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chapter22 - Chapter 22. Carbonyl Alpha-Substitution...

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Unformatted text preview: Chapter 22. Carbonyl Alpha-Substitution Reactions Based on McMurry's Organic Chemistry, 7th edition 2 Housekeeping Items DROP DATE IS TUESDAY (March 25th) Scantron Scores Now Available for only those that need to know if they should drop the course. guarantees! I will try to have the exams graded by Monday's lecture. No STUDENTS! For this Chapter, please focus on the slide material where the slide heading is highlighted in RED. EXCEL Spreadsheet on Blackboard with QUIZ and EXAM scores under student I.D. number, including Scantron scores, but not Essay scores. Will update tomorrow (Tuesday) afternoon with Exam 2 scores. I will update Quiz Scores and EXAM #1 corrections by Thursday afternoon. 3 The Position The carbon next to the carbonyl group is designated as being in the position Electrophilic substitution occurs at this position through either an enol or enolate ion 4 Why this Chapter? Many schemes make use of carbonyl a- substitution reactions. These reaction are one the few general methods for making C-C bonds. 5 22.1 KetoEnol Tautomerism A carbonyl compound with a hydrogen atom on its a carbon rapidly equilibrates with its corresponding enol Compounds that differ only by the position of a moveable proton are called tautomers 6 Tautomers Are Not Resonance Forms Tautomers are structural isomers Resonance forms are representations of contributors to a single structure Tautomers interconvert rapidly while ordinary isomers do not 7 Enols The enol tautomer is usually present to a very small extent and cannot be isolated However, since it is formed rapidly, it can serve as a reaction intermediate 8 Acid Catalysis of Enolization 9 Base Catalysis of Enolization 10 22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions Enols behave as nucleophiles and react with electrophiles because the double bonds are electronrich compared to alkenes 11 General Mechanism of Addition to Enols 12 22.3 Alpha Halogenation of Aldehydes and Ketones Aldehydes and ketones can be halogenated at their positions by reaction with Cl2, Br2, or I2 in acidic solution 13 Mechanism of Acid-Catalyzed Bromination 14 Evidence for the Rate-Limiting Enol Formation The rate of halogenation is independent of the halogen's identity and concentration In D3O+ the H's are replaced by D's at the same rate as halogenation This because the barrier to formation of the enol goes through the highest energy transition state in the mechanism 15 Elimination Reactions of -Bromoketones -Bromo ketones can be dehydrobrominated by base treatment to yield ,-unsaturated ketones 16 Elimination Reactions of -Bromoketones -Bromo ketones can be dehydrobrominated by base treatment to yield ,-unsaturated ketones 17 Elimination Reactions of -Bromoketones -Bromo ketones can be dehydrobrominated by base treatment to yield ,-unsaturated ketones A good base for elimination reactions Aldehydes and Ketones undergo alpha halogenation, via an enol. 18 22.4 Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii Reaction Carboxylic acids do not react with Br2 (unlike aldehydes and ketones), but must be converted into an acid halide first. 19 22.4 Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii Reaction Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) They are brominated by a mixture of Br2 and PBr3 (HellVolhardZelinskii reaction) O CH3CH2CH2CH2CH2 C Br This happens very fast. 20 22.4 Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii Reaction Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) They are brominated by a mixture of Br2 and PBr3 (HellVolhardZelinskii reaction) H O Tautomerization. CH 3CH2CH2CH2CH C Br 21 22.4 Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii Reaction Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) They are brominated by a mixture of Br2 and PBr3 (HellVolhardZelinskii reaction) O CH 3CH2CH2CH 2CH C Br Br Electrophilic addition to an alkene 22 22.4 Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii Reaction Carboxylic acids do not react with Br2 (unlike aldehydes and ketones) They are brominated by a mixture of Br2 and PBr3 (HellVolhardZelinskii reaction) 23 Mechanism of Bromination PBr3 converts -COOH to COBr, which can enolize and add Br2 tautomerization PBr3 Br2 24 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60) The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen 25 Reagents for Enolate Formation Ketones are weaker acids than the OH of alcohols so a a more powerful base than an alkoxide is needed to form the enolate Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form the enolate 26 Lithium Diisopropylamide (LDA) LDA is from butyllithium (BuLi) and diisopropylamine (pKa 40) Soluble in organic solvents and effective at low temperature with many compounds Not nucleophilic 27 -Dicarbonyls Are More Acidic When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced (Table 22.1) Negative charge of enolate delocalizes over both carbonyl groups 28 Table 22.1: Acidities of Organic Compounds 29 22.6 Reactivity of Enolate Ions The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive) Reaction on oxygen yields an enol derivative Reaction on carbon yields an -substituted carbonyl compound 30 22.7 Alkylation of Enolate Ions Base-promoted reaction occurs through an enolate ion intermediate 31 Constraints on Enolate Alkylation SN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate R should be primary or methyl and preferably should be allylic or benzylic Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination 32 The Malonic Ester Synthesis For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms 33 Formation of Enolate and Alkylation Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an -substituted malonic ester 34 Dialkylation The product has an acidic -hydrogen, allowing the alkylation process to be repeated 35 Hydrolysis and Decarboxylation The malonic ester derivative hydrolyzes in acid and loses CO2 ("decarboxylation") to yield a substituted monoacid 36 Decarboxylation of -Ketoacids Decarboxylation requires a carbonyl group two atoms away from the 2H CO 37 Overall Conversion The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms 38 Preparation Cycloalkane Carboxylic Acids 1,4-dibromobutane reacts twice, giving a cyclic product Three-, four-, five-, and six-membered rings can be prepared in this way 39 Acetoacetic Ester Synthesis Overall: converts an alkyl halide into a methyl ketone 40 Acetoacetic Ester (Ethyl Acetoacetate) carbon is flanked by two carbonyl groups, so it readily becomes an enolate ion This can be alkylated by an alkyl halide and also can react with a second alkyl halide 41 Generalization: -Keto Esters 42 Generalization: -Keto Esters The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to -keto esters in general Cyclic -keto esters give 2-substituted cyclohexanones 43 Generalization: -Keto Esters The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to -keto esters in general Cyclic -keto esters give 2-substituted cyclohexanones 44 Predict the products of the following reactions. p. 869 45 C2H O + C2 O p. 869 46 C3 H H C2H O + C2 O O O p. 869 47 C3 H H C2H O + C2 O O O O C 3C2C C B HHH r B r p. 869 48 C3 H H C2H O + C2 O O O O C 3C2C C B HHH r B r O C3C 2C C O HHH H B r p. 869 49 C3 H H C2H O + C2 O O O O C 3C2C C B HHH r B r O C3C 2C C O HHH H B r O C C3 I Good Leaving Group p. 869 50 C3 H H C2H O + C2 O O O O C 3C2C C B HHH r B r O C3C 2C C O HHH H B r O C C3 I O C O N a p. 869 51 Identify the reagents needed to complete the following synthesis. p. 871 52 Identify the reagents needed to complete the following synthesis. 1. NaOCH3, CH3OH 2. CH3Br p. 871 53 Identify the reagents needed to complete the following synthesis. 1. NaOCH3, CH3OH 2. CH3Br H3O+ Heat p. 871 54 Identify the reagents needed to complete the following synthesis. 1. NaOCH3, CH3OH 2. CH3Br H3O+ Heat 1. LDA 2. CH3I p. 871 55 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. p. 873 56 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. (a) O Ph3P+-CH2THF C2 H p. 873 57 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. (a) (b) C2 H 1. 2. BH3, THF H2O2, HO- C2O HH PBr3 C 2B Hr p. 873 58 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. (c) O O LDA C6H5CH2 Br 1. 2. C2CH H65 p. 873 59 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. C2C(C2E 2 H H O t) C2C2C2H HHO (d) CH2(CO2Et)2 1. 2. NaOEt Product of (b) H3O+, heat p. 873 60 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. HINT (e) O O H ? C N p. 873 61 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. HINT (e) O O NaCN O H H3O+ heat C N C2H O p. 873 62 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. HINT (e) O O NaCN O2 H H3O+ heat C N C2H O p. 873 63 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. HINT O (f) ? O B r ? O p. 873 64 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. HINT O Br2 CH3CO2H O B r (f) ? O p. 873 65 How would you synthesize the following compounds from cyclohexanone? More than one step may be required? May need to use chemistry from previous chapters to solve these problems. HINT O Br2 CH3CO2H O B r N Pyridine heat O (f) p. 873 66 Biological Alkylations 67 ...
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This note was uploaded on 04/07/2008 for the course CHGN 222 taught by Professor Cowley during the Spring '08 term at Mines.

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