Computational study of the reactions of phosphinylidenes, fluoroquinolones and hydrazones: molecules of commercial and pharmaceutical interest

Abstract

The formation of P-C bonds is of interest for many commercial, as well as pharmaceutical applications. Current production relies on the use of PCl3 in an energy intensive process that produces large amounts of environmentally toxic HCl as a by-product. The Montchamp group has long had an interest in an alternative process for the green synthesis of P-C bond-containing compounds. In a collaborative experimental and computational study, it was demonstrated that using phosphinylidenes are viable starting feedstock for P-C bond formation, taking advantage of their P(V) to reactive P(III) tautomerization. Computational and experimental results demonstrate the stabilization of the P(III) tautomer by electron withdrawing groups. Furthermore, with a high tautomerization energy, catalysis is necessary for viable commercial application. Computational screening of a variety of simple organic molecules showed good agreement with experimental data and highlighted their potential for future development. Fluoroquinolones require the formation of a water-metal ion bridge between the molecule and topoisomerase IV for antibiotic efficacy. A computational study of the pH dependent binding to Mg(H2O)N2+ showed good agreement with experimental in vitro binding affinities and efficacy. The approach produced an average magnesium binding affinity for efficacious fluoroquinolones at neutral and basic pH, demonstrating viability as a screening method for future drugs within the class. The study also identified systematic modulation of pKas as a possible future direction for drug design.

Hydrazones are of commercial and pharmaceutical interest due to their pH lability. Previously, it was demonstrated that triazinylhydrazones exhibited greater stability to hydrolysis at pH 5 compared to acetylhydrazones. In a collaborative follow-up, the effect of substituents at N2 were investigated. It was shown that electron donating groups increase the proton affinity of N1 and hence the rate of hydrolysis, while electron withdrawing groups decreased the proton affinity and hydrolysis rate. The same stabilization at pH 5 was observed, with computational and experimental results in good agreement. Outside of this trend lay N2 phenyl substituents. While electron withdrawing by induction they appeared to exhibit hyperconjugation stabilization of the protonated N1. This observation may become the focus of future work.