Oxygen-based soft nucleophile

It is appropriate at this point to summarize the tendency of various nucleophiles to add to the carbonyl group. In general, the strong bases (organometallics, hydrides, negative ions) are most effective among the neutral nucleophiles, the soft ones, for example the sulfur bases, tend to be more effective in addition than the hard ones, for example the oxygen bases. 

Both oxygen and nitrogen nucleophiles react more rapidly with fluoroaromatics than corresponding sulphur and carbon nucleophiles, in accordance with Hard-Soft Acid-Base principles [51]. It should be remembered, however, that the situation can become more complex with, for example, base catalysis, where the rate of the second stage becomes important under these rather unusual conditions, an order of replacement Br > Cl > F has been observed [52]. 

Sulfoxonium salts react with hard bases at sulfur and with soft nucleophiles at the oxygen end. Although the acid-catalyzed oxidation of isonitriles to isocyanates (139) has been formulated as involving an a addition of H and DMSO at the carbon atom of the isonitrile, the alternative mechanism shown below appears more viable in the HSAB context. 

The magnitude of general-acid-base catalysis by oxygen and nitrogen bases depends only on their pATa s, and is independent of their chemical natures (apart from an enhanced activity of oximes in general-acid catalysis). Nucleophilic reactivity depends markedly on the nature of the reagents. These reactions may be divided into two broad classes nucleophilic attack on soft and on hard electrophilic centers.47... 

Arenols 4 and their conjugate arenolate bases are both (a) oxygen- and (b) carbon-based nucleophiles, which react with a wide range of electrophilic reagents (Figure 3). Their reactions with soft electrophiles can lead directly to cyclohexadienone derivatives this is the case, for example, with electrophilic halogenation, which effectively occurs at the electron-rich carbon centers (4 —> 5b) [29, 30]. 

We should compare the S reaction at silicon with the S 2 reaction at carbon. There are some iportant differences. Alkyl halides are soft electrophiles but silyl halides are hard electrophiles. Alkyl halides react only very slowly with fluoride ion but silyl halides react more rapidly with fluoride [than with any other nucleophile. The best nucleophiles for saturated carbon are neutral and/or based on elements down the periodic table (S, Se, I). The best nucleophiles for silicon are charged and based on highly electronegative atoms (chiefly F, Cl, and O). A familiar example is the reaction of enolates at carbon with alkyl halides but at oxygen with silyl chlorides (Chapter 21). 

Taking into account the fact that the solvation of ambident anions in the activated complex may differ considerably from that of the free anion, another explanation for the solvent effect on orientation, based on the concept of hard and soft acids and bases (HSAB) [275] (see also Section 3.3.2), seems preferable [366]. In ambident anions, the less electronegative and more polarizable donor atom is usually the softer base, whereas the more electronegative atom is a hard Lewis base. Thus, in enolate ions, the oxygen atom is hard and the carbon atom is soft, in the thiocyanate ion the nitrogen atom is hard and the sulfur atom is soft, etc. The mode of reaction can be predicted from the hardness or softness of the electrophile. In protic solvents, the two nucleophilic sites in the ambident anion must interact with two electrophiles, the protic solvent and the substrate RX, of which the protic solvent is a hard and RX a soft acid. Therefore, in protic solvents it is to be expected that the softer of the two nucleophilic atoms (C versus O, N versus O, S versus N) should react with the softer acid RX. 

According to the concept of the hard-soft acid base, the carbon is considered more nucleophilic than the oxygen, thus more likely to react than the oxygen atom because the leaving... 

Thiols are more acidic than the corresponding alcohols and are converted into their salts using alkali metal hydroxides or alkoxides. The thiolate salts are powerful nucleophiles, a property which has been used in the cleavage of methyl esters and methyl ethers. The combination of a hard acid and a soft base such as lithium propanethiolate (Li SPr) may favour attack on the methyl group of an ester and lead to alkyl-oxygen fission of the ester, rather than the more common addition of a nucleophile to the carbonyl group and consequently acyl-oxygen fission. This is particularly useful in the hydrolysis of hindered esters. 

The azide procedure for peptide synthesis and particularly for fragment condensations is considered to be a mainly racemization free method. This low racemization tendency of azides was explained by several theories, which have been reviewed.t l The most plausible cause of racemization is the formation of oxazoles (Scheme 3) and the related enolization. In presence of bases the a-carbon proton is readily abstracted to form an anionic oxazol-5(4//)-one resonance system.For the formation of the oxazol-5(4//)-one the influence of the substituent Y on the a-carbonyl is essential. Since the a-carbonyl group of amino acid azides are less activated and thus relatively insensitive to oxygen containing nucleophiles such as water and alcohols, oxazol-5(4//)-one formation is largely prevented. It was proposed that the soft electron shell of the azide shields the a-carbonyl atom, so that only strong nucleophiles can attack it.t 1 The reactivity towards amines can be explained in a manner analogous to the aminolysis of anchimerically assisted active esters.h 1... 

Nucleophiles with two sites that could react with electrophiles are called ambident nucleophiles. The Hard and Soft Acids and Bases (HSAB) principle applies because a hard electrophile reacts at the harder nucleophilic site and a soft electrophile at the softer nucleophilic site. For instance, the sulfenate ion 70 is an ambident nucleophile, because it reacts (a) with methyl fluorosulfonate, a hard electrophile, at the oxygen atom, where most of the negative charge is concentrated, to give the sulfenate ester 71 and (b) with methyl iodide, a soft electrophile, to give the sulfoxide 72. Sulfur atom is the softer of the two nucleophilic sites available in the sulfenate ion and, furthermore, it is rendered more nucleophilic by the a-effect arising from the adjacent oxygen atom. 

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