Reinvestigation of the Organocatalyzed Aerobic Oxidation of Aldehydes to Acids Laurent Vanoye, † Mohamed Abdelaal, † Kacy Grundhauser, † Boris Guicheret, † Pascal Fongarland, † Claude De Bellefon, † and Alain Favre-Re ́ guillon* ,‡,† † Université Lyon, Laboratoire de Gé nie des Procé dé s Catalytiques UMR 5285, CNRS-CPE Lyon-UCBL, 43 boulevard du 11 novembre 1918, F-69100 Villeurbanne, France ‡ Conservatoire National des Arts et Mé tiers, EPN 7, 2 rue Conté , 75003 Paris, France * S Supporting Information ABSTRACT: The organocatalyzed aerobic oxidation of aldehydes to acids was reproduced from the original report. In- and ex- situ analysis of the reaction mixture as the function of time reveals that, unlike the claim in the publication, the aerobic oxidation of aromatic and aliphatic aldehydes leads predominantly to the formation of peracids. The latter are transformed into the corresponding carboxylic acids during the workup procedure. The buildup of peracids in solution poses safety problems that should not be overlooked. This finding has also an influence on the way new catalysts are investigated to improve this reaction as well as on aerobic aldehyde-mediated co-oxidation. T he development of methods for the selective and atom- economic oxidation of organic substrates belongs to the most challenging fields of contemporary chemical research, in both the academic and the industrial environment. In terms of sustainability, O 2 is a highly attractive option. 1 The importance of developing better aerobic oxidation catalysts means there is now an increasing emphasis on this challenge in terms of reactivity and selectivity. A plethora of homogeneous and heterogeneous catalysts have been reported for a wide range of oxidation reactions ranging from alcohol oxidation to C-H bond functionalization. 2 Although aerobic oxidation of aldehydes can be performed without catalysts, 3 numerous homogeneous catalysts have been described for this particular reaction and, in particular, first-row transition metals. 4 Recently, Y.-B. Kang et al. described the use of an organocatalyst, i.e. N-hydroxyphtalimide (NHPI), for the aerobic oxidation of aldehydes to acids. 5 Alkyl aldehydes were selectively oxidized into the corresponding carboxylic acids in 3 h at 30 °C in the presence of 1 atm of O 2 with 5 mol % of NHPI, whereas aromatic aldehydes required harsh conditions (1.5 d, 90 °C, 10 mol % of NHPI, 1 atm of O 2 ). 5 A mechanism was proposed (Figure 1) where a phthalimido-N-oxyl radical (PINO) acts as a nonterminating chain propagation radical. In this generally accepted mechanism, 3b,5,6 the aerobic oxidation proceeds via a two-step process. The first step is a free radical chain reaction with acyl radical A as the intermediate, the latter being generated by PINO. Upon reaction with 3 O 2 , an acylperoxy radical B is formed. The abstraction of hydrogen from NHPI by B regenerated PINO and produced peracid C (Figure 1). Then, by analogy with the mechanism of the Baeyer-Villiger (BV) oxidation, 7 a second step was postu- lated. 3b,5,6 The peracid C should react with a remaining aldehyde 2 through a nucleophilic addition to form the Criegee intermediate D. Rearrangement of D afforded 2 mol of the corresponding carboxylic acid 3 (Figure 1) through migration of hydride, whereas migration of the alkyl group gives an equimolar mixture of carboxylic acid and formate. The ratio of hydride to alkyl migration was found to depend critically on the structure of aldehydes, temperature, solvent, etc. 4d,6a,8 In the case of organocatalyzed oxidation, one can suppose that the differences lie in the initiation and in the propagation steps, the products (C and 3) and intermediates (A, B, and D) being the same. However, several experimental pieces of evidence suggested that the proposed mechanism of aerobic oxidation of aldehyde might be somewhat incorrect: (i) In contrast to ketones, BV oxidations of aldehydes with peroxyacids are less studied because a mixture of carboxylic acids and formates are generally obtained. 9 The oxidation of hydroxybenzaldehydes Received: November 22, 2019 Letter pubs.acs.org/OrgLett Cite This: Org. Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.9b04193 Org. Lett. XXXX, XXX, XXX-XXX Downloaded via UPPSALA UNIV on December 7, 2019 at 04:09:46 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.