Hydrogen-Bonding Interactions in Cinchonidine-2-Methyl-2-Hexenoic Acid Complexes: A Combined Spectroscopic and Theoretical Study Daniel M. Meier, Atsushi Urakawa, Natascia Turra `, Heinz Ru ¨ egger, and Alfons Baiker* Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Ho ¨nggerberg, HCI, 8093 Zurich, Switzerland ReceiVed: March 03, 2008; ReVised Manuscript ReceiVed: April 16, 2008 Molecular interactions between cinchonidine (CD) and 2-methyl-2-hexenoic acid (MHA) have been studied by means of NMR, ATR-IR MES, DFT, and ab initio molecular dynamics. These interactions are of particular interest due to their pivotal role in the chiral induction occurring in the heterogeneous catalytic asymmetric hydrogenation of R,-unsaturated acids. The population density of the Open(3) conformer of CD, the most populated one at room temperature in apolar solvents, considerably increased to a maximum by addition of MHA to CD in toluene. The CD-MHA complex showed prominent symmetric and asymmetric carboxylate stretching vibrations in the regions of 1350-1410 and 1520-1580 cm -1 , respectively. DFT calculations revealed that these vibrational frequencies are expected to significantly shift depending on the chemical surrounding of MHA, that is, the hydrogen bond network. Earlier postulated 1:1 binding between CD and MHA was considered unlikely; instead, a dynamic equilibrium involving the MHA monomer and dimer, the 1:3 and possibly 1:2 CD-MHA complexes, were rationalized. Stable CD-MHA structures suggested by DFT calculations are the “1:3, halfN, cyclic” and the “1:3, halfN, cyclic tilted” complexes, where three MHA molecules are connected in wire by hydrogen bonding, two having direct interaction with CD. The confinement of CD’s torsional motions in the complexes, leading to a slightly distorted Open(3) conformer via specific hydrogen-bonding interactions, was clearly reproduced by ab initio molecular dynamics, and the stable and flexible nature of the interaction was verified. Theoretical IR spectra of the complexes reproduced the characteristic vibrational frequencies of the complexes observed experimentally, supporting the stability of the 1:3 and implying the possibility of even higher molecular weight CD-MHA complexes. Introduction Intermolecular hydrogen bonding, which is largely responsible for the generation of supramolecular complexes, is an eminent and still expanding research field. The noncovalent structures of flexible nature play key roles in a broad chemical range, including chiral recognition and catalysis. 1 The interactions are well-known in liquid-phase chemistry, for example, homoge- neous catalysis where they promote regioselective reactions 2 or induce stereoselectivity. 3 Such interactions are also under- stood to occur in heterogeneous catalysis, as, for example, in the asymmetric hydrogenation of activated ketones 4 or, as studied here, of R,-unsaturated carboxylic acids. Thereby, metal surfaces are modified by adsorbing a chiral molecule, the so- called chiral modifier or simply modifier. In general, Pd chirally modified by cinchona alkaloids, employed in the enantioselective hydrogenation of the carboxylic acid’s substituted C-C double bond, are proven to be efficient for this reaction. 5 An overview of the reaction and a variety of prochiral acids hydrogenated in this way are summarized in different reviews. 6–12 In contrast to the continuous improvement of the enantiomeric excess (ee) up to 92% 13 by systematically varying the reaction conditions, 14 substrates, 15 and additives, 16 the mechanistic understanding of the reaction lags somewhat behind and is a matter of debate in the literature. This is certainly in part due to the inherent complexity of the reaction involving a substrate, modifier, solvent, and catalyst surface. Better insight into the reaction mechanism, especially the interaction between the modifier and substrate, is crucial towards the rational design of the catalytic system. The focus of the current study is on the interaction between the chiral modifier, cinchonidine (CD), and 2-methyl-2-hexenoic acid (MHA) in solution, in view of the commercial importance of chiral carboxylic acids 17,18 and the good ee afforded for this reaction using CD and MHA. 19,20 A combined spectroscopic and theoretical approach was deemed suitable to study the CD-MHA interaction and gain deeper insight into the reaction mechanism. In solution phase, two very powerful spectroscopic techniques are IR and NMR, being largely complementary due to their significantly different sensitivity relative to structural changes and bonding information. An absolute necessity, considering the complexity of the system, was theoretical support, in particular, for the IR signal assignment and the structural characterization. From earlier spectroscopic 21–27 and theoretical 28,29 studies, it is known that CD and other cinchona alkaloids exist preferably in the Open(3) conformation, especially in apolar solvents. 22 Upon addition of an acidic substrate to CD or employing an acidic solvent, the population of the Open(3) conformer is further enhanced. 30–32 Similarly, simple protonation of the quinuclidine N of CD and the presence of a counterion can drastically influence the conformational behavior and leads also to an increase in Open(3). 31 In the case of the CD-acid interaction, the origin of the enhancement of the Open(3) population has been assigned to the confinement of two characteristic torsion angles of CD (τ 1 and τ 2 , Figure 1) via a * To whom correspondence should be addressed. E-mail: baiker@ chem.ethz.ch. J. Phys. Chem. A 2008, 112, 6150–6158 6150 10.1021/jp801866p CCC: $40.75  2008 American Chemical Society Published on Web 06/17/2008