Advanced Synthesis and Catalysis ─ Carbene Chen Free carbene Carbenes can be generated by α-elimination or decomposition of ketene, diazo, or diazirine compounds. Carbenes can also Carbenes can exist in either singlet or triplet state whereas the be generated by thermolysis. Flash vacuum pyrolysis (FVP) ground state of nitrene is always singlet. If there is a large gap allows heating the reactant at very high temperature for a short between the σ and p orbitals of the carbene, the ground state period of time, typically > 500 ºC for 0.01 s in gas phase. will be singlet due to the relatively lower energy cost in electron Carbene is normally unstable and undergoes rearrangement pairing. Carbenes with a p-donor atom (N, O, or halogen) can readily. also promote electron pairing. Advanced Synthesis and Catalysis ─ Carbene Chen Carbenes can also be formed by Bamford–Stevens reaction in The Corey–Fuch reaction is also a one-carbon homologatioin aprotic solvents. In protic solvents, the carbenium ion is formed reaction that generates terminal alkyne from aldehyde through instead. This reaction is mechanistically similar to the Shapiro a vinylidene–acetylene rearrangement. The Seyferth–Gilbert reaction that generates vinyl carbanion. reaction can be viewed as the Horner–Emmons version of the Wittig-type Corey–Fuch reaction. The Bestmann-Ohira reaction is a modified Seyferth–Gilbert reaction with the generation of the diazo nucleophile by deacetylation under milder conditions. In Wolff rearrangement and the Arndt–Eistert homologation, carbene is generated by decomposition of diazoketone promoted by photolysis or Ag(I) or Cu(II) catalysts. Advanced Synthesis and Catalysis ─ Carbene Chen Skattebøl rearrangement generates a carbene from Thiamine (vitamine B1) is a N-heterocyclic carbene (NHC) that dibromocyclopropane. Subsequent rearrangement yields catalyzes benzoin condensation. This organocatalysis reaction allene. When an adjacent olefin is present, cyclopentadiene is was first documented more than six decades ago, and the formed. mechanism of this umpolung reaction was established by Breslow. Buchner reaction is a method for seven-membered ring synthesis via ring-expansion. Cyclopropanation of a six- membered aromatic ring with diazo compounds followed by a rearrangement gives cycloheptatrienes. Advanced Synthesis and Catalysis ─ Carbene Chen Various NHC catalysts, including chiral versions, have been Bode reported the use of NHC to catalyze internal redox of developed. The scope of this carbonyl umpolung reaction has epoxyaldehyde to generate activated carboxylate for also been explored extensively. Stetter demonstrated in 1976 esterification. He has further shown that NHC can catalyze that thiazolium-catalyzed nucleophilc addition also work with asymmetric Diels-Alder reaction of azadienes and electron- Michael acceptors. Both intra- and intermolecular variants of deficient enals. the Stetter reaction have been reported. Glorius also found that cross-condensation of aldehydes/imines with enals gives γ- or β-lactones depending on the reaction conditions. Advanced Synthesis and Catalysis ─ Carbene Chen Metal carbenoid Fischer carbenes are typically prepared by electrophilic O- alkylation of acyl complexes that was synthesized by The reactivity of metal carbenoids is largely determined by the nucleophilic alkylation of carbonyl complexes. Cationic π-donor ability of the carbene ligand. Metal carbenoids with carbenoids can be prepared by alkylation or protonation of substituents capable of π-interactions, for example, N, O, Cl, neutral acyl complexes. and Ph, are call Fischer carbenes. These electrophilic complexes react with nucleophiles through the coordinating carbon of the singlet carbene ligand. Metal carbenoids without these substitutions, for example, methylene and alkylidene, require substantial π-donation from the meal are called Schrock carbene. These nucleophilic complexes react with electrophiles through the coordinating carbon of the triplet carbene ligand. However, reversed reactivity has been observed. For example, methylene ligands on a positively charged metal complex can be electrophilic. Schrock carbenes are typically prepared by removal of an α hydrogen from an alkyl ligand. The loss of the α hydrogen atom can be induced by steric crowding or α-elimination. They can also be prepared by alkylidene transfer from phosphoranes or other metals. Advanced Synthesis and Catalysis ─ Carbene Chen Dötz discovered in 1975 that Fischer carbenes can react with Wulff has extended the scope of Dötz reaction to vinyl Fischer alkyne to give naphthols. Increasing the electrophilicity of the carbenes. Vinyl and alkynyl Fischer carbenes are also good carbenoids leads to more reactive complexes. The order of dienophiles. The Diels–Alder reaction product of alkynyl reactivity is :CPh2 > :C(OR)Ph > :C(NR2)Ph and CO >> PR3, Fischer carbenes is a vinyl Fischer carbene that can participate but the reactivity is suppressed when performing the reaction in in Dötz reaction. the presence of excess CO. Terminal alkynes react to yield 2- substituted naphtols selectively whereas internal alkynes react with low regioselectivity. Advanced Synthesis and Catalysis ─ Carbene Chen In addition to participating in Dötz reaction, Fischer carbenes Fischer carbenes can also react with C=X groups through can react with alkynes to give indenes, enones, or pyrones. ketene-type chemistry under photolytic conditions and enolate- type chemistry under thermal conditions. Vinyl Fisher carbenes undergo conjugate addition with hindered enolates and 1,2- addition with unhindered enolates. Advanced Synthesis and Catalysis ─ Carbene Chen Schrock carbenes can be viewed as the metal version of Wittig Tebbe’s reagent is also very reactive toward olefins, forming reagents but much more reactive because of the oxophilicity of stable metallacylces in the presences of base. These the metal. In addition to aldehydes, they also react with esters metallacycles readily exchange with other olefins via and amides to give enol ethers and enamides. The most useful metathesis to give new metallacycles. carbene for this type of reaction is the Tebbe’s reagent Cp2TiCH2ClAlMe2. In the presence of pyridine, Tebbe’s reagent is synthetically equivalent to Cp2Ti=CH2. Fischer carbenes can react with olefins to form cyclopropanes but the efficiency is low. Electrophilic, cationic iron carbenes, however, are exceptionally efficient cyclopropanating agents as first demonstrated by Helquist and Brookhart. Carreira has recently shown that Fe(TPP)Cl catalyzes cyclopropanation in 6 M KOH with in situ generation of diazomethane. Advanced Synthesis and Catalysis ─ Carbene Chen Simmons–Smith cyclopropanation reaction can be directed by Copper(I), cobalt(II), palladium(II), irridium(III), ruthenium(II) and polar functional groups. The generally accepted mechanism, rhodium(0/II) complexes can all catalyze the decomposition of however, does not involve copper that consists up to 10% of diazo compounds to give carbenoids that cyclopropanate the alloy. The activation of Zn by Cu possibly at the surface of olefins. Doyle has demonstrated the intermediacy of metal the alloy is essential to this reaction. The use of Et2Zn/CH2I2 to carbenoid and the coordination of olefin to metal. One or two generate the carbenoid suppresses polymerization. Various electron-withdrawing or vinyl/aryl groups are typically used to chiral auxiliaries and additives have been developed to effect stabilize the diazo compounds. Asymmetric cyclopropanation asymmetric cyclopropanation. was first achieved by Evans using the Cu-BOX catalyst system. In addition to diazos, phenyliodonium ylides can also be used as the carbene source. Advanced Synthesis and Catalysis ─ Carbene Chen In addition to cyclopropanation, metal carbenoids are also Doyle and Davies have each developed a chiral rhodium highly reactive toward C–H and X–H insertion. The distribution catalyst system for asymmetric C–H insertion reactions. of the products can be controlled by the catalyst ligands. Davies has also coupled C–H insertion with sigmatropic Intramolecular C–H insertion generally gives five-membered rearrangement to establish allylic quaternary centers. ring products. Researchers at Merck successfully applied the rhodium-catalyzed N–H insertion to the synthesis of thienamycin. Advanced Synthesis and Catalysis ─ Carbene Chen Ibata found in 1974 that decomposition of diazo compounds in Decomposition of diazo compounds in the presence of an the presence of a nearby carbonyl group gives carbonyl ylides allylic sulfide, halide, amine, or ether gives hetero ylides that that undergo 1,3-dipolar cycloaddition. This type of chemistry undergo sigmatropic rearrangement to give C–X insertion was later studied by Padwa extensively. products. Early studies under photo or thermal conditions leads to considerable cyclopropanation products. Krimse found in 1968 that copper carbenoids favor the nucleophilic addition of the heteroatom. The scope of this reaction was expanded by Doyle and later by Wood. Advanced Synthesis and Catalysis ─ Carbene Chen Nitrene Du Bois later developed nitrene insertion chemistry for the synthesis of cyclic ureas and guanidines. Bridged ligands were Breslow showed in 1982 that inter- and intramolecular C–H introduced as mechanistic studies indicated that ligand amination can be catalyzed by Mn(III)-tetraphenylporphyrin dissociation is the major pathway for catalyst decomposition. (TPP), Fe(III)-TPP, or Rh2(OAc)4. Intermolecular nitrene C–H insertion