Site selectivity in the synthesis of O-methylated hydroxamic acids with diazomethane

In this paper we report the results obtained by treating some selected hydroxamic acids with diazomethane in ethereal media. The multitask reagent diazomethane was used either as a base to induce deprotonation of the chosen hydroxamic acids or as conjugated acid which undergoes one-pot methylation processes of the generated anions. Product distributions clearly showed that a high site selectivity is expressed by the different deprotonated species in the alkylation processes. Under the adopted conditions, the prevalent site of methylation is in all the cases the oxygen of the hydroxamic acid. While in aliphatic hydroxamic acids only O-alkylation is observed, in the aromatic substrates, the NH group competes with the OH function as the nucleophilic site, although the OH reactivity still dominates.     

Mass spectra of 2H-1,4-benzoxazine and-benzothiazine hydroxamic acids

The mass spectra of various benzoxazine and benzothiazine hydroxamic acids and related lactams have been recorded and interpreted. Proposed fragmentations have been substantiated by means of deuterium-labeling and accurate mass measurements. Abundant molecular ions were observed in all spectra. The benzoxazine hydroxamic acids fragmented initially by expelling an oxygen atom and a COOH radical from the molecular ion. The corresponding benzothiazine hydroxamic acids lost an oxygen atom and an OH radical, whereas their 1,1-dioxides decomposed by losing an oxygen atom and a ketene or substituted ketene molecule. The expulsion of CO, HCN, CS and SO₂ molecules, as well as alkyl and NO radicals were common subsequent fragmentations.     

Adsorption and self-assembly of octyl hydroxamic acid at a fluorite surface as revealed by sum-frequency vibrational spectroscopy

In the study described here, the surface structure of a self-assembly octyl hydroxamic acid at a calcium fluoride (CaF(2)) surface is evaluated using sum-frequency vibrational spectroscopy (SFVS). Of particular significance are the results that show octyl hydroxamic acid adsorbs at the fluorite surface from octanol solution and has more ordering and molecular conformation than the octyl hydroxamic acid adsorbed from solution. At the fluorite/0.1 M octyl hydroxamic acid octanol solution interface a bilayer-like structure consisting of an octyl hydroxamic acid layer in contact with fluorite and a tilted alcohol layer was observed by SFVS. The alcohol molecules are oriented with respect to the hydroxamic acid monolayer with the OH groups directed towards the bulk alcohol phase and the terminal CH(3) group oriented to face the alkyl chains of the hydroxamic acid monolayer.     

Formation and structure of 1:1 complexes between aryl hydroxamic acids and vanadate at neutral pH

Although aryl hydroxamic acids are well-known to form coordination complexes with vanadate (V(V)), the nature of these complexes at neutral pH and submillimolar concentrations, the conditions under which such complexes inhibit various serine amidohydrolases, is not well established. A series of qualitative and quantitative experiments, involving UV/vis, (1)H NMR, and (51)V NMR spectroscopies, established that both 1:1 and 1:2 vanadate/hydroxamate complexes form at pH 7.5, with the former dominating at submillimolar concentrations. Formation constants for the complexes of several aryl and alkyl hydroxamic acids were determined; for example, for benzohydroxamic acid, the stepwise formation constants of the 1:1 and 1:2 complexes were 3000 and 400 M(-1), respectively. The (51)V chemical shift of the 1:1 4-nitrobenzohydroxamic acid complex was -497 ppm, and that of its unsubstituted analogue was -498 ppm. A (1)H-(15)N HSQC spectrum of the 4-nitrobenzo-(15)N-hydroxamic acid/vanadate complex indicated the presence of an N-H group with (15)N and (1)H chemical shifts of 115 and 5.83 ppm, respectively. A (13)C NMR spectrum of the complex of 4-nitrobenzo-(13)C-hydroxamic acid with vanadate displayed a resonance at 170.1 ppm and thus a coordination-induced shift (CIS) of +3.8 ppm. In contrast, the CIS value of an established 1:2 complex, thought to contain chelated hydroxamic acid ligands, was +11.9 ppm. These spectral data led to the following structural picture of 1:1 complexes of vanadate and aryl hydroxamic acids. They contain penta- or hexa-coordinated vanadium. The ligand is in the hydroxamate rather than hydroximate form. The ligand is presumably bound to vanadium through the hydroxamic hydroxyl oxygen, but the hydroxamic acid carbonyl oxygen interacts weakly with vanadium. These species are the most likely candidates for the inhibitors of serine amidohydrolases found in vanadate/hydroxamic acid mixtures.     

Hydroxamic acid polymers. II. Design of a polymeric chelating agent for iron

The iron chelating ability of hydroxamic acid polymers was studied as a function of the atomic chain spacing separating neighboring hydroxamic acid units. Two polymers were prepared, one having the hydroxamic acid group separated by 11 atoms and the other by three atoms. The iron binding of these polymers was compared with the model compound desferrioxamine B (DFO) and with a previously prepared polymer having a nine-atom spacing. Mole ratio plots indicated the following order of stability: DFO ≈ 11 atom > 9 atom > 3 atom. These results are in accordance with the picture derived from molecular models which shows that with a spacing of 11 atoms, three neighboring hydroxamic acids can fit the octahedral arrangement of the iron (III) complex without appreciable strain. Some strain is introduced when the spacing becomes only nine atoms, and with three atoms, complex formation between three neighboring groups becomes virtually impossible.     

Dioxygenation of styrenes with molecular oxygen in water

Employing Triton X-100 as a surfactant, the tert-butyl hydroperoxide-mediated dioxygenation of styrene with molecular oxygen and N-hydroxyphthalimide was achieved in water at room temperature, providing the corresponding dioxygenated products in 9–93% yield. This facile method is eco-friendly, feasible on gram scale, and applicable to a wide range of styrene derivatives with a variety of functional groups.     

Theoretical study of the uranyl complexation by hydroxamic and carboxylic acid groups

A theoretical study on the complexation of uranyl cation (UO2(2+)) by three different functional groups of a calix[6]arene cage, that is, two hydroxamic and a carboxylic acid function, has been carried out using density functional theory calculations. In particular, interaction energies between the uranyl and the functional groups have been used to determine their affinity toward uranyl, whereas pKa calculations give some information on the availability of the functional groups in the extraction conditions. On the one hand, calculations of the interaction energies have pointed out clearly a better affinity with the hydroxamic groups. The stabilization of this complex was rationalized in terms of a stronger electrostatic interaction between the uranyl cation and the hydroxamic groups. The presence of a water molecule in the first coordination sphere of uranyl does not destabilize the complex, and the most stable complex is obtained with two functional groups and two water molecules, leading to a coordination number of 8 for the central uranium atom. On the other hand, pKa theoretical evaluation shows that both hydroxamic (deprotonated on the oxygen site) and carboxylic groups are potential extractants in aqueous medium with a preference for carboxylic functions at low pH. Moreover, these data allowed to unambiguously identify the oxygen of the alcohol function as the favored deprotonation site on the hydroxamic function.     

Complexation of uranium(VI) with aromatic acids in aqueous solution: a combined computational and experimental study

The complexes of uranium(VI) with salicylhydroxamate, benzohydroxamate, and benzoate have been investigated in a combined computational and experimental study using density functional theory methods and extended X-ray absorption fine structure spectroscopy, respectively. The calculated molecular structures, relative stabilities, as well as excitation spectra from time-dependent density functional theory calculations are in good agreement with experimental data. Furthermore, these calculations allow the identification of the coordinating atoms in the uranium(VI)-salicylhydroxamate complex, i.e. salicylhydroxamate binds to the uranyl ion via the hydroxamic acid oxygen atoms and not via the phenolic oxygen and the nitrogen atom. Carefully addressing solvation effects has been found to be necessary to bring in line computational and experimental structures, as well as excitation spectra.     

Detoxification of VX and Other V‐Type Nerve Agents in Water at 37 °C and pH 7.4 by Substituted Sulfonatocalix[4]arenes

Sulfonatocalix[4]arenes with an appended hydroxamic acid residue can detoxify VX and related V‐type neurotoxic organophosphonates with half‐lives down to 3 min in aqueous buffer at 37 °C and pH 7.4. The detoxification activity is attributed to the millimolar affinity of the calixarene moiety for the positively charged organophosphonates in combination with the correct arrangement of the hydroxamic acid group. The reaction involves phosphonylation of the hydroxamic acid followed by a Lossen rearrangement, thus rendering the mode of action stoichiometric rather than catalytic. Nevertheless, these calixarenes are currently the most efficient low‐molecular‐weight compounds for detoxifying persistent V‐type nerve agents under mild conditions. They thus represent lead structures for novel antidotes that allow treatment of poisonings by these highly toxic chemicals.     

Quantum-chemical calculations of the methylation of hydroxamic and thiohydroxamic acids with diazomethane

We made calculations about the methylation of both hydroxamic and thiohydroxamic acids with CH₂N₂. The potential-energy surfaces of several proposed pathways leading to possible site-selective products (N-methylated and O-methylated hydroximates) are presented. Our results agree satisfactorily with an experimental observation by Liguori et al. who found site selectivity in the formation of dimethylated products. Simultaneous deprotonation and methylation occurs in both forms (E and Z) of hydroxamic acid and thiohydroxamic acid, and the net energy barrier via this pathway is the smallest. In most corresponding processes the energy barriers are smaller for thiohydroxamic acid, and the Z-form has an energy barrier smaller than that of the E-form in both hydroxamic and thiohydroxamic acids.     

Protonation and deprotonation of hydroxamic acids. An MO ab initio study

Ab initio molecular orbital calculations with 4-31G//4-31G, 6-31G^*//4-31G and 6-31+G//4-31G basis sets have been used to examine the structure, relative energy, protonation and deprotonation of a series of seven hydroxamic acids in the gas phase. The results show that hydroxamic acids are predominantly in the E-TS form and that the most probable protonation site is the carbonyl oxygen atom, while deprotonation proceeds by loss of NH hydrogen.     

Infrared spectroscopic studies of siderophore-related hydroxamic acid ligands adsorbed on titanium dioxide

The adhesion of bacteria to metal oxide and other mineral surfaces may involve bacterial siderophores, many of which contain hydroxamic acid (Ha) ligands. The adsorption behavior of the siderophore-related ligands acetohydroxamic acid, N-methylformohydroxamic acid, N-methylacetohydroxamic acid, and 1-hydroxy-2-piperidone on titanium dioxide thin films has been investigated using in situ ATR-IR spectroscopy with variation of concentration and pH. All the ligands were found to adsorb strongly on the TiO2 surface as hydroxamate ions and form bidentate surface complexes. Vibrational modes involving C=O stretching and N-O stretching of these ligands were assigned by comparing observed IR spectra with those calculated by the density functional method at the B3LYP/6-31+G(d) level. Calculated spectra of the complex [Ti(Ha)(OH)4]-, used to model the TiO2 surface, were compared with observed spectra of adsorbed hydroxamic acids. These results suggest that hydroxamic acid ligands in siderophores would be expected to bind to metal (oxide) and mineral surfaces during bacterial adhesion processes.     

The Interaction of Zinc(II) and Hydroxamic Acids and a Metal‐Triggered Lossen Rearrangement

The structure and reactivity of a complex of zinc(II), water, acetic acid, and acetohydroxamic acid, in which one of the acids is deprotonated, is investigated by means of mass spectrometry, labeling studies, and density functional calculations to unravel the exceptional binding properties of hydroxamic acids towards zinc‐containing enzymes at the molecular level. It is shown that acetohydroxamic acid is deprotonated in the complex, whereas acetic acid is present in its neutral form. The binding energies of the ligands towards zinc increase in the following order: water<acetic acid<acetohydroxamic acid. The structure of the complex and its fragmentation provide experimental evidence for the proposed mode of operation of drugs based on hydroxamic acids. Furthermore, coordinatively unsaturated complexes of zinc and acetohydroxamic acid undergo a zinc‐assisted Lossen rearrangement followed by elimination of water if acetohydroxamic acid is present as a neutral ligand, or by loss of methylisocyanate if acetohydroxamic acid is deprotonated.     

Studies of Rare Earth Metal Complexes of Hydroxamic Acids

A cyclic hydroxamic acid, 2–hydroxyquinoline–N–oxide and an aromatic hydroxamic acid, benzohydroxamic acid were obtained in the form of free acids. Their acid dissociation constants and a total of seventy of the formation constants for twenty five complexes formed by these two hydroxamic acids with rare earth metals and yttrium in aqueous solution have been determined by Bjerrum potentiometric titration technique.     

Hydroxamic acid polymers. Effect of structure on the chelation of iron in water: II

The effect of structure on the ability of hydroxamic acid polymers to chelate iron(III) was examined. The polymers were derived from acryloyl or methacryloyl backbones that bore side chains terminated in hydroxamic acids. The side chain length, which establishes the atomic chain distances between hydroxamic acid groups, had the most pronounced effect on the stability constant of the iron chelate. It was this atomic chain distance that determined how easily the three neighboring hydroxamic acids could fit the octahedral sphere of the iron. Other structural changes such as the presence or absence of methyl groups on the backbone or on the hydroxamic acid nitrogen had little measurable effect. The stability of the iron complexes appeared to be optimum at an 11-atom spacing between hydroxamic acids and decreased with shorter or longer spacing distances.     

Organophotocatalytic Generation of N‐ and O‐Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes

A cooperative TEMPO and photoredox catalytic strategy was applied for the first time to the direct conversion of N?H and O?H bonds into N‐ and O‐centred radicals, enabling a general and selective oxidative radical oxyamination and dioxygenation of various β,γ‐unsaturated hydrazones and oximes. In the reaction, O₂ was employed not only as a terminal oxidant but also as the oxygen source. This protocol provided efficient access to the synthesis of various synthetically and biologically important pyrazoline, pyridazine and isoxazoline derivatives under metal‐free and mild reaction conditions. Mechanistic studies revealed that the cooperative organophotocatalytic system functions through two single‐electron‐transfer (SET) processes.     

Hydroxamic acid polymers

A polymer bearing hydroxamic acid groups and having a high affinity for iron(III) was prepared through the following procedure. Acryloylalanine (III), prepared by the reaction of acryloyl chloride with alanine, was treated with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide to give the N-hydroxysuccinimide ester (IV). The ester IV was polymerized by using AIBN in dioxane to give polymer V. Treatment of polymer V with methylhydroxylamine in DMF gave the hydroxamic acid polymer II. The water-soluble polymer II was purified by dialysis or by gel-permeation chromatography (GPC) on Sephadex G-25. Analytical GPC on Sephadex G-200 and Sepharose 4B indicate that the average molecular weight of the polymer is in the range of 5 × 10⁵ to 1 × 10⁶. The presence of hydroxamic acid groups is confirmed by the intense red-brown color produced by the addition of iron(III) to a 50% aqueous DMF solution of the polymer under acidic conditions. In pure water the polymer-iron complex precipitates as a tan solid. Iron-binding studies of the polymer reveal that the iron(III) trihydroxamic acid complex FeA₃ forms at low concentrations of iron. At higher iron levels a lower order of stability is apparent, which can be accounted for by the conversion of FeA₃ to FeA₂⁺. In contrast, the FeA₃ complex of the trihydroxamic acid deferoxamine-B is stable at all iron levels. These results are consistent with the polymer structure, which for steric reasons would favor a stable complex, FeA₂⁺, between iron and two adjacent hydroxamic acid groups. An FeA₃ complex would be expected to have a lower stability as a result of either bond angle strain and atomic compression, or a lower probability in bringing a third hydroxamic acid into position to form the octahedral complex.     

Toward a fragment-based approach to MMPs inhibitors: an expedite and efficient synthesis of N-hydroxylactams

Matrix metalloproteinases (MMPs), a class of zinc-enzymes over-activated in many pathologies, such as arthritis and cancer, can be efficiently inhibited by a variety of molecules bearing zinc-binding groups (ZBGs). The hydroxamic acid moiety represents one of the most potent and widely exploited ZBG but the poor target selectivity and in vivo toxicity have tempered the initial enthusiasm for this class of potential therapeutics. These drawbacks might be circumvented, at least in part, by increasing the structural constraints around the hydroxamic moiety. Following this strategy we designed and prepared N-hydroxylactam molecules of different size through a synthetic protocol based on a ring closing metathesis amenable to a fragment-based approach potentially leading to a large molecular diversity.     

Reaction of singlet oxygen with tryptophan in proteins: a pronounced effect of the local environment on the reaction rate

Singlet molecular oxygen, O(2)(a(1)Δ(g)), can influence many processes pertinent to the function of biological systems, including events that result in cell death. Many of these processes involve a reaction between singlet oxygen and a given amino acid in a protein. As a result, the behavior of that protein can change, either because of a structural alteration and/or a direct modification of an active site. Surprisingly, however, little is known about rate constants for reactions between singlet oxygen and amino acids when the latter are in a protein. In this report, we demonstrate using five separate proteins, each containing only a single tryptophan residue, that the rate constant for singlet oxygen reaction with tryptophan depends significantly on the position of this amino acid in the protein. Most importantly, the reaction rate constant depends not only on the accessibility of the tryptophan residue to oxygen, but also on factors that characterize the local molecular environment of the tryptophan in the protein. The fact that the local protein environment can either appreciably inhibit or accelerate the reaction of singlet oxygen with a given amino acid can have significant ramifications for singlet-oxygen-mediated events that perturb cell function.     

Investigation of nitrogen- and sulfur-containing heterocycles

The corresponding N-(3-pyridyl)hydroxamic acid derivatives were obtained by reductive desulfuration of [2-(ethoxycarbonylmethylthio)-6-chloro-3-pyridyl]hydroxamic acid amide, benzylamide, and morpholide. The amides were synthesized by reaction of [2-(ethoxycarbonylmethylthio)-6-chloro-3-pyridyl]hydroxamic acid ester with diethylaminoethylamine and pyrrolidine. Heating of the ester and morpholide of [2-(ethoxycarbonylmethylthio)-6-chloro-3-pyridyl]hydroxamic acid with H₂SO₄ gives 2-chloropyrido[2,3-b] [1,4]thiazin-6-one.See [1] for communication XXVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 676–678, May, 1973.