Nucleophilic Substitutions

1
Nucleophilic Substitutions
Sn1
Sn2
E2
2
Alkylation and bromination
Activating methyl group
Deactivating group
Because of steric effects, sulphonation of
alkylbenzenes gives mainly the para isomer
Clemmensen reduction
Reduction of the carbonyl group gives an alkyl
benzene which might be difficult to synthesize by
direct alkylation. Direct alkylation might result
in rearrangement of the side chain.
3
Dibromoalkane and alkyne
A conjugated diene is preferred over a
trisubstituted diene
Repeated dehydrobromination of a dibromoalkane
gives an alkyne
Sn2
4
Introducing Two para-directing groups in a meta
relationship
I
II
III
An ethyl substituent is introduced by
Friedel-Crafts Acylation followed by a Clemmensen
reduction step later in the synthesis
I - Friedel-Crafts Acylation with CH3COCl and
AlCl3
II - Chlorination with Cl2, Iron
III -Clemmensen Reduction with Zn/Hg in conc. HCl
5
Electrophilic Substitution
6
Reactions with aromatic compounds
Side-chain oxidation with alkaline KMnO4 is
carried out first so as to introduce
meta-directing -COOH group
The resonance-stabilized carbonium ion
intermediate is formed by electrophilic addition
in the rate-determining step
7
Examples of isomers
Trans-hept-1,4-diene
Cis-
Cis- isomer
5-methylhex-1,4-diene
Trans-4-methylhex-1,4-diene
8
Structural Isomers
C2H7N
Small dipole moment
Due to intramolecular hydrogen bonding,
cis isomer dehydrates at 100oC
100oC
Cis-isomer show intramolecular H-bond via a
seven-membered cyclic structure between -OH and
another electronegative atom. A lower m.p. is
expected as intermolecular interaction is
weakened.
9
Elimination
2,3-dihydroxybutanedioic acid
3-bromo-2-hydroxybutanal
Br-
95I3c
10
Other Examples

• Draw at least 4 possible structures for an
  optically active acyclic bromoalkane, C5H9Br

2-methylpropene reacts with I-Cl and alkaline
MnO4-. . Give the major products. Outline the
mechanism for ICl 87II7
11
Some other examples

• Draw structures for the ozonolysis proucts of
  1-methylcyclohexene C2H5CHCHCH(CH3)2

State the mechanisms of these reactions
82II5c (CH3)3C-O- CH3Cl --gt (CH3)3C-Cl CH3O-
--gt Outline the mechanism for the reaction
between toluene Br2 in the presence of light.
12
Typical reactions

• Write down equations for the change from
• 2-Bromo-1-phenylethane to phenylethyne
• 1-bromo-2-phenylethane to acetophenone 81II2a
• Outline a mechanism for the E1 reaction of
  2-chloro-3-methylbutane in ethanoic acid
• Explain why sodium phenolate reacts faster with
  CH3I than with sodium 4-nitrophenolate 86II7b

13
Further Examples

• 2-bromopropane hydrolyses to give propan-2-ol as
  the major product. Write a mechanism for the
  formation of the alcohol assuming that the
  hydrolysis reaction is SN1. Draw a labelled
  energy diagram for this reaction. What is the
  most probable side product in this hydrolysis
  reaction? Suggest a mechanism for its formation.
  83II5b
• Compounds A B have formulae C4H10O. A reacts
  with Na, liberating H2. A reacts with conc. HI to
  form C, C4H9I and with conc. H2SO4to form D,
  C4H8. B does not react with Na, but reacts with
  conc. HI to form E, C2H5I. Identify A-E.
• Compare the reactivity of 3-chloro-2-methylpentane
  and 1-chloro-4-methylpentane toward ethanolic
  KOH

14
Conversion of -OH group to -Cl or -CO
PCl5 or PCl3 is best for changing -OH to -Cl,
conc HCl is not a convenient reagent. C2H5OH
PCl5 --gt C2H5Cl HCl POCl3
Complete the following nucleophilic
substitutions Bromocyclohexane and ammonia in
ethanol solvent C2H5ONa and CH2CHCH2Cl 2-bromopro
pane and methanol (SN1)
15
Other examples

• Predict the major alkene formed in the acid-
  catalysed dehydration of 3-methylbutan-2-ol,
  2-methylcyclopentanol, 2-methylbutan-2-ol
• 1-bromobutane 2-bromo-2-methylpropane undergo
  hydrolysis, but under different conditions. The
  hydrolysis of 1-bromopropane becomes faster in an
  alkaline medium while the rate of hydolysis of
  2-bromo-2-methylpropane is fast even in water.
  Explain

16
Reaction mechanism

• Give the structure of the nucleophile needed for
  the synthesis via an SN2 mechanism
• 2,2-dimethylpropanol
• 3-methylbutanonitrile
• 2-methoxy-2-methylpropane
• Anisole
• Outline briefly a method to extract phenol from a
  mixture of benzoic acid phenol
• 89I4c

17
Dominant reaction

• Predict whether each reaction proceeds mainly by
  substitution, elimination, or whether the two
  compete. Write structural formulae for major
  product(s)
• 2-chloro-2-methylbutane and NaOH at 80oC
• 1-bromo-2-methylpropane (CH3)3N in toluene at
  30oC
• 3-iodopentane and CH3ONa in methanol
• C6H5CH2CH2Br and NaCN in methanol

18
Problems

• Outline the E1 mechanism for the dehydration of
  3-methylbutan-2-ol by H2SO4
• Intramolecular dehydration occurs to give side
  products when ethanol reacts with conc.H2SO4 at
  180oC. Explain briefly.
• Both 2-methylpropan-2-ol butan-1-ol are primary
  alkanols.Only the former alkanol shows turbidity
  in Lucas test. Explain in terms of rearrangement.
• Indicate how you obtain a pure specimen of (1)
  phenol from a mixture of benzoic acid, phenol and
  benzene,(2) ethanal from a mixture of ethanal,
  methoxyethane and propan-1-ol.

19

• When 2-nitrophenol is treated with NaOH, an anion
  is formed. Draw 5 resonance structures of this
  anion. Why is 2-nitrophenol a strong acid.
• Arrange 4-chloroaniline. 4-methylaniline,
  aniline, 4-methoxyaniline in order of their
  strength as a base, putting the weakest base
  fist.
• If a mixture of aniline, phenol and propylbenzene
  is obtained, suggest a flow-chart for separating
  them.
• C6H10O2 (X) is acidic enough to give off CO2 from
  NaHCO3, and is optically active. It absorbs 1
  mole of H2 to form an acidic substance, but which
  is optically inactive. Deduce the structure of
  compound X, explain your answer briefly.

20

• Toluene 4-chlorobenzoic acid
• Benzene 3-nitrobenzenesulphonic acid
• The nitration of benzoic acid occurs mainly at
  the meta-position. Suggest a synthesis of
  3-aminobenzoic acid from toluene, indicating
  the necessary reagents for each step. 85II7bi