N‐Hydroxyphthalimide Catalyzed Aerobic Oxidation of Aldehydes under Continuous Flow Conditions

Abstract

The efficacy of synthetic methodologies is based not only on potent chemistries but also on processing strategies that amplify reaction performance and overall safety. The N-hydroxyphtalimide-catalyzed aerobic oxidation of aldehydes is an environmentally reliable and inexpensive approach for the synthesis of valuable carboxylic acids. However, the reaction may lead to the accumulation of significant amounts of peracid in crude product mixtures thereby generating a considerable safety hazard. Also, in the case of deactivated substrates, long reaction times, high catalyst loading, and stoichiometric additives are required to promote oxidation. Therefore, we developed a flow chemistry-based process for N-hydroxyphtalimidecatalyzed aldehyde oxidations and exploited its benefits to minimize peracid buildup, thereby enhancing the process safety. By performing the aerobic oxidation of aldehydes under continuous flow conditions, chemically intensified and scalable carboxylic acid formation was obtained even in the reactions of deactivated substrates. Our findings are presented herein.

Light-promoted oxidation of aldehydes to carboxylic acids under aerobic and photocatalyst-free conditions

“…In addition, in recent literature, it is suggested that the formation of the Criegee intermediate V is a slow process and alternative pathways are proposed for the generation of acid under non-irradiating conditions, however, we could not detect such intermediates in our study. 10 b ,32,33 Thus, fast trapping of IV by acetone to VI could explain the faster formation of acid. Collectively, the study of the reaction mechanism by DI-HRMS suggests a solvent-accelerating process, which involves a dioxirane oxidant in situ generated under these reaction conditions, highlighting the importance of DI-HRMS as a tool to study organic chemistry reactions.…”

Selective aerobic oxidation of aliphatic aldehydes: the critical role of percarboxylate anion on the selectivity

“…We have shown that pathway B, via the Criegee intermediate, could be neglected for aliphatic and aromatic aldehydes. 8 In particular, we 8,9 and others 10,11 have shown that the peracid 4 accumulated in the reaction mixture. Peracid 4 is converted into carboxylic acid 6 during workup (Scheme 1, pathway C) or using a metal catalyst.…”

“…Nevertheless, the problem of selectivity for aliphatic aldehydes, particularly for β-substituted aliphatic aldehydes remains. 8,10,11,[13][14][15][16][17] A carboxylic acid selectivity between 70% and 90% without additives was observed for 2-ethylhexanal 1, an industrially important chemical intermediate. 18 It has already been shown that the selectivity towards 2-ethylhexanoic acid 6 was also dependent on the solvent.…”

“…8 -The reaction mixture was heated to 100 °C under O 2 pressure with a residence time of 20 min. 10 Under those conditions, as the dissociation energy of the peroxy bond of peracids is low (ca. 50 kcal mol −1 ), 12 the peracid 4 formed in situ is decomposed.…”

“…18 It has already been shown that the selectivity towards 2-ethylhexanoic acid 6 was also dependent on the solvent. 8,10,13,14,17 On the other hand, the oxidations of aromatic aldehydes and linear aliphatic aldehydes are highly selective (>95%), even if high concentrations of peracids are found during the reaction. 9 It should be mentioned that selectivities were determined after workup or by GC analysis of the crude.…”