8th Liquid Matter Conference September 6-10, 2011 Wien, Austria ...

P2.56Tue 611:23-14:00Rationalizing the stereoselectivity of paroline-catalyzedasymmetric aldol reactions in waterMarco Masia, 1 Jordi Ribas, 2 Maria Angels Carvajal, 3 and Alain Chaumont 41 Universita’ di Sassari, Dipartimento di Chimica, Via Vienna, 2 07100, Sassari,Italy2 Universitat de Barcelona, Barcelona, Spain3 Universitat Rovira i Virgili, Tarragona, Spain4 Universite’ de Strasbourg, Strasbourg, FranceOver the last decade, organocatalysis has witnessed tremendous growth and has become a thrivingarea of general concepts and widely applicable asymmetric reactions [1]. The proline-catalyzedaldol condensations are both origin and prototype of such reactions [2-4]. In this contribution wewill present an ab initio molecular dynamics study [5] of the proline amide-catalyzed self aldolreaction of propanaldehyde (PAD) in water, which is the first organocatalytic aldol reaction carriedout in water featuring a good enantioselectivity [6]. We will focus on the stereogenic step of thewhole catalytic cycle, which consists of a C-C bond formation by means of a nucleophilic additionof an enamine intermediate to the carbonyl group of PAD. Based on extensive CPMD simulations[5] in the condensed phase we have computed the activation free energies of the four differentattacks leading to the corresponding four different stereoisomers. These activation free energieshave been obtained from ”blue moon” constrained molecular dynamics [7] by thermodynamicintegration [8]. Not only the computed enantiomeric excesses are in good agreement with theexperimental ones but our simulations also provide a hitherto elusive rationale for the observedstereoinduction. Specifically, we have unveiled the key role played by the number of hydrogenbonds (coming either from the solvent water molecules or the amido group of proline amide)stabilizing the developing alkoxide as the C-C bond is formed.[1] D. W. C. MacMillan, Nature 455, 304 (2008).[2] B. List et al. J. Am. Chem. Soc. 122, 2395 (2000).[3] B. M. Trost, C. S. Brindle. Chem. Soc. Rev. 39, 1600 (2010).[4] M. Raj, V. K. Singh, Chem. Commun. 6687 (2009),[5] R. Car, M. Parrinello, Phys. Rev. Lett. 55, 2471 (1985),[6] S. Aratake et al. Chem. Commun. 2524 (2007).[7] E. Carter et al. Chem. Phys. Lett. 156, 472 (1989).[8] M. Sprik, G. Ciccotti, J. Chem. Phys. 109, 7737 (1998).56