Patel, Manojbhai Kashibhai; (1998) Synthesis and characterisation of metal chelators: Mannich bases of hydroxy-pyrones and hydroxy-pyridones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Kojic acid (5-hydroxy-2-hydroxymethy1-4(1H)-pyrone) undergoes a rapid Mannich reaction with formaldehyde and morpholine, under aqueous conditions at 25 °C. The implications of the kinetic analysis on the mechanism of the Mannich reaction were discussed. The kinetics was conveniently monitored spectrophotometrically (280nm) under pseudo first-order conditions, with respect to kojic acid. The kinetics was not consistent with the reaction between kojic acid and a freely diffusing iminium ion, a mechanism which appears widely in the literature. Instead, the kinetics requires a rate limiting reaction between kojic acid and both hemi-aminal and bis-aminal. A rate equation was formulated which expresses the equilibrium concentrations of the condensation species of formaldehyde and morpholine, as well as the ionisation of kojic acid. The equation which follows was shown to be valid over a wide range of pH and concentration of reagents. Rate = (kojic acid]. 1 / (1 + Ka / [H+]) . [formaldehyde]. [amine]. (k1 . β1 + k2 . β2 . [amine]) Ka is the acid dissociation constant of kojic acid, β1 and β2 are the formation constants and k1 and k2 the rate constants for the hemi- and bis-aminal, respectively. With values of logβ1 = 2.898 and logβ2 = 4.192, pKa = 7.534 and the optimised values of k1 and k2 are 0.65 (±0.04) and 0.77 (±0.05) M-1S-1, respectively. The bell-shaped pH dependence of kobs was correctly modeled and the pH giving maximum kobs was predicted within 0.05 pH units. This occurs at pH 7.1 (kobs = 1.0 x 10-2 sec-1) with formaldehyde at 30 mM and morpholine at 147 mM. However, the pH of maximum rate was predicted to rise to 7.3 while kobs falls to 0.31 x 10-2 sec-1 at the lower morpholine concentration of 14.7 mM. 3-Hydroxy-2 (1H)-pyridinone (3HP) was covalendy coupled to the condensation product(s) of formaldehyde and poly(ethyleneimine) via a Mannich reaction and form novel metal chelating polymeric resins, called poly-Mannich bases. Poly-Mannich bases (e.g.. MKP-DP9-4) with random orientation of 3-hydroxy-2(1H)-pyridinone chelating moieties on the organic polymeric backbone were isolated by method of precipitation, using an aqueous solution of mineral acid and acetone. Rapid uptake of Fe3+ accompanied by a spontaneous colour reaction was observed on addition of aqueous solution of iron (III) nitrate to the poly-Mannich base (MKP-DP9-4). The amount of iron bound per gram of poly-Mannich base was 40 m g and showed 4 times or more affinity for F e3+ compared with other ion-exchange resins. The site of aminomethylation of N-unsubstituted 3-hydroxy-2(1H)-pyridinones and 3-hydroxy-4(1H)-pyridinones, under Mannich reaction conditions was directed by the unprotected hydroxyl group or by the keto group, when the hydroxyl was protected as an ether. This offered a convenient route to a variety of Mannich base synthons useful in the synthesis of derivatives of these clinically important, bidentate, metal-ion chelators. This was exemplified by the reactions of 3-hydroxy-2(1H)-pyridinones, 3-methoxy-2(1H)-pyridinone and 3-benzyloxy-2-methyl-4(1H)-pyridinone.

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