Jozef Hodyl PhD Thesis - Theses - Flinders University

The methodology chosen was adapted from relatively recent developmentsestablished by Boldrini, 131 and Yoo. 109Synthesis of the tri-formyl protected cyclen derivative 52 proceeded by thereaction of cyclen, 21, with an excess of chloral hydrate at 60 o C in anhydrousethanol. This adduct was attained in quantitative yield and a high degree of purity asthe residual chloral hydrate and reaction by-products, chloroform and water werereadily removed in vacuo. 131Due to restricted rotation around the N-CHO bonds both 1 H NMR and 13 C NMRspectra for 52 show broad peaks due to superimposition of the slightly separatedresonances from the four geometrical isomers illustrated in Figure 2.4. 166HONNOHHONNOHOHNNOHOHNNHOOHNHNHONHNHONHNHONHNFigure 2.4Schematic illustration of the four geometrical isomers originating from restrictedrotation around the amidic C-N bond.Remarkably this synthetic procedure gives, exclusively, the triformyl protectedcyclen derivative 52 as shown in Scheme 2.2, even in the presence of excess chloralhydrate. Boldrini et al. explain this phenomenon as arising from intramolecular basecatalysis of the formylation reaction by the cyclen nitrogen atoms. This implies thatfor substitution to occur at one of the nitrogen atoms a second unsubstituted nitrogenatom is required. Therefore, after three of the nitrogen atoms have been reacted thefourth nitrogen atom is bereft of a basic nitrogen atom able to provide the necessarycatalytic cooperation for substitution to occur. 131 Another twist on this interpretation40