Total turnover number

In respect of designing an economic production process, the stoichiometric cofactor required in carbonyl reductions or the respective oxidation reactions needs to be minimized that is, enabled by recycling of the cofactor. The measure for the efficiency of the recycling process is the total turnover number (TTN), which describes the moles of product synthesized in relation to the moles of cofactor needed. The different approaches in cofactor recycling were recently reviewed by Goldberg et at. [12]. 

Solvent-free hydrogenations of 1-octene, 2-pentene, cyclohexene, and styrene were carried out with catalyst loadings as low as 0.05 mol.% of the dimer, in some cases with TOF values as high as 6000 IT1 [71]. Total turnover numbers of almost 2000 were obtained in most of these cases. Solvent-free hydrogenation of ketones such as Et2C=0, cyclohexanone, and diisopropyl ketone were also reported at the same temperature and H2 pressure, but with somewhat lower TOFs for the hydrogenation of C=0 compared to C=C hydrogenations. 

The unmodified complex can be applied in very dilute concentrations allowing total turnover numbers (TONs), or a substrate (NAD(P)) to catalyst (rhodium complex) ratio of up to 400 [41]. This efficiency was due to the design of a three-dimensional electrode, which also resulted in an extraordinary space-time yield of the reduced cofactor of up to 1 kg IT1 per day. 

There is huge potential in the combination of biocatalysis and electrochemistry through reaction engineering as the linker. An example is a continuous electrochemical enzyme membrane reactor that showed a total turnover number of 260 000 for the enantioselective peroxidase catalyzed oxidation of a thioether into its sulfone by in situ cathodic generated hydrogen peroxide - much higher than achieved by conventional methods [52],... 

Probably the first isolated tungsten alkylidene complex active in metathesis and completely characterised is the one shown in Figure 16.10 reported by Wengrovius and Schrock the analysis included an X-ray structure determination by Churchill and co-workers [18], The alkylidene was transferred from a tantalum complex to yield the hexacoordinate tungsten complex containing two PEt3 ligands. One of these can be removed by the addition of half an equivalent of palladium chloride. The total turnover number of these catalysts with Lewis acids added was 50 in 24 hours. 

Unlike the whole-cell system, enzymatic reductions require the addition of a hydride donating cofactor to regenerate the reduced form of the enzyme. Depending on the chosen ADH, the cofactor is usually NADH or NADPH, both of which are prohibitively expensive for use in stoichiometric quantities at scale. Given the criticality of cofactor cost, numerous methods of in situ cofactor regeneration, both chemical and biocatalytic, have been investigated. However, only biocatalytic regeneration has so far proven to be sufficiently selective to provide the cofactor total turnover numbers of at least 10 required in production. 

The rhodium catalyst was recycled batch-wise four times. It was found that a short induction period occurred during the first reaction cycle. The following cycles showed a constant rate and no loss of activity was detected. A ligand-to-rhodium ratio of 5 1 led to a constant yield of 95% per cycle after 1 h. Within the four cycles a total turnover number of 1000 with a maximum turnover frequency of 234 h was achieved. The leaching of rhodium and phosphorus into the aqueous layer was determined by inductively coupled plasma atomic emission spectrometry. Rhodium leaching amounted to 14.2 ppm in the first run, then dropped to 3.6 ppm (second run) and reached values of 0.95 and 0.63 ppm in the third and fourth runs, respectively. 

Heterogenization of homogeneous metal complex catalysts represents one way to improve the total turnover number for expensive or toxic catalysts. Two case studies in catalyst immobilization are presented here. Immobilization of Pd(II) SCS and PCP pincer complexes for use in Heck coupling reactions does not lead to stable, recyclable catalysts, as all catalysis is shown to be associated with leached palladium species. In contrast, when immobilizing Co(II) salen complexes for kinetic resolutions of epoxides, immobilization can lead to enhanced catalytic properties, including improved reaction rates while still obtaining excellent enantioselectivity and catalyst recyclability. 

Since these two biocatalysts possess complementary stereoselectivity, they enable the synthesis of both enantiomers of the desired products. The applicability of enzymatic reduction of aryl alkynones on a preparative scale was optimized with regard to the amount of cofactor and enzyme, resulting in high total turnover numbers and almost quatitative conversion [41]. 

All of these oxidoreductases reduce aromatic and aliphatic a-chloropropargyhc ketones (27a-27c) with high activity. a-Bromopropargylic ketone 27d is also accepted as a substrate however, the enzymatic activity of TBADH and recLBADH decreases, probably for steric reasons. Due to the low solubility of substrate 27a about 25% of a short-chained alcohol was added. The large excess of short-chained alcohol shifted the substrate/product equilibrium toward the desired propargylic alcohol 28a, resulting in almost quantitative conversions with high total turnover numbers (TTN) of the cofactor. 

The main task in technical application of asymmetric catalysis is to maximize catalytic efficiency, which can be expressed as the ttn (total turnover number, moles of product produced per moles of catalyst consumed) or biocatalyst consumption (grams of product per gram biocatalyst consumed, referring either to wet cell weight (wcw) or alternatively to cell dry weight (cdw)) [2]. One method of reducing the amount of catalyst consumed is to decouple the residence times of reactants and catalysts by means of retention or recycling of the precious catalyst. This leads to an increased exploitation of the catalyst in the synthesis reaction. 

Fig. 3.1.3 Total turnover numbers (ttn) for different types of chemzymes 1, a,a-diphenyl-L-prolinol chemzyme ...

Seelbach K, van Deurzen MPJ, van Rantwijk F, Sheldon RA, Kragl U (1997) Improvement of the Total Turnover Number and Space-Time Yield for Chloroperoxidase Catalyzed Oxidation. Biotechnol Bioeng 55 283... 

Enzyme reactions are saddled with limited space-time yield. The notion that biocatalysts are slow catalysts is false. Slow catalysts, applied at low concentrations, certainly lead to low space-time yields. However, optimized syntheses not only produce very good selectivities or total turnover numbers but also satisfactory to excellent space-time yields. Examples with such good s.t.y. values are... 

Every (bio)catalyst can be characterized by the three basic dimensions of merit -activity, selectivity and stability - as characterized by turnover frequency (tof) (= l/kcat), enantiomeric ratio (E value) or purity (e.e.), and melting point (Tm) or deactivation rate constant (kd). The dimensions of merit important for determining, evaluating, or optimizing a process are (i) product yield, (ii) (bio)catalyst productivity, (iii) (bio)catalyst stability, and (iv) reactor productivity. The pertinent quantities are turnover number (TON) (= [S]/[E]) for (ii), total turnover number (TTN) (= mole product/mole catalyst) for (iii) and space-time yield [kg (L d) 11 for iv). Threshold values for good biocatalyst performance are kcat > 1 s 1, E > 100 or e.e. > 99%, TTN > 104-105, and s.t.y. > 0.1 kg (L d). ... 

As in all catalytic processes, catalyst stability is a key process criterion. In contrast to mere temperature or storage stability, which refer to the catalyst independently of a process, the operating stability or process stability is the relevant and decisive dimension of merit. It is determined by comparing the amount of product generated with the amount of catalyst spent. The relevant quantity, also sometimes found in homogeneous catalysis, is the total turnover number (TTN) [Eq. (2.25)]. 

Relationship between Deactivation Rate Constant lrd and Total Turnover Number TTN... 

To convert the specific enzyme consumption into the total turnover number TTN, the specific enzyme consumption, sp.e.c. [U (kg product)-1] [Eq. (2.32)] first has to be converted into the enzyme consumption number e.c.n. [g enzyme (kg product)-1] [Eq. (2.26)]. 

Some of those criteria have been discussed above in the context of the catalyst or the process, such as enantioselectivity or diastereoselectivity instead of simple selectivity to product, and catalyst performance data such as turnover frequency (tof), turnover number (TON), total turnover number (TTN), and space-time-yield (s.ty.). 

While a number of dendritic catalysts have been described, catalyst recyclization in most cases is an unsolved problem. Diaminopropyl-type dendrimers bearing Pd-phosphine complexes have been retained by ultra- or nanofiltration membranes, and the constructs have been used as catalysts for allylic substitution in a continuously operating chemzyme membrane reactor (CMR) (Brinkmann, 1999). Retention rates were found to be higher than 99.9%, resulting in a sixfold increase in the total turnover number (TTN) for the Pd catalyst. 

Isolated enzymes are advantageous over whole cells owing to the absence of side activities compromising selectivity and the greater ease of repeated re-use to achieve high total turnover numbers (TTNs). Principal disadvantages are the requirement for a purification protocol, the yield loss upon purification, and the requirement for external addition of cofactors. 

The highest space-time yield (120 g 1. 1 d 1) was achieved in a continuously operated enzyme membrane reactor for the chloroperoxidase-catalyzed oxidation of indole to oxindole with H202 in aqueous t-BuOH, whereas a fed-batch reactor obtained the highest total turnover number (TTN 860 000) (Seelbach, 1997). 

Catalyst stability and productivity Interestingly, a comparison of catalyst stability and productivity for the different technologies is not straightforward, as practitioners of homogeneous catalysis seem to prefer to reference turnover numbers (TONs) and substrate/catalyst ratios ([S]/[C] ratios) whereas researchers in biocatalysis quote biocatalyst loading (Units L-1) and total turnover numbers... 

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