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  1. 1. Chapter 18Carboxylic Acids and TheirDerivatives. Nucleophilic Addition-Elimination at the Acyl Carbon
  2. 2. Chapter 18 2 IntroductionThe carboxyl group (-CO2H) is the parent group of a family ofcompounds called acyl compounds or carboxylic acidderivatives
  3. 3. Chapter 18 3 Nomenclature and Physical PropertiesIn IUPAC nomenclature, the name of a carboxylic acid isobtained by changing the -e of the corresponding parentalkane to -oic acidThe carboxyl carbon is assigned position 1 and need not be explicitlynumberedThe common names for many carboxylic acids remain in useMethanoic and ethanoic acid are usually referred to as formic and aceticacidCarboxylic acids can form strong hydrogen bonds with eachother and with waterCarboxylic acids with up to 4 carbons are miscible with water in allproportions
  4. 4. Chapter 18 4
  5. 5. Chapter 18 5 Acidity of Carboxylic AcidsThe carboxyl proton of most carboxylic acids has a pKa = 4 -5Carboxylic acids are readily deprotonated by sodium hydroxide or sodiumbicarbonate to form carboxylate saltsCarboxylate salts are more water soluble than the corresponding carboxylicacidElectron-withdrawing groups near the carboxyl groupincrease the carboxylic acid’s acidityThey stabilize the carboxylate anion by inductive delocalization of charge
  6. 6. Chapter 18 6 Dicarboxylic AcidsDicarboxylic acids are named as alkanedioic acids in theIUPAC systemCommon names are often used for simple dicarboxylic acids
  7. 7. Chapter 18 7 EstersThe names of esters are derived from the names of thecorresponding carboxylic acid and alcohol from which theester would be madeThe alcohol portion is named first and has the ending -ylThe carboxylic acid portion follows and its name ends with -ate or -oateEsters cannot hydrogen bond to each other and thereforehave lower boiling points than carboxylic acidsEsters can hydrogen bond to water and have appreciable water solubility
  8. 8. Chapter 18 8
  9. 9. Chapter 18 9 Acid AnhydridesMost anhydrides are named by dropping the word acid fromthe carboxylic acid name and adding the word anhydride Acid ChloridesAcid chlorides are named by dropping the -ic acid from thename of the carboxylic acid and adding -yl chloride
  10. 10. Chapter 18 10 AmidesAmides with no substituents on nitrogen are named byreplacing-ic acid in the name with amideGroups on the nitrogen are named as substitutents and are given thelocants N- or N,N-Amides with one or two hydrogens on nitrogen form verystrong hydrogen bonds and have high melting and boilingpointsN,N-disubstituted amides cannot form hydrogen bonds to each other andhave lower melting and boiling points
  11. 11. Chapter 18 11Hydrogen bonding between amides in proteins and peptidesis an important factor in determining their 3-dimensionalshape NitrilesAcyclic nitriles are named by adding the suffix -nitrile to thealkane nameThe nitrile carbon is assigned position 1Ethanenitrile is usually called acetonitrile
  12. 12. Chapter 18 12 Preparation of Carboxylic Acids By Oxidation of Alkanes By Oxidation of Aldehydes and Primary Alcohols By Oxidation of Alkylbenzenes
  13. 13. Chapter 18 13 By Oxidation of the Benzene Ring By Oxidation of Methyl Ketones (The HaloformReaction) By Hydrolysis of Cyanohydrins and Other NitrilesHydrolysis of a cyanohydrin yields an α-hydroxy acid
  14. 14. Chapter 18 14Primary alkyl halides can react with cyanide to form nitriles and these canbe hydrolyzed to carboxylic acids By Carbonation of Grignard Reagents
  15. 15. Chapter 18 15 Relative Reactivity of Acyl CompoundsThe relative reactivity of carboxylic acids and theirderivatives is as follows:In general, reactivity can be related to the ability of theleaving group (L) to departLeaving group ability is inversely related to basicityChloride is the weakest base and the best leaving groupAmines are the strongest bases and the worst leaving groupsAs a general rule, less reactive acyl compounds can besynthesized from more reactive onesSynthesis of more reactive acyl derivatives from less reactive ones isdifficult and requires special reagents (if at all possible)
  16. 16. Chapter 18 16 Acid Chlorides Synthesis of Acid ChloridesAcid chlorides are made from carboxylic acids by reactionwith thionyl chloride, phosphorus trichloride or phosphoruspentachlorideThese reagents work because they turn the hydroxyl group of thecarboxylic acid into an excellent leaving group
  17. 17. Chapter 18 17Reactions of Acyl ChloridesAcyl chlorides are the most reactive acyl compounds andcan be used to make any of the other derivativesSince acyl chlorides are easily made from carboxylic acidsthey provide a way to synthesize any acyl compound from acarboxylic acidAcyl chlorides react readily with water, but this is not asynthetically useful reaction
  18. 18. Chapter 18 18
  19. 19. Chapter 18 19 Carboxylic Acid Anhydrides Synthesis of Carboxylic Acid AnhydridesAcid chlorides react with carboxylic acids to form mixed orsymmetrical anhydridesIt is necessary to use a base such as pyridineSodium carboxylates react readily with acid chlorides toform anhydrides
  20. 20. Chapter 18 20Cyclic anhydrides with 5- and 6-membered rings can besynthesized by heating the appropriate diacid Reactions of Carboxylic Acid AnhydridesCarboxylic acid anhydrides are very reactive and can beused to synthesize esters and amidesHydrolysis of an anhydride yields the corresponding carboxylic acids
  21. 21. Chapter 18 21
  22. 22. Chapter 18 22 Esters Synthesis of Esters: EsterificationAcid catalyzed reaction of alcohols and carboxylic acids toform esters is called Fischer esterificationFischer esterification is an equilibrium processEster formation is favored by use of a large excess of either the alcohol orcarboxylic acidEster formation is also favored by removal of water
  23. 23. Chapter 18 23Esterification with labeled methanol gives a product labeledonly at the oxygen atom bonded to the methyl groupA mechanism consistent with this observation is shown below
  24. 24. Chapter 18 24The reverse reaction is acid-catalyzed ester hydrolysisEster hydrolysis is favored by use of dilute aqueous acidEsters from Acid ChloridesAcid chlorides react readily with alcohols in the presence of a base ( e.g.pyridine) to form esters
  25. 25. Chapter 18 25Esters from Carboxylic Acid AnhydridesAlcohols react readily with anhydrides to form esters
  26. 26. Chapter 18 26 Base-Promoted Hydrolysis of Esters:SaponificationReaction of an ester with sodium hydroxide results in theformation of a sodium carboxylate and an alcoholThe mechanism is reversible until the alcohol product isformedProtonation of the alkoxide by the initially formed carboxylicacid is irreversibleThis step draws the overall equilibrium toward completion of the hydrolysis