Excited-State Tautomerization of 7‑Azaindole in Nonpolar Solution: A Theoretical Study Based on Liquid-Phase Potential Surfaces of Mean Force

Excited state tautomerization of a 7-azaindole (7AI) complex with one methanol molecule in heptane was studied using variational transition state theory including multidimensional tunneling (VTST/MT) with the dielectric continuum model for the solvent effect. Electronic structures and energies for reactants and transition state (TS) in solution were computed at the complete active space self-consistent field (CASSCF) level with second-order multireference perturbation theory (MRPT2) to take into consideration of dynamic electron correlation. The polarizable continuum model using the integral equation formalism (IEFPCM) and the SMD model were used for the excited-state solvent effect. Excited-state surfaces of potential of the mean force in solution were generated for the first time at the MRPT2//SMD/CASSCF­(10,9)/6-31G­(d,p) level. The position of TS on the reaction coordinate substantially depended on the dynamic electron correlation. The two protons in the excited-state tautomerization were transferred in a concerted but asynchronous process. Calculated HH/DD kinetic isotope effect (KIE) and the ratio of Arrhenius pre-exponential factors, <i>A</i>(HH)/<i>A</i>(DD), agreed very well with the corresponding experimental values. The shape of the adiabatic energy surfaces in the excited-state strongly depended on the position of isotopes due to the asynchronicity of the reaction path, and the tunneling effect was essential for reproducing experimental KIEs. The pyrrolic proton moved a twice longer distance by tunneling than the hydroxyl proton in the most probable tunneling path at 292 K. This study strongly suggests that the mechanism of the excited-state double proton transfer in heptane is triggered by proton transfer from the pyrrolic nitrogen of 7AI to alcohol (protolytic pathway), rather than by proton transfer from alcohol to the pyridine nitrogen of 7AI (solvolytic pathway)

Is It Fe(III)-Oxyl Radical That Abstracts Hydrogen in the C–H Activation of TauD? A Theoretical Study Based on the DFT Potential Energy Surfaces

Taurine:α-ketoglutarate dioxygenase (TauD) is one of the most important enzymes in the α-ketoglutarate dioxygenase family, which are involved in many important biochemical processes. TauD converts taurine into amino acetaldehyde and sulfite at its nonheme iron center, and a large H/D kinetic isotope effect (KIE) has been found in the hydrogen atom transfer (HAT) of taurine suggesting a large tunneling effect. Recently, highly electrophilic Fe­(III)-oxyl radicals have been proposed as a key species for HAT in the catalytic mechanism of C–H activation, which might be prepared prior to the actual HAT. In order to investigate this hypothesis and large tunneling effect, DFT potential energy surfaces along the intrinsic reaction path were generated. The predicted rate constants and H/D KIEs using variational transition-state theory including multidimensional tunneling, based on these potential surfaces, have excellent agreement with experimental data. This study revealed that the reactive processes of C–H activation consisted of two distinguishable parts: (1) the substrate approaching the Fe­(IV)-oxo center without C–H bond cleavage, which triggers the catalytic process by inducing metal-to-ligand charge transfer to form the Fe­(III)-oxyl species, and (2) the actual HAT from the substrate to the Fe­(III)-oxyl species. Most of the activation energy was used in the first part, and the actual HAT required only a small amount of energy to overcome the TS with a very large tunneling effect. The donor–acceptor interaction between σ_C–H and σ_Fe–O^* orbitals reduced the activation energy significantly to make C–H activation feasible

Kinetic Isotope Effects as a Probe for the Protonolysis Mechanism of Alkylmetal Complexes: VTST/MT Calculations Based on DFT Potential Energy Surfaces

Protonolysis by platinum or palladium complexes has been extensively studied because it is the microscopic reverse of the C–H bond activation reaction. The protonolysis of (COD)­Pt^IIMe₂, which exhibits abnormally large kinetic isotope effects (KIEs), is proposed to occur via a concerted pathway (S_E2 mechanism) with large tunneling. However, further investigation of KIEs for the protonolysis of ZnMe₂ and others led to a conclusion that there is no noticeable correlation between the mechanism and magnitude of KIE. In this study, we demonstrated that variational transition state theory including multidimensional tunneling (VTST/MT) could accurately predict KIEs and Arrhenius parameters of the protonolysis of alkylmetal complexes based on the potential energy surfaces generated by density functional theory. The predicted KIEs, <i>E</i>_a^<i>D</i> – <i>E</i>_a^H values, and <i>A</i>_H/<i>A</i>_D ratios for the protonolysis of (COD)­Pt^IIMe₂ and Zn^IIMe₂ by TFA agreed very well with experimental values. The protonolysis of ZnMe₂ with the concerted pathway has a very flat potential energy surface, which produces a very small tunneling effect and therefore a small KIE. The predicted KIE for the stepwise protonolysis (S_E(ox) mechanism) of (COD)­Pt^IIMe₂ was much smaller than that of the concerted pathway, but greater than the KIE of the concerted protonolysis of ZnMe₂. A large KIE, which entails a significant tunneling effect, could be used as an experimental probe of the concerted pathway. However, a normal or small KIE should not be used as an indicator of the stepwise mechanism, and the interplay between experiments and reliable theory including tunneling would be essential to uncover the mechanism correctly

Large Tunneling Effect on the Hydrogen Transfer in Bis(μ-oxo)dicopper Enzyme: A Theoretical Study

Type-III copper-containing enzymes have dicopper centers in their active sites and exhibit a novel capacity for activating aliphatic C–H bonds in various substrates by taking molecular oxygen. Dicopper enzyme models developed by Tolman and co-workers reveal exceptionally large kinetic isotope effects (KIEs) for the hydrogen transfer process, indicating a significant tunneling effect. In this work, we demonstrate that variational transition state theory allows accurate prediction of the KIEs and Arrhenius parameters for such model systems. This includes multidimensional tunneling based on state-of-the-art quantum-mechanical calculations of the minimum-energy path (MEP). The computational model of bis­(μ-oxo)­dicopper enzyme consists of 70 atoms, resulting in a 204-dimensional potential energy surface. The calculated values of <i>E</i>_a^H – <i>E</i>_a^D, <i>A</i>_H/<i>A</i>_D, and the KIE at 233 K are −1.86 kcal/mol, 0.51, and 28.1, respectively, for the isopropyl ligand system. These values agree very well with experimental values within the limits of experimental error. For the representative tunneling path (RTP) at 233 K, the pre- and post-tunneling configurations are 3.3 kcal/mol below the adiabatic energy maximum, where the hydrogen travels 0.54 Å by tunneling. We found that tunneling is very efficient for hydrogen transfer and that the RTP is very different from the MEP. It is mainly heavy atoms that move as the reaction proceeds from the reactant complex to the pretunneling configuration, and the hydrogen atom suddenly hops at that point

Proton Transfer Dependence on Hydrogen-Bonding of Solvent to the Water Wire: A Theoretical Study

The mechanism and dynamics of double proton transfer dependence on hydrogen-bonding of solvent molecules to the bridging water in a water wire were studied by a direct ab initio dynamics approach with variational transition-state theory including multidimensional tunneling. Long-range proton transfers in solution and within enzymes may have very different mechanisms depending on the p<i>K</i>_a values of participating groups and their electrostatic interactions with their environment. For end groups that have acidic or basic p<i>K</i>_a values, proton transfers by the classical Grotthuss and “proton-hole” transfer mechanisms, respectively, are energetically favorable. This study shows that these processes are facilitated by hydrogen-bond accepting and donating solvent molecule interactions with the water wire in the transition state (TS), respectively. Tunneling also depends very much on the hydrogen bonding to the water wire. All molecules hydrogen bonded to the water wire, even if they raised and narrowed energy barriers, reduced the tunneling coefficients of double proton transfer, which was attributed to the increased effective mass of transferring protons near the TS. The theoretical HH/DD KIE, including tunneling, was in good agreement with experimental KIE values. These results suggest that the classical Grotthuss and proton-hole transfer mechanisms require quite different solvent (or protein) environments near the TS for the most efficient processes

Determination of Spin Inversion Probability, H‑Tunneling Correction, and Regioselectivity in the Two-State Reactivity of Nonheme Iron(IV)-Oxo Complexes

We show by experiments that nonheme Fe^IVO species react with cyclohexene to yield selective hydrogen atom transfer (HAT) reactions with virtually no CC epoxidation. Straightforward DFT calculations reveal, however, that CC epoxidation on the <i>S</i> = 2 state possesses a low-energy barrier and should contribute substantially to the oxidation of cyclohexene by the nonheme Fe^IVO species. By modeling the selectivity of this two-site reactivity, we show that an interplay of tunneling and spin inversion probability (SIP) reverses the apparent barriers and prefers exclusive <i>S</i> = 1 HAT over mixed HAT and CC epoxidation on <i>S</i> = 2. The model enables us to derive a SIP value by combining experimental and theoretical results