Active electrophile

As the medium is still further diluted, until nitronium ion is not detectable, the second-order rate coefficient decreases by a factor of about 10 for each decrease of 10% in the concentration of the sulphuric acid (figs. 2.1, 2.3, 2.4). The active electrophile under these conditions is not molecular nitric acid because the variation in the rate is not similar to the correspondii chaise in the concentration of this species, determined by ultraviolet spectroscopy or measurements of the vapour pressure. " ... 

Step 1 The bromine-iron(III) bromide complex is the active electrophile that attacks benzene... 

In the presence of strongly acidic media, such as triflic acid, hydrogen cyanide or trimethylsilyl cyanide formylates aromatics such as ben2ene. Diprotonotated nittiles were proposed as the active electrophilic species in these reactions (119). 

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

The iacreased chemical stabiUty of the 6-deoxytetracyclines allows chemical modification with retention of biological activity electrophilic substitutions have been carried out at C-7 and C-9 under strongly acidic conditions (46—53). Reactions of 6-deoxy-6-demethyltetracycline [808-26-4] (16), C21H22N2O7, with electrophiles, such as nitrate ion (49), bromomium ion (46,47) (from N-bromosuccinimide), or N-hydroxymethylphthalimide (53), yielded 7-substituted tetracyclines. In the case of the nitration reaction, both the 7- and 9-nitro isomers (17, X = NO2, Y = H) and (17, X = H, Y = NO2) were obtained. 

TWo types of rate expressions have been found to describe the kinetics of most aromatic nitration reactions. With relatively unreactive substrates, second-order kinetics, first-order in the nitrating reagent and first-order in the aromatic, are observed. This second-order relationship corresponds to rate-limiting attack of the electrophile on the aromatic reactant. With more reactive aromatics, this step can be faster than formation of the active electrq)hile. When formation of the active electrophile is the rate-determining step, the concentration of the aromatic reactant no longer appears in the observed rate expression. Under these conditions, different aromatic substrates undergo nitration at the same rate, corresponding to the rate of formation of the active electrophile. 

An important general point to be drawn from the specific case of nitration is that the active electrophile is usually some species that is more reactive than the added reagents. 

The active electrophile is formed by a subsequent reaction, often involving a Lewis acid. As discussed above with regard to nitration, the formation of the active electrophile may or may not be the rate-determining step. Scheme 10.1 indicates the structure of some of the electrophihc species that are involved in typical electrophilic aromatic substitution processes and the reactions involved in their formation. 

The general mechanistic framework outlined in this section must be elaborated by other details to fully describe the mechanisms of the individual electrophilic substitutions. The question of the identity of the active electrophile in each reaction is important. We have discussed the case of nitration, in which, under many circumstances, the electrophile is the nitronium ion. Similar questions arise in most of the other substitution reactions. 

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

The question of what other species can be the active electrophile in nitration arises in the case of nitration using solutions of nitric acid in acetic anhydride. The solutions are very potent nitrating mixtures and effect nitrations at higher rates than solutions of nitric acid in inert organic solvents. Acetyl nitrate is formed in such solutions, and mty be the actual nitrating agent. 

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. ... 

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. 

Friedel-Crafts acylation usually involves the reaction of an acyl halide, a Lewis acid catalyst, and the aromatic substrate. Several species may function as the active electrophile, depending on the reactivity of the aromatic compound. For activated aromatics, the electrophile can be a discrete positively charged acylium ion or the complex formed... 

This provides unequivocal evidence that the acylium ion can act as the active electrophile. 

The table below gives first-order rate constants for reaction of substituted benzenes with w-nitrobenzenesulfonyl peroxide. From these data, calculate the overall relative reactivity and partial rate factors. Does this reaction fit the pattern of an electrophilic aromatic substitution If so, does the active electrophile exhibit low, moderate, or high substrate and position selectivity ... 

Nitration (Section 12.3) The active electrophile in the nitration of benzene and its... 

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. 

Carbon monoxide, hydrogen cyanide, and nitriles also react with aromatic compounds in the presence of strong acids or Friedel-Crafts catalysts to introduce formyl or acyl substituents. The active electrophiles are believed to be dications resulting from diprotonation of CO, HCN, or the nitrile.64 The general outlines of the mechanisms of these reactions are given below. 

These electrons can activate oxygen leading to very active electrophile 02 species. In another attempt, Nakamura et al. [104] have shown that oxygen vacancies are created by plasma excitation of TiOz and that electrons can be trapped on these vacancies, finally leading to the same electrophile species. Ogata et al [105] suggested that plasma action on TiOz directly activates lattice oxygen and OH in the TiOz. Actually, all these superficial electrophile species, which are extremely active, can very easily transform NO into N02. 

Electrophilic addition to spiro phosphenium cations 258 provides a route to spirophosphoranes. However, only very active electrophiles are suitable, for example, benzenesulfonyl azide which on reflux in acetonitrile with 258 yields 259 (Equation 70) <1998RJC530>. 

Lithiated epoxides have been found to react with a number of different activated electrophiles. A new study examines the reactivity of lithiated epoxides with nitrones to prepare 3,y-epoxyhydroxylamines, 46, and oxazetidine, 47 <06OL3923>. Upon deprotonation of styrene oxide, the lithiated reactant was then added to nitrone 45 to form the P,y-epoxyhydroxylamine 46 in good yield as a single diastereomer. A number of additional nitrones were examined as well and all provided similar yields of the 3,y-epoxyhydroxylamines. Treatment of 46 with additional base provided the 1,2-oxazetidine ring system 47 in excellent yield. Interestingly, none of the five-membered isoxazolidines from the 5-endo-tet cyclization were formed in this cyclization. 

The best results were achieved by employing N-(3-dimethylaminopropyl)-N -ethylcar-bodiimide hydrochloride (EDC) as coupling agent. After Fmoc deprotection with piperidine in N,N-dimethylformamide, additional diversity could be introduced by acylation of the liberated amine position. Finally, the acyl cyano phosphoranes could be efficiently cleaved by ozonolysis at -78 °C or by utilizing freshly distilled 3,3-dimethyloxirane at room temperature [65]. The released compounds constituted highly activated electrophiles, which could be further converted in situ with appropriate nucleophiles. 

Choice of Tissue. The next choice is that of source tissue. Preparations derived from liver are the most useful, as this tissue is a rich source of mixed-function oxygenases capable of converting procarcinogens to genetically active electrophiles. However,... 

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... 

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