Article

pubs.acs.org/JPCB

Conformational Flexibility of Mephenesin

Patricia Ecija, Luca Evangelisti,, Montserrat Vallejo, Francisco J. Basterretxea,*, Alberto Lesarri,
Fernando Castano, Walther Caminati, and Emilio J. Cocinero*,

Departamento de Qumica Fsica, Facultad de Ciencia y Tecnologa, Universidad del Pas Vasco (UPV/EHU), Campus de Leioa, Ap.
644, E-48080 Bilbao, Spain

Departamento de Qumica Fsica y Qumica Inorganica, Facultad de Ciencias, Universidad de Valladolid, E-47011 Valladolid, Spain

Dipartimento di Chimica G. Ciamician, dellUniversita di Bologna, Via Selmi 2, 1-40126 Bologna, Italy
*
S Supporting Information

ABSTRACT: The mephenesin molecule (3-(2-methylphenoxy)propane-1,2-diol) serves as a test

bank to explore several structural and dynamical issues, such as conformational exibility, the
orientation of the carbon linear chain relative to the benzene plane, or the eect of substituent
position on the rotational barrier of a methyl group. The molecule has been studied by rotational
spectroscopy in the 418 GHz frequency range by Fourier-transform methods in a supersonic
expansion. The experiment has been backed by a previous conformational search plus
optimization of the lowest energy structures by ab initio and density functional quantum
calculations. The three lowest-lying conformers that can interconvert to each other by simple
bond rotations have been detected in the jet. Rotational parameters for all structures have been
obtained, and methyl torsional barriers have been determined for the two lowest-lying rotamers. The lowest-lying structure of
mephenesin is highly planar, with all carbon atoms lying nearly in the benzene ring plane, and is stabilized by the formation of
cooperative intramolecular hydrogen bonding. An estimation of the relative abundance of the detected conformers indicates that
the energetically most stable conformer will have an abundance near 80% at temperatures relevant for biological activity.

INTRODUCTION
The immensely large number of dierent biomolecules, such as
proteins, nucleic acids, carbohydrates or lipids, existing in all
living organisms can be obtained by combining a relatively
small number of dierent building-block molecules.1 Examples
of these primordial biomolecules are amino acids, nitrogenated
bases, several monosaccharides or some individual molecules
such as glycerol and its derivatives. Mephenesin (3-(2-
methylphenoxy)propane-1,2-diol, Scheme 1) belongs to the
Scheme 1. Structure and Atom Numbering for the
Mephenesin Molecule
family of glycerol ethers that are common constituents of lipids.
Lipids with ether bonds to long-chain alkyl groups are common
membrane constituents. Findings of elevated levels of ether
lipids in cancer tissues, followed by the discovery of distinctive
ether lipids with important biological activities, have greatly
stimulated the interest in these compounds.24 Mephenesin is a
chiral molecule that has been used for its muscle relaxant
properties,5,6 with the R enantiomer being known to be more
active in vivo than the S mirror image or the racemate.7
Related to its biological relevance, mephenesin poses some
interesting structural questions. The molecule can be conceived
as composed of dierent subunits (propane-1,2-diol, toluene,
methoxybenzene), each with several conformational prefer-
ences when considered separately. The subunits can interact
between them (for example, by intramolecular hydrogen
bonding or interaction with the electronic charge of the
aromatic ring), presumably restricting the conformational
possibilities of the whole molecule. What will be the preferred
orientation of the propane-1,2-diol chain relative to the
benzene ring plane? Previous studies of anisole810 have
proven that the methoxy substituent arranges in coplanar
structures that enable conjugation of the oxygen lone pair with
the aromatic ring.11,12 Other issues worth studying are the
eect of the phenoxy group on the oppy structure of propane-
1,2-diol found in previous studies,1315 or the eect of
substituents on the (nearly) free rotation of the methyl
group,1620 adding a V3 term to the V6 barrier in toluene.
Similar topics have been explored recently in the lignin
monomers (p-coumaryl alcohol, coniferyl alcohol, and sinapyl
alcohol)21 and their fundamental subunits (such as guaiacol and
syringol),22 nding that the presence of multiple exible
substituents locks in specic orientations of the molecular
substituents.
Energetic and structural information on building blocks in
the gas phase can be obtained by the various high-resolution
spectroscopic techniques developed during the last years.23,24
Double-resonance laser electronic spectroscopy methods oer
Received: February 11, 2014
Revised: April 22, 2014
Published: April 22, 2014

2014 American Chemical Society 5357 dx.doi.org/10.1021/jp5014785 | J. Phys. Chem. B 2014, 118, 53575364
The Journal of Physical Chemistry B Article

Figure 1. Two sections of the pure rotational spectrum of mephenesin and details of four example transitions with their assignments. The 91,8 81,7
transition (corresponding to conformer C) shows only an instrumental Doppler doublet. The 124,9 114,8 and 123,10 113,9 transitions of
conformer A experience an additional splitting in two components (A and E) of 125.3 and 15.9 kHz due to quantum tunnelling. The 101,9 91,8
transition of conformer B also presents tunnelling splitting.

the possibility of mass and conformer selectivity and can be
applied to fairly large systems. However, these experiments
yield information about vibronic levels, which are not directly
related to geometrical parameters. In consequence, conformer
assignment usually requires careful and elaborate interpretation
aided by quantum chemical calculations, and, even so,
assignments are not always unequivocal. Rotational spectros-
copy in the microwave region is an alternative that provides
higher resolution (line widths <10 kHz) and unambiguous
discrimination between dierent species like tautomers,25
conformers,26,27 isotopomers,28,29 or even enantiomers,30
producing a very accurate description of molecular structure
that serves as a test of the predictive value of the quantum-
mechanical methods accurately describing the properties of
isolated molecules.31
In previous works, we have examined the conformational
properties and noncovalent interactions of related molecules in
a supersonic jet, such as several methoxyphenols like eugenol
and guaiacol by electronic spectroscopy32,33 or vanillin and its
derivatives using Fourier transform microwave spectrosco-
py.34,35 The present work targets structural questions on
5358
mephenesin, such as the eect of exible substituents in the
conformational properties, that can be relevant to the biological
activity of related molecular moieties, such as cell membrane
functioning, as commented previously. Mephenesin has been
studied in the solid state by single-crystal X-ray diraction,36
nding that there are two symmetry-independent molecules in
the unit cell. The existence of two hydroxyls per molecule leads
to a complex system of hydrogen bonds in the crystal.
EXPERIMENTAL AND COMPUTATIONAL
METHODS
Rotational spectra were recorded in the 418 GHz Fourier
transform microwave (FT-MW) spectrometer built at the
UPV/EHU, previously reported,34 and based on the original
design of Balle and Flygare.37 Solid samples of mephenesin
were obtained from a commercial supplier (Sigma-Aldrich, 98%
purity) and placed inside a customized nozzle heated at 423 K
by a resistive element wrapped around it to obtain sucient
sample vapor pressure. Gaseous mephenesin was diluted with a
ow of pure Ne carrier gas at ca. 0.7 MPa backing pressure. The
mixture was expanded through a 0.8 mm diameter hole in the
dx.doi.org/10.1021/jp5014785 | J. Phys. Chem. B 2014, 118, 53575364
The Journal of Physical Chemistry B Article

Table 1. Experimental and Quantum Mechanically Calculated Results for the Observed Conformers of Mephenesin
conformer A conformer B conformer C
calculated calculated calculated
experiment MP2/M06-2X/B3LYP experiment MP2/M06-2X/B3LYP experiment MP2/M06-2X/B3LYP
A/MHza 1707.78960 (75)b 1691.4/1725.6/1715.3 1978.986 (11) 1973.9/2002.4/1980.6 1615.04911(25) 1614.6/1630.2/1609.3
B/MHz 388.661705 (60) 392.1/390.9/382.8 349.300307 (73) 351.3/351.4/344.96 455.423567(58) 455.8/460.9/448.8
C/MHz 331.331684 (61) 334.1/333.5/326.9 305.408511 (68) 306.5/306.9/302.3 385.954447(36) 388.1/388.5/381.0
DJ/kHz 0.01262 (10) 0.019/0.012/0.011 0.004.3 (21) 0.006.9/0.004.8/0.003.6 0.01163(21) 0.013/0.097/0.010
DJK/kHz 0.04192 (93) 0.097/0.016/0.026 0.037/0.069/0.071 0.1008(34) 0.126/0.075/0.087
DK/kHz 0.350 (61) 0.661/0.410/0.408 0.22/0.13/0.13 0.054/0.0016/0.010
d1/Hz 1.422 (80) 1.32/1.24/1.27 0.8/1.0/0.5 1.40(12) 0.89/1.0/1.2
d2/Hz 0.03/0.05/0.02 0.04/0.05/0.04 0.52/0.022/0.029
Pc/u2 35.47 37.58 23.72 23.06 56.59 59.75
|a|/D observed 1.15/1.16/1.08 observed 2.36/2.35/2.17 observed 1.47/1.58/1.40
|b|/D observed 0.56/0.63/0.64 0.48/0.42/0.38 observed 1.32/1.04/1.15
|c|/D observed 1.12/1.10/1.06 0.04/001/0.03 observed 1.62/1.77/1.66
TOT/D 1.70/1.72/1.65 2.41/2.39/2.20 2.56/2.59/2.46
(a,i)/degc 79.09 (19) 77.66/81.89/78.01 71.74 (0.69) 72.46/72.02/72.46 59.69/59.12/59.11
(b,i)/deg 12.00 (95) 12.37/8.11/12.09 19.96 (5.13) 18.44/18.78/18.44 31.15/31.51/31.51
(c,i)/deg 85.10 (1.60) 89.09/90.00/88.49 82.22 (9.55) 84.50/84.77/84.50 83.49/84.35/84.40
I/u 2 3.172d 3.172 3.172d 3.172/3.147/3.172 3.170d 3.170/3.143/3.143
V3/kJ mol1e 5.736 (18)f 5.55g 5.710 (66)f 5.55g >9 7.86g
Nh 65 75 54
/kHz 1.57 2.89 1.33
a
Rotational constants (A, B, C); Watsons quartic centrifugal distortion constants in the S reduction (DJ, DK, DJK, d1, d2); planar moment of inertia
around the c axis (Pc = 1/2(Ia + Ib Ic)); dipole moment components (a, b, c in debye units, 1 D 3.336 1030 C m). bStandard error in
parentheses in units of the last digit. c(g,i): Angles dening the orientation of the internal rotor axis (i) with respect to the principal inertial axes (g
= a, b, c); moment of inertia (I) of the internal rotor with respect to its C3 axis. dThis value cannot be experimentally determined and has been xed
in the t to the MP2-calculated value eThree-fold barrier height. fError in the torsional barrier is that given from the tting, although its real value will
ultimately depend on the model used in the Hamiltonian. gMP2 calculated value. hNumber of transitions (N) and rms deviation () of the t.

nozzle in pulses of 250 s duration into a high vacuum
chamber (1 105 Pa under stand-by conditions). The
supersonic expansion thus produced molecules into their lowest
vibrational and rotational energy levels at very low temper-
atures, substantially simplifying their rotational spectrum (Trot
2 K).
functional that empirically accounts for dispersive interac-
tions.41,42 Finally, B3LYP is a well-known method used
extensively. All methods run at a reasonable computational
cost and have been selected also to test their predictive
performance by comparison with the experimental rotational
data.

The pulsed jet is excited in a FabryPerot resonator built
into the vacuum chamber by a synchronized 1 s low-power
(<150 mW) microwave pulse, after which the molecular
spontaneous emission carrying the spectroscopic information is
detected in the time domain. The nal frequency spectra are
obtained by Fourier transforming the time signal. The accuracy
of frequency measurements is better than 3 kHz, and lines
separated ca. <10 kHz can be resolved. As a result of the coaxial
arrangement of the jet and resonator axis, all rotational
transitions appear split in two components by an instrumental
Doppler eect.
Rotational spectra were backed by molecular mechanics
(MM) ab initio and density functional quantum chemical
calculations to aid in the conformational search, spectral
characterization, and calculation of the principal features of the
potential energy surface of mephenesin. First, a systematic
conformational search was carried about with a fast MM
method (Merck molecular force eld (MMFFs))38 and
advanced Monte Carlo and large-scale low-mode conforma-
tional search algorithms. The lowest-lying conformations were
reoptimized using ab initio (MP2) and density-functional M06-
2X and B3LYP methods combined with triple- 6-311+
+G(d,p) basis functions using the Gaussian 09 software.39
MP2 perturbation theory is a well-established method that
includes the majority of electron correlation,40 whereas M06-
2X is a recently developed highly parametrized meta-hybrid
5359
RESULTS
In view of the a priori broad range of coexisting conformers, a
systematic conformational search was carried out within a large
energy window of 55 kJ/mol. The 155 obtained structures by
MM were reduced to a total number of 30 feasible conformers
after recalculation with MP2 theory (M06-2X gave 28
structures) in the 017 kJ/mol energy range. As some of the
conformers converged to the same structure, nally 23 dierent
structures were obtained. The rotational constants of the
energetically more stable conformers were used to predict the
rotational transitions from the lowest-lying rotational levels
subject to the well-known electric dipole selection rules.43 This
allowed carrying out a preliminary search for microwave
transitions in narrow spectral ranges. Several intense lines were
observed, that could be assigned to a single structure
(conformer A). A preliminary determination of rotational
constants from the observed lines allowed predicting new
transitions. In this way, a total number of 34 transitions were
detected and assigned in the 6.112.4 GHz range. Most of the
lines appear as doublets, with a measured splitting in the 11
220 kHz range, much dierent from the 5080 kHz doubling
caused by the instrumental Doppler eect. Transitions arise
from lower state rotational quantum numbers J = 614, K1 =
06, and K+1 = 314 of an asymmetric rotor. All transitions
obeyed the selection rules J = +1 (R branch), most of them a
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The Journal of Physical Chemistry B
Table 2. Energetically Lowest-Lying Conformers and Their Structures Calculated by MP2 Quantum Methoda
a
In the bottom gures, the benzene ring plane is perpendicular to the sheet plane.
allowed, with a few b- and c-type transitions. A short section of
the spectrum is depicted in Figure 1, showing line splittings of
dierent magnitude. All measured and assigned transitions of
conformer A are shown in Table S1 of the Supporting
Information.
The small splitting detectable in the majority of the
transitions was attributed to tunnelling doubling arising from
the hindered internal rotation of a single C3-symmetric methyl
group, splitting each torsional level into two symmetry species
A and E.44 The splitting cannot arise from the internal rotation
of the terminal OH groups, as they connect dierent energy
minima. Furthermore, both hydroxyl groups anchor to each
other to form hydrogen bonds and do not rotate. A similar
behavior was observed in several monosaccharides.26,4547
After the assignment of conformer A, a large set of weaker
lines remained in the spectrum. These lines originated from
two additional structures (conformers B and C). The lines
coming from species B appeared as doublets (line splitting
about 1022 kHz), as in conformer A. Lines coming from
species C did not show any doubling. Sample transitions can be
seen in Figure 1. The observed transitions comprise similar
ranges of quantum numbers and selection rules as for
conformer A (conformer B: J=713, K1 = 02, all lines
a-type; conformer C: J=314, K1 = 04, most lines a-type,
a few b- and c-type). Their rotational constants are not far from
the values obtained for conformer A. These facts strongly
support the hypothesis that the weaker transitions come from
two additional conformers of mephenesin. All measured and
assigned transitions from conformers B and C are shown in
Tables S2 and S3 of the Supporting Information, respectively. A
few lines in the spectrum remained unassigned, possibly
corresponding to decomposition products as a result of sample
heating at 423 K.
A joint analysis of the rotational parameters and the internal
rotation for each of the conformers used a Watson semirigid
rotor Hamiltonian48 in the S-reduction with the addition of
internal rotation terms according to the combined axis method
(CAM) formalism.4951,44 The XIAM computer code52 was
used for these calculations. The periodicity of the potential
energy function arising from the internal rotation was assumed
to be 120, as expected from the CH3 group. The internal
5360
Article
rotation analysis allows us to calculate the torsional barrier
height and the orientation of the internal rotor with respect to
the principal inertial axes of the molecule.
Table 1 presents the tted rotational parameters, the angles
dening the orientation of the internal rotor axis with respect to
the principal inertial axes for conformers A and B, as well as the
three-fold barrier heights of 5.7 kJ/mol. Because conformer C
does not show any line doubling, only a lower limit for the
barrier of 9 kJ/mol has been estimated. The agreement between
the tted quantities and the computed values is excellent. The
standard deviations of the three global ts are below the
assumed uncertainty of the frequency measurements.
Table 2 presents the predictions for the structures, rotational
constants, and geometrical parameters (dihedral angles) of the
ve lowest-lying conformations of mephenesin. By comparing
the theoretical rotational constants with the experimental values
in Table 1, it turns out that the dierence among the rotational
constants of the various structures is suciently large to
straightforwardly assign conformers A and B to structures I and
III, respectively. The rotational constants show the smallest
deviation from the MP2 calculation (less than or near 1% in A,
B, and C for both A and B conformers), with M06-2X
calculations giving close values. In principle, conformer C could
be assigned to either structure II or V of Table 2 because their
rotational constants do not dier largely; however, the
dierence among all rotational constants is smaller for II (for
II, 0.03%, 0.1% and 0.56% for A, B and C, respectively,
versus 0.2, 4.7, and 1.9% for V). Moreover, comparison of the
planar moment of inertia Pc of II and V with that of conformer
C strongly favors II. Additionally, structure II is predicted to be
of lower energy than V (1.3 vs 5.1 kJ/mol), so its population
will be larger in the supersonic expansion. These facts allow us
to condently assign conformer C to structure II. The rest of
conformations can be excluded on this basis, as the percentage
dierences between computed and tted rotational constants
are typically one order of magnitude larger. Energetically higher
lying structures were discarded in view of the low temperatures
attained in the jet that would preclude substantial population of
these conformers.
The complete computed MP2, M06-2X, and B3LYP
structures of the observed conformers are supplied in Tables
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The Journal of Physical Chemistry B
S4S6 of the Supporting Information. The computed energies
of the observed conformers by MP2, M06-2X, and B3LYP
methods are also given in Table S7 of the Supporting
Information.
DISCUSSION
The three lowest-energy conformers of mephenesin have been
observed in a supersonic jet, and precise rotational constants
and centrifugal distortion constants have been obtained. The
rotational barrier heights of the methyl group for two of the
conformers have been measured to be 5.7 kJ/mol, almost the
same for both species. For the third conformer, a lower limit
barrier of 9 kJ/mol has been obtained. From the tted
transitions of conformers A and B, the orientation of the methyl
rotor axis with respect to the principal inertial axes of the
molecule has been determined. The experimental values are in
very good concordance with quantum mechanical computa-
tions, so the whole set of data allows us to condently assign
the observed transitions of the most abundant species
(conformer A) to structure I depicted in Table 2. This
conformation is stabilized by two intramolecular hydrogen
bonds OHOHO involving the two hydroxyl groups and
the ether oxygen, which act cooperatively (d(O3H7) = 2.20
, d(O6H10) = 2.32 ). The molecule somehow has a planar
frame of the heavy atoms, with atoms of the benzene ring and
the O3C4C5C8 backbone almost lying in the same plane.
This is in agreement with the relatively small value of the planar
moment of inertia around the c axis (Pc), which lies
approximately perpendicular to the benzene plane. (See
Table 1.) This conformation enables conjugation of the oxygen
lone pair with the aromatic ring. Conformer B, having weaker
transitions than A, must correspond to the structure III, lying
3.9 kJ/mol (MP2) above I. Structure III can be roughly
obtained by a 120 rotation of the terminal CH2OH group
around the C5C8 axis, still preserving the two intramolecular
hydrogen bonds. Although in this case the O6H10O9 bond
is shorter than in I (d(O6H10)=2.29 ), the O3H7O6
bond length is larger (d(O3H7) = 2.31 ), so the total
electronic energy is raised. Finally, conformer C can be assigned
to structure II, which is predicted at 1.3 kJ/mol above I. Both
dier in the rotation of the CHOHCH2OH molecular subunit
ca. 120 around the C4C5 bond. Signicantly, the third
conformer maintains the cooperative OHOHO double
hydrogen bond, although in a less favorable geometry (d(O3
H7) = 2.87 , d(O6H10) = 2.97 ). Cooperativity associated
with multiple hydrogen bonds originated by hydroxyl groups is
observed in other biomolecules, notably sugars.26,4547,5355
Besides the eect of the intramolecular hydrogen bond, the
inuence of the benzene ring on the conformational variability
of the propane-1,2-diol chain can be noticed in mephenesin by
examining the conformational preferences of glycerol
(CH2OHCHOHCH2OH). For this molecule, seven con-
formers were predicted in the 05 kJ/mol range, while ve of
them were observed.56,57 In contrast, in mephenesin, only four
structures are predicted (MP2) in the same range, suggesting
that the presence of benzene ring limits the conformational
possibilities.
The observation of three dierent conformers allows an
estimation of their population ratio in the jet, indicative of their
relative stability. The jet population ratios can be calculated
from the approximate formula N1/N2 = Int1|a|2/Int2|a|1,
where Int1 and Int2 are the measured intensities for each
conformer for a given transition and |a|1 and |a|2 are the MP2
Article
calculated dipole moment components for both conformers.
For this purpose, the relative intensities of various rotational
transitions in the three conformers were measured. A total
number of 10 a-type transitions were selected for each
conformer, assuming ideal /2 polarization conditions.
Averaging the results for the stated set of transitions gives
NA:NB:NC = 71.5:17.3 2.1:11.2 0.5. From these values, the
energy dierence between the three conformers prior to the
supersonic expansion could be extracted from the usual
MaxwellBoltzmann relationship, assuming no prior conforma-
tional relaxation and complete vibrational cooling to the
respective ground states. This calculation yields GAB(423 K)
= 4.6 1.8 kJ mol1 and GAC(423 K)=6.4 0.9 kJ mol1.
It is instructive to compare the magnitude of the
experimental three-fold methyl barrier in mephenesin (5.7 kJ
mol1 in conformers A and B) with other internal rotation
barriers of methylbenzenes. We have observed internal rotation
splittings in conformers of acetovanillone,35 originated by the
acetyl group. The measured internal rotation barriers (6.6 and
7.4 kJ mol1) were not substantially aected by the intra-
molecular hydrogen bonding. These values are slightly higher
than the value in mephenesin. Conversely, the absence of
torsional tunnellings due to the methoxy group in acetova-
nillone conformers indicated torsional barriers above 10.2 and
8.9 kJ mol1. In vanillin34 and o-vanillin,58 line splittings were
not observed, indicating a barrier higher than 12 kJ mol1 for
vanillin. A pictorial comparative of the various methyl barriers is
shown in Figure 2. In mephenesin conformer C, the absence of
Figure 2. Comparison of dierent methyl barriers to internal rotation.
spectral line splitting indicates a higher rotational barrier, for
which we give the lower limit, at least 9 kJ/mol. The results
suggest that the presence of a neighboring O atom aects the
methyl internal rotation barrier, mainly breaking the symmetry
and rising the V3 term.
The gas-phase structural data of mephenesin can be
compared with diraction results from the crystalline solid.
The structure in the solid state of (R)-mephenesin enantiopure
form has been studied by single-crystal X-ray diraction.36
There are two dierent conformations, consisting of the sc,sc
and sc,sc conformations of the O3C4C5C8O9 chain.
(See Scheme 1 and Figure 3.) This results in the fragment C8
O9H10 lying out of the benzene plane, in contrast with gas
phase A and C conformer structures, in which all C atoms are
nearly contained in the benzene ring plane.
For gas-phase conformer B, the C8O9H10 subunit lies
out of the benzene plane, as in the crystal; however, the relative
orientation of the O and H atoms is dierent between both
structures. These dierences can be explained due to the
system of intermolecular hydrogen bonds that takes place in the
crystal, in which every molecule participates in two interactions
as a donor and in other two as an acceptor, thus replacing the
intramolecular hydrogen bonds in the gas-phase structures.
Some representative structural data of gas phase (quantum
5361 dx.doi.org/10.1021/jp5014785 | J. Phys. Chem. B 2014, 118, 53575364
The Journal of Physical Chemistry B
Figure 3. Packing of mephenesin units in the unit cell of crystalline
mephenesin. Data taken from ref 36 of the manuscript.
mechanically computed) and the crystal are included in Table
S8 of the Supporting Information for comparison purposes.
The basic dierence between gas-phase and crystal structures is
evident from examination of the dihedral angles. Most bond
distances are practically coincident in both phases, with the
exception of both OH distances, which are shorter in the
crystal (O6H7: 0.93 in crystal, 0.97 in gas; O9H10:
0.90 in crystal, 0.96 in gas) as result of the intermolecular
hydrogen bonds. As to bond angles, both COH angles are 35
larger in the crystal, again as a result of the implication of the
involved atoms in intermolecular hydrogen bonds. The rest of
the bond angles tend to be a couple of degrees larger in the
crystal, with the exception of the C5C8O9 bond angle,
which is 3 smaller in the crystal.
A nal consideration about the performance of quantum
mechanical calculations in mephenesin can be useful. Despite
the dierent meanings of the ab initio and experimental
geometries, both MP2 and M06-2X quantum calculations give
values very close to the experimental rotational constants (A, B,
C), the dierences not going further than 1% in both methods.
The well-known B3LYP functional also gives very close
rotational constants, deviations only reaching 1.5%. The angles
dening the orientation of the internal rotor axis with respect to
the principal inertial axes are predicted with similar perform-
ance with the three methods, with no remarkable dierences
among them. The dierences with the experimental angles do
not go over 5 for conformers A and B. The V3 barriers to
internal rotation, calculated by MP2 theory, are satisfactorily
reproduced for conformers A and B (errors not going further
than 3%), for which the experimental value has been
determined. In the case of conformer C, only a lower limit
value has been determined, so the calculation result cannot be
compared. All MP2, M06-2X, and B3LYP methods give very
similar results for the structure of the three lowest-lying
conformers (Tables S4S6 of the Supporting Information).
CONCLUSIONS
Three distinct conformers of mephenesin have been detected
by Fourier-transform microwave spectroscopy in a supersonic
jet, obtaining rotational constants and centrifugal distortion
parameters for all structures. The tted methyl torsional barrier
is 5.7 kJ/mol for the two lowest-lying rotamers, whereas a lower
limit of 9 kJ/mol has been obtained for the remaining species.
The three observed conformers have been unambiguously
5362
Article
assigned to the three lowest lying conformers in the 04 kJ/
mol energy range via precise electronic structure calculations.
These structures can interconvert to each other by simple bond
rotations. The lowest-lying structure of mephenesin has all C
atoms lying nearly in the benzene ring plane and is stabilized by
the formation of cooperative intramolecular hydrogen bonding.
The most stable conformer clearly predominates over the rest,
with a natural estimated abundance near 71% at 423 K (prior to
the expansion). That implies that at lower temperatures more
relevant to biological systems (e.g., 298 K) the relative
abundance of this conformer should be over 80% of the total,
assuming that the contribution of the unobserved conformers is
negligible.
Several issues regarding the conformational dynamics of
mephenesin have been claried. The primary control on
molecular conformation is exerted by the cooperative double
hydrogen bond. The OCH2 moiety has been shown to be
coplanar to the benzene ring in all observed structures. This
result agrees with previous studies on anisole and other
methoxybenzene derivatives by electronic spectroscopy10 but
contrasts with the results for diphenoxymethane, which has an
out-of-plane distortion of the ether chain relative to anisole.59
The greater exibility of the related diphenoxyethane molecule
makes the PheOC()C() in a plane for both phenyl
rings.60 In mephenesin, the rest of the diol chain shows some
exibility. The diol chain is coplanar to the benzene ring for
two of the structures observed, whereas the other experiences a
torsion that raises its energy 1.3 kJ/mol respect to the lowest-
lying structure. The obtained results contrast with the
observations in glycerol, for which ve conformers have been
observed in the 05 kJ/mol range (and seven predicted). Thus,
the eect of the neighboring benzene ring limits the available
number of conformational minima.
The eect of the neighboring subunits on the rotation of the
benzene CH3 group has been analyzed. When the diol chain is
linked to the benzene ring, the methyl rotation barrier is 5.7 kJ/
mol in the two most stable conformers. This barrier can be
attributed to the interaction between the CH3 and the nearby
O lone electron pair, which originates an interelectronic
repulsion, and the propane-1,2-diol chain. Similar results for
methyl rotation barriers close to a O bond support this
conclusion. The nearly planar conformer A is stabilized by two
intramolecular cooperative hydrogen bonds, which are less
favored in conformer B. However, this fact seems to have no
inuence on the methyl rotation barrier. Conformer C must
have a considerably higher barrier than A and B (>9 kJ/mol
according to the tted values). The raise in electronic energy
brought about by rotating the terminal CH2OH around the
C5C8 axis in A to give C seems enough to aect the CH3 at
the other end of the molecule by increasing the methyl rotation
barrier at least ca. 4 kJ/mol.
ASSOCIATED CONTENT
*
S Supporting Information
Measured rotational transitions, computed structures and
energies for the three lowest energy conformers, and
comparison between crystal and gas phase structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
dx.doi.org/10.1021/jp5014785 | J. Phys. Chem. B 2014, 118, 53575364
The Journal of Physical Chemistry B
AUTHOR INFORMATION
Corresponding Authors
*F.J.B: Phone: +34 94 601 2532. Fax: +34 94 601 3500. E-mail:
franciscojose.basterretxea@ehu.es.
*E.J.C.: Phone: +34 94 601 5387. E-mail: emiliojose.cocinero@
ehu.es.
Notes
The authors declare no competing nancial interest.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministry of Science and
Innovation (MICINN, 2010/CSD2007-00013, CTQ2011-
22923, CGL2011-22441, CTQ2012-39132), the Basque
Government (Consolidated Groups, IT520-10), and the
UPV/EHU (UFI11/23) is gratefully acknowledged. E.J.C.
and M.V. also acknowledge a Ramon y Cajal contract and an
FPI grant, respectively, from the MICINN. Computational
resources and laser facilities of the UPV-EHU were used in this
work (SGIker and I2Basque).
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