Imidazole reactivity

Hydroxide versus imidazole reactivity in displacement reactions at the carbonyl... 

Imidazole reactivity was fully covered in CHEC-I, and only a brief summary is included here. The neutral molecule is Jt-excessive, being subject to electrophilic attack at N-3, less readily at C-4(5), and seldom at C-2. In benzimidazole electrophiles preferentially attack N-3 and the benzene ring carbons. Nucleophilic substitution reactions usually require some form of electron withdrawal elsewhere in the system, with displacements of groups at C-2 often favored. Imidazolium species are naturally more susceptible to nucleophilic attack, and they only undergo electrophilic substitutions with difficulty (e.g. nitration, sulfonation). The corresponding imidazole anions, when they can form, are highly reactive towards electrophiles. 

Selenium heterocycles receive far less mention in the literature than do such homologs as oxazole, thiazole, or imidazole. In fact, preparative methods of selenium heterocycles are much more limited than for the other series, mainly because of manipulatory difficulties arising from the toxicity of selenium (hydrogen selenide is even more toxic) that can produce severe damage to the skin, lungs, kidneys, and eyes. Another source of difficulty is the reactivity of the heterocycle itself, which can easily undergo fission, depending on the reaction medium and the nature of the substituents. 

The bimodal profile observed at low catalyst concentration has been explained by a combination of two light generating reactive intermediates in equihbrium with a third dark reaction intermediate which serves as a way station or delay in the chemiexcitation processes. Possible candidates for the three intermediates include those shown as "pooled intermediates". At high catalyst concentration or in imidazole-buffered aqueous-based solvent, the series of intermediates rapidly attain equihbrium and behave kineticaHy as a single kinetic entity, ie, as pooled intermediates (71). Under these latter conditions, the time—intensity profile (Fig. 2) displays the single maximum as a biexponential rise and fall of the intensity which is readily modeled as a typical irreversible, consecutive, unimolecular process ... 

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. 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

Diazo coupling is expected to occur only with highly reactive systems, and experiment bears this out. Diazonium ions couple with the anions of N-unsubstituted imidazoles at the 2-position (e.g. 125 yields 126) and with indazoles (127) in the 3-position. In general, other azoles react only when they contain an amino, hydroxyl, or potential hydroxyl group, e.g. the 4-hydroxypyrazole (128), the triazolinone (129) and the thiazolidinedione (130) (all these reactions occur on the corresponding anions). 

The 2-position in imidazoles, thiazoles and oxazoles is electron deficient, and substituents in the 2-position (332) generally show the same reactivity as a- or y-substituents on pyridines. 2-Substituents in azoliums of this type, including 1,3-dithiolyliums, are highly... 

Substituents in the 4-position of these compounds are also a to a multiply-bonded nitrogen atom, but because of bond fixation they are relatively little influenced by this nitrogen atom even when it is quaternized (333). This is similar to the situation for 3-substituents in isoquinolines, cf. Chapter 2.02. In general, substituents in the 4- and 5-positions of imidazoles, thiazoles and oxazoles show much the same reactivity of the same substituents on benzeneoid compounds (but see Section 4.02.3.9.1). 

Ac-Imidazole, PtCl2(C2H4), 23°, 0.5-144 h, 51-87% yield. Platinum(II) acts as a template to catalyze the acetylation of the pyridinyl alcohol, C5H4N(CH2) CH20H. Normally acylimidazoles are not very reactive acy-lating agents with alcohols. 

Two new sections on the protection for indoles, imidazoles, and pyrroles, and protection for the amide — NH are included. They are separated from the regular amines because their chemical properties are sufficienth different to affect the chemistry of protection and deprotection. The Reactivity Charts in Chapter 8 are identical to those in the first edition. The chart number appears beside the name of each protective group when it is first discussed. 

By using imidazole catalysis, it is possible to get a better understanding of the active forms that water takes in enzymatic processes Thus, at low concentrations m the presence of an enzyme, the water may not be fully hydrogen bonded and therefore more reactive [61] The rate of hydrolysis of p-nitrotrifluoroacetanilide in acetonitrile shows a strong dependence on water concentration at low levels in the presence of imidazole The imidazolium complex is the approximate transition state (equation 60)... 

Another commercially available imidazole scaffold upon which a number of other functionalized cations have been constructed is l-(3-aminopropyl)imidazole. The appended amino group in this material is a versatile reactive site that lends itself to conversion into a variety of derivative functionalities (Scheme 2.3-2). 

The reactivity of 4-phenylimidazo[5,l-c][l,2,4]triazin-8-carboxamide 485 toward hydrazine has been studied [82JCS(P 1) 1811], whereby pyrazol-4-ylidenehydrazino)imidazole-4-carboxamide 486 was formed (Scheme 102). 

Most electrophilic substitutions in benzimidazole (31 R = H) occur primarily in the 5-position. In multiple bromination the order followed, 5 > 7 > 6,4 > 2, parallels molecular orbital calculations. In benzimidazole itself the 4(7)- and 5(6)-positions are tautomerically equivalent. Fusion of a benzene ring deactivates C-2 to electrophilic attack to such an extent that it is around 5000 times less reactive than the 2-position of imidazole. Strong electron donors at C-5 direct halogenation to the 4-position, whereas electron-withdrawing groups favor C-4 or C-6 substitution (84MI21). 

Bromination follows the same general pattern as chlorination [78JCS(P2)865] (Scheme 22). A comprehensive kinetic study has demonstrated that benzo derivatives are much less reactive than imidazole itself. Partial rate factors for the bromination of 31 (R = H) were 5-bromination, 6.37 x I07 7-bromination, 2.88 x 106. For the 7-bromination of 6-bromobenzimidazole the factor was also 2.88 x 106, confirming that... 

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