molecular-rearrangements-pps.ppt

MOLECULAR
REARRANGEMENTS
Dr. Mishu Singh, Pt. D.D.U Govt. Girls P.G. College, Lucknow. .

Rearrangements
•In a rearrangement reaction an atom or gro moves from one
atom to another in the same molecule i.e. connectivity of atoms
changed within the molecule.
• Most of the migrations are from an atom to an adjacent one
(called 1,2-shifts),
but some are over longer distances.
The migrating gro (W) may migrate with electron
pair(nucleophilic rearrangement) or without electron
pair(electrophilic rearrangement) or with one electron(free
radical rearrangement) as the case may be.
Dr. Mishu Singh, Pt. D.D.U Govt. Girls P.G. College, Lucknow

NOTE-
• The nucleophilic 1,2-shifts are much more common than
electrophilic or free-radical 1,2-shifts.
• The reason for this can be understood by a consideration of the
transition states (or in some cases intermediates) involved.
Scheme 2
Scheme 2 represents the transition state
or intermediate for all three
cases(nucleophilic, electrophilic and free
radical rearrangements).

Rearrangement to Electron Deficient
Carbon
Carbon Migration(nucleophilic
rearrangement)
• Wagner-Meer-wein Rearrangement
• In this rearrangement less stable carbocation is converted into more
stable through the migration of Aryl, alkyl or hydrogen which leads
the formation of most stable carbocation.
• It is one of the simplest systems where an alkyl gro migrates,
with its bonding pair, to an electron-deficient carbon atom.
The driving force for the rearrangement resides in the greater
stability of a tertiary carbo-cation compared to that of primary
carbo-cation

isoborneol camphene
Meerwein rearrangement of norbornyl systems:

Features of this migration
• The carbocation may be produced by a variety of ways.
•Hydrogen can also migrate in this system.
• Less stable cyclic carbocations also converted into more stable
through exansion or contraction of ring.

Degenerate carbo-cations & re-
arrangements
Carbocations that rearrange to give products of identical
structure (e.g., 6=6’, 7= 7’) are called degenerate carbocations
and such rearrangements are degenerate rearrangements.

•Aryl gros have a greater migratory aptitude than alkyl gro or
hydrogen due to the formation of lower-energy bridged
phenonium ion

• Rearrangements in bicyclic systems are
common.
•The rearrangement is stereo-sepecific and intra-
molecular.
•Two or more rearrangements may take place
simultaneously.

Pinacol Rearrangement
•Treatment of 1,2-diols (pinacol) with acid lead to rearrangement
to give ketone.
• This rearrangement fundamentally is similar to the above
described Wagner-Meerwein rearrangement .
•The characteristics of the Wagner-Meerwein apply to the pinacol
rearrangement.

Mechanism

Migratory aptitudes of different
gros
The following are a few of the relative migratory aptitudes
determined for aryl gros by Bachmann and Ferguson:
p-anisyl, 500; p-tolyl, 15.7; m-tolyl, 1.95; phenyl, 1.00; p-
chlorophenyl, 0.7; o-anisyl, 0.3.
For the o-anisyl gro, the poor migrating ability probably has a
steric cause, while for the others there is a fair correlation with
activation or deactivation of electrophilic aromatic substitution,
which is what the process is with respect to the benzene ring.
If other things are same normal migratory aptitude follow the
order
Ph> Me3C > Me2CH > CH3

Examples

Benzilic Acid Rearrangement
•1,2-Diketones that have no α-hydrogen react with hydroxide ion to
give α –hydroxy-acid.
• The best known example is the rearrangement of benzil to
benzilic acid( benzil is PhCOCOPh; benzilic acid is Ph2COHCOOH).

Arndt-Eistert Homologation
Reaction
The reaction of acid chloride with diazomethane gives a
diazoketone which is in the presence of silver oxide under heating
proceeds the Wolff rearrangement to yield a ketene that is directly
converted into an acid in the presence of water.

Halogen, Oxygen, Sulfur,
and Nitrogen Migration

•In the system X-C-C-Y, an atom X with an unshared pair of
electrons (X= O, N, S, Cl) can assist the heterolysis of the C-Y
bond. In case of unsymmetrical system, nucleophilic attack
predominates at the less substituted carbon of the bridged ion
that leads to rearranged skeleton.
no

Re Rearrangement
α-acetylenic alcohols converted into α,β- unsaturated ketones.

In case of a neighbouring acetoxy gro, the solvolysis is assisted
via a five-membered acetoxonium ion.

REARRANGEMENT TO
ELECTRON DEFICIENT
NITROGEN

Hofmann Rearrangement
•In the Hofmann rearrangement, an un-substituted amide is
treated with sodium hypobromite (or sodium hydroxide and
bromine, which is essentially the same thing) to give a primary
amine that has one carbon fewer than the starting amide.
• The actual product is the isocyanate, but this compound is
seldom isolated since it is usually hydrolyzed under the reaction
conditions.
• The R gro may be alkyl or aryl, but if it is an alkyl gro of more
than about six or seven carbons, low yields are obtained unless
Br2 and NaOMe are used instead of Br2 and NaOH.

Features of this reaction
• The intermediate N-halo amides have been isolated in the first
step.
• In the second step, N-halo amides lose a proton to the base as it
is acidic.
• The third step is actually two steps:
(1)loss of bromide to form a nitrene.
(2) followed by the actual migration, but most of the available
evidence favors the concerted reaction.
• The reaction is intra-molecular and stereo-specific.

Mechanism
The work can also be with alcohol or amine to give urethane or
urea, respectively

Curtius Rearrangement
This rearrangement describes the transformation of acyl azide
into isocyanate by decomposition on heating and its application
for the synthesis of primary amines, urethanes and ureas as
presented in Hofmann rearrangement .

Schmidt Rearrangement
Carboxylic acid reacts with hydrazoic acid in the presence of
conc. H2SO4 to give acid azide which is present in the form of
conjugate acid eliminates nitrogen to afford isocyanate that
could be converted into amine as reported in Hofmann
rearrangement
The reaction is also effective with aldehydes, ketones,
tertiary alcohols and substituted alkenes.

Lossen Rearrangement
Ester of hydroxamic acid reacts with base to give isocyanate that
could be converted into amine as shown in Hofmann
rearrangement.

Beckmann Rearrangement
•Oximes rearranges in acidic conditions to give amides.
•The reaction is intramolecular and stereospecific: the substituent
trans to the leaving gros migrates.

An interesting application of this method is the synthesis
caprolactam from cyclo-hexanone oxime. Caprolactam is the
substrate precursor for nylon-6 preparation.

Neber Rearrangement
• a-Amino ketones can be prepared by treatment of keto-xime
tosylates with a base, such as ethoxide ion or pyridine.
• This reaction is called the Neber rearrangement.
• The R gro is usually aryl, though the reaction has been
carried out with R= alkyl or hydrogen. The R’ gro may be alkyl,
or aryl but not hydrogen.

Mechanism
The mechanism of the Neber rearrangement is via an azirine
intermediate 79.
•The best evidence for this mechanism is that the azirine
intermediate has been isolated.
•Both a syn and an anti ketoxime give the same product.
•The mechanism as shown above consists of three steps.
However, it is possible that the first two steps are concerted, and it
is also possible that what is shown as the second step is actually
two steps: loss of OTs to give a nitrene, and formation of the
azirine Dr. Mishu Singh, Pt. D.D.U Govt. Girls P.G. College, Lucknow

REARRANGEMENT TO
ELECTRON DEFICIENT
OXYGEN

Baeyer Villiger Reaction
•Treatment of ketones with peroxyacid gives ester.
•The reaction is effective with acid or base and the mechanism is
closely related to pinacol rearrangement.
•Nucleophilic attack by the peroxyacid on the carbonyl gro gives
an intermediate that rearranges with the expulsion of the anion of
the acid.

Mechanisms

Mechanisms
• Migratory Aptitude: 3◦ > 2◦ > PhCH2 > Ph > 1◦ > Me > H.
• Electron withdrawing gros in peracids and electron
releasing gros in migrating gro increases the rate of
reaction.

Hydro-peroxide
Rearrangement
•Tertiary hydroperoxide with acid undergoes rearrangement to
give ketone and alcohol or phenol.
• The mechanism is similar to that of Baeyer-Villiger reaction.
•For example, cumene forms hydroperoxide by autoxidation which
rearranges in the presence of an acid to give phenol and acetone.

Dienone–Phenol
Rearrangement
•Cyclohexadienone derivatives that have two alkyl gros in the
4 position undergo, on acid treatment,1,2 migration of one of
these gros from 64 to give the phenol.
•Note that a photochemical version of this reaction has been
observed

Mechanism
The driving force in the overall reaction (the dienone–
phenol rearrangement) is of course creation of an aromatic
system.

Dakin Reaction
Benzaldehyde or acetophenone bearing hydroxyl substituent in
the ortho or para position proceed rearrangement to give catechol
or quinol, respectively. The reaction is performed in the presence
of alkaline hydrogen peroxide and the mechanism is similar to that
of Baeyer-Villiger reaction.

REARRANGEMENT TO
ELECTRON-RICH
CARBON
Electro-philic
rearrangement

General
This gro of reaction has been less explored, and is less of
synthetic importance compared to the rearrangements to electron
deficient carbons.
The rearrangements to electron deficient hetero atom may be
generally explained as follows.

Stevens Rearrangement
Quaternary ammonium salt which has β-hydrogen proceeds E2
(Hofmann) elimination with base.

Mechanism
In case of quaternary ammonium salts containing β-ketone or
ester or aryl gro, an α- hydrogen is removed by base to give an
ylide and then the rearrangement occurs.

Sommelet-Hauser
Rearrangement
•In the absence of β-carbonyl gro, the α-hydrogen is too weakly
acidic for hydroxide ion induced rearrangement.
• Thus, a strong base, such as amide ion in liquid ammonia, is to
be used, when the rearrangement takes a different course:
instead of [1,2] shift (Steven’s rearrangement), a [3,2]-sigma-
tropic rearrangement takes place which is called Sommelet-
Hauser rearrangement.

Mechanism
There can be competition between Stevens and Sommelet-Hauser
rearrangement mechanisms.

Wittig Rearrangement
Ethers undergo [1,2]-sigmatropic rearrangement in the presence
of strong base such as amide ion or phenyllithium to give more
stable oxyanion.
The mechanism is analogous to that of Stevens rearrangement

Favorskii Rearrangement
α-Haloketones with base afford enolates which rearrange to give
esters via cyclo-propa-nones.

Mechanism
The direction of ring opening of cyclo-propa-
none is determined by the more stable
carbanion, formed in the reaction.

AROMATIC
REARRANGEMENTS

General
A number of rearrangements occur in aromatic
compounds of the type
X is usually nitrogen or oxygen. Both
intermolecular and intra-molecular migrations are
known.

Fries Rearrangement
•Aryl esters with Lewis acid undergo rearrangement to give
phenols having keto substituent at ortho and para positions.
• The complex between the ester and Lewis acid gives an
acylium ion which reacts at the ortho and para positions as in
Friedel-Crafts acylation.

Mechanism
In general, low temperature favors the formation of
para-product (kinetic control) and high temperature
lead to the formation ortho-product (thermodynamic
control )

Claisen Rearrangement
Aryl allyl ethers undergo [3,3]-sigma-tropic
rearrangement on being heating to allyl-phenols

Mechanism
If the ortho position is blocked, rearrangement continues to give
para-product.

molecular-rearrangements-pps.ppt

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