© 2006 Thomson Higher Education Chapter. Carboxylic Acid 2. Derivatives

Carboxylic Acid Derivatives Carboxylic acid derivatives Compounds in which acyl group is bonded to an electronegative atom or substituent that can act as a leaving group Converted to parent carboxylic acid by hydrolysis reaction

Naming Carboxylic Acid Derivatives Acid Anhydrides, RCO 2 COR′ Symmetrical anhydrides of monocarboxylic acids and cyclic anhydrides of dicarboxylic acids named by replacing acid with anhydride

Naming Carboxylic Acid Derivatives Amides, RCONH 2 Amides with unsubstituted –NH 2 group named by replacing the –oic acid or –ic acid ending with –amide, or by replacing the –carboxylic acid ending with - carboxamide

Naming Carboxylic Acid Derivatives If nitrogen is further substituted the compound is named by first identifying the substituent groups and then the parent amide Substituents are preceded by N

Naming Carboxylic Acid Derivatives Esters, RCO 2 R′ Esters are named by first identifying the alkyl group attached to the oxygen and then the carboxylic acid with the –ic acid ending replaced by -ate

Naming Carboxylic Acid Derivatives Thioesters, RCOSR′ Thioesters are named like the corresponding esters If ester has common name the prefix thio- is used If ester has a systematic name the –oate or –carboxylate ending is replaced by –thioate or -carbothioate

Naming Carboxylic Acid Derivatives Acyl Phosphates, RCO 2 PO 3 2- and RCO 2 PO 3 R′ - Acyl phosphates are named by citing the acyl group and adding the word phosphate If alkyl group is attached to one of the phosphate oxygens it is identified after the name of the acyl group

Naming Carboxylic Acid Derivatives

16.2 Nucleophilic Acyl Substitution Reactions Nucleophilic Acyl Substitution Nucleophile adds to carbonyl of carboxylic acid derivative forming a tetrahedral intermediate C=O bond is restored by elimination of one of the two substituents originally bonded to the carbonyl carbon leading to substitution

Nucleophilic Acyl Substitution Reactions Aldehydes and ketones do not undergo nucleophilic acyl substitution reactions Aldehydes and ketones do not possess a suitable leaving group C=O bond is not restored Carbon of original carbonyl group remains sp 3 -hybridized, singly bonded to four substituents

Nucleophilic Acyl Substitution Reactions Relative reactivity of carboxylic acid derivatives Both addition and elimination steps affect the overall rate of nucleophilic acyl substitution reaction Addition step is generally rate-limiting due to steric and electronic factors Sterically unhindered acid derivatives are more accessible to approaching nucleophile

Nucleophilic Acyl Substitution Reactions Strongly polarized acyl groups make the C=O carbon atom more electrophilic

Nucleophilic Acyl Substitution Reactions Usually possible to convert more reactive acid derivatives to less reactive ones Acid halides and acid anhydrides do not persist in living organisms because they react rapidly with water

Nucleophilic Acyl Substitution Reactions Four common reactions for carboxylic acid derivatives Hydrolysis Reaction with water to yield carboxylic acid Alcoholysis Reaction with alcohol to yield ester Aminolysis Reaction with ammonia or amine to yield amide Reduction Reaction with hydride reducing agent to yield aldehyde or alcohol

Worked Example 16.1 Predicting the Product of a Nucleophilic Acyl Substitution Reaction Predict the product of the following nucleophilic acyl substitution reaction of benzoyl chloride with propan-2-ol

Worked Example 16.1 Predicting the Product of a Nucleophilic Acyl Substitution Reaction Strategy A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl - in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate.

Worked Example 16.1 Predicting the Product of a Nucleophilic Acyl Substitution Reaction

16.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Direct nucleophilic acyl substitution of a carboxylic acid is difficult because –OH group is a poor leaving group Reactivity is enhanced by Protonating carbonyl oxygen of carboxyl group making the carbonyl carbon atom more electrophilic Converting –OH into better leaving group

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Conversion of Carboxylic Acids into Acid Chlorides Laboratory conversion accomplished by treatment of carboxylic acid with thionyl chloride, SOCl 2

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Reaction proceeds through chlorosulfite intermediate, thereby replacing the –OH group with a better leaving group Chlorosulfite intermediate then reacts with a nucleophilic chloride ion

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Conversion of Carboxylic Acids into Acid Anhydrides Two molecules of carboxylic acid will lose 1 equivalent of water by heating Preparation is uncommon due to high temperatures required for the dehydration

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Conversion of Carboxylic Acids into Esters Most useful reaction of carboxylic acids Several methods for accomplishing transformation S N 2 reaction with carboxylate anion with primary alkyl halide

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Fischer esterification reaction Acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol Excess liquid alcohol used as solvent limits reaction to methyl, ethyl, propyl and butyl esters

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Mechanism of Fischer esterification reaction

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Isotopic labeling experiments provide experimental evidence for Fischer esterification mechanism

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Conversion of Carboxylic Acids into Amides Amides difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions Amides are first activated with dicyclohexylcarbodiimide (DCC) Intermediate then treated with amine Key step in laboratory synthesis of small proteins

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Mechanism of amide formation by reaction of carboxylic acid with DCC

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Conversion of Carboxylic Acids into Alcohols Carboxylic acids reduced by LiAlH 4 to give primary alcohols by nucleophilic acyl substitution of –H for –OH Reaction proceeds through reactive aldehyde intermediate

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Hydride ion is a base and a nucleophile Reaction involves carboxylate anion and gives high- energy dianion intermediate complexed to a Lewis acidic aluminum species Reaction requires high temperatures and extended reaction times

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Biological Conversions of Carboxylic Acids Direct conversion of carboxylic acid to acyl derivative by nucleophilic acyl substitution does not occur in biological chemistry Acid must first be activated In living organisms, activation often accomplished by reaction of acid with ATP to give acyl adenosyl phosphate, or acyl adenylate Acyl adenylate is a mixed anhydride between carboxylic and adenosine monophosphate (AMP), also known as adenylic acid Occurs in biosynthesis of fats

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids Fatty-acid biosyntheses proceeds through acyl adenylate Acyl adenylate undergoes nucleophilic acyl substitution with –SH group on coenzyme A

16.4 Chemistry of Acid Halides Conversion of Acid Halides into Acids: Hydrolysis Acid halides are among the most reactive of carboxylic acid derivatives Acid chlorides react with water to give tetrahedral intermediate Tetrahedral intermediate expels Cl - and loses H + to give carboxylic acid and HCl

Chemistry of Acid Halides Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution of an acid chloride with a carboxylate anion gives an acid anhydride Both symmetrical and unsymmetrical anhydrides prepared this way

Chemistry of Acid Halides Conversion of Acid Halides into Esters: Alcoholysis Acid chlorides react with alcohols to yield esters Most common method for preparing esters in laboratory Reaction is carried out in presence of pyridine or NaOH to react with HCl that is formed

Chemistry of Acid Halides Reaction of alcohol with acid chloride strongly affected by steric hindrance Bulky groups on either partner slow down reaction Often possible to esterify an unhindered alcohol selectively in presence of hindered alcohol

Chemistry of Acid Halides Conversion of Acid Halides into Amides: Aminolysis Acid halides rapidly react with ammonia and amines to form amides Most common laboratory preparation of amides using monosubstituted and disubstituted amines Trisubstituted amines cannot be used

Chemistry of Acid Halides Because HCl is formed during reaction, 2 equivalents of amine must be used First equivalent reacts with acid chloride Second equivalent reacts with HCl by-product NaOH is used if amine reactant is valuable, as in synthesis of trimetozine

16.5 Chemistry of Acid Anhydrides Similar chemistry to acid anhydrides Acid anhydrides react more slowly than acid halides

Chemistry of Acid Anhydrides Acetic anhydride is used to prepare acetate esters from alcohols and N-substituted acetamides from amines More nucleophilic –NH 2 group reacts rather than less nucleophilic –OH group

16.6 Chemistry of Esters Esters are among most widespread of all naturally occurring compounds Dibutyl phthalate is a common plasticizer Esters undergo nucleophilic substitution reactions more slowly than acid halides or acid anhydrides All reactions of esters are equally applicable to acyclic and cyclic esters, called lactones

Chemistry of Esters Conversion of Esters into Carboxylic Acids: Hydrolysis Esters undergo both acidic and basic hydrolysis to yield carboxylic acids and alcohols Saponification Basic ester hydrolysis Named after the Latin word sapo, meaning soap Soap is made from boiling animal fat with base Basic hydrolysis occurs through nucleophilic acyl substitution pathway Isotopic labeling experiments support mechanism Occurs by cleavage of C-OR′ bond rather than the CO-R′ bond

Chemistry of Esters Mechanism of base- induced ester hydrolysis (saponification)

Chemistry of Esters Acid-catalyzed ester hydrolysis occurs by more than one mechanism Most common mechanism is reverse of Fischer esterification reaction Protonation of carboxyl oxygen activates ester toward nucleophilic attack Nucleophilic addition of water occurs A proton is removed from the water oxygen The alcohol oxygen is protonated making it a better leaving group Alcohol is eliminated forming the carboxylic acid

Chemistry of Esters Mechanism of acid- catalyzed ester hydrolysis

Chemistry of Esters Ester hydrolysis is common in biological chemistry Digestion of fat and oils involves two sequential nucleophilic acyl substitution reactions

Chemistry of Esters Conversion of Esters into Alcohols: Reduction and Grignard Reaction Esters are reduced by treatment with LiAlH 4 to yield primary alcohols Reaction proceeds through an aldehyde intermediate