Substitution in Heterocyclic Aromatic Compounds

Two sites are available for substitution in naphthalene, C-1 and C-2, C-1 being normally the preferred site of electrophilic attack. 

C-1 is more reactive because the arenium ion formed by electrophihc attack there is a relatively stable one. Benzenoid character is retained in one ring, and the positive charge is delocalized by ally lie resonance. 

To involve allylic resonance in stabilizing the arenium ion formed during attack at C-2, the benzenoid character of the other ring is sacrificed. 

PROBLEM 12.20 Sulfonation of naphthalene is reversible at elevated temperature. A different isomer of naphthalenesulfonic acid is the major product at 160°C than is the case at 0°C. Which isomer is the product of kinetic control Which one is formed under conditions of thermodynamic control Can you think of a reason why one isomer is more stable than the other Hint Build space-filling models of both isomers.) 

The great variety of available structural types causes heterocyclic aromatic compounds to range from exceedingly reactive to practically inert toward electrophilic aromatic substitution. 

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

One reason for the low reactivity of pyridine is that nitrogen is more electronegative than carbon, which causes the tt electrons of pyridine to be held more tightly and raises the activation energy for bonding to an electrophile. Another is that the nitrogen of pyridine is protonated in sulfuric acid and the resulting pyridinium ion is even more deactivated than pyridine itself. 

Lewis acid catalysts such as aluminum chloride and iron(lll) halides also bond to nitrogen to strongly deactivate the ring toward Friedel-Crafts reactions and halogenation. 

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Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 474 Substituent Effects in Electrophilic Aromatic Substitution Activating Substituents 476 Substituent Effects in Electrophilic Aromatic Substitution Strongly Deactivating Substituents 480 Substituent Effects in Electrophilic Aromatic Substitution Halogens 482 Multiple Substituent Effects 484 Retrosynthetic Analysis and the Synthesis of Substituted Benzenes 486 Substitution in Naphthalene 488 Substitution in Heterocyclic Aromatic Compounds 489... 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

M n Part II we spend a lot of time and pages on aromatic systems, starting with benzene. You examine benzene s structure, its resonance stabilization, and its stability. Next you study benzene derivatives and heterocyclic aromatic compounds, and then we address the spectroscopy of these aromatic compounds. And in Chapters 7 and 8 we introduce you to aromatic substitution by both electrophiles and nucleophiles, and you get to see a lot of reactions and a lot of examples. In this part you also start working with many more named reactions. 

Organomagnesium compounds usually resemble organolithium compounds in their reactions with nitrogen heterocyclic aromatic compounds [E, G], but they generally give inferior results for preparative purposes. Thus, as in the case of organolithium compounds, addition normally occurs at the 2-position of pyridine, and subsequent elimination or oxidation gives the 2-substituted pyridine [1] ... 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

Heterocyclic aromatic compounds such as pyrrole are readily metallated with Grignard reagents. The resulting compounds have N"Mg bonds and are, therefore, not organometallic compounds, but on reaction with electrophiles give 2-substituted pyrroles [14] (eq (4)). The reaction of chloroform or bromoform with PrMgCl at -78 °C in THF-HMPA (4 1) is mild and convenient method for the generation of an unstable carbenoid in the solution [15] (eq (5)). 

There is, for example, no end-of-text chapter entitled Heterocyclic Compounds. Rather, heteroatoms are defined in Chapter 1 and nonaromatic heterocyclic compounds introduced in Chapter 3 heterocyclic aromatic compounds are included in Chapter 11, and their electrophilic and nucleophilic aromatic substitution reactions described in Chapters 12 and 23, respectively. Heterocyclic compounds appear in numerous ways throughout the text and the biological role of two classes of them—the purines and pyrimidines—features prominently in the discussion of nucleic acids in Chapter 27. 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

The chemical reactivity of simple heterocyclic aromatic compounds varies widely in electrophilic substitution reactions, thiophene is similar to benzene and pyridine is less reactive than benzene, while furan and pyrrole are susceptible to polymerization reactions conversely, pyridine is more readily susceptible than benzene to attack by nucleophilic reagents. These differences are to a considerable extent reflected in the susceptibility of these compounds and their benzo analogues to microbial degradation. In contrast to the almost universal dioxygenation reaction used for the bacterial degradation of aromatic hydrocarbons, two broad mechanisms operate for heterocyclic aromatic compounds ... 

Compounds in the two groups differ in a number of ways. The two differ chemically in that the aliphatic undergo free-radical substitution reactions and the aromatic undergo ionic substitution reactions. In this chapter you examine the basics of both aromatic and heterocyclic aromatic compounds, concentrating on benzene and related compounds. 

More and more, solid catalysts like zeolites, clays or resins are used instead of traditional catalysts. Thus, zeolites are good catalysts for the acylation of non-heterocyclic aromatic compounds, both in the gas phase [2] and in the liquid phase [3]. The acylation of thiophene and of furan can also be carried out in the gas phase with M-5 catalysts [4]. Lasdo and co-woikers have shown that modified clays like montmorillonite doped with ZnCl2 can catalyse the reactioi of arenes with substituted benzoyle chlorides in good yields [5] (70 to 100%). Delmas and co-workers have reported the acylation of furan by carboxylic acids with nafion-H [6] (sulfonic resin) and duolite [7] (ion exchanged phosphonic resin). One of the advantages of these catalysts is the safety of environment. Actually, the use of homogeneous catalysts causes problems of corrosion, waste and troublesome workups [8,9]. 

Oxadiazoles and 1,2,4-oxadiazoles are heterocyclic aromatic compounds that appear in many bioactive molecules. Previous methods for the synthesis of 1,2,4-oxadiazoles include the coupling of amidoximes with carboxylic acid derivatives, aerobic C—H oxygenation of amidoximes, or a cyclization of nitrile oxides to nitriles. Telvekar and Takale developed the preparation of 1,2,4-oxadiazoles from substituted diketone derivatives through a Beckmann rearrangement process tScheme S.3S1. When treated with diphosphorus tetraiodide in dichloromethane at room temperature, dioximes 150 formed the Beckmann products, 1,2,4-oxadiazoles 151, in excellent yields. 

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