Chemistry 303

Fall, 2010
Final Examination

1:30 pm January 13th, 2011

Duration: 20 minutes reading and then 3.0 hr to write

Name__________________KEY____________________________

This is an “open book” examination; you may use anything that is not alive nor connected to the Web.
Note: if you do not know the complete or specific answer, give a partial or general answer—
We love to give partial credit.
If there seems to be more than one good answer, explain your thinking.
If you invoke resonance delocalization as part of your answer, draw the relevant resonance structures.
If you draw a chair cyclohexane, be sure to orient the bonds carefully.
If you do not know a structure and need to write a mechanism, write a general mechanism for partial
credit.
USE THE ARROW FORMALISM CAREFULLY FOR ALL MECHANISMS
BE SURE TO INCLUDE ALL FORMAL CHARGES

p2.______/18 p3.______/16 p4.______/12 p5._______/18

p6.______ /25 p7.______/28 p8.______/22 p9._______/18 Lab Problem__________/26

p10.______/18 p11.______/24

Total: ___________/200

There are 15 pages in this exam including a spectral data page and a Glossary; please check now to be sure you have a complete
set.

Pledge:____________________________________________________________________________

1
 I. (18 pts). For each of the following pairs of reactions, pick that member of the pair that will proceed with the
highest rate. Give the single most likely product from that reaction. Give the single most important reason for the difference in
rates.

A. (06 pts).
O O
AgNO3 Much slower; cation destabilized by strong electron
Br
withdrawing effect of the C=O.
EtOH solvent

Et H
O
Et
AgNO3 O H O H O O
O Br
H
EtOH solvent H H
strong resonance stabilization -H+
Et
O O

B. (06 pts).

H H H
O H
O H O
Cl AgNO3, H2O -H+

product
silver forces loss of -Cl, and this substrate avoids the primary cation by
a concerted rearrangement. Lower transition state energy because
a resonance-stabilized cation is formed.
Cl AgNO3, H2O

C. (06 pts).

Cl NaSMe, THF

Cl NaSMe, THF SMe Standard SN2: strong nucleophile, weak base.

Relatively unhindered substrate (compared to the
top one)
MeS:

2
 II. (16 pts). Note the related molecules, P and Q. With Q, substitution occurs to give a single enantiomer U with
inversion. Kinetic studies showed that Q reacts in a bimolecular, one step process. On the other hand, P reacts rapidly to give
intermediates that then go on to produce T (with "retention of configuration").

O O O O
:NH3 :NH3
MeO MeO HO HO
Q Cl U Cl P Cl T NH2
NH3

A. (06 pts). Write the best mechanism consistent with the facts to account for the formation of U as a single stereoisomer.

O :NH3 O
SN2
MeO MeO U
H
Q Cl N
H
H H

B. (10 pts). Write the best mechanism consistent with the facts to account for the formation of T as a single stereoisomer.

:NH3
internal
O O
O O SN2 SN2 P.T.
O
H O O HO
O O
H N T NH2
P Cl Cl H3N: H H H
reactive intermediate H

3-membered ring formation is intrinsically favored by entropy factors.

Initial formation of the carboxylate anion allows an internal SN2 by inversion.
Then the 3-membered ring is opened by an intermolecular SN2 and
another inversion. Double inversion = overall retention of configuation.

3
 III. (30 pts). The reagent, N-bromosuccinimide (NBS) functions as a source of electrophilic Br, for example in the
addition to alkenes. Various solvents give good results, such as CH2 Cl2 and DMSO.

A. Note the formation of X (one diastereomer as a racemic mixture).

O
solvent Br
+ Br N + H2O
(no stereochemistry intended)
O OH
NBS X
1. (08 pts). Write the best mechanism for the formation of X. Draw the product X in the more stable chair form. Show clearly
the byproduct from the NBS.

O
Br -H+ Br Br
Br
+ Br N OH
OH2 OH
O X
H2O: X

addition to the less hindered carbon

O
O
N H+
H N byproduct
O
O

OH
2. (04 pts). In terms of your mechanism, explain why the regioisomer Y
is only a minor product (no stereochemistry intended)
Br
Y
As indicated in part 1, the water adds to the bromonium ion
at the less crowded carbon—a simple steric effect.

Br

H2O OH2

Continued….
4
 3. (08 pts). A funny thing happens in DMSO solvent. Using normal water (H2O16) but with the DMSO solvent labeled
with O , the product X now has the oxygen labeled with O18. In addition, using normal DMSO (O16), and H2O18, there is no O18
18

incorporated into the product X. Obviously, the solvent DMSO is participating somehow. Please write a new mechanism that
accounts for these observations.
O18
O
S Br
Me Me
+ Br N + H2O16 (no stereochemistry intended)
O18
O X H
NBS

O
Br -H+ Br
Br
+ Br N
O18 O18
O
O18 S
H+
S
O
The DMSO solvent acts as the nucleophile, H H
adding to the bromonium ion. Then water cleaves
Br
the S-O bond to detach the O18

O18
H

B. (10 pts). Now consider the more complicated example of the same kind of reaction. Write the best mechanism for
the formation of Z (racemic mixture). Your mechanism and product Z structure (either enantiomer) should make clear the exact
stereochemistry of Z.
O
LiCl Br
O O O
Br N
MeCN Br Cl Cl
O
Y Z

Br N
SN2 Br
Br Br SN2 O
O O
O O
Cl
Cl Z

5
 IV. (32 pts). Consider the following four molecules, A-D.
H3C H
Br Br CN
H HO
H
C H Cl
CH2Br
Br BrH2C HO
A B C OH D

A. (04 pts). Which of the structures have enantiomers? Circle all correct answers:
Explain any ambiguity. A B C D

B. (07 pts). Which of the structures has the most acidic proton? Redraw that structure here and circle the acidic proton.
Explain your choice.

H3C H H3C H H3C H

Br Br CN Br CN
CN conjugate base stabilized by resonance delocalization
-H+
into the benzene ring. One of three additional
structures shown.

O O
C OH

C. (07 pts). Which of the structures will react fastest in an SN2 process, with one mol-equivalent of NaI? Draw that
reaction here, showing the product clearly and explain your choice.

good orbital overlap in transition state for SN2

Like a simple allylic halide
I !-
I
H H H
H H H
C C H C I
H
BrH2C BrH2C BrH2C
H
Br
B Br
!-

D. (07 pts). Which of the structures will react fastest with one mol-equivalentof silver nitrate in ethanol solution? Draw
that reaction here, showing the major product clearly and explain your choice.

O
Et H
Et H Et
H H O -H+ O
H H H
H
C H C H C H either
BrH2C BrH2C BrH2C acceptable
H H H
H H H H
H H H H H -H+ H H
C C C C H
H H H
BrH2C BrH2C BrH2C BrH2C
H O
Br Ag+ O
B O Et H Et
Et H
resonance-stabilized cation

Continued….

6
 E. (07 pts). Which of the structures would show highest solubility in water? Draw that structure and show its
interaction with water as a means of explaining your choice.

H
H O
H O small molecule,with minimum van derWaals association;
H strong double H-bonding opportunity
Cl
H O
D
H H
O

_______________________________________________________________________________________________________
V. (21 pts). For each of the following reactions, draw the most likely product. If racemic, just draw one enantiomer and label
“racemic”. Explain any ambiguity.

OH H3C H
H
A. (05 pts). H3C CH3 a. BH3 H3C H3C CH3
H or S R
CH3 b. H2O2/HO- R S
H3C CH3 H OH

racemic
A

CH3
B. (05 pts). a. BH3
H3C H OH H3C CH3
b. H2O2/HO- H3C H3C
CH3 H
CH3 or S S
R R
H3C H H OH

racemic
B

C. (03 pts). What is the relationship between A and B? Circle all correct answers.

same enantiomers diastereomers regioisomers

CH3 H
OH
D. (05 pts). H2O
H3C H3C
H2SO4 H
CH3
H3C CH3
symmetrical
C

E. (03 pts). What is the relationship between B and C? Circle all correct answers.

same enantiomers diastereomers regioisomers

7
 VI. (22 pts). Morphine is a fairly complex molecule that undergoes some interesting changes in the presence of acid.

HO HO HO HO
H+
(catalytic) H+ HO steps HO
O O
H Me
-H2O N Me N Me -H+ N
N Me

HO
G H I
morphine

A. (08 pts). A simple change is the conversion to G, catalyzed by acid. Please write the best mechanism for this
process, indicating clearly the catalytic role of the acid. The templates i-iii are provided for your convenience; add/remove bonds
and arrows as appropriate [you may not need all of them, and if you need more, please draw them].

HO HO HO HO
:OH2
-H2O
H+
O O O H O + H3O+
N Me N Me N Me N Me
H
HO O
i ii iii G
H

B. (14 pts). More interesting (!) is the acid-promoted ring opening to cation H which then leads to rearrangement to I.
Please draw the best mechanism for the formation of I from H. Hint #1: you will need two carbon migrations. Hint #2: note the
location of the carbon indicated with a dark dot.

HO HO HO HO
HO

HO HO HO HO HO
H H H Me
• N Me
• N Me N Me N Me N

H • • H
• :OH
very stabilized cation 2

-H3O+

HO

HO
Me
N

•
I

8
 VII. (18 pts). Nature likes to form 6-membered rings by polyolefin cyclization, but other rings are possible. Note the
following conversion of G to H under conditions much like the formation of steroids from squalene. Please write the best
mechanism for this process. Show all intermediates. Do not worry about relative stereochemistry.

H+
HO
H2O
O G H

H2O HO HO
O G O
H
H+ concerted pathway

HO
HO HO

H
+ H3O+ H
:OH2 catalytic H2O:

9
 VIII. (18 pts). We have not emphasized doing organic synthesis yet, but this requires nothing more than recognizing
the standard reactions (one or several steps) that connect a starting material with a synthesis target. Proper sequencing of steps can
lead to contrasting structures. For example, consider the conversion of methylamine and alcohol K selectively into Ecstasy.

Suggest how you might produce Ecstasy, through a series of one or more intermediate molecules. Draw the series with an arrow
connecting one to the next, and above the arrow draw the reagents that will bring about this conversion. You need not draw
mechanisms.

You may choose any of the reagents we discussed in class. Shorter sequences are better. You can receive partial credit for a
reasonable partial synthesis, either in the forward direction or in the reverse direction, working backwards from the product.

Possibly useful reagents:

HBr, AgNO3, CrO3, NaH, BH3, HOOH, NaOH, LDA, NaCN, NaI, RCO3H, HCl, NaBr, MeI, H2O, Br2, OsO4, MsCl, KOtBu

O reagents, O Me
OH steps "Ecstasy"
Me NH2 ,
N -H+
O O Me H
K O

H2SO4 (acid-catalyzed elimination) O N

Me H
H-Br H
(convert OH to leaving group)
MeNH2

O K OtBu O H-Br O
Br
O THF O addition Br
O
E2

other possibilities?

10
 IX. (24 pts).
A. (08 pts). Note the reaction of W with chromium trioxide, following one of our standard processes. Draw the
structure of the product X and the mechanism for its formation.

O O
O H
OH Cr Cr
O OH
O Cr O O O P.T.
O O OH
H O + + H+
P.T H H Cr
Me Me Me O O
Me Me Me Me
W Me
X
typical IR absorption for a 5-membered ring ketone.

B. (16 pts). Substrate Y obviously cannot follow the same mechanism, so it finds another way to proceed. Consider the
IR data here, and the other spectral data at the end of the exam.

OH CrO3
Me Z [IR: 1720 cm-1]
Me
Me
Y

1. (10 pts). Draw the structure of the product Y and the mechanism for its formation.

H O H O O
O O Cr O O Cr O O
O Cr O H
O- OH Me
Me Me Me Me
Me Me Me Me
Me Me Me
Y

O
Me
Me
Me Z

2. (06 pts). Explain carefully how the 1H NMR data are consistent with
chemical pattern
your structure for Z. Draw the structure again here and label the H label shift
or groups of equivalent H with letters, a,b,c,d,e,f according to the table
provided. Then complete the table by describing the pattern for each 1.7 s
a:
proton type (s,d,t,quar, quin, etc).
e s
b: 1.7 accidental overlap
d H H
H O
c: 2.1 s
H

H Me d: 2.3 quar
Me f c
b
Me e: 2.5 t
a t
f: 5.2 with small additional
couplings
11
 X. (26 pts; Lab-related problem).
A. (12 pts). When trans-anethole (1) is allowed to react with N-bromosuccinimide (NBS) in “moist” dimethyl sulfoxide (DMSO),
a mixture of two isomeric bromohydrins is produced, as indicated by the 1H NMR spectrum of the crude reaction mixture taken in
CDCl3
H CH3
NBS
AnCH CHCH3 AnCH CHCH3
DMSO and/or
An H H2O
1 OH Br Br OH
2 3
An = 4-CH3OC6H4

In principle, the two isomeric bromohydrins could be regioisomers 2 and 3, or stereoisomers of either 2 or 3. When the two
isomeric bromohydrins produced in this reaction are oxidized with chromium trioxide (CrO3), a single !-bromoketone 4 is
produced.
CrO3
2/3 4
(oxidation)
Spectral data for !-bromoketone 4 are summarized below:

!"Bromoketone 4 IR (film): 1670 (s) cm-1

1
H NMR (CDCl3): #1.89 (d, J = 6.6 Hz, 3H); 3.89 (s, 3H); 5.27 (q, J = 6.6 Hz, 1H); 6.96 (d, J = 9.0 Hz, 2H);
8.01 (d, J = 9.0 Hz, 2H)

1. (09 pts). Deduce the structure of !-bromoketone 4. (Hint: There are only two possible structures for this
!-bromoketone.) Explain how the IR and 1H NMR spectral data are consistent with your proposed structure for !-bromoketone 4.

The possible !-bromoketones are 4 and 4'.

-1
The IR spectrum of the !-bromoketone shows a strong carbonyl stretch at 1670 cm . The low frequency of this
carbonyl stretch is suggestive of a conjugated ketone, such as 4, rather than 4'. The proton NMR spectrum of the !"
bromoketone is even more diagnostic. For !-bromoketone 4', all of the NMR resonances (except for the aromatic
protons) would appear as singlets. The proton NMR assignments for !-bromoketone 4 are summarized below:

The methyl group (HA) at # 1.89 ppm is split into a doublet by HC with JAC = 6.6 Hz. The methine proton (H C) at #
5.27 ppm is, in turn, split into a quartet by the three methyl protons (HA) with JAC = 6.6 Hz. Although you will not be
held responsible for the specific aromatic proton assignments this semester, they are fairly straight-forward. The
equivalent HD protons at # 6.96 ppm are shielded by the resonance effect of the methoxy oxygen and split into a
doublet by the adjacent HE proton with JDE = 9.0 Hz, consistent with ortho coupling. The equivalent HE protons at #
8.01 ppm are deshielded by the adjacent carbonyl group and split into a doublet by the adjacent HD proton again with
JDE = 9.0 Hz.

12
 2. (03 pts). Now that you know the structure of !-bromoketone 4, circle the number (i-v) of the best conclusion from the
choices shown below:

i) the two isomeric bromohydrins are regioisomers 2 and 3

ii) the two isomeric bromohydrins are enantiomers of regioisomer 2

iii) the two isomeric bromohydrins are diastereomers of regioisomer 2

iv) the two isomeric bromohydrins are enantiomers of regioisomer 3

v) the two isomeric bromohydrins are diastereomers of regioisomer 3

Since both bromohydrins afford the same !-bromoketone 4 upon oxidation, and we now know the structure of 4, the
two bromohydrins canʼt be regioisomers. The two bromohydrins must be stereoisomers of regioisomer 2; i.e.,

(Regioisomer 3 would give !-bromoketone 4' upon oxidation.) What type of stereoisomers of 2? Since the proton
NMR spectrum of the crude bromohydrin reaction mixture taken in CDCl3 shows two bromohydrins, the two
bromohydrins must be diastereomers. Enantiomers are not distinguishable in an achiral NMR solvent such as CDCl3.

B. (14 pts). When trans-anethole epoxide (5) is warmed in acetic acid in the presence of a drop of concentrated sulfuric acid,
an isomerization occurs to yield isomer 6.

O HOAc
H CH3
6
An H H2SO4
5 !

An = 4-CH3OC6H4
Spectral data for isomer 6 are summarized below:

Isomer 6 IR (film): 1705 (s) cm-1

1
H NMR (CDCl3): # 2.12 (s, 3H); 3.61 (s, 2H); 3.78 (s, 3H); 6.86 (d, J = 9.0 Hz, 2H); 7.11 (d, J = 9.0 Hz, 2H)

1. (08 pts). Deduce the structure of isomer 6. Explain how the IR and 1 H NMR spectral data are consistent with your
proposed structure for isomer 6.

6 is an isomer of 5, which means that the molecular formula of 6 is C10H12O2. For this molecular formula, there should
be 5 degrees of unsaturation. From the proton NMR spectrum (i.e., 3H singlet at d 3.78 ppm, and 2H doublets at #
6.86 and 7.11 ppm), it appears that the anisyl group (4-CH3OC6H4) is still present in 6, which accounts for 4 of the 5
degrees of unsaturation. What is the 5th degree of unsaturation? The IR spectrum of 6 displays a strong carbonyl
-1
stretch at 1705 cm , which accounts for the 5th and last degree of unsaturation. The remaining signals in the proton
NMR spectrum occur as the 3H singlet at # 2.12 ppm and the 2H singlet at # 3.61 ppm. Looks like a methyl and
methylene group, respectively. Since both of these signals are singlets, the methyl and methylene groups canʼt be
connected to each other. The only structure for isomer 6 that is compatible with the spectral data is
1-(4-methoxyphenyl)-2-propanone. The proton NMR spectral assignments are summarized below:

13
 Again, you will not be held responsible for the specific aromatic proton assignments this semester. (The
equivalent HD protons at # 6.86 ppm are shielded by the resonance effect of the methoxy oxygen and split into a
doublet by HE with J DE = 9.0 Hz, consistent with ortho coupling. The 2H doublet at # 7.11 ppm must then be due to the
equivalent HE protons.) Although it is not required, you can confirm the chemical shifts of the HA and HB protons by
quick calculations.

#(HA) = 0.90 + 1.25 = 2.15 ppm

#(HB) = 1.20 + 1.10 + 1.45 = 3.75 ppm

2. (06 pts). Propose an arrow formalism mechanism for the isomerization of epoxide 5 into isomer 6. Please show all
intermediates and every step in exquisite detail. What is the “driving force” for this isomerization?

The isomerization of epoxide 5 to ketone 6 is a variant of the pinacol rearrangement (see Problem 18.17 in Sorrell).
The isomerization starts with the protonation of the epoxide oxygen. The protonated epoxide then preferentially opens
to give the resonance-stabilized benzylic carbocation A. Carbocation A then undergoes a hydride shift, assisted by the
oxygen lone pair electrons, to give a new resonance-stabilized carbocation, the protonated ketone B. Finally,
deprotonation of B affords the observed isomer 6 and regenerates the acid catalyst.

(The base B:, shown in the figure, is probably another molecule of the epoxide 5.) The driving force for this
isomerization is the relief of ring strain in the three-membered epoxide ring of 5, as well as the formation of the strong
carbonyl bond in 6.

14
 Spectral Data for Z, problem IX

1
H NMR. 400 MHz 3H
All J = 7 Hz 6H

2H 2H
1H

6 5 4 3 2 1 0
PPM

IR: 1720 cm-1

UV: no strong absorption (n-$* only)
MS: C8H14O

13C NMR: broad band H decoupled q

s s d q q
t t

220 200 180 160 140 120 100 80 60 40 20 0

PPM

15
 Glossary

= THF
O
O
Me S Cl = MsCl
O
O
S = DMSO
Me Me

N-Li = LDA

N Br = NBS

That’s it!

(until next semester)

Enjoy your break

16