Multicomponent Assembly of Macrocycles

Let us start by considering the reaction of the copper(n) complex 6.49 with formaldehyde. Initially we might expect the diimine 6.50 to be formed, but this ignores the nature of the intermediates. As we saw earlier, the reaction of an amine with an aldehyde initially produces an aminol. Consider the addition of the second molecule of formaldehyde to 6.49. The product will be 6.51, which contains an imine and an aminol (Fig. 6-43). The imine is co-ordinated to a metal ion, and the polarisation effect is likely to increase the electrophilic character of the carbon. The hydroxy group of the aminol is nucleophilic and it is correctly oriented for an intramolecular attack upon the co-ordinated imine. The result is the formation of the copper(n) macrocyclic complex 6.52. 

The important feature is that the imine that is initially formed is susceptible to attack by a nucleophile. What would happen if we were to have another nucleophile present in the solution Conceptually this is exactly the situation when we react 6.49 with a mixture 

The remarkable feature is that the mixture of these three reactants follows a precisely coded reaction sequence to give the macrocyclic product. A series of electrophiles and nucleophiles of different relative strengths are involved. The reaction may be extended a stage further, as shown in Fig. 6-45. The reaction of [Cu(en)2]2+ with formaldehyde and nitroethane results in the formation of the macrocyclic complex 6.55. 

The nature of the additional nucleophile may be varied. For example, the reaction of the nickel(n) complex 6.56 with formaldehyde and methylamine gives the macrocyclic complex 6.57 (Fig. 6-46). Again, it is not clear whether the first steps of the reaction involve reaction with formaldehyde, followed by attack of amine upon the imine, or initial formation of an electrophile such as H2C=NMe, which attacks 6.56. 

As a final example, we illustrate the reaction of [Cu(en)2]2+ with formaldehyde and methylamine to give the macrocyclic complex 6.58 (Fig. 6-47). 

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