Solvents dipolar non-HBD

Acceptor numbers are less than 10 for nonpolar non-HBD solvents, they vary between about 10... 20 for dipolar non-HBD solvents, and they cover a wide range of about 25... 105 for protic solvents cf. Table 2-5). Surprisingly, benzene and tetra-chloromethane have stronger electrophilic properties than diethyl ether and tetrahy-drofuran. Acceptor numbers are also known for binary solvent mixtures [70, 213]. 

In principle, such interactions should also apply to other solvents resembling water, and therefore the more general term solvophobic interactions has been proposed [80, 343]. In fact, analogous water-like behaviour has been observed with self-associated solvents other than water, e.g. ethanol [81], glycerol [82], ethylammonium nitrate [227], and some dipolar non-HBD solvents [228]. 

Since hydrogen-bonding is a hard acid-hard base interaction, small basic anions prefer specific solvation by protic solvents. Hence, the reactivity of F , HO , or CH3O is reduced most on going from a dipolar non-HBD solvent such as dimethyl sulfoxide to a protic solvent like methanol. Dipolar non-HBD solvents are considered as fairly soft compared to water and alcohols [66],... 

Bordwell et al [135] have pointed out that solvents referred to as dipolar aprotic are in fact not aprotic. In reactions employing strong bases their protic character can be recognized. Therefore, instead of dipolar aprotic the designation dipolar nonhydroxylic or better dipolar non-HBD solvents is strongly recommended. Cf. Section 2.2.5 and 3.4 (footnote). In order to avoid confusion, the nomenclature proposed by Chastrette et al [138] is retained in Fig. 3-6. 

The ionisation constants of many acidic organic compounds determined in water [110a] and in twelve of the most popular dipolar non-HBD solvents [110b] have been compiled, as have the methods of determination [111] and prediction [112] of p.Ka values. Particular attention has been paid to C—H acidic compounds [113]. Whereas the ionisation constants of Bronsted acids and bases for aqueous solutions are well known, the corresponding pAa values for nonaqueous solutions are comparatively scarce. 

This differential solvation of reactants and activated complex is greater for protic solvents because protic, i.e. HBD solvents, are more sensitive to charge delocalization than aprotic, i.e. non-HBD solvents, due to reduced hydrogen-bonding with increasing charge delocalization. This is the main reason for the large rate enhancements in dipolar non-HBD solvents relative to protic solvents cf. Table 5-2) [6]. 

If one compares the rate constants for the same Menschutkin reaction with Kirkwood s parameter in thirty-two pure aprotic and dipolar non-HBD solvents [59, 64], one still finds a rough correlation, but the points are widely scattered as shown in Fig. 5-11. 

Fig. 5-15. Correlation between g[k/krx,) and 1/sr for the alkaline hydrolysis of methyl propionate in eight acetone/water mixtures at 25 °C (o) [252], and for the Sn2 reaction between the azide anion and 1-bromobutane in six pure dipolar non-HBD solvents at 25 °C ( ) [67] (rate constants relative to the solvent with the largest dielectric constant).

These results are supported by the observation that dipolar non-HBD solvents such as A,A-dimethylformamide or dimethyl sulfoxide, in spite of their high relative permittivities (36.7 and 46.5) and their high dipole moments (12.3 10 and 13.0-10 Cm), favour neither the ionization of haloalkanes nor SnI reactions cf. Section 2.6). Dipolar non-HBD solvents cannot act as hydrogen-bond donors and are therefore poor at solvating the departing anions. Thus, the anchimerically assisted ionization of 4-methoxyneophyl tosylate, shown in Eq. (5-102), is nine times faster in acetic acid than in dimethyl sulfoxide. This is in spite of the fact that the relative permittivity of acetic acid is eight times smaller than that of dimethyl sulfoxide also the dipole moment of acetic acid is smaller than that of dimethyl sulfoxide [265],... 

Table 5-15. Relative nucleophilic reactivities of free anions for Sn2 reactions in various protic and dipolar non-HBD solvents (nos. 1... 5) as well as in molten salts (no. 6 and no. 7) and in the gas phase (no. 8).

It is apparent that the order of anion nucleophilicity is almost completely reversed on transfer from protic to dipolar non-HBD solvents. Especially for halide ions, the relative reactivity is completely reversed in the two classes of solvents whereas the order of reactivity is I > Br > Cl > F in the protic solvent methanol (reactions no. 1 and no. 2 in Table 5-15), in dipolar non-HBD solvents such as iV,iV-dimethylformamide (no. 2), acetone (no. 3), dimethyl sulfoxide (no. 4), and acetonitrile (no. 5) the sequence of nucleophilicity is reversed. The traditional order of halide nucleophilicities, I > Br > Cl [261], applies only when the nucleophile is deactivated through solvation by... 

Reaetions no. 6 and no. 7 in Table 5-15 demonstrate that with molten quaternary ammonium salts as solvents, where deaetivation by anion solvation is absent, the halide ions show the same nueleophilie order as in dipolar non-HBD solvents [283, 284], This is in aeeordanee with the theory of protie/dipolar non-HBD medium effeets on X nueleophilieity [6j. It has been suggested that fused-salt experiments should provide a good model for the determination of intrinsie relative nueleophilieities of anions towards saturated earbon atoms [284],... 

The results for reaetion no. 8 in Table 5-15 indieate that nueleophilie reaetivities of anions obtained in the gas phase are essentially in the same order as in molten salts and in dipolar non-HBD solvents [285, 290]. This again suggests that speeifie solvation of the anions is responsible for the reversed order obtained in protie solvents relative to dipolar non-HBD solvents. Whereas the relative nueleophilieities in aeetonitrile are similar to those found in the gas phase [282, 285, 290], the absolute gas-phase rates are some orders of magnitude greater than those in aeetonitrile. The speeifie rates of displacement reactions of anions with halomethanes exceed those in solution by factors of up to >10 [285, 290]. These large differences in absolute rates demonstrate the moderating influence of the solvent on all the reactivities [282]. See also Chapter 5.2. 

Aeeordingly, gas-phase results for the clustering of Cl , Br , and I with Me2SO and H2O show that the bonding to dimethyl sulfoxide also deereases in the order Cl > Br > I , i.e. with increasing ion radius [596], Thus, anion solvation deereases with an inerease in the ion radius for both protic and non-HBD solvents however, the deerease is appreeiably less in dipolar non-HBD solvents. This is the prineiple reason for the mueh higher rates of anion-molecule Sn2 reactions in dipolar non-HBD solvents [596]. 

Since anions are solvated to a much lesser extent in dipolar non-HBD solvents than in protic solvents, they exist in these solvents as more or less naked and therefore extremely reactive ions. For Sn2 and SNAr reactions involving anionic nucleophiles, a change from protic to dipolar non-HBD solvent often causes a very dramatic acceleration of these reactions [6] f Some typical examples are reactions (5-110) to (5-113), for... 

To speak of dipolar non-HBD solvents having an accelerating effect on the rates of bimolecular substitution reactions involving anionic nucleophiles seems to be looking at things in reverse order. The view that protic solvents have a retarding effect on such reactions seems to be much more consistent with the experimental data. However, the above mentioned description of the protic/ dipolar non-HBD solvent effect on reaction rates has been widely used in the literature. 

The rate increases (relative to methanol) involve factors in the range of 10 to 10 going from a protic to a dipolar non-HBD solvent. Even larger factors, as in the reaction 2,4-(N02)2C6H3l with Cl in hexamethylphosphoric triamide (ca. 10 ) are not uncommon [291]. For reaction (5-112), the solvent change from methanol to hexame-... 

All the features discussed for protic/dipolar non-HBD solvent transfer are also observed for transfer from protic to dipolar non-HBD/protic mixtures, but to a slightly lesser extent. In general, all Sn2 anion-molecule reactions are faster in mixtures than in pure protic solvents. They show a continuous, but not necessarily linear, rate increase with an increase in the dipolar non-HBD component of the protic/dipolar non-HBD mixture [6]. Even small amounts of dipolar non-HBD component may cause a considerable acceleration in reaction rate. 

The use of dipolar non-HBD instead of protic solvents as reaction media often has considerable practical synthetic advantages, which have been summarized by Parker [6], Madaule-Aubry [294], Liebig [295], and Schmid [26], A selection of common and less common dipolar non-HBD solvents is given in Table 5-18, together with some physical constants useful for their prachcal application. Reviews on particular dipolar non-HBD solvents have appeared these are included in Table 5-18 [cf. also references [75-91] in Chapter 3). 

Finally, some important examples emphasizing the versatility and synthetic utility of dipolar non-HBD solvents as reaction media will be given. 

RCO , an indifferent nucleophile in prohc solvents, enjoys a large rate enhancement, permitting rapid alkylation with haloalkanes in hexamethylphosphoric triamide [301, 302], When the Williamson ether synthesis is carried out in dimethyl sulfoxide [303], the yields are raised and the reaction time shortened. Displacements on unreactive haloarenes become possible [304] (conversion of bromobenzene to tert-butoxybenzene with tert-C UgO in dimethyl sulfoxide in 86% yield at room temperature). The fluoride ion, a notoriously poor nucleophile or base in protic solvents, reveals its hidden capabilities in dipolar non-HBD solvents and is a powerful nucleophile in substitution reactions on carbon [305],... 

Table 5-18. A selection of twenty-one organic dipolar non-HBD solvents in order of increasing dipole moment (c/ also Appendix, Table A-1).

The observation that bimolecular reactions of anions are often much faster in dipolar non-HBD solvents than in protic solvents of comparable relative permittivity is of great practical significance, not only for substitution reactions but also for elimination, proton abstraction, and addition reactions [6]. 

Reduced solvation of commonly used E2 bases (HO , RO ) in dipolar non-HBD solvents may elevate their reactivities to such an extent that E2 reactions of quite inert substrates occur [306]. Halide ions in dipolar non-HBD solvents are sufficiently strong bases to promote dehydrohalogenations of haloalkanes [73, 74]. Even the fluoride ion is the most efficient in this reaction [307, 308, 600] the elimination rates decrease in the order F > Cl > Br > I . 

Addition of anionic nucleophiles to alkenes and to heteronuclear double bond systems (C=0, C=S) also lies within the scope of this Section. Chloride and cyanide ions are effieient initiators of the polymerization and copolymerization of acrylonitrile in dipolar non-HBD solvents, as reported by Parker [6], Even some 1,3-dipolar cycloaddition reactions leading to heterocyclic compounds are often better carried out in dipolar non-HBD solvents in order to increase rates and yields [311], The rate of alkaline hydrolysis of ethyl and 4-nitrophenyl acetate in dimethyl sulfoxide/water mixtures increases with increasing dimethyl sulfoxide concentration due to the increased activity of the hydroxide ion. This is presumably caused by its reduced solvation in the dipolar non-HBD solvent [312, 313]. Dimethyl sulfoxide greatly accelerates the formation of oximes from carbonyl compounds and hydroxylamine, as shown for substituted 9-oxofluorenes [314]. Nucleophilic attack on carbon disulfide by cyanide ion is possible only in A,A-dimethylformamide [315]. The fluoride ion, dissolved as tetraalkylammo-nium fluoride in dipolar difluoromethane, even reacts with carbon dioxide to yield the fluorocarbonate ion, F-C02 [840]. 

The superoxide ion, O , produced by the electron-transfer reduction of dioxygen (O2 + e O ), is a strong Bronsted base and an effective nucleophile. Because of rapid hydrolysis and disproportionation, the lifetime of O in aqueous solution is limited. This has led to investigations of its reaction chemistry in dipolar non-HBD solvents [632]. Under these conditions, the superoxide ion attacks haloalkanes by Sn2 displacement of the halides to eventually give dialkyl peroxides in a multi-step reaction [632]. 

Further examples of the dissection of initial state and transition state medium effeets for reaetions in protie and dipolar non-HBD solvents have been given by Buncel [467, 636], Abraham [23, 64, 637], Haberfield [638], and Blandamer et al. [639]. 

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