Part 6. The Chemistry of  Carboxylic Acids and their Derivatives

6.7B The chemistry of acid/acyl anhydrides

Doc Brown's Chemistry Advanced Level Pre-University Chemistry Revision Study Notes for UK KS5 A/AS GCE IB advanced level organic chemistry students US K12 grade 11 grade 12 organic chemistry preparation and chemical properties of acid/acyl anhydrides reactions with water, alcohols and phenols making aspirin

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6.7B The chemistry of acid/acyl anhydrides

Sub-index for this page

6.7B.1 Structure and preparation of acid/acyl anhydrides

6.7B.2 Reaction of acid/acyl anhydrides with water - hydrolysis to the parent acid

6.7B.3 Reaction of acid/acyl anhydrides with alcohols to form esters (acylation)

6.7B.4 Reaction of acid/acyl anhydrides with phenols including aspirin (acylation)

6.7B.5 The preparation and purification of aspirin

6.7B.6 Reaction of acid/acyl anhydrides with ammonia and amines (acylation)

See also Organic Chemistry Parts

6.7A The susceptibility of carboxylic acid derivatives to nucleophilic attack - relative reactivity and preparation & reactions of acid chlorides with water, alcohols, ammonia, amines & mechanisms

6.8 Esters - preparation, reactions including hydrolysis and transesterification, uses

6.7B.1 Structure and preparation of acid/acyl anhydrides

(a) The structure of acid/acyl anhydrides

As the name implies, anhydride means water has been lost.

The name is derived from the acid name followed by anhydride

In the case of  acid/acyl anhydrides, they are formed by loss of water on condensing together two molecules of a carboxylic acid .

2RCOOH  ===>  (RCO)₂  +  H₂O   (R = alkyl or aryl)

e.g.  or ethanoic anhydride  (from ethanoic acid, bpt 140^oC)

or pentanoic anhydride  (from pentanoic acid)

The lower members of the aliphatic  acid/acyl anhydrides are colourless liquids with a pungent odour and harmful to the skin as they turn to acid with moisture (see 6.7B.2 hydrolysis)

Preparation from a carboxylic acid by heating it with phosphorus(V) oxide e.g. preparation of butanoic anhydride

2  == P₄O₁₀ ==>    +   H₂O

Preparation of mixed acid/acyl anhydrides

All the above are symmetrical  acid/acyl anhydrides, but it is possible to synthesise mixed/unsymmetrical  acid/acyl anhydrides by heating an  acid/acyl chloride with the sodium salt of a different carboxylic acid e.g.

heating ethanoyl chloride with sodium propanoate

CH₃COCl  + CH₃CH₂COONa  ===>  (CH₃CO)O(OCCH₂CH₃)  +  NaCl

This would be a costly process and I'm not sure about the use of a mixed  acid/acyl anhydride?

 

Uses of acid/acyl anhydrides in organic synthesis

In chemistry, acylation (or alkanoylation) is the process of adding an acyl group (R-C=O) to a compound.

The compound providing the acyl group is called the acylating agent

e.g. acid/acyl chlorides RCOCl or acid/acyl anhydrides (R-C=O)₂O, where R = alkyl or aryl.

With ethanoic anhydride, the reaction is called ethanoylation - a particular case of acylation, adding an CH₃-C=O group to a molecule.

 

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6.7B.2 Reaction of acid/acyl anhydrides with water to yield the parent acid

Just like acyl/acid chlorides, anhydrides undergo nucleophilic addition-elimination reactions with water.

(but at this pre-university level you do not need to know the mechanism details)

This is a hydrolysis reaction and is much slower than with the equivalent acid chloride because acid/acyl chlorides are not as reactive. (See discussion in section 6.7A).

Each molecule of the acyl/acid anhydride yields two molecules of the parent acid.

(RCO)₂O  +  H₂O  ===>  2RCOOH  (R = alkyl or aryl)

e.g. hydrolysis of ethanoic anhydride

  +  H₂O  ===>  2

and the hydrolysis of butanoic anhydride

  +  H₂O  ===>  2

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6.7B.3 Reaction of acid/acyl anhydrides with alcohols to form esters

Just like acyl/acid chlorides, anhydrides undergo nucleophilic addition-elimination reactions with alcohols.

(but at this pre-university level you do not need to know the mechanism details)

Gentle heating of the mixture (perhaps plus a strong acid catalyst) produces the ester.

All the apparatus should be dry to avoid hydrolysis of the acyl/acid anhydride.

This is an example of an a acylation reaction - a reaction where an R-C=O group is inserted into another molecules

Acid/acyl anhydrides are cheaper and safer to use than  acid/acyl chlorides, they also have the advantages of being less easily hydrolysed and less violent i.e.  acid/acyl anhydrides are less reactive than  acid/acyl chlorides, less corrosive and less susceptible to nucleophilic attack (see section 6.7B.5).

(RCO)₂O  +  2R'OH  ===>  RCOOR'  +  RCOOH   (R  = alkyl or aryl, R' = alkyl)

With ethanoic anhydride, the reaction is called ethanoylation - a particular case of acylation, adding an CH₃-C=O group to a molecule.

e.g.  ethanoic anhydride  +  ethanol  ===> ethyl ethanoate  +  ethanoic acid

  +    ===>     + 

and

pentanoic anhydride  +  propan-1-ol  ===>  propyl pentanoate  +  pentanoic acid

  +    ===>     + 

 

This anhydride from a dicarboxylic acid, is formed by eliminating a molecule of water from just one acid molecule and water is a product in the formation of the di-ester (common name a ...'phthalate' derived from phthalic acid)

In this equation and product I have assumed excess alcohol.

With a 1:1 molar ratio, you would only esterify one of the carboxylic acid groups -COOR, the other would become a carboxylic acid group -COOH.

This esterification is made to manufacture plasticisers

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6.7B.4 Reaction of acid/acyl anhydrides with phenols

Just like acyl/acid chlorides, anhydrides undergo nucleophilic addition-elimination reactions with alcohols.

(but at this pre-university level you do not need to know the mechanism details)

Gentle heating of the mixture (perhaps plus a strong acid catalyst) produces the ester.

All the apparatus should be dry to avoid hydrolysis of the acyl/acid anhydride.

(a) Examples of the reaction of  acid/acyl anhydrides and phenols

e.g. with phenol

ethanoic anhydride  +  phenol  ===> phenyl ethanoate  +  ethanoic acid

(RCO)₂O  +  C₆H₅OH  ===>  C₆H₅OCOR  +  RCOOH   (R  = alkyl or aryl, R' = alkyl)

and with 2-hydroxybenzoic acid

  +    ===>    + 

Note that 2-hydroxybenzoic acid is both a phenol and a carboxylic acid, both functional groups can react independently of each other (see synthesis of aspirin in (b))

With ethanoic anhydride, the reaction is called ethanoylation - a particular case of acylation, adding an CH₃-C=O group to a molecule.

This is an example of an a acylation reaction - a reaction where an R-C=O group is inserted into another molecules

 

(b) A brief history and industrial production of aspirin

By the late 1830s, the active ingredient of willow bark, a traditional herbal recipe for pain relief, as -hydroxybenzoic acid (salicylic acid) an effective analgesic.

Although a moderately effective pain-killer, medicines from natural products do have some disadvantages e.g.

The concentration in the plant might be low or too variable for economic exploitation.

The plant extract might contain harmful substances that may be difficult or costly to isolate.

The source may be rare or difficult to grow plus seasonal variation in production.

Therefore, there is a big commercial; advantage for the pharmaceutical industry if you can synthesis the same molecule that was extracted from the plant source, and is often the case, develop an even better synthetic product, as in the case of aspirin.

The important step to synthesise 2-hydroxybenzoic acid on a large and economic scale was achieved by the German chemist Kolbe in 1860. The 'Kolbe Process' involves reacting phenol with carbon dioxide in the presence off sodium hydroxide, the mixture is heated under high pressure.

  +  2NaOH  +  CO₂  ===>    +  2H₂O  == + H₂SO₄(aq) ==> +  Na₂SO₄

The double sodium salt of 2-hydroxybenzoic acid is formed and the free acid liberated on addition of dilute sulfuric acid.

Despite the manufacturing success of the Kolbe synthesis, there were problems with using 'salicylic acid' as a painkiller.

Although technically it is a weak acid, salicylic acid is strong enough to have serious side-effects including stomach pain - gastric inflammation also dehydration of skin leading to irritation e.g. itching and acne.

Therefore the search began to modify salicylic acid and produce a pain-killer with less harmful side effects.

In 1898 Hoffmann succeeded in synthesising 'acetylsalicylic acid (IUPAC name 2-ethanoylbenzoic acid) which proved to be effective as a pain-killer for his father who suffered from rheumatism - instant success!

  +    ===>    + 

Hoffmann reacted 2-hydroxybenzoic acid with ethanoic anhydride

Old names: Ethanoic anhydride was called acetic anhydride, an acylating agent, in this case an acetylating agent, hence the old name of acetylsalicylic acid, which we know as 'aspirin'.

Using ethanoic anhydride is much cheaper than using ethanoyl chloride. It is also much safer to use, less corrosive (the by-product CH₃COOH easier to manage than fumes of HCl), also less hazardous to control, less susceptible to hydrolysis (lesser nucleophilic reactivity towards the nucleophile water)

  +    ===>    +  HCl

But this can be done as a demonstration in the school laboratory.

 

The advantages of 'aspirin' over 'salicylic acid'

Aspirin is more rapidly absorbed and less gastric irritation in the stomach.

 6.7B.5 The laboratory preparation and purification of aspirin

It easy to do in school and college laboratories and involves several important laboratory techniques, which you are expected to describe in written examinations too.

A summary, with explanation, of the steps to required to prepare a pure sample of aspirin.

The procedural details and apparatus are common to many organic preparations in a laboratory.

I'm not supplying specific amounts of materials needed and note the use of phosphoric(V) acid catalyst.

(1) Measuring out the ingredients and assembling the apparatus

When handling ethanoic anhydride (and other potentially hazardous chemicals) wear safety glass, thin plastic gloves and work in a fume cupboard. The ethanoic anhydride can be measured with a reasonably accurate measuring cylinder but avoid inhaling the harmful corrosive fumes - hence the need to work in a fume cupboard.

Irritant, harmful and corrosive

Take care in weighing out the solid 2-hydroxybenzoic acid, make sure there is no skin contact.

The phosphoric(V) acid is a very concentrated solution, so take care again.

You need a hot water bath to speed up the reaction and the reaction flask must be dry to avoid the ethanoic anhydride reacting with water.

The hot water bath also avoids the use of a bunsen burner, naked flames and flammable materials need to avoid each other!

(2) Getting the reaction going

Weigh the solid 2-hydroxybenzoic acid into a small conical flask.

Add the liquid ethanoic anhydride plus a small amount of the phosphoric(V) acid catalyst.

Heat the flask in a hot water bath and the reaction will start (equation below).

  +    ===>    + 

Remove the reaction flask from the hot water bath and let it cool down.

(3) The first crystallisation of the crude product

Add ice-cold water slowly to the conical flask and stirring with a glass rod should start the precipitation of aspirin.

You can get the maximum precipitate by cooling the flask in an ice-water bath until no more crystals seem to form.

The term 'crude' just means it hasn't been purified i.e. small amounts of impurities like unreacted chemicals are still present in the precipitated crystals.

(4) Separating the crude product by filtration

The crude solid is separated from the liquid residue by vacuum filtration using a Buchner flask and Buchner funnel.

This is a reduced pressure filtration technique. The Buchner flask has thick walls to withstand the reduced pressure produced by a suction pump operated by the water pressure of a tap.

The Buchner flask has a side-arm to connect it to the pump which creates the reduced pressure inside the flask.

The Buchner funnel fits into the neck of the Buchner flask, made air-tight by a snug rubber bung with a hole in it to hold the funnel in place (diagram below).

The Buchner funnel has a flat perforated surface over which a circular filter paper fits.

The pump is switched on and the crude solid and liquid (suspension) is carefully poured into the Buchner funnel.

The liquid is sucked through leaving the crude solid on the filter paper.

The collected solid can be washed with a little iced water to remove some of the impurities while it is still on the filter paper in the Buchner funnel.

The solid is then collected off the filter paper and dried before recrystallisation.

(5) Recrystallization of the collected crude product

Recrystallisation is a simple method of producing reasonably pure crystals from a solvent.

The idea is to form pure crystals and leaving the remaining impurities in the crystallising solvent.

You can use ethanol, aqueous ethanol or ethyl ethanoate as the solvent - but take care, both are flammable, so using a hot bath is a good idea instead of a bunsen burner as a source of heat.

 The crude solid product is dissolved in the minimum of hot solvent to make a saturated solution in a boiling tube or small conical flask.

(If there is still solid impurities left in suspension, they should be filtered off, BUT this is really tricky with a hot saturated solution, so hope the solution looks clear!)

The hot concentrated solution is allowed to cool down to room temperature and then cooled further using an ice bath.

The pure crystals should form and separate out, leaving the impurities dissolved in the recrystallization solvent.

The pure crystals are filtered off, washed with a little pure solvent, collected and dried in an oven, at a temperature well below the melting point of aspirin, see (6) next.

(6) Determining the melting point as a simple test of purity

A sample of the dried crystals is tapped into a cold thin glass capillary tube, sealed at one end (via a bunsen flame). About 5 mm depth of the solid is sufficient.

The sample tube and a thermometer (of appropriate scale and range) are placed side by side in the melting point apparatus illustrated below.

You should be able to read the thermometer clearly to the nearest 0.5^o.

The bottom of the sample tube should be alongside the bottom of the thermometer i.e. next to the mercury bulb.

The temperature is raised slowly so that the sample does not melt (change state) so fast that you register a melting point that is too high.

The melting point apparatus has a small window that allows you to see the state of the solid in the capillary tube.

You try and reduce the rate of heating as you approach the expected melting point.

If it is an unknown compound, you do a quicker test to get an idea of the melting point, and then repeat much more slowly to get an accurate value.

If the sample is pure, it will melt quite sharply over a very narrow temperature range.

In the case of aspirin, this should be 134 to 136^oC.

If it is extremely pure and temperature rise is very slow, you might get a sharp mpt of 135 to 136^oC.

If the sample is impure, it slowly melts over a larger temperature range.

In the case of aspirin you would see signs of melting a few degrees below 136^oC.

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6.7B.6 Reaction of acid/acyl anhydrides with ammonia and amines

Examples of acylation reactions - a reaction where an R-C=O group is inserted into another molecules

With ethanoic anhydride, the reaction is called ethanoylation - a particular case of acylation, adding an CH₃-C=O group to a molecule.

Gentle heating of the mixture (perhaps plus a strong acid catalyst) produces the ester.

Ammonia forms primary amides with  acid/acyl anhydrides

(RCO)₂O  +  NH₃  ===>  RCONH₂  +  RCOOH   (R  = alkyl or aryl)

and

primary amines from N-substituted amides with  acid/acyl anhydrides

(RCO)₂O  +  R'NH₂  ===>  RCONHR'  +  RCOOH   (R or R'  = alkyl or aryl)

Examples

(i) Formation of a primary acid/acyl amide

propanoic anhydride  +  ammonia  ===>  propanamide  +  propanoic acid

  +  NH₃  ===>    + 

  +  NH₃  ===>    + 

(ii) Formation of a secondary acid/acyl amide (an N-substituted amide)

ethanoic anhydride  +  methylamine  ===> N-methylethanamide  + ethanoic acid

  +  CH₃NH₂  ===>    + 

and

ethanoic anhydride  +  phenylamine  ===>  N-phenylethanamide  +  ethanoic acid

  +    ===>    + 

The case of paracetamol

Paracetamol is another common analgesic and manufactured by acylating 4-aminophenol with ethanoic anhydride.

The reaction is similar to the final stage in manufacturing aspirin.

  +    ===>    + 

Its IUPAC name is N-(4-hydroxyphenyl)ethanamide, so its not name as an aromatic compound, but as a derivative of ethanoic acid, namely its amide - that's enough to give you a headache on naming!

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