Chapter 17

 Carboxylic Acids and Their Derivatives Nucleophilic Addition–Elimination at the Acyl Carbon

Ch. 17 - 1 1. Introduction  Carboxylic Acid Derivatives

O O O O

R OH R Cl R O R' carboxylic acid acid chloride acid anhydride

O O

R OR' R NR'2 ester amide

Ch. 17 - 2 2. Nomenclature and Physical Properties  Nomenclature of Carboxylic Acids and Derivatives ● Rules  Carboxylic acid as parent (suffix): ending with “–oic acid”  Carboxylate as parent (suffix): ending with “–oate”

Ch. 17 - 3  Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word “anhydride”  Acid chloride as parent (suffix): ending with “–oyl chloride”  Ester as parent (suffix): ending with “–oate”  Amide as parent (suffix): ending with “amide”  Nitrile as parent (suffix): ending with “nitrile”

Ch. 17 - 4  Examples

O O

OH OCH3 Ethanoic acid Methyl propanoate (acetic acid)

O O O

O NH'2 Ethanoic anhydride Ethanamide (acetic anhydride)

Ch. 17 - 5  Examples

O

O Cl

O Na Sodium benzoate Benzoyl chloride

H3C C N Ethanenitrile

Ch. 17 - 6 2C. Acidity of Carboxylic Acids

O H R O

pKa ~ 4-5  Compare

● pKa of H2O ~ 16

● pKa of H2CO3 ~ 7

● pKa of HF ~ 3 Ch. 17 - 7  When comparing acidity of organic compounds, we compare the stability of their conjugate bases. The more stable the conjugate base, the stronger the acid

CH3COOH CH3CH2OH

pKa 4.75 16

Ch. 17 - 8 O O + + H2O + H3O CH3 O H CH3 O

A1 B1

+ CH3CH2 O H + H2O CH3CH2 O + H3O

A2 B2

Ch. 17 - 9  The conjugate base B1 is more stable (the anion is more delocalized) than B2 due to resonance stabilization

O O O

CH3 O CH3 O CH3 O

● Thus, A1 is a stronger acid than A2

Ch. 17 - 10  Acidity of Carboxylic Acids, Phenols and Alcohols

H H O O O H O

pKa = 4.20 pKa = ~ 10 pKa = ~ 17

Ch. 17 - 11  Acidity of Carboxylic Acids, Phenols and Alcohols O O H O O + H2O + + H3O

O

O

Ch. 17 - 12  Acidity of Carboxylic Acids, Phenols and Alcohols

O O H + + H3O

+ H2O

O O O

Ch. 17 - 13  Acidity of Carboxylic Acids, Phenols and Alcohols

O O H + + H2O + H3O

(NO resonance stabilization)

Ch. 17 - 14 Question  If you are given three unknown samples: one is benzoic acid; one is phenol; and one is cyclohexyl alcohol; how would you distinguish them by simple chemical tests? ● Recall: acidity of H H O O O H O > >

Ch. 17 - 15 O O H + Na OH + H2O R O R O Na (soluable in water)

O O Na H + NaOH

(soluble in water)

O H + NaOH No Reaction

(immiscible with H O) 2 Ch. 17 - 16 O O H O O Na + NaHCO3

+ CO2(g) + H2O (gas evolved)

O H + NaHCO3 No Reaction

O H + NaHCO3 No Reaction

Ch. 17 - 17 O O O O Cl Cl Cl H > > > Cl OH Cl OH H OH H OH Cl H H H pKa 0.70 1.48 2.86 4.76

 Stability of conjugate bases

O O O O Cl Cl Cl H

Cl > O > Cl O > H O > H O Cl H H H

Ch. 17 - 18 O Cl O >

> OH OH Cl 2-Chlorobutanoic acid 3-Chlorobutanoic acid (pKa = 2.85) (pKa = 4.05)

O Cl OH

4-Chlorobutanoic acid (pKa = 4.50) Ch. 17 - 19 2D. Dicarboxylic Acids

pKa (at 25oC) Common o Structure Name mp ( C) pK1 pK2

HO2C CO2H Oxalic acid 189 dec 1.2 4.2

HO2CCH2CO2H Malonic acid 136 2.9 5.7

HO2C(CH2)4CO2H Adipic acid 153 4.4 5.6

CO2H Phthalic acid 206-208 dec 2.9 5.4

CO2H Ch. 17 - 20 2J. Spectroscopic Properties of Acyl Compounds  IR Spectra ● The C=O stretching band occurs at different frequencies for acids, esters, and amides, and its precise location is often helpful in structure determination ● Conjugation and electron-donating groups bonded to the carbonyl shift the location of the C=O absorption to lower frequencies

Ch. 17 - 21  IR Spectra ● Electron-withdrawing groups bonded to the carbonyl shift the C=O absorption to higher frequencies ● The hydroxyl groups of carboxylic acids also give rise to a broad peak in the 2500-3100-cm-1 region arising from O– H stretching vibrations ● The N–H stretching vibrations of amides absorb between 3140 and 3500 cm-1

Ch. 17 - 22 Ch. 17 - 23 Ch. 17 - 24  1H NMR Spectra ● The acidic protons of carboxylic acids are highly deshielded and absorb far downfield in the δ 10-12 region ● The protons of the a carbon of carboxylic acids absorb in the δ 2.0-2.5 region

Ch. 17 - 25 Ch. 17 - 26  13C NMR Spectra ● The carbonyl carbon of carboxylic acids and their derivatives occurs downfield in the δ 160-180 region (see the following examples), but not as far downfield as for aldehydes and ketones (δ 180- 220) ● The nitrile carbon is not shifted so far downfield and absorbs in the δ 115-120 region Ch. 17 - 27  13C NMR chemical shifts for the carbonyl or nitrile carbon atom

O O O C C C H3C OH H3C OEt H3C Cl δ 177.2 δ 170.7 δ 170.3

O

C H3C C N H3C NH2 δ 172.6 δ 117.4 Ch. 17 - 28 3. Preparation of Carboxylic Acids  By oxidation cleavage of alkenes

● Using KMnO4 − 1. KMnO4, OH , heat Ph + 2. H3O

OH O + Ph O OH ● Using ozonolysis HO OH O O 1. O3

2. H2O2 Ch. 17 - 29  By oxidation of aldehydes & 1o alcohols ● e.g. H OH 1. Ag2O O+ O 2. H3 O OH − 1. KMnO4, OH , heat OH + O 2. H3O O O H2CrO4 H or OH OH Ch. 17 - 30  By oxidation of alkyl benzene

O

R − 1. KMnO4, OH , heat OH + 2. H3O

(R = 1o or 2o alkyl groups)

Ch. 17 - 31  By oxidation of benzene ring ● e.g.

O 1. O3, CH3COOH 2. H O 2 2 OH

Ch. 17 - 32  By hydrolysis of cyanohydrins and other nitriles ● e.g. O O HCN NC OH H+ HO C OH

Ph CH3 Ph CH3 H2O Ph CH3

O HCN H+ Br CN C OH H2O, heat

Ch. 17 - 33  By carbonation of Grignard reagents ● e.g. Br MgBr Mg

Et2O

1. CO2 + 2. H3O O

OH

Ch. 17 - 34 4. Acyl Substitution: Nucleophilic Addition-Elimination at the Acyl Carbon

O O Nu + Nu R Y R Y O Y + R Nu

(Y = leaving group, e.g. OR, NR2, Cl)

 This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination

mechanism Ch. 17 - 35  This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives

O O O O

R OH R Cl R O R' carboxylic acid acid chloride acid anhydride

O O

R OR' R NR'2 ester amide

Ch. 17 - 36  Unlike carboxylic acids and their derivatives, aldehydes & ketones usually do not undergo this type of nucleophilic acyl substitution, due to the lack of an acyl leaving group A good O leaving O O group R Y R H R R' a carboxylic acid derivative Not a good leaving group Ch. 17 - 37  Relative reactivity of carboxylic acid derivatives towards nucleophilic acyl substitution reactions ● There are 2 steps in a nucleophilic acyl substitution  The addition of the nucleophile to the carbonyl group  The elimination of the leaving group in the tetrahedral intermediate

Ch. 17 - 38 ● Usually the addition step (the first step) is the rate-determining step (r.d.s.). As soon as the tetrahedral intermediate is formed, elimination usually occurs spontaneously to regenerate the carbonyl group ● Thus, both steric and electronic factors that affect the rate of the addition of a nucleophile control the reactivity of the carboxylic acid derivative

Ch. 17 - 39 ● Steric factor e.g. O O reactivity of > Cl Cl

● Electronic factor  The strongly polarized acid derivatives react more readily than less polar ones

Ch. 17 - 40 ● Thus, reactivity of O O O O O > > > R Cl R O R' R OR' R NR'2 most least reactive reactive ● An important consequence of this reactivity  It is usually possible to convert a more reactive acid derivative to a less reactive one, but not

vice versa Ch. 17 - 41 5. Acyl Chlorides 5A. Synthesis of Acyl Chlorides  Conversion of carboxylic acids to acid chlorides O O

R OH R Cl ● Common reagents

 SOCl2  (COCl)2  PCl3 or PCl5 Ch. 17 - 42 ● Mechanism O Cl O Cl O O O Cl R OH R O Cl O O O Cl Cl R O O O O O Cl + CO2 + CO + Cl R O R Cl Cl O Ch. 17 - 43  Nucleophilic acyl substitution reactions of acid chlorides ● Conversion of acid chlorides to carboxylic acids

O base O + H2O R Cl R OH

Ch. 17 - 44 ● Mechanism

O O OH H R O R OH R Cl H2O Cl H Cl

H O B: O B H + R OH R OH

Ch. 17 - 45 ● Conversion of acid chlorides to other carboxylic derivatives

O R'OH (ester) pyridine R OR'

O O R'2NH (amide) R Cl R NR'2 O

O O R' O Na (acid anhydride) R O R' Ch. 17 - 46 6. Carboxylic Acid Anhydrides 6A. Synthesis of Carboxylic Acid Anhydrides O O + + R OH R' Cl N

O O + Cl R O R' N H Ch. 17 - 47 O O O O + + Na Cl R O Na R' Cl R O R'

O O

OH 300oC O + H2O OH

Succinic O Succinic O acid anhydride

O O

OH 230oC O + H2O OH Phthalic Phthalic anhydride O O acid (~100%) Ch. 17 - 48 6B. Reactions of Carboxylic Acid Anhydrides  Conversion of acid anhydrides to carboxylic acids

O O O O H+ + H2O + R O R' R OH HO R'

Ch. 17 - 49 ● Mechanism

H O O H+ O O OH O

R O R' R O R' H2O R O R' O H H

H O O OH O H2O + R'COOH R OH R OH R O R' OH H

Ch. 17 - 50  Conversion of acid anhydrides to other carboxylic derivatives O O R'OH + R OR' R OH

O O

R O R'

O O + R2'NH R NR'2 R O NR'2H2

Ch. 17 - 51 7. Esters

7A. Synthesis of Esters: Esterification

O O H+ + R'OH + H2O R OH R OR'

Ch. 17 - 52  Mechanism

H O H+ O OH H H H R O R O R'OH R O OH "activated" R'

H O O OH H2O 2

R OR' R OR' R OR' HO

Ch. 17 - 53  Esters from acyl chlorides e.g. O

Cl + EtOH + N Benzoyl chloride O

OEt + Cl N Ethyl benzoate (80%) H Ch. 17 - 54  Esters from carboxylic acid anhydrides e.g. O O OH + O Acetic Benzoyl anhydride alcohol O

O O + OH Benzoyl acetate Ch. 17 - 55 7B. Base-Promoted Hydrolysis of Esters: Saponification  Hydrolysis of esters under basic conditions: saponification

O OH− O + R'OH H O R OR' 2 R O

Ch. 17 - 56  Mechanism

O O

R OR' R OR' OH HO

O H + OR' R O + O H O R'OH + R OH R O

Ch. 17 - 57  Hydrolysis of esters under acidic conditions

O H+ O + R'OH H O R OR' 2 R OH

Ch. 17 - 58  Mechanism

H O H+ O OH

R OR' R OR' H2O R OR' O H H

H O O OH H2O + R'OH R' R OH R OH R O OH H

Ch. 17 - 59 7C. Lactones  Carboxylic acids whose molecules have a hydroxyl group on a γ or δ carbon undergo an intramolecular esterification to give cyclic esters known as γ- or δ-lactones

Ch. 17 - 60 O H O H H γ α R δ β OH O H O O H O H HO O H A a δ-hydroxyacid R R

O O H

A + H O H + O O + O H H H R R a δ-lactone Ch. 17 - 61  Lactones are hydrolyzed by aqueous base just as other esters are O O + H /H2O O C6H5 O HA, slight excess OH C6H5 0oC O HA, exactly 1 equiv. C6H5 OH

OH Ch. 17 - 62 8. Amides 8B. Amides from Acyl Chlorides O O

R Cl R Cl H N R" :NHR'R" R'

O O R" Cl + R'R"NH2 + R" :Cl: R N R N R' R' H R"R'HN: Ch. 17 - 63 8C. Amides from Carboxylic Anhydrides

O O H R' + 2 N R O R R"

O O H R' + H N R' R N R O R" R" R', R" can be H, alkyl, or aryl.

Ch. 17 - 64 O O

H2O NH2 O + 2 NH3 warm O NH4

O O Phthalamic O Ammonium anhydride phthalamate + (94%) NH2 H3O + OH (- NH4 ) Phthalamic acid O (81%)

Ch. 17 - 65 O O

o NH2 150-160 C N H OH

+ H O O 2 O Phthalamic acid Phthalimide (~ 100%)

Ch. 17 - 66 8D. Amides from Esters O O H R' R' + N R N + R'"OH R OR'" R" R"

R' and/or R" may be H. e.g. O O Me OMe MeNH2 N heat H + MeOH Ch. 17 - 67 8E. Amides from Carboxylic Acids and Ammonium Carboxylates

O O

+ NH3 R OH R O NH4

heat

O

H2O + R NH2

Ch. 17 - 68  DCC-Promoted amide synthesis

O O 1. DCC R' + DCU R OH 2. R'NH2 R N H

Ch. 17 - 69  Mechanism

C6H11 : :

N: O: R N C6H11

R C + C C O: C :

: : O H :N H O: : N:

C6H11 C6H11 Dicyclohexyl-

carbodiimide : R N C H (DCC) : 6 11

C O: C :

H O: N:

C6H11

Ch. 17 - 70

:  Mechanism (Cont’d) : : : O R N C6H11 N C6H11 proton C : :

C O C R O: C : transfer : H O: N: N: HC6H11

C6H11 reactive intermediate

: : :

O : : N C6H11 : R' NH2

R C O: C

NH2 N: HC6H11 : : R' O: NHC6H11 :

R C + O: C

NHR' N: HC6H11

an amide N,N'-Dicyclohexylurea (DCU) Ch. 17 - 71 8F. Hydrolysis of Amides

 Acid hydrolysis of amides

O O H+ + NH4 R NH2 H2O, heat R OH

Ch. 17 - 72  Mechanism

H : :O: + O OH H H2O

R N: H2 R NH2 R NH2 H O H

H :O: O :OH : + NH3 R OH R OH R NH3 HO

Ch. 17 - 73  Basic hydrolysis of amides

O O OH− + NH3 R NH2 H2O, heat R O

Ch. 17 - 74  Mechanism

O OH O O H + NH2 R NH2 R NH2 R O HO

O

NH3 + R O

Ch. 17 - 75 8G. Nitriles from the Dehydration of Amides :O: P4O10 or (CH3CO)2O

: R C N: + H3PO4 heat R NH2 (a nitrile) (or CH3CO2H) (−H2O)

 This is a useful synthetic method for preparing nitriles that are not available by nucleophilic substitution reactions between alkyl halides and cyanide ions

Ch. 17 - 76  e.g.

O C N NH2 P4O10

dehydration

Ch. 17 - 77  Example ● Synthesis of C N

NaCN Br CN DMSO

1o alkyl bromide

⇒ SN2 reaction with ⊖CN works fine

Ch. 17 - 78 CN But synthesis of

Br NaCN No Reaction! DMSO

3o alkyl bromide

⇒ No SN2 reaction

Ch. 17 - 79 Solution O

1. Mg, Et O Br 2 OH 2. CO2 + 3. H3O

O 1. SOCl2 2. NH3 CN NH2 P4O10 dehydration

Ch. 17 - 80 8H. Hydrolysis of Nitriles

O base or acid R C N H2O, heat R OH

 Catalyzed by both acid and base

Ch. 17 - 81  Examples

H2SO4 OH CN H2O, ∆ O (82%)

OH CN

1. NaOH, H2O, ∆ O + 2. H3O (68%)

Ch. 17 - 82 protonated nitrile  Mechanism H

R C N: R C NH R C NH + :O: H H

H O: H slow amide

tautomer : H : H : H H H2O O: O: :O H + H O: H C C C

R N: H R NH2 R N: H protonated amide H O: several steps O + NH C (amide hydrolysis) 4

R N: H2 R OH Ch. 17 - 83

: :  Mechanism : N H OH NH

:

R C N: + : O: H

: : R OH R OH

O: H

H O HO O HO H OH : : :

R NH2 R NH2 R N: H O H OH OH OH OH H HO HO H

O O : H OH R NH2 + NH3 + OH R O O Ch. 17 - 84 8I. Lactams O O O α α NH α NH β δ NH β β γ γ a β-lactam a γ-lactam a δ-lactam

R = C H CH Penicillin G H 6 5 2

R N S CH3 R = C6H5CH Ampicillin O N CH3 NH2 O CO2H R = C6H5OCH2 Penicillin V Ch. 17 - 85 9. Derivatives of Carbonic Acid 9A. Alkyl Chloroformates and Carbamates (Urethanes)

 Alkyl chloroformate

O O ROH + + HCl Cl Cl RO Cl alkyl chloroformate

Ch. 17 - 86  e.g.

O OH + RO Cl

O

O Cl HCl +

Benzyl chloroformate Ch. 17 - 87  Carbamates or urethanes

O O + R'NH 2 − RO Cl OH RO NHR' a carbamate (or urethane)

Ch. 17 - 88  Protection protected amine O O R O Cl OH− N O R NH2 + H

 Deprotection

R NH2 + CO2 + O H2, Pd R N O H Br R NH3 + CO2 + HBr, CH2CO2H Ch. 17 - 89 10. Decarboxylation of Carboxylic Acids

O decarboxylation R H + CO2 R OH

O O O 100-150oC + CO2 R OH R A β-keto acid

Ch. 17 - 90  There are two reasons for this ease of decarboxylation H H O O O O −CO2 R O R R

β-keto acid enol ketone

: : :

O O O O : −CO2 HA :

: R O: : R R acylacetate ion

: :

O : resonance-stabilized anion R Ch. 17 - 91 11. Chemical Tests for Acyl Compounds

 Recall: acidity of H H O O O H O > >

Ch. 17 - 92 O O H + Na OH + H2O R O R O Na (soluable in water)

O O Na H + NaOH

(soluble in water)

O H + NaOH No Reaction

(immiscible with H O) 2 Ch. 17 - 93 O O H O O Na + NaHCO3

+ CO2(g) + H2O (gas evolved)

O H + NaHCO3 No Reaction

O H + NaHCO3 No Reaction

Ch. 17 - 94 12. Polyesters and Polyamides: Step-Growth Polymers

 Polyesters O O

HO OH + HO n OH m

-H2O

O O O O n m

(a polyester) Ch. 17 - 95  Polyamides O O

H N N H + Cl n Cl 2 m H -HCl

H H O O N N n m (a polyamide) Ch. 17 - 96  Example: Nylon 66 O

OH NH2 n HO + n H2N O

heat

O H N N + 2n H2O

O H (Nylon 66) n ● Applications: clothing, fibers, bearings Ch. 17 - 97  Example: Dacron (Mylar) O O OH n + n HO CH3O OCH3

200oC

O O O + 2n CH3OH O n (Dacron) ● Applications: film, recording tape Ch. 17 - 98 13. Summary of the Reactions of Carboxylic Acids and Their Derivatives  Reactions of carboxylic acids O O C 1. P, X R O R C 2 OH 2. H2O NaOH or NaHCO3 X or other bases O O RCH2OH 1. LiAlH R OH + C 4 R'OH, H , ∆ R OR' + 2. H2O, H

SOCl2 O O O O or PCl3 C C C or PCl5 R O R' R' Cl R Cl base Ch. 17 - 99  Reactions of acyl chlorides O O

R NR' R OH

H2O R'2NH O

R Cl R'OH, base R'COOH base O O O

R O R' R OR' Ch. 17 - 100  Reactions of acyl chlorides (Cont’d) O

R R OH

1. LiAlH benzene 4 + AlCl3 2. H3O O

t o R Cl 1. LiAlH(O Bu)3, -78 C + 2. H3O

OH 1. R'MgX O + 2. H3O R R' R H R' Ch. 17 - 101  Reactions of acid anhydrides O O + R OH HO R'

H2O

O O R"2NH R"OH R O R' O O O O + + R NR" R' O NR"2H2 R OR" HO R'

Ch. 17 - 102  Reactions of esters O O R H R OH 1. DIBAL, -78oC R OH 2. H O+ 1. LiAlH 3 + 4 H O, H , ∆ + 2 2. H3O O OH O 1. OH- R OH R" 1. R"MgX R OR' R + + R" 2. H3O 2. H2O, H + NH R"OH, H , ∆ O 3 O

R NH2 R OR" Ch. 17 - 103  Reactions of nitriles O

R NH2 R OH

1. LiAlH + 4 H , H2O, ∆ + 2. H3O R C N

OH−, H O, ∆ t 2 1. LiAlH(O Bu)3 o O O or DIBAL, -78 C 2. H O+ 3 R O R H

Ch. 17 - 104  Reactions of amides O

+ HNR'2 R OH

+ - H2O, H or OH

P4O10 (P2O5) or Ac2O, D O 1. LiAlH4 + (R' = H only) R' 2. H3O R N R'

R C N R NR'2

Ch. 17 - 105  END OF CHAPTER 17 

Ch. 17 - 106