Aryl chlorides oxidative step

Palladium(II) complexes provide convenient access into this class of catalysts. Some examples of complexes which have been found to be successful catalysts are shown in Scheme 11. They were able to get reasonable turnover numbers in the Heck reaction of aryl bromides and even aryl chlorides [22,190-195]. Mechanistic studies concentrated on the Heck reaction [195] or separated steps like the oxidative addition and reductive elimination [196-199]. Computational studies by DFT calculations indicated that the mechanism for NHC complexes is most likely the same as that for phosphine ligands [169], but also in this case there is a need for more data before a definitive answer can be given on the mechanism. 

While the sequence of steps for the Heck reaction remains the same for many catalysts, the kinetics may vary enormously and also the detailed composition of all intermediates may vary in the type and number of ligands. It had often been assumed that the oxidative addition is the slowest step and that may well be true for many systems based on PPh3 definitely for aryl chlorides it seems to be the rule. 

Buchwald [127] and Lohse [128] have independently reported coupling reactions using aryl chlorides. In order to overcome the sluggish oxidative addition step of aryl chlorides in... 

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. 

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. 

It is P-C-bond cleavage and subsequent isomerizations that are responsible for the deactivation in the case of aryl chlorides and not a missing reactivity for oxidative addition as previously suggested Furthermore, the nature of the anion seems to dominate the subsequent steps in the catalytic cycle. Recently, these problems have been solved by the application of defined catalyst systems such as pallacycles. 

In general, highly activated aryl chlorides (e.g. 4-chlorobenzonitrile or 4-chlorobenzo-phenone) react similarly to bromobenzene in the oxidative addition step. Thus the standard arylphosphine ligands are suitable for palladium-catalyzed chemistry with these substrates77. ... 

The amination of aryl chlorides is significantly more difficult than the amination of aryl bromides because of the decreased reactivity of chloroarenes. Their low cost, however, makes them important substrates for mild coupling chemistry. In general, highly activated aryl chlorides such as 4-chlorobenzonitrile or 4-chlorobenzophenone react similarly to bromobenzene in the oxidative addition step, and the standard arylphosphine ligands are, therefore, suitable for Pd-catalyzed chemistry with these substrates. Indeed, the first amination of aryl chlorides was conducted with these activated substrates and the standard ligand systems. ... 

The Heck reaction can be used to couple alkenyl, aryl, allyl (the intramolecular Heck reaction on aUyUc substrates is called a palladaene reaction),f ° t f benzyl, methyl, alkoxycarbonyhnethyl, alkynyl, certain alkyl, and silyl fragments to a variety of alkenes. The nature of the leaving group greatly affects the reaction rate aryl iodides react faster than bromides, and aryl chlorides are notoriously unreactive unless special catalysts or ligands and elevated temperatures are used to enhance the reaction rate. This has been taken to indicate that the oxidative addition of the haloarene (haloalkene) to pal-ladium(O) is the rate-determining step. " It has been shown that the Heck reaction can be performed with aryldiazonium salts, A -nitroso-Af-arylacetamides, and hy-pervalent iodo compounds " at room temperature. 

The Stille reactions of aryl chlorides, as the least reactive electrophilic substrates can be successfully performed by applying a palladium-complex of electron-rich and sterically encumbered Pt-Bus as Pd(0)-stabilizing ligand [78]. The latter increases the electron-density at palladium metallic centre and thus facilitates the oxidative addition step of unreactive electron-rich aryl chlorides to the Pd(Pt-Bu3)2- For instance, even 4-chloroanisole (76), among the least reactive chlorides, was reacted with phenyltri-n-butylstannane (184) to give 4-methoxybiphenyl (78) in 94% yield [78], respectively,... 

The efficiency of bulky and electron-rich phosphines in Mizoroki-Heck reactions seems to be due to their ability to generate monophosphine-Pd(O) or -Pd(II) complexes in each step of the catalytic cycle (Scheme 1.55). Steric factors are probably more important than electronic factors. One sees from Fu s studies that the last step of the catalytic cycle in which the Pd(0) complex is regenerated in the presence of a base may be rate determining. The role of this last step has been underestimated for a long time. Provided this step is favoured (e.g. with P-r-Bus as ligand and Cy2NMe as base), the oxidative addition of aryl chlorides would appear to be rate determining. However, Mizoroki-Heck reactions performed from the same aryl chloride with the same Pd(0) catalyst and same base but... 

A common ground that is explicitly or implicitly defended in the majority of studies on Mizoroki-Heck reactions is that the limiting stage for the whole cycle is the oxidative addition step. By this criterion, the most important substrates, aryl halides, are subdivided into very reactive (aryl iodides and electron-deficient aryl bromides), less reactive (all other aryl bromides and electron-deficient aryl chlorides) and very unreactive (all other aryl chlorides). As evident as this classification may seem, it is not based on any solid proof. Indeed, if it were really so important, the oxidative addition step should have been characterized by very strong dependence on substituent effects in these substrates. However, this has not been observed in either Mizoroki-Heck reactions or in any other palladium-catalysed reaction of aryl hahdes. The Hammett reaction constant values p, whenever measured, are rather modest in valne [5]. Such values could hardly have accounted for the well-known enormous distance between the reactivity of, for example, a typical activated substrate 7 and a typical deactivated substrate 8 (Figure 2.1). 

Indeed, there is ample data showing that none of the individual stages or the catalytic cycle as a whole require high temperatures to occur. Even the oxidative addition step proceeds with all substrates (including aryl chlorides) at room temperature or very modest temperatures (below 50-60 °C). High temperature is not necessarily needed and might even be detrimental to both type 3 and, particularly, typed processes because both rely on a defined coordination sphere, which cannot be maintained at high temperatures. 

The low reactivity of aryl chlorides is usually attributed to the strength of the C—Cl bond (bond dissociation energies for Ph-X Cl, %kcalmor Br, SlkcalmoT I, 65kcalmoT ), which leads to a reluctance by aryl chlorides to oxidatively add to either Pd(0) or Ni(0), which is a critical initial step in palladium- and nickel-catalyzed coupling reactions (Scheme 2.1) [6, 7]. 

In 1989 Milstein and colleagues realized the reductive carbonylation of aryl chlorides [25]. Under the assistant of Pd(dippp)2 complex, aryl chlorides were transformed into the corresponding aldehydes in good yields in the presence of CO and sodium formate (Scheme 3.4). In a step-by-step study, they also proved that the oxidative addition of chlorobenzene to palladium is the rate determining step, which undergoes easy carbonylation in the presence of CO and will produce aldehyde in the presence of sodium formate in THF at 100 °C. 

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