Theoretical Studies On Mechanism And Stereoselectivity Of Asymmetric Reactions Catalyzed By Nitrogen-Containing Organic Small Molecules

Nitrogen-containing organic small molecules,including organic bases and amino acids,have good catalytic activity,which were widely applied in various asymmetric catalytic reactions.However the understanding of asymmetric reactions catalyzed by nitrogen-containing organic small molecules is not deep enough and comprehensive.Therefore it is of great significance to carry out theoretical study on asymmetric reactions catalyzed by nitrogen-containing organic small molecules,which can promote the development of corresponding experimental studies.The asymmetric decarboxylative aldol reaction,asymmetric semipinacol rearrangement reaction,and asymmetric inter/intramolecular aldol reaction were theoretically investigated in this thesis,and some innovative progresses were made in the following aspects:(1)Based on experimental results,by means of theoretical calculations,the most possible mechanism of nitrogen-containing organic small molecules-catalyzed reactions were proposed.(2)The actual ways nitrogen-containing organic small molecules controlled reaction stereoselectivity were investigated in depth.(3)The influence of nitrogen-containing organic small molecules on organic chemistry reactions were studied.(4)The influence of different structures of nitrogen-containing organic small molecules on the reaction stereoselectivity and yield were illustrated.The thesis consisted of six chapters,the brief introduction of each chapters is as follows:Chapter 1,introduction.In this chapter,the categories of organocatalysts,the ways nitrogen-containing organic small molecules catalyze(or promote)the reaction and control the reaction stereoselectivity,the research progresses of asymmetric reactions catalzyed(or promoted)by chiral oxazoline,cinchona alkaloids and their derivatives,and chiral amino acids and their derivatives were introduced,the problems in current researches were also analyzed.Chapter 2,theoretical basis and computational methods.In this chapter,the relative knowledge of density functional theory(DFT)and widely-used DFT methods,implicit solvation model,dispersion correction,natural population analysis(NPA),transition state theory,conceptual density functional theory(CDFT),distortion-interaction energy analysis,quantum theory of atom-in-molecule(QTAIM),non-covalent interaction(NCI)analysis and stereochemistry were briefly introduced.Chapter 3,theoretical study on mechanism and stereoselectivity of asymmetric decarboxylative aldol reaction catalyzed by chiral bisoxazoline.In this chapter,the asymmetric decarboxylative aldol reaction between?-carbonyl carboxylic acid and trifluoroacetaldehyde as well as corresponding hemiacetal were theoretically investigated,in which the product with high stereoselectivity(95%ee)will be obtained when trifluoroacetaldehyde hemiacetal was used as substrate,however the stereoselectivity of product will be lower(28%ee)when trifluoroacetaldehyde was used as substrate.Combined with relative content of CDFT,the mechanisms of the two reactions by means of DFT calculations were investigated;Meanwhile the origin of reaction stereoselectivity and the role of chiral bisoxazoline catalyst in reaction were studied by applying methods of QTAIM analysis,NCI analysis and distortion-interaction analysis.When trifluoroacetaldehyde hemiacetal was used as substrate,the reaction proceeded via hemiacetal decomposition,nucleophilic addition,decarboxylation and enol-keto tautomerization,in which nucleophilic addition is stereo-determining step,chiral bisoxazoline obviously improved the nucleophilicity of?-carbonyl carboxylic acid;both distortion energy and interaction energy can affect transition state energy of rate-determining step,further influencing reaction rates of different reaction pathways;reaction stereoselectivity can be mainly attributed to the?(-TS)values of stereo-determining step transition states.When trifluoroacetaldehyde was used as substrate,the reaction proceeded via nucleophilic addition,decarboxylation and enol-keto tautomerization,in which nucleophilic addition is rate-determining step,however chiral bisoxazoline does not improve the nucleophilicity of?-carbonyl carboxylic acid obviously.The theoretically predicted stereoselectivity is in agreement with experimental results.Chapter 4,theoretical study on mechanism and stereoselectivity of asymmetric semipinacol rearrangement reaction catalyzed by quinine-derived primary amine.When Br?nsted acid was used as additive,quinine-derived primary amine can catalyze the asymmetric semipinacol rearrangement of 3-(1-hydroxylcyclobutyl)-cyclohexenone.For the reaction which N-Boc-_L-Phenylglycine(NBLP)served as Br?nsted acid additive,the mechanism was investigated by DFT calculations,the reaction proceeded via reactant-catalyst-Br?nsted acid additive complexation,nucleophilic addition,dehydration,carbon atom migration,enamine-imine tautomerization,imine hydrolysis,Walden inversion and catalyst regeneration,the carbon atom migration is stereo-determining step.When NBLP was replaced by its enantiomer N-Boc-_D-Phenylglycine(NBDP),the reaction stereoselectivity would obviously decrease,the theoretically predicted reaction stereoselectivities were in agreement with experimental results.Distortion-interaction analysis and NCI analysis revealed that intramolecular steric repulsion controlled the reaction stereoselectivity,and the?(-TS)values of stereo-determining step transition states influenced the reaction stereoselectivities in NBLP-and NBDP-assisted reactions.Chapter 5,theoretical study on catalytic activity and reaction stereoselectivity of asymmetric Aldol reaction catalyzed by chiral amino acids and their derivatives.Two reactions were investigated by means of theoretical calculations in this chapter.In the asymmetric Aldol reaction between acetone and 4-nitrobenzaldehyde catalyzed by chiral amino acids and their derivatives,for most catalysts the condensed-to-atom Fukui function of N atom in primary or secondary amine can give reasonable predictions to relative Gibbs free energy of nucleophilic addition transition states between catalyst and acetone;Catalyst structure will affect the stability of enamine originated from acetone and catalyst,further influencing the relative Gibbs free energy of Aldol reaction transition states and reaction yield;Catalyst structure will also affect the steric repulsion between itself and 4-nitrobenzaldyhyde,further influencing the reaction stereoselectivity.In the asymmetric intramolecular Aldol reaction of dicarbonyl compound,the total distortion degree of Aldol reaction transition state structure will determine the reaction stereoselectivity;The intramolecular steric repulsion in Aldol reaction transition state structure will be higher when catalyst have lager molecular size,which improving the reaction stereoselectivity;The increasing acidity of catalyst will lower the energy of transition state,and the transition state structure is more close to Aldol reaction product.All theoretically predicted reaction stereoselectivities are in agreement with experimental results.Chapter 6,summary and outlook.In this chapter,the research contents of this thesis were summarized,the research progress we have made were illustrated,and the unsolved problems and directions for further in-depth research were also pointed out.