Nucleophilic substitution of substituents

The tremendous difference in reactivity towards electrophiles, that distinguishes ir-deficient and tt-excessive heterocycles, is considerably diminished for nucleophilic substitution reactions in which ring 

For both nucleophiles, 2,5-dinitrofuran is the most active substrate, the thiophene derivative follows. On the other hand, the relative reactivity of 1-methyl-2,5-dinitropyrrole and 1,4-dinitrobenzene depends on the nature of the nucleophile. For the 4-MeC6H4S anion, the former is more active by about two powers of ten, but in the piperidinolysis reaction the 1,4-benzene is superior. These phenomena appear to be caused by differences in the polarizability of both substrate and nucleophiles. p-Tolylthiolate anion is a softer nucleophile in comparison with piperidine and the pyrrole system is certainly more polarizable than the benzene molecule. Therefore soft-soft interaction of 1-methyl-2,5-dinitropyrrole with 4-MeC6H4S and hard-hard interaction of 1,4-dinitrobenzene with piperidine should occur easier than interactions between reagents with opposite types of softness and hardness. 

Carbazole (292), dibenzofuran (293 Z=0) and dibenzothiophene (293 Z=S) behave as diphenylamine, diphenyl ether and diphenyl sulfide, respectively, in their substitution reactions and 

The positional reactivity of dibenzofuran in electrophilic substitution reactions depends on the electrophile. Reaction occurs mostly at the 2- and 3-positions but the ratio of the two products varies (91JOC4671). The reaction of cyanogen bromide catalyzed by aluminum chloride gives an 80% yield of the 2-substituted product together with 15% of the 3-cyano-derivative (92ACS312). Oxidative acetoxylation of dibenzofuran occurs predominantly at the 3-position ( 60%) together with attack at the 1-position ( 30%) (92ACS802). In this latter reaction, the attack by acetate is on the dibenzofuranium radical cation. 

The possibility of activating the benzene ring of the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from N-methylindole (294) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (295) which can be transformed into l-methylindole-7-carbaldehyde (296) (78CC1076). 

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Considerably fewer examples have been reported for the nucleophilic attack on the pseudoazulene ring or for the nucleophilic substitution of substituents in the pseudoazulene ring. Apparently there is no example of a reaction of a free radical with a pseudoazulene. 

The usual nucleophilic substitution of substituents directly bound to the heterocyclic ring was observed for monocyclic and condensed 1,2,3-triazines. These reactions may be accompanied by a ring opening of the 1.2,3-triazine ring after the nucleophilic attack at the 4-position. 1,2,3-Benzotriazines and monocyclic 1,2,3-triazines seem to be less stable than 1,2,3-triazines condensed with heterocycles. 

Nucleophilic substitution of benzene itself is not possible but the halogeno derivatives undergo nucleophilic displacement or elimination reactions (see arynes). Substituents located in the 1,2 positions are called ortho- 1,3 meta- and 1,4 para-. 

Nucleophilic substitution of the 5-halo substituent on a thiazole ring by a thiocyanato group (348, 362, 370-376) or a thiouronium group (364, 377) affords the thiocyanato and thiouronium precursors."... 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Very strong bases such as sodium or potassium amide react readily with aryl halides even those without electron withdrawing substituents to give products corresponding to nucleophilic substitution of halide by the base... 

In contrast, substituents in 1,2,4-triazoles are usually rather similar in reactivity to those in benzene although nucleophilic substitution of halogen is somewhat easier, forcing conditions are required. 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

A 1-pyridinium substituent has an activating effect on nucleophilic substitution of pyrazines and s-triazines. °... 

Nucleophilic substitution of pyridines is discussed in previous sections in relation to the following cyclic transition states (Section II, B, 5), hydrogen bonding and cationization (Section II, C), the leaving group (Section II, D,) and the effect of other substituents (Section II, E) and of the nucleophile (Section II, F). 

Nucleophilic substitution of as-triazines is discussed in relation to hydrogen bonding and the effects of the leaving group and of other nuclear substituents in Sections II,C,D, and E, respectively. 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

The nucleophilic substitution of quinoline as affected by cationiza-tion and hydrogen bonding is discussed in Section II, C, by the leaving group and other substituents in Sections II, D and II, E, respectively, and in Section III, A, 2, and by the nucleophile in Section II, F. 

The effect of the leaving group and of other substituents on nucleophilic substitution of cinnolines is discussed in Sections II, D and II, E, respectively. 

The effect of nuclear substituents on nucleophilic substitution of quinoxalines is included in Section II, E, and in section III, A,... 

The nucleophilic substitution of a halogen atom at C-5 in the isoxazole nucleus without further functional substituents is so far unknown, but recently reports appeared on the nucleophilic substitution reactions at C-5 in isoxazole derivatives with benzoyl (78 79), ester, and cyano groups (81—>80, 82) in the 4-position. ... 

Although this particular series of reactions involves nucleophilic substitution of an alkyl p-toluenesulfonate (called a tosylate) rather than an alkyl halide, exactly the same type of reaction is involved as that studied by Walden. For all practical purposes, the entire tosylate group acts as if it were simply a halogen substituent. In fact, when you see a tosylate substituent in a molecule, do a mental substitution and tell yourself that you re dealing with an alkyl halide. 

The general applicability of this type of synthesis of quinone diazides is nevertheless limited since, depending on the type and number of substituents in the 2-, 4-, and 6-positions of benzenediazonium ions, either hydroxy-de-diazoniation (reaction A in Scheme 2-20) or nucleophilic substitution of one of the groups in the 2-, 4-, or 6-position (reaction B) will predominate. It is difficult to predict the ratio of the two reactions in a specific case. This is exemplified by two investigations carried... 

Preparation of poly(dichlorophosphazene), (NPCl2)n> a polymeric intermediate from which the great majority of POPs have been prepared by nucleophilic substitution of the highly reactive chlorine atoms with carefully selected organic substituents... 

As noted in Section 11.2.2, nucleophilic substitution of aromatic halides lacking activating substituents is generally difficult. It has been known for a long time that the nucleophilic substitution of aromatic halides can be catalyzed by the presence of copper metal or copper salts.137 Synthetic procedures based on this observation are used to prepare aryl nitriles by reaction of aryl bromides with Cu(I)CN. The reactions are usually carried out at elevated temperature in DMF or a similar solvent. 

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