Heck reaction neutral mechanism

Recent development of the Heck reaction has also led to greater understanding of its mechanistic details. The general outlines of the mechanism of the Heck reaction have been appreciated since the 1970s and are discussed in numerous reviews [2,3]. More recently, two distinct pathways, termed the neutral and cationic pathways, have been recognized [2c-g,3,7,8,9]. The neutral pathway is followed for unsaturated halide substrates and is outlined in Scheme 8G. 1 for the Heck cyclization of an aryl halide. Thus, oxidative addition of the aryl halide 1.2 to a (bisphosphine)Pd(O) (1.1) catalyst generates intermediate 1.3. Coordination of... 

The mechanism of the Heck reaction is not fully understood and the exact mechanistic pathway appears to vary subtly with changing reaction conditions. The scheme shows a simplified sequence of events beginning with the generation of the active Pd catalyst. The rate-determining step is the oxidative addition of Pd into the C-X bond. To account for various experimental observations, refined and more detailed catalytic cycles passing through anionic, cationic or neutral active species have been proposed. ... 

The mechanism of the Heck reaction catalyzed by a neutral palladium complex is illustrated below. 

Research into the mechanism of the Heck reaction continues and the understanding of the reaction is increasing. Recent research has revealed that in some intramolecular cases another mechanism is observed. Cationic intermediate 68 can be accessed by associative displacement via the pentacoordinate intermediate 70, leading to high enantioselectivity from a reaction that might be thought to proceed via a neutral pathway. Other studies have also identified key roles for pentacoordinate intermediates as well as anionic complexes.f ... 

Regioselectivity is one of the major problems of Mizoroki-Heck reactions. It is supposed to be affected by the type of mechanism ionic versus neutral, when the palladium is ligated by bidentate P P ligands. The ligand dppp has been taken as a model for the investigation of the regioselectivity. Cabri and Candiani [Ig] have reported that a mixture of branched and linear products is formed in Pd°(P P)-catalysed Mizoroki-Heck reactions performed from electron-rich alkenes and aryl halides (Scheme 1.26a) or aryl ttiflates in the presence of halide ions (Scheme 1.26b). This was rationalized by the so-called neutral mechanism (Scheme 1.27). The neutral complex ArPdX(P P) is formed in the oxidative addition of Pd°(pAp) yj Qj. Q aj.yj triflates in the presence of halides. The carbopalladation... 

In more recent studies by Xiao and coworkers [40m,n], Mizoroki-Heck reactions catalysed by Pd(OAc)2 associated with dppp and performed from the eleclron-rich alkene ( -butylvinyl ether) and aryl halides (without any halide scavenger, i.e. under the conditions of the textbook neutral mechanism of Scheme 1.27 proposed by Cabri and Candiani [Ig]) give a mixture of branched and linear products in DMF, whereas the branched product is exclusively produced in ionic liquids (in the absence of halide scavengers) in a faster reaction. Whatever the medium, the cationic complex ArPd5(dppp)+ is always the sole reactive complex with electron-rich alkene (Scheme 1.33) [53]. Consequently, the regioselectivity should not vary with the experimental conditions. 

Scheme 1.51 Neutral mechanism for Mizoroki-Heck reactions catalysed by Pd(0) coordinated to a bidentate P Cb ligand.

A tentative catalytic cycle for ligand-accelerated Mizoroki-Heck reactions is shown in Scheme 2.14. A pivotal feature of this mechanism is the requirement to have neutral complex 4 with a single ancillary ligand, as related coordinatively saturated species 1 or... 

The most common Mizoroki-Heck reaction mechanism is called the neutral mechanism, because its intermediates are uncharged. The catalytic cycle for the neutral manifold of the intramolecular Mizoroki-Heck reaction of alkenyl and aryl halides is shown in Scheme... 

Scheme 12.2 Neutral mechanism of the intramolecular Mizoroki-Heck reaction.

Much of the recent hteiature on the mechanism of the enantioselective intramolecular Mizoroki-Heck reaction has focused on the anionic mechanism, o-iodoanilide substrates, pathways involving neutral pentacoordinate palladium intermediates and the influence of additives. The new examples and mechanistic findings indicate that the potential may exist to control the stereoselectivity of the intramolecular Mizoroki-Heck reaction through pathways other than the cationic mechanism. However, further research is needed to obtain the level of effectiveness of the traditional cationic pathway. 

A detailed discussion of the current understanding of the mechanism of the Mizoroki-Heck reaction can be found in earUer chapters of this book and in several excellent reviews [7]. Two mechanistic pathways, typically termed neutral and cationic, have been proposed to account for the differences in reactivity and enantioselectivity observed in asymmetric Mizoroki-Heck cycUzations of unsaturated trillates and halides. These pathways differ in the degree of positive charge and the number of available coordination sites assignable to the palladium(II) intermediates of the catalytic cycle. Because catalytic asymmetric Mizoroki-Heck cyclizations are typically carried out with bidentate Ugands, these pathways will be illustrated with a chelating diphosphine Ugand. 

Another of the standard palladium-catalyzed C—C bond formations is the Mizoroki-Heck reaction. This reaction is based on the palladium-catalyzed coupling of olefins with aryl or vinyl halides under basic conditions [21]. The catalytic cycle that is typically proposed for this reaction is outlined in Scheme 7.7. The first step of the reaction postulated in the mechanism is an oxidative addition of R -X to a Pd(0) complex. The next step is the insertion of the alkene to the Pd complex II. In order for this to be possible, an uncharged ligand has to break away giving a neutral Pd(II) complex that will be coordinated by the olefin. The insertion of the alkene into the Pd— bond results in the C C bond-forming step to give BO. Rotation around the C—C bond and 3-hydride elimination yields the new substituted olefin and intermediate 131. Regeneration of the active catalytic species occurs by the addition of a base. 

The mechanism for the Heck reaction is shown in Scheme 4.63. The first step involves the oxidative addition of an aryl or vinyl halide, R -X, to a palladium(O) species. This species normally contains an auxiliary donor, L, where L is often a phosphine. This may be preceded by a reduction of the metal if a palladium(II) salt is employed initially. Thereafter, two different pathways are possible depending on which group dissociates to provide a vacant coordination site for the incoming alkene. If a neutral ligand (such as a phosphine) detaches and the halide is retained, the active species immediately prior to the C-C coupling step is the neutral complex III-90. Conversely, if the anionic ligand (such as a halide) dissociates, the active species is the cationic complex III-91. 

During the carbopalladation two possible alkylpalladium(II) intermediates can be formed resulting in two different products 1,1- or 1,2-disubstitued olefins. A number of strategies have been disclosed regarding the control of the regiose-lectivity in the Heck reaction, which can be influenced by factors such as the ligands, solvents, additives and the nature of the electrophile and the olefin. The difference between the two possible outcomes originates from the fundamental mechanisms of the carbopalladation, represented by the neutral and the cationic pathway (Schemes 1.11 and 1.19) [73, 74]. 

These fundamental steps of the catalytic cycle have been confirmed by stoichiometric reactions starting from isolated stable complexes, and by DFT calculations [11], Although many aspects of the Heck olefination can be rationalized by this textbook mechanism , it provides no explanation of the pronounced influence that counter-ions of Pd(II) pre-catalysts or added salts have on catalytic activity [12], This led Amatore and Jutand to propose a slightly different reaction mechanism [13]. They revealed that the preformation of the catalytically active species from Pd(II) salts does not lead to neutral Pd(0)L2 species a instead, three-coordinate anionic Pd(0)-complexes g are formed (Scheme 3, top). They also observed that on the addition of aryl iodides la to such an intermediate g, a new species forms quantitatively within seconds and the solution remains free of iodide and acetate anions. It may then take several minutes before the expected stable, four-... 

Scheme 6-1 Mechanism of Heck substitution reactions proceeding via the neutral pathway. ...

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