Efficient benzoins-to-benzils oxidation under air with reduced iron powder additive

1. Introduction

Benzils are essential scaffolds in the organic chemical and pharmaceutical industries. A number of synthetic approaches to benzils using various starting materials such as benzoins, tolanes, diarylalkenes, and 1,3-diketones have been developed and are well reviewed [1].

Considering the low cost of benzoins or their convenient synthesis via benzoin condensation, oxidation of benzoins to benzils using various oxidants has emerged as a major research approach. Among these methods, the use of air as an oxidant has attracted significant attention due to its alignment with sustainable development principles (Scheme 1) [2-11].

Close

Scheme 1. Air oxidation of benzoins to benzils [2-11].

Export to PPT

Nevertheless, there remain certain limitations in these studies that warrant further investigation and optimization. First, the catalyst or additive required is not readily available and must be additional synthesized under cumbersome and harsh conditions. Second, highly reactive reagents like sodium hydride (NaH) or trichlorooxovanadium (VOCl₃) react vigorously with water, releasing flammable hydrogen or environmentally hazardous hydrogen chloride [12,13]. Thus, handling requires strict moisture exclusion, which often limits solvent choice. Nevertheless, the risks of inappropriate solvent selection can be overlooked—for instance, combining NaH with polar aprotic solvents may cause unexpected heat and gas evolution, potentially resulting in runaway reactions or explosions [14]. In other hand, the reaction typically requires high temperatures and/or extended reaction times to proceed to completion. Although several studies have suggested that substituting air with pure oxygen can significantly reduce reaction times [15-17], the use of pure oxygen is associated with increased operational costs. Furthermore, the combination of organic solvents with oxygen gas poses a significant safety risk, as it may lead to the formation of a flammable atmosphere [18].

Table 1 [2-7,11-13], [19]. evaluates the various air oxidation methods for benzoin outlined in Scheme 1. The performance of these literature methods has limitations when considering critical factors such as reaction time, solvent, temperature, catalyst/additive availability, and yield.

Therefore, the development of air oxidation methods for benzoins under mild reaction conditions offers significant advantages in terms of cost-effectiveness, safety, and process efficiency.

In 1970, Chen demonstrated an experiment of the autoxidation of benzoin under air in a basic medium [20]. This demonstrative experiment has attracted our interest. Under alkaline conditions, benzoin transforms into a hydrogen radical and purple-structured benzoin radical anion, which is subsequently oxidized by air to produce yellow benzil and a superoxide radical anion [21]. Under alkaline conditions, the hydrogen radical and superoxide radical anion generated from the oxidation reaction rapidly combine to form hydrogen peroxide anions (Scheme 2). Unfortunately, the original references fail to offer detailed information regarding the yield of benzil.

Close

Scheme 2. The mechanism of Chen’s aerobic oxidation of benzoin. (a) Benzoin is oxidized to benzil via a free radical mechanism. (b) The oxidation to benzil is accompanied by the formation of the by-product HOO⁻ [20,21].

Export to PPT

Upon re-examination of the reported protocol in the laboratory, it was observed that the reaction mixture changed from purple to yellow, as expected. However, the color intensity was significantly lighter than anticipated based on the theoretical product concentration [22]. Subsequent analytical investigations confirmed that the primary product was a colorless solid, identified as potassium benzoate with a yield of 62% [23], while the anticipated oxidation product, benzil, was obtained in a significantly lower yield of 5%.

Fortunately, the mechanism proposed by Han, Yang, et al. can effectively explain the observed lighter color and extremely low benzil yield in the demonstration experiment (Scheme 3) [24]. Initially, benzoin was oxidized to benzil; however, the oxidation of benzoin also resulted in the formation of a byproduct hydroperoxide anion (HOO⁻), which subsequently nucleophilic attacked benzil, leading to the over-oxidation of benzil to benzoic acid.

Close

Scheme 3. Proposed mechanism underlying benzil over-oxidation leading to benzoic acid formation [24].

Export to PPT

We propose that a decrease in the concentration of HOO⁻ may improve the yield of benzil, thereby enabling the efficient synthesis of benzil and its derivatives using air as the oxidant at room temperature.

Herein, we report a simple, convenient procedure for the synthesis of benzils from their corresponding benzoins at room temperature with air as the oxidizing reagent. Reduced iron powder is used as an additive to prevent the over-oxidation of benzils to benzoic acid.

2. Materials and Methods

3. Results and Discussion

To optimize the yield of benzil, slight modifications were introduced to the demonstration experiment [20]. Key results are presented in Table 2. Under the original experimental conditions, benzoin oxidation proceeded as expected, but the main product obtained was potassium benzoate, with a low yield of benzil (entry 1). In addition, the solvent and base consumption is extremely high in the original protocol: 53 mL of methanol and 18.9 mmol of potassium hydroxide (1,060 mg) for 2 mmol of benzoin (424 mg) (entry 1). To resolve these limitations, modifications were implemented. Methanol was replaced by 75% (v/v) ethanol in water as the solvent, significantly reducing solvent consumption and ensuring safety and sustainability. While 25% and 50% (v/v) aqueous ethanol also afforded full conversion, the reaction times were prohibitively long, presumably due to the poor solubility of benzoin at these concentrations. In contrast, the 75% ethanol/water mixture was chosen to ensure both a short reaction time and the sufficiently fast dissolution of sodium hydroxide. Next, an inorganic base and its usage amounts were screened. Employing 0.5 equivalent (1 mmol) of NaOH under the same conditions resulted in an incomplete reaction, with benzoin remaining detectable by TLC analysis after 36 hrs. Increasing the amount of NaOH beyond 1.0 equivalent enabled the reaction to complete within 2 h (entries 2-4). Although potassium hydroxide (KOH) afforded a faster reaction rate than NaOH, it resulted in a slightly lower yield (entry 5). In contrast, the weakly basic carbonates (K₂CO₃ and Na₂CO₃) failed to initiate the reaction, and no desired product, benzil, was observed (entries 6 and 7). The optimal reaction conditions include 2 mmol of benzoin with 4 mmol of NaOH dissolved in 5 mL of 75% (v/v) ethanol in water as the solvent, resulting in a 29% benzil yield (entry 4).

Table 2. Optimization of solvents and bases for benzil synthesis reaction.^a

Entries	Solvent	Base (mmol)	Time (h)	Yield (%)
1	Methanol (53.0 mL)	KOH (18.9 mmol)	0.5	5
2	Ethanol, 75% (5.0 mL)	NaOH (2.5 mmol)	1.8	21
3	Ethanol, 75% (5.0 mL)	KOH (2.5 mmol)	1.0	20
4	Ethanol, 75% (5.0 mL)	NaOH (4.0 mmol)	1.0	29
5	Ethanol, 75% (5.0 mL)	KOH (4.0 mmol)	0.5	20
6	Ethanol, 75% (5.0 mL)	K2CO3 (4.0 mmol)	4	n.o.b
7	Ethanol, 75% (5.0 mL)	Na2CO3 (4.0 mmol)	4	n.o.b

^aAll reaction mixtures containing benzoin (2.0 mmol) were stirred at 25°C in an open flask^.

^b n.o. = not observed.

It is proposed that the low yield of benzil may be attributed to the presence of one of its oxidation byproducts, HOO⁻, which can subsequently react with benzil, leading to the formation of benzoic acid, as illustrated in Scheme 3 [24]. Based on this mechanism, it is suggested that the incorporation of an additive capable of reducing the concentration of HOO⁻ could potentially improve the yield of benzil. Therefore, a modified experimental procedure was designed and developed, incorporating such an additive with the aim of improving benzil production while simultaneously minimizing over-oxidation.

As expected, the addition of some metal reducing agents, such as zinc dust or reduced iron powder, could increase benzil yield. As an additive, potassium iodide (KI) also slightly increased benzil yield. As listed in Table 2, the optimized additive, reduced iron powder (2 equivalents, 100 mesh), can not only increase benzil yield but also shorten reaction time (Table 3, entry 2 vs Table 2, entry 4).

Table 3. Optimization of additives for benzil synthesis reaction.^a

Entries	Additive (mmol)	Time (h)	Yield (%)
1	Fe (3) 100 mesh	0.5	59
2	Fe (4) 100 mesh	0.5	77
3	Fe (4) 400 mesh	0.4	71
4	Fe (5)	0.3	61
5	Zn (4)	1.0	46
6	KI (4)	0.2	36

^aAll reactions were conducted at 25°C open to air, employing a mixture of benzoin (2.0 mmol), NaOH (4.0 mmol), and the appropriate additive suspended in 75% aqueous ethanol.

The detailed mechanism by which reduced iron powder plays a role in the reaction has been proposed. The oxidation of iron in an alkaline environment by air leads to the formation of both Fe²⁺ and Fe³⁺ ions [25-27]. Under strongly alkaline conditions, Fe³⁺ undergoes hydrolysis and polymerization reactions, resulting in a heterogeneous hydrolytic species with an oxide surface, which is denoted as ≡Fe^III–OH [28]. This hydrolytic species can capture the HOO⁻ radical generated during the oxidation of benzoin, forming a surface complex, [H₂O₂]_S⁻ (Equation 1). The surface complex [H₂O₂]_S⁻ then undergoes a reversible electron transfer to ≡Fe^III–OH, leading to the formation of ≡Fe^II and the superoxide radical anion (O2^•−) (Equation 2). Subsequently, ≡Fe^II is re-oxidized by atmospheric oxygen under alkaline conditions, regenerating ≡Fe^III–OH, while producing another superoxide radical anion (O₂^•−) (Equation 3). Finally, two O₂^•− radicals combine in the presence of water to form H₂O₂ and O₂, while releasing two molecules of OH⁻ (Equation 4) [25].

It should be noted that free radical reactions are generally complex in mechanism. The process described here represents the simplest pathway. In reality, other free radicals, such as hydroxyl radicals (HO^•) and O₂^•−, may also be involved in the generation and transformation processes. Most free radicals do not have sufficient time to diffuse into the solution [29]. In contrast, some benzoins can interact with these radicals on the surface and undergo oxidation, leading to a relatively short reaction time. Similarly, benzil may be further oxidized by these radicals, which could result in a slight decrease in yield. Subsequent studies on iron powders with different specific surface areas showed that under the same 2 equivalents condition, the yield was 71% when using 400-mesh powder (Table 3, entry 3). This yield decrease is likely because the larger surface area increases contact between the benzil and radicals on the iron, promoting excessive oxidation. Likewise, when the amount of 100-mesh iron powder was increased to 5 equivalents, the yield also decreased, presumably for the same reason (Table 3, entry 4).

Although zinc dust can perform a function similar to that of reduced iron powder, its high reducibility can lead to the re-reduction of the originally oxidized benzil back to benzoin. This results in an extended oxidation reaction time and increases the risk of over-oxidation of benzil, ultimately leading to a relatively low yield (Table 3, entry 5). The observed increase in yield upon the addition of KI may be attributed to the decomposition of hydrogen peroxide (H₂O₂) generated in Equation 4, which accelerates the scavenging of O₂^•− radical anion, thereby slightly enhancing the reaction yield (Table 3, entry 6).

To confirm that the oxidant is oxygen in the air, we conducted experiments with pure oxygen and nitrogen. Under pure oxygen conditions, the oxidation reaction rate increased; however, under nitrogen conditions, a large amount of benzoin was detected even after 4 h (the reaction time completed using air under identical conditions is 0.5 h). The results indicated that the main oxidant in the reaction is oxygen in the air.

We next examined the preparation of various benzils through air oxidation; the results are summarized in Table 4. In general, the enhancement of the electron-donating ability and the presence of steric hindrance of the substituent groups increase the yield of benzils. In particular, the electron-donating effect and steric hindrance reduce the reactivity of the oxidized products toward HOO⁻, the nucleophilic byproduct, minimizing the possibility of over-oxidation (Scheme 3). In contrast, the introduction of electron-withdrawing groups enhances the electrophilicity of the carbonyl groups in the oxidized products, increasing their ease of reaction with HOO⁻ and leading to over-oxidation. The most typical example of this result is compound 1b–1d, which has different positions of methoxy substitution on the benzene ring (Table 4, entries 2–4). The methoxy group at the ortho and para positions induces electron-donating properties, providing products at excellent yields of 99% (entry 4) and 91%, respectively (entry 2), higher than the benzoin yield (77%; entry 1). The methoxy group in the meta position in the ring possesses electron-withdrawing characteristics, which leads to a 67% yield (entry 3) less than the benzoin oxidation yield (entry 1). Table 4 lists similar findings. The methyl group in the ortho and para positions provides product yields of 90% (entry 7) and 92% (entry 5), respectively. However, when the methyl substituent is in the meta position, its impact on the benzil yield is minimal, with it being only 77% (entry 6) identical to that of unsubstituted benzoin (77%).

Table 4. Optimization of reactants for benzil synthesis reaction.^a

Entries	Reactant	Product	Time (min)	Yield (%)
1	C6H4	2a	31	77
2	p-CH3OC6H4	2b	35	91
3	m-CH3OC6H4	2c	35	67
4	o-CH3OC6H4	2d	47	99
5	p-CH3C6H4	2e	25	92
6	m-CH3C6H4	2f	23	77
7	o-CH3C6H4	2g	60	90
8	3-FC6H4	2h	60	18
9b	3-FC6H4	2h	25	53
10	4-FC6H4	2i	18	55
11	2-furanyl	2j	22	44
12c	2-furanyl	2j	25	16
13	2-thienyl	2k	25	84
14	o-CH3CH2OC6H4	2l	150	96
15	p-(CH3)3CC6H4	2m	73	89

^aUnless explicitly noted, the reactions were conducted in open air at 25°C with a mixture of substrate (2.0 mmol), NaOH (4.0 mmol) and iron powder (100 mesh, 4.0 mmol) in 75% aqueous ethanol. An exception was made for substrate 1m, where dimethyl sulfoxide (DMSO) was introduced as a cosolvent to facilitate dissolution.

^bThe reaction was carried out at -10°C.

^cThe reaction was conducted in the absence of iron powder.

As substituents, fluorine atoms have both inductive and mesomeric effects [30]. Because of the strong electronegativity of fluorine atoms, fluorinated derivatives mainly exhibit electron-withdrawing properties and, therefore, are prone to over-oxidation; this results in a decreased yield (entries 8 and 10). This is because the mesomeric effect prevails over the inductive effect in the para position, providing a relatively high yield. In addition, when an electron-withdrawing group is attached, the electron density of the carbonyls decreases, making accepting electrons easier and thus facilitating reduction reactions. Moreover, during the monitoring of the oxidation reaction of compound 1h, we observed a small amount of starting material that remained unreacted, which led to an extension of the reaction time. Consequently, this increases the likelihood of over-oxidation, significantly reducing the yield. Because of the inductive effect of the ring oxygen, furoin is also prone to over-oxidation, resulting in a relatively low yield (entry 11). The low yields observed with electron-withdrawing group-substituted substrates prompted an investigation into whether iron powder also suppresses over-oxidation. A comparative experiment using furoin confirmed that it likewise exerts a marked inhibitory effect, demonstrating that the product yield increased from 16% (entry 12) without iron powder to 44% with its addition.

In contrast to 1h, the prolonged reaction times for 1g (entry 7), 1l (entry 13), and 1m (entry 15) are due to the poor solubility of the compounds or oxidation products in the ethanol solutions. In particular, 1m requires the addition of 3 mL of dimethyl sulfoxide (DMSO) to ensure reaction completion. For instance, the reaction solution for 1g changes color quickly, indicating reaction completion at a relatively high overall oxidation reaction rate. However, when continuing to track the reaction process, yellow solids, potentially encapsulating a small amount of starting materials, precipitate in the reaction solution and thus extend the reaction time. Notably, extending the reaction time does not reduce the yields of 2g (entry 7), 2l (entry 14), and 2m (entry 15) significantly.

In addition to using room temperature and air oxidation, the oxidation product obtained via our methodology requires no additional purification to meet general application standards. This is because the byproducts are carboxylates, which are relatively soluble in aqueous solutions. Therefore, these byproducts can be readily removed through a simple water wash. According to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Elemental Impurities Q3D (R2), elemental impurities are classified into three categories based on their toxicity (permitted daily exposure, PDE) and the likelihood of their occurrence in drug products. Elements with low inherent toxicity and/or those subject to varying regional regulatory requirements, for which PDEs have not been established, are not included in the guideline and are categorized as “Other Elements.” Iron (Fe) falls under this category. Although iron is not considered a critical impurity according to the guideline, we still conducted an ICP-MS analysis to determine the residual iron content in the synthesized benzoin. The result was 41.1 μg/g, with the work-up process using tap water. When the extraction solvent was replaced with deionized water, no detectable iron residue was observed.

Considering that the substrates with electron-withdrawing groups exhibit relatively low yields, we adopted the approach proposed by Han, Yang, et al. and selected the compound with the lowest yield, 1,2-bis(3-fluorophenyl)-2-hydroxyethan-1-one (Table 4, entry 8), as a model to investigate the effect of low temperature on reaction yield [10]. It was found that at -10°C, the yield of 2h increased from 18% to 53% (Table 4, entry 9). It is worth noting that the reaction temperature has a significant impact on the initiation of the reaction. When the reaction temperature of 1a was decreased to -10°C, the reaction mixture did not immediately change color as observed under room temperature conditions, indicating that the reaction of 1a is difficult to initiate at low temperatures. Given the critical role of the radical anion formation in this oxidation, we observed a purple radical species for compound 1a in ethanol. Although elevated temperatures accelerate the reaction [22], we recommend maintaining 25°C for benzoins with electron-donating groups to avoid a potential benzilic acid rearrangement under the strongly basic conditions at higher temperatures. Furthermore, excessive elevation of the temperature reduces the solubility of air in the ethanol solution, thereby preventing the reaction from proceeding to completion. For electron-withdrawing group-substituted benzoins, a slightly lower temperature is advisable. Given that these radical anions are typically colored, preliminary screening based on the color development rate is recommended. Since the oxidation reaction was conducted in an open vessel, the stirring rate affects the contact between the reactants and air. A higher stirring rate facilitates the completion of the reaction.

An additional reason for the low yield of 2h can be attributed to the extended reaction time caused by the detection of extremely faint starting material spots during TLC monitoring (entry 8). Consequently, under low-temperature reaction conditions (entry 9), when TLC analysis revealed particularly faint starting material spots, the reaction was promptly terminated and subjected to a simple water wash followed by ethyl acetate extraction. Fortunately, after the extraction process, negligible amounts of starting material were observed in the ethyl acetate phase.

Although reduced iron powder is widely available and low-cost, in order to maximize its reuse, the iron powder was filtered and washed with water after the reaction. It was then air-dried and reused within the same reaction, with the yield of benzoin being observed. The iron powder can be reused four times. The yields for the first three reuses were slightly higher and the reaction times slightly shorter compared to using fresh reduced iron powder (Table 5). The observed shorter reaction times and the slightly higher yields may be attributed to the accumulation of iron ions, which facilitates the formation of active species such as ≡Fe^III–OH or ≡Fe^II during the oxidation process. This hypothesis is consistent with the appearance of the recovered iron powder. After air-drying, the powder showed visible rust, indicating significant oxidation had occurred. For the fourth reuse, the noticeable loses of the iron powder resulted in an extended reaction duration. Based on the above findings, we recommend weighing the recovered iron powder before each reaction to ensure that the amount used is consistent with that of 2 equivalents of fresh iron powder. This practice will help achieve reproducible results across multiple reaction cycles.

Based on the understanding of the reaction mechanism and the findings from the iron powder recycling experiments, we hypothesize that the additive iron reagent, in its zero-valent, two-valent, or three-valent forms, could improve the yield of the oxidation reaction by reducing over-oxidation. To validate this hypothesis, both Ferrous sulfate heptahydrate (FeSO₄·7H₂O) and ferric chloride (FeCl₃) were selected for testing, and both reagents produced satisfactory results (Table 6).

The mechanism underlying our approach—employing ferric chloride, ferrous sulfate, and iron powder is fundamentally different from established literature. While most documented iron-based methods oxidize benzoin via Fe³⁺ (e.g., using FeCl₃ in refluxing acetic acid) [31], and while Fe₃O₄ magnetic nanoparticles (MNPs) achieve aerobic oxidation only under prolonged heating [32], our system functions effectively at ambient temperature and pressure. The key distinction is that our iron species act as a hydroperoxide anion scavenger, thereby inhibiting undesired over-oxidation.

The data from four times iron powder recovery experiments also provide a significant indication that catalytic amounts of various valence state iron ions dissolved in the solution may suffice to meet the demand for preventing over-oxidation. Consequently, an important proof-of-concept experiment was designed and conducted.

A mixture of FeCl₃ in NaOH ethanol solution was stirred in air for 1 h. The mixture was then filtered to remove any insoluble substances, and the light-yellow filtrate was used directly in the benzoin air oxidation reaction. The results showed a significant improvement in yield (70%) compared to the ethanol solution (21%), thus validating our proposed catalytic additive scheme. Screenings of catalytic amounts of iron reagents have been conducted in our laboratory, and the results will be reported subsequently.

Despite avoiding tedious column chromatography, the work-up procedure for this transformation still relied heavily on ethyl acetate for extraction, generating substantial solvent waste, a critical issue for pharmaceutical scale-up. Optimization revealed that the reaction mixture turned homogeneous, and the by-product, sodium benzoate, exhibited high water solubility. Consequently, for a gram-scale synthesis, the work-up was modified as follows: the crude mixture was directly filtered, and water was added to the filtrate to precipitate the product. The resulting solid filter cake was rinsed with a minimal amount of ethyl acetate. The aqueous filtrate was concentrated to afford an additional portion of the product, which was combined with the solid obtained from the initial precipitation to deliver a comparable isolated yield (73%). This revised protocol reduced ethyl acetate consumption by 90%.

Finally, an attempt was made to broaden the substrate scope (Scheme 4), and it was demonstrated that 9-fluorenol could be efficiently oxidized under the established reaction conditions, affording the desired product in an excellent yield (94%). Surprisingly, the omission of iron powder did not affect the reaction, which reached completion in an identical timeframe with a comparable product yield. This demonstrates that 9-fluorenol is robust against over-oxidation, a common side reaction with benzoin. The specific reaction pathway is the subject of ongoing study.

Close

Scheme 4. Air oxidation of 9-fluorenol at room temperature.

Export to PPT

4. Conclusions

A novel method for the oxidation of benzoins to benzils has been developed, utilizing air as the oxidant. The reaction proceeds efficiently under ambient conditions, affording benzil products in high purity with moderate-to-high yields. This approach is especially suitable for acid-sensitive and thermally labile substrates. Furthermore, it offers new perspectives on the design of iron-based catalysts in multiple oxidation states, facilitating rapid oxidation of benzoins under mild conditions. Although this new protocol presents advantages such as low cost, readily available reagents, short reaction times, and straightforward work-up compared to conventional methods, several issues remain to be addressed: efficient trapping of hydroperoxide anions to suppress over-oxidation; effective interconversion between the captured species, ≡FeII and ≡FeIII–OH; reduction of solvent consumption during work-up; and improvement of reaction yields for benzoins bearing strong electron-withdrawing groups.