Alkynes from acetylides, mechanism

In the synthesis of propargylic alcohols, we saw the reaction of an alkynyl nucleophile (either the anion RC=CNa or the Grignard RC CMgBr, both prepared from the alkyne RC CH) with a carbonyl electrophile to give an alcohol product. Such acetylide-type nucleophiles will undergo Sn2 reactions with alkyl halides to give more substituted alkyne products. With this two-step sequence (deprotonation followed by alkylation), acetylene can be converted to a terminal alkyne, and a terminal alkyne can be converted to an internal alkyne. Because acetylide anions are strong bases, the alkyl halide used must be methyl or 1° otherwise, the E2 elimination is favored over the Sn2 substitution mechanism. 

Fig. 13.22. Mechanism of the Pd(0)-catalyzed arylation of a copper acetylide. Step 1 formation of a 7T complex between the catalytically active Pd(0) complex and the arylating agent. Step 2 oxidative addition of the arylating agent and formation of a Pd(II) complex with a

Several studies of the kinetics and effects of structure on reactivity lend support to a mechanism of oxidative coupling of the type first proposed by Bohlmann and coworkers The rate is second order with respect to Cu(ii) and alkyne, and varies inversely with [H+] . This is interpreted in terms of rapid steps involving displacement of a solvent molecule or other ligand from the coordination sphere of Cu(n) by an alkyne molecule, followed by acid dissociation of the coordinated alkyne to give an acetylide complex. In the rate-determining step, copper(ii) is reduced and simultaneously the alkynyl groups are coupled. These steps are summarized in equations (6), (7) and (8), where L represents a ligand—solvent, for... 

The mechanism of the Sonogashira cross-coupling follows the expected oxidative addition-reductive elimination pathway. However, the structure of the catalytically active species and the precise role of the Cul catalyst is unknown. The reaction commences with the generation of a coordinatively unsaturated Pd species from a Pd " complex by reduction with the alkyne substrate or with an added phosphine ligand. The Pd " then undergoes oxidative addition with the aryl or vinyl halide followed by transmetallation by the copper(l)-acetylide. Reductive elimination affords the coupled product and the regeneration of the catalyst completes the catalytic cycle. 

Whatever the details of the interactions of Cu with alkyne during the CuAAC reaction, it is clear that Cu-acetylide species are easily formed and are productive components of the reaction mechanism. Early indications that azide activation was rate-determining came from the CuAAC reaction of diazide 15, shown in Scheme 10.5, which afforded ditriazole 17 as the predominant product, even when 15 was used in excess [113]. The same phenomenon was observed for 1,1-, and 1,2-diazides, but not for 1,4-, 1,5-, and conformationally flexible 1,3-diazide analogues. The dialkyne 18, in contrast to its diazide analogue 15, gave statistical mixtures of mono- and di-triazoles 19 and 20 under similar conditions. Independent kinetics measurements showed that the CuAAC reaction of 16 was slightly slower than that of 15, ruling out the intermediacy of 16 in the efficient production of 17. The Cu-triazolyl precursor 21 is, therefore, likely to be converted to 17 very rapidly. 

Investigations with deuterated alkynes and deuterated zeolites proved that this Cu(I)-zeolite-catalysed click reaction exhibited a mechanism different from the one reported for the Meldal-Sharpless version, which relies on the intermediate formation of copper acetylides (Scheme 5.15). Therefore, if such species were also formed within zeolites, deuteroalkynes would not give deuterated triazoles as observed. (Scheme 5.16)... 

The reaction is explained by the following mechanism. At first, Cul activates 1-alkynes 1 by forming the Cu acetylides 6, which undergo transmetallation with arylpalladium halides to form the alkynylarylpalladium species 7, and reductive elimination to give 2 is the final step. However, the coupling proceeds even in the absence of Cul under certain conditions, and it may be possible to form the alkynylarylpalladium species 7 directly from 1-alkynes. As another less likely possibility, carbopalladation of a triple bond with Ar-Pd-X (or insertion of the triple bond to Ar-Pd-X) generates the alkenylpalladium 8 which undergoes dehydropal-ladation to afford disubstituted alkynes 2. In this mechanism, Cul plays no role. The mechanism of -H elimination of alkenylpalladium to form alkynes is not clearly known. 

Internal alkynes can be made from terminal alkynes by converting the terminal alkyne to an acetylide anion and then treating the anion with a primary alkyl halide. Propose a mechanism for the alkylation. (See Section 8.15.)... 

This reaction process takes advantage of the ease with which a copper acetylide will oxidatively insert into an alkynyl halide bond. The postulated mechanism begins with and in situ base- and Cu(I)-induced formation of a copper acetylide (1) from a terminal alkyne (33). This intermediate undergoes oxidative addition into the activated C-X bond of an alkynyl halide (34) to afford the copper(III) species 35. Reductive elimination of the bis-alkyne 32 from complex 35 delivers the reaction product and regenerates the copper(l) halide 36 which may re-enter the catalytic cycle. 

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