Synthesis and NMR spectroscopic conformational analysis of benzoic acid esters of mono- and 1,4-dihydroxycyclohexane, 4-hydroxycyclohexanone and the -ene analogue – The more polar the molecule the more stable the axial conformer

Article abstract of DOI:10.1016/j.tet.2017.04.029

para-Substituted benzoic acid esters of cyclohexanol, 1,4-dihydroxycyclohexane, 4-hydroxy-cyclohexanone and of the corresponding exo-methylene derivative were synthesized and the conformational equilibria of the cyclohexane skeleton studied by low temperature ¹H and ¹³C NMR spectroscopy. The geometry optimized structures of the axial/equatorial chair conformers were computed at the DFT level of theory. Only one preferred conformation of the ester group was obtained for both the axial and the equatorial conformer, respectively. The content of the axial conformer increases with growing polarity of the 6-membered ring moiety; hereby, in addition, the effect of sp² hybridization/polarity of C(4)=O/C(4)=CH₂ on the present conformational equilibria is critically evaluated. Another dynamic process could be studied, for the first time in this kind of compounds.

Full text of DOI:10.1016/j.tet.2017.04.029

Accepted Manuscript
Synthesis and NMR spectroscopic conformational analysis of benzoic acid esters
of mono- and 1,4-dihydroxycyclohexane, 4-hydroxycyclohexanone and the -ene
analogue – The more polar the molecule the more stable the axial conformer
Erich Kleinpeter, Peter Werner, Torsten Linker
PII:
S0040-4020(17)30401-5
10.1016/j.tet.2017.04.029
TET 28630
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 February 2017
Accepted Date: 12 April 2017
Please cite this article as: Kleinpeter E, Werner P, Linker T, Synthesis and NMR spectroscopic
conformational analysis of benzoic acid esters of mono- and 1,4-dihydroxycyclohexane, 4-
hydroxycyclohexanone and the -ene analogue – The more polar the molecule the more stable the axial
conformer, Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.029.
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[1]
ACCEPTED MANUSCRIPT
Synthesis and NMR spectroscopic conformational analysis of
benzoic acid esters of mono- and 1,4-dihydroxycyclohexane, 4-
hydroxycyclohexanone and the -ene analogue − the more polar the
molecule the more stable the axial conformer
Erich Kleinpeter,* Peter Werner, Torsten Linker
Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam
(Golm), Germany
Corresponding author. Tel. +49-331-977-5210; fax: +49-331-977-5064;
e-mail address: ekleinp@uni-potsdam.de (E. Kleinpeter).
A B S T R A C T
para-Substituted benzoic acid esters of cyclohexanol, 1,4-dihydroxycyclohexane, 4-hydroxy
cyclohexanone and of the corresponding exo-methylene derivative were synthesized and the
conformational equilibria of the cyclohexane skeleton studied by low temperature 1H and 13C
NMR spectroscopy. The geometry optimized structures of the axial/equatorial chair
conformers were computed at the DFT level of theory. Only one preferred conformation of
the ester group was obtained for both the axial and the equatorial conformer, respectively.
The content of the axial conformer increases with growing polarity of the 6-membered ring
moiety; hereby, in addition, the effect of sp2 hybridization/polarity of C(4)=O/C(4)=CH2 on
the present conformational equilibria is critically evaluated. Another dynamic process could
be studied, for the first time in this kind of compounds.
Keywords: Conformational analysis; A-Values of COOAr on cyclohexane; Benzoic acid
esters; Dynamic NMR; DFT calculations.

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1. Introduction
Previously, the ester analogues (CR3−CO−) of cyclohexanol, 1,4-
dihydroxycyclohexane and 4-hydroxycyclohexanone [CR3 = Me, Et, i-Pr, t-Bu, CH2F,
CHnCl(Br)n-1] have been synthesized and the conformational equilibria of the cyclohexane
moiety determined by low temperature NMR spectroscopy.1-3 The axial/equatorial position of
the substituent −C(O)OCR3 on the cyclohexyl moiety proved to be an interplay of
hyperconjugation and steric bulk of the substituent.1-3 In addition, the polarity of the
cyclohexyl rest could be identified as another influence on present conformational equilibria
which stabilizes the axial conformation of the CR3 substituent by a certain amount.3,4
The corresponding substituted benzoic acid esters of cyclohexanol, 1,4-
dihydroxycyclohexane and 4-hydroxycyclohexanone, respectively, have not been synthesized
yet and studied adequately with respect to the conformational equilibria. In addition to the
former studies,1-5 the effect of substituents at the aromatic moiety can be investigated with
regard to their effect on the conformation of the cyclohexane ring. First studies on the
influence of p-substitution were relevant and the interplay of these electronic substituent
effects with the polarity influence of the cyclohexyl rest could further clear up the topic. In
addition, the aromatic substituent on cyclohexane could increase the coalescence temperature
of the six-membered ring interconversion of the 4-hydroxycyclohexanone esters by transition
state stabilization;6 these compounds have barriers to six-membered ring interconversion of
only 5 to 6 kcal/mol and cannot be readily studied by low temperature dynamic NMR
spectroscopy.3
2. Results
2.1 Syntheses
The cyclohexyl esters 1-7 and the diesters 8-9 (cf. Scheme 1) could be conventionally
synthesized from cyclohexanol and 1,4-dihydroxycyclohexane, respectively, and the
corresponding benzoic acid chlorides; all mono-esters 1-7 and the di-esters 8-9 were purified
by column chromatography and could be isolated as analytically pure crystals (cf. Scheme 1).
Di-esters 10-14 could not be isolated in analytically pure form.
The cyclohexanone esters 15-17 were synthesized from 1,4-dihydroxycyclohexane in
high yield in two steps: Selective oxidation of one hydroxy group by Jones reagent afforded
4-hydroxycyclohexanone in 75 % yield.7 This intermediate and the final esters 15-17 are quite

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labile; thus, esterification with the various benzoic acid chlorides required mild conditions.
After 4 hours reaction time in dichloromethane/pyridine at 45° C the crude mixtures were
washed, the solvent removed and purified by column chromatography; three esters 15-17
could be isolated as analytically pure crystals in good yields (cf. Scheme 1). Cyclohexanone
esters 18-21 could not be isolated in analytically pure form.
The synthesis of the exo-methylene ester 22 was accomplished by Wittig reaction8 of
the cyclohexanone ester 17 in 92% yield. Isolation of the analytically pure product on neutral
aluminum oxide was important (cf. Experimental section), due to the instability of the alkene
and possible binding to silica gel.
O
X = Br(1), Me(2), Cl(3), I(4)
NMe2(5), NO2(6), OMe(7)
O
O
O
X
X
X
X
O
O
O
O
O
X = Me(8), Cl (9), NO2(10), Br(11)
I(12), NMe2(13), OMe(14)
X = NO2(15), Me(16), Cl(17), I(18)
NMe2(19), Br(20), OMe(21)
H2C
O
O
22
Cl
Scheme 1. Compounds studied.
2.2 Theoretical calculations
The geometries of cyclohexyl mono- (1−7), di-esters (8−14), the cyclohexanone
esters (15–21) and the corresponding exo-methylene analogue 22 were fully optimized using
the Gaussian099 program employing ab initio calculations at the B3LYP/6-311G(d,p) level of
theory.10,11 The self-consisted reaction field (SCRF) method and the Integral Equation
Formalism using Polarized Continuum Model (IEFPCM)12 were used at the B3LYP/6-
311G(d,p) level of theory to consider the solvent; chloroform was used in the calculations.

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The chemical shifts were calculated using the gauge-including atomic orbital (GIAO)
method;12 at the B3LYP/6-311(d,p) level of theory,13 by subtracting the shieldings of the
protons and carbon atoms from tetramethylsilane (TMS) used as a reference and calculated at
the same level of theory. The 3D structures were visualized using SYBYL7.3 molecular
modelling software.14
In the molecules 1–7 internal rotation around the C(4)–O and C(=O)−CX3 bonds (cf.
Scheme 1) can generate stable conformations of different energy. A number of minima were
located on the energy hypersurface and only two conformations each were found to be
significant for describing the equatorial and the axial conformers, those labelled syn and anti
in Fig. 1. The anti conformer proved to be more stable than the syn analogue by ca. 10
kcal/mol. The same is true for the di-esters 8−14, the cyclohexanone esters 15−21 and the
exo-methylene analogue 22. Thus, only the preponderant anti conformations of both the
equatorial (a) and the axial conformers (c) of 1–22 were considered further.
As measure for the quality of the computed structures of 1−22, the proton chemical
shifts of the latter compounds (cf. Experimental section) have been correlated with the
corresponding computed δ-values; the regression coefficient of 0.99 proves an excellent
correlation and hereby completely reliable structures to be discussed with respect to
conformational items.

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(a)
(b)
(c)
(d)
Figure 1. Preferred conformations syn/anti concerning C(4)–O and O–C(=O)CX3 bonds of
the equatorial (a,b) and axial (c,d) conformers of p-bromo-benzoic acid ester of cyclohexanol
(4).
The relevant information concerning the conformational equilibria of 1−22 is the free
energy difference between the corresponding axial/equatorial conformers (in case of 8−14 of
the axial,axial/equatorial,equatorial conformers) in CDCl3 as solvent; these values are
collected in Table 1.
Table 1. Energy differences (kcal/mol) between axial/equatorial conformers of 1−7, 15−21,
22 and of the axial,axial/equatorial,equatorial conformers of 8−14 in CDCl3 as solvent as
computed at the DFT B3LYP/6−311G* level of theory.
___________________________________________________________________________
mono-esters
di-esters
cyclohexanone
esters
exo-methylene
ester
___________________________________________________________________________
1
2
3
4
5
6
7
0.80
0.79
0.78
0.91
0.79
0.76
0.83
8
9
0.73
0.71
0.74
0.74
1.02
0.82
0.78
15
16
17
18
19
20
21
0.00
0.08
0.03
0.08
0.09
0.02
0.02
22
0.38
10
11
12
13
14
__________________________________________________________________________

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2.3 Dynamic NMR studies
To begin with mono- (1−7) and di-esters (8−9) the six-membered ring interconversion,
which is fast at ambient temperature, could be readily frozen at lower temperatures; at 173 K
the different signals of O-CH protons of the corresponding axial/equatorial conformers are
completely resolved and sharp enough to be quantified. The two signals of axial/equatorial
conformers could be differentiated by their signal widths due to the different size of Jax,ax (ca.
12 Hz) and Jeq,eq and Jax,eq both ca. 3 Hz only; variable temperature spectra of O-CH protons
for the mono-ester 3 and di-ester 9 are given in Fig. 2 and 3, respectively. In Fig. 3 the
1
corresponding H NMR spectrum of the di-ester 9 at 173 K is remarkable. The readily
assignable O-CH proton signals are clearly visible; because two isomers of the di-esters 8−9
are synthetically obtained, two sets of signals can be differentiated. The larger set (at 5.04 and
5.26 ppm) belongs to the cis-isomer − O-CH signals of the axial proton and the corresponding
equatorial proton at the ratio of 1:1 − the smaller set (at 4.98 and 4.37 ppm, respectively)
belongs to the trans isomer (with the ax,ax and eq,eq conformers in equilibrium). The ratio of
the latter signals (as in case of the mono-esters) was measured and is the initial information,
the equilibrium constant −K = [ax,ax]/[eq,eq] for the calculation of present conformational
equilibria (−ꢀG° = RT ln K). The same procedure could be applied for the exo-methylene
ester 22 but not for the cyclohexanone esters 15−17.
Figure 2. 1H NMR Spectra of O-CH proton of the mono-ester 3 at various temperatures.

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Figure 3. 1H NMR Spectra of O-CH proton of the di-ester 9 at various temperatures.
In the latter case, the coalescence temperature of the six-membered ring
interconversion Tc/K proves to be too low to be even studied with the local probe head, which
is good enough down to 98 K,3 even when studying the corresponding 13C NMR spectra (in a
13
freon mixture which is at 98 K still liquid for sufficient signal resolution).3 In case of C
NMR spectra, due to the multiple elongation of the resonance range, sufficiently raised Tc/K
values can be expected6 (cf. Fig. 4), however, not high enough to be studied with the local
dynamic NMR equipment.3

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Figure 4. 13C NMR Spectra of the O-CH carbon (at 68.6 ppm) of the cyclohexanone ester 17
at various temperatures.
Thus, direct information about the conformational equilibria of 15−17 is not available
by dynamic NMR spectroscopy, at least with the present equipment. The 13C signal of C(4)H
proves to be very near to Tc/K (cf. Fig. 4), but not yet decoalesced to extract quantitatively the
conformational equilibrium. However, indirect conformational information is accessible from
the width of the O-CH proton signal at 1/12 signal height ꢀν(1/12)/Hz; in this position the
remarkably different and discriminating vicinal H,H coupling constant are adequately
respected and the data thus obtained sufficiently visualize the position of present
conformational equilibria.6 As references the values of the mono-ester 3 at 173 K were
employed [ꢀν(1/12-axial) = 16 Hz and ꢀν(1/12-equatorial) = 30 Hz]; with the experimental
value for cyclohexanone ester 17 at 273 K [ꢀν(1/12 = 19 Hz), K = 3.7 and −ꢀG° = −0.71
kcal/mol] with heavy preference of the axial conformer and this in opposite to mono- and di-
esters.
Finally, the 1H NMR spectrum of the exo-methylene analogue 22 could be analyzed at
103 K: the equilibrium constant K = 2.17 from [0.647]/[0.297] and −ꢀG° = 0.17 kcal/mol at
103 K, still preferring the equatorial conformer (cf. Fig. 5). The dynamic NMR results have
been collected in Table 1.

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Table 2. Conformational equilibria (−ꢀG°/kcal/mol) of mono-esters (1−7), di-esters (8, 9)
cyclohexanone ester 17 and the exo-methylene analogue 22.
___________________________________________________________________________
mono-esters
di-esters
cyclohexanone ester exo-methylene ester
___________________________________________________________________________
1
2
3
4
5
6
7
0.58
0.53
0.53
0.57
0.58
0.57
0.47
8
9
0.23
0.23
17
−0.71
22
0.17
__________________________________________________________________________
When carefully studying the dynamic 13C NMR spectra of the cyclohexanone ester 17,
another dynamic process could observed unexpectedly (cf. Fig. 6). At 123 K the signals of the
two ortho/meta CH carbon atoms of the aromatic moiety start to get broadened and are
completely decoalesced at 103 K, the lowest temperature obtained. The basic dynamic
process can be analyzed:
Tc/K ꢀν/Hz
118 90
kc
ꢀGc#/kcal/mol at Tc
(ortho) =CH−
(meta) =CH−
200
150
5.4
5.3
113 67.5
The ratio of the decoalesced signal is 1:1 in both cases and the free energy of activation was
calculated to be 5.35 kcal/mol and can be only the restricted rotation about the OCO−Cipso
bond of the aromatic moiety. This kind of dynamic process was not observed yet and,
obviously, proved to be a combined electronic/steric effect of the 4-aromatic moiety on
cyclohexanone skeleton.

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1
Figure 5. H NMR Spectra of the O-CH proton of the exo-methylene analogue 22 of
cyclohexanone ester 20 at 243 K (above) and at low temperature (112 K), respectively.
13
Figure 6. C NMR Spectra of the O-CH carbon of the cyclohexanone ester 17 at various
temperatures.

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3. Discussion
The axial conformer in the mono-esters (and the axial/axial conformer in the di-esters)
remarkably contributed to the conformational equilibrium but the equatorial (and
equatorial/equatorial conformers in 8−14) are preferred. There is no clear trend in the
dependence of the position of the conformational equilibria (−ꢀG°) on the substituent at the
aromatic moiety, and this in both the experimental and the computed values, respectively (cf.
Tables 1 and 2). The portion of the axial (axial/axial) conformers prove to be less in the
mono-esters (−ꢀG° ca. 0.5 to 0.6 kcal/mol) than in the di-esters (−ꢀG° = 0.23 kcal/mol); this
is experimentally observed but not confirmed by the computational results. The reason
therefore is the second ester group in the di-ester molecules which increases the polarity of the
cyclohexane moiety and hereby the content of the axial conformer.3
The preference of the equatorial conformer in 1−7 is impressively confirmed by the
results of the X-ray analysis: from 1, 6 and 7 crystals could be obtained which appear in
equatorial conformation (cf. Fig. 7). The same can be concluded for the di-esters, however,
adequate crystals for 8−14 could not be obtained. Differently behave the cyclohexanone
esters; from the p-chloro ester 17 crystals could be provided and the X-ray analysis confirmed
the different preferred conformation, the axial conformer, for this group of compounds; the
solid state structure of 17 is included into Fig. 7 as well.

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(a)
(b)
(d)
(c)
Figure 7. X-ray structures of the mono-ester 1(a), 6(b), 7(c) and of the cyclohexanone ester
17 (d).
The immense increase of the axial conformer in the conformational equilibria of the
cyclohexanone ester 15−21 (17: −ꢀG° = −0.71 kcal/mol; the computation results in about
similar portions of axial/equatoral conformers at the conformational equilibrium) can have
two reasons, (i) the increasing polarity of the cyclohexanone moiety due to the additional
carbonyl group and (ii) the simultaneous sp2 hybridization of C(4). The latter effect proves to
be responsible for the flattening of the saturated six-membered ring chair conformation which
is responsible for the ground state destabilization (with respect to the transition state) of the
dynamic ring interconversion process lowering the coalescene temperature down to <100 K,
the reason why this dynamic process could not be frozen in case of the studied cyclohexanone
esters. The effect of the position on the corresponding conformational equilibria [heavily
preferring the axial conformer (vice infra)], in similar compounds have been attributed to the
polar influence of the cyclohexanone skeleton.3 The same reason could be important for the
position of the conformational equilibria of the present cyclohexanone esters 15−21.
However, this effect on the position of the conformational equilibria of 15−21 can be
understood as the combined influence of both sp2 hybridization and the polarity of the

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carbonyl group on the other hand. In order to separate the two effects, the exo-methylene
analog 22 of the cyclohexanone ester 17 has been synthesized; X-ray compatible crystals
could not be isolated but the liquid dynamic NMR study is really informative (cf. Fig. 5 and
Table 2): The portion of the equatorial conformer in 22 is lowered compared with the mono-
esters, but far from that in the cyclohexanone esters. Thus, sp2 hybridization of C(4) has some
influence on the increase of the portion of the axial conformer: the corresponding effect
proves to be ca. 0.3 to 0.4 kcal/mol but with the corresponding effect of the carbonyl group in
17 (> 1 kcal/mol) remains the (now cleanly separated) 0.6 to 0.7 kcal/mol impact which
comes from the polarity influence of the carbonyl group.
The effect of sp2 hybridization on the conformational equilibrium of the mono-esters is
obviously of about the same size as the polarity effect of the second ester group in the
corresponding di-esters (cf. Table 2).
4. Conclusions
The conformational equilibria of a collection of para-substituted benzoic acid esters of
cyclohexanol, 1,4-dihydroxycyclohexane, 4-hydroxycyclohexanone 1−21 and of the exo-
methylene analog 22 of the para-chloro ester of cyclohexanone 17 have been studied by
quantum chemistry and characteristic examples of all four groups of compounds also
experimentally by low temperature dynamic NMR spectroscopy. Free energy differences
between axial and equatorial conformers [K = [eq]/[ax]; −ꢀG° = RT lnK] have been
determined: the equatorial conformer proved to be the preferred one in mono-esters (1−7) >
di-esters (8−14) > exo-methylene ester (22), only in the cyclohexanone ester 15−21 the
portion of the axial conformer increases to be the strongly preferred conformer:
(i) Substitution on the para-position of the aromatic moiety is without influence on the
position of the conformational equilibrium.
(ii) The axial,axial conformer in the di-esters is 0.3 to 0.4 kcal/mol more stable than
the axial conformer in the conformational equilibria of the mono-esters due to the increased
polarity of the cyclohexyl moiety.
(iii) Similarly, the axial conformer in the exo-methylene ester is of about the same
larger stability than the axial,axial conformer in the conformational equilibrium of the di-
esters. Thus, the effect of C(4) sp2 hybridization (mainly due to flattening of the cyclohexane
skeleton) on the position of the conformational equilibrium of 22 agrees with the polarity
effect of the ester-substituted cyclohexane skeleton in the diesters.

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(iv) The reason for the high preference of the axial conformer in the cyclohexanone
esters proves to be (in addition to C(4) sp2 hybridization − vide supra) the polarity of the
cyclohexanone moiety (ca. 0.9 kcal/mol).
(v) In addition to the elucidation of conformational properties of the present
cyclohexane esters, in the cyclohexanone esters, the restricted rotation about the OCO−Cipso
bond of the aromatic moiety to be 5.35 kcal/mol (in 17) could be identified. This usually free
rotation gets restricted due to the combined electronic effect of the para-chloro substituent
and the steric effect of the whole benzoic acid ester moiety.
5. Experimental section
5.1 General
All solvents and commercially available chemicals were used as purchased or were
purified. The synthesis for the cyclohexanone esters were performed under argon atmosphere
with the use of standard Schlenk techniques. For the column chromatography silica gel
(Kieselgel 60) or neutral aluminum oxide was used. TLC was performed on silica gel sheets
(F 254). The NMR spectra were recorded with a Bruker spectrometer AVANCE 300. CD2Cl2
(≥ 99.5 %, ARMAR GmbH, Leipzig, Germany) and CDCl3 (≥ 99.5 %, ARMAR GmbH,
Leipzig, Germany) were used as solvent and TMS as internal standard, the chemical shifts,
related to CH2Cl2 [δ (1H) 5.31 ppm, δ (13C) 53.7 ppm] and CHCl3 [δ (1H) 7.26 ppm, δ (13C)
1
13
77.0 ppm] are given in parts per million downfield to TMS. Low temperature H and C
NMR spectra were performed on the Bruker AVANCE III 600 spectrometer in the solvent
mixture of CD2Cl2 (≥ 99.5 %, ARMAR GmbH, Leipzig, Germany) : CHFCl2 : CHCl2F = 1 : 1
: 3 (the latter two from abcr GmbH, Karlsruhe, Germany). IR spectra were performed on a
Perkin-Elmer 1600 FT-IR spectrometer (PerkinElmer LAS GmbH, Rodgau, Germany). For
the elementary analysis an ELEMENTAR vario EL analysator (Elementar Analysensysteme
GmbH, Langenselbold, Germany) was used. The X-ray analyses were performed on an
Imaging Plate Diffraction System, IPDS-2 (Stoe & Cie GmbH, Darmstadt, Germany).

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Ester
1
R
Yield (%)
Br
67
71
73
61
64
83
71
58
61
70
65
67
92
mono-ester
mono-ester
mono-ester
mono-ester
mono-ester
mono-ester
mono-ester
di-ester
2
CH3
Cl
3
4
I
5
N(CH3)2
NO2
OCH3
CH3
Cl
6
7
8
9
di-ester
15
16
17
22
NO2
CH3
Cl
cyclohexanone
cyclohexanone
cyclohexanone
exo-methylene
Cl
5.2 Synthesis of mono-esters 1−7.
1.0 g of cyclohexanol (10 mmol) was dissolved in a mixture of 150 mL dried
dichloromethane and 1.61 mL pyridine (20 mmol) at 25 °C in a 250 mL one-necked round-
bottom flask, the corresponding acid chloride (1.1 equiv.) was added and the solution stirred
and heated up to 45 °C. The reaction was performed under stirring and reflux for 4 hours at
45 °C. Subsequently, the reaction mixture was cooled down to room temperature and was
extracted three times with a HCl/water solution (2.3 mL HCl (1 N), 100 mL deionized water).
The organic phase was isolated, dried with sodium sulfate and filtered. The solvent was
removed under vacuum and the esters purified by column chromatography (ethyl
acetate/hexane 4:1); esters 1-3 and 5-7 were isolated as crystallized solids. Only ester 4 was
isolated as a yellowish oil.
1
5.2.1. Cyclohexyl-4-bromobenzoate (1) Rf = 0.73 (hexane/ethyl acetate 10:1); H NMR (300
MHz, CD2Cl2, ppm) δ = 7.90 (d, 2H, 11-H, 15-H), 7.56 (d, 2H, 12-H, 14-H), 5.01 (sept, 1H,
4-H), 1.89 (m, 2H, 3-H, 5-H), 1.74 (m, 2H, 3-H, 5-H), 1.59-1.29 (m, 6H, 1-H, 2-H, 6-H); 13C-
NMR (75 MHz, CD2Cl2, ppm) δ = 165.4 (C-8), 131.7 (C-12, C-14), 131.2 (C-11, C-15),
130.1 (C-10), 127.86 (C-13), 73.5 (C-4), 31.7 (C-3, C-5), 25.6 (C-1), 23.8 (C-2, C-6). MS
(ESI): m/z calculated for C13H15O2Br: [M+H]+: 282.0255; found: 282.0245.

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1
5.2.2. Cyclohexyl-4-methylbenzoate (2) Rf = 0.71 (hexane/ethyl acetate 10:1); H-NMR
(300 MHz, CD2Cl2, ppm) δ = 7.84 (d, 2H, 11-H, 15-H), 7.12 (d, 2H, 12-H, 14-H), 4.92 (sept,
1H, 4-H), 2.29 (s, 3H, 16-H), 1.82 (m, 2H, 3-H, 5-H), 1.65 (m, 2H, 3-H, 5-H), 1.51-1.21 (m,
13
6H, 1-H, 2-H, 6-H); C-NMR (75 MHz, CD2Cl2, ppm) δ = 166.1 (C-8), 143.3 (C-12, C-14),
129.6 (C-11, C-15), 129.0 (C-10), 128.46 (C-13), 72.8 (C-4), 31.8 (C-3, C-5), 25.6 (C-3, C-5),
23.8 (C-1), 21.7 (C-16). MS (ESI): m/z calculated for C14H18O2: [M+H]+: 218.1307; found:
218.1309.
5.2.3. Cyclohexyl-4-chlorobenzoate (3) Rf = 0.74 (hexane/ethyl acetate 10:1);1H-NMR (300
MHz, CD2Cl2, ppm) δ = 7.97 (d, 2H, 11-H, 15-H), 7.4 (d, 2H, 12-H, 14-H), 5.01 (sept, 1H, 4-
13
H), 1.98 (m, 2H, 3-H, 5-H), 1.71 (m, 2H, 3-H, 5-H), 1.64-1.39 (m, 6H, 1-H, 2-H, 6-H); C-
NMR (75 MHz, CD2Cl2, ppm) δ = 165.3 (C-8), 139.24 (C-12, C-14), 131.1 (C-11, C-15),
129.7 (C-10), 128.75 (C-13), 73.57 (C-4), 31.7 (C-3, C-5), 25.6 (C-1), 23.82 (C-2, C-6). MS
(ESI): m/z calculated for C13H15O2Cl: [M+H]+: 238.0761; found: 238.0765.
1
5.2.4. Cyclohexyl-4-iodobenzoate (4) Rf = 0.65 (hexane/ethyl acetate 10:1); H-NMR (300
MHz, CD2Cl2, ppm) δ = 7.78 (d, 2H, 11-H, 15-H), 7.73 (d, 2H, 12-H, 14-H), 5.00 (sept, 1H,
4-H), 1.98 (m, 2H, 3-H, 5-H), 1.81 (m, 2H, 3-H, 5-H), 1.67-1.46 (m, 6H, 1-H, 2-H, 6-H); 13C-
NMR (75 MHz, CD2Cl2, ppm) δ = 165.5 (C-8), 137.72 (C-12, C-14), 131.1 (C-11, C-15),
130.6 (C-10), 100.43 (C-13), 73.5 (C-4), 31.7 (C-3, C-5), 25.6 (C-1), 23.7 (C-2, C-6). IR
(film): ν = 2953, 2857, 1716, 1586, 1280, 1055, 753 cm−1. elemental analysis calculated (%)
for C13H15O2I (329.55): C 47.3, H 4.5; found: C 47.66, H 4.3. MS (ESI): m/z calculated for
C13H15O2I: [M+H]+: 330.0117; found: 330.0110.
1
5.2.5. Cyclohexyl-4-(dimethylamino)benzoate (5); H-NMR (300 MHz, CD2Cl2, ppm)
δ = 7.85 (d, 2H, 11-H, 15-H), 6.57 (d, 2H, 12-H, 14-H), 4.90 (sept, 1H, 4-H), 2.96 (s, 6H, 16-
13
H), 1.82 (m, 2H, 3-H, 5-H), 1.68 (m, 2H, 3-H, 5-H), 1.67-1.21 (m, 6H, 1-H, 2-H, 6-H); C-
NMR (75 MHz, CD2Cl2, ppm) δ = 166.6 (C-8), 153.4 (C-13), 131.35 (C-12, C-14), 118.1 (C-
10), 110.9 (C-11, C-15), 128.75 (C-13), 72.1 (C-4), 40.2 (C-3, C-5), 31.9 (C-16), 25.8 (C-1),
23.9 (C-2, C-6). IR (solid): ν = 2932, 2855, 1688, 1601, 1314, 1179, 1037, 770 cm−1. MS
(ESI): m/z calculated for C15H21O2N: [M+H]+: 247.1572; found: 247.1562.

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1
5.2.6. Cyclohexyl-4-nitrobenzoate (6) Rf = 0.69 (hexane/ethyl acetate 10:1); H-NMR (300
MHz, CD2Cl2, ppm) δ = 8.28 (d, 2H, 11-H, 15-H), 8.20 (d, 2H, 12-H, 14-H), 5.06 (sept, 1H,
4-H), 2.02 (m, 2H, 3-H, 5-H), 1.87 (m, 2H, 3-H, 5-H), 1.67-1.47 (m, 6H, 1-H, 2-H, 6-H); 13C-
NMR (75 MHz, CD2Cl2, ppm) δ = 164.2 (C-8), 149.5 (C-10), 136.5 (C-12, C-14), 130.8 (C-
13), 123.6 (C-11, C-15), 74.6 (C-4), 31.7 (C-3, C-5), 25.5 (C-1), 23.8 (C-2, C-6). MS (ESI):
m/z calculated for C13H15O4N: [M+H]+: 249.1001; found: 249.1004.
5.2.7. Cyclohexyl-4-methoxybenzoate (7) Rf = 0.56 (hexane/ethyl acetate 10:1); 1H-NMR (300
MHz, CD2Cl2, ppm) δ = 7.99 (d, 2H, 11-H, 15-H), 6.89 (d, 2H, 12-H, 14-H), 4.98 (sept, 1H,
4-H), 3.83 (s, 3H, 16-H), 1.91 (m, 2H, 3-H, 5-H), 1.83 (m, 2H, 3-H, 5-H), 1.65-1.39 (m, 6H,
13
1-H, 2-H, 6-H); C-NMR (75 MHz, CD2Cl2, ppm) δ = 165.8 (C-8), 163.3 (C-10), 131.6 (C-
12, C-14), 123.6 (C-13), 113.6 (C-11, C-15), 72.7 (C-4), 55.5 (C-16), 31.8 (C-3, C-5), 25.6
(C-1), 23.8 (C-2, C-6). MS (ESI): m/z calculated for C14H18O3: [M+H]+: 234.1256; found:
234.1248.
5.3. Synthesis of di-esters 8−15.
1.74 g of 1,4-cyclohexanediol (15 mmol) was dissolved in 100 mL of dried
dichloromethane at room temperature in a 250 mL one-necked round-bottom flask. 4.8 mL
pyridine (60 mmol) and the corresponding acid chloride (2.2 equiv) were added and
dissolved. The reaction mixture was stirred and heated up to 45 °C. The reaction was
performed under stirring and reflux for 4 hours at 45 °C. Afterwards, the solution was cooled
down to room temperature and extracted three times with a HCl/water solution (2.3 mL HCl
(1 N), 100 mL deionized water). The mixture was dried by adding sodium sulfate and filtering
afterwards. The solvent was removed under vacuum and the esters purified by column
chromatography (methyl-tert-butyl ether/hexane 2:5); both the cis- and the trans-diesters as
mixtures were obtained (cf. Fig. 3). Only the esters 8-9 could be isolated as crystalline solids.
1
5.3.1. Cyclohexane-1,4-diyl bis(4-methylbenzoate) (8); H-NMR (300 MHz, CD2Cl2, ppm)
δ = 7.98 (d, 4H, 11-H, 15-H, 21-H, 25-H), 7.26 (d, 4H, 12-H, 14-H, 22-H, 24-H), 5.11 (sept,
2H, 1-H, 4-H), 2.4 (s, 6H, 16-H, 26-H), 2.16-1.6 (m, 8H, 2-H, 3-H, 4-H, 6-H); 13C-NMR (75
MHz, CD2Cl2, ppm) δ = 166.4 (C-8, C-18), 144.2 (C-13, C-23), 131.1 (C-10, C-20), 130.1 (C-
11, C-15, C-21, C-25), 129.6 (C-12, C-14, C22, C-24), 71.6 (C-1, C-4), 28,3 (C-2,C-3, C-5,
C-6), 21,9 (C-16, C-26). IR (solid): ν = 2954, 2926, 2855, 1719, 1360, 1270, 1102, 754 cm−1.
MS (ESI): m/z calculated for C22H24O4: [M+H]+: 352.1675; found: 352.1654.

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1
5.3.2. Cyclohexane-1,4-diyl bis(4-chlorobenzoate) (9); H-NMR (300 MHz, CD2Cl2, ppm)
δ = 7.93 (d, 4H, 11-H, 15-H, 21-H, 25-H), 7.35 (d, 4H, 12-H, 14-H, 22-H, 24-H), 5.07 (sept,
2H, 1-H, 4-H), 2.1-1.5 (m, 8H, 2-H, 3-H, 4-H, 6-H); 13C-NMR (75 MHz, CD2Cl2, ppm)
δ = 165.3 (C-8, C-18), 139.6 (C-13, C-23), 131.1 (C-11, C-15, C-21, C-25), 129.3 (C-10, C-
20), 129.2 (C-12, C-14, C22, C-24), 71.8 (C-1, C-4), 28.0 (C-2,C-3, C-5, C-6). IR (solid):
ν = 3056, 2945, 2869, 1704, 1612, 1273, 1034, 752 cm−1. MS (ESI): m/z calculated for
C20H18O4Cl2: [M+H]+: 392.0582; found: 392.0561.
5.4. Synthesis of cyclohexanone esters 15−21.
In a precursor step, 1.5 mL of 4-hydroxylcyclohexanone (15 mmol) were synthesized7
and dissolved directly under argon atmosphere in 150 mL dried dichloromethane in a 250 mL
one-necked round-bottom flask. Afterwards, 2.4 mL of pyridine (30 mmol) and the
corresponding acid chloride (1.1 equiv) were added. The reaction mixture was stirred and
heated up to 45 °C. The esterification was performed under stirring for 4 hours at 45 °C. After
cooling down to room temperature the solution was extracted three times with a HCl/water
solution (2.3 mL HCl (1 N), 100 mL deionized water). The organic phase was dried over
sodium sulfate and filtered. The solvent was removed under vacuum and the esters purified by
column chromatography (methyl-tert-butyl ether/hexane 8:1). Only the cyclohexanone esters
15-17 could be isolated as crystalline solids.
1
5.4.1. 4-Oxo-cyclohexyl 4-nitrobenzoate (15) Rf = 0.77 (hexane/dichlormethane 1:4); H-
NMR (300 MHz, CD2Cl2, ppm) δ = 8.25 (d, 2H, 11-H, 15-H), 8.15 (d, 2H, 12-H, 14-H), 5.41
(sept, 1H, 4-H), 2.55 (m, 2H, 2-H, 6-H), 2.4 (m, 2H, 3-H, 5-H), 2.31-2.16 (m, 4H, 3-H, 5-H,
13
2-H, 6-H); C-NMR (75 MHz, CD2Cl2, ppm) δ = 209.2 (C-1), 164.1 (C-8), 150.9 (C-13),
135.7 (C-10), 130.7 (C-11, C-15), 123.7 (C-12, C-14), 70.5 (C-4), 37.2 (C-2, C-6), 30.4 (C-3,
C-5). IR (solid): ν = 3107, 2956, 1720, 1524, 1274, 1119, 874 cm−1. elemental analysis
calculated (%) for C13H13O5N (262.91): C 59.3, H 4.9, N 5.3; found: C 59.4, H 4.96, N 5.1.
MS (ESI): m/z calculated for C13H13O5N: [M+H]+: 263.0794; found: 263.0780.
1
5.4.2. 4-Oxo-cyclohexyl 4-methylbenzoate (16) Rf = 0.61 (hexane/MTBE 2:5); H-NMR (300
MHz, CD2Cl2, ppm) δ = 7.87 (d, 2H, 11-H, 15-H), 7.18 (d, 2H, 12-H, 14-H), 5.34 (sept, 1H,
4-H), 2.58 (m, 2H, 3-H, 5-H), 2.34 (m, 2H, 2-H, 6-H), 2.3-2.0 (m, 4H, 3-H, 5-H, 2-H, 6-H);

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13C-NMR (75 MHz, CD2Cl2, ppm) δ = 210.1 (C-1), 166.1 (C-8), 144.2 (C-13), 130.5 (C-12,
C-14), 129.5 (C-11, C-15), 127.8 (C-10), 69.1 (C-4), 37.6 (C-2, C-6), 30.9 (C-3, C-5), 21.2
(C-16). IR (solid): ν = 2953, 2898, 1715, 1612, 1275, 1152, 754 cm−1. MS (ESI): m/z
calculated for C14H16O3: [M+H]+: 232.1099; found: 232.1103.
1
5.4.3. 4-Oxo-cyclohexyl 4-chlorobenzoate (17) Rf = 0.88 (hexane/MTBE 2:5); H-NMR (300
MHz, CD2Cl2, ppm) δ = 7.92 (d, 2H, 11-H, 15-H), 7.37 (d, 2H, 12-H, 14-H), 5.31 (sept, 1H,
4-H), 2.49 (m, 2H, 3-H, 5-H), 2.31 (m, 2H, 2-H, 6-H), 2.2-2.0 (m, 4H, 3-H, 5-H, 2-H, 6-H);
13C-NMR (75 MHz, CD2Cl2, ppm) δ = 208.9 (C-1) 164.8 (C-8), 139.3 (C-13), 130.9 (C-12,
C-14), 129.3 (C-10), 128.95 (C-11, C-15), 69.6 (C-4), 37.2 (C-2, C-6), 30.4 (C-3, C-5). IR
(solid): ν = 2953, 2853, 1716, 1592, 1268, 1118, 909 cm−1. MS (ESI): m/z calculated for
C13H13O3Cl: [M+H]+: 252.0553; found: 252.0557.
5.5. Synthesis of the exo-methylene analog 22.
In analogy to ethyl exo-methylene cyclohexane,15 a 2M solution of butyl lithium in
hexane (5 mL, 10.0 mmol) was mixed with 100 mL of anhydrous diethyl ether under nitrogen
atmosphere at room temperature. Solid triphenylmethylphosphonium bromide (3.60 g, 10.0
mmol) was added in small portions within 30 min at this temperature and the mixture was
stirred for 4 h. A solution of cyclohexanone ester 17 (2.52 g, 10.0 mmol) in 10 mL of
anhydrous diethyl ether was added within 2 min and the mixture was stirred for additional 20
h. The mixture was poured onto 100 mL of water, extracted with pentane (3 x 100 mL), and
the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude
product was purified on 50 g of neutral aluminum oxide to afford 2.90 (92%) of the exo-
methylene analog 22 as a colorless liquid in analytically pure form.
5.5.1. 4-Methylene-cyclohexyl 4-chlorobenzoate (22) Rf = 0.17 on aluminum oxide (pentane);
1H NMR (600 MHz, CDCl3 ppm) δ = 7.96 (d, 2H, 11-H, 15-H), 7.38 (d, 2H, 12-H, 14-H),
5.17 (sept, 1H, 4-H), 4.70 (s, 2H, 9-H), 2.40 (m, 2H, 2-H, 6-H), 2.19 (m, 2H, 2-H, 6-H), 1.98
(m, 2H, 3-H, 5-H), 1.76 (m, 2H, 3-H, 5-H); 13C NMR (150 MHz, CDCl3, ppm) δ = 165.1 (C-
8), 147.1 (C-1), 139.3 (C-13), 131.0 (C-11, C-15), 129.3 (C-10), 128.7 (C-12, C-14), 108.5
(C-9), 72.2 (C-4), 32.3 (C-2, C-6), 31.4 (C-3, C-5). IR (film): ν = 2979, 1714, 1594, 1269,
1086, 893 cm−1. elemental analysis calculated (%) for C14H15ClO2 (250.72): C 67.07, H 6.03;
found: C 66.82, H 6.29.

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Acknowledgements
We thank Tobias Krüger for the synthesis, Dr. Matthias Heydenreich und Angela Krtitschka
for the NMR spectroscopic study, and Dr. Andreas Koch for the computation of the
conformational equilibrium of the exo-methylene analog 22.
References and notes
1.
2.
3.
4.
5.
6.
Kleinpeter, E.; Taddei, F.; Wacker, Ph. Chem., A Eur. J. 2003, 9, 1360.
Kleinpeter, E.; Rolla, N.; Koch, A.; Taddei, F. J. Org. Chem. 2006, 71, 4393.
Kleinpeter, E.; Heydenreich, M.; Koch, A.; Linker, T. Tetrahedron 2012, 68, 2363.
Kleinpeter, E.; Thielemann, J. Tetrahedron 2007, 63, 9071.
Kleinpeter, E.; Bölke, U.; Frank, A. Tetrahedron 2008, 64, 10014.
Kleinpeter, E. Adv. Heterocycl. Chem. 2004, 86, 41 − Conformational analysis of
Saturated Heterocyclic Six-Membered Rings.
7.
Seo, J. W.; Comninos, J. S.; Chi, D. Y.; Kim, D. W.; Carlson, K. E.;
Katzenellenbogen, J. A. J. Med. Chem. 2006, 49, 2496; (b) 4-Hydroxycylo-
hexanone in Org. Prep. Proced. Int. 1969, 1, 127.
8.
9.
Wittig, G.; Schoell, U. Organic Syntheses Coll, Vol. 5 1973, 751.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, T. A.; Peralta, Jr. J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers,
E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02,
Gaussian, Inc., Wallingford CT, 2009.
10
Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618.
11.
Hehre, J. W.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; Wiley & Sons: New York, NY, 1986.
12.
13.
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
Becke, A. D.; Density-functional thermochemistry. III. The role of exact exchange, J.
Chem. Phys. 1993, 98, 5648; Lee, C.; Yang, W.; Parr, R. G.; Development of the
Colle-Salvetti correlation-energy formula into a functional of the electron density,
Phys. Rev. B 1988, 37, 785.
14.
15.
SYBYL7.3, Tripos Inc., 1699 South Hanley Road, St. Louis, Missouri 63144, USA,
2007.
Roth, W. R.; Unger, C. Liebigs Ann. 1995, 1361.

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Graphical Abstract:
Synthesis and NMR spectroscopic conformational analysis of benzoic acid esters of
mono- and 1,4-dihydroxycyclohexane, 4-hydroxycyclohexanone and the -ene
analogue−the more polar the molecule the more stable the axial conformer
Erich Kleinpeter,* Peter Werner, Torsten Linker
O-COPh
O-COPh
and
O-COPh
but
H2C
O