Faculty of Pharmacy

Research Project Title

Submitted by:
Student Name: ‫ﻋﺒﺪاﻟﺮﺣﻤﻦ ﻋﻼء ﻋﺒﺪه أﺣﻤﺪ اﻟﺸﻮرﺑﺠﻲ‬ Student ID: 101601327

PHC 1203-Organi Chemistry 2

Supervised by:
Dr. Yasser Mohamed Ali Loksha

Spring 2020
 List of Contents
List of Figures .................................................................................................................................. i
Abstract ........................................................................................................................................... 1
Introduction ..................................................................................................................................... 2
Nomenclature .................................................................................................................................. 2
Acid Halides ................................................................................................................................ 2
Acid Anhydrides ......................................................................................................................... 2
Synthesis ......................................................................................................................................... 3
Acid Chlorides............................................................................................................................. 3
Acid Anhydrides ......................................................................................................................... 3
Physical Properties .......................................................................................................................... 4
Acid Halides ................................................................................................................................ 4
Acid Anhydrides ......................................................................................................................... 5
Reactions ......................................................................................................................................... 5
Acid Halides ................................................................................................................................ 5
Acid Anhydrides ......................................................................................................................... 8
Uses ................................................................................................................................................. 9
Conclusion ...................................................................................................................................... 9
References ..................................................................................................................................... 10
 List of Figures
Figure 1. Representation of acid anhydride. ................................................................................................. 2
Figure 2. Structures of some acid halides with official name on top and common name below. ................. 2
Figure 3. Structures of some acid anhydrides with official name on top and common name below............ 3
Figure 4. Synthesis of acid halides via PCl3, PCl5 and SOCl2. ..................................................................... 3
Figure 5. Mechanism of synthesis of acid anhydrides via dehydration of carboxylic acids. ........................ 4
Figure 6. Mechanism of synthesis of acid anhydrides via dehydration of carboxylic acids. ........................ 4
Figure 7. Boiling points and molecular weights of some acid halides.......................................................... 5
Figure 8. Nucleophilic attack on acid halides. Figure 9. Summary of acid halide reactions. ...... 5
Figure 10. Aldehyde formation from acid chloride. ..................................................................................... 6
Figure 11. Further reduction of aldehyde to primary alcohol. ...................................................................... 6
Figure 12. Tertiary alcohol production via acid chloride. ............................................................................. 6
Figure 13. Ester formation from acid chlorides. ........................................................................................... 6
Figure 14. Reaction with organocuprate agents. ........................................................................................... 7
Figure 15. Reaction with water giving carboxylic acids. .............................................................................. 7
Figure 16. Reactions of acid halides with primary and secondary amines. .................................................. 7
Figure 17. Acid halide and carboxylic acid reaction..................................................................................... 7
Figure 18. Friedel-Crafts Acylation .............................................................................................................. 8
Figure 19. Clemmenson reduction. ............................................................................................................... 8
Figure 20. Acid anhydride and alcohol reactions producing ester.................................................. 8
Figure 21. Acid anhydride and amine reactions producing amide. ................................................ 9

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 Abstract
Acid halides and acid anhydrides are major classes of organic compounds. Organic compounds
have numerous applications in the pharmaceutical, chemical, paints, biological and food
processing industries, among others. This paper reviews the nomenclature, structures, physical
properties, uses, synthesis and reactions of acid halides and acid anhydrides. This provides the
basis for a robust and adequate understanding of how these chemicals behave physically and
chemically and familiarity with technical terms and names.
Key Words
Acid halides
Acid Anhydrides
Organic Synthesis
Organic Reactions
Friedel-Crafts Acylation

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Introduction
An acyl halide is an organic compound consisting of an acyl group and a halide (halogen anions
such as fluoride, bromide, chloride, iodide and astatide) as shown in figure 1. An acyl group is a
group that is obtained by the removal of one or more hydroxyl (OH) groups from an oxoacid, an
oxoacid being simply and oxygenated acid such as carboxylic acid, and has an alkyl group bound
to a carbonyl group. An acyl group can be further classified based on the group attached via the
remaining bond of carbon atom of the carbonyl group. An acyl group can form an aldehyde
(hydrogen atom is bonded to carbonyl carbon atom), ketone (alkyl group), ester (oxygen + alkyl
group; OR), acyl amide (amine group) or acyl/acid halide (halogen atom). An acid anhydride is an
organic compound resulted from the condensation of 2 oxoacid molecules (usually carboxylic
acids) and consists of 2 acyl groups connected by an oxygen atom as shown in figure 1. Acid
Halides and acid anhydrides are major classes of organic compounds and by studying their
reactions and properties a lot of insight can be acquired in the understanding of chemical reactions
and their applications in industry1.

Figure 1. Representation of acid anhydride.

Nomenclature

Acid Halides

To name an acid halide the name of the corresponding carboxylic group is altered to end with the
suffix ‘-oyl’ instead of –‘oic’, and the name of the halogen atom is ended with the “-ide” suffix.
For example, propanoyl bromide or 2-methylbutanoyl chloride (figure 2)1.

Figure 2. Structures of some acid halides with official name on top and common name below.

Acid Anhydrides

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To name acid anhydrides the name of the parent acid is taken and proceeded by the suffix
anhydride as in propanoic anhydride or ethanoic anhydride (figure 3)1.

Figure 3. Structures of some acid anhydrides with official name on top and common name below.

Synthesis

Acid Chlorides

Acyl chloride synthesis is difficult as it involves the introduction of an excellent leaving group
(Cl) so synthesis via phosphorous (III) chloride (PCl3), phosphorous (V) chloride (PCl5) and sulfur
dichloride oxide (thionyl chloride or SOCl2) is used as it first converts a carboxylic acid hydroxyl
group into a better leaving group that can be replaced with Cl (figure 4). PCl3 is a liquid that reacts
with carboxylic acid to produce a mixture of acyl chloride and phosphoric (III) acid (separation
occurs via fractional distillation). PCL5 is a solid that can be reacted with carboxylic acid to
produce a mixture of acyl chloride and phosphorous oxychloride (separated by fractional
distillation in addition to hydrochloric acid fumes. Thionyl chloride is a liquid that can react with
carboxylic aid, giving acyl chloride as well as HCl and SO2 gases2.

Figure 4. Synthesis of acid halides via PCl3, PCl5 and SOCl2.

Acid Anhydrides

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Anhydrides can be synthesized via the dehydration of carboxylic acids. The hydroxyl group
oxygen of carboxylic acid acts as a nucleophile and attacks the carbonyl carbon of the other
molecule (figure 5). This acyl substitution results in loss of water. To stop the reaction after the
formation of a symmetrical anhydride, a drying agent like acetic anhydride or phosphorous
pentoxide is used to react with the water byproduct. Mixed anhydrides can be created by reaction
of an acid chloride of a carboxylic acid with another different carboxylic acid in the existence of a
base (figure 6)2.

Figure 5. Mechanism of synthesis of acid anhydrides via dehydration of carboxylic acids.

Figure 6. Mechanism of synthesis of acid anhydrides via dehydration of carboxylic acids.

Physical Properties

Acid Halides

Acid halides are usually colorless fuming liquids. Are considered insoluble in water as they can
react violently in water resulting in carboxylic acid and hydrogen halide formation. As they do not
form intermolecular hydrogen bonds, their boiling points are lower than that of water and are
similar to those of, for example ethanoyl chloride boils at 51°C. Figure 7 shows some common
acid halides and their boiling points3.

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 Figure 7. Boiling points and molecular weights of some acid halides.

Acid Anhydrides

Acid anhydrides are colorless liquids, insoluble in water as they instantly react to form parent acid
and have boiling points lower than those of their parent acids due to lack of intermolecular
hydrogen bonds. Ethanoic anhydride boils at 140°C3.

Reactions

Acid Halides

Most reactions in which acyl halides are involved are called acyl transfer reactions and involve
addition and elimination reactions. These reactions depend on the use of nucleophiles, which are
molecules or ions that are attracted strongly to an area of positive charge. Nucleophiles can be
negatively charged anions or molecules with a strong partial negative charge. The most common
reactions involve nucleophilic attack by compounds with and oxygen or nitrogen atom with a lone
pair of electrons. These nucleophiles attack the acyl halide at the carbonyl group carbon atom, as
it is partially positively charged as the attached oxygen and halide atoms are electronegative, so
pull electrons towards themselves. The first step in these types of reactions are nucleophilic attack
on carbonyl group forming an unstable tetrahedral intermediate (figure 8). Figure 9 shows a
summary of the reactions of acid anhydrides4.

Figure 8. Nucleophilic attack on acid halides. Figure 9. Summary of acid halide reactions.

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Acid chlorides can be changed to aldehydes via lithium tri-tert-butoxyaluminum hydride
(LiAlH(Ot-Bu)3) (figure 10). Acid chlorides are the most reactive acyl derivatives with the
nucleophilic hydride ion supplied by metal hydrides. However, lithium aluminum hydride
(LiAlH4) is a very powerful reducing agent such that the aldehydes produced are further reduced
to primary alcohols (figure 11). Tertiary alcohols can be obtained by reaction with Grignard
reagents (figure 12)4.

Figure 10. Aldehyde formation from acid chloride.

Figure 11. Further reduction of aldehyde to primary alcohol.

Figure 12. Tertiary alcohol production via acid chloride.

Acid chlorides can be used to form esters by reacting them with alcohols. Pyridine is added to
reaction mixture to neutralize HCl end product (figure 13)4.

Figure 13. Ester formation from acid chlorides.

Ketones can be formed from organocuprate agents (figure 14) and acid halides react with water to
produce carboxylic acids (figure 15)4.

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 Figure 14. Reaction with organocuprate agents.

Figure 15. Reaction with water giving carboxylic acids.

When ammonia, primary amines or secondary amines react with acid chlorides a primary,
secondary or tertiary amide is formed respectively (figure 16). Amides are weak bases, after the
reaction an additional step occurs in which a proton from the amide is transferred to the amine
reactant4.

Figure 16. Reactions of acid halides with primary and secondary amines.

When carboxylic acids are reacted with acid halides an acid anhydride plus hydrochloric acid is
formed (figure 17)4.

Figure 17. Acid halide and carboxylic acid reaction.

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In Friedel-Crafts Acylation if benzene is reacted with ethanoyl chloride in the presence of
aluminum chloride as a catalyst, the end product is an acylated benzene ring called phenylethanone
and hydrochloric acid (figure 18). The reaction is exactly carried out by adding ethanoyl chloride
to a cold mixture of benzene and solid AlCl3. The mixture is then heated at 60oC for 30 minutes
until reaction is complete4.

Figure 18. Friedel-Crafts Acylation

The product of this reaction can be reduced to form ethylbenzene by bey heating the
phenylethanone ketone with amalgamated zinc (zinc + mercury) and concentrated HCl for a period
of time. This is called a Clemmensen reduction (figure 19)4.

Figure 19. Clemmenson reduction.

This whole process can be considered as an indirect alkylation of benzene ring, and allow the
substitution of only one hydrocarbon group, in contrast to direct alkylation which renders the
benzene ring highly reactive, thus making multiple alkyl substitutions the only option4.

Acid Anhydrides

Acid anhydrides react like acid halides but only one of the 2 acyl groups of the anhydride react
with nucleophiles. They can react with alcohols to form esters using pyridine as a solvent (figure
20). Acid anhydrides react with amines to form amides (figure 21)4.

Figure 20. Acid anhydride and alcohol reactions producing ester.

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 Figure 21. Acid anhydride and amine reactions producing amide.

Uses
Acid halides are used as acetylating agents in industry and to produce esters and amides. Acid
anhydrides have an electrophilic center with a good leaving group, so are reactive compounds that
can act as useful intermediates in organic synthesis. They are used in the production of many
products such as pharmaceuticals, industrial chemicals, explosives and perfumes. Acid anhydrides
are also used for esters synthesis by acetylation of alcohols and synthesis of aspirin (Acetyl
salicylic acid)5.

Conclusion
Acid halides and acid anhydrides are organic compounds that are colorless liquids synthesized
from carboxylic acids. They are reactive and undergo numerous reactions like acyl transfer
reactions which involve addition and elimination reactions. and are used in industry for
synthesizing of useful chemicals. It is important to understand the basic properties and reactions
of different organic compound classes so as to expand our knowledge in order to apply it for
beneficial reasons.

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References
1. James R, Jefferson J. Carboxylic Acid Derivatives. Organic Chemistry. 2014;:699-745.
2. Starkey L. INTRODUCTION TO STRATEGIES FOR ORGANIC SYNTHESIS. 4th ed.
London: Wiley; 2013.
3. Acetyl chloride | C2H3ClO | ChemSpider [Internet]. Chemspider.com. 2020 [cited 14 June
2020]. Available from: http://www.chemspider.com/Chemical-
Structure.6127.html?rid=9643393b-2036-4ff1-877c-0b72955b5201
4. Ouellette R, Rawn J. Principles of organic chemistry. 5th ed. Toronto: AP Cell Press;.
5. Scott Obach R, Kalgutkar A. Reactive Electrophiles and Metabolic Activation. Comprehensive
Toxicology. 2010;:309-347.

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