Theoretical Studies Of The Mechanism Of The Metal-Catalyzed Functionalization Of Csp~2-H Bonds With Directing Group

An efficient method for synthesis of heterocyclic compounds has been developed via transition metal-catalyzed functionalization reaction of C-H bonds, but the regioselective C-H bond activation is also a big challenge. Although the different hydrocarbon activation patterns of catalytic reaction have been reported, coordination oriented C-H bond activation reaction is one of the most reported method. Moreover, the development of its theoretical research is slightly lagging behind,and the mechanism details involved in these reactions remain unclear from the viewpoint of theory. In this paper, we set out to investigate the reaction mechanism of transition-metal(Pd/Rh) catalyzed C-H bond selective cleavage reaction and Cu catalyzed C-H amination reaction with the aid of DFT calculations.In Chapter 3, DFT calculations have been performed to study the Pd(OAc)2-catalyzed activation of Csp~2-H bonds with 1,2,3-triazole directing groups. The competing cyclization and substitution pathways were calculated for the Pd(OAc)2-catalyzed activation of Csp~2-H bonds.The results of these calculations indicated that the cyclization pathways of both the TAA(N1-aryl-1,2,3-triazole-4-carboxylic acid) and TAPy(N2-pyridine-1,2,3-triazole-4-carboxylic acid) systems proceeded as follows:(1) the activation of the arene C-H bonds via a CMD mechanism in which the Pd(II) oxidation state was retained;(2) the oxidation of the arylpalladium(II) intermediate with PhI(OAc)2 to give the corresponding arylpalladium(III) intermediate;(3) the deprotonation of the imino group with Pd(III); and(4)the reductive elimination and C-N bond formation reactions. For the substitution pathway, our calculations supported a three-step pathway involving(1) C-H activation of the arene C-H bonds with Pd(II) via a CMD process;(2) oxidation of the Pd(II) intermediate; and(3) the coupling of Ph-OAc via a five-membered transition state from Pd(III). For the TAA-directed Csp~2-H activation, the cyclization pathway was kinetically favored over the substitution pathway.In contrast, the TAPy-directed Csp~2-H activation kinetically favored the substitution pathway over the cyclization. The kinetic preference of the TAPy directing group for the substitution process can be attributed to a reduced level of bond cleavage in the transition structure of the substitution step because the pyridine moiety of the TAPy directing group can act as a ligand for the Pd center.In Chapter 4, the mechanism of the Rh(III)-catalyzed C-H activation of O-substituted N-hydroxybenzamides with cyclohexadienone-containing 1,6-enynes has been studied using density functional theory with the M06 method. The impact of different O-substituted internal oxidants(-OPiv versus-OMe) on the arylative cyclization(i.e., ?-Michael addition versus?-Michael addition) has been evaluated in detail. The ?-Michael addition pathway proceeded via a Rh(I) species, while Rh(III) remained unchanged throughout the ?-Michael addition pathway. The Rh(III)/Rh(I) catalytic cycle in the ?-Michael addition pathway was different from those reported previously where the Rh(III)/Rh(V) catalytic cycle was favored for the Rh(III)-catalyzed C-H activation of O-substituted N-hydroxybenzamides. The first three steps were similar for the OPiv- and OMe-substituted substrates, which involved sequential N-H deprotonation, C-H activation(a concerted metalation-deprotonation process), and 1,6-enyne insertion steps. Starting from a seven-membered rhodacycle, the alternative mechanism would be controlled by the OR substituent. When the substituent was OMe, the unstable seven-membered rhodacycle was readily coordinated by a double bond of the cyclohexadienone which enabled the?-Michael addition reaction. However, the presence of an N-OPiv moiety stabilized the seven-membered rhodacycle through a bidentate coordination which facilitated the ?-Michael addition process.In Chapter 5, the reaction mechanism of Cu(II)-catalyzed synthesis of pyrido[1,2-a]benzimidazoles was theoretically investigated with the aid of density functional theory calculations(DFT) at the B3 LYP level. Five possible mechanisms for the synthesis were proposed:(1) C-H-bond-breaking step preceding deprotonation of imino group, and finally C-N bond formation(Pathway a),(2) deprotonation of imino group preceding C-H-bond-breaking step, and finally C-N bond formation(Pathway b),(3) C-H-bond-breaking as the first step, then C-N bond formation preceding deprotonation of imino group(Pathway c),(4) the anti-imino-cupration mechanism(Pathway d),(5) the Friedel-Crafts alkylation mechanism(Pathway e). The calculation results indicate that the most favorable pathway involves C-H bond breaking by concerted metalation/deprotonation(CMD), followed by N-H deprotonation along the triplet state and C-N bond formation(Pathway a).