CHAPTER 20

Carboxylic Acid Derivatives

20-1 Relative Reactivities, Structures, and Spectra of
Carboxylic Acid Derivatives
Carboxylic acid derivatives undergo substitution reactions via the
(often acid- or base-catalyzed) addition-elimination sequence:
The relative reactivities of the substrates follow a consistent
order:
The order of reactivity depends upon the ability of L to act as a
leaving group and what effect it has on the adjacent carbonyl
function.
Lone pairs on L can be delocalized onto the carbonyl oxygen:

The rightmost resonance form is most important

in amides and somewhat less important in esters.
Amides and esters are strongly stabilized by
resonance.
Anhydrides are more reactive than esters because
the lone pairs on the central oxygen are shared
over two carbonyl groups.
Alkanoyl halides are least stable because of their
electronegatives and the poor overlap between
their p-orbitals and those of carbon.
20-1 Relative Reactivities, Structures, and Spectra of
Carboxylic Acid Derivatives
The greater the resonance, the shorter the C-L
bond.
The structures of carboxylic acid derivatives are directly related to
the extent of resonance.
In progressing from alkanoyl halides to exters and amides, the C-
L bond becomes progressively shorter (increased double bond
character).
The NMR spectra of N,N-dimethylformamide at room temperature
exhibits two singles for the two methyl groups.
•Bond rotation about the C-N bond in this molecule is very
slow on the NMR time scale.
•The measured barrier to this rotation is about 21 kcal mol-1.

The amide nitrogen possesses sp2 hybridization.

The resultant planarity of the amide group is the single most
important determinator of structure (thus function) in peptides
and proteins.
IR spectra of amides and esters also indicate the presence of
resonance in the structures.
The C=O bond is weakened which causes a corresponding
decrease in the carbonyl stretching frequency.

The IR spectra of monomeric acetic acid displays a carbonyl

stretching frequency of 1780 cm-1, similar to that of anhydrides.
The 13C NMR signals of the carbonyl carbons in carboxylic acid
derivatives are less sensitive and fall into a narrow range near
170 ppm.
The mass spectra of carboxylic acid derivatives typically contain
peaks resulting from both -cleavage and McLafferty
rearrangement.
Carboxylic acid derivatives are basic and acidic.
Resonance in carboxylic acid derivaties affects their basiciy
(protonation at the carbonyl oxygen) and their acidity (enolate
formation).
Protonation becomes easier as L becomes more electron-
donating.
The acidity of the -hydrogens also increases along the series:
20-2 Chemistry of Alkanoyl Halides
The alkanoyl halides are named after the alkanoic acid from which
they are derived.
The halides of cycloalkanecarboxylic acids are called
cycloalkanecarbonyl halides.
Alkanoyl halides undergo addition-elimination reactions:
Water hydroyzes alkanoyl chlorides to carboxylic
acids.
Alkanoyl chlorides react with water to give the corresponding
carboxylic acids and hydrogen chloride.
Water hydroyzes alkanoyl chlorides to carboxylic
acids.
Alkanoyl chlorides react with water to give the corresponding
carboxylic acids and hydrogen chloride.
Alcohols convert alkanoyl chlorides into esters.
Esters can be effectively produced by the reaction of alkanoyl
chlorides with alcohols.
An alkali metal hydroxide, pyridine or a tertiary amine is usually
added to neutralize the HCl produced by the reaction.

The basic or neutral conditions employed in this method, avoids

the equilibrium problem of acid catalyzed ester formation.
Amines convert alkanoyl chlorides into amides.
Ammonia, primary amines, and secondary amines convert
alkanoyl chlorides into amides.
Aqueous ammonia can be used for the synthesis of simple amines
since it is a much stronger nucleophile than water.
The HCl formed is neutralized by base, which can be excess
amine.
The mechanism of amide formation from alkanoyl chlorides is
addition-elimination:

Tertiary amines cannot form amides since they do not possess a

proton to lose during the last step of the reaction.
Organometallic reagents convert alkanoyl chlorides
into ketones.
Ketone formation is best achieved by using diorganocuprates
rather than RLi or RMgX. The latter are unselective and tend to
attack more than once leading to alcohol formation.
Reduction of alkanoyl chlorides results in
aldehydes.
Alkanoyl chlorides are reduced to alcohols when sodium
borohydride or lithium aluminum hydride are used directly.
The reaction stops at the aldehyde if LiAlH4 is first reacted with
three molecules of 2-methyl-2-propanol (tert-butyl alcohol) which
reduces the nucleophilicity of the remaining hydride ion.
20-3 Chemistry of Carboxylic Anhydrides

Carboxylic anhydrides are named by adding the term anhydride

to the acid name (or names, if a mixed anhydride). This method
also applies to cyclic derivatives.
The reactions of anhydrides with nucleophiles are the same as for
alkanoyl halide, only less vigorous.
The leaving group is a carboxylate instead of a halide.
Cyclic anhydrides undergo similar reactions which lead to ring
opening.

Alkanoyl halides are difficult to store for extended periods without

undergoing hydrolysis from atmospheric moisture.
Anhydrides, although less reactive towards nucleophiles, are more
stable and many are commercially available.
For these reasons anhydrides are often preferred for the
preparation of many carboxylic acid derivatives.
20-4 Chemistry of Esters
Esters are alkyl alkanoates.
Esters are named alkyl alkanoates, and the ester grouping as a
substitutent is called alkoxycarbonyl.
Cyclical esters are named oxa-2-cycloalkanone (common name, lactone).
The common name is preceeded by , , ,etc., depending upon ring size.
Esters are prevalent in plants and play biological roles in the
animal kingdom, often as pheromones.
(Z)-7-dodecenyl acetate is a component in the pheromone
mixture of several species of moths, as well as the mating
pheromone of the elephant.

In industry, lower esters such as ethyl acetate and butyl acetate

are used as solvents.
Butyl butanoate has replaced trichloroethane as a cleaning
solvent in the electronics industry.
Higher nonvolatile esters are used as softeners (plasticizers) for
brittle polymers.
Esters hydrolyze to carboxylic acids.
Esters undergo nucleophilic substitution reactions by means of
addition-elimination pathways, altho with reduced reactivity
compared to halides and anhydrides.
Esters are cleaved to carboxylic acids and alcohols in the presence
of excess water an a strong acid. This reaction requires heating
to proceed at a reasonable rate, however.
The acid catalyzed hydrolysis of esters proceeds via the reverse of
the acid-catalyzed esterification mechanism.
Strong bases catalyze the hydrolysis of esters through an
addition-elimination mechanism. The strong base converts the
poor nucleophile, H2O, into the more highly nucleophilic ion, OH-.

Unlike acid catalyzed hydrolysis, base catalyzed hydrolysis is

driven to completion by the last step, which converts the
carboxylic acid into a carboxylate ion.
Ester hydroysis is often carried out using hydroxide ion itself, in at
least stoichiometric amounts.
Transesterficiation takes place with alcohols.
The direct conversion of one ester into another without
proceeding through the free carboxylic acid can be carried out by
reacting a second alcohol with an ester in the presence of strong
acid.
This process is called transesterification and is reversible. To shift
the equilibrium, a large excess of the second alcohol is used.
Lactones may be ring opened by transesterification.

Acid catalyzed transesterifications proceed by protonation of the

carbonyl oxygen and subsequent attack by the alcohol.
Base catalyzed transesterifications proceed by deprotonation of
the alcohol and subsequent attack at the carbonyl carbon.
Amines convert esters into amides.
Amines are more nucleophilic than alcohols.
Esters readily transform into amides by treatment with an amine
and subsequent heating (catalyst not required).
Grignard reagents transform esters into alcohols.
Two equivalents of a Grignard reagent with react with a normal
ester to form a tertiary alcohol. In the case of a formate ester, a
secondary alcohol is formed.
Esters are reduced by hydride reagents to give
alcohols or aldehydes.
LiAlH4 will reduce an ester to an alcohol. Only ½ equivalent of
LiAlH4 is required per ester function.
The use of the milder reducing agent, bis(2-
methylpropyl)aluminum hydride at low temperatures in toluene,
allows the reaction to be stopped at the aldehyde oxidation state.
Esters form enolates that can be alkylated.
Treatment of esters with strong base at low temperatures
produces ester enolates (acidic -hydrogens). These enolates
react like ketone enolates, undergoing alkylations.

The pKa of esters is about 25, thus the ester enolates behave as
strong bases. Side reactions include E2 processes and
deprotonations.
20-5 Esters in Nature: Waxes, Fats, Oils, and Lipids
Waxes are simple esters, whereas fats and oils are
more complex.
Waxes are esters containing a long-chain carboxylic acid and a
long-chain alcohol.
Waxes are found in nature as hydrophobic and insulating coatings
on skin, fur, feathers, fruits and leaves.
Some waxes are liquid or very soft at room temperature and are
used as lubricants (spermaceti, beeswax).

Lanolin, a sheep’s wool wax, is used as a cosmetic base.

Carnauba wax, from the leaves of a Brazilian palm, is a mixture of
several waxes used as a floor and automobile wax.
Triesters of 1,2,3-propanetriol (glycerol) with long chain
carboxylic acids, triaglycerides, constitute fats and oils

The acids in triglycerides are generally unbranched and contain an

even number of carbon atoms.
Any double bonds present are usually cis.
Fats:
•Biological energy reserves
•Solvents for food flavors and colors
•Contribute to feeling of “fullness” after eating
•Implicated in atherosclerosis when containing the saturated
fatty acids hexadecanoic-, tetradecanoic-, and dodecanoic-
acids.
•(Z)-9-octadecenoic (oleic) acid found in olive oil implicated in
low rates of heart disease.
Lipids are biomolecules soluble in nonpolar
solvents.
Nonpolar solvent extracts a wide range of non-polar substances
from biological materials: terpenes, steroids, fats, oils, and other
lipids.
Among the other lipids are phospholipids, important components
of cell membranes. Lecithin is a phosphoglyceride lipid found in
the brain and central nervous system.
Long chain carboxylic acids and phospholips are termed
amphipathic: they have hydrophobic and hydrophilic ends.
When disolved in water, fatty acids and some phospholipids form
structures called micelles. Most phospholipids form a more
complicated structure called a lipid bilayer when dissolved in
water.

Lipid bilayers are the basic components of cell membranes.

20-6 Amides: The Least Reactive Carboxylic Acid
Derivatives
Amides are named alkanamides, cyclic amides are
lactams.
Amides are called alkanamides, the –e in alkane having been
replaced by –amide.
In the common names, -ic is replaced by –amide.
In cyclic systems –carboxylic acid is replaced by –carboxamide.
Nitrogen substituents are indicated by the prefix N- or N,N-.
Amides can be primary, secondary, or tertiary.
Derivatives of carbonic acid, H2CO3, include ureas, carbamic acids
and carbamic esters.
Cyclic amides are called lactams – the systematic name is aza-2-
cycloalkanones. The naming rules follow those used for lactones.
Amide groups link the amino acid subunits that make up peptides
and proteins.
Many simpler amides possess biological activity.
Anandamide, the amide of arachidonic acid with 2-
aminoethanol binds to the same brain receptor as does
tetrahydrocannabinol, the active ingredient in marijuana.

Anandamide is also found in chocolate, which may account for

the phrase, “addicted to chocolate”.
Amide hydrolysis requires strong heating in
concentrated acid or base.
Amides are the least reactive of the carboxylic acid derivatives.
Nucleophilic addition-elimination reactions of amides generally
require relatively harsh conditions.
Basic hydrolysis produces the carboxylate salt and the amine.
Amides can be reduced to amines or aldehydes.
Unlike alcohols, reduction of amines using LiAlH4 produces amines
instead of alcohols.
Reduction of amides using bis(2-methylpropyl) aluminum hydride
produces aldehydes (the same as the reaction with esters).
20-7 Amidates and Their Halogenation: The Hofmann
Rearrangement
In amides, the hydrogens on both the nitrogen and -carbon are
acidic. Deprotonation of the nitrogen to form an amidate ion is
more favorable, however.

From a practical point of view, deprotonation of the -carbon can

only occur for tertiary amines, in which the nitrogen is blocked.
In the presence of base, a primary amide undergoes a special
halogenation reaction called the Hofmann rearrangement.
When the alkyl group is chiral, its original stereochemistry is
retained during the course of the rearrangement.
20-8 Alkanenitriles: A Special Class of Carboxylic Acid
Derivatives
Nitriles, RC N, are considered derivatives of carboxylic acids
because the carbon atom is in the same oxidation as the carboxy-
carbon, and nitriles can be converted into other carboxylic acid
derivatives.
In IUPAC nomenclature, nitriles are named from
alkanes.
The systematic naming of nitriles is as alkanenitriles. The –ic
acid ending of the carboxylic acid is usually replaced with –
nitrile.
The chain is numbered as in carboxylic acids.
Similar rules apply to dinitriles derived from carboxylic acids.
As a substituent, -CN is called cyano.
Cyanocycloalkanes are called cycloalkanecarbonitriles.
The common name, benzonitrile, is generally used rather than the
systematic benzenecarbonitrile.
The C N bond in nitriles resembles the C C bond in
alkynes.
Both atoms in the nitrile group are sp hybridized with a lone
electron pair occupying an sp orbital pointing away from the
molecule along the C-N axis.

In the IR spectrum, the C N stretching vibration appears at about

2250 cm-1 (same range as C C but more intense).
The 13C NMR absorption for the nitrile carbon is at lower field
( ~112-126 ppm) than that of the alkynes ( ~65-85 ppm)
because nitrogen is more electronegative than carbon.
Nitriles undergo hydrolysis to carboxylic acids.
Nitriles can be hydrolyzed to carboxylic acids, however the reaction
conditions are stringent, requiring concentrated acid or base at high
temperatures.
Organometallic reagents attack nitriles to give
ketones.
Strong nucleophiles, such as organometallic reagents, add to
nitriles to give anionic imine salts. Work-up with aqueous acid
gives the neutral amine, which is rapidly hydrolyzed to the
ketone.
Reduction of nitriles by hydride reagents leads to
aldehydes and amines.
Bis(2-metehylpropyl)aluminum hydride (DIBAL) adds to a nitrile
only once (as with esters and amides) to give an imine derivative.
Aqueous hydrolysis then produces an aldehyde.
Treatment of nitriles with strong hydride reducing agents results
in double hydride addition, yielding an amine upon aqueous work-
up. LiAlH4 is the best reagent for this purpose.
20 Important Concepts

1. Electrophilic Reactivity - of the carbonyl carbon

in carboxylic acid derivatives:
• Weakened by good electron-donating substituents.
• Effect accounts for increased basicity:
• Alkanoyl halides < anhydrides < esters < amides.
• With amides the large effect causes hindered rotation
about the amide bond on the NMR time scale.
2. Nomenclature – of carboxylic acid derivatives:
• Alkanoyl halides
• Carboxylic anhydrides
• Alkyl alkanoates
• Alkanamides,
• Alkanenitriles
20 Important Concepts

3. IR Spectroscopy – of carboxylic acid derivatives:

• Alkanoyl chlorides – 1790-1850 cm-1
• Anhydrides – 1740-1790 cm-1 and 1800-1850 cm-1
• Esters – 1735-1750 cm-1
• Amides – 1650-1690 cm-1
4. Reactions Of Carboxylic Acid Derivatives –
• Water – (acid or base catalysis) hydrolyze to
corresponding carboxylic acid.
• Alcohols – react to form esters.
• Amines – react to form amides.
• Grignard Reagents – react to form ketones
• Esters may react further to form alcohols.
• Hydrides – react to form aldehydes, alcohols, or
amines.
20 Important Concepts

5. Natural Products –
• Waxes – Long-chain esters.
• Oils and Fats – Triesters of glycerol
• Hydrolysis yields soaps.
• Phospholipids – Triglycerides containing phosphoric
acid ester subunits.
• From micelles and lipid bilayers due to polar head and
hydrophobic tail.
6. Transesterification – Used to convert one ester
into another.
20 Important Concepts

7. Nitrides - Similar to alkynes. Carbon and Nitrogen

are sp2 hybridized.
• IR - ~2250 cm-1 stretch.
• NMR – adjacent protons are deshielded. 13C
absorption for nitrile carbon is at low field (δ ~ 112-
126 ppm)
8. Mass Spectrometry – Magnetic separation of
ionized molecules on the basis of molecular weight.
• Ionizing beam may fragment molecules into smaller
particles which are separated and recorded as the
mass spectrum.
• Certain elements (Cl, Br) produce recognizable
isotopic patterns.
• The fragmentation patterns can be used to deduce
the structure of a molecule.
20 Important Concepts

9. High-Resolution Mass Spectrometry – Allows

molecular formula determination from exact mass
values.