1. ALCOHOLS Dr. Sheppard CHEM 2412 Summer 2015 Klein (2 nd ed.) sections 13.1, 13.2, 13.3, 13.5, 13.4, 13.6, 13.7, 13.10, 13.9, 13.13

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 13 C-NMR: 1 H-NMR: singlet at  2.5-5.0

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 1. Parent chain is longest chain containing C bonded to –OH 2. Change suffix from “-e” to “-ol” 3. Number from end closest to –OH Show location of –OH 4. Name/number substituents Cyclic alcohols 1. Ring is the parent 2. 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 3. Name/number substituents

8. Naming Alcohols (Review) Multiple hydroxyl groups 1. Two –OH groups is a diol; 3 is a triol 2. Two adjacent –OH groups is a glycol 3. Name as acyclic alcohols, except keep the “-e” suffix and add “-diol” 4. Indicate numbers for all –OH groups Examples:

9. 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 Physical Properties of Alcohols

10. Which molecule in each pair has the higher boiling point? a) b) c) d)

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: Steric Effect For example, compare CH 3 CH 2 O - and (CH 3 ) 3 CO - Sterically accessible; less hindered and more easily solvated Sterically less accessible; more hindered and less easily solvated

14. Acidity of Alcohols: Inductive Effect

15. Acidity of Alcohols: Resonance Effect Phenols are more acidic than alcohols Cyclohexanol vs. phenol Resonance-stabilized phenoxide anion Electron-withdrawing groups make phenols more acidic Ex: p-nitrophenol pK a = 7.15 Electron-donating groups make phenols less acidic Ex: p-aminophenol pK a = 10.46

16. Chemistry of Alcohols I. Preparation of Alcohols II. Reactions of Alcohols

17. Preparation of Alcohols From alkyl halides Substitution reactions (compete with elimination)

18. Preparation of Alcohols From alkenes 1. Acid-catalyzed hydration (Markovnikov, can rearrange) 2. Oxymercuration-reduction (Markovnikov, no rearrangement) 3. Hydroboration-oxidation (anti-Markovnikov, no rearrangement)

19. Preparation of Alcohols From alkenes 4. Hydroxylation (yields glycol)

20. Preparation of Alcohols From carbonyl compounds 1. Reduction 2. 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 NaBH 4 or LiAlH 4 Mechanism:

23. Reduction of Carbonyls Sodium borohydride (NaBH 4 ) Selectively reduce aldehydes and ketones Conditions: H 2 O, MeOH or EtOH

24. Reduction of Carbonyls Lithium aluminum hydride (LiAlH 4 or LAH) Stronger reducing agent than NaBH 4 Reduces aldehydes and ketones Also reduces carboxylic acids and esters (to primary alcohols) Conditions: aprotic solvent (ether or THF) LAH + H 2 O → H 2 (boom!)

25. Reduction of Carbonyls Ester Mechanism: More detail in Chapter 21

26. Draw the product of this reduction.

27. Reduction of Carbonyls In addition to metal hydrides, carbonyls can be reduced with H 2 Catalyst = Raney nickel Or, could use Pd, Pt, Ni with increased temperature and pressure Reduce aldehydes and ketones only Will also reduce double bonds and triple bonds

28. Summary of Reducing Agents Functional Group NaBH 4 LiAlH 4 H 2 Raney Ni H 2 Pt, Pd, Ni Aldehyde Ketone Carboxylic acid Ester C=C, C≡C

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 1. Reduction 2. 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 Mg 0 to Mg 2+ Reagents form on metal surface; solvated by ether (Et 2 O) Radical mechanism (slow)

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

35. Grignard Reaction Mechanism 1. Nucleophilic Grignard reagent attacks electrophilic carbonyl; new bond formed between R of RMgX and C of C=O 2. Alkoxide ion (a strong base) reacts with acid (usually HCl/H 2 O or H 3 O + ) 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 1. Ester/acid chloride → ketone 2. Ketone → tertiary alcohol Mechanism: Product = tertiary alcohol; two alkyl groups are the same

38. Grignard Reaction Product CarbonylAlcohol Formaldehyde1° Aldehyde2° Ketone3° Ester/acid chloride3°

39. Provide starting materials in the boxes below to complete the following reactions: a) b) c)

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

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

42. 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

43. Protection of Alcohols Three-step process 1. Introduce protecting group 2. Carry out reaction 3. Remove protecting group

44. Protection of Alcohols Protecting group is chlorotrimethylsilane (TMS-Cl) Nitrogen base promotes reaction S N 2-like reaction is allowed with tertiary Si Less sterically crowded due to longer bonds To remove TMS group React with H 3 O + or F - (from TBAF)

45. Grignard Reaction with Protecting Groups

46. Chemistry of Alcohols I. Preparation of Alcohols II. Reactions of Alcohols