The relevant effect of an intramolecular hydrogen bond on the conformational equilibrium of cis-3-methoxycyclohexanol compared to trans-3-methoxycyclohexanol and cis-1,3-dimethoxycyclohexane

Article abstract of DOI:10.1016/j.saa.2004.07.004

¹H NMR data show that an increase in the concentration of cis-3-methoxycyclohexanol (cis-3-MCH) shifts the conformational equilibrium from the 1aa conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the 1ee conformer [X_ee = 44% (at 0.05 mol L^-1) to 59% (at 0.40 mol L^-1), in CCl₄], which forms intermolecular hydrogen bonds (IEHB), as confirmed by IR data. The percentage of 1ee conformer increases with the solvent polarity, from 33% (ΔG_ee-aa = 1.72 kJ mol^-1) in cyclohexane (C₆D₁₂) to 97% (ΔG_ee-aa = -8.41 kJ mol^-1) in DMSO. For trans-3-methoxycyclohexanol (trans-3-MCH), 1ae and 1ea conformers are almost equally present in the studied solvents, 1ae increasing from 41%, in C ₆D₁₂ (ΔG_ae-ea = 0.84 kJ mol ^-1), to 49%, in DMSO (ΔG_ae-ea = 0.13 kJ mol ^-1). A value of 18.4 kJ mol^-1 for the strength of IAHB in cis-3-MCH was obtained, from the theoretical data, through the CBS-4M method.

Full text of DOI:10.1016/j.saa.2004.07.004

Spectrochimica Acta Part A 61 (2005) 1737–1745
The relevant effect of an intramolecular hydrogen bond on the
conformational equilibrium of cis-3-methoxycyclohexanol compared to
trans-3-methoxycyclohexanol and cis-1,3-dimethoxycyclohexane
Paulo R. de Oliveira, Roberto Rittner∗
Physical Organic Chemistry Laboratory, Instituto de Qu´ımica, UNICAMP, Caixa Postal 6154, 13084-971 Campinas, SP, Brazil
Received 21 June 2004; accepted 8 July 2004
Abstract
1H NMR data show that an increase in the concentration of cis-3-methoxycyclohexanol (cis-3-MCH) shifts the conformational equilibrium
from the 1aa conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the 1ee conformer [Xee = 44% (at 0.05 mol L−1) to 59%
(at 0.40 mol L−1), in CCl4], which forms intermolecular hydrogen bonds (IEHB), as confirmed by IR data. The percentage of 1ee conformer
increases with the solvent polarity, from 33% (ꢀGee–aa = 1.72 kJ mol−1) in cyclohexane (C6D12) to 97% (ꢀGee–aa = −8.41 kJ mol−1) in
DMSO. For trans-3-methoxycyclohexanol (trans-3-MCH), 1ae and 1ea conformers are almost equally present in the studied solvents, 1ae
increasing from 41%, in C6D12 (ꢀGae–ea = 0.84 kJ mol−1), to 49%, in DMSO (ꢀGae–ea = 0.13 kJ mol−1). A value of 18.4 kJ mol−1 for the
strength of IAHB in cis-3-MCH was obtained, from the theoretical data, through the CBS-4M method.
© 2004 Elsevier B.V. All rights reserved.
Keywords: Conformational analysis; Theoretical calculations; Intramolecular hydrogen bond; NMR spectroscopy; IR spectroscopy
1. Introduction
will affect their conformational equilibria, and improving
the understanding of the factors that govern the hydrogen
bond strength. Thus, this paper describes: (i) a study of con-
Substituted six-membered rings are useful models
for studies of conformational analysis. Mono- and 1,2-
disubstituted cyclohexanes have been thoroughly studied
[1–5], but publications on 1,3-disubstituted cyclohexanes are
quite scarce [6,7]. Previous workers have shown that the OH
groups of a dihydroxy compound, if sufficiently close to each
other, may form an intramolecular hydrogen bond (IAHB)
[8]. Abraham et al. [9] have also demonstrated, through 1H
NMR and theoretical data, that the strong OH · · · F hydrogen
bond, in trans-2-fluorocyclohexanol, is responsible for the
predominance of an eq–eq conformation of this molecule.
The aim of the present work is to study the behavior of 1,3-
disubstituted cyclohexanes at different concentrations and in
different solvents, giving emphasis to how intermolecular hy-
drogen bonds (IEHB) and intramolecular hydrogen bonds
1
centration effect, by H NMR and IR spectroscopy, on the
conformational equilibrium of cis and trans isomers of 3-
methoxycyclohexanol (3-MCH); (ii) a study of solvent effect,
by 1H NMR, on the conformational equilibrium of cis- and
trans-3-MCH and 1,3-dimethoxycycloexane (1,3-DMCH);
and (iii) a determination of the more stable conformers of
cis- and trans-3-MCH and 1,3-DMCH, and determination of
the IAHB energy for the cis-3-MCH in the gas phase, using
theoretical calculations.
2. Experimental
The IR spectra were recorded on a BOMEM Model 100
FTIR spectrometer, from 0.005, 0.01 and 0.03 mol L−1 solu-
tions of the cis and trans isomer of compound 1, in a NaCl
cell with spacing of 0.5 mm. They were performed with 32
∗
Corresponding author. Tel.: +55 19 3788 3150; fax: +55 19 3788 3023.
E-mail address: rittner@iqm.unicamp.br (R. Rittner).
1386-1425/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2004.07.004

1738
P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
scans and resolution of 2 cm−1. The H NMR spectra, for
the study of solvent and concentration effects, were recorded
on an INOVA 500 spectrometer with probe temperature at
20 ◦C, operating at 499.88 (1H) and 125.70 MHz (13C). Spec-
tra were recorded at concentrations of 0.05 mol L−1 for the
study of solvent effects, and at 0.01–0.40 mol L−1 in CDCl3
and in CCl4 (CCl4/C6D6 9:1, the latter for the deuterium lock)
for the study of concentration effects. In all cases, SiMe4
(TMS) was used as internal reference. The spectral window
ensured a digital resolution of at least 0.04 Hz per point, and
zero-filling helped to further define line shapes. Most FIDs
were processed with Gaussian multiplication, typically gf
= 0.25 and gf = 0.35, for spectral resolution improvement.
cis: H NMR (500 MHz, CDCl3), δ 3.71 (tt, 8.18, 3.95,
1
1
1H), 3.35 (s, 3H), 3.34 (m, 1H), 2.08 (m, 1H), 1.84 (m, 1H),
1.78 (m, 1H), 1.77 (m, 1H), 1.54 (m, 1H), 1.45 (m, 1H), 1.43
(m, 1H), 1.29 (m, 1H). 13C NMR (500 MHz, CDCl3), δ 77.5,
68.4, 56.0, 38.9, 34.2, 30.0, 19.0; C7H14O2, calcd.: 131.1046,
found: 131.1072 (HRMS).
trans: 1H NMR (500 MHz, CDCl3), δ 4.02 (tt, 7.95, 3.87,
1H), 3.59 (tt, 6.04, 3.13, 1H); the remaining signals could
not be attributed because the trans isomer is in conforma-
tional equilibrium at room temperature. 13C NMR (500 MHz,
CDCl3), δ 75.9, 66.8, 55.8, 39.1, 34.2, 29.8, 18.4; C7H14O2,
calcd.: 131.1046, found: 131.1072 (HRMS).
1
The typical conditions for H spectra were: 128 transients,
2.2. cis-1,3-dimethoxycyclohexane (2)
32k data points, pulse width 37o, sweep width ca. 3000 Hz
and acquisition time (AT) ca. 2.7 s; and for 13C NMR spec-
tra: 1024 transients, 32k data points, pulse width 45o, sweep
width ca. 10,000 Hz and AT 1 s. Assignment of the signals in
1H and 13C NMR spectra of compounds 1 and 2 were per-
formed through gCOSY and HSQC experiments. The quan-
tum chemical calculations were made with the Gaussian 98
package. Optimized geometries were computed at the B3LYP
levels of theory, using the 6-311+G** basis sets. The strength
of IAHB were computed by Hartree–Fock (HF) and B3LYP
levels of theory, using the 6-31G** and 6-311+G** basis
sets, and also with the CBS-4M method. The potential en-
ergy surfaces (PES) were obtained at HF and B3LYP levels,
with 6-311+G** as basis sets, by changing the C2 C1 O H
dihedral angle for the 1aa2 rotamer by 10o until completing
360o. For each 10o, the structure obtained was optimized.
The same procedure as described above for 3-
methoxycyclohexanol was used, by changing the proportions
of NaH and CH3I to 100.0 and 86.2 mmol, respectively. The
product was distilled to give cis- and trans-1,3-DMCH in
a ratio of 91:9 (4.3 g, 69%); bp 96–100 oC/27 mmHg. The
cis-1,3-DMCH was also purified through a chromatography
column using hexane as solvent.
cis: 1H NMR (500 MHz, CDCl3), δ 3.35 (s, 3H), 3.12 (tt,
10.75, 4.02, 2H), 2.45 (m, 1H), 2.02 (m, 2H), 1.82 (m, 1H),
1.16 (m, 1H), 1.11 (m, 3H). 13C NMR (500 MHz, CDCl3),
δ 77.9, 55.8, 38.1, 31.3, 20.7; C8H16O2, calcd.: 145.1197,
found: 145.1228 (HRMS).
3. Results and discussion
3.1. Concentration effects
2.1. cis- and trans-3-methoxycyclohexanol (1)
It was observed that the coupling constant values of H-1
and H-3 hydrogens for cis-3-MCH (Fig. 1) changed with the
increase in solvent polarity, but did not follow the expected
order, suggesting a study of concentration effects.
5.0 g (43.1 mmol) of a cis and trans mixture of 1,3-
cyclohexanediol and 50 mL of dry THF were placed in a
two-necked 125 mL round-bottomed flask fitted with a cal-
cium chloride protected reflux condenser, a dropping funnel
and a magnetic stirrer. 1.2 g (50.0 mmol) of sodium hydride
was added and the reaction mixture stirred at room temper-
ature for 1 h. The reaction mixture was cooled to 0 ◦C and
6.12 g (43.1 mmol) of methyl iodide in 15 mL of dry THF
was gradually added. The ice bath was removed and stirring
continued for a further 1.5 h, with heating under reflux, and
the solution was then cooled to 20 ◦C and water was gradually
added to the reaction flask. The organic layer was separated,
dried over MgSO4, filtered and the solvent was evaporated.
The product was distilled to give cis- and trans-3-MCH in a
ratio of 71:29 (3.1 g, 55%); bp 96–98 oC/15 mmHg.
Thus, 1H NMR spectra of nine samples in CCl4 (with 10%
C6D6) and nine samples in CDCl3, with concentrations of
0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35and0.40 mol L−1
were recorded and the results are displayed in Table 1 .
,
Table 1 shows that the coupling constant (3J) values for
the H-1 hydrogen of cis-3-MCH increase significantly on in-
cis and trans-3-MCH (1) were purified through a chro-
matography column, using hexane-ethyl acetate (7:1) as elu-
ent and 230–400 mesh silica gel. The main fractions were
analyzed by gas chromatography utilizing a GC/MS Class
5000, with helium as carrier gas and a Chirasil-DEX chi-
ral GC-column (30 m × 0.25 mm × 0.25 ␮m), with similar
fractions being combined before the solvent was evaporated.
Fig. 1. Conformational equilibrium for cis-3-MCH (1aa ↔ 1ee) and trans-
3-MCH (1ae ↔ 1ea).

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
1739
Table 1
Hydrogen H-1a coupling constants (3J),b OH chemical shifts,c equatorial–equatorial molar fractions (Xee)d and energy differences (ꢀGee–aa
)
d,e for cis-3-MCH
in different concentrations,f in CCl4 and in CDCl3
g
CCl4
CDCl3
d
d
Concentrationf
3J H1/H2a or H6a
3J H1/H2e or H6e
Xee
ꢀGd,e
δOH
3J H1/H2a or H6a
3J H1/H2e or H6e
Xee
ꢀGd,e
δOH
0.01
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
a
–
–
–
–
0.63
0.46
0.29
2.04
2.16
2.25
2.38
2.42
2.55
2.55
2.69
2.83
7.41
–
3.75
–
0.45
–
0.54
–
0.04
−0.13
−0.21
−0.25
−0.38
−0.42
−0.46
2.48
2.51
2.56
2.59
2.63
2.66
2.70
2.74
2.76
7.34
7.47
7.56
7.72
7.89
8.00
8.27
8.34
3.67
3.71
3.77
3.80
3.87
3.92
3.98
4.06
0.44
0.46
0.47
0.49
0.52
0.53
0.57
0.59
7.73
7.86
7.92
7.94
8.02
8.06
8.09
3.82
3.80
3.87
3.90
3.93
3.92
3.92
0.49
0.51
0.52
0.53
0.54
0.54
0.55
0.08
−0.17
−0.33
−0.75
−0.84
H-3 hydrogen was overlapped by the OCH3 hydrogens.
b
c
d
e
f
In Hz.
In ppm, from TMS.
Molar fraction and ꢀGee–aa obtained from experimental coupling constants (3J H1/H2a or H6a) and calculated by the PCMODEL program.
In kJ mol−1
Concentration in mol L−1
.
.
g
For a mixture of CCl4/C6D6 (9:1).
creasing the concentration, both in CCl4 and CDCl3, which
is clearly due to a change in the conformer populations.
For dilute solutions, the 1aa conformer is favored, but the
increase in concentration makes 1ee the predominant con-
former.
T = 298 K and K1 = Xee/Xaa for cis-3-MCH and K2 = Xae/Xea
for trans-3-MCH isomer.
∆G◦ = −RTln K1
(2)
Themolarfractionofthediequatorialconformer(1ee)andthe
free energy (ꢀGee–aa) between the 1ee ↔ 1aa conformers,
for a concentration range of 0.01–0.40 mol L−1 in CCl4 and
in CDCl3, are given in Table 1. Positive ꢀGee–aa values show
that 1aa conformer predominates for low concentrations, up
to 0.20 mol L−1 in CCl4 and up to 0.10 mol L−1 in CDCl3
(51%, for both). Its stability can be attributed to an IAHB,
while an increase in concentration makes ꢀGee–aa negative,
favoring the 1ee conformer due to the prevalence of an IEHB
over the IAHB.
The possible occurrence of intermolecular hydrogen
bonding, in the conformational equilibrium of cyclohexanol,
had been already suggested by Eliel and Schroeter [12]. Later,
Abraham et al. [13] observed significant changes in the cyclo-
hexanol H-1 hydrogen chemical shift, on changing the con-
The molar fraction (X) and free energy difference
(ꢀGee–aa) for 1ee and 1aa conformers (Fig. 1) of cis-3-
MCH were determined through Eqs. (1) and (2), taking the
H-1 coupling constant values of the 1ee and 1aa conform-
3
ers individually (3JH1e/H2e or H6e = 4.40 and JH1a/H2a or H6a
= 11.14 Hz), obtained through the PCMODEL [10] program,
using Haasnoot–Altona equations [11], since the experimen-
tal data for vicinal coupling constants (3Jobs) are averaged
values (Table 1).
ꢀ
ꢁ
3
3Jobs − JH1e/H2e
Xee
=
(1)
3JH1a/H2a − JH1e/H2e
3
Since Xee + Xaa = 1, the free energy difference (ꢀGo) can be
readily obtained from Eq. (2), where R = 8.3145 J mol K−1
,
Table 2
Hydrogen H-1 coupling constants (3J)a for trans-3-MCH, in different concentrations,b in CCl4 and CDCl3
c
CCl4
CDCl3
Concentrationc
3J H1/H2e or H6e
3J H1/H2e or H6e
3J H1/H2e or H6e
3J H1/H2e or H6e
0.01
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
8.02
7.95
8.08
7.95
7.97
8.02
7.93
7.96
8.03
3.89
3.75
3.91
3.87
3.88
3.90
3.86
3.88
3.90
7.88
7.95
7.99
7.95
7.96
7.96
7.93
7.93
8.00
3.81
3.92
3.88
3.86
3.88
3.87
3.87
3.87
3.88
a
In Hz.
b
Concentration in mol L−1
.
c
For a mixture of CCl4/C6D6 (9:1).

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P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
Fig. 2. Infrared spectra of cis- and trans-3-MCH in CCl4 solutions: 0.005 (a, d), 0.01 (b, e) and 0.03 mol L−1 (c, f).
centration, inCCl4 andCDCl3, confirmingEliel’shypothesis.
The results, presented here for cis-3-MCH, are in agreement
with these literature findings. Moreover, to the best of our
knowledge, this paper is the first report that shows coupling
constant (3J) changes with a change of concentration on the
conformational equilibrium of cyclohexanes, when an IAHB
can be formed.
Table 1 shows that the intermolecularly bonded OH chem-
ical shift strongly depends on concentration, increasing from
2.04 to 2.83 ppm in CCl4, and from 2.48 to 2.76 ppm in
CDCl3, with the increase in concentration, while the in-
tramolecularly bonded OH chemical shift is rather constant
(∼4.70 ppm). Thus, the observed changes demonstrate that
the OH chemical shift has the typical behavior of intermolec-
ular hydrogen bonding [14].
The IAHB effect in the cis isomer conformational equi-
librium can be proved by a comparison of the H-1 coupling
constants of this cis isomer (Table 1), with the ones for the
trans isomer (Table 2), whose conformational equilibrium is
presented in Fig. 1. The results in Table 2 show that there are
no significant changes in the coupling constants for the trans
isomer with the increase in concentration, since this isomer
cannot form an IAHB.
The IR spectra of cis- and trans-3-MCH at 0.005, 0.01
and 0.03 mol L−1, in CCl4, were recorded and are shown in
Fig. 2. Spectra of cis-3-MCH at low concentrations (0.005
and 0.01 mol L−1) show two OH bands attributed to the two
conformers, the high frequency vibration corresponding to
the free OH (diequatorial conformer) and the other to OH
bonded to the OCH3 substituent (diaxial conformer), which

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
1741
Table 3
indicates that the IAHB energy is larger than that for the re-
lated diols, probably because the OCH3 oxygen is a better
hydrogen acceptor than the OH group [17].
OH infrared frequenciesa for cis- and trans-3-MCH
Isomer
Concentrationb
Free OH
Bonded OHc
ꢀνd
cis
0.005
0.01
0.03
3620
3624
3622
3530
3529
3528
90
95
94
3.2. Solvent effects
Table 4 presents the H-1 and H-3 coupling constants for
cis-3-MCH, at a low concentration (0.05 mol L−1), in differ-
ent solvents, to avoid interference of IEHB. H-1 coupling
constants for the cis isomer increase with the increase of sol-
vent polarity, showing that 1aa is more stable than the 1ee
conformer in less polar solvents, such as C6D12 and CCl4,
due to the favorable formation of an IAHB (Fig. 1), in the
absence of solvation effects.
trans
0.005
0.01
0.03
3626
3627
3627
–
–
–
–
–
–
a
In cm−1, with 2 cm−1 digital resolution.
Concentration in mol L−1
b
c
d
.
The OH intermolecularly bonded frequency is ∼3450 cm−1
.
Frequency difference between free and bonded OH bands in cm−1
.
predominates in relation to the diequatorial conformer. A
third band, at lower frequency, arises in the spectrum of a
more concentrated solution (0.03 mol L−1), which is due to
an intermolecularly bonded OH, as shown in Fig. 2c. In con-
trast, the IR spectra of the trans isomer (Fig. 2d and e) present
a sharp single band due to free OH, in agreement with the re-
sults from H-1 coupling constants, which are almost constant
(Table 2), confirming that this isomer does not form an IAHB.
Fig. 2f shows that, for a higher concentration (0.03 mol L−1),
the trans isomer can also form an IEHB, similarly to the cis
isomer, but the corresponding coupling constants (Table 2)
do not change, since this equilibrium is fast at room temper-
ature. The OH stretching frequency and the frequency shifts
(ꢀν), between free and bonded OH, are given in Table 3.
It has been reported by Kuhn [15] that the confor-
mational equilibria of trans-cyclohexane-1,2-diol and cis-
cyclohexane-1,3-diol are shifted towards the diequatorial and
diaxial conformers, respectively, which have the OH groups
close to each other, allowing the formation of hydrogen
bonds. Kuhn [15] noted that the frequency shifts (ꢀν) in-
crease from the trans-1,2-diol (32 cm−1) to the cis-1,3-diol
(75 cm−1), while Badger [16] showed that the strength of
the hydrogen bond increases with the increase in ꢀν values.
Thus, it can be concluded that the ꢀν average value 92
3 cm−1 (Table 3), which was obtained for the cis-3-MCH,
The experimental coupling constant (6.65 Hz), in C6D12,
associated with the calculated values, obtained from the PC-
MODEL program, were introduced in Eq. (1), leading to 33%
for the 1ee conformer in the conformational equilibrium, at
room temperature. Therefore, the steric effect is less impor-
tant or smaller than the effect of stabilization provided by
IAHB, for less polar solvents, while the opposite is observed
in more polar solvents, when the 1ee conformer becomes
more stable. This behavior can be explained by taking into
account that a polar solvent has a larger affinity for the OH
and OCH3 groups [13]. Then, the solvent molecules can eas-
ily approach those groups when they are equatorial, and the
1ee conformer can be more efficiently solvated. The increas-
ing stabilization of 1ee conformer by the solvation effect is
confirmedbythedatainDMSO, averypolarsolvent. Thus, 3J
(H1/H2a or H6a) is 10.92 Hz in DMSO, leading to 1ee con-
former population of 97%. Large couplings were also ob-
tained for the pure liquid, for H-1 and H-3 with other ring
hydrogens, that is, 10.55 and 10.73 Hz, respectively, clearly
indicating that the conformational equilibrium is shifted to-
wards the 1ee conformer due to IEHB, as has already been
shown in the study of concentration effects (see Section 3.1).
Table 5 presents the H-1 and H-3 coupling constants for
trans-3-MCH, at a low concentration (0.05 mol L−1), in dif-
ferent solvents, to avoid also the interference of IEHB.
Table 4
Hydrogen H-1 and H-3 coupling constants (3J),a equatorial–equatorial molar fractions (Xee)b and energy differences (ꢀGee–aa
of different dielectric constants (ε)
)
b,c for cis-3-MCH, in solventsd
Solvent
ε
3J H1/H2a or H6a
3J H1/H2e or H6e
3J H3/H2a or H4a
3J H3/H2e or H4e
Xee
ꢀGee–aa
e
e
e
e
e
C6D12
CCl4
CDCl3
CD2Cl2
Pure liquid
Pyridine-d5
Acetone-d6
CD3CN
DMSO-d6
2.05
2.24
4.81
9.08
–
12.40
20.70
37.50
46.70
6.65
7.34
7.57
8.40
10.55
10.75
–
3.42
3.67
4.19
4.28
4.03
4.16
–
–
–
–
–
–
–
–
–
0.33
0.44
0.47
0.59
0.91
0.94
–
1.72
0.63
0.29
−0.92
−5.82
−6.90
–
e
e
e
10.73
10.54
10.42
10.31
11.00
3.88
4.12
3.97
4.02
4.09
–
–
4.18
–
0.97
–
10.92
−8.41
a
In Hz.
b
Molar fraction and ꢀGee–aa obtained from experimental coupling constants (3J H1/H2a or H6a) and calculated by the PCMODEL program.
c
d
e
In kJ mol−1
Concentration: 0.05 mol L−1
Overlapped by the OCH3 hydrogens.
.
.

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P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
Table 5
Hydrogen H-1 and H-3 coupling constants (3J),a equatorial–axial molar fractions (Xea
of different dielectric constants (ε)
)
and energy differences (ꢀGae–ea
)
for trans-3-MCH, in solventsd
b
b,c
Solvent
ε
3J H1/H2a or H6a
3J H1/H2e or H6e
3J H3/H2a or H4a
3J H3/H2e or H4e
Xea
ꢀGae–ea
C6D12
CCl4
CDCl3
CD2Cl2
Pure liquid
Pyridine-d5
Acetone-d6
CD3CN
DMSO-d6
2.05
2.24
4.81
9.08
–
12.40
20.70
37.50
46.70
8.11
–
8.02
–
7.98
7.69
7.73
7.80
7.60
3.95
–
3.94
–
3.86
3.76
3.87
3.85
3.69
5.84
–
5.92
–
–
6.18
–
3.14
–
3.20
–
–
3.21
–
0.59
–
0.57
–
0.57
0.53
0.53
0.54
0.51
0.84
–
0.71
–
0.67
0.25
0.33
0.42
0.13
–
6.48
–
3.25
a
In Hz.
b
Molar fraction and ꢀGea–ae obtained from experimental coupling constants (3J H1/H2a or H6a) and calculated by the PCMODEL program.
c
In kJ mol−1
.
Concentration: 0.05 mol L−1
.
d
For the trans isomer (Fig. 1), the coupling constants
pling constants, which do not change with solvent polarity,
in contrast to cis-3-MCH, and these couplings indicate that
the eq–eq conformer is predominant in the conformational
equilibrium of cis-1,3-DMCH.
change randomly and are very close to each other in solvents
of very different dielectric constants. For H-1, a small
decrease was noted when increasing the solvent polarity,
while a reverse behavior was observed for H-3. These
changes indicate that, in less polar solvents such as C6D12,
the conformational equilibrium is displaced in favor of the
1ea conformer, while, on increasing the solvent polarity,
the proportion of 1ae and 1ea conformers becomes almost
the same, since H-1 coupling constants decrease from
8.11 (C6D12) to 7.60 Hz (DMSO). The molar fraction (X)
and free energy difference (ꢀGae–ea) values, calculated
from the coupling constants obtained through PCMODEL
3.3. Theoretical calculations
The geometry for the stable conformers, of cis and trans
isomersof3-MCH(1)andofthecisisomerof1,3-DMCH(2),
were obtained through theoretical calculations using Gaus-
sian 98 [18], with the 6-311+G** basis set [19] from Becke’s
three-parameter functional using the Lee–Yang–Parr corre-
lation functional (B3LYP) [20–23] level of theory. The rela-
tive energies and dipole moments of conformers with ꢀE <
12.6 kJ mol−1 are given in Table 7 for rotamers of compounds
1 and 2. The rotamers with ꢀE > 12.6 kJ mol−1 were not con-
sidered because they represent a very small proportion in the
equilibrium.
(3JH1e/H2e or H6e = 3.92 and JH1a/H2a orH6a = 11.08 Hz)
3
and from the experimental value (3Jobs), show that the
population of the 1ea conformer changes from 59 to 51%,
from C6D12 to DMSO, respectively, with the corresponding
small changes in ꢀGae–ea from 0.84 to 0.13 kJ mol−1
.
A further proof that an IAHB occurs in cis-3-MCH can be
obtained from a similar study of solvent effects with cis-1,3-
dimethoxycyclohexane, labeled as 2 and chosen as a model
compound, since it occurs as a single conformer, exhibiting
the two methoxyl groups in the equatorial orientation, sim-
ilarly to the target compound, but lacking an OH group. 1H
NMR spectrum from cis-1,3-DMCH shows that the experi-
mental H-1 and H-3 couplings are equal, as expected from the
molecular symmetry. Thus, Table 6 presents just the H-1 cou-
Table 7
Conformer relative energies (ꢀE)a and dipole moments (µ)b for cis- (1aa
and 1ee) and trans-3-MCH (1ea and 1ae), and for cis-1,3-DMCH (2aa and
2ee) at the B3LYP/6-311+G** level
cis-3-MCH
trans-3-MCH
cis-1,3-DMCH
Rotamer
1aa1
µ
ꢀE Rotamer
µ
ꢀE Rotamer
µ
ꢀE
c
c
2.85 1.30 1ea1
3.46 0.00 1ea2
0.67 0.33 2aa1
2.20 1.80 2aa2
2.18 1.59 2aa3
2.17 0.29 2ee1
3.15 1.88 2ee2
2.35 0.00 2ee3
1.87 1.34 2ee4
0.78 6.23 2ee5
1.67 2.22 2ee6
2.03 1.34 2ee7
2.40 6.11 2ee8
0.29 0.92
–
–
–
–
1aa2
c
1aa3
1ee1
1ee2
1ee3
1ee4
1ee5
1ee6
–
–
1ea3
1.82 12.18
Table 6
3.08 3.39 1ea4
2.18 3.01 1ea5
2.13 3.51 1ea6
0.77 3.22 1ae1
2.30 2.76 1ae2
2.35 3.26 1ae3
1ae4
2.69
2.09
2.03
1.88 10.38
2.09 0.00
1.88 10.38
0.54
0.00
0.42
Hydrogen H-1 coupling constants (3J)a for cis-1,3-DMCH, in solvents of
different dielectric constants (ε)
Solvent
ε
3J H1/H2a or H6a
3J H1/H2e or H6e
CCl4
CDCl3
Pure liquid
Pyridine-d5
Acetone-d6
CD3CN
2.24
4.81
–
12.40
20.70
37.50
46.70
10.62
10.75
10.98
10.84
10.98
10.98
10.98
3.99
4.02
4.02
4.16
4.08
4.08
4.12
0.28
0.28
9.67
9.67
1ae5
1ae6
a
b
c
In kJ mol−1
In Debye.
ꢀE > 12.6 kJ mol−1
.
DMSO-d6
a
In Hz.
.

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
1743
Fig. 4. Possible rotamers for trans-3-MCH, obtained at the B3LYP/6-
311+G** level.
Fig. 3. Stable rotamers for cis-3-MCH (1, R H) and cis-1,3-DMCH (2,
R
CH3), obtained at the B3LYP/6-311+G** level.
solvent because solvation is more important than the dipole
moment effect.
Fig. 4 presents the possible rotamers for trans-3-MCH,
1ea and 1ae conformers, which were obtained through the-
oretical calculations. The corresponding energies are shown
in Table 7. The most stable rotamers for the 1ea and 1ae con-
formers are 1ea6 and 1ae6, respectively, and the 1ea6 rotamer
is 0.92 kJ mol−1 more stable than 1ae6. This is in a very good
agreement with the values of ꢀGae–ea = 0.84 kJ mol−1, ob-
tained for C6D12 solution (Table 5). The conformation equi-
librium for the trans isomer is also not dependent on the
dipole moments, since there is a small increase in the per-
centage of 1ae conformer (µ = 0.29 D) with the increase of
solvent polarity (Table 5), despite the larger dipole moment
of 1ea6 (µ = 2.35 D) (Table 7).
Table 7 shows two and six stable rotamers for 1aa and 1ee
conformers, respectively, and the corresponding geometries
are presented in Fig. 3. The rotamers 1aa2 and 1ee5, for 1aa and
1ee conformers, respectively, are the most stable ones, and
1
aa2 is more stable than 1ee5 by 2.76 kJ mol−1, reinforcing the
important role of an IAHB in the conformational equilibrium
of cis-3-MCH, and showing good agreement with the value of
1.72 kJ mol−1, obtained for the C6D12 solution, in the solvent
effect study presented above (Table 4), since this solvent has
a dielectric constant value (ε = 2.05), the nearest solvent to
the conditions of the theoretical calculations (ε = 1.0).
Moreover, it can be noted that 1aa1 is also more stable than
1
ee5, since it can also form an IAHB, but it is 1.30 kJ mol−1
Fig. 3 also shows the possible rotamers for the 2aa and
2ee conformers of cis-1,3-DMCH (2), and the corresponding
energies are presented in Table 7. Compound 2, which can-
not form an IAHB, is expected to occur mostly as a single
conformer (2ee), since the diaxial conformer (2aa) energy is
very large. The most stable rotamers for 2ee and 2aa are 2ee3
and 2aa3, respectively, but the 2ee3 rotamer is 12.18 kJ mol−1
(corresponding to 99.3%) more stable than 2aa3. These values
are in agreement with the values of solvent effect (Table 6).
less stable than 1aa2 because in the 1aa1 rotamer, one OCH3
oxygen lone pair is pointing inside the cyclohexane ring,
increasing the steric effect, a rather different geometry in
comparison to 1aa2. Along with 1aa1 and 1aa2, there are
other possible rotamers for the diaxial conformer (ꢀE >
12.6 kJ mol−1), which are less stable because they cannot
be stabilized by an IAHB. Consequently, these rotamers are
also much less stable than the 1ee5 rotamer (Table 7), due to
the 1,3-diaxial interactions, which are large and decisive in
the conformational equilibrium of the cis isomer. It can also
be observed that most of the other possible rotamers (1ee1
,
3.3.1. Hydrogen bonding
1
ee2, 1ee3, 1ee4 and 1ee6) of the 1ee conformer present sta-
Studies of the potential energy surface through HF and
B3LYP levels with the 6-311+G** basis set, for the 1aa
conformer of cis-3-MCH, were performed to observe how
changes in the position of the OH hydrogen, near or far from
OCH3, which is followed by changes in the C2 C1 O H
dihedral angle from the 1aa2 geometry, would affect the ro-
tamer energy and the formation of a hydrogen bond (IAHB).
Fig. 5 shows two minima, one corresponding to the most sta-
ble rotamer (1aa2), which forms an IAHB, and another one
for a less stable (1aa3) rotamer (Fig. 3) with the hydrogen far
bilities near to 1ee5, which indicate that the rotation of the
C O bond does not introduce large changes in their ener-
gies.
Data from Table 7 also show that the 1aa2 rotamer presents
a larger dipole moment than the 1ee5 rotamer. Therefore, an
increase in solvent polarity should shift the equilibrium to-
wards the 1aa conformer. However, an opposite behavior was
observed, 1ee being favored in polar solvents (Table 4). This
means that, for cis-3-MCH, 1ee is more stable in more polar

1744
P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
lar to what was observed for 3-substituted ␤-thioxoketones
by Millefiori and Di Bella [32]. Therefore, the total energy
of 1aa3 would contain a considerable amount of Pauli non-
bonded repulsion energy, when the geometry is not opti-
mized.
Two model compounds, cyclohexanol and methoxycy-
clohexane, were chosen to check which theoretical method
would give the best result for the conformer energy dif-
ferences. From an inspection of the results presented in
Table 8, it can be concluded that the CBS-4M method gave
calculated values for cyclohexanol (4.06 kJ mol−1) and for
methoxycyclohexanol (2.34 kJ mol−1), which are closer to
the experimental values [33–35] of 4.23 and 2.30 kJ mol−1
,
respectively, than any of the other methods. Therefore, it
seems that the best value for the IAHB energy must be
near to 18.45 kJ mol−1 (ꢀE1, Table 8), which was obtained
using the optimized structure of the reference compound,
and it indicates that this procedure must be followed for
the determination of IAHB strength for other similar com-
pounds.
Fig. 5. PESforthe1aa2 rotamer:(a)B3LYP/6-311+G**, (b)HF/6-311+G**.
4. Conclusion
from the OCH3 group. Both theory levels (Fig. 5a and b) lead
to similar results.
This work reports the relevant concentration effect in the
conformational equilibrium of cis-3-MCH, showing that at
higher concentration, there is a competitive effect in the for-
mationofanintramolecularhydrogenbondbyintermolecular
hydrogen bonds.
The study of the solvent effect showed that, in a less polar
solvent, the 1aa conformer predominates (67% in C6D12),
which was attributed to the formation of an intramolecular
hydrogen bond, while in more polar solvents, the equilibrium
is shifted to the 1ee conformer (97% in DMSO).
Moreover, hydrogen bond energies are usually calculated
as the difference between the energies of a non-bonded and
a bonded species (ꢀE = Eref − Ebonded). There are two es-
tablished ways to estimate the strength of an IAHB, either
by optimizing [24–26] or not [17,27] the reference structure,
which, in the present case, is the 1aa3 rotamer (Fig. 3).
The calculated energy of IAHB for conformer 1aa, with
(ꢀE1) and without (ꢀE2) optimization of the reference
structure, through HF and B3LYP levels with 6-31G** and
6-311+G** basis sets, and also by the CBS-4M method
[28–31], are presented in Table 8. The values obtained, for
the IAHB, using the optimized reference structure (ꢀE1), are
in agreement for different theory levels, and are smaller than
the values obtained without optimization (ꢀE2). The larger
values of ꢀE2 are probably due to the small distance, of
Theoretical calculations agree with the data from 1H NMR
and IR spectra, showing that, for the cis isomer, the IAHB is
very important for the stabilization of the diaxial conformer
(1aa), and supersedes the well-known 1,3-diaxial steric inter-
actions, present in 1,3-disubstituted cyclohexanes.
The calculated dipole moment led to the conclusion that
it is not the driving force, which determines the conforma-
tional equilibria of the cis- and trans-3-MCH, on changing
the solvent polarity. It could also be concluded that the PC-
MODEL program gave very good coupling constant values
for a qualitative analysis of energy changes in the study of
solvent effects in the conformational equilibria.
The CBS-4M method gave the best values for the strength
of the IAHB of 3-MCH (18.45 kJ mol−1) and this result sug-
gests that optimization of the reference structure must be rec-
ommended in the estimation of hydrogen bond energies for
1,3-disubstituted cyclohexanes.
˚
2.825 A, between O · · · O (obtained as the average value from
the theoretical calculations), which is slightly larger than the
˚
sum of the appropriate van der Waals radii (2.80 A), simi-
Table 8
Relative energiesa for rotamer 1aa2 in comparison to 1aa3, of the cis-3-MCH
diaxial conformer, with (ꢀE1) and without (ꢀE2) optimization of conformer
1aa3, and also the relative energiesa for the cyclohexanol [ꢀEOH(a–e)] and
methoxycyclohexane [∆EOCH (a−e)] most stable rotamers
3
Theory level
HF/6-31G**
HF/6-311+G**
B3LYP/6-31G**
B3LYP/6-311+G**
CBS-4M
ꢀE1
ꢀE2
ꢀEOH(e–a)
1.67
2.01
3.18
3.72
∆EOCH (a−e)
3
22.34
21.46
23.93
20.00
18.45
30.84
29.58
33.89
31.97
1.55
1.84
2.76
3.05
2.34
Acknowledgments
b
–
4.06
a
In kJ mol−1
Cannot be obtained by the CBS-4M method.
.
The authors thank FAPESP for financial support of this
research and for a fellowship (to P.R.O.), CNPq for a fel-
b

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 61 (2005) 1737–1745
1745
lowship (to R.R.) and CENAPAD-SP for computer facilities
(Gaussian 98). Professor C. H. Collins’ assistance in revising
this manuscript is also gratefully acknowledged.
Replogle, R. Gomperts, J.L. Andres, K. Raghavachavi, J.S. Blink-
ley, C. Gonzalez, R.L. Martin, D.J. Fox, D.J. Defrees, J. Baker,
J.P. Stewart, T. Keith, G.A. Peterson, J.A. Montgomery, M.A. Al-
Laham, V.G. Zakrzewski, J.V. Ortiz, J. Cioslowski, B.B. Stefanov,
A. Nanayakkara, M. Challacombe, C.Y. Peng, P.Y. Ayala, W. Chen,
M. Head-Gordon, J.A. Pople, Gaussian 98, revision A.7, Gaussian,
Pittsburgh, 1998.
References
[19] J.B. Foresman, A. Frish, Exploring Chemistry with Electronic Struc-
ture Methods, Gaussian, Pittsburgh, 1996.
[1] E.L. Eliel, S.H. Wilen, L.N. Mander, Stereochemistry of Organic
Compounds, Wiley, New York, 1994, p. 690.
[2] K.B. Wiberg, J.D. Hammer, H. Castejon, W.F. Bailey, E.L. Deleron,
R.M. Jarret, J. Org. Chem. 64 (1999) 2085.
[3] E.A. Basso, P.R. Oliveira, J. Caetano, I.T.A. Schuquel, J. Braz.
Chem. Soc. 12 (2001) 215.
[20] A.D. Becke, J. Chem. Phys. 98 (1993) 5648.
[21] C. Lee, W. Yang, P.G. Parr, Phys. Rev. B 37 (1988) 785.
[22] A.D. Becke, Phys. Rev. A 38 (1988) 3098.
[23] B. Michels, A. Savin, H. Stoll, H. Preuss, Chem. Phys. Lett. 157
(1989) 200.
[24] P. George, C.W. Bock, M. Trachtman, J. Mol. Struct. (Theochem.)
133 (1985) 11.
[4] D. Kost, N. Peor, G.S. Moriah, Y. Sharabi, D.T. Durocher, M. Raban,
J. Org. Chem. 67 (2002) 6938.
[25] J.S. Craw, G.B. Bacskay, J. Chem. Soc. Faraday Trans. 88 (1992)
2315.
[5] M.P. Freitas, C.F. Tormena, P.R. Oliveira, R. Rittner, J. Mol. Struct.
589 (2002) 147.
[26] T. Schaefer, R. Sebastian, D.M. Mckinnon, P.W. Spevack, K.J. Cox,
C.S. Takeuchi, Can. J. Chem. 71 (1993) 960.
[27] H. Lampert, W. Mikenda, A. Karpfen, J. Phys. Chem. 100 (1996)
7418.
[28] M.R. Nyden, G.A. Petersson, J. Chem. Phys. 75 (1981) 1843.
[29] G.A. Petersson, M.A. Al-Laham, J. Chem. Phys. 94 (1991)
6081.
[30] G.A. Petersson, T. Tensfeldt, J.A. Montgomery, J. Chem. Phys. 94
(1991) 6091.
[31] J.A. Montgomery, J.W. Ochterski, G.A. Petersson, J. Chem. Phys.
101 (1994) 5900.
[6] E.J. Corey, N.F. Feiner, J. Org. Chem. 45 (1980) 765.
[7] B. Franzus, B.E. Hudson, J. Org. Chem. 28 (1963) 2238.
[8] H. Finegold, H. Kwart, J. Org. Chem. 27 (1962) 2361.
[9] R.J. Abraham, T.A.D. Smith, W.A. Thomas, J. Chem. Soc. Perkin
Trans. 2 (1996) 1949.
[10] PCMODEL, Version 75, Serena Software, Bloomington, 2001.
[11] C.A.G. Haasnoot, F.A.A.M. Leeuw, C. Altona, Tetrahedron 36
(1980) 2783.
[12] E.L. Eliel, S.H. Schroeter, J. Am. Chem. Soc. 87 (1965) 5031.
[13] R.J. Abraham, E.J. Chambers, W.A. Thomas, J. Chem. Soc. Perkin
Trans. 2 (1993) 1061.
[32] S. Millefiori, S. Di Bella, J. Chem. Soc. Faraday Trans. 87 (1991)
1297.
[14] E. Breitmaier, Structure Elucidation by NMR in Organic Chemistry,
Wiley, 1993, p. 60.
[33] H.J. Schneider, V. Hoppen, J. Org. Chem. 43 (1978) 3866.
[34] T. Pehk, H. Kooskora, E. Lippmaa, Org. Magn. Reson. 8 (1976)
5.
[35] F.R. Jensen, C.H. Bushweller, B.H. Beck, J. Am. Chem. Soc. 91
(1969) 344.
[15] L.P. Kuhn, J. Am. Chem. Soc. 74 (1952) 2492.
[16] R.F. Badger, J. Chem. Phys. 8 (1940) 288.
[17] A. Simperler, W. Mikenda, Monatsh. Chem. 128 (1997) 969.
[18] M.J. Frisch, G.W. Trucks, H.B. Schlegel, J.R. Cheeseman, P.M.W.
Gill, M.W. Wong, J.B. Foresman, B.G. Johnson, M.A. Robb, E.S.