Mechanistic Insights into the Aerobic Oxidation of Aldehydes: Evidence of Multiple Reaction Pathways during the Liquid Phase Oxidation of 2-Ethylhexanal

Abstract

The liquid-phase aldehyde oxidation by molecular oxygen (autoxidation) has been known for about 2 centuries and is a critical organic transformation in both industrial applications and academic research. However, the general reaction pathway proposed for the aerobic oxidation of aldehydes into the corresponding carboxylic acid exhibits some inconstancies, in particular, for β-substituted aliphatic aldehydes. Thus, the liquid-phase aerobic oxidation of 2-ethylhexanal was further studied in acetonitrile at 20 °C with O2 at atmospheric pressure. By precisely monitoring the primary intermediate (peracid), product (carboxylic acid), and byproducts as a function of time and catalysts used, we demonstrated the pivotal role of the acylperoxy radical. The direct formation of peracid and carboxylic acid from the latter was highlighted by analyzing the composition of the reaction mixture at low conversion. Peracid could be converted into carboxylic acid by metal catalysts or through reaction workup. Consequently, the commonly accepted pathway of aerobic oxidation of aldehyde via a Criegee intermediate can be overlooked under these conditions.

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

“…In order to understand the considerable reduction of peracid content at high substrate concentrations, the fast formation of acylperoxy radical IV in the presence of NHPI catalyst should be taken into account (Scheme 1). [12,13] Because of the high concentration of IV, dimerization is favored over hydrogen atom transfer (HAT). Moreover, according to the data shown in Table 1, the precise tuning of the O 2 excess also contributed notably to the reduction of the peracid content.…”

“…Compounds were visualized by means of UV or by using KMnO4. 1 H-, 13 C-and 19 F-NMR spectra were recorded on a Bruker Avance III 300 MHz instrument at ambient temperature, in CDCl 3 or in DMSO-d 6 as solvent, at 300 MHz, 75 MHz and 282 MHz, respectively. Chemical shifts (δ) are reported in ppm using TMS as internal standard.…”

“…In this manner, the formation of the carboxylic acid product ( III ) should rather be explained by the decomposition of the peracid, for example, during aqueous work‐up [12] . It was recently demonstrated that carboxylic acid III may also be formed via dimerization of acylperoxy radical IV [13] . In this manner, peracid and carboxylic acid buildup takes place simultaneously and the ratio between these substances is dependent on the reaction conditions (Scheme 1).…”

“…[12] It was recently demonstrated that carboxylic acid III may also be formed via dimerization of acylperoxy radical IV. [13] In this manner, peracid and carboxylic acid buildup takes place simultaneously and the ratio between these substances is dependent on the reaction conditions (Scheme 1). [13] Considering that percarboxylic acids are highly energetic materials that are prone to explosive decomposition, [14] their accumulation in solution exhibits a significant safety hazard that should not be overlooked during process development.…”

“…[19] By employing continuous flow technologies, inherent process challenges associated with gas-liquid transformations can be minimized, [20] whilst enabling protocols to be safely scalable. [21] Taking into account the limitations of the current batch protocols, [7,12,13] continuous flow chemistry appeared to be a reasonable strategy for organocatalyzed aerobic aldehyde oxidations. In our recent report on the flow synthesis of optically active γ-nitrobutyric acids as key intermediates of GABA analogues, we disclosed some preliminary data suggesting the potential benefits of NHPI-catalyzed aerobic aldehyde oxidations performed within a continuous flow reaction environment.…”