Chemistry 213
Clark College
Carbonyl Compounds I: Carboxylic Acids and Their Derivatives
Carbonyl groups are excellent starting materials because they can be turned into so many different
things and are so common in bioactive molecules and synthetic polymer systems.
O
R = H, alkyl, aryl
Y = variety of things!
R
Y
Acyl
Group
The basic functional group:
The reactivity of this functional group relies on 2 factors:
1) Resonance contributors
O
O
C
C
!O
C
The carbon is an electrophile!
The partial positive charge
attracts a nucleophile for attack!
!+
2) The nature of “Y” – “Y” fits into two groups:
Y = H, C then Y is NOT a leaving group.
Y = halogen, O, N then Y IS a leaving group
We will first consider Class I carbonyl compounds, where Y is a leaving group. These compounds fall
under the category of carboxylic acids and derivatives.
Introduction and Nomenclature
O
O
O
O
O
O
O
R'
R
OH
R
Cl
R
Br
R
O
R'
R
OR'
R
N
R''
ester
acid
acyl/acid chloride
acyl/acid bromide
acid anhydride
-oate
-oic acid
-oyl chloride
-oyl bromide
amide
-oic anhydride
-amide
Typically carboxylic acids are named by naming the parent chain, dropping the –e and adding –oic
acid. The carbonyl carbon is assigned the #1 carbon in the chain. Please see p.671in your text book
for common names.
Examples:
O
OH
3-methylbutanoic acid
Z-2-methyl-4-hexenoic acid
OH
O
In addition to the common names, positions along the carbon chain are often referred to by greek
letters, not numbers.
O
$
"
OH
#
%
!
To name the various derivatives, it is often easier to name the parent carboxylic acid, and then modify
the acid name to reflect the derivative. We will show this, using 3-methylbutanoic acid as the parent:
Carbonyl Compounds I: Carboxylic Acids and Derivatives
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Chemistry 213
Clark College
OH
3-methylbutanoic acid
O
Cl
3-methylbutanoyl chloride
O
O
O
3-methylbutanoic anhydride
O
OCH2CH3
ethyl 3-methylbutanoate
O
* the -oate ending is also used
for carboxylate anions.
NH2
3-methylbutanamide
O
H
N
N-methyl-3-methylbutanamide
O
Some other acid derivatives:
• Cyclic esters are called lactones
O
O
H+, !
O
HO
1 2 3 4 5 OH
•
Cyclic amides are call lactams
O
H2N
1 2 3 4 5 OH
•
+ H2O
heat
H
N
O
+ H2O
Nitriles are considered derivatives since they can be converted into acids with water
(hydrolysis)
R C N
H3C C N
A nitrile
Ethanenitrile, common name is acetonitrile,
a common polar, aprotic solvent.
NMR/IR Review
NMR: acid H: δ = 11-15 ppm – very far downfield!
α – H: δ = 2.2 – 2.6 ppm – similar for all derivatives and aldehydes, ketones.
O
C
H
O
H
IR: C=O stretch = 1700 – 1800 cm-1 (strong) all derives are in this range, but vary
slightly.
C–O stretch = 1050 – 1250 cm-1 (medium) for acids, esters.
-O–H stretch = centered around 3000 – 3100 cm-1, very broad.
Carbonyl Compounds I: Carboxylic Acids and Derivatives
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Chemistry 213
O
O
H
C
Clark College
NMR: ester: C–H δ = 4.1 – 4.9 ppm
O
NMR: N–H: δ = 5 – 8 ppm, variable
N
IR: N–H = 3500 – 3700 cm-1 (medium)
H
Physical Properties of Acids and Derivatives
All derivatives have the following resonance structures:
O
R
O
O
R
R
O
R
The results:
• carbonyl bond strength weakens
• planarity/rigidity of functional group
• increased acidity of a carboxylic acid (pKa ~ 3–5)
Amides, acids hydrogen bond with each other.
O
H
"dimer" increases bpoiling points or acids and amides.
O
O
Hydrogen bonding in general contributes to the 2° and 3°
H
structure of proteins.
O
Reactions of Carboxylic Acids and Derivatives
Due to the partial positive charge on the carbonyl carbon, carbonyl compounds are susceptible to
nucleophilic attack at that position. The pi bond opens to form the tetrahedral intermediate. From this
point, three things can happen:
1) If Y is not a leaving group (aldehydes and ketones), the product is typically an alcohol (next
chapter!)
2) If Y is a leaving group, but Y- is a stronger base than Nuc-, the reaction goes backwards
(equilibrium favors reactants) so no net reaction occurs.
3) If Y is a leaving group, and Y- is a weaker base than Nuc-, the carbonyl is reformed and Y is
eliminated.
OH
O
O
R
Y
+
Nuc
R
Y
Nuc
Tetrahedral
Intermediate
H+
no LG
R
Y = LG
Y
Nuc
O
R
Nuc
For carboxylic acids and derivatives, the basic mechanism is: attack the carbonyl, generate the
tetrahedral intermediate, and regenerate the carbonyl by kicking off the leaving group.
R
O
O
O
Y
+
Nuc
R
Y
Nuc
R
Nuc
+ Y
All of the carbonyl reactions that we will consider in this chapter use this basic mechanism.
Carbonyl Compounds I: Carboxylic Acids and Derivatives
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Chemistry 213
Clark College
Reactivity of Acids and Derivatives
Most reactive
Compound
Leaving groups
O
Acid chloride
Cl
R
Cl
O
O
O
Anhydride
R
O
R'
R'
O
O
Ester
R’O
R
OR'
O
Acid
HO
R
OH
O
Amide
NH2
R
NH2
Relative Basicity
Very weak
HCl pKa ~ -2
Resonance of carboxylate
anion, acid pKa = 3 – 5
Weak
Moderate
Alcohol pKa = 14 – 17
Moderate
H2O pKa = 15.7
Strong
NH3 pKa ~ 33
Least reactive
A derivative is as reactive as the stability of the leaving group, the weaker the base, the more reactive!
This reactivity scale will determine how all derivatives react and are made  You can only convert a
derivative to another one lower on the list.
Example: an acid chloride can be turned into anything, but an ester can only be converted into an acid
or an amide.
Reactions and Syntheses
Carboxylic acids are very common starting materials, but are not very reactive, so we need to convert
them to another derivative first. There are two derivatives that can be made directly (and easily) from
an acid, an acid chloride and an ester.
1) Converting an Acid to an Acid Chloride
*Isn’t this going up the reactivity scale? Like an alcohol, we can convert an acid OH to a halogen by
making a better leaving group first!
O
O
SOCl
2
OH pyridine
R
O
R
Cl
Same mechanism as before!
O
PX3
X = Cl, Br
pyridine
OH
X
R
R
From the acid chloride all other derivatives can be made!
O
O
Cl
+
Nuc
O
O
O
Cl
O
Nuc
R
Carbonyl Compounds I: Carboxylic Acids and Derivatives
+ Cl
General Reaction
O
O
R
+ Cl
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Chemistry 213
Clark College
O
O
HO CH2CH3
You can also start with RO-
Cl
O
CH2CH3 + HCl
Often soaked up by
solvent/base
O
O
H
2
Cl
CH3
N
CH3
CH3
N
CH3
+ N(CH3)2H2Cl
When making an amide, there must be at least one hydrogen on the amine. 2 equivalents
of the amine is needed to react as a base with the HCl generated. If the amine is
expensive/precious, pyridine or triethylamine (TEA) is used as a solvent and base
You can also remake the acid through a hydrolysis reaction, where water is added to the acid chloride.
O
O
H2O
Cl
R
R
OH
Mechanism for the amide synthesis:
O
O
O
H
Cl
CH3
N
CH3
Cl
N H
H
O
Cl
CH3
N
CH3
CH3
N
CH3
N
2) From an acid, we can also directly make the ester, since the pKa’s of alcohols and water are
similar. The Fischer Esterification is an acid catalyzed mechanism, and is entirely an
equilibrium process and controlled by Le Châtelier’s Principle. Often, ethanol is often used as
the alcohol – it comes from renewable feedstocks (corn) and is cheap! An acid catalyst is
necessary to enhance the electrophilicity of the carbonyl carbon, as the alcohol is a weak
nucleophile.
Acid-catalyzed Esterification (Fischer Esterification)
O
O
H+
CH2CH3 + H O
HO CH2CH3
OH
2
O
Mechanism:
O
H
H+
O
OH
OH
OH
HO CH2CH3
EtOH
H
O
O
O
Et
H
O
H
O
OH
OH
Et
O
OH
Et
O
OH
Et
H
EtO H
OH2
Et
O
O
Et
Carbonyl Compounds I: Carboxylic Acids and Derivatives
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Chemistry 213
Clark College
From the ester, amides can be made.
O
Et
CH3
H
O
N
CH3
O
+
CH3
N
CH3
EtOH
Only 1 equivalent of the amine is needed, since the other product is an alcohol, which is not nearly as
acidic as HCl (pKa of 16 vs -2).
Hydrolysis
Esters can also be hydrolyzed back into the carboxylic acid, either through the reverse reaction of the
Fischer Esterification, or through a base-promoted reaction known as saponification (because it is the
same reaction used in the soap-making process).
O
O
H+/ H2O
+ CH3OH
Acid-catalyzed:
O H
O CH3
O
Base-promoted:
(saponification)
O CH3
O
1) OH-, H2O
2) H+
+ CH3OH
O H
Mechanism:
O
O
O
OH
HO O CH3
O CH3
+
CH3O
O H
O
H+
O
O H
O
Why would you make an ester, if only to remove it? Why would there be two methods to do this?
Esters as Protecting Groups
A protecting group is used to protect a functional group from possible side reactions in a synthetic
scheme. An example:
O
OH
Synthesize
from benzoic acid.
This carbon group can be added by a Friedel-Crafts alkylation or with a Gilman
reagent, but both methods fail in the presence of an acid! We will use an ester
to protect the acid group, and then remove it after the carbon group is added.
O
O
OH
EtOH
H+
O
OEt Cl
AlCl3
O
OEt
1) OH2) H+
OH
Basic hydrolysis is used since aqueous
acid will convert the alkene to an alcohol.
Carbonyl Compounds I: Carboxylic Acids and Derivatives
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Chemistry 213
Clark College
General Examples:
O
O
O
F
Et
O
F
Cl
O
O
H2N
HO
pyridine
N
H
F
O
F
O
O
O
EtOH
O
O
O
H
N
O
O
heat
O
Et
N
O
Cl
O
OH
O
O
OH
pyridine
2 NH3
O
OEt OEt
Carbonyl Compounds I: Carboxylic Acids and Derivatives
O
NH2 NH2
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