Modeling Rate-Controlling Solvent Effects. The Pericyclic Meisenheimer Rearrangement of N-Propargylmorpholine N-Oxide

The activation parameters of the pericyclic Meisenheimer rearrangement and a competitive rearrangement of N-propargylmorpholine N-oxide were determined by experimental and computational methods. A number of aprotic and protic solvents of different polarities and hydrogen bond-forming abilities and the roles of electron-pair acceptor additives were investigated. The reaction kinetics were followed by means of NMR. In protic solvents, isotope-labeling experiments revealed a novel inverse secondary kinetic isotope effect (k H/k D about 0.8) for the rate-determining cyclization step, probably occurring because of a C(sp) → C(sp2) change in hybridization at the reaction center. In molecular computations at the B3LYP/6-31++G(d,p) level of theory, implicit, explicit, and joint explicit−implicit solvent models were used. The explicit−implicit model and molecular dynamic simulations gave the most accurate results. The components of the rate-controlling solvent effect are discussed, and general equations are proposed for accurate prediction of the solvent-dependent activation parameters.