Carbonyl Compounds II: Chapter 18

Transcription

1 arbonyl ompounds II: hapter 18 eaction of Aldehydes and Ketones More eactions of arboxylic Acid Derivatives eactions of, - Unsaturated arbonyl ompounds

2 Two lasses of arbonyl ompounds lass I: Undergo nucleophilic acyl substituion. Includes carboxylic acid derivatives (last chapter). lass II: Do NT contain a group that can be replaced by a nucleophile (this chapter). formaldehyde an aldehyde a ketone arbanions ( ) and hydride ions ( ) are to be displaced by nucleophiles under normal conditions. lass II carbonyls undergo. 2

3 elative eactivities See section 1 for nomenclature of the class 2 compounds. lass II compounds are also polarized with + on carbon and on oxygen. Nucleophilic attack on the carbonyl carbon often results. Aldehydes are usually reactive than ketones in nucleophilic addition reactions: 1. Aldehydes 2. Aldehydes an aldehyde a ketone 3

4 elative eactivities Aldehydes and ketones are moderately reactive compared to other carbonyl compounds: acyl halide > acid anhydride > aldehyde > ketone > ester ~ carboxylic acid > amide Aldehydes/ketones are not as resonance stabilized as some: Y Y Y Aldehydes/ketones are more stable (less reactive) than others: l an acyl chloride a ketone 4

5 eactivity onsiderations Aldehydes and ketones do NT undergo nucleophilic acyl substitution. Why? ' + Z: Z ' Z + ': Aldehydes and ketones react via nucleophilic addition: ' + Z 5

6 eactivity onsiderations Nucleophilic addition can occur with a less electronegative nucleophile (Z = or ): ' + Z: r with a more electronegative nucleophile (Z = or N): ' + Z 6

7 Addition of arbon Nucleophiles Addition of carbon nucleophiles to aldehydes and ketones results in the formation of new - bonds. The following carbon nucleophiles will be discussed: 1. Grignard reagents ( ) and organolithium compounds ( ) 2. Acetylide anions ( ) 3. ydrogen cyanide ( ) 7

8 arbon Nucleophiles: MgX and Li eagents Grignard reagents (MgX) and organolithium compounds (Li) are both powerful nucleophiles. 3 2 Br + Mg Et MgBr reacts as if it were 3 2 Br + 2Li 3 2 Li reacts as if it were They react with carbonyl compounds (both class 1 and 2) resulting in new - bond formation. 8

9 arbon Nucleophiles: MgX and Li eaction with formaldehyde to form a 1º alcohol: MgX + + eaction with other aldehydes to form 2º alcohols: MgX + ' ' + 9

10 arbon Nucleophiles: MgX and Li eaction with other ketones to form 3º alcohols: MgX + ' '' ' '' + eaction with carbon dioxide to form a carboxylic acid: MgX + 10

11 arbon Nucleophiles: MgX and Li eaction with ethylene oxide to form a 1º alcohol : MgBr S 4 Note that two carbons are added to the Grignard reagent. 11

12 arbon Nucleophiles: MgX and Li eaction with carboxylic acid derivatives to form 3º alcohols : MgX + ' Et ' Et 1. + MgX Mgl l 2. 3 Note that two of the alkyl groups on the alcohol are identical. 12

13 arbon Nucleophiles: Acetylide Ions An acetylide ion also is an effective carbon nucleophile. Acetylide ions add to aldehydes and ketones to form acetylenic alcohols. 3 : + ' '' aldehyde or ketone 13

14 arbon Nucleophiles: N N adds to aldehydes and ketones to form cyanohydrins. The reaction is usually done in basic soln (p 9-10) so that both N and N are present. N + ' aldehyde or ketone 2 S 4, 2 N N 2, Pt 14

15 Addition of ydrogen Nucleophiles The hydride ion ( ) is a powerful nucleophile and reducing agent that can add to both class I and class II carbonyl compounds. The two most common sources of hydride are: sodium borohydride lithium aluminum hydride is the weaker and more selective reactant: eacts only with is more reactive and is used to reduce less reactive compounds like 15

16 Addition of ydrogen Nucleophiles eaction of NaB 4 with aldehydes to form 1º alcohols: eaction of NaB 4 with ketones to form 2º alcohols: + ' ' + ' 16

17 Addition of ydrogen Nucleophiles eaction of LiAl 4 with carboxylic acids to form 1. LiAl mechanism for the reaction of a carboxylic acid with hydride ion 3 + Al 3 17

18 Addition of ydrogen Nucleophiles eaction of LiAl 4 with esters to form ' 1. LiAl mechanism for the reaction of an ester with hydride ion 3 + Al 3 Al 3 18

19 Addition of ydrogen Nucleophiles 1 equiv of diisobutylaluminum hydride (DIBAl) reduces an ester to an. Low temps. (-78 º) are required. 1. DIBAl DIBAl = diisobutylaluminum hydride [( 3 ) 2 2 ] 2 Al 1 equiv of lithium tri-t-butoxyaluminum hydride reduces an acyl halide to an. Low temps. (-78 º) are required. l 1.LiAl[(( 3 )]

20 Addition of ydrogen Nucleophiles eaction of LiAl 4 with amides to form amines 1. LiAl 4 N º and 3º amines also possible if start with N-substituted amides. N 1. LiAl N 3 1. LiAl

21 Addition of Nitrogen Nucleophiles Aldehydes and ketones react with 1º amines, and other ammonia derivatives to form : + Z 2 N N N

22 Addition of Nitrogen Nucleophiles + 2 N N 2 3 hydrazine + 2 N N N 2 semicarbazide N N N 2 a semicarbazone + N 2 N N N 2,4-dinitrophenylhydrazine 3 2 N N N 2 2 N a 2,4-dinitrophenylhydrazone 22

23 Addition of Nitrogen Nucleophiles mechanism for imine formation: A nucleophilic addition-elimination mechanism + N 2 N 2 proton transfer N B N 23

24 Addition of Nitrogen Nucleophiles Imine formation is slow at both high p and low p but reaches a maximum rate at p 4-5. At low p (high [ 3 + ]) the reaction is slow because At high p (low [ 3 + ]) A p between is an effective compromise. 24

25 Addition of Nitrogen Nucleophiles Aldehydes and ketones react with 2º amines to form. 2 ' + '' N '' N N 25

26 Addition of Nitrogen Nucleophiles mechanism for enamine formation + N N proton transfer N B N N 26

27 Addition of Nitrogen Nucleophiles Amines can be synthesized in a single step by treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent = reductive amination. N 3 2 /cat ' aldehyde or ketone ''N 2 2 /cat '' 2 N 2 /cat ommon catalysts include aney Ni, Pd/ or NaB 3 N (sodium cyanoborohydride) 27

28 Addition of Nitrogen Nucleophiles The mechanism of reductive amination is thought to proceed via reduction of an imine intermediate for N 3 and 1 amines: + N excess reductive amination proceeds via reduction of an enamine intermediate for 2 amines: + N

29 Addition of Nitrogen Nucleophiles The Wolff-Kishner eduction In hap. 15 we learned that an aldehyde or ketone can be converted into a methylene (- 2 -) group under basic conditions in the presence of hydrazine. 29

30 Addition of Nitrogen Nucleophiles The mechanism of the Wolff-Kishner reduction is thought to proceed via a hydrazone intermediate. The presence of and heat pushes the reduction of the hydrazone. 3 + N 2 N 2 N N 3 N N + N N

31 Addition of xygen Nucleophiles The two oxygen nucleophiles we will discuss are: 1. water 2. alcohols Water adds reversibly to aldehydes and ketones to form a '() + 2 Note the reversibility of the reaction. The catalyst has no affect on the position of the equilibrium. 31

32 Addition of xygen Nucleophiles Mechanism of acid-catalyzed hydrate formation: The position of the equilibrium depends on the relative stabilities of the carbonyl compound and the hydrate

33 Addition of xygen Nucleophiles Therefore, formaldehyde has the greatest tendency to form hydrates while ketones are least likely to do so:

34 Addition of xygen Nucleophiles ne equivalent of an Alcohol adds reversibly to aldehydes to form a. Addition of a second equivalent forms an l ne equivalent of an Alcohol adds reversibly to ketones to form a. Addition of a second equivalent forms an l 34

35 Addition of xygen Nucleophiles The mechanism of acetal/ketal formation is similar to that of imines. B

36 Acetals & Ketals as Protecting Groups The reversibilty of these reactions allows acetals and ketals to be used as protecting groups. Ketones and aldehydes react with 1,2-diols and 1,3-diols to form five and six membered rings, respectively l + l For example: how can the following synthesis be performed? 3 3?

37 Acetals & Ketals as Protecting Groups Selective reduction of the ester is not possible. Why? NaB owever, the ester can be selectively reduced if the ketone is protected first as a ketal

38 Alcohol Protecting Groups The trimethylsilyl (TMS) group is an excellent alcohol protecting group: Si l Et 3 N 3 chlorotrimethylsilane (TMSl)

39 Alcohol Protecting Groups Br Ph Ph 39

40 arboxylic Acid Protecting Groups The group of a carboxylic acid can be protected by converting it to an : 40

41 The Wittig eaction The Wittig reaction is the standard method of preparing alkenes. The reaction involves the reaction of aldehydes or ketones with phosphonium ylides. A ylide is a compound with opposite charges on adjacent covalently bonded atoms, each of which has an octet of electrons. ( 6 5 ) 3 P 2 ( 6 5 ) 3 P 2 a phosphonium ylide + ( 6 5 ) 3 P " ' ''' 41

42 The Wittig eaction By Wittig eaction: ( 6 5 ) 3 P 2 By elimination: Br 3 Base ( 6 5 ) 3 P 42

43 The Wittig eaction The Wittig reaction involves an addition-elimination mechanism. Mechanism of the Wittig eaction ( 6 5 ) 3 P 2 43

44 The Wittig eaction The phosphorus ylides are easily prepared from triphenylphoshine (an excellent nucleophile and weak base) with 1º and 2 º alkyl halides via an S N 2 mechanism. A strong base (usually an alkyllithium or phenyllithium) is required to remove a proton from the intermediate alkyltriphenylphosphonium salt. ( 6 5 ) 3 P Br 44

45 The Wittig eaction The Wittig reaction has several advantages over E1 or E2 reactions The reaction is completely regioselective there is no question as to where the double bond will be. It is also stereoselective the E form dominates. Synthesize the molecule below using both dehydrohalogenation and the Wittig reaction

46 Nucleophilic Addition to - Unsaturated arbonyl ompounds, -unsaturated aldehydes and ketones contain two sites that are susceptible to nucleophilic attack. Two modes of nucleophilic addition are possible: 1. direct (1,2) addition nucleophile adds to the. 2. conjugate (1,4) addition nucleophile adds to the forming an enolate ion intermediate. 46

47 Nucleophilic Addition to - Unsaturated arbonyl ompounds Direct (1,2) addition Y: + onjugate (1,4) addition Y: + 47

48 1,2 (Direct) vs 1,4 (onjugate) Addition eversible with weak bases 1,2 addtion + Nu irreversible 2 Nu 1,2-addition is usually the kinetic product 1,4 addtion Nu 1,4-addition is the thermodynamic product: 48

49 1,2 (Direct) vs 1,4 (onjugate) Addition Direct addition (v. strong bases) onjugate addition (weak bases) LiAl 4 N 3, N 2, & 2 N NaB 4 (esp. with aldehydes) N and S Li or ArLi 2 uli (Gilman) MgX (subject to sterics) -carbanions (Michael addition) 1. ( 3 ) 2 uli 2., MgBr 2., 2 49

50 Nucleophilic Addition to - Unsaturated arbonyl ompounds utline two ways in which 4-methyl-2-octanone can be prepared by conjugate additon of an organocuprate to an -unsaturated ketone

51 Nucleophilic Addition to - Unsaturated arbonyl ompounds, -Unsaturated carboxylic acid derivates can also undergo the same two modes of nucleophilic attack. Nucleophilic acyl substitution is favored with acyl chlorides and anhydrides. l + 3 onjugate addition is favored with esters and amides: