Doctor of Philosophy in Chemistry (PhD)
The Development and Application of an Automated Reaction Monitoring Prototype to Elucidate Catalytic Reaction Mechanisms
A new class of N-heterocyclic carbene (NHC) organocatalysts were developed based on the 1,2,3-triazolium core architecture. These catalysts were found to facilitate the oxidative esterification of aromatic aldehydes, and a small substrate scope was examined. Using reaction progress monitoring by HPLC, a detailed kinetic analysis was performed. Mechanistic studies showed the reaction to be positive order in both aldehyde and base, and zero order in oxidant and methanol. A key carbene-aldehyde adduct was isolated and characterized by X-ray crystallography, and it was shown to exhibit catalytic activity.The NHC-catalyzed oxidative acylation of electron-poor nucleophiles was also developed, using a 1,2,4-triazolium salt precatalyst. A brief substrate scope was examined, and a kinetic analysis was performed using ¹H NMR reaction monitoring. The mechanistic analysis revealed that the reaction is positive order in aldehyde and base, and zero order in catalyst, oxidant, and sulfonamide nucleophile. In addition, the origin of catalyst deactivation was investigated in the NHC-catalyzed oxidative amidation of aldehydes with amines. Two carbene-amine adducts were discovered, and they were characterized by 1-D and 2-D NMR techniques. A minor carbene-carbene condensation product was also discovered, and characterized by X-ray crystallography.Finally, a new method of synthesizing dihydropyrimidone precursors for isothiourea organocatalysts was developed, and a brief substrate scope was examined. Experimental and computational results showed that the cyclization reaction proceeds through an alpha,beta-unsaturated mixed imide intermediate, rather than by direct conjugate addition to the alpha,beta-unsaturated amide starting material. These computational results also revealed a 7.6 kcal/mol difference between the imide cyclization pathway and the direct acrylamide cyclization pathway. Using HPLC reaction monitoring methods, a preliminary mechanistic analysis was performed. These preliminary results showed that electron-withdrawing substituents on the benzothiazole ring slow down the reaction, while electron-donating substituents do not enhance the reaction rate.
Kinetic studies were conducted on three unrelated reaction types using traditional and modified reaction monitoring tools. The Aza-Piancatelli rearrangement was studied through ReactIR and HPLC-MS to obtain a better understanding of why the substrate scope was limited. It was found that the Lewis acid catalyzed reaction is often zero-order, dependent on the lanthanide metal used. Off-cycle binding of the nucleophile to the Lewis acid was proposed to help explain the zero-order profile. Differences between Lewis and Brønsted acid catalysts were found through subsequent experiments assessing catalyst deactivation and the chemoselectivity of the products in the Aza-Piancatelli rearrangement. An automated sampling system was created for hands-free reaction monitoring and offline analysis by HPLC-MS to provide detailed information about more complicated reactions. The automated sampling system was modified for the study of microwave assisted reactions. This application allowed for more information to be derived from the field of poorly-understood microwave chemistry than allowed by previous technology. Comparisons were made between microwave-assisted and conventionally heated reactions, using a Claisen rearrangement as a model reaction. As expected, it was found that the Claisen rearrangement of allylphenyl ethers displayed similar kinetics between the two heating modes. The technology was also used briefly to search for the existence of non-thermal effects. It was shown that the sampling apparatus could be useful for collecting data observed from microwave-specific effects. Mechanistic studies were also conducted on the Kinugasa reaction to obtain a better understanding of why the reaction generally behaves poorly in regards to the formation of β-lactam product. To study the reaction, samples for HPLC-MS analysis were taken manually, then by a liquid handler, and then through direct-injection to the HPLC. It was found that its side-product formation was directly coupled to the desired product formation, suggesting that both the product and imine side-product stem from a common intermediate. Another little-known side-product was isolated, suggesting the common intermediate could be intercepted by select nucleophiles to form an amide. This finding will direct future attempts to find conditions to favor either β-lactam or amide formation.