The subtle electronic effects of alkyl groups on the conformational equilibria and intramolecular hydrogen-bond strength in cis-3-alkoxycyclohexanols

Article abstract of DOI:10.1016/j.saa.2007.10.016

¹H NMR data for cis-3-n-propoxycyclohexanol (cis-3-PCH) and cis-3-isopropoxy-cyclohexanol (cis-3-ICH) show that a concentration increase shifts the conformational equilibrium from the diaxial (aa) conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the diequatorial (ee) conformer [X_ee = 42% and 21% (at 0.01 mol L^-1) to 58% and 56% (at 0.40 mol L^-1), in CCl_4, respectively] due to intermolecular hydrogen bonds (IEHB), as confirmed by IR data. The Δν values, obtained by IR spectra, indicated that increasing the size of the OR group [R = CH₃, CH₂CH₂CH₃ and CH(CH₃)₂], increases the IAHB strength, due to an increase in the inductive effect of R group, which makes the oxygen lone pairs more available for an IAHB with OH group, in opposition to the steric effect. The percentage of ee conformer increases with the solvent basicity for cis-3-PCH and cis-3-ICH, from 48% and 36% in CCl₄ to 97% and 96% in DMSO, respectively. Values of 4.58, 6.06 and 6.33 kcal mol^-1 for the IAHB strength in cis-3-PCH, cis-3-ICH and cis-3-TCH (cis-3-tert-butoxycyclohexanol), respectively, were obtained, from the theoretical data through the CBS-4M method, confirming the experimental results and indicating that the IAHB strength increases with the increasing bulk of OR substituent in this series of compounds.

Full text of DOI:10.1016/j.saa.2007.10.016

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Spectrochimica Acta Part A 70 (2008) 1079–1086
The subtle electronic effects of alkyl groups on the conformational
equilibria and intramolecular hydrogen-bond strength in
cis-3-alkoxycyclohexanols
Paulo R. de Oliveira1, Roberto Rittner∗
Physical Organic Chemistry Laboratory, Chemistry Institute, State University of Campinas, Caixa Postal 6154,
13084-971 Campinas, SP, Brazil
Received 29 August 2007; received in revised form 8 October 2007; accepted 15 October 2007
Abstract
1H NMR data for cis-3-n-propoxycyclohexanol (cis-3-PCH) and cis-3-isopropoxy-cyclohexanol (cis-3-ICH) show that a concentration increase
shifts the conformational equilibrium from the diaxial (aa) conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the diequatorial
(ee) conformer [Xee = 42% and 21% (at 0.01 mol L−1) to 58% and 56% (at 0.40 mol L−1), in CCl4, respectively] due to intermolecular hydrogen
bonds (IEHB), as confirmed by IR data. The ꢀν values, obtained by IR spectra, indicated that increasing the size of the OR group [R = CH3,
CH2CH2CH3 and CH(CH3)2], increases the IAHB strength, due to an increase in the inductive effect of R group, which makes the oxygen lone
pairs more available for an IAHB with OH group, in opposition to the steric effect. The percentage of ee conformer increases with the solvent
basicity for cis-3-PCH and cis-3-ICH, from 48% and 36% in CCl4 to 97% and 96% in DMSO, respectively. Values of 4.58, 6.06 and 6.33 kcal mol−1
for the IAHB strength in cis-3-PCH, cis-3-ICH and cis-3-TCH (cis-3-tert-butoxycyclohexanol), respectively, were obtained, from the theoretical
data through the CBS-4M method, confirming the experimental results and indicating that the IAHB strength increases with the increasing bulk of
OR substituent in this series of compounds.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Conformational analysis; Theoretical calculations; Intramolecular hydrogen bond; Cyclohexanes 1,3-disubstituted; IR spectroscopy
1. Introduction
(IEHB) and of intramolecular hydrogen bonds (IAHB), the
latter being responsible for the stabilization of the axial–axial
conformer at low concentrations, while the former effect pre-
dominates with the increase in concentration or in solvent
polarity favoring the equatorial–equatorial conformer.
Related work on substituted cyclohexanes has also been per-
formed by Taddei and Keinpeter [4,5]. The first paper [4] dealt
with the anomeric effect in alkoxy- and alkylcyclohexanes,
where it is shown that ꢀEhyp. is of similar magnitude as ꢀEster.
for the former series, but for the latter series ꢀEster. is much
larger. The other paper [5] describes the relationship between
hyperconjugation and bulk of OCOCX3 substituents for trans-
1,4-disubstituted cyclohexanes. This work led to very interesting
results, since hyperconjugation is more effective in the diaxial
conformer and steric effects, which occur in the whole molecule,
also destabilize the diequatorial conformer with the increasing
bulk of the CX3 group.
Recent work on the cis isomer of 3-X-cyclohexanols (X=Cl,
Br, I, CH3) and 3-X-1-methoxycyclohexanes (X=F, Cl, Br, I,
CH3) has shown that their conformational equilibra is neither
controlled by conformer dipole moments nor by solvent polar-
ity [1], but mostly by the classical syn-1,3-diaxial steric effects.
This paper was followed by two other papers on the conforma-
tional equilibria of the cis isomers of 3-methoxycyclohexanol
(cis-3-MCH) [2] and of 3-N,N-dimethylaminocyclohexanol [3],
at different concentrations and in different solvents. Both sys-
tems showed the importance of intermolecular hydrogen bonds
∗
Corresponding author at: Instituto de Qu´ımica, UNICAMP, Caixa Postal
6154, 13084-971 Campinas, SP, Brazil. Tel.: +55 19 3521 3150;
fax: +55 19 3521 3023.
E-mail address: rittner@iqm.unicamp.br (R. Rittner).
Present address: Universidade Tecnolo´gica Federal do Parana´, Depto. Qu´ım
1
The main objective of the present work is the anal-
ysis of the influence of increasing bulk substituent on
e Biologia, Curitiba, PR 80230-901, Brazil.
1386-1425/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2007.10.016

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P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
2.2. Theoretical calculations
Quantum chemical calculations were made with the Gaus-
sian 98 package [10]. Optimized geometries were computed
at the Becke’s three-parameter functional level using the
Lee–Yang–Parr correlation functional B3LYP level of theory
[11–14] with 6–311 + G** basis sets [14]. IAHB strengths were
computed by Hartree–Fock (HF), MP2 and B3LYP levels of
theory, using the 6–311 + G** basis sets, and also with the CBS-
4M method [15–18]. The PES (potential energy surfaces) were
obtained at the B3LYP level, with 6–311 + G** basis sets, by
changing the C2–C1–O–H dihedral angle for the diaxial (aa1)
rotamer by 10◦ until completing 360◦. For each 10◦, the structure
obtained was optimized.
Fig. 1. Conformational equilibrium for cis-3-PCH (R = n-propyl) (1), cis-3-ICH
(R = isopropyl) (2) and cis-3-TCH (R = tert-butyl) (3).
the formation of hydrogen bonds (IEHB and IAHB)
and how this affects the conformational equilibrium of
unexplored cis-3-n-propoxycyclohexanol (cis-3-PCH, 1), cis-
3-isopropoxycyclohexanol (cis-3-ICH, 2) and cis-3-tert-
butoxycyclohexanol (cis-3-TCH, 3) in comparison to the already
reported cis-3-methoxycyclohexanol (cis-3-MCH) [2] (Fig. 1).
Thus, it is reported: (i) the study of concentration effects, by 1H
NMR and IR spectroscopy, on the conformational equilibrium
of compounds 1–2; (ii) the study of solvent effects, by 1H NMR,
on the conformational equilibrium for the same compounds; (iii)
determination of the more stable conformers (diequatorial and
diaxial) and of the IAHB strength for compounds 1–3, in the gas
phase, using theoretical calculations.
Understanding the stability of hydrogen bonds is a rather
important subject since they play an important role in determin-
ing the three-dimensional structures adopted by proteins, nucleic
acids and DNA/RNA structure, where the double/triple helixes
are formed due to the presence of hydrogen bonds between the
strands [6–9].
2.3. Compounds
Cis-3-n-propoxycyclohexanol (cis-3-PCH, 1): 8.3 g (60
mmol) of aluminum chloride was placed in a round-bottomed
flask, fitted with a magnetic stirrer, and ice bath. Three grams
(30 mmol) of 2-cyclohexen-1-one was added gradually, and
the mixture was homogenized with mechanical stirring. Fifty
microlitres of propanol were added, and the reaction mixture
was stirred at room temperature for 2 h. Water was then added to
destroy the excess AlCl3. The organic layer was separated with
diethylether, driedoverMgSO4, andfiltered, andthesolventwas
evaporated. The product obtained (3-n-propoxycyclohexanone)
was added gradually to a 3-necked 250 ml round-bottomed flask
containing a suspension of lithium aluminum hydride (0.6 g,
16 mmol) in tetrahydrofuran (60 ml), under stirring, at −10 ◦C
in a nitrogen gas atmosphere. The mixture was allowed to reach
room temperature and stirred for another 1.5 h. Water was care-
fully added to destroy the excess lithium aluminum hydride.
The organic layer was separated with diethyl ether, dried over
MgSO4 filtered, and the solvent was evaporated. The prod-
uct could not be distilled, since it is unstable at temperatures
above 100 ◦C, but analysis through GC/MS showed a mixture
of cis-3-PCH and 2-cyclohexen-1-ol, the former correspond-
ing to 67% (2.0 g). Furthermore, the cis-3-PCH was purified
through column chromatography using hexane–ethyl acetate
(10:1) as eluent and silica gel 230–400 mesh. The main frac-
tions were analyzed by gas chromatography, utilizing a GC/MS
Class 5000 spectrometer, with helium as the carrier gas and a
DB1 SUPELCO GC-column. The similar fractions were com-
bined before the solvent was evaporated to yield 1.4 g (47%) of
the pure product.
2. Experimental
2.1. Spectra
IR spectra were recorded on a BOMEM Model 100 FT-
IR spectrometer, from 0.01, 0.03 and 0.10 mol L−1 solutions,
in CCl4 for cis-3-PCH (1) and cis-3-ICH (2), using a NaCl
cell with spacing of 0.5 mm. They were performed with 64
scans and resolution of 1 cm−1. NMR spectra were recorded
on an INOVA 500 spectrometer with a probe temperature of
1
20 ◦C, operating at 499.88 (1H) and at 125.70 MHz (13C). H
NMR spectra 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
CCl4 (CCl4/C6D6 9:1, the later for the deuterium lock) for the
study of concentration effects. In all cases, SiMe4 (TMS) was
used as an internal reference. The spectral window ensured
a digital resolution of at least 0.04 Hz/point, and zero-filling
helped to further define line shapes. Most FIDs were pro-
cessed with Gaussian multiplication, typically gf = 0.25 and
gf = 0.35, for spectral resolution improvement. The typical con-
1H NMR (500 MHz, CDCl3): δ 3.75 (tt, 7.42, 3.65, 1H), 3.46
(m, 1H), 3.40 (m, 2H), 1.98 (m, 1H), 1.84 (m, 1H), 1.70 (m,
1H), 1.67 (m, 1H), 1.62 (m, 1H), 1.58 (m, 2H), 1.52 (m, 1H),
1.48 (m, 1H), 1.28 (m, 1H), 0.92 (t, 7.42, 3H).
1
ditions for H spectra were: 128 transients, 32 k data points,
pulse width 37◦, sweep width ca. 3000 Hz and acquisition
time (AT) ca. 2.7 s; and for 13C NMR spectra: 1024 tran-
sients, 32 k data points, pulse width 45◦, sweep width ca.
10000 Hz and AT 1 s. Assignment of the signals in 1H and
13C NMR spectra of cis-3-PCH and cis-3-ICH, at concentration
of 0.30 mol L−1, were performed through gCOSY and HSQC
experiments.
13C NMR (125 MHz, CDCl3): δ 75.7, 70.1, 68.1, 38.8, 34.0,
30.1, 23.2, 17.7, 10.6.
Cis-3-isopropoxycyclohexanol(cis-3-ICH, 2):Thesamepro-
cedure described for cis-3-PCH was used here. The product
could not be distilled, for the same reason, but analyzed
by GC/MS, showing to be a mixture of cis-3-ICH and 2-
cyclohexen-1-ol, the former corresponding to 58% (1.7 g).

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
1081
Table 1
Hydrogen H1 coupling constants (3J),a equatorial–equatorial molar fractions (Xee)b and energy differences (ꢀGee–aa b,c for cis-3-PCH (1) at several concentrations,d
)
in CCl4 as solvente
Concentrationd
3JH1/H2aand 3JH1/H6a
3JH1/H2e and 3JH1/H6e
Xee
ꢀGee–aa
b
b,c
0.01
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
6.26
6.48
6.73
6.88
7.06
7.19
7.35
7.53
7.62
3.13
3.27
3.42
3.44
3.56
3.59
3.67
3.71
3.76
0.42
0.44
0.47
0.49
0.51
0.53
0.54
0.57
0.58
0.20
0.14
0.07
0.03
−0.02
−0.06
−0.11
−0.16
−0.18
a
In Hz.
b
Molar fraction and ꢀGee–aa obtained from experimental coupling constants (3J H1/H2a and H6a) and calculated by the PCMODEL program for H1 hydrogen
(3JH1a/H2a = 3JH1a/H6a = 11.23 and 3JH1e/H2e = 3JH1e/H6e = 2.72).
c
In kcal mol−1
.
d
e
In mol L−1
.
For a mixture of CCl4/C6D6 (9:1).
Furthermore the cis-3-ICH was purified in the same way as
compound 1, giving 1.2 g (40%) of pure product.
1H NMR (500 MHz, CDCl3): δ 3.75 (tt, 7.81, 3.67, 1H), 3.70
(m, 1H), 3.55 (tt, 7.39, 3.63,1H), 1.94 (m, 1H), 1.85 (m, 1H),
1.69 (m, 1H), 1.62 (m, 2H), 1.49 (m, 2H), 1.29 (m, 1H), 1.15 (d,
6.23, 3H), 1.14 (d, 6.23, 3H).
3), only theoretical data are reported, since it was not possible
to synthesize this compound.
Tables 1 and 2 show that the coupling constant (3J) values for
H1 and H3 of cis-3-PCH and cis-3-ICH, respectively (Fig. 1),
increase significantly on increasing the concentration in CCl4,
which is clearly due to a change in the conformer populations.
For dilute solutions, the diaxial (aa) conformer is favored, but
the increase in concentration makes diequatorial (ee) the pre-
dominant conformer.
13C NMR (125 MHz, CDCl3): δ 72.9, 69.0, 68.2, 39.5, 34.1,
31.0, 23.0, 22.5, 17.9.
The molar fraction (X) and free energy difference (ꢀGee–aa
)
3. Results and discussion
for ee and aa conformers (Fig. 1) of cis-3-PCH and cis-3-ICH
were determined through Eq. (1) and (2), taking the hydro-
gen coupling constant values of the ee and aa conformers
individually (see footnotes of Tables 1 and 2), obtained from
the optimized structure utilizing MM3 method, through the
PCMODEL program [19], with Haasnoot–Altona equations
[20], since the experimental data for vicinal coupling constants
(3Jobs) are averaged values (Tables 1 and 2):
3.1. Concentration effects
1H NMR spectra of nine samples in CCl4 (with 10% C6D6),
with concentrations of 0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30,
0.35 and 0.40 mol L−1, were recorded both for cis-3-PCH and
for cis-3-ICH, and the results are displayed in Tables 1 and 2,
respectively. For the cis-3-tert-butoxycyclohexanol (cis-3-TCH,
Table 2
Hydrogen H3 coupling constants (3J),a equatorial–equatorial molar fractions (Xee)b and energy differences (ꢀGee–aa
)
b,c for cis-3-ICH (2) at several concentrations,d
in CCl4 as solvente
Concentrationd
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xee
ꢀGb,c
b
f
0.01
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
4.92
6.12
6.28
6.78
7.02
7.21
7.36
7.57
7.73
–
0.21
0.36
0.38
0.44
0.47
0.49
0.51
0.54
0.56
0.79
0.36
0.30
0.14
0.07
3.29
3.36
3.44
3.50
3.55
3.60
3.68
3.77
0.02
−0.03
−0.09
−0.14
a
In Hz.
Molar fraction and ꢀGee–aa obtained from experimental coupling constants (3JH3/H2a and H4a) and calculated by the PCMODEL program for H3 hydrogen
b
(3JH3a/H2a = 3JH3a/H4a = 11.28 and 3JH3e/H2e = 3JH3e/H4e = 3.24).
c
In kcal mol−1
.
In mol L−1
.
d
e
f
For a mixture of CCl4/C6D6 (9:1).
At this concentration it was not possible to obtain a reliable value for this coupling constant.

1082
P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
3Jobs − JH1e/H2e
3
Table 3
OH infrared frequenciesa for cis-3-PCH (1) and cis-3-ICH (2)
Xee
=
(1)
3JH1a/H2a − JH1e/H2e
3
Compounds
Concentrationb
Free OH Bonded OHc
ꢀνd
ꢀνe
Since Xee + Xaa = 1, the free energy difference (ꢀG◦) can be
0.01
0.03
0.10
3620
3620
3621
3522
3523
3521
98
97
100
readily obtained from Eq. (2), where R = 0.00199 kcal mol K−1
T = 298 K and K1 = Xee/Xaa for cis-3-PCH and for cis-3-ICH:
,
98
1
2
0.01
0.03
0.10
3623
3623
3624
3515
3517
3514
108
106
110
ꢀG◦ = −RT ln K1
(2)
108
2
2
The molar fraction of the ee conformers and the free energy
difference (ꢀGee–aa), between the ee and aa conformers, for a
concentration range of 0.01–0.40 mol L−1 in CCl4, are given in
Tables 1 and 2. Positive ꢀGee–aa values show that aa conformer
predominates for low concentrations, in CCl4. Its stability can
be attributed to an IAHB, while an increase in concentration
decreases the ꢀGee–aa values, and increases the proportion of
the ee conformer due to the prevalence of an IEHB over the
IAHB.
In cm−1, with 1 cm−1 digital resolution.
a
b
c
d
e
In mol L−1
.
The OH intermolecularly bonded frequency is ∼3450 cm−1
.
Frequency difference between free and bonded OH bands in cm−1
.
Averaged value.
respectively, leading to an increase in the steric effect and, con-
sequently, destabilizing the IAHB, but an opposite and larger
effect arises from the increase in the inductive effect of the R
group, which leaves the oxygen lone pairs more available to
form an IAHB with the OH hydrogen.
The IR spectra of cis-3-PCH and cis-3-ICH at 0.01 and
0.10 mol L−1, in CCl4, were recorded and are shown in Fig. 2.
IR spectra at low concentrations (0.01 mol L−1) show two OH
bands attributed to the two conformers, the high frequency vibra-
tion corresponding to the free OH (conformer ee) and the other to
OHbondedtotheORsubstituent(conformeraa), whichpredom-
inates in relation to the ee conformer. A third band (shoulder), at
lower frequency, arises in the spectrum of a more concentrated
solution (0.10 mol L−1), which is due to an intermolecularly
bonded OH, as shown in Fig. 2b and d. OH stretching frequency
and the frequency shifts (ꢀν), between free and bonded OH, are
given in Table 3.
3
3
The JH1a/H2a and JH1a/H6a coupling constants for cis-
3-MCH [2], cis-3-PCH and cis-3-ICH, in CCl4 and at a
concentration of 0.05 M are 7.34, 6.48 and 6.12 Hz, respectively
(Tables 1 and 2). These values decrease with increasing bulk of
OR substituent group. For a qualitative analysis, the 3J value of
H1 and H3 was used, obtained through the PCMODEL pro-
gram, for the ee and aa conformers of compounds 1, 2 and
3
cis-3-MCH, optimized with the MM3 method. From these J
values for H1 and H3 and Eq. (1), it was possible to conclude
that the aa conformer occurs as 46% (56% optimized by MMX
method, Ref. [2]), 56% and 64% for cis-3-MCH [2], cis-3-PCH
and cis-3-ICH, respectively. These percentages indicate that the
strength of IAHB increases with increasing bulk of substituent
OR(R = CH3, CH2CH2CH3, CH(CH3)2). Forthesesubstituents,
the carbon bonded to oxygen is primary, secondary and tertiary,
Fig. 2. Infrared spectra of cis-3-PCH (1) (a, b) and cis-3-ICH (2) (c, d) in CCl4 solutions: 0.01 (a, c) and 0.10 mol L−1 (b, d).

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
1083
Table 4
b,c
Hydrogen H1 and H3 coupling constants (3J),a equatorial–equatorial molar fractions (Xee)b and energy differences (ꢀGee–aa
different dielectric constants (ε) and basicities (B)e
)
for cis-3-PCH (1), in solventsd of
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xee
ꢀGb,c
b
Solvent
B
ε
CCl4
C2D2Cl4
CDCl3
CD3CN
Acetone-d6
Pyridine-d5
DMSO-d6
0.04
–
2.24
8.50
4.81
37.50
20.70
12.40
46.70
6.76
6.85
–
9.79
9.85
10.73
–
3.45
3.47
–
4.02
4.00
4.14
–
–
6.75
7.08
10.10
10.25
10.52
10.97
–
0.48f
0.42
0.47
0.86
0.88
0.91
0.97
0.06f
0.18
0.08
−1.05
−1.15
−1.37
−2.00
3.41
3.53
3.91
3.97
4.08
4.08
0.07
0.29
0.48
0.58
0.65
a
In Hz.
b
Molar fraction and ꢀGee–aa obtained from experimental coupling constants (3JH3/H2a and H4a
) and calculated by the PCMODEL program
(3JH3a/H2a = 3JH3a/H4a = 11.23 and 3JH3e/H2e = 3JH3e/H4e = 3.42).
c
In kcal mol−1
.
d
e
f
Concentration: 0.05 mol L−1
From Ref. [25].
.
For the CCl4 solution, these values were obtained from experimental coupling constants (3J H1/H2a and H6a) and calculated by the PCMODEL program
(3JH1a/H2a = 3JH1a/H6a = 11.23 and 3JH1e/H2e = 3JH1e/H6e = 2.72).
1
3.2. Frequency shifts and hydrogen bonding
stant values obtained from the H NMR spectra and indicated
that the donor effect of electron density of the iso-propyl group
is larger than that of n-propyl and methyl groups and this effect
is more important than the steric effect provoked by the bulki-
ness of the substituents, which would lead to a decrease in the
IAHB strength.
It has been reported by Kuhn [21] that the conformational
equilibria of trans-cyclohexane-1,2-diol and cis-cyclohexane-
1,3-diol are shifted towards the ee and aa conformers,
respectively, which have the OH groups close to each other
allowing the formation of hydrogen bonds. Kuhn [21] has also
noted that the frequency shifts (ꢀν) increase from the trans-
1,2-diol (32 cm−1) to the cis-1,3-diol (75 cm−1), while Badger
[22] 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 98 2 and 108 2 cm−1 (Table 3), which
was obtained for cis-3-PCH and cis-3-ICH, respectively, indi-
cates that the IAHB energy is larger than for the related diols,
probably because the OCH2CH2CH3 and OCH(CH3)2 oxy-
gen are better hydrogen acceptors than the OH group [23].
The ꢀν values indicated also that increasing bulk of the sub-
stituent increases the IAHB strength, since it was observed
that it follows the order: cis-3-ICH (108 2 cm−1) > cis-3-PCH
(98 2 cm−1) > cis-3-MCH (ꢀν = 92 3 cm−1; from Ref. [2]).
These results are in very good agreement with the coupling con-
3.3. Solvent effects
Tables 4 and 5 present the H1 and H3 coupling constants for
cis-3-PCH and cis-3-ICH, respectively, at a low concentration
(0.05 mol L−1), to avoid interference of IEHB, in several sol-
vents. It can be observed that the H1 and H3 coupling constants
increase with an increase in solvent polarity, showing that the
aa conformer is more stable than the ee conformer in less polar
solvents, such as CCl4, CDCl3 and C2D2Cl4, due to the favor-
able formation of an IAHB (Fig. 1), in the absence of solvation
effects.
The experimental coupling constants, in less polar solvents
(CCl4, CDCl3 and C2D2Cl4) associated with the calculated cou-
pling constant values, obtained from the PCMODEL program
Table 5
b
b,c
Hydrogen H1 and H3 coupling constants (3J),a equatorial–equatorial molar fractions (Xee
different dielectric constants (ε) and basicities (B)e
)
and energy differences (ꢀGee–aa
)
for cis-3-ICH (2), in solventsd of
c,d
Solvent
B
ε
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xee
ꢀGc,d
CCl4
C2D2Cl4
CDCl3
CD3CN
Acetone-d6
Pyridine-d5
DMSO-d6
0.04
–
2.24
8.50
4.81
37.50
20.70
12.40
46.70
–
6.90
–
9.83
9.90
10.69
–
–
3.38
–
4.07
4.05
4.16
–
6.12
6.40
7.00
10.02
10.10
10.41
10.92
3.29
3.38
3.46
3.91
4.00
4.04
4.13
0.36
0.39
0.47
0.84
0.85
0.89
0.96
0.36
0.26
0.08
−1.00
−1.04
−1.25
−1.81
0.07
0.29
0.48
0.58
0.65
a
In Hz.
b
Molar fraction and ꢀGee–aa obtained from experimental coupling constants (3J H3/H2a and H4a) and calculated by the PCMODEL program
(3JH3a/H2a = 3JH3a/H4a = 11.28 and 3JH3e/H2e = 3JH3e/H4e = 3.24).
In kcal mol−1
Concentration: 0.05 mol L−1
From Ref. [25].
.
c
d
e
.

1084
P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
(Tables 4 and 5), indicated that the proportion of aa conformer of
cis-3-ICH is larger than cis-3-PCH, in less polar solvents, con-
firming that the steric effect is less important or smaller than the
effect of stabilization provided by IAHB, which is stronger for
the former compound. The steric effect predominates in more
polar solvents, when the ee conformer becomes more stable.
This behavior can be explained by taking into account that a
polar solvent has a larger affinity for the OH, OCH2CH2CH3
and OCH(CH3)2 groups. Then, the solvent molecules can eas-
ily approach those groups when they are equatorial, and the ee
conformer can be more efficiently solvated [24]. The increasing
stabilization of ee conformer by the solvation effect is confirmed
3
by the data in DMSO, a very polar solvent. Thus, J(H3/H2a
Fig. 3. Stable rotamers for cis-3-PCH (R = n-propyl) (1), obtained at the
B3LYP/6-311 + g** level of theory.
and H4a) is 10.97 and 10.92 Hz in DMSO, leading to an ee
conformer population of 97% and 96% for cis-3-PCH and cis-
3-ICH, respectively.
However, data from Tables 4 and 5 show that the ee pro-
portion is larger when the solvent is pyridine (91% and 89%,
for cis-3-PCH and cis-3-ICH, respectively), which is less polar
than acetone and acetonitrile. Therefore, these results show that
the conformational equilibrium is shifted more by the solvent
basicity [25] (B, Tables 4 and 5) than by the solvent polarity,
estimated by the relative permittivity (or dielectric constant).
3.4. Theoretical calculations
The geometry for the stable conformers of cis-3-PCH (1),
cis-3-ICH (2) and cis-3-TCH (3) were obtained through theoret-
ical calculations using Gaussian 98 [10], with the 6–311 + G**
basis set [14] and at the B3LYP [11–13] level of theory.
The relative energies and dipole moments of conformers with
ꢀE < 3.0 kcal mol−1 are given in Table 6 for all rotamers of
compounds 1–3, presented in Figs. 3 and 4. The rotamers with
ꢀE > 3.0 kcal mol−1 were not considered because they represent
a negligible proportion in the equilibrium.
Fig. 4. Stable rotamers for cis-3-ICH (R = isopropyl) (2) and cis-3-TCH
(R = tert-butyl) (3), obtained at the B3LYP/6-311 + g** level of theory.
in the conformational equilibrium of compounds 1–3 and are in
1
very good agreement with experimental data of H NMR and
IR spectra. There is also a striking difference in the geometries
between rotamer 1aa1 and rotamers 2aa1 and 3aa1. Thus, in the
rotamer 1aa1 and 1aa2 both oxygen lone pairs of the alcoxy
group are in a gauche relationship with the ring C–C bonds,
while in the two latter rotamers (2aa1 and 3aa1) the oxygen lone
pairs of the alcoxy group are always eclipsed with these C–C
bonds. Then, these two compounds (3-ICH and 3-TCH) present
only one conformation, which allows the formation of an IAHB.
The rotamers 1aa1 and 1aa2 are the most stable for cis-3-
PCH, and 1aa1 is more stable than 1ee1 by 1.22 kcal mol−1
.
Moreover, 2aa1 and 3aa1 rotamers are more stable than 2ee2 and
3ee2 by 1.35 and 1.39 kcal mol−1 for cis-3-ICH and cis-3-TCH,
respectively. These results show the important role of an IAHB
Table 6
Rotamers relative energies (ꢀE)a and dipole moments (μ)b for cis-3PCH (1), cis-3-ICH (2) and cis-3-TCH (3) at the B3LYP/6-311 + G** level
Rotamerc,d
ꢀE
μ
Rotamere
ꢀE
μ
Rotamere
ꢀE
μ
1aa1
1aa2
1ee1
1ee2
1ee3
1ee4
1ee5
1ee6
0.00
0.18
1.22
1.33
1.41
1.39
1.30
1.28
3.32
2.77
2.27
2.29
2.86
2.11
0.97
2.03
2aa1
2aa2f
2ee1
2ee2
2ee3
2ee4
2ee5
2ee6
0.00
–
3.41
–
3aa1
3aa2f
3ee1
3ee2
3ee3
0.00
–
1.43
1.39
1.47
3.39
–
2.58
1.72
2.58
1.39
1.35
1.43
1.46
1.78
1.54
2.64
1.71
2.61
0.41
2.39
2.21
a
In kcal mol−1
.
b
c
d
e
f
In Debye.
Fig. 3.
Rotamer 1aa3 give ꢀE > 3.0 kcal mol−1
.
Fig. 4.
ꢀE > 3.0 kcal mol−1
.

P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
1085
Moreover, it can be noted that 1aa2 is also more sta-
ble than 1ee1, since it can also form an IAHB, but it is
0.18 kcal mol−1 lessstablethan1aa1becauseinthe1aa2rotamer
one OCH2CH2CH3 oxygen lone pair is pointing inside the
cyclohexane ring, increasing the steric or electronic repulsion,
a rather different geometry in comparison to 1aa1. Along with
aa1 and aa2, there are other possible rotamers for the aa con-
former (ꢀE > 3.0 kcal mol−1), which are less stable because
they cannot be stabilized by an IAHB. Consequently, these
rotamers are also much less stable than the ee1 rotamer (Table 6)
due to the classical 1,3-diaxial steric effect, which is large
and decisive in the conformational equilibrium of cis isomers
[1]. It can also be observed that most of the other possible
rotamers (ee2, ee3, ee4, ee5 and ee6) of the ee conformer
present stabilities similar to ee1, which indicate that the rota-
tion of the C–O bond does not introduce large changes in their
energies.
Data from Table 6 also show that the aa1 rotamer presents a
larger dipole moment than the ee1 or ee2 rotamer. Therefore, an
increase in solvent polarity should shift the equilibrium towards
the aa conformer. However, an opposite behavior was observed,
ee being favored in polar solvents (Tables 4 and 5). This means
that, for cis-3-PCH and cis-3-ICH, ee is more stable in more
polar solvents due to solvation effects, which are more important
than the dipole moment effect.
3.4.1. Hydrogen bonding
Studies of the PES (potential energy surface) at the B3LYP
level with the 6–311 + G** basis set, for the aa conformer
of compounds 1–3, were performed to observe how changes
in the position of the OH hydrogen, near or far from OR
[R = CH2CH2CH3, CH(CH3)2 and C(CH3)3], which are fol-
lowed by changes in the C2–C1–O–H dihedral angle of the aa1
geometry, would affect the rotamer energy and the formation of
an intramolecularhydrogenbond(IAHB). Fig. 5 showstwomin-
ima, one corresponding to the most stable rotamer (1aa1, 2aa1
and 3aa1), which forms an IAHB, and another one for a less
stable (1aa3, 2aa2 and 3aa2) rotamer (Fig. 3) with the hydrogen
far from the OR group.
Moreover, hydrogen bond energies are usually calculated
as the difference between the energies of a non-bonded and a
bonded species (ꢀE = Eref − Ebonded). The calculated energy of
IAHB for conformer aa, with optimization of the reference struc-
ture (ꢀEHB), at HF, B3LYP and MP2 levels with 6–311 + G**
basis sets, and also by the CBS-4M method [15–18], are pre-
sented in Table 7.
HF/6-311 + g** level shows that ꢀEHB values are very sim-
ilar for compounds 1–3 and cis-3-MCH, indicating that the
Hartree–Fock method is not a good one for calculating the
IAHB strength because it does not include a full treatment of
electron correlation effects [14]. B3LYP and MP2 levels of
theory with 6–311 + g** basis sets showed a similar tendency
in that the IAHB strength increases with the increase of OR
group size from cis-3-MCH to compound 2. It is in very good
agreement with IR data but indicated that the IAHB strength of
compound 3 is smaller than that of compound 2. However, the
CBS-4M method is in better agreement with our results since
Fig. 5. PES (potential energy surface) for the aa1 rotamer, calculated at the
B3LYP/6-311 + g** level of theory for: (a) cis-3-PCH (1), (b) cis-3-ICH (2) and
(c) cis-3-TCH (3).
it indicates that the IAHB strength increases from cis-3-MCH
to compound 3. Previous work on cis-3-MCH [2] had clearly
shownthattheCBS-4Mmethodleadstoresults, whichareinbet-
ter agreement with experimental data in comparison to the other
methods. Thus, it can also be concluded here that the results from
the CBS-4M method show the real tendency for this series of
compounds.
Table 7
Intramolecular hydrogen bond energy (ꢀEHB)a for the aa1 rotamer in compar-
ison to aa3 [cis-3-PCH (1)] or aa2 [cis-3-ICH (2) and cis-3-TCH(3)] rotamer at
different levels of theoryb
Compounds
ꢀEHB
HF
B3LYP
MP2
CBS-4M
Average
cis-3-MCHc
1
2
3
5.13
5.12
5.14
5.01
4.78
5.42
5.61
5.52
5.71
6.21
6.33
5.93
4.41
4.58
6.06
6.33
5.01
5.33
5.79
5.70
In kcal mol−1
Basis set: 6–311 + g**.
Cis-3-methoxycyclohexanol, from Ref. [2].
.
a
b
c

1086
P.R. de Oliveira, R. Rittner / Spectrochimica Acta Part A 70 (2008) 1079–1086
[3] P.R. Oliveira, D.S. Ribeiro, R. Rittner, J. Phys. Org. Chem. 18 (2005) 513.
4. Conclusions
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M.W. Wong, J.B. Foresman, B.G. Johnson, M.A. Robb, E.S. Replogle,
R. Gomperts, J.L. Andres, K. Raghavachavi, J.S. Blinkley, 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,
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6091.
This work reports the relevant concentration and solvent
effects in the conformational equilibrium of cis-3-PCH and cis-
3-ICH, showing that at low concentrations and in a non-basic
solventtheaaconformerpredominatesduetotheformationofan
intramolecular hydrogen bond (IAHB). However, at higher con-
centrations and in basic solvents the formation of intermolecular
hydrogenbonds(IEHB)supersedestheintramolecularhydrogen
bond (IAHB), shifting the equilibrium toward the ee conformer.
1
The results obtained by H NMR and IR spectra indicated
that the strength of IAHBs increases with increasing bulk of
substituent OR [R = CH3, CH2CH2CH3 and CH(CH3)2], prob-
ably due to an increase in the inductive effect of the R group.
This makes the oxygen lone pairs more available to make the
IAHB with the OH group, in opposition to the steric effect. The
CBS-4M method agrees with the tendency shown by experimen-
tal data and includes the cis-3-TCH (3) as the one which has the
strongest IAHB.
Acknowledgments
[18] J.A. Montgomery, J.W. Ochterski, G.A. Petersson, J. Chem. Phys. 101
(1994) 5900.
[19] PCMODEL, Version 75, Serena Software, Bloomington, 2001.
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2783.
The authors thank FAPESP for financial support of this
research and for a fellowship (to P.R.O.), CNPq for a fellowship
(to R.R.) and CENAPAD-SP for computer facilities (Gaussian
98).
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