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Tert-Amyl alcohol
Tert-Amyl alcohol
Tert-Amyl alcohol
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tert-Amyl alcohol
Stereo, skeletal formula of 2-methyl-2-butanol
Stereo, skeletal formula of 2-methyl-2-butanol
Ball-and-stick model of 2-methyl-2-butanol
Ball-and-stick model of 2-methyl-2-butanol
Space-filling model of the 2-methyl-2-butanol
Space-filling model of the 2-methyl-2-butanol
Names
Preferred IUPAC name
2-Methylbutan-2-ol
Other names
2-Methyl-2-butanol
tert-Amyl alcohol
t-Amylol
TAA
tert-Pentyl alcohol
2-Methyl-2-butyl alcohol
t-Pentylol
Amylene hydrate
Dimethylethylcarbinol
Identifiers
3D model (JSmol)
1361351
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.827 Edit this at Wikidata
EC Number
  • 200-908-9
KEGG
MeSH tert-amyl+alcohol
RTECS number
  • SC0175000
UNII
UN number 1105
  • InChI=1S/C5H12O/c1-4-5(2,3)6/h6H,4H2,1-3H3 checkY
    Key: MSXVEPNJUHWQHW-UHFFFAOYSA-N checkY
  • CCC(C)(C)O
Properties
C5H12O
Molar mass 88.150 g·mol−1
Appearance Colorless liquid
Odor Camphorous
Density 0.805 g/cm3[1]
Melting point −9 °C; 16 °F; 264 K
Boiling point 101 to 103 °C; 214 to 217 °F; 374 to 376 K
120 g·dm−3
Solubility soluble in water, benzene, chloroform, diethylether and ethanol[2]
log P 1.0950.5:1 volume ratio
Vapor pressure 1.6 kPa (at 20 °C)
−7.09×10−5 cm3/mol
1.405
Viscosity 4.4740 mPa·s (at 298.15 K)[1]
Thermochemistry
229.3 J K−1 mol−1
−380.0 to −379.0 kJ mol−1
−3.3036 to −3.3026 MJ mol−1
Hazards
GHS labelling:
GHS02: Flammable GHS07: Exclamation mark
Danger
H225, H315, H332, H335
P210, P261
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 3: Liquids and solids that can be ignited under almost all ambient temperature conditions. Flash point between 23 and 38 °C (73 and 100 °F). E.g. gasolineInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
3
0
Flash point 19 °C (66 °F; 292 K)
437 °C (819 °F; 710 K)
Explosive limits 9%
Safety data sheet (SDS) hazard.com
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

tert-Amyl alcohol (TAA) or 2-methylbutan-2-ol (2M2B), is a branched pentanol.

Historically, TAA has been used as an anesthetic[3] and more recently as a recreational drug.[4] TAA is mostly a positive allosteric modulator for GABAA receptors in the same way as ethanol.[5] The psychotropic effects of TAA and ethanol are similar, though distinct. Impact on coordination and balance are proportionately more prominent with TAA, which is significantly more potent by weight than ethanol. Its appeal as an alternative to ethanol may stem from its lack of a hangover (due to different metabolic pathways) and the fact that it is often not detected on standard drug test.[6]

TAA is a colorless liquid with a burning flavor[7] and an unpleasant odor[8] similar to paraldehyde with a hint of camphor.[9] TAA remains liquid at room temperature, making it a useful alternative solvent to tert-butyl alcohol.

Production

[edit]

TAA is primarily made by the hydration of 2-methyl-2-butene in the presence of an acidic catalyst.[10][3]

Natural occurrence

[edit]

Fusel alcohols like TAA are grain fermentation byproducts, and therefore trace amounts of TAA are present in many alcoholic beverages.[11] Traces of TAA have been detected in other foods, like fried bacon,[12] cassava[13] and rooibos tea.[14] TAA is also present in rabbit milk and seems to play a role in pheromone-inducing suckling in the newborn rabbit.[15]

History

[edit]

From about the 1880s to the 1950s, TAA was used as an anesthetic with the contemporary name of amylene hydrate, but it was rarely used because more efficient drugs existed.[3] In the 1930s, TAA was mainly used as a solvent for the primary anesthetic tribromoethanol (TBE). Like chloroform, TBE is toxic for the liver, so the use of such solutions declined in the 1940s in humans. TBE-TAA-solutions remained in use as short-acting anesthetics for laboratory mice and rats. Such solutions are sometimes called Avertin, which was a brand name for the now discontinued TAA and TBE solution with a volume ratio of 0.5:1 made by Winthrop Laboratories.[16] TAA has emerged recently as a recreational drug.[4]

Use and effects

[edit]

Ingestion or inhalation of TAA causes euphoria, sedative, hypnotic, and anticonvulsant effects similar to ethanol.[17] When ingested, the effects of TAA may begin in about 30 minutes and can last up to 1–2 days.[18] 2–4 grams of TAA is sufficient to produce a hypnotic effect. About 100 g of ethanol induces a similar level of sedation.[8]

Overdose and toxicity

[edit]

The smallest known dose of TAA that has killed a person is 30 mL.[18]

An overdose produces symptoms similar to alcohol poisoning and is a medical emergency due to the sedative/depressant properties which manifest in overdose as potentially lethal respiratory depression. Sudden loss of consciousness, simultaneous respiratory and metabolic acidosis,[18] fast heartbeat, increased blood pressure, pupil constriction, coma, respiratory depression[19] and death may follow from an overdose. The oral LD50 in rats is 1 g/kg. The subcutaneous LD50 in mice is 2.1 g/kg.[20]

Metabolism

[edit]

In rats, TAA is primarily metabolized via glucuronidation, as well as by oxidation to 2-methyl-2,3-butanediol. It is likely that the same path is followed in humans,[21] though older sources suggest TAA is excreted unchanged.[3]

TAA oxidises to 2-methyl-2,3-butanediol.

The use of TAA cannot be detected with general ethanol tests or other ordinary drug tests. Its use can be detected from a blood or a urine sample by using gas chromatography–mass spectrometry for up to 48 hours after consumption.[19]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Tert-Amyl alcohol

View on Grokipedia
from Grokipedia
Tert-amyl alcohol, systematically 2-methylbutan-2-ol, is a branched-chain tertiary alcohol with the molecular C₅H₁₂O and CAS number 75-85-4. It exists as a clear, colorless at , exhibiting a camphor-like and slight in (approximately 12 g/L at 20°C). This compound finds primary industrial utility as a in the formulation of pharmaceuticals, flavors, inhibitors, resins, , and materials, owing to its ability to dissolve a range of organic substances while resisting easy oxidation due to the tertiary structure. It also serves as a chemical intermediate in and a flotation agent in , with additional applications as a fuel additive to enhance and reduce emissions. Boiling at 102°C and with a of 0.81 g/mL, its physical properties support these roles, though its volatility contributes to environmental release during production and use. Tert-amyl alcohol poses flammability hazards, with a of 27°C and explosive limits of 1.3–9.0% in air, necessitating storage away from ignition sources. Exposure can cause and eye irritation, respiratory effects upon inhalation, and mild if ingested, classifying it under GHS categories for and corrosion. Despite these risks, its and reactivity in forming esters or ethers underpin its value in synthetic processes.

Chemical and Physical Properties

Molecular Structure and Nomenclature

Tert-amyl alcohol, systematically named 2-methylbutan-2-ol, is a tertiary alcohol with the molecular formula C₅H₁₂O. Its molecular structure features a central tertiary carbon atom bonded to a hydroxyl group (-OH), two methyl groups (-CH₃), and an ethyl group (-CH₂CH₃), rendering the carbon bearing the hydroxyl quaternary in substitution but tertiary in alcohol classification due to three alkyl substituents. This configuration distinguishes it from primary and secondary alcohols, where the hydroxyl-bearing carbon has one or two alkyl groups, respectively. The IUPAC derives from the parent chain of , with a methyl at position 2 and the hydroxyl prioritized at the same carbon, yielding 2-methylbutan-2-ol to indicate the lowest for the -OH group. Common names such as tert-amyl alcohol or tert-pentyl alcohol reflect its historical association with amyl (pentyl) derivatives, where "tert-" denotes the tertiary nature of the alcohol, a convention retained in older chemical literature but superseded by systematic naming in modern IUPAC recommendations. The CAS 75-85-4 uniquely identifies this compound across chemical databases. In structural depictions, the omits hydrogens and emphasizes carbon-carbon bonds, showing the branched chain as a carbon with three attachments (two methyls and one ethyl) plus the -OH. This alcohol's avoids ambiguity by specifying substitution level, crucial for distinguishing it from isomers like 2-methyl-1-butanol (primary) or 3-methyl-2-butanol (secondary).

Physical Characteristics

Tert-amyl alcohol is a colorless at and standard pressure, exhibiting a camphor-like . It has a of -12 °C, a of 102 °C, and a of 0.805 g/mL at 25 °C. The is approximately 1.405 at 20 °C. Tert-amyl alcohol shows moderate solubility in water, approximately 120 g/L at 20 °C, and is miscible with organic solvents such as , , , , , and oils. Its vapor pressure is 12 mmHg (1.6 kPa) at 20 °C. The compound's is 4.47 mPa·s at 25 °C.

Chemical Reactivity and Stability

Tert-amyl alcohol, a tertiary alcohol, demonstrates high stability under ambient conditions, remaining in the absence of catalysts or extreme environments, though it may degrade upon prolonged exposure to elevated temperatures or oxidative agents. It is highly flammable, with a of 70°F (21°C), and its vapors can form explosive mixtures with air. Incompatibility with strong oxidizing agents, such as , can lead to violent reactions producing esters and , while it also attacks certain plastics. In terms of reactivity, tert-amyl alcohol resists oxidation to carbonyl compounds, a property typical of tertiary alcohols lacking an alpha hydrogen on the carbinol carbon. Under acidic conditions, such as with concentrated or , it undergoes via an E1 mechanism, facilitated by the stable tertiary carbocation intermediate, yielding primarily 2-methylbut-2-ene and smaller amounts of 2-methylbut-1-ene. It can also participate in SN1 substitution reactions, as exemplified by its conversion to tert-amyl with concentrated HCl. Esterification with acyl chlorides, such as , proceeds to form the corresponding and HCl. In the gas phase, tert-amyl alcohol reacts with photochemically generated hydroxyl radicals at a rate constant of 4.9 × 10^{-12} cm³ molecule^{-1} s^{-1}, indicating moderate atmospheric persistence before degradation. Microbial degradation occurs slowly, reflecting the recalcitrance of branched tertiary alcohols.

Production and Occurrence

Industrial Synthesis Methods

The primary industrial synthesis of tert-amyl alcohol (2-methyl-2-butanol) involves the acid-catalyzed hydration of isoamylene (2-methylbut-2-ene), a C5 alkene derived from petroleum refining or cracking processes. In this method, the alkene reacts with water under elevated temperature (typically 50–100°C) and pressure (up to 3 MPa), facilitated by heterogeneous catalysts such as sulfonic acid-functionalized ion-exchange resins (e.g., Amberlyst-15 or equivalent strong acid cation exchangers) to minimize side reactions like oligomerization or diene formation. The reaction proceeds via carbocation intermediate formation, with Markovnikov addition yielding the tertiary alcohol selectively, achieving conversions of 50–80% per pass and overall yields exceeding 90% after recycling unreacted alkene. Reactive distillation represents an advanced variant of this hydration process, integrating reaction and separation in a single column to shift equilibrium toward product formation by continuously removing tert-amyl alcohol via . Here, a catalytic packing section (e.g., with beds) hydrates isoamylene fed from the top, while water enters midway; the alcohol-water is distilled overhead and purified downstream, enabling higher single-pass conversions (up to 95%) compared to conventional fixed-bed reactors. This technique, commercialized since the 1990s, reduces energy costs and capital investment by avoiding separate units. Alternative routes, such as the hydration of mixed from units or older processes involving chlorination of followed by aqueous , are less prevalent today due to lower selectivity and higher byproduct generation. An - pathway, involving acetylide to acetone followed by , has been reported but is not widely adopted industrially owing to costs and safety concerns with acetylene handling. Global production capacity, led by facilities in the U.S. and (e.g., via companies like Vinati Organics), emphasizes the isoamylene hydration route for its efficiency and alignment with feedstocks.

Natural Occurrence in the Environment

Tert-amyl alcohol, also known as 2-methyl-2-butanol, occurs in trace amounts in select natural sources, primarily as a volatile compound associated with biological processes such as . It has been identified among the volatiles emitted from (Manihot esculenta), a root crop, during processing or degradation, as detected through gas chromatography-mass spectrometry analyses of plant materials. Similarly, it appears as a minor volatile component in fried bacon, likely arising from thermal degradation or Maillard reactions involving lipids and amino acids in meat. As a —a class of higher alcohols produced during yeast-mediated of sugars—tert-amyl alcohol forms in small quantities from the metabolism of branched-chain or isoamyl precursors in grain-based fermentations. These traces are detectable in naturally fermented alcoholic beverages, such as those from or other grains, though concentrations remain low (typically below 0.1% of total fusel oils) due to the preference for primary and secondary alcohols in microbial pathways. Despite these occurrences, tertiary alcohols like tert-amyl alcohol are rare in unperturbed environments, with most environmental detections linked to anthropogenic inputs such as additives rather than widespread biogenic production. Natural biosynthesis is limited, as microbial enzymes favor less sterically hindered alcohols, resulting in negligible contributions to global atmospheric or aquatic cycles outside localized sites like decaying matter or anaerobic sediments.

Historical Development

Early Discovery and Synthesis

Tert-amyl alcohol, historically termed amylene hydrate, emerged in 19th-century through the acid-catalyzed hydration of amylene—a mixture including 2-methyl-2-butene (trimethylethylene). This synthesis involved absorbing amylene in concentrated to form the alkyl hydrogen sulfate intermediate, followed by with to yield the tertiary alcohol, with yields improved by distillation under reduced pressure to separate it from primary and secondary pentanol byproducts. The process exploited the Markovnikov addition principle, favoring the tertiary carbocation pathway due to the alkene's structure, though early yields were modest (around 50-60%) owing to side reactions like and ether formation. Preparations traceable to Charles-Adolphe Wurtz in the involved similar hydration but faced structural misidentification, with Wurtz and others initially classifying amylene as a secondary alcohol based on oxidation products and analyses. By 1863, and Emil Erlenmeyer independently critiqued this, proposing alternative structures via rigorous degradation studies, though definitive confirmation of its tertiary nature—2-methyl-2-butanol—awaited advanced spectroscopic and synthetic corroboration in the early . These debates underscored the era's challenges in distinguishing alcohol isomers without modern tools, relying instead on boiling points (approximately 102°C), refractive indices, and reactivity with dehydrating agents. By 1887, the method gained pharmaceutical traction as a , with documented doses of 7 grams inducing without the toxicity of , prompting scaled preparations for clinical trials; however, its adoption waned due to inconsistent potency and emergence of barbiturates. Early industrial analogs foreshadowed later optimizations, such as vapor-phase hydration over solid acids, but 19th-century efforts remained batch-wise and lab-scale, limited by amylene sourcing from or fusel oil .

Evolution of Medical and Industrial Applications

Tert-amyl alcohol, also known as 2-methyl-2-butanol, was initially explored for medical applications in the late . From the to the , it served as an under the name amylene hydrate, valued for its , , and effects due to similar to but with greater potency per unit volume. However, its clinical use was limited, often not as a standalone agent, owing to side effects such as prolonged recovery times and potential toxicity, leading to preference for safer alternatives like or derivatives. By the mid-20th century, medical applications waned as pharmaceutical advancements favored more selective sedatives and anesthetics, shifting tert-amyl alcohol toward industrial roles. In the 1930s, it found niche use as a for certain anesthetics, but post-World War II petrochemical developments enabled scalable synthesis via hydration of isoamylenes, facilitating broader solvent applications in resins, gums, and . This transition aligned with growing demand for branched alcohols in inhibitors and coating materials, where its stability and low reactivity proved advantageous. Industrial expansion accelerated in the 1970s, particularly in , with tert-amyl alcohol integrated into synthetic production, pharmaceutical intermediates, and color dyes as a . By the and , its role extended to fuel additives through conversion to tert-amyl methyl ether (TAME), an for blending to enhance ratings and reduce emissions, mirroring MTBE but with lower environmental persistence concerns. Processes involving catalytic etherification of isoamylenes with methanol, sometimes yielding tert-amyl alcohol as an intermediate or recyclable component, supported this application amid regulatory pushes for cleaner fuels. In contemporary contexts, tert-amyl alcohol's industrial footprint has diversified into pharmaceutical synthesis as a for esterifications and fine chemicals, alongside emerging uses like polyurethane deconstruction for via base-catalyzed processes. Medically, isolated reports since the highlight recreational misuse as an surrogate for its effects, though without formal therapeutic revival due to profiles exceeding ethanol's. Market analyses project steady growth driven by solvent and additive demands, reflecting optimized production efficiencies.

Applications and Uses

Industrial and Solvent Uses

Tert-amyl alcohol serves as a versatile in industrial coatings and paints, particularly for formulations based on resins and s, where its properties facilitate even application and formation. It is incorporated into two-component (2K) systems, such as those used in automotive repair coatings, due to its ability to dissolve resins effectively while maintaining stability during curing processes. Additionally, it functions as a in the production of varnishes, resins, and gums, enhancing control and compatibility with other organic compounds. In chemical processing, tert-amyl alcohol is utilized as a reaction medium in , including the oxidation of olefins and esterification reactions, owing to its with most organic solvents and thermal stability. Its role extends to inhibitors and formulations, where it aids in dissolving contaminants without aggressive reactivity. These applications leverage its liquid state at and relatively low volatility compared to lighter alcohols, making it suitable for solvent blends in industrial settings.

Role in Fuel Additives and Oxygenates

Tert-amyl alcohol (TAA), also known as 2-methyl-2-butanol, functions primarily as a precursor or intermediate in the synthesis of tert-amyl methyl ether (TAME), a key ether oxygenate blended into gasoline to elevate oxygen content, enhance octane ratings, and curtail carbon monoxide emissions from combustion. TAME production typically involves the etherification of C5 olefin fractions, such as isoamylene derived from TAA dehydration or refinery streams, with methanol under acidic catalysis, yielding an additive with approximately 15.7% oxygen by weight that complies with reformulated gasoline standards. This ether has been incorporated into fuels since the 1970s as a lead-phaseout alternative, with blending levels up to 15% volume in some markets to meet U.S. Clean Air Act requirements for oxygenated fuels in non-attainment areas. Directly, TAA has been employed as an and co-solvent in formulations, particularly in methanol- blends where it mitigates by boosting water tolerance—allowing up to 15-20% methanol incorporation without formation under humid conditions. With an oxygen content of about 18.2% by weight, TAA contributes to emissions reductions akin to other alcohols, though its tertiary structure limits corrosivity and reactivity compared to primary . U.S. EPA regulations under 40 CFR Part 80 permit TAA in reformulated to satisfy the 2.0-2.7% oxygen minimum by weight, positioning it as a viable substitute amid MTBE contamination concerns, though usage remains limited due to higher and blending cost relative to ethers./.pdf) Environmental persistence of TAA arises post-blending, as it forms via hydrolysis in aqueous environments or microbial degradation, complicating remediation in contaminated sites but underscoring its stability as a component. Studies indicate TAA biodegrades slowly under aerobic conditions, with half-lives exceeding months in , prompting scrutiny in oxygenate transition policies.

Recreational and Pharmaceutical Contexts

Tert-amyl alcohol, also known as 2-methyl-2-butanol or 2M2B, has limited historical pharmaceutical applications primarily as a sedative-hypnotic agent and , though it is not approved for clinical use in modern . Early investigations explored its effects, attributed to modulation of GABA-A receptors similar to , but its volatility, odor, and toxicity profile precluded widespread adoption. Currently, it serves as a and intermediate in pharmaceutical synthesis, facilitating reactions such as esterifications for active pharmaceutical ingredients, due to its aprotic properties and compatibility with organic transformations. In recreational contexts, tert-amyl alcohol has emerged as a misused substitute among psychonaut communities, valued for its potent , , and effects at doses far lower than —approximately 20 times more potent by volume. Users report intoxication lasting 8–24 hours, characterized by exceeding that of , with minimal but heightened risks of respiratory depression and . Its camphor-like odor and liquid form facilitate oral or inhalational consumption, often marketed online as a novel high-potency alternative. Documented cases highlight severe acute intoxication risks, including deep and acute requiring , as in a 2014 report of a 28-year-old found unresponsive after recreational . The compound's narrow therapeutic window— with an oral LD50 around 1 g/kg in animal models, equivalent to roughly 100 mL potentially lethal for an adult —amplifies overdose potential compared to . Greater relative to other pentanols has been observed in preclinical studies, underscoring its unsuitability as a safer intoxicant. Despite anecdotal claims of enhanced potency or unique effects, such as without typical alcohol aftereffects, medical literature emphasizes the absence of and prevalence of presentations.

Pharmacological Effects and Human Impact

Mechanisms of Intoxication

Tert-amyl alcohol (2-methyl-2-butanol) induces intoxication via (CNS) depression, mirroring the pharmacodynamic actions of but with potentially greater potency due to its branched tertiary structure. Like other short-chain alcohols, it primarily enhances inhibitory by potentiating GABA_A receptors, increasing conductance and neuronal hyperpolarization, which manifests as , , and anxiolysis. This GABAergic modulation underlies the depressant effects observed in recreational use, where doses of 2–4 grams can produce profound states. In parallel, tert-amyl alcohol inhibits N-methyl-D-aspartate (NMDA) glutamate receptors, suppressing excitatory signaling and contributing to impairments in cognition, coordination, and memory—hallmarks of . These dual actions on enhancement and inhibition disrupt the balance of excitatory-inhibitory , leading to dose-dependent progression from mild to in severe cases, as documented in acute overdose reports involving blood concentrations exceeding 1 g/L. models confirm comparable CNS depression to via GABA_A stimulation, though tert-amyl alcohol's may amplify membrane fluidization effects on ion channels. Unlike primary alcohols, tert-amyl alcohol's tertiary hydroxyl group renders it a poor substrate for , minimizing rapid oxidation to aldehydes and resulting in slower elimination ( approximately 3–5 hours), which prolongs intoxication relative to ethanol's shorter duration. This pharmacokinetic distinction intensifies and extends CNS effects without the acetaldehyde-mediated of ethanol metabolism, though direct receptor interactions remain the proximal cause of behavioral impairment. Limited species-specific studies highlight greater than linear pentanols, underscoring structure-dependent variations in receptor affinity.

Short-Term Physiological and Behavioral Effects

Tert-amyl alcohol, also known as 2-methyl-2-butanol (2M2B), exerts short-term effects primarily through (CNS) depression, akin to other alcohols but with greater potency per unit mass due to its tertiary structure enhancing GABA_A receptor modulation. Ingested or inhaled doses lead to rapid onset of , , and anxiolysis, with users reporting at low to moderate levels comparable to but with disproportionately amplified impairment in and balance. Physiologically, acute exposure induces respiratory depression, , and potential progression to in overdoses exceeding 30 mL, as documented in case reports of recreational intoxication where patients presented with deep unconsciousness and required . , , and lacrimation occur commonly, targeting the CNS and liver as primary organs, with effects persisting 12-24 hours or longer due to slower metabolism relative to . Inhalation at concentrations above 225 ppm has elicited and CNS symptoms in animal models extrapolated to human risk, including and disorientation. Behaviorally, intoxication manifests as ataxia, reduced cognitive function, and mood lability, with high doses precipitating delirium characterized by confusion and agitation, as observed in a 25-year-old patient requiring prolonged hospitalization. These effects stem from enhanced inhibitory neurotransmission, fostering disinhibition and impaired judgment similar to ethanol but with extended recovery times, complicating detection in standard toxicology screens. Overdose thresholds remain imprecise, but symptoms mirror alcohol poisoning, underscoring risks in unsupervised use.

Toxicity and Health Risks

Acute Overdose Symptoms and Case Studies

Acute overdose of tert-amyl alcohol (2-methyl-2-butanol, TAA) primarily manifests as severe , akin to but potentially more profound than intoxication due to its tertiary limiting rapid . Symptoms include deep , , slurred speech, gross motor incoordination, impaired , concentration, and judgment, often progressing to hypoxic/hypercapnic requiring . In a documented case from 2014, a 28-year-old male presented in deep with acute following recreational of TAA, necessitating and supportive care; and confirmed TAA concentrations consistent with overdose, with recovery after 48 hours of monitoring. Another report detailed a admitted to intensive care for respiratory depression-induced hypoxic/hypercapnic failure after TAA , with electrocardiographic changes and prolonged complicating ; relied on history and exclusion of other toxins, as standard assays may not detect TAA. A 2022 case involved a 25-year-old with protracted and intoxication symptoms including and cognitive deficits persisting beyond typical clearance, attributed to TAA's slower elimination and effects, highlighting risks in misuse as an substitute.

Chronic Exposure and Long-Term Effects

Chronic exposure to tert-amyl alcohol primarily involves or dermal routes in occupational settings, such as use or additive production, though epidemiological data remain scarce due to limited widespread long-term use. Subchronic provide the primary evidence base, with a 13-week study in Fischer 344 rats (10/sex/group) exposed 6 hours/day, 5 days/week to 0, 300, 1300, or 3000 ppm revealing dose-related increases in absolute and relative liver weights in both sexes at ≥1300 ppm, accompanied by centrilobular hepatocellular suggestive of metabolic adaptation or mild . Male rats at 3000 ppm showed elevated weights and higher incidences of chronic progressive nephropathy, a common age-related lesion in this strain potentially exacerbated by exposure. A (NOAEL) of 300 ppm was established, with no significant reproductive, developmental, or neurotoxic effects noted across doses. No dedicated chronic-duration mammalian studies (e.g., lifetime exposure) exist, limiting direct assessment of carcinogenicity or multi-year organ damage; assays, including Ames bacterial mutagenicity and mammalian cell tests, were negative, indicating low mutagenic potential. The U.S. EPA's provisional values, derived from the subchronic , screen for reference concentrations (RfC) but highlight gaps for oral chronic reference doses (RfD), with no human chronic exposure studies identified. Occupational sheets variably note possible cumulative target organ effects from repeated exposure, particularly to liver and kidneys, but classify it as lacking sufficient for specific repeated-dose under GHS criteria. In contexts of recreational misuse as an substitute, where repeated ingestion occurs at low cost but high volume, long-term remains unestablished, with animal comparisons suggesting exceeding 's but no longitudinal outcomes reported as of 2022. Potential for tolerance development exists, akin to other alcohols, yet without controlled studies, risks of insidious hepatic or renal impairment cannot be ruled out, especially given slower compared to primary alcohols—tert-amyl alcohol undergoes primarily non-oxidative elimination, prolonging systemic presence. Overall, while acute dominates short-term concerns, chronic protocols emphasize monitoring liver enzymes and renal function in exposed workers, with exposure limits informed by subchronic NOAELs rather than definitive long-term thresholds.

Comparative Toxicity with Other Alcohols

Tert-amyl alcohol (2-methyl-2-butanol), a tertiary alcohol, demonstrates acute oral in rats with an LD50 of 1.0–2.0 g/kg, indicating higher potency for compared to (LD50 ≈7.1 g/kg in rats) but similar to or less than (LD50 ≈5.6 g/kg in rats) and isopropanol (LD50 ≈4.7 g/kg in rats). This suggests greater per unit dose relative to , consistent with reports of intoxicating effects at approximately one-twentieth the volume equivalent of , though human has been documented at doses as low as 30 mL in adults.
AlcoholTypeOral LD50 (rat, mg/kg)Key Metabolic Product(s)
EthanolPrimary~7100Acetaldehyde (mildly toxic)
MethanolPrimary~5600Formaldehyde, formic acid (highly toxic, cause acidosis)
IsopropanolSecondary~4700Acetone (less toxic, ketosis without acidosis)
Tert-amyl alcoholTertiary1000–2000Minimal; resistant to oxidation
Unlike primary alcohols such as methanol, which are rapidly oxidized by alcohol dehydrogenase (ADH) to formaldehyde and formic acid—resulting in severe metabolic acidosis, optic neuropathy, and renal failure—tertiary alcohols like tert-amyl alcohol lack a hydrogen on the carbon bearing the hydroxyl group, rendering them poor substrates for ADH and preventing formation of such cytotoxic metabolites. This metabolic inertness contrasts with secondary alcohols like isopropanol, which yield acetone and induce ketosis but avoid anion gap acidosis, yet tert-amyl alcohol's profile aligns more closely with direct CNS and respiratory depression without significant delayed organ toxicity beyond acute overdose. In vitro assessments, such as MTT cell viability assays on neuronal cells, reveal 's cytotoxicity to be comparable to 's, though substantially lower than certain fusel alcohols like 3-methyl-1-butanol. Clinically, overdose manifests with symptoms akin to ethanol poisoning—, , —but with prolonged duration (12–24 hours) due to slower elimination, and without acetaldehyde-mediated hangovers. Case reports confirm survival with supportive care, including in severe instances, underscoring lower metabolite-driven morbidity relative to or , though its higher acute potency necessitates caution in recreational contexts.

Metabolism and Environmental Fate

Biotransformation in Mammals

In mammals, tert-amyl alcohol (2-methyl-2-butanol) is primarily biotransformed in the liver via phase II conjugation, with serving as the dominant pathway in rats, yielding tert-amyl alcohol as the major urinary metabolite following exposure. This conjugate is rapidly eliminated, reflecting efficient detoxification and excretion kinetics observed after oral or administration. A secondary oxidative route, mediated by enzymes rather than , produces 2-methyl-2,3-butanediol as an intermediate, which undergoes further dehydrogenation to carboxylic acids such as 2-hydroxy-2-methylbutyric acid and 3-hydroxy-3-methylbutyric acid. This avoids intermediates typical of , contributing to the absence of acetaldehyde-related effects like hangovers in recreational contexts. Pharmacokinetic studies in rats demonstrate rapid clearance of tert-amyl alcohol, with peak plasma levels declining quickly post-exposure due to these metabolic processes; for instance, after of related tert-amyl methyl (a precursor yielding tert-amyl alcohol), concentrations stabilized at approximately 8.1 μM in rats. In humans, pathways are qualitatively comparable, as evidenced by metabolite profiles from tert-amyl methyl , where tert-amyl alcohol and its appear as minor but detectable products prior to further oxidation. differences may exist in the relative emphasis on conjugation versus oxidation, with rats showing higher rates of diol formation and of downstream metabolites. occurs predominantly via , with over 90% of dose recovered as metabolites within 24-48 hours in models, underscoring low persistence in mammalian systems. Limited direct on isolated tert-amyl alcohol necessitate extrapolation from precursors, but consistency across studies supports conserved hepatic involvement.

Microbial Degradation and Persistence

Tert-amyl alcohol (TAA), a tertiary alcohol, exhibits slow microbial compared to primary or secondary alcohols, owing to the steric hindrance at the , which limits access by degradative enzymes. Studies indicate that TAA biodegradation requires specialized bacterial strains capable of initiating desaturation rather than direct oxidation. In identified pathways, such as those employing the Rieske nonheme mononuclear iron oxygenase MdpJ perform a tertiary alcohol desaturase function, converting TAA to the hemiterpene intermediate 2-methyl-3-buten-2-ol. This unsaturated alcohol undergoes subsequent , potentially via hydration or oxidation steps, though complete mineralization is inefficient and strain-dependent. For instance, a ruber strain degrades TAA via this route but fails to utilize primary or secondary alcohol analogs, highlighting specificity to tertiary structures. Environmental persistence of TAA is elevated due to its recalcitrance; in aerobic or microcosms, degradation half-lives exceed those of n-butanol by factors of 10 or more, with incomplete breakdown often yielding persistent intermediates. Under anoxic conditions, such as in , TAA persists longer, as methanogenic or sulfate-reducing consortia show minimal activity against tertiary alcohols. Safety data sheets note low bioaccumulation potential but underscore risks from slow dissipation in aquatic systems, where volatility and promote leaching rather than microbial uptake. Overall, TAA's environmental in uncontaminated settings ranges from weeks to months, contingent on microbial and co-substrate availability.

Regulatory Framework and Debates

Current Regulations and Restrictions

Tert-amyl alcohol, also known as 2-methyl-2-butanol, is not classified as a under and does not appear on the Drug Enforcement Administration's schedules of controlled substances. It is similarly unregulated as a or scheduled drug in , where has determined it does not meet criteria for control under the . Lacking ethanol-like beverage alcohol restrictions, it can be purchased and possessed by adults without age limits or licensing requirements typical of intoxicating liquors, though it is primarily sold as an industrial solvent or reagent. As a and irritant, tert-amyl alcohol is subject to occupational safety and environmental regulations. The (OSHA) mandates safe handling, storage, and labeling under hazard communication standards, classifying it as a combustible with potential for eye, , and respiratory irritation. The Environmental Protection Agency tracks it under the Toxic Substances Control Act for industrial uses, requiring reporting for significant new activities, but imposes no outright bans on production or distribution. Transportation follows guidelines as a Class 3 , necessitating UN-approved containers and placarding. In the , tert-amyl alcohol is registered under the REACH Regulation (EC) No 1907/2006, subjecting it to safety data assessments and potential restrictions on manufacturing, market placement, or use in consumer products if risks to human or the environment are identified; it appears on XVII lists for certain chemical restrictions applicable to alcohols. Specific applications, such as blending into , face state-level constraints; for instance, prohibits sales of alcohol-blended fuels unless meeting federal EPA specifications, explicitly referencing tert-amyl alcohol as an allowable within limits. No evidence exists of international treaties prohibiting its trade, though import/export may trigger hazardous materials declarations under conventions like the for chemical shipments.

Controversies Surrounding Fuel Use and Recreation

Tert-amyl methyl ether (TAME), a that metabolizes or hydrolyzes to tert-amyl alcohol (TAA, or 2-methyl-2-butanol), has faced scrutiny for environmental persistence and contamination risks similar to those of methyl tert-butyl ether (MTBE), prompting regulatory evaluations in regions like where TAME was listed under Proposition 65 in 2009 for . TAA itself serves as a high-octane additive in specialized applications, such as racing fuels, due to its combustion properties, but its direct fuel use remains limited amid broader debates over byproducts' biodegradability and aquatic . Long-term rodent bioassays on TAME have indicated potential carcinogenic effects, including increased incidences of renal and hepatic tumors, fueling calls for restricted formulations in reformulated . Recreational misuse of TAA has emerged as a concern since the early , with individuals consuming it as an unregulated alternative, often sourced as an industrial to evade beverage alcohol taxes and restrictions. A 2014 case documented acute intoxication in a with a blood TAA concentration of 83 μg/mL, presenting with severe , , and requiring supportive care. This pattern reflects TAA's higher potency compared to —producing stronger effects at lower doses—but amplifies risks of overdose, including and organ damage, as evidenced by its historical use at controlled medical doses. reports highlight an increasing trend in such intoxications, particularly in online forums promoting it for its rapid onset and muscle-relaxant properties, though without the safety data available for regulated alcohols. Additionally, TAA metabolites can trigger false-positive (EtG) tests, complicating forensic alcohol monitoring.

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