Stabilization of glyphosate zwitterions and conformational/tautomerism mechanism in aqueous solution: insights from ab initio and density functional theory-continuum model calculations

Abstract

In this work, a comparative theoretical conformational analysis of the commercially most successful herbicide compound, glyphosate (N-phosphonomethylglycine), has been made at various quantum chemical levels of theory, in the gas phase and aqueous solution, using the integral equation-formalism polarizable continuum model (IEFPCM) and the solvation model density (SMD) approaches. The stable conformers of non-ionized (NE) and ionized or zwitterionic (ZW) neutral forms of glyphosate and the inter-conversions between them are described. Calculations revealed that several NE conformers of glyphosate exist in the gas phase but the zwitterionic form (ZW) is unstable in vacuo at all levels of theory. In aqueous solution, the stabilization of the zwitterion form of glyphosate was unable to be predicted satisfactorily within the equilibrated framework of the IEFPCM polarizable continuum model and using the standard UFF-radii cavity. However, the calculation with the density-based solvation model (SMD) was consistent with the experimental findings and led to the identification of the phosphonate zwitterionic (ZWP) structure as the global minimum energy in aqueous solution. The ZWP NE tautomeric equilibrium between the non-ionized and zwitterionic forms of glyphosate was studied in aqueous solution at the SMD-B3LYP-D3/6-311++(2d,2p) level. Zwitterion formation in solution could occur by means of a concerted intramolecular proton transfer from the nitrogen to the oxygen of the phosphonate group. An analysis of the intermolecular mechanism shows that the addition of one water molecule favours the process either thermodynamically or kinetically. The possibility that the tautomerization process of glyphosate via a nonconcerted mechanism with zwitterion carboxylate (ZWC) as the intermediate can be excluded and the ZWP → ZWC proton transfer conversion can be a nearly barrierless process in PES and FES surfaces. comparison with similarly related biologically active systems was made.