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Alkyl nitrite
Alkyl nitrite
Alkyl nitrite
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alkyl nitrites
General formula of alkyl nitrites

In organic chemistry, alkyl nitrites are a group of organic compounds based upon the molecular structure R−O−N=O, where R represents an alkyl group. Formally they are alkyl esters of nitrous acid. They are distinct from nitro compounds (R−NO2).

The first few members of the series are volatile liquids; methyl nitrite and ethyl nitrite are gaseous at room temperature and pressure. The compounds have a distinctive fruity odor. Another frequently encountered nitrite is amyl nitrite (3-methylbutyl nitrite).

Alkyl nitrites were initially, and largely still are, used as medications and chemical reagents, a practice which began in the late 19th century. In their use as medicine, they are often inhaled for relief of angina and other heart-related symptoms of disease. However, when referred to as "poppers", alkyl nitrites represent recreational drugs.

Synthesis and properties

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Organic nitrites are prepared from alcohols and sodium nitrite in sulfuric acid solution. They decompose slowly on standing, the decomposition products being oxides of nitrogen, water, the alcohol, and polymerization products of the aldehyde.[1] They are also prone to undergo homolytic cleavage to form alkyl radicals, the nitrite C–O bond being very weak (on the order of 40–50 kcal ⋅ mol−1).[citation needed] Alkyl nitrites are generally weak nitrosating agents, but nitrosate amines in the presence of a nucleophile catalyst.[2]

Reactions

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An isolated but classic example of the use of alkyl nitrites can be found in Woodward and Doering's quinine total synthesis:[10]

Key step in quinine total synthesis by Woodward / Doering

for which they proposed this reaction mechanism:

Reaction mechanism for ring opening

References

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Alkyl nitrite

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Alkyl nitrites are a class of organic compounds that function as esters of and an alkyl alcohol, with the general R–O–N=O, where R denotes an such as pentyl, butyl, or isopropyl. These volatile, pale yellow liquids are highly flammable and exhibit strong vasodilatory properties upon inhalation, leading to rapid but brief effects like lowered , increased , and a sensation of warmth or euphoria. Commonly encountered examples include (also known as pentyl nitrite or isopentyl nitrite), , and , which have been synthesized since the mid-19th century and are notable for their dual roles in and . The history of alkyl nitrites dates back to 1844, when French chemist Antoine Jérôme Balard first synthesized by reacting with . By 1867, British physician Thomas Lauder Brunton introduced inhalation as a treatment for pectoris, capitalizing on its ability to dilate blood vessels and relieve by improving blood flow to the heart. In the 1930s, it was incorporated into cyanide poisoning antidotes due to its capacity to convert to , which binds cyanide more effectively, though this use has since been phased out in favor of safer alternatives like . Medically, alkyl nitrites like remain approved in some regions for acute relief, administered via inhalation to produce rapid and reduce cardiac workload, but their prescription has declined with the advent of more stable nitrates such as . Recreationally, alkyl nitrites gained prominence in the and , particularly within the gay community in the United States and , where they became known as "" due to the distinctive popping sound of ampoules when broken to release vapors for inhalation. Users seek the intense, short-lived "rush" of euphoria, heightened sensory perception, muscle relaxation, and enhanced sexual pleasure, often during intimate activities, as the compounds relax smooth muscles including those in the anus and vagina. By the 1980s, formulations shifted from to cheaper, more stable alternatives like isobutyl and isopropyl nitrites, which are sold as room odorizers or leather cleaners to circumvent regulations in many countries. Despite their popularity, recreational use is not without , as alkyl nitrites are classified as inhalants with potential for abuse. While effective for their intended purposes, alkyl nitrites carry significant health risks, primarily due to their mechanism of releasing , which can oxidize to , impairing oxygen transport and potentially causing life-threatening , especially with ingestion or overuse. Inhalation may lead to headaches, , , allergic reactions, or skin burns from spills, and chronic exposure has been linked to vision impairment, such as retinal damage reported in case studies. Regulatory bodies like the U.S. have issued warnings against non-medical use, citing increased hospitalizations and deaths from severe injury or toxicity, while the banned certain variants like in 2007 over concerns including potential carcinogenicity. Overall, these compounds exemplify a balance between therapeutic utility and challenges.

Overview

Definition and Nomenclature

Alkyl nitrites are a class of organic compounds formally recognized as alkyl esters of (HONO), characterized by the general molecular structure R–O–N=O, where R denotes an such as methyl (CH₃–), ethyl (CH₃CH₂–), or higher homologues. These compounds feature the nitrosooxy (-ONO), which links the alkyl chain to the via an oxygen atom. A key structural distinction exists between alkyl nitrites (R–ONO) and nitro compounds (R–NO₂), the latter being isomers where the nitro group is bonded directly to the carbon atom of the alkyl chain; this difference leads to divergent chemical behaviors, with alkyl nitrites classified as nitroso derivatives rather than nitroalkanes. In IUPAC nomenclature, these compounds are systematically named by specifying the alkyl group followed by "nitrite," such as methyl nitrite (CH₃ONO), ethyl nitrite (C₂H₅ONO), isopropyl nitrite ((CH₃)₂CHONO), and isobutyl nitrite ((CH₃)₂CHCH₂ONO). Common names are also widely used, exemplified by amyl nitrite as a designation for pentyl nitrite (C₅H₁₁ONO), reflecting branched or straight-chain variants in historical and practical contexts. Additionally, ethyl nitrite has been historically referred to in medicinal preparations as "sweet spirit of niter," an alcoholic solution employed in early pharmacology.

General Properties

Alkyl nitrites are typically volatile compounds at , with their physical state depending on the length of the alkyl chain. Shorter-chain variants, such as methyl nitrite (boiling point -12°C) and (boiling point 17°C), exist as gases under standard conditions, while longer-chain homologs like propyl nitrite (boiling point 46–48°C), (boiling point 40°C), (boiling point 67.5°C), and (boiling point 96–99°C) are liquids. Boiling points generally increase with increasing alkyl chain length due to enhanced van der Waals interactions. These compounds possess a characteristic fruity or ethereal , often described as fragrant, which aids in their sensory identification. They exhibit high in organic solvents, such as alcohols and hydrocarbons, owing to their nonpolar alkyl components, but are only moderately soluble or insoluble in . Densities typically range from 0.8 to 1.0 g/cm³, with examples including 0.792 g/mL for , 0.868 g/cm³ for , 0.886 g/cm³ for propyl nitrite, and 0.872 g/cm³ for . Chemically, alkyl nitrites are weakly polar molecules attributed to the -ONO , which imparts a moderate dipole moment of approximately 2.4–2.6 D, as observed in ethyl (2.41 D) and isopropyl (2.57 D) nitrites. This polarity is reflected in their , where characteristic N=O stretching vibrations appear as strong absorbances around 1620–1665 cm⁻¹, corresponding to and anti conformers of the R-O-N=O moiety. Thermally, they are generally unstable above 100°C and can undergo decomposition when subjected to , limiting their handling to controlled conditions.

Synthesis

Laboratory Methods

The primary laboratory method for preparing alkyl nitrites involves the reaction of an alcohol (ROH) with (NaNO₂) in aqueous (H₂SO₄), where is generated to form the ester. The balanced equation for this process is ROH + NaNO₂ + H₂SO₄ → RONO + NaHSO₄ + H₂O. This approach is conducted under controlled conditions, typically at low temperatures (0–5°C) to minimize , with the alcohol added slowly to a mixture of the nitrite and acid in . Variations of this method employ other nitrite salts (e.g., ) and acids (e.g., ) to generate in , followed by isolation of the volatile product via under reduced pressure to prevent thermal breakdown. For instance, the reaction mixture is cooled, the organic layer separated, and the crude product distilled at 20–50 mmHg to collect the alkyl nitrite fraction. A specific example is the preparation of by bubbling nitrogen oxides, such as , into cooled , which directly forms the through nitrosation while maintaining an inert atmosphere to limit side products. Purification typically involves to separate the alkyl nitrite from unreacted alcohol and , with strict avoidance of moisture during storage and handling to prevent back to the alcohol and . Typical yields for these laboratory procedures range from 50–80%, depending on the alkyl chain length and reaction scale; challenges include side reactions such as oxidation to alkyl nitrates if excess oxidant (e.g., from air exposure or impure ) is present, which can be mitigated by using fresh and conditions.

Industrial Methods

Industrial production of alkyl nitrites primarily employs continuous flow processes to achieve and , involving the reaction of alcohols with gaseous oxides in specialized reactor systems. In one established method, is reacted with C1-C6 alcohols in a counterflow-operated absorption column, where an alcohol-water mixture is introduced at the upper part and a dioxide-inert gas mixture at the lower part, facilitating absorption and formation of the alkyl nitrite alongside as a byproduct. This setup minimizes secondary products like alkyl nitrates and enables high-purity output, with the overhead vapor stream containing the alkyl nitrite separated via after washing to remove impurities. Another variant utilizes a column reactor where C1-C4 alkanols react with oxides in the presence of oxygen, followed by to isolate the organic layer for further purification. These continuous processes support high throughput, with column loadings up to 3000 liters (STP) per liter of reactor volume per hour, making them suitable for commercial-scale operations. Catalyzed methods enhance reaction rates, particularly for longer-chain alkyl nitrites, by incorporating strong acids such as sulfuric or phosphoric acid to promote the interaction between alcohols and inorganic nitrites. In a continuous synthesis approach, the alcohol is reacted with sodium nitrite in an aqueous strong acid medium (e.g., sulfuric acid at concentrations ≥35%), maintained at low temperatures (0-15°C) in a stirred reactor with simultaneous reagent addition, yielding the alkyl nitrite in the organic phase after phase separation and washing. This acid catalysis accelerates the formation of nitrous acid in situ, improving efficiency over uncatalyzed routes and reducing decomposition, with reported yields exceeding 95% for select alkyl nitrites. Phosphoric acid serves similarly for longer chains, where its milder properties help control exothermicity in larger batches. A specific industrial example is the production of (primarily isoamyl nitrite), conducted via the reaction of pentanol with in within batch or semi-continuous reactors, allowing for controlled addition of to manage and gas evolution. Acid streams are recycled post-reaction by separation and reconcentration, minimizing waste and reagent costs while maintaining reaction efficiency. At commercial scales, alkyl nitrite production for pharmaceutical precursors is driven by in applications. Energy inputs are significant due to and cooling requirements, while waste management focuses on handling emissions from off-gases, often by treating residual alkyl nitrites with amidosulfuric acid to decompose them into nitrogen gas (N₂), alcohol, and . Economic viability is largely determined by the cost of alcohol feedstocks, which constitute the primary and vary with market fluctuations in or bio-based sources; for instance, pentanol pricing directly impacts production expenses. Medical-grade products require purity levels exceeding 95% (GC), achieved through rigorous and impurity removal to meet pharmacopeial standards.

Chemical Reactivity

Stability and Decomposition

Alkyl nitrites exhibit inherent instability due to the weakness of the O-NO bond, which undergoes homolytic cleavage under conditions, with a bond dissociation energy of approximately 41 kcal/mol. This process generates alkoxy radicals (RO•) and (•NO) as primary products, initiating a radical chain reaction that can propagate further . The overall can be simplified as 2 RONO → 2 RO• + N₂O + •NO, though subsequent reactions of the radicals lead to a mixture of aldehydes, ketones, and nitrogen oxides, particularly at temperatures above 150–200°C. Lower alkyl homologs, such as methyl nitrite, decompose more readily and release significant heat (up to 4300 J/g), posing risks in confined environments. Photochemical instability arises from exposure to ultraviolet light, particularly at wavelengths around 254 nm, where absorption leads to rapid O-NO bond fission, producing and excited alkoxy radicals. These radicals may decompose further, yielding alcohols, aldehydes, and gases () as secondary products. The quantum yields for this process vary by structure—for instance, approximately 0.87 for tert-butoxy radicals from —highlighting the sensitivity of alkyl nitrites to , which accelerates breakdown even at ambient temperatures. Hydrolytic decomposition occurs via nucleophilic attack by water on the group, forming the corresponding alcohol and (HNO₂) as primary products. The is enhanced under acidic conditions due to of the nitrite, increasing its electrophilicity, and proceeds slowly in neutral water. This sensitivity to moisture underscores the need for handling to prevent unintended . To maintain stability, alkyl nitrites must be stored in cool (2–15°C), dark, and dry conditions, typically in sealed amber glass bottles to minimize light exposure and moisture ingress. Under these optimal conditions, they have a limited , after which may lead to pressure buildup from gas evolution. Their volatility contributes to handling challenges, as can concentrate residues prone to rapid breakdown. The potential of alkyl nitrites stems from exothermic in confined spaces, especially for lower homologs like methyl or , where the weak O-NO bond facilitates runaway reactions under or . While not classified as high explosives, rapid gas production (e.g., NO and N₂O) can cause ruptures in sealed containers, necessitating careful ventilation and avoidance of ignition sources during storage and use.

Principal Reactions

Alkyl nitrites serve as effective nitrosating agents in organic synthesis, primarily by generating the nitrosonium ion (NO⁺) under acidic conditions to facilitate N-nitrosation of secondary amines. The reaction proceeds via nucleophilic attack of the amine on the electrophilic nitrogen of the alkyl nitrite, yielding an N-nitrosamine and the corresponding alcohol: R2NH+R′ONO→R2N−NO+R′OH\mathrm{R_2NH + R'ONO \rightarrow R_2N-NO + R'OH} This process is particularly useful for preparing N-nitrosamines, which are valuable intermediates in heterocyclic synthesis and diazotization reactions. The kinetics of this reaction in nonaqueous solvents reveal that the rate-determining step involves the formation and decomposition of a transient intermediate, with alkyl nitrites showing high efficiency under mild conditions compared to other nitrosating agents like nitrosyl chloride. In radical chemistry, alkyl nitrites are employed in the Barton nitrite photolysis, a photochemical method for remote functionalization at the δ-position of alcohols. The process involves irradiation of the alkyl nitrite (R-CH₂-CH₂-CH₂-CH₂-ONO) to generate an alkoxy radical (RO•), which abstracts a hydrogen atom from the δ-carbon, leading to a δ-carbon radical that rearranges to form an oxime or nitroso derivative after trapping by nitric oxide. R−(CH2)3−CH2−ONO→hνR−(CH2)3−CH2O∙+⋅NO→δ−functionalizedproducts\mathrm{R-(CH_2)_3-CH_2-ONO \xrightarrow{h\nu} R-(CH_2)_3-CH_2O^\bullet + \cdot NO \rightarrow \delta-functionalized products}
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