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Acyl Chloride: Reactions & Synthesis

Instructor: Kristen Procko

Kristen has taught chemistry and biochemistry at the undergraduate and Master's level and has a PhD in chemistry.

This lesson describes the formation and use of acyl chlorides in organic synthesis. You will see how this functional group is formed, and the ways it can be reacted to form different carboxylic acid derivatives.

Acyl Chlorides and Related Functional Groups

Acyl chlorides, sometimes called acid chlorides, are often smelly organic compounds that are very reactive. The term acyl chloride describes a functional group containing a carbonyl group (C=O) and a chlorine atom (Cl). Molecules containing this functional group can be referred to as acyl chlorides themselves. They are used in organic synthesis to convert carboxylic acids into other functional groups because of their high reactivity.

Remember, a functional group is simply an arrangement of atoms in a particular orientation on a molecule. Some of the atoms in a functional group can have multiple bonds to them. The functional groups that are most important in this lesson are carboxylic acid, acyl chloride, acid anhydride, ester and amide:

Carboxylic acid functional group and derivative functional groups
carboxylic acid derivatives

Notice that each of these functional groups contains a carbonyl group (a carbon double bonded to an oxygen). If there is an OH group next to the carbonyl group, the molecule is a carboxylic acid; if there is a Cl atom, the molecule is an acyl chloride.

Acyl Chlorides in Synthesis

Acyl chlorides, acid anhydrides (or just 'anhydrides'), esters, and amides are all derivatives of carboxylic acids, but it is difficult to make them directly from this functional group. This is because the OH group in the carboxylic acid is hard to replace with a new group; carboxylic acids are not very reactive in this way. By converting a carboxylic acid to the more reactive acyl chloride, we can then synthesize many carboxylic acid derivatives.

Acyl Chloride Formation

Let's put on our safety glasses and check out some of the reactions we can do in the lab involving acyl chlorides. First of all, carboxylic acids can be made into acyl chlorides by treatment with thionyl chloride. Make sure you have good ventilation, because thionyl chloride is one smelly compound! The reaction looks like this:

Reaction of a carboxylic acid to form an acyl chloride
reaction of a carboxylic acid to form an acyl chloride

Notice in the reaction intermediate shown in braces that the oxygen atom of the carboxylic acid becomes attached to the sulfur atom of thionyl chloride. A reaction intermediate is formed when reactions have multiple distinct steps on the way to forming the product. To form the intermediate shown, one chlorine atom leaves the thionyl chloride molecule. The intermediate contains a good leaving group, which are the pieces of the molecule that are able to depart the molecule because they are relatively stable on their own. When the intermediate is converted to the product, the chlorine atom that was released in the first step comes back and replaces the sulfur-containing leaving group, forming the acid chloride.

Reaction of Acyl Chlorides with a Generic Nucleophile

Acid chlorides then react with nucleophiles to produce carboxylic acid derivatives. Nucleophiles are groups that have electrons that are available to form bonds in an organic reaction. Their name, quite literally, means 'nucleus loving,' which implies that they are attracted to positive, or partially positive portions of a molecule. We say that nucleophiles 'attack' electrophiles in an organic reaction. Electrophiles 'love electrons' and are parts of an organic molecule that are positive or partially positive.

In an organic reaction mechanism, we show arrows to keep track of where the electrons go, and these arrows always originate from a nucleophile and point to the electrophile. The general mechanism for the reaction of an acid chloride with a nucleophile is:

Acyl chloride general reaction mechanism
Acyl chloride general reaction mechanism

In the first step of our mechanism, the generic nucleophile (Nu with a pair of electrons in the image) attacks the carbonyl carbon atom. The oxygen atom of the carbonyl group is electronegative, in other words, it likes to pull electrons toward itself through bonds. This electron attracting effect pulls electrons away from the carbon atom it is bonded to. Oxygen in the carbonyl is therefore an electron rich spot on the molecule (a nucleophile) and the adjacent carbon atom that has had its electron density 'stolen' from it by oxygen is electron deficient, or slightly electropositive (which makes it an electrophile).

So, our first arrow in the mechanism originates from the nucleophile, and attacks the carbonyl carbon atom. So that we don't break the octet rule, we must show a second arrow that makes the electrons from the double bond into a lone pair on oxygen when the nucleophile attacks. This forms an intermediate that is bonded to four groups, called a tetrahedral intermediate.

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