Carbene-addition reactions

An important synthetic application of this reaction is in dehalogenation of dichloro- and dibromocyclopropanes. The dihalocyclopropanes are accessible via carbene addition reactions (see Section 10.2.3). Reductive dehalogenation can also be used to introduce deuterium at a specific site. The mechanism of the reaction involves electron transfer to form a radical anion, which then fragments with loss of a halide ion. The resulting radical is reduced to a carbanion by a second electron transfer and subsequently protonated. 

Metal-Catalyzed. Cyclopropanation. Carbene addition reactions can be catalyzed by several transition metal complexes. Most of the synthetic work has been done using copper or rhodium complexes and we focus on these. The copper-catalyzed decomposition of diazo compounds is a useful reaction for formation of substituted cyclopropanes.188 The reaction has been carried out with several copper salts,189 and both Cu(I) and Cu(II) triflate are useful.190 Several Cu(II)salen complexes, such as the (V-f-butyl derivative, which is called Cu(TBS)2, have become popular catalysts.191... 

Ismaili, H., F.o. Lagugnei-Labarthet, and M.S. Workentin, Covalently assembled gold nanoparticle-carbon nanotube hybrids via a photoinitiated carbene addition reaction. Chemistry of Materials, 2011. 23(6) p. 1519-1525. 

Intramolecular carbene addition reactions have a special importance in the synthesis of strained ring compounds. Because of the high reactivity of carbene or carbenoid species, the formation of highly strained bonds is possible. The strategy for synthesis is to construct a potential carbene precursor, such as diazo compounds or di- or trihalo compounds, which can undergo intramolecular addition to the desired structure. Section E of Scheme 10.5 gives some representative examples. 

Extreme cases were reactions of the least stabilized, most reactive carbene (Y = CF3, X = Br) with the more reactive alkene (CH3)2C=C(CH3)2, and the most stabilized, least reactive carbene (Y = CH3O, X = F) with the less reactive alkene (1-hexene). The rate constants, as measured by LFP, were 1.7 x 10 and 5.0 X lO M s, respectively, spanning an interval of 34,000. In agreement with Houk s ideas,the reactions were entropy dominated (A5 —22 to —29e.u.). The AG barriers were 5.0 kcal/mol for the faster reaction and 11 kcal/ mol for the slower reaction, mainly because of entropic contributions the AH components were only —1.6 and +2.5 kcal/mol, respectively. Despite the dominance of entropy in these reactive carbene addition reactions, a kind of de facto enthalpic control operates. The entropies of activation are all very similar, so that in any comparison of the reactivities of alkene pairs (i.e., ferei)> the rate constant ratios reflect differences in AA//t, which ultimately appear in AAG. Thus, car-benic philicity, which is the pattern created by carbenic reactivity, behaves in accord with our qualitative ideas about structure-reactivity relations, as modulated by substiment effects in both the carbene and alkene partners of the addition reactions. " Finally, volumes of activation were measured for the additions of CgHsCCl to (CH3)2C=C(CH3)2 and frani-pentene in both methylcyclohexane and acetonitrile. The measured absolute rate constants increased with increasing pressure Ayf ranged from —10 to —18 cm /mol and were independent of solvent. These results were consistent with an early, and not very polar transition state for the addition reaction. 

K. N. Houk, N. G. Rondan, and J. Mareda, Theoretical Studies of Halocarbene Cycloaddition Selectivities. A New Interpretation of Negative Activation Energies and Entropy Control of Selectivities, Tetrahedron 1985, 41, 1555. Calculations on carbene addition reactions led to a general explanation of why it is possible for very exothermic, bimolecular reactions to have negative activation enthalpies. 

Quite recently a modification of the carbene addition reaction has been published and applied to the synthesis of phoracantholide I (11/88) [70]. The silyl enol ether 11/85 prepared from ( )-8-nonanolide underwent addition of chlorocarbene to give the intermediate bicyclic adduct 11/86, which rearranged into an E/Z-mixture of a,/J-unsaturated lactones 11/87 by heating. Phoracantholide I (11/88) was formed by hydrogenation of the latter, Scheme 11/12. 

Metal-catalyzed cyclopropanation of an alkene by a diazo compound, reaction 7.33, is another reaction where new C-C bonds are formed. This reaction finds use in the industrial manufacture of synthetic pyrethroids. The precatalysts for carbene addition reactions are coordination complexes of copper or rhodium. It should be noted that reaction 7.33 gives a mixture of isomers (syn plus anti) of the cyclopropane derivative. However, with some chiral catalysts, only one optical isomer with good enantioselectivity is obtained (see Section 9.5). 

In a very different area of organic chemistry Ken produced a series of landmark theoretical papers on carbene reactions. He developed a general theory, showing how orbital interactions influence reactivity and selectivity in carbene additions to alkenes. Ken also showed how entropy control of reactivity and negative activation barriers in carbene addition reactions could both be explained by a new, unified model. 

Ligand Design in Metal Chemistry 11.3.1 Carbene addition reactions... 

As I synthesized ( )-sabina ketone in 1976 by intramolecular carbene addition reaction, as shown in Figure 4.11, the similarity of A with sabina ketone led me to synthesize the proposed structure A of... 

Several instructive experiments describing singlet carbene addition reactions to styrene and styrene derivatives (a-, p-methyl styrene and 4-methyl styrene) were submitted by... 

Despite the dominance of entropy in these reactive carbene addition reactions a kind of defacto enthalpic control operates the entropies of activation are all very similar, so that in any comparison of the reactivities of alkene pairs (i.e., rgi), the rate constant ratios reflect differences in AAHi, which ultimately appear in AAGf Thus carbenic philicity, which is the pattern created by carbenic reactivity, behaves in accord with our qualitative ideas about structure/reactivity relations, as modulated by substituent effects in both the carbene and alkene partners of the addition reactions. [66,99]... 

All-ezs cyclononatetraenide salts have usually been made from bicyclo[6.1.0]nonatriene derivatives, the latter in turn having been got by carbene addition reactions to cyclooctatetraene. Thus the first preparations were as follows [52,60,61,66] ... 

Among other polymer-bound catalysts, onium compounds can be used successfully in halogen exchange reactions between activated and nonactivated halides. This is the case, for instance, in additions to the double bonds of dichlorocarbene to form substituted cyclopropanes and in C-alkylating nitriles. When optically active polymeric ammonium compounds are used as catalysts in carbene addition reaction, chiral products form. ... 

Structure and Reactivity of Carbenes Generation of Carbenes Addition Reactions Insertion Reactions Rearrangement Reactions Related Reactions Nitrenes and Related Intermediates Rearrangements to Electron-Deficient Nitrogen... 

Because the additions are normally stereospecific with respect to the alkene, if an open-chain intermediate is involved, it must collapse to product at a rate more rapid than that of single-bond rotations, which would destroy the stereoselectivity. Entries 5-10 in Scheme 10.5 are examples of transition-metal-catalyzed carbene addition reactions. 

Triphase catalysts were also used for C-alkylations (Komeili-Zadeh, 1978) and have been shown to promote asymmetric addition in carbene addition reactions (Chiellini and Solaro, 1977 Colonna et al., 1978). Ammonium groups have been replaced by phosphoric triamides (Tomoi et al., 1978), phosphonium groups (Tundo, 1978), and polyethylene glycol (Regen and Dulak, 1977) to provide alternate phase-transfer agents. 

Although interesting from a mechanistic point of view, these carbene addition reactions are limited to the laboratory and do not occur in biological processes. 

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