Nomenclature of Carboxylic Acid Derivatives
 

Acyl Halides or Acid Halides

• Acyl or acid halides are derivatives of carboxylic acids.
• The root name is based on the longest chain including the carbonyl group of the acyl group.
• Since the acyl group is at the end of the chain, the C=O carbon must be C1.
• The acyl halide suffix is appended after the hydrocarbon suffix minus the "e" : e.g.  -ane + -oyl halide = -anoyl halide etc.
• The most common halide encountered is the chloride, hence acyl or acid chlorides, e.g. ethanoyl chlorid

Acid Anhydrides

• As the name implies, acid anyhydrides are derivatives of carboxylic acids.
• In principle, they can be symmetric (where the two R groups are identical) or asymmetric (where the two R groups are different).
• Symmetric anhydrides are the most common, they are named as alkanoic anhydrides
• Asymmetric anhydrides are name in a similar fashion listing the alkyl groups in alphabetical order.
• Cyclic anhydrides derived from dicarboxylic acids are name as -dioic anhydrides.

 Back to the top

Esters

• Esters are alkyl derivatives of carboxylic acids.
• The easiest way to deal with naming esters is to recognise the carboxylic acid and the alcohol that they can be prepared from.
• The general ester, RCO₂R' can be derived from the carboxylic acid RCO₂H and the alcohol HOR'
• The first component of an ester name, the alkyl is derived from the alcohol, R'OH.
• The second component of an ester name, the -oate is derived from the carboxylic acid, RCO₂H.
• Alcohol component
  • the root name is based on the longest chain containing the -OH group.
  • The chain is numbered so as to give the -OH the lowest possible number.
• Carboxylic acid component
  • the root name is based on the longest chain including the carbonyl group.
  • Since the carboxylic acid group is at the end of the chain, it must be C1.
  • The ester suffix for the acid component is appended after the hydrocarbon suffix minus the "e" : e.g.  -ane + -oate = -anoate etc.
• The complete ester name is the alkyl alkanoate

 Back to the top

Amides

• Amides are amine derivatives of carboxylic acids.
• The root name is based on the longest chain including the carbonyl group of the amide group.
• Since the amide group is at the end of the chain, the C=O carbon must be C1.
• The amide suffix is appended after the hydrocarbon suffix minus the "e" : e.g.  -ane + -amide = -anamide etc.
• If the amide nitrogen is substituted, the these substituents are given N- as the locant.
• The N- locant is listed first.

Back to the top

Nitriles

Cyano substituent style:

• The root name is based on the longest chain with the -C≡N as a substituent.
• This root give the alkane part of the name.
• The chain is numbered so as to give the -C≡N group the lowest possible locant number

Nitrile style:

• The root name is based on the longest chain including the carbon of the nitrile group.
• This root give the alkyl part of the name.
• Since the nitrile must be at the end of the chain, it must be C1 and no locant needs to be specified.
• Nitriles can also be named by replacing the -oic acid suffix of the corresponding carboxylic acid with -onitrile.

Structure of Carboxylic Acid Derivatives

• The carbonyl group consists of an O atom bonded to a C atom via a double bond in a planar, sp² hybridisation model similar to that of a ketone or an alkene.
• The heteroatom group is connected to this C=O unit via a s bond.
• To see these features, compare the JMOL images to the below.
• JMOL images of the other carboxylic acid derivatives can be found on the previous page.

• The resonance interaction of the carbonyl C=O with the lone pair of the adjacent heteroatom (structure III) has important implications on the reactivity

Reactivity of Carboxylic Acid Derivatives

Carboxylic acid derivatives react tend to react via nucleophilic acyl substitution where the group on the acyl unit, R-C=O undergoes substitution:

 
The observed reactivity order is shown below:

This reactivity order is important. You should be able to understand, rationalise and use it.

Back to the top

There are 3 resonance structures to consider for carboxylic acid derivatives.

Use the following series of electrostatic potential  maps to look at the electrophilicity of the carbonyl C in a example of each the more common carboxylic acid derivatives. Note how the blue colour gradually reduces in intensity down the series.

It is also useful to appreciate where aldehydes and ketones fit into the reactivity scale towards nucleophiles:

acyl halides > anhydrides > aldehydes > ketones > esters = carboxylic acids > amides

Overview of Nucleophilic Acyl Substitution

Overall nucleophilic acyl substitution is most simply represented as follows:

What does the term "nucleophilic acyl substitution" imply ?

A nucleophile is an electron rich species that will react with an electron poor species (Nu in scheme).
An acyl group is R-C=O (where R can be alkyl or aryl).... note the acyl group in both the starting material and the product.
A substitution note that the leaving group (LG) is replaced by the nucleophile (Nu).

There are two fundamental events in a nucleophilic acyl substitution reaction:

• formation of the new s bond to the nucleophile, Nu.
• breaking of the s bond to the leaving group, LG.

The difference in nucleophilic acyl substitution is that when the nucleophile adds to the electrophilic C, it becomes tetrahedral and an intermediate forms, then the leaving group departs as shown below:

Back to the top

Reactions for Interconverting Carboxylic Acids Derivatives

Here is a table that summarises the methods for interconverting carboxylicacid derivatives.  The more important reactions in emphasised in bold,and the reactions of the parent carboxylic acids in blue.

 Reactions of Carboxylic Acid Derivatives

Interconversion Reactions of Acyl Chlorides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Acyl chlorides are the most reactive of the carboxylic acid derivativesand therefore can be readily converted into all other carboxylic acid derivatives(see above).
• They are sufficiently reactive that they react quite readily with coldwater and hydrolyse to the carboxylic acid.
• The HCl by-product is usually removed by adding a base such as pyridine,C₆H₅N, or triethyl amine, Et₃N.

Interconversion Reactions of Acid Anhydrides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Acid anhydrides are the second most reactive of the carboxylic acid derivatives and can therefore, be fairly readily converted into the other less reactive carboxylic acid derivatives (see above).
• A base in often added to neutralise the carboxylic acid by product that is formed.

Back to the top

 Interconversion Reactions of Esters

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Esters can be converted into other esters (transesterification), the parent carboxylic acid (hydrolysis) or amides  (see above).
  • Transesterification : heat with alcohol and acid catalyst
  • Hydrolysis:  heat with aq. acid o base (e.g. aq. H₂SO₄ or aq. NaOH) .
  • Amide preparation :  heat with the amine, methyl  or ethyl esters are the most reactive

 Interconversion Reactions of Amides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Amides are the least reactive of the neutral carboxylic acid derivatives.
• The only interconversion reaction that amides undergo is hydrolysis back to the parent carboxylic acid and the amine.
• Reagents : Strong acid (e.g. H₂SO₄) or strong base (e.g. NaOH) / heat.
• More details on the following page.

 Reactions of Nitriles

Reaction type:  Nucleophilic Addition

Overview

• Nitriles typically undergo nucleophilic addition to give products that often undergo a further reaction.
• The chemistry of the nitrile functional group, C≡N, is very similar to that of the carbonyl, C=O of aldehydes and ketones. Compare the two schemes:

        versus 

• However, it is convenient to describe nitriles as carboxylic acid derivatives because:
  • the oxidation state of the C is the same as that of the carboxylic acid derivatives.
  • hydrolysis produces the carboxylic acid
• Like the carbonyl containing compounds, nitriles react with nucleophiles via two scenarios:

• Strong nucleophiles (anionic) add directly to the C≡N to form an intermediate imine salt that protonates (and often reacts further) on work-up with dilute acid.

            Examples of such nucleophilic systems are :  RMgX, RLi, RC≡CM, LiAlH₄
 

• Weaker nucleophiles (neutral) require that the C≡N be activated prior to attack of the Nu.
       This can be done using a acid catalyst which protonates on the Lewis basic N and makes the system more electrophilic.

 Examples of such nucleophilic systems are :  H₂O, ROH
 

Back to the top

Friedel-Crafts Acylation of Benzene

 

Reaction type: Electrophilic Aromatic Substitution

Summary

• Overall transformation :  Ar-H to Ar-COR(a ketone)
• Named after Friedel and Crafts who discovered the reaction.
• Reagent : normally the acyl halide (e.g. usually RCOCl) with aluminum trichloride, AlCl₃, a Lewis acid catalyst
• The AlCl₃ enhances the electrophilicity of the acyl halide by complexing with the halide
• Electrophilic species : the acyl cation or acylium ion (i.e. RCO ⁺ ) formed by the "removal" of the halide by the Lewis acid catalyst
• The acylium ion is stabilised by resonance as shown below. This extra stability prevents the problems associated with the rearrangement of simple carbocations:

• The reduction of acylation products can be used to give the equivalent of alkylation but avoids the problems of rearrangement  (more details)
• Friedel-Crafts reactions are limited to arenes as or more reactive than mono-halobenzenes
• Other sources of acylium can also be used such as acid anhydrides with AlCl₃

 Back to the top

Hydrolysis of Esters

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Carboxylic esters hydrolyse to the parent carboxylic acid and an alcohol.
• Reagents : aqueous acid (e.g. H₂SO₄) / heat,or aqueous NaOH / heat (known as "saponification").
• These mechanisms are among some of the most studied in organic chemistry.
• Both are based on the formation of a tetrahedral intermediate which then dissociates.
• In both cases it is the C-O bond between the acyl group and the oxygen that is cleaved.

Reaction under BASIC conditions:

• The mechanism shown below leads to acyl-oxygen cleavage (see step2).
• The mechanism is supported by experiments using ¹⁸O labeled compounds and esters of chiral alcohols.
• This reaction is known as "saponification" because it is the basis of making soap from glycerol triesters in fats.
• The mechanism is an example of the reactive system type.

Reaction under ACIDIC conditions:

• Note that the acid catalysed mechanism is the reverse of the Fischer esterification.
• The mechanism shown below also leads to acyl-oxygen cleavage (see step 5).
• The mechanism is an example of the less reactive system type.

Back to the top

Preparation of Esters

Reaction type:  Nucleophilic Acyl Substiution

Summary

• This reaction is also known as the Fischer esterification.
• Esters are obtained by refluxing the parent carboxylic acid with the appropraite alcohol with an acid catalyst.
• The equilibrium can be driven to completion by using an excess of either the alcohol or the carboxylic acid, or by removing the water as it forms.
• Alcohol reactivity order :  CH₃OH > 1^o > 2^o > 3^o (steric effects)
• Esters can also be made from other carboxylic acid derivatives, especially acyl halides and anhydrides, by reacting them with the appropriate alcohol in the presence of a weak base .
• If a compound contains both hydroxy- and carboxylic acid groups, then cyclic esters or lactones can form via an intramolecular reaction. Reactions that form 5- or 6-membered rings are particularly favourable.

Back to the top

Reduction of Esters
 

Reactions usually in Et₂O or THF followed by H₃O⁺work-ups

Reaction type:  Nucleophilic Acyl Substitution then NucleophilicAddition

Summary

• Carboxylic esters are reduced give 2 alcohols, one from the alcohol portion of the ester and a 1^o alcohol from the reduction of the carboxylate portion.
• Esters are less reactive towards Nu than aldehydes or ketones.
• They can only be reduced by LiAlH₄ but NOT by the less reactive NaBH₄
• The reaction requires that 2 hydrides (H^-) be added to the carbonyl group of the ester
• The mechanism is an example of the reactive system type.
• The reaction proceeds via a aldehyde intermediate which then reacts with the second equivalent of the hydride reagent (review)
• Since the aldehyde is more reactive than the ester, the reaction is not normally used as a preparation of aldehydes .

 Reactions of RLi and RMgX with Esters
 

Reaction usually in Et₂O followed by H₃O⁺ work-up

Reaction type:  Nucleophilic Acyl Substitution then NucleophilicAddition

Summary

·         Carboxylic esters, R'CO₂R'', react with 2 equivalents of organolithium or Grignard reagents to give tertiary alcohols.

·         The tertiary alcohol that results contains 2 identical alkyl groups (from R in the scheme)

·         The reaction proceeds via a ketone intermediate which then reacts with the second equivalent of the organometallic reagent (review)

·         Since the ketone is more reactive than the ester, the reaction cannot be used as a preparation of ketones.

·         The mechanism is an example of the reactive system type.

Hydrolysis of Amides

Reaction type:  Nucleophilic Acyl Substitution

Summary

• Amides hydrolyse to the parent carboxylic acid and the appropriate amine.
• The mechanisms are similar to those of esters.
• Reagents : Strong acid (e.g. H₂SO₄) / heat (preferred) or strong base (e.g. NaOH) / heat.

Reaction under ACIDIC conditions:

• Note that the acid catalysed mechanism is analogous to the acid catalysed hydrolysis of esters.
• The mechanism shown below proceeds via protonation of the carbonyl not the amide N (see step 1).
• The mechanism is an example of the less reactive system type.

Back to the top

Reduction of Amides
 

Reactions usually in Et₂O or THF followed by H₃O⁺ work-ups

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

Summary

• Amides, RCONR'₂, can be reduced to the amine, RCH₂NR'₂ by conversion of the C=O to -CH₂-
• Amides can be reduced by LiAlH₄ but NOT the less reactive NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followedby aqueous work-up.
• Note that this reaction is different to that of other C=Ocompounds which reduce to alcohols
• The nature of the amine obtained depends on the substituents present onthe original amide.
  ook at the N substituents in the following examples (those bonds don'tchange !)

• R, R' or R" may be either alkyl or aryl substituents.
• In the potential mechanism note that it is an O system that leaves.This is consistent with O systems being better leaving groups thatthe less electronegative N systems.

Hydrolysis of Nitriles

Reaction type:  Nucleophilic Addition then NucleophilicAcyl Substitution

Summary

• Nitriles, RC≡N, can be hydrolysedto carboxylic acids, RCO₂H via the amide, RCONH₂.
• Reagents : Strong acid (e.g. H₂SO₄) or strongbase (e.g. NaOH) / heat.

Reduction of Nitriles
 

Reactions usually in Et₂O or THF followed by H₃O⁺work-up

Reaction type: Nucleophilic Addition

Summary

• The nitrile, RC≡N, gives the 1^o amine by conversion of the C≡N to -CH₂-NH₂
• Nitriles can be reduced by LiAlH₄ but NOT the less reactive NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followed by aqueous work-up.
• Catalytic hydrogenation (H₂ / catalyst) can also be used giving the same products.
• R may be either alkyl or aryl substituents

Reactions of RLi or RMgX with Nitriles

Reaction usually in Et₂O or  THF

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

Summary:

• Nitriles, RC≡N, react with Grignard reagents or organolithium reagents to give ketones.
• The strongly nucleophilic organometallic reagents add to the C≡Nbond in a similar fashion to that seen for aldehydes and ketones.
• The reaction proceeds via an imine salt intermediate that is then hydrolysed to give the ketone product.

• Since the ketone is not formed until after the addition ofwater, the organometallic reagent does not get the opportunity to react with the ketone product.
• Nitriles are less reactive than aldehydes and ketones.
• The mechanism is an example of the reactive system type.

Back to the top

Spectroscopic Analysis

Spectroscopic Analysis of Acyl Chlorides

• IR  - presence of high frequency C=O, C-Cl too low to be useful

• ¹H NMR - only the protons adjacent to the C=O are particularly characteristic.

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  two absorption maxima p→p^* (<200 nm) n→p^* (~235 nm)
  • p electron from p of C=O
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Prominent peak corresponds to formation of acyl cations (acylium ions)

Spectroscopic Analysis of Anhydrides

• IR  - presence of two, high frequency C=O

• ¹H NMR - only the protons adjacent to the C=O are particularly characteristic.

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  two absorption maxima p→p^* (<200 nm) n→p^* (~225nm, diagnostic)
  • p electron from p of C=O
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Prominent peak corresponds to formation of acyl cations (acylium ions)
  

Spectroscopic Analysis of Esters

• IR  - presence of C=O, and two C-O bands (Csp²-O and Csp³-O bonds)

• ¹H NMR - deshielded proton of H-C-O is often recognisable, and H-C-C=O.

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  two absorption maxima p→p^* (<200 nm) n→p^* (~207 nm)
  • p electron from p of C=O
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Prominent peak corresponds to formation of acyl cations (acylium ions)

Spectroscopic Analysis of Amides

• IR  - presence of low frequency C=O, N-H stretches for 1^o or 2^o amides.

• ¹H NMR - N-H protons often broad,

• ¹³C NMR
  C=O typically 160-180 ppm (deshielding due to O)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  absorption maxima n→p^* (~215 nm)
  • n electron from O lone pair
  • p^* antibonding C=O

• Mass Spectrometry
  Molecular ion M+ often visible.
  A prominent peak corresponds to formation of acyl cations (acylium ions)

Spectroscopic Analysis of Nitriles

• IR  - very characteristic C≡N stretch (only C≡C is similar region)

• ¹H NMR - only protons adjacent to C≡N are likely to be characterisitic.

• ¹³C NMR
  C≡N typically 115 -125 ppm (deshielding due to N)
  • minimal intensity, characteristic of C's with no attached H's

•   UV-VIS
  Simple nitriles usually show no absorption above 200 nm.
   
   
• Mass Spectrometry

Molecular ion M+ is often weak or absent, but a weak M-1 peak due to loss of an a-H is often present.

Back to the top

                                                                                                                                                                                                                 Alcohols

                                                                                                                                                                                                                 Aldehydes & Ketones

                                                                                                                                                                        Alkyl Halide Reaction