chemistry 125: lecture 63 march 30, 2011 aromatic substitution the friedel-crafts reaction synthetic...
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Chemistry 125: Lecture 63March 30, 2011
Aromatic SubstitutionThe Friedel-Crafts Reaction
Synthetic AccessibilityBenzylic Stabilizationand Triphenylmethyl
This
For copyright notice see final page of this file
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Charles Friedel(1832-1890)
James Mason Crafts(1839-1917)
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
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Par
is (W
urtz
- M
édic
ine)
Cor
nell
MIT
MIT
Par
is (F
ried
el -
Min
es)
Pre
side
nt
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
1877
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AlCl3/C-Electrophile: The Friedel-Crafts Reaction
EtI + BuI + 2 Na = Et-Bu + 2 NaI
Adolphe Wurtz (1855)
On a New Class of Radicals
C4H5I + C8H9I + 2 Na = + 2 NaI
Low Yield (Crossover; Radical or EtNa + BuI or…)
The infamous “Wurtz Reaction”
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?
AlCl3/C-Electrophile: The Friedel-Crafts Reaction
EtI + BuI + 2 Na = Et-Bu + 2 NaI
Might other metals work better?
RCl + 3 AlPhH
6 3 R2 + AlCl3 + HCl .R-Ph
Chemistry!Aromatic Substitution: C for H
LOTSinitiallyslow;
rate depends on [AlCl3]
HR
or “SN1” version
via AlCl4- R+
littlelittlenot needed
completely different from Wurtz Reaction!
distillateis high boiling, “poor in
hydrogen”
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AlCl3/C-Electrophile: The Friedel-Crafts Reaction
R-Cl + H-Ar R-Ar + HCl AlCl3
“On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877)
C1, C2,C5
also Br, I
benzene, toluene
both previously unknown!
“several hundred grams” m.p. 164°(modern, 165°)
mol. wt. within 2%by vapor density
KMnO4
cold> 2 months
known since 1799
CH3Cl
80°
“day andnight”
Friedel-Crafts Alkylation
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AlCl3/C-Electrophile: The Friedel-Crafts Reaction
R-Cl + H-Ar R-Ar + HCl AlCl3
“On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877)
C1, C2,C5
also Br, I
benzene, toluene
AlCl3Ph-H + Ph-CH2Cl Ph2CH2
3 Ph-H + CHCl3AlCl3
Ph3CH
4 Ph-H + CCl4AlCl3
Ph4C
200°Ph-H + PhCl
AlCl3No Reaction
3 Ph-H + CCl4AlCl3
Ph3CClH2O
Ph3COH
known
known
unknown
Benzyl but Not Aryl
Too Crowded
Friedel-Crafts Alkylation
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AlCl3/C-Electrophile: The Friedel-Crafts Reaction
R-Cl + H-Ar R-Ar + HCl AlCl3
“On a New General Method for Synthesizing Hydrocarbons, Ketones, etc.” (1877)
C1, C2,C5
also Br, I
benzene, toluene
Benzyl but Not Aryl
knownAlCl3
Ph-H + Ph-C-Cl Ph-C-PhO O
knownAlCl3
Ph-H + CH3-C-Cl Ph-C-CH3
O O
known
+AlCl3
Ph-H +
unknown?
Acyl(R-CO)
Friedel-Crafts Alkylation
Acylation
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Warning: PhCH3 reacts 25 times faster than PhH
Rearrangement in Friedel-Crafts Alkylation (e.g. J&F Sec. 14.5)
AlCl3+ ? Cl
~45% “yield" ofmono substitution
5 hr +
40% : 60%
Good News:
Bad News:
Cl
AlCl3
+
H
60% : 40% (-6°C)
(35°C)gives
n-PrPh product
gives i-PrPh product
Compared to what?~15% of C6H6 consumed
Ipatieff (1940)
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Rearrangement in Friedel-Crafts Alkylation (e.g. J&F Sec. 14.5)
AlCl3+ Cl
“Clemmensen”Reduction
Zn / HCl
Stable Acylium IonNo Rearrangement
O
O
Cl
AlCl3
C O+
Acylation+1 eq.
AlCl3
or
“Wolff-Kishner”Reduction
H2N-NH2
KOH200°C !
+ H2O
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Synthetic Accessibility (e.g. J&F Sec. 14.7)
BrBr2
FeBr3
NO2 H2SO4
HNO3
RCOAlCl3
RCOCl
D
D2SO4
R
RCl AlCl3
ClCl2
AlCl3SO3
H2SO4
SO
OHO
CHO HCl
AlCl3
CO
H2O
180°C
H2 / Pd / Cor
Sn / HCl
NH2
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“aniline yellow”(1861)
Synthetic Accessibility (e.g. J&F Sec. 14.7)
NO2
H2 / Pd / Cor
Sn / HCl
NH2i.e.
H-O-N=O(nitrous acid)
N N Cl-+
NaNO2
HCl, 0°C
benzene diazonium chloride
Fabulous leaving group
N N +
N N +
N
NH2N
the first of hundreds of azo dyes
Bismarck Brown
clic
k fo
r so
urce
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Catalysis in these “Sandmeyer” reactions probably involves electron transfer and radical couplingand radical coupling.
Diazonium Uses (e.g. J&F Sec. 14.7)
Br
HBrCuBr
Cl
HCl / CuCl
N N+ CuCN
N C
N N+
+ BrCuBr
N N + CuBrBr
from Br- + CuBr very unstable
Br-
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Diazonium Uses (e.g. J&F Sec. 14.7)
NO2
NaNO2
I
KI
Cu+
H3PO2
H
OH
H2O
Br
CuBrCl
CuCl
N N+ CuCN
N C
Utility?
Utility?
F
BF4
ProbablySN1
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Preparation ProblemsNO2
Cl
NO2
Cl2
FeCl3
NO2
Cl
Cl2FeCl3
(Cl+ FeCl4-)
NH2
Cl
OH
Cl
“reduction”
(Zn/HCl?)
H2O
100°C
HONO
(NaNO2/HCl)
N2
Cl
+
diazonium salt
Cl-
or :HalCNNO2
H
Cl
both o,p-directing!
HNO3
H2SO4
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Yale ‘98S
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CH3
CH3H3C
NH2
Indirect Synthesis
HNO3
H2SO4 AlCl3
CH3Cl
“reduction”
(Zn/HCl)
HONO
(NaNO2/HCl)
CH3 CH3
CH3H3C
NO2
CH3
NH2
CH3
CH3C
O
AlCl3
CH3Cl
CH3C
O
N2
+Cl-
CH3
CH3H3C
H3PO2 !
wrong group?wrong place?
if necessary
stronger o,p-director than CH3
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Preparation Problem:
NO2
NO2
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Nucleophilic Aromatic SubstitutionNO2
F
NO2
Sanger’s Regent
H2N-R
NO2
NO2
HN-RUsed to visualize fragments with exposed amine
groups in chromatography. Amino acid sequence
of insulin (1955)
NHRFNO2
NO2
+HWhy F?
(generally a poorleaving group)
SlowStep
Identify the amino acid at the end of a chain
or fragment of a chain1958 Nobel Prize to
Frederick Sanger
activated by two NO2
groups
activated by F
also won 1980 Nobel for DNA sequencing!
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NAD+ NADH (e.g. J&F p. 679)
(closely enough balanced to run both ways)
key molecules in biological
Oxidation & Reduction(H- acceptor) (H- donor)
+
H
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Benzylic Reactivity - Anion - pKa (e.g. J&F Sec. 13.12)
Ph2CH-H pKa = 33.5
~109 Ka Alkyl-H ~12 kcal/molefrom benzylic
~108 Ka PhCH2-H ~11 kcal/molefrom 2nd benzylic
102 Ka Ph2CH-H ~3 kcal/molefrom 3rd benzylic
Ph3C-H pKa = 31.5
Steric hindrance in triphenylmethyl causes
twists that reduce overlap with 2pC by 25%
from diphenylmethyl.
PhCH2-H pKa = 41
H2C=CH-CH2-H pKa = 43 ~107 Ka Alkyl-H ~9 kcal/molefrom allylic stabilization
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TriphenylmethylFree Radical
110 years old
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Chemistry
Metallurgy Geology &
Mineralogy Scientific Free-Hand Drawing
ChemicalLiteraturein German& French
French RhetoricLogicPsychology
Physics Math
b. Elizabetgrad, Ukraine (1866) University of Michigan (1886) Chicago (1884)
Speaker at Dedication of SCL (1923)
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MG as Student
Gomberg in the Analytical Laboratory
After freshman yearGomberg averaged
9.5 ChemistryLabs per Week.
2/3 of them wereAnalytical
Labs(not hours!)
(no spectroscopy)
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Adolf v. Baeyerage 61
R. Willstätterage 24
Munich 1896
Moses Gombergage 30
Johannes Thieleage 31
"Moses Gomberg was Thiele's coworker in the student laboratory. He was very reserved and modest, kept entirely to himself, and never chatted in or out of the laboratory. Some years later the work he carried out in the United States on the triphenylmethyl radical, a case of trivalent carbon, became famous."
"This brilliant Experiment, one of the most beautiful in organic chemistry and one which few people credited at first, gave great impetus to chemistry and would have been worthy of any distinction." R. Willstätter
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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...
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Victor Meyer 9/8/48 - 8/8/97“Geliebte Frau! Geliebte Kinder! Lebt wohl! Meine Nerven sind zerstört; ich kann nicht mehr.” Victor Meyer
(1848 - 1897)
Third TermHeidelberg
with
who hadintroduced the idea of
StericHindrance
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Friedel-Craftsor
Ph2Mg
Tetraphenylmethane (1897)
“I have tried to solve this problem in a completely different way.”
?
8 g
110°
Cu
0.3 gSolubilityAnalysis : 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)
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End of Lecture 63March 30, 2011
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