23.1 Introduction To Amines: Amines Are Derivatives of Ammonia

23.
1 Introduction to Amines
• Amines are derivatives of ammonia:
• Amines are designated as primary, secondary, or tertiary.

• The terms 1°, 2°,and 3° are used differently for amines
than for alcohols. HOW?
Copyright 2012 John Wiley & Sons, Inc.
23-1 Klein, Organic Chemistry 1e
23.1 Introduction to Amines
• There are hundreds of examples of amines found in
natural products.

• Some naturally occurring amines take part in
neurochemistry.

• The trigonal pyramidal nitrogen atom of an amine
carries a partial negative charge on its lone pair.
• HOW do you think the amine is likely to react?

• Amines often react as a base or as a nucleophile.
• What feature(s) of the amine do you think might

determine whether it is more likely to act as a base or
as a nucleophile?

23.3 Properties of Amines
• The N atom in typical amines is sp3 hybridizes.
• The angles are 108 degrees. WHY?

• The C–N bond lengths are 147 pm, which is slightly
shorter than C–C bonds. WHY?
• Under what circumstances would the nitrogen be sp2
hybridized?

• N atoms with three
different alkyl groups are
chiral.
• Chiral compounds are

generally optically active.
WHAT does that mean?
• Amine are generally not

optically active. WHY?


• Amines with fewer than 5 carbons are typically soluble
in water. WHY?
• Explain the boiling points below.

• Many small molar mass amines have unpleasant odors.

• Amines are generally stronger bases than alcohols and
ethers. WHY?
• Amines can be readily protonated by strong and weak
acids.
• Explain the direction of the equilibrium.

• HOW can basicity be quantified using pKa values?

12
Why does the conjugate acid of pyrrole have a lower pKa
(making pyrrole a weaker base) than pyridine or
pyrimidine?
H N N
N
N
pyrrole pyridine pyrimidine
a. Because pyrrole is smaller and more compact and this prevents its lone pair
from reacting as much.
b. Because pyrrole has less carbons and therefore the lone pair is more active.
c. Because pyrrole's lone pair participates in the delocalized electron cloud,

while pyridine's and pyrimidine's lone pairs do not.
d. Because pyrimidine has more lone pairs than pyrrole does.
Klein, Organic Chemistry 1e

which is more basic?
**Electrons in sp2 orbitals are held more strongly than sp3
15
Basicity of arylamines
17
• In general, amines with more than FIVE carbons are
only slightly soluble in water.
• Solubility is enhanced in the presence of aqueous acid.
WHY?
• Describe how an amine could be EXTRACTED from
organic impurities using an aqueous acid.

• The pKa of most alkyl amine conjugate acids are
between 10 and 11.
• Ammonium ions of aryl amines are more acidic. WHY?
• Are amides also basic? WHY?

Amines + R-X
20
explain
21
Gabriel Synthesis:
Avoids multiple alkylations
• step 1
• Step 2
• Step 3
22
• Many biomolecules exhibit amine moieties.
• Let’s examine the equilibrium between amine and
ammonium ion at physiological pH (7.3).
• The amine and the conjugate acid make a buffer. HOW?
• Recall that the Henderson-Hasselbalch equation can be
used to calculate the pH of a buffer.

• Assuming the pKa of the conjugate acid is 8.3 in the

example of an antihistamine, calculate the ratio of
amine/ammonium ion.
• Practice with CONCEPTUAL CHECKPOINT 23.9.

25
26
27
23.4 Preparation of Amines: A
Review
• Let’s review all of the methods we’ve learned in
previous chapters to synthesize amines.
1.
– Carbon skeleton expanded by 1 carbon.

2.
– Carbon skeleton is not changed.

3.
– Reduction with a metal is a bit more mild than reduction

with H2. WHY might mild conditions be preferred?
– Why is NaOH used in a final step?

23.5 Preparation of Amines via
Substitution Reactions
• Let’s learn some new amine syntheses.
• Explain WHY the reaction will not stop at the primary

amine but will continue to form a QUATERNARY
AMMONIUM SALT.

• Let’s learn some new amine syntheses.

• N2 is a great leaving group. WHY?
• Does the N2 technically act as a leaving group in the
mechanism?

23.6 Preparation of Amines via
Reductive Amination
• Recall the method for forming imines.
– If a reducing agent is present, the imine can be reduced in situ

to form an amine.
– Reductive amination can be accomplished with a variety of
reducing agents.
• SODIUM CYANOBOROHYDRIDE, which is similar to
NaBH4, is commonly used.
– The inductive effects of the –CN group make the

cyanoborohydride reagent more selective.

• Why can’t NaBH4 be used for reductive
aminations? (it would just reduce the ketone
first)

23.7 Synthetic Strategies
• Let’s review reactions that form amines:

23.8 Acylation of Amines
• Recall that amines can attack acyl chlorides.
• Two moles of the amine are used. WHY?

– Removes HCl which otherwise protonates the amine
• Polysubstitution is not observed. WHY?
• An acyl group can act as a protecting group. HOW?
• An acyl group can help to limit the reactivity of amines
in EAS reactions.
23.8 Acylation of Amines
• How might you perform monobromination of aniline??
– Adding bromine won’t work because polysubstitution cannot

be avoided.

• How might you perform the following synthesis?
• The disadvantage of this synthesis is that amide

hydrolysis requires harsh conditions.
• Aromatic amines also cannot undergo Friedel Crafts
directly.
• How does the addition of the AlCl3 group deactivate the

ring?
• To achieve ring alkylation, first, the amine must be
acylated.

23.9 The Hofmann Elimination
• Like alcohols, amines can be converted into leaving
groups for elimination reactions.

• Like alcohols, amines can be converted into leaving
groups for elimination reactions.
• Unexpectedly, the less substituted (less stable) product

is observed.

23.9 The Hofmann Elimination
• Sterics in the anticoplanar conformation hinder attack
at the more substituted site. Draw an energy diagram.

23.10 Reaction of Amines with
Nitrous Acid
• Nitrous acid is formed and reacted in situ.

Nitrous Acid
• The nitrosonium ion is extremely electrophilic (very
unstable), so its formation is NONSPONTANEOUS.
• If the nitrosonium ion forms in the presence of a 1° or

2° amine, the equilibrium can be pushed forward.
HOW?

Nitrous Acid
• A nitrosamine is formed.

Nitrous Acid
• If the nitrosonium reacts with a 1° amine, a different
product results.

Nitrous Acid
product results.
– Draw the product of the step below.

Nitrous Acid
product results.
Read from right to left
– A diazonium salt is produced.

23.11 Reactions of Aryl Diazonium
Ions
• Alkyl diazonium salts are extremely reactive (potentially
explosive) because of the excellent N2 leaving group.
• Aryl diazonium salts are a bit more stable and
synthetically versatile.

Ions
• Treatment with a copper salt yields an aryl halide or
nitrile.

Ions
• Explain each step in the synthesis below.
• A fluorine can also be installed.

Ions
• There are many other diazonium salt substitutions.
• Using this synthesis, amines can be used as directing

groups and subsequently replaced with –H atoms.

Ions
• Diazonium salts can also be attacked by aromatic rings
with an activating group (EAS mechanism).
• Draw each resonance contributor of the sigma complex.

Ions
• Azo coupling produces azo dyes.
• WHY are azo compounds colored?
• Varying the substitution on the rings affects the specific

dye color.

23.12 Nitrogen Heterocycles
• Heterocycles are ring compounds that incorporate a
noncarbon atom in the backbone of the ring.

• Pyrrole is a simple heterocycle that is aromatic. HOW?

• Imidazole is another simple heterocycle that is aromatic.
HOW?
• Histamine contains an imidazole ring.

• Pyridine is a six-membered heterocycle.
• The lone pair on the nitrogen in pyridine is not
necessary to achieve 4n+2 pi electrons.
• Yet, pyridine is significantly less basic than typical alkyl
amines. WHY?

• Pyrimidine is similar to pyridine.
• Pyridine and pyrimidine can undergo EAS reactions,

however usually with low yields.

23.13 Spectroscopy of Amines
• Amines generally give broad IR peaks between
3300–3500 cm-1 that are less intense than O–H
stretching.
– Recall that 1° amines give two N–H stretch IR signals
(symmetric and asymmetric stretching).
– 2° amines give one N–H stretch IR signal.
– 3° amines do not give N–H stretching signals.
– 3° amines can give a N–H stretching signal if treated with an
acid like HCl. HOW?

• N–H protons generally appear between 0.5 and 5.0 ppm
in the 1H NMR.
– Solvent, concentration, and temperature can affect the
chemical shift.
• Because N–H protons are generally exchanged at a
faster rate than the NMR timescale, N–H protons
generally give broad signals with no splitting.
• If a deuterated solvent is used, N–H proton peaks
disappear completely. HOW?

• Explain the shifts for each of the 1H and 13C signals in
the molecule below.
– Predict the 1H splitting patterns.
1H signals
13C signals

• Compounds with an odd number of N atoms should
have an odd mass molecular ion in their mass spectra.
• How does the molecular ion form?
• Can you think of a compound with one nitrogen atom

that does not have an odd mass molecular ion?

• Amines also typically undergo alpha cleavage in the
mass spectrometer giving predictable mass fragments.
• Practice with CONCEPTUAL CHECKPOINTs 23.34 and
23.35.


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23.

• Amines are designated as primary, secondary, or tertiary.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

• HOW do you think the amine is likely to react?

Copyright 2012 John Wiley & Sons, Inc.

• What feature(s) of the amine do you think might

Copyright 2012 John Wiley & Sons, Inc.

• The angles are 108 degrees. WHY?

Copyright 2012 John Wiley & Sons, Inc.

• Chiral compounds are

• Amine are generally not

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

• Explain the direction of the equilibrium.

Copyright 2012 John Wiley & Sons, Inc.

c. Because pyrrole's lone pair participates in the delocalized electron cloud,

d. Because pyrimidine has more lone pairs than pyrrole does.

Klein, Organic Chemistry 1e

**Electrons in sp2 orbitals are held more strongly than sp3

Copyright 2012 John Wiley & Sons, Inc.

• Are amides also basic? WHY?

Copyright 2012 John Wiley & Sons, Inc.

• Assuming the pKa of the conjugate acid is 8.3 in the

• Practice with CONCEPTUAL CHECKPOINT 23.9.

Copyright 2012 John Wiley & Sons, Inc.

– Carbon skeleton expanded by 1 carbon.

Copyright 2012 John Wiley & Sons, Inc.

– Carbon skeleton is not changed.

Copyright 2012 John Wiley & Sons, Inc.

– Reduction with a metal is a bit more mild than reduction

Copyright 2012 John Wiley & Sons, Inc.

• Explain WHY the reaction will not stop at the primary

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

– If a reducing agent is present, the imine can be reduced in situ

– The inductive effects of the –CN group make the

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

• Two moles of the amine are used. WHY?

– Adding bromine won’t work because polysubstitution cannot

Copyright 2012 John Wiley & Sons, Inc.

• The disadvantage of this synthesis is that amide

• How does the addition of the AlCl3 group deactivate the

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

• Unexpectedly, the less substituted (less stable) product

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

• If the nitrosonium ion forms in the presence of a 1° or

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

– A diazonium salt is produced.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.

Copyright 2012 John Wiley & Sons, Inc.