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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
- 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 LiAlH4
- 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 1. Acyclic acetal or ketal 2. Cyclic acetal or ketal 3. Dithio acetal or ketal 4. Hemithio acetal or ketal 2CH3OH 2CH3OH Aldehyde Acetal Acetone Ketal
- 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. - H2O ROH - H+ + H+ Trimethyl ortho formate • Other reagent can be trimethyl ortho formate Acetaldehyde
- 11. Cleavage 2N H2SO4, ROH H2O OR 3N HCl, ROH Mechanism H+ - ROH
- 12. H2O - 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+ - H2O - H2O + 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 LiAlH4 1,3 diol 1,3 dioxane + - H+
- 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 + BF3.Et2O / CHCl3 − H2O Dithio ketal
- 20. + Cleavage • Acid catalyzed cleavage is not satisfactory • Cleavage can be done in 2 ways i. Using Hg+2 salt like HgCl2, HgClO4 in the presence of BF3.Et2O complex as a solvent BF3.Et2O, Hg(ClO4) + 2
- 21. I2 / NaHCO3, HCl II. Cleavage through oxidation Following oxidizing agents can be used • I2 / NaHCO3, HCl • H2O2, BF3.Et2O, HCl • NaIO4, BF3.Et2O, HCl • O2, BF3.Et2O, 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 + + BF3.Et2O / CH2Cl2 − H2O 1,2 dithiol 1,3 dithiol 1,2 dithiolane 1,3 dithiane
- 24. Cleavage Cleavage can be done by using Hg+2 salt or oxidizing agents Following oxidizing agents can be used • I2 / DMSO aq. MeOH • BF3.Et2O, H2O2, CH2Cl2 CH2Cl2 / BF3.Et2O, HgCl2 or I2 / DMSO aq. MeOH or BF3.Et2O, H2O2, CH2Cl2 +
- 25. Mechanism of cleavage using HgCl2 + H2O − 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 + O2, hν Cleavage Dioxane / NaOAc ZnCl2
- 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
- 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? i. OHCH2CH2CHCHO ii. CH3COCH2CH2COOH iii. CH2COCH2CH2CH2CHO Alcohol > amine > aldehyde > ketone > carboxylic acid iii. CH2COCH2CH2CH2CHO i. OHCH2CH2CHCHO ii. CH3COCH2CH2COOH Answer
- 39. References • https://profiles.uonbi.ac.ke/andakala/files/sch_5 04_protecting_groups_in_organic_synthesis.pdf • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC 6859800/ • https://www.organic chemistry.org/protectivegroups/carbonyl.shtm