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CHAPTER 18: E.A.S. REACTIONS
ELECTROPHILIC AROMATIC SUBSTITUTIONS (E.A.S.)
GENERALITIES
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HALOGENATION REACTION
GENERAL REACTION
(X = Cl, Br)
MECHANISM
APPLICATIONS
2,4-D
The mostly widely used herbicide in the world
2,4,5-T
Another herbicide
Agent Orange (defoliant used in Vietnam War): equal parts 2,4-D
and 2,4,5-T. Much of health effects were due to dioxin in
Agent Orange. Biosynthesis of Thyroxine1 (hormone secreted by the thyroid gland)
1 Solomons, G., Fryhle, C.B., Organic Chemistry, 8th ed., Wiley, 2004, pp. 691.
HNO
OH
HO
HN
O
Tyrosine
Tyrosine
HNO
OH
HO
HN
O
I
II
I
HNO
O
I
I
HO I
HN
O
enzymeH3N O
O
O
I
I
OH
I
I
Thyroxine
I
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NITRATION REACTION
GENERAL REACTION
MECHANISM
APPLICATIONS
The reason airport security uses full-body scanners.
NO2
NO2
O2N
HNO3H2SO4 Pentaerythritol tetranitrate
“Underwear bomber”Dec 25, 2009
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SULFONATION REACTION
GENERAL REACTION
MECHANISM
FYI: You really only need H2SO4 because: 2 H2SO4 à SO3 + H3O+ + HSO4–
APPLICATIONS
Sulfacetamide (Klaron, Plexion)
Antibiotic for acne + rosacea
Hyrochlorothiazide Diuretic for hypertension, congestive heart failure
Ethoxzolamide Anticonvulsant for epilepsy, and
treatment of glaucoma
SOH
O O
SO
O ONaHCO3
SO3 (g)
H2SO4
H2N
S
H2N
OH
O O
NN
NH2H2N
SNH2
O O
SO3 (g)
H2SO4
Prontosil First antibiotic (1932) Overtaken in popularity by penicillin in mind 1940’s.
Micelle (dirt goes in the middle)
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FRIEDEL CRAFTS ALKYLATION / ACYLATIONS (EAS RXNS)
ALKYLATION REACTION
X= Cl, Br
ALKYLATION MECHANISM
WITH 1˚ RX OR METHYL RX
WITH 2˚ OR 3˚ RX
ALKYLATION VARIATIONS
CH3CH2X
AlCl3
They predate Nobel Prizes, which began in 1906.
Charles Friedel (left, French) and James Craft (right, American), published this reaction in 1876.
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ISSUES WITH F.C. ALKYLATIONS
REARRANGEMENTS
Product ratio with 1-chloropropane2
OVER-ALKYLATION
CHEM 22 lab in Spring 2010:
2 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 690.
Br
AlCl3
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ACYLATION REACTION
X= Cl, Br
ACYLATION MECHANISM
APPLICATION
AlCl3
X
O
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E.A.S. RXNS ON SUBSTITUTED AROMATICS
SUBSTITUENT’S EFFECT ON ELECTRON DENSITY OF RING
ELECTRON WITHDRAWING GROUPS (EWG) Through “Inductive Effects” (effects felt through σ bonds):
Through “Resonance Effects” (effects felt through π bonds):
ELECTRON DONATING GROUPS (EDG) Through “Inductive Effects” (σ bonds):
Through “Resonance Effects” (π bonds):
Least reactive Most reactive
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RATE EXPERIMENTS
GENERAL IDEA
RATE DATA Rates of Nitration3
Relative Rate:
3 Rate of nitration of toluene from: Solomons, G., Fryhle, C.B., Organic Chemistry, 8th ed., Wiley, 2004, pp. 679. Rate of nitration of chlorobenzene from pp. 681.
OH CH3 Cl CF3 NO2
Phenol Nitrobenzene
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ORTHO, META, AND PARA DIRECTORS
EXPERIMENTAL RESULTS
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METHYL (O,P DIRECTOR)
Product composition4
METHOXY (O,P DIRECTOR)
Product composition5
4 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 712. 5 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 709.
CH3 CH3 CH3CH3
COPhCOPh
COPhCl
O
Ph
AlCl3
ortho: 9.3% meta: 1.5% para: 89.2%
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NITRO (M DIRECTOR)
Product composition6
RELATIVE ENERGIES OF NITRATION
6 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 714.
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PRACTICE PROBLEM Which type of director (o,p or m) is the chloro group?
Product composition7
REACTIONS ON MONOSUBSTITUTED RINGS
Ortho-Para directors: Meta directors:
7 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 719.
Page 14
REACTIONS ON POLYSUBSTITUTED RINGS
STRONGEST ACTIVATOR DIRECTS
SOMETIMES CONSIDER STERICS
PRACTICE
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AROMATIC SHIFTS IN NMR SPECTRA
CHEMICAL SHIFT + ELECTRON DENSITY
POLYSUBSTITUTED RINGS
Resonance structures, considering methoxy group:
Resonance structures, considering carbonyl group:
ab
c
2H 2H 1H
NO
O
a
b
c
d
2H 1H 2H 1H
HO
O
OCH3
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PROBLEM
ü Use resonance structures to show why Hd absorbs at a lower frequency (ppm) than Ha.
ü Assign the 1H NMR spectrum to hydrogen atoms in the structure.
SYNTHESIS USING E.A.S. REACTIONS
LIMITATIONS OF PREVIOUS RXNS
1. Friedel Craft Reactions don’t work on strongly deactivated rings (halobenzenes OK).
2. Friedel Craft Reactions don’t work with anilines.
3. Anilines react with Lewis acids (e.g. FeBr3) and thus react unexpectedly.
Br2, FeBr3NH2
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IMPORTANCE OF THE STEP ORDER Design a synthesis to convert benzene into the compound shown below.
Route 1: Route 2:
NEW REACTIONS (OF SYNTHETIC UTILITY)
NITRO REDUCTION
FYI Mechanism:
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CLEMMENSEN REDUCTION
FYI Mechanism:
REMOVING SULFONIC ACID GROUP
FYI Mechanism:
SO3HH+, H2O
SOH
O O
H+
SO
O OH
H2O
OS
O
O
+
CH3Cl
