Visible Light-Induced Aerobic Amine Oxidation to Imine in Aqueous Salt Solutions: Saline and Sustainable

Abstract

The selective photooxidation of C–N bond in amines is a process of prime importance but remains challenging. Herein, we report the application of aqueous salt solutions as reaction media for the selective synthesis of imine from benzylamine. Oxidation of benzylamine as the representative amine using aqueous salt solutions as reaction media resulted in much higher conversion (~99%) as compared to that obtained in conventionally used solvents such as acetonitrile. Control experiments indicate that the reaction outcome is relatively unaffected by the type of ions used – indicating limited contribution from ion-specific pathways and implicating synergistic contributions of various species at the catalytic interface. Gram-scale synthesis and reusability of the reaction system for at least five reaction cycles indicates good catalyst stability. This is the first report using aqueous salt solutions for oxidation of benzylamine using cooperative TiO₂–TEMPO photocatalyst. The approach has the potential to be extended to other photocatalytic oxidations with promising results.

Keywords

Photocatalysis - Amine oxidation - Aqueous solution - Interfacial effect - Heterogeneous catalysis

Significance

High efficiency of aqueous salt solutions as reaction media for photooxidation of secondary amines is demonstrated successfully for the first time. The method requires visible light, aerobic conditions, and ambient temperature. Selective conversion to imine is obtained, with the yields surpassing the ones obtained by widely used organic solvents, providing a sustainable and affordable alternative to organic solvents.

Introduction

Photocatalyzed oxidation of amines as a synthetic methodology to yield imines has evolved significantly since it was first reported in 2011.[1] Subsequent reports focused on tuning the bandgap of TiO₂ to enhance photocatalytic performance through various modification strategies, including coupling with narrow bandgap semiconductors, metal or nonmetal ion doping, co-doping with multiple foreign ions, and surface sensitization using organic dyes or molecules.[2] [3] [4] [5] [6] [7] Numerous synthetic attempts focused on use of co-catalysts like TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl].[8] [9] [10] [11]

The use of aqueous media for amine photooxidation was reported almost immediately after the initial reports but little progress was made in this direction subsequently.[12] Later, aqueous medium was successfully employed for imine generation in photocatalytic conditions with high selectivity using bismuth oxybromide photocatalyst.[13] Swaminathan et al. utilized plasmonic catalysis to achieve 64% conversion using the gold nanoparticle catalyst system under plasmonic conditions in aqueous system.[14] The limited data about photooxidation of amines is highly surprising when compared to the numerous reports on thermal alcohol and amine oxidations carried out in aqueous media.[15] Given the wide range of organic transformations using water or aqueous solutions as the reaction medium,[16] [17] [18] it is logical to expect that the beneficial effects of aqueous media extend to the amine photooxidation reaction as well.

Recent results from our research group indicate that the overall photocatalytic performance of the TEMPO-TiO₂ system is significantly diminished in aqueous media. It is known that the presence of water enhances the local acidity at the TiO₂ interface.[19] This increased acidity promotes the acid-catalyzed disproportionation of TEMPO to TEMPOL, a process that irreversibly deactivates the catalytic species as TEMPOL cannot be regenerated to TEMPO under aqueous conditions.[20] Another major limitation could be the limited solubility of TEMPO in water (~70 mM). To address this limitation, it is imperative to design an alternative system that ensures adequate TEMPO solubility while simultaneously mitigating the formation of an acidic microenvironment at the TiO₂ interface, thereby maintaining the redox stability and catalytic efficiency of TEMPO. A notable development in this respect is the enhanced solubility of TEMPO in the aqueous salt solutions of NTF₂– as compared to that in water, reported by Pedraza et al.[21] Interestingly, recent reports have employed salt solutions for amine oxidation in thermal conditions with encouraging results. For example, Hazra and coworkers have reported that NaCl acts as a catalyst for self-oxidation of amines to imines in the presence of 4 equiv of TBHP as an oxidant and 70 °C, leading to 70–90% conversion.[22] Other examples where aqueous salt solutions had been employed as catalytic media include oxidation of amines to acids and oxidative coupling of benzylamines to methyl-N-heteroarenes.[23] [24]

This led us to consider the possibility of exploring aqueous salt solutions to replace the reaction medium in the photooxidation reactions. In the present report, we address this gap by designing an efficient synthetic strategy for photocatalyzed oxidation of benzylamine in aqueous salt solutions with TEMPO-TiO₂ as catalyst. The plausible origin and factors contributing to the catalytic activity of salt solution is discussed. The scalability of the methodology is demonstrated for gram-scale synthesis. The reaction media can be reused for at least five reaction cycles making it a green protocol.

Results and Discussion

Oxidation of benzylamine to the corresponding imine catalyzed by TiO₂–TEMPO under visible light irradiation was chosen as the model reaction ([Scheme 1]). Various salt solutions with varied concentrations were used as reaction media included solutions of NaNO₃, KNO₃, LiNTf₂, urea, and guanidinium chloride (GdnCl). The first three salts are known to be kosmotropic but are reported to increase the solubility of TEMPO. The latter two salts (urea and GdnCl) are chaotropic – chosen explicitly to explore the role of salting-in and salting-out effects on the reaction outcome. The initial results summarized in [Table 1] are surprisingly reassuring.

Scheme 1 Photocatalyzed oxidation of benzylamine to imine in aqueous salt solutions.

Table 1 Photocatalyzed oxidation of amine to imine with (TiO₂ + TEMPO) catalyst and irradiation by 30 W blue light (~450 nm) for 24 h^a.

Entry	Solvent	[Salt] (M)	Amount of Bz (mmol)	% Conversionb
1	Acetonitrile	–	0.3	69
2	Water	–	0.3	52
3	NaNO3	5	0.3	92
4	NaNO3	1	0.3	92
5	KNO3	5	0.3	91
6	KNO3	1	0.3	91
7	LiNTf2	5	0.3	99
8	LiNTf2	1	0.3	99
9	urea	5	0.3	86
10	urea	1	0.3	70
11	GdmCl	5	0.3	89
12	GdmCl	1	0.3	84
13	NaNO3	1	3.0	44
14	KNO3	1	3.0	56
15	LiNTf2	1	3.0	54

^a50 mg TiO₂, 0.015 mmol TEMPO, 0.3 mmol benzylamine or Bz (except when mentioned otherwise) in 1 mL solvent

^b% conversion determined using GC analysis by calibrating the benzylamine signal with anisole as internal standard

After exposure to blue light irradiation for 24 h, only 52% of the benzylamine was converted to imine in water (entry 1, [Table 1]). The relatively lower conversion in water can be attributed to the increase in the local acidity of the TiO₂ under aqueous conditions[25] and the low solubility of TEMPO in the aqueous system. The addition of NaNO₃, KNO₃, and LiNTf₂ salt solutions increased the conversion from 52% to 92%, 91%, and 99% conversion of amine to imine, respectively. Interestingly, when pure acetonitrile was used as the solvent under the identical conditions, the yield was only 69% after 24 h of blue light irradiation. The results indicate that the proposed methodology is better than the currently established photochemical protocol for such conversions. The surprising enhancement in the conversion can be attributed to several factors, and the interactions of numerous components on the TiO₂ interface need to elucidated.

It must also be noted that the concentration of the salt solutions (1 M compared to 5 M) does not affect the conversion significantly at 24 h of irradiation. This suggests that a salt concentration of 1 M is enough to generate the requisite ionic environment around the catalytic site at the TiO₂ interface, and further increase in ionic strength does not affect the photocatalytic activity. The high conversion observed in both kosmotropic salts like NaNO₃ or KNO₃ and in chaotropic salts like urea indicates that the hydrophobic effect (characterized by the salting-in and salting-out behavior) is not directly responsible for the increase in conversion efficiency. The amount of TEMPO used (1 mL of salt solution containing 0.015 mmol of TEMPO) corresponds to a concentration of 0.015 M and is much lower than the reported solubility limit of TEMPO – for example, solubility of TEMPO in 5 M LiNTF₂ solution is reported to be 5.6 M. This is additional evidence, which rules out solubility as the driving force causing the observed enhancement in reactivity. The results also meant that there would be no additional incentive of using a costly salt like LiNTf₂ in lieu of a more affordable alternative. With these optimal reaction conditions in hand, all further experiments were performed in 1M NaNO₃ solution.

To further optimize the reaction conditions, the concentration of the substrate (benzylamine) was varied from 0.3 to 3 mmol while maintaining the salt concentration at 1 M. However, under these reaction conditions the reaction was sluggish and resulted in moderate conversion for NaNO₃, KNO₃, and LiNTf₂. The decrease in the oxidation reaction at higher concentrations of benzylamine could be due to saturation of the active site on the photocatalyst surface. Alternatively, high concentrations of the organic substrate may diminish the unique mechanistic contributions of the aqueous media and, hence, lead to lower conversion. In order to ascertain these possibilities, further mechanistic investigations were carried out.

The results from the control experiments are summarized in [Table 2]. The decrease in conversion in the absence of light and oxygen from air (entry 1 and 2, [Table 2]) confirm the role of irradiation and O₂ in the reaction mechanism. Only 26% yield was observed in the presence of p-benzoquinone, which was used as a trap for the superoxide radical O₂ ^−• (entry 3, [Table 2]). The decrease in conversion in the presence of an electron scavenger like AgNO₃ is accepted for strong evidence for the enthrone transfer step in the mechanism. The absence of either oTiO₂ or TEMPO led to a decrease in the conversion of benzylamine; therefore, it is important to note that both work synergistically to catalyze the oxidation reaction (entry 5, 6, [Table 2]). When the reaction was carried out in the absence of TiO₂, up to 32% conversion was observed. A plausible explanation for the same could be a parallel photochemical pathway (albeit less efficient) resulting from the interaction of TEMPO with the organic substrate. Recent reports have reported the role of TEMPO in hydrogen atom transfer (HAT) catalyst, leading to aerobic oxidative dehydrogenation under mild conditions.[26] While the overall mechanism that can be deduced from these results is consistent with the previously reported literature in organic solvents, there may be some critical differences especially for the processes taking place at the TiO₂ interface.

Table 2 Control experiments for the photocatalytic oxidation of amine to imine in aqueous salt solution photocatalyzed by TiO₂–TEMPO^a.

Entry	Control condition	% Conversionb
1	No light	10
2	N2 Atm	10
3	Benzoquinonec	26e
4	AgNO3 d	7e
5	No TEMPO	20e
6	No TiO2	32e

^a50 mg TiO₂, 0.015 mmol TEMPO, 0.3 mmol benzylamine in 1 mL solvent, irradiation by 30W blue light ((~450 nm) for 24 h

^bGC analysis with anisole as internal standard

^c22 mg (0.2 mmol) of benzoquinone added

^d51 mg (0.3 mmol) of silver nitrate added

^eNo further increase with time

Previously, Lang et al. proposed a possible mechanism for cooperative catalysis by TiO₂–TEMPO in acetonitrile as reaction media.[10] According to this mechanistic scheme, two important processes are initiated at the photocatalyst interface. The benzylamine adsorbed on the surface of TiO₂ acts as a surface ligand and is oxidized to a radical cation. Meanwhile, photoexcitation also results in the transfer of the excited electron from the TiO₂ surface to oxygen, giving rise to the superoxide radical. In the next stage, the benzylamine cation radical is restored by TEMPO, which is converted to the TEMPO⁺ species in this process. This TEMPO⁺ then converts benzylamine to imine in a two-step process while getting reduced to TEMPOH. The original state of TEMPO is regenerated by the superoxide radical to complete the photocatalytic cycle ([Fig. 1]). Our control experiments are consistent with the involvement of all these key intermediates in the mechanism. When aqueous salt solution is employed as the reaction media, it is reasonable to expect that it may influence one or more aspects of this multistep mechanism, and the details still need to be elucidated.

Fig. 1 Possible mechanism for visible light–mediated selective aerobic oxidation of amine.

It is noteworthy that the mechanisms proposed for explaining the catalytic role of NaCl implicate the formation of chlorite or hypochlorite ion in highly oxidative conditions (4 equivalent TBHP), which, in turn, initiated the further process.[15] [24] This pathway cannot be extended to the current scenario, where no halide ions can be generated (with the exception of GdmCl) and oxidation is driven under much milder conditions. The role of nitrate ions as activating elements in TiO₂-induced photocatalytic generation of bromine has been demonstrated.[27] However, the comparable yields obtained in all salts used, including the salts not containing halide or nitrate ions, may rule out the contributions from any ion-specific pathways. The aqueous–TiO₂ interface is a complex system – with chemisorbed and physisorbed water molecules – and is known to give rise to complex interactions when irradiated.[28] [29] Recent reports have confirmed that TiO₂ photocatalysis is expected to involve a proton coupled electron transfer (PCET) mechanistic in the presence of TEMPO derivatives.[30] It is reasonable to expect that all these factors may converge synergistically to give rise to the enhanced reactivity observed in our results. Detailed experimental and computational data would be required to ascertain the same.

A crucial aspect of the sustainability of the process is the recycling of the catalyst and solvent. The salt solution as a solvent gave a comparable yield of up to five cycles with marginal loss in the catalytic activity ([Fig. 2]). After the first cycle, the reaction mixture was extracted by simple addition of ethyl acetate. The lower layer was used for the next run after addition of TEMPO and benzylamine without any vacuum drying. There was no appreciable loss in conversion until the third cycle from 92% to 85%. After the third cycle, a relatively high loss of conversion was seen from 85% to 69%. This loss in the system was because of the agglomeration of the TiO₂.

Fig. 2 Percent conversion of amine and successive recycling of solvent and photocatalyst.

To further demonstrate the synthetic utility of the green solvent–catalytic system, we scale up the current oxidation protocol to gram scale using 1 g of benzylamine, 74.88 mg of TEMPO, and 1.6 g of TiO₂ in 32 mL of 1M aqueous salt solution. The product was separated by the simple addition of ethyl acetate in the reaction mixture that gave the product in 78% conversion at 24 h of irradiation, indicating the ease of scaling up the current protocol.

Conclusions

A simple and highly efficient protocol for photocatalyzed amine oxidation using the TiO₂–TEMPO coupled system has been developed in aqueous salt solutions for the first time. The method can be carried out at ambient temperature using visible light and aerobic conditions to yield quantitative conversions. Addition of salt doubles the yield of the imine product as compared to that observed in pure water, indicating the critical contribution of the dissolved salt. Further experiments would be needed to confirm the contributions from the various components of the aqueous electrolyte reaction medium in accentuating the reactivity. The use of aqueous reaction media as a replacement for organic solvents and the possibility to scale-up the synthesis to gram scale or more are the key highlights. These features make this protocol a more sustainable and cost-effective alternative, which can potentially be scaled up to commercially relevant quantities.

Experimental Section

Material and Methods

Anatase titanium dioxide (TiO₂) 99.9% purity was purchased from Thermo Fisher Scientific India Pvt. Ltd. Benzylamine (98% purity) and TEMPO were purchased from Sisco Research Laboratories Pvt Ltd and sigma Aldrich Pvt Ltd, respectively. Ethyl acetate LR grade was purchased from SD fine chemicals and HPLC grade water was used. The chemicals procured were used without any purification unless mentioned otherwise.

General Procedure for Photocatalyzed Amine Oxidation

Anatase TiO₂ (50 mg), TEMPO (0.015 mmol), and benzylamine (0.3 mmol) were added in a round bottom flask containing 1 mL of the solvent media. The reaction mixture was ultrasonicated for 5 min and then stirred in the dark for 30 min to attain the adsorption equilibrium. The reaction was stirred in blue LED light (~450 nm, 30 W) at 1500 rpm. The reaction mixture was analyzed by using TLC (5% EtOAc in n-hexane). Ethyl acetate and water were added to the reaction mixture for work-up. The reaction mixture is passed through the sodium sulfate and silica gel by using 5% ethyl acetate in n-hexane. The pure product was isolated as a yellow viscous liquid and characterized using NMR and GC–MS (Fig. S1 and S2 of Supplementary Information).

GC Analysis for % Conversion

GC analysis was conducted on Young Lin Autochro-3000 (6500GC system) equipped with column Elite 1701 with dimensions 15 m × 0.53 mm × 1 μm and flame ionization detector (FID) using N₂ as a carrier gas. Analysis conditions: Injector temperature 250 °C, detector temperature 280 °C, and column temperature program 80 °C (hold 2 min) raised up to 280 °C (hold 2 min) at a rate of 40 °C min⁻¹. Conversion (%) was determined using the following equation:

$$\text{Conversion}\left(\%\right)=\frac{\left(C_0-C_{\mathrm{f}}\right)}{C_{\mathrm{f}}}\times 100$$

where C ₀ is the initial concentration of reactant and C _f is the final concentration. Anisole was used as the internal standard to determine the % conversion.

Contributors’ Statement

V.K.: Data curation, Project administration, Validation, Visualization. Y.P.: Formal analysis, Investigation, Writing – original draft. S.T.: Conceptualization, Supervision, Writing – review & editing.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 03 November 2025

Accepted after revision: 16 December 2025

Accepted Manuscript online:
16 December 2025

Article published online:
13 January 2026