Influence of OH?N and NH?O inter- and intramolecular hydrogen bonds in the conformational equilibrium of some 1,3-disubstituted cyclohexanes through NMR spectroscopy and theoretical calculations

Article abstract of DOI:10.1016/j.saa.2011.02.010

The analysis of concentration effects in the ¹H NMR data of cis-3-aminocyclohexanol (ACOL) showed that its diequatorial conformer changes from 60% at 0.01 mol L^-1 to 70% at 0.40 mol L^-1 in acetone-d₆. A similar

Full text of DOI:10.1016/j.saa.2011.02.010

Spectrochimica Acta Part A 78 (2011) 1599–1605
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Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
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Influence of OH· · ·N and NH· · ·O inter- and intramolecular hydrogen bonds in the
conformational equilibrium of some 1,3-disubstituted cyclohexanes through
NMR spectroscopy and theoretical calculations
Paulo R. de Oliveiraa, Renan V. Viessera, Palimécio G. Guerrero Jr.a, Roberto Rittnerb,∗
a Laboratory of Organic Synthesis and Natural Products, Department of Chemistry and Biology, Federal University of Technology-Paraná, Av. Sete de Setembro 3165,
80230-901 Curitiba, PR, Brazil
b Physical Organic Chemistry Laboratory, Chemistry Institute, State University of Campinas, POB 6154, 13083-970 Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
The analysis of concentration effects in the 1H NMR data of cis-3-aminocyclohexanol (ACOL) showed that
its diequatorial conformer changes from 60% at 0.01 mol L−1 to 70% at 0.40 mol L−1 in acetone-d6. A similar
increase was also observed for the diequatorial conformer of cis-3-N-methylaminocyclohexanol (MCOL),
from 32% (CDCl3 0.01 mol L−1) to 55% (CDCl3 0.40 mol L−1). The increase in solvent basicity leads to a large
stabilization effect for the diequatorial conformer of both compounds too. For ACOL, it changes from 47%
(ꢀGeqeq–axax = 0.06 kcal mol−1) in CCl4 to 93% (ꢀGeqeq–axax = −1.53 kcal mol−1) in DMSO, while for MCOL it
goes from 7% (ꢀGeqeq–axax = 1.54 kcal mol−1) in CCl4 to 82% (ꢀGeqeq–axax = −0.88 kcal mol−1) in pyridine-d6.
These results indicate that the intramolecular hydrogen bonds (IAHB) OH· · ·N and NH· · ·O stabilize the
diaxial conformers of these compounds in a non-polar solvent. For cis-3-amino-1-methoxycyclohexane
(ACNE) and cis-3-N-methylamino-1-methoxy-cyclohexane (MCNE) no changes were observed in equilib-
rium with the variation of solvent polarity. These results indicate for the first time that the IAHB NH· · ·O
is not strong enough to stabilize the diaxial conformer of these compounds and that the conformation
equilibria of the cis isomers of compounds ACOL and MCOL are influenced only by the IAHB OH· · ·N. More-
over, the presence of a secondary amino group (93% of diaxial conformer in CCl4) leads to an IAHB OH· · ·N
stronger than in primary and tertiary amino-derivatives (53 and 54% of diaxial conformer, respectively)
for 1,3-disubstituted cyclohexanes. Values obtained from the theoretical data through the B3LYP func-
tional are in agreement with the experimental results and indicate that the IAHB strength that influences
the conformational equilibrium of these compounds is the IAHB OH· · ·N. Thus, the IAHB NH· · ·O do not
stabilize the diaxial conformer of the cis isomer of compounds ACNE and MCNE showing that the diequa-
torial conformer will always be more stable than the diaxial conformer, independent of concentration or
solvent.
Article history:
Received 8 November 2010
Received in revised form 13 January 2011
Accepted 7 February 2011
Keywords:
Conformational analysis
NMR spectroscopy
Theoretical calculations
Intramolecular hydrogen bond
Aminocyclohexanols
© 2011 Elsevier B.V. All rights reserved.
Abraham et al. [3] have also demonstrated, through 1H NMR and
1. Introduction
theoretical data, that the strong OH· · ·F hydrogen bond in trans-2-
Previous work on cis isomers 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 equilibria are neither controlled
by conformer dipole moments nor by solvent polarity [1], but
mostly by the classical syn-1,3-diaxial steric effects. However, the
presence of some substituents in the six-membered ring has shown
that is possible to favour the diaxial conformer through intramolec-
ular hydrogen bonding (IAHB). For example, it was shown that
if OH groups, of a dihydroxy compound, are sufficiently close to
each other, they may form an intramolecular hydrogen bond [2].
fluorocyclohexanol is responsible for the predominance of its eq–eq
conformer. Recently, the occurrences of IAHB in cis-3-methoxy- [4],
cis-3-ethoxy- [5] and cis-3-N,N-dimethylamino-cyclohexanols [6],
which stabilize the diaxial conformer and suppress the 1,3-diaxial
steric interactions, have been reported.
Oliveira and Rittner emphasized the importance of IAHB on 1,3-
diaxial interactions of cis-3-alkoxycyclohexanols. They established
that the strength of IAHB increases with the increasing size and
with the inductive effect of the cis-3-alkoxy substituent [7]. The
importance of hydrogen bonding is well known, since it determines
the three-dimensional structures adopted by proteins and nucleic
acids, like in DNA and RNA structures where the double helixes
are formed due to the presence of hydrogen bonds between the
strands [8–11]. The strength of a H-bond strongly depends on both
∗
Corresponding author. Tel.: +55 19 3521 3150; fax: +55 19 3521 3023.
E-mail address: rittner@iqm.unicamp.br (R. Rittner).
1386-1425/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2011.02.010

1600
P.R. de Oliveira et al. / Spectrochimica Acta Part A 78 (2011) 1599–1605
13C NMR (500 MHz, acetone-d6), ı 58.1, 54.9, 41.3, 35.7, 33.4,
20.9.
Catalyst: Rhodium oxide catalyst, Rh(Ox)Li, was prepared
by lithium nitrate fusion with rhodium chloride trihydrate, as
described by Nishimura et al. [18].
OR1
NR2R3
H3
NR2R3
H1
R1O
eq-eq
ax-ax
Anhydrous methylamine. 70 mL of 40% methylamine solution
were slowly dropped (ca. 2 h) onto 70 g of sodium hydroxide con-
tained in a 250 mL three-neck round-bottomed flask, equipped
with a Vigreux micro-distilling apparatus equipped with a col-
lecting flask cooled at −30 ◦C, to prevent loosing the amine (b.p.
−7 ◦C).
Fig. 1. Conformational equilibrium for the cis isomers of compounds ACOL
(R1 = R2 = R3 = H), MCOL (R1 = R3 = H, R2 = CH3), ACNE (R1 = CH3, R2 = R3 = H) and MCNE
(R1 = R2 = CH3, R3 = H).
the orientation of the acceptor X–H bond relative to the lone pair of
ı
the donor Y and the electrostatic strength of the acceptor–Hı+··· Y
cis-3-N-methylaminocyclohexanol (MCOL) (2): 35 mL of anhy-
drous methylamine was placed in a round-bottomed flask fitted
with a magnetic stirrer at −25 ◦C. 2 g of 2-cyclohexen-1-one were
added dropwise and the reaction mixture was stirred at −25 ◦C
for 2 h. The excess of methylamine was evaporated at room tem-
perature. The product obtained (3-methylaminocyclohexanone)
was added dropwise to a 250 mL three-necked round-bottomed
flask containing a suspension of lithium aluminum hydride (0.4 g,
0.11 mmol) in tetrahydrofuran (60 mL), with stirring, at −10 ◦C and
under a nitrogen atmosphere. The mixture was allowed to warm to
room temperature and stirred for one more hour. Water was added,
carefully, to destroy the excess lithium aluminum hydride. The
organic layer was separated with diethyl ether, dried over MgSO4
and filtered. The solvent was evaporated. MCOL was purified by
column chromatography, using hexane:ethyl acetate as eluent and
230–400 mesh silica gel to eliminate the 2-cyclohexen-1-ol. Then
using methanol as eluent gave 1.4 g (52%) of MCOL.
dipole/dipole interaction [12].
The present work describes how inter- and intramolecular
hydrogen bonds (IEHB and IAHB, respectively) influence the con-
formational equilibria of new cis-3-aminocyclohexanol (ACOL),
cis-3-N-methylaminocyclohexanol (MCOL) and of the correspond-
ing new methoxy-derivatives ACNE and MCNE (Fig. 1), through
1H NMR and theoretical calculations. Thus, this paper reports: (i)
the study of concentration and solvent effects by 1H NMR spec-
troscopy and (ii) the determination of the more stable conformers
(diequatorial and diaxial) in the isolated molecule, using theoretical
calculations, for these new compounds and discusses the implica-
tions of these results.
2. Experimental
2.1. Spectra
1H NMR (500 MHz, CDCl3), ı 3.75 (tt, 7.83, 3.76, 1H), 2.61 (tt,
7.90, 3.82, 1H), 2.42 (s, 3H), 1.91 (m, 1H), 1.85 (m, 1H), 1.75 (m, 2H),
1.45 (m, 2H), 1.32 (m, 1H), 1.30 (m, 1H). 13C NMR (500 MHz, CDCl3),
ı 68.6, 56.3, 38.6, 34.4, 33.8, 31.4, 19.1.
The 1H and 13C NMR spectra were recorded on a INOVA 500
spectrometer with probe temperature at 20 ◦C, operating at 499.88
(1H) and 125.70 MHz (13C). Spectra were recorded at concentra-
tions of 0.05 mol L−1 for the study of solvent effects for compounds
1–4, and at 0.01–0.40 mol L−1 in acetone-d6 and CDCl3 for the study
of concentration effects in ACOL (1) and MCOL (2), respectively. In
all cases, SiMe4 (TMS) was used as internal reference. The spec-
tral window ensured a digital resolution of at least 0.18 Hz/point,
and zero-filling helped to further define line shapes. Most FIDs
were processed with Gaussian multiplication, typically gf = 0.25
and 0.35, for spectral resolution improvement, without changes
in the lb parameter. The typical conditions for 1H spectra were:
128 transients, 16k data points, pulse width 37◦, spectral width ca.
3000 Hz and acquisition time (AT) ca. 2.7 s; and for 13C NMR spec-
tra: 1024 transients, 16k data points, pulse width 45◦, sweep width
ca. 10,000 Hz and AT 1 s. Assignment of the signals in 1H and 13C
NMR spectra of the studied compounds (1–4), at a concentration
of 0.30 mol L−1, were performed through gCOSY and HSQC exper-
iments. The quantum chemical calculations were made with the
Gaussian 03 package [13]. Optimized geometries were computed
at the B3LYP level of theory [14–16], using the 6-311+G** basis set
[17].
cis-3-Amino-1-methoxycyclohexane (ACNE) (3): Obtained by the
same method used for ACOL, by replacing 3-aminophenol by 3-
methoxyanilin gave 1.7 g (81%) of ACNE.
1H NMR (500 MHz, CDCl3), ı 3.35 (s, 3H), 3.15 (tt, 10.67, 4.07,
1H), 2.67 (tt, 11.04, 3.82, 1H), 2.21 (m, 1H), 2.01 (m, 1H), 1.77 (m,
2H), 1.21 (m, 1H), 1.07 (m, 1H), 1.00 (m, 2H). 13C NMR (500 MHz,
CDCl3), ı 78.0, 55.5, 49.0, 42.0, 35.9, 30.9, 21.6.
cis-3-N-methylamino-1-methoxycyclohexane
(MCNE)
(4):
Obtained by the same method used for ACOL, replacing 3-
aminophenol by 3-methoxy-N-methylanilin gave 1.8 g (86%) of
MCNE.
1H NMR (500 MHz, CDCl3), ı 3.35 (s, 3H), 3.15 (tt, 10.75, 4.06,
1H), 2.43 (s, 3H), 2.36 (tt, 11.02, 3.78, 1H), 2.29 (m, 1H), 2.03 (m,
1H), 1.89 (m, 1H), 1.80 (m, 1H), 1.24 (m, 1H), 1.11 (m, 1H), 0.99 (m,
2H). 13C NMR (500 MHz, CDCl3), ı 78.4, 57.2, 55.7, 38.9, 33.7, 32.4,
31.6, 21.8.
3. Results and discussion
3.1. Concentration effects
2.2. Compounds
Acetone-d6 was used for the experiments with ACOL, since this
compound was not soluble enough in CCl4 or in CDCl3, while for
MCOL a less polar solvent could be used (CDCl3).
cis-3-Aminocyclohexanol (ACOL) (1): 2.0 g of 3-aminophenol in
15 mL of tert-butyl alcohol were hydrogenated, in a 100 mL auto-
clave, in the presence of 0.5 g of rhodium oxide catalyst, Rh(Ox)Li,
at 60 ◦C, under a hydrogen pressure of 1400–1500 psi. The reduc-
tion was allowed to proceed for 6 h. The catalyst was removed by
filtration and the clear solution was concentrated to give 1.9 g of a
mixture containing 75% of cis-3-aminocyclohexanol (ACOL). It was
purified by column chromatography, using hexane as eluent and
230–400 mesh silica gel, to remove unreacted 3-aminophenol. The
addition of acetone gave 1.3 g (62%) of ACOL.
Tables 1 and 2 present 3JHH values for its H-1 hydrogen of ACOL
and MCOL, respectively, showing that their conformational equilib-
rium changes with their concentration. These results indicate that
an intramolecular hydrogen bond (IAHB) predominates for MCOL,
but is only more prevalent for ACOL, in dilute solutions, since the
diequatorial conformer is in greater concentration even at 0.01 M. A
concentration increase favours self-association due to intermolec-
ular hydrogen bonds (IEHB). Therefore, the study of solvent effects
(next section) was performed at the lowest concentration observ-
able in an NMR experiment.
1H NMR (500 MHz, acetone-d6), ı 3.75 (tt, 8.94, 4.35, 1H),
3.41 (tt, 9.69, 3.57, 1H), 1.8 (m, 2H), 1.6 (m, 2H), 1.3 (m, 4H).

P.R. de Oliveira et al. / Spectrochimica Acta Part A 78 (2011) 1599–1605
1601
Table 1
b
b,c
Hydrogen H-1 and H-3 coupling constants (3J)a equatorial–equatorial molar fractions (Xeq–eq
)
and energy differences (ꢀGeqeq–axax
)
for cis-3-aminocyclohexanol (ACOL) at
different concentrationsd in acetone-d6 as solvent.
Conc.
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xb,c
ꢀGb,c
0.01
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
8.37
8.45
8.53
8.62
8.71
8.78
8.85
8.94
9.02
4.13
4.17
4.19
4.23
4.27
4.29
4.32
4.35
4.39
9.02
9.11
9.19
9.31
9.38
9.47
9.58
9.69
9.77
4.45
4.31
4.23
4.14
4.02
3.89
3.75
3.57
3.39
0.60
0.61
0.63
0.64
0.65
0.66
0.67
0.69
0.70
−0.25
−0.28
−0.31
−0.34
−0.37
−0.40
−0.43
−0.46
−0.49
a
In Hz.
b
3
Molar fraction and ꢀGeqeq–axax obtained from experimental coupling constants (3JH1/H2a and JH1/H6a) and calculated by the PCMODEL program for H-1 hydrogen
[3JH1a/H2a
=
3JH1a/H6a = 11.13 and 3JH1e/H2e
=
3JH1e/H6e = 4.18, obtained from Eq. (1)].
c
In kcal mol−1
.
Concentration in mol L−1
.
d
Table 2
b
b,c
Hydrogen H-1 and H-3 coupling constants (3J)a equatorial–equatorial molar fractions (Xeq–eq
(MCOL) at different concentrationsd in CDCl3 as solvent.
)
and energy differences (ꢀGeqeq–axax
)
for cis-3-N-methylaminocyclohexanol
Conc.
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xb,c
ꢀGb,c
0.01
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
6.37
6.79
7.02
7.21
7.42
7.53
7.69
7.85
8.00
3.29
3.41
3.57
3.57
3.64
3.67
3.77
3.81
3.85
6.36
6.69
6.93
7.15
7.28
7.52
7.65
7.69
7.96
3.26
3.37
3.48
3.69
3.63
3.68
3.72
3.74
3.89
0.32
0.38
0.41
0.44
0.47
0.48
0.51
0.53
0.55
0.45
0.29
0.21
0.15
0.08
0.04
0.02
−0.07
−0.12
a
In Hz.
b
3
Molar fraction and ꢀGeqeq–axax obtained from experimental coupling constants (3JH1/H2a and JH1/H6a) and calculated by the PCMODEL program for H-1 hydrogen
[3JH1a/H2a
=
3JH1a/H6a = 11.16 and 3JH1e/H2e
=
3JH1e/H6e = 4.13, obtained from Eq. (1)].
c
In kcal mol−1
.
Concentration in mol L−1
.
d
The molar fraction (X) and free energy difference (ꢀGeqeq–axax
)
These values show that in less polar solvents, where there is a
small interaction with the solvent, an IAHB is favoured, stabiliz-
ing the diaxial conformer, superseding the 1,3-diaxial steric effect
between the substituents and with the H5ax hydrogen. An increase
in the solvent polarity favours the diequatorial conformer due to an
increase in the interaction between the substituents and the sol-
vent, since these substituents are more available in this conformer.
It is known that for 1,2-disubstituted cyclohexanes the main
effects due to the solute are their interactions with the sol-
vent, where a polar solvent stabilizes the more polar conformer
(diequatorial) [21–23]. For the corresponding 1,3-disubstituted
cyclohexanes there is a competition with the occurrence of an IAHB,
whenever possible [4–7].
for eq–eq and ax–ax conformers (Fig. 1) were determined through
Eqs. (1) and (2), taking the hydrogen coupling constant values of the
eq–eq and ax–ax conformers individually, obtained from optimized
structures using the MM3 method through the PCMODEL [19]
program, with Haasnoot–Altona equations [20], since the exper-
imental data for vicinal coupling constants (3Jobs) are averaged
values.
3Jobs
3JH1a/H2a
Since Xeq–eq + Xax–ax = 1, the free energy difference (ꢀG◦) can be
−
3JH1e/H2e
Xeq–eq
=
(1)
−
3JH1e/H2e
readily obtained from Eq. (2), where R = 0.00199 kcal mol−1 K−1
,
A comparison of 3JHH values from MCOL (Table 4) and from cis-
3-N,N-dimethylaminocyclohexanol (3JH1/H2a and 3JH1/H6a = 7,50 Hz;
in CCl4) [6] shows that the presence of a tertiary amino-group leads
to a larger coupling, indicating a smaller population of the diaxial
conformer than for a secondary amino-group (MCOL), which means
that for this compound the IAHB is stronger than in cis-3-N,N-
dimethylaminocyclohexanol. This is opposite to what was observed
for some previously reported alkoxy-derivatives [7], where there
was an increase in the IAHB with the size of the substituent, increas-
ing the population of the diaxial conformer.
T = 298 K and K1 = Xeq–eq/Xax–ax
.
ꢀG◦ = −RT ln K1
(2)
The results from these calculations showed that a concentration
increase shifts the conformational equilibrium towards the diequa-
torial conformer from 60% (at 0.01 mol L−1) to 70% (at 0.40 mol L−1
)
for ACOL (Table 1), in acetone-d6, while for MCOL it changes from
32% (at 0.01 mol L−1) to 55% (at 0.40 mol L−1) (Table 2), in CDCl3
solution. The differences in the percentages, obtained in different
solvents, will be discussed in the next section.
Thus, although the presence of two methyl groups in cis-3-
N,N-dimethylaminocyclohexanol could lead to an increase in the
electronic density on the nitrogen, it would allow the occurrence of
only a single hydrogen bond (OH· · ·NR2), while for MCOL there are
two possible hydrogen bonds (OH· · ·NHR and RNH· · ·OH). More-
over, in the former there is a larger steric effect between the
substituents. Both effects may explain why 93% of the diaxial
conformer is observed for MCOL (Table 4) but only 54% of cis-3-
3.2. Solvent effects
A large increase in the diequatorial populations of ACOL (Table 3)
occurs on going from CCl4 (47%; ꢀGeqeq–axax = 0.06 kcal mol−1) to
DMSO (93%; ꢀGeqeq–axax = −1.53 kcal mol−1) and of MCOL (Table 4)
on going from CCl4 (7%; ꢀGeqeq–axax = 1.54 kcal mol−1) to pyridine-
d5 (82%; ꢀGeqeq–axax = −0.88 kcal mol−1).

1602
P.R. de Oliveira et al. / Spectrochimica Acta Part A 78 (2011) 1599–1605
Table 3
b
b,c
Hydrogen H-1 and H-3 coupling constants (3J)a equatorial–equatorial molar fractions (Xeq–eq
solvents of different dielectric constants (ε)d and basicities (SB)e.
)
and energy differences (ꢀGeqeq–axax
)
for cis-3-aminocyclohexanol (ACOL) in
Solvent
SB
ε
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xb,f
ꢀGb,c,f
CCl4
CDCl3
0.04
0.07
–
0.29
0.48
0.58
0.65
2.24
4.81
8.50
37.50
20.70
12.40
46.70
7.46
8.32
8.47
9.87
8.45
3.67
4.02
4.07
3.89
4.17
4.02
4.15
7.42
8.49
9.11
10.03
9.07
10.50
–
3.81
4.06
4.39
3.74
4.30
3.75
–
0.47
0.60
0.62
0.82
0.61
0.88
0.93
0.06
−0.23
−0.28
−0.89
−0.28
−1.18
−1.53
C2D2Cl4
CD3CN
Acetone-d6
Pyridine-d5
DMSO-d6
10.29
10.64
a
In Hz.
b
3
Molar fraction and ꢀGeqeq–axax obtained from experimental coupling constants (3JH1/H2a and JH1a/H6a) and calculated by the PCMODEL program for H-1 hydrogen
(3JH1a/H2a
=
3JH1a/H6a = 11.13 and 3JH1e/H2e
=
3JH1e/H6e = 4.18).
c
In kcal mol−1
.
Concentration: 0.05 mol L−1
Ref. [24].
.
d
e
f
Values obtained from experimental coupling constants (3JH1/H2a and 3JH1/H6a).
Table 4
b
b,c
Hydrogen H-1 and H-3 coupling constants (3J)a equatorial–equatorial molar fractions (Xeq–eq
(MCOL) in solvents of different dielectric constants (ε)d and basicities (SB)e.
)
and energy differences (ꢀGeqeq–axax
)
for cis-3-N-methylaminocyclohexanol
Solventf
SB
ε
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xb,g
ꢀGb,c,g
CCl4
CDCl3
C2D2Cl4
CD3CN
Acetone-d6
Pyridine-d5
0.04
0.07
–
0.29
0.48
0.58
2.24
4.81
8.50
37.50
20.70
12.40
4.62
6.79
7.29
8.90
8.66
9.86
4.62
3.41
3.55
3.04
4.07
3.96
4.65
6.69
7.39
9.22
9.19
9.92
4.65
3.37
3.55
3.01
3.28
3.65
0.07
0.38
0.45
0.68
0.64
0.82
1.54
0.29
0.12
−0.44
−0.35
−0.88
a
In Hz.
b
3
Molar fraction and ꢀGeqeq–axax obtained from experimental coupling constants (3JH1/H2a and JH1a/H6a) and calculated by the PCMODEL program for H-1 hydrogen
(3JH1a/H2a
=
3JH1a/H6a = 11.16 and 3JH1e/H2e
=
3JH1e/H6e = 4.13).
c
In kcal mol−1
.
Concentration: 0.05 mol L−1
Ref. [24].
.
d
e
g
Values obtained from experimental coupling constants (3JH1/H2a and 3JH1/H6a).
N,N-dimethylaminocyclohexanol of the same conformer [6], both
in 0.05 mol L−1 in CCl4.
shift the equilibrium towards the diaxial conformer, despite the
presence of the methyl group in OCH3 making the oxygen lone
electron pairs more available than in the OH group.
An extension of this comparison shows, unexpectedly, that 53%
of the ACOL diaxial conformer occurs in CCl4 (Table 3) while for
MCOL it is 93% (Table 4). Three IAHB are possible for ACOL (2
HNH· · ·OH and one OH· · ·NH2) and a smaller steric effect from NH2
in relation to NHCH3 should lead to opposite results. Thus, it seems
that the increase in the electronic density on the nitrogen due to
the presence of a methyl group is responsible for this anomalous
results.
Studies with cis-1,2-diaminocyclohexane by Tomé et
al. [25] showed that there was no suitable geometry for
establishing intramolecular hydrogen bonding, although the
donor–hydrogen–acceptor angle was close to the cutoff con-
ventionally adopted for the existence of this bond type. It
was concluded that the steric effects remain the dominant
interaction ruling the conformational equilibrium of these
diamino-derivatives.
3
An analysis of the solvent effects showed that JHH values do
not increase as the solvent dielectric constant (ε) increases, but
they generally follow the order of solvent basicity (SB) [24]. This
relationship was observed for the first time in other papers from
this laboratory [5–7]. Thus, for example, the MCOL diequatorial con-
former is more solvated, and more stabilized, in a basic solvent,
pyridine-d5 (Xeqeq = 0.82; ε = 12.40; SB = 0.58) than in a very polar
solvent CD3CN (Xeqeq = 0.68; ε = 37.50; SB = 0.29). Note that the SB
value for C2D2Cl4 was not included in the tables since it was not
available [24].
Compounds 3 (cis-3-amino-1-methoxycyclohexane; ACNE) and
4 (cis-3-N-methylamino-1-methoxycyclohexane; MCNE) (Fig. 1)
were used for an analysis of the OH removal effect in the IAHB
stabilization provoked by the presence of only NH2 and NHCH3
groups. The corresponding data are presented in Tables 5 and 6,
respectively.
Thus, it is concluded that the amino-derivatives present an
opposite behaviour when compared to the alkoxy-derivatives,
where an increase in the substituent size showed an increase in
the IAHB strength [7].
3.3. Theoretical calculations
The geometries for the stable conformers were obtained
through theoretical calculations using Gaussian03 [13], with the
6-311+G** basis set [17] from B3LYP [14–16] level of theory. The
relative energies of the conformers and dipole moments with
ꢀE < 3.0 kcal mol−1 are given in Table 7, while the ones with
ꢀE > 3.0 kcal mol−1 were not considered, since they represent a
very small proportion in the equilibria.
Nine possible rotamers for the diaxial and also nine rotamers for
the diequatorial conformers are presented in Fig. 2. ꢀE values show
that ACOL 1aa1 diaxial rotamer is 1.80 kcal mol−1 more stable than
the 1ee7 diequatorial rotamer and that MCOL 2aa1 diaxial rotamer
is 2.11 kcal mol−1 more stable than the 2ee1 diequatorial rotamer
(Table 7, Fig. 2). This supports the results in solution that the equi-
These data (Tables 5 and 6) show that 3JHH values do not change
appreciably with the solvent and that the diequatorial conformer
occurs almost exclusively (>90%) for both compounds, indicating
that the main interaction for compounds ACOL and MCOL is the
OH· · ·N (IAHB) and that the NH· · ·O (IAHB) is not strong enough to

P.R. de Oliveira et al. / Spectrochimica Acta Part A 78 (2011) 1599–1605
1603
Table 5
b
b,c
Hydrogen H-1 and H-3 coupling constants (3J)a equatorial–equatorial molar fractions (Xeq–eq
(ACNE) in solvents of different dielectric constants (ε)d and basicities (SB)e.
)
and energy differences (ꢀGeqeq–axax
)
for cis-3-amino-1-methoxycyclohexane
Solvent
SB
ε
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xb,f
ꢀGb,c,g
CCl4
CDCl3
0.04
0.07
–
0.29
0.48
0.58
0.65
2.24
4.81
8.50
37.50
20.70
12.40
46.70
10.78
11.04
10.85
11.15
11.12
10.99
–
3.78
3.82
3.73
3.77
4.11
3.87
–
10.49
10.67
10.52
10.84
10.98
10.48
10.90
4.05
4.07
4.02
4.10
4.11
4.02
4.11
0.94
0.98
0.95
0.99
0.99
0.97
0.91g
−1.66
−2.19
−1.77
−2.71
−2.52
−2.05
−1.39g
C2D2Cl4
CD3CN
Acetone-d6
Pyridine-d5
DMSO-d6
a
In Hz.
b
3
Molar fraction and ꢀGeqeq–axax obtained from experimental coupling constants (3JH1/H2a and JH1a/H6a) and calculated by the PCMODEL program for H-1 hydrogen
(3JH1a/H2a
=
3JH1a/H6a = 11.23 and 3JH1e/H2e
=
3JH1e/H6e = 3.39) and H-3 hydrogen (3JH3a/H2a
=
3JH3a/H4a = 11.70 and 3JH3e/H2e 3JH3e/H4e = 2.57).
=
c
In kcal mol−1
.
Concentration: 0.05 mol L−1
Ref. [24].
.
d
e
f
Values obtained from experimental coupling constants (3JH1/H2a and 3JH1/H6a).
Values obtained from experimental coupling constants (3JH3/H2a and 3JH3/H4a).
g
Table 6
b
b,c
Hydrogen H-1 and H-3 coupling constants (3J)a equatorial–equatorial molar fractions (Xeq–eq
methoxycyclohexane (MCNE) in solvents of different dielectric constants (ε)d and basicities (SB)e.
)
and energy differences (ꢀGeqeq–axax
)
for cis-3-N-methylamino-1-
Solvent
SB
ε
3JH1/H2a and 3JH1/H6a
3JH1/H2e and 3JH1/H6e
3JH3/H2a and 3JH3/H4a
3JH3/H2e and 3JH3/H4e
Xb,f
ꢀGb,c,f
CCl4
CDCl3
0.04
0.07
–
0.29
0.48
0.58
0.65
2.24
4.81
8.50
37.50
20.70
12.40
46.70
10.43
10.75
10.03
10.89
10.98
10.57
10.95
4.02
4.06
3.46
4.10
4.08
4.09
3.98
10.76
11.02
–
11.21
10.90
10.98
–
3.72
3.78
–
3.76
3.76
3.79
–
0.90
0.94
0.85
0.96
0.97
0.92
0.97
−1.29
−1.63
−1.02
−1.85
−2.05
−1.42
−1.97
C2D2Cl4
CD3CN
Acetone-d6
Pyridine-d5
DMSO-d6
a
In Hz.
b
3
Molar fraction and ꢀGeqeq–axax obtained from experimental coupling constants (3JH1/H2a and JH1a/H6a) and calculated by the PCMODEL program for H-1 hydrogen
(3JH1a/H2a
=
3JH1a/H6a = 11.22 and 3JH1e/H2e
=
3JH1e/H6e = 3.43).
c
In kcal mol−1
.
Concentration: 0.05 mol L−1
Ref. [24].
.
d
e
f
Values obtained from experimental coupling constants (3JH1/H2a and 3JH1/H6a).
Table 7
Conformer relative energies (ꢀE)a and dipole moments (ꢁ)b for the cis isomer of compounds 1–4 at B3LYP/6-311+G** level.
Rotamerc,d
ꢁ (D)
ꢀE
Rotamerc,d
ꢁ (D)
ꢀE
Rotamerc
ꢁ (D)
ꢀE
Rotamerc
ꢁ (D)
0.93
2.01
1.89
1,98
ꢀE
Rotamerc
ꢁ (D)
ꢀEc
1aa1
1aa4
1ee1
1ee2
1ee3
1ee4
1ee5
1ee6
1ee7
1ee8
1ee9
3.41
1.32
2.60
2.61
1.79
1.38
1.40
1.27
1.66
2.89
2.81
0.00
2.95
1.96
2.04
1.91
2.16
1.93
2.06
1.80
2.21
2.05
2aa1
2ee1
2ee2
2ee3
2ee4
2ee5
2ee6
2ee7
2ee8
2ee9
3.26
2.10
2.32
1.49
1.50
1.26
1.37
1.66
2.69
2.47
0.00
2.11
2.25
2.13
2.59
2.39
2.47
2.29
2.68
2.54
3aa3
3aa4
3aa5
3aa7
3aa8
3aa9
3ee1
3ee2
3ee3
3ee4
3ee5
3ee6
3ee7
3ee8
3ee9
2.41
1.08
2.36
2.40
2.41
2.46
2.36
2.36
1.28
1.36
1.28
1.14
1.31
2.54
2.29
1.56
0.98
1.40
1.56
1.56
1.97
0.09
0.17
0.06
2.48
0.06
0.18
0.00
2.55
0.15
4aa4
4aa5
4ee1
4ee2
4ee3
4ee4
4ee5
4ee6
4ee7
4ee8
4ee9
1.09
1.47
0.00
1.80
2.31
2.74
0.33
0.43
0.29
2.84
0.42
4aa16
4aa18
4ee10
4ee11
4ee12
4ee14
4ee15
4ee16
4ee18
2.18 1.43
2.10 1.92
2.21 0.15
2.11 2.36
2.09 0.21
0.99
1.36
1.03
1.08
1.24
2.32
1.96
1,06
1.86
1.90
1.77
1.96
1,26
1,39
2,05
a
In kcal mol−1
In debye.
.
b
c
Fig. 2. Other rotamers of Fig. 2 are much too unstable (ꢀE > 3.0 kcal mol−1).
d
No data were obtained for 1aa2, 1aa6 and 1aa8 and for 2aa7, since in the optimization process they change to 1aa1 and to 2aa3, respectively. The same occurs with 2aa6 and
2aa8 which change to 2aa1
.
librium is more displaced towards the diaxial conformer for MCOL
in relation to ACOL, due to a stronger IAHB (OH· · ·N), as discussed
above. The dipole moments for 1aa1 (ꢁ = 3.41) and 2aa1 (ꢁ = 3.26)
could indicate that these rotamers would predominate in a more
polar solvent, but the results from Tables 3 and 4 show a reversed
behaviour, similar to that observed for 3-halocyclohexanols [1],
since the main effect in the conformational equilibria of these com-
pounds is the possible formation of an IAHB.
It is very interesting to note that 1aa4, 1aa5, 1aa7 and 1aa9
rotamers (Fig. 2) present energy values larger than 3 kcal mol−1
(2.95 kcal mol−1 for 1aa4) in comparison to the 1aa1 rotamer. This
may be attributed to the unfavourable geometry to form an IAHB
(OH· · ·N) and that the IAHB (NH· · ·O) is not strong enough for their
stabilization. Their geometries are very similar to 1aa3 geometry,
which do not allow the formation of any intramolecular hydrogen
bond. It was also observed that 1aa2, 1aa6 and 1aa8 convert to the

1604
P.R. de Oliveira et al. / Spectrochimica Acta Part A 78 (2011) 1599–1605
R3
R1
R2
R3 R1
R2
O
O
R1
R2
R3
N
N
O
N
aa2(aa11)
aa3(aa12)
aa1(aa10)
R2
R1
R2
R1
R2
R1
R3
R3
R3
O
O
N
O
N
N
N
aa6(aa15)
aa5(aa14)
aa4(aa13)
R2
R1
R1
R2
R2
R1
R3
R3
R3
O
O
N
O
N
aa9(aa18)
aa8(aa17)
aa7(aa16)
R2
R1
R2
R1
R3
R2
R1
R3
N
N
N
O
O
O
O
ee2(ee11)
ee1(ee10)
ee3(ee12)
R3
R3
R3
R1
R1
R1
R2
N
N
N
O
O
R2
R2
ee4(ee13)
ee7(ee16)
ee5(ee14)
ee8(ee17)
ee6(ee15)
R3
R2
R1
R2
R1
R2
R1
R3
R3
N
N
N
O
O
O
ee9(ee18)
R3
Fig. 2. Possible rotamers for cis isomers of compounds ACOL (R1 = R2 = R3 = H), MCOL (R1 = R3 = H, R2 = CH3), ACNE (R1 = R2 = H, R3 = CH3), MCNE (4aa1–aa9 and 4ee1–ee9, R1 = H,
2 = R3 = CH3) and (4aa10–18 and 4ee10–18, R2 = H, R1 = R3 = CH3) obtained, at the B3LYP/6-311+G** level.
R
more stable conformer (1aa1) in the optimization process, since they
do not correspond to minima in energy.
occurrence of the large number of rotamers with energies below
3 kcal mol−1, it can be seen that there is a clear predominance of
the diequatorial rotamers and that a comparison of the most sta-
ble diequatorial rotamer (4ee1) with the most stable diaxial rotamer
(4aa4) leads to a difference in energy of 1.09 kcal mol−1, correspond-
ing to 86% of the former in relation to the later rotamer.
These results are clearly in agreement with the experimental
data from Tables 5 and 6, where the diequatorial conformer pop-
ulations largely predominate (0.91–0.99, for ACNE; 0.85–0.97 for
MCNE) in all solvents, allowing to conclude that the NH· · ·O IAHB is
not strong enough to stabilize the diaxial conformer.
Lammermann et al. [26] also did not observe a minimum
in the potential energy scans, with formation of intramolecular
H-bonding (N–H· · ·O) in 1,3-amino-␣,␤-naphthols. The observed
conformations were not influenced by the possible formation of
N–H· · ·O intramolecular H-bonds.
A similar behaviour was observed for MCOL. The relative energy
values for 2aa4, 2aa5 and 2aa9 (Fig. 2) were larger than 3 kcal mol−1
,
in comparison to the most stable rotamer (2aa1). The 2aa7 rotamer
also does not correspond to a minimum and it is converted to 2aa3
,
2aa6 and 2aa8, which turn into the 2aa1 rotamer. It was expected that
the possible formation of an IAHB (NH· · ·O) would stabilize those
rotamers, but this does not occur and they present energies very
similar to the diaxial rotamers which cannot form any IAHB.
Theoretical calculations for compound 3 (ACNE) shows that
there are several diequatorial rotamers with similar relative ener-
gies, but the most stable diequatorial rotamer is 3ee7 which is more
4. Conclusions
The experiments with ACOL and MCOL showed that an increase
in the concentration shifts the equilibrium towards the diequatorial
conformer. At a low concentration the diaxial conformer is stabi-
lized by an IAHB (HO· · ·N), but at higher concentrations the IEHB
predominates and this favours the diequatorial conformer.
Moreover, in non polar solvents the IAHB is favoured due
to smaller interactions with the solvent resulting in significant
amounts of the diaxial conformer in the equilibrium (e.g., 53% of
ACOL and 93% of MCOL, in CCl4). However, in more polar solvents
this situation is reversed leading to high populations of the diequa-
torial conformers for both compounds (e.g., 93% of ACOL and 82% of
MCOL, in DMSO).
stable than the most stable diaxial rotamer (3aa4) by 0.98 kcal mol−1
,
meaning that there is ∼84% of the former rotamer in the equilib-
rium. It can also be observed that 3aa4 (0.98 kcal mol−1), which
can establish an IAHB (NH· · ·O), is more stable than the 3aa3
(1.56 kcal mol−1), but this small stabilization is not strong enough
to make it more stable than the 3ee7 diequatorial rotamer.
The analysis of the results for compound 4 (MCNE) is more com-
plex since it depends on the relative orientation of the NH hydrogen
and of the methoxyl group. Thus, they were grouped as 4aa1–9
4aa10–18, 4ee1–9 and 4ee10–18 (Fig. 2). However, despite the possible
,
The results for ACNE and for MCNE showed a different behaviour.
They do not present an OH group and, thus, the only IAHB possi-

P.R. de Oliveira et al. / Spectrochimica Acta Part A 78 (2011) 1599–1605
1605
ble is NH· · ·O, which is not strong enough to stabilize the diaxial
conformer. Therefore, the diequatorial conformers largely predom-
inates (>90%), for both compounds, in all studied solvents.
Lastly, it was also observed that the presence of a methylamino
group leads to a stronger hydrogen bonding than for an amino
group, probably due to an increase in the electronic density at the
nitrogen atom, provoked by the methyl group. However, this effect
is not extended to the dimethylamino group, where the steric effect
predominates.
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Acknowledgments
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
CAPES for a fellowship (to R.V.V.). CENAPAD-SP is also gratefully
acknowledged for the computer facilities as is Professor Carol H.
Collins’ assistance in revising this manuscript.
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