Download amine

Chapter 18
Amines and Heterocycles
© 2006 Thomson Higher Education
Amines and Heterocycles
Amines are organic derivatives of ammonia
• Amines contain a nitrogen atom with a lone pair of
electrons
•
Amines are basic and nucleophilic
• Amines occur widely in both plants and animals
18.1 Naming Amines
Amines can be either aklyl-substituted (alkyamines) or arylsubstituted (arylamines)
•
Amines are classified depending on the number of organic
substituents attached to nitrogen:
• Primary (RNH2)
•
•
Secondary (R2NH)
•
•
One organic substituent such as methylamine (CH3NH2)
Two organic substituents such as dimethylamine [(CH3)2NH]
Tertiary (R3N)
•
Three organic substituents such as trimethylamine [(CH3)3N]
Naming Amines
Quaternary ammonium salts
• Nitrogen containing compounds with four groups
attached to the nitrogen atom
•
Compound carry a formal positive charge
Naming Amines
Primary amines are named in the IUPAC system in
several ways
• For simple amines the
suffix –amine is added
to the name of the alkyl
substituent
• The suffix –amine can by
used in place of the final
–e in the name of the
parent compound
Naming Amines
Complex amines with more than one functional group
are named by considering the –NH2 as an amino
substituent on the parent molecule
Naming Amines
Symmetrical secondary and tertiary amines are named
by adding the prefix di- or tri- to the alkyl group
Naming Amines
Unsymmetrically substituted secondary and tertiary
amines are named as N-substituted primary amines
• Largest alkyl group is chosen as the parent name
•
Other alkyl groups are considered N-substituents on
the parent
• N because they are attached to nitrogen
Naming Amines
Heterocyclic amines
•
Compounds in which the nitrogen atom occurs as part of a ring
• Each different heterocyclic ring system has its own parent
name
• The heterocyclic nitrogen atom is always numbered as
position 1
18.2 Properties of Amines
Nitrogen atom in alkylamines is sp3-hybridized
• Three substituents occupy the three corners of a
tetrahedron and the lone pair of electrons occupies
the fourth corner
• Bond angles are close to 109°
Properties of Amines
Nitrogen with three different substituents is chiral
•
Chiral amines cannot be resolved because the two
enantiomeric forms rapidly interconvert by a pyramidal
inversion
•
•
•
Inversion occurs by momentary rehybridization of nitrogen
atom to planar, sp2 geometry, to give planar intermediate
Rehybridization of planar intermediate to tetrahedral, sp3
geometry
Barrier to inversion is about 25 kJ/mol
Properties of Amines
Alkylamines are starting materials for insecticides and
pharmaceuticals
• Labetalol is a b-blocker used for the treatment of
high blood pressure
•
Prepared by SN2 reaction of an epoxide with a primary
amine
Properties of Amines
Amines with fewer than five carbons are generally
water-soluble
• Amines form hydrogen bonds and are highly
associated
•
H-bonding results in higher boiling points than alkanes
of similar molecular weights
• Amines possess characteristic odors
18.3 Basicity of Amines
Chemistry of amines dominated by the lone pair of
electrons on nitrogen
• Lone pair makes amines both basic and nucleophilic
Basicity of Amines
Amines are much stronger bases than alcohols and
ethers
• Base strength measured by basicity constant, Kb
RNH 2 + H 2O
RNH 3+ + OH -
 RNH 3+  OH - 
Kb =
 RNH 2 
pK b = - log K b
Basicity of Amines
Kb values are not often used
• Basicity of the amine is commonly measured by
determining the acidity of its conjugate acid
RNH 3+ + H 2O
Ka
RNH 2 + H 3O +
  RNH 2   H 3O +     RNH 3+  OH -  
 Kb = 


+
RNH
RNH




 
 
3 
2

=  H 3O +  OH -  = K w = 1.0  10-14
Ka =
and
Kw
Kb
and
Kb =
pK a + pK b = 14
Kw
Ka
Basicity of Amines
Weaker base: Smaller
pKa for ammonium
ion
Stronger base: Larger
pKa for ammonium
ion
Basicity of Amines
Amides (RCONH2) are nonbasic
• Amides do not undergo substantial protonation when
treated with acids
• Amides are poor nucleophiles
• Nitrogen lone-pair electrons are stabilized through
orbital overlap with the carbonyl group
Basicity of Amines
Primary and secondary amines are very weak acids
• N-H proton can be removed by a sufficiently strong
base
•
Diisopropylamine (pKa ≈ 40) reacts with butyllithium to
yield lithium diisopropylamide (LDA)
18.4 Basicity of Arylamines
Aryl amines are generally less basic than alkylamines
• Nitrogen lone-pair electrons are delocalized by
interaction with the aromatic ring p electron system
and less available for bonding to H+
Basicity of Arylamines
Arylamines have a larger
positive DG° for
protonation and are
therefore less basic
than alkylamines,
primarily because of
resonance
stabilization of the
ground state
• Nitrogen lone-pair
electron density is
delocalized in the
amine but the charge
is localized in the
corresponding
ammonium ion
Basicity of Arylamines
Electron-donating
substituents which
increase the reactivity
for an aromatic ring
toward electrophilic
substitution also
increase the basicity of
the aryl amine
Electron-withdrawing
substituents which
decrease ring
reactivity toward
electrophilic
substitution also
decrease arylamine
basicity
18.5 Biological Amines and the
Henderson-Hasselbalch Equation
Amines exist essentially 100% in their protonated conjugate acid
forms at physiological pH of 7.3
•
Use Henderson-Hasselbalch equation to determine relative
concentrations of amines and their conjugate acids
 A - 
pH = pK a + log
 HA
 A - 
log
= pH - pK a
 HA
Biological Amines and the
Henderson-Hasselbalch Equation
•
For a 0.0010 M solution of methylamine at pH = 7.3
• pKa of methylammonium ion = 10.64
log
CH NH 
3
2
+
3
= pH - pK a = 7.3 - 10.64
CH 3 NH 
CH 3 NH 2  = antilog(-3.34) = 4.6  10-4
CH 3 NH 3+ 
so CH 3 NH 2  =
 4.6
 10-4  CH 3 NH 3+ 
and CH 3 NH 2  + CH 3 NH 3+  = 0.0010 M
Solving simultaneously gives:
and
CH 3 NH 3+  = 0.0010M
CH 3 NH 2  = 5  10-7 M
Biological Amines and the
Henderson-Hasselbalch Equation
Cellular amines are written in their protonated forms
• Amino acids shown in their ammonium carboxylate
form to reflect their structures at physiological pH
18.6 Synthesis of Amines
Reduction of Nitriles, Amides and Nitro Compounds
•
Nitriles and amides are reduced by LiAlH4 into amines
•
•
SN2 displacement with CNfollowed by LiAlH4 reduction
of the nitrile converts a
primary alkyl halide into a
primary alkylamine having
one more carbon
Amide reduction with LiAlH4
converts carboxylic acids and
their derivatives into amines
with the same number of
carbon atoms
Synthesis of Amines
• Aryamines are usually prepared by nitration of an
aromatic starting material
Synthesis of Amines
SN2 Reaction of Alkyl Halides
• Ammonia and other amines are good nucleophiles in
SN2 reactions
•
Aklylamines are synthesized most simply by SN2
alkylation of ammonia or an alkylamine with an alkyl
halide
Synthesis of Amines
•
Alkylations of ammonia and alkylamines often yield
mixtures of products
Synthesis of Amines
Reductive Amination of Aldehydes and Ketones
• Amines can be synthesized in a single step from
aldehydes or ketones with ammonia in the presence
of a reducing agent
•
Synthesis called a reductive amination
Synthesis of Amines
Mechanism of reductive amination
•
Imine intermediate is
formed by nucleophilic
addition reaction
• C=N bond of imine
is then reduced
Synthesis of Amines
• Ammonia, primary amines, and secondary amines
can all be used in reductive amination yielding
primary, secondary, and tertiary amines, respectively
Synthesis of Amines
• Reductive aminations occur in biological pathways
• Biosynthesis of amino acid proline
• Glutamate 5-semialdehyde undergoes internal imine
formation to give 1-pyrrolinium-5-carboxylate
• 1-pyrrolinium-5-carboxylate is reduced by nucleophilic
addition of hydride ion by NADH
Worked Example 18.1
Using a Reductive Amination Reaction
How might you prepare N-methyl-2-phenylethylamine
using a reductive amination reaction?
Worked Example 18.1
Using a Reductive Amination Reaction
Strategy
• Look at the target molecule, and identify the groups
attached to nitrogen
• One of the groups must be derived from the aldehyde
or ketone component and the other must be derived
from the amine component
• In the case of N-methyl-2-phenylethylamine there are
two combinations that can lead to the product:
•
•
Phenylacetaldehyde plus methylamine
Formaldehyde plus 2-phenylethylamine
• In general, it’s usually better to choose the
combination with the simple amine component –
methylamine in this case – and to use an excess of
that amine as reactant
Worked Example 18.1
Using a Reductive Amination Reaction
Solution
18.7 Reactions of Amines
Alkylation and Acylation
• Primary and secondary (not tertiary) amines can be
acylated by reaction with acid chlorides or acid
anhydrides to yield amides
Reactions of Amines
Hofmann Elimation
•
Amines can be converted into alkenes by an elimination reaction
• NH2 is a poor leaving group and must be converted into a
better leaving group
• Hofmann elimination
• Amine is methylated with excess iodomethane to
produce a quaternary ammonium salt
• Quaternary ammonium salt undergoes elimination upon
heating with silver oxide
Reactions of Amines
•
•
•
•
Silver oxide exchanges hydroxide ion for iodide ion in
the quaternary salt
Elimination is E2
Major product is the less highly substituted alkene
Base abstracts hydrogen from least hindered position
due to the sterically bulky trialkylamine leaving group
Reactions of Amines
• Biological eliminations analogous to the Hofmann
elimination occur frequently
•
In the biosynthesis of nucleic acids adenylosuccinate
undergoes elimination of a positively charged nitrogen
to give fumarate plus adenosine monophosphate
Reactions of Amines
Electrophilic Aromatic Substitution
• Amino substituents are strongly activating, ortho- and
para-directing groups in electrophilic aromatic
substitution
•
Often give polysubstituted products
Reactions of Amines
• Amido- substituted (-NHCOR) benzenes are less
strongly activated because the nitrogen lone-pair
electrons are delocalized by neighboring carbonyl
group
Reactions of Amines
• Sulfa drugs are prepared by chlorosulfonation of
acetanilide
•
•
Reaction of p-(N-acetylamino)benzenesulfonyl chloride
with ammonia gives a sulfonamide
Amide can be hydrolyzed in presence of sulfonamide
group
18.8 Heterocyclic Amines
Pyrrole and Imidazole
• Heterocyclic amines are common in biological
systems
Heterocyclic Amines
• Most heterocycles have the same chemistry as their
open-chain counterparts
•
•
Many unsaturated ring heterocycles exhibit unique
chemistry
Pyrrole is an aromatic heterocycle prepared by
reacting furan with ammonia over alumina
Heterocyclic Amines
• Each carbon of pyrrole contributes one p electron
and the sp2-hybridized nitrogen contributes two from
its lone pair
Heterocyclic Amines
• Nitrogen atom in pyrrole is less electron-rich, less
basic, and less nucleophilic than nitrogen atom in an
aliphatic amine
• Carbon atoms or pyrrole are more electron-rich and
more nucleophilic than typical double-bond carbons
Heterocyclic Amines
• Chemistry of pyrrole is similar to activated benzene
rings
•
•
Heterocycles are more reactive toward electrophiles
than benzene rings and often require low temperatures
Halogenation, nitration, sulfonation, and Friedel-Crafts
acylation can all be accomplished with aromatic
heterocycles
Heterocyclic Amines
• Electrophilic substitution normally occurs at C2 next
to the nitrogen atom
•
Substitution at C2 gives more stable intermediate with
three resonance forms
Heterocyclic Amines
• Imidazole (a constituent of histidine) and thiazole (on
which the structure of thiamin is based) are common
five-membered heterocyclic amines
•
Only the lone-pair electrons of nitrogen atoms that are
not participating in the aromatic p system are basic
Heterocyclic Amines
Pyridine and Pyrimidine
•
The five carbon atoms and the sp2-hybridized nitrogen atom of
pyridine contribute one p electron to the aromatic sextet
• The lone-pair electrons of nitrogen atom occupy an sp2
orbital in the plane of the ring
• Pyridine is less basic that alkylamines because the lone-pair
electrons are in an sp2 orbital and are held more closely to
the positively charged nucleus and thus less available for
bonding
Heterocyclic Amines
•
Pyridine does not readily undergo electrophilic aromatic
substitution reactions
•
•
Substitutions occur only slowly and usually at the C-3 of the ring
Low reactivity of pyridine due to two factors:
1.
Electrophile complexes in and acid-base reaction with the ring
nitrogen placing a positive charge on the ring and deactivating
it toward electrophilic aromatic substitution
2.
Electron density of the ring is decreased by the inductively
withdrawing electronegative nitrogen atom
• Pyridine has substantial dipole moment (m = 2.26 D)
Heterocyclic Amines
• Pyrimidine is a constituent of nucleic acids
• Pyrimidine is substantially less basic than pyridine due
to the inductive effect of the second nitrogen atom
18.9 Fused-Ring Heterocycles
Quinoline, isoquinoline, indole, and purine are common
fuse-ring heterocycles
• Quinoline alkaloid quinine is an antimalarial drug
• The amino acid tryptophan is an indole derivative
• The purine adenine is a constituent of nucleic acids
Fused-Ring Heterocycles
Quinoline and isoquinoline both undergo electrophilic
substitutions less easily than benzene
• Reaction occurs on the benzene ring
Fused-Ring Heterocycles
Indole has a nonbasic-pyrrole-like nitrogen and
undergoes electrophilic substitution more easily than
benzene
• Substitution occurs at C3 of electron-rich pyrrole ring
Fused-Ring Heterocycles
Purine has three basic, pyridine-like nitrogens with lonepair electrons in sp2 orbitals in the plane of the ring
• The remaining purine nitrogen is non-basic and
pyrrole-like with its lone-pair electrons part of the
aromatic p system
18.10 Spectroscopy of Amines
Infrared Spectroscopy
• Primary amines show a pair of bands at about 3350
and 3450 cm-1
• Secondary amines show a single band at 3350 cm-1
Spectroscopy of Amines
Nuclear Magnetic Resonance Spectroscopy
• Amine N-H absorptions can appear over a wide
range and are best identified by adding a small
amount of D2O to the sample tube
•
N-H is exchanged for N-D and the N-H signal
disappears from the 1H NMR spectrum
Spectroscopy of Amines
• Hydrogens on the carbon next to nitrogen are
deshielded because of the electron-withdrawing
effect of the nitrogen
•
•
Absorb at lower field than alkane hydrogens
N-methyl groups are distinctive and absorb as a sharp
three-hydrogen singlet at 2.2 to 2.6 d
Spectroscopy of Amines
• Carbons next to amine nitrogens are slightly
deshielded in the 13C NMR spectrum and absorb
about 20 ppm downfield from where they would
otherwise absorb in an alkane of similar structure
Spectroscopy of Amines
Mass Spectrometry
•
•
Nitrogen rule of mass spectrometry
• A compound with an odd number of nitrogen atoms has an
odd-numbered molecular weight
• Nitrogen is trivalent thus requiring an odd number of
hydrogen atoms
Alkylamines undergo characteristic a cleavage
• C-C bond nearest the nitrogen atom is broken
Spectroscopy of Amines
•
Mass spectrum of N-ethylpropylamine has peaks at m/z = 58 and
m/z = 72 corresponding to the two possible modes of a cleavage