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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2021)
Understanding chemical processes facilitates reaction optimization to make synthetic procedures more efficient while also enabling reaction discovery. Temporal profiling of chemical reactions provides the gold standard for increasing mechanistic understanding. Unfortunately, obtaining time-course information reproducibly, accurately, and also minimizing analyst intervention is a significant challenge. Combining in situ spectroscopic methods with automated sampling techniques provides a robust method to generate kinetic profiles enabling increased mechanistic understanding. This thesis explores the development and application of online HPLC as an analytical technique to obtain concentration data while minimizing workload for the analyst. By utilizing commercially available laboratory equipment and software we have created a sampling device capable of automatically monitoring both homogeneous and heterogeneous reactions, as well as those performed under an inert atmosphere. The ability of the platform to sample, dilute, mix, and analyze reaction aliquots reproducibly has been validated, thereby ensuring accuracy of acquired time-course data. This automated reaction monitoring device has been used to delineate reaction mechanisms for a series of chemically distinct transformations. The Kinugasa reaction for the synthesis of beta-lactams was investigated. A novel retrocycloaddition step accounts mechanistically for byproducts associated with the transformation. A telescoped synthesis yielding cyanoimidazoles via combining an imidazole forming condensation annulation with a functional group conversion was also investigated. A series of Buchwald-Hartwig aminations performed within a glovebox using various aryl halide components were explored. Lastly, the mechanism of a synthetic procedure to synthesize Spiro-OMeTAD, a state-of-the-art organic material used in modern solar cells, was probed. By leveraging automated reaction monitoring devices, mechanistic understanding for each transformation was increased, ultimately making these transformations more efficient.
The desire for cheaper, faster, energy-conscious, and more sustainable chemical processes often necessitates the design and development of new catalytic methods. Once a catalytic transformation is conceived, the reaction conditions must be optimized to maximize yield and selectivity. Traditional optimization protocols stipulate the correlation of these end-metrics at a fixed time point to variable reaction parameters such as temperature, time, concentration, stoichiometry, etc. By systematically varying these parameters, researchers hope to develop empirical trends relating properties of the chemical species involved to the observed reactivity. What underpins these efforts is an attempt to account for and control the complex, dynamic, and numerous chemical equilibria within a catalytic environment. However, while idealized catalytic mechanisms can be easily envisioned, the reality is that these processes are often plagued by off-cycle equilibria and decomposition pathways that lead to reduced yield and efficiency. In order to rapidly assess what inhibits productive chemistry, focus must be redirected towards scrutinizing the mechanisms within a catalytic environment. To facilitate this, the acquisition of high-density, trustworthy, and time-resolved reaction progress information for all observable species present within a chemical transformation (starting reagents, intermediates, by-products, products, etc.) by modern in situ reaction monitoring tools offers unmatched opportunities for mechanistic understanding. Ultimately, these time-course profiles provide temporal signatures of dynamic processes active during the chemical transformation that inform process development. This Thesis reports on case studies in which the construction and application of automated technology enabled the solution to difficult problems in complex chemical and physical processes.
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.
Master's Student Supervision (2010 - 2020)
Mechanistic insight is fundamental to understanding a reaction and essential towards accessing desired product(s) in high yield, enantiopurity, and efficiency. Key to unlocking these investigations are developing tools that can monitor as many reactive species, intermediates, and products over the course of a reaction as possible. In the case of heterogeneous and biphasic systems, this analysis requires the development of new monitoring methodologies that can probe the complex equilibria, solubilities, mass transfer events, and catalytic cycles associated with the reaction. Herein, the development and deployment of reaction monitoring methods for the study of heterogeneous and biphasic reactions is discussed. These methodologies were deployed in two case studies, the first of which involved investigation of stereoselectivities of a proline catalyzed aldol reaction, while the second probed a biphasic reaction for an enantioselective spirocyclization catalyzed by a doubly quaternized cinchona alkaloid. The monitoring platforms allowed for the identification of water as the primary source of stereoselectivity in the proline-catalyzed aldol reaction, while also identifying the observed rate law, catalyst deactivation, and gaining insight into product behaviours. Investigations suggest that stereoselectivity likely originates from differences in transition states arising from the presence of water, rather than through kinetic phenomena. In the case of biphasic systems, a combined approach utilizing phase selective and heterogeneous sampling allowed for tracking of reaction species across both phases, allowing for insight into the reaction rate law, catalyst degradation, mass transfer behaviour, and temperature dependence studies. These results suggest that productive spirocyclization is balanced against inescapable catalyst degradation, with future optimization likely requiring new catalyst designs to counteract this relationship. The deployment of these monitoring methods provided the data necessary to carry out in-depth analysis of these two reactions which would not be accessible through end-point analysis. These methodologies promise excellent utility in the study of other heterogeneous and biphasic systems, with potential applications in mechanistic investigations and reaction optimizations.