Computational Studies Of Transition-metal Catalyzed C-H Activation And Diels-Alder Ligation Reaction

Physical organic chemistry is an emerging study of the interrelationships between structure and reactivity in organic molecules. Understanding the relationships (i.e. mechanism) could provide important insights into the principles and rationale of organic chemistry as well as the design of new substrates, reagents and reactions. In this dissertation, with the aid of computational methods, mechanistic studies of several interesting organic reactions were performed in detail qualitatively and quantificationally.Firstly, popular experimental and computational methodologies were briefly reviewed as well as basic concepts and principles of physical organic chemistry. Up to now, several experimental methods were developed, such as kinetic isotope experiment, intermediate trapping, reaction order measurement and substitution effect. Modern computational methods mainly include quantum mechanics (such as density functional theory) and molecular mechanics. By combination of two types of methods, we are able to deduce mechanisms more effectively and reasonably.There are two main ways to investigate mechanisms by combination of experimental and computational methods. One approach is experiments first and then computations. Based on several possible mechanisms inferred according to experimental information, the kinetically favored pathway is obtained by calculating the barriers. This way is involved in Chapter2and3. In Chapter2, three mechanistic possibilities (i.e. SEAr&migration, metalation-deprotonation, and Heck-type arylation mechanisms) were examined by DFT methods to understand ligand-controlled α/β-selectivity in Pd-catalyzed C-H activation of thiophenes with the special ligand P(OCH(CF3)2)3reported by Itami’s group. Heck-type arylation mechanism is found to be responsible for Cp-arylation of thiophenes whereas metalation-deprotonation could cause Cα-arylation. We successfully explained the mechanistic origin of ligand-controlled regioselectivity. Understanding of this unusual ligand-controlled α/β-selectivity may provide important insights into the development of more efficient catalyst systems for selective C-H arylation.In Chapter3, to further understand the H elimination of Heck-arylation mechanism mentioned in Chapter2, three mechanistic possibilities, i.e. isomerization and syn-βH elimination, aH elimination and1,2-H shift and anti-βH elimination, were also carefully examined by DFT methods. Base-assisted anti-βH elimination is found to be the most energetically favored in substituted thiophenes systems as well as furan and N-methylpyrrole. These results could not only offer a more comprehensive understanding of the Heck mechanism, but also help to develop Heck-type arylation reactions of heterocyclic substrates.The other approach is computation first and then experiments. After calculations of several widely accepted mechanisms, the energetically preferred mechanism is given. To confirm the computational results, experiments are designed. This way is involved in Chapter4. Cu-catalyzed inert C-H functionalization is a challenging question. In this field, we carried out the first comprehensive theoretical study (together with experimental tests) on the mechanism of Cu-catalyzed intramolecular ortho-C-H activation/C-X(X=N,O) couplings. The two reactions are found to share the same mechanism. Cu(Ⅱ) species is first found to mediate the C-H activation process through a OAc/OTf assisted six-membered concerted metalation-deprotonation (CMD) transition state. The above theoretical conclusions are consistent with the experimental kinetic isotope effects and substituent effects.In addition, we tried to predict the important parameter (rate constant) accurately in physical organic chemistry. In Chapter6, we focus on the rate constant of Diels-Alder reaction because this reaction is a promising and attractive method for ligation in bioorthorgonal chemistry and the development of the nucleophile-tolerant Diels-Alder ligation reactions is urgent. We initially found that M06-2X/6-31+G(d)//B3LYP/6-31G(d) was capable to accurately predict the barriers of Diels-Alder reactions with a precision of1.4kcal/mol. Subsequently, the electronic effect and ring-strain effect on Diels-Alder reaction were studied and three new cyclopropenes were designed for efficient and selective Diels-Alder ligation in living systems. The results were proved experimentally by Prescher et al. in their recent work.