Selective hydrogenation of nitro compounds to amines by coupled redox reactions over a heterogeneous biocatalyst

Abstract

Cleaner synthesis of amines remains a key challenge in organic chemistry because of their prevalence in pharmaceuticals, agrochemicals and synthetic building blocks. Here, we report a different paradigm for chemoselective hydrogenation of nitro compounds to amines, under mild, aqueous conditions. The hydrogenase enzyme releases electrons from H₂ to a carbon black support which facilitates nitro-group reduction. For 30 nitroarenes we demonstrate full conversion (isolated yields 78 - 96%), with products including pharmaceuticals benzocaine, procainamide and mesalazine, and 4-aminophenol - precursor to paracetamol (acetaminophen). We also showcase gram-scale synthesis of procainamide with 90% isolated yield. We demonstrate potential for extension to aliphatic substrates. The catalyst is highly selective for reduction of the nitro group over other unsaturated bonds, tolerant to a wide range of functional groups, and exhibits excellent stability in reactions lasting up to 72 hours and full reusability over 5 cycles with a total turnover number over 1 million, indicating scope for direct translation to fine chemical manufacturing.

Fig. 1. Current state of the art and catalytic approach exploited in this work.

A Examples of amine pharmaceuticals relevant to this work. B Currently-used methods for the reduction of nitro compounds to generate amines. C Hydrogenase enzyme (gold) immobilised on the surface of carbon black particle as a catalyst for efficient chemoselective synthesis of amines (this work).

Fig. 2. Onset potential for nitrobenzene reduction and H₂ oxidation on a carbon electrode at 25 °C, pH 6.0.

Cyclic voltammograms for A: nitrobenzene at a stationary graphite electrode under a N₂ atmosphere, scan rate 10 mV/s; and B: a film of Hyd-1 adsorbed onto the electrode under a H₂ atmosphere with electrode rotation at 3000 rpm, scan rate 1 mV/s. Potentials are quoted vs the standard hydrogen electrode, SHE. Dashed vertical line: potential of the 2H⁺/H₂ couple at the experimental conditions, Eʹ(2H⁺/H₂); solid black vertical line: measured onset potential for H₂ oxidation by Hyd-1; solid grey vertical line: measured onset for nitrobenzene reduction (see Supplementary Table 6).

Fig. 3. Substrate scope of hydrogenation reactions achieved with the Hyd-1/C catalytic system (unless specified, single catalyst loading: 1.06 mg of C, 26 µg of Hyd-1 per reaction) at 10 mM concentration of substrate, 2 mL reaction volume, 0% or 10% v/v of MeCN in sodium phosphate buffer (PB, 50 mM, pH 6.0, unless stated otherwise), room temperature, 1 bar H₂.

*Double catalyst loading. **Quadruple catalyst loading. ^#Double catalyst loading, pH 8.0.

Fig. 4. Isolated yields, mechanistic insight and large-scale synthesis of procainamide.

A Isolated yields (%) for 1a–30a. Conditions: as in Fig. 3 caption. *¹H-NMR yields. B ¹H-NMR traces of hydrogenation of 1 at indicated time points. Conditions: Hyd-1/C (1.06 mg of C, 26 µg of Hyd-1), 10 mM 1, 2 mL reaction volume, PB (50 mM, pH 6.0), room temperature, 1 bar H₂. Traces for 1, 1b, and 1a are labelled with red, green, and blue, respectively. C Synthesis of substrate 31 and its hydrogenation on a gram-scale. Conditions: Hyd-1/C (264 mg of C, 6.63 mg of Hyd-1), 10 mM 31, 500 mL reaction volume, 10% MeCN v/v in PB (50 mM, pH 6.0), room temperature, 1 bar H₂.