Chapter 18 Carboxylic Acids And Their Derivatives .

Chapter 18Carboxylic Acids and TheirDerivatives.Nucleophilic Addition-Elimination atthe Acyl CarbonCarboxylic Acidst Organic compoundsOcharacterized by their acidityt Contains COOH group (mustROHbe at the end of a chaint Widely distributed in natureRCO2 Ht Easily separated because ofacidityRCOOH1

Physical Properties of Carboxylic AcidsHigh Boiling PointsAcetic acid, melting point 16o CCarboxylic acids soluble in organic solventsCarboxylic acids with 5 or fewer carbons are water solubleCarboxylic acids with longer chains insoluble (called “fatty acids”)Nomenclaturet In IUPAC nomenclature, a carboxylic acid is named changingthe -e of the corresponding parent alkane to -oic acidl The carboxyl carbon is position 1 and is not numberedt The common names for many carboxylic acids remain in use2

Some straight chain acidsNaming Carboxylic AcidsCOOHCOOHClOHt a-chlorobutyric acidt 2-chlorobutanoic acidm-hydroxybenzoic acid3

Some other acids with common namest Diacidsl OxalicHOOC-COOHl MalonicHOOC-CH2-COOHl SuccinicHOOC-CH2CH2-COOHCOOHl PhthalicCOOH Hydroxyacid Lactic acid(S)-2-hydroxypropanoic acidAmino Acids Amino acids contain two functional groups—an amine group(NH2) and a carboxy group (COOH). Amino acids are the building blocks of proteins. The simplest amino acid, glycine, has R H. When R is any othergroup, the α carbon is a stereogenic center.*4

Unsaturated acidsOleic acid cis-9-octadecenoic acid75% of olive oil is oleic acidCarboxylic Acid Saltt Most carboxylic acids have a pKa 4 - 5l Carboxylic acids are readily deprotonated by sodiumhydroxide or sodium bicarbonate to form carboxylate saltsl Carboxylate salts are more water soluble than thecorresponding carboxylic acid5

Naming Carboxylic Acid SaltsSodium salts of fatty acids are soaps6

Acidity of Carboxylic AcidsElectron-withdrawing groups increase thecarboxylic acid’s acidity1. By inductive delocalization of chargePredict the pKa of p-nitrobenzoic acidCO2 HpKa 4.2O2 NCO2 HpKa ?A. 4.2B. 4.2pKa 3.48C. 4.27

Acidity of Substituted Benzoic Acids[2] Electron-withdrawing groups stabilize the conjugate base,making an acid more acidicelectron density removed from the carboxylate anion.Stabilization effect muchgreater in anionAcidity of Benzoic AcidsX COOHH4.19CH34.31NH24.92Cl3.98NO23.48X8

Acidity of Amino AcidsSince amines are basic and carboxylic acid groups areacidic, the two groups undergo a proton transferRNH2 RCOOH-------- RNH3 RCO2 -Amino acids exist in three different forms depending on pH.The “zwitterion” exists at neutral pH (7)At low pH ( 2),alanine exists as apositive ionAt high pH ( 11),alanine exists ananion9

t The carboxyl group is the parent group of a family of compoundscalled acyl compounds or carboxylic acid derivativesEsterst Esters are named from the corresponding carboxylic acid andalcohol from which the ester would be madel The alcohol portion is named first and has the ending -yll The carboxylic acid is named ending with -ate or –oate.t Esters cannot hydrogen bond to each other and therefore have lowerboiling points than carboxylic acidsl Esters can hydrogen bond to water and have appreciable watersolubility10

t Acid Anhydridesl Most anhydrides are named by dropping the word acid fromthe carboxylic acid name and adding the word anhydridet Acid Chloridesl Acid chlorides are named by dropping the -ic acid from thename of the carboxylic acid and adding -yl chloride11

t Amidesl Amides are named by replacing -ic acid in the name withamideè Groups on the nitrogen are named as substitutents and are given thelocants N- or N,N-l Amides with one or two hydrogens on nitrogen form very stronghydrogen bonds and have high melting and boiling pointsè N,N-disubstituted amides cannot form hydrogen bonds to each other andhave lower melting and boiling pointst Hydrogen bonding between amides in proteins andpeptides is an important factor in determining their3-dimensional shape12

Nitrilest Acyclic nitriles are named by adding the suffix -nitrile to the alkane namel The nitrile carbon is assigned position 1l Ethanenitrile is usually called acetonitrileInfrared Spectra of Acyl Compoundst The 1700 carbonyl stretching frequency varies slightlyaccording to the type of carboxylic acid derivative presentl O-H stretching vibrations of the carboxylic acid give a broadband at 2500-3100 cm-1l N-H stretching vibrations of amides appear at 3140-3500 cm-113

t 1H NMR Spectral The α hydrogens of carboxylic derivatives appear at δ 2.0-2.5l The carboxyl group proton appears downfield at δ 10-12t13CNMR Spectral The carbonyl carbon signal for carboxylic acids and theirderivatives appears at δ 160 to 18014

Preparation of Carboxylic Acidst By Oxidation of Alkenest By Oxidation of Aldehydes and Primary Alcoholst By Oxidation of Alkylbenzenesl By Oxidation of the Benzene Ringl By Oxidation of Methyl Ketones (The Haloform Reaction)l By Hydrolysis of Cyanohydrins and Other NitrilesH Hydrolysis of a cyanohydrin yields an α -hydroxy acid15

t Primary alkyl halides can react with cyanide to form nitrilesand these can be hydrolyzed to carboxylic acidst By Carbonation of Grignard ReagentsNucleophilic Addition-Elimination at an Acyl Carbont Recall that aldehydes and ketones undergo nucleophilicaddition to the carbon-oxygen double bondTetrahedral intermediate is created andmaintained, unless it can easily dehyrate16

Nucleophilic Addition-Elimination at the Acyl Carbont The carbonyl group of carboxylic acids and theirderivatives undergo nucleophilic addition-eliminationl The nucleophile reacts at the carbonyl group to form atetrahedral intermediatel The tetrahedral intermediate eliminates a leaving group (L)l The carbonyl group is regenerated; the net effect is an acylsubstitutiont To undergo nucleophilic addition-elimination the acylcompound must have a good leaving group or a group thatcan be converted into a good leaving groupl Acid chlorides react with loss of chloride ionl Anhydrides react with loss of a carboxylate ion17

t Esters, carboxylic acids and amides generally react with loss ofthe leaving groups alcohol, water and amine, respectivelyl These leaving groups are generated by protonation of the acylcompoundt Aldehydes and ketones cannot react by this mechanism becausethey lack a good leaving groupRelative Reactivity of Acyl Compoundst Based on the ability of the leaving group (L) to departl Leaving group ability is inversely related to basicityl Chloride is the weakest base and the best leaving groupl Amines are the strongest bases and the worst leaving groupst As a general rule, less reactive acyl compounds can besynthesized from more reactive onesè Synthesis of more reactive acyl derivatives from less reactive ones isdifficult and requires special reagents (if at all possible)18

t Acid Chloridesl Synthesis of Acid Chloridesè Acid chlorides are made from carboxylic acids by reaction withthionyl chloride, phosphorus trichloride or phosphoruspentachlorideH These reagents work because they turn the hydroxyl group of the carboxylic acidinto an excellent leaving groupl Reactions of Acyl Chloridesè Acyl chlorides are the most reactive acyl compounds and can beused to make any of the other derivativesè Since acyl chlorides are easily made from carboxylic acids theyprovide a way to synthesize any acyl compound from a carboxylicacidè Acyl chlorides react readily with water, but this is not asynthetically useful reaction19

t Carboxylic Acid Anhydridesl Synthesis of Carboxylic Acid Anhydridesè Acid chlorides react with carboxylic acids to form mixed orsymmetrical anhydridesH It is necessary to use a base such as pyridineè Sodium carboxylates react readily with acid chlorides to formanhydrides20

t Cyclic anhydrides with 5- and 6-membered rings can besynthesized by heating the appropriate diacidt Reactions of Carboxylic Acid Anhydridesl Carboxylic acid anhydrides are very reactive and can beused to synthesize esters and amidesè Hydrolysis of an anhydride yields the corresponding carboxylicacids21

t Estersl Synthesis of Esters: Esterificationè Acid catalyzed reaction of alcohols and carboxylic acids to formesters is called Fischer esterificationè Fischer esterification is an equilibrium processH Ester formation is favored by use of a large excess of either the alcohol orcarboxylic acidH Ester formation is also favored by removal of watert Esterification with labeled methanol gives a product labeledonly at the oxygen atom bonded to the methyl group22

t The reverse reaction is acid-catalyzed ester hydrolysisl Ester hydrolysis is favored by using lots of watert Esters from Acid Chloridesl Acid chlorides react readily with alcohols in the presence of a base(e.g. pyridine) to form esterst Esters from Carboxylic Acid Anhydridesl Alcohols react readily with anhydrides to form esters23

Base-Promoted Hydrolysis of Esters: Saponificationt Reaction of an ester with sodium hydroxide results in theformation of a sodium carboxylate and an alcoholt The mechanism is reversible until the alcohol product is formedt Protonation of the alkoxide by the initially formed carboxylic acid isirreversible, driving the overall reaction go to completionLactonest γ- or δ-Hydroxyacids undergo acid catalyzed reaction to givecyclic esters known as γ- or δ-lactones, respectively24

t Lactones can be hydrolyzed with aqueous basel Acidification of the carboxylate product can lead back to theoriginal lactone if too much acid is addedSynthesis of Amidest From Acyl Chloridesl Ammonia, primary or secondary amines react with acidchlorides to form amidesl Excess amine is needed to neutralize the HCl formedl Carboxylic acids can be converted to amides via thecorresponding acid chloride25

t Amides from Carboxylic Anhydridesl Anhydrides react with 2 equivalents of amine to produce anamide and an ammonium carboxylatet Reaction of a cyclic anhydride with an amine, followed byacidification yields a product containing both amide andcarboxylic acid functional groupst Heating this product results in the formation of a cyclic imide26

t Amides from Carboxylic Acids and Ammonium Carboxylatesl Direct reaction of carboxylic acids and ammonia yields ammoniumsaltsl Some ammonium salts of carboxylic acids can be dehydrated to theamide at high temperaturesl This is generally a poor method of amide synthesist A better way to prepare an amide is to convert a carboxylic acid to an acidchloride and react the acid chloride with ammonia or an aminet Dicylohexylcarbodiimide (DCC) is a reagent used to formamides from carboxylic acids and amines in one stept DCC activates the carbonyl group of a carboxylic acidtoward nucleophilic addition-elimination27

t Hydrolysis of Amidesl Heating an amide in concentrated aqueous acid or basecauses hydrolysisè Hydrolysis of an amide is slower than hydrolysis of an ester28

t Nitriles from the Dehydration of Amidesl A nitrile can be formed by reaction of an amide withphosphorous pentoxide or boiling acetic anhydridet Hydrolysis of Nitrilesl A nitrile is the synthetic equivalent of a carboxylic acidbecause it can be converted to a carboxylic acid by hydrolysis29

Hydrolysis in acidHydrolysis in base30

Decarboxylation of Carboxylic Acidst β-Keto carboxylic acids and their salts decarboxylate readilywhen heatedl Some even decarboxylate slowly at room temperaturel The mechanism of β-keto acid decarboxylation proceedsthrough a 6-membered ring transition statet Carboxylate anions decarboxylate rapidly because theyform a resonance-stabilized enolatet Malonic acids also decarboxylate readily31

10 tThe carboxyl group is the parent group of a family of compounds called acyl compounds or carboxylic acid derivatives tEsters are named from the corresponding carboxylic acid and alcohol from which the ester would be made lThe alcohol portion is named first and has the ending -yl lThe carboxylic acid is na