Conventional electrophilic substitutions

In both imidazoles and their /V-substituted derivatives, halogenation occurs preferentially in the 4(5)-positions there is a slight preference for 5-substitution in 1-substituted substrates. Although the 2-position is much less reactive, it is difficult to prevent substitution at that site. Indeed, polyhalogenation is so facile that it is seldom feasible to make monohalogenated imidazoles directly. Both sodium hypochlorite and NCS convert imidazole into its 4,5-dichloro derivative contaminated by the 2,4,5-trichloro product. Even very mild conditions are unlikely to promote monochlorination, and bromination and iodination arc similar. Mechanisms can vary, however, from substrate to substrate. It is likely that C-2 halogenations are the result of addition-elimination [1]. 

Monohalogcno compounds are more likely to be accessible when imidazoles with an electron-withdrawing substituent are halogenated, by nucleophilic methods (see Section 7.3.1), and via oiganolithium derivatives (see Section 7.2.2), Alternatively, it may be possible to polyhalogenate, then selectively reduce one or more of the halogen substituents. 

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If acetoxylation were a conventional electrophilic substitution it is hard to understand why it is not more generally observed in nitration in acetic anhydride. The acetoxylating species is supposed to be very much more selective than the nitrating species, and therefore compared with the situation in (say) toluene in which the ratio of acetoxylation to nitration is small, the introduction of activating substituents into the aromatic nucleus should lead to an increase in the importance of acetoxylation relative to nitration. This is, in fact, observed in the limited range of the alkylbenzenes, although the apparently severe steric requirement of the acetoxylation species is a complicating feature. The failure to observe acetoxylation in the reactions of compounds more reactive than 2-xylene has been attributed to the incursion of another mechan-104... 

This procedure provides a method for functionalizing the pyrrole ring in the 3-position, normally a difficult synthetic step when conventional electrophilic substitution is used, The technique has been extended to... 

Substituents can be introduced into the 4-position of sydnones by conventional electrophilic substitution but there are also several examples of electrophilic substitution following metallation at C-4 <95H(41)1525). Standard transformations of functional groups at C-4 of sydnones have also been extensively investigated. In particular, these reactions have been used to synthesize sydnones bearing a variety of heterocyclic substituents at the 4-position <92Mi 403-01). Sydnones can act as... 

Electrochemical fluorination of pyridine in the presence of a source of fluoride ion gave 2-fluoropyridine in 22% yield (85M11). With xenon difluoride, pyridine formed 2-fluoropyridine (35%), 3-fluoropyridine (20%), and 2,6-difluoropyridine (11%) in a reaction unlikely to be a conventional electrophilic substitution. Xenon hexafluoride has also been used (76JFC179). With cesium fluoroxysulfate at room temperature in ether or chloroform, the major product was 2-fluoropyridine (61 and 47%, respectively). Some 2-chloropyridine was also formed in chloroform solution. In methanol the entire product was 2-methoxypyridine (90TL775). Fluorine, diluted with argon in acetic acid, gave a 42% yield of the 5-fluoro derivative of l-methyl-2-pyridone [82H( 17)429],... 

Side-chain reactions are able to give accurate quantitative values for the electrophilic reactivities of the free bases, but there have as yet been far fewer such studies than of the conventional electrophilic substitutions already discussed. Reactions can be carried out in solution or in the gas phase. Solution work has been due to Noyce and co-workers using the solvolysis of either 1-arylethyl chlorides, 2-arylprop-2-yl chlorides, or the corresponding p-nitrobenzoates. Results for thiazole, isothiazole, and N-methylimidazole (in terms of cr+ values) are given in Scheme 7.12 (73JOC3316, 73JOC3762 75JOC3381). These demonstrate a number of points. 

These results do not, as noted above, give any direct indication of the difference in transmission ability of =N versus =CH—. For this, one must compare the effects of substituents in 9.113 with 9.114, though even here the results are blurred because of the dual transmission pathway. It is difficult to make the comparison using a conventional electrophilic substitution (except by prelabeling, e.g., as in detritiation) because substitution at the desired point is likely to be a minor component and difficult to measure accurately. The side-chain carbocation method has therefore been used. 

This procedure provides a method for functionalizing the pyrrole ring 1n the 3-pos1t1on, normally a difficult synthetic step when conventional electrophilic substitution is used. The technique has been extended to addition of several aldehydes and acetone and to a number of pyrroles.4 The generality Includes photoaddition to imidazoles which are substituted in the 4-posltion. Pyrrole photoadduct alcohols are readily dehydrated to 3-alkenylpyrroles or oxidized to 3-acyl derivatives. 

The bromination and acetylation reactions show that the calixarenes are capable of undergoing conventional electrophilic substitution reactions without rupture of the macrocyclic ring. Zinke et al.18) reported the nitration of p-tert-butylcalixarene (ring size uncertain) and obtained a material that failed to melt up to 400 °C, exploded when heated more strongly, and had a nitrogen analysis in agreement with a tetranitro-calixarene. Attempts to obtain a nitration product from calix[4]arene 59,... 

Selenophene itself is commercially available, but is fairly expensive. It can be conveniently obtained in 70% yield via a one-step thermal reaction between selenium and acetylene at 450 °C (Scheme 6.1) unfortunately, this pyrolytic reaction requires a troublesome gas-flow system equipped with an electric furnace, thus hindering the large-scale production of selenophene [17]. The conventional electrophilic substitution reactions of selenophene, like thiophene, can provide its substituted derivatives, but the yields are generally lower compared with those of similar reactions of thiophene [32]. Moreover, the conversions... 

This second example provides a comparison between two different synthetic strategies. One method uses a pathway that maintains the integrity of the core throughout, whereas the other, newer, method builds the core up with the substituents already attached and in place. This second technique is very powerful when complex core structures are required or where lateral substitution in the core is difficult to achieve using conventional electrophilic substitution techniques [39],... 

This is an electrophilic substitution we have not seen before—but we do know the mechanisms for the various components of it (Figure 13.47). The first step is protonation of the formaldehyde to make it into a better electrophile (when we look at carbonyl chemistry in the next chapter, we will find this is a very common process). This is then attacked by the aromatic ring in a conventional electrophilic substitution to give benzyl alcohol. Under the reaction conditions, the benzyl alcohol undergoes an S,.j2 substitution to give chloromethylbenzene (Figure 13.48). This process can be... 

Reactions that occur with the development of an electron deficiency, such as aromatic electrophilic substitutions, are best correlated by substituent constants based on a more appropriate defining reaction than the ionization of benzoic acids. Brown and Okamoto adopted the rates of solvolysis of substituted phenyldimeth-ylcarbinyl chlorides (r-cumyl chlorides) in 90% aqueous acetone at 25°C to define electrophilic substituent constants symbolized o-. Their procedure was to establish a conventional Hammett plot of log (.k/k°) against (t for 16 /wcra-substituted r-cumyl chlorides, because meta substituents cannot undergo significant direct resonance interaction with the reaction site. The resulting p value of —4.54 was then used in a modified Hammett equation. 

Other electrophilic substitutions proceed with difficulty, or not at all. Nitrosation and diazo coupling require the presence of the strongly activating dimethylamino group (see Section VIII). Bromine adds, in the presence of sunlight, to give tetrabromotetrahydrobenzofuroxan (48) the initial attack is probably free-radical in nature. The product can be dehydrobrominated to form 4,7-, or a mixture of 4,5- and 4,6-dibromobenzofuroxan, depending upon the conditions. More conventional electrophilic bromination conditions have been tried in an attempt to obtain a monosubstituted product, but without success. 

In any heterolytic reaction in which a new carbon-carbon bond is formed one carbon atoms attacks as a nucleophile and the other as an electrophile. The classification of a given reaction as nucleophilic or electrophilic is a matter of convention and is usually based on analogy. Although not discussed in this chapter, 11-12-11-28 and 12-14-12-19 are nucleophilic substitutions with respect to one reactant, though, following convention, we classify them with respect to the other. Similarly, all the reactions in this section (10-93-10-123) would be called electrophilic substitution (aromatic or aliphatic) if we were to consider the reagent as the substrate. 

For toluene fluorination, the impact of micro-reactor processing on the ratio of ortho-, meta- and para-isomers for monofluorinated toluene could be deduced and explained by a change in the type of reaction mechanism. The ortho-, meta- and para-isomer ratio was 5 1 3 for fluorination in a falling film micro reactor and a micro bubble column at a temperature of-16 °C [164,167]. This ratio is in accordance with an electrophilic substitution pathway. In contrast, radical mechanisms are strongly favored for conventional laboratory-scale processing, resulting in much more meta-substitution accompanied by imcontroUed multi-fluorination, addition and polymerization reactions. 

Direct fluorinations with elemental fluorine still are not feasible on an industrial scale today they are even problematic when carried out on a laboratory-scale [49-53]. This is caused by the difficulty of sustaining the electrophilic substitution path as the latter demands process conditions, in particular isothermal operation, which can hardly be realized using conventional equipment. As a consequence, uncontrolled additions and polymerizations usually dominate over substitution, in many cases causing large heat release which may even lead to explosions. 

For the same reasons as outlined for pyrrole (Section 6.1.2), there is preference for 2- rather than 3-substitution. However, conventional electrophilic reactions, such as nitration, sulfonation, etc., carried out under acidic conditions, are very difficult to control. 

The Hammett cr+ constant for the 4(5)-position of imidazole is around -1 for C-2 it is of the order -0.8 (86CHE587). The electrophilic substitutions which do occur at the 2-position invariably involve preformation of an anion at that position. The 2-proton, which should be the least active in a conventional SEAr sense, turns out to be the most labile over a wide pH range, and there is a marked rate acceleration on going from imidazole to imidazolium cation. Any negative charge generated at C-2 is stabilized by the adjacent pyrrole-type nitrogen (see Section 3.4.1.8.2). 

A specific feature of these reactions is that the substitution occurs in the ortho and para positions. This is typical of nucleophilic reactions whereas the meta-orienting influence of the nitro group (i.e. the conventional substitution rule) can be observed when electrophilic substitution occurs. 

Pyrimidine forms 4-bromopyrimidine when the hydrochloride is heated with bromine at 160°C (or at 130°C in nitrobenzene) (73JHC153), the process being preceded by a vigorous reaction at lower temperature (57CB1837 58AG571). It is likely that N-bromo compounds and perbro-mides are implicated in these reactions, which occur (3 to the ring nitrogens, and they are not conventional electrophilic aromatic substitutions. 

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