Theoretical Study On Palladium-and Cobalt-Catalyzed Cyclization Reactions For Constructing Spiro-Compounds

Transition metal-catalyzed cycloaddition is a common method for obtaining highly functionalized and structurally diversed molecules.It is an effective way to obtain three-dimensional spirocyclic skeletons from simple planar aromatic hydrocarbons.Transition metals,such as palladium and cobalt,are widely used as catalysts in these reactions for their excellent catalytic properties.In recent years,there have been many reports on the synthesis of spirocyclic compounds through palladium-and cobalt-catalyzed cycloaddition reactions,however,corresponding theoretical studies are scarce,and thus insufficient for comprehensive and in-depth understanding about the microscopic reaction mechanisms,reaction selectivities,and ligand effects of these reactions.In this thesis,the palladium-catalyzed[2+2+1]cycloaddition reaction of 4-bromocoumarin with alkynes,and the cobalt-catalyzed[3+2]cycloaddition reaction of N-heteroarenes with alkynes,were studied at the IDSCRF-B3LYP/DGDZVP and IDSCRF-M06-2X/DGDZVP computational levels respectively,by employing density functional theory（DFT）.Optimizations and vibrational frequency analyses of all possible stationary points involved in the whole reaction process were conducted for exploring probable reaction mechanisms.Based on this,the experimentally observed substituent effect,ligand effect and reaction selectivities were rationalized.These mechanism and energy results can shed some light on designing new reactions,screening effective substrates and improving reaction yields.Detailed research contents and conclusions are as follows:1.Based on computational investigations of palladium-catalyzed[2+2+1]cycloaddition reaction of 4-bromocoumarin with alkynes by using B3LYP method,it’s found that,when the R substituent on alkyne is an electron-donating group or H,the most likely reaction mechanism is as follows:oxidative addition of C-Br bond,two consecutive alkyne insertions,isomerization,ring shrinkage,removal of HOAc·KBr clusters accompanied by KOAc-assisted C-H activation,and C-C reductive elimination in sequence.Among which,the first alkyne insertion is the rate-determining step（RDS）of the whole reaction,requiring to get over a Gibbs free energy barrier of 28.7 kcal·mol^-1.This free energy barrier is in good agreement with corresponding experimental yield of 78%P1a at 85℃after reacting 8 h.By applying different DFT methods（B3LYP、M06-2X and B3LYP-D3）for computations of the rate-determining step,we found the Gibbs free energy barrier corresponding to RDS(28.7 kcal·mol^-1)and transferred half-life（12.3 h）obtained by employing B3LYP method were in the best agreement with corresponding experimental reaction time（8.0 h）.Computational results about substituent effect show that,when R substituents on the alkynes are Me and OMe,the energy barriers along Path II for generation of P1 are 27.5 and 28.4 kcal·mol^-1,respectively,which can be easily overcome at 85℃;while R substituent on alkyne is F group,the reaction needs to overcome a free energy barrier of 31.4 kcal·mol^-1before product P1 is formed along the dominant Path II,which is difficult to be overcome at an experimental temperature of 85℃.These results explain reasonably corresponding experimental data that the product P1can only be generated when the R substituents on alkynes are electron donor groups（Me,OMe）or H group.Wiberg bonding index and frontier molecular orbital analyses show that,when R substituent is F group,the elevation of RDS free energy barrier is mainly caused by electronic effect.Further mechanism explorations shows that:when the R substituent is F group,reaction may generate product P2 along Path III,by getting through the following processes in sequence:oxidative addition of C-Br bond,removal of KBr assisted by KOAc,two consecutive alkyne insertions,isomerization,ring shrinkage,isomerization,and hydrogen migration.Among which,the first alkyne insertion is the rate-determining step of the whole reaction,features a Gibbs free energy barrier of29.7 kcal·mol^-1.When the R substituents on alkynes are H,Me and OMe,the free energy barriers of RDS for P2’s formation along Path III are 29.8,28.9 and 28.4kcal·mol^-1,respectively,all higher than those corresponding to P1’s formation along Path II.When the R substituent on alkyne is CF₃,the free energy barriers for P1’s formation along Path II and that for P2’s formation along Path III are 32.4 and 31.2kcal·mol^-1,respectively,which is significantly higher and difficult to be overcome（when comparing with other substituents）at an experimental temperature of 85℃.Therefore,when the R substituents on alkynes are H,Me,and OMe groups,P1 is formed along Path II;when the R substituent is F group,the reaction forms P2 along Path III;when the substituent is CF₃group,neither P1 nor P2 could be obtained.Our computational results reproduce well the selective formation of P1 and P2 which was observed in experiments.In addition,the energy barrier of RDS assisted by TFP ligand(28.7 kcal·mol^-1)was significantly lower than that of PPh₃-and PCy₃-assisted ones(31.0 and 34.5 kcal·mol^-1,respectively),which agrees well with corresponding experimental fact that the product yield assisted by TFP ligand is higher than that of PPh₃-and PCy₃-assisted ones.2.Based on computational investigations of cobalt-catalyzed[3+2]cycloaddition reaction between N-heteroarenes and alkynes by using M06-2X method,it’s found that,the reaction may undergo the following reaction processes:oxidative addition of C-Br bond,insertion of alkyne’s C≡C bond into the C-Co bond,alkene-carbon attack on the carbon atom of the substrate benzene ring,and protonation.Among which the protonation process is RDS of the whole reaction,and needs to get across a free energy barrier of 26.7 kcal·mol^-1,which can be overcome at corresponding experimental temperature（60℃）.According to computational results by employing different DFT（B3LYP、CAM-B3LYP、ωB97XD、M06-2X and B3LYP-D3）methods,it is found that the free energy barrier corresponding to RDS(26.7 kcal·mol^-1)and transferred half-life（13.4 h）obtained by employing M06-2X method are in best accordance with corresponding experimental reaction time（36 h）.Computational results about substituent effect show that,when the substituents are acetamide group（reaction b）and phenyl group（reaction c）,the free energy barriers of RDS are 31.0and 29.9 kcal·mol^-1respectively,both are higher than that of reaction a(26.7kcal·mol^-1,in which the substituent is H).These results are consistent with corresponding experimental data that the yields of reaction b and c are both lower than that of reaction a.Finally,computationally predicted enantioselectivity is also consistent with corresponding experimental ee values.