Characterization of Low-Barrier Hydrogen Bonds. 8. Substituent Effects on the Strength and Geometry of the Formic Acid−Formate Anion Model System. An ab Initio and DFT Investigation

Abstract

High-level ab initio and density functional theory calculations have been used to investigate the relationship between pKa mismatch and hydrogen bond strength in a typical low-barrier hydrogen bond system. It is found that a difference of 1 pKa unit between the pKa values of the two substituted formate anions vying for a proton in the substituted formic acid−formate anion complex will result in a weakening of the corresponding hydrogen bond by approximately 1.8 kcal/mol. This suggests that small differences in pKa values (i.e. 1−2 pKa units) of proton donors and proton acceptors in enzyme active sites should not preclude the importance or significance of LBHBs during the reactions catalyzed by many enzymes. On the other hand, larger differences in relative pKa values (on the order of 5−6 pKa units) should be sufficient to cause a considerable weakening of any purported SSHB that might be formed during such an enzyme reaction. It is thus concluded that, just as Gerlt and Gassman suggested in their original...