Reactive electrophiles

Reactive electrophiles used in synthesis, e g. RCH2COCI plus (CIjC NMeir, gives (Me N)C1C = C(R)COCl. 

Synthesis Since a-halo-carbonyl compounds are very reactive electrophiles, we can use a short cut ... 

Again the uncertainty about the proportion of an observed result which is due to nitration and the proportion which is due to nitrosation exists. Thus, in expt. 11 phenol was being nitrated above the encounter rate and the observed isomer distribution could arise from a combination of nitration by whatever is the usual electrophile with nitration by a new, less reactive electrophile, or with nitrosation, or all three processes could be at work. 

It is noteworthy that some catalysts convert thioethers to quaternary salts where the reactive electrophilic center is no longer one of the two C centers but the C sp center of the thiazolium salt (284. 285). Thus... 

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequentiy, an active site nucleophile in close proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via S 2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

Indole undergoes add-catalyzed dimerization the 3H-indoIium ion acts as an electrophile and attacks an unprotonated molecule to give the dimer (46). Protonation of the dimer in turn gives an electrophilic species from which a trimeric product can be derived (77CPB3122). Af-Methylisoindole undergoes acid-catalyzed polymerization, indicating that protonation at C-1 gives a reactive electrophilic intermediate. 

Pyrroles react with the conjugate acids of aldehydes and ketones to give carbinols (e.g. 67) which cannot normally be isolated but which undergo proton-catalyzed loss of water to give reactive electrophiles (e.g. 68). Subsequent reaction may lead to polymeric products, but in the case of reaction of pyrrole and acetone a cyclic tetramer (69) is formed in high yield. 

The cyano, nitro, and quaternary ammonium groups are strongly deactivating and weto-directing. Electrophilic substitutions of compounds with these substituents require especially vigorous conditions and fail completely with all but the most reactive electrophiles. 

There is, however, no direct evidence for the formation of Cl", and it is much more likely that the complex is the active electrophile. The substrate selectivity under catalyzed conditions ( t j = 160fcbenz) is lower than in uncatalyzed chlorinations, as would be expected for a more reactive electrophile. The effect of the Lewis acid is to weaken the Cl—Cl bond, which lowers the activation energy for o-complex formation. 

Equation (7-85) is a selectivity-reactivity relationship, with lower values of Sf denoting lower selectivity. Lower values ofpt correspond to greater reactivity, with the limit being a partial rate factor of unity for an infinitely reactive electrophile. This selectivity-reactivity relationship is followed for the electrophilic substitution reactions of many substituted benzenes, although toluene is the best studied of these. 

Less reactive electrophilic reagents like those involved in acylation or alkylation apparently do not react with phenyl-substituted pyrylium salts the p-acylation of a phenyl group in position 3 of the pyrylium salt obtained on diacylation of allylbenzene (Section II, I), 3, a), and the p-l-butylation of phenyl groups in y-positions of pyrylium salts prepared by dehydrogenation of 1,5-diones by means of butyl cations (Section II, B, 2, f) probably occur in stages preceding the pyrylium ring closure. 

The malonic ester required for synthesis of cyclopal (107) can be obtained by alkylation of diethyl allylmalonate (115) with 1,2-dibromocyclopentane in the presence of excess base. It is probable that the reaction proceeds by elimination of hydrogen bromide from the dihalide as the first step. The resulting allilic halide (116) would be the most reactive electrophile in the reaction mixture and thus would quickly alkylate the anion of the malonate to afford 117. 

Figure 16.4 The mechanism of electrophilic nitration of an aromatic ring. An electrostatic potential map of the reactive electrophile N02+ shows that the nitrogen atom is most positive (blue).

Benzene and alkyl-substituted benzenes can be hydroxylated by reaction with H2O2 in the presence of an acidic catalyst. What is the structure of the reactive electrophile Propose a mechanism for the reaction. 

Measured activation energies, which are not independent of temperature nor of the acid concentration, vary between 13.3 and 24.2, show a minimum at the acid concentration giving the maximum rate and these fairly low energies for such unreactive substrates are consistent with a highly reactive electrophile. 

From an analysis of the results, the values of k and k. were determined as 13 x 10-3 and 132 x 10-3 respectively, which implies, not unreasonably, that NO+ is a more reactive electrophile than N204 the nitrosation rate was also relatively independent of the water concentration. 

An investigation of the relative rates of bromination of benzene, toluene, m-and p-xylene by bromine in acetic acid, catalysed by mercuric acetate, revealed relative rates almost identical with those obtained with molecular bromine322, though as in the bromination of biphenyl by bromine acetate (p. 129) it is quite inconsistent for a much more reactive electrophile to have the same selectivity. Relative rates were (molecular bromination values in parenthesis) benzene 1.0 toluene, 480 (610) p-xylene, 2.1 x 103 (2.2 x 103) m-xylene 2.0 x 10s (2.1 x 10s). 

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