Syntheses and conformational analyses of mono- and trans-1,4-dialkoxy substituted cyclohexanes-the steric substituent/skeleton interactions

Article abstract of DOI:10.1016/j.tet.2007.06.094

Mono- and trans-1,4-dialkoxy substituted cyclohexanes (alkyl=Me, Et, i-Pr, t-Bu) were prepared using the solvomercuration-demercuration (SM-DM) procedure. The axial?axial and axial,axial?equatorial, equatorial conformational equilibria of the products wer

Full text of DOI:10.1016/j.tet.2007.06.094

Tetrahedron 63 (2007) 9071–9081
Syntheses and conformational analyses of mono- and trans-1,4-
dialkoxy substituted cyclohexanes—the steric substituent/skeleton
interactions
*
Erich Kleinpeter and Jorg Thielemann
€
Department of Chemistry, University of Potsdam, PO Box 60 15 53, D-14415 Potsdam, Germany
Received 25 May 2007; revised 26 June 2007; accepted 26 June 2007
Available online 5 July 2007
Abstract—Mono- and trans-1,4-dialkoxy substituted cyclohexanes (alkyl¼Me, Et, i-Pr, t-Bu) were prepared using the solvomercuration–
demercuration (SM–DM) procedure. The axial!axial and axial,axial!equatorial, equatorial conformational equilibria of the products
1
were studied by low temperature H and 13C NMR spectroscopy in CD2Cl2. The structures and relative energies of the participating con-
formers were calculated at both the B3LYP (6-311G*//6-311+G*) and MP2 (6-311+G*//6-311G*) levels of theory. In the case of DFT,
good correlations of DGocalcd versus DGeoxptl were obtained. Both the structures and the energy differences of the conformers have been dis-
cussed with respect to established models of conformational analysis, viz. steric and hyperconjugative interactions. In addition, 1JH,C coupling
constants were considered with respect to the hyperconjugation present.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
steric effect (i.e., an increasing R volume increasingly favors
the axial conformation) results from the interaction between
the substituents and the cyclohexane skeleton, or is a conse-
quence of interactions within the ester moieties of the cyclo-
hexyl esters and the diesters studied. Both possible causes
were investigated and it is the topic of this paper to report
on the steric substituent/cyclohexane skeleton interactions.
For this purpose, both mono- and the trans-1,4-dialkoxy
substituted cyclohexanes 1–8 (cf. Scheme 1) were synthe-
sized, their conformational equilibria studied and the results
compared with the accompanying theoretical study at the ab
initio MP2 and DFT levels of theory.
There is a continuing interest in both the torsional barrier and
the preferred staggered conformer of ethane. As the underly-
ing causes, both hyperconjugation and steric hindrance have
been preferred1–3 but it seems that conventional steric repul-
sion is the principal reason for the conformation and mole-
cular dynamics of this fundamental molecule.4 We obtained
similar results when studying the conformational equilibria
of mono- and trans-1,4-disubstituted cyclohexanes with sub-
stituents of variable polarity and volume.5–9 However, sur-
prisingly special substituent influences proved to be active:
(i) there was no influence on the position of the axial/equato-
rial, axial,axial/equatorial, equatorial conformational equi-
libria from 1,3-diaxial steric interactions,6 which should
destabilize the axial arrangements (in contradiction to the
generally accepted model of substituent influences on cyclo-
hexane,10 but this result has since been proven to be true also
by others);11,12 (ii) substituent influences were found to be
partly based on their polarity (hyperconjugation by way of
sC2ꢀH2ax/s*C1ꢀO7 and sC2ꢀC3/s*C1ꢀO7), but also partly
on (iii) their steric effects, but by destabilization of the equa-
torial conformer with increasing substituent volume. Actu-
ally, only ester groups as substituents in the mono- and
trans-1,4-disubstituted cyclohexanes (–OCOR; R¼Me, Et,
i-Pr, t-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, and
CBr3) were studied and the question arose if this strange
The conformational equilibrium of methoxycyclohexane 1
has been studied both experimentally13–16 and theoretically
by calculations at various levels.11,17,18 The rotamer popula-
tions about the C–OMe bond were investigated by the 13C
chemical shifts of the methoxy and ring carbons and the
3JH,C coupling constants.19 Although the conformational pe-
culiarities of cyclohexanes have been reviewed,10,20 not
much is actually known about 1,4-disubstituted derivatives
despite their behavior being of interest.20–27
Wiberg28 ab initio MO calculated the conformational equi-
libria of trans-1,4-dihalocyclohexanes in solution and ob-
tained results in good agreement with experimental
measurements;29–33 the conformational equilibria of the
1,4-dihalocyclohexanes could be predicted by simple addi-
tion34 and deviations were considered to stem from the
additional contribution of electrostatic effects.28 Similar
* Corresponding author. Tel.: +49 331 977 5210; fax: +49 331 977 5064;
e-mail: kp@chem.uni-potsdam.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.094

9072
E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
OAlk
1
OAlk
5
5
6
6
1
AlkO
OAlk
OAlk
4
4
3
3
2
2
OAlk
Iax
Ieq
IIax,ax
IIeq,eq
[Ieq; IIeq,eq]
[Iax; IIax,ax]
;
-ΔG°
= RT lnK
K =
Substituent
monosubstituted
trans-1,4-disubstituted
OMe
OEt
OiPr
OtBu
1
2
3
4
5
6
7
8
Scheme 1.
transannular interactions were found to be responsible for
the preferred axial orientation of polar substituents in
4-substituted cyclohexanones.35 On the other hand, dipole–
dipole interactions between two polar substituents in cyclo-
hexane proved to be negligible and inductive effects, due to
the low polarizability of the intervening aliphatic ring, were
also considered minimal.36
For determination of the equilibrium constants, K
(cf. Scheme 1), the H and 13C NMR spectra of 1–8 were
recorded in CD2Cl2 at low temperature wherein two sets of
signals, one for each of the axial/diaxial and equatorial/di-
equatorial conformers, were obtained. The set of cyclohexane
ring carbon atoms that were more shielded were assigned to
the axial/diaxial conformers.42 The equilibrium constants K
(cf. Scheme 1) of the conformational equilibria were evalu-
1
1
Thus, the relative activity of steric and hyperconjugative
substituent effects (and in the case of 1,4-disubstituted ana-
logs, also, the effect of transannular interactions) on the
position of the conformational equilibria of substituted
cyclohexanes is not yet completely understood;37 the present
paper tries to make further progress.
ated by careful integration of well-separated H (H-1 and
OCaHn) and 13C signals (depending on the S/N, up to five
pairs of signals were evaluated; cf. Table S1 in Supplemen-
tary data) at 180 K, which subsequently provided the free en-
ergy differences (DGo¼ꢀRT ln K). For the 13C NMR, NOEs
were suppressed by inverse-gated decoupling experiments
and addition of Cr(acac)3 to reduce T1 relaxation; parallel in-
version-recovery T1 measurements proved the T1 values of
even quaternary carbon atoms to be <1 s; thus, pulse repeti-
tion times could be set to 5 s only. Cr(acac)3, besides, proved
to be of negligible influence on conformational equilibria.42
Of the disubstituted compounds examined here, trans-1,4-
dimethoxy cyclohexane (5) has already been synthesized
and studied with respect to both the conformational equilib-
rium and the barrier to ring interconversion13a,38,39 whereby
quantitative information on the population of the conformers
was obtained (ꢀDGo¼1.4 kcal molꢀ1).
1
In this manner, H and 13C analyses were comparable in
determining the conformational equilibria.
1
In Table 1, both the H and 13C chemical shifts of the two
2. Results and discussion
conformers for 1–8 are presented. In addition, calculated
(DFT and MP2) values are given which, in addition to gen-
eral expectations,42 provided the correct assignments. For
2.1. Synthesis of the compounds and NMR
spectroscopic studies
1
the H NMR, only the chemical shifts of H-1/H-4 and the
protons of R substituents (H-10) are provided, as protons
H-2, H-3, H-5, and H-6 furnished subspectra of higher order
which, due to the poor state of homogeneity at the lower tem-
peratures, were not amenable to simulation. Table 2 summa-
rizes the conformational energy differences between the
axial/diaxial and equatorial/diequatorial conformers of
1–8. The values of 1 and 4 agree well with data reported pre-
viously. For 1, Anteunis et al.13a in CHFCl2 and Schneider
and Hoppen13b–d in CFCl3 determined ꢀDGo to be 0.89
and 0.75 kcal molꢀ1, respectively, Robinson14 and Eliel15
both measured 0.6 kcal molꢀ1 whilst Mateos et al.16 mea-
sured 0.64 kcal molꢀ1. For 5, Hammarstroem et al.39 mea-
sured 1.4 kcal molꢀ1 (in CHClF2); the value Fuchs et al.43
measured for 4, 0.75 kcal molꢀ1, hardly deviates from that
measured here. Two conclusions can readily be drawn
from present conformational equilibria and are quite expect-
able: (i) with increasing volume of the alkoxy substituent(s),
the equatorial/diequatorial conformers predominate ever
The synthesis of cyclohexyl methyl ether (1) has been
reported previously7 and the cyclohexyl ethyl ether (2)
was obtained by the Williamson ether synthesis.40 The re-
maining mono-ethers (3 and 4) were synthesized by Brown’s
solvomercuration–demercuration (SM–DM) procedure.41a,b
The disubstituted cyclohexyl ethers 5 and 6 were synthe-
sized by the SM–DM procedure modified by Berger
et al.41c The synthesis of the remaining 1,4-disubstituted cy-
clohexyl ethers, employing the same procedure, was not pos-
sible in case of 8; Compound 7 was obtained in very low
yield only. When using mercury trifluoroacetate instead of
mercury acetate, however, 7 and 8 could be synthesized in
high purity and good yield. The ethers, obtained as clear col-
orless liquids, except for 8, which formed white crystals,
were distilled in vacuo; the purity of the products was con-
firmed by 1H, 13C NMR, IR spectroscopy, and mass spectral
analysis.

Table 1. Experimental (at 180 K in CD2Cl2) and calculated (DFT, MP2) 1H and 13C d (ppm) of mono- and trans-1,4-dialkoxy cyclohexanes 1–8
H-4e
H-4a
H-3e, H-5e
H-3a, H-5a
H-2e, H-6e
H-2a, H-6a
H-1
OCaH
OCbH
C-4
C-3, C-5
C-2, C-6
C-1
OCa
OCb
DFT
1
ax
eq
ax
eq
ax
eq
ax
eq
1.78
1.68
1.81
1.7
1.81
1.68
1.8
1.47
1.38
1.49
1.40
1.49
1.38
1.46
1.34
1.45
1.84
1.48
1.85
1.50
1.83
1.51
1.80
1.94
1.45
1.97
1.47
2.01
1.46
2.06
1.50
2.04
2.11
2.08
2.15
1.92
2.02
1.76
1.89
1.40
1.28
1.42
1.36
1.45
1.38
1.51
1.48
3.47
3.18
3.65
3.37
3.64
3.34
3.75
3.37
3.38
3.43
3.53
3.64
3.64
3.73
—
—
—
30.3
29.8
30.4
29.8
30.3
29.7
30.2
29.3
24.5
28.9
24.7
28.9
24.7
29.1
24.6
29.4
32.7
35.2
33.4
35.8
34.4
36.6
37.0
39.3
80.9
84.4
80.2
83.3
75.6
78.8
70.6
74.1
56.6
56.4
67.2
67.0
73.0
72.3
78.1
78.0
—
—
2
3
4
1.33
1.28
1.17
1.15
1.22
1.2
17.5
17.5
23.1
23.2
28.3
28.5
1.66
—
MP2
1
ax
eq
ax
eq
ax
eq
ax
eq
1.84
1.74
1.85
1.74
1.84
1.72
1.82
1.7
1.51
1.38
1.52
1.39
1.49
1.38
1.46
1.34
1.49
1.89
1.51
1.88
1.53
1.88
1.54
1.85
2.02
1.45
2.05
1.45
2.11
1.44
2.16
1.47
2.10
2.19
2.10
2.20
1.93
2.04
1.75
1.88
1.46
1.33
1.47
1.37
1.46
1.40
1.50
1.50
3.55
3.14
3.68
3.30
3.61
3.20
3.68
3.23
3.32
3.35
3.40
3.47
3.53
3.59
—
—
—
31.2
30.6
31.2
30.6
31.0
30.6
30.9
30.2
24.5
29.4
24.7
29.5
25.0
29.8
25.0
30.1
34.2
36.8
34.8
37.3
35.4
38.2
38.3
40.7
81.4
85.9
80.9
85.3
76.7
81.2
71.2
76.1
58.2
58.3
68.0
68.3
74.3
73.8
78.5
78.3
—
—
2
3
4
1.30
1.25
1.18
1.14
1.23
1.2
18.8
18.8
25.0
25.0
30.3
30.3
—
exptl
5
ax
eq
ax
eq
ax
eq
ax
eq
n.o.
1.49
n.o.
n.o.
n.o.
1.65
n.o.
n.o.
n.o.
1.94
n.o.
n.o.
3.38
2.96
3.58
3.17
3.68
3.24
3.77
3.3
3.17
3.22
3.39
3.49
3.62
3.75
—
—
—
27.1
26.4
26.4
26.0
26.4
29.9
n.o.
21.2
25.0
20.8
25.1
22.7
25.2
n.o.
29.6
32.4
29.9
32.8
30.3
33.4
n.o.
75.1
79.6
73.6
78.3
69.5
74.6
65.1
70.3
61.0
55.7
66.6
63.2
67.1
67.5
n.o.
—
—
6
7
8
1.50–2.00a
1.58
n.o.
1.27–1.50a
1.02–1.25a
n.o.
1.27–1.50a
1.74
n.o.
1.50–2.00a
1.02–1.25a
n.o.
1.50–2.00a
2.02
n.o.
1.27–1.50a
1.02–1.25a
n.o.
1.27–1.50a
1.16
n.o.
15.8
16.0
20.9
22.8
n.o.
28.2
1.57
n.o.
1.55
1.03–1.25a
n.o.
1.72
n.o.
1.69
1.03–1.25a
n.o.
1.92
n.o.
1.75
1.03–1.25a
n.o.
1.1
n.o.
1.16
0.98–1.28a
0.98–1.28a
0.98–1.28a
—
25.6
25.7
35.8
73.5
H-1, H-4
H-2e, H-3e, H-5e, H-6e
H-2e, H-3e, H-5e, H-6e
OCaH
OCbH
C-1, C-4
C-2, C-3, C-5, C-6
OCa
OCb
B3LYP
5
ax
eq
ax
eq
ax
eq
ax
eq
3.44
3.22
3.66
3.42
3.64
3.37
3.78
3.42
1.74
2.10
1.79
2.14
1.65
1.99
1.53
1.84
1.83
1.30
1.91
1.40
1.97
1.41
2.09
1.57
3.38
3.42
3.54
2.42
3.66
3.68
—
—
—
81.0
83.8
80.1
82.7
76.1
78.5
70.8
73.5
26.8
33.1
27.6
33.7
28.8
34.7
31.4
37.5
56.5
56.8
67.0
67.4
73.2
73.0
77.9
78.0
—
—
6
7
8
1.32
1.27
1.17
1.16
1.22
1.20
17.5
17.4
23.1
23.2
28.3
28.4
—
MP2
5
ax
eq
ax
eq
ax
eq
3.54
3.20
3.68
3.35
3.63
3.28
1.80
2.18
1.81
2.17
1.67
2.01
1.99
1.36
2.03
1.40
2.07
1.41
3.34
3.34
3.43
2.30
3.56
3.58
—
—
1.30
1.25
1.8
81.6
85.4
81.1
84.9
76.7
80.7
27.6
34.4
28.3
35.0
29.4
36.0
58.4
58.6
68.2
68.6
73.9
74.1
—
—
18.8
18.8
25.0
25.0
6
7
1.14
exptl
5
ax
eq
ax
eq
ax
eq
ax
eq
n.o.
3.15
3.58
3.24
3.84
3.30
—
n.o.
2.08
n.o.
2.06
n.o.
1.94
—
1.32
1.15
n.o.
1.16
n.o.
1.18
—
3.30
3.33
3.39
3.48
3.64
3.71
—
—
—
76.2
78.6
77.7
77.3
n.o.
73.8
—
n.v.
55.8
56.3
62.8
63.7
n.o.
68.1
—
—
—
29.8
26.6
30.2
24.4
31.0
—
6
7
8
1.35
1.16
1.28–1.78a
1.10
—
23.9
15.9
27.3
22.8
—
3.32
1.73
1.24
—
1.15
69.4
33.7
73.7
28.0
n.o.: not obtained for technical reasons.
Detailed assignments not possible due to signal overlap.
a

9074
E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
Table 2. Theoretical and experimental conformational energies (kcal molꢀ1) of compounds 1–8
Compd
B3LYP6-311G*//B3LYP 6-311G*
ꢀDGo
MP26-311+G*//MP26-311G*
ꢀDGo
exptl
ꢀDE
0.19
0.30
0.49
ꢀDEsolv
ꢀDE
ꢀDEsolv
ꢀDGo (1H)
ꢀDGo
—
(
13C)
1
2
3
4
5
6
7
8
0.49
0.40
0.66
1.11
0.27
0.10
0.65
0.70
0.62
0.56
0.82
0.94
0.50
0.53
1.17
1.61
ꢀ0.05
ꢀ0.23
ꢀ0.01
ꢀ0.01
ꢀ1.03
ꢀ1.27
ꢀ0.84
ꢀ0.60
0.17
0.01
0.09
0.16
ꢀ0.61
ꢀ0.82
—
0.32
0.11
0.51
0.48
ꢀ0.19
ꢀ0.73
—
0.847
1.09
1.09
1.60
1.31
1.30
1.63
—
1.03
1.10
1.45
1.25
1.34
1.67
—
0.57
ꢀ0.26
ꢀ0.10
0.29
0.59
—
—
more (indeed, the diaxial conformer of 8 could not even be
detected), and (ii) the substituent effect on the conforma-
tional equilibria is not additive. In the case of 5–8 they are
up to 0.8 kcal molꢀ1 smaller than expected by simple addi-
tion of the ꢀDGo values of the monosubstituted analogs
1–4.
2.2. Computational studies
Ab initio MO and DFT calculationswereperformed using the
Gaussian 98 program package.44 Different levels of theory
have previously been used to evaluate 1 and its sulfur ana-
logue.5 Results at the B3LYP (6-311G*//6-311+G*) and
MP2 (6-311+G*//6-311G*) levels of theory proved to be
the most reliable and were therefore used to calculate the en-
ergies of the fully relaxed structures for both the axial/diaxial
and equatorial/diequatorial conformers of 1–8. In addition,
the solvent effect of dichloromethane was also considered
whereby a self-consistent isodensity polarized continuum
model (SCI-PCM)45 using a dielectric constant 3¼8.93 was
employed. The results are summarized in Table 2 together
with the experimentally determined values. In Table 4,
Since trans-1,4-di-tert-butyl cyclohexane (8) was obtained
as a white solid, crystals were grown and examined by sin-
gle-crystal X-ray crystallography (data presented in Table
S2 in Supplementary data). As expected, the molecule
adopts the diequatorial conformation and the cyclohexane
resides in a chair conformation with the O-tert-butyl substit-
uents in staggered dispositions (cf. Fig. 1).
Table 4. Experimental and theoretically calculated geometries for the equa-
torial, equatorial conformer of compound 8
˚
Bond lengths (A)
X-ray
1.526
DFT
MP2
1.525
1.427
1.53
1.525
1.437
1.529
1.529
1.524
C2–C3
C2–O1
C3–C1
C1–C2
O1–C4
C4–C7
C4–C6
1.532
1.43
1.435
1.533
1.524
1.442
1.519
1.532
1.525
1.535
1.532
1.443
1.536
1.536
1.53
Figure 1. ORTEP structure of trans-1,4-di-tert-butyl cyclohexane 8.
C4–C5
Bond angles (ꢁ)
C2–O1–C4
C2–C1–C3
O1–C2–C1
O1–C2–C3a
C1–C2–C3a
C1–C3–C2a
O1–C4–C5
O1–C4–C6
O1–C4–C7
C5–C4–C6
C5–C4–C7
C6–C4–C7
The acquisition of standard HMQC spectra without decou-
pling allowed evaluation of the JH1,C1 coupling constants
(cf. Table 3); because of the strongly biased conformational
1
118.9
119.8
112.1
109.1
109.1
110.7
112.1
103.3
111.1
111.1
110.0
110.0
111.0
117.6
111.6
109.3
109.4
110.1
111.4
103.2
110.4
111.7
109.4
111.5
110.4
111.5
108.9
108.9
110.9
111.5
103.3
111.0
111.0
110.0
110.0
111.3
equilibria of 1–8, the interesting 1JH2ax,C2 coupling constants
could be not obtained. The values of the JH1,C1 couplings,
1
however, are constant within the margin of error and thus in-
criminating information on any hyperconjugation present
subject to substituent variation could be drawn.
Table 3. Experimental and calculated (DFT) 1JH,C coupling constants (Hz)
of 1–8
1JH1,C1, exptl
1JH1,C1, calcd
1JH2,C2, calcd
some structural parameters of trans-1,4-di-tert-butyl cyclo-
hexane (8) are compared with the X-ray data and strikingly
corroborate the quality of the calculations.
ax
eq
ax
eq
ax
eq
1
2
3
4
5
6
7
8
143.7
143.5
142.1
143.8
142
143
n.o.
—
137.7
137.7
137.9
136.1
141.6
142
136.3
136.4
136.0
134.6
136.8
136.8
136.3
135.0
132.4
132.4
132.0
130.9
133.2
133.2
132.8
131.7
121.9
121.8
121.2
120.5
125.5
125.2
124.9
124.3
125.7
125.7
126.2
126.6
125.4
125.4
125.8
125.9
Hyperconjugation was studied using the NBO option in-
cluded in the Gaussian 98 package with B3LYP/6-311G*
wave functions and B3LYP/6-311G* optimized molecular
structures and following a protocol reported previously.7–9
A number of interactions between filled NBO’s and anti-
bonding orbitals were considered as most representative
141.9
140.9
n.o., not obtained for technical reasons.

E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
9075
Table 5. Hyperconjugative stabilization energies Ehyp (kcal molꢀ1) of the bonding/antibonding interactions between C2–C3/C5–C6 and C2–H2ax/eq/C6–H6ax/eq
orbitals with both bonding and antibonding orbitals of the C1–O bond (DFT calculations) in 1–8 (cf. Scheme 2)
1
2
3
4
5a
6a
7a
8a
Acceptor
ax
eq
Donor
10.79
7.92
10.79
7.92
10.86
7.97
10.95
8.00
10.87
7.83
10.91
7.83
10.96
7.89
11.08
7.97
ax
eq
2.47
3.31
2.52
3.26
2.49
3.28
2.44
3.32
2.43
3.29
2.40
3.27
2.43
3.26
2.39
3.28
Donor-LP
ax
eq
S (donor, donor-LP, acceptor)
1.72
1.91
1.69
1.87
1.85
2.01
2.15
2.44
1.68
1.90
1.66
1.89
1.82
2.03
2.08
2.42
ax
eq
14.98
13.14
1.84
15.00
13.05
1.95
15.20
13.26
1.94
15.54
13.76
1.78
14.98
13.02
1.96
14.97
12.99
1.98
15.21
13.18
2.03
15.55
13.67
1.88
DEHYP¼SE(ax)ꢀSE(eq)
a
One substituent only studied.
for delocalization and retained for all the molecules studied.
The interactions considered are those between the filled
bonding and unfilled antibonding NBO’s of the exocyclic
C1–O 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 en-
ergies of the two conformers resulting from hyperconjuga-
tion are presented in Table 5.
sC2–Hax/s*C1ꢀO7 hyperconjugation for axial and
sC2ꢀC3/s*C1ꢀO7 for the equatorial conformers are given;
identical interactions are also active). In addition, the corre-
sponding interactions between all orbitals in 1–8 were
summed and are provided in Table 6.
Furthermore, interesting one-bond C, H coupling constants
(1JH1,C1 and, for comparison, also 1JH2,C2 values) were cal-
culated at the DFT level of theory (cf. Table 3). Despite
the experimental observations wherein the one-bond cou-
plings remained constant within a margin of error, the calcu-
lated values revealed interesting tendencies, which will be
discussed further on.
The most important hyperconjugative interactions for axial
and equatorial conformers are represented by the Lewis
bond/nonbonded structures depicted in Scheme 2 (only
2.3. Relative stability of conformers of the mono-
and trans-1,4-disubstituted cyclohexanes
H
O
H
O
O
With internal rotation about the C1–O bond, non-degenerate
but stable conformers could be assessed for various orienta-
tions of the alkoxy group. For each of 1–8, one preferred
conformer was obtained. In Figure 2 they are visualized
for the monosubstituted cyclohexanes 1–4; analogous orien-
tations were found for 5–8 wherein syn and anti orientations
of the two substituents proved to be of about the same en-
ergy. Only one other preferred conformer was obtained,
which proved to be less stable (>3.2 kcal molꢀ1 for the
equatorial and >8 kcal molꢀ1 for the axial conformer)7
and hence was not studied further.
H
H
H
O
H
H
Scheme 2.
Table 6. Hyperconjugative stabilization energies Ehyp (kcal molꢀ1) of the bonding/antibonding interactions between all orbitals with both bonding and antibond-
ing orbitals of the C1–O bond (DFT calculations) in 1–8
1
2
3
4
5a
6a
7a
8a
Acceptor
ax
eq
Donor
16.57
14.28
15.66
13.40
15.55
13.30
16.63
14.33
16.65
14.16
15.78
13.26
15.64
13.20
16.77
14.28
ax
eq
3.98
4.77
4.80
5.54
4.88
5.61
4.28
5.12
3.93
4.74
4.74
5.56
4.82
5.57
4.21
5.10
Donor-LP
ax
eq
S (donor, donor-LP, acceptor)
34.48
35.02
33.02
33.46
32.19
32.81
34.20
34.70
34.30
35.06
32.78
33.46
31.97
32.82
34.09
34.63
ax
eq
55.03
54.07
0.96
53.48
52.40
1.08
52.62
51.72
0.90
55.11
54.15
0.96
54.88
53.96
0.92
53.30
52.28
1.02
52.43
51.59
0.84
55.07
54.01
1.06
DEHYP¼SE(ax)ꢀSE(eq)
a
One substituent only studied.

9076
E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
additional electrostatic interactions35,49,50 between the two
C1–O dipoles, have been considered.
2.4. Hyperconjugation
When studying the conformational equilibria of the corre-
sponding mono- and trans-1,4-disubstituted cyclohexyl es-
ters of the acetic acid analogs CX3COOH (CX3¼Me, Et,
i-Pr, t-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2,
CBr3), hyperconjugation was identified as a significant con-
tributor to the different stabilities of the two conformers
ax/ax,ax, and eq/eq,eq.9 In case of 1–8, which are alkyl
ethers of the former cyclohexyl esters,9 the stereoelectronic
interactions sC2ꢀHax/s*C1ꢀO for the axial and sC2ꢀC3
/
s*C1ꢀO for the equatorial conformers as the main contribu-
tors to the hyperconjugation present (cf. Scheme 2) were
compared and found to be sufficiently stronger in the axial
conformer (cf. Table 5). Thus, hyperconjugation could be
employed for understanding at least partly the correspond-
ing conformational equilibria of these compounds. In addi-
tion to the above interactions, all of the interactions of the
orbitals with s*C1ꢀO and sC1ꢀO were considered and are
presented in Table 6.
The results of these calculations were unequivocal: (i) when
the stereoelectronic interactions of the bonding and anti-
bonding C2–C3, C5–C6, C2–H(ax,eq), and C6–H(ax,eq)
with the bonding and anti-bonding C1–O orbitals for the
axial/diaxial and equatorial/diequatorial conformers were
compared, they were again found to be stronger in the
axial/diaxial conformers (by ca. 1.8–2 kcal molꢀ1). If all
orbital interactions are considered the axial conformer is sta-
bilized by ca. 1 kcal molꢀ1. (ii) Further, this hyperconjuga-
tive stabilization proved to be slightly larger in the diaxial
and diequatorial conformers than by simple doubling of
the monosubstituted conformational energies (cf. Table 5).
The difference, though, is small, and if considering all hy-
perconjugative interactions (cf. Table 6) it is even smaller.
Thus, overall, hyperconjugative stabilization of the two con-
formers in mono- and disubstituted cyclohexanes by a single
substituent is about the same. In addition (iii), there is no
dependence on the different substituents in 1–4 and 5–8,
respectively; i.e., there are no substituent effect changes in
the two series of compounds on hyperconjugative stabiliza-
tion of the corresponding conformers. This result is corro-
borated by an attempted correlation of hyperconjugative
stabilization energies versus ꢀDGo, which could not be
found.
Figure 2. Preferred structures of both axial and equatorial conformers of 1–4.
While the preferred equatorial/diequatorial conformers were
correctly calculated by both theoretical methods, only with
DFT could the conformational energies of the participating
conformers be reasonably reproduced. For all three parame-
ters (cf. Table 2), the correlation coefficients obtained were
fair (DE, thermodynamically uncorrected, R2¼0.73; DG,
corrected, R2¼0.80; DE, with inclusion of the solvent,
R2¼0.82). With MP2 no correlation was obtained. Thus,
only the results of the DFT calculations were employed to
study and discuss the experimentally obtained sequences.
In the two series, the increasing volume of the alkoxy sub-
stituent(s) destabilizes the axial/diaxial conformers with re-
spect to the equatorial/diequatorial analogs in complete
agreement with general stereochemical rules, i.e., the
axial/diaxial conformers are assessed to be less stable due
to increased steric hindrance. In the case of trans-1,4-
di-tert-butyl cyclohexane (8), the corresponding diaxial
conformer could not even be detected in solution at low
temperature, only the diequatorial conformation could be
observed (corroborated by the X-ray structure analysis).
As potential causes for the conformational changes, both hy-
perconjugation of the C–H/C–C orbitals of the cyclohexane
skeleton with the bonding/antibonding orbital of the C1–O
bond(s)5–9,46–48 and steric substituent effects,5–10 and in
case of the trans-1,4-disubstituted cyclohexanes 5–8 also
Examinations of theoretical calculations and the NBO
analysis of cyclohexane derivatives have afforded precise
structural (bond lengths) and spectroscopic (1JH,C NMR
coupling constants) data to show the consequences of ster-
eoelectronic hyperconjugative effects in these systems.48
The same conclusions can be drawn from the theoretical
calculations (cf. Table 3). Unfortunately, the hyperconju-
1
gation-indicating coupling constants, JH2ax,C2, could not
be measured in 1–8 for technical reasons.8 On the other
hand, the very recent calculations of 1JH,C coupling constants
in saturated six-membered rings by Perrin et al.51,52
1
showed that whilst JH,C coupling is dependent to a degree
on hyperconjugation, it is much more dependent on polar
interactions.

E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
9077
2.5. Steric substituent effects
The evaluation of steric substituent influences on the confor-
mational equilibria of substituted cyclohexanes by Steiner
and Saenger26 is based on the inclination angle (a) between
the C1–C3–C5 plane and the C1–O bond in the axial con-
former and the C1–H1 bond in the equatorial analogs (cf.
Fig. 4). Rising inclination angles indicate increasing steric
substituent influences. Cyclohexanes with axial O-substitu-
ents proved to be virtually strain-free.26 Examination of
the inclination angles in compounds 1–8 (cf. Table 4) sug-
gests that the steric substituent effect even decreases with in-
creasing volumes of the alkyl moieties (in the axial/diaxial
conformers, a decreases by ca. 1ꢁ, in the equatorial/diequa-
torial conformers it remained almost constant). This conclu-
sion contradicts the notion of the increasing steric hindrance
with increasing volume of the alkoxy substituents.
Steric substituent effects were also found to be present. In
Figure 3, experimental free energy differences of 1–8 are
correlated to the volume of the alkoxy groups (in the case
of 5–8, doubled volumes were applied). Actually not one,
but two correlations for the two sets of compounds were ob-
tained. The excellent correlations strikingly corroborate the
important role steric effects influencing the present confor-
mational equilibria.
Instead, as a measure of the steric substituent effect of the
alkoxy substituents in 1–8, both the spatial distances C1–
Ca and the bond angles C1–O–Ca were employed (cf. Table
7). The supposition is that the increasing volume of an alk-
oxy group should both increase the C1–Ca distance and
widen the C1–O–Ca bond angle. In Table 4, the continuous
ascent of these two parameters in the two series 1<2<3<4
and 5<6<7<8 can be seen. In Figure 5, supporting this
notion, the volumes of the alkyl groups at the ether oxygen
correlate very well with the C1–Ca distances. Accordingly,
successful correlations for the bond angles C1–O–Ca were
also obtained.
Figure 3. Correlation of experimental free energies of activation, ꢀDGo
(kcal molꢀ1), with the volumes VR of the O-alkyl substituents.
The steric alkoxy substituent effect is larger in the axial/di-
axial than in the equatorial/diequatorial conformers, and is
revealed by correlating ꢀDGo values to the same parameters
(cf. Fig. 6). Two almost parallel correlations are obtained,
which prove that the same steric substituent influences in
the conformational equilibria are present in both the
mono- (1–4) and disubstituted (5–8) compounds.
This steric substituent effect due to the alkoxy substituents
can be estimated simply from the ꢀDGo values of 1–4 to
be ca. 1.9 kcal molꢀ1 (OMe), ca. 2.0 kcal molꢀ1 (OEt), ca.
Figure 4. Visualization of the inclination angle a (Steiner and Saenger26).
Table 7. Steric substituent effects as determined by DFT calculations in mono- and trans-1,4-dialkoxy substituted cyclohexanes 1–8
Inclination
angle a (ꢁ)
Torsion angle
(ꢁ) H1–C1–O7–Ca
Distance
C1–Ca (A)
Bond length
˚
O–Ca (A)
Bond length
˚
C1–O (A)
Bond angle
C1–O–Ca (ꢁ)
˚
ax
1
2
3
4
5
6
7
8
eq
1
2
3
4
5
6
7
8
94.19
94.26
93.96
92.91
93.95
94.13
93.59
92.85
53.7
54.2
34.7
0.0
53.7
54.4
36.1
0.1
2.3953
2.4089
2.4299
2.4874
2.3955
2.4091
2.4301
2.4893
1.4106
1.4180
1.4310
1.4428
1.4105
1.4177
1.4306
1.4420
1.4314
1.4310
1.4338
1.4365
1.4328
1.4329
1.4357
1.4386
114.88
115.45
116.03
119.51
114.81
115.37
115.95
119.58
92.87
92.83
92.54
93.02
93.04
92.88
92.63
92.98
50.3
51.8
34.1
0.0
51.0
52.4
34.5
0.0
2.3937
2.4074
2.4300
2.4875
2.3924
2.4060
2.4290
2.4864
1.4115
1.4187
1.4318
1.4426
1.4120
1.4193
1.4324
1.4432
1.4258
1.4258
1.4278
1.4313
1.4247
1.4247
1.4267
1.4304
115.05
115.63
116.38
119.89
115.01
115.56
116.33
119.83

9078
E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
3. Conclusions
A variety of mono- and trans-1,4-dialkoxy substituted
cyclohexanes 1–8 (alkyl¼Me, Et, i-Pr, t-Bu) have been
synthesized and their axial!equatorial and axial,
axial!equatorial, equatorial conformational equilibria
studied. Depending on the volume of the alkoxy substitu-
ents, the equatorial and diequatorial conformers were in-
creasingly preferred with respect to the corresponding
axial and diaxial conformers and in harmony with the results
of theoretical calculations at various levels of theory (DFT,
MP2). Although hyperconjugation stabilizes the axial and
diaxial conformers with respect to the equatorial and diequa-
torial analogs, this effect is constant along the present substi-
tution pattern and additive when comparing 1–4 and 5–8,
respectively. An increasing volume of an alkoxy substituent,
however, increasingly destabilizes axial and diaxial con-
formers due to steric hindrance within the –C2(H2)–C1H
(OAlkyl)–C6(H2)– segments(s) and is thus responsible for
the steric substituent influences. Though the substituent ef-
fects on the conformational equilibria of the monosubsti-
tuted cyclohexanes 1–4 should be additive in determining
the corresponding equilibria in 5–8, in reality they are not.
Differences of 0.5–0.7 kcal molꢀ1 were determined and
have been assigned to transannular electrostatic interactions
between the C–O dipoles, which additionally stabilize the
diaxial conformers in 5–8 with respect to their diequatorial
analogs, as has been suggested previously.28,35,49,50
Figure 5. Correlation of the C1/Ca distances in 1–8 versus the volumes VR
of the O-alkyl substituents.
2.1 kcal molꢀ1 (Oi-Pr), and ca. 2.6 kcal molꢀ1 (Ot-Bu), tak-
ing ca. 1 kcal molꢀ1 hyperconjugative stabilization of the
axial conformer (vide supra) additionally into account.
Since similar, almost identical and additive, hyperconjuga-
tive substituent effects are present in the mono- and disubsti-
tuted cyclohexanes, together with the result discussed above,
it implies that both effects on the conformational equilibria
of 1–4 can simply be added to determine the conformational
equilibria of the disubstituted analogs 5–8. However, the
diequatorial conformers of 5–8 are less stabilized than
expected. In other words, they are additionally destabilized
by a third, additional effect which can only be represented
by the polar interactions between the two C–O dipoles of
the alkoxy substituents, obviously more effective in the di-
axial than in the diequatorial conformation. It can be antici-
pated that the C–Oalkyl dipoles only change negligibly in 5–8
due to the modest alkyl variation. Thus, this transannular
electrostatic interaction effect, which stabilizes the diaxial
conformers with respect to their diequatorial counterparts
can be expected to be between 0.5 and 0.7 kcal molꢀ1
(cf. Table 2).
4. Experimental section
4.1. Syntheses
Purchased chemicals were used without further purification.
The cyclohexyl ethers 1–8 were characterized by 1H
(300 MHz) and 13C (75 MHz) NMR spectroscopy (APT,
H,H-COSY, HMQC, HMBC), FTIR spectroscopy, and
ESI-Q-TOF mass spectrometry.
4.1.1. Cyclohexyl methyl ether (1). Compound 1 was avail-
able from a previous preparation7 by the Williamson ether
synthesis.40
4.1.2. Cyclohexyl ethyl ether (2). Elementary sodium
(0.165 mol, 3.8 g) was first dispersed under toluene after
which the toluene was replaced by anhydrous ether
(50 mL). A solution of cyclohexanol (0.165 mol, 16.5 g) in
50 mL anhydrous ether was then added and the solution
left to stir. After 3 h, ethyl iodide (0.170 mol, 28.9 g) was
added dropwise and the solution left to stir for another 3 h.
The ether was then evaporated and the residue distilled to
yield 3 g (15%) of a clear colorless liquid, bp 100 ꢁC
(22 mbar); HRMS [M+H]+ calcd for C8H17O 129.1275,
1
found 129.1279; H NMR d (ppm) 1.13–1.26 (m, 5H, H-
2ax–H-6ax), 1.17 (t, 3H, J¼7.0 Hz, CH3), 1.52 (m, 1H,
H-4eq), 1.71 (m, 2H, H-3eq, H-5eq), 1.92 (m, 2H, H-2eq,
H-6eq), 3.20 (m, 1H, H-1), 3.48 (q, 2H, J¼7.0 Hz, OCH2);
13C NMR d (ppm) 15.7 (CH3), 24.3 (C-3, C-5), 25.8 (C-4),
32.4 (C-2, C-6), 62.9 (OCH2), 77.3 (C-1); IR n (cmꢀ1
2932, 1449, 1371 (CH3, CH2), 1111 (CH2–O–CH2), 976,
895.
)
Figure 6. Correlation of experimental free energies of activation, ꢀDGo
(kcal molꢀ1), with the C1/Ca distances in 1–8.

E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
9079
4.1.3. Synthesis of cyclohexyl ethers 3 and 4. Compounds 3
and 4 were synthesized by Brown’s solvomercuration–
demercuration procedure.41 To Hg(OCOCF3)2 (25 mmol,
10.7 g) dissolved in 30 mL of the corresponding anhydrous
alcohol, cyclohexene (25 mmol, 2.05 g) was added dropwise
under rapid stirring. After stirring the mixture for 15 min,
25 mL of 3 M KOH solution was added to the reaction mix-
ture whilst cooling in an ice bath. After 2 min, 25 mL of
0.5 M NaBH4 solution in 3 M KOH solution was added
causing the precipitation of colloidal black mercury. The re-
action product was extracted with hexane (3ꢂ20 mL) after
which the organic phase was washed with distilled water
(15ꢂ60 mL) and then dried with anhydrous Na2SO4. The
hexane was then removed and the products distilled in vacuo.
IR n (cmꢀ1) 2937, 1454, 1378 (CH3, CH2), 1199, 1103
(CH2–O–CH2), 1031, 982, 914.
4.1.8. trans-1,4-Diethoxy cyclohexane (6). Yield 5.35 g
(62%) of a clear, colorless liquid, bp 103–107 ꢁC
(38 mbar); HRMS [M+H]+ calcd for C10H21O2 173.1542,
1
found 173.1543; H NMR d (ppm) 1.17 (t, 6H, J¼7.0 Hz,
CH3), 1.26 (m, 4H, H-2ax, H-3ax, H-5ax, H-6ax), 2.00 (m,
4H, H-2eq, H-3eq, H-5eq, H-6eq), 3.24 (m, 2H, H-1, H-4),
3.48 (Q, 4H, J¼7.0 Hz, OCH2); 13C NMR d (ppm) 15.7
(CH3), 29.7 (C-2, C-3, C-5, C-6), 63.4 (OCH2), 76.7 (C-1,
C-4); IR n (cmꢀ1) 2936, 1447, 1374 (CH3, CH2), 1108
(CH2–O–CH2), 1035, 991, 957, 882.
4.1.9. trans-1,4-Di-iso-propyl cyclohexane (7). Yield
1.93 g (70%) of a clear, colorless liquid, bp 110–115 ꢁC
(36 mbar); HRMS [M+Na]+ calcd for C12H24O2Na
223.1698, found 223.1698; 1H NMR d (ppm) 1.09 (d,
12H, J¼6.0 Hz, CH3), 1.22 (m, 4H, H-2ax, H-3ax, H-5ax,
H-6ax), 1.89 (m, 4H, H-2eq, H-3eq, H-5eq, H-6eq), 3.28
(m, 2H, H-1, H-4), 3.48 (sp, 2H, J¼6.0 Hz, OCH2); 13C
NMR d (ppm) 22.9 (CH3), 30.7 (C-2, C-3, C-5, C-6), 68.6
(OCH2), 74.3 (C-1, C-4); IR n (cmꢀ1) 2970, 1453, 1377
(CH3, CH2), 1126, 1088 (CH2–O–CH2), 1035, 982, 914.
4.1.4. Cyclohexyl iso-propyl ether (3). Yield 3 g (61%) of
a clear, colorless liquid, bp 120–124 ꢁC (23 mbar); HRMS
1
[M+H]+ calcd for C9H19O 143.1436, found 143.1439; H
NMR d (ppm) 1.15–1.27 (m, 5H, H-2ax, H-6ax), 1.12 (d,
6H, J¼6.2 Hz, CH3), 1.51 (m, 1H, H-4eq), 1.71 (m, 2H,
H-3eq, H-5eq), 1.85 (m, 2H, H-2eq, H-6eq), 3.25 (m, 1H,
H-1), 3.48 (sp, 1H, J¼6.2 Hz, OCH2); 13C NMR d (ppm)
22.9 (CH3), 24.5 (C-3, C-5), 25.8 (C-4), 33.2 (C-2, C-6),
68.1 (OCH2), 74.8 (C-1); IR n (cmꢀ1) 2932, 1450, 1376
(CH3, CH2), 1157, 1125, 1083 (CH2–O–CH2), 1042, 1013,
916.
4.1.10. trans-1,4-Di-tert-butyl cyclohexane (8). Yield
6.35 g (70%), white crystals, mp 91–98 ꢁC; HRMS
[M+Na]+ calcd for C14H28O2Na 251.1987, found
4.1.5. Cyclohexyl tert-butyl ether (4). Yield 1.31 g (33%)
of a clear, colorless liquid, bp 79–81 ꢁC (38 mbar); HRMS
1
251.1999; H NMR d (ppm) 1.16 (s, 18H, CH3), 1.32 (m,
1
[M+H]+ calcd for C10H21O 157.1592, found 157.1595; H
4H, H-2ax, H-3ax, H-5ax, H-6ax), 1.76 (m, 4H, H-2eq, H-
3eq, H-5eq, H-6eq), 3.31 (m, 2H, H-1, H-4); 13C NMR
d (ppm) 28.8 (CH3), 34.1 (C-2, C-3, C-5, C-6), 70.0 (C-1,
C-4), 73.6 (OCH2); IR n (cmꢀ1) 2972, 1456, 1362 (CH3,
CH2), 1195, 1079 (CH2–O–CH2), 978, 896.
NMR d (ppm) 1.05–1.27 (m, 5H, H-2ax–H-6ax), 1.15 (s,
9H, CH3), 1.53 (m, 1H, H-4eq), 1.71 (m, 4H, H-2eq,
H-3eq, H-5eq, H-6eq), 3.33 (m, 1H, H-1); 13C NMR
d (ppm) 24.5 (C-3, C-5), 25.2 (C-4), 28.5 (CH3), 35.6 (C-
2, C-6), 70.2 (C-1), 73.0 (OCH2); IR n (cmꢀ1) 2933, 1449,
1361 (CH3, CH2), 1199, 1076 (CH2–O–CH2), 1042, 1023,
1004, 885.
4.2. NMR measurements
1H and 13C NMR spectra were recorded on Bruker Avance
500 and 300 NMR spectrometers using 5 mm probes operat-
4.1.6. Synthesis of cyclohexyl ethers 5–8. Dialkoxy cyclo-
hexyl ethers 5–8 were synthesized by a procedure analogous
to the above. To Hg(OCOCH3)2 (0.12 mmol, 38.2 g) [in
the case of 7 and 8, Hg(OCOCF3)2 was used in place of
Hg(OCOCH3)2] dissolved in the appropriate alcohol
(800 mL), cyclohexadi-1,4-ene (0.05 mol, 4 g) was added
whilst stirring. After 7 days, during which time any mercury
salts that had precipitated were removed, the solution was
poured into 0.5 M NaCl solution (500 mL). The precipitated
mercury salt was filtered by suction and washed carefully
with 20 mL of water, ethanol, and then ether. The precipitate
was dispensed into a 0.5 M KOH solution (250 mL) at 0 ꢁC
whilst vigorously stirring the reaction mixture. During con-
tinuous cooling, 1 M NaBH4 solution in 0.5 M KOH was
then added and stirring continued for further 20 min. At
completion, the reaction mixture was extracted with
CH2Cl2 (3ꢂ50 mL) and the organic phase dried over anhy-
drous Na2SO4 followed by removal of the solvent.
1
ing at 500 and 300 MHz for H, respectively, and 125 and
75 MHz for 13C, respectively. For all measurements,
CDCl3 (for lower temperatures CD2Cl2) was employed as
the solvent using TMS as an internal reference (¼0 ppm
for both nuclei). Signal assignment was performed at
298 K and utilized standard Bruker pulse sequences (1H,
13C, COSY, HMQC, and HMBC); digital resolution in 2D
heteronuclear experiment 0.1 Hz.
For 1H NMR spectra, the digital resolution was set to 16 data
points Hzꢀ1 and for 13C spectra, to 1.6 data points Hzꢀ1. For
2D NOESY experiments, an optimal value for the mixing
time tm was assessed as 400 ms. To avoid confusion arising
from spin diffusion, 2D ROESY spectra were also recorded
for comparison and also utilized mixing times of 400 ms. For
both NOESYand ROESYexperiments as well as the T1 mea-
surements, paramagnetic oxygen was displaced from the
NMR solutions by ultrasonification for 30 min under argon
prior to measurement. T1 values were measured using the in-
version recovery pulse sequence with a total of 16 different
delay times. T1 values were calculated using standard Bruker
software and are reported with an uncertainty of 50 ms. Vic-
4.1.7. trans-1,4-Dimethoxy cyclohexane (5). Yield 3.11 g
(43%) of a clear, colorless liquid, bp 74–76 ꢁC (26 mbar);
1H NMR d (ppm) 1.27 (m, 4H, H-2ax, H-3ax, H-5ax,
H-6ax), 1.99 (m, 4H, H-2eq, H-3eq, H-5eq, H-6eq), 3.17
(m, 2H, H-1, H-4), 3.30 (s, 6H, CH3); 13C NMR d (ppm)
29.0 (C-2, C-3, C-5, C-6), 56.3 (OCH3), 78.4 (C-1, C-4);
1
inal H–1H coupling constants were measured using the
JRESQF pulse sequence where the spectral widths were

9080
E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
4. Mo, Y.; Gao, J. Acc. Chem. Res. 2007, 40, 113.
5. Kleinpeter, E.; Taddei, F. J. Mol. Struct. (Theochem) 2002,
585, 223.
set to 4125 and 40 Hz for the f2 and f1 dimensions, respec-
tively, with digital resolutions of 4 and 0.2 Hz in f2 and f1,
respectively.
6. Kleinpeter, E.; Taddei, F.; Wacker, Ph. Chem.—Eur. J. 2003, 9,
1360.
4.3. Theoretical calculations
7. Taddei, F.; Kleinpeter, E. J. Mol. Struct. (Theochem) 2004,
683, 29.
8. Taddei, F.; Kleinpeter, E. J. Mol. Struct. (Theochem) 2005,
718, 141.
9. Kleinpeter, E.; Rolla, N.; Koch, A.; Taddei, F. J. Org. Chem.
2006, 71, 4393.
10. Bushweller, C. H. Conformational Behaviour of Six-Membered
Rings; Stereodynamics of Cyclohexane and Substituted
Cyclohexanes. Substituent A Values; Juaristi, E., Ed.; VCH:
New York, NY, 1995; p 25.
Ab initio calculations were carried out with the GAUSSIAN
98 program44 using the 6-311G** basis set at the B3LYP and
MP2 levels of theory. Geometry optimization of all configu-
rations were performed without constraints. The SCI-PCM
(Self-Consistent Reaction Field/Self-Consistent Isodensity
Polarized Continuum Model)45 method was used to consider
the solvent effect; the dielectric constant of 3¼8.93 was
applied.
11. Salzner, U.; von R. Schleyer, P. J. Org. Chem. 1994, 59,
2138.
Hyperconjugation was studied using the NBO option in-
cluded in the Gaussian 98 package with B3LYP/6-311G*
wave functions and B3LYP/6-311G* optimized molecular
structures and following a protocol reported previously.7–9
12. Wiberg, K. B.; Hammer, J. D.; Castejon, H.; Bailey, W. F.;
DeLwon, E. L.; Jarrett, R. M. J. Org. Chem. 1999, 64, 2085.
13. (a) Anteunis, M.; Geens, A.; van Cauwenberghe, R. Bull. Soc.
Chim. Belg. 1973, 82, 573; (b) Schneider, H. J.; Hoppen, V.
Tetrahedron Lett. 1974, 579; (c) Schneider, H. J.; Hoppen, V.
J. Org. Chem. 1978, 43, 3866; (d) Schneider, H. J.; Freitag,
W.; Hoppen, V. Org. Magn. Reson. 1980, 13, 266.
14. Robinson, M. J. T. Tetrahedron 1974, 30, 1971.
15. Eliel, E. L.; Gianni, M. H. Tetrahedron Lett. 1962, 97.
16. Mateos, J. L.; Chao, O.; Flores, R. H. Rev. Soc. Quim. Mex.
1969, 13, 269A.
17. Allinger, N. L.; Chung, D. Y. J. Am. Chem. Soc. 1976, 98, 6798.
18. Weldon, A. J.; Vickrey, T. L.; Tschumper, G. S. J. Phys.
Chem. A 2005, 109, 11073.
19. Haines, A. H.; Shandiz, M. S. J. Chem. Soc., Perkin Trans. 1
1981, 1671.
Chemical shift calculations were performed using the GIAO
approach. The values of the coupling constants were calcu-
lated with the Amsterdam Density Functional (ADF)53
program. The VWN+BLYP (Vosko–Wilk–Nusiar+Becke–
Lee–Yang–Parr) generalized gradient approximation (GGA)
was used to determine the unperturbed molecular orbitals.
All calculations were performed using a core double zeta,
valence triple zeta, and double polarized basis (TZ2P) im-
plemented in the ADF program. The spin–spin coupling
constants were calculated using Fermi-contact interactions
including the spin-dipolar (FC–SD), the paramagnetic
spin-orbit (PSO), and the diamagnetic spin-orbit (DSO)
contributions.
20. Kleinpeter, E. Adv. Heterocycl. Chem. 2004, 86, 41 and refer-
ences cited therein.
21. Ref. 9 and references cited therein.
The quantum chemical calculation was processed on SGI
Octane (R 12000) computers and a Linux cluster computer
at Potsdam University.
€
22. Kleinpeter, E.; Kohler, H.; Tschierske, C.; Zaschke, H. J. Prakt.
Chem. 1988, 330, 484.
€
23. Kleinpeter, E.; Kohler, H.; Krieg, R.; Deutscher, H.-J. J. Prakt.
Chem. 1989, 331, 171.
24. Thiem, J.; Vill, V.; Fischer, F. Mol. Cryst. Liq. Cryst. 1989,
170, 43.
Acknowledgements
Both the X-ray structural analyses of trans-1,4-di-tert-butyl
cyclohexane 8 by Alexandra Kelling from our Department of
Chemistry and language correction of the manuscript by Dr.
Karel D. Klika from the University of Turku, Finland are
gratefully acknowledged.
25. Remillard, P. B.; Brisse, F. Acta Crystallogr. 1982, B38, 1220.
26. Steiner, Th.; Saenger, W. J. Chem. Soc., Perkin Trans. 2 1998,
371.
27. Echeverria, G. A.; Baron, M.; Punte, G. Struct. Chem.
2000, 11, 35.
28. Wiberg, K. B. J. Org. Chem. 1999, 64, 6387.
29. Richardson, A. D.; Hedberg, K.; Wiberg, K. B. J. Phys. Chem.
A 1999, 103, 7709.
Supplementary data
30. Eliel, E. L.; Kandasamy, D. J. Org. Chem. 1976, 44, 3899.
31. Kozima, K.; Yoshino, T. J. Am. Chem. Soc. 1953, 75, 166.
32. Abraham, R. J.; Rossetti, Z. L. Tetrahedron Lett. 1972, 4965.
33. Meyer, A. Y. J. Mol. Struct. 1977, 40, 127.
34. Abraham, R. J.; Bretschneider, E. Internal Rotation in
Molecules; Orville-Thomas, W. J., Ed.; Wiley: New York,
NY, 1974.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.06.094.
References and notes
35. Borsdorf, R.; Arnold, M.; Kleinpeter, E. Z. Chem. 1977, 17,
378.
36. Salz, E.; Hummel, J. P.; Flory, P. J. J. Phys. Chem. 1981, 85,
3211.
37. Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006.
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.

E. Kleinpeter, J. Thielemann / Tetrahedron 63 (2007) 9071–9081
9081
38. Usmanov, A. G.; Sterin, Kh. E.; Bragin, O. V.; Tatarinova, V. I.;
Liberman, A. L. Zh. Strukt. Khim 1970, 11, 1061 and references
cited therein.
39. Hammarstroem, L. G.; Berg, U.; Liljefors, T. J. Chem. Res.,
Synop. 1990, 152.
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul,
A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, L.; Gomperts, R.; Martin, L. R.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision
A.12; Gaussian: Pittsburgh, PA, 2002.
€
40. Organikum, 6th ed.; VEB Deutscher fur Grundstoffindustrie:
Berlin, 1967.
41. (a) Brown, H. C.; Kurek, J. T.; Rei, M. H.; Thomson, K. L.
J. Org. Chem. 1984, 49, 2551; (b) Brown, H. C.; Kurek, J. T.;
Rei, M. H.; Thomson, K. L. J. Org. Chem. 1985, 50, 1171;
(c) Berger, J.; Thomas, B.; Vogel, T. J. Prakt. Chem. 1991,
333, 447.
45. Forseman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.;
Frisch, M. J. J. Phys. Chem. 1996, 100, 16098.
46. Alabugin, I. V.; Manoharan, M.; Zeidan, T. A. J. Am. Chem.
Soc. 2003, 125, 14014.
42. Pihlaja, K.; Kleinpeter, E. Carbon-13 NMR Chemical Shifts
in Structural and Stereochemical Analysis; Methods in
Stereochemical Analysis; Marchand, A. P., Ed.; VCH: New
York, NY, 1994; p 207.
43. Senderowitz, H.; Abramson, S.; Aped, P.; Schleifer, L.; Fuchs,
B. Tetrahedron Lett. 1989, 48, 6765.
44. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.;
Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M.; Farkas, C. O.; Tomasi, J.; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
C. S.; Ochterski, J.; Petersson, G. A.; Ayala, P.; Cui, Y. Q.;
Morokuma, K. D.; Malick, K.; Rabuck, A. D.; Raghavachari,
47. Alabugin, I. V.; Manoharan, M. J. Org. Chem. 2004, 69, 9011.
48. Martinez-Mayaorga, K.; Juaristi, E.; Cuevas, G. J. Org. Chem.
2004, 69, 7266.
49. Wood, G.; Woo, E. P.; Miskow, M. H. Can. J. Chem. 1969,
47, 429.
50. Zefirov, N. S.; Samoshin, V. V.; Nikulin, A. V.; Zyk, N. V.
Zh. Organ. Khim. 1978, 14, 2617.
ꢀ
51. Perrin, C. L.; Erdelyi, M. J. Am. Chem. Soc. 2005, 127, 6168.
ꢀ
52. Cuevas, G.; Martınez-Mayorga, K.; Fernandez-Alonso, M. Del
C.; Jimenez-Barbero, J.; Perrin, C. L.; Juaristi, E.; Lopez-Mora,
ꢀ
ꢀ
ꢀ
N. Angew. Chem. 2005, 117, 2412.
53. Vosko, S. H.; Wilk, L.; Nusiar, M. Can. J. Phys. 1989, 58, 1200;
Becke, A. D. J. Chem. Phys. 1993, 98, 5648; Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B 1988, 37, 785.