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

Abstract

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(sp(2)) 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.

Kinetic and Theoretical Studies of a Facile, One‐Pot Preparation of a Spirocyclohexylindolinone Derivative

“…The energies of the different species were calculated at the B3LYP/ 6311++(2d,2p) level of theory, using the explicit-implicit solvent model. [35] Thus, one molecule of DMSO was considered to be hydrogen-bonded to the N(1)H of 2b or 13b and the OH of tBuOH, and these molecules or DMSO complexes were embedded in a solvent cavity modelled by the IEF-PCM[DMSO] method.…”

Energy Managements in the Chemical and Biochemical World, as It may be Understood from the Systems Chemistry Point of View

“…Nowadays, in modern organic and medicinal chemistry a typical molecule may involve several analogous functional groups, which are able to react with a reagent dissimilarly, resulting in different products, therefore the fast determination or at least estimation of the reactivity of these functional groups is essential for planning synthetic routes. Nevertheless, in the case of theoretical methods, which can predict reactivities by modeling the reaction mechanism, it is typical that behind a seemingly simple chemical reaction, the real mechanism is quite complex, involving many species in each individual elementary step, like reactants, reagents, solvent molecules, catalysts, and acid or base as co-reagents [1][2][3][4][5]. All these species should be involved in the calculation to investigate the real and detailed mechanism, in order to obtain a correct and accurate view of the reaction taking place in a real media.…”

“…In fact, determination of the minimal size of the appropriate chemical model (e.g. number of explicit solvent molecules necessary) is very difficult, time and resource consuming [1]. Moreover, an incorrect chemical model provides not only inaccurate energy values, but frequently absolutely wrong or opposite results, questioning the competence of theoretical methods in the applied science [1].…”

“…number of explicit solvent molecules necessary) is very difficult, time and resource consuming [1]. Moreover, an incorrect chemical model provides not only inaccurate energy values, but frequently absolutely wrong or opposite results, questioning the competence of theoretical methods in the applied science [1]. Reactions taking place in media usually require the consideration of a base or an acid as catalyst together with many solvent molecules in an appropriate 3D arrangement [1,2,5].…”

“…Moreover, an incorrect chemical model provides not only inaccurate energy values, but frequently absolutely wrong or opposite results, questioning the competence of theoretical methods in the applied science [1]. Reactions taking place in media usually require the consideration of a base or an acid as catalyst together with many solvent molecules in an appropriate 3D arrangement [1,2,5]. Taking into consideration of all of these criteria, it seems nearly impossible to model even a simple acylation reaction.…”