Chemistry 303

fall 1994
FINAL EXAMINATION
7:30 pm, January 12th, 1995
Duration: 3 hr
There will be an additional 30 min allotted for the course evaluation before the exams are collected
Name________________________________________________
Lab TA______________________________________________

This is an "open book" examination; you may use anything which is not alive.
NOTE: if you do not know the complete or specific answer, give a partial or general answer-WRITE SOMETHING
NOTE: write your mechanisms CAREFULLY. A good answer will require precision in the use of the
arrows and description of spectral information.
Grade:
1._______/20
2._______/33
3._______/28
4._______/29
5._______/40
6._______/20
7._______/30
total: _____/200
There are 11 pages in this exam; please check now to be sure you have a complete set. The last page is the
NMR chemical shift table for your convenience.

EVALUATION FORMS ARE AVAILABLE IN THE FRONT OF THE ROOM.

PLEASE FILL THEM OUT BEFORE YOU LEAVE AND LEAVE THEM HERE.
Pledge:______________________________________________________________________________

3
II. (33 pts)
(A) ( 5 pts) Amines are better nucleophiles than alcohols (or water). Why?

(B) (6 pts) The reaction of a primary amine with methyl chloride in water is pretty slow (reaction
(a)), as monitored by measuring the rate of disappearance of the CH3Cl. Write a mechanism for this
reaction, showing carefully the electron flow.
+
water
a. RCH2 NH 2 +
CH3 Cl
CH3 NH 2 CH2 R
(slow)

Cl

(C) (6 pts) Having heard somewhere that nucleophilic substitution reactions can be catalyzed by
acid, an Orgo student (not at Princeton, of course), tried to speed the reaction shown in (a) by adding excess
sulfuric acid (as in (b)). He was shocked and surprised to find that he got only methyl alcohol under
conditions (b) AND the reaction rate was even slower than in (a). Explain carefully how the addition of
acid led to the different product and slower reaction.
b. RCH2 NH 2

CH3 Cl

water
H2 SO4

CH3 OH

(slower)

(D) (6 pts) He then tried the other extreme, adding excess NaOH to make the solution basic. The
reaction was now much faster, but he found the same problem: CH3OH was the main substitution product.
Explain how the addition of base gave the observed product and a faster reaction compared to (b).
c. RCH2 NH 2

CH3 Cl

water
NaOH

CH3 OH

(faster)

continued
(E) (5 pts) Give a specific example of an SN2 reaction which is accelerated (higher rate) by acid.
Show reactants and products, and the role of the acid.

(F) (5 pts) As noted in part (C) above, the substitution of methyl chloride was not accelerated by the
addition of sulfuric acid. This is a general observation for methyl chloride in SN2 reactions. Why are
substitution reactions of methyl chloride not accelerated by the presence of acid?

____________________________________________________________________________________
3. (28 pts). Consider each of the following four pairs of molecules in turn. For each pair, give
ONE form of spectroscopy (UV, IR, MS, 1H NMR) which will clearly distinguish the two. You may use
each form of spectroscopy only ONCE. Explain carefully the single most important spectral feature which
will distinguish the molecules.
O
A.

CH3

Cl

vs

CH3

Cl

_____________________________________________________________
B.

O
O

vs

continued

HN

C.

O
NH

vs

CH3

_____________________________________________________________
O

Cl

I
vs

D.
HO

HO

____________________________________________________________________________________
4. (29 pts) It is an important fact of life (required for life!!) that carbon does not invert configuration
(racemize) rapidly at room temperature:
H
Ph
CH3

very
slow

CH3
Ph

CH2CH3

CH2CH3
H B

A. (4 pts) What is the configuration of A in the R,S nomenclature?

What is the relationship between A and B? Circle best answer.
enantiomers

diastereoisomers

meso

identical

B. (8 pts) Certain compounds, however, such as C, do undergo inversion just on standing in water at
25
Explain the mechanism for this inversion, taking into account the role of the carbonyl and -CN
groups. Your answer should accommodate the additional fact that base accelerates the rate of inversion.
oC.

H
Ph
NC

H2O
fast
CH 3

NC
Ph

O
CH3
H D

C. (7 pts) The simple amines such as E do undergo inversion rapidly at 25 oC. Draw the transition 6
state for this isomerization. Specify the hybridization of the nitrogen atom in E and in the transition state.

..
H
CH3

fast

N
E

CH2CH3

CH3
H

CH2CH3
N

..

D. (10 pts) An exception to the general rule for amines are the aziridines, an example of which is G.
The barrier to inversion for G is much higher compared to E. Explain this observation using reaction
coordinate diagrams which nicely represents the energies of the reactants, transition states, and products
for the two processes (E F compared to G H). You might use words also. Indicate Gfor each
reaction clearly on the diagrams.

..

slow

N
G

CH2CH3

CH2CH3
N

..

IT IS BEST IF YOU READ ALL OF THIS QUESTION BEFORE ANSWERING

5. (40 pts) Enzymes are wonderful catalysts, typically associating with a substrate and then using
acidic and basic functional groups in the enzyme structure to promote conventional organic reactions by
conventional mechanisms. One of the key reactions involved in glucose metabolism is the E2 elimination of
water from citric acid (Fischer projection A) to form aconitic acid. By isotope labeling, it has been shown
that the H which is lost is the one indicated by the asterisk in the structure of citric acid, below.
CO2H
H
H*
HO
CH2CO2H
CO2H

Aconitase
-H2 O

H
HO2C

CO2H

HO2C

OR
CH 2CO2H HO2 C

H
CH2CO2H

one of these
is aconitic
acid

A
A. (4 pts) If you were an enzyme, and wanted to associate strongly with citric acid (A), what
functional groups would you choose to use? Suggest TWO different common functional groups which
could provide association with A and explain with words and pictures how the association works. You
need not try to represent the enzyme.

B. (7 pts) Assuming the usual E2 mechanism, which of the two isomers shown above is correct
for aconitic acid? Draw it here, specify whether the C=C is E or Z, and show your analysis of how it
formed selectively. It may be advantageous to use Newman projections.

C. (3 pts) Which common functional group might an enzyme use to provide ACID catalysis?
Specify one possibility and explain why it is more acidic than, for example, water.

D. (3 pts) Which common functional group might an enzyme use to provide BASE catalysis?
Specify one possibility and explain why it is more basic than, for example, water.

E. (9 pts) Using those two functional groups and the structure of citric acid, show how the E2
elimination might be assisted by both acid and base. That is, write a mechanism for the E2 elimination of
water from citric acid which involves both acid and base. Newman projections will be advantageous.

F. Isocitric acid is an isomer of citric acid, also involved in metabolism. It has the general structure
B shown below. The same enzyme (aconitase) also converts it into aconitic acid, by the same mechanism of
E2 dehydration.
OH
isocitric acid
HO2C CH CH CH2CO 2H
B CO 2H
1. (4 pts) Using either the sawhorse projections , Newman projections, or the Fischer projections,
draw here all of the stereoisomers possible with the general structure B. Indicate clearly which carbons
are stereogenic (chiral) in one of your isomers.

2. (6 pts) Which isomer can lead to aconitic acid (only one possible by the E2)? Explain your
9
choice by showing the anti relationship required for the E2. The Newman projection may be advantageous.

G. (4 pts). Under acidic conditions, certain alcohols such as tert-butyl alcohol readily undergo
elimination of water by an E1 mechanism. Why does Nature not take advantage of the E1 pathway and
design a dehydration enzyme for citric acid based on this mechanism? There are several answers of greater
or lesser significance; give as many as you can (no more than three).

_____________________________________________________________________________________
6. (20 pts) Write a detailed multi-step pathway for following process. Use the usual arrow
formalism carefully. Show all intermediates carefully. Give a name for each mechanistic type you use (same
old mechanisms).
H
Me + DMSO
+
S O + Et3 N
+
Me
S
I +
+
Et
NH I 2
3
solvent
O
Me
DMSO

7. (30 pts). We have not emphasized doing organic synthesis, but this requires nothing more than 10
recognizing the standard reactions (one or several) which connect a starting material with a synthesis target.
Suggest how you might convert 1-methyl-1-cyclohexene into product A and (by different sequences)
products B and C. For each case, write down the key reagents for each step in the proper sequence. Each
conversion might require one or two steps. You need not write a mechanism.
Possibly useful reagents: HBr, EtOH, EtI, CrO3,

H2O, RO-OR, MeI, RCO3H, HOOH, NaOH, BH3,

_______________________________________________
NaH, pyridine, BH3, HCl, NaI, SOCl2
OCH2CH3
?
A

________________________________________________
H

?
B

(racemic)

________________________________________________
OH
OH

?
C

(racemic)

That's it! Best wishes in Chem 304. Please stop by and let me know how things are going. MFS