Imidazole, aromaticity basicity

Let us consider just one more nitrogen heterocycle here, and that is imidazole, a component of the amino acid histidine (see Box 11.6). The imidazolium cation has pATa 7.0, making imidazole less basic than a simple amine, but more basic than pyridine. Imidazole has two nitrogen atoms in its aromatic ring system. One of these nitrogens contributes its lone... 

Imidazole and its derivatives form an interesting and important class of hetero cyclic aromatic amines Imidazole is approximately 100 times more basic than pyndme... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

Benzimidazole is also aromatic (65AX573, 97T13111), less acidic and more basic in the gas phase than imidazole (83AGE323), although in solution the basicity trend is reverted. This is ascribed to the polarization effects of the annulation. 

Further divergence from classical benzamide structure is represented by the synthesis of ondansetron (GRF 38032F, (33)), a potent 5-HT3 receptor antagonist where the basic nitrogen atom is part of an imidazole ring and the aromatic ring is part of tetrahydrocarbazolone ring system [27],... 

Sheradsky has found that the hydroxyl function of a ketoxime such as acetophenone oxime can be made to react with DMAD when the reaction is carried out in methanol with a basic catalyst, to give mixture of the fumarate and maleate isomers (164) in the ratio 2 1. This mixture on heating undergoes a hetero-Cope rearrangement followed by cyclization and dehydration to give dimethyl 5-phenylpyrrole-2,3-dicarboxylate (168) (Scheme 25). Similarly, Heindel and Chun have reported that vinyl ether adducts (171), obtained by the condensation of arylamide oximes with DMAD, get thermally converted into oxa-diazolines (172) or imidazolinones (174), depending on the reaction conditions. A similar reaction occurs with aromatic amidoxime-methyl propiolate adducts to give imidazoles (170) (Scheme 26). 1,2,4-Dioxazoles have been reported to be formed in the reaction of hydrox-amic acids with DMAD. - ... 

Pyrazole and Imidazole. These are five-membered ring heterocycles containing two nitrogens, one basic and one neutral. Two common forms are pyrazole (1,2-diazole) and imidazole (1,3-diazole) both are prone to aromatic hydroxylation. 

Problem 20.35 (a) What makes imidazole (Prob. 20.37a) aromatic (6) Explain why imidazole, unlike pyrrole, is basic. Which N is the basic site ... 

The azoles (oxazole, imidazole, and thiazole) are five-membered aromatic heterocycles that have two heteroatoms in the ring. One of the heteroatoms in each of these heterocycles is an sp2-hybridized nitrogen that contributes one electron to the 6n aromatic system and has a basic nonbonded lone pair. The other heteroatom (oxygen, nitrogen, or sulfur) contributes two electrons to the 6n system. The imidazole skeleton is present in the amino acid histidine. The thiazole ring occurs in thiamin (vitamin B. ... 

SAR studies have shown that a weakly basic imidazole or 1,2,4-triazole rings substituted only at the N-l position are essential for activity. The substituent must be lipophilic in character and usually contains one or more five or six membered ring systems, some of which may be attached by an ether, secondary amine or thioether group to the carbon chain. The more potent compounds have two or three aromatic substituents, which are singly or multiply chlorinated or fluorinated at positions 2, 4 and 6. These nonpolar structures give the compounds a high degree of lipophilicity, and hence membrane solubility. 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

All of the common 5-membered aromatic nitrogen heterocycles are quite acidic with pKa s ranging from 16.2 in the case of indole (comparable to methanol) to 5 in the case of tetrazole (comparable to acetic acid). Indoles and pyrroles devoid of electron withdrawing substituents are also very susceptible to electrophilic attack and oxidation whilst imidazole, 1,2,4-triazole and tetr azole are also quite basic. In the case of imidazole, a pKan = 7 corresponds to 50% of the... 

From the comparative experiments in DjO the catalysis by the cyclic dipeptides was confirmed to be nucleophilic, which is the same as the imidazole catalysis. It is seen in Table 16 that in the hydrolysis of PNPA kc for the cyclic peptides is onfy 1/10-1/5 as much as that for imidazole. The lower reactivity of the cyclic dipeptides is explained partly in terms of the lower pKj values and partly because of the larger steric hindrance for the nucleophilic reaction. Only when the pattern of the substrate binding—intramolecular catalysis of the cyclic peptides excels the decrease of basicity and the increase of steric hindrance, an enhanced catalysis by the cyclic dipeptides is possible. With regard to an increase of reactivity was expected for the hydro-phobic interactions by a sli tly larger acyl chain and for the aromatic-amide interaction (see Sections 3.3 and 3.6) between the p-phenyl group of the substrate and... 

The effects of substituents on the basic nature of imidazole are summarized in Section 4.02.1.3.4. Tables 1 and 2 list the basic pKa values of some representative imidazoles and benzimidazoles. From these it can be seen that methyl and other alkyl substituents exert a weak, base-strengthening inductive effect which is additive. Aromatic substituents decrease basic strength, while groups attached to these aryl rings exert their normal behavior. In fact, Hammett studies have permitted prediction with reasonable accuracy and correlation of p/Ca values for a variety of imidazoles. In a study of meta- and para-substituted 1-phenylimidazoles Pozharskii <70CHE194) has shown not only that 1-phenylimidazole is a... 

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