Amines

Rebecca DeVasher
CHEM253 Organic Chemsitry III
Rose-Hulman Institute of Technology
Department of Chemistry & Biochemistry
Spring 2021
Updated schedule for Exam 2 on Moodle

1 Apr.
• Amine basicity and heterocycles (in class
only, slides)
• Amine note packet pages 1-6, 15-21 (lecture
4 videos to assist)

(Tuesday) & April 8th (Thursday):

• In-class lecture Aldol and
Halogenation note packets

6 Apr.
Amines

• Amines are nucleophilic and act as organic bases

• The nitrogen of an amine functional group is sp3 hybridized
• Quaternary amines can be resolved
Quantifying Amine basicity: pKa of conjugate acid

Amine basicity Conjugate acid pKa

Why is this the case?

1. Conjugate acid-base
relationship is inverse
2. pKa and Ka have an inverse
relationship
Qualifying amine basicity: EWG/EDG and resonance (electronic effects)

• EWG stabilize the

conjugate acid. What
does this do to the
basicity?
• EDG destabilize the
conjugate acid. What
effect does this have
on the basicity?
• Resonance structures
will identify delocalized
electrons, which are
less available for Lewis
acid-base reactions
Amine basicity trends

Amine basicity Conjugate acid pKa

5-membered heterocycles
Pyrrole resonance contributors
•If you go to jail, I hope you get
Pyrrole resonance contributors
Acid-base properties of pyrrole

Pyrrole polymerizes in strongly acidic solution

Bruice, table 19.1 pKa values of various
Assessing relative basicity

• Put these compounds in order of increasing basicity

• order them from least basic to most basic

How-to check point -- goes by degrees of delocalization:

1. Will protonation destroy aromaticity? (In other words, are
the nitrogen lone pairs a part of an aromatic system?)
2. Is the lone pair on the nitrogen delocalized as a part of a
nonaromatic system?
3. Saturated systems are more basic because of the EDG ability
of the alkyl systems as well as electronegativity trends of
hybridization
Assessing relative basicity

• Put these compounds in order of increasing basicity

• order them from least basic to most basic

How-to check point -- goes by degrees of delocalization:

1. Will protonation destroy aromaticity? (In other words, are
the nitrogen lone pairs a part of an aromatic system?)
2. Is the lone pair on the nitrogen delocalized as a part of a
nonaromatic system?
3. Saturated systems are more basic because of the EDG ability
of the alkyl systems as well as electronegativity trends of
hybridization
Electrophilic aromatic substitution reactions of nitrogen containing heterocycles

• Pyrrole, furan, and thiophene undergo electrophilic aromatic

substitution, preferentially at C-2.
Mechanism for Electrophilic Aromatic Substitution

• The electrophile adds to the 2-position of the pyrrole ring.

• A base (:B) in the reaction mixture removes the proton from the
carbon that formed the bond with the electrophile.
Mechanism for Electrophilic Aromatic Substitution

• Structures of the intermediates that would be formed from the

reaction of pyrrole with an electrophile at C-2 and C-3.
Electrophilic Aromatic Substitution

• If both positions adjacent to the heteroatom are occupied,

electrophilic substitution will take place at C-3.
Relative reactivity correlates to the electron-donation ability of the heteroatom

• Pyrrole, furan, and thiophene are more reactive than benzene

toward electrophilic aromatic substitution.
6-membered ring heterocycles
Pyridinium
ion
•Stronger acid than a
typical ammonium ion
because its proton is
attached to
an sp2 nitrogen, which
is more
electronegative than
an sp3 nitrogen
(Section 2.6).
Pyridine

• Pyridine is nucleophlic, and will undergo Sn2 reactions

Pyridine is deactivated toward EAS
Pyridine is relative unreactive toward electrophilic aromatic substitution
Pyridine is
relatively inert
to Electrophilic
aromatic
substitution
• When reactions are
vigorous enough,
substitution occurs at
the C-3 position.
• Pyridine does not
participate in F-C
alkylation or acylation.
 AMINES NOTE PICK UP 7-14
PACKET PAGES AFTER CARBONYL
1-6 INTRODUCTION
Amines

AMINES NOTE
PACKET 15-21
Preparation of amines

• Amines ARE NOT prepared by a nucleophilic substitution

• Problems: overalkylation due to the increased nucleophilic character of the
secondary amines formed as products
 Preparation of
SYNTHESIS OF PRIMARY AMINES
amines: alkyl
azide
reduction
•To make primary amines, a nitrogen nucleophile
is needed that can only be alkylated once.
Alternatively, a higher oxidation state of
nitrogen can be reduced to a primary amine.

•Azide a good nucleophile and gives alkyl azides.

Alkyl azides are not nucleophilic, so the reaction
stops after adding one alkyl group. Reduction of
the azide with LiAlH4 gives a primary amine.
Preparation of
amines: alkyl
azide reduction SN2
Gabriel Synthesis

•Phthalimide can only be

alkylated once after it is
deprotonated.

•Treatment of phthalimide
with hydrazine releases the
primary amine
Preparation of amines:
Reduction of higher oxidation
state nitrogen functional groups
• Aromatic nitro groups
• Nitro groups can be reduced by a variety of
reagents. We will use Fe and HCl

• Nitriles
• Nitriles can be reduced with LiAlH4 to give
primary amines
• Another way to convert an alkyl halide into a
primary amine
• Make sure you number or keep track of your
carbon chain. In this case, another carbon will
be added to the chain from the nitrile
 • Amines can be prepared by reacting a ketone or
Reductive amination aldehyde with an amine in the presence of a reducing
agent (NaBH3CN)
• The amine reacts with the carbonyl to make an
NaBH3CN
imine (or iminium), which is reduced by the
Sodium cyanoborohydride reducing agent to an amine.
Reductive amination mechanism follows a double trans elimination
Nucleophilic Aromatic Substitution: SNAr

p.18 in note packet

Nucleophilic Aromatic Substitution: SNAr

p.18 in note packet

Reduction of Amides

• Treatment of an amide with LiAlH4 gives an amine rather than

an alcohols as other carboxylic acid derivatives do.
• We get an amine because the oxygen is a better leaving group than the amine.
• This method can be used to add an alkyl group to an amine starting by making the
amide from an acid chloride.
Reduction of amides: Synthetic pathway
You are not responsible for the mechanism
Hoffman
rearrangement
• Treatment of the
primary amide with a
basic solution of liquid
bromine results in loss
of the amide carbonyl
to give a primary
amine with one less
carbon
Synthesis
examples
• Notice the first example is a
secondary amine attached to
a SECONDARY carbon (think
reductive amination)
• In the second example, since
there is no secondary carbon
attached to the amine, we
can use azides and amides
 • Alkyl amines produce unstable diazonium ions
Diazonium ions • Aryl amines produce diazonium ions stable at
low temperature
Nucleophilic Aromatic Substitution: SNAr

• Third mechanism for nucleophilic aromatic substitution

• Likely involves free radical species
• Nitrogen gas great leaving group (entropically favorable)