Alcohols Properties & Synthetic Preps

1. Alcohols Properties & Synthetic Preps

2. Alcohols • Hydroxyl groups in natural compounds.

3. Phenols • Naturally occurring phenols: a hydroxyl group directly attached to an aromatic ring.

4. Physical Properties of Alcohols • The –OH of an alcohol has a profound effect on physical properties. • Compare the boiling points below. b.p. -24 oC

5. Physical Properties of Alcohols • The hydrogen- (H-) in hydroxyl groupsintermolecularly attracts water molecules • Alcohols with small carbon chains are miscible in water (they mix in any ratio). • Alcohols with large carbon chains do not readily mix with water.

6. Physical Properties of Alcoholsoctanol-water partitioning • Molecules with large hydrophobic groups are generally insoluble in water. • Alcohols with three or less carbons are generally water miscible. • Alcohols with more than three carbons are not miscible, and their solubility decreases as the size of the hydrophobic group increases. • Partition Coefficient: relative solubility of a compound (ratio) in octanol vs. water (Drug absorbtion & transport)

7. Stress? memory? cognition? …cheating? Propranolol: orally administered anti-hypertensive-Blocker: blocks the action of epinephrine and norepinephrine on both β1- and β2-adrenergic receptors “Basic sciences in the history of cardiovascular pharmacology” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC325477/

8. Nobel Prize 1988 Sir James W. Black Born:14 June 1924 Died: 21 March 2010 Affiliation at the time of the award: University of Glasgow, Scotland

9. Acidity of Alcohols and Phenols

10. Preparation of Alcohols • What reagents did we use to accomplish this transformation? • Substitution can occur by SN1 or SN2.

11. Preparation of Alcohols

12. Catalytic Reduction Hydration of alkenes Hydroboration-oxidation of alkenes Hydrolysis of alkyl halides New Syntheses using Grignard reagents Organolithium reagents Alcohol Preps Reactions:

14. Reduction of aldehydes and ketones Reduction of carboxylic acids Reduction of esters Reaction of Grignard reagents with epoxides Alcohols • Diols by hydroxylation of alkenes New methods or reagents:

15. Which compound is produced when cyclohexene reacts with OsO4, (CH3)3COOH, tert-butyl alcohol, HO-? A) B) C) D) Question

16. Reduction of Aldehydes and Ketones

17. R R H OH C O C H H Reduction of Aldehydes Gives Primary Alcohols

18. O + CH3O CH H2 CH3O CH2OH Example: Catalytic Hydrogenation Pt, ethanol (92%)

19. R H OH C R' Reduction of Ketones Gives Secondary Alcohols R C O R'

20. O Example: Catalytic Hydrogenation H OH Pt + H2 ethanol (93-95%)

21. R R C O H OH C H H R R H:– H OH C O C R' R' Retrosynthetic Analysis H:–

22. Which isomer of C4H10O can be prepared by hydrogenation of a ketone? A) B) C) D) Question

23. Act as hydride donors (H-) The analagous deuterated agents NaBD4 and LiAlD4 produce (D-) and work in the same way H – + Na H H B H Metal Hydride Reducing Agents Li+

24. Mechanism

25. O2N O2N O CH2OH CH (82%) H OH O (84%) Examples: Sodium Borohydride Aldehyde NaBH4 methanol Ketone NaBH4 ethanol

26. Reduction of acetaldehyde (CH3CH=O) with NaBD4 in H2O produces: A) B) C) D) Question

27. More reactive than sodium borohydride. Cannot use protic solvents: water, ethanol, methanol, etc.. Diethyl ether is most commonly used solvent. Lithium Aluminum Hydride

28. O CH3(CH2)5CH2OH CH3(CH2)5CH (86%) OH O (C6H5)2CHCHCH3 (84%) Examples: Lithium Aluminum Hydride Aldehyde 1. LiAlH4diethyl ether 2. H2O Ketone 1. LiAlH4diethyl ether (C6H5)2CHCCH3 2. H2O

29. Which one of the isomeric alcohols of formula C5H12O can be prepared by LiAlH4 reduction of a ketone? A) 1-pentanol B) 2-methyl-2-butanol C) 3-methyl-2-butanol D) 2,2-dimethyl-1-propanol Question

30. Neither NaBH4 or LiAlH4reduces carbon-carbondouble bonds. O 1. LiAlH4diethyl ether 2. H2O (90%) H OH Selectivity

31. Preparation of Alcohols By Reductionof Carboxylic Acids and Esters

32. lithium aluminum hydride is only effective reducing agent; not sodium borohydride R H OH C H Reduction of Carboxylic AcidsGives Primary Alcohols R C O HO

33. O COH CH2OH Example: Reduction of a Carboxylic Acid 1. LiAlH4diethyl ether 2. H2O (78%)

34. Mechanism • To reduce an ester, two hydride equivalents are needed.

35. Reduction of EstersGives Primary Alcohols Lithium aluminum hydride is overwhelmingly preferred for reductions of esters. Sodium borohydride reduction is too slow. Catalytic hydrogenation is used in industry,but requires a special catalyst, hightemperature, and high pressure.

36. O COCH2CH3 1. LiAlH4diethyl ether 2. H2O + CH3CH2OH CH2OH (90%) Example: Reduction of an Ester

37. Which of the esters shown, after reduction with LiAlH4 and aqueous workup, will yield two molecules of only a single alcohol? A) CH3CH2CO2CH2CH3 B) C6H5CO2CH2C6H5 C) C6H5CO2C6H5 D) none of these Question

38. Answer: D. Reduction with sodium borohydride reduces only the ketone, not the acid. For more examples of this type of problem, SEE: Skillbuilder 13.4.

39. Preparation of Alcohols From Epoxides

40. R MgX R CH2 CH2 CH2 OMgX H2C O H3O+ RCH2CH2OH Reaction of Grignard Reagentswith Epoxides

41. CH3(CH2)4CH2CH2CH2OH (71%) Example CH2 H2C CH3(CH2)4CH2MgBr + O 1. diethyl ether 2. H3O+

42. Select the best combination of reagents to prepare 2-phenylethanol from bromobenzene. A) 1. Mg, diethyl ether; 2. ethylene oxide; 3. H3O+ B) 1. Mg, diethyl ether; 2. acetaldehyde (CH3CH=O); 3. H3O+ C) 1. Mg, diethyl ether; 2. 2-chloroethanol; 3. H3O+ D) 1. Mg, diethyl ether; 2. CH3CH2OCH2CH3; 3. H3O+ Question

43. Preparation of Diols: Reduction of dicarbonyl compounds

44. Preparation of Diols • If two carbonyl groups are present, and enough moles of reducing agent are added, both can be reduced.

45. O O HCCH2CHCH2CH CH3 HOCH2CH2CHCH2CH2OH CH3 3-Methyl-1,5-pentanediol (81-83%) Example: Reduction of a Dialdehyde H2 (100 atm) Ni, 125°C

46.  Question Which of the following reactions produce alcohols? a, b a, b, c a, b, c, d a, b, c, e a, b, c, d, e