CHAPTER 7 CARBOXYLIC ACIDS AND THEIR DERIVATIVES

Objectives: Determine the names using structures and structures using names, and Describe and explain the properties Describe, explain and predict the preparation methods and the reactions of carboxylic acids and their derivatives.

7.1. Structure
O R OH R O OR' R O O O R' Carboxylic Acids O R NR'2 R Esters O X Anhydrides

Amides

Acid Halides

R, R' = Carbon structures Amides: R' = H or C structures X = Halogens: F, Cl, Br, I.

7.2. Nomenclature

Carboxylic Acids: Read 20-2, pg 935 Esters: Read # 21-2A, pg 979 Amides: Read # 21-2B, pg 980 Acid Halides: Read # 21-2D, pg 982 Acid anhydrides: Read # 21-2E, pg 983 Spectroscopy: read # 21-4, pg 988

7.3. Properties
a. Physical Properties * Carboxylic Acids: Read # 20-3, pg 939 Derivatives: Read 21-3, pg 985 b. Spectroscopy * Carboxylic Acids: Read #20-7, pg 949 * Derivatives: Read #21-4, pg 988

c. Acidity.

General Reaction: RCO2H + acid

:B -> base BH(+) conjugate acid

-> RCO2(-) + carboxylate anion

Acidity (Examples)
O OH + NaOH -----> Ethanoic acid O OH Propanoic acid + NH3 Ammonia O + H2O O(-)(+)Na Sodium ethanoate O O(-)(+)NH4 Ammonium propanoate

Acidity Measurement
Acids Ionize in water RCO2H + H2O --------> RCO2(-) + H3O(+) Measure of acid strength = Ka = [RCO2-][H3O+] / [RCO2H] = dissociation constant of an acid. Ka values are usually small and hard to measure Remedy = pKa = -logKa Examples : acid Ka pKa acetic 1.8E-5 4.7 (3) oxalic 6.23E-2 1.2 (1) Benzoic 6.5E-5 4.2 (2)

Substituent Effects on Acidity

Acidity of R-CO2H depends on the properties of substituent R. Reference: H-CO2H General Rules Electron donating substituents decrease the acidity Electron withdrawing substituents increase the acidity

Substituent Effects on Acidity (Examples)

O H H H pKa = 4.74 O OH O Cl OH H H pKa = 2.86 OH O OH Cl Cl H pKa = 1.26 OH O OH O Cl OH Cl Cl pka = 0.64 O OH

OH NO2

NO2 O pKa = 4.19 pKa = 4.46 pKa = 3.47 NO2 pKa = 3.41 pKa = 2.16

Substituent Effects on Acidity (Exercises)

Answer questions 20-3 a-c(*), pg 944

6.4. Preparation

* *

a. Carboxylic Acids *1. Oxidation of primary Alcohols Substrate: R-CH2-OH. Reaction site: C carrying the OH group. Reagent: Oxidizing reagent. Most used: compounds of Mn(VII). Example: KMnO4 compounds of Cr(VI). Active ingredient: H2CrO4. Forms: Na2Cr2O7 in sulfuric acid (Jones Reagent) Na2Cr2O7 in acetic acid Reaction: oxidation of the reaction site

Oxidation of primary Alcohols (Examples)

H2CrO4 R OH (KMnO4) O H KMnO4 -------> O O O Jones reagent OH ----------> OH H R O OH

Oxidation of primary Alcohols (Exercises)

Answer Questions 20-35e & g, pg 972

*2. Carboxylation of Grignard Reagents

Substrate: CO2. Reaction site: C. Reactive property: electrophilic. Reagents: * R(-)(+)MgX (Grignard reagent) R(-) is a nucleophile. Binds to C of CO2. Result: a carboxylate anion * Acid: source of H(+). Provides the H to O of the carboxylate. Reaction: Nucleophilic addition Product: carboxylic acid

Carboxylation of Grignard Reagents (Illustration)

O O C 1. R(-)(+)MgX R O ---------> 2. H3O+ H3O+ O (-) (+)MgX CO2 (-) (+)MgCl O H3O+ O (-) (+)MgCl O OH OH

O R

Cl Mg

Carboxylation of Grignard Reagents (Exercises)

Answer Questions 20-35 i, pg 972 20-39 d, pg 973

*3. Oxidation of Alkenes and Alkynes

Substrate: Alkene / Alkyne. Rxn site: C=C or CC bond Reagent: KMnO4, Oxidizing agent, source of O atoms Products: * Carboxylic acids for the side of the C=C bond carrying a H * Ketones for the side of the C=C bond without a H

*3. Oxidation of Alkenes / Alkynes (Illustration)

R1 H R2 R3 KMnO4 R1 H R2 O H O R3 H R1 O O H R2 O R3

KMnO4 H H

H O H

O O H

Oxidation of Alkenes / Alkynes (Exercises)

Answer Questions 20-35 D & G, pg 972

*4. Ozonolysis of alkynes

Substrates: Alkynes. Rxn site: C-C triple bond. Reagents: * Ozone. Binds the Os to the CC bond. * Water. Provides the necessary Hs to form the expected carboxylic Acids.

Ozonolysis of Alkynes ( Illustration)

O R1 R2 R1 O O 1. O3 HO 2. H2O O R2 R1 O O H O

R2

HO

*5. Oxidation of Side-chains of Aromatic Compounds

Substrates: Alkylated aromatic compounds Reagents: Oxidizing agents. Most common: Mn(VII) as in KMnO4 and Cr(VI) as in H2CrO4. Reaction: oxidation of the C next to the aromatic ring to a CO2H group.

Oxidation of Side-chains of Aromatic Compounds (Illustration)

R Na2Cr2O7, H2SO4, heat z or KMnO4, H2O, heat O OH z

Z = non-oxidizable substituent in any position on the ring O 1. KMnO4, KOH/H2O, heat 2. HCl OH

Preparation of Carboxylic acids (Exercises)

Answer the following questions: 20-11 a-c, pg 955

*6. Formation and Hydrolysis of Nitriles

Substrates: alkyl halides. Reaction site: C that carries the halogen. Reactive property: electrophilic. Reagents: * compounds of cyanide (CN(-)) ion: nucleophile. CN(-) replaces the halogen on the electrophilic site. Result: fomration of a nitrile * Acidic or basic H2O. Brings O and OH to the C of the CN group. Result: carboxilic acid.

Formation and Hydrolysis of Nitriles (Illustration)

H(+)/H2O R-X + Na(+)(-)CN R-CN or HO(-)/H2O Br NaCN CN H3O(+) O OH R O O H

Formation and Hydrolysis of Nitriles (Exercises)

Answer Questions: 20-35 a & b, pg 972

b. Preparation of Esters (R-CO-OR)

*1. Fischer esterification Substrates: R-CO2Hs. Reaction site: C of C=O group. Reactive property: electrophile Reagents: R-OHs. Nucleophile: O. The O binds to the C of the C=O group and replaces the OH group. Reaction conditions: presence of an acid> The H(+) of the acid help: (1) in making the electrophile available; (2) removing the OH of the R-CO2H. Reaction: nucleophilic substitution of OH by OR on the CO2 group.

Fischer Esterification (General Pathway)

O R :O .. H R' O O H R H(+) - H(+) O H R :O (+) H .. : O H R' R O R' : O (+) H H2O O R'

H2O

Fischer Esterification (Examples)

O OH H2SO4 + CH3OH ----> O OH HCl OH O O O

Fischer Esterification (Exercises)

Answer questions * 20-35 j, pg 972 * 21-48 c, pg 1033

c. Preparation of Acid Halides (R-CO-X)

Substrates: R-CO2H. Rxn site: C of C=O. Reactive property: electrophile Reagents: sources of halogens (X). Most common: SOCl2, COCl2 Reaction : Nucleophilic substitution of OH of R-CO2H by X.

Preparation of Acid Halides (General Pathway)

O R H O: . . R Cl O: . .

SO2

HCl

Cl

S O

Cl

H . . H O : Cl : R Cl O S O

. . R (+) O : Cl S Cl O(-)

7.5. Reactions
a. Carboxylic Acids Types of reactions: * Reactions with bases. Result Carboxylic acid salts * Reactions with nucleophiles. Electrophile: C of C=O group * Reactions with electrophiles. Nucleophile: O of OH group.

*1. Reactions with bases Read 20-5, pg 944

*2. Reduction of Carboxylic acids to primary alcohols

Substrate: R-CO-OH Site: C of C=O Reagents: * Source of H(-) (the nucleophile). Most common sources: BH3 (best), LiAlH4. BH3 reacts with C=O group of CO2H preferentially to C=O of Aldehydes / Ketones. H(-) binds to C of C=O group. Result: Aldehyde which react with one more H(-). Ultimate result: alkoxide * Acidic water solution: source of H(+). H(+)s binds to the alkoxide. Result: primary alcohol

Reduction of Carboxylic acids to primary alcohols (General Pathway)

O R OH H(-) 1. BH3 R 2. H3O+ H3O+ OH

O H(-) R O(-) R

O H + O2-

O(-) H(-) R H H

Reduction of Carboxylic acids to primary alcohols (Examples)

O OH

1. BH3 2. H3O+

O OH

O OH

1. LiAlH4 2. H3O+

HO

Reduction of Carboxylic acids to primary alcohols (Exercises)

Answer questions 20-19 a and c, pg 965.

*3. Conversion of Carboxylic Acids to tertiary alcohols

Substrate: R-CO-OH Site: C of C=O Reagents: * Sources of C nucleophiles. Most common: Alkyl lithium (R(-)(+)Li) and Grignard reagents (R(-)(+)MgX). Nucleophiles bind to C of C=O group. Ultimate result: Tertiary alkoxides. * Acidic water. Source of H(+). H(+) binds to tertiary alkoxide. Products: Tertiary alcohols

Conversion to tertiary alcohols (General Pathway)

O 1. R'(-)(+)MgX R OH R'(-) 2. H3O+ R OH H3O+ O R O(-) R'(-) R R' O R'(-) R R' R' O(-) R' R'

H2O

R'-H

Conversion to tertiary alcohols (Example)

O OH OH

1. 3 CH3MgBr 2. H3O+

Conversion of Carboxylic Acids to Ketones

Substrate: R-CO-OH Site: C of C=O Reagents: Sources of C nucleophiles. Most common: Alkyl lithium (R(-)(+)Li) and Grignard reagents (R(-)(+)MgX). Nucleophiles bind to C of C=O group. Reaction Condition: Use no more that 2 equivalents of reagent. Products: ketones

Conversion to Ketones (General Pathway)

O R'(-) R OH R O(-) R'-H O R'(-) R R' O

Conversion to Ketones (Example)

O OH Extra exercise: #20-21 a, pg 965 2 CH3Li O

b. Reactions of Carboxylic Acid Derivatives

*1. Nucleophilic Substitutions Substrates: R-CO-X. X = halogen, OR, NR2, O-CO-R. Most reactive: acid halides. Reaction site: C of C=O. Reactive property: electrophile. Reagents: any nucleophile. Nucleophile replaces the X on the C=O group. Products: R-CO-Nu. The high reactivity of R-CO-X (as a halide)and the wide variety of nucleophiles lead to a wide variety of products

Nucleophilic Substitutions of Acid Halides (General Pathway)

O R' N R' (R')2NH O R'-OH R OR' R O X O R' O R O O R' O H H2O R O OH

Nucleophilic Substitutions of Acid Halides (Examples)

O Cl O OH O O O

O Cl

OH O O

O Cl

NH2

O N H

Nucleophilic Substitutions of Other Carboxylic Acid Derivatives

Other carboxylic acid derivatives react similarly but less readily compared to acid halides

Nucleophilic Substitutions of Carboxylic Acid Derivatives (Exercises)

Answer to Questions * 21-48 a & b, pg 1033 * 21-50 a, b, d, g, pg 1035

*2. Nucleophilic Addition Reactions of Carboxylic Acid Derivatives

Substrates: R-CO-X Reagents: sources of H(-) or C(-) nucleophiles Reactions: Addition of H(-) or C(-)to C of C=O group. Products: aldehydes/ketones or alcohols

*2a. Reduction of carboxylic Acid Derivatives to primary alcohols

Substrates: R-CO-X Reaction site: C of C=O Reagents: * Source of H(-) (the nucleophile). Most common sources: LiAlH4 (LAH) . The H(-) binds C of C=O group. Ultimate result: primary alkoxides. * Acidic water. Source of H(+) which binds to the alkoxides. Products: primary alcohols. Note: Mild reagents: used to form adehydes. Example: LiAlH(t-butoxide)3 (LTTBAH)

Reduction to primary alcohols (General Pathway)

O 1. LiAlH4 R X 2. H3O+ H(-) H3O+ O(-) H(-) H R H H R OH

O R

Reduction to primary alcohols (Examples)

O 1. LAH 2. H3O+ OH

Cl

Note: Aldehydes can be obtained by using mild reducing agents like LiAlH(tBuO) 3 (LTTBAH) O 1. LTTBAH 2. H3O+

Cl

Reduction to primary alcohols (Exercises)

Answer question 21-50 e & f, pg 1034

*2b. Conversion of Carboxylic Acid Derivatives to Tertiary Alcohols

Substrates: R-CO-X. Reaction site: C of C=O group. Reactive property: electrophile. Reagents: * Sources of C nucleophiles (R(-)). Most common: Alkyl Lithium (R(-)(+)Li) and Grignard Reagents (R(-)(+)MgX). R(-) binds to C of C=O group. Ultimate result: Alkoxides. * Acidic water. Source of H(+). H(+) binds to the O(-) of the alkoxides. Products: tertiary alcohols. Note: using mild reagents can lead to formation of ketones. Examples: Dialkyl Li Cuprates (R2CuLi)

Acid Derivatives to Tertiary Alcohols (General Pathway)

O 1. R'(-)(+)MgX R X R'(-) 2. H3 O+ R OH H3O+ R' R'

H2O

O R'(-) R R' R R'

O(-) R'

Acid Derivatives to Tertiary Alcohols (Examples)

O Cl 1.CH3MgBr 2. H3O+ OH

NOTE: using alkylcuprates instead of grignard reagents produces ketones. Dialky cuprates do not react with esters or anhydrides. O (CH3-CH2(-))2(2+)CuLi Cl H3O+ O

Acid Derivatives to Tertiary Alcohols (Exercises)

Answer Questions: * 21-54 d, pg 1034 * 21-55, pg 1035