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SERP course A. Mickiewicz University,
Poznań 2016
Jan Milecki
Organic Chemistry
5th Edition
Paula Yurkanis Bruice
Based on
Molecular rearrangements
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Neighboring group participation
O Cl Cl
Cl
SCl
TsO TsO
Reacts with Nu: 106 x faster then
Hydrolyses 600x faster then
Reacts with AcOH 1011 faster then
Some reactions proceed just too easy!
What is the reason?
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O ClO
HO RO O
R
Oxygen atom lone pair „pushes away” chloride ion, creating resonance-stabilized cation
OO
Lone pair on the sulfur atom (strong nucleophile) expels chloride ion giving rise
to three-membered cyclic cation
SCl
SPhPh HO RS
OPh
R
SCl ClThis mechanism is responsible for alkylating
activity (and hence toxicity) of mustard gas! for in
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Other examples of the lone pair assistance:
OTs
O
O
Me
O O
Me
AcOH
OAc
OAc
OTs
OAc
=
Retention of configuration in the SN2 substitution indicates the neighboring group assistance!
Assisting electrons do not have to come from the lone pair – p orbital assistance
TsOAcOH
AcO
+
Appropriate structurefor
inter
nal u
se on
ly
O
Ts
LUMO
HOMO
What happens, when the participating group becomes trapped and remains in the place, which was
the aim of electron attack? In this case isomeric product is formed – result of REARRANGEMENT
„Simple” substitution:
Et2N
Cl
Et2N
OH
HO
NEt2NaOH, H2O
Expected product Real product (57% yield) .
Rearrangements
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Et2N
Me
Cl Good leaving group.
Secondary reaction center - slow substitution by an external nucleophile.
Good nucleophile,bad leaving group
Alkyl group can migrate too
MeI
Me
MeMe
OH
Me
MeAgNO3,
H2O X
MeI
Me
MeMe
Me
Me
Toocrowded for SN2 Primary cation, too unstable for SN1
MeI
Me
Me
MeI
Me
MeAgAg
C
Me
Me
HH
H
+
=
Me
Me
Me
Me
Me
Me
OH
H2O
Transition state, rather than intermediate
Et2NMe
Cl
Et2NMe
OH
HOMe
NEt2
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Molecule rearranges to form
more stable cation MeMe
H
Me
H
Me
Secondary Tertiary
Me
H
HH
H
H
H
HOMO filled orbital
LUMO empty p orbital
Me migrates
Me
H
H
H
H
H H
Me
Me
H
H
H
HOMO
LUMO_=
Me
Me
H
H
H
H migrates
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Carbocations rearrange easily!
How to produce a carbocation?
1. Dissociation of halogenides (promoted by silver ions)
2. Protonatiion of alcohols
3. Nitrosation of amines
(aliphatic)
RX Ag R AgX
H3C C
CH3
CH3
H2
C NH2
HONO
H3C C
CH3
CH3
CH2 +N2 + 2H2O
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4. Protonation of alkenes
Aryl amines – dissociation only (stable salts)
HH
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How to predict the direction of rearrangement?
H3C C
Ph
CH2
C4H9
H3C C CH2
C4H9
C
Ph
CH2
C4H9
CH3
H3C C
Ph
CH2 C4H9
Ph
Migration of phenyl group – very stable intermediate
(benzil and tertiary carbon atoms in the three
membered ring, charge spread over phenyl ring).
Favors this direction of migration C4H9 H
H3C H
CH3 shift
Ph shift
C4H9 shift
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The rearrangement was first discovered in bicyclic terpenes for example the
conversion of isoborneol to camphene
The story of the rearrangement reveals that many scientists were puzzled with this
and related reactions and its close relationship to the discovery of carbocations as
intermediates
OHOH2
H
H+ -H2O
Wagner-Meerwein rearrangement
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Rearrangement of camphenilol to santene
Ring strain release can be a driving
force for rearrangement
Cl
Four-membered ring Five-membered
ring
HCl
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Pinacol Rearrangement
In the conversion that gave its name to this reaction, the acid-catalyzed
elimination of water from pinacol gives t-butyl methyl ketone
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Mechanism of the Pinacol Rearrangement
This reaction occurs with a variety of fully substituted 1,2-diols, and can be understood to
involve the formation of a carbonium ion intermediate that subsequently undergoes a
rearrangement. The first generated intermediate, an α-hydroxycarbonium ion, rearranges
through a 1,2-alkyl shift to produce the carbonyl compound. If two of the substituents form a
ring, the Pinacol Rearrangement can constitute a ring-expansion or ring-contraction reaction.
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OH
OH
CH3
CH3
CH3
O
CH3 CH3
O
CH3
H H
trans group migrates
OH
CH3
OHCH3
OH2
CH3
OCH3
H
CH3
OCH3
H
CH3
O
CH3
H
H
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OH OH OH OH2 O
H
O
H
H
-H2O
Ring expansion
OH
OH
CH3
CH3
OH2
OH
CH3
CH3
CH3
O
OH2
CH3H
H3C
OCH3H
H
CH3
O
CH3
H
Ring contraction
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Epoxides undergo similar rearrangement (pinacol-type)
Grignard reagents not always open epoxides in desired way!
O
Ph Ph Ph Ph
O
MgBr
OPh
Ph
HMgBr2
ORLi RMgBr
OH
R
R
OH
O MgBr
OMgBr
O
HRMgBr
R
OH
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Baeyer-Villiger Oxidation
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R R
O
BF3
R R
OBF3
R R
OBF3
O
O
R'
O
H
R R
OBF3
O
O
R'
O
H
R
R
O BF3
O
O
R'
O
R
R
O BF3
H+
O
O
R'
O
R
R
O BF3
O OR'
O
R
R
O BF3
OR
R
O-RCOO
-BF3
+
-H
Mechanism of Bayer-Villiger Oxidation
Order of migration: R= tertiary alkyl >secondary alkyl >aryl >primary alkyl >methyl for in
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Benzilic Acid Rearrangement
1,2-Diketones undergo a rearrangement in the presence of strong base to yield
α-hydroxycarboxylic acids. The best yields are obtained when the subject
diketones do not have enolizable protons.
The reaction of a cyclic diketone leads to an interesting ring contraction:
Ketoaldehydes do not react in the same manner, where a hydride shift is
preferred (see Cannizzaro Reaction)
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Mechanism of Benzilic Acid Rearrangement
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Cannizzaro Reaction
This redox disproportionation of non-enolizable aldehydes to carboxylic acids and alcohols is
conducted in concentrated base.
α-Keto aldehydes give the product of an intramolecular disproportionation in excellent yields.
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Mechanism of the Cannizzaro Reaction
The Cannizzaro Reaction should be kept in mind as a source of potential side
products when aldehydes are treated under basic conditions. for in
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Favorskii Rearrangement
O
Br
O
Br:
O EtO
EtO
O OEt O
OEt
O
OEt
Alpha-halogeno ketones
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Hofmann Rearangement (Degradation)
R1NH2
R
OR1
R
N C OR1 N
H
C
R O
OH R1 NH2
RH2O
NaOH, X2
X=Cl, Br -CO2
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RN
H
O
R1 H
OHR
N
O
R1 H
X
O NaR
NX
O
R1
RN
X
O
R1 H
H2O RN
X
O
R1H -H
R R1
N
C
O
-X
Mechanism
Intermediate
Nitrene
-X
RN
O
R1
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Isocyanates are versatile starting materials:
Isocyanates are also of high interest as monomers for polymerization work and in
the derivatisation of biomacromolecules.
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Beckmann Rearrangement
An acid-induced rearrangement of oximes to give amides.
This reaction is related to the Hofmann and Schmidt Reactions and
the Curtius Rearrangement, in that an electropositive nitrogen is
formed that initiates an alkyl migration.
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Mechanism of the Beckmann Rearrangement
Oximes generally have a high barrier to inversion, and accordingly this reaction is
envisioned to proceed by protonation of the oxime hydroxyl, followed by migration
of the alkyl substituent "trans" to nitrogen. The N-O bond is simultaneously
cleaved with the expulsion of water, so that formation of a free nitrene is avoided.
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Claisen Rearrangement
The aliphatic Claisen Rearrangement is a [3,3]-sigmatropic rearrangement in
which an allyl vinyl ether is converted thermally to an unsaturated carbonyl
compound. The aromatic Claisen Rearrangement is accompanied by a
rearomatization:
The etherification of alcohols or phenols and their subsequent Claisen
Rearrangement under thermal conditions makes possible an extension of the
carbon chain of the molecule.
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Mechanism of the Claisen Rearrangement The Claisen Rearrangement may be viewed as the oxa-variant of the Cope Rearrangement
Mechanism of the Cope Rearrangement
Mechanism of the Claisen Rearrangement
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The aromatic Claisen Rearrangement is followed by a rearomatization:
When the ortho-position is substituted, rearomatization cannot take place. The
allyl group must first undergo a Cope Rearrangement to the para-position
before tautomerization is possible.
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