Chapter 6 Reactions of Carbonyl Compounds 羰基化合物的反应

1. Chapter 6 Reactions of Carbonyl Compounds 羰基化合物的反应 6-1 Nucleophilic Addition Reacitions亲核加成反应 6-2 Nucleophilic Addition-Elimination Reactions 亲核加成消除反应 6-3 Condensation Reactions 缩合反应 6-4 The Nucleophilic Substitutions of Carbonyl Acid and Their Derivatives 羧酸及其衍生物的亲核取代

2. Key Terms Involved in This Chapter carbonyl (羰基) aldehyde(醛) ketone (酮) nucleophilic(亲核的) nucleophile (亲核试剂) electrophilic (亲电的) electrophile(亲电试剂) carbanion（碳负离子） diastereomer （非对映体）

3. Introduction Several functional groups contain the carbonyl group. • Structure of the Carbonyl Group • The carbonyl carbon is sp2 hybridized and is trigonal planar. All three atoms attached to the carbonyl group lie in one plane.

4. The carbonyl group is polarized. • There is substantial + charge on the carbon. nucleophilic at oxygen H+ or E+ electrophiles add here .. .. - d- : : : O O d+ C C + electrophilic at carbon nucleophiles attack here Nu: Nu: nucleophile 亲核试剂

5. 6-1 Nucleophilic Addition Reactions（亲核加成反应） • Carbonyl groups can undergo nucleophilic addition. • The nucleophile adds to the + carbon. • The  electrons shift to the oxygen. • The carbon becomes sp3 hybridized and therefore tetrahedral.

6. Mechanismsin Basic or Neutral Solutions An alkoxide ion or adding acid An alcohol A strong nucleophile attacks the carbonyl carbon, forming an alkoxide ion that is then protonated.

7. Acid Catalyzed Mechanisms more reactive to addition than the un-protonated precursor Acid catalysis speeds the rate of addition of weak nucleophiles and weak bases (usually uncharged). ACIDIC SOLUTION pH 5-6 stronger acid protonates the nucleophile

8. Typical Nucleophilies Nu-: -CN, CC-, RMgX, RLi, RZnBr, Witting Reagents, H-, -OH, RO-, HSO3-, Nu: H2O, ROH, RNH2, NH2OH, H2NNHR

9. 1. Cyanides act as nucleophiles toward C=O Buffered to pH 6-8 a cyanohydrin In acid solution there would be little CN-, and HCN (g) would be a problem (poison).

10. (1) Reactivity of Aldehydes and Ketones formaldehyde acetaldehyde acetone Methyl ketones Aldehydes are generally more reactive than ketones in nucleophilic additions.

11. (2) Factors affecting the nucleophilicaddition Electronic effects of alkyl groups Electron-donating group makes C=O less electrophilic less reactive Electron-withdrawing group makes C=O more electrophilic more reactive HCN: hydrocyanic acid

12. Steric effect Hybridization: sp2 sp3 The bond angle: 120° 109.5° The crowding in the products is increased by the larger group

13. (3) Sterochemistry Watch out for the possibility of optical isomerism inhydroxynitriles CN¯ attacks from above Enantiomers CN¯ attacks from below

14. CN¯ attacks from above Enantiomers CN¯ attacks from below

15. 非对映体 C X * diastereomeric X = C, O, N Chiral center Cram’s Rule How does this center control the direction of attack at the trigonalcarbon?

16. S O N u N u O H O H M Perspective drawing R L R L Less steric More steric Nu: Nu: S M O L L R R M M S S Minor product Major product

17. 2. Grignard reagents act as nucleophiles toward C=O Grignard reagents are prepared by the reaction of organic halides with magnesium turnings

18. Aldehydes and ketones react with Grignard reagentsto yield different classes of alcohols depending on the starting carbonyl compound

19. Esters react with two molar equivalents of a Grignard reagent to yield a tertiary alcohol A ketone is formed by the first molar equivalent of Grignard reagent andthis immediately reacts with a second equivalent to produce the alcohol. The final product contains two identical groups at the alcohol carbon that are both derived from the Grignard reagent.

21. Planning a Grignard Synthesis • Example : Synthesis of 3-phenyl-3-pentanol

22. Restrictions on the Use of Grignard Reagents • Grignard reagents are very powerful nucleophiles and bases. • They react as if they were carbanions. • Grignard reagents cannot be made from halides which contain acidic groups or electrophilic sites elsewhere in the molecule.

23. The substrate for reaction with the Grignard reagent cannot contain any acidic hydrogen atoms. • Two equivalents of Grignard reagent could be used, so that the first equivalent is consumed by the acid-base reaction , whilethe secondequivalent accomplishes carbon-carbon bond formation.

24. Sterochemistry-Cram’s rule 1 RMgX 2 H2O R major minor CH3 2.5 : 1 C6H5 > 4 : 1 (CH3)2CH 5 : 1 (CH3)3C 49 : 1 + minor major

25. 3. Organolithium act as nucleophiles toward C=O Organolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do.

26. 4. Sodium alkynidesact as nucleophiles toward C=O NaNH2: sodium amide propine Sodium alkynide

27. 5. Reformatskii Reactions (Organozinc Addition to C=O ) Organozinc is not as reactive as Grignard reagent, so it will not reactive with esters

28. 6. Wittig reaction (Ylides addition to C=O ) Synthetic method for preparing alkenes. Ylide - .. + X Y A compound or intermediate with both a positive and a negative charge on adjacent atoms. BOND Betaine or Zwitterion 内铵盐 两性离子 + A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in different parts of the molecule. Y MOLECULE - X :

29. R A + – •• C O (C6H5)3P C •• •• B R' R A + – •• + C C (C6H5)3P O •• •• B R' + triphenyl phosphine oxide An alkene （三苯基氧膦）

30. Preparation of a Phosphorous Ylide ( WITTIG REAGENT ) phosphonium salt Substrates: 1°, 2°Alkyl halides benzene : SN2 reaction - .. : O-CH3 .. .. ether strong base - + .. Triphenylphosphine ( Ph = C6H5 ) an ylide

31. The Wittig Reaction MECHANISM - .. + ylide betaine 内磷盐 INSOLUBLE synthesis of an alkene very thermodynamically stable molecule oxaphosphetane (UNSTABLE)

32. + + : ylide - SYNTHESIS OF AN ALKENE - WITTIG REACTION

33. + Br- PhLi .. - + ylide + .. : .. - + triphenylphosphine oxide (insoluble) ANOTHER WITTIG ALKENE SYNTHESIS

34. Synthesis of β-Carotene （β-胡萝卜素） Georg F. K. Wittig received the Nobel Prize in Chemistry in 1979.

35. German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry. In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene- triphenylphosphorane, (C6H5)3P=CR2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR2) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D3 Georg Wittig 1/2 of the prize University of Heidelberg Heidelberg, Federal Republic of Germany b. 1897d. 1987

36. 7.Hydride Addition to C=O Sources of hydride ("H-"), such as NaBH4, LiAlH4, all convert aldehydes and ketones to the corresponding alcohols by nucleophilic addition of hydride to C=O, followed or concurrently with protonation of the oxygen

37. LiAlH4 H2O Ethyl ether + 75% 25%

38. H3C CH3 O H3C CH3 H3C CH3 OH H OH H 80% NaBH4 20%

39. – H3B—H preferred direction of approach is to less hindered (bottom) face of carbonyl group Steric Hindrance to Approach of Reagent this methyl group hindersapproach of nucleophilefrom top

40. O CH3CCO2H Biological reductions are highly stereoselective pyruvic acid  S-(+)-lactic acid CO2H NADH HO H H+ CH3 enzyme is lactate dehydrogenase

41. One face of the substrate can bind to the enzyme better than the other.

42. Change in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially from one side rather than the other.

43. 8. Hydration of C=O hydrates or gem-diols

44. steric hindrance in the product

45. Very electrophilic C=O carbon because of nearby highly electronegative atoms favorable

46. Knock out drops

47. Hydrate formation relieves some ring strain by decreasing bond angles