Chapter 21Carboxylic Acid DerivativesJo BlackburnRichland College, Dallas, TXDallas County Community College District 2003, Prentice HallOrganic Chemistry, 5th Edition L. G. Wade, Jr.

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Acid DerivativesAll can be converted to the carboxylic acid by acidic or basic hydrolysis.Esters and amides common in nature.

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Naming EstersEsters are named as alkyl carboxylates.Alkyl from the alcohol, carboxylate from the carboxylic acid precursor. isobutyl acetate2-methylpropyl ethanoate

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Cyclic EstersReaction of -OH and -COOH on same molecule produces a cyclic ester, lactone.To name, add word lactone to the IUPAC acid name or replace the -ic acid of common name with -olactone.

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AmidesProduct of the reaction of a carboxylic acid and ammonia or an amine.Not basic because the lone pair on nitrogen is delocalized by resonance.

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Classes of Amides1 amide has one C-N bond (two N-H).2 amide or N-substituted amide has two C-N bonds (one N-H).3 amide or N,N-disubstituted amide has three C-N bonds (no N-H). =>

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Naming AmidesFor 1 amide, drop -ic or -oic acid from the carboxylic acid name, add -amide.For 2 and 3 amides, the alkyl groups bonded to nitrogen are named with N- to indicate their position.

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Cyclic AmidesReaction of -NH2 and -COOH on same molecule produces a cyclic amide, lactam.To name, add word lactam to the IUPAC acid name or replace the -ic acid of common name with -olactam.

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Nitriles-CN can be hydrolyzed to carboxylic acid, so nitriles are acid derivatives.Nitrogen is sp hybridized, lone pair tightly held, so not very basic. (pKb about 24).

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Naming NitrilesFor IUPAC names, add -nitrile to the alkane name.Common names come from the carboxylic acid. Replace -ic acid with -onitrile.5-bromohexanenitrile-bromocapronitrileCyclohexanecarbonitrile =>

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Acid HalidesMore reactive than acids; the halogen withdraws e- density from carbonyl.Named by replacing -ic acid with -yl halide.benzoyl chloride3-bromobutanoyl bromide-bromobutyryl bromide =>

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Acid AnhydridesTwo molecules of acid combine with the loss of water to form the anhydride.Anhydrides are more reactive than acids, but less reactive than acid chlorides.A carboxylate ion is the leaving group in nucleophilic acyl substitution reactions.

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Naming AnhydridesThe word acid is replaced with anhydride.For a mixed anhydride, name both acids.Diacids may form anhydrides if a 5- or 6-membered ring is the product.ethanoic anhydrideacetic anhydride

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Multifunctional CompoundsThe functional group with the highest priority determines the parent name.Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne.

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Boiling PointsEven 3 amides havestrong attractions.

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Melting PointsAmides have very high melting points.Melting points increase with increasing number of N-H bonds.m.p. -61Cm.p. 28C

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SolubilityAcid chlorides and anhydrides are too reactive to be used with water or alcohol.Esters, 3 amides, and nitriles are good polar aprotic solvents.Solvents commonly used in organic reactions:Ethyl acetateDimethylformamide (DMF)Acetonitrile =>

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IR Spectroscopy=>=>

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1H NMR Spectroscopy=>

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13C NMR Spectroscopy=>

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Interconversion ofAcid DerivativesNucleophile adds to the carbonyl to form a tetrahedral intermediate.Leaving group leaves and C=O regenerates.

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ReactivityReactivity decreases as leaving group becomes more basic.=>

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Interconversion of DerivativesMore reactive derivatives can be converted to less reactive derivatives.=>

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Acid Chloride to AnhydrideAcid or carboxylate ion attacks the C=O.Tetrahedral intermediate forms.Chloride ion leaves, C=O is restored, H+ is abstracted. =>

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Acid Chloride to EsterAlcohol attacks the C=O.Tetrahedral intermediate forms.Chloride ion leaves, C=O is restored, H+ is abstracted. =>

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Acid Chloride to AmideAmmonia yields a 1 amideA 1 amine yields a 2 amideA 2 amine yields a 3 amide

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Anhydride to EsterAlcohol attacks one C=O of anhydride.Tetrahedral intermediate forms.Carboxylate ion leaves, C=O is restored, H+ is abstracted. =>

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Anhydride to AmideAmmonia yields a 1 amideA 1 amine yields a 2 amideA 2 amine yields a 3 amide

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Ester to AmideNucleophile must be NH3 or 1 amine.Prolonged heating required.

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Leaving GroupsA strong base is not usually a leaving group unless its in an exothermic step.

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TransesterificationOne alkoxy group can be replaced by another with acid or base catalyst.Use large excess of preferred alcohol.

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Hydrolysis of Acid Chlorides and AnhydridesHydrolysis occurs quickly, even in moist air with no acid or base catalyst.Reagents must be protected from moisture.

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Acid Hydrolysis of EstersReverse of Fischer esterification.Reaches equilibrium.Use a large excess of water.

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SaponificationBase-catalyzed hydrolysis of ester.Saponification means soap-making.Soaps are made by heating NaOH with a fat (triester of glycerol) to produce the sodium salt of a fatty acid - a soap.One example of a soap is sodium stearate, Na+ -OOC(CH2)16CH3. =>

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Hydrolysis of AmidesProlonged heating in 6 M HCl or 40% aqueous NaOH is required.

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Hydrolysis of NitrilesUnder mild conditions, nitriles hydrolyze to an amide.Heating with aqueous acid or base will hydrolyze a nitrile to an acid.

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Reduction to AlcoholsLithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols.

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Reduction to AldehydesAcid chlorides will react with a weaker reducing agent to yield an aldehyde.

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Reduction to AminesLithium aluminum hydride reduces amides and nitriles to amines.Nitriles and 1 amides reduce to 1 amines.A 2 amide reduces to a 2 amine.A 3 amide reduces to a 3 amine.

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Organometallic ReagentsGrignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.=>

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Grignard Reagentsand NitrilesA Grignard reagent or organolithium reagent attacks the cyano group to yield an imine which is hydrolyzed to a ketone.=>

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Acid Chloride SynthesisUse thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2.Other products are gases.

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Acid Chloride Reactions (1)acidesteramide

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Acid Chloride Reactions (2)3 alcoholketone1 alcohol aldehyde

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Industrial Synthesis of Acetic AnhydrideFour billion pounds/year produced.Use high heat (750C) and triethyl phosphate catalyst to produce ketene.

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Lab Synthesisof AnhydridesReact acid chloride with carboxylic acid or carboxylate ion. Heat dicarboxylic acids to form cyclic anhydrides.

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Anhydride Reactionsacidesteramide

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Anhydride vs. Acid ChlorideAcetic anhydride is cheaper, gives a better yield than acetyl chloride.Use acetic formic anhydride to produce formate esters and formamides. Use cyclic anhydrides to produce a difunctional molecule.

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Synthesis of Esters

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Reactions of Estersacidesteramide1 alcohol

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LactonesFormation favored for five- and six-membered rings. For larger rings, remove water to shift equilibrium toward products

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Synthesis of Amides

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Reactions of Amidesacid and amineamine1 amine

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Lactam FormationFive- and six-membered rings can be formed by heating - and -amino acids. Smaller or larger rings do not form readily. =>

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-LactamsHighly reactive, 4-membered ring.Found in antibiotics isolated from fungi.

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Synthesis of Nitriles

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Reactions of Nitriles1 amine

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ThioestersMore reactive than esters because:-S-R is a better leaving group than -O-RResonance overlap is not as effective.

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Carbonic Acid EstersCO2 in water contains some H2CO3.Diesters are stable.Synthesized from phosgene.

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Urea and UrethanesUrea is the diamide of carbonic acid.Urethanes are esters of a monoamide of carbonic acid.

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PolymersPolycarbonates are long-chain esters of carbonic acid.Polyurethanes are formed when a diol reacts with a diisocyanate.

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End of Chapter 21

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