Calculated and experimental NMR chemical shifts of p-menthane-3,9-diols. A combination of molecular dynamics and quantum mechanics to determine the structure and the solvent effects

Article abstract of DOI:10.1021/jo0016982

NMR chemical shifts have been experimentally measured and theoretically estimated for all the carbon atoms of (1R,3S,4S,8S)-p-menthane-3,9-diol in chloroform solution. Theoretical estimations were performed using a combination of molecular dynamics simula

Full text of DOI:10.1021/jo0016982

J . Org. Chem. 2001, 66, 3775-3782
3775
Ca lcu la ted a n d Exp er im en ta l NMR Ch em ica l Sh ifts of
p-Men th a n e-3,9-d iols. A Com bin a tion of Molecu la r Dyn a m ics a n d
Qu a n tu m Mech a n ics to Deter m in e th e Str u ctu r e a n d th e Solven t
Effects
J ordi Casanovas,*,† Adriana M. Namba,‡ Salvador Leo´n,§ Gilberto L. B. Aquino,‡
Gil Valdo J ose´ da Silva,*,‡ and Carlos Alema´n*,|
Departament de Quı´mica, Escola Universita`ria Polite`cnica, Universitat de Lleida, c/ J aume II No. 69,
Lleida 25001, Spain, Departamento de Quı´mica, Faculdade de Filosofia, Cieˆncia e Letras de Ribeira˜o
Preto, Universidade de Sa˜o Paulo, Av. Bandeirantes No. 3900, 14040-901, Ribeira˜o Preto, SP, Brazil,
Dipartamento di Chimica “G. Ciamician”, Universita` di Bologna, via Selmi 2,
Bologna I-40126, Italy, and Departament d’Enginyeria Quı´mica, E.T.S. d’Enginyers Industrials de
Barcelona, Universitat Polite`cnica de Catalunya, Diagonal 647, Barcelona E-08028, Spain
aleman@eq.upc.es
Received December 4, 2000
NMR chemical shifts have been experimentally measured and theoretically estimated for all the
carbon atoms of (1R,3S,4S,8S)-p-menthane-3,9-diol in chloroform solution. Theoretical estimations
were performed using a combination of molecular dynamics simulations and quantum mechanical
calculations. Molecular dynamics simulations were used to obtain the most populated conformations
of the (1R,3S:4S,8S)-p-menthane-3,9-diol as well as the distribution of the solvent molecules around
it. Quantum mechanical calculations of NMR chemical shifts were performed on the most relevant
conformations employing the GIAO-DFT formalism. A special emphasis was put in evaluating the
effects of the surrounding solvent molecules. For this purpose, supermolecule calculations were
performed on complexes constituted by the solute and n chloroform molecules, where n ranges
from 3 to 16. An excellent agreement with experimental data has been obtained following this
computational strategy.
In tr od u ction
i.e., the molecular conformation and the interactions with
solvent molecules.1d
The problem of predicting accurate NMR chemical
shifts and interpreting them using ab initio quantum
mechanical calculations has attracted considerable at-
tention in recent years.1 Nowadays, theoretical methods
such as IGLO,2 LORG,3 and GIAO4 can provide accurate
chemical shifts of small molecules in the gas phase.5
However, it is well-known that these NMR parameters
are considerably affected by the chemical environment,
NMR chemical shift calculations on very flexible
compounds such as peptides revealed a strong depen-
dence with the conformation.6 Molecular geometries
required for NMR calculations of small molecules are
usually obtained from ab initio calculations or from
crystal structures. However, the structure in the crystal
can differ considerably from that in solution for flexible
molecules, while an ab initio conformational search is
difficult or even impracticable for large molecules. On the
other hand, solvent effects can be included by continuum
models and by supermolecule calculations.1d Continuum
models take into account only the description of long-
range purely electrostatic interactions,7 whereas the
supermolecule approach describes mainly short-range
interactions.8 A recent study about the spectrum of
acetylene indicated that coupling constants are mainly
affected by long-range interactions, whereas the solvent-
induced changes of the NMR chemical shifts are due to
short-range specific interactions.9
* To whom correspondence should be addressed. Additional E-mail
adresses: (J .C.) E-mail: J Casanovas@quimica.udl.es. (G.V.J .S.) E-
mail: gvjdsilv@usp.br.
† Universitat de Lleida.
‡ Universidade de Sa˜o Paulo.
§ Universita` di Bologna.
| Universitat Polite`cnica de Catalunya.
(1) (a) Chesnut, D. B. In Reviews in Computational Chemistry;
Lipkowitz, K. B., Boyd, D. B., Eds.; VCH Publ., Inc.; New York, 1996;
Vol. 8; p 245. (b) J ameson, C. J . Annu. Rev. Phys. Chem. 1996, 47,
135. (c) Schreckenbach, G.; Ziegler, T. Theor. Chem. Acc. 1998, 99, 71.
(d) Helgaker, T.; J aszunski, M.; Ruud, K. Chem. Rev. 1999, 99, 293.
(2) (a) Kutzelnigg, W. Isr. J . Chem. 1980, 19, 193. (b) Kutzelnigg,
W.; Fleischer, U.; Schindler, M. NMR Basic Principles and Progress;
Springer-Verlag: Berlin, 1990; Vol. 23, p 165.
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(b) Hansen, A. E.; Bouman, T. D. J . Chem. Phys. 1989, 91, 3552.
(4) (a) Ditchfield, R. J . Chem. Phys. 1972, 56, 5688. (b) Ditchfield,
R. Mol. Phys. 1974, 27, 789. (c) Pulay, P.; Wolinski, K.; Hinton, J . F.
J . Am. Chem. Soc. 1990, 112, 8251.
Some difficulties emerge when the supermolecule
approach is applied. The most important one is the
computational cost of calculations. Therefore, the number
of solvent molecules explicitly included in the calculations
(5) (a) Hnyk, D.; Vajda, E.; Bu¨hl, M.; Scheleyer, P. v. R. Inorg. Chem.
1992, 31, 2464. (b) Mebel, A. M.; Charkin, O. P.; Schleyer, P. v. R.
Inorg. Chem. 1993, 32, 469. (c) Bu¨hl. M.; Thiel, W.; Fleischer, U.;
Kuzelnigg, W. J . Phys. Chem. 1995, 99, 4000. (d) Sundholm, D. J . Am.
Chem. Soc. 1995, 117, 11523. (e) Gauss, J .; Stanton, J . F. THEOCHEM
1997, 398/ 399, 73. (f) J iao, H.; Scheleyer, P. v. R.; Beno, B. R.; Houk,
K. N.; Warmuth, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 2761.
(6) (a) Sulzbach, H. M.; Scheleyer, P. v. R.; Schaefer, H. F., III. J .
Am. Chem. Soc. 1994, 116, 3967-3972. (b) Laws, D. D.; Le, H.; de Dios,
A. C.; Havlin, R. H.; Oldfield, E. J . Am. Chem. Soc. 1995, 117, 9542.
(7) Tomasi, J .; Persico, M. Chem. Rev. 1994, 94, 2027.
(8) (a) Alema´n, C. Chem. Phys. Lett. 1999, 302, 461. (b) Alema´n, C.
Chem. Phys. 1999, 244, 151.
(9) Pecul, M.; Sadlej, J . Chem. Phys. 1998, 234, 111.
10.1021/jo0016982 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/01/2001

3776 J . Org. Chem., Vol. 66, No. 11, 2001
Casanovas et al.
Sch em e 2. Syn th esis of
Sch em e 1. (1R,3S,4S,8S)-p-Men th a n e-3,9-d iol
(1R,3S,4S,8S)-p-Men th a n e-3,9-d iol
has been usually reduced to one,9,10 and additionally,
supermolecule calculations of realistic systems have been
restricted to the Hartree-Fock level.1d However, the
proper theoretical description of chemical shifts requires
electron correlation effects to be included.1 Furthermore,
the number of solvent configurations is very large, and
the most representative ones should be included in the
clusters built for supermolecule calculations.
and at room temperature. 13C NMR spectra were recorded at
75.47 MHz. Samples were prepared by dissolving ca. 10 mg of
(1R,3S,4S,8S)-p-menthane-3,9-diol (Scheme 2) in 0.5 mL of
deuteriochloroform containing 0.03% (v/v) of TMS as an
internal reference. GC-MS spectra were obtained on a HP GC/
MS System 5988A by EI ionizaion at 70 eV. IR spectra were
recorded on a Perkin-Elmer 1600FT.
In this work, we have investigated the effects of both
the geometry and the solvent on the NMR chemical shifts
of a complex organic molecule in order to determine its
structure. This is the (1R,3S,4S,8S)-p-menthane-3,9-diol
(Scheme 1), which belongs to a family of compounds with
considerable interest in many fields of organic chemistry.
Thus, p-menthane-3,9-diols are obtained from two ter-
penoids frequently used in the synthesis of natural
products, called (-)-isopulegol and (+)-neo-isopulegol.11
As can be seen, (1R,3S,4S,8S)-p-menthane-3,9-diol con-
sists of a cyclohexane ring with methyl, hydroxyl, and
1-methyl-2-hydroxyethyl substituents attached at C1, C3,
and C4 carbon atoms, respectively. The substituents
bonded at C3 and C4 are cis to one another, both of them
being trans with respect to the methyl group attached
to C1. It should be mentioned that the two hydroxyl
groups are close in the space conferring an amphiphilic
character to the compound. Moreover, in some p-methane-
3,9-diols these hydroxyl groups form an intramolecular
hydrogen bond stabilizing an unusual conformation for
the cyclohexane ring.12
The goal of the present study is not only to obtain
structural information from NMR spectra but also to
propose a computational approach to study flexible
organic compounds from chemical shift calculations. In
this approach, both the conformational preferences of the
solute and the most representative configurations of
solvent molecules are obtained from molecular dynamics
(MD) simulations using empirical potential functions.
Shielding properties of the atoms in a magnetic field are
then computed by means of ab initio quantum mechanical
techniques that include electron correlation effects. This
methodology allows us to evaluate accurate NMR chemi-
cal shifts not only on the geometry of the lowest energy
minimum but also on the geometries of other populated
conformers.
(1R,3S,4S)-3-Meth oxym eth yl-p-m en th a n e (2). To a solu-
tion of (+)-neo-isopulegol (1) (0.4871 g; 3.15 mmol) in dry CH2-
Cl2 (15 mL) and chloromethyl methyl ether (0.29 mL; 3.79
mmol), mantained at 0 °C under nitrogen atmosphere was
added dropwise N,N-diisopropylethylamine (1.1 mL; 6.3 mmol).
The resultant mixture was stirred at room temperature for 4
h. The reaction mixture was diluted with ethyl acetate, and
the organic phase was washed twice with saturated aqueous
sodium bicarbonate solution and twice with saturated aqueous
sodium chloride solution. The organic phase was separated,
dried with MgSO4, and concentrated under vacuum. The crude
product was purified by column chromatography on silica gel
eluting with hexane/ethyl acetate (9:1) to yield compound 2
(0.5321 g; 86%) as a colorless liquid. 1H NMR (CDCl3), δ
(ppm): 0.82 (d, J ) 6.5 Hz, 3H), 1.02 (m, 3H), 1.76 (m, 3H),
1.79 (s, 3H), 1.92 (m, 1H), 3.26 (s, 3H), 3.92 (broad s, 1H), 4.51
(d, J ) 6.4 Hz, 1H), 4.64 (d, J ) 6.4 Hz, 1H), 4.74 (m, 1H),
4.81 (m, 1H). 13C NMR (CDCl3), δ (ppm): 22.3 (CH3); 22.4
(CH3); 24.9 (CH2); 26.4 (CH); 34.9 (CH2); 39.5 (CH2); 47.9 (CH);
55.2 (CH3); 73.8 (CH); 95.3 (CH2) 110.5 (CH2); 147.3 (C). MS
m/z (rel intensity): 138 (4), 121 (8), 94 (13), 45 (100), 42 (10).
IR (film) (cm-1): 1042, 1147, 1643, 3080.
(1R,3S,4S,8S)-3-Met h oxym et h yl-p -m en t h a n -9-ol (3a ).
Diborane generated from NaBH4 (0.1092 g; 2.87 mmol) and
BF3‚Et2O (0.35 mL; 2.87 mmol) in diglyme was passed through
a solution of compound 2 (0.1903; 0.96 mmol) in dry THF (6
mL) maintained at 0 °C. After addition of diborane, the
reaction mixture was stirred for 4 h at room temperature.
Then, THF (1 mL of a 50% aqueous solution) was added to
the reaction mixture. The resultant solution was cooled at 0
°C, and then KOH (1 mL of a 12% ethanolic solution) and H2O2
(0.5 mL of a 30% aqueous solution) were added and the
resulting mixture was stirred for 0.5 h. The product was
extracted with ethyl acetate, and the organic phase was
washed with water, dried with MgSO4, and concentrated under
vacuum. The crude product was purified by column chroma-
tography on silica gel eluting with hexane/ethyl acetate (7:3)
to yield two epimers: compound 3a (0.1350 g; 65%) and
compound 3b (0.0451 g; 21.7%) as colorless liquids. Compound
1
3a . H NMR (CDCl3), δ (ppm): 0.86 (d, J ) 6.5 Hz, 3H), 0.93
(m, 3H), 1.03 (d, J ) 7.2 Hz, 3H), 1.27 (m, 1H), 1.43 (m, 1H),
1.62 (m, 1H), 1.68 (m, 1H), 1.73 (m, 1H), 2.01 (m, 1H), 2.90
(broad s, 1H), 3.28 (s, 3H), 3.46 (dd, J ) 11.8 Hz and J ) 0.6
Hz, 1H), 3.83 (dd, J ) 11.8 Hz and J ) 1.9 Hz, 1H), 3.95 (broad
s, 1H), 4.66 (d, J ) 4.5 Hz, 1H), 4.79 (d, J ) 4.5 Hz, 1H). 13C
NMR (CDCl3), δ (ppm): 16.6 (CH3); 22.3 (CH3); 22.9 (CH2);
26.3 (CH); 35.0 (CH2); 37.5 (CH); 38.6 (CH2); 44.8 (CH); 56.0
(CH3); 65.6 (CH2); 75.0 (CH); 95.0 (CH2). MS m/z (rel inten-
sity): 167 (49), 153 (86), 137 (36), 109 (23), 95 (55), 45 (100).
IR (film) (cm-1): 1039, 1151, 3415.
Exp er im en ta l Section
1
Exp er im en ta l Meth od s. H NMR spectra were obtained
on a Bruker DPX 300 spectrometer operating at 300.13 MHz
(10) Malkin, V. G.; Malkina, O. L.; Steinebrunner; Huber, H. Chem.
Eur. J . 1996, 2, 452.
(11) Dev, S. In Terpenoids Handbook; CRC Press: Boca Raton, FL,
1985.
(12) Namba, A. M.; Leo´n, S.; da Silva, G. V. J .; Alema´n, C.
Tetrahedron 2000, 56, 6089.

Structure and Solvent Effects of p-Menthane-3,9-diols
J . Org. Chem., Vol. 66, No. 11, 2001 3777
1
Compound 3b. H NMR (CDCl3), δ (ppm): 0.86 (d, J ) 6.6
vided by the LYP functional20 (B3LYP) was used. The Kohn-
Sham orbitals were constructed using Gaussian-type atomic
orbital (AO) basis sets. All the calculations were performed
using the 6-311G(d) basis set21 to describe the C, H, and O
atoms of the molecule under study.
Carbon isotropic shielding constants of (1R,3S,4S,8S)-p-
menthane-3,9-diol, σ(13Ci)diol, were computed using perturba-
tion theory and the Gauge Invariant Atomic Orbitals (GIAO)
method4 implemented in the Gaussian 94 program package.22
Chemical shifts, δ(13Ci), are referred to a usual standard as
TMS through the relation
Hz, 3H), 0.87 (m, 3H), 0.98 (d, J ) 7 Hz, 3H), 1.26 (m, 1H),
1.51 (m, 2H), 1.73 (m, 2H), 1.98 (m, 1H), 2.90 (broad s, 1H),
3.48 (s, 3H), 3.52 (d, J ) 4.9 Hz, 2H), 3.93 (broad s, 1H), 4.59
(d, J ) 4.5 Hz, 1H), 4.73 (d, J ) 4.5 Hz, 1H). 13C NMR (CDCl3),
δ (ppm): 15.2 (CH3); 22.3 (CH3); 24.7 (CH2); 26.3 (CH); 35.2
(CH2); 37.3 (CH); 38.7 (CH2); 43.5 (CH); 55.9 (CH3); 65.7 (CH2);
73.9 (CH); 95.2 (CH2). MS m/z (rel intensity): 199 (29), 153
(48), 95 (45), 71 (15), 45 (100). IR (film) (cm-1): 1093, 1147,
1039, 3409.
(1R,3S,4S,8S)-p-Men th a n e-3,9-d iol (4). To a solution of
compound 3a (0.1350 g; 0.62 mmol) in acetone (4 mL) was
added HCl (1 mL of a 10% aqueous solution). The resultant
solution was stirred at room temperature for 4 h. The acetone
was removed under vacuum, and the crude product was
dissolved in CH2Cl2 (15 mL) and washed twice with saturated
aqueous sodium bicarbonate solution, twice with saturated
aqueous sodium chloride solution, and with water. The organic
phase was separated, dried with MgSO4, and concentrated
under vacuum. The crude product was purified by column
chromatography on silica gel eluting with hexane/ethyl acetate
(6:4) to yield compound 4 (0.0943 g; 87.7%) as a colorless liquid.
On the basis of 1H, 13C, and COSY NMR spectra, the
hydrogen and carbon atoms of 4 were assigned. The 13C
chemical shifts of this compound were validated through
HBMC and HMQC NMR experiments. The data are sum-
marized in Tables 1 and 2 of the Supporting Information.
F or ce-F ield Ca lcu la tion s. MD simulations in chloroform
solution were carried out using the program package AMBER
4.0.13,14 The force-field parameters used in this work were
taken from a previous study.15 The (1R,3S,4S,8S)-p-menthane-
3,9-diol molecule was placed in the center of an equilibrated
box of chloroform molecules with density 1.48 g/mL. The
solvent molecules that overlapped the (1R,3S,4S,8S)-p-men-
thane-3,9-diol were discarded. The resulting system had
dimensions of 25.60 × 25.60 × 25.60 Å3 and contained 125
chloroform molecules. The OPLS model was used to describe
the chloroform molecules.16 Periodic boundary conditions were
applied using the nearest image convention. We updated the
list of nonbonding interactions every 25 steps, and imposed
an 8 Å cutoff for these interactions. Accordingly, the simulation
boxes are large enough to mimic a dilute solution. The SHAKE
algorithm17 was used to constrain bond lengths of the solvent
molecules to their equilibrium values.
After initial minimization of the whole system, MD simula-
tion was begun with initial velocities set to zero. The system
was coupled to a thermal bath using the algorithm developed
by Berendsen et al.,18 which applied a velocity scaling at each
step. The system was heated to 300 K in 25 ps using a
temperature coupling parameter of 0.2 ps in a constant volume
simulation. The time step was 0.001 ps, and the coordinates
were stored every 1000 steps. The simulation was run for a
total of 3 ns after 25 ps of equilibration.
Qu a n tu m Mech a n ica l Ca lcu la tion s. The most relevant
conformations provided by MD simulations have been used to
predict NMR properties of the (1R,3S,4S,8S)-p-menthane-3,9-
diol molecule. The electronic structure of these conformations
was determined using density functional theory (DFT) meth-
ods, which include some electron correlation effects not present
at the Hartree-Fock level. More specifically, the Becke19 three-
parameter hybrid functional with gradient corrections pro-
δ(13Ci) ) σ(13C)TMS - σ(13Ci)diol
(1)
where, to have accurate chemical shifts, the isotropic shielding
constant of carbon atoms in TMS, σ(13C)TMS ) 184.2 ppm, was
computed at the same level of calculation described above.23
Solvent effects in NMR parameters were taken through the
supermolecule approach by including explicit solvent molecules
in the study. Thus, calculations of the wave functions and of
nuclear shieldings were carried out on (1R,3S,4S,8S)-p-men-
thane-3,9-diol-nCHCl3 complexes, where n ranges from 3 to
16. The position of the chloroform molecules around the solute
was chosen by analyzing the solvent configurations obtained
in MD simulations. Small basis sets were used for the atoms
of the chloroform molecules by the following two reasons: (i)
the size of the (1R,3S,4S,8S)-p-menthane-3,9-diol and (ii) the
large number of explicit solvent molecules involved in this
study. Specifically, the chloroform molecules included in the
complexes were described using the STO-3G,24 3-21G,25 and
3-21G(d)26 basis sets.
The statistical evaluation of the similarity between experi-
mental and calculated chemical shifts was carried out consid-
ering (i) the scaling coefficient (c) and the Pearson correlation
coefficient (r) for a fitting of the type y ) cx and (ii) the root-
mean-square deviation (rms).
Both force-field and quantum mechanical calculations were
performed at the Centre de Supercomputacio´ de Catalunya
(CESCA).
Resu lts
Molecu lar Dyn am ics Sim u lation s. Molecu lar Con -
for m a tion . Two chair conformations can be predicted
for the compound under study (Scheme 3). The first one
presents the methyl and 1-methyl-2-hydroxyethyl sub-
stituents in equatorial position and the hydroxyl sub-
stituent in axial position (I). Calculations using different
theoretical methods clearly indicated that this conforma-
tion is several kcal/mol more stable than the other one
with the methyl and 1-methyl-2-hydroxyethyl substitu-
ents in axial positions (II). Therefore, conformer I was
used as starting point for MD simulations.
(20) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(21) McLean, A. D.; Chandler, G. S. J . Chem. Phys. 1980, 72, 5639.
(22) Gaussian 94, Revision B.3., Frisch, M. J .; Trucks, H. B.;
Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman,
J . R.; Keith, T.; Petersson, G. A.; Montgomery, J . H. B.; Schlegel, H.
B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith,
T.; Petersson, G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham,
M. A.; Zakrzewski, V. G.; Ortiz, V. G.; Foresman, J . B.; Peng, C. Y.;
Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.; Replogle,.G.;
Foresman, J . B.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M.W.;
Andres, J . L.; Replogle, le, E. S.; Gomperts, R.; Martin, R. L.; Fox, D.
J .; Binkley, J . S.; Defrees, D. J .; Baker, J .; Stewart, J . J . P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian, Inc., Pittsburgh, PA,
1995.
(13) Weiner, S. J .; Kollman, P. A.; Nguyen, D. T.; Case, D. A. J .
Comput. Chem. 1986, 7, 230.
(14) Pearlman, D. A.; Case, D. A.; Caldwell, J . W.; Ross, W. S.;
Cheatham, T. E., III; Ferguson, D. M.; Seibel, G. L.; Singh, U. C.;
Weiner, P. K.; Kollman, P. A. Amber 4.1, University of California, San
Francisco, 1995.
(15) Namba, A. M.; Leo´n, S.; da Silva, G. V. J .; Alema´n, C. J .
Comput. Aided. Mol. Design. 2000, in press.
(16) J orgensen, W. L.; Briggs, J . M.; Contreras, M. L. J . Phys. Chem.
1990, 94, 1683.
(17) Ryckaert, J .-P.; Ciccotti, G.; Berendsen, H. J . C. J . Comput.
Phys. 1977, 23, 327.
(23) Casanovas, J .; Pacchioni, G.; Illas, F. Mater. Sci. Eng. B 1999,
68, 16.
(24) Hehre, W. J .; Stewart, R. F.; Pople, J . A. J . Chem. Phys. 1969,
51, 2657.
(18) Berendsen, H. J . C.; Postma, J . P. M.; van Gunsteren, W. F.;
DiNola, A.; Haak, J . R. J . Chem. Phys. 1984, 81, 3684.
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3778 J . Org. Chem., Vol. 66, No. 11, 2001
Casanovas et al.
Sch em e 3. Ch a ir Con for m a tion s of
(1R,3S,4S,8S)-p-Men th a n e-3,9-d iol
tions between the ring and the 1-methyl-2-hydroxyethyl
substituent.
On the other hand, the conformational preferences of
the dihedral angle C4-C8-C9-O are led by the forma-
tion of a hydrogen bonding interaction between the two
hydroxyl groups. As can be seen in Figure 1b, C4-C8-
C9-O changes with C3-C4-C8-C9 allowing to preserve
such intramolecular interaction. Thus, the former changes
from gauche- to gauche+ when the conformation of the
latter varies from gauche+ to gauche-. Figure 1c shows
the preferences for the two hydroxyl groups, the pre-
dominant conformations for the dihedral angles C2-C3-
O-H and C8-C9-O-H being the trans and skew-,
respectively. It is interesting to note the C8-C9-O-H
dihedral angles changes from skew- to gauche+ around
800 ps and retains the latter conformation by about 1300
ps. This conformational transition is related with a swap
in the hydrogen bonding pattern, in which the two
hydroxyl groups interchange their donor and acceptor
roles.
Figure 1a represents the variation with time of the
torsional angles C1-C2-C3-O, C2-C3-C4-C8, and
C5-C6-C1-C7 obtained during the MD simulation. The
most immediately noticeable feature is the large stability
of the chair conformation used as starting point. Thus,
it remains essentially unaltered along the entire trajec-
tory and no transition toward another conformation is
detected. On the other hand, the evolution of the dihedral
angles C3-C4-C8-C9 and C4-C8-C9-O, which is
displayed in Figure 1b, have been used to describe the
conformational preferences of the 1-methyl-2-hydroxy-
ethyl substituent. The gauche+ is the most populated
conformation for the dihedral angle C3-C4-C8-C9,
although it changes to gauche- after 900 ps. However the
latter conformation transforms again into the former one
in about 1200 ps. It is worth noting that the gauche+ and
gauche- conformations avoid unfavorable steric interac-
A list with the population of the unique conformations
of (1R,3S,4S,8S)-p-menthane-3,9-diol was organized. Con-
formations were discarded by comparing the dihedral
angles of both the cyclohexane ring and the substituents
with the corresponding dihedrals of the conformations
already listed. A conformation was kept if at least one of
the dihedral angles differed in more than 30°; otherwise,
the conformation was rejected. Results indicated that two
conformations (Figure 2), denoted A and B, are the most
populated ones, i.e., about 31% and 23%, respectively,
F igu r e 1. Trajectory plots of the torsional angles: (a) C1-C2-C3-O (thick dark line), C2-C3-C4-C8 (thick gray line) and
C5-C6-C1-C7 (thin dark line); (b) C3-C4-C8-C9 (dark line) and C4-C8-C9-O (gray line); and (c) C2-C3-O-H (dark line)
and C8-C9-O-H (gray line); as observed for (1R,3S,4S,8S)-p-menthan3-3,9-diol from MD simulations in chloroform solution.

Structure and Solvent Effects of p-Menthane-3,9-diols
J . Org. Chem., Vol. 66, No. 11, 2001 3779
F igu r e 3. Radial pair distribution function, rpdf(r), of chlo-
roform atoms about the atoms of (1R,3S,4S,8S)-p-menthane-
3,9-diol.
Ta ble 1. Th eor etica l Ch em ica l Sh ifts (δ; in p p m ) of 13C
for th e Most P op u la ted Con for m a tion s of
(1R,3S,4S,8S)-p-Men th a n e-3,9-d iola
conformation A
isolated complex
∆δ
2.1 25.0 -1.2 26.4
1.5 42.0 -0.3 41.1 -1.2
conformation B
isolated complex
∆δ ∆δ
0.2
atom no.
δ
∆δ
δ
δ
δ
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
29.4
44.7
69.1
3.2 28.3
2.4 43.8
2.6 67.8
1.3 70.1
3.6 69.9
0.8 46.9
2.8 28.1
1.0 38.4
3.4
0.9
2.7
3.0
44.4 -1.6 42.4 -3.6 46.8
28.8
36.0
24.3
42.3
68.8
3.4 26.6
0.6 37.2
1.9 24.6
4.2 38.2
1.2 28.2
1.8 36.4
2.2 21.2 -1.1 21.0 -1.4
0.1 38.6 0.5 35.5 -2.6
3.8 62.7 -2.3 63.8 -1.2 62.1 -2.8
15.3 -0.6 17.5
1.6 16.3 0.4 17.4 1.5
a
F igu r e 2. View of the conformations selected for NMR
chemical shifts calculations. These conformations were the
most populated in MD simulations (see text). Distances (in Å)
between the hydrogen bonded hydroxyl groups are indicated.
The values listed correspond to those obtained for the isolated
molecule and the complex with all the solvent molecules at a
distance closer than 4.5 Å (see text; the structures of these
complexes are displayed in Figure 5). The solvent molecules are
described with the STO-3G basis set. Differences with respect to
the experimental values (Table 3) (∆δ; in ppm) are also displayed.
the population of the remaining 19 unique conformations
being lower than 7%. Accordingly, conformations A and
B were selected for NMR chemical shifts calculations. As
can be seen in Figure 2, these two conformations are
stabilized by an intramolecular hydrogen bond which is
in good agreement with previous experimental results.12
Thus, 1H NMR spectra of (1R,3S,4S,8S)-p-menthane-3,9-
diol in deuterated chloroform exhibited an intramolecular
interaction involving the hydroxyl groups. The dihedral
angles of the two conformations are listed in the Sup-
porting Information. As expected from the results dis-
played in Figure 1, they mainly differ in the arrangement
of the 1-methyl-2-hydroxyethyl substituent.
On the other hand, conformation II (see Scheme 3) was
used as starting geometry of a 500 ps MD simulation.
This initial arrangement becomes into a twist conforma-
tion in 50 ps, which transforms into the chair conforma-
tion I after 300 ps. The unique conformations of the
resulting trajectory were selected using the procedure
described in the previous paragraph. The most populated
twist conformation (more than 40%), which was denoted
C, presents the 1-methyl-2-hydroxyethyl and hydroxyl
substituents in equatorial and axial positions, respec-
tively. This conformation is also displayed in Figure 2
and was used to explore the differences in NMR chemical
shifts between the most stable chair and twist conforma-
tions of the cyclohexane ring.
Moreover, analysis of the maximum residence time for
the chloroform molecules nearest to the solute reveal that
they have a large mobility and exchange very rapidly
with the bulk chloroform. According to this, the chloro-
form molecules required for chemical shift calculations
were chosen using a distance criterion, the rpdf(r) being
used to find the solvent molecules closest to the solute.
NMR Ch em ica l Sh ifts of th e Isola ted Molecu le.
Prior to study in depth, the environment effects, NMR
chemical shifts of carbon atoms in (1R,3S,4S,8S)-p-
menthane-3,9-diol, δ(13Ci), were computed considering the
isolated molecule in the gas-phase. The carbon chemical
shifts evaluated for conformations A and B at the B3LYP/
6-311G(d) level of calculation are displayed in Table 1.
The statistical data in Table 2 demonstrate excellent
agreement between experimental and theoretical values.
Thus, Pearson correlation coefficients are r ) 0.99 with
rms values of about 2-3 ppm. It should be noted that
for conformation A the similarity between experimental
and theoretical data is excellent for all the carbon atoms
with exception of C1, C5, C8, and C9, which are overes-
timated by about 3-4 ppm. The chemical shifts measured
for these four carbon atoms are better reproduced by B
than by A. Moreover, for conformation B the only value
overestimated by more than 3 ppm is the chemical shift
of C3. Indeed, our statistical analysis indicates that B
provides better results, in general, than A.
Distr ibu tion of th e Solven t a r ou n d th e Solu te.
Figure 3 presents the computed radial pair distribution
function, rpdf(r), of chloroform atoms about the atoms of
(1R,3S,4S,8S)-p-menthane-3,9-diol. No sharp peak as-
sociated to a well-defined first hydration shell was found.
On the other hand, carbon chemical shits calculated
for conformation C (data not shown) indicated that the
change from chair to twist implies a considerable dete-
rioration in the agreement between the theoretical and

3780 J . Org. Chem., Vol. 66, No. 11, 2001
Casanovas et al.
Ta ble 2. Sta tistica l Resu ltsa of th e Com p a r ison betw een
th e Exp er im en ta l a n d Th eor etica l NMR Ch em ica l Sh ifts
in (1R,3S,4S,8S)-p-Men th a n e-3,9-d iol
conf conf conf
environment
A
B
C
isolated diol at the B3LYP/6-311G(d) level
0.99 0.99 0.97
1.05 1.02 0.97
2.7
1.7
4.3
diol at the B3LYP/6-311G(d) level +
3 CHCl3 around the polar region at
the STO-3G level
1.00 0.99
1.02 1.01
1.8
1.7
diol at the B3LYP/6-311G(d) level +
3 CHCl3 around the nonpolar region at
the STO-3G level
0.99 0.99
1.06 1.02
3.4
1.8
diol at the B3LYP/6-311G(d) level +
3 CHCl3 around the polar region at
the 3-21G level
1.00 0.99
F igu r e 4. View of the complexes selected for NMR chemical
shifts calculations on conformations A and B of solvated
(1R,3S,4S,8S)-p-menthane-3,9-diol. Complexes contain three
solvent molecules around the polar (a) or nonpolar (b) regions
of the solute.
1.03 1.01
2.0
1.7
diol at the B3LYP/6-311G(d) level +
3 CHCl3 around the polar region at
the 3-21G(d) level
1.00 0.99
As can be seen, the agreement between the experi-
mental chemical shifts and those predicted for conforma-
tion A improves when the solvent molecules are distrib-
uted around the polar region. Thus, the rms is lower than
that obtained for the isolated molecule by 0.9 ppm.
Furthermore, there is also an improvement in the scaling
and Pearson correlation coefficients. However, when the
chloroform molecules are located at the nonpolar region
of A, the statistical parameters are similar, or even worst,
than those obtained for the isolated molecule. A different
situation appears for conformation B since the chemical
shifts predicted for the isolated molecule are very similar
to those obtained for the complex with three solvent
molecules, independently of their position around the
solute. Thus, no clear improvement is induced by explic-
itly considering the three solvent molecules around this
conformation.
Effect of th e Ba sis Set on th e Descr ip tion of th e
Solven t. The importance of the basis set used to describe
the solvent in the supermolecule approximation was
investigated by considering the complexes containing
three chloroform molecules around the polar region of the
solute (Figure 4a). For this purpose, calculations were
performed using the STO-3G, 3-21G, and 3-21G(d) basis
sets for the solvent, whereas the solute was described in
all cases with the 6-311G(d) basis set. The statistical
analysis of the results has been included in Table 2, and
the δ(13Ci) predicted with the 3-21G(d) basis set are listed
in Table 3.
Comparison of the results displayed in Tables 2 and 3
indicates that the effect of the basis set is similar for
conformation A and B. Thus, the chemical shifts pre-
dicted for the two conformations with the three basis sets
are very similar suggesting that the STO-3G basis set is
able to capture the solvent effects. Furthermore, it is
worth noting that the two conformations present a
similar agreement with experimental when solvent ef-
fects are included.
Effect of the Number of Explicit Solvent Molecules. To
ascertain the influence of the number of explicit solvent
molecules on δ(13Ci) calculations, we investigated com-
plexes with more than three solvent molecules. First,
complexes with six chloroform molecules were generated
by joining those closest to the polar and nonpolar regions
1.03 1.01
2.0
1.7
diol at the B3LYP/6-311G(d) level +
0.99 0.99
6 CHCl3 at the STO-3G level
1.03 1.02
2.6
2.6
diol at the B3LYP/6-311G(d) level + all the 0.99 0.99
CHCl3 molecules at a distance closer
than 4.5 Å described at the STO-3G level
1.00 1.01
1.9
2.2
a
Standard font indicates the Pearson correlation coefficient,
bold font indicates the scaling coefficient, and italic font indicates
the root-mean-square deviation (rms; in ppm).
experimental chemical shifts (Table 2). Accordingly,
conformation C was not considered in the analysis of the
solvent effects.
NMR Ch em ica l Sh ifts in Ch lor ofor m Solu tion .
Solvent-induced changes in δ(13Ci) were estimated using
the supermolecule approach. More specifically, we inves-
tigated the influence of (i) the position of the solvent
molecules around the solute, (ii) the basis set used to
describe the solvent, and (iii) the number of explicit
solvent molecules.
Dep en d en ce on th e P osition of th e Solven t Mol-
ecu les a r ou n d th e Solu te. As was mentioned in the
Introduction, p-menthane-3,9-diols are amphiphilic mol-
ecules with the polar and nonpolar regions clearly de-
fined. The influence of the chloroform molecules arranged
in each region on the chemical shifts was investigated
by considering complexes constituted by (1R,3S,4S,8S)-
p-menthane-3,9-diol and three solvent molecules. The
position of the solvent molecules around these regions
was taken from the MD trajectories previously shown.
Thus, the chloroform molecules closest to the solute were
used for these calculations. Figure 4 shows the arrange-
ment of the solvent molecules around the polar and
nonpolar regions for the conformations A and B of
(1R,3S,4S,8S)-p-menthane-3,9-diol. The calculated NMR
chemical shifts for these four complexes are listed in
Table 3, the statistical analyses of the results being
included in Table 2. Calculations were performed con-
sidering the 6-311G(d) and STO-3G basis sets for the
(1R,3S,4S,8S)-p-menthane-3,9-diol and chloroform mol-
ecules, respectively.

Structure and Solvent Effects of p-Menthane-3,9-diols
J . Org. Chem., Vol. 66, No. 11, 2001 3781
Ta ble 3. Th eor etica l Ch em ica l Sh ifts (in p p m ) of 13C for th e Com p lexes Con stitu ted by
(1R,3S,4S,8S)-p-Men th a n e-3,9-d iol a n d Th r ee Solven t Molecu lesa Distr ibu ted a r ou n d Eith er th e P ola r or Non p ola r
Region s of th e Solu te
conformation A
polar
conformation B
polar
nonpolar
STO-3G
nonpolar
STO-3G
atom
STO-3G
3-21G(d)
STO-3G
3-21G(d)
exptl
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
28.9
44.9
69.6
44.6
26.6
35.9
23.9
38.3
64.7
14.2
29.1
45.1
69.8
44.9
27.7
35.8
23.9
39.6
65.5
14.4
29.4
44.5
69.1
44.4
29.3
40.8
26.5
42.1
68.7
16.2
26.1
41.8
70.2
46.7
28.5
36.1
21.1
38.5
63.2
16.3
26.4
41.7
70.2
46.7
28.4
36.1
21.2
38.5
63.5
16.2
26.1
41.6
70.2
46.6
28.1
38.0
20.8
38.5
63.7
16.3
26.2
42.3
66.5
46.0
25.4
35.4
22.4
38.1
65.0
15.9
a
The solvent molecules are described using the STO-3G and 3-21G(d) basis sets, as indicated in the columns. Experimental values (in
ppm) are listed in the last column for comparison. The complexes are displayed in Figure 4.
phase and with three solvent molecules around the polar
region by 5% and 2%, respectively. On the other hand,
no improvement was obtained for conformation B. Ac-
cordingly, it can be concluded that the large computa-
tional cost of calculations with a complete solvation shell
is not compensated by a significant improvement of the
chemical shifts.
Discu ssion
The 13C NMR chemical shifts of (1R,3S,4S,8S)-p-
menthane-3,9-diol have been calculated using a combina-
tion of MD simulations and quantum chemical calcula-
tions, the resulting values being compared with experi-
mental data. MD simulations were used to investigate
the conformational preferences of (1R,3S,4S,8S)-p-men-
thane-3,9-diol in chloroform solution. Results allowed to
identify the most populated conformations of this mol-
ecule, which correspond to two chair conformations with
the methyl and 1-methyl-2-hydroxyethyl substituents in
equatorial position and the hydroxyl substituent in axial
position. Chemical shifts were computed for such con-
formations as well as for a less populated twist confor-
mation at the B3LYP/6-311G(d) level using the GIAO
method.
The computed chemical shifts depend strongly on the
conformation, the agreement with experimental data
being better for the chair conformations than for the twist
one. The rms for the former conformations is lower than
3 ppm whereas for the latter is larger than 4 ppm.
Indeed, for conformation A the agreement between the
theoretical and experimental chemical shifts is very good
for all the carbon atoms excepting C1, C5, C8 and C9.
For conformation B only the chemical shift predicted for
C3 differs by more than 3 ppm with respect to the
experimental value. The discrepancies found for these
atoms are largely improved by including solvent effects.
Thus, when conformation A is surrounded by chloroform
molecules only C4 presents a difference between the
calculated and the experimental values larger than 3
ppm.
F igu r e 5. Conformations A and B of (1R,3S,4S,8S)-p-men-
thane-3,9-diol surrounded by 15 and 16 chloroform molecules.
of the solute; i.e., for each conformation the solvent
molecules displayed in Figure 4a,b were joined. The
chemical shifts (data not shown) obtained for these
complexes did not provide any improvement with respect
to those obtained with less solvent molecules. Indeed, the
statistical analysis of the results, which has been in-
cluded in Table 2, indicates that the new NMR param-
eters are similar or even worst than those calculated for
the complexes with only three solvent molecules.
As a final step, we decided to evaluate the NMR
chemical shifts of (1R,3S,4S,8S)-p-menthane-3,9-diol but
considering a number of solvent molecules enough to
mimic the solution state. This was done by selecting all
the chloroform molecules arranged at less than 4.5 Å of
the solute, i.e., a complete solvation shell. The resulting
systems are displayed in Figure 5. It is worth noting that
now 15 and 16 explicit chloroform molecules surround
conformations A and B, respectively. The computed
chemical shifts and the results of the statistical analysis
are listed in Tables 1 and 2, respectively.
The effects of the solvent on the chemical shifts have
been analyzed using the supermolecule approach. Thus,
complexes constituted by the (1R,3S,4S,8S)-p-menthane-
3,9-diol and a different number of chloroform molecules
have been generated for each conformation. The position
of the solvent molecules around the solute was taken
from the MD results. The analysis of the calculated
It should be mentioned that calculations took more
than 100 h each on an IBM-SP2 computer. Results reveal
a small improvement of the chemical shifts predicted for
conformation A. Thus, scaling coefficients indicate that
the error associated to the predicted chemical shifts is
lower than that obtained for the molecule in the gas

3782 J . Org. Chem., Vol. 66, No. 11, 2001
Casanovas et al.
chemical shifts for the smallest complexes, in which three
chloroform molecules are considered, revealed an im-
provement of the results. This improvement is more
notorious for conformation A than for conformation B.
Thus, when the surrounding solvent molecules are
distributed around the polar region of conformation A,
the best agreement between experimental and theoretical
chemical shifts is reached.
periods. However, these 19 conformations present a total
population of 46%, even although the population of each
conformation is lower than 7%. Thus, the consideration
of the low populated conformations could improve the
predicted chemical shifts. Moreover, it should be consid-
ered that the molecule spends some time moving between
these conformations, this effect being recorded by NMR
experiments but not by the calculations.
The small differences found for the solvated conforma-
tions may be due to several sources of error. The first
one is the level of theory at which the geometry of
(1R,3S,4S,8S)-p-menthane-3,9-diol was determined. Thus,
computed chemical shifts are considerably influenced
by the geometric parameters, i.e., bond lengths and
angles.1d In this case, the molecular geometry was taken
from a force-field explicitly designed to study p-men-
thane-3,9-diols.15 Other sources of error in the calcula-
tion of δ(13Ci) may be the level of theory used and, at
a lesser extend, the quality of the basis set used to
describe the (1R,3S,4S,8S)-p-menthane-3,9-diol molecule.
Electron correlation effects largely influence the NMR
parameters1d,9,27 These effects are partially included in
B3LYP calculations at a reasonable computational cost.
Indeed, DFT methods allow calculations on large organic
systems, like (1R,3S,4S,8S)-p-menthane-3,9-diol, that
cannot be treated by conventional correlated methods.
However, it should keep in mind that better results can
be obtained with other correlated methods such as MP2.28
On the other hand, the choice of the basis set is a crucial
decision in any quantum mechanical calculation. For
reliable calculations of chemical shifts, there is a need
for flexibility in the outer-core inner-valence regions.1d,29
However, such basis sets lead to more time-consuming
calculations and in practice cannot be applied to large
organic molecules.
Con clu sion s
13C NMR chemical shifts, δ(13Ci), of (1R,3S,4S,8S)-p-
menthane-3,9-diol were experimentally measured and
computed using a combination of MD simulations and
quantum mechanical calculations. MD simulations were
used to explore the conformational preferences of this
molecule in chloroform solution. The NMR parameters
were calculated in the gas phase and in chloroform
solution. The solvent effects were considered using the
supermolecule approach, where the arrangement of
the chloroform molecules around the solute was provided
by MD simulations. Calculations were performed with
the B3LYP method, which partially collects the effects
of correlation, the basis sets used to describe the
(1R,3S,4S,8S)-p-menthane-3,9-diol and the solvent mol-
ecules being the 6-311G(d) and STO-3G, respectively.
Following this theoretical strategy, we found that the
chemical shifts calculated for the most populated con-
formations compare favorably with the experimental
values. The agreement between theoretical and experi-
mental δ(13Ci) improves when chloroform molecules are
distributed around the polar region of (1R,3S,4S,8S)-p-
menthane-3,9-diol. The computational strategy used in
this work seems to be a promising tool for both predicting
and interpreting NMR spectra of complex organic mol-
ecules.
It should be also mentioned that the experimentally
measured δ(13Ci) refer to a hypothetical average confor-
mation of (1R,3S,4S,8S)-p-menthane-3,9-diol. MD simu-
lations indicate that this is a quite flexible compound,
the number of unique conformations being 21. Our
calculations were performed considering the most popu-
lated conformations, i.e., A and B, which represent a
population of about 54%. The remaining conformations
were neglected since they appeared during very short
Ack n ow led gm en t. We thank the CESCA (Centre
de Supercomputacio´ de Catalunya) for computational
facilities. We also wish to thank the Fundac¸a˜o de
Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP)
and Coordenadoria de Aperfeic¸oamento de Pessoal de
N´ıvel Superior (CAPES) for financial support.
Su p p or tin g In for m a tion Ava ila ble: Tables of 1H and 13C
NMR shifts, dihedral angles, and complete computational
results. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) Stanton, J . F.; Gauss, J .; Siehl, H. U. Chem. Phys. Lett. 1996,
262, 183.
(28) Cheeseman, J . R.; Trucks, G. W.; Keith, T. A.; Frisch, M. J . J .
Chem. Phys. 1996, 104, 5497.
(29) Carmichael, I. J . Phys. Chem. 1993, 97, 1789.
J O0016982