Hydroxamic acids structural effects

The structures of these molecules show the effects of intramolecular electrostatic interactions. Two examples are the lone pair—lone pair repulsion that is an important determinant of hydroxylamine and oxime conformations, and the intramolecular hydrogen bonding in hydroxamic acids that promotes the near-planarities of their —C(=0)—NO frameworks. 

The intimate relationship between NMR parameters such as chemical shifts and spin-spin coupling constants and molecular geometry is particularly evident for derivatives with rigid frameworks. Therefore, structural and conformational effects are treated first as a separate topic and then in conjunction with specific compounds. As data on hydroxylamines, oximes and hydroxamic acids are not as extensive as those for other types of systems containing nitrogen or oxygen, comparisons with their respective parameters or effects have also been included wherever they are considered relevant. 

Structural effects on reactivity and properties of oximes and hydroxamic acids... 

Examples of the application of correlation analysis to oxime and hydroxamic acid pK data sets are considered below. In the best of all possible worlds all data sets have a sufficient number of substituents and cover a wide enough range of substituent electronic demand, steric effect and intermolecular forces to provide a clear reliable description of the kind and magnitude of structural effects on the property of interest. In the real world this is often not the case. We will therefore try to show how the maximum amount of information can be extracted from small data sets. 

Hydroxamic acids have been the subject of six papers 43 90 94 Earlier the operation of the a-effect in the reaction of p-nitrophcnyl acetate with benzohydroxamates in aqueous MeCN was discussed.43 The conformational behaviour of series of mono- (105) and di-hydroxamic acids (106) in MeOH, DMSO, and chloroform and in the solid state has been examined witii IR and NMR spectroscopy.90 X-ray crystal structure determinations of (105 X = Me, R = Me) and die monohydrate of glutarodihydroxamic acid (106 n = 3, R = H) together widi ab initio MO calculations for several hydrated and non-hydrated acids have been performed. The cis-Z conformation of the hydroxamate groups is preferentially stabilized by H-bonding witii water. 

We next decided to study the effect on MMP-inhibitory potency of a fluoroalkyl group installed in a more distant position from the hydroxamic acid group, in order to better understand the unique stereoelectronic properties of fluoralkyl groups in a purely aliphatic position [39], For this purpose we chose as a model system a structurally simple class of hydroxamic acid inhibitors bearing an arylsulfone moiety at the P-position such as D (see Figure 4.5), which showed nanomolar inhibitory potency for MMP-2, MMP-3, and MMP-13 [40-42]. 

An interesting structure-activity observation is that the 3-isoxazolidinones (8) are only slightly more active than their synthetic precursor hydroxamic acids (9) (Table X). For example, the difference in activity between FMC 57020 and its precursor hydroxamic acid toward these 4 species of weeds is very small. They both show a bleaching herbicidal response with excellent soybean tolerance. They also demonstrate a parallel substituent effect, i.e. they both follow the same relative activity order among different substituents such as those shown in Table X. 

The iron chelating ability of DFB is due to the hydroxamic acid, a functional group that possesses a natural affinity for iron(III). Also inherent in this structure is a powerful chelate effect due to the 9 atom spacing between hydroxamic acid groups, tdiich permits three neighboring hydroxamic acids to fit the octahedral coordination sphere of the iron(III) without severe steric strain. 

Enantiomerically pure manganese complexes using ligands other than the salen structure have been reported, but so far with lower enantioselectiv-ities. Better results have been achieved using molybdenum complexes bearing hydroxamic acid ligands and TBHP or cumylhydroperoxide as oxidant. This system has been used to effect the epoxidation of a range of olefins with up to 96% ee. 

Hydroxamic acid is the fimctional group responsible for binding the iron in DFO. It has been known since 1869. The first hydroxamic acid polymer was made in 1946. A number of hydroxamic acid polymers with controlled spacing have been developed that effectively bind iron with iron binding log K values around 30. The structure of one of these is given below, where R] is the spacer. 

It has been generally demonstrated that pyrazine 1-oxides are biologically active but that the deoxy derivatives are not. The hydroxamic acid moiety of these compounds is probably a major structural requirement for the exhibition of their biological activity, because the compounds containing the hydroxamic acid moiety show an antibiotic effect on microorganisms and a convulsive effect on animals. The naturally occurring fungal pyrazine 1-oxides are shown in Table II. 

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