Acetic anhydride

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Legality: DEA Listed Chemicals

Production of this substance may be illegal in some jurisdictions under certain circumstances.

21CFR1310.02 a & b

In 1995/6, two lists were created "List I" and "List II", for which commercial manufacturers and distributors must register, and for which possession with the intent to manufacture illegal substances (such as methamphetamine, ecstasy, etc) is illegal. On these a few dozen "precursor" compounds commonly used in the manufacture of illegal drugs. [1] [2]

Bottom line: Do not produce this chemical without checking to make sure that you may do so legally.

 
 
Acetic anhydride
DEA LIST I/II SUBSTANCE
Chemical formula (CH3CO)2O
Molar Mass(g/mol) 102 
Density(g/cc) 1.082 
Melting Point(°C) -73 
Boiling Point(°C) 139.8
NFPA 704
NFPA704.png
2
2
1
W

Almost exclusively used in organic chemistry, primarily in the production of medicines, acetic anhydride is such a phenomenally effective acetylating agent that even though the routes to its production invariably involve lethal intermediates and difficult reaction conditions, it has been and is still a widely produced chemical.

Uses

Primary

Secondary

  • In organic synthesis, attaching an acetyl blocking group.
  • Generic acetylations

Hazards

NB: The syntheses of this product is in most cases extremely dangerous. Like sulfuric acid extreme care in production is more than warranted. This should only be attempted by people who are familiar enough with the ins and outs of chemistry that they can handle problems when things go wrong.

Synthesis

Several factors limit the need to produce AA in less than industrial quantities

  1. It is monetarily inexpensive in most markets
  2. It is easy and to store and transport
  3. Most efficient routes to AA involve highly toxic reactants or side-products
  4. Its manufacture and sale is broadly regulated, forming a barrier to entry for production which makes less-than-industrial-scale production uneconomic.

Things that don't work

  • Gerhardt (1852/3) showed that dehydration via sulfuric acid did not work.
  • Gal (1863) showed that dehydration via phosphorus pentoxide was impractically inefficient, with the acid/anydride Keq being miniscule.

History of production

Gerhardt

In 1852 the French chemist Charles Frédéric Gerhardt produced AA by heating potassium acetate with benzoyl chloride.[3] Potassium acetate and benzoyl chloride react to form potassium chloride, and an intermediate: acetyl-O-benzoyl complex, which promptly breaks down into two anhydrides with very different volatilities, easily separated

(CH3COO)K + (C7H5O)Cl KCl + (CH3CO)O(C7H5O)
2 (CH3CO)O(C7H5O) (CH3CO)2O + (C7H5O)2O

The acetate and acetyl products can be reversed without changing the result, and the salt components can be changed as well

(C7H5OO)K + (CH3CO)Cl KCl + (CH3CO)O(C7H5O)
(CH3CO)Na + (C7H5OO)I NaI + (CH3CO)O(C7H5O)

Gal

In 1863 M. Gal published[4] a method reacting acetyl chloride and barium oxide in a sealed container kept in a water bath for cooling.

2 (CH3CO)Cl + BaO (CH3CO)2O + BaCl2

Later others attribute the use of calcium oxide to Gal as well:

2 (CH3CO)Cl + CaO (CH3CO)2O + CaCl2

Broughton

In 1865 Broughton published[5] a method involving lead (II) acetate and carbon disulfide which was later summarised in The Chemical News[6].

2 Pb(CH3COO)2 + CS2 2 (CH3CO)2O + CO2 + 2 PbS

He recounts the process in detail:

Crystallised acetate of lead was dried for several hours at about 120 C and reduced to as fine a state of division as possible and a small quantity was placed in a strong glass tube which was then one third filled with dry bisulphide of carbon sealed and heated in an oil bath to a temperature of 165 C. It was found advisable to open the tubes once a day. With this precaution the digestion was continued till it was found that on opening the tubes only a slight rush of gas took place. The reaction was then judged to have practically terminated.

The whole fluid product thus obtained was submitted to distillation. The first product passing over was the excess of bisulphide used after which the temperature of the boiling liquid gradually rose when some acetic acid with a trace of propanone made its appearance till the temperature gradually rose to 137 C and remained constant till the [acetic anhydride] had passed over.

The above is slightly confusing, since it would seem that a reaction temperature of 160°C would cause the acetic anhydride (bp 139.8°C) to boil away. Even if it were kept liquid by the pressure in the vessel, it should flash-boil as soon as the vessel is opened. Perhaps there was a cooling phase to get the temperature below 135°C before the vessels were opened?

In 1873 Friedel (Of Freidel-Crafts fame) and Ladenburg suggest[7] that this is actually a two-stage process, producing a large intermediate molecule, carbon tetraacetate.

2 Pb(CH3COO)2 + CS2 C(CH3COO)4 + 2 PbS
C(CH3COO)4 2 (CH3CO)2O + CO2
lead acetate production

Lead acetate is made by reacting lead, oxygen and acetic acid, yielding lead acetate and water. The insolubility and unreactive nature of lead and its compounds makes this a time consuming process.

2 Pb + O2 + 4 CH3COOH 2 Pb(CH3COO)2 + 2 H2O // Expose lead to vinegar-laced steam and air
Pb + H2O2 + 2 CH3COOH Pb(CH3COO)2 + 2 H2O // Boil hydrogen peroxide and acetic acid mixture with high-surface area lead
PbO + 2 CH3COOH Pb(CH3COO)2 + H2O // Apply acetic acid directly to lead (II) oxide

dichlorocarbonyl

By 1884, patents were being issued in Germany[8] for the production of acetic anhydride from dichlorocarbonyl and sodium/potassium acetates.[9] dichlorocarbonyl being approximately as toxic as most cyanides, this is a very dangerous path to production.

COCl2 + 2 CH3COONa (CH3CO)2O + 2 NaCl + CO2

Alternately, dichlorocarbonyl can be combined with acetic acid to produce acetyl chloride, which can be used as above.

Wacker Chemie

In 1922, Wacker Chemie combined ethenone with acetic acid producing acetic anhydride, [10] but ethenone is nearly as toxic as dichlorocarbonyl, so this route was not ideal.

CH2CO + CH3COOH (CH3CO)2O

Modern production

Tennessee-Eastman process

The Tennessee-Eastman process is a modern, single-pot, catalytic method of producing acetic anhydride. [11] The net reaction is: methyl acetate + carbon monoxide = acetic anyhydride.

CH3(CH3COO) + CO (CH3CO)2O
Methyl acetate production

Water is generated in step one and must be removed completely before proceeding or the AA will be hydrolized.

  1. Combine acetic acid and methanol forming the ester: methyl acetate.
    CH3OH + CH3COOH CH3(CH3COO) + H2O
The reaction steps

The process involves both a coreactant, lithium iodide, and a catalyst, rhodium diiodide dicarbonyl RhI2(CO)2. The reactions take place at a pressure of 30–60 atm and a temperature of 150–200 °C.

  1. Methyl acetate and lithium iodide exchange ligands, producing iodomethane and lithium acetate
    CH3(CH3COO) + LiI CH3I + (CH3COO)Li
  2. Iodomethane and carbon monoxide combine to produce acetyl iodide
    CH3I + CO CH3COI
  3. Acetyl iodide and lithium acetate combine to give acetic anhydride and lithium iodide.
    CH3COI + CH3COOLi (CH3CO)2O + LiI

Laboratory production

via sodium pyrosulfate

Combine anydrous sodium pyrosulfate with anhydrous sodium acetate, possibly in a solution of glacial acetic acid and/or acetic anhydride. [12][13]

2 CH3COONa + Na2S2O7
{AcOH
}
2 Na2SO4 + (CH3CO)2O
2 CH3COONa + SO3
{AcOH
}
Na2SO4 + (CH3CO)2O

via acetyl iodide

This method is very lossy:

  • Iodine is lost unless the hydroiodic acid is captured and recycled
  • Phosphorus is lost as phosphorus pentoxide or H3PO4
  • The equipment and all the reagents must be made and kept anhydrous.
  1. Combine acetyl iodide and sodium acetate, giving acetic anhydride and sodium iodide
    CH3COI + CH3COONa (CH3CO)2O + NaI
acetyl iodide prep
  1. Combine anhydrous (glacial) acetic acid with solid iodine and red phosphorus, producing acetyl iodide
    10 CH3COOH + 10 I2 + P4 10 CH3COI + 10 HI(g) + 2 P2O5(s) // vent HI through potash solution to recycle iodine
  2. Distil the solution at 108°C
  3. Discard the residue (or recycle for iodine and phosphorus)
  4. Retain the distillate, it is acetyl iodide

via nitrogen dioxide

  1. Combine sodium acetate with nitrogen dioxide:
    3 NO2 + 2 NaCH3COO NO + (CH3CO)2O + 2 NaNO3
  2. Extract the acetic anhydride from the resulting mixture using dichloromethane

See Also

References

  1. "Emphasizing the "Control" in controlled substances"
    United States Drug Enforcement Agency
    link last accessed 11 September 2012.
  2. "Controlled Substances Act; Title 21; Chapter 13; Subchapter I"
    United States Food & Drug Administration
    link last accessed 11 September 2012.
  3. Gerhardt, Charles (1852) "Investigations into the anhydrides of organic acids"
    Comptes rendus 34; pp755-758. 
  4. Gal, M. (1863) "On a New Method of Formation of Anhydrides of Monobasic Acids"
    Comptes Rendus 56; pp360-361. 
  5. Broughton, John (1865) "On a new reaction for the production of anhydrides and ethers"
    Journal of the chemical Society 18; pp21-26. 
    DOI:10.1039/JS8651800021
  6.  (1865) "The Proceedings of the Chemical Society"
    The Chemical News XL; pp88. 
  7. Friedel; Ladenburg (1873) "Silico-Acetic Anydride"
    Journal of the Chemical Society 26; pp52. 
  8. DE patent 29669, "Method for the Preparation of the Anhydrides of Acids", 1884
  9.  (1885) "Method for the production of the anhydrides of organic acids"
    The journal of the society of chemical industry IV Emmott and Company
  10. "Milestones in the history of WACKER"
    Wacker Chemie AG.
  11. Zoeller, J. R.; Agreda, V. H.; Cook, S. L.; Lafferty, N. L.; Polichnowski, S. W.; et al. (1992) "Eastman Chemical Company Acetic Anhydride Process".
    Catalysis Today 13(1); pp73–91. 
    DOI:10.1016/0920-5861(92)80188-S
  12. US patent 1368789 "Process of making acetic anhydrid"
    Link courtesy Google
  13. US patent 1430304 "Manufacture of acetic anhydride"
    Link courtesy Google