Comprehensive Problems Set

PROBLEM SESSION PROBLEMS -- CHEM 33
Enols, Enolates and Condensation Chemistry
1. Give the missing products for the following reactions.
a.
b.
c.
d.
e.
f.
g.
h.
i.
O O 1) LDA
O
O
2) CH 3CH 2Br
OH
H + , H 2O
heat
O O 1) NaOH
O
H 3CO
O
H
1) LDA
2) CH 3I
2) CH 3CH 2Br
O NaOEt
O
EtOH, ²
LDA
O O
O NaOCH 3
+
OCH 3
CH 3OH
O
OCH 3
O
H H
H 3O +
NaOCH 3
CH 3OH
NaOCH 3
CH 3OH
H 3O +
H 3O +
H 3O +
Chem 33 Problems pg 1

j.
k.
l.
m.
n.
Br
O O
O
OEt
O 1) LDA
CN
OH
O
1) LDA
2)
2) CH 3CH 2Br
1) NaOEt
2) Br
1) LDA
2)
3) H3O +
O
O
Br 2, AcOH
2. Give the missing products for the following reactions.
a.
b.
H 3CO
O
O
O
O
OCH 3
H
OCH 3
1) NaOCH 3
2)
3) H + , H 2O, heat
H + , H 2O
heat
I
Chem 33 Problems pg 2
1) NaOEt
2)
Br
3) NaOH, then H + , H 2O, ²
TsOH, ²

c.
d.
e.
f.
O
O
O
O 1) LDA
O
O
O
OH
1) LDA
2)
O
2) CH 3I
1) LDA
2) PhCH 2Br
Br
N O
(NBS)
K 2CO 3
Br
3. Predict the initial product from the following reaction, and then draw a mechanism to show the
subsequent conversion of this intermediate product to the final lactone (or cyclic ester) product. The
overall reaction proceeds spontaneously to the lactone, which is isolated after a typical acid/water
quench.
O
OCH 3
1) LDA
2) O
?
Chem 33 Problems pg 3
O
O
+ HOCH 3
4. Give the missing products or reagents for the following reactions. If appropriate, give all possible
products, but indicate which should be the major product.
a.
b.
HO
O
H
O
1) LDA
2)
3) H 3O +
O
H
1 equiv. LDA

c.
d.
e.
f.
O
O
O
O
+
O
1) ?
2) ?
H
1) LDA
2)
3) H 3O +
O
NaOCH 3
O
H
OCH 3
OH
O
NaOCH 3
5. Determine the starting materials required to form the following compounds by an aldol reaction.
H 3CO
O OH
O OH
O
H 3CO
Chem 33 Problems pg 4
O
O OH
A B C D
6. Predict the products of these intramolecular variants of the aldol and Claisen reactions.
a.
b.
H
O
O
O
O
H
H
NaOCH 3
heat
NaOCH 2CH 3

c.
H 3CO
O
O
H 3CO NaOCH 3
7. Determine the missing reagents used to produce Cyclopentolate, a drug used to produce mydriasis
(pupil dilation) and cycloplegia (paralysis of the ciliary muscle, which is responsible for focusing the
eye), from ester 1. (Note: in the first step use a reagent that converts 1 completely to 2). Describe what is
unusual about the sequence.
O
OR
O
OR
O
O
Chem 33 Problems pg 5
OR
? ? ?
1 2 3
OH
O
Cyclopentolate
OR
R = CH 2CH 2N(CH 3) 2
8. Propose syntheses to accomplish the following transformations. A couple of them may take four
steps, and several can be accomplished more than one way.
a.
b.
c.
d.
any 3-or-fewer
carbon compounds
OH
O
OH
?
?
?
?
O O
OCH 3
O O
O
O
O
OH

e.
f.
g.
h.
O
Br
CN
Br
O
?
?
?
?
9. Propose syntheses to accomplish the following transformations. A couple of them may take four
steps, and several can be accomplished more than one way.
a.
b.
c.
d.
O
OH
H 3CO OCH 3
O
?
O O ?
Br
?
?
O
O
O
O
O
O
OH
OCH 3
Chem 33 Problems pg 6
O
OH

e.
f.
g.
H 3CO
O
O ?
O
O
O
?
OCH 3
?
OH
H 3CO
10. Practice mechanisms for the following reactions. Draw all reaction arrows, intermediates, and formal
charges.
a.
b.
c.
EtO
O O
O
NaOEt
O
O
H
O
OEt
EtOH
OH NaOH, H 2O
NaOEt
EtOH
O
11. Propose a mechanism to account for the following observation and explain (in words) why you think
it occurs.
O O
OEt
1) NaOEt
2) H 3O +
O
O
Chem 33 Problems pg 7
O
O
OEt
O
O O
OEt

12. Determine which is the stronger acid in the following sets of compounds, and give a brief
explanation of your reasoning. As part of your answer, clearly indicate which hydrogen in each
molecule is the most acidic, and try to estimate the pKa's. The pKa's of the indicated protons in the
reference compounds below may be helpful in your analysis. Remember that these pKa's provide an
experimental measure of the electron withdrawing ability of the functional groups.
a.
b.
c.
d.
e.
f.
H H O
H O H H O
EWG N
C N
S
O
O
pKa 20 10 31 29
O O
Cl
H 3CO OCH 3
Cl
HO
O
O 2N
O
O
NO 2
O
CN
O
OH
HO
Cl
O
O
N
O
O OCH 3
H 3CO OCH 3
Cl
NC
O
CN
O
O
O
O
OH
Chem 33 Problems pg 8
Ph

13. Identify the following compound from the given spectra.
Chem 33 Problems pg 9

14. Give the expected major products for the following reactions.
a.
b.
c.
d.
e.
f.
H 3CO
O
O
O
N
O
O
CN
1) LDA
2) CH 3I
O
NaOCH 3
CH 3OH
OCH 3
O H
OCH 3
1) (CH 3) 2CuLi
2) H 3O +
NH 2
NaOCH 3
CH 3OH
H 2O
O
CH 3OH
1) LDA
2)
O
Chem 33 Problems pg 10
H
H 3O +
1) CH 3Br
2) H + , H 2O, ²
15. Give the missing products or reagents for the following reactions. If appropriate, give all possible
products, but indicate which should be the major product.
a.
O 1) LDA
2)
O
H

.
c.
d.
e.
CH 3O
H 3CO
O O
O
O
C
OCH 3
OCH 3
N
+
1) ?
2) ?
1) ?
O O
+
2) ?
3) H + , H 2O, heat
OCH 3
O
OCH 3
NaOCH 3
NaOCH 3
H 3CO
16. Give the missing products or reagents for the following reactions. If appropriate, give all possible
products, but indicate which should be the major product.
a.
b.
c.
H 3CO
O
O
C
O
N
O
H
+
O 2N
NaOC(CH 3) 3
NaOCH 3
NaOCH 3
O
O
Chem 33 Problems pg 11
O
C
N

d.
e.
f.
g.
O
O
O
1) LDA
2)
O
OCH 3
O
H
OCH 3
O
NaOCH 3
1) (CH 3) 2CuLi
2) H 3O +
?
(multiple steps)
O O
17. Determine the most likely product of each of the following intramolecular cyclization reactions.
a.
b.
O
O
H
O
O
NaOH
NaOH
heat
18. Each reaction below shows a plausible but unlikely product. Examine each reaction closely to
determine why the product shown is not favored, then provide what should be the favored product.
Briefly explain your reasoning.
a.
O
O
H
NaOH
OH
O
H
Chem 33 Problems pg 12

.
c.
O
O
H 3CO
O
O
NaOCH 3
1) LDA
2) CH 3CH 2Br
3) LDA
4) CH 3I
H 3CO
O
O
19. When compound 1 is treated with one equivalent of base and then one equivalent of ethyl bromide,
the ethyl ester 2 is formed (top reaction). However, when 1 is treated with two equivalents of base and
then one equivalent of ethyl bromide, the carbon-alkylated product 3 is formed (bottom reaction).
Explain these results.
O O
1) LDA (1 equiv.)
2) CH3CH2Br 3) H3O +
H3CO OH
H3CO O
1 2
O O
H 3CO OH
1
1) LDA (2 equiv.)
2) CH 3CH 2Br
3) H 3O +
O
Chem 33 Problems pg 13
O O
O O
H 3CO OH
20. Label the most acidic protons in each of the following molecules, and give an estimate of their pKa
values.
O
O
OH
O O
H 3CO OCH 3
H 3CO
O O O
H 3CO OH H 3CO
O O
O
NO 2
O
3
H 3CO
O
OCH 3
OH

21. Provide mechanisms for the following reactions. Draw all reaction arrows, intermediates, and formal
charges.
a.
b.
O
O O
NaOCH 3
HOCH 3
O
NaOCH 3
22. Draw a stepwise mechanism for the conversion of A to B. If this reaction is allowed to go for several
hours, most of A is converted to B. Explain why B would be favored.
CH 3
O
NaOCH 3
HOCH 3
A B
23. Propose syntheses to accomplish the following transformations.
a.
b.
c.
O
O
H
?
?
O O O
?
O
O
HO
O
H
Chem 33 Problems pg 14
O
CH 3
O

d.
e.
f.
g.
HO
Br
O
CN
H
O
?
?
?
OH
H 2N
O
O
NH 2
H H
?
O H
O
h. Here’s a labeling problem. The starting material is isotopically enriched with carbon 13 at the
indicated carbon. You want to make each of the differently di-labeled products. Note that at some point
in each synthesis, you will have to use isotopically enriched reagents.
i.
13 C
OH
O
?
?
i)
ii)
13 C
13 C
NH 2
O
O O
Chem 33 Problems pg 15
13 C
13 C

j.
O OH
H
?
24. Propose syntheses to accomplish the following transformations.
a.
b.
c.
d.
O
O
O
O
OCH 3
O
O
CH 3
CH 3
?
?
?
?
O
O
HO
HO
Hint: via
25. Propose syntheses for the following molecules. In each case your restriction is that all starting
materials and reagents must not contain more than 4 carbons. Look carefully for signatures. Every case
involves chemistry of carbonyl compounds in one form or another -- enolates in SN2, aldol, Claisen, and
Michael/conjugate addition reactions. Sometimes more than one of these is necessary. Be on the lookout
also for cases where a useful carboxylic acid/ester may have been removed by decarboxylation after
some of the reactions. The molecules roughly increase in difficulty as you go down.
Chem 33 Problems pg 16
O
O
O
O
O
O
Hint: via
O
O
OCH 3
O
O

a.
b.
c.
d.
e.
f.
g.
h.
NC
O
O
OH
O
O
NH
OH
O
O
O
O
OH
OH
NO 2
OEt
Chem 33 Problems pg 17

26. Determine the structure of the compound that corresponds to the following spectra. Hint: This
product could be obtained by an aldol reaction followed by oxidation with PCC.
Chem 33 Problems pg 18

Conjugated Alkenes and Radical Reactions
27. Give the expected major products for the following reactions.
a.
b.
c.
d.
e.
f.
g.
h.
i.
O
O
O
H
O
HBr
+
heat
O
H
heat
O
H 3CO 2C
heat
O
heat
Br 2
CCl 4
HBr
heat
²
CO 2CH 3
Chem 33 Problems pg 19
H 2, Pd/C

j.
k.
l.
m.
n.
o.
Br 2, hν
NBS, hν
O
heat
1) NBS, hv
2) NaCN
Br 2
hν
O
heat
O
28. Give the missing products for the following reactions. Make sure to show stereochemistry where
appropriate.
a.
b.
1) NBS, light
2) KOtBu
HBr
Chem 33 Problems pg 20

c.
d.
e.
f.
+
C
O
O
O +
O
NH
CH 3
CH 3
+
+
H 3C
H 3C
H 3CO
H 3C
O
O
O
O
heat
OCH 3
OCH 3
heat
heat
heat
29. The following reactions show plausible but incorrect products. Give the correct products, and briefly
explain the problem with the products shown.
a.
b.
+
+
CH 3
O
CN
OCH 3
heat
heat
CH 3
Chem 33 Problems pg 21
H
O
CN
OCH 3

30. Use your knowledge of the Diels-Alder reaction to predict mechanisms for the following
transformations. Draw all reaction arrows, intermediates, and formal charges. Do the reactions seem
plausible?
a.
b.
O
O O
heat
O
heat
33. Propose a synthesis to accomplish the following transformation.
Chem 33 Problems pg 22
+
31. Provide a reasonable mechanism to explain the reaction shown below. Draw all reaction arrows,
intermediates, and formal charges.
O
O
+
CO 2CH 3
CO 2CH 3
heat
O
C
O
CO 2CH 3
CO 2CH 3
+ CO 2
32. Give the starting materials necessary to make each of the following compounds by a Diels-Alder
reaction.
a.
b.
c.
d.
CH 3
CH 3
CO 2CH 3
C
N
CO 2CH 3
NO 2
CO 2CH 3
CO 2CH 3

O
? CH3 hint: via
CH3 34. Propose syntheses to accomplish the following transformations.
a.
b.
c.
d.
e.
f.
g.
?
HO
HO
O O O
OH
O
O
H
?
?
?
?
H
H 3CO
?
Br SCH3 O
O
O
OH
O H
NH 2
O
Chem 33 Problems pg 23
H
O
O

h.
i.
O
?
?
H 3CO OCH 3
O
O
COOH
O ? OH
O
35. Give all the possible products one might expect from the following reaction. In practice, only one
product is formed. Its 13 C NMR spectrum contains peaks at 30.1, 47.8, 115.2 and 122.5 ppm. Based on
this information, which product is the one that is formed? Give an explanation why this is the only
product.
NBS, hν
36. Evaluate each of the sets of compounds according to the criterion given. Circle your choice and
explain your reasoning.
a. Which dienophile should undergo Diels-Alder cycloaddition more easily?
H
O O O
b. Which compound do you expect to absorb at a longer UV wavelength?
c. Which diene should undergo Diels-Alder cycloaddition more easily?
d. Which dienophile should undergo Diels-Alder cycloaddition more easily?
O
H
NH 2
e. Which isomer do you expect to be lower in energy?
O
O
Chem 33 Problems pg 24
OH

f. Which isomer do you expect to be lower in energy?
Cl
Cl
37. Provide a mechanism for the following transformation. Draw all reaction arrows, intermediates, and
formal charges.
Br 2
hν
Chem 33 Problems pg 25
Br

Aromaticity
38. Determine whether the following molecules are aromatic.
N
O
N
O
O
N
N
O N H
O O
O N
O O
39. Azulene (shown below) has a strong experimental dipole moment. Predict the direction of the dipole
and give an explanation for why it is observed.
40. Which of the following hydrocarbons is the most acidic? To answer this question, first make sure to
consider what is the most acidic hydrogen for each individual molecule before comparing the three
different molecules.
A B C
41. Evaluate each of the sets of compounds according to the criterion given. Circle your choice and
explain your reasoning.
a. Which substrate should react faster under SN1 conditions?
Br Br
b. Which anion is a better nucleophile?
c. Which borohydride is more reactive (think Lewis acid)?
B H B H
d. Which ketone is more reactive toward nucleophiles?
O O
Chem 33 Problems pg 26
O

42. The following reaction does not occur with the corresponding seven-membered ring analog. Explain
this apparent anomaly.
PhLi
PhLi
Li
No Reaction
43. Substituted benzene derivatives often have many ways they can be named, and more than one
version is often sanctioned by IUPAC. Try naming each of the following compounds, and look at the
answers to see variations you may not have considered. Each is a compound you might find as an
unknown in your laboratory work.
a.
b.
H 3CO
O
OH
NH 2
44. Give the expected major products for the following reactions.
a.
b.
c.
d.
Br 2
CCl 4
AlCl 3
HNO 3
H 2SO 4
Cl
O
AlCl 3
Cl
Chem 33 Problems pg 27
HNO 3
H 2SO 4
Ph

e.
f.
g.
h.
i.
j.
HOOC
NC
O
Cl
I 2, CuCl 2
+
Br
HNO 3
H 2SO 4
HS Br 2
HNO 3
H 2SO 4
I 2, CuCl 2
FeBr 3
AlCl 3
45. For additional practice, draw out the mechanisms for the reactions in problem 44 above.
46. Evaluate each of the sets of compounds according to the criterion given. Circle your choice and
explain your reasoning.
a. Which compound do you expect to undergo electrophilic substitutions more easily?
OH Br
b. Which compound should undergo electrophilic aromatic substitutions more readily?
BH 2 PH2
c. Which phenol is more acidic?
H3CO OH O2N OH
Chem 33 Problems pg 28

47. The pesticide DDT is synthesized by the reaction shown below. Provide a mechanism to account for
its formation.
Cl
+
O
H CCl 3
H 2SO 4
Cl
H
CCl 3
Chem 33 Problems pg 29
Cl
+
Cl
H
48. You perform the reaction shown below and get a product with molecular formula C12H18.
a. Identify the product based on the proton and carbon NMR spectra.
b. Is this product what you would have expected? Give a rationalization for its formation.
AlCl 3
Cl
C 12H 18
CCl 3
Cl

49. Give the expected major products for the following reactions.
a.
b.
c.
d.
e.
f.
O
H 3C
O
O
Br
CH 3
O
Cl
+
CH 3
AlCl 3
KMnO 4, NaOH
Cl
1) NaOH
O
AlCl 3
2) H 2, Pd/C
Br 2
FeBr 3
Li, NH 3, EtOH
50. Give the expected major products for the following reactions.
a.
O
1) HNO 3, H 2SO 4
2) H 2, Pd/C
Chem 33 Problems pg 30

.
c.
d.
e.
f.
g.
h.
NH 2
NH 2
OCH 3
1) NaNO 2, HCl
2) CuCl
1) NaNO 2, HCl
2) CuCN
3) LiAlH 4; then H 3O +
1) Na, NH 3, EtOH
2) H + , H 2O
1) FeBr 3, Br 2
2) KMnO 4
H 3CO 1) HNO 3, H 2SO 4
F
F
N 2
NO 2
NaOH
2) H 2, Pd/C
1) H 2O, Cu 2O, Cu(NO 3) 2
2) NaOH, then CH 3I
51. Provide the missing products and reagents for each reaction.
a.
NH 2
1) ?
2) ?
3) ?
NH 2
Chem 33 Problems pg 31

.
c.
d.
e.
NH 2
HNO 2
H 2SO 4
?
OH O
?
N
N ? OH
NH 2
?
O
CN
52. Explain why the top reaction occurs but the bottom one does not. Use your mechanistic knowledge
of aromatic substitution reactions.
Br
Br
O
O
OCH 3
OCH 3
CH 3O
CH 3O
CuI
H 3CO
Chem 33 Problems pg 32
no reaction
?
O
OCH 3
54. Estimate the pKa's of the following substituted phenols by considering the effect of the electron
withdrawing and electron donating substituents. The reference pKa for phenol is 10.
HO HO
pKa = 10
CH 3
HO
56. Which hydrogen in ascorbic acid is most acidic? Explain your answer briefly.
N
CH 3
CH 3
HO
CF 3
HO
CO 2CH 3

HO
H
HO
OH
O
OH
O
Chem 33 Problems pg 33
ascorbic acid
57. Propose syntheses for each of the following molecules from the stated starting material.
a. Using benzene as your starting material:
HOOC
NO 2
b. Using any mono-substituted benzene as your starting material:
Br
Br Br
OH
Br
c. This product is an herbicide called Trifluralin. Based on your synthesis, how would you characterize
the electron donating/withdrawing properties of the CF3 substituent?
F 3C
Cl
?
Cl
F 3C
NO 2
O
NO 2
58. Synthesize the following molecules from the starting material provided.
a.
b.
OH
?
?
O
OCH 3
Br
59. Researchers in the Food Preservatives Group have found that the amino analogue of BHT makes
food (such as 7-11 hot dogs) last 10 to 15 years (even while on the rotating hot dog cooker). Synthesize
this derivative from aniline in the most efficient manner.
N
O
NO 2
N N
NH 2
OH

NH2 NH2 OH
?
Chem 33 Problems pg 34
butylated hydroxytoluene
(BHT)
60. Synthesize trichlorosalicyclanilide from any monosubstituted benzenes and non-aromatic reagents
you require.
OH
Cl
O
N
H
Cl
Cl
trichlorosalicyclanilide, an antiseptic

61. Provide structures for the products of the reactions below and draw mechanisms that account for
their formation.
a.
b.
O 2N
NO 2
NO 2
OCH 3 D 2SO 4
CH 3NH 2
D 2O
C 7H 7N 3O 4
C 7H 5D 3O
62. Give the expected major products for the following reactions.
a.
b.
c.
d.
O
S
OH
Cl
N Cl
O
AlCl 3
O
(KSO 3) 2NO
1) SnCl 2, H 3O +
2) K 2CO 3, CH 3I
Cl
NaO
63. Propose syntheses for each of the following molecules from the stated starting material.
a.
b.
any monosubstituted
benzene ring
NH 2
?
?
H 3CO
O
O
OCH 3
Chem 33 Problems pg 35

64. You observe that the following reaction takes place with pyridine.
CH 3Li
N N
a. Propose a mechanism that would account for the formation of the product.
b. How could you use your knowledge of this reaction to devise a simple synthesis of coniine, the active
ingredient in poison hemlock, from pyridine (shown below).
Amines
N
?
Chem 33 Problems pg 36
NH
Coniine

53. The "availability" of the electron pair on nitrogen can be used to estimate its basicity in different
systems. Determine the more basic compound in each pair below and briefly explain your reasoning.
a.
b.
c.
d.
N H
H3CO NH2 O2N O 2N
NH
CH 3
N CH3
N
O 2N
N
H
NH 2
N CH3
55. Rank the following substituted anilines from most basic to least basic, and briefly explain your
reasoning.
H 2N
CH 3
H 2N
SCH 3
65. Circle the most basic/nucleophilic nitrogen in each of the natural products below.
N
nicotine
N
CH 3
N
H
serotonin
CH 3
H 2N
NH 2
Chem 33 Problems pg 37
CF 3
CH 3O
H 2N
HO
quinine
N
N
NO 2

N
strychnine
N
O O
H 3C
O
Chem 33 Problems pg 38
N
O
N
CH 3
caffeine
N
N
CH 3

66. Identify the following compounds from the spectra given.
a.
Chem 33 Problems pg 39

.
Chem 33 Problems pg 40

c.
Chem 33 Problems pg 41

67. Give the expected major products for the following reactions.
a.
b.
c.
d.
e.
f.
g.
O
O
N
O 1) NaN 3
H
N
OH
Cl
Br
Br
O
2) ² , H 2O
1) NaN 3
2) LiAlH 4
3) H 3O +
1) NaOH,
O
2) LiAlH 4; then H 3O +
OH
1) CH 3I
2) AgOH, ²
OH
H 2N
1) NaN 3
2) LiAlH 4
3) H 3O +
1) CrO 3, H 2SO 4
Cl
2) H 2NCH 3, H 2, Pd/C
68. Provide the missing products and reagents for each reaction.
a.
O
NH 2
1) Br 2, NaOH, H 2O
2) heat
Chem 33 Problems pg 42
H 2
Pd/C
note -- think of reaction
with benzyl ethers

.
c.
d.
e.
f.
NH 2
CH 3
HO OCH 3
O
1) CH 3I (excess)
2) NaOH, heat
?
? H 2N OCH 3
O NH 2
NH 2
O
Cl
?
1) NaN 3
2) heat, H 2O
O
N
H
Chem 33 Problems pg 43
a nasal decongestant
69. Propose syntheses for each of the following molecules from the stated starting material.
a.
b.
c.
d.
e.
O
O
Br
OH
O
?
?
?
?
?
N
NH 2
H
N
O
H
N