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Chemistry 345
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Problem Set 17
In addition to the problems listed below, it is highly recommended that you thoroughly understand the
practice problems in Loudon Chapter 17.
I.
Using exclusively reactions from CHEM 343/345, ibuprofen (isobutylphenylpropionic acid) can be
synthesized from isobutylbenzene in a multi-step synthesis, as shown below (adapted from J. Chem.
Educ. 2011, 88, 825–828). Use the spectroscopic and computational data provided to analyze the
substitution of –OH to –Cl (relevant to Chapter 17).
A. Explain why HCl is required for this reaction, and it is not simply carried out using sodium chloride
(NaCl). Provide an explanation of the role that acid plays in the reaction mechanism.
B. Draw a series of resonance structures that rationalize the estimated charge distribution in the C12H17+
carbocation shown below (estimated B3LYP/6-31G(d) C-atom charge data provided). Use the charge
data to suggest which resonance structures are likely the greatest contributors.
top view
side view
+0.100
−0.238
−0.232
+0.149
−0.157
−0.754
−0.099
−0.502
1
−0.688
C. Using a potential energy surface, explain how the charge distribution in the C12H17+ carbocation
impacts the SN1 reactivity of 1-(4-Isobutylphenyl)ethanol in the presence of hydrochloric acid.
D. Fully assign the product NMR spectra, labeling each 1H- and 13C-NMR signal on the structure of 1chloro-1-(4-isobutylphenyl)ethane. See part E for an expansion of the signal at 1.84 ppm.
A
A
B
B
C
D
2
E
F
3
1
A
B
4
7 8 9
5
2
6
C
D
9
8
7
6
5
4
3
2
1
3
E
F
E. The 1H-NMR signal at 1.84 ppm (shown below) has a non-standard appearance. Explain its origin.
Consult the 1H-NMR and HSQC spectra on the previous pages.
F. The mass spectrum of 1-chloro-1-(4-isobutylphenyl)ethane has a base peak at 161. Justify its
existence as the base peak, and rationalize its formation from the molecular ion m/z values of 198
and 196 using an electron-pushing mechanism.
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II.
Draw a set of resonance structures and molecular orbitals that depict the electronic structure of the
allyl radical shown below. Rationalize the structure and reactivity of the allyl radical from its
resonance structures and molecular orbital depictions.
III.
Draw a set of resonance structures and the 1 molecular orbital of the benzyl cation shown below.
Describe two reasons for the enhanced stability of the benzyl cation relative to other carbocations.
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IV.
The radical chlorination of alkane C–H bonds is a kinetically controlled process that is not highly
selective. The reaction data presented here were obtained by undergraduate students (J. Chem. Educ.
2020, 97,2286-2290). (10.4 & 17.2)
A. As shown for hexane below, the reaction has a slight selectivity for substituting a C–H bonds at a 2°
carbon atom relative to a 1° carbon atom. Provide an electron-pushing mechanism that can be used
to rationalize the observed regiochemical outcome. Identify the mechanistic step that can be used to
rationalize the observed stereochemical outcome. Use the provided data to rank the relative stability
of the radical intermediates, based solely upon the experimental outcome (assuming kinetic control).
B. The computed structures and relative energies of the radical intermediates of the reaction in part A
are provided below. Rationalize the relative energies provided and describe whether or not they are
consistent with the experimental observation and inferred relative stabilities in part A.
4.0 kcal/mol
0.0 kcal/mol
6
0.3 kcal/mol
C. As shown below, when the reaction is repeated for propylbenzene, the reaction is much more
selective. Provide an electron-pushing mechanism for this reaction, showing the formation of all
products.
D. Rationalize the observed, enhanced selectivity of the reaction of propylbenzene (part C) relative to
the reaction of hexane (part A) with chlorine using the optimized and relative energies of the radical
intermediates provided below.
0.0 kcal/mol
11.1 kcal/mol
14.9 kcal/mol
E. Rationalize the relative stability of the lowest-energy radical intermediate, including a depiction of its
1 molecular orbital and a series of resonance structures to support your explanation.
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V.
While there are many similarities in the chemistry of benzylic and allylic species, there are some key
differences in reactivity illustrated by the reactions below. For each pair of reactions, rationalize the
different observed outcome. (17.2)
A. Isopropyl benzene undergoes a highly selective substitution when reacted with bromine, while
cyclohexene can undergo both substitution and addition reactions.
B. (2-Bromopropan-2-yl)benzene undergoes a highly selective SN1 reaction with methanol, while the
same reaction of 1-bromo-3-methylbut-2-ene results in a mixture of products.
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VI.
When the bromination of cyclohexene is carried out in a cyclohexane solvent, only the C–H bonds of
the cyclohexene are brominated. Explain why no appreciable bromination of the C–H bonds in the
solvent occurs, making reference to both reaction pathways. (17.2)
VII.
Rationalize the differences in the pKa values of the compounds provided below. (17.3)
toluene
methylcyclohexane
pKa = 41
pKa ~ 50
trans-2-butene
butane
pKa ~ 43
pKa ~ 50
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VIII.
The electron impact-mass spectrum (EI-MS) of toluene (methylbenzene) contains a large molecular
ion signal at m/z = 92 and a base peak signal at m/z = 91. (15.7 & 17.1)
A. The dominant fragmentation pathway for toluene in an EI-MS from a molecular ion is the loss of
hydrogen radical (H●). Identify the C–H bond(s) in toluene radical cation that are mostly likely to lose
an H●. Provide an electron-pushing mechanism for this reaction and rationalize why it is so favorable.
Include a set of resonance structures or depiction of molecular orbitals to support your explanation.
B. The intensity of the base peak at m/z = 91 is due to the rapid formation of two C7H7+ ions and their
slow decomposition, due to their relative stability. One of the C7H7+ ions was depicted in part A; the
other is a more stable rearrangement product. Provide a set of resonance structures for the
rearranged C7H7+ cation and rationalize its relative stability.
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IX.
The rate of reaction and the stereochemical outcome of SN2 reactions can be well understood from
an examination of the transition states of the reaction. Use the reactions of 1-bromobutane and E-1bromo-2-butene with cyanide to explore this reaction. (9.4 & 17.4)
A. In order for a new bond to form between an electrophile and a nucleophile, the donor and acceptor
orbitals must overlap. The C-atom lone-pair orbital of cyanide (nucleophile) and the C–Br bond of 1bromobutane (electrophile) are displayed below. Use those orbitals to rationalize the transition-state
geometry depicted. (9.4)
cyanide
1-bromobutane
C-atom lone pair
C–Br
TS
B. The equivalent orbitals are depicted below for the reaction of E-1-bromo-2-butene with cyanide.
Describe the steric differences in the SN2 reactions of 1-bromobutane and E-1-bromo-2-butene.
(17.4)
cyanide
E-1-bromo-2-butene
TS
C-atom lone pair
C–Br
11
C. The steric differences between the two reactions cannot fully explain the rate enhancement for the
reaction of E-1-bromo-2-butene with cyanide. Using the  molecular orbital depicted below for the
transition state, rationalize the rate enhancement for the SN2 reaction of E-1-bromo-2-butene. (17.4)
D. On the PES shown below, the energy of the reaction is already depicted for the reaction of cyanide
with 1-bromobutane in acetonitrile. Fill in the missing reagents, transition state, and products.
Starting the reaction of cyanide with E-1-bromo-2-butene at the same relative energy, depict its
potential energy surface. Explain any differences between the two surfaces. (17.4)
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X.
Predict the major product(s) of the following reactions. (17.1 – 17.5)
A.
Why is this substitution highly regioselective?
B.
The oxidation of MnO2 involves the formation of a radical at the carbon atom with the –OH group. Why
is this reaction highly selective?
C.
What would be the major product of this reaction if bromine were substituted for chlorine? Why is the
reaction more selective?
D.
How would the reaction outcome change if the reaction were run at room temperature for a shorter
duration with dilute acid?
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E.
Why is this reaction much faster than it would be for the substrate below?
F.
Why are the rates of the E2 reaction enhanced at each benzyl position?
G.
What is the purpose of the water workup (step #2)?
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H.
How would the reaction outcome change if the reaction were carried out using a light source with a
nonpolar solvent like carbon tetrachloride (CCl4)?
I.
Why is this reaction highly regioselective?
J.
What would the reaction outcome be if concentrated sulfuric acid were reacted for a longer duration, at
elevated temperatures?
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XI.
Provide the missing reagents and conditions for the transformations displayed below. Include all
reaction conditions and isolated intermediates produced in each step of your synthetic scheme and
number each separate step. No reaction mechanisms are required. You are highly encouraged (but
not required) to complete a retrosynthetic analysis on any assessment.
A.
Retrosynthesis (not graded):
Forward Synthesis (graded):
B.
Retrosynthesis (not graded):
Forward Synthesis (graded):
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C.
Retrosynthesis (not graded):
Forward Synthesis (graded):
D.
Retrosynthesis (not graded):
Forward Synthesis (graded):
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