Carboxylic acids and Derivatives

O O O O O O

C C R C C C C
R OH R O R O R R Cl R NH2
Carboxylic Ester Carboxylic Acid Chloride Amide
Acid Acid
Anhydride
Preparation: Oxidation (Which of the follow reactions will produce carboxylic acids?

O
HO
KMnO4/NaOH
KMnO4/NaOH
H

O
H3C
KMnO4/NaOH KMnO4/NaOH
CH3

Carbonyl compounds 1
 Nucleophilic Addition-Elimination at the Acyl Carbon
Recall that aldehydes and ketones undergo nucleophilic addition to
the carbon-oxygen double bond

The nucleophile reacts at the carbonyl group to form a tetrahedral

intermediate
The tetrahedral intermediate eliminates a leaving group (L)
The carbonyl group is regenerated; the net effect is an acyl substitution

Carbonyl compounds 2
 To undergo nucleophilic addition-elimination the acyl compound must have a
good leaving group or a group that can be converted into a good leaving group
Acid chlorides react with loss of chloride ion
Anhydrides react with loss of a carboxylate ion
Esters, carboxylic acids and amides generally react with loss of the
leaving groups alcohol, water and amine, respectively (These leaving
groups are generated by protonation of the acyl compound)
Aldehydes and ketones cannot react by this mechanism because they
lack a good leaving group

Carbonyl compounds 3
 Relative Reactivity of Acyl Compounds
The relative reactivity of carboxylic acids and their derivatives is as follows:

In general, reactivity can be related to the ability of the leaving group to depart
Leaving group ability is inversely related to basicity
Chloride is the weakest base and the best leaving group
Amines are the strongest bases and the worst leaving groups
As a general rule, less reactive acyl compounds can be synthesized from more
reactive ones

Synthesis of more reactive acyl derivatives from less reactive ones

is difficult and requires special reagents (if at all possible)

Carbonyl compounds 4
 Acid Chlorides
Synthesis of Acid Chlorides
Acid chlorides are made from carboxylic acids by reaction with thionyl chloride,
phosphorus trichloride or phosphorus pentachloride
These reagents work because they turn the hydroxyl group of the carboxylic acid
into an excellent leaving group

Carbonyl compounds 5
 Mechanism with Thionyl Chloride
Mechanism 1 (Nucleophilic addition-elimination reaction)

Carbonyl compounds 6
 Mechanism with Phosphorous Trichloride
(Nucleophilic addition-elimination reaction)
δ Cl O
O O
- Cl
+ δ+ C Cl +

C P
+
R C O P
R O P + Cl
R OH Cl Cl Cl
δ δ Cl Cl H
H
- -
O
Cl
+ reacts two more times
C HO P
R Cl Cl
Reactions of Acyl Chlorides
Acyl chlorides are the most reactive acyl compounds and can be used to make any of
the other derivatives
Since acyl chlorides are easily made from carboxylic acids they provide a way to
synthesize any acyl compound from a carboxylic acid
Acyl chlorides react readily with water, but this is not a synthetically useful reaction

Carbonyl compounds 7
 δ
-
δ+

Carbonyl compounds 8
Mechanism 2

Mechanism 3

Carbonyl compounds 9
 All the Mechanisms are similar.
The main difference is the nucleophile

R C O
R OH
R NH2
δ O O
O +
- +

δ+ C H3C C Nu H H3C C Nu H + Cl
H-Nu
H3 C Cl δ
- Cl
sp3 tetrahedral H-Nu
intermediate or solvent

O
+

H3C C Nu + NuH2

Carbonyl compounds 10
 Carboxylic Acid Anhydrides
Acid chlorides react with carboxylic acids to form mixed or symmetrical anhydrides
It is necessary to use a base such as pyridine to remove the proton on the –OH group

This is not a mechanism

It is a thought process forms tetrahedral intermediate
δ
-
δ+

chloride leaves

Sodium carboxylates react readily with acid chlorides to form anhydrides

δ
-
δ+

Carbonyl compounds 11
Cyclic anhydrides with 5- and 6-membered rings can be synthesized
by heating the appropriate diacid
δ
-
δ+

Reactions of Carboxylic Acid Anhydrides

Carboxylic acid anhydrides are very reactive and can be used to
synthesize esters and amides
Hydrolysis of an anhydride yields the corresponding carboxylic acids

Carbonyl compounds 12
 δ
-
δ+

Carbonyl compounds 13
Mechanism 4

Carbonyl compounds 14
 Esterification
Mechanism (acid catalyzed)
O O
H2SO4 or HCl
C C R2
R1 OH R2 OH R1 O
H
+ H H O
O
H + O O
R2 OH R1 C OH
C
C C
R1 OH +
R1 OH R1 + OH O
H R2
H
Proton O O
+
Transfer
R1 C OH2 C R2 + H2O + H+
R1 O (regenerates catalyst)
O
R2
Esterification is an equilibrium reaction. To make the reaction favor the ester
side use excess of either reagent (the alcohol or acid) and remove water. To
push the reaction to the hydrolysis side of the equilibrium use a large excess of
water by refluxing with a dilute acid.
Carbonyl compounds 15
Mechanism 5

H This is not a mechanism

O O +
O O It is a thought process
OH
+ O H+ O

Carbonyl compounds 16
 Examples
+ 3
O O
O O CH3OH O O 4
1
4 H
1 H2SO4 2

2 3 This is not a mechanism

It is a thought process

H
+
O
H2SO4
H3C C OCH2CH3 + CH2OH

Excess Trans-Esterification

O sp2
Br Br
+ acetone
C +
H3C ONa

Carbonyl compounds 17
 Lactones
γ­ or δ­Hydroxyacids undergo acid catalyzed reaction to give cyclic esters 
known as γ­ or δ­lactones, respectively

Carbonyl compounds 18
 Amides
Amides can be prepared from acyl chlorides, acid anhydrides, esters,
carboxylic acids and carboxylic salts

O NH3
O
C R NH2
+ H-Leaving Group
R Leaving Group + C
R NH R NR2

Carbonyl compounds 19
 nucleophile
(base) Examples
CH3 O H O H
Oδ HN + +
- H3C C N CH3 H3C C N CH3 + Cl
CH3CCl +
δ+ Cl
electrophile
(acid)

O CH3
NH +
NH2 + H3C C N
CH3
Excess CH3

O O O

NHCH3 H 3 O+ NHCH3
O + H2N CH3
O +
OH
NH3CH3
O O O

Carbonyl compounds 20
 Examples
δ
-
O Oδ O
δ+ -
+ NH3 HOCH2CH2CH2CNH2

O O O
+
heat
CH3COH + NH3 CH3CO + NH4 CH3CNH2 + H2O
solid salt
dehydration of the salt produces the amide
but generally in poor yield

A good way to synthesize an amide is to convert a carboxylic acid to an acid

chloride and to then to react the acid chloride with ammonia or an amine
Dicylohexylcarbodiimide (DCC) is a reagent used to form amides from carboxylic
acids and amines

Carbonyl compounds 21
DCC activates the carbonyl group of a carboxylic acid toward
nucleophilic addition-elimination

Carbonyl compounds 22
 Hydrolysis (acid or base) of Carboxylic Acid Derivatives

δ
O
-O
Dilute acid or base C
C H3C
δ+ H OH + H Derivative
H3C Derivative Heat
O
H
When using acid conditions it is called a hydrolysis reaction.
When using basic conditions it is called saponification

O O
C H2SO4/H2O
C
H3C OCH3 H3C OH + H OCH3

O O
C NaOH/H2O C
H3C NH2 H3C OH + H NH2

Carbonyl compounds 23
Mechanism 6 Mechanism for the acid catalyzed Hydrolysis of an Ester:

Carbonyl compounds 24
Mechanism 7 Mechanism for the Saponification of an Ester:

Carbonyl compounds 25
 Mechanism for the hydrolysis of the Nitrile

H+ + +
H2O R C N H
R C N R C N H R C N H
OH2
+

Proton +
H O H
R -H + H+
Transfer C N R C N
H
O H H
amide
H H
H H O O
+ H Proton H
O H O H H2O Transfer
+

R C N R C N H
R C N R C N
+ H H
H H OH2 OH
+

O
- H+ H+ +
R C OH + NH3 NH4

Carbonyl compounds 26
 What are the products of the following reactions: (not balanced)
+ O +

δ+ δ NaOH/H2O NaOH/H2O
R C -N R C NH2 RCO2 + NH3 + HO
O
+
+ H2SO4/H2O
H2SO4/H2O R C NH R C NH2 RCO2H + NH4
R C N

O O
+
C NaOH/H2O C NH2 RCO2 + NH3
R NH2 R
OH
O
+ H
O
+
H2SO4/H2O
C RCO2H + NH4
R C
NH2 R NH2
O
O
C NaOH/H2O
C RCO2 + Cl
R Cl
R Cl H
O OH
+
O
H2SO4/H2O RCO2H + Cl
C
R Cl C
R compounds
Carbonyl Cl 27
Mechanism 8 Urethane

Carbonyl compounds 28
Mechanism 9 Urea

Carbonyl compounds 29
 O
Summary
R Cl
O
NaCl
R ONa

ROH O O

R O R RR'NH
HCl
HCl
O

ROH
R OH RR'NH
O

R OH

R
R O

All downward arrows ROH

RR'NH
indicates that this
conversion is possible in
O
one step
R
R N
R' R' could be a hydrogen

Carbonyl compounds 30
 Aldehydes and Ketones
The carbonyl group is susceptible to
nucleophilic attack.
Electrophile Nucleophile
(acid) (base)

Addition of a Strong Nucleophile

Carbonyl compounds 31
 Reactivity of Aldehydes and Ketones
Aldehydes are generally more reactive than ketones

Two factors: 1) the amount of positive charge on the carbonyl carbon and
2) steric interaction.
The tetrahedral carbon resulting from addition to an aldehyde is less sterically
hindered than the tetrahedral carbon resulting from addition to a ketone
Aldehyde carbonyl groups are more electron deficient because they have only
one electron-donating group attached to the carbonyl carbon
δ− O δ− O δ− O

R δ+ R R δ+ H H δ+ H
alkyl groups are electron donating
increasing reactivity
O O
O

decreasing steric interaction increasing reactivity

Carbonyl compounds 32
Acid catalyzed Nucleophilic Addition of a Nucleophile

Carbonyl compounds 33
 Reaction with Water

δ− O base OH
nucleophile H +

δ + H2O hydrate (generally

R
+ R R not stable)
R OH
acid
electrophile
δ− O OH
H+ chloral hydrate chief
+ H2O ingredient in knock out drops
Cl3C δ H Cl3C H
OH
+
chloral
electron withdrawing makes carbonyl carbon
more reactive (more positive)
Formalin is a 10% solution of formaldehyde
OH in water; used as a disinfectant or to
O H+ preserve biological specimens.
methylene hydrate HOCH2OH reacts
+ H 2O H
H with various parts of proteins to form
H H OH methylene cross-links to fix and stabilize
formaldehyde
the proteins and stop decomposition.
no alkyl groups Carbonyl compounds 34
 Oxygen Nucleophiles
Reaction with alcohols: Acetal and Ketal formation
OH OR2
O
R2OH H 3 O+
R C R1 R C R1 + H 2 O + H +
R R1 H 3 O+
OR2 OR2

R1 = alkyl or H hemi-ketal R1 = alkyl ketal R1 = alkyl

memi-acetal R1 = H acetal R1 = H
acid catalyst

Example
OH OCH2CH3
O CH3CH2OH, H +
H 3 O+
H3 C C H H3 C C H + H 2O + H+
C -H2O
H3C H OCH2CH3
OCH2CH3

memi-acetal
acetal R1 = H

Carbonyl compounds 35
 base Mechanism H
acid nucleophile O
δ + H H
electrophile
- O H+ O O CH3CH2OH
H3 C C H
H3 C C H H3 C C H H3 C C H O CH2CH3
δ+ + +
H
resonance structures
both are occurring at the same time

H2O great leaving group

base H acid H +
H
O O
- H+ H+ - H2O +

H3 C C H H3 C C H H3 C C H
acid/base O CH2CH3
not shown O CH2CH3 O CH2CH3
hemi-acetal
H electrophile
+

O CH2CH3 O CH2CH3
-H + CH3CH2OH H3 C C H
H3 C C H H3 C C H
nucleophile O CH2CH3
acid/base +
O CH2CH3 not shown O CH2CH3

acetal resonance stabilized

Carbonyl compounds carbocation 36
 OH OR2
O
R2OH H 3 O+
R C R1 R C R1 + H 2 O + H +
R R1 H 3 O+
OR2 OR2

R1 = alkyl or H hemi-ketal R1 = alkyl ketal R1 = alkyl

memi-acetal R1 = H acetal R1 = H
acid catalyst

This is a reversible reaction and usually the reverse reaction is favored (aldehyde).
The reaction can be made to go forward by dissolving the aldehyde in an excess of
anhydrous alcohol and add an anhydrous acid or by removing the water that is
formed in the reaction. This can be done by azeotropic distillation with benzene, or
adding molecular sieves that absorb water or by using a quenching agent like AlCl2

Carbonyl compounds 37
 Acetal formation from ketones and simple alcohols is less
favorable than formation from aldehydes

Formation of cyclic 5- and 6- membered ring acetals from ketones is,

however, favorable
Such cyclic acetals are often used as protecting groups for aldehydes
and ketones
These protecting groups can be removed using dilute aqueous acid

Carbonyl compounds 38
Mechanism 10

Carbonyl compounds 39
 Nitrogen Nucleophiles
The Addition of Primary and Secondary Amines
Aldehydes and ketones react with primary amines (and ammonia)
to yield imines
They react with secondary amines to yield enamines

Carbonyl compounds 40
Mechanism 11

The reaction is pH dependant. If it is too acidic RNH2 will protonate (RNH2 + H+ → RNH3+) and will
no longer be a nucleophile. Elimination of water increases with increasing pH but will slow
down the first step of the reaction. The optimal pH is 3-4. Some of the amine will be protonated
but there will be enough free base for a reaction to occur.
Carbonyl compounds 41
 Reactions

reagent (R) – NH2 Product

hydroxylamine (HO) - NH2 OH an oxime
N

R1 R2
NH2
hydrazine (H2N)-NH2 a hydrazone
N

R1 R2

R1
arylhydrazine (Ar-NH)-NH2 an
N H arylhydrazone
R2 N

Ar

O
H
semi- O N C NH2 a semi-
carbazide H2N C NH NH2 N carbazone

R1 R2

Carbonyl compounds 42
 Common aromatic compounds used:
NH NH2 phenylhydrazine Note: When R = H (i.e. a
reaction with NH3) the
O unsubstituted imine results
CH3 S NH NH2 is unstable and will
tosylhydrazine
O
polymerize.

O2N NH NH2 2,4-dinitrophenylhydrazine (2,4-DNPH)

NO2
leaves as H2O
Example
δ O
-
δ+
H3C C H + NH2 H3C CH N

electrophile R nucleophile R
(acid) (base)
R R
C6H5-NH-NH2 + CH3CH2COH C6H5-NH-N=CHCH2CH3
O
nucleophile
(base) CH3CH2CH
electrophile Carbonyl compounds 43
(acid)
 Enamines
Secondary amines cannot form a neutral imine by loss of a second proton on nitrogen
An enamine is formed instead

Mechanism 12

Carbonyl compounds 44
 Carbon Nucleophiles
OH
Grignard Reactions (previously looked at)
H
C
Cyanohydrin Formation CH2NH2
• LiAlH4/Et2O
• H2O
H-C≡N
δ O + O OH
- NaCN-HCN
H H
C + NaCN
δ+ buffer C
H Slightly C N
alkaline
C N
95% H2SO4
HCl
heat
H2O
heat
CH3CH2CH=CH-COOH
OH O
α, β unsaturated
carboxylic acid CH COH

α-hydroxy acid

Carbonyl compounds 45
 Aldol Condensations
The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Anions
Hydrogens on carbons a to carbonyls are unusually acidic
The resulting anion is stabilized by resonance to the carbonyl

Carbonyl compounds 46
The enolate anion can be protonated at the carbon or the oxygen
The resultant enol and keto forms of the carbonyl are formed
reversibly and are interconvertible

Carbonyl compounds 47
 Keto and Enol Tautomers
Enol-keto tautomers are constitutional isomers that are easily interconverted
by a trace of acid or base
Most aldehydes and ketones exist primarily in the keto form because of the
greater strength of the carbon-oxygen double bond relative to the carbon-
carbon double bond

Carbonyl compounds 48
 Aldol Condensations
aldol – aldehyde and alcohol
A condensation reaction is one in which two or more smaller
molecules combine to form a larger molecule often with the loss
of a small molecule
O HO¯ OH O
2 CH3CH CH3CH CH2CH
acetaldehyde
3-hydroxybutanol (50%)
(acetaldol or aldol)
δ-
O O O O
HO¯
CH3CH CH2CH H2C C H CH3CH
δ+
stronger base than OH¯

O aldehyde more
O OH O
H2O reactive than ketones
CH3CH CH2 C H CH3CH CH2 C H - more positive carbonyl
carbon – less steric
Carbonyl compounds
interaction 49
 The reaction between 2 moles of an Aldehyde is called
Mechanism 13 a self condensation reaction

Carbonyl compounds 50
 Dehydration of the Aldol Product
If the aldol reaction mixture is heated, dehydration to an α,β-
unsaturated carbonyl compound takes place
Dehydration is favorable because the product is stabilized by
conjugation of the alkene with the carbonyl group

In some aldol reactions, the aldol product cannot be isolated

because it is rapidly dehydrated to the α,β-unsaturated compound

Carbonyl compounds 51
 Acid-Catalyzed Aldol Condensation
This reaction generally leads directly to the dehydration product

Carbonyl compounds 52
 What is the product of the following reaction?
Mechanism 14 Crossed Aldol condensation

Readily dehydrates to an α,β-
unsaturated aldehyde. Forms a
stable conjugated product. Helps
drive the reaction to products
hydroxide is considered a
poor leaving group but because
this step is intermolecular and
the product is stabilized by
conjugation even a poor leaving
group such as a hydroxide can
Carbonyl compounds leave 53
 Practical Crossed Aldol Reactions
Crossed aldol reactions give one predictable product when one of the reaction
partners has no α hydrogens
The carbonyl compound without any α hydrogens is put in basic solution, and
the carbonyl with one or two α hydrogens is added slowly
Dehydration usually occurs immediately, especially if an extended conjugated
system results

Carbonyl compounds 54
 Claisen-Schmidt Reactions

Crossed-aldol reactions in which one partner is a ketone are called Claisen-

Schmidt reactions
The product of ketone self-condensation is not obtained because the
equilibrium is not favorable

Carbonyl compounds 55
 What is the product of the following reaction?

O O
O
O
2 OH
NaOH
H+ 1
Heat Ph 1 Ph Ph Ph
2
α hydrogens + H2O + HO¯
no α hydrogens
85%
δ−
O O O
NaOH OH O
δ+
+
Ph H b Heat
a c b Ph b
Ph a c
a c
α hydrogens α hydrogens
no α hydrogens
O O
O OH

Ph H
Ph b Ph
Ph b Ph a c
a c
94%
Carbonyl compounds 56
 Cyclization via Aldol Condensations

Intramolecular reaction of dicarbonyl compounds proceeds to form five-

and six-membered rings preferentially
In the following reaction the aldehyde carbonyl carbon is attacked
preferentially because an aldehyde is less sterically hindered and
more electrophilic than a ketone

Carbonyl compounds 57
 Lithium Enolates

In the presence of a very strong base such as lithium diisopropyl amide

(LDA), enolate formation is greatly favored
Weak bases such as sodium hydroxide produce only a small amount of
the enolate

Carbonyl compounds 58
Regioselective Formation of Enolate Anions
• Unsymmetrical ketones can form two different enolates
• The thermodynamic enolate is the most stable enolate i.e. the one with
the more highly substituted double bond
– A weak base favors the thermodynamic enolate because an
equilibrium between the enolates is estabilished

• The kinetic enolate is the enolate formed fastest and it usually is the
enolate with the least substituted double bond
– A strong, sterically hindered base such as lithium diisopropyl
amide favors formation of the kinetic enolate

Carbonyl compounds 59
 Lithium Enolates in Directed Aldol Reactions

Crossed aldol reactions proceed effectively when a ketone is first

deprotonated with a strong base such as LDA and the aldehyde is
added slowly to the enolate

Carbonyl compounds 60
 Direct Alkylation of Ketones via Lithium Enolates

Enolates can also be alkylated with primary alkyl halides via an SN2
reaction
Unsymmetrical ketones can be alkylated at the least substituted
position if LDA is used to form the kinetic enolate

Carbonyl compounds 61
 Enolates and Carbanions:
Building blocks for organic synthesis
Acidity of the Alpha Hydrogen

H O O O OH
R C C R B: R C C R R C C R R C C R
H H H H
enol
ketone resonance stabilized alcohol and
enolate ion alkene

H O H O Minor resonance structure but

R C C O R R C C O R oxygen caries a partial
H
negative charge on the
H carbonyl carbon. Thus the
B:
ester carbonyl group is less able to
O help stabilize the negative
charge of the enolate ion.
R C C O R
Carbonyl compounds 62
H
 Acidity of the α hydrogen next to the carbonyl carbon
O O O O O
acetone
CH3CCHCCH3 CH3CCHCCH3 acetoacetone CH2CCH3
pKb =14 – 9 = 5 H pKa = 20
H pKa = 9
O
O O
CH2COCH3 ethyl acetate
CH3CCHCOCH2CH3
ethyl acetoacetate
pKa = 11 H pKa = 25
H

O O
CH3CCCOCH2CH3 an alkylacetoacetic acid CH3CH2OH pKa = 16
R H pKa = 13
CH3OH pKa = 15.5
O O
CH3CH2OCCHCOCH2CH3 HNH2 NH2
diethyl malonate pKa = 35 pKb =14 – 35 = -21
H pKa = 13 (malonic ester)
O O O O O O

Compounds that are separated by C C C R C C C OR RO C C

α
C OR
β α β α β
two carbonyl compounds are called
β-dicarbonyl compounds a β-keto ester a malonic ester
Carbonyl compounds 63
 Synthesis

O O
CH3CH2ONa O O
CH3CH2OC-C-COCH2CH3 CH3CH2- Br
CH3CH2OH
H H EtOCCHCOEt
or NaNH2 SN2
enolate
diethyl malonate or NaH in a
aprotic solvent Et  -CH2CH3
O O O O O O
NaH
EtOC-C-COEt EtOC-C-COEt CH3-Br EtOC-C-COEt
SN2
Et H enolate Et Me Et

O O O O
H+, H2O
HOC-C-COH heat HOC-CH or HOC-CHCH2CH3
heat -CO2
Me Et Me Et CH3
or base
hydrolysis 2-methylbutanoic acid
a β-diacid
Carbonyl compounds 64
Mechanism for decarboxylation

H
H O
O O
O O C C H + CO2
C O
C C R C R
C R R
C O
R R
R
R R
enol tautomers

H
H O
O O
O O
C C H + CO2
C O
C C HO C R
O HO C R
HO C
R R
R R

Carbonyl compounds 65
Mechanism 15

Li N[CH(CH3)2]2, cold CH3Br

LDA – lithum diisopropylamide
warm

Carbonylenolate
compounds 66