The critical influence of solvent effects on proline-catalyzed aldol reactions has been extensively described. Herein, we apply multivariate regression strategies to probe the influence of different solvents on an aldol reaction catalyzed by proline modified at its secondary sphere with boronic acids. In this system, both in situ binding of the boronic acid to proline and the outcome of the aldol reaction are impacted by the solvent-controlled microenvironment. Thus, with the aim of uncovering mechanistic insight and an ancillary aim of identifying methodological improvements, we designed a set of experiments, spanning 15 boronic acids in five different solvents. Based on hypothesized intermediates or interactions that could be responsible for the selectivity in these reactions, we proposed several structural configurations for the library of boronic acids. Subsequently, we compared the statistical models correlating the outcome of the reaction in different solvents with molecular descriptors produced for each of these proposed configurations. The models allude to the importance of different interactions in controlling selectivity in each of the studied solvents. As a proof-of-concept for the practicality of our approach, the models in chloroform ultimately led to lowering the ketone loading to only two equivalents while retaining excellent yield and enantio- and diastereo-selectivity.
Reactive intermediates are key to halting and promoting chemical transformations, however due to their elusive nature, they are seldom harnessed for reaction design. Herein, we describe studies aimed at stabilizing reactive intermediates in the N-heterocyclic carbene (NHC) catalytic cycle, which enabled fully shutting down the known benzoin coupling pathway, while rerouting its intermediates toward deuteration. The reversible nature of NHC catalysis and the selective stabilization of reaction intermediates facilitated clean hydrogen-deuterium exchange reactions of aromatic aldehydes by D<sub>2</sub>O, even for challenging electron withdrawing substrates. The addition of catalytic amounts of phenyl boronic acid was used to further stabilize highly reactive intermediates and mitigate the formation of benzoin coupling by-products. The mechanistic understanding at the foundation of this work resulted in unprecedented mild conditions with base and catalyst loadings as low as 0.1 mol%, and a scalable deuteration reaction applicable to a broad substrate scope with outstanding functional group tolerance. More importantly, adopting this approach enabled the construction of a machine-learning derived guideline for identifying the appropriate catalyst and conditions for different substrates based on a logistic regression classification model. Experimental studies combined with machine learning and computational methods shed light on the non-trivial mechanistic underpinnings of this reaction.
In this work, we provide a brief overview of the role of N-aryl substituents on triazolium N-heterocyclic carbene (NHC) catalysis. This synopsis provides context for the disclosed synthetic protocol for new chiral N-heterocyclic carbene (NHC) triazolium salts with brominated aromatic motifs. Incorporating brominated aryl rings into NHC structures is challenging, probably due to the substantial steric and electronic influence these substituents exert throughout the synthetic protocol. However, these exact characteristics make it an interesting N-aryl substituent, because the electronic and steric diversity it offers could find broad use in organometallic- and organo-catalysis. Following the synthetic reaction by NMR guided the extensive modification of a known protocol to enable the preparation of these challenging NHC pre-catalysts.
Reactive intermediates are key to halting and promoting chemical transformations, however due to their elusive nature, they are seldom harnessed for reaction design. Herein, we describe studies aimed at stabilizing reactive intermediates in the N-heterocyclic carbene (NHC) catalytic cycle, which enabled fully shutting down the known benzoin coupling pathway, while rerouting its intermediates toward deuteration. The reversible nature of NHC catalysis and the selective stabilization of reaction intermediates facilitated clean hydrogen-deuterium exchange reactions of aromatic aldehydes by D<sub>2</sub>O, even for challenging electron withdrawing substrates. The addition of catalytic amounts of phenyl boronic acid was used to further stabilize highly reactive intermediates and mitigate the formation of benzoin coupling by-products. The mechanistic understanding at the foundation of this work resulted in unprecedented mild conditions with base and catalyst loadings as low as 0.1 mol%, and a scalable deuteration reaction applicable to a broad substrate scope with outstanding functional group tolerance. More importantly, adopting this approach enabled the construction of a machine-learning derived guideline for identifying the appropriate catalyst and conditions for different substrates based on a logistic regression classification model. Experimental studies combined with machine learning and computational methods shed light on the non-trivial mechanistic underpinnings of this reaction.
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