Basic Concepts Of Retrosynthesis (Part1)

RETROSYNTHETIC APPROCH TO ORGANIC SYNTHESIS Prof. Dr. Shaikh S. Nizami Department of Chemistry University of Karachi

CONTENTS Definition of synthesis Importance of synthesis Polarity of bonds Arrow notations Basic concepts of Retrosynthesis

DEFINATION The preparation of a desired organic compound from a readily available starting material is known as organic synthesis [Synthesis---- singular] [Syntheses--- plural]

DESIRED ORGANIC COMPOUND The compound we wish to prepare It is called Target Molecule Desired Organic Compound is denoted by TM

STARTING MATERIAL Readily available Commercial Inexpensive contains five carbon atoms or less apart from aromatic ring

OBJECTIVE To get a pure sample of the desired organic compound To avoid the reactions that will produce a mixture of products

PURE COMPOUND To study Physical properties Chemical properties Pharmacological properties

Reasons for synthesizing Organic Compound 1. Proof of structure of a natural compound 2. To prepare compounds that are useful to mankind e.g. pharmaceutical, polymers, dyes etc.

Reasons for synthesizing Organic Compound 3. To prepare specific compounds to study reaction mechanisms or biological metabolism e.g. labelled compounds 4. For the intellectual challenges – new problems demand new solutions and can lead to the development of NEW CHEMISTRY, reagents, etc .

BOND POLARITY (Polar covalent bond) Most heteroatom are more electronegative than carbon i.e. O, N, Br, Cl, Partial positive charge appears on carbon (  +)

BOND POLARITY (Polar covalent bond) Si, Mg,Li are electropositive compared with the carbon The polarity in these case is reversed partial negative charge appears on carbon (  -)

ARROW NOTATION Simple reaction arrow “ reacts to give” Delocalisation arrow “ two different ways to draw the same delocalised structures” Equilibrium arrow Curved arrow “ two structures are interconverting” “ motion of two electrons” Fish-hook arrow “ motion of one electron” Retrosynthesis arrow “ could be made from”

RETROSYNTHESIS It is reverse of the synthetic steps We have a reliable reaction in mind

RETROSYNTHETIC ANALYSIS 1. The process of WORKING BACKWARD from the TM in order to devise suitable synthetic route 2. Retrosynthetic Analysis can be done by two methods a) Disconnection b) Functional Group Interconversion

DISCONNECTION 1.A paper operation involving an imagined cleavage of a bond. 2.As a result of disconnection usually negative ion and positive ion are formed which are called ‘ SYNTHONS ’ 3.Disconnection is shown by a wavy line like ~ or VVVVVVVV

FUNCTIONAL GROUP INTERCONVERSION ( FGI ) The process of writing one functional group for another to help synthetic planning is known as FGI

FUNCTIONAL GROUP INTERCONVERSION ( FGI ) FGI can be done by ADDITION SUBSTITUTION ELIMINATION OXIDATION / REDUCTION FREE RADICAL REACTION

SYNTHONS These are idealized fragments Synthons are shown by a + or – sign like anion or cation (Not real anion or cation) May or may not be intermediate in the corresponding reactions

SYNTHETIC EQUIVALENT The actual compound used to function as synthon Denoted by a triple line  Known as REAGENT

Retrosynthetic analysis, Synthons & Synthetic equivalents R — R  ……………………………………………………………………… R + + R - R - + R +     TM RBr, RI, ROMe, ROTs RMgBr, RLi, LiCuR 2 Synthons Synthetic equivalents

DESIGNING A SYNTHESIS Recognize the functional groups in the target molecule Disconnect by methods corresponding to known and reliable reactions Repeat as necessary to reach available starting material

SYNTHESIS Write out the plan according to the analysis, adding reagents and conditions Modify the plan according to unexpected failure in the laboratory

RETOSYNTHETIC ANALYSIS Hawthorn perfume

EFFECTIVE SYNTHESIS An understanding of reaction mechanism A working knowledge of reliable reactions

EFFECTIVE SYNTHESIS An appreciation that some compounds are available An understanding of stereochemistry

1 st RETROSYNTHETIC ANALYSIS CH 3 CH 2 OH

2 nd RETROSYNTHETIC ANALYSIS CH 3 CH 2 OH & SYNTHESIS

3 rd RETROSYNTHETIC ANALYSIS CH 3 CH 2 OH & SYNTHESIS

4 th RETROSYNTHETIC ANALYSIS CH 3 CH 2 OH & SYNTHESIS

Basic Concepts Of Retrosynthesis (Part1)

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Basic Concepts Of Retrosynthesis (Part1)