rearrangement reaction

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

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Page 1: rearrangement reaction

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Prepared by:Ashwini.M.Londhe(F. Y. Mpharm)

Guided by:Dr.A.R.ChabukswarMAEER”S Maharashtra institute of pharmacy.

REARRANGEMENT REACTION

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CONTENT

1) Pinacol rearrangement2) Bechmann rearrangement3) Heck reaction4) Ozonolysis5) Grignard reaction6) Use of diazomethane

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PINACOL REARRANGEMENT

Pinacol are ditertiary 1,2-diols. the simplest member of this class is Me2C(OH).C(OH)Me2.

Wilhelm Rudolph Fittig (6 December 1835 – 19 November 1910) was a German chemist. Fittig discovered the pinacol coupling reaction.

R C

OH

R

C

OH

R

R

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when pinacol is treated with dilute moderately conc. H2SO4 a rearrangement reaction takes place which leads to the formation of Me3C.CO.Me(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.

CH3 C

OH

CH3

C

OH

CH3

CH3

HCH3 C

CH3

CH3

CH3C

O

Pinacol Pinacolone

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Mechanisms:

R C

OH

R

C

OH

R

R

H

R C

OH2

R

RC

R

OH

C C

R

R

R

R

OH

C C

R

R

R

R

OH

C C

R

R

R

ROH

Bridged intermediate

Step1: reversible protonation to a hydroxyl group and elimination of water molecule

Step2: formation of non-classical carbenium ion ,a bridged intermediate.

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R3C C

R

O H

R3C C

R

O

+ H

C C

R

R

R

ROH

Bridged intermediate

R C

OH

R

C

R

OH

R3C C

R

O H

Step3:actual migration of a group to form the classical carbenium ion.

Step4: The loss of proton and the formation of oxo compound.

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STEREOCHEMISTRY:

Reaction is intra molecular. When different group are present on C atom bearing the hydroxyl

groups ,two question arise.

C C

HO

Ph Me

OH

MePh

2-methyl-1,1-diphenylpropane

1. Which of the two OH group will be protonated.

2. Which of the group will migrate?

1. Which of the two OH

group will be Protonated?

2. Which of the group will migrate?

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Stability order of the carbenium ions. Decreasing stability order of carbenium ion is

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.

Ph2CH > Ph CMe > PhCH >(CH3)2C .CH3CH

Answer of Q1

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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.

Answer of Q2

C C

HO

Ph Me

OH

MePhH2SO4

C C

Ph

Ph Me

O

Me

2-methyl-1,1-diphenylpropane-1,2-diol

Page 10: rearrangement reaction

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.

oGenerally Aldehyde formation is favored by use of mild condition (lower temp,weker acid)oUnder more drastic condition aldehyde may be converted to ketone.

Me C

O

CPh2

Me

cold

H2SO4

Ph2C CMe

OH OH

CH3COOH

a trace of H2SO4

Ph C

O

CMe2

Ph

ketone B compound Acompound C

10

Do the reaction conditions (i.e. type of acid, concentration, solvent and temperature) influence the course of rearrangement?

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Application:

1) synthesis of carbonyl compounds from alkenes.

2) Ring expansion of cyclic ketone

CH3 C CH2

CH3

Cl2CH3 C

CH3

CH2Cl

Cl

moist

Ag2OCH3 C

CH3

CH2OH

OHl

CH3 CH

CH3

CH

O

Dimethyl acetaldehyde

O

EtONsa

CH3NO2

HO CH3NO2

H

HO CH3NH2

NaNO2

HCl

HO CNH N

-N2-H

O

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3) Ketones from cyclic diols. Pinacol rearrangement has been employed to produce ketone which are other wise very difficult to synthesize.

4) highly branched oxo comp are very difficult to produce by other reaction pinacol rearrangement has interesting application in synthesis.

O

1 Mg,ether

2 H2O

OH OH

cyclopentanone pinacol

H

O

H3O

Heat(CH3)2C.Cl.CHCl.CH3 (CH3)2C.OH.CHOH.CH3

H (CH3)2C.OH.C

O

CH3

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BEKMANN REARRANGEMENT

It is

reaction

C

OH

R'

R

1.PCL5/ether

or H2SO4

2.H2OR C

O

NHR'

N

The Beckmann rearrangement, named after the German chemist ERNST OTTO BECKMAN (1853–1923),

It is an acid catalyzed conversion of keto oximes to N substituted amides usually called the Bechmann rearrangement.

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R2CO

NH2OH

R2C=NOH

H+RCHO RHC=NOH

+

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.

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MECHANISM

Step1) Formation of a better leaving group

Step2) Ionization step

migration of anti group (w.r.t.leaving group) loss of leaving group

C

R

R'

N

OHH2SO4 C

R

R'

N

OH2

C

R

R'

N

OH2

C

R

N

OH2

R'

R.D.stepR C N R'

R C N R'

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Step3) Nucleophilic attach by water molecule to carbenium ion

R C N R'H2O

C N R'

OH2H

R

-HC N R'

R

O H

R C

O

NHR

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STEREOCHEMISTRY

Reaction is intramolecular.

In high polarity solvent rate of reaction is fast. Rate of reaction also increase as stability of leaving group(anion)increase.

CH3COO-< ClCH2COO<PhSO3-

Me

Ph

c N +Me

Me

c N

OH1. H2SO4

2. H2OMeCONHPh + MeCONHMe

OH

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E.g.the rearrangement of the two isomeric oximes of 2-bromo-5-nitrophenyl isooxamines.

H2N

Br

C

Me

N

OHCold

NaOH

H2N

O

C

Me

N

(1) (3)

H2N

Br

C

Me

(2)

N

OH

NaOH

No reaction

OH and Me gr.in isomer (1)are close enough for reaction ,and anti(trans)to each other.

oIt is found that the migrating group is always anti(i.e. tras)to the hydroxy group.thus the reaction is steriospecific

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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.

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APPLICATION

This reaction offers good method of preparing anilides.

Synthesis of isoquinoline

CH CH

C NH

OH

cinnamaldehyde oxime

P2O5

-H2O

CH

CH

N

CH

Isoquinoline

Me

Ph

c N

OH

1.H2SO4

2. H20

PhCONHMe

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Ph

p-CH3C6H4

C N

OH1. PCl5/ether

2. H2OPh.CNH

O

C6H4CH3(P)H3O

PhCOOH +

P-CH3C6H4NH2

B-isomeranti-p-tolyl phenyl ketoxime

Ph

C6H4H3p-C

C1. PCl5/ether

2. H2O

H3O

P-CH3C6H4COOH

O

OH

C6H4CH3(P) CNHPh

o

PhNH2

A-iomer

anti-phenyl-p-tolyl ketoxime

oConfigration of ketoxime can be assigned

. StepsI. Conversion of oxime into n-substituted amides.II. Hydrolysis of N- substituded amide.III. Isolation and identification of the product.

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Synthesis of nylone-6,textile polymer

O

NH2OH

N

OH

1. PCl5/ether

2. H2ON

OH

O

NH(CH2)5.C

O

NH

(CH2)5C

O

heat base

22

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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.

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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

CH2 + RPdX R2C CH R'CR2

Preparation of reagent:

:treatment of an aryl iodide with palladium acetate in presence of base.

:from iodine and P(OA)2 in presence of weak base such as Bu3N.

ArPdI

RPdI

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MECHANISM

RPdX + R'

R"

R'

R"

RPdX syn additionPdX

R"

R

HR'

Rotation

PdX

R"

H

R'R

Syn elimination

R

R'

R"H

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STERIOCHEMISTRY: The reaction are steriospecific.

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..

CH4 + RPdX R2C CH R'CR2

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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

N

H

SBD

MeO

OBn

I

Heak reaction

NMe

O

OH

OH

Morphin

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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.

OZONOLYSIS

C C + O3

O

CHZn + HOAc

C O

+

OC

O

CH

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 aldehyde or Ketones.

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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.

O2 O3

electric discharge

orcosmic rays

OZONE

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OZONIDE AND MOLOZONIDE STRUCTURES

ozonide

forms initially forms after rearrangement

molozonide

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MECHANISM

R

R

R'

H

R

R

O

O

OR'

H

H2OO

R

R

+

OH

O R'

H

HO

OH

O R'

H

HO

O

R'HO

+ H2O

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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.  

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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

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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).

Anhydrous etherRX + Mg

RMgX

Grignard

reagent

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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 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.

Anhydrous ether

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Mechanism:

RMgXC O + C

R

OH + Mg(OH)X

Alcohol

Reaction:

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STEREOCHEMISTRY

the reaction of carbonyl group can establish a steriocenter.if the reactant are symmetric ,equal amount of the two enantiomers are formed,

Ph Et

O 1)MeMgI

2)HPh Et

OHMe

1Parts

+

Ph Et

MeHO

1 part

•If one of the reactant are asymmetric, there is a predominance of the one of the two possible diastereomers

Ph CHO

MeH

1)MeMgI

2)HPh

H Me

Mr

HHO

+Ph

H Me

Mr

OHH

2 PART 1 PART

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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:

Grignard reagent react at the carbonyl carbon of aldehyde and ketone to give alcohols.

XMg R + O

R'

"R

R'

"R

R O MgXH

R'

"R

R OH

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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 + RMgXEtO

EtO

OEt + RMgOEt + X

oKetones: Three methods are available1)from nitriles.

RMgX + R C NR

R

O

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2)from N-substituted amides.

3)from acid chlorides

RMgX + O

R

N2"R

O

R'

R

+ MgX + R"2NH

C6H11MgBr1)PhCOCl

2)HO

PhC6H11

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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

2) Thiols

Me3C MgX

O2

Me3CO

OMgX H

Mg3C CO2H

RMgX + S R S MgX

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4)iodide.

5)amines

RMgX + I I R I + MgXI

RMgX + NH2 OCH3 R NH2 + MgX(OCH3)

3) sulfinic acids

RMgX + SO2 R S

O

O

MgXH

R S

OH

O

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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 .

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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.

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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.

DIAZOMETHANE

CH2 N NH CH3 N N CH2+ N N-

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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

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Reaction:

Mechanism;

R C

O

N

CH3

NO + NaOHEther

CH2N2+ H2O + RCOONa

N

N O

C

O

CH3CH3 N N O

N-methyl-N-nitrosoacetamide

C CH3

OMethanediazoaetate

+ HH2C N N OCOCH3 CH2 N N

Diazomethane+ H2O + CH3COONa

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several N-nitoso-N-methyl compound have been used to prepare diazomethane.

1.from (N-nitoso-N-alkyl) terephtalimide.

2. from (N-nitoso-N-alkyl)-p-toluenesulphonamide.

3.from (N-nitoso-N-alkyl)-N’-nitroguanidine with pottassium hydroxide.

CH3 N

NO

C

O

C N

NO

CH3

2NaOH2CH2N2 + COONaCOONa

O

CH3 SO2 N

NO

CH3

Ethanlic

KOHCH3 SO2OK +

CH2N2

CH3 N C

NO

NH

NHNO2

KOH

WarmCH2N2

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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.

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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.

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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.

RCOOHCH2N2

-N2RCOOCH3 C6HOH

CH2N2

-N2C6H5OCH3

CH2 COOH

2-cyclopropylacetic acid

CH2N2CH2COOCH3

methyl 2-cyclopropylacetate

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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.

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R OH + BF3 R O

H

BH3

CH2N2R O CH3 + BF3 + N2

CH3(CH2)CH2OH + CH2N2

HBF4CH3(CH2)6CH2OCH3

1-methoxyoctanepropan-1-ol

+ N2

Page 54: rearrangement reaction

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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

N-PENTANE

n-hexane

2-methyl pentane

3-methyl pentane

CH2N2

UV+

+

(E)

2-BUTENE

+ CH2N2

1,2-dimethyl cyclopropane

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Amines:

primary aliphatic amines gives mixture of primary,secondary,and tertiary amines are obtained. The acidity of amines is less so catalyst like BF3.

Aldehyde and ketone:

Converted in to the next higher analogue.

CR2N2 + R'2NHBF3

CHR2NR'2

R

R O

CH2N2R

O

R

N N-N2

R

R

R

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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

O

CH2N2

R

O

N N-H

R

O

N N

R

O

N N-N2

RC

HC O

RC

HC O + H2O R COOH

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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.

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