Imines kinetic template reactions

The most dramatic formation of cages has been provided by kinetic template reactions of ligands attached to cobait(III). The deprotonated amine ligands undergo reaction with formaldehyde to produce bound imines which can be trapped by a variety of nucleophiles (Schemes 66 and 67).205-208 The synthesis of cages of this type will be considered further in Section 61.1.2. 

The most important reaction of this type is the formation of imine bonds and Schiff bases. For example, salicylaldehyde and a variety of primary amines undergo reaction to yield the related imines, which can be used as ligands in the formation of metal complexes. However, it is often more desirable to prepare such metal complexes directly by reaction of the amine and the aldehyde in the presence of the metal ion, rather than preform the imine.113 As shown in Scheme 31, imine formation is a reversible process and isolation of the metal complex results from its stability, which in turn controls the equilibrium. It is possible, and quite likely, that prior coordination of the salicylaldehyde to the metal ion results in activation of the carbonyl carbon to amine nucleophilic attack. But it would be impossible for a precoordinated amine to act as a nucleophile and consequently no kinetic template effect could be involved. Numerous macrocyclic chelate systems have been prepared by means of imine bond formation (see Section 61.1.2.1). In mechanistic terms, the whole multistep process could occur without any geometrical influence on the part of the metal ion, which could merely act to stabilize the macrocycle in complex formation. On the other hand,... 

New chelate rings can be formed by the nucleophilic addition of alcohols to imine complexes. For example, the nickel(II) TAAB complex is susceptible to attack by bis-alkoxides (equation 31).127 It is not clear whether or not a kinetic template effect operates by prior coordination of the central oxygen or sulfur atom. However, such an effect is not necessary, as simple alkoxides undergo a similar addition reaction.128... 

Two primary types of template reaction have been identified and these demonstrate equilibrium template (see Box 5.4) and kinetic template effects. An example of an equilibrium template effect is provided by the reaction between butane-2,3-dione and 2-aminoethanethiol which produces, as its major product, a heterocycle in equilibrium with smaller amounts of the acyclic imine (Scheme 5.3). However, in the presence of Ni " ions the acyclic product forms in high yield as its nickel complex. 

The reaction was shown to follow step-growth kinetics in its early stages and to stop abruptly at the length defined by the template. No products were detected in the absence of any template. As the hydrogen bonding between the nucleobases and the imine formation are reversible, error correction occurs to some extent in this system. In this sense, this report matches the spirit of DCC more closely than many others. Unfortunately, no follow-up using the entire nucleic acid alphabet has been published hitherto. 

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