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Lectures 27 and 28. Carboxylic Acids and derivatives Chapter 10. The Importance of Carboxylic Acids (RCO 2 H). Starting materials for acyl derivatives (esters, amides, and acid chlorides) Abundant in nature from oxidation of aldehydes and alcohols in metabolism

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Lectures 27 and 28 l.jpg

Lectures 27 and 28

Carboxylic Acids and derivatives

Chapter 10

Chemistry 243 - Lecture 27 and 28


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The Importance of Carboxylic Acids (RCO2H)

  • Starting materials for acyl derivatives (esters, amides, and acid chlorides)

  • Abundant in nature from oxidation of aldehydes and alcohols in metabolism

    • Acetic acid, CH3CO2H, - vinegar

    • Butanoic acid, CH3CH2CH2CO2H (rancid butter)

    • Long-chain aliphatic acids from the breakdown of fats

Chemistry 243 - Lecture 27 and 28


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Naming Carboxylic Acids and Nitriles

  • Carboxylic Acids, RCO2H

  • If derived from open-chain alkanes, replace the terminal -e of the alkane name with -oic acid

  • The carboxyl carbon atom is C1

Chemistry 243 - Lecture 27 and 28


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Alternative Names

  • Compounds with CO2H bonded to a ring are named using the suffix -carboxylic acid

  • The CO2H carbon is not itself numbered in this system

  • Use common names for formic acid (HCOOH) and acetic acid (CH3COOH) – see Table 20.1

Chemistry 243 - Lecture 27 and 28


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Structure and Physical Properties of Carboxylic Acids

  • Carboxyl carbon sp2 hybridized: carboxylic acid groups are planar with C–C=O and O=C–O bond angles of approximately 120°

  • Carboxylic acids form hydrogen bonds, existing as cyclic dimers held together by two hydrogen bonds

  • Strong hydrogen bonding causes much higher boiling points than the corresponding alcohols

Chemistry 243 - Lecture 27 and 28


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Dissociation of Carboxylic Acids

  • Carboxylic acids are proton donors toward weak and strong bases, producing metal carboxylate salts, RCO2+M

  • Carboxylic acids with more than six carbons are only slightly soluble in water, but their conjugate base salts are water-soluble

Chemistry 243 - Lecture 27 and 28


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Acidity Constant and pKa

  • Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2, but H3O+ is a much stronger acid

  • The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5)

Chemistry 243 - Lecture 27 and 28


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Acidity Compared to Alcohols

  • Carboxylic acids are better proton donors than are alcohols (The pKa of ethanol is ~16, compared to ~5 for acetic acid)

  • In an alkoxide ion, the negative charge is localized on oxygen while in a carboxylate ion the negative charge is delocalized over two equivalent oxygen atoms, giving resonance stabilization

Chemistry 243 - Lecture 27 and 28


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Substituent Effects on Acidity

  • Electronegative substituents promote formation of the carboxylate ion

Chemistry 243 - Lecture 27 and 28


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Preparation of Carboxylic Acids

  • Oxidation of a substituted alkylbenzene with KMnO4 or Na2Cr2O7 gives a substituted benzoic acid

  • 1° and 2° alkyl groups can be oxidized, but tertiary groups are not

Chemistry 243 - Lecture 27 and 28


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From Alkenes

  • Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen

Chemistry 243 - Lecture 27 and 28


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From Alcohols

  • Oxidation of a primary alcohol or an aldehyde with CrO3 in aqueous acid

Chemistry 243 - Lecture 27 and 28


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Carboxylation of Grignard Reagents

  • Grignard reagents react with dry CO2 to yield a metal carboxylate

  • Limited to alkyl halides that can form Grignard reagents

Chemistry 243 - Lecture 27 and 28


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Mechanism of Grignard Carboxylation

  • The organomagnesium halide adds to C=O of carbon dioxide

  • Protonation by addition of aqueous HCl in a separate step gives the free carboxylic acid

Chemistry 243 - Lecture 27 and 28


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Reactions of Carboxylic Acids: An Overview

  • Carboxylic acids transfer a proton to a base to give anions, which are good nucleophiles in SN2 reactions

  • Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl group

  • In addition, carboxylic acids undergo other reactions characteristic of neither alcohols nor ketones

Chemistry 243 - Lecture 27 and 28


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Reduction of Carboxylic Acids

  • Reduced by LiAlH4 to yield primary alcohols

  • The reaction is difficult and often requires heating in tetrahydrofuran solvent to go to completion

Chemistry 243 - Lecture 27 and 28


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Carboxylic Compounds

  • Acyl group bonded to Y, an electronegative atom or leaving group

  • Includes: Y = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates)

Chemistry 243 - Lecture 27 and 28


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General Reaction Pattern

  • Nucleophilic acyl substitution

Chemistry 243 - Lecture 27 and 28


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Naming Carboxylic Acid Derivatives

  • Acid Halides, RCOX

    • Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide

Chemistry 243 - Lecture 27 and 28


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Naming Acid Anhydrides, RCO2COR'

  • If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid (for symmetrical anhydrides)

  • From substituted monocarboxylic acids: use bis- ahead of the acid name

  • Unsymmetrical anhydrides— cite the two acids alphabetically

Chemistry 243 - Lecture 27 and 28


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Naming Amides, RCONH2

  • With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide

  • If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide

Chemistry 243 - Lecture 27 and 28


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Naming Esters, RCO2R

  • Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate”

Chemistry 243 - Lecture 27 and 28


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Nucleophilic Acyl Substitution

  • Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave

  • A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution

Chemistry 243 - Lecture 27 and 28


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Relative Reactivity of Carboxylic Acid Derivatives

  • Nucleophiles react more readily with unhindered carbonyl groups

  • More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least)

  • The intermediate with the best leaving group decomposes fastest

Chemistry 243 - Lecture 27 and 28


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Substitution in Synthesis

  • We can readily convert a more reactive acid derivative into a less reactive one

  • Reactions in the opposite sense are possible but require more complex approaches

Chemistry 243 - Lecture 27 and 28


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General Reactions of Carboxylic Acid Derivatives

  • water ˝ carboxylic acid

  • alcohols ˝esters

  • ammonia or an amine ˝ an amide

  • hydride source ˝ an aldehyde or an alcohol

  • Grignard reagent ˝a ketone or an alcohol

Chemistry 243 - Lecture 27 and 28


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Nucleophilic Acyl Substitution Reactions of Carboxylic Acids

  • Must enhance reactivity

  • Convert OH into a better leaving group

  • Specific reagents can produce acid chlorides, anhydrides, esters, amides

Chemistry 243 - Lecture 27 and 28


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Conversion of Carboxylic Acids into Acid Chlorides

  • Reaction with thionyl chloride, SOCl2

Chemistry 243 - Lecture 27 and 28


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Mechanism of Thionyl Chloride Reaction

  • Nucleophilic acyl substitution pathway

  • Carboxylic acid is converted into a chlorosulfite which then reacts with chloride

Chemistry 243 - Lecture 27 and 28


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Conversion of Carboxylic Acids into Esters

  • Methods include reaction of a carboxylate anion with a primary alkyl halide

Chemistry 243 - Lecture 27 and 28


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Fischer Esterification

  • Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid

Chemistry 243 - Lecture 27 and 28


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Mechanism of the Fischer Esterification

  • The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid

  • When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled

Chemistry 243 - Lecture 27 and 28


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Fischer Esterification: Detailed Mechanism

1

3

2

4

Chemistry 243 - Lecture 27 and 28


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Chemistry of Acid Halides

  • Acid chlorides are prepared from carboxylic acids by reaction with SOCl2

  • Reaction of a carboxylic acid with PBr3 yields the acid bromide

Chemistry 243 - Lecture 27 and 28


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Reactions of Acid Halides

  • Nucleophilic acyl substitution

  • Halogen replaced by OH, by OR, or by NH2

  • Reduction yields a primary alcohol

  • Grignard reagent yields a tertiary alcohol

Chemistry 243 - Lecture 27 and 28


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Hydrolysis: Conversion of Acid Halides into Acids

  • Acid chlorides react with water to yield carboxylic acids

  • HCl is generated during the hydrolysis: a base is added to remove the HCl

Chemistry 243 - Lecture 27 and 28


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Conversion of Acid Halides to Esters

  • Esters are produced in the reaction of acid chlorides react with alcohols in the presence of pyridine or NaOH

  • The reaction is better with less steric bulk

Chemistry 243 - Lecture 27 and 28


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Aminolysis: Conversion of Acid Halides into Amides

  • Amides result from the reaction of acid chlorides with NH3, primary (RNH2) and secondary amines (R2NH)

  • The reaction with tertiary amines (R3N) gives an unstable species that cannot be isolated

  • HCl is neutralized by the amine or an added base

Chemistry 243 - Lecture 27 and 28


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Reduction: Conversion of Acid Chlorides into Alcohols

  • LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols

Chemistry 243 - Lecture 27 and 28


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Reaction of Acid Chlorides with Organometallic Reagents

  • Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same

Chemistry 243 - Lecture 27 and 28


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Formation of Ketones from Acid Chlorides

  • Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu

  • Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone

Chemistry 243 - Lecture 27 and 28


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Chemistry of Acid Anhydrides

  • Prepared by nucleophilic of a carboxylate with an acid chloride

Chemistry 243 - Lecture 27 and 28


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Reactions of Acid Anhydrides

  • Similar to acid chlorides in reactivity

Chemistry 243 - Lecture 27 and 28


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Acetylation

  • Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines

Chemistry 243 - Lecture 27 and 28


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Chemistry of Esters

  • Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers

  • Also present in fats and vegetable oils

Chemistry 243 - Lecture 27 and 28


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Preparation of Esters

  • Esters are usually prepared from carboxylic acids

Chemistry 243 - Lecture 27 and 28


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Reactions of Esters

  • Less reactive toward nucleophiles than are acid chlorides or anhydrides

  • Cyclic esters are called lactones and react similarly to acyclic esters

Chemistry 243 - Lecture 27 and 28


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Hydrolysis: Conversion of Esters into Carboxylic Acids

  • An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol

Chemistry 243 - Lecture 27 and 28


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Mechanism of Ester Hydrolysis

  • Hydroxide catalysis via an addition intermediate

1

3

2

4

Chemistry 243 - Lecture 27 and 28


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Acid Catalyzed Ester Hydrolysis

  • The usual pathway is the reverse of the Fischer esterification

Chemistry 243 - Lecture 27 and 28


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Aminolysis of Esters

  • Ammonia reacts with esters to form amides

Chemistry 243 - Lecture 27 and 28


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Reduction: Conversion of Esters into Alcohols

  • Reaction with LiAlH4 yields primary alcohols

Chemistry 243 - Lecture 27 and 28


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Mechanism of Reduction of Esters

  • Hydride ion adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde

  • Reduction of the aldehyde gives the primary alcohol

Chemistry 243 - Lecture 27 and 28


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Reaction of Esters with Grignard Reagents

  • React with 2 equivalents of a Grignard reagent to yield a tertiary alcohol

Chemistry 243 - Lecture 27 and 28


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Chemistry of Amides

  • Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines

Chemistry 243 - Lecture 27 and 28


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Reactions of Amides

  • Heating in either aqueous acid or aqueous base produces a carboxylic acid and amine

  • Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia

Chemistry 243 - Lecture 27 and 28


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Basic Hydrolysis of Amides

  • Addition of hydroxide and loss of amide ion

Chemistry 243 - Lecture 27 and 28


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Reduction: Conversion of Amides into Amines

  • Reduced by LiAlH4 to an amine rather than an alcohol

  • Converts C=O  CH2

Chemistry 243 - Lecture 27 and 28


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Mechanism of Reduction

  • Addition of hydride to carbonyl group

  • Loss of the oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine

Chemistry 243 - Lecture 27 and 28


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Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives

  • Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate

  • These have unique binding properties and are readily activated by enzymes

Chemistry 243 - Lecture 27 and 28


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Polyamides and Polyesters: Step-Growth Polymers Derivatives

  • Reactions occur in distinct linear steps, not as chain reactions

  • Reaction of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide

  • A diol with a diacid leads to a polyester

Chemistry 243 - Lecture 27 and 28


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Polyamides (Nylons) Derivatives

  • Heating a diamine with a diacid produces a polyamide called Nylon®

  • Nylon 66® is from adipic acid and hexamethylene-diamine at 280°C

Chemistry 243 - Lecture 27 and 28


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Polyesters Derivatives

  • The polyester from dimethyl terephthalate and ethylene glycol is called Dacron® and Mylar® to make fibers

Chemistry 243 - Lecture 27 and 28


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For Next Class Derivatives

  • Read Chapter 11

    • Alpha-substitution reactions

Chemistry 243 - Lecture 27 and 28


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