Theoretical Study On The Organocatalysis Of Bifunctional-amine Catalyst

Asymmetric catalysis represents one of the major challenges in modern organic chemistry. It plays a key role in drug discovery and Pharmaceuticals. In the last decade, more attention has been paid to transition metal catalysis, and the success in this field led to the Nobel Prize in Chemistry in 2001. However, in recent years, many chemists are getting acquainted with the advantages of organic catalysts, and organocatalysis has received considerable attention. Great progress in organocatalysis has been made theoretically and experimentally. Organocatalysis as a new concept emerged at the 21st century has been developing within organic chemistry into its own subdiscipline, and its Golden Age has already dawned.The term "organocatalysis" describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons.The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, and their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with transition metal catalysts. Moreover, the design and use of synergic systems and bifunctional organocatalysts, which have two distinct functionalities (e.g. a Lewis base and a Bronsted acid) within the same molecule, is becoming more and more common.As realization grows that organic molecules not only are green and easy to manipulate but also can be very efficient and remarkably enantioselective catalysts, asymmetric organocatalysis gradually catch up with the spectacular advancements of transition metal catalysis. Despite thorough experimental investigations and possible catalytic mechanism proposal, relative little is understood about the intricacies of organocatalysis, a situation that needs to be addressed to enable catalyst design to advance on a rational basis. Therefore, further thorough investigations on organocatalysis will be of important theoretical and practical values.Theoretical studies of reaction mechanism by computational methods have been greatly facilitated by innovation of computer technology and development of the methods. Recently, B3LYP methods have been applied for non-metal small molecular catalytic reaction and have achieved the considerable results.In this dissertation, we studied the bifunctional amine catalysis with density functional theory (DFT) calculations. Our purposes are to a) shed light on the mechanistic details of the bifunctional amine catalysis and hence obtain a better interplay between theory and experiment, b) understand the roles of bifunctional group of the catalyst and the origin of enantioselectivity for the catalyzed reaction, and c) provide a general profile of the catalytic reaction by bifunctional amine catalysts. Our results provide detailed information on the transition states of bifunctional amine catalyzed organic reaction and should be helpful for the designing the new efficient bifunctional catalyst examples.The valuable results in this dissertation can be summarized as follows:1. The research history and current state on organocatalysis have been briefly reviewed. A number of asymmetric organocatalytic reactions have recently been developed, and new asymmetric reactions are constantly being reported. Most organocatalysts used currently are bifunctional, commonly with a Br(?)msted acid and a Lewis base center. These compounds activate both the donor and the acceptor, thus resulting in a considerable acceleration of the reaction rate. Moreover, the general mechanisms of organocatalysis have been illustrated: covalent bonded interactions and non-covalent bonded interactions.2. A general profile of the Michael reaction of 1, 3-Dicarbonyl compounds and nitroolefins catalyzed by bifunctional-urea catalyst has emerged clearly via the DFT calculations on the prototype reaction between the malonate and nitroolfins. Four reaction channels, corresponding to the approach modes of the nitroolfins to chiral scaffold and the second proton transfer processes, have been characterized in detail. It is found that the enantioselectivity of the catalyzed Michael reaction is controlled by the C-C bond-formation step, while the rate determining step is the proton transfer from the amino group of catalyst to α-carbon of nitronate. Our calculated results confirm the amino group has a significant effect on the reaction rate, but only slight effect on the enantioselectivity. The present DFT study well explains the experimental finding and provides the details of the reaction mechanisms.3. The α-amination reaction of cyclic 1, 3-dicarbonyl compounds with azodicarboxylate catalyzed by a urea-based chiral bifunctional organocatalyst is investigated using density functional theory (DFT) calculations. The predicted mechanism involves first nucleophile activation via protonation of the amino group and electrophile activation through substrate binding to urea; then C-N bond formation between these two activated components; and finally, the proton transfer from the protonated amino group to adduct, followed by the dissociation of the H-bonded complex to give amination product along with the catalyst. The structures of the catalyst and two substrates as well as the catalyst-substrate complexes have been discussed in detail. Four reaction channels have been shown for the C-N bond-forming. The rate determining step is the nucleophilic center of the enolate anion attacks the electron-deficient dimethyl azodicarboxylate (DMAD). The calculations show that the amino group activates 1, 3-dicarbonyl compounds via deprotonation, while the urea and amine moieties stabilize the intermediates throughout the reaction via the multiple hydrogen bonds between the catalyst and substrates. The origin of enantioselectivity for the investigated reaction is also discussed. Our calculated results confirm the urea moiety of the catalyst has a significant effect on the title reaction. The present DFT study well explains the experimental findings and provides the details of the mechanisms.4. The Michael reaction of malononitrile to α, β-unsaturated imides in the presence of bi-functional thiourea catalyst has been investigated by DFT calculations. The computational results support the proposed mechanism, which involves: (i) The conjugate hydrogen bonding interactions of α, β-unsaturated imides and catalyst. (ii) A plausible transition state in which imide derivatives and the anion of tautomer of malononitrile coordinates to the thiourea moiety and the tertiary amine group, respectively. The rate determining step is nucleophilic carbon of the anion of tautomer of malononitrile attacking α, β-unsaturated imides. The enantioselectivity for the investigated reaction is originated from the different coordination modes of α, β-unsaturated imides to catalyst. The calculated results show that the reaction prefers R-configurational products, which is consistent with the experimental results.5. Design and synthesis of biodegradable polymers have attracted considerable attention due to the rapid development of the biomedical science and engineering. One of the most promising and practical materials is polylactide (PLA). Because of its bioresorbability and biocompatibility, PLA is recognized as an important material for medical and pharmaceutical applications as well as for industrial applications such as food packaging and paper. PLA is obtained from the corresponding monomers by ring opening polymerization (ROP). Hedrick detailed an organocatalytic approach to the living ROP of lactide with bifunctional thiourea catalysts. In this dissertation a computational DFT study with the B3LYP method on the mechanism of the thiourea-catalyzed ROP has been performed. All the structures are optimized completely at the B3LYP/6-31G(d) level. The catalysis property of bifunctional amine catalyst is notable. That is catalysis proceeds by bifunctional activation of the carbonyl of a lactide monomer via hydrogen bonding to the thiourea group and of the initiating/propagating alcohol by the Bronsted basic (tertiary amino) group of the catalyst. Nucleophilic ring-opening of the lactide leads to propagation, whereby the ring-opened lactide forms the propagating alcohol for the subsequent addition of monomer.6. The tandem O-nitroso aldol/Michael reaction between nitrosobenzene and cyclohexenone catalyzed by pyrrolidine-based catalyst in gas phase and solution is studied using density functional theory, to determine the detailed mechanism and key factors controlling the regioselectivity. Two regioselective channels (0- and N-selective) have been characterized in detail. The rate determining step is the Michael reaction, and the corresponding barriers for 0- and N-selective channels are 14.05 and 31.96 kcal mol^-1, respectively. The key factor controlling the selectivity is the proton transfers between the tetrazolic acid and the nitroso group. It was found that the Michael reaction along the O-selective channel is both thermodynamically and kinetically feasible, which corroborates the early experimental findings. Finally, our calculations show that solvent effects stabilize all relevant stationary points, but do not change the profile of the PES.Although substrate dependence remains an important issue in many of the reactions discussed, more and more transformations now meet the standards of established asymmetric reactions. Despite the considerable progress that has been made in the elucidation of transition states, we are only beginning to understand the basic factors that control reactivity and selectivity in these reactions, and the rational design of catalysts remains in most cases a dream. The number of organocatalytic (non-asymmetric) reactions is steadily increasing, which provides a solid basis for the development of novel enantioselective reactions. New asymmetric reactions are constantly being reported. Although creativity and persistence will certainly remain the major factors in the success of this research, the increasing use of automatization and computational techniques may facilitate both the discovery of novel catalyst structures and the screening of reactions for catalysts of the next generations.In this dissertation, the valuable results have provided reliable verification and theoretical guide for further studying of bifunctional amine catalysis even for the development of organocatalysis.