8Chapter 20

8Chapter 20 - Chapter 20 Enols and Enolates Dr. Wolf's CHM...

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Unformatted text preview: Chapter 20 Enols and Enolates Dr. Wolf's CHM 201 & 202 20-1 20.1, 20.2 Aldehyde, Ketone, and Aldehyde, Ester Enolates Ester Dr. Wolf's CHM 201 & 202 20-2 Terminology O CH3CH2CH2CH γ βα The reference atom is the carbonyl carbon. Other carbons are designated α, β, γ , etc. on the Other etc. basis of their position with respect to the carbonyl carbon. carbon. Hydrogens take the same Greek letter as the Hydrogens carbon to which they are attached. carbon Dr. Wolf's CHM 201 & 202 20-3 Acidity of α-Hydrogen Acidity •• •• O• R2C • CR' – R2C •• O• • CR' + H+ H enolate ion pKa = 16-20 R2C Dr. Wolf's CHM 201 & 202 •• – •O • •• CR' 20-4 Acidity of α-Hydrogen Acidity O (CH3)2CHCH pKa = 15.5 Dr. Wolf's CHM 201 & 202 O CCH3 CC pKa = 18.3 20-5 β-Diketones are much more acidic O H3C O C C C H H O H3C Dr. Wolf's CHM 201 & 202 C CH3 pKa = 9 O – •• C H C CH3 + H+ 20-6 β-Diketones are much more acidic – •• •O• • H3C C •• O• • C C • enolate of β-diketone -diketone is stabilized; negative charge is shared by both oxygens both CH3 H •• •O • H3C Dr. Wolf's CHM 201 & 202 C •• O• •• C– H C • CH3 20-7 β-Diketones are much more acidic – •• •O• • H3C C •• •O • O• • C C • H3C CH3 H •O • Dr. Wolf's CHM 201 & 202 C C C CH3 H •• H3C •• – •O • •• •• C •• O• •• C– H C • CH3 20-8 Esters O O OR H O OR H OR H Hydrogens α to an ester carbonyl group are less Hydrogens acidic, pKa ≅ 24, than α of aldehydes and acidic, ketones, pKa ≅ 16-20. ketones, The decreased acidity is due the decreased The electron withdrawing ability of an ester carbonyl. electron Electron delocalization decreases the positive Electron character of the ester carbonyl group. character Dr. Wolf's CHM 201 & 202 20-9 Esters O R O C C H C OR' H A proton on the carbon flanked by the two proton carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions. quantitatively Dr. Wolf's CHM 201 & 202 20-10 O R O C C C H – CH3CH2O R Dr. Wolf's CHM 201 & 202 pKa ~ 11 H O C OR' O •• –C H C OR' 20-11 •• O• R C – •• • O• •• •O • • •• –C H C • OR' R C •• •O • • C C OR' H The resulting carbanion is stabilized by The enolate resonance involving both carbonyl groups. groups. Dr. Wolf's CHM 201 & 202 20-12 •• O• R C O• •O • • •• –C H C •• – •O • •• •• •• OR' R C • C C OR' H The resulting carbanion is stabilized by The enolate resonance involving both carbonyl groups. groups. Dr. Wolf's CHM 201 & 202 20-13 20.3 The Aldol Condensation Dr. Wolf's CHM 201 & 202 20-14 Some thoughts... O O – •• RCH2CH + • OH pKa = 16-20 • •• •• RCHCH + HOH •• •• – pKa = 16 A basic solution contains comparable amounts basic of the aldehyde and its enolate. of Aldehydes undergo nucleophilic addition. Enolate ions are nucleophiles. What about nucleophilic addition of enolate to What aldehyde? aldehyde? Dr. Wolf's CHM 201 & 202 20-15 •• O• •• •• O• • – RCHCH O• • •• • RCHCH RCHCH RCH2CH RCH2CH RCH2CH O• •O • •• – •• • OH •• • •• • O 2RCH2CH O NaOH RCH2CH OH Dr. Wolf's CHM 201 & 202 CHCH R 20-16 Aldol Addition O RCH2CH OH CHCH R product is called an "aldol" because it is product both an aldehyde and an alcohol both Dr. Wolf's CHM 201 & 202 20-17 Aldol Addition of Acetaldehyde O 2CH3CH O NaOH, H2O 5°C CH3CH CH2CH OH Acetaldol (50%) Dr. Wolf's CHM 201 & 202 20-18 Aldol Addition of Butanal O 2CH3CH2CH2CH KOH, H2O 6°C O CH3CH2CH2CH OH CHCH CH2CH3 (75%) Dr. Wolf's CHM 201 & 202 20-19 Aldol Condensation O 2RCH2CH O NaOH RCH2CH OH Dr. Wolf's CHM 201 & 202 CHCH R 20-20 Aldol Condensation O 2RCH2CH O NaOH RCH2CH OH CHCH R heat NaOH heat O RCH2CH CCH R Dr. Wolf's CHM 201 & 202 20-21 Aldol Condensation of Butanal O 2CH3CH2CH2CH NaOH, H2O 80-100°C O CH3CH2CH2CH CCH CH2CH3 (86%) Dr. Wolf's CHM 201 & 202 20-22 Dehydration of Aldol Addition Product C H C O C O C C OH C dehydration of β-hydroxy aldehyde can be dehydration catalyzed by either acids or bases Dr. Wolf's CHM 201 & 202 20-23 Dehydration of Aldol Addition Product Dehydration C H O NaOH C C OH C O – C• • C OH iin base, the enolate is formed n Dr. Wolf's CHM 201 & 202 20-24 Dehydration of Aldol Addition Product C H O C C NaOH C O – C• OH • C OH the enolate loses hydroxide to form the the α,β-unsaturated aldehyde Dr. Wolf's CHM 201 & 202 20-25 Aldol reactions of ketones O 2CH3CCH3 2% 98% OH O CH3CCH2CCH3 CH3 the equilibrium constant for aldol addition the reactions of ketones is usually unfavorable reactions Dr. Wolf's CHM 201 & 202 20-26 Intramolecular Aldol Condensation O O O Na2CO3, H2O heat heat O (96%) via: OH Dr. Wolf's CHM 201 & 202 20-27 Intramolecular Aldol Condensation O O O Na2CO3, H2O heat heat (96%) even ketones give good yields of aldol even condensation products when the reaction is intramolecular Dr. Wolf's CHM 201 & 202 20-28 20.4 Mixed Aldol Condensations Dr. Wolf's CHM 201 & 202 20-29 What is the product? O O NaOH CH3CH + CH3CH2CH There are 4 possibilities because the There reaction mixture contains the two aldehydes plus the enolate of each aldehyde. aldehyde. Dr. Wolf's CHM 201 & 202 20-30 What is the product? O O CH3CH + CH3CH2CH O CH3CH O – • CH2CH • Dr. Wolf's CHM 201 & 202 O – CH3CHCH CH2CH OH •• 20-31 What is the product? O O CH3CH + CH3CH2CH O CH3CH2CH O – • CH2CH • Dr. Wolf's CHM 201 & 202 O – CH3CHCH OH CHCH CH3 •• 20-32 What is the product? O O CH3CH + CH3CH2CH O CH3CH O – • CH2CH • Dr. Wolf's CHM 201 & 202 O – CH3CHCH OH CHCH CH3 •• 20-33 What is the product? O O CH3CH + CH3CH2CH O CH3CH2CH O – • CH2CH • Dr. Wolf's CHM 201 & 202 O – CH3CHCH CH2CH OH •• 20-34 In order to effectively carry out a mixed aldol condensation: need to minimize reaction possibilities usually by choosing one component that cannot usually form an enolate form Dr. Wolf's CHM 201 & 202 20-35 Formaldehyde O HCH formaldehyde cannot form an enolate formaldehyde is extremely reactive toward formaldehyde nucleophilic addition nucleophilic Dr. Wolf's CHM 201 & 202 20-36 Formaldehyde O O HCH + (CH3)2CHCH2CH O K2CO3 waterether (CH3)2CHCHCH CH2OH (52%) Dr. Wolf's CHM 201 & 202 20-37 Aromatic Aldehydes O CH3O CH aromatic aldehydes cannot form an enolate Dr. Wolf's CHM 201 & 202 20-38 Aromatic Aldehydes O O CH3O CH3CCH3 CH + NaOH, H2O 30°C O CH3O Dr. Wolf's CHM 201 & 202 CH CHCCH3 CHCCH (83%) 20-39 Deprotonation of Aldehydes, Ketones, and Esters Simple aldehydes, ketones, and esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original carbonyl, and Aldol or Claisen condensation occurs. Are there bases strong enough to completely deprotonate simple carbonyls, giving enolates quantitatively? Dr. Wolf's CHM 201 & 202 20-40 Lithium diisopropylamide Li + CH3 H C CH3 – •• N •• CH3 C H CH3 Lithium dialkylamides are strong bases (just as NaNH2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups. Dr. Wolf's CHM 201 & 202 20-41 Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. O CH3CH2CH2COCH3 + LiN[CH(CH3)2]2 pKa ~ 22 O – CH3CH2CHCOCH3 + •• Dr. Wolf's CHM 201 & 202 HN[CH(CH3)2]2 pKa ~ 36 + + Li 20-42 Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated. O CH3CH2CHCOCH3 CH2CH3 O CH3CH2I (92%) – CH3CH2CHCOCH3 •• Dr. Wolf's CHM 201 & 202 20-43 Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. O CH3COCH2CH3 1. LiNR2, THF 2. (CH3)2C 2. (CH 3. H3O+ O HO H3C Dr. Wolf's CHM 201 & 202 O C CH2COCH2CH3 CH3 (90%) 20-44 Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. O CH3CH2CC(CH3)3 1. LDA, THF O 2. CH3CH2CH 2. CH 3. H3O+ O CH3CHCC(CH3)3 Dr. Wolf's CHM 201 & 202 HOCHCH2CH3 (81%) 20-45 20.5 The Claisen Condensation (gives β-keto esters) Dr. Wolf's CHM 201 & 202 20-46 The Claisen Condensation O 2RCH2COR' O 1. NaOR' 2. H3O + O RCH2CCHCOR' + R'OH R β-Keto esters are made by the reaction shown, which is called the Claisen condensation. Ethyl esters are typically used, with sodium ethoxide as the base. Dr. Wolf's CHM 201 & 202 20-47 Example O 2CH3COCH2CH3 O 1. NaOCH2CH3 2. H3O + O CH3CCH2COCH2CH3 (75%) Product from ethyl acetate is called ethyl acetoacetate or acetoacetic ester. Dr. Wolf's CHM 201 & 202 20-48 Mechanism Step 1: CH3CH2 Dr. Wolf's CHM 201 & 202 •• •• – O• •• • O• H CH2 • COCH2CH3 20-49 Mechanism Step 1: CH3CH2 •• O• •• – O• •• • CH2 H • COCH2CH3 •• CH3CH2 Dr. Wolf's CHM 201 & 202 •• O •• H – • CH2 • O• • COCH2CH3 20-50 Mechanism Step 1: CH2 Anion produced is stabilized by electron delocalization; it is the enolate of an ester. COCH2CH3 •• – • CH2 • Dr. Wolf's CHM 201 & 202 •• – • O• •• O• • COCH2CH3 20-51 Mechanism Step 2: •• O• • CH3COCH2CH3 Dr. Wolf's CHM 201 & 202 •• – • CH2 • O• • COCH2CH3 20-52 Mechanism •• – •O• •• Step 2: CH3C CH •• O• • CH2 COCH2CH3 • OCH2CH3 •• • •• O• • CH3COCH2CH3 Dr. Wolf's CHM 201 & 202 •• – • CH2 • O• • COCH2CH3 20-53 Mechanism Step 2: •• – •O• •• CH3C •• O• CH2 • COCH2CH3 • OCH2CH3 •• • Dr. Wolf's CHM 201 & 202 20-54 Mechanism •• – •O• •• Step 3: CH3C •• O• CH2 • COCH2CH3 • OCH2CH3 •• • •• •• O• CH3C • Dr. Wolf's CHM 201 & 202 O• CH2 • COCH2CH3 + – •• • OCH2CH3 • •• 20-55 Mechanism Step 3: The product at this point is ethyl acetoacetate. However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small. Something else does happen. Ethoxide abstracts a proton from the CH2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable. •• •• O• CH3C • Dr. Wolf's CHM 201 & 202 O• CH2 • COCH2CH3 + – •• • OCH2CH3 • •• 20-56 Mechanism Step 4: •• •• O• CH3C • – CH •• •• CH3C Dr. Wolf's CHM 201 & 202 • COCH2CH3 •• +H OCH2CH3 •• •• O• • O• O• CH2 • COCH2CH3 + – •• • OCH2CH3 • •• 20-57 Mechanism Step 5: •• •• O• CH3C • O – CH •• COCH2CH3 In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate. Dr. Wolf's CHM 201 & 202 20-58 Mechanism Step 5: •• •• O• CH3C • – CH •• •• CH3C Dr. Wolf's CHM 201 & 202 + H O• COCH2CH3 •H •• O• • H O H O• CH H • COCH2CH3 + •O • •• H 20-59 Another example O 2 CH3CH2COCH2CH3 Reaction involves bond formation between the αcarbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other. Dr. Wolf's CHM 201 & 202 1. NaOCH2CH3 2. H3O+ O O CH3CH2CCHCOCH2CH3 CH3 (81%) 20-60 20.6 Intramolecular Claisen Condensation: The Dieckmann Reaction Dr. Wolf's CHM 201 & 202 20-61 Example O O CH3CH2OCCH2CH2CH2CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ O O COCH2CH3 COCH Dr. Wolf's CHM 201 & 202 (74-81%) 20-62 via •• O• O • CH3CH2OCCH2CH2CH2CH2COCH2CH3 NaOCH2CH3 •• O• •• O• • • – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• Dr. Wolf's CHM 201 & 202 20-63 via •• O• •• O• • • – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• Dr. Wolf's CHM 201 & 202 20-64 via •• CH3CH2O •• H2C H2C •• O• •• – • O • •• • • O• C • CHCOCH2CH3 CH2 •• O• • • – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• Dr. Wolf's CHM 201 & 202 20-65 via •• CH3CH2O •• H2C H2C Dr. Wolf's CHM 201 & 202 •• – • O • •• • • O• C • CHCOCH2CH3 CH2 20-66 via •• CH3CH2O •• H2C H2C •• – • O • •• • • O• C • CHCOCH2CH3 CH2 •• •O • •• – CH3CH2O • CH •• • Dr. Wolf's CHM 201 & 202 •• O• C + H2C H2C • CHCOCH2CH3 CH2 20-67 20.7 Mixed Claisen Condensations Dr. Wolf's CHM 201 & 202 20-68 Mixed Claisen Condensations As with mixed aldol condensations, mixed Claisen condensations are best carried out when the reaction mixture contains one compound that can form an enolate and another that cannot. Dr. Wolf's CHM 201 & 202 20-69 Mixed Claisen Condensations These types of esters cannot form an enolate. O HCOR O ROCOR O ROC O COR O COR COR Dr. Wolf's CHM 201 & 202 20-70 Example O O COCH3 + CH3CH2COCH3 1. NaOCH3 2. H3O+ O O CCHCOCH3 (60%) CH3 Dr. Wolf's CHM 201 & 202 20-71 20.8 Acylation of Ketones with Esters Dr. Wolf's CHM 201 & 202 20-72 Acylation of Ketones with Esters Esters that cannot form an enolate can be used to acylate ketone enolates. Dr. Wolf's CHM 201 & 202 20-73 Example O O CH3CH2OCOCH2CH3 + 1. NaH 2. H3O+ O O COCH2CH3 (60%) Dr. Wolf's CHM 201 & 202 20-74 Example O O COCH2CH3 + CH3C 1. NaOCH2CH3 2. H3O+ O O CCH2C (62-71%) Dr. Wolf's CHM 201 & 202 20-75 Example O O CH3CH2CCH2CH2COCH2CH3 1. NaOCH3 2. H3O+ O O CH3 Dr. Wolf's CHM 201 & 202 (70-71%) 20-76 20.9 Alkylation of Enolate Anions Dr. Wolf's CHM 201 & 202 20-77 Enolate Ions in SN2 Reactions Enolate ions are nucleophiles and react with alkyl halides. However, alkylation of simple enolates does not work well. Enolates derived from β-diketones can be alkylated efficiently. Dr. Wolf's CHM 201 & 202 20-78 Example O O CH3CCH2CCH3 + CH3I K2CO3 O O CH3CCHCCH3 CH3 (75-77%) Dr. Wolf's CHM 201 & 202 20-79 20.10 The Acetoacetic Ester Synthesis Dr. Wolf's CHM 201 & 202 20-80 Acetoacetic Ester O H3C O C C C OCH2CH3 H H Acetoacetic ester is another name for ethyl acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. Dr. Wolf's CHM 201 & 202 20-81 Deprotonation of Ethyl Acetoacetate O H3C O C C H C H pKa ~ 11 Dr. Wolf's CHM 201 & 202 OCH2CH3 + – CH3CH2O Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. 20-82 Deprotonation of Ethyl Acetoacetate O H3C O C C C H O H3C OCH2CH3 H pKa ~ 11 C + K ~ 105 O •• –C Dr. Wolf's CHM 201 & 202 H C CH3CH2O – Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. OCH2CH3 + CH3CH2OH pKa ~ 16 20-83 Alkylation of Ethyl Acetoacetate O H3C C O •• –C C OCH2CH3 H R Dr. Wolf's CHM 201 & 202 X The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). 20-84 Alkylation of Ethyl Acetoacetate O H3C C O •• –C C OCH2CH3 H R O H3C O C C X C H Dr. Wolf's CHM 201 & 202 OCH2CH3 The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). R 20-85 Conversion to Ketone O H3C C O C H C R 1. HO–, H2O 2. H+ O H3C OH O C C C H Dr. Wolf's CHM 201 & 202 OCH2CH3 Saponification and acidification convert the alkylated derivative to the corresponding β-keto acid. The β-keto acid then undergoes decarboxylation to form a ketone. R 20-86 Conversion to Ketone O H3C C O C H C OH R O H3C C CH2R Dr. Wolf's CHM 201 & 202 + CO2 Saponification and acidification convert the alkylated derivative to the corresponding β-keto acid. The β-keto acid then undergoes decarboxylation to form a ketone. 20-87 Example O O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br 2. CH Dr. Wolf's CHM 201 & 202 20-88 Example O O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br 2. CH O O CH3CCHCOCH2CH3 CH2CH2CH2CH3 Dr. Wolf's CHM 201 & 202 (70%) 20-89 Example O CH3CCH2CH2CH2CH2CH3 (60%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CCHCOCH2CH3 CH2CH2CH2CH3 Dr. Wolf's CHM 201 & 202 20-90 Example: Dialkylation O O CH3CCHCOCH2CH3 CH2CH Dr. Wolf's CHM 201 & 202 CH2 20-91 Example: Dialkylation O O CH3CCHCOCH2CH3 CH2CH CH2 1. NaOCH2CH3 2. CH3CH2I 2. CH OO CH3CCCOCH2CH3 CH3CH2 Dr. Wolf's CHM 201 & 202 CH2CH (75%) CH2 20-92 Example: Dialkylation O CH3CCH CH2CH CH2 CH3CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 OO CH3CCCOCH2CH3 CH3CH2 Dr. Wolf's CHM 201 & 202 CH2CH CH2 20-93 Another Example O O COCH2CH3 H β-Keto esters other than ethyl acetoacetate may be used. Dr. Wolf's CHM 201 & 202 20-94 Another Example O O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br 2. O O COCH2CH3 CH2CH CH2 Dr. Wolf's CHM 201 & 202 (89%) 20-95 Another Example O O COCH2CH3 CH2CH CH2 Dr. Wolf's CHM 201 & 202 20-96 Another Example O H CH2CH O CH2 (66%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 O COCH2CH3 CH2CH CH2 Dr. Wolf's CHM 201 & 202 20-97 20.11 The Malonic Ester Synthesis Dr. Wolf's CHM 201 & 202 20-98 Malonic Ester O CH3CH2O O C C C OCH2CH3 H H Malonic ester is another name for diethyl malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. Dr. Wolf's CHM 201 & 202 20-99 An Analogy O O O O CH3CCH2COCH2CH3 CH3CH2OCCH2COCH2CH3 O O CH3CCH2R HOCCH2R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids. Dr. Wolf's CHM 201 & 202 20-100 Example O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H2C O CHCH2CH2CH2Br O CH3CH2OCCHCOCH2CH3 CH2CH2CH2CH Dr. Wolf's CHM 201 & 202 (85%) CH2 20-101 Example O HOCCH2CH2CH2CH2CH CH2 (75%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2CH Dr. Wolf's CHM 201 & 202 CH2 20-102 Dialkylation O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH3Br 2. CH O O CH3CH2OCCHCOCH2CH3 (79-83%) CH3 Dr. Wolf's CHM 201 & 202 20-103 Dialkylation OO CH3CH2OCCCOCH2CH3 CH3 CH3(CH2)8CH2 1. NaOCH2CH3 2. CH3(CH2)8CH2Br 2. CH O O CH3CH2OCCHCOCH2CH3 CH3 Dr. Wolf's CHM 201 & 202 20-104 Dialkylation OO CH3CH2OCCCOCH2CH3 CH3 CH3(CH2)8CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3(CH2)8CH2CHCOH CH3 Dr. Wolf's CHM 201 & 202 (61-74%) 20-105 Another Example O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH2CH2CH2Br O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Dr. Wolf's CHM 201 & 202 20-106 Another Example This product is not isolated, but cyclizes in the presence of sodium ethoxide. O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Dr. Wolf's CHM 201 & 202 20-107 Another Example OO CH3CH2OCCCOCH2CH3 H2C CH2 (60-65%) C H2 NaOCH2CH3 O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Dr. Wolf's CHM 201 & 202 20-108 Another Example OO CH3CH2OCCCOCH2CH3 H2C CH2 C H2 H 1. NaOH, H2O 2. H+ 3. heat, -CO2 CO2H C H2C Dr. Wolf's CHM 201 & 202 CH2 C H2 (80%) 20-109 Barbiturates Dr. Wolf's CHM 201 & 202 21-110 Barbituric acid is made from diethyl malonate O COCH2CH3 H2N + H2C COCH2CH3 C O H2N O Dr. Wolf's CHM 201 & 202 21-111 Barbituric acid is made from diethyl malonate and urea O O COCH2CH3 C COCH2CH3 C O Dr. Wolf's CHM 201 & 202 C O H2N O N H2C C + H2C H H2N O 1. NaOCH2CH3 2. H+ N H (72-78%) 21-112 Barbituric acid is made from diethyl malonate and urea O COCH2CH3 + H2C COCH2CH3 C O H2N O H O H2N 1. NaOCH2CH3 2. H+ N O N O Dr. Wolf's CHM 201 & 202 H (72-78%) 21-113 Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate O COCH2CH3 H2C COCH2CH3 O Dr. Wolf's CHM 201 & 202 O 1. RX, 1. R NaOCH2CH3 2. R''X, 2. R R' NaOCH2CH3 COCH2CH3 C COCH2CH3 O 21-114 Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate O O R H N O R' O N H (H2N)2C O R R' COCH2CH3 C COCH2CH3 O Dr. Wolf's CHM 201 & 202 21-115 Examples O CH3CH2 H N O CH3CH2 O N H 5,5-Diethylbarbituric acid (barbital; Veronal) Dr. Wolf's CHM 201 & 202 21-116 Examples H3C O CH3CH2CH2CH H N O CH3CH2 O N H 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) Dr. Wolf's CHM 201 & 202 21-117 Examples H3C O CH3CH2CH2CH H2C H N O CHCH2 O N H 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) Dr. Wolf's CHM 201 & 202 21-118 20.13 Enolization and Enol Content Dr. Wolf's CHM 201 & 202 20-119 Mechanism of Enolization (In general) H •• O• H •O • H• • R2C • CR' O• •• • H •• Dr. Wolf's CHM 201 & 202 H R2C •O • CR' H 20-120 Mechanism of Enolization (Base-catalyzed) •• O• – •• – •O • H• • Dr. Wolf's CHM 201 & 202 R2C • CR' H 20-121 Mechanism of Enolization (Base-catalyzed) R2C •• •O H• Dr. Wolf's CHM 201 & 202 •• – •O • •• CR' H H O• •• • H 20-122 Mechanism of Enolization (Base-catalyzed) R2C Dr. Wolf's CHM 201 & 202 •• – •O • •• CR' H H O• •• • 20-123 Mechanism of Enolization (Base-catalyzed) •• R2C Dr. Wolf's CHM 201 & 202 •O • CR' H H – •O • • •• • 20-124 Mechanism of Enolization (Acid-catalyzed) H •• O• R2C • CR' H O• + • H H Dr. Wolf's CHM 201 & 202 20-125 Mechanism of Enolization (Acid-catalyzed) + •• O R2C CR' H H •O • •• H H Dr. Wolf's CHM 201 & 202 20-126 Mechanism of Enolization (Acid-catalyzed) + •• O H •O • H• • Dr. Wolf's CHM 201 & 202 R2C H CR' H 20-127 Mechanism of Enolization (Acid-catalyzed) •• H+ •O H• Dr. Wolf's CHM 201 & 202 R2C •O • H CR' H 20-128 Enol Content O R2CHCR' OH R2C keto CR' enol percent enol is usually very small keto form usually 45-60 kJ/mol more stable than enol Dr. Wolf's CHM 201 & 202 20-129 Enol Content Acetaldehyde O CH3CH OH H2C CH K = 3 x 10-7 Acetone O CH3CCH3 Dr. Wolf's CHM 201 & 202 OH H2C CCH3 K = 6 x 10-9 20-130 20.14 α Halogenation of Aldehydes and Ketones Dr. Wolf's CHM 201 & 202 20-131 General Reaction O R2CCR' + O X2 H+ H R2CCR' + HX X X2 is Cl2, Br2, or I2. Substitution is specific for replacement of Substitution α hydrogen. hydrogen. Catalyzed by acids. One of the products is an acid Catalyzed (HX); the reaction is autocatalytic. autocatalytic Not a free-radical reaction. free-radical Dr. Wolf's CHM 201 & 202 20-132 Example O O + Cl2 Cl H2O + HCl (61-66%) Dr. Wolf's CHM 201 & 202 20-133 Example O O CH H + Br2 CH CHCl3 Br + HBr Br (80%) Notice that it is the proton on the α carbon Notice that is replaced, not the one on the carbonyl carbon. carbon. Dr. Wolf's CHM 201 & 202 20-134 Mechanism of α Halogenation Mechanism Experimental Facts specific for replacement of H at the α carbon specific equal rates for chlorination, bromination, and equal iodination iodination first order in ketone; zero order in halogen Interpretation no involvement of halogen until after the rate-determining step Dr. Wolf's CHM 201 & 202 20-135 Mechanism of α Halogenation Mechanism Two stages: first stage is conversion of aldehyde or first ketone to the corresponding enol; is rateketone determining second stage is reaction of enol with halogen; second is faster than the first stage is Dr. Wolf's CHM 201 & 202 20-136 Mechanism of α Halogenation Mechanism O RCH2CR' OH slow RCH CR' O X2 fast enol RCHCR' X Enol is key intermediate Dr. Wolf's CHM 201 & 202 20-137 Mechanism of α Halogenation Mechanism Two stages: first stage is conversion of aldehyde or first ketone to the corresponding enol; is rateketone determining second stage is reaction of enol with halogen; second is faster than the first stage is examine second stage now examine second stage now Dr. Wolf's CHM 201 & 202 20-138 Reaction of enol with Br2 •• R2C •• • Br •• • • OH • CR' •• Br • •• • carbocation is carbocation stabilized by electron release from oxygen from Dr. Wolf's CHM 201 & 202 •• • OH • R2C Br • Br • •• • • •• – CR' + • Br • •• + •• •• •• + OH R2C • Br • •• • • CR' 20-139 Loss of proton from oxygen completes the process H •• Br • •• • •• +O O• R2C • CR' • Br • •• 202 Dr. Wolf's CHM•201 & • •• – • Br • •• •• •• R2C • Br • •• • • H CR' 20-140 20.15 α-Halogenation of Carboxylic Acids: The Hell-Volhard-Zelinsky Reaction Dr. Wolf's CHM 201 & 202 20-141 α --Halogenation of α Halogenation of Carboxylic Acids Carboxylic Acids O R2CCOH + X2 H O R2CCOH + HX X analogous to α-halogenation of aldehydes and ketones key question: Is enol content of carboxylic acids high enough to permit reaction to occur at reasonable rate? (Answer is NO) Dr. Wolf's CHM 201 & 202 20-142 But... But... O R2CCOH + X2 P or PX3 O R2CCOH + HX H X reaction works well if a small amount of phosphorus or a phosphorus trihalide is added to the reaction mixture this combination is called the Hell-VolhardZelinsky reaction Dr. Wolf's CHM 201 & 202 20-143 Example Example O CH2COH + Br2 CH PCl3 benzene 80°C O CHCOH CHCOH (60-62%) Br Dr. Wolf's CHM 201 & 202 20-144 Value Value O CH3CH2CH2COH Br2 P O CH3CH2CHCOH Br (77%) α-Halogen can be replaced by nucleophilic -Halogen substitution substitution Dr. Wolf's CHM 201 & 202 20-145 Value Value O CH3CH2CH2COH Br2 P O CH3CH2CHCOH Br (77%) O CH3CH2CHCOH K2CO3 H2O heat OH (69%) Dr. Wolf's CHM 201 & 202 20-146 Synthesis of α --Amino Acids Synthesis of α Amino Acids O (CH3)2CHCH2COH Br2 PCl3 O (CH3)2CHCHCOH Br O NH3 H2O (88%) (CH3)2CHCHCOH NH2 (48%) Dr. Wolf's CHM 201 & 202 20-147 The Haloform Reaction Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage. Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products. Dr. Wolf's CHM 201 & 202 20-148 Example O (CH3)3CCCH3 Br2, NaOH, H2O O (CH3)3CCONa + CHBr3 H+ O (CH3)3CCOH Dr. Wolf's CHM 201 & 202 (71-74%) 20-149 The Haloform Reaction The haloform reaction is sometimes used as a The method for preparing carboxylic acids, but works well only when a single enolate can form. only O (CH3)3CCCH3 yes Dr. Wolf's CHM 201 & 202 O O ArCCH3 RCH2CCH3 yes no 20-150 Mechanism First stage is substitution of all available α hydrogens First by halogen O O RCCH3 RCCX3 X2, HO– O RCCH2X Dr. Wolf's CHM 201 & 202 X2, HO– X2, HO– O RCCHX2 20-151 Mechanism Formation of the trihalomethyl ketone is followed by Formation its hydroxide-induced cleavage its •• – •O• •• •• O• •• HO • – + RC RC •• • CX3 RC • HO • •• •• •• O• • •• – RC O • + •• • Dr. Wolf's CHM 201 & 202 CX3 • O• HCX3 RC – OH + • CX3 • •• •• • 20-152 20.16 Some Chemical and Stereochemical Consequences of Enolization Dr. Wolf's CHM 201 & 202 20-153 Hydrogen-Deuterium Exchange O H H H H + 4D2O KOD, heat O D D Dr. Wolf's CHM 201 & 202 D D + 4DOH 20-154 Mechanism •• H •O • H H H Dr. Wolf's CHM 201 & 202 H H + – •• • OD • •• •• – •O• •• H •• + HOD HO •• 20-155 Mechanism •• H •O • H H H Dr. Wolf's CHM 201 & 202 D H + – •• • OD • •• •• – •O• •• H D •• OD •• 20-156 Stereochemical Consequences of Enolization H3O+ H H3C C O CC6H5 CH3CH2 100% R 100% R Dr. Wolf's CHM 201 & 202 50% R 50% R 50% S 50% S H2O, HO– 50% R 50% R 50% S 50% S 20-157 Enol is achiral H O H3C H3C C CC6H5 C OH CC6H5 CH3CH2 CH3CH2 R R Dr. Wolf's CHM 201 & 202 20-158 Enol is achiral H3C H S S C O CC6H5 50% CH3CH2 H H3C R R C H3C OH C O 50% CC6H5 CH3CH2 CC6H5 CH3CH2 Dr. Wolf's CHM 201 & 202 20-159 Results of Rate Studies H H3C C CH3CH2 Dr. Wolf's CHM 201 & 202 O CC6H5 Equal rates for: racemization H-D exchange bromination iodination Enol is intermediate and Enol its formation is rateits determining 20-160 20.17 Effects of Conjugation in Effects α,β -Unsaturated Aldehydes and α ,β -Unsaturated Ketones Ketones Dr. Wolf's CHM 201 & 202 20-161 Relative Stability aldehydes and ketones that contain a carboncarbon double bond are more stable when the carbon double bond is conjugated with the carbonyl group than when it is not group compounds of this type are referred to as α,β compounds unsaturated aldehydes and ketones unsaturated Dr. Wolf's CHM 201 & 202 20-162 Relative Stability γ CH3CH O βα CHCH2CCH3 (17%) K = 4.8 O CH3CH2CH γβ Dr. Wolf's CHM 201 & 202 (83%) CHCCH3 α 20-163 Acrolein O H2C Dr. Wolf's CHM 201 & 202 CHCH 20-164 Acrolein O H2C Dr. Wolf's CHM 201 & 202 CHCH 20-165 Acrolein O H2C Dr. Wolf's CHM 201 & 202 CHCH 20-166 Acrolein O H2C Dr. Wolf's CHM 201 & 202 CHCH 20-167 Resonance Description C C •• C O• • C +C Dr. Wolf's CHM 201 & 202 C •• – O• •• C+ • C •• – O• •• • C 20-168 Properties α,β-Unsaturated aldehydes and ketones are -Unsaturated more polar than simple aldehydes and ketones. α,β-Unsaturated aldehydes and ketones contain α,β-Unsaturated two possible sites for nucleophiles to attack carbonyl carbon carbonyl β-carbon Dr. Wolf's CHM 201 & 202 βC C •• C O• • 20-169 Dipole Moments Dipole δ– O δ+ δ+ O δ– δ+ µ = 2.7 D 2.7 µ = 3.7 D 3.7 Butanal trans-2-Butenal greater separation greater of positive and negative charge negative Dr. Wolf's CHM 201 & 202 20-170 20.18 Conjugate Addition to Conjugate α,β -Unsaturated Carbonyl Compounds α ,β Dr. Wolf's CHM 201 & 202 20-171 Nucleophilic Addition to Nucleophilic α,β-Unsaturated Aldehydes and Ketones α,β-Unsaturated 1,2-addition (direct addition) nucleophile attacks carbon of C=O 1,4-addition (conjugate addition) nucleophile attacks β-carbon nucleophile Dr. Wolf's CHM 201 & 202 20-172 Kinetic versus Thermodynamic Control attack is faster at C=O attack at β-carbon gives the more stable attack -carbon product product Dr. Wolf's CHM 201 & 202 20-173 O C C C +H Y 1,2-addition H O C C C Dr. Wolf's CHM 201 & 202 Y formed faster major product under major conditions of kinetic control (i.e. when addition is not readily reversible) reversible) 20-174 O C C C +H Y 1,4-addition enol goes to keto form goes under reaction conditions conditions Dr. Wolf's CHM 201 & 202 H O C Y C C 20-175 O C C C +H Y 1,4-addition keto form is isolated keto product of 1,4-addition product iis more stable than s 1,2-addition product 1,2-addition Dr. Wolf's CHM 201 & 202 O C Y C C H 20-176 O C C 1,4-addition C=O is stronger C=O is stronger tthan C=C han C=C O C C +H 1,2-addition H C C Dr. Wolf's CHM 201 & 202 Y O C Y Y C C H 20-177 20.19 Addition of Carbanions to α,β -Unsaturated Carbonyl Compounds: The Michael Reaction Dr. Wolf's CHM 201 & 202 20-178 Michael Addition Stabilized carbanions, such as those Stabilized derived from β-diketones undergo conjugate addition to α,β-unsaturated ketones. addition Dr. Wolf's CHM 201 & 202 20-179 Example Example O O CH3 CH + H2C CHCCH3 O KOH, methanol O CH3 CH O CH2CH2CCH3 (85%) O Dr. Wolf's CHM 201 & 202 20-180 Michael Addition The Michael reaction is a useful method for forming carbon-carbon bonds. It is also useful in that the product of the It reaction can undergo an intramolecular reaction aldol condensation to form a six-membered aldol ring. One such application is called the Robinson ring. annulation. Dr. Wolf's CHM 201 & 202 20-181 Example O CH3 CH O CH2CH2CCH3 O CH3 NaOH heat O O OH not isolated; dehydrates under dehydrates reaction conditions reaction O CH3 (85%) O Dr. Wolf's CHM 201 & 202 20-182 Stabilized Anions O H3C C O •• –C C OCH2CH3 H O CH3CH2O C O •• –C H Dr. Wolf's CHM 201 & 202 C OCH2CH3 The anions derived by deprotonation of β-keto esters and diethyl malonate are weak bases. Weak bases react with α,βunsaturated carbonyl compounds by conjugate addition. 20-183 Example O O CH3CH2OCCH2COCH2CH3 + Dr. Wolf's CHM 201 & 202 O H2C CHCCH3 20-184 Example O O O CH3CH2OCCH2COCH2CH3 + H2C CHCCH3 KOH, ethanol O O CH3CH2OCCHCOCH2CH3 (85%) CH2CH2CCH3 Dr. Wolf's CHM 201 & 202 O 20-185 Example O O CH3CCH2CH2CH2COH (42%) 1. KOH, ethanol-water 2. H+ 3. heat O O CH3CH2OCCHCOCH2CH3 CH2CH2CCH3 Dr. Wolf's CHM 201 & 202 O 20-186 20.20 Conjugate Addition of Organocopper Reagents to to α,β -Unsaturated Carbonyl Compounds α ,β Dr. Wolf's CHM 201 & 202 20-187 Addition of Organocopper Reagents to α,β-Unsaturated Aldehydes and Ketones The main use of organocopper reagents is to form carbon-carbon bonds by conjugate form addition to α,β-unsaturated ketones. Dr. Wolf's CHM 201 & 202 20-188 O Example + LiCu(CH3)2 CH3 CH 1. diethyl ether 2. H2O O CH3 CH Dr. Wolf's CHM 201 & 202 CH3 (98%) 20-189 End of Chapter 20 Dr. Wolf's CHM 201 & 202 20-190 ...
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