1. ALCOHOLS Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8 th 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 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 Unsaturated alcohols (enol or ynol) 1. Parent chain contains carbon bonded to –OH and both carbons of C=C or C≡C 2. Suffix is “-ol”, infix is “-en-” or “-yn-” 3. Number chain so –OH has the lowest number 4. Show numbers for –OH and the unsaturation 5. Name/number substituents

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 For example, compare CH 3 O - and (CH 3 ) 3 CO -

14. Acidity of Alcohols Inductive effect:

15. Acidity of Phenols More acidic than alcohols Phenol pK a = 9.89 Resonance-stabilized 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 S N 2 reaction (competes with E2)

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: H 3 O + as a second step to form alcohol

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

26. Draw the product of this reduction.

27. Reduction of Carbonyls In addition to metal hydrides, carbonyls can be reduced with H 2 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 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. 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 1. Introduce protecting group 2. Carry out reaction 3. Remove protecting group 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

43. Grignard Reaction with Protecting Groups

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

45. A. Oxidation B. Formation of alkyl halides C. Formation of tosylates D. Dehydration E. Formation of esters

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

47. Oxidation with PCC Pyridinium chlorochromate (PCC) This reagent is not covered in McMurry! Complex of CrO 3 + pyridine + HCl Mild oxidizing agent 1° alcohol → aldehyde 2° alcohol → ketone 3° alcohol → no reaction Solvent = CH 2 Cl 2

48. Oxidation with H 2 CrO 4 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 KMnO 4 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 = S N 1 Product = racemic mixture (if stereocenter is present) Secondary ROH can react, but requires heat and can rearrange Evidence of reaction = formation of second layer

51. Formation of Alkyl Halides If alkyl halide is primary or secondary, reagents are thionyl chloride (SOCl 2 ) or phosphorous tribromide (PBr 3 ) Milder conditions than HCl or HBr (better option for 2°)

52. Reaction with SOCl 2 or PBr 3 Reaction mechanisms are S N 2 Inversion of configuration

53. C. Formation of Tosylates Used to convert alcohols into other functional groups Alcohol reacts with tosyl chloride (TsCl) to make tosylate Tosylate ion (TosO - or TsO - ) is an excellent leaving group

54. Formation of Tosylates Stereochemical configuration of alcohol does not change when the alcohol forms the tosylate Reaction occurs at O, not at C If tosylate undergoes S N 2 reaction, inversion of configuration will occur

55. Reduction of Tosylates Tosylates can be reduced to alkanes with LiAlH 4 Can you think of another method we can use to make an alkane from alcohol?

56. D. Dehydration Formation of alkene Reaction = E1 Tertiary alcohols react fastest Major product = Zaitsev Reagents = acid (H 3 O +, H 2 SO 4 or H 3 PO 4 );  (sometimes) Protonate -OH to create a better leaving group

57. E. Formation of Esters Reaction of an alcohol with a carboxylic acid or a carboxylic acid derivative We will cover this later in the semester

58. Synthesis Problem Propose a synthesis for 3-pentanone from ethanol. You may use any other organic molecule(s) as a source of carbon atoms.

59. Draw the major organic products formed in the following reactions, clearly showing all appropriate regio- and stereochemistry.

61. Reactions of Primary Alcohols Provide reagents for each reaction

62. Reactions of Secondary Alcohols Provide reagents for each reaction

63. Reactions of Tertiary Alcohols Provide reagents for each reaction