Protonation activating electrophiles

Molecular chlorine is believed to be the active electrophile in uncatalyzed chlorination of aromatic compounds. Simple second-order kinetics are observed in acetic acid. The reaction is much slower in nonpolar solvents such as dichloromethane and carbon tetrachloride. Chlorination in nonpolar solvents is catalyzed by added acid. The catalysis by acids is probably the result of assistance by proton transfer during the cleavage of the Cl-Cl bond. ... 

Thus it seems clear that, in the absence of interactions with the reaction medium, SOR groups behave as — R substituents and activate electrophilic substitution. However, they are prone to protonation or at least to act as hydrogen bond acceptors, in which condition they behave as + R substituents, deactivate electrophilic substitution and are metadirecting. 

Like the piperidones, a wide variety of TV-heterocyclic aromatic compounds show an ability to activate electrophilic functional groups. It is known that acetophenone is completely protonated in CF3SO3H, however in the presence of benzene there is no hydroxyalkylation (condensation) reaction.12 On the other... 

A cyclohexadienyl Lewis adduct or salt formed by the reaction of a Lewis base with an aromatic compound. Such an adduct is apparently formed from the reaction of OH with 4-(A/-2-aminoethyl-2 -pyridyl disulfide)- -nitrobenzo-2-oxa-l,3-diazole (2PROD). 2PROD is a two-protonic-state electrophile used as a probe for enzyme active site nucleophiles and as a fluorescent re-... 

The mechanism of aromatic nitration is shown in Figure 1. It may be seen that the sulfuric acid serves as the source of hydrogen ion (proton) which protonates nitric acid to form nitronium ion and water. The NO, ion is the active electrophile that causes the nitration reactions. 

In the absence of efficient Nps-Q (92) capture, this intermediate reacts with the indole side chain of tryptophan residues to produce the related 2-Nps derivatives 96 (Scheme 48). Although reaction of sulfenyl hahdes with indoles was exploited by Wieland et al.t for the synthesis of phaUoidin, this side reaction leads to irreversible modification of Trp-containing peptides.This side reaction does not occur via an intramolecular electrophilic substitution as postulated previously,but by a direct attack of the Nps-Cl (92) in fact, it is efficiently suppressed by the addition of a large excess of an indole derivative as a scavenger.These scavengers serve also to decrease the proton activity of the acids vide supra). Due to the unpleasant odor of 2-methylindole the less volatile 1-acetyltryptophan butyl ester has been proposed as scavenger.f ... 

More potent electrophilic activators can be used with 1,4-dihydropyridines more stable to acid conditions. Considerable stabilization is achieved by fusion of an aromatic ring to the 5,6-positions. For example (85) will reduce benzaldehyde to benzyl alcohol in moderate yield in the presence of benzene-sulfonic acid (equation 37). An optically active variant analogous to (81) has also been studied. In addition to proton sources, electrophiles like AICI3 and TiCU may also be used. - ... 

Control of an electrolytic reaction often requires that the proton activity remains within acceptable limits during the electrolysis. For small-scale electrolytic preparations (less than about 10 g/liter of substrate), a sufficiently high initial concentration of buffer, acid, or base is adequate in aqueous solution for large-scale electrolysis a controlled addition of protons during a reduction must be provided. This addition may be controlled by a pH-stat or coupled to the current integrator. In aprotic media a proton donor, electrophile, or nucleophile may play a similar role as buffers in aqueous media. 

Friedel-Crafts acylation usually involves the reaction of an acyl halide, a Lewis acid catalyst, and the aromatic reactant. Several species may function as the active electrophile, depending on the reactivity of the aromatic compound. For activated aromatics, the active electrophile can be a discrete positively charged acylium ion or a complex formed between the acyl halide and the Lewis acid catalyst. For benzene and less reactive aromatics, it is believed that the active electrophile is a protonated acylium ion or an acyiium ion complexed by a Lewis acid. Reactions using acylium salts are slow with toluene or benzene as the reactant and do not proceed with chlorobenzene. The addition of triflic acid accelerates the reactions with benzene and toluene and permits reaction with chlorobenzene. These results suggest that a protonation step must be involved. 

Certain other reactions of aromatic molecules are closely related to the Friedel-Crafts reaction. The introduction of chloromethyl groups is brought about by formaldehyde in concentrated hydrochloric acid in the presence of halide salts, especially zinc chloride. The reaction is restricted in scope to benzene and derivatives with electron-releasing substituents. Several mechanistic pathways could be operative in the chloromethylation reaction, but the active electrophile is probably protonated chloromethyl alcohol. 

A proposed mechanism for this reaction involves the following three steps to generate the nitronium ion. The trifluoromethanesulfonate (triflate) ions act as spectators. The ytterbium cation is believed to be hydrated by the water present in the aqueous nitric acid solution. Nitric acid binds strongly to the hydrated ytterbium cation, as shown in equation 1. A proton is generated, as shown in equation 2, by the strong polarizing effect of the metal. Nitronium ion is then formed by the process shown in equation 3. Although the nitronium ion may serve as the active electrophilic species, it is more likely that a nitronium carrier, such as the... 

Preformed enolates can be obtained not only from aldehydes and ketones, but also from carboxylic esters, amides, and the acids themselves. The corresponding carbonyl compound aWays acts irreversibly as the CH-acidic component. Thus, the term aldol reaction is no longer restricted to aldehydes and ketones but extended to all additions of preformed enolates to an aldehyde or a ketone. In contrast vith the traditional aldol reaction, this novel approach is based on a three-step procedure (usually, ho vever, performed as a one-pot reaction). First, the metal enolate 25 is generated irreversibly, vith proton sources excluded, and, second, the compound serving as the carbonyl active, electrophilic component is added. The metal aldolate 26 thus formed is finally protonated, usually by addition of vater or dilute acidic solutions, to give the aldol 27 (Scheme 1.4) [45, 46]. 

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