N-Heterocyclic Carbene-Catalyzed Aerobic Oxidation of Aromatic Aldehydes into Carboxylic Acids: A Critical Review

Abstract

N-heterocyclic carbenes (NHCs) have demonstrated their versatility as catalysts for new activations and synthetic transformations of aldehydes. NHCs were originally applied in benzoin condensation and the Stetter reaction, while the development of new protocols under oxidative conditions has further expanded the potential of this methodology for the formation of carbon−carbon and carbon−heteroatom bonds. Among these reactions, NHCs are recognized as promising organocatalysts for the aerobic oxidation of aldehydes to carboxylic acids. However, to our knowledge, a comparison with other metal-free protocols has never been conducted. This review is intended to provide a perspective on aldehyde oxidation into the corresponding carboxylic acid catalyzed by NHCs, from its first practical description in 2009 until the beginning of 2025, and to compare it with other metal-free methods.

1. Introduction

N-heterocyclic carbenes (NHCs) have emerged as powerful organocatalysts in numerous carbon–carbon and carbon–heteroatom bond formation reactions [1,2]. In particular, NHCs have demonstrated their versatility as catalysts for new activations and synthetic transformations of aldehydes [2,3,4,5]. Among these transformations, NHCs have been identified as promising organocatalysts for the aerobic oxidation of aldehydes to carboxylic acids. Since the pioneering work of Yoshida et al. in 2009 [6], numerous protocols utilizing various oxidants and conditions have been developed for this transformation. However, to our knowledge, no comparison of the efficiency of NHCs for this particular reaction to metal-free protocols has been made, and studies have even questioned some results obtained using NHCs [7,8,9].

To understand how these different protocols have been developed, it is important to review the two main aldehyde transformation mechanisms involving NHCs, focusing on ester and carboxylic acid formation, specifically NHC-mediated carbonyl umpolung (Section 2.1) and the oxidation of the Breslow intermediate (Section 2.2) [10]. Next, the various procedures for the transformation of aromatic aldehydes into the corresponding carboxylic acids will be reviewed (Section 3). The results obtained will be discussed and compared to other metal-free protocols (Section 4).

2. NHCs as Catalysts for Transformation of Aldehydes

2.1. Products from NHC-Mediated Carbonyl Umpolung

The benzoin condensation (Figure 1, left) constitutes one of the earliest known carbon–carbon bond-forming reactions catalyzed by NHCs [11]. Breslow postulated a mechanistic pathway for the benzoin condensation in 1958 using vitamin B1 as an NHC pre-catalyst [12], and Figure 1 (on the left) describes the general pathway. Deprotonation of a precursor salt 1 generates the NHC 2. Nucleophilic addition of NHC 2 to an aldehyde 3 generates the tetrahedral intermediate 4. The latter then undergoes a proton shift to form the nucleophilic enaminol intermediate, known as the Breslow intermediate 5. Thus, NHC-organocatalyzed umpolung reactions of aldehydes lead to the formation of nucleophilic acyl anion intermediates 6, which can react with various electrophiles, including aldehydes (benzoin condensation), ketones [13], imines [14], and activated, polarized C = C double bonds (Stetter reaction) [15,16]. In the benzoin condensation (Figure 1, left), intermediate 5 reacts with the same aldehyde 3, resulting in the formation of an alkoxide intermediate 7. Following a proton transfer that leads to 8, a subsequent release of NHC 2 affords the final product, an α-hydroxy ketone 9. The Stetter reaction [15,16] (Figure 1, right) involves the 1,4-addition of 5 to an α,β-unsaturated carbonyl compound 10, forming the intermediate 11. After a proton transfer resulting in 12, a subsequent release of NHC 2 yields the final product, a 1,4-diketone 13.

The reaction of the acyl anion intermediates 6 with sp²-carbon-centered electrophiles (Figure 1, right) has been used for the preparation of unique reactive intermediates [17]. However, comparable reactions with sp³-centered electrophiles have been less reported [18,19,20,21].

To synthesize ketones, W. Du and W.-P. Deng [18] studied the reaction of the Breslow intermediate with activated halides. It was expected that the equivalent of the Breslow intermediate 6 would react directly with benzyl bromide to yield the desired aryl ketone (Scheme 1, path (a). However, a mixture of ketone and ester was obtained. To explain the formation of the ester, alkylation of the tetrahedral intermediate by the halide, followed by oxidation by O₂ from air, was proposed (Scheme 1, path (b). Under N₂ and using a stoichiometric amount of NHC, various aryl ketones were obtained in 22–63% yields, but trace amounts of esters (0 to 15%) were still present [18]. For p-bromobenzaldehyde, 63% of ketone was obtained with 5% of ester (Scheme 1).

Using catalytic NHC, F. Glorius et al. [19] described an efficient method for the formation of diaryl acetophenone derivatives in good yields. However, reactions carried out using benzyl bromide as the electrophile in the alkylation reaction did not yield any alkylated product [19]. More recently, the synthesis of ketones from the deprotonated Breslow intermediates has been described, starting from alkyl iodines via a single-electron reduction process [21].

2.2. Products from Oxidation of Breslow Intermediate

The scope of NHCs chemistry may be further expanded with protocols under oxidative conditions to access a wide range of organic compounds [22,23,24]. The oxidative NHC-catalytic cycle pathway (Figure 1) relies on the oxidation of the initially formed nucleophilic NHC-aldehyde adduct (Breslow intermediate 5) into an acyl azolium intermediate 14 (Figure 2). The latter is electrophilic at the carbonyl carbon and undergoes acyl substitutions with nucleophiles [2,3,4,5], including alcohols, to give the corresponding ester 15 and regenerates NHC 2. The process can be viewed as a double umpolung.

von Wangelin et al. [10] have classified these reactions as being either “oxidative” (i.e., the oxidation of the Breslow intermediate 5 by an added oxidant) or “oxygenative” (i.e., the oxidation of the Breslow intermediate 5 by oxygen or oxygen from air). Other authors have used the same terms to describe different pathways during the aerobic oxidation of aldehydes [25,26]. To ensure clarity, the nomenclature of von Wangelin et al. will be used in this review [10].

2.2.1. Oxidative NHC Catalysis

The key step in this protocol is the oxidation of the Breslow intermediate 5 (Figure 1). Various nucleophiles can be used, and under these conditions, efficient oxidative esterification of aromatic aldehydes catalyzed by N-heterocyclic carbenes at room temperature has been reported using stoichiometric oxidants, such as nitrobenzene [27], azobenzene [28], DPQ [29,30,31], PIDA [32], or TEMPO and TEMPO derivatives [33] (Scheme 2). However, these oxidants are used in stoichiometric amounts, resulting in large amounts of waste, which limits the scalability of these reactions, even if TEMPO derivatives could be regenerated after the reaction using O₂ [33].

2.2.2. Oxygenative NHC Catalysis

The reactivity of the Breslow intermediate with oxygen or with atmospheric oxygen has been noticed several times in the literature [18,20,34]. In 2009, Goswami et al. [34] described the first use of air as the oxidant for the oxidative esterification reaction of heterocyclic aldehydes using thiamine hydrochloride (Scheme 3). High yields were obtained in under mild conditions (MeOH at reflux, air), but the reaction was limited to heterocyclic aldehydes. Under N₂, no ester was obtained [34].

The oxidation of the Breslow intermediate by trace amounts of oxygen was also supposed by W.P. Deng et al. [18] and X.-W. Liu et al. [20] to explain the formation of ester during the NHCs-catalyzed synthesis of ketones from aromatic aldehydes. However, the first practical protocol was published by Sudalai et al. in 2013 [35]. They described the use of oxygen as an oxidant for the oxidative aerobic esterification reaction of aromatic aldehydes [35]. The reaction could be performed in air, but the best results were obtained under pure O₂ (Scheme 4). The absence of a carboxylic acid intermediate was confirmed by the lack of esterification between carboxylic acid and methanol under the reaction conditions [35]. This protocol could be extended to the synthesis of lactones [36,37].

Shortly thereafter, A. Studer et al. [38] described the oxidative esterification of aldehydes using air as the terminal oxidant, employing a ruthenium-based redox catalysis to oxidize the Breslow intermediate (Scheme 5).

A mechanism (Figure 3) was proposed in which the Breslow intermediate 5 is oxidized by Ru/O₂, leading to the formation of the acylazolium ion 14, which reacts with the alcohol to yield the corresponding ester and regenerate the NHC 2. It should be mentioned that, in the absence of the Ru catalyst and alcohol, aromatic and aliphatic aldehydes, under otherwise identical conditions, are oxidized to the corresponding acids (Scheme 12b) [38].

The same year, S. J. Connon et al. showed that by using different NHCs and a higher amount of base, high yields of the corresponding ester could be obtained under air (Scheme 6) [39].

A detailed mechanistic investigation of the NHC-catalyzed aerobic esterification of bromobenzaldehyde was conducted by O. Bortolini et al. [25,26] (Figure 4) in order to explain the formation of carboxylic acid during the aerobic esterification of aromatic aldehydes.

The formation of carboxylic acid can be explained by the competition between two pathways (Figure 4). As previously described, NHC 2 reacts with aromatic aldehyde 3 to form the Breslow intermediate 5. In the presence of O₂, a single-electron transfer process is thought to occur, leading to the formation of a peroxide anion 16 (Figure 4). In path (a), 16 could react with a second molecule of aldehyde 3 to yield 18. The rearrangement of 18 releases one molecule of carboxylic acid 17 and 19. The regeneration of carbene 2 occurs with the release of a second molecule of carboxylic acid 17. In path (b), a tautomeric equilibrium gives the hydroperoxy intermediate 20 [25], which is then converted into the acyl cation equivalent 14. Substitution by methanol yields the bromomethyl benzoate 15 and hydrogen peroxide 21.

A similar mechanism has already been proposed by several authors [10,18,25]. They also suggested the formation of the peroxide anion 16 (Figure 4) to explain the ester formation during the NHC-catalyzed oxidative esterification of aldehydes using sp³-centered electrophiles, i.e., halides [40]. X.-W. Liu et al. [20] studied the experiment in which ¹⁸O₂ was used to elucidate the mechanism (Figure 5) [20].

In the presence of NHC 2, cinnamaldehyde 22 yields the corresponding Breslow intermediate 23. In the presence of ¹⁸O₂, the peroxide anion 16 is formed (Figure 5). Rearrangement of the latter produces peroxyacid anion 24, which can react with another cinnamaldehyde 22 to give a Criegee intermediate 25. The rearrangement of 25 results in the formation of two carboxylic acids 26. In the presence of a base and cinnamyl bromide 27, the corresponding ester 28 is formed. The same intermediate was also confirmed by an isotopic labelling experiment using ¹⁸O_2, which involved the NHC-catalyzed aerobic oxidation of aromatic aldehydes to aryl esters using boronic acids [41].

3. Oxidation of Aromatic Aldehydes into Carboxylic Acids Using an Oxygenative NHC-Catalytic Cycle

As previously noted, the presence of carboxylic acids during oxygenative NHC catalysis has been reported by several authors but was regarded as an intermediate in the oxidative esterification of aldehydes using halides [20] or a by-product [25,26,38].

In 1977, J. Castells et al. [42] studied the oxidative esterification of aldehydes catalyzed by the conjugate bases of thiazolium ions in methanol. Carboxylic acid was obtained in the absence of alcohol, but it was not quantified.

In 2009, M. Yoshida et al. [6] were the first to report the oxidation of aromatic aldehydes with an electron-withdrawing group using an NHC catalyst (Scheme 7). It should be mentioned that the authors suggested a nucleophilic addition of water to the Breslow intermediate. The possibility of oxidation by atmospheric oxygen cannot be excluded, as the reaction was performed at r.t. for 10 to 24 h without mention of the use of an inert atmosphere. Under these conditions, benzoic acid was obtained in less than 10% yield (Table 1, entry 1). Using methanol or dimethylamine, the corresponding ester and amide were obtained in 68 and 60% yield, respectively.

In the same year, Y. Zhang et al. [43] described the oxidation of aromatic aldehydes with NHC using CO₂ as the oxidant and 2 as the precursor (Scheme 8). The reaction takes 3 to 5 days at r.t. under an atmospheric pressure of CO₂. It was proposed that NHC reacts with CO₂, generating an intermediate that can react with the aldehyde, leading to the formation of carboxylic acid and the release of CO.

Shortly after, V. Nair et al. [44] described an improved protocol for the NHC-mediated oxidation of aromatic aldehydes using a stream of carbon dioxide (Scheme 9). In less than 10 min. at r.t., a high yield (36–92%) of the corresponding carboxylic acid was obtained (Scheme 9). The best results were obtained in THF at r.t., with the exception being benzaldehyde and 3,4-dimethoxybenzaldehyde which gave better results in acetonitrile under reflux [44].

The mechanism suggested for this transformation involves the transfer of an oxygen atom from CO₂ to the aldehyde, representing a process that is counterintuitive and thermodynamically questionable [9,45]. Furthermore, the reaction was carefully checked by J.W. Bode et al. [7], and the results of Y. Zhang et al. [43] and V. Nair et al. [44] could not be reproduced (Scheme 10) [7]. It was demonstrated by J.W. Bode et al. that exogenous O₂ was the effective oxidant [7]. H. Wang et al. [8] also challenged the role of CO₂, concluding that this reaction cannot be performed at room temperature, which further questions the work of Y. Zhang et al. [43] and V. Nair et al. [44]. However, following these works, the use of CO₂ as an oxidant for the transformation of aldehydes into the corresponding carboxylic acids continues to be explored, but these results have also faced scrutiny [9].

Under air, the results of M. Yoshida et al. [6] were reproduced and improved by J.W. Bode et al. (Scheme 11) [7]. Benzoic acid could be obtained using air with a 57% yield at 60 °C over 40 h (Table 1, entry 2). Using acetonitrile at reflux, a similar yield could be obtained in 14 h, but using 0.4 eq. of DBU (Table 1, entry 3) [36].

In 2013, W.-F. Fu et al. [46], A. Studer et al. [38], and S. J. Connon et al. [47] (Scheme 12) simultaneously reinvestigated the work of M. Yoshida et al. [6]. Using new NHCs and similar experimental conditions (r.t., solvent/H₂O, air [38,46,47], or oxygen [48]), various aromatic aldehydes were oxidized in high yield to their corresponding carboxylic acids (Table 1, entries 4 to 9). Under these conditions, yields of up to 95% of benzoic acid could be obtained using atmospheric oxygen as the oxidant (Scheme 12).

Scheme 12. NHC-catalyzed transformation of aromatic aldehydes into acids using atmospheric oxygen as an oxidant: (a) [46]; (b) [38]; (c) [47].

Scheme 12. NHC-catalyzed transformation of aromatic aldehydes into acids using atmospheric oxygen as an oxidant: (a) [46]; (b) [38]; (c) [47].

O₂ at atmospheric pressure can also be used as an oxidant (Scheme 13) [48,49], but the impact on the chemical reaction rate could only be observed with one example (Table 1, entries 8 and 9) [48].

The aerobic oxidation of biomass-derived furfural to furoic acid was studied under oxygen using an NHC catalyst (Scheme 14) [50]. Quantitative yields were obtained under mild conditions (40 °C, 1 atm of O₂), and the procedure was extended to other biomass-derived furfurals (5-methylfurfural, HMF, etc.).

A polymerized NHC catalyst was evaluated in a continuous-flow reactor for the oxidation of benzaldehyde (Scheme 15) [51]. Water containing 0.25 eq. of K₂CO₃ was used as the solvent, and the mixture was continuously pumped through a reaction tube maintained at 80 °C, which contained the catalyst (∅ = 10 mm) and fed back to a stirred batch open to air. The solution was continuously recycled, and after 12 h, 96% of benzoic acid was obtained (Table 1, entry 10).

To compare the different systems described in the literature, the aerobic oxidation of benzaldehyde to benzoic acid using an NHC catalyst will be considered, and the results are summarized in Table 1. The yields of benzoic acid obtained are good to excellent. However, it is striking to observe that the concentration of NHC precursor salts, the type of base (inorganic/organic), and the amount of base used to form the NHCs are highly variable, ranging from 0.4 to 20 mol% and 0.25 to 80 eq., respectively (Table 1). The same applies to the experimental conditions, which vary from room temperature to 80 °C, using air or O₂ as an oxidant. It is worth noting that these oxidations occur in organic solvents, unlike reactions that do not utilize NHCs, which primarily proceed in water (Table 2).

To go beyond yield or reaction time, the productivity of these reactions, determined as the amount of benzaldehyde converted by volume of liquid phase by hour and for 0.21 atm of O₂ (i.e., air), could be calculated according to Equations (1) and (2) [52].

Using atmospheric oxygen, Equation (1) was used:

$$\mathrm{Productivity} \left(\mathrm{mM} {\mathrm{L}}^{-1} {\mathrm{h}}^{-1}\right)={\displaystyle \frac{\mathrm{quantity} \mathrm{of} \mathrm{benzaldehyde} \left(\mathrm{mM}\right) \times \mathrm{yield}}{\mathrm{volume} \mathrm{of} \mathrm{solvent} \left(\mathrm{L}\right) \times \mathrm{time} \left(\mathrm{h}\right)}}$$

(1)

Using oxygen, Equation (2) was used:

$$\mathrm{Productivity} \left(\mathrm{mM} {\mathrm{L}}^{-1} {\mathrm{h}}^{-1}\right) = {\displaystyle \frac{\mathrm{quantity} \mathrm{of} \mathrm{benzaldehyde} \left(\mathrm{mM}\right) \times \mathrm{yield} \times 0.21}{\mathrm{volume} \mathrm{of} \mathrm{solvent} \left(\mathrm{L}\right) \times \mathrm{time} \left(\mathrm{h}\right)}}$$

(2)

Using atmospheric oxygen as the oxidant, productivity correlates with the concentration of benzaldehyde used, with one exception (Table 1, entry 5) [38], which shows the highest productivity, regardless of the type of oxidant used. Based on these observations, it is impossible to propose standard conditions for this type of transformation or to justify the use of pure oxygen. There is only one experiment [49] that compares the use of oxygen with air (Table 1, entries 8 and 9), but surprisingly, the productivity calculated with oxygen is lower than with air, despite a higher yield (for comparison, see Table 2, entries 1 and 2).

Table 1. Comparison of experimental conditions for the oxidation of benzaldehyde using NHC catalysts and calculated productivity.

Entry	Conc. (mol/L)	Precur. Salt (a)	Base	Oxidant	Solvent(s)	Temp. (°C)	Time (h)	Yield (%)	Prod. (b) (mM L−1 h−1)	Ref.
1	0.34	5 mol%	BDU (2 eq.)	air	DMF/H2O	r. t.	24	10 (b)	1.43	[6]
2	0.10	5 mol%	K2CO3 (2 eq.)	air	DMSO/1 eq. H2O	60 °C	40	57	1.43	[7]
3	0.20	20 mol%	DBU (0.4 eq.)	air	CH3CN	80 °C	14	65	9.29	[36]
4	0.20	5 mol%	K2CO3 (80 eq.)	air	DMSO/1 eq. H2O	60 °C	36	91	5.06	[46]
5	0.25	2.5 mol%	TBD (1.2 eq.)	air	CH3CN	r. t.	24	92	115.00	[38]
6	0.40	15 mol%	DBU (7.3 eq.)	air	THF/H2O (10/1)	r. t.	24	95	15.83	[47]
7	1.00	2 mol%	DBU (1.1 eq.)	O2	CH3CN /2 eq. H2O	r. t.	4	97	48.50	[48]
8	0.17	5 mol%	DABCO (10 eq.)	O2	THF	r. t.	16	92	1.92	[49]
9	0.17	5 mol%	DABCO (10 eq.)	air	THF	r. t.	16	76	7.92	[49]
10	1.00	0.2 mol% (c)	K2CO3 (0.25 eq.)	air	H2O	80 °C	12 (d)	96	80.00	[51]
11	0.33	1 mol%	K3PO4 (4 eq.)	air (e)	H2O	80 °C	24	92	12.78	[53]
12	1.00	10 mol%	DBU (1.2 eq.)	O2	THF	25 °C	16	40 (f)	5.00	[54]

^(a) The structure of the precursor salt could be found in Scheme 7, Scheme 8, Scheme 9, Scheme 10, Scheme 11, Scheme 12, Scheme 13, Scheme 14 and Scheme 15. ^(b) Productivity was calculated as mM aldehyde converted per volume of liquid phase per hour at 0.21 atm O₂ (i.e., air), see Equations (1) and (2). ^(c) A polymerized catalyst (see Scheme 15) was used in a continuous-flow reactor. ^(d) The aqueous reaction mixture was continuously pumped through a reaction tube containing the catalyst (∅ = 10 mm) and fed back to the stirred reaction mixture open to air. ^(e) Pd(OAc)₂ (1 mol%) was added. ^(f) Carboxylic acid was transformed in situ into organotin (IV) carboxylates with nBu₃SnCl. Quantitative yield was assumed for this reaction.

Table 1. Comparison of experimental conditions for the oxidation of benzaldehyde using NHC catalysts and calculated productivity.

Entry	Conc. (mol/L)	Precur. Salt (a)	Base	Oxidant	Solvent(s)	Temp. (°C)	Time (h)	Yield (%)	Prod. (b) (mM L−1 h−1)	Ref.
1	0.34	5 mol%	BDU (2 eq.)	air	DMF/H2O	r. t.	24	10 (b)	1.43	[6]
2	0.10	5 mol%	K2CO3 (2 eq.)	air	DMSO/1 eq. H2O	60 °C	40	57	1.43	[7]
3	0.20	20 mol%	DBU (0.4 eq.)	air	CH3CN	80 °C	14	65	9.29	[36]
4	0.20	5 mol%	K2CO3 (80 eq.)	air	DMSO/1 eq. H2O	60 °C	36	91	5.06	[46]
5	0.25	2.5 mol%	TBD (1.2 eq.)	air	CH3CN	r. t.	24	92	115.00	[38]
6	0.40	15 mol%	DBU (7.3 eq.)	air	THF/H2O (10/1)	r. t.	24	95	15.83	[47]
7	1.00	2 mol%	DBU (1.1 eq.)	O2	CH3CN /2 eq. H2O	r. t.	4	97	48.50	[48]
8	0.17	5 mol%	DABCO (10 eq.)	O2	THF	r. t.	16	92	1.92	[49]
9	0.17	5 mol%	DABCO (10 eq.)	air	THF	r. t.	16	76	7.92	[49]
10	1.00	0.2 mol% (c)	K2CO3 (0.25 eq.)	air	H2O	80 °C	12 (d)	96	80.00	[51]
11	0.33	1 mol%	K3PO4 (4 eq.)	air (e)	H2O	80 °C	24	92	12.78	[53]
12	1.00	10 mol%	DBU (1.2 eq.)	O2	THF	25 °C	16	40 (f)	5.00	[54]

^(a) The structure of the precursor salt could be found in Scheme 7, Scheme 8, Scheme 9, Scheme 10, Scheme 11, Scheme 12, Scheme 13, Scheme 14 and Scheme 15. ^(b) Productivity was calculated as mM aldehyde converted per volume of liquid phase per hour at 0.21 atm O₂ (i.e., air), see Equations (1) and (2). ^(c) A polymerized catalyst (see Scheme 15) was used in a continuous-flow reactor. ^(d) The aqueous reaction mixture was continuously pumped through a reaction tube containing the catalyst (∅ = 10 mm) and fed back to the stirred reaction mixture open to air. ^(e) Pd(OAc)₂ (1 mol%) was added. ^(f) Carboxylic acid was transformed in situ into organotin (IV) carboxylates with nBu₃SnCl. Quantitative yield was assumed for this reaction.

Table 2. Comparison of experimental conditions for the aerobic oxidation of benzaldehyde using metal-free, light-induced transformation, and base metal catalysts.

Entry	Conc. (mol/L)	Catalyst	Activation Additive	Oxidant	Solvent	Temp.	Time (h)	Yield (%)	Prod. (a) (mM L−1 h−1)	Ref.
1	0.33	∅	∅	air	H2O	r.t.	12 h	83%	23.05	[55]
2	0.33	∅	∅	O2	H2O	r.t.	2 h	81%	27.67	[55]
3	0.05	∅	∅	O2	H2O	37 °C	24 h	90%	0.07	[56]
4	0.01	∅	∅	O2	H2O	37 °C	24 h	99%	0.02	[56]
5	0.025	∅	365 nm LED	O2	H2O	r.t.	30 h	86%	0.14	[57]
6	0.2	CF3SO2Na 25 mol%	400 nm LED	O2	CH3CN	r.t.	12 h	95%	3.17	[58]
7	0.3	∅	370 nm LED	air	Acetone/10%H2O	r.t.	7 h	87%	37.66	[59]
8	0.75	FeIIIMo6 0.1 mol%	Na2CO3 0.1 eq.	O2	H2O	70 °C	8 h	96%	18.00	[60]
9	0.1	[Cu(acac)2]SIMes 10 mol%	NaOH 1 eq.	O2	H2O	50 °C	12 h	99%	1.65	[61]

^(a) Productivity was calculated as mM aldehyde converted per volume of liquid phase per hour at 0.21 atm O₂ (i.e., air), see Equations (1) and (2). The symbol ∅ indicates that no catalyst, activation method, or additive is used.

Table 2. Comparison of experimental conditions for the aerobic oxidation of benzaldehyde using metal-free, light-induced transformation, and base metal catalysts.

Entry	Conc. (mol/L)	Catalyst	Activation Additive	Oxidant	Solvent	Temp.	Time (h)	Yield (%)	Prod. (a) (mM L−1 h−1)	Ref.
1	0.33	∅	∅	air	H2O	r.t.	12 h	83%	23.05	[55]
2	0.33	∅	∅	O2	H2O	r.t.	2 h	81%	27.67	[55]
3	0.05	∅	∅	O2	H2O	37 °C	24 h	90%	0.07	[56]
4	0.01	∅	∅	O2	H2O	37 °C	24 h	99%	0.02	[56]
5	0.025	∅	365 nm LED	O2	H2O	r.t.	30 h	86%	0.14	[57]
6	0.2	CF3SO2Na 25 mol%	400 nm LED	O2	CH3CN	r.t.	12 h	95%	3.17	[58]
7	0.3	∅	370 nm LED	air	Acetone/10%H2O	r.t.	7 h	87%	37.66	[59]
8	0.75	FeIIIMo6 0.1 mol%	Na2CO3 0.1 eq.	O2	H2O	70 °C	8 h	96%	18.00	[60]
9	0.1	[Cu(acac)2]SIMes 10 mol%	NaOH 1 eq.	O2	H2O	50 °C	12 h	99%	1.65	[61]

^(a) Productivity was calculated as mM aldehyde converted per volume of liquid phase per hour at 0.21 atm O₂ (i.e., air), see Equations (1) and (2). The symbol ∅ indicates that no catalyst, activation method, or additive is used.

4. Other Metal-Free Aerobic Oxidation of Aromatic Aldehydes into Carboxylic Acids

More than 195 years ago, it was recognized that benzaldehyde is prone to aerobic oxidation, yielding benzoic acid (autoxidation) [62,63]. Since then, numerous procedures have been described [64], and we have recently discussed the mechanism of this oxidation [65]. Table 2 lists recent publications for the metal-free aerobic oxidation of benzaldehyde. Additional publications were added, i.e., light-induced transformation and base metal catalysts.

Among these catalyst- and activation-free methods, the work of A. Vigalok et al. [55] is a landmark publication in the field of autoxidation of benzaldehyde. They rediscovered that by simply mixing benzaldehyde with water in the presence of air or O₂, high yields of benzoic acid could be obtained (Table 2, entries 1 and 2). It should be noted that by using the correction for the partial pressure of O₂, similar productivity can be obtained for the same reaction performed with O₂ or air (Table 2, entries 1 and 2), i.e., ∼ approximately 20 mM L⁻¹ h⁻¹. However, a total conversion could not be obtained under those conditions, despite using O₂. This can be attributed to the poor aqueous solubility of benzoic acid (i.e., 0.03 M) [66]. For high benzaldehyde conversion, crystals of benzoic acid are expected under those conditions. Benzaldehyde could form a host−guest complex in these crystals or form a complex with benzoic acid, protecting it from oxidation [67]. It was later demonstrated that total conversion could be obtained using a diluted solution (Table 2, entries 3 and 4) [56], but under these conditions, productivity drops down to 0.1 mM L⁻¹ h⁻¹. To achieve total conversion in water for higher concentrations, a base is necessary to form benzoate, which has a solubility of up to 4 M in water (Table 2, entry 8).

The photochemical aerobic catalyst-free oxidation of benzaldehyde to benzoic acid has been studied. Using water as a solvent, very low productivities were obtained (Table 2, entries 5 and 6), despite the use of a photosensitizer [58]. Using acetone/water as a solvent, G. Kokotos et al. [59] obtained an impressive productivity of up to 35 mM L⁻¹ h⁻¹ (Table 2, entry 7). A detailed mechanism study suggests a solvent-assisted oxidative transformation.

The use of base metal catalysts (Table 2, entries 8 and 9) did not show any improvement in productivity, despite the use of oxygen and temperature. High conversions were obtained through the use of base (Table 2, entry 8).

5. Conclusions

The aerobic oxidation of benzaldehyde into benzoic acid is a spontaneous process (autoxidation). Under these conditions, the formation of benzoic acid in the presence of oxygen (or air) does not indicate a catalytic activity, especially for reaction times up to 12 h. To compare different catalytic systems, we propose using productivity, which is defined by the amount of benzaldehyde converted per volume of liquid phase per hour at 0.21 atm of O₂ (i.e., atmospheric oxygen) [52]. The results obtained by A. Vigalok et al. [55], achieved by simply stirring benzaldehyde in water in the presence of air, can serve as a reference. For productivity below 20 mM L⁻¹ h⁻¹ (Table 2, entries 1 and 2), the impact of the catalytic systems on the oxidation of benzaldehyde may be questioned.

According to data from the literature, catalytic systems using NHCs demonstrate particularly interesting activities [38,48,51], which justify their significance (Table 1, entries 5, 7, and 10). However, many other catalytic systems exhibit low productivity, which fails to distinguish them from the natural autoxidation process. These conclusions also extend to other catalytic systems where only two catalytic systems show similar [60] or better productivity [59] than A. Vigalok et al. [55] (Table 2, entries 2, 7, and 8).

In addition to the well-established NHCs catalysis, the aerobic oxidation of aromatic aldehydes into carboxylic acids using NHCs expands the capabilities and applications of organocatalysis. Despite these exciting advances, several challenges still warrant special attention. (1) The structure of the NHC precursor needs justification. In this review, the structure of the NHC precursor has been simplified because, in the literature, structure–performance relationships have never been studied or the structure of the NHC precursor was never justified from previous studies. (2) The amounts of NHCs precursor and base need optimization. In particular, the number of base equivalents should be optimized to minimize the formation of by-products. The nature of the base (whether organic or inorganic) should also be rationalized. (3) The choice of solvent is equally important. Biobased polar solvents, solvent mixtures, and water-miscible solvents should be explored.

I hope that this critical review will attract more attention to NHCs’ catalysis applied to the aerobic oxidation of benzaldehyde and lay the groundwork for the further development of efficient catalysts for this important transformation.