PEPPSI

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A schematic of a generic Pd-PEPPSI type precatalyst. R1, R2, and R3 represent carbon or heteroatom substituents. Generic PEPPSI.png
A schematic of a generic Pd-PEPPSI type precatalyst. R1, R2, and R3 represent carbon or heteroatom substituents.

PEPPSI is an abbreviation for pyridine-enhanced precatalyst preparation stabilization and initiation. It refers to a family of commercially available [1] [2] [3] palladium catalysts developed around 2005 by Prof. Michael G. Organ and co-workers at York University, [4] [5] which can accelerate various carbon-carbon and carbon-heteroatom [6] bond forming cross-coupling reactions. In comparison to many alternative palladium catalysts, Pd-PEPPSI-type complexes are stable to air and moisture and are relatively easy to synthesize and handle.

Contents

Structure and synthesis

In the basic structure of Pd-PEPPSI, R1 can be a methyl (CH3, Me), ethyl (C2H5, Et), isopropyl (C 3 H 7, iPr), isopentyl (C5H11, iPent), or isoheptyl (C7H15, iHept) group, and starting from the second in the row the resulting catalysts are thus labeled as PEPPSI-IEt, PEPPSI-IPr, PEPPSI-IPent, and PEPPSI-IHept respectively, with or without "Pd-" added in front. [7] Commonly used PEPPSI catalysts such as Pd-PEPPSI-IPr [8] contain an unsubstituted imidazole core (R2=H) and a 3-chloro substituted pyridine ligand (R3=3-Cl). However, structural modifications of the imidazole backbone [9] [10] [11] [12] [13] and pyridine ligand [7] [10] [11] can profoundly affect the catalytic activity of these complexes.

The synthesis and structure of Pd-PEPPSI catalysts were presented in 2005 [4] [1] and published in 2006. [14] PEPPSI catalysts are organopalladium complexes containing N-heterocyclic carbene (NHC) ligands. They can be obtained by reacting an imidazolium salt, palladium(II) chloride, and potassium carbonate in 3-chloropyridine as a solvent, under vigorous stirring at 80 °C for 16 hours in air. The yield of PEPPSI in this reaction is 97–98%. [1] [14] Contrary to other common palladium-based catalysts, such as tetrakis(triphenylphosphine)palladium(0), PEPPSI is stable to exposure to air [15] and moisture. [16] Even heating in dimethyl sulfoxide at 120 °C for hours does not result in significant decomposition or deactivation of PEPPSI catalysts. [1]

iPEPPSI

Examples of abnormal NHCs based on the mesoionic 1,2,3-triazol-5-ylidene structure have been used for palladium catalysis. In this manner, pyridine fused tzNHCs were prepared to yield palladium complexes with pyridine attached to the carbene core. With this ligand, air stable and highly active palladium complexes of iPEPPSI (as in internal PEPPSI) were synthesized. [17]

An example of iPEPPSI complex. PyNHC-PEPPSI-water.png
An example of iPEPPSI complex.

Properties and applications

PEPPSI can catalyze various palladium cross-coupling reactions including Negishi coupling, [15] Suzuki coupling, Sonogashira coupling, Kumada coupling, [18] and the Buchwald–Hartwig amination [6] as well as aryl sulfination [19] [10] [6] and the Heck reaction. [1] [20] In Negishi coupling, PEPPSI promotes reaction of alkyl halides, aryl halides or alkyl sulfonates with alkylzinc halides, [21] and the important advantage of PEPPSI over alternative catalysts is that the reaction can be carried out in a general chemical laboratory, without a glove box. PEPPSI contains palladium in the +2 oxidation state and is thus a "precatalyst", that is the metal must be reduced to the active Pd(0) form in order to enter the cross-coupling catalytic cycle. This is usually achieved in situ in the presence of active transmetalating agents such as organo-magnesium, -zinc, -tin, or -boron reagents. [7] Once activated, the NHC-Pd(0) species becomes rather air-sensitive. [15] [1] [22] [23]

Suzuki coupling (a) and Buchwald-Hartwig reaction (b) can be activated by PEPPSI complexes. Peppsi-couplings.png
Suzuki coupling (a) and Buchwald-Hartwig reaction (b) can be activated by PEPPSI complexes.

An efficient, cationic palladium catalyst of iPEPPSI (internal PEPPSI) type was demonstrated to efficiently catalyse the copper-free Sonogashira reaction in water as the only solvent, under aerobic conditions, in the absence of copper, amines, phosphines and other additives. [17]

Sonogashira coupling under green reaction conditions using iPEPPSI. Sonogashira-peppsi.png
Sonogashira coupling under green reaction conditions using iPEPPSI.

Additionally, the cationic palladium iPEPPSI complex shown above was used in the hydroamination of alkynes as well. The authors have demonstrated that the ligands actively participate in the reaction mechanism since the pyridine group acts as an internal base to enable the intramolecular proton transfer between active sites of intermediates. [24] [25]

Palladium iPEPPSI complex with designated catalytic region and pyridine wingtip that actively participates in the catalytic reactions as internal base. Virant-OrgLett-2020.png
Palladium iPEPPSI complex with designated catalytic region and pyridine wingtip that actively participates in the catalytic reactions as internal base.

Related Research Articles

The Heck reaction is the chemical reaction of an unsaturated halide with an alkene in the presence of a base and a palladium catalyst to form a substituted alkene. It is named after Tsutomu Mizoroki and Richard F. Heck. Heck was awarded the 2010 Nobel Prize in Chemistry, which he shared with Ei-ichi Negishi and Akira Suzuki, for the discovery and development of this reaction. This reaction was the first example of a carbon-carbon bond-forming reaction that followed a Pd(0)/Pd(II) catalytic cycle, the same catalytic cycle that is seen in other Pd(0)-catalyzed cross-coupling reactions. The Heck reaction is a way to substitute alkenes.

The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, and he shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichi Negishi for their contribution to the discovery and development of palladium-catalyzed cross-couplings in organic synthesis. This reaction is also known as the Suzuki–Miyaura reaction or simply as the Suzuki coupling. It is widely used to synthesize polyolefins, styrenes, and substituted biphenyls. Several reviews have been published describing advancements and the development of the Suzuki reaction. The general scheme for the Suzuki reaction is shown below, where a carbon-carbon single bond is formed by coupling a halide (R1-X) with an organoboron species (R2-BY2) using a palladium catalyst and a base.

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.

A transition metal carbene complex is an organometallic compound featuring a divalent organic ligand. The divalent organic ligand coordinated to the metal center is called a carbene. Carbene complexes for almost all transition metals have been reported. Many methods for synthesizing them and reactions utilizing them have been reported. The term carbene ligand is a formalism since many are not derived from carbenes and almost none exhibit the reactivity characteristic of carbenes. Described often as M=CR2, they represent a class of organic ligands intermediate between alkyls (−CR3) and carbynes (≡CR). They feature in some catalytic reactions, especially alkene metathesis, and are of value in the preparation of some fine chemicals.

<span class="mw-page-title-main">Persistent carbene</span> Type of carbene demonstrating particular stability

A persistent carbene (also known as stable carbene) is a type of carbene demonstrating particular stability. The best-known examples and by far largest subgroup are the N-heterocyclic carbenes (NHC) (sometimes called Arduengo carbenes), for example diaminocarbenes with the general formula (R2N)2C:, where the four R moieties are typically alkyl and aryl groups. The groups can be linked to give heterocyclic carbenes, such as those derived from imidazole, imidazoline, thiazole or triazole.

The Negishi coupling is a widely employed transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon-carbon bonds (C-C) in the process. A palladium (0) species is generally utilized as the metal catalyst, though nickel is sometimes used. A variety of nickel catalysts in either Ni0 or NiII oxidation state can be employed in Negishi cross couplings such as Ni(PPh3)4, Ni(acac)2, Ni(COD)2 etc.

In organic chemistry, the Buchwald–Hartwig amination is a chemical reaction for the synthesis of carbon–nitrogen bonds via the palladium-catalyzed coupling reactions of amines with aryl halides. Although Pd-catalyzed C-N couplings were reported as early as 1983, Stephen L. Buchwald and John F. Hartwig have been credited, whose publications between 1994 and the late 2000s established the scope of the transformation. The reaction's synthetic utility stems primarily from the shortcomings of typical methods for the synthesis of aromatic C−N bonds, with most methods suffering from limited substrate scope and functional group tolerance. The development of the Buchwald–Hartwig reaction allowed for the facile synthesis of aryl amines, replacing to an extent harsher methods while significantly expanding the repertoire of possible C−N bond formation.

In organic chemistry, the Kumada coupling is a type of cross coupling reaction, useful for generating carbon–carbon bonds by the reaction of a Grignard reagent and an organic halide. The procedure uses transition metal catalysts, typically nickel or palladium, to couple a combination of two alkyl, aryl or vinyl groups. The groups of Robert Corriu and Makoto Kumada reported the reaction independently in 1972.

<span class="mw-page-title-main">XPhos</span> Chemical compound

XPhos is a phosphine ligand derived from biphenyl. Its palladium complexes exhibit high activity for Buchwald-Hartwig amination reactions involving aryl chlorides and aryl tosylates. Both palladium and copper complexes of the compound exhibit high activity for the coupling of aryl halides and aryl tosylates with various amides. It is also an efficient ligand for several commonly used C–C bond-forming cross-coupling reactions, including the Negishi, Suzuki, and the copper-free Sonogashira coupling reactions. It is especially efficient and general when employed as a (2-aminobiphenyl)-cyclometalated palladium mesylate precatalyst complex, XPhos-G3-Pd, which is commercially available and stable to bench storage. The ligand itself also has convenient handling characteristics as a crystalline, air-stable solid.

In organic chemistry, a cross-coupling reaction is a reaction where two different fragments are joined. Cross-couplings are a subset of the more general coupling reactions. Often cross-coupling reactions require metal catalysts. One important reaction type is this:

<span class="mw-page-title-main">Dichlorotris(triphenylphosphine)ruthenium(II)</span> Chemical compound

Dichlorotris(triphenylphosphine)ruthenium(II) is a coordination complex of ruthenium. It is a chocolate brown solid that is soluble in organic solvents such as benzene. The compound is used as a precursor to other complexes including those used in homogeneous catalysis.

In chemistry, mesoionic carbenes (MICs) are a type of reactive intermediate that are related to N-heterocyclic carbenes (NHCs); thus, MICs are also referred to as abnormal N-heterocyclic carbenes (aNHCs) or remote N-heterocyclic carbenes (rNHCs). Unlike simple NHCs, the canonical resonance structures of these carbenes are mesoionic: an MIC cannot be drawn without adding additional charges to some of the atoms.

Decarboxylative cross coupling reactions are chemical reactions in which a carboxylic acid is reacted with an organic halide to form a new carbon-carbon bond, concomitant with loss of CO2. Aryl and alkyl halides participate. Metal catalyst, base, and oxidant are required.

Diiminopyridines are a class of diimine ligands. They featuring a pyridine nucleus with imine sidearms appended to the 2,6–positions. The three nitrogen centres bind metals in a tridentate fashion, forming pincer complexes. Diiminopyridines are notable as non-innocent ligand that can assume more than one oxidation state. Complexes of DIPs participate in a range of chemical reactions, including ethylene polymerization, hydrosilylation, and hydrogenation.

<span class="mw-page-title-main">CPhos</span> Chemical compound

CPhos is a phosphine ligand derived from biphenyl. It is a white solid that is soluble in organic solvents.

<span class="mw-page-title-main">Palladium–NHC complex</span>

In organometallic chemistry, palladium-NHC complexes are a family of organopalladium compounds in which palladium forms a coordination complex with N-heterocyclic carbenes (NHCs). They have been investigated for applications in homogeneous catalysis, particularly cross-coupling reactions.

<span class="mw-page-title-main">Transition metal NHC complex</span>

In coordination chemistry, a transition metal NHC complex is a metal complex containing one or more N-heterocyclic carbene ligands. Such compounds are the subject of much research, in part because of prospective applications in homogeneous catalysis. One such success is the second generation Grubbs catalyst.

Dialkylbiaryl phosphine ligands are phosphine ligands that are used in homogeneous catalysis. They have proved useful in Buchwald-Hartwig amination and etherification reactions as well as Negishi cross-coupling, Suzuki-Miyaura cross-coupling, and related reactions. In addition to these Pd-based processes, their use has also been extended to transformations catalyzed by nickel, gold, silver, copper, rhodium, and ruthenium, among other transition metals.

In organic chemistry, hydrovinylation is the formal insertion of an alkene into the C-H bond of ethylene. The more general reaction, hydroalkenylation, is the formal insertion of an alkene into the C-H bond of any terminal alkene. The reaction is catalyzed by metal complexes. A representative reaction is the conversion of styrene and ethylene to 3-phenybutene:

Heterogeneous metal catalyzed cross-coupling is a subset of metal catalyzed cross-coupling in which a heterogeneous metal catalyst is employed. Generally heterogeneous cross-coupling catalysts consist of a metal dispersed on an inorganic surface or bound to a polymeric support with ligands. Heterogeneous catalysts provide potential benefits over homogeneous catalysts in chemical processes in which cross-coupling is commonly employed—particularly in the fine chemical industry—including recyclability and lower metal contamination of reaction products. However, for cross-coupling reactions, heterogeneous metal catalysts can suffer from pitfalls such as poor turnover and poor substrate scope, which have limited their utility in cross-coupling reactions to date relative to homogeneous catalysts. Heterogeneous metal catalyzed cross-couplings, as with homogeneous metal catalyzed ones, most commonly use Pd as the cross-coupling metal.

References

  1. 1 2 3 4 5 6 PEPPSI Catalysts, Sigma-Aldrich
  2. ↑ PEPPSI™-IPent for Demanding Cross-Coupling Reactions, Sigma-Aldrich
  3. ↑ PEPPSI Catalyst, Sigma-Aldrich ChemFiles
  4. 1 2 Hadei, N.; Kantchev, E.A.B.; O'Brien, C.J.; Chass, G.; Hunter, H.H.; Penner, G.; Hopkinson, A.C.; Organ, M.G. (2005). Rational catalyst design and its application in sp3-sp3 couplings. 230th ACS National Meeting. Washington, DC: American Chemical Society. pp. Abstract 308.
  5. ↑ Hadei, N.; Kantchev, E.A.B.; O'Brien, C.J.; Organ, M.G. (2005). "The First Negishi Cross-Coupling Reaction of Two Alkyl Centers Utilizing a Pd−N-Heterocyclic Carbene (NHC) Catalyst". Org. Lett. 7: 3805–3807. doi:10.1021/ol0514909. PMID   16092880.
  6. 1 2 3 Valente, C.; Pompeo, M.; Sayah, M.; Organ, M.G. (2014). "Carbon–Heteroatom Coupling Using Pd-PEPPSI Complexes". Organic Process Research & Development . 18: 180–190. doi:10.1021/op400278d.
  7. 1 2 3 Nasielski, J.; Hadei, N.; Achonduh, G.; Kantchev, E.A.B.; O'Brien, C.J.; Lough, A.; Organ, M.G. (2010). "Structure-Activity Relationship Analysis of Pd-PEPPSI Complexes in Cross-Couplings: A Close Inspection of the Catalytic Cycle and the Precatalyst Activation Model". Chem. Eur. J. 16: 10844–10853. doi:10.1002/chem.201000138. PMID   20665575.
  8. ↑ PEPPSI™-IPr catalyst, Sigma-Aldrich
  9. ↑ Pompeo, M.; Froese, R.D.J; Hadei, N.; Organ, M.G. (2012). "Pd-PEPPSI-IPentCl: A Highly Effective Catalyst for the Selective Cross-Coupling of Secondary Organozinc Reagents". Angew. Chem. Int. Ed. 51: 11354–11357. doi:10.1002/anie.201205747. PMID   23038603.
  10. 1 2 3 Sayah, M.; Lough, A.J.; Organ, M.G. (2013). "Sulfination by Using Pd-PEPPSI Complexes: Studies into Precatalyst Activation, Cationic and Solvent Effects and the Role of Butoxide Base". Chem. Eur. J. 19: 2749–2756. doi:10.1002/chem.201203142. PMID   23296748.
  11. 1 2 Pompeo, M.; Farmer, J.L.; Froese, R.D.J; Organ, M.G. (2014). "Room-Temperature Amination of Deactivated Aniline and Aryl Halide Partners with Carbonate Base Using a Pd-PEPPSI-IPentCl-o-Picoline Catalyst". Angew. Chem. Int. Ed. 53: 3223–3226. doi:10.1002/anie.201310457. PMID   24677620.
  12. ↑ Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M.J.; Pompeo, M.; Froese, R.D.J.; Organ, M.G. (2015). "The Selective Cross-Coupling of Secondary Alkyl Zinc Reagents to Five-Membered-Ring Heterocycles Using Pd-PEPPSI-IHeptCl". Angew. Chem. Int. Ed. 127: 9638–9642. doi:10.1002/anie.201503941. PMID   26110577.
  13. ↑ Lu, D.-D.; Xu, X.-X.; Liu, F.-S. (2017). "Bulky Yet Flexible Pd-PEPPSI-IPentAn for the Synthesis of Sterically Hindered Biaryls in Air". J. Org. Chem. 82: 10898–10911. doi:10.1021/acs.joc.7b01711. PMID   28925697.
  14. 1 2 O'Brien, C.J.; Kantchev, E.A.B.; Valente, C.; Hadei, N.; Chass, G.A.; Lough, A.; Hopkinson, A.C.; Organ, M.G. (2006). "Easily Prepared Air- and Moisture-Stable Pd–NHC (NHC=N-Heterocyclic Carbene) Complexes: A Reliable, User-Friendly, Highly Active Palladium Precatalyst for the Suzuki–Miyaura Reaction". Chem. Eur. J. 12: 4743–8. doi:10.1002/chem.200600251. PMID   16568494.
  15. 1 2 3 Li, Jia Jack; Corey, E.J. (2009). Name reactions for homologations, Part 1. John Wiley and Sons. ISBN   978-0-470-48701-3.
  16. ↑ Valente, C.; Belowich, M.E.; Hadei, N.; Organ, M.G. (2010). "Pd-PEPPSI Complexes and the Negishi Reaction". Eur. J. Org. Chem. : 4343–4354. doi:10.1002/ejoc.201000359.
  17. 1 2 3 4 Gazvoda, M.; Virant, M.; Pevec, A.; Urankar, D.; Bolje, A.; Kočevar, M.; Košmrlj, J. (2016). "A mesoionic bis(Py-tzNHC) palladium(II) complex catalyses green Sonogashira reaction through an unprecedented mechanism". Chem. Commun. 52: 1571–1574. doi: 10.1039/c5cc08717a . PMID   26575368.
  18. ↑ Ackerman, Lutz (2009). Modern Arylation Methods. Verlag: Wiley-VCH. doi:10.1002/9783527627325. ISBN   9783527319374.
  19. ↑ Sayah, M.; Organ, M.G. (2011). "Carbon–Sulfur Bond Formation of Challenging Substrates at Low Temperature by Using Pd-PEPPSI-IPent". Chem. Eur. J. 12: 11719–11722. doi:10.1002/chem.201102158. PMID   21898625.
  20. ↑ Luis, Santiago V.; Garcia-Verdugo, Eduardo (2009). Chemical Reactions and Processes Under Flow Conditions. Green Chemistry Series. Royal Society of Chemistry. doi:10.1039/9781847559739. ISBN   978-0-85404-192-3.
  21. ↑ Cazin, Catherine S.J. (2010). N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis. Catalysis by Metal Complexes. Vol. 32. Netherlands: Springer. pp. 169–173. doi:10.1007/978-90-481-2866-2. ISBN   978-90-481-2866-2.
  22. ↑ Organ, M.G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E.A.; O'Brien, C.J.; Valente, C. (2006). "A User-Friendly, All-Purpose Pd–NHC (NHC=N-Heterocyclic Carbene) Precatalyst for the Negishi Reaction: A Step Towards a Universal Cross-Coupling Catalyst". Chem. Eur. J. 12: 4749–4755. doi:10.1002/chem.200600206. PMID   16568493.
  23. ↑ PEPPSI: Instructions for Use, Sigma-Aldrich
  24. 1 2 Virant, M.; Mihelač M.; Gazvoda M.; Cotman, A.E.; Pinter, B.; Košmrlj, J. (2020). "Pyridine Wingtip in [Pd(Py-tzNHC)2]2+ Complex Is a Proton Shuttle in the Catalytic Hydroamination of Alkynes". Org. Lett. 22: 2157–2161. doi: 10.1021/acs.orglett.0c00203 . PMC   7308070 . PMID   31999464.
  25. 1 2 Virant, Miha (2019). Development of homogeneous palladium catalytic systems for selected transformations of terminal acetylenes (PhD). University of Ljubljana.
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