Thermodynamic templation

Two possible roles for the metal ion in a template reaction have been delineated (Thompson Busch, 1964). First, the metal ion may sequester the cyclic product from an equilibrium mixture such as, for example, between products and reactants. In this manner the formation of the macrocycle is promoted as its metal complex. The metal ion is thus instrumental in shifting the position of an equilibrium - such a process has been termed a thermodynamic template effect. Secondly, the metal ion may direct the steric course of a condensation such that formation of the required cyclic product is facilitated. This process has been called the kinetic template effect. 

The ability of a chemical to act as a template is frequently attributed to a combination of thermodynamic and kinetic factors. As has been defined by Busch [3] a thermodynamic template binds more strongly to one of the products present in an equilibrium (i.e. a mixture under thermodynamic control) shifting the reaction towards the formation of this specific product which is then obtained in higher yields. In contrast, kinetic templates operate under irreversible conditions by stabilising the transition state leading to the final product. 

Reactions Predominantly Involving Thermodynamic Template Effects 434... 

The template effect has been recognized to show two or three aspects. The thermodynamic template effect involves the removal of a product from an equilibrium by stabilization of its metal complex (Scheme 29). This phenomenon has also been termed the equilibrium template effect,112 but some authors5 draw a distinction between these two types of effects. They reserve the equilibrium template effect for reactions which result in the formation of different products in the metal-assisted and metal-free reactions. 

The hexahydropyrimidine (58), formed from l-phenylpropane-l,2-dione and propane-1,3-diamine, is an excellent precursor for the a-diimine macrocyclic complexes (60), presumably via the amino ketone (59) (Scheme 36).126 In this case, intramolecular cyclization of (59) to (58) is reversible, so that the metal ion can exert a thermodynamic template effect in formation of the complex (60). This represents a further example of a long-known phenomenon in which a metal ion can stabilize an a-diimine structure by virtue of the formation of stable five-membered chelate rings. Many 2-hydroxy- or 2-mercapto-amines undergo reaction with a-dicarbonyl compounds to yield heterocyclic compounds rather than a-diimines. However, in the presence of suitable metal... 

The stabilization of an amino acetal by nickel ions has been reported very recently and although no mechanistic information is available, a thermodynamic template effect is likely (equation 33).132... 

Many reactions in this section probably owe a thermodynamic template effect for part of their success, but it is the kinetic effect which is most clearly illustrated. Reactions have been chosen to display a range of geometrical features and also various types of bond formation. The coverage will be selective and many topics will be developed more fully in Chapter 61.1 The present section will be subdivided according to the involvement or otherwise of donor atoms. 

Simple Imines Formed by Thermodynamic Template Reactions 156... 

SYNTHESIS AND REACTIONS OF IMINE CHELATES 61.1.2.1 Simple Imines Formed by Thermodynamic Template Reactions... 

The synthesis of quadridentate imine chelates usually requires the combination of two equivalents of the carbonyl compound and a diamine, as in the formation of complexes of ligands (6),17 18 (7)19 and (8).20,21 In similar fashion, thermodynamic template reactions allow the very effective synthesis of quinquedentate and sexadentate metal complexes of ligands such as (9),22 (10),23 (ll),24 (12)25 and (13).26 Condensation of 1,1,1-tris(aminomethyl)ethane with pyridine-2-carbaldehyde alone yields... 

Template reactions between a-diketones and diamines have been used for the synthesis of complexes of macrocyclic ligands such as (38)78 and (39).79 Some insight into the mechanism of the formation of these macrocycles has been provided by some recent work which shows the value of the thermodynamic template effect (Scheme 6).80... 

Thermodynamic template reactions allow the formation of hydrazones from hydrazines and carbonyl compounds, in the same manner as simple imines are formed. However, in many cases it is more convenient to form hydrazones in non-template reactions, as they are generally easier carbonyl derivatives to isolate than are simple imines. Hydrazone complexes often are capable of further manipulation and both aspects of synthesis and reactivity will be combined in this section. 

We have already looked at three key Schiff base macrocycles (Figure 3.56), which were amongst the first artificial metal macrocycle compounds to be synthesised. These compounds are generally formed by thermodynamic template effects because, unless water is removed during the course of the reaction, the condensation is reversible, allowing complexation to sequester the most stable metal-product... 

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. 

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). 

Macrocycles formed by reactions that are described as proceeding by the thermodynamic template effect can take place in the absence... 

Template-directed synthesis has also been exploited for combinatorial purposes in which a reversible reaction and the use of thermodynamic templates have been used. Two different processes have been envisaged and validated, both of which consider the dynamic optimization of a receptor-ligand interaction where one of the partners is the template that drives the self-assembly of a reversible library of other partners from which the best binder for the template is selected (Fig. 8.53). If the receptor is a template, a library made using a reversible reaction is incubated with the receptor and... 

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