Unsymmetrical Coupling

OCH2CH2OMe Chem Fhaim Bull 33 1016 (1984) (arenes, pyridines) 

E+ = H20, DA Br2, RX, epoxide, RCHO, R O, RCO2H, RC02R, RCOCL HCONR RCONR2, C02, RCN, PhNCO, imioes, Michael acceptors 

R = allylic, benzylic, cyclopropylcaibinyl R = 1° alkyl, aiyl, alkynyl 

For other oiganometallics, see page 392, Section 22 and page 585, Section 1. 

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The two reactions described above can be applied for the synthesis of symmetrical -acetylenes only. Unsymmetrical bis-acetylenes can be prepared by using the Cadiot-Chodkiew icz reaction For that method a terminal alkyne 1 is reacted with a bromoalkyne 8 in the presence of a copper catalyst, to yield an unsymmetrical coupling product 9 ... 

Benzyl radicals and a- and 3- substituted derivatives also undergo unsymmetrical coupling through the aromatic ring (Section 2.5). The formation of the (i-o and a—p coupling products is reversible. Consequently, these materials are often only observed as transient intermediates. 

Kolbe electrolysis is a powerful method of generating radicals for synthetic applications. These radicals can combine to symmetrical dimers (chap 4), to unsymmetrical coupling products (chap 5), or can be added to double bonds (chap 6) (Eq. 1, path a). The reaction is performed in the laboratory and in the technical scale. Depending on the reaction conditions (electrode material, pH of the electrolyte, current density, additives) and structural parameters of the carboxylates, the intermediate radical can be further oxidized to a carbocation (Eq. 1, path b). The cation can rearrange, undergo fragmentation and subsequently solvolyse or eliminate to products. This path is frequently called non-Kolbe electrolysis. In this way radical and carbenium-ion derived products can be obtained from a wide variety of carboxylic acids. 

Faraday, in 1834, was the first to encounter Kolbe-electrolysis, when he studied the electrolysis of an aqueous acetate solution [1], However, it was Kolbe, in 1849, who recognized the reaction and applied it to the synthesis of a number of hydrocarbons [2]. Thereby the name of the reaction originated. Later on Wurtz demonstrated that unsymmetrical coupling products could be prepared by coelectrolysis of two different alkanoates [3]. Difficulties in the coupling of dicarboxylic acids were overcome by Crum-Brown and Walker, when they electrolysed the half esters of the diacids instead [4]. This way a simple route to useful long chain l,n-dicarboxylic acids was developed. In some cases the Kolbe dimerization failed and alkenes, alcohols or esters became the main products. The formation of alcohols by anodic oxidation of carboxylates in water was called the Hofer-Moest reaction [5]. Further applications and limitations were afterwards foimd by Fichter [6]. Weedon extensively applied the Kolbe reaction to the synthesis of rare fatty acids and similar natural products [7]. Later on key features of the mechanism were worked out by Eberson [8] and Utley [9] from the point of view of organic chemists and by Conway [10] from the point of view of a physical chemist. In Germany [11], Russia [12], and Japan [13] Kolbe electrolysis of adipic halfesters has been scaled up to a technical process. 

The reaction between primary and secondary halides and allyltributylstannane provides another method for unsymmetrical coupling RX + CH2=CHCH2 SnBu3 RCH2CH=CH2. ° ... 

Alkylboranes can be coupled by treatment with silver nitrate and base." Since alkylboranes are easily prepared from alkenes (15-16), this is essentially a way of coupling and reducing alkenes in fact, alkenes can be hydroborated and coupled in the same flask. For symmetrical coupling (R = R ) yields range from 60 to 80% for terminal alkenes and from 35 to 50% for internal ones. Unsymmetrical coupling has also been carried out, but with lower yields. Arylboranes react similarly, yielding biaryls. The mechanism is probably of the free-radical type. 

Unsymmetrical coupling of vinylic, alkynyl, and arylmercury compounds was achieved in moderate-to-good yields by treatment with alkyl and vinylic dialkylcopper reagents (e.g., PhCH=CHHgCl -t- Mc2CuLi PhCH=CHMe). Unsymmetrical biaryls were prepared by treating a cyanocuprate ArCu(CN)Li (prepared from ArLi and CuCN) with an aryllithium Ar Li. ... 

Much more subtle are those molecules which exhibit only potential symmetry. Usnic acid (21), for instance, which does not exhibit any kind of symmetry, can be synthesised in two steps by the unsymmetrical coupling of two molecules of the same phenoxy radical 19 (Scheme 4.4) [17], which is prepared from readily accessible starting materials 13 and 14. 

Electron donating a-substituents favour the non-Kolbe reaction but the radical intermediates in these anodic processes can be trapped during co-electrolysis with an alkanoic acid. Anodic decarboxylation of sugar uronic acids leads to formation of the radical which is very rapidly oxidised to a carbonium ion, stabilised by the adjacent ether group. However, in the presence of a tenfold excess of an alkanoic acid, the radical intermediate is trapped as the unsymmetrical coupling product [101]. Highly functionalised nucleotide derivatives such as 20 will couple successfully in the mixed Kolbe reaction [102], Other examples include the co-electrolysis of 3-oxa-alkanoic acids with an alkanoic acid [103] and the formation of 3-alkylindoles from indole-3-propanoic acid [104], Anodic oxidation of indole-3-propanoic acid alone gives no Kolbe dimer [105],... 

However, this process requires a reaction time of 2 days and is inapplicable to unsymmetrical couplings (two different epoxides). As the study described in equation 24 revealed a dramatic solvent effect on similar Brook isomerizations in the adduct of lithio dihalo(triaIkylsilyl)methanes with epoxides (isomerization did not occur following metalation and initial alkylation in THF but proceeded readily upon addition of HMPA), the effect of HMPA for promoting the Brook isomerization was studied once the first alkylation was complete (equation 28) . ... 

Unsymmetrical coupling can be achieved by treating an alkyl halide directly with 114, in a polar aprotic solvent.1333 In this case too, unsymmetrical allylic groups couple at the less... 

Clerici Porta/. Org. Chem. 1982,47,2852, Tetrahedron 1983,39,1239. For some other unsymmetrical couplings, see Hou Takamine Aoki Shiraishi Fujiwara Taniguchi /. Chem. Soc., Chem. Commun. 1988, 668 Delair Luche /. Chem. Soc.. Chem. Commun. 1989, 398 Takahara Freudenberger Konradi Pedersen Tetrahedron Lett. 1989,... 

As stated above, intermolecular coupling reactions between carbon atoms are of limited use. In the classical Wurtz reaction two identical primary alkyl iodide molecules are reduced by sodium. n-Hectane (C100H202), for example, has been made by this method in 60% yield (G. Stallberg, 1956). The unsymmetrical coupling of two alkyl halides can be achieved via dialkylcuprates. The first halide, which may have a branched carbon chain, is lithiated and allowed to react with copper(I) salts. The resulting dialkylcuprate can then be coupled with alkyl or aryl iodides or bromides. Although the reaction probably involves radicals it is quite stereoselective and leads to inversion of chiral halides. For example, lithium diphenyl-cuprate reacts with (R)-2-bromobutane with 90% stereoselectivity to form (S)-2-phenylbutane (G.M. Whitesides, 1969). 

Following the study of the simple coupling of radicals derived from the salt of a single carboxylic acid, it was found that the electrolysis of a mixture of carboxylate anions or of the salts of half esters of dicarboxylic acids increased the synthetic value of the method. This arises from the possibility of the formation of symmetrical and unsymmetrical coupled products of the derived radicals. These anodic syntheses are illustrated in the synthesis of hexacosane (Expt 5.11), sebacic acid (decanedioic acid), octadecanedioic acid and myristic acid (tetra-decanoic acid), in Expt 5.131. 

This type of symmetrical coupling of two molecules of an alkyl halide will obviously give better yields than the alternative unsymmetrical coupling process which must be used, for example, to make a straight chain alkane having an odd number of carbon atoms. 

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