N-Heterocyclic Carbenes

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N-Heterocyclic carbenes: Structure, Properties And Applications:

N-Heterocyclic carbenes : Structure, Properties And Applications Presented By : Mohammad Ovais Dar M.S(pharm.) 3 rd Sem Medicinal Chemistry

N-Heterocyclic Carbene:

N-Heterocyclic Carbene Neutral compound Divalent carbon with 6- electron valence shell Usually adjacent to electronegative atom Highly nucleophilic Stable carbenes due to steric /electron effects Structurally versatile

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NHCs: Early Beginnings Ofele (1968): Attempt to generate dihydro -complexes Wanzlick (1968): Isolation as a mercury dimer

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Arduengo (1991): Deprotonation of a imidazolium salt This synthesis of the first N-heterocyclic carbene (NHC) 1,3-di( adamantyl )imidazol-2-ylidene ( IAd ) led to an explosion of experimental and theoretical studies with libraries of novel NHCs being synthesized and analysed

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Histogram of the SciFinder search of “heterocyclic carbene

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Nature of the carbene: Overview Hybridization of carbon breaks degeneracy of the p orbitals Ground state spin multiplicities for carbenes Singlet carbenes have filled & vacant orbital ambiphillic If singlet-triplet gap is >2 eV , singlet state predominant Both steric and electronic factors play a large role in influencing the orbital separation

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Nature of the carbene: Electronics Inductive effects of σ-withdrawing substituents favor singlet state The σ nonbonding orbital has increased “s” character Smaller gap of σ-donating substituents favor triplet state

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Nature of the carbene: Electronics Mesomeric effects involve π-donating/withdrawing substituents π-donating (X) include: -F, -Cl, -Br, -I, -NR2, -PR2, -SR π- withdrawing (Z) include: -COR, -CN, -CF3, -BR2, -SiR3, -SR The energy of the vacant pπ is increased with the combination of the lone pairs and as the σ orbital is unchanged, the σ- p π gap increases.

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Nature of the carbene: Sterics If electronic effects are insignificant, sterics can dictate ground state Linear geometries favor triple state One p orbital is left perpendicular to the plane, unaffected, becomes pπ Other p orbital is stabilized and acquires more “s” character, becomes σ With significant steric bulk, the carbene substituents broaden the bond angle

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Nature of the NH carbene: Stability Nitrogen heteroatoms are σ-electron withdrawing and π-donating. Therefore this breaks the degeneracy of the p x / p y energy level N-C-N bond is bent, forced by the structure of the ring. Singlet state is made more favorable Steric bulk helps to kinetically stabilize. Steric bulk is distal from carbene, which avoids making the bond more linear

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Properties of NHCs: Sterics of Ligand The steric properties of NHCs can be conveniently quantified using the ‘buried volume’ parameter (% V bur ) developed by Nolan, Cavallo and co-workers The % V bur value of an NHC refers to the percentage of a sphere occupied or ‘buried’ by the ligand upon coordination to a metal at the centre of the sphere The buried volume can be determined from crystallographic data or from theoretical calculations with the free NHC, various NHC–metal complexes or the azolium salt precursor being suitable data sources

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Properties of NHCs: pKa’s Compiled p Ka values (DMSO) Significant rate difference between salts cores

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Properties of NHCs: Electronic Character The electronic properties of NHCs are most commonly described using the Tolman electronic parameter (TEP) Originally developed for phosphines Electron donating into metal caused CO ligand to weaken and can be examined by IR The lower the TEP, the more electron donating the NHC

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NHC Applications Palladium cross-coupling reactions can be improved Aside from increased thermal stability of the catalyst, NHC can influence catalytic cycle More electron-rich Pd for OA Increased steric properties, as compared to phosphines aid reductive elimination Avoidance of Pd black through Pd(0) stabilization

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Grubbs Z-selective Ruthenium Olefin Metathesis The steric environment in this catalyst is fixed by a key sp 3 -C-H activation at the adamantyl group, which leads to the high Z-selectivity and, in this case, enantioselectivity with complex ‘A’ being used as a single stereoisomer. e.e ., enantiomeric excess.

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Yang’s Cross- Benzoin Reaction

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NHCs Tested in the Benzoin Reaction (2007−2014)

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Seminal Intramolecular Stetter Reactions

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Recent Chiral Catalysts for the Intramolecular Stetter Reaction

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Annulation Reactions Glorius Synthesis of γ- Butyrolactones Enantioselective Annulation of Enals and Trifluoromethyl Ketones

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Proposed Mechanism for γ- Lactone Formation

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Enantioselective Hetero-Diels−Alder Reaction

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Postulated Catalytic Cycle for NHC-Catalyzed Hetero-Diels−Alder Reaction

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Conclusion Stabilization a combination of steric and electronics properties Methods for quantifying NHC properties are improving Can be an improvement over use of phosphines High thermal and oxidative stability in NHC-metal complexes

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