Organic Chemistry

1. Organic Chemistry William H. Brown & Christopher S. Foote

2. Aldehydes & Ketones Chapter 15 Chapter 16

3. The Carbonyl Group • In this and several following chapters we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O • aldehydes and ketones (Chapter 16) • carboxylic acids (Chapter 17) • acid halides, acid anhydrides, esters, amides (Chapter 18) • enolate anions (Chapter 19)

4. The Carbonyl Group • The carbonyl group consists of • one sigma bond formed by the overlap of sp2 hybrid orbitals, and • one pi bond formed by the overlap of parallel 2p orbitals

5. The Carbonyl Group • pi bonding and pi antibonding MOs for formaldehyde.

6. Structure • The functional group of an aldehyde is a carbonyl group bonded to a H atom and a carbon atom • The functional group of a ketone is a carbonyl group bonded to two carbon atoms

7. Nomenclature • IUPAC names: • the parent chain is the longest chain that contains the functional group • for an aldehyde, change the suffix from -e to -al • for an unsaturated aldehyde, show the carbon-carbon double bond by changing the infix from -an- to -en-; the location of the suffix determines the numbering pattern • for a cyclic molecule in which -CHO is bonded to the ring, name the compound by adding the suffix -carbaldehyde

8. Nomenclature: Aldehydes

9. Nomenclature: Ketones • IUPAC names: • select as the parent alkane the longest chain that contains the carbonyl group • indicate its presence by changing the suffix -e to -one • number the chain to give C=O the smaller number

10. Order of Precedence • For compounds that contain more than one functional group indicated by a suffix

11. Common Names • for an aldehyde, the common name is derived from the common name of the corresponding carboxylic acid • for a ketone, name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone

12. Physical Properties • Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar • aldehydes and ketones are polar compounds and interact in the pure state by dipole-dipole interaction • they have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight

13. Reaction Themes • One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound

14. Reaction Themes • A second common theme is reaction with a proton or Lewis acid to form a resonance-stabilized cation • protonation in this manner increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles

15. Add’n of C Nucleophiles • Addition of carbon nucleophiles is one of the most important types of nucleophilic additions to a C=O group; a new carbon-carbon bond is formed in the process • We study addition of these carbon nucleophiles

16. Grignard Reagents • Given the difference in electronegativity between carbon and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with C- and Mg+ • in its reactions, a Grignard reagent behaves as a carbanion • Carbanion:an anion in which carbon has an unshared pair of electrons and bears a negative charge • a carbanion is a good nucleophile and adds to the carbonyl group of aldehydes and ketones

17. Grignard Reagents • Addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol

18. Grignard Reagents • Addition to any other RCHO gives a 2° alcohol

19. Grignard Reagents • Addition to a ketone gives a 3° alcohol

20. Grignard Reagents Problem:2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination.

21. Organolithium Compounds • Organolithium compounds are generally more reactive in C=O addition reactions than RMgX, and typically give higher yields

22. Salts of Terminal Alkynes • Addition of an acetylide anion followed by H3O+ gives an -acetylenic alcohol

23. Salts of Terminal Alkynes

24. Addition of HCN • HCN adds to the C=O group of an aldehyde or ketone to give a cyanohydrin • Cyanohydrin:a molecule containing an -OH group and a -CN group bonded to the same carbon

25. Addition of HCN • Mechanism of cyanohydrin formation

26. Cyanohydrins • The value of cyanohydrins • acid-catalyzed dehydration of the 2° or 3° alcohol • catalytic reduction of the cyano group gives a 1° amine

27. Wittig Reaction • The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.

28. Phosphonium Ylides • Phosphonium ylidesare formed in two steps:

29. Wittig Reaction • Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene

30. Wittig Reaction • Examples:

31. Addition of H2O • Addition of water (hydration) to the carbonyl group of an aldehyde or ketone gives a gem-diol, commonly referred to as a hydrate • when formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated

32. Addition of H2O • the equilibrium concentration of a hydrated ketone is considerably smaller

33. Addition of Alcohols • Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal • Hemiacetal:a molecule containing an -OH and an -OR or -OAr bonded to the same carbon

34. Addition of Alcohols • Hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form (the model is of the trans isomer)

35. Addition of Alcohols • Formation of a hemiacetal is base catalyzed • Step 1: proton transfer from HOR gives an alkoxide • Step 2: Attack of RO-on the carbonyl carbon • Step 3: proton transfer from the alcohol to O-gives the hemiacetal and generates a new base catalyst

36. Addition of Alcohols • Formation of a hemiacetal is also acid catalyzed Step 1: proton transfer to the carbonyl oxygen Step 2: attack of ROH on the carbonyl carbon Step 3: proton transfer from the oxonium ion to A- gives the hemiacetal and generates a new acid catalyst

37. Addition of Alcohols • Hemiacetals react with alcohols to form acetals Acetal:a molecule containing two -OR or -OAr groups bonded to the same carbon

38. Addition of Alcohols Step 1: proton transfer from HA gives an oxonium ion Step 2: loss of water gives a resonance-stabilized cation

39. Addition of Alcohols Step 3: reaction of the cation (a Lewis acid) with methanol (a Lewis base) gives the conjugate acid of the acetal Step 4: (not shown) proton transfer to A- gives the acetal and generates a new acid catalyst

40. Addition of Alcohols • With ethylene glycol, the product is a five-membered cyclic acetal

41. Dean-Stark Trap

42. Acetals as Protecting Grps • Suppose you wish to bring about a Grignard reaction between these compounds

43. Acetals as Protecting Grps • If the Grignard reagent were prepared from 4-bromobutanal, it would self-destruct! • first protect the -CHO group as an acetal • then do the Grignard reaction • hydrolysis (not shown) gives the target molecule

44. Acetals as Protecting Grps • Tetrahydropyranyl (THP) protecting group • the THP group is an acetal and, therefore, stable to neutral and basic solutions and to most oxidizing and reducting agents • it is removed by acid-catalyzed hydrolysis

45. Add’n of S Nucleophiles • Thiols, like alcohols, add to the C=O of aldehydes and ketones to give tetrahedral carbonyl addition products • The sulfur atom of a thiol is a better nucleophile than the oxygen atom of an alcohol • A common sulfur nucleophile used for this purpose is 1,3-propanedithiol • the product is a 1,3-dithiane

46. Add’n of S Nucleophiles • The hydrogen on carbon 2 of the 1,3-dithiane ring is weakly acidic, pKa approximately 31

47. Add’n of S Nucleophiles • a 1,3-dithiane anion is a good nucleophile and undergoes SN2 reactions with methyl, 1° alkyl, allylic, and benzylic halides • hydrolysis gives a ketone

48. Add’n of S Nucleophiles • Treatment of the 1,3-dithiane anion with an aldehyde or ketone gives an -hydroxyketone

49. Add’n of N Nucleophiles • Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases)

50. Add’n of N Nucleophiles • Formation of an imine occurs in two steps Step 1: carbonyl addition followed by proton transfer Step 2: loss of H2O and proton transfer to solvent