Chemistry
Aldol Condensation
Aldol condensation is a reaction in organic chemistry where an enol or enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to produce an α,β-unsaturated carbonyl compound. The reaction involves the formation of a carbon-carbon bond and is commonly used in the synthesis of complex organic molecules.
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11 Key excerpts on "Aldol Condensation"
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2016(Publication Date)
- Wiley(Publisher)
The major product from the dehydration of an aldol product is one in which the carbon–carbon double bond is conjugated with the carbonyl group; that is, the product Aldol reaction A carbonyl condensation reaction between two aldehydes or ketones to give a β‐hydroxyaldehyde or a β‐hydroxyketone. Mechanism Base‐Catalyzed Aldol Reaction STEP 1: Take a proton away. The removal of an α‐hydrogen by base gives a resonance‐stabilized enolate anion: An enolate anion O C H CH 2 O – C H H O H + – CH 2 H O C H O – + H CH 2 STEP 2: Reaction of an electrophile and a nucleophile to form a new covalent bond. Because the equilibrium favors the left in Step 1, there is plenty of unreacted aldehyde (or ketone) remaining in the reaction mixture. Nucleophilic addition of the enolate anion to the carbonyl carbon of an unreacted molecule of aldehyde (or ketone) gives a tetrahedral carbonyl addition intermediate: A tetrahedral carbonyl addition intermediate (an electrophile) (a nucleophile) CH 3 O C H + – CH 2 O C H CH 3 O – CH CH 2 O C H the newly formed covalent bond STEP 3: Add a proton. Reaction of the tetrahedral carbonyl addition intermediate with a proton donor gives the aldol product and generates another hydroxide ion: CH 3 O – C H CH 2 O C H + H OH CH 3 O C H H CH 2 O C H + – OH © Jesus Conde/iStockphoto 510 C H A P T E R 1 5 Enolate Anions is an α, β‐unsaturated aldehyde or ketone (so named because the site of unsaturation, the double bond, is between the α and β carbons). Product of an aldol reaction An α,β-unsaturated aldehyde CH 3 C β H C α H O CH + H 2 O warm in either acid or base CH 3 O C H HCH 2 O CH Base‐catalyzed aldol reactions are readily reversible, and generally little aldol product is present at equilibrium. Equilibrium constants for dehydration, however, are usually large, so that, if reaction conditions are sufficiently vigorous to bring about dehydration, good yields of product can be obtained.
eBook - PDF- David R. Klein(Author)
- 2021(Publication Date)
- Wiley(Publisher)
Under these basic conditions, the aldol addition reaction occurs, followed by dehydration to give an α,β-unsaturated product. H O H O + H 2 O Heat NaOH, H 2 O 21.3 Aldol Reactions 1013 This two-step process (aldol addition plus dehydration) is called an Aldol Condensation. The term condensation is used to refer to any reaction in which two molecules undergo addition accompanied by the loss of a small molecule such as water, carbon dioxide, or nitrogen gas. In the case of Aldol Condensations, water is the small molecule that is lost. Notice that the product of an aldol addition is a β-hydroxy aldehyde or ketone, while the product of an Aldol Condensation is an α,β-unsaturated aldehyde or ketone. H O H O OH H O H O β-Hydroxy aldehyde α, β-Unsaturated aldehyde Aldol addition Aldol Condensation + + H 2 O MECHANISM 21.6 Aldol Condensation PART 2: ELIMINATION OF H 2 O H O Proton transfer Loss of a leaving group The α position is deprotonated to form an enolate Hydroxide is ejected to afford the product H H O O OH H H O H H O PART 1 : ALDOL ADDITION Nucleophilic attack Proton transfer Proton transfer The α position is deprotonated to form an enolate The enolate serves as a nucleophile and attacks an aldehyde The resulting alkoxide ion is protonated O OH OH H H H H H O O - OH - OH - O - O - An Aldol Condensation (Mechanism 21.6) has two parts. The first part is just an aldol addition reaction, which has three mechanistic steps. The second part has two steps that accomplish the elim- ination of water. Normally, alcohols do not undergo dehydration in the presence of a strong base, but here, the presence of the carbonyl group renders the α position mildly acidic, thereby enabling the dehydration reaction to occur. The α position is first deprotonated to form an enolate ion, fol- lowed by expulsion of a hydroxide ion to produce α,β unsaturation. This two-step process, which is different from the elimination reactions we saw in Chapter 7, is called an E1cb mechanism.
eBook - PDF- David R. Klein(Author)
- 2020(Publication Date)
- Wiley(Publisher)
Athletes ca an run faster in a sprinting race, which relies mostly on glycol lysis for energy produ c - tion. Long-distan nce running requires the citric acid cycle f for energy productio on. 1014 CHAPTER 22 Alpha Carbon Chemistry: Enols and Enolates Practically, this transformation is most readily achieved when an aldol addition is performed at elevated temperature. Under these basic conditions, the aldol addition reaction occurs, followed by dehydration to give an α,β-unsaturated product. H O H O + H 2 O Heat NaOH, H 2 O This two-step process (aldol addition plus dehydration) is called an Aldol Condensation. The term conden- sation is used to refer to any reaction in which two molecules undergo addition accompanied by the loss of a small molecule such as water, carbon dioxide, or nitrogen gas. In the case of Aldol Condensations, water is the small molecule that is lost. Notice that the product of an aldol addition is a β-hydroxy aldehyde or ketone, while the product of an Aldol Condensation is an α,β-unsaturated aldehyde or ketone. H O H O OH H O H O β-Hydroxy aldehyde α, β-Unsaturated aldehyde Aldol addition Aldol Condensation + + H 2 O MECHANISM 22.6 Aldol Condensation Part 2: Elimination of H 2 O Part 1 : Aldol Addition H O H H O OH OH H O OH Proton transfer Loss of a leaving group The α position is deprotonated to form an enolate Hydroxide is ejected to afford the product H H O OH H H O H H H O OH H H H O O Nucleophilic attack Proton transfer Proton transfer The α position is deprotonated to form an enolate The enolate serves as a nucleophile and attacks an aldehyde The resulting alkoxide ion is protonated ⊝ ⊝ ⊝ ⊝ ⊝ O O An Aldol Condensation (Mechanism 22.6) has two parts. The first part is just an aldol addition reac- tion, which has three mechanistic steps. The second part has two steps that accomplish the elimina- tion of water.
eBook - PDF- William H. Brown, Thomas Poon(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
15.2 What Is the Aldol Reaction? A. Formation of Enolate Anions of Aldehydes and Ketones Treatment of an aldehyde or a ketone containing an acidic α‐hydrogen with a strong base, such as sodium hydroxide or sodium ethoxide, gives an enolate anion as a hybrid of two major contributing structures: An enolate anion ) d i c a r e g n o r t s ( ) d i c a r e k a e w ( pK a 15.7 pK a 20 H C H O C CH 3 H C H O CCH 3 Na H 2 O CH 3 O CCH 3 NaOH – – Given the relative acidities of the two acids in this equilibrium, the position of equilibrium lies considerably to the left. However, the existence of just a small amount of enolate anion is enough to allow the aldol reaction to proceed. B. The Aldol Reaction Addition of the enolate anion derived from an aldehyde or a ketone to the carbonyl group of another aldehyde or ketone is illustrated by these examples: Ethanal Ethanal 3-Hydroxybutanal (Acetaldehyde) (Acetaldehyde) Propanone Propanone 4-Hydroxy-4-methyl-2-pentanone (Acetone) (Acetone) (a β-hydroxyketone) CH 3 OH β C CH 3 C α H 2 O C CH 3 NaOH CH 3 O C CH 3 + H CH 2 O C CH 3 (a β-hydroxyaldehyde) CH 3 O β C H H C α H 2 O C H NaOH CH 3 O C H + H C H 2 O C H 508 C H A P T E R 15 Enolate Anions 15.2 1 5 . 2 What Is the Aldol Reaction? 509 The common name of the product derived from the reaction of acetaldehyde in base is aldol, so named because it is both an aldehyde and an alcohol. Aldol is also the generic name given to any product formed in this type of reaction. The functional group of the product of an aldol reaction is a β‐hydroxyaldehyde or a β‐hydroxyketone. The key step in a base‐catalyzed aldol reaction is nucleophilic addition of the enolate anion from one carbonyl‐containing molecule to the carbonyl group of another carbonyl‐ containing molecule to form a tetrahedral carbonyl addition intermediate. This mecha- nism is illustrated by the aldol reaction between two molecules of acetaldehyde.
eBook - PDF- David R. Klein(Author)
- 2016(Publication Date)
- Wiley(Publisher)
The first part is just an aldol addition reac- tion, which has three mechanistic steps. The second part has two steps that accomplish the elimina- tion of water. Normally, alcohols do not undergo dehydration in the presence of a strong base, but here, the presence of the carbonyl group renders the α position mildly acidic, thereby enabling the dehydration reaction to occur. The α position is first deprotonated to form an enolate ion, followed by expulsion of a hydroxide ion to produce α,β unsaturation. This two-step process, which is differ- ent from the elimination reactions we saw in Chapter 7, is called an E1cb mechanism. Unlike an E1 process, in which the intermediate is a cation, the intermediate in this case is an anion (an enolate). 21.3 Aldol Reactions 971 This enolate is formed via deprotonation, so it is a conjugate base (thus the letters “cb”), and the “1” indicates that the reaction is first order (see Section 5.5 for a description of first-order reactions). In cases where two stereoisomeric π bonds can be formed, the product with fewer steric interac- tions is generally the major product. H O H O Major H O + Minor NaOH Heat In this example, formation of the trans π bond is favored over formation of the cis π bond. The driving force for an Aldol Condensation is formation of a conjugated system. The reaction conditions required for an Aldol Condensation are only slightly more vigorous than the conditions required for an aldol addition reaction. Usually, an Aldol Condensation can be achieved by simply performing the reaction at an elevated temperature. In fact, in some cases, it is not even possible to isolate the β-hydroxyketone. As an example, consider the following case: O O NaOH O OH Not isolated In this case, the aldol addition product cannot be isolated. Even at moderate temperatures, only the condensation product is obtained, because the condensation reaction involves formation of a highly conjugated π system.
eBook - PDF- T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
- 2017(Publication Date)
- Wiley(Publisher)
Both the kinetic and thermodynamic enolates would have been formed from the ketone, and each of these would have added to the carbonyl carbon of the aldehyde: An Aldol Reaction that Produces a Mixture via Both Kinetic and Thermodynamic Enolates (Using a Weaker Base Under Protic Conditions) Kinetic enolate A mixture of crossed aldol products results. + Thermodynamic enolate H 2 O H 2 O protic solvent HO − O O − O − O OH OH O O O − O H O H O enolate O O 19.6 CYCLIZATIONS VIA Aldol CondensationS 867 19.6 CYCLIZATIONS VIA Aldol CondensationS The Aldol Condensation also offers a convenient way to synthesize molecules with five- and six-membered rings (and sometimes even larger rings). This can be done by an intramolecular Aldol Condensation using a dialdehyde, a keto aldehyde, or a diketone as the substrate. For example, the following keto aldehyde cyclizes to yield 1-cyclopentenyl methyl ketone: HO – O H O 73% O This reaction almost certainly involves the formation of at least three different eno- lates. However, it is the thermodynamic enolate from the ketone side of the molecule that adds to the aldehyde group leading to the product. The reason the aldehyde group undergoes addition preferentially may arise from the greater reactivity of aldehydes toward nucleophilic addition generally. The carbonyl car- bon atom of a ketone is less positive (and therefore less reactive toward a nucleophile) because it bears two electron-releasing alkyl groups; it is also more sterically hindered. O R R O H R In reactions of this type, five-membered rings form far more readily than seven-membered rings, and six-membered rings are more favorable than four- or eight-membered rings, when possible. Selectivity in aldol cyclizations is influenced by carbonyl type and ring size. HINT Ketones are less electrophilic than aldehydes, and hence less reactive with nucleophiles, because ketones have two electron- releasing alkyl groups and more steric hindrance.
eBook - PDF- T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
- 2016(Publication Date)
- Wiley(Publisher)
Both the kinetic and thermodynamic enolates would have been formed from the ketone, and each of these would have added to the carbonyl carbon of the aldehyde: An Aldol Reaction that Produces a Mixture via Both Kinetic and Thermodynamic Enolates (Using a Weaker Base Under Protic Conditions) Kinetic enolate A mixture of crossed aldol products results. + Thermodynamic enolate H 2 O H 2 O protic solvent HO - O O - O - O OH OH O O O - O H O H O enolate O O 19.6 CYCLIZATIONS VIA Aldol CondensationS 867 19.6 CYCLIZATIONS VIA Aldol CondensationS The Aldol Condensation also offers a convenient way to synthesize molecules with five- and six-membered rings (and sometimes even larger rings). This can be done by an intramolecular Aldol Condensation using a dialdehyde, a keto aldehyde, or a diketone as the substrate. For example, the following keto aldehyde cyclizes to yield 1-cyclopentenyl methyl ketone: HO – O H O 73% O This reaction almost certainly involves the formation of at least three different eno- lates. However, it is the thermodynamic enolate from the ketone side of the molecule that adds to the aldehyde group leading to the product. The reason the aldehyde group undergoes addition preferentially may arise from the greater reactivity of aldehydes toward nucleophilic addition generally. The carbonyl car- bon atom of a ketone is less positive (and therefore less reactive toward a nucleophile) because it bears two electron-releasing alkyl groups; it is also more sterically hindered. O R R O H R In reactions of this type, five-membered rings form far more readily than seven-membered rings, and six-membered rings are more favorable than four- or eight-membered rings, when possible. [ HELPFUL HINT ] Selectivity in aldol cyclizations is influenced by carbonyl type and ring size. [ HELPFUL HINT ] Ketones are less electrophilic than aldehydes, and hence less reactive with nucleophiles, because ketones have two electron-releasing alkyl groups and more steric hindrance.
eBook - PDFMicrowave-Assisted Organic Synthesis
A Green Chemical Approach
- Suresh C. Ameta, Pinki B. Punjabi, Rakshit Ameta, Chetna Ameta, Suresh C. Ameta, Pinki B. Punjabi, Rakshit Ameta, Chetna Ameta(Authors)
- 2014(Publication Date)
- Apple Academic Press(Publisher)
CHAPTER 10 CONDENSATION SANYOGITA SHARMA, ABHILASHA JAIN, and RAKSHIT AMETA CONTENTS 10.1 Aldol Condensation ....................................................................... 182 10.2 Bayer Condensation ...................................................................... 184 10.3 Claisen Condensation .................................................................... 184 10.4 Claisen-Schimdt Condensation ..................................................... 185 10.5 Cyclocondensation ........................................................................ 185 10.6 Friedlander Condensation ............................................................. 190 10.7 Isay Condensation ......................................................................... 191 10.8 Knoevenagel Condensation .......................................................... 192 10.9 Pechmann Condensation ............................................................... 196 10.10 Ugi Condensation Reaction ......................................................... 196 10.11 Miscellaneous ............................................................................... 198 Keywords .................................................................................................. 203 References ................................................................................................. 203 182 Microwave-Assisted Organic Synthesis: A Green Chemical Approach Condensation is a class of organic reactions, where two molecules combine, usually in the presence of a catalyst, with elimination of water or some other simple mol-ecule. The combination of two identical molecules is known as self-condensation. Aldehydes, ketones, esters, alkynes (acetylenes) and amines are among several or-ganic compounds that combine with each other and except for amines, among them-selves to form larger molecules, many of which are useful intermediate compounds in organic syntheses.
- David R. Klein(Author)
- 2017(Publication Date)
- Wiley(Publisher)
Intramolecular aldol reactions show a preference for formation of ______ and ____-membered rings. When an ester is treated with an alkoxide base, a Claisen condensation reaction occurs, and the product is a ________________. The α position of a ketone can be alkylated by forming an enolate and treating it with an _________________. For unsymmetrical ketones, reactions with _____ at low temperature favor formation of the kinetic enolate, while reactions with ______ at room temperature favor the thermodynamic enolate. When LDA is used with an unsymmetrical ketone, alkylation occurs at the __________________ position. The ______________________ synthesis enables the conversion of an alkyl halide into a carboxylic acid with the introduction of two new carbon atoms. The ______________________ synthesis enables the conversion of an alkyl halide into a methyl ketone with the introduction of two new carbon atoms. Aldehydes and ketones that possess _____-unsaturation are susceptible to nucleophilic attack at the β position. This reaction is called a ____________ addition, or 1,4-addition, or a Michael reaction. Review of Skills Fill in the blanks and empty boxes below. To verify that your answers are correct, look in your textbook at the end of Chapter 21. The answers appear in the section entitled SkillBuilder Review. 21.1 Drawing Enolates CHAPTER 21 831 21.2 Predicting the Products of an Aldol Addition Reaction 21.3 Drawing the Product of an Aldol Condensation 21.4 Identifying the Reagents Necessary for a Crossed Aldol Reaction 21.5 Using the Malonic Ester Synthesis 832 CHAPTER 21 21.6 Using the Acetoacetic Ester Synthesis 21.7 Determining When to Use a Stork Enamine Synthesis 21.8 Determining which Addition or Condensation Reaction to Use 21.9 Alkylating the and Positions CHAPTER 21 833 Review of Reactions Identify the reagents necessary to achieve each of the following transformations.
eBook - PDF- T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
- 2022(Publication Date)
- Wiley(Publisher)
+ Thermodynamic H 2 O H 2 O protic solvent HO − O O − O − O OH OH O O O − O − O H O H O enolate O A single crossed aldol product results. 75% LDA, THF −78 °C H 2 O O H O O OH O − Li + O O − Li + Outline a directed aldol synthesis of the following compound. O OH Strategy and Answer Retrosynthetic Analysis O – Li + + H O O OH Synthesis O O – Li + O OH (1) LDA H O (2) (3) H 2 O SOLVED PROBLEM 19.7 19.6 Cyclizations via Aldol Condensations 891 19.6 Cyclizations via Aldol Condensations The Aldol Condensation also offers a convenient way to synthesize molecules with five- and six-membered rings (and sometimes even larger rings). This can be done by an intramolecular Aldol Condensation using a dialdehyde, a keto aldehyde, or a diketone as the substrate. For example, the following keto aldehyde cyclizes to yield 1-cyclopentenyl methyl ketone: HO – O H O 73% O This reaction almost certainly involves the formation of at least three different enolates. However, it is the thermodynamic enolate from the ketone side of the molecule that adds to the aldehyde group leading to the product. The reason the aldehyde group undergoes addition preferentially may arise from the greater reactivity of aldehydes toward nucleophilic addition generally. The carbonyl carbon atom of a ketone is less positive (and therefore less reactive toward a nucleophile) because it bears two electron-releasing alkyl groups; it is also more sterically hindered. O R R O H R In reactions of this type, five-membered rings form far more readily than seven-membered rings, and six-membered rings are more favorable than four- or eight-membered rings, when possible. HELPFUL HINT Selectivity in aldol cyclizations is influenced by carbonyl type and ring size. HELPFUL HINT Ketones are less electrophilic than aldehydes, and hence less reactive with nucleophiles, because ketones have two electron-releasing alkyl groups and more steric hindrance.
eBook - PDF- James Morrison(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
2 The Aldol Addition Reaction Clayton H. Heathcock Department of Chemistry University of California Berkeley, California I. Simple Diastereoselection Ill A. Introduction Ill B. Stereostructural Notation 112 C. Aldol Stereostructural Assignments 115 D. Kinetic Stereoselectivity: The Relationship between Enolate Geometry and Aldol Stereostructure 119 E. Transition-State Hypotheses 154 F. Aldol Equilibration: Thermodynamic Stereoselection. . . . 161 II. Diastereofacial Selectivity 165 A. Reactions of Achiral Enolates with Chiral Aldehydes . . . 165 B. Reactions of Achiral Aldehydes and Ketones with Chiral Enolates 174 C. Reactions of Chiral Aldehydes with Chiral Enolates . . . . 191 D. Chiral Auxiliaries 200 References 206 I. Simple Diastereoselection A. Introduction Although the aldol addition reaction was first reported in 1838 (/), there were only scattered observations pertaining to its stereochemistry before 1970 (2). During the 1970s, stereochemical investigations of this venerable ASYMMETRIC S Y N T H E S I S V O L U M E 3 111 Copyright © 1984 by Academic Press, Inc. All rights of reproduction in any form reserved. ISBN 0-12-507703-3 112 c. H. Heathcock reaction began in earnest, mainly because of the advent of reliable meth-ods, particularly , 3 C-NMR spectroscopy and high-performance liquid chromatography, for the analysis of diastereomer mixtures. The reader should be aware that progress in this area is still very rapid and that some of the tentative conclusions drawn in this review are sure to change. Because of the mass of data that has accrued in this field, this chapter is selective and critical rather than exhaustive. The reader is referred to earlier reviews for further discussion of individual points {3, 4). The reaction of an enolate having homotopic double-bond faces with an aldehyde or a ketone having prochiral carbonyl faces gives a pair of enantiomeric aldols.
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