Phosphonates as Mimics of Phosphate Biomolecules: Ab Initio Calculations on Tetrahedral Ground States and Pentacoordinate Intermediates for Phosphoryl Transfer

The use of phosphonates as analogs of phosphate biomolecules was explored using ab initio SCF calculations at the 3-21G(*) and 3-21+G(*) levels. Fully optimized geometries were obtained for the tetrahedral ground-state monoanions CHF₂PO₃H⁻, CH₂FPO₃H⁻, CH₃PO₃H⁻, BH₃PO₃H₂-, H₂PO₃⁻, and [formula omitted] and torsional energy profiles obtained for CH₂FPO₃H⁻ and H₂PO₃⁻. Comparison was made of (1) structure and conformational dependence for these species and (2) electrostatic potential maps for ethylene phosphate and its monofluoromethylene phosphonate analog. The results suggest that, despite the isopolar relationship of fluoromethyl phosphonates and the parent phosphates, binding at a receptor site may be considerably perturbed for the phosphonate analogs. Fully optimized geometries were located for isomers of the pentacoordinate trigonal bipyramidal species PH₄X (X = CH₃, CF₃, CF₂H, CFH₂, BH₃⁻, BF₃⁻, O⁻, OH) and [formula omitted]. Torsional energy profiles were explored for PH₄X (X = CH₃, CF₃₎ CF₂H, CFH₂). The calculated relative apicophilicity scale in PH₄X (CF₃ > CF₂H > CFH₂ > CH₃ > OH > O⁻ ≫ BF₃⁻ > BH₃⁻) varies in the five-membered cyclic phosphoranes by reversal of CH₃ and OH. It is concluded that mono- and difluoromethylene phosphonates have similar ligand preferences to the parent phosphates in the pentacoordinate state and by consideration of the fully optimized geometry of the pentacoordinate dianion [formula omitted] that these phosphonates are capable of forming transition-state analogs at the active site of phosphoryl transfer enzymes.