Heck reaction mechanism/catalytic cycle

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... 

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 Mizoroki-Heck reaction is a metal catalysed transformation that involves the reaction of a non-functionalised olefin with an aryl or alkenyl group to yield a more substituted aUcene [11,12]. The reaction mechanism is described as a sequence of oxidative addition of the catalytic active species to an aryl halide, coordination of the alkene and migratory insertion, P-hydride elimination, and final reductive elimination of the hydride, facilitated by a base, to regenerate the active species and complete the catalytic cycle (Scheme 6.5). 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

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-... 

The palladium-catalysed addition of aryl, vinyl, or substituted vinyl groups to organic halides or triflates, the Heck reaction, is one of the most synthetically useful palladium-catalysed reactions. The method is very efficient, and carries out a transformation that is difficult by more traditional techniques. The mechanism involves the oxidative addition of the halide, insertion of the olefin, and elimination of the product by a p-hydride elimination process. A base then regenerates the palladi-um(0) catalyst. The whole process is a catalytic cycle. 

A general catalytic cycle proposed for Heck reaction is shown in Fig. 7.17. While all the steps in the catalytic cycle have precedents, the proposed reaction mechanism lacks direct evidence. The basic assumption is that under the reaction conditions, the precatalyst is converted to 7.64, a coordinatively unsaturated species with palladium in the zero oxidation state. Oxidative addition of ArX, followed by alkene coordination, leads to the formation of 7.65 and 7.66, respectively. Alkene insertion into the Pd-C bond followed by /3-H abstraction gives 7.67 and 7.68, respectively. Reductive elimination of HX, facilitated by the presence of base B, regenerates 7.64 and completes the catalytic cycle. The C-C coupled product is formed in the 7.67 to 7.68 conversion step. 

These reactions are commonly interpreted to be composed of three main steps, namely a) oxidative addition of an aryl-X species to palladium(0) with formation of an arylpalladiumffi) bond b) insertion of a terminal olefin and c) reductive elimination regenerating palladium(0). To achieve a catalytic cycle, the rates of these steps have to match each other. The basic process was discovered by Heck in 1968. The mechanism has not yet been well defined and several variants have been proposed. A widely accepted scheme is reported in Figure 6. 

The basic mechanism of the Heck reaction (as shown below) of aryl or alkenyl halides or triflates involves initial oxidative addition of a pal-ladium(O) species to afford a a-arylpalladium(II) complex III. The order of reactivity for the oxidative addition step is I > OTf > Br > Cl. Coordination of an alkene IV and subsequent carbon-carbon bond formation by syn addition provide a a-alkylpalladium(II) intermediate VI, which readily undergoes 3-hydride elimination to release the product VIII. A base is required for conversion of the hydridopalla-dium(II) complex IX to the active palladium(O) catalyst I to complete the catalytic cycle. 

The hydroformylation mechanism for phosphine-modified rhodium catalysts follows with minor modifications the Heck-Breslow cycle. HRh(CO)(TPP)3 [11] is believed to be the precursor of the active hydroformylation species. First synthesized by Vaska in 1963 [98] and structurally characterized in the same year [99], Wilkinson introduced this phosphine-stabilized rhodium catalyst to hydroformylation five years later [100]. As one of life s ironies, Vaska even compared HRh(CO)(TPP)3 in detail with HCo(CO)4 as an example of structurally related hy-drido complexes [98]. Unfortunately he did not draw the conclusion that the rhodium complex should be used in the oxo reaction. According to Wilkinson, two possible pathways are imaginable the associative and the dissociative mechanisms. Preceding the catalytic cycle are several equilibria which generate the key intermediate HRh(CO)2(TPP)2 (Scheme 4 L = ligand). 

As an alternative to the classical reaction mechanism, they investigated the possibility of a direct deprotonation of the y5-agostic insertion product by the amine base, which is usually required for successful Heck coupling reactions. The new proposal actually replaces the last two steps of the classical catalytic cycle, P-Vi elimination and base-assisted reductive elimination of HX (Scheme 2). 

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 (Scheme la) with bidentate phosphine ligands is generally thought to follow the four-step catalytic cycle shown in Scheme lb, with the individual steps being A) oxidative addition of 1 to the Pd°... 

The key step in the catalytic cycle with regard to enantioselectivity is clearly B), association of the alkene 2 and insertion of it into the Pd-R bond. As with the Heck reaction itself, the mechanism for this process remains a matter for conjecture, with the overall rationale currently in favor having been proposed in 1991 by Ozawa and Hayashi [18] and independently by Cabri [19] (although the cationic pathway via 8 and 9 had been proposed as early as 1990 [20]). Its development and subsequent evolution has recently been reviewed by the latter author [ 12]. 

Apart from intuitions based on experimental observations and support from computational work, the arguments in favor of Pd(II)/Pd(IV) mechanisms in the Heck reactions catalyzed by Pd pincer complexes are scarce. On the contrary, there is conclusive evidence indicating that in many cases the actual catalytic species results from the decomposition of pincer complexes [62, 76, 77, 97,100, 101, 103]. This conclusion can probably be extended to all systems that achieve exceptionally high TON numbers, such as 2 and 3, since the rate of the processes based on Pd(II)/Pd(IV) cycles would be always Hmited by the low reactivity of Pd(II) toward aryl halides. The observed influence of pincer ligands on the catalytic activity or the ability to catalyze difficult couplings (e.g., with aryl chlorides) can be rationalized on the basis of their ability to regulate the production of the actual catalytic species [11, 12, 96]. This, however, does not prevent the possibility that, in some specific cases, pincer complexes could act as true molecular catalysts for the Heck reaction or other closely related processes. In recent years, a couple of examples have been provided that demonstrate this possibility, as discussed below. 

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