Protection of carbonyl and carboxyl group

Protection of carbonyl and carboxyl group

1. Organic synthesis Protecting groups of carbonyl and carboxyl group

2. Protection of carbonyl and carboxyl group Submitted to Ms. Arifa Submitted by Khadija Nasir Roll number 1922107019 BS. Chemistry Semester 7 Government Graduate College for Women, Gulberg, Lahore

3. Content Protecting group Carbonyl protecting group Protection by alcohol Protection by diol Protection by thiol and dithiol Protection by hemiacetal formation Carboxyl group protection t-butyl ester formation Silyl ester formation Benzyl and phenyl ester formation Ethyl ester formation Past paper’s questions References

4. Protecting group

5. Protecting groups A protecting group or protective group is a group that is introduced into a molecule by chemical modification of a functional group to obtain chemo selectivity in a subsequent chemical reaction LiAlH4 It can be used in a poly functional molecule to block the reactivity of selective functional group under reaction condition Order of reactivity is as follows Alcohol > amine > aldehyde > ketone > carboxylic acid

6. Properties Easy to introduce It should leave easily It should be cheaply available It should not react with other components in a reaction After introduction of protecting group asymmetric carbon should not generate Every functional group has specific protecting groups PG LiAlH 4

7. Protection of carbonyl group Carbonyl group is present in aldehyde and ketone Carbonyl group is highly reactive because it acts as both electrophile and nucleophile Aldehyde is more reactive than ketone Protecting groups for carbonyl are alcohol, diol, thiol, dithiol, hemiacetal in the presence of acid Semicarbazides, cyanohydrins, imines, hydrazones can protect carbonyl group but its de protection is difficult

8. Decreasing order of reactivity of carbonyl compounds is as follows Aliphatic aldehyde > aromatic aldehyde > acyclic ketones > cyclohexanones > cyclopentanone > alpha beta unsaturated ketone > > aromatic ketone Following compounds are generally formed while using protecting groups Acyclic acetal or ketal Cyclic acetal or ketal Dithio acetal or ketal Hemithio acetal or ketal 2CH 3 OH 2CH 3 OH Aldehyde Acetal Acetone K etal

9. 1. Acyclic acetal and ketal It is formed by using alcohol in the presence of acid This protecting group is good for aldehyde not for ketones specially dimethyl ketone. 2 ROH H + ROH Dry HCl Acetaldehyde methyl acetal Mechanism

10. - H 2 O ROH - H + + H + Trimethyl ortho formate Other reagent can be trimethyl ortho formate Acetaldehyde

11. Cleavage 2N H 2 SO 4 , ROH H 2 O OR 3N HCl, ROH Mechanism H + - ROH

12. H 2 O - ROH - H + 2. Cyclic acetal and ketal This is better due to entropic advantage because aliphatic acetal formation includes (1 carbonyl group and 2 alcoholic group) while it includes (1 carbonyl and 1 diol) It is acid catalyzed reaction of carbonyl and 1,3 diol or 1,2 diol Solvents can be dry HCl or TsOH, acetone

13. + H + H + - H 2 O - H 2 O + Mechanism 1,2 dioxalane 1,3 dioxane H +

14. + + + Advantage Cyclic acetals and ketals do not react with base, Grignard reagent and reducing agents like LiAlH 4 1,3 diol 1,3 dioxane + - H +

15. + H + H 2 O - H + Dimethyl ketone Cleavage

16. + + H + Hydrolysis Cleavage rate for substituted 1,3 dioxane (decreasing reactivity order) > > Reason

17. < Reactivity order for ketal Reactivity order for acetal > 1,3 dioxane 1,3 dioxalane 1,3 dioxalane 1,3 dioxane Ketal will cleave more easily than acetal

18. Selective protection of carbonyls Aldehydes can be selectively protected in the presence of ketone When both ketone or both aldehyde are present the selectively less hindered ketone will be protected H + H +

19. Conjugated carbonyl will be protected slower than saturated carbonyl 3. Dithio acetal and ketal Carbonyl group can be protected by sulphur derivative + BF 3 .Et 2 O / CHCl 3 − H 2 O Dithio ketal

20. + Cleavage Acid catalyzed cleavage is not satisfactory Cleavage can be done in 2 ways Using Hg +2 salt like HgCl 2 , HgClO 4 in the presence of BF 3 .Et 2 O complex as a solvent BF 3 .Et 2 O, Hg(ClO 4 ) + 2

21. I 2 / NaHCO 3 , HCl II. Cleavage through oxidation Following oxidizing agents can be used I 2 / NaHCO 3 , HCl H 2 O 2 , BF 3 .Et 2 O, HCl NaIO 4 , BF 3 .Et 2 O, HCl O 2 , BF 3 .Et 2 O, HCl Note This protection is not suitable if the reaction is occurring in basic condition because thio acetal and ketal are sensitive toward base +2

22. 3. Cyclic dithio acetal and ketal + + BF 3 .Et 2 O / CH 2 Cl 2 − H 2 O 1,2 dithio l 1,3 dithiol 1,2 dithiolane 1,3 dithiane

23. H + - H 2 O Mechanism H +

24. Cleavage Cleavage can be done by using Hg +2 salt or oxidizing agents Following oxidizing agents can be used I 2 / DMSO aq. MeOH BF 3 .Et 2 O, H 2 O 2 , CH 2 Cl 2 CH 2 Cl 2 / BF 3 .Et 2 O , HgCl 2 or I 2 / DMSO aq. MeOH or BF 3 .Et 2 O, H 2 O 2 , CH 2 Cl 2 +

25. Mechanism of cleavage using HgCl 2 + H 2 O − HCl + + + + − HCl

26. - OH⁻ - RSOH OH⁻ - RSH Oxidative cleavage

27. Reason of dominance of thio acetal and ketal Sulphur derivatives selectively protect aldehyde in the presence of ketone It protects alpha beta unsaturated carbonyl group without migration of double bond 1,3 dioxolane or 1,3 dioxane is readily converted into1,3 dithiolane or 1,3 dithiane

28. 4.Hemithio acetal and ketal + O 2 , h ν Cleavage Dioxane / NaOAc ZnCl 2

29. Carbonyl Protection Alcohol T hiol Diol Hemithiol Dithiol Aliphatic acetal Cyclic acetal Aliphatic thio acetal Aromatic thio acetal Hemithio acetal Acid catalysed Acid catalysed Hg +2 Or oxidative H g +2 Or oxidative Oxidative deprotection

30. Protection of carboxyl group Protection of carboxyl group is done by converting it to ester Following esters could be formed Methyl and ethyl ester ( less used due to difficulty in deprotection ) Silyl ester t-butyl ester Benzyl ester Phenyl ester

31. 2-methyl prop-1-ene Formation of t-butyl ester Mechanism

32. Cleavage Silyl ester formation Trialkyl silyl can be used as a protecting group

33. Mechanism Cleavage It can take place in presence of acid, H with metal or alcohol

34. Benzyl ester formation DCC (1,3 dicyclohexyl carbimide) Mechanism

35. Cleavage Ethyl ester formation

36. Cleavage Carboxyl Protection 2-methyl prop-1-ene t -butyl ester Tri alkyl silyl chloride Silyl ester Acid catalyzed Benzyl alcohol Acid catalyzed Benzyl ester Ethanol Ethyl ester Oxidative Acid catalyzed deportection

37. Question 1 (2016) Give two method for the protection of carbonyl and hydroxyl group? Answer Carbonyl group can be protected by 1.Acyclic acetal and ketal formation 2.Cyclic acetal and ketal formation 3.Acyclic and cyclic thio acetal and ketal formation 4.Hemiacetal and hemiketal formation Past paper

38. Question 2 (2018) Give the protection of following functional group present in following compound? OHCH 2 CH 2 CHCHO CH 3 COCH 2 CH 2 COOH CH 2 COCH 2 CH 2 CH 2 CHO Alcohol > amine > aldehyde > ketone > carboxylic acid iii. CH 2 COCH 2 CH 2 CH 2 CHO i . OH CH 2 CH 2 CHCHO ii. CH 3 CO CH 2 CH 2 COOH Answer

39. References https://profiles.uonbi.ac.ke/andakala/files/sch_504_protecting_groups_in_organic_synthesis.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859800/ https:// www.organic chemistry.org/ protectivegroups / carbonyl.shtm