Nucleophilic Additions and Substitutions in Water

Additions of nucleophiles to unsaturated species such as C=X multiple bonds or substitutions of electrophilic species such as C—X by nucleophiles are among the most common and important reactions in organic chemistry. Most of these reactions are catalyzed by either bases or acids the use of a base as catalyst generally increases the amount or the strength of the nucleophile, whereas the presence of an acid as catalyst allows the use of neutral nucleophiles by complexation, and so further polarization, of the electrophile. 

This chapter will focus on nucleophilic additions to unsaturated bonds catalyzed by bases or acids, excluding the use of organometallic species, which is discussed in Chapter 4, and on nucleophilic substitutions including ring opening of epoxides and allylic substitutions. 

The addition of nucleophiles such as carbon nucleophiles to electrophiles such as unsaturated carbon-heteroatom bonds is an important reaction in organic chemistry, allowing carbon-carbon bond formation. Although these reactions are usually performed in organic or eventually in organic/aqueous two-phase system, it was recently shown that they could be performed in water alone or in a monophasic water/organic system. This development has also allowed reactions to proceed under less drastic conditions. 

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Diaring the last decade a large amount of nucleophilic addition and substitution reactions have been performed in water alone or in monophasic water/organic solvent systems. The yields obtained, as well as the diastereo- and enantioselectivities, are often as high, and sometimes even better, than those obtained in traditional organic solvents. Sometimes completely new reactivities can be discovered using water as the solvent. Moreover, the substitution of common organic solvents by water should be of real benefit to our health and environment. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

It is more difficult to interpret micellar effects upon reactions of azide ion. The behavior is normal , in the sense that k /kw 1, for deacylation, an Sn2 reaction, and addition to a carbocation (Table 4) (Cuenca, 1985). But the micellar reaction is much faster for nucleophilic aromatic substitution. Values of k /kw depend upon the substrate and are slightly larger when both N 3 and an inert counterion are present, but the trends are the same. We have no explanation for these results, although there seems to be a relation between the anomalous behavior of the azide ion in micellar reactions of aromatic substrates and its nucleophilicity in water and similar polar, hydroxylic solvents. Azide is a very powerful nucleophile towards carboca-tions, based on Ritchie s N+ scale, but in water it is much less reactive towards 2,4-dinitrohalobenzenes than predicted, whereas the reactivity of other nucleophiles fits the N+ scale (Ritchie and Sawada, 1977). Therefore the large values of k /kw may reflect the fact that azide ion is unusually unreactive in aromatic nucleophilic substitution in water, rather than that it is abnormally reactive in micelles. 

On the other hand, with less basic nucleophiles, especially under acidic conditions, the ready reversibility of carboxylate formation may permit nucleophilic addition to compete and ultimately lead to substitution through the addition-elimination mechanism. A typical example is the esterification of a carboxylic acid (Section 9-4), in which an alcohol and a carboxylic acid react to yield an ester and water. The nucleophile, an alcohol, is a weak base, and acid is present to protonate both the carbonyl oxygen, activating it toward nucleophilic addition, and the carboxy OH, converting it into a better leaving group, water. 

Hydrolysis of diphenyl phosphorochloridate (DPPC) in 2.0 M aqueous sodium carbonate is also believed to be a two-phase process. DPPC is quite insoluble in water and forms an insoluble second phase at the concentration employed (i.e. 0.10 M). It seems highly significant that the hydrophobic silicon-substituted pyridine 1-oxides (4,6,7) are much more effective catalysts than hydrophilic 8 and 9. In fact, 4 is clearly the most effective catalyst we have examined for this reaction (ti/2 < 10 min). Since derivatives of phosphoric acids are known to undergo substitution reactions via nucleophilic addition-elimination sequences 1201 (Equation 5), we believe that the initial step in hydrolysis of DPPC occurs in the organic phase. Moreover, the... 

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