Hard electrophiles

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

O-Alkylation of A-unsubstituted /3-lactams to give the corresponding 2-alkoxy-l- etines can be achieved by reaction of the azetidin-2-ones with hard electrophiles (trialkyloxonium tetrafluoroborates) followed by treatment with base (cf. Section 5.09.4.3.1) (67JHC619, 69LA(725)124). In contrast, reaction of the A-unsubstituted azetidin-2-ones (73) or their derived anions with a variety of softer electrophiles results in A-substitution, and some representative reactions are illustrated in Scheme 7. 

N-Acylation. Acyl chlorides or carboxylic anhydrides, which generally have a hard electrophilic character, can selectively convert OZTs into IV-acylated derivatives.59... 

To the extent that the N+ correlation is successful it means that the pattern of nucleophilic reactivity is not influenced by the nature of the electrophilic center at which substitution takes place. On the other hand, according to the concepts of the theory of hard and soft acids and bases (HSAB) as applied to nucleophilic substitution reactions (Pearson and Songstad, 1967) one would expect that a significant change in the HSAB character of the electrophilic center as an acid should lead to changes in the pattern of nucleophilic reactivity observed. Specifically, in substitutions occurring at soft electrophilic centers, soft-base nucleophiles should be more reactive relative to other nucleophiles than they are in substitutions at harder electrophilic centers, and in substitutions at hard electrophilic centers hard-base nucleophiles should appear relatively more reactive compared to other nucleophiles than they do in substitutions at softer electrophilic centers. 

In HSAB terms sulfonyl sulfur should be a relatively hard electrophilic center, sulfenyl sulfur a relatively soft electrophilic center, and sulfinyl sulfur should occupy a position somewhere in between. 

Nucleophilic acyl complexes can be 0-alkylated with hard electrophiles to yield the corresponding alkoxy- or (acyloxy)carbene complexes. The first carbene complex ever isolated [61] was prepared by this route the intermediate, anionic acyl complex was generated by addition of phenyllithium to tungsten hexacarbonyl (Figure 2.3). 

Since biological systems are rich in nucleophiles (DNA, proteins, etc.) the possibility that electrophilic metabolites may become irreversibly bound to cellular macromolecules exists. Electrophiles and nucleophiles are classified as hard or soft depending on the electron density, with hard electrophiles generally having more intense charge localization than soft electrophiles in which the charge is more diffuse. Hard electrophiles tend to react preferentially with hard nucleophiles and soft electrophiles with soft nucleophiles. 

Hard electrophiles attack pyran-2-ones at the carbonyl oxygen atom. 

In the case of mercuration (soft electrophile), attack at the 2-position is favoured. These observations accord with predictions based on molecular orbital calculations, that hard electrophiles (nitronium ions) should attack at C-4 and soft electrophiles (e.g. HgS04) at C-2 (68JA223). Furthermore, very hard electrophiles (e.g. S03) are predicted to attack at C-3. This is hard to verify because pyridine 1-oxide reacts at C-3 as its conjugate acid (or... 

Hard electrophiles, such as bromo- or chloroalkanes, tend to favor the formation of 3-substi-tuted 1-alkenamines more than soft electrophiles such as iodoalkanes. 

Trifluoroethanol is an extremely attractive building block. The alcohol is available in industrial quantities and is a stable liquid with a rich chemistry. The initial contributions in the area were made by Nakai et al. [126] conversion to the tosylate (itself a stable, crystalline commercial material) followed by exposure to LDA in THF at -78 °C led to the formation of difluorovinyl tosylate which reacted efficiently with hard electrophiles such as aldehydes and ketones. Ichikawa has converted this initial result into a powerful and versatile metho-... 

Electrophiles can be hard or soft. Thus hard electrophiles react with nucleophilic sites in molecules such as O, N, C in nucleic acids or the S in methionine in proteins. Hard electrophiles are typically genotoxic such as the benzo(a)pyrene diol epoxide (see chap. 7). 

For pyrroles with electron acceptor substituents in the 1-position electrophilic substitution with soft electrophiles can be frontier orbital controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles can be charge controlled and occur at the 3-position. 

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... 

Swain and Scott found satisfactory correlations with Equation (27) which provided 5 values for a number of reactants. However, as indicated in Scheme 33, for the limited number of substrates conveniently studied,158,186 variations in 5 did not show a clearly discernible pattern (and no obvious correlation with reactivity). Moreover, Pearson and Songstad demonstrated that the correlations break down if extended to extremes of soft and hard electrophilic centers such as platinum, in the substitution of trara,s-[Pt(pyridine)2Cl2], or hydrogen in proton transfer reactions.255 Despite this, Swain and Scott s equation has stood the test of time and it is noteworthy that a serious breakdown in the correlations occurs only when the reacting atoms of both nucleophile and electrophile are varied. In this chapter we will restrict ourselves to carbon as an electrophilic center, and particularly, although not exclusively, to carbocations. 

---