Reaction Mechanisms: Rates, Solvent Effects, Enzyme Catalysis and New Methodologies

The Thorpe-Ingold hypothesis for the gem-dimethyl effect in the cyclization reactions of 2-chloroethoxide derivatives has been investigated computationally in the gas phase and in aqueous solution. Ab initio MP2/6-311+G(d,p) and CBS-Q calculations reveal little intrinsic difference in reactivity with increasing alpha-methylation. However, inclusion of continuum hydration or of explicit hydration through mixed quantum and statistical mechanics (MC/FEP) simulations does reproduce the substantial, experimentally observed rate increases with increasing alpha-methylation. Analysis of the MC/FEP results provides clear evidence that the rate increases stem primarily from increased steric hindrance to hydration of the nucleophilic oxygen atom with increasing a-methylation. Thus, the gem-dimethyl acceleration of oxirane formation is found to be predominantly a solvent effect.;Next, a combined computational and experimental kinetic study on the uncatalyzed Henry reaction is presented. The reaction between formaldehyde and nitromethane was investigated with the AM1 semiempirical molecular orbital (SMO) method in the gas phase, where its performance was gauged against higher level ab initio and density functional calculations. Subsequent AM1/MM simulations reproduced well experimental differences in the free energies of activation for the stereoselective reaction between benzaldehyde and nitropropane in water and DMSO. The observed rate enhancement in DMSO over water is found to arise from poorer relative solvation of the charge-localized reactants in the aprotic solvent. Computationally, the anti diastereomers of the beta-nitrbalkoxide were favored over syn in the gas phase and in solution owing to the intrinsic preference for the anti conformations of the ethyl/phenyl and nitro/alcohol substituent pairs. Supported by computations, present experimental study confirmed that the beta-nitroalkoxide product immediately isomerizes to yield a corresponding nitronate alcohol, which upon protonation yields the final beta-nitroalcohol product as a 3:1 ratio of syn: anti diastereomers in both water and DMSO.;Next, the exo/endo selectivity of cyclization reactions of trans-disubstituted epoxy alcohols was investigated computationally in the gas phase and in aqueous solution. Baldwin's rules and solvent effects along with the steric and electronic role of a tetrahydropyran (THP) template attached to the backbone of the reactants were methodically evaluated. While gas-phase calculations were found to favor the smaller heterocycle, simulations in solution showed that, in agreement with experiment, the inclusion of the THP template results in selectivity for the otherwise disfavored endo-pathway. This can be in large attributed to the lessened distortion in the attack angle, i.e. the angle between the nucleophilic oxygen and the C--C bond of the epoxide (O--C--C), in the transition state (TS) of the larger heterocycle and to the greater relative strain in the backbone angles in the smaller-heterocycle TS.;Next, the keto--enol tautomerization of p-hydroxyphenylpyruvate (HPP) by the macrophage inhibitory factor (MIF) is reported. Past studies have shown that a terminal proline residue (Pro1) can act as a general base deprotonating the substrate; nearby Lys32 and Tyr95 residues were suggested to assume the role of a general acid. Present PDDG/PM3/MM simulations indicate a dual acid/base role of the terminal Pro1 residue. The Lys32 and Tyr95 pK a's are too high for favorable reprotonation of the substrate; moreover, neither is positioned as close to the enolate intermediate as Pro1. Additionally, intermolecular tautomerization was compared to an intramolecular process, which was expectedly less favorable due to the strain in the transition state.;Lastly, a program interface between BOSS (biochemical and organic simulation system) and GAMESS (general atomic and molecular electronic structure system) is presented. This interface was developed to allow for the use of mixed quantum and statistical mechanics (MC/FEP) simulations with the QM region described by higher-level ab initio or density-functional methods. Supplementing the semiempirical methods that are available in the standalone BOSS code, higher-level QM methods provide more accurate reaction energetics, and can be applied to small systems in the context of MC/FEP simulations. The Henry reaction between nitromethane nitronate and formaldehyde is presented as an examplatory study of a system that benefits from a combined MC/FEP--MP2/6-31+G(d) approach.