Hyperconjugation and the increasing bulk of OCOCX3 substituents in trans-1,4-disubstituted cyclohexanes destabilize the diequatorial conformer

Article abstract of DOI:10.1021/jo0600858

The trans diesters of 1,4-cyclohexanediol with a number of acetic acid analogues, CX₃COOH, of varying steric hindrance and polarity (CX ₃ = Me, Et, iso-Pr, tert-Bu, CF₃, CH₂Cl, CHCl₂, CCl₃,

Full text of DOI:10.1021/jo0600858

Hyperconjugation and the Increasing Bulk of OCOCX3 Substituents
in Trans-1,4-Disubstituted Cyclohexanes Destabilize the Diequatorial
Conformer
Erich Kleinpeter,*,† Nadja Rolla,† Andreas Koch,† and Ferdinando Taddei‡
Department of Chemistry, UniVersity of Potsdam, P.O. Box 60 15 53, D-14415 Potsdam, Germany, and
Dipartimento di Chimica, UniVersita degli Studi di Modena e Reggio Emilia, Via Campi 183,
I-41100 Modena, Italy
kp@chem.uni-potsdam.de
ReceiVed January 16, 2006
The trans diesters of 1,4-cyclohexanediol with a number of acetic acid analogues, CX3COOH, of varying
steric hindrance and polarity (CX3 ) Me, Et, iso-Pr, tert-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2,
CBr3) were synthesized, and the axial,axial/equatorial,equatorial conformational equilibria were studied
by low-temperature 1H NMR spectroscopy in CD2Cl2. The structures and relative energies of the axial,axial
and equatorial,equatorial conformers were calculated at both the MP2/6-311G* and the MP2/6-311+G*
levels of theory, and it was only by including diffuse functions that a good correlation of ∆G°calcd vs
∆G°exptl could be obtained. Both the structures and the energy differences of the axial,axial and
equatorial,equatorial conformers are discussed with respect to the established models of conformational
analysis, viz., steric 1,3-diaxial and hyperconjugative interactions. Interestingly, the hyperconjugative
interactions σC-C/σC-Hfσ*C-O, together with a steric effect which also destabilizes the equatorial,equatorial
conformers on increasing bulk of the substituents, proved to dominate the position of the conformational
equilibria. In addition, the preference of the axial,axial conformers with respect to their equatorial,equatorial
analogues was greater than expected from the conformational energies of the corresponding substituents
in the monosubstituted cyclohexyl esters. The reason for this very interesting and unexpected result is
also discussed.
Introduction
conformation,3 whereas 2.9 kcal mol-1 of stabilization was
attributed to the former. We obtained a similar result when
studying the conformational equilibria of monosubstituted
cyclohexanes with substituents of variable polarity and volume.4-7
However, the two substituent influences were active in different
directions: (i) there was no perceived influence on the position
of the axial/equatorial equilibria Ia vs Ib (cf. Scheme 1) from
In the very recent discussion concerning the reason for the
preferred staggered conformation of ethane,1-3 the origin of the
torsional barrier was attributed to both traditional steric hin-
drance and hyperconjugation, the latter stabilizing by 1 kcal
mol-1 the staggered conformation with respect to the eclipsed
* To whom correspondence should be addressed. Phone: 0049-331-977-5210.
Fax: 0049-331-977-5064.
(4) Kleinpeter, E.; Taddei, F. J. Mol. Struct. (THEOCHEM) 2002, 585,
† University of Potsdam.
223.
‡ Universita degli Studi di Modena e Reggio Emilia.
(1) Bickelhaupt, F. M.; Baerends, E. J. Angew. Chem. 2003, 115, 4315.
(2) Weinhold, F. Angew. Chem. 2003, 115, 4320.
(3) Mo, Y.; Wu, W.; Song, L.; Lin, M.; Zhang, Q.; Gao, J. Angew. Chem.
2004, 116, 2020.
(5) Kleinpeter, E.; Taddei, F.; Wacker, Ph. Chem.-Eur. J. 2003, 9, 1360.
(6) Taddei, F.; Kleinpeter, E. J. Mol. Struct. (THEOCHEM) 2004, 683,
29.
(7) Taddei, F.; Kleinpeter, E. J. Mol. Struct. (THEOCHEM) 2005, 718,
141.
10.1021/jo0600858 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/11/2006
J. Org. Chem. 2006, 71, 4393-4399
4393

Kleinpeter et al.
SCHEME 1
acetylcholinesterase, wherein their conformation and stereo-
chemistry are of decisive influence on their activity.13 Although
the conformational peculiarities of cyclohexanes have been
reviewed,8,14 not so much is known about 1,4-disubstituted
derivatives despite their behavior being of interest. For example,
the conformation of trans 1,4-disubstituted cyclohexane deriva-
tives determines their liquid crystalline properties,15-17 wherein
participation of the 1,4-diaxial conformer lowers considerably
the corresponding clearing points. In the solid state, a strong
general preference for the diequatorial form has been ascer-
tained14,18 and only in the cases of trans-1,4-diisocyanocyclo-
hexane and two organometallic and inorganic complexes have
the 1,4-diaxial conformers been isolated.19 In that compound,
slight bending (5.1-8.2°) from the C1-C3-C5 plane was
observed indicating steric hindrance between the axial NC
substituents and the axial protons at C3/5 and C2/6, respectively.
Interestingly, trans-1,4-dibromo-1,4-dicarboxymethylcyclohex-
ane is a rigid chair conformer with the Br and COOCH3
substituents axially and equatorially orientated, respectively.20
The chance to observe trans 1,4-ax,ax-disubstituted cyclohexanes
in solution, obviously, is much greater: Wood et al.,21 Borsdorf
et al.,12 and Zefirov et al.22 studied the conformational equilibria
of trans 1,4-disubstituted cyclohexanes substituted symmetrically
by polar substituents and found the diaxial form to be more
stable than expected by simple addition of the conformational
energies of the singly substituted compounds. Furthermore, this
additional stabilization increased with increasing polarity of the
substituents. This nonadditivity of the -∆G° values was
discussed in terms of transannular polar12,22 and electrostatic
interactions.21 Later, Wiberg23 ab initio MO calculated the
conformational equilibria of trans-1,4-dihalocyclohexanes (in
addition to the 1,2- and 1,3-analogues) and obtained results in
good agreement with experimental measurements;24-28 the
conformational equilibria of the 1,4-dihalocyclohexanes were
predictable by simple addition,29 and deviations were considered
to stem from the additional contribution of electrostatic effects.23
Similar transannular interactions were found to be responsible
for the preferred axial orientation of polar substituents in
4-substituted cyclohexanones.30 On the other hand, dipole-
dipole interactions between two ester substituents in cyclohexane
SCHEME 2
the 1,3-diaxial steric effect which should destabilize the axial
arrangement (this result is in full contradiction to the generally
accepted model of substituent influence on cyclohexane con-
formational equilibria,8 but this result has since been proven to
be true also by others9,10); (ii) substituent influences were found
to be partly based on their polarity (hyperconjugation by way
of σC2-H2axfσ*C1-O7 and σC2-C3fσ*C1-O7) but also partly
based on (iii) their steric effects, but by destabilizing the
equatorial conformer with increasing volume of the substituent.
Thus, the theoretically formulated pretext that not only in
heterosubstituted analogues but also in cyclohexanes substituent
influences can also be of electronic origin, i.e., hyperconjuga-
tion11 has been corroborated experimentally and theoretically.4-7
Previously,12 we studied the conformational equilibria of the
1,4-disubstituted analogues IIa vs IIb (Scheme 2) of the
monosubstituted cyclohexanes (CX3 ) Me, CH2Cl, CHCl2,
CCl3) and found the same influences to be present. However,
the effect of substituent polarity on the conformational equilibria
was found to be stronger than expected from simple additive
considerations. For this reason and to (i) find further support
for the stereoelectronic origin of substituent effects in cyclo-
hexane, (ii) obtain fresh information regarding the competition
of both steric and electronic substituent effects of ester groups
bound to cyclohexane on its conformational equilibrium, and
finally (iii) study the differences of the conformational equilibria
of Ia vs Ib and IIa vs IIb, the full set of trans 1,4-disubstituted
cyclohexanes was synthesized and studied accordingly.
(13) Kay, J. B.; Robinson, J. B.; Cox, B.; Polkonja, D. J. Pharm.
Pharmacol. 1970, 22, 214.
(14) Kleinpeter, E. AdV. Heterocycl. Chem. 2004, 86, 41 and references
therein.
(15) Kleinpeter, E.; Ko¨hler, H.; Tschierske, C.; Zaschke, H. J. Prakt.
Chem. 1988, 330, 484.
(16) Kleinpeter, E.; Ko¨hler, H.; Krieg, R.; Deutscher, H.-J. J. Prakt.
Chem. 1989, 331, 171.
(17) Thiem, J.; Vill, V.; Fischer, F. Mol. Cryst. Liq. Cryst. 1989, 170,
43.
(18) Remillard, P. B.; Brisse, F. Acta Crystallogr. 1982, B38, 1220.
(19) Steiner, Th.; Saenger, W. J. Chem. Soc., Perkin Trans. 2 1998, 371.
(20) Echeverria, G. A.; Baron, M.; Punte, G. Struct. Chem. 2000, 11,
35.
(21) Wood, G.; Woo, E. P.; Miskow, M. H. Can. J. Chem. 1969, 47,
429.
(22) Zefirov, N. S.; Samoshin, V. V.; Nikulin, A. V.; Zyk, N. V. Zh.
Org. Khim. 1978, 14, 2617.
Cyclohexyl acetates are of special interest in pharmaceutical
chemistry because they can act, for example, as substrates for
(23) Wiberg, K. B. J. Org. Chem. 1999, 64, 6387.
(24) Richardson, A. D.; Hedberg, K.; Wiberg, K. B. J. Phys. Chem. A
1999, 103, 7709.
(25) Eliel, E. L.; Kandasamy, D. J. Org. Chem. 1976, 44, 3899.
(26) Kozima, K.; Yoshino, T. J. Am. Chem. Soc. 1953, 75, 166.
(27) Abraham, R. J.; Rossetti, Z. L. Tetrahedron Lett. 1972, 4965.
(28) Meyer, A. Y. J. Mol. Struct. 1977, 40, 127.
(29) Abraham, R. J.; Bretschneider, E. In Internal Rotation in Molecules;
Orville-Thomas, W. J., Ed.; Wiley: New York, 1974.
(30) Borsdorf, R.; Arnold, M.; Kleinpeter, E. Z. Chem. 1977, 17, 378.
(8) Bushweller, C. H. In Conformational BehaViour of Six-Membered
Rings; Stereodynamics of Cyclohexane and Substituted Cyclohexanes.
Substituent A Values; Juaristi, E., Ed.; VCH: New York, 1995; p 25.
(9) Salzner, U.; von R. Schleyer, P. J. Org. Chem. 1994, 59, 2138.
(10) Wiberg, K. B.; Hammer, J. D.; Castejon, H.; Bailey, W. F.; DeLwon,
E. L.; Jarrett, R. M. J. Org. Chem. 1999, 64, 2085.
(11) (a) Alabugin, I. V. J. Org. Chem. 2000, 65, 3910. (b) de Oliveira,
P. R.; Rittner, P. J. Org. Chem. 2003, 68, 6780.
(12) Borsdorf, R.; Arnold, M.; Kleinpeter, E. Z. Chem. 1977, 17, 378.
4394 J. Org. Chem., Vol. 71, No. 12, 2006

Cyclohexanes to Destabilize the Diequatorial Conformer
TABLE 1. Diaxial/Diequatorial Conformational Equilibria (K )
[eq,eq]/[ax,ax]) and ∆G° (∆G°exptl ) -RT ln K) for Diesters 1-11
SCHEME 3
compd
K170
-∆G° (kcal mol-1
)
1
2
3
4
5
6
7
8
7.96
7.82
3.77
0.92
1.58
3.17
1.08
0.41
3.19
1.20
0.37
0.70
0.70
0.45
-0.03
0.16
0.39
0.03
-0.30
0.42
9a
10a
11
0.07
-0.33
a At 183 K.
proved to be negligible and inductive effects, due to the low
polarizability of the intervening aliphatic ring, were also
considered minimal.31
levels of theory were previously tested on three of the
compounds (1, 3, and 6) and a number of sulfur analogues.4
The results at the MP2/6-311G*//MP2/6-311G* and MP2/6-
311+G*//MP2/6-311G* theoretical levels proved to be the most
reliable and were therefore used to calculate the energies of the
fully relaxed structures for both the diaxial and diequatorial
conformers of 1-11. In addition, the solvent effect of dichlo-
romethane was considered; a self-consistent isodensity polarized
continuum model (SCIPCM)34 in a solvent of the dielectric
constant ꢀ ) 8.93 was employed in the MP2/6-311G* calcula-
tions. The results are collected in Table S2 of the Supporting
Information. In Table 2, some structural parameters (inclination
angles R and C1-O7 bond lengths) of the two conformers
subject to OCOCX3 are collected.
Results and Discussion
Synthesis of the Compounds and NMR Spectroscopic
Studies. The cyclohexyl diesters were prepared from a mixture
of cis- and trans-1,4-cyclohexane diols and the corresponding
carboxylic acid either in dry toluene (for acid-catalyzed condi-
tions) or diethyl ether (for base-catalyzed conditions) and were
obtained as white solids after separation from the monosubsti-
tuted and cis disubstituted products by column chromatography.
The purity of the products was confirmed by 1H and 13C NMR
spectroscopy and mass spectral analysis.
The hyperconjugative effect was studied using the NBO
option included in the Gaussian 98 package, performed on the
MP2 density, following the same protocol as that reported
previously.6,7 A number of interactions between filled NBOs
and antibonding orbitals were considered as most representative
for delocalization and were retained for all the molecules studied.
The interactions considered are those between the filled and
antibonding NBOs of the exocyclic C1-O7 bond and those of
the C2-Hax, C6-Hax, C2-C3, and C5-C6 bonds for the
substituent at C-1 and those between the C4-O bond and the
C3-Hax, C5-Hax, C2-C3, and C5-C6 bonds for the substituent
at C-4. The stabilization of the two conformers by hypercon-
jugation is given in Table S3 of the Supporting Information;
the different hyperconjugative interactions are represented by
the Lewis bond/nonbonded structures depicted in Scheme 3
(only σC2-Haxfσ*C1-O7 hyperconjugation for the diaxial and
For determination of the equilibrium constants K (cf. Scheme
1
2), the H and 13C NMR spectra of the trans-diesters were
recorded in CD2Cl2 at low temperature, wherein two sets of
signals, one for each of the diaxial and diequatorial conformers,
were obtained. The set of cyclohexane ring carbon atoms that
were more shielded was assigned to the diaxial conformers in
each case because of the steric compression effects they
experience.32 The equilibrium constants (K ) [1eq,eq]/[1ax,ax])
of the conformational equilibria were evaluated by careful
integration of the well-separated H-1 and H-4 signals at both
170 and 183 K which subsequently provided the free-energy
differences (∆G° ) -RT ln K). 13C chemical shifts of the two
conformers for 1-11 are given in Table S1 of the Supporting
Information. For the 1H NMR, only the chemical shifts of H-1/
H-4 and the protons of the R substituents (H-10) are provided,
as protons H-2, H-3, H-5, and H-6 furnished subspectra of higher
order which, because of the poor state of homogeneity at the
lower temperatures, were not amenable to simulation. In Table
1, the conformational energy differences between the diaxial
and diequatorial conformers of 1-11 are summarized. These
values differ appreciably from those reported previously12 as
they are dependent both on the method used and on the solvent
employed. However, the sequence order with respect to the R
substituent remains intact. From standard HMQC spectra without
σ
C2-C3fσ*C1-O7 for the diequatorial conformers are given;
another three identical interactions are active).
Relative Stability of Diequatorial and Diaxial Conformers
of 1,4-Disubstituted Cyclohexanes. With internal rotation about
(33) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.12; Gaussian,
Inc.: Pittsburgh, PA, 1998.
1
proton decoupling, JH,C coupling constants were determined
(also given in Table S1 of the Supporting Information).
Computational Studies. Ab initio MO calculations were
performed using the Gaussian 98 program package.33 Different
(31) Salz, E.; Hummel, J. P.; Flory, P. J. J. Phys. Chem. 1981, 85, 3211.
(32) Pihlaja, K.; Kleinpeter, E. In Carbon-13 NMR Chemical Shifts in
Structural and Stereochemical Analysis; Methods in Stereochemical
Analysis; Marchand, A. P., Ed.; VCH: New York, 1994; p 207.
(34) Forseman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.; Frisch,
M. J. J. Phys. Chem. 1996, 100, 16098.
J. Org. Chem, Vol. 71, No. 12, 2006 4395

Kleinpeter et al.
TABLE 2. Selected Geometrical Parameters for Compounds 1-11 as Calculated at the MP2/6-311G* Level of Theory
compd
CX3
Me
conformer
a axa
a eqa
C-Oaxb
C-Oeqb
CO‚‚‚Hc
1
ax,ax
eq,eq
ax
90.96
1.453
2.382
2.369
2.381
2.365
157.67
157.80
1.445
1.447
91.13
1.452
eq
2
3
Et
ax,ax
eq,eq
ax
90.96
91.14
1.453
1.453
2.383
2.370
2.382
2.366
157.67
157.79
1.446
1.448
eq
i-Pr
ax,ax
eq,eq
ax
90.87
91.07
1.453
1.452
2.387
2.367
2.386
2.364
157.75
157.88
1.445
1.447
eq
4
t-Bu
ax,ax
eq,eq
ax
90.87
91.07
1.453
1.453
2.380
2.360
2.379
2.357
157.73
157.87
1.446
1.448
eq
5
CF3
ax,ax
eq,eq
ax
89.67
90.10
1.461
1.462
2.453
2.419
2.451
2.418
157.44
157.66
1.453
1.457
eq
6
CH2Cl
CHCl2
CCl3
CH2Br
CHBr2
CBr3
ax,ax
eq,eq
ax
90.12
90.50
1.457
1.457
2.426
2.390
2.418
2.387
157.45
157.42
1.448
1.452
eq
7
ax,ax
eq,eq
ax
89.73
90.19
1.460
1.460
2.431
2.396
2.428
2.400
157.89
157.60
1.448
1.454
eq
8
ax,ax
eq,eq
ax
89.73
90.20
1.461
1.462
2.430
2.400
2.427
2.400
157.36
157.59
1.452
1.457
eq
9
ax,ax
eq,eq
ax
90.34
90.71
1.457
1.457
2.421
2.388
2.412
2.386
157.45
157.63
1.448
1.451
eq
10
11
ax,ax
eq,eq
ax
89.89
90.36
1.460
1.460
2.426
2.399
2.421
2.397
157.37
157.56
1.451
1.454
eq
ax,ax
eq,eq
ax
89.96
90.44
1.462
1.463
2.422
2.396
2.419
2.395
157.35
157.57
1.453
1.457
eq
a Inclination angle of the C1-O7 bond to the C1-C3-C5 plane. b Bond length of C1-O7. c Spatial distance between C8dO9 and H1.
the C1-O7 (O4-C11) and O7-C8 (C11-C12) bonds [rotation
about the C8-C10 (C12-C14) bond was not taken into consid-
eration], a number of nondegenerate, but stable, conformers were
assessed for each of the orientations of the ester group. Only
two conformers, syn and anti (cf. Figure 1), were found to be
significant for each of the diequatorial and diaxial orientations
(cf. Scheme 2). The four conformers (ax,ax and eq,eq in both
syn and anti orientations) adopt staggered orientations for the
groups at C-1 (C-4) and O-7 (C-11) with, in each case, an
oxygen lone pair oriented toward the cyclohexane ring (see
Figure 1).4 That cyclohexyl acetates intrinsically prefer a
staggered conformation,35,36 whereas eclipsed exocyclic C-O
bonds are preferred in methoxycyclohexanes and their hetero-
cyclic analogues,37,38 has already been reported. In addition, the
dihedral angle H1-C1-O7-C8 for the various conformers
proves to be nearly constant (37.5-41°) and corroborates the
stable conformation of the substituents in all conformers studied.
The ester group was generally found to be in the Z
configuration.39 The effect of the syn or anti orientation of the
substituents is negligible (anti is more stable by less than 0.05
kcal mol-1) when compared with the difference in stability of
the eq,eq and ax,ax conformers. The more stable orientation of
syn and anti was checked for all the compounds examined, and
the results reported refer to the global minimum.
The free-energy differences of the 1,4-disubstituted cyclo-
hexanes 1-11 exhibit distinct trends: (i) The more polar/
(37) Anderson, J. E.; Iljeh, A. I. J. Chem. Soc., Perkin Trans. 2 1994,
1965.
(35) Schneider, H.-J.; Freitag, W.; Weigand, E. Chem. Ber. 1978, 111,
2656.
(38) Anderson, J. E.; Angyal, St. J.; Craig, D. C. J. Chem. Soc., Perkin
Trans. 2 1997, 729.
(36) Gonzalez-Outeirino, J.; Nasser, R.; Anderson, J. E. J. Org. Chem.
2005, 70, 2486.
(39) Neuvonen, H.; Neuvonen, K.; Koch, A.; Kleinpeter, E. J. Phys.
Chem. A 2005, 109, 6279.
4396 J. Org. Chem., Vol. 71, No. 12, 2006

Cyclohexanes to Destabilize the Diequatorial Conformer
FIGURE 1. Preferred conformers of the 1,4-disubstituted cyclohexanes 1 (CX3 ) Me).
voluminous the substituents are, the greater the preference of
the diaxial conformer (Table 1). For example, with an increasing
number of halogen atoms, the free-energy differences are
COCH3 (0.70 kcal mol-1) < COCH2Cl (0.39 kcal mol-1) <
COCHCl2 (0.03 kcal mol-1) < COCCl3 (-0.30 kcal mol-1);
the same sequence was obtained for the bromo analogues 9-11.
(ii) Similarly, the more voluminous the substituents are, the more
they prefer the diaxial conformer; COCH3 (0.70 kcal mol-1) )
COC2H5 (0.70 kcal mol-1) < COCH(CH3)2 (0.45 kcal mol-1
)
< COC(CH3)3 (-0.03 kcal mol-1). This result corroborates the
observations obtained for the monosubstituted analogues Ia and
Ib and, in particular, does not bode well for the interpretation
of substituent influences on the cyclohexane ring in terms of
destabilizing steric 1,3 nonbonding interactions. Finally, (iii)
the substituent influences on the conformational equilibria of
1-11 are obviously larger than those in the monosubstituted
analogues (cf. Table 1).
FIGURE 2. Plot of ∆E°calcd (MP2/6-311+G*//MP2/6-311G*) vs
∆G°exptl for compounds 1-11.
The free-energy differences of the global minima of the two
conformers ax,ax and eq,eq are given in Table S2 of the
Supporting Information, together, for reasons of comparison,
with the energies of the corresponding monosubstituted ana-
logues as calculated at the same levels of theory. The correlation
between the experimental ∆G° values for 1-11 and the
theoretically calculated values is only reasonable if calculations
take into consideration both electron correlation and diffuse
functions; the best results were obtained using MP2/6-311+G*
calculations (R2 ) 0.72; the correlation considering the solvent
effect is less successful, R2 ) 0.68), and the corresponding plot
is depicted in Figure 2. In this case, the correct order of the
conformational energies as a function of the -OCOCX3
substituent was obtained. However, the theoretical calculations
obviously overestimate the ax,ax conformer, by 2-2.5 kcal
mol-1, in comparison to the experimental results, and more so
if polar (5-11) rather than nonpolar CX3 substituents (1-4)
are present.
MP2/6-311+G* calculations are presented. Of note, the inclina-
tion angle (i.e., the angle between the axis of the C1-O7 bond
and the plane defined by C-3, C-1, and C-5), employed as a
sensible measure of the CH(1,3)‚‚‚O7 intramolecular interac-
tions,19 was found to lie in the range 90-91° in the diaxial
conformers, which is the smallest distortion obtained so far,
and therefore, negligible strain only can be expected. Obviously,
destabilizing 1,3-diaxial interactions play no role at all because
of the 1,4-positioning of the substituents; in the 1,3-positioning
of two substituents, however, there is steric destabilization
competing with stabilization via intramolecular hydrogen bond-
ing.40
The same can be said for the conformational distances H-1‚
‚‚O-9 in the two conformers which do not change significantly
along the variation of the substituents in 1-11. Also, when the
Molecular Geometries. In Table 2, selected geometrical
parameters of the preferred conformers of 1-11 resulting from
(40) (a) de Oliveira, P. R.; Rittner, P. Spectrochim. Acta, Part A 2005,
62, 30. (b) de Oliveira, P. R.; Rittner, P. J. Mol. Struct. 2005, 743, 69.
J. Org. Chem, Vol. 71, No. 12, 2006 4397

Kleinpeter et al.
geometries of the 1-11 conformers are compared with those
of their monosubstituted analogues Ia and Ib, there are only
very small differences to be found. Thus, the change in
substitution of 1-11 does not result in considerable changes in
either the geometry or the conformation of the cyclohexane ring
for the two conformers. The same is also true for the mono-
substituted analogues, and results are similar if corresponding
members are compared across the two series. This is the major
result of this theoretical study; the molecular structures of the
two conformers participating in the conformational equilibria
of 1-11 are very similar to each other and do not indicate
immediately the substituent variation with respect to either
polarity or volume.
Hyperconjugation. When studying the conformational equi-
libria of the monosubstituted analogues of 1-11, viz., Ia vs
Ib, hyperconjugation was identified as a significant contributor
to the different stabilities of the two conformers Ia and Ib.5,7
Hereby, the stereoelectronic interactions σC2-Haxfσ*C1-O7 for
the axial and σC2-C3fσ*C1-O7 for the equatorial conformers
were compared and found to be sufficiently stronger in the axial
conformer, thus hyperconjugation could be employed for
understanding at least partly the conformational equilibria of
Ia vs Ib. Thus, the same stereoelectronic interactions were
calculated for the 1,4-disubstituted cyclohexane derivatives
1-11 and were compared with the amount of hyperconjugation
in the monosubstituted analogues. The results are presented in
Table S3 of the Supporting Information. In the case of the
disubstituted cyclohexanes, however, the diequatorial conformer
will be additionally destabilized by the competitive (“anti-
FIGURE 3. Plot of the volumes of the CX3 substituents in compounds
1-11 vs ∆G°exptl. Linear regression provided two linear dependen-
cies: for the monosubstituted cyclohexanes, y ) -0.025 + 1.12 (R2
) 0.90); for the 1,4-disubstituted cyclohexanes 1-11 (>), y ) -0.028
+ 1.44 (R2 ) 0.81).
However, in the present theoretical study, adequate structural
changes are available (cf. Table 2) and the same conclusions
as those derived from the energetic hyperconjugation study (cf.
Table S3 of the Supporting Information) can be drawn, viz.:
(i) The C1-O7 bond lengths in the diaxial conformers are longer
(greater hyperconjugation) than those in the diequatorial con-
formers (e.g., 1.453 Å for the ax,ax but 1.445 Å for the eq,eq
conformer if CX3 ) CH3). (ii) This phenomenon is larger than
in the monosubstituted analogues (e.g., ∆C1-O7 ) 0.008 Å in
1 but only 0.005 Å in the monosubstituted analogue; cf. Table
2) because greater hyperconjugation stabilizes the diaxial
conformer (in equilibrium with diequatorial) with respect to the
axial analogue (in equilibrium with equatorial). (iii) However,
the additional effect of (ii) comes not from the diaxial conformer
(hyperconjugation remains roughly constant in ax,ax and ax:
∆C1-O7 ) (0.001 Å) but from the diequatorial conformer
(decreased hyperconjugation in eq,eq with respect to eq: ∆C1-
O7 ) -0.002 to -0.006 Å), altogether stabilizing the diaxial
conformer in the present conformational equilibria. (iv) This
effect is somewhat larger in 5-11, the cyclohexanes substituted
with polar CX3 substituents. Thus, the main conclusion from
this section is that hyperconjugation stabilizes the diaxial
conformers in 1-11 by ca. 0.3-0.5 kcal mol-1 more effectively
than the axial conformers in the monosubstituted analogues and
that this influence on the conformational equilibria eq,eq vs
ax,ax is somewhat higher in the case of polar substituents (5-
11) in comparison to their nonpolar analogues (1-4).
Steric Substituent Effects. Steric substituent effects were
also found to be in effect. In Figure 3, experimental free-energy
differences of 1-11 (and of their monosubstituted analogues
Ia h Ib) are correlated to the volume of the CX3 groups (in
the case of 1-11, doubled volumes were applied). Actually,
not one but two correlations for the two sets of compounds were
obtained. However, this is not really surprising, and as the two
correlations are parallel, identical dependencies must be under-
lying. Because the span of volumes is much wider for the 1,4-
disubstituted cyclohexyl derivatives 1-11, the steric hindrance
of the CX3 volume destabilizing the diequatorial conformer has
a more decisive influence on the position of the conformational
equilibrium than in the monosubstituted analogues. The differ-
ence between the two dependencies amounts to approximately
cooperative”)41
σC2-C3fσ*C1-Oeq hyperconjugation which ren-
ders the antiperiplanar arrangement of the two acceptor sub-
stituents to the same σ-bride unfavorable.42
The outcome of these calculations was unequivocal: if, in
the disubstituted cyclohexyl derivatives 1-11, the stereoelec-
tronic interactions σC2-Haxfσ*C1-O7 for the diaxial and
σC2-C3fσ*C1-O7 for the diequatorial conformers were com-
pared, they were found again to be stronger in the diaxial
conformer and larger than simple doubling of the monosubsti-
tuted conformational energy (cf. Table S3 of the Supporting
Information). The difference, though small, is significant, ca.
0.3 kcal mol-1, for nonpolar substituents and is 0.4-0.5 kcal
mol-1 in the case of polar substituents.
Theoretical examinations (ab initio calculations and NBO/
NCS analysis) of cyclohexane derivatives have afforded precise
structural (bond lengths) and spectroscopic (1JH,C NMR coupling
constants) data to show the consequences of stereoelectronic
hyperconjugative effects in these systems.43 The corresponding,
1
hyperconjugation-indicating coupling constants JHax,C2, how-
ever, could not be measured in 1-11 because of technical
reasons.5 On the other hand, the very recent calculations of 1JH,C
coupling constants in saturated six-membered rings by Perrin
1
et al.44,45 determined that JH,C coupling not only is dependent
on hyperconjugation but also is more dependent on polar
interactions.42
(41) Alabugin, I. V.; Manoharan, M.; Zeidan, T. A. J. Am. Chem. Soc.
2003, 125, 14014.
(42) Alabugin, I. V.; Manoharan, M. J. Org. Chem. 2004, 69, 9011.
(43) Martinez-Mayorga, K.; Juaristi, E.; Cuevas, G. J. Org. Chem. 2004,
69, 7266.
(44) Perrin, C. L.; Erde´lyi, M. J. Am. Chem. Soc. 2005, 127, 6168.
(45) Cuevas, G.; Mart´ınez-Mayorga, K.; Ferna´ndez-Alonso, M. del C.;
Jime´nez-Barbero, J.; Perrin, C. L.; Juaristi, E.; Lo´pez-Mora, N. Angew.
Chem. 2005, 117, 2412.
4398 J. Org. Chem., Vol. 71, No. 12, 2006

Cyclohexanes to Destabilize the Diequatorial Conformer
1
TABLE 3. ESI-MS
TABLE 5. Selected H and 13C NMR Chemical Shifts (ppm) for
Compounds 1-11
compd
ion
mass m/z
calcd mass
13C δ (ppm)
1H δ (ppm)
2
3
4
[M + H]+
[M + Na]+
[M + H]+
229.1421
279.1574
285.2068
229.1440
279.1572
285.2066
compd C-1 C-2
C-8
C-10 H-1 H-2eq H-2ax H-10
1
2
3
4
5
6
7
8
9
69.9 27.2 170.4
69.7 27.9 173.8
70.3 27.6 176.5
70.0 27.1 177.9
21.2 4.78
27.3 4.80
34.1 4.84
38.9 4.85
1.97
1.95
1.94
1.91
2.07
2.01
2.03
2.11
1.99
2.05
2.13
1.53
1.56
1.55
1.58
1.79
1.62
1.76
1.91
1.66
1.79
1.92
2.04
2.30
2.53
TABLE 4. EI-MS (Negative Ion Mode)
compd
ion
mass m/z
calcd mass
74.2 26.6 156.8 114.5 5.12
72.6 27.1 166.6
73.6 26.0 163.8
75.4 25.2 161.2
72.4 26.0 166.5
73.5 25.8 164.1
75.5 25.0 161.4
41.1 4.97
64.5 5.05
89.2 5.18
26.9 4.92
32.8 5.00
29.7 5.20
4.05
5.95
5
6
8
9
10
11
[M - F]-
[M]-
289.0516
268.0249
368.9029
277.0068
432.8264
588.6503
289.0499
268.0269
368.9022
277.0075
432.8286
588.6496
[M - Cl]-
[M - Br]-
[M - Br]-
[M - Br]-
3.84
5.82
10
11
dissolved in 50 mL of toluene followed by the addition of p-toluene
sulfonic acid (1 mg). The resulting solution was heated under reflux
for 8 h with an attached Dean-Stark trap. After cooling, the mixture
was extracted with 10 mL of a saturated sodium hydrogen carbonate
solution and, afterward, with water (10 mL). The resulting organic
phase was then dried over sodium sulfate. The white solid obtained
after removal of the toluene in vacuo was purified by column
chromatography (silica; ethyl acetate-n-hexane, 1:3). The structure
and purity of the compounds were determined by 1H and 13C NMR
spectroscopy (see Table 5) and accurate mass measurements by
ESI-MS or EI-MS (see Tables 3 and 4; compounds 1 and 7
excluded).
0.3-0.4 kcal mol-1, similar to the energy difference in ∆G°
due to hyperconjugation between the two groups of compounds,
and thus it makes sense that the difference in hyperconjugation
between identically substituted di- and monosubstituted cyclo-
hexane derivatives is the reason for the two correlations.
The larger effect of the CX3 groups with heavier halogens is
consistent with the greater σ-acceptor ability of C-Cl and C-Br
bonds compared with C-F bonds.46 This effect may accentuate
the steric bulk effect of the ester substituents in 1-11.
General Procedure for the Synthesis of Compounds 2-4 and
11. A mixture of cis- and trans-1,4-cyclohexanediol (1.16 g, 10
mmol) and pyridine (21 mmol) was dissolved in 50 mL of dried
diethyl ether followed by the slow addition of the corresponding
carboxylic acid (21 mmol) at 0 °C (cooling strongly recommended).
The mixture was stirred at room temperature for 10 h and then
extracted using 10 mL of each of the following solvents: saturated
sodium hydrogen carbonate solution, water, hydrochloric acid (0.1
M), and finally, water again. The resulting organic phase was then
dried over sodium sulfate. After removal of the diethyl ether, the
diesters were obtained as white solids which were purified by
column chromatography (silica; ethyl acetate-n-hexane, 1:3). The
structure and purity of the compounds were determined by 1H and
13C NMR spectroscopy (see Table 5) and accurate mass measure-
ments by ESI-MS or EI-MS (see Tables 3 and 4).
Conclusions
Long-range substituent influences on the conformational
equilibria of a number of 1,4-disubstituted cyclohexanes are
based in part on electronic factors, hyperconjugation by way
of σC2-Haxfσ*C1-O7 and σC2-C3fσ*C1-O7, but also in part on
steric influences. Surprisingly, this is by destabilization of the
diequatorial conformers with increasing volumes of the CX3
substituents. The hyperconjugation σC2-Haxfσ*C1-O7 in the
diaxial conformer is more effective than the hyperconjugation
σC2-C3fσ*C1-O7 in the diequatorial counterpart, thereby leading
to a preference of the former conformer with increasingly
stronger stereoelectronic interactions between the -OCOCX3
substituent and the cyclohexane skeleton. This stereoelectronic
stabilization of the diaxial conformer is 0.3-0.5 kcal mol-1
higher in the 1,4-disubstituted cyclohexanes 1-11 in comparison
with their monosubstituted analogues.5 In addition, steric
interactions, occurring throughout the whole molecule and not
just by way of the 1,3-diaxial interaction model, further
destabilize the diequatorial conformer with increasing bulk of
the CX3 group, and obviously, this too has a perpetuating effect
on the conformational equilibria of 1-11.
Acknowledgment. The authors gratefully acknowledge very
useful references of one of the referees regarding the additional
presence of anticooperative hyperconjugative interactions of
antiperiplanar substituents in the trans-1,4-disubstituted cyclo-
hexanes and language correction of the manuscript by Dr. Karel
K. Klika.
Supporting Information Available: Experimental 1H and 13
C
NMR chemical shifts, 1JC,H coupling constants, ab initio calculated
conformational equilibria of 1-11 (and also of all Ia vs Ib), the
corresponding hyperconjugation effects, and the coordinates and
absolute energies at the MP2/6-311G* level of theory for com-
pounds 1-11. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experimental Section
General Procedure for the Synthesis of Compounds 1 and
5-10. A mixture of cis- and trans-1,4-cyclohexanediol (1.16 g,
10 mmol) and the corresponding carboxylic acid (21 mmol) was
(46) Alabugin, I. V.; Zeidan, T. A. J. Am. Chem. Soc. 2002, 124, 3175.
JO0600858
J. Org. Chem, Vol. 71, No. 12, 2006 4399