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N-heterocyclic carbenes (NHC) are a class of ligand that are typically employed in palladium-catalyzed coupling reactions. The structural and electronic properties of NHC ligands afford them a wide array of utility and general scope in palladium-catalyzed coupling. NHC ligands thus enjoy widespread use and are therefore considered privileged ligands.
Palladium-NHC bonding
editHistorically, N-heterocyclic carbenes were thought to mimic properties of phosphines, another type of privileged ligand. Recent discoveries, however, have unveiled a myriad of steric and electronic differences between the two ligands.[1]
Firstly, compared to phoshphine ligands, NHC ligands' cone angle is much more complex. The imidazole ring of the NHC ligand is angled away from the palladium center, yet the substituents at the 1,3 positions of the imidazole ring are angled towards it. The presence of the ligand inside of the metal coordination sphere affects the metal reactivity. Secondly, the electronics of the Pd-NHC bond differ from that of the palladium-phosphine bond. The palladium-NHC bond is typified by strong sigma donation from the ligand to the palladium center. This is the result of the unshared valence electrons of the carbene. Furthermore, the π-backbonding and ligand-palladium π donation must also be considered as contributory elements of the Pd-NHC bond. As a result, the Pd-NHC bond is very strong.[1][2]
Synthesis of Pd-NHC complexes
editVarious methods exist for the synthesis of Pd-NHC complexes. One method involves the in-situ generation of the free carbene in the presence of a palladium compound. Deprotonation of the imidazolium salt with strong base affords the free carbene, which subsequently binds to the palladium.
Pd-NHC complexes can also be synthesized through transmetalation of imidazolium salts with silver complexes. The transmetallated NHCs can either be isolated for subsequent reaction with palladium in a two step method, or generated in the presence of palladium in a one-pot reaction. However, generation of Pd-NHC complexes by Ag transmetallation is cost-prohibitive and hampered by Ag complexes’ light sensitivity.[1]
The synthesis of Pd-NHC complexes can also be achieved through substitution of a labile ligand L in a Pd-L complex. Labile ligands typically include cyclooctadiene, Dibenzylideneacetone, bridging halides or phosphines. This process can be used in conjunction with the in-situ generation of free carbenes.
Pd-NHC complexes in catalytic cross-coupling
editThe features and advantages of various palladium-catalyzed cross-coupling reactions are enhanced by the use of N-heterocyclic carbene ligands. Their benefit is seen through NHCs' proliferation as a ligand in Suzuki-Miyaura, Negishi, Sonogashira, Kumada-Tamao-Corriu, Hiyama, and Stille cross-coupling. By using the NHC ligands in palladium-catalyzed carbon-carbon cross-coupling reactions, reaction times can be reduced, substrate scope expanded, reaction conditions ameliorated, and turnover number increased.[1]
Suzuki-Miyaura cross-coupling
editSuzuki-Miyaura cross-coupling typically involves the coupling of organobromides and organoboron compounds. While Suzuki-Miyaura cross-couplings typically employ organobromides as coupling partners, organochlorides are more desirous electrophiles for cross-coupling due to their comparative low cost and abundance. However, their high bond dissociation energy renders them relatively unreactive towards the mild reaction conditions typical of Suzuki-Miyaura cross-coupling. However, with the advent of Pd-NHC complexes, organochlorides have emerged as viable partners in Suzuki-Miyaura cross coupling.[1][3]
Negishi coupling
editThe use of NHC-Pd-PEPPSI complexes in Negishi cross-coupling has resulted in high turnover numbers and turnover frequencies. [4]Additionally, NHC-Pd complexes can be used to couple sp3 centers to sp3 centers in higher yield than their non-NHC Pd analogs.[5] However, studies of Pd-NHC complexes and their utility in Negishi coupling are currently lacking despite these promising results.[1]
Sonogashira coupling
editPd-NHC complexes used in Sonogashira cross-coupling effect temperature stability in the complex.[6] As in other Pd-NHC mediated cross-coupling reactions, the use of Pd-NHC complexes also allow higher turnover numbers than their NHC-free counterparts.[7] NHC-palladacycles permit copper-free Sonogashira reactions to be carried out.[8][9]
Heck-Mizoroki coupling
editThe use of Pd-NHC complexes in Heck-Mizoroki cross-coupling permits the use of cheaper, ample supplies of aryl chloride substrates.[1] Additionally, the activity and stability of the catalyst in Heck-Mizoroki coupling can be enhanced by adjusting the 1,3 substituents on the imidazole ring.[10]
Notes
edit- ^ a b c d e f g Fortman, George; Nolan, Steven (2011). "N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union". Chemical Society Reviews. 40: 5151–5169. doi:10.1039/C1CS15088J.
- ^ Eastman, K. "N-Heterocyclic Carbenes (NHCs)" (PDF). www.scripps.edu.
- ^ Gstöttmayr, Christian; Volker, Böhm; Eberhardt, Herdtweck; Grosche, Manja; Herrmann, Wolfgang (2002). "A Defined N-Heterocyclic Carbene Complex for the Palladium-Catalyzed Suzuki Cross- Coupling of Aryl Chlorides at Ambient Temperatures". Angewandte Chemie International Edition. 41 (8): 1363–1365.
- ^ Nasielski, J.; Hadei, N.; Achonduh, G; E. A. B., Kantchev; O'Brien, C.J. (2010). "Structure–Activity Relationship Analysis of Pd–PEPPSI Complexes in Cross-Couplings: A Close Inspection of the Catalytic Cycle and the Precatalyst Activation Model". Chemistry - A European Journal. 16: 10844–10853. doi:10.1002/chem.201000138.
- ^ Niloufar, Hadei; Kantchev, Eric; O'Brien, Christopher (2005). "The First Negishi Cross-Coupling Reaction of Two Alkyl Centers Utilizing aPd − N-Heterocyclic Carbene (NHC) Catalyst". Organic Letters. 7 (17): 3805–3807.
- ^ Batey, Robert; Shen, Ming; Lough, Alan (2002). "Carbamoyl-Substituted N-Heterocyclic Carbene Complexes of Palladium(II): Application to Sonogashira Cross-Coupling Reactions". Organic Letters. 14: 1411–1414. doi:10.1021/ol017245g.
- ^ Kim, Jong-Ho; Lee, Dong-Ho; Jun, Bong-Hyun; Lee, Yoon-Sik (2007). "Copper-free Sonogashira cross-coupling reaction catalyzed by polymer-supported N-heterocyclic carbene palladium complex". Tetrahedron Letters. 48 (40): 7079–7084. doi:10.1016/j.tetlet.2007.08.015.
- ^ Chinchilla, Rafael; Nàjera, Carmen (2007). "The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry". Chemical Reviews. 107: 874–922.
- ^ McGuinness, David; Cavell, Kingsley (2000). "Donor-Functionalized Heterocyclic Carbene Complexes of Palladium(II): Efficient Catalysts for C - C Coupling Reactions". Organometallics. 19: 741–748.
- ^ Taige, Maria; Zeller, Alexander; Ahrens, Sebastian; Goutal, Sigrid; Hardtweck, Eberhardt (2006). "New Pd–NHC-complexes for the Mizoroki–Heck reaction". Journal of Organometallic Chemistry. 692: 1519–1529.