| Since the concept of organocata lysis proposed in 2000,metal-free organocatalysts have attracted more and more attention.Due to advantages of mild reaction conditions,low toxicity,and high selectivity,this type of organocatalytic reaction becomes an important component in the field of asymmetric synthesis.However,the mechanism of this type of catalytic reaction and the origin of selectivity are often not clearly explained in experiment.Therefore,revealing the detailed mechanism and origin of selectivity by performing theoretical calculations has become an urgent task in this field.This thesis uses density functional theory（DFT）to deeply study the reaction mechanism and chemoselectivity of three types of reactions catalyzed by Lewis bases,and provides valuable insights and reference for experimental workers to rationally design more efficient organocatalysts.The first chapter of this thesis mainly includes:（1）a brief introduction to the computational background of quantum chemistry,density functional theory,and transition state theory;（2）the introduction of analytical methods commonly used in organocatalyst systems;（3）a brief summary of the two types of Lewis base catalysts involved in the thesis;（4）the introduction of novel insights of the research and the significance of this thesis.In the second chapter,the reaction mechanisms of[2+4]cyclization of allenic ester and cyclic ketimine catalyzed by 4-dimethylaminopyridine（DMAP）for forming highly functionalized hydropyridine derivatives were studied theoretically using density functional theory（DFT）.Three possible reaction channels,including DMAP-catalyzed[β,γ]–/[α,β]–[2+4]cyclization channel（i.e.,channel A/B）and direct[β,γ]–[2+4]cyclization channel（i.e.,channel C）were considered.According to t he calculated results,channel A was concluded to be the most energetically favorable among the three channels,and the corresponding product is the main product,which is consistent with the experimental observation.The channel A consists of four steps,i.e.,nucleophilic addition on the Cβatom of allenic ester by DMAP,the stepwise[β,γ]–[2+4]cyclization with ketimine,and the dissociation of DMAP with product.The analyses of global reactivity index（GRI）and frontier molecular orbital（FMO）suggested that DMAP not only enhances the nucleophilicity of allenic ester but also narrows the energy gap of the FMOs involved in the[2+4]cyclization,and thus makes the reaction more easily to occur.Moreover,the non-covalent interaction（NCI）analysis explored the origin of regioselectivity of the reaction.In the third chapter,the possible mechanisms and origin of the enantioselectivity of the reaction between 2H-azirine and an aldehyde catalyzed by an N-heterocyclic carbene（NHC）were theoretically studied andM06-2X/6-31G（d,p）/IEF-PCMMTBE//M06-2X-GD3/6-311++G（2df,2pd）/IEF-PCMMTBE level.The most favorable reaction pathway consists of four steps,i.e.,complexation of the NHC by the aldehyde,stepwise[1,2]-proton transfer,C–C bond formation coupled with another proton transfer,and recycling of the NHC.The computational results indicate that the stereoselectivity-determining step is also the rate-determining step,which is the third step（i.e.,intermolecular addition）.The calculated 99%ee is very close to the experimentally observed 96%ee,demonstrating that the calculations are reliable.Two important roles of the NHC were identified by global reaction index（GRI）analysis and natural population analysis（NPA）,i.e.realizing the umpolung reactivity of the aldehyde and facilitating the deprotonation of aldehyde.Moreover,the efficiency of different NHC catalysts can be mainly predicted by computing the nucleophilic index of the corresponding Breslow intermediates.Furthermore,d istortion/interaction and noncovalent interaction（NCI）analyses revealed that theπ···πinteractions between the NHC and substrates were the key factor in the reaction enantioselectivity.In the fourth chapter,the possible mechanisms and origin of the regio-/enantioselectivity of intramolecular hydroacylation-Stetter reaction of alkynyl bisbenzaldehyde catalyzed by N-heterocyclic carbene（NHC）were studied by performing the density functional theory（DFT）calculations.The calculated results show that the whole system includes two catalytic cycle stages,the first stage of the hydroacylation reaction and the second stage of the Stetter reaction Computational results show that the hydroacylation process was irreversible and will quickly proceed to the next Stetter reaction.The first stage of the catalytic cycle is divided into four steps:complexation of NHC and aldehyde,formation of Breslow intermediate through[1,2]proton transfer,formation of intramolecular C–C bond following proton transfer,and desorption of NHC catalyst.The third step of the reaction is the step of regioselectivity.The second stage of the catalytic cycle is divided into five steps:complexation of NHC and aldehyde,formation of Breslow intermediate through[1,2]proton transfer,formation of intramolecular C–C bond,intramolecular[1,4]proton transfer Formation of a six-membered ring and desorption of the N HC catalyst,in which the third and fourth steps of the reaction produce different stereoisomers（RR,RS,SR and SS）.Four different stereoisomers were considered and the lowest energy mode agreed with the reported enantioselectivity in experiment.Global reaction index（GRI）analysis showed that N HC catalyst can convert alkynyl bisbenzaldehyde electrophilic carbonyl carbon into nucleophilicity to initiate the reaction.Moreover,electron localization function and intrinsic reaction coordinate analyses were performed to show the difference between the process of hydroacylation and Stetter reaction.On the one hand,both C–C bond formation and hydrogen transfer are involved in the hydroacylation process;on the other hand,C–C bond formation and hydrogen transfer are synergistic asynchrony involved in the Stetter processThe fifth chapter of this paper is the summary of the above work and the prospect for the study in future. |
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