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Chemistry 125: Lecture 63
March 30, 2011
Aromatic Substitution
The Friedel-Crafts Reaction
Synthetic Accessibility
Benzylic Stabilization
and Triphenylmethyl
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AlCl3/C-Electrophile: The Friedel-Crafts Reaction
Charles Friedel
James Mason Crafts
(1832-1890)
(1839-1917)
MIT
President
Paris (Friedel - Mines)
MIT
Cornell
Paris (Wurtz - Médicine)
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
1877
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
On a New Class of Radicals
Adolphe Wurtz (1855)
C4H5I + C8H9I + 2 Na =
+ 2 NaI
The infamous “Wurtz Reaction”
EtI + BuI + 2 Na = Et-Bu + 2 NaI
Low Yield
(Crossover; Radical or EtNa + BuI or…)
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
6 RCl + 3 Al
PhH
R-Ph
3 R2 + AlCl3 +?HCl .
not
needed
initially
LOTS
little
distillate
little
slow;
is high
rate depends
boiling,
completely different
Chemis“poor
try!in on [AlCl3]
from Wurtz Reaction!
hydrogen”
Aromatic Substitution: C for H
or “S+
EtI + BuI + 2 Na = Et-Bu
2 version
NaI
N1”
- R+
via
AlCl
4
R
H
Might other
metals work better?
AlCl3/C-Electrophile: The
Friedel-Crafts
Reaction
Friedel-Crafts
Alkylation
“On a New General Method for Synthesizing
Hydrocarbons, Ketones, etc.” (1877)
C1, C2,
C5
also
Br, I
benzene,
toluene
R-Cl + H-Ar
AlCl3
R-Ar + HCl
“day and
night”
CH3Cl
both previously
unknown!
80°
KMnO4
known
since
1799
cold
> 2 months
“several hundred
grams” m.p. 164°
(modern, 165°)
mol. wt. within 2%
by vapor density
AlCl3/C-Electrophile: The
Friedel-Crafts
Reaction
Friedel-Crafts
Alkylation
“On a New General Method for Synthesizing
Hydrocarbons, Ketones, etc.” (1877)
C1, C2,
C5
also
Br, I
benzene,
toluene
R-Cl + H-Ar
Ph-H + Ph-CH2Cl
3 Ph-H + CHCl3
3 Ph-H + CCl4
4
Ph-H + PhCl
AlCl3
AlCl3
AlCl3
AlCl3
200°
AlCl3
R-Ar + HCl
Ph2CH2 known
Ph3CH
known
H2O
Ph34CCl
C unknownPh3COH
Ph
Too
Crowded
Benzyl
but
No
Reaction
Not
Aryl
AlCl3/C-Electrophile: The
Friedel-Crafts
Reaction
Friedel-Crafts
Alkylation
“On a New General Method for Synthesizing
Hydrocarbons, Ketones, etc.” (1877)
Benzyl but
Not Aryl
also
C1, C2,
Br, I
C5
benzene,
toluene
R-Cl + H-Ar
Acylation
O
Ph-H + Ph-C-Cl
O
Ph-H + CH3-C-Cl
AlCl3
AlCl3
AlCl3
Acyl
R-Ar + HCl
O
Ph-C-Ph
O
Ph-C-CH3
known
known
(R-CO)
Ph-H +
AlCl3
+
unknown?
known
Rearrangement in Friedel-Crafts Alkylation
(e.g. J&F Sec. 14.5)
+
?
gives i-PrPh
product
H
+
gives
n-PrPh
product
Cl
AlCl3
Cl
AlCl3
5 hr
+
Warning: PhCH3 reacts
Bad News:
40% : 60% (35°C)
25 times faster than PhH
60% : 40%
Good News:
(-6°C)
~45% “yield" of
mono substitution
Compared to what?
~15% of C6H6 consumed
Ipatieff (1940)
Rearrangement in Friedel-Crafts Alkylation
(e.g. J&F Sec. 14.5)
O
Acylation
+
Cl
+ H2O
AlCl33
AlCl
1 eq.
O
AlCl3
Cl
+
C O
Stable Acylium Ion
No Rearrangement
+
“Clemmensen”
Reduction
Zn / HCl
or
“Wolff-Kishner”
Reduction
H2N-NH2
KOH
200°C !
Synthetic Accessibility
(e.g. J&F Sec. 14.7)
H 2O
O
NO2
D
O 180°C
S
OH
H2SO4
SO3
Cl
D2SO4
AlCl3
H2 HNO
/ Pd /3 C
H2or
SO4
Sn / HCl
HCl
AlCl3
Br2
NH2
FeBr3
RCOCl
CO
O
CH
Cl2
RCl
AlCl3
R
AlCl3
O
RC
Br
(e.g. J&F Sec. 14.7)
click for source
Synthetic Accessibility
Bismarck Brown
NO2
H2 / Pd / C
NH2
or
Sn / HCl
NaNO2
HCl,
0°C
i.e.
H-O-N=O
(nitrous acid)
+
N N
+
N N
the first of hundreds of azo dyes
Fabulous
leaving
group
+
N N Cl-
benzene
diazonium
chloride
N
N
“aniline yellow”
(1861)
NH2
Diazonium Uses
Br
(e.g. J&F Sec. 14.7)
Cl
HBr
CuBr
+
N N
HCl / CuCl
CuCN
N C
Catalysis in these “Sandmeyer” reactions probably
involves electron transfer and radical coupling.
coupling
+
N N
+
BrCuBr
-
from Br + CuBr
N N
very unstable
Br-
+ BrCuBr
Diazonium Uses
Utility?
Br
H
Cl
CuBr
H3PO2
Cu+
NO2
CuCl
+
NaNO2
Utility?
(e.g. J&F Sec. 14.7)
CuCN
N N
H 2O
KI
BF4
OH
Probably
SN1
F
I
N C
Preparation Problems
NO2
NO2
NO2
Cl2
FeCl3
HNO
Cl2 3
HFeCl
2SO43
Cl
“reduction”
(Zn/HCl?)
(Cl+ FeCl4-)
Cl
Cl
+
NH2
N2 Cl-
OH
HONO
H2O
(NaNO2/HCl)
100°C
Cl
Cl
diazonium salt
or :
Hal
CN
NO2
H
Cl
both o,p-directing!
Yale ‘98S
wrong group?
wrong place?
Indirect Synthesis
NO2
HNO3
CH3Cl
H2SO4
AlCl3
CH3
CH3
“reduction”
(Zn/HCl)
O
stronger
o,p-director
CH3C NH2 than CH
3
if necessary
CH3
CH3
H3PO2 !
O
CH3C NH2
H3C
CH3Cl
+
N2 ClCH3
H3C
CH3
HONO
AlCl3
CH3
H3C
(NaNO2/HCl)
CH3
CH3
Preparation Problem:
NO2
NO2
Nucleophilic Aromatic Substitution
NO2
NO2
Slow
Step
activated by
two NO2
groups
activated
by F
NO2
F
F
H2N-R
Sanger’s
Regent
NO2
NO2
NHR
+
H
Why F?
(generally a poor
leaving group)
NO2
HN-R
Used to visualize
fragments with
exposed amine
groups in
chromatography.
Amino acid sequence
Identify the amino acid
of insulin (1955)
1958 Nobel Prize to also won 1980 Nobel at the end of a chain
Frederick Sanger for DNA sequencing! or fragment of a chain
NAD+  NADH (e.g. J&F p. 679)
H
+
(closely enough balanced to run both ways)
key molecules in biological
Oxidation
(H acceptor)
&
Reduction
(H donor)
Benzylic Reactivity - Anion - pKa
H2C=CH-CH2-H
pKa = 43
~107  Ka Alkyl-H
(e.g. J&F Sec. 13.12)
~9 kcal/mole
from allylic stabilization
PhCH2-H
pKa = 41
~109  Ka Alkyl-H
~12 kcal/mole
from benzylic
Ph2CH-H
pKa = 33.5
~108  Ka PhCH2-H ~11 kcal/mole
from 2nd benzylic
Ph3C-H
pKa = 31.5
102  Ka Ph2CH-H
~3 kcal/mole
from 3rd benzylic
Steric hindrance in
triphenylmethyl causes
twists that reduce
overlap with 2pC by 25%
from diphenylmethyl.
Triphenylmethyl
Free Radical
110 years old
b. Elizabetgrad, Ukraine (1866)  Chicago (1884)  University of Michigan (1886)
Metallurgy
Geology
French
Chemical
& Physics
Math
Rhetoric
Literature
Mineralogy
Logic
in German
Scientific
Psychology
& French
Free-Hand
Drawing Chemistry
Speaker at Dedication of SCL (1923)
After freshman year
Gomberg averaged
MG
9.5 Chemistry
Labs per Week.
as Student
(not hours!)
2/3 of them were
Analytical
(no spectroscopy)
Gomberg in the Analytical Laboratory
"Moses
Gomberg
was Thiele's
in beautiful
the student
"This brilliant
Experiment,
onecoworker
of the most
in laboratory.
organic
He
was very
andfew
modest,
kept
entirely
himself,
and
chemistry
andreserved
one
which
people
credited
at to
first,
gave great
Munich
Johannes
Thiele
never chatted
in or out
of would
the
laboratory.
Some
years
later the
impetus
to chemistry
and
have
worthy
of any
age
31
Adolf
v.been
Baeyer
1896
work he carried out in the United States on the triphenylmethyl
distinction."
age 61
radical, a case of trivalent carbon, became famous."
R. Willstätter
Moses Gomberg
R. Willstätter
age 30
age 24
Thiele & Heuser (January 1896)
Hydrazine Derivatives of Isobutyric Acid
AIBN
50%
Gomberg (Ann. 300, 59) Under the sponsorship of
Prof. Thiele I have followed up these reactions...
Victor Meyer 9/8/48 - 8/8/97
“Geliebte Frau! Geliebte Kinder!
Lebt wohl! Meine Nerven sind
zerstört; ich kann nicht mehr.”
Third Term
Heidelberg
with
Victor Meyer
(1848 - 1897)
who had
introduced
the idea of
Steric
Hindrance
Tetraphenylmethane (1897)
“I have tried to solve this problem
in a completely different way.”
Friedel-Crafts
or
Ph2Mg
?
110°
Cu
0.3 g
8g
Solubility
Analysis : C 93.32 (93.75) H 6.36 (6.25)
100 mg for Mol. Wt. : 0.289°
306 (320 calc.)
(by solvent b.p. elevation)
End of Lecture 63
March 30, 2011
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