Basic Principles of Medicinal Chemistry PHR 143M

Example Questions for EXAM #1

LECTURE

Fill in the ScanTron sheet with the SINGLE BEST ANSWER to the following
questions. ONLY the ScanTron sheet will be graded; you will receive no
credit for answers marked on this question sheet.

1. Below is a table listing the boiling points of a series of alkane hydrocarbons. What
forces are responsible for the trend observed in this table?

Alkane Boiling Point

n-hexane 69.0 °C
n-heptane 98.4 °C
n-octane 126.0 °C

A. Decreasing Inductive destabilization of the intermolecular attraction between

alkanes with an increase in the number of bond dipoles (e.g., C–H bonds).
B. Increasing Inductive stabilization of the intermolecular attraction between
alkanes with a decrease in the number of bond dipoles (e.g., C–H bonds).
C. Increasing van der Waals intermolecular attraction between alkanes with an
increase in molecular size (e.g., number of electrons).
D. Decreasing van der Waals intermolecular attraction between alkanes with an
increase in molecular size (e.g., number of electrons).

2. Partition co-efficients are expressed as logP values. These logP values relate to the
partitioning of the drug between an aqueous phase and an organic phase, typically
water-saturated n-octanol. The logP value is defined as:

A. The negative log of the ratio of the concentration of the drug in the aqueous phase
over the concentration of the drug in the organic phase.
B. The log of the negative of the ratio of the concentration of the drug in the aqueous
phase over the concentration of the drug in the organic phase.
C. The log of the ratio of the concentration of the drug in the organic phase over the
concentration of the drug in the aqueous phase.
D. The negative log of the ratio of the water solubility of the drug over the organic
phase solubility of the drug.
3. Based upon the structures of the two barbiturates below, predict their relative
partition co-efficients and water solubilities (NOTE THE CORRECTED DRUG
NAMES).

O NH O O NH O

NH
NH

O
O

Butethal Butabarbital

A. Butabarbital is more water soluble and has a higher LogP than butethal
B. Butabarbital is less water soluble and has a higher LogP than butethal.
C. Butabarbital is more water soluble and has a lower LogP than butethal.
D. Butabarbital is less water soluble and has a lower LogP than butethal.

4. Two isomers of 2-butene exist due to:

A. The variation in the position of the carbon-carbon double bond.

B. The variation in the disposition of the methyl groups attached to the two carbons
that are connected with a double bond.
C. The variation in the numbering system used to name this compound.
D. The variation in the electronegativity of the sp3 and sp2 carbons in this compound.

5. Which of the following molecules is not aromatic (i.e., does not follow Huckel’s
rule)?

A. OH C.

N
B. D.

6. Which of the following lists is in increasing order of size (smallest molecule to

largest molecule):

A. chloromethane, bromomethane, iodoform (CHI3 ), methanol

B. methanol, bromomethane, iodoform (CHI3 ), chloromethane
C. methanol, chloromethane, bromomethane, iodoform (CHI3 )
D. iodoform (CHI3 ), chloromethane, methanol, bromomethane
7. Which of the following molecules is most lipophilic?

A. O C. CH3

Cl
Cl
B. CCl3 D.

Cl
Cl

8. Which of the following has the larger molecular dipole:

A. CHCl3 C. CHF3
B. C2 F6 D. CH3 CH2 CH3

9. Which of the following alcohols is most water soluble?

A. 2-butanol C. 1-hexanol
B. 1-butanol D. 1-octanol

10. If the pKa of an acid is 4.5, at equilibrium at pH 7.0:

A. There is 4.5-times as much deprotonated form of the acid as the protonated

form.
B. There is 2.5-times as much protonated form of the acid as the deprotonated
form.
C. There is over 102 -times as much protonated form of the acid as the
deprotonated form.
D. There is over 102 -times as much deprotonated form of the acid as the
protonated form.
11. Which of the following statements concerning the relative acidities of trifluoroacetic
acid and acetic acid is most correct?

A. Trifluoroacetic acid is more acidic, because the deprotonated form

(trifluoroacetate anion) is more inductively stabilized than is the
deprotonated form of acetic acid (acetate anion).
B. Trifluoroacetic acid is more acidic, because the deprotonated form of acetic
acid (acetate anion)l is more inductively stabilized than is the deprotonated
form of trifluoroacetic acid.
C. Acetic acid is more acidic because the deprotonated form (acetate anion) is
more inductively stabilized than is the deprotonated form of trifluoroacetic
acid.
D. Acetic acid is more acidic because the deprotonated form of trifluoroacetic
acid is more inductively stabilized than is the deprotonated form of acetic
acid.

12. Which of the functional groups shown in the compound is a tertiary alcohol?
H

OH 1

OH
CH2OH 2
3
A. Functional Group 1
B. Functional Group 2
C. Functional Group 3
D. Functional Groups 1 and 3
E. None of the functional groups are tertiary

13. Which of the following ethers would be expected to undergo a chemical reaction in
the presence of a nucleophile?

A. O C.

O
O
B. O D. O
14. Which of the following two compounds is less basic (lower pKa for the conjugate
acid) and why?

NH2 NH2

O2N

4-Ethyl-phenylamine 4-Nitro-phenylamine

A. 4-Nitro-phenylamine is more basic because there is more resonance

stabilization of the positive charge in the protonated form than in the case
of 4-ethyl-phenylamine.
B. 4-Ethyl-phenylamine is more basic because there is more resonance
stabilization of the positive charge in the protonated form than in the case
of 4-nitro-phenylamine.
C. 4-Nitro-phenylamine is more basic because there is less resonance
delocalization of the nitrogen lone pair in the conjugate base form than in
the case of 4-ethyl-phenylamine.
D. 4-Ethyl-phenylamine is more basic because there is less resonance
delocalization of the nitrogen lone pair in the conjugate base form than in
the case of 4-ethyl-phenylamine.

15. Which of the following chemical equations best represents the oxidation of a phenol?

A OH O

Air

B OH O

Air

O
C OH CO2H

Air

D OH

O
Air
16. At neutral pH, which of the following amines would exist predominantly as the
protonated, ionized form?

A. NH2 C. H
N

O2N

B. NH2 D. O

NH

17. Which of the functional groups in the following compound is a tertiary amine?
2

OH
3 HN N

NH2 1
A. Functional group 1
B. Functional group 2
C. Functional group 3
D. Functional group 1 and 3
E. None of the functional groups indicated are tertiary amines.
18. Which of the following expressions best represents the predicted water solubility of
the compound shown below?

OH
HN N

NH2
A. Each of the three amine functional groups can solubilize approximately 3-
4 carbon atoms (9–12 carbons for the three amine functional groups) and
the hydroxyl functional group can solubilize 3–4 carbons. Because the
number of carbon atoms in the molecule (14) is equivalent to the
estimated number of carbons that can be solubilized (12–16), we can
predict that the compound is water soluble.
B. Each of the three amine functional groups can solubilize approximately 1
carbon atom (3 carbons for the three amine functional groups) and the
hydroxyl functional group can solubilize 1 carbon. Because the number
of carbon atoms in the molecule (14) is greater than the estimated number
of carbons that can be solubilized (4), we can predict that the compound
is insoluble in water.
C. Each of the three amine functional groups can solubilize approximately
0.7 carbon atoms (2.1 carbons for the three amine functional groups) and
the hydroxyl functional group can solubilize 1 carbon. Because the
number of carbon atoms in the molecule (14) is greater than the estimated
number of carbons that can be solubilized (3.1), we can predict that the
compound is water soluble.
D. Each of the three amine functional groups can solubilize approximately 6-
7 carbon atoms (18–21 carbons for the three amine functional groups) and
the hydroxyl functional group can solubilize 5–6 carbons. Because the
number of carbon atoms in the molecule (14) is less the estimated number
of carbons that can be solubilized (23–27), we can predict that the
compound is insoluble in water.
19. Which of the following expressions best represents the predicted LogP of the
compound shown below?

OH
HN N

NH2
A. Each of the three amine functional groups has a π amine value of –1.0, and
the hydroxyl functional group has a π hydroxyl value of 2.0, so the predicted
logP is (3 x –1.0) + 2.0 = -1.0 for this compound.
B. Each of the three amine functional groups has a π amine value of –1.0, and
the hydroxyl functional group has a π hydroxyl value of –1.0. The phenyl ring
has a πphenyl of 2.0 and each of the remaining 8 carbons have a π C (aliphatic)
value of 0.5. There is an additional πIMHB value associated with the
intramolecular hydrogen bond that can occur between the primary amine
and hydroxyl functional groups (0.65) so the predicted logP is (3 x –1.0)
+ (-1.0) + 2.0 + (8 x 0.5) + 0.65 = 2.65 for this compound.
C. Each of the three amine functional groups has a π amine value of 3–4, and the
hydroxyl functional group has a πhydroxyl value of 3–4. The phenyl ring has
a πphenyl of 2.0 and each of the remaining 8 carbons have a π C (aliphatic) value
of 0.5. There is an additional π IMHB value associated with the
intramolecular hydrogen bond that can occur between the primary amine
and hydroxyl functional groups (0.65) so the predicted logP is (3 x 3.5) +
(3.5) + (2.0) + (8 x 0.5) + 0.65 = 20.65 for this compound.
D. The compound contains at least one amine functional group so there is a
π amine value of –1.0, and it also contains one or more hydroxyl functional
groups with a π hydroxyl value of –1.0. The compound contains one or more
phenyl rings, so there is a π phenyl of 2.0. There are additional carbons, so
there is a π C (aliphatic) value of 0.5. So the predicted logP is (–1.0) + (-1.0) +
(2.0)+(0.5) = 0.5 for this compound.
20. Which of the functional groups in the following compound would be expected to
have a pKa of around 10 (i.e., higher than 5, but lower than 15)?
Me Me
N 2

NH2 1

OH
OH O OH O O

3
A. Functional group 1
B. Functional group 2
C. Functional group 3
D. Functional groups 1 and 3

21. Which of the chemical equilibria shown below is most likely to occur when chloral
(Cl3 CCHO) is dissolved in water?

O O
Cl
Cl
H + H2 O OH
Cl Cl Cl
A. Cl

O O
Cl
Cl
H + H2O + H3O +
Cl Cl Cl Cl
B.

O HO OH
Cl
Cl
H + H2O H
Cl Cl Cl Cl
C.

O O
Cl + H2O
HO
H
+ HCl
H
Cl Cl Cl Cl
D.

E. No chemical equilibrium is involved.

22. Which of the following best explain the difference in pKa between benzoic acid
and para-nitrobenzoic acid?

CO2 H O2 N CO2 H

pKa = 4.21 pKa = 3.50

A. In the ionized form of benzoic acid there is complete delocalization of the

carboxylate negative charge throughout the benzene ring; whereas, in the
ionized form of para-nitrobenzoic acid, the is no delocalization of the
carboxylate charge by the benzene ring.
B. In the ionized form of para-nitrobenzoic acid there is complete delocalization
of the carboxylate negative charge throughout the benzene ring; whereas, in
the ionized form of benzoic acid, the is no delocalization of the carboxylate
charge by the benzene ring.
C. In the ionized form of para-nitrobenzoic acid there is a favorable inductive
interaction; whereas, in the ionized form of benzoic acid, this inductive
interaction is missing.
D. In the ionized form of benzoic acid there is a favorable inductive interaction;
whereas, in the ionized form of para-benzoic acid, this inductive interaction is
missing.
E. The ionized form of para-nitrobenzoic acid, being larger than the ionized
form of benzoic acid, is better solvated and thus more stable in solution.

23. The sodium salt of benzoic acid is:

A. More water soluble than benzoic acid.

B. Less water soluble than benzoic acid.
C. Has approximately that same water solubility as benzoic acid.
D. Is unstable in water because is undergoes a fast reaction to form carbon
dioxide.

23-25.
For each of the structures presented below, match the circled functional group with the
proper name from the list of names below. NOTE: Each lettered functional group name
can be used once, more than once, or not at all in answering the following three
questions.

A. Amide
B. Alkene
C. Phenol
D. Amine
23. 24. O
H H2N
N
S
CH C
OH
O N CH2
O
CO2H
A

HO

C
25. CO2H

N
Me

HN
B
Basic Principles of Medicinal Chemistry Lab PHR 143P
Example Questions for EXAM #1
ARROW PUSHING AND REVIEW LABS

Fill in your answers to the questions below ON THIS SHEET. Keep your
answers brief. ONLY ANSWERS WITHIN THE BOXED AREAS WILL BE
GRADED.

1. Examine the aqueous equilibrium below.

OH OH

O OH O O OH
O + H+

HO -
HO OH O

(A) (5 points) Are there one or more reasonable resonance structures for the conjugate
base that appears in the box? If so, draw them in the space below.

OH OH

O O OH - O
O OH

HO - HO
O O

(B) (5 points) Based upon your answer to part A above, predict the approximate pKa
associated with the above equilibrium. HINT: would you predict the pKa is most
similar to an alcohol (pKa ~15), a phenol (pKa ~ 10), or a carboxylic acid (pKa ~5).
Explain how you made your prediction.

The pKa is most similar to a carboxylic acid because both the carboxylate anion and the
anion above can be represented as two resonance forms in which the negative charge is
delocalized onto two different oxygen atoms.

2. (2 points) Draw the Lewis dot structure for formic acid (HCO2 H).
 O
H
H O
3. (3 points) Draw the Lewis dot structure and any reasonable resonance forms for
methylazide (CH3 N3 ).

H H
H N N N H N N N
H H

4. (3 points) Draw the Lewis dot structure and any reasonable resonance forms for
dimethylsulfoxide (CH3 SOCH3 ).

O O
H S H H S H
H H H H
H H H H

5. (2 points) Circle the atoms that bear a partial positive charge in the following
compound:

O
6. (2 points) Circle the atoms that bear a negative charge or a partial negative charge in
the following compound:

– O–
O

NH2
NH2
OH
OH OH O OH O O
OH O OH O O

7. (8 points) Show the electron flow (push arrows) for the following reaction:
Show the movement of electrons by curved arrow notation for the following
transformation:

O O –
H3C S CH3 O O
S CH3
O
O O
O

CH3
H O H O

N N
N N
O O
CH3 H CH3 H

8. (10 points) Show the electron flow (push arrows) for the following reaction:

Cl- -
Cl
Me
Cl N+ MeOH OMe OMe MeOH OMe
Me N Me N Me N
Cl Cl OMe
Cl N+
Me
+ HCl
+ HCl
9. (10 points) Using the pKa values given, decide whether the equilibrium will lie toward
the right or the left. Give a justification for your choice.
O O

O2N C O– + CH3NO2 O2N C OH + –CH2NO2

pKa 10.2 3.44

Towards the left because benzoica acid (pKa = 3.44) is a stronger acid than nitromethane
(pKa 10.2).

10. (5 points) A solution of formic acid (0.01 M) is 13% ionized. What is the pH of this
solution?

The [H+] is 0.13 * 0.01M = 0.0013 M

The pH is –log(0.0013) or 2.88
11. Below are two isomers of nitrophenol with their corresponding pKa’s.
(A) (5 points) Write out the chemical equations for the ionization of these two
phenols (the chemical equation to which the pKa’s refer).
OH
OH

NO2 NO2
pKa = 7.2 pKa = 8.3

OH O-
+
+ H

NO2 NO2

OH -
O

+ H+
NO2 NO2

(B) (10 points) With regards to the ionized form of each phenol, indicate the
difference, if any in the contribution of the following in terms of stabilizing or
destabilizing effects on one isomer versus the other:

- Inductive Effects
- Resonance

O- O O O

NO2 NO2 NO2 +

-
O N O-
For 4-nitro phenolate, there is extensive resonance stabilization, including delocalization
of the charge onto the nitro group (Resonance form on right), in addition to inductive
stabilization of the charge (first three resonance forms)
 O- O O

NO2 NO2 NO2

In 3-nitro pehnolate, there is resonance stabilization involving delocalization of the
charge, but there are no resonance forms involving delocalization onto the nitro group.
There is inductive stabilization similar to that for 4-nitrophenolate.

(C) (5 points) Based upon your answer to part B, explain the observed difference in
pKa as a consequences of differences in one or more of these effects.

The increase resonance stabilization available to 4-nitrophenolate makes 4-nitrophenol

slightly more acidic (∆pKa = 0.9)

12. Lidocaine is a weak organic base that exist in aqueous solution as a mixture of
Lidocaine and the protonated form, LidocaineH +.
Me

NH N

Me O

(A) (5 points) Draw out the equilibrium involving the protonated and non-protonated
froms of Lidocaine in water. Draw out the complete structure of the protonated form,
showing the site of protonation.

Me Me

NH N+ NH N
H
+ H+
Me O Me O

(C) (5 points) What is the pK a for Lidocaine?

The pKa is ~ 10
13. (2 points) Show the electron flow (push arrows) for the following reaction:
Show the movement of electrons by curved arrow notation for the following
transformation:

Br
+ Br–

14. (A)(4 points) You need to prepare 30 mL of a 10 mM solution of KCl.. How much
of a 2.5M solution of KCl would you need in order to make your 10 mM solution?

30 mL X 0.01 M = V mL X 2.5 M

V mL = 0.12 mL

(B) (4 points) The 10 mM KCl solution that you prepared was further diluted to a total
volume of 250 mL. What is the final chloride ion concentration of this 250 mL of
solution (assuming that the water you used has no chloride ions).

30 mL X 0.01 M = 250 mL X C

C = 0.0012 M
15. (A) (5 points) You are in charge of a biopharmaceutical laboratory and you are
extracting drug metabolites from a patient’s blood. You extracted 3 mL of blood plasma
with with 20 mL of dichloromethane. A 2 mL aliquot of the bottom, dichloromethane
layer was removed and diluted with 2 mL of acetonitrile. A 1 mL aliquot of the resulting
solution was diluted to 25 mL total volume with 1:1 dichloromethane/acetonitrile in a
volumetric flask. Approximately 0.5 mL of this solution was removed and placed in a
cuvette. By measuring the absorbance of this solution, it was determined that the
concentration of drug metabolite in this solution was 0.04 nM. What was the
concentration of drug metabolite in the original dichloromethane solution (underlined
above)?

2 mL X C1 = 4mL X C2
1 mL X C2 = 25 mL X 0.04 nM

C2 = 1 nM
C1 = 2 nM

The original 20 mL of dichloromethane was 2 nM in drug metabolite

15(B) (5 points) Assuming that the extraction step was quantitative, how much drug
metabolite was present in the 3 mL of blood plasma? What was the concentration of
metabolite in the blood plasma?

20 mL X 2 nM = 4 x 10-11 moles o fdrug metabolite in the 3 mL plasma

4 x 10-11 moles/3 mL = 1.33x10 -8 M drug metabolite in plasm