Sonogashira mechanism, copper-free

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. 

Two alternative mechanisms are proposed for the copper-free Sonogashira reactions, performed from Phi and HO—CH GHj—C=CH (Scheme 19.34) path A when the alkyne is a better ligand than the amine for the Pd center in PhPdlL [43a, c] or path B when the amine is a better ligand than the alkyne [43a]. This explains why the catalytic reactions are very sensitive to the base (path B more efficient than path A) [43a]. Consequently, the amine does not react as a simple base in copper-free Sonogashira reactions but may also be involved as ligand for aryl-Pd complexes [43a, b]. 

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 ... 

Fig. 5.2 Proposed reaction mechanisms for the copper-free Sonogashira reaction deprotonation left) and carbopalladation right) mechanisms...

The first step in all the proposed mechanisms for the copper-free Sonogashira reaction corresponds to the oxidative addition of the organic halide R-X to the starting [Pd(0)] complex. This step has been extensively studied (see Chap. 1) and is well known that in the case of organic iodides does not use to be rate-limiting. Even so, we decided to examine it for completeness. Hence, the oxidative addition of Phi to the complex [Pd(PH3)2] was computed. The optimized structures for this process are shown in Fig. 5.4. 

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. 

In the study presented in this chapter, the reaction mechanism for the model copper-free Sonogashira reaction between iodobenzene and several 4-substituted phenylacetylenes (R = H, CF3, OMe, NMe2) was investigated by means of DFT calculations. Importantly, to the best of our knowledge, this study was the first theoretical study that investigated all the reported mechanistic proposals for the copper-free Sonogashira reaction. 

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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