Bisimidazoles

The next subject is to examine bisimidazole ligands in which two imidazole rings are connected by a covalent bond. Thus, we have prepared a number of bisimidazole derivatives as listed in 38-44 according to the synthetic methods of Breslow 18)... 

The results are shown in Table 4. In CTAB micelles, the complexes of the lipophilic bisimidazole ligands, 38c, 38d, 39, and 44 are much more reactive than those of the lipophilic monoimidazole ligands, 29 and 36, and the rate enhancement by the 38c-Zn2+ ion is 21500 fold as compared to the rate in CTAB alone. 

However, the kc values of monoimidazole complexes are larger than those of bisimidazole complexes although each of the former complexes have two hydroxyl groups so that statistical correction by factor 2 may be necessary for comparison. 

As described previously, lipophilic monoimidazole ligands form 2 1 complexes with the Zn2 + ion (n = 2 in Scheme 2) as active catalysts except for some sterically hindered ligands (Table 3, 5, 7), and bisimidazole ligands form 1 1 complexes (n = 1 in Scheme 2, Table 5). In this chiral system, the latter 1 1 complex accords with kinetic analyses for both L-47 and L,L-49 ligands as shown in Fig. 12 and Table 11. These conclusions seem to be reasonable since monoimidazole derivatives have only one imidazole nitrogen, while the other bisimidazole and chiral ligands have more than two nitrogen atoms which can effectively coordinate to the Zn2 + ion. 

Several model systems related to metalloenzymes such as carboxypeptidase and carbonic anhydrase have been reviewed. Breslow contributed a great deal to this field. He showed how to design precise geometries of bis- or trisimidazole derivatives as in natural enzymes. He was able to synthesize a modified cyclodextrin having both a catalytic metal ion moiety and a substrate binding cavity (26). Murakami prepared a novel macrocyclic bisimidazole compound which has also a substrate binding cavity and imidazole ligands for metal ion complexation. Yet the catalytic activities of these model systems are by no means enzymic. 

The redox system consists of pyrene or 9,10-phenanthrene quinone as oxidant and an alkyl ester of 3,3, 3"-nitrilopropionic acid as reductant.121 This system deactivates oxidation by bisimidazole when irradiated at 380-550nm, since the quinone is reduced to hydroquinone and thus stabilizing the previously generated dye image.122,123... 

Formation of angular-substituted dimethylene-bisimidazole derivatives 386 has been achieved by reaction of the parent bisimidazole 385 with either l-bromo-2-chloroethane or 1,2-dibromoethane (Equation 102) <1997CJC28>. Reaction of the bisimidazole with a bis-chloroiminium salt has also been used to generate a related core structure <2006T731>. 

An interesting bisimidazole adduct has been reported by Breslow et al. (12). The imidazole derivative (3) was prepared from the capped disulfonate (2) originally made by Tabushi et al. (97). The cycloamylose (3) was used as... 

Two iron(III) complexes of unsymmetrically substituted tris(2-pyridylmethyl)amine (tpa, (58)) tripodal ligands, [Fe(59)Cl3] and [Fe(60)Cl3], have been synthesized and structurally characterized." The crystal structure, magnetic susceptibility, Mossbauer spectroscopy and photomagnetism of the iron(II) complex [Fe(bpmae)(2,2 -bisimidazole)](C104)2 2F[20, where bpmae is the unsymmetrical tripod N CH2(2-pyridyl)2 (CH2CH2NH2), have been established." ... 

At around the same time, Breslow and co-workers described bifunctional cyclo-dextrin-based catalysts that were capable of hydrolysis of a bound phosphate ester [88]. In later studies, an AD isomer (Scheme 4.9) of a P-cyclodextrin bisimidazole catalyst turned out to be the fastest catalyst for enolization of p-tert-butylacetophe-none (Scheme 4.9) [89]. Here, the extra binding is provided by the P-cyclodextrin... 

The Ni(II) complex of a 16-membered macrocycle, 2,7-dimethyl-3,6 -(1,1 - (2,2 - biimidazole) -1,3,6,8,11,14 - hexaazacyclohexadeca -1,7 -diene, 22, was synthesized by Schiff base condensation of the Ni(II)-triethylenetetramine complex and 1,1 -diacetyl-2,2 -bisimidazole (29). The Ni(II) complex formed square-planar geometry with iodide or perchlorate anions and an octahedral structure with chloro or bromo ligands. 

Breslow, R., Doherty, J.B., Guillot, G. and Lipsey, C. (1978) p-Cyclodextrinyl-bisimidazole, a model for ribonuclease. 

In the series of the IV-methyl-2,2,-bisimidazole (MBI) complexes R2SnX2 (MBI)130 (R = Me, Et, Bu, Ph X = Cl, Br) the butyl derivatives were the most active against KB (oral epidermoid human carcinoma) cell line. The nature of the halogen bound to the metal atom does not seem to have any influence on activity, except for the butyl complexes, for which the chloride is much more active (ID50 = 0.023 pgml-1), than bromide (ID50 = 0.170 pgml-1). 

Either the C -capped or the O -capped material can be heated with an excess of imidazole to produce /3-cyclodextrin bisimidazole (VII). On the basis of the above discussion, we believe that the material produced from the C-capped compound is a 6A,6C and 6A,6D isomeric mixture, while that produced from the O-capped compound is largely the 6A,6D isomer. As it turns out, we have not detected yet significant differences between these two materials as catalysts in our kinetic and product studies. 

With the existence of this new cyclodextrin lock, it was again important to select a key to fit it and to serve as substrate. For this we wanted a cyclic phosphate ester that this cyclodextrin bisimidazole could hydrolyze. The enzyme ribonuclease hydrolyzes cyclic phosphates as the second step in the hydrolysis of RNA, and cyclic phosphates are used as assay substrates for the enzyme. The advantage to us of such a substrate was that the geometry of the transition state would be relatively well-defined, so that it should be possible to design congruence between the catalyst and the transition state. Molecular model building indicated that a possible substrate was the cyclic phosphate derived from 4-f-butylcatechol (VIII). Indeed, the cyclodextrin bisimidazole (VII) is a catalyst for the cleavage of cyclic phosphate (VIII) (14). 

We have done a little lock and key chemistry with cyclodextrin imidazoles. For instance, Bovy (18) has prepared the cyclic phosphate derived from naphthalenediol (XI) and from a tetralindiol (XII). Both of these are hydrolyzed by our 6A,6D cyclodextrin bisimidazole (VII) but these substrates are hydrolyzed less effectively than is the f-butylcatechol cyclic phosphate (VIII). In XI and XII, the phosphorus atom will lie on the axis of the cavity, rather than displaced to one side as with t-butylcatechol, and in particular the attacking water mole-... 

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