Computational investigation of organic reactions via mechanistic approaches

The importance of the theoretical approaches and computational tools has arised significantly in the past decades. The increase in performance of scientific computation has enabled fast and accurate calculations by parallel computing. Moreover, the recent developments in the Density Functionals Theory, such as new realease of advanced hybrid functionals facilitated fast and satisfactory results to explain the complex reaction network of various systems. The main concept and purpose of this Ph.D. thesis is understanding the mechanisms of different classes of organic reactions. For this purpose, for each specific reaction system, all the possible transition states and intermediate structures through the reaction coordinate are evaluated and the detailed mechanism is investigated. Next step is focusing on the several possible pathways of the process which lead to various products and analyze them by means of thermodynamics and kinetics. Herein, computational chemistry methods have been utilized which are powerful tools to explain the outcome of the experiments. Understanding the mechanism in detail will enable synthesizing custom made products and is crucial for both the development of the currently employed procedures. In the scope of this thesis, several computational modeling approaches have been utilized in order to investigate the reaction mechanisms of several systems. The thesis contains four chapters. First one is an organometallic cycloaddition reaction, following two are different reactions of tropolone and diosphenol derivatives and the last one is a co-catalyst assisted reductive amination reaction. Triazoles are the building blocks of many biologically important compounds. They are utilized in many biological applications, including treatment of tumors, HIV, allergy, fungal infection and microbial diseases, since they can mimic peptide bonds. For the first time, 1,2,3-triazoles were assembled synthetically via Huisgen 1,3-dipolar cycloaddition of azides and alkynes (AAC). However, synthesis with this procedure is not regioselective and the reaction rate is very low even at high temperatures. In 2001, Sharpless et al. reported the first study on Cu catalyzed Click chemisty and since then, this methodology has found widespread usage, varying from functional to biological materials. Triazoles can be synthesized regioselectively with a very high rate in bening reaction conditions, in different solvents, both protic and aprotic, via Click procedure. After the successful application of the Cu catalyst, several transition metals which have been effectively used in alkyne cyclization reactions were tested. In 2005, ruthenium metal, whose catalytic activity on alkynes has been formerly known, was found as a catalyst for AAC that produces 1,5-disubstituted triazoles with internal alkynes. Ag and Au metals have also been tested as good candidates since they are congeners of the efficient Cu catalyst. In 2011, McNulty et al. reported the first Ag (I) catalyzed reaction at room temperature in the absence of Cu metal. This reaction is promising in the sense that it is the first successful application of Ag catalyst alone in AAC reaction and has the advantage of being non toxic, which is especially crucial in biological applications. In the first chapter, this first successful and promising Ag catalyzed azide alkyne cycloaddition has been investigated by quantum mechanical calculations. The feasibility of the experimentally proposed reaction mechanism was investigated by modelling the profound intermediates and the transition state structures connecting them. Then, the number of metal atoms involved in the reaction process was examined comparatively, which is one of the main questions considered in mechanistic studies of Click reactions. Elucidating the reaction mechanism will enable more control over the synthesis and help to obtain tailor made products in good yields without involving toxic copper. Tropolone is classified as a diosphenol, whose derivatives are known to act as medicaments. Stipitatic acid, puberulonic acid, colchicine, and hinokitol are some examples of tropolone derivatives, which have been isolated from natural products and have antimitotic, antiviral, antibacterial, anticancer effects. Tropolone and its derivatives are also used in some reactions as a starting material for synthetic purposes. Therefore, finding new and easy synthetic methods for obtaining tropolone derivatives is a valuable task in synthetic organic chemistry. Thus, quantum mechanical calculations are substantial in order to provide insights into the synthetic pathway and the nature of the regioselectivity in comparison to its analogous. Second chapter deals with experimentally obtained regioselectivity of a system with different ring sizes. DFT calculations were performed on the key elimination step of the mechanism in order to elucidate the factors that led to different regioselectivity in the five-membered diosphenols and seven-membered tropolone. For this purpose, the key steps were modeled for both reagents by using computational tools to account on the proposed reaction mechanism and to investigate the structural and electronic effects that caused the difference in these two cases. The experimentally observed regioselectivity was correlated to the calculated activation barriers on five and seven-membered systems in the elimination step such that in both cases, experimentally observed product was favored over the alternative one. Thus, quantum mechanical calculations have provided insights into the synthetic pathway and regioselectivity of the reaction, in comparison to the analogous five-membered system. Third chapter focuses on the radicalic reactions of 6- and 7-membered diosphenol derivatives with a significant difference in reactivity, ring size, aromaticity and stability. While the former is producing a mixture of products, the latter is resulting with a single product, regioselectively. DFT calculations were performed following the experimental studies in order to describe the outcomes correctly. Therefore, all possible reaction pathways were investigated for both structures to shed light on different selectivity routes governed by several factors. The driving factors for the observed regioselectivity was discussed in terms of the charge distribution at the reactive atoms, entropy factors, variation of dihedral torsion angle between the radicalic center and functionalized double bond and aromatization of the ring. Amines are among the most important and frequently used chemical compounds due to their biologically active features and wide applications in industry. Reductive amination reactions are efficient and facile routes to synthesize long chain amines by using a diversity of aldehydes and ketones, and a variety of amines. The general route for the reductive amination is well documented. The exact mechanism, however, is dependent on the pH of the reaction medium and thus, the protonation state of the intermediates and the role of a coordinating solvent. The parameters affecting reaction performance and the selectivity such as type of the substrate and reaction conditions are still not fully understood. Fourth chapter presents a computational work on the mechanism of reductive amination including neutral and co-catalyst assisted (as explicit water and acid) reaction conditions. The reaction mechanism and the energy profile were characterized by MP2 calculations and an implicit SMD approach to account for polarity effects of the solvent. With explicit water assistance, the addition step proceeded in a stepwise fashion rather than concerted and the activation barrier was lowered. In the co-catalyst assisted system, the first part of the reaction (nucleophile addition) is kinetically disfavored compared to the neutral one and second half of the reaction is thermodynamically driven by the presence of an acid as a co-catalyst. Consequently, altering the reaction parameters does not only influence the reaction kinetics, but also the thermodynamic profile of the pathways in all cases. Further understanding on the reaction dynamics is essential to develop a microkinetic model of the reaction, to control and steer the process in order to rationally design reaction routes. Optimizing the reaction conditions requires realising each mechanism in detail, through the process. In this study, we aim to investigate the feasibility of the experimentally proposed reaction mechanism by modelling the profound intermediates and the transition state structures connecting them. The overall interpretation of the results of this thesis will serve to a better understanding of the reaction thermodynamics, as well as kinetics of the processes. Elucidating the reaction mechanism will enable more control over the synthesis, help to obtain tailor made products in good yields and develop new alternatives for chemistry and beyond.