Carbopalladative mechanism

A mechanistic rationale for the Pd-catalyzed addition of a C-H bond at nitriles to allenes is outlined in Scheme 3. The oxidative insertion of Pd(0) into the C-H bond of nitrile 1 produces the Pd(II) hydride species 16 (or alternatively a tautomeric structure E E2C=C=N PdH Ln may be more suitable, where E = H, alkyl, aryl and/or EWG). Carbopalladation of the allene 2 would afford the alkenylpalladium complex 17 (carbopalladation mechanism), which would undergo reductive coupling to give the addition product 3 and regenerates Pd(0) species. As an alternative mechanism, it may be considered that the hydropalladation of allenes with the Pd(II) intermediate 16 gives the jr-allylpalladium complex 18 which undergoes reductive coupling to afford the adduct 3 and a Pd(0) species (hydropalladation mechanism). 

Scheme 3. C-H transformation to allenes hydropalladation or carbopalladation mechanism.

Addition of CO to C=C and C=C bonds provides an alternative approach to lactones distinct from that of C—X and C—M carbonylation [6, 24]. In particular, hydrocarbonylation involves the formation of new C—H and C—C bonds (Scheme 2.12). Pd-catalyzed transformations of this type proceed through either hydropalladative or carbopalladative pathways [6]. In the carbopalladative mechanism, a Pd alkoxide undergoes carbonylation, yielding an acylpalladium species. Subsequent insertion into the C=C or C=C bond generates the desired lactone. Hydropalladation, on the other hand, is favored under reducing or acidic conditions and occurs via Pd hydride addition to the unsaturation, followed by CO insertion, and reductive elimination. 

Despite Martensson et al. [43] experimentally showed that the carbopalladation mechanism can not be operative, in order to have a comprehensive mechanistic understanding of the reaction we decided to investigate this mechanism together with the deprotonation mechanism including their cationic and anionic alternatives (see below). 

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. 

Overall, the reaction is exergonic by 21.5 kcal mol but the carbopalladation mechanism has a very high energy barrier (40.4 kcal mol ), which makes this... 

Fig. 5.5 Gibbs energy profile in DCM AGdcm, kcal mol ) at 298 K for the carbopalladation mechanism with R = H, and Base = pyrrolidine...

Fig. 5.6 Optimized structures for the transition states involved in the carbopalladation mechanism with phenylacetylene (R = H). Distances are shown in A...

With the carbopalladation reaction pathway established for phenylacetylene (R = H) and for the sake of completeness, the effect of the alkyne R substituent on the overall carbopalladation mechanism was next examined. With this purpose, the Gibbs energy profiles for the Sonogashira reaction with several 4-substituted pheny-lacetylenes (R = CF3, OMe, NMe2) through a carbopalladation mechanism were computed (Table 5.1). 

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. 

The theoretical calculations presented so far demonstrate that the carbopalladation mechanism is not operating under the reaction conditions. Furthermore, calculations also show that the other three investigated mechanisms (i.e. cationic, anionic and ionic mechanisms) may have competitive rates. Thus, a change on the reaction conditions (i.e. solvent, ligands, substrates, base, etc.) might favor one or another mechanism. 

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