3-Hydroxy-4-pyridinones

APM-3,4-HOPY is a bidentate 3-hydroxy,4-pyridinone featuring a propylamine moiety attached to the pyridine N and a methyl group on carbon 2 of the pyridine ring. sThis value is reported as a lh n-... 

Fig. 1. General formulae for hydroxypyranones and hydroxypyridinones 1, 3-hydroxy-2-pyranone 2, 3-hydroxy-4-pyranones 3, 3-hydroxy-2-pyridi-nones 4, 3-hydroxy-4-pyridinones 5, l-hydroxy-2-pyridinone. In each case the ring atoms are numbered anticlockwise, starting with the ring-oxygen or ring-nitrogen atom.

The fact that pyromeconic acid and allomaltol were only available with difficulty meant that direct synthesis of certain 3-hydroxy-4-pyridinones was not possible. However the demonstration that some of these compounds were accessible from maltol or ethylmaltol by functionalizing the position adjacent to the ring-oxygen by an aldol condensation and N-oxide intermediates led to the preparation of 2-(l -hydroxyalkyl) and 2-amido derivatives with usefully high affinities for Fe + (70). 

Alkyl-3-hydroxy-4-pyridinones can be converted into analogues containing, e.g., anilino-, phenylthio-, or 2-hydroxyethylthio-substitu-ents by silver(I) oxidation (Ag20 in ethanol) followed by Michael addition (71). In aminomethylation of 3-hydroxy-4- and -2-pyridinones under Mannich conditions the position of substitution can be tailored, by reaction conditions to position C4 or C6, or by converting the OH into OMe, which directs substitution to C5 (72). 

Stereochemistry and Degree of Hydration of 3-Hydroxy-4-pyridinonate Complexes of... 

Structures of l-hydroxy-2-pyridinonate and 3-hydroxy-2-p5rridino-nate complexes may be compared with those of the more extensively studied 3-hydroxy-4-pyridinonates through the published crystal structures of their tris-ligand iron(III) complexes. The iron(III) tris-ligand complex of l-n-butyl-3-hydroxy-2-pyridinone has fac geometry it crystallizes as a trihydrate 135). 

BMOV, was reported in 1972 159) and in 1987 160). Its electrochemical preparation was described in 1978 92a), and EPR monitoring of its redox behavior, in chloroform, in 1987 160). However this now-important compound seems not to have been properly characterized until 1992 161). Since then complexes of several 3-hydroxy-4-pyridinones 162—164), and of l-hydroxy-2-pyridinone 165), have been synthesized and characterized, especially by EPR 164). VO(malt)2 exists as a cis trans equilibrium mixture in aqueous solution, and generally crystallizes as a mixture of the two isomers. However the crystal structure of the trans structure was eventually solved, confirming the expected square-pyramidal stereochemistry 166). The relative stabilities of the cis and trans forms of V 0L2 complexes depend on the nature of the bidentate ligand L , with the cis configuration favored by VO(malt)2 and VO(koj)2 167), but the trans by 3-hydroxy-4-pyridinonate ligands 164). 

L — maltolate the coordination environment of the vanadium in K[V02(malt)2] H2O is approximately octahedral, the two 0x0 ligands being in cis positions. [K(H20)e] units link adjacent vanadium(V) complex anions to give a chain structure 166). The main products of aerobic oxidation of [V O(dmpp)2l in aqueous solution are [V02(dmpp)] and [VOo(dmpp)2]. High pH favors these V products, whereas at low pH V species predominate 171). Vanadium(V) also forms a VO(OR)(malt)2 series, readily prepared from ammonium vanadate, maltol, and the appropriate alcohol in a water-alcohol-dichloromethane medium 172), and 3-hydroxy-4-pyridinonate analogues V0(0R)L2 on oxidation of their oxovanadium(IV) precursors in solution in the appropriate alcohol ROH 168). 

To put hydroxypyranonate and hydroxypyridinonate complexes in context, stability constants for kojate and l,2-dimethyl-3-hydroxy-4-pyridinonate complexes of Mg, Al, Fe, and Gd are compared with stability constants for complexes of these cations with a few other ligands in Table III. That these hydroxypyranonate and hydroxyp5rr-idinonate ligands form stable complexes is immediately apparent. In this section we shall present and discuss a generous, but far from... 

Comparisons of Stability Constants (Log K f for Selected Complexes of Kojate AND OF 1,2-Dimethyl-3-hydroxy-4-pyridinonate with Those for a Range of Other... 

Stepwise stability constants decrease regularly in the normal manner 178), log > log K2 > log K, as may be exemplified by the values for the Ni -maltolate system, viz. 5.5, 4.3, and 2.7, respectively 179). Stability constants (log Kf) for a selection of 3-hydroxy-4-pyranonate and 3-hydroxy-4-pyridinonate complexes of some first-row transition metal 2+ cations are listed in Table IV 10,128,180—184). The values for the 3d transition metal cations conform to the long-established Irving-Williams order... 

Stability constants (log Kn and log P3) have been determined for a number of iron(III) complexes of 3-hydroxy-4-pyridinones bearing hydrophilic substituents, including those with Rr = CH2CH2OH and CH2CH2CO2H, — Et (200) and with the secondary alcohol group CH(0H)CH3 (201). Log Kn and log P3 have also been determined for the iron(III) complexes of meconate (202), and for the sequence of iron(III) complexes with R = H, Me, Et, "Pr at constant R = Me all four log Ps lie between 37.2 and 37.7 (43). 

A range of values for the pFe of this most-studied 3-hydroxy-4-pyridinone will he found in the literature, down to 19.4 (see e.g. Ref 212)). 

Despite their importance in many pharmacological uses and potential applications, solubilities of hydroxypyranones, hydroxypyridinones, and their complexes have not been extensively and systematically investigated and established. This situation contrasts sharply with that for partition coefficients, as will become apparent in the following section. The solubility of maltol in water is approximately 0.1moldm , of ethyl maltol 0.13 mol dm, at 298 K. 1,2-Alkyl-3-hydroxy-4-pyridinones show the expected decrease in water-solubility as the sizes of the alkyl groups increase solubilities - in water at 298 K - of l-aryl-2-methyl-3-hydroxy-4-pyridinones decrease from 9 X 10 mol dm for the 1-phenyl compound through 6 x lO- moldm for l-(4 -tolyl) to 6 x 10 mol dm for l-(4 -re-hexyl-phenyl) (37). 

We present a selection of solubilities of 3-hydroxy-4-pyridinonate complexes of cations in Table XVII 114,143,144,233-241) and Table XVIII (237), to give some impression of the effects of their variation with the nature of the complex and of the solvent. It is very difficult... 

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