Chem 263
Dec 7, 2010
Reactions of amines
Halogenation
NH3
I2
NI3
This kind of reaction was shown in the demo in a previous class.
Aminal and Imine Formation from Ketones and Aldehydes (review – see below also)
O
NH2R
Acylation
Amines can be acylated by the following:
O
R
Y
Acid chlorides (Y = Cl)
Anhydrides
Esters
O
O
H
Cl
N
CH3
H
N
CH3
HCl
H
H2NCH3
Note that 2 equivalents of the amine are needed,
1 for the acylation and the second forms a salt with the acid byproduct
H
H
N
H
CH3
Cl
Alkylation
Amines are good nucleophiles and can displace leaving groups in SN2 reactions.
NH3
H3N
I
H3N
H2N
SN2
I
NH4
For the reaction of ammonia with an alkyl halide, two equivalents of ammonia are
needed. One to do the alkylation, and the other one to react with the acidic proton that is
produced from the first SN2 reaction (here it is shown as an ammonium salt, it could also
occur as an HX acid)
For reactions of primary alkyl halides with substituted amines, the alkylation is difficult
to stop after the first alkylation because the product amine is also nucleophilic, and
usually more so than the starting material. The result is generally a mixture of alkylated
products. Depending on how many hydrogens the starting amine has, the alkylation will
continue until all protons are removed, or even further to make an ammonium salts. This
is usually undesirable as mixtures are often formed.
CH3
H 3C
NH2
CH3I
H 3C
CH3I
NH
H3C
N
CH3
CH3I
CH3
H 3C
CH3
N
I
CH3
CH3
tetraammonium iodide
Example:
HO
CH3I
(excess)
NH2
HI
HO
2-aminoethanol
N
H
CH3
CH3I
HO
N
CH3
CH3
HI
CH3I
O
H3 C
O
O
CH3
CH3
N
H3 C
Cl
CH3
CH3
N
HO
CH3
CH3
acetylcholinesterase
Acetylcholine
Choline
In this example, the nitrogen of amine has alkylated 3 times, whereas the oxygen is not
alkylated at all. Alcohols are much less reactive than amines. Oxygen is more
electronegative than nitrogen and is less nucleophilic. The oxygen can be alkylated by
making an alkoxide anion and then adding yet more methyl iodide.
Choline can react with acetyl chloride to form acetylcholine, a neurotransmitter. An
enzyme called acetylcholinesterase removes the acetyl group in vivo. Parathion and sarin
are inhibitors of this enzyme. Parathion is used as an insecticide (which is also toxic to
humans), while sarin has been used as a chemical weapon.
S
O
P
O
O
O
P
O
parathion
F
CH3
sarin
NO2
Amides are more stable than esters, and an amine is more reactive than an alcohol
(oxygen is more electronegative than nitrogen):
O
O
HO
NH2
Alternative syntheses of amines:
1) Reductive amination
2) Reduction of nitriles
3) Reduction of nitro groups
4) Gabriel Synthesis
Cl
HO
N
H
1) Reductive amination (via imine formation with ketone or aldehyde)
When the carbon-nitrogen double bond (an imine) is reduced to give primary or
secondary amine, this process is called reductive amination.
R
NH2
+
O
H2O
N
R
imine
1) NaBH4 or LiAlH4
2) HCl
or
H2 / Pd
HN
R
Examples:
H2 / Pd
NH2CH3
N
O
HN
N-methylamphetamine
aka methedrine
aka speed
O
O
O
1) NH2CH3
2) H2 / Pd
HN
O
O
ecstasy
methylene dioxy group
2) Reduction of nitriles (cyanides)
Primary amines can also be formed from the reduction of alkyl cyanides with a reducing
agent. The reaction occurs by nucleophilic addition of hydride ion to the carbon of the
polar nitrile bond, yielding an imine that undergoes further addition of a second
equivalent of hydride to yield the primary amine. The nitrile can be formed from SN2
displacement of an alkyl halide (X = Cl, Br, I) with sodium cyanide (NaCN) as shown
below.
H2 / Pd
NaCN
R
or
R
X
NH2
R
CN
NaBH4
or
LiAlH4
Alkyl halide (X=Cl, Br, I)
nitrile
H
1) LiAlH4
C
primary amine
N
C
2) H2O
NH2
H
The hydrogens that are circled come from the hydrides of LiAlH4, whereas the hydrogens
that are on the nitrogen come from the water
An example of this process is in the formation of mescaline. Mescaline or 3,4,5trimethoxyphenethylamine is a psychedelic hallucinogenic drug. It is found from
members of the Cactaceae. The effective human dosage is 200–400 milligrams (3.75
mg/kg), with the effects lasting for up to twelve hours. It is not physically addictive.
Users typically experience visual hallucinations and altered states of consciousness, in
some cases experienced as pleasurable and illuminating, but in others cases
accompanied by feelings of intense fear and anxiety.
Addition of sodium cyanide to 3,4,5-trimethoxybenzyl chloride yields the nitrile,
which is then reduced with hydrogen gas and palladium to yield mescaline. Since
mescaline has no stereogenic centers, it is formed as only a single isomer.
CN
Cl
H3CO
NaCN
H3CO
H2 / Pd
H3CO
H3CO
OCH3
3,4,5-trimethoxybenzyl chloride
H3CO
NH2
H3CO
OCH3
OCH3
Mescaline
3) Reduction of NO2
Amines can be prepared by the reduction of a nitro group. The reduction step can be
carried out in many different ways, depending on the circumstances. Catalytic
hydrogenation over platinum or palladium is clean but incompatible with the presence
of other reducible groups such as double bonds. Lithium aluminum hydride followed
by acid treatment is a useful method to obtain amines from nitro groups but
incompatible with carbonyl groups present. Other methods involve the use of iron,
zinc, or tin in acidic aqueous solutions.
H2 / Pd
or
R NO2
R NH2
Sn / HCl
or
LiAlH4
Example:
NO2
NH2
Sn
HCl
An example is the preparation of amphetamine from benzyl bromide and nitroethane.
Treatment of nitroethane with base removes the α-hydrogen to the nitro group
forming an anion, which then displaces the bromine in an SN2 type mechanism. The
α-hydrogens are easily removed because the nitro group is similar in properties to a
carbonyl group and is electron withdrawing making these hydrogen’s acidic.
Treatment of the resulting nitro compound with hydrogen gas and palladium then
yields amphetamine.
:B
H
O
O
N
N
H2 / Pd
O
NO2
O
NH2
Br
nitroethane
benzyl bromide
Amphetamine
Amphetamine, also known as speed, is a synthetic stimulant that has been used to
suppress the appetite, control weight, and treat disorders including narcolepsy and
attention-deficit hyperactivity disorder. It is also used recreationally and for
performance enhancement (these uses are illegal in most countries).
Why would amphetamine not be synthesized in the following manner?
NH2
Br
NH3
Polyalkylations would occur, which would make it very difficult to achieve a good
yield of the desired product.
4) Gabriel Synthesis
The Gabriel amine synthesis uses phthalimide alkylation in preparing a primary
amine from an alkyl halide (where X=Cl, Br, I). Imides (-CONHCO-) are similar to
ethyl acetoacetate in that the NH hydrogen is flanked by two carbonyl groups. Thus,
imides are deprotonated by such bases as KOH, and the resultant anions are readily
alkylated. Reaction with hydrazine (H2NNH2) of the N-alkylated imide then yields a
primary amine product along with a byproduct that is similar to luminol (seen in
demo).
O
R
X
N
K+
O
O
N
H2NNH2
R
NH2
R
O
potassium phthalimide
O
N-alkylated imide
HN
HN
O
primary amine
An example is the preparation of p-chlorophenylalanine from the chirally pure
brominated starting material in the (S) configuration. The phthalimide displaces the
bromine in an SN2 mechanism, which is then followed by hydrazine treatment,
yielding ( R )-p-chlorophenylalanine as shown below. P-chlorophenylalanine is an
unnatural amino acid, which was found to be an aphrodisiac (sexual stimulant).
O
N
O
K+
OH
O
O
H2NNH2
Br
Cl
OH
NH2
Cl
p-chlorophenylalanine
Alkaloids
Alkaloids are nitrogen-containing substances usually from plant sources. The study of
alkaloids provided much of the growth in organic chemistry in the nineteenth century
and remains today a fascinating area of research. Many alkaloids have pronounced
biological properties, and many pharmaceutical agents used today are derived from
naturally occurring amines. Morphine (as shown previously) and related alkaloids
from the opium poppy, for example, are used from pain relief. In the next section, we
will look at some important and well-known alkaloids from various sources of plant
material from the Solanaceae plant family (includes peppers, tobacco, potato, and
tomato) including nicotine, solanine, and atropine.
Nicotine is found naturally in tobacco and is shown below. It constitutes 0.3 to 5% of
the tobacco plant by dry weight. It is a potent nerve poison and is included in many
insecticides. In lower concentrations, the substance is a stimulant and is one of the
main factors leading to the habit-forming qualities of tobacco smoking. Nicotine
seems to provide both a stimulant and a depressant effect, and it is likely that the
effect it has at any time is determined by the mood of the user, the environment and
the circumstances of use. The body converts nicotine into nicotinic acid or better
known as niacin. Niacin, also known as vitamin B3, is a water-soluble vitamin whose
derivatives such as NADH, NAD, NAD+, and NADP play essential roles in energy
metabolism in the living cell and DNA repair. Severe lack of niacin causes the
deficiency disease pellagra, whereas a mild deficiency slows down the metabolism,
which in turn decreases cold tolerance and is a potential contributing factor towards
obesity.
H
N
Nicotine
N
CO2H
body
N
Nicotinic acid
Solanine is a glycoalkaloid (contains a steroidal alkaloid linked to a sugar) poison
found primarily in the green parts of potato (stems, leaves) and greening potatoes. It is
very toxic even in small quantities. Studies suggest that 2-5 mg/kg body weight can
cause toxic symptoms and a dosage of 3-6 mg/kg body weight can be fatal. Solanine
has both fungicidal and pesticide properties, and it is one of the plant's natural
defenses. A few people fall ill or die each year from eating green potatoes, which is
attributed to the consumption of solanine. Potatoes naturally produce solanine as a
defense mechanism against insects, disease, and predators.
H
N
H
OH
OH
HO
O
O
O
H
H
O
O
OH
HO
HO
O
OH
OH
OH
Solanine
Atropine is a tropane alkaloid extracted from the deadly nightshade (Atropa
belladonna) and other plants of the family Solanaceae. It is a secondary metabolite of
these plants and serves as a drug with a wide variety of effects. Being potentially
deadly, it derives its name from Atropos, one of the three Fates who, according to
Greek mythology, cut the thread of life. In the Renaissance times, women used the
juice of the berries of Atropa belladonna to enlarge the pupils of their eyes, for
cosmetic reasons; "belladonna" is Italian for "beautiful lady".
N
H
Ph
H
O
OH
O
Atropine
Generally, atropine lowers the "rest and digest" activity of all muscles and glands
regulated by the parasympathetic nervous system. This occurs because atropine is a
competitive antagonist of the acetylcholine receptors (Acetylcholine is the
neurotransmitter used by the parasympathetic nervous system). Therefore, it may
cause swallowing difficulties and reduced secretions. Atropine is the name of the
racemic mixture, while the enantiomer shown above (refered to as hyoscyamine) is
isolated from Hyoscyamus species known as henbane and from Datura species (e.g.
D. stramonium), many of which have trumpet shaped flowers.
Scopolamine is closely structurally related to atropine. Isolated from Datura
stramonium (Jimson weed), it has been used to help fight sea sickness.
N
O
H
Ph
H
O
OH
O
Scopolamine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca
plant (Erythroxylum coca). This is not in the Solanaceae family, but rather is in
family Erythroxylaceae. It is a stimulant of the central nervous system and an appetite
suppressant, creating what has been described as a euphoric sense of happiness and
increased energy. Though most often used recreationally for this effect, cocaine is
also a topical anesthetic that was used in eye and throat surgery in the 19th and early
20th centuries. Cocaine is addictive, especially in free base form (e.g. Crack). Shown
below are two representations of cocaine:
N
CO2CH3
H
O
H
O
OCH3
H 3C
O
Cocaine
N
OOCPh
The addictive properties of cocaine hindered its use as an anesthetic. Derivatives were
synthesized to isolate the anesthetic properties from the addictive properties.
Novocain and Benzocaine are non-addictive, local anesthetics commonly used in
dentistry and as a topical pain reliever respectively.
O
N
O
O
O
NH2
Novocaine
NH2
Benzocaine