Theoretical Study On Palladium-Catalyzed [2+2+1] And [3+2] Cycloaddition Reaction For Constructing The Frameworks Of Spiro-Compounds

In recent years,due to the advantages of palladium catalyst with various stable oxidation states,wide catalytic range and good selectivity,etc,research about palladium-catalyzed cycloaddition reaction has attracted extensive attention in both organic synthesis and theoretical study areas.In this thesis,palladium-catalyzed[2+2+1]cycloaddition reaction of 1-Iodo-2-（5-phenylpent-4-yn-1-yl）benzene with o-bromophenol,as well as palladium-catalyzed[3+2]cycloaddition reaction of2-vinyl cyclopropane-1,1-dimethylnitrile/vinyl epoxide with azadiene have been explored in detail by employing density functional theory（DFT）and DGDZVP-SDD（Cs）basis set.All reactants,intermediates,transition states,complexes and products were optimized,with frequency calculations performed accordingly.Based on exploration on possible reaction mechanism,the potential energy profiles were further drawed,to help people understand the mechanism of these reactions deeply from a microscopic view,and providing possible theoretical references for further mechanism research and improvement of experimental conditions about similar reactions.The whole thesis is divided into five chapters.In Chapter 1,the experimental and theoretical research progress on palladium-catalyzed[2+2+1]and[3+2]cycloaddition reactions for constructing spiro-frameworks were reviewed briefly,with the significance of topics summarized in the end.In Chapter 2,related computational background knowledge and common theoretical methods employed in this thesis were introduced briefly.In Chapter 3,detailed computaitonal results about palladium-catalyzed[2+2+1]cycloaddition reaction of 1-Iodo-2-（5-phenylpent-4-yn-1-yl）benzene with o-bromophenol was introduced,respectively.In Chapter 4,detailed computaitonal results about palladium-catalyzed[3+2]cycloaddition reaction of 2-vinyl cyclopropane-1,1-dimethylnitrile/vinyl epoxide with azadiene was introduced,respectively.Finally,a conclusion for the whole thesis was made in Chapter 5.Main contents and conclusions of this thesis are as follows:1.Based on computations about the palladium-catalyzed[2+2+1]cycloaddition reaction of 1-iodo-2-（5-phenylpent-4-yn-1-yl）benzene with o-bromophenol,the possible reaction mechanism was explored.The reaction mainly undergoes C-I oxidative addition,intramolecular alkyne migratory insertion sequence,aryl C（sp~2）-H activation,C-Br oxidative addition,C（sp~2）-C（sp~2）aryl coupling,O-H activation,arene dearomatization and reduction elimination processes,etc.Among them,The rate-determining step（RDS）is calculated to be the C-Br oxidative addition,with a Gibbs free energy barrier of 29.4 kcal·mol^-1,which can be overcome at 130℃.The Gibbs free energy barrier for Cs₂CO₃-assisted palladium-catalyzed aryl C（sp~2）-H activation is 13.0 and 49.3 kcal·mol^-1lower than that of iodine atom-assisted C-H activation and C-H oxidative addition,explains the important role of base additives in this reaction.According to computational results on the reaction paths of Cs₂CO₃-and K₂CO₃-assisted ones,the rate-determining step’s Gibbs free energy barrier increases by 2.8 kcal·mol^-1when K₂CO₃is used instead of Cs₂CO₃as the base additive,explains the best role of Cs₂CO₃additive in this reaction.By comparing computational results obtained in gas phase and solvent about the optimal reaction path,it’s found that the RDS’s Gibbs free energy barrier in the gas phase is as high as40.3 kcal·mol^-1,too high at an experimental temperature of 130°C,indicates the necessity of computations in solution.Research on the effect of DMF shows that,DMF can be used as ligand to participate in the reaction,with its RDS’s Gibbs free energy barrier of the same level with that of PPh₃ligand,explains corresponding experimental fact that DMF can participate in the reaction as ligand;In addition,the Gibbs free energy barrier of DMF-assisted palladium-catalyzed aryl C（sp~2）-H activation is 10.9/13.9 kcal·mol^-1higher than that of Cs₂CO₃/K₂CO₃-assisted ones,it shows that the effect of DMF-assisted C-H activation is not as good as that of base-assisted C-H activation..2.Based on computations about the palladium-catalyzed[3+2]cycloaddition of2-vinylcyclopropane-1,1-dicarbonitrile/vinyl oxirane with azadiene,the possible reaction mechanism was explored.The reaction mainly undergoes ring-opening of cyclopropane,the formation of C-C/C-O bond and ring-closure reaction processes.Among them,The RDS is calculated to be the formation of C-C/C-O bond,with a Gibbs free energy barrier of 19.7 or 24.8 kcal·mol^-1,which can be achieved at an experimental temperature of 25℃.By comparing with B3LYP,CAM-B3LYP,LC-ωPBE,M062X and TPSSH methods,it is found that the RDS’s Gibbs free energy barrier by emplying LC-ωPBE method is 24.5 kcal·mol^-1,thus gives out a prediction of half-life time（40.7 h）which fits best with corresponding experimental reaction time（12 h）and temperature（25℃）.