The Oxidative Addition Step

The oxidative addition of aryl and vinyl halides and triflates was presented in Chapter 7. A few features of this mechanism that are important for understanding the scope and limitations of the cross-coupling processes are presented here. 

CHAPTER 19 TRANSITION METAL-CATALYZED COUPLING REACTIONS 

Effect of steric hindrance on ligand dissociation and C-X bond cleavage. 

Nickel(O) complexes tend to undergo oxidative addition of aryl halides faster than palladium(O) complexes. There are some drawbacks to the use of the nickel complexes, described above, that can outweigh the lower cost of nickel. Nevertheless, the ruckel complexes containing triarylphosphines do undergo oxidative addition of aryl chlorides (Equation 19.39) and tosylates (Equation 19.40), and some mild conditions have been developed for nickel-catalyzed cross couplings of aryl chlorides and aryl tosylates with ligands such as triphenylphosphine or tricyclohexylphosphine.  

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. 

As expected the calculated energy barrier for the oxidative addition reaction was rather low (17.0 kcal mol ) and involves the concerted formation of the Pd-I and Pd-C bonds, and the cleavage of the C-I bond through a three-centered transition state (OA-TS). This transition state results in the oxidative addition product OA-P, which evolves to the more stable trans isomer through a cis-to-trans isomerization. This isomerization is known that may take place following different pathways, [54] but in any case it is an easy process [64]. Thus, we focused our further analysis on the proposed mechanisms starting from the trans-[Pd(Ph)(I)(PH3)2] (1) complex. 

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A plausible mechanism accounting for the catalytic role of nickel(n) chloride has been advanced (see Scheme 4).10 The process may be initiated by reduction of nickel(n) chloride to nickel(o) by two equivalents of chromium(n) chloride, followed by oxidative addition of the vinyl iodide (or related substrate) to give a vinyl nickel(n) reagent. The latter species may then undergo transmetala-tion with a chromium(m) salt leading to a vinyl chromium(m) reagent which then reacts with the aldehyde. The nickel(n) produced in the oxidative addition step reenters the catalytic cycle. 

A mechanistic pathway is proposed based upon the observed regioselectivities and other results that were obtained during the exploration of the scope and limitations of the Alder-ene reaction.38 Initially, coordination of the alkene and alkyne to the ruthenium catalyst takes place (Scheme 5). Next, oxidative addition affords the metallocycles 42 and 43. It is postulated that /3-hydride elimination is slow and that the oxidative addition step is reversible. Thus, the product ratio is determined by the rate at which 42 and 43 undergo /3-hydride elimination. 

While the transmetalation step is often the rate-determining step for Pd-catalyzed reactions with organometallics, the oxidative addition step is often the rate-determining step in the Heck reactions, although olefin insertion can be rate-limiting in some cases — this is why the Heck reactions of tri- and tetra-substituted olefins sometimes proceed slower than those of di-substituted and terminal olefins. 

A one-pot synthesis of 3,3-disubstituted indolines was achieved by taking advantage of a sequential carbopalladation of allene, nucleophile attack, intramolecular insertion of an olefm and termination with NaBPh4 (Scheme 16.6) [10]. First, a Pd(0) species reacts with iodothiophene selectively to afford ArPdl, probably because the oxidative addition step is facilitated by coordination with the adjacent sulfur atom. Second, the ArPdl adds to allene, giving a Jt-allylpalladium complex, which is captured by a 2-iodoaniline derivative to afford an isolable allylic compound. Under more severe conditions, the oxidative addition of iodide to Pd(0) followed by the insertion of an internal olefm takes place to give an alkylpalladium complex, which is transmetallated with NaBPh4 to release the product. 

As for the oxidative addition (step i), both cyclic and acyclic hydrogen phosphonates, 4a and 4b, react with Pd(0) to generate the corresponding adducts 12a and 12b (Scheme 29). Although five-membered 4a is somewhat more reactive, this small difference in reactivity does not account for the lack of catalytic addition of 4b. 

At constant CO partial pressure, the rate determining step is a function of the HX bond strength. In the case of HSnR, the rate determining step is CO dissociation, Equation 9. For HSiR and H, it is the oxidative addition step. Equation 10. ... 

This mechanism differs from the commonly accepted mechanism of catalytic asymmetric hydrogenation, because the accepted one proposed an irreversible oxidative addition (the oxidative addition step should have the largest energy barrier), but it does agree with recent experimental results that show irreversible and stereodetermining migratory insertion [78]. 

The general catalytic cycle for this carbonylation coupling reaction is analogous to direct carbon-heteroatom coupling [scheme (39)] except that carbon monoxide insertion takes place after the oxidative addition step and prior to the nucleophilic attack of the amine [scheme (40)] ... 

This electron-richness of N-heterocyclic carbenes has an impact on many elementary steps of catalytic cycles, for example, facilitating the oxidative addition step. Therefore, NHC metal complexes are well suited for crosscoupling reactions of non-activated aryl chlorides—substrates that challenge the catalyst with a difficult oxidative addition step [28]. Furthermore, as a consequence of their strong electron-donor property, N-heterocyclic carbenes are considered to be higher field as well as higher trans effect ligands than phosphines. 

The Stille coupling may be combined with carbonylation in two ways. Acid chlorides may be used as substrates for the reaction with vinyl or aryl stannanes. However, an atmosphere of carbon monoxide is frequently required to prevent decarbonylation after the oxidative addition step. 

Another key feature of the metal complex cycle in which the iodide acts most effectively is the nature of the active catalyst itself. The oxidative addition step is considered to be nucleophilic in nature, based on activation parameters and relative rate data (23, 24a) (Section II,C), and the presence of a negative charge on the metal center appears to significantly enhance the nucleophilicity (and hence reactivity toward methyl iodide) of the metal relative to neutral rhodium(I) species (20). Extrapolations of available data (24-26) indicate that, at 25°C, the diiododicarbonylrhodium(I) species has a Pearson nucleophilicity parameter (25) toward methyl iodide of 5.5. In relation to other common nucleophiles, this value corresponds to nucleophilic reactivity toward methyl iodide comparable to that of pyridine (n = 5.2), an order of magnitude greater than chloride (n = 4.4), and two orders of magnitude slower than iodide (n = 7.4). 

The reaction rates and/or yields sometimes vary with the choice of Pd(0) or Pd(II). Although the reason is not simple, it seems that the stoichiometric ratio between palladium and ligand is important in most of such cases. In the early stage of Stille s investigation, he reported that an excess of phosphine retards the oxidative-addition step that is often the rate-determining step [5]. The transmetallation step is also the rate-determining step in many cases, however, detailed mechanism is still not clear [21,34]. Detailed studies on the transmetallation step has been underway [35-38]. Those would provide useful informations for determining the best conditions for specific cases. Recent development... 

Moreover, the energy gap between Pt(ll) and Pt(IV) increases when soft ligands are present, because they behave as electron-attracting entities from the metal and the oxidative addition step therefore becomes more difficult. 

The transition metal activates the C-X bond in the oxidative addition step and normally the substrates have sp or sp carbons at or immediately adjacent to an electrophilic centre. The reactivity of aliphatic C-X bond towards the oxidative addition with a transition metal is somewhat low. However, in 1992, Suzuki and co-workers discovered that Pd(PPh3)4 can catalyze couplings of alkyl iodides with alkyl boranes at 60°C in moderate yields (50-71%). These conditions tolerated a wide variety of functional groups such as esters, ketals and cyanides. 

Mechanism The Pd complex such as Pd(PPh3)4 activates the organic halides by oxidative addition into the carbon-halogen bond. The copper(I) halides react with the terminal alkyne and produce copper acetylide, which acts as an activated species for the coupling reactions. The oxidative addition step is followed by the transmetallation step. The proposed catalytic cycle is shown in Scheme 5.21. 

Others have investigated the kinetics of amination reactions mediated by catalyst systems employing the new electron-rich monodentate ligands. In particular, Hartwig has shown that for catalysis by a 1 1 palladium to Xn tert-butyl)phosphine system, a mechanism in which oxidative addition of aryl chlorides follows coordination of base to the palladium competes with the standard nonanionic pathway. Finally, Caddick, Cloke, and coworkers have studied amination reactions of aryl chlorides performed by palladium complexes of N-heterocyclic carbene ligands. They found the rate to be limited by the oxidative addition step, which occurs first through the dissociation of an NHC ligand. 

Reaction of the Pt complex (13) with (11) gives a silylplatinum complex (14), the silyl group of which has the same configuration as that of (11). The oxidative addition is thus assumed to take place from the front side of the Si—H bond (equation 7). The hydrosilane (11) reacts with a manganese complex (15) to give rise to a complex (16 equation 8), which has a structure similar to the intermediate of the oxidative addition step. °... 

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. 

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