Nucleophile deactivated

It should be noted, however, that Scheme 8.2 depicts a highly simplified mechanism for living carhocationic polymerizations and it is in most cases not possible to find a counteranion with intermediate reactivity that spontaneously establishes an equilibrium between cationic and covalent species. Instead, the counteranion is generally a halide that preferably forms a covalent species with the carbenium ion. The addition of a Lewis acid as coinitiator is required to activate the covalently bound halide, resulting in the cationic carbenium ion. Alternatively, a nucleophile or electron donor can be added to the cationic polymerization, to reversibly form a stable cationic addition product with the carbenium ion. Both these deactivation mechanisms are depicted in Scheme 8.3. To achieve a living cationic polymerization it is of critical importance to have fast deactivation equilibria. In addition, the position of the equilibria should be carefully optimized for each monomer by variation of, for example, temperature, solvent, initiator, as well as the addition of halide activators or nucleophilic deactivators. 

Scheme 8.3 Schematic representation of the hving carbocationic polymerization based on covalent hahde species and an activator (left) or based on the addition of a nucleophilic deactivator (right). X represents a halide M, a metal and Nu, a nucleophile.

Excess sulfuric acid serves to shift the equilibrium and thus to speed the reaction by producing a higher concentration of hydrobromic acid. The sulfuric acid also protonates the hydroxyl group of n-butyl alcohol so that water is displaced. The acid also protonates the water as it is produced in the reaction and deactivates it as a nucleophile. Deactivation of water keeps the alkyl halide from being converted back to the alcohol by nucleophilic attack of water. The reaction of the primary substrate proceeds via an Si 2 mechanism. 

Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

A diazonium salt is a weak electrophile, and thus reacts only with highly electron-rich species such as amino and hydroxy compounds. Even hydroxy compounds must be ionized for reaction to occur. Consequendy, hydroxy compounds such as phenols and naphthols are coupled in an alkaline medium (pH > of phenol or naphthol typically pH 7—11), whereas aromatic amines such as N,N diaLkylamines are coupled in a slightly acid medium, typically pH 1—5. This provides optimum stabiUty for the dia2onium salt (stable in acid) without deactivating the nucleophile (protonation of the amine). 

There is a difference of opinion about the net effect of resonance between the leaving group and an electron-attracting heterocycle, carbocycle, or substituent- This conjugation (101, 102) has been regarded as a deactivating influence on nucleophilic substitution since the C— Le bond is lower in polarity and higher in... 

The ortho indirect deactivating effect of the two methyl groups in 2,6-dimethyl-4-nitropyridine 1-oxide (163) necessitates a much higher temperature (about 195°, 24 hr) for nucleophilic displacement of the nitro group by chloride (12iV HCl) or bromide ions N HBr) than is required for the same reaction with 4-nitropyridine 1-oxide (110°). With 5-, 6-, or 8-methyl-4-chloroquinolines, Badey observed 2-7-fold decreases in the rate of piperidino-dechlorination relative to that of the des-methyl parent (cf. Tables VII and XI, pp. 276 and 338, respectively). 

Amination of the deactivated carbanion of 4-benzylpyridine formed with excess sodamide presumably proceeds because the strong indirect deactivation is overcome by electrophilic attack by Na+ at the partially anionic azine-nitrogen and by concerted nucleophilic attack by H2N at the 2-position via a 6-membered cyclic transition state (75). However, in simple nucleophilic displacement a carbanion will be more deactivating than the corresponding alkyl group, as is true in general for anionic substituents and their non-ionic counterparts. 

The selective reaction of anionic 3,6-dichloro-4-sulfanilamidopy-ridazine with excess methanolic methoxide at the 3-position is another indication of the absence of major steric effects in most nucleophilic substitutions, as a result of the direction of nucleophilic attack (cf. Section II, A, 1). The selectivity at the 3-position is an example of the interaction of substituent effects. The sulfonamide anion deactivates both the 3-chloro (ortho direct deactivation) and... 

The much greater ease of disubstitutionof 2,4-dichloropy-rimidines with hydrazine (20°) than with ammonia (180°) is not a valid indication of less deactivation by the hydrazirvo group in the intermediate since hydrazine is a far better nucleophile than ammonia. This difference is illustrated by the failure to aminate 4-chloropyridazine-3,6-dione with ammonia at 160° overnight while it reacted with hydrazine at 20° in a few minutes (with heat evolution). 

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