(472a) First Principle Simulations Of Reactions In Organic Solvents

Probably the simulation of reactions in organic solvents is one of the most challenging tasks nowadays in the field of molecular modelling. In many literature works the solvent is just omitted or simulated by using continuum solvation models. In such dielectric model, the solvent is modelled as a continuous medium, usually assumed homogeneous and isotropic, characterized solely by a scalar, static dielectric constant. In some cases, these results give the correct reactive behaviour, provided there are no essential explicit solvent interactions with the solute. In many cases the behaviour of the solvent close to the chemically active part is different from the bulk and specific effects play in the first solvation shell. A possible method to include these explicit solvent interactions might be achieved by placing a few solvent molecules around the chemically active species. Of course then the question arise on how many solvent species to incorporate explicitly. Mostly this number is determined by the value at which the coordination solvation energy is converged. To account also for entropic effects of solvation the Gibbs free energy change of solvation must also be evaluated. [1,2]

A variety of approximations varying from simple gas phase calculation, including solvent implicitly and including solvent with a combined explicit and implicit approach is tested to study the reactive behaviour of a series of aziridinium salts towards regio- and stereospecific ring opening. The aziridine moiety represents one of the most valuable three-membered ring systems in organic chemistry due to its widely recognized versality as a building block towards a large variety of ring opened or ring expanded amines. Unactivated aziridines, i.e. aziridines without an electron-withdrawing group at nitrogen, can easily be transformed into aziridinium salts upon treatment with alkyl halides, which are subsequently opened by a suitable nucleophile (usually the counter ion). As depicted in Scheme 1, the reaction of a chiral aziridine 1 with an alkyl halide may lead to three different amines 4-6 depending on the reaction mechanism. In this way, the initial chiral center at the substituted aziridine carbon atom can be retained (pathway a, amine 4), inverted (pathway b, amine 5) or razemized (pathway c, amine 6). Consequently, the elucidation of the underlying reaction mechanism is of primordial importance when the design of asymmetric syntheses towards chiral amines is contemplated starting from chiral 2-substituted aziridines such as 1.

At first instance the key steps involved in the unprecedented regiospecific ring opening of intermediate 2-(cyanomethyl)aziridinium salts by bromide and pyrrolidine in acetonitrile are investigated theoretically. Experimentally it was found that the ring opening occurred exclusively at the substituted aziridine carbon atom. For the ring opening with pyrrolidine, the correct reaction preference was always found, independent of the solvation model. The quantitative values of the reaction barriers vary substantially with or without solvation. The ring opening with bromide, is found to be more sensitive to the degree of solvation that is taken into account. The correct regioselectivity was only found if a sufficient number of explicit solvent molecules were taken into account and additionally the whole system is placed in a continuum with fixed dielectric constant. Another example which is addressed is the ring opening of 2-(cyanomethyl)aziridines with HBr in acetic acid and acetonitrile or dichloromethane, affording 3-(arylmethyl)amino-4-bromobutyronitriles via regiospecific ring opening at the unsubstituted carbon atom. The factors governing the switch in regioselectivity as compared to the reaction with benzyl bromide are thoroughly investigated. In this case we are dealing with a combination of various solvent species, i.e. acetic acid in combination with acetonitrile or dichloromethane, and thus the initial set up for the cluster model is more complicated. The cluster model is determined on basis of coordination free energies of solvation. The theoretical description of the regioselectivity in the ring opening of C-substituted aziridinium salts is a complex issue, in which the nature of the substrate, the nucleophile and the solvent are be important. These systems constitute ideal examples to test the reliability of a variety of solvent models to describe the correct reaction behaviour.

[1]Matthias D'hooghe, Veronique Van Speybroeck,Michel Waroquier, and Norbert De Kimpe, CHEMICAL COMMUNICATIONS (14): 1554-1556, 2006

[2]Matthias D'hooghe, Veronique Van Speybroeck, Andries Van Nieuwenhove,Michel Waroquier, and Norbert De Kimpe, "Novel synthesis of 3,4-diaminobutanenitriles and 4-amino-2-butenenitriles from 2-(cyanomethyl)aziridines through intermediate aziridinium salts: an experimental and theoretical approach", to be published in J. Org. Chem.