Download Name Page 1 F.05.215e3p1 I.

Name _______________________
Page 1 F.05.215e3p1
I. (22 points)
In the mid/late 1950s, mainly in Europe, a racemic mixture of thalidomide (see below) was prescribed to
alleviate "morning sickness" in first trimester pregnant women. This was a tragic incident in the history
of modern medicine because while the (R)-stereoisomer is an effective sedative, the (S)-stereoisomer
turned out to be a potent mutagen in foetuses, and until this was tracked down there were thousands of
babies born with severe birth defects. A naive response to this discovery was "We should separate the
enantiomers, purify the (R)-isomer and only use it as the drug." The problem with this solution could be
identified with a simple experiment: in acidic solutions, pure samples of thalidomide undergo
mutarotation. As indicated below, solutions of pure samples of either the (R) or (S)-stereoisomer, when
placed in mild, aqueous acid solution, becomes optically inactive solution of thalidomide.
O
O
N
N
H
O
O
O
O
N
O
N
H
H
optically
inactive solution
of thalidomide
(R)-(+)-thalidomide
optical rotation = +63° 2% H SO /H O
2
4 2
room temp
H
(S)-(-)-thalidomide
optical rotation = -63°
optically
inactive solution
of thalidomide
2% H2SO4/H2O
room temp
O
(a) Explain, in a few words, the observation of mutarotation to an optically inactive solution of
thalidomide in terms of the mechanism that must be taking place.
An optically inactive solution of thalidimode means a racemic mixture (1:1 R:S),
so the molecule is undergoing a change that equilibrates the configuration of the stereocenter.
basic idea about racemization
4
(b) Using H3O+/H2O as your Bronsted acid/base pair, provide the curved arrow mechanism for the
acid-catalyzed process that explains the observation of mutarotation, starting with the (R)-isomer.
O
N
O
H
O
O
N
N
H
O
H2O
O
H
OH2
N
H
O
O
mech = 2
intermed = 2
N
O
H
O
O
O
N
O
H
H2O
H
O
O
N
N
H
+
N
H
O
H
O
H
H
O
N
H
O
14
O
(c) Why are the results of these mutarotation experiments enough to be skeptical that just prescribing
the (R)-thalidomide to pregnant women is a good idea?
racemization in acid would mean that the molecule cound also undergo racemization,
and so the bad (S) form would be formed
basic idea about the S isomer forming
4
Name _______________________
Page 2 F.05.215e3p2
II. (33 points)
A. When the !-form of the following carbohydrate derivative (Compound A) is treated with methanol in
acid, the "-form of the glycoside (Compound B) is observed to be the major product due to the
anomeric effect, but when the same starting material is treated with iodomethane and sodium hydride,
the !-glycoside (Compound C) is formed.
H3CO
O
H
CH3OH
H3CO
H3CO
O
O
cat. H2SO4
H3CO
Compound B OCH3
H
CH
I
3
H
Compound A
H3CO
O
OCH3
NaH H CO
3
Compound C
H
(a) Draw the structure of the key intermediate (b) Explain, briefly, using words and drawings,
in the conversation of Compound A to
why the formation of Compound C takes
Compound B that explains its ability to
place with no change in the configuration at
undergo inversion of configuration?
the anomeric center.
deprotonation of the OH both does not impact the
stereochemistry of the CO bond
H3CO
O
main idea = 2
H3CO
O
relevant pic = 2
H3CO
O
H
H3CO
open shell res form OK
B. (a) Using the Fischer projection,
draw the structure for L-histidine
that will be in greatest proportion
in a solution of pH = 3.9. See
front cover for pKa values
wrong
O
O
imidazole
= -2
H3N
H
connect = 3
prot state = 2
H
N
H
4
(b) Galactose is the C-4 epimer
of glucose. Draw the structure
for "-L-galactopyranose.
epi-glu = 2
alpha = 1
L=2
HO
O
OH
HO
N H
OH
HO
4
(c) Draw the open chain
(Fischer) form of an
aldotetrose that becomes
optically inactive when
treated with sodium
borohydride and acid.
O H OR O H
H
H
H
OH HO
H
OH HO
CH2OH
CH2OH
5 no partial
5
(d) Using the Fischer projection, (e) Draw the amphipathic (amphiphilic) molecule:
draw the structure for the methyl
ammonium hexadecanoate
ester of L-proline that will be in
greatest proportion in a solution
O
of pH = 5.
O
H2N
NH4
OCH3
H
connnectivity = 3
correct protonation = 2
O
ammonium = 2; hexadecanoate = 3 must be ionic!
5
5
5
Name _______________________
Page 3 F.05.215e3p3
III. (31 points)
A. You will recall, perhaps, that when alkenes such as styrene (Compound D) are treated with OsO4 or
related oxidizing agents, a 1,2-diol is formed. When phenylacetylene (Compound E) is treated with
oxidizing agents such as OsO4, the corresponding addition reaction product is not observed; instead it
is proposed that the initial addition reaction product, which is an ene-diol, undergoes an isomerization
reaction to give a mixture of two different C8H8O2 isomers.What are these two isomers?
Compound D
Compound E
can be in either box
OH
O
OH
O
+
OH
H
OH
ene-diol
intermediate
no partial
no partial
3
3
B. The two most acidic protons in ascorbic acid (also known as Vitamin C) have pKa values of 4.17 and
11.59. Which of the protons in ascorbic acid corresponds to the most acidic one, and why?
circle the
use words and drawings to explain
H
most acidic H
best resonance
O
O
H
H
proton
stability in
O
O
O
O
conjugate base
H
H
O
O
H
O
O
O
O
O
O
words 3
O
O
pix 3
O
O
H
H
H
no partial
6
2
O
C.
C
H3N
O
(1)
H
O
(H3C)3C
(2) H3O
which amino acid is this?
use its abbreviation as your
answer
D. D-Fructose is the
ketose derived from Dglucose; show the
Fischer projections for
the pair of epimeric
alcohols that result
from the sodium
borohydride reduction
of D-fructose.
O
C
C(CH3)3
O
with (CH3CH2)3N
Cl
CH2Ph
O
O
C
HN
connectivity = 3
state of protonation 2
Phe
OH
C
H
CH2Ph
5
4
can be in either box
CH2OH
CH2OH
H
HO
OH
HO
H
H
HO
H
H
OH
H
OH
H
OH
H
OH
CH2OH
4
CH2OH
OK as long
as true epimer
4
Name _______________________
Page 4 F.05.215e3p4
IV. (18 points)
A. An acid-catalyzed aldol reaction is observed when dihydroxyacetone is combined with
glyceraldehyde.
O
CH2OH
C H
H
CH2OH
C
C O
OH
CH2OH
O
acid catalyst
H2SO4
CH2OH
dihydroxyacetone
H
C
OH
H
C
OH
H
mixture of
stereoisomers
here
OH
CH2OH
(a) Using HB as a Bronsted acid and B as its conjugate base, show the step-wise mechanism for
the formation of the nucleophilic form of dihydroxyacetone required for this reaction.
CH2OH
C
CH2OH
B
H
C
O
CH2OH
B-
O
H C
H
nucleophilic form
CH2OH
H
C
O
mech 2
intermed 2
H mech 2
OH
6
H
C
2
OH
(b) Given the prior formation of the nucleophilic form of dihydroxyacetone, provide the complete
step-wise mechanism for the reaction between dihydroxyacetone and glyceraldehyde.
O
H
CH2OH
H
C H
B
C
OH
CH2OH
H
O
H
C H
H
C
H
O
CH2OH
OH
OH
CH2OH
prot mech = 2
prot ald = 2
addn mech = 2
prot prod = 2
deprot mech = 2
PLEASE NOTE: THIS IS
EXACTLY THE SAME
SET-UP AND PROBLEM
AS PAGE V ON THE
SECOND EXAM
H
C O H
C OH
H
C
H
B-
OH
OH
CH2OH
CH2OH
C O
H
C
OH
H
C
OH
H
OH
CH2OH
10
Name _______________________
Page 5 F.05.215e3p5
V. (16 points)
A. An interesting, yet complex, molecule was recently prepared (JOC 2005, 70, 7585). For the
sake of clarity, the molecule is represented according to some of its properties rather than its
actual structure.
Molecular Shape in organic Molecular Shape in water
THIS IS A COMPLEX MOLECULAR solvent
FRAGMENT: ONE SIDE OF IT IS
HYDROPHOBIC WHILE THE
OTHER SIDE IS HYDROPHILIC
hydrophobic side
hydrophilic side
FOUR OF THESE MOLECULAR UNITS
HAVE BEEN ATTACHED TO A
CIRCULAR MOLECULAR
FRAMEWORK (shown on the right).
O
O
OO
NH NH NHHN
O
O
OO
NH NH NHHN
O
W
In an organic solvent, the molecule takes on the shape represented by Structure O, where the
hydrophilic groups gather together and hydrogen bond to each other. In water, the molecule
spontaneously takes on the shape suggested by Structure W. Describe briefly why the spontaneous
reorganization in molecular structure takes place is thermodynamically rational when this molecule is
placed in water.
the hydrophobic effect: the hydrophobic portions of the molecule turn in toward each other
in order to minimize the surface contact between these parts of the molecule with water...
the reason for this is that water at a hydrophobic surface has a lower entropy, so sheding these
water molecules into the bulk of the solvent increases the entropy of the system
description of hydrophobic effect/phenomenon = 3; impact on entropy = 3
B.
Draw the Fischer projection for the open chain form of D-idose, an aldohexose
whose IUPAC name is (2S, 3R, 4S, 5R)-2,3,4,5,6-pentahydroxyhexanal.
O
6
H
C. The titration curve for L-lysine is shown below. Provide the main
HO
H
structures in equilibrium at the point indicated below.
H
OH
12
HO
H
11
H
OH
10
9
CH2OH
8
4
no partial
pH 7
6
can be
either
O
O O
5
O
box
4
H3N
H
H3N
H
3
CH2CH2CH2CH2NH3
CH2CH2CH2CH2NH2
2
3
3
1
OK IF THE DEPROTONATION
IS SHOWN FOR THE OTHER
0
1
2
3
0.5
1.5
2.5
N GROUP INSTEAD
equivalents of based added