Amines and Amides
Chapter 17
Bonding characteristics of nitrogen
atoms in organic compounds
• We saw already that carbon atoms (Group 4A) form four bonds to
other atoms in organic compounds.
• And oxygen atoms (Group 6A) form two bonds.
..
..
..
..
• Nitrogen atoms (Group 5A) require three bonds to give them
octets. Normally, nitrogen atoms are involved in three covalent
bonds to other atoms.
The important arrangement
for this chapter
..
..
..
Structure and classification of amines
• Amines are organic derivatives of ammonia
(NH3), in which one or more alkyl, cycloalkyl,
or aromatic groups replace hydrogen and
bond to the nitrogen atom.
Structure and classification of amines
• Amines are classified as primary, secondary, and tertiary, as
we have seen previously for alcohols.
• For alcohols, the type of carbon atom (1o, 2o, 3o) bound to the
–OH group determined whether the alcohol was primary,
secondary, or tertiary.
• For amines, it is the number of carbon groups that are bound
to the nitrogen atom.
1o amine
2o amine
3o amine
Structure and classification of amines
• This is an important difference in the way that 1o, 2o, and 3o
classification is given.
tert-butylamine
a 1o amine
tert-butanol
a 3o alcohol
• The –NH2 group of a primary amine can be thought of as an
“amino” group. Thus secondary and tertiary amines possess
substituted amino groups.
amino group
1o
Monosubstituted
amino group
Disubstituted
amino group
2o
3o
Structure and classification of amines
Nomenclature for amines
• Common and IUPAC systems are used extensively for naming
amines.
• In the common system, rules similar to what we have seen for
ethers are employed, naming the alkyl/aromatic groups
attached to the functional group, and then following these
with “amine”
Methylamine
Trimethylamine
Methylphenylamine
Methylpropylamine
Cyclohexyldimethylamine
Nomenclature for amines
• The IUPAC system for naming amines is as follows:
– Select the longest carbon chain bound to the nitrogen as
the parent chain
– Name the chain by changing the alkane name for this
chain: drop the “e” and add “amine”
– Number the chain to give the nitrogen the lowest
numbering
– The number and identity of other substituents (including
any on the main chain) are indicated at the beginning of
the amine name (some are attached to N)
Structure and classification of amines
• Some examples. First, 1o amines
1-Butanamine
2-Butanamine
4-C chain (“butane”; - “e” + “amine”)
# to indicate placement of NH2 group
Structure and classification of amines
• For di- and trisubstituted amines, the nonparent chains are indicated as N-bonded:
N,N-Dimethyl-1-propanamine
N-Ethyl-N-methyl-2-butanamine
Structure and classification of amines
• For diamines, the molecule is named as an “alkane-diamine”
with NH2 groups numbered.
1,4-Butanediamine
• And for cases where NH2-substituted alcohols or other
compound cases are involved, the NH2-group is called an
“amino” substituent.
3-Aminobutanoic acid
4-Amino-4-chloro-2-pentanone
Structure and classification of amines
• In cases where substituted parent chains are
encountered, the substituents are named at
the beginning of the compound’s name:
4,N-dimethyl-2-pentanamine
Parent chain: pentane
Amino-position: C-2 of parent chain
CH3- substituents on parent chain (C-4) and N
Structure and classification of amines
• Aromatic amines involve an amine-type
nitrogen bound to an aromatic ring. The
simplest case for these is aniline.
Aniline
3-Bromo-2-chloroaniline
Structure and classification of amines
• For substituted anilines, the substituent
names are treated in a manner similar to what
was shown for substituted parent chain cases:
Aniline
N-Ethyl-N-methylaniline
3,N-Dimethylaniline
Isomerism for amines
• Skeletal and positional isomers for amines are
possible.
• In skeletal isomers, the carbon chain
components of the amines differ
3-Hexanamine
2-Methyl-3-pentanamine
Isomerism for amines
• Positional isomers differ in the placement of
the –NH2 group along the parent chain.
3-Hexanamine
2-Hexanamine
• Positional isomers are possible for substituted
amines as well:
N-Ethyl-1-propanamine
N-Methyl-1-butanamine
Physical properties of amines
• Amines tend to be gases for low molecular weight cases (e.g.
up to (CH3)3N, trimethylamine) and many heavier ones are
liquids at room temperature.
• One very noticeable thing about amines is that they tend to
exhibit strong odors. For example, some have a “fishy” smell
Putrescine
(1,4-Buntanediamine)
Cadaverine
(1,5-Pentanediamine)
Physical properties of amines
• Amine boiling points are intermediate of those for alcohols
and alkanes of similar molar mass.
• Because of the presence of N-H bond(s) in primary and
secondary amines, hydrogen-bonding is sometimes possible;
however, because N is not as electronegative as O, the N-H
bond is not as polar as an O-H bond (weaker H-bonding).
Physical properties of amines
• Amines tend to be water-soluble because of H-bonding
interactions with water molecules. In fact, amines having
fewer than six carbon atoms are infinitely water-soluble.
• Water-solubility decreases as:
– Chain length increases, and,
– The degree of N-substitution increases
Basicity of amines
• Ammonia is one of the few examples of a weak base we
looked at in the first semester. It reacts with water molecules
to produce OH- ions, making the resulting solution basic:
ammonium ion
NH3 + H2O D NH4+ + OH-
• The resulting ion (NH4+) is called an ammonium ion.
• Amines react with water to produce ammonium-like species.
CH3NH2 + H2O D CH3NH3+ + OH-
..
.. .
...
..
-
Basicity of amines
• A substituted ammonium ion results from the
reaction between an amine and water.
..
...
..
.. .
-
substituted
ammonium ion
Nitrogen tends to bond to three other atoms to get an octet; when it forms four bonds
(in an ammonium salt), the nitrogen structure carries a positive charge
Basicity of amines
• Naming substituted ammonium ions:
– Named similar to amine, but with the term “ammonium
ion” instead of amine
Methylammonium ion
+
Methylamine
-
Others:
Trimethylammonium ion
Anilinium ion
Tetraethylammonium ion
Basicity of amines
• Amines are better bases than oxygencontaining compounds.
• A comparison:
A carboxylate ion
Ethylamine:
0.1 M sol'n in water has pH ~ 11.9
Ethanoate ion:
0.1 M sol'n in water has pH ~ 8.9
(from ethanoic acid)
• Ethers and alcohols have no significant
basicity in water
Amine salts
• Amines, because they are basic, can react with
acids in neutralization reactions. The reaction
produces an amine salt, as follows:
amine
amine salt
R-NH2 + H-Cl D R-NH3+ClNaming: named as an ammonium chloride
Example: (CH3)3N+Cl- is Trimethylammonium chloride
Amine salts are ionic compounds in which the positive ion comes from the substituted
ammonium and the negative ion comes from an acid used to react with the parent amine.
Amine salts
• Amine salts are water-soluble; many amines (having higher molar masses)
are not. Thus, in order to introduce an amine-based drug into he body, it
is often converted into the salt form.
• Many pharmaceuticals possess nitrogen centers that are protonated to
the ammonium form, to make them water-soluble, or to stabilize them
(they are often called “hydrochlorides”).
Paxil
. HCl
Amine salts
• The neutral form of an amine drug is often called its “freebase” form. In this neutral form, the drug may be vaporized
(because the intermolecular forces that keep it in a
condensed state at room temperature can be overcome by
heating).
• The ionic form has a very high boiling point and usually
cannot be vaporized without decomposing the structure.
+Cl-
cocaine
cocaine hydrochloride
Preparation of amines and quaternary ammonium salts
• Preparation of amines from ammonia is
possible under basic conditions:
base
NH3 + alkyl halide  1o amine
base
1o amine + alkyl halide  2o amine
base
2o amine + alkyl halide  3o amine
base
3o amine + alkyl halide  quaternary ammonium salt
Preparation of amines and quaternary ammonium salts
• When ammonia or an amine is treated with an
alkyl halide in the presence of a strong base,
the following reaction occurs:
alkyl halide
ammonia
..
X-
X-
NaOH
..
substituted amine
NaCl
H2O
Preparation of amines and quaternary ammonium salts
• When this reaction is being carried out, it is necessary to
remove the amine as it is formed before a following alkylation
step occurs:
NaOH
1o amine
NaCl
NaOH
NaOH
H2O
2o amine
NaCl
H2O
NaCl
H2O
3o amine
+
Cl-
4o amine
Heterocyclic amines
• Heterocylic compounds involve ring structures that possess
non-carbon atoms. We saw some examples in earlier
chapters (cyclic ethers, cyclic esters, etc.)
• Nitrogen heterocycles are frequently encountered in
biochemistry. Some examples are:
Caffeine
Nicotene
Heterocyclic amines
• The following nitrogen heterocycles are found frequently in
biologically relevant structures. For example, the purine
structure is present in caffeine (drug), adenine and guanine
(DNA).
Heterocyclic amines
• The nitrogen heterocycle shown below is used for oxygen
transport in the body. The heme structure (right) is present in
the bloodstream as a component of a much bigger molecule
(hemoglobin) and acquires/releases O2.
porphyrin ring
Heme, a component of hemoglobin
Selected biologically important amines
• Neurotransmitters: substances that are released at the end of
a nerve which travel across the synaptic gap to another nerve
and trigger a nerve impulse by binding to a chemical receptor
site.
Selected biologically important amines
Dopamine
Norepinepherine
+
Acetylcholine
Seratonin
Selected biologically important amines
• Epinepherine (adrenaline): a central nervous system
stimulant. Its release causes blood glucose levels to rise,
blood pressure to increase, increased heart rate and muscle
strength.
Epinepherine
Selected biologically important amines
• Histamine: responsible for the symptoms experienced during
hay fever. The body stores histamines, which are released in
the presence of pollen/dust/allergens. The response is
produced when histamines bind to receptor sites in complex
molecules.
• Antihistamines (present in a medication) bind to these same
receptor sites, and block the histamine response.
Histamine
Alkaloids
• There are some very
important nitrogencontaining plant
extracts (alkaloids)
that are used in
medicinal science (all
of which are amines):
Morphine
Codeine
Heroin
Hydrocodone
Oxycodone
Structure and classification of amides
• Amides possess a functional group that consists of a C=O
(carbonyl) directly bound to a nitrogen:
• The amide functional group involves a nitrogen atom (and
lone pair), but unlike an amine, the nitrogen center is not
basic, due to the electron-withdrawing effect of the C=O
group.
Structure and classification of amides
• Amides may be primary, secondary, or teritary:
1o amine
2o amine
3o amine
Structure and classification of amides
• In terms of their structure, amines may be aromatic (benzene
substituents); for example, benzamide:
• They may also be cyclic, or even involve multiple amide
groups in a single ring:
A d-lactam
Structure and classification of amides
• In Ch-16, we looked at lactones, which were
cyclic esters:
-lactone
-lactam
-lactam
d-lactam
Lactams
• Lactams are cyclic amides (and heterocycles)
Nomenclature of amides
• IUPAC system for naming amides:
– Like esters, amides are made using carboxylic acids. The
portion that comes from the carboxylic acid is named as a
carboxylic acid first, before dropping the “-oic acid” from
the name and adding “-amide”
– Substituents attached to the nitrogen are prefixed with “N” to indicate their position; other substituents on the
parent chain are named as part of the parent chain (unlike
for amines)
Ethanoic acid
(carboxylic acid)
Methyl ethanoate
(ester)
Ethanamide
(amide)
Nomenclature of amides
• Some examples:
Propanamide
N-Methylbutnamide
N,N-Diethyl-3-methylbutanamide
• For aromatic cases:
Benzamide
N,N-Dimethylbenzamide
N,N,3,5-Tetramethylbenzamide
Selected amides and their uses
• Urea is one of the simplest amides, formed by reaction
between CO2 and ammonia in a series of metabolic reactions.
• Acetominophen is an aromatic amide
Urea
• Barbiturates derive from barbituric acid
(sedatives/tranquilizers) are cyclic amides, made from urea
and malonic acid:
2H2O
Urea
Pentanedioic acid
Malonic acid
Barbituric acid
Physical properties of amides
• Amides do not have a basic non-bonding pair of electrons, like
amines (as mentioned)
• The simplest amides (methanamide, N-methyl, and N,Ndimethyl derivatives) are liquids at room temperature, and all
unbranched amides having 2 or more carbons on their C-chain
side are solids.
Methanamide
N-Methylmethanamide
N,N-Dimethylmethanamide
• The secondary and teritary amides have lower melting points,
with tertiary amides having lower melting points than
secondary amides (less opportunity for H-bonding).
Physical properties of amides
4 locations on a primary amide group
that may participate in intermolecular
H-bonding
Preparation of amides
• Amides are prepared in a manner similar to
what we’ve already seen for esters. A
condensation reaction involving a carboxylic
acid is needed, this time with an amine:
100 oC
catalyst
H2O
Preparation of amides
• For amide formation to happen, the temperature must be
high (at room temperature, an acid-base neutralization
reaction happens instead).
Room Temp.
acid
base
carboxylate salt
• Also, the amine used in the reaction must be either a primary
or secondary amine (can’t be a tertiary amine).
100 oC
catalyst
Preparation of amides
Ammonia + carboxylic acid  1o amide
100oC
..
H2O
catalyst
1o amine + carboxylic acid  2o amide
100oC
..
catalyst
H2O
2o amine + carboxylic acid  3o amide
100oC
..
catalyst
H2O
Preparation of amides
• Reactions that make esters from carboxylic acids and alcohols
are called esterification reactions.
• Reactions that make amides from carboxylic acids and amines
(or ammonia) are called amidification reactions. Thus
amidification reactions are condensation reactions.
• In the condensation, the carboxylic acid loses the OH and the
amine loses a H atom:
100 oC
catalyst
H2O
Hydrolysis of amides
• Like esters, amides can undergo hydrolysis. This
reaction results in the amide being broken up into
amine and carboxylic acid starting materials:
Amidification
carboxylic acid
amine
amide
Amide hydrolysis
carboxylic acid
amine
amide
Hydrolysis of amides
• The products of the hydrolysis reaction will depend on the
acidity/basicity of the reaction conditions.
Amide hydrolysis
heat
amide
acidic/basic
conditions used
carboxylic acid
(derivative?)
amine
(derivative?)
Remember what an acid does: donates protons (H+ ions); bases accept protons.
Acids react with bases, not with other acids.
Hydrolysis of amides
• Under basic conditions, the carboxylic acid is produced as an
carboxylic acid salt:
Amide hydrolysis
H2O
basic pH
heat
amide
carboxylic acid
amine
NaOH
Remember,:
carboxylic acids are acids
amines are bases
Amide hydrolysis carried out under basic
conditions is called amide saponification.
- Na+
carboxylic acid salt
H2O
Hydrolysis of amides
• Overall, the reaction would look like this:
NaOH
- Na+
H2O
heat
carboxylic acid salt
amide
amine
• Example:
NaOH
- Na+
H2O
heat
amide
carboxylic acid salt
amine
Hydrolysis of amides
• Under acidic conditions, the amine is produced as an
ammonium salt:
Amide hydrolysis
acidic pH
H2O
heat
amide
carboxylic acid
amine
HCl
Remember,:
carboxylic acids are acids
amines are bases
Cl-
ammonium salt
Hydrolysis of amides
• Overall, under acidic conditions, the reaction would look like
this:
HCl
H2O
Clheat
carboxylic acid
amide
• Example:
ammonium salt
HCl
H2O
Clheat
amide
carboxylic acid
ammonium salt
Polyamides
• Like we saw for esters, amide condensation reactions can be
used to make polymers (another polycondensation reaction).
• As for polyesters, di-functional reactants are needed for
polymerization (i.e. a diamine and a dicarboxylic acid):
heat
a dicarboxylic acid
a diamine
...
...
a polyamide
n
Polyamides
• Nylon-6,6 is a polyamide. It can be synthesized from
Hexanedioic acid and 1,6-Hexanediamine:
n
Nylon-6,6
a polyamide
Polyamides
• Kevlar (bullet-proof
vests) is also a
polyamide: