Rerouting the Organocatalytic Benzoin Reaction toward Aldehyde Deuteration

Abstract

Reactive intermediates are key to halting and promoting chemical transformations; however, due to their elusive nature, they are not straightforwardly harnessed for reaction design. Herein, we describe studies aimed at stabilizing reactive intermediates in the N-heterocyclic carbene (NHC) catalytic cycle, which enabled the full shutdown of 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 D2O, even for challenging electron-withdrawing substrates. In several cases, the addition of catalytic amounts of phenyl boronic acid was used to further stabilize highly reactive intermediates and mitigate the formation of benzoin coupling byproducts. 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 guideline for identifying the appropriate catalyst and conditions for different substrates. Experimental studies combined with machine learning and computational methods shed light on the nontrivial mechanistic underpinnings of this reaction.

Recent Advances in Enantioselective Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes (NHCs) Containing Triazolium Motifs

“…N-Heterocyclic carbenes (NHCs) are the most studied family of nucleophilic carbenes. [1][2][3][4][5][6][7][8][9] They are generally well known as excellent nitrogen ligands for transition metal-based catalysis, [10][11][12][13][14][15][16][17] various types of carbon-carbon (C-C), carbon-halogen (C-X) and carbon-heteroatom (C-HA) mediated cross-coupling reaction, [18][19][20] and olefin metathesis, [21][22][23][24][25] but there is growing interest in the role of nucleophilic carbenes in field of organocatalytic reactions. [26][27][28][29][30][31] Metal-free organocatalytic processes are more interesting alternatives to classical organic transformations method since they are often more economical, most of the catalytic systems possibly recover back active catalyst with good turnover rate, less air-sensitive NHC-salts and non-toxic reagents.…”

Recent Advances in the Practical Synthesis of C1 Deuterated Aromatic Aldehydes Enabled by Catalysis and Beyond

“…Herein, we exploit recent NHC catalysis studies and mechanistic insights on the stabilization of such reactive intermediates for the selective deuteration of aromatic, alkene and alkyl aldehydes. We showed that intercepting a stabilized reactive aldehyde intermediate can work as a facile starting point to introduce the deuterium Isotope labeling and eliminating the generation of classical homo‐benzoin by‐product [30–31] …”

Quantum Tunneling on Carbene Organocatalysis: Breslow Intermediate Formation via Water-Bridges

“…The high transition state results from a highly strained three-membered ring, which almost requires the complete breaking of the C–H bond before forming the O–H one . Consequently, it was shown that a base (such as DBU or K 2 CO 3 ), water- or alcohol-assisted HAT is a much more plausible alternative. − …”

“…Since we can guesstimate that normally accessible dried solvents can still have a water content of the order of millimolar, it is clear that water-assisted HAT is the preferred mechanism. It is possible that a two-water-molecule mechanism can also participate at high concentration (we estimate more than millimolar concentration to make this pathway relevant), , an effect that we will study in the future.…”

“…We showed that the transition state imaginary frequency and the reaction energy play a decisive role in the QMT rates of this type of reaction. Since a trace of H 2 O was found to be essential as a cocatalyst in many intramolecular H transfer reactions, ,,, it stands to be tested if quantum tunneling is a common factor for many catalytic reactions, including HAT steps.…”