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William H. Brown Thomas Poon www.wiley.com/college/brown Chapter Fifteen Functional Derivatives of Carboxylic Acids 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 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 15-2 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) O CCl Ben zoyl ch loride 15-3 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 O O O O COC CH3 COC Benzoic anhydride Acetic benzoic anhydride 15-4 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. 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 15-5 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) O O O Diethyl bu tanedioate (Diethyl succinate) 15-6 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) 1 O 2 3 4 15-7 Phosphoric esters • Phosphoric acid forms mono-, di-, and triesters. • Name by giving the name of the alkyl or aryl group(s) bonded to oxygen(s) 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 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 15-8 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 N-. O CH3 CNH2 A cetamide (a 1° amide) 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) 15-9 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. 2 1O 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). 15-10 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 N O H H S CH3 N CH3 COOH 15-11 The Penicillins • Amoxicillin, a -lactam antibiotic. HO O H H S HN NH2 N O COOH 15-12 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) 15-13 Characteristic Reactions • Nucleophilic acyl substitution: an addition-elimination 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 R + Lv - Nu Su bstitu tion product 15-14 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. 15-15 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. 15-16 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 O CH3 COH + HCl 15-17 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 O O CH3 COH + HOCCH3 15-18 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 15-19 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. 15-20 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 + OCH3 O R-C O + H-OCH3 15-21 Hydrolysis - Esters • There are two major differences between acid-catalyzed 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. 15-22 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 H2 O heat + - OH + NH4 Cl Ph 2-Phen ylb utanoic acid 15-23 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) NaOH H2 O heat O + CH3 CO Na + H2 N Sodiu m acetate Aniline 15-24 Hydrolysis • Summary of reactions with water (hydrolysis) 15-25 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 15-26 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) COOH O O Acetylsalicylic acid (Asp irin ) + CH3 COOH Acetic acid 15-27 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 1,2-Ethanediol (Ethylene glycol) A dies ter of eth ylen e glycol) 15-28 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 N o Reaction 15-29 Reaction with NH 3 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 O + NH2 + NH4 Cl Hexanamide Ammonium chloride 15-30 Reaction with NH 3 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 + 2 NH3 O O CH3 CNH2 + CH3 COH O CH3 CO- NH4 + O O CH3 CNH2 + CH3 CO- NH4 + 15-31 Reaction with NH 3 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. 15-32 Reaction with NH 3 & Amines • Summary of reaction with ammonia and amines. 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 15-33 Interconversion • FIGURE 15.1 Interconversion of functional groups. 15-34 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 magnes ium H O, HCl 2 alkoxide salt OH CH3 C-R + CH3 OH R A 3° alcohol 15-35 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 • Steps 3 and 4 4 3 3 O CH3 -C + R MgX O [MgX] CH3 -C-R R A ketone R Magn esium salt - + + CH3 O - [ MgX] + CH3 -C R A ketone 4 H O H, HCl OH CH3 -C-R R A 3° alcohol 15-36 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 NaBH4 Et OH OH O OEt 15-37 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 NMe2 N ,N-D imeth ylb enzylamine 15-38 Some Interconversions • from Example 15.7 O Ph SOCl2 CH3 OH, H2 SO4 OH Fischer Phenylacetic esterification acid 1 . LiAlH4 2 . H2 O NH3 ( 2 eq) CH3 OH O Ph Cl O O Ph NH3 Ph OCH3 (a) 1 . LiAlH4 2 . H2 O Ph OH (d ) NH2 (b ) 1 . LiAlH4 2 . H2 O Ph NH2 (c) 15-39 Functional Derivatives of Carboxylic Acids End Chapter 15 15-40