. Acridinylidene (N) and anthronylidene (A) include strong donor and acceptor groups. Theseries N, O, and S varies the bond length and angle of the hetero atom. A six-membered ring system with additional annelated benzene rings (B) was also included in order to investigate the effects of enhanced rigidity and delocalization. All polycyclic aromatic enes (PAEs) that can be composed of any combination of two of these moieties were included in the study. They may be classified into 9 homomerous and 36 heteromerous PAEs. For each of these 45 molecules, 4 conformations were calculated and optimized with the symmetry constraints indicated in Table 3. For simplicity, folded-twisted conformations (e.g., homomerous PAEs with point group C2) were not included. Due to the symmetry constraints, the optimized structures may correspond to minimum energy conformations, transition states, or even to higher-order saddle points. In particular, the biradical orthogonally twisted conformation is a model for the transition state of the E,Z-isomerization or -automerization of the twisted conformations. Vibrational frequencies were not calculated. These pure symmetrical conformations are representative points in the conformational space of the overcrowded enes and thus may serve to characterize their conformational behavior, especially when comparing a series of PAEs. The systematic names of the 45 PAEs and the heats of formation of their four optimized structures are listed in Table 4. The semi-empirical method PM3 as implemented in the program MOPAC61~ was used for the calculations.
"0
0
-o
~
~.
~
m
0 u..
I.I-
"o 9 ~. -6.u_
u_
-r
om I--_
om
0
0
t'-
~-
o
0
._u
0 " ~
0
~-E' -
0 ~9
E o
o ~
o
e~
Table 4. Semiempirical PM3 Heat of Formations of the Anti-Folded, Syn-Folded, Twisted, and OrthoRonally Twisted ., Conformations of Bistricyclic Enes 1 <1
e~
PM3 AHf" [kcal/mol]
o'~
~D
0
,.~
183.949
co e~
e~ u~ t'~ ~D ~0 ,--
~
~ ~
~
O~ ~#"
vm
I~ ~O
~..
~
I~ 0
0
,.-u~
~D
153.659
~
,--
107.486
~..
0
140.958
u'~
134.055
vm
-9-
110.060
~'4
~
101.123
0
o
130.391
~" ,--
176.532
~
~0
165.41 8
~
0
~
.~
123.763
120.433
u-:,
154.453
,~
c~
c~
~
c~
~
c~
~m
~
o'
c~
124.41 4
136.055
,
~
,_
145.045
126.606
6
,
104.1 17
~1
,
~
c
150.966
140.874
o
"~"
165.880
9
0
~
149.034
145.482
90°-twisted
6
~-
c
~
FO
e-
~
u_
~
260
0
.-
~-
u_
FN
~, ~ E
FA
-~._~
u_
FI
949Kfluoren-9-yl idene)-9K fluorene 9-(9Kfluoren-9-ylidene)- 9,10dihydro-anthracene 9-(9/--fluoren-9-yl idene)-9,10dihydro-l0,l Odimethylanthracene 9-(9Kfluoren-9-ylidene)-9(1 OH)anthracenone 9-(9H-fIuoren-9-ylidene)-9,10dihydro-1 0-methyl-acridine 9-(9Kfluoren-9-ylidene)-9K xanthene 949H-fluoren-9-yl idene)-g/ithioxanthene 6-(9Kfluoren-9-yl idene)-6/-/benzo[cd]pyrene 5-(9Kfluoren-9-yl idene)-5Hdibenzo[a,dlcycloheptene 9-(9(1OH)-anthracenylidene)-9,10dihydro-anthracene 10-(9(1OH)-anthraceny1idene)- 9,lOdihydro-9,9-dimethyl-anthracene 10-(9(1OH)-anthracenylidenel9(1OH)-anthracenone
twisted
6
u_
FM
syn-folded
anti-folded
-~
u_
FF
Name
~
~,~
.8
Symbol
162.376
CO
0",
~
173.91 9
I'~
,
~
"0
163.829
~O
,
144.931
~ID
e-
161.200
~
142.652
~
~-
"ID
~
u_
FH
o-~O
u_
FB
~ ~ .
u_
FS
~'-
c~
136.565
108.1 58
0
125.1 62
~
130.607
oO
104.081
109.851
89.738
~m
87.007
e~
,--
130.81 6
0
' - ~-
115.643
~
~
~ ~
106.546
,--
6
113.113
_~
~-
~--,- ~-o
~
~
MA
~._~
MI
~-~ ~"9 ~'-~
MM
MN MO MS MB
MH II
N
2
IA
IN
1 0 IS
IB
IH
AA
9-(9(1OH)-anthracenylidene)-g, 1 0dihydro-1 0-methyl-acridine 9490 OH)-anthracenylidene)-gHxanthene 9-(9(1OH)-anthracenylidene)-9Hthioxanthene 6-(9(1OH)-anthracenylidene)-6Hbenzolcd] pyrene 5-(9(1OH)-anthracenylidene)-5Hdibenzo[a,d]cycloheptene 10410,l Odimethyl-9(1O H ) anthracenylideneL9,l Odihydro9,gdirnethyLanthracene 10410,1 Odimethyld(1 OH)anthracenylidene)-9(1O H ) anthracenone 9410,l Odimethyl-9(1 OManthracenylidenel-9,l Odihydro10-methyl-acridine 9410,l Odimethyld(1 OManthracenylideneL9H-xanthene 9410,l Odimethyl-9(1 OH)anthracenylidene)-9Hth ioxanthene 6410,l Odimethyl-9(1 OH)anthracenylideneL6Hbenzo[cd] pyrene 5-(10,l Odirnethyl-9(1OManthracenylidene)-5Hdibenzo[a,d]cycloheptene 10410-oxod(1 O H ) anthracenylidene)-9(1OManthracenone
120.145
123.133
136.1 73
140.294
89.262
92.487
102.576
109.333
129.148
131.741
148.073
151.150
145.444
148.906
156.91 0
162.086
133.654
135.469
168.484
170.356
99.949
103.445
119.501
124.652
80.427
83.608
98.461
103.91 0
113.616
117.184
130.572
134.378
82.834
86.471
96.927
103.400
122.437
125.601
142.396
145.194
139.031
142.889
151.266
156.1 46
126.777
128.894
162.750
163.986
61.196
64.624
78.361
83.594
(continued)
Table 4. (Continued) PM3 AHf' &ca//mo/]
Symbol NA
OA SA BA
HA NN
ON SN BN HN
00
so
Name 1 0 4 O-methyl-%1OH)acridinylidene)-9(1OH)anthracenone 1O-(gH-xanthen-9-ylidene)-9(1OH)anthracenone 1049Kthioxanthen-9-ylidene)9(1OH)-anthracenone 10-(6H-benzo[cd]pyren-6-ylideneb 9(1OH)-anthracenone 10-(5H-dibenzo[a,d]cycIohepten-5yl idene)-9(1OH)-anthracenone 9,10dihydro-10-methyl-9-(10methyl41OH)-acridiny1idene)acridine 9,l Odihydro-1O-methyl-9-(9Hxanthen-g-ylidene)-acridine 9,l Odihydro-1O-methyl-9-(9Hthioxanthen-9-ylidene)-acridine 9-(6Kbenzo[cd] pyen-6-ylideneb 9,l Odihydro-10-methyl-acridine
9-(5H-dibenzo[a,dlcyclohepten-5yl idene)-9,1 Odihydro-1O-methylacridine 9-(9 H-xanthend-y Iidene)-9Hxanthene 949 H-thioxanthen-9-ylidene)dHxanthene
anti-folded
syn-folded
twisted
90°-wisted
93.864
97.204
108.358
113.272
63.254
66.931
75.688
82.667
103.162
106.433
121.499
124.547
119.520
123.421
130.320
135.492
107.310
109.342
141.382
143.270
127.247
130.861
142.383
144.237
96.363
100.157
108.1 55
112.991
136.015
139.391
153.202
154.865
152.666
156.649
161.861
165.707
140.741
142.801
174.105
174.065
65.728
69.777
74.378
82.081
105.260
108.888
119.908
123.925
BO HO
ss BS HS BB N Q,
W
HB HH
9-(6Kbenzo[cd]pyren-6-ylidene)9H-xanthene 9-(5Kdibenzo[a,d]cyclohepten-5y1idene)dKxanthene 9-(9Kthioxanthend-ylidene)-9Hthioxanthene 9-(6H-benzo[cd]pyren-6-ylidene)9H-thioxanthene 9-(5Kdibenzo[a,d]cyclohepten-5yl idenek9Kthioxanthene 6-(6Kbenzo[cd]pyren-6-ylidene)6H-benzo[cd] pyrene 6-(5Hdibenzo[a,d]cyclohepten-5ylidene)-6KbenzoIcd]pyrene 5-(5Kdibenzo[a,dlcyclohepten-5ylidene)-5Hd ibenzo[a,dl cycloheptene
122.227
126.384
128.621
134.832
109.170
111.952
140.476
144.585
145.191
148.497
165.31 1
165.844
161.422
165.356
174.1 28
176.694
149.636
151.504
185.548
184.818
179.146
183.277
182.965
187.651
164.842
167.989
194.390
195.649
155.407
155.924
205.924
203.720
264
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
2.1. Conformational Energies The anti-folded conformation is the most stable conformation for all but one PAE. Therefore it is convenient to discuss the conformational energies as differences relative to the respective energies of the anti-folded conformations.
2.1.1. Conformational Energy of the Twisted Conformations The most important aspect pertaining to the phenomenon of thermochromism is the energy difference between the twisted and anti-folded conformations. This determines the thermochromic equilibrium A ~-- B. The conformational energies of the twisted conformations relative to the ant/-folded conformations are given in Table 5 and illustrated in Figure 8. The table is arranged such that the values of the homomerous enes appear in the diagonal in increasing order. This arrangement emphasizes trends and thus helps in the analysis of the data. It will be applied to all the tables discussing properties of the 45 PAEs below. The energy difference Et~isted - Eana.fo~ded, calculated by PM3 ranges from --4.6 kcal/mol for bifluorenylidene (FF) to +50.5 kcal/mol for bisdibenzo[a,d]cycloheptenylidene (HI-I). For bisfluorenylidene, the twisted conformation is calculated to have a lower energy than the anti-folded conformation. This is in accord with the experimental results. 6'29'3~In the series of the homomerous enes, the relative energy of the twisted conformation with respect to the anti-folded is increasing in the order (diagonal in Table 5): FF << BB < OO << NN < AA < M M < II < SS << HH Heteromerous enes allow a fine tuning of this energy gap. The energy difference of heteromerous enes is between that of the two corresponding homomerous enes. Furthermore, the energy difference is increasing according to the same order, F < B < O < N < A < M < I < S < H, when any given moiety is combined with a variable
Table 5. Conformational Energies of the Twisted Conformations, Relative to the Anti-Folded Conformations a F
F B O
-O
B
O
N
A
M
I
S
H
O
NCH 3
CO
CH 2
C(CH3) 2
S
CH=CH
17.7 18.6 18.9 34.8
19.6 20.0 36.0
--4.6 1.2 3.4
3.8 6.4
8.7
N A
NCH 3 CO
6.9 8.9
9.2 10.8
11.8 12.4
15.1 14.5
17.2
M I S H
CH 2 C(CH3) 2 S CH=CH
9.4 10.0 11.0 29.0
11.5 12.2 12.7 29.5
13.3 14.1 14.6 31.3
16.0 17.0 17.2 33.4
17.1 18.0 18.3 34.1
Note: "Values in kcal/mol.
20.1 35.9
50.5
265
cO
k~
..Q "0
~
E
,o cO "0
0 . n
c-' 0
cO
c-"
L_
0 ~
~
!.__
E cO
266
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
second moiety, i.e., on going from right to left, or from the top down in Table 5. There are only two minor exceptions: MA has a slightly lower energy than AA, and HS has a slightly lower energy than IH. For dixanthylene (OO), bianthrone (AA), and xanthylidene-anthrone (OA), energy differences of 8.7, 17.2, and 12.4 kcal/mol, respectively, have been calculated, while experimental values are 4.9 75 and 5.6 76 kcal/mol for dixanthylene (OO), 3.0 67, 3.274, 3.4 75, and 3.5 76 kcal/mol for bianthrone (AA), and 3.5 76 kcal/mol for xanthylidene-anthrone (OA). For fluorenylidene-xanthene (FO), the antifolded conformation is calculated to be more stable than the twisted conformation by 3.4 kcal/mol, while experimentally a deep-purple compound is observed, indicating a twisted conformation. ~~ The heteromerous FH adopts an anti-folded conformation in solution. 46 Comparison of the calculated and experimental data suggests a systematic bias of the PM3 calculated heats of formation in favor of the anti-folded conformations. This qualification has to be kept in mind when making qualitative or quantitative predictions based on the calculated data. On the other hand, the bias may be sufficiently systematic to allow the analysis of trends and insight into the mechanism of thermochromism. Previous semiempirical (PM3) and ab initio (HF/6-31G//PM3) calculations on bianthrone (AA) give a conformational energy (twisted vs. anti-folded) of 14 kcal/mol and 16.3 kcal/mol, respectively. 9~
2.1.2. Conformational Energy of the Sgn-Folded Conformations Syn-folded conformations have been observed in a crystal structure of bisdibenzo[a,d]-cycloheptenylidene (HH), 39 and as reversible photoisomers 68'69'71'72 (see Section 1.5). Of the PAEs with fluorenylidene moieties, syn-folded conformations could be found only for FF and FB. For the other fluorenylidene derivatives, all trial structures converged to anti-folded conformations. The conformational energy of the syn-folded conformations, relative to the anti-folded conformations, is given in Table 6 and illustrated in Figure 9. The syn-folded conformations generally have a higher energy than the anti-folded conformations, but compared to the conformational energies of the twisted conformations the values are much smaller. The energy difference, Esyn.folded-Eanti.folde d, is between +0.5 kcal/mol for HH to +4.2 kcal/mol for BO. The considerable destabilization of the syn-folded conformation of II, relative to MM, may be due to a repulsive interaction of the axial methyl groups in II, which approach to within an H..-H distance of 1.64/~, a highly overcrowded situation. For the homomerous enes, the energy difference Esyn.folded- Eanti.folded is decreasing in the series: BB > O O > N N > F F > II > A A > S S > M M > HH For the heteromerous compounds the situation is quite irregular. Only for 23 of the 29 heteromerous enes with syn-folded conformations is the energy difference between that of the respective homomerous enes.
267
e~ >,, ..Q -0
u
r
u
0
o m
L__
E
o~
0 u
0
"0
r 0
etl r-. O
r
L_
o,...
~
o~ I__.
E 0
or
268
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT Table 6. Conformational Energies of the Syn-Folded Conformations, Relative to the Anti-Folded Conformations a B
B
O
N
O
NCH 3
F u
I
A
S
C(CH3) 2
CO
S
M
H
CH 2 C H = C H
4.1
O
O
4.2
4.0
N F
NCH 3 u
4.0 2.6
3.8
3.6
I A
C(CH3) 2 CO
3.9 3.9
3.6 3.7
3.6 3.3
3.5 3.2
3.4
S M H
S
3.9 3.5 3.1
3.6 3.2 2.8
3.4 3.0 2.0
3.2
3.3
3.3
1.6
2.7
2.1
2.0
2.6 1.9
CH 2 CH=CH
3.6
2.5 1.8
0.5
Note: aValuesin kcal/mol.
A previous PM3 calculation on bianthrone (AA) gave a similar value for the conformational energy of the syn- versus anti-folded conformation, 3.4 kcal/mol. 9~
2.1.3. ConformationalEnergyof the Orthogonally TwistedConformations In the orthogonally twisted conformation the two tricyclic (polycyclic) moieties of the PAEs are planar and perpendicular with respect to each other, resulting in a 90 ~ twist of the double bond. The structures were optimized using the BIRADICAL option of MOPAC6 in order to treat the unpaired electrons. It should be noted that the energies of the orthogonally twisted biradicals relative to the corresponding global minimum conformations serve as lower bounds for the thermal E,Z-Isomerization bamers in the bistricyclic enes (see Section 4). The energies of the orthogonally twisted vs the anti-folded conformations are given in Table 7. The conformational energy ranges between +8.5 to +48.3 kcal/mol for BB and HI-I, respectively. For homomerous enes the energy difference Ec~ogonallytwisted- Eanti-folded is increasing in the series: B B << O O < N N < F F < SS < A A < M M < II << H H
The rows and columns of Table 7 increase form left to right and from top to bottom in the same order, with the exception of fluorenylidene compounds, which have higher values than expected according to this trend and of HO, which has a higher value than the respective HN. It should be noted that for HH the orthogonal biradical is calculated to be more stable than the respective twisted conformation (see Table 4). This is probably due to the fact that in MOPAC6 biradical states are treated as open-shell species, using a configuration interaction (C.I.) calculation with the two frontier orbitals as the active space. To be comparable, the twisted
Overcrowded Polycyclic Aromatic Enes
269
Table 7. Conformational Energies of the Orthogonally Twisted Biradicals, Relative to the Anti-Folded Conformations a B
B
O
N
O
NCH 3
F ~
S
A
M
S
CO
CH 2
I
H
C(CH3) 2 C H = C H
8.5
O
O
12.6
16.4
N F
NCH 3 m
13.0 15.3
16.6 19.6
17.0 20.4
20.4
S
S
15.3
18.7
18.9
22.8
20.7
A
CO
16.0
19.4
19.4
23.3
21.4
M
CH 2
16.6
20.1
20.1
24.4
22.0
22.8
23.5
I
C(CH3) 2
17.1
20.6
20.8
24.6
22.8
23.5
24.0
24.7
H
CH=CH
30.8
35.4
33.3
39.0
35.2
36.0
36.7
37.2
22.4
48.3
Note: aValuesin kcal/mol.
conformations should also be calculated using C.I. = 2. Indeed, a C.I. = 2 singlepoint calculation at the optimized geometry of the twisted conformation of HH resulted in an energy lowering of 2.5 kcal/mol and brings the energy of the twisted conformation below that of the orthogonally twisted biradical.
2.2. Strain Energies Derived from Isodesmic Reactions In order to gain further insight into the energetic contributions of strain and overcrowding to the energy of the various conformations, a scheme was designed to analyze the energy of each conformation by itself, rather than as a difference of two conformations. This requires a definition of a reference energy for each compound under investigation, which has to correspond to the energy of the "chemical structure" (i.e., atoms and bonds in the molecules), but should be independent of the conformation. In particular, it should be free of contributions from steric strain and intramolecular overcrowding. It also should not introduce new contributions due to a different electronic state as, e.g., the orthogonally twisted conformation that is a biradical rather than a closed-shell ground state. Such a reference energy may be defined via the following isodesmic reaction:
Cl"~ + H2C
XCHz
-
YCHz
"
1"12C=CH2+
C2H4
XY
270
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
Knowing the energies of the dibenzofulvenes XCH z, and YCH 2 and of ethylene, (C2Ha), and assuming a zero energy of the reaction, the energy of the tetrabenzofulvalene XY in a hypothetical, unstrained reference state may be calculated: Ereference(XY) = E(XCH2) + E(YCH 2) -E(C2H4) Since the molecules XCH z, YCH 2, and C2H 4 are hardly overcrowded, this reference energy should be relatively strain-free. It may, however, lack certain long-range electronic-energy contributions due to the delocalized n-electron system. For example, in certain combinations of X and Y, the push-pull effect may be significant in the tetrabenzofulvalene XY, as compared with the dibenzofulvenes XCH z and YCH z. This point has to be kept in mind when analyzing 'strain energies,' SE, defined by the equation:
SE(XY)= Econfonrzr(XY) - Ereference(XY) Using SE, the amount of strain energy in PAE conformations due to overcrowding in the fjord region may be evaluated. In particular, SE allows comparison of the strain energies in the various PAEs, unbiased by their distinct heats of formation. There are certain advantages in this approach, which is based on real molecules: (a) it can be used in an ab-initio framework where decomposition of the energy of a molecule into terms due to bond stretching, angle bending, torsions, and nonbonding interactions is not defined; and (b) no empirical parameters are required in order to calculate the strain-free reference energy. Isodesmic reactions have previously been used to compute, e.g., bond separation energies, 1~ aromatic stabilization energies in cyclic conjugated hydrocarbons, 54'1~176 strain energies in cyclic hydrocarbons, ~~ and resonance energies of acyl and carbonyl compounds, l~
2.2.1. Conformation and Energy of the Dibenzofulvenes The dibenzofulvenes do not have a fjord region and thus are not overcrowded in the way the bistricyclic enes are. Thus, the conformation is determined by the central ring or the bridging group, which is varied in the series considered here. The dibenzofulvenes derived from fluorenylidene (F), benzo[cd]pyrenylidene (B), and xanthenylidene (O) are planar, while the other dibenzofulvenes have a folded conformation with a boat conformation of the central ring. 6-Methylene-6Hbenzo[cd]pyrene is a tetrabenzofulvene. The planar conformations were calculated with C2v symmetry (neglecting the methyl group of the acridinylidene) and the folded conformations with C s symmetry. PM3 calculated heats of formation, conformational energies, folding dihedrals, and the lowest vibrational frequencies are given in Table 8. The folding dihedral is defined as the dihedral angle formed by the least-squares-planes of the two benzene rings. The lowest vibrational frequency corresponds to a folding mode, and thus indicates how much energy will be involved in changing the degree of folding of this moiety. For those dibenzofulvenes with a folded global minimum, the planar conformations have one negative
271
Overcrowded Polycyclic Aromatic Enes
Table 8. PM3 Results for Dibenzofulvenes Bridge
PM3 AHf ~ Conformation [kcal/mol]
9-Methylene-9 H-fluorene planar
Erela
[kcal/mol]
Folding dihedral [o]
72.149
6-Methylene-6H-benzo[cd]pyrene
planar 86.855 9-Methylene-9H-xanthene O planar 33.189 9,10- Dihydro- 10-methyl- 9-methylene-acridine NCH 3 folded 65.040 NCH 3 planar 66.234 1.2 9,10-Dihydro-9-methylene-anthracene CH 2 folded 59.708 CH 2 planar 59.753 0.05 folded planar
33.200 33.314
[A1
1.464
86
1.480
51
1.353
43
folded planar
11.5
2.512 2.51 7
38 -27
13.2
2.532 2.540
29 -23
14.3
2.520 2.533
42 -71
15.7
2.736 2.739
41 --42
55.4
3.086 3.215
56 -139
0.1
9-Methylene-9 H-thioxanthene
S S
folded planar
52.791 53.799
1.0
75.909 76.298
0.4
5-Methylene-5 H-dibenzo[a,d]cycloheptene
CH=CH CH=CH Notes:
folded planar
83.673 98.332
14.7
23 -178/34 c
2.471 2.473
9,10- Dihyd ro- 10,10-d imethyl-9-methylene-anth racene C(CH3) 2 C(CH3) 2
Lowestb frequency
0.3
10-Methylene-9(10 H)-anth racenone
CO CO
C4a-.C'1oa
'rrhe energy of the planar conformation relative to that of the folded conformation is the barrier of inversion for the dibenzofulvenes, except for 5-methylene-5H-clibenzo[a,d]cycloheptene,where the planar conformation has two negative frequencies. Ethylene: PM3 A/'-flf= 16.630 kcal/mol. bin [cm-1]. The negative frequenciesare actually imaginary (although MOPAC6 givesthem as negative numbers). Cl"hetwo frequenciesgiven correspond to the normal modes of pyramidalizing the nitrogen atom and folding the dibenzofulvene, respectively.
frequency. Thus the planar conformations are the transition states for the conformational inversion and the relative conformational energy is the barrier of inversion. However, in the case of 5-methylene-5H-dibenzo[a,d]cycloheptene, the planar conformation has two negative frequencies and is a second-order saddle point, with the conformational energy being an upper limit for the barrier of inversion. This is the only dibenzofulvene that has a substantial barrier of inversion. 9,10-Dihydro-10-methyl-9-methylene-acridine is an interesting borderline case. Apparently the dibenzofulvene with a nitrogen atom in the central ring would prefer to be planar, as can be seen from the very small degree of folding and positive (real)
272
P.U. B I E D E R M A N N , J. J. STEZOWSKI, and I. A G R A N A T
vibrational frequency of the folding mode (+34 cm-l). The negative (imaginary) frequency of-178 c m -1 corresponds to pyramidalization of the nitrogen atom. In the context of the overcrowded bistricyclic enes, it is interesting to note that most of the dibenzofulvenes considered here are nonplanar. This probably is an intrinsic property of the central ring of the tricyclic moiety and not due to intramolecular overcrowding. The vibrational frequency corresponding to the folding mode of the planar conformations may be used as an indicator for the capability of the tricyclic moieties to fold. This suggests that the relative foldability of the moieties increases in the series: F
2.2.2. Strain Energy in the Anti.Folded Conformations The energy differences of the PM3 calculated anti-folded conformations of the bistricyclic enes vs the strain flee reference energy defined by the isodesmic reaction are given in Table 9 and illustrated in Figure 10. The most strained anti-folded conformation is that of BB, with SE = 22.1 kcal/mol, the least strained is HH with SE = 4.7 kcal/mol. The strain energy of the homomerous anti-folded conformations is decreasing in the series: BB > FF > OO > NN > AA > II > M M > SS > H H Bifluorenylidene (FF) is the second most-strained homomerous ene (SE = 17.8 kcal/mol), but the heteromerous fluorenylidene PAEs have unexpectedly low strain energies, making exceptions in the otherwise monotonous decrease along the rows of Table 9. There is also a monotonous decrease from the top down in the columns
Table 9. Strain Energies of the Anti-Folded Conformations ~ B
B F O N A I M S H
-O NCH 3 CO C(CH3) 2 CH 2 S CH=CH
22.1 18.8 18.8 17.4 16.1 16.0 I 5.5 15.3 10.9
Note: ~/alues in kcal/mol.
F
17.8 15.4 13.5 12.4 12.1 11.4 11.2 5.7
O
N
A
I
M
S
H
O
NCH 3
CO
C(CH3) 2
CH 2
S
CH--CH
13.8 12.3 12.4
11.4 11.1
12.0 11.7 8.7
10.7 10.7 7.1
11.0 10.7 10.4 6.9
10.3 10.1 6.9
10.0 6.7
4.7
16.0 14.8 13.5 13.5 13.0 12.8 8.9
273
0 u ~
0 t~ L--
E 0 tO
I
" 00
~
e-. o
~o
e--
e-
t.._
274
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
of Table 9, with only one exception: NA. This compound is a candidate for a push-pull system, with a stable aromatic, zwitterionic mesomeric form (14)"
HaC
14
Since the push-pull effect is expected to be smaller in the reference energy, i.e., the dibenzofulvenes, this could be an explanation for the low SE of these compounds. On the other hand, there are many more combinations of strong donor and acceptor moieties in Table 9 that do not show an unusual stabilization. Thus, the low SE is not a conclusive argument for the push-pull effect. Another possible indicator for the push-pull effect is the charge distribution. The charges on the nitrogen and oxygen atoms in NA are +0.13 and --0.31, as compared to +0.12 and --0.30 on the nitrogen in the biacridan NN and on the oxygen in bianthrone (AA). The total charge on the acridinylidene and anthronylidene moieties are +0.06 and --0.06, and the dipole moment of the compound is 4.0 debye. The small charges and very small differences relative to the homomerous compounds argue against a significant zwitterionic contribution in acridinylidene-anthrone (NA).
2.2.3. Strain Energy in the Syn-Folded Conformations The strain energies, SE, of the syn-folded conformations are listed in Table 10 and illustrated in Figure 11. The most strained syn-folded conformer is BB (+26
Table 10. Strain Energies of the Syn-Folded Conformations a B
B F
F
O
N
A
I
S
M
H
O
NCH 3
CO
C(CH3)2
S
CH 2
CH=CH
17.4 15.6 16.0 15.1 15.0 10.7
14.9 14.2 14.0 13.5 9.1
14.5 13.5 12.3 9.1
13.3 12.8 8.6
12.9 8.8
5.2
26.2 --
21.5
21.4
O N A
O NCH 3 CO
23.0 21.4 20.0
20.0 18.6 17.2
I S M H
C(CH3)2 S CH 2 CH=CH
19.9 19.2 19.0 14.1
17.1 16.4 16.2 11.7
Note: *'Valuesin kcal/mol.
275
:E
0
U r--
U
"0
..Q
~
r~
L.
E ~o 0 u "0
-0
!
t~
eo
L_
o,~
e'-
e-
t_
276
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
kcal/mol). The strain energy is decreasing in the homomerous enes series in the order: BB > FF > OO > NN > AA > II > S S > M M > HH The strain energy in the rows and columns of Table 10 mostly follow the same order, although there are many exceptions. It is interesting to note that the strain energy of anti- and syn-folded enes decreases in almost the same order. Only M M and SS interchange positions. The two types of folded conformations differ in the relative direction of the folding, but the out-of-plane deformation of the moieties themselves is similar, as is the amount of strain energy involved.
2.2.4. Strain Energy in the Twisted Conformations Twisted conformations are highly strained, as can be seen from the strain energies in Table 11 and Figure 12. The strain energy ranges from +13.2 kcal/mol for bifluorenylidene (Fl0, to +55.2 kcal/mol for HH. In the series of the homomerous enes, the strain energy of the twisted conformers increases: FF << OO < BB < MM < AA < NN < SS < II << HH The rows and columns of Table 11 essentially follow the same order, but there are several exceptions, most of which are related to acridinylidene and anthronylidene derivatives. In particular, NA shows a special stabilization of about 2 kcal/mol, but the charges that should be indicative of the push-pull effect are not supportive. The nitrogen and oxygen atoms in twisted NA have partial charges of +0.20 and -0.34, respectively. For comparison the partial charge of nitrogen in NN is +0.17, and of oxygen in bianthrone (AA) is -0.32. While bifluorenylidene has the least-strained twisted conformation, its anti-folded conformation is highly strained. On the other hand, HIt with an extremely strained
Table 11. Strain Energies of the Twisted Conformations a F
O
B
O F
--
O B
O
M A N S I H
CH 2 CO NCH 3 S C(CH3)2 CH----CH
13.2 18.8 20.0
24.6 25.2
25.9
20.8 21.3 20.4 22.2 22.1 34.7
26.3 25.9 26.6 27.4 27.6 40.2
27.0 26.9 26.6 28.0 28.3 40.5
Note: aValuesin kcal/mol.
M
A
N
S
CH 2
CO
NCH 3
S
28.0 27.8 28.1 29.1 29.3 41.7
28.6 26.7 29.0 29.1 41.1
28.9 28.9 29.4 42.0
30.1 30.3 42.6
I
H
C(CH3) 2 CH=CH
30.5 42.9
55.2
277
_Q "0 e~
e~ cO
e~
o m
E co "o ~
0 t~O ee, ~
278
P.U. BIEDERMANN, I. I. STEZOWSKI, and I. AGRANAT
twisted conformation has little strain in the anti-folded conformation. This reversal of the trend explains the very large range of conformational energies Etwistexl- Eanti.folded (vide supra).
2.2.5. Strain Energy in the Orthogonally Twisted Conformations In the case of the orthogonal biradicals, the strain energy SE as defined by the isodesmic reactions combines, most likely, steric effects, due to the planarization of the tricyclic moieties, and electronic effects, due to breaking of the double bond. Table 12 gives the "strain energies" calculated using the heats of formation for fully optimized (folded) dibenzofulvenes. The computed values range from 30.6 kcal/mol for BB, which has a planar fulvene derivative, and a large delocalized n-system, which stabilizes the biradical, to 53.0 kcal/mol for HH, with the highest planarization energy for the dibenzofulvene derivative (see Table 8). For the homomerous PAEs, SE is increasing in the series: BB < SS < NN < O O < M M < AA < II < FF << H H Most acridinylidenes and anthronylidenes make exceptions from the row and column order in Table 12. In the isodesmic reaction, use of planar dibenzofulvenes rather than of their fully optimized conformations subtracts the energy due to planarizing the moieties, thus showing the electronic contribution with less conformational bias. The isodesmic energies of the orthogonally twisted biradicals using the planar conformations of the dibenzofulvenes are given in Table 13. Under this constraint, bisfluorenylidene (FF) has the highest isodesmic energy (38.2 kcal/mol), while HH has the lowest isodesmic energy (23.7 kcal/mol). In the homomerous PAEs, the isodesmic energies calculated using planar dibenzofulvenes decrease in the series:
Table 12. Strain Energies of the Orthogonally Twisted Biradicals a B
B S N O M A I F H
S NCH 3 O CH 2 CO C(CH3)2 -CH=CH
30.6 30.6 30.4 31.4 32.1 32.1 33.1 34.2 41.8
Note: '~/aluesin kcal/mol
S
N
0
M
A
I
S
NCH 3
O
CH 2
CO
C(CH3)2
30.7 30.5 31.5 32.2 32.1 33.1 34.0 41.9
30.8 31.4 32.2 31.7 33.2 33.9 42.0
32.3 33.1 32.9 34.1 35.1 44.4
33.8 33.6 34.7 35.7 43.6
33.8 34.5 35.7 43.0
35.7 36.7 44.2
F
H
CH=CH
38.2 44.8
53.0
279
Overcrowded Polycyclic Aromatic Enes Table 13. Isodesmic Energies of the Orthogonally Twisted Biradicals Using Planar Dibenzofulvenes as Referencea
F
E
F
M
I
A
O
--
CH 2
C(CH3) 2
CO
O
33.6 32.8 32.0 31.7 30.4 28.3
32.3 31.4 31.1 30.2 29.7
S S
N
H
NCH 3 C H = C H
38.2
M
CH 2
35.7
33.7
I
C(CH3) 2
35.7
33.7
33.7
A
CO
35.6
33.4
33.4
O B S N H
O
35.1 34.2 33.6 32.7 30.1
33.0 32.1 31.7 30.9 28.9
33.0 32.1 31.7 31.0 28.5
S NCH 3 CH:CH
B
30.6 30.2 29.2 27.1
29.9 29.0 26.8
28.4 26.1
23.7
Note: *'Valuein kcal/mol.
FF > MM > II > AA > OO > BB > SS > NN > HH The rows and columns of Table 13 follow the same order, with several minor exceptions. In particular there is no indication for a strong push-pull effect in heteromerous enes as, e.g., NA. It is interesting to note that the biradical of bifluorenylidene (FF) with its central five-membered rings is substantially destabilized (4.5 kcal/mol) relative to MM and II, where the cyclic conjugation in the central ring is broken by an sp3-carbon atom. On the other hand, the conjugated seven-membered ring system in HH is the most stabilizing system (10 kcal/mol relative to II), even more stabilizing than the large delocalized r~-system of BB. The carbonyl group in bianthrone (AA) has little effect, and heteroatoms O, S, and N stabilize the biradical.
2.3. Conformational Parameters The overall conformations of the bistricyclic enes are characterized by the pure twist of the central ethylene group and by the folding dihedral or propeller twist of the tricyclic (polycyclic) moieties. The pure twist to of the ethylene group is defined as the average of the signed torsional angles C9a-C9---C9,--C9a, and C8a-C9-C9,---C8a, (see Section 1.3). In the twisted conformations with D 2 or C 2 symmetry, these two torsional angles are symmetry equivalent and thus are both equal to the pure twist. In the anti-folded conformations with C2h or C s symmetry, and the syn-folded conformations with C2v or C s symmetry, the two torsional angles are also symmetry related, but have opposite signs. Thus, their average is zero and there is no pure twist in the symmetric anti-folded and syn-folded conformations.
280
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
The folding dihedral is defined as the dihedral of the least-squares-planes of the carbon atoms C 1, C 2, C3, C4, C,ta, C9aand C 5, C 6, C 7, C 8, Caa, C10a of the two benzene rings of a tricyclic (polycyclic) moiety. This angle is used to characterize anti-folded and syn-folded conformations. Heteromerous enes have independent folding dihedrals for each moiety. In homomerous enes, both moieties have symmetry equivalent folding dihedrals (C2h or C2v symmetry). In twisted conformations, the C 2 symmetry axis through X, C 9, C 9, and Y does not allow folding of the tricyclic moieties about the X...C 9 or C9,...Y axis. However, the tricyclic moieties may be twisted like a propeller about an axis perpendicular to the C 2 symmetry axis. This will also result in a dihedral of the least-squares-planes of the two benzene rings. Therefore, the propeller twist may also be measured by this dihedral. In heteromerous enes with C 2 symmetry, the two moieties may have different propeller twist, but in homomerous enes with D 2 symmetry, the propeller twist of the two moieties is symmetry equivalent. Propeller twist is not allowed in anti- or syn-folded structures with C2h, C2v, or C s symmetry because it is not compatible with a symmetry plane through X, C 9, C9,, and Y. Thus, for the symmetrical conformations considered in this study folding and propeller twist are mutually exclusive. The orthogonally twisted conformations with D2a or C2v symmetry all have a symmetry defined pure twist of 90 ~ and planar tricyclic moieties with zero folding and zero propeller twist. These orthogonally twisted conformations are not overcrowded in the vicinity of the central C9--C9, bond. For simplicity, the geometrical parameters of these conformations will not be discussed in this chapter.
2.3.1. Folding Dihedrals in Anti.Folded Conformations The folding dihedrals of the least-squares-planes of moieties X in the anti-folded conformations of enes XY are found in the columns of Table 14. The second moiety Y of the ene is indicated in the row header. For example, the folding dihedrals of
Table 14.
Folding Dihedrals in the F
B
O
O F
B O N I A S M H
--
O NCH 3 C(CH3) 2
CO S CH 2
CH=CH
20.8
17.4 14.9 12.7 11.7 12.2 10.3 11.2 3.3
33.9
31.2 28.9 27.6 27.3 27.4 26.8 26.8 23.2
46.3
43.2 40.4 38.8 38.3 38.4 37.5 37.7 32.8
N
Anti-Folded C o n f o r m a t i o n s I
NCH 3 C(CH3)2 50.9
48.5 46.0 44.7 44.2 44.2 43.5 43.7 34.6
51.5
49.2 46.7 45.5 45.2 45.3 44.8 44.7 41.0
[o]
A
S
M
H
CO
S
CH 2
CH=CH
53.3
50.8 48.3 46.8 46.3 46.6 45.8 45.8 41.3
53.9
51.7 49.3 47.8 47.2 47.4 46.8 46.8 42.3
55.4
52.9 50.4 48.9 48.4 48.5 47.8 47.9 43.2
67.5
67.4 65.9 65.5 64.2 64.8 64.4 64.5 61.6
281
0
0 1
E 0 "0 "0
0 - -
~
"0 "0 0 - -
"0
,._o
282
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
the fluorenylidene moieties F are given in column one of Table 14. The fluorenylidene moieties have the smallest folding dihedrals of all enes studied. On the other hand, the folding dihedral of the second moieties, Y of these fluorenylidene derivatives FY, given in row 1 of Table 14, are the highest folding dihedrals found for these moieties Y. In Figure 13 the data is illustrated as bar graph. In the homomerous enes, the dihedrals increase from 20.8 ~ in bifluorenylidene FF, to 61.6 ~ in HH in the series (see diagonal in Table 14): FF << BB << OO < NN < II < AA < SS < MM << HH This also is the trend in the rows of Table 14. The order in the columns is essentially reversed, with two exceptions; A > I and M > S is retained. Thus, the folding dihedral of a given moiety X, when combined with Y, is decreasing according to the series
Y:
F>B>O>N>A>I>M>S>H
The changes down the column are much smaller than those along the rows and there are some exceptions in the column order. In heteromerous enes the folding is highly unequal. Comparing the heteromerous PAE XY with the homomerous PAEs XX and YY, when XX is more folded than YY, X in XY will have an even higher folding dihedral and Y a lower folding dihedral than in the corresponding homomerous PAEs. The most extreme example is fluorenylidene-dibenzo[a,d]cycloheptene FH, which combines the highest and lowest folding dihedrals, 67.5 ~ and 3.3 ~, in the same molecule. There are two exceptions in cases where the folding dihedrals are very close, IA and MS. It may be concluded that there are two factors that determine the folding dihedral of a moiety in anti-folded PAEs: 1. The main factor is the intrinsic ability of the moiety to fold, which is reflected in the row order and also in the degree of folding observed in homomerous PAEs. 2. The steric demand of the second PAE moiety, as reflected in the column order, has a smaller effect. In general, a more folded moiety is sterically less demanding. This explains the reversed trend in the rows vs. columns of Table 14. The exceptions due to M and I indicate that other factors may also play a role. This interpretation is confirmed by the observation that the strain energy correlates with the column order, i.e., the steric demand. A comparison with the folding dihedrals of the dibenzofulvenes shows a substantial increase in the degree of folding for all moieties. It is interesting to note that both series, for the diagonal (or rows) and for the columns are similar to the series of the vibrational frequency of the folding mode in the planar dibenzofulvenes (see
Overcrowded Polycyclic Aromatic Enes
283
Table 8). Again, the exceptions are M and I. Previous PM3 calculations on
anti-folded AA gave a puckering angle of 48o. 90 2.3.2. Folding Dihedrals in Syn-Folded Conformations The least-squares-planes folding dihedrals of the syn-folded conformations are given in Table 15 and illustrated in Figure 14. It is arranged analogously to Table 14. In the syn-folded conformations, the folding dihedral is 1 to 6 ~ larger than in the anti-folded conformations. Exceptions are HN, where the acridinylidene moiety has a 10 ~ higher folding dihedral in the syn-folded conformation and FB, where the fluorenylidene moiety is hardly folded, 14 ~ less than in the anti-folded conformation. Since FB is the only heteromerous fluorenylidene derivative with a syn-folded conformation, this most likely is an exceptional case. Excluding fluorenylidenes, the folding dihedrals range from 26.8 ~ to 70.5 ~ In the syn-folded homomerous enes folding is increasing in the series: FF << BB << OO < II < NN < AA < SS < MM << HH The folding is monotonously increasing in the rows of Table 15 in the same order. On the other hand, folding in the columns of Table 15, i.e., for a given moiety X, is decreasing according to the series:
F> B>O>I>N>A>S=M>H The folding dihedral of moieties bound to thioxanthenylidene (S) and M are so close that no preference is evident. There are several exceptions, of which II is noteworthy. According to the trend in the columns, in syn-folded II a higher folding dihedral would be expected, but the folding is limited by a close contact of the axial methyl groups (vide supra).
Table 15.
F o l d i n g D i h e d r a l s in the F
B
O O
F B O I N A S M H
m O C(CH3)2 NCH 3 CO S CH 2 CH--CH
22.5 3.6
35.6 32.8 31.1 30.0 30.0 30.0 29.6 29.4 26.8
46.1 44.0 42.7 42.6 42.3 41.6 41.9 38.4
I
Syn-Folded N
C(CH3)2 NCH 3 51.3 49.6 46.3 48.2 48.2 47.2 46.7 44.7
51.4 49.7 48.6 48.4 48.1 47.4 47.8 44.5
C o n f o r m a t i o n s [~
A
S
CO
S
53.5 51.8 50.3 50.4 50.2 49.5 49.8 46.4
54.4 52.8 51.8 51.5 51.3 50.4 50.9 47.2
M
H
CH 2 C H : C H 56.0 54.2 53.8 53.0 52.6 52.0 52.2 48.8
70.5 69.0 67.8 68.2 68.0 67.7 67.6 64.7
284
0
,g
E 0
0
"0
0
"0
"o 0.,,.
0
0~ "o
n_
285
Overcrowded Polycyclic Aromatic Enes
The similarity of the folding dihedrals in syn-folded and anti-folded conformations and the similarity of the order of the homomerous enes and rows (only I and N are interchanged) indicate that the propensity of folding is an intrinsic property of the moieties. The steric strain is a second factor determining the folding dihedral. The latter depends on the second moiety. Indeed, the column order is identical to the order of strain energies, with the exception of F and I moieties. A previous PM3 calculation on syn-folded AA gave a puckering angle of 62o. 90
2.3.3. Pure Ethylenic Twist in Twisted Conformations The pure twist in the central C 9 = C 9, double bond of the PAEs is given in Table 16 and illustrated in Figure 15. In the twisted conformations, most of the out-ofplane deformation is in the ethylene group. The pure ethylenic twist ranges from 30.2 ~ in bifluorenylidene (FF) to 58.0 ~ in HH. Fluorenylidene derivatives have an 8 ~ to 10 ~ lower ethylenic twist than the respective xanthenylidene derivatives (compare the first and second column in Table 16). In the homomerous PAEs, the twist is increasing in the series: FF <<< OO < MM < AA < NN < II < BB < SS < HH Both rows and columns of Table 16 follow the same sequence, although there are several exceptions. Nevertheless, the pure twist of heteromerous PAEs is always between that of the two corresponding homomerous PAEs. Only NA has a higher ethylenic twist than both AA and NN. A comparison with the strain energies in twisted conformations shows that benzo[cd]pyrenylidenes (BY) have a very high ethylenic twist relative to their strain energy. Also, thioxanthenylidenes (SY) have a somewhat higher ethylenic twist, as may be expected from their strain energy. A previous PM3 calculation on twisted AA gave a twist angle of 580. 90
Table 16. Pure Ethylenic Twist in Twisted Conformations [o] F
F O M A N I B S H
-O CH 2 CO NCH 3 C(CH3) 2 S CH=CH
30.2 41.4 42.5 42.6 43.0 42.0 42.9 43.7 42.8
O
M
A
O
CH 2
CO
49.2 50.7 51.3 50.9 50.9 51.4 52.3 52.5
52.3 52.8 52.6 52.8 53.0 54.0 54.6
53.0 53.8 53.3 53.5 54.6 55.4
N
I
B
NCH 3 C(CH3)2
53.2 53.4 53.7 54.5 55.0
53.3 53.4 54.6 55.4
53.8 54.8 55.5
S
H
S
CH=CH
55.9 56.7
58.0
286
0
E
Q)
0 L)
L_
~o
~
u%
.c
~
L) Q) >.
&..
L) L)
Overcrowded Polycyclic Aromatic Erle5
287
2.3.4. Propeller Twist in Twisted Conformations In addition to the twist in the central double bonds, the tricyclic (polycyclic) moieties themselves also twist like the blades of a propeller in order to distribute the steric strain in the twisted conformations. The dihedral angles of the leastsquares-planes of the two benzene tings is given in Table 17. Table 17 is arranged analogously.to Table 14. Propeller twist becomes significant in thioxanthenylidenes (S) (>_6.7~ dibenzo[a,d]cycloheptenylidenes (H) (>26.9~ and in moieties bound to fluorenylidene (row 2 in Table 17). On the other hand, xanthenylidenes (O) have unusually low propeller twist. In the series of the homomerous PAEs, the propeller twist increases according to: OO < FF < II < MM < BB < NN < AA < SS << H H The general trend in the rows of Table 17 is increasing from fight to left, but decreasing in the columns from top to bottom. There are many exceptions. Also, there is no obvious correlation with the steric strain in the twisted conformations or with the ethylenic twist. The phenomenon of the propeller twist in the tricyclic moieties is not well understood.
2.4. Double Bonds
2.4.1. Length of the Central Double Bond in Anti-Folded Conformations The lengths of the central C9=C9, double bond in the anti-folded conformations are given in Table 18. The values are between 1.347/~ (HH) and 1.360/~ (BB). There is very little variation (0.013 A). In the homomerous PAEs, the length of the central double bond is decreasing in the series: BB > O O > FF > N N > SS > A A > II > M M > H H
Table 17. 0
P r o p e l l e r Twist in the Twisted C o n f o r m a t i o n s [~
F
I
M
B
A
H
S
CH--CH
O
~
O
2.3
2.5
6.8
4.8
4.8
5.7
5.4
8.8
31.0
F I M B N A S H
m C(CH3) 2
5.2 1.4 1.6 1.4 1.5 1.4 1.0 0.7
2.5 3.0 3.0 3.0 2.8 3.1 3.3 3.5
13.0 3.6 4.3 4.2 4.0 4.1 2.1 1.1
8.2 3.7 3.9 3.7 3.8 3.7 3.2 2.9
7.4 4.0 4.2 4.2 3.9 4.1 3.7 3.5
8.8 4.6 4.9 4.5 4.4 4.5 4.2 3.8
9.3 4.4 4.6 4.4 4.1 4.6 3.9 3.5
12.5 7.6 7.9 7.7 7.6
35.6 28.9 29.5 29.2 29.3 29.1 28.3 26.9
NCH 3 CO S CH=CH
NCH3 CO
S
O
CH 2
C(CH3)2 CH2
N
7.7
7.1 6.7
288
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
Table 18. Length of the Central Double Bond in the Anti-Folded Conformations ~ B
B
0
O
F N
--
S
A I
NCH 3
S CO C(CH3) 2
M
CH 2
H
CH=CH
O
F
N
S
A
I
O
--
NCH 3
S
CO
C(CH3) 2
1.353 1.353 1.353 1.353 1.351
1.353 1.353 1.353 1.351
1.352 1.352 1.350
1.360 1.357 1.355 1.357 1.357 1.357 1.357 1.356
1.354 1.351 1.354 1.354 1.354 1.353 1.353
1.355
1.351
1.354 1.351 1.354 1.350 1.354 1.350 1.354 1.350 1.350 1.347
1.353 1.353 1.352
M
H
CH 2 CH--CH
1.352 1.350
1.347
Note: aValuesin ,~.
Due to the small variation, the trends in the columns and rows of Table 18 are barely visible. Nevertheless, there are but few exceptions. Only the heteromerous fluorenylidenes have considerably shorter double bonds than would be in agreement with the sequence of the homomerous enes. Except for dithioxantylene (SS), the order is identical to the series of the overcrowded C...C distance in the fjord region (vide infra). Moreover, the strain energies of the anti-folded conformations have a similar trend, with only three exceptions: FF, OO, and SS. The folding dihedrals of the anti-folded conformations also have a similar trend, with three exceptions: FF, II, and SS. This suggests that, at least in the PM3-calculated structures, the lengthening of the double bond may be due to the steric strain caused by the intramolecular overcrowding.
2.4.2. Length of the Central Double Bond in Syn-Folded Conformations Table 19 gives the lengths of the C9----C9, double bonds in the syn-folded conformations of the PAEs. As in the anti-folded conformations, the double bonds in the syn-folded conformations show little variation (0.015 A). They range from 1.347/~ (HI-I) to 1.361 .~ (BB). The order of the homomerous PAEs is: BB > II > F F > O O > N N > SS > A A > M M > H H In the rows and columns of Table 19, the heteromerous dimethylanthracenylidenes have shorter double bonds than anticipated by the order of the homomerous PAEs. The series order is similar to that of the overcrowded C...H distances in the fjord regions (one exception: SS), but not to the more overcrowded H...H distances (vide infra). There is some similarity to the strain energies (exceptions: II and SS). Thus,
289
Overcrowded Polycyclic Aromatic Enes Table 19. Length of the Central Double Bond in the 5yn-Folded Conformations a B B
I
F
O
N
S
A
M
C(CH3)2
--
O
NCH 3
S
CO
CH 2
H CH=CH
1.353 1.353 1.353 1.353 1.352 1.350
1.352 1.352 1.352 1.351 1.349
1.352 1.352 1.351 1.349
1.352 1.351 1.349
1.350 1.349
1.347
1.361
I F O
C(CH3) 2 -O
1.356 1.358 1.357
N S
NCH 3 S
1.356 1.356
A
CO
1.356
M H
CH 2 CH=CH
1.356 1.354
Note:
a
1.356 1.355 1.353 1.352 1.352 1.352 1.350 1.349
Values in k.
as in the anti-folded conformations, the lengthening of the double bond in the calculated syn-folded structures may be due to the steric strain and overcrowding.
2.4.3. Length of the Central Double Bond in Twisted Conformations The lengths of the central ethylenic bond in the twisted conformations of the PAEs are given in Table 20. Except for bifluorenylidene, they are substantially longer than the double bonds of the corresponding anti- or syn-folded conformations. The variation is also more significant in the twisted structures (0.065/~). The
Table 20. Length of the Central Double Bond in the Twisted Conformations a O
M
I
A
N
O
CH 2
C(CH]) 2
CO
NCH 3
S
1.374 1.374 1.374 1.378 1.377 1.378
1.386 1.390 1.390 1.393 1.392 1.394 1.395
1.393 1.394 1.395 1.396 1.397 1.398
1.396 1.401 1.399 1.401
1.397 1 . 4 0 1 1.401 1.402 1.403
1.404
CH=CH
1.385
1.403
1.407
1.395 1.396 1.398 1.398 1.399 1.408
1.410
1.410
1.413
F
F O M I A N B S H
O CH 2 C(CH3)2 CO NCH 3
1.358 1.372
Note: "Values in t1~.
B
1.412
S
H
S
CH=CH
1.423
290
P.U. BIEDERMANN, J. I. STEZOWSKI, and I. AGRANAT
shortest twisted double bond was calculated for bifluorenylidene (FF), 1.358/~, and the longest for twisted HH, 1.423 A. All fluorenylidenes have particularly short double bonds, and all dibenzo[a,d]cycloheptenylidenes have relatively long double bonds. The lengths of the double bonds are increasing in the series of the homomerous enes according to" FF <<< OO < MM < II < AA < NN < BB < SS << HH The rows and columns of Table 20 show a similar trend. Most of the (minor) deviations are connected to acridinylidenes (NY). There are correlations with the pure twist and the strain energy in the twisted conformations. The exceptions are II and BB. This suggests a mechanism involving overcrowding, twist, and steric strain elongating the central double bonds in twisted bistricyclic enes. There is no strong indication of a push-pull effect, e.g., in NA.
2.5 Pyramidalization In the symmetrical folded conformations (point groups C2h, C2v, and Cs) the central double bond has no pure twist; nevertheless, it is not planar. The carbon atoms C 9 and C 9, are pyramidalized (see Section 1.3).48 Pyramidalization of C 9 and C 9, may lead to syn- and to anti-pyramidalization. The pyramidalization angles x(C 9) and X(Cg,) of syn-pyramidalized double bonds have the same sign, whereas in anti-pyramidalized double bonds they have opposite signs (see Section 1.3).
2.5.1. Pyramidalization in Anti.Folded Conformations The pyramidalization angles z(C9) of the anti-folded conformations are given in Table 21. It is arranged analogously to Table 14. Thus, the values refer to the pyramidalization of C 9 in the moiety indicated in the column header of the PAE with the second moiety given in the row header. The central double bond in the
Table 21. Pyramidalization x(Cg) in the Anti-Folded Conformations [o] F
B
O O
F B O I N A M S H
~
O C(CH3)2 NCH 3 CO CH 2 S CH=CH
7.9 -6.0 -5.3 -3.3 -4.0 -3.6 -3.2 -2.7 0.4
8.1 6.5 -6.4 -6.0 -6.3 -6.0 -6.1 -6.2 -6.7
7.2 4.8 4.8 -4.2 -4.6 -4.3 -4.4 -4.5 -4.9
I
N
C(CH3)2 NCH 3 7.0 4.5 4.6 4.0 -4.5 -4.2 -4.3 -4.7 -5.3
6.6 4.0 4.1 3.3 3.9 -3.5 -3.6 -3.7 -4.8
A
M
S
H
CO
CH 2
S
CH=CH
6.5 3.9 3.9 3.2 3.7 3.5 -3.6 -3.7 -3.9
6.9 3.9 3.9 3.1 3.6 3.4 3.4 -3.6 -3.6
5.7 3.0 3.2 2.3 3.0 2.7 2.8 2.9 -3.2
2.9 -0.6 -0.0 -1.5 -0.2 -0.4 -0.2 -0.2 0.1
291
Overcrowded Polycyclic Aromatic Enes
anti-folded conformations is anti-pyramidalized, as can be seen from the opposite signs of the angles z(C9) of the two moieties in heteromerous enes in Table 21. Also, all homomerous anti-folded conformations are anti-pyramidalized (only the positive value is given in Table 21). Exceptions are the heteromerous dibenzo[a,d]cycloheptenylidenes (HY), which show syn-pyramidalized double bonds. Most pyramidalization angles are small. Only benzo[cd]pyrenylidenes (B) and most moieties bound to fluorenylidenes (F) have Ixl > 6~ In the homomerous enes, the absolute values of the pyramidalization decrease in the series: FF > BB > OO > II > NN > AA > MM > SS > HH The magnitude of the pyramidalization in heteromerous anti-folded enes is quite irregular, following the above trend only approximately and with numerous exceptions. There is some similarity with the series order of the folding dihedrals and the strain energies, although the exceptions indicate that multiple factors determine the pyramidalization.
2.5.2. Pyramidalization in Syn-Folded Conformations The pyramidalization angles ~(C9)of the syn-folded conformations are given in Table 22. It is organized analogously to Table 21. In all homomerous and heteromerous enes, the central double bond of the syn-foldedconformation is syn-pyramidalized. The Z angles are much higher than in the anti-folded conformations. The highest pyramidalization values at C 9 were calculated for FF, 22.2 ~ and BB, 16.8 ~ In the homomerous enes, the X values decrease in the series: FF >> BB > OO > NN > AA > MM > II > SS >> I-IH In the rows and columns of Table 22 most I moieties have higher pyramidalization angles than anthronylidenes (A). Also, the M moieties make several exceptions.
Table 22. Pyramidalization x(Cg)in the Syn-Folded Conformations [~ F
F B
--
N A M I S H
NCH 3 CO CH 2 C(CH3) 2 S CH=CH
0
0
22.2 9.4
O
N
A
M
I
S
H
O
NCH 3
CO
CH 2
C(CH3) 2
S
CH=CH
12.0 16.8
16.6
15.5
14.8
15.0
15. I
12.6
6.9
15.4 15.2 14.9 15.4 14.4 11.7
14.8 14.6 14.2 14.6 13.7 10.5
13.9 13.8 13.3 13.6 12.9 9.5
13.5 13. I 13.0 13.4 12.4 9.3
13.5 13.3 13.0 15.6 12.5 9. I
13.3 13.5 14.4 10.3 12.5 I 0.0
11.6 11.4 11.2 11.6 10.7 7.9
5.5 5.6 5. I 6.2 5.I 2. I
B
16.0
15.6
14.6
14.0
14.0
14. I
12.0
5.9
292
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
In the syn-folded conformations the pyramidalization does not correlate well with folding or strain energy, but with the exception of I, there is a correlation with the pyramidalization in the anti-folded conformations. 2.6.
Cga-Cg-C8a B o n d A n g l e
2.6.1. CgrCs~C~ Bond Angle in Anti-Folded Conformations The C9a---C9---C8abond angles in the anti-folded conformations are given in Table 23. The values pertain to the moiety indicated in the column header. The second moiety of the bistricyclic ene is given in the row header. The values range from 103.3 ~ in FF to 114.7 ~ in liB. Fluorenylidenes (F) necessarily have particularly small values (103.3 ~ to 104.9 ~ because of the central five-membered ring. The bond angle at the ethylenic carbon atom C 9 of a given moiety X may vary by up to approximately 4 ~ depending on the second moiety. In the homomerous enes, the C9a--C9-C8abond angle is increasing in the series: FF << OO < NN < II < MM < AA < BB < SS < H H With regard to the order in the rows of Table 23, moieties B have the largest bond angles. The angles in H are smaller than those in S. Moieties M have very similar, but mostly smaller values as compared to I. In the column order, A should come before M, and B before O: F
This latter series is very similar to the column order of the folding dihedrals in C9a-C9-Csabond
anti-folded conformations (A and I are interchanged). Thus, the
Table 23.
Cga-Cg-C~ Bond Angles in the F
O
O F O N I M A B S H
103.3 O 104.3 NCH 3 104.4 C(CH3)2 104.4 CH 2 104.5 104.5 103.9 S 104.6 CH=CH 104.9 -
-
108.4 109.8 110.2 110.3 110.4 110.3 109.0 110.5 111.5
N
I
Anti-Folded C o n f o r m a t i o n s M
NCH3 C(CH3)2 CH2 108.5 109.9 110.3 110.4 110.6 110.4 109.1 110.6 112.2
108.8 110.3 110.7 110.8 110.9 110.8 109.4 110.9 112.0
108.7 110.2 110.6 110.8 110.9 110.8 109.4 110.9 112.1
A
B
CO 109.2 110.7 111.2 111.3 111.4 111.3 109.9 111.4 112.6
111.8 113.3 113.6 113.7 113.8 113.7 112.5 113.8 114.7
[o]
S
H
S
CH=CH
110.4 112.1 112.6 112.7 112.8 112.7 111.2 112.9 114.2
110.I 110.9 111.0 111.8 111.6 111.5 110.I 111.6 112.9
Overcrowded Polycyclic Aromatic Enes
293
angle is probably determined by the size of the ring, and to a lesser extent by the degree of folding or the steric demand of the second moiety.
2.6.2. Cga-Cg-CsaBond Angle in Syn.Folded Conformations The C9a-C9-Csa bond angles in the syn-folded conformations are given in Table 24. In the syn-folded conformations the bond angle at the ethylenic carbon atom is between 103.2 ~ (FF) and 113.6 ~ (liB). Within a given moiety the values may vary up to 4 ~ The angles C9a---f9---Csaincrease in the homomerous PAEs according to: FF << OO < II < NN < MM < AA < SS < BB < HH Within the rows of Table 24, H comes before S, and I, in most cases, has values between M and A. The angles in B are larger than in H. In the columns of Table 24, M comes after S (for most cases), and B before O: F
This order is identical to the column order of the folding dihedrals. Thus, as in
the anti-folded conformations, the steric demand of the second moiety has an effect on the Cga--C9--Csa bond angle.
2.6.3. Cga-Cg-CnaBond Angle in Twisted Conformations The C9a---C9-.Csabond angles in the twisted conformations are given in Table 25. In the twisted conformations, the smallest C9a---C9---Csabond angles, 104.7 ~ to 105.1~ are calculated for fluorenylidenes, which include central five-membered rings, and the largest bond angles, 125.6 ~ to 127.0 ~ for dibenzo[a,d]cycloheptenylidenes, which have central seven-membered rings. In the homomerous enes, the angles increase in the series:
Table 24.
Cga-Cg-C~ B o n d Angles in the S y n - F o l d e d C o n f o r m a t i o n s [~ F
O
O F O I N M A S B H
-O
N
C(CH3)2 NCH 3
M
A
$
CH 2
CO
S
103.2
C(CH3)2 NCH 3 CH 2 CO S 104.0 CH=CH
I
108.6 108.9 108.9 109.1 109.0 109.2 107.9 110.I
109.0 108.7 109.3 110.2 109.5 109.7 108.4 110.8
108.5 108.8 108.9 109.1 109.0 109.2 107.9 110.2
108.8 109.5 109.2 109.5 109.3 109.5 108.2 110.5
109.4 109.8 109.8 110.0 109.8 110.0 108.7 111.1
110.6 111.0 111.0 111.3 111.1 111.3 109.9 112.5
B
H
CH=CH 110.9 112.3 112.6 112.6 112.8 112.6 112.7 111.6 113.6
110.I 110.6 110.3 110.6 110.5 110.5 109.2 111.8
294
P.U. BIEDERMANN, J. I. STEZOWSKI, and I. AGRANAT
Table 25.
Cga--Cg-CsaBond O
F
O F O N I M A B S H
-O NCH 3 C(CH3)2 CH 2 CO S CH--CH
104.7 105.1 105.1 104.9 104.9 104.9 105.0 104.9 104.8
114.8 114.9 115.0 114.8 114.8 114.8 114.9 114.9 114.9
Angles in the Twisted Conformations [o]
N
I
M
NCH 3 C(CH3)2 CH 2 116.6 116.7 116.9 116.6 116.6 116.7 116.8 116.8 116.8
117.1 117.4 118.6 117.4 117.4 117.5 117.5 117.5 117.6
117.3 117.5 117.5 117.5 117.4 117.5 117.6 117.6 117.6
A
B
S
H
S
CH=CH
117.6 117.8 118.1 117.8 117.8 117.8 117.9 117.9 118.0
120.2 120.6 120.9 120.6 120.6 120.6 120.7 120.7 120.9
125.6 126.3 126.7 126.6 126.5 126.6 126.7 126.7 127.0
CO 117.6 117.9 118.1 117.9 117.9 117.9 118.0 118.0 118.1
F F < < O O < N N < II < M M < A A < B B < SS < H H
Within the rows of Table 25, moieties B have a slightly smaller bond angle than A. The variation within the columns of Table 25 is very small (> 1.5 ~ and exceptions from the order of the homomerous enes are frequent. The C9a--Cg---Csa bond angle in twisted bistricyclic enes does not correlate with pure ethylenic twist, propeller twist, or strain energy. It is determined by the ring size and the size of the bridging function in the six-membered ring. These constrains are much stronger in the almost planar central tings of the twisted conformations.
2.7. Overcrowding in the Fjord Regions The bistricyclic enes show severe intramolecular overcrowding with very short C...C, C...H, and H...H distances in the fjord regions in the anti-folded, syn-folded, and twisted conformations. The van der Waals radii of hydrogen and carbon atoms are 1.15 and 1.71 /~, respectively, t~ Thus, the shortest non-overcrowded distances are H...H = 2.30 ,~, C...H = 2.86/~, and C.-.C = 3.42 ,/~. These values may serve as a reference. For brevity, the analysis of the C...H distances in the various conformations is omitted.
2. 7.1. H... H Distances in Anti-Folded Conformations The intramolecular nonbonded HI...H l, (and Hs...Hs,) distances in the anti-folded conformations of the PAEs are listed in Table 26. Bifluorenylidene (FF) is the only compound with an overcrowded H...H distance (1.86 A) in the anti-folded conformation. Fluorenylidene-xanthene (FO) has a H...H distance of 2.47 A, considerably larger than the sum of the van der Waals radii. In the homomerous enes the H...H distances increase in the series" F F < < O O < B B < N N < A A < II < SS < M M << H H
Overcrowded Polycyclic Aromatic Enes
295
Table 26. H...H Distances in the Anti-Folded Conformations a
F O
--
F
O
--
O
B
N
A
I
S
NCH 3
CO
C(CH3) 2
S
O
1.86 2.47
N A
NCH 3 CO
2.53 2.52 2.53
2.91 2.99 3.00 3.04
3.07 3.07 3.11
3.10 3.14
3.19
I S
C(CH3) 2 S
2.55 2.55
3.05 3.07
3.12 3.14
3.15 3.17
3.19 3.21
3.20 3.22
3.24
M H
CH 2 CH=CH
2.64 2.80
3.19 3.51
3.26 3.54
3.29 3.60
3.33 3.67
3.34 3.67
3.36 3.69
B
M
H
CH 2 C H = C H
3.47 3.80
4.23
Note: 'Values in ~.
The rows and columns of Table 26 increase monotonously according to same order. There is only one exception, which is off by 0.01/~, FN. Apart from bifluorenylidene, anti-folding effectively increases the distance between the hydrogen atoms in the fjord region to a value larger than the sum of the van der Waals radii.
2.7.2. H...H Distances in Syn-Folded Conformations The nonbonded H...H distances in the fjord regions of the syn-folded conformations are given in Table 27 and illustrated in Figure 16. In the syn-folded conformations the H~...H l, and Ha...H 8, distances are extremely short. For most
Table 27. H...H Distances in the Syn-Folded Conformations a F
I
O
N
A
M
C(CH3) 2
O
NCH3
CO
CH 2
1.73 1.74 1.74
1.74 1.74
1.74 1.75 1.83
1.75 1.75 1.82
F
--
I O
C(CH3) 2 O
1.71 1.74
1.72
N A
NCH 3 CO
1.73 1.74
1.73 1.74
M B
CH 2
1.76 1.75
1.74 1.73
S H
S CH=CH
1.75 1.83
1.76 1.86
Note:
~'Valuesin ,~.
B
S
H
S
CH=CH
1.76 1.81
1.81
1.64
1.86
1.74 1.75
1.74
1.75 1.82
1.77 1.88
296
O
o..,.
E O
!
"O
~
o ~
T
4"D
Overcrowded Polycyclic Aromatic Enes
297
compounds they are in the range of 1.7 to 1.9/~. Syn-folded bifluorenylidene has an even shorter H...H distance of 1.64 A. All conformations have H...H distances shorter than the sum of the van der Waals radii. In the homomerous enes the H...H distances increase in the series: FF < II < OO < NN < AA ~ MM _=BB < SS < HH The rows and columns of Table 27 essentially show the same trend, but there are numerous exceptions in the row order and several exceptions in the column order. The extremely short H...H contacts and their relatively small variation suggest that this is the dominating factor determining the syn-folded conformations. The degree of folding is such that the nonbonded H..-H distances in the fjord region have a minimum length of 1.7 to 1.9 /~. The higher degree of folding in the syn-folded conformations and these extremely short and very repulsive H...H contacts probably are the main reason why syn-folded conformations generally are less stable than anti-folded conformations in the PAEs.
2.7.3. H...H Distances in Twisted Conformations The nonbonded distances H1...H l, (and Hs...Hs,) in the twisted conformations of the PAEs are given in Table 28. The values range from 1.88/~ for bifluorenylidene (FF) to 3.43/~ for HH. In the homomerous enes, the H...H distances increase in the series: FF << OO < NN < MM < II < BB < AA < SS << HH Apart from six minor exceptions, the rows and columns of Table 28 follow the same order. Only the twisted conformation of bifluorenylidene is overcrowded with respect to the hydrogens of the fjord region. It is interesting to note that the H...H distances
Table 28. H...H Distances in the Twisted Conformations a F
F
0 N M I B A S H
--
0 NCH 3 CH 2 C(CH3) 2 CO S CH=:CH
1.88
2.43 2.49 2.50 2.52 2.49 2.51 2.58 2.87
Note: '~Valuesin ,~.
O
N
M
I
O
NCH 3
CH2
C(CH3)2
2.61 2.67 2.68 2.69 2.68 2.70 2.76 3.06
2.73 2.74 2.76 2.75 2.76 2.83 3.12
2.74 2.75 2.75 2.76 2.83 3.12
2.76 2.76 2.77 2.83 3.11
B
2.77 2.77 2.84 3.14
A
S
H
CO
S
CH:=CH
2.78 2.85 3.14
2.91 3.20
3.43
298
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
increase with the non-bonding bridge distance C4a'"CI0 a in the twisted conformations (vide infra).
2.7.4. C...C Distances in Anti-Folded Conformations The close nonbonded C...C distances in the fjord regions of the anti, folded conformations are given in Table 29 and illustrated in Figure 17. The C~...C I, (and C8...C~,) distances in the anti-folded Conformations range from 2.88 A in BB to 3.66 A in HH, indicating that the former is severely overcrowded with a C...C distance approximately 15% below the sum of the van der Waals radii, while the latter is not overcrowded with respect to the carbon atoms in the fjord region. In the homomerous enes the C...C distance is increasing in the series: BB < OO < FF < NN < A A < II < M M < SS < I-IH Rows and columns of Table 29 follow the same order with occasional exceptions smaller than 0.03/~. This trend has similarity with that of the folding dihedrals and the strain energies in the anti-folded conformations, leading to the conclusion that with increasing degree of folding the C...C distance is increasing and thus overcrowding is reduced. It is interesting to note that the correlation with the vibrational frequencies of the folding mode of the planar dibenzofulvenes is even better (cf. Section 2.2.1). Only FF and II are exceptions.
2.7.5. C...C Distances in Syn.folded Conformations The C...C distances in the fjord regions of the syn-folded conformations are given in Table 30. The syn-folded conformations show a much smaller range of nonbonding C...C distances than the anti-folded conformations: 2.88/~ to 3.11/~. They
Table 29. B
2.88 2.92 2.93 2.95 2.97 2.97 2.98 3.01 3.22
B O F N A I M S H
CO C(CH3)2 CH 2 S CH==CH
Note:
aValuesin ~.
O -NCH 3
C-..C D i s t a n c e s in the
Anti-Folded C o n f o r m a t i o n s
a
O
F
N
A
I
M
S
H
O
--
NCH 3
CO
C(CH3)2
CH 2
S
CH=::~H
2.95 2.99 2.98 3.00 3.00 3.01 3.04 3.27
2.99 3.02 3.04 3.03 3.05 3.06 3.24
3.02 3.03 3.04 3.04 3.08 3.29
3.05 3.06 3.06 3.09 3.33
3.06 3.07 3.10 3.33
3.07 3.10 3.34
3.13 3.37
3.66
299
~
tO
E O k) "O
r"
r--
k3 r-
o ~ .
"D
u "D
k)
300
P.U. BIEDERMANN, I. I. STEZOWSKI, and I. AGRANAT
Table 30. C...C Distances in the Syn-Folded Conformations a B
B I S O A N M H F
I
S
0
A
N
M
H
C(CH3) 2
S
O
CO
NCH 3
CH 2
CH=CH
2.99 3.02 3.03 3.03 3.03 3.05 3.07
3.01 3.02 3.02 3.02 3.03 3.06
3.03 3.03 3.03 3.04 3.08
3.03 3.03 3.04 3.07
3.04 3.05 3.08
3.06 3.08
3.09
2.90 C(CH3) 2 S O CO NCH 3 CH 2 CH==CH --
2.97 2.97 2.97 2.97 2.97 2.99 3.04 2.88
3.11
Note: aValuesin A.
are all severely overcrowded. In the homomerous enes, the C...C distances are increasing in the seiies: B B < II < S S < O O = A A < N N < M M < H H < F F
This also is the general trend in the rows and columns of Table 30, although there are many exceptions. This series is quite different from the sequences for the folding dihedrals and for the strain energies in the syn-foldedconformations. Thus, in spite of the considerable overcrowding, the very short C.--C distances probably are not the most important factor determining the folding and energy in the syn-folded conformations.
2.7.6. C...C Distances in Twisted Conformations The overcrowded C...C distances in the twisted conformations are given in Table 31 and illustrated in Figure 18. The values range from 2.97/~ to 3.08 A and thus are almost constant within 0.1/~. This is a remarkably small variation for a nonbonded distance. Evidently, the molecules twist just sufficiently to accommodate a CI...C l, and C8...C 8, distance of approximately 3.0 A. In the series of the homomerous enes, the C...C distance slightly increases according to:
M M = II = O O < A A < N N < S S = B B < H H = F F
This trend is also seen in the rows and columns of Table 31, although there are many (minor) exceptions. These (almost) constant, highly overcrowded C...C distances in the fjord region apparently are the main factors determining the twist in the central double bond of the twisted conformations.
301
O
o m
E O
o ~
o ~
o ~
0
302
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
Table 31. C..-C Distances in the Twisted Conformations a M
I
O
A
N
S
O
CO
NCH 3
S
2.99 3.00 3.00 3.00 3.02 3.01
3.00 3.00 3.01 3.02 3.03
3.01 3.01 3.04 3.00
CH 2
C(CH3) 2
M I O
CH 2 C(CH3) 2 O
2.98 2.98 2.98
2.98 2.98
2.98
A N S B H F
CO NCH 3 S
2.99 2.99 2.99 3.00 3.01 3.02
2.99 2.99 2.99 3.00 3.02 3.00
2.99 2.99 2.99 2.99 3.00 3.04
CH::=CH --
B
H
F
CH==CH
3.01 3.03 3.03
3.08 2.97
3.08
Note: "Values in )k.
2.8. Geometrical Parameters of the Bridges The geometry of the bridges X and Y in the PAEs is defined by their bond lengths and bond angles. The nonbonding Caa...C10a bridge distance may be used as a single parameter measuring the combined effect of the C-X bond lengths and C-X-C bond angle. This latter approach also has the advantage of treating five-, six- and seven-membered rings in a consistent way.
2.8.1. Bond Lengths at the Bridges The C,ta-X and Cl0a-X bond lengths in the bridge of the six-membered rings are a characteristic parameter of the tricyclic moieties. For comparison, the C4a-C4b bond in fluorenylidenes (F), and the C4a-CI0 and Cll--C11a single bonds and Cl0---Cll double bond of the dibenzo[a,d]cycloheptenylidenes (H) are included in Table 32. These bonds change somewhat from one conformation to the other, but very little from one PAE to the other. The second moiety of the PAEs has very little effect on the bond lengths. Therefore, only the longest and shortest values for each moiety and conformation are listed in Table 32. In the anti-folded and syn-folded conformations, the bridge bonds are constant within 0.006/~. In the moieties with central six-membered tings the C-X bond lengths increase in the series: O
Overcrowded Polycyclic Aromatic Enes
303
Table 32. Bridge Bond Lengths in Anti-Folded, Syn-Folded, and Twisted Conformations a
F8
O
B
O
N
A
NCH 3
CO
M
I
CH 2 C(CH3)2
S
Hc
S
CH==CH
anti-folded conformations Min.: Max.:
1.458 1.460
1.387 1.393
1.432 1.432
1.445 1.448
1.489 1.493
1.495 1.498
1.516 1.519
1.763 1.769
1.458 1.460
1.339 1.340
syn-folded conformations Min.: 1.456 1.389 1.432 Max.: 1.459 1.393 1.437
1.445 1.449
1.491 1.493
1.496 1.498
1.517 1.519
1.766 1.769
1.459 1.460
1.339 1.339
twisted conformations Min.: 1.457 1.377 Max.: 1.460 1.379
1.417 1.421
1.482 1.484
1.486 1.487
1.506 1.509
1.741 1.745
1.445 1.447
1.335 1.337
1.430 1.431
Notes: aValuesin A.
4a-C~ bond. CC4a-C10 and Cll -Clla single bonds and C10=Cll double bond.
conformations by up to 0.03 A. In the moieties with central six-membered rings the C-X bond lengths increase in the series (note the interchange of B and N): O
2.8.2. Bond Angles at the Bridges Fluorenylidene moieties are excluded here since there is no bond angle in the bridge. The values for dibenzo[a,d]cycloheptenylidenes given in the last column of Table 33 to Table 35 refer to the symmetry equivalent angles C4a-C10--Cll and Cl0=Cll--Cll a, which are not directly comparable to the C4a--X10--C10a angles in the moieties with central six-membered rings. The angles in the seven-membered rings are listed for reference.
2.8.2.1. C4a-Xl0-CloaAngles in the Anti-Folded Conformations. The bond angles at the bridges of the anti-folded conformations are given in Table 33. The bond angle C-X--C in the moieties with central six-membered tings may be as small as 98.0 ~ at the S atom of FS, and as large as 119.0 ~ for the sp 2 carbon atom in the benzo[cd]pyreneylidene moiety of BH. In the homomerous enes, the C - X - C bond angle is decreasing in the series: BB >> N N > A A > O O > M M > II >> SS
304
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. A G R A N A T
Table 33.
B r i d g e B o n d A n g l e s in the B
F B N A O M I S H
m NCH 3 CO O CH 2 C(CH3)2 S CH=CH
N
118.3 118.4 118.7 118.7 118.6 118.8 118.7 118.8 119.0
A
Anti-Folded C o n f o r m a t i o n s
O
M
I
[o]
S
H
NCH 3
CO
O
CH 2
C(CH3)2
S
CH=CH
111.6 111.9 112.6 112.8 112.4 112.8 112.7 112.8 114.4
111.5 111.8 112.4 112.4 112.2 112.5 112.5 112.6 113.2
111.4 111.9 112.6 112.7 112.3 112.8 112.7 112.8 113.6
108.5 108.8 109.5 109.6 109.3 109.7 109.6 109.7 110.5
108.1 108.3 108.9 108.9 108.7 109.0 108.9 109.0 109.5
98.0 98.3 98.8 98.9 98.6 99.0 99.0 99.0 99.6
125.4 125.3 125.6 125.7 125.5 125.7 125.8 125.7 126.0
The rows show an identical order, with the exception that in all but one case the xanthenylidenes have a slightly larger bond angle at the oxygen atom than the respective anthronylidenes at the carbonyl group. The bond angle in any given moiety is constant within 3 ~ indicating that it is a property of the bridging group and is hardly affected by the second moiety. Nevertheless, there is an increasing trend visible in the columns of Table 33. As in the order of rows, O comes before A. Moreover, I comes either before or after A. There are a number of additional exceptions. The bond angles in the bridges of dibenzo[a,d]cycloheptenylidenes are between 125.3 ~ and 126.0 ~ increasing more or less according to the same trend seen in the other columns.
2.8.2.2. C4a--Xlo-CloaAngles in the Syn-FoldedConformations.
The bond
angles at the bridges of the syn-folded conformations is given in Table 34. As in the
Table 34.
B r i d g e B o n d A n g l e s in the B
F
m
118.0
B N A O I /91 S H
NCH 3 CO O C(CH3) 2 CH 2 S CH=CH
118.3 118.6 118.6 118.5 118.6 118.6 118.6 118.8
Syn-Folded C o n f o r m a t i o n s
[o]
N
A
O
I
M
S
H
NCH 3
CO
O
C(CH3)2
CH 2
S
CH=CH
111.4 111.9 112. I 111.7 111.8 112.0 112.3 112.7
111.3 111.8 111.9 111.6 111.9 111.9 112.0 112.5
111.4 111.9 112. I 111.7 111.9 112.0 112.2 112.7
108.0 108.5 108.5 108.3 109.2 108.7 108.6 109.0
108.3 108.8 108.9 108.6 108.4 109.0 109.0 109.6
97.8 98.3 98.3 98. I 98.2 98.4 98.4 99.0
124.8 125.1 125.2 125.0 125.2 125.2 125.2 125.6
305
Overcrowded Polycyclic Aromatic Enes
anti-folded conformations, in the syn-folded conformations the smallest bond angle in the six-membered ring bridges is calculated for sulfur in BS, 97.8 ~ and the largest value for the carbon atom of B in BH, 118.8 ~ In the homomerous enes with central six-membered rings, the C-X--C bond angles are decreasing according to the series: BB >> NN > AA > OO > II > M M >> SS In the rows order, O comes before A, and M before I. Thus, the row order is identical to the row order in the anti-folded conformations. The values in the columns are constant within 1.3 ~ There is a generally increasing trend from top to bottom following the sequence of the homomerous compounds, except for O, which comes before N. There are a number of additional irregularities. The angles in the bridges of dibenzo[a,d]cycloheptenylidenes are between 124.8 ~ and 125.6 ~, and follow the same trend as the other columns in Table 34.
2.8.2.3. C4a-Xl0-Cl0aAngles in the Twisted Conformations. The bond angles at the bridges of the twisted conformations are given in Table 35. In the twisted conformations, the C - X - C angles are essentially independent of the second moiety of the enes. The values in the columns of Table 35 are mostly constant within 0.5 ~ The acridinylidenes, with a bond angle of 120.3 ~ have the largest values in the six-membered ring moieties. The smallest values are again those of the thioxantenylidenes with 102.9 ~ The values decrease according to the series: NN > BB > AA > OO > MM > II > SS The bond angle in the bridge of the dibenzo[a,d]cycloheptenylidenes is between 129.6 ~ and 130.1 ~. Due to the more planar conformation of the central rings, the bond angles are larger than in the anti- and syn-folded conformations.
Table 35. Bridge Bond Angles in the Twisted Conformations [~ N
B
NCH 3 F N B A O M
-NCH 3
I S H
A
O
/Vl
I
S
H
CO
O
CH 2
C(CH3)2
S
CH=CH
CO O CH 2
120.3 120.3 120.3 120.3 120.3 120.3
119.5 119.5 119.5 119.5 119.5 119.5
116.9 116.9 116.9 116.9 116.9 116.9
116.8 116.6 116.7 116.8 116.7 116.7
115.1 114.9 115.0 115.0 115.0 115.0
113.3 114.4 113.4 113.4 113.4 113.4
102.9 102.9 102.9 102.9 102.9 102.9
129.6 130.0 130.0 130.0 129.9 130.0
C(CH3)2 S CH=CH
120.3 120.3 120.3
119.5 119.5 119.6
116.9 116.9 116.9
116.7 116.7 116.7
115.0 115.0 115.0
113.4 113.4 113.4
102.9 102.9 102.9
130.0 130.1 130. I
306
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
2.8.3. C4a'"CloaDistances in the Anti.folded Conformations The distances C~...CIo a, spanned by the bridge are given in Table 36. The shortest is found in bifluorenylidene (FF), 1.458 /~, and the longest in HI-I, 3.056 ~. However, the variation within any given moiety is less than 0.04 /~. In the homomerous enes and also in the rows of Table 36, the Caa...C10a distance is increasing in the series: FF << OO < NN < M M < BB < II < AA < SS < H H The columns show a similar increasing trend, but B comes before O, and A before M. The column order is similar to the order of the strain energies in the anti-folded conformations and the column order of the folding dihedrals. This suggests that the small variations in the bridge distance may be due to steric strain and overcrowding.
2.8.4. C4a'"CloaDistances in the Syn.folded Conformations The C4a...Cl0a distances in the syn-folded conformations are given in Table 37. The non-bonding distances across the central tings are between 1.456 ,/k (FB) and 3.038/1, (HI-I). In the homomerous enes, the C4a...CI0 a distance is increasing in the series: FF << OO < NN < M M < BB < AA < II < SS < HH In the rows order, I comes before A in most cases. Thus, the rows have the same order as the rows order of the anti-folded conformations. The second moiety has little effect on the C4a...CI0a distance in the first moiety. The variation in the columns of Table 37 is very small: 0.03/~,. There is an increasing trend in the columns of Table 37, similar to the sequence of the homomerous enes. Only B comes before O, and the relative position of A and I is ambiguous. C4a...C|0 a Distances in the Anti-Folded Conformations"
Table 36,
F O N M B I
F
O
N
M
--
O
NCH 3
CH 2
2.301 2.309 2.312 2.313 2.304 2.313
2.395 2.404 2.407 2.408 2.398 2.408
2.432 2.441 2.444 2.446 2.435 2.445
~ O NCH 3 CH 2
1.458 1.460 1.459 1.459 1.459 C(CH3)2 1.459
B
I
A
S
H
C(CH3)2
CO
S
CH--CH
2.458 2.462 2.464 2.464 2.460 2.464
2.458 2.465 2.468 2.469 2.460 2.469
2.468 2.474 2.477 2.479 2.470 2.479
2.670 2.678 2.682 2.684 2.673 2.685
3.030 3.035 3.036 3.042 3.026 3.044 3.040 3.042 3.056
A
CO
1.460
2.312
2.407
2.445
2.464
2.468
2.478
2.682
S H
S CH=CH
1.460 1.460
2.314 2.321
2.409 2.430
2.44 7 2.456
2.464 2.468
2.469 2.476
2.4 79 2.487
2.684 2.694
Note: aValuesin/~.
Overcrowded Polycyclic Aromatic Enes
Table 37.
C.4a-..Cloa Distances in the F
O
N
/91
O
NCH 3
CH 2
2.397 2.400 2.401 2.393 2.400 2.399 2.401 2.408
2.433 2.435 2.437 2.428 2.436 2.430 2.437 2.445
F
--
O N M B A
O NCH 3 CH 2 CO
2.304 2.306 2.307 2.300 2.306
1.459
I S H
C(CH3) 2 S CH=CH
2.306 2.308 2.313
1.456
Note: 'Values in
307
Syn-Folded Conformations a B
2.454 2.461 2.462 2.462 2.459 2.462 2.462 2.462 2.465
A
I
5
CO
C(CH3) 2
S
CH=CH
2.469 2.471 2.472 2.465 2.472 2.472 2.474 2.479
2.461 2.464 2.466 2.457 2.464 2.474 2.466 2.471
2.670 2.674 2.675 2.665 2.674 2.674 2.676 2.685
3.014 3.019 3.022 3.006 3.020 3.021 3.022 3.038
,/~.
2.8.5. C4a'"CloaDistances in the Twisted Conformations The C4a...C10a distances in the twisted conformations are given in Table 38. The distance spanned by the bridging groups is between 1.457/~ and 3.213/~. In the homomerous enes, the values increase in the series: FF << OO < NN < BB < MM < II < AA < SS < HH
The rows follow the same order. The values in the columns of Table 38 are constant within 0.01/~. There is only one exception: I in IN. Apart from MM, the order is identical to the order in the anti-folded conformations.
Table 38, C4a...C10 a Distances in the Twisted Conformations a F
F O N B M I A S H
m 1.458 O 1.459 NCH 3 1.457 1.459 CH 2 1.458 C(CH3)2 1.458 CO 1.460 S 1.459 C H = C H 1.458
Note: '~Values in ,~.
O
N
O
NCH 3
2.345 2.346 2.346 2.345 2.346 2.345 2.344 2.345 2.346
2.461 2.463 2.465 2.460 2.462 2.462 2.458 2.461 2.463
B
2.473 2.472 2.472 2.472 2.472 2.472 2.472 2.472 2.473
M
I
A
S
H
CH 2
C(CH3)2
CO
S
CH=CH
2.529 2.527 2.525 2.528 2.527 2.528 2.529 2.528 2.527
2.723 2.726 2.729 2.725 2.726 2.726 2.723 2.726 2.728
2.507 2.507 2.507 2.507 2.507 2.507 2.507 2.508 2.508
2.519 2.522 2.532 2.522 2.522 2.523 2.522 2.522 2.523
3.202 3.208 3.211 3.209 3.209 3.210 3.208 3.210 3.213
308
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT 2.9. Summary
The above results show that many of the properties of the homomerous and heteromerous PAEs vary in a systematic and predictab" " way, depending on the bridges, although the order of increase or decrease ma~ ..,range from property to property. This situation should allow tailoring of the structural and physical properties according to the requirements of a particular application. We hope that the present work will encourage such undertakings. In particular, the energy difference between the twisted and anti-folded conformations, which determines the global minimum conformation and the thermochromic behavior, may be adjusted in a very wide range, from -5 kcal/mol to + 50 kcal/mol in the PAEs studied, increasing in the series: FF << BB < OO << NN < AA < MM < II < SS << HH. The relative energy of the twisted conformation may be fine-tuned when heteromerous enes are considered. Keeping in mind the bias of PM3, which energetically disfavors twisted conformations relative to anti- and syn-folded conformations, the hitherto unknown compounds FB and BB, are expected to have twisted conformations, in spite of the positive conformational energies calculated by PM3 for the twisted versus the anti-folded conformations (Table 5). Syn-folded conformations were found to be higher in energy than the anti-folded conformations for all PAEs studied. The energy differences are less than 5 kcal/mol, and may be as low as 0.5 kcal/mol in PAEs with flexible moieties allowing high degrees of folding. Thus, although the syn-folded conformations are never the global minimum conformations, they can easily be populated in thermal equilibrium and should not be neglected in the analysis of dynamic processes and thermochromism. Twisted conformations are highly strained (13 to 55 kcal/mol), as may be expected from the highly twisted central double bonds (30 ~ to 60~ required to bring the nonbonding distances C I...C 1, and C8...C 8, to an acceptable value of approximately 3.0 + 0.1/~ (12% overlap of the van der Waals radii). This unexpectedly constant feature is seen in all twisted conformations of the PAEs in this study. Folding in the anti- and syn-folded conformations may vary between 3 ~ and 70 ~ In heteromerous enes, the folding is highly unequal for the two moieties. The degree of folding depends on the intrinsic foldablity of the moiety itself, which can already be seen in the dibenzofulvenes. Another factor is the steric demand of the second moiety of the specific PAE. In this context, highly folded moieties are sterically less demanding. In syn-folded conformations, the moieties are 1o to 6 ~ more folded than in the corresponding anti-folded conformation of the same PAE. The extremely overcrowded situation of the bucking hydrogen atoms in the fjord region of the syn-folded conformation with 20 to 25% overlap of the van der Waals radii may explain both the higher energy and the higher degree of folding. On the other hand, anti-folding increases efficiently the hydrogen-hydrogen distances in the fjord regions to values larger than the sum of the van der Waals radii. In the anti-folded
Overcrowded Polycyclic Aromatic Enes
309
conformations, the overcrowding of the carbon atoms in the fjord region is more important (0 to 15% overlap of the van der Waals radii). There is a good correlation of the C1...C l, and C8...C 8, distances with the degree of folding and a reverse correlation with the strain energies, suggesting that the anti-folded conformations are defined by a compromise between folding and carbon--carbon overcrowding. A geometrical parameter of the bridge has been used by Feringa et al. to rationalize the relative height of the barriers for thermal inversion of the anti-folded conformations. 62 This approach does not work for the physical and structural properties of the large number of PAEs studied here. Fluorenylidene PAEs, and in particular bifluorenylidene (FF), with their central five-membered rings are exceptional in many respects. The fluorenylidene moiety is extremely reluctant with respect to folding but induces high folding in the second moiety of heteromerous PAEs. At the same time, F is sterically tess demanding in twisted conformations. Thus, it causes low ethylenic twist angles and low strain energies in twisted conformations, but relatively high strain in anti-folded conformations. In this series, syn-folded conformations were found only for FF and FB. The hydrogens in the fjord region of bifluorenylidene (FF) show extremely short intramolecular non-bonding contacts in the syn-folded conformation (29% overlap of the van der Waals radii). Furthermore, bifluorenylidene is the only PAE with an overcrowded H...H contact in the twisted and in the anti-folded conformations.
3. COMPARISON OF CALCULATED AND CRYSTAL STRUCTURES Crystals of bistricyclic enes have been laying on the benches of crystallographers since 1877. ~l~ The crystal structures of bistricyclic enes have previously been reviewed. 1'6 In the present section we list the reported structures of bistricyclic enes determined by X-ray crystallography and summarize the main structural features pertaining to overcrowding (Table 39). Furthermore, for the unsubstituted bistricyclic enes, these structural parameters are compared with the corresponding PM3optimized parameters. The conformations observed in the crystal structures are in accord with the global-minimum conformation calculated by PM3. In the case of HH (8), a 0.5 kcal/mol higher energy conformation, the syn-folded conformation, is observed in a crystal, in addition to the global-minimum anti-folded conformation. It is noteworthy that in solution, syn-HH irreversibly isomerizes to anti-HH at elevated temperatures) ~ The PM3 method predicts reasonably well the geometries of the overcrowded bistricylic enes, including the pure twist, the folding, the nonbonding distances in the fjord regions and across the bridges, and the central double bond. Notable exceptions are the folding in syn-folded HH and the nonbonding C1-..Cl, and C8...C 8, in anti- and syn-folded HH.
Table 39. Conformations and Selected Geometrical Parameters of Bistricyclic Enes Derived from Crystal Structures and PM3 Calculations Compound
2-a FF243 FF 2
w, 0
15 16 16 17 18 7 19 19 20 20 4 4 21 21
Bridges
-
Method
X-ray X-ray FF PM3 X-ray X-ray X-ray X-ray X-ray X-ray II C(CH3)z C(CH-Jz X-ray II C(CH3)z C(CH3)z PM3 FA co X-ray FA co PM3 AACO co X-ray AACO co PM3 co co X-ray co co X-ray
Conformation twisted twisted twisted twisted twisted twisted twisted twisted twisted anti-folded anti-folded anti-folded anti-folded anti-folded anti-folded anti-folded anti-folded
C9=Cq
[A]
1.367 1.364 1.358 1.368 1.397 1.390 1.38 1.366 1.345 1.352 1.367 1.350 1.364 1.353 1.340 1.365
Pure TwisP 33.0 31.9 30.2 34.3 37.5 37.9 40.3 67 24.7 0.0 0.0 3.1 0.0 0.0 0.0
0.0 0.0
Folding‘.b 5.2 2.7 2.5 7.4 7.5 6.2
4.2 4.5 2.5 5.3 7.5 2.4
0.9 52.9 45.2 11.8 12.2 40.0 46.6 45.2 37.2
4.0 52.9 45.2 51.2 53.3 40.0 46.6 45.2 37.2
Cl-CI’
C8-C8‘
/A1
[A/
MI
/A1
3.18 3.15 3.08 3.30
3.19 3.20 3.08 3.15
1.46 1.45 1.46 1.48 1.43 1.44 1.46
1.45 1.46 1.46 1.45 1.43 1.43 1.46
1.41
1.41
3.31 3.16
3.31 3.17
3.13 3.06 3.10 3.04 2.94 3.05
3.13 3.06 3.02 3.04 2.94 3.05
C4a...Cl&
C4a’-ClOa’
2.47
2.47
1.46
2.47
2.48 2.49 2.50
2.48 2.49 2.50
Space Group
R%
Pbcn P212121
7.4 5.0
I2/c
9.5
P2 1/c
4.3
1990’ 5r44 1988’
P21/n
7.2
1988’
P21lc
6.9
1978”37’c
Year and References
1 98530*44 198530’44 1990“*~~ 197829*44 197829*44 1 9972’ 1gg1’1’.’12
2
3-a 00 0 3-8 00 0 3 000 22 SO5 23 SO5 8 HH CH=CH 8 HHCH=CH 8 HHCH=CH 8 HH C H X H 8 HHCHSH 24 CH,-CH2 25 CC(CN), 26 27 0 C(CH,), 28
-
Note:
0 0 0 0 0 CHSH CH=CH CH=CH CH=CH CH=CH CH,-CH, CCKN), CCKN), CCKN), PdCI,
X-ray X-ray PM3 X-ray PM3 X-ray PM3 X-ray X-ray PM3 X-ray X-ray X-ray X-ray X-ray
anti-folded anti-folded anti-folded anti-folded anti-folded anti-folded anti-folded syn-folded syn-folded syn-folded anti-folded anti-folded anti-folded anti-folded anti-folded
1.369 1.401 1.354 1.336 1.354 1.348 1.347 1.344 1.341 1.347 1.350 1.354 1.355 1.355 1.346
0.0 0.0 0.0 4.8 0.0 0.0 0.0 1.1 3.9 0.0 3.1 0.0 4.5 2.0 0.2
43.0 40.1 40.4 51.1 49.3 55.7 61.6 56.6 54.5 64.7 58.4 47.6 16.1 41.5
43.0 40.1 40.4 36.2 37.5 55.7 61.6 61.8 63.3 64.7 57.2 47.6 53.1 50.9
2.97 3.02 2.95
2.97 3.02 2.95
3.04 3.48 3.66 3.25 3.24 3.11 3.38 3.03 3.03 3.03
3.04 3.48 3.66 3.32 3.27 3.11 3.40 3.03 2.99 3.08
2.32 2.35 2.31 2.65 2.68 3.1 3 3.06 3.1 3 3.14 3.04 3.1 2
2.32 2.35 2.31 2.33 2.31 3.1 3 3.06 3.11 3.1 0 3.04 3.11
A2/n c2/c
21 21
196333’44 196333*44 1993-
P21/c
3.8
1 97439*44
P2/c P21/c
5.9 5.9
197439*44 197439*44
P21/n P2 1/c P21 P2 1/c
7.2 6.4 4.5 7.9
1990443”4 1988’’d 1988’ 1988’ 1996’15
Walues in degrees. bFolding is measured using the dihedral ofthe least-squares-planesof the benzene rings of each moiety. In the PM3calculated structure of 2 this refers to pure propeller twist. Tor the first X-ray structure of this compound see Ref. 36. ‘%or another X-ray structure of this compound see Ref. 11 6.
312
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
c,
15
C
16
17
CI Cl C l
~
0
C
I
c~' Cl
CI
Cl
H3C CH3
18
20
19
0
0
21
NC
22
23
ON
25
24
I-.~q C~
26
27
28
Overcrowded Polycyclic Aromatic Enes
313
4. DYNAMIC STEREOCHEMISTRY The dynamic stereochemistry of bistricyclic enes has been reviewed very recently. 23 The controversial dynamic stereochemistry of bifluorenylidenes 56'57'61'117-122 has recently been clarified. 31 The dynamic processes of the homomerous bistricyclic enes with central six-membered rings have been extensively studied. 35'38''.7'123'1~ Free energies of activation for thermal E,Z-isomerization (Figure 19) of representative homomerous 2,2'-dimethyl-substituted bistricyclic enes are given in Table 40. The remarkably low barriers associated with the E,Z-isomerization of the bistricyclic enes with central six-membered rings were interpreted predominantly in terms of ground-state destabilization due to steric strain and overcrowding, rather than in terms of stabilization of the diradical transition state. ~23'124E,Z-isomerizations of the bianthrone analogues 29, 30, and 31 carrying azulene and naphthalene moieties should also be noted: AGc* = 14.6 kcal/mol, 125 21.6 kcal/mol, 3s and 22.7 kcal/mol, 3s respectively. Table 41 gives free energies of activation for the thermal conformational inversion of representative homomerous and heteromerous bistricyclic enes. Bistricyclic enes may undergo three fundamental dynamic processes: (1) E,Z-isomerization (e.g., te ~ tz, ae ~ az); (2) conformational inversion, i.e., inversion of the helicity in twisted 1 (re ~ tu), or inversions of the boat conformations in the central tings of folded 1 (e.g., at, ~ aM); (3) syn, anti-isomerization (a ~ s). It should be noted that enantiomerization and racemization may also be considered in processes (1) and (2). In the mechanisms of the fundamental dynamic processes, the following four elemental steps should be considered (Figure 20): (i) E,Z-isomerization of the twisted conformations via an orthogonally twisted transition state involving simultaneous inversion of the helicity, e.g., te-e ~ tu-z; (ii) a,t-isomerization via a folded-twisted transition state with two opposing benzene rings passing one another, e.g., aPE ~--- re-n; (iii) s,t-isomerization, via a syn-folded, twisted transition state, e.g., SP - E ~ - " t p - s ;
(iv) a,s-isomerization via an unequally folded transition state, e.g., IIp-E ~ -
SP-E.
Figure 21 is a symbolic representation of the pathways for thermal isomerizations and topomerizations of bistricyclic enes that may be constructed from these elemental steps.
314
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
Figure 19. Thermal E,Z-isomerization of a 2,2'-dimethyl-substituted bistricyclic ene.
Table 40.
Free Energies of Activation for Thermal E,Z-lsomerizations of 2,2'-DimethyI-Substituted H o m o m e r o u s Bistricyclic Enes
System FF OO
X, Y
/~cc [kcal/mol]
Method
--
25.2 17.5 20.0 20.8 27.4
DNMR31 DNMR3s DNMR38 DNMR47 HPLC62
0 CO NCH3 S
AA
NN SS
o
o
I-k,c
o
I%C
I%c
c
o 29
30
Table 41.
Free Energies of Activation for Thermal Conformational Inversions of Representative Bistricyclic Enes
System
x
FF O0
_
AA SS SI SN
31
O CO S S S
Y -O CO S C(CH3)2 NCH3
R, ~ 2-CH(CH3)2 2,2'-di-CH(CH3)2 2,2'-di-OCH(CH3)2 2-CH3 2-CH3 2-CH3
/ ~ [kcal/mol!
Method
10.5 17.7 21.0 27.4 25.1 21.3
DNMR31 DNMR3s DNMR 11B HPLC62 HPLC62 HPLC62
Overcrowded Polycyclic Aromatic Enes
315
R
t,.E
)
(
S,-c
<
R~R'
tM-z
)
t..E
a ,.E
(
a ,.E
(
)
t,.E
>
s ,-E
Figure 20. Elemental steps in the dynamic processes of overcrowded bistri-
cyclicenes.
Isomerization Pathways for Bistricyclic Enes t M-E
4#
<
>
%
..d.'j s ..~
.'.~ s /~. . : : ~. .4; .... ........-...-
t P-E
t P-Z
/;+y >
t ~z
Figure 21. Pathways for thermal isomerization of substituted bistricyclic
enes.
j
1"
316
V
v
a.
A
:i
N
V
a.
~g
o.m
om
..Q "D ~
O
O o ~
> o ~
O
om
E O
O
N
ow
o
E
E L_
t'-
.,-,
E
O o.,.
e~
317
e
^
uJ
E U U
E
..Q "D
w
.O
E O U "O
E
v
N
O
o m
E
t~ N "~. 0 ._~
e~
E t_
e-
,...
,~
e-' I,U
u
r-
r-
E ._~
0
,4
v
*"
^
I,u
v
318
P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
A comparison between the dynamic stereochemistries of bifluorenylidene (2), a representative twisted bistricyclic ene, and dixanthylene (3), a representative antifolded bistricyclic ene, is illustrative. Contrary to dixanthylenes, which have identical barriers for E,Z-isomerization and conformational inversion of AGc* = 17.9 kcal/mol and a common (highest) transition state for the two processes, as in bifluorenylidenes, the E,Z-isomerization barrier is higher (24.9 kcal/mol) and the conformational inversion barrier is lower (10.5 kcal/mol). 31 The different dynamic behavior can be explained by the fact that in dixanthylenes, the ground state is anti-folded (an, az), the twisted conformations (tn, tz) are intermediates (local minima) in both the E,Z-isomerization and conformational inversion processes, and the barriers for a ~ t are higher than the te ~ tz barriers. On the other hand, in bifluorenylidenes, the ground state is twisted, the anti-folded conformations are intermediates in the conformational inversion process but not in the E,Z-isomerization process, and the t ~ a barriers are lower than the te ~ tz barriers. The mechanisms of thermal E,Z-isomerization and conformational inversion are shown in Figure 22 and Figure 23 for twisted and for anti-folded bistricyclic enes, respectively. It should be noted that the overall dynamic stereochemistries of twisted and anti-folded bistricyclic enes have identical networks of interconversion (Figure 21). Only the relative energies of the participating species vary. In twisted bistricyclic enes, the dynamic E,Z-isomerization and conformational inversion processes follow different pathways, and distinct barriers may be observed. On the other hand, in anti-folded bistricyclic enes, both the E,Z-isomerization and the conformational inversion have a common highest transition state. In substituted dithioxantylenes (derivatives of 1, X,Y: S), the barriers for E,Z-isomerization and conformational inversion are significantly higher (e.g., 27.4 kcal/mo162) than in dixanthylene (3), allowing an elegant separation of the stereoisomers. The syn-8 ~ anti-8 isomerization was found to be even higher, AG'347 = 36.4 kcal/mol. 4~
5. CONCLUSIONS The combination of thermochromic, photochromic, and piezochromic properties, intrinsic chirality and dynamic stereochemistry of the overcrowded polycyclic aromatic enes has inspired chemists to challenging experiments, leading to a progressive insight into these fascinating phenomena and the underlying basic concepts of structural and physical organic chemistry. Furthermore, bistricyclic enes pose a challenge for theoretical chemists to analyze and explain these phenomena and to test and develop reliable and feasible predictive computational methods. Finally, these unusual physicochemical properties call for applications in high-tech molecular electronic and optical devices. Thus, the overcrowded polycylic aromatic enes will continue to be a fruitful and inspiring arena for the interplay of theoretical, experimental, and applied chemistry, with each field enhancing the others.
Overcrowded Polycyclic Aromatic Enes
319
ACKNOWLEDGMENTS We thank the late Dr. Yitzhak Tapuhi, Dr. Shmuel Cohen, Dr. Michal Rachel Suissa, Ms. Amalia Levy, and Mr. Sergey Pogodin. Their continued research contributed significantly to our understanding of the overcrowded PAEs. We acknowledge computing resources provided by the US National Science Foundation under grant number CHE9508600.
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P.U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
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Overcrowded Polycyclic Aromatic Enes
321
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322
R U. BIEDERMANN, J. J. STEZOWSKI, and I. AGRANAT
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Aznmi, A.Z. Z Kristalogr., 1877,1,433; cited by Groth, R Chem. Kristalogr., 19116-1919,5, 431. Herbstein, EH. Acta Cryst. B, 1991, 47, 288. Ballester, M.; Cast,after, J.; Riera, J.; de la Fuente, G.; Camps, M. J. Org. Chem., 1985, 50, 2287. MUller, U.; Enkelmatm, V.; Adam, M.; MUllen, K. Chem. Ber., 1993, 126, 1217. Shoham, G.; Cohen, S.; Suissa, R.M.; Agranat, I. Acta Cryst. C, 1990, 46, 1457. Smid, W.I.; Schoevaars, A.M.; Knmnaga, W.; Veldman, N.; Smeets, W.J.J.; Spek, A.L.; Feringa, B.L. Chem. Commun., 1996, 2265. Yamaguchi, S.; Hanafusa, T.; Tanaka, T.; Sawada, M.; Kondo, K.; Irie, M.; Tatemitsu, H.; Sakata, Y.; Misumi, S. Tetrahedron Lett., 1986, 27, 2411. Gault, I.R.; Ollis, W.D.; Sutherland, I.O. Chem. Commu~, 1970, 269. Sutherland, I.O. Ann. Reports on NMR Spetcroscopy, 1971, 4, 71. Agranat, I.; Rabinovitz, M.; Weizen-Dagan, A.; Gosnay, I. Chem. Commun., 1972, 732. Agranat, I.; Rabinovitz, M.; Gosnay, I.; Weizen-Dagan, A. J. Am. Chem. Soc., 1972, 94, 2889. Rabinovitz, M.; Agranat, I.; Weitzen-Dagan, A. Tetrahedron Lett., 1974, 1241. Grieser, U.; Hafner, K. Tetrahedron Lett., 1994, 35, 7759. Agranat, I.; Tapulfi, Y. J. Am. Chem. Soc., 1976, 98, 615. Agranat, I.; Tapuhi, Y. Noveau J. Chim., 1977, 1, 361. Bind, J.; Burgemeister, T.; Daub, J. Chem. Ber., 1985, 118, 4934.
116. 117. 118. 119. 120. 121. 122. 123. 124. 125.
AUTHOR IN DEX
Abelt, C.J., 194, 201 Achiba, Y., 79 Adam, M., 322 Adam, W., 154 Admas, R., 49 Agarwal, R., 198 Agatsuma, T., 52 Agosta, W.C., 83, 106, 114, 151,152 Agranat, I., 79, 245, 319-322 Ahlberg, E., 321 Aida, M., 79 Aihara, J., 56, 57, 79 Albert, A., 319 Alder, R.W., 79, 83, 151 Aleksiuk, O., 319 Ali, S., 52 Allen, EH., 320 Allen, P.R., 79 Allinger, N.L., 153 Almlof, J.E., 80 Altenbach, H.-J., 151 Alvarez, M.M., 79 Amaike, M., 152 Anders, J., 321 Anderson, L.B., 199 Ando, A., 198 Anet, F.A.L., 169, 179, 183, 196, 199, 244 Anthony, I.J., 49 Aotani, Y., 52
Apeloig, Y., 50 Apgar, EA., 320 Applegate, L.E., 242 Applequist, D.E., 197 Arad, D., 50 Arney, B.E. Jr., 51 Artis, D.R., 51 Ashton, P.R., 57-59, 79 Askani, R., 168, 173-176, 187, 198200 Ashton, P.R., 50, 79 Aso, Y., 80 Assmann, L., 52 Avoyan, R.L., 319 Aydin, R., 183,200 Azruni, A.Z., 322 Bach, R.D., 51 Badger, G.M., 50 Bailey, J.H., 52 Bailey, N.A., 320 Baker, R.W., 51 Baker (nee Nicoletti), T.M., 51 Baker, W., 152 Balaban, A.R., 196 Balaban, A.T., 56, 79, 155, Baldridge, K.K., 50, 155 Ball, P., 78 Ballester, M., 322 Bally, T., 201 323
324
Banavali, R., 52 Banciu, M., 196 Banks, M.R., 51 Barbier, M., 51 Barker, J.M., 51 Barrett, J.W., 153 Barth, D., 153, 154 Bartlett, P.D., 52 Bartlett, R.J., 243 Bartmess, J.E., 154 Barton, J.W., 49 Batt, D.G., 51 Bauer, S.H., 198 Bauer, W., 242 Baze, M.E., 243 Beard, j., 244 Beasley, G.H., 196 Bechgaard, K., 321 Beck, A., 321 Becker, C., 200 Behr, L.C., 243 Bell, E 247, 310, 319 Benesi, A., 200 Benner, S.A., 155 Bennett, M.A., 244 Bergmann, E.D., 320, 321 Berkowitz, D.B., 52 Bemadinelli, G., 51 Berrie, R.L., 52 Berson, J.A., 216, 217, 243 Best, W.M., 50 Beurskens, P.T., 154 Bickelhaupt, E, 79 Biedermann, P.U., 245, 319-321 Bigi, E, 51 Bigler, P., 83, 84, 152 Billups, W.E., 50, 51 Bindl, J., 322 Bingham, R.C., 170, 198 Binkley, R.W., 166, 179, 180, 198 Bird, C.W., 164, 197 Birkbeck, A.A., 51 Birladeanu, L., 162, 196
AUTHOR INDEX
Birnberg, G.H., 199 Birney, D.M., 197 Bishop, W.R., 52 Bitterwolf, T.E., 154 BjCrnholm, T., 321 Black, K.A., 196 Bladauski, D., 153 BIKer, D., 50 Blatter, K., 50, 79 Blomquist, A.T., 204, 241 Blum, R.B., 68, 80 Bock, C.W., 321,322 Bock, H., 319 Bodwell, G.J., 79 Boekenoogen, H.A., 241 Boese, R., 50, 198 B6gge, H., 153-155 B6hm, M.C., 155 Bohrer, J.C., 204, 241 Borden, W.T., 155, 172, 196-198, 320 Bossenbroek, B., 51 Bowne, A.T., 242 Boyd, D.R., 198 Boyd, R.H., 153 Braig, C., 199 Brandes. E.B., 83, 152 Braun, M., 151,244 Bredenk6tter, B., 153 Breimann, D., 49 Breslow, R., 196 Brett, A.M., 321,322 Bridson, J.N., 79 Brinker, U.H., 193, 200 Brown, G.R., 79 Browne, A.R., 155 Brune, H.-A., 168, 198 Brunfeldt, K., 321 Brunvoll, J., 83, 84, 115, 152 Buck, P., 242 Burge, R.E., 204, 241 Burgemeister, T., 322 Biirgi, H.-B., 154 Burson, R.L., 192, 196, 199, 200
Author Index
Busch, A., 181,200 Busch, R.W., 321 Bussenius, J., 51 Buttery, J.H., 50, 52 Byrne, H., 321 Caille, J.-C., 152 Calabrese, J.C., 80 Calais, J.-I., 321 Calder, G.V., 241 Calder, I.C., 197 Calvin, E.W., 214, 215,243 Camps, M., 322 Carlsen, J., 174, 199, 200 Carlson, D., 242 Carroll, P.J., 198 Carrozzella, D., 80 Carullo, E, 19, 49 Casnati, G., 51 Castafiner, J., 322 Catel, J., 49 Caubere, P., 10, 35, 49 Cava, M.P., 49 Ceccon, A., 154 Cedarbaum, EE., 67, 80 Cessar, G.P., 200 Chadrasekhar, J., 155 Chaloner, L.M., 50 Chamberlain, N.F., 197 Chamot, E., 190, 199 Chang, S.-J., 153 Chao, I., 79 Chapman, O.L., 56, 79, 206, 241,242, 244 Chauhan, K., 177, 195, 197, 199 Chee, J., 51 Chen, C.-T., 155 Chen, M.H.M., 198 Chen, N., 241 Cheng, A.K., 169, 196 Cheung, L.D., 320 Chiang, J.E, 244 Chiang, P., 320
325 Chiba, S., 52 Chiba, T., 62, 79 Chida, K., 79 Childs, R.E, 195-197 Chou, T, -C., 52 Christ, J., 183, 199, 200 Christi, M., 244 Christoph, G.G., 199 Christopher, T.A., 242 Christen, D., 50 Ciorba, V., 196 Clar, E., 49 Clardy, J., 196, 199 Clark, B.C., 196 Clark, J.D., 83, 152 Clark, R.A., 244 Clayton, M.D., 79 Cloudsdale, I.S., 243 Clough, A.E., 199 Cochran, J.E., 52 Cohen, S., 319, 322 Cole, T.W., Jr., 241 Collins, M.J., 50 Collins, P.A., 50 Collis, G.E., 51 Colson, K.L., 200 Colvin, E.W., 243 Contreras, L., 51 Cook, J.M., 83, 84, 115, 125, 151153, 174, 199 Cooks, R.G., 242 Cooney, M.J., 166, 197, 198 Cope, A.C., 196 Copper, W., 243 Corbett, R.E., 154 Cory, R.M., 53, 80 Couldwell, C.M., 154 Coulter, C.V., 52 Coval, S.J., 52 Cowe, H.J., 51 Cox, P.J., 51 Cragg, G.L., 51 Cram, D.J., 154
326
Cremer, D., 164, 172, 191,195, 197 Crew, A.P.A., 50 Crews, P., 244 Criegee, R., 168, 198 Crimmins, M.T., 83, 152 Curci, R., 153, 154 Curl, R.E, 54,.78 Curtin, D.Y., 213, 243 Curtis, EJ., 51 Cvetanovic, R.J., 243 Cynkowski, T., 165, 197 Dahm, J., 244 Dai, S., 194, 201 Daniels, E, 196 Dannenberg, J.J., 170, 177, 190, 191, 198, 199 Danishefsky, S.J., 52 Danovich, D.D., 197 Daoust, K.J., 227, 244 Dashevskii, V.G., 319 Daub, J., 322 Dauben, H.J., Jr., 197 Dauben, W.G., 83, 152 Davidson, E.R., 196, 197 Davidson, E, 200 Davies, A.G., 50 Davis, B., 52 Day, J.H., 320 Deana, A.A., 49 Debaerdemaeker, T., 51, 52 DeCicco, G.J., 197, 198 Decker, H., 319 de Haan, J.W., 244 Dejroongruang, K., 166, 197 Delbecq, E, 50 de Meijere, A., 196-198 Dent, B.R., 51 Derflinger, G., 55, 79 Desphande, M.N., 83, 84, 152 Dev, S., 152 Devys, M., 51 DeWall, G., 51
AUTHOR INDEX
Dewar, M.J.S., 162, 163, 168, 169171,180, 181,196-197, 198, 225,226, 244 deWinter, M.L., 153 Dibble, EW., 15, 49 Dichmann, K.S., 320 Diederich, E, 79, 198, 241 Dietrich, H., 153 Dietz, T., 174, 177, 199 Dikmans, A.J., 80 Dilettato, D., 242 di Maio, G., 197 Dinoi, A., 154 Disch, R.L., 197 Disteldoff, W., 243 Ditchfield, R., 321 Dodzuik, H., 83, 151 Doering, W.v.E., 160-162, 196, 197 Doherty, A.M., 152 Dolbier, W.R., Jr., 243 Dorsch, J.A., 321 Doubleday, C., Jr., 244 Dresselhaus, G., 78, 79 Dresselhaus, M.S., 78, 79 Drickamer, H.G., 321 Drysdale, N.E., 67, 68, 80 Dudek, D., 198 Dugall, B., 199 Dull, B., 177, 193, 199, 201 Duncan, EJ., 241 Dupuis, M., 196, 197 Dfirr, H., 244 Eaton, EE., 241 Eberbach, W., 51 Eckert-Maksic, M., 50 Eckhardt, C.J., 321 Eckrich, R., 153 Edwards, L.S., 79 Ege, G., 55, 56, 79 Eilbracht, E, 153 Eisenbein, S.A., 52 Eklund, E C., 78, 79
Author Index
Elia, G., 195 Eliel, E.L., 153 Elix, J.A., 197 Eked, C.D., 25, 50 Endo, Y., 51 Engel, W., 168, 198 English, R.B., 155 Enkelmann, V., 50, 60, 79, 322 Erickson, K.L., 207, 242 Eriksson, L., 321 Erker, G., 52, 152 Ermer, O., 145, 155 Ettl, R., 79 Eugster, C.H., 51 Evans, D.H., 321 Evans, J.C., 51 Exner, H.-D., 52 Factor, R.E., 198 Faggiani, R., 197 Falk, H., 152 Farley, B., 164, 197 Fastrez, J., 80 Faust, R., 197 Favini, G., 321 Favorskii, A.E., 242 Fayos, J., 196 Fecht, H., 153 Feller, D., 197 Ferderiksen, J., 321 F6r6zou, J..-P., 51 Feringa, B.L., 255, 309, 320-322 Fernandes, E., 177, 199 Ferrier, B.M., 196 Fessner, W.-D., 198 Feyereisen, M.W., 80 Fiato, R.A., 244 Fieser, L.F., 5, 49 Fiorentino, M., 153, 154 Firouzabadi, H., 49 Fischer, E., 320, 321 Fitch, A., 321
327
Fitjer, L., 209, 219, 220, 225,232, 237, 239, 242, 243 Fitzgerald, J.J., 67, 68, 80 Fleischer, J., 319 Foglio, E, 51 Ford, G.P., 196 Ford, R.A., 243 Fomarini, S., 154 Forsey, S.P., 52 Fossel, E.T., 196 Foster, E.G., 196 Fostiropoulos, K., 78 Fowler, P.W., 79, 164, 197 Fox, D.P., 243 Frank, N.L., 50 Franselow, D.L., 321 Fray, G.I., 79 Frederiksen, P., 321 Freeman, D., 319 Freimanis, Ya.E, 92, 93, 106, 153 Frey, H.M., 243 Freyer, A.J., 174, 180, 183, 199, 200 Friedheim, G., 321 Friedrichsen, W., 47-49, 51, 52 Fritz, H., 51,198 Fr6stl, W., 152 Fu, X., 125, 151,152, 199 de la Fuente, G., 322 Fujise, V., 152 Fuller, K.E., 79 Fumagalli, S.E., 51 Fusco, C., 153, 154 Fusco, R., 243 Gadgil, V.R., 177, 195, 199 Gajek, K., 196 Oajewski, J.J., 162, 196 Gallo, G., 319 Gambaro, A., 154 Gandour, R.W., 165, 196 Ganis, P., 154 Gano, J., 206, 242 Gantzel, P., 155
328 Gao, Y.-D., 79 Gaoni, Y., 197 Garratt, P.J., 49, 79, 164, 197 Gault, I.R., 322 Geels, E., 51 Geissler, E., 200 George, C.E, 83, 106, 152 George, P., 321,322 Georgian, V., 83, 152 Gerber, P., 83, 84, 114, 152, 154 Gescheidt, G., 198 Gestmann, D., 153-155 Gewald, K., 51 Ghosez, L., 243 Ghosh, T., 244 Giamalva, D.H., 243 Gieren, A., 50 Gilbert, J.C., 203, 214, 233,234, 243, 244 Gilchrist, T.L., 241 Giles, R.G.F., 51 Gingrich, H.L., 244 Girreser, U., 19, 49, 50, 57-59, 79 Giuffrida, D., 50, 57-59, 79 Givens, R.S., 168, 179, 180, 198 Gl/inzer, K., 198 Gleicher, G.J., 197 Gleiter, R., 155,241 Glendening, E.D., 197 Glidewell, C., 49 Glukhovtsev, M.N., 197 Godt, A., 60, 79 Gold, M.H., 49 Gompper, R., 187, 200, 321 Gonzalez, J., 196 G6pel, W., 321 Gordon, A.J., 243 Gore, P.M., 79 Gorgues, A., 52 Gorlach, Y., 174, 180, 183, 199, 200 Goscinski, O., 321 Gosnay, I., 322 Gould, L.D., 152
AUTHOR INDEX
Goulle, V., 321 Graham, R.J., 79 Gready, J.E., 50 Green, J., 200 Greenberg, A., 151,320 Greene, ED., 320 Greifenstein, L.G., 183,200 Gribble, G.W., 50 Grieco, P.A., 83, 152 Grieser, U., 322 Griffin, G.W., 241 Grohmann, K.G., 170, 177, 180, 183, 190, 191,197-200 Grosse, M., 153 Groth, P., 322 Grove, J.E, 51 Grubb, W.T., 321 Grunewald, G.L., 161, 168, 179, 180, 196, 198 Grtitzmacher, H.-F., 153, 155 Guidetti-Grept, R., 83-84, 115, 152, 153 Gund, P., 152 Gund, T.M., 152 Giinther, H., 181, 183, 200 Gupta, A.K., 125, 151,152, 199 Gurgenjanz, G., 319 Guyot, A., 49 Guyton, C.A., 162, 196 Haak, P., 243 Haas, G., 153 Haase, M.A., 56, 79 Haddadin. M.J., 4, 49 Haddon, R.C., 164, 167, 197, 198, 320 Haenel, M.W., 242 Hafner, K., 196, 322 Hagen, S., 319, 321 Hagenbuch, J.P., 52 Hagman, E.W., 200 Haley, M.M., 50 Halton, B., 51 Hameroff, S., 78
Author Index
Hamill, B.J., 214, 215,243 Hammerich, O., 321 Hammond, G.S., 243 Han, W., 152 Hanafusa, T., 322 Hanumaiah, T., 51 Harary, E, 155 Hargittai, I., 83, 84, 115, 152 Harlow, R.L., 80 Harnik, E., 320 de la Harpe, C., 319 Harper, M.E, 51 Hart, H., 17, 49, 50 Hartenstein, J.H., 196 Hartzler, H.D., 242 Hassenrtick, K., 183, 196, 198, 200 Haumann, T., 198 Healy, E.E, 244 Heath, J.R., 78 Hehre, W.J., 243, 321 Heilbronner, E., 55, 77, 79 Heinze, J., 198, 199 Herbstein, EH., 320, 322 Herges, R., 198 Herkert, T., 189, 200 Herndon, W.C., 13, 49, 79, 320 Herzog, B., 153 Hess, B.A., Jr., 79, 197, 321 Hext, N.M., 79 Heyn, J., 205,206, 234, 235,242 Hiberty, P.C., 50, 197 Hickey, M.R., Sr., 153 Hilbert, P.H., 243 Hildebrandt, K., 52 Hildenbrand, T., 319, 321 Hirsch, A., 153 Hirschberg, Y., 321 Hirschi, D., 114, 154 Hitchcock, P.B., 51 Hite, G.E., 153 Ho, D.M., 155 Ho, T.-S., 51 Hoffman, H.M.R., 181,200
329
Hoffman, R., 83, 92, 151, 162, 170, 180, 181,190, 197, 198,242, 243 Hoke U, S.H., 242 Holder, A.J., 197 Holmes, J.L., 154 Holmes, S.J., 67, 80 Hommes, J.R.v.E., 197 Hossain, .B., 177, 199 Hosoya, H., 79 Hou, D.-R., 235-237, 239, 244 Houghton, T.J., 79 Houk, K.N., 165, 196, 197, 198, 222, 223, 243 House, S.D., 199 Howie, R.A., 51 Hrovat, D.A., 196 Huang, J.L., 319 Huang, N.Z., 50 Huang, Y.-c.J., 50 Htibner, T., 50 Huck, N.P.M., 255,320, 321 Htickel, E.Z., 163, 164, 197 Huddleston, P.R., 51 Huffman, D.R., 78 Hulbert, P.B., 153 Hull, S.E., 320 Humbert, H., 52 Hunkler, D., 198 Hiirbin, M., 241 Hyun, J.L., 197, 198 Ibar, G., 174, 180, 183, 199, 200 Ikemoto, I., 79 Imamura, A., 243 Irie, M., 322 Iriye, R., 52 Isaacs, L., 198 Isaacs, N.S., 79 Ishibi, N., 198 Ito, S., 152, 196 Ittah, Y., 319 Iwamura, H., 169, 170, 198
330
Iwasaki, T., 51 Iyengar, R., 199, 200 Jackman, L.M., 174, 177, 180, 183, 199, 200 Jager, W.E, 255,309, 320, 321 Jagoe, C.T., 83, 152 James, D.R., 199 Jammulla, S.R., 51 Janiak, R., 174, 199, 200 Jarboe, C.H., 243 Jawdosiuk, M., 83, 84, 152 Jay, M.J., 242 Jayatilaka, D., 51 Jemmis, E.D., 155 Jiao, H., 162, 171,172, 194, 196-198 Jie, C.J., 162, 171,196-198 Johnels, D., 198 Johnson, R.P., 227, 244 Jones, D.G., 51 Jones, M.J., Jr., 196, 241,242, 244 de Jong, J.C., 321 Jordan, K.D., 198 JCrgenson, M., 321 Jozefiak, T.H., 80 Jung, K.-y., 50 Jung, M.E., 68, 80 Kahr, B., 242 Kainosho, M., 79 Kalinowski, H.-O., 187, 200 Kalisky, O., 320 Kam, C.K., 244 Kamal, A., 51 Kampmeier, J.A., 213, 243 Kappe, C.O., 52 Karichiappan, K., 51 Kato, H., 52 Kato, S., 197 Kauer, J., 200 Kawada, K., 198 Kawakama, Y., 321 Kawamoto, A., 80
AUTHOR INDEX
Kawamoto, I., 52 Keese, R., 83, 84, 99, 114, 115, 125, 135, 145, 151-154, 319 Kelly, W.J., 50 Kelly, S.C., 198 Kempe, T., 199 Kennard, O., 320 Kennedy, J.W.J., 79 Kennedy, S.M.E, 49 Kenney, J.W., 243 Kenny, P.W., 62, 79 Kesselmayer, M.A., 199 Kessler, H., 181,200 Khan, A.Z.-Q., 320 Kikuchi, K., 79 Kikuchi, O., 321 Kim, K., 242 King, R.B., 155 Kirmse, W., 222, 223,243 Kirschner, S., 203,225,226, 244 Kirsten, R., 199 Kistiakowsky, G.B., 321 Kitagawa, T., 162, 196 Kivelson, S., 56, 79 Klarner, E-G., 166, 197 Klaubert, C.A., 199 Klein, D.J., 153 Kleinert. H., 51 Kliebisch, U., 242 Klix, R.C., 51 Kluge, A.E, 243 Klumpp, G., 196 Klyne, W., 153 Knoll, K., 189, 200 Knox, G.R., 154 Kobayashi, T., 52 Kobayashi, Y., 198 K6brich, G., 242 Kohnke, F.H., 19, 49, 50, 57-59, 79 Kohnz, H., 193, 201 Kollmar, H.W., 226, 244 Kondo, H., 52 Kondo, K., 51,322
Author Index
K6nig, B.-M., 52 Konstanecki, St., 319 Kopecky, K.R., 243 Koreeda, M., 50 Korenstein, R., 321 Koroniak, H., 243 Korttim, G., 320, 321 Koruga, D., 78 Koyama, J., 52 Kozhushkov, S., 198 Kozlowski, P.M., 196 Kraka, E., 195, 197 Kramer, J.D., 155 Kratschmer, W., 78 Krause, R.A., 154 Krebs, A., 205,206, 242 Krespan, C.G., 199 Krohn, K., 151 Kroto, H.W., 54, 78, 153 Krow, G.R., 180, 200 Kruzinaga, W., 322 Kubiak, G. 83-84, 152 Kuck, D., 81,152-155 Kuhn, R., 253, 320 Kumadaki, I., 198 Kumagai, R., 79 Kumazaki, H., 79 Kunii, T.L., 169, 170, 198 Kuo, C.-H., 319 Kuratowski, C., 155 Kuroda, T., 51 Kurtz, H.A., 164, 172, 191,193, 196198, 200 Laarhoven, W.H., 152, 154 Laber, G., 197 Laber, N., 51 LaGreca, S., 51 Lahti, P.M., 216, 217,243 Lai, C.-y., 50 Laity, J.L., 197 Lakkaraju, P.S., 194, 195,201 LaUemand, J.Y., 320
331
Lamb, L.D., 78 Lambert, J.B., 183, 196, 200 de Lange, B., 255,309, 320, 321 Langer, E., 152 Lau, D.Y.K., 50 Lauren, D.R., 154 Laventine, E, 319 Lavie, D., 319 Lavie, G., 319 LeBel, J.A., 83, 151 Leber, W., 183,200 LeCoq, A., 52 Lee, G.-A., 51 Lee, J.-S., 320 Leegwater, A., 51 Leermakers, EA., 243 Lehn, J.-M., 321 Lehner, H., 152 Lemmen, E, 155, 321 Lennartz, H.-W., 162, 166, 196, 197 Lenoir, D., 321 Lepage, Y., 51 Lerstrup, K., 321 Leuehs, H., 152 Leung, M.-k., 50 Levin, B., 319 Levin, R.D., 154 Levin, R.H., 242 Levine, B.H., 152 Levy, A., 319, 320 Ley, S.V., 174, 199 Li, Y., 196 Liao, C.C., 196 Lias, S.G., 154 Liebes, L., 319 Liebman, J.E, 154, 166, 197, 320 Liebman, J.L., 151 Lii, J.-H., 153 Lijten, EA.T., 152, 154 Lin, X., 195 Lindberg, I'., 195 Linde, K., 319 Lindenthal, T., 153
332
Lindner, H.J., 153 Linstead, R.P., 153 Littmann, M., 174, 199 Liu, L.H., 204, 241 Liu, J.-M., 198 Liu, L.H., 241 Liu, R.S.H., 199 Lloyd, D., 49 Lo, D.H., 168-170, 180, 181,198 Lock, C.J.L., 197 Lock, L., 152 Lombardo, L., 50 Loncharich, R.J., 196 Loubinoux, B., 10, 49 Loutfy, R., 78 Luef, W., 99, 114, 125, 135, 145, 151, 153, 154, 319 Luh, T.-Y., 319, 320 Luo, J., 50, 199 Luo, W., 51 Lutz, G., 198 Luyten, M., 83, 84, 152 Lynch, V.M., 52 Maas, G., 206, 242 Macho, V., 200 MacLean, D.B., 51 Maeng, J.-H., 52 Maggio, J.E., 154, 155 Magnus, N.A., 52 Magnus, P., 52 Mahendran, M., 197 Majeste, R., 320 Mak, T.C.W., 320 Makhlouf, M.A., 51 Maksic, Z.B., 50 Maleki, N., 49 Mallard, W.G., 154 Mangum, M.G., 212, 243 Mani, J., 83, 84, 152 Mannion, M.R., 79 Manoli, E, 154 Manolopoulos, D.E., 79
AUTHOR INDEX Marchand, A, P., 241 Markstein, J., 242 Marmar, R.M., 243 Marsden, D.E., 51 Marshall, D.C., 243 Marshall, D.S., 51 Martin, H.-D., 196, 198 Maryanoff, B., 243 Mascarella, S.W., 83, 152 Mathias, J.P., 50, 57-59, 79 Matsuda, Y., 52 Matsushita, K.-I., 321 Matsuura, T., 49 Mattes, K., 241 Matthias, C., 154 Maulitz, A.H., 50 Mayer, A., 199, 200 Mayer, J., 197 Mayer, R., 51 Mayer, U., 242 Mazur, Y., 319 McCann, S., 83, 152 McCulloch, R., 49, 50 McGrath, M.P., 83, 151 McGrath, P., 152 Mclntosh, C.L., 241 McKee, M.L., 196 McKinley, E.G., 233, 234, 244 McNally, D., 153 McOmie, J.EW., 152 McPhail, C.L., 53, 80 Meador, M.A., 50 Mechoulam, R., 319 Meerholz, K., 199 Meetsma, A., 321 Mehta, G., 152 Meichsner, G., 174, 199 Meier, H., 241 Meinwald, J., 169, 196 Meisinger, R.H., 174, 199 Mekelburger, H.B., 57-59, 79 Melchart, D., 319 Mer~nyi, R., 196
Author Index
Merger, R., 241 Meruelo, D., 319 Messmer, R.E, 197 Meyer, A.Y., 321 Meyer, H., 319 Mijs, W.J., 7, 49 Miki, S., 49 Miller, J.A., 67, 80 Miller, L.L., 62, 64, 79, 80 Miller, L.S., 170, 177, 183, 190, 191, 198-200 Miller, M.A., 197 Miller, M.L., 197 Miller, L.S., 200 Miller, R.D., 200 Mills, LED., 320 Mills, W.H., 22-25, 50 Minkin, V.I., 197 Mioduski, J., 169, 196 Mir-Mohamad-Sadeghy, B., 49 Mirsadeghi, S., 40, 52 Mislow, K., 155 Misumi, S., 80, 322 Mitchell, M.J., 49 Mitchell, R.H., 50 Mitschka, R., 115, 153 Mittal, R.S.D., 152 Miyake, Y., 79 M6, O., 50 Mobraaten, E.C., 244 Modaressi, S., 210-212, 220, 242, 243 Mohler, D.L., 50 Molstad, J., 242 Moncrieff, H.M., 154 Montaigne, R., 243 Montgomery, L.K., 242 More O'Ferrall, R.A., 198 Moriarty, R.M., 183, 198, 199 Morihashi, K., 321 Morio, K., 169, 170, 198 Morley, J.O., 51 Morokuma, K., 196, 197 Moskau, D., 183, 200
333
Moss, R.A., 242 Moursounidis, J., 49, 50 Moyano, A., 49 Mukai, T., 198 Mtillen, K., 62-64, 80, 177, 193, 199, 200, 201,322 Miiller, A., 154 Muller, C., 83, 84, 152 MUller, G., 244 Miiller, P., 50 Muller, U., 322 Mialrow, C.D., 319 Mulzer, J., 151 Munzel, N., 50 Miirata, I., 196 Murray, C., 197 Murray, R.W., 154 Murty, B.A.R.C., 198 Muszkat, K.A., 321 Muthard, J.L., 165, 197 Nachtkamp, K., 193,200 Nagel, J., 52 Nagelkerke, R., 172, 198 Nfthlovsk~, Z., 198 N,(dalovsk~, B.D., 198 Nakahara, N., 79 Nakanishi, K.S., 52 Nakata, A., 49 Nakayama, M., 321 Nauta, W., 153 Negishi, E., 67, 80 Neidlein, R., 50 Neta, P., 321 Neudeck, H.K., 152 Neumann, B., 155 Neumann, E., 153 Newman, M.S., 243 Ng, D.K.P., 320 N g, K.M., 50 Ng, L., 198 Ng, T.-K., 50 Ng, W., 51
AUTHOR INDEX
334 Nickon, A., 196 Nightingdale, D.V., 51 Niu, T-q., 242 Nixon, I.G., 22-25, 50 Nobes, R.H., 83, 152 Noordijk, J.H., 154 N6th, H., 199 Nowak, P.C., 79, 320 Nozoe, S., 51 Nozoe, T., 196 Nuechter, M., 319 Nuechter, U., 319 Nugent, W.A., 80 Nwokogu, G.C., 50 Nyburg, S.C., 320 Oatil, B.B., 83, 84, 152 O'Bfien, S.C., 78 Ochiai, K., 52 O'Connor, B.O., 213, 243 Oehldrich, J., 115, 153 Ogiku, T., 51 Ogura, E, 80 Ogura, T., 52 Ohanessian, G., 50 Ohmizu, H., 51 Ohta, T. 51 Ohuchi, M., 79 Okazaki, M.E., 152 Okorodudu, A.O.M., 243 Oku, M., 174, 199 Olah, G.A., 196, 198 Olivella, S., 225, 244 Ollis, W.D., 322 Olofson, R.A., 67, 68, 80 Olsen, B.A., 321 O'Neill, P.M., 50 Orr, G., 241 Osamura, Y., 197 Osawa, E., 78 Oth, J.EM., 196 Otsubo, T., 80 Ott, K.-H., 196
Ott, W., 181,200 Otte, C., 198 Pacansky, J., 241 Padwa, A., 52 Pairhurst, R.A., 52 Paisdor, B., 153, 155 Palmer, M.H., 49 Paquettr L.A., 79, 152, 155, 158, 165, 166, 173, 174, 183, 190, 192, 195-200 Parfitt, S.D., 152 Parker, V.D., 321 Parriagua, J, -C., 49 Parisi, M., 50 Parisot, D., 51 Pascal, R.A., 79 Paske, D., 177, 199 Pasky, J.Z., 153 Patai, S., 151,241,321 Patel, M., 52 Patil, B.B., 152 Patrick, T.J., 243 Patton, R.W., 52 Pauls, A., 319 Payne, D., 79 Pelech, B., 187, 200 Pepalla, S.B., 51 Pericas, M.A., 225,244 Perkin, W.H.Jr., 2, 48 Perry, M.H., 79 Pesmnovich, V.A., 92, 106, 153 Petch, W., 319 Peters, E.-M., 174, 177, 183, 189, 199, 200 Peters, K., 174, 177, 183, 189, 199, 200 Peters, O., 52 Peterson, J.R., 166, 197 Petit, C.M., 198 Pfenninger, A., 83, 84, 152, 154 Pfyffer, J., 51 Phife, D.W., 52
Author Index
Philp, D., 57-59, 79 Pickard, EH., 320 Pifia, R., 199, 200 Pinkerton, A.A., 52 Pinkos, R., 198 Platz, M.S., 241 Podosenin, A., 166, 197 Pogodin, S., 319 Pohl, S., 154 Pohlke, R., 205, 206, 242 Pohmer, L., 5, 49 Poign6e, V., 50 Polborn, K., 321 Pollmann, M., 62-64, 80 Popelis, Yu.Yu., 92, 106, 153 Poplawski, J., 321 Pople, J.A., 321 Posteher, E, 154 Potworowski, J.A., 320 Pr~ifcke, K., 320 Pratt, A.J., 52 Prelog, V., 153 Preston, P.N., 51 Prinzbach, H., 198 Pritzkow, H., 154, 155 Puar, M.S., 52 Puls, C., 198 Purvis, G.D., 243 Quast, H., 174, 177, 180, 183, 188190, 199, 200 Qureshi, A.A., 51 Rabideau, P.W., 79, 319 Rabinovitz, M., 320, 322 Radhakrishnan, T.P., 320 Radom, L., 83, 151,152, 320, 321 Raghavachari, K., 167, 198 Rajapaksa, D., 52 Raju, N., 50 Ramey, K.C., 180, 183, 199, 200 Ramey, K.Z., 199 Ramirez, G., 319
335
Rao, C.P., 51 Rao, G.S.R., 51 Rao, K.S., 152 Rao, K.V.J., 51 Rao, S.N., 198 Rao, V.B., 83, 106, 152 Rapoport, H., 153 Rappoport, Z., 151,195, 241, 321 Raston, C.L., 50 Raymo. EM., 19, 49, 50, 57-59, 79 Read, R.W., 52 Rees, C.W., 243 Regitz, M., 206, 242, 243 Reich, S.D., 196 Reichel, E, 197 Reinecke, M., 241 Reinhardt, G., 197, 198 Reissig, H.-U., 151 Reitz, M., 243 Rewicki, D., 153 Rheingold, A.L., 154 Richter, S., 51 Rickards, R.W., 51 Rickborn, B., 8, 49, 51, 52 Riera, A., 225,244 Riera, J., 322 Riggs, N.V., 320 Rihs, G., 51 Ringshandl, R., 177, 199 Roberts, J.D., 197, 242 Roberts, R.M., 50 Robinson, W.T., 52 Rodrigo, R., 44, 49, 52 Rodriguez, D., 51 Roesle, A., 83, 84, 152, 154 Rogers, D.W., 166, 197 Rogers, R.D., 199 Rondan, N.G., 165, 196, 222, 223, 243 Roos, G.H.P., 51 Rohr, J., 52 Rondan, N.G., 196, 198, 243 Roth, H.D., 194, 195,201 Roth, K., 153
336
Roth, S., 321 Roth, W.R., 52, 160, 162, 166, 196, 197 Rothe, W., 174, 199 Rottger, D., 152 Rouvray, D.H., 155 Roy, D., 197 Rubin, R.M., 196 Ruiz-P6rez, C., 50 Runsink, J., 181,200 Russell, R.A., 51 Russel, R.K., 174, 183, 199, 200 Ruzicka, L., 204, 241 Rye, A.R., 49 Rzepa, H.S., 196 Saak, W., 154 Sahyun, M.R.V., 154 Saito, I., 49 Saito, K., 79, 198 Saito, Y., 52 Sakata, Y., 322 Saltzman, M., 83, 152 Samuel, S.P., 242 Sandborn, R.E., 49 Sandstrtim, J., 247, 319, 320 Sarel, S., 319 Sargent, M.V., 51, 52, 197 Sarkozi, V., 198 Sartori, G., 51 Sasaoka, M., 17, 49 Sattari, S., 51 Sauer, J., 177, 199 Saunders, M., 196 Sawada, M., 322 Scardiglia, E, 242 Schaad, L.J., 79, 197, 321 Schaefer III, H.E, 83, 151 Schaller, J.-P., 51 Schang, P., 155 Schaumburg, J., 321 Schaumburg, K., 321 Schechter, H., 244
AUTHOR INDEX
Schenck, G.E., 199 Schirmer, H., 50 Schleyer, P.v.R., 155, 162, 164, 171172, 194, 196-198, 242 Schl6gl, K., 152 Schltiter, A.D., 50, 60, 61, 79 Schmalz, T.G., 153 Schmickler, H., 181,200 Schmidt, G.M.J., 320 Schmidt, P., 181,200 Schmidt, W., 49 Schnieders, C., 199 von Schnering, H.G., 174, 177, 183, 189, 199, 200 Schoeller, W.W., 169, 170, 198, 244 Schoevaars, A.M., 255,320-322 Scholler, K.L., 253, 320 Sch6nberg, A., 86, 153,320, 321 Schtining, A., 51, 52 Schori, H., 83, 84, 152 Schr6der, A., 57-59, 79 Schroder, G., 161, 196 SchiJller, J., 206, 242 Schulman, J.M., 197 Schultz, P.A., 197 Schuster, A., 153-155 Schuster, H., 199 Schtittel, S., 83, 84, 152 Schwarzenbach, D., 52 Schwarzensteiner, M.-L., 187, 200 Schweig, A., 50 Scott, A.P., 320 Scott, C.J., 80 Scott, L.T., 79, 166, 196-198, 319 Seger, G., 321 Seifert, M., 153, 154 Seitz, W.A., 153 Sellner, I., 177, 199 Sethi, S.C., 152 Seyferth, D., 243 Shafiee, A., 51 Shaik, S., 197 Shair, M.D., 52
Author Index
Shamouilian, S., 50 Shao, M.-C., 319 Shary-Tehrany, S., 153 Sheridan, R.S., 244 Sherwin, M.A., 168, 179, 180, 198 Sheu, C., 243 Shih, C.N., 196 Shiromaru, H., 79 Shoham, G., 319, 322 Shternberga, I. Ya., 92, 106, 153 Shurki. A.S., 197 Sianipar, H., 52 Sibi, M.P., 50 Sichert, H., 177, 199 Sidky, M.M., 86, 153, 321 Siegel, J.S., 22, 50, 155 Siehl, H.-U., 200 Siepert, G., 166, 197 Silversmith, E.E, 196 Silverton, J.V., 115, 153 Simkin, B.Y., 197 Simmons III, H.E., 154, 155 Simon, J., 155 Simonetta, M., 321 Simons, J., 243 Sims, C.G., 51 Singh, M., 154 Skell, P.S., 243 Skelton, B.W., 51 Slawin, A.M.Z., 50, 79 Slemon, C.E., 51 Slowen, A.M.Z., 57-59, 79 Smalley, R.E., 54, 78 Smeets, W.J.J., 322 Smerz, A.K., 154 Smid, W.I., 322 Smith. A.B., III, 198 Smith, A.M.E, 51 Smith, D.R., 79 Smith, J.G., 49 Smits, J.M.M., 152, 154 Snatzke, G., 153 Snow, R.A., 165, 197
337
Snyder, J.P., 49, 125, 151, 199 Sodtke, U., 320 Sofer, H., 55, 79 Sol~, A., 225,244 Sommer-Larsen, P., 321 Sondheimer, E, 197 Sotheeswaran, S., 52 Sottocomola, M., 321 Spek, A.L., 322 Spellmeyer, D.C., 198 Spencer, C.M., 79 Springer, J.P., 199 Spurr, P.R., 198 Squillacote, M.E., 244 Stang, P.J., 212, 241-243 Stanger, A., 50 Stawitz, J., 180, 200 Steiner, E., 164, 197 Stephan, D., 52 Sternhell, S., 50 Stems, M., 51 Stevens, E.D., 155 Stewart, J.J.P., 244, 321 Stezowski, J.J., 245, 319-321 Stock, L.M., 243 Stoddard, J.E, 19, 49, 50 Stoddart, J.E, 49, 57-59, 61, 79 Stohrer, W.-D., 170, 180, 181,190, 198 Storer, J.W., 197 Storr, R.C., 50, 243 Story, P.R., 196 Streitwieser, A., 197 Stringer, M.B., 49 Strozier, R.W., 165, 196 Struchkov, Yu.T., 319 Suda, H., 52 Suissa, M.R., 319, 320 Suissa, R.M., 319, 322 Sukornick, B., 51 Sulzbach, H.M., 198 Sundareshan, M., 78 Surya Prakash, G.K., 198
338
Suscy, A.C., 204, 241 Sutherland, I.O., 322 Suzuki, S., 79 Swanson, D.R., 67, 80 Sygula, A., 79, 319 Szabo, K.J., 191 Tagahara, K., 52 Takahashi, K., 115, 153 Takahashi, M., 51 Takahashi, T., 67, 80 Takase, H., 52 Tambunan, U.S.F., 152 Tanaka, J., 80 Tanaka, K., 49 Tanaka, T., 52, 322 Tansey, C., 50 Tapuhi, Y., 321,322 Tatemitsu, H., 322 Taylor, N.J., 52 Telikepalli, H., 51 Tellenbr6ker, T., 153 Ten Hoeve, W., 90, 91-93, 106, 108110, 153 Tennant, S., 51 Teshiba, S., 52 Theilacker, W., 321 Thiericke, R., 52 Thilgen, C., 79 Thomas, A.R., 79 Thommen, M., 83-84, 152 Thomson, R.H., 51 Thompson, H.W., 155 Thorn, D.L., 80 Thummel, R.P., 79, 151,320 Tisler, M., 51 Toda, E, 49 Todaro, L., 177, 180, 183, 199, 200 Todeschini, R., 321 Tollefson, M.B., 198 Tolmie, M., 51 Toscano, V.G., 196 Tour, J.M., 67, 80
AUTHOR INDEX
Trachtman, M., 321,322 Trahanovsky, W.S., 50 Trefonas, L.M., 320 Troe, J., 198 Trost, B.M., 152 Trova, M.P., 199 Truttmann, L., 201 Tsotinis, A., 79 Tsukuda, E., 52 Tsunoda, T., 152 Tu, N.P.W., 15, 49 Turner, K.S., 79 Turro, N.J., 198 Ugi, I., 155 Uhlenbrock, W., 10, 49 Underiner, G.E., 199 Valle, G., 154 van Bolhuis, E, 320 van Bruchem, D., 52 van Engen, D., 200 van der Helm, D., 177, 199 van der Plas, H.C., 25, 50 van de Ven, L.J.M., 244 van der Waals, A., 83, 84, 152 Vanderwaart, B.E., 242 Van Dorp, W.A., 319 van Kranenburg, K., 319 Van't Hoff, J.H., 83, 151 Vazeux, M., 155 Veldman, N., 322 Venepalli, B.R., 83, 106, 114, 151, 152 Venkatachalam, M., 83, 84, 152 Venzo, A., 154 Viavettene, R.L., 320 Viehe, G., 242 Viehe, H.G., 198 Vieke, H.G., 168, 198 Villessot, D., 51 Vittal, J.J., 80 Vogel, E., 196, 200 Vogel, P., 52
Author Index
Vogel, T., 79 Vogle, E., 160, 193, 196, 200 Vogler, H., 55, 56, 79 V'6gtle, E, 57-59, 79 Vollhardt, K.P.C., 49, 50, 197 vonder Saal, W., 199 von Geldern, T.W., 152 von Schnering, H.G., 174, 177, 183, 189, 199, 200 Vonderwahl, R., 197 Vrijhof, P., 25, 50 Wade, L.E., 162, 196, 226, 244 Wagenseller, EE., 197 Wagner, H.-U., 187, 200, 321 Wakabayashi, T., 79 Walker, D.M., 83, 152 Wallis, T.G., 199 Walsh, R., 196, 198 Waiters, W.D., 243 Wang, J.T., 194, 201 Wang, X.-J., 320 Wang, Y.C., 198 Ward, D.L., 50 Waring, D.H., 247, 319 Warmuth, R., 241 Warner, P.M., 196, 241 Warnock, G.E, 244 Warrener, R.N., 6, 49, 51 Waser, E., 48 Wassen, J., 193,200 Wasserman, E., 320 Watanabe, K., 79 Watldns, D.A.M., 152 Weavers, R.T., 154 Weerasoodya, U., 214-218, 243 Wege, D., 1, 49-52 Wegener, G., 52 Wehle, D., 242 Wehrli, S., 83, 84, 152 Wehrsig, A., 198 Weidenhammer, W., 319 Weiner, D., 319
339 Weinhold, EJ., 197 Weinhold, P., 10, 49 Weinlich, J., 205,206, 242 Weiss, R., 198 Weiss, U., 83, 84, 115, 152, 153 Weissman, M., 320 Weizen-Dagan, A., 322 Wender, P.A., 152 Weng, D.T.-C., 319 Weniger, K., 154 Wenkert, E., 200 Werth, W.D., 168, 198 West, P.R., 206, 242 Weuste, B., 187, 200 Whetten, R.L., 79 White, A.H., 50, 51 White, W.R., 241 Whitney, J., 200 Wiberg, K.B., 51,153 Wiersum, U.E., 7, 25, 49, 50 Wiest, O., 196 Wilbrandt, R., 321 Wilcox, C.E, 83, 151,244 Wilen, S.H., 153 Wilkinson, S.P., 50 Williams, B.L., 154 Williams, D.J., 50, 57-59, 79 Williams, E, 194, 201 Williams, R.B., 197 Williams, R.V., 155, 164, 172, 177, 191,193, 195-200 Willst~tter, R., 2, 48 Wilson, E.R., 205, 206, 242 Wilson, J.D., 197 Win, W.W., 180, 183,200 Winchester, W.R., 242 Wingard, R.E., Jr., 196, 200 Winstein, S., 164, 165, 196, 197 Wirth, W.D., 198 Withers, J., 78 Wittig, G., 5, 10, 49, 205,206, 207-209, 214-218, 234, 235, 242, 244
340 Witzel, A., 189, 200 Witzel. M., 200 Wolff, S., 83, 196, 152 Wolinsky, J., 207-209, 242 Wolovsky, R., 197 Wolthius, E., 51 Wong, H.N.C., 50 Wong, T.-Y., 50 Woodward, R.B., 162, 197, 243 Woodworth, R.C., 243 Wudl, F., 198 Wurthwein, E.U., 155 Wynberg, H., 90, 91-93, 106, 108-110, 153 Xie, N., 321 Xing, Y.D., 50 Yamaguch, S., 322 Y,~ez, M., 50 Yannoni, C.S., 200 Yano, H., 52
AUTHOR INDEX
Yarborough, R., 52 Yeh, C.-L., 183, 198, 199 Yeh, E.-L., 183, 199 Yelland, M., 50 Yinnin, H., 321 Yip, J.C., 15, 49 Yip, Y.C., 320 Yoon, T., 52 Yoshida, M., 49, 52 Yoshida, Z., 49 Yuh, Y.H., 153 Zahn, H., 253, 320 Zander, M., 51 Zefirov, Y.V., 321 Zhang, C., 83-84, 152 Zimmerman, H.E., 161, 168, 169, 179, 180, 186, 196, 198 Zimmermann, G., 319 Zimmermann, K., 242 Zoebisch, E.G., 244 Zoellner, R.W., 56, 79
SU BJECT IN DEX acenaphthenone, 207 acenaphthoquinone, 207 acenaphthyne, 207 acetaldehyde enolate, 74 acetylenic dienophile, 39, 47 acridinylidene, 259, 274, 278 AIBN, 34 albidin, 34 alkene trap, 222 3-alkoxy- 1-cyclobutene, 223 alkyl-substituted cyclacene, 61 all-cis annelation, 97 1-amino- 1,2,3-triazoles, 206 9-aminomethylidenefluorene, 213 angucycline antibiotics, 42 angular (difuso) triindane, 117 anisotropy calculations, 162 annelated spirodiols, 108 anthra[2,3-c]furan, 15 anthracene cyclophane 71 anthracenylidene, 259 9-(9(10H)-anthracenylidene-9,10dihydroanthracene, 257 anthraquinone cyclophane, 75 anthraquinone-tetraketone, 73 anthronylidene, 259, 274, 278, 291, 304 anti-4b,8b-fenestrindanediol, 123 aryne, 39 aryne-furan, 28
Askani synthesis, 174
aufbau strategy, 88 azulene, 313
barbaralane, 160, 161,168, 171,180, 181-183, 185, 188, 194 barbaralone, 161 barrelene, 168, 173 [ 12]beltene, 58 benz[a]anthraeene, 42 1-benzenesulfonyl-2-trimethylsilylacetylene, 158 benzhydrol, 87 benzo[ 1,2-c:3,4-c':5,6-c"]tfifuran, 17 benzo[ 1,2-c:4,5-c']difuran, 19 benzo[ 1,6-cd]-pentalenes, 90 benzo[c,d]pyrenylidene, 270, 285, 291,303 benzo[c]thiophene, 27 benzoannelated centrohexaquinanes, 142 benzoannelated diquinanes (diindanes), 84 benzoannelation, 101,149 benzocentrohexaquinane, 138 benzonorbornadiene, 21 benzvalene, 168 2-benzhydrylindane- 1,3-diols, 85 2-benzylindan- 1-ol, 85 benzyne, 204, 210, 225 341
SUBJECTINDEX
342
BHT (2,6-di-tert-butyl-4-methylphenol), 69
bi-4H-cyclopenta[d, eaq-phenanthren4-ylidene, 247 biacridan, 274, 276 bianthrone, 246, 257, 266, 268, 274, 276, 279, 313 bibenzo[a,d]cycloheptenylidenes, 290 bicyclo[3.2.0]hept- 1(5)-ene, 228 bicyclo[4.1.0]hepta- 1(6),3-diene, 31 bicyclo[4.1.0]hepta- 1(6),3-diene-2,4dione (benzocyclopropene-pquinone), 29 bicyclo[4.3.0]nona- 1(6),3-diene, 230 bicyclo[4.3.0]nonanes (hydrindanes), 100 biphenyleno[2,3-c]furan, 15 2,5-biradicaloid, 162 Birch reduction, 58 bis(endodisulfide), 139, 145 bis(endoperoxide), 139, 145 bis(phenylthio)tetramethoxy anthracenes, 74 bis(semibullvalene), 174 bis(thienyl)-substituted spirotriketones, 110 bis(trimethylsilylthio)ethane, 140 5,5'-bis-5H-dibenzo[a,d]cycloheptenylidene, 249, 264, 266 bisdiene, 67-69, 75, 76 bisdiene cyclophane, 71 bishomoantiaromaticity, 168, 170 bishomobenzene, 169 bishomocubyl systems (diazabasketanes), 173 bismaleimide, 62 bissecododecahedradiene, 168 bistricyclic ene, 252, 272, 303, 309, 313,318 bond dissociation energy, 221 bond fixation, 22 bond separation energies, 270 bovines, 172
bridged[ 10]annulenes, 167 2-bromo-biphenylene, 15 ~-bromocamphene, 207 1-bromocyclopentene, 208, 219 (bromocyclohexylidenemethyl)trimethy lsilane, 239 2-bromo-3,4-dihydroxy-5-methoxybenz aldehyde, 34 6-bromo-2,2-dimethylcyclohexanone, 31 9-bromophenanthrene, 10 9-bromo- 1,4,5,8-tetrahydro- 1,4:5,8-diep oxyanthracene, 17 1-bromo-2-trimethylsilylcyclopropene, 28 bullvalene, 161,165, 168, 171 13C CP-MAS NMR, 187,188,189 13C dynamic NMR, 183 calfene 160 camphyne, 207 Cape Aloe (Aloeferox Miller), 42 Caubere's base, 35 centrohexacyclane, 136, 137 [5.7.5.7.5.5]centrohexacyclane, 140 centrohexacyclanetriones, 142 centrohexacyclic enol ethers, 140 centrohexacyclic rings, 137 centrohexaindane, 119, 138-140, 142, 143, 145, 146, 149 centrohexaquinacene, 136, 143 centrohexaquinane, 136, 142 centropentacyclane, 136, 137 centropentaindane, 119, 138, 143, 145, 146, 148, 149 centropolyindanes, 84, 117, 119 centropolyquinanes, 84 centrotriindanes, 97 ceric ammonium nitrate (CAN), 68, 74 charge-transfer process, 255 chemiluminescent, 247 chiral lignan, 47 chloranil, 35
Subject Index circular polarized light, 255,257 circumpolyacenes, 54 cis-bicyclo[3.3.0]octane, 100 cis-cyclopropyl fused diene, 160 cis-di(2-thienyl)spirodiol, 96 cis-diphenylspirotriols, 102 cis-diphenylspirotriketone, 102 cis-c~,~-dioxoethano bridge, 143 Clavularia siddiqui, 34 Cnidoscolus phyllacanthus, 31 computational methods AM1, 99, 162, 171,191,125, 227, 232, 257 density functional theory (DFT), 171 force-field 145, 166 HF/6-31G/PM3,266 PM3 method, 252, 257, 259, 266, 268, 284, 285,289, 309 MNDO, 56, 99, 168, 170, 190, 191 MOPAC6, 259, 268 MP2 and MP4, 191 n-orbital axis vector (POAV) analysis, 167 Saunders' isotopic perturbation method, 186, 187, 194 semi-empirical methods, 226 semi-empirical structure count (SC) theory, 13 STO-3G, 222 [ 12]collarene, 58 Cope activation energy, 181, 183 corannulene, 56 cubane, 204 curved bisdiene, 57 curved bisdienophile, 58 (-)-curvulol, 34, 35 cyclacene, 56, 57 [2]-, 56 [3]-, 56 [6]-, 60 [8]-, 65, 72, 75, 76 [9]-, 76 [ 10]-, 76
343 [12]-, 56-58 [141-, 59 [~5]-, 57 tetrahexyl[8]-, 61 cyclic polyacetylenes, 166 cyclic polyalkadiyines, 166 cycloaddition, 222 [2+2]-, 83, 20, 209, 210, 222, 224, 225 [2+4]-, 219, 217, 233 -cycloreversion, 19, 36 cycloanthracene, 56 cyclobutane 1-( l'-bromo- l'-trimethylsilyl)-, 236 1-(bromomethylene)-, 207, 209, 219 1-dibromomethylene-, 209, 236, 239 1-diazomethylene-, 236, 239 cyclobutanone, 218, 234 cyclobutylidenecarbene, 209, 218, 219 cyclobutyne, 230 cyclodecapentaene, 190 cyclodehydration, 87, 90, 93, 96, 97, 102, 113 cycloheptadecyne, 204 cycloheptatriene, 164 1,3,5-cycloheptatriene, 166 cycloheptyne, 206, 230 1,3-cyclohexanediones, 92 cyclohexyne, 206, 230 cyclooctatetraene, 168, 173, 193 cyclo6ctyne, 204, 230 cyclopentadecyne, 204 cyclopentanedione, 146, 148, 205 cyclopentanone-2,4-dinitrophenylhydrazone, 218 cyclopentyne, 204, 206-212 cyclopropa-fused naphthalene-1,4-dione, 28, 31 cyclopropa-fused quinones, 29 cycloproparene, 22 cycloreversion, 4, 6, 7, 36 DAMP, 215, 216, 233, 236
344
DDQ, 35, 70 decarbonylation, 3, 4, 6, 206 decarboxylation, 6 dehydrobromination, 17 1,8-dehydronaphthyne, 211 (E)- 1-deuterio- 3,3-dimethyl- 1butene, 210 Dewar model, 163 di(p-anisyl)spirodiol, 113 di(o~-naphthyl)spirotriols, 109 di(ffnaphthyl)spirotfiols, 110 diarylspiroketones, 108 1,3-diaryl-substituted [2,2'] spirodiindanes, 86 diatropic, 164 diazasnoutane, 173 diazasnoutene, 173, 177 diazoethene, 212 diazomethane, 213 dibenzo[a,d]cycloheptenylidenes, 287, 291,293, 302-305 dibenzo[c,g]phenanthrene ([5]helicene], 247 dibenzofenestranes, 108 dibenzofulvene, 270-272, 274, 278, 284 2,2'-dibenzylindane- 1,3-diol, 85, 94 3,5-dibromoanthranilic acid, 17 3,6-dibromoanthranilic acid, 19 3,5-dibromobenzyne, 17 1,2-dibromocyclopentene, 205,209, 234, 236, 239 1,4-dibromo-2,5-dimethoxyben zene, 74 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), 27 1,2-didehydrobiphenylene, 15 9,10-didehydrophenanthrene, 10 Diels-Alder, 57 retro-, 4, 6 -adduct, 72, 74, 222
SUBJECT INDEX
-cycloaddition, 25, 27, 28, 31, 58, 61, 62, 64, 69, 75, 76 158, 206, 211 intramolecular-, 25, 47 tandem-, 6 diethoxy cyclophanes, 73 diethoxytetraketone-anthraquinones, 73 diethyl diazomethylphosphonate (DAMP), 214 tx,~t'-dihaloxylenes, 86 10,10'-dihydro- 10,10'-dihydroxybianthrylidene, 254 1,4-dihydro- 1,4-epoxybiphenylene, 10 1,3-dihydrofuro[3,4-c] furan, 40 2,3-dihydrophenalene- 1,3-dione, 109 9,10-dihydro- 10-methyl-9-methyleneacridine, 271 dihydropyran, 210, 232 dihydroxycentropentaindanes, 139 8,9-dihydroxy- 1-methylnaphtho[2,3-c]furan, 42 5,8-dihydroxynaphtho[2,3-c]furan4,9-dione, 37 diindanedione, 87 diindane, 85, 117 1,4-dimethoxybenzene, 37 5,8-dimethoxy- 1,4-dihydro- 1,4epoxynaphthalene, 47 5,5-dimethoxy-l,2,3,4-tetrachlorocyclopentadiene, 8 7,8-dimethylbenzo[ 1,2-c:3,4-c']difuran, 19 3,3-dimethylcyclopropene, 217 dimercaptoethane, 140 dimethyl acetylenedicarboxylate, 8, 40, 42, 45 dimethyl fumarate, 4, 6, 8 dimethyl-anthracenylidene, 259 10,10'-dimethylbiacridan, 254 dimethylcentropentaindane, 146 1,2-dimethylcyclopropane, 213 dimethyldioxirane, 121
Subject Index
dimethylvinylidene, 212 dinaphthalene cyclophane, 58 diphenyl spirotriol, 109 diphenyl-substituted dispirodiols, 111 l',Y-diphenyl-[2,2']spirobiindanes, 87 diphenylthieno[2,3-c] furan, 28 diphenylspirodiol, 86 3,6-di(pyridin-2'-yl)diazine, 6 3,6-di(pyridin-2'-yl)diazine, 8 3,6-di(pyridin-2'-yl)-s-tetrazine, 6, 8, 11, 17, 25, 27 dipyridyl-s-tetrazine, 39 diquinone, 67-69, 73, 74 diquinone bisdienophile, 73 dispiroketaldiols, 102 1,4-dithiafulvenyl substituted bianthrones, 255 dithioxanthylene, 254, 257, 288 dixanthrylidene, 249 dixanthylene, 246, 257, 266, 315 DNMR, 145 dodecahedrane, 158 domino Diels-Alder reaction, 62, 67, 158 "double-crown" molecules, 54 dynamic stereochemistry, 313 dynamic syn-dibromide, 131 Dynemicin A, 47 E,Z-isomerization, 313, 315, 318 EI- 1507-2, 44 elassovalene 192 electrophilic aromatic chlorination, 221 endodisulfide, 139, 145 endoperoxide, 139, 145 epoxy-bridged quinone, 37
1,4-epoxynaphthalene 1,4-dihydro-, 4 1,4-di-t-butyl-1,4-dihydro-, 8 1,2,3,4-tetrahydro-, 7 1-ethoxyphthalan, 40 ethylenic twist, 294
345 Faberge Easter egg, 54 Farfugin A, 47 famesyl protein transferase, 42 favelanone, 31, 33 Favorskii rearrangement, 104 fenestra-2,5,8,11-tetraenes, 135 fenestrane, 82, 92, 94, 96, 97, 99, 103, 110, 125 tetrabenzo-, 140 non-benzoannelated-, 120 homocyclic-, 83 alicyclic-, 83, 84, 120 benzoannelated cis, cis, cis, trans-, 102, 103 benzoannelated all-cis, 123 bridgehead-unsaturated-, 84 broken-, 88, 109 [5.5.5.5]fenestrane, 82, 83, 90, 100, 120 all-cis-, 114, 115 all-cis-tetrabenzo-, 119 all-cis-tribenzo-, 121 bridgehead-brominated-, 123 cis, cis, cis, tram-, 104 4b,8b-di(ethylthio)-, 124 epi-, 99, 101 tetrabenzo-, 91 tribenzo-, 90, 104, 120, 121,137 [5.5.5.5]fenestraene, 114, 135 all-cis-2, 5, 8, 11,125, 131,135 cis, cis, cis, trans-, 1O1 dibenzo-, 142 [5.5.5.5]fenestrene, 83 tribenzo-, 96, 104 tribenzocarboxylic acid, 104 [5.5.5.6]fenestrane, 97, 112, 114 all-cis-tribenzo-, 104 benzoannelated-, 94, 96, 106 benzodithieno-, 111 cis, cis, cis, trans-, 102, 103, 111 tribenzo-, 96, 97 [5.5.5.6] fenestranols, 97 tribenzo-, 94, 102
346
[5.5.5.6] fenestranone, 96 all-cis-, 102, 112 benzoannelated-, 94, 96 cis, cis, cis, trans-, 102, 113 tribenzo-, 142 [5.5.5.6]fenestratrienes, 101 [5.6.5.6.5.5]centrohexacyclane, 139 [5.6.5.6]fenestranes, 108, 109 dibenzo-, 108 naphtho-annelated-, 109 [6.6.6.6]fenestrane, 93 [6.6.6.6] fenestranetetraone, 93 fenestrindane 99 all-cis-, 99, 114 all-cis-4b,8b-dibromo- 12b, 16bdicyano-, 131 anti-dibromo-anti-dicyano-, 129 bridgehead-substituted-, 124 bromotricyano-, 131 4b,8b-dibromo-, 131 epi-, 99, 103 tetraamino-, 120, 128, 139 tetrabenzoannelated all-cis-[5.5.5.5]-, 84 tetrabromo-, 125, 126, 133 tetracyano-, 129 tetrakis(methylamino)-, 129 tetrakis(trifluoroacetoxy)-, 121 tetrakis(trifluoroacetyl)-, 126 tetramethyl-, 120, 129, 133, 134 fenestranol, 102, 110 all-cis-benzodi (naph tho-a )[5.5.5.6]-, 109 fenestranones, 97 Fitjer's conjecture, 237 fjord region, 257, 270, 297, 298 flash vacuum pyrolysis (I~P), 7 florenylidene moieties, 268, 270, 281, 288, 291 fluorenylidenedibenzo[a,d]cycloheptene, 282 9-fluorophenanthrene, 10 folded transition state, 315
SUBJECT INDEX
folded-twisted transition state, 315 forbidden electrocyclic reactions, 230 force constant analyses, 228 Fredericamycin A, 28 Fremy's salt, 35, 36 Friedel-Crafts acylation, 37 Fritsch-Buttenberg-Wiechell rearrangement, 207 fullerenes 54 buckminster-, 54, 167 cyclopropyl bridged-, 167 fulleroids, 167 furan-3,4-dicarbonyl chloride, 37 furan-3,4-dicarbonyl chloride, 37 furo[3,4-b]furan, 25, 27, 28 furo[3,4-c]pyridine, 25 fuso-diindane 87, 90 gas-liquid chromatography, 224 Gassman reduction, 104 Grob fragmentation, 86, 102 Grohmann's tetraester, 183 1H-cyclopropa[b]naphthalene-2,7dione, 29 hexabromobenzene, 19 1,5-hexadiene, 162, 168 (E, E)-2,4-hexadiene, 224 1,2,3,4,4a,4b-hexahydrobenzo [ 1,3]cyclopropa[ 1,2-b] naphthalene, 31 HOMO/LUMO interactions, 222 homoaromaticity, 164-167, 191,194 homoazulene, 167 homoconjugation, 165, 166 homocubene, 204 homodesmotic schemes, 163 homonaphthalene, 167 homotropilidine, 160, 168 homotropylium cation, 165 Hilckel (4n + 2), 164 2(c~-hydroxybenzyl)-1-indanol, 86 hypericin, 246
Subject Index
1,3-indanedione, 86, 92, 104, 140 2-indanone, 90 induced ring current, 164 intramolecular overcrowding, 247, 269, 289, 294 isobenzofuran (IBF) 1-alkoxy-, 28 aryne-adducts, 28 benzannulated-, 25 cyclobuta-fused-, 24 cyclobut[e]-, 15 cyclobut[]]-, 15 5,6-dibromo-, 23 4,7-dihydro-, 42 4,7-dimethoxy-, 47 5,6-dimethyl-, 23 -4,5-dione, 35, 36 -4,7-dione, 36 1,3-diphenyl-, 9, 28 2,5-diphenyl-, 205-207,234 1,3-di-t-butyl-, 8 1-ethylthio-, 44 5H-cyclopropaD']-, 22, 23 intramolecular-trapping, 47 5,6-methylenedioxy-, 45 push-pull-, 29, 31 3-silyloxy- 1-carbonitriles, 33 3-trimethylsilyloxy- 1-carbonitrile, 28 4,5,6-tri-t-butyl-, 9 1,3-isobenzofurandione, 33 isodesmic energy, 278 isodesmic reaction, 269, 270, 278 isofuranonaphthoquinones, 38 isolated pentagon rule, 91
347
linearly polarized light, 256 lithium aluminum hydride, 71, 96 lithium bromide, 234 Lucigenin, 246 macroannulation, 73 macrocyclic cylophanes, 60 macrocyclization, 58, 70 magnetic anisotropy, 164 magnetic susceptibility, 164 m-bromoanisole, 44 m-chloroperoxybenzoic acid, 44 mesoscopic phase, 256 3-methoxybenzyne, 44 (Z)- 1-methoxypropene, 222 methyl trimethylsilyl sulfide, 124 methyl(trifluoromethyl)dioxirane, 121,123, 133 3-O-methyl- 18-hydroxyestrone, 47 6-methylene-6H-benzo[c,d]pyrene, 270 5-methylene-5H-dibenzo[a,d]cycloheptene, 271 2-methylfuran-3,4-dicarbonyl chloride, 38 methylmagnesium iodide, 72 Michael addition, 92, 93 Microspora sp KY7123, 42 Mills-Nixon effect, 22, 24, 25 molecular, belt, 60-62 molecular ribbon, 60, 62, 64 molecular switches, 255 monobenzocentrohexaquinane, 142 monohomobenzene, 165 MS-444, 42 myosin light chain kinase, 42
Justicidin C, 45 Ks molecules, 139 kohnkene, 58 Kuratowski graph K5, 137 linear polyacene, 54
N,N'-dimethylbiacridan, 257 naphthacene diquinone, 75 naphthalene, 313 naphthalene epoxide 71 naphtho[2,3-c]furan, 13, 15, 42 naphtho[2,3-c]furan-4,9-dione, 36, 37
348
naphtho[5.6.5.6] fenestranol 109 naphtho{ 2,3-c]furan-4,9-dione, 42 N-bromosuccinimide, 41 [N]pericyclynes, 166 Nectria haematococca, 37 nectriafurone, 37 nematic liquid crystalline phase, 256 neopentane, 108 neutral homoaromaticity, 163, 165, 168, 194 N-nitrosooxazolidones, 213 non-benzoannelated spirodiols, 96 norbomenones, 3 norcaradienes, 166
SUBJECT INDEX
polyindane, 143 polyquinane, 143, 148 porcine pancreatic lipase (PPL), 45 potassium tert-butoxide, 216 potential energy surface, 227, 230 propellane, 82, 143 p-toluenesulfonic acid, 71 push-pull system, 274 pyramidalization, 40, 257, 272, 290-292 ct-pyrone, 5 pyridinium chlorochromate (PCC) 72, 75 retroelectrocyclization, 207, 223
octavalenes, 168 1-octynyllithium, 67, 76 o-dibenzoylbenzene, 10 oligomerization, 70, 237 orbital isomerism, 235 orbital symmetry, 228, 235 7-oxabicyclo[2.2.1 ]heptyl system, 31, 42 o-xylylene, 4 P-388 murine leukemia, 31 paratropic ring current, 15 Pdophyllum lignans, 44 Penicillium albidum, 34 pentalenopentalene, 88 pericyclic reactions, 228, 229 permethyl [5]pericyclyne, 166 perturbed azulenes, 167 perturbed naphthalenes, 167 phenanthro[9,10-c]furan, 10, 11 9-phenanthrylamine, 10 phenylfluoradene, 91 photochromism, 254 piezochromism, 246, 254 platinum(0)-cyclopentyne complex, 236 p-nitrobenzaldehyde, 215 polycyclic aromatic enes (PAEs), 255, 257, 259
saddle points, 259 SCH 58450, 42, 44 semibullvalenes 1,5-annelated-, 174 annelated-, 190, 191 bisannelated-, 177, 193 Dewar-Hoffmann-, 170, 173, 180 diaza-, 170 1,5-dimethyl-, 183, 187 3-dimethyl-, 174 2,6-disubstituted-, 176, 177 homoaromatic-, 181 octamethyl-, 183 1,3,5,7-substituted-, 177 3,7-substituted-, 183 1,5-substituted tetramethyl-2,4,6,8tetracarboxylates, 177 Simmons-Paquette molecule, 136 singlet oxygen, 8 sodium dimethyl phosphate, 216 solid CP-MAS spectra, 194 spiranes, 86, 90, 92 spiro annelation, 136 2,2'-spirobiindane, 84, 143 - 1, l'-diols, 86 - 1, l'-dione, 86 spiro[4.2]-hepta- 1,3-diene, 233
Subject Index spiro[4.4]-nona- 1,3-diene, 237 spiro[5.5]undecane, 108 spiro[5.5]undecanetriol, 108 spiro[cyclohexane- 1,2'-indane], 92, 108 spiro[cyclohexane- 1,2'-indane]-diol, 97, 102, 107, 109, 112 spiroannelation, 86 spiroconjugation, 237 spirodiol, 86, 108 spiro-fused cyclohexane, 108 spiroketone, 102 spirotriketones, 94 spirotriols, 96, 102 St. John's Wort, 246 stereorandomization, 225 s-tetrazine, 26 Streptomyces sp, 42 1,5-substituted tetramethyl-2,4,6,8tetracarboxylates, 177 syn, anti-isomerization, 315 syn-folded enes, 276 syn periplanarity, 143 Taiwanin C, 45 Taiwanin E, 45 7-t-butylisobenzofuran-4,5-dione, 35, 36 tetraaryethylenes, 246 tetrabenzofulvalene, 246, 270 tetrabromide, 76 1,2,4,5-tetrabromobenzene, 19 10,10,10', 10'-tetrahydrobianthrylidene, 254 9,9', 10,10"-tetrahydrodianthracene, 249 tetrachlorothiophene S,S-dioxide, 104 tetracyclone 5 tetra-fuso-centrotetraindane, 114 tetrahedranes, 149 1,4,5,8-tetrahydro-l,4:5,8-diepoxyanthracene, 19
349
1,2,3,4-tetrahydro- 1,4-epoxytriphenylene, 11 tetrahydroindeno[ 1,1-a]indenes, 84 1,2,3,4-tetraphenylbenzene, 8 tetraphenyl-substituted tetrayne, 76 theory of orbital isomerism, 228 thermochromism, 246, 253, 264, 266 Thiafarfugin A, 47 thieno[2,3-c]furan, 25, 47 thieno[3,4-b]furan, 25, 27, 28 thieno[3,4-b]furan-3-carboxylate, 27 thioxanthenylidenes, 287, 305 topological analysis, 228 topomerizations, 315 trans- 2,2-di (benzhy dryl )- 1,3indanediol, 94 transannular homoconjugation, 167 trans-bicyclo[3.3.0]octane, 100 trans-diphenylspirotriols, 94 1,7,7-tribromo-5,5-dimethylbicyclo[4.1.0]heptane, 31 (tribenzo)triquinacene, 143 1,3,5-tribromobenzene, 17 tribenzo[3.3.3]propellanes, 140 tribenzocentrohexaquinane, 142 tribenzotriquinacene, 85, 94, 119 tributylstannane, 34 tricyclo[6.3.0.02'7]undec - 1(8)-ene, 209 trifuso-centrotetraindane, 87 triindane, 85, 90 trimethylaluminum, 120 trimethylsilyl cyanide, 120 triphenylene, 11 triplet hypersurface, 212 triptindane, 117, 140 triptindanetrione, 140 triquinacene, 166 triquinone, 65, 73, 75 twisted transition state, 315 van der Waals radii, 247, 298 Ventilag o made raspatana (Rhamnaceae), 38
350
Ventilago vitensis, 38 ventilone A, 38, 40, 41 ventilone F, 38 ventilone G, 38 vespirenes, 91 vinyl triflate, 212 vinylidene, 212 vinyllithium, 205, 210, 234
SUBJECT INDEX
Wadsworth-Emmons modification, 214,215 Weiss-Cook reaction, 177 Wittig reaction, 214 Wolff-Kishner reduction, 102, 142 Woodward-Hoffmann, 162 xanthenylidene, 270, 304 zigzag carbon nanotubes, 54