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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Summary
Amines (e.g. RNH2) are organic derivatives of ammonia, NH3 (replace the N-H with N-C
bonds) and so have certain similarities with ammonia (e.g. basicity, nucleophilicity).
Nitrogen containing compounds are biologically very important (examples) amines, amino acids,
amides, proteins, vitamins etc.
The important organic reactions of amines (nucleophiles) are with the common electrophiles as
we have already encountered:
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via nucleophilic substitution with alkyl halides
via nucleophilic addition aldehydes or ketones
via nucleophilic acyl substitution with carboxylic acid derivatives, especially acid
chlorides or anhydrides
Amines
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Nomenclature
Physical Properties
Structure
Reactivity
Basicity
Preparation of Amines
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Overview of alkylations
Alkylation of Ammonia by Alkyl Halides
Alkylation of Phthalimide (Gabriel synthesis of primary amines)
Reductions of nitrogen containing functional groups:
o Azides
o Nitriles
o Nitro
o Amides
Reductive Amination via Imines
Reactions of Amines
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Alkylation of Amines by Alkyl Halides
Reaction of Amines with Aldehydes and Ketones
Preparation of Amides
Hofmann Elimination
Electrophilic Aromatic Substitution of Aryl Amines
Nitrosation
o Transformations of Aryl Diazonium salts
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Amines
Nomenclature:
Functional group suffix = -amine (review)
Functional group prefix = amino
Primary, secondary, tertiary or quaternary ? Amines are described as primary (1o), secondary
(2o), tertiary (3o) or quaternary (4o) depending on how many alkyl substituents are attached to the
N atom (note the difference compared with alcohols). Quaternary amines are also known as
ammonium cations.
Physical Properties:
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The polar nature of the N-H bond (due to the electronegativity difference of the two
atoms) results in the formation of hydrogen bonds with other amine molecules, see
below, or other H-bonding systems (e.g. water). The implications of this are:
o high melting and boiling points compared to analogous alkanes
o high solubility in aqueous media
intermolecular H-bonding in amines
Structure:
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The amine functional group consists of an N atom bonded either to C or H atoms via σ
bonds.
Both the C-N and the N-H bonds are polar due to the electronegativity of the N atom.
The trigonal pyramidal arrangement of bonds around nitrogen is shallower in aryl amines
vs alkyl amines.
This is a result of resonance delocalisation of the lone pair into the aromatic π system
(such delocalisation is also responsible for the decreased basicity of aryl vs alkyl amines).
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Reactivity:
The image shows the electrostatic potential for
methylamine, CH3NH2. The more red an area is, the higher the
electron density and the more blue an area is, the lower the
electron density.
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The amine N atom is a region of high electron density
(red) due to the lone pair.
Amine N atoms are Lewis bases, (alkyl ammonium pKa
~ 10, aryl ammonium pKa ~ 5)
Amines can react as either bases or nucleophiles at the
nitrogen.
There is low electron density (blue) on H atom of the NH group.
Removal of the proton generates the amide ion
(care : not to be confused with the carboxylic acid
derivative RCONH2)
The -NH group is a very poor leaving group and needs
to be converted to a better leaving group before
substitution can occur.
The image shows the electrostatic potential for
methylammonium, CH3NH3+. The more red an area is, the
higher the electron density and the more blue an area is, the
lower the electron density.
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The ammonium N atom is a region of low electron
density (blue) due to the positive charge.
Ammonium ions are not nucleophilic.
There is low electron density (blue) on H atom of the NH3 group.
Removal of the proton regenerates the amine.
The -NH3 group is a potential leaving group.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Basicity:
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Amines are more basic than analogous alcohols (R-NH3+ pKa~ 10, R-OH2+ pKa~ -3)
o Factors (e.g. resonance, electronegativity) that affect the availabilty of the lone
pair will affect the basicity.
o N is less electronegative than O and therefore N is a better electron donor.
o alkyl and non-aromatic heterocyclic amines are slightly stronger bases than
ammonia
o aryl amines are much weaker bases than ammonia, a result of the delocalisation of
the lone pair into the π system of the ring.
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The anion derived by the deprotonation of an amine is the amide ion, NH2Amide ions are important bases in organic chemistry (example)
Amines react with Na (or K) to give the amide ion.
The basicity of aryl amines is:
o
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Increased by the presence of
electron-donating substituents on the
ring, by counter-acting the delocalisation
of the lone pair into the πsystem of the
ring.
Decreased by the presence of
electron-withdrawing substituents which
enhance the delocalisation of the lone
pair into the πsystem of the ring
(especially those ortho or para to the
amine functional group, see right).
Inclusion of a heteroatom into an aromatic ring generally decreases basicity, unless
protonation leads to an ion that can be stabilised by electron delocalisation:
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Alkylation of Ammonia
Reaction type: Nucleophilic Substitution
Summary
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Ammonia reacts as a nucleophile with alkyl halides to give primary amines in a
nucleophilic substitution reaction.
Yields are often poor as the product, a primary amine, RNH2, is itself a nucleophile and
can react with more alkyl halide.
The result are mixtures containing primary amines, secondary amines, tertiary amines
and quaternary ammonium salts.
This can be avoided if a large excess of ammonia is used.
As aryl halides do not undergo simple nucleophilic substitution, they cannot be prepared
using this method.
Related reactions
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Alkylation of Amines
Acylation of Amines
Williamson ether synthesis
Substitution reactions of Alkyl Halides
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
MECHANISM OF AMMONIA ALKYLATION
Step 1:
The N in ammonia functions as the nucleophile and
attacks the electrophilic C of the alkyl halide displacing
the bromide and creating the new C-N bond.
Step 2:
An acid/base reaction. The base (excess ammonia)
deprotonates the positive N (ammonium) center creating
the alkylation product, the primary amine.
Alkylation of Phthalimide (Gabriel synthesis of Primary Alkyl
Amines)
Reaction type: Nucleophilic substitution then Nucleophilic Acyl Substitution
Summary
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The advantage of this method is that over alkylation is avoided (see previous page)
Reaction of phthalimide with KOH removes the N-H proton giving an imide ion, a good
nucleophile.
Nucleophilic substitution by the imide ion on the alkyl halide generates an intermediate,
N-alkyl phthalimide.
Hydrolysis or hydrazinolysis liberates a primary alkyl amine.
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Organic Chemistry 233: Amines Lecture Notes
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Aryl amines cannot be prepared via this method since aryl halides do not undergo simple
nucleophilic substitution.
Related reactions
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Dr. Farshid Zand
Alkylation of Ammonia
Substitution reactions of Alkyl Halides
MECHANISM OF THE GABRIEL SYNTHESIS
Step 1:
An acid/base reaction. Deprotonation of the imide N-H
proton by the base, hydroxide. This proton is more
acidic than a simple amine due to the resonance
stabilisation by the two adjacent C=O groups. This
generates a strong nucleophile, the -ve N.
Step 2:
The N nucleophile attacks the electrophilic C of the
alkyl halide displacing the bromide and creating the new
C-N bond. This product can be compared to an N-alkyl
amide.
Step 3:
The imide can be cleaved via a mechanism analogous to
that of amides. Hydrolysis creates the dicarboxylic acid
and the required amine.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Reduction of Azides
Reaction type : Oxidation - Reduction
Summary
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Azides, R-N3, can be reduced to primary amines, R-NH2
Reagents : either lithium aluminum hydride (LiAlH4) / ether solvent or catalytic
hydrogenation (e.g. H2/Pd)
Alkyl azides are prepared by nucleophilic substitution (SN2) by azide ion, N3-, of primary
or secondary alkyl halides.
Related reactions
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Reduction of Nitriles
Reduction of Nitro compounds
Reduction of Amides
Reduction of Nitriles
Reaction type : Oxidation - Reduction or Nucleophilic Addition
Summary
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The nitrile, RC≡N, is reduced to the 1o amine by conversion of the C≡N to R-CH2-NH2
Reagents : either lithium aluminum hydride (LiAlH4) / ether solvent or catalytic
hydrogenation (e.g. H2/Pd).
Alkyl nitriles are prepared by nucleophilic substitution (SN2) by cyanide ion, CN-, of
primary or secondary alkyl halides.
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Organic Chemistry 233: Amines Lecture Notes
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Dr. Farshid Zand
Aryl nitriles can also be reduced to aryl amines.
QUESTIONS
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What is the oxidation state of the nitrile C in acetonitrile, CH3CN ?
What is the oxidation of the same C atom in acetonitrile, CH3CN after reaction with
LiAlH4 ?
Related reactions
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Reduction of Azides
Reduction of Nitro compounds
Reduction of Amides
Reduction of Nitro Compounds
Reaction type : Oxidation - Reduction
Summary
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Nitroarenes can be reduced to primary aryl amines (see scheme).
Typical reducing agents include, Fe / H+, Sn / H+ or catalytic hydrogenation (e.g. H2 / Pd)
Nitroarenes are prepared by the nitration of aromatics.
This is probably the most important method for the synthesis of anilines (Ar-NH2) and,
therefore, accessing the chemistry of diazonium compounds (see later)
Related reactions
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Reduction of Azides
Reduction of Nitriles
Reduction of Amides
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Reduction of Amides
Reactions usually in Et2O or THF followed by H3O+ work-ups
Reaction type: Nucleophilic Acyl Substitution then Nucleophilic Addition
Summary
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Amides, RCONR'2, can be reduced to the amine, RCH2NR'2 by conversion of the C=O
to -CH2Amides can be reduced by LiAlH4 but NOT the less reactive NaBH4
Typical reagents : LiAlH4 / ether solvent, followed by aqueous work-up.
Note that this reaction is different to that of other C=O compounds which reduce to
alcohols (for example esters)
The nature of the amine obtained depends on the substituents present on the original
amide.
Look at the N substituents in the following examples (those bonds don't change !)
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Organic Chemistry 233: Amines Lecture Notes
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R, R' or R" may be either alkyl or aryl substituents.
In the potential mechanism shown below, note that it is an O system that leaves.
This is consistent with O systems being better leaving groups that the less
electronegative N systems.
Related reactions
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Dr. Farshid Zand
Reduction of Azides
Reduction of Nitriles
Reduction of Nitro compounds
Reduction of Carboxylic acids and Esters
REACTION OF LiAlH4 WITH AN AMIDE
Step 1:
The nucleophilic H from the hydride reagent adds to the
electrophilic C in the polar carbonyl group of the ester. Electrons
from the C=O move to the electronegative O creating an
intermediate metal alkoxide complex.
Step 2:
The tetrahedral intermediate collapses and displaces the O as part
of a metal alkoxide leaving group, this produces a highly reactive
iminium ion an intermediate.
Step 3:
Rapid reduction by the nucleophilic H from the hydride reagent as
it adds to the electrophilic C in the iminium system. π electrons
from the C=N move to the cationic N neutralising the charge
creating the amine product.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Reductive Amination via Imines
Reaction type : Nucleophilic Addition then Oxidation - Reduction
Summary
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Aldehydes and ketones react (chapter 17) with 1o amines to give substituted imines and
2o amines to give enamines
 These N species can then be reduced to amines.
 The method provides access to 1o, 2o, or 3o amines.
 Typical reagents : step 1 : acidic buffer step 2 : most commonly catalytic
hydrogenation (e.g. H2/Pd)
 Sodium cyanoborohydride (NaBH3CN) (which is like NaBH4) can be used for
smaller scale reductions.
 R, R' and R" may be either hydrogen, alkyl, or aryl.
Related reactions
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Reduction of Aldehydes and Ketones
Reduction of Alkenes
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Overview of Amine reactions
The important organic reactions of amines (nucleophiles) are with thecommon electrophiles :
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alkyl halides via nucleophilic substitution
aldehydes or ketones via nucleophilic addition
carboxylic acid derivatives, especially acid chlorides or anhydrides, vianucleophilic acyl
substitution.
Alkylation of Amines
Reaction type : Nucleophilic Substitution
Summary
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Amines can react as a nucleophiles with alkyl halides via substitution reactions (SN2)
Yields are often poor as the product amines, are still nucleophilic and can react with more
halide.
The result is often a mixture of amines in various states of alkylation.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Related reactions
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Alkylation of Ammonia
Acylation of Amines
Williamson Ether synthesis
Substitution reactions of Alkyl Halides
MECHANISM OF AMINE ALKYLATION
Step 1:
The amine N functions as the nucleophile and attacks
the electrophilic C of the alkyl halide displacing the
bromide and creating the new C-N bond.
Step 2:
An acid/base reaction. The base (excess amine)
deprotonates the positive N (ammonium) center
creating the alkylation product, here a secondary
amine.
Reactions of Primary Amines with Aldehydes and Ketones
(review of Chapter 17)
Reaction type: Nucleophilic Addition then Elimination
Summary
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Primary amines, R-NH2 or ArNH2, undergo nucleophilic addition with aldehydes or
ketones to give carbinolamines which then dehydrate to give substituted imines.
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Organic Chemistry 233: Amines Lecture Notes
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Dr. Farshid Zand
The reactions are usually carried out in an acidic buffer to activate the C=O and facilitate
dehydration but without inhibiting the nucleophile.
Systems of the general type Z-NH2 (review table in Ch17) undergo this type of reaction
and can be used as derivatives to aid in the identification of aldehydes and ketones.
Related Reactions
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Formation of Acetals
Dehydration of Alcohols
Formation of Enamines
NUCLEOPHILIC ADDITION OF A PRIMARY AMINE GIVING AN IMINE
Step 1:
An acid/base reaction. Protonation of the carbonyl activates it and makes it more
susceptible to attack by a neutral nucleophilic like the N of a primary amine.
Step 2:
Attack of the N nucleophile at the electrophilic C of the C=O group with the electrons from
the π bond going to the +ve O.
Step 3:
An acid/base reaction. Removal of the proton neutralises the +ve charge on the N and forms
the carbinolamine intermediate.
Step 4:
To form the imine we need to dehydrate. However, before -OH leaves it needs to be
protonated, so a simple acid/base reaction.
Step 5:
Use the electrons of the N to help push out the leaving group, a neutral water molecule, this
leaves us with an iminium ion.
Step 6:
An acid/base reaction. Deprotonation of the iminium N reveals the imine product and
regenerates the acid catalyst.
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Organic Chemistry 233: Amines Lecture Notes
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Dr. Farshid Zand
Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Reactions of Secondary Amine Derivatives with Aldehydes and
Ketones
(review of Chapter 17)
enamine
Reaction type: Nucleophilic Addition then Elimination
Summary
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Secondary amines, R2NH, react with aldehydes or ketones to give carbinolamines which
then dehydrate to give enamines.
The carbinolamine in these reactions can only eliminate to give a C=C since there is no
N-H in the carbinolamine.
The products are called enamines because they are "alkene amines".
Enamines are useful reagents in synthetic organic chemistry and biochemical
transformations.
Related Reactions
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Formation of Acetals
Dehydration of Alcohols
Formation of Imines
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
NUCLEOPHILIC ADDITION OF A SECONDARY AMINE GIVING AN
ENAMINE.
Step 1:
An acid/base reaction. Protonation of the carbonyl
activates it and makes it more susceptible to attack by a
neutral nucleophilic like the N of a secondary amine.
Step 2:
Attack of the N nucleophile at the electrophilic C of the
C=O group with the electrons from the π bond going to
the +ve O.
Step 3:
An acid/base reaction. Removal of the proton neutralises
the +ve charge on the N and forms the carbinolamine
intermediate.
Step 4:
To form the enamine we need to dehydrate. However,
before -OH leaves it needs to be protonated, so a simple
acid/base reaction.
Step 5:
Removal of a proton from an adjacent C allows the π bond
to form and loss of the leaving group, a neutral water
molecule, creating the enamine.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Preparation of Amides
(review of Chapter 20)
Reaction type: Nucleophilic Acyl Substitution
Summary
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Primary amines, R-NH2 and secondary amines, R2-NH undergo nucleophilic acyl
substitution with carboxylic acid derivatives to give amides.
The most common examples are the reactions of acid chlorides and anhydrides, though
esters do react with amines.
Hofmann Elimination
Reaction type: Elimination
Summary
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Like alcohols, amines can undergo elimination reactions.
Quaternary ammonium salts undergo an E2 elimination when heated with silver oxide,
Ag2O, in water.
Amines can readily be converted into quaternary ammonium iodides by treating them
with excess methyl iodide.
Ag2O / H2O reacts giving the quaternary ammonium hydroxide, silver iodide precipitates.
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Organic Chemistry 233: Amines Lecture Notes
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Dr. Farshid Zand
When heated the hydroxide induces a base promoted 1,2- or β-elimination giving an
amine and alkene.
The regioselectivity is opposite to that predicted by Zaitsevs rule in that it leads to the
less highly substituted alkene.
The less highly substituted alkene is sometimes referred to as the Hofmann product.
The outcome is dictated by steric effects of the large leaving group and the alkyl chain
(more details ?)
NH2- and NR2- are very poor leaving groups (both anionic), but NR3 is much better
(neutral)
Compare this with with -OH and H2O in the dehydration of alcohols.
Related reactions
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Dehydration of Alcohols
Dehydrohalogenation of Alkyl Halides
MECHANISM OF THE HOFMANN ELIMINATION
The initial steps are an example of the
alkylation of an amine by methyl iodide. The
mechanism of the elimination step is shown.
When heated, the hydroxide removes the more
accessible proton, the π bond of the alkene C=C
forms and the leaving group, a neutral amine
departs.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Electrophilic Aromatic Substitution of Aryl Amines
Summary
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Arylamines are potentially very reactive towards electrophilic aromatic substitution
This is because -NH2, -NHR2 and -NR2 are very strong activators and are ortho, paradirecting.
However the basicity of the amino group means it is unsuitable for reactions with acids
(e.g. H2SO4 or AlCl3) such as nitration, sulfonation and Friedel-Crafts alkylation or
acylation.
Polysubstitution can also be a problem. For example, bromination is very rapid, even in
the absence of a catalyst, leading to bromination in all available ortho- and parapositions:
To avoid these problems, it is customary to "protect" aryl amines by converting them to
their N-acyl derivatives i.e. amides.
The protecting group (an amide) can later be removed by either acid or base hydrolysis.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
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The amide is a less powerful activating group than the simple amino group, -NH2 since
resonance within the N-acetyl group of the amide (see below) competes with
delocalisation of the N lone pair into the ring.
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Steric effects in the amide also often lead to a decrease in the amount of the orthoproducts.
In principle, the sequence protect - substitute - deprotect is equivalent to being able to
substitute the aniline directly.
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Nitrosation of Amines
Summary
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Typical reagents : sodium nitrite and aq. HCl or H2SO4 (this mixture yields nitrous acid,
HNO2)
The most useful reactions are probably those of primary aryl amines, Ar-NH2, which
give aryl diazonium salts, Ar-N2+ which can then be used to prepare substituted benzenes
(see next page)
The actual nitrosation reagent is the nitrosyl cation, NO+ which is formed in situ:
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
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The nature of the product depends on the nature of the initial amine
Primary alkyl or aryl amines yield diazonium salts (hence the diazotisation reaction)
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Alkyl diazonium salts are very unstable and yield carbocation-derived products by loss of
the very good leaving group, N2:
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Secondary alkyl or aryl amines yield N-nitrosoamines:
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Tertiary alkyl amines do not react in a useful fashion.
Tertiary aryl amines undergo nitrosation of the ring (an electrophilic aromatic
substitution reaction)
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Synthetically Useful Transformations Involving Aryl Diazonium
Ions
Summary
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Aryl diazonium salts can be converted into a range of systems as shown above.
These reactions can be useful as the methodology can be complementary to other
methods of introducing aromatic substitutents
Of particular note are the methods for introducing -F using HBF4 (the Schiemann
reaction) and -OH using H2O.
The reactions of copper salts (CuCl, CuBr and CuCN) are known as the Sandmeyer
reactions.
Coupling with phenols gives azo-compounds which are important as yellow-red dyes or
pigments.
Aryl diazonium salts are prepared from aryl amines (previous page) which in turn can be
obtained by the reduction of nitrobenzene
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Spectroscopic Analysis
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IR - The -N-H should be apparent. -NH one band, -NH2 two bands (symmetric and
asymmetric)
Absorbance (cm-1)
Interpretation
3500 - 3100
NH stretch
1350 - 1000
C-N stretch
1H
NMR - The -N-H proton(s) tend to be broad peaks. N is less electronegative than O so
it deshields less.
Resonance (ppm)
0.5 - 5.0 (broad, exchangeable)
Interpretation
-NH proton
1.5 - 3.0
CH2-NR2
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13C
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UV-VIS
maxima due to n→s* (190 nm)
o n electron from N lone pair
o s* antibonding C-N
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Mass Spectrometry
Peak for the molecular ion, M+, is usually apparent.
The nitrogen rule : compounds composed of only C, H, O have an even molecular
weight.
If a compound contains an odd number of N atoms will have an odd molecular weight.
(the Nitrogen rule).
Since N is very good at stabilising positive charge, cleavage at the b-carbon are common.
NMR
C-N typically 35 - 50 ppm (deshielding due to N)
note: the deshielding is less than that observed in alcohols, C-O = 50 - 65 ppm)
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Amine Questions
Q1:
For each of the following series of compounds, arrange the molecules in order of
Q
decreasing basicity (most basic to least basic):
(a)
(b)
(c)
(d)
Q
Q 2:
What would be the major products of the following reactions:
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Organic Chemistry 233: Amines Lecture Notes
Q 3:
Q 4:
Dr. Farshid Zand
Design syntheses of the following amines using ethene as the only source of
Q
carbon atoms:
1-aminoethane, 1-aminopropane, 1-aminobutane
What would be the major products of the reactions of cyclohexylamine with each
Q
of the following:
(a) ethanoyl chloride / Et3N
(c) cyclohexanone in an acidic
buffer
(e) excess ethyl iodide
(b) hydrogen bromide
(d) ethylene oxide followed by dilute
acid work-up.
(f) excess methyl iodide then Ag2O /
H2O / heat
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Amine Answers
Q
Q1
(
a)
Use the Lewis base definition to start and try to look at the lone pair
availability (more available = stronger base). Each system in N centered,
so we can ignore that as a factor. The amide ion is the strongest base
since it has two pairs of non-bonding electrons (more electron-electron
repulsion) compared to ammonia which only has one. Ammonium is not
basic since it has no lone pair to donate as a base.
(
b)
Amines are stronger bases than alcohols. Again we can use lone pair
availability.... N is less electronegative than O so it is a better electron
donor. What about the alcohol and the thiol ? Acidity increases down a
group, so the thiol is a worse base than the alcohol.... larger atoms tend to
form weaker bonds with the small proton.
(
c)
Since these are all substituted anilines, we need to look at the role of the
substituent (after all, it is the only thing changing across the series).
Substituents that are electron donors will make the N lone pair more
available (electron donating ability -OCH3 > -CH3) , whereas electron
withdrawing groups will make the N lone pair less available (electron
withdrawing ability -NO2 > Cl)
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
(
d)
We can still use lone pair availability. Piperidine is the most basic
(conjugate acid pKa = 11.2). The lone pair is in an sp3 hybrid orbital and
there is no resonance (no π system). In pyridine (conjugate acid pKa =
5.2) the N lone pair is in an sp2 hybrid orbital but is not part of the 6π
electron aromatic system nor is it involved in any resonance
(perpendicular). The sp2 hybrid is smaller than the sp3 hybrid, so there is
a stronger attraction to the nucleus, so less basic. In aniline (conjugate
acid pKa = 5.2), the N lone pair can interact with the π system of the
aromatic ring which makes them less available for donation. In pyrrole is
a very weak base (conjugate acid pKa = -4). The N lone pair is involved
in the 6π electron aromatic system. Protonation will destroy the
aromaticity of the 6π electron aromatic system and this makes it an
unfavourable process.
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Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Q
Q2
Nitriles, R-C≡N, are reduced to 1o amines by conversion of the R-C≡N
to R-CH2-NH2 so the product would 1-aminopentane.
Benzyl bromide is an alkyl halide and will therefore undergo
nucleophilic substitution by the nucleophilic N of ammonia giving
benzylamine.
Toluene undergoes nitration to give mainly para-nitrotoluene.
Reduction of the nitro group gives the amine, para-aminotoluene (or
para-methylaniline if you prefer).
Cyclohexanone, a ketone, will react with a secondary amine to give an
enamine (more stable alkene preferred) which on catalytic hydrogenation
reduces to the tertiary amine, N,N-dimethylaminocyclohexane.
Q
30
Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Q3
First, note that we have a homologous series of C2 to C4 amines we are
trying to make.
Here is a scheme collecting possible syntheses together. These are based
on important reactions and to be short syntheses.
31
Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
(a) 1-aminoethane : we can't add NH3 directly to the alkene, so introduce
a halogen, bromide is a good choice as it is a good leaving group then
substitute using excess ammonia.
(b) 1-aminopropane : we need to add a C atom to get from C2 to C3. For
an amine a good way to do that is via the nitrile. So after preparing ethyl
bromide, nucleophilic substitution with NaCN ( in a polar aprotic solvent
such as DMSO) will give the nitrile which can be reduced to the amine.
(c) 1-aminobutane : now we need to add 2C to get to C4.... addition of
the Grignard ethyl magnesium bromide to ethylene oxide gives 1-butanol.
Ammonia will not react with an alcohol to give substitution (poor leaving
group), our best choice here is either to convert the alcohol to the
bromide or we could use a tosylate (both better leaving groups) then
substitute with the ammonia.
32
Organic Chemistry 233: Amines Lecture Notes
Dr. Farshid Zand
Q4
Q
In each of the reactions the primary amine is the nucleophilic species
reacting with a variety of electrophiles.....
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Organic Chemistry 233: Amines Lecture Notes
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Dr. Farshid Zand