¹⁶O/¹⁸O Exchange of Aldehydes and Ketones caused by H₂¹⁸O in the Mechanistic Investigation of Organocatalyzed Michael, Mannich, and Aldol Reactions

Abstract

Organocatalyzed Michael, Mannich, and aldol reactions of aldehydes or ketones, as nucleophiles, have triggered several discussions regarding their reaction mechanism. H2 (18) O has been utilized to determine if the reaction proceeds through an enamine or enol mechanism by monitoring the ratio of (18) O incorporated into the final product. In this communication, we describe the risk of H2 (18) O as an evaluation tool for this mechanistic investigation. We have demonstrated that exchange of (16) O/(18) O occurs in the aldehyde or ketone starting material, caused by the presence of H2 (18) O and amine catalysts, before the Michael, Mannich, and aldol reactions proceed. Because the newly generated (18) O starting aldehydes or ketones and (16) O water affect the incorporation ratio of (18) O in the final product, the use of H2 (18) O would not be appropriate to distinguish the mechanism of these organocatalyzed reactions.

Direct Asymmetric Michael Reaction of α,β‐Unsaturated Aldehydes and Ketones Catalyzed by Two Secondary Amine Catalysts

“…(3), Figure ]. To monitor the reaction by mass spectrometry, we used 3‐(3,4‐dimethoxyphenyl)propenal ( 7 ) instead of cinnamaldehyde, and 7 was treated with amine catalyst 1 or 2 in the presence of H 2 18 O (4 equiv) and p ‐nitrophenol (10 mol %) . As the iminium ion would react with H 2 18 O to afford 18 O‐labeled aldehyde 7 , the generation of the 18 O‐labeled aldehyde reflected the generation of the iminium ion.…”

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

“…Conversely, complete or partial retention of 16 O in the α‐functionalized carbonyl oxygen suggests an enol pathway because this mechanism does not involve a hydrolysis step. Two complications make this experiment an unreliable probe of enamine versus enol pathways: (1) explicit addition of water alters the reaction kinetics and might also change the mechanism of the specific reaction in question; and (2) Hayashi has recently shown that both the product and starting material can reversibly form enamines with amine catalysts, resulting in the generation of a statistically significant amount of 16 O water, which can lead to retention of 16 O in the product even if the enamine mechanism is operational . This suggests that, although 18 O incorporation studies can support an enamine mechanism, these experiments should be conducted and interpreted with an overabundance of caution.…”

“…Twoc omplications make this experiment an unreliable probe of enamine versus enol pathways:( 1) explicit addition of water alters the reactionk inetics and might also change the mechanism of the specific reaction in question; [5] and (2) Hayashi has recently shown that both the product and starting material can reversibly form enamines with amine catalysts, resulting in the generation of as tatistically significant amounto f 16 Ow ater,w hich can lead to retention of 16 Oi nt he product even if the enamine mechanism is operational. [6] This suggestst hat, although 18 O incorporation studies can support an enamine mechanism, these experiments should be conducted and interpreted with an overabundance of caution.M ore importantly,i td emonstrates the need for an additional robustquantitative probe for these sister mechanismsi na minocatalysis. We report herein the use of heavy atom ( 13 C) kinetic isotope effectsi nc onjunction with theoretical calculations as aquantitative probe to distinguish between enamine ande nol mechanismsi na minocatalysis withoutmodifyinge xperimental conditions.…”

Recent Developments in Enantioselective Organocatalytic Michael Reactions in Aqueous Media

“…In order to determine whether the organocatalytic Michael reaction between nitroalkenes and aldehydes catalyzed by diphenylprolinol trimethylsilyl ether in water evolved through enamine or enol mechanism, Hayashi et al recently investigated this reaction in the presence of H 2 18 O, by monitoring the ratio of 18 O incorporated into the final Michael product [28]. This study demonstrated, however, that a 16 O/ 18 O exchange in the aldehyde starting material, occurring through an enamine intermediate, was faster than the Michael reaction.…”