Week # 8: Amines and Amides
Lectures: 20,21, 22
Concepts:
Classification of amines - primary, secondary, tertiary
Properties of amines and amides - solubility, hydrogen bonding
Basic property - self ionization
Amine salts
Heterocyclic amines
Reaction Summary: Write the word equations
Self ionization of amines in water:
Neutralization (Salt formation) of amines with acid:
Amide Synthesis:
Amide Hydrolysis (acidic conditions)
Ques. 1. Identify the following amines as primary, secondary, tertiary, or
ammonium ion. Also name each one.
H2
C
H
N
H3C
C
H2
H 3C
CH 2
CH3
H2 C
H3 C
H2
C
N
H2C
H2N
H2
C
H2
C
C
H2
CH3
H3 C
Cl NH3
+
CH3
Ques. 2. For the following amines in Health and Medicine list all functional
groups present, and identify the amines as primary, secondary, or tertiary, and
finally list the use or occurrence of each compound.
Histamine
Diphenylhydramine
Epinephrine
Dopamine
Benzedrine
Neo-Synephrine or phenylephrine
methedrine
Ques. 3. A. Draw three molecules of ethylamine engaged in hydrogen bonding.
b. Explain why trimethylamine can not form hydrogen bonds.
Ques. 4. Explain the difference and rank them in order of lowest to highest
boiling points of ethyl methylamine, 1-propanol, trimethyl amine, and
propylamine,. Include points about relative polarity and hydrogen bonding.
Ques. 5. Write the ionization reactions for
dimethylamine
trimethylamine
ethylamine.
Neutralization Reaction or Salt Formation
Reaction Name
Word Equation
Example
21. Amine Salt reaction
Amine + HX X = Cl, Br, I
 amine halogen ion
salt
methylamine + HCl
22. Acid / amine salt
reaction
Acid + amine
 acid amine salt
Methylamine + ethanoic
acid
Ques. 6. Write the following neutralization reactions:
a. ethylamine + HCl --->
b. ethyl propylamine + HBr --->
c.
H
N
H3C
+ HCl
CH3
Ques. 7. Why are many drugs listed in the ingredients as the hydrochloride example Sudafed is listed as ephedrine hydrochloride; Novocain, local anesthetic
is the hydrochloride salt of procaine. Think about polarity of amines , salts, and
solubility in water.
Ques. 8: Name the amides in the above structures:
Ques. 9. For each of the heterocyclic amines or alkaloids list the following:
Number and type of amine present, whether a heterocyclic amine is present,
source and or use.
Nicotine
Caffeine
Quinine
Atropine
Heroin
Morphine
Codeine
Cocaine
Meperidine (Demerol)
Ques. 10. Look carefully at the structures of: Morphine, Codeine, Cocaine and
draw them. Point out the differences.
If morphine is naturally produced from the poppy, what chemical reactions are
used to change it to codeine and heroin. Be specific and show the reactions you have studied them previously.
13. Amide Synthesis
Amine + acid
 amide + water
Ethanoic acid +
methylamine
Ques 11. Write the products of reactions for the amidation or synthesis of
amides. Give the names of both the reactants and the products.
O
a. H 3C
C
H2
b.
OH
H2N
CH 3
O
H
N
H3C
H2
C
+
C
+
CH3
H 3C
C
OH
O
H2
C
H3C
H2
C
+
NH2
H3C
C
C
H2
OH
d.
H2
C
H2N
H2
C
C
H2
O
+
CH3
C
H 3C
OH
O
H3C
NH2
+
H3C
C
C
H2
OH
e.
d.
H3C
O
CH2
O
NH2
+
H3 C
C
OH
acetaminophen
Tylenol
Ques. 12. Discuss the relative basic properties of amines vs. amides. Which is
more polar and can have more possibilities for hydrogen bonding? Ethylamine or
ethanamide. Explain
Ques. 13. For each of the amides in Health and Medicine, identify those that
have amide groups only and those that have both amides and amines, those that
are heterocyclic amines. Give the uses.
Aspartame
Saccharin
Phenobarbitol
Valium
18. Amide Hydrolysis
Amide + HOH
 amine + acid
N-methylpropanamide +
HOH
Ques. 14. Complete the acid hydrolysis of the following amides. Give the names
of the reactants and the products. Note: First make the amine and the acid, then
if an acid is used as a catalyst, then the amine must form a salt with the excess
acid.
O
a. H3C
C
H2C
NH
CH3
b.
+ HOH + HCl
CH2
CH3
O
H2C
+ HOH + HCl
H2
C
C
N
C
H2
CH3
CH2
H3C
O
HN
H3C
+
C
H2C
CH3
HOH
HCl
second step
c.
d.
O
H2
C
H3C
H2
C
C
N
H
C
H2
+
HOH
CH3
HCl
second step
Focus on Molecular vs. Ionic Structures of acids & bases:
Whether an acid or base exists predominately in the molecular, undissociated
form, or the ionic form, is determined by the pKa or pKb and the pH. pKa is the
negative logarithim of the Ka and likewise for pKb. Ka and Kb are the equilbirum
constants which give information about the strength of the acid or base. Forour
discussions here the acids and bases are weak. The mathematical equations
show that when pKb or pKb = pH, there are equal concentrations of the
molecular and ionic forms of the acid or base
ACIDS
Acid Equilibrium: HA  A- + H+
If the pH is less than the pKa, the acid is predominately in the molecular form.
This occurs because excess H+ ions are attracted to the negative acid ion
A- + excess H+ 
ionic form
HA
molecular form
If the pH is greater than the pKa, the acid is predominately in the ionic form
because an excess of OH- ions has neutralized the H+ ions leaving the ionic form
of the acid.
HA + excess OH- 
A- + HOH
molecular form
Summary:


ionic form


pH increasing
pH less than < pKa
<
pH greater than
[ HA ]
[ A-]
molecular form
predominates
ionic form
predominates
Example:
If Acetic acid (pKa = 4.7) is in a solution of pH 2, what is the form, molecular
or ionic, using the summary diagram above?
Solution: pH 2 < pKa 4.7 therefore the form is molecular (CH3COOH)
Example:
If acetic acid (pKa = 4.7) is in a solution of pH of 10, what is the form,
molecular or ionic?
Solution: pKa = 4.7 < pH 10, therefore the form is ionic (CH3COO-).
BASES - Amines:
If the pH is less than pKb, the base is predominately in the ionic
form because excess H+ ions are attracted to the amine nitrogen. If the
pH is greater than the pHb, the base is predominately in the molecular
form because an excess of OH- ions has neutralized the H+ ions attached
to the amine
Amine Equilibrium: B + HOH  BH+ + OH
Summary:



pH less than < pKb

pH increasing
<
pH greater than
[BH+ ]
ionic form
predominates
[B]
molecular form
predominates
QUES. 15: Complete the equations below which are derived from the
statements above. Which form ionic or moleulcar is the end result?
a) If pH is less than pKb = B + H+ 
b) If pH is greater than b: BH+ + OH- 
QUES. 16 : If methylamine (pKb = 3.6) is at pH 2 and 10, what is the
form: molecular or ionic in each case?
Summary Diagram:



pH <
increasing pH
pKa
< pH
A-
HA
BH+
pKb
B
Example:
Ammonia (NH3) may be formed by kidney cells when blood pH is low. It can
pass through a lipid membrane by filtration into the developing urine. Under
these conditions, the aqueous urine has a pH of 4.0. If the pKb for NH3 is 4.7,
what is the form (ionic or molecular) for ammonia in urine? Can this form
repenetrate the kidney cells? Explain on the basis of solubility principles.
Solution
pH
< pKb
4.0
BH+
NH4+
4.7
< pH
B
NH3
The above analysis shows that NH4+ ions are present at a pH of 4. The ionic form
is soluble in water and insoluble in the lipid membranes. Therefore, NH4+ ions
will not repenetrate kidney cells but will be excreted.
Ques. 17: Many drugs are weak acids (pKa = 3-10) and are absorbed in the
acidic environment of the stomach. These drugs include barbiturates, penicillin,
and sulfonamides. Which form (ionic or molecular) are the weak acid drugs
absorbed through the lipid bilayers in the stomach with a pH of 1.
Solution:
HA 
H+
pH
1
HA
< pKa
3-10
+ A< pH
A- + H+
The analysis shows that the ___?___ form is present. The ___?___ form will be
more non-polar and thus more lipid soluble than the ionic form.
Ques. 18: Weak bases such as amphetamines, antihistamines, erythromycin,
and opiates, tend to be absorbed in the small intestine rather than the stomach. If
the weak bases have pKb of 3-9, the stomach pH = 1, and the small intestine pH
= 10. What is the form (ionic or molecular) for the weak base drugs in the
stomach and small intestine? Explain the solubility behavior of the drug in each
area. Solution (next page)
Solution:
B + HOH  BH+ + OHstomach
small intestine
pH
< pKb
< pH
1
3-9
10
BH+
ionic
B
molecular
The above analysis shows that the __?___ form of the drug is present in the
stomach. The __?__ form is insoluble in the lipid bilayer of the stomach. On the
other hand, the __?___ form is present in the small intestine. The __?__ form is
non-polar and is soluble in the lipid bilayer.
QUES. 19: Acute phenobarbital (weak acid) (pKa - 7.2) poisoning can be treated
by an intravenous solution of sodium bicarbonate. The bicarbonate raises the pH
of the blood and urine (normal pH is 7.4) to a pH of 8. If the pH remains normal
the barbiturate, phenobarbital, is removed only very slowly from the body lipid
tissues. Suggest the form (ionic or molecular) of the phenobarbital in both cases
- normal pH and after bicarbonate treatment and explain how it is excreted using
solubility principles.
QUES. 20: The bases acetanilid (phenacetin) and caffeine with pKb of 0.3 and
0.5, respectively, are absorbed in the stomach at rates of about 30% per hour.
On the other hand, quinine (pKb = 8.4) is not appreciably absorbed in the
stomach. Suggest the form (ionic or molecular) of all three drugs and explain
their solubility behavior.
QUES. 21: Studies on the distribution of certain chemicals and dyes in the body
led to the belief in the existence of a blood-brain barrier. Studies with
sulfonamides (weak acids) show that those with pKa values of 3-7 do not enter
the brain. On the other hand, sulfonamides with a pKa of 10 do enter the brain.
General plasma pH is about 7.4. Can you suggest a reason for this behavior and
suggest whether this blood-brain barrier is made from a polar or nonpolar
material.