Metal-ion-templated synthesis

The metal-ion-templated synthesis of a peraza macrocycle was reported more than 30 years ago. The macrocycle resulted from the reaction of tris(l,2-diaminoethane)nickel(ll) perchlorate with acetone to form a 14-membered macrocyclic ligand-Ni(ll) complex (5) (Curtis, 1960 Curtis and House, 1961). Numerous examples of this and other metal-ion-templated reactions have been investigated in the intervening years (Black and Hartshorn, 1972-1973 Busch, 1964 Curtis, 1968). Slightly earlier, the methyl-substituted peroxa-... 

This approach can arguably be traced back to the nineteenth century, and the studies of Emil Fischer on carbohydrates and of Werner on coordination complexes. When Watson and Crick discovered the DNA double hehx in 1953 they reahzed immediately that its repHcation involved a templated synthesis [11]. In retrospect, it is dear that the metal-ion-templated synthesis had been achieved as early as 1926 when Seidel reacted 2-aminobenzaldehyde with ZnCh [12]. An imine-based macrocycle bound to zinc was formed, but was not identified until much later (Scheme 1.1a) [13]. A few years later, Fe(ll) phthalocyanine was formed... 

Gotor et al. have used imine exchange for the metal-ion-templated synthesis of N-macroheterocycles from (K,l )-cyclohexane-l,2-diamine 49 and pyridine-1,2-di-carboxaldehyde 50. In the absence of template a mixture of macrocycles ranging from the [2 -i- 2] to [6 -i- 6] products is observed in MeOH. However, the main product depended on the added cation addition of Ba led to the [2 + 2] cyclic imine 51, whereas addition of Cd resulted in almost quantitative formation of the cyclic [3 -i- 3] derivative 52 (Scheme 3.11). 

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 ... 

The application of Schiff base chemistry to the synthesis of heterophanes possessing diverse subunits has been reviewed in part (82MI52202, B-79MI52201). An example of this procedure is the treatment of (19) with 2,3-diaminopyridine, with or without metal ion templation, to give (20) as an isomeric mixture (75MI52200). 

The highest flexibility for a variation of the functional group and the chains X and Y (i.e. the size of the rim of the lamp shade) will be realiad when the synthesis of 3 is convergent and modular (Scheme 1). Amide bonds can easily be formed in macrocyclizations [13], therefore macrocyclic diamines 7 and diacyl dichlorides 8 had to be prepared. For the synthesis of macrocyclic diamines 7, also a large number of reactions are known. However, in this case a reduction of a macrocyclic diamide could not be achieved [11]. Therefore, another route was used the formation of macrocyclic diimines 6 (bis-Schiff bases) followed by NaBH4 reduction to the macrocyclic diamines 7. This approach has the advantage that for the construction of macrocyclic diimines 6, the metal ion template effect [14] may be exploited. 

The synthetic strategy used for the construction of concave pyridine bislactams 3 (Scheme 1) can also be applied to other concave bases. When instead of a pyridine-2,6-dialdehyde 4, l,10-phenanthroline-2,9-dicarbaldehyde (9) was used in a metal ion template directed synthesis of macrocyclic diimines, after reduction, also macrocyclic 1,10-phenanthroline diamines 10 could be obtained in good yields. Here too, the crude diamines 10 were used in the next reaction step. Bridging of 10 with diacyl dichlorides 8 gave concave 1,10-phenanthroline bislactams 11. Scheme 2 summarizes the synthesis and lists the synthesized bimacrocycles 11 [18]. 

The use of metal ions as kinetic synthetic templates is extremely widespread, and is an excellent way in which to bring about the organisation of a number of reacting components in order to direct the geometry of the product. Because some metal ions, such as the transition metals, often have preferred coordination geometries (e.g. tetrahedral, square planar, octahedral etc), changes in metal ion may have a profound effect on the nature of the templated product. Metal-ion-templated syntheses may be classified more generally as examples of self-assembly with covalent postmodification. For example, the synthesis of the artificial siderophore 10.2 is effected by the use of an octahedral Fe3+ template.8 In this case, the macrobicyclic product is obtained as the Fe3+ complex from which it is difficult to separate. 

In contrast, the thermodynamic template effect in macrocycle synthesis is a process by which the presence of a metal ion template stabilises thermodynamically, or removes (e.g. by precipitation) one particular (usually cyclic) product from an equilibrating mixture, driving the equilibrium towards this thermodynamic minimum. This leads us to the conclusion that any thermodynamically stabilising influence may drive an equilibrium mixture towards a particular product according to Le Chatalier s Principle (in an equilibrating situation, the system will react to diminish the effects of externally applied changes in conditions). 

The variety of macrocycles that have already been prepared by template reactions (see Sections III and VI) suggest that, in designing a macrocycle synthesis to meet a future need, the use of a metal ion template should not be ignored. 

Quadridentate ligands such as (237) are prepared by what must be one of the first (1944) uses of metal ion template ligand synthesis (Figure 5). ... 

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." ... 

The use of the metal ion template procedure for producing topologically sophisticated structures is well illustrated by the synthesis of composite molecular knots such as 105 and 106 (Figure 6.41) in this case two topological diasteromers are... 

Chen H, Olmstead MM, Albright RL, Devenyi J, Fish RH (1997) Metal-ion-templated polymers Synthesis and structure of N-(4-vinylbenzyl)- l,4,7-triazacyclononanezinc(II) complexes, their copolymeiization with divinylbenzene, and metal-ion selectivity studies of the demetalated resins - evidence for a sandwich complex in the polymer matrix. Angew Chem Int Ed Engl 36 642... 

Although the term dynamical combinatorial chemistry has only been coined at the end of the last century, the template effect has been used for a much longer time. Some of the best known macrocyclic ligands such as cyclam probably would not have been known so well if their synthesis had not implied the template effect. Probably the first example of a metal ion template for the formation of imino-macrocycles N. F. Curtis, D. A. House, Structure of some aliphatic Schiff-base complexes of nickel (II) and copper (II), Chem. and End., 1961, 42, 1708-1709. 

Lo, H.C. Chen, H. Fish, R.H. Metal-ion-templated polymers, 3. Synthesis of a [ mono-V-(4-vinylbenzyl)-l,4,7-triazacyclononane 2Hg](OT02 sandwich complex, polymerization of this monomer with divinylbenzene, and Hg ion selectivity studies with the demetallated resin. Eur. J. Inorg. Chem. 2001, 2217-2220. 

Table 11-1. Metal ion templates in the synthesis of homoleptic and mixed donor atoms macrocycles. 

Generally, the kind of macrocycle that can be assembled using metal ion templates depends on the ability of the corresponding metal ion to react with specific donor atoms. Thus the metal ions of the elements of Groups la and Ila, which generally react with donor ether oxygen atoms by an ion-dipole interaction (exceptions are magnesium and in some cases lithium and calcium), are the most appropriate templates for the synthesis of crown ethers. 

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