Solvent Effects on Selectivity

Solvent effects on enzyme selectivity or specificity are very important. One of the attractions of non-aqueous media is the ability to tune these key properties, and substantial effects can certainly be observed. Unfortunately, it is not yet possible to give confident predictions in most cases. 

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Calo et al. (ref. 5) studied solvent effects on selective bromination of phenol with NBS and found the selectivity of bromination depended on the polarity of the solvents. But thereafter no investigation concerning the solvent effects was reported. We report the effects systematically. 

Solvent effect on selectivity, S, and catalytic activity in the hydrogenation of 2-Butyne-1,4-diol, rT, on the catalyst Ni2o/AlP04 P liquid-phase ... 

There are numerous studies concerning solvent effects on selectivity in heterogeneous hydrogenations (1). Similar effects are observed in oxidation or acid catalysed reactions. In addition, molecular sieves can be viewed as solvents for the species that they contain (2) and therefore, even in vapor phase reactions, modifications of activity or selectivity can be attributed to solvent effects. 

The titanosilicate catalysed the hydroxylation of phenol by H2O2 to afford a mixture of hydroquinone and catechol. The following curves due to C. Naccache et al. (27) show a great solvent effect on selectivity when methanol vs acetone is used. 

Most of the a-oxygenated aldehydes in Table 19 display the characteristic trend toward (Z)-enoate formation with Ph3P=CHC02R" (2j). A simple example of this phenomenon was discussed in connection with Table 16 (2-formyltetrahydropyran entries), but a number of others had been reported much earlier (Table 19, entries 61-93) (126-127). Table 19 also includes the first systematic solvent comparisons (entries 61-67) for an a-alkoxy aldehyde reaction with an ester-stabilized ylide (126). This series of experiments represents the most dramatic known example of solvent effects on selectivity (92 8 Z E in methanol 14 86 Z E in DMF), but the results are qualitatively similar to the solvent study in Table 16. In several other examples, the isomer ratios in methanol are reported to reach synthetically useful levels (> 90%) of the (Z)-enoate (Table 19, entries 19, 20, 23-25). However, most of the methanol entries fall in the more typical range of 70-85% (Z)-enoate. No similar trend is seen with p or y-oxygenated aldehydes (Table 19, entries 102-113) that lack an a-alkoxy group. 

Illuminati, G. Solvent effects on selected organic and organometallic reactions. Guidelines to synthetic applications. In Chemistry 8/2, Dack M. R. J. (ed.), pp. 159-233. New York Wiley 1976... 

Fuchigami T (2007) Unique solvent effects on selective electrochemical fluorination of organic compounds. J Fluorine Chem 128 311-316... 

Table 4. Solvent Effects on Selected /h

FIGURE 10.25 Solvent effects on selectivity between 5 2 and E2 reactions. 

Solvents exert their influence on organic reactions through a complicated mixture of all possible types of noncovalent interactions. Chemists have tried to unravel this entanglement and, ideally, want to assess the relative importance of all interactions separately. In a typical approach, a property of a reaction (e.g. its rate or selectivity) is measured in a laige number of different solvents. All these solvents have unique characteristics, quantified by their physical properties (i.e. refractive index, dielectric constant) or empirical parameters (e.g. ET(30)-value, AN). Linear correlations between a reaction property and one or more of these solvent properties (Linear Free Energy Relationships - LFER) reveal which noncovalent interactions are of major importance. The major drawback of this approach lies in the fact that the solvent parameters are often not independent. Alternatively, theoretical models and computer simulations can provide valuable information. Both methods have been applied successfully in studies of the solvent effects on Diels-Alder reactions. 

The solvent effect on the diastereofacial selectivity in the reactions between cyclopentadiene and (lR,2S,5R)-mentyl acrylate is dominated by the hydrogen bond donor characteristics of the solvent... 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

Table 2,8, Solvent effect on the endo-exo selectivity (% endo -% exo) of the nncatalysed and Cu" -ion catalysed Diels-Alder reaction between 2,4c and 2,5 at 25°C.

The effect of temperature, although significant, is not nearly as great as that from the ethanol content and is greatest at low concentrations of the polar solvent. It is clear, that the solute retention is the least at high ethanol concentrations and high temperatures, which would provide shorter analysis times providing the selectivity of the phase system was not impaired. The combined effect of temperature and solvent composition on selectivity, however, is more complicated and to some extent... 

It is seen that the curves in Figure (24) become horizontal between 40°C and 45 °C as predicted by the theory. It is also clear that there is likely source of error when exploring the effect of solvent composition on retention and selectivity. It would be important when evaluating the effect of solvent composition on selectivity to do so over a range of temperatures. This would ensure that the true effect of solvent composition on selectivity was accurately disclosed. If the evaluation were carried out at or close to the temperature where the separation ratio remains constant and independent of solvent composition, the potential advantages that could be gained from an optimized solvent mixture would never be realized. 

Because the key operation in studying solvent effects on rates is to vary the solvent, evidently the nature of the solvation shell will vary as the solvent is changed. A distinction is often made between general and specific solvent effects, general effects being associated (by hypothesis) with some appropriate physical property such as dielectric constant, and specific effects with particular solute-solvent interactions in the solvation shell. In this context the idea of preferential solvation (or selective solvation) is often invoked. If a reaction is studied in a mixed solvent. 

Remarkable solvent effects on the selective bond cleavage are observed in the reductive elimination of cis-stilbene episulfone by complex metal hydrides. When diethyl ether or [bis(2-methoxyethyl)]ether is used as the solvent, dibenzyl sulfone is formed along with cis-stilbene. However, no dibenzyl sulfone is produced when cis-stilbene episulfone is treated with lithium aluminum hydride in tetrahydrofuran at room temperature (equation 42). Elimination of phenylsulfonyl group by tri-n-butyltin hydride proceeds by a radical chain mechanism (equations 43 and 44). 

In the following text, examples of solvent effects on enzyme selectivity, referred either to systems based (i) on water-miscible organic cosolvents added to aqueous buffers or (ii) on organic media with low water activity, are discussed. 

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

Narasaka et al.16 reported that 53 catalyzes Diels-Alder reactions of 54-type substrates with diene in the presence of 4 A molecular sieves (Scheme 5-18). A remarkable solvent effect on the enantioselectivity is observed. High enantio-selectivity is attained using mesitylene as the solvent. As shown in Scheme 5-18, the reaction of 54a with isoprene proceeds smoothly in this solvent, affording product 55a with 92% ee. Other 3-(3-substituted acryloyl)-l,3-oxazolidin-2-ones 54b-d also give good results (75-91% ee) when reacted with cyclopentadiene. 

Evans et al. (220) have also shown that this reaction is amenable to a catalyst recycling protocol. This cycloaddition is tolerant of a variety of solvents including hexanes, conditions under which Complex 266c is apparently insoluble. Nevertheless, in the presence of adsorbent (florisil), this reaction proceeds at reasonable rates to provide the cycloadduct in undiminished yields and selectivities. Indeed, the catalyst could be efficiently recycled by removal of the supernatant liquid and recharging the flask with fresh solvent and reagents. Under this protocol, five cycles may be executed with only a slight diminution in rate and no effect on selectivities, Eq. 182. 

In this chapter we wish to review the collected evidence for the astonishing effects of water on reactivities and selectivities as exemplified by the Diels-Alder reactions of dienes. Examples of Lewis acid and micellar catalysis in aqueous media are also presented. Finally, the newest computational investigations including solvent effects on Diels-Alder reactions are put forward in order to rationalize some of the remarkable observations. 

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