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404 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
10. Acidic and basic functional groups and their pKa ranges are provided below.
Drug Name Acidic Functional Groups Basic Functional Groups
Bromfenac Carboxylic acid (2; pKa = 2.5-5) Primary aromatic amine; aniline
Sorbinil Imide/β-Dicarbonyl (3; pKa =
Zanamivir Carboxylic acid (4; pKa = 2.5-5) Guanidine (5; pKa = 12-13)
Experimental antidiabetic
agent
Experimental oral coagulant Sulfonamide (11; pKa = 4.5-11) Amidine (10; pKa = 10-11)
4.5-8.5)
Phenol (6; pKa = 9-10) Heterocyclic aromatic nitrogen
Sulfonamide (8; pKa = 4.5-11) Secondary amine (9; pKa = 9-11)
(1; pKa = 2-5)
atoms (7; pKa = 1-6)
11. Unlike the side chain of the amino acid arginine, the guanidine group of clonidine is directly
attached to an aromatic ring. As such, the nitrogen atom directly attached to the aromatic
ring (highlighted below) can donate electrons into the aromatic ring, thus making it less
available for resonance stabilization of a positive charge. In addition, the aromatic ring of
clonidine is attached to two ortho chloro groups. Each of these halogens is electron withdrawing and further decreases the basicity of the guanidine group. The combination of
these two effects decreases the basicity of the guanidine group by more than four orders
of magnitude.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 405
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12. The acid/base character of each drug molecule is provided below.
Drug Molecule Acid/Base Character of Drug Molecule
Hydrocortisone Nonelectrolyte: does not contain any acidic or basic
Oxacillin Acidic: contains only an acidic carboxylic acid
Dorzolamide Amphoteric: contains a basic secondary amine and
Diltiazem Basic: contains only a basic tertiary amine
Amobarbital Acidic: contains only an acidic imide group
functional groups
an acidic sulfonamide
CHAPTER 4
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
1. Part A: The two aromatic amines are weakly basic due to the presence of other electron
withdrawing groups attached to their respective phenyl rings. As discussed in Chapter 3,
aromatic amines are much less basic than aliphatic or alicyclic amines due to their ability
to donate electrons into the aromatic ring through resonance. This donating ability can be
either enhanced or hindered due to the presence of other functional groups. For aromatic
amine 1, the para carbonyl on the aromatic ring is electron withdrawing, mostly through
inductive effects, and enhances the flow of electrons away from the nitrogen and further
decreases its basicity. Additionally, the meta ether oxygen atom may play a role. Although
both the aromatic amine and the ether oxygen can donate electrons into the aromatic
ring, the oxygen atom is more electronegative than the nitrogen atom and thus withdraws
406 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
electrons from the nitrogen atom via induction. Both of these effects decrease the availability of the lone pair of electrons and thus the basicity of aromatic amine 1.
For aromatic amine 2, the ortho nitro group is electron withdrawing in character and greatly
decreases the basicity of the amine through resonance delocalization, as shown below.
Part B: The normal pKa range for a tertiary amine is 9 to 11. Given this piece of information,
the pKa of 8.0 should be assigned to this basic functional group. The lower basicity may be
due to steric hindrance or adjacent functional groups. This leaves the heterocyclic nitrogen
atom (basic) and the sulfonamide (acidic) and the pKa values of 3.5 and 4.3. The normal
pKa range for a sulfonamide is 4.5 to 11, and the normal pKa range for heterocyclic nitrogen
atoms is 1 to 6. Although both of these pKa values fall with the normal range for heterocyclic nitrogen atoms, the pKa value of 3.5 belongs to the heterocyclic nitrogen atom. This is
because the pKa value of 4.3 is only slightly lower than the normal range for sulfonamides,
whereas the pKa value of 3.5 is too far outside this range. A full explanation of the pKa value
for the sulfonamide can be found in the answers for Chapter 3.
2. Part A: The primary amine and the heterocyclic nitrogen are primarily ionized, and the sul-
fonamide is primarily unionized.
Part B: The primary amine and the sulfonamide are primarily ionized, and the heterocyclic
nitrogen is primarily unionized.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 407
[BaseForm]
[AcidForm]
[BaseForm]
[AcidForm]
[BaseForm]
==0.06
[AcidForm]
1
[AcidForm]
+=0.063molecules in Base Form 1.0moleculeinAcidForm1.063 TotalMolecules
==Base Form IonizedFormand Acid Form UnionizedForm
=×
1MoleculeinUnionized Form
1.063Total Molecules
%
=×
0.063Molecules in IonizedForm
1.063Total Molecules
5.9%
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Part C: The primary amine and the sulfonamide are primarily ionized, and the heterocyclic
nitrogen is primarily unionized.
3. Part A: To use the Rule of Nines, the difference between the pH and the pKa must be an
integer (i.e., 1, 2, 3). In evaluating the above nine scenarios, there is only one scenario that
meets this criterion: the sulfonamide at a urine pH of 5.3. For this sulfonamide, the absolute value between the pH and the pKa is equal to 1; thus, there is a 90:10 ratio. Because the
sulfonamide (pKa = 4.3) is acidic, it is primarily ionized in a basic environment (pH = 5.3).
We can then use this ratio to determine that it is 90% ionized.
Part B: Two methods allow the Rule of Nines to approximate the percent to which a func-
tional group is ionized, even if the difference between the pH and the pKa is not an integer.
The first method is to round either the pH of the environment or the pKa of the functional
group so that there is an integral difference. Using the tertiary amine, absolute value
between the pH and the pK
is approximately equal to 6; thus, there is an approximate ratio
a
of 99.9999:0.0001. Because the tertiary amine (pKa = 8.0) is basic, it is primarily ionized in
an acidic environment (pH = 1.8). We can then use this ratio to determine that it will be
approximately 99.9999% ionized. The second method is to establish a range. Using the
sulfonamide, the absolute value between the pH and the pKa is 2.5. Because the sulfonamide (pKa = 4.3) is acidic, it is primarily unionized in an acidic environment (pH = 1.8). If
the absolute value were 2, then 99% would be unionized, and if the absolute value were 3,
then 99.9% would be unionized. Because the absolute value lies between 2 and 3, we can
conclude that the percent to which the sulfonamide is unionized is somewhere between
99% and 99.9%.
4. Part A: As determined in question 1B, the pKa of 4.3 belongs to the acidic sulfonamide
functional group; thus, the ionized form is the Base Form and the unionized form is the Acid
Form.
3
=+
HpKlog
a
=+
14.3 log
=1.2log
[BaseForm]
[AcidForm]
0.063
or
[BaseForm]
This ratio indicates that for every one molecule that contains the functional group in the
acid (or unionized) form, there are 0.063 molecules that contain the functional group in
the base (or ionized) form. The following equations can then be used to correctly calculate
the percentage of the molecules that are ionized and the percentage that are unionized.
rcentinUnionized Form
rcentinIonized Form
=
100% 94.1
=
100%
408 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
[AcidForm]
[BaseForm]
m]
[BaseForm]
m]
==0.20
[BaseForm]
0.20
[BaseForm]
m]
+=0.20 moleculesinBaseForm1.0 molecule in Acid Form 1.20 TotalMolecules
==Base Form UnionizedFormand Acid Form IonizedForm
=×
0.20 Molecule in UnionizedForm
1.20 TotalMolecules
%
=×
1.0Molecules in IonizedForm
1.2Total Molecules
%
[BaseForm]
70
30
=+pH3.5 log2.3
=+pH3.5 0.36
=pH3.86
The question asks for the percent that is ionized, so the correct answer is 5.9%.
Part B: As determined in question 1B, the pKa of 8.0 belongs to the basic tertiary amine
functional group; thus, the ionized form is the Acid Form, and the unionized form is the Base
Form.
=+
HpKlog
a
=+
38.0 log
[BaseForm]
[AcidFor
[AcidForm]
=0.7log
[AcidFor
or
1
[AcidFor
This ratio indicates that for every one molecule that contains the functional group in the
acid (or ionized) form, there are 0.20 molecules that contain the functional group in the
base (or unionized) form. The following equations can then be used to correctly calculate
the percentage of the molecules that are ionized and the percentage that are unionized.
rcentinUnionized Form
=
100% 16.7
rcentinIonized Form
=
100% 83.3
The question asks for the percent that is ionized, so the correct answer is 83.3%.
Part C: As determined in Question 1B, the pKa of 3.5 belongs to the basic heterocyclic
nitrogen atom; thus, the ionized form is the Acid Form, and the unionized form is the Base
Form. The functional group is 30% ionized. This means that for every 100 molecules of
venetoclax, 30 of them have an ionized heterocyclic nitrogen atom and 70 have an unionized heterocyclic nitrogen atom. Thus, the [Base Form]/[Acid Form] ratio is 70:30. Using this
ratio and the given pKa, the pH can be determined.
=+
HpKlog
a
=+
H3.5 log
[AcidForm]
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 409
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Checkpoint Drug 2: Elamipretide
1. Answer provided in table below.
Character: Acidic,
Name of Functional Group
A Guanidine (arginine side chain) Basic ∼12.5
B Primary amine (lysine side chain) Basic ∼10.5
C Phenol (modified tyrosine side chain) Acidic ∼10.5
D Primary amine (peptide backbone) Basic ∼10.5
2. To determine the extent to which a functional group is ionized in a given physiological
environment (qualitatively or quantitatively), you must know several facts and select how
to set the problem up. You need to know the pK
environment (facts) and then, to set the problem up, you must know whether the functional group is acidic or basic.
For example, using the Henderson-Hasselbalch equation to solve the problem qualitatively,
you must be able to identify the base form (ionized form for acids; unionized form for
bases) and the acid form (unionized form for acids; ionized form for bases) of the drug
molecule. When using qualitative methods, remember that when pH < pKa (for acids), the
functional group is predominantly unionized; but, when pH < pKa (for bases), the functional
group is predominantly ionized.
3. Answers provided in the tables below.
Basic, Neutral pKa Value or Range
of the functional group and the pH of the
a
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
D Primary amine (amino
terminus)
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
D Primary amine (amino
terminus)
Primarily Ionized
(> 50%)
Character: Acidic,
Basic, Neutral
Basic ∼12.5 Primarily ionized
Basic ∼10.5 Primarily ionized
Acidic ∼10.5 Primarily unionized
Basic ∼10.5 Primarily ionized
pKa Value or
Range
Primarily Unionized
(< 50%) pH = 2
Primarily Ionized
(> 50%)
Character: Acidic,
Basic, Neutral
Basic ∼12.5 Primarily ionized
Basic ∼10.5 Primarily ionized
Acidic ∼10.5 Primarily unionized
Basic ∼10.5 Primarily ionized
pKa Value or
Range
Primarily Unionized
(< 50%) pH = 5
410 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Primarily Ionized
(> 50%)
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
D Primary amine (amino
terminus)
Character: Acidic,
Basic, Neutral
Basic ∼12.5 Primarily ionized
Basic ∼10.5 Primarily ionized
Acidic ∼10.5 Primarily unionized
Basic ∼10.5 Primarily ionized
pKa Value or
Range
Primarily Unionized
(< 50%) pH = 7.4
Functional group A (guanidine) is basic in character with a pKa = ∼12.5. It is primarily ion-
ized in all three physiologic locations because the environmental pH < pKa of the functional
group. In its ionized form, a guanidine is a proton donor (acidic).
Functional group B (primary amine) is basic in character with a pKa = ∼10.5. It is primarily
ionized in all three physiologic locations because the environmental pH < pKa of the functional group. In its ionized form, a primary amine is a proton donor (acidic).
Functional group C (phenol) is acidic in character with a pKa = ∼10.5. It is primarily union-
ized in all three physiologic locations because the environmental pH < pKa of the functional
group.
Functional Group D (amino terminus primary amine) is basic in character with a pKa =
∼10.5. It is primarily ionized in all three physiologic locations because the environmental pH
< pKa of the functional group. In its ionized form, a primary amine is a proton donor (acidic).
4. Answers provided in the tables below.
Name of Functional
Group
A Guanidine (arginine
side chain)
B Primary amine
(lysine side chain)
C Phenol (modified
tyrosine side chain)
D Primary amine
(amino terminus)
Name of Functional
Group
A Guanidine (arginine
side chain)
B Primary amine
(lysine side chain)
C Phenol (modified
tyrosine side chain)
D Primary amine
(amino terminus)
Character: Acidic,
Basic, Neutral
Basic ∼12.5 99.9999921%
Basic ∼10.5 99.99921%
Acidic ∼10.5 0.00079%
Basic ∼10.5 99.99921%
Character: Acidic,
Basic, Neutral
Basic ∼12.5 99.99%
Basic ∼10.5 99.01%
Acidic ∼10.5 0.99%
Basic ∼10.5 99.01%
pKa Value or
Range
pKa Value or
Range
Percent Ionized
pH = 5.4
Percent Ionized
pH = 8.5
Part A: pH = 5.4
[AcidForm]
[BaseForm]
m]
[BaseForm]
==0.00000007
[BaseForm]
0.000000079
[BaseForm]
+
=
1.000000079Total Molecules
==Base Form UnionizedFormand Acid form IonizedForm
=×
1.000000079Total Molecules
0.0000079%
=×
1.000000079Total Molecules
1%
[AcidForm]
[BaseForm]
[BaseForm]
==0.000007
[BaseForm]
[AcidForm]
1
[BaseForm]
[AcidForm]
+=0.0000079molecules in Base Form 1.0moleculeinAcidForm1.0000079total molecules
==Base Form UnionizedFormand Acid Form IonizedForm
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For the guanidine functional group at pH=5.4:
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 411
=+
9
[AcidForm]
HpKlog
a
=+
412.5log
=7.1log
[BaseForm]
[AcidFor
[AcidForm]
or
1
[AcidForm]
This ratio indicates that for every one molecule that contains the functional group in the
acid (or ionized) form, there are 0.000000079 molecules that contain the functional group
in the base (or unionized) form. The following equations can then be used to correctly
calculate the percentage of the molecules that are ionized and the percentage that are
unionized.
rcentinUnionized Form
0.000000079MoleculeinUnionized Form
100%
=
rcentinIonized Form
1.0MoleculeinIonized Form
=
100% 99.999992
The question asks for the percent that is ionized, so the correct answer is
For both primary amine functional groups at pH = 5.4:
=+
9
HpKlog
a
=+
410.5log
=5.1log
[BaseForm]
[AcidForm]
[AcidForm]
0.0000079
or
This ratio indicates that for every one molecule that contains the functional group in the
acid (or ionized) form, there are 0.0000079 molecules that contain the functional group in
the base (or unionized) form. The following equations can then be used to correctly calculate the percentage of the molecules that are ionized and the percentage that are unionized.
.
412 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
=×
0.0000079MoleculeinUnionized Form
1.0000079Total Molecules
0.00079%
=×
1.0MoleculeinIonized Form
1.0000079Total Molecules
%
[BaseForm]
[AcidForm]
[AcidForm]
[BaseForm]
==0.000007
[AcidForm]
1
m]
[AcidForm]
+=0.0000079molecules in Base Form 1.0moleculeinAcidForm1.0000079Total Molecules
==Base Form IonizedFormand Acid Form UnionizedForm
=×
0.0000079MoleculeinUnionized Form
1.0000079Total Molecules
0.00079%
=×
1.0MoleculeinIonized Form
1.0000079Total Molecules
%
[BaseForm]
[AcidForm]
[BaseForm]
m]
[BaseForm]
[AcidForm]
==0.0001
[BaseForm]
[AcidForm]
0.0001
1
[BaseForm]
[AcidForm]
rcentinUnionized Form
rcentinIonized Form
100% 99.99921
100%
=
=
The question asks for the percent that is ionized, so the correct answer is
For the phenol functional group at pH = 5.4:
[BaseForm]
9
g
=+
410.5log
=5.1log
or
[BaseForm]
[AcidForm]
0.0000079
[BaseFor
This ratio indicates that for every one molecule that contains the functional group in the
acid (or unionized) form, there are 0.0000079 molecules that contain the functional group
in the base (or ionized) form. The following equations can then be used to correctly calculate the percentage of the molecules that are ionized and the percentage that are unionized.
.
rcentinIonized Form
100%
=
rcentinUnionized Form
=
100% 99.99921
The question asks for the percent that are ionized, so the correct answer is
Part B: pH = 8.5
For the guanidine functional group at pH = 8.5
=+
HpKlog
a
=+
512.5log
=4log
[AcidFor
or
This ratio indicates that for every one molecule that contains the functional group in the
acid (or ionized) form, there are 0.0001 molecules that contain the functional group in the
.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 413
+=0.0001 moleculesinBaseForm1.0 molecule in Acid Form 1.0001 TotalMolecules
==Base Form UnionizedFormand Acid Form IonizedForm
=×
0.0001 Molecule in UnionizedForm
1.0001 TotalMolecules
0.009999%
=×
1.0MoleculeinIonized Form
1.0001 TotalMolecules
99%
[BaseForm]
m]
[AcidForm]
[BaseForm]
[AcidForm]
==0.01
[BaseForm]
0.01
[BaseForm]
+=0.01 moleculesinBaseForm1.0 molecule in Acid Form 1.01 TotalMolecules
==Base Form UnionizedFormand Acid Form IonizedForm
=×
0.01 Molecule in UnionizedForm
1.01 TotalMolecules
%
=×
1.0MoleculeinIonized Form
1.01 TotalMolecules
%
[BaseForm]
[BaseForm]
[AcidForm]
[BaseForm]
[AcidForm]
==0.01
[BaseForm]
0.01
[BaseForm]
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base (or unionized) form. The following equations can then be used to correctly calculate
the percentage of the molecules that are ionized and the percentage that are unionized.
rcentinUnionized Form
100%
=
rcentinIonized Form
=
100% 99.
The question asks for the percent that is ionized, so the correct answer is
For both primary amine functional groups at pH = 8.5:
=+
HpKlog
[AcidForm]
a
=+
510.5log
=2log
or
[AcidForm]
[BaseFor
1
[AcidForm]
This ratio indicates that for every one molecule that contains the functional group in the
acid (or ionized) form, there are 0.0000079 molecules that contain the functional group in
the base (or unionized) form. The following equations can then be used to correctly calculate the percentage of the molecules that are ionized and the percentage that are unionized.
.
rcentinUnionized Form
=
100% 0.99
rcentinIonized Form
=
100% 99.01
The question asks for the percent that is ionized, so the correct answer is
.
For the phenol functional group at pH = 8.5:
[AcidForm]
g
[AcidForm]
=+
510.5log
=2log
or
1
[AcidForm]
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