Imidazole in Histidine

It seems to be fair to say that the difficulties still experienced in the synthesis of arginine containing peptides should stimulate further-studies-toward more satisfactory guanidine blocking groups. 

The NH group in the imidazole nucleus of the histidine side chain has often been left unprotected with no obvious detriment to the procedure or the product of the synthesis. Some side reactions, however, can be attributed to the effect of imidazole. It acts as catalyst in the (undesired) O-acylation of serine and tyrosine side chains and also, if water is not excluded from the medium, in the hydrolysis of active esters. Furthermore, because the basic character of the imidazole is weak but not negligible, histidine containing peptides are sometimes isolated in more than one form, for instance as the base and the trifluoro-acetate or as the mixture of the hydrochloride and the acetate, etc. Therefore, masking of the imidazole offers certain advantages. 

Acylation of the NH group is not a real remedy because acyl-imidazoles are reactive compounds. For instance, the p-toluenesulfonyl group might be transferred onto other nucleophiles, such as the amino group, alcoholic or phenolic hydroxyls and quite readily to the hydroxyl group of the additive 1-hydroxy-benzotriazole  

Less acyl-transfer was noted with the benzyloxycarbonyl, the tert.butyl-oxycarbonyl and the adamantyloxycarbonyl groups. The acid stable piperi-dinocarbonyl group 

Dinitrophenylation of the imidazole NH practically eliminates its basic character, yet the 2,4-dinitrophenyl (DNP) group also shares a less desirable property with real acyl groups it can migrate to free amines  

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P. E. Blatz The pKa of the imidazole in histidine is between 6.6 and perhaps 8.0. It seems that what you are looking at is the protonation of histidine. In the base form it is active and in the acid form it is not. How do you separate this from hydrogen bonding. 

Imidazole-4-catbonitrile, 5-amino-synthesis, 5, 463 Imidazolecarboxamide, cyano-reactions, 5, 436 Imidazole-4-carboxamide Hofmann reaction, 5, 435 Imidazole-4-carboxamide, 5-amino-in histidine biosynthesis, 1, 90 reactions... 

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-... 

Pyrimidine and imidazole rings are particularly important in biological chemistry. Pyrimidine, for instance, is the parent ring system in cytosine, thymine, and uracil, three of the five heterocyclic amine bases found in nucleic acids An aromatic imidazole ring is present in histidine, one of the twenty amino acids found in proteins. 

Problem 24.21 What is the percent protonation of the imidazole nitrogen atom in histidine at a physiological pH of 7.3 (See Section 24.5.)... 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

The 2-adamantyloxycarbonyl group has been found suitable for protection of the imidazole function in histidine during peptide synthesis.[7a]... 

Tanokura M (1983) 1 II-NMstudy R on the tautomerism of the imidazole ring of histidine residues I. Microscopic pK values and molar ratios of tautomers in histidine-containing peptides. Biochim Biophys Acta 742 576-585. 

Histidine residues are, however, generally regarded as major possible binding sites for ruthenium-arene complexes in proteins. To model this interaction, we also studied the reaction of [RuCl(en)(rj6-bip)]+ (10) with L-histidine at 310 K in aqueous solution (91). The reaction was quite sluggish and did not reach equilibrium until 24 h at 310 K, by which time only about 22% of the complex had reacted. Two isomeric imidazole-bound histidine adducts could be discerned, with more or less equal binding of Ne... 

Increased understanding of reaction mechanisms in the 1940s and 1950s pinpointed general acid or base catalysis as likely to be of importance in many hydrolytic reactions. The imidazole nucleus in histidine was the obvious center in proteins to donate or accept protons at physiological pH. The involvement of histidine was shown by photochemical oxidation in the presence of methylene blue (Weil and Buchert, 1951) which destroyed histidine and tryptophan and inactivated chymotrypsin and trypsin. 

The distorted octahedral species [10] and [11] are the essential part of the cytochromes acting as redox catalysts. In these, a very specific porphyrin redox potential may have been adjusted by an appropriate choice of the axial ligands exerting a cis effect on the porphyrin system transmitted through the iron atom. In cytochrome c, these axial ligands are the imidazole of a histidine and the thioether function of methionine, as in [10], and in the cytochromes a or b5 they are presumably two imidazoles of histidine, as in [77] (7). 

Fe-Np is the bond distance to porphyrin nitrogen ligand atoms. Fe-Ni, is the bond distance to histidine (or imidazole in model compounds) nitrogen ligand atoms. 

Hubbard and Kirsch (1972) have recently proposed that histidine may act as a nucleophile in a-chymotrypsin acylation reactions of esters having a good leaving group (jO-nitrophenol). This suggestion was based on a similarity in p-value for acylation by p-substituted nitrophenyl and dinitrophenyl benzoates and nucleophilic attack on these compounds by imidazole, in contrast with less positive p-values for hydroxide ion catalysis. Hammett p-values for hydrolysis of substituted phenyl esters are given in Table 6 and show little apparent trend. The values for hydroxide ion and alcoholate ions are... 

Dunnet, M. and Harris, R. C. (1997). High-performance liquid chromatographic determination of imidazole dipeptides, histidine, 1-methylhistidine and 3-methylhistidine in... 

The imidazole groups in histidine side chains are parts of the active sites of many enzymes. Like other basic groups in proteins they also may bind metal ions. 

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