Operation of the Template Effect

Many of the crown ether syntheses with which we are concerned in this book are one form or another of the Williamson ether synthesis. Although the simplest example of such a reaction would involve an co-haloethylene glycol oligomer which undergoes intramolecular cyclization, it is more common for two new bonds to be formed in crown syntheses. An early example of the formation of a crown by a double-Williamson can be found in Dale s synthesis of 18-crown-6. The rather obvious chemical steps are shown in Eq. (2.1). 

Tire first C—O bond formation is probably not influenced strongly by the presence of a templating cation. Since it is not crucial for one end of the chain to meet the other rather than reacting with a different molecule, it is not necessary to superimpose either a template or dilution condition on the reaction to prejudice the statistics. In the second step, however, such a prejudicial condition is required. This is available in the form of an 

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Newkome and co-workers have demonstrated the operation of a template effect in the formation of a pyrido-ester-crown. In the reaction shown in Eq. (2.8), they treated 2-clTloronicotinoyl cliloride with either the disodium or dipotassium salt of pentaethylene glycol. TJie two reactions were conducted under identical conditions except for the presence of sodium vs. potassium cations. Since the product is a six-oxygen macrocycle, its formation would be expected to be favored by K" rather than Na" counter ions for the glycolate. In fact, the yields of crown-lactone were 30% and 48% respectively when Na" and K" were the templating cations. 

Higher yields are obtained when the reaction rate is increased by using dipolar aprotic solvents, with the possible operation of a template effect (77) of a precomplexed cation (64). Again, this shows that high dilution techniques are not necessary in many cases, but they would certainly increase the yields. Synthesis of polyether-sulfides are generally facilitated by the greater reactivity of — S compared to — O- in nucleophilic displacement reactions. However, the yield is low when path b) is followed (74). 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

The operation of the mismatch effects may be seen to best advantage when a range of products is possible from a single reactant or set of reactants. The reaction of ethylene oxide with metal salts results in the formation of crown ethers (Fig. 6-30). Obviously, a whole range of different cyclic oligomers and acyclic polymers could be formed from ethylene oxide. If we specifically wanted to obtain 18-crown-6, with a hole size of about 1.4 A, we would expect to use a potassium ion as template (r = 1.38 A). In fact, 18-crown-6 is obtained in good yield from the reaction of ethylene oxide with potassium tetra-fluoroboratc. In contrast, if we wanted 12-crown-4, with a hole size of about 0.8 A, it... 

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. 

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. 

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. 

Myriad polydentate aza-macrocycles have been reported 41. The extent of the subject forces limitation of this discussion to only macrocycles containing a pyridine or dipyridine subunit. Most of these coronands have been synthesized by a SchifF base condensation of an aldehyde or ketone with a hfc-primary amine in the presence of a metal ion. The metal ion acts as a template, resulting in dramatic increases in yield of the desired cyclic product over linear polymerization products42 46. Lindoy and Busch45 have described this effect in two ways, kinetic and thermodynamic. If the metal ion controls the steric course of a series of stepwise reactions, the template effect is considered to be kinetic. If the metal ion influences an equilibrium in an organic reaction sequence by coordination with one of the reactants, the template effect is termed thermodynamic. It is the kinetic effect that is believed to be operative in most metal ion-assisted (in situ) syntheses of... 

Dial monoesters. l,n-Diacetates (n = 2,3,4) are converted to the monoesters by transesterification to methanol in the presence of the tin oxide. The catalytic effect ari.ses from cooperation of two different tin metal atoms held in proximity. For long-chain diacetates (n > 5) the selectivity vanishes because the template effect cannot operate. 

Busch classified templates as thermodynamic [13a, 27] or kinetic [ 13b, 28], A thermodynamic template shifts the position of equilibrium of a reversible reaction by preferentially binding one product. Kinetic templates operate on irreversible reactions by stabilizing the main transition states leading to the desired product. Kinetic templates almost invariably bind the product more strongly than the starting material, so they also favor the formation of the product thermodynamically. Conversely, thermodynamic templates are likely to accelerate formation of the product by transition state stabilization, so classification of the observed effect depends crucially on the reaction conditions and time scale. 

Most of the templates diseussed in this chapter are kinetic templates. Some of the early examples of metal cation templated macrocyclization studied by Curtis and Busch [7,9] (Schemes 1-1 and 1-2) are thought to operate under thermodynamie eontrol. The clearest evidence for a thermodynamic template effect comes when the template-free product is not stable under the reaction conditions. For example, treatment of 1,2-dicyanoben-zene 11 with boron trichloride or uranyl chloride results in the formation of subphthalo-... 

In recent years a more extensive exploration of other non-covalent interactions has led to the development of new templates. In principle, almost all design principles operative in the field of supramolecular chemistry [2-4] can be used to generate the template effect. They range from metal-ligand coordinate interactions - the strongest of the non-covalent interactions - to weak coulombic interactions. 

It is not clear exactly when the association illustrated above actually takes place. It is certainly involved by the final ring closure stage, but it seems reasonable to assume that there is some cation-glyme type interaction taking place from the instant of solution. The fact that wrapping occurs in such a way that the two ends of the molecule are held in proximity, allows the reaction to be conducted at much higher concentrations than might otherwise be practical. Tlie evidence for the operation of such a template effect is presented and considered below. 

A range of direct syntheses have been performed under conditions of moderate to low dilution but have still led to isolation of the required cyclic product in reasonable to high yields. In some of these so-called direct syntheses, ions such as sodium or potassium were present in the reaction solution. It has often been suspected (and has been documented for a number of systems) that these ions may also undertake a template role. In this manner, such syntheses may fall between the extreme direct and in situ categories mentioned at the beginning of this chapter. There is little doubt that such an effect is the source of the larger-than-expected yields obtained in some syntheses of this type. Nevertheless, this is not always the case and there are further mechanisms for assisting cyclization which may operate for particular systems. For such systems, special circumstances usually appear to be present. Examples of this latter type are discussed later in this chapter. 

Examples of the operation of both types of effect have been documented. Nevertheless, while these effects are useful concepts, as mentioned previously, very often the role of the metal ion in a given in situ reaction may be quite complex and, for instance, involve aspects of both effects. As well, the metal may play less obvious roles in such processes. For example, it may mask or activate individual functional groups or influence the reaction in other ways not directly related to the more readily defined steric influences inherent in both template effects. 

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