Labeling reactions electrophilic substitution

Nucleophilic aromatic substitution is much less common than electrophilic substitution but nevertheless does have certain uses. One such use is the reaction of proteins with 2,4-dinitrofluorobenzene, known as Sanger s reagent, to attach a "label" to the terminal NH2 group of the amino acid at one end of the protein chain. 

It is possible to replace the ring hydrogens of many aromatic compounds by exchange with strong acids. When an isotopically labeled acid such as D2S04 is used, this reaction is an easy way to introduce deuterium. The mechanism is analogous to other electrophilic substitutions ... 

In contrast to direct electrophilic substitution in which the astatine attacks one of the C—H bonds, astatination through demetalation can be used to label a substrate at a preferred site in a regiospecific manner not affecting other sensitive sites of the molecule. Since the C—M bond is more sensitive to electrophilic attack than C—H, higher yields can be obtained in short reaction times under milder experimental conditions56. Organometallic compounds of mercury, thallium and tin have been used so far for astatination via demetalation. 

In the case of bimolecular aliphatic electrophilic substitution reactions, there are three principal pathways, namely SE2 (front), SE2 (back), and the internal electrophilic substitution, SEi (otherwise known as SF2 or SE2 (cyclic)). Inversion would occur with SE2 (back), while retention would occur with the other two. Experiments to distinguish between these latter two have indicated that the situation may be even more complicated, in that an alternative pathway, which is labelled either SE2 (co-ord), or SEC, may operate. 

F-2-fluoro-2-deoxyglucose (2-FDG) is normally produced in places where a cyclotron is locally available. Its molecular formula is CsHn FOs with molecular weight of 181.3 daltons. 18F-2-FDG can be produced by electrophilic substitution with 18F-fluorine gas or nucleophilic displacement with 18F-fluoride ions. The radiochemical yield is low with the electrophilic substitution, so the nucleophilic displacement reaction has become the method of choice for 18F-FDG synthesis. Deoxyglucose is labeled with 18F by nucleophilic displacement reaction of an acetylated sugar derivative followed by hydrolysis (Hamacher et al, 1986). In nucleophilic substitution, a fluoride ion reacts to fluorinate the sugar derivative. A solution of 1,3,4,6-tetra-O-acetyl-2-0-trifluoromethane-sulfonyl-/ -D-mannopyranose in anhydrous acetonitrile is added to a dry residue of 18F-fluoride containing aminopolyether (Kryptofix 2.2.2) and potassium carbonate (Fig. 8.1). Kryptofix 2.2.2 is used as a catalyst to enhance the reactivity of the fluoride ions. The mixture is heated... 

In general, the electrophile is labeled with E+ and its addition to the benzene ring is analogous to protonation (see scheme below). If the cationic reaction intermediate loses a proton, the electrophile remains attached to the ring. The final product has the structure in which hydrogen is replaced with the incoming electrophile and such a reaction is called an electrophilic substitution on the unsaturated carbon atom. 

A review of the arylation and alkenylation of arenes includes studies of the pheny-lation of benzoic acid derivatives. " There has been an investigation of the reactions of methylquinolines with tritium-labelled nucleogenic phenyl cations, which may result in electrophilic substitution or in the formation of A-phenylquinolinium derivatives. ... 

Probably the most important development of the past decade was the introduction by Brown and co-workers of a set of substituent constants,ct+, derived from the solvolysis of cumyl chlorides and presumably applicable to reaction series in which a delocalization of a positive charge from the reaction site into the aromatic nucleus is important in the transition state or, in other words, where the importance of resonance structures placing a positive charge on the substituent - -M effect) changes substantially between the initial and transition (or final) states. These ct+-values have found wide application, not only in the particular side-chain reactions for which they were designed, but equally in electrophilic nuclear substitution reactions. Although such a scale was first proposed by Pearson et al. under the label of and by Deno et Brown s systematic work made the scale definitive. 

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