Chemistry 20
Weekly Review Lecture: Module 9 Solutions
Harvard University
April 15, 2016
Office Hours
this Sunday
2:30 – 4 Hall E
2:30 - 4
Science Center
room 102
Electrophilic aromatic substitution
Nucleophilic aromatic substitution
Benzene Mechanisms: Identifying EAS versus NAS
Benzene substitutions occurring in acid conditions typically means EAS.
Me
Me
H2SO4
Me
(+/-)
OH
Me
sol
Me
Me H
Me
OH
H
OSO3H
Me
Me
Me
Me
OH2
Chem 20 Weekly Review Lecture: Module 9 Solutions
Me
Me
Me
Page 1 of 10
Benzene Mechanisms: Identifying EAS versus NAS
Benzene substitutions under basic conditions typically means NAS. It will be addition-elimination if that option exists; if not, then
benzyne (elimination-addition) will want to happen.
SCH3
Cl
NaSCH3
H3CO
A nucleophile is reacting with
benzene. Leaving group is
both ortho and para to
resonance withdrawing
groups. We need this for
NAS addition-elimination.
NO2
H3CO
O
NO2
O
SCH3
SCH3
Cl
H3CO
H3CO
NO2
NO2
O
O
elimination
addition
SCH3
Cl
Cl
SCH3
H3CO
O
N
O
O
Chem 20 Weekly Review Lecture: Module 9 Solutions
SCH3
H3CO
O
N
O
O
Page 2 of 10
Benzene Mechanisms: Identifying EAS versus NAS
Benzene substitutions under basic conditions typically means NAS. It will be addition-elimination if that option exists; if not, then
benzyne (elimination-addition) will want to happen.
F
A nucleophile is reacting MeO
with benzene. There is a
leaving group, but there are
no resonance withdrawing
groups on this benzene
ring. Since it cannot be
NAS addition-elimination, it
defaults to benzyne
elimination-addition.
Me
N
MeO
NaNH2 (excess)
NH3 (l)
NHMe
F
Me
N
MeO
MeO
H2N
NMe
H
H
NH2
MeO
anion forms
again on
benzene at
the end
Me
N
Tempting, but don't do this:
F
MeO
H
F
NH2
MeO
H
NH2
NMe
F
NMe
E2
MeO
MeO
NMe
Chem 20 Weekly Review Lecture: Module 9 Solutions
addition
anion forms on
benzene at beginning
elimination
NMe
MeO
NMe
Page 3 of 10
Benzene Mechanisms: Be Prepared for Variations on the Themes (1)
As you know by now, organic chemistry problems often test you on things that seem like you haven't seen them before, but really,
you have. Benzene chemistry and mechanisms opens the door for a lot of opportunity in this area.
An annoying side reaction that sometimes occurs when tert-butylbenzene is treated with strong acid is dealkylation. This side
reaction is not a problem when the alkyl group is secondary or primary (that’s a bit of a hint as to what is going on).
Propose a curved-arrow mechanism for the following reaction.
HNO3,
H2SO4
HO3SO
H
H
H
sol
H
+
Chem 20 Weekly Review Lecture: Module 9 Solutions
Page 4 of 10
Benzene Mechanisms: Be Prepared for Variations on the Themes (2)
As you know by now, organic chemistry problems often test you on things that seem like you haven't seen them before, but really,
you have. Benzene chemistry and mechanisms opens the door for a lot of opportunity in this area.
Propose a curved-arrow mechanism for the following reaction. Hint: radicals are involved.
CH3
O
O
CH3
hv
+
O
(plus another product)
CH3
O
CH3
CH3
O
O
O
CH3
O
O
O
O
O
Chem 20 Weekly Review Lecture: Module 9 Solutions
2 eq. CO2
Page 5 of 10
Synthesis Involving Benzene: When Directing Effects Conflict
When substituents do not direct the next addition to the same carbons, you need to know which group wins.
Two ortho/para-directing activating groups: the stronger donor wins
H3C
weaker
donor
(o/p directing)
SO3,
OCH2CH3
H3C
SO3H
H2SO4
OCH2CH3
stronger donor
(o/p directing)
Two meta-directing deactivating groups: the stronger withdrawing group wins
NC
weaker
withdrawing
(meta directing)
Br2,
NO2
FeBr3
NC
Br
NO2
stronger withdrawing
(meta directing)
One resonance donor, one resonance withdrawer: the donor group wins
resonance
withdrawing
(meta directing)
O2N
Br
Br2,
OCH2CH3
FeBr3
Br
+
O2N
OCH2CH3
O2N
OCH2CH3
resonance donor
(o/p directing)
Alkyl groups lose to resonance contributors
resonance
withdrawing
(meta directing)
O2N
Cl
donor
(o/p directing)
CH3
Chem 20 Weekly Review Lecture: Module 9 Solutions
Cl2,
AlCl3
O2N
CH3
Page 6 of 10
Synthesis Involving Benzene: Functional Groups on Side-Chains Cannot be Ignored
For any substitution reactions you want to do on the actual benzene ring, you need to be careful about functional groups on the side
chains. In most cases, reactions on the side chains will be easier to do than reactions on benzene.
alkene addition doesn't
have to break aromaticity
Identify what is wrong with each synthesis and propose a way to fix it.
Br
Br
Cl
The
critical
error!
AlCl3
O
NaBH4
conc.
MeOH
H2SO4
O
Br
Br2, FeBr3
Br2, FeBr3
Solution to this synthesis:
Start with bromination of
benzene, then do all the other
steps in the order shown.
OH
Cl
OCH3
NO2
OCH3
NO2
NO2
Br
Cl
NBS,
(PhCO2)2
Br
Chem 20 Weekly Review Lecture: Module 9 Solutions
NaOCH3
NO2
NaOCH3
Solution to this synthesis:
Do the two steps in reversed
order.
Page 7 of 10
Synthesis Involving Benzene: Directing Effects and Choosing Correct Benzene
Benzene synthesis is all about understanding the directing effects and the activating/deactivating influences.
O
Cl
+
any inorganic and
organic compounds
+
Starting Material
O
O
Cl
OH
NaBH4,
AlCl3
+
EtOH
PBr3
O
Br
AIBN,
Cl
HSnBu3
AlCl3
O
HNO3,
H2SO4
Br
Br2,
NO2
O
FeBr3
NO2
O
Desired Product
Chem 20 Weekly Review Lecture: Module 9 Solutions
Page 8 of 10
Synthesis Involving Benzene: When to Use EAS, When to Use NAS
Synthesis on benzene usually involve combinations of EAS and NAS reactions. It takes practice getting used to this.
EAS
O
EAS
EAS
Cl2, AlCl3
Cl2, AlCl3
NAS
NaNMe2,
Cl
AlCl3
Me
Cl
Cl
EAS
O
Me
HNO3, H2SO4
EAS
Cl
Br2, FeBr3
Br
Mg, Et2O
Me
O2N
N
HNMe2
NAS
O
Me
Me
N
1.
2. H+ w/u
EAS
MgBr
N
HNO3,
H2SO4
Me
OH
O2N
Me
Hg2+, H+, H2O
O
O
N
CrO3 · pyr
Me
O
Me
N
NO2
Chem 20 Weekly Review Lecture: Module 9 Solutions
O2N
Me
Page 9 of 10
Synthesis Involving Benzyne as a Diels-Alder dienophile: Ortho-alkylation
When you see two new C-C bonds have formed on adjacent benzene carbons, you should be considering benzyne in a Diels-Alder
reaction.
+
any inorganic and
organic compounds
Starting Material
Cl
Cl2,
AlCl3
NaNH2
O
1. O3
2. Me2S
O
NaBH4, MeOH
OH
HO
Desired Product
(disregard stereochemistry)
Chem 20 Weekly Review Lecture: Module 9 Solutions
Page 10 of 10