ÁCIDOS CARBOXÍLICOS

1. ESTRUCTURA
2. NOMENCLATURA
3. FUENTES NATURALES Y COMERCIALES
4. PROPIEDADES FÍSICAS
5. SÍNTESIS
6. PROPIEDADES QUÍMICAS
 Structure
• The functional group of a carboxylic acid is a
carboxyl group
:
O:
C COOH CO 2 H
:O
:

H
– the general formula of an aliphatic carboxylic
acid is RCOOH
– that of an aromatic carboxylic acid is
ArCOOH
The entire molecule is approximately planar. The sp 2 hybrid carbonyl carbon
atom is planar, with nearly trigonal bond angles. The O-H bond also lies in this
plane, eclipsed with the C=O bond.

We can draw the following resonance forms to represent this delocalization:

 Nomenclature
• IUPAC names: drop the -e from the parent alkane and
add the suffix -oic acid
– if the compound contains a carbon-carbon double
bond, change the infix -an- to -en-

COO COO
C6 H 5
H H
3-Methylbutanoic acid t rans -3-Phenylpropenoic
(Isovaleric acid) acid (Cinnamic acid)
 Nomenclature

• The carboxyl group takes precedence

over most other functional groups
OH
COOH
(R)-5-Hydroxyhexanoic acid

O
COOH H 2N
5-Oxohexanoic acid COOH
4-Aminobutanoic acid
 Nomenclature
– dicarboxylic acids: add -dioic acid to the name of the
parent alkane containing both carboxyl groups
– there is no need to use numbers to locate the
carboxyl groups; they can only be on the ends of the
chain O
O
HO
OH O
HO
O
OH
Ethanedioic acid
(Oxalic acid) Propanedioic acid
(Malonic acid)
O O O O
HO HO
OH HO OH
O OH O
Butanedioic acid Pentanedioic acid Hexanedioic acid
(Succinic acid) (Glutaric acid) (Adipic acid)
 Nomenclature

– if the carboxyl group is bonded to a ring,

name the ring compound and add the
suffix -carboxylic acid
2
1 COOH
3
H OOC COOH

2-Cyclohexene- trans- 1,3-Cyclopen

carboxylic acid tane- dicarboxylic
acid
 Nomenclature

– benzoic acid is the simplest aromatic carboxylic

acid
– use numbers to show the location of
substituents
COOH
COOH COOH COOH
OH
COOH

Benzoic 2-Hydroxybe nzoic 1,2-Benzene- 1,4-Benzene-

COOH
acid acid dicarboxylic acid dicarboxylic acid
(Salicylic acid) (Phthalic acid) (Tereph thalic acid)
 Nomenclature
– when common names are used, the letters
    etc. are often used to locate substituents
O O O
  
 H2 N  
5 4 1 OH OH OH
3 2
NH2
4-A minobutanoic 2-Aminopropanoic acid
acid (-Aminobutyric (-Aminop ropionic
acid; GABA)
acid; alanine)

– in common nomenclature, keto indicates the

presence of a ketone, and CH3CO- is named an aceto
group O O
O
OH
CH3
3-oxobutanoic acid
-Ketobutyric acid; C-
acetoacetic acid) Acetyl group
(aceto
 FUENTES NATURALES Y COMERCIALES
Acetic acid. Vinegar is a 5% aqueous solution of acetic acid used in foods.

Vinegar for food is produced by fermentation of sugars and starches.

As a solvent, a starting material for synthesis, and a catalyst for a wide variety of
reactions
Long-chain aliphatic acids are obtained from the hydrolysis of
fats and oils. These fatty acids are generally straight-chain acids
with even numbers of carbon atoms ranging between about C-6
and C-18
The hydrolysis of animal fat gives mostly saturated fatty acids.
Plant oils give large amounts of unsaturated fatty acids with one
or more olefinic double bonds.
Aromatic carboxylic acids:

Benzoic acid is used as an ingredient in medications, a preservative in

foods, and a starting material for synthesis.

Two important commercial diacids are adipic acid (hexanedioic acid)

and terephthalic acid (benzene-1,4-dicarboxylic acid). Adipic acid is
used in making nylon 66, and terephthalic acid is used to make
polyesters
GREEN SYNTHESIS
Another synthesis of adipic acid
involves the microbial degradation of
toluene to muconic acid (hexa-2,4-
dienedioic acid), which undergoes catalytic
hydrogenation to give adipic acid.
If this process can be made economically
competitive, it might produce less
environmental impact than the chemical
synthesis from benzene.
NOMBRES Y PROPIEDADES FÍSICAS DE ALGUNOS ÁCIDOS CARBOXILICOS
ÁCIDOS DICARBOXÍLICOS
 Physical Properties
• In the liquid and solid states, carboxylic acids
are associated by hydrogen bonding into dimeric
structures
 Physical Properties
• Carboxylic acids have significantly higher boiling
points than other types of organic compounds
of comparable molecular weight
– they are polar compounds and form very strong
intermolecular hydrogen bonds
• Carboxylic acids are more soluble in water than
alcohols, ethers, aldehydes, and ketones of
comparable molecular weight
– they form hydrogen bonds with water molecules
through their C=O and OH groups
 Physical Properties

– water solubility decreases as the relative

size of the hydrophobic portion of the
molecule increases
 Acidity
• Carboxylic acids are weak acids
– values of pKa for most aliphatic and aromatic
carboxylic acids fall within the range 4 to 5

the greater acidity of carboxylic acids relative to

alcohols, both of which contain an OH group, is due
to resonance stabilization of the carboxylate anion
 Acidity
electron-withdrawing substituents near the carboxyl group
increase acidity through their inductive effect
 Acidity

– the acid-strengthening effect of a halogen

substituent falls off rapidly with
increasing distance from the carboxyl
group
COO COOH Cl COOH
H Cl
COOH
Cl
2-Chlorob utanoic 3-Chlorobutan 4-Ch Butan oic
acid oic acid lorobutanoic acid
(pK a 2.83) (p Ka 3.98) acid (pK a 4.82)
(pK a 4.52)
Decreas ing acid strength
Acidity
 Reaction with Bases
• Carboxylic acids, whether soluble or insoluble in water, react with
NaOH, KOH, and other strong bases to give water-soluble salts

COOH N aOH -
COO Na
+ + H2 O
H2 O
+ Sodium benzoate
(60 g/100 mL wate r)
Benzoic acid
(slightly soluble
in water)
• They also form water-soluble salts with ammonia and
amines

COOH + NH 3 COO- NH4 +

H2 O
Ammonium benzoate
Benzoic acid (20 g/100 mL wate r)
(slightly soluble
in water)
 Reaction with Bases

• Carboxylic acids react with sodium bicarbonate and

sodium carbonate to form water-soluble salts and
carbonic acid
– carbonic acid, in turn, breaks down to carbon
dioxide and water
- H2 O
+
CH3 COOH + Na HCO3 CH3 COO-Na+ + H CO
2 3

H2 CO3 CO2 + H2 O

CH3 COOH + Na+ HCO3 - CH3 COO- Na+ + CO2 + H2 O

 Carboxylic Acid Salts
Nomenclature
Salts of carboxylic acids are named simply by naming the cation,
then naming the carboxylate ion by replacing the -ic acid part
ofthe acid name with -ate.
 Carboxylic Acid Salts
Properties of Acid Salts
Salts are solids with little odor. Generally melt at high
temperatures, and they often decompose before reaching their
melting points. Carboxylate salts of the alkalimetals and
ammonium carboxylates are generally soluble in water but
relatively insoluble in nonpolar organic solvents.
Soap is a common example of carboxylate salts, consisting of the
soluble sodium salts of long-chain fatty acids. Carboxylate salts of
most other metal ions are insoluble in water. For example, when
soap is used in “hard” water containing calcium, magnesium, or
iron ions, the insoluble carboxylate salts precipitate out as “hard-
water scum.”
Salt formation can be used to:
Identify Carboxylic acids are deprotonated by the weak base sodium bicarbonate,
forming the sodium salt of the acid, carbon dioxide, and water. An unknown
compound that is insoluble in water, but dissolves in a sodium bicarbonate solution
with a release of bubbles of carbon dioxide, is almost certainly a carboxylic acid.

Purify acids
Some purification methods take advantage of the different solubilities of acids and
their salts. Nonacidic (or weakly acidic) impurities can be removed from a carboxylic
acid using acid–base extractions
SÍNTESIS
2. Cold, dilute potassium permanganate reacts with ALKENES to give
glycols. Warm, concentrated permanganate solutions oxidize the
glycols further, cleaving the central carbon–carbon bond. Depending
on the substitution of the original double bond, ketones or acids may
result
3. With ALKYNES, either ozonolysis or a vigorous
permanganate oxidation cleaves the triple bond to give
carboxylic acids
4. Side chains of ALKYLBENZENES are oxidized to benzoic acid derivatives
by treatment with hot potassium permanganate or hot chromic acid.
Because this oxidation requires severe conditions, it is useful only for
making benzoic acid derivatives with no oxidizable functional groups.
Oxidation-resistant functional groups such as -Cl, -NO2, -SO3H, and -COOH
may be present
5. Formation and Hydrolysis of Nitriles
Another way to convert an alkyl halide to a carboxylic acid with
an additional carbon atom is to displace the halide with sodium
cyanide. The product is a nitrile with one additional carbon
atom. Acidic or basic hydrolysis of the nitrile gives a carboxylic
acid.
6. The haloform reaction converts methyl ketones to
acids and iodoform
REACCIONES DE LOS ÁCIDOS CARBOXÍLICOS
 Nucleophilic acyl substitution
Carboxylic acids (and their derivatives) more commonly react
by nucleophilic acyl substitution, where one nucleophile
replaces another on the acyl 1C“O2 carbon atom.

Acid derivatives differ in the nature of the nucleophile

bonded to the acyl carbon:
Nucleophilic Acyl Substitution in the Basic Hydrolysis of an Ester
 Condensation of Acids with Alcohols:
The Fischer Esterification

The Fischer esterification converts carboxylic acids and alcohols directly to

esters by an acid-catalyzed nucleophilic acyl substitution. The net reaction
is replacement of the acid -OH group by the -OR group of the alcohol
Mechanism Fischer Esterification
EXAMPLE: Acid-catalyzed formation of methyl benzoate from methanol
and benzoic acid.
 Esterification Using Diazomethane
Carboxylic acids are converted to their methyl esters very simply by adding an ether solution
of diazomethane. The only by-product is nitrogen gas, and any excess diazomethane
also evaporates. Purification of the ester usually involves only evaporation of the solvent.
Yields are nearly quantitative in most cases.

Application: Drug Analysis

Diazomethane is often used to esterify polar or reactive
compounds for mass spectrometry analysis. For
example, a urine test for cocaine might involve
treating the sample with diazomethane to convert
benzoylecgonine, the major urinary metabolite of
cocaine, to its volatile methyl ester for MS analysis.
 Esterification Using Diazomethane

Diazomethane is a toxic, explosive yellow gas that dissolves in ether and is

fairly safe to use in ether solutions. The reaction of diazomethane with
carboxylic acids probably involves transfer of the acid proton, giving a
methyldiazonium salt. This diazonium salt is an excellent methylating agent,
with nitrogen gas as a leaving group.
 Condensation of Acids with Amines:
Direct Synthesis of Amides
Amides can be synthesized directly from carboxylic acids, using heat to
drive off water and force the reaction to completion. The initial acid–base
reaction of a carboxylic acid with an amine gives an ammonium carboxylate
salt. The carboxylateion is a poor electrophile, and the ammonium ion is
not nucleophilic, so the reaction stops at this point. Heating this salt to well
above 100 °C drives off steam and forms an amide. This direct synthesis is
an important industrial process, and it often works well in the laboratory.
 Reduction
The carboxyl group is very resistant to reduction
– it is not affected by catalytic hydrogenation under
conditions that easily reduce aldehydes and ketones to
alcohols, and reduce alkenes and alkynes to alkanes
– Reduction whith LiAlH4. It is not reduced by NaBH4.
 Alkylation of Carboxylic Acids to form
Ketones
Carboxylic acids react with two equivalents of an
organolithium reagent to give ketones
The first equivalent of the organolithium reagent simply deprotonates the
acid. The second equivalent adds to the carbonyl to give a stable dianion.
Hydrolysis of the dianion (by adding water) gives the hydrate of a ketone.
Because the ketone is formed in a separate hydrolysis step
 Synthesis and Use of AcidChlorides

Halide ions are excellent leaving groups for nucleophilic acyl substitution. Therefore,
acyl halides are useful intermediates for making acid derivatives. In particular, acid
chlorides (acyl chlorides) are easily made and are commonly used as an activated form
of a carboxylic acid. Both the carbonyl oxygen and the chlorine atom withdraw
electron density from the acyl carbon atom, making it strongly electrophilic. Acid
chlorides react with a wide range of nucleophiles, generally through the addition–
elimination mechanism of nucleophilic acyl substitution
 Syntesis of acid chlorides
The best reagents for converting carboxylic acids to acid chlorides are thionyl
chloride SOCl2 and oxalyl chloride (COCl)2 because they form gaseous by-products
that do not contaminate the product. Oxalyl chloride is particularly easy to use
because it boils at 62 °C and any excess is easily evaporated from the reaction
mixture.
Acid chlorides react with alcohols to give esters through a nucleophilic acyl
substitutionby the addition–elimination mechanism

This reaction provides an efficient two-step method for converting a

carboxylic acid to an ester. The acid is converted to the acid chloride,
which reacts with an alcohol to give the ester. Pyridine or other bases are
often added to neutralize the HCl generated. Otherwise, alcohols
(especially tertiary alcohols) may dehydrate under strongly acidic
conditions.
 RESUMEN DE REACCIONES DE ÁCIDOS CARBOXILICOS

1. Salt formation
2. Conversion to esters
3. Conversion to amides
4. Conversion to anhydrides

5. Reduction to primary alcohols

6. Reduction to aldehydes

7. Alkylation to form ketones

8 . Alkylation to form ketones

 Decarboxylation

• Decarboxylation: loss of CO2 from a carboxyl group

– most carboxylic acids, if heated to a very high
temperature, undergo thermal decarboxylation
O
decarboxylation
RCOH heat RH + CO2

– most carboxylic acids, however, are quite resistant to

moderate heat and melt or even boil without
decarboxylation
 Decarboxylation

– exceptions are carboxylic acids that have a

carbonyl group beta to the carboxyl group
– this type of carboxylic acid undergoes
decarboxylation on mild heating
O O
O warm +
OH CO2
3-Oxobu tan oic Acetone

acid (Acetoacetic
acid)
 Decarboxylation

– thermal decarboxylation of a -ketoacid

involves rearrangement of six electrons in
a cyclic six-membered transition state
enol of
a ketone
H H
O O O O O
(1) (2)
+
C O CO 2
O
(A cyclic six-membere d
transition state )
 Decarboxylation

– thermal decarboxylation of malonic acids

also involves rearrangement of six
electrons in a cyclic six-membered
transition state
H H
O O O O O
(1) (2)
+
C O CO 2
HO O HO HO
A cyclic six-membered Enol of a
transition state carboxylic acid
Functional Derivatives of Carboxylic
Acids
 Carboxyl Derivatives
• In this chapter, we study four classes of organic
compounds
– under the general formula of each is a drawing to help
you see how it is related to the carboxyl group

O O O O O
RCC RCOC RCO RCNH
l R' R' 2
An acid An acid An
An
chlorid e-H2 O -H2 O
anhydride ester -H2 O
amide
-H2 O
O O O O O
RC-OH H- RC-OH H-OCR' RC- H- RC-OH H-NH2
Cl OH OR'
 Acid Chlorides
• The functional group of an acid halide is an acyl
group bonded to a halogen
– the most widely used are the acid chlorides
– to name, change the suffix -ic acid to -yl
chloride
O O

CH3
CCl CCl chloride
Benzoyl

Eth anoyl chlorid

e (Acetyl chlorid
e)
 Acid Anhydrides
• The functional group of an acid anhydride is two acyl
groups bonded to an oxygen atom
– the anhydride may be symmetrical (two identical
acyl groups) or mixed (two different acyl
groups)
– to name, replace acid of the parent acid by
anhydride
O O O O O O

CH 3 COCCH 3 COC CH 3 COC

Acetic anhydride Benzoic anhydride Acetic be

nzoic
anhydride
 Acid Anhydrides
• A phosphoric acid anhydride contains two phosphoryl
groups bonded to an oxygen atom
– shown here are two phosphoric anhydrides
– each is shown on the right as it would be ionized at
pH 7.4, the pH of blood
O O O O
-
HO-P-O-P- O-P-O-P-
O- O-
OH O-
OH
Diphosphate ion
OH (Pyroph osphate ion)
Diphosphoric acid
(Pyrophosphoric
- O O -O
O-P-O-P-O-P-O
HO-P-O-P-O-P- acid)
O- O- O-
OH OH OH
Triph O O O
OHosphoric Triphosphate ion
acid
 Esters
• The functional group of an ester is an
acyl group bonded to -OR or -OAr
– name the alkyl or aryl group bonded to
oxygen followed by the name of the acid
– change the suffix -ic acid to -ate
O
O O
O
CH3 COCH2 CH3
O
Ethyl Ethan Diethyl butanedioate
oate (Eth yl (Diethyl succinate)
acetate)
 Lactones
• Lactone: a cyclic ester
– IUPAC: name the parent carboxylic acid,
drop the suffix -ic acid, and add -olactone
– the location of the oxygen atom on the
carbon chain is commonly indicated by a
Greek letter
O
4-Butan olactone  2
1
O
(A -lacton e) 3

4

 Phosphoric esters
• Phosphoric acid forms mono-, di-, and triesters
– name by giving the name of the alkyl or aryl
group(s) bonded to oxygen followed by the word
phosphate
– in more complex phosphate esters, it is common
to name the organic molecule followed by
phosphate
CH
O
H OH CH O
O HO H
H H O CH2 O-P-O-
CH3 O-P-
OH O O O-
OH OC 3 H
CH2 -O-P-O- H3 C N
H OH
O-
Dimethyl D-Glucose Pyrid oxal phosphate
6-ph os phate
phosp hate
 Amides
• The functional group of an amide is an acyl group
bonded to a trivalent nitrogen
– IUPAC: drop -ic acid from the name of the parent acid
and add -amide
– if the amide nitrogen is bonded to an alkyl or aryl
group, name the group and show its location on
nitrogen by N-

O O H O CH3
CH3 CNH2 CH3 C- H-C-
N CH3 N CH3
Acetamide N-Methylacetamide N,N-Dimethyl-
(a 1° amide) (a 2° amide) formamide (DMF)
(a 3° amide)
 Lactam
• Lactam: a cyclic amide
– name the parent carboxylic acid, drop the suffix -ic acid and
add
-lactam
– the location of the nitrogen atom in the ring is
commonly indicated by a Greek letter, , , etc.

 2 O
 O 3 1
1
2
3 N  4 NH
H3 C 5 6 
H
3-Butanolactam 6-Hexanolactam
A -lactam) An -lactone)

– 6-hexanolactam is an intermediate in the synthesis of nylon

6
 The Penicillins
• The penicillins are a family of -lactam
antibiotics
– one of the first discovered was penicillin
G
the pe nicillins diffe
r in the group
bonded to the acyl H
carbon H H
N S
CH2 C CH3
N
O
Penicillin GO COOH
CH 3
 The Penicillins
– amoxicillin, a -lactam antibiotic
HO
O
H
HN S
H
NH2
N
O
COO
H
 Cephalosporins
• The cephalosporins are also -lactam
antibiotics
...and the group
O to this carbon of the
bonded
H H six-membered rin g
S
The cephalosporins N
differ in the group
bonded to the H N
NH2 CH3
carbonyl
O COOH
carbon...
Keflex
(a -lactam antibiotic)
 Characteristic Reactions
• Nucleophilic acyl substitution: an addition-elimination
sequence resulting in substitution of one nucleophile for
another
– the reaction depends on having a suitable leaving
group bonded to the acyl carbon, here indicated Lv
-
O O O
C + Nu- C + Lv -
R Lv R Nu R Nu
C
Lv
Tetrah edral carbonyl Su bstitu tion
addition intermediate product
 Characteristic Reactions
– in the general reaction, we showed the nucleophile as
an anion; this need not be the case
– neutral molecules such as water, alcohols, ammonia,
and amines can also serve as nucleophiles
– in the general reaction, we showed the leaving group
as an anion to illustrate an important point about
them: the weaker the base, the better the leaving
group
O
NR2 OR OCR
X
Increasing leaving ability
Increasing basicity
 Characteristic Reactions
– halide ion is the weakest base and the best
leaving group; acid halides are the most reactive
toward nucleophilic acyl substitution
– amide ion is the strongest base and the poorest
leaving group; amides are the least reactive
toward nucleophilic acyl substitution
O O O O O
RC-NH2 RC-OR' RC- RC-
Amide Ester OCR X
Increasing reactivity towardAnhydrid
nucleophilic acylAcid
substitution
e halide
Hydrolysis - Acid Chlorides
– low-molecular-weight acid chlorides react
rapidly with water
– higher molecular-weight acid chlorides are
less soluble in water and react less
readily
O O
CH3 CCl + H2 CH3 COH +
O HCl
Hydrolysis - Acid Anhydrides
– low-molecular-weight acid anhydrides react
readily with water to give two molecules of
carboxylic acid
– higher-molecular-weight acid anhydrides
also react with water, but less readily
O O O O

CH3
+ H O + HOCCH
2 CH3
COCCH3 COH 3
 Hydrolysis - Esters
• Esters are hydrolyzed only slowly, even in boiling
water
• Hydrolysis becomes more rapid if they are heated
with either aqueous acid or aqueous base
• Hydrolysis in aqueous acid is the reverse of Fischer
esterification
O OH O
C H+ C H+ +
OC + H2 O R CH3 OH
R 3 OH R
H H3 CO C OH

Tetrah edral carbonyl

addition
intermediate
 Hydrolysis - Esters
• Hydrolysis of an ester in aqueous base is often called
saponification
– each mole of ester hydrolyzed requires 1 mole of
base; for this reason, ester hydrolysis in aqueous
base is said to be base promoted
O O
H2 O
RCOCH3 + RCO- Na+ + CH3
NaOH OH
– base-promoted ester hydrolysis involves formation of
a tetrahedral carbonyl addition intermediate followed
by its collapse
 Hydrolysis - Esters
– step 1: addition of hydroxide ion to the carbonyl
carbon O O
R-C-OCH3 + R-C
OH OCH 3
OH
– step 2: collapse of the addition intermediate

O O
R-C R-C OH
+
OCH3
OCH
OH3
– step 3: proton transfer completes the reaction

O O
R-C O H + OCH3 R-C O + H-OCH3
 Hydrolysis - Esters
• There are two major differences between acid-
catalyzed and base-promoted ester hydrolysis
1. for acid-catalyzed hydrolysis, acid is
required in only catalytic amounts; for base-
promoted hydrolysis, base is required in
equimolar amounts
2. hydrolysis of an ester in aqueous
acid is reversible; base-promoted
hydrolysis is irreversible
 Hydrolysis - Amides
• Hydrolysis of an amide requires much more vigorous
conditions than hydrolysis of an ester
– hydrolysis in aqueous acid requires 1 mole of acid
for each mole of amide
– the products are a carboxylic acid and an
ammonium or an amine salt
O O
H2 O + -
NH2 + H2 O + HCl hea
OH + NH4
Ph t P Cl
2- h
2-Phenylbutanoic acid
Phenylbutanamide
 Hydrolysis - Amides
– hydrolysis of an amide in aqueous base
requires 1 mole of base per mole of amide
– the products are a carboxylate salt and an
amine
O
O H2 O - +
heat
CH3 CO Na + H2 N
CH3 CNH + NaOH
N-Phenylethanamide Sodium acetate Aniline
(N-
Phenylacetamide,
Acetanilide)
 Hydrolysis
• A summary

O O
R- R-C-OH + HCl
C-
O
Cl O
R-C-O-C-R + H2 O R-C-OH + HO-C-R
+ NaOH O
O
R-C-O-Na+ +
R-C-OR' + H2 O H2SO4 R'OH O
H2
O R-C-OH + R'OH
O O NaOH
O O 3
R-C-NH2 + H O O -Na+ + NH
R-C-O
2 HCl
R-C-OH + NH4 + Cl-
 Reaction with Alcohols
• Acid chlorides react with alcohols to
give an ester and HCl
O
Cl + HO

Butanoyl Cyclohexanol
chloride O
O + HCl

Cyclohexyl butanoate
 Reaction with Alcohols
• Acid anhydrides react with alcohols to give 1 mole of
ester and 1 mole of carboxylic acid
O O O O
CH3 + HOCH2 CH3 CH3 COCH2 CH3 + CH3 COH
Acetic anhydride Ethan ol Ethyl acetate Acetic acid
COCCH3
– aspirin is prepared by the following reaction:

COOH COOH
OH O O O
+ CH3 + CH3
O
2-Hydroxybenzoic COCCH
Acetic
3 Acetylsalicylic COOH
acid anhyd rid acid Acetic
(Salicylic acid) e (Aspirin ) acid
 Reaction with Alcohols
• Esters undergo an exchange reaction
called transesterification
– the exchange is acid catalyzed
– the original -OR group is exchanged for
a new
-OR group
O
H 2 SO4
O P
Ph O OCH3 + HO OH Ph O + 2 CH3OH
h
O
Methyl 1,2-Ethanediol A diester of
benzoate (Ethylene glycol) ethylene glycol)
 Reaction with Alcohols
• Amides to not react with alcohols under
any conditions
• Summary of reactions with alcohols
O O
R-C-Cl + R-C-OR" + HCl
HOR" O
O
O O
R-C-O-C-R + R"OH R-C-OR" + HO-C-
O
H2SO4 R O
R-C-OR' +
R"OH R-C-OR" + R'OH
R-C-NH No Reaction
O 2 +

R"OH
 Reaction with NH3 and
Amines
• Acid halides react with ammonia, 1°
amines, and 2° amines to form amides
– 2 moles of the amine are required per mole
of acid chloride; one to form the amide
and toO neutralize the HCl formed
one
O
Cl + 2 NH 2 + NH4 + Cl-
Hexan oyl NH3 A mmonia Hexanamide Ammonium
chloride
chloride
 Reaction with NH3 and Amines
• Acid anhydrides react with ammonia, and with 1° and 2°
amines to form amides
– 2 moles of ammonia or amine are required; one to
form the amide and one to neutralize the carboxylic
acid byproduct
– here the reaction is broken into two steps

O O O
CH3 + NH3 O
COCCH3 CH3 CNH2 + CH3
- +
CH CO NH
CH3 COHO + NH3 COH
3 4

O O OO O
CH3 + 2 3 CH3 CNH2 + CH3 CO- NH4+
COCCH3 NH
 Reaction with NH3 and Amines
• Esters react with ammonia, and with 1° and 2° amines to
form amides
– esters are less reactive than either acid halides or
acid anhydrides
O O
Ph Ph
O + NH 3 NH 2 + HO
Ethyl phenylacetate Phenyl Ethanol
acetamide
• Amides do not react with ammonia, or with 1° or 2°
amines
 Reaction with NH3 &
Amines
•Summary
O O
+ -
R-C-Cl + 2 3 R-C-NH2 + NH4 Cl
O NHO O
O
R-C-O-C-R + 2 NH 3 -
R-C-NH2 + R-C-O NH4
+

O
O
R-C-OR' +
NH3 R-C-NH2 + R'OH
O
R-C-NH2 No reaction with ammonia or amines
• Interconversion
interconversion of functional groups
 Esters with Grignard Reagents
• a formic ester with 2 moles of Grignard reagent followed
by hydrolysis gives a 2° alcohol
O magnes ium OH
H2 O,
HCOCH + 2 RMgX alkoxide HC-R + CH3
salt HCl
An OH
3 ester
of formic A 2° alcohol
R
acid
• reaction of an ester other than a formate gives a 3°
alcohol
O OH
magnes ium H O,
+ alkoxide 2 CH3 C-R + CH3
HCl
salt
AnCH 3 COCH
ester of any 2 RMgX
3 acid OH R
other than formic A 3° alcohol
acid
 Esters with Grignard Reagents
1 O – Steps 1 and 2 2 O - [ MgX]
+ O
MgX CH3 -C OCH3 CH3 -C + CH3 O - [ MgX]+
CH3 -C-OCH3 + R
R 2 R
1
A magnesium salt A ketone

– Steps 3 and 4 4

3 4
3 O O - [MgX] + OH
CH3 -C MgX H O H, HCl
+ R CH3 -C-R CH3 -C-R
R R R
A Magnesium A 3°
ketone alcohol
 Some Interconversions
– from Example O
P
Cl
h
NH3 ( 2 eq)
SOCl2 CH3 OH

O O
O
P CH3 OH, H2 SO4 NH3 P
O P NH2
h Fischer OC 3 h
H
Phenylaceti h (a H (b
esterificatio )
c acid ) 1. 1.
n 4 4
2LiAlH
. H2 O 2LiAlH
. H2 O
1 . LiAlH4
P P
2 . H2 O O NH2
h h
(d H
(c
)
)
Amines
 Structure & Classification
• Classification
– 1°, 2°, or , 3° amines: amines in which 1, 2, or 3
hydrogens of NH3 are replaced by alkyl or aryl groups
– 4° amines: ions in which nitrogen is bonded to four
carbons and bears a positive charge

CH 3 CH 3 -
+ Br
CH 3 - NH 2
CH 3 - N- 3
CH 3 - N CH
C CH 3
Methylamine Tetrameth ylammonium
(a 1° H3 bromide
amine) Trimethylamin e (a 4° ammonium salt)
(a 3° amine)
 Structure & Classification
• Amines are further divided into aliphatic, aromatic,
and heterocyclic amines
– aliphatic amine: an amine in which nitrogen is
bonded only to alkyl groups
– aromatic amine: an amine in which nitrogen is
bonded to one or more aryl groups
CH3
CH3
NH2 CH2 -N-CH3
N-Methylaniline
N- Benzyldim ethylamine
Aniline (a 2° aromatic (a 3° aliphatic amine)
H
(a 1° aromatic amine)
amine)
 Structure & Classification
– heterocyclic amine: an amine in which nitrogen is one
of the atoms of a ring

N N N N

H
Piperidine H H Pyridine
Pyrrole
Pyrrolidine (heterocyclic
(heterocyclic aromatic
aliph atic amines) amines)
 Structure & Classification

• Example: classify each amino group by type

H
H N
(a) (b)
N
N CH3

H3 C H (S)-(-)-Nicotine
N O (S)-
(c (+)-
OCH3
) Coni
ine
O
Cocain e
O
 Nomenclature
• Aliphatic amines: replace the suffix -e of the parent
alkane by -amine
NH2 NH2
NH2
H2 N
C6 H5
2- (S)-1-Phenylethanamine 1,6-Hexanediamine
Propan amin e
• The IUPAC system retains the common name aniline

NH2 NH2 NH2 NH2

CH3

OCH3
NO2
Aniline 4-Nitroaniline 2-Meth 3-Methoxyan iline
(p- ylaniline (o- (m-Anisidine)
N itroaniline) Toluidine)
 Nomenclature
• Among the various functional groups discussed in the
text, -NH2 has one of the lowest priorities
COOH
OH
H2 N
NH2
2-Aminoethanol 2-Aminobenzoic acid
(Anthranilic acid)
 Nomenclature
• Common names for most aliphatic
amines are derived by listing the alkyl
groups bonded to nitrogen in one word
ending with the suffix -amine
H
CH 3 NH 2 NH 2 N
N
Methylamine tert- Butylamine Dicyclopentylamine Triethylamine
 Physical Properties
• Amines are polar compounds, and both 1° and
2° amines form intermolecular hydrogen
bonds
– N-H- - - -N hydrogen bonds are weaker than
O-H- - - -O hydrogen bonds because the
difference in electronegativity between N and
H (3.0 - 2.1 = 0.9) is less than that between O
and H (3.5 - 2.1 = 1.4)

molecular weight 30.13

CH3 CH 31.1 32.0
(g/mol) boiling -88.6 -6.3 65.0
point (°C) CH3 NH2
 Basicity
• All amines are weak bases, and
aqueoHus solutions of aminHes are
+
basic
-
CH3 -N: + H-O-H CH3 -N-H :O-
H H H
Methylamm onium
Meth ylamine hyd roxide

[CH 3 NH3 + ][OH - ] = 4.37 x 10-4

Kb = K [H O]
eq 2
[CH 3 NH2 ]
=
 Basicity
• it is also common to discuss the basicity of amines by
reference to the acid ionization constant of the
corresponding conjugate acid

CH3 NH3 + + H2 O CH3 NH2 + H3 O+

[ CH3 NH2 ][ H3
Ka + = 2.29 x 10-1 1 pK a = 10.64
+
O ][CH3 NH3 ]
=

– for any acid-conjugate base pair

pKa 14. 00

+
 Basicity
• Using values of pKa, we can predict the
position of equilibrium in acid-base reactions

-
CH3 NH2 + CH3 COOH CH3 NH3 + + CH3 COO
p Ka 4.76 pKa 10.64
(stron ger (stron ger (w (w eaker
base) acid) eaker base)
acid)
– acetic acid is the stronger acid and, therefore, the
position of this equilibrium lies to the right
 Basicity
– aliphatic amines have about the same base strength,
pKb 3.0 - 4.0, and are slightly stronger bases than
ammonia
Amine Structu re pKb pKa
Ammonia NH3 4.74 9.26
Primary Amines
methylamine CH3 NH2 3.36 10.64
ethylamine CH3 CH2 NH2 3.19 10.81
cyclohexylamine C6 H1 1 NH2 3.34 10.66
Secondary Amines
dimethylamin e ( CH3 ) 2 NH 3.27 10.73
diethylamine 3.02 10.98
( CH3 CH2 ) 2
Tertiary Amines
trimethylamine NH 4.19 9.81
triethylamine 3.25 10.75
( CH3 ) 3 N
 Basicity
– aromatic amines are considerably weaker
bases than aliphatic amines
pKb 3.34
NH2 + H2 O NH3 +
OH-
Cyclohexyl Cyclohexylammon ium
- amine hydroxide

pKb 9.37
-
NH2 + H2 O NH3 + OH

A niline Anilinium hydroxide

 Basicity
– aromatic amines are weaker bases than
aliphatic amines because the
resonance stabilization of the free base
is lost on protonation
H H + H H H
H+ +
N H N H N N

Interaction of th e electron pair on

nitrogen with the pi system of
the
aromatic rin g
 Basicity
• Electron-withdrawing groups, such as
halogen, nitro, and carbonyl, decrease
the basicity of aromatic amines by
decreasing the availability of the
electron pair on nitrogen

O2 N NH2
NH2
4-Nitroanilin
Aniline e (pK b 15.0)
(pK b 9.37)
 Basicity
• Example: select the stronger base in
each pair of amines
O
(a) or
N N

(A) H
(B
NH2 )
CH2 NH2
(b) CH3 or

(C (D)
 Guanidine
• Guanidine, pKb 0.4, is the strongest base among
neutral organic compounds
+
NH p Kb 0.4 NH2
-
H2 N-C-NH2 + H O H2 N-C-NH2 +
2
Guan OH Guanidinium ion
idine
– its basicity is due to the delocalization of the
positive charge over the three nitrogen atoms
+
NH2 NH2
NH2 +
H2 N C NH2 H2 +
N C NH2 H2 N C NH2
Three equivalent contrib uting structures
 Reaction with Acids
• All amines, whether soluble or insoluble
in water, react quantitatively with
strong acids to form water-soluble salts
OH

OH H2 O
+ -
HO NH + HO NH3
HO 2 HO
HCl Cl
(R)-Norep ineph rin (R)-Norepinephrine
e (only slightly hyd roch loride
soluble in water) (a water-soluble
salt)
 Synthesis of 1° Arylamines
• Most are synthesized by nitration of an
aromatic ring followed by catalytic
reduction of the nitro group to a primary
amine
COOH COOH

Ni
+ 3 H2 (3 atm) + 2 H2 O
NO2 NH2
3-Nitroben 3-Aminobenzoic
zoic acid acid
 Reaction with Nitrous Acid
• Nitrous acid is a weak acid, most commonly
prepared by treating an aqueous solution of NaNO2 with
H2SO4 or HCl

-
HNO2 + H2 O H 3 O+ + 2 Ka = 4.26 x 10-4
pKa = 3.37
NO

– nitrous acid reacts with amines of different types,

depending on whether the amine is 1°, 2°, 3°
and whether it is aliphatic or aromatic
– we concentrate on the reaction of nitrous acid with 1°
aromatic amines because this reaction is useful in
organic synthesis
 Reaction with Nitrous Acid
• Treating a 1° aromatic amine with HNO2 gives a
diazonium salt

NH2 + NaNO2 + H2 O + N Cl- + H2 O

N
HCl 0°C
Aniline Sodium Ben zenediazoniu m
(a 1° nitrite chloride
aromatic
amine)
– warming the aqueous solution of the diazonium salt
gives a phenol and N2 gas
+ -
N N Cl + H2 O OH + N2
Ben zenediazoniu m Ph enol chloride
 Reaction with Nitrous Acid
• Example: show how to bring about each
step in this conversion
CH3 CH3 COOH COOH
COOH
(1) (2) (3) (4)

NO2 NO2 NH2 OH

Toluene 4-Hydroxy-
benzoic
acid