Chemistry 17: Module 6 Problems

Workshop Problems - Part A

Lectures 16-19 Problems

Workshop Problem 1. Identify each of the following structures as either chiral or achiral by writing the appropriate
word under each structure. Additionally, classify each pair of molecules as either identical, structural isomers,
enantiomers, or diastereomers by writing the appropriate word or phrase in the box provided.

Relationship
Br Br
1-a.
identical
Br Br
achiral (meso) achiral (meso)

Remember that meso compounds do not have an enantiomer.

The structure you would draw for the enantiomer will be identical.

1-b.
Br Br structural isomers

chiral chiral

Cl H Cl
1-c. H 3C Cl
CH3 enantiomers
H 3C
H CH3
Cl H
H
chiral chiral

Good practice converting Newman projections into skeletal structures (and vice versa!)

1-d.
diastereomers

achiral chiral

Good practice converting chair conformations into cyclohexanes (and vice versa!)
Workshop Problem 2: Assigning R/S and E/Z (Absolute Configurations)
For each of the small molecules shown below, use the CIP convention to identify absolute configuration for the
alkenes (E or Z).
2-a. 2-b.

(E)
O Me Me
O
O H
O OH Me (Z)
(Z) (Z)
O (E)
H
OH OH
O
Bonus: why no E/Z on this alkene?
Both groups on the terminal Codling moth compound
Eucannabinolide carbon are the same!

Workshop Problem 3: Conformational Analysis of Cyclic Systems Key point:

- drawing chairs
For each of the compounds below: - axial vs equatorial positioning
i) Draw all the energetically accessible chair conformations. - stable conformation of a chair
ii) Circle the most stable conformation(s).
iii) In each conformation, label the non-hydrogen substituents as axial or equatorial.

3-a. Me Me ax. [Link]

H
OH eq. Me eq.
OH H
H H

3-b.
Me ax. ax.
H eq. Me Me
Br eq. Me H H
Br H H
Me H
Me CN eq. H Br CN eq.
H [Link] ax.

3-c. H H Only need to draw this structure: trans-

decalins actually cannot be flipped (build
Me a model and try!) so you’re only required
Me Me eq. ax. to draw the lowest energy conformation
H H Me
based on the substituents.
Workshop Problem 4: Conformational Analysis of Acyclic Systems
4-a.
i) Provide a Newman projection corresponding to each local energy minimum and maximum for rotation about the
central bond of 2-methylbutane, starting from the structure provided below. In your Newman projections, rotate
the substituents on the back carbon. Key point:
ii) For each conformer, identify all of the gauche and eclipsing interactions. - Newman projections
H H Me - Gauche/eclipsing positioning
Me H H
=
Cl
H Me H Me 2 x Me/H
Cl Cl/Me 1 x Cl/H
2 x Cl/Me Eclipsing Cl/Me
Me/H Eclipsing Gauche Eclipsing
Gauche
Me H Me Me Cl Me Me H Me
H H H Cl Cl H
Cl H H
H Me H Me H Me H Me H Me H Me
Cl H H Me/H H Cl
Cl/Me H H/H
H/H Eclipsing Eclipsing
Cl/Me Eclipsing
Gauche Eclipsing

A B C D E F

A and E will be lowest energy, due to least amount of gauche interactions between Me and Cl.

B and D will be highest energy, due to Cl/Me eclipsed interactions and H/H and Me/H eclipsed.
F is the next highest energy, due to the Cl/Me eclipsed interaction no longer is present. Eclipsed interactions with an H still contribute energy but
not as much as having two larger non-hydrogen groups eclipsed.

4-b. In the space below, construct an energy diagram that shows the qualitative relative conformational energies
of 2-methylbutane upon 360-degree rotation about the central bond. All local energy minima and maxima should
be connected with a smooth curve. For clarity, you may label the Newman projections in part 2-a (A, B, C . . . )
and use those labels on your diagram below starting from the given structure as structure A.
Key point: note: a Me-Me eclipse and an H-H eclipse, is more
- Mapping Newman projections destabilizing than 2 Me-H eclipses
onto energy diagram

B D

A E A

0º 60º 120º 180º 240º 300º 360º

Dihedral Angle
Workshop Problem 5: SN1 and SN2 Reactions
For each of the following reactions:
i) Predict the product(s) and provide a curved-arrow mechanism. Recall Lecture 17 for how to account for
creating new stereocenters and forming multiple stereoisomers in a mechanism.
ii) Label each mechanism as SN1 or SN2.
iii) Provide all possible stereoisomers of the product.
5-a. Note: NaH is a very strong base, pKa of H2 is 35. The Na-H bond is polar covalent and this compound
does not dissociate in solution to form hydride ions.

Me Me NaH
O O Me
Br H
H Na ii) SN2 Me

-H2 Key point:

Me Me
- SN1 vs SN2 reactions
O - predicting products (stereochem. included)
Br
- Mechanism of SN1 & SN2 mechanisms

5-b. Me Et Me Et Et Me
MeOH
Br OMe + OMe

ii) SN1

Me Me Et Et Me

Et OMe OMe
+
H H
MeOH MeOH MeOH

Can use (+/-) notation in mechanism to show racemic mixture of enantiomers formed:

Me Me Et
Me Et
Et OMe
OMe
H
MeOH MeOH

(+/-) (+/-)
 Practice Problems
Problem 1. Identify each of the following structures as either chiral or achiral by writing the appropriate word under
each structure. Additionally, classify each pair of molecules as either identical, structural isomers, enantiomers, or
diastereomers by writing the appropriate word or phrase in the box provided.

Br H
H H
1-a.
NC H Br CN
enantiomers
chiral chiral

HO OH
1-b. identical
Br Br
chiral chiral
note the two methyls on the carbon with the OH - not a chiral center!

OH O OH O
1-c.
HO H HO H
diastereomers
OH OH OH OH
chiral chiral

Problem 2. For each of the following structures:

i) Assign absolute configuration to all stereocenters.
ii) Classify each pair of molecules as either identical, structural isomers, enantiomers, or diastereomers by writing
the appropriate word or phrase in the box provided.

2-a.

O Me
(R) (S)
-O P Me O (R)
O- (S) identical
O -O P O
-O

2-b. HO (R) Me
(S)
Me OH
OH Diastereomers
OH H2N (S)
H 2N (S) O
O
 (S)
2-c. HN HN (S) structural isomers
Me
Me (R)
(R)
H H

2-d. (R)
HO O HO
(R) (R) OH
OH (S)
Enantiomers
HO (S) (R) HO (S)
(S) OH
OH O

Problem 3: Assigning E/Z

For each of the small molecules shown below, use the CIP convention to assign absolute configurations to the
alkenes (E or Z).

3-a. Progesterone You never have to assign

3-b. Morphine
configurations to aromatic
ring double bonds! Alkenes
O only!
Me HO
Me
H
Me H
O H
H H
H N Me
O (Z)
HO (Z)

3-d. Epothilone
3-c. Tretinoin
O
(E) (E) N H
OH S
(Z) (E) (E) OH
O (Z)
(E)
O
Tretinoin
O OH O

3-e. Lycopene

(Z)
(E) (E) (E)

(Z) (E) (Z) (E)

(Z)
(E)
(Z)
Problem 4: Conformational Analysis of Cyclic Systems
For each of the compounds below:
i) Draw all possible chair conformations derived from each cyclohexane.
ii) Label the most stable conformation.
iii) In each conformation, label the non-hydrogen substituents as axial or equatorial.

H ax.
4-a. Me OH
Me eq.
OH eq. H
OH H
H Me ax.
Favored

4-b. t-Bu ax.

H OH H
eq. OH eq.
tBu H
tBu
OH H
ax.
Favored (the only
accessible conformation) Don’t need to draw this
one since the other chair
will ‘lock’ the tBu group
equatorial

4-c. Me ax. OH i-Pr ax.

eq.
Me H H
i-Pr OH eq.
OH H H
Favored

ax.
4-d. Et Et
eq.
Me
Et
Me
Me eq.
Favored
ax.

ax. eq.
4-e. Ph ax. BrPh Ph
Br eq.
Favored
Br
 Me eq. ax.
4-f. Me ax.
Br Me eq.
OH
Br
HO
HO eq. Cl Br
eq. ax. Cl
Cl ax.
Favored

4-g. H H
i-Pr eq.
eq. Me
tBu
tBu Me
H H
Only need to draw this structure: trans-decalins actually
cannot be flipped (build a model and try!) so you’re only
required to draw the lowest energy conformation based on
the substituents.

Problem 5:
i) Draw the two chair conformations of both A and B of these structures.
ii) Identify any mirror planes that exist in A and B and clearly indicate them on the structures provided or on your
drawings .
ii) Label A and B as either chiral or achiral.
iii) What is the relationship between structures A and B.

A B

HO OH HO OH
The structures are diastereomers.

OH HO OH OH HO
OH
OH OH

Both chair conformations have internal Neither chair conformation has internal
mirror plane symmetry, and this compound mirror plane symmetry - this structure is chiral
is therefore achiral
Problem 6: For the molecules below:
i) Indicate whether each structure below is chiral or achiral.
ii) Indicate whether the pairs of structures represent identical molecules, structural/constitutional isomers,
diasteromers, or enantiomers.

chiral chiral achiral achiral

6-a. OH 6-b. CO2H
CH3 CO2H

OH OH
H 3C
identical molecules both up substituents OH
(convert these to cyclohexane skeletal OH is down
structures if that’s helpful - The relationship
between substituents is OH down, CH3 up) diastereomers

OH
do a pancake flip
HO

chiral OH chiral
6-c. Me
t-Bu t-Bu
Me OH
enantiomers

Problem 7: SN1 and SN2 Reactions

For each of the following reactions:
i) Predict the product and provide a curved-arrow mechanism.
ii) Label each mechanism as SN1 or SN2.
iii) Provide all possible stereoisomers of the product.

racemic mixture of enantiomers

7-a.
EtOH
O O + O
ii) SN1
Cl OEt OEt

O + O
O
OEt OEt
EtOH H EtOH H

EtOH

much more stable intermediate Other way to represent racemic product formation in
than the carbocation mechanism is shown in 7-e
7-b.
I CN
KCN single stereoisomer produced
CN
“enantiopure” is sometimes
HO HO
Me Me used when a single
ii) SN2 stereoisomer is produced.

7-c.

O N3
NaN3 single
S
O stereoisomer
O produced.
ii) SN2 SN2, inversion

N
N
This reaction has a very good tosylate leaving group
N (consider all of the resonance forms of the anionic
leaving group to justify this).

OH
7-d.
O
O
NaOH

OH
Cl ii) SN2 Me
Me single
stereoisomer
produced.
 water is not a great
7-e. Br nucleophile or base OH

OEt H 2O OEt

H3CO H3CO
ii) SN1 (+/-)
OCH3 OCH3

H 2O

H H
H 2O O

OEt
OEt
H3CO (+/-)
H3CO OCH3
OCH3

Rationalization for SN1 reactivity: strong resonance stabilization

of the key benzylic carbocation.

SN1 via

OEt
OEt
H3CO
H3CO
OCH3
OCH3

7-f. Br
Br
SNa S S
NaS
ii) SN2

Na SNa
S

Br Br
Br S
S

Na

S anion is an exceptional nucleophile: anionic (raises HOMO) and is highly polarizable. 1,2-dibromo
ethane is a good electrophile for SN2 because it is sterically unhindered, and the Br groups are good
leaving groups.
 Challenge Problems
Challenge Problem 1:
Two of the stereoisomers of 2,3-dibromobutane are shown below. Draw the lowest and highest energy
conformations of each molecule as Newman projections. Indicate clearly the presence of an internal mirror plane in
any of these projections, and decide which of the two stereoisomers is the meso compound.
We should have told you bromine is actually larger than a methyl group (I know, right?) so the Br/Br eclipsed
interactions are actually higher energy than Me/Me eclipsed.
On PSets/Exams we would give you this information to help inform your answer.
Br Br
no conformation you can draw
has an internal mirror plane.
Br Br This compound is therefore
R, S stereoisomer R, R stereoisomer chiral.

lowest lowest

Me H Br Br Br H
H Br Br H

Br Me Me H Me
Me Br
H
Me Me
Br H H Me

highest highest
Me Me
mirror plane
Me Me here, so this is meso Me Br
Br H H Br
H Me and achiral. Br
Br
Br H H Me
Br Br H H H Me
mirror between front and back carbons

2. For each of the following structures:

i) Assign absolute configuration to all stereocenters.
ii) Classify each pair of molecules as either identical, structural isomers, enantiomers, or diastereomers by writing
the appropriate word or phrase in the box provided.

2-a.

N N

O
O H OH HN
N N (R) B (R)
N (R) OH identical molecule
H O
O
N NH
(R)
B OH
Bortezomib
multiple myeloma and HO
mantle cell lymphoma treatment

2-b.
 2-b. S

(S) OH HN O
O
(R) HO
O O B (S)
S N B
O enantiomers
H OH (R)
O

Vaborbactam OH
β-lactamase inhibitor

2-c.

OAc
OAc
(S) (R)
H H
AcO O H O
(R) identical molecule
(R)
O MeO OAc
Cl Cl H

sugar-derived
electrophile

Challenge Problem 3:
Consider the following reaction:

NaNH2
Cl H 2N

3-a. Is this reaction likely to proceed by an SN1 or SN2 mechanism? Explain.

A leaving group attached to a primary carbon will be displaced via an SN2 mechanism.

3-b. Provide a rate law for this reaction.

rate = k[alkyl chloride][NaNH2]

3-c. Draw and label the molecular orbital(s) involved in the transition state of this reaction. Include the appropriate
sizes, phasing, and geometry of any orbitals. NOTE: it is helpful to draw the TS first the draw the relevant orbitals
over this drawing.

LUMO: σ*C-Cl HOMO: nN

Cl

3-d.
i) Provide the product of the following reaction.
ii) identify the mechanism as SN1 or SN2.
NaN3
Cl N3

ii) SN2

3-e. The rate of this reaction can be increased by adding a catalytic amount of sodium iodide.
i) Provide a mechanism for this catalytic reaction, explicitly showing the regeneration of catalyst.
ii) Explain the observed rate acceleration.

NaN3, NaI (cat.) N3 + NaI

Cl

N N N

I N3

Iodide is a better nucleophile and a better leaving group than azide and chloride, respectively. Increasing nucleophile
strength increases the rate of an SN2 reaction. Departure of the leaving group occurs in the rate determining step, so a
better leaving group increases the rate of the reaction.