The question of the nature of the proton bridge involved in general acid-base catalysis in both enzymic and non-enzymic systems is considered in the light of long-known but insufficiently appreciated work of Jencks and his coworkers and of more recent results from neutron-diffraction crystallography and NMR spectroscopic studies, as well as results from isotope-effect investigations. These lines of inquiry lead toward the view that the bridging proton, when between electronegative atoms, is in a stable potential at the transition state, not participating strongly in the reaction-coordinate motion. Furthermore they suggest that bond order is well-conserved at unity for bridging protons, and give rough estimates of the degree to which the proton will respond to structural changes in its bonding partners. Thus if a center involved in general-catalytic bridging becomes more basic, the proton is expected to move toward it while maintaining a unit total bond order. For a unit increase in the pK of a bridging partner, the other partner is expected to acquire about 0.06 units of negative charge. The implications are considered for charge distribution in enzymic transition states as the basicity of catalytic residues changes in the course of molecular evolution or during progress along a catalytic pathway.

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Schowen et al. / Isotope Effects in Transniethylation and Transalkylation435 1 course of its f~r m a t i o n .~ If this occurs, microcrystalline hydrolysis product is formed which interferes with the spectrophotometric observations.Reagent-grade chemicals and double-distilled deionized water were employed throughout the investigation.Kinetics. The apparatus previously d e~c r i b e d ,~ in which the photomultiplier signal of a Cary 16 spectrophotometer is digitized and stored in a Hewlett-Packard 2lOOA computer so as to generate 1000 kinetic points in each run, was used. The points were subjected to weighted, nonlinear least-squares fitting to the first-order kinetic law to produce the observed first-order rate constants. The reactions were carried out in 1 -mL cuvettes thermostated by a Lauda circulating constant-temperature bath. Absorbance data were collected at 380 nm. In most cases, runs with protiated and deuterated substrates were conducted in alternation, using the same stock reaction solutions.

Arrhenius curves of selected hydrogen transfer reactions in organic molecules and enzymes are reviewed with the focus on systems exhibiting temperature‐independent kinetic isotope effects. The latter can be rationalized in terms of a ‘pre‐tunneling state’ which is formed from the reactants by heavy atom motions and which represents a suitable molecular configuration for tunneling to occur. Within the Bell–Limbach tunneling model, formation of the pre‐tunneling state dominates the Arrhenius curves of the H and the D transfer even at higher temperatures if a large energy Em is required to reach the pre‐tunneling state. Tunneling from higher vibrational levels and the over‐barrier reaction via the transition state which lead to temperature‐dependent kinetic isotope effects dominate the Arrhenius curves only if Em is small compared to the energy of the transition state. Using published data on several hydrogen transfer systems, the type of motions leading to the pre‐tunneling state is explored. Among the phenomena which lead to large energies of the pre‐tunneling state are (i) cleavage of hydrogen bonds or coordination bonds of the donor or acceptor atoms to molecules or molecular groups in order to allow the formation of the pre‐tunneling state, (ii) the occurrence of an energetic intermediate on the reaction pathway within which tunneling takes place, and (iii) major reorganization of a molecular skeleton, requiring the excitation of specific vibrations in order to reach the pre‐tunneling state. This model suggests a solution to the puzzle of Kwart's findings of temperature‐independent kinetic isotope effects for hydrogen transfer in small organic molecules. Copyright © 2010 John Wiley & Sons, Ltd.

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