Conformational analysis of cis-2-halocyclohexanols; Solvent effects by NMR and theoretical calculations

Article abstract of DOI:10.1021/jo101819u

Conformational problems often involve very small energy differences, even low as 0.5 kcal mol^-1. This accuracy can be achieved by theoretical methods in the gas phase with the appropriate accounting of electron correlation. The solution behavio

Full text of DOI:10.1021/jo101819u

pubs.acs.org/joc
Conformational Analysis of cis-2-Halocyclohexanols; Solvent Effects by
NMR and Theoretical Calculations
Ernani A. Basso,* Layara A. Abiko, Gisele F. Gauze, and Rodrigo M. Pontes
´
ꢀ
Departamento de Quımica, Universidade Estadual de Maringa, Av. Colombo, 5790, 87020-900 Maringa-PR, Brazil
ꢀ
eabasso@uem.br
Received September 15, 2010
Conformational problems often involve very small energy differences, even low as 0.5 kcal mol-1
.
This accuracy can be achieved by theoretical methods in the gas phase with the appropriate
accounting of electron correlation. The solution behavior, on the other hand, comprises a much
greater challenge. In this study, we conduct and analysis for cis-2-fluoro-, cis-2-chloro-, and cis-2-
bromocyclohexanol using low temperature NMR experiments and theoretical calculations (DFT,
perturbation theory, and classical molecular dynamics simulations). In the experimental part, the
conformers’ populations were measured at 193 K in CD2Cl2, acetone-d6, and methanol-d4 solutions;
the preferred conformer has the hydroxyl group in the equatorial and the halogen in the axial position
(ea), and its population stays at about 60-70%, no matter the solvent or the halogen. Theoretical
calculations, on the other hand, put the ae conformer at a lower energy in the gas phase (MP2/
6-311þþG(3df,2p)). Moreover, the theoretical calculations predict a markedly increase in the
conformational energy on going from fluorine to bromine, which is not observed experimentally.
The solvation models IEF-PCM and C-PCM were tested with two different approaches for defining
the atomic radii used to build the molecular cavity, from which it was found that only with explicit
consideration of hydrogens can the conformational preference be properly described. Molecular
dynamic simulations in combination with ab initio calculations showed that the ea conformer is
slightly favored by hydrogen bonding.
Introduction
the possible conformers lies below 1 kcal mol-1, and it is not
rare to find cases in which this conformational energy stays
3
Six-membered rings constitute the classical problem in
conformational analysis and are closely connected to the
birth of modern stereochemistry.1 The conformational pref-
erence is usually rationalized as a delicate compromise
among the so-called stereoelectronic effects, which in this
context means repulsion between the substituent and the
axial hydrogens (1,3-diaxial repulsions) and hyperconjuga-
tion.1,2 These effects are intrinsic to each molecule and have
been extensively investigated in the gas phase through theo-
retical calculations.3-6 Often, the energy difference between
as low as 0.2 kcal mol .
-1 7,8 Attaining such a level of accu-
3
racy in solution is one of the greatest challenges for con-
temporary computational chemistry.
Much of what we know about conformational analysis
came from the study of substituted cyclohexanes.1,2,9-12
(5) Goodman, L.; Gu, H.; Pophristic, V. J. Phys. Chem. A 2005, 109,
1223–1229.
(6) Basso, E. A.; Oliveira, P. R.; Caetano, J.; Schuquel, I. T. A. J. Braz.
Chem. Soc. 2001, 12, 215–222.
(7) Freitas, M. P.; Tormena, C. F.; Rittner, R.; Abraham, R. J. J. Phys.
Org. Chem. 2003, 16, 27–33.
(8) Oliveira, P. R. O.; Rittner, R. Magn. Reson. Chem. 2008, 46, 250–255.
(9) Bjornsson, R.; Arnason, I. Phys. Chem. Chem. Phys. 2009, 11, 8689–8697.
(10) Jensen, F. R.; Bushweller, C. H.; Beck, B. H. J. Am. Chem. Soc. 1969,
91, 344–351.
(11) Schneider, H. J.; Hoppen, V. J. Org. Chem. 1978, 43, 3866–3873.
(12) Aliev, A. E.; Harris, K. D. M. J. Am. Chem. Soc. 1993, 115, 6369–
6377.
(1) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994.
(2) Wiberg, K. B.; Hammer, J. D.; Castejon, H.; Bailey, W. F.; DeLeon,
E. L.; Jarret, R. M. J. Org. Chem. 1999, 64, 2085–2095.
(3) Ribeiro, D. S.; Rittner, R. J. Org. Chem. 2003, 68, 6780–6787.
(4) Pophristic, V.; Goodman, L. Nature 2001, 411, 565–568.
DOI: 10.1021/jo101819u
r
Published on Web 12/01/2010
J. Org. Chem. 2011, 76, 145–153 145
2010 American Chemical Society

Basso et al.
JOCArticle
SCHEME 1. Conformational Equilibrium of trans-2-
Halocyclohexanols and cis-2-Halocyclohexanols
Cyclohexane rings and analogous heterocyclics appear in the
structure of innumerous biologically important molecules
and, of course, the role played by these molecules depends on
how the substituents interact among themselves and with
the solvent media. In this respect, several research groups
devoted considerably efforts to dissect the solvent effects on
conformational equilibria.7,8,13-15
A typical case of solvent effect on conformational equilib-
ria was provided by Wiberg et al.15 while studying trans-1,2-
difluorocyclohexane. In the gas phase, the most stable con-
former has both fluorine in the axial position (diaxial), but
in solution this preference is completely reversed, i.e., the
diequatorial conformer becomes progressively more stable
as the medium polarity increases. In other cases, the proxim-
ity of two substituents allows the formation of intramolec-
ular hydrogen bonds, as for instance in trans-2-fluorocyclo-
hexanol.13 Moreover, the presence of the OH group leads to
strong interactions with some solvents, such as CDCl3 and
CD2Cl2, that can affect the conformational trend. Abraham
et al.13 suggested that an equatorial OH group is solvated
differently than an axial one, with direct consequences to the
conformational behavior. Oliveira and Rittner8 investigated
the conformational equilibrium of trans-3-X-cyclohexanols,
finding that the most stable conformer is the one with the halogen
in the axial position, even for a bulky substituent like bromine.
Rationalizing the conformational preference is usually
easier for the trans-1,2-configuration because in most cases
both substituents act in the same direction to make the
diequatorial conformer more stable by avoiding 1,3-diaxial
interactions, Scheme 1. On the other hand, in the cis config-
uration the substituents work in opposite ways, i.e., whereas
one substituent directs the preference to the ae conformer,
the other tend to lead to ea. Surprisingly, there is a silence in
the literature about the conformational behavior of the cis
isomers for 1,2-disubistituted halocyclohexanols.
FIGURE 1. Variable-temperature spectra for cis-2-chlorocyclohexanol
in CD2Cl2. (Atom numbering follows from Scheme 1.)
among others, failed sometimes in the calculation of reliable
energy differences for six-membered rings. Bjornsson and
Arnason9 evaluated the performance of a class of functionals
that include dispersion interactions and concluded that this
kind of correction is essential for obtaining reliable confor-
mational energies. On the other hand, perturbation theory
up to second order is enough to achieve results comparable
to the highly accurate CCSD(T) method. However, the
solvent has not been considered in those studies.
As mentioned above, trans-2-halocyclohexanols as well as
trans-3-halocyclohexanols have been investigated by NMR
spectroscopy and theoretical calculations.7,8,13,14 In con-
trast, the cis isomer was left aside over the years, maybe
because of the experimental difficulties in preparing some of
the halo derivatives as well as by the need of a very refined
theoretical approach to correctly reproduce and interpret the
experimental data in solution. As we go from fluorine to
bromine, it is expected that the ae conformer becomes more
stable because it has a much more bulky substituent in the
equatorial position. Moreover, since the two conformers
have different dipole moments, we expect some sort of
solvent effect. Our present NMR data for cis-2-X-cyclo-
hexanols (X = F, Cl, and Br) shows no such trends but rather
an apparent insensitivity while changing the solvent and
the substituent, with the halogen always being in the axial
position. In the following, we report the conformational
analysis of cis-2-halocyclohexanols by a combination of
experimental and theoretical approaches.
Another crucial question in the study of conformational
equilibrium is the choice of an appropriate theoretical model.
Density functional theory became very popular since the
1990s, mostly because of the success of Becke’s three param-
eter method16 with correlation by Lee, Young, and Parr
(B3LYP).17 However, recent analyses showed that this functional,
(13) Abraham, R. J.; Smith, T. A. D.; Thomas, W. A. J. Chem. Soc.,
Perkin Trans. 2 1996, 1949–1955.
(14) Duarte, C. J.; Freitas, M. P. J. Mol. Struct. 2009, 930, 135–139.
(15) Wiberg, K. B.; Hinz, W.; Jarret, R. M.; Aubrecht, K. B. J. Org.
Chem. 2005, 70, 8381–8384.
(16) Becke, A. D. J. Chem. Phys. 1993, 98, 1372–1377.
(17) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
Results and Discussion
Measuring the Conformational Populations by Low Tempera-
ture Experiments. Figure 1 illustrates the variable temperature
146 J. Org. Chem. Vol. 76, No. 1, 2011

Basso et al.
JOCArticle
TABLE 1. NMR Measurements of Conformers’ Populations and Relative Conformational Energies at -80 °C for cis-2-Halocyclohexanols
1H 13C
average
ΔG° (ea - ae)a ΔG° (ea - ae)a
ΔG° (ea - ae) ((0.04)
% of ea
% of ea
% of ea ((2%)
Fluorine
Chlorine
Bromine
CD2Cl2
acetone-d6
methanol-d4
70
66
76
-0.33
-0.26
-0.44
75
70
74
-0.42
-0.33
-0.40
73
68
75
-0.38
-0.22
-0.19
CD2Cl2
acetone-d6
methanol-d4
63
64
69
-0.20
-0.22
-0.31
65
62
69
-0.24
-0.19
-0.31
64
63
69
-0.29
-0.20
-0.24
CD2Cl2
acetone-d6
methanol-d4
62
65
74
-0.19
-0.24
-0.40
62
64
70
-0.19
-0.22
-0.33
62
65
72
-0.42
-0.31
-0.36
aIn kcal mol-1. A negative value means that the ea conformer is more stable
3
1H NMR spectra of cis-2-chlorocyclohexanol in CD2Cl2. Gen-
erally, we could observe well-resolved signal split at -80 °C for
all of the studied compounds, and the populations were deter-
mined by integration of the spectra at this temperature using
both 1H and 13C spectra. The individual conformers are identi-
fied by their coupling constants and chemical shifts. In Figure 1,
for instance, we see three sets of signals at -80 °C. The left one
(4.56 ppm) must belong to an equatorial H2 (geminal to
chlorine) since it has the largest chemical shift and is unresolved,
i.e., has small coupling constants because of the ∼60° arrange-
ment relative to the vicinal hydrogens. The H1 signal is expected
to present a more resolved shape, a lower chemical shift and the
same integral as H2. The signal that meets these requirements
appears at 3.71 ppm and, together with the previous one,
identifies the ea conformer. By a similar analysis, the signals in
the vicinity of 4.1 ppm are attributed to the H1 and H2
hydrogens of the ae conformer, and after integration we get
63% of ea and 37% of ae. These values can be inserted into the
thermodynamical equation bellow to give the experimental
conformational energies:
observed in the past for 2-halocyclohexanones,18 and in that
case the conformational preference was justified on the basis of
the hyperconjugative effect. For the cyclohexanones, however,
the populations were significantly more sensible to the solvent
polarity. More recently, Oliveira and Rittner8 found the same
axial preference for trans-3-halocyclohexanols. Before trying to
propose any explanation to this behavior, it is crucial to
establish the conformational preference in the gas phase, given
the decisive role the solvent can play. Since we cannot measure
the conformers’ populations in the gas phase, this answer has to
be obtained through theoretical calculations, which we are
going to describe.
Theoretical Study. Conformational Preference in the Gas
Phase. In order to determine the lowest energy orientation
for the OH group in each conformer, we built a potential
energy surface (PES) by varying the H1-C1-O-H dihedral
angle, Figure 2. The three minimum candidates that appear
in the PES (g-, trans, and gþ) were optimized using both
B3LYP/6-311þG(2d,p) and MP2/6-311þG(2d,p) levels of
theory, Table 2. Although MP2 is probably the best choice to
obtain accurate conformational energies,9 it has the draw-
back of being very expensive for vibrational frequencies. In
this way, thermal corrections were obtained from the B3LYP
calculations. The three rotamers from the PES resulted in
converged geometries with MP2. With B3LYP the g-
rotamer was not found to be stable and converged to gþ in
ae. In each case, the minimum energy conformer has the OH
bond directed to the halogen, which are gþ for ae and trans
for ea. These arrangements are not completely adequate for a
hydrogen bond between OH and the halogen, but they still
ΔG° ¼ - RT ln K
ð1Þ
where Ris the gas constant, T is the absolute temperature (in this
case 193.15 K), and K is the equilibrium constant, K = nea/nae,
where nea and nae are the ea and ae conformer populations,
respectively. Table 1 presents the experimental populations and
conformational energies determined from the above analysis for
the remaining compounds.
Generally, the results from 1H and 13C spectra are coherent
to one another, and in every case the ea conformer is found
to be the more stable. A rough estimate of the uncertainties
involved in these determinations can be done by regarding the
1H and 13C spectra measurements as replicates. This gives an
error of 2% in the populations for the average population
lead to a strong interaction requiring ca. 2.6 kcal mol-1 to be
3
broken by a rotation in the ea conformer and more than
3.0 kcal mol-1 for ae. In the gas phase, the rotamers labeled
3
as g- and trans for ae and g- and gþ for ea contribute
practically nothing to the conformers’ populations. There-
fore, we initially confined our analysis in solution to the
lowest energy rotamers (ae-gþ and ea-trans).
1
calculated from H and 13C. The observed variations are in
most cases too close to the experimental errors to allow the
identification of clear trends, from which we conclude that
neither the solvent nor the halogen seems to modify the
conformer’s populations significantly. This is quite surprising,
since the bulky bromine atom would be expected to prefer the
equatorial position on the basis of steric repulsions. In other
words, for a given solvent we would expect the population of
the ae conformer to become increasingly larger while passing
from F to Br. A similar axial preference of the halogens was
The relative energies calculated with the larger basis set,
6-311þþG(3df,2p), are in most cases smaller than those
obtained with 6-311þG(2d,p). For instance, the energy
difference between the most stable conformers of the bromine
(18) Basso, E. A.; Kaiser, C.; Rittner, R.; Lambert, J. B. J. Org. Chem.
1993, 58, 7865–7869.
J. Org. Chem. Vol. 76, No. 1, 2011 147

Basso et al.
JOCArticle
FIGURE 3. 1H NMR signal of the OH proton of cis-2-chloro-
cyclohexanol in acetone-d6 at -80 °C.
It is noteworthy that the lower energy structures are
coherent with the experimental NMR results. More specifi-
cally, in the ae conformer the H1-C1-O-H dihedral angle is
calculated to be about 64°, whereas for the ea conformer it is
about 180°. Hence, we expect to observe two OH proton
resonances, one with a low coupling (3.18 Hz, for ae) and
another with a large coupling constant (6.13 Hz, for ea),
which is exactly what the 1H spectrum shows in the solvents
where the OH resonance could be recorded, Figure 3. As
mentioned above, the ea conformer is the most stable in
solution according to the NMR measurements on the cyclo-
hexane ring nuclei. The OH resonance also shows the ea
conformer in greater proportion (Figure 2), but more than
this, it strongly suggests that the solvent effect originates
from the medium polarity (and maybe from short-range
interactions) and not from a substantial structural modifica-
tion, since the optimized gas phase geometries have struc-
tural parameters compatible with the experimental results. It
must be noted, however, that the OH group of the cyclo-
hexane ring is probably involved in hydrogen bonding when
the solvent is methanol. The question is if this interaction
provides some advantage to one or the other conformer.
More about this point will be discussed in the next sections.
According to the gas phase calculations, Table 2, the ae
conformer is the more stable (except for fluorine in B3LYP),
as someone could anticipate on the basis of steric hindrance.
Moreover, the preference for the ae conformer, which has the
halogen in the equatorial position, is intensified while pass-
ing from fluorine to bromine, except for the higher basis set
(6-311þþG(3df,2p)), which shows the fluorine and chlorine
derivatives with about the same conformational energy.
These results suggest (at least comparing F to Br) that 1,3-
diaxial repulsions operate to allocate the bulky bromine
atom in the equatorial position. Since this conclusion has
the support of MP2 results with a sufficiently large basis set,
we can trust in the gas phase calculations, so that agreement
with experiments has to be searched in the solvent effects.
FIGURE 2. Potential energy surfaces (PESs) for the hydroxyl
group rotation at the B3LYP/6-311þþG(d,p) for F (blue), Cl
(red), and Br (yellow): ae (top) and ea (bottom).
TABLE 2. Relative Energiesa Obtained after Optimizing the Possible
Minima in the PES for Rotation over the H1-C1-O-H Dihedral
ae
ea
g-
trans
gþ
gþ
trans
g-
B3LYP/6-311þG(2d,p)
b
F
Cl
Br
-
-
-
4.022
4.117
4.155
0.000
0.000
0.000
2.617
3.249
3.367
-8.1 ꢀ 10-4
0.514
0.636
2.674
3.428
3.563
b
b
MP2/6-311þG(2d,p)
F
Cl
Br
3.203
3.270
3.197
4.284
4.278
4.213
0.000
0.000
0.000
2.890
3.132
3.148
0.431
0.684
0.813
2.833
3.218
3.254
MP2/6-311þþG(3df,2p)// MP2/6-311þG(2d,p)
F
Cl
Br
3.030
3.243
3.197
3.935
4.069
4.053
0.000
0.000
0.000
2.886
2.966
3.107
0.453
0.450
0.640
2.807
3.037
3.174
aIn kcal mol-1, without thermal corrections. bNot stable at this level.
3
derivative decreases from 0.813 to 0.640 kcal mol-1 with the
MP2 method; this seemingly small variation has indeed
important consequences for the quantitative calculation of
the conformer’s populations. The variation is much less
important for the fluorine derivative, which suggests that
the correct description of the conformational equilibrium of
compounds bearing the heavier atoms chlorine and bromine
requires a basis set of the 6-311þþG(3df,2p) quality.
148 J. Org. Chem. Vol. 76, No. 1, 2011

Basso et al.
JOCArticle
TABLE 3. Differences in Conformational Energiesa in Solution for the
Most Stable Rotamers (ae-gþ and ea-trans) of cis-2-Halocyclohexanols
Calculated Using the Solvation Models IEF-PCM and C-PCM at the
MP2/6-311þþG(3df,2p)//MP2/6-311þG(2d,p) Level
TABLE 4. Gas Phase Dipole Momentsa Calculated at the MP2/6-
311þþG(3df,2p) Level
ae
ea
g-
trans
gþ
gþ
trans
g-
IEF-PCM
C-PCM
UAHF
Bondi
UAHF
Bondi
Vacuum
1.90
2.02
F
Cl
Br
3.25
3.45
3.63
3.77
3.85
3.96
3.02
3.08
3.15
2.27
2.41
2.51
3.26
3.56
3.71
Fluorine
-0.167
-0.223
-0.181
CH2Cl2
acetone
methanol
þ0.139
þ0.101
-0.249
þ0.128
þ0.096
-0.262
-0.219
-0.223
-0.175
2.11
aIn debyes.
Chlorine
-0.269
-0.353
-0.264
results, although qualitatively correct, overestimate too
much the conformational preference for fluorine and under-
estimate it for the heavy atoms. MP2 with the 6-311þG(2d,p)
basis set improves the results over B3LYP for fluorine to a
quantitative level when using Bondi’s radii, but for chlorine
and bromine the agreement with experiments was still
unsatisfactory.
Regarding the efficiency of the solvation models, IEF-
PCM and C-PCM are essentially equivalent. It is evident that
UAHF, with includes hydrogens implicitly in the heavy atom
spheres, cannot capture the molecular cavity nuances with
the accuracy required for this problem. With the use of the
larger basis set, the IEF-PCM results using Bondi’s radii
are quantitatively correct. Probably, a basis set like 6-311þ
G(2d,p) is enough to deal with second raw elements, but for
the heavier atoms we could only obtain quantitative agree-
ment using the 6-311þþG(3df,2p) basis set. In conclusion,
the correct description of the conformational preference in
this system requires the use of explicit hydrogens to build the
molecular cavity in the PCM model and a sufficiently large
basis set to describe the heavier halogens.
Let us now consider the reasons for the conformational
preference in solution. As we said above, the gas phase
calculations show that the ae conformer (with the halogen
in the equatorial position) is the more stable, and this pref-
erence is intensified for bromine because of its large volume.
On the other hand, the experimental conformational popu-
lations show that the ea conformer, which has the halogen in
the axial position, is more stable even for bromine and,
moreover, that this preference is practically unchanged.
The quantity most easily associated to the solvation energy
is the dipole moment, Table 4. Fixing our attention only on
the most stable rotamers (ae-gþ and ea-trans), we see that the
dipole moment of ea is a little larger than that of ae in the gas
phase, and as the solvent effect is proportional to μ2,21 it is
expected that the ea conformer will be more stabilized in
solution than ae, which is actually what the PCM calculations
showed. However, then we have to ask why the conformers’
populations, for a given solvent, remain almost unaffected by the
size of the substituent in solution. For instance, the ea popula-
tions in acetone are 66%, 64%, and 65% for fluorine, chlorine,
and bromine, respectively (1H results, Table 1). Again, the dipole
moments are the key. As we go from fluorine to bromine, the
dipole moment increases (Table 4), and thus the solvent effect is
expected to be the largest for bromine, then chlorine and fluorine.
Therefore, there are two effects acting in opposite directions,
namely, the steric repulsions (pushing the halogen to the equa-
torial position) against the solvent effect (that stabilizes the halo-
gen in the axial position). In this way, as we go from fluorine to
CH2Cl2
acetone
methanol
þ0.189
þ0.168
-0.009
þ0.202
þ0.175
-0.007
-0.257
-0.345
-0.254
Bromine
-0.103
-0.119
-0.127
CH2Cl2
acetone
methanol
þ0.231
þ0.196
þ0.112
þ0.225
þ0.195
þ0.114
-0.086
-0.107
-0.118
aIn kcal mol-1. Negative values mean that the ea conformer is more
stable.
Conformational Preference in Solution with the Polarizable
Continuum Model. One of the most complete approaches to
deal with solvent effects is the polarizable continuum model
(PCM),19,20 which breaks the solvation free energy into
electrostatic and nonelectrostatic contributions. The former
describes how the solute electron density is affected by
the electric field created by the bulk of solvent molecules,
whereas the latter takes into account the energy required for
building a molecular cavity within the liquid (cavitation), as
well as solute-solvent dispersion and repulsion energies.
There are several ways to construct the molecular cavity,
which basically consist in selecting a set of atomic radii and a
method for defining the molecular surface from those radii.
While selecting atomic radii, it is possible to describe hydro-
gens explicitly or to include them implicitly into a single
sphere together with heavy atoms (united atom models). Our
first choice for this work was the well-known UAHF atomic
radii method, which treats hydrogens implicitly. This option,
however, gave conformational trends opposing the NMR
experiments. Since we are dealing with solute-solvent sys-
tems in which hydrogen bonds can effectively occur, we
could be tempted to attribute the divergence to theses inter-
actions. Nevertheless, before judging these deviations from
experiments as a real phenomenon, we also considered the
possibility of an inadequacy of the theoretical model to treat
a so delicate case of conformational equilibrium. In this way,
we performed a series of calculations in which the cavity was
build with explicit hydrogen atoms, more specifically, using
Bondi’s radii. Additionally, we carried out calculations using
two versions of the PCM approach, namely, the integral
equation formalism (IEF-PCM)19 and the conductor-like
polarizable continuum model (C-PCM).20 Table 3 lists the
conformational energies for the most stable rotamers of each
conformer (ae-gþ and ea-trans). We present here only the
MP2/6-311þþG(3df,2p) results, whereas the complete set of
calculations including B3LYP and MP2 with the smaller basis
set are collected as Supporting Information. The B3LYP
(19) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032–
3041.
(20) Barone, V.; Cossi, M. J. Phys. Chem. A. 1998, 102, 1995–2001.
(21) Onsager, L. J. Am. Chem. Soc. 1936, 58, 1486–1493.
J. Org. Chem. Vol. 76, No. 1, 2011 149

Basso et al.
JOCArticle
TABLE 5. Relative Conformational Energies Calculated at the IEF-
TABLE 6. Experimental and Calculated Conformers’ Populationsa,b
PCM-MP2/6-311þþG(3df,2p) Level a
ae
% ea
exptc ((2%)
ΔG°193 (kcal mol-1
)
ea
calcd
expt ((0.04)
calc
g-
trans
gþ
gþ
trans
g-
Dichloromethane
Dichloromethane
F
Cl
Br
73
64
62
63
72
60
-0.38
-0.22
-0.19
-0.20
-0.36
-0.16
F
Cl
Br
0.920
0.968
1.196
1.161
1.107
1.450
0.167
0.305
0.103
0.716
0.500
0.803
0.000
0.000
0.000
0.673
0.574
0.893
Acetone
F
Cl
Br
68
63
65
66
74
66
-0.29
-0.20
-0.24
-0.26
-0.40
-0.26
Acetone
0.223
0.353
0.119
F
Cl
Br
0.630
1.076
0.858
0.803
1.203
1.169
0.389
0.557
0.376
0.000
0.000
0.000
0.395
0.631
0.433
Methanol
F
Cl
Br
75
69
72
71
74
62
-0.42
-0.31
-0.36
-0.34
-0.40
-0.19
Methanol
0.181
0.309
0.127
F
Cl
Br
0.682
0.959
0.663
0.941
1.180
0.935
0.239
0.405
0.414
0.000
0.000
0.000
0.206
0.456
0.527
aT = 193 K. bIEF-PCM-MP2/6-311þþG(3df,2p)//MP2/6-311þ
G(2d,p) with thermal corrections at the B3LYP/6-311þG(2d,p) level
in the gas phase at T = 193 K. cAverage from 1H and 13C. dCalculated by
taking into account the contributions of all rotamers.
aIn kcal mol-1; single-point over the optimized MP2/6-311þG(2d,p)
structure. Thermal corrections (at 193.15 K) are taken from the gas
phase B3LYP/6-311þG(2d,p) frequencies; for the g- rotamer of ae,
which is not stable at B3LYP, we used the same thermal correction of the
trans rotamer.
bromine, there should be a decrease in the preference of ea due to
the greater size of this latter, but this trend is actually counter-
balanced by the solvent effect, which tends to make the ea con-
former of bromine more stable relative to ae in comparison to
fluorine, since the dipole moment of the bromine derivative is larger.
Now, if we want to be able to make a close comparison
between measured and calculated data, it is necessary to take
into account the small contributions of the other rotamers.
In this way, the optimized structures that generated the
energies in Table 2 were submitted to single-point calcula-
tions at the MP2/6-211þþG(3df,2p) level with the IEF-
PCM solvation model, giving the energies in Table 5. It is
interesting to note that the higher energy rotamers all have
dipole moments (Table 4) larger than those of the lowest
energy ones (ae-gþ and ea-trans), so they will become more
stable as the solvent polarity increases. This is exactly what
the data of Table 5 shows. For instance, the g- rotamer of ea
is 3.17 kcal mol-1 above the trans rotamer in the gas phase
3
for the bromine derivative (Table 2). In methanol, this
difference falls to 0.53 kcal mol-1 (Table 5), since the g-
rotamer has a dipole moment of 3.71 D against only 2.51 D
3
of the trans rotamer. As the relative energy of many rotamers
fall bellow 1.0 kcal mol-1 in solution, they begin to make
3
important contributions to the total population of each
conformer (ae or ea). In Table 6 we compare the experi-
mental and calculated conformers’ populations in solution
taking into account the contribution of all rotamers. The
calculated and experimental values can be considered in very
good agreement, since the energy differences for this prob-
lem are in the vicinity of 0.2 kcal mol-1, and this was actually
achieved by the theoretical method.
FIGURE 4. Radial distribution functions (RDFs) for cis-2-
chlorocyclohexanol (blue line for the ae conformer and red line for ea).
Effect of Hydrogen Bonding. In order to get a more
detailed insight about the solute-solvent interactions, we
ran a set of molecular dynamics simulations. Basically, we
are looking for hydrogen bonding patterns that could affect
the individual conformers in different ways. The solvent
arrangement around the solute molecule can be investigated
through the radial distribution functions (RDFs). These func-
tions are constructed with the aim of recognizing structured
portions of the solution, presenting a unitary value in the
bulk liquid (distant from the solute) and peaks differing from
unity (close to the solute) whenever there is a high degree of
organization among the solvent molecules. A hydrogen
bonding, for instance, can be identified by a sharp peak at
˚
about 2 A (for O H RDFs).
3 3 3
For most cases, both conformers interact in very similar
ways with the solvent molecules. In Figure 4 we present the
150 J. Org. Chem. Vol. 76, No. 1, 2011

Basso et al.
JOCArticle
TABLE 7. Relative Conformational Energies for the Most Stable
Rotamers of ae and ea Obtained at the IEF-PCM-MP2/6-311þþ
G(3df,2p)//MP2/6-31þG(d,p) Level
a
ΔE (kcal mol-1
)
complexed
isolated
F
Cl
Br
-0.252
-0.366
-0.131
-0.036
-0.232
-0.021
aWithout thermal corrections, including nonelectrostatic contribu-
tions in the solvation energies.
to the methanol oxygen. Apparently, there is no space to
accommodate two methanol molecules complexing to the
cyclohexane, so that only the strongest interaction prevails.
In the case of dichloromethane, for which there is no such
strong interaction, we observe complexations at both the OH
oxygen and at the halogen, but these interactions happen
with the solvent molecules more distant from the cyclo-
hexane ring than the previous one.
Now, classical force fields are parametrized in a process in
which agreement with the majority of available experimental
data is pursued. Nonetheless, we always must keep in mind
that these parameters may eventually be unable to correctly
describe a new situation. In order to better understand the
solute-solvent interactions, we took advantage of the sta-
tistical information provided by the classical simulations and
combined it with a refined ab initio treatment. This approach
was adopted for the solvent methanol. From the RDFs
(Figure 4), we see that the OH of the cyclohexane ring acts
essentially as a proton donor in hydrogen bonding between
the solute and the methanol molecules. Moreover, integra-
FIGURE 5. Solute-methanol complexes. The energy differences
were obtained with IEF-PCM-MP2/6-311þþG(3df,2p)//MP2/6-
31þG(d,p); distances are in angstroms.
RDFs for cis-2-chlorocyclohexanol, and the remaining ones
are included as Supporting Information. The interaction of
the OH hydrogen with methanol molecules, for instance,
gives rise to marked peaks that identify hydrogen bonds.
Despite that, there is no appreciable difference in the solva-
tion pattern for the OH group in the axial or in the equatorial
arrangement. Nonetheless, Figure 4 shows that the differ-
ences in the hydrogen bond peaks for the two conformers are
substantially different for the chlorine derivative in acetone.
The ae conformer has more hydrogen bonds than ea and
hence is more stabilized by this kind of interaction. As a
result, hydrogen bonds are expected to decrease somewhat
the ea population, which is evidently not reproduced by a
continuum model like PCM. Note that, in Table 6, the
calculated ea populations for chlorine in acetone is larger
than those of the other two derivatives, whereas the experi-
mental values behave in the opposite way. If we take into
account the behavior evidenced in the RDFs, we can suppose
that part of this difference comes from these specific inter-
actions. There are other differences in the calculated and
observed population, like that of the fluorine derivative in
dichloromethane, but in this case we found no evidence in the
RDFs that these difference come from distinct solvation
patterns.
tion of the OH
Ο(methanol) RDFs gives about one
3 3 3
molecule of methanol complexed to the solute. On the basis
of these data, we optimized the geometries of solute-methanol
complexes for the lowest energy conformers, Figure 5.
The optimized structures for the complexes were obtained
in the gas phase using MP2 with a smaller basis set
(6-31þG(d,p)) and further used for a IEF-PCM single point
calculation with the larger basis set (6-311þþG(3df,2p)).
For comparison, we also calculated the relative conforma-
tional energies for the isolated molecules at the same level of
theory, Table 7. Complexation with a methanol molecule,
according to the above combination of methods, favors the
ea conformer for the three compounds. This complexation is
more important for the F and Br derivatives and is helpful in
understanding the small differences between the calculated
and experimental values of Table 6 for methanol. For the
chlorine derivative, on the other hand, hydrogen bonding as
calculated above tends to accentuate the slightly overesti-
mated relative conformational energy (Table 6). Even so,
it is important to say that these relative energies are calcu-
lated to within 0.2 kcal mol-1 compared to experiments,
which is a more than acceptable deviation for condensed
phase calculations.
The halogen is not involved in hydrogen bonding. The
D RDFs actually show a slight protruberance that
X
suggests some kind of complexation; the same happens to
3 3 3
the HO D RDFs but with a somewhat more intense peak.
3 3 3
In both cases, there is no substantial difference between the
two conformers so that, again, this interaction is not ex-
pected to affect the conformational preference. It is interest-
ing to note that the OH acts as a better hydrogen bonding
acceptor in dichlorometane than in methanol, which should
be in principle a better hydrogen donor. In this case, there is
Conclusions
Despite the marked differences from one halogen to
another, the experimental conformers’ populations are very
close for the three substituents in the solvents tested. Theo-
retically, the conformational equilibrium of cis-2-halocyclo-
hexanols requires a careful account of each possible rotamer
an intense OH O interaction, i.e., the OH hydrogen binds
3 3 3
J. Org. Chem. Vol. 76, No. 1, 2011 151

Basso et al.
JOCArticle
generated by rotation of the hydroxyl group, while solvation
effects are crucial for the correct description of the confor-
mational equilibrium in these compounds. The solvent model
has to be applied with the due care in order to capture the
detailed features of the solute-solvent interactions in each
conformer. The united atom model (UAHF) fails to predict
the correct conformational trend, whereas the use of
Bondi’s radii with explicit consideration of all hydrogens
brings experiment and theory very close. Molecular dynamics
simulations show that in most cases the solute complexes
with about the same number of solvent molecules. This
information, in conjunction to MP2 calculations, shows that
complexation to a methanol molecule is likely to favor the ea
conformer. After all, cis-2-halocyclohexanols can be taken as
a good example of the richness still hidden in the conforma-
tional analysis of small molecules.
(cis-2-fluorocyclohexanol, bp 69 °C/14 mmHg; cis-2-chlorocyclo-
hexanol, bp 75 °C/8 mmHg; cis-2-bromocyclohexanol, bp 55 °C/
2 mmHg).
cis-2-Fluorocyclohexanol: 1H NMR (CDCl3, 300.06 MHz) δ
3.77 (1H, m, H1), 4.68 (1H, m, H2), 2.03 (1H, m, H3e), 1.80-1.48
(5H, m, H3a, H4e, H5e, H6a, H6e), 1.46-1.24 (2H, m, H4a, H5a),
2.10 (1H, s, OH). 13C (CDCl3, 75.46 MHz, σ): 70.0 (C1), 92.87
(C2), 28.5 (C3), 20.9 (C4), 22.0 (C5), 30.1 (C6).
cis-2-Chlorocyclohexanol1H NMR (CDCl3, 300.06 MHz) δ
3.83 (1H, m, H1), 4.30 (1H, m, H2), 2.04 (1H, m, H3e), 1.90-1.60
(5H, m, H3a, H4e, H5e, H6a, H6e), 1.46-1.28 (2H, m, H4a, H5a)),
2.10 (1H, d, OH). 13C (CDCl3, 75.46 MHz, σ): 70.6 (C1), 66.21
(C2), 31.9 (C3), 21.6 (C4), 22.4 (C5), 30.7 (C6).
cis-2-Bromocyclohexanol1H NMR (CDCl3, 300.06 MHz)
δ 3.70 (1H, m, H1), 4.51(1H, m, H2), 1.92 (1H, m, H3a), 2.12
(1H, m, H3e), 1.82-1.58 (4H, m, H4e, H5e, H6a, H6e), 1.50-1.30
(2H, m, H4a, H5a). 13C (CDCl3, 75.46 MHz, σ): 70.6 (C1), 62.3
(C2), 33.3 (C3), 22.4 (C4), 23.8 (C5), 32.2 (C6).
NMR Measurements. NMR spectra were acquired on a
Varian Mercury Plus BB Spectrometer, operating at 300.059
MHz for 1H and 75.457 MHz for 13C, in solutions of 20 mg/mL
in CD2Cl2, acetone-d6, and methanol-d4 using TMS as internal
reference. Typical 1H NMR pectra were ran with spectral width
of 4000 Hz and 32 K data points, which was further zero filled to
128 K to give a digital resolution of 0.03 Hz. COSY and HSQC
experiments were also run in order to aid signal attributions.
Variable temperature experiments were conducted at intervals
of about 30 °C down to -80 °C, which was enough the get the
conformers signals well split apart for all solvents.
Theoretical Calculations. The potential energy surfaces (PES)
were constructed by varying the H1-C1-O-H angle in incre-
ments of 10° through 360° at the B3LYP/6-311þþG(d,p) level.
The minimum structures we optimized at the at B3LYP/
6-311þG(2d,p) and MP2/6-311þG(2d,p) levels with tight con-
vergence criterium and ultrafine grid for DFT. Frequency
calculations were performed over the B3LYP geometries to
characterize the stationary points according to the number of
imaginary frequencies (which must be zero for true minima). All
thermochemistry analysis was conducted at 193.15 K to match
the NMR experimental conditions. Solvation effects were in-
cluded with the IEF-PCM and C-PCM models using T=193.15 K
and dielectric constants stored in the program database.
Molecular cavities were constructed using the GEPOL protocol
combined with two different choices of atomic radii, namely,
UAHF (united atoms optimized for Hartree-Fock) and Bondi.
All electronic structure calculations were performed with the
GAUSSIAN 0326 suite of programs.
Experimental Section
Compound Preparations. 2-Bromocyclohexanone22. Prepared
by dropping liquid bromine in a mixture of water and cyclo-
hexanone as described in ref 20. Yields were about 58% (bp 45 °C/
0.5 mmHg). The product was protected from light and stored at
low temperature to avoid decomposition.
2-Chlorocyclohexanone. Obtained commercially and purified
by distillation through a Vigreux column (bp 60-64 °C/10 mmHg).
trans-2-Fluorocyclohexanol23. Cyclohexene oxide (6.4 mL),
KHF2 (7.4 g), and di(ethylene glycol) (13.0 mL) were placed
on a round-bottom flask and kept at 175 °C with magnetic
€
stirring for 1 h. The solid residue was separated on a Buchner
funnel, and the collected liquid was distilled under reduced
pressure in a Vigreux column, yielding 4.3 g (58%) of a colorless
liquid (bp 69-71 °C/15 mmHg).
2-Fluorocyclohexanone23. trans-2-Fluorocyclohexanol (3.0 g)
was dissolved in acetone (50 mL, free of isopropyl alcohol) in a
round-bottom flask. Chrome VI oxide (3,0 g) was dissolved in
sulfuric acid (2.4 mL) and water (6.0 mL), and this mixture was
added dropwise from a addition funnel while keeping the
temperature at about 35 °C. The mixture was then allowed to
react for 24 h under magnetic stirring at room temperature.
Isopropyl alcohol was subsequently added until the solution
became green. After filtration of the solid and removal of the
remaining acetone, the product was dissolved in methylene
dichloride and washed with distilled water. The organic phase
was dried with Na2SO4, and the solvent was removed on a rotary
evaporator. Distillation through a Vigreux column gave 1.43 g
(48%) of a colorless liquid (bp 65-69 °C/13 mmHg).
Molecular dynamics simulations were performed with the
TINKER27,28 package of programs using the OPLS-AA29 force
field. This force field was applied since it has been successful in
cis-2-Halocyclohexanols24,25. The halogenated ketone (17 mmol)
was dissolved in dried THF (25 mL) in a round-bottom flask under
N2 atmosphere and magnetic stirring. After the temperature was
lowered to -78 °C, K-selectride (20 mL) was added, and the reactor
was kept under stirring for 4 h. The reaction mixture was allowed to
attain ambient temperature, after which it was hydrolyzed with
water (3.0 mL) and ethanol (11.5 mL). The organoborane was
oxidized with NaOH 6.0 mol/L (7.5 mL) and 30% H2O2 (11.5 mL).
The aqueous phase was than saturated with CaCO3 and extracted
with ethyl ether. The two organic portions were joined, dried with
MgSO4, and carried to a rotary evaporator where the solvent
was removed. Distillation through a Vigreux column under reduced
pressure gave the pure compounds with yields of about 50%
(26) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., J.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
E; Gaussian, Inc.: Wallingford, CT, 2004.
(22) Allinger, J.; Allinger, N. L. Tetrahedron 1958, 2, 64–74.
(23) Wittig, G.; Mayer, U. Chem. Ber. 1963, 96, 335.
(24) Akiyama, T.; Nishimoto, H.; Kuwata, T.; Ozaki, S. Bull. Chem. Soc.
Jpn. 1984, 67, 180–188.
(25) Vogel, A. I. Vogel’s Textbook of Practical Organic Chemistry,
5th ed.; Longman Scientific and Technical, 1989; p 526.
(27) Ponder, J. W. TINKER: Software Tools for Molecular Design,
Version 5.1; Washington University School of Medicine: St. Louis, 2010.
(28) Ren, P.; Ponder, J. W. J. Phys. Chem. B 2003, 107, 5933–5947.
152 J. Org. Chem. Vol. 76, No. 1, 2011

Basso et al.
JOCArticle
ran in the NVT ensemble with time step of 0.25 fs. Equilibration
periods last 25 ps with accumulations for more 250 ps.
reproducing the properties of liquid alcohols.30 Boxes containing
300 solvent molecules were minimized and used to accom-
modate the solute under investigation, with further minimiza-
tion to rms = 0.01 before starting the molecular dynamics simula-
tions. Simulations used flexible models (solute and solvent) and
deuterated solvent molecules with T = 193 K. The box dimen-
Acknowledgment. The authors would like to thank the
Brazilian Council for Scientific and Technological Develop-
ment (CNPq) for financial support (Grant 47271/2006-6),
for a fellowship to E.A.B. and a scholarship to L.A.A.
sions were (31.7765)3
A
for CD2Cl2-d2, (33.2367)3
A
3
3
˚
˚
A for
for methanol-d4. Simulations
acetone-d6, and (27.2298)3
3
˚
Supporting Information Available: Cartesian coordinates
for the optimized structures, complementary energy tables and
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
(29) Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. J. Am. Chem. Soc.
1996, 118, 11225–11236.
€
(30) Lehtola, J.; Hakala, M.; Hamalainen, K. J. Chem. Phys. B 2010, 114,
€ €
6426–6436.
J. Org. Chem. Vol. 76, No. 1, 2011 153