Nitrooxy Group Research Articles

Practical and regioselective halonitrooxylation of olefins to access β-halonitrates

Organic nitrates, as effective donors of the signaling molecule nitric oxide, are widely applied in the pharmaceutical industry. However, practical and efficient methods for accessing organic nitrates are still scarce, and achieving high regiocontrol in unactivated alkene difunctionalization remains challenging. Here we present a simple and practical method for highly regioselective halonitrooxylation of unactivated alkenes. The approach utilizes TMSX (X: Cl, Br, or I) and oxybis(aryl-λ3-iodanediyl) dinitrates (OAIDN) as sources of halogen and nitrooxy groups, with 0.5 mol % FeCl3 as the catalyst. Remarkably, high regioselectivity in the halonitrooxylation of aromatic alkenes can be achieved even without any catalyst. This protocol features easy scalability and excellent functional group compatibility, providing a range of β-halonitrates (127 examples, up to 99% yield, up to >20:1 rr). Notably, 2-iodoethyl nitrate, a potent synthon derived from ethylene, reacts smoothly with a variety of functional units to incorporate the nitrooxy group into the desired molecules.

Modular and Practical 1,2‐Aryl(Alkenyl) Heteroatom Functionalization of Alkenes through Iron/Photoredox Dual Catalysis**

AbstractEfficient methods for synthesizing 1,2‐aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2‐aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2‐aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.

Modular and Practical 1,2-Aryl(Alkenyl) Heteroatom Functionalization of Alkenes through Iron/Photoredox Dual Catalysis.

Efficient methods for synthesizing 1,2-aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2-aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.

Ionic Strength Effect Triggers Brown Carbon Formation through Heterogeneous Ozone Processing of Ortho-Vanillin.

Methoxyphenols are an important class of compounds emerging from biomass combustion, and their reactions with ozone can generate secondary organic aerosols in the atmosphere. Here, we use a vertical wetted wall flow tube reactor to evaluate the effect of ionic strength on the heterogeneous reaction of gas-phase ozone (O3) with a liquid film of o-vanillin (o-VL) (2-hydroxy-3-methoxybenzaldehyde), as a proxy for methoxyphenols. Typical for moderately acidic aerosols, at fixed pH = 5.6, the uptake coefficients (γ) of O3 on o-VL ([o-VL] = 1 × 10-5 mol L-1) increase from γ = (1.9 ± 0.1) × 10-7 in the absence of Na2SO4 to γ = (6.8 ± 0.3) × 10-7 at I = 0.2 mol L-1, and then, it decreases again. The addition of NO3- ions only slightly decreases the uptakes of O3. Ultrahigh-resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) reveals that the formation of multicore aromatic compounds is favored upon heterogeneous O3 reaction with o-VL, in the presence of SO42- and NO3- ions. The addition of NO3- ions favors the formation of nitrooxy (-ONO2) or oxygenated nitrooxy group of organonitrates, which are components of brown carbon that can affect both climate and air quality.

Structural and biological characterization of new hybrid drugs joining an HDAC inhibitor to different NO-donors

HDAC inhibitors and NO donors have already revealed independently their broad therapeutic potential in pathologic contexts. Here we further investigated the power of their combination in a single hybrid molecule. Nitrooxy groups or substituted furoxan derivatives were joined to the α-position of the pyridine ring of the selective class I HDAC inhibitor MS-275. Biochemical analysis showed that the association with the dinitrooxy compound 31 or the furoxan derivative 16 gives hybrid compounds the ability to preserve the single moiety activities. The two new hybrid molecules were then tested in a muscle differentiation assay. The hybrid compound bearing the moiety 31 promoted the formation of large myotubes characterized by highly multinucleated fibers, possibly due to a stimulation of myoblast fusion, as implicated by the strong induction of myomaker expression. Thanks to their unique biological features, these compounds may represent new therapeutic tools for cardiovascular, neuromuscular and inflammatory diseases.

Synthesis of γ-carbolines containing NO-donor fragment and assessment of their anticholinesterase activity

Hybrid γ-carboline-based compounds containing a nitrooxy group as an NO-donor were prepared. It was shown that the introduction of this group did not affect the inhibitory activity of γ-carboline pharmacophore against acetyl- and butyrylcholinesterase.

Aerosol size distribution characteristics of organosulfates in the Pearl River Delta region, China

Organosulfates (OSs) have been detected in various atmospheric environments, but their particle size distribution characteristics are unknown. In this work, we examined their size distributions in ambient aerosols to gain insights into the formation processes. Size-segregated aerosol samples in the range of 0.056–18 μm were collected using a ten-stage impactor at a receptor site in Hong Kong in both summer and winter and in Nansha in the Pearl River Delta in winter. The humic-like substances fraction in the size-segregated samples was isolated and analyzed using electrospray ionization coupled with an Orbitrap Ultra High Resolution Mass Spectrometer. Through accurate mass measurements, ∼190 CHOS and ∼90 CHONS formulas were tentatively identified to be OS compounds. Among them, OS compounds derived from isoprene, α-/β-pinene, and limonene and alkyl OSs having low double bond equivalents (DBE = 0,1) and 0–2 extra O beyond those in –OSO3 were found with high intensity. The biogenic volatile organic compounds-derived OS formulas share a common characteristic with sulfate in that the droplet mode dominated, peaking in either 0.56–1.0 or 1.0–1.8 μm size bin, reflecting sulfate as their common precursor. Most of these OSs have a minor coarse mode, accounting for 0–45%. The presence of OSs on the coarse particles is hypothesized to be a result of OSs on small particle (<0.32 μm) coagulating with coarse particles, as the abundance ratios of OS to non-sea-salt sulfate present on the coarse particles were similar to those on particles <0.32 μm. Among a few pairs of CHONS and CHOS that could be linked up through hydrolysis of a nitrooxy group in the CHONS form (e.g., m/z 294: C10H16O7NS− vs. m/z 249 C10H17O5S− from α/β-pinene, differing by (+H2O–HNO3)), the CHONS compounds had an enhanced coarse mode presence. This could be interpreted as a result of slower hydrolysis of the CHONS compounds on the alkali coarse particles. The low DBE alkyl OS compounds have a dominant droplet mode at the Hong Kong site, but a more significant coarse mode presence was observed for CnH2n+1O4S−, CnH2n−1O4S−, and CnH2n−1O5S− formulas in the Nansha site, possibly suggesting site-specific mixed secondary and primary sources for these formulas.

Alkyl Nitrate Formation from the Reactions of C8–C14n-Alkanes with OH Radicals in the Presence of NOx: Measured Yields with Essential Corrections for Gas–Wall Partitioning

In this study, C8-C14 n-alkanes were reacted with OH radicals in the presence of NO(x) in a Teflon film environmental chamber and isomer-specific yields of alkyl nitrates were determined using gas chromatography. Because results indicated significant losses of alkyl nitrates to chamber walls, gas-wall partitioning was investigated by monitoring the concentrations of a suite of synthesized alkyl nitrates added to the chamber. Gas-to-wall partitioning increased with increasing carbon number and with proximity of the nitrooxy group to the terminal carbon, with losses as high as 86%. The results were used to develop a structure-activity model to predict the effects of carbon number and isomer structure on gas-wall partitioning, which was used to correct the measured yields of alkyl nitrate isomers formed in chamber reactions. The resulting branching ratios for formation of secondary alkyl nitrates were similar for all isomers of a particular carbon number, and average values, which were almost identical to alkyl nitrate yields, were 0.219, 0.206, 0.254, 0.291, and 0.315 for reactions of n-octane, n-decane, n-dodecane, n-tridecane, and n-tetradecane, respectively. The increase in average branching ratios and alkyl nitrate yields with increasing carbon number to a plateau value of ∼0.30 at about C13-C14 is consistent with predictions of a previously developed model, indicating that the model is valid for alkane carbon numbers ≥C3.

Water‐Soluble Nitric‐Oxide‐Releasing Acetylsalicylic Acid (ASA) Prodrugs

A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH 1) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO-donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. Simple NO-donor benzoic acids 3-hydroxy-4-(3-nitrooxypropoxy)benzoic acid (28) and 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoic acid (48) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300 μM. Only 28 displays quite potent NO-dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2-(acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3-(nitrooxy)propoxy]benzoate⋅HCl (38) and {[2-(acetyloxy)benzoyl]oxy}methyl 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoate oxalate (49), revealed that their anti-inflammatory activities are similar to that of ASA when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO-donor ASA prodrugs warrant further investigation for clinical application.

2,4-Bis(dimethylamino)-1,3,5-trimethyl-6-(nitrooxy)borazine

In the title compound, C7H21B3N6O3, the r.m.s. deviation of the borazine ring atoms is 0.019 Å. The dimethyl­amino groups are orientated at 41.80 (7) and 36.43 (7)° with respect to the borazine ring. The nitro­oxy group is almost normal to the borazine ring [dihedral angle = 85.33 (14)°]. The methyl C atom trans to the NO3 group is displaced by −0.512 (3) Å from the ring plane, whereas the two ortho-methyl C atoms are displaced by 0.239 (3) and 0.178 (3) Å.

ChemInform Abstract: Direct Oxidative Installation of Nitrooxy Group at Benzylic Positions and Its Transformation into Various Functionalities.

AbstractCAN /NHPI is the successful system for the title reactions.

Direct oxidative installation of nitrooxy group at benzylic positions and its transformation into various functionalities

C–H Nitrooxylation at benzylic positions has been achieved by employing the N-hydroxyphthalimide (NHPI) catalyst/cerium(IV) ammonium nitrate (CAN) reagent system. The nitrooxy groups were demonstrated to function as tentative hydroxy protecting groups, as well as excellent leaving groups for N- and C-substitution reactions. Hence, the present method offers a unique way to synthesize diverse O-, N-, or C-functionalized benzylic compounds from simple alkyl aromatics.

(Nitrooxyacyloxy)methyl Esters of Aspirin as Novel Nitric Oxide Releasing Aspirins

A series of (nitrooxyacyloxy)methyl esters of aspirin were synthesized and evaluated as new NO-donor aspirins. Different amounts of aspirin were released in serum from these products according to the nature of nitrooxyacyloxy moiety present. In the aromatic series, there is a rather good linear correlation between the amount of aspirin released and the potencies of the products in inhibiting platelet aggregation induced by collagen. Both the native compounds and the related nitrooxy-substituted acid metabolites were able to relax rat aorta strips precontracted with phenylephrine, in keeping with a NO-induced activation of the sGC as a mechanism that underlies the vasodilator effect. The products here described are new improved examples of NO-donor aspirins containing nitrooxy groups. They could represent an alternative to the use of aspirin in a variety of clinical applications.

The Atmospheric Fate of C3−C6 Hydroxyalkyl Nitrates

Rate coefficients for the reaction of OH radical with eleven C3−C6 hydroxyalkyl nitrates and with two C4 hydroxy nitrates containing a double bond were determined at atmospheric pressure and 296 ± 2 K. The rate coefficients were measured in a photochemical reactor by the relative rate technique, employing solid-phase microextraction (SPME) coupled to gas chromatography (GC) for detection of the organic reactants. Hydroxyalkyl nitrates react faster than alkyl nitrates with the OH radical. The rate coefficients increase with increasing chain length and separation between the hydroxy and the nitrooxy groups. By including different loss processes such as photolysis, gas-phase reactions, and solubility, the tropospheric lifetime of C3−C6 hydroxyalkyl nitrates is estimated to range between 0.5 and 4.5 days. Due to their higher reactivity and solubility, hydroxyalkyl nitrates have a shorter atmospheric lifetime than alkyl nitrates.

ChemInform Abstract: Synthesis and Antihypertensive Activities of New 1,4‐Dihydropyridine Containing Nitroimidazolyl Substituent with a Nitrooxy Group at the 3‐Ester Position.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Rate Coefficients for the Reactions of Cl Atoms with a Series of C3−C6 Hydroxyalkyl Nitrates at 296 ± 2 K

Rate coefficients for the gas-phase reactions of chlorine atoms with a series of C3−C6 hydroxyalkyl nitrates of atmospheric interest have been determined at 296 ± 2 K and atmospheric pressure. The experiments were conducted using the relative rate technique combined with solid-phase microextraction (SPME) sampling followed by gas chromatography (GC) analysis with an electron capture detector (ECD). The experiments were performed in a collapsible 100 L PVF-film (Tedlar) reaction chamber. It is shown that the presence of the hydroxy group enhances the reactivity of the hydroxyalkyl nitrates toward the Cl atom as compared to the corresponding alkyl nitrates and alkyl dinitrates. The Cl atom reactivity toward the hydroxyalkyl nitrates increases with the length of the alkyl chain and with increasing separation between the hydroxy and the nitrooxy groups. Tropospheric lifetimes are calculated using the determined rate coefficients and the atmospheric implications are briefly discussed.

Synthesis and antihypertensive activities of new 1,4-dihydropyridine containing nitroimidazolyl substituent with a nitrooxy group at the 3-ester position.

New analogues of nifedipine, in which the ortho nitrophenyl group of position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl or 1-methyl-5-imidazolyl with a nitrooxy group at the 3-ester position were synthesized, and the antihypertensive activity of the compounds was examined by the tail-cuff method and compared with TNG and nifedipine. Compounds 11g, 11i-11m, 11o, 11r, and 11v showed activity similar to nifedipine and TNG.

Measurement of octanol–air partition coefficients using solid-phase microextraction (SPME)—application to hydroxy alkyl nitrates

Multifunctional organic compounds are thought to constitute a major component of the organic matter found in atmospheric particles. Their partitioning into the organic matter depends on their structure, their chemical properties and the properties of the absorbing matrix. It was recently shown that octanol is a suitable surrogate for organic particles and the octanol–air partition coefficient ( K OA) was suggested as a useful tool for estimating the partitioning of organic compounds into atmospheric particles that contain high organic mass fractions. In this paper, we present a new and simple technique for the determination of K OA using solid phase microextraction (SPME) relative to a known Henry's law constant. We apply the technique for the determination of K OA of β-, γ- and δ-C 3–C 5 hydroxy alkyl nitrates. The temperature dependence of K OA for some of the compounds is also measured. It is shown that the solubility constants of these compounds are higher in octanol than in water and that the solubility in octanol increases with the length of the hydrophobic chain and with increasing distance between the hydroxy and the nitrooxy groups. Partition coefficients between the gas and particulate phase ( K p) are calculated using the determined K OA values and their atmospheric implications are discussed.

Separation of Diastereomeric and Enantiomeric Alkyl Nitrates-Systematic Approach to Chiral Discrimination on Cyclodextrin LIPODEX-D.

High-resolution gas chromatographic separation of all diastereomeric monomethyl-substituted cyclohexyl nitrates is shown on a nonpolar methylpolysiloxane stationary phase, and the first application of this procedure to the environmental diastereomeric analysis of alkyl nitrates is presented. Two characteristic signals in the achiral analysis of atmospheric samples could be assigned to the smallest alkyl nitrate containing two asymmetric carbon atoms, 3-methyl-2-pentyl nitrate. Retention indices in the temperature-programmed separation based on the n-alkanes were determined. The homologous series of 1-alkyl nitrates were found to be useful as ECD-visible n-alkanes. Enantiomeric separation of alkyl nitrates was achieved on heptakis(3-O-acetyl,-2,6-di-O-pentyl)-β-cyclodextrin (LIPODEX-D). The influence of the nitrooxy group and the alkyl chain length on the chiral discrimination on LIPODEX-D is discussed for 25 chiral alkyl nitrates. The absolute configurations of some alkyl nitrates were assigned by asymmetric synthesis of enantiomerically pure references. The complexity of the alkyl nitrate mixtures present in air samples does not allow a direct chiral separation as the alkyl nitrates partly coelute on the LIPODEX-D column. Column coupling of LIPODEX-D with a polar achiral stationary phase like polyalkylenglycol (PAG) was successfully applied to solve this problem, and the chiral alkyl nitrates present in a typical air sample were separated. A systematic nomenclature for alkyl nitrates is introduced to handle the steadily growing number of branched and long-chain alkyl nitrates detected in environmental analysis.