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The structural factors responsible for the rapid rates (kcats) of enzyme-catalyzed reactions are not well understood. In this paper, we outline an analysis that we believe can provide a quantitative understanding of the kcats of three types of reactions: abstraction of the alpha-protons from carbon acids, acyl-transfer reactions, and displacement reactions of phosphodiesters. We propose that these reactions proceed via the formation of intermediates in which negative charge develops on the carbonyl or phosphoryl oxygens. Our analysis is based on Marcus formalism that separates the activation energy barrier for conversion of bound substrate to the intermediate, delta G++, into contributions from a thermodynamic barrier, delta G zero, and an intrinsic kinetic barrier, delta G++int. We propose that one (or more) general acid catalyst positioned adjacent to the carbonyl or phosphoryl oxygens of the substrate is primarily responsible for reducing both delta G zero and delta G++int from the values that characterize nonenzymatic reactions. The proton donors (1) stabilize the intermediates via the formation of short, strong hydrogen bonds (the pKas of the protonated intermediates and the general acid catalysts are matched), thereby reducing delta G zero, and (2) stabilize the transition states for formation of the intermediates by negating the developing charge on the oxygens without the requirement for significant structural reorganization, thereby reducing delta G++int. The possible reductions in delta G zero and delta G++int are sufficient to understand the rapid kcats of these reactions.

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Ab initio calculations including geometry optimization at the Hartree-Fock, MP2, and LDF levels have been carried out for free-base porphyrin and for the tautomers of free-base chlorin, using polarized basis sets. TheHartree-Fock approximation artificially favors frozen resonance structures with alternating single and double bonds for these compounds. This incorrect behavior is completely reversed when correlation effects are accounted for. Correct, delocalized structures of tetrapyrroles are obtained with the MP2 and LDF levels of approximation.

Recently, we reported that essentially "anhydrous hydroxide" was an excellent reagent for the hydrolysis of tertiary amides at ambient temperatures.1 This reagent was generated via the reaction of 2 equiv of potassium tert-butoxide with 1 equiv of water.2 Mechanistically, it appeared that the relatively unsolvated hydroxide added to the tertiary amide, 1, to produce 2. Removal of a hydroxylic proton from 2 would then produce the dianion, 3. Fragmentation of 3 then produced the most stable pair of anions, which in this case was 4 and 5. Utilizing this concept, a series of tertiary amides was

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The electronic effects of a wide variety of peripheral substituents in free base porphyrins have been evaluated using X-ray photoelectron spectroscopy (XPS) and all-electron ab initio calculations. Both methods have identified the 1s energies of the central nitrogens as excellent sensors of the electronic effects of peripheral substituents. Core level photoelectron spectra are reported for nine porphyrins, including unsubstituted porphyrin, octaethylporphyrin, and seven tetraphenylporphyrins. Substituents on the phenyl groups in tetraphenylporphyrins have been found to modulate the electronic environment of the central region of the porphyrin nucleus in a significant manner. Thus, between tetraphenylporphyrin and tetrakis(pentafluorophenyl)porphyrin, the XPS nitrogen 1s ionization potentials shift by 0.9 eV. Ab initio self-consistent field calculations were carried out on substituted porphyrins, with multiple alkyl, aryl, fluoro, chloro, bromo, cyano, and nitro groups, using basis sets of double-{quality. Calculations on selected porphyrins with larger, polarized basis sets suggest that both the absolute values of the orbital energies and the substituent effects are reasonably well-converged at the double-{ level of basis sets. Very large substituent effects (up to 4.1 eV, relative to octamethylporphyrin, in our calculations) on the 1s energies of the central nitrogens of the porphyrin nucleus are predicted for certain arrays of electron-withdrawing peripheral substituents. Valence orbital energies have also been computed, and the differences in the ultraviolet photoelectron spectra of porphyrin and octaalkylporphyrins are well reproduced by the calculations. Suitable arrays of strongly electron-withdrawing substituents result in large stabilizations of the porphyrin T orbitals, which should translate into enhanced stability of the porphyrins toward oxidative degradation. The molecules studied by the ab initio calculations range in size from porphyrin, C20H,4N4, to 8-octafluoro-meso-tetrakis(pentafluorophenyl)porphyrin, C4,H2F2,N4. Use of the direct SCF formalism, in which integrals do not need to be stored, has made these large calculations feasible. These calculations demonstrate that at present ab initio calculations can be performed routinely for molecules containing 50-100 atoms.