© 2011 Pearson Education, Inc. 1 Organic Chemistry 6 th Edition Paula Yurkanis Bruice Chapter 19 Carbonyl Compounds III Reactions at the  -Carbon

© 2011 Pearson Education, Inc. 2 The  -Hydrogen Is Acidic The anion is stabilized by resonance A carbon acid is a compound with a relatively acidic hydrogen bonded to an sp 3 -hybridized carbon

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4 Esters Are Less Acidic Than Aldehydes and Ketones The electrons are not as readily delocalized because of resonance electron release by -OR (green arrows)

© 2011 Pearson Education, Inc. 5 In the following compounds, the anion resulting from deprotonation can be delocalized into electronegative atoms (oxygen and nitrogen):

© 2011 Pearson Education, Inc. 6 The acidity of the  -hydrogens is attributed to anion stabilization by resonance:

© 2011 Pearson Education, Inc. 7 Keto–Enol Tautomerism

© 2011 Pearson Education, Inc. 8 The enol tautomer can be stabilized by intramolecular hydrogen bonding: In phenol, the enol tautomer predominates because it is aromatic:

© 2011 Pearson Education, Inc. 9 Mechanism for base-catalyzed keto–enol interconversion:

© 2011 Pearson Education, Inc. 10 Mechanism for acid-catalyzed keto–enol interconversion:

© 2011 Pearson Education, Inc. 11 An Enol Is a Better Nucleophile Than an Alkene Carbonyl compounds that form enol undergo substitution reactions at the  -carbon: an  -substitution reaction

© 2011 Pearson Education, Inc. 12 Mechanism for base-catalyzed  -substitution:

© 2011 Pearson Education, Inc. 13 Mechanism for acid-catalyzed  -substitution:

© 2011 Pearson Education, Inc. 14 An Enolate Is an Ambident Nucleophile Reaction at the C or O site depends on the electrophile and on the reaction condition Protonation occurs preferentially on the O site Otherwise, the C site is likely the nucleophile

© 2011 Pearson Education, Inc. 15 Acid-Catalyzed Halogenation Under acidic conditions, one  -hydrogen is substituted for a halogen

© 2011 Pearson Education, Inc. 16 Mechanism for acid-catalyzed halogenation:

© 2011 Pearson Education, Inc. 17 Base-Promoted Halogenation Under basic conditions, all the  -hydrogens are substituted for halogens

© 2011 Pearson Education, Inc. 18 Mechanism for base-promoted halogenation:

© 2011 Pearson Education, Inc. 19 Conversion of a Methyl Ketone to a Carboxylic Acid

© 2011 Pearson Education, Inc. 20 Halogenation of the  -Carbon of Carboxylic Acids Mechanism for the Hell–Volhard–Zelinski reaction:

© 2011 Pearson Education, Inc. 21  -Halogenated Carbonyl Compounds Are Useful in Synthesis Removing a proton from an  -carbon makes the  - carbon a nucleophile:

© 2011 Pearson Education, Inc. 22 When the  -carbon is halogenated, it becomes electrophilic: An E2 elimination will occur if a bulky base is used:

© 2011 Pearson Education, Inc. 23 LDA is a strong base but a poor nucleophile Why? Because the steric bulk of the isopropyl groups prevents an S N 2 reaction

© 2011 Pearson Education, Inc. 24 Using LDA to Form an Enolate

© 2011 Pearson Education, Inc. 25 Keto–Enol Tautomerization

© 2011 Pearson Education, Inc. 26 Alkylation of the  -Carbon of Carbonyl Compounds This method can be used to alkylate ketones, esters, and nitriles at the  -carbon; however, aldehydes give a poor yield

© 2011 Pearson Education, Inc. 27 Enol and Enolate Reactions: Halogenation and Alkylation

© 2011 Pearson Education, Inc. 28 Two different products can be formed if the ketone is not symmetrical:

© 2011 Pearson Education, Inc. 29 The less substituted  -carbon can be alkylated if the hydrazone is used:

© 2011 Pearson Education, Inc. 30 Alkylation and Acylation of the  -Carbon Using an Enamine Intermediate

© 2011 Pearson Education, Inc. 31 The alkylation step is an S N 2 reaction:

© 2011 Pearson Education, Inc. Direct alkylation of a carbonyl compound yields several products: In contrast, alkylation of an aldehyde or a ketone using an enamine intermediate yields the monoalkylated product 32

© 2011 Pearson Education, Inc. 33 Aldehydes and ketones can be acylated via an enamine intermediate:

© 2011 Pearson Education, Inc. 34 The  -carbon of an aldehyde or a ketone can be made to react with an electrophile: The  -carbon of an aldehyde or a ketone can also be made to react with a nucleophile:

© 2011 Pearson Education, Inc. 35 The Michael Addition

© 2011 Pearson Education, Inc. 36 Michael reactions form 1,5-dicarbonyl compounds:

© 2011 Pearson Education, Inc. 37 Mechanism for the Michael Addition Reaction

© 2011 Pearson Education, Inc. 38 The Stork Enamine Reaction Enamines are used in place of enolates in these Michael addition reactions:

© 2011 Pearson Education, Inc. 39 Aldol Addition Reaction

© 2011 Pearson Education, Inc. 40 One molecule of a carbonyl compound acts as a nucleophile, and the other carbonyl compound acts as an electrophile:

© 2011 Pearson Education, Inc. 41 Ketones are less susceptible than aldehydes to attack by nucleophiles for steric reasons:

© 2011 Pearson Education, Inc. 42 An aldol addition product loses water to form an aldol condensation product:

© 2011 Pearson Education, Inc. 43 Conjugation stabilizes the dehydrated product:

© 2011 Pearson Education, Inc. 44 The Mixed Aldol Addition

© 2011 Pearson Education, Inc. 45 One product will be formed if one of the carbonyl compounds does not have any  -hydrogen:

© 2011 Pearson Education, Inc. 46 Primarily one product can be formed by using LDA to deprotonate one of the carbonyl compounds:

© 2011 Pearson Education, Inc. 47 Condensation of Two Ester Molecules: The Claisen Condensation

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© 2011 Pearson Education, Inc. 50 The Claisen condensation requires an ester with two  -hydrogens and an equivalent amount of base The reaction can be driven to completion by removing a proton from the  -keto ester: Anion formation results in an irreversible reaction

© 2011 Pearson Education, Inc. 51 The Crossed Claisen Condensation The excess reactant has no  protons

© 2011 Pearson Education, Inc. 52 Because of the difference in the acidities of the  -hydrogens in the two carbonyl compounds, primarily one product is obtained

© 2011 Pearson Education, Inc. Enolate Reactions of Carboxylic Acids and Esters No  protons permitted in this reactant 53

© 2011 Pearson Education, Inc. 54 Intramolecular Condensation and Addition Reaction The Dieckmann condensation:

© 2011 Pearson Education, Inc. 55 Intramolecular Aldol Additions 1,4-Diketones afford five-member rings:

© 2011 Pearson Education, Inc. 56 1,6-Diketones also afford five-member rings:

© 2011 Pearson Education, Inc. 57 1,5- and 1,7-diketones afford six-member rings:

© 2011 Pearson Education, Inc. 58 The Robinson Annulation The Robinson annulation affords a product with a fused 2-cyclohexenone ring: Annulation: addition of a new ring fused 2-cyclohexenone ring

© 2011 Pearson Education, Inc. 59 Robinson annulation mechanism:

© 2011 Pearson Education, Inc. 60 Decarboxylation of 3-Oxocarboxylic Acids

© 2011 Pearson Education, Inc. 61 Acid catalyzes the intramolecular transfer of the proton:

© 2011 Pearson Education, Inc. 62 A malonic ester synthesis forms a carboxylic acid with two more carbon atoms than the alkyl halide:

© 2011 Pearson Education, Inc. 63 Mechanism for the malonic ester synthesis:

© 2011 Pearson Education, Inc. 64 Preparation of Carboxylic Acids with Two Substituents Bonded to the  -Carbon

© 2011 Pearson Education, Inc. 65 Synthesis of Methyl Ketone by Acetoacetic Ester Synthesis

© 2011 Pearson Education, Inc. 66 Mechanism for the acetoacetic ester synthesis:

© 2011 Pearson Education, Inc. 67 Enolate Reactions of Carboxylic Acids

© 2011 Pearson Education, Inc. 68 Decarboxylation and Synthesis

© 2011 Pearson Education, Inc. 69 Designing a Synthesis to Make New Carbon–Carbon Bonds Synthetic goal: Strategies:

© 2011 Pearson Education, Inc. 70 Solution:

© 2011 Pearson Education, Inc. 71 Synthetic goal: Solution:

© 2011 Pearson Education, Inc. 72 Synthetic goal: Solution:

© 2011 Pearson Education, Inc. 73 A Biological Aldol Condensation

© 2011 Pearson Education, Inc. 74 A Biological Claisen Condensation

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© 2011 Pearson Education, Inc. 76 A Biological Decarboxylation