RETROSYNTHETIC RETROSYNTHETIC APPROCHAPPROCH

TOTOORGANIC SYNTHESISORGANIC SYNTHESIS

Dr. Shaikh S. NizamiDr. Shaikh S. NizamiDepartment of ChemistryDepartment of ChemistryUniversity of KarachiUniversity of Karachi

RETROSYNTHESIS RETROSYNTHESIS

OFOF

AROMATIC AROMATIC

COMPOUNDSCOMPOUNDS

CONTENTSCONTENTS

1.Aromatic Eletrophilic Substitution Reactions

2.Aromatic Nucleophilic Substitution Reactions

Retrosynthesis of Aromatic Retrosynthesis of Aromatic Electrophilic Substitution Electrophilic Substitution

ReactionsReactions

TM

C X

SYNTHON REAGENT

R

_

+X

+

R

H

?R

X

Addition of cationic synthons to the aromatic ring

Reagents forReagents for Aromatic Aromatic Electrophilic SubstitutionElectrophilic Substitution

REAGENT REACTION

R+

RBr + AlCl3 Friedel-Crafts Alkylation

+ROH H+

+ H+Alkene

RCO+

+RCOCl AlCl3 Friedel-Crafts Acylation

SYNTHON

Reagents forReagents for Aromatic Aromatic Electrophilic SubstitutionElectrophilic Substitution

REAGENT REACTIONNO2

+

Cl2 FeCl3+

HNO3 H2SO4+ NitrationCl

+Chlorination

Br+ Br2 Fe+ Bromination

H2SO4 Sulphonation+SO2Cl

+SO2OH

ClSO2OH Chloro-Sulphonation

ArN2+

ArN2+Cl

-Diazocoupling

SYNTHON

Friedel-CraftsFriedel-Crafts AlkylationAlkylation

TM'BHT' butyled hydroxytoluenean antioxidant used in foodF.C. alkylation useful reactionfor tertiary halides

OH

Retrosynthesis of BHT & Retrosynthesis of BHT & SynthesisSynthesis

TM

C C

FriedelCrafts

_

OH

HH

+ +

Synthesis OH

+ H+

ort BuCl/AlCl3

TM

OH

Friedel-Crafts AcylationFriedel-Crafts Acylation

TM

C C

FriedelCrafts

_ + Cl

Rearrangement is possible in primary alkylhalide

Friedel-Crafts AcylationFriedel-Crafts Acylation

Cl

AlCl3

+

COCl

AlCl3

O

Zn,Hg

HCl(conc.)TM

One-carbon electrophile One-carbon electrophile for aromatic synthesisfor aromatic synthesis

TM

R

H

+ X+

REAGENT REACTION+CH2Cl CH2O/HCl/ZnCl2 Chloromethylation

+CHO CHCl3/

-OH Reimer-Tieman

Me2NCHO/POCl3VilsmeierHaak

-

R

X

SYNTHON

Retrosynthesis of Piperonol Retrosynthesis of Piperonol (perfumery compound) & (perfumery compound) &

SynthesisSynthesis

FGI

OO

CH2Cl

C-C

chloro-methylation

OO

H

Synthesis

OO

CH2O/ZnCl2HCl

OO

CH2Cl

Oxidation

hexamine

TM

TM

CHO

OO

AROMATIC SIDE CHAINS BY AROMATIC SIDE CHAINS BY Function Group Function Group InterconversionInterconversion

Y

R R

X

Y X Reagent

Reduction

-NO2

-NH2

H2, Pd, CSn,

conc.HCl-COR -CH(OH)R NaBH4

-COR -CH2R

Zn/Hg/conc.HCl

AROMATIC SIDE CHAINS BY AROMATIC SIDE CHAINS BY Functional Group Functional Group InterconversionInterconversion

Y

R R

X

OxidationY X Reagent

-CH2Cl -CHO hexamine-CH2R -CO2H KMnO4

-CH3

-COR-OCOR R’CO3H

Aromatic Side Chains by Aromatic Side Chains by Functional Group Functional Group InterconversionInterconversion

Y

R R

X

SubstitutionY X Reagent

-CH3

-CCl3 Cl2,PCl

5-CCl3

-CF3 SbF5-CN -COOH HO-, H2O

Nucleophilic Aromatic Nucleophilic Aromatic Substitution ReactionsSubstitution Reactions

Addition of an oxygen atomto an aromatic ring

Add anionic reagents RO- to an Aromatic compound with a leaving Group.

Nucleophilic Aromatic Nucleophilic Aromatic SubstitutionSubstitution

•Nucleophilic aromatic substitution works best when the leaving groups is N2 (diazonium salts)

•The synthetic sequence is nitration, reduction,diazotisationand substitution

Nucleophilic Aromatic Nucleophilic Aromatic SubstitutionSubstitution

RHNO3

H2SO4R

NO2 H2

Pd,C

R

NH2NaNO2

HCl, 5oCR

N2+

H2O

R

OH

Retrosynthesis of PhenolRetrosynthesis of Phenol

OH

BrMe

TM

subst.

via N2+

NH2

BrMe

C Br

bromination

NH2

Me

FGINO2

Me

C N

NitrationMe

SynthesisSynthesis

Me

HNO3

H2SO4

NO2

Me

Sn/H+

NH2

Me

HOAcNHAc

Me

Br2

NaOH

NH2

BrMe

NaNO2/HCl

H2OTM

Aromatic compounds made by Aromatic compounds made by nucleophilic displacement of nucleophilic displacement of

daizonium saltsdaizonium saltsArNH2

NaNO2

HClArN2

+ Z-

ArZ

Reagent_____ HO H2ORO ROHCN Cu(I)CNBr/Cl Cu(I)Br/Cu(I)ClI KIH H3PO2 or EtOH/H+

____Z_____

Retrosynthetic analysis & Retrosynthetic analysis & synthesissynthesis

Me

CNSubst.

Me

NH2

FGI

Me

NO2

Me

SYNTHESISSYNTHESIS

MeHNO3

H2SO4

Me

NO2

H2

Pd,c

Me

NH2

NaNO2,HClCu(I)CN

TM

NUCLEOPHILIC NUCLEOPHILIC SUBSTITUTION OF SUBSTITUTION OF

HALIDESHALIDESDirect displacement of halide from anaromatic ring is possible only if :

There are ortho and para nitro groupsOR

Similar electron-withdrawing groups

NUCLEOPHILIC NUCLEOPHILIC SUBSTITUTION OF SUBSTITUTION OF

HALIDESHALIDESCl

HNO3H2SO

4

Cl

NO2

NO2Nu-

Nu

NO2

NO2

Retrosynthetic analysisRetrosynthetic analysisTrifluralin B- a herbicideTrifluralin B- a herbicide

NC3H7

CF3

NO2O2N

Cl

CF3

NO2O2N

Cl

CF3

SYNTHESISSYNTHESIS

Cl

CF3

HNO3

H2SO

4

Cl

CF3

NO2O2N base

N-Pr2NH

TM