Protecting Groups In Organic Synthesis

When there are two functional groups of unequal reactivity within a molecule, the more reactive group can be made to react alone, but it may not be possible to react the less reactive functional group selectively.

A group the use of which makes possible to react a less reactive functional group selectively in presence of a more reactive group is known as protecting group.

A protecting group blocks the reactivity of a functional group by converting it into a different group which is inert to the conditions of some reaction(s) that is to be carried out as part of a synthetic route

1. A Seminar Report On Protecting Groups In Organic Synthesis Submitted By Apoorva Rastogi M.SC IV sem. Roll no.- 17045010914, Batch(2016-2018) Submitted To- Department of Chemistry Lucknow Christian Degree College Lucknow

2. I wish to convey my sincere regards and thanks to Dr. Renu Gupta, Head Department of Chemistry Lucknow Christian P.G College, Lucknow for her keen interest, encouragement and fruitful suggestions and for providing library facilities. I would like to place on record my deep gratitude to Mr. Mayank Joseph under whose guidance this project entitled “Protecting Groups In Organic Synthesis ” is being submitted, but for the constant support and encouragement at every stage, it would not have been possible complete this study. My sincere thanks are to Dr. Stuti Gupta & Dr. Abhas Asthana for their co-operation during the completion of the project. Apoorva Rastogi Acknowledgement

3. Protecting Groups In Organic Synthesis

4. Introduction

5. When there are two functional groups of unequal reactivity within a molecule, the more reactive group can be made to react alone, but it may not be possible to react the less reactive functional group selectively . A group the use of which makes possible to react a less reactive functional group selectively in presence of a more reactive group is known as protecting group . A protecting group blocks the reactivity of a functional group by converting it into a different group which is inert to the conditions of some reaction(s) that is to be carried out as part of a synthetic route

6. When we choosing a suitable protecting group, the following features must be considered :- Cheap and commercially available. Simple to put in high yield. Stable to reaction conditions. Easy to remove in high yield Choosing a suitable protecting group

7. Protection of Alcohols. Protection of Carbonyl Groups in Aldehyde And Ketones . Protection of Carboxylic acid. Protection of amines. PROTECTING GROUPS FOR DIFFERENT FUNCTIONAL GROUPS:-

8. Protection of Alcohols

9. By putting a bulky protecting group on the hydroxyl oxygen which can sterically prevent it from competing effectively for electrophiles . Principle Of Protection Of Alcohols

10. By delocalising the lone pairs of electrons by conjugation

11. Acetals Or Ketals As Protecting Groups For Alcohols Ether As Protecting Groups For Alcohals Ester As Protecting Groups For Alcohals Protecting Groups For Alcohols-

12. Acetals or Ketals As Protecting Groups For Alcohols

13. Acelals or ketals not only serve as useful protecting groups for aldehydes and ketones but they also find widespread use in the protection of alcohols. Commonly used ketals include Tetrahydropyranyl (THP) derivatives, methoxyethoxymethyl (MEM) derivative and methoxymethyl (MOM) derivative . Acetals / ketals are simply removed by treatment with aqueous acid .

14. Ether as Protecting Groups For Alcohols-

15. Alcohols may be simply converted to ethers by nucleophilic attack on a suitable alkyl halide . Ethers are stable to basic and mildly acidic conditions; they do not react with oxidizing / reducing agents and are inert to organo -metallic reagents. However, this stability means that many others are not easily cleaved to their parent alcohol under mild conditions. Therefore, only certain ethers, which are easily cleaved under mild conditions, are commonly used as protecting groups for alcohols.

16. Benzyl ether which are converted to alcohols under neutral conditions by catalytic hydrogenolysis . For example:-

17. t-butyl ethers which are readily hydrolyzed with dilute acid .

18. Tri- phenylmethyl group is the most important for the protection of 1°-alcoholic group. Only 1°-alcohols react at a useful rate with trityl -chloride in pyridine so selective protection of primary hydroxyl groups is possible .

19. Trimethylsilyl ethers as protecting groups:-

20. Esters As Protecting Group For Alcohol

21. Trichloroacetate esters [Cl 3 CCOOR ]: Pivoloate ester [Me 3 CCOOR]:-

22. Protection of 1,2 & 1,3 diols

23. Cis 1, 2 diols and cis and trans-1,3 diols can be protected as cyclic acetals and ketals (e.g., dioxlanes and dioxanes ) or cylic ortho esters that are cleaved by acidic hydrolysis or as cylic esters ( e.g , carbonates) that are cleaved by basic hydrolysis . Cyclic ortho esters are more readily cleaved by acidc hydrolysis than cyclic acetals or ketals .  

24. Isopropylidene ( acetonides ):- 1, 2 acetanoid formation is usually favored over 1, 3 acetonidess Cleavage :-mild aqueous acid   Cyclic acetals and ketals :-

25. Protection of carbonyl groups in aldehyde and ketones

26. The acetal / ketals protective group is introduced by treating the carbonyl compounds with an alcohol, an ortho -ester, or a diol in the presence of a Lewis acid as catalyst. Acetals / ketals are stable to strong aqueous bases, nucleophilic reducing agents, organometallic reagents, oxidation under non-acidic conditions, Na or Li/NH 3 reductions . Acetals / ketals are cleaved by acid-catalyzed hydrolysis Acetal / ketals as protective group

27. General order of reactivity of various carbonyl groups (probably due to the steric effect ). 1,3-dioxanes (six- membered ring) hydrolyze faster than the corres-ponding 1,3-dioxolanes (five- membered ring acetal )

28. Acyclic acetals is prepared by the reaction of aldehyde with monohydric alcohal in the presence of dry HCl . Prepration of acyclic ketals and acetals

29. Acylic ketones cannot be prepared with monohydric alcohols under the same condition of acetals formation because of the unfavourable entropy, which the equillbrium towards the ketones So acyclic ketals are prepared by the reaction of ketones with ethylorthoformate in presence of the NH 4 Cl.

30. Preparation of cyclic acteal & ketals :-

31. Thioacetals / thioketals are quite stable toward hydrolysis; there is no special need to remove the H 2 O formed during the reaction. Thioacetal / Thioketals as protective group:-

32. Protection of the Carboxyl Group

33. Protecting groups for carboxylic acids are used to avoid reaction of the acidic -COOH hydrogen with bases and nucleophiles or to prevent nucleophilic additions at the carbonyl carbon.

34. Most common group for the protection of acid is ester. Protecting group for carboxylic acid

35. Protection of Amines

36. The basic problem of peptide synthesis is one of protecting the amino group. In bringing about interaction between the carboxyl group of one amino acid and the amino group of a different amino acid, one must prevent interaction between the carboxyl group and the amino group of the same amino acid. In preparing glycylalanine , for example, one must prevent the simultaneous formation of glycylglycine . Reaction can be forced to take place in the desired way by attaching to one amino acid a group that renders the NH 2 unreactive .

37. Protecting Groups for Amines (RNH 2 , RNHR’ , RNR’ R’’) groups:-

38. Benzyl carbamate [ benzyloxycarbonyl or CBZ group (RR҆NCOOCH2Ph)]:-

39. Amides as Protecting groups for Amines:- Amides are readily prepared from an amine and an acid chloride or anhydride. These are relatively more stable compounds that, classically, are cleaved by heating in strongly acidic or basic solutions.

40. Cyclic Imides As Protecting Group For Primary Amines:-

41. [1] Singh, J ; Yadav , L.D.S; Organic Synthesis ;Pragati Publicaton ; thirteenth edition- 2017; pp. 696- 721 .   [2] Kar , K.R.; Application of Redox and Reagents in Organic Synthesis ; New Central Book Agency (P) Ltd; volume-1; pp 376-385.   [3] Clayden , J; Greeves , N; Warren, S; Wothers , P; Organic Chemistry; pp 633-637 & 657 References:-

42. [ 4] Hanson, J.R.; Protecting Groups in Organic Synthesis ; Sheffield Academic Press ; pp 8- 80.   [ 5] Morrison, R.T.; Boyd R.N.; Organic Chemistry ; Prentice-Hall of India Private Limited; Sixth Edition-2002; pp. 1147   [ 6] March, J; Smith, M.B.; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure ; Wiley Publication; Sixth Edition; pp 1271-1279

43. Thank You