TOPIC 6: ALDOL REACTIONS AND THE SYNTHESIS AND. COMPOUNDS (Chapters 17 and 19)

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1 L TPI 6: ALDL EATINS AND TE SYNTESIS AND EATINS F β-diabnyl MPUNDS (hapters 17 and 19) BJETIVES 1. Provide a rationale for the acidity of α-hydrogens 2. Illustrate the behavior of enols and enolates as nucleophiles in reactions with a variety of electrophiles 3. Develop stategies for the formation of complex molecules form simple starting ti materials by making carbon-carbon b bonds 4. Describe the reactions of ester enolates (nucleophiles) with esters (electrophiles) to give β-keto esters via laisen and crossed laisen condensatiions. 5. Describe the synthesis of ketones using the above products. 6. Describe the reactions of other active methyene compounds and the synthesis of acid derivatives. 7. Describe the preparation and alkylation of enamines. 8. Use this knowledge to predict the products of reactions of this type and to be able to synthesize compounds using these procedures. EM2312: Spring 2009

2 EVIEW F TE ELETPILIITY F ABNYLS Aldehydes and ketones undergo addition-elimination pathways Nucleophile: -Nu N 2 -Nu. Nu 3 P- 2 Nu Acid Derivatives undergo substitution via additionelimination pathways l () 2 ' L Nu Nu N' 2 Nu ' PEVIEW F ENLATE EMISTY ydrogens α- to a carbonyl are acidic NaEt LDA NaEt Enolates are nucleophilic EM2312: Spring 2009

3 Enolates react with. Alkyl halides Br Aldehydes and ketones Esters TE AIDITY F TE α-ydgens F ABNYL MPUNDS: ENLATE ANINS S:17.1 Prob: Protons α- to arbonyl Groups are More Acidic Than ther Protons on arbon pkp pk a a Note: Protons attached to the carbonyl carbon of aldehydes are not particularly acidic, the conjugate base is not resonance stabilized. EM2312: Spring 2009

4 KET AND ENL TAUTMES S17.2 Base atalyzed Tautomerization B B- Keto and enol forms are in equilibrium apidly interconverting are called tautomers Acid atalyzed Tautomerization A e.g., 3 + A A The keto form is usually more stable K eq EM2312: Spring 2009

5 Equilibrium onstants for Tautomerization K = 3 x 10-7 K = 6 x 10-9 K = 1 x 10-2 K = 4 K > a b D D b a EM2312: Spring 2009

6 EATINS VIA ENLS AND ENLATE ANINS Preview: Both Enols and enolates are nucleophilic S:17.3 Prob:17.37,39 E E E compare to: 2 2 Diethylpropion is a stimulant, is marketed as Tenuate for appetite suppression. Propose a synthesis of diethylpropion from benzene and any other starting materials. N? EM2312: Spring 2009

7 α-alogenation of Aldehydes and Ketones Under Acidic conditions Enolizable protons are subject to substitution with bromine upon treatment with Br 2. Br 2, + Br 3 2 Mechanistic ationale: The nucleophilic enol undergoes reaction with bromine 3 + Br Br 2 Under basic conditions: All of the enolizable protons are substituted with bromine and the resulting trihalomethyl group itself is cleaved. Br 2, - Br 3 3 Mechanistic ationale: 1. The nucleophilic enolate undergoes reaction with bromine Br Br 2 2 All enolizable s substituted with Br EM2312: Spring 2009

8 Br 3 l 2 l 3 -chloroform Br 2 Br 3 - bromoform I 2 I 3 - iodoform pale yellow solid good test for presence of a methyl ketone hemical Tests for Functional Groups Methyl ketones give positive iodoform test I 2, Na in Et, 2 EM2312: Spring 2009

9 α-alo arboxylic Acids ell-volhard-zelinski reaction 1. P, Br eactions of α-halo acids Br 1. Na Br N 3 Br KN acemization of Aldehydes and Ketones Experimental bservation: ompounds with a stereogenic center bearing a hydrogen atom adjacent to a carbonyl group undergo rapid racemization in mildly acidic or basic conditions. Me or Me EM2312: Spring 2009

10 Mechanistic ationale: Me Ibuprofen 3 Ibuprofen marketed as racemate nly the S isomer is active Body converts to S by inversion of stereogenic center adjacent to carbonyl /D Exchange eactions Experimental bservation: Treatment of ketones with NaD/D 2 results in replacement of α-hydrogen atoms with deuerium. NaD via D 2 NaD D 2 D D via D D D EM2312: Spring 2009

11 NaD D 2 D D D D via allylic anion NaD D 2 -D exchange EM2312: Spring 2009

12 ? Problems 17.37,39? L TE ALDL EATIN: ADDITIN F ENLATES T ALDEYDES & KETNES SYNTESIS F 3-YDXY ABNYL MPUNDS AND α,β-unsatuated ABNYL MPUNDS S:17.4,5 Prob:17.31, 33,35 The Aldol l eaction: The eaction of an Aldehyde d with an Aldehyde Enolate 3 Na, 2 5 o EM2312: Spring 2009

13 Aldol ondensation eating causes dehydration to form α,β-unsaturated aldehyde Mechanism: 3 Na, 2 Δ 3 e.g. Na, 2 Δ ecognizing Products and Starting Materials of Aldol eactions Aldol condensations give α,β-unsaturated carbonyl compounds EM2312: Spring 2009

14 EM2312: Spring 2009 rossed-aldol (or Mixed Aldol ) eactions Problem: Propose starting materials to prepare 2-methyl-2-pentenal by an aldol reaction Mixed aldols between two aldehydes with enolizable protons can give four different products Na, 2 Δ

15 rossed aldol condensations are only useful when one of the components is non-enolizable and a good electrophile (e.g., an aldehyde) e.g., Na, 2 Δ Examples of Aldol eactions with Ketones Na, 2 Δ 3 3 Na, 2 Δ 3 3 emember: Avoid proposing crossed-aldol reactions if both components are enolizable EM2312: Spring 2009

16 Problem [Solomons 17.31b] - ow would you achieve the following transformation?? Aldol eactions are also atalyzed by Acid. Problem: Write the mechanistic steps of the following reaction (show curved arrows and intermediates) 3 + Δ protonation elimination protonation acid catalyzed dehydration (rg-i) 2 3 deprotonation nucleophilic addition = deprotonation 3 EM2312: Spring 2009

17 and eversible The aldol reaction is reversible. The reverse reaction proceeds through exactly the same intermediates as the forward reaction. Problem: Write the mechanistic steps of the following reaction (show curved arrows and intermediates). deprotonation Δ addition deprotonation 2 3 protonation = protonation elimination Problem: Pulegone, which has a pleasant peppermintcamphor smell, is isolated from the oil of pennyroyal (pennyroyal tea is commonly used as an herbal remedy; pulegone is extremely toxic). Treatment of pulegone with steam yields 3-methylcyclohexanone. Propose a pathway for this reaction. What is the byproduct of this reaction. EM2312: Spring 2009

18 yclizations via Aldol ondensations S:17.6 Na, 2 Δ not + Na, 2 Δ 3 major product S: EM2312: Spring 2009

19 Problem [Solomons 17.33] Identify the structures of compounds A-.? 1. NaN 2 2. acetone 3. N 4 l, 2 g 2+, Na A ( 5 8 ) B ( ) ( )? Problems 17.31,33,35? EM2312: Spring 2009

20 L ALKYLATIN F ALDEYDES AND KETNES S Prob Problem: With or Et, enolates are generated in equilibrium. They are not isolated, but react in situ with a second molecule of carbonyl compound (aldehyde or ketone) in an aldol reaction. K eq =10-4 Na Na pk a = 20 pk a = 16 NaEt Br Solutions: 1. Use a much stronger base lithium diisopropylamide (LDA) 1. LDA 2. Br 2. onvert ketone to enamine, alkylate and hydrolyze N N 1. Br amine enamine EM2312: Spring 2009

21 Lithium Enolates Use of a stronger base (e.g., lithium diisopropylamide, LDA) allows for S:17.7 Prob:17.34 generation of the lithium enolate, and then, in a separate step, the addition of an electrophile. N Li K =10 18 eq Li N pk a = 20 pk a = 38 Lithium Enolates in Alkylation eactions 1. LDA in TF, -78 o 2. -Br (1 o ) 3. 3 The Effect of Temperature on the Alkylation of Lithium Enolates: Kinetic and Thermodynamic Products The regiochemistry of lithiation is controlled by temperature Major Product via: o 1. LDA -78 o 2. Br 1. LDA room temp 2. Br kinetic product thermodynamic product EM2312: Spring 2009

22 Lithium Enolates in Directed rossed-aldol eactions 1. LDA in TF, -78 o 2. not: 3. 3 Synthesis of Enamines ecall that aldehydes and ketones react with primary amines to form imines. Analogous reactions with secondary amines form enamines. 1 amines N 3 N N imine 2 amines 3 N 3 N 3 + N enamine 3 EM2312: Spring 2009

23 Examples of Enamines eacting as Nucleophiles N 1. 3 l l N( 3 ) N 1. N α,β-unsatuated ABNYL MPUNDS Synthesis of α,β-unsaturated arbonyl ompounds S17.8,9 Prob:17.32 Aldol reactions (see above) α-selenation 1. LDA in TF, -78 o 2. Sel EM2312: Spring 2009

24 Selective eduction of α,β-unsaturated arbonyl ompounds 3 2 (high pressure) Ni 2 (2-3 atm) Pd LiAl 4 Electron Distribution in α,β-unsaturated Ketones In the absence of the electron-withdrawing =, akenes are weakly nucleophilic. EM2312: Spring 2009

25 Nucleophilic Additions to α,β-unsaturated Ketones 1,2-addition Nu conjuga jugate addition Nucleophile (Nu ) MgBr Li N N 2 2 uli enolate anions Use of Nucleophilicity of Enolates and Electrophilicity of Enones in the Design of Syntheses. Br M EM2312: Spring 2009

26 L β-diabnyl MPUNDS: INTDUTIN S.19.1 β α ' ' ' β dicarbonyl b l β keto ester β diketone β diester + B + B pk a ~10 Question: Why is the β-dicarbonyl system more acidic than an alcohol (pk a ~18)? Answer: The anion is stabilized by resonance onsequently, there is a lot of enol in equilibrium EM2312: Spring 2009

27 SYNTESIS F 1,3-DIABNYL MPUNDS: TE LAISEN NDENSATIN S:19.2 Prob:19.25,41 verall eaction: The eaction of Ester Enolates with Esters 2 1. NaEt Et Et Et + Et Et Et 2 Et 1. NaEt Et Mechanism First step formation of enolate Et Et Question: ow much enolate forms? What are the pk a values? EM2312: Spring 2009

28 Second step - attack of enolate (nucleophile) on the carbonyl carbon (electrophile) of another molecule of ester Et Et Question: Is this reaction favorable? Third step - deprotonation of β-dicarbonyl compound (product) to form enolate Et Et Question: Is this reaction favorable? What are the pk a values? EM2312: Spring 2009

29 Fourth step - protonation of enolate to form the β-dicarbonyl product by addition of acid Et Question: It this reaction favorable? What are the pk a values? free energy Gibbs 2 2 Et Na Deprotonation K<1 (ester is weaker acid than ethanol) Et 2 Et Na Nucleophilic addition K<1 (= -) Et Et Na Elimination Deprotonation K>1 (1,3-dicarbonyl is stronger acid than ethanol) Na 2 Et Et Et 2 Et Na Et Et Et 2 Et EM2312: Spring 2009

30 So, why does the reaction fail when the ester has two substituents on the α carbon? 1. NaEt 2 Et Et No eaction Et Et Et Et Et Et yclizations via laisen ondensation Et Et 1. NaEt Et Et not Et Et Et Et Et Et + Et Et EM2312: Spring 2009

31 rossed laisen and other ondensations emember the rule for crossed aldol condensation reactions (i.e., one component cannot form an enolate) Et + 3 Et 1. NaEt Et Et 1. NaEt Et Et + Et ethyl oxalate 1. NaEt Et Problem ow would you achieve the following transformations? Et Et? Et Et EM2312: Spring 2009

32 ? Problems 19.25,41? L TE AETAETI ESTE SYNTESIS: SYNTESIS F METYL KETNES S:19.3 Prob: verall reaction Et 1. NaEt, Et 2. -X 3. 2 Et 1. Na heat = 3, 1 eminder: Simple esters cannot be alkylated in this fashion Et 1. NaEt, Et 2. -X 3. 2 Et EM2312: Spring 2009

33 Pathway Deprotonation: Enolate formation Et NaEt Et + Et Alkylation X Et Saponification Et 1. Na S:18.10 Decarboxylation of β-keto arboxylic Acids heat to EM2312: Spring 2009

34 Examples 1. NaEt, 3 I 2. NaEt, 3 2 Br Et Na , heat 1. NaEt Br 2 2 Et Et Na , heat Synthetic Design EM2312: Spring 2009

35 TE MALNI ESTE SYNTESIS: SYNTESIS F SUBSTITUTED AETI AIDS verall reaction Et 1. NaEt, Et 2. -X Et 3. 2 = 3, 1 (2 ) Et Et 1. Na heat S:19.4 Prob: EM2312: Spring 2009

36 Mechanism Deprotonation: Enolate formation Et Et NaEt Et Et + Et Alkylation X Et Et Et Et Ester hydrolysis (see 18.7B) and decarboxylation (see 18.10) Et Et Examples 1. NaEt, 3 I Et Et 2. 2, Na , heat 1. NaEt Br 2 Et Et 2. 2, Na , heat 1. 2NaEt Br( 2 ) 3 Br Et Et 2. 2, Na , heat EM2312: Spring 2009

37 PS What is the major organic product of the following sequence of reactions? Et 1. NaEt, Et 2. 2 Br 1. Na, heat 1. LiAl Et Synthetic Design Using Malonate Ester Synthesis EM2312: Spring 2009

38 Problem [Solomons 19.26e,27] - ow would you achieve the following transformations? Et? Et Et EM2312: Spring 2009

39 ? Problems 19.36? S:19.12 Prob: Et Et + 2 N 2 N NaEt -2Et N N barbituric acid (pk a ~4) Et Et 2 N + 2 N NaEt -2Et N N ow would you synthesize this malonic ester? (see prob ) phenobarbital - a highly addictive sleep inducer and tranquilizer EM2312: Spring 2009

40 TE - BND FMING EATINS Michael addition onjugate addition of a stabilized enolate to an α,β-unsaturated carbonyl compound Et Et EtNa obinson annulation Michael addition and subsequent aldol cyclization Na, 2 Michael Aldol EM2312: Spring 2009

41 The Knoevenagel ondensation Aldol condensation of a stabilized enolate 1. base - 2 S:19.8 Prob: e.g., Na L TE MPUNDS WIT AIDI YDGEN ATMS N ABN Esters, nitriles and nitroalkanes can also be deprotonated with a strong base (LDA) S: N 2 N 3 N 2 N.and the conjugate bases react as nucleophiles with alkyl halides (alkylation via S N 2), carbonyls (addition, or addition-elimination, e.g., aldol reaction), and esters (addition-elimination, e.g., laisen condensation). EM2312: Spring 2009

42 ompounds with two electron withdrawing groups attached to the same carbon are deprotonated with weaker bases (NaEt, Na). N N N Et N N cyanoacetaldehyde cyanoacetone ethyl cyanoacetate malonitrile N phenylacetone benzylcyanide Direct Alkylation of Esters, Nitriles, Nitroalkanes S:19.6 Et 1. LDA 2. 2 Br N 1. NaEt 2. 3 Br N 2 1. LDA Br EM2312: Spring 2009

43 Methadone, a synthetic opioid, is used to treat addiction to heroin. Methadone occupies the opioid receptor in the brain hereby blocking the binding of other drugs from attaching to the receptor. Br Br 2 N N All 3 bromination via enol Friedel-rafts alkylation N S N Na l N N l N N 1. EtMgBr 2. l(aq) N L TPI 5 EVIEW Enolate Anions Protons α- to carbonyl groups are more acidic than other protons on carbon; enotates are nucleophilic pk a 19.2 enolate (50) E Enols are nucleophilic E enol EM2312: Spring 2009

44 The aldol reaction: The reaction of an aldehyde with an aldehyde enolate 3 Na, 2 5 o heat - 2 Na, 2 Δ 3 3 Na, 2 Δ rossed aldol condensations are only useful when one of the components is non-enolizable and a good electrophile (e.g., an aldehyde). e.g., Na, 2 Δ Na, 2 Δ 3 3 EM2312: Spring 2009

45 Lithium enolates are useful in directed crossed-aldol reactions and in alkylation reactions 1. LDA in TF, -78 o LDA in TF, -78 o 2. -Br (1 o ) Additions to α,β-unsaturated ketones MgBr Li N N 2 2 uli enolate anions Michael addition and subsequent aldol cyclization (obinson annulation) Na, 2 EM2312: Spring 2009

46 The ß-dicarbonyl system more acidic than an alcohol (pk a ~18). The anion is stabilized by resonance The laisen condensation: the synthesis of ß-keto esters 2 Et 1. NaEt Et + Et 1. NaEt 2 Et N rossed laisen and other ondensations emember the rule for crossed aldol condensation reactions (i.e., one component cannot form an enolate) Et + 3 Et 1. NaEt Et Et 1. NaEt Et Et + Et 1. NaEt Et EM2312: Spring 2009

47 The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones 1. NaEt, Et 1. Na 2. -X Et Et 2 = 3, heat The Malonic Ester Synthesis: Synthesis of Substituted Acetic Acids 1. NaEt, Et 1. Na Et Et 2 Et Et = 3, X heat Synthesis f Enamines Stork Enamine eactions eaction of ketones and aldehydes with secondary amines form enamines + N N nitrogen nucleophilic carbon nucleophilic N N 2 amine enamine N 3 I EM2312: Spring 2009

48 PBLEM SLVING AND SYNTETI STATEGIES Problem - Propose a synthetic pathway to achieve the following transformation.? Problem [Solomons 19.39] - ow could you prepare Darvon, a powerful analgesic, from ethyl phenyl ketone? N February 20, 2009 FDA Panel ecommends Davron Be emoved From Market An FDA panel, citing safety risks, voted Jan. 30 to remove a pair of painkillers from pharmacy shelves. The panel of outside experts voted to end sales of Davron because of concerns that their safety risks outweigh their benefits. Davron (propoxyphene) is a opioid painkiller used for mild to moderate pain. Like all opioids, it carries a high potential for addiction and abuse and are not safe when combined with alcohol. EM2312: Spring 2009

49 ? Problem [Solomons 19.38] - Fenchone is a terpenoid isolated from fennel oil. Provide the structure of intermediates and reagents (a)-(n) in the following scheme (cont. next slide). Fenchone + (a) Δ 2 3 (b) (c) (d) mixture of (e) and (f) 1. (g) (h) (i) (j) (l) (k) (m) (n) EM2312: Spring 2009

50 Problem [Solomons 17.32] Describe the key mechanistic steps in the following reaction (i.e., write a mechanism). + Na?? Problems 19.30,31,50? EM2312: Spring 2009

51 TPI 6 (APTE 17,19) N EXAM 5 Types of Questions - Predict the products obtained from given starting materials - ationalize the outcome of a reaction (i.e., propose a mechanism, draw key intermediates) - Develop multistep synthetic strategies. Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for Exam 5 - Get up-to-date NW! - Work as many problems as possible. Do the problems first, then consult the solutions manual. - Work in groups, discuss chemistry, teach and test each other. - Do the Learning Group Problem at the end of the chapter. EM2312: Spring 2009