Crabtree’s Catalyst 40 years Later: Air-stability and ortho-directed selectivity in hydrogen-isotope-exchange (HIE) sustain importance of a well-known catalyst
The incorporation of isotopic tags in candidate drug molecules enables facile determination of key pharmacological properties including absorption, distribution, metabolism, excretion, and toxicology (ADMET).1 Unsurprisingly, therefore, transition-metal-mediated exchange of C-H bonds with either deuterium (2H or D) or tritium (3H or T) has become an essential process utilized in drug discovery. Selective catalysts for hydrogen isotope exchange (HIE) circumvent the need for isotopically labeled precursors by enabling late-stage enrichment of complex molecules with isotopic hydrogen gas (i.e. D2 or T2).2
Although initially developed for application as a selective hydrogenation catalyst nearly 40 years ago,3 more recently, Crabtree’s catalyst ([(COD)Ir(PCy3)(py)]PF6) is regarded as the industry standard in catalysis of HIE. The Ir(I) catalyst is indefinitely stable in air and remains among the most widely-investigated catalysts for ortho-directed hydrogen isotope exchange.4-6 The figures below show two recent examples7 demonstrating regioselective exchange of ortho-CH groups, directed by the presence of proximal anchoring groups:
References:
(1) J. Label. Compd. Radiopharm., 2010, 53, 662.
(2) J. Label. Compd. Radiopharm., 2010, 50, 779.
(3) Acc. Chem. Res., 1979, 12, 9, 331.
(4) J. Label. Compd. Radiopharm., 2009, 52, 376.
(5) J. Label. Compd. Radiopharm., 2001, 44, 209.
(6) J. Label. Compd. Radiopharm., 1995, 36, 497.
(7) Nature, 2016, 529, 195.
Product mentioned in this blog and related products:
77-1845: Chloro(1,5-cyclooctadiene)[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)
imidazol-2-ylidene] iridium(I), min. 98%; CAS #1118917-09-1
77-1850: Dimethylphenylphosphine(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)
77-1830: (Dimethylphenylphosphine)(1,5-cyclooctadiene)[1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene]iridium(I) hexafluorophosphate, min. 98%; CAS # 1019853-03-2
77-1810: Tribenzylphosphine(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)
imidazol-2-ylidene]iridium(I) hexafluorophosphate, min. 98%; CAS #1019853-01-0
77-1840: Triphenylphosphine(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)
imidazol-2-ylidene] iridium(I) tetrakis(3,5-bis(trifluoromethyl)phenylborate, min. 98%; 1628471-64-6
77-1825: Triphenylphosphine(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)
imidazol-2-ylidene]iridium(I) hexafluorophosphate, min. 98%; CAS #1019853-00-9
Related Products:
Iridium Catalysts for Hydrogen Isotope Exchange & Catalytic Hydrogenation Processes