Theoretical studies of excited state 1,3 dipolar cycloadditions
Bellucci, Michael A.
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The 1,3 dipolar photocycloaddition reaction between 3-hydroxy-4',5,7-trimethoxyflavone (3-HTMF) and methyl cinnamate is investigated in this work. Since its inception in 2004 [JACS, 124, 13260 (2004)], this reaction remains at the forefront in the synthetic design of the rocaglamide natural products. The reaction is multi-faceted in that it involves multiple excited states and is contingent upon excited state intramolecular proton transfer (ESIPT) in 3-HTMF. Given the complexity of the reaction, there remain many questions regarding the underlying mechanism. Consequently, throughout this work we investigate the mechanism of the reaction along with a number of other properties that directly influence it. To investigate the photocycloaddition reaction, we began by studying the effects of different solvent environments on the ESIPT reaction in 3-hydroxyfiavone since this underlying reaction is sensitive to the solvent environment and directly influences the cycloaddition. To study the ESIPT reaction, we developed a parallel multi-level genetic program to fit accurate empirical valence bond (EVB) potentials to ab initio data. We found that simulations with our EVB potentials accurately reproduced experimentally determined reaction rates, fluorescence spectra, and vibrational frequency spectra in all solvents. Furthermore, we found that the ultrafast ESIPT process results from a combination of ballistic transfer and intramolecular vibrational redistribution. To investigate the cycloaddition reaction mechanism, we utilized the string method to obtain minimum energy paths on the ab initio potential. These calculations demonstrated that the reaction can proceed through formation of an exciplex in the S1 state, followed by a non-adiabatic transition to the ground state. In addition, we investigated the enantioselective catalysis of the reaction using α,α,α',α'-tetraaryl-1,3-dioxolan-4,5-dimethanol alcohol (TADDOL). We found that TADDOL lowered the energy barrier by 10-12 kcal/mol through stabilizing hydrogen bond interactions. Using temperature accelerated molecular dynamics, we obtained the potential of mean force (PMF) associated with 3-HTMF attacking the TADDOL/methyl cinnamate complex. We found that the exo reaction is inhibited through steric interactions with the aryl substituents on TADDOL. Furthermore, we found that the exo configuration breaks the intramolecular hydrogen bond in TADDOL, which stabilizes the individual reactants apart from each other. The role of the T1 state is also discussed.
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