Hydrazone, macrocyclic

Cousins, G. R. L. Poulsen, S.-A. Sanders, J. K. M. Dynamic combinatorial libraries of pseudo-peptide hydrazone macrocycles. Chem. Commun. 1999, 1575-1576. 

Figure 6-13. The templated formation of a hydrazone macrocycle. This ligand contains five nitrogen donor atoms and was designed to investigate the properties of metal complexes containing a pentagonal planar donor set. In practice, the complexes of these ligands usually acquire one or two axial ligands to give six- or seven-co-ordinate complexes.

Rifamycin SV (133, Fig. 23) is a naturally occurring macrocycle isolated from Nocardia mediterranei by Senti, Greco and Ballotta in 1959. It shows a high in vitro antibiotic activity through inhibition of DNA-dependent RNA polymerase, but bioavailability is low due to its poor water solubility. The semisynthetic derivative rifampicin (135) displays markedly higher water solubility and in vivo activity. We chose 3-formylrifamycin (134) as model macrocycle for the possibility of binding it to solid phase by hydrazone bond formation in a manner similar to rifampicin (Fig. 24). 

Benzaldehyde monohydrazone, 2,3-butanedione monohydrazone and related hydrazones have been found to react with some ketones in the presence of nickel(II), affording compounds which, in turn, condense with either en or propane-1,2-diamine giving macrocyclic complexes (Scheme 49).2656 2657... 

A variety of macrocyclic complexes which have adjacent nitrogen atoms (cyclic hydrazines, hydrazones or diazines) are formed by condensations of hydrazine, substituted hydrazines or hydrazones with carbonyl compounds. The reactions parallel in diversity those of amines, but are often more facile since the reacting NH2 groups is generally not coordinated and the electrophile is thus not in competition with the metal ion. The resulting macrocycles may be capable of coordination isomerism, since either of the adjacent nitrogen atoms can act as donor atom. 

Condensation of a monocarbonyl compound with a dihydrazone initially yields a macrocycle with a tetraaza six-membered chelate ring, e.g. (21 Scheme 8) or (23 Scheme 9), but this can isomerize to give a triaza five-membered chelate ring, as for (27 Scheme 10), where cyclization is by a reaction subsequent to the hydrazone/carbonyl condensation,21 or for the isomeric pair of compounds (25) and (26) of Scheme 9. Compounds with triaza (28) and tetraaza (22) seven-membered chelate rings have also been prepared.22 Tetradentate and pentadentate aza macrocycles are formed by condensations of 2,6-diacetylpyridine with hydrazine (29) or with dihydrazines (30).21... 

The reaction of the nickel(II) perchlorate complex (89) with acetone and related ketones yields simple hydrazone complexes rather than macrocyclic complexes resulting from a Curtis-type reaction. Acetylacetone also fails to bridge the bis(hydrazine) and instead yields a pyrazole derivative (Scheme 37).197 198 In contrast to this result, 1,4-dihydrazinophthalazine undergoes a template reaction with 2,2-dimethoxypropane, a source of acetone, in the presence of nickel(II) fluoroborate and a trace of fluoroboric acid (Scheme 38).199... 

The co-ordination chemistry of macrocyclic ligands containing imine or hydrazone groups has been widely studied and, as expected, the presence of the imine functionality in the ring confers unusual redox properties to the complexes. 

In the initial station 35, the walker is connected to the track through a hydrazone 1-A and a disulfide (for a hydrazone-disulfide macrocycle and its dynamic covalent ring-opening under acidic and basic conditions, see [47]) 2-B bond, while the placeholder HSCH2CH2COOCH3 (the source is the corresponding disulfide) is connected through a disulfide bond 4-C to the other thiol group of the track... 

Fig. 15 (a) Formation of a polymer (53 or 55) on reaction of a pyridine-hydrazone-pyridine derived dialdehyde 50 with 1 equiv. of diamine (51 or 52), and its reversible conversion into a macrocycle (54 or 56) in the presence of the appropriate metal ions (b) stylized representation of the polymer/macrocycle reversible switch... 

Oxidative versus Nonoxidative Conversion of a Macrocyclic Tosyl Hydrazone... 

When the reaction of the hydrazones 304 was carried out in dioxane instead of acetonitrile the macrocyclic compounds 310-313 were obtained instead of compounds 305 [189],... 

Figure 9. Bis(hydrazone)/bis(azine) tautomerism of a 14-membered macrocycle upon complexation of metal salts.

A wide range of nucleophiles has been shown to attack coordinated carbonyl compounds. The products depend upon the fate of the tetrahedral hydroxy intermediate formed. In the reaction of carbonyl compounds and amines the loss of water results in the formation of imines, and this methodology has widespread synthetic application. A novel sexidentate macrocyclic ligand (26) has been prepared by template methods. The formation of the hydrazone from hydrazine and... 

---