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Achiral Hydrogenation

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

General Overview

Achiral hydrogenation is a very common transformation in organic synthesis. In terms of atom economy, the most efficient transformation is hydrogenation with a recyclable precious metal (PMC) or base metal catalyst. The most common and widely used achiral hydrogenation employs a heterogeneous metal catalyst that can be filtered off and potentially recycled (or reused). The metals most frequently used in heterogeneous catalytic hydrogenation are palladium, platinum, rhodium, nickel, cobalt, and ruthenium. Sporadically, iridium, copper and rhenium have been employed as the metal catalyst. It is becoming increasingly common to see mixed metal catalysts employed to enhance the specificity of reductions. The metals can be present as small particles of the parent metal salts, that are reduced in situ in the presence of hydrogen to give small particles of the desired active metal. In the majority of cases, metals used in achiral hydrogenations are supported on an inert carrier such as carbon, silica, zeolite, or Al2O3 based materials. Occasionally free metal particles may be used – usually generated in situ as noted above. Other materials may also be added to the heterogeneous catalyst or reaction mixture to modify reactivity, reduce activity to enable selective hydrogenations, or to make the catalyst more resilient to any potential “poisons” present. There are homogeneous metal catalysts such as Wilkinson’s catalyst (RhCl(PPh3)3) that can be used for achiral hydrogenation, but in practice heterogeneous catalysis is much more widely employed due to cost and the more facile removal of the catalyst from the reaction stream post-hydrogenation.

Most commonly, hydrogen gas (from steam-reforming of methane) is used as the reductant (typically at 1 – 5 bar pressure) being both cheap and readily available. Less widely used though convenient in research settings is transfer hydrogenation in which an added donor compound decomposes on the catalyst surface to generate hydrogen gas in situ (for example NaBH4, formate, phosphinates, N2H4 etc). Other organic donors such as isopropanol or cyclohexene are capable of transferring H2 to a reactant on the catalyst surface. In addition, laboratory-scale flow reactors (H-Cube) are available that produce hydrogen continually via electrolysis of water for convenience thus removing the requirement for a hydrogen gas supply.

Many functional group reductions (nitro, alkyne, etc.) are very exothermic reactions and need to be designed and scaled up in suitable equipment with appropriate safety testing to ensure safe operability. The application of new technologies like flow processing and process analytical technology (PAT) can remove some of the potential hazards involved in large scale hydrogenation with a number of these topics further explored within specific references provided within this guide.  


General Literature Reviews: Achiral Hydrogenation

Hattori, T.; Tsubone, A.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Systematic Evaluation of the Palladium-Catalyzed Hydrogenation under Flow Conditions. Tetrahedron 2014, 70 (32), 4790–4798.

Xia, Y.; Yuan, X. Toward Cost-Effective and Sustainable Use of Precious Metals in Heterogeneous Catalysts. Acc. Chem. Res. 2017, 50 (3), 450–454.

Tungler, A.; Szabados, E. Overcoming Problems at Elaboration and Scale-up of Liquid-Phase Pd/C Mediated Catalytic Hydrogenations in Pharmaceutical Production. Org. Process Res. Dev. 2016, 20 (7), 1246–1251.

 Friend, C. M.; Xu, B. Heterogeneous Catalysis: A Central Science for a Sustainable Future. Acc. Chem. Res. 2017, 50 (3), 517−521.

Augustine, R. L. Organic Functional Group Hydrogenation. Catalysis Rev. 1976, 13 (1), 285–316.

Schmidt, O. The Mechanism of Heterogeneous Catalytic Organic Reactions. I. Catalytic Hydrogenation. Chem. Rev. 1933, 12 (3), 363–417.

Augustine, R. L. Selectively Heterogeneously Catalyzed Hydrogenations. Catalysis Today 1997, 37 (4), 419–440.

Ben Said, M.; Baramov, T.; Herrmann, T.; Gottfried, M.; Hassfeld, J.; Roggan, S. Continuous Selective Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA over Raney Cobalt Catalyst at kg/day Scale with Online UV–Visible Conversion Control. Org. Process Res. Dev. 2017, 21 (5), 705−714.

Pietrowski, M. Recent Developments in Heterogeneous Selective Hydrogenation of Halogenated Nitroaromatic Compounds to Halogenated Anilines. Curr. Org. Synth. 2012, 9 (4), 470–487.

Filonenko, G. A.; Van Putten, R.; Hensen, E. J. M.; Pidko, E. A. Catalytic (De)hydrogenation Promoted by Non-Precious Metals – Co, Fe and Mn: Recent Advances in an Emerging Field. Chem. Soc. Rev. 2018, 47 (4), 1459–1483.

Liu, L.; Corma, A. Metal Catalysts for Heterogeneous Catalysis: From Single Atoms to Nanoclusters and Nanoparticles. Chem. Rev. 2018, 118 (10), 4981–5079.


Transfer Hydrogenation with Pt-group and Base Metals

Wang, D.; Astruc, D. The Golden Age of Transfer Hydrogenation. Chem. Rev. 2015, 115 (13), 6621−6686.

Ram, S.; Ehrenkaufer, R. E. Ammonium Formate in Organic Synthesis. A Versatile Agent for Catalytic Hydrogen Transfer Reductions. Synthesis 1988, 1998 (2), 91–95.

Brieger, G.; Nestrick, T. J. Catalytic Transfer Hydrogenation. Chem. Rev. 1974, 74 (5), 567–580.

Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Heterogeneous Catalytic Transfer Hydrogenation and its Relation to Other Methods for Reduction of Organic Compounds. Chem. Rev. 1985, 85 (2), 129–170.

Prasad, K.; Jiang, X.; Slade, J. S.; Clemens, J.; Repič, O.; Blacklock, T. J. New Trends in Palladium-Catalyzed Transfer Hydrogenations using Formic Acid. Adv. Synth. Catal. 2005, 347 (14), 1769–1773.


Green Criteria for Achiral Hydrogenation

  1. Catalytic reduction with H2 gas (or transfer hydrogenation) is preferred over stoichiometric reagents such as hydrides.
  2. Solvents should be chosen to minimise any potential safety and/or environmental impact. If possible, H340/H341/H360/H361 (potentially or suspected carcinogenic, mutagenic, reprotoxic substances) labelled dipolar aprotic or ethereal solvents should be avoided and substituted for.
  3. Base metal catalysts are preferred to Pt group metals though this is critically dependent on the demands of the required transformation.
  4. Adequate consideration has been given to optimization of the catalyst loading.
  5. H2 gas pressure should be minimized.
  6. For transfer hydrogenation, the amount of H2 donor is minimized.
  7. Can the reaction be run in flow/continuously, and/or can PAT (process analytical technology) be used for reaction monitoring?
  8. Reaction conditions preclude (or minimize) leaching of metal residues into the reaction mixture (see Reagent Guide on Metal Scavenging).
  9. Work-up/downstream processing should ensure metal levels are reduced to within any relevant specifications for both the product and any waste streams. In addition, if a precious metal catalyst is used, recovery and recycle of the metal is optimized.


Updated ICH Guidelines for Metals in API’s

ICH q3d guideline for elemental impurities 2019
When using metal catalysts, it is important to monitor any wastes discharged to the environment to ensure that levels of precious/heavy metals are less than those permitted by local legislation. There are also strict limits for metals in API/finished medicines to ensure patient safety.

For guidance see limits in µg gram-1 and permitted daily exposures (accessed August 30th, 2021).