Hydroxylamines and Hydroxamic acids

The 0-(2-Hydroxyethyl)-oximes of several ketones have been 

187) reaction of the latter with silver fluoride regenerates 

The reduction of aromatic nitro compounds to N-aryl-hydroxylamines by o-xylene-a,a -dithiol occurs when an iron 

N-Hydroxyamino acids, and in particular hadacidin (113) can be prepared by reaction of a-halogenocarboxy1ic acid derivatives (115) 

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FIGURE 10. Histograms showing the distributions of N—O bond lengths in crystal phase hydroxylamines and hydroxamic acids. The horizontal axes are the same in both cases... 

The main first part of the review (Section HI) summarizes preparation of hydroxylamine derivatives through alkylation, arylation, and addition reaction of hydroxylamine, or its derivatives such as hydroxamic acids and A-oxysulfonamides. The second main part (Sections IV-VIII) describes methods of creation of hydroxyamino groups de novo from other functionalities. Due to easy interconversion outlined in Section II, syntheses of hydroxylamines and hydroxamic acids are considered together. For the same reason, the chapter also relates to synthesis of A-oxysulfonamides and V-oxyphosphonamides as far as these methods are of interest for the preparation of hydroxylamines. 

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

This review describes electrochemical reactions of hydroxylamines, oximes and hydroxamic acids. In addition, utilization of hydroxylamines and hydroxamic acids as redox mediators are shown. Since the electroorganic chemistry of hydroxylamines, oximes and hydroxamic acids is rather a minor area in the electrochemistry of organic compounds, the reader is advised to refer to texts which are written for organic chemists unfamiliar with the electroorganic chemistry. 

IV. HYDROXYLAMINES AND HYDROXAMIC ACIDS AS REDOX CATALYSTS A. Hydroxylamines... 

There is some evidence that the form of the chemical carcinogen that ultimately reacts with cellular macromolecules must contain a reactive electrophilic center, that is. an electron-deficient atom that can attack the numerous electron-rich centers in polynucleotides and proteins. As examples, significant electrophilic centers include free radicals, carbonium ions, epoxides, the nitrogen in esters of hydroxylamines and hydroxamic acids, and some metal cations. It is believed that carcinogens, which in themselves are not electrophiles, are metabolized to electrophilic derivatives that then become the ultimate" carcinogens. 

Weisburger, H. H., Weisburger, E. K. Biochemical Formation and Pharmacological, Toxicological and Pathological Properties of Hydroxylamines and Hydroxamic Acids. Baltimore Williams Wilkins 1973. 

The N—O bond in hydroxylamines and hydroxamic acids is rapidly cleaved by Sml2.- However, a bridged oxazine has been found to undergo ring contraction at or above room temperature." ... 

Weiner LM, Rosenblatt M, Howes HA (1963) The detection of humoral antibodies directed against salicylates in hypersensitivity states. J Immunol 90 788-792 Weisburger JH, Weisburger EK (1973) Biochemical formation and pharmacological, toxicological, and pathological properties of hydroxylamines and hydroxamic acids. Pharmacol Rev 25 1-66... 

Formation of Hydroxylamines and Hydroxamic Acids by N-Hydroxylation in Vitro by Liver Microsomes from... 

Other alkylation processes include the O-methylation of oximes, A-oxides, hydroxylamines, and hydroxamic acids. The preparation of oxime ethers using dimethyl sulfate has proven an effective methodology for the construction of sidechains designed for new cephalosporin antibiotics. Treatment of a-oxime esters with dimethyl sulfate afforded the a-methoximino esters, which were subsequently hydrolyzed to the acid and used as sidechains via acylation chemistry (eq 8). ... 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

The structural link between hydroxylamines (1), oximes (2) and hydroxamic acids (3) is the N—OH group ... 

Formally, they can all be viewed as derivatives of hydroxylamine, H2N—OH indeed, oximes can be prepared by the addition of hydroxylamine to aldehydes and ketones (equations 1 and 2), and hydroxamic acids by its reactions with acetyl halides and esters (equations 3 and 4). ... 

However, there are also important features that very significantly differentiate between hydroxylamines, oximes and hydroxamic acids the C=N double bond in 2 and the acetyl group in 3. 

Three fundamental properties that play key roles in determining covalent and/or nonco-valent interactions are the electrostatic potential V(r), the ionization energy 7 (sometimes written IE) and the polarizability a. All three can be obtained experimentally. It is primarily in terms of these properties that we will examine the inter- and intramolecular interactions of hydroxylamines, oximes and hydroxamic acids. Accordingly we shall first briefly discuss F(r), I and a. 

Hydroxylamines, oximes and hydroxamic acids all have adjacent nitrogen and oxygen atoms, as part of their characteristic N—OH group. Since both of these atoms commonly have significant lone pairs, a major determinant of these molecules conformations is the need to minimize the repulsion between these lone pairs. This will be illustrated by the example of hydroxylamine, H2N—OH. 

Features of hydroxylamines, oximes and hydroxamic acids V. COMPARISON OF PROTOTYPICAL EXAMPLES... 

We shall now compare some properties of prototypical examples of hydroxylamines, oximes and hydroxamic acids. These will be structures 1, 2 and 3 with methyl groups at the remaining positions, i.e. dimethylhydroxylamine (6), acetoxime (7) and acetohydroxamic acid (8). 

The resulting estimated average polarizabilities for the hydroxylamines, oximes and hydroxamic acids that we have discussed are given in Table 8. (It should be noted that Miller s approach does not distinguish between oxime isomers.) As anticipated from the correlation between average polarizability and volume (equation 10), the a in Table 8 increase with molecular size. 

In this chapter, we have looked at some of the intrinsic features of hydroxylamine, oxime and hydroxamic acid molecules. The insights obtained, particularly concerning the electrostatic potentials on their molecular surfaces, should provide a useful basis for proceeding to their gas phase and crystal structures and properties. 

In Table 2 are listed the hydroxylamines, oximes and hydroxamic acids for which we have determined the gas phase structures. We tried to select a representative group in each category. There are two types of oximes, as indicated, aldoximes and ketoximes. Due to restricted rotation around the C=N double bond, these can exist in two isomeric forms (except when R = H for an aldoxime and R = R" for a ketoxime). We have investigated both isomers in nearly every instance. For aldoximes, they are generally labeled syn when the H and OH are on the same side of the double bond and anti when on opposite sides. Note that the ketoximes in Table 2 contain one pair of isomers in which the >C=NOH group is not bonded to two carbons instead one bond is to a chlorine. One of these isomers wiU be of interest in Section B.D in the context of hydrogen bonding vi lone pair—lone pair repulsion. 

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