Low barrier hydrogen bonds (LBHBs) are postulated to impart immense rate enhancements to enzyme catalyzed reactions. LBHBs have three requirements for their formation: low dielectric media, matched pk/a/s between donor and acceptor conjugate acid (deltapK/a=0), and heteroatom distances of 2.5A or lower. The original interpretation of how LBHBs would effect enzyme catalysis involved a """"""""special stabilization"""""""". However, it is more likely that the strength of a hydrogen bond simply becomes stronger as deltapK/a approaches during zero during a catalytic reaction, and that the extent of the increase in strength is dependent upon the three factors listed above. The sensitivity of the increase in strength to the change in pK/a is a Bronsted alpha-value. Hence, the experimental data required for distinguishing how well hydrogen bonds and/or general-acids effect catalysis are alpha-values. To date, only thermodynamic measurements have been used to determine alpha-values relevant to the LBHB debate; no kinetic measures have been performed. Using kinetics to determine how alpha-values depend upon hydrogen bond geometry, solvent dielectric and donor/accepted pk/a/s, is critical to a full understanding of catalysis by enzymes. This proposal describes four model systems, each with a distinctly different hydrogen bond geometry, in which alpha-values for both hydrogen-bonding and general-acid catalysis will be determined. The experiments involve synthesis, pK/a determinations in non-aqueous solvents, kinetic measurements, crystallography, and LBHB characterization using NMR. We will determine how alpha-values vary with hydrogen bond distances/angles and the dielectric/protic nature of the solvent. The manner in which alpha-values vary as a function of these parameters has not been previously determined, but we predict that aprotic/low dielectric solvents, and short hydrogen bonds, will give the largest alpha-values. The significance of such a result goes beyond an increased basic science understanding of enzymology, and has clear ramifications in the design of synthetic catalysts for biomedical and synthetic applications.
