Structure and Synthesis of Alcohols

1. Structure and Synthesis of Alcohols Biological Activity Nomenclature Preparation Reactions

2. Structure of Water and Methanol • Oxygen is sp3 hybridized and tetrahedral. • The H—O—H angle in water is 104.5°. • The C—O—H angle in methyl alcohol is 108.9°.

3. C H C H 3 3 C H C H C H O H C H C O H * 3 2 3 * C H 3 O H * C H C H C H C H 3 2 3 Examples of Classifications Primary alcohol Secondary alcohol Tertiary alcohol Phenol

5. Some Alcohols

6. Alcohols are Found in Many Natural Products

7. Paralytic Shellfish Poisoning

9. Ethanol: the Beverage

10. Enzymatic Oxidation of Ethanol Ethanol oxidizes to acetaldehyde, then acetic acid, which is a normal metabolite.

11. Excess NADH can cause Metabolic Problems

12. Methanol: Not a Beverage

13. Synergistic and Metabolic Effects • In men, ethanol lowers levels of testosterone (and sperm count) due to lack of enzymes needed for the steroid biosynthesis. • The enzyme CYP2E1, which is responsible for converting acetaminophen into liver toxins, is activated by ethanol. • Ethanol has a caloric value of 7.1Cal/g (fat has a value of 9 Cal/g). • Alcohol can cause a degenerative muscle disease called alcoholic myopathy (3 times more common than cirrhosis).

14. Synergistic Effects • Women will have higher BAL’s with the consumption of an equal number of drinks due to lower ADH activity and lower % H2O in blood. • Estradiol levels increase in women (and men). This has been associated with higher incidences of heart disease and a change in bone density. • A higher than normal concentration of Cytochrome P-450 enzymes (in the liver) are activated by ethanol creating a potential dependency.

15. Antitumor Agents • Often functionalized with alcohols • Designed to fit into specific geometic sites on proteins • Hydrogen bonding is crucial for binding • Water solubility is crucial for cell membrane transport

16. From the Bark of the Pacific Yew TreeTaxol (Paclitaxel)

17. How Taxol Works • A large number of microtubules are formed at the start of cell division, and as cell division comes to an end, these microtubules are normally broken down into tubulin – a protein responsible for the cell’s structural stability. • Taxol promotes tubulin polymerization then binds to the microtubules and inhibits their depolymerization back into tubulin. • The cell can't divide into daughter cells and therefore the cancer can’t spread.

18. May be More Effective than Taxol

19. DNA Cross-linker

20. Prevents DNA from Unraveling

21. IUPAC Nomenclature • Find the longest carbon chain containing the carbon with the —OH group. • Drop the -e from the alkane name; add -ol. • Number the chain, giving the —OH group the lowest number possible. • Number and name all substituents and write them in alphabetical order.

22. Alcohol Nomenclature

23. Nomenclature

24. Naming Diols • Two numbers are needed to locate the two —OH groups. • Use -diol as suffix instead of -ol. 1 2 3 4 5 6 hexane-1,6-diol

25. Who am I?

27. Boiling Points of Alcohols • Alcohols have higher boiling points than ethers and alkanes because alcohols can form hydrogen bonds. • The stronger interaction between alcohol molecules will require more energy to break, resulting in a higher boiling point.

28. Physical Properties CH3CH2CH3 -42 0.08 i CH3OCH3 -25 1.3 ss CH3CH2OH 78 1.7 vs b.p. oC m D sol. in H2O

29. Acidity of Alcohols • Due to the electronegativity of the O atoms, alcohols are slightly acidic (pKa 16-18). • The anion dervived by the deprotonation of an alcohol is the alkoxide. • Alcohols also react with Na (or K) as water does to give the alkoxide (red-ox):

30. Formation of Alkoxide Ions • Ethanol reacts with sodium metal to form sodium ethoxide (NaOCH2CH3), a strong base commonly used for elimination reactions. • More hindered alcohols like 2-propanol or tert-butanol react faster with potassium than with sodium.

31. Withdrawing Groups Enhance Acidity alcohol pKa CH3OH 15.54 CH3CH2OH 16.00 CF3CH2OH 12.43 (CH3)3COH 18.00 (CF3)3COH 5.4

32. Formation of Phenoxide Ion The aromatic alcohol phenol is more acidic than aliphatic alcohols due to the ability of aromatic rings to delocalize the negative charge of the oxygen within the carbons of the ring.

33. Charge Delocalization on the Phenoxide Ion • The negative charge of the oxygen can be delocalized over four atoms of the phenoxide ion. • The true structure is a hybrid between the four resonance forms.

34. Intermolecular H-Bonding

35. Preparation of Alcohols • Reduction of ketones and aldehydes • Reduction of esters and carboxylic acids • Hydration of Alkenes • Nucleophilic addition • Grignard reaction • Acetylide addition • Substitution • Epoxide opening

36. Oxymercuration HydrationMarkovnikov

37. Hydroboration HydrationAnti-Markovnikov

38. Oxidation and Reduction3 hydrocarbon oxidation levels

39. Oxidation levels of oxygen- halogen- and nitrogen-containing molecules

40. Grignard Reagents • Formula R—Mg—X (reacts like R:–+MgX). • Ethers are used as solvents to stabilize the complex. • Iodides are most reactive. Fluorides generally do not react. • May be formed from primary, secondary, or tertiary alkyl halides.

41. Organometallic ChemistryGrignard Reaction

42. Formation of Grignard Reagents

43. Grignard Reagents React With Aldehydes to form secondary alcohols

44. Grignard Reagents React With Ketones to form tertiary alcohols

45. Grignard Reagents React With Formaldehyde to form primary alcohols

46. Grignard Reagents open Epoxides

47. Grignard Reagentsreact (twice) withEstersto form3o Alcohols

48. Reaction of Grignards with Carboxylic Acid Derivatives

49. Grignard Summary

50. Grignard Summary