Amyl nitrite

Amyl nitrite
Clinical data
Other names	Isoamyl nitrite,; Isopentyl nitrite,; Nitramyl,; 3-methyl-1-nitrosooxybutane,; Pentyl alcohol nitrite (ambiguous),; poppers (ambiguous, colloquial, slang)
ATC code	V03AB22 (WHO) ;
Legal status
Legal status	DE: Unscheduled (unauthorized sale and purchase illegal); UK: Controlled Drug (Medicines Act 1968); US: Unscheduled (illegal under Crime Control Act of 1990);
Identifiers
	IUPAC name (3-methylbutyl) nitrite;
CAS Number	110-46-3 ;
PubChem CID	8053;
DrugBank	DB01612 ;
ChemSpider	7762 ;
UNII	5N0U5TUC9Z;
KEGG	D00517 ;
ChEBI	CHEBI:2691 ;
CompTox Dashboard (EPA)	DTXSID9025455 ;
Chemical and physical data
Formula	C5H11NO2
Molar mass	117.148 g·mol−1
3D model (JSmol)	Interactive image;
Density	0.872 g/cm3
Boiling point	99 °C (210 °F)
Solubility in water	Slightly soluble mg/mL (20 °C)
	SMILES CC(C)CCON=O;
	InChI InChI=1S/C5H11NO2/c1-5(2)3-4-8-6-7/h5H,3-4H2,1-2H3 ; Key:OWFXIOWLTKNBAP-UHFFFAOYSA-N ;
	(verify)

Amyl nitrite is a chemical compound with the formula C₅H₁₁ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrite functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group. Like other alkyl nitrites, amyl nitrite is bioactive in mammals, being a vasodilator, which is the basis of its use as a prescription medicine.^[1] As an inhalant, it also has a psychoactive effect, which has led to its recreational use, with its smell being described as that of old socks or dirty feet.^[2] It was first documented in 1844 and came into medical use in 1867.^[3]

Uses

Amyl nitrite was historically employed medically to treat heart diseases as well as angina.
Amyl nitrite was sometimes used as an antidote for cyanide poisoning.^[4]^[5] It was thought to act as an oxidant, to induce the formation of methemoglobin. Methemoglobin in turn can sequester cyanide as cyanomethemoglobin.^[6] However, it has been replaced by hydroxocobalamin which had better efficacy,^[7] and the use of amyl nitrite has been found to be ineffective and unscientific ^[8]
Amyl nitrite is used as a cleaning agent and solvent in industrial and household applications. It replaced dichlorodifluoromethane, an industrial chemical universally banned in 1996 due to damage to the ozone layer,^[9] as a printed circuit board cleaner.^{[citation needed]} Trace amounts are added to some perfumes.^[10]
It is also used recreationally as an inhalant drug that induces a brief euphoric state, and when combined with other intoxicant stimulant drugs such as cocaine or MDMA, the euphoric state intensifies and is prolonged. Once some stimulative drugs wear off, a common side effect is a period of depression or anxiety, colloquially called a "come down"; amyl nitrite is sometimes used to combat these negative after-effects. This effect, combined with its dissociative effects, has led to its use as a recreational drug (see poppers).^[4]

Nomenclature

The term "amyl nitrite" encompasses several isomers. In older literature, the common non-systematic name amyl was often used for the pentyl group, where the amyl group is a linear or normal (n) alkyl group, and the resulting amyl nitrite would have the structural formula CH₃(CH₂)₃CH₂ONO, also referred to as n-amyl nitrite.

A common form of amyl nitrite is the isomer with the formula (CH₃)₂CHCH₂CH₂ONO, which may be more specifically referred to as isoamyl nitrite.

The similarly named amyl nitrate has very different properties. At the same time, isopropyl nitrite has a similar structure and similar uses (also called 'poppers') but with worse side-effects.^[11]

Amyl nitrite is sometimes referred to colloquially as banapple gas.^[12]

Synthesis and reactions

Alkyl nitrites are prepared by the reaction of alcohols with nitrous acid:^[13]

ROH + HONO → RONO + H₂O, where R = alkyl group

The reaction is called esterification. Synthesis of alkyl nitrites is, in general, straightforward and can be accomplished in home laboratories. A common procedure includes the dropwise addition of concentrated sulfuric acid to a cooled mixture of an aqueous sodium nitrite solution and an alcohol. The intermediately-formed stoichiometric mixture of nitrogen dioxide and nitric oxide then converts the alcohol to the alkyl nitrite, which, due to its low density, will form an upper layer that can be easily decanted from the reaction mixture.

Isoamyl nitrite decomposes in the presence of base to give nitrite salts and the isoamyl alcohol:

C₅H₁₁ONO + NaOH → C₅H₁₁OH + NaNO₂

Amyl nitrite, like other alkyl nitrites, reacts with carbanions to give oximes.^[14]

Amyl nitrites are also useful as reagents in a modification of the Sandmeyer reaction. The reaction of the alkyl nitrite with an aromatic amine in a halogenated solvent produces a radical aromatic species, this then frees a halogen atom from the solvent. For the synthesis of aryl iodides diiodomethane is used,^[15]^[16] whereas bromoform is the solvent of choice for the synthesis of aryl bromides.^[17]

Physiological effects

Amyl nitrite, in common with other alkyl nitrites,^[18] is a potent vasodilator; it expands blood vessels, resulting in lowering of the blood pressure. Amyl nitrite may be used during cardiovascular stress testing in patients with suspected hypertrophic cardiomyopathy to cause vasodilation and thereby reduce afterload and provoke obstruction of blood flow towards the aorta from the ventricle by increasing the pressure gradient, thereby causing left ventricular outflow obstruction. Alkyl nitrites are a source of nitric oxide, which signals for relaxation of the involuntary muscles. Physical effects include decrease in blood pressure, headache, flushing of the face, increased heart rate, dizziness, and relaxation of involuntary muscles, especially the blood vessel walls and the internal and external anal sphincter. There are no withdrawal symptoms. Overdose symptoms include nausea, vomiting, hypotension, hypoventilation, shortness of breath, and fainting. The effects set in very quickly, typically within a few seconds and disappear within a few minutes. Amyl nitrite may also intensify the experience of synesthesia.^[19] Amyl nitrite, when given as a medication for patients with angina, can also be administered as an ampule. The ampule is put in a gauze pad and then inhaled by the patient during an angina attack and repeated every fifteen minutes. However, oral dosing of amyl nitrite is ineffective due to poor absorption and extensive hepatic metabolism. Amyl nitrite has been widely replaced by nitroglycerin for the treatment of acute angina.

Toxicity

Although there are case reports of life-threatening toxicity involving unusually large amounts,^[20] typical inhaled doses of amyl nitrite are considered relatively safe.^[21]^[22] However, liquid amyl nitrite is highly toxic when ingested because of the unsafely high concentration it causes in blood.^[23] Regardless of the form or route of administration, acute toxicity principally results when the nitrite oxidizes a significant proportion of hemoglobin in the blood without oxygen, forming methemoglobin, which cannot carry oxygen. Severe poisoning cases will progress to methemoglobinemia, characterized by a blue-brown discoloration under the skin which could be mistaken for cyanosis.^[20]^[23] Treatment with oxygen and intravenous methylene blue frustrates visual confirmation further as methylene blue itself is, as its name suggests, a blue dye; the patient's changes in different shades of blue notwithstanding, it is an effective antidote by way of catalyzing the production of the enzyme responsible for reducing the methemoglobin in the blood back to hemoglobin.

The discoloration does mean that regular near-infrared–based pulse oximetry becomes useless. More fundamentally, blood gas analysis on the whole has limited effectiveness, as the increased methemoglobin level increases the oxygen binding affinity of regular hemoglobin.^[20] Therefore, the measurement of actual ratios and levels of methemoglobin and hemoglobin must accompany any blood gas partial pressure sample in these cases.

In popular culture

The Columbo episode titled "Troubled Waters" (1974–1975) features amyl nitrite inhaled by the antagonist Hayden Danziger – played by Robert Vaughn – to help him feign a heart attack for his alibi. However, the episode consistently refers to the substance incorrectly as amyl nitrate.^[24]

The 1978 Derek Jarman film Jubilee features a character named Amyl Nitrate (a misspelled reference to amyl nitrite).

The punk band Amyl and the Sniffers reference recreational use of amyl nitrite in their name.^[25]

References

^ "Amyl Nitrite (Inhalation Route) Description and Brand Names - Mayo Clinic". www.mayoclinic.org. Retrieved 2023-12-05.
^ "Drugs - Amyl, Butyl or Isobutyl Nitrite, Nitrates, Poppers". urban75.com.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. XXX. ISBN 9783527607495.
^ ^a ^b Giannini AJ, Slaby AE, Giannini MC (1982). The Handbook of Overdose and Detoxification Emergencies. New Hyde Park, NY.: Medical Examination Publishing Co. pp. 48–50.
^ Mason DT, Braunwald E (November 1965). "The effects of nitroglycerin and amyl nitrite on arteriolar and venous tone in the human forearm". Circulation. 32 (5): 755–766. doi:10.1161/01.cir.32.5.755. PMID 4954412.
^ Vale JA (2001). "Cyanide Antidotes: from Amyl Nitrite to Hydroxocobalamin – Which Antidote is Best?". Toxicology. 168 (1): 37–38.
^ Hall AH, Saiers J, Baud F (2009). "Which cyanide antidote?". Crit Rev Toxicol. 39 (7): 541–552. doi:10.1080/10408440802304944. PMID 19650716.
^ Lavon O, Bentur Y (July 2010). "Does amyl nitrite have a role in the management of pre-hospital mass casualty cyanide poisoning?". Clin Toxicol (Phila). 48 (6): 477–484. doi:10.3109/15563650.2010.505573. PMID 20653465.
^ "Dichlorodifluoromethane". LearnChemistry. Royal Society of Chemistry.
^ "Amyl Nitrite Use and Manufacturing". PubChem. U.S. National Library of Medicine.
^ Cantrell F (2014). "Nitrite Inhalants". Encyclopedia of Toxicology. Elsevier. pp. 530–531. doi:10.1016/b978-0-12-386454-3.00042-7. ISBN 9780123864550.
^ Nordegren T (2002). The A-Z Encyclopedia of Alcohol and Drug Abuse. Brown Walker Press. p. 94. ISBN 158112404X. Retrieved 5 February 2017.
^ Noyes WA (1943). "n-Butyl Nitrite". Organic Syntheses; Collected Volumes, vol. 2, p. 108.
^ Chen YK, Jeon SJ, Walsh PJ, Nugent WA (2005). "(2S)-(−)-3-exo-(Morpholino)isoborneol ((−)-MIB)". Organic Syntheses. 82: 87.
^ Smith WB, Ho OC (1990). "Application of the isoamyl nitrite-diiodomethane route to aryl iodides". The Journal of Organic Chemistry. 55 (8): 2543–2545. doi:10.1021/jo00295a056.
^ Cornforth J, Kumar A, Stuart AS (1987). "Synthesis of substituted dibenzophospholes. Part 6. Preparation of symmetrical and non-symmetrical quaterphenyl intermediates". Journal of the Chemical Society, Perkin Transactions 1: 859. doi:10.1039/P19870000859.
^ Cadogan JI, Roy DA, Smith DM (1966). "An alternative to the Sandmeyer reaction". Journal of the Chemical Society C: Organic: 1249. doi:10.1039/J39660001249.
^ Nickerson M, Parker JO, Lowry TP, Swenson EW (1979). Isobutyl Nitrite and Related Compounds (PDF) (1st ed.). San Francisco California: PHARMEX. Archived from the original (PDF) on 2007-09-27.
^ Cytowic R (2003). The Man Who Tasted Shapes. MIT Press. ISBN 978-0-262-53255-6.
^ ^a ^b ^c Modarai B, Kapadia YK, Kerins M, Terris J (May 2002). "Methylene blue: a treatment for severe methaemoglobinaemia secondary to misuse of amyl nitrite". Emergency Medicine Journal. 19 (3): 270–271. doi:10.1136/emj.19.3.270. PMC 1725875. PMID 11971852.
^ Nutt D, King LA, Saulsbury W, Blakemore C (March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet. 369 (9566): 1047–1053. doi:10.1016/S0140-6736(07)60464-4. PMID 17382831. S2CID 5903121.
^ O'Malley MF, O'Malley R (May 2020). "Volatile Nitrites". MSD Manual. 2023 Merck & Co., Inc.
^ ^a ^b "Amyl Nitrite". Toxbase. UK National Poisons Information Service. December 2018. Retrieved September 29, 2020.
^ "Episode review: Columbo Troubled Waters". Columbophile blog. 29 September 2018. Retrieved 8 April 2023.
^ "Amyl and The Sniffers: 'It's just charmingly violent powerful fun'". 2019-05-14. Retrieved 2023-12-02.