CH 19 - Amines

Organic Chemistry,
9th Edition,
Global Edition
L. G. Wade, Jr.
Chapter 19
Lecture
Amines
© 2017 Pearson Education, Ltd.
© 2014 Pearson Education, Inc.
Biologically Active Amines
• The alkaloids are an important group of biologically active

amines, mostly synthesized by plants to protect them from
being eaten by insects and other animals.
• Many drugs of addiction are classified as alkaloids.

Biological Activity of Amines
Classes of Amines
• Primary (1°): Has one alkyl group bonded to

the nitrogen (RNH2)
• Secondary (2°): Has two alkyl groups
bonded to the nitrogen (R2NH)
• Tertiary (3°): Has three alkyl groups bonded
to the nitrogen (R3N)
• Quaternary (4°): Has four alkyl groups
bonded to the nitrogen and the nitrogen
bears a positive charge (R4N+)

Classification of Amines
Quaternary Ammonium Salts
• The nitrogen atom has four alkyl groups

attached.
• The nitrogen is positively charged.

Common Names
• Common names of amines are formed from the

names of the alkyl groups bonded to nitrogen,
followed by the suffix -amine.
Amine As Substituent
• On a molecule with a higher-priority functional

group, the amine is named as a substituent.

IUPAC Names
• Name is based on longest carbon chain.

• The -e of alkane is replaced with -amine.
Aromatic Amines
• In aromatic amines, the amino group is bonded to

a benzene ring.
• The parent compound is called aniline.

Heterocyclic Amines
When naming a cyclic amine, the nitrogen is
assigned position number 1.
Structure of Amines
• Nitrogen is sp3 hybridized with a lone pair of

electrons.
• The angle is less than 109.5°.
Interconversion of
Chiral Amines
• Nitrogen may have three different groups and a

lone pair, but enantiomers cannot be isolated due
to inversion around N.
Chiral Amines
• Amines whose chirality stems from the presence of

chiral carbon atoms
• Inversion of the nitrogen is not relevant because it
will not affect the chiral carbon.
Chiral Quaternary
Ammonium Salts
• Quaternary ammonium salts may have a chiral nitrogen

atom if the four substituents are different.
• Inversion of configuration is not possible because there is
no lone pair to undergo nitrogen inversion.
Chiral Cyclic Amines
• If the nitrogen atom is contained in a small ring, for

example, it is prevented from attaining the 120° bond
angle that facilitates inversion.
• Such a compound has a higher activation energy for
inversion, the inversion is slow, and the enantiomers may
be resolved.

Boiling Points
• N—H is less polar than O—H.

• Weaker hydrogen bonds, so amines will have a lower
boiling point than the corresponding alcohol
• Tertiary amines cannot hydrogen-bond, so they have lower
boiling points than primary and secondary amines.
Hydrogen Bonding and

Boiling Points

Solubility and Odor
• Small amines (< six Cs) are soluble in water.
• All amines accept hydrogen bonds from water
and alcohol.
• Branching increases solubility.
• Most amines smell like rotting fish.
Basicity of Amines
• Lone pair of electrons on nitrogen can accept a
proton from an acid.
• Aqueous solutions are basic to litmus.
• Ammonia pKb = 4.74.
• Alkyl amines are usually stronger bases than
ammonia.
• Increasing the number of alkyl groups decreases
solvation of ion, so 2° and 3° amines are similar
to 1° amines in basicity.

Reactivity of Amines
Base-Dissociation Constant
of Amines
• Amines are strongly basic and as such they can abstract a

proton from water, giving an ammonium ion and a
hydroxide ion.
• The equilibrium constant for this reaction is called the
base-dissociation constant for the amine, symbolized
by Kb.
Amine Basicity
Base Dissociation of an Amine
• Alkyl groups stabilize the ammonium ion, making

the amine a stronger base.
Alkyl Group Stabilization
of Amines
• Alkyl groups make the nitrogen a stronger base

than ammonia.
Resonance Effects
• Any delocalization of the electron pair weakens the base.

Protonation of Pyrrole
• When the pyrrole nitrogen is protonated, pyrrole

loses its aromatic stabilization.
• Therefore, protonation on nitrogen is unfavorable
and pyrrole is a very weak base.
Hybridization Effects
• Pyridine is less basic than aliphatic amines, but it is

more basic than pyrrole because it does not lose
its aromaticity on protonation.

Ammonium Salts
• Ionic solids with high melting points

• Soluble in water
• No fishy odor
Purifying an Amine

IR Spectroscopy
• N—H stretch between 3200 and 3500 cm–1

• Two peaks for 1° amine, one for 2°
NMR Spectroscopy of Amines
• Nitrogen is not as electronegative as oxygen, so

the protons on the  carbon atoms of amines are
not as strongly deshielded.

NMR Spectrum
Carbon NMR Chemical Shifts

Mass Spectroscopy of Amines
• Nitrogen has an odd valence and an even

mass number.
• When a nitrogen atom is present in a stable
molecule, the molecular weight is odd.
• Whenever an odd number of nitrogen atoms
are present in a molecule, the molecular ion
has an odd mass number.
Alpha Cleavage of Amines
• The most common fragmentation of amines is α

cleavage to give a resonance-stabilized cation—an
iminium ion.

MS of Butyl Propyl Amine
Fragmentation of
Butyl Propyl Amine

Reaction of Amines with
Ketones and Aldehydes
Aromatic Substitution
of Arylamines
• —NH2 is a strong activator and an ortho-,

para-director.
• Multiple substitution is a problem.
• Protonation of the amine under acidic
conditions converts the group into a strong
deactivator (—NH3+).

Multiple Substitutions
Ortho and Para

Substitution of Aniline

Protonation of Aniline in
Substitution Reactions
• Strongly acidic reagents protonate the amino group,

producing an ammonium salt.
• The —NH3+ group is strongly deactivating (and
meta-allowing).
• Therefore, strongly acidic reagents are unsuitable for
substitution of anilines.
Aromatic Substitution
of Pyridine
• Strongly deactivated toward electrophilic attack by the

electronegative nitrogen atom
• Substitutes in the 3-position in a manner analogous to the
meta substitution
• Electrons on N may react with the electrophile.
Electrophilic Aromatic
Substitution of Pyridine
Attack on 2-Position
• Attack at the 2-position would have an unfavorable

resonance structure in which the positive charge is
localized on the nitrogen.
• Substitution at the 2-position is not observed.
Nucleophilic Substitution
of Pyridine
• Activated toward nucleophilic aromatic substitution

• Nucleophile will replace a good leaving group in the
2- or 4-position.
Nucleophilic Attack
on 3-Position
• Attack at the 3-position does not place the negative

charge on the nitrogen.
• Substitution at the 3-position is not observed.

Alkylation of Amines
by Alkyl Halides
• Proceeds by the SN2 mechanism

• Secondary alkyl halides will give elimination products.
• Multiple alkylations are a major problem. Complex
mixtures are obtained.
Exhaustive Alkylation
• Exhaustive alkylation forms the

tetraalkylammonium salt.
• Mild basic conditions (NaHCO3) are used to
deprotonate the intermediates and neutralize
the acid formed.

Alkylations with
Excess Ammonia
• Reaction with large excess of NH3 to form

the primary amine in good yields
• Excess ammonia is allowed to evaporate
after reaction.
Acylation of Amines
• Primary and secondary amines react with acid

halides to form amides.
• This reaction is a nucleophilic acyl substitution.

Mechanism of Acyl Substitution
Step 1: Nucleophile attacks the carbonyl carbon, forming the tetrahedral
intermediate.
Step 2: Expulsion of the chloride ion Step 3: Loss of a proton gives

the amide.
Acylation of Aromatic Amines
• The resulting amide is still activating and ortho,

para-directing.
• The acyl group can be removed later by acidic or basic
hydrolysis.

Solved Problem 1
Show how you would accomplish the following synthetic conversion in good yield.
Solution
An attempted Friedel–Crafts acylation on aniline would likely meet with disaster. The free
amino group would attack both the acid chloride and the Lewis acid catalyst.
Solved Problem 1 (Continued)

Solution (Continued)
We can control the nucleophilicity of aniline’s amino group by converting it to an amide, which
is still activating and ortho, para-directing for the Friedel–Crafts reaction. Acylation, followed
by hydrolysis of the amide, gives the desired product.

Formation of Sulfonamides
• Sulfonyl chlorides are the acid chlorides of

sulfonic acids.
• Sulfonyl chlorides are strongly electrophilic.
Formation of Sulfonamides
• Primary or secondary amines react with sulfonyl

chloride to produce an amide.
• Amides of sulfonic acid are called sulfonamides.

Synthesis of Sulfanilamide
• The sulfa drugs are a class of sulfonamides used

as antibacterial agents.
• In 1936, sulfanilamide was found to be effective
against streptococcal infections.
Biological Activity of
Sulfanilamide
• Sulfanilamide is an analogue of p-aminobenzoic acid.

• Streptococci use p-aminobenzoic acid to synthesize folic
acid, an essential compound for growth and reproduction.
Sulfanilamide cannot be used to make folic acid.
• Bacteria cannot distinguish between sulfanilamide and
p-aminobenzoic acid, so it will inhibit their growth and
reproduction.
Amines As Leaving Groups
• Amines can undergo elimination reactions to

form alkenes.
– –
• The NH2 or NHR groups are not good
leaving groups because they are very
strong bases.
• Exhaustive methylation can convert the
amino group into a quaternary ammonium
salt, which can leave as the neutral amine.
Hofmann Elimination
• A quaternary ammonium salt has a good

leaving group—a neutral amine.
• Heating the hydroxide salt produces the least
substituted alkene.

Exhaustive Methylation
of Amines
• Methyl iodide is usually used as a methylating

agent.
• The leaving group is the neutral amine.
Conversion to the
Hydroxide Salt
• The iodide salt is converted to the hydroxide

salt by treatment with silver oxide and water.
• The hydroxide will serve as the base in the
elimination step.

Mechanism of the
Hofmann Elimination
• The Hofmann elimination is a one-step, concerted

E2 reaction in which the amine is the leaving group.
Regioselectivity of the
Hofmann Elimination
• The least substituted product is the major product

of the reaction (Hofmann product).
E2 Mechanism
Solved Problem 2
Predict the major product(s) formed when the following amine is treated with excess
iodomethane, followed by heating with silver oxide.
Solution
Solving this type of problem requires finding every possible elimination of the methylated salt.
In this case, the salt has the following structure:

Solved Problem 2 (Continued)
Solution (Continued)
The green, blue, and red arrows show the three possible elimination routes. The
corresponding products are as follows:
The first (green) alkene has a disubstituted double bond. The second (blue) alkene is
monosubstituted, and the red alkene (ethylene) has an unsubstituted double bond. We
predict that the red products will be favored.
Oxidation of Amines
• Amines are easily oxidized, even in air.

• Common oxidizing agents: H2O2 , MCPBA
• 2° amines oxidize to hydroxylamine (—NOH).
• 3° amines oxidize to amine oxide (R3N+—O–).

Preparation of Amine Oxides
• Tertiary amines are oxidized to amine oxides, often in

good yields.
• Either H2O2 or peroxyacid may be used for this oxidation.
• The N-oxide can undergo elimination to form alkenes in a
reaction analogous to the Hofmann elimination.
Cope Rearrangement
• E2 mechanism
• The amine oxide acts as its own base through a cyclic
transition state, so a strong base is not needed.

Solved Problem 3
Predict the products expected when the following compound is treated with H2O2 and heated.
Solution
Oxidation converts the tertiary amine to an amine oxide. Cope elimination can give either of
two alkenes. We expect the less hindered elimination to be favored, giving the Hofmann
product.
Nitrous Acid Reagent
• Nitrous acid is produced in situ by

mixing sodium nitrite with HCl.
• The nitrous acid is protonated, loses
water to form the nitrosonium ion.
=>
Chapter 19 74
Formation of Diazonium Salts
• Primary amines react with nitrous acid (HNO2) to

form dialkyldiazonium salts.
• The diazonium salts are unstable and decompose
into carbocations and nitrogen.
Diazotization of an Amine
Step 1: The amine attacks the nitrosonium ion and forms
N-nitrosoamine.
Step 2: A proton transfer (a tautomerism) from nitrogen to

oxygen forms a hydroxyl group and a second N—N bond.

Diazotization of an Amine
(Continued)
Step 3: Protonation of the hydroxyl group, followed by the loss
of water, gives the diazonium ion.
Arenediazonium Salts
• By forming and diazotizing an amine, an activated

aromatic position can be converted into a wide
variety of functional groups.

Reactions of
Arenediazonium Salts
The Sandmeyer Reaction

Replacement of the Diazonium
Group by Fluoride and Iodide
Reduction of Diazonium Group

to Hydrogen: Deamination
of Anilines

Diazonium Salts as
Electrophiles: Diazo Coupling
Synthesis of Amines by
Reductive Amination
• The most common amine synthesis begins with ammonia

or an amine and addition of another alkyl group.
• Reductive amination is the most general synthesis, capable

of adding a primary or secondary alkyl group to an amine.
Reductive Amination: 1° Amines
• Primary amines result from the condensation of

hydroxylamine (zero alkyl groups) with a ketone or an
aldehyde, followed by reduction of the oxime.
• LiAlH4 or NaBH3CN can be used to reduce the oxime.
• Condensation of a ketone or an aldehyde with a

primary amine forms an N-substituted imine (a
Schiff base).
• Reduction of the N-substituted imine gives a
secondary amine.

• Condensation of a ketone or an aldehyde with a secondary

amine gives an iminium salt.
• Iminium salts are frequently unstable, so they are rarely
isolated.
• A reducing agent in the solution reduces the iminium salt to
a tertiary amine.
Solved Problem 3
Show how to synthesize the following amines from the indicated starting materials.
(a) N-cyclopentylaniline from aniline (b) N-ethylpyrrolidine from pyrrolidine
Solution
(a) This synthesis requires adding a cyclopentyl group to aniline (primary) to make a
secondary amine. Cyclopentanone is the carbonyl compound.
(b) This synthesis requires adding an ethyl group to a secondary amine to make a tertiary
amine. The carbonyl compound is acetaldehyde. Formation of a tertiary amine by
Na(AcO)3BH reductive amination involves an iminium intermediate, which is reduced by
sodium triacetoxyborohydride.

Synthesis of 1° Amines by
Acylation–Reduction
• Acylation of the starting amine by an acid chloride gives

an amide with no tendency toward overacylation.
• Reduction of the amide by LiAlH4 gives the
corresponding amine.
• Acylation–reduction converts a primary amine

to a secondary amine.
• LiAlH4, followed by hydrolysis, can easily
reduce the intermediate amide to the amine.
• Acylation–reduction converts a secondary

amine to a tertiary amine.
• Reduction of the intermediate amide is
accomplished with LiAlH4.
Solved Problem 4
Show how to synthesize N-ethylpyrrolidine from pyrrolidine using acylation–reduction.
Solution
This synthesis requires adding an ethyl group to pyrrolidine to make a tertiary amine. The
acid chloride needed will be acetyl chloride (ethanoyl chloride). Reduction of the amide gives
N-ethylpyrrolidine.
Compare this synthesis with Solved Problem 19-5(b) to show how reductive amination and
acylation–reduction can accomplish the same result.

The Gabriel Synthesis
• The phthalimide ion is a strong nucleophile, displacing the

halide or tosylate ion from the alkyl halide (SN2).
• Heating the N-alkyl phthalimide with hydrazine displaces the
primary amine and the very stable hydrazide of phthalimide.
The Gabriel Synthesis

Reduction of Azides
• Azide ion, –N3, is a good nucleophile.

• React azide with unhindered 1° or 2° halide or tosylate (SN2).
• Alkyl azides are explosive, so reduction is carried out without
purifying the azide.
Reduction of Nitriles
• Nitrile (CN) is a good SN2 nucleophile.

• Reduction with H2 or LiAlH4 converts the nitrile
into a primary amine.

Reduction of Nitro Compounds
• The nitro group can be reduced to the amine by

catalytic hydrogenation or by an active metal
and H+.
• Commonly used to synthesize anilines

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Organic Chemistry,

© 2017 Pearson Education, Ltd.

© 2014 Pearson Education, Inc.

Biologically Active Amines

• The alkaloids are an important group of biologically active

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• Primary (1°): Has one alkyl group bonded to

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

Quaternary Ammonium Salts

• The nitrogen atom has four alkyl groups

© 2017 Pearson Education, Ltd.

• Common names of amines are formed from the

© 2017 Pearson Education, Ltd.

• On a molecule with a higher-priority functional

© 2017 Pearson Education, Ltd.

• Name is based on longest carbon chain.

© 2017 Pearson Education, Ltd.

• In aromatic amines, the amino group is bonded to

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• Nitrogen is sp3 hybridized with a lone pair of

• Nitrogen may have three different groups and a

• Amines whose chirality stems from the presence of

• Quaternary ammonium salts may have a chiral nitrogen

Chiral Cyclic Amines

• If the nitrogen atom is contained in a small ring, for

© 2017 Pearson Education, Ltd.

• N—H is less polar than O—H.

© 2017 Pearson Education, Ltd.

Hydrogen Bonding and

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• Amines are strongly basic and as such they can abstract a

© 2017 Pearson Education, Ltd.

Base Dissociation of an Amine

• Alkyl groups stabilize the ammonium ion, making

• Alkyl groups make the nitrogen a stronger base

• Any delocalization of the electron pair weakens the base.

© 2017 Pearson Education, Ltd.

• When the pyrrole nitrogen is protonated, pyrrole

• Pyridine is less basic than aliphatic amines, but it is

© 2017 Pearson Education, Ltd.

• Ionic solids with high melting points

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• N—H stretch between 3200 and 3500 cm–1

© 2017 Pearson Education, Ltd.

NMR Spectroscopy of Amines

• Nitrogen is not as electronegative as oxygen, so

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

Carbon NMR Chemical Shifts

© 2017 Pearson Education, Ltd.