Imidazole NH-group

The dinitrophenyl group has been used to protect the imidazole — NH group in histidines (45% yield)" by reaction with 2,4-dinitrofluorobenzene and potassium carbonate. Imidazole —NH groups, but not a-amino acid groups, are quantitatively regenerated by reaction with 2-mercaptoethanol (22°, pH 8, 1 h)." The 2,4-... 

Figure 3-30 Spectra of the pyridoxal phosphate (PLP), pyridoxamine phosphate (PMP) and apoenzyme forms of pig cytosolic aspartate aminotransferase at pH 8.3, 21 °C. Some excess apoenzyme is present in the sample of the PMP form. Spectra were recorded at 500 MH2. Chemical shift values are in parts per million relative to that of HzO taken as 4.80 ppm at 22°C. Peak A is from a proton on the ring nitrogen of PLP or PMP, peaks B and D are from imidazole NH groups of histidines 143 and 189 (see Fig. 14-6), and peaks C and D are from amide NH groups hydrogen bonded to carboxyl groups.

Protection of imidazole NH, The imidazole NH group of the histidine derivative 2 is protected as the p-methoxysulfonamide 3 by reaction with 1 and EtsN. This sulfonamide derivative is stable to the acidic conditions required to remove the... 

Table 7. NH stretching frequencies and rNH/vND isotopic frequency ratios of the imidazolic NH group depending on the environment (1 to 7) and of the NH+ group of some protonated nitrogen bases depending on the anion (8 to 14)...

SCHEME 2.1 Reaction of -NH2 groups, imidazole =NH group, and -SH groups of lysine (Lys, K), histidine (His, H), and cysteine (Cys, C) side-chains, respectively, in proteins with 4-hydroxy-2-nonenal (HNE) through MA (a, -tl56 Da). HNE can also form SB adducts (b, h-138 Da) with -NH2 groups. 

Azole anions are derived from imidazoles, pyrazoles, triazoles or tetrazoles by proto loss from a ring NH group. In contrast to the neutral azoles, azole anions show enhance reactivity toward electrophiles, both at the nitrogen (Section 4.02.1.3.6) and carbon aton (Section 4.02.1.4.1(i)). They are correspondingly unreactive toward nucleophiles. 

Imidazoles and pyrazoles with free NH groups form hydrogen-bonded dimers and oligomers (66AHC(6)347). 

Annular nitrogen atoms can form hydrogen bonds, and if the azole contains an NH group, association occurs. Imidazole (84) shows a cryoscopic molecular weight in benzene 20 times that expected. Its boiling point is 256 °C, which is higher than that of 1-methyl-imidazole (198 °C). 

Pyrazoles and imidazoles with free NH groups are readily alkylated, e.g. by Mel or Me2S04. A useful procedure is to use the alkyl salt of the azole in liquid ammonia (80AHC(27)241). However, alkylation can also occur under neutral conditions, particularly with imidazoles. 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Azoles can form stable compounds in which metallic and metalloid atoms are linked to nitrogen. For example, pyrazoles and imidazoles Af-substituted by B, Si, P and Hg groups are made in this way. Imidazoles with a free NH group can be Af-trimethylsilylated and Af-cyanated (with cyanogen bromide). Imidazoles of low basicity can be Af-nitrated. 

Under alkaline conditions, alkyl nitrites nitrosate imidazoles which possess a free NH group in the 4-position (70AHC(12)103). Nitrosation of 3,5-dimethylpyrazole gives the 4-diazonium salt by further reaction of the nitroso compound with more NO". 5-Pyrazolinones are often nitrosated readily at the 4-position. 3-Alkyl-5-acetamidoisothiazoles undergo 4-nitrosation. 

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. 

Fyrazoles and indazoles, imidazoles and benzimidazoles/ and benzotriazoles which possess a free NH group are associated and have been considered to exhibit mesohydric tautomerism see discussion in Volume 1, article I, Section I,C. 

The imidazole carbamate group is more stable to hydrolysis in aqueous buffer than the NHS-carbonate group, which is similar in reactivity to an NHS ester. However, this means that the imidazole carbamate also is slower to react and couple with amines. NHS-carbonate reactions usually go to completion within 1-2 hours at room temperature, whereas imidazole carbamates typically require higher pH conditions and overnight incubations to get maximal yield of ligand coupling. 

Fig. 9.7 Crystal structure of the H2-antagonist metiamide with an intramolecular hydrogen bond (yellow dots) between the imidazole nitrogen and an NH group of the side chain.

The Tsuji-Trost reaction is the Pd(0)-catalyzed allylation of a nucleophile [48-51]. The NH group in imidazole can take part as a nucleophile in the Tsuji-Trost reaction, whose applications are found in both nucleoside and carbohydrate chemistry. Starting from cyclopentadiene and paraformaldehyde, cyclopentenyl allylic acetate 64 was prepared in diastereomerically-enriched form via a Prins reaction [52], Treating 64 with imidazole under Pd(0) catalysis provided the N-alkylated imidazole 65. 

It seems reasonable to assume that the open-chain compound 5-(formyl-amino)-4-[(A -/3-aminoethyl)formamidino]imidazole (70) is intermediate for the formation of both products 68 and 69. RecycUzation can occur to either the N -derivative 68 or to 5-(formylamino)-4-(2-aminoimidazolin-2-yl)imidazole (71). A subsequent internal cyclization between the NH group and the carbonyl functionality gives the ethano derivative 69 (Scheme IV.30). Support for this mechanism comes from the observation that adenosine 67, being N-labeled on the 6-amino group, yields unlabeled 69 [95H(41)1399]. 

Finally, in imidazole-4,5-dicarboxaldehydes groups such as — CH2OCH2 CH2SiMc3 were used to protect the heterocyclic NH group during aldol condensation (91MI1). 

When simple substituted benzimidazoles such as 2-azidomethyl benzimidazole are employed, their iminophosphoranes (148) react with isocyanate to give carbodiimide 149. The free NH group of the imidazole can intercept the carbodiimide intermolecularly. Thus, upon addition of a second equivalent of isocyanate, cyclization affords 2,3-dihydro-l//-imidazo[l,5-a]benzimidazole 150 (Scheme 59) (89T1823 94S1197). 

As shown in Fig. 5, the pX,s of the azoles (imidazoles, 1,2,4-triazoles, and tetrazoles) which do not protonate next to an NH group are linearly related to the pX,s of the corresponding pyridines. It is interesting to notice that the... 

Table 42 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NH groups in the conjugate acid, e.g. in (197 EWG = electron-withdrawing group) the 2-NH is more acidic than 1-NH and hence, for the neutral compound, the 3-substituted pyrazole is the more stable. 

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