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1. Aldehydes & Ketones Chapter 16 Chapter 16

2. 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)

3. 16.1 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. • pi bonding and pi antibonding MOs for formaldehyde.

4. H C H C H C H C H C C H 3 3 3 Methanal Ethanal Propanone (Formaldehyde) (Acetaldehyde) (Acetone) 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. O O O

5. 16.2 A.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, change 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, add the suffix –carbaldehyde.

6. B. Nomenclature: Aldehydes • the IUPAC retains the common names benzaldehyde and cinnamaldehyde, as well formaldehyde and acetaldehyde.

7. Nomenclature: Ketones • IUPAC names • the parent alkane is the longest chain that contains the carbonyl group. • indicate the ketone by changing the suffix -e to -one. • number the chain to give C=O the smaller number. • the IUPAC retains the common names acetone, acetophenone, and benzophenone.

8. Order of Precedence, Table 16.1 • For compounds that contain more than one functional group indicated by a suffix.

9. C. 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.

10. 16.3 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.

11. 16.4 Reaction Themes , Nu attack at C • One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound.

12. Reaction Themes , O attack at H • A second common theme is reaction with a proton or other Lewis acid to form a resonance-stabilized cation. • protonation increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles.

13. Reaction Themes, stereochemistry • often the tetrahedral product of addition to a carbonyl is a new chiral center. • if none of the starting materials is chiral and the reaction takes place in an achiral environment, then enantiomers will be formed as a racemic mixture.

14. 16.5 Addition 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.

15. A. 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.

16. Grignard Reagents, 1o alcohols • addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol. • Note that these reactions require two steps.

17. Grignard Reagents, 2o alcohols • addition to any other aldehyde, RCHO, gives a 2° alcohol (two steps).

18. Grignard Reagents, 3o alcohols • addition to a ketone gives a 3° alcohol (two steps).

19. Grignard Reagents Problem:2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination. Work backwards to get starting materials.

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. Look at: Acetophenone Propiophenone 2-butanone + EtMgBr + MeMgBe + PhMgBr

21. B. Organolithium Compounds • Organolithium compounds, RLi, give the same C=O addition reactions as RMgX but generally are more reactive and usually give higher yields. • Lithium is monovalent and does not insert between C and X like Mg. • Like the Grignard this requires two steps.

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

23. Salts of Terminal Alkynes • Addition of water or hydroboration/oxidation of the product gives an enol which rearranges.

24. O H C H C H H C C H C - C 3 3 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin) D. 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. O + N N H

25. Addition of HCN • Mechanism of cyanohydrin formation: • Step 1: nucleophilic addition of cyanide to the carbonyl carbon. • Step 2: proton transfer from HCN gives the cyanohydrin and regenerates cyanide ion.

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

27. acid O O H H catalyst C H C H C C H - C H COOH H O 3 3 2 2-Hydroxypropanenitrile 2-Hydroxypropanoic acid (Acetaldehyde cyanohydrin) Cyanohydrins • The value of cyanohydrins: • 3. acid-catalyzed hydrolysis of the nitrile gives a carboxylic acid. N

28. 16.6 Wittig Reaction • The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.

29. Phosphonium Ylides (Wittig reagent) • Phosphonium ylidesare formed in two steps: • Step 1: nucleophilic displacement of iodine by triphenylphosphine. • Step 2: treatment of the phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2.

30. Wittig Reaction • Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene. • Step 1: nucleophilic addition of the ylide to the electrophilic carbonyl carbon. • Step 2: decomposition of the oxaphosphatane.

31. Wittig Reaction • Examples:

32. Wittig Reaction • some Wittig reactions are Z selective, others are E selective. • Wittig reagents with an anion-stabilizing group, such as a carbonyl group, adjacent to the negative charge are generally E selective. • Wittig reagents without an anion-stabilizing group are generally Z selective.

33. Wittig Reaction Modification • Horner-Emmons-Wadsworth modification: • uses a phosphonoester. • phosphonoester formation requires two steps (see next slide).

34. Wittig Reaction Modification • phosphonoesters are prepared by successive SN2 reactions: attack by the phosphite, then attack by Br-

35. Wittig Reaction Modification • treatment of a phosphonoester with a strong base produces the modified Wittig reagent, • an aldehyde or ketone is then added to give an alkene. • a particular value of using a phosphonoester-stabilized anion is that they are almost exclusively E selective.

36. 16.7 A.Addition of H2O, hydrates • Addition of water (hydration) to the carbonyl group of an aldehyde or ketone gives a geminal diol, commonly referred to a gem-diol. • gem-diols are also referred to as hydrates.

37. Addition of H2O, hydrates • when formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated. • the equilibrium concentration of a hydrated ketone is considerably smaller.

38. B. Addition of Alcohol, hemiacetals • 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.

39. Addition of Alcohol, cyclic hemiacetals • hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form.

40. Addition of Alcohol, cyclic hemiacetals • at equilibrium, the b anomer of glucose predominates because the -OH group on the anomeric carbon is equatorial.

41. Addition of Alcohols, in base • Formation of a hemiacetal can be base catalyzed. • Step 1: proton transfer 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.

42. Addition of Alcohols, in acid • Formation of a hemiacetal can be 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.

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

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

45. Addition of Alcohols, acetals Step 3: reaction of the cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal. Step 4: proton transfer to A- gives the acetal and generates a new acid catalyst.

46. Addition of Alcohols, cyclic acetals • with ethylene glycol and other glycols, the product is a five-membered cyclic acetal. • these are used as protective groups.

47. Dean-Stark Trap, Fig. 16.1

48. C. Acetals as Protecting Grps • Suppose you wish to bring about a Grignard reaction between these compounds. • But a Grignard reagent prepared from 4-bromobutanal will self-destruct! (react with C=O)

49. Acetals as Protecting Groups • So, first protect the -CHO group as an acetal, • then do the Grignard reaction. • hydrolysis (not shown) gives the target molecule.

50. D. Acetals as Protecting Groups • Tetrahydropyranyl (THP), as a protecting group for an alcohol. • 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.

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