Functional Derivatives Of Carboxylic Acids. Chapter 4

Chapter 4 Functional Derivatives of Carboxylic Acids 1 1 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 2 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 Ethanoyl chlorid e (Acetyl chlorid e) O CCl Ben zoyl ch loride 3 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 4 4 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 CH3 COCH2 CH3 Ethyl Ethan oate (Eth yl acetate) O O O O D iethyl bu tanedioate (D iethyl succinate) 5 5 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   6 6 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 CH 3 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) 7 7 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 6 NH   6-Hexanolactam An -lactone) 5 8 8 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 9 9 The Penicillins HO O  amoxicillin, a -lactam antibiotics H H S HN NH2 N O COOH  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) 10 10 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 R + C Lv Nu- R O O C C Nu Lv Tetrah edral carbonyl addition in termediate R + Nu Lv - Su bstitu tion product 11 11 Characteristic Reactions  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 O NR2 OR OCR X Increasin g leaving ability Increasin g b asicity O RC-NH2 Amide O RC-OR' Ester O O RC-OCR Anhydride O RC-X A cid h alide Increasin g reactivity tow ard n ucleoph ilic acyl su bstitu tion 12 12 Reactivity of Acid Derivatives 13 13 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 14 14 Synthesis of Acid Chlorides  The best reagent for converting carboxylic acids to acid chlorides are thionyl chloride (SOCl2) and oxalyl chloride (COCl2) because they form gaseous by-products that do not contaminate the product.  Thionyl chloride reaction produces SO2 while the oxalyl chloride reaction produces HCl, CO, and CO2 (all gaseous). 15 15 Mechanism of Acid Chloride Formation Step 1 Step 2 Step 3 16 16 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 17 17 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 OCH 3 + H2 O OH + H R C H3 CO O + H OH R C OH + CH3 OH Tetrah edral carbonyl addition in termediate 18 18 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 19 19 Hydrolysis - Esters  step 1: addition of hydroxide ion to the carbonyl carbon O R-C-OCH3 + OH O R-C OCH 3 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 20 20 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; basepromoted hydrolysis is irreversible 21 21 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 NH2 + Ph 2-Phenylbutan amide H2 O + HCl H2 O heat O + - OH + NH4 Cl Ph 2-Phen ylb utanoic acid 22 22 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 + NaOH N-Phenylethanamide (N-Phenylacetamide, Acetanilide) H2 O heat O + CH3 CO Na + H2 N Sodiu m acetate Aniline 23 23 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 NaOH H2 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 + Cl- 24 24 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 25 25 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 26 26 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 H 2 SO4 OH Ph O Ph + 2 CH OH 3 O O Meth yl benzoate 1,2-Ethan ediol (Ethylene glycol) A dies ter of eth ylen e glycol) 27 27 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 H 2 SO4 R-C-OR' + R"OH O R-C-OR" + R'OH O R-C-NH2 + R"OH N o Reaction 28 28 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 NH 3 Hexan oyl A mmonia ch loride O + - NH 2 + NH4 Cl Hexan amid e Ammonium chloride 29 29 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 CH 3 COH + NH3 O O CH3 COCCH3 + 2 NH3 O O CH 3 CNH2 + CH 3 COH O + CH 3 CO NH4 O O + CH 3 CNH2 + CH 3 CO NH4 30 30 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 31 31 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 Cl O 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 32 32 Interconversion  interconversion of functional groups 33 33 Esters with Grignard Reagents  a formic ester with 2 moles of Grignard gives a 2° alcohol O HCOCH3 + 2 RMgX 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 34 34 Esters with Grignard Reagents 1 O  Steps 1 and 2 CH3 -C-OCH3 + R MgX 1  Steps 3 and 4 2 O - [ MgX] + O CH3 -C OCH3 R 2 A magnes ium s alt CH3 -C + CH3 O - [ MgX] + R A ketone 4 - + 3 3 O CH3 -C + R MgX CH3 -C-R R A ketone R Magn esium salt O [MgX] 4 H O H, HCl OH CH3 -C-R R A 3° alcohol 35 35 Reduction  esters are reduced by LiAlH4 to two alcohols  the alcohol derived from the carbonyl group is primary O Ph OCH3 1 . LiA lH 4 , 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 36 36 Reduction  LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide O NH 2 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 37 37 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) 38 38