This document discusses the synthon approach to retrosynthetic analysis in organic synthesis. It defines key terms like disconnection, synthon, and functional group interconversion. The document outlines basic rules for disconnection, such as generating stable fragments and minimizing the number of fragments. It provides guidelines for good retrosynthesis and discusses the use of synthons in the multi-step synthesis of benzocaine from toluene as an example.

1. By
Mr. Dhiraj S. Bhagwat
B.Pharm
University Department of Pharmaceutical Sciences,
R.T.M. Nagpur University, Nagpur-440033
2017-2018
Synthon Approach
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2. Contents
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1. Introduction
2. Definition of terms
a. Disconnection
b. Synthon
c. Functional Group Interconversion
3. Basic rule in disconnecion
4. Use of synthon approach in synthesis of some medical or organic synthesis
5. References

3. 1. Introduction
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• Synthon term was coined by Prof. E.J.Corey in mid 1960’s
• Elegant and more systematic approach
• Depends on perception of structural feature in the reaction product and manipulation of
structures in the reverse synthetic sense.
• Designate ‘structural units within a molecule which are related to possible synthetic
operations’.
• Helps in eliminations of low probability variants.

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Target
Molecule
Disconnected
Precursors
Process called Analysis
• This process of analysis produces simple starting material and shows different pathway.
• From this precursor the cheap starting material has been selected for the synthesis of the
target molecule or desired molecule.

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• Synthon can be divided in to following two types –
They are derived from a reagents with functional groups
1. Donor Synthon eg. - C2H5
- is ethyl donor synthon from - C2H5Li
2. Acceptor Synthon eg. - C2H5
+ is ethyl acceptor synthon from - C2H5I

6. 2. Definition of Terms
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a. Disconnection :
It is an imaginary process in which the bonds are broken to get simple possible starting
materials. This is also called as "transform". A curred line is used at the point of
disconnection of bond and a double line arrow (=>) is used for representing
disconnection.
b. Synthon :
It is an idealized fragment obtained by disconnection and may or may not be
involved in the reaction but helps us to work out reagents to be used.
Example – R X => R+ + X- (Synthon)

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Chemical bond can be cleaved :

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a. Functional Group Identification :
It is the operation of changing one functional group to another either by interconversion,
substitution, elimination, oxidation or reduction, so that the disconnection becomes easier.
Example :
NO2
NH2 FGI
CH3 COOH CH3 CN
FGI

9. 3. Basic Rules In Disconnection
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• When one thinks of retrosynthetic analysis of a target molecule, it is a question ‘where
the disconnection is to be done?’. This is generally governed by certain rules :
Rule -1
Disconnection of a bond should be done in such a way that it produces stable fragments.
While carrying out a disconnection the molecule is broken down by one bond at a time.
e.g.
R
O2N
C NO2
- + C R+

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Rule -2
The number of fragments generated by disconnection should be as small as possible. So,
the synthesis of target molecule can be carried out in possible steps.
e.g.
O O O O
+

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Rule -3
A bond joining a carbon to a hetero atom always broken with the electron pair on hetero
atom. e.g
Rule -3
Sometimes a disconnection carried out does not generate sufficient stabilised fragments,
but such fragments can be obtained by using FGI or by introducing an additional electron
withdrawing group and then removing it after synthesis.
C N C
+
+ N
-

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Guidelines For Disconnection :
(i) Make the analysis in such a way that the synthesis become as short as possible.
(ii) Use the only disconnections corresponding to known reliable reaction.
(iii) Disconnect C-X bonds especially two group disconnections.
(iv) Choose the disconnection corresponding to the highest yielding reaction, if known.
(v) Disconnect back to recognisable starting materials or to compounds which can be
easily be made.
(vi) Disconnect C-C bonds according to the functional groups in the molecule , if possible
- disconnect at the middle of the molecule.

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Guidelines For Good Synthesis :
In retrosynthetic approach, there are usually more than one way to synthesize a
compound. But the selection of a best desirable route is important. Thereafter the
following factors are considered in order to decide which one of the routes is safe and
simple to employ.
(i) Availability of starting material.
(ii) Which route involves the least number of separation operations ?
(iii) Which route gives the highest overall yield ?
(iv) How expensive are the starting materials and reagents ?
(v) Which route includes least time and effort ?

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Retrosynthetic pathway : Benzocaine from toluene
4. Use of Synthon In Synthesis of Some Medical or Organic
OEth
O
NH2
C-O
NH2
OH
O
FGI
O2N
OH
O
O2N
Me
C-NMe
Benzocaine :
• Toluene is readily available starting material
• Me is activating and ortho-/para- directing
• We know reagents for the synthon NO2

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Me H2SO4
HNO3
CH3
O2N
KMnO4
Oxidation O2N
OH
O
H2Pd/C
Oxidation
H2N
OH
O
EtOH/H
+
H2N
OEt
O
Synthesis :

16. 1. Inamdar NN. A companion to Medicinal Chemistry. 1st ed. Career publication 2012. p. 408-422.
2. Algarsamy V. Textbook of Medicinal Chemistry. Vol. 2. 1st ed. Elsevier Health Sciences,
2012. p. 88-129
3. Lemke TL, Williams DA, Roche VF, Zito WS. Foye’s Principles of Medicinal Chemistry 6th ed.
Lippincott Williams and Wilkins. 2010. p. 504
4. J.March “Advance organic chemistry” 3rd edition, Wiley New York P-184 (1985).
5. E.J. Corey, J.Am.Soc. 98, 189, (1976).
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5. References

17. THANK YOU
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