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General chemical structure of an acyl chloride
Example of an acyl chloride:
acetyl chloride or ethanoyl chloride

In organic chemistry, an acyl chloride (or acid chloride) is an organic compound which is a reactive derivative of a carboxylic acid. As part of its molecular structure, an acyl chloride has the reactive functional group -CO-Cl and has the general formula RCOCl, where R is an organic radical group.

Acyl chlorides are a subset of acyl halides and undergo many of the same chemical reactions. A specific example of an acyl chloride is acetyl chloride, CH3COCl.

Contents

Nomenclature

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

Acyl chlorides tend to be liquids, which may react with atmospheric moisture to give fumes in air. Lacking the ability to form hydrogen bonds, they have lower boiling points than similar carboxylic acids (e.g. acetic acid, b.p. 118 °C; acetyl chloride, b.p. 51 °C). Like all carbonyl compounds, infrared spectroscopy reveals a band near 1800 cm−1.

Synthesis

Acyl chlorides are generally prepared in the same manner as alkyl chlorides: by replacing the corresponding hydroxy substituents with chlorides. Acyl chlorides are often prepared by reacting a carboxylic acid with thionyl chloride (SOCl2), phosphorus trichloride (PCl3), or phosphorus pentachloride (PCl5):[2]

R-COOH + SOCl2 → R-COCl + SO2 + HCl
3 R-COOH + PCl3 → 3 R-COCl + H3PO3
R-COOH + PCl5 → R-COCl + POCl3 + HCl

The reaction with thionyl chloride may be catalyzed by dimethylformamide.[3] In this reaction, the sulfur dioxide (SO2) and hydrogen chloride (HCl) generated are both gases which can leave the reaction vessel, driving the reaction forward. Excess thionyl chloride (b.p. 79 °C) is easily evaporated as well.[2] The reaction mechanism involving thionyl chloride and phosphorus pentachloride are similar; the mechanism with thionyl chloride is illustrative:[3]

Action of thionyl chloride on carboxylic acid.png

Another method involves the use of oxalyl chloride:

R-COOH + ClCOCOCl → R-COCl + CO + CO2 + HCl

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

Reaction of oxalyl chloride with DMF.png

The iminium intermediate reacts with the carboxylic acid, abstracting an oxygen atom, and regenerating the DMF catalyst.[3]

Reaction to give acyl chloride and DMF.png

Finally, methods that do not form HCl are also known, such as the Appel reaction:[4]

R-COOH + Ph3P + CCl4 → R-COCl + Ph3PO + HCCl3

and the use of cyanuric chloride (C3N3Cl3):[5]

Synthesis of acyl chlorides with cyanuric chloride.png

Reactions

Nucleophilic reactions

Acyl chlorides are very reactive. The presence of the chlorine on the carbonyl carbon makes it a very good electrophile, since both the oxygen and chlorine are strongly electron withdrawing, giving the carbon a large partial positive charge. This means even a weak nucleophile can attack the carbon. Since a chloride ion is a good leaving group, it will be readily replaced with the nucleophile. The simplest reaction is with water, to give a carboxylic acid:

R-COCl + HO-H → R-COOH + 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,[2] or excess amine (when preparing amides)[3] 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, and 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.[2]

With carbon nucleophiles such as Grignard reagents, acyl chlorides generally react first to 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.[2] 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.[6]

Electrophilic reactions

With Lewis acid catalysts like ferric chloride or aluminium chloride, acyl chlorides participate in Friedel-Crafts acylations, to give aryl ketones:[2]

The first step is the dissociation of the chlorine atom:

FC acylation step 1

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

FC acylation step II

Finally, a chlorine atom reacts to form HCl, and the AlCl3 catalyst is regenerated:

FC acylation step III

Hazards

Because acyl chlorides are such reactive compounds, they are generally toxic and special precautions should be taken while handling them. They are lachrymatory chemicals 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. ^ a b c d e f Boyd, Robert W.; Morrison, Robert (1992). Organic chemistry. Englewood Cliffs, N.J: Prentice Hall. pp. 666–762. ISBN 0-13-643669-2.  
  3. ^ a b c d Clayden, Jonathan (2001). Organic chemistry. Oxford: Oxford University Press. pp. 276–296. ISBN 0-19-850346-6.  
  4. ^ "Triphenylphosphine-carbon tetrachloride Taschner, Michael J. e-EROS: Encyclopedia of Reagents for Organic Synthesis, 2001
  5. ^ K. Venkataraman, and 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.  
  6. ^ William Reusch. "Carboxylic Acid Derivatives". VirtualText of Organic Chemistry. Michigan State University. http://www.cem.msu.edu/~reusch/VirtualText/crbacid2.htm.  







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