Theoretical Exploration On Active Intermediates Of Oxygenases In Biomimetic Systems

There's no doubt that activation of molecular oxygen for inserting oxygen atom into the organic substrates is a fundamentally important process to aerobic life.However,ground state molecule oxygen owns a triplet biradical structure which requires high kinetic energy barriers when binding to organic substrates,so its inherent activity is very low.Oxygenase can overcome this obstacle,activate molecular oxygen,and then mediate a variety of oxygenations.Heme has attracted much attention because it contains oxygenase,which performs many vital metabolic reactions in living organisms.In order to make oxygenase better serve the organism itself,and to extend these environmentally friendly and efficient active intermediates to the external industrial production,people have carried out in-depth exploration on their structural parameters and mechanism of action for many years.According to the important informations obtained from these studies,a series of biomimetic metal oxygenase intermediates have been designed and synthesized by adjusting metal species and changing ligands.They have been applied to various important fields such as biology,chemistry,medicine and so on,and achieved good results.This provides a basis for further understanding the details of the reaction mechanism of various active intermediates.Traditionally,it is generally believed that high valent metal-oxygen complexes are the only active intermediates for various oxidation reactions,and they do exhibit good reactivity.However,with more and more extensive researches,it has been found that there exist other active intermediates in the reaction system containing oxygenase,which can be used in different systems in the appropriate environment.Based on the importance and richness of the intermediates of metal oxygenase,the detailed mechanism of non-heme high valent iron-oxygen active intermediates participating in the reaction,the factors affecting the equilibrium transformation among various active intermediates,and the active intermediates of palladium,the representative element in the later period of element periodic table,were calculated by quantum chemistry method in order to get more precise results for achieving better theoretical guidances to provide a basis for designing and synthesizing more effective catalysts.The main research contents are summarized as follow:1.Combined Multistate and Kohn-Sham Density Functional Theory Studies of the elusive mechanism of N-dealkylation of N,N-dimethylanilines Mediated by the biomimetic nonheme oxidant Fe^IV?O??N4Py??ClO₄?₂The oxidative C-H bond activation mediated by heme and nonheme enzymes and related biomimetics is one of the most interesting processes in bioinorganic and oxidative chemistry.However,the mechanisms of these reactions are still elusive and controversy due to the involvement of highly reactive metal-oxo intermediates with multiple spin states,despite extensive experimental efforts,especially for the N-dealkylation of N,N-dialkyalinines.In this work,we employed multistate density functional theory?MSDFT?and the Kohn-Sham DFT to investigate the mechanism of N-demethylation of N,N-dimethyalinines oxidized by the reaction intermediate Fe^IV?O??N4Py??ClO₄?₂.The Kohn-Sham DFT study demonstrated that the reaction proceeds via a rate-limiting hydrogen atom transfer step and a subsequent barrier-free oxygen rebound step to form the carbinol product.The MSDFT investigation on the first C-H activation further showed that this step is an initial hydrogen atom abstraction that is highly correlated between CEPT and HAT,i.e.,both CEPT and HAT processes make significant contributions to the mechanism before reaching the diabatic crossing point,then the valence bond character of the adiabatic ground state is switched to the CEPT product configuration.The findings from this work may be applicable to other hydrogen abstraction process.2.What Factors Tune the Chemical Equilibrium between the Metal-Iodosylarene Oxidants and the High-Valent Metal-Oxo OnesMetal-iodosylarene complexes?1?and high-valent metal-oxo complexes?2?are two key reactive intermediates in oxygenation reactions.Extensive experimental efforts have been carried out to explore the structure-function relatioship of these two elusive oxidants,however,controversial proposals based on these experimental results and the missing mechanistic detals call for the interplay of the theoretical approach with these existing experimental one,especially for the factors which tune the chemical equilibrium between two oxidants 1 and 2.Herein,density functional calculations had been performed and the results demonstrated that the effect of triflate counterions?OTf?is not the well known axial ligand effect.Instead,it works via a novel halogen bond interaction.Such halogen bond interaction not only increases the reaction rate of reversible reactions,but also makes the equilibrium point shift to the direction of the metal-iodosylarene oxidant,compared with the non-halogen bond case.Experimental observed species with a signal of S=5/2 was identified as an OTf-halogen-bonding iron?III?-iodosylbenzene species?1d?.The substituent effects of iodoarenes were also studied and the results show that the more fluorine-substitution,the higher reaction barrier and the smaller amount of the metal-iodosylarene oxidant in the oxidation system.Our theoretical study will help the researchers in the biomimetic oxidation field have a more profound knowledge on the metal-iodosylarene chemistry and design more rational catalysts3.Why Normal Palladium Catalysts can Efficiently Mediate Aerobic C-H Hydroxylation of Arylpyridines by Intercepting Aldehyde Autoxidation?A Nascent Palladium?III?-Peracid Intermediate Makes a DifferenceThe direct C?sp2?-H hydroxylation of 2-arylpyridines catalyzed by normal palladium catalysts via interception of the aldehyde autoxidation possesses a number of advantages,including convenient operating conditions,nontoxic and inexpensive aldehydes,and step and atom economy.In this paper,we report a computational study of the mechanism of this catalytic process using density functional theory,revealing a novel catalytic cycle.We found that the rate-limiting step is the C-H bond activation via a concerted metalation deprotonation mechanism.The byproduct of the C-H bond activation,a br?nsted acid HCl,promotes formation of a hexa-coordinated Pd?III?-peracid intermediate.It provides a reservoir for the robust high-valent Pd?IV?-OH species via an easy O-O homolysis.The non-HCl-involving pathway is also energetically feasible,albeit less probable.Furthermore,the involvement of another radical OOH^·,besides of the acyl peroxo radical nPrOO^·,is obligatory to recover the tetra-coordinated Pd?II?catalyst in the catalytic cycle.Our computational work sheds lights on the elusive radical-involving oxygenation mediated by palladium catalysts and will play a positive role in further design of rational reaction strategy and new catalysts.4.Ring Contraction of 2,2,6,6-Tetramethylpiperidine in Drug Metabolism:P450Catalyzed N-H Bond Activation Occurs via a Concerted Proton Coupled Electron Transfer MechanismRing contraction of piperidine drugs by cytochrome P450 enzymes?P450s?is among the most important drug metabolisms for human beings.However,the underlying mechanism remains elusive and controversy even after decades of experimental efforts.Kohn-Sham density functional theory?KS-DFT?combined with multistate density functional theory?MSDFT?were used to explore the chemical nature of ring contraction of 2,2,6,6-tetramethylpiperidine?2,2,6,6-TMPi?mediated by the active species Compound I of P450s.Our calculated results demonstrate that ring contraction is initiated by N-H bond activation.MSDFT combined with KS-DFT methods revealed that N-H bond activation involves an initial tightly coupled electron-proton pair,essentially of hydrogen atom transfer?HAT?character prior to the diabatic crossing point,after which the mechanism is dominated by the concerted electron proton transfer?CEPT?product formation.The excellent performance herein proves that MSDFT is a powerful tool to study the elusive proton coupled electron transfer process.Meanwhile,to the best of our knowledge,this is the first comprehensive theoretical report on the ring contraction by P450,in which the revealed new mechanism will undoubtedly promote relative rational drug design.