MEDCH 402 [Answer Key] FALL PROBLEM S I. ACID/B CHEMISTRY

[Pages:8]MEDCH 402 FALL 2007 PROBLEM SET #1

[Answer Key]

I. ACID/BASE CHEMISTRY

A. Predict which compound is more acidic. Why?

1. O

F3C

O

+

+

H

-

+

H

O

F3C

OH

O

H3C

OH

The CF3 group is more electron withdrawing than the CH3 group. This helps to stabilize the conjugate base via the inductive effect.

2.

O

O

OH

OH

N

O N+

O

Here's why:

:N

O

OH

+

N

Strongly electron donating, thereby increasing the

electron density of RCOOand destabilizing it.

O _

OH

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O N+ O

O OH

-

+

H

NO2 is strongly electron withdrawing, making it easier for the oxygen of the carboxyl group to lose a proton because of the + charge on the carbon adjacent to the carboxylate

anion (- charge).

O N+ O

O O

O+ N O

B. Predict which compound is more basic. Why? 1.

O

O

O +

O

+

N OO

O N+

- O O-

CH3

NO2 is strongly electron withdrawing, thereby stabilizing the conjugate base. CH3, on the other hand, is an electron

donating group that will lend more negative character to the O- of the conjugate base, making it more likely to

pick up a proton.

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2.

H N

H

H

H

N

N

N

The lone pair of electrons of pyrrole (right) is tied up in sustaining

aromaticity, as is evidenced by the resonance forms shown above & to the right. On the other hand, the lone pair

of electrons in pyrrolidine (left), a 20 amine, is readily available to bond to a proton. Hence, pyrrolidine is a stronger

base.

H N

H H

H NH

H

C. Given the structure of Flurbiprofen below, answer the following questions:

HO

F

O

Flurbiprofen 1. What is the approximate pKa of this acid?

4-5, due to the carboxylic acid group.

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2. Draw the structure of the potassium salt of Flurbiprofen. What are the advantages of administering the salt form of this drug?

+

KO

F

O

The salt form will dissolve more rapidly/completely from its oral dosage form into physiological fluids, resulting in increased rate/extent of drug absorption. This has the added effect of decreasing intersubject variability.

3. Using the Henderson-Hasselbach equation, calculate the ionized/unionized ratio of this drug at pH 7.

Taking the pKa of the drug to be 4:

10 -

=

10(7-4)

= 103

=

[] []

Since, in this case, the unprotonated form of the drug is ionized, the ionized/unionized ratio of the drug will be:

103 1000

= = 1 = 1

4. If a large fraction of the administered dose of Flurbiprofen is cleared renally in its unprotonated form, would this drug have a longer duration of action at a urinary pH of 5 or 8? Explain your answer.

At pH 5: At pH 8:

10( - )

=

[] [] [] = [] =

10(5-4)

10 =1

10( - ) =

[] []

=

[] []

=

10(8-4)

=

104 1

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At pH 8, a greater fraction of the drug will be in its ionized form compared with pH 5. Thus, it'll have better solubility in the (aqueous) urine. Hence, the drug at pH 8 will be excreted easily, resulting in a shorter duration of action compared to at pH 5.

II. REACTION MECHANISMS

A. General base-catalyzed hydrolysis:

HH O

O

O

CH3

:B

H2O

CH3

B. Base-catalyzed elimination:

O O

OH

B+ H CH3

CH3

O OH

+ CH3CH2OH + :B CH3

KOH

Br HH

+

K

-OH

+ KBr + H2O

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C. Acid-catalyzed elimination:

H+ H+ SO42-

H : OH

H3C

CH3

HH

H2SO4

H H

O+ H

H3C

CH3

HH

-HSO4

+ H2SO4 + H2O

D. Nucleophilic addition:

O H

NaCN H2O

+Na -CN

HH O

O CN H

OH CN H + NaOH

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E. Special nucleophilic addition (Michael addition):

S SH

O

B:

O

+

B H

S

+ B: O

III. STEREOCHEMISTRY

A. The drug pictured below, Dexfenfluramine, exists as the S-isomer. Circle the asymmetric center and draw the configuration of the S-isomer. What does "dex" imply?

4

HN

1

F3C

CH3

2

3

Dexfenfluramine

"Dex" is equivalent to the (+) sign, and indicates the physical property of this enantiomer to rotate plane polarized light in a dextrorotatory fashion.

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B. For each pair of compounds below, identify whether they are: 1. Geometric Isomers 2. Enantiomers 3. Diastereomers 4. Positional Isomers

Geometric Isomers

Br H

H CH3

H Br

H CH3

OH

N N

NN H

OH

N

N

NN H

H H3C C COOH

NH2

COOH H C NH2

CH3

Diastereomers Positional Isomers Enantiomers

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