Mechanistic Study of Regio-selective Epoxide Ring Opening Reactions Using Lewis Acid CatalystsPublic Deposited
Lewis acids are an important class of catalysts for chemical synthesis and manufacturing. Tris-(pentafluorophenyl)borane (FAB) catalyst has been discovered as an excellent Lewis acid catalyst for a great variety of reactions in organic and organometallic chemistry, particularly for alkoxylation reactions which is relevant to the industrial production of polyether alcohols. This dissertation seeks to understand the fundamental catalytic mechanism of FAB-catalyzed epoxide ring-opening reactions using alcohol nucleophiles and to rationalize the effects of different alcohols and various reaction conditions on the reactivity and selectivity, using computational methods. Specifically, selectivity in this thesis refers to the regio-selectivity to 1° alcohol products over 2° alcohol products for ring-opening reactions of mono-substituted epoxides. Two model systems were considered in this mechanistic study, featuring either 2-propanol (model system I) or 1-methoxy-2-propanol (model system II) as the alcohol nucleophile. A non-conventional catalytic framework was proposed for the two model systems and was validated by high accuracy in both model fits and model predictions against experimental kinetic results. Major effects on reactivity and regio-selectivity were revealed from quantitative model analysis: (i) the effect of ether moiety in alcohol nucleophile on decreasing the regio-selectivity, (ii) the substantial effect of water concentration on decreasing reactivity, (iii) the profound influence of methyl tert-butyl ether (MTBE) as an additive on enhancing regio-selectivity in model system I, and (iv) the effect of ring-opened products on rapidly retarding ring-opening reactions in model system II. These effects that were unveiled, together with the strong descriptive and predictive power of the mechanistic model, provide a solid platform for rational design of reaction conditions and other Lewis acid catalysts for regio-selective ring-opening reactions of industrial and academic significance. The first part of this thesis explores the catalytic mechanism of the more basic model system: model system I. Possible species and reactions are proposed in addition to the classical Lewis acid catalysis based on quantum chemical calculations. The binding between FAB and H2O is found to be highly energetically favorable, and the resulting adduct enables a strong hydrogen bond network that can incorporate epoxide or other hydrogen bond-acceptor (HBA) molecules for water-mediated ring-opening reactions. The unusually high regio-selectivity upon using MTBE additive was qualitatively explained by a novel hydrogen-bonding-directed mechanism in which MTBE serves as a co-catalyst that distinctively stabilizes the pathway to the 1º-OH product. Key insights of the additive effect have the potential to tune or further increase the regio-selectivity by using and designing additives for related industrial chemical processes. The second part of this dissertation extends the mechanistic study of model system I into microkinetic modeling and investigates the reaction kinetics quantitatively. The catalytic mechanism proposed in the first part is simulated using rate parameters derived from quantum chemical calculations, and is validated against experimental data at a variety of reaction conditions. Analysis of catalyst speciation and net rates elucidated the substantial effects of water concentration on decreasing reactivity through a mechanism that ties up the catalyst in an inactive state and the profound influence of MTBE as an additive on enhancing regio-selectivity through a new catalytic pathway that was kinetically favorable. The success of the quantitative model lays the foundation for rational design of reaction conditions and catalyst screening, as well as further mechanistic study on Lewis acid catalysis. The third part investigates the catalytic mechanism of the more complex and industrially relevant model system II, which shows a much lower regio-selectivity and similar effect of water on reactivity compared with model system I. A difference in the reactivity pattern is the much faster deceleration as a function of conversion. A catalytic mechanism is proposed and later validated based on the validated mechanism for model system I, with the addition of new binding modes through a hydrogen bonding network and new intra-molecular ring-opening reactions under the category of water-mediated catalysis. The effect of different alcohol on regio-selectivity is elucidated with the much lower regio-selectivity corresponding to the kinetically dominant catalytic pathways in model system II. The rapid deceleration over conversion is rationalized through a favorable binding mode that ties up FAB catalyst in inactive states by residual water and ring-opened products. These mechanistic insights provide recommendation for reaction conditions to achieve fast kinetics and facilitate future improvement of regio-selectivity with a verified mechanistic basis. These mechanistic models further enable quantitative research in catalyst discovery for Lewis acid-catalyzed ring-opening of epoxides. Overall, this dissertation makes contributions towards mechanistic understanding and rational design of catalytic reaction systems for future production of chemicals with higher efficiency.