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.

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

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.

The simplest stable acyl chloride is ethanoyl chloride or acetyl chloride; methanoyl chloride (formyl chloride) is not stable at room temperature, although it can be prepared at –60 °C or below.[2][3] Acyl chloride is not soluble in water. Instead, it decomposes in water.

Synthesis

Industrial routes

The industrial route to acetyl chloride involves the reaction of acetic anhydride with hydrogen chloride:[4]

(CH3CO)2O + HCl → CH3COCl + CH3CO2H

Propionyl chloride is produced by chlorination of propionic acid with phosgene:[5]

CH3CH2CO2H + COCl2 → CH3CH2COCl + HCl + CO2

Benzoyl chloride is produced by the partial hydrolysis of benzotrichloride:[6]

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),[7] phosphorus trichloride (PCl3),[8] phosphorus pentachloride (PCl5) or oxalyl chloride27⁠ ([COCl]2):[9][10]

3 RCO2H + PCl3 → 3 RCOCl + H3PO3
RCO2H + PCl5 → RCOCl + POCl3 + HCl

Thionyl chloride[11]⁠ is a well-suited reagent as all the by-products (HCl, SO2) are gases and residual thionyl chloride can be easily removed as a result of its low boiling point (76 °C). Relative to thionyl chloride, oxalyl chloride is more expensive but also a milder reagent and therefore more selective. Acyl bromides and iodides are synthesized accordingly but are less common.[12]

The reaction with thionyl chloride may be catalyzed by dimethylformamide.[13] 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.[10] The reaction mechanisms involving thionyl chloride and phosphorus pentachloride are similar.

Another method involves the use of oxalyl chloride:

RCO2H + ClCOCOCl → RCOCl + CO + CO2 + HCl

The reaction is catalysed by dimethylformamide (DMF), which reacts with oxalyl chloride in the first step to give an iminium intermediate, which reacts with the carboxylic acid, abstracting an oxide, and regenerating the DMF catalyst.[13]

Acid chlorides can be used as a chloride source.[14]

Other methods that do not form HCl include the Appel reaction:[15]

RCO2H + Ph3P + CCl4 → RCOCl + Ph3PO + HCCl3

Another is the use of cyanuric chloride:[16]

RCO2H + C3N3Cl3 → RCOCl + C3N3Cl2OH

Reactions

Nucleophilic reactions

Acyl chlorides react with water yielding the carboxylic acid:

This hydrolysis is usually a nuiscance rather than intentional. Acyl chlorides are used to prepare acid anhydrides, amides and esters, by reacting acid chlorides with: a salt of a carboxylic acid, an amine, or an alcohol, respectively.

Base catalysed reactions

The use of a base, e.g. aqueous , is desirable to remove the hydrogen chloride byproduct, and to catalyze the reaction. During the nucleophilic substitution, the equilibrium can be shifted towards the product by capturing the hydrogen chloride with a base such as dilute sodium hydroxide solution or a basic solvent like pyridine or N,N-dimethylformamide.[10]

The use of dilute sodium hydroxide solution results in formation of two phases (aqueous/organic): this type of reaction is called Schotten-Baumann reaction. Both pyridine as solvent and the two-phase reaction are used in the synthesis of polyesters and polyamides (e. g. for the so-called nylon rope trick[17]⁠).

Amines like pyridine catalyse the reaction of the acyl chlorides via an nucleophilic catalysis mechanism. The amine attacks the carbonyl bond and presumably[18]⁠ forms first a transient tetrahedral intermediate and afterwards, by the displacement of the leaving group, a quaternary acylammonium salt. This quaternary acylammonium salt is more susceptible to attack by alcohols or other nucleophiles.

Excess amine may be used as catalyst when preparing amides.[13]

Other nucleophilic reactions

With carbon nucleophiles such as Grignard reagents, acyl chlorides generally give the ketone, which is susceptible to the attack by second equivalent to yield the tertiary alcohol. The reaction of acyl halides with certain organocadmium reagents stops at the ketone stage, although cadmium compounds are highly toxic and carcinogenic.[19][20] The nucleophilic reaction with Gilman reagents also afford ketones, reflecting the low reactivity to these lithium diorganocopper compounds.[10] 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 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.[21]

Electrophilic reactions

With Lewis acid catalysts like ferric chloride or aluminium chloride, acyl chlorides participate in Friedel-Crafts acylations, to give aryl ketones:[8][10]

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

Reactivity

Carboxylic acid halides are among the most reactive and versatile compounds in organic chemistry, and the full range of possible reactions has been reviewed.[22] Acyl chlorides have a greater reactivity than other carboxylic acid derivatives like acid anhydrides, esters or amides:

Acid chlorides can therefore be used to synthesize all compounds listed as being of lower reactivity. The high reactivity of the acid chloride is based on the chloride ion being a weak base and an excellent leaving group so that even weak nucleophiles attack the carbonyl group. When compared to its parent compound (the carboxylic acid) the higher reactivity can be explained by the hydroxyl group being a much worse leaving group.

Mechanism

The alcoholysis of acyl halides (the alkoxy-dehalogenation) is believed to proceed via an SN2 mechanism (Scheme 10).[23]⁠ However, the mechanism can also be tetrahedral or SN1 in highly polar solvents[24]⁠ (while the SN2 reaction involves a concerted reaction, the tetrahedral addition-elimination pathway involves a discernible intermediate).[25]

Mechanism of ester formation via the alcoholysis of an acyl chloride.

Hazards

Low molecular weight acyl chlorides are often lachrymators, and they react violently with water, alcohols, and amines.

References
  1. Nomenclature of Organic Chemistry, R-5.7.6 Acid halides
  2. Sih, John C. (2001-04-15), "Formyl Chloride", in John Wiley & Sons, Ltd (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Ltd, doi:10.1002/047084289x.rf026, ISBN 9780471936237
  3. Richard O.C. Norman; James M. Coxon (16 September 1993). Principles of Organic Synthesis, 3rd Edition. CRC Press. p. 371. ISBN 978-0-7487-6162-3.
  4. US patent 5672749, Phillip R. DeVrou, W. Bryan Waites, Robert E. Young, "Process for preparing acetyl chloride"
  5. Samel, Ulf-Rainer; Kohler, Walter; Gamer, Armin Otto; Keuser, Ullrich (2005). "Propionic acid and derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a22_223.
  6. Maki, Takao; Takeda, Kazuo (2002). "Benzoic acid and derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a03_555.
  7. Helferich, B.; Schaefer, W. (1929). "n-Butyrl chloride". Organic Syntheses. 9: 32. doi:10.15227/orgsyn.009.0032.
  8. Allen, C. F. H.; Barker, W. E. (1932). "Desoxybenzoin". Organic Syntheses. 12: 16. doi:10.15227/orgsyn.012.0016.
  9. Adams, Roger (1923). "p-Nitrobenzoyl chloride". Organic Syntheses. 3: 75. doi:10.15227/orgsyn.003.0075.
  10. Boyd, Robert W.; Morrison, Robert (1992). Organic chemistry. Englewood Cliffs, N.J: Prentice Hall. pp. 666–762. ISBN 0-13-643669-2.
  11. J. S. Pizey, Synthetic Reagents, Vol. 1, Halsted Press, New York, 1974.
  12. Keinan, Ehud; Sahai, M. (June 1990). "Diiodosilane. 3. Direct synthesis of acyl iodides from carboxylic acids, esters, lactones, acyl chlorides and anhydrides". The Journal of Organic Chemistry. 55 (12): 3922–3926. doi:10.1021/jo00299a042. ISSN 0022-3263.
  13. Clayden, Jonathan (2001). Organic chemistry. Oxford: Oxford University Press. pp. 276–296. ISBN 0-19-850346-6.
  14. L. P. Kyrides (1940). "Fumaryl Chloride". Organic Syntheses. 20: 51. doi:10.15227/orgsyn.020.0051.
  15. "Triphenylphosphine-carbon tetrachloride Taschner, Michael J. e-EROS: Encyclopedia of Reagents for Organic Synthesis, 2001
  16. K. Venkataraman; D. R. Wagle (1979). "Cyanuric chloride : a useful reagent for converting carboxylic acids into chlorides, esters, amides and peptides". Tetrahedron Lett. 20 (32): 3037–3040. doi:10.1016/S0040-4039(00)71006-9.
  17. Morgan, Paul W.; Kwolek, Stephanie L. (April 1959). "The nylon rope trick: Demonstration of condensation polymerization". Journal of Chemical Education. 36 (4): 182. doi:10.1021/ed036p182. ISSN 0021-9584.
  18. Hubbard, Patricia; Brittain, William J. (February 1998). "Mechanism of Amine-Catalyzed Ester Formation from an Acid Chloride and Alcohol". The Journal of Organic Chemistry. 63 (3): 677–683. doi:10.1021/jo9716643. ISSN 0022-3263.
  19. Spiridonova EIa (1991). "[Experimental study of toxic properties of dimethylcadmium]". Gigiena Truda I Professional'nye Zabolevaniia (in Russian) (6): 14–7. PMID 1916391.
  20. http://monographs.iarc.fr/ENG/Monographs/vol100C/mono100C-8.pdf%5B%5D
  21. William Reusch. "Carboxylic Acid Derivatives". VirtualText of Organic Chemistry. Michigan State University. Archived from the original on 2016-05-16. Retrieved 2009-02-19.
  22. Sonntag, Norman O. V. (1953-04-01). "The Reactions of Aliphatic Acid Chlorides". Chemical Reviews. 52 (2): 237–416. doi:10.1021/cr60162a001. ISSN 0009-2665.
  23. Bentley, T. William; Llewellyn, Gareth; McAlister, J. Anthony (January 1996). "SN2 Mechanism for Alcoholysis, Aminolysis, and Hydrolysis of Acetyl Chloride". The Journal of Organic Chemistry. 61 (22): 7927–7932. doi:10.1021/jo9609844. ISSN 0022-3263.
  24. C. H. Bamford and C. F. H. Tipper, Comprehensive Chemical Kinetics: Ester Formation and Hydrolysis and Related Reactions, Elsevier, Amsterdam, 1972.
  25. Fox, Joseph M.; Dmitrenko, Olga; Liao, Lian-an; Bach, Robert D. (October 2004). "Computational Studies of Nucleophilic Substitution at Carbonyl Carbon: the S N 2 Mechanism versus the Tetrahedral Intermediate in Organic Synthesis". The Journal of Organic Chemistry. 69 (21): 7317–7328. doi:10.1021/jo049494z. ISSN 0022-3263.
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