Macrocyclic syntheses Schiff base condensation

The standard synthesis for cyclam was developed by Barefield and Wagner in 1976.29 They used similar starting materials to the van Alphen procedure but the cyclisation yield is improved through the use of a nickel (II) template. Glyoxal completes the macrocycle by a Schiff base condensation reaction. The resulting imine functionalities are reduced with sodium borohydride to leave the complexed macrocycle. The metal ion is then removed by reaction with cyanide and the free ligand extracted with chloroform (Scheme 3.19). Yields are typically in the region of 60%. 

Macrocycles that are saturated or have double bonds in only one part of the ring can be made independently or can be made by template synthesis96 where the presence of a metal ion controls the ligand synthesis. An important route is the Schiff base condensation reaction (eq. 9-3),... 

The synthesis of a tripyrrane containing porphyrinogen-like macrocycle was reported by Sessler et al. in 1987 [59]. As discussed in the previous section (4.3), the first representative of this new class of expanded porphyrins (e.g. 115) was formed by the Schiff base condensation between a diformyltripyrrane 114 and... 

Metal ion template mediation in macrocyclic synthesis has been a part of the field since its inception, its importance having been realized early in the development of this area. Two specific roles for the metal ion in template reactions have been proposed. These are, in turn, kinetic and thermodynamic in origin." In the kinetic template effect, the arrangement of ligands already coordinated to the metal ion provides control in a subsequent condensation during which the macrocycle is formed. The thermodynamic effect serves to promote stabilization of a structure which would not be favored in the absence of a metal ion. Schiff base condensations tend to be dependent on this latter type of template effect. Some of the more routine and general synthetic procedures will be described here. A more in-depth treatment can be found in a review by Curtis, with particular emphasis on general methods as well as modifications of preformed macrocycles." ... 

In some of the earliest experiments involving in situ macrocyclic ligand synthesis, it was shown that the reaction of 2,6-diacetylpyridine with certain polyamines in the presence of metal ions leads to the preparation of new macrocyclic complexes. As is often the case with Schiff-base condensations of the type, the addition of a small amount of acid catalyzes the reaction. Thus treatment of 2,6-diacetylpyridine with 3,3 -diaminodipropylamine [A-(3-aminopropyl)-l,3-pro-panediamine] in the presence of nickel(II) leads to the isolation of nickel complexes of the macrocyclic ligand (Me2-Pyo[14] trieneN4). " ... 

Macrocyclic ligands with all-nitrogen donor sets are much studied and both tin and, in particular, lead are popular subjects in coordination studies of these ligands. Examples of such ligands used to complex tin include (66) and (67), prepared by Schiff-base condensations. The complex (68) was isolated from an attempted template synthesis of a macrocycle in which the condensation of the component parts of the ligand was incomplete. 

The macrocycle L1 [structure (1)] having an inner ring of 18-member atoms has been synthesized (as its metal complexes) by the use of large metal ions as templates for the [2 + 2] Schiff base condensation of two molecules of 2,6-pyridinedicarboxaldehyde with two molecules of 1,2-benzenediamine.2 The template action of the metal ion is evidenced by the observation that only oils or gums are obtained in metal-free reactions. When the Ba2+ ion (ionic diameter 2.84 A)2 is employed as template, the product complex has a 2 1 ligand metal stoichiometry (Part A), whereas, for the Ca2+, Sr2 or Pb2+ ions (ionic diameter 2.24, 2.52, and 2.58 A, respectively), the products have a 1 1 metal-to-ligand stoichiometry. Smaller metal ions are ineffective as templates for the synthesis of L1. 

Thiophene aldehydes have been used earlier for the construction of macrocyclic Schiff bases <81CC628>. An example is the synthesis of the macrocyclic tetraimine Schiff base (479) from thiophene 2,5-dicarbaldehyde and l,3-diamino-2-hydroxypropane <87JCS(D)219>. The synthesis does not involve use of a metal template. An interesting extension is the synthesis of the macrocyclic Schiff base (481) containing four thiophene units from the dialdehyde (480) <89BCJ1346>. The condensation is achieved at room temperature in CHCI3. 

Schiff base macrocyclic complexes of lanthanides have been prepared by a metal-template condensation of a diamine and 2,6-diacetyl or 2,6-diformyl derivative of pyridine or p-cresol [74]. The yield of these complexes depends on the radius of the metal ion and the donor ability of the counterion [75]. The acetate anion gave high yields while chloride and perchlorate anions gave poor yields [76]. In general the template synthesis... 

The synthesis of a variety of dibenzodiaza-crowns from salicylaldehyde or its derivatives has been reported by Lindoy and coworkers (Adam et al., 1981a, 1981b Armstrong and Lindoy, 1975 Armstrong et al., 1977 Baldwin et al., 1987 Grimsley et al., 1977). The macrocycles were obtained via the corresponding diimines (Schiff bases), which were obtained by condensations of the appropriate dialdehydes and diamines as shown (method U-14). It was... 

The vast majority of the macrocyclic complexes of the lanthanide(III), yttrium(III) and uranyl ions obtained so far by metal-templated synthesis are of the Schiff-base type even the few known examples of simple polyamine complexes actually result from the cyclic condensation of a diamine with a (modified) carbonyl precursor. In general, the metal-templated synthesis is facilitated by the presence of oxygen-donor anions, such as nitrate, acetate, or trifluoromethylsulfonate lanthanide(III) thiocyanates have also been successfully used. With a few exceptions, the outcome of the synthesis appears to be independent of the order of addition of the reactants. No deliberate attempts have been made to investigate the detailed mechanism of these metal-templated cyclic condensation reactions. 

The reactions of nickel(II) and copper(II) amino complexes with acetone have been studied extensively. Condensation reactions of coordinated amines with acetone proceed relatively easily, but further reactions follow. The initially formed complexes, which contain Schiff bases, undergo intramolecular rearrangements to form complexes containing macrocyclic ligands. Scheme 11.15. This reaction is the basis for the synthesis of a large number of macrocyclic ligands. 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

---