The Kharasch Reaction

The Kharasch Reaction. Normal alkyl halides are not very reactive in coupling reactions with Grignard reagents. In general, good yields of coupling are obtained only by addition of transition metal catalysts. 3 Kharasch showed (Table 8.4) the effectiveness of several transition metals to promote the 

Chapter 8. Nucleophilic Species That Form Carbon-Carbon Bonds 

Cuprous [ Cu(I) ] salts are readily available and when mixed with Grignard reagents give excellent yields of cross-coupled products with very little disproportionation. This reaction will be discussed in greater detail in Section 8.7.A. However, a simple example is the reaction of isopropylmagnesium bromide with bromoethane in the presence of cuprous bromide (CuBr) to give 2-methylbutane. The origins of this reaction date 

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The addition of halocarbons (RX) across alkene double bonds in a radical chain process, the Kharasch reaction (Scheme 9.29),261 has been known to organic chemistry since 1932. The overall process can be catalyzed by transition metal complexes (Mt"-X) it is then called Atom Transfer Radical Addition (ATRA) (Scheme 9.30).262... 

Polymer formation during the Kharasch reaction or ATRA can occur if trapping of the radical (123), by halocarbon or metal complex respectively, is sufficiently slow such that multiple monomer additions can occur. Efficient polymer synthesis additionally requires that the trapping reaction is reversible and that both the activation and deactivation steps are facile. 

Andrus et al.44 employed a C2-symmetric bis(oxazoline) copper catalyst in the Kharasch reaction. When cyclohexene was used as the reaction substrate, yields ranging from 34% to 62% and ee from 30% to 81% were observed (Scheme 8-15). 

The Kharasch reaction has also been employed by Gennari and coworkers to synthesize, from (i)-carvone, a potential functionalized precursor of sarcodictyins and eleuther-obin (Scheme 62). 

Recently, immobilized metal ion-containing ionic liquids were presented for the Kharasch reaction [85]. Whereas copper salts proved to be suitable catalysts in the addition of CCI4 to styrene, FeCl2 gave poor results (12% product yield). 

The development of ruthenium complexes for other applications in radical chemistry is still in its infancy, but seems well suited to future expansion, thanks to the versatility of ruthenium as a catalytically active center. Large avenues have not been explored yet and remain open to research. For instance, the development of methodologies for the asymmetric functionalization of C-H bonds remains a challenge. The Kharasch-Sosnovsky reaction [51,52],in which the allylic carbon of an alkene is acyloxylated, its asymmetric counterpart, and the asymmetric version of the Kharasch reaction itself are practically terra incognita to ruthenium chemistry, and await the discovery of improved catalysts. 

Selective trapping of alkyl radicals from the alkyl halide component during the course of the catalytic disproportionation is the same as the previous observation with silver, and it indicates that the prime source of radicals in the Kharasch reaction lies in the oxidative addition of alkyl halide to reduced iron in Equation 47. Separate pathways for reaction of i-propyl groups derived from the organic halide and the Grignard reagent are also supported by deuterium labelling studies which show that they are not completely equilibrated.(49) Furthermore, the observation of CIDNP (AE multiplet effect) In the labelled propane and propene... 

The addition of polyhaloalkanes and related halo-genated compounds to alkenes can occur via a classical radical chain process (Scheme 13), which is often called the Kharasch reaction.38 In 1961, Minisci et al.39 and Asscher and Vofsi40 discovered that this reaction is catalyzed by transition metal ions in their lower valent state such as Cu+ and Fe2+, and they formulated the mechanism in Scheme 14. The catalysis of the additions by simple metal salts or complexes such as Cu(I)-2,2 -bipyridyl41a and ruthe-... 

Radicals are postulated to be important intermediates in a variety of chemical reactions, e.g. the Kharasch reaction and mechanism,... 

Scheme 26 (a) The Kharasch reaction, (b) The commonly proposed mechanism for... 

The dormant species in ATRP arises from the polymer chain being capped with a halogen atom (P -X), while in the active state the halogen is chelated to a metal complex, thus allowing monomer to add. This takes advantage of the Kharasch reaction in which halo-genated alkanes add to vinyl monomers by a free-radical reaction that is catalysed by transition-metal ions in their lower-valent state (Fischer, 2001). 

Fig. 30 Use of Red-Ox initiators in the Kharasch reaction mechanism of initiation in case of FeCli [39]...

There are numerous publications on the improvements to the Kharasch reaction. The primary method for improvement was the introduction of more sophisticated initiators (instead of peroxides [22-26, 37]). It was shown that various Red-Ox type initiators, like metal salts in different oxidation states (Cu", Cu ", Fe ", etc.), salts with organic acids (Co acetoacetate, Mn stearate), and a metal carbonyl - Fe(CO)5 give adducts with practical yields [38, 39] and allow to carry the reaction at near room temperatures (Fig. 30). 

Telomer mixtures can be separated by rectification. Congeners containing up to 15 C atoms can be easily prepared this way [57]. Formation of telomers of general formula C H2 2Cl4 with n - 20-50 was reported [58]. The Kharasch reaction with CCI4 yields ot,ot,ot,y-tetrachloroalkanes, while telomerization opens a way to a,a,a,co-tetrachloroalkanes. In the beginning free-radical initiators like azo-(bis)-diisobutyronitrile or benzoyl peroxide [57-60] were used later, metal complexes became popular. 

The intermediate 1,4,4,6-tetrachloro-2-hexyl radical may not only form 1,3,3,5,6-pentachlorohexane via abstraction of the Cl atom from 1,1,1,3-trichloropropane, but may eliminate the Cl radical as well with the formation of 4,4,6-trichlorohexene-1. This compound in turn gets involved into the Kharasch reaction... 

Conjugate additions. The Kharasch reaction using CuI-ZLiCl and MCjSiCl as. atalysts has been evaluated. Another report delineates synthetic and spectroscopic aspects f the conjugate allylation. 

The first proof of the existence of a negative dendritic effect was given by van Koten et al. in 2000 [90,118]. His group examined the influence of generation as well as the linker nature and length on the catalytic activity of car-bosilane dendrimer-supported Ni catalysts employed in the Kharasch reaction. The lower activity of higher generations with catalyst-crowded surfaces was attributed to site-site interactions with formation of inactive Ni"/Ni" complexes. 

This type of approach has also been used to attach antioxidants to unsaturated polymers. The novel approach of Scott in the 1970s (Scott, 1984) using the technique employed by Watson enabled the attack of substituted allyl mercap-tans and disulfides to olefinic double bonds employing the Kharasch reactions. 

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