Kinetic selectivity factor

It is rare that a catalyst can be chosen for a reaction such that it is entirely specific or unique in its behaviour. More often than not products additional to the main desired product are generated concomitantly. The ratio of the specific chemical rate constant of a desired reaction to that for an undesired reaction is termed the kinetic selectivity factor (which we shall designate by 5) and is of central importance in catalysis. Its magnitude is determined by the relative rates at which adsorption, surface reaction and desorption occur in the overall process and, for consecutive reactions, whether or not the intermediate product forms a localised or mobile adsorbed complex with the surface. In the case of two parallel competing catalytic reactions a second factor, the thermodynamic factor, is also of importance. This latter factor depends exponentially on the difference in free energy changes associated with the adsorption-desorption equilibria of the two competing reactants. The thermodynamic factor also influences the course of a consecutive reaction where it is enhanced by the ability of the intermediate product to desorb rapidly and also the reluctance of the catalyst to re-adsorb the intermediate product after it has vacated the surface. 

In sharp contrast, Bartoli showed that the (salen) Co catalyst system could be applied to the kinetic resolution of terminal epoxides with unprotected tert-butyl carbamate as nucleophile with extraordinarily high selectivity factors (Scheme 7.40) [72]. Excellent yields and selectivities are also obtained with use of ethyl, Cbz,... 

The kinetic resolution of rac-1 was chosen as a model reaction using the WT lipase from PAL as the catalyst [6]. The WT shows a very low selectivity factor E = 1.1 in slight favor of (S)-2 (Scheme 2.1). 

Several libraries of mutant ANEHs were prepared by applying epPCR at various mutation rates and transforming into E. coli BL21 (DE3). About 20 000 clones were screened, the most selective ANEH variant showing a selectivity factor of only E= 10.8 in the kinetic resolution of rac-19 [58]. Thus, this enzyme appeared to be difficult to evolve. 

The choice of the particular upward pathway in the kinetic resolution of rac-19, that is, the specific order of choosing the sites in ISM, appeared arbitrary. Indeed, the pathway B C D F E, without utilizing A, was the first one that was chosen, and it led to a spectacular increase in enantioselectivity (Figure 2.15). The final mutant, characterized by nine mutations, displays a selectivity factor of E=115 in the model reaction [23]. This result is all the more remarkable in that only 20000 clones were screened, which means that no attempt was made to fully cover the defined protein sequence space. Indeed, relatively small libraries were screened. The results indicate the efficiency of iterative CASTing and its superiority over other strategies such as repeating cycles of epPCR. 

Sigman et al. have optimized their system too [45]. A study of different solvents showed that the best solvent was f-BuOH instead of 1,2-dichloroethane, which increased the conversion and the ee. To ensure that the best conditions were selected, several other reaction variables were evaluated. Reducing the catalyst loading to 2.5 mol % led to a slower conversion, and varying temperature from 50 °C to 70 °C had little effect on the selectivity factor s. Overall, the optimal conditions for this oxidative kinetic resolution were 5 mol % of Pd[(-)-sparteine]Cl2, 20 mol % of (-)-sparteine, 0.25 M alcohol in f-BuOH, molecular sieves (3 A) at 65 °C under a balloon pressure of O2. 

The variables that control the extent of a chromatographic separation are conveniently divided into kinetic and thermodynamic factors. The thermodynamic variables control relative retention and are embodied in the selectivity factor in the resolution equation. For any optimization strategy the selectivity factor should be maximized (see section 1.6). Since this depends on an understandino of the appropriate retention mechanism further discussion. .Jll be deferred to the appropriate sections of Chapters 2 and 4. 

If kinetic resolution is being studied, the ratio of pseudo-e nantiomers can be measured by MS, allowing for the determination of ee-values (and/or of selectivity factors E). The same applies to the reaction of pseudo prochiral compounds. This system has been used successfully in the directed evolution of enantioselective enzymes. However, it should work equally well in the case of asymmetric transition metal catalyzed reactions. In the original version about 1,000 ee-deter-minations were possible per day (Figure 6).94 The second-generation version based on an 8-channel multiplexed spray system enables about 10,000 samples to be handled per day, the sensitivity being 2% ee.96... 

It is apparent from early observations [93] that there are at least two different effects exerted by temperature on chromatographic separations. One effect is the influence on the viscosity and on the diffusion coefficient of the solute raising the temperature reduces the viscosity of the mobile phase and also increases the diffusion coefficient of the solute in both the mobile and the stationary phase. This is largely a kinetic effect, which improves the mobile phase mass transfer, and thus the chromatographic efficiency (N). The other completely different temperature effect is the influence on the selectivity factor (a), which usually decreases, as the temperature is increased (thermodynamic effect). This occurs because the partition coefficients and therefore, the Gibbs free energy difference (AG°) of the transfer of the analyte between the stationary and the mobile phase vary with temperature. 

It is not clear why the selectivity factor is not higher in this resolution, as might be expected from Fig. 7.10. One possible explanation is that the kinetics with Me2Zn might be more complicated than with the other zinc reagents, in which case the formula in Ref 67a would no longer be valid see also D. G. Blackmond, /. Am. Chem. Soc. 2001, 123, 545. 

Enantioselective enzyme-catalyzed reactions may involve the transformation of a prochiral substrate into a chiral product, in which case the selectivity is measured by the enantiomeric excess (ee). The transformations can also involve kinetic resolution of racemic substrates, in which case enantioselectivity is measured by the selectivity factor E reflecting the relative rates of reaction of the R)- and (5)-enantiomer. 

The kinetic resolution of (5, 7 )-l-methoxy-2-propylacetate was investigated using various commercially available hydrolases. The agreement between the apparent selectivity factor app and the actual value true determined by GC turned out to be excellent at low enantioselectivity E — 1.4— 13), but less so at higher enantioselec-tivity (20% variation at E— 80). This limitation may cause problems when attempting to enhance enantioselectivity beyond E — 50. 

However, these limitations do not reduce the value of the basic research conducted with this particular lipase. As a model substrate the chiral ester 1 was chosen. Kinetic resolution of 1 using the WT lipase from P. aeruginosa as the catalyst shows a very low selectivity factor E— 1.1 in slight favor of (5)-2. 

Note (1) The number of equilibria in Case II is manifold compared to Case I and the equilibrium constants arc quite different, however, they are kinetic terms and thus also responsible for chromatographic efficiency. (2) Selectivity factor x becomes oc when A approaches 0 a becomes 1 when B(S) or B(f ) approaches 0. 

All of the kinetic resolutions described above have been characterized in terms of yields and ee values of the recovered substrate and the product. In principle the efficiency of a kinetic resolution can also be described by the selectivity factor S [lu], the ratio of the rate constants for the reactions of the enantiomers of the substrate with the catalyst. For a Pd-catalyzed kinetic resolution of an allylic substrate obeying first-order kinetics in regard to the reaction of the substrate with the catalyst (unimolecularity) S can be calculated according to Eq. (1), which contains as variables the conversion (c) and the ee value of the substrate (ee ). 

The catalyst exhibited high enantiomer selectivity in the reaction of the six-membered cyclic acetate roc-lab with KSAc on a 2.5 mmol scale. This led to the isolation of the thioacetate 19aa with 97% ee in 48% yield and the acetate ent-lab with >99% ee in 43% yield (entry 8). The reaction came to a practically complete halt after 51% conversion of the substrate. In order to determine the selectivity factor S, the kinetic resolution of roc-lab was repeated and the ee values of the acetate and thioacetate were monitored over the whole course of the reaction (Fig. 

Nonlinear regression of the selectivity factor S for ten pairs of ee and c values [6m, 27] gave S = 72 19. This value corresponds well with S = 74 7 for the Pd/BPA-catalyzed kinetic resolution of roc-laa with lithium t-butylsul-finate in CH2CI2/H2O and with S = 77 11 for that of rac-laa with 2-pyrimidine-thiol inCH2Cl2 [26]. 

The selectivity factors determined in potentiometric studies (K[,ot) should therefore be identical to the ones (Kjj) determined in transport experiments. In Fig. 4 selectivities obtained potentiometrically on a membrane containing ligand 11 (3 wt.% carrier 11, 65 wt.% dibutyl sebacate 32 wt.% polyvinyl chloride, thickness =100 /xm) are compared with those obtained in electrodialytic transport experiments.55 Although widely different methods have been used to determine the ion selectivity, the agreement between the two sets of data is evident and corroborates the model presented. The deviation for CsH may possibly be due to kinetic limitations suggesting a loss in transport selectivity (see Section IV.D). 

Kinetic resolution.l33 Since enantiomers react with chiral compounds at different rates, it is sometimes possible to effect a partial separation by stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on p. 102. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane,134 since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as 45 with one enantiomer of a chiral epoxidizing agent (see 5-36).135 In the case of 45 the discrimination was extreme. One enantiomer was converted to the epoxide and the other was not, the rate ratio (hence the selectivity factor)... 

Assuming that A and C react according to first-order kinetics and that the rate constants fe, and k2 refer to unit surface area, the selectivity factor, a, is given by the ratio fe, /k2 and the relative fractions, a, of A and C reacted at any given time are given by the equation... 

The kinetic and thermodynamic selectivity factors are quantities which are functions of the chemistry of the system. When an active catalyst has been selected for a particular reaction (often by a judicious combination of theory and experiment) we ensure that the kinetic and thermodynamic factors are such that they favour the formation of desired product. Many commercial processes, however, employ porous catalysts since this is the best means of increasing the extent of surface at which the reaction occurs. Chemical engineers are therefore interested in the effect which the porous nature of the catalyst has on the selectivity of the chemical process. 

After further optimization of catalyst structure, phosphine catalyst 2 was found to be very effective in the kinetic resolution of aryl alkyl carbinols (fcrei=31-369, Scheme 3) [12]. Reactions exhibit high selectivity factors when... 

Despite the fact that both normal and monomethyl-substituted paraffins readily enter the pores of ZSM-5 and ZSM-11, preferential sorption of the normal isomer is observed under thermodynamic equilibrium, non-kinetically controlled conditions. Whereas small-pore zeolites, such as 5A and erionite, totally exclude branched hydrocarbons, and large-pore zeolites exhibit little preference, the intermediate pore-size zeolites ZSM-5 and ZSM-11 show a marked preference for sorption of the linear paraffin, even under equilibrium conditions. Competitive liquid phase sorption studies at room temperature indicated selectivity factors greater than ten in favor of n-hexane relative to... 

The chiral bicyclic phosphines 5 (and in particular 5a [7b]) are currently the most active phosphorus-based acylation catalysts, enabling use of low reaction temperatures. Under these conditions (i.e. —40 °C) selectivity factors as high as 370-390 were achieved (Scheme 12.2). This is the best selectivity factor ever reported for metal-free, non-enzymatic kinetic resolution. As a consequence, very good enantiomeric purity of both the isobutyric esters 7 and the remaining alcohols 6 was obtained, even at substrate conversions approaching 50% (Scheme 12.2) [7, 8],... 

Later, the chiral bicyclic phosphine catalyst 5a was also used for kinetic resolution of allylic alcohols with isobutyric anhydride [8, 9]. The best results were obtained for trisubstituted allylic alcohols - selectivity factors ranged from 32 to 82 at -40 °C. 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

The DMAP derivative 19a was tested for kinetic resolution of a variety of mono esters of cyclic cis diols (rac-20a-i) (Scheme 12.5) [15]. Catalyst 19a afforded selectivity factors up to 12.3 and highly enantioenriched mono esters 20 with conversions of 65-73%. For this type of reaction the selectivity of the Campbell catalyst 19b was similar (selectivity factor 13.2, Scheme 12.5) [16a], The latter catalyst was identified by screening of a 31-mer library prepared from the parent N-(4-pyridyl)-a-methylproline and a variety of amines [16a], The solid-phase-bound forms of N-(4-pyridyl)-a-methylproline, as reported by Anson et al. [16b], are easily recyclable acylation catalysts affording selectivity factors up to 11.9 in the kinetic resolution of the secondary alcohol rac-20b (Scheme 12.5). In the kinetic resolution of N-acylated amino alcohols, selectivity factors up to 21 were achieved by use of the Kawabata-Fuji catalyst 19a, and up to 18.8 by use of the Campbell system 19b (Scheme 12.5) [15, 16a]. 

Later studies focused on the planar chiral DMAP derivative 21c as catalyst and use of acetic anhydride as an inexpensive and readily available acyl donor [19]. Under these conditions (2 mol% catalyst loading, r.t.) kinetic resolution of several racemic alcohols could be achieved with selectivity factors up to 52 (Scheme 12.7). As a consequence, enantiomerically highly enriched alcohols (> 95% ee) could be obtained at conversions only slightly above 50%. 

Jeong, Kim et al. reported use of the chiral DMAP derivative 22e, which was synthesized from 3-amino-DMAP, Kemp s triacid, and N-acetyl-2,2 -diamino-l,l -binaphthyl [26], As summarized in Scheme 12.11, selectivity factors up to 21 were observed with 1 mol% modular catalyst 22e in the kinetic resolution of a variety of secondary alcohols with acetic anhydride in tert-amyl alcohol as solvent, conditions first described by Fu et al. [20]. 

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