Chemistry 353 Problem Solving Session

1. Chemistry 353 Problem Solving Session • The problem solving session will not be held this Thursday (April 20) • For this week only, the problem solving session will be moved to Wednesday, April 19, at 5:00 PM. • Chemistry Building 385 WWU Chemistry

2. Addition of Water (16.9) In general, the equilibrium does not favor formation of the hydrate. WWU Chemistry

3. Hydrate Formation: • Important only for low-molecular-weight aldehydes • Examples: WWU Chemistry

4. “Practical” Example WWU Chemistry

5. Mechanism of Hydration NOTE: The reaction is acid-catalyzed. The reverse process must follow exactly the same pathway as the forward process. WWU Chemistry

6. Addition of Alcohols (16.10) NOTE: A hemiacetal formed from a ketone is sometimes known as a hemiketal. Aldehydes form hemiacetals faster than ketones WWU Chemistry

7. Mechanism of Hemiacetal Formation NOTE: The reaction is acid-catalyzed The reverse reaction must follow the same pathway as the forward process. WWU Chemistry

8. The formation of hemiacetals is spontaneously reversible. The equilibrium between carbonyl compound and hemiacetal is constantly going back and forth. • Hemiacetal formation is a very important process in the chemistry of the sugars (Section 16.12) WWU Chemistry

9. Reaction With a Second Molecule of Alcohol: Formation of Acetals heat This reaction is also reversible. But, in this case, the equilibrium can be driven to the right by an application of Le Châtelier’s Principle. WWU Chemistry

10. Removal of Water: Le Châtelier’s Principle in Action 1) Remove water from the reaction as quickly as it is formed. This is accomplished by anazeotropicdistillation(see next image). 2) The acid catalyst must bedry. It cannot contain water. Catalysts that are used include: Hydrogen chloride gas (dry) Hydrogen chloride gas dissolved in an alcohol solvent p-Toluenesulfonic acid (dry crystals) -- “HOTs” WWU Chemistry

11. Dean-Stark Water Separator When the azeotrope condenses, the water and benzene form separate layers (immiscible). As water forms in the reaction, it distills out of the solution in the form of an azeotrope with benzene. (c.f.Introduction to Organic Laboratory Techniques, Sections 10.7, 10.8) Benzene layer Water layer Aldehyde or ketone, alcohol, and benzene WWU Chemistry

12. Mechanism of Acetal Formation Notice that this mechanism combines features of the SN1 reaction and carbonyl addition. WWU Chemistry

13. The Overall Picture heat Technically, both steps are reversible, but only the firststep isspontaneouslyreversible. The second step requires more stringent conditions and heating to be reversed. WWU Chemistry

14. Formation of 2,2-Dimethoxy-propane heat Dry acid = HCl gas HCl in methanol HOTs WWU Chemistry

15. A second example... heat WWU Chemistry

16. Starting with acrolein: heat WWU Chemistry

17. Formation of a Cyclic Acetal heat This reaction is important in the preparation ofprotective groups(see Section 16.11) WWU Chemistry

18. Do you remember this? heat WWU Chemistry

19. So, why not do this? heat Because sulfur is a stronger nucleophile than oxygen, and because the products are more stable, this reaction goes much more readily toward theright. WWU Chemistry

20. Introduction to Protective Groups (16.11) • When a molecule has more than one functional group, it is sometimes difficult to carry out a reaction on one functional group without having the other group interfere. • Sometimes the non-target functional group will react at the same time as the target group, giving a mixture of products. • Sometimes the non-target group reacts fasterthan the target group, leading to the wrong product. • Sometimes the non-target group will destroy the reagent, thereby making the desired synthesis impossible. WWU Chemistry

21. What we need, then, is some means of covering up the non-target functional group while we operate on the target group. • We need aprotective group. • Ideally, the protective group should be something that we can attach easily and in high yield. • It must be stable under the conditions of the reaction that are used to modify the target functional group. It needs to be inert during the reaction. • It should be easily removed without decomposing the entire structure. WWU Chemistry

22. NON-TARGET TARGET Acetals are very important protective groups. They are inert under basic conditions, and they undergo rapid hydrolysis when heated with aqueous acid PROTECT NON-TARGET TARGET MODIFY TARGETGROUP NON-TARGET NON-TARGET TARGET TARGET DEPROTECT WWU Chemistry

23. Example of an acetal used as functional group: A 1,3-Dioxolane This is anacetal. If you’re dying to know why the “dioxolane” name, I can be talked into digressing about IUPAC nomenclature of heterocyclic rings. WWU Chemistry

24. Use of a Cyclic Acetal as a Protective Group Suppose I wanted to do... Try to make a Grignard reagent and then add ethylene oxide. BUT: If you attempt to make the Grignard reagent, it will try to react with itself! WWU Chemistry

25. Protect Use of a Protective Group Deprotect WWU Chemistry

26. A Useful Variation • Boron trifluoride is a Lewis acid -- this reaction goes under much milder conditions of acid catalysis. • The advantage of the 1,3-oxathiolanes is that they can be removed (deprotect step) easily without hydrolysis in an acid medium. WWU Chemistry

27. Deprotecting a 1,3-Oxathiolane • Raney Nickel is a specially-prepared nickel catalyst. • These deprotection conditions are much milder than acid hydrolysis. WWU Chemistry

28. Raney Nickel • A specially-prepared form of nickel metal, in an active, finely-divided state. • A nickel-aluminum alloy is treated with aqueous sodium hydroxide. The NaOH dissolves away the aluminum, leaving behind the nickel in a finely-divided state, almost as a colloidal suspension. • The nickel has the hydrogen already adsorbed on its surface. WWU Chemistry

29. One More Variation What’s the 1,3-dithiolane good for? Wait until Chapter 17. WWU Chemistry

30. What if I wanted to make a Grignard reagent of this compound? This wouldn’t work. The –OH groups are too acidic to permit the formation of a Grignard reagent. WWU Chemistry

31. But if we protect the –OH groups… heat This is called an acetonide. WWU Chemistry

32. … and now we can make the Grignard reagent … WWU Chemistry

33. … use it in a reaction… WWU Chemistry

34. … and, finally, deprotect We get back our original diol functional groups. WWU Chemistry

35. Use of Protective Groups • The synthesis of a complex molecule requires a careful strategy. • When to use protective groups? • Which ones to use? • When is the best time to put them on? • When is the appropriate time to deprotect? WWU Chemistry

36. Tetrahydropyranyl Ethers The dry acid can be HCl in methanol or HOTs The reaction is an addition of ROH across the double bond of dihydropyran. WWU Chemistry

37. Tetrahydropyranyl Ethers • Excellent protective group for alcohols • THP Ether is an acetal. • THP Ether is stable under strongly basic conditions • THP Ether can be deprotected by hydrolysis in aqueous acid. WWU Chemistry

38. Example: Use of THP Ether as Protective Group Problem: Devise a strategy for making the following conversion WWU Chemistry

39. Step One: Protect –OH Group WWU Chemistry

40. Step Two: Alkylate Alkynyl Carbon WWU Chemistry

41. Step Three: Deprotect The acetal (THP ether) can be removed easily by hydrdolysis in acid. WWU Chemistry

42. Carbohydrates -- Cyclic Structures • Read Sections 16.15 through 16.18 • Review Chapter 5, Sections 5.14 through 5.16 WWU Chemistry

43. Carbohydrates contain the functional groups of alcohols and aldehydes or ketones in the same molecule. They are polyhydroxyaldehydes or polyhydroxyketones. • Thus they can form acetal-type products through the intramolecular interaction of these functional groups. • As a model, consider the reaction: WWU Chemistry

44. Cyclization of Monosaccharides WWU Chemistry

45. Redrawing the linear structure as a ring... Note the hemiacetal position The product of the cyclization is ahemiacetal. WWU Chemistry

46. furan pyran FURANOSE AND PYRANOSE RINGS 6 a pyranose ring two anomers are possible in each case a furanose ring 5 for clarity no hydroxyl groups are shown on the chains or rings WWU Chemistry

47. ANOMERS anomeric carbon (hemiacetal) for clarity hydroxyl groups on the chain are not shown anomers differ in configuration at the anomeric carbon -- they arediastereomers WWU Chemistry

48. Linear Forms of Anomers WWU Chemistry

49. HAWORTH PROJECTIONS It is convenient to view the cyclic sugars (glucopyranoses) as a “Haworth Projection”, where the ring is flattened. HAWORTH PROJECTION upper-right back This orientation is always used for a Haworth Projection a-D-(+)-glucopyranose WWU Chemistry

50. HAWORTH PROJECTIONS HERE ARE SOME CONVENTIONS YOU MUST LEARN 1) The ring is always oriented with the oxygen in the upper right-hand back corner. D 2) The -CH2OH group is placed UP for a D-sugar 3) a-Sugars have the -CH2OH group and the anomeric hydroxyl group trans. a 4) b-Sugars have the -CH2OH group and the anomeric hydroxyl group cis. b WWU Chemistry