A DFT computational study on the molecular mechanism of reaction between pyridinium salts and π-deficient ethylenes: Why furan derivatives are formed instead of feasible cyclopropane derivatives and [3 + 2] cycloadducts?

Abstract

The reaction between 1-(2-amino-2-oxoethyl)pyridinium ylide 4 (PY4) and 1-methylene-3,4-dihydronaphthalen-2(1H)-one 5 (MDN5) in the presence of acetonitrile (CH3CN) was theoretically studied at the M06-2X/6-31G(d,p) computational level. Calculated relative Gibbs free energies indicate that encounters between PY4 and MDN5 in the reaction mixture result in the formation of the highly zwitterionic betaine-like intermediate IM1ca in an entirely C1C5 regio- and a cisoid-anti stereoselective manner over the course of a Michael addition reaction through a very low barrier (4.2kcal/mol) and a highly exergonic (24.7kcal/mol) pathway. While C1C5 regioselectivity can be rationalized via the analysis of the computed nucleophilic and electrophilic Parr functions at the reactive sites of reagents, the cisoid-anti stereoselectivity predominance over the cisoid-syn one can nicely be portrayed within the non-covalent interactions (NCIs) analysis at the cisoid-anti transition state TS1ca and cisoid-syn transition state TS1cs involved in the Michael addition reaction. The electron-localization function (ELF) quantum topological analysis obviously demonstrates that the C1 carbon atom in PY4 exhibits a pseudoradical character indicating the high reactivity of PY4 toward C5 electrophilic attack of MDN5 which is characterized with a very low barrier associated with the C1C5 single bond formation along the Michael addition step. Upon formation of IM1ca, in excellent agreement with the experimental outcomes, an SNi-like reaction converts IM1ca into trans-furan derivative 8 together with pyridine via a high barrier (23.9kcal/mol) but a highly irreversible pathway making compound 8 as the only reachable product under “thermodynamically-controlled” conditions (refluxing over 8h). In other words, neither [3+2] cycloadduct 6 (as the kinetically most favourable but thermodynamically most unfavourable product) nor cyclopropane derivative 7 (as both kinetically and thermodynamically most undesirable product) can be obtained under the reaction conditions. From the molecular mechanism point of view, the ELF analyses indicate that while C1C5 single bond formation within the Michael addition reaction takes place via a C- to -C coupling of two pseudoradical C1 and C5 centers, formation of C1O8 single bond accompanied with the C1N15 single bond breaking at the generated IM1ca to afford compound 8 is a direct consequence of donation of some electron density of O8 oxygen lone electron pairs to the C1 carbon atom.