Hydroxamic acids conjugates

When primary nitro compounds are treated with sulfuric acid without previous conversion to the conjugate bases, they give carboxylic acids. Hydroxamic acids are intermediates and can be isolated, so that this is also a method for preparing them. Both the Nef reaction and the hydroxamic acid process involve the aci form the difference in products arises from higher acidity, for example, a difference in sulfuric acid concentration from 2 to 15.5 M changes the product from the aldehyde to the hydroxamic acid. The mechanism of the hydroxamic acid reaction is not known with certainty, but if higher acidity is required, it may be that the protonated aci form of the nitro compound is further protonated. 

The formation of the latter compounds can be attributed to the result of the direct attack of the nucleophile R on the a- or p-carbon atoms of SENAs after elimination of the corresponding protons. However, it is most likely that the reaction proceeds through nitrile oxides or conjugated nitrosoalkenes (see Scheme 3.93). This interpretation is evidenced by generation of silyl esters of hydroxamic acids R CONHOSi as by-products. The reactions with more saturated solutions give the latter compounds as the major products. 

Aldehyde 54 and the hydroxamic acids 55 were generated together in an acid-catalysed elimination reaction (Scheme 7 pathway (ii)). A crossover experiment indicated that esters are formed in a concerted rearrangement concomitant with the likely formation of the hydroxynitrene 57 (Scheme 7 pathway (iii)) while there is no evidence to date for the formation of hydroxynitrene, joint solvolysis of equimolar quantities of /V-acetoxy-/V-butoxy-/>-chlorobenzamide 26e and N- acetoxy-/V-benzyloxybenzamide 27a afforded significant quantities of butyl p-chlorobenzo-ate (36%) and benzyl benzoate (54%) as the only esters. This is an example of a HERON reaction, which has been identified in these laboratories as a characteristic rearrangement of bisheteroatom-substituted amides.32,33,42 43 155 158 Since ester formation was shown to prevail in neutral or low acid concentrations, it could involve the conjugate anion of the hydroxamic acid (vide infra).158... 

Hydroxamic acids have been extensively investigated at Abbott, where a hypothetical binding site hypothesis was based on examination of many simple Gj-aralkylhydroxamic acids [294]. Several series of conjugated hydroxamic acids were explored based on this hypothesis, yielding potent 5-LO inhibitors (0.02-2 //M) exemplified by (116)-(119). The most potent of these (119) also inhibited purified porcine leukocyte 5-LO (0.5 //M) [202]. As other workers have found, A-methylation was beneficial for potency. Activity was also seen in a rat peritoneal anaphylaxis model following i.p. (0.2 mg/kg), but not oral, dosing [47]. 

The conversion of hydroxamic acids 589 to a, S-unsaturated amides 592 reported by Hoffmagn and Madan appears to be a first-order reaction of bis-anion 590 characterized by an intramolecular proton rearrangement to one of the anionic oxygen atoms to give conjugated ion 591 (equation 260). 

It is in the realm of detoxification that the hydroxylamines/oximes/hydroxamic acids and their conjugate bases are of direct use, since a number of these compounds have been found to be especially reactive in the destruction of toxins. The fundamental reasons underlying such enhanced reactivity is an important part of this chapter. 

Photoexcited nitrobenzene may be used for benzylic hydroxylation (at C-9) of 17/3-acetoxy-3-methoxyoestra-l,3,5(10)-triene. The photochemistry of the 17/3-nitro-steroid (217) is markedly solvent dependent, the major products being in ether the 17-desnitro-compound (218), in propan-2-ol the hydroxylamine (219), and in EtOH-NaOEt the hydroxamic acid (220) and the cyclopropane (221). The hydroxamic acid (220) is probably formed through the oxaziridine (Scheme 7). Although there are analogies to this in the photochemistry of nitrones and oximes, the photoreduction of a nitroalkane in propan-2-ol to an alkyl-hydroxylamine appears to have no precedent. Further studies of photochemistry of conjugated... 

The first term of the rate law requires acid-catalyzed decomposition of the conjugated acid of the ester. This term predominates only under strongly acidic conditions. It has not been investigated in detail, but the major product of the acid catalyzed reaction is the corresponding hydroxylamine. The second term predominates under neutral to mildly acidic conditions. This term is consistent with uncatalyzed heterolysis of the N—O bond of the neutral ester to generate a heteroaryinitrenium ion. " The rate law is more complicated than that for reactive esters of carbocyclic hydroxylamines or hydroxamic acids that show pH-independent decomposition over a wide pH range. The kinetic behavior of the heterocyclic esters is caused by protonation of a pyridyl or imidazolyl N under mildly acidic conditions. The protonated substrates are not subject to spontaneous uncatalyzed decomposition, so decreases under acidic conditions until acid-catalyzed... 

First of all, natural products with functional groups associated with chemical reactivity or toxicity can be discarded. For example, many are phenolic, and these are generally impromising because they are prone to oxidation and conjugation within a plant. Quinones and other redox-reactive compoimds are also unattractive, as are natural products which are likely to be metal-chelators, such as hydroxamic acids and catechols. 

---