Sonogashira mechanism, with copper

Mechanism of Sonogashira Reaction with Copper Co-Catalyst... 

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

The theoretical investigation of the copper-free Sonogashira reaction with pheny-lacetylene as a model substrate (R = H) through a carbopalladation mechanism afforded the reaction profile shown in Fig. 5.5. 

With the carbopalladation mechanism ruled out as operative mechanism, the copper-free Sonogashira reaction through a deprotonation mechanism was next investigated. As commented in the introduction, for this mechanism two different alternatives have been proposed, namely the cationic and the anionic mechanisms (Fig. 5.3) [43]. This two mechanistic alternatives only differ in the order in which the steps in the deprotonation mechanism occur. 

As above stated, the reaction steps in the anionic mechanism take place in reverse order than in the cationic mechanism (Fig. 5.8). Thus, in the anionic mechanism the deprotonation of the alkyne by the external base in complex 2 occurs first, followed by the iodide-for-phosphine substitution. The Gibbs energy profile obtained for the copper-free Sonogashira reaction with phenylacetylene (R = H) through the anionic mechanism is shown in Fig. 5.10. 

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. 

Bohm, V. P. W., Herrmann, W. A. Coordination chemistry and mechanisms of metal-catalyzed C-C coupling reactions, 13 a copper-free procedure for the palladium-catalyzed Sonogashira reaction of aryl bromides with terminal alkynes at room temperature. Eur. J. Org. Chem. 2000,3679-3681. 

In copper-free Sonogashira coupling the competition of ligand and amine base determines the reaction mechanism. The oxidative addition of Arl with (Ph3P)4Pd is faster when amine is present. With the proposed mechanisms the efficiency of PhsP > PhsAs is explained. 

Over the last years, two reaction mechanisms proposed for the copper-free Sonogashira reaction have been somewhat discussed in the literature. Recently, the experimental group of Martensson demonstrated that one of them can be discarded, and further proposed two alternatives for the other mechanism on the basis of the electronic nature of the alkyne s substituents. Hence, in order to shed light on the reaction mechanism for this process, we decided to carry out a theoretical study in close contact with the experimental group of Prof. Carmen Nijera with the following main objectives ... 

For the copper-free Sonogashira reaction, the mechanistic study reported in this thesis revealed that, just like in other cross-coupling reactions (i.e. Stille, Negishi), there are several competing reaction pathways and a change on the reaction conditions (e.g. solvent, ligands, substrates, base) might favor one over the other ones. Moreover, a new mechanism in which the acetylide (formed by deprotonation of the alkyne) directly reacts with the catalyst was also proposed. 

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