Theoretical Studies On Radical Cyclization Reactions

Free radical chemistry has established its status of indispensability to life science and organic synthesis. By now, the research on reactions towards product-oriented organic synthesis has grown to be the mainstream of radical chemistry, and the application of radical-based methods in natural product total synthesis directs the future progress. However, the application of radical reactions in organic synthesis is neither systematic nor profound. The factor restraining the application lies in the shortage of research on its selectivity and universality. In this regard, this dissertation focuses on the regioselectivity of radical chemistry and conducts theoretical studies on product-oriented radical cyclization reactions. It is devoted to develop a scientific methodology based on first principles to deal with radical cyclization reactions.In Chapter 1, the history, recent development and prospect on radical chemistry are summarized. And an overview of experimental and theoretical background of radical cyclization reactions is included.In Chapter 2, a brief introduction of computational chemistry and its application is presented. Some computational methods including Density Functional Theory, Many-Body Perturbation Theory, Configuration Interaction, Coupled-Cluster, Model Chemistry and Force Field Method are also introduced. Especially focus on the Density Functional Theory, which is the primary method of this dissertation.In Chapter 3, the cyclization of allenic radicals is systematically studied for the first time by computational methods. It is found that the theoretical results at the ONIOM(QCISD(T)/6-311+G(2df,2p):UB3LYP/6-311+G(2df,2p)) level are in good agreement with all the experimental data. Marcus theory analysis indicates that the intrinsic energy barrier favored the olefinic radical product, whereas the allylic radical product is favored by the thermodynamic terms. For the cyclization of substituted hexa-4,5-dien-l-yl radicals, substitution at the allene moiety does not affect the regioselectivity where the allylic radical product is always favored. For the cyclization of hepta-5,6-dien-1-yl radicals, substitution at the allene moiety dramatically affects the regioselectivity, where some radical stabilizing groups such as -CN and -COMe may even completely reserve the regioselectivity.In Chapter 4, the radical cyclizations of methyleneamino and imino compounds containing C=N double bonds are studied. The theoretical study aims to systematically determine what factors affect the N-philic versus C-philic selectivity in the radical cyclization onto C=N double bonds. The results indicate that 4-(methyleneamino)butan-1-yl radical favors the C-philic cyclization process. For the cyclization of substituted 4-(methyleneamino)butan-1-yl radicals, substitution at the terminal carbon atom dramatically affects the regioselectivity, where some radical stabilizing groups such as -Ph, -CN and -COOEt may reserve the regioselectivity. The regioselecitivity of 5-iminopentan-1-yl radical cyclization is in accordance with the Baldwin-Beckwith rules, where 5-exo product is observed via the C-philic cyclization.In Chapter 5, the preparation ofβ-Lactams through four different radical cyclization reactions is studied by Density Functional Theory calculations at the UB3LYP/6-311++G (3df, 2p) level. Thermodynamics and kinetics of these radical cyclizations are analyzed using the Marcus theory. The calculated results indicate that the 4-exo cyclization of carbamoyl radical is an ideal kinetic-control process. The 4-exo cyclization of carbamoylalkyl radical is predicted to be kinetically competitive with the 5-endo process. The 4-exo cyclization of amido radical is less favorable both kinetically and thermodynamically. Finally, the 4-exo ring closure of an acyl radical onto an imine acceptor is thermodynamically competitive with the 5-endo process but less favorable kinetically.In chapter 6, we conduct the first, systematic study on the regioselectivity in the rearrangement of various synthetically relevant cyclobutylcarbinyl radicals. It is found that a two-layer ONIOM(QCISD(T)/6-311+G(2df,2p):B3LYP/6-311+G(2df,2p)) method could accurately predict the free energy barriers of the ring openings of cyclobutylcarbinyl radicals with a precision of 0.3 kcal/mol. The regiochemistry for the ring opening of monocyclic cyclobutylcarbinyl radicals could be easily predicted by the relative stability of the two possible carbon radical products. The rearrangement of bicyclic cyclobutylcarbinyl radicals could undergo both ring opening and expansion pathway. When the radical center is located at the bridge methyl group, ring expansion is the favored rearrangement pathway unless a radical-stabilizing substituent is placed in the cyclobutyl ring adjacent to the bridge methyl group. On the other hand, when the radical center is located at the 2-position of bicyclic cyclobutylcarbinyl radicals, ring opening pathway is favored unless a radical-stabilizing substituent is placed in the cyclobutyl ring at the bridge position.