Benzene nucleophilic aromatic substitution

When 2-chloronicotinoyl chloride is allowed to react with pentaethylene glycol and sodium hydride in benzene solution, acylation followed by nucleophilic aromatic substitution occurs resulting in the formation of a macrocyclic lactone (48% yield) as shown in Eq. (2.8), in Chap. 2. 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

Bifunctional catalysis has also been observed by Pietra and Vitali35 for a more typical nucleophilic aromatic substitution reaction, that of 2,4-dinitrofluorobenzene and piperidine in benzene. For this reaction triethylamine does not have an... 

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

A long series of studies of aromatic nucleophilic substitution included the kinetics of reactions of l-chloro-2,4-bis(trifluoromethylsulfonyl)benzene, 3-nitro-4-chlorophenyl trifluoromethyl sulfone and 2-chlorophenyl trifluoromethyl sulfone with sodium methox-ide or ammonia in methanol . The SO2CF3 group was found to have an enormous accelerating effect, in accord with the value of 1.65, based on the dissociation of anilinium ion. Further examples of the promotion of nucleophilic aromatic substitution by fluoro-substituted sulfonyl groups are given by Yagupol skii and coworkers . 

The reactions between 2,4-dinitrohalogenobenzenes and X-substituted anilines in benzene produce the usual diphenylamines 109 by nucleophilic aromatic substitution reaction 28. The inspection of reaction mixtures by UV/VIS spectroscopy at zero reaction... 

The usual kinetic law for S/v Ar reactions is the second-order kinetic law, as required for a bimolecular process. This is generally the case where anionic or neutral nucleophiles react in usual polar solvents (methanol, DMSO, formamide and so on). When nucleophilic aromatic substitutions between nitrohalogenobenzenes (mainly 2,4-dinitrohalogenobenzenes) and neutral nucleophiles (amines) are carried out in poorly polar solvents (benzene, hexane, carbon tetrachloride etc.) anomalous kinetic behaviour may be observed263. Under pseudo-monomolecular experimental conditions (in the presence of large excess of nucleophile with respect to the substrate) each run follows a first-order kinetic law, but the rate constants (kQbs in s 1 ruol 1 dm3) were not independent of the initial concentration value of the used amine. In apolar solvents the most usual kinetic feature is the increase of the kabs value on increasing the [amine]o values [amine]o indicates the initial concentration value of the amine. 

Pyridine, on the other hand, is more reactive than benzene towards nucleophilic aromatic substitution. This is effectively reaction towards the C=N imine function, as described above. Attack is... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antihypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aromatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is conden.sed with piperidine. There is thus obtained ofornine (11) [3]. 

Polyetherimides (PEI) are polyimides containing sufficient ether as well as other flexibi-lizing structural units to impart melt processability by conventional techniques, such as injection molding and extrusion. The commercially available PEI (trade name Ultem) is the polymer synthesized by nucleophilic aromatic substitution between 1,3-bis(4-nitrophthalimido) benzene and the disodium salt of bisphenol A (Eq. 2-209) [Clagett, 1986]. This is the same reaction as that used to synthesize polyethersulfones and polyetherketones (Eq. 2-206) except that nitrite ion is displaced instead of halide. Polymerization is carried out at 80-130°C in a polar solvent (NMP, DMAC). It is also possible to synthesize the same polymer by using the diamine-dianhydride reaction. Everything being equal (cost and availability of pure reactants), the nucleophilic substitution reaction is probably the preferred route due to the more moderate reaction conditions. 

Nucleophilic aromatic substitutions Pyridine is more reactive than benzene towards nucleophilic aromatic substitutions because of the presence of electron-withdrawing nitrogen in the ring. Nucleophilic aromatic substitutions of pyridine occur at C-2 (or C-6) and C-4 positions. 

Dinitration of p-chloro(trifluoromethyl)benzene will take place at the ring positions ortho to the chlorine. Compound A is 2-chloro-5-(trifluoromethyl)-l,3-dinitrobenzene. Trifluralin is formed by nucleophilic aromatic substitution of chlorine by dipropylamine. Trifluralin is N, A-dipropyl-4-(trifluoromethyl)-2,6-dinitroaniline. 

Kita and Tohma found that exposure of p-substituted phenol ethers to [bis(tri-fluoroacetoxy)iodo]benzene 12 in the presence of some nucleophiles in polar, less nucleophilic solvents results in direct nucleophilic aromatic substitution [Eq. (84)] [156]. Involvement of a single-electron transfer (SET) from phenol ethers to A3-iodane 12 generating arene cation radicals was suggested by the detailed UV-vis and ESR studies. SET was involved in the oxidative biaryl coupling of phenol ethers by 12 in the presence of BF3-Et20 [157]. 

In order to prepare these macrocycles it was necessary to synthesize the previously unknown o -bis(phosphino)benzene (IV). Lithium aluminum hydride reduction of the o-bis(phosphonate) III gave IV in 50% yield (31P NMR, 6 -123.8 ppm, Jpy = 207 Hz). The phosphonate III could be obtained in modest yields by the photo-activated nucleophilic aromatic substitution by sodium diethyl-phosphite on o-chloroiodobenzene in liquid ammonia solution (4). 

So far we have concentrated on making complete heterocycles with substituents. So indomethacin 87 was made with one substituent (OMe) on the benzene ring and two on the pyrrole ring. Only the substituent on nitrogen was added after the indole was formed. Now we shall consider what reactions can be used to add substituents to heterocycles after they are formed. This will usually be by electrophilic or nucleophilic aromatic substitution. The most important distinction between... 

Aromatic compounds undergo many reactions, but relatively few reactions that affect the bonds to the aromatic ring itself. Most of these reactions are unique to aromatic compounds. A large part of this chapter is devoted to electrophilic aromatic substitution, the most important mechanism involved in the reactions of aromatic compounds. Many reactions of benzene and its derivatives are explained by minor variations of electrophilic aromatic substitution. We will study several of these reactions and then consider how substituents on the ring influence its reactivity toward electrophilic aromatic substitution and the regiochemistry seen in the products. We will also study other reactions of aromatic compounds, including nucleophilic aromatic substitution, addition reactions, reactions of side chains, and special reactions of phenols. 

Nucleophilic aromatic substitution provides one of the common methods for making phenols. (Another method is discussed in Section 19-17.) Show how you would synthesize the following phenols, using benzene or toluene as your aromatic starting material, and explain why mixtures of products would be obtained in some cases. 

A reactive intermediate in some nucleophilic aromatic substitutions, benzyne is benzene with two hydrogen atoms removed. It can be drawn with a highly strained triple bond in the six-membered ring. (p. 789)... 

Large positive p values usually indicate extra electrons in the transition state delocalized into the ring itself. A classic example is nucleophilic aromatic substitution by the addition-elimination mechanism (Chapter 23). The p value is +4.9, but even this large value does not mean a complete anion on the benzene ring as the nitro group, present in all cases, takes most of the negative charge. The substituent X merely helps. 

Nucleophilic aromatic substitution of the fluorine substituents by benzene-dithiolate sulfur atoms (step a), reduction of the nitro compound (step b), diazotization, reaction with KSaCOEt, alkaline hydrolysis, and acidification gave tpS4 H2 (step c). It could be purified via the [Ni(tpS4)]2 complex (Fig. 1), which is readily hydrolyzed with dilute hydrochloric acid to give pure tpS4 H2. 

For cleavage processes involving the loss of chloride ion, then, one might expect to find similarities to the regiochemistry that is observed in nucleophilic aromatic substitution. Assuming for the purpose of analysis that route (a) is predominant, one can use the rate data of Chambers et al. [34] to calculate the activating effects of chlorine vs. hydrogen in nucleophilic aromatic substitution in benzene systems (ortho meta para = 12.1 4.85.1.00) and then the relative rates for nucleophilic substitution (Chart I, numbers in parentheses). Note that the... 

Now, because we have a pyridine and not a benzene ring, nucleophilic aromatic substitution can... 

Pyridine is the six-membered-ring, nitrogen-containing heterocyclic analog of benzene. The pyridine ring is electron-poor and undergoes electrophilic aromatic substitution reactions with difficulty. Nucleophilic aromatic substitutions of 2- or 4-halopyridines take place readily, however. 

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