Dr. Wolf's CHM 201 & Chapter 20 Enols and Enolates
Dr. Wolf's CHM 201 & Aldehyde, Ketone, and Ester Enolates
Dr. Wolf's CHM 201 & The reference atom is the carbonyl carbon. Other carbons are designated , , , etc. on the basis of their position with respect to the carbonyl carbon. Hydrogens take the same Greek letter as the carbon to which they are attached. Terminology CH 3 CH 2 CH 2 CH O
Dr. Wolf's CHM 201 & Acidity of -Hydrogen + H + R2CR2CR2CR2C CR' O – R2CR2CR2CR2C CR' O – O R2CR2CR2CR2C CR' H pK a = enolate ion
Dr. Wolf's CHM 201 & Acidity of -Hydrogen (CH 3 ) 2 CHCH O CCH 3 O pK a = 15.5 pK a = 18.3
Dr. Wolf's CHM 201 & H3CH3CH3CH3C C CH 3 OC C O H H H3CH3CH3CH3C C O C C O H H+H+H+H+ + – -Diketones are much more acidic pK a = 9
Dr. Wolf's CHM 201 & -Diketones are much more acidic H3CH3CH3CH3C C CH 3 O C C O H – H3CH3CH3CH3C C CH 3 O C C O H– enolate of -diketone is stabilized; negative charge is shared by both oxygens
Dr. Wolf's CHM 201 & -Diketones are much more acidic H3CH3CH3CH3C C CH 3 O C C O H – – H3CH3CH3CH3C H C CH 3 O C C O H3CH3CH3CH3C C CH 3 O C C O H–
Dr. Wolf's CHM 201 & Esters Hydrogens to an ester carbonyl group are less acidic, pK a 24, than of aldehydes and ketones, pK a The decreased acidity is due the decreased electron withdrawing ability of an ester carbonyl. Electron delocalization decreases the positive character of the ester carbonyl group.
Dr. Wolf's CHM 201 & Esters A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions. C CR C OR' HHOO
Dr. Wolf's CHM 201 & C CR C OR' HHOO C CR C OR' HOO – pK a ~ 11 CH 3 CH 2 O –
Dr. Wolf's CHM 201 & The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups. C CR C OR' H OO – C CR C OR' H OO –
Dr. Wolf's CHM 201 & The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups. C CR C OR' H OO – C CR C OR' H OO–
Dr. Wolf's CHM 201 & The Aldol Condensation
Dr. Wolf's CHM 201 & A basic solution contains comparable amounts of the aldehyde and its enolate. Aldehydes undergo nucleophilic addition. Enolate ions are nucleophiles. What about nucleophilic addition of enolate to aldehyde? RCH 2 CH O+ OH – RCHCHO+HOH – pK a = pK a = 16 Some thoughts...
Dr. Wolf's CHM 201 & RCHCH O – RCH 2 CH O – RCH 2 CH O RCHCH O RCH 2 CH O RCHCH O H 2RCH 2 CH ONaOH RCH 2 CH OH CHCHOR
Dr. Wolf's CHM 201 & product is called an "aldol" because it is both an aldehyde and an alcohol Aldol Addition RCH 2 CH OH CHCHOR
Dr. Wolf's CHM 201 & Aldol Addition of Acetaldehyde Acetaldol (50%) NaOH, H 2 O 5°C 2CH 3 CH O CH 3 CH OH CH 2 CH O
Dr. Wolf's CHM 201 & Aldol Addition of Butanal KOH, H 2 O 6°C 2CH 3 CH 2 CH 2 CH O (75%) CH 3 CH 2 CH 2 CH OH CHCHO CH 2 CH 3
Dr. Wolf's CHM 201 & RCH 2 CH ONaOH RCH 2 CH OH CHCHOR Aldol Condensation
Dr. Wolf's CHM 201 & RCH 2 CH ONaOH RCH 2 CH OH CHCH OR Aldol Condensation R heat RCH 2 CH CCH O NaOH heat
Dr. Wolf's CHM 201 & Aldol Condensation of Butanal NaOH, H 2 O °C 2CH 3 CH 2 CH 2 CH O (86%) CH 3 CH 2 CH 2 CH CCHO CH 2 CH 3
Dr. Wolf's CHM 201 & dehydration of -hydroxy aldehyde can be catalyzed by either acids or bases Dehydration of Aldol Addition Product C O C C OH H C O C C
Dr. Wolf's CHM 201 & in base, the enolate is formed Dehydration of Aldol Addition Product OH H C O C C NaOH OH C O C C –
Dr. Wolf's CHM 201 & the enolate loses hydroxide to form the , -unsaturated aldehyde Dehydration of Aldol Addition Product OH H C O C C NaOH OH C O C C –
Dr. Wolf's CHM 201 & Aldol reactions of ketones the equilibrium constant for aldol addition reactions of ketones is usually unfavorable 2% 98% 2CH 3 CCH 3 OO CH 3 CCH 2 CCH 3 OH CH 3
Dr. Wolf's CHM 201 & Intramolecular Aldol Condensation Na 2 CO 3, H 2 O heatOO O(96%) OOH via:
Dr. Wolf's CHM 201 & Intramolecular Aldol Condensation Na 2 CO 3, H 2 O heatOO O(96%) even ketones give good yields of aldol condensation products when the reaction is intramolecular
Dr. Wolf's CHM 201 & Mixed Aldol Condensations
Dr. Wolf's CHM 201 & What is the product? There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde. NaOH CH 3 CH O CH 3 CH 2 CH O+
Dr. Wolf's CHM 201 & What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH OH CH 2 CH O
Dr. Wolf's CHM 201 & What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH 2 CH OH CHCHO CH 3
Dr. Wolf's CHM 201 & What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH OH CHCHO CH 3
Dr. Wolf's CHM 201 & What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH 2 CH OH CH 2 CH O
Dr. Wolf's CHM 201 & In order to effectively carry out a mixed aldol condensation: need to minimize reaction possibilities usually by choosing one component that cannot form an enolate
Dr. Wolf's CHM 201 & Formaldehyde formaldehyde cannot form an enolate formaldehyde is extremely reactive toward nucleophilic addition OHCH
Dr. Wolf's CHM 201 & FormaldehydeOHCH + (CH 3 ) 2 CHCH 2 CH O (CH 3 ) 2 CHCHCH O CH 2 OH (52%) K 2 CO 3 water- ether
Dr. Wolf's CHM 201 & Aromatic Aldehydes CH 3 O CHO aromatic aldehydes cannot form an enolate
Dr. Wolf's CHM 201 & Aromatic Aldehydes CH 3 O CHO+ CH 3 CCH 3 O NaOH, H 2 O 30°C CH 3 O CH CHCCH 3 O(83%)
Dr. Wolf's CHM 201 & 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 & Lithium diisopropylamide Lithium dialkylamides are strong bases (just as NaNH 2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups. Li+ CNC HH CH 3 –
Dr. Wolf's CHM 201 & Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. CH 3 CH 2 CH 2 COCH 3 O+ pK a ~ 22 LiN[CH(CH 3 ) 2 ] 2 CH 3 CH 2 CHCOCH 3 O+ HN[CH(CH 3 ) 2 ] 2 – + Li+ pK a ~ 36
Dr. Wolf's CHM 201 & Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated. CH 3 CH 2 CHCOCH 3 O O – CH 3 CH 2 I CH 2 CH 3 (92%)
Dr. Wolf's CHM 201 & Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. CH 3 COCH 2 CH 3 O 1. LiNR 2, THF 2. (CH 3 ) 2 C O 3. H 3 O + C H3CH3CH3CH3C CH 3 HO CH 2 COCH 2 CH 3 O(90%)
Dr. Wolf's CHM 201 & Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. CH 3 CH 2 CC(CH 3 ) 3 O 1. LDA, THF 2. CH 3 CH 2 CH O 3. H 3 O + CH 3 CHCC(CH 3 ) 3 O HOCHCH 2 CH 3 (81%)
Dr. Wolf's CHM 201 & The Claisen Condensation (gives -keto esters)
Dr. Wolf's CHM 201 & The Claisen Condensation -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. 2RCH 2 COR' O 1. NaOR' 2. H 3 O + + R'OHOO RCH 2 CCHCOR' R
Dr. Wolf's CHM 201 & Example Product from ethyl acetate is called ethyl acetoacetate or acetoacetic ester. 2CH 3 COCH 2 CH 3 O 1. NaOCH 2 CH 3 2. H 3 O + OO CH 3 CCH 2 COCH 2 CH 3 (75%)
Dr. Wolf's CHM 201 & Mechanism Step 1: CH 3 CH 2 O – COCH 2 CH 3 O CH 2 H
Dr. Wolf's CHM 201 & Mechanism Step 1: CH 3 CH 2 O – COCH 2 CH 3 O CH 2 H – COCH 2 CH 3 O CH 2 CH 3 CH 2 O H
Dr. Wolf's CHM 201 & Mechanism Step 1: – COCH 2 CH 3 O CH 2 – COCH 2 CH 3 O CH 2 Anion produced is stabilized by electron delocalization; it is the enolate of an ester.
Dr. Wolf's CHM 201 & Mechanism Step 2: – COCH 2 CH 3 O CH 2 CH 3 COCH 2 CH 3 O
Dr. Wolf's CHM 201 & Mechanism Step 2: – COCH 2 CH 3 O CH 2 CH 3 COCH 2 CH 3 O CH 3 C – O COCH 2 CH 3 O CH 2 OCH 2 CH 3
Dr. Wolf's CHM 201 & Mechanism Step 2: CH 3 C – O COCH 2 CH 3 O CH 2 OCH 2 CH 3
Dr. Wolf's CHM 201 & Mechanism Step 3: CH 3 C – O COCH 2 CH 3 O CH 2 OCH 2 CH 3 – OCH 2 CH 3 CH 3 C O COCH 2 CH 3 O CH 2 +
Dr. Wolf's CHM 201 & Mechanism– OCH 2 CH 3 CH 3 C O COCH 2 CH 3 O CH 2 + 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 CH 2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable.
Dr. Wolf's CHM 201 & Mechanism– OCH 2 CH 3 CH 3 C O COCH 2 CH 3 O CH2CH2CH2CH2 + Step 4: + OCH 2 CH 3 H – COCH 2 CH 3 O CH 3 C O CHCHCHCH
Dr. Wolf's CHM 201 & Mechanism Step 5: – COCH 2 CH 3 O CH 3 C O CHCHCHCH In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate.
Dr. Wolf's CHM 201 & Mechanism + Step 5: – COCH 2 CH 3 O CH 3 C O CHCHCHCH + O H HH O H H CH 3 C O COCH 2 CH 3 O CHCHCHCH H
Dr. Wolf's CHM 201 & Another example Reaction involves bond formation between the - carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other. 2 CH 3 CH 2 COCH 2 CH 3 O 1. NaOCH 2 CH 3 2. H 3 O + (81%)OO CH 3 CH 2 CCHCOCH 2 CH 3 CH 3
Dr. Wolf's CHM 201 & Intramolecular Claisen Condensation: The Dieckmann Reaction
Dr. Wolf's CHM 201 & CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 OO 1. NaOCH 2 CH 3 2. H 3 O + Example COCH 2 CH 3 OO(74-81%)
Dr. Wolf's CHM 201 & CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 OO NaOCH 2 CH 3 via CH 3 CH 2 OCCH 2 CH 2 CH 2 CHCOCH 2 CH 3 OO –
Dr. Wolf's CHM 201 & via CH 3 CH 2 OCCH 2 CH 2 CH 2 CHCOCH 2 CH 3 OO –
Dr. Wolf's CHM 201 & via CH 3 CH 2 OCCH 2 CH 2 CH 2 CHCOCH 2 CH 3 OO – CHCOCH 2 CH 3 O – CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O CH 3 CH 2 O
Dr. Wolf's CHM 201 & via CHCOCH 2 CH 3 O – CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O CH 3 CH 2 O
Dr. Wolf's CHM 201 & via CHCOCH 2 CH 3 O – CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O CH 3 CH 2 O – CHCOCH 2 CH 3 O CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O +
Dr. Wolf's CHM 201 & Mixed Claisen Condensations
Dr. Wolf's CHM 201 & 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 & Mixed Claisen Condensations These types of esters cannot form an enolate. HCOROROCOROROCOCOR O CORO
Dr. Wolf's CHM 201 & Example 1. NaOCH 3 2. H 3 O + (60%) COCH 3 O+ CH 3 CH 2 COCH 3 O OO CCHCOCH 3 CH 3
Dr. Wolf's CHM 201 & Acylation of Ketones with Esters
Dr. Wolf's CHM 201 & Acylation of Ketones with Esters Esters that cannot form an enolate can be used to acylate ketone enolates.
Dr. Wolf's CHM 201 & Example 1. NaH 2. H 3 O + (60%) + CH 3 CH 2 OCOCH 2 CH 3 O O O COCH 2 CH 3 O
Dr. Wolf's CHM 201 & Example 1. NaOCH 2 CH 3 2. H 3 O + (62-71%) COCH 2 CH 3 O+ O CH3CCH3CCH3CCH3CO O CCH2CCCH2CCCH2CCCH2C
Dr. Wolf's CHM 201 & Example 1. NaOCH 3 2. H 3 O + (70-71%) CH 3 CH 2 CCH 2 CH 2 COCH 2 CH 3 OO OO CH 3
Dr. Wolf's CHM 201 & Alkylation of Enolate Anions
Dr. Wolf's CHM 201 & Enolate ions are nucleophiles and react with alkyl halides. However, alkylation of simple enolates does not work well. Enolates derived from -diketones can be alkylated efficiently. Enolate Ions in S N 2 Reactions
Dr. Wolf's CHM 201 & Example CH 3 CCH 2 CCH 3 OO+ CH 3 I K 2 CO 3 CH 3 CCHCCH 3 OO CH 3 (75-77%)
Dr. Wolf's CHM 201 & The Acetoacetic Ester Synthesis
Dr. Wolf's CHM 201 & Acetoacetic Ester Acetoacetic ester is another name for ethyl acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C
Dr. Wolf's CHM 201 & Deprotonation of Ethyl Acetoacetate CH 3 CH 2 O C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C + – pK a ~ 11 Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
Dr. Wolf's CHM 201 & Deprotonation of Ethyl Acetoacetate pK a ~ 16 CH 3 CH 2 O C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C + C C C HOO – H3CH3CH3CH3C + CH 3 CH 2 OH – pK a ~ 11 Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. K ~ 10 5
Dr. Wolf's CHM 201 & Alkylation of Ethyl Acetoacetate C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).RX
Dr. Wolf's CHM 201 & Alkylation of Ethyl Acetoacetate C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).RX C C C OCH 2 CH 3 HOO H3CH3CH3CH3C R
Dr. Wolf's CHM 201 & Conversion to Ketone Saponification and acidification convert the alkylated derivative to the corresponding -keto acid. The -keto acid then undergoes decarboxylation to form a ketone. C C C OCH 2 CH 3 HOO H3CH3CH3CH3C R C C C OH HOO H3CH3CH3CH3C R 1. HO –, H 2 O 2. H +
Dr. Wolf's CHM 201 & Conversion to Ketone Saponification and acidification convert the alkylated derivative to the corresponding -keto acid. The -keto acid then undergoes decarboxylation to form a ketone. C C C OH HOO H3CH3CH3CH3C R C CH 2 R CO 2 O H3CH3CH3CH3C +
Dr. Wolf's CHM 201 & Example 1. NaOCH 2 CH 3 2. CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CCH 2 COCH 2 CH 3
Dr. Wolf's CHM 201 & Example (70%) 1. NaOCH 2 CH 3 2. CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CCH 2 COCH 2 CH 3 OO CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3
Dr. Wolf's CHM 201 & Example (60%)O CH 3 CCH 2 CH 2 CH 2 CH 2 CH 3 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 OO CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3
Dr. Wolf's CHM 201 & Example: DialkylationOO CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2
Dr. Wolf's CHM 201 & Example: Dialkylation 1. NaOCH 2 CH 3 2. CH 3 CH 2 I OO CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CCCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CH 2 (75%)
Dr. Wolf's CHM 201 & NaOH, H 2 O 2. H + 3. heat, -CO 2 O CH 3 CCCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CH 2 Example: Dialkylation CH 3 CCH CH 2 CH CH 2 O CH 3 CH 2
Dr. Wolf's CHM 201 & Another ExampleOO H COCH 2 CH 3 -Keto esters other than ethyl acetoacetate may be used.
Dr. Wolf's CHM 201 & Another ExampleOO H COCH 2 CH 3 1. NaOCH 2 CH 3 2. H 2 C CHCH 2 Br OO CH 2 CH COCH 2 CH 3 CH 2 (89%)
Dr. Wolf's CHM 201 & Another ExampleOO COCH 2 CH 3 CH 2 CH CH 2
Dr. Wolf's CHM 201 & Another Example O HOO COCH 2 CH 3 CH 2 CH CH 2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 CH 2 CH CH 2 (66%)
Dr. Wolf's CHM 201 & The Malonic Ester Synthesis
Dr. Wolf's CHM 201 & Malonic Ester Malonic ester is another name for diethyl malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. C C C OCH 2 CH 3 HHOO CH 3 CH 2 O
Dr. Wolf's CHM 201 & An AnalogyOO CH 3 CCH 2 COCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 O CH 3 CCH 2 R O HOCCH 2 R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.
Dr. Wolf's CHM 201 & Example 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 H2CH2CH2CH2C CHCH 2 CH 2 CH 2 Br 2. CH 2 CH 2 CH 2 CH 2 CH OO CH 3 CH 2 OCCHCOCH 2 CH 3 (85%)
Dr. Wolf's CHM 201 & Example (75%) 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 CH 2 CH 2 CH 2 CH CH 2 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O HOCCH 2 CH 2 CH 2 CH 2 CH CH 2
Dr. Wolf's CHM 201 & Dialkylation 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 2. CH 3 Br CH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 (79-83%)
Dr. Wolf's CHM 201 & Dialkylation 1. NaOCH 2 CH 3 O O CH 3 CH 2 OCCCOCH 2 CH 3 2. CH 3 (CH 2 ) 8 CH 2 Br CH 3 CH 3 (CH 2 ) 8 CH 2 CH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3
Dr. Wolf's CHM 201 & DialkylationO O CH 3 CH 2 OCCCOCH 2 CH 3 CH 3 O CH 3 (CH 2 ) 8 CH 2 CHCOH CH 3 CH 3 (CH 2 ) 8 CH 2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 (61-74%)
Dr. Wolf's CHM 201 & Another Example 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 2. BrCH 2 CH 2 CH 2 Br CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3
Dr. Wolf's CHM 201 & Another Example This product is not isolated, but cyclizes in the presence of sodium ethoxide. CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3
Dr. Wolf's CHM 201 & Another Example NaOCH 2 CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3 OO CH 3 CH 2 OCCCOCH 2 CH 3 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 (60-65%)
Dr. Wolf's CHM 201 & Another ExampleOO CH 3 CH 2 OCCCOCH 2 CH 3 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 CH CO 2 H (80%)
Dr. Wolf's CHM 201 & Barbiturates
Dr. Wolf's CHM 201 & Barbituric acid is made from diethyl malonate H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N
Dr. Wolf's CHM 201 & H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N 1. NaOCH 2 CH 3 2. H + H2CH2CH2CH2COC C O C N O N H H (72-78%) Barbituric acid is made from diethyl malonate and urea
Dr. Wolf's CHM 201 & H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N 1. NaOCH 2 CH 3 2. H + O O N O N H H (72-78%) Barbituric acid is made from diethyl malonate and urea
Dr. Wolf's CHM 201 & Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate H2CH2CH2CH2CO COCH 2 CH 3 O 1. RX, NaOCH 2 CH 3 2. R'X, NaOCH 2 CH 3 CO COCH 2 CH 3 O R R'
Dr. Wolf's CHM 201 & Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonateOO N O N H H R R' CO COCH 2 CH 3 O R R' (H 2 N) 2 C O
Dr. Wolf's CHM 201 & ExamplesOO N O N H H CH 3 CH 2 5,5-Diethylbarbituric acid (barbital; Veronal)
Dr. Wolf's CHM 201 & Examples O O N O N H H CH 3 CH 2 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) CH 3 CH 2 CH 2 CH H3CH3CH3CH3C
Dr. Wolf's CHM 201 & Examples O O N O N H H 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) CH 3 CH 2 CH 2 CH H3CH3CH3CH3C CHCH 2 H2CH2CH2CH2C
Dr. Wolf's CHM 201 & Enolization and Enol Content Enolization and Enol Content
Dr. Wolf's CHM 201 & Mechanism of Enolization (In general) OCR' R2CR2CR2CR2C H OHH OHH R2CR2CR2CR2C CR' O H
Dr. Wolf's CHM 201 & Mechanism of Enolization (Base-catalyzed) O R2CR2CR2CR2C CR' H O H –
Dr. Wolf's CHM 201 & Mechanism of Enolization (Base-catalyzed) H O H O R2CR2CR2CR2C CR'– OHH
Dr. Wolf's CHM 201 & Mechanism of Enolization (Base-catalyzed) OHH O R2CR2CR2CR2C CR'–
Dr. Wolf's CHM 201 & Mechanism of Enolization (Base-catalyzed) HO R2CR2CR2CR2C CR' OH –
Dr. Wolf's CHM 201 & Mechanism of Enolization (Acid-catalyzed) OHH H R2CR2CR2CR2C H O CR' +
Dr. Wolf's CHM 201 & Mechanism of Enolization (Acid-catalyzed) O R2CR2CR2CR2C CR' H O H H H +
Dr. Wolf's CHM 201 & Mechanism of Enolization (Acid-catalyzed) O R2CR2CR2CR2C CR' H H + O H H
Dr. Wolf's CHM 201 & Mechanism of Enolization (Acid-catalyzed) H OHH + O R2CR2CR2CR2C CR' H
Dr. Wolf's CHM 201 & percent enol is usually very small keto form usually kJ/mol more stable than enol Enol Content R 2 CHCR' O R2CR2CR2CR2C CR'OHenolketo
Dr. Wolf's CHM 201 & Enol Content CH 3 CH O H2CH2CH2CH2C CHOH K = 3 x Acetaldehyde CH 3 CCH 3 O H2CH2CH2CH2C CCH 3 OH K = 6 x Acetone
Dr. Wolf's CHM 201 & Halogenation of Aldehydes and Ketones Halogenation of Aldehydes and Ketones
Dr. Wolf's CHM 201 & X 2 is Cl 2, Br 2, or I 2. Substitution is specific for replacement of hydrogen. Catalyzed by acids. One of the products is an acid (HX); the reaction is autocatalytic. Not a free-radical reaction. General Reaction O R 2 CCR' H + X2X2X2X2O X + HXHXHXHX H+H+H+H+
Dr. Wolf's CHM 201 & Example H2OH2OH2OH2O (61-66%) Cl 2 +O HCl OCl +
Dr. Wolf's CHM 201 & Example CHCl 3 (80%) Br 2 + HBr + H CHOBr CHO Notice that it is the proton on the carbon that is replaced, not the one on the carbonyl carbon.
Dr. Wolf's CHM 201 & specific for replacement of H at the carbon equal rates for chlorination, bromination, and iodination first order in ketone; zero order in halogen Mechanism of Halogenation Experimental Facts Interpretation no involvement of halogen until after the rate-determining step
Dr. Wolf's CHM 201 & first stage is conversion of aldehyde or ketone to the corresponding enol; is rate- determining second stage is reaction of enol with halogen; is faster than the first stage Mechanism of Halogenation Two stages:
Dr. Wolf's CHM 201 & Mechanism of Halogenation RCH 2 CR' O X2X2X2X2 fast RCHCR'OX RCH CR'OHslow enol Enol is key intermediate
Dr. Wolf's CHM 201 & first stage is conversion of aldehyde or ketone to the corresponding enol; is rate- determining second stage is reaction of enol with halogen; is faster than the first stage Mechanism of Halogenation Two stages: examine second stage now
Dr. Wolf's CHM 201 & Reaction of enol with Br 2 carbocation is stabilized by electron release from oxygen BrBr R2CR2CR2CR2C CR' OH Br R2CR2CR2CR2C CR' OH + Br – + Br R2CR2CR2CR2C CR' OH +
Dr. Wolf's CHM 201 & Loss of proton from oxygen completes the process Br – O CR' Br R2CR2CR2CR2C H Br HBr R2CR2CR2CR2C CR' O +
Dr. Wolf's CHM 201 & -Halogenation of Carboxylic Acids: The Hell-Volhard-Zelinsky Reaction
Dr. Wolf's CHM 201 & analogous to -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) -Halogenation of Carboxylic Acids + X2X2X2X2 + HXHXHXHX R 2 CCOH OH OX
Dr. Wolf's CHM 201 & 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-Volhard- Zelinsky reaction But... + X2X2X2X2 + HXHXHXHX R 2 CCOH OH OX P or PX 3
Dr. Wolf's CHM 201 & Example CH 2 COH O PCl 3 benzene 80°C CHCOHOBr (60-62%) + Br 2
Dr. Wolf's CHM 201 & Value CH 3 CH 2 CH 2 COH O Br 2 P CH 3 CH 2 CHCOH OBr (77%) -Halogen can be replaced by nucleophilic substitution
Dr. Wolf's CHM 201 & Value CH 3 CH 2 CH 2 COH O Br 2 P CH 3 CH 2 CHCOH OBr OOH (77%) (69%) K 2 CO 3 H 2 O heat
Dr. Wolf's CHM 201 & Synthesis of -Amino Acids (CH 3 ) 2 CHCH 2 COH O Br 2 PCl 3 (CH 3 ) 2 CHCHCOH OBr O NH 2 (88%) (48%) NH 3 H 2 O
Dr. Wolf's CHM 201 & 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. The Haloform Reaction
Dr. Wolf's CHM 201 & Example (CH 3 ) 3 CCCH 3 O Br 2, NaOH, H 2 O CHBr 3 + (CH 3 ) 3 CCONa O (CH 3 ) 3 CCOH O H+H+H+H+ (71-74%)
Dr. Wolf's CHM 201 & The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well only when a single enolate can form. The Haloform Reaction ArCCH 3 O (CH 3 ) 3 CCCH 3 O RCH 2 CCH 3 Oyesyesno
Dr. Wolf's CHM 201 & RCCH 3 O X 2, HO – RCCH 2 X O X 2, HO – RCCHX 2 O X 2, HO – RCCX 3 OMechanism First stage is substitution of all available hydrogens by halogen
Dr. Wolf's CHM 201 & Mechanism Formation of the trihalomethyl ketone is followed by its hydroxide-induced cleavage HO – RC O CX3CX3CX3CX3 –RC O HO CX3CX3CX3CX3 + – HCX 3 RC O O + – CX3CX3CX3CX3 RC O OH +
Dr. Wolf's CHM 201 & Some Chemical and Stereochemical Consequences of Enolization
Dr. Wolf's CHM 201 & Hydrogen-Deuterium Exchange OH HH H + 4D2O4D2O4D2O4D2OOD DD D + 4DOH KOD, heat
Dr. Wolf's CHM 201 & Mechanism ODODODOD – + HOD + H O H H – O H H H H
Dr. Wolf's CHM 201 & Mechanism H O H H – ODODODOD – + O H H D H ODODODOD D
Dr. Wolf's CHM 201 & Stereochemical Consequences of Enolization C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C 100% R H3O+H3O+H3O+H3O+ H 2 O, HO – 50% R 50% S
Dr. Wolf's CHM 201 & Enol is achiral C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C R R CC 6 H 5 OH C H3CH3CH3CH3C CH 3 CH 2
Dr. Wolf's CHM 201 & Enol is achiral C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C R R CC 6 H 5 OH C H3CH3CH3CH3C CH 3 CH 2 C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C S S 50% 50%
Dr. Wolf's CHM 201 & Results of Rate Studies C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C Equal rates for: racemization H-D exchange bromination iodination Enol is intermediate and its formation is rate- determining
Dr. Wolf's CHM 201 & Effects of Conjugation in -Unsaturated Aldehydes and Ketones
Dr. Wolf's CHM 201 & Relative Stability aldehydes and ketones that contain a carbon- carbon double bond are more stable when the double bond is conjugated with the carbonyl group than when it is not compounds of this type are referred to as , unsaturated aldehydes and ketones
Dr. Wolf's CHM 201 & Relative Stability CH 3 CH O CHCH 2 CCH 3 (17%) K = 4.8 (83%) O CH 3 CH 2 CH CHCCH 3
Dr. Wolf's CHM 201 & Acrolein H2CH2CH2CH2C CHCHO
Dr. Wolf's CHM 201 & Acrolein H2CH2CH2CH2C CHCHO
Dr. Wolf's CHM 201 & Acrolein H2CH2CH2CH2C CHCHO
Dr. Wolf's CHM 201 & Acrolein H2CH2CH2CH2C CHCHO
Dr. Wolf's CHM 201 & Resonance Description C O C C +–C O C C + – C O C C
Dr. Wolf's CHM 201 & -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones. -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack carbonyl carbon -carbon Properties C O C C
Dr. Wolf's CHM 201 & Dipole Moments Butanal trans-2-Butenal = 2.7 D = 3.7 D O O –––– –––– ++++ ++++ ++++ greater separation of positive and negative charge
Dr. Wolf's CHM 201 & Conjugate Addition to -Unsaturated Carbonyl Compounds
Dr. Wolf's CHM 201 & ,2-addition (direct addition) nucleophile attacks carbon of C=O 1,4-addition (conjugate addition) nucleophile attacks -carbon Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
Dr. Wolf's CHM 201 & attack is faster at C=O attack at -carbon gives the more stable product Kinetic versus Thermodynamic Control
Dr. Wolf's CHM 201 & HY+ C C CO1,2-addition C C C OHY formed faster major product under conditions of kinetic control (i.e. when addition is not readily reversible)
Dr. Wolf's CHM 201 & HY+ C C CO1,4-addition C C C OHY enol goes to keto form under reaction conditions
Dr. Wolf's CHM 201 & HY+ C C CO1,4-addition keto form is isolated product of 1,4-addition is more stable than 1,2-addition product C C COH Y
Dr. Wolf's CHM 201 & HY+ C C CO1,2-addition C C C OHY 1,4-addition C C COH Y C=O is stronger than C=C
Dr. Wolf's CHM 201 & Addition of Carbanions to -Unsaturated Carbonyl Compounds: The Michael Reaction
Dr. Wolf's CHM 201 & Stabilized carbanions, such as those derived from -diketones undergo conjugate addition to , -unsaturated ketones. Michael Addition
Dr. Wolf's CHM 201 & Example (85%)O H2CH2CH2CH2C CHCCH 3 CH 3 OO O OO CH 2 CH 2 CCH 3 KOH, methanol +
Dr. Wolf's CHM 201 & The Michael reaction is a useful method for forming carbon-carbon bonds. It is also useful in that the product of the reaction can undergo an intramolecular aldol condensation to form a six-membered ring. One such application is called the Robinson annulation. Michael Addition
Dr. Wolf's CHM 201 & Example O CH 3 OO CH 2 CH 2 CCH 3 NaOH heat (85%) O O CH 3 OHO O not isolated; dehydrates under reaction conditions
Dr. Wolf's CHM 201 & Stabilized Anions The anions derived by deprotonation of -keto esters and diethyl malonate are weak bases. Weak bases react with , - unsaturated carbonyl compounds by conjugate addition. C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C C C C HOO CH 3 CH 2 O –
Dr. Wolf's CHM 201 & ExampleOO CH 3 CH 2 OCCH 2 COCH 2 CH 3 + H2CH2CH2CH2C CHCCH 3 O
Dr. Wolf's CHM 201 & Example KOH, ethanol OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 (85%) + H2CH2CH2CH2C CHCCH 3 O CH 2 CH 2 CCH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O
Dr. Wolf's CHM 201 & Example 1. KOH, ethanol-water CH 2 CH 2 CCH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O 2. H + 3. heat CH 3 CCH 2 CH 2 CH 2 COH OO (42%)
Dr. Wolf's CHM 201 & Conjugate Addition of Organocopper Reagents to -Unsaturated Carbonyl Compounds
Dr. Wolf's CHM 201 & The main use of organocopper reagents is to form carbon-carbon bonds by conjugate addition to , -unsaturated ketones. Addition of Organocopper Reagents to -Unsaturated Aldehydes and Ketones
Dr. Wolf's CHM 201 & ExampleO CH 3 (98%) + LiCu(CH 3 ) 2 O CH 3 1. diethyl ether 2. H 2 O
Dr. Wolf's CHM 201 & End of Chapter 20