Amines

Chemistry of Amines

– Organic derivatives of NH3 with one or more alkyl or aryl

groups bonded to N.

– Include some of the most important biological

compounds.

– Like NH3, amines contain a N atom with a lone pair of

electrons, making amines both basic &
nucleophilic.
 Chemistry of Amines

– Serve many functions in living organisms, e.g

bioregulation,
neurotransmission, &
defense against predators.

– Occur widely in all living organisms.

 Amines

Trimethylamine occurs in animal tissues & is partially

responsible for the distinctive odor of fish;

Nicotine is found in tobacco; &

Cocaine -stimulant found in the leaves of the South American

coca bush.
 Chemistry of Amines

– Alkaloids are an important group of biologically active

amines.

– Mostly synthesized by plants to protect them from being

eaten by insects & animals.

– Although some alkaloids are used medicinally(chiefly as

painkillers), all alkaloids are toxic & cause death if taken
in large quantities.
 Chemistry of Amines

– Greeks chose the alkaloid coniine to kill

Socrates, although morphine, nicotine, or cocaine would
have served equally well.

– affects the motor nerves, causing paralysis & asphyxia.

Amines
 Chemistry of Amines

– Mild cases of alkaloid poisoning can produce psychological effects

that resemble peacefulness, euphoria, or hallucinations.

– People seeking these effects often become addicted to alkaloids.

– Alkaloid addiction often ends in death.

 Chemistry of Amines

Nomenclature of Amines
– Classified as primary (10), secondary (2°), or tertiary (3°),
corresponding to 1, 2, or 3 alkyl or aryl groups bonded to
N.
 Chemistry of Amines

– Quaternary ammonium salts have 4 alkyl or aryl bonds to

a N atom.
• N atom bears a +ve charge, just as it does in simple
ammonium salts such as NH4Cl.
– examples of quaternary(4°) ammonium salts:
 Chemistry of Amines

Common Names
 formed from the names of the alkyl groups bonded to
N, followed by the suffix-amine.
– The prefixes di-, tri-,& tetra- are used to describe 2, 3, or
4 identical substituents.
Chemistry of Amines
 Chemistry of Amines

– In naming amines with more complicated structures, the -

NH2 group is called the amino group.

– It is treated like any other substituent, with a number or

other symbol indicating its position on the ring or carbon
chain
 Chemistry of Amines

 IUPAC Names
– IUPAC nomenclature for amines is similar to that for
alcohols.

– The longest continuous chain of C atoms determines the

root name.

– The-e ending in the alkane name is changed to -amine, & a

number shows the position of the amino group along the
chain.
 Chemistry of Amines

– Other substituents on the C chain are given numbers, and

the prefix N-is used for each substituent on nitrogen.
 Physical Properties and Structure of
Amines
Moderately polar substances;
– have boiling points that are higher than those of alkanes
but generally lower than those of alcohols of comparable
molecular weight.

– Molecules of 1o & 2o amines can form strong H bonds to

each other & to water.
 Physical Properties and Structure of
Amines
– Molecules of 3o amines cannot form H bonds to each
other, but they can form H bonds to molecules of water or
other hydroxylic solvents.

– So 3o amines generally boil at lower temperatures than 1o

& 2o amines of comparable molecular weight, but all low-
molecular-weight amines are very water soluble.
Physical Properties and Structure of
Amines
 Basicity of Amines
– An amine is a nucleophile (a Lewis base) because its lone pair of
electrons can form a bond with an electrophile.
– Can also act as a Bronsted-Lowry base by accepting a proton from a
proton acid.
Basicity of Amines
 Basicity of Amines

– the lone pair of electrons on N makes amines both basic &

nucleophilic.

– Amines are much stronger bases than alcohols and ethers,

their oxygen containing analogs
 Synthesis of Amines

Reduction of Nitriles, Amides, & Nitro Compounds

– Can be prepared by reduction of nitriles & amides with LiAlH4.

– The two-step sequence of SN2 displacement with CN- followed by

reduction thus converts an alkyl halide into a 1o alkyl amine having an
additional C atom.

– Amide reduction converts carboxylic acids & their derivatives into

amines with same number of C atoms.
Synthesis of Amines
 Synthesis of Amines

– Arylamines usually prepared by nitration of an aromatic

starting material, followed by reduction of the nitro group
 Synthesis of Amines
– Reduction step carried out in many different ways, depending
on the circumstances.
– Catalytic hydrogenation over Pt works well but often
incompatible with the presence elsewhere in the molecule of
other reducible groups, eg C=C bonds or carbonyl groups.
– Iron, zinc, tin, and tin(II) chloride (SnCl2) also effective
when used in acidic aqueous solution.

– Tin(II) chloride particularly mild often used when other

reducible functional groups are present.
 Synthesis of Amines

SN2 Reactions of Alkyl Halides

– NH3 & other amines are good nucleophiles in SN2 reactions.

– As a result, the simplest method of alkylamine synthesis is by

SN2 alkylation of NH3 or an alkylamine with an alkyl halide.
 Synthesis of Amines

Limitations of this Synthesis Method

– Unfortunately, these reactions don’t stop cleanly after a
single alkylation has occurred.

– Because NH3 & 1o amines have similar reactivity, the

initially formed mono-alkylated substance often undergoes
further reaction to yield a mixture of products.
 Synthesis of Amines
– Even 2o & 3o amines undergo further alkylation, although to a lesser
extent.
– eg, treatment of 1-bromooctane with a twofold excess of NH3 leads to
a mixture containing only 45% octylamine.

– nearly equal amount of dioctylamine produced by double alkylation,

along with smaller amounts of trioctylamine & tetraoctylammonium
bromide.
 Synthesis of Amines

– Better method for preparing 1o amines is to use azide ion,

N3-, rather than NH3, as the nucleophile for SN2 reaction
with a 1o or 2o alkyl halide.

– Product is an alkyl azide, ---not nucleophilic, so

overalkylation can’t occur.

– Reduction of alkyl azide with LiAlH4 leads to the desired 1o

amine.
 Synthesis of Amines

– NOTE: low-molecular-weight alkyl azides are explosive &

must be handled carefully.
Synthesis of Amines
 Synthesis of Amines
– Another alternative for preparing a 1o amine from an alkyl halide is
the Gabriel amine synthesis
– for making 1o amines without danger of overalkylation.
– Use of phthalimide anion as a protected form of NH3 that cannot
alkylate more than once.
– Phthalimide has one acidic N- H proton (pKa 8.3) that is abstracted by
KOH to give phthalimide anion.
 Synthesis of Amines
– Phthalimide anion is a strong nucleophile, displacing a halide or tosylate
ion from a good SN2 substrate.

– Heating the N-alkyl phthalimide with hydrazine displaces the 1o amine,

giving the very stable hydrazide of phthalimide.
Synthesis of Amines
Synthesis of Amines
 Synthesis of Amines

 Alkylation of Tertiary Amines

– Multiple alkylations are not a problem when 3o amines are
alkylated with methyl or primary halides.

– Reactions such as the following take place in good yield:

 Synthesis of Amines

Preparation of Aromatic Amines through Reduction

of Nitro Compounds
– The most widely used method for preparing aromatic
amines involves nitration of the ring & subsequent
reduction of the nitro group to an amino group:
 Synthesis of Amines

– Reduction of the nitro group can be carried out in a

number of ways.

– Most frequently used methods employ catalytic

hydrogenation, or treatment of the nitro compound with
acid and iron.

– Zinc, tin, or a metal salt such as SnCl2 can also be used.

Synthesis of Amines
 Synthesis of Amines

– most common reason for reducing aromatic nitro

compounds is to make substituted anilines.

– Much of this chemistry was developed by the dye industry,

which uses aniline derivatives for azo coupling reactions to
make aniline dyes.

– Nitration of an aromatic ring (by electrophilic aromatic

substitution) gives a nitro compound, which is reduced to
the aromatic amine
 Synthesis of Amines: The Hofmann
Rearrangement
– In presence of a strong base, 1o amides react with Cl2 or
Br2 to form shortened amines with loss of the carbonyl
carbon atom.
– This reaction, called the Hofmann rearrangement, is used
to synthesize primary amines & aryl amines.
 Synthesis of Amines

– Although several other methods for making 1o amines,

most of them depend on SN2 displacements, which fail
with 3° alkyl groups.

– The Hofmann rearrangement can produce 1o amines with

1 °, 2°, or 3° alkyl groups, or aryl amines.
 Synthesis of Amines

– Wide variety of amines that are accessible by the Hofmann

rearrangement:
 Synthesis of Amines

Mechanism
– 1st step is replacement of one of the H on N by a halogen.

– Step is possible because the amide N-H protons are slightly

acidic, & a strong base deprotonates a small fraction of the
amide molecules.

– The deprononated amide is a strong nucleophile-it attacks

bromine to form the N-bromoamide
Synthesis of Amines
Synthesis of Amines
 Synthesis of Amines

Curtius Rearrangement
– is a rearrangement that occurs with acyl azides.

– resembles Hofmann rearrangement in that an R group

migrates from the acyl C to the N atom as the leaving
group departs.

– In this instance the leaving group is N2

Synthesis of Amines: Curtius Rearrangement

– Acyl azides are easily prepared by allowing acyl chlorides to react with
sodium azide.

– Heating the acyl azide brings about the rearrangement; afterward,

adding water causes hydrolysis & decarboxylation of the isocyanate:
 Reactions of Amines

– most of the chemistry of amines is the ability of N to share

an electron pair.
– Can thus undergo a number of reactions.
Reactions of Amines
Reactions of Amines: Oxidation Reactions

– 1o & 2o aliphatic amines are subject to oxidation, although

in most instances useful products are not obtained.
– Complicated side reactions often occur, causing the
formation of complex mixtures.

Tertiary amine oxides undergo a useful elimination

reaction to be discussed later
Reactions of Amines: Oxidation Reactions

– Arylamines are very easily oxidized by a variety of

reagents, including the oxygen in air.
– Oxidation is not confined to the amino group but also
occurs in the ring.
The amino group through its electron-donating ability makes
the ring electron rich & hence especially susceptible to
oxidation.
–
Reactions of Amines: Oxidation Reactions

– Oxidation of other functional groups on an aromatic

ring cannot usually be accomplished when an amino group
is present on the ring, because oxidation of the ring takes
place first.
Alkylation of Amines by Alkyl Halides
– Amines react with 1o alkyl halides to give alkylated
ammonium halides.

– Alkylation proceeds by the SN2 mechanism, so it is not

feasible with 3o halides because they are too hindered.

– 2o halides often give poor yields, with elimination

predominating over substitution.
Alkylation of Amines by Alkyl Halides
– Unfortunately, initially formed salt may become
deprotonated.
– Resulting 2o amine is nucleophilic, & it can react with
another molecule of the halide.
Alkylation of Amines by Alkyl Halides
– Disadvantage of direct alkylation lies in stopping it at the
desired stage.
– Even if just one equivalent of the halide is added, some
amine molecules will react once, some will react twice,
and some will react three times (to give the
tetraalkylammonium salt).
– Others will not react at all. A complex mixture results.
 Alkylation of Amines by Alkyl Halides

– Alkylation of amines can give good yields of the desired

alkylated products in 2 types of reactions:
1. "Exhaustive" alkylation to the tetraalkylammonium salt.

Mixtures of different alkylated products are avoided if

enough alkyl halide is added to alkylate the amine as
many times as possible.
 Alkylation of Amines by Alkyl Halides

– This exhaustive alkylation gives a tetraalkylammonium

salt.
– A mild base (often NaHC03 or dilute NaOH) is added to
deprotonate the intermediate alkylated amines and to
neutralize the large quantities of HX formed
Alkylation of Amines by Alkyl Halides
 Acylation of Amines by Acid Chlorides
– Primary and secondary amines react with acid halides to
form amides.
– This reaction is a nucleophilic acyl substitution: the
replacement of a leaving group on a carbonyl carbon by a
nucleophile.

– The amine replaces chloride ion

Acylation of Amines by Acid Chlorides
 Acylation of Amines by Acid Chlorides
– A base such as pyridine or NaOH is often added to
neutralize the HCI produced.