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‐
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
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‐
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
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‐
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
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‐
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
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‐
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
‐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.
[9] Z. Chen, H. Jiao, J. I. Wu, R. Herges, S. B. Zhang, P. v. R. Schleyer, J. Phys. Chem. A
2008, 112, 10586–10594.
[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,
N. V. Riggs, L. Radom, J. Org. Chem. 1997, 62, 2026–2038.
[11] F. R. Jensen, L. A. Smith, J. Am. Chem. Soc. 1964, 86, 956–957.
[12] F. A. L. Anet, J. Am. Chem. Soc. 1964, 86, 458–460.
[13] For example: a) Determination of “Nuclear Independent Chemical Shift” (NICS(0),
benzene –8.0 ppm,71 –4.2 ppm of 1), T. Nishinaga, Y. Izukawa, K. Komatsu J. Phys.
Org Chem. 1998, 11, 475–477. b) An “Anisotropy of the Current‐Induced Density”
(ACID) plot shows through space interaction bridging the methylene‐group, R.
Herges, D. Geuenich, J. Phys. Chem. A. 2001, 105, 3214–3220.
[14] a) G. Maier, Angew. Chem. 1967, 79, 827; Angew. Chem. Int Ed. 1967, 6, 812. b) T.
H. Lowry, K. S. Richardson, in Mechanism and Theory in Organic Chemistry, 4th
edition, Harper and Row, Lonon, 1990.
[15] A. Menzek, M. Baler, Tetrahedron 1993, 49, 6071–6078, and references therein.
[16] M. B. Ruben, J. Am. Chem. Soc. 1981, 103, 7791–7792.
[17] a) G. E. Hall, J. D. Roberts, J. Am. Chem. Soc. 1971, 93, 2203–2207; b) T. –H. Tang,
C. S. Q. Lew, Y. –P. Cui, B. Capon, I. G. Csizmadia, J. Mol. Struc., Theochem. 1994,
305, 149–164.
[18] W. G. Woods, J. Org. Chem. 1958, 23, 110–112.
[19] K. N. Klump, J. P. Chesick, J. Am. Chem. Soc. 1963, 85, 130–132.
[20] a) J. A. Berson, M. R. Willcott III, J. Am. Chem. Soc. 1965, 87, 2751–2752. b) J. A.
Berson, M. R. Willcott III, J. Am. Chem. Soc. 1965, 87, 2752–2753.
[21] a) K.‐G. Klärner, Angew. Chem. 1974, 86, 270–272; Angew. Chem. Int. Ed. 1974,
13, 268–270. b) K.‐G. Klärner, S. Yaslak, M. Wette, Chem. Ber. 1977, 110, 107–
123. c) K.‐G. Klärner, S. Yaslak, M. Wette, Chem. Ber. 1979, 112, 1168–1188. d) K.‐
G. Klärner, B. Brassel, J. Am. Chem. Soc. 1980, 102, 2469–2470.
[22] a) A. P. Ter Borg, H. Kloosterziel, N. Van Meurs, Proc. Chem. Soc. 1962, 359. b) E.
Weth, A. S. Dreiding, Proc. Chem. Soc. 1964, 59–60.
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
‐27‐
[23] For the methyl‐substituted analogues, see: J. A. Berson, M. R. Willcott III, J. Am.
Chem. Soc. 1966, 88, 2494–2502.
[24] a) E. Vogel, R. Schubart, W. A. Böll, Angew. Chem. 1964, 76, 535; Angew. Chem.
Int. Ed. 1964, 3, 510. b) E. Vogel, W. A. Böll, H. Günther, Tetrahedron Lett. 1965,
46, 609–615.
[25] E. E. van Tamelen, D. Carty, J. Am. Chem. Soc. 1967, 89, 3922–3923.
[26] E. Vogel, H. Günther, Angew. Chem. 1967, 79, 429–446; Angew. Chem. Int. Ed.
1967, 6, 385–401.
[27] For synthesis and reactivity of the heterocycles, see: A. R. Katritzky, C. W. Rees, E.
F. Scriven, In Complehensive Heterocyclic Chemistry II; Seven Membered and
Larger Rings with Fused Derivatives, Vol. 9; G. R. Newkome Ed.: Elsevier Science
Ltd.: Oxford, 1996. a) Oxepines: p 45–66. b) Azepines: p 1–43. c) Thiepines: p 67–
111. d) Phosphepines: p 947–950.
[28] C. W. Bock, P. George, J. J. Stezowski, J. P. Glusker, Struct. Chem. 1989, 1, 33–39.
[29] D. M. Hayes, S. D. Nelson, W. A. Garland, P. A. Kollman J. Am. Chem. Soc. 1980,
102, 1255–1262.
[30] a) D. M. Jerina, J. W. Daly, B. Witkop, In Biogenic Amines and Physiological
Membranes in Drug Therapy, Part B; J. H. Biel, L. G. Abood, Ed.; Marcel Dekker:
New York, 1971; p 413–476. b) J. W. Daly, D. M. Jerina, B. Witkop, Experientia,
1972, 28, 1129–1149. c) D. M. Jerina, J. W. Daly, Science 1974, 185, 573–582. d)
D. R. Boyd, N. D. Sharma, Chem. Soc. Rev. 1996, 25, 289–296.
[31] a) B. Klotz, I. Barnes, K. H. Becker, B. T. Golding, J. Chem. Soc., Faraday Trans.
1997, 93, 1507–1516. b) A. P. Henderson, E. Mutlu, A. Leclercq, C. Bleasdale, W.
Clegg, R. A. Henderson, B. T. Golding, Chem. Commun. 2002, 1956–1997.
[32] H. Günther, Tetrahedron Lett. 1965, 46, 4085–4090.
[33] a) In the presence of acid, protonation results in a carbocation intermediate and
does not generate a radical species, see: P. George, C. W. Bock, J. P. Glusker J.
Phys. Chem. 1990, 94, 8161–8168. b) for photoisomerisation, see: J. M. Holovka,
P. D. Gardner, J. Am. Chem. Soc. 1967, 89, 6390–9391.
Chapter 1
‐28‐
[34] J. R. Gillard, M. J. Newlands, J. N. Bridson, D. J. Burnell, Can. J. Chem. 1991, 69,
1337–1343.
[35] C. C. Pye, J. D. Xidos, R. A. Poirier, D. J. Burnell J. Phys. Chem. A. 1997, 101, 3371–
3376.
[36] L. Field, D. L. Tuleen, In Seven‐Membered Heterocyclic Compounds Containing
Oxygen and Sulfur, Chapter 10; Rosowsky A., Ed.; Wiley Interscience, New York,
1972.
[37] W. L. Karney, C. J. Kastrup, S. P. Oldfield, H. S. Rzepa, J. Chem. Soc., Perkin Trans.
2, 2002, 388–392.
[38] K. J. Miller, K. F. Moschner, K. T. Potts, J. Am. Chem. Soc. 1983, 105, 1705–1712.
[39] R. Gleiter, G. Krennrich, D. Cremer, K. Yamamoto, I. Murata, J. Am. Chem. Soc.
1985, 107, 6874–6879.
[40] K. Nishino, M. Takagi, T. Kawata, I. Murata, J. Inanaga, K. Nakasuji, J. Am. Chem.
Soc. 1991, 113, 5059–5060.
[41] D. N. Reinhoudt, C. G. Kouwenhoven, Tetrahedron 1974, 30, 2093–2098.
[42] K. Yamamoto, S. Yamazaki, Y. Kohashi, I. Murata, Y. Kai, N. Kanehisa, K. Miki, N.
Kasai, Tetrahedron Lett. 1982, 23, 3195–3198.
[43] a) I. Ueda, Y. Sato, S. Maeno, S. Umio, Chem. Pharm. Bull. 1978, 26, 3058–3070.
b) Y. Higashi, Y. Momotani, E. Suzuki, T. Kaku, Pharmacopsychiatry 1987, 20, 8–
11.
[44] For reviews, see: a) K. Yamamoto, S. Yamazaki, In Comprehensive Heterocyclic
Chemistry II; Vol. 9, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Eds.; Elsevier:
Amsterdam, 1996; pp 67–111. b) A. L. Schwan In Science of Synthesis; Vol. 17, S.
M. Weinreb, Ed.; Thieme: Stuttgart, 2004; p 717–748. c) M. Protiva, J. Heterocycl.
Chem. 1996, 33, 497–521.
[45] L. A. Paquette, Angew. Chem. 1971, 83, 11–20; Angew. Chem. Int. Ed. 1971, 10,
11–20.
Valence Isomerization of Cyclohepta‐1,3,5‐triene and its Heteroelement Analogues
‐29‐
[46] K. Hafner, Angew. Chem. 1963, 75, 1041–1050; Angew. Chem. Int. Ed. 1964, 3,
165–173.
[47] E. Vogel, H. –J. Altenbach, J. –M. Drossard, H. Schmickler, H. Stegelmeier, Angew.
Chem. 1980, 92, 1053–1054; Angew. Chem. Int. Ed. 1980, 19, 1016–1018.
[48] A. R. Katritzky, C. W. Rees, In Complehensive Heterocyclic Chemistry, Vol 7; G. R.
Newkome, Ed.; Elsevier Science Ltd., Oxford, 1984. a) p. 491 b) p. 543.
[49] M. Z. Kassaee, S. Arshadi, B. N. Haerizade, E. Vessally, J. Mol. Struc., Theochem.
2005, 731, 29–37.
[50] H. Prinzbach, H. Babach, H. Fritz, P. Hug, Tetrahedron Lett. 1977, 18, 1355–1358.
[51] L. A. Paquette, D. E. Kuhla, J. H. Barrett, L. M. Leichter, J. Org. Chem. 1969, 34,
2888–2896.
[52] J. H. van den Hende, A. S. Kende, Chem. Commun. 1965, 384–385.
[53] a) L. A. Paquette, J. H. Barrett, J. Am. Chem. Soc. 1966, 88, 2590–2591. b) L. A.
Paquette, J. H. Barrett, D. E. Kuhla, J. Am. Chem. Soc. 1969, 91, 3616–3624.
[54] L. A. Paquette, J. H. Barrett, J. Am. Chem. Soc. 1966, 88, 1718–1722.
[55] L. A. Paquette, D. E. Kuhla, J. H. Barrett, J. Org. Chem. 1969, 34, 2879–2884.
[56] For more details on azepines, see ref 27b.
[57] For more synthetic routes, see: J. –P. K. Meigh, in Science of Synthesis, Vol 17, S.
M. Weinreb, E. Schaumann, Eds.; Thieme Chemistry, 2004, p 825–927.
[58] R. L. Robey, C. R. Copley‐Merriman, M. A. Phelps, J. Heterocycl. Chem. 1989, 26,
779–783.
[59] G. Steinez, A. Franke, E. Hädicke, D. Lenke, H. –J. Teschendorf, H. –P. Hofmann, H.
Kreiskott, W. Worstmann, J. Med. Chem. 1986, 29, 1877‐1888.
[60] M. Z. Kassaee, S. M. Musavi, M. Majdi, A. Cheshmehkani, E. Motamedi, A.
Aghaee, J. Mol. Struct., Theochem. 2008, 848, 73–78.
[61] C. A. Muedas, D. Schröder, D. Sülzle, H. Schwarz, J. Am. Chem. Soc. 1992, 114,
7582–7584.
Chapter 1
‐30‐
[62] G. Märkl, H. Schubert, Tetrahedron Lett. 1970, 11, 1273–1276.
[63] G. Märkl, W. Burger, Angew. Chem. 1984, 96, 896–897; Angew. Chem. Int. Ed.
Engl. 1984, 23, 894–895.
[64] a) G. Märkl, W. Burger, Tetrahedron Lett. 1983, 24, 2545–2548. b) J. Kurita, S.
Shiratori, S. Yasuike, T. Tsuchiya, J. Chem. Soc., Chem. Commun. 1991, 1227‐1228.
c) S. Yasuike, H. Ohta, S. Shiratori, J. Kurita, T. Tsuchiya J. Chem. Soc., Chem.
Commun. 1993, 1817–1819. d) Y. Segall, E. Shirin, I. Granoth, Phosphorus Sulfur
Silicon, 1980, 8, 243–254. e) S. Yasuike, T. Kiharada, J. Kurita, T. Tsuchiya, Chem.
Commun. 1996, 2183–2184. f) S. Yasuike, T. Kiharada, T. Tsuchiya, J. Kurita, Chem.
Pharm. Bull. 2003, 51, 1283–1288.
[65] a) D. Cremer, B. Dick, D. Christeu, J. Mol. Struct., Theochem 1984, 110, 277–291.
b) J. Kao, J. Comput. Chem. 1988, 9, 905–923.
[66] W. B. Jennings, M. Rutherford, S. K. Agarwal, D. R. Boyd, J. F. Malone, D. A.
Kennedy, J. Chem. Soc., Chem. Commun. 1986, 970–972.
[67] H. J. Lindner, B. von Gross, Chem. Ber. 1972, 105, 434–440.
[68] D. A. Smith, J. Bitar, J. Org. Chem. 1993, 58, 6–8.
[69] W. B. Jennings, M. Rutherford, D. R. Boyd, S. K. Agarwal, N. D. Sharma,
Tetrahedron 1988, 44, 7551–7558.
[70] a) M. J. S. Dewar, N. Trinajstić, J. Am. Chem. Soc. 1970, 92, 1453–1459. b) B. A.
Hess Jr., L. J. Schaad, J. Am. Chem. Soc. 1973, 95, 3907–3912.
[71] The NICS value is obtained from NMR calculations of a ghost atom (Bq) at the
geometrical ring center (NICS(0)), but the value 1 Å above the ring (NICS(1)) is
recommended, because lack of shielding makes it a better measure of ‐
electron delocalization. Z. Chen, C. S. Wannere, C. Corminboeuf, R. Puchta, P. v.
R. Schleyer, Chem. Rev. 2005, 105, 3842–3888.
[72] GIAO‐B3LYP/6‐311G(d)//B3LYP/6‐311G(d) level of theory, see: M. Z. Kassaee, S.
M. Musavi, M. R. Momeni, F. A. Shakib, M. Ghambarian, J. Mol. Struct.,
Theochem. 2008, 861, 117–121.