Organic Chemistry II / CHEM 252 Chapter 18 – Carboxylic .

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Organic Chemistry II / CHEM252Chapter 18 – Carboxylic Acids andTheir Derivatives.Bela TorokDepartment of ChemistryUniversity of Massachusetts BostonBoston, MA1

Introduction The carboxyl group (-CO2H) is the parent group of a family ofcompounds called acyl compounds or carboxylic acid derivatives2

Nomenclature and Physical Properties In IUPAC nomenclature, the name of a carboxylic acid is obtained bychanging the -e of the corresponding parent alkane to -oic acid– The carboxyl carbon is assigned position 1 and need not beexplicitly numbered The common names for many carboxylic acids remain in use– Methanoic and ethanoic acid are usually referred to as formic andacetic acid Carboxylic acids can form strong hydrogen bonds with each other andwith water– Carboxylic acids with up to 4 carbons are miscible with water inall proportions3

Nomenclature and Physical Properties4

Acidity The carboxyl proton of most carboxylic acids has a pKa 4 - 5– Carboxylic acids are deprotonated by NaOH or NaHCO3– Carboxylate salts are more water soluble than the acid Electron-withdrawing groups increase the acidity– They stabilize the carboxylate anion by inductive delocalization ofcharge5

Dicarboxylic Acids Dicarboxylic acids are named as alkanedioic acids in the IUPACsystem– Common names are often used for simple dicarboxylic acids6

Esters The names of esters are derived from the names of the correspondingcarboxylic acid and alcohol from which the ester would be made– The alcohol portion is named first and has the ending -yl– The carboxylic acid portion follows and its name ends with -ate or oate Esters cannot hydrogen bond to each other and therefore have lowerboiling points than carboxylic acids– Esters can hydrogen bond to water and have appreciable watersolubility7

Esters8

Acid Anhydrides, Chlorides– Acid Anhydrides Most anhydrides are named by dropping the word acid from thecarboxylic acid name and adding the word anhydride– Acid Chlorides Acid chlorides are named by dropping the -ic acid from the name of thecarboxylic acid and adding -yl chloride9

Amides Amides with no substituents on nitrogen are named by replacing-ic acid in the name with amide– Groups on the nitrogen are named as substitutents and are given thelocants N- or N,N- Amides with one or two hydrogens on nitrogen form very stronghydrogen bonds and have high melting and boiling points– N,N-disubstituted amides cannot form hydrogen bonds to each other10and have lower melting and boiling points

Amides, Nitriles Hydrogen bonding between amides in proteins and peptides is animportant factor in determining their 3-dimensional shape– Nitriles Acyclic nitriles are named by adding the suffix -nitrile to thealkane name– The nitrile carbon is assigned position 1– Ethanenitrile is usually called acetonitrile11

Preparation of Carboxylic Acids– By Oxidation of Alkenes– By Oxidation of Aldehydes and Primary Alcohols– By Oxidation of Alkylbenzenes12

Preparation of Carboxylic Acids– By Oxidation of the Benzene Ring– By Oxidation of Methyl Ketones (The Haloform Reaction)– By Hydrolysis of Cyanohydrins and Other Nitriles– Hydrolysis of a cyanohydrin yields an α-hydroxy acid13

Preparation of Carboxylic Acids– Primary alkyl halides can react with cyanide to formnitriles and these can be hydrolyzed to carboxylic acids– By Carbonation of Grignard Reagents14

Nucleophilic Addition-Elimination Recall that aldehydes and ketones undergo nucleophilic addition to thecarbon-oxygen double bond The carbonyl group of carboxylic acids and their derivatives undergonucleophilic addition-elimination– The nucleophile reacts at the carbonyl group– The tetrahedral intermediate eliminates a leaving group (L)– The carbonyl group is regenerated; the net effect: acyl substitution15

Nucleophilic Addition-Elimination To undergo nucleophilic addition-elimination the acylcompound must have a good leaving group or a group that canbe converted into a good leaving group– Acid chlorides react with loss of chloride ion– Anhydrides react with loss of a carboxylate ion16

Nucleophilic Addition-Elimination Esters, carboxylic acids and amides generally react with loss ofthe leaving groups alcohol, water and amine, respectively– These leaving groups are generated by protonation of theacyl compound Aldehydes and ketones cannot react by this mechanismbecause they lack a good leaving group17

Relative Reactivity– Relative Reactivity of Acyl Compounds The relative reactivity of carboxylic acids and their derivatives is asfollows: Reactivity can be related to the ability of the leaving group (L) to depart– Leaving group ability is inversely related to basicity– Chloride is the weakest base and the best leaving group– Amines are the strongest bases and the worst leaving groups Less reactive acyl compounds can be synthesized from more reactive ones– Synthesis of more reactive acyl derivatives from less reactive ones isdifficult and requires special reagents (if at all possible)18

Acyl ChloridesSynthesis of Acid Chlorides Acid chlorides are made from carboxylic acids by reaction withthionyl chloride, phosphorus trichloride or phosphorus pentachloride– These reagents work because they turn the hydroxyl group of thecarboxylic acid into an excellent leaving group19

Acyl Chlorides– Reactions of Acyl Chlorides Acyl chlorides are the most reactive acyl compounds and canbe used to make any of the other derivatives Since acyl chlorides are easily made from carboxylic acidsthey provide a way to synthesize any acyl compound from acarboxylic acid Acyl chlorides react readily with water, but this is not asynthetically useful reaction20

Acyl Chlorides21

Carboxylic Acid Anhydrides– Synthesis of Carboxylic Acid Anhydrides Acid chlorides react with carboxylic acids to form mixed or symmetricalanhydrides– It is necessary to use a base such as pyridine Sodium carboxylates react readily with acid chlorides to formanhydrides22

Carboxylic Acid Anhydrides Cyclic anhydrides with 5- and 6-membered rings can besynthesized by heating the appropriate diacid– Reactions of Carboxylic Acid Anhydrides Carboxylic acid anhydrides are very reactive and can be usedto synthesize esters and amides– Hydrolysis of an anhydride yields the correspondingcarboxylic acids23

Carboxylic Acid Anhydrides24

Carboxylic Acid EstersSynthesis of Esters: Esterification Acid catalyzed reaction of alcohols and carboxylic acids to form estersis called Fischer esterification Fischer esterification is an equilibrium process– Ester formation is favored by use of a large excess of either thealcohol or carboxylic acid– Ester formation is also favored by removal of water25

Carboxylic Acid Esters Esterification with labeled methanol gives a product labeled only at theoxygen atom bonded to the methyl group– A mechanism consistent with this observation is shown below26

Carboxylic Acid Esters The reverse reaction is acid-catalyzed ester hydrolysis– Ester hydrolysis is favored by use of dilute aqueous acid Esters from Acid Chlorides– Acid chlorides react readily with alcohols in the presence of a base(e.g. pyridine) to form esters27

Carboxylic Acid Esters Esters from Carboxylic Acid Anhydrides– Alcohols react readily with anhydrides to form esters28

Carboxylic Acid Esters– Base-Promoted Hydrolysis of Esters: Saponification Reaction of an ester with sodium hydroxide results in the formationof a sodium carboxylate and an alcohol The mechanism is reversible until the alcohol product is formed Protonation of the alkoxide by the carboxylic acid is irreversible– This step draws the overall equilibrium toward the hydrolysis29

Carboxylic Acid Esters– Lactonesγ- or δ-Hydroxyacids undergo acid catalyzed reaction to givecyclic esters known as γ- or δ-lactones, respectively30

Carboxylic Acid Esters Lactones can be hydrolyzed with aqueous base– Acidification of the carboxylate product can lead back to theoriginal lactone if too much acid is added31

AmidesSynthesis of Amides Amides From Acyl Chlorides– Ammonia, primary or secondary amines react with acidchlorides to form amides– An excess of amine is added to neutralize the HCl formedin the reaction– Carboxylic acids can be converted to amides via thecorresponding acid chloride32

Amides Amides from Carboxylic Anhydrides– Anhydrides react with 2 equivalents of amine to produce an amideand an ammonium carboxylate– Reaction of a cyclic anhydride with an amine, followed byacidification yields a product containing both amide and carboxylicacid functional groups– Heating this product results in the formation of a cyclic imide33

Amides Amides from Carboxylic Acids and Ammonium Carboxylates– Direct reaction of carboxylic acids and ammonia yields ammoniumsalts– Some ammonium salts of carboxylic acids can be dehydrated to theamide at high temperatures– This is generally a poor method of amide synthesis– A good way to synthesize an amide is to convert a carboxylic acid toan acid chloride and to then to react the acid chloride with ammoniaor an amine34

Amides– Dicylohexylcarbodiimide (DCC) is a reagent used to form amidesfrom carboxylic acids and amines– DCC activates the carbonyl group of a carboxylic acid35

Amides– Hydrolysis of Amides Heating an amide in concentrated aqueous acid or base causes hydrolysis– Hydrolysis of an amide is slower than hydrolysis of an ester36

Amides37

Amides38

Amides– Nitriles from the Dehydration of Amides A nitrile can be formed by reaction of an amide with phosphorouspentoxide or boiling acetic anhydride– Hydrolysis of Nitriles A nitrile is the synthetic equivalent of a carboxylic acid because it can beconverted to a carboxylic acid by hydrolysis39

Amides40

Amides41

Decarboxylation Decarboxylation of Carboxylic Acidsβ-Keto carboxylic acids and their salts decarboxylate readily whenheated– Some even decarboxylate slowly at room temperature The mechanism of β-keto acid decarboxylation proceeds through a6-membered ring transition state42

Decarboxylation Carboxylate anions decarboxylate rapidly because they form aresonance-stabilized enolate Malonic acids also decarboxylate readily43

– Methanoic and ethanoic acid are usually referred to as formic and acetic acid Carboxylic acids can form strong hydrogen bonds with each other and . carboxylic acid name and adding the word anhydride – Acid Chlorides Acid chlorides are named by dropping the -ic acid from

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