Template effects in synthesis

and Kolchinski, A. G., Molecular template effect historical view, principles and perspectives , in Comprehensive Supramolecular Chemistry, Atwood, J. L., Davies, J. E. D., MacNicol, D. D. and Vdgtle, F. (eds), Pergamon New York, 1996, vol. 9, 1-42. 

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 Fe template. In this case, the macrobicyclic product is obtained as the Fe complex from which it is difficult to separate. 

In contrast, use of metalloid elements, such as silicon, tin antimony or boron, which can form weak covalent bonds with oxygen, nitrogen or sulfur substituents during the course of the reaction, results in templated products that may be obtained metal-free by simple hydrolysis. These covalent template reactions (the M—bond is essentially covalent in these cases) also have the advantage that the 

Ions other than metal cations may also act as templating agents, for example in the synthesis of zeolites and mesoporous silicas by templating about alkali metal cations and large quaternary ammonium ions (Section 9.2.2). Similarly the synthesis of large polyoxovanadate cages is templated by the presence of ions such as Cl or a combination of NH4+ and Cl . 

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). 

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The various aspects of template synthesis of macrocyclic compounds have been discussed in a series of monographs and reviews [1-21]. However, there is no strict definition of what can be called a template reaction. A synthetic chemist who takes advantage of the template effect in synthesis will have his own view of what constitutes a template process. It is therefore appropriate to conamence here with a general definition, which is that the template eflFect is the enhancement of chemical reaction by complementary surfaces [22, 23]. One of the first examples was connected with the discovery of the double helix structure of DNA (Figure 1-1) by Watson and Crick in 1953 [24]. The template effect is operative in its rephcation. Each chain of the DNA double helix serves as template, or mould, for the formation of the second chain. 

Another important insight from the crown ether work was the template effect in synthesis (Figure 4.7). Crown ethers are macrocycles, and the synthesis of macrocycles is often... 

The one-pot synthesis of 9 described above appears to afford only modest yields of azacrowns. One might wonder why any crown at all would be formed under non-high dilution conditions intended to yield only open-chained material. Vogtle suggests that this can be explained in terms of template, steric and entropy effects . These factors are of doubtless significance, but it is interesting to note that in the synthesis of poly-azamacrocycles, Richman and Atkins found that there was no significant template effect observed. The question of the template effect in Ihe syntheses of 9 has recently been addressed by Kulstad and Malmsten They conclude that the formation of 9 is assisted by the presence of alkali metal cations. 

It is interesting to note that although the first examples of template effects were observed in nitrogen macrocycles (see chapter 2) no template effect appears to operate in the synthesis of 72. Richman and Atkins note this in their original report . The authors replaced the sodium cation with tetramethylammonium cations and still obtained greater than 50% yield of tetra-N-tosyl-72. Shaw considered this problem and suggested that because of the bulky N-tosyl groups, .. . the loss of internal entropy on cyclization is small He offered this as an explanation for the apparent lack of a template effect in the cyclization. 

Such complexes form a precursor to a full discussion of the vast and highly topical field of self-assembly (Chapter 10). We consider them here since they resemble structurally the types of compounds discussed in Section 4.7, but unlike metal-based anion receptors the simple thermodynamic equilibrium between host, anion and complex is not the only process occurring in solution. In fact multiple equilibria are occurring covering all possible combinations of interaction between anions, cations and ligands. These systems have the appeal that the formation of particular metal coordination complexes are thus subject to thermodynamic anion templating (cf. the thermodynamic template effect in macrocycle synthesis, Section 3.9.1) and vice versa. 

Cryptophane synthesis is accomplished by one of two methods. Initial procedures employed a covalent template effect in which one CTV-derived bowl preorganised the cyclisation of the second under high dilution conditions (Scheme 6.16a). More recently, a much more straightforward procedure has been developed in which cryptophanes are formed directly in a double trimerisation reaction (Scheme 6.16b). 

Synthesis of macroheterocycles, monographs 87MI19, 87M137. Synthesis of macroheterocycles, some problems of 87YGK571. Template effect in macroheterocycle formation 86PAC1485. 

Sayari et al. [209-212] followed another path to the synthesis of mesolamellar aluminophosphates. They used AI2O3, H3PO4 and primary or tertiary amines as surfactants in aqueous media. The surfactant was found to be protonated while acting as template. Effects of synthesis parameters such as Al/P, P/amine, P/H2O ratios were studied systemically by XRD and Al and P NMR. The connectivity between Al and P was found to be dependent on the synthesis parameters. 

A tetraphenyl substituted derivative of [12]mercuracarborand-4 (40), which binds one iodide ion in its cavity due to steric hinderance, has been reported. The stereochemistry of the phenyl groups was found to depend on the mercury counteranion used during the synthesis (106). This observation provided yet further evidence for a direct anion templating effect in mercuracarborane syntheses. Most recently, the C—Hg—C link in this type of host has been replaced with a B—Hg—B link, which alters the electron demands of the mercury centers (reducing their electron deficiency) and apparently switches off anion complexation (107). 

Biernat and Luboch have shown a definite template effect in the synthesis of tetra-N-tosylaza-18-crown-6 by the following reaction sequence (Biernat and Luboch, 1984). 

A further application of the metal-template effect in the ortho-regioselective acylation of phenols is represented by the direct synthesis of salicyloyl chloride and derivatives by the reaction of bromomagnesium phenolates 4 with phosgene. The reaction affords the unstable salicyloyl chloride-magnesium complexes 5 by a pathway similar to the mechanism depicted in Scheme 5.2. These intermediates can be in situ converted into the corresponding acids 6 (Scheme 5.3), esters, amides, or ketones by reaction with suitable reagents. 

Another celebrated example of the template effect is the synthesis of crown ethers by Pedersen [11], but it was Busch who first intentionally used templates in synthesis and who first articulated the concept of the template effect in the 1960s [12]. Busch used the reaction of a nickel(Il) dithiolate complex 7 with l,2-bis(bromomethyl)benzene 8 to illustrate his ideas (Scheme 1-3) [13]. Once one end of the l,2-bis(bromomethyl)ben-zene has reacted with the nickel complex, the nickel template induces the reactive ends of the intermediate 9 to come into close proximity and favors cyclization. The metal template allows the synthesis of a metallated macrocycle 10 the free ligand cannot be prepared by the reaction of l,2-bis(bromomethyl)benzene with the unbound thiol (in the absence of a template other cyclic and acyclic products are formed). 

The first proposal that a template effect is operative in such cases has been made by Greene, although a perusal of Pederson s original paper suggests that its seminal crown ether synthesis also relies on this effect. Cf. (a) C. J. Pedersen, J. Am. Chem. Soc. 1967,89, 7017-7036 (b) R. N. Greene, Tetrahedron Lett. 1972, 1793-1796. For a comprehensive treatise of the template effect in crown ether syntheses see [4] and literature cited therein. 

An early demonstration of the template effect in the synthesis of macrocyclic ligands was the metal-ion-controlled cyclic condensation of 2,6-diacetylpyridine with 3,3 -diaminodipropylamine to give complexes of the 14-membered N4 ring (118), usually abbreviated (Me2pyo[14]triene i ). Effective template ions include Ni", Co" and Cu". Well-characterized iron complexes have not been... 

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