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Chapter 15: Functional Derivatives of Carboxylic Acids Sections 15.1-15.9 Chemistry 2060, Spring 2060, LSU 15-1 Sections Chapter 15: Aldehydes and Ketones 1. 2. 3. 4. 5. 6. 7. 8. 9. Introduction Structure and nomenclature Characteristic properties Reaction with water: hydrolysis Reaction with alcohols Reactions with ammonia and amines Interconversion of functional derivatives Esters with Grignard reagents Reduction Chemistry 2060, Spring 2060, LSU 15-2 Carboxyl Derivatives In this chapter, we study four classes of organic compounds • under the general formula of each is a drawing to help you see how it is related to the carboxyl group O RCCl An acid chlorid e -H2 O O RC-OH H-Cl Chemistry 2060, Spring 2060, LSU O O RCOCR' An acid an hydride -H2 O O O RC-OH H-OCR' O RCOR' An ester -H2 O O RC-OH H-OR' O RCNH2 An amid e -H2 O O RC-OH H-NH2 15-3 Acid Chlorides The functional group of an acid halide is an acyl group bonded to a halogen • the most widely used are the acid chlorides • to name, change the suffix -ic acid to -yl chloride O CH3 CCl Eth anoyl chlorid e (Acetyl chlorid e) Chemistry 2060, Spring 2060, LSU O CCl Ben zoyl ch loride 15-4 Acid Anhydrides The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom • the anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups) • to name, replace acid of the parent acid by anhydride O O CH3 COCCH3 Acetic anhydride Chemistry 2060, Spring 2060, LSU O O O O COC CH3 COC Benzoic anhydride Acetic benzoic anhydride 15-5 Acid Anhydrides A phosphoric acid anhydride contains two phosphoryl groups bonded to an oxygen atom • shown here are two phosphoric anhydrides • each is shown on the right as it would be ionized at pH 7.4, the pH of blood Chemistry 2060, Spring 2060, LSU O O HO-P-O-P-OH OH OH D iph os phoric acid (Pyrop hosph oric acid ) O O O-P-O-P-O O- OD iphosp hate ion (Pyroph os phate ion) O O O HO-P-O-P-O-P-OH OH OH OH Triph os phoric acid O O O O-P-O-P-O-P-O O- O- OTriphosph ate ion 15-6 Esters The functional group of an ester is an acyl group bonded to -OR or -OAr • name the alkyl or aryl group bonded to oxygen followed by the name of the acid • change the suffix -ic acid to -ate O O CH3 COCH2 CH3 Ethyl Ethan oate (Ethyl acetate) Chemistry 2060, Spring 2060, LSU O O O Diethyl bu tanedioate (Diethyl succinate) 15-7 Lactones Lactone: a cyclic ester • IUPAC: name the parent carboxylic acid, drop the suffix -ic acid, and add -olactone • the location of the oxygen atom on the carbon chain is commonly indicated by a Greek letter O 4-Butan olactone (A -lacton e) Chemistry 2060, Spring 2060, LSU 1 O 2 3 4 15-8 Phosphoric esters Phosphoric acid forms mono-, di-, and triesters • name by giving the name of the alkyl or aryl group(s) bonded to oxygen followed by the word phosphate • in more complex phosphate esters, it is common to name the organic molecule followed by phosphate O CH3 O-P-OH OCH3 D imethyl phosp hate Chemistry 2060, Spring 2060, LSU CHO H OH HO H H OH H OH O CH2 -O-P-OOD -Glucose 6-ph os phate CHO HO H3 C O CH2 O-P-OO- N Pyrid oxal p hosph ate 15-9 Amides The functional group of an amide is an acyl group bonded to a trivalent nitrogen • IUPAC: drop -ic acid from the name of the parent acid and add -amide • if the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by NO CH3 CNH2 A cetamide (a 1° amide) Chemistry 2060, Spring 2060, LSU O H CH3 C-N CH3 O CH3 H-C-N CH3 N-Methylacetamide N ,N-D imethyl(a 2° amid e) formamid e (DMF) (a 3° amide) 15-10 Lactam Lactam: a cyclic amide • name the parent carboxylic acid, drop the suffix -ic acid and add -lactam • the location of the nitrogen atom in the ring is commonly indicated by a Greek letter, , , etc. O 2 1 3 NH H3 C 3-Bu tanolactam A-lactam) O 2 3 4 1 NH 6-Hexanolactam An -lactone) 5 6 • 6-hexanolactam is an intermediate in the synthesis of nylon 6 (Section 17.5A) Chemistry 2060, Spring 2060, LSU 15-11 The Penicillins The penicillins are a family of -lactam antibiotics • one of the first discovered was penicillin G the penicillins differ in the group bonded to the acyl carbon H CH2 C O Penicillin G Chemistry 2060, Spring 2060, LSU N O H H S CH3 N CH3 COOH 15-12 The Penicillins • amoxicillin, a -lactam antibiotic HO O H H S HN NH2 N O COOH Chemistry 2060, Spring 2060, LSU 15-13 Cephalosporins The cephalosporins are also -lactam antibiotics O The cep halosporins differ in th e grou p bonded to th e carbonyl carbon... N H NH2 O H H N S ...and th e group b on ded to th is carbon of the six-memb ered rin g CH3 COOH Keflex (a -lactam antibiotic) Chemistry 2060, Spring 2060, LSU 15-14 Characteristic Reactions Nucleophilic acyl substitution: an additionelimination sequence resulting in substitution of one nucleophile for another • the reaction depends on having a suitable leaving group bonded to the acyl carbon, here indicated Lv - O + C R Lv Nu- R O O C C Nu Lv Tetrah edral carbonyl addition in termediate Chemistry 2060, Spring 2060, LSU R + Lv - Nu Su bstitu tion product 15-15 Characteristic Reactions • in the general reaction, we showed the nucleophile as an anion; this need not be the case • neutral molecules such as water, alcohols, ammonia, and amines can also serve as nucleophiles • in the general reaction, we showed the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group NR2 OR O OCR X Increasin g leaving ability Increasin g b asicity Chemistry 2060, Spring 2060, LSU 15-16 Characteristic Reactions • halide ion is the weakest base and the best leaving group; acid halides are the most reactive toward nucleophilic acyl substitution • amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution O RC-NH2 Amide O RC-OR' Ester O O RC-OCR Anhydride O RC-X Acid h alide Increasin g reactivity toward nucleophilic acyl su bstitu tion Chemistry 2060, Spring 2060, LSU 15-17 Hydrolysis - Acid Chlorides • low-molecular-weight acid chlorides react rapidly with water • higher molecular-weight acid chlorides are less soluble in water and react less readily O CH3 CCl + H2 O Chemistry 2060, Spring 2060, LSU O CH3 COH + HCl 15-18 Hydrolysis - Acid Anhydrides • low-molecular-weight acid anhydrides react readily with water to give two molecules of carboxylic acid • higher-molecular-weight acid anhydrides also react with water, but less readily O O CH3 COCCH3 + H2 O Chemistry 2060, Spring 2060, LSU O O CH3 COH + HOCCH3 15-19 Hydrolysis - Esters Esters are hydrolyzed only slowly, even in boiling water Hydrolysis becomes more rapid if they are heated with either aqueous acid or aqueous base Hydrolysis in aqueous acid is the reverse of Fischer esterification O R C OH + OCH3 + H2 O H R O + H C OH R C OH + CH3 OH H3 CO Tetrah edral carbonyl addition in termediate Chemistry 2060, Spring 2060, LSU 15-20 Hydrolysis - Esters Hydrolysis of an ester in aqueous base is often called saponification • each mole of ester hydrolyzed requires 1 mole of base; for this reason, ester hydrolysis in aqueous base is said to be base promoted O RCOCH3 + NaOH H2 O O - RCO Na + + CH3 OH • base-promoted ester hydrolysis involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse Chemistry 2060, Spring 2060, LSU 15-21 Hydrolysis - Esters • step 1: addition of hydroxide ion to the carbonyl carbon O R-C-OCH3 + OH O R-C OCH3 OH • step 2: collapse of the addition intermediate O R-C OCH3 O R-C OH + OCH3 OH • step 3: proton transfer completes the reaction O R-C O H Chemistry 2060, Spring 2060, LSU + OCH3 O R-C O + H-OCH3 15-22 Hydrolysis - Esters There are two major differences between acidcatalyzed and base-promoted ester hydrolysis 1. for acid-catalyzed hydrolysis, acid is required in only catalytic amounts; for base-promoted hydrolysis, base is required in equimolar amounts 2. hydrolysis of an ester in aqueous acid is reversible; base-promoted hydrolysis is irreversible Chemistry 2060, Spring 2060, LSU 15-23 Hydrolysis - Amides Hydrolysis of an amide requires much more vigorous conditions than hydrolysis of an ester • hydrolysis in aqueous acid requires 1 mole of acid for each mole of amide • the products are a carboxylic acid and an ammonium or an amine salt O O NH2 + H2 O + HCl Ph 2-Phenylbutan amide Chemistry 2060, Spring 2060, LSU H2 O heat + + NH OH 4 Cl Ph 2-Phen ylb utanoic acid 15-24 Hydrolysis - Amides • hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide • the products are a carboxylate salt and an amine O CH3 CNH + N-Phenylethanamide (N-Phenylacetamide, Acetanilide) Chemistry 2060, Spring 2060, LSU NaOH H2 O heat O + CH3 CO Na + H2 N Sodiu m acetate Aniline 15-25 Hydrolysis A summary O R-C-Cl + H2 O O O R-C-O-C-R + H2 O O R-C-OR' + H2 O O R-C-NH2 + H2 O Chemistry 2060, Spring 2060, LSU NaOH H 2 SO4 NaOH HCl O R-C-OH + HCl O O R-C-OH + HO-C-R O + R-C-O Na + R'OH O R-C-OH + R'OH O R-C-O-Na+ + NH3 O R-C-OH + NH4 + Cl15-26 Reaction with Alcohols Acid chlorides react with alcohols to give an ester and HCl O Cl + HO Butanoyl chloride Cyclohexanol O O + HCl Cyclohexyl butanoate Chemistry 2060, Spring 2060, LSU 15-27 Reaction with Alcohols Acid anhydrides react with alcohols to give 1 mole of ester and 1 mole of carboxylic acid O O O CH3 COCCH3 + HOCH2 CH3 Acetic anhydride Ethan ol O CH3 COCH2 CH3 + CH3 COH Ethyl acetate Acetic acid • aspirin is prepared by the following reaction: COOH OH O O + CH3 COCCH3 2-Hydroxyben zoic Acetic acid anh yd rid e (Salicylic acid) Chemistry 2060, Spring 2060, LSU COOH O O Acetylsalicylic acid (Asp irin ) + CH3 COOH Acetic acid 15-28 Reaction with Alcohols Esters undergo an exchange reaction called transesterification • the exchange is acid catalyzed • the original -OR group is exchanged for a new -OR group O Ph HO OCH3 + O H2 SO4 OH Ph O Ph + 2 CH OH 3 O O Methyl benzoate Chemistry 2060, Spring 2060, LSU 1,2-Ethanediol (Ethylene glycol) A dies ter of eth ylen e glycol) 15-29 Reaction with Alcohols Amides to not react with alcohols under any conditions Summary of reactions with alcohols O R-C-Cl + HOR" O R-C-OR" + HCl O O R-C-O-C-R + R"OH O O R-C-OR" + HO-C-R O H2 SO4 R-C-OR' + R"OH O R-C-OR" + R'OH O R-C-NH2 + R"OH Chemistry 2060, Spring 2060, LSU N o Reaction 15-30 Reaction with NH3 and Amines Acid halides react with ammonia, 1° amines, and 2° amines to form amides • 2 moles of the amine are required per mole of acid chloride; one to form the amide and one to neutralize the HCl formed O Cl + 2 NH3 Hexanoyl Ammonia chloride Chemistry 2060, Spring 2060, LSU O + NH2 + NH4 Cl Hexanamide Ammonium chloride 15-31 Reaction with NH3 and Amines Acid anhydrides react with ammonia, and with 1° and 2° amines to form amides • 2 moles of ammonia or amine are required; one to form the amide and one to neutralize the carboxylic acid byproduct • here the reaction is broken into two steps O O CH3 COCCH3 + NH3 O CH3 COH + NH3 O O CH3 COCCH3 Chemistry 2060, Spring 2060, LSU + 2 NH3 O O CH3 CNH2 + CH3 COH O CH3 CO- NH4 + O O CH3 CNH2 + CH3 CO- NH4 + 15-32 Reaction with NH3 and Amines Esters react with ammonia, and with 1° and 2° amines to form amides • esters are less reactive than either acid halides or acid anhydrides O Ph O O Ethyl phenylacetate + N H3 Ph N H2 + HO Phenyl acetamide Ethanol Amides do not react with ammonia, or with 1° or 2° amines Chemistry 2060, Spring 2060, LSU 15-33 Reaction with NH3 & Amines Summary O R-C-Cl + 2 NH3 O O R-C-O-C-R + 2 NH3 O R-C-OR' + NH3 O R-C-NH2 + NH4 + ClO O R-C-NH2 + R-C-O-NH4 + O R-C-NH2 + R'OH O R-C-NH2 N o reaction w ith ammonia or amines Chemistry 2060, Spring 2060, LSU 15-34 Interconversion interconversion of functional groups Chemistry 2060, Spring 2060, LSU 15-35 Esters with Grignard Reagents a formic ester with 2 moles of Grignard reagent followed by hydrolysis gives a 2° alcohol O HCOCH3 + 2RMgX An es ter of formic acid OH magnes ium H O, HCl 2 alkoxide salt HC-R + CH3 OH R A 2° alcohol reaction of an ester other than a formate gives a 3° alcohol O CH3 COCH3 + 2 RMgX An es ter of any acid oth er th an formic acid Chemistry 2060, Spring 2060, LSU magnes ium H O, HCl 2 alkoxide salt OH CH3 C-R + CH3 OH R A 3° alcohol 15-36 Esters with Grignard Reagents • Steps 1 and 2 1 O 2 CH3 -C-OCH3 + R MgX 1 O - [ MgX] + O CH3 -C OCH3 R 2 A magnes ium s alt + CH3 O - [ MgX] + CH3 -C R A ketone • Steps 3 and 4 4 - + 3 3 O CH3 -C + R MgX CH3 -C-R R A ketone R Magn esium salt Chemistry 2060, Spring 2060, LSU O [MgX] 4 H O H, HCl OH CH3 -C-R R A 3° alcohol 15-37 Reduction • esters are reduced by LiAlH4 to two alcohols • the alcohol derived from the carbonyl group is primary O Ph OCH3 1 . LiAlH4 , e t he r 2 . H2 O, HCl Methyl 2-phenylpropanoate Ph OH + CH3 OH 2-Phenyl-1propanol Methanol • NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones O O OEt Chemistry 2060, Spring 2060, LSU NaBH4 Et OH OH O OEt 15-38 Reduction • LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide O NH2 Octanamide 1 . LiAlH4 2 . H2 O NH2 1-Octanamine O NMe2 1 . LiAlH4 2 . H2 O N,N -D imethylben zamide Chemistry 2060, Spring 2060, LSU NMe2 N ,N-D imeth ylb enzylamine 15-39 Some Interconversions • from Example 15.7 O Ph SOCl2 CH3 OH, H2 SO4 OH Fischer Phenylacetic esterification acid 1 . LiAlH4 2 . H2 O O O Ph NH3 Ph OCH3 (a) 1 . LiAlH4 2 . H2 O Ph OH (d ) Chemistry 2060, Spring 2060, LSU NH3 ( 2 eq) CH3 OH O Ph Cl NH2 (b ) 1 . LiAlH4 2 . H2 O Ph NH2 (c) 15-40