Abstract
A computational study on Pinnick oxidation of aldehydes into carboxylic acids using density functional theory (DFT) calculations has been evaluated with the (SMD)-M06-2X/aug-pVDZ level of theory, leading to an important understanding of the reaction mechanism that agrees with the experimental observations and explaining the substantial role of acid in driving the reaction. The DFT results elucidated that the first reaction step (FRS) proceeds in a manner where chlorous acid reacts with the aldehyde group through a distorted six-membered ring transition state to give a hydroxyallyl chlorite intermediate that undergoes a pericyclic fragmentation to release the carboxylic acid as a second reaction step (SRS). 1H NMR experiments and simulations showed that hydrogen bonding between carbonyl and t-butanol is unlikely to occur. Additionally, it was found that the FRS is a rate-determining and thermoneutral step, whereas SRS is highly exergonic with a low energetic barrier due to the Cl(III) → Cl(II) reduction. Frontier molecular orbital analysis, intrinsic reaction coordinate, molecular dynamics and distortion/interaction analysis further supported the proposed mechanism.
Highlights
The oxidation of aldehydes to carboxylic acids is a fundamental transformation in organic chemistry that is applied in many syntheses
A computational study on Pinnick oxidation of aldehydes into carboxylic acids using density functional theory (DFT) calculations has been evaluated with the (SMD)-M06-2X/ aug-pVDZ level of theory, leading to an important understanding of the reaction mechanism that agrees with the experimental observations and explaining the substantial role of acid in driving the reaction
The oxidation of aldehyde to carboxylic acid was considered to occur on two steps; first reaction step (FRS) represents the addition of chlorite ion to carbonyl moiety with or without acid additives, whereas second reaction step (SRS) depicts the pericyclic fragmentation to release the carboxylic acid and hypochlorous acid (ClOH)
Summary
The oxidation of aldehydes to carboxylic acids is a fundamental transformation in organic chemistry that is applied in many syntheses (examples of the use of Pinnick oxidation in synthesis of some bioactive molecules [1,2,3,4,5], Pinnick-type protocol for amidation of aldehyde [6]). Pinnick oxidation has been widely used in organic synthesis due to the flexibility with many sensitive functionalities and suitability for sterically hindered aldehydes [22,23] (for development of Pinnick oxidation, see [24,25,26,27,28,29,30,31,32,33,34]) This reaction was first developed by Lindgren & Nilsson [27] and by Kraus [26,28] modifications developed by Pinnick were later demonstrated to be an efficient approach to oxidize α,β-unsaturated aldehydes to their corresponding acids by using sodium chlorite under mild conditions (figure 1a) [31]. — EDG and EWG effects — FMO and MD analysis — conformational analysis — distortion/interaction analysis concerted TS 8
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