Aromatic N-oxides Research Articles

ChemInform Abstract: A Computational Analysis of the Structural Features and Reactive Behavior of Some Heterocyclic Aromatic N-Oxides

Abstract An ab initio self-consistent-field molecular orbital analysis of the structural features and reactive behavior of pyridine, pyrazine and some of their N -oxide and nitro derivatives has been carried out. Optimized structures have been computed at the 6-31G ∗ level, yielding geometries in good agreement with experiment. These structures have been used to compute STO-5G electrostatic potentials and average local ionization energies on the respective molecular surfaces. There is considerable conjugation between the N -oxide groups and the aromatic rings, leading to significant para -quinonoid influence, manifested both in terms of structures and reactive properties. The charge-donor role of the N -oxide group allows the aromatic ring in pyridine N -oxide to be susceptible to electrophiles (at the para position) as well as nucleophiles; however, the rings in the pyrazine oxides are only receptive to the latter. The local ionization energies have permitted predictions of pK a values for pyrazine N -oxide and p -nitropyridine.

ChemInform Abstract: Molecular Complexes of Aromatic N-Oxides with Tetracyanoethylene.

Donor—acceptor interaction of tetracyanoethylene with aromatic N-oxides leads to the formation of two kinds of molecular complexes of the π,π-type: π-complexes and charge-transfer complexes. A correlation is observed between the reactivity of the N-oxides and the electronic properties of the substituents in the N-oxides.

A chemoselective deoxygenation of N-oxides by sodium borohydride–Raney nickel in water

A simple and convenient protocol for deoxygenation of aliphatic and aromatic N-oxides to the corresponding amines in good to excellent yield using sodium borohydride–Raney nickel in water is reported. Other functional moieties such as alkenes, halides, ethers, and amides are unaffected under the present reaction condition.

Aromatic N-oxide bridged copper(II) coordination polymers: Synthesis, characterization and magnetic properties

The complexes [Cu 2( o-NO 2–C 6H 4COO) 4(PNO) 2] ( 1), [Cu 2(C 6H 5COO) 4(2,2′-BPNO)] n ( 2), [Cu 2(C 6H 5COO) 4(4,4′-BPNO)] n ( 3), [Cu( p-OH–C 6H 4COO) 2(4,4′-BPNO) 2·H 2O] n ( 4), (where PNO = pyridine N-oxide, 2,2′-BPNO = 2,2′-bipyridyl- N, N′-dioxide, 4,4′-BPNO = 4,4′-bipyridyl- N, N′-dioxide) are prepared and characterized and their magnetic properties are studied as a function of temperature. Complex 1 is a discrete dinuclear complex while complexes 2– 4 are polymeric of which 2 and 3 have paddle wheel repeating units. Magnetic susceptibility measurements from polycrystalline samples of 1– 4 revealed strong antiferromagnetic interactions within the {Cu 2} 4+ paddle wheel units and no discernible interactions between the units. The complex 5, [Cu(NicoNO) 2·2H 2O] n ·4 nH 2O, in which the bridging ligand to the adjacent copper(II) ions is nicotinate N-oxide (NicoNO) the transmitted interaction is very weakly antiferromagnetic.

Variation in coordination modes of aromatic N-oxides in lanthanum(III) coordination polymers

Two new coordination polymers of lanthanum(III) benzoate having pyridine N-oxide and 4,4′-bipyridyl-N,N′-dioxide as ancillary ligands are synthesized and characterized. Different binding modes of the N-oxide are demonstrated; pyridine N-oxide binds as a bridging ligand, whereas 4,4′-bipyridyl-N,N′-dioxide is monodentate.

Molecular Recognition of Pyridine N-Oxides in Water Using Calix[4]pyrrole Receptors

The incorporation of four carboxylic acids or four amino groups to the upper rim of an aryl extended calix[4]pyrrole produces water-soluble receptors which are able to effectively bind aromatic N-oxides in water by a combination of hydrogen bonding, pi-pi, CH-pi, and hydrophobic interactions.

Identification of Aliphatic and Aromatic Tertiary N-Oxide Functionalities in Protonated Analytes via Ion/Molecule and Dissociation Reactions in an FT-ICR Mass Spectrometer

A mass spectrometric method is presented for the identification of compounds that contain the aliphatic or aromatic N-oxide functional group. This method utilizes gas-phase ion/molecule reactions of tri(dimethylamino)borane (TDMAB), which rapidly derivatizes protonated aliphatic and aromatic tertiary N-oxides, amides, and some amines via loss of dimethylamine in a Fourier transform ion cyclotron resonance mass spectrometer. The mechanism involves proton transfer from the protonated analyte to the borane, followed by addition of the analyte to the boron center and elimination of dimethylamine. The derivatized analytes are readily identified on the basis of their m/z value which is 98 Th (thomson) greater than that of the protonated analyte, and the characteristic boron isotope patterns. SORI-CAD of the product ions (adduct-(CH3)2NH) yields different fragment ions for aliphatic tertiary N-oxides, aromatic tertiary N-oxides, amides, and pyridines. Therefore, these analytes can be identified based on their characteristic fragment ions. This method was tested by examining two drug samples, Olanzapine and Olanzapine-4' N-oxide.

B···π-aromatic and C–H···B interactions in co-crystals of aromatic amine N-oxides with p-phenylenediboronic acid

Co-crystals of p-phenylenediboronic acid with four aromatic N-oxides namely pyridine N-oxide, quinoline N, N′-dioxide, isoquinoline N, N′-dioxide and 4,4′-dipyridine N, N′-dioxide are prepared and are structurally characterized. The stacking pattern in each case is found to be different. An interesting stacking effect that, sandwiches the boronic acid groups by pyridine N-oxide rings and associated through η 2 and η 3 type B–π interactions is presented. In the structures of co-crystals of aromatic amine N-oxides with p-phenylenediboronic acid B···π aromatic and C–H···B interactions are observed.

Kinetic Modeling of Oxidation of Antibacterial Agents by Manganese Oxide

Several groups of popular antibacterial agents (i.e., phenols, fluoroquinolones, aromatic N-oxides, and tetracyclines) were demonstrated in earlier studies to be highly susceptible to oxidation by manganese oxides, a common oxidant in soils. However, because of the high complexity, the reaction kinetics were not fully characterized. A mechanism-based kinetic model has now been developed to successfully describe the entire range of kinetic data for a total of 21 compounds of varying structural characteristics (with R2 > 0.93). The model characterizes the reaction kinetics by two independent parameters, the reaction rate constant (k) and total reactive surface sites (S(rxn)). The model fitting indicates that the reaction kinetics of antibacterials with MnO2 are controlled by either the rate of surface precursor complex formation (for tetracyclines) or by the rate of electron transfer within the precursor complex (for phenols, fluoroquinolones, and aromatic N-oxides). The effect of reactant concentration, pH, and cosolutes on the reaction kinetics was evaluated and correlated to kand S(rxn). All the trends are consistent with the proposed rate-limiting steps. This new model improves the ability to quantitatively evaluate the kinetics of oxidative transformation of organic contaminants by manganese oxides in well-defined systems.

Identification of the Aromatic Tertiary N-Oxide Functionality in Protonated Analytes via Ion/Molecule Reactions in Mass Spectrometers

A mass spectrometric method is presented for the rapid identification of compounds that contain the aromatic N-oxide functional group. This method utilizes a gas-phase ion/molecule reaction with 2-methoxypropene that yields a stable adduct for protonated aromatic tertiary N-oxides (and with one protonated nitrone) in different mass spectrometers. A variety of protonated analytes with O- or N-containing functional groups were examined to probe the selectivity of the reaction. Besides protonated aromatic tertiary N-oxides and one nitrone, only three protonated amines were found to form a stable adduct but very slowly. All the other protonated analytes, including aliphatic tertiary N-oxides, primary N-oxides, and secondary N-oxides, are unreactive toward or react predominantly by proton transfer with 2-methoxypropene.

N-Oxides in Metal-Containing Multicomponent Molecular Complexes

Syntheses and structures of three-component rare cocrystals of 4-nitrobenzoic acid, aromatic N-oxides, and aqua complexes of manganese and zinc and their transformation to metal complexes as well as coordination polymers are presented.

Recent Trends in the Chemistry of Molecular Complexes of Heteroaromatic N-Oxides

Literature review on molecular complexes of aromatic N-oxides with various electron acceptors published in the last decade is presented. Structure, chemistry, and new preparation methods of these complexes are discussed.

Syntheses, crystal structures and magnetic study of two binuclear manganese(II) complexes with aromatic N-oxide as bridging ligand

Two new binuclear complexes, [Mn2(μ-dmpo)2(SCN)4(H2O)2] (1) (where dmpo = 3,5-dimethylpyridine N-oxide), [Mn2(μ-po)2(H2O)6I2]I2 (2) (where po = pyridine N-oxide), have been synthesized and their crystal structures determined by X-ray crystallography. Complexes 1 and 2 crystallize in monoclinic, space group P21/c, with unit cell dimensions a = 8.8836(18) Å, b = 15.450(3) Å, c = 15.484(3) Å, β = 91.020(3)° for 1, and a = 8.8352(13) Å, b = 17.927(3) Å, c = 8.3338(12) Å, β = 103.765(2)° for 2. In each binuclear complex two Mn(II) were bridged by two 3,5-dimethylpyridine N-oxides or by two pyridine N-oxides and the distances between the bridged Mn(II) ions are 3.599 Å for 1 and 3.552 Å for 2. Variable temperature (4–300 K) magnetic measurements were performed for 1 and the susceptibility data were fitted by using a binuclear Mn(II) magnetic coupling formula producing the 2J = −2.17 cm−1.

Alkyl radical adducts of aromatic N-oxides as hydrogen-abstracting agents: The reactivity of phenazine-N,N′-dioxide-methyl radical adduct

An O-methylated analog of protonated phenazine-di-N-oxide radical anion abstracts hydrogen from primary and secondary alcohols in a slow (k 1 < 500 M−1 s−1) bimolecular reaction. No kinetic evidence has been found for the unimolecular release of free methoxyl radicals through the homolytic N-OMe bond cleavage in these species. DFT calculations at the UB3LYP 6-31G(d) level indicate that protonated and O-alkylated radical anions of pyrazine, quinoxaline and phenazine di-N-oxides are close analogues of aromatic nitroxyl radicals with the highest spin density localized on the oxygen and nitrogen of the nitrone moiety.

A general method for the deoxygenation of aromatic N-oxides using RuCl 3· xH 2O

An efficient, simple and selective method for the deoxygenation of aromatic N-oxides, such as N-arylnitrones, azoxybenzenes, N-heteroarene N-oxides using ruthenium(III) chloride to afford deoxygenated products in excellent yields, is described.

Quinoxaline 1,4-dioxides: hypoxia-selective therapeutic agents.

A problem that confronts clinicians in the treatment of cancer is the resistance of hypoxic tumors to chemotherapy and radiation therapy. Thus, the development of new drugs that are toxic to hypoxic cells found in solid tumors is an important objective for effective anticancer chemotherapy. We recently showed that the heterocyclic aromatic N-oxides, quinoxaline 1,4-dioxides (QdNOs), are cytotoxic to tumor cells cultured under hypoxia. In this study, we evaluated the hypoxia-selective toxicity of four diversely substituted QdNOs and determined their effect on the expression of hypoxia inducible factor (HIF) 1alpha in the human colon cancer cell line T-84. The various QdNOs were found to possess a 50- to 100-fold greater cytotoxicity to T-84 cells cultured under hypoxia compared with oxia. Interestingly, the hypoxia cytotoxicity ratio (HCR), the ratio of equitoxic concentrations of the drug under aerobic/anoxic conditions, was highly structure related and depended on the nature of the substituents on the QdNO heterocycle. The most cytotoxic 2-benzoyl-3-phenyl-6,7-dichloro derivative of QdNO (DCQ) was potent at a dose of 1 microM with an HCR of 100 and significantly reduced the levels of HIF-1alpha transcript and protein. The 2-benzoyl-3-phenyl derivative (BPQ) had a hypoxia potency of 20 microM and an HCR of 40. By contrast, the 2-aceto-3-methyl and the 2,3-tetramethylene (TMQ) derivatives of QdNO were much less cytotoxic under hypoxia (HCRs of 8.5 and 6.5, respectively) and reduced the expression of HIF-1alpha mRNA to a much lesser extent. Because the nonchlorinated analogue BPQ did not demonstrate behavior similar to that of DCQ, we hypothesize that the C-6, C-7-chlorine of DCQ might play a significant role in the selective hypoxic cytotoxicity of the drug.

Microwave-induced organometallic reactions in aqueous media. Use of Ga and Bi for the allylation of aromatic N-oxides and hydrazones

Homoallylic hydroxylamines and homoallylic hydrazides were synthesised in excellent yields by the reaction of allylgallium or allylbismuth reagent, generated in situ in the presence of 0.1 equivalent of NH4Cl–Bu4NBr, with aldonitrones and hydrazones in aqueous media. The reaction rate can be increased dramatically under microwave activation.

Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia.

Hypoxia is a feature of some regions of many tumours, ischaemic events, and arthritis. Drugs activated in hypoxia have wide potential application, particularly in overcoming the resistance of hypoxic tumour cells to radiotherapy. Key features of such drugs include redox properties appropriate for activation by reductase enzymes (typically flavoproteins), and oxygen-sensitive reduction chemistry such that normal levels of oxygen inhibit or reverse reduction. In many cases this selectivity is achieved by a fast, free-radical reaction in which the drug radical (often an obligate intermediate in drug reduction) reduces oxygen to form superoxide radicals and thus 'futile cycles' the drug in normoxic tissues. However, this enhances cellular oxidative stress, which may be linked to normal tissue toxicity. Appropriate redox properties are found with nitroarene, quinone, or aromatic N-oxide moieties. A particularly promising and versatile exploitation of bioreductive activation is for reduction of such 'triggers' to activate release of an 'effector', an agent that can obviously be active against diverse conditions associated with hypoxia. The same approach can also be used in diagnosis of hypoxia. Much information concerning the reactions of intermediates in drug action and the quantitative prediction of redox properties of analogues has been accrued. Drug design can be mechanism-led, with the wealth of literature quantifying redox properties of drug candidates a rich source of potential new leads. There is a clear appreciation of the kinetic factors that limit drug efficacy or selectivity. Thus the potential for rapid expansion of these concepts to diverse diseases is considerable.

Quinoxaline 1,4-dioxides as anticancer and hypoxia-selective drugs.

Hypoxic cells which are found in solid tumors are resistant to anticancer drugs and radiation therapy. Thus, for effective anticancer chemotherapy, it is important to identify drugs with selective toxicity towards hypoxic cells. Quinoxaline 1,4-dioxides (QdNOs) are heterocyclic aromatic N-oxides that have been found to possess potent antibacterial activities (inhibit microbial DNA synthesis) especially under anaerobic conditions; thus they are under evaluation as bioreductive drugs for the treatment of solid tumors (1). We investigated the ability of four differently substituted QdNOs to inhibit cell growth and induce cell cycle changes in two human tumorigenic epithelial cell lines under oxic conditions. We also evaluated the toxicity of these drugs to cancer cells cultured under hypoxic conditions. Two epithelial cell lines (the T-84 human colon cancer-derived cell line, and the SP-1 keratinocyte cell line) were treated with various doses of the QdNOs and harvested at different times after treatment. Proliferation and cell cycle results showed a structure-function relationship in the activity of the various QdNO compounds with the 2-benzoyl-3-phenyl-6,7-dichloro-derivative of QdNO (DCBPQ) being the most potent cytotoxin and hypoxia-selective drug. The 2-benzoyl-3-phenyl (BPQ) and the 2-acyl-3-methyl-derivative of QdNO (AMQ) were less cytotoxic but arrested almost 50% of the cells in the G2M phase of the cell cycle at doses of 30 and 120 microM, respectively. The tetramethylene derivative of QdNO (TMQ) did not affect the growth and cycling of cells cultured in air and was the least potent cytotoxin to hypoxic cells. Our results indicate that the QdNOs are hypoxia-cytotoxic drugs whose activity varies according to the substituents on the quinoxaline 1,4-dioxide heterocycle. Because of their selective toxicity to hypoxic cells (cells found in human tumors), these drugs may provide useful therapeutic agents against solid tumors.

N-oxidation of pyridines by hydrogen peroxide in the presence of TS-1

In the production of aromatic N-oxides using the oxidation of N-containing heterocyclic aromatic substrates with H2O2 as oxidant, the non-catalysed homogeneous oxidation is found to play an important part in the overall reaction. In addition, when TS-1 is used as a catalyst, there are many potential competitive interactions between the catalyst, the reactants and the products, which limit the effectiveness of the catalyst. It is concluded that the use of TS-1 and other microporous catalysts for the heterogeneous N-oxidation of pyridine and substituted pyridines needs to be interpreted with caution.