Examples of Substitutions

1
Examples of Substitutions
Benzyl radical is stabilized by mesoemric effect
Without catalyst, chlorine does not have
electrophilic substitution with the benzene
ring. 4-chlorotoluene will not be formed
2
Examples of Nucleophilic Substitution


95II 9 b (v)
The lone pair on N-atom of the nucleophile
attacks the substrate CH3I via a SN2 attack,
producing a quaternary compound as a result of
methylation
Reduction of CN bond
Toluene, 30 oC
N(C2H5)3 is a good nucleophile but a weak base,
it reacts with a 1o R-X via SN2 without
elimination
1-bromo-2-methylpropane
3
Acid-catalyzed Dehydration
2-phenylethanol
94 II8a (i) 3
4
Dehydrohalogenation of R-X in alkaline medium
As the attacking nucleophile CH3O- is a very
strong base capable of abstracting a proton from
the tertiary R-X, giving major elimination
product. The stable tertiary carbonium ion,
C(CH3)3 is not formed as intermediate leading to
substitution product because elimination is
favored in the presence of CH3O-
Due to steric hindrance, transition state is not
formed via the SN2 mechanism.

CH3Cl has no elimination product
Ether is formed from Williamson synthesis
5
Examples of Reaction Mechanism
EA
98 II5c 7
2o Alkanol
6
Dehydrohalogenation in alcoholic KOH
OH -
HO-
3-chloro-2-methylpentane reacts with ethanolic
KOH to give trisubstituted alkene
(2-methylpent-2-ene) disubstituted alkene
(4-methylpent-2-ene)
The secondary R-X reacts faster than the primary
R-X does
7
Major Elimination Products

1-phenylpropan-2-ol produces 3-phenylpropene,
cis- trans- 1-phenylpropene by dehydration
with hot concentrated sulphuric acid. Being a
monosubstituted alkene, 3-phenylpropene is the
minor product. Trans-1-phenylpropene is the major
product
or E2
The dehydration of 3-methylbutan-2-ol by H2SO4
proceeds via the E1 mechanism. Protonation
produces a good leaving group, leading to a
secondary carbonium ion. The removal of a proton
from an adjacent C-atom produces an
alkene.2-methylbut-2-ene, a trisubstituted alkene
is the major product. 3-methylbut-1-ene is the
minor product.
8
Elimination..
160 oC
But-1-ene
1-butanol
methanol
3-iodopentane can be dehydrated by a strong
base (CH3ONa) to form cis- and trans-2-pentene
Saytzeff (Zaitsevs) rule
The higher the degree of substitution of an
alkene, the greater its stability will be.
9
Elimination ...
Ni
3-bromo-2,4-dimethylpentane is not a primary
halogenoalkane (C7H15Br). As its structure is
highly symmetrical, it forms a single alkene on
heating with sodium ethoxide in ethanol by
dehydrohalogenation (2,4-dimethylpent-2-ene) Hydr
ogenation of the alkene produces
2,4-dimethylpentane.
C2H5OH
OH-
10
Examples of Nucleophilic Substitution and
elimination
Backside SN2 attack produces an inversion of
configuration
87II8c
With strong base 2o RX favors elimination
11
Williamson synthesis vs elimination
Both CH3O- and (CH3)2CHO- are strong bases
(nucleophiles). Their attack on simple substrate,
CH3I, causes no elimination.
CH3O- reacts with CH3I via SN2 to produce
CH3O-CH3 (Williamson synthesis)
12
Examples of nucleophilic Reaction
Elimination by the strong base is not possible
here
Steric hindrance is important in bromocyclohexane
and it is likely that it will not react with a
weak nucleophile like NH3 via a SN2 reaction.
SN1 is favored especially in ethanol.
13
Examples of Nucleophilic Substitution
SN1
Because of the high stability of the carbonium
ion, SN1 is favored a weak nucleophile like H2O
reacts with it rapidly forming a tertiary alcohol.
Discuss the reaction between 3-bromopropene and
H2 / PtO2 and KCN
14
Examples of Organic syntheses
Benzyl ion is stable
E2 is possible
15
Stereochemistry in Nucleophilic Substitutions
Sn2
2-Iodopentane is dissolved in propanone and
treated with KOH(aq) and it is found that
optical activity is lost gradually. In a SN1
reaction, the 2o R-I probably dissociates into a
planar carbonium ion and the nucleophile OH-
attacks it from above and below the plane
resulting in a racemic mixture of 2-pentanol. If
2-iodopentane proceeds via a SN2 reaction,
optically active 2-pentanol will be formed and
the optical activity reverses as the backside Sn2
attack results in an inversion of configuration.
The eventual optical activity should not be zero
for an SN2 reaction.
84II4b
94 II 7b (ii)
C5H9Cl , an acyclic chloroalkene, is optically
active
Cis- or trans- isomer
Deduce 3 possible structures
16
Ozonolysis

• Ozonolysis identify the position of the CC bond
  in an alkene chain/ring.
• Upon ozonolysis, disubstituted carbons at the CC
  bond gives ketones monosubstituted carbons give
  aldehydes CH2 group of a terminal alkene gives
  CO2 or HCHO.
• O3 is a highly reactive electrophile and reacts
  with CC bond to yield a five membered ring.
  Since the -O-O-O- unit is unstable, the
  intermediate rapidly rearranges with rupture of
  the C-C bond to give the more stable ozonide. The
  ozonide is cleaved with zinc in aqueous solution
  to form aldehydes and/or ketones. The Zn/H3O
  couple helps to decompose H2O2 formed in the
  course of the reaction and prevents H2O2 from
  further oxidizing the aldehydes into acids.

17
Ozonolysis Mechanism and Examples

18
Structural determination with O3
95 II 9a (iii)
19
Oxidative cleavage of alkenes

• Cis Hydroxylation MnO4- stereo-specifically
  oxidizes an alkene to cis-1,2-diol via the
  formation of cyclic intermediate Cold, dilute
  basic KMnO4(aq) is used to limit the oxidation to
  hydroxylation as MnO4- is a strong oxidant.
• Oxidative cleavage Hot alkaline permanganate
  solutions can oxidize alkenes to salts of
  carboxylic acids by oxidation. Disubstituted
  carbon of a CC bond yields ketone by oxidation.
  Terminal CH2 group is oxidized to CO2 H2O by
  hot MnO4-.

3 isomers of C4H8 were treated with ozone
followed by hydrolysis. Isomer E gives methanal
propanal but F and G, two geometric isomers give
ethanal only. Give structures for E, F G. 94
I 3a(ii)4
20
Oxidation of the side chains in aromatic compounds
MnO4-/OH-
heat, H
Oxidation of alkylbenzenes occurs at
the (phenylmethyl) carbon, hydrogen by the
oxidant. Oxidation occurs along the site
scissors the rest of the side chain until a
-COOH group is left. 2-methyl-2-phenylpropane has
no (phenylmethyl) hydrogen, it resists side chain
oxidation
92 I 1b
-COOH is a meta-director, -CH2CH3 is a
para-director
21
Comparing reactions of cyclohexene and Benzene

22
Electrophilic Aromatic Substitution

• The concentration of negative charges above and
  below the plane of the benzene ring makes the
  molecule highly unsaturated. Unlike alkenes,
  benzene does not undergo electrophilic addition
  because pi electron delocalization confers upon
  it considerable aromatic stabilization, so that
  it would generally involve the expenditure of a
  considerable amount of energy to activate the
  ring before any reaction could occur. As a result
  of resonance stabilization, the benzene ring
  needs higher temperatures and possibly catalysis
  before it can react.
• Benzene undergoes electrophilic substitution
  which allows the aromatic sextet of p electrons
  of benzene to be regenerated after electrophilic
  attack, so that the resonance stabilization of
  the ring is preserved.
• Electrophiles include Br, NO2, SO3H, CH3 and
  CH3CO.
• FeBr3 Br-Br FeBr4- Br
• H2SO4 HNO3 HSO4- NO2 H2O
• CH3CH2Cl AlCl3 AlCl4- CH3CH2

50-55 oC
23
Mechanism of electrophilic Substitution
When heated with a mixture of conc. HNO3 conc.
H2SO4 benzene reacts readily by substituting a
ring hydrogen for a nitro -NO2 group At 50 oC,
nitration of benzene gives a 85 yield of
nitrobenzene. NO2, the electrophile in the
nitrating mixture, attacks the electron-rich
benzene forming a high-energy positively charged
intermediate which easily loses a proton to
regenerate the stable nitrobenzene with aromatic
stabilization.
Nitration is exothermic and swirling of the
reaction flask is necessary. Disubstitution may
happen if the temperature rises above 55 oC and
1,3-dinitrobenzene (yellow crystal) may be
formed.
24
Electrophilic Substitution
Benzene
AlCl3 FeBr3 serve as Lewis acid catalyst to
enhance the electrophilicity of the
alkylating/brominating agent. Under the
Friedel-Crafts alkylation conditions, primary R-X
can form secondary/tertiary carbonium ions by
rearrangement
Classification of substituents in electrophilic
aromatic substitution ? All activating
substituents are ortho, para directors ? Halogen
substituents are slightly deactivating but are
ortho, para directors ? Substituents more
deactivating than halogen are meta directors
Activating -NH2, -NHR, -NR2, -OH gt -NHCOR, -OR,
-OCOR gt -R, -C6H5, -CHCR2
Deactivating -X, -CH2X gt -COH, -COR, -COOH,
-COOR, -COCl, -CN, -SO3H, -NO2
25
Examples of Electrophilic Substitution
FeBr3
Br2
26
Examples of Electrophilic Substitution
27
Examples of Electrophilic Substitution
This is not an electrophilic substitution
Side-chain halogenation occurs in light
28
Further examples of aromatic Substitution
29
Examples of Electrophilic Substitution
30
Special Examples of Electrophilic Substitution
Alkylation of benzene with isobutyl chloride
yields tert-butylbenzene by rearrangement
acylation
reduction
2 ortho, para-directing groups are in a meta
relationship an ethyl substituent can be
introduced by Friedel-Crafts Acylation, followed
by a Clemmensen reduction step later in the
synthesis