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22.4 Claisen Condensations • Esters also undergo reversible condensations reactions • Unlike a ketone or aldehyde, an ester has a leaving group Copyright 2012 John Wiley & Sons, Inc. 22-1 22.4 Claisen Condensations • Esters also undergo reversible condensations reactions • The resulting doubly-stabilized enolate must be treated with an acid in a last step. WHY? • A beta-keto ester is produced Copyright 2012 John Wiley & Sons, Inc. 22-2 22.4 Claisen Condensations • There are some limitations to the Claisen condensation 1. The starting ester must have 2 alpha protons, because removal of the second proton by the alkoxide ion is what drives the equilibrium forward 2. Hydroxide cannot be used as the base to promote Claisen condensations, because a hydrolysis reaction occurs between hydroxide and the ester 3. An alkoxide equivalent to the –OR group of the ester is a good base, because transesterification is avoided • Practice conceptual checkpoints 22.28 and 22.29 Copyright 2012 John Wiley & Sons, Inc. 22-3 22.4 Claisen Condensations • Crossed Claisen reactions can also be achieved using the same strategies employed in crossed aldol reactions • Practice with conceptual checkpoint 22.30 Copyright 2012 John Wiley & Sons, Inc. 22-4 22.4 Claisen Condensations • Intramolecular Claisen condensations can also be achieved • This Diekmann cyclization proceeds through the expected 5-membered ring transition state. DRAW it • Practice with conceptual checkpoints 22.31 and 22.32 Copyright 2012 John Wiley & Sons, Inc. 22-5 22.4 Claisen Condensations • Give reagents necessary to synthesize the following molecules Copyright 2012 John Wiley & Sons, Inc. 22-6 22.5 Alkylation of the Alpha Proton • The alpha position can be alkylated when an enolate is treated with an alkyl halide • The enolate attacks the alkyl halide via an SN2 reaction Copyright 2012 John Wiley & Sons, Inc. 22-7 22.5 Alkylation of the Alpha Proton • When 2° or 3° alkyl halides are used, the enolate can act as a base in an E2 reaction. SHOW a mechanism • The aldol reaction also competes with the desired alkylation, so a strong base such as LDA must be used • Regioselectivity is often an issue when forming enolates • If the compound below is treated with a strong base, two enolates can form – see next few slides Copyright 2012 John Wiley & Sons, Inc. 22-8 22.5 Alkylation of the Alpha Proton • What is meant by kinetic and thermodynamic enolate? See next few slides for details Copyright 2012 John Wiley & Sons, Inc. 22-9 22.5 Alkylation of the Alpha Proton • For clarity, the kinetic and thermodynamic pathways are exaggerated below • Explain the energy differences below using steric and stability arguments Copyright 2012 John Wiley & Sons, Inc. 22-10 22.5 Alkylation of the Alpha Proton • LDA is a strong base, and at low temperatures, it will react effectively in an irreversible manner • NaH is not quite as strong, and if heat is available, the system will be reversible • Practice with conceptual checkpoints 22.33 and 22.24 Copyright 2012 John Wiley & Sons, Inc. 22-11 22.5 Alkylation of the Alpha Proton • Give necessary reagents to synthesize the compound below starting with carbon fragments with 5 carbons or less Copyright 2012 John Wiley & Sons, Inc. 22-12 22.5 Alkylation of the Alpha Proton • The malonic ester synthesis allows a halide to be converted into a carboxylic acid with two additional carbons • Diethyl malonate is first treated with a base to form a doubly-stabilized enolate Copyright 2012 John Wiley & Sons, Inc. 22-13 22.5 Alkylation of the Alpha Proton • The enolate is treated with the alkyl halide • The resulting diester can be hydrolyzed with acid or base using heat Copyright 2012 John Wiley & Sons, Inc. 22-14 22.5 Alkylation of the Alpha Proton • One of the resulting carboxylic acid groups can be decarboxylated with heat through a pericyclic reaction • Why isn’t the second carboxylic acid group removed? Copyright 2012 John Wiley & Sons, Inc. 22-15 22.5 Alkylation of the Alpha Proton • Here is an example of the overall synthesis Copyright 2012 John Wiley & Sons, Inc. 22-16 22.5 Alkylation of the Alpha Proton • Double alkylation can also be achieved • Practice with SkillBuilder 22.5 • The acetoacetic ester synthesis is a very similar process Copyright 2012 John Wiley & Sons, Inc. 22-17 22.5 Alkylation of the Alpha Proton • Give a complete mechanism for the process below • Practice with SkillBuilder 22.6 Copyright 2012 John Wiley & Sons, Inc. 22-18 22.6 Conjugate Addition Reactions • Recall that α,β-unsaturated carbonyls can be made easily through aldol condensations • α,β-unsaturated carbonyls have three resonance contributors • Which contributors are electrophilic? Copyright 2012 John Wiley & Sons, Inc. 22-19 22.6 Conjugate Addition Reactions • Grignard reagents generally attack the carbonyl position of α,β-unsaturated carbonyls yielding a 1,2 addition • In contrast, Gilman reagents generally attacks the beta position giving 1,4 addition or conjugate addition Copyright 2012 John Wiley & Sons, Inc. 22-20 22.6 Conjugate Addition Reactions • Conjugate addition of α,β-unsaturated carbonyls starts with attack at the beta position • WHY is the nucleophile generally favored to attack the beta position? Copyright 2012 John Wiley & Sons, Inc. 22-21 22.6 Conjugate Addition Reactions • More reactive nucleophiles (e.g. Grignard) are more likely to attack the carbonyl directly. WHY? • Enolates are generally less reactive than Grignards but more reactive than Gilman reagents, so enolates often give a mixture of 1,2- and 1,4- addition products • Doubly-stabilized enolates are stable enough to react primarily at the beta position Copyright 2012 John Wiley & Sons, Inc. 22-22 22.6 Conjugate Addition Reactions • When an enolate attacks a beta carbon, the process is called a Michael addition Copyright 2012 John Wiley & Sons, Inc. 22-23 22.6 Conjugate Addition Reactions • Give a mechanism showing the reaction between the two compounds shown below • Practice with conceptual checkpoints 22.44 through 22.46 Copyright 2012 John Wiley & Sons, Inc. 22-24 22.6 Conjugate Addition Reactions • Because singly-stabilized enolates do not give high yielding Michael additions, Gilbert Stork developed a synthesis using an enamine intermediate • Recall the enamine synthesis from chapter 20 Copyright 2012 John Wiley & Sons, Inc. 22-25 22.6 Conjugate Addition Reactions • Enolates and enamines have reactivity in common • The enamine is less nucleophilic and more likely to act as a Michael donor Copyright 2012 John Wiley & Sons, Inc. 22-26 22.6 Conjugate Addition Reactions • Water hydrolyzes the imine and tautomerizes and protonates the enol Copyright 2012 John Wiley & Sons, Inc. 22-27 22.6 Conjugate Addition Reactions • Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis • Practice with SkillBuilder 22.7 Copyright 2012 John Wiley & Sons, Inc. 22-28 22.6 Conjugate Addition Reactions • The Robinson Annulation utilizes the a Michael addition followed by an aldol condensation • Practice checkpoints 22.49 and 22.50 Copyright 2012 John Wiley & Sons, Inc. 22-29 22.7 Synthetic Strategies • Most of the reactions in this chapter are C-C bond forming • Three of the reactions yield a product with two functional groups • The positions of the functional groups in the product can be used to design necessary reagents in the synthesis – see next few slides • Practice with SkillBuilder 22.8 Copyright 2012 John Wiley & Sons, Inc. 22-30 22.7 Synthetic Strategies • Stork enamine synthesis 1,5-dicarbonyl compounds • Aldol and Claisen 1,3-difunctional compounds Copyright 2012 John Wiley & Sons, Inc. 22-31 22.7 Synthetic Strategies • We have learned two methods of alkylation 1. The alpha position of an enolate attacks an alkyl halide 2. A Michael donor attacks the beta position of a Michael acceptor • These two reactions can also be combined • Give a reasonable mechanism • Practice with SkillBuilder 22.9 Copyright 2012 John Wiley & Sons, Inc. 22-32 22.7 Synthetic Strategies • Give reagents necessary for the following synthesis Copyright 2012 John Wiley & Sons, Inc. 22-33 Study Guide for Sections 22.4-22.7 DAY 25, Terms to know: Sections 22.4-22.7 Claisen Condensations, alkylation, malonic ester synthesis, beta position, conjugate addition, Michael addition DAY 25, Specific outcomes and skills that may be tested on exam 4: Sections 22.4-22.7 •Given a desired product, be able to describe ideal reaction conditions and reagents for reactions discussed including crossed or mixed aldol, Claisen Condensations, alkylation of alpha position, malonic ester synthesis, including ring-closing reactions •Be able to predict products and give a complete mechanism for any of the reactions we discussed including crossed or mixed aldol, Claisen Condensation, alkylation of alpha position, malonic ester synthesis, including ring closing reactions •Be able to describe and fully explain how to achieve either kinetic or thermodynamic control over alkylation of alpha position reactions •Given a desired product, be able to describe ideal reaction conditions and reagents for reactions discussed where a nucleophile attacks either the carbonyl carbon or the beta carbon of an α,β-unsaturated carbonyl •Be able to predict products and give a complete mechanism for any of the reactions we discussed where a nucleophile attacks either the carbonyl carbon or the beta carbon of an α,βunsaturated carbonyl •Be able to solve syntheses with up to 3 steps including setting the syntheses up retrosynthetically •Be able to fill in blank reagents, intermediates, or products in a synthesis involving any of the reactions discussed in this chapter Extra Practice Problems for Sections 22.4-22.7 Complete these problems outside of class until you are confident you have learned the SKILLS in this section outlined on the study guide and we will review some of them next class period. 22.28 22.29 22.30 22.31 22.32 22.77 22.33 22.34 22.35 22.37 22.38 22.39 22.41 22.42 22.44 22.45 22.46 22.47 22.49 22.51 22.52 22.54 22.56 22.90 22.92 22.93 22.94 Prep for Day 26 Must Watch videos: https://www.youtube.com/watch?v=STIamn93rds (naming amines, Leah) https://www.youtube.com/watch?v=nvJHBQZoOBw (properties of amines, JP McCormick) https://www.youtube.com/watch?v=qwFH8EYZxvg (primary amine synthesis, Organic Chemistry Tutor) https://www.youtube.com/watch?v=Cu1D6Y9AvIg (Gabriel synthesis, Organic Chemistry Tutor) Other helpful videos: https://www.youtube.com/watch?v=Kpov3GS6tjM and https://www.youtube.com/watch?v=CJzuu_k9Nv0 (naming amines, Khan) https://www.youtube.com/watch?v=_1gf6b7FyIo&index=21&list=PLqOZ6FD_RQ7nqVjmYjBSZOkjln _K31ATj (properties of amines, UC-Irvine) https://www.youtube.com/watch?v=Wi9P3h_lTFY&index=22&list=PLqOZ6FD_RQ7nqVjmYjBSZOkjl n_K31ATj (preparation of amines, UC-Irvine) watch first 24 minutes https://www.youtube.com/watch?v=NR_jnYvZC_0 (amines, UC-Irvine) watch first 42 minutes Read Sections 23.1-23.5