Part 6. The Chemistry of  Carboxylic Acids and their Derivatives

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 reaction of acid/acyl chlorides with water, alcohols, phenols, ammonia, ammines, nucleophilic addition mechanisms

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Part 6.7A An introduction to the reactivity of carboxylic acid derivatives towards nucleophiles and the preparation and reactions of acid chlorides (acyl chlorides)

Sub-index for this page

6.7A.0a Introduction to the reactivity of carboxylic acid derivatives towards nucleophiles

6.7A.0b Preparation and physical properties of acid chlorides

6.7A.1 Introduction to the specific reactivity of acyl chlorides

6.7A.2 Hydrolysis reaction of acid/acyl chlorides and mechanism

6.7A.3 Reaction of acid/acyl chlorides with alcohols/phenols (acylation) - esterification and mechanism

6.7A.4 Reaction of acid/acyl chlorides with ammonia (acylation) - primary amide formation & mechanism

6.7A.5 Reaction of acid/acyl chlorides with amines (acylation) - secondary/tertiary amide formation, mechanism

6.7A.6. The reduction of acid/acyl chlorides with LiAlH₄ - conversion to primary alcohol

6.7A.0a An introduction to the reactivity of carboxylic acids and their derivatives

A theoretical mechanism by which L, in a carboxylic acid derivative, is substituted by an incoming nucleophile

One approach to the understanding the comparative reactivity of carboxylic acid derivatives is to consider the theoretical attack of a negative or neutral nucleophile (^-:Nuc or :Nuc) which ultimately displaces, what is referred to, as the leaving group (:L^- or :L), shown in the mechanism diagrams above.

The diagrams are a recognised mechanistic pathway for the derivatives of carboxylic acids.

In the mechanisms to follow look for the electron pair donation from the nucleophile:

e.g. :OH₂, :NH₃, lone pairs on the oxygen atom of alcohols or phenols RÖH

A reminder that nucleophiles are electron pair donors (also classed as Lewis bases).

In the actual mechanism, L usually combines with a H atom in the elimination step, and this will be shown in all the nucleophilic-addition mechanism shown from now on.

e.g. for the following leaving groups: Cl is eliminated as HCl, RCOO is eliminated as RCOOH, O-R' is eliminated as R'OH and NH₂ is eliminated as NH₃.

Note that both steps are reversible.

This means a 'poor' leaving group may not allow the reaction to proceed forwards to a significant extent, or a very slow reaction leading to an equilibrium situation e.g. the slow uncatalysed hydrolysis of an ester with pure water.

The carbonyl bond is polar, ^δ+C=O^δ-, due to the difference in electronegativity of carbon (2.5) and oxygen (3.5).

The nucleophile (electron pair donor) attacks the ^δ+C atom , forming a sigma bond with it, and displaces the leaving group L - examples of the theoretical leaving groups are also shown in the diagram.

The blue arrows show the electron shifts that must happen to effect this change.

Always look for the lone pair on the nucleophile e.g. on the oxygen atom of water and alcohols/phenols or the nitrogen atom of ammonia and amines and mention this in your description of the mechanism.

The ease of this reaction depends on several factors.

(i) The strength of the single C-L bond

Bond enthalpies = kJ/mol: C-O = 360  >  C-Cl = 338  >  C-N = 305;

On the basis of bond enthalpies, amides should be the most reactive, but this is not the case - so we must now consider other factors.

However acid chlorides (weaker C-Cl bond) are more reactive than acid anhydrides and esters (stronger C-O bonds).

(ii) The electron-donating or electron-withdrawing power of the L group towards the carbonyl carbon atom

The chlorine atom, has the more powerful electron-withdrawing group effect as well as a very stable leaving group (chloride ion, a weak base), see (iii) below.

The effect of C-O polarity is reduced in esters because the leaving group L, has a C-O-C linkage, and amides have a C-N-H linkage, both of which reduce the effective delta plus of the carbon atom of the carbonyl group.

This again favours increasing the reactivity of acid chlorides (just the polar C-Cl bond).

(iii) The stability of the leaving group :L^-

The leaving group is poor if it is a strong base i.e. a strong electron pair donor

The amide ion, NH₂^-, is a very strong base and a weak leaving group, it would prefer to rejoin the carbonyl carbon atom, this greatly reduces its reactivity towards nucleophiles.

Note that in the case of aldehydes and ketones, the H^- or R^- potential leaving groups are very strong bases and not displaced.

(iv) The polarity of the C-L bond

In the case of acid/acyl chlorides, the highly polarised situation of the carbon - oxygen and carbon - chlorine bonds (electronegativities C 2.5, Cl 3.0 and O 3.5) i.e. ^δ–Cl–C^δ2+=O^δ– makes the bond highly susceptible to nucleophilic attack.

BUT, note there is no 2nd atom attached to the chlorine to reduce its polarising effect,

e.g. as in the case of O=C-O-H (acid), O=C-O-C (ester), O=C-N-H (amide)

 

The combination of the these factors 'usually' results in the reactivity order:

acid chloride  >  acid anhydride  >  ester  >  amide

and this is why acid chlorides are so reactive and very useful in organic synthesis reactions.

To illustrate this trend consider the following:

Acid chlorides and acid anhydrides readily react with alcohols and ammonia to yield esters and amides respectively. They are also readily hydrolysed by water.

Esters react with ammonia and ammines to yield amides, but are slow to hydrolyse in water without an acid or alkali catalyst.

But the simple reversal of any of these reactions on an amide is very difficult.

 

Carboxylic acid derivatives not behave in the same way as aldehydes and ketones

Despite the its polarity, the reactivity of the carbonyl C=O group is considerably modified by the presence of the L group and these carboxylic acid derivatives do not as readily undergo the addition - elimination reactions like aldehydes and ketones e.g. they do not react with 2,4-dinitrophenylhydrazine.

 

Attack of a neutral nucleophile on the ^δ+C atom of the carbonyl group in a carboxylic derivative

You can construct a similar mechanistic pathway for a neutral nucleophile like water as it hydrolyses and acid chloride. though this requires you clearly show the elimination of the hydrogen chloride molecule (more on this in 6.7A.1)

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6.7A.0b The preparation of acyl/acid chlorides

or RCOCl in very abbreviated formulae

There are three basic ways of synthesising acid chlorides in the laboratory, all starting with the corresponding carboxylic acid. In each case R = alkyl or aryl.

In each case the -OH hydroxy group of the carboxylic acid is replaced by the -Cl chloride group.

The name is derived from the parent acid with oyl replacing oic and suffixed with chloride i.e. ethanoyl chloride is derived from ethanoic acid.

The lower aliphatic members of the  acid/acyl series are colourless liquids that fume in moist air - don't leave open when not in use.  They are highly corrosive hazardous chemicals.

 

(a) Reaction with phosphorus(V) chloride (phosphorus pentachloride)

RCOOH  +  PCl₅  ===>  RCOCl  +  POCl₃  +  HCl

  +  PCl₅  ===>    +  POCl₃  +  HCl

From ethanoic acid, a preparation of ethanoyl chloride, boiling point 51^oC.

The acid chloride can be separated from the POCl₃ by distillation.

The ease of hydrolysis can be seen as the volatile liquid will fume in air from hydrolysis if in contact with water vapour in the air. More visible 'white clouds' are seen if ethanoyl chloride vapour meets fumes from conc. ammonia solution due to the formation of ammonium chloride.

Three reactions can be going on ...

CH₃COCl  +  H₂O  ===>  CH₃COOH  +  HCl

CH₃COCl  +  NH₃  ===>  CH₃CONH₂  +  HCl

NH₃  +  HCl  ===>  NH₄Cl

Similarly to give butanoyl chloride bpt. 80^oC

  +  PCl₅  ===>    +  POCl₃  +  HCl

 

(b) Reaction with phosphorus(III) chloride (phosphorus trichloride)

RCOOH  +  PCl₃  ===>  RCOCl  +  H₃PO₃

  +  PCl₃  ===>    +  H₃PO₃

  +  PCl₃  ===>    +  H₃PO₃

From pentanoic acid, preparation of pentanoyl chloride, boiling point 128^oC

The acid chloride would have to be separated from the H₃PO₃ by distillation.

 

(c) Reaction with thionyl chloride

RCOOH  +  SOCl₂  ===> RCOCl  +  SO₂  +  HCl

  +  SOCl₂  ===>     +  SO₂  +  HCl

From benzoic acid, preparation of benzoyl chloride, boiling point 197^oC

This last method has the advantage of producing gaseous waste products and just leaving the acid chloride behind for further purification.

Notes:

Ethanoyl chloride and pentanoyl chloride are aliphatic acyl chlorides and benzoyl chloride is an aromatic acyl chloride.

There is no methanoyl chloride, HCOCl is too unstable a molecule, which is why R is only alkyl or aryl.

 

Uses of acid/acyl chlorides 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.

 

Physical properties

Acid/acyl chlorides are usually colourless liquids at room temperature.

Some boiling points are quoted under the preparations given above.

They dissolve in 'dry' organic solvents, insoluble in water, but they do react with it - see hydrolysis reaction.

Lower members like ethanoyl chloride are quite volatile at room temperature so take care ....

... the fumes are acrid and dangerous, especially in the eyes, because the acid chloride vapour fumes in contact with water - they hydrolyse to acidic hydrogen chloride, which becomes hydrochloric acid in your body fluids!

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6.7A.1 Introduction to the reaction mode and reactivity of acid chlorides (acyl chlorides)

The high reactivity of acyl chlorides is towards nucleophilic attack is partly due to the relatively weak C-Cl bond, BUT, the highly polarised situation of the carbon - oxygen and carbon - chlorine bonds (electronegativities C 2.5, Cl 3.0 and O 3.5) i.e.

^δ–Cl–C^δ2+=O^δ– makes the bond highly susceptible to nucleophilic attack

Note there is no 2nd atom attached to the chlorine to reduce its polarising effect,

e.g. as in the case of O=C-O-H (acid), O=C-O-C (ester), O=C-N-H (amide)

The ensuing mechanism is called a nucleophilic addition elimination (because of the two principal stages of the mechanism i.e. an addition followed by an elimination), but overall it amounts to a nucleophilic substitution mechanism.

The initial point of attack is the δ+ carbon atom with the addition of a nucleophiles (Nuc: in diagram) like water, alcohols, ammonia and amines (mechanism diagram 78a above).

These are all neutral nucleophiles all of which are lone pair donors from the oxygen (:OR₂) or nitrogen (:NR₃) atom where R = H, alkyl or aryl.

The oxygen atom of the carbonyl group becomes negative (-) as the pi bond pair shift on to it.

Simultaneously,  the oxygen or nitrogen atom of the nucleophile must carry a balancing positive charge (+) when they form the C-O or C-N bond with the δ+ carbon atom to complete the addition step 1 of the mechanism.

Note

(i) Acyl chlorides are more reactive towards nucleophiles than carboxylic acids because the hydrogen on the hydroxy group weakens the effect of the oxygen atom in making the carbon atom less δ+ AND the C-OH bond is stronger than the C-Cl bond.

(ii) The δ+ of the carbon atom is subjected to an electron shift away from it by two, more electronegative atoms (electronegativities: C = 2.5, Cl = 3.0 and O = 3.5), which increases its δ+ and susceptibility to nucleophilic attack.

(iii) The C-Cl bond is weaker than C-C, C-O or C-H bonds, so Cl is relatively mobile leaving group.

(iv) Points (ii) and (iii) added together, explain why acid chlorides undergo addition elimination reactions in which the Cl atom leaves and is replaced by the nucleophile - and more so than carboxylic acids.

After the addition of the nucleophile, there are several electron and atom shifts before a small molecule is eliminated, in this case hydrogen chloride - full and simplified mechanisms are described in the following sections.

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6.7A.2 The reaction of acid chlorides (acyl chlorides) with water - hydrolysis

The hydrolysis of acyl chloride with water is a  nucleophilic addition–elimination

Examples of nucleophilic addition of water to acid/acyl chlorides,  subsequent elimination on hydrolysis to give the carboxylic acid and hydrochloric acid (hydrogen chloride

(i)   +  H₂O  ===>    +  HCl

ethanoyl chloride + water ===> ethanoic acid + hydrogen chloride (fuming in damp air)

With excess water, you will form an aqueous solution mixture of the carboxylic acid and hydrochloric acid e.g.

CH₃COCl_(l)  +  2H₂O_(l)  ===>  CH₃COOH_(aq)  +  H₃O⁺_(aq)  +  Cl^-_(aq)

 

(ii)    +  H₂O  ===>    +  HCl

pentanoyl chloride + water ===> pentanoic acid + hydrogen chloride (fuming in damp air)

or  CH₃(CH₂)₃COCl_(l)  +  2H₂O_(l)  ===>  CH₃(CH₂)₃COOH_(aq)  +  H₃O⁺_(aq)  +  Cl^-_(aq)

 

(iii)   +  H₂O  ===>    +  HCl

benzoyl chloride  + water ===> /benzoic acid + hydrogen chloride (fuming in damp air)

or  C₆H₅COCl_(l)  +  2H₂O_(l)  ===>  C₆H₅COOH_(aq)  +  H₃O⁺_(aq)  +  Cl^-_(aq)

 

The mechanism for the hydrolysis of acid/acyl chlorides

e.g. R–COCl + H₂O ==> R–COOH + HCl  (in damp air)

R–COCl + 2H₂O ==> R–COOH + H₃O⁺ + Cl^–  (with excess water)

The reaction is effectively overall a nucleophilic substitution of -Cl by -OH (via H₂O), but the reaction has a nucleophilic addition - elimination mechanism.

The organic hydrolysis product is a carboxylic acid.

mechanism 14 – nucleophilic addition–elimination reaction for the hydrolysis of an acid/acyl chloride

[mechanism diagram 14 above] The mechanism involves several rearrangements and assumes excess water.

Step (1) The >C^δ+=O^δ– carbonyl is highly polarised and the positive carbon is attacked by the nucleophilic water molecule, acting as an electron pair donor.

The water adds to form a highly unstable ionic intermediate via a C–O bond from the lone pair donation and simultaneously the π electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

The water is the nucleophile - the electron pair donor to a partially positive carbon atom.

Step (2) The C–Cl bond pair moves onto the chlorine atom which leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen atom shifts back to complete (reform) the C=O carbonyl bond.

Step (3) A water molecule abstracts a proton to form the oxonium ion and the carboxylic acid product.

If only limited water is available, e.g. like when the acid chloride liquid fumes in air, step (3) could be written as a chloride ion removing the proton to form hydrogen chloride i.e.

RCOOH₂⁺  +  Cl^–  ===> RCOOH  +  HCl

In the above mechanism diagram 78b, I've kept the initial step the same - the nucleophile water attacking the δ+ carbon atom of the carbonyl group.

However, I've 'conflated' steps 2 and 3 from the general mechanism shown in mechanism diagram 14 into a single step to summarise the 2nd phase of the mechanism.

In this simplified version of the mechanism, the equivalent of H⁺ and Cl^- leave as HCl gas - the elimination part of the mechanism to yield ethanoic acid.

The HCl product would react with excess water to yield H₃O⁺  and  Cl^-.

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6.7A.3 The reaction of acid chlorides (acyl chlorides) with alcohols and phenols - esterification

(a) The reaction acyl/acid chlorides with alcohols/phenols

Acid/acyl chlorides form esters with alcohols and phenols, an example of an a acylation reaction - a reaction where an R-C=O group is inserted into another molecules

Acyl chloride esterification by nucleophilic addition–elimination reaction between an acid chloride and an alcohol.

Because acid chlorides react with water, the reaction is usually carried in anhydrous conditions - all reagents and glassware should be dry.

The organic synthesis of esters from the reaction of acid/acyl chloride with alcohols

Unlike the acid catalysed reversible esterification reaction between a carboxylic acid and an alcohol with ~2/3rds yield, this is a non-reversible esterification reaction giving very high yields.

The acyl chloride and alcohol usually readily react at room temperature, especially if both are aliphatic.

Examples of nucleophilic addition of an alcohol to acid/acyl chlorides,  followed by elimination to give the ester and hydrogen chloride.

(i) ethanoyl chloride  +  ethanol ===>  ethyl ethanoate  +  hydrogen chloride

  + CH₃-CH₂-OH  ===>    +  HCl

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

(ii) ethanoyl chloride  +  phenol  ===>  phenyl ethanoate  +  hydrogen chloride

  +    ===>    +  HCl

(iii) pentanoyl chloride  +  propan-1-ol  ===>  propyl pentanoate  +  hydrogen chloride

  +    ===>    +  HCl

 

The mechanism for the formation of an ester from an alcohol and an acid/acyl chloride

e.g. R–COCl  +  R'OH  ===>  R–COOR'  +  HCl   [see mechanism 15 below]

effectively overall a nucleophilic substitution of -Cl by -OR (via ROH)

mechanism 15 – nucleophilic addition–elimination reaction for the esterification of an acyl chloride

[mechanism 15 above] The mechanism involves several rearrangements and is essentially the same mechanism as for water, i.e. one of the H's is replaced by R'.

Step (1) The >C^δ+=O^δ– carbonyl is highly polarised and the positive carbon is attacked by the nucleophilic alcohol molecule, acting as an electron pair donor.

The alcohol adds to form a highly unstable ionic intermediate via a C–O bond from the lone pair donation and simultaneously the π electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

The alcohol is the nucleophile - the electron pair donor to a partially positive carbon atom.

Step (2) The C–Cl bond pair moves onto the chlorine atom and leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen atom shifts to complete (reform) the C=O carbonyl bond.

Step (3) The previously formed chloride ion abstracts a proton to form the oxonium ion and the ester product.

The reaction is effectively, overall, the substitution of the –Cl chlorine atom with an –OR group where R' =alkyl or aryl.

 

In the above mechanism diagram 78c, I've kept the initial step the same - the nucleophile ethanol attacking the δ+ carbon atom of the carbonyl group.

However, I've 'conflated' steps 2 and 3 from the general mechanism shown in mechanism diagram 15 into a single step to summarise the 2nd phase of the mechanism to yield ethyl ethanoate.

In this simplified version of the mechanism, the equivalent of H⁺ and Cl^- leave as HCl gas - the elimination part of the mechanism.

 

(b) The reaction of aromatic acid chlorides with phenols

The acyl chloride and alcohol usually readily react at room temperature, especially if both are aliphatic.

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

However, phenols may require the presence of aqueous sodium hydroxide to facilitate the reaction, especially if the acyl chloride itself is itself a less reactive (than aliphatic) aromatic e.g. C₆H₅COCl.

The alkali generates a negative phenoxide ion (e.g. C₆H₅O^– from phenol C₆H₅OH), which is a more powerful nucleophile than the original neutral phenol molecule.

benzoyl chloride  +  phenol  ===>  phenyl benzoate  +  hydrochloric acid

  +    ===>    +  H⁺  +  Cl^-

Notes:

Phenols are distinguished from alcohols by having the OH hydroxy group directly to the benzene ring.

You can use aqueous conditions because benzoyl chloride is more stable in water than the aliphatic acid chlorides like ethanoyl chloride.

If you shake benzoyl chloride with phenol dissolved in sodium hydroxide, you get an immediate white precipitate of the ester phenyl benzoate.

The reaction is particularly fast because the sodium hydroxide reacts with phenol (a very weak acid) to form the negative phenate ion - a much more powerful nucleophile than a neutral alcohol OR water molecules. The structure of sodium phenoxide is shown on the left.

 

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6.7A.4 The reaction of acid chlorides (acyl chlorides) with ammonia

Ammonia forms amides with  acid/acyl chlorides

The organic synthesis of amides from acid/acyl chlorides and ammonia, and again, another example of an a acylation reaction - a reaction where an R-C=O group is inserted into another molecules

Because acid chlorides react with water, the reaction is usually carried in anhydrous conditions - all reagents and glassware should be dry.

Examples of nucleophilic addition of ammonia to acid/acyl chlorides, subsequent elimination gives the primary amide and hydrogen chloride/hydrochloric acid

(i) ethanoyl chloride + ammonia ==> ethanamide + hydrogen chloride

+ NH₃  ===>  +  HCl

This equation illustrates the formation of the primary aliphatic amide, ethanamide

 

(i) pentanoyl chloride + ammonia ==> pentanamide + hydrogen chloride

+ NH₃  ===>  +  HCl

This equation illustrates the formation of the primary aliphatic amide, pentanamide

 

(iii) benzoyl chloride  +  ammonia  ===>  benzamide  +  hydrogen chloride

+ NH₃  ===>  +  HCl

This equation illustrates the formation of the primary aromatic amide, benzamide

 

Amines form N-substituted amides with  acid/acyl chlorides

(iv)  benzoyl chloride  +  phenylamine  ===> N-phenylbenzamide  + hydrogen chloride

  +    ===>     +  HCl

This equation illustrates the formation of the secondary aromatic amide, benzamide

(v) need aliphatic example

Table illustrating and explaining the differences between primary, secondary and tertiary amines and amides

 

The mechanism for the formation of a primary amide from an acid/acyl chloride and ammonia

e.g. R–COCl + 2NH₃ ==> R–CONH₂ + NH₄⁺ + Cl^–   [see mechanism 16 below]

The reaction is effectively overall a nucleophilic substitution of -Cl by -NH₂ (via NH₃)

R = alkyl or aryl

mechanism 16 – nucleophilic addition–elimination reaction for an acyl chloride forming an amide from ammonia

[mechanism 16 above] The mechanism involves several rearrangements and assumes excess ammonia.

Step (1) The >C^δ+=O^δ– carbonyl bond is highly polarised and the positive carbon is attacked by the nucleophilic ammonia molecule, acting as an electron pair donor.

The ammonia adds to form a highly unstable ionic intermediate via a C–N bond from the lone pair donation and simultaneously the π electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

The ammonia is the nucleophile - the electron pair donor to a partially positive carbon atom.

Step (2) The C–Cl bond pair moves onto the chlorine atom and leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen atom shifts to complete (reform) the C=O carbonyl bond.

Step (3) Another ammonia molecule abstracts a proton to form the ammonium ion and the primary amide product.

In the above mechanism diagram 78d, I've kept the initial step the same - the nucleophile ammonia attacking the δ+ carbon atom of the carbonyl group.

The product is a primary amide called ethanamide.

However, I've 'conflated' steps 2 and 3 from the general mechanism shown in mechanism diagram 16 into a single step to summarise the 2nd phase of the mechanism.

In this simplified version of the mechanism, the equivalent of H⁺ and Cl^- leave as HCl gas - the elimination part of the mechanism.

In reality, the HCl will combine with excess ammonia to give ammonium chloride, NH₄Cl.

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6.7A.5 The reaction of acid chlorides (acyl chlorides) with a primary amine

The organic synthesis of secondary amides from acid/acyl chlorides reacting with a primary amine,

AND the formation of tertiary amides by acid chlorides reacting with secondary amines.

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

Table illustrating and explaining the differences between primary, secondary and tertiary amines and amides

Because acid chlorides react with water, the reaction is usually carried in anhydrous conditions - all reagents and glassware should be dry.

Examples of nucleophilic addition of ammonia to acid/acyl chlorides, subsequent elimination gives the amide and hydrogen chloride/hydrochloric acid

(i) ethanoyl chloride  +  methylamine  ===>  N-methylethanamide  +  hydrogen chloride

  +    ===>    +  HCl

This illustrates the formation of a secondary amide, N-methylethanamide

 

(ii) ethanoyl chloride  +  phenylamine  ===>  N-phenylethanamide  +  hydrogen chloride

  +    ===>    +  HCl

These illustrates the formation of a secondary amide, N-phenylethanamide

 

(iii) ethanoyl chloride  +  dimethylamine  ===> N,N-dimethylethanamide + hydrogen chloride

  +    ===>    +  HCl

  +    ===>    +  HCl

This illustrate the formation of a tertiary amide, N,N-dimethylethanamide

 

In each case the hydrogen chloride will react with excess amine to give a salt

Table illustrating and explaining the differences between primary, secondary and tertiary amines and amides

 

The mechanism for the formation of a secondary amide from an acid/acyl chloride and a primary amine

e.g. R–COCl + 2R'NH₂ ==> R–CONHR' + RNH₃⁺ + Cl^–   [see mechanism 17 below]

The reaction is effectively overall a nucleophilic substitution of -Cl by -NHR' (via R'NH₂) or -NR'₂ (via R'₂NH).

R and R' = alkyl or aryl

 

mechanism 17 – nucleophilic addition–elimination reaction for an acyl chloride forming a secondary amide (N–substituted amide) from a primary amine

[mechanism 17 above] The mechanism involves several rearrangements and assumes excess of the primary amine and is in principal no different than the reaction with ammonia.

Step (1) The >C^δ+=O^δ– carbonyl is highly polarised and the positive carbon is attacked by the nucleophilic primary amine molecule, acting as an electron pair donor.

The alcohol adds to form a highly unstable ionic intermediate via a C–N bond from the lone pair donation and simultaneously the π electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

Step (2) The C–Cl bond pair moves onto the chlorine atom and leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen shifts to complete (reform) the C=O carbonyl bond.

Step (3) Another primary molecule abstracts a proton to form an alkylammonium ion and the free secondary amide.

FURTHER COMMENTS

The reaction is effectively, overall, the substitution of the –Cl chlorine atom with an amine/amino (–NH₂) group or a substituted amide (–NHR) group.

 

In the above mechanism diagram 78e, I've kept the initial step the same - the nucleophile ethylamine attacking the δ+ carbon atom of the carbonyl group.

The product is a secondary amide called N-ethylethanamide.

However, I've 'conflated' steps 2 and 3 from the general mechanism shown in mechanism diagram 17 into a single step to summarise the 2nd phase of the mechanism.

In this simplified version of the mechanism, the equivalent of H⁺ and Cl^- leave as HCl gas - the elimination part of the mechanism.

The HCl product would actually react with excess amine to yield CH₃CH₂NH₃⁺Cl^- in this case.

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Table illustrating and explaining difference between primary, secondary and tertiary amines and amides

Functional group	PRIMARY	SECONDARY	TERTIARY	Comments
AMINES				There are prim/sec/tert aliphatic (alkyl) or aromatic (aryl) amines.
Aliphatic amine examples	ethylamine	ethylmethylamine	triethylamine	Aliphatic amine examples. The N of the amine group NOT directly attached to a benzene ring
Aromatic amine examples	phenylamine	diphenylamine	N,N-diethylphenylamine	Aromatic amine examples The N of the amine group directly attached to a benzene ring.
Acyl or acid AMIDES				The amide group comprises an amine group attached to the C of a C=O carbonyl group, which gives it its own unique chemistry i.e. its neither an amine, aldehyde or ketone!
Examples of amides	ethanamide	N-methylbenzamide	N,N-dimethylethanamide	Examples of amides both aliphatic and aromatic

6.7.6 The reduction of acid/acyl chlorides - conversion to primary alcohol

Acyl/acid chlorides, like carboxylic acids esters, are reduced by the powerful reducing agent lithium tetrahydridoaluminate(III), LiAlH₄, giving the corresponding primary alcohol.

LiAlH₄ reacts with water and ethanol, therefore the reaction must be carried out in a dry inert solvent e.g. ethoxyethane ('ether') and NOT water or ethanol.

The general equation is:

RCOCl  +  4[H]  ===>  RCH₂OH  +  HCl

The LiAlH₄ effectively generates the equivalent of a hydride ion (:H^-) which is a powerful nucleophile - lone pair of electrons donor.

Examples

(i) pentanoyl chloride  +  hydrogen  ===>  pentan-1-ol

  +  4H  ===> +  HCl

(ii) benzoyl chloride  +  hydrogen  ===>  phenylmethanol ('benzyl alcohol')

  +  4[H]  ===>     +  HCl

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6.7.7 The reaction of acyl/acid chlorides with aromatic hydrocarbons - ketone formation

Acid chlorides will react with aromatic hydrocarbons like benzene and methylbenzene to form ketones.

This is an example of a Friedel-Crafts acylation reaction

The reaction must be carried out in dry conditions using an aluminium chloride catalyst.

You reflux the mixture of the acid chloride, aromatic hydrocarbon and aluminium chloride in a fume cupboard.

Fumes of hydrogen chloride are given off.

 

Examples

(i) benzene  +  ethanoyl chloride  == AlCl₃  ==>  1-phenylethanone  + hydrogen chloride

  +  ===>    +  HCl

The IUPAC preferred name is 1-Phenylethan-1-one.

The product is also called 'acetophenone' 'methyl phenyl ketone' or just 'MEK' in the chemical industry!

You might describe the product is half an aliphatic and half an aromatic ketone.

 

(ii) benzene  +  benzoyl chloride  == AlCl₃  ==>  1-phenylmethanone  + hydrogen chloride

  +  ===>    +  HCl

The product is also called 'diphenyl ketone'.

You can describe this product as a completely aromatic ketone.

 

Mechanism of acylation to give aromatic ketones [Friedel-Crafts reaction]

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