Multiparameter kinetic analysis of alkaline hydrolysis of a series of aryl diphenylphosphinothioates: models for P=S neurotoxins

Abstract

Alkaline hydrolysis of a series of X‐substituted‐phenyl diphenylphosphinothioates (2a‐i) in 80 mol%/20 mol% DMSO at 25.0 ± 0.1°C has been studied kinetically and assessed through a multiparameter approach. Substrates 2a to 2i are approximately 12 to 22 times less reactive than their P=O analogues 1a to 1i (ie, the thio effect). The Brønsted‐type plot for the reactions of 2a to 2i is linear with βlg = −0.43, consistent with a concerted mechanism. Hammett plots correlated with σo and σ− constants also support a concerted mechanism; the Yukawa‐Tsuno plot results in an excellent linear correlation with ρX = 1.26 and r = 0.30, indicating that expulsion of the leaving group occurs in the rate‐determining step (RDS). The ΔH‡ value increases from 10.5 to 11.7 and 13.9 kcal/mol as substituent X in the leaving group changes from 3,4‐(NO2)2 to 4‐NO2 and H, in turn, while TΔS‡ remains constant at −6.0 kcal/mol. The strong dependence of ΔH‡ on the electronic nature of substituent X also indicates that the leaving group departs in the RDS. The reaction mechanism and origin of the thio effect are discussed by comparison of the current kinetic results with those reported for the reactions of 1a to 1i. The results suggest that for useful OP neurotoxins the mechanism of abiotic hydrolysis is concerted (with varying degrees of asynchronicity) when the substrate bears good leaving groups.

Evaluation of 3′-phosphate as a transient protecting group for controlled enzymatic synthesis of DNA and XNA oligonucleotides

“…Hence, we questioned whether a minimal perturbation of the phosphate moiety such as the substitution of an oxygen moiety by a sulfur atom could improve the substrate capacity of 3’-phosphate-modified LNA nucleotides. We rationalized that the introduction of a sulfur atom could decrease the capacity of polymerases at hydrolyzing the phosphate moiety since reaction at P = S centers is slower than for the native P = O centers 60 , 61 and concentrating the negative charge on sulfur could increase interactions with polymerases 62 . Docking experiments comforted these assumptions since the sulfur atom is predicted to interact mainly with an arginine of the active site of the TdT and the overall free energy is very favorable (−17.50 kcal/mol; see Supplementary Fig.…”

Structure‐Reactivity Insights on the Alkaline Hydrolysis of Organophosphates: Non‐Leaving and Leaving Group Effects in a Bilinear Brønsted‐Like Relationship

“…[36,37] Other works attributed the reactivity differences to the thermodynamic parameters such as activation enthalpy. [35,38] In other cases, changes from P=O to P=S changed the preferential electrophilic center, from phosphorus to an aromatic or aliphatic carbon. [15,33] Regarding the mechanistic interpretation of the β values, firstly, the reactions shown for both phosphate and thiophosphate triesters should occur via a concerted nucleophilic attack (Figure 4).…”

“…Some explanations to this are based on the differences of sulfur and oxygen properties such as oxygen being more electronegative than sulfur, and sulfur a better electron donor than oxygen, characteristics that influence directly on the phosphorus electrophilicity [36,37] . Other works attributed the reactivity differences to the thermodynamic parameters such as activation enthalpy [35,38] . In other cases, changes from P=O to P=S changed the preferential electrophilic center, from phosphorus to an aromatic or aliphatic carbon [15,33] …”

Molecular electrostatic potential as a general and versatile indicator for electronic substituent effects: statistical analysis and applications

“…4.2.2 Alkaline hydrolysis of diphenylphosphinate and diphenylphosphinothioates 93 . Um et al attempted to investigate the kinetics of the alkaline hydrolysis of diphenylphosphinate, in which two phenyl groups and a phenolate group with a single substituent (X) are attached to the PQO motif and its thio analogue as depicted in Scheme 2.…”