Chapter 17: Alcohols and Phenols

1. Chapter 17: Alcohols and Phenols Based on McMurry’s Organic Chemistry, 7th edition

2. Alcohols and Phenols • Alcohols contain an OH group connected to a a saturated C (sp3) • They are important solvents and synthesis intermediates • Phenols contain an OH group connected to a carbon in a benzene ring • Methanol, CH3OH, called methyl alcohol, is a common solvent, a fuel additive, produced in large quantities • Ethanol, CH3CH2OH, called ethyl alcohol, is a solvent, fuel, beverage • Phenol, C6H5OH (“phenyl alcohol”) has diverse uses - it gives its name to the general class of compounds • OH groups bonded to vinylic, sp2-hybridized carbons are called enols

3. Why this Chapter? • To begin to study oxygen-containing functional groups • These groups lie at the heart of biological chemistry

4. 17.1 Naming Alcohols and Phenols • General classifications of alcohols based on substitution on C to which OH is attached • Methyl (C has 3 H’s), Primary (1°) (C has two H’s, one R), secondary (2°) (C has one H, two R’s), tertiary (3°) (C has no H, 3 R’s),

5. IUPAC Rules for Naming Alcohols • Select the longest carbon chain containing the hydroxyl group, and derive the parent name by replacing the -e ending of the corresponding alkane with -ol • Number the chain from the end nearer the hydroxyl group • Number substituents according to position on chain, listing the substituents in alphabetical order

6. Naming Phenols • Use “phenol” (the French name for benzene) as the parent hydrocarbon name, not benzene • Name substituents on aromatic ring by their position from OH

7. 17.2 Properties of Alcohols and Phenols • The structure around O of the alcohol or phenol is similar to that in water, sp3 hybridized • Alcohols and phenols have much higher boiling points than similar alkanes and alkyl halides • A positively polarized OH hydrogen atom from one molecule is attracted to a lone pair of electrons on a negatively polarized oxygen atom of another molecule • This produces a force that holds the two molecules together • These intermolecular attractions are present in solution but not in the gas phase, thus elevating the boiling point of the solution

8. Properties of Alcohols and Phenols: Acidity and Basicity • Weakly basic and weakly acidic • Alcohols are weak Brønsted bases • Protonated by strong acids to yield oxonium ions, ROH2+

9. Alcohols and Phenols are Weak Brønsted Acids • Can transfer a proton to water to a very small extent • Produces H3O+ and an alkoxide ion, RO, or a phenoxide ion, ArO

10. Acidity Measurements • The acidity constant, Ka, measures the extent to which a Brønsted acid transfers a proton to water [A] [H3O+]Ka = ————— and pKa = log Ka [HA] • Relative acidities are more conveniently presented on a logarithmic scale, pKa, which is directly proportional to the free energy of the equilibrium • Differences in pKa correspond to differences in free energy • Table 17.1 presents a range of acids and their pKa values

11. pKa Values for Typical OH Compounds

12. Relative Acidities of Alcohols • Simple alcohols are about as acidic as water • Alkyl groups make an alcohol a weaker acid • The more easily the alkoxide ion is solvated by water the more its formation is energetically favored • Steric effects are important

13. Inductive Effects • Electron-withdrawing groups make an alcohol a stronger acid by stabilizing the conjugate base (alkoxide)

14. Generating Alkoxides from Alcohols • Alcohols are weak acids – requires a strong base to form an alkoxide such as NaH, sodium amide NaNH2, and Grignard reagents (RMgX) • Alkoxides are bases used as reagents in organic chemistry

15. Phenol Acidity • Phenols (pKa ~10) are much more acidic than alcohols (pKa ~ 16) due to resonance stabilization of the phenoxide ion • Phenols react with NaOH solutions (but alcohols do not), forming salts that are soluble in dilute aqueous solution • A phenolic component can be separated from an organic solution by extraction into basic aqueous solution and is isolated after acid is added to the solution

16. Nitro-Phenols • Phenols with nitro groups at the ortho and para positions are much stronger acids

17. 17.3 Preparation of Alcohols: A Review • Alcohols are derived from many types of compounds • The alcohol hydroxyl can be converted to many other functional groups • This makes alcohols useful in synthesis

18. Review: Preparation of Alcohols by Regiospecific Hydration of Alkenes • Hydroboration/oxidation: syn, non-Markovnikov hydration • Oxymercuration/reduction: Markovnikov hydration

19. 1,2-Diols • Review: Cis-1,2-diols from hydroxylation of an alkene with OsO4 followed by reduction with NaHSO3 • Trans-1,2-diols from acid-catalyzed hydrolysis of epoxides

20. 17.4 Alcohols from Reduction of Carbonyl Compounds • Reduction of a carbonyl compound in general gives an alcohol • Note that organic reduction reactions add the equivalent of H2 to a molecule

21. Reduction of Aldehydes and Ketones • Aldehydes gives primary alcohols • Ketones gives secondary alcohols

22. Reduction Reagent: Sodium Borohydride • NaBH4 is not sensitive to moisture and it does not reduce other common functional groups • Lithium aluminum hydride (LiAlH4) is more powerful, less specific, and very reactive with water • Both add the equivalent of “H-”

23. Mechanism of Reduction • The reagent adds the equivalent of hydride to the carbon of C=O and polarizes the group as well

24. Reduction of Carboxylic Acids and Esters • Carboxylic acids and esters are reduced to give primary alcohols • LiAlH4 is used because NaBH4 is not effective

25. 17.5 Alcohols from Reaction of Carbonyl Compounds with Grignard Reagents • Alkyl, aryl, and vinylic halides react with magnesium in ether or tetrahydrofuran to generate Grignard reagents, RMgX • Grignard reagents react with carbonyl compounds to yield alcohols

26. Reactions of Grignard Reagents with Carbonyl Compounds

27. Reactions of Esters and Grignard Reagents • Yields tertiary alcohols in which two of the substituents carbon come from the Grignard reagent • Grignard reagents do not add to carboxylic acids – they undergo an acid-base reaction, generating the hydrocarbon of the Grignard reagent

28. Grignard Reagents and Other Functional Groups in the Same Molecule • Can't be prepared if there are reactive functional groups in the same molecule, including proton donors

29. Mechanism of the Addition of a Grignard Reagent • Grignard reagents act as nucleophilic carbon anions (carbanions, : R) in adding to a carbonyl group • The intermediate alkoxide is then protonated to produce the alcohol

30. 17.6 Reactions of Alcohols • Conversion of alcohols into alkyl halides: • 3˚ alcohols react with HCl or HBr by SN1 through carbocation intermediate • 1˚ and 2˚ alcohols converted into halides by treatment with SOCl2 or PBr3 via SN2 mechanism

32. Conversion of Alcohols into Tosylates • Reaction with p-toluenesulfonyl chloride (tosyl chloride, p-TosCl) in pyridine yields alkyl tosylates, ROTos • Formation of the tosylate does not involve the C–O bond so configuration at a chirality center is maintained • Alkyl tosylates react like alkyl halides

33. Stereochemical Uses of Tosylates • The SN2 reaction of an alcohol via a tosylate, produces inversion at the chirality center • The SN2 reaction of an alcohol via an alkyl halide proceeds with two inversions, giving product with same arrangement as starting alcohol

34. Dehydration of Alcohols to Yield Alkenes • The general reaction: forming an alkene from an alcohol through loss of O-H and H (hence dehydration) of the neighboring C–H to give  bond • Specific reagents are needed

35. Acid- Catalyzed Dehydration • Tertiary alcohols are readily dehydrated with acid • Secondary alcohols require severe conditions (75% H2SO4, 100°C) - sensitive molecules don't survive • Primary alcohols require very harsh conditions – impractical • Reactivity is the result of the nature of the carbocation intermediate

36. Dehydration with POCl3 • Phosphorus oxychloride in the amine solvent pyridine can lead to dehydration of secondary and tertiary alcohols at low temperatures • An E2 via an intermediate ester of POCl2 (see Figure 17.7)

37. Conversion of Alcohols into Esters

38. 17.7 Oxidation of Alcohols • Can be accomplished by inorganic reagents, such as KMnO4, CrO3, and Na2Cr2O7 or by more selective, expensive reagents

39. Oxidation of Primary Alcohols • To aldehyde: pyridinium chlorochromate (PCC, C5H6NCrO3Cl) in dichloromethane • Other reagents produce carboxylic acids

40. Oxidation of Secondary Alcohols • Effective with inexpensive reagents such as Na2Cr2O7 in acetic acid • PCC is used for sensitive alcohols at lower temperatures

41. Mechanism of Chromic Acid Oxidation • Alcohol forms a chromate ester followed by elimination with electron transfer to give ketone • The mechanism was determined by observing the effects of isotopes on rates

42. 17.8 Protection of Alcohols • Hydroxyl groups can easily transfer their proton to a basic reagent • This can prevent desired reactions • Converting the hydroxyl to a (removable) functional group without an acidic proton protects the alcohol

43. Methods to Protect Alcohols • Reaction with chlorotrimethylsilane in the presence of base yields an unreactive trimethylsilyl (TMS) ether • The ether can be cleaved with acid or with fluoride ion to regenerate the alcohol

44. Protection-Deprotection • An example of TMS-alcohol protection in a synthesis

45. 17.9 Phenols and Their Uses • Industrial process from readily available cumene • Forms cumene hydroperoxide with oxygen at high temperature • Converted into phenol and acetone by acid

46. 17.10 Reactions of Phenols • The hydroxyl group is a strongly activating, making phenols substrates for electrophilic halogenation, nitration, sulfonation, and Friedel–Crafts reactions • Reaction of a phenol with strong oxidizing agents yields a quinone • Fremy's salt [(KSO3)2NO] works under mild conditions through a radical mechanism

47. Quinones in Nature • Ubiquinones mediate electron-transfer processes involved in energy production through their redox reactions

48. 17.11 Spectroscopy of Alcohols and Phenols • Characteristic O–H stretching absorption at 3300 to 3600 cm1 in the infrared • Sharp absorption near 3600 cm-1 except if H-bonded: then broad absorption 3300 to 3400 cm1 range • Strong C–O stretching absorption near 1050 cm1 (See Figure 17.11) • Phenol OH absorbs near 3500 cm-1

49. Nuclear Magnetic Resonance Spectroscopy • 13C NMR: C bonded to OH absorbs at a lower field,  50 to 80 • 1H NMR: electron-withdrawing effect of the nearby oxygen, absorbs at  3.5 to 4 (See Figure 17-13) • Usually no spin-spin coupling between O–H proton and neighboring protons on C due to exchange reactions with moisture or acids • Spin–spin splitting is observed between protons on the oxygen-bearing carbon and other neighbors • Phenol O–H protons absorb at  3 to 8

50. Mass Spectrometry • Alcohols undergo alpha cleavage, a C–C bond nearest the hydroxyl group is broken, yielding a neutral radical plus a charged oxygen-containing fragment • Alcohols undergo dehydration to yield an alkene radical anion