1. Introduction
Toluene oxidation is currently one of the most important industrial processes: through oxidation, such simple aromatic hydrocarbon can be converted in high added value products, namely benzyl alcohol, benzaldehyde, benzoic acid, and benzoates. The importance of such process resides in toluene oxidation products that are essential molecules, playing a central role in our everyday life. In fact, they are widely used in the manufacture of perfumes, dyes, plasticizers, flame-retardants, preservatives, pesticides, as well as pharmaceuticals [
1]. Among the others, benzaldehyde is the most diffused one [
2,
3], being extensively applied also in food and fragrance industries, as an additive for aroma compositions (due to its bitter almond scent) and as starting material for aliphatic fragrances [
4].
Benzaldehyde is a natural product, so it can be easily obtained by extraction or distillation from different botanical sources, like almond, and peach and apricot kernel. However, natural sources are not sufficient to satisfy the market demand, therefore, it is necessary to synthetize benzaldehyde on a large scale, so that its production can exceed 90,000 tons per year globally [
5]. Accordingly, in 1887 Étard proposed the first synthetic route to produce benzaldehyde [
6]. Thanks to the peculiar high yield and selectivity, such process has been normally used over the years. However, it must be pointed out that Étard reaction occurred in the presence of highly toxic reagents (i.e., CrO
2Cl
2) and solvents (CCl
4, CS
2, or CHCl
3). Hence, through the years, that process has been entirely replaced. Nowadays the industrial methodology to produce benzaldehyde involves liquid-phase chlorination of toluene, followed by hydrolysis in the presence of a base [
7]. Nevertheless, harsh working conditions (i.e., the use of halogens at high temperature) and hazardous and corrosive by-products make this process ‘environmental unfriendly’. Furthermore, the presence of chlorine contaminants in the product excludes benzaldehyde use in food industry. Also, vapor-phase oxidation has been considered, but it generally produces a large amount of CO
2 (as over oxidation product) and several by-products, because of the requested high temperature and high pressure. For these reasons, research of new, sustainable, selective, and industrially attractive synthetic pathways for benzaldehyde production is required.
It is important to highlight that selective synthesis of benzaldehyde is a very challenging task, because of its much easier oxidation aptitude in aerobic conditions with respect to that of toluene [
8]. Nevertheless, great efforts have been made to develop suitable catalytic systems for the selective toluene oxidation to benzaldehyde, with a special attention to the sustainability aspect. As an example, homogenous catalysts in combination with ionic liquids [
9] or deep eutectic solvents (DES) [
10] as reaction media, heterogeneous catalytic systems [
11,
12,
13,
14], photocatalytic aerobic oxidation [
15,
16] and electrooxidation in ionic liquids [
17] have been reported. Although the majority of these synthetic pathways show good selectivity, efficient catalyst recycling, and safe reaction conditions, the conversion rate is not enough yet to allow an industrial application [
9,
15,
16]. Among homogenous catalytic systems, transition metal complexes [
18,
19,
20,
21,
22,
23], and metal/bromide catalysts [
24] have been extensively investigated. Unfortunately, the main issues are still the low conversion rate and the lack of selectivity. Indeed, in many cases, conversion rate increase is accomplished with a decrease in selectivity towards benzaldehyde, due to the formation of benzoic acid and benzyl alcohol. Furthermore, although reaction conditions are defined essentially green by authors, often catalysts synthesis requires multi-step reactions or involves hazardous reagents and solvents, that sensibly raise-up the environmental impact of the whole process [
25].
A real breakthrough in benzaldehyde synthesis from toluene was proposed by Pappo’s group [
26]. Specifically, toluene oxidation was proposed in the presence of Co(OAc)
2 (2 mol%) and
N-hydroxyphthalimide (NHPI) (10 mol%) in aerobic condition (O
2 1 atm), using hexafluoropropan-2-ol (HFIP) as solvent. 91% of toluene conversion and 90% of selectivity to benzaldehyde were achieved, and authors highlighted the key role of the solvent in preventing over oxidation to benzoic acid. Despite the outstanding results achieved by Pappo’s group, an industrial application is still not acceptable.
Quite recently, we have been involved in the study of the oxidative bromination of toluene, using NH
4VO
3 as the catalyst [
27]. Next to bromination products at the benzylic position, we found that, changing parameters, also benzaldehyde formation could be observed. Such interesting result prompted us to investigate more in detail this uncommon reaction. Therefore, herein, vanadium catalysed toluene oxidation is proposed.
Vanadium is the 20th most abundant element on earth, and it is a relatively non-toxic metal: not surprisingly, it is the ‘natural choice’ for homogeneous oxygenation/oxidation biocatalytic processes [
28,
29]. Therefore, its use in combination with environmental friendly oxidants, as hydrogen peroxide or molecular oxygen, constitutes a sustainable strategy to perform oxidation reactions. For this reason, Vanadium-based catalysts have been successfully used in oxidation and oxidative bromination of different substrates, with very good results in yield and selectivity [
30,
31,
32,
33,
34,
35,
36]. As well, toluene oxidative bromination was efficiently performed with the Conte’s method using a two-phase system (H
2O, pH=1 / CH
2Cl
2) containing a cheap and safe V-salt (i.e., NH
4VO
3), H
2O
2 and KBr. The most relevant feature of such approach is that the reaction occurred in a biphasic system, where water was the medium to dissolve all the reagents, and chloroform or dichloromethane were needed as co-solvent to dissolve the substrate.
In this work, toluene oxidation is presented, exploiting the same experimental conditions, but avoiding the use of chlorinated solvents, with the aim to raise-up the sustainability of the process. Hence, toluene is used as substrate and co-solvent at the same time. Additionally, KF is adopted as inorganic salt to replace KBr, in order to avoid formation of brominated products (
Scheme 1). As a matter of fact, the use of such a green system may constitute an appealing approach to selectively achieve toluene oxidation.
2. Results and Discussion
Toluene oxidation reaction was initially explored by varying NH4VO3 and H2O2 amounts, inorganic salt nature and quantity, and temperature. As well, it was performed either under O2 or N2 atmosphere. Importantly, in such conditions, toluene oxidation occurs at the interphase between the aqueous media and the organic solvent, hence a powerful stirring (≥1000-rpm) in a large flask is required.
Product analysis was carried out after the complete H
2O
2 consumption (usually 4 or 24 h, as checked with the iodide starch paper test). Interestingly, in all experiments, chemospecific formation of benzaldehyde was detected by GC-MS analysis. In fact, no over-oxidation products were found. It is important to underline that, being toluene used in large excess, yields have been calculated with respect to H
2O
2, i.e., the limiting reagent in the mixture. Results are summarized in
Table 1.
Toluene oxidation performed with 10% of NH4VO3 with respect to H2O2 selectively led to the formation of benzaldehyde, but yields were not satisfactory (entries 1,2). Raising-up the amount of the vanadium salt to 50% (entries 3,4) increased significantly benzaldehyde yield. Because of the concomitant vanadium catalysed H2O2 decomposition, stepwise addition of the oxidant was performed not achieving better performances. Conversely, working with equimolar amount of NH4VO3 and H2O2 led to a drastic drop of the yield (entry 5). Likely, in these conditions, hydrogen peroxide degradation was faster than toluene oxidation. So reagents concentration in solution was decreased: 15% of benzaldehyde after only 4 h was detected working with 0.05 mmol of both H2O2 and NH4VO3. Furthermore, the reaction with 50% of vanadium with respect to H2O2 showed a decrease of the yield (entry 7). To establish the role of the inorganic salt, a blank experiment in the absence of KF was performed but neither benzaldehyde nor other products were detected (entry 8).
Despite the promising yield accomplished using toluene as solvent and substrate (15%,
Table 1 entry 6), its conversion was still too low to be considered acceptable in a sustainable modern process. Therefore, inspired by previous results with similar systems [
37], the reaction was performed adding a stoichiometric amount of the substrate with respect to H
2O
2, in water (
Table 2).
Yet, performing reactions with a stoichiometric amount of toluene in a large flask, with a condenser on the top, caused substrate loss: at the end of the reaction, only 1% of benzaldehyde was detected in the mixture, while toluene almost completely disappeared (entries 1–3). Hence, reaction was repeated in a closed vessel achieving 12% of benzaldehyde after 48 h (entry 4). Although yield was encouraging, result was not acceptable yet. Therefore, a classical two-phase system was exploited [
30]: toluene was dissolved in CH
2Cl
2 (entry 5) or cyclohexane (entry 6), a more sustainable alternative to the chlorinated solvent. In both cases, no reaction was observed. Inspired by the excellent results achieved in previous studies [
32,
38,
39], a hydrophobic ionic liquid (i.e., [pmim]Tf
2N 1-propyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) was adopted as co-solvent. In fact, in the last years ionic liquids became a valid alternative to the conventional molecular solvents, due to their unique properties such as non-volatility, high thermal stability and reusability [
40]. 0.5 mmol of toluene were dissolved in 1 mL of [pmim]Tf
2N; 10 mL of an aqueous solution containing NH
4VO
3 were then added, with H
2O
2 and KF. After 24 h, 24% of benzaldehyde was detected in the mixture, together with traces of the benzyl alcohol.
The best compromise, hitherto, in terms of yield and selectivity remains the one achieved using toluene as substrate-solvent, where 15% yield of benzaldehyde was obtained after only 4 h (
Table 1, entry 6). Therefore, such conditions have been adopted to investigate the process by changing inorganic salt, atmosphere composition and temperature.
Importantly, the blank experiment without KF (
Table 1, entry 8) showed that such inorganic salt is pivotal to obtain benzaldehyde. To confirm such evidence, other different inorganic salts were screened, with the aim to increase yield and to understand the salt role in the reaction mechanism. However, KF remained the best choice, since no improvement was observed varying the nature of cation or anion (
Table 3).
Notably, with KBr, a slight increase of benzaldehyde yield was observed, probably because of the presence of Br
− ions in solution, which hamper the radical degradation of H
2O
2 usually occurring in the presence of vanadium (entry 8) [
41,
42]. Such effect results in an increasing amount of H
2O
2 available for toluene oxidation. However, with KBr, also bromination products were obtained in good yields [
27]. Therefore, KF is the best compromise between yield and selectivity.
KF concentration in the reaction mixture was then varied (
Table 4).
Results showed that an equimolar amount of NH4VO3 and KF was necessary to attractively form benzaldehyde. In particular, working with 0.025 mmol of both (entry 3), 19% yield of benzaldehyde was obtained after 24 h.
In an attempt to further improve yield and to understand reaction mechanism, toluene oxidation was carried out also under O
2 or N
2 atmosphere (
Table 5).
Interestingly, under O
2 atmosphere, a significant increase of the yield was observed. Indeed, up to 33% of benzaldehyde was obtained (entry 1). To note, working in the absence of KF, but using 0.05 mmol of both NH
4VO
3 and H
2O
2 in the presence of dioxygen led to a remarkable yield (40%, entry 2). If 50% of NH
4VO
3 was used with respect to H
2O
2, 30% of benzaldehyde was obtained (entry 3). Conversely, reactions performed with 20% of NH
4VO
3 with respect to the oxidant (entry 4) or in the absence of H
2O
2 (entry 5) were not successful. Under N
2 atmosphere, using the standard conditions reported in
Table 1, entry 6, a decrease in benzaldehyde conversion was observed, obtaining 12% of benzaldehyde.
Thus likely, in this process, hydrogen peroxide is the actual oxidant, being involved in the formation of the vanadium(V)-peroxido complex [
43], while O
2 and KF have a promoting effect in the oxidation of toluene.
Attempting to increase benzaldehyde yield, temperature and reaction time were changed (
Figure 1,
Table S1).
Working with an equimolar amount of H2O2 and NH4VO3, in the presence of KF led to 22% yield after 72 h at 25 °C. Increasing the temperature to 40 °C, produced a 28% yield in 72 h, while at 60 °C the same amount of benzaldehyde was obtained after only 24 h. Consequently, in order to increase the catalyticity, reactions were carried out at 60 °C, decreasing the amount of the V(V)-salt.
To note, an appreciable yield of 28% was obtained using 20% of NH
4VO
3 under dioxygen at 60 °C (
Table 6, entry 3). The same result was attained in the presence of KF (
Table 6, entry 4). To recap, the best performances were obtained with 50% NH
4VO
3 at 25 °C (
Table 5, entry 3), or 20% NH
4VO
3 at 60 °C (
Table 6, entry 3) both under O
2 atmosphere.
It is important to stress out that, after 24 h, H
2O
2 and HClO
4 total consumption is usually observed. Therefore, the possibility to recharge H
2O
2 and HClO
4, thus restoring the V(V)-monoperoxido complex in solution was explored, taking advantage from the two-phase system (water/toluene). The recyclability assays were carried out using the optimized reaction conditions reported (
Table 5, entry 3 and
Table 6, entry 3). Four additions have been performed every 24 h; at each round, benzaldehyde quantification has been carried out. Regarding the system at 25 °C (
Figure 2,
Table S2) a significant increase in benzaldehyde formation was observed after the second addition, i.e., round 2.
Indeed, up to 25 × 10
−3 mmol of benzaldehyde were obtained, with a round yield of 30% and an overall yield of 25%. The third and fourth additions did not cause an appreciable improvement in benzaldehyde production. In fact, throughout third and fourth round, a plateau was reached, and consequently a decrease of the overall yield was observed. On the other hand, the reaction performed with 20% of NH
4VO
3 at 60 °C continuously produced benzaldehyde after each oxidant addition. (
Figure 3,
Table S3)
Remarkably, at the end of the fourth round, 74 × 10−3 mmol of benzaldehyde were detected in solution, with a constant round yield and an overall yield of 37%. Such an exciting result opens the possibility to continuously add H2O2 to the solution, likely fully converting toluene.
From a mechanistic point of view, in the adopted experimental conditions, the V- catalysed toluene oxidation likely occurs through a radical pathway. Therefore, a plausible catalytic cycle has been proposed (
Figure 4).
In fact, it is already well established that the dissolution of NH
4VO
3 in acid water (pH = 1) containing H
2O
2 leads to the formation of a vanadium (V) peroxido-complex (
1), which is a very effective oxidant [
34,
43,
44]. In the first step of the cycle, the homolytic cleavage of the O–O bond possibly occurs, forming the radical V-complex (
2), that can abstract a H
• from toluene in solution, thus forming vanadium complex (
3) and benzyl radical. The latter can react in two different pathways: with complex (
3) itself, to form V-complex (
4) in a non-productive way, or it can react with O
2 in solution, to obtain the benzyl peroxy radical. The coupling of two benzyl peroxy radicals forms benzaldehyde, benzyl alcohol and O
2 through a well-established mechanism [
45]. The formed by-product, namely benzyl alcohol, is then immediately oxidized to benzaldehyde through a similar radical pathway, passing through H-abstraction from the OH group.
As a matter of fact, due to the higher reactivity of benzyl alcohol with respect to toluene, it has never been detected as by-product, since it is readily converted to benzaldehyde. As a verification, benzyl alcohol oxidation in the optimised experimental conditions (H2O2 = 0.05 mmol; NH4VO3 = 0.01 mmol; T = 60 °C; O2) selectively produces benzaldehyde.
Notably, in the presence of KF, fluoride coordination to vanadium likely occurs, leading to V-fluorooxoperoxido complex [
46,
47]. UV–vis absorption spectrum of V-monoperoxido complex in aqueous solution shows appreciable variations in the presence of KF, possibly supporting fluoride coordination to vanadium (
Figure S1). However, due to the reported instability, such V-species have not been isolated and further characterized, therefore, no experimental verification about their structure in solution have been obtained. For this reason, such complexes have not been included in further mechanistic studies.
To better explicate the mechanism, DFT calculations have been carried out, using Gaussian 16 rev. A.03. Geometry optimization of reagents, intermediates and transition states (TS) has been performed in vacuum using B3LYP functional. 6-31G(d) basis set was used for H, C, and O atoms, while LanL2DZ basis set was adopted for vanadium [
48]. The relative energy diagram vs. reaction coordinate is represented in
Figure 5.
In the adopted experimental conditions, tetrahedral V-monoperoxido complex (
1) is the catalytically active species in solution. Importantly, the positively charged complex (
1) has been modelled with one water molecule coordinated to the V-center, being this species the most abundant one experimentally observed [
43]. V=O, V–O and O–O distances have been calculated and they resulted in line with previously published data (calculated distances = 1.56 Å, 1.77 Å and 1.42 Å, respectively) [
49]. Calculations clearly indicate that the first step is the rate determining one, since the activation energy to form complex (
2) is 46.4 kcal∙mol
−1 (
Figure 5). In fact, in the first step, the homolytic cleavage of O–O bond occurs, leading to the vanadium diradical species (
2) (calculated O–O distance = 2.89 Å), 14.4 kcal∙mol
−1 higher in energy than (
1). At this stage, H-abstraction from toluene is predictable, to form benzyl radical and tetrahedral V-radical complex (
3), thus gaining a significant stabilization of the system (relative energy = −95.5 kcal∙mol
−1). Here, the activation energy barrier resulted about 5.3 kcal∙mol
−1.
Afterwards, two different routes have been hypothesized: (i) benzyl radical and V-radical complex (3) coupling, leading to V-complex (4); (ii) reaction between benzyl radical and molecular dioxygen in solution, to form benzyl peroxy radical.
In this context, DFT calculations have been carried out to predict the energetically favoured pathway. However, a direct comparison between the two possible routes is not appropriate, since very different species are involved.
Nevertheless, experimental data underline the key role of O2 for the successful outcome of the reaction: experiments performed under N2 atmosphere led to a remarkable yield drop-off, while under O2 a sensible improvement of benzaldehyde yield was detected.
As a matter of fact, DFT calculations revealed that benzyl radical reaction with dioxygen is energetically favored, being the activation energy barrier of about 0.6 kcal∙mol
−1 (
Figure 6). Consequently, benzyl peroxy radical formation is highly probable. Moreover, it can be speculated that reactions performed under O
2 atmosphere are even more favored because of statistic reasons.
Conversely, coupling between benzyl radical and V-complex (3) appears energetically disfavoured and it would lead to complex (4), which cannot produce benzaldehyde.
To conclude, reaction of benzyl radical with O
2 is pivotal in the process and it readily occurs in solution. Indeed, coupling between two benzyl peroxy radicals leads to a very unstable species that immediately disproportionates forming benzaldehyde, O
2, and benzyl alcohol [
45]. The latter, being more reactive than toluene, is easily converted to the aldehyde, as experimentally demonstrated.