N-heterocyclic carbenes are sources of divalent carbon that have made tremendous impact in many areas of synthetic chemistry since their first report in 1991 by Arduengo and colleagues.[1] These compounds can be conveniently accessed by deprotonating their protonated azolium precursors, which have generally very long shelf-lives.
One of the most commonly used precursors is the bulky 1,3-Bis(2,6-diisopropylphenyl)imidazolium salt, also known by the acronyms IPr-HX or IDip-HX, where X is the counteranion. Although the essence of its synthesis has remained largely unchanged since conception, several tweaks have increased the product yields over the years.[2] The current best method involves two steps, converting 2,6-diisopropylaniline and glyoxal into the diazabutadiene, followed by cyclization with paraformaldehyde to afford the product.[3]
Procedure:[3]
Synthesis of 1,4-(2,6-diisopropylphenyl)-1,4-diazadiene: In a 1L beaker or Erlenmeyer flask with magnetic stirring, technical-grade, 90% 2,6-diisopropylaniline (197g, 1mol) was diluted in 250mL of methanol and 1mL of glacial acetic acid. After heating the aniline solution to 50degC, a solution of 40% aqueous glyoxal (72.6g, 0.50mol) in 250mL methanol was added to the reaction flask in one portion. The ensuing mixture was stirred overnight, affording a bright yellow solid which was isolated by vacuum filtration and washed with methanol to remove brown impurities. The product diazadiene was isolated as a bright yellow, crystalline solid (158.3g, 84%).
Synthesis of 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride: A 2L round-bottom flask with stir bar was charged with 1,4-(2,6-diisopropylphenyl)-1,4-diazadiene (50.5g, 0.134mol), paraformaldehyde (4.06g, 0.135mol), and 1.2L of ethyl acetate (predried for 48h with 4-Angstrom molecular sieves). The mixture was heated to 70degC, and a solution of TMSCl (17mL, 135mol) in 20mL of ethyl acetate were added over the course of 45min. via dropping funnel. After heating at 70degC for 2h, the mixture was cooled in an ice bath, and the insoluble precipitate was isolated by vacuum filtration. After washing with ethyl acetate and ether, the imidazolium chloride salt was isolated as an off-white solid (46.0g, 81%).
Notes:
- Although IPr-HCl is indefinitely air/moisture stable, it is hygroscopic. Unless it is deprotonated immediately after synthesis, it should be dried in an oven at 100degC for a day to ensure removal of water. Failure to do this results in lower carbene yields upon deprotonation.
- The tetrafluoroborate analog, IPr-HBF4 is far less hygroscopic than the chloride. It can be synthesized from IPr-HCl via anion exchange by subjecting an aqueous suspension of the imidazolium salt to 40% aqueous HBF4.[4]
- Although these carbene precursors are commercially available, they are quite expensive and are thus better to make in bucket-scales in-house.
[1] Arduengo, A. J.; Harlow, R. L.; Kline, M. A stable crystalline carbene. J. Am. Chem. Soc. 1991, 113, 361-363.
[2] Hans, M.; Lorkowski, J.; Demonceau, A.; Delaude, L. Efficient synthetic protocols for the preparation of common N-heterocyclic carbene precursors. Beilstein J. Org. Chem. 2015, 11, 2318-2325.
[3] Hintermann, L. Expedient syntheses of the NHC precursor imidazolium salts IPr-HCl, IMes-HCl, and IXy-HCl. Beilstein J. Org. Chem. 2007, 3, 22. DOI: 10.1186/1860-5397-3-22.
[4] Bantreil, X.; Nolan, S. P. Synthesis of NHC ligands and derived ruthenium olefin metathesis catalysts. Nature Protocols 2011, 6, 69-77.