The document discusses several rearrangement reactions including the pinacol rearrangement, Beckmann rearrangement, Heck reaction, ozonolysis, and Grignard reaction. The pinacol rearrangement involves the acid-catalyzed rearrangement of vicinal diols to ketones or aldehydes. The Beckmann rearrangement converts ketoximes to N-substituted amides. The Heck reaction is a palladium-catalyzed coupling of aryl or alkenyl halides with alkenes. Ozonolysis uses ozone to cleave alkenes and alkynes, replacing the multiple bond with a carbonyl. Grignard reagents are important in organic synthesis.

1. REARRANGEMENT REACTION
Prepared by:Ashwini.M.Londhe
(F. Y. Mpharm)
Guided by:Dr.A.R.Chabukswar 1
MAEER”S Maharashtra institute of pharmacy.

2. CONTENT
1) Pinacol rearrangement
2) Bechmann rearrangement
3) Heck reaction
4) Ozonolysis
5) Grignard reaction
6) Use of diazomethane
2

3. PINACOL REARRANGEMENT
Wilhelm Rudolph Fittig
(6 December 1835 – 19 November 1910) was a
German chemist. Fittig discovered the pinacol
coupling reaction.
R R
R C C R
OH OH
 Pinacol are ditertiary 1,2-diols.
 the simplest member of this class is Me2C(OH).C(OH)Me2.
3

4.  when pinacol is treated with dilute moderately conc. H2SO4 a
rearrangement reaction takes place which leads to the formation of
Me3C.CO.Me(pinacolone).
O
CH3 CH3 CH3
H
CH3 C C CH3 CH3 C C CH3
OH OH CH3
Pinacol Pinacolone
 The acid catalysed rearrangement of vic diols (1-2 diols) to ketone or
aldehyde with elimination of water is known as Pinacol pinacolone
rearrangement.
 Example shows that the migration origin and migration terminus
are the two adjacent carbon atoms.
 the migrating group may be aryl group, or alkyl an H atom.
4

5. Mechanisms:
Step1: reversible protonation to a hydroxyl group and elimination of water
molecule
R
R R R R R
H
R C C R R C C R C C R
OH OH OH2 R OH
OH
Step2: formation of non-classical carbenium ion ,a bridged intermediate.
R R
R
C C R C C
R R
R
OH R OH
Bridged intermediate 5

6. Step3:actual migration of a group to form the classical carbenium ion.
R
R
R R
C C R C C R3C C
R
R
OH OH O H
R OH
Bridged intermediate
Step4: The loss of proton and the formation of oxo compound.
R R
R3C C R3C + H
C
O H O
6

7. STEREOCHEMISTRY:
 Reaction is intra molecular.
 When different group are present on C atom bearing the hydroxyl groups
,two question arise.
Ph Me 1. Which of the two OH group will
1. Which of the two OH group
be protonated.
will be Protonated?
Ph C C Me
2. Which of the group will migrate?
HO OH 2. Which of the group will
migrate?
2-methyl-1,1-diphenylpropane
7

8. Answer of
Q1
 Stability order of the carbenium ions. Decreasing stability order of
carbenium ion is
Ph2CH > Ph CMe > PhCH >(CH3)2C .CH3CH
 Usually that OH receives the proton which produces the more stable
carbenium ion by elimination of water molecule.
 thus in this example OH gr. On the C atom holding the phenyl gr Will
receive the proton since the stability of diphenyl carbenium ion is greater
than that OH dimethyl carbenium ion.
 Stability of carbenium ion depend on the delocalization of positive charge on
the C atom either through resonance or through hyper conjugation.
8

9. Answer of
Q2
 There is no clear cut answer in so far as migratory preference is concern.
 It has found that a gr in anti or trance position with respect to the leaving
group ,H2O, in the more stable conformation of the Protonated substrate
migrate preferentially.
Ph Me Me
H2SO4
Ph C C Me
Ph C C Me
HO OH
Ph O
2-methyl-1,1-diphenylpropane-1,2-diol
9

10. Do the reaction conditions (i.e. type of acid, concentration, solvent
and temperature) influence the course of rearrangement?
oThus the action Of cold ,concentrate H2SO4 on comp A produces mainly
the ketone B while treatment of A with acetic acid containing traces H2SO4 of
gives mostly C phenyl migration.
cold CH3COOH
Me Ph C CMe2
C CPh2 Ph2C CMe
H2SO4 a trace of H2SO4
O Ph
O Me
OH OH
ketone B compound C
compound A
oGenerally Aldehyde formation is favored by use of mild condition (lower
temp,weker acid)
oUnder more drastic condition aldehyde may be converted to ketone.
10

11. Application:
1) synthesis of carbonyl compounds from alkenes.
CH3 CH3 CH3
Cl2 moist
CH3 C CH2 CH3 C CH2Cl CH3 C CH2OH
Ag2O
Cl OHl
O
CH3
CH3 C CH
H
Dimethyl acetaldehyde
2) Ring expansion of cyclic ketone
O
HO CH3NO2 HO CH3NH2 N
HO CNH
EtONsa H NaNO2
HCl
CH3NO2
-H -N2
O
11

12. 3) Ketones from cyclic diols. Pinacol rearrangement has been employed to
produce ketone which are other wise very difficult to synthesize.
O
OH OH
1 Mg,ether H
O
2 H2O
cyclopentanone pinacol
4) highly branched oxo comp are very difficult to produce by other reaction
pinacol rearrangement has interesting application in synthesis.
O
H3O H
(CH3)2C.Cl.CHCl.CH3 (CH3)2C.OH.CHOH.CH3 (CH3)2C.OH.C CH3
Heat
12

13. BEKMANN REARRANGEMENT
The Beckmann rearrangement, named
after the German chemist ERNST OTTO
BECKMAN (1853–1923),
It is It is an acid catalyzed conversion of keto
oximes to N substituted amides usually called
the Bechmann rearrangement.
 reaction
R'
1.PCL5/ether O
C N
or H2SO4
R C NHR'
R 2.H2O
OH
13

14. OXIMES
oIn organic chemistry, compounds containing the grouping C = N-OH, derived
from aldehyde and Ketones by condensing them with hydroxylamine.
oTwo types of oximes are known:
Aldoxime: combination of aldehyde with hydroxylamine.
Ketoxime: Combination of Ketones with hydroxylamine.
RCHO + RHC=NOH
H
+ NH2OH
R2CO R2C=NOH
14

15. MECHANISM
Step1) Formation of a better leaving group
R R OH2
OH
H2SO4 C N
C N
R' R'
Step2) Ionization step
migration of anti group (w.r.t.leaving group) loss of leaving group
R
R OH2
OH2
C C R.D.step
N N R C N R'
R'
R'
R C N R' 15

16. Step3) Nucleophilic attach by water molecule to carbenium ion
O H
H OH2
H2O
R C N R' -H
C N R' C N R'
R R
O
R C NHR
16

17. STEREOCHEMISTRY
 Reaction is intramolecular.
Me OH OH
Me
c N + 1. H2SO4
c N MeCONHPh + MeCONHMe
2. H2O
Ph
Me
 In high polarity solvent rate of reaction is fast. Rate of
reaction also increase as stability of leaving
group(anion)increase.
CH3COO-< ClCH2COO<PhSO3-
17

18. oIt is found that the migrating group is always anti(i.e. tras)to the
hydroxy group.thus the reaction is steriospecific
Me
Me
H2N C
H2N C N
N
Cold
OH
NaOH
O
Br
(1) (3)
Me
OH
H2N C
No reaction
N NaOH
Br
(2)
E.g.the rearrangement of the two isomeric oximes of 2-bromo-5-
nitrophenyl isooxamines.
OH and Me gr.in isomer (1)are close enough for reaction ,and 18
anti(trans)to each other.

19.  Direct exchange of the leaving group and the migrating group do not
occure between N and C atom.
H218O
Ph2CNOH PhCONHP + PhC 18ONHPh
Bechmann
rearrangemen
Oxygen atom come from medium.
19

20. APPLICATION
 This reaction offers good method of preparing anilides.
Me 1.H2SO4
c N PhCONHMe
2. H20
Ph
OH
 Synthesis of isoquinoline
OH
H CH
C N
CH
CH CH P2O5
-H2O N
C
cinnamaldehyde oxime H
Isoquinoline
20

21. oConfigration of ketoxime can be assigned
. Steps
I. Conversion of oxime into n-substituted amides.
II. Hydrolysis of N- substituded amide.
III. Isolation and identification of the product.
O
Ph OH
1. PCl5/ether H3O
C N Ph.CNH C6H4CH3(P) PhCOOH +
2. H2O
P-CH3C6H4NH2
p-CH3C6H4
B-isomer
anti-p-tolyl phenyl ketoxime o
Ph
1. PCl5/ether H3O
C O C6H4CH3(P) CNHPh PhNH2
2. H2O
C6H4H3p- OH P-CH3C6H4COOH
C
A-iomer
anti-phenyl-p-tolyl ketoxime 21

22.  Synthesis of nylone-6,textile polymer
NH2OH 1. PCl5/ether
O
2. H2O
N
OH
O N
OH
heat base
O
NH(CH2)5.C NH
C (CH2)5
O
22

23. HEAK REACTIONS
oRichard Fred Heck (born August 15, 1931)is
an American chemist.
oHeck was jointly awarded the Nobel Prize.
owith the Japanese chemists Ei-chi-negishi
and akira suzuki for their work in palladium
catalysed coupling reaction in organic
synthesis.
23

24. Introduction:
 This is coupling reaction in which the R group in RPdX
(X=halied or acetate)replace hydrogen at the less hindered
carbon atom of an alkene.
 (R =aryl,alkenyl,alkyl group).
 The palladium(0) catalyst is then regenerated using a base in
the reductive elimination step
CR2 CH2 + RPdX R2C CH R'
Preparation of reagent:
ArPdI :treatment of an aryl iodide with palladium acetate
in presence of base.
RPdI :from iodine and P(OA)2 in presence of weak base
such as Bu3N.
24

25. MECHANISM
PdX
RPdX syn addition R
RPdX + R' R'
R" R"
R" R' H
Rotation
H
R" PdX
Syn elimination H
R R"
R' R R'
25

26. STERIOCHEMISTRY:
 The reaction are steriospecific.
CR2 CH4 + RPdX R2C CH R'
 occur by syn-addition of RPdX followed by syn-elimination of HPdX..
 there is inversion of configuration.
 ethylene is the most effective olefin.
 increasing substitution lowers the reactivity.
 thus substitution take place at the less highly substituted side of double
bond. The rate of coupling is strongly dependent on steric effect: for e.g.
in the reactivity sequence..
26

27. APPLICATION:
It has many applications in target oriented synthesis
 The Heck reaction has been used in more than 100 different
syntheses of natural products and biologically active compounds
 The first example is for the synthesis of Taxol®, where the Heck
reaction was employed for creating the eight-membered ring.
 In the other example an intramolecular Heck-type coupling provides
the morphine skeleton and the product is transformed to morphine in
a few steps
OH
SBD N
OH
H O
Heak reaction
Me N
Morphin
MeO I 27
OBn

28. OZONOLYSIS
Ozonolysis is the cleavage of an alkene
or alkyne with ozone to form organic
compounds in which the multiple carbon–
carbon bond has been replaced by a
double bond to oxygen.
O O
Zn + HOAc
C C CH CH C O C O
+ O3
O
+
Ozonolysis is the process by which ozone (O3) reacts with alkenes
(olefins) to break the double bond and form two carbonyl groups.
If the double bond of the alkenes is substituted with hydrogen or
carbon atoms, the carbonyl groups that are formed are either 28
aldehyde or Ketones.

29. Preparation:
Generally, ozone is generated from air or oxygen and passed through
a cold solution (from 0 to -78 °C) of solvent and substrate until a blue
color is observed, indicating destruction of the double bond.
OZONE
electric discharge
O2 or
O3
cosmic rays
29

30. OZONIDE AND MOLOZONIDE STRUCTURES
molozonide ozonide
forms initially forms after rearrangement 30

31. MECHANISM
R O O
R' R' R HO O R'
R H 2O
O +
R H H
O OH
R H R
HO O R'
HO R'
+ H2 O
H
OH
O
31

32. STEREOCHEMISTRY:
 alkynes are less reactive than alkene
 Olefins in which the double bond is connected to electron
donating group react many time faster than those in which it is
connected to electron withdrawing group.
 Ozonolysis of triple bond is less common and the reaction
proceeds less easily, since ozone is electrophilic agent.
 The benefits of ozonolysis:
 Ozone oxidation is very economical during organic synthesis
because it only uses air and electricity to convert olefins to
carbonyl compounds
Ozone oxidation is a very green technology because the only
by-product of the organic syntheses is oxygen. That means that
there aren’t any metal waste-streams to dispose of afterward.
32

33. APPLICATIONS:
 The safe use of ozone as an oxidant in organic synthesis is
becoming increasingly popular.
 Industrial-Scale Ozonolysis;
 It is used in preparation of
 a generic steroid on a multikilo scale.
 vitamin D analog. S)-Hydroxyvitamin D
 Oxandrolone is an anabolic steroid used to promote weight gain
following extensive surgery,
 Ceftibuten and Cefaclor
 Ceftibuten is a third-generation oral cephalosporin, hasexcellent
Gram-negative activity, and possesses a high degree of â-
lactamase stability
33

34. GRIGNARD REACTION
François Auguste Victor Grignard (May 6, 1871 in
Cherbourg - December 13, 1935 in Lyon) was a
Nobel Prize-winning French chemist.
 Introduction
 Formula RMgX.it is prepared by the reaction of
metallic magnesium with the appropriate
organic halide.(R=ALKYL/ARYL/ALKENYL)
halied in order of reactivity (I> Br> Cl>> F).
RX + Mg RMgX
Anhydrous ether
Grignard
reagent
34

35.  Organolithium compound:
 Less prone to unwanted side reaction. Lithium is more electropositive
than magnesium. Carbon lithium bond are more polar than carbon
magnesium bond. This are more reactive than Grignard reagent.
 halide.(R=ALKYL/ARYL/ALKENYL) halide in order of reactivity (I>
Br> Cl>> F).
RX + 2Li Anhydrous ether RLi +LiX
Grignard reagent
 WHY GRIGNARD SYNTHESIS IS SO IMPORTANT?
 because it unable us to take two organic molecules and convert them
in to bigger one.
35

36. Reaction:
C O + RMgX C OH + Mg(OH)X
R
Mechanism: Alcohol
36

37. STEREOCHEMISTRY
 the reaction of carbonyl group can establish a steriocenter.if the
reactant are symmetric ,equal amount of the two enantiomers are
formed,
O Me HO
1)MeMgI OH Me
+
2)H
Ph Et Ph Et Ph Et
1Parts 1 part
•If one of the reactant are asymmetric, there is a predominance of the
one of the two possible diastereomers
H Me H Me
H Me
Mr Mr
1)MeMgI +
Ph Ph
Ph CHO 2)H HO H 37
H OH
2 PART 1 PART

38. REACTIONS:
reactions are classified with reference to the type of compound
which is obtained.
 Hydrocarbons:
XMg R + CH3 X R CH3 + MgX2
Grignard reagent react with alkyl halides and related compounds in the
SN2manner.the reaction with saturated halide are slow and the yields poor ,but
allyl and benzyl halide(more reactive than alkyl halide)react Efficiently.
oAlcohol:
R' R' R'
H
XMg R + O R O MgX R OH
"R "R "R
Grignard reagent react at the carbonyl carbon of aldehyde and ketone to give
alcohols. 38

39.  Aldehyde:
The reaction of Grignard reagent with ethyl orto format gives an
acetal which is converted by mild acid hydrolysis into the
aldehyde
EtO EtO
OEt + RMgX OEt + RMgOEt + X
EtO EtO
oKetones:
Three methods are available
1)from nitriles.
R
RMgX + R C N O
R 39

40.  2)from N-substituted amides.
R R'
MgX + R"2NH
RMgX + O O+
N2"R R
 3)from acid chlorides
C6H11 Ph
1)PhCOCl
C6H11MgBr
2)H
O 40

41.  Reaction at element other than carbon:
 Grignard reagent may be used to attach various other element
to carbon. The following type of compound can be obtained.
1) hydro peroxide
O2 O MgX H
Me3C MgX Me3C O Mg3C CO2H
2) Thiols
RMgX + S R S MgX
41

42. 3) sulfinic acids
O OH
H
RMgX + SO2 R S MgX R S
O O
4)iodide.
RMgX + I I R I + MgXI
5)amines
RMgX + NH2 OCH3 R NH2 + MgX(OCH3)
42

43. Limitation:
 Solvent must be scrupulously dried and freed of the alcohol from
which it was very probably made.
 Grignard reagent will not even form in the presence of water.
Apparatus must be complelty dry before start. Protect reaction from
reaction from water vapors.
 Grignard reagent can not prepare from a compound (HOCH2CH2Br)
that contain addition halogen/some other group (-OH) that will react
with a Grignard reagent.
 In preparation of aryl magnesium halide substituent present on
benzene ring like –COOH.-OH,-NH2,-SO3H contain hydrogen attach
to O or N are so acidic that they decompose Grignard reagent .
43

44.  Protecting group (THP) tetrahydropyranyl:
 Used to prevent unwanted reaction. The unsaturated cyclic ether 2,3-
dihydro-4H-pyran (DHP)react with alcohol in presence of acid to give
alkyl tetrahydropyranyl ether.
 THPether resistant to base and many other reagent
 It is easily attached and easily removed.
44

45. DIAZOMETHANE
 Introduction
 Frmula:CH2N2
 USES: ethylating agent for
acids,alcohols,amines,carbines,aldehydes.
 Physical properties: diazomethane is yellow gas.(b.p.-23°c).it is
highly toxic and explosive. It explodes even iv gaseous state. It
decompose redially.
 Storage condition: it's ethereal solution may be stoared at 0°c for
about 24 hrs without appreciable decomposition. Diazomethane is a
resonance hybrid of the following canonical structures.
CH2 N NH CH3 N N CH2+ N N-
45

46. Various N-nitoso-N-alkyl amides
undergo elimination with a base to give
diazomethane. The most use full and
convenient general method foe the
preparation of diazomethane is the
treatment of N-nitoso-N-methyl amide
with alkali in ether
46

47.  Reaction:
O
Ether
R C N NO + NaOH CH2N2 + H2O + RCOONa
CH3
 Mechanism;
N O
N C CH3 CH3 N N O C CH3
O O
N-methyl-N-nitrosoacetamide Methanediazoaetate
H2
+ H C N N OCOCH3 CH2 N N + H2O + CH3COONa
47
Diazomethane

48. several N-nitoso-N-methyl compound have been used to prepare
diazomethane.
 1.from (N-nitoso-N-alkyl) terephtalimide.
NO NO
2NaOH
CH3 N C C N CH3 2CH2N2 + COONa COONa
O O
 2. from (N-nitoso-N-alkyl)-p-toluenesulphonamide.
CH3 Ethanlic
SO2 N CH3 CH3 SO2OK +
KOH
NO
CH2N2
 3.from (N-nitoso-N-alkyl)-N’-nitroguanidine with pottassium
hydroxide.
NH
KOH
CH3 N C NHNO2 CH2N2
Warm 48
NO

49. Safety:
oDiazomethane is toxic by inhalation or by contact with the
skin or eyes (TLV 0.2ppm). Symptoms include chest
discomfort, headache, weakness and, in severe cases,
collapse.
oLike any other alkylating agent it is expected to be
carcinogenic, but such concerns are overshadowed by its
serious acute toxicity.
oCH2N2 may explode in contact with sharp edges, such as
ground-glass joints, even scratches in glassware.
oGlassware should be inspected before use
The compound explodes when heated beyond 100 °C.
49

50.  Advantages:
 Used as a methylating agent for reasonably acidic
compounds.
 It provides method for the conversion of acids into their higher
homolog.
 it react rapidly even without catalyse.and the yield is high. The
reaction is clean since other product is nitrogen.
 It is the most use full and versatile reagent foe preparative
purpose.
 Process:
The reaction is carried out at about 0°c by adding ethereal
solution of diazomethane to the solution of the substrate in
ether till evolution of nitrogen ceases and yellow colour
persist.
50

51. Application:
 METHYLATION
 Carboxylic acids:
 it is methylating agent for acidic compound such as carboxylic
and mineral acids. Carboxylic acids can be converted to
esters .reactivity of reagent increases with acidity.
 Reaction is used where the acid is sensitive to higher
temperature.
CH2N2 CH2N2
RCOOH -N RCOOCH3 C6HOH C6H5OCH3
-N2
2
CH2N2
CH2 COOH CH2COOCH3
methyl 2-cyclopropylacetate 51
2-cyclopropylacetic acid

52.  Alcohols:
1) it produce a methyl ethers.
2) Alcohols do not react at all unless a catalyst such as HBF3
or silica gel is present.
3) Hydroxyl compound react better as their acidity increases.
4) it is used chiefly to methylate alcohol and phenol that are
expensive are available in small amount ,since the
conditions are mild and high yield are obtained.
52

53. CH2N2
R OH + BF3 R O BH3 R O CH3 + BF3 + N2
H
HBF4
CH3(CH2)CH2OH + CH2N2 CH3(CH2)6CH2OCH3 + N2
propan-1-ol 1-methoxyoctane
53

54.  carbenes:
 the reaction is non selective.carbene react with hydrocarbon by
insertion into carbon-hydrogen bond. not used in synthesis.
C H + CH2 C CH2 H
CH2N2
+
UV n-hexane
N-PENTANE
+
2-methyl pentane
3-methyl pentane
(E)
+ CH2N2
54
2-BUTENE
1,2-dimethyl cyclopropane

55.  Amines:
primary aliphatic amines gives mixture of primary,secondary,and
tertiary amines are obtained. The acidity of amines is less so
catalyst like BF3.
BF3
CR2N2 + R'2NH CHR2NR'2
 Aldehyde and ketone:
Converted in to the next higher analogue.
N N R
R O
CH2N2 -N2 R
R
R
R O R
55

56.  Acid chloride:
 It gives diazo ketone. If diazo ketone is heated in presence of silver
oxide, under go wolff rearrangement to give ketene.
 When this is carried out in presence of water or alcohol, the ketene
is directly converted into acid or ester.
R Cl R R
-H
CH2N2 N N N N
O O O
R R
C C O -N2
N N
H
O
R R COOH
C C O + H2O 56
H

57. REFERANCE
1) Kalsi p.s..organic reaction and their mechanism.2nd
edition, new age international publishers.509,634,635.
2) Stuart warren. Organic synthesis, the disconnection
approch.wily student edition.52,262,201,252,299.
3) Jerry march a.wiley.advance organic chemistry ,reaction
mechanism, and structure,4th edition a wiley interscience
publication.1072-1097.
4) Francis a. carey,richard j. sunberg.advanced organic
chemistry, a reaction and synthesis. Part B.5th
edition.springer publication.p.no.883-889,1091,715-723.
5) S.n.sanyal.reaction rearrangement and reagent.bharathi
bhawan publication and distrubutors.206-210,158-159
6) Sachin kr ghosh.organic chemistry a modern
approch.2nd.books and allied (p) ltd.702-706,715-710.
57

58. 58