Application of the Systems Chemistry Approach on the Ammonolysis of 1-Ethoxycarbonyl- and 1-Phenoxycarbonyl-3-(2-thienyl)oxindoles. A Method to Predict Reactivity

Abstract

The routine prediction of the reactivity of a complex, multifunctional molecule is a challenging and time-consuming procedure. In the last step of the synthesis of the well-known drug substance tenidap, a nonexpected difference was observed between the reactivities of two closely related carbamate moieties, the N-ethoxycarbonyl and the N-phenoxycarbonyl group. A detailed kinetic study, necessitating a significant computational effort, is described in the present paper for this reaction step. On the other hand, the systems chemistry concept, by analyzing the details of the electronic structure and the connections between functional groups in a fast and simple way, is also able to answer this question using various "-icity" parameters (aromaticity, carbonylicity, olefinicity). The complete systems chemistry approach involves all these conjugativicity parameters, while its further simplified version is based on only one key parameter, which is carbonylicity in the present case. The above methods were compared in terms of their predictive power. The results show that the systems chemistry concept, even its one-parameter version, is applicable for the characterization of this challenging reactivity issue.

Preparation of 2-phospholene oxides by the isomerization of 3-phospholene oxides

“…The conversion of 3-phospholene oxides 1 to the corresponding 2-phospholene derivatives 4 was first interpreted by means of thermodynamic data, and the olefinicity concept [69][70][71][72]. The calculations were performed at a high MP2/6-311G++(2d,2p) level of theory ( Table 5).…”

An experimental and theoretical study of reaction mechanisms between nitriles and hydroxylamine

“…The method and basis sets were chosen for their reliability in agreement with the studies established earlier. 27,31,41,42 The vibrational frequencies were computed at the same levels of theory as those used for geometry optimization in order to properly confirm all structures as residing at minima on their potential energy hypersurfaces (PESs). Thermodynamic functions U, H, G and S were computed at 298.15 K, using the quantum chemical, rather than the conventional, thermodynamic reference state.…”

A quantum chemical study on the mechanism and energetics of the direct esterification, thioesterification and amidation of 1-hydroxy-3-methyl-3-phospholene 1-oxide

“…Using numerous modelling efforts, the necessity of the hydrogen bond acceptor solvent network and the participation of another P-acid molecule (1) as the catalyst were proved by our high level calculations. It was found that the sophisticated explicit-implicit solvent model 14,15 is suitable to compute the kinetic parameters accurately, where the relative permittivity of the implicit polarizable continuum model (PCM) 18 was set to 3 ¼ 17.33 corresponding to 1-butanol. The proposed mechanism and the calculated enthalpies are shown in Scheme 2 and Table 1, respectively.…”

“…Taking into consideration all necessary factors, it seems nearly impossible to model even a simple acylation reaction. In the literature, 14,15 one of the most frequently used methods to model the surrounding media properly is the implicit-explicit solvent model, where the most important association of species is considered only in the closest layer as an explicit model and the remaining part of the bulk is considered as an average by the relative permittivity (3) as an implicit model. It is like a "nanodrop" surrounded by media.…”

“…In addition to the aims outlined above, we wished to obtain precise energetics for the course of the esterication, thio-esterication and amidation of a selected phosphinic acid. For this, high level B3LYP/6-31G(d,p) 16 calculations were planned with the application of the explicit-implicit solvent model, 14,15 by Gaussian 09. 17…”