synthon approach

introduction, disconnection, basic rules in disconnection, functional group disconnection

1. By Vinay.R I M.PHARM. DEPT. OF PHARMACHEMISTRY SJMCP, CHITRADURGA 1 SYNTHON APPROACH

2. 1 1 /1 /2 17 2 Contents Introduction Definition of terms Disconnection Synthon Functional Group Interconversion Basic rule in disconnecion Use of synthon approach in synthesis of some medical or organic synthesis References

3. 1. Introduction A logical approach for designing organic synthesis which involves breaking down of the target molecule into available starting material by imaginary breaking of bonds (disconnection) or by functional group interconversion (FGC) is known as disconnection approach or retrosynthetic analysis or synthesis backward. 1 1 /1 /2 17 3

4. Target Molecule Disconnected Process called Analysis 1 1 /1 /2 17 4 Precursors 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.

5. Retrosynthetic pathway : Benzocaine from toluene 4. Use of Synthon In Synthesis of Some Medical or Organic O E t h O H 2 N C - O H 2 N O H O F G I O 2 N O H O 2 O N Me C - N Me Benzocaine : Toluene is readily available starting material Me is activating and ortho-/para- directing We know reagents for the synthon NO 2 1 1 /1 /2 17 5

6. Me H SO 2 4 HNO 3 C H 3 O 2 N KMnO 4 Oxidation 2 O N OH H 2 P d / C Oxidation H 2 N O OH EtOH/H + H 2 N O E t O 1 : Toluene Nitro Toluene O 5 Nitro benzoic acid 5 Amino benzoic acid Benzocaine

7. Ex : 2 Synthon are 1 and 2 1 2

8. 3 1 2 Synthon are 1 and 2

9. 1 1 /1 /2 17 9 Synthon can be divided in to following two types – They are derived from a reagents with functional groups Donor Synthon eg. - C 2 H 5 is ethyl donor synthon from - C 2 H 5 Li Acceptor Synthon eg. - C 2 H 5 is ethyl acceptor synthon from - C 2 H 5 I

10. 1 1 /1 /2 17 10 2. Definition of Terms 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 . 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)

11. Chemical bond can be cleaved : 1 1 /1 /2 17 11

12. 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 : NO 2 NH 2 FGI H 3 C C O O H H 3 C CN FGI 1 1 /1 /2 17 12

13. 3. Basic Rules In Disconnection 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. 1 1 /1 /2 17 13

14. 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 1 1 /1 /2 17 14 +

15. Rule -3 A bond joining a carbon to a hetero atom always broken with the electron pair on hetero atom. e.g Rule - 4 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 1 1 /1 /2 17 15

16. 1 1 /1 /2 17 16 Guidelines For Disconnection : Make the analysis in such a way that the synthesis become as short as possible. Use the only disconnections corresponding to known reliable reaction. Disconnect C-X bonds especially two group disconnections. Choose the disconnection corresponding to the highest yielding reaction, if known. Disconnect back to recognisable starting materials or to compounds which can be easily be made. Disconnect C-C bonds according to the functional groups in the molecule , if possible - disconnect at the middle of the molecule.

17. 1 1 /1 /2 17 17 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. Availability of starting material. Which route involves the least number of separation operations ? Which route gives the highest overall yield ? How expensive are the starting materials and reagents ? Which route includes least time and effort ?

18. Retrosynthetic pathway : Benzocaine from toluene 4. Use of Synthon In Synthesis of Some Medical or Organic O E t h O H 2 N C - O H 2 N O H O F G I O 2 N O H O 2 O N Me C - N Me Benzocaine : Toluene is readily available starting material Me is activating and ortho-/para- directing We know reagents for the synthon NO 2 1 1 /1 /2 17 18

19. Me H SO 2 4 HNO 3 C H 3 O 2 N KMnO 4 Oxidation 2 O N OH O H 2 P d / C Oxidation H 2 N O OH EtOH/H + H 2 N O E t O Synthesis : 1 1 /1 /2 17 19

20. 1 1 /1 /2 17 20 Inamdar NN. A companion to Medicinal Chemistry. 1 st ed. Career publication 2012. p. 408-422. Algarsamy V. Textbook of Medicinal Chemistry. Vol. 2. 1 st ed. Elsevier Health Sciences, 2012. p. 88-129 Lemke TL, Williams DA, Roche VF, Zito WS. Foye’s Principles of Medicinal Chemistry 6 th ed. Lippincott Williams and Wilkins. 2010. p. 504 J.March “Advance organic chemistry” 3rd edition, Wiley New York P-184 (1985). 5. E.J. Corey, J.Am.Soc. 98, 189, (1976). 5. References

21. THANK YOU 1 1 /1 /2 17 21