Quinone-mediated hydrogen anode for non-aqueous reductive electrosynthesis

Abstract

Electrochemical synthesis can provide more sustainable routes to industrial chemicals^1-3. Electrosynthetic oxidations may often be performed 'reagent-free', generating hydrogen (H₂) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications⁴, but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option^1,5,6, but many reductions require anhydrous, air-free reaction conditions. In such cases, H₂ represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions^7-12. Here we report a mediated H₂ anode that achieves indirect electrochemical oxidation of H₂ by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H₂ anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry^13-15. Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H₂ anode technology disclosed here offers a general strategy to support H₂-driven electrosynthetic reductions.

Fig. 1.. Strategy to enable the use of H₂ as a source of electrons for Ni-catalyzed cross-electrophile coupling (XEC) in organic solvent.

(a) The electrochemical H₂ oxidation reaction (HOR) is a key feature of fuel cells. The essential role of water in supporting HOR and transport of water through the membrane limits use of this method in non-aqueous electrochemistry. (b) Catalytic hydrogenation quinones and electrochemical oxidation of hydroquinones are facile in organic solvents. (c) Ni-catalyzed cross-electrophile coupling (XEC) is an important and growing class of reduction reactions that would benefit from the ability to use H₂ as a reductant. (d) Quinone-mediated H₂ anode concept, designed to support electrochemical Ni-catalyzed XEC.

Fig. 2.. Voltammetric analysis and electrochemical Ni XEC using a mediated H₂ anode in an H–cell.

(a) Redox potentials measured for H₂, the anthraquinone mediator, and Ni catalyst species show that the potential of H₂ is insufficient to drive Ni XEC in the absence of an electrochemical bias. (b) H–cell schematic illustrating the electrochemical and chemical processes in the anolyte and catholyte compartments. (c) XEC substrates used for reaction testing and optimized reaction conditions. (d) Ni XEC products obtained using the H–cell with a mediated H₂ anode, shown in b, under conditions identical or similar to those in c (see section 10 of the Supplementary Information for details). ^aHeteroaryl chloride used instead of the bromide.

Fig. 3.. Quinone-mediated H₂ anode flow cell.

(a) Schematic diagram of the mediated H₂ anode flow system, integrating a hydrogenation loop with a packed-bed reactor for AQS hydrogenation and an electrolysis loop interfaced with a parallel-plate reactor for anodic oxidation of AQSH₂. (b) Analysis of redox states of the quinone mediator in the anolyte reservoir, using in situ UV-visible spectroscopy, while circulating only through the hydrogenation loop, only through the electrolysis loop, and through both the hydrogenation and electrolysis loops. (c) Operation of the mediated hydrogen anode shows stable cell voltage at current densities well beyond that needed to support Ni-catalyzed cross-electrophile coupling (XEC). (d) Assessment of Ni XEC product selectivity at different current densities. Optimal yield and selectivity are obtained at 4 mA/cm².

Fig. 4.. Scalable demonstration of the mediated H₂ anode to prepare molecules of pharmaceutical interest.

(a) Gram-scale Ni-catalyzed XEC using a small parallel-plate flow reactor (5 cm² electrode surface area) to synthesize molecules including an intermediate to the drug, rolipram. (b) Synthesis of an intermediate to the drug, cenerimod, in three different formats: an H–cell batch reactor, a small parallel-plate flow reactor (5 cm² electrode surface area), and a large parallel-plate flow reactor (1600 cm² electrode surface area). See sections 8 and 9 in the Supplementary Information for full reaction conditions and experimental details.