Amines
NOMENCLATURE: Amines may be considered as organic derivatives of ammonia. Amines are
classified as being primary (1°), secondary (2°), or tertiary (3°) on the basis of the number of
organic groups attached to the nitrogen. In common nomenclature, most primary amines are
named as alkylamines. In systematic nomenclature they are named by adding the suffix -amine
to the name of the chain or ring system to which the NH2 group is attached with replacement of
the final -e.
In the IUPAC system, the substituent —NH2 is called the amino group.
Arylamines
1
Heterocyclic Amines: The important heterocyclic amines all have common names. In systematic
replacement nomenclature the prefixes aza-, diaza-, and triaza- are used to indicate that nitrogen
atoms have replaced/carbon atoms in the corresponding hydrocarbon.
2
Physical Properties: Amines are moderately polar substances; they have boiling points that are
higher than those of alkanes but generally lower than those of alcohols of comparable molecular
weight. Molecules of primary and secondary amines can form strong hydrogen bonds to each
other and to water. Molecules of tertiary amines cannot form hydrogen bonds to each other, but
they can form hydrogen bonds to molecules of water or other hydroxylic solvents. As a result,
tertiary amines generally boil at lower temperatures than primary and secondary amines of
comparable molecular weight, but all low-molecular-weight amines are very water soluble.
Structure of Amines: sp3 hybridized, trigonal pyramidal, if we were to consider the unshared
electron pair as being a group we would describe the geometry of the amine as being tetrahedral
The bond angles are what one would expect of a tetrahedral structure; they
are very close to 109.5°. The bond angles for trimethylamine, for example,
are 108°. If the alkyl groups of a tertiary amine are all different, the amine
will be chiral. Resolution is usually impossible because the enantiomers
interconvert rapidly, This interconversion occurs through what is called a
pyramidal or nitrogen inversion. The barrier to the interconversion is
about 25 kJ mol-1 for most simple amines, low enough to occur readily at
room temperature.
Ammonium salts cannot undergo inversion because they do not have an unshared pair. Therefore,
those quaternary ammonium salts with four different groups are chiral and can be resolved into
separate (relatively stable) enantiomers.
3
BASICITY OF AMINES: AMINE SALTS: Amines are relatively weak bases. They are stronger
bases than water but are far weaker bases than hydroxide ions, alkoxide ions, and alkanide anions
The aminium ion from a more basic amine will have a smaller Ka (larger pKa) than the aminium
ion of a less basic amine. Primary alkylamines (RNH2) are more basic than ammonia (NH3).
We can account for this on the basis of the electron-releasing ability of an alkyl group. An alkyl
group releases electrons, and it stabilizes the alkylaminium ion that results from the acid-base
reaction by dispersing its positive charge. It stabilizes the alkylaminium ion to a greater extent than
it stabilizes the amine:
In the gas phase the basicities of the following amines increase with increasing methyl substitution:
4
Basicity of these amines in aqueous solution
In aqueous solution the aminium ions formed from secondary and primary amines are stabilized
by solvation through hydrogen bonding much more effectively than are the aminium ions formed
from tertiary amines. The aminium ion formed from a tertiary amine such as (CH3)3NH+ has only
one hydrogen to use in hydrogen bonding to water molecules, whereas the aminium ions from
secondary and primary amines have two and three hydrogens, respectively.
Basicity of Arylamines: They are much weaker bases than the corresponding nonaromatic
amine:
Structures 3–5, however, delocalize the unshared electron pair of the nitrogen over the ortho and
para positions of the ring. This delocalization of the electron pair makes it less available to a proton,
and delocalization of the electron pair stabilizes aniline.
5
Another important effect in explaining the lower basicity of aromatic amines is the electron-
withdrawing effect of a phenyl group. Because the carbon atoms of a phenyl group are sp2
hybridized, they are more electronegative (and therefore more electron withdrawing) than the
sp3-hybridized carbon atoms of alkyl groups.
Amines versus Amides Although amides are superficially similar to amines, they are far less
basic (even less basic than arylamines). The pKa of the conjugate acid of a typical amide is
about zero. An amide is stabilized by resonance involving the nonbonding pair of electrons on the
nitrogen atom. However, an amide protonated on its nitrogen atom lacks this type of resonance
stabilization.
A more important factor accounting for amides being weaker bases than amines is the powerful
electron-withdrawing effect of the carbonyl group of the amide.
Aminium Salts and Quaternary Ammonium Salts When primary, secondary, and tertiary amines
act as bases and react with acids, they form compounds called aminium salts. In an aminium
salt the positively charged nitrogen atom is attached to at least one hydrogen atom.
6
When the central nitrogen atom of a compound is positively charged but is not attached to a
hydrogen atom, the compound is called a quaternary ammonium salt.
Quaternary ammonium halides, because they do not have an unshared electron pair on the
nitrogen atom, cannot act as bases. Quaternary ammonium hydroxides, however, are strong bases.
As solids, or in solution, they consist entirely of quaternary ammonium cations (R4N+) and
hydroxide ions (OH-); they are, therefore, strong bases—as strong as sodium or potassium
hydroxide. Quaternary ammonium hydroxides react with acids to form quaternary ammonium salts:
7
Solubility of Amines in Aqueous Acids: Almost all alkylaminium chlorides, bromides, iodides,
and sulfates are soluble in water. Thus, primary, secondary, or tertiary amines that are not soluble
in water do dissolve in dilute aqueous HCl, HBr, HI, and H2SO4. Solubility in dilute acid provides a
convenient chemical method for distinguishing amines from nonbasic compounds that are
insoluble in water.
Biologically important amines:
2-phenylethylamines
8
Adrenaline and noradrenaline are two hormones; released into the bloodstream when an animal
senses danger, adrenaline causes an increase in blood pressure, a strengthening of the heart rate,
and a widening of the passages of the lungs. Noradrenaline also causes an increase in blood
pressure, and it is involved in the transmission of impulses from the end of one nerve fiber to the
next. Dopamine and serotonin are important neurotransmitters in the brain.
Morphine, codeine: analgetics
Amphetamine: a powerful stimulant; mescaline: hallucinogen
Vitamins
Preparation
1. Alkylation of Ammonia
Salts of primary amines can be prepared from ammonia and alkyl halides by nucleophilic
substitution reactions. Subsequent treatment of the resulting aminium salts with a base gives
primary amines. very limited synthetic application
9
2. Alkylation of Azide Ion and Reduction A much better method for preparing a primary amine
from an alkyl halide is first to convert the alkyl halide to an alkyl azide (R—N3) by a nucleophilic
substitution reaction:
Alkyl azides are explosive, and low-molecular-weight alkyl azides should not be isolated.
3. Gabriel Synthesis: This synthesis avoids the complications of multiple alkylations that
occur when alkyl halides are treated with ammonia. Syntheses of amines using the Gabriel
synthesis are, as we might expect, restricted to the use of methyl, primary, and secondary alkyl
halides. The use of tertiary halides leads almost exclusively to eliminations.
10
4. Alkylation of Tertiary Amines: Multiple alkylations are not a problem when tertiary amines are
alkylated with methyl or primary halides. Reactions such as the following take place in good yield:
5. Preparation of Aromatic Amines through Reduction of Nitro Compounds
The 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. Overall,
this is a 6e– reduction.
Selective reduction of one nitro group of a dinitro compound can often be achieved through the
use of hydrogen sulfide in aqueous (or alcoholic) ammonia.
11
6. Preparation of Primary, Secondary, and Tertiary Amines through Reductive Amination
Aldehydes and ketones can be converted to amines through catalytic or chemical reduction in the
presence of ammonia or an amine. Primary, secondary, and tertiary amines can be prepared this
way. reductive amination
The reducing agents employed include hydrogen and a catalyst (such as nickel) or NaBH3CN or
LiBH3CN (sodium or lithium cyanoborohydride). The latter two reducing agents are similar to
NaBH4 and are especially effective in reductive aminations. 12
7. Preparation of Primary, Secondary, or Tertiary Amines through Reduction of Nitriles,
Oximes, and Amides: Nitriles, oximes, and amides can be reduced to amines. Reduction of a
nitrile or an oxime yields a primary amine; reduction of an amide can yield a primary, secondary,
or tertiary amine
8. Hofmann and Curtius Rearrangements: Amides with no substituent on the nitrogen react
with solutions of bromine or chlorine in sodium hydroxide to yield amines through a reaction
known as the Hofmann rearrangement or Hofmann degradation
13
From this equation we can see that the carbonyl carbon atom of the amide is lost (as CO32-) and
that the R group of the amide becomes attached to the nitrogen of the amine. Primary amines
made this way are not contaminated by 2° or 3° amines.
mechanism
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An examination of the first two steps of this mechanism shows that, initially, two hydrogen atoms
must be present on the nitrogen of the amide for the reaction to occur. Consequently, the Hofmann
rearrangement is limited to amides of the type RCONH2. The reaction occurs with retention of
configuration. Thus, the R group migrates to nitrogen with its electrons, but without inversion.
The Curtius rearrangement is a rearrangement that occurs with acyl azides. It resembles the
Hofmann rearrangement in that an R group migrates from the acyl carbon to the nitrogen atom
as the leaving group departs.
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Reactions of amines: Acid—Base Reactions
Alkylation
Acylation
Electrophilic Aromatic Substitution
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Oxidation of Amines:Tertiary amines can be oxidized cleanly to tertiary amine oxides. This
transformation can be brought about by using hydrogen peroxide or a peroxy acid:
REACTIONS OF AMINES WITH NITROUS ACID: Nitrous acid (HONO) is a weak, unstable acid.
It is always prepared in situ, usually by treating sodium nitrite (NaNO2) with an aqueous solution
of a strong acid:
Reactions of Primary Aliphatic Amines with Nitrous Acid:Primary aliphatic amines react with
nitrous acid through a reaction called diazotization to yield highly unstable aliphatic diazonium salts.
Even at low temperatures, aliphatic diazonium salts decompose spontaneously by losing nitrogen
to form carbocations.
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Reactions of Primary Arylamines with Nitrous Acid: Primary arylamines react with nitrous
acid to give arenediazonium salts. Even though arenediazonium salts are unstable, they are still
far more stable than aliphatic diazonium salts; they do not decompose at an appreciable rate in
solution when the temperature of the reaction mixture is kept below 5°C:
18
Reactions of Secondary Amines with Nitrous Acid : Secondary amines - both aryl and alkyl –
react with nitrous acid to yield N-nitrosoamines. N-Nitrosoamines usually separate from the
reaction mixture as oily yellow liquids:
Reactions of Tertiary Amines with Nitrous Acid: When a tertiary aliphatic amine is mixed with
nitrous acid, an equilibrium is established among the tertiary amine, its salt, and an N-nitroso-
ammonium compound:
While N-nitrosoammonium compounds are stable at low temperatures, at higher temperatures
and in aqueous acid they decompose to produce aldehydes or ketones. Tertiary arylamines react
with nitrous acid to form C-nitroso aromatic compounds.
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Syntheses Using Diazonium Salts: Diazonium salts are highly useful intermediates in the
synthesis of aromatic compounds, because the diazonium group can be replaced by any one of a
number of other atoms or groups, including —F, —Cl, —Br, —I, —CN, —OH, and —H.
The Sandmeyer Reaction: Replacement of the Diazonium Group by —CI, —Br, or —CN
Arenediazonium salts react with cuprous chloride, cuprous bromide, and cuprous cyanide to give
products in which the diazonium group has been replaced by —Cl, —Br, and —CN, respectively.
These reactions are known generally as Sandmeyer reactions.
20
Replacement by —I:
21
Replacement by —F: The diazonium group can be replaced by fluorine by treating the diazonium
salt with fluoroboric acid (HBF4). The diazonium fluoroborate that precipitates is isolated, dried,
and heated until decomposition occurs. An aryl fluoride is produced:
Replacement by —OH: The diazonium group can be replaced by a hydroxyl group by adding
cuprous oxide to a dilute solution of the diazonium salt containing a large excess of cupric nitrate.
Replacement by Hydrogen: Deamination by Diazotization Arenediazonium salts react with
hypophosphorous acid (H3P02) to yield products in which the diazonium group has been
replaced by —H.
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COUPLING REACTIONS OF ARENEDIAZONIUM SALTS
Arenediazonium ions are weak electrophiles; they react with highly reactive aromatic compounds –
with phenols and tertiary arylamines - to yield azo compounds. This electrophilic aromatic
substitution is often called a diazo coupling reaction.
general reaction
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REACTIONS OF AMINES WITH SULFONYL CHLORIDES
Primary and secondary amines react with sulfonyl chlorides to form sulfonamides:
When heated with aqueous acid, sulfonamides are hydrolyzed to amines:
The Hinsberg Test
A Hinsberg test involves two steps. First, a mixture containing a small amount of the amine and
benzenesulfonyl chloride is shaken with excess potassium hydroxide. Next, after allowing time for
a reaction to take place, the mixture is acidified. Each type of amine - primary, secondary, or
tertiary - gives a different set of visible results after each of these two stages of the test. Primary
amines react with benzenesulfonyl chloride to form N-substituted benzenesulfonamides. These,
in turn, undergo acid—base reactions with the excess potassium hydroxide to form water-soluble
potassium salts. Acidification of this solution will, in the next stage, cause the water-insoluble24N-
substituted sulfonamide to precipitate:
Secondary amines react with benzenesulfonyl chloride in aqueous potassium hydroxide to form
insoluble N,N-disubstituted sulfonamides that precipitate after the first stage. N,N-Disubstituted
sulfonamides do not dissolve in aqueous potassium hydroxide because they do not have an acidic
hydrogen. Acidification of the mixture obtained from a secondary amine produces no visible
result—the nonbasic N,N-disubstituted sulfonamide remains as a precipitate and no new
precipitate forms:
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If the amine is a tertiary amine and if it is water insoluble, no apparent change will take place in
the mixture as we shake it with benzenesulfonyl chloride and aqueous KOH. When we acidify the
mixture, the tertiary amine dissolves because it forms a water-soluble salt
Sulfa Drugs
26
Sulfapyridine was shown to be effective against pneumonia in 1938. Sulfacetamide was first used
successfully in treating urinary tract infections in 1941. Succinoylsulfathiazole and the related
compound phthalylsulfathiazole were used as chemotherapeutic agents against infections of the
gastrointestinal tract beginning in 1942. Sulfathiazole saved the lives of countless wounded
soldiers during World War II.
Mode of action:
Elimination involving ammonium compounds
The Hofmann Elimination: Although most eliminations involving neutral substrates tend to follow
the Zaitsev rule, eliminations with charged substrates tend to follow what is called the Hofmann
rule and yield mainly the least substituted alkene.
The transition states of elimination reactions with charged substrates have considerable
carbanionic character. Therefore, these transition states show little resemblance to the final alkene
product and are not stabilized appreciably by a developing double bond
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With a charged substrate, the base attacks the most acidic hydrogen instead. A primary hydrogen
atom is more acidic because its carbon atom bears only one electron-releasing group
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The Cope Elimination
Tertiary amine oxides undergo the elimination of a dialkylhydroxylamine when they are heated.
This reaction is called the Cope elimination:
The Cope elimination is a syn elimination and proceeds through a cyclic transition state:
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