Alcohols & Thiols - 10

1. Sources Structure, Nomenclature, Properties Acidity and Basicity Reaction with active metals Conversion to R-X, inorganic acid halides Reactions with HX SN1/SN2, sulfonates Dehydration of alcohols Oxidation of 1o and 2o alcohols Oxidation of glycols [Pinacol & Thiols/Sulfur chemistry - skip] Alcohols & Thiols - 10

2. Hydration O H 1. Hg(OAc)2 /H2O 2. NaBH4 H or H+/H2O C C H H 3 H H C OH HOOH C + H3B H H NaOH H SN1 / SN2 Reduction Preparation of alcohols - (review)

3. H C 3 oxygen also sp3 hybridized Structure - Alcohols • Alcohol functional group: • -OH group bonded to an sp3 hybridized carbon • bond angles ~ 109.5° H H H C O

4. IUPAC names Longest chain that contains the -OH = root Give -OH group lowest number Change suffix -e to -ol (S)-2-methyl-1-butanol Nomenclature-Alcohols

5. H O H H H C C C 3 C C C H 3 H H H Nomenclature of Alcohols • Unsaturated alcohols: • The double bond becomes infix -en- • The hydroxyl group is the suffix -ol • numbering give OH the lower number (S,E)-4-hexen-2-ol

6. R H R H O O O H R R H O Physical Properties Hydrogen bonding: H bonded to an electronegative atom (F, O, or N) etc. Hydrogen bond weak (~ 5 kcal/mol) But have significant effects on properties and reactions

7. ethanol & dimethyl ether - constitutional isomers but weak hydrogen bonds (& dipole-dipole interactions) have dramatic effects: Physical Properties hydrogen bonds no hydrogen bonds

8. alcohols weak acids Acidity of Alcohols conjugate bases strong

9. 8.5 RSH Acidity of Alcohols

10. Acidity of Alcohols Hydrophobic cage Acidity  on: solvationand stabilization bulky alkyl groups decreases solvation

11. Acidity of Alcohols Acidity  on: stabilization and solvation electron donation destabilize alkoxides Steric BULK decreases solvation

12. (-) Basicity of Alcohols like water -Lewis base

13. Alcohols + Li, Na, K (active metals) form metalalkoxides Reaction with Metals metal alkoxide sodium methoxide

14. Reaction with Metals sodium cyclohexoxide

15. Conversion to R-X (with HX) 3° alcoholsreact very rapidly with HCl, HBr, HI. Low-molecular-weight 1° and 2° alcohols are unreactive under these conditions

16. 2° alcohols + HBr (or HI ) Reaction with HX may afford racemization, rearrangement, olefins

17. -H+ +X- +X- -H2O good leaving group 2o or 3o ROH with HX - SN1

18. X- displace +OH2 1o RX with HX - SN2

19. 1° and 2° alcohols Reaction with SOCl2 18 With amine -stereoselective

20. + a good leaving group Reaction with SOCl2 Reaction of an 1o/2o alcohol w/ SOCl2 in and a 3° amine is ‘stereoselective’; inversion.

21. Synthesis of 1° and 2° alkyl bromides via alcohol + PBr3(less rearrangement) Reaction with PBr3

22. Good leaving group Reaction with PBr3

23. Alkyl Sulfonates, good leaving group

24. good leaving group for SN reaction DMF S R alkyl sulfonates S S

25. Alkyl Sulfonates - Commonly p-toluenesulfonyl chloride (Ts-Cl) is used pyridine

26. OR Alkyl Sulfonates

27. 2° alcohols dehydrate at lower temperatures 3° alcohols at or slightly above room temperature Dehydration of ROH 1° ROH heated with acid catalyst, (H2SO4 or H3PO4)

28. where isomeric alkenes are possible, the alkene having the greater number of substituents on the double bond (the more stable alkene) usually predominates (Zaitsev rule) Dehydration of ROH

29. 80% 20% rearrangement & ease of dehydration (3°>2°>1°) suggest: • E1 mechanism for 2° and 3° ROH • [R+ formed in the rate-limiting step] ROH dehydration is often accompanied by rearrangement

30. Dehydration and alkene hydration compete Dehydration of ROH

31. Based on evidence of ease of dehydration (3° > 2° > 1°) prevalence of rearrangements Chemists propose a three-step mechanism for the dehydration of 2° and 3° alcohols because this mechanism involves formation of a carbocation intermediate in the rate-determining step, it is classified as E1 Dehydration of ROH

32. Step 1: proton transfer to the -OH group gives an oxonium ion Step 2: loss of H2O gives a carbocation intermediate Dehydration of ROH

33. Step 3: proton transfer from a carbon adjacent to the positively charged carbon to water; the sigma electrons of the C-H bond become the pi electrons of the carbon-carbon double bond Dehydration of ROH

34. Acid-catalyzed alcohol dehydration and alkene hydration are competing processes Principle of microscopic reversibility:the sequence of transition states and reactive intermediates in the mechanism of a reversible reaction must be the same, but in reverse order, for the reverse reaction as for the forward reaction Dehydration of ROH

35. Pinacol Rearrangement This section out [rearrangement under dehydration conditions]

36. Oxidation

37. Pyridinium chlorochromate (PCC): pyridine + CrO3 [Cr(VI)] + HCl Oxidation: 1° ROH PCC converts 1° alcohols to aldehydes and 2o alcohols to ketones

38. Oxidation aldehyde acid ketone NR (no reaction)

39. eliminate chromate ester (leaving group) Oxidation: 2° ROH

40. + -elimination of H and chromate 3o alcohols - NR - no “b-hydrogen”

41. [O] = CrO3 PCC Oxidation: 1° ROH acid aldehyde O H O O R R R [O] [O] C C C H H H OH

42. PCC oxidation of a 1° alcohol => aldehyde H2CrO4 Oxidation: 1° ROH But…... (also K2CrO7)

43. -elimination Oxidation: 1° ROH Rxn: chromate ester

44. Oxidation: 1° ROH hydrate

45. K2Cr2O7 and many other reagents Oxidation 1o and 2o ROH

46. Oxidation of Glycols with H5IO6 (or HIO4•2H2O) acyclic or cis-1,2 cyclic diols

47. OsO4 / HIO4equivalent to O3/reduction OsO4source of diols

48. Oxidation of Glycols with H5IO6 (or HIO4•2H2O) mechanism

49. Oxidation of Glycols with H5IO6 (or HIO4•2H2O)

50. biological systems do not use chromic acid or the oxides of other transition metals to oxidize 1° alcohols to aldehydes or 2° alcohols to ketones what they use instead is a NAD+ the Ad part of NAD+ is composed of a unit of the sugar D-ribose (Chapter 25) and one of adenosine diphosphate (ADP, Chapter 28) Oxidation of Alcohols by NAD+