摘要:
P. Butz,a G. E. Tranterb and J. P. Simons*a Molecular conformation in the gas phase and in solution aPhysical and Theoretical Chemistry Laboratory, South Parks Road, Oxford, UK OX1 3QZ bBiological Chemistry, Division of Biomedical Science, Imperial College of Science Technology and Medicine, Exhibition Road, London, UK SW7 2AZ Received 19th April 2002, Accepted 12th June 2002 Published on the Web 20th June 2002 The article explores the correlation between the ultra-violet circular dichroism of chirally substituted benzene molecules in solution, and their absolute configurations determined on the basis of infrared (or ultraviolet) spectroscopy, coupled with ab initio computation, in the gas phase. New results for isolated and solvated molecules in the ephedra class of drugs are presented.They lead to a revision of the current ‘sector rules’ associated with excitation into the 1Lb state of the benzene ring and suggest a new strategy for bridging the gap between isolated molecular and solvated cluster structures determined in the gas phase and the structures adopted in condensed media. 1. Introduction In the last few years, using strategies ‘borrowed’ from chemical physics and quantum chemistry, it has become possible to explore the architectures of small (and not so small) bio-active molecules and of individual biomolecular building blocks, both neutral and ionic, and to characterise quantitatively, the local molecular interactions that determine their structures – in the gas phase.1,2 This has come about through the development of techniques such as laser ablation, for transferring them into the gas phase; the availability of rapid cooling techniques (free jet expansion or trapping in large helium clusters) to stabilise their conformers and/or clusters; highly selective and sensitive combinations of laser-based optical spectroscopy, coupled with mass spectrometry, to probe their structures; and the ready accessibility of powerful ab initio quantum chemical computational codes for their interpretation.The challenge now, is to establish a link between the investigation of structure and molecular interactions in individual biomolecules and molecular complexes, particularly hydrated clusters, isolated in the gas phase, and the architecture and function of ‘real’ biomolecules and bio-molecular assemblies in the condensed phase, and in the organised ‘bio-phase’.In the condensed phase, the chirality of virtually all bioactive molecules makes them ideal targets for conformational analysis through spectroscopic measurements of their electronic or vibrational circular dichroism (CD, VCD) or their Raman optical activity (ROA) – properties that are uniquely sensitive to their conformational structure(s) and composition. Electronic CD spectra are the most easily measured but their structural interpretation depends upon the availability of a firm correlation between molecular configuration (in the condensed phase) and the sign (and magnitude) of the measured CD signals.3 Such correlations are generally expressed in terms of empirical ‘sector rules’ which relate the sign of the observed CD signal to the absolute configuration of the chiral centre which generates it; several rules have been developed assuming ‘known’ conformations of ‘bench-mark’ molecules.The simplest relate to chirally substituted benzene rings,4 where vibronic coupling in the 1Lb state introduces optical activity into the p A p* electronic transition,3 see Fig. 1. The negative CD of (R)-1-phenyl ethanol (R1 ~ OH, R2 ~ CH3: (R)-1-PE) for example, was originally explained by assuming CH3 made the stronger contribution.3 When ‘sector rules’ of this kind were subsequently used to determine absolute DOI: 10.1039/b203810b molecular configurations from the CD signals of ‘new’ systems, as has been done very widely,3 the logic was reversed. Unfortunately, the absolute structure of (R)-1-PE, which has recently been determined spectroscopically, in the gas phase,5,6 actually places the methyl group almost perpendicular to the aromatic plane.If this structure were retained in solution, the methyl group contribution would be negligible and the negative CD could only fit the revised rule, shown in Fig. 2. Fig. 1 The CD (Cotton effect) signal associated with absorption into the 1Lb state of the aromatic ring is taken to be a summation of the influence of the two groups, R1 and R2, lying below/above the plane of the ring (as viewed along the bond linking the chiral substituent to the aromatic ring).Fig. 2 Revised sector rule correlating the negative 1Lb CD signal for (R)-1-phenyl ethanol in solution, with its structure in the gas phase (viewed along the bond linking the side-chain to the aromatic ring). This journal is # The Royal Society of Chemistry 2002 Paper 91 PhysChemComm, 2002, 5(14), 91–932. CD spectroscopy of ephedrine and pseudoephedrine The two chiral molecules, ephedrine and pseudo-ephedrine, represent an important class of drugs, the ephedra. They are also readily accessible to structural investigation in the gas phase via ultra-violet and infra-red laser spectroscopy and in the condensed phase, through CD spectroscopy, and are small enough to be accessible to high level ab initio computation. Recent gas phase studies7–10 have already revealed the sensitivity of their ethanolamine side chain conformations to the chirality of the carbon atom adjacent to the aromatic ring – the two diastereoisomers, (2)(1R 2S)-ephedrine and (1)(1S 2S)-pseudo-ephedrine, have quite different conformational landscapes.8,9 Some preliminary ultra-violet CD spectra of the two diastereo-isomers, recorded in aprotic and protic solvents, are shown in Fig.3. As with (R)-1-PE, the signs of the CD signals can be understood using the known gas phase structures9 and the revised sector rule represented in Fig. 2 and 4 – note that the OH group, now taken to make the dominant contribution, lies in the positive (negative) sectors for ephedrine (pseudo-ephedrine), Fig.3 CD and absorption spectra of (a) (1R 2S)-ephedrine and (b) (1S 2S)-pseudo-ephedrine in cyclohexane (blue) and acetonitrile (orange), and in the H-bonding solvents, methanol (green) and water (magenta). 92 PhysChemComm, 2002, 5(14), 91–93 Fig. 4 The revised sector diagram for (a) (1R 2S)-ephedrine and (b) (1S 2S)-pseudoephedrine (viewed along the bond linking the ethanolamine side chain to the aromatic ring). but the bond linking the ethylamino group to the C1 chiral centre, lies near perpendicular to the aromatic plane and will only make a small contribution to the CD signal. The negative CD signals associated with another pair of diastereoisomers, (1S 2R)-norephedrine and (1S 2S)-norpseudo-ephedrine, were also ‘explained’ under the conventional rule, by assuming structures in which the ethylamino and OH groups were located in the ‘‘negative’’ and ‘‘positive’’ sectors, respectively, with OH again exerting a lesser influence.3 However the gas phase structure of (1S 2R)-norephedrine8 again indicates a near perpendicular orientation for the ethylamino group and the operation of the revised sector rule – now set on a much firmer experimental foundation by the correlation of known gas phase structures with condensed phase CD spectra.{ {The combination of erroneous sector rules with incorrect conformational assignments, actually cancel and fortuitously, existing stereochemical assignments based upon them do not require re-evaluation, despite the incorrect conformational assumptions upon which the existing sector rules are based.Fig. 5 Conformational structures of hydrated and protonated clusters of (a) (1R 2S)-ephedrine and (b) (1S 2S)-pseudo-ephedrine based upon the analysis of their infrared spectra recorded under jet-cooled conditions in the gas phase and/or ab initio computation.10 The changes in magnitude of the CD signals shown in Fig.3 (which are far greater than the changes of a few percent, arising from simple Lorentz dielectric polarizability effects11) imply further, solvent dependent variations in the side chain conformation about each (or either) of the two chiral centres. In the gas phase, the binding of one, two or even three water molecules to ephedrine or pseudo-ephedrine, does not significantly alter the gross side chain structure reflected in the orientation about C1, the contiguous chiral centre,10 cf.Fig. 4. Consistent with this, the sign of the 1Lb CD signals remains either positive, or negative. However, the binding of water molecules and/or a proton in the gas phase can dramatically alter the configuration of the ethanolamine group around the second chiral centre, C2, and/or the orientation of the OH group, which is controlled by its H-bonded environment,10 see Fig. 5. The changes (antiAgauche) in the preferred side chain conformation when water binds to (1S 2S)-pseudoephedrine or a proton is added to (1R 2S)-ephedrine (which reverses the H-bond orientation), reflect the delicate balance between H-bonded and steric interactions in the side chain, and H-bonded interactions with the ring.The CD signals associated with ephedrine in the two H-bonding solvents are much smaller than those measured in aprotic solvents. In pseudo-ephedrine, where there is a conformational change in the 1 : 1 hydrated cluster, they are much larger. For pseudo-ephedrine solutions, titration experiments confirm that the role of water can be mimicked by methanol – but not for ephedrine. In acidified water, where the OH orientation will be reversed, they both present much smaller near UV CD peaks. 3. Conclusions This exploratory investigation, which has led to a re-appraisal of one of the conventional ‘sector rules’ used to derive the absolute configurations of chiral molecules in solution, suggests the possibility of setting them on a firmer foundation by basing them on the structural determinations which can now be conducted on isolated and clustered chiral molecules, made in the gas phase.Attempts at the calculation of electronic CD spectra of flexible chiral molecules have, in part, been hampered by inadequate knowledge of the conformational populations and explicit solvation clusters.12 Since these can now be determined through gas phase measurements1,2 made under free jet expansion conditions, there is a real chance of bridging the gap between the gas phase and solution by using the Boltzmann averaged set of gas phase conformer (and cluster) structures to provide a ‘basis set’ for the distribution of free and explicitly solvated solute structures present in solution.Acknowledgement We gratefully acknowledge the support provided by EPSRC and GlaxoSmithKline (Case studentship, PB and GSK Biospectroscopy Laboratory, ICSTM). 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Woody, ‘‘Theoretical approaches to natural electronic optical activity’’, in Circular Dichroism, Principles and Applications, ed. K. Nakanishi, N. Berova and R. W. Woody, VCH Publishers, New York, 1994, p. 59. 93 PhysChemComm, 2002, 5(14), 91–93
ISSN:1460-2733
DOI:10.1039/b203810b
出版商:RSC
年代:2002
数据来源: RSC