Imidazoles basicity

It was unusual to find that both enantiomers had similar activity in vitro, but these are relatively planar molecules in which the asymmetric centre is well separated from the basic end group, so there is close coincidence of the key recognition sites of the indole nucleus, carbonyl function and basic imidazole nitrogen atom. The quaternary derivative (20) of ondansetron retained activity (RVN p 2 8.4), suggesting that the imidazole ring is pro-tonated in the binding interaction with the receptor. 

Within the last decade many variations of the basic imidazole-2-ylidene structure (Scheme 2,A) have been synthesized [14-19]. They are not limited to sterically hindered unsaturated cyclic diaminocarbenes like 1, also 1,2,4-triazolin-5-ylidenes (Scheme 2,B), saturated imidazolidin-2-ylidenes [6,7,20] (Scheme 2,C), tetrahydropyrimid-2-yhdenes [21,22] (Scheme 2,D), acychc structures [23,24] (Scheme 2,E), systems with larger ring sizes [25,26] (Scheme 2,F) or constrained geometry [27,28] (Scheme 2,G). Reviews on the different possible synthetic routes from various precursors can be found in the literature [29-31]. 

Agonist analogs of TRH have been synthesized, showing that the n electron system and the basic imidazole ring are necessary for activity the N-formyl-Pro-Met-His-Pro-NHj (5.69) has 40% of the full activity of TRH but is resistant to serum inactivation. Some... 

In the case of unsymmetrical phosphamethin-cyanines 18, the signal of the CH3 protons of the more basic imidazole ring appears at lower field than that of the CH3 protons of the quinoline ring. 

At pH 7 the weakly basic imidazole group of histidine may be partially protonated. Both the -SH group of cysteine and the phenolic -OH of tyrosine are weakly acidic and will dissociate and thereby acquire negative charges at a sufficiently high pH. 

The general concept of facilitated proton transfer can be applied to RNase (520) (see Fig. 30). A basic imidazole group removes the proton... 

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. 

Considerable effort has been applied to studies of ester hydrolysis catalyzed by imidazoles (76MI40700, 80AHC(27)241). Certainly, 1-acetylimidazole can be made enzymically, probably by the sequence acetyl phosphate + coenzyme A acetylcoenzyme A+phosphate, acetyl-coenzyme A + imidazole l-acetylimidazole+coenzyme A. In addition, the imidazolyl group of histidine appears to be implicated in the mode of action of such hydrolytic enzymes as trypsin and chymotrypsin, thereby engendering further interest in the process of imidazole catalysis. The two pathways which have been found to be involved are general base catalysis and nucleophilic catalysis. In the former (Scheme 26) a basic imidazole molecule can activate a water molecule to attack the ester at the carbonyl carbon, this being followed by the usual sequence of steps as in simple hydroxide ion hydrolysis. At high imidazole concentrations the imidazole molecules may be involved directly. 

Although imidazole is too basic to form the 1-nitro derivative when treated with nitric acid-acetic anhydride (indeed, the nitrate salt forms in preference), less basic imidazoles can be Af-nitrated under these conditions. Thus, 4-nitroimidazole gives 1,4-dinitroimidazole (81UP40700, 80AHC(27)24l), and the corresponding 2- and 5-methyl-4-nitroimidazoles react in the same way. Of interest is the orientation of Af-nitration which parallels that of methylation of the anion. Whether the anion reacts in the nitronium acetate medium or whether steric factors control the site of attack is not known. 

The mechanism of CDI-mediated acylation of amines is well understood. The first step involves a partial protonation of the basic imidazole-nitrogen, protonated A-acetylimidazole has a p a of 3.6,f l leading to an activated species which is then attacked by the carboxylate. The resulting mixed anhydride extrudes carbon dioxide giving rise to A-acylimidazole which on treatment with an amine compound leads to the desired anoide (Scheme 1). An important advantage of this method over the carbodiimide method is that the byproducts carbon dioxide and imidazole are readily and quantitatively separated from the reaction product by simple washing procedures. 

The reactivity of amines (Fig. 14) is about ten times greater than that of oxygen anions of the same basicity. Imidazole and N-methylimidazole (not shown in Fig. 14) (Bender and Tumquest, 1957b), which have similar reactivities, are about 30 times more reactive than alkylamines or P3Tridines of the same basicity. Histidylhistidine (HH) shows a similar acceleration. 

TMS ethers are too labile to acid-catalysed hydrolysis to be preparatively useful, but tert-butyldimethylsilyl (TBDMS) ethers are around 10 times less susceptible to acid hydrolysis.The steric restriction about the central silicon atom presumably is the cause of the reduced reactivity, which also makes their introduction with tert-butyldimethylsilyl chloride (TBDMSCl) in pyridine selective for the primary position, but very slow. With the more basic imidazole 1 rather than 5.2 for pyridine) in DMF as base catalyst, the reaction is readier but loses its absolute selectivity for primary positions (Figure 6.25). Reaction of methyl a-o-glucopyranoside with two equivalents of TBDMS... 

High working temperatures benefit PEMFC performances because of faster electrode kinetics, higher CO tolerance and the possibility to use the residual heat for energy cogeneration [5, 6]. Among the polybenzimidazole derivatives, the most widely studied are the commercially available poly[2,2 -(m-phenylene)-5,5 -bibenzimidazole] with the acronyms w-PBI and poly(2,5-benzimidazole), AB-PBI (see Fig. 8.1). The polymers contain a basic imidazole functionality that allows the uptake of the acid protic electrolyte, which is responsible, and required, for the proton... 

Phosphoric acid, as well as other protic electrolytes with a sufficient acidity, can be adsorbed by PBI-type polymers, because of their basic imidazole structural units. The resulting PBI-protic electrolyte systems exhibit proton cOTiductivities of about one order of... 

Histidine (margin) contains another new subsituent, the basic imidazole ring (see Problem 6 of Chapter 25). In this aromatic heterocycle, one of the nitrogen atoms is hybridized as in pyridine and the other is hybridized as in pyrrole. 

Histidine (o -amino-/3-imidazolepropionic acid), the last entry in this list, contains the only weakly basic imidazole system (pK = 6.1). In many enzyme proteins it functions as a proton donor or acceptor. 

Despite general acceptance of the catalytic mechanism, the order of the microscopic steps through which the acid-base catalysis occurs remains arguable. An acid-base buffer system, with or without zinc ion, that promotes the chemical catalysis of cyclization and cleavage of phosphodiester bonds provides some insight into the mechanism. In this nonenzymatic system, acidic imidazolium (Im+) ion initiates the conversion to a pentacoordinate phosphorane intermediate then the basic imidazole (Im) catalyzes the decomposition of this intermediate to a... 

Takizawa and Sasai developed a new class of acid-base chiral organocatalysts (122 and 123) bearing an imidazole unit for aza-MBH reaction of conjugated nitroalkenes (Scheme 31.32) [46]. The acidic phenolic hydroxy groups and basic imidazole unit cooperatively activate nitroalkenes to promote the aza-MBH reaction in good yields with moderate enantioselectivities. They also investigated the substrate scope of this catalytic system under the optimized reaction conditions. Regardless of whether the aromatic substituent of imine 125 is electron-... 

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