CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
2012March21
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Aromatic Electrophilc Substitution
I. arenium ion mechanism - AE + DE
X
X
E+
X
X
E
E
E
E
+ X+
A. first step is usually rate determining
B. evidence 1. usually no primary deuterium isotope effect (X = H)
2. arenium ions observed by NMR in superacid solutions
3. mechanism is consistent with distribution of products
II. -complex
A. probably forms prior to arenium ion
B. may be rate determining step certain cases
III. electron-transfer mechanism
X
X
E+
E
X
E
+ others resonance forms
X
+ others resonance forms
oxidation of anisole and other electron rich aromatic in presence of NO 2 gave same
product distribution as direct nitration (common intermediate)
IV. DE + AE (SE1)
E
G+
V. single directing and activating groups
G
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
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A. rationalized using arenium ion
B. electron donating groups accelerate versus H and direct toward ortho and para
positions
H
H
E
G
G
H
E
E
G
G
C. electron withdrawing groups slow down versus H and direct toward meta
D. Cl, Br, and I deactivate but are ortho and para directors
E. ipso attack - five possible fates:
E
E
H
E
H
Nu
migration, ipso group loss, electrophile
X
X
X
electrophile migration, ipso group
-E+
-X+
X
loss, nucleophile addition
E
H
X
E
1. known groups displaced after ipso
attack: stable alkyl cations, electro positive groups (SiR3 and SnR3)
2. silicon and tin are good ipso directors because of stabilization of -carbocation
(hyperconjugation)
SiR3
X-
H
VI. Multiple groups
A. strongest activating group controls
H
NO2
NO2
Cl
Cl
NO2
position of substitution
Cl
Cl
Cl2
B. position between meta goups
Cl
Cl
NO2
NO2
NO2
H
Cl
disfavored
Cl
Cl
Cl
Cl
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
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C. ortho effect: meta and ortho-para directors meta to each other - substitution occurs
ortho to meta director. Initial attack is ipso which does not place charge at NO 2 carbon
VII. structure/reactivity
A. Partial rate factors – rate relative to single benzene position
1. f o 
k obs
k benzene
 fraction (ortho ) 
6(benzene )
2(ortho )
2. for example: if nitration of trichloromethylbenzene were 15 times slower than
benzene and 29% of product is para then f p 
1
6
 0.29   0.116
15
1
B. reactive electrophiles have early transition state, rates and product distribution are
less sensitive to substitutents:
Partial rates factors for toluene

fm
fp
alkylation (RBr, GaBr3)
-2.4
1.4
5.0
bromination (Br2, AcOH)
-13.1
5.5
2420
C. early versus late transition state
E
H
E
H
E
E
late transition state
H
E
H
E
early transition state
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
2012March21
1. late transition state structure is like intermediate: using perturbation theory o,p
substituents overlap with MO at positions with non-zero coefficients, m
substituents have limited interactions due to node
0.6
LUMO coefficients
0.0
0.6
2. early transition state structure is like reactant – determined by electron density
CH3
NO2
0.52
HOMO coefficents
0.51
0.31
0.53
0.23
0.50
0.24
energies
0.26
-0.48
-0.57
III. other ring systems
A. multiple rings
1. more reactive than benzene
2. form intermediate with most stable resonance forms (1 substitution is
kinetically preferred, 2 substitution is thermodynamically preferred)
H E
E+
E
H
+
-H+
-H+
E
E
B. heterocyclic
1. five membered rings- heteroatom donates a pair of electrons to aromatic ring:
more reactive than benzene and directs  (2) substitution (pyrrole)
4
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
2012March21
NH
NH
E+
H
NH
H
NH
NH
E
H
E
H
NH
H
E
NH
H
E
E
E
5
2. six member ring: heteroatom donates only single electron to aromatic ring:
less reactive than benzene and directs to 3 position (pyridine) avoiding charge on
heteroatom
N
E+
N
N
N
EE
E H
H
H
IX. electrophiles
A. NO2+ (AcONO2 or HNO3/H2SO4), i-Pr+ (iPrCl/GaCl3), SO3 (H2SO4), NO+ (HNO2,
HCl), Cl2, H+, RCO+ (RCOCl/AlCl3)
X. selected reactions
A. deuteration - general-acid catalyzed
B. nitration 2SO 4
HNO 3  H2SO4  H2ONO 2  HSO 4 H2ONO 2  H2O  NO2 H
H3O  HSO4
NO 2  C 6H6  product
1. reaction is zero order in aromatic compound if aromatic is very reactive
indicating formation of nitronium ion is rate determining or formation of
nitronium ion is slow.
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
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2. Reaction is first order in aromatic if aromatic is moderately reactive.
D. Freidel Crafts Acylation either goes by acylium or complexed acid halide
1.Other Lewis acids include SbF5, TiCl4, SnCl4, BF3
2. F-C acylation is more selective than alkylation indicating acylium ions are less
reactive than alkyl cation toward aromatic
Cl
Cl
O
+
R
Cl
Al Cl
O
Cl
Cl
Al Cl
R
Cl
Cl
O
Al
Cl
Cl
R
Cl
Cl
O
C Cl
Cl
R
O Al Cl
Cl
Cl
R
H
Al
R
H
Cl
Cl
Cl
O Al Cl
Cl
Cl
R
O Al Cl
Cl
Cl
E. Halogenation
1. halogenation with I2 < Br2 < Cl2 (order of reactivity) occurs directly only with more
reactive aromatics
2. Lewis acid catalysts are often used, for example AlCl3, FeBr3
3. Other reagents are used HOCl, HOBr, HOI, ICl, CH3CO2Cl, CF3CO2Br
4. Note that rate laws are often complex
E. Kolbe-Schmitt
+
O Na O
C
O
+
+
H O Na O
O Na OH
C
C
O
O
F. deacylation and dealkylation (lone pair on CO)
+
HCl
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
O
H
7
O
O
H H2SO4
2012March21
C
H
H
O
+ H+
C
G. protonate oxygen first? Other mechanisms? Distinguish by experiment?
O
O
N Cl
O
NH Cl
HCl
O
NH
-
Cl
Cl
O
O
NH
NH
NH
H Cl
H Cl
Cl
Cl
.H. Formylation with chloroform
Cl
Cl
Cl
-
OH
Cl
Cl
H
C
Cl
Cl
-
O
O
Cl
-
H2O
O
CH
-
O
Cl
O
O
CH H
H
OH
-
HO
Cl CH
Cl
-
Cl
-
O
Cl
Cl
Cl CH
Cl
C
CH
Cl
-
O CH
O
-
O
-
HO
Aromatic Nucleophilic Substitution
I. SNAr (AN + DN), bimolecular kinetics
A. electron-withdrawing groups ortho and para, ussually requires 2 or more
activating groups
OMe
OEt
+ MeO
O2N
NO2
OMe
OEt
-
O2N
NO2
O2N
NO2
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B. first step is usually rate determining so rate shows little dependence on L
C. replacement of halogens: F > Cl > Br > I because first step is rate determining.
II. SN1 (DN + AN)
A. usually with diazonium group
-
Y
+ N2
+
Y
N2
B. first-order in diazonium, independent of nucleophile
C. tight-ion pair probably occurs
D. normally occurs by radical process in the presence of Cu salts (Sandmeyer)
III. benzyne (AxhDH + DN + AN + AHDxh) - favored by strong base
A.
NH3
NH2
14
14
14
Cl
Cl
NH2
14
NH2
14
+
14
NH3
NH2
14
Cl
NH2
14
14
+
NH2
NH2
B. first or second step is rate determing depending on leaving group
1. proton loss is rate determining for Br and I
2. leaving group loss is rate determining for F and Cl
C. formation of most stable carbanion intermediate determines position of
nucleophile attack
NH2
+
14
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
OMe
OMe
NH2
OMe
-
Cl
OMe
NH2
OMe
2012March21
OMe
-
NH3
Cl
NH2
OMe
NH2
OMe
NH2
9
-
OMe
NH3
Cl
NH2
NH2
IV. SRN1 - favored by reducing agents

A. ArX  G  ArX   G 

ArX   Ar   X 

Ar   Y   ArY 


ArY  ArX  ArY  ArX 
B. initiated by electron transfer
V. leaving groups
A. for SNAr: F > NO2 > OTs > SOPh > Cl, Br, I > N3 > NR3 > OR, SR, NH2 (ipso
activation)
B. for SRN1: N2, halide, SPh, NMe3+, OPO(OEt)2 ????
VI. selected reactions???
A. Bucherer reactions: enamine hydroylsis
CHEM 73/8311 CS9 Aromatic electrophilic Substitution.docx
NH2
NH2
2012March21
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O
NH2
-
OH
+ NH3
NaHSO3
H
H2O
SO3-
SO3- several
steps
H H
SO3H
H
H H
H
several
steps
concerted?
OH
OH
- NaHSO3
SO3H H
H
B. von Richter reaction: http://www.answers.com/topic/list-of-organic-reactions#wp-V
-
NO2
-C
O N O
-
-
N
O N O
C
H
N
-
-
N
-
O N O
O N O
C N-
C
C NH
O N O
H2O
C N-H
H2O
H2O
-
O
C
N N
OH
C
O
N N
OH
C O-
O
-
-
OH
C O
OH2
OH
HO N NH
C O
C. Sommelet-Hauser rearrangement (start from more stable anion)
http://books.google.com/books?id=w9lTxIaPCQIC&pg=PA438&lpg=PA438&dq=%22so
mmelet+hauser%22+rearrangement+mechanism&source=web&ots=Kve7pICAT1&sig=
Dt5xzAwfRzCT2B_w71yiYKcp-F0
H H
N
CH3
CH3
H
H H
H
CH3 NH 2
CH3
N
CH3
CH3
2 steps
note most stable anion is not reactive.
N
CH3
H
N
CH3
CH2
CH2
H
CH3
CH3
CH3
2 steps
CH3
N CH3
CH2