Copper-Catalyzed Continuous-Flow Transfer Hydrogenation of Nitroarenes to Anilines: A Scalable and Reliable Protocol

Abstract

A robust supported catalyst that is made up of copper nanoparticles on Celite has been successfully prepared for the selective transfer hydrogenation of aromatic nitrobenzenes to anilines under continuous flow. The method is efficient and environmentally benign thanks to the absence of hydrogen gas and precious metals. Long-term stability studies show that the catalytic system is able to achieve very high nitrobenzene conversion (>99%) when working for up to 145 h. The versatility of the transfer hydrogenation system has been tested using representative examples of nitroarenes, with moderate-to-excellent yields being obtained. The packed bed reactor (PBR) permits the use of a setup that can provide products via simple isolation by SPE without the need for further purification. The recovery and reuse of either EG or the ion-exchange resin leads to consistent waste reduction; therefore, E-factor distribution analysis has highlighted the environmental efficiency of this synthetic protocol.

Scheme 1. Cu-Catalyzed TH of Nitrobenzene

Figure 1

TH of nitrobenzene to aniline in batch in the presence of CuNP catalysts. Reaction conditions: nitrobenzene (1 mmol), KOH (2 mmol), CuNPs/support (5 mol %), and glycerol (7 mL). T, 130 °C; t, 30 min; magnetic stirring. Conversion (%) determined by GC-MS analysis.

Figure 2

TH of nitrobenzene to aniline in batch in the presence of Celite, CuNPs, CuNPs + Celite, and CuNPs/Celite. Reaction conditions: nitrobenzene (1 mmol), KOH (2 mmol), catalyst (5 mol %), and glycerol (7 mL). T, 130 °C; t, 30 min and 1 h; magnetic stirring. Conversion determined by GC-MS.

Figure 3

TH kinetics of nitrobenzene reduction. Reaction conditions: nitrobenzene (1 mmol), KOH (2 mmol), catalyst (5 or 20 mol %), and EG or glycerol (7 mL). T, 130 °C. Conversion was determined by GC-MS. (▲) Glycerol (Cu 5 mol %), (■) EG (Cu 5 mol %), and (●) EG (Cu 20 mol %).

Figure 4

Outline of the apparatus adopted for the continuous test in a packed bed reactor (PBR). Reaction conditions: nitrobenzene (1 mmol), base (2 mmol), hydrogen donor, and CuNPs/Celite.

Figure 5

Influence of base equivalents in the nitrobenzene TH. Reaction conditions: nitrobenzene in EG (0.5 M, 1 eq) and KOH. Flow rate: 0.03 mL/min, 250 mg of CuNPs/Celite 5% w/w, setup B (see Figure S1B). Reaction temperature: 130 °C, and the reaction is monitored after 18 reactor volumes. Reaction yield was determined by GC-MS.

Figure 6

Influence of DMA, CH₃CN, and water on TH of nitrobenzene. (a) Batch reaction condition: nitrobenzene (2.5 mmol), KOH (5 mmol), CuNPs/Celite (158 mg, 5 mol % or 632 mg, 20 mol %), EG (5 mL), and DMA or CH₃CN or H₂O (2 mL). T, 130 °C, t, 3 h. (b) Continuous-flow condition: nitrobenzene in EG (5 mL of 0.5 M, 1 equiv) and 2 equiv of KOH; 2 mL of DMA or CH₃CN or H₂O; flow rate, 0.03 mL/min; and 250 mg of CuNPs/Celite 5% w/w. The reaction was monitored after 18 reactor volumes, and conversion was determined by GC-MS.

Figure 7

Long-run studies for the continuous reduction of nitrobenzene in the presence of CuNPs + Celite (blue curve) and CuNPs/Celite (black curve). Reaction conditions: nitrobenzene in EG (0.5 M, 1 equiv) and 2 eq KOH. Flow rate: 0.03 mL/min, 500 mg of CuNPs/Celite 5% w/w, setup B (see Figure S1B). Reaction temperature: 130 °C. Reaction yield determined by GC-MS.

Figure 8

XRD patterns of the CuNPs/Celite catalyst before (green line) and after reaction (dark green line) and of the reactivated CuNPs/Celite (black line).

Figure 9

Influence of DMA as a solubilizing solvent. Tests were performed at different DMA-to-EG ratios and different nitronaphthalene concentrations. Reaction conditions: nitronaphthalene (1 equiv) in EG/DMA (concentration 0.4 or 0.5 M), 2 equiv of KOH, flow 0.03 mL/min, reaction temperature 130 °C.

Scheme 2. Scope of Nitrobenzene Reduction

Reaction conditions: nitrobenzene derivatives (1 eq) 0.5 M in EG, 2 eq KOH, flow rate 0.03 mL/min, reaction temperature 130 °C. (a) Reaction was performed in EG/DMA 5:2. (b) Concentration of nitronaphthalene 0.4 M.

Figure 10

E-factor distribution analysis.