Nucleophile aggregation

The order of enolate reactivity also depends on the metal cation which is present. The general order is BrMg < Li < Na < K. This order, too, is in the order of greater dissociation of the enolate-cation ion pairs and ion aggregates. Carbon-13 chemical shift data provide an indication of electron density at the nucleophilic caibon in enolates. These shifts have been found to be both cation-dependent and solvent-dependent. Apparent electron density increases in the order > Na > Li and THF/HMPA > DME > THF >ether. There is a good correlation with observed reactivity under the corresponding conditions. 

Thus, we discovered the first asymmetric nucleophilic addition of acetylides to kehmines. The reaction mechanism was unfortunately not clear during this study but we felt that aggregation of lithium species might play an important role. 

The water-soluble calix[n]arenes 6.3 (n = 4, 6 and 8) containing trimethylammonium groups act as efficient inverse phase-transfer catalysts in the nucleophilic substitution reaction of alkyl and arylalkyl halides with nucleophiles in water (Eq. 6.19).40 In the presence of various surfactants (cationic, zwitterionic and anionic), the reactions of different halides and ketones show that the amount of ketone alkylation is much higher and that the reactions are faster in the presence than in the absence of surfactant aggregates.41 The hydrolysis of the halide is minimized in the presence of cationic or zwitterionic surfactants. 

Hydrophobic ammonium ions which are phase transfer catalysts such as tri-n-octylalkylammonium ions (C8H17)3NR+X (R = Me, Et, CH2CH2OH X = Cl, Br, MeS03) are surface active but appear to form small nonmicellar aggregates (Okahata et al., 1977 Kunitake et al., 1980). The salts of these ions are only sparingly soluble in water, but they are very effective at speeding reactions of hydrophobic nucleophilic anions. 

Little is known about the structures of these kinetically effective complexes, or even about the aggregates of the amphiphile. Both hydrophobic and coulombic interactions are important because these aggregates are much less effective than micelles at assisting reactions of hydrophilic nucleophilic anions. These observations are consistent with the view that the aggregates are much smaller than micelles. It is probable that the structures and aggregation numbers of these aggregates depend on the nature of the solutes which bind to them and Piszkiewicz (1977) has suggested that such interactions play a role in micellar kinetics. 

Rate constants of bimolecular, micelle-assisted, reactions typically go through maxima with increasing concentration of inert surfactant (Section 3). But a second rate maximum is observed in very dilute cationic surfactant for aromatic nucleophilic substitution on hydrophobic substrates. This maximum seems to be related to interactions between planar aromatic molecules and monomeric surfactant or submicellar aggregates. These second maxima are not observed with nonplanar substrates, even such hydrophobic compounds as p-nitrophenyl diphenyl phosphate (Bacaloglu, R. 1986, unpublished results). 

As mentioned in Section 2, trioctylmethylammonium chloride [7] appears to form small, highly hydrophobic aggregates. Okahata et al. (1977) found that the reactivity of hydrophobic nucleophiles (hydroxamate and imidazole anion) was very much enhanced in the presence of this aggregate. Thus, the combination of LImAm [60] and [7] (7 x 10-5 M) was more than 10 times more reactive toward PNPA than [60] in micellar CTAB (1 x 10-3 M). Less hydrophobic nucleophiles were not activated. 

The ease of formation of hydrophobic ion pairs, and hence the rate acceleration, will be determined by the hydrophobic and electrostatic interactions between the anionic and cationic species. Lapinte and Viout (1974) found that the nucleophilic order OH- > CN > C6H50- in water was completely reversed in CTAB micelles hydrophobic phenoxide ion is activated better by the micelle. The micellar binding of phenols and phenoxides was determined by Bunton and Sepulveda (1979). Similarly, hydrophobic hydroxamates are activated much better than their hydrophilic counterparts. In the same vein, the extent of activation correlates approximately with the hydrophobic nature of aqueous aggregates as estimated by Amax of methyl orange (Table 7) and of picrate ion (Bougoin et al., 1975 Shinkai et al., 1978f Table 5). 

The downward curvature observed in this and other systems could be easily explained in terms of a mixed aggregate between the catalyst and the nucleophile. A hydrogen-bond donation to the amide catalyst would render the amine a better nucleophile, up to a value of saturation , after which increasing amounts of catalysts should have no further effect. The results in Table 15 can be easily explained in the same terms, where K measures the equilibrium of the association between the amine and the catalyst. 

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