Chapter 21 Carboxylic Acid Derivatives Organic Chemistry, 5th Edition L. G. Wade, Jr. Chapter 21 Carboxylic Acid Derivatives Jo Blackburn Richland College, Dallas, TX Dallas County Community College District ã 2003, Prentice Hall

Acid Derivatives All can be converted to the carboxylic acid by acidic or basic hydrolysis. Esters and amides common in nature. => Chapter 21

2-methylpropyl ethanoate Naming Esters Esters are named as alkyl carboxylates. Alkyl from the alcohol, carboxylate from the carboxylic acid precursor. isobutyl acetate 2-methylpropyl ethanoate benzyl formate benzyl methanoate => Chapter 21

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 => Chapter 21

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. Bond angles around N are close to 120. => Chapter 21

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). => Chapter 21

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 => Chapter 21

4-aminopentanoic acid lactam 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 => Chapter 21

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). => Chapter 21

Naming Nitriles For IUPAC names, add -nitrile to the alkane name. Common names come from the carboxylic acid. Replace -ic acid with -onitrile. 5-bromohexanenitrile -bromocapronitrile Cyclohexanecarbonitrile => Chapter 21

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 Chapter 21

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. => Chapter 21

1,2-benzenedicarboxylic anhydride 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 => Chapter 21

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 => Chapter 21

Boiling Points Even 3 amides have strong attractions. => Chapter 21

Melting Points Amides have very high melting points. Melting points increase with increasing number of N-H bonds. m.p. -61C m.p. 28C m.p. 79C => Chapter 21

Solubility Acid 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 acetate Dimethylformamide (DMF) Acetonitrile => Chapter 21

IR Spectroscopy => => Chapter 21

1H NMR Spectroscopy => Chapter 21

13C NMR Spectroscopy => Chapter 21

Interconversion of Acid Derivatives Nucleophile adds to the carbonyl to form a tetrahedral intermediate. Leaving group leaves and C=O regenerates. => Chapter 21

Reactivity Reactivity decreases as leaving group becomes more basic. => Chapter 21

Interconversion of Derivatives More reactive derivatives can be converted to less reactive derivatives. => Chapter 21

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. => Chapter 21

Acid Chloride to Ester Alcohol attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is abstracted. => Chapter 21

Acid Chloride to Amide Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide => Chapter 21

Anhydride to Ester Alcohol attacks one C=O of anhydride. Tetrahedral intermediate forms. Carboxylate ion leaves, C=O is restored, H+ is abstracted. => Chapter 21

Anhydride to Amide Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide => Chapter 21

Ester to Amide Nucleophile must be NH3 or 1 amine. Prolonged heating required. Surprise! => Chapter 21

Leaving Groups A strong base is not usually a leaving group unless it’s in an exothermic step. => Chapter 21

Transesterification One alkoxy group can be replaced by another with acid or base catalyst. Use large excess of preferred alcohol. => Chapter 21

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. => Chapter 21

Acid Hydrolysis of Esters Reverse of Fischer esterification. Reaches equilibrium. Use a large excess of water. => Chapter 21

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. => Chapter 21

Hydrolysis of Amides Prolonged heating in 6 M HCl or 40% aqueous NaOH is required. => Chapter 21

Hydrolysis of Nitriles Under mild conditions, nitriles hydrolyze to an amide. Heating with aqueous acid or base will hydrolyze a nitrile to an acid. => Chapter 21

Reduction to Alcohols Lithium aluminum hydride reduces acids, acid chlorides, and esters to primary alcohols. => Chapter 21

Reduction to Aldehydes Acid chlorides will react with a weaker reducing agent to yield an aldehyde. => Chapter 21

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. => Chapter 21

Organometallic Reagents Grignard reagents and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation. => Chapter 21

Grignard Reagents and Nitriles A Grignard reagent or organolithium reagent attacks the cyano group to yield an imine which is hydrolyzed to a ketone. => Chapter 21

Acid Chloride Synthesis Use thionyl chloride, SOCl2, or oxalyl chloride, (COCl)2. Other products are gases. => Chapter 21

Acid Chloride Reactions (1) ester amide acid anhydride => Chapter 21

Acid Chloride Reactions (2) 3° alcohol ketone 1° alcohol aldehyde acylbenzene => Chapter 21

Industrial Synthesis of Acetic Anhydride Four billion pounds/year produced. Use high heat (750°C) and triethyl phosphate catalyst to produce ketene. => Chapter 21

Lab Synthesis of Anhydrides React acid chloride with carboxylic acid or carboxylate ion. Heat dicarboxylic acids to form cyclic anhydrides. => Chapter 21

Anhydride Reactions acid ester amide => acylbenzene Chapter 21

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. => Chapter 21

Synthesis of Esters acid acid chloride acid anhydride => methyl ester => Chapter 21

Reactions of Esters acid ester amide 1° alcohol 3° alcohol => Chapter 21

Lactones Formation favored for five- and six-membered rings. For larger rings, remove water to shift equilibrium toward products => Chapter 21

Synthesis of Amides acid acid chloride acid anhydride ester nitrile => Chapter 21

Reactions of Amides acid and amine amine 1° amine nitrile => Chapter 21

Lactam Formation Five- and six-membered rings can be formed by heating - and -amino acids. Smaller or larger rings do not form readily. => Chapter 21

-Lactams Highly reactive, 4-membered ring. Found in antibiotics isolated from fungi. Amide  ester !! => Chapter 21

Synthesis of Nitriles 1° amide alkyl halide diazonium salt aldehyde or ketone cyanohydrin => Chapter 21

Reactions of Nitriles amide acid 1° amine ketone => Chapter 21

Thioesters More reactive than esters because: -S-R is a better leaving group than -O-R Resonance overlap is not as effective. => Chapter 21

Carbonic Acid Esters CO2 in water contains some H2CO3. Diesters are stable. Synthesized from phosgene. => Chapter 21

Urea and Urethanes Urea is the diamide of carbonic acid. Urethanes are esters of a monoamide of carbonic acid. => Chapter 21

Polymers Polycarbonates are long-chain esters of carbonic acid. Polyurethanes are formed when a diol reacts with a diisocyanate. => Chapter 21

End of Chapter 21 Chapter 21