Theoretical Study Of Transition-Metal Catalyzed Radical–Radical Cross-coupling Reactions

The development of radical chemistry has entered a new stage after more than one hundred years of studies.Recently,with the successful application of radical reactions in the total synthesis of drug molecular and natural product,more attentions are focused on radical chemistry.Moreover,the rapid development of transition metal catalysis and visible light catalysis greatly enriched the species of radicals,and broadened the scope of radical reactions,which brought new opportunities and challenges to radical chemistry.How to explain the mechanism of radical reactions,understand the nature of radical bonding,and reveal the fundamental rules in radical chemistry,have become the research emphasis.In this thesis,theoretical calculation was employed to study the reactivity of radical species and uncover the detailed mechanism of transition metal-catalyzed radical-radical cross-coupling reactions.Based on computational results,a stepwise coupling mode was summarized for this type of reactions.The origin of cross-coupling selectivity was also explained by the differences in electrophility and nucleophilicity of radicals.Details are as followings:1.Density functional theory(DFT)calculation was used to study nickel-catalyzed radical addition of ?-carbonyl alkyl halide and olefin.Computational results suggested that the single electron transfer between ?-carbonyl alkyl halide and Ni(I)complex would cause the homolytic cleavage of C–Br bond,and generate a tertiary carbon radical.Subsequent radical addition toward olefin formed a stable carbon radical.The new C–O bond is proven to be constructed through the carbon radical addition to the carbonyl.Another possible pathway which occurs through the nucleophilic addition of carbocation to carbonyl was ruled out due to the instability of carbocation.2.Theoretical study of visible light-mediated decarboxylative amidation of ?-keto acids revealed that the acidamide product was formed through the nucleophilic addition of phenylamine to acyl radical.A dipolar intermediate was obtained in calculation.The electrostatic potential analysis of this key structure indicated that the positive charge was located on nitrogen atom and the negative charge was located on oxygen atom,respectively.Thus,this process is different from the classical radical addition as the radical was always remained on acyl carbon during the C–N bond formation.3.An in-depth theoretical study of synergistic Cu(II)/Cu(I)-mediated alkyne coupling was performed to reveal the detailed mechanism for C–C bond formation,which proceeded via an unusual dinuclear 1,2-reductive elimination.Because the reactant for dinuclear 1,2-reductive elimination was calculated to be triplet while the products were singlet,the minimum energy crossing point(MECP)was introduced to Cu/TMEDA/alkyne system to clarify the spin crossing between triplet state and singlet state potential energy surfaces.The C–C bond formation was proven to be realized through Cu(II)-mediated dinuclear 1,2-reductive elimination after the MECP.Computational results suggested that C–H bond cleavage solely catalyzed by Cu(I)cation was the rate-determining step of this reaction,and the C–C bond formation was a facile process.Theoretical study showed that the nature of this reaction is the homocoupling of two Cu(II)radicals.4.A stepwise coupling pathway,which involves the combination of a carbon radical with a Cu(II)–N species before C–N bond formation,was proposed and proved for copper-catalyzed C–N radical-radical cross-coupling reaction.This Cu(II)–N species preferentially combines with a carbon radical and forms a Cu(III)complex through a MECP.A subsequent two-electron transfer process constructs the C–N bond.Moreover,the computational results of global electrophilicity ?° and nucleophilicity N° for radicals suggested the carbon radical is a strong nucleophile while the nitrogen radical and the Cu(II)–N ?-diketonate intermediate are strong electrophiles.The matching of the electrophilicity of the Cu(II)–N intermediate with the strong nucleophilicity of the carbon radical makes it easier for the combination of Cu(II)with the carbon radical and the subsequent C–N bond formation.In this pathway,the transition metal could successively stabilizes two radical species at different oxidation states,and the electron compatibility of radicals would determine the cross-coupling selectivity.5.In order to verify the generality of stepwise coupling mode,this reaction mode was further applied to explain nickel-catalyzed oxidative C–N coupling of N-methoxybenzamide with tetrahydrofuran.Computational results suggested this stepwise coupling mode is also suitable for nickel-catalyzed C–N radical–radical cross-coupling.The chemoselectivity could also be clarified by the global electrophilicity ?° and nucleophilicity N°.The differences in electron compatibility of radicals control the chemoselectivity.This study provides a practical theoretical guide for the design of transition metal-catalyzed radical-radical cross-coupling.