Isoamyl Nitrite Research Articles

Comparison of the Relative Propensities of Isoamyl Nitrite and Sodium Nitrite to Ameliorate Acute Cyanide Poisoning in Mice and a Novel Antidotal Effect Arising from Anesthetics

Isoamyl nitrite has previously been considered acceptable as an inhaled cyanide antidote; therefore, the antidotal utility of this organic nitrite compared with sodium nitrite was investigated. To facilitate a quantitative comparison, doses of both sodium nitrite and isoamyl nitrite were given intraperitoneally in equimolar amounts to sublethally cyanide-challenged mice. Righting recovery from the knockdown state was clearly compromised in the isoamyl nitrite-treated animals, the effect being attributable to the toxicity of the isoamyl alchol produced during hydrolysis of the isoamyl nitrite to release nitrite anion. Subsequently, inhaled aqueous sodium nitrite aerosol was demonstrated to ameliorate sublethal cyanide toxicity, when provided to mice after the toxic dose, by the more rapid recovery of righting ability compared to that of the control animals given only the toxicant. Aerosolized sodium nitrite has thus been shown by these experiments to have promise as a better alternative to organic nitrites for development as an inhaled cyanide antidote. The inhaled sodium nitrite led to the production of NO in the bloodstream as determined by the appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. The aerosol delivery was performed in an unmetered inhalation chamber, and in this study, no attempt was made to optimize the procedure. It is argued that administration of an effective inhaled aqueous sodium nitrite dose in humans is possible, though just beyond the capability of current individual metered-dose inhaler designs, such as those used for asthma. Finally, working at slightly greater than LD50 NaCN doses, it was fortuitously discovered that (i) anesthesia leads to significantly prolonged survival compared to that of unanesthetized animals and that (ii) the antidotal activity of nitrite anion was completely abolished under anesthesia. Plausible explanations for these effects in mice and their practical consequences in relation to testing putative cyanide antidotes are discussed.

P63: The antidotal action of nitrites toward cyanide intoxication: An example of medicine disguised as quackery

Sodium nitrite ameliorates sub-lethal cyanide toxicity in mice when given from ∼1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. In most experiments nitrite was given intraperitoneally, but may also be administered as an inhaled aqueous vapor-contrary to recommended EMR protocols, it is not necessary to infuse the antidote intravenously and the co-administration of adjuvants (specifically thiosulfate) is unnecessary. Intraperitoneally administered nitrite rapidly produces NO in the bloodstream as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. However, the commonly held belief that the antidotal mechanism of nitrites involves the scavenging of cyanide anion by methemoglobin is firmly contraindicated by recent evidence. Intriguingly, the FDA-approved and clinically tested cyanide scavenger cobalamin has, in fact, rather indifferent binding affinity for cyanide anion. It follows that the clinical usefulness of cobalamin may be dependent on endogenous nitric oxide displacing the cyanide from the active site of cytochrome c oxidase to facilitate the cyanide-scavenging action of cobalamin. Antagonism of cyanide inhibition of cytochrome c oxidase by NO appears to be the crucial antidotal activity rather than any methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood results in the production of sulfidomethemoblobin as detected by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase; the effects of the two inhibitors being essentially additive under standard assay conditions, rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sub-lethal levels of cyanide intoxication. Isoamyl nitrite, given intraperitoneally in equimolar amounts to sodium nitrite, is comparatively less effective at restoring the righting recovery of cyanide-challenged mice. The results of investigations with the hydrolysis products of isoamyl nitrite, isoamyl alcohol and nitrite anion, suggest that the toxicity of isoamyl alcohol renders the organic nitrite a less desirable antidotal agent than sodium nitrite. Disclosure Supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grant No. NS063732 to J.P and L.L.P and Bruce R. Pitt.

Rapid determination of isoamyl nitrite in pharmaceutical preparations by flow injection analysis with on‐line UV irradiation and luminol chemiluminescence detection

Isoamyl nitrite is used as a therapeutic reagent for cardiac angina and as an antidote for cyanide poisoning, but it is abused because of its euphoric properties. Therefore, a method to determine isoamyl nitrite is required in many fields, including pharmaceutical and forensic studies. In this study, a simple, rapid and sensitive method for the determination of isoamyl nitrite was developed using a flow injection analysis system equipped with a chemiluminescence detector and on-line photoreactor. This method is based on on-line ultraviolet irradiation of isoamyl nitrite and subsequent luminol chemiluminescence detection without the addition of an oxidant. A linear standard curve was obtained up to 1.0 μM of isoamyl nitrite with a detection limit (blank + 3SD) of 0.03 μM. The method was successfully applied to determine isoamyl nitrite content in pharmaceutical preparations.

Prevalence of New Designer Drugs and Their Legal Status in Japan

In recent years, many analogs of narcotics have been widely distributed as easily available psychotropic substances and have become a serious problem in Japan. To counter the spread of these non-controlled substances, the Pharmaceutical Affairs Law in Japan was amended in 2006 to establish a new category; Designated Substances in order to more strictly control these substances. In April 2007, 31 compounds and 1 plant were first controlled as Designated Substances. Before 2007, the major compounds distributed in the Japanese illegal drug market were tryptamines, phenethylamines and piperazines. Alkyl nitrites, such as isobutyl nitrite and isopentyl nitrite, were also widely distributed. After they were listed as Narcotics or Designated Substances in 2007, these compounds, especially the tryptamines, quickly disappeared from the market. In their place, cathinone derivatives have been widely distributed, as well as different phenethylamines and piperazines. Additionally, in recent years, new herbal products containing synthetic cannabinoids have appeared globally. As at July 2012, 78 substances (including 1 plant; Salvia divinorum) were listed in the category of Designated Substances. They were 13 tryptamines, 17 phenethylamines, 11 cathinones, 4 piperazines, 23 synthetic cannabinoids, 6 alkyl nitrites, 3 other compounds and 1 plant. In this review, we show our survey of the spread of new designer drugs in Japan, focusing especially on synthetic cannabinoids and cathinone derivatives. Also, the prevalence and legal status of these substances in other countries will be presented.

Comparative study of the covalent diazotization of graphene and carbon nanotubes using thermogravimetric and spectroscopic techniques

The direct diazotization of the sp(2) carbon network of graphene and multi-walled carbon nanotubes (MWNTs) is one of the many methods employed to introduce functional groups into these nanostructures. Herein, a methodical study on solvent-free diazotization with ethynylaniline in the presence of isoamyl nitrite is reported. Thermogravimetric analysis and UV-visible, infrared and Raman spectroscopies are used to precisely determine the degree of modification, confirm the presence of physisorption and describe the mechanism of elimination of the modifying groups. The results suggest that the same synthetic protocol in both cases leads to a certain degree of covalent modification, whilst a proportion of the modifying groups remains adsorbed to the carbon nanostructure. A higher level of global modification was observed for MWNTs. It was found that the elimination mechanism of the covalently-linked modifiers is identical for both nanostructures and involves two steps; acetylenic-aromatic bond rupture in the modifier followed by modifier-carbon nanostructure cleavage.

ChemInform Abstract: Synthesis of 3‐Diazopyrrolidin‐2‐ones.

AbstractTitle compounds (II) and (VI) are synthesized by reaction of amines (I) or (V), resp., with isopentyl nitrite.

Elucidation of the therapeutic enhancer mechanism of poly-S-nitrosated human serum albumin against multidrug-resistant tumor in animal models

Human serum albumin (HSA) is the most abundant circulating protein and its S-nitrosated form serves as a reservoir of nitric oxide (NO). Previously, we prepared poly-S-nitrosated HSA (Poly-SNO-HSA) by incubation with Traut's Reagent and isopentyl nitrite and evaluated its potential as a novel anticancer agent through apoptosis involving the caspase-3 pathway. Recently, NO donors such as nitroglycerin were reported to revert the resistance to anticancer agents. Therefore, now we have evaluated the effect of the above type of Poly-SNO-HSA on the resistance to doxorubicin (dx) in human myelogenous leukemic cells (K562 cells). P-gp expression and dx accumulation in K562 and dx-resistant K562 cells (K562/dx cells) were quantified using Western blot and FACS analysis, respectively. Compared with parent K562 cells, higher expression of P-gp and lower accumulation of dx were shown in K562/dx cells. Poly-SNO-HSA caused increased dx accumulation in K562/dx cells by decreasing the expressions of P-gp and HIF-1α. Other experiments with the guanylate cyclase inhibitor ODQ and 8-Br-cGMP revealed that also a cGMP signaling pathway is involved in the Poly-SNO-HSA induced increase in dx accumulation. Furthermore, in vivo studies showed that co-treatment with Poly-SNO-HSA enhanced the anticancer effect of dx in K562/dx cells-bearing mice. Thus, in addition to its proapoptotic effect Poly-SNO-HSA can in an efficient manner revert drug resistance both in vitro and in vivo, and two pathways for this effect have been identified.

Cold-Surface Photochemistry of Primary and Tertiary Alkyl Nitrites

Reflection-absorption infrared spectroscopy (RAIRS) is used to explore the photochemistry of primary and tertiary alkyl nitrites deposited on a gold surface. The primary alkyl nitrites examined for this study were n-butyl, isobutyl, and isopentyl nitrite. These compounds showed qualitatively similar spectra to those observed in previous condensed-phase measurements. The photolysis of the primary nitrites involved the initial formation of an alkoxy radical and NO, followed by production of nitroxyl (HNO) and an aldehydic species. In addition, the formation of nitrous oxide, identified from its distinctive transition near 2230 cm(-1), was observed to form from the self-reaction of nitroxyl. The reaction rates for cis and trans conformer decay, as tracked through their intense N═O stretching modes, were found to be significantly different, potentially due to a structural bias that favors HNO formation for the initial trans conformer photoproducts over recombination. Tert-butyl nitrite demonstrates only the trans conformer in the RAIRS spectra prior to photolysis; however, recombination of the initial NO and RO(•) photoproducts was observed to produce the cis conformer in the photolyzed samples. The primary photoproducts from tert-butyl nitrite can also react to form acetone and nitrosomethane, but the absence of HNO prohibits the formation of N(2)O that was observed for the primary alkyl nitrites. Additionally, the RAIRS spectrum of isobutyl nitrite co-deposited with water was measured to examine the photolysis of this species on a water-ice surface. No change in the identity of the photoproducts was observed in this experiment, and minimal frequency shifting (1-3 cm(-1)) of the vibrational modes occurred. In addition to being a known atmospheric source of NO and various aldehydes, our results point to cold surface processing of alkyl nitrites as a potential environmental source of nitrous oxide.

Synthesis of 3-Diazopyrrolidin-2-ones

In the present work we succeeded in developing a procedure for the synthesis of previously unknown 3-diazopyrrolidin-2-ones from 3-aminopyrrolidin-2-one (I) and 5-amino-3-exo-azatricyclo[5.2.1.0 2,6 ]decan-4one (II). Stable 3-diazodihydropyrroles or 3-diazopyrrolidinediones have been reported [6–8], but attempts to obtain 3-diazopyrrolidin-2-one or its alkyl-substituted derivatives were unsuccessful [14]. In particular, diazotization of 5-amino-3-exo-azatricyclo[5.2.1.0 2,6 ]decan-4-one led to a mixture of isomeric 3-acetoxypyrrolidinones [14]. We have found that heating of a solution of 3-aminopyrrolidin-2-one (I) or 5-amino-3-exo-azatricyclo[5.2.1.0 2,6 ]decan-4-one (II) with isopentyl nitrite in chloroform in the presence of ~15 mol % of glacial acetic acid gives 3-diazopyrrolidin-2-one (III) and 5-diazo-3-exo-azatricyclo[5.2.1.0 2,6 ]decan-4-one (IV) in 36 and 65% yield, respectively. We failed to isolate diazo lactam III as individual substance; it decomposed in diethyl ether even at room temperature to produce a mixture of compounds which were difficult to identify. Therefore, the formation of III was proved by trapping it with triphenylphosphine. The latter reacted with 3-diazopyrrolidin-2-one (III) to give stable crystalline phosphazene V. In the synthesis of diazo lactam III, acetic acid was neutralized with solid NaHCO3, for a saturated aqueous solution of NaHCO3

ChemInform Abstract: One‐Pot Synthesis of 2‐Nitrooxyalkoxylated Inosine Analogues Using Cyclic Ether and Isoamyl Nitrite.

AbstractFirst examples of 2‐nitrooxyalkoxylated nucleosides are obtained by using cyclic ethers and isoamyl nitride.

New insights into the functionalization of multi-walled carbon nanotubes with aniline derivatives

Multi-walled carbon nanotubes (MWCNT) were functionalized with a variety of chemical groups by reaction of p-substituted anilines (R–Ph–NH2) in the presence and absence of isopentyl nitrite used for the in situ generation of diazonium species. All materials were characterized by X-ray photoelectron spectroscopy, thermogravimetry and infrared spectroscopy.In the presence of isopentyl nitrite, the extent of functionalization was high and nearly independent on the amount of isopentyl nitrite and on the aniline substituents (R=F, Cl, I, NH2, NO2, OH, COOH, COOEt and Et). Unexpectedly, the functionalization of MWCNT with anilines bearing electron withdrawing groups was also observed in the absence of isopentyl nitrite. In the case of OH–Ph–NH2, the reaction leads to MWCNT with the highest degree of functionalization and this can be considered as a new and efficient methodology for CNT functionalization with phenol groups. The overall reaction mechanism is discussed for both reaction conditions: confirmation of a radical chain mechanism was obtained for the reaction performed in the presence of isopentyl nitrite, while the formation of stabilized dipolar intermediate species seems to be involved in the absence of isopentyl nitrite. The materials with the highest degree of functionalization showed very good dispersions in acetonitrile even after 1month.

Oxidation of gem-chloronitroso- and vic-chloronitroso-alkanes and -cycloalkanes to respective chloronitro compounds by novel cetyltrimethylammonium hypochlorite reagent

Cetyltrimethylammonium hypochlorite (CTAHC) is prepared and used as an oxidizing agent for nitroso group to nitro group. The gem-chloronitroso and vic-chloronitroso compounds are prepared respectively from ketoximes and olefins by reacting with NOCl generated in situ from chlorotrimethylsilane (TMSCl) and iso-amyl nitrite. CTAHC oxidizes gem-chloronitroso and vic-chloronitroso compounds to the corresponding chloronitro derivatives. While gem-chloronitro compounds are obtained in good yields, the vic-chloronitro derivatives are formed in moderate yields, because of the propensity of the vic-chloronitroso group to tautomerize to α-chlorooxime. The present method is simple and practical, particularly for the preparation of vic-chloronitro compounds, considering the fact that the known methods of their preparation are few and quite involved. gem-Chloronitroso and vic-chloronitroso compounds obtained by the reaction of NOCl with oximes and olefins respectively are oxidized to gem-chloronitro and vic-chloronitro compounds by cetyltrimethylammonium hypochlorite prepared by reacting cetyltrimethylammonium bromide with sodium hypochlorite.

Regioselective hydrodehalogenation of 3,5-dihaloisothiazole-4-carbonitriles: synthesis of 3-haloisothiazole-4-carbonitriles

3,5-Dibromoisothiazole-4-carbonitrile 1 treated with Zn or In dust (5 equiv) and HCO 2H undergoes regioselective hydrodebromination to give 3-bromoisothiazole-4-carbonitrile 3 in 70–74% yield. Similarly, 5-bromo and iodo 3-chloroisothiazole-4-carbonitriles 8 and 9 give 3-chloroisothiazole-4-carbonitrile 4 in 77 and 85% yields, respectively. Also hydrodeamination of 5-amino-3-chloroisothiazole-4-carbonitrile 7 using isoamyl nitrite gives the latter in 95% yield. The dibromoisothiazole 1 reacts with Zn dust in either DCO 2D or HCO 2D to give 3-bromo-5-deuterioisothiazole-4-carbonitrile 10 in 71 and 58% yields, respectively. The 3-bromoisothiazole 3 reacts with cyclic dialkylamines to give the corresponding 2-(dialkylaminomethylene)-malononitriles and not the expected 3-dialkylaminoisothiazole-4-carbonitriles. Finally, the 3-bromoisothiazole 3 is readily converted into both 3-bromoisothiazole-4-carboxamide 19 and the carboxylic acid 20. All products are fully characterized.

Syntheses of terminally functionalized polyisobutylene derivatives using diazonium salts

AbstractA new strategy for the synthesis of end‐functionalized polyisobutylene (PIB) oligomers is detailed. Commercially available vinyl‐terminated PIB oligomers were modified to form aniline‐terminated PIB via an aromatic electrophilic substitution reaction. The PIB‐bound aryl amines so formed were then converted into diazonium salts using isopentyl nitrite and an acid in methylene chloride. These salts served as versatile intermediates in synthetic reactions affording azo dye‐containing PIB derivatives and other terminally‐functionalized PIB derivatives not readily available by other reactions. The advantages and limitations of various name reactions including diazo couplings, Sandmeyer reactions, dediazoniations, and Heck reactions are discussed. The kinetics of polar substitution reactions at the termini of these nonpolar oligomers and the effects of solvent on these reactions were also examined. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

One-Pot Synthesis of 2-Nitrooxyalkoxylated Inosine Analogs Using Cyclic Ether and Isoamyl Nitrite

An O 6 -methylguanosine derivative (1) was treated with isoamyl nitrite in the presence of a cyclic ether such as trimethylene oxide, tetrahydrofuran, or tetrahydropyran to give the corresponding 2-nitrooxyalkoxy-6-methoxypurine riboside derivatives (2a-c).

Synthesis of Sulfonated Carbon Nanocage and Its Performance as Solid Acid Catalyst

A carbon nanocage material (CKT) was first successfully sulfonated by introducing sulfophenyl groups on the surface of pore channels through benzenesulfonic acid-containing aryl radical in situ generated from the reaction of 4-aminobenzenesulfonic acid and isoamyl nitrite in water. The sulfonated carbon nanocage material (S-CKT) was characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, powder small-angle X-ray diffraction and nitrogen sorption measurements. The results showed that the S-CKT still possess the high specific surface area (787 m2/g) and uniform mesoporous (pore diameter 4.7 nm) structures, although the structure of S-CKT is slightly disorder, compared with its unsulfonated precursor. S-CKT, as a carbon-based solid acid catalyst, showed good catalytic performance and reusability in the cross-Aldol condensation of ketones with aromatic aldehydes under solvent-free condition. [Dispersibility of S-CKT in H2O, DMF, EtOH (from left to right) after 6 month]

Influence of Ethanol and Cetane Number (CN) Improver on the Ignition Delay of a Direct-Injection Diesel Engine

As a kind of alternative energy, ethanol is widely and successfully used in the gasoline engine. However, when it is used in the diesel engine, a cetane number (CN) improver, such as isoamyl nitrite, is generally added in diesel/ethanol blends to compensate for the decrease of CN because of ethanol addition. A combined complicated mechanism for the autoignition of n-heptane/ethanol/isoamyl nitrite mixtures was validated against the shock-tube data and homogeneous charge compression ignition (HCCI) engine combustion experiment. The effects of ethanol and isoamyl nitrite addition on the ignition delay of diesel were studied, where n-heptane was used to simulate diesel. Numerical analyses showed that the addition of ethanol decreased the amount of OH radicals and, consequently, retarded the ignition. The reactive i-C5H11O and NO radicals generated in the isoamyl nitrite thermal decomposition process accelerated the low-temperature reactions and shortened the ignition delay.

ChemInform Abstract: Synthesis of Azido Arylselenides and Azido Aryldiselenides: A New Class of Selenium—Nitrogen Compounds.

AbstractThe title compounds are prepared by treatment of the amine precursors with TmsN3 and isoamyl nitrite.

Solid Sulfonic Acid-Promoted Oxidation of Benzyl Alcohol Catalyzed by Isoamyl Nitrite

Solid Sulfonic Acid-Promoted Oxidation of Benzyl Alcohol Catalyzed by Isoamyl Nitrite

Generation of nitryl chloride from chlorotrimethylsilane-acetyl nitrate reaction: A one-pot preparation of gem-chloronitro compounds from oximes

While iso-amyl nitrite reacts with chlorotrimethylsilane to give NOCl, iso-amyl nitrate does not yield NO2Cl with silicon reagent. However, acetyl nitrate reacts successfully with chlorotrimethylsilane to give nitryl chloride, which is characterized by its UV spectrum. If it is generated in presence of ketoximes, gem-chloronitro as well as gem-chloronitroso compounds are formed in almost equal amounts, which together account for up to 80% yield. This is possibly the simplest one-pot reaction for the preparation of gem-chloronitro compounds which find several synthetic applications. If NO2Cl is generated in presence of cycloalkenes, the corresponding 1,2-dichlorocycloalkanes are obtained. Considering the evidence in hand, it is proposed that NO2Cl, initially formed by chlorotrimethylsilane-acetyl nitrate reaction, decomposes to Cl2, and N2O4. Then chlorine reacts with oximes to produce first gem-chloronitroso compounds, which are oxidized by NO2Cl or N2O4 to gem-chloronitro compounds, and with cycloalkenes it gives dichlorocycloalkanes.