Article pubs.acs.org/JPCB
Conformational Flexibility of Mephenesin Patricia Écija,† Luca Evangelisti,†,§ Montserrat Vallejo,‡ Francisco J. Basterretxea,*,† Alberto Lesarri,‡ Fernando Castaño,† Walther Caminati,§ and Emilio J. Cocinero*,† †
Departamento de Química Física, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Campus de Leioa, Ap. 644, E-48080 Bilbao, Spain ‡ Departamento de Química Física y Química Inorgánica, Facultad de Ciencias, Universidad de Valladolid, E-47011 Valladolid, Spain § Dipartimento di Chimica “G. Ciamician”, dell’Università 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 flexibility, the orientation of the carbon linear chain relative to the benzene plane, or the effect of substituent position on the rotational barrier of a methyl group. The molecule has been studied by rotational spectroscopy in the 4−18 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.
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INTRODUCTION The immensely large number of different biomolecules, such as proteins, nucleic acids, carbohydrates or lipids, existing in all living organisms can be obtained by combining a relatively small number of different 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-(2methylphenoxy)propane-1,2-diol, Scheme 1) belongs to the
methoxybenzene), each with several conformational preferences when considered separately. The subunits can interact between them (for example, by intramolecular hydrogen bonding or interaction with the π 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 anisole8−10 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 effect of the phenoxy group on the floppy structure of propane1,2-diol found in previous studies,13−15 or the effect of substituents on the (nearly) free rotation of the methyl group,16−20 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 finding that the presence of multiple flexible substituents locks in specific 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 offer
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.2−4 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 different subunits (propane-1,2-diol, toluene, © 2014 American Chemical Society
Received: February 11, 2014 Revised: April 22, 2014 Published: April 22, 2014 5357
dx.doi.org/10.1021/jp5014785 | J. Phys. Chem. B 2014, 118, 5357−5364
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.
mephenesin, such as the effect of flexible 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 diffraction,36 finding 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.
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 spectroscopy in the microwave region is an alternative that provides higher resolution (line widths 9 54 1.33
calculated MP2/M06-2X/B3LYP 1614.6/1630.2/1609.3 455.8/460.9/448.8 388.1/388.5/381.0 0.013/0.097/0.010 0.126/0.075/0.087 −0.054/−0.0016/−0.010 −0.89/−1.0/−1.2 0.52/0.022/0.029 59.75 1.47/1.58/1.40 −1.32/−1.04/−1.15 −1.62/−1.77/−1.66 2.56/2.59/2.46 59.69/59.12/59.11 31.15/31.51/31.51 83.49/84.35/84.40 3.170/3.143/3.143 7.86g
a Rotational constants (A, B, C); Watson’s 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 (μa, μb, μc in debye units, 1 D ≈ 3.336 × 10−30 C m). bStandard error in parentheses in units of the last digit. c∠(g,i): Angles defining the orientation of the internal rotor axis (i) with respect to the principal inertial axes (g = a, b, c); moment of inertia (Iα) of the internal rotor with respect to its C3 axis. dThis value cannot be experimentally determined and has been fixed in the fit to the MP2-calculated value eThree-fold barrier height. fError in the torsional barrier is that given from the fitting, although its real value will ultimately depend on the model used in the Hamiltonian. gMP2 calculated value. hNumber of transitions (N) and rms deviation (σ) of the fit.
nozzle in pulses of ∼250 μs duration into a high vacuum chamber (∼1 × 10−5 Pa under stand-by conditions). The supersonic expansion thus produced molecules into their lowest vibrational and rotational energy levels at very low temperatures, substantially simplifying their rotational spectrum (Trot ≈ 2 K). The pulsed jet is excited in a Fabry−Perot resonator built into the vacuum chamber by a synchronized 1 μs low-power (
