Problem Set 5 – 25 pts
Chem 3013-01
Due Dec 8 in Class
Complete the 5 problems below on separate paper. Clearly indicate the exercise number and
ensure all writing and illustrations are legible. Please write your full name on all pages and
submit a stapled copy of your solutions. The point value of each question is given in brackets at
the end of each exercise.
1. Explain why the following molecule participates in neither SN1 nor SN2 reactions. [5 pts]
Br
2. In a classic experiment designed to reveal the relationship between stereochemistry and
nucleophilic substitution, the initial rate of the racemization of 2-iodooctane by sodium iodide in
acetone was compared to the initial rate of incorporation of radioactive iodine into 2-iodooctane.
Huges et al. J. Chem. Soc. 1935, 1525-1529. [5 pts]
I
NaI*
acetone
2-iodooctane (radioactive)
I* = radioactive iodide
Without assuming anything about the stereochemical course of this reaction, explain how the
rate of racemization compares with the rate of incorporation of radioactivity if
a) Each act of substitution proceeds with stereospecific retention of configuration?
b) Each act of substitution proceeds with inversion of configuration?
c) Each act of substitution proceeds in a stereorandom manner, in which retention and inversion
are equally likely?
What outcome do you expect for this experiment? What does it suggest about the
stereochemical course of the SN2 reaction?
3. Reagent 1 was designed to convert cysteine to dehydroalanine on peptides and proteins.
This reaction is useful for the study of protein post-translational modifications (Chem. Sci. 2011,
2, 1666-1676; Angew. Chem. Int. Ed. 2012, 51, 1835-1839). Propose a mechanism for the
reaction below and explain why the reagent is selective for cysteine over other nucleophilic side
chains such as lysine. [5 pts]
O
SH
1
H2N
N
H
O
Br Br
S
H2N
O
Dehydroalanine in peptide or protein
Cysteine in peptide or protein
O
+
N
H
pH 8.0 buffer
O
O
NH2
NH2
4. Consider the following experiment where products A, B, C, and D were formed in equal
amounts. What do these results suggest regarding the mechanism of the substitution reaction?
Can this reaction be exclusively an intramolecular substitution reaction? Explain with a
discussion of relevant stereoelectronic considerations. Finally, suggest a convenient method by
which the product distribution could be analyzed. [5 pts]
O
O
O
S
O
CD3
O S O
CH3
O
S
+
O
CH3
O S O
CD3
Equimolar in this reaction
O
NaH
1,4-dioxane
O
O
S
ONa
CH3
O S O
+
O
O
S
ONa
CD3
O S O
+
O
O
S
ONa
CH3
O S O
O
S
+
ONa
CD3
O S O
CH3
CH3
CD3
CD3
A
B
C
D
5. The following synthesis is a route to AZT, a critical drug in the treatment of HIV.
H
N
O
O
Cl
O
HO
Ph
Ph
HO Thymidine
1
NaOH
H2O
Ph
Ph
H
N
O
O
Me S Cl
O
O
O
H
N
O
AcOH
MsO
Ph
Ph
H
N
O
LiN3
DMF
5
MsO
Ph
Ph
H
N
O
Ph
O
O
3
O
O
O
6
N3
O
O
HO
O
Ph
O
O
O
2
pyridine
4
HO
Ph
Ph
H
N
O
Ph
pyridine
HO
O
O
Me S Cl
O
O
O
O
DMSO
Ph
H
N
O
Ph
AZT
N3
A) Identify an SN1 reaction in the synthesis above. Justify your proposal. [1 pt]
B) Identify an SN2 reaction in the synthesis above. Justify your proposal [1 pt]
C) In the conversion of 3 to 4, an SN2 reaction is not in operation. Using the information
provided below, propose an alternative mechanism. Based on your mechanism, predict the
product in the isotopic labeling experiment shown. [3 pts]
O
Ph
Ph
Ph
O
H
N
O
O
N
Ph
NaOH
O
Ph
Ph
H2O
MsO
O
O
NaOH
O
H2O
Ph
Ph
O
O
HO
3
4
7
This intermediate can be isolated
O
Ph
Ph
Ph
O
Ph
O
O
H
N
O
Na18OH
H2O18
MsO
3
?
H
N
O