RETROSYNTHETIC RETROSYNTHETIC APPROCH APPROCH

TOTOORGANIC SYNTHESISORGANIC SYNTHESIS

FUNCTIONAL GROUPFUNCTIONAL GROUPINTERCONVERSIONINTERCONVERSION

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

FUNCTIONAL FUNCTIONAL GROUPS GROUPS

INTERCONVERSIONINTERCONVERSIONSS

CONTENTSCONTENTS

Definition of Functional Group Interconversion (FGIs)

Importance of FGIs Functional group containing

heteroatoms Unsaturated hydrocarbons Removal of Functional Groups

Definition of Functional Group InterconversionThe process of writing The process of writing one functional group one functional group for another to help for another to help synthetic planning is synthetic planning is known as known as FGIFGI

Definition of Functional Group Interconversion FGI can be done by Substitution Addition Elimination Oxidation Reduction

Why FGI is needed?

A A TMTM containing more than containing more than one functional group, one one functional group, one functional group may functional group may interfere with desired interfere with desired reaction on second reaction on second functional group during a functional group during a synthesis.synthesis.

Why FGI is needed?

This problem can be solved This problem can be solved into waysinto ways

a) Use of protecting groupa) Use of protecting group b) Change in synthetic b) Change in synthetic

strategy (using FGI) strategy (using FGI)

Importance of FGIs

It helps in identifying It helps in identifying suitable disconnection.suitable disconnection.

Consider the synthesis of Consider the synthesis of ketone containing a double ketone containing a double bond.bond.

Alkenes may be prepared Alkenes may be prepared by the dehydration of by the dehydration of alcohol.alcohol.

Importance of FGIs

Ph Ph

O

TM

First step in the retrosynthetic analysis of TM could be functional group interconversion to an alcohol

But which alcohol ?

Importance of FGIs

Ph Ph

O

FGI

i

FGI

ii

Ph Ph

O OH

Ph

OH

Ph

OTM

RETROSYNTESISRETROSYNTESIS

Ph Ph

OFGI

Ph Ph

O OH

_

O

Ph

+

+Ph

OH

Ph

O

H Ph

O

TMMatched Latent Polarity(Consonant)

i

RETROSYNTESISRETROSYNTESIS

Ph Ph

OFGI

iiPh

OH

Ph

O

Mismatched Latent Polarity(Dissonant)

Functional group containing

heteroatomsFor convenience these For convenience these

functional groups will be functional groups will be initially divided into initially divided into three major classes three major classes depending upon their depending upon their oxidation leveloxidation level

a) Carboxylic acid and a) Carboxylic acid and their derivativestheir derivatives

Compounds in this class are the Compounds in this class are the highest oxidation level of organic highest oxidation level of organic compoundscompounds

It includes It includes Carboxylic acid (RCOCarboxylic acid (RCO22H)H)

Esters/lactone (RCOOEsters/lactone (RCOO22R)R) Amide/lactam (RCONHR)Amide/lactam (RCONHR) They may be interconverted by a They may be interconverted by a

series of simple reactionsseries of simple reactions

Transformations of Transformations of carboxylic acid carboxylic acid

derivativesderivatives

R OH

O

R Cl

O

SOCl2

or PCl5

H2O

R NH2

ONH3

R OR'

ORO-

H2OH2O

H+/R’OH

R C NH2O

R O

O

R'

O

b) Aldehydes, ketones b) Aldehydes, ketones and their derivativesand their derivatives

Functional groups in this Functional groups in this class are at lower oxidation class are at lower oxidation level than class (a)level than class (a)

It includes the features It includes the features C=X in which the carbon C=X in which the carbon atom is bonded directly to atom is bonded directly to either hydrogen or carbon.either hydrogen or carbon.

b) Aldehydes, ketones b) Aldehydes, ketones and their derivativesand their derivatives

The group includesThe group includes Aldehydes (RHC=O)Aldehydes (RHC=O) Ketones (RR’C=O)Ketones (RR’C=O) Imines (RR’C=NR”)Imines (RR’C=NR”) Hydrazones (RR’C=NNHR”)Hydrazones (RR’C=NNHR”) Oximes (RR’C=NOH)Oximes (RR’C=NOH)

Transformations of Transformations of aldehydes aldehydes

R H

O

R H

NR'

aldehyde

R’NH2

R’=alkyl, aryl,(imine)R’=NMe2 (hydrazones)R’=OH (oxime)

H2O

H H

SS

HS(CH2)3SH/H+R H

OR'R'O2R’OH/H+

c) Alcohols and their c) Alcohols and their derivativesderivatives

Apart from Alcohols (ROH) Apart from Alcohols (ROH) themselves, this class themselves, this class includesincludes

Amines (RNH2)Amines (RNH2) Thiols (RSH)Thiols (RSH) Disulphides (RSSR)Disulphides (RSSR) Ethers (ROR) Ethers (ROR) Alkyl halides (RX)Alkyl halides (RX)

Interconversions of Interconversions of alcohols and halidesalcohols and halides

R OH R Cl

SOCl2 orPCl5

HO-R Br

HBr

HO-

Use of a sulphonic esterUse of a sulphonic esteras a leaving groupas a leaving group

R OH R OSO2R'R’SO2Cl

Nu-

R Nu + R’SO3-

Interconversions Interconversions between the three between the three oxidation levels oxidation levels a,b & c above a,b & c above To move between groups To move between groups

classified in the previous classified in the previous section, it is necessary to section, it is necessary to perform a perform a reductionreduction or or oxidationoxidation at some stage. at some stage.

OxidationOxidation

Many methods have been Many methods have been developed for the oxidation developed for the oxidation of organic compounds.of organic compounds.

It is possible to transform a It is possible to transform a low oxidation level FG into low oxidation level FG into any group of higher level.any group of higher level.

OxidationOxidation

R OHR H

OPrimary alcohol

PCCor PDC R OH

OCrO3 /H+

Secondary alcohol

R R

OH

R R

OPCC or PDC

PCC= pyridinium chlorochromatePDC= pyridinium dichromate

ReductionReduction

Esters

R OR'

OR OH

LiAlH4

+ R’OH

Amides

R NH2

O

R NH2

LiAlH4

Nitriles

R CNR NH2LiAlH4

R H

O1 eq.DIBAL-H

Low temp.

Unsaturated Hydrocarbons

Br

HO OH

CHO

CHO

OH

O HH

H2,Pd/C

OsO4

O3

HBrRCO3H

BH3,NaOH/H2O2

Removal of Functional Removal of Functional GroupGroup

Alcohol to corresponding hydrocarbon

Alcohol

Dehydration

Alkene

Alkane

Hydrogenation

Removal of Functional Removal of Functional GroupGroup

R R'(H)

O

R R'(H)

H H

Clemmensen

Wolf-Kishner

Zn,HCl

NH2NH2,KOH

Aldehydes/ ketones to hydrocarbons