Basic Principles of Medicinal Chemistry Lab PHR 143P

EXAM #1 October 1, 2003

ARROW PUSHING AND REVIEW LABS

NAME________________________________________

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. (3 points) Draw the Lewis dot structure for the simple amide formamide (HCONH2 ).

O
H
H N
H

2. (6 points) Draw the Lewis dot structure and any reasonable resonance forms for
nitromethane (CH3 NO2 ).

O
O
H N H N
H O
H O
H
H
3. Examine the structure below. For each of the functional groups or bonds given in parts
A–C, re-draw the molecule and indicate the un-equal sharing of electrons, if any, using
either dipoles or resonance structures.
O
H CF3
N

O N
HO O

HO

(A) (5 points) The carbon-fluorine bonds.

O F F
H
N F
O N
HO O

HO

(B) (5 points) The carbonyl group (C=O).

O F O F F O F F O F F
F
H H H H
N F N F N F N F
O N O N O
O N O N
HO O or HO or HO O HO O
or

HO HO HO HO

O F F O F F O F F
H H
N F H
N F N F
O N O O N
HO O N
or or HO O or HO O

HO HO HO
(C) (5 points) The Alkene functionality (Carbon-carbon double bond)
O F F O F O F F
O F F F
H H H
H N F N F N F
N F or
O N O N O N
O N HO O HO O or HO O
HO O or

HO HO HO
HO
4. (4 points) Circle the atom or atoms in the following compound that might undergo
attack by a nucleophile (e.g., ethyl thiolate: EtS– )
O

5. (4 points) Circle the atom or atoms in the following compound that might serve as a
nucleophile by attacking an electrophile (e.g., : iminium ion: H2 C=NH2 +)

O
O
HO

6. (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:

Ph
Ph O
O H
H H H
7. (12 points) The equilibrium below involves aniline and morpholine. Based upon the
functional groups involved, estimate the pKa values for each of the conjugate acids and
write these in the appropriate boxes below the equilibrium (Note: only write the pKa
values in the boxes corresponding to the acid forms * two boxes should remain empty *).
Based on these pKa values, decide whether the equilibrium will lie toward the right or the
left. Give a justification for your choice.

NH2 N+H3

+ N+H2 + NH
O O
pKa = pKa =5
10

The equilibrium lies to the left

Because aniline conjugate acid is the stronger acid and thus will prefer the unprotonated
form shown on the left at equilibrium.

Or

Because morpholine is the stronger base, and will prefer the protonated form shown on
the left at equilibrium.
8. Procaine and chlorprocaine are weak organic bases that exist in aqueous solution
as a mixture of the free base and their protonated, ionized form.
Cl
H2 N O H2 N O
O O
N N

Procaine Chlorprocaine
(A) (3 points) Draw out the equilibrium involving the protonated and non-protonated
forms of Procaine in water. Draw out the complete structure of the protonated form,
showing the site of protonation.

H2N O H2N O
O O

+
H + H+
N N

(B) (3 points) Draw out the equilibrium involving the protonated and non-protonated
froms of Chlorprocaine in water. Draw out the complete structure of the protonated
form, showing the site of protonation.

Cl Cl

H2N O H2N O
O O
H + H+
N+ N

(C) (3 points) Based upon the equilibrium that you have indicated in part A, estimate
the the pK a for Procaine?

The pKa for procaine is ~ 10 (amine functional group)

(D) (3 points) The actual pKa for Procaine is higher than that of Chlorprocaine by 0.2
pKa units. To what effect do you attribute this difference in pKa?
This is an example of the inductive effect: the bond dipole for the carbon-chlorine bond
in chlorprocaine destabilizes the protonated, conjugate acid form (unfavorable ion-dipole
interaction). This dipole is absent in procaine. This results in an increase in acidity for
the conjugate acid of chlorprocaine relative to procaine (decreased basicity of
chlorprocaine relative to procaine).

9. (12 points) Show the electron flow (push arrows) for the following reaction:
Show the movement of electrons by curved arrow notation for the following
transformation:

HO OCH3

O
H :B
O
OH OH OH H3C O
H

B H

HO OCH3

HB
OH OH OH CH3 O

C
HO
B: O
H
10. (A) (6 points) You are in charge of a biopharmaceutical laboratory and you are
extracting drug metabolites from a patient’s blood. You extracted 5 mL of blood plasma
with 20 mL of diethyl ether. You remove 2 mL of the top, ethereal layer and dilute this
with 2 mL of acetonitrile. You remove 1 mL aliquot of the resulting solution and add it
to a clean, dry 250 mL volumetric flask, which you then bring to volume with 1:1 diethyl
ether/acetonitrile. 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 0.09 nM. What was the
concentration of drug metabolite in the original diethyl ether solution (underlined above)?

The 20 ml of diethyl ether was 45 nM in drug metabolite

10(B) (6 points) Assuming that the extraction step was quantitative, how much drug
metabolite was present in the 5 mL of blood plasma? What was the concentration of
metabolite in the blood plasma?

9 x 10-10 moles of drug metabolite in the 5 mL of plasma

The concentration of drug metabolite in the plasma was 180 nM

Honor Code Statement

“I have neither participated in nor witnessed any acts of academic dishonesty pertaining
to this examination”

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