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 the electronegativity of the Cl’s, N’s and O’s causing electron density to be withdrawn from the carbon making the carbon more positive and more attractive to nucleophiles- This factor makes them more reactive. 2.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
- Oδ :O- O O CH Cδ+ + + 3 H C C OH 3 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 Detailed method for Preparation of Aspirin Aspirin is made from 2-hydroxybenzoic O acid which contains a phenol group. In the CO2H CO2H reaction the phenol group is turned into an CH3 C O ester by reacting it with the reactive + O O C CH3 ethanoic anhydride OH + CH3CO2H CH3 C Ethanoic anhydride is used instead of O Aspirin Add to a 50 cm3 pear-shaped flask 2.0 g of 2-hydroxybenzoic acid and acid chlorides because it is cheaper, less 4 cm3 of ethanoic anhydride. corrosive, less vulnerable to hydrolysis, To this mixture add 5 drops of 85% phosphoric(v) acid and swirl to and less dangerous to use. mix, Fit the flask with a reflux condenser and heat the mixture on a The excess ethanoic anhydride will boiling water bath for about 5 minutes. Without cooling the mixture, hydrolyse and the contents of the flask carefully add 2 cm3 of water in one portion down the condenser. will boil. When the vigorous reaction has ended, pour the mixture into 40 cm3 of cold water in a 100 cm3 beaker, stir and rub the sides of the beaker with a stirring rod necessary to induce crystallisation and, finally, allow the mixture to stand in ice bath to complete crystallisation. Collect the product by suction filtration and wash it with a little water.
Purification stage: recrystallisation Using a measuring cylinder, measure out 15 cm3 of ethanol into a boiling tube. Prepare a beaker half-filled with hot water from a kettle at a Avoid naked flames due to temperature of approximately 75 °C. flammability of ethanol Use a spatula to add the crude aspirin to the boiling tube with ethanol and place the tube in the beaker of hot water. Stir the contents of the boiling tube until all of the aspirin dissolves into the ethanol. Pour the hot solution containing dissolved aspirin through a warmed This step will remove any insoluble filter funnel and fluted filter paper to hot filter impurities and heat will prevent crystals Then pour filtrate into 40 cm3 of water in a conical flask. reforming during filtration Allow the conical flask to cool slowly and white needles of aspirin should separate. Soluble impurities will remain in solution form Cool the whole mixture in an ice bath. because they are present in small quantities Filter off the purified solid under reduced pressure and allow it to dry so solution is not saturated. Ice will increase on filter paper. the yield of crystals Record the mass of the dry purified solid
N Goalby chemrevise.org 5