Derivatives of Carboxylic Acid acid chloride carboxylate nitrile amide acid anhydride ester Nomenclature of Acid Halides IUPAC: alkanoic acid → alkanoyl halide Common: alkanic acid → alkanyl halide I: 3-aminopropanoyl chloride I: 4-nitropentanoyl chloride c: b-aminopropionyl chloride c: g-nitrovaleryl chloride I: hexanedioyl chloride c: adipoyl chloride Rings: (IUPAC only): ringcarbonyl halide I: benzenecarbonyl bromide I: 3-cylcopentenecarbonyl chloride c: benzoyl bromide Nomenclature of Acid Anhydrides Acid anhydrides are prepared by dehydrating carboxylic acids acetic anhydride ethanoic acid ethanoic anhydride I: benzenecarboxylic anhydride I: butanedioic acid I: butanedioic anhydride c: benzoic andhydride c: succinic acid c: succinic anhydride Some unsymmetrical anhydrides I: ethanoic methanoic I: benzoic methanoic anhydride anhydride I: cis-butenedioic c: benzoic formic anhydride anhydride c: acetic formic anhydride Nomenclature of Esters Esters occur when carboxylic acids react with alcohols I: phenyl methanoate I: t-butyl benzenecarboxylate I: methyl ethanoate c: phenyl formate c: methyl acetate c: t-butyl benzoate I: isobutyl I: cyclobutyl 2- I: dimethyl ethanedioate cyclobutanecarboxylate methylpropanoate c: cyclobutyl a- c: dimethyl oxalate c: none methylpropionate Cyclic Esters Reaction 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. 4-hydroxy-2-methylpentanoic acid lactone -methyl- -valerolactone Amides Product of the reaction of a carboxylic acid and ammonia or an amine. Not basic because the lone pair on nitrogen is delocalized by resonance. Classes of Amides 1 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). => Naming Amides For 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. N-ethyl-N,2-dimethylpropanamide N-ethyl-N-methylisobutyramide Cyclic Amides Reaction 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. 4-aminopentanoic acid lactam -valerolactam Relative Reactivity of Carbonyl Carbons Nucleophiles (electron donors), like OH-, bond with the sp2 hybridized carbonyl carbon. The order of reactivity is shown. Nitriles -C≡N 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). Naming Nitriles For IUPAC names, add -nitrile to the alkane name. Common names come from the carboxylic acid. Replace -ic acid with - onitrile. Cyclohexanecarbonitrile 5-bromohexanenitrile => -bromocapronitrile Acid Halides More reactive than acids; the halogen withdraws e- density from carbonyl. Named by replacing -ic acid with -yl halide. 3-bromobutanoyl bromide -bromobutyryl bromide benzoyl chloride => Acid Anhydrides Two 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. Naming Anhydrides The 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 anhydride acetic anhydride 1,2-benzenedicarboxylic anhydride phthalic anhydride Multifunctional Compounds The functional group with the highest priority determines the parent name. Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne. ethyl o-cyanobenzoate Boiling Points Even 3º amides have strong attractions. Melting Points Amides have very high melting points. Melting points increase with increasing number of N-H bonds. m.p. -61ºC m.p. 28ºC m.p. 79ºC Solubility Acid chlorides and anhydrides are too reactive to be used with water or alcohol. Esters, 3º amides, and nitriles are good polar aprotic solvents. Solvents commonly used in organic reactions: Ethyl acetate Dimethylformamide (DMF) Acetonitrile => IR Spectroscopy 1H NMR Spectroscopy 13C NMR Spectroscopy Interconversion of Acid Derivatives Nucleophile adds to the carbonyl to form a tetrahedral intermediate. Leaving group leaves and C=O regenerates. Reactivity Reactivity decreases as leaving group becomes more basic. Interconversion of Derivatives More reactive derivatives can be converted to less reactive derivatives. Acid Chloride to Anhydride Acid or carboxylate ion attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is abstracted. => Acid Chloride to Ester Alcohol attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is abstracted. => Acid Chloride to Amide Ammonia yields a 1º amide A 1º amine yields a 2º amide A 2º amine yields a 3º amide Anhydride to Ester Alcohol attacks one C=O of anhydride. Tetrahedral intermediate forms. Carboxylate ion leaves, C=O is restored, H+ is abstracted. => Anhydride to Amide Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide Ester to Amide Nucleophile must be NH3 or 1 amine. Prolonged heating required. Leaving Groups A strong base is not usually a leaving group unless it’s in an exothermic step. Transesterification One alkoxy group can be replaced by another with acid or base catalyst. Use large excess of preferred alcohol. Hydrolysis of Acid Chlorides and Anhydrides Hydrolysis occurs quickly, even in moist air with no acid or base catalyst. Reagents must be protected from moisture. Acid Hydrolysis of Esters Reverse of Fischer esterification. Reaches equilibrium. Use a large excess of water. Saponification Base-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. => Hydrolysis of Amides Prolonged heating in 6 M HCl or 40% aqueous NaOH is required. Hydrolysis of Nitriles Under mild conditions, nitriles hydrolyze to an amide. Heating with aqueous acid or base will hydrolyze a nitrile to an acid. Reduction to Alcohols Lithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols. Reduction to Aldehydes Acid chlorides will react with a weaker reducing agent to yield an aldehyde. Reduction to Amines Lithium 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. Organometallic Reagents Grignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation. Grignard Reagents and Nitriles A Grignard reagent or organolithium reagent attacks the cyano group to yield an imine which is hydrolyzed to a ketone. Acid Chloride Synthesis Use thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2. Other products are gases. Acid Chloride Reactions (1) acid ester amide acid anhydride Acid Chloride Reactions (2) 3° alcohol ketone 1° alcohol aldehyde acylbenzene Industrial Synthesis of Acetic Anhydride Four billion pounds/year produced. Use high heat (750°C) and triethyl phosphate catalyst to produce ketene. Lab Synthesis of Anhydrides React acid chloride with carboxylic acid or carboxylate ion. Heat dicarboxylic acids to form cyclic anhydrides. Anhydride Reactions Anhydride vs. Acid Chloride Acetic 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. Synthesis of Esters Reactions of Esters Lactones Formation favored for five- and six- membered rings. For larger rings, remove water to shift equilibrium toward products Synthesis of Amides Reactions of Amides acid and amine amine 1° amine nitrile Lactam Formation Five- and six-membered rings can be formed by heating - and -amino acids. Smaller or larger rings do not form readily. -Lactams Highly reactive, 4-membered ring. Found in antibiotics isolated from fungi. Synthesis of Nitriles Reactions of Nitriles Thioesters More reactive than esters because: ◦ -S-R is a better leaving group than -O-R ◦ Resonance overlap is not as effective. Carbonic Acid Esters CO2 in water contains some H2CO3. Diesters are stable. Synthesized from phosgene. Urea and Urethanes Urea is the diamide of carbonic acid. Urethanes are esters of a monoamide of carbonic acid. Polymers Polycarbonates are long-chain esters of carbonic acid. Polyurethanes are formed when a diol reacts with a diisocyanate. .