Theoretical Study On The Mechanism Of Pyrrolidine Catalyzed Ammonia-Transfer And Cycloaddition Of Nitrone

Nitrone contains-C=N-O-group which is the N-oxide of imines.Due to the presence of N?O polar bonds,nitrone is considered to be used as important1,3-dipoles and widely used in free radical trapping and other special reactions.In addition,a large number of nitrone compounds have biological activity,also and have wide application value and prospects in drug development and synthesis of natural product.However,at present,the synthesis of nitrone is generally deficiencies such as low yield,high cost,and narrow substrate scope,so there is still a great demand for the development of efficient synthesis methods.It is generally believed that a deeply understanding of the mechanism of complex reactions,and mastering the regulation of various factors on the reaction path,has important guiding significance in optimizing reactions and designing new high-efficiency catalysts.However,due to the complexity of the reaction,there is still generally lags in the research on the relevant reaction mechanism.In view of this,this paper(1)pyrrolidine catalyzed the formation of nitrone with N-monosubstituted hydroxylamine hydrochloride with benzaldehyde;and(2)the cycloaddition between N-phenyl-C-ethoxycarbonyl nitrone and styrene were taken as examples,the density functional theory method is used to optimized the reactants,intermediates and transition states of the reaction process.confirming the most favorable reaction path by energy comparison,and explored the regulation of electronic effect,spatial effect and environment on the reaction mechanism.It aims to provide important basic data to understand the reaction process deeply.The specific research contents mainly include the following:In the first part,the mechanism of pyrrolidine catalyzed N-monosubstituted hydroxylamine hydrochloride with benzaldehyde for the formation of nitrone was mainly studied.It was found that the reaction mainly undergoed(1)the nucleophilic reaction of benzaldehyde with pyrrolidine to generate C-N bond;(2)H extraction reaction of pyrrolidine N-H bond;(3)dehydration to form imine;(4)the formation of C-N bond for the nucleophilic attack of hydroxylamine to imine;(5)regeneration of pyrrolidine;(6)the formation of nitrone.The results show that the HCl generated by the decomposition of hydroxylamine hydrochloride can promote the formation of imine.However,the generated Cl ions have strong electrostatic interaction with imine,which makes it difficult to carry out the reaction of hydroxylamine and imine.However,the clusters constructed with hydroxylamine,hydrochloride benzaldehyde and pyrrolidine serve as the initial structure,since the Cl ions in the reaction process can be stabilized by the hydroxylamine and the generated water molecules and kept it away from imine,the reaction can be carried out.In this case,the rate-limiting step is the regeneration of pyrrolidine,and the activation energy is 15.0 kcal/mol,which is consistent with the reaction carried out at room temperature.In addition,we also found that the water molecules produced by step(3)playing an important role in accelerating the reaction.Subsequently,N-tert-butyl monosubstituted hydroxylamine hydrochloride was substituted for N-methyl monosubstituted hydroxylamine hydrochloride to explore the effect of electronic and steric effect on the reaction mechanism.It was found that the tert-butyl substitutied undergoed the same reaction pathway as the methyl-substituted hydroxylamine hydrochloride.However,the effect on energy is not controlled by single factor,and is the synergistic effect of steric hindrance and electronic effects.The overall activation energy of pyrrolidine regeneration is up to 20.2 kcal/mol,the substituent effect is obvious,which is consistent with the experimental that best substituent is methyl.The second part of this work mainly introduces the mechanism of the 1,3-dipolar cycloaddition reaction of N-phenyl-C-ethoxycarbonyl nitrones with styrene to form five-membered heterocyclic product.The calculation results show that the electronic energy of Z-nitrones is 1.5 kcal/mol lower than E-nitrones,and the structure is more stable.The Z-nitrones and 5-site substituted styrene is easier to carry out cycloaddition,and the energy barrier is 10.2 kcal/mol,which is more favorable in kinetics and thermodynamics.Exo-is more stable than endo-whatever in 4-or 5-site substitutes.Under the general reaction conditions,the conclusions are well explained theoretically that the best reaction is between Z-nitrones and styrene,and the product is mainly exo-type and 5-site substitution(Zexo-5).The theoretical calculation results are consistent with the experiment.It has deeping guiding significance for the designing of more efficient experimental scheme.