Mechanistic insights for β-cyclodextrin catalyzed phosphodiester hydrolysis

Hydrolysis of phosphodiester bond in different substrates containing alkyl or aryl substituents, in the presence of β-cyclodextrin (β-CD) as a catalyst, has been investigated employing the density functional theory. It has been shown that the mechanism of β-CD catalyzed phosphodiester hydrolysis in modeled substrates viz. [p-nitrophenyl][(2,2) methylpropan] phosphodiester (G1); [p-nitrophenyl] [(2,2)methyl butan] phosphodiester (G2); (p-nitrophenyl) (2-methyl pentan) phosphodiester (G3); (p-nitrophenyl) (phenyl) phosphodiester (G4); (p-nitrophenyl) (m-tert-butyl phenyl) phosphodiester (G5) and (p-nitrophenyl) (p-nitrophenyl) phosphodiester (G6) involves net phosphoryl transfer from p-nitrophenyl to the catalyst. The hydrolysis occurs in a single-step D(N)A(N) mechanism wherein the β-CD acts as a competitive general base. The nucleophile addition is facilitated via face-to-face hydrogen-bonded interactions from the secondary hydroxyl groups attached to the top rim of β-CD. The insights for cleavage of phosphodiester along the dissociative pathway have been derived using the molecular electrostatic potential studies as a tool. The activation barrier of substrates containing alkyl group (G2 and G3) are found to be lower than those containing aryl groups (G4, G5 and G6).