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Valence Isomerization of

Cyclohepta-1,3,5-triene 1 and its Heteroelement

Analogues

‐13‐

Chapter 1

1.1 Introduction

Valence isomerization of cyclohepta‐1,3,5‐triene (1) into bicyclo[4.1.0]hepta‐2,4‐

diene (2) has captured the attention of chemists for over five decades.[1] This

interest extended to the related heterocyclic compounds 38, bearing one

oxygen, sulfur or nitrogen atom, after the discovery of their biological

importance[2] (Scheme 1). In contrast, phosphane analogue 9 and

phosphanorcaradiene 10 have received only limited attention with their

application as phosphinidene precursor being the most notable.[3,4] Because the

synthesis and isolation of the parent and substituted heteropines 5, 7, 9 remains

challenging, computational chemistry has played an important role in

understanding their chemical properties.

Reviewing the influence of the heteroelement on the cyclohepta‐

trienenorcaradiene valence isomerization necessitates a brief overview of the

parent all‐carbon system. This will be followed by examining the experimental

data on the heteropine valence isomerization in conjunction with the computed

geometrical and aromaticity features of the parent isomers. Whereas it is not the

focus of this review, selected examples of substituted heteropines and their

synthesis will be given.

Scheme 1. Valence isomerization of cyclohepta‐1,3,5‐triene (1) and its

heteroelement analogues.

‐14‐

Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues

1.2 Cycloheptatriene Valence Isomerization

Cyclohepta‐1,3,5‐triene (1), first isolated in 1883,[5] has a boat shaped

conformation, as determined by electron diffraction,[6] a microwave study,[7] and

an X‐ray structure analysis of its derivative thujic acid,[8] but these methods give

different tilt angles and (see Scheme 2). More accurate data on the

geometrical features of 1, come from a B3LYP/6‐311+G(d,p) study that gave an

angle of 52.9° and a angle of 25.4°.[9,10] Low temperature 1H NMR

measurements showed that the slightly homo‐aromatic boat conformation

undergoes a degenerate ring flip via an anti‐aromatic C2v transition state with a

free energy barrier of 5.7 kcal.mol‐1 in CBrF3[11] and 6.3 kcal.mol‐1 in CF2Cl2.

[12,13]

Scheme 2. Conformational ring inversions.

Cycloheptatriene 1 is in equilibrium with bicyclo[4.1.0]hepta‐2,4‐diene (2) via a

Woodward‐Hoffmann symmetry‐allowed disrotatory ring closure.[14] Although the

equilibrium strongly favors the seven‐membered ring, the presence of small

quantities of the bicyclic isomer 2 was inferred by Diels‐Alder trapping

reactions.[15] In 1981, Ruben was the first to directly observe norcaradiene 2

employing low‐temperature photolysis.[16] He determined an activation barrier of

112 kcal.mol‐1 for the formation of 2 and a free energy difference between the

isomers of about 4 kcal.mol‐1.[16] Strong electron‐withdrawing groups at the

methylene bridge influence the equilibrium in favor of the norcaradiene isomer,

as is the case for the thermally stable 1,1‐dicyano‐derivative.[17] At the B3LYP/

6‐311+G(d,p) level of theory, the geometry of the parent norcaradiene was shown

to have a straighter bow ( = 65.8°) but flatter stern ( = 18.9°) as compared to

cyclohepta‐1,3,5‐triene.[9]

‐15‐

Chapter 1

In addition to the 12 interconversion, the parent C7H8 has a rich rearrangement

chemistry (Scheme 3). In 1957, Woods observed the rearrangement of

bicyclo[2.2.1]hepta‐2,5‐diene (12) into cycloheptatriene 1, which was postulated

to proceed via diradical 11 and norcaradiene 2.[18] Instead pyrolysis of 1 yields

toluene by a [1,3]‐H shift.[19] Norcaradiene 2 can also undergo a [1,5]‐carbon

“walk” as was discovered by Berson and Willcott in 1965.[20] Although, this

process should proceed with retention of configuration according to the

Woodward‐Hoffmann rules, studies of optically active substituted

cycloheptatrienes showed that the “forbidden” path is favored so that the walk

occurs with inversion of configuration.[21,9] The fourth and last rearrangement, a

[1,5]‐hydrogen shift, was discovered by a high‐temperature NMR study of

hydrogen isotopomers of cycloheptatriene. At 100–140 °C, 1 undergoes

suprafacial [1,5]‐H shifts with an activation energy of approximately 31 kcal.mol‐1

(Scheme 3).[22,23]

Scheme 3. Rearrangements of the parent cycloheptatriene 1 and norcaradiene 2.

y

e [

1.3 Valence Isomerization of Heteropines

1.3.1 Oxepine / Benzene oxide

Oxepine (3) was first isolated in 1964 b Vogel et al. by double dehalogenation of

1,2‐dibromo‐4,5‐ poxycyclohexane. 24] Oxepine can also be synthesized by

epoxidation of Dewar benzene followed by photolytic or thermal ring

‐16‐


expansion.[25] In contrast to the cycloheptatrienenorcaradiene (12) pair, the

equilibrium constant for oxepin 3 and 7‐oxa‐bicyclo[4.1.0]hepta‐2,4‐diene (4,

benzene oxide) varies widely with solvent polarity and to some extent with

temperature, making it po sible to work with solutions highly enriched with either

one of the two isomers.[s

30] In addition, also photo‐oxidation of

z

n

due to the destabilizing eclipsing of the two methyl

groups in benzene oxide 4.[24,35]

24b,26] The facile 34 valence isomerization[27a,28,29] is of

considerable interest as arene oxides are intermediates in the oxidative

metabolism of aromatic substrates.[

benzene creates this isomeric pair.[31]

Using 1H NMR spectroscopy, Vogel and Günther determined that bicyclic ben ene

oxide 4 is 1.7 kcal.mol‐1 more stable than monocyclic 3 in apolar solvents[24b,32]

with an activation barrier for the conversion from 4 to 3 of 9.1 kcal.mol‐1 and

7.2 kcal.mol‐1 for the reverse reaction. Calculations at QCISD(T)/6‐31G(d) confirm

the bicyclic isomer to be the most stable one, albeit with a very small energy

differe ce of only 0.1 kcal.mol‐1 with a barrier for interconversion of 9.1 kcal.

mol‐1.[35] By changing to more polar solvents, the oxepine isomerization

equilibrium shifts further toward benzene oxide (more positive G), suggesting a

larger dipole moment for benzene oxide than for oxepine. Methyl substitution at

the 2‐ and 7‐positions reverses the stability order, rendering the oxepine as the

energetically favored isomer

Scheme 4. Reactivity of oxepine (3) and benzene oxide (4).

‐17‐

Chapter 1

Depicted in Scheme 4 are the most important reactions that the parent oxepine

(3) and benzene oxide (4) can undergo. Irradiation of oxepine results in ring

contraction yielding 2‐oxabicyclo[2.3.0]hepta‐3,6‐diene (13).[24] Under thermal,

photochemical or acidic conditions, the three‐membered ring of bicyclic 4 opens

generating phenol,[24a,33] in analogy to the all‐carbon norcaradiene 2 that gives

toluene. In addition, 4 undergoes highly selective Diels‐Alder reactions with

N‐phenylmaleimide and dimethylacetylenedicarboxylate providing single anti‐

adducts (e.g. 14; Scheme 4).[31b,34] Calculations on model structures show that the

anti cycloadditions are kinetically controlled, although syn addition is

thermodynamically favored.[35]

1.3.2 Thiepine / Benzene sulfide

The parent thiepine (5) is 7.0 kcal.mol‐1 less stable than benzene sulfide (6). This

energy difference is much larger than for the oxygen homologues because sulfur

is better accommodated in three‐membered rings.[35] Nevertheless, bicyclic 6 has

never been isolated due to the low activation barrier for sulfur extrusion,[35,36,37]

which occurs via a sequence of low energy reactions involving several sulfur‐

containing intermediates.[38,39]

Thiepine 5 can be stabilized by Fe(CO)3‐complexation (15)[40] or by decorating the

seven‐membered ring with substituents. The first isolated metal‐free thiepine (16)

was reported in 1974 by Reinhoudt and Kouwenhoven using electron‐

withdrawing groups to delocalize the ‐electrons of the thiepine ring, but this

species still eliminates sulfur at room temperature.[41] With the synthesis of the

sterically shielded 2,7‐di‐tert‐butylthiepine 17, a relatively simple and thermally

stable thiepine was obtained allowing experimental studies on its chemical and

physical properties.[42] The thermally robust dibenzo[b,f]thiepines are of interest

for their potent biological activity, which is illustrated by the psycho sedative and

antipsychotic properties of zotepine (18).[27c,43,44]

‐18‐


1.3.3 1H‐Azepine / Benzene imine

The parent 1H‐azepine (7)[45] was first generated in 1963 by Hafner after

hydrolysis of ethyl‐1H‐azepine‐N‐carboxylate with potassium hydroxide and

subsequent protonation.[46] Because 1H‐azepine is highly unstable and rearranges

to 3H‐azepine via a [1,3]‐H shift, its characterization was accomplished 17 years

later at –78 °C by Vogel et al.[47,48] N‐substitution stabilizes the 1H‐azepine. As for

the all‐carbon analogues, the valence isomerization equilibrium strongly favors

the monocyclic form, which was estimated at 7.9 kcal.mol‐1 at B3LYP/6‐31G(d) for

the parent system (7 ⇄ 8).[49] Also low temperature 1H and 13C NMR

measurements on 19 display only small amounts of the bicyclic isomers 20

(Scheme 5).[48,50]

Scheme 5. Valence isomerization of 1H‐azepines.

The reluctance to form the bicyclic isomer dictates the reactivity of azepines as

they exhibit the characteristics of cyclic polyene chemistry, which is illustrated by

the ability of the monocyclic isomer to undergo cycloadditions as 2 (→ 21),[51]

‐19‐

Chapter 1

4 (→ 2 )[2 5152 or 6 (→ 23, 24)[53] component (Scheme 6). In addition, azepine 7

rearranges photochemically to bicyclic 25[54] and in the presence of an acid yields

aniline derivatives 26[55] in analogy to the cycloheptatriene and oxepine.[56]

Scheme 6. Reactivity of 1H‐azepine.

Azepines have received considerable attention because of their biological

importance and pharmaceutical relevance.[57] For instance, 3H‐3‐benzazepin‐2‐

amines 27 possess antihypertensive activity[58] and all tricyclic

dibenzo[b,f]azepines (e.g., 28) bearing a basic side chain affect the central

nervous system.[59]

‐20‐


1.3.4 1H‐Phosphepine / Benzene phosphane

Although the parent 1H‐phosphepine (9) and its 2.5 kcal.mol‐1 more stable valence

isomer benzene phosphane (10)[60] have never been isolated, there is evidence for

the existence of the parent phosphatropylium ion (29), which was generated in

the gas phase by collision activation between PI3 and benzene.[61] The thermal

instability of the phosphepines is due to the facile decomposition of its bicyclic

isomer 10 into benzene and phosphinidene R–P.[62] However, the 7‐membered

ring can be stabilized by phosphorus oxidation (30),[62] the introduction of bulky

substituents at the 2 and 7 positions (33),[63] or benzannulation (e.g. 3H‐

benzophosphepine 32).[3c,64]

The thermal lability of the transition metal‐complexed 3H‐benzophosphepine 33

has been explored by Lammertsma et al. for the synthesis of a variety of

organophosphorus compounds by means of [1+2]‐cycloadditions of the in situ

generated singlet phosphinidene 35 with olefins or acetylenes (Scheme 7).[3,4]

Scheme 7. Phosphinidene generation from metal‐complexed benzophosphepine 33.

‐21‐

Chapter 1

1.4 Geometry and Boat Inversion

Determining the conformations of the heteropines has been a challenge, since

only the parent oxepine (3) can be isolated as a liquid at room temperature.

Although spectroscopic measurements indicated a boat shape for the monocyclic

structures with alternating C=C bond lengths, attempts for more exact

measurements came from single‐crystal X‐ray structure analysis of simple

derivatives, later complemented by high‐level calculations on the parent systems

(see Table 1). Determining the conformation for the bicyclic norcaradienes is far

more challenging and currently depends solely on calculations.

Table 1. Summary of the relative energies (kcal.mol‐1) of isomerization from the parent

bicyclic forms norcaradiene (NCD) 2 (C), 4 (O), 6 (S), 8 (N), 10 (P)) to the monocyclic

cycloheptatrienes (CHT) 1 (C), 3 (O), 5 (S), 7 (N), 9 (P)) and their ring inversion.[a]

NCD TS CHT TSinv Method Ref

C (1,2) 4 11[c] 0.0 ~6 Exp [11,12,16]

O (3,4) 0.0 9.1[b] 1.7 – Exp [24b,32]

0.0 7.0 0.1 3.5 QCISD(T)/6‐31G(d) [35]

S (5,6) 0.0 20.5[b] 7.0 7.3 QCISD(T)/6‐31G(d) [35]

N (7,8) 7.9 11.4[c] 0.0 ~3 B3LYP/6‐31G(d) [49,65]

P (9,10) 0.0 15.7 2.5 5.2 B3LYP/6‐311+G(d,p) [60]

[a] Gibbs free energies for experimental data (first two entries) and enthalpies for

computational data. [b] Equilibrium from NCD to CHT. [c] Equilibrium from CHT to NCD.

The molecular structure of the simple 2‐tert‐butoxycarbonyl oxepine (36) shows a

boat configuration with bow () and stern () fold angles of 56.5 ° and 26.0 °,

respectively,[66] making it slightly more curved than cyclohepta‐1,3,5‐triene (1; =

52.9 °, = 25.4 °).[9] This structure differs little from the MP2/6‐31G(d) optimized

geometry of the parent oxepine (3) (Cs symmetry; = 58.3 °, = 30.8 °) and

‐22‐


illustrates that the tert‐butoxycarbonyl substituent hardly influences the

geometry.[35] A single‐crystal X‐ray analysis for sulphur analogue 2,7‐di‐tert‐

butylthiepine (17) shows on the other hand a less curved structure ( = 49.6 ° and

= 28.0 °),[42] which was supported by an MP2/6‐31G(d) optimized geometry of

the parent thiepine 5 ( = 50.3 ° and = 30.8 °).[35]

The molecular structure of N‐substituted azepine 37 displays a shallower boat

structure ( = 43.4 ° and = 21.6 °).[67] This behavior is solely due to the

N‐substituent as the CASSCF/3‐21G optimized geometry shows a more curved

angle of 36.4 ° for the parent 7.[68] For the P analogues, the single‐crystal X‐ray

structure analysis of a (OC)5W‐complexed, benzannulated phosphepines 33

(Scheme 7) also shows a flattened boat conformation ( = 40.5 °, = 28.2 °)[3a]

compared to the computed parent structure that is more curved ( = 48.3 °,

= 27.8 °).[3c]

Although the boat form prevails in all monocyclic heteropines, Cremer et al.

indicated that this presents an incomplete picture.[65] They determined that the

parent 1, 3 and 5 posses at least 22% chair character, leading to an almost

constant boat puckering for the cycloheptatrienes. By studying the racemization

of substituted benzene oxides (Scheme 2), the oxepine ring inversion barrier was

estimated at 6.5 kcal.mol‐1 at 135 K,[66,69] which is similar 4.5 kcal.mol‐1 calculated

for the parent oxepine (3) at QCISD(T)/6‐31G(d).[35] The barrier for thiepine 5 is

with 8.3 kcal.mol‐1 nearly twice as large (same level of theory), probably because

the flattened thiepine ring leads to higher antiaromatic destabilization.[35] The

interconversion of the boat forms of the azepines and phosphepines is also facile,

requiring only 3 (N)[65a] and 5.2 kcal.mol‐1 (P),[60] respectively.

‐23‐

Chapter 1

1.5 Aromaticity

One of the issues in the cyclohepta‐1,3,5‐triene valence isomerization has been

whether the heteropines display aromaticity. The flattened transition structure

for ring inversion (Scheme 2) bears 8‐electrons and should display

antiaromaticity according to the Hückel theory and, in fact, the inherent instability

of thiepine 5 has been ascribed to this.[70] However, the monocyclic boat‐shaped

structures can exhibit homoaromaticity by conjugative interaction of the triene

part through 1,6‐overlap of 2p‐orbitals,[65] as is the case for cyclohepta‐1,3,5‐

triene (1).[13] With the use of nucleus‐independent chemical shifts (NICS(1)),[71]

it has been shown that thiepine (–2.3 ppm)[72] and phenylphosphepine (–4.8

ppm)[3c] indeed display aromatic character when compared to the well‐known six

‐electron Hückel‐aromatic tropylium cation,[71] which has a NICS(1) value of –8.2

ppm. Adding electronegative substitutents enhances the effect and fully aromatic

systems are obtained after complete fluorination of the heteropines.[37]

In contrast, the flattened transition structures for ring inversion of thiepine and

phosphepine are indeed highly antiaromatic, with positive NICS(1) values of

19.3[72] and 6.4 ppm,[3c] respectively.

1.6 Summary

Valence isomerization of cyclohepta‐1,3,5‐triene into bicyclo[4.1.0]hepta‐2,4‐

diene and their corresponding heteroelement analogues have been reviewed

giving insight into the chemical and physical properties of these fascinating

species.

‐24‐


‐25‐

1.7 References and Notes

[1] G. Maier, Angew. Chem. 1967, 79, 827; Angew. Chem. Int. Ed. 1967, 6, 402–413.

[2] For example, see: a) L. Rodriguez‐Hahn, B. Esquivel, A. A. Sánchez, J. Cárdenas,

O.G. Tovar, M. Soriano Garcia, A. Toscano, J. Org. Chem. 1988, 53, 3933–3936. b)

M. Güney, A. Daştan, M. Balci, Helv. Chim. Acta 2005, 88, 830–838.

[3] a) M. L. G. Borst, R. E. Bulo, D. J. Gibney, A. W. Ehlers, M. Schakel, M. Lutz, A. L.

Spek, K. Lammertsma, J. Am. Chem. Soc. 2005, 127, 5800–5801. b) M. L. G. Borst,

R. E. Bulo, D. J. Gibney, Y. Alem, F. J. J. de Kanter, A. W. Ehlers, M. Schakel, M.

Lutz, A. L. Spek, K. Lammertsma, J. Am. Chem. Soc. 2005, 127, 16985–16999. c) H.

Jansen, J. C. Slootweg, A. W. Ehlers, K. Lammertsma, Organometallics 2010, 29,

submitted.

[4] a) E. P. A. Couzijn, A. W. Ehlers, J. C. Slootweg, M. Schakel, S. Krill, M. Lutz, A. L.

Spek, K. Lammertsma, Chem. Eur. J. 2008, 14, 1499–1507. b) H. Jansen, A. J.

Rosenthal, J. C. Slootweg, A. W. Ehlers, M. Lutz, A. L. Spek, K. Lammertsma,

Organometallics 2008, 27, 2868–2872.

[5] A. Ladenburg, Liebigs Ann. Chem. 1883, 217, 74–149.

[6] M. Traetteberg, J. Am. Chem. Soc. 1964, 86, 4265–4270.

[7] S. S. Butcher, J. Chem. Phys. 1965, 42, 1833–1836.

[8] Suitable crystals for an accurate X‐ray determination could not be obtained for

cyclohepta‐1,3,5‐triene, see: T. B. Reed, W. N. Libscomb, Acta Cryst. 1953, 6, 108.

However the derivative 7,7‐dimethylcycloheptatriene‐3‐carboxylic acid did result

in suitable crystals, see: R. E. Davis, Tulinksy, Tetrahedron Lett. 1962, 3, 839–846.

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[10] For similar computational geometrical studies, see: a) = 52.1 °, = 25.2 °

determined at the CASSCF(6,6)/6‐31G(d) level; A. A. Jarzęcki, J. Gajewski, E. R.

Davidson, J. Am. Chem. Soc. 1999, 121, 6928–6935. b) = 57.5 °, = 27.6 °

Chapter 1

‐26‐

determined at the B‐LYP/6‐31G(d) level; A. P. Scott, I. Agranat, P. U. Biedermann,

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Org Chem. 1998, 11, 475–477. b) An “Anisotropy of the Current‐Induced Density”

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‐27‐

[23] For the methyl‐substituted analogues, see: J. A. Berson, M. R. Willcott III, J. Am.

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[24] a) E. Vogel, R. Schubart, W. A. Böll, Angew. Chem. 1964, 76, 535; Angew. Chem.

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[27] For synthesis and reactivity of the heterocycles, see: A. R. Katritzky, C. W. Rees, E.

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Chapter 1

‐28‐

[34] J. R. Gillard, M. J. Newlands, J. N. Bridson, D. J. Burnell, Can. J. Chem. 1991, 69,

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