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Acetic anhydride
Acetic anhydride
Acetic anhydride
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Acetic anhydride
Acetic anhydride
Acetic anhydride
Acetic anhydride
Acetic anhydride
Names
Preferred IUPAC name
Acetic anhydride
Systematic IUPAC name
Ethanoic anhydride
Other names
Ethanoyl ethanoate
Acetic acid anhydride
Acetyl acetate
Acetyl oxide
Acetic oxide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.003.241 Edit this at Wikidata
EC Number
  • 203-564-8
RTECS number
  • AK1925000
UNII
UN number 1715
  • InChI=1S/C4H6O3/c1-3(5)7-4(2)6/h1-2H3 checkY
    Key: WFDIJRYMOXRFFG-UHFFFAOYSA-N checkY
  • InChI=1/C4H6O3/c1-3(5)7-4(2)6/h1-2H3
    Key: WFDIJRYMOXRFFG-UHFFFAOYAH
  • O=C(OC(=O)C)C
  • CC(=O)OC(=O)C
Properties
C4H6O3
Molar mass 102.089 g·mol−1
Appearance colorless liquid
Density 1.082 g cm−3, liquid
Melting point −73.1 °C (−99.6 °F; 200.1 K)
Boiling point 139.8 °C (283.6 °F; 412.9 K)
2.6 g/100 mL, reacts (see text)
Vapor pressure 4 mmHg (20 °C)[1]
−52.8·10−6 cm3/mol
1.3901
Thermochemistry[2]
−624.4 kJ/mol
Pharmacology
Legal status
Hazards
GHS labelling:
GHS02: FlammableGHS05: CorrosiveGHS07: Exclamation mark
Danger
H226, H302, H314, H330
P210, P233, P240, P241, P242, P243, P260, P261, P264, P270, P271, P280, P301+P312, P301+P330+P331, P303+P361+P353, P304+P312, P304+P340, P305+P351+P338, P310, P312, P321, P330, P363, P370+P378, P403+P235, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazard W: Reacts with water in an unusual or dangerous manner. E.g. sodium, sulfuric acid
3
2
1
W
Flash point 49 °C (120 °F; 322 K)
316 °C (601 °F; 589 K)
Explosive limits 2.7–10.3%
Lethal dose or concentration (LD, LC):
1000 ppm (rat, 4 h)[3]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 5 ppm (20 mg/m3)[1]
REL (Recommended)
 C 5 ppm (20 mg/m3)[1]
IDLH (Immediate danger)
 200 ppm[1]
Safety data sheet (SDS) ICSC 0209
Related compounds
Propionic anhydride
Related compounds
 Acetic acid
Acetyl chloride
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is one the simplest anhydrides of a carboxylic acid and is widely used in the production of cellulose acetate as well as a reagent in organic synthesis. It is a colorless liquid that smells strongly of acetic acid, which is formed by its reaction with moisture in the air.

Structure and properties

[edit]
Acetic anhydride in a glass bottle

Acetic anhydride, like most organic acid anhydrides, is a flexible molecule with a nonplanar structure. The C=O and C-O distances are 1.19 and 1.39 Å.[4] The pi system linkage through the central oxygen offers very weak resonance stabilization compared to the dipole-dipole repulsion between the two carbonyl oxygens. The energy barriers to bond rotation between each of the optimal aplanar conformations are quite low.[5]

Production

[edit]

Acetic anhydride was first synthesized in 1852 by the French chemist Charles Frédéric Gerhardt (1816-1856) by heating potassium acetate with benzoyl chloride.[6]

Acetic anhydride is produced by carbonylation of methyl acetate:[7]

CH3CO2CH3 + CO → (CH3CO)2O

The Tennessee Eastman acetic anhydride process involves the conversion of methyl acetate to methyl iodide. Carbonylation of the methyl iodide produces acetyl iodide, which reacts with acetate source to give the desired anhydride. Rhodium chloride in the presence of lithium iodide is employed as the catalyst. Because acetic anhydride is not stable in water, the conversion is conducted under anhydrous conditions.

To a decreasing extent, acetic anhydride is also prepared by the reaction of ketene (ethenone) with acetic acid at 45–55 °C and low pressure (0.05–0.2 bar).[8]

H2C=C=O + CH3COOH → (CH3CO)2O
(ΔH = −63 kJ/mol)

The route from acetic acid to acetic anhydride via ketene was developed by Wacker Chemie in 1922,[9] when the demand for acetic anhydride increased due to the production of cellulose acetate.

Due to its low cost, acetic anhydride is usually purchased, not prepared, for use in research laboratories.

Reactions

[edit]

Acetic anhydride is a versatile reagent for acetylations, the introduction of acetyl groups to organic substrates.[10] In these conversions, acetic anhydride is viewed as a source of CH3CO+.

Acetylation of alcohols, amines, aromatics

[edit]

Alcohols and amines are readily acetylated.[11] For example, the reaction of acetic anhydride with ethanol yields ethyl acetate:

(CH3CO)2O + CH3CH2OH → CH3CO2CH2CH3 + CH3COOH

Often a base such as pyridine is added to function as catalyst. In specialized applications, Lewis acidic scandium salts have also proven effective catalysts.[12]

Aromatic rings are acetylated by acetic anhydride. Usually acid catalysts are used to accelerate the reaction. Illustrative are the conversions of benzene to acetophenone[13] and ferrocene to acetylferrocene:[14]

(C5H5)2Fe + (CH3CO)2O → (C5H5)Fe(C5H4COCH3) + CH3CO2H

Preparation of other acid anhydrides

[edit]

Dicarboxylic acids are converted to the anhydrides upon treatment with acetic anhydride.[15] It is also used for the preparation of mixed anhydrides such as that with nitric acid, acetyl nitrate.

Precursor to geminal diacetates

[edit]

Aldehydes react with acetic anhydride in the presence of an acidic catalyst to give geminal diacetates.[16] A former industrial route to vinyl acetate involved the intermediate ethylidene diacetate, the geminal diacetate obtained from acetaldehyde and acetic anhydride:[17]

CH3CHO + (CH3CO)2O → (CH3CO2)2CHCH3

Hydrolysis

[edit]

Acetic anhydride dissolves in water to approximately 2.6% by weight.[18] Aqueous solutions have limited stability because, like most acid anhydrides, acetic anhydride hydrolyses to give carboxylic acids. In this case, acetic acid is formed, this reaction product being fully water miscible:[19]

(CH3CO)2O + H2O → 2 CH3COOH

Enolate formation

[edit]

Acetic anhydride forms the enolate in the presence of acetate as base. The enolate can be trapped by condensation with benzaldehyde. In the 19th century, this chemistry, the Perkin reaction, was used for the production of cinnamic acid:[20]

(CH3CO)2O + C6H5CHO → C6H5CH=CHCO2H + CH3CO2H

Lewis base properties

[edit]

The carbonyl groups in acetic anhydride are weakly basic. A number of adducts are known, such as the derivative of titanium tetrachloride, TiCl4((CH3CO)2O).[21]

Applications

[edit]

As indicated by its organic chemistry, acetic anhydride is mainly used for acetylations leading to commercially significant materials. Its largest application is for the conversion of cellulose to cellulose acetate, which is a component of photographic film and other coated materials, and is used in the manufacture of cigarette filters. Similarly it is used in the production of aspirin (acetylsalicylic acid), which is prepared by the acetylation of salicylic acid.[22] It is also used as an active modification agent via autoclave impregnation and subsequent acetylation to make a durable and long-lasting timber.[23]

Acetic anhydride is commonly used for the production of modified starches (E1414, E1420, E1422).

[edit]

Because of its use for the synthesis of heroin by the diacetylation of morphine, acetic anhydride is listed as a U.S. DEA List II precursor and is restricted in many other countries.[24][25]

Safety

[edit]

Acetic anhydride is an irritant and combustible liquid; it is highly corrosive to skin and any direct contact will result in burns. Because of its reactivity toward water and alcohol, foam or carbon dioxide are preferred for fire suppression.[26] The vapour of acetic anhydride is harmful.[27]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Acetic anhydride

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from Grokipedia
Acetic anhydride ((CH₃CO)₂O) is an acyclic carboxylic anhydride derived from acetic acid, appearing as a clear, colorless with a strong odor resembling . It has a of 139 °C, a of 1.08 g/cm³, and is flammable with a of 54 °C. In industrial applications, acetic anhydride functions primarily as an acetylating agent, facilitating the production of for fibers, photographic , cigarette filter tow, and plastic sheets, as well as pharmaceuticals, dyes, explosives, and detergents. Its high reactivity, including violent decomposition with water to form acetic acid and heat, renders it corrosive to metals, , and eyes, necessitating protective equipment and ventilation in handling; it is classified under GHS as flammable, acutely toxic if inhaled or swallowed, and causing severe burns. Additionally, as an essential precursor for acetylating into , acetic anhydride is regulated as a List II chemical by the U.S. to curb diversion for illicit narcotic synthesis.

History

Early Discovery and Synthesis

Acetic anhydride was first synthesized in 1852 by French chemist Charles Frédéric Gerhardt (1816–1856), who prepared the compound as part of his investigations into organic acid derivatives and chemical types theory. Gerhardt's method involved heating with an acid chloride, facilitating nucleophilic attack by the acetate ion on the acid chloride carbonyl to form the anhydride and displace chloride. This reaction represented an early application of acyl substitution principles to carboxylic derivatives, enabling the isolation of the pure liquid, which Gerhardt termed "anhydride acétique." The synthesis yielded a colorless, pungent with around 139–140 °C, confirming its identity through reactions such as of to form , which Gerhardt reported the same year. Early procedures relied on dry conditions to prevent , as the anhydride reacts vigorously with water to regenerate acetic acid. Availability of , produced by treating acetic acid with or trichloride, constrained scalability, but the method established acetic anhydride's utility in organic transformations. Subsequent refinements in the 19th century included variations using for improved yields, typically 70–80% under controlled heating and .

Industrial Development and Scale-Up

The ketene process for acetic anhydride production, involving the thermal cracking of acetic acid at approximately 700–800 °C to generate followed by its rapid reaction with excess acetic acid, marked the transition to industrial-scale manufacturing. This method was developed by in 1922, enabling economical production without reliance on costly and corrosive intermediates like used in prior laboratory syntheses. The innovation addressed scalability challenges inherent in early dehydration techniques, such as sulfuric acid-catalyzed , which suffered from low yields, equipment , and energy inefficiency. Commercial implementation rapidly followed, driven by surging demand for acetic anhydride in acetylating cellulose to produce acetate films, fibers, and plastics, as well as pharmaceuticals like aspirin. By the mid-1920s, plants employing the ketene route achieved capacities sufficient to support these applications, with process optimizations focusing on continuous flow reactors, precise temperature control to minimize ketene polymerization, and recycling of unreacted acetic acid to enhance yields exceeding 90%. This scale-up transformed acetic anhydride from a specialty chemical into a high-volume commodity, with global production growing to support derivative industries. Subsequent advancements in the late further refined production efficiency. The Halcon process, commercialized in 1983, utilized of with under , allowing integrated co-production with acetic acid and reducing reliance on pure intermediates. Concurrently, launched the first coal-derived synthesis in 1983 via syngas , achieving immediate product quality in a facility producing acetic anhydride as its largest-volume chemical, thereby diversifying feedstocks amid oil price volatility. These developments prioritized catalytic selectivity and energy integration, elevating capacities to millions of tons annually while mitigating environmental impacts from 's high-temperature generation.

Structure and Properties

Molecular Structure

Acetic anhydride possesses the molecular formula C₄H₆O₃ and the condensed structural formula (CH₃CO)₂O, consisting of two acetyl moieties (CH₃C=O) connected via a bridging oxygen atom to form the anhydride linkage. The central structural feature is the O(C=O)₂ core, where the carbonyl carbons are sp² hybridized, contributing to a planar arrangement around each . In the gas phase, electron diffraction studies reveal average bond lengths of 1.405 for the anhydride C-O bonds, 1.183 for the C=O bonds, and 1.495 for the methyl C-C bonds; corresponding bond angles include 115.8° for C-O-C, 121.7° for O-C=O, and 108.3° for O-C-C. The exhibits a non-planar conformation with torsional flexibility around the C-O-C linkage, featuring low barriers to rotation between and anti orientations of the acetyl groups. The solid-state , first determined at 100 K, shows acetic anhydride crystallizing in the orthorhombic Pbcn (Z=4), with molecules adopting an exactly C₂-symmetric conformation aligned along a crystallographic twofold axis. Dense molecular packing in the lattice is stabilized by short intermolecular C-H···O contacts (approximately 2.5-2.6 ) between methyl hydrogens and neighboring carbonyl oxygens, interpretable as weak hydrogen bonds. This arrangement contrasts with the more dynamic gas-phase geometry, highlighting solvent-free packing effects on conformational preference.

Physical Properties

Acetic anhydride is a clear, colorless liquid at , exhibiting a strong, pungent reminiscent of acetic acid. It is hygroscopic and highly reactive toward , undergoing exothermic rather than forming a stable solution. The compound is miscible with common organic solvents such as , , , and . Key thermophysical properties include a of -73 °C and a of 140 °C at 760 mmHg. Its is 1.082 g/mL at 20 °C, with a of 1.390 at 20 °C. measures approximately 4 mmHg at 20 °C, indicating moderate volatility.
PropertyValueConditions
Melting point-73 °C-
Boiling point140 °C760 mmHg
1.082 g/mL20 °C
Refractive index1.39020 °C (n_D)
Vapor pressure4 mmHg20 °C
Flash point54 °CClosed cup

Chemical Properties

Acetic anhydride, with the formula (CH₃CO)₂O, exhibits high reactivity as an electrophilic acylating agent due to the strained anhydride linkage and electron-deficient carbonyl carbons, facilitating nucleophilic acyl substitution reactions. In these processes, nucleophiles such as alcohols or amines attack one carbonyl carbon, forming a tetrahedral intermediate that collapses with elimination of acetate ion, yielding acetylated products like esters (R'OH → R'OCOCH₃) or amides (R'NH₂ → R'NHCOCH₃). This reactivity is enhanced under acidic or basic catalysis, with pyridine often employed as a base to neutralize the released acetic acid. Hydrolysis represents the most prominent chemical transformation, wherein acetic anhydride reacts with water to produce two molecules of acetic acid: (CH₃CO)₂O + H₂O → 2 CH₃COOH. This proceeds via nucleophilic attack by water on a carbonyl, followed by elimination, and is pseudo-first-order in anhydride concentration under typical conditions, with rates increasing in the presence of acid or base catalysts such as . The process generates significant heat—approximately 57 kJ/mol—and can become vigorous or violent when catalyzed by mineral acids like nitric or , necessitating careful handling to avoid runaway reactions. Acetic anhydride demonstrates limited stability in moist environments, slowly hydrolyzing upon exposure to atmospheric to release acetic acid vapors, which contribute to its characteristic pungent odor. It is incompatible with strong oxidizers, producing violent reactions or ignition, and with alcohols or amines, leading to rapid even without catalysts. Under conditions, it remains stable at but decomposes at elevated temperatures above 140 °C, potentially forming (CH₂=C=O) and acetic acid.

Production

Industrial Processes

The principal industrial processes for producing acetic anhydride are the ketene process and the rhodium-catalyzed carbonylation of . In , the ketene process accounts for the majority of production, involving the thermal dehydration of acetic acid to followed by its reaction with additional acetic acid. In the ketene process, acetic acid is pyrolyzed in the vapor phase at temperatures of 650–800 °C, typically in the presence of a catalyst such as supported on carbon, to generate (CH₂=C=O) and via the reaction CH₃COOH → CH₂=C=O + H₂O. The is then absorbed into a separate stream of glacial acetic acid, where it reacts exothermically to form acetic anhydride: CH₂=C=O + CH₃COOH → (CH₃CO)₂O. The process includes purification steps such as to separate the product from unreacted acetic acid and byproducts, with acetic acid recovery via to minimize waste. This method is energy-intensive due to the high-temperature but benefits from straightforward integration with acetic acid feedstock supplies. The carbonylation process, commercialized by in the 1980s as the Tennessee Eastman process, involves the reaction of with : CH₃COOCH₃ + CO → (CH₃CO)₂O. This liquid-phase reaction occurs under moderate conditions (150–200 °C, 30–50 bar) using a homogeneous rhodium-iodide catalyst system, often promoted by or other halides, in a nearly medium to achieve high selectivity (>95%). is typically derived from and acetic acid co-produced in the same facility, enabling efficient use of syngas-derived feedstocks and coupling with acetic acid production via methanol carbonylation. The process features reactive distillation for product separation and catalyst recycling, reducing operational costs compared to ketene-based routes in integrated acetyls complexes. An older method, the oxidation of (2 CH₃CHO + O₂ → (CH₃CO)₂O), has largely been supplanted by the above processes due to lower efficiency and feedstock availability constraints. Global production emphasizes these routes, with capacities scaled to integrated facilities producing over 100,000 metric tons annually per plant.

Laboratory Preparation

Acetic anhydride is commonly prepared in the laboratory by the nucleophilic acyl substitution reaction of with anhydrous , yielding the anhydride and as a . The reaction proceeds as follows: \ceCH3COCl+CH3COONa−>(CH3CO)2O+NaCl\ce{CH3COCl + CH3COONa -> (CH3CO)2O + NaCl}. This method is favored for its relative simplicity and avoidance of highly viscous byproducts compared to dehydration with , which generates residues requiring extensive purification. The procedure typically employs a tubulated or equipped with a reflux condenser and setup to manage the and volatile products. Approximately 70 g of finely pulverized anhydrous is placed in the vessel, followed by the dropwise addition of 50 g of while stirring to form a pasty ; rapid addition must be avoided to prevent excessive foaming or loss of volatile . After complete addition, the is gently heated—often with a or water bath—and the acetic anhydride is distilled at around 138°C. The distillate is then redistilled in the presence of 3 g of additional anhydrous to convert any residual . Yields are approximately 50 g (theoretical yield based on is about 55 g), corresponding to 70-80% efficiency, though moisture in can reduce this by promoting . Anhydrous conditions are critical, as both and the product anhydride react with water to regenerate acetic acid; commercial must be dried (e.g., by fusion or over a dehydrating agent) prior to use. The reaction is conducted under a due to the lachrymatory and corrosive nature of , which hydrolyzes to HCl, and the flammable, irritant properties of acetic anhydride ( 139-140°C, 1.08 g/mL). Alternative laboratory routes, such as treating glacial acetic acid with , produce gaseous byproducts (CO, CO₂, HCl) but require careful gas management and yield similar purity after .

Reactions

Acetylation Reactions

Acetic anhydride functions as an acetylating agent in nucleophilic acyl substitution reactions, where a attacks one of its carbonyl carbons, leading to the transfer of an (CH₃CO–) and elimination of (CH₃COO⁻). The mechanism involves formation of a tetrahedral intermediate, followed by collapse and proton transfer, with the enhanced by bases that deprotonate the nucleophile or catalysts that activate the anhydride. In the acetylation of alcohols (ROH), the oxygen lone pair attacks the anhydride's carbonyl, yielding acetate esters (ROCOCH₃) and acetic acid; this is commonly performed in pyridine solvent with 1.5–2.0 equivalents of acetic anhydride per hydroxy group at room temperature, often monitored by thin-layer chromatography. Catalysts such as 4-(dimethylamino)pyridine hydrochloride (DMAP·HCl), bismuth triflate (0.1 mol% in acetonitrile), or phosphomolybdic acid enable efficient, solvent-free conditions for primary, secondary, and sterically hindered alcohols, achieving yields often exceeding 90%. Amines (RNH₂ or R₂NH) undergo at the atom to form acetamides (RNHCOCH₃ or R₂NCOCH₃), proceeding via similar nucleophilic attack; primary aromatic amines like react readily at , sometimes without added catalyst, though mild acidic catalysts improve selectivity and yields for sulfonamides or thiols. Acetylation of aromatic rings occurs via , requiring a Lewis acid such as AlCl₃ to generate the acylium ion (CH₃C⁺=O) from the anhydride, which then attacks electron-rich arenes like or ; this Friedel-Crafts process is typically conducted in or at 0–25°C to minimize polyacylation.

Hydrolysis and Stability

Acetic anhydride undergoes hydrolysis in the presence of to yield two equivalents of acetic acid, according to the reaction (CH₃CO)₂O + H₂O → 2 CH₃COOH. This process is exothermic and proceeds via nucleophilic attack by on one of the carbonyl carbons, forming a tetrahedral intermediate that collapses to release acetic acid and . The reaction is catalyzed by acids, with the rate increasing in the presence of strong acids due to enhancing electrophilicity. The kinetics of hydrolysis follow pseudo-first-order behavior in excess water, with a half-life of approximately 4.4 minutes at 25°C under aqueous conditions. Rate constants vary with temperature, showing Arrhenius dependence; for instance, measurements between 20°C and 50°C indicate activation energies around 50–60 kJ/mol depending on solvent composition. In mixed solvents like acetonitrile-water, the rate decreases with increasing organic content, reflecting reduced water activity. Autocatalytic effects arise as produced acetic acid accelerates further decomposition. Acetic anhydride exhibits low stability toward moisture, decomposing readily upon exposure to humid air or to form acetic acid. It remains chemically stable under conditions at ambient temperatures but must be stored in tightly sealed containers in cool, dry, well-ventilated areas to prevent . Contact with triggers violent reaction, generating and potentially leading to buildup in confined spaces. Long-term stability requires exclusion of , metals, and ignition sources, as partial can propagate uncontrollably.

Other Transformations

Acetic anhydride decomposes thermally via at temperatures between 600 and 1200 °C to produce (CH₂=C=O) and acetic , following the (CH₃CO)₂O → CH₂=C=O + CH₃COOH. This process is industrially significant for generation, which serves as an intermediate in the synthesis of compounds like acetic derivatives and polymers, with contact times typically on the order of milliseconds to minimize side . The involves a concerted pericyclic elimination, favored under gas-phase conditions to achieve high yields of , often exceeding 90% with optimized flow systems. Acid anhydrides, including acetic anhydride, undergo reduction with lithium aluminum hydride (LiAlH₄) to yield primary alcohols, specifically from acetic anhydride via successive reduction of the acyl groups: (CH₃CO)₂O + 4 [H] → 2 CH₃CH₂OH. This transformation requires excess and conditions to prevent , producing two equivalents of alcohol per anhydride due to the bifunctional nature of the . Selective reduction to aldehydes can be achieved using modified reagents like lithium tri-t-butoxyaluminum hydride, though yields for acetic anhydride specifically are moderate (around 60–70%) owing to over-reduction tendencies. In the presence of strong bases or organometallic reagents such as organocopper species, acetic anhydride can form ketones via controlled , for example, reacting with dialkylcuprates to give methyl ketones: (CH₃CO)₂O + R₂CuLi → CH₃COR + CH₃COOLi + RCu. This avoids the tertiary alcohol formation seen with Grignard reagents, providing a synthetic route to unsymmetrical ketones with good selectivity under low-temperature conditions (-78 °C).

Applications

Industrial Uses

Acetic anhydride's primary industrial application is the acetylation of cellulose to produce , which accounts for approximately 95% of U.S. production. serves as a key material in manufacturing cigarette filter tow, fibers such as acetate rayon, films, and sheets for applications including and coatings. In the detergents sector, acetic anhydride is used to synthesize (TAED), a activator that enhances low-temperature whitening in formulations. It also functions as an acetylating agent in the production of modified starches for industrial applications like adhesives, paper sizing, and textile processing. Additional bulk uses include the manufacture of plasticizers, explosives through of nitro compounds, and coatings, where it contributes to modification for enhanced durability and flexibility. Globally, demand for these applications drives market growth, with derivatives dominating due to their versatility in consumer and industrial products.

Pharmaceutical and Fine Chemical Synthesis

Acetic anhydride functions primarily as an acetylating agent in the synthesis of pharmaceuticals, enabling the introduction of acetyl groups to enhance , stability, or bioactivity of molecules. This role is critical in esterification and formation reactions, where it reacts with alcohols, amines, or under acidic or basic conditions to produce acetylated intermediates. In production, it supports the creation of high-purity acetyl derivatives used as building blocks for active pharmaceutical ingredients (APIs), agrochemicals, and specialty compounds, often in multi-step processes requiring selective protection of functional groups. A prominent example is the industrial-scale synthesis of aspirin (acetylsalicylic acid), where acetic anhydride reacts with in the presence of a catalyst such as or , yielding aspirin and acetic acid as a ; this process, developed in the late , remains a benchmark for efficiency, with global aspirin production exceeding 100,000 metric tons annually as of recent estimates. Similarly, acetaminophen () is produced by acetylating with acetic anhydride, followed by purification steps, accounting for a significant portion of the pharmaceutical-grade acetic anhydride demand. In the synthesis of derivatives, acetic anhydride hydroxyl or amino groups to form congeners used in treating respiratory conditions like and , with reactions typically conducted in solvents such as to control selectivity and yield. For fine chemicals, acetic anhydride facilitates the of carbohydrates and , producing intermediates for antiviral drugs or antibiotics; for instance, it is employed in the protection of sugar hydroxyl groups during nucleoside analog synthesis, enabling subsequent glycosylations with high . These applications underscore its versatility, though yields and purity depend on reaction conditions like temperature (often 50–100°C) and excess use to drive equilibrium toward product formation.

Other Applications

Acetic anhydride serves as an acetylating agent in the synthesis of various , where it facilitates the introduction of acetyl groups to dye intermediates, enhancing their and color properties. In the perfumery industry, it is used to acetylate fragrance compounds, producing esters that act as fixatives or modifiers to stabilize and prolong scent profiles in perfumes. The compound finds application in explosives manufacturing, contributing to the of precursors for certain detonators and materials, though specific formulations vary by process. In the sector, acetic anhydride is utilized for the of starches to produce modified starches with improved thickening and stability properties, and it is recognized by the Flavor and Extract Manufacturers Association for flavor-related applications. Additionally, it supports the synthesis of agrochemicals, including certain pesticides and herbicides, by acetylating intermediates. It is also employed in detergent additives, where acetylated derivatives enhance formulation performance.

Safety and Toxicity

Health Hazards


 Acetic anhydride is highly corrosive to skin and eyes, causing severe chemical burns upon contact due to its rapid hydrolysis to acetic acid in the presence of moisture. Skin exposure leads to immediate irritation, redness, and blistering, with prolonged contact resulting in deep tissue damage and potential necrosis. Eye contact produces intense pain, lacrimation, conjunctivitis, corneal opacity, and photophobia, often requiring immediate medical intervention to prevent permanent vision loss. Inhalation of vapors irritates the , causing coughing, nasal discharge, and throat burning at low concentrations, while higher exposures can induce and fatal . The compound is classified as fatal if inhaled, with symptoms including asthma-like reactions such as reactive airways dysfunction syndrome (RADS). Occupational exposure limits include a NIOSH of 5 ppm (20 mg/m³) and an OSHA of 5 ppm TWA, reflecting its via this route. Ingestion results in severe gastrointestinal corrosion, with symptoms of , , , and potential of the or lining. Oral LD50 in rats is approximately 1,780 mg/kg, indicating moderate acute oral , though cases emphasize the of systemic absorption leading to . Dermal LD50 exceeds 1,000 mg/kg in rabbits, but practical hazards arise from its irritant properties rather than systemic . No significant chronic effects or carcinogenicity have been established in available data, with hazards primarily acute.

Handling and Storage Precautions

Acetic anhydride requires handling under a or in well-ventilated areas to minimize exposure to vapors, which can cause severe respiratory irritation and upon inhalation. Personnel must wear appropriate , including chemical-resistant gloves, safety goggles, face shields, and respiratory protection with organic vapor cartridges when potential exposure exceeds permissible limits. Avoid skin contact, as the substance causes severe burns and is harmful if swallowed; wash thoroughly after handling and do not eat, drink, or smoke in the vicinity. For storage, maintain acetic anhydride in a cool, dry, well-ventilated area below 25°C (77°F) in tightly sealed containers made of compatible materials such as , , or certain plastics, away from direct and ignition sources. It is incompatible with , alcohols, strong bases, oxidizers, and metals like or , which can lead to violent reactions, , or ; segregate from these materials and /feedstuffs. Store in flammable or corrosive-resistant cabinets compliant with local fire codes, ensuring secondary containment to prevent spills, and monitor for signs of such as pressure buildup from ingress.

Precursor Chemical Controls

Acetic anhydride is regulated internationally as a precursor chemical under Table I of the 1988 Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances due to its critical role in converting to through , a step essential for illicit production. The (INCB) oversees global monitoring, including mandatory pre-export notifications for shipments via the PEN Online system to prevent diversion, with voluntary assessments of suspicious consignments. These measures aim to track legitimate industrial uses—such as in pharmaceuticals, plastics, and dyes—while curbing illicit diversion, though enforcement varies by country and has prompted adaptations like smuggling or substitution in labs. In the United States, acetic anhydride is designated a List II regulated chemical by the (DEA) under the Comprehensive Drug Abuse Prevention and Control Act of 1970, as amended, with DEA Chemical Code Number 8519. Handlers, including manufacturers, distributors, and importers, must obtain DEA registration, maintain detailed records of acquisitions and distributions, and file reports for transactions exceeding cumulative thresholds—such as 1,023 kilograms for domestic distributions or imports without corresponding exports. Suspicious orders, thefts, or losses must be reported immediately to the DEA's Diversion Control Division, with import/export permits required and subject to quota limitations to minimize diversion risks. National implementations extend these controls; for instance, requires licensing, inspections, and monitoring of acetic anhydride alongside other precursors like . In the , Regulation (EC) No 273/2004 mandates authorization for operators handling scheduled substances, including acetic anhydride, with competent authorities verifying end-users and imposing penalties for non-compliance. Empirical analyses indicate that such controls have disrupted supply chains, with acetic anhydride restrictions correlating to reduced purity and availability in markets like the during intensified enforcement periods. However, persistent seizures—over 100 tons globally in 2020—underscore ongoing diversion challenges despite regulatory frameworks.

International Regulations and Impacts

Acetic anhydride is classified as a substance in Table I of the 1988 United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, subjecting it to stringent international controls as a key precursor for heroin production from morphine. Parties to the convention, numbering over 180 countries as of 2023, are required to implement licensing systems for import, export, and domestic distribution, maintain detailed records of transactions exceeding specified thresholds (e.g., 1 kilogram equivalent), and report suspicious activities to the International Narcotics Control Board (INCB). The INCB, through its Pre-Export Notification Online (PEN Online) system established in 2008, facilitates pre-shipment verification to prevent diversion, with over 1.2 million notifications processed annually by 2022. These regulations mandate voluntary assessments of applications to distinguish legitimate uses (e.g., in pharmaceuticals and textiles) from potential illicit diversion, with the INCB issuing annual guidelines on estimating legitimate requirements and monitoring discrepancies. Exporting countries must verify end-user declarations, while importing nations enforce quantitative restrictions based on verified needs; for instance, Afghanistan's annual legitimate demand is estimated at under 100 metric tons, far below illicit production requirements exceeding 500 tons. Non-compliance can result in trade suspensions, as seen in INCB recommendations to halt shipments to high-risk regions without adequate controls. The controls have demonstrably reduced heroin precursor availability in regulated markets, with U.S. purity dropping and availability decreasing for 2-5 years following tightened acetic anhydride restrictions in the , correlating with a 20-30% reduction in supply metrics. Global seizures fell to approximately 25,600 liters (about 27.6 metric tons) in 2022 from higher levels in prior years, indicating effective interdiction but persistent smuggling challenges, particularly via overland routes to where regulated prices have risen, incentivizing black-market entry by new actors. Legitimate trade faces elevated compliance costs, including licensing and verification, potentially constraining supply chains in developing economies, though pharmaceutical and industrial sectors report minimal long-term disruptions due to established monitoring. Delays in implementation, such as Mexico's 18-year lag until 2019, have amplified regional vulnerabilities, underscoring uneven enforcement impacts.

Environmental Considerations

Fate in the Environment

Acetic anhydride hydrolyzes rapidly in the presence of , forming acetic as the primary degradation product, with an estimated of 4.4 minutes under environmental conditions based on a hydrolysis rate constant of 3.0 × 10⁻⁴ M/s. This proceeds via nucleophilic attack by , rendering the compound non-persistent in aquatic systems where moisture is abundant. Consequently, direct exposure to unaltered acetic anhydride in surface or is minimal, as dominates over other fate processes such as volatilization or . In soil environments, acetic anhydride's fate is similarly governed by hydrolysis upon contact with soil moisture, leading to acetic acid formation that is readily biodegradable by soil microorganisms. Prior to full hydrolysis, the compound may exhibit moderate mobility and leach toward due to its and low affinity to , though modeled releases indicate concentrations remain below 10⁻⁹ µg/g in . No of long-term accumulation in or compartments exists, as the degradation product acetic acid does not bind strongly or persist. Atmospheric persistence is limited by acetic anhydride's relatively low vapor pressure (approximately 1.5 kPa at 20°C) and its tendency to hydrolyze in humid air, forming acetic acid aerosols or vapor. Direct emissions to air from environmental releases are negligible, with modeled air concentrations on the order of 10⁻¹⁵ mg/m³, precluding significant transport or deposition. Overall, comprehensive assessments confirm no substantial environmental effects from acetic anhydride due to its reactivity and transformation into non-hazardous, biodegradable acetic acid.

Production and Use Impacts

The production of acetic anhydride occurs mainly through the -acetic acid route, involving thermal cracking of acetic acid to followed by reaction with additional acetic acid, or via catalytic of with . These processes demand substantial energy, with energy intensity reaching 37 MJ per kg of product. Greenhouse gas emissions associated with across the total 1.2 kg CO₂-equivalent per kg of acetic anhydride. Independent lifecycle assessments estimate a broader of 3.57 kg CO₂-equivalent per kg, incorporating feedstock, processing, agriculture-related inputs, and transport contributions. Environmental releases during manufacturing remain limited, with atmospheric emissions from facilities such as one Canadian at 30 kg per day and managed via deepwell injection or treatment to minimize discharge. Acetic anhydride exhibits rapid upon any aqueous release, with a of 4.4 minutes at 25°C, yielding acetic acid that undergoes >95% within 5 days under aerobic conditions. Atmospheric photooxidation of the resultant acetic acid proceeds with a of about 22 days. Predicted environmental concentrations (PEC) for acetic anhydride stand at 1.7 × 10⁻¹¹ mg/L, yielding a PEC/PNEC ratio of 1.9 × 10⁻¹⁰, far below thresholds indicating ecological risk. In applications such as cellulose acetate production for fibers and films (accounting for roughly 42% of U.S. consumption in the 1990s, with similar patterns persisting), pharmaceutical acetylation, and fine chemical synthesis, acetic anhydride functions as a reactive intermediate, often in closed systems that recover acetic acid byproducts. Use-phase releases hydrolyze equivalently to production effluents, exhibiting low persistence, negligible bioaccumulation potential (log K_ow = -0.58), and aquatic toxicity thresholds of 18–3,400 mg/L for fish, algae, and invertebrates—concentrations orders of magnitude above modeled exposures. Canadian import volumes of 10,000–100,000 kg annually underscore contained industrial handling, with assessments concluding no significant hazard to environmental compartments under typical conditions. Improper disposal, however, risks localized water contamination via acetic acid formation, potentially affecting aquatic pH and biota at high concentrations.

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