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Hydrogen/Metal Catalysts (Precious and Base Metal)

Mechanism + Description

Typical heterogeneous reaction mechanism with the imine intermediate ( formed in situ or preformed) binding to the metal surface, then being reduced by hydrogen gas.

Mechanism shown for Pd/C

General comments

Typically the aldehyde and ketone are reacted under fairly traditional hydrogenation conditions – supported metal catalyst and H2 gas from atmospheric to ~ 100 psi. The most common metals are Pd and Pt, but other precious metals are occasionally used as well as cheaper base metals like Raney Nickel, Cobalt, Copper and Iron. Generally regarded as the greenest reductive amination since no borate by-products are formed, and down stream workup is simplified. Metal catalysts should be recovered and recycled and reaction products and waste effluent should be checked for metal content. Occasionally transfer hydrogenation is employed instead of H2 gas.

Homogeneous metals can be used as catalysts, but these are usually confined to chiral hydrogenation in the presence of chiral ligands to give enantioenriched amine products.

Key references

J. Am. Chem. Soc., 1948, 70, 1315-1316 A Low Pressure Reductive Alkylation Method for the Conversion of Ketones to Primary Amines

J. Am. Chem. Soc., 1948, 70, 2811-2812 Aminative Reduction of Ketones

Org. Lett., 2005, 7, 4967–4970 Evolution of Titanium(IV) Alkoxides and Raney Nickel for Asymmetric Reductive Amination of Prochiral Aliphatic Ketones

Adv. Synth. Catal., 2002, 344, 1037–1057 The Reductive Amination of Aldehydes and Ketones and the Hydrogenation of Nitriles: Mechanistic Aspects and Selectivity Control

J. Med. Chem., 1973, 16(5), 480-483. Asymmetric synthesis of psychotomimetic phenylisopropylaminesreductive amination with Pd/C catalyst

Tetrahedron, 2002, 58, 5669-5674 A modified palladium catalysed reductive amination procedure

Current Organic Chem., 2008, 12,1093-1115 Recent Development on Catalytic Reductive Amination and Applications

Chemistry – An Asian Journal, 2011, 6, 2240–2245 An Easy and General Iron-catalyzed Reductive Amination of Aldehydes and Ketones with Anilines

ChemSusChem 2014, 7, 3012 – 3016 Iron-Catalyzed Synthesis of Secondary Amines: On the Way to Green Reductive Aminations

Green Chem., 2012,14, 2371-2374 Copper-catalyzed reductive amination of aromatic and aliphatic ketones with anilines using environmental-friendly molecular hydrogen

ChemCatChem 2015, 7, 62-64 Synthesis of Amines by Reductive Amination of Aldehydes and Ketones using Co3O4/NGr@C Catalyst

See also catalysts for reductive amination in:

Relevant scale up examples

Org. Process Res. Dev., 2011, 15, 1116–1123
5 kg scale

Org. Process Res. Dev., 2000, 4, 520-525
3 kg scale

Org. Process Res. Dev., 2011, 15, 1052–1062
3 kg scale

Org. Process Res. Dev., 2008, 12, 596–602
300 g scale

Org. Process Res. Dev., 2011, 15, 1010–1017
400 g scale

Org. Process Res. Dev., 2002, 6, 323-328
112 g scale

Org. Process Res. Dev., 2014, 18, 546–551
250 kg scale

Org. Process Res. Dev., 2010, 14, 592–599
4 kg scale

Org. Process Res. Dev., 2012, 16, 1090 – 1097

Green Review

  1. Atom efficiency (by-products Mwt)
    With optimized catalytic efficiency, hydrogenolysis is an atom efficient process using heterogeneous catalysts that can be recovered and recycled, or with homogeneous catalysts optimized for turnover number.
  2. Safety Concerns
    Typified by normal hazards around hydrogenation reactions. Catalytic transfer hydrogenation may avoid the need to handle H2 gas, but these reactions may generate H2 in situ. Heterogeneous metal catalysts can be pyrophoric in air when dry.
  3. Toxicity and environmental/aquatic impact
    Main concern is around solubilisation and loss of precious metal/heavy metal catalysts into waste streams. Most precious and heavy metal levels are tightly regulated. The same applies to potential carry through into the API. Some Ni salts are sensitizers and carcinogens and listed on the EU SVAH list – this is of less concern for metallic hydrogenation catalysts.
  4. Cost, availability & sustainable feedstocks
    H2 and H2 obtained via CTH (catalytic transfer hydrogenation) is cheap and non-polluting – can be from renewable resources.
  5. Sustainable implications
    All metals have a high LCA impact from mining and refining operations, so use should be catalytic with efficient recovery and recycle. Pd is most commonly used precious metal for hydrogenation, and this is rated at high risk of depletion. No concern for abundant base metals such as Ni.