Advances in Theoretically Interesting Molecules (Volume 4: 1998)

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

.,, oO

u

64

ROBERT M. CORY and CAMERON L. McPHAIL

R,~

.,,~ __.

/,d"i

/R

"'i ~

-.

R ~)

~) R

> i !"

R .~~

I
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 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

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 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

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 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 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 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 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 _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 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 > 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