Carboxylic acid derivatives: Acyl Chlorides and Acid Anhydrides

Acyl Chlorides Acid Anhydrides Acid anhydrides have a similar reactivity to O Acyl chlorides are much O acyl chlorides and therefore bring about the CH3 C more reactive than same changes in functional groups. carboxylic acids CH3 C Cl O ethanoyl chloride The main difference is the by-products. CH3 C Acyl chlorides mostly give off HCl. Acid O anhydrides give off RCOOH ethanoic anhydride.

Explaining reactivity Many of the reactions of the carboxylic acid derivatives follow the pattern below with an attack by an nucleophile. O O

CH3 C + :X- CH3 C + :W- On a simplistic level, the stronger the electron attracting power of ‘W’, the W X more positive the carbon, and the more attractive the carbon is to Where –W: and :W- can be –Cl and Cl- (acyl chlorides) nucleophiles. - or -OCH3 and OCH3 (esters) The relative attractive powers of the –W: are - `or -NH2 and NH2 (amides) -Cl > -OH > -OCH3 > -NH2

Therefore in the case of hydrolysis reactions, acyl chlorides are highly reactive and will be hydrolysed by weak nucleophiles such as water. Amides and Esters contain only weak electron attracting W groups and need strong nucleophiles such as hydroxide ions in NaOH to hydrolyse. This difference in reactivity is caused by a combination of two factors 1. the electronegativity of the Cl’s, N’s and O’s causing electron density to be withdrawn from the carbon making the carbon more positive and more attractive to nucleophiles- This factor makes them more reactive 2. delocalisation of the lone pairs on these atoms into the carbonyl system which reduces the reactivity

Comparing the reactivity of Acyl chlorides to amides Acyl Chloride O O Amide CH 3 C CH3 C

Cl NH2

Acyl chloride are more reactive than amides

Cl and N have similar electronegativities and so should attract electron density from the carbon by similar amounts, making the carbons equally positive However, the lone pair on the nitrogen delocalises with the π bond in the carbonyl group which decreases its reactivity.

The Cl is too big (3p orbital rather than 2p orbital in N) to be able to delocalise. This difference in the ability to delocalise explains the difference in reactivity

N Goalby chemrevise.org 1 Reaction with water

Change in functional group: acyl chloride  Change in functional group: acid anhydride  carboxylic acid carboxylic acid Reagent: water Reagent: water Conditions: room temp. Conditions: room temp.

RCOCl (l) + H2O  RCO2H + HCl (g) (RCO)2O + H2O  2RCO2H O O O O  CH3 C CH3 C + H2O CH3 C + HCl (g)  O + H2O 2CH3 C OH Cl OH Observation: Steamy white fumes of HCl are CH3 C given off O

Nucleophilic Addition Elimination Mechanism

δ- - O :O O O δ+ CH3 C + + H3C C OH H3C C OH CH3 C Cl δ- : OH Cl H H OH H

Reaction with alcohol

Change in functional group: acyl chloride  ester Change in functional group: acid anhydride  ester Reagent: alcohol Reagent: alcohol Conditions: room temp. Conditions: room temp.

RCOCl (l) + CH3CH2OH  RCO2CH2CH3 + HCl (g) (RCO)2O + CH3CH2OH  RCO2CH2CH3 +RCO2H H H H O O O  CH 3 C + CH3CH2OH H C C O C C H + HCl H O H H CH3 C Cl H H H O H C C O C C H + CH3CH2OH  H CH3 C H H Observation: Steamy white fumes of HCl + CH CO H are given off O 3 2 - δ- :O O O O + + + CH3 C δ H3C C OCH2CH3 H3C C OCH2CH3 C H3C OCH2CH3 Cl Cl H H : OCH2CH3 Nucleophilic Addition Elimination Mechanism H

This reaction for making esters is much better than using carboxylic acids as the reaction is much quicker and it is not a reversible reaction

N Goalby chemrevise.org 2 Reaction with ammonia

Change in functional group: acyl chloride  Change in functional group: acid anhydride  primary amide primary amide Reagent: ammonia Reagent: ammonia Conditions: room temp. Conditions: room temp.

- + RCOCl (l) +2NH3  RCONH2 + NH4Cl (s) (RCO)2O + 2NH3  RCONH2 + RCO2 NH4 O O O CH C O CH3 C  CH3 C 3 + 2NH3 + NH4Cl (s)  + CH CO -NH + O + 2NH3 CH3 C 3 2 4 Cl NH2 NH CH3 C 2 Observation: white smoke of NH4Cl is given off O

Nucleophilic Addition Elimination Mechanism

δ- :O- O O O + + CH C δ + 3 H3C C NH2 H3C C NH2 C Cl H C NH2 Cl H H 3 :NH3 Reaction with primary amines

Change in functional group: acyl chloride  Change in functional group: acid anhydride  secondary amide secondary amide Reagent: primary amine Reagent: primary amine Conditions: room temp. Conditions: room temp.

 + - - + RCOCl +2CH3NH2 RCONHCH3 + CH3NH3 Cl (RCO)2O +2CH3NH2  RCONHCH3 + RCO2 CH3NH3 O O O + - + CH3NH3 Cl CH3 C 3 + 2CH NH  CH C NH CH O + CH CO -CH NH + CH C 3 2 3 3  3 2 3 3 O +2CH3NH2 Cl CH C NH CH N-methylethanamide 3 3 CH3 C N-methylethanamide O

Nucleophilic Addition Elimination Mechanism

- Oδ :O O δ+ + + CH C H C C NHCH CH 3 H3C C NHCH2CH3 3 2 3 Cl Cl H H : NHCH2CH3 H O C H3C NHCH2CH3

N Goalby chemrevise.org 3 Reaction with phenol

 Change in functional group: acyl chloride ester Phenols do not easily form esters with carboxylic Reagent: phenol acids but do so readily with acyl chlorides Conditions: room temp.

RCOCl (l) + C6H5OH  RCO2C6H5 + HCl (g) O O O + HCl CH 3 C + OH C Cl H3C Observation: Steamy white fumes of HCl are given off O O C  + HCl OH + C O Cl

phenol Benzoyl Phenyl chloride benzoate

Making Aspirin

Aspirin is made from 2-hydroxybenzoic acid which contains a phenol group. In the reaction the phenol group is turned into an ester by reacting it with the reactive ethanoic anhydride

O CO2H CO2H CH3 C O + O  O C CH3 OH + CH3CO2H CH3 C O Aspirin

Ethanoic anhydride is used instead of acid chlorides because it is cheaper, less corrosive, less vulnerable to hydrolysis, and less dangerous to use.

Making Paracetamol

Paracetamol is made by the reaction of an aromatic amine with an acyl chloride to produce an amide O

CH3 C Cl O

HO NH2 HO NH C CH3

Paracetamol

4 N Goalby chemrevise.org