Tertiary phosphines are some of the most well known ligands employed in transition metal reactivity and catalysis. Many of the best performing homogeneous catalysts are stabilized by phosphines. For example, Wilkinson’s hydrogenation catalyst uses triphenylphosphine, Grubb’s generation I olefin metathesis catalyst uses tricyclohexylphosphine, and palladium cross coupling catalysts use a variety of mono- and bidentate phosphines. These ligands are great sigma-donors, imparting electron density to the metal and encouraging reactivity, while concurrently stabilizing it via steric effects.
Among the tertiary phosphine family, triphenylphosphine is by far the cheapest, commercially available congener (Oakwood Chemical sells it for $20USD per 100g). On the other hand, its saturated analog, tricyclohexylphosphine is much more expensive (Oakwood Chemical sells it for $252USD per 100g). The reason for this price discrepancy might be attributed to two factors: 1) The high air-sensitivity of the latter, which increases synthetic difficulty; and 2) the fact that tricyclohexylphosphine cannot be synthesized via the standard method employed for triphenylphosphine - the one-pot, phospha-Wurtz reaction of PCl3, PhCl, and Na.[1] After all, one could argue that the superior donor properties of tricyclohexylphosphine really come at a price.
To my knowledge, the most appropriate synthetic protocol for tricyclohexylphosphine is based on that of Issleib and Brack in 1954, via reaction of PCl3 and cyclohexylmagnesium bromide, as shown below:[2]
Procedure:[2] In a 1L two-neck round-bottom flask equipped with a reflux condenser and attached to the Schlenk line under argon, a Grignard solution was prepared from fresh magnesium turnings (32g, 1.32mol) and bromocyclohexane (220g, 1.35mol) (or chlorocyclohexane) in 500mL of anhydrous ether. The flask was cooled below 0degC using an ice-salt bath, and PCl3 (54g, 0.393mol) slowly added. The reaction mixture was subsequently stirred at room temperature for 1h, followed by 2h under reflux. After cooling to room temperature, the reaction was placed back under ice-salt bath and carefully quenched with 300mL of aqueous, argon-sparged NH4Cl (50g in 280mL water). The ether layer was quickly separated using a separatory funnel, dried with sodium sulfate, and decanted into a separate flask connected to the Schlenk line via a swivel-frit apparatus under argon flow. Approximately half the ether was removed in vacuo, and 15mL of CS2 were added to the residue. The Cy3P-CS2 precipitate was collected by filtration, washed with pentane (2x60mL) and dried in vacuo. The adduct can be recrystallized from methanol, ethanol, or dioxane under argon (reported yield: 66g, 47%).
The CS2 adduct was suspended in 400mL of anhydrous ethanol and heated to a boil, which induced the compound to dissolve. The alcohol was distilled off, alongside CS2, causing the previously red solution to decolorize. If the residue was still slightly red, more ethanol was added and the distillation repeated. The residue was recrystallized from anhydrous acetone under argon to yield tricyclohexylphosphine as a white, crystalline solid. Product was transferred into the glovebox for storage.
Notes:
- Carbon disulfide needs to be added to induce PCy3 to crystallize as the adduct, which can be separated from the reaction byproducts (bicyclohexane and partially substituted phosphines) via filtration and pentane or hexane wash.
- Ether can be dried using sodium-benzophenone and distilled before use. The rest of the solvents can be dried with molecular sieves. Acetone needs a minimum of two rounds of drying over activated sieves for 48h before use. Keep in mind that 3-Angstrom molecular sieves are needed for methanol, ethanol, and CS2 (although the latter should be okay to use from the stock bottle since it does not absorb significant water).
- Tricyclohexylphosphine is soluble in organic solvents such as benzene, toluene, diethyl ether, chloroform, pyridine, acetone, THF, but insoluble in water.
- There is a patented literature method that synthesizes tricyclohexylphosphine via hydrogenation of triphenylphosphine with a niobium catalyst, but it requires a steel reactor and 1200psi of dihydrogen pressure. In other words, not amenable to the average synthetic chemist.[3]
- An interplay of several factors has been attributed to the superior air-stability of some phosphines over others: 1) Sterically bulky groups protect the phosphorus atom from reacting with oxygen in air; 2) Aryl rings stabilize the phosphorus lone pair via conjugation; 3) Solid phosphines are further protected by their crystal lattices in comparison to their liquid counterparts.
- Tertiary arylphosphines such as triphenylphosphine, tris(o-tolyl)phosphine, trimesitylphosphine, JohnPhos,[5a] XPhos, SPhos, RuPhos, BrettPhos, DavePhos,[5b] and Pad-DalPhos[5c] are air stable in the solid state, and very slowly oxidize in solution (many of these displayed <10% decomposition after being stirred as toluene solutions in air for 65h).
- Tertiary alkylphosphines such as trimethylphosphine, triethylphosphine, tricyclohexylphosphine, and tri-tbutylphosphine are air sensitive and should be handled under strict exclusion of oxygen.
[1] a) Michaelis, A.; Reese, A. Liebigs Ann. Chem. 1901, 315, 75, 98. b) Müller, H.; Stübinger, A. Process for the preparation of triarylphosphines. BASF SE Patent, DE2007535A1, February 19, 1970.
[2] Issleb, K.; Brack, A. Z. Darstellung des Tricyclohexylphosphins und seiner Derivate. Anorg. Allg. Chem. 1956, 277, 258-270.
[3] Yu, J. S.; Rothwell, I. P. J. Chem. Soc., Chem. Commun. 1992, 632-633.
[5] a) Barder, T. E.; Buchwald, S. L. Rationale Behind the Resistance of Dialkylbiaryl Phosphines toward Oxidation by Molecular Oxygen. J. Am. Chem. Soc. 2007, 129, 5096-5101. b) Altman, R. A.; Buchwald, S. L. Pd-catalyzed Suzuki-Miyaura reactions of aryl halides using bulky biarylmonophosphine ligands. Nature Protocols 2007, 2, 3115-3121. c) Lavoie, C. M.; Stradiotto, M. et al. Challenging nickel-catalysed amine arylations enabled by tailored ancillary ligand design. Nat. Commun. 2016, 7, 11073.