this presentation contains retrosynthesis (disconnection) of functional groups

1. DESIGNING
ORGANIC
SYNTHESIS

2. Content
Retro synthesis of:
• Acyclicsaturated systems
• Acyclicunsaturated systems
• Monocyclic compound
• Bicycliccompound
• Aromatic compounds

3. Retrosynthetic analysis is a problem-solving technique for transforming
the structure of a synthetic target (TGT) molecule to a sequence of
progressively simpler structures along a pathway which ultimately
leads to simple or commercially available starting materials for a
chemicalsynthesis.

4. Criteria for a good disconnection
• A good mechanism
• Greatest simplification
• Recognisable starting material

5. Disconnection of alcohols

6. Analysis
Synthesis
Cyanide is agood anionand cation is stabilised by the lone pair of electron on
oxygen

7. The acetelyne anion is the most stable anion
Analysis
Synthesis
Ph OH
Me CH

8. The reactions mentioned in previous slides doesn’t gives us stable anion
Et-Synthon
synthetic equivalent of Et– the grignard reagent (Et-MgBr) or the alkyllithium(Et-
Li).
Analysis
Synthesis

9. Route a) gives another target to be made
Route b) gives to equal simplified pieces – acetone and cyclohexyl bromide

10. Disconnection of tertiary alcohol with two group same
Analysis
Removing both the group at single disconnection getting anester and two
grignard’s reagents
Synthesis

11. Double bond in six membered ring with an electron withdrawing group, we use
diels-alder disconnection
Analysis

12. Disconnection of an alcohol with one group as a
hydrogen
Synthon - H-
Synthetic equivalents -sodium borohydride and lithium aluminiumhydride
The disconnection involving H- does not alter thecarbon skeleton;they
are not disconnections but functionalgroup interconversion (FGI).
Analysis

13. Sodium boromohydride onlyreduces the aldehyde and lithium aluminium
hydride reduces almost allcarbonyl compounds neither reagents reduces the
double bond
Analysis
One or both the hydrogen can be removed and either starting materialscan be
made by diels-alder reactions.
Synthesis

14. Synthesis of most compounds is often best by first going back to alcohols by a
straightforward FGI and disconnections
List of compounds you can make alcohols from FGI.

16. Analysis
Synthesis

17. Disconnection of halide

18. Reagentfor Synthon A is an epoxide. Works wellwithmono-substituted
epoxides
Analysis
Synthesis
It is a poor tactic to chop off carbon at once, also this route gives us only 40% yeild
asthe benzyl grignard reagents easily gives radicalsand polymerises.

19. Disconnection of alkenes

20. Designing an alkenesynthesis is to add water across the double bond thus on
dehydration A willgive cyclohexanone but B willgive another Alkene
Analysis

21. Analysis
Synthesis
Dehydration of A gives C (another alkene)but dehydration of B gives
only thetarget molecule and notless substitutedD

22. Alternate route for disconnection of olefins is from the double bond. Corresponds
to wittig reactions
Analysis

23. The halide in route B is easilyrecognisable and the aldehyde can be
synthesised usingthe diels-alder reaction
The route A can also be used butthe startingmaterials are not so readily
available.
Analysis
Synthesis

24. Disconnection of ketones

25. Disconnectionof bond joining aromatic ring and aliphaticrind is carried
out by friedel-crafts reaction usingacetyl chloride and aluminium
chloride
Analysis

26. Routea is better as it will give us an acyl rather thanalkyl halideand an
activated benzenering
Analysis

27. Routeb disconnection is notpossible as nitro group is metadirecting
and also a nitrobenzene will not react under friedel-crafts
Routea is fine as MeO is ortho-directing.
Analysis

28. Analysis

29. Disconnections of acids

30. An acid is an hydroxyl compound and hence canbe disconnected as alcohols
Analysis
Acid derivatives are made directly from acids or conversion of other acid
derivatives depending on their stability.

31. Analysis
Synthesis

32. Disconnection of saturated
hydrocarbons

33. Compounds with no functional groups are made by hydrogenation of a double
bond

34. Analysis
Synthesis

35. Analysis
Synthesis

36. Controlling disconnections
Protection and activation

37. The grignard reagent might attack ketone giving wrong product
To avoidthis, protect the ketone by reversible FGI. A common method is to make a
cyclicketal
Any functional group can be a protecting group providing
•It can be added easily
•It can be easily removed
•It should not react with the reagent

38. This reactions gives a poor yield
The product is as reactive asthe starting material and further reaction occurs

39. So we activateone position of carbonyl group by adding CO2Et group using ester
Now removing the activated group just asthe protecting group. Here, by
hydrolysis anddecarboxylation.

40. Analysis
Synthesis

41. Analysis
Synthesis

42. Application of disconnections
In 1936, robinson carried out thisreaction to get thealcohol A
He got an alcohol B
Even with modern spectroscopic method the quickest way to identify a compound
is to synthesise and compare the N.M.R, Fingerprint and I.R. region.
Analysis
Synthesis

43. References
• Stuart Warren.Organicsynthesis:thedisconnectionapproach. Wiley
India Pvt. Ltd, Publishers.
• Stuart Warren. Designing organicsyntheses:Aprogrammed
introductiontothesynthonapproach. Wiley India Pvt. Ltd, Publishers.
• E. J. Corey. Thelogicofchemicalsynthesis.Jon Wiley and Sons,
Publishers

44. "Long multistep syntheses
of 20 or more steps could
be undertaken with
confidence despite
the Damocles sword of
synthesis - only one step
need fail for the entire
project to meet sudden
death.“
- E. J. Corey. The logic of
chemical synthesis. Jon
Wiley and Sons, Publishers