Acylation A4 1

DERIVATIVES OF CARBOXYLIC ACIDS

ACYL (ACID) CHLORIDES - RCOCl ACID ANHYDRIDES - (RCO)2O

named from corresponding acid named from corresponding acid remove -ic add -yl chloride remove acid add anhydride

CH3COCl ethanoyl chloride (CH3CO)2O ethanoic anhydride

C6H5COCl benzene carbonyl chloride δ− δ+ O δ− CH C O 3 δ− δ+ O δ+ CH3 C δ− CH3 C δ− Cl O bonding in acyl chlorides bonding in acid anhydrides

Chemical Properties • colourless liquids which fume in moist air • acyl chlorides are more reactive than anhydrides • attacked at the positive carbon centre by nucleophiles • nucleophiles include water, alcohols, ammonia and amines • undergo addition-elimination reactions

Uses of Acylation

Industrially Manufacture of Cellulose acetate - making fibres Aspirin (acetyl salicylic acid) - analgaesic

Ethanoic anhydride is more useful • cheaper • less corrosive • less vulnerable to hydrolysis • less dangerous reaction

Laboratory Used to make carboxylic acid, esters, amines, N-substituted amines Ethanoyl chloride is used as it • is more reactive • gives a cleaner reaction

Q.1 Investigate how aspirin is made industrially and in the laboratory. Why are the reagents and chemicals different? What properties of Aspirin make it such a useful drug? 2 A4 Acylation

ADDITION ELIMINATION REACTIONS - OVERVIEW

Mechanism • species attacked by nucleophiles at the positive carbon end of the C=O bond • the nucleophile adds to the molecule • either Cl or RCOO¯ is eliminated • a proton is removed

General example - with water

ACID CHLORIDES

H Cl + Cl H O O C O R C O C O R C HCl R OH H O + R Cl H O H H

RCOCl + H2O ——> RCOOH + HCl

ACID ANHYDRIDES

O R O C H O + R C H O O O R C O C O R C RCOOH OH R C + R O H O H O H RCOO H

(RCO)2O + H2O ——> 2RCOOH

Use these mechanisms to help construct others in the spaces which follow

SYNTHETIC POSSIBILITIES

PRODUCT WITH By-product WATER ALCOHOLS AMMONIA AMINES CARBOXYLIC N-SUBSTITUTED ACYL CHLORIDE ESTER AMIDE HCl ACID AMIDE CARBOXYLIC N-SUBSTITUTED CARBOXYLIC ACID ANHYDRIDE ESTER AMIDE ACID AMIDE ACID Acylation A4 3

ADDITION ELIMINATION - the reactions

ACYL (ACID) CHLORIDES - RCOCl

Water Product(s) carboxylic acid + HCl (fume in moist air / strong acidic solution formed) Conditions cold water

Equation CH3COCl(l) + H2O(l) ——> CH3COOH(aq) + HCl(aq) Mechanism addition-elimination

H Cl + Cl H O O C O CH C HCl 3 O C O CH3 C CH OH 3 H O + CH3 Cl H O H H

Alcohols Product(s) ester + hydrogen chloride Conditions reflux in dry (anhydrous) conditions

Equation CH3COCl(l) + CH3OH(l) ——> CH3COOCH3(l) + HCl(g) Mechanism addition-elimination

CH3 Cl + Cl H O O C O CH C HCl 3 O C O CH3 C CH OCH 3 H O + CH3 3 Cl H O CH3 CH3

Q.2 What organic product is formed when the following pairs react?

• C3H7COCl and H2O • C2H5COCl and C2H5OH

Q.3 How would you synthesis the following? • methyl butanoate • butyl methanoate

• C6H5COOCH3 • CH3COOC(CH3)2 4 A4 Acylation

Ammonia Product(s) Amide + hydrogen chloride Conditions Low temperature and excess ammonia. Vigorous reaction.

Equation CH3COCl(l) + NH3(aq) ——> CH3CONH2(s) + HCl(g)

or CH3COCl(l) + 2NH3(aq) ——> CH3CONH2(s) + NH4Cl(s)

Mechanism addition-elimination

H Cl + Cl H N H O C O CH C HCl 3 O C O CH3 C CH + NH 3 H N H CH3 2 H H Cl H N H

Amines Product(s) N-substituted amide + hydrogen chloride Conditions anhydrous

Equation CH3COCl(l) + C2H5NH2(aq) ——> CH3CONHC2H5(s) + HCl(g)

or CH3COCl(l) + 2C2H5NH2(aq) ——> CH3CONHC2H5(s) + C2H5NH3Cl(s)

Mechanism addition-elimination - similar to that with ammonia

H Cl + Cl R N H O C O CH C HCl 3 O C O CH3 C CH + NH 3 H N H CH3 R H R Cl R N H

Q.4 Why are two moles of ammonia (or amine) required in each equation?

Q.5 What pairs of chemicals would you use to synthesis the following?

• butanamide • C2H5CONH2

• CH3CON(CH3)2 • N-phenylethanamide Acylation A4 5

ACID ANHYDRIDES - (RCO)2O

Water Product(s) carboxylic acid (weak acidic solution formed) Conditions cold water - but can be slow

Equation (CH3CO)2O(l) + H2O(l) ——> 2CH3COOH(aq)

Mechanism

O H O CH3 C O + CH C H O O 3 C O CH C O O CH3 C CH3COOH 3 OH CH3 C + CH3 O H O H O H CH COO H 3

Alcohols Product(s) ester + carboxylic acid Conditions reflux in dry (anhydrous) conditions

Equation (CH3CO)2O(l) + CH3OH(l) ——> CH3COOCH3(l) + CH3COOH(aq)

Mechanism

Q.6 What organic product(s) is/are formed when the following pairs react?

• (C3H7CO)2O and H2O

• (CH3CO)2O and C2H5OH

• (CH3CO)2O and (CH3)2CHOH 6 A4 Acylation

Ammonia Product(s) Amide + carboxylic acid Conditions Low temperature and excess ammonia.

Equation (CH3CO)2O(l) + NH3(aq) ——> CH3CONH2(s) + CH3COOH(aq)

+ or (CH3CO)2O(l) + 2NH3(aq) ——> CH3CONH2(s) + CH3COO¯NH4 (s)

Mechanism

Amines Product(s) N-substituted amide + carboxylic acid

Equation (CH3CO)2O(l) + C2H5NH2(aq) ——> CH3CONHC2H5(s) + CH3COOH(aq)

+ or (CH3CO)2O(l) + 2C2H5NH2(aq) ——> CH3CONHC2H5(s) + CH3COO¯NH4 (s)

Mechanism

Q.7 What organic product(s) is/are formed when the following pairs react?

• (C3H7CO)2O and NH3

• (CH3CO)2O and C2H5NH2

• (CH3CO)2O and (CH3)2NH