Substrate-to-catalyst-ratio

Reaction experiments were performed at the substrate to catalyst ratios between 250 and 5000 (Table 1). The immobilized catalyst showed a rather constant values of TOP and enantioselectivity in spite of the increase in the S/C ratio, even though these values were slightly lower than those of the homogeneous Ru-BINAP catalyst. After the reaction, the Ru content in the reaction mixture was measured by ICP-AES and was found to be under 2 ppm, the detecting limit of the instrument, indicating the at Ru metal didn t leach significantly during the reaction. These results show that the immobilized Ru-BINAP catalyst had stable activity and enantioselectivity and that the Ru metal complex formed a stable species on the alumina support. 

Initial or steady state rates in mol/mol/s at the temperatme indicated in parentheses Substrate to catalyst ratio, for which the reaction reaches at least the thermodynamic... 

An investigation of different organic solvents, buffer, surfactants, and organorhodium compounds established that the catalytic reduction of tetralin using [ Rh(l,5-hexadiene)Cl 2] proceeds with high efficiency at high substrate-to-catalyst ratios. The reaction occurs at r. t. and 1 atm. pressure in a biphasic mixture of hexane and an aqueous buffer containing a low concentration of a surfactant which stabilizes the catalysts.314... 

The optimized process is carried out in a loop reactor at 80 bar (8 x 10 hPa) hydrogen and 50°C with a catalyst generated in situ from [lr(cod)Cl]2 and the Josiphos hgand R = Ph, R = Xyl at a substrate-to-catalyst ratio of >1000000 in the presence of trace amounts of HI. Complete conversion is reached within 3—4h, the initial TOFs exceed 1800000b, and the ee-value is about 80%. The product (S)-NAA is distilled and the catalyst discarded. Today, this process is operated by Syngenta on a scale of >10000ty". ... 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

More recently, the Noyori group described an organic solvent- and haUde-free oxidation of alcohols with aqueous H202 . The catalyst system typically consists of Na2W04 and methyltrioctylammonium hydrogen sulfate, with a substrate-to-catalyst ratio of 50-500. Secondary alcohols are converted to ketones, whereas primary alcohols, in particular substituted benzyUc ones, are oxidized to aldehydes or carboxylic acid by selecting appropriate reaction conditions This system also catalyzed the chemoselective oxidation of unsaturated alcohols, the transformation exemplified in equation 65, with a marked prevalence for the hydroxy function. 

Figure 5.2 Catalytic efficiency of 4-Ba in the methanolysis of aryl acetates calculated for a substrate-to-catalyst ratio of 10 1 (curve a) and 100 1 (curve b) versus ester reactivity (as measured by the log kbg values).

The catalytic efficiency, as conveniently measured by the ratio of the catalyzed process under steady state conditions to the rate of background methanolysis (Figure 5.2), is a function of the substrate-to-catalyst ratio and reaches maximum values in the reaction of pCPOAc. 

It is apparent that an increase in the substrate-to-catalyst ratio dramatically decreases the catalytic efficiency for the pNPOAc reactions, but affects to a much lower extent the POAc reaction. This is easily understood with reference to Table 5.3. Since in the reaction of pN POAc the rate-determining step is mainly deacetylation, an increase in ester concentration causes a proportional increase in the rate of background methanolysis, but hardly affects the rate of deacetylation, with the result that catalytic efficiency varies inversely to ester concentration. Conversely, the reaction of POAc approaches a situation in which acetylation of the catalyst is rate determining, which implies that both acetylation and background reactions increase on increasing ester concentration. 

Dimerization of phenyl isocyanate, catalyzed by lanthanide complexes, has been reported by Deng et al. <2003CHJ574>. A number of lanthanide complexes were tried and Sm(SPh)3(hmpa)3 was found to be the most effective catalyst. Conversion was as high as 96% with 2500 1 of substrate to catalyst ratio (Scheme 47). 

Whichever catalyst system is used to prepare an a-amino acid derivative at scale, the cost of the ligand can play a major economical role, often more than the metal. The cost of the catalyst can be offset by large substrate-to-catalysts ratios that can be improved by recycles and fast reactions. However, because metal hydride species are invariably involved in the catalytic cycle, recycles usually mean reuse in a short time span. The conclusion is that expensive ligands must be extremely good at the desired reduction. This is particularly true with amino acid derivatives because almost all are crystalline and offer the possibility of enantioenrichment during the purification process. Thus, high ee s may not be required in the reduction itself. In many cases, the synthesis of the substrate is the difficult part of the synthesis. This problem has been highlighted in the synthesis of [3-amino acids (see Section 2.6). 

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

Biotin (60), a water-soluble vitamin with widespread application in the growing market for health and nutrition, acts as a co-factor for carboxylase enzymes and its essential fatty acid synthesis. The key step in the chemical synthesis of biotin is the asymmetric reduction of the tetrasubstituted olefins 61 by in situ Rh(I)-4i catalyst (Scheme 12.1 S).79-83-85-86 Substrate-to-catalyst ratios of 2000 with diastereoselectivities of 99% de were achieved with Rh-4i at the multi-ton scale before production was terminated.87... 

The discovery by the recent Nobel-laureate, Ryoji Noyori, of asymmetric hydrogenation of simple ketones to alcohols catalyzed by raras-RuCl2[(S)-binap][(S,S)-dpen] (binap = [l,l -binaphthalene-2,2/-diyl-bis(diphenylphosphane)] dpen = diphenylethylenediamine) is remarkable in several respects (91). The reaction is quantitative within hours, gives enantiomeric excesses (ee) up to 99%, shows high chemoselecti-vity for carbonyl over olefin reduction, and the substrate-to-catalyst ratio is >100,000. Moreover, the non-classical metal-ligand bifunctional catalytic cycle is mechanistically novel and involves heterolytic... 

---