Heck reaction catalyst turnover

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. 

In 1995 Herrmann discovered highly efficient palladacyde catalysts in Heck and related reactions of aryl halides with catalyst turnover numbers (TONs) up to 500,000 [ 117]. Later, TONs of the intermolecular Heck reaction reached up to 8,900,000 [ 118]. On the other hand, few syntheses of chiral palladacyde catalysts were envisioned and most of these attempts failed. Recently, the first AHR using a chiral phosphapalladacycle catalyst was reported by Buono et al. [ 119]. The chiral phosphapalladacycle catalyst 129, which was prepared from Pd(OAc)2... 

The palladium) ) complex was used as a catalyst for the Heck reaction between 4-bromoacetophenone and n-butyl acrylate [368], Although the catalyst proved to be active in this reaction, it shows singularly low conversion rates (7%) and turnover numbers (TONs) (66(X)). 

The search for more stable or more reactive catalysts has produced many new leads. One of the most promising is represented by the paUadacycle (14), known as Hermann s catalyst. This can be used in Heck reactions at high temperatures (above 140 °C), which leads to high turnover numbers of up to 10 with electron-poor aryl bromides. ... 

With the variety of transformations that can be promoted by organopalladium reagents, it is unfortunate that palladium is such a rare metal. Biochemical processes might be much more exotic if palladium had been more abundant in the earth s crust at the origin of life (although selenium, which is an essential trace nutrient, is only approximately five times as concentrated as palladium in the earth s crust). The discovery of high turnover number catalysts has allowed several palladium-catalyzed reactions to be used in fine chemical and pharmaceutical synthesis. Naproxen (29) can be made using a Heck reaction. Ibuprofen s (30) synthesis... 

The influence of high pressure on the Heck reactions of selected alkenyl and aryl halides, respectively, i.e., 1-iodocyclohex-l-ene, iodobenzene, bromobenzene, with methyl acrylate has been investigated and the activation parameters of these reactions determined [142], Two different catalyst cocktails were used in this study, the classical system (Pd(OAc)2, NEtg, PPhg) and the one reported by Herrmann, Beller and others [16] (la). The temperature-dependent and the pressure-dependent rate coefficients both follow the order PhI/Pd(OAc)2 > 1-iodocyclohexene/Pd(OAc)2 > Phl/la > PhBr/la and the activation enthalpies as well as the activation entropies exhibit the trend 1-iodocyclohexene/Pd(OA)2 < Phl/Pd(OAc)2 < Phl/la < PhBr/la. The absolute values of the activation volumes, which were ascertained from the pressure-dependent rate coefficients, increase as follows l-iodocyclohexene/Pd(OAc)2 < PhI/Pd(OAc)2 Phl/la < PhBr/la. Under high pressure, the lifetime of the active palladium catalyst and thereby the turnover numbers are greatly enhanced [88]. 

The intramolecular Heck cyclizations highlighted in this chapter were typically conducted with 5-20 mol% of a palladium catalyst. In few, if any, of these studies were catalyst loadings and cyclization conditions carefully optimized. As a result, we have not included catalyst loadings in the schemes in this chapter. Only recently has serious attention been directed to optimizing catalyst turnover in Heck reactions and to the development of more robust catalyst systems. It seems likely that in the future many Heck cyclizations will be accomplished with catalyst loads of 1 % or lower [76]. 

The Pd-catalyzed coupling reaction of an aryl halide and olefin is a very efficient and practical method for making C—C bonds. The Heck alkenylation of aryl bromides with ethylene was used by Dow Chemical to make high-purity 2- and 4-vinyltoluenes, which are of interest as co-monomers in styrene polymers [159]. The monomer, o-vinyltoluene (99), has a low toxicity and an attractive co-monomer for styrene polymers. o-Vinyltoluene improved heat distortion properties of styrene and polymerization rate. It also minimized color formation or cross-linking and it was difficult to make by other routes [159]. Catalyst turnover, rate, and lifetime were significantly improved. 

The increase of the catalyst turnover numbers is indeed one other major area where further improvements could be expected. Such improvements have recently been achieved for the standard Heck reaction by the use of high pressure conditions [86], the use of preformed palladacycles as catalysts [87], or by using a macrocyclic tetraphole as hgand [88].Dendritic diphosphine-palladium complexes as catalysts for Heck reactions have also been reported to possess superior stabihty compared to the monomeric parent compounds [89]. Transferring such iimovations to the AHR remains an important goal. 

The outstanding features of metal clusters prepared in block copolymer micelles [81] are their high catalytic activity combined with high stability. Such micellar catalyst systems can be recovered after reaction by precipitation or ultrafiltration. In many cases high selectivity and stability have been observed. Cyclohexadiene, for instance, is selectively hydrogenated by Pd colloids just to cyclo-octene [69]. High activity and stability of such catalyst particles have been reported for the Heck-reaction with unusually high turnover numbers of... 

Another interesting case illustrating the utility of high pressure, has been presented by Reiser et al. showing that in the Heck reaction of dihydrofuran 11 and iodobenzene 12 to give the products 13-15, the turnover number (TON) of this catalytic process can be improved by stabilizing the catalyst (Scheme 8.4) [16] (cf. Chapter 7). 

An immobilized version of a Heck reaction catalyzed by Pd nanoparticles has been very recently described by Kaiimi and Enders [289]. The nanoparticles were obtained as a result of the covalent anchoring of a N-heterocyclic carbene palladium/ionic liquid matrix on a silica surfece and their nature was confirmed by TEM coupled with EDX analysis. The catalyst showed high thermal stability (up to 280 °C) and could be recycled four times for the reaction of bromobenzene with methylacrylate achieving a total turnover number of 36600. After carrying out a hot filtration process, the authors could not detect any Pd in the filtrate. The filtrate also showed no further reaction progress. Erom these findings the authors concluded that the reaction was, in their case, indeed catalyzed by the heterogeneous Pd particles and not from monomolecular Pd-complexes leached from the sur ce. 

Gladysz showed that a thermomorphic fluorous paUadacyde acts as a PdNP catalyst precursor for the Heck reaction at 80-140 C in DMF with very high turnover numbers [24a]. Molecular palladium complexes such as palladacycles and other palladium salts have also been used as PdNP precursors upon treatment with CO in DMF or toluene at room temperature, and these PdNPs catalyzed nudeophiUc substitution/carbonylation/amination affording iso-indolinones at room temperature [24bj. PdNPs capped with spedal ligands such as polyoxometal-... 

The Pd is leaching and is redeposited at the end of the reaction, which provides an excellent recovery of the precious metal from the reaction mixture. The precipitation of the catalyst at the end of the reaction significantly changes its state and decreases its activity, however, making its re-use unattractive. Kohler et al. also showed that optimization of the Pd/C catalyst (temperature, solvent, base and Pd loading) allows turnover frequencies (TOFs) of up to 9000 to be reached and Pd concentration down to 0.005 mol% to be developed for the Heck reaction of unac-tivited bromobenzene at 140 °C [44]. The turnover numbers (TONs) are surpassed, however, by those of the best homogeneous catalysts. 

Nair and co-workers [8] have coupled of semi-continuous NF with the Heck reaction. The objective was the synthesis of trans-stilbene from styrene and iodobenzene using Pd(OAc)2(PPh3)2 as catalyst and Pjo-tolyljj as stabilizing agent. They used solvent-resistant membranes and different aqueous/solvent systems (ethyl acetate and acetone/H20 methyl tert-butyl ether and acetone/H20 tetra-hydrofuran/H20). The best conversion was obtained with the first-mentioned solvent mixture. A selectivity of 100% of trans-stilbene with a cumulative turnover number of 1200 was reported, where the rejection of the catalyst turned out to be as high as 97%. Therefore, the authors concluded that NF was a convenient technique to run catalytic reactions with catalyst recycling, since this method saves the catalyst, prevents the metal contamination of the products, and increases reactor productivity. 

In 1997, Antonietti et al. reported on catalytically active palladium nanoparticles prepared by reduction of palladium(II) compounds in inverse block copolymer micelles, namely polystyrene-ib-poly(4-vinylpyridine) (PS-b-P4VP). Activated aryl bromides were coupled reproducibly in Heck reactions [18]. Small partide sizes were a prerequisite for high conversions, as indicated by qualitative TEM investigations. Very high total turnovers were reported (0.0012 mol% palladium, 68% conversion in five days, corresponding to 56 000 TO) (Table 1). Catalyst activity was found to be dependent on the structure of the block copolymer employed, which was attributed to a better accessibility of the metal particles in smaller micelles with a high surfacer area and thinner polystyrene layer. 

The Suzuki-Miyaura cross-coupling reaction is a standard method for carbon-carbon bond formation between an aryl halide or triflate and a boronic acid derivative, catalyzed by a palladium-metal complex. As with the Mizoroki-Heck reaction, this cross-coupling reaction has been developed in ionic liquids in order to recycle and reuse the catalyst. In 2000, the first cross-coupling of a halide derivative with phenylboronic acid in [bmim] [BF4] was described. As expected, the reaction proceeded much faster with bromobenzene and iodobenzene, whereas almost no biphenyl 91 was obtained using the chloride derivative (Scheme 36). The ionic liquid allowed the reactivity to be increased, with a turnover number between 72 and 78. Furthermore, the catalyst could be reused repeatedly without loss of activity, even when the reaction was performed under air. Cross-coupling with chlorobenzene was later achieved - although with only a moderate yield (42%) - using ultrasound activation. 

Using a fluorous palladacycle catalyst 10 originating from the corresponding fluorous Schiff base and palladium acetate, a fluorous Mizoroki-Heck reaction was achieved with an excellent turnover number (Scheme 12). A homogeneous catalytic reaction system was obtained when DMF was used as the solvent. After the reaction, perfluorooctyl bromide was added to facilitate the separation of DMF (containing the products and amine salts) from the catalyst phase. The resulting lower fluorous layer was condensed under vacuum and the catalyst residue was used in a second run. In this reaction, the palladacycle catalyst appears to act as a source of palladium nanoparticles, which are thought to be the dominant active catalyst. 

Bulky tri(o-tolyl)phosphine was used first by Heck [11]. A palladacycle obtained from it is known as the Herrmann complex (XVIII-1) and is used extensively in HR [12]. Also, palladacycles XVIII-7 [13] and XVIII-2 [14] are high performance catalysts. Turnover numbers as high as 630-8900 were achieved by tetraphosphine Tedicyp (X-1) [15]. Recently, the remarkable effect of electron-rich and bulky phosphines, typically P(t-Bu)3 and other phosphines shown in Tables 1.4, 1.5 and 1.6, have been vmveiled. Smooth reactions of aryl chlorides using these ligands are treated later. Electron-rich ligands accelerate oxidative addition of aryl chlorides, and reductive elimination is accelerated by bulky ligands. HR can be carried out in an aqueous solution by use of a water-soluble sulfonated phosphine (TPPMS, II-2) [16]. 

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