Chapter 22 Carboxylic Acid Derivatives Organic Chemistry, 6th Edition L. G. Wade, Jr. Chapter 22 Carboxylic Acid Derivatives http://www.study-organic-chemistry.com/

Carboxylic Acid Derivatives STRUCTURE AND PROPERTIES PREPARATIONS OF CARBOXYLIC ACID DERIVATIVES REACTIONS ENOLATE REACTIONS

Sec 1 Acid Derivatives All can be converted to the carboxylic acid by acidic or basic hydrolysis. Esters and amides common in nature.

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

1,2-benzenedicarboxylic anhydride 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

2-methylpropyl ethanoate Naming Esters Esters are named as alkyl carboxylates. Alkyl from the alcohol, carboxylate from the carboxylic acid precursor. ethanol ethyl alcohol ethanoic acid acetic acid ethyl ethanoate ethyl acetate Name These isobutyl acetate 2-methylpropyl ethanoate benzyl formate benzyl methanoate

Cyclic Esters Reaction of —OH and —COOH on same molecule produces a cyclic ester called lactone. To name, add the word lactone to the IUPAC acid name or replace the -ic acid of common name with -olactone. 7

(g-butyrolactone) g －丁内酯 (d-valerolactone) d －戊内酯 (g-valerolactone) g －戊内酯

Amides Not basic because the lone pair on nitrogen is delocalized by resonance. The C—N bond has double-bond character. Classes of Amides 1 amide ; 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). Bond angles around N are close to 120.

Protonation of Amides Under acidic conditions, the double-bonded oxygen will get protonated. 10

N-ethyl-N,2-dimethylpropanamide 4-aminopentanoic acid lactam 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. 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. N-ethyl-N,2-dimethylpropanamide N-ethyl-N-methylisobutyramide 4-aminopentanoic acid lactam -valerolactam

丙酰胺 N-甲基乙酰胺 N,N－二甲基甲酰胺

(g-butyrolactam) 丁内酰胺 (d-valerolactam) d-戊内酰胺 (g-valerolactam) g-戊内酰胺 Succinimide 丁二酰亚胺 Maleimide 丁烯二酰亚胺 Phthalimide 邻苯二甲酰亚胺

Boiling Points

Intermolecular Forces of Amides Even 3 amides have strong attractions. 15

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

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

Sec 2 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.

1. Acid Chloride 羧酸衍生物的三解反应 水解、醇解、氨解 w/ R2CuLi or 2 w/ LiAlH(t-OBu)3 w/ LiAlH4

Acid Chloride Reactions (1) ester amide acid anhydride

Acid Chloride Reactions (2) 3° alcohol ketone 1° alcohol aldehyde acylbenzene AlCl3

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 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide

2. Anhydrides ( low T) w/ Na2Fe(CO)4 w/ LiAlH4

Anhydride Reactions acid ester amide acylbenzene AlCl3

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.

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

3. Esters Prepared by The nucleophilic substitution of acid chlorides or acid anhydrides with alcohols, The nucleophilic substitution of carboxylic acids with alcohol in the presence of a catalytic amount of mineral acid, The SN2 nucleophilic substitution of an alkyl halide with a carboxylate ion, The reaction of carboxylic acids with diazomethane to give methyl esters.

Synthesis of Esters acid acid chloride acid anhydride methyl ester

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

Polyesters Dacron® thread Mylar® tape Glyptal resin PET bottles

Reactions of Esters ( low T) w/ DIBAH; LiAlH2(i-Bu)2 w/ LiAlH4

Reactions of Esters acid ester amide 1° alcohol 3° alcohol

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

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

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

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.

4. Amides Synthesis of Amides acid acid chloride acid anhydride ester nitrile

Reactions of Amides acid and amine amine 1° amine nitrile

Hofmann 重排

Questions

缩二脲反应

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. Amide  ester !!

Polyamides Nylon 6.6

Sec 3 羧酸衍生物的还原

Summary of Reactions of Derivatives of Acids Derivative H2O ROH NH3 [H] RMgX Acid Chloride acid ester amide (ald)/alc (ket)/alc Anhydride acid ester amide (ald)/alc (ket)/alc Ester acid ester amide (ald)/alc (ket)/alc Amide acid (NR) (NR) amine (NR) Nitrile amide ester (NR) amine/ket/acid (ald)

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.

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.

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

Sec 4 ENOLATE REACTIONS Enolates Alkylations Claisen condensation

Enolate ion formation

乙酰乙酸乙酯的性质 互变异构现象 一般性质： 酮式： 烯 醇式： 羰基试剂 FeCl3显色 氯代 Na 酯水解 溴水褪色 酮式： 烯 醇式： 羰基试剂 FeCl3显色 氯代 Na 酯水解 溴水褪色 碘仿反应？XXXXX

Alkylations

Claisen Condensation缩合

酸式、酮式分解

－负碳的反应

三乙合成应用

The End Of Chap 22 P762: 22-19(a-f)