¹³C Kinetic Isotope Effects as a Quantitative Probe To Distinguish between Enol and Enamine Mechanisms in Aminocatalysis

Abstract

A combination of experimental C kinetic isotope effects (KIEs) and high-level density functional theory (DFT) calculations is used to distinguish between "enamine" and "enol" mechanisms in the Michael addition of acetone to trans-β-nitrostyrene catalyzed by Jacobsen's primary amine thiourea catalyst. In light of the recent findings that the widely used O-incorporation probe for these mechanisms is flawed, the results described in this communication demonstrate an alternative probe to distinguish between these pathways. A key advantage of this probe is that quantitative mechanistic information is obtained without modifying experimental conditions. This approach is expected to find application in resolving mechanistic debates, while providing valuable information about the key transition state of organocatalyzed reactions involving the α-functionalization of carbonyls.

Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

“…33,34 This approach has been employed with great success to measure competitive intermolecular 13 C kinetic isotope effects (KIE) in mechanistic studies of 6 catalytic reactions. [35][36][37][38][39][40][41][42][43] This commonly relies on running the reaction to high conversion and examining the 12 C/ 13 C ratio in recovered starting material. However, in the asymmetric addition to 3, the isolation of small amounts of starting material at high conversions isn't possible as 3 is too sensitive to be reliably purified and may be configurationally labile during reaction or work-up conditions.…”

Evidence for an enolate mechanism in the asymmetric Michael reaction of α,β-unsaturated aldehydes and ketones via a hybrid system of two secondary amine catalysts

“…3 In the Mannich reaction of acetone catalysed by a primary amine-thiourea organocatalyst, an enol mechanism was proposed, 9 while an enamine mechanism is proved by calculation and 13 C kinetic isotope effects in the Michael reaction of acetone catalysed by a similar catalyst. 10 In the Michael reaction of propanal and methyl vinyl ketone catalysed by pyrrolidine, both enamine and enol mechanisms were computationally investigated, and an enamine is concluded to be a key nucleophile. 11 The discrimination of the reaction mechanism of enamine and enol is difficult, and the asymmetric reaction involving an enol is rare.…”

NMR and Computational Studies on the Reactions of Enamines with Nitroalkenes That May Pass through Cyclobutanes

“…We wish to account for the cases in which the stoichiometric reactions are feasible but do not work under catalytic conditions, as well as for the differences in the stereochemical outcome using aldehydes and ketones as Michael donors. Thus, we aim to answer question (a) and to find an explanation for points (b)–(d):Can cyclobutanes be formed in all reactions between enamines and polarized C–C double bonds?When reacting with β-nitrostyrene in the presence of appropriate secondary amines, aldehydes afford syn adducts (usually 2R,3S) in excellent yields and stereoselectivities, whereas ketones afford the other syn adducts (usually 2S,3R), 1,7−10 with exceptions in special cases; 11 this is known since the pioneering works on this Michael reaction. 8 However, poor results are obtained with ( S )-proline, often with disappointing enantiomeric ratios (er’s), as shown in Figure 3, eqs 1 and 2.…”

“…When reacting with β-nitrostyrene in the presence of appropriate secondary amines, aldehydes afford syn adducts (usually 2R,3S) in excellent yields and stereoselectivities, whereas ketones afford the other syn adducts (usually 2S,3R), 1,7−10 with exceptions in special cases; 11 this is known since the pioneering works on this Michael reaction. 8 However, poor results are obtained with ( S )-proline, often with disappointing enantiomeric ratios (er’s), as shown in Figure 3, eqs 1 and 2.…”