Theoretical Study On The Mechanisms Of Metal-free Catalyzed Reactions For Synthesis Of Phenanthridines

Phenanthridines are essential core structures in a variety of natural product and other pharmaceutically important molecules,such as trispheridine or chelerythrine,etc.Many new synthesis reactions for phenanthridines preparation have been reported,some of which were performed under metal-free,or even acid-free conditions.In this thesis,I present the theoretical results on the mechanisms of two metal-free reactions for phenanthridines synthesis:（1）phenanthridines synthesis from the nitrogenation of 2-acetylbiphenyls（1）by TMSN₃ catalyzed by strong acid（TFA）;（2）phenanthridines synthesis by the coupling of2-aryldiazonium tetrafluoroborates salts with acetonitriles under metal-free and acid-free conditions.The results are as followes:1)Mechanism for phenanthridines synthesis by nitrogenation of 2-acetylbiphenyls in acidic solutionThemechanismofphenanthridinessynthesisfromthenitrogenationof2-acetylbiphenyls by TMSN₃ in TFA have been studied by DFT calculations.Results at the PCM-B3LYP/6-311G（d）level showed that:（1）in the reaction of TMSN₃/HN₃ with the protonated form of 1（1H⁺）,-OH in 1H⁺is replaced by–N3 to generate the key intermediate C^x+.This step is the rate determining one for the consumpation of reactants,and its barrier heights is 43.6/54.4 kcal/mol.Theoretical results suggested that TMSN₃ as the nitrogen source is clearly preferred over HN₃.2)from C^x+,the two pathways lead to 2^x H⁺and 3^x H⁺are both thermodynamically and kinetically feasible and competitive to each other.3)due to the extreme stability of the protonated form of products 2^x H⁺and 3^x H⁺,and the high barriers of120 kcal/mol for the reverse reactions suggest that the reverse reaction can not occur under the experimental condition.Thus the ratio of the final products 2^x:3^x should be determined by the branching ratio of reaction rates of C^x+to intermediates D^x+in passway I and E^x+in passway II,2^x H⁺:3^x H⁺?k:k’.The theoretical conclutions are in consistent with the experimental facts Theoretical results also showed that different substitutents at 4’site（1^a,R=CH₃;1^b,R=OMe;1^c,R=t-Bu;1^d,R=Cl;1^e,R=OH）have less influence to the kinetical propoties of the each step of the reaction.2)Mechanism for phenanthridines synthesis by the reaction of 2-aryldiazonium tetrafluoroborates salts with acetonitriles in acidic solution:A DFT study.The details of the mechanism for phenanthridines synthesis by the reaction of2-aryldiazonium tetrafluoroborates salts with acetonitriles in acidic solution was studied by B3LYP method incombination of standard 6-311G（d,p）basis set for all atoms and SMD solvent model.The theoretical results showed that:1)the 2-aryldiazonium cation transforms to key intermediate a by removal of N₂ via SN1 reaction;2)under H₂O-free condition,intermediate a can transform to 3H⁺which contains the phenanthridines ring structure,via intramolecular electrophilic annulation reaction;3)when H₂O is present,intermediate a firstly combines with H₂O to form intermediate b,which can convert to intermediate 2H⁺via H-migration reaction.Two configurations of 2H⁺（denoted by 2H⁺and 2’H⁺）,finally transform to protonated product 3H⁺.Theoretical results showed that,the barrier of the H₂O-free mechanism is lower than that of the water-mediated mechanism,thus the water-mediated reaction should be performed at more harsh conditions.This theoretical inference is in consistent with the experiments of Ramanathan etc.that the reaction was carried out at 120℃in sealed tube but 135℃/170℃when open to air.The ratio of product 2and 3,should be affected by the water amount absorbed from air.Addition H₂O in the reaction system may increase the yield of product 2.