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

2024
Views:

268

Pages:

110
Author:

Mahitab S.

CHAPTER 18 FUNCTIONAL DERIVATIVES OF CARBOXYLIC ACIDS ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • • • • • • • (18.1) (18.2) (18.3) (18.4) (18.5) (18.6) (18.7) • (18.8) • (18.9) • (18.10) Structure and nomenclature Acidity of amides, imides, and sulfonamides Characteristic reactions Reaction with water: Hydrolysis Reaction with alcohols Reactions with ammonia and amines Reaction of acid chlorides with salts of carboxylic acids Interconversion of functional derivatives Reactions with organometallic compounds Reduction ©2018 Cengage Learning. All Rights Reserved. Carboxyl Derivatives • In this chapter, five classes of organic compounds related to carboxylic acids are discussed • Under the general formula of each functional group is an illustration to show how the group is formally related to a carboxylic acid ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Acid Halides • Functional group: An acyl group bonded to a halogen • Acyl group: RCO— group • Named by changing the suffix -ic acid in the name of the parent carboxylic acid to -yl halide 6 5 Acylgroup 43 2 I Hexandioylcholoride Ethanoylcholoride chloride Benzoyl • Most common acid halides are acid chlorides (Cl, Br, F) ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Acid Halides • Replacement of —OH of a sulfonic acid by —Cl gives a sulfonyl chloride • Example - Structural formulas for sulfonic acids and the acid chloride derived from each are shown below i sulfonic Methane group Methanesulfonyl chloride P toupenesulfonic group ©2018 Cengage Learning. All Rights Reserved. p Toulenesulfong choloride Structure and Nomenclature - Acid Anhydrides • Carboxylic anhydrides • Functional group - Two acyl groups bonded to an oxygen atom • Derived from two carboxylic acids by loss of water • May be symmetrical (two identical acyl groups) or mixed (two different acyl groups) • Named by replacing the word acid in the name of the parent carboxylic acid with the word anhydride ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived • Phosphoric anhydrides • Functional group - Two phosphoryl groups bonded to an oxygen atom ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Esters • Carboxylic esters • Functional group: An acyl group bonded to —OR or —OAr • IUPAC and common names are derived from the names of the parent carboxylic acids • Alkyl or aryl group bonded to oxygen is named first, and the suffix -ic acid in the name of the acid is replaced with the suffix -ate 123 ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Esters • Lactones: Cyclic esters • Simple lactones are named by replacing the suffix -ic acid or -oic acid from the name of the parent carboxylic acid with the suffix -olactone • Location of the oxygen atom is indicated by a number if the IUPAC name of the acid is used or by the Greek letter α, β, γ, δ, ε, and so forth, if the common name is used 4 2 3 I 4butanolactone 3 butanolactone ©2018 Cengage Learning. All Rights Reserved. f Hexanolactone Structure and Nomenclature - Esters • Esters of phosphoric acid • Phosphoric acid forms mono-, di-, and triesters and has three —OH groups • Named by giving the name(s) of the alkyl or aryl group(s) bonded to oxygen followed by the word phosphate • In more complex phosphoric esters, the organic molecule is named first and then the presence of the phosphoric ester is indicated by the word phosphate or the prefix phospho- ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Amides and Imides • Amides • Functional group: An acyl group bonded to a nitrogen atom • Named by dropping the suffix -oic acid from the IUPAC name of the parent acid (or -ic acid from its common name) and adding -amide • If the amide nitrogen is bonded to an alkyl or an aryl group, the group is named, and its location on nitrogen is indicated by N- ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Amides and Imides • Lactams: Cyclic amides • Names are derived in the same manner as those of lactones • The suffix -lactone is replaced by -lactam • Imides • Functional group: Two acyl groups bonded to nitrogen • Both succinimide and phthalimide are cyclic imides ©2018 Cengage Learning. All Rights Reserved. β-Lactam Antibiotics • Penicillins and cephalosporins are families of β-lactam antibiotics ©2018 Cengage Learning. All Rights Reserved. Structure and Nomenclature - Nitriles • Functional group: cyano (C≡N) group bonded to a carbon atom • IUPAC names follow the pattern alkanenitrile • Common names • Derived by replacing the suffic -ic or -oic acid from the name of the parent carboxylic acid with -onitrile ©2018 Cengage Learning. All Rights Reserved. Example 18.1 - Naming Carboxylic Acid Derivatives • Write the IUPAC name for each compound 4 3 2 I Methy 3methylbatonate 65 y 3 3 2 4 oxobutonate 3 y Hexandiamids ©2018 Cengage Learning. All Rights Reserved. 3 Example 18.1 - Solution • The IUPAC name is provided first, followed by the common name in parentheses a. Methyl 3-methylbutanoate (methyl isovalerate, from isovaleric acid) b. Ethyl 3-oxobutanoate (ethyl β-ketobutyrate, from β-ketobutyric acid) c. Hexanediamide (adipamide, from adipic acid) d. Phenylethanoic anhydride (phenylacetic anhydride, from phenylacetic acid) ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following is not an ester? 1. 2. 3. 4. ©2018 Cengage Learning. All Rights Reserved. Ester RN oxygenconnectdirectly a to Example • All lactams can be classified as amides and vice versa 1. True 2. False ©2018 Cengage Learning. All Rights Reserved. Example • Determine the IUPAC name for the following molecule I 2 3 4 s 6 7 heptane 1. 2. 3. 4. 5. Ethyl-N-2-butylmethylamide N-(2-Methylbutyl)propanamide N-Methylbutylpropane amide N-(2-Methylbutyl)propane amide N-(2-Methylbutylethyl) amide ©2018 Cengage Learning. All Rights Reserved. Example • Determine the IUPAC name for the following molecule 5 y 3 2 1 pentane 1. 2. x 3. x x4. 5. 3,4-Dimethylphenyl pentanoate 3,4-Dimethylpentyl benzenoate 3,4-Dimethylpentyl benzoate Benzyl 3,4-dimethylpentanoate Phenyl 3,4-dimethylpentanoate ©2018 Cengage Learning. All Rights Reserved. Example • What is the IUPAC name of this compound? 32 1. 2. 3. 4. 5. I 3 ethyl 3-Ethyl-3-phenylpropanoyl bromide 3-Phenyl-3-ethylpropanoyl bromide 1-Ethyl-1-phenylpropanoyl bromide 1-Phenyl-1-ethylpropanoyl bromide 3-Phenylpentanoyl bromide ©2018 Cengage Learning. All Rights Reserved. Example • Select the correct IUPAC name for the following molecule 2 1. 2. 3. 4. 5. 0 39 s 7 1 Pentylpropylnitrile octane 4-Cyanooctane 5-Cyanooctane 2-Propylhexanenitrile 2-Butylpentanenitrile ©2018 Cengage Learning. All Rights Reserved. Acidity of Amides • Amides are comparable in acidity to alcohols • Values of pKa for amides are in the range of 15–17 • Water-insoluble amides do not react with aqueous solutions of NaOH or other alkali metal hydroxides to form watersoluble salts ©2018 Cengage Learning. All Rights Reserved. Acidity of Imides • Imides (pKa 8–10) are more acidic than amides • Readily dissolve in 5% aqueous NaOH by forming watersoluble salts • Stabilization of imide anion by delocalization of its negative charge accounts for its acidity • More important contributing structures for the anion formed by ionization of an imide delocalize the negative charge on nitrogen and the two carbonyl oxygens ©2018 Cengage Learning. All Rights Reserved. Acidity of Imides • Saccharin, an artificial sweetener, is an imide • Ammonium salt is used to make liquid saccharin • Saccharin in solid form is the Ca2+ salt ©2018 Cengage Learning. All Rights Reserved. Acidity of Sulfonamides • Sulfonamides derived from ammonia and primary amines are sufficiently acidic to dissolve in aqueous solutions of NaOH or other alkali metal hydroxides by forming water-soluble salts (pKa around 10) • Acidity is accounted for by the resonance stabilization of the resulting anion ©2018 Cengage Learning. All Rights Reserved. Example 18.2 - Properties of Phthalimide • Phthalimide is insoluble in water • Will phthalimide dissolve in aqueous NaOH? • Solution • Phthalimide is the stronger acid, and NaOH is the stronger base • Position of equilibrium lies to the right • Phthalimide dissolves in aqueous NaOH by forming a water-soluble sodium salt • pKeq = −7.4 • Keq = 2.5×107 ©2018 Cengage Learning. All Rights Reserved. Characteristic Reactions - Nucleophilic Acyl Addition under Basic Conditions • Negatively charged nucleophile adds directly to the carbonyl carbon to form a tetrahedral carbonyl addition intermediate, which adds a proton from a proton donor, HA ©2018 Cengage Learning. All Rights Reserved. Characteristic Reactions - Nucleophilic Acyl Addition under Acidic Conditions • Protonation (add a proton) of the carbonyl oxygen precedes the attack of the nucleophile ©2018 Cengage Learning. All Rights Reserved. Characteristic Reactions - Nucleophilic Acyl Addition (Basic vs. Acidic Conditions) • An addition-elimination sequence resulting in substitution of the nucleophile bonded to the carbon of an acyl group for another ©2018 Cengage Learning. All Rights Reserved. Characteristic Reactions - Relative Reactivity • Carboxylic acid derivatives discussed in this chapter have relative reactivity toward nucleophilic acyl substitution i t Ii • Trend is led by the following effects: • (1) Relative leaving group ability • Weakest base in the series is the best leaving group • (2) Relative resonance stabilization of the carboxylic acid derivatives ©2018 Cengage Learning. All Rights Reserved. Characteristic Reactions - Relative Reactivity • Combined effects of (1) leaving group ability and (2) susceptibility to nucleophilic attack (resonance stabilization) reinforce each other • Result in the following order of reactivity: ©2018 Cengage Learning. All Rights Reserved. Characteristic Reactions - Catalysis • Reactivity of acid halides and acid anhydrides is high • Common nucleophiles used to interconvert carboxylic acid derivatives will react directly with them without catalysis • Acid or base catalysis is required for esters and amides as they are more stable • Acid catalysis is used to: • Increase electrophilicity of the carboxylic acid derivatives • Facilitate leaving group departure • Base catalysis is used to increase nucleophilicity by converting a neutral nucleophile to an anionic nucleophile • Under basic conditions, the tetrahedral addition intermediates are more apt to expel a negatively charged leaving group ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Acid Chlorides • Low-molecular-weight acid chlorides react rapidly with water to form carboxylic acids and HCl • Higher molecular-weight acid chlorides react less rapidly than low-molecular weight acid chlorides, but much more rapidly than esters or amides • Does not require acid or base catalysis ©2018 Cengage Learning. All Rights Reserved. Steps in the Hydrolysis of Acid Chlorides • Step 1: Make a new bond between a nucleophile and an electrophile (nucleophilic addition): Water attacks the carbonyl carbon directly to give a tetrahedral carbonyl addition intermediate (key step) • Step 2: Take a proton away (deprotonation): Proton transfer is rapid and reversible ©2018 Cengage Learning. All Rights Reserved. Steps in the Hydrolysis of Acid Chlorides • Step 3: Break a bond to give stable molecules or ions (collapse of the tetrahedral intermediate): Expulsion of the chloride anion gives the carboxylic acid product ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Acid Anhydrides • Low-molecular-weight anhydrides react readily with water to give two molecules of carboxylic acid • Higher-molecular-weight anhydrides also react with water, but less readily than low-MW anhydrides (much faster than esters or amides) • Hydrolysis occurs without an added acid or base catalyst as with hydrolysis of acid chlorides ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Esters • Occurs very slowly at neutral pH, even when heated to reflux • More rapid when esters are heated to reflux in aqueous acid or base (requires acid or base catalysis) ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Ester Hydrolysis • Step 1: Add a proton: protonation increases the electrophilicity of the ester carbonyl carbon • Step 2: Make a new bond between a nucleophile and an electrophile: Water adds to the carbonyl carbon atom (key step 1) ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Ester Hydrolysis • Step 3: Take a proton away: Deprotonation gives a tetrahedral addition intermediate (proton transfer) • Step 4: Add a proton: Placing a proton on —OR′ converts it to —OHR′, a better leaving group (proton transfer) ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Ester Hydrolysis • Step 5: Break a bond to give stable molecules or ions: R′OH departs (collapse of tetrahedral intermediate) (key step 2) • Step 6: Take a proton away: Final deprotonation gives the ester product and regenerates the acid catalyst (proton transfer) ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Esters - Microscopic Reversibility • Principle of microscopic reversibility - For any reversible reaction, the sequence of intermediates and transition states must be the same but in reverse order for the backward versus forward reaction (Section 10.6) • Fischer esterification and the hydrolysis of an ester in acidic water are the reverse of each other • Reverse of protonation (add a proton) is deprotonation (take a proton away) • Reverse of nucleophilic attack (make a bond between a nucleophile and an electrophile) is leaving group departure (break a bond to give stable molecules or ions = collapse) ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Esters - Microscopic Reversibility Fischer esterification mechanism (Ch.17) ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Esters - Saponification • Saponification = Hydrolysis of an ester in aqueous base • Each mole of ester hydrolyzed requires one mole of base (1:1 molar ratio) • For this reason, ester hydrolysis in aqueous base is said to be base-promoted (vs. catalyzed) ©2018 Cengage Learning. All Rights Reserved. Steps in Saponification • Step 1: Make a new bond between a nucleophile and an electrophile (nucleophilic attack): Addition of OH− ion to the carbonyl group gives a tetrahedral carbonyl addition intermediate (key step 1) ©2018 Cengage Learning. All Rights Reserved. Steps in Saponification • Step 2: Break a bond to give stable molecules or ions: Collapse of the intermediate gives a carboxylic acid and an alkoxide ion (key step 2) • Step 3: Take a proton away: Proton transfer between the carboxyl group and the alkoxide ion gives the carboxylate anion, which drives the reaction to completion ©2018 Cengage Learning. All Rights Reserved. Example 18.3 - Ester Hydrolysis • Complete and balance equations for the hydrolysis of each ester in aqueous sodium hydroxide • Show all products as they are ionized under these conditions ph on at y 2 of pro ©2018 Cengage Learning. All Rights Reserved. Example 18.3 - Ester Hydrolysis • The products of hydrolysis of (a) are benzoic acid and 2-propanol • In aqueous NaOH, benzoic acid is converted to its sodium salt. Therefore, one mole of NaOH is required for hydrolysis of one mole of this ester • Compound (b) is a diester of ethylene glycol • Two moles of NaOH are required for its hydrolysis ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Acid • Gives a carboxylic acid and an ammonium ion • Driven to completion by the acid-base reaction between the amine or ammonia and acid to form an ammonium salt • Requires one mole of acid per mole of amide ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Acid • Step 1: Add a proton: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate and increases the electrophilic character of the carbonyl carbon • Step 2: Make a new bond between a nucleophile and an electrophile: Addition of water to the carbonyl carbon (key step 1) ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Acid • Step 3: Take a proton away/add a proton: Proton transfer between O and N atoms gives a tetrahedral carbonyl addition intermediate • Step 4: Break a bond to make stable molecules or ions: The leaving group is a neutral amine (a weaker base), a far better leaving group than an amide ion (a much stronger base) (key step 2) ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Acid • Step 5: Take a proton away: Proton transfer between the acidic protonated carbonyl and relatively basic amine gives the carboxylic acid and ammonium ion products ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Base • Products are a carboxylate salt and ammonia or an amine • Driven to completion by the acid-base reaction between the resulting carboxylic acid and base to form a salt • Requires one mole of base per mole of amide O amide ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Base • Step 1: Make a new bond between a nucleophile and an electrophile: Addition of hydroxide ion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate (key step 1) • Step 2: Take proton away: This step creates a dianionic tetrahedral intermediate, which has enough negative charge to expel the amide anion ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Amides in Aqueous Base • Step 3: Break a bond to give stable molecules or ions/add a proton (collapse): The amide anion has little to no lifetime in water because it is basic and will be instantly protonated by water upon its formation (key step 2) ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Nitriles • The cyano group of a nitrile is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion • Mechanism: Protonation of the nitrogen atom gives a cation that reacts with water to give an imidic acid (the enol of an amide) • Keto-enol tautomerism of the imidic acid gives an amide • Amide is then hydrolyzed to a carboxylic acid and an ammonium ion ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Nitriles • Hydrolysis of a cyano group in aqueous base gives a carboxylate anion and ammonia • Reaction is driven to completion by the acid-base reaction between the carboxylic acid and base to form a carboxylate anion • Acidification converts the carboxylate anion to the carboxylic acid ©2018 Cengage Learning. All Rights Reserved. Hydrolysis of Nitriles • Valuable way to synthesize carboxylic acids from 1° or 2° haloalkanes: One carbon extension in the form of a cyano group to the carbon chain and convert this to a carboxyl group • Hydrolysis of cyanohydrins (Section 16.5D) provides a valuable way to create α-hydroxycarboxylic acids (from aldehydes) ©2018 Cengage Learning. All Rights Reserved. Example 18.5 - Nitrile Hydrolysis • Show how to bring about the following conversions using as one step the hydrolysis of a cyano group ©2018 Cengage Learning. All Rights Reserved. Example 18.5 - Solution (a) • (1) Treatment of 4-chloroheptane with KCN in aqueous ethanol gives a nitrile • (2) Hydrolysis of the cyano group in aqueous sulfuric acid gives the product • Another method: This synthesis can also be accomplished by conversion of the chloroalkane to a Grignard reagent followed by carbonation and hydrolysis in aqueous acid ©2018 Cengage Learning. All Rights Reserved. Example 18.5 - Solution (b) • (1) Treatment of cyclohexanone with HCN/KCN in aqueous ethanol gives a cyanohydrin • (2) Hydrolysis of the cyano group in concentrated sulfuric acid gives the carboxyl group of the product ©2018 Cengage Learning. All Rights Reserved. Example • Which of the statements is true concerning the following two carboxylic acid derivatives? 1. 2. 3. 4. 5. Only molecule A can be hydrolyzed Only molecule B can be hydrolyzed Both molecules can be hydrolyzed, but A will react faster than B Both molecules can be hydrolyzed, but B will react faster than A A and B can be hydrolyzed at roughly the same rate ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following steps occurs first in the mechanism of Fischer esterification? 1. 2. 3. 4. 5. Attack of the nucleophile on the carbonyl carbon Protonation of the carbonyl oxygen Loss of water from the tetrahedral carbonyl addition intermediate Protonation of the alcohol oxygen Formation of the tetrahedral carbonyl addition intermediate ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following is the tetrahedral intermediate that appears in the Fischer esterification of ethanol and benzoic acid? 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Reaction of Acid Halides with Alcohols • Gives esters • No catalyst is necessary as acid halides are extremely reactive • When the alcohol or resulting ester is sensitive to acid, reaction is carried out in the presence of a 3° amine to neutralize the HCl as it is formed • Amines, pyridine and triethylamine, are converted to their hydrochloride salts ©2018 Cengage Learning. All Rights Reserved. Reaction of Acid Halides with Alcohols • Sulfonic acid esters are prepared by the reaction of an alkane- or arene-sulfonyl chloride with an alcohol or phenol • Common sulfonyl chlorides: p-toluenesulfonyl chloride (TsCl) and methanesulfonyl chloride (MsCl) • —OH is converted from a poor leaving group (hydroxide ion) in nucleophilic displacement to an excellent leaving group, the p-toluenesulfonate (tosylate) or methanesulfonate (mesylate) anions ©2018 Cengage Learning. All Rights Reserved. Reaction of Acid Anhydrides with Alcohols • Gives one mole of ester and one mole of a carboxylic acid (1:1) • Catalyzed by acids and by tertiary amines ©2018 Cengage Learning. All Rights Reserved. Reaction of Acid Anhydrides with Alcohols • Aspirin is synthesized by treating salicylic acid with acetic anhydride ©2018 Cengage Learning. All Rights Reserved. Reaction of Esters and Amides with Alcohols • Transesterification: Reaction of esters with alcohols in the presence of an acid catalyst at equilibrium • Can be driven in either direction by control of experimental conditions • Amides, the least reactive of the functional derivatives of carboxylic acids, do not react with alcohols ©2018 Cengage Learning. All Rights Reserved. Example 18.6 - Transesterification Reactions • Complete the following transesterification reactions (the stoichiometry of each is given in the problem) • Solution ©2018 Cengage Learning. All Rights Reserved. Acid Halides - Reaction with Ammonia/Amines • Acid halides react with ammonia and 1° and 2° amines to form amides • Two moles of ammonia or amine are required per mole of acid halide: One mole is used to form the amide, and one mole is used to neutralize the hydrogen halide formed ©2018 Cengage Learning. All Rights Reserved. Acid Halides - Reaction with Ammonia/Amines • Step 1: Ammonia adds to the carbonyl carbon (key step 1) • Step 2: Proton transfer gives a tetrahedral carbonyl addition ©2018 Cengage Learning. All Rights Reserved. Acid Halides - Reaction with Ammonia/Amines • Step 3: Tetrahedral carbonyl addition intermediate expels chloride as a leaving group (collapse) (key step 2) ©2018 Cengage Learning. All Rights Reserved. Acid Anhydrides - Reaction with Ammonia/Amines • Acid anhydrides react with ammonia and 1° and 2° amines to form amides • Two moles of ammonia or amine are required: One mole is used to form the amide, and one mole is used to neutralize the carboxylic acid by product ©2018 Cengage Learning. All Rights Reserved. Esters and Amides - Reaction with Ammonia/Amines • Esters react with ammonia and with 1° and 2° amines to form amides • Esters are less reactive toward ammonia, 1° amines, and 2° amines than acid halides or acid anhydrides • Reaction requires heating or high concentrations of amine or both • Amides do NOT react easily with ammonia or with 1° or 2° amines ©2018 Cengage Learning. All Rights Reserved. Example 18.7 - Amide Formation • Complete the following reactions (the stoichiometry of each reaction is given in the equation) • Solution ©2018 Cengage Learning. All Rights Reserved. Acid Chlorides - Reaction with Carboxylic Acid Salts • Gives anhydrides • Sodium or potassium salts of carboxylic acids are most commonly used (e.g. PhCO2K or PhCO2Na) • Useful method for synthesis of mixed anhydrides ©2018 Cengage Learning. All Rights Reserved. Figure 18.2 - Reactivities of Carboxyl Derivatives toward Nucleophilic Acyl Substitution (very important) ©2018 Cengage Learning. All Rights Reserved. Esters - Reaction with Grignard Reagents • Treating a formic ester (HCO2R, ester of formic acid) with two moles of a Grignard reagent followed by hydrolysis of the magnesium alkoxide salt in aqueous acid gives a 2° alcohol • 2 steps: (1) Grignard addition, (2) alkoxide hydrolysis ©2018 Cengage Learning. All Rights Reserved. Esters - Reaction with Grignard Reagents • Treating an ester other than a formate (formate = formic ester) with two moles of a Grignard reagent followed by hydrolysis of the magnesium alkoxide salt gives a 3° alcohol • Two groups bonded to the carbon bearing the OH group are the same ©2018 Cengage Learning. All Rights Reserved. Esters - Reaction with Grignard Reagents • Step 1: Make a new bond between a nucleophile and an electrophile: Reaction of a carbonyl carbon with one mole of Grignard reagent forms a tetrahedral carbonyl addition intermediate (key step 1) • Step 2: Break a bond to give stable molecules or ions: Collapse of the intermediate and expulsion of alkoxide ion give a ketone and a magnesium alkoxide salt ©2018 Cengage Learning. All Rights Reserved. Esters - Reaction with Grignard Reagents • Step 3: Make a new bond between a nucleophile and an electrophile: The ketone reacts with a second mole of Grignard reagent to give a second tetrahedral carbonyl addition intermediate (key step 2) • Step 4: Add a proton: The resulting hydrolysis gives a tertiary alcohol ©2018 Cengage Learning. All Rights Reserved. Esters - Reaction with Organolithium Compounds • Organolithium compounds are more powerful nucleophiles than Grignard reagents • React with esters to give the same types of 2° and 3° alcohols as do Grignard reagents, often in higher yields ©2018 Cengage Learning. All Rights Reserved. Acid Chlorides - Reactions with Gilman Reagents • Acid chlorides react with lithium diorganocopper (Gilman) reagents to give ketones • Reaction is carried out at −78°C in either diethyl ether or tetrahydrofuran • Under these conditions, the tetrahedral carbonyl addition intermediate is stable (tetrahedral carbonyl intermediate does not collapse) ©2018 Cengage Learning. All Rights Reserved. Acid Chlorides - Reactions with Gilman Reagents • Gilman reagents react ONLY with very reactive acid chlorides • Do NOT react with aldehydes, ketones, acid anhydrides, esters, amides, or nitriles. • Gilman reagents are highly selective (chemoselective) ©2018 Cengage Learning. All Rights Reserved. Example 18.9 - Reactions of Carboxylic Acid Derivatives • Show how to bring about each conversion in good yield ©2018 Cengage Learning. All Rights Reserved. Example 18.9 - Reactions of Carboxylic Acid Derivatives a. Treat the acid chloride with lithium dimethylcopper followed by H2O b. (1) Treat the carboxylic acid with thionyl chloride to form the acid chloride, (2) followed by treatment with lithium diallylcopper and (3) then aqueous acid ©2018 Cengage Learning. All Rights Reserved. Example • Predict the product of the following reaction I 6 as x1. 4. 2. x 5. 173456 3. ©2018 Cengage Learning. All Rights Reserved. Reduction of Esters - LiAlH4 • Esters are reduced by LiAlH4 to two alcohols • Alcohol derived from the acyl group is 1° ©2018 Cengage Learning. All Rights Reserved. Reduction of Esters - LiAlH4 • Step 1: Nucleophilic addition of hydride ion to the carbonyl carbon gives a tetrahedral carbonyl intermediate (key step 1) • Step 2: Collapse of the intermediate gives a new carbonylcontaining compound ©2018 Cengage Learning. All Rights Reserved. Reduction of Esters - LiAlH4 • Step 3: Nucleophilic addition of a second hydride ion to the newly formed carbonyl group gives an alkoxide ion (key step 2) • Step 4: Addition of water (proton) gives a 1° alcohol ©2018 Cengage Learning. All Rights Reserved. Reduction of Esters - NaBH4 • Sodium borohydride (NaBH4) is not normally used to reduce esters as the reaction is very slow • One can reduce the carbonyl group of an aldehyde or a ketone to a hydroxyl group with this reagent without reducing an ester or carboxyl group in the same molecule ©2018 Cengage Learning. All Rights Reserved. Reduction of Esters - DIBAL-H • Reduction of an ester to a 1° alcohol involves two successive hydride ion transfers (LiAlH4) • A useful modified reducing agent, diisobutylaluminum hydride (DIBALH) can reduce an ester to an aldehyde ©2018 Cengage Learning. All Rights Reserved. Reduction of Esters - DIBAL-H • DIBAL-H reductions are carried out in toluene or hexane at −78 °C followed by warming to room temperature and adding aqueous acid to hydrolyze the Al salts and liberate the aldehyde • Temperature control is critical • At room temperature, the ester is reduced to a 1° alcohol • At low temperature, the tetrahedral carbonyl addition intermediate does not eliminate alkoxide ion, and the more reactive aldehyde is not formed until after workup when the hydride ion has been destroyed (inefficient reaction) ©2018 Cengage Learning. All Rights Reserved. Reduction of Amides - LiAlH4 • LiAlH4 reduction of amides gives 1°, 2°, or 3° amines, depending on the degree of substitution of the amide ©2018 Cengage Learning. All Rights Reserved. Reduction of Amides - LiAlH4 • Step 1: Addition of hydride ion to the carbonyl carbon gives a Lewis acid-base adduct (key step 1) ©2018 Cengage Learning. All Rights Reserved. Reduction of Amides - LiAlH4 • Step 2: Rearrangement of electron pairs ejects H3AlO2− and generates an iminium ion • Step 3: The iminium ion adds a second hydride ion to complete the reduction (key step 2) ©2018 Cengage Learning. All Rights Reserved. Reduction of Nitriles - LiAlH4 • LiAlH4 reduces the cyano group of a nitrile to a 1° amino group • Reduction of a cyano group is useful for the preparation of ONLY 1° amines ©2018 Cengage Learning. All Rights Reserved. Example 18.11 - Reactions of Carboxylic Acid Derivatives • Show how to convert phenylacetic acid to each compound (phenylacetic acid = PhCH2CO2H) ©2018 Cengage Learning. All Rights Reserved. Example 18.11 - Reactions of Carboxylic Acid Derivatives (very important) ©2018 Cengage Learning. All Rights Reserved. Example 18.11 - Reactions of Carboxylic Acid Derivatives • Prepare methyl ester (a) by Fischer esterification of phenylacetic acid with methanol • Then treat this ester with ammonia to prepare amide (b) • Alternatively, treat phenylacetic acid with thionyl chloride to give an acid chloride • Then treat this acid chloride with ammonia to give amide (b) • Reduction of the amide (b) by LiAlH4 gives the primary amine (c) • Similar reduction of either phenylacetic acid or ester (a) gives alcohol (d) ©2018 Cengage Learning. All Rights Reserved. Example • Predict the outcome of the following reaction 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Example • What is the expected product for the following reaction? 1. 4. 2. 5. 3. ©2018 Cengage Learning. All Rights Reserved. Example • What sequence of reagents will accomplish the following transformation? 1. 4. x2. 5. 3. ©2018 Cengage Learning. All Rights Reserved. Example • Predict the product of the following reaction 1. 4. 2. 5. None of these 3. ©2018 Cengage Learning. All Rights Reserved. Example • What sequence of reagents will accomplish the following transformation? 1. 4. 2. 5. 3. ©2018 Cengage Learning. All Rights Reserved. Example • Identify the compound that will react fastest when heated in aqueous NaOH 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Problem 18.38 • A step in a synthesis of PGE1 (prostaglandin E1, alprostadil) is the reaction of a trisubstituted cyclohexene with bromine to form a bromolactone • Propose a mechanism for formation of this bromolactone and account for the observed stereochemistry of each substituent on the cyclohexane ring (bromolactonization) ©2018 Cengage Learning. All Rights Reserved. Problem 18.38 • Step 1: Make a new bond between a nucleophile (π bond) and an electrophile • Step 2: Make a bond between a nucleophile and an electrophile ©2018 Cengage Learning. All Rights Reserved. Problem 18.38 • Step 3: Take a proton away (deprotonation) • The stereochemistry is fixed by the bicyclic structure • The bromine atom is axial, while the —CH2COOH and methyl groups are equatorial ©2018 Cengage Learning. All Rights Reserved.