organic chemistry i university of illinois at chicago...
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![Page 1: Organic Chemistry I University of Illinois at Chicago UICramsey1.chem.uic.edu/chem232/page7/files/Chem 232 Lecture 28.pdf · University of Illinois at ChicagoUIC CHEM 232 Organic](https://reader030.vdocuments.mx/reader030/viewer/2022033123/5d53533288c9932e748bc33d/html5/thumbnails/1.jpg)
University of Illinois at ChicagoUICCHEM 232
Organic Chemistry I
Lecture 28Organic Chemistry 1
Professor Duncan Wardrop
April 22, 2010
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Topics Covered:1. Aryl Halides - Bonding, Physical Properties and
Reactions
2. Nucleophilic Aromatic Substitution of Chlorobenzene
3. Nucleophilic Aromatic Substitution: Addition-Elimination
4. Floxcin - Application of Nucleophilic Aromatic Substitution
5. Nucleophilic Aromatic Substitution: Elimination-Addition
Today’s Lecture
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What’s the Difference Between Ar- and Ph-?
Phenyl refers specifically to this:
Aryl is a general term for all aromatic ring systems:
C
N
N
O
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Chapter 23Aryl Halides
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23.1Bonding in Aryl Halides
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Aryl Halides
Aryl halides are halides in which the halogen is attached directly to an aromatic ring.
Carbon-halogen bonds in aryl halides are shorter and stronger than carbon-halogen bonds in alkyl halides.
X
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sp3
X = H
410 (98)
X = Cl
339 (81)
H2C CHX sp2 452 (108) 368 (88)
X sp2 469 (112) 406 (97)
Bond Energy:kJ/mol (kcal/mol)
CH3CH2X
Dissociation Energies of Selected Compounds
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Resonance Picture
X X
HH
X
C-X bonds in aryl halides have more double bond character than C-X bonds in alkyl halides
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23.2Sources of Aryl Halides
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Preparation of Aryl Halides
Halogenation of arenes (Section 12.5)
HBr2
FeBr3Br
HBr
electrophilic aromatic substitution
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Preparation of Aryl Halides
The Sandmeyer reaction (Section 22.17)
PrimaryArylamine
Aryl DiazoniumSalt
NH H
N
NaNO2
HCl, H2O
N
CuCl
heat
Aryl Chloride
Cl
N+
O–
ON+
O–
ON+
O–
O
Cl
diazotization-nucleophilic aromatic substitution
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Preparation of Aryl Halides
The Schiemann reaction (Section 22.17)
PrimaryArylamine
Aryl DiazoniumSalt
NH H
N1. NaNO2 HCl, H2O
2. HBF4
N
H2O
heat
Aryl Fluoride
FBF4
O
Me
O
Me
O
Me
diazotization-nucleophilic aromatic substitution
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Preparation of Aryl Halides
Reaction of aryl diazonium salts with iodide ion (Section 22.18)
PrimaryArylamine
Aryl DiazoniumSalt
NH H
N
NaNO2
HCl, H2O
N
KI
roomtemp.
Aryl Iodide
I
Me Me MeCl
diazotization-nucleophilic aromatic substitution
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23.3Physical Properties of Aryl Halides
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resemble alkyl halidesare essentially insoluble in waterless polar than alkyl halides
Cl
Cl
µ 1.7 Dµ 2.2 D
Physical Properties of Aryl Halides
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23.4Reactions of Aryl Halides:A Review and a Preview
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Reactions Involving Aryl Halides
Electrophilic aromatic substitution (Section 12.14)
Bromobenzene
Br BrBrOH
(hypobromousacid) Br
Br
Br
Br
Br
35.7% 1.0% 64.3%
halide substituents are ortho-para directing & deactivating
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Reactions Involving Aryl Halides
Electrophilic aromatic substitution (Section 12.14)
ADD DDT SYNTHESIS
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Reactions Involving Aryl Halides
Formation of aryl Grignard reagents (Section 14.4)
Bromobenzene
Br MgBrMg
Et2O
Phenylmagnesiumbromide
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Substitution Reactions Involving Aryl Halides
We have not yet seen any nucleophilic substitution reactions of aryl halides.
Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required.
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Nucleophilic Substitution of Chlorobenzene
Cl OH
(97%)
1. NaOH, H2O 370°C
2. H+
This reaction does not proceed via SN2……..
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the SN2 is not reasonable because the aromatic ring blocks back-side approach of the nucleophile. Inversion is not possible.
Why is Chlorobenzene Unreactive?
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SN1 Also Unlikely:Aryl Cations are Highly Unstable
Cl
C
+ Cl
SN1
emptysp2 orbital
Aryl Cation
SN1 not reasonable because:
1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process
2) aryl cations are highly unstable
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SN1 Reaction is Possible with VeryPowerful Leaving Groups such as Dinitrogen
N
CSN1
N
H2O
OH
Aryl Cation
This is a unique case: halides are not good enough leaving groups for this process to occur.
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What is the Mechanism of This Reaction?
Cl OH
(97%)
1. NaOH, H2O 370°C
2. H+
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23.5Nucleophilic Substitution in
Nitro-Substituted Aryl Halides
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Nucleophilic Aromatic Substitution (SNAr)?
HE E
Electrophilic Aromatic Substitution
H E-H+
Nuc
Nucleophilic Aromatic Substitution?
XNuc
X Nuc-X-
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Cl
NO2
+ NaOCH3
OCH3
NO2
+ NaCl
(92%)
CH3OH
85°C
In contrast to chlorobenzene, nitro-substituted aryl halides undergo nucleophilic aromatic substitution at reasonable temperatures
Electron-Deficient Haloarenes Undergo Nucleophilic Aromatic Substitution
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1.0 7 x 1010 2.4 x 1015 too fast to measure
The More Electron-Deficient theHaloarene, the Faster the Substitution
ClCl Cl
N+–O O
N+O–
O
N+–O O
Cl
N+O–
O
N+–O O
N+O–
O
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Direct Displacement Doesn’t Occur!
Br
Nuc:
Nuc
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Kinetics of Nucleophilic Aromatic Substitution
follows second-order rate law:
rate = k [aryl halide] [nucleophile]inference:
both the aryl halide and the nucleophile are involved in rate-determining step
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Reaction Rate Depends on X: I > Br > Cl > F
Effect of Leaving Group Upon Rate of SN2
During SN2 reactions, the C-X bond breaks during the rate-determining step
C-F (485 kJ/mol), C-Cl (327 kJ/mol)
C-Br (285 kJ/ml, C-I (213 kJ/mol)
R'
CR X
R''
R'
CR R''
XNucδ+ δ−
R'
CNuc R
R''
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X Relative Rate*
F
Cl
Br
I
312
1.0
0.8
0.4
*NaOCH3, CH3OH, 50°C
Effect of Leaving Group in Nucleophilic Aromatic Substitution
X
NO2
C-F (485 kJ/mol), C-Cl (327 kJ/mol)
C-Br (285 kJ/ml, C-I (213 kJ/mol)
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General Features of Mechanism
1. bimolecular rate-determining step in whichnucleophile attacks aryl halide
2. rate-determining step precedes carbon-halogenbond cleavage
3. rate-determining transition state is stabilized byelectron-withdrawing groups (such as NO2)
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23.6The Addition-Elimination
Mechanismof
Nucleophilic Aromatic Substitution
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Addition-Elimination Mechanism
Two step mechanism:
Step 1nucleophile attacks aryl halide and bonds to the carbon that bears the halogen(slow: aromaticity of ring lost in this step)
Step 2intermediate formed in first step loses halide(fast: aromaticity of ring restored in this step)
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Addition-Elimination Mechanism
F
NO2
+ NaOCH3
OCH3
NO2
+ NaF
(92%)
CH3OH
85°C
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Addition-Elimination Mechanism
Step 1 - Addition
F
NO2
CH3 Obimolecularconsistent with second-order kinetics;
first order in aryl halide, first order in nucleophile
Rate = k [CH3ONa] [arene]
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Addition-Elimination Mechanism
Step 1 - Addition
F
NO2
Slow HCH3O
F
NO2
CH3 O
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intermediate is negatively charged
formed faster when ring bears electron-withdrawing groups such as NO2 because negative charge is stabilized……..
Reaction Involves an Anionic Intermediate
FH
CH3O
NO O
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Stabilization of Addition Productby Electron-Withdrawing Group
FCH3OH
NO O
N
FCH3O
O O
H
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Rapid Collapse of CyclohexadienylAnion Intermediate
Step 2 - Elimination
Fast
OCH3
NO2
FCH3OH
NO O
F
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carbon-halogen bond breaking does not occuruntil after the rate-determining step
electronegative F stabilizes negatively charged intermediate
F > Cl > Br > I is unusual, but consistentwith mechanism
The Role of Leaving Groups
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The Role of Leaving Groups
FNucH
NO O
ClNucH
NO O
BrNucH
NO O
INucH
NO O
Most Stabilized Least Stabilized
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23.7Related Nucleophilic Aromatic
Substitution Reactions
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(72%)
OCH3
FF
FF
F
F
FF
F F
F
NaOCH3
CH3OH65°C
FFF
F F
F
CH3O
Anionic Intermediate
Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic substitution.
Substitution of Hexafluorobenzene
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Substitution of 2-Chloropyridine
N Cl N OCH3
NaOCH3
CH3OH50°C
2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions.
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N Cl N OCH3
N Cl
OCH3
NaOCH3
CH3OH50°C
Anionic Intermediate
CH3O
Substitution of 2-Chloropyridine
Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and increases the rate at which it is formed.
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Compare 2-Chloropyridine with Chlorobenzene
N Cl N OCH3
NaOCH3
CH3OH50°C
Cl OH
1. NaOH, H2O 370°C
2. H+
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Synthetic Application ofNucleophilic Aromatic Substitution
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Ofloxacin
http://www.ofloxacin.com/
Ofloxacin (trade name Floxin) is a broad-spectrum quinolone antibiotic
Ofloxacin
N
O
O O
OEt
Me
H
N
F
NMe
H
N
O
O O
OH
Me
H
N
F
NMe
H
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Synthesis of Ofloxacin, Part 1
F
F
O O
OEt
F
F
OMe
H
F
F
O O
OEt
F
F
OMe
H
HN
MeOH
F
F
O O
OEt
F
F
H
NH
MeOH
NH2
MeOH -MeO
1,4-Addition
Elimination
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Synthesis of Ofloxacin, Part 2
N
O O
OEt
F
F
H
FMe
OH
N
O O
OEt
F
F
H
FMe
OHF
F
F
O O
OEt
F
F
H
NH
MeOH
Elimination
Addition
NucleophilicAromatic Substition
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Synthesis of Ofloxacin, Part 3
N
O
O O
OEt
Me
H
F
F
H
N
O
O O
OEt
Me
H
F
F
H
N
O O
OEt
F
F
H
FMe F
HHO
Addition
EliminationNucleophilicAromatic Substition
-F
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Synthesis of Ofloxacin, Part 4
N
O
O O
OEt
Me
H
N
F
NMe
H
N
O
O O
OEt
Me
H
F
F
H
N
NMe
N
O
O O
OEt
Me
H
F
F
H
NH
NMe
NucleophilicAromatic Substition
Addition
Elimination
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Synthesis of Ofloxacin, Part 5
Ofloxacin
N
O
O O
OH
Me
H
N
F
NMe
H
N
O
O O
OEt
Me
H
N
F
NMe
H
NaOHH2O
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Synthetic Application ofNucleophilic Aromatic Substitution
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Page 238 Furosemide
http://www.ofloxacin.com/
Ofloxacin (trade name Floxin) is a broad-spectrum quinolone antibiotic
Prozac another good idea
Ofloxacin
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23.8 Benzyne & the Elimination-
Addition Mechanismof Nucleophilic Aromatic
Substitution
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Aryl Halides Undergo Substitution WhenTreated With Very Strong Bases
Cl NH2
(52%)KNH2, NH3
-33 °C
Ammonia: pKa = 34; b.p. = -33 °C
Potassium Amide: strong base
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new substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon adjacent to it
CH3
NaNH2, NH3
-33 °C
CH3
NH2
CH3
NH2
Br
Regiochemistry
Cine substitutionproduct
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Cine Substitution Defined
cine-substitutionA substitution reaction (generally aromatic) in which the entering group takes up a position adjacent to that occupied by the leaving group.
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new substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon adjacent to it
Regiochemistry
CH3
NaNH2, NH3
-33 °C
CH3 CH3
NH2
Br NH2 Cine substitutionproduct
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CH3
NaNH2, NH3
-33 °C
CH3CH3
NH2
NH2
CH3
NH2
Br
Regiochemistry
Cine substitutionproduct
Cine substitutionproduct
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Further Proof of Cine Substitution via 14C Label
Cl NH2
KNH2, NH3
-33 °C
* *NH2
*
(52%)(48%)
Cine substitutionproduct
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compound formed in this step is called benzyne
Rationalization of Cine Substitution
Step 1 - Elimination
ClCl
H NH
H
H
H
H
H
H
H
H
H
NH
HH
Benzyne
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Benzyne - A Reactive MoleculeWith an Abnormal π-Bond
Benzyne has a reactive triple bond.It cannot be isolated in this reaction, but is formed as a reactive intermediate.
H
H
H
HBenzyne
H
H
H
H2pZ-2pZπ Bond
H
H
H
Hsp2-sp2
π Bond
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Benzyne - A Reactive Aromatic MoleculeWith An Abnormal, In-Plane π-Bond
CC
R
R
'Normal' C-C Triple Bond
CC
C
CCCH
H H
H
Benzyne C-C Triple Bond
overlapping sp2 orbitalspoor overap resultsin a weak, reactive bond
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Arynes are Highly Reactive Electrophiles
Step 2 - Addition
H
H
H
H NH
HN
H
H
H
H
H
H
Aryl AnionBenzyne
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Aryl Anions are Strongly Basic
NH
H
N
H
H
H
H
H
H
SubstitutionProductBenzyne
N
H
H
H
H
H
H
HH
NH
H
Step 3 - Protonation
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Hydrolysis of Chlorobenzene
Cl
OH
NaOH, H2O395 °C
*
* *
(43%)(54%)
OH
14C labeling indicates that the high-temperature reaction of chlorobenzene with NaOH proceeds via benzyne.
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Substitution of ChlorobenzeneProceeds via Benzyne
Cl
HBenzyne
NaOH NaOH
H2O
* *
OH
OH*
*Cine substitution
product
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Why the Temperature Difference?
Cl OH
Cl NH2
KNH2, NH3
-33 °C
1. NaOH, H2O 370°C
2. H+
Sodium amide is a considerably stronger base than hydroxide and consequently better able to carry out the rate-determining step
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All is Revealed
CH3 CH3 CH3
NH2
CH3
NaNH2 1. NaNH2
2. NH3
Br NH2
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All is Revealed
CH3 CH3 CH3
NH2
Br NH2
CH3
NaNH2 1. NaNH2
2. NH3
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All is Revealed
CH3 CH3
NH2
NH2
CH3
NH2
CH3
Br
CH3
NaNH2
CH3
1. NaNH2
2. NH3
1. NaNH22. NH3
1. NaNH22. NH3
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Other Methods for the Preparation of Benzyne
Benzyne can be prepared as a reactive intermediate by methods other than treatment of chlorobenzene with strong bases.
Another method involves loss of fluoride ion from the Grignard reagent of 1-bromo-2-fluorobenzene.
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Other Methods for the Preparation of Benzyne
Br MgBrMg
THFheatF F
Benzyne
MgFBrAryl bromide faster with Mg than aryl fluoride
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Preparation of Benzyne viaDiazotization of Anthranilic Acid
See Question 23.23
AnthranilicAcid
Aryl DiazoniumSalt
NH
H
NaNO2
HCl, H2OCl
OH
O
N
OH
O
N
NaOH
N
O
O
N
Heat
N2 + CO2Benzyne
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23.9Cycloaddition Reactions of
Benzyne
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What is a Cycloaddition?
Cycloaddition, n.a reaction in which two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity.
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The Diels-Alder Reaction Revisited
Section 10.12
BA
X Y
A
X
B
Y
cycloaddition
diene dienophile cycloadduct
H
H
H
H
isoprene maleic anhydride cycloadduct
O
O
O
H3C H3C
O
O
O
100°C
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Electron-Deficient AlkynesBehave as Dienophiles
butadiene but-3-yn-2-one cycloadduct
120°C
CH3O
HH
CH3
O
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Benzyne Behaves as a Dienophile
Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.
CH3O
H
H
H
O
O
O
H
H
H
H
Benzyne
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Benzyne Participates in Diels-Alder Reactions
BrMg
THFheatF
Dienophilie
+
(46%)CycloadductDiene
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In the Absence of Dienes (or other nucleophiles) Benzyne Undergoes Dimerization and Trimerization
BrMg
THFheatF
BiphenyleneTriphenylene
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Topics Covered:
1. Aryl Halides - Bonding, Physical Properties and Reactions
2. Nucleophilic Substitution of Chlorobenzene
3. Nucleophilic Aromatic Substitution: Addition-Elimination
4. Synthetic Application of Nucleophilic Aromatic Substitution
5. Nucleophilic Aromatic Substitution: Elimination-Addition
6. Benzyne: Generation, Bonding and Reactions
Today’s Lecture
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Information & Suggested Problems
Suggested Problems: 23.10-23.27
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