University:
Rutgers University Newark
Course:
CHEM 336 | Organic Chemistry ||
Academic year:

2024
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178

Pages:

125
Author:

Mahitab S.

CHAPTER 16 ALDEHYDES AND KETONES ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • • • • • • • • (16.1) (16.2) (16.3) (16.4) (16.5) (16.6) (16.7) (16.8) Structure and bonding Nomenclature Physical properties Reactions Addition of carbon nucleophiles The Wittig reaction Addition of oxygen nucleophiles Addition of nitrogen nucleophiles ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • • • • (16.9) (16.10) (16.11) (16.12) Keto-enol tautomerism Oxidation Reduction Reactions at an α-carbon ©2018 Cengage Learning. All Rights Reserved. The Carbonyl Group • In this and several following chapters, we study the physical and chemical properties of classes of compounds containing the carbonyl group (C=O) O • Functional group of: b • Aldehydes and ketones (Chapter 16) bond double • Carboxylic acids (Chapter 17) • Acid halides, acid anhydrides, esters, and amides (Chapter 18) • Enolate anions (Chapter 19) ©2018 Cengage Learning. All Rights Reserved. Functional Group of Aldehydes and Ketones • Aldehydes: Carbonyl group to H atom and C atom • Exception - Carbonyl group in formaldehyde is bonded to two hydrogen atoms (H2CO, HC(O)H, H2C=O) • Ketones: Carbonyl group bonded to two carbon atoms Carbonylgroup RI p ©2018 Cengage Learning. All Rights Reserved. Aldehyde ketone Higherprecedence Nomenclature of Aldehydes (IUPAC = International Union of Pure and Appl. Chemistry) • Select the longest chain of carbon atoms that contains the functional group as the parent alkane • Change the suffix from -e to -al • Numbering is not required to locate the position of the carbonyl group as it can only appear at the end of a parent chain, and numbering must start with it as carbon-1 • For unsaturated aldehydes, presence of a C=C or C≡C bonds is indicated by the infix -en- or -yn• Location of the group 32 I corresponding to the I 23 4 suffix determines the 2 methylbutanal 2 propenal numbering pattern for molecules with both an infix and a suffix ©2018 Cengage Learning. All Rights Reserved. 3,7 Dimethyl 2,6octadienal Nomenclature of Aldehydes ceptions • For a cyclic molecule in which —CHO is bonded to the ring, add the suffix -carbaldehyde to the name of the ring 5 y 3 21 cycolopentane aldehyde carb 4 Texan tyg Carbaldehy • Retains the common names benzaldehyde and cinnamaldehyde, as well as 3 formaldehyde and acetaldehyde benzanaldehyde ©2018 Cengage Learning. All Rights Reserved. 2 3phenyl 2 propenal IUPAC Nomenclature of Ketones • Select the longest chain that contains the carbonyl group as the parent alkane • Indicate the presence of the C=O group by changing the suffix -e to -one • Number the parent chain to give the carbonyl carbon the smaller number • Common names acetone, acetophenone, and benzophenone have been retained 2 t 2 ©2018 Cengage Learning. All Rights Reserved. L phenyl 345 Example 16.1 - Naming Aldehydes and Ketones • Write IUPAC names for each compound • Specify the configuration of all chiral centers in (a) and (c) 5 4 32 3 I 4 start with pentane start no. with C=O (S)-3-ethyl-2-hydroxypentanal 3-methyl-2-cyclohexenone gym 3ethyl 2 hydroxypentanal ©2018 Cengage Learning. All Rights Reserved. s 6 (2S,5R)-2-isopropyl-5methylcyclohexanone 5MethylCycolonexanone 2isopropyl Order of Precedence of Functions • Established by IUPAC for naming compounds that contain more than one functional group that might be indicated by a suffix front 123 ©2018 Cengage Learning. All Rights Reserved. Example 16.3 - Naming Aldehydes and Ketones • Write the IUPAC name for each compound, being certain to specify configuration where appropriate 4 3 2 3 I 3-Oxobutanal 3 oxobutanal 2 at pro pan 2 3 Dihydroxy (R)-2,3-Dihydroxypropanal 7 6 4 2 o hydroxy 2he ptanone (R)-6-Hydroxy-2-heptanone -aldehyde has higher precedence than a ketone -carbonyl group of the ketone is indicated by the prefix oxo©2018 Cengage Learning. All Rights Reserved. Common Names for Aldehydes and Ketones • Aldehyde: Derived from the common name of the corresponding carboxylic acid by dropping the word acid and changing the suffix -ic or -oic to -aldehyde • Ketone: Derived by naming the two alkyl or aryl groups bonded to the carbonyl carbon as separate words followed by ethyl the word ketone isopod Tayolohexane J 9 ©2018 Cengage Learning. All Rights Reserved. 0 O Example • Select the correct IUPAC name for the following molecule: H 1. 2. 3. 4. 5. I 2 3 4 5 tan at pen 2 ethyl 4 methyl (R)-2-ethyl-4-methylpentanal (R)-4-ethyl-2-methylpentanal (R)-2-tert-butylbutanal (R)-3-tert-butylbutanal (R)-2-ethyl-4-methylpentane carbaldehyde ©2018 Cengage Learning. All Rights Reserved. Example • Select the correct IUPAC name for the following molecule I 1. 2. 3. 4. 5. 2 3 4 s b 7 4isopropylheptanone (S)-4-isopropylheptan-5-one (S)-5-methyl-4-propylhexan-3-one (S)-2-methyl-3-propylhexan-4-one (S)-4-isopropylheptan-3-one (S)-1-propyl-1-isopropylheptan-2-one ©2018 Cengage Learning. All Rights Reserved. Example • Select the correct IUPAC name for the following molecule 5 4 1. 2. 3. 4. 5. I 2 3 2 ethyl 2 eyetohePtenone 2-ethyl-3-cyclopentenone 1-ethyl-5-cyclopenten-2-one 2-ethylcyclopent-2-en-1-one 1-ethyl-2-cyclopenten-5-one 2-ethyl-1-keto-2-cyclopentene ©2018 Cengage Learning. All Rights Reserved. Physical Properties of Aldehydes and Ketones Aldehydeand ketone • Both are polar compounds that engage in dipole-dipole interactions in pure liquid • C=O bond is polar since oxygen is more electronegative than carbon (3.5 compared with 2.5) • Have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight ©2018 Cengage Learning. All Rights Reserved. Table 16.2 - Boiling Points of Six Compounds of Comparable Molecular Weight Note boiling pointsthanketone Alcoholhaveheigher 1 ©2018 Cengage Learning. All Rights Reserved. Table 16.3 - Physical Properties of Selected Aldehydes and Ketones highestboilingpointandleastsolubality has Arid aldehyde ©2018 Cengage Learning. All Rights Reserved. Reaction Themes of a Carbonyl Group • Nucleophilic acyl addition: Nucleophile makes a new bond to the electrophilic carbonyl carbon atom • Forms a tetrahedral carbonyl addition compound • Facilitated by reaction with a proton or other Lewis acid to form a resonance-stabilized cation • Protonation increases the electron deficiency of the carbonyl e carbon and makes it more reactive toward nucleophiles • All proton-transfer reactions are fast and reversible ©2018 Cengage Learning. All Rights Reserved. Reaction Themes of a Carbonyl Group ©2018 Cengage Learning. All Rights Reserved. Reaction Themes of a Carbonyl Group • Reactivity can be predicted based on the large bond dipole of the carbonyl group • Electrophiles such as protons are attracted to the partial negative charge of the carbonyl oxygen • Nucleophiles are attracted to the partial positive charge of the carbonyl carbon ©2018 Cengage Learning. All Rights Reserved. Reaction Themes of a Carbonyl Group • Tetrahedral product of nucleophile addition to a carbonyl group is often a new chiral center • If the starting materials are achiral, the nucleophile will approach the carbonyl from either side with equal probability • Results in a carbonyl addition product consisting of a racemic mixture ©2018 Cengage Learning. All Rights Reserved. Addition of Carbon Nucleophiles • Addition of carbon nucleophiles is one of the most important type of carbonyl addition reactions. New carbon-carbon bond is formed in the process (C-C) • We study nucleophilic acyl addition of aldehydes and ketones with the following types of carbon nucleophiles • Reactions follow the mechanistic two-step pattern of: • (1) Making a bond between the carbon nucleophile and the electrophilic carbonyl carbon atom to give the tetrahedral carbonyl addition compound • (2) Adding a proton to give an —OH group in the product ©2018 Cengage Learning. All Rights Reserved. Addition of Grignard Reagents • Given the difference in electronegativity between carbon and magnesium (2.5 − 1.2 = 1.3), the C—Mg bond of Grignard reagents is polar covalent • C bears a partial negative charge, and Mg bears a partial positive charge • Thus, Grignard reagents are good nucleophiles and add to the carbonyl group of an aldehyde or a ketone to form tetrahedral carbonyl addition compounds • Attraction between the partial negative charge on the C of the organometallic compound and the partial positive charge on the carbonyl C assists the reaction • Alkoxide ions formed are strong bases ©2018 Cengage Learning. All Rights Reserved. Example – Addition of Grignard Reagents • Treatment of a Grignard reagent with formaldehyde (H2CO) followed by protonation in aqueous acid gives a 1° alcohol ©2018 Cengage Learning. All Rights Reserved. Example – Addition of Grignard Reagents • Step 1: Make a new bond between a nucleophile and an electrophile (key step) Audiophile electrophile • Step 2: Add a proton ©2018 Cengage Learning. All Rights Reserved. Addition of Grignard Reagents • Treatment of a Grignard reagent with: • Any aldehyde other than formaldehyde followed by protonation in aqueous acid gives a 2° alcohol • A ketone followed by protonation in aqueous acid gives a 3 alcohol ©2018 Cengage Learning. All Rights Reserved. Example 16.4 - Reactions of Grignard Reagents • Racemic 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone • Show each combination ©2018 Cengage Learning. All Rights Reserved. Example 16.4 - 2-phenyl-2-butanol • In each solution, curved arrows show formation of the new carbon-carbon bond and the alkoxide ion • The new carbon-carbon bond formed by each set of reagents is labeled in the final product ©2018 Cengage Learning. All Rights Reserved. Addition of Organolithium Compounds • RLi compounds are generally more reactive than RMgX in nucleophilic acyl addition reactions and typically give higher yields • Must be prepared and used under an atmosphere of nitrogen or another inert gas • Following reaction illustrates the use of an RLi compound to form a sterically hindered 3° alcohol ©2018 Cengage Learning. All Rights Reserved. RLi Reagent Reacting with a Ketone • Step 1: Make a new bond between a nucleophile and an electrophile (key step) • Step 2: Add a proton ©2018 Cengage Learning. All Rights Reserved. Anions of Terminal Alkynes • Addition of the anion of a terminal alkyne to the carbonyl group of an aldehyde or a ketone gives an alkynyl alcohol (can be 1°, 2° or 3°) • Example - Addition of sodium acetylide to cyclohexanone followed by hydrolysis in aqueous acid gives 1ethynylcyclohexanol A Nadipolice electrophile ©2018 Cengage Learning. All Rights Reserved. Anions of Terminal Alkynes+Hydration (2 steps to make hydroxy-ketone or hydroxy-aldehyde) • Hydration of a terminal alkyne gives either an aldehyde or a ketone, depending on the alkyne and the method of hydration • Acid-catalyzed hydration of 1-ethynylcyclohexanol gives an α-hydroxyketone • Hydroboration followed by oxidation gives a terminally re β-hydroxyaldehyde ©2018 Cengage Learning. All Rights Reserved. Addition of HCN • HCN adds to the C=O group of an aldehyde or ketone to give a cyanohydrin CN • Cyanohydrin: Molecule containing an —OH group and a —CN group bonded to the same carbon • Cyanohydrin formation is carried out by dissolving th NaCN or KCN in water and adjusting the pH of the ar leg Er solution to approximately 10.0 • Concentration of cyanide ion in aqueous HCN is too low for cyanohydrin formation to proceed at a reasonable rate since HCN is a weak acid ©2018 Cengage Learning. All Rights Reserved. Formation of a Cyanohydrin • Step 1: Make a new bond between a nucleophile and an electrophile (key step) • Step 2: Add a proton ©2018 Cengage Learning. All Rights Reserved. Value of Cyanohydrins as Synthetic Intermediates • Cyanohydrins can be converted into new functional groups: • 2 or 3 hydroxyl group of the cyanohydrin may undergo acid-catalyzed dehydration to form an unsaturated nitrile • Nitrile is reduced to a 1° amine by H2 in the presence of Ni or another transition metal catalyst ©2018 Cengage Learning. All Rights Reserved. Example • The following reaction will occur as shown 1. 2. True False ©2018 Cengage Learning. All Rights Reserved. Example • What would be the expected outcome if one equivalent of a Grignard reagent were reacted with the molecule shown below? 1. 2. 3. 4. 5. Nucleophilic addition exclusively at carbonyl A Nucleophilic addition exclusively at carbonyl B Equal addition at both carbonyls Greater percentage of addition at carbonyl A Greater percentage of addition at carbonyl B ©2018 Cengage Learning. All Rights Reserved. Example • Which sequence will produce the following transformation? 1. 2. 3. 4. Both (1) and (2) are possible 5. Both (2) and (3) are possible ©2018 Cengage Learning. All Rights Reserved. Example (incl. nitrile hydrolysis, Ch.18) • Which sequence of reagents will accomplish the following transformation? 1. 2. 3. 4. ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction • Method for the synthesis of alkenes from aldehydes or ketones using compounds called phosphonium ylides • Ylides: Neutral molecules with positive and negative charges on adjacent atoms • Valuable as a synthetic tool for the following reasons: • Takes place under mild conditions • Location of the carbon-carbon bond is unambiguously determined ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction • Two stages • (1) Formation of phosphonium ylides • Involves treatment of a phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2 • Phosphonium salts are prepared by treatment of a phosphine with a methyl, 1°, or 2° alkyl halide by an SN2 pathway • (2) Reaction of a phosphonium ylide with the carbonyl group of an aldehyde or a ketone to give an alkene ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction – Mechanism • Step 1: Make a new bond between a nucleophile and an electrophile to give a dipolar intermediate called a betaine (key step 1) • Step 2: The betaine collapses to a four-membered oxaphosphetane ring ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction – Mechanism • Step 3: Break a bond to give stable molecules or ions (retro 2+2 cycloaddition). The driving force is the formation of strong P-O bond. (key step 2) ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction - Examples n y s nags ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction - Examples • Some Wittig reactions are Z selective, while others are E selective • Wittig reagents with an anion-stabilizing group, such as a carbonyl group, adjacent to the negative charge are E selective • Wittig reagents without an anion-stabilizing group are Z selective ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction: Horner-Emmons-Wadsworth Modification • Uses a phosphonoester derived from an α-haloester or a ketone to generate the Wittig carbanion • α-phosphonoesters or ketones used in this variation of the Wittig reaction are formed by two successive SN2 reactions ©2018 Cengage Learning. All Rights Reserved. The Wittig Reaction: Horner-Emmons-Wadsworth Modification • Treatment of a phosphonoester with a strong base followed by an aldehyde or a ketone gives an alkene • Advantages of phosphonate-stabilized carbanions as Wittig reagents • They are almost exclusively E selective • The by-product of the reaction, dimethylphosphate anion, is water-soluble and can be easily separated from the desired organic product ©2018 Cengage Learning. All Rights Reserved. Example 16.5 - Reactions of Wittig Reagents • Show how this alkene can be synthesized by a Wittig reaction ©2018 Cengage Learning. All Rights Reserved. Example 16.5 - Solution • Starting materials are either (1) cyclopentanone and the triphenylphosphonium ylide derived from bromoethane or (2) acetaldehyde and the triphenylphosphonium ylide derived from chlorocyclopentane • Either route is satisfactory Total of 3 steps Total of 3 steps ©2018 Cengage Learning. All Rights Reserved. Example • Which combination of reagents will yield the following compound? 1. 2. 3. 4. Both (1) and (2) 5. Both (2) and (3) ©2018 Cengage Learning. All Rights Reserved. Addition of H2O to C=O Group • Gives a geminal diol (gem-diol) • Also referred to as the hydrate of the corresponding aldehyde or ketone • Gem-diols are unstable and are rarely isolated • Readily reversible and the diol can eliminate water to regenerate the aldehyde or ketone • In most cases, equilibrium strongly favors the carbonyl group ©2018 Cengage Learning. All Rights Reserved. Addition of H2O to C=O Group • Exception: When formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated • Compare: An aqueous solution of acetone consists of less than 0.1% of the hydrate at equilibrium ©2018 Cengage Learning. All Rights Reserved. Addition of Alcohols • Nucleophilic acyl addition of one molecule of alcohol to the C=O group of an aldehyde or ketone forms a hemiacetal (two molecules give acetal) • As a functional group, hemiacetal: Molecule containing an —OH and an —OR (—OAr) group at the same carbon • —C bonded to an —OH group and an —OR group ©2018 Cengage Learning. All Rights Reserved. Hemiacetals • Similar to hydrates, minor components of an equilibrium mixture, except where a five- or six-membered ring can form • Example: ᴅ-glucose exists as a six-membered cyclic hemiacetal form as both α and β anomers ©2018 Cengage Learning. All Rights Reserved. Hemiacetals • At equilibrium, the β anomer of ᴅ-glucose predominates because the OH group on the anomeric carbon is in the equatorial position of the more stable chair conformation • In α-ᴅ-glucose, the -OH group on the anomeric carbon is axial ©2018 Cengage Learning. All Rights Reserved. Base-Catalyzed Synthesis of a Hemiacetal • Step 1: Take a proton away (Deprotonation) • Step 2: Make a new bond: nucleophile and electrophile (key step) • Step 3: Add a proton ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Synthesis of a Hemiacetal • Step 1: Add a proton (Protonation) • Step 2: Add a proton to obtain the conjugate acid of the aldehyde or ketone (C=O Activation) ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Synthesis of a Hemiacetal • Step 3: Make a new bond: nucleophile and electrophile (key step) • Step 4: Take a proton away ©2018 Cengage Learning. All Rights Reserved. Acetals • Hemiacetals react with alcohols to form acetals and one molecule of water • As functional groups, acetals: Molecules containing two OR (OAr) groups at the same C • More stable than hemiacetals and can be isolated in good yield under the proper conditions • Since the OH group cannot be displaced directly by nucleophiles, formation of acetals and its reverse is catalyzed by acids ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Synthesis of an Acetal • Step 1: Add a proton (Protonation) • Step 2: Break a bond to give stable molecules or ions (key step) ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Synthesis of an Acetal • Step 3: Make a new bond between a nucleophile and an electrophile (key step 2) • Step 4: Take a proton away ©2018 Cengage Learning. All Rights Reserved. Formation of Acetals • Could involve the use of alcohol as the solvent and dissolving either dry HCl (hydrogen chloride gas) or p-toluenesulfonic acid in the alcohol • Alcohol is present in large molar excess, which forces the equilibrium to the right and favors acetal formation • Is reversible: addition of excess water to an acetal causes hydrolysis to the ketone ©2018 Cengage Learning. All Rights Reserved. Figure 16.1 - A Dean-Stark Trap for Removing Water by Azeotropic Distillation with Benzene • Azeotrope: Liquid mixture of constant composition with a boiling point that is different from that of any of its components ©2018 Cengage Learning. All Rights Reserved. Example 16.6 - Formation of an Acetal • Show the reaction of the carbonyl group of each aldehyde or ketone with one molecule of alcohol to give a hemiacetal and then with a second molecule of alcohol to give an acetal • Solution ©2018 Cengage Learning. All Rights Reserved. Acetals as Carbonyl-Protecting Groups • For example, the synthesis of 5-hydroxy-5-phenylpentanal from benzaldehyde and 4-bromobutanal (Ch.15) • Reaction of benzaldehyde with the Grignard reagent from 4bromobutanal could form a new C—C bond, but the reagent reacts with the C=O group of another molecule of 4bromobutanal • Can be avoided by protecting the carbonyl group of the bromoaldehyde by conversion to an acetal ©2018 Cengage Learning. All Rights Reserved. Acetals as Carbonyl-Protecting Groups • The synthesis if performed in 3 steps: Step 1 Step 2 Step 3 • Cyclic acetals are often used because they are easy to prepare ©2018 Cengage Learning. All Rights Reserved. Tetrahydropyranyl (THP) Ethers: Protecting an Alcohol as an Acetal • Treating an alcohol with dihydropyran in the presence of an acid catalyst converts the alcohol into a THP ether • Commonly used acid catalysts: Anhydrous HCl or a sulfonic acid (RSO3H) • THP group is stable in neutral and basic solutions and to most oxidizing and reducing agents since it is an acetal • Removed by treatment with dilute aqueous acid to regenerate the original 1° or 2° alcohol ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following represents an acetal? 1. 2. 3. 4. 5. ©2018 Cengage Learning. All Rights Reserved. Example • Select the starting material used to make the following acetal 1. 2. 3. 4. 5. ©2018 Cengage Learning. All Rights Reserved. Addition of Nitrogen Nucleophiles • Ammonia and 1° amines (aliphatic or aromatic) react with the C=O group of aldehydes and ketones to give an imines (Schiff bases) • Imines are unstable unless the C=N group is part of an extended system of conjugation and are not isolated ©2018 Cengage Learning. All Rights Reserved. Synthesis of Imines from Aldehydes or Ketones • Step 1: Make a new bond: nucleophile and electrophile (key step 1) • Step 2: Take a proton away ©2018 Cengage Learning. All Rights Reserved. Synthesis of Imines from Aldehydes or Ketones • Step 3: Add a proton (H+ transfer) • Step 4: Add a proton (H+ transfer) ©2018 Cengage Learning. All Rights Reserved. Synthesis of Imines from Aldehydes or Ketones • Step 5: Break a bond to give stable molecules (key step 2) • Step 6: Take a proton away ©2018 Cengage Learning. All Rights Reserved. Nitrogen Nucleophiles – Example • Rhodopsin (biological pigment in retina) is the imine formed in the human retina in the reaction between 11cis-retinal (vitamin A aldehyde) and the protein opsin • Primary amino group of opsin for this reaction is provided by the side chain of the amino acid lysine ©2018 Cengage Learning. All Rights Reserved. Example 16.8 - Imine Chemistry • Write a structural formula for the imine formed in each reaction • Solution ©2018 Cengage Learning. All Rights Reserved. Addition of Nitrogen Nucleophiles • 2° amines react with the C=O groups of aldehydes and ketones to form enamines • Mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acidcatalyzed dehydration (more in Chapter 19) ©2018 Cengage Learning. All Rights Reserved. Hydrazine and Related Compounds • Aldehydes and ketones react with hydrazine to form compounds called hydrazones, as illustrated below by treating cyclopentanone with hydrazine ©2018 Cengage Learning. All Rights Reserved. Table 16.4 - Derivatives of Ammonia or Hydrazine Used for Forming Imines and Derivatives (Important!) ©2018 Cengage Learning. All Rights Reserved. Pyridoxine (Vitamin B6) • Reversible formation of imines from amino groups and carbonyls is the key mechanistic step in biochemical transamination reactions ©2018 Cengage Learning. All Rights Reserved. Pyridoxine (Vitamin B6) • Transaminations are catalyzed by a specific group of enzymes called transaminases that require pyridoxal phosphate (PLP), a coenzyme derived from pyridoxine • Serum levels of transaminase in blood help clinicians determine the extent of heart or liver damage ©2018 Cengage Learning. All Rights Reserved. Pyridoxine (Vitamin B6) – Mechanism ©2018 Cengage Learning. All Rights Reserved. Example • What is the correct functional group assignment for each of the following nitrogen-containing compounds? 1. 2. 3. 4. 5. A - imine, B - amine, C - enamine, D - oxime A - oxime, B - amine, C - enamine, D - imine A - oxime, B - amine, C - imine, D - enamine A - oxime, B - enamine, C - oxime, D - amine A - oxime, B - imine, C - amine, D - enamine ©2018 Cengage Learning. All Rights Reserved. r Acidity of α-Hydrogens of Ketones • α-Hydrogens: Hydrogen on a carbon adjacent to a carbonyl group (more in Ch.19) • Hydrogens alpha to a carbonyl group are more acidic than acetylenic, vinylic, and alkane hydrogens but less acidic than —OH hydrogens of alcohols HOF ©2018 Cengage Learning. All Rights Reserved. Acidity of α-Hydrogens of Ketones • α-Hydrogens are more acidic because the enolate anion is stabilized by: • (1) Delocalization of its negative charge by resonance • (2) The electron-withdrawing inductive effect of the electronegative oxygen ©2018 Cengage Learning. All Rights Reserved. Example 16.9 - Enolate-Forming Reactions • Predict the position of the following equilibrium PRen ©2018 Cengage Learning. All Rights Reserved. around20 Example 16.9 - Solution • pKa of ethanol is approximately 16 • pKa of acetophenone is approx. equal to that of acetone (i.e., about 20) • Ethanol is the stronger acid; therefore, the equilibrium lies to the left ©2018 Cengage Learning. All Rights Reserved. Base-Catalyzed Equilibration of Keto and Enol Tautomers • Protonation of the enolate anion on the α-carbon gives the keto form, and protonation at oxygen gives an enol form • Step 1: Take a proton away (Deprotonation) (key step) • Step 2: Add a proton ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Equilibration of Keto and Enol Tautomers • Step 1: Add a proton (Protonation) • Step 2: Take a proton away (key step) ©2018 Cengage Learning. All Rights Reserved. Position of Equilibrium in Keto-Enol Tautomers • Aldehydes and ketones with at least one α-hydrogen are in equilibrium with their enol forms • Position of keto-enol equilibrium for simple aldehydes and ketones lies far on the side of the keto form ©2018 Cengage Learning. All Rights Reserved. Equilibrium in Keto-Enol Tautomers • For certain types of molecules, the enol is the major form or the only form present at equilibrium • For β-diketones, the enol is stabilized by conjugation of the systems of the carbon-carbon double bond and the carbonyl group. (Conjugation: interaction of the electrons of adjacent π bonds interact with each other) • For acyclic β-diketones, the enol is further stabilized by intramolecular hydrogen bonding ©2018 Cengage Learning. All Rights Reserved. Example 16.10 - Keto-Enol Equilibrium • Write two enol forms for each compound • Which enol of each has the larger concentration at equilibrium? • Solution. Note that in each case, the major enol form has the more substituted (and more stable) double bond Minor enol Minor enol ©2018 Cengage Learning. All Rights Reserved. Note themoststable onethathave doublebondmoresubsitat Oxidation of Aldehydes • Aldehydes are oxidized to carboxylic acids by: • Chromic acid (H2CrO4) • Ag(I) (for example, Ag2O) • In one method, a solution of the aldehyde in aqueous ethanol or THF is shaken with a slurry of Ag2O ©2018 Cengage Learning. All Rights Reserved. Oxidation of Aldehydes • Tollens’ reagent: another form of Ag(I), is prepared by dissolving Ag2O in aqueous ammonia • When added to an aldehyde, the aldehyde is oxidized to a carboxylic anion and Ag(I) is reduced to metallic silver • molecular oxygen (O2) • hydrogen peroxide (H2O2) • Reaction with oxygen is a radical chain reaction • Liquid aldehydes are so sensitive to air that they must be stored under N2 ©2018 Cengage Learning. All Rights Reserved. Oxidation of Aldehydes: Pinnick Oxidation • Inexpensive method to oxidize an aldehyde to a carboxylic acid • Uses sodium chlorite (NaClO2) with a phosphate buffer (NaH2PO4) • Selective procedure and will not oxidize alcohols (!) • Mechanism • Step 1: Creation of chlorous acid • Step 2: Add a proton ©2018 Cengage Learning. All Rights Reserved. Oxidation of Aldehydes: Pinnick Oxidation • Step 3: Make a bond between a nucleophile and an electrophile • Step 4: Take proton away and simultaneously break bonds (key step) • Step 5: Scavenge the hypochlorous acid ©2018 Cengage Learning. All Rights Reserved. Example 16.11 - Using Oxidation Reactions • Draw a structural formula for the product formed by treating each compound with NaClO2 and NaH2PO4, along with 2methyl-2-butane a. Pentanal b. Cyclopentanecarbaldehyde • Solution (aldehyde to carboxylic acid oxidation) ©2018 Cengage Learning. All Rights Reserved. Oxidation of Ketones • Ketones are NOT normally oxidized by chromic acid or potassium permanganate (H2CrO4, KMnO4) • Ketones undergo oxidative cleavage, via their enol form, when treated with strong oxidants at higher temperatures and higher concentrations of acid or base ©2018 Cengage Learning. All Rights Reserved. Reduction • Aldehydes can be reduced to 1° alcohols • Ketones can be reduced to 2° alcohols • The C=O group of an aldehyde or a ketone can be reduced to a —CH2— group (methylene) ©2018 Cengage Learning. All Rights Reserved. Metal Hydride Reductions • The most common laboratory reagents for the reduction of aldehydes and ketones are NaBH4 (sodium borohydride), LiAlH4 (LAH, lithium aluminum hydride) and their derivatives • Behave as sources of hydride ion, a powerful nucleophile ©2018 Cengage Learning. All Rights Reserved. NaBH4 Reduction of Aldehydes or Ketones • Reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or ethanol • One mole of NaBH4 reduces four moles of aldehyde or ketone ©2018 Cengage Learning. All Rights Reserved. NaBH4 Reduction of Aldehydes or Ketones • Step 1: Make a new bond between a nucleophile and an electrophile to give a tetrahedral carbonyl addition compound (key step) • Step 2: Add a proton ©2018 Cengage Learning. All Rights Reserved. LiAlH4 Reduction of Aldehydes or Ketones • More powerful than NaBH4 • LiAlH4 reacts violently with water, alcohols, and other protic solvents: reductions are carried out in diethyl ether (Et2O) or tetrahydrofuran (THF) • One mole of LiAlH4 is used per four moles of aldehyde or ketone (mechanism as for NaBH4) ©2018 Cengage Learning. All Rights Reserved. Catalytic Reduction of Aldehydes/Ketones • H2 in the presence of a metal catalyst (Pt, Ni) • Carried out at temperatures from 25° to 100°C and at pressures of hydrogen from 1 to 5 atm. Yields are high, and isolation of the final product is easy • Disadvantage: Carbon-carbon double or triple bonds may also be reduced under these conditions ©2018 Cengage Learning. All Rights Reserved. Selective Reduction of C=C Bond in α,βUnsaturated Aldehydes or Ketones • Performed using rhodium on powdered charcoal as a catalyst (Rh/C) • Rh/C: Selective reduction of a carbon-carbon double bond • LiAlH4: Selective reduction of a carbonyl group ©2018 Cengage Learning. All Rights Reserved. Example 16.12 - Aldehyde and Ketone Reduction • Complete these reductions • Solution. Aldehyde to 1° alcohol reduction and ketone to 2° alcohol reduction. ©2018 Cengage Learning. All Rights Reserved. Reductive Amination (!) • Method of preparing substituted amines by treating an aldehyde or a ketone with an amine in the presence of or followed by a reducing agent • Used to reduce carbon-nitrogen double bond to a carbon-nitrogen single bond (1) in the presence of a Ni or another transitionmetal-catalyst or (2) NaBH3CN (sodium cyanoborohydride) ©2018 Cengage Learning. All Rights Reserved. Reductive Amination • Can be carried out in two steps (sequential addition of reagents) or in a single step: using a reducing agent that is not powerful enough to reduce the starting aldehyde or ketone, but is strong enough to reduce the more easily reduced imine that is formed • Sodium cyanoborohydride, NaBH3CN, is the reducing agent used for the single-step procedure ©2018 Cengage Learning. All Rights Reserved. Clemmensen Reduction • Reduction of the C=O group of an aldehyde or a ketone to a CH2 group using Zn(Hg) and HCl • Cannot be used to reduce: • A carbonyl group in a molecule that also contains acid-sensitive groups that might undergo dehydration • An acetal that is hydrolyzed so that its resulting carbonyl group is also reduced ©2018 Cengage Learning. All Rights Reserved. Wolff-Kishner Reduction • Reduction of the C=O group of an aldehyde or a ketone to a CH2 group using hydrazine and base (e.g., H2NNH2/KOH/glycol) • Mixture of the aldehyde or ketone, hydrazine, and concentrated potassium hydroxide is heated at reflux in a high-boiling solvent such as diethylene glycol • The same reaction can be brought about using hydrazine and potassium tert-butoxide in DMSO (H2NNH2/t-BuOK/DMSO) ©2018 Cengage Learning. All Rights Reserved. Wolff-Kishner Reduction • Step 1: Reaction of the carbonyl group with hydrazine gives a hydrazone (condensation) (key step 1) • Step 2: Take a proton away (deprotonation) (key step 2) ©2018 Cengage Learning. All Rights Reserved. Wolff-Kishner Reduction • Step 3: Add a proton (protonation) • Step 4: Take a proton away (deprotonation) ©2018 Cengage Learning. All Rights Reserved. Wolff-Kishner Reduction • Step 5: Break a bond to give stable molecules or ions (collapse) • Step 6: Add a proton (protonation) ©2018 Cengage Learning. All Rights Reserved. Example 16.13 - Reduction Reactions • Complete the following reactions • Solution. Clemmensen and Wolff-Kishner reductions. ©2018 Cengage Learning. All Rights Reserved. Reactions at an α-Carbon – Racemization • Occurs when at least one α-hydrogen exists through the formation of an achiral enol (more in Ch.19) End • May be catalyzed by either acid or base • Rate of racemization is proportional to the concentration of acid or base ©2018 Cengage Learning. All Rights Reserved. opposite Reactions at an α-Carbon – Deuterium Exchange • Involves exchange of α-hydrogens to deuterium at a rate that is proportional to the concentration of the acid or base catalyst • Exchange occurs when an aldehyde or a ketone with one or more α-hydrogens is dissolved in an aqueous solution that is enriched with D2O and contains catalytic amounts of either D+ or OD− • May be catalyzed by either acid or base ©2018 Cengage Learning. All Rights Reserved. Reactions at an α-Carbon – Deuterium Exchange • Significance of deuterium exchange • (1) Number of exchangeable α-hydrogens in a molecule can be determined by observing changes in hydrogen ratios • (2) Exchange of α-hydrogens is a convenient way to introduce an isotopic label into molecules (medicine, drug discovery) • Presence of deuterium is indicated by the symbol “d” • Number of atoms is shown by a subscript following the symbol (CDCl3-d1, CD3CO2D-d4) ©2018 Cengage Learning. All Rights Reserved. Reactions at an α-Carbon – α-Halogenation • Aldehydes and ketones with at least one α-hydrogen react at an α-carbon with Br2 or Cl2 to form αhaloaldehydes and α-haloketones M • Reaction is catalyzed by both acid and base ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed α-Halogenation of a Ketone • Step 1: Keto-enol tautomerism • Step 2: Make a new bond: π bond and electrophile (key step) • Step 3: Take a proton away ©2018 Cengage Learning. All Rights Reserved. Base-Promoted α-Halogenation of a Ketone • Step 1: Take a proton away (deprotonation) • Step 2: Make a new bond: nucleophile (π bond) and electrophile (key step) ©2018 Cengage Learning. All Rights Reserved. Acid- and Base-Catalyzed α-Halogenation • Acid-catalyzed α-halogenation • Introduction of a second halogen is slower than the first • Electronegative α-halogen decreases the basicity of the carbonyl oxygen toward protonation (H+ coordination) • Can be stopped at a single substitution • Base-promoted α-halogenation • Each successive halogenation is more rapid than the previous one • Introduction of the electronegative halogen on the αcarbon increases the acidity of the remaining α-hydrogens • Generally not a useful synthetic reaction (cannot be stopped) ©2018 Cengage Learning. All Rights Reserved. Example – Nucleophilic Addition • Rank the following carbonyl compounds from most to least reactive when treated with a nucleophile Aldehyde 1. A > C > B > A 2. C > B > A > D 3. A > B > C > D 4. A > C > B > D 5. C > B > D > A The following is also correct depending on conditions: C>A>B>D Note Aldehyde is the reactive ©2018 Cengage Learning. All Rights Reserved. most compound thanketone Example – Reductions/Oxidations • Which of the following will not produce an aldehyde or a ketone? 1. Ch 18 2. 3. 4. hydration ozonation ©2018 Cengage Learning. All Rights Reserved. Problem 16.27 – Ylides (Wittig reaction) • Sulfur ylides react with ketones to give epoxides • Suggest a mechanism for this reaction (ylides = Wittig) ©2018 Cengage Learning. All Rights Reserved. Problem 16.27 – Ylides (Wittig reaction) • Step 1: Make a bond between a nucleophile and an electrophile (key step) • Step 2: Make a new bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions ©2018 Cengage Learning. All Rights Reserved.