# Acylation reactions

> Chemistry · CIE A-Level
> Source: https://www.owlsprep.com/study/cie-9701-u26-acylation-reactions/

This module covers acylation, the addition of an acyl group ($RCO-$) to a nucleophilic substrate. You will learn the general nucleophilic acyl substitution mechanism, reactivity of common acylating agents, and key synthetic applications of acylation.

**Prerequisites:** [Nucleophilic substitution mechanisms](https://www.owlsprep.com/study/cie-9701-u20-nucleophilic-substitution/); [Structure of carboxylic acid derivatives](https://www.owlsprep.com/study/cie-9701-u26-intro-carboxylic-acid-derivatives/)

## Learning objectives

- Describe the mechanism of nucleophilic acyl substitution
- Compare reactivity of different common acylating agents
- Identify products of acylation of alcohols, amines and arenes
- Outline key synthetic and industrial applications of acylation

## Key Definitions and Common Acylating Agents

**Acylation** — A chemical reaction that introduces an acyl group ($RCO-$ or $ArCO-$) into an organic molecule. The acyl group is always covalently bonded to a carbon in the product.

*Notation:* General product: $RCO-Nu$

*Example:* Ethanoyl chloride adds an ethanoyl group ($CH_3CO-$) to ethanol to form ethyl ethanoate.

Acylating agents are electron-deficient compounds that donate the acyl group in acylation reactions. The two most common acylating agents tested in CIE 9701 are acyl chlorides (acid chlorides) and acid anhydrides.

- **Acyl chlorides ($RCOCl$)**: Highly reactive, often used in small-scale laboratory synthesis.
- **Acid anhydrides ($(RCO)_2O$)**: Less reactive than acyl chlorides, cheaper and less corrosive for large-scale industrial use.

> **info**
>
> Acyl chlorides react readily at room temperature, while acid anhydrides often require gentle heating to react.

**Worked example:** Identify the acylating agent and acyl group in the formation of $CH_3CONH_2$ from $CH_3COCl$ and ammonia.

1. Step 1: Identify the acyl group in the product: it is the $CH_3CO-$ group bonded to nitrogen.
2. Step 2: The acylating agent is the reactant that provides the acyl group: this is ethanoyl chloride ($CH_3COCl$).
3. The leaving group lost from the acylating agent is the chloride ion $Cl^-$.

## Nucleophilic Acyl Substitution Mechanism

**Nucleophilic acyl substitution** — The two-step addition-elimination mechanism for all acylation reactions, where a leaving group $Y^-$ on the acyl carbon is replaced by a nucleophile $Nu^-$.

*Notation:* $RCOY + Nu^- \rightarrow RCONu + Y^-$

The acyl carbon is electron-deficient because the electronegative oxygen of the carbonyl group withdraws electron density, creating a δ+ charge that attracts nucleophiles.

**Worked example:** Outline the mechanism for the reaction of ethanoyl chloride with a hydroxide nucleophile ($OH^-$).

1. Step 1 (Addition): The lone pair on the negatively charged hydroxide nucleophile attacks the δ+ acyl carbon. The C=O π bond breaks, pushing electrons onto the oxygen atom to form a negatively charged tetrahedral intermediate.
2. $$CH_3COCl + OH^- \rightarrow [CH_3C(O^-)(OH)Cl]^-$$
3. Step 2 (Elimination): The lone pair on the negatively charged oxygen reforms the C=O double bond, eliminating the best leaving group (chloride ion $Cl^-$).
4. $$[CH_3C(O^-)(OH)Cl]^- \rightarrow CH_3COOH + Cl^-$$
5. The final organic product is ethanoic acid, with chloride as the leaving group.

> **Exam tip:** Always draw curly arrows starting from the lone pair or negative charge on the nucleophile, and explicitly show the negative charge on the tetrahedral intermediate to gain full marks.

## Acylation of Common Nucleophiles

CIE exams commonly test acylation of three nucleophiles, each producing a different carboxylic acid derivative product:

| Nucleophile | Acyl Chloride Product | Acid Anhydride Product |
| --- | --- | --- |
| Water ($H_2O$) | Carboxylic acid + HCl | Carboxylic acid + Carboxylic acid |
| Alcohol ($ROH$) | Ester + HCl | Ester + Carboxylic acid |
| Primary Amine ($RNH_2$) | N-substituted amide + HCl | N-substituted amide + Carboxylic acid |

> **tip**
>
> For acylation of amines, you need two moles of amine: one acts as the nucleophile, and the other neutralises the HCl by-product.

**Worked example:** Predict the organic product of the reaction between propanoyl chloride ($CH_3CH_2COCl$) and methylamine ($CH_3NH_2$).

1. Step 1: Identify the nucleophile: methylamine is a primary amine nucleophile.
2. Step 2: The leaving group $Cl^-$ is replaced by the $CH_3NH-$ nucleophile, so the product is an N-substituted amide.
3. Step 3: The parent chain is the acyl group from propanoic acid, and the methyl group is bonded to nitrogen. The product name is N-methylpropanamide, with formula $CH_3CH_2CONHCH_3$.
4. The HCl by-product reacts with excess methylamine to form methylammonium chloride $CH_3NH_3^+Cl^-$.

## Friedel-Crafts Acylation

Friedel-Crafts acylation is the acylation of arenes (aromatic compounds) to form aromatic ketones. It is an electrophilic substitution reaction that requires a Lewis acid catalyst (usually aluminium chloride, $AlCl_3$).

**Friedel-Crafts Acylation** — Electrophilic substitution of an arene that introduces an acyl group, producing an aromatic ketone. It avoids carbocation rearrangements seen in Friedel-Crafts alkylation.

**Worked example:** Outline the reaction of benzene with ethanoyl chloride, name the product and state the role of $AlCl_3$.

1. Step 1: The Lewis acid catalyst $AlCl_3$ reacts with ethanoyl chloride to generate the reactive electrophile: the acylium ion $CH_3C^+=O$.
2. $$CH_3COCl + AlCl_3 \rightarrow CH_3C^+O + AlCl_4^-$$
3. Step 2: The acylium ion attacks the benzene ring, followed by elimination of a proton to reform the stable aromatic ring. $H^+$ reacts with $AlCl_4^-$ to regenerate the $AlCl_3$ catalyst.
4. The organic product is phenylethanone (common name: acetophenone) with formula $C_6H_5COCH_3$.
5. Role of $AlCl_3$: it is a Lewis acid catalyst that generates the reactive acylium ion electrophile.

> **Exam tip:** Unlike Friedel-Crafts alkylation, only one acyl group is added because the ketone product is less reactive than the starting arene.

## Common pitfalls

- **Wrong:** Directing nucleophilic attack to the leaving group carbon instead of the acyl carbonyl carbon.
  - Why it fails: Only the acyl carbonyl carbon is electron-deficient (δ+) and susceptible to nucleophilic attack.
  - Correct: Always draw the nucleophile attacking the carbonyl carbon of the acyl group.
- **Wrong:** Forgetting to show the negative charge on the tetrahedral intermediate in the addition-elimination mechanism.
  - Why it fails: CIE exam markers require explicit charge to award full marks for mechanism questions.
  - Correct: Add the negative charge to the oxygen atom that was originally part of the carbonyl group.
- **Wrong:** Naming N-substituted amides by taking the parent chain from the alkyl group on nitrogen.
  - Why it fails: The parent chain is always the carbon chain from the acyl group, not the substituent on nitrogen.
  - Correct: Name the amide after the carboxylic acid the acyl group came from, add the N- prefix for the alkyl group on nitrogen.
- **Wrong:** Claiming the direct product of Friedel-Crafts acylation of benzene is an alkylbenzene.
  - Why it fails: Acylation adds an acyl group, not an alkyl group. Reduction is required to remove the carbonyl group to get an alkylbenzene.
  - Correct: The direct product of Friedel-Crafts acylation of any arene is always an aromatic ketone.

## Cheatsheet

| Component | Details |
| --- | --- |
| Acyl chlorides ($RCOCl$) | High reactivity, lab use, leaving group: $Cl^-$ |
| Acid anhydrides ($(RCO)_2O$) | Moderate reactivity, industrial use, leaving group: $RCOO^-$ |
| Water + Acylating agent | Product: Carboxylic acid |
| Alcohol + Acylating agent | Product: Ester |
| Amine + Acylating agent | Product: N-substituted amide |
| Friedel-Crafts Acylation | Catalyst: $AlCl_3$, product: Aromatic ketone |
| General Mechanism | Two-step addition-elimination, tetrahedral intermediate |

## What's next

Acylation reactions are a core part of organic synthesis for CIE A-Level Chemistry, and regularly appear in multi-step synthesis questions in papers 2, 3 and 4. The nucleophilic acyl substitution mechanism you learned here is shared by all reactions of carboxylic acid derivatives, so mastering it will help you understand other reactions including ester hydrolysis and amide formation. Friedel-Crafts acylation is a key synthetic tool for producing straight-chain alkylbenzenes, as it avoids the carbocation rearrangements that occur during Friedel-Crafts alkylation. It is widely used in industrial production of pharmaceuticals and fine chemicals. Explore the related topics below to build out your knowledge of carboxylic acid derivatives and aromatic chemistry.

- [Organic synthesis](https://www.owlsprep.com/study/cie-9701-u27-overview/)
- [Synthetic route planning](https://www.owlsprep.com/study/cie-9701-u27-synthetic-route-planning/)
- [Yield and purity calculations](https://www.owlsprep.com/study/cie-9701-u27-yield-and-purity-calculations/)

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