Acyl chloride

This article is about the functional group. For the chemical compound, see Acetyl chloride.
General chemical structure of an acyl chloride

In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group -COCl. Their formula is usually written RCOCl, where R is a side chain. They are reactive derivatives of carboxylic acids. A specific example of an acyl chloride is acetyl chloride, CH3COCl. Acyl chlorides are the most important subset of acyl halides.

Nomenclature

Where the acyl chloride moiety takes priority, acyl chlorides are named by taking the name of the parent carboxylic acid, and substituting -yl chloride for -ic acid. Thus:

acetyl chloride CH3COCl
benzoyl chloride C6H5COCl

When other functional groups take priority, acyl chlorides are considered prefixes — chlorocarbonyl-:[1]

(chlorocarbonyl)acetic acid ClOCCH2COOH

Properties

Lacking the ability to form hydrogen bonds, acid chlorides have lower boiling and melting points than similar carboxylic acids. For example, acetic acid boils at 118 °C, whereas acetyl chloride boils at 51 °C. Like most carbonyl compounds, infrared spectroscopy reveals a band near 1750 cm−1.

Synthesis

Industrial routes

The industrial route to acetyl chloride involves the reaction of acetic anhydride with hydrogen chloride.[2] For benzoyl chloride, the partial hydrolysis of benzotrichloride is useful:[3]

C6H5CCl3 + H2O → C6H5C(O)Cl + 2 HCl

Laboratory methods

In the laboratory, acyl chlorides are generally prepared in the same manner as alkyl chlorides, by replacing the corresponding hydroxy substituents with chlorides. Thus, carboxylic acids are treated with thionyl chloride (SOCl2),[4] phosphorus trichloride (PCl3),[5] or phosphorus pentachloride (PCl5):[6][7]

RCOOH + SOCl2 → RCOCl + SO2 + HCl
3 RCOOH + PCl3 → 3 RCOCl + H3PO3
RCOOH + PCl5 → RCOCl + POCl3 + HCl

The reaction with thionyl chloride may be catalyzed by dimethylformamide.[8] In this reaction, the sulfur dioxide (SO2) and hydrogen chloride (HCl) generated are both gases that can leave the reaction vessel, driving the reaction forward. Excess thionyl chloride (b.p. 74.6 °C) is easily evaporated as well.[7] The reaction mechanisms involving thionyl chloride and phosphorus pentachloride are similar; the mechanism with thionyl chloride is illustrative:[8]

Another method involves the use of oxalyl chloride:

RCOOH + ClCOCOCl → RCOCl + CO + CO2 + HCl

The reaction is catalysed by dimethylformamide (DMF), which reacts with oxalyl chloride in the first step to give the iminium intermediate.

The iminium intermediate reacts with the carboxylic acid, abstracting an oxide, and regenerating the DMF catalyst.[8]

Finally, methods that do not form HCl are also known, such as the Appel reaction:[9]

RCOOH + Ph3P + CCl4 → RCOCl + Ph3PO + HCCl3

and the use of cyanuric chloride (C3N3Cl3):[10]

Reactions

Nucleophilic reactions

Acyl chlorides are very reactive. Consider the comparison to its RCOOH acid analogue: the chloride ion is an excellent leaving group while the hydroxide is not under normal conditions; i.e. even weak nucleophiles attack the carbonyl. A common reaction which is usually a nuisance is in fact with water yielding the carboxylic acid:

RCOCl + H2O → RCO2H + HCl

Acyl chlorides can be used to prepare carboxylic acid derivatives, including acid anhydrides, esters, and amides by reacting acid chlorides with: a salt of a carboxylic acid, an alcohol, or an amine respectively. The use of a base, e.g. aqueous sodium hydroxide or pyridine,[7] or excess amine (when preparing amides)[8] is desirable to remove the hydrogen chloride byproduct, and to catalyze the reaction. While it is often possible to obtain esters or amides from the carboxylic acid with alcohols or amines, the reactions are reversible, often leading to low yields. In contrast, both reactions involved in preparing esters and amides via acyl chlorides (acyl chloride formation from carboxylic acid, followed by coupling with the alcohol or amine) are fast and irreversible. This makes the two-step route often preferable to the single step reaction with the carboxylic acid.[7]

With carbon nucleophiles such as Grignard reagents, acyl chlorides generally react first to give the ketone and then with a second equivalent to the tertiary alcohol. A notable exception is the reaction of acyl halides with certain organocadmium reagents which stops at the ketone stage. The nucleophilic reaction with Gilman reagents (lithium diorganocopper compounds) also afford ketones, due to their lesser reactivity.[7] Acid chlorides of aromatic acids are generally less reactive those of alkyl acids and thus somewhat more rigorous conditions are required for reaction.

Acyl chlorides are reduced by strong hydride donors such as lithium aluminium hydride and diisobutylaluminium hydride to give primary alcohols. Lithium tri-tert-butoxyaluminium hydride, a bulky hydride donor, reduces acyl chlorides to aldehydes, as does the Rosenmund reduction using hydrogen gas over a poisoned palladium catalyst.[11]

Electrophilic reactions

With Lewis acid catalysts like ferric chloride or aluminium chloride, acyl chlorides participate in Friedel-Crafts acylations, to give aryl ketones:[5][7]

The first step is the Lewis acid-induced dissociation of the chloride:

This step is followed by nucleophilic attack of the arene toward the acyl group:

Finally, a chloride atom combines with the released proton to form HCl, and the AlCl3 catalyst is regenerated:

Because of the harsh conditions and the reactivity of the intermediates, this otherwise quite useful reaction tends to be messy, as well as toxic to the health and environment.

Hazards

Because acyl chlorides are such reactive compounds, precautions should be taken while handling them. They are lachrymatory because they can react with water at the surface of the eye producing hydrochloric and organic acids irritating to the eye. Similar problems can result if one inhales acyl chloride vapors.

References

  1. ↑ Nomenclature of Organic Chemistry, R-5.7.6 Acid halides
  2. ↑ US patent 5672749, Phillip R. DeVrou, W. Bryan Waites, Robert E. Young, "Process for preparing acetyl chloride"
  3. ↑ Takao Maki, Kazuo Takeda “Benzoic Acid and Derivatives” Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi: 10.1002/14356007.a03_555
  4. ↑ Helferich, B.; Schaefer, W. (1929). "n-Butyrl chloride". Organic Syntheses. 9: 32. doi:10.15227/orgsyn.009.0032.
  5. 1 2 Allen, C. F. H.; Barker, W. E. (1932). "Desoxybenzoin". Organic Syntheses. 12: 16. doi:10.15227/orgsyn.012.0016.
  6. ↑ Adams, Roger (1923). "p-Nitrobenzoyl chloride". Organic Syntheses. 3: 75. doi:10.15227/orgsyn.003.0075.
  7. 1 2 3 4 5 6 Boyd, Robert W.; Morrison, Robert (1992). Organic chemistry. Englewood Cliffs, N.J: Prentice Hall. pp. 666–762. ISBN 0-13-643669-2.
  8. 1 2 3 4 Clayden, Jonathan (2001). Organic chemistry. Oxford: Oxford University Press. pp. 276–296. ISBN 0-19-850346-6.
  9. ↑ "Triphenylphosphine-carbon tetrachloride Taschner, Michael J. e-EROS: Encyclopedia of Reagents for Organic Synthesis, 2001
  10. ↑ K. Venkataraman; D. R. Wagle (1979). "Cyanuric chloride : a useful reagent for converting carboxylic acids into chlorides, esters, amides and peptides". Tet. Lett. 20 (32): 3037–3040. doi:10.1016/S0040-4039(00)71006-9.
  11. ↑ William Reusch. "Carboxylic Acid Derivatives". VirtualText of Organic Chemistry. Michigan State University.
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