DFT Computational Investigation On The Mechanism Of Organocatalytic Multicomponent And Aza-pinacol Rearrangement Reactions

In recent years,organic catalysis has become a very dynamic field in chemical research and flourished in a very large and diverse field over the past two decades.Organocatalysis enjoys many advantageous properties compared to enzyme-and metal-catalyzed reactions include the easier trial procedure,reduce chemical waste,and save cost,time,and energy.Moreover,small organic molecules are usually less toxic,safer,easy to use,and environmentally friendly.Understanding the mechanism of organocatalytic reactions is helpful to reveal the function of catalysts,and provide theoretical support for organic synthesis chemists to develop catalysts with multifunctional catalytic activity.This thesis focuses on using density functional theory（DFT）theoretical studies to gain insight into the reaction mechanisms and stereoselectivity of organocatalyzed multicomponent-assisted synthesis of[1,3]oxazine-fused heterocycles and aza-pinacol rearrangement reactions.Some key issues related to the reaction condition still need to be addressed such as the role of solvents,auxiliaries and substrates,and the activation mode of catalysts continues to remain vague.The new insights into the reaction mechanisms rationalize the effect of different reaction conditions on the mechanisms and the stereoselectivity outcome of the asymmetric reactions,thus contributing to the green synthesis of atom economy of the related reactions and the development of the chiral ligands for asymmetric catalysis.Therefore,the research contents of this paper are as follows:DFT calculations are employed to disclose the detailed reaction mechanism of the synthesis of 3-phenyl-2,5-dihydro-1H-benzo[d]imidazo[5,1-b][1,3]oxazine-1-thione under unassisted,water-assisted,and trifluoroacetic acid（TFA）assisted conditions by2,2-dihydroxy-1-phenylethanone（1）,（2-aminophenyl）methanol（2）,and KSCN（3）.The computational results show that the title mechanism can be altered and accelerated by TFA,water,and substrate 2.Three types of mechanisms are reported by DFT calculations differing in the reaction sequence of substrates,such as M1:1+2 then 3;M2:1+3 then 2;M3:2+3 then 1.It is found that the nucleophilicity of substrate 2 is stronger than 3.The DFT calculations suggest that the TFA-water co-assisted pathway of M1 is the most favorable case.The rate-determining step is the process of[3+2]cyclo-addition.More importantly,we found that TFA and water molecules play critical roles in the whole reaction,by acting as efficient catalysts,proton shuttle,and stabilizer to stabilize the structures of transition states and intermediates via N-H···O,O-H···O,and C-H···O interactions.And they also act as hydrogen bonds（HBs）donor and acceptor to improve the reactive activity of the substrates by changing the reaction form of glyoxal monohydrates and KSCN.Substrate 2 as HBs acceptor promotes the enol-ketone tautomerization and favors the proton transfer process.Interestingly,our computations revealed that the title reaction can be performed in water instead of CH₃CN,which paves the way to design a greener synthetic strategy for oxazine N-fused imidazole-2-thiones and their derivatives.A comprehensive mechanistic study on the chiral phosphoric acid catalyzed an enantioselective asymmetric aza-pinacol rearrangement of 4-chloro-N-（2-（3’-hydroxy-1’-phenylspiro[cyclopentane-1,2’-indolin]-3’-yl）ethyl）1a is investigated at the M062X/6-311+G**level.Our computational results suggest that the whole catalytic cycle proceeds through dehydration of 1a,enantioselective aza-pinacol rearrangement,intramolecular cyclization and catalyst regeneration to deliver the fused indoline product.The aza-pinacol rearrangement is the key stereocontrolling step of the title reaction.The chiral catalyst controls the orientation of the transition states of the enantioselective step through two potential binding sites between the bifunctional chiral phosphate and the aza-ortho-xylylene intermediate.Moreover,theoretical studies identified that the multipl C-H···π,C-H···O,and C-H···N hydrogen bonds and N-H···O^?electrostatic interactions between the substrates and the arms as well as functional oxygen anion of the the chiral catalyst（R）-4c play a crucial role in determining the stereochemical outcomes.And the strong N-H···O^?interaction in the major transition state was found to contribute to the high levels of enantioselectivity.Additionally,the 1.5 kcal/mol energy difference between the enantioselective TS-2-major and TS-2-minor predicted ee of 89%is in excellent agreement with the experimental results 90%.