Amides as nucleophiles in dephosphorylation processes: reactivity favored by tautomerism

Obsolete stocks of pesticides require sustainable methods of degradation.[1] Therefore, studies involving dephosphorylation processes of phosphate triesters — an important class of pesticides — have attracted great interest. We hypothesized that primary and secondary amides could represent candidates for this purpose, once its inherent tautomerization (e.g. formamide (FMD), Scheme 1) leads to a small formation (Keq=10-8)[2] of the iminol species. Consequently, iminol could act as a N-nucleophile towards phosphorus atom (Scheme 1) supported by a hydrogen bond during the nucleophilic substitution. In this study we have assessed the reactivity of FMD, thioacetamide (TCM), N-N-dimethylformamide (NDMF), urea and succinimide (SCD) with the phosphotriester diethyl 2-4-dinitrophenylphosphate (DEDNPP) in DMSO. Probably due to the electron withdrawing character — and the steric hindrance — of carbonyl group, no nucleophilic activity was observed for SCD. In contrast, FMD and urea presented interesting reactivity, showing experimental kN values of 1,3x10-2 and 8,8x10-4 M-1 s-1, respectively. These values become 108-fold larger considering only the concentration of the reactive tautomer (iminol; estimated in 10-6 %). Since no reactivity was detected by NDMF (which does not present tautomerism) and TCM (which tautomerizes to an iminothiol), two important evidences were verified for FMD and urea, respectively: (i) the reactivity is governed by tautomerism and (ii) OH hydrogen bonding plays an important role by lowering the activation barrier. DFT calculations at the B3LYP/6-31+g(d,p) level of theory have been performed for the reaction of FMD(B) with DEDNPP. Results suggest the nucleophilic attack by nitrogen lone pair occurs simultaneously to a prototropic shift (TS1). A pentacoordinate intermediate (INT1) is formed followed by a proposed intramolecular acid catalysis, which is still under investigation (Scheme 1).