Alcohols

1. Alcohols Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8th ed.) sections 10.5-6, 17.2-8, 17.11

2. Alcohols • Important in synthesis • Easily converted to or prepared from other functional groups • Used as solvents • Especially low molecular weight alcohols • Types of alcohols: • Phenols and enols have different reactivity from alcohols

3. Structure of Alcohols • Hybridization of C? • Bond angle around C? • Hybridization of O? • Classification as primary, secondary, or tertiary:

4. Spectroscopy of Alcohols: IR • IR absorptions at 1050 cm-1 and 3300-3600 cm-1

5. Spectroscopy of Alcohols: NMR • Atoms bonded to O are deshielded • 13C-NMR: • 1H-NMR: singlet at d2.5-5.0

6. Spectroscopy of Alcohols: MS • M+ usually small or absent • M-18 comes from loss of water • Ex: 1-butanol

7. Naming Alcohols (Review) • Acyclic alcohols • Parent chain is longest chain containing C bonded to –OH • Change suffix from “-e” to “-ol” • Number from end closest to –OH • Show location of –OH • Name/number substituents • Cyclic alcohols • Ring is the parent • Number ring so –OH is at carbon 1 and other substituents have lowest possible numbers • You do not need to show the location of the –OH • Name/number substituents

8. Naming Alcohols (Review) • Multiple hydroxyl groups • Two –OH groups is a diol; 3 is a triol • Two adjacent –OH groups is a glycol • Name as acyclic alcohols, except keep the “-e” suffix and add “-diol” • Indicate numbers for all –OH groups • Unsaturated alcohols (enol or ynol) • Parent chain contains carbon bonded to –OH and both carbons of C=C or C≡C • Suffix is “-ol”, infix is “-en-” or “-yn-” • Number chain so –OH has the lowest number • Show numbers for –OH and the unsaturation • Name/number substituents

9. Physical Properties of Alcohols • Alcohols are polar • Intermolecular forces • Dipole-dipole and hydrogen bonding • Boiling points • High; increase with number of carbons; decrease with branching • Solubility • Low MW soluble in water; decreases as MW increases

10. Which molecule in each pair has the higher boiling point?

11. Acidity/Basicity of Alcohols • Alcohols are weak bases and weak acids • As a base: • A strong acid is needed to protonate a neutral alcohol

12. Acidity/Basicity of Alcohols • As an acid: • A strong base (alkoxide ion) is formed • Methoxide, ethoxide, tert-butoxide, etc. • Alcohols that are stronger acids yield anions that are more stable or can be more easily solvated

13. Acidity of Alcohols • For example, compare CH3O- and (CH3)3CO-

14. Acidity of Alcohols • Inductive effect:

15. Acidity of Phenols • More acidic than alcohols • Phenol pKa = 9.89 • Resonance-stabilized anion • Electron-withdrawing groups make phenols more acidic • Ex: p-nitrophenolpKa = 7.15 • Electron-donating groups make phenols less acidic • Ex: p-aminophenol pKa= 10.46

16. Chemistry of Alcohols • Preparation of Alcohols • Reactions of Alcohols

17. Preparation of Alcohols • From alkyl halides • SN2 reaction (competes with E2)

18. Preparation of Alcohols • From alkenes • Acid-catalyzed hydration (Markovnikov, can rearrange) • Oxymercuration-reduction (Markovnikov, no rearrangement) • Hydroboration-oxidation (anti-Markovnikov, no rearrangement)

19. Preparation of Alcohols • From alkenes • Hydroxylation (yields glycol)

20. Preparation of Alcohols • From carbonyl compounds • Reduction • Grignard reaction

21. Reduction of Carbonyls • Type of alcohol formed depends on carbonyl

22. Reduction of Carbonyls • Reducing agent [H] = metal hydride • Hydride (H:-) • From NaBH4 or LiAlH4 • Mechanism: • H3O+ as a second step to form alcohol

23. Reduction of Carbonyls • Sodium borohydride (NaBH4) • Selectively reduce aldehydes and ketones • Conditions: H2O or aqueous MeOH or EtOH

24. Reduction of Carbonyls • Lithium aluminum hydride (LiAlH4 or LAH) • Stronger reducing agent than NaBH4 • Reduces aldehydes and ketones • Also reduces carboxylic acids and esters (to primary alcohols) • Conditions: aprotic solvent (ether or THF) • LAH + H2O → H2 (boom!)

25. Reduction of Carbonyls

26. Draw the product of this reduction.

27. Reduction of Carbonyls • In addition to metal hydrides, carbonyls can be reduced with H2 • This reagent is not mentioned in McMurry! • Catalyst = Raney nickel • Reduce aldehydes and ketones only • Will also reduce double bonds and triple bonds

28. Summary of Reducing Agents

29. What methods can be used to synthesize a primary alcohol?

30. What starting materials/reagents could be used to synthesize 4-methyl-2-penten-1-ol?

31. Preparation of Alcohols • From carbonyl compounds • Reduction • Grignard reaction

32. The Grignard Reaction • Carbonyl + Grignard reagent → Alcohol • Carbonyl = aldehyde, ketone, ester, or acid chloride • Grignard reagent = an organometallic reagent (R-Mg-X) • Alcohol = 1°, 2°, or 3° depending on carbonyl • This is a C-C bond making reaction!

33. Formation of Grignard Reagent • R cannot contain acidic hydrogens • Mg oxidized from Mg0 to Mg2+ • Reagents form on metal surface; solvated by ether (Et2O) • Radical mechanism (slow)

34. Reactivity of Grignard Reagent • C-Mg is a polar covalent bond with partial ionic character • d- makes C nucleophilic (~carbanion) • Will react with d+ of a carbonyl • Carbon is also basic • Will react with acidic hydrogens

35. Grignard Reaction Mechanism • Nucleophilic Grignard reagent attacks electrophilic carbonyl; new bond formed between R of RMgX and C of C=O • Alkoxide ion (a strong base) reacts with acid (usually HCl/H2O or H3O+) to produce alcohol

36. Grignard Reaction Product • Alcohol produced depends on type of carbonyl reacting • Formaldehyde: • Aldehyde: • Ketone:

37. Grignard with Esters/Acid Chlorides • Esters and acid chlorides react with TWO equivalents of Grignard reagent • Ester/acid chloride → ketone • Ketone → tertiary alcohol • Mechanism: • Product = tertiary alcohol; two alkyl groups are the same

38. Grignard Reaction Product

39. Show how the following compound can be synthesized from an acid chloride using the Grignard reaction.

40. How can 2-phenyl-2-butanol be synthesized using the Grignard reaction?

41. Grignard Reaction Limitations • Grignard reagents cannot react with or be formed from any molecule containing an acidic hydrogen • O-H, N-H, S-H, -C≡C-H • RMgX will pick up acidic H and “kill” the reagent • To allow the reaction to occur even with an -OH present in the starting material, we must “protect” the alcohol

42. Protection of Alcohols • Three-step process • Introduce protecting group • Carry out reaction • Remove protecting group • Protecting group is chlorotrimethylsilane (TMS-Cl) • Nitrogen base promotes reaction • SN2-like reaction is allowed with tertiary Si • Less sterically crowded due to longer bonds

43. Grignard Reaction with Protecting Groups

44. Chemistry of Alcohols • Preparation of Alcohols • Reactions of Alcohols

45. II. Reactions of Alcohols • Oxidation • Formation of alkyl halides • Formation of tosylates • Dehydration • Formation of esters

46. A. Oxidation • Gain of O, loss of H, or both • Degree of oxidation depends on reagents

47. Oxidation with PCC • Pyridiniumchlorochromate (PCC) • This reagent is not covered in McMurry! • Complex of CrO3 + pyridine + HCl • Mild oxidizing agent • 1° alcohol → aldehyde • 2° alcohol → ketone • 3° alcohol → no reaction • Solvent = CH2Cl2

48. Oxidation with H2CrO4 • Chromic acid • Chromium trioxide or sodium dichromate in aqueous acid • Stronger oxidizing agent • 1°alcohol → carboxylic acid (aldehyde intermediate) • 2°alcohol → ketone • 3°alcohol → no reaction

49. Oxidation with KMnO4 • Same results as chromic acid • Less expensive • Better for the environment

50. B. Formation of Alkyl Halides • Substitution reactions • If alkyl halide is tertiary, reagents are HCl or HBr (aq) • Mechanism = SN1 • Product = racemic mixture (if stereocenter is present) • Secondary ROH can react, but requires heat and can rearrange • Evidence of reaction = formation of second layer