Chapter 20: Carboxylic Acids and Nitriles The Importance of Carboxylic Acids (RCO2H) Abundant in nature from oxidation of aldehydes and alcohols in metabolism ◦ Acetic acid, CH3CO2H, - vinegar ◦ Butanoic acid, CH3CH2CH2CO2H (rancid butter) ◦ Long-chain aliphatic acids from the breakdown of fats Carboxylic acids present in many industrial processes and most biological processes An understanding of their properties and reactions is fundamental to understanding organic chemistry 2 The Importance of Carboxylic Acids (RCO2H) They are the starting materials from which other acyl derivatives are made 20.1 Naming Carboxylic Acids & Nitriles Carboxylic Acids, RCO2H If derived from open-chain alkanes, replace the terminal -e of the alkane name with -oic acid The carboxyl carbon atom is C #1 Propanoic acid 4-Methylpentanoic acid 3-Ethyl-6-methyloctanedioic acid 4 Alternative Names Compounds with CO2H bonded to a ring are named using the suffix -carboxylic acid The CO2H carbon is not itself numbered in this system trans-4-Hydroxycyclohexanecarboxylic acid 1-cyclopentenecarboxylic acid 5 Common Names: Names accepted by IUPAC Carboxylic acids some of the 1st compound studied so some of their common names are still used. Especially for those with biological interest. Common Names: Nitriles, RCN Closely related to carboxylic acids named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon numbered C #1 4-Methylpentanenitrile 8 Nitriles, RCN Complex nitriles are named as derivatives of carboxylic acids. ◦ Replace -ic acid or -oic acid ending with -onitrile Acetonitrile (From acetic acid) Benzonitrile (From benzoic acid) 2,2-Dimethylcyclohexanecarbonitrile (From 2,2-dimethylcyclohexanecarboxylic acid) 9 Learning Check: Give IUPAC names for the following: Solution: Give IUPAC names for the following: 3-Methylbutanoic acid 4-Bromopentanoic acid 2-ethylpentanoic acid 2,4-Dimethylpentanenitrile cis-4-hexenoic acid cis-1,3cyclopentanedicarboxylic acid) 20.2 Structure & Properties Carboxyl carbon sp2 hybridized: planar with bond angles of approximately 120° 12 20.2 Structure & Properties: Carboxylic acids form hydrogen bonds, exist as cyclic dimers held together by 2 hydrogen bonds Strong hydrogen bonding causes much higher boiling points than the corresponding alcohols 1-Propanal (MW = 58) O Boiling Point CH3CH2C H 49oC 1-Propanol (MW = 60) CH3CH2CH2-OH 97oC Ethanoic Acid (Acetic acid) MW = 60 O CH3C OH 118oC Dissociation of Carboxylic Acids Carboxylic acids are proton donors toward weak and strong bases, producing metal carboxylate salts, RCO2 +M Carboxylic acids with more than six carbons are only slightly soluble in water, but their conjugate base salts are water-soluble 14 Acidity Constant and pKa Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2, but H3O+ is a much stronger acid pKa = ~5 pKa = 15.7 (acts as a base here) pKa = -1.7 Lower pKa means stronger acid so equilibrium favors starting materials The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5) 15 Substituent Effects on Acidity Electron withdrawing (electronegative) substituents (like F, Cl, Br, I) promote formation of the carboxylate ion so raise the Ka (lower the pKa) The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5) Ka,, ~10-15 to -16 for alcohols and water (pKa ~ 15 to 16) CH3OH H2O 15.5 15.7 CH3CH2OH 15.9 16 Resonance Effects on Acidity Phenols Alcohols Carboxylic acid Inorganic acids 17 Resonance Effects on Acidity Alcohols weaker acids since O- not stabilized by resonance C=O Bond length (120 pm) Negative charge spread over O-C-O C-O Bond length (134 pm) Carboxylic acids more acidic since O- stabilized by resonance C-O Bond lengths same (127 pm) 20.3 Biological Acids and the Henderson-Hasselbalch Equation If pKa of given acid and the pH of the medium are known, % of dissociated and undissociated forms can be calculated using the Henderson-Hasselbalch eqn 19 Learning Check: Calculate the % of acid form (undissociated = HA) and carboxylate ion form (dissociated = A-) present in a 0.0020 M propanoic acid solution at pH = 5.30. (pKa = 4.87) Solution: Calculate the % of acid form (undissociated = HA) and carboxylate ion form (dissociated = A-) present in a 0.0020 M propanoic acid solution at pH = 5.30. (pKa = 4.87) HA O CH3CH2C OH A- + H2O pH - pKa = log [A-] [HA] 5.30 - 4.87 = 0.43 = log [A-] [HA] 100.43 = 2.69 = [A-] [HA] 1 O CH3CH2C O + H3O 2.69 x 100 = 73 % [A-] 2.69 + 1 and 1 x 100 = 27 % [HA] 2.69 + 1 20.4 Substituent Effects on Acidity Electron withdrawing (electronegative) substituents (like F, Cl, Br, I) promote formation of the carboxylate ion so raise the Ka (lower the pKa) They stabilize the carboxylate anion by induction 22 Aromatic Substituent Effects electron-donating electron-withdrawing (activating) group (like OCH3) ( activating) groups (like -NO2) decreases acidity by destabilizing the carboxylate anion increase acidity by stabilizing the carboxylate anion 23 Aromatic Substituent Effects 24 Learning Check: Rank the following in order of increasing acidity: (#1 is least acidic) (Don’t look at a table of pKa data to help you.) A. O O C C OH O H3C B. O C C OH C HO O2N O OH C OH Cl O OH O CH3 C OH OH Solution: Rank the following in order of increasing acidity: (#1 is least acidic) (Don’t look at a table of pKa data to help you.) A. O O C C OH O H3C 3 C OH O C HO 4 O C OH 1 O OH CH3 C OH O2N 2 3 C OH Cl 2 B. O 1 OH 20.5 Preparation of Carboxylic Acids: From Oxidation of Benzylic Carbons Oxidation of a substituted alkylbenzene with KMnO4 or Na2Cr2O7 gives a substituted benzoic acid 1° and 2° alkyl groups can be oxidized, but 3° are not 1o CH2CH3 H3C H3C 3o O C OH KMnO4 H3C C CH3 CH CH3 CH3 2o H3C 3o C CH3 C OH O 27 From Oxidative Cleavage of Alkenes Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen CH3CH2 H C C CH3 CH3 CH3CH2 H3O+ H KMnO4 H H3O+ C C H KMnO4 CH3CH2 OH C O + O C CH3 CH3 CH3CH2 OH C O + O C HO OH CO2 28 From Oxidation of 1o Alcohols & Aldehydes Oxidation of a 1o alcohols or aldehydes with CrO3 in aqueous acid 29 Hydrolysis of Nitriles Hot acid or base yields carboxylic acids O + CH3 CH2 CH2 C N H3O or 1) NaOH 2) H3O+ CH3 CH2 CH2 C OH 30 Halides Nitriles Carboxylic Acids Conversion of an alkyl halide to a nitrile (by an SN2 with cyanide ion) followed by hydrolysis produces a carboxylic acid with one more carbon (RBr RCN RCO2H) Best with 1o halides because competing elimination reactions occur with 2o or 3o alkyl halides 31 Carboxylation of Grignard Reagents Grignard reagents react w/ dry CO2 to yield a metal carboxylate ◦ Limited to alkyl halides that can form Grignard reagents The organomagnesium halide adds to C=O of carbon dioxide Protonation by addition of aqueous HCl in a separate step gives the free carboxylic acid 32 Halides Nitriles Carboxylic Acids Halides Grignard Carboxylic Acids 20.6 Reactions of Carboxylic Acids: An Overview Like ketones, Carboxylic acids transfer a proton to a base to give anions, which are good nucleophiles in SN2 reactions carboxylic acids undergo addition of nucleophiles to the carbonyl group NaOH 1) LiAlH4 2) H3O+ Carboxylic acids undergo substitutions reactions characteristic of neither alcohols nor ketones 34 Learning Check: Prepare 2-phenylethanol from benzyl bromide. OH CH2 Br CH2 CH2 Solution: Prepare 2-phenylethanol from benzyl bromide. CH2 Br 1) NaCN 2) H3O+, heat OH CH2 CH2 3) LiAlH4 4) H3O+ 1) LiAlH4 2) H3O+ Na C N O CH2 C N + H3O heat CH2 C OH 20.7 Chemistry of Nitriles Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and contain a bond C’s of nitriles and carboxylic acids are electrophilic d- d- d+ d+ d+ d- 37 Preparation of Nitriles: Dehydration of Amides Reaction of primary amides RCONH2 with SOCl2 or POCl3 (or other dehydrating agents) Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN) 38 Mechanism: Dehydration of Amides Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination Nucleophilic amide oxygen atom attacks SOCl2 Deprotonation of acidic H on N Elimination of the SO2 and Cl leaving groups 39 Reactions of Nitriles RCN is strongly polarized and with an electrophilic carbon Attacked by nucleophiles to yield sp2-hybridized imine anions 40 Hydrolysis: Nitriles Carboxylic Acids Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia or an amine 41 Mechanism: Hydrolysis of Nitriles Nucleophilic addition of hydroxide to CN bond Protonation gives a hydroxy imine, which tautomerizes to an amide A second hydroxide adds to the amide carbonyl group and loss of a proton gives a dianion Expulsion of NH2 gives the carboxylate 42 Mechanism: Step 4: Hydrolysis of Amides Reduction: Nitriles 1o Amines ◦Reduction of a nitrile with LiAlH4 gives a primary amine Nucleophilic addition of hydride ion (H-) to the polar CN bond, yields an imine anion The C=N bond undergoes a second nucleophilic addition of hydride (H-) to give a dianion, which is protonated by water 44 Reaction of Nitriles with Organometallic Reagents Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone 45 Reactions of Nitriles: Overview Learning Check: Prepare 2-methyl-3-pentanone from a nitrile. Solution: Prepare 2-methyl-3-pentanone from a nitrile. A couple of possibilities: 20.8 Spectroscopy of Carboxylic Acids and Nitriles Infrared Spectroscopy O–H bond of the carboxyl group gives a very broad absorption 2500 to 3300 cm1 C=O bond absorbs sharply between 1710 and 1760 cm1 Free carboxyl groups absorb at 1760 cm1 Commonly encountered dimeric carboxyl groups absorb in a broad band centered around 1710 cm1 49 Infrared Spectroscopy O–H bond of the carboxyl group gives a very broad absorption 2500 to 3300 cm1 Commonly encountered dimeric carboxyl groups absorb in a broad band centered around 1710 cm1 IR of Nitriles Nitriles show an intense CN bond absorption near 2250 cm1 for saturated compounds and 2230 cm1 for aromatic and conjugated molecules This is highly diagnostic for nitriles 51 C-13 NMR Carboxyl 13COOH signals are at d165 to d185 Aromatic and ,b-unsaturated acids are near d165 and saturated aliphatic acids are near d185 13C N signal d115 to d130 52 Proton NMR The acidic CO2H proton is a singlet near d 12 When D2O is added to the sample the CO2H proton is replaced by D causing the absorption to disappear from the NMR spectrum 53 Which of the following is not an acyl derivative? 20% 1. 20% 20% 20% 3 4 20% 2. O O O Cl 3. H N 4. O O O O 5. O O 1 2 5 Learning Check: Name the following: O A. O 4. benzoic acid 1-cyclohexenoic acid 2-cyclohexenoic acid 1-cyclohexenecarboxylic acid 5. 2-cyclohexenecarboxylic acid 1. 2. 3. B. OH 1. 2. 3. 4. 5. Br OH 3-bromo-4-methylbenzoic acid 4-methyl-3-bromobenzoic acid phthalic acid 4-carboxy-2-bromotoluene 5-carboxy-2-methyl-1bromobenzene Solution: Name the following: O A. O 4. benzoic acid 1-cyclohexenoic acid 2-cyclohexenoic acid 1-cyclohexenecarboxylic acid 5. 2-cyclohexenecarboxylic acid 1. 2. 3. B. OH 1. 2. 3. 4. 5. Br OH 3-bromo-4-methylbenzoic acid 4-methyl-3-bromobenzoic acid phthalic acid 4-carboxy-2-bromotoluene 5-carboxy-2-methyl-1bromobenzene Learning Check: Name the following: A. B. CN OH O 1. 2. 3. 4. 5. 2-propylhexanoic acid 4-propylhexanoic acid 2-butylpentanoic acid 4-carboxyoctane 5-carboxyoctane 1. 2. 3. 4. 5. pentylpropylnitrile 4-cyanooctane 5-cyanooctane 2-propylhexanenitrile 2-butylpentanenitrile Solution: Name the following: A. B. CN OH O 1. 2. 3. 4. 5. 2-propylhexanoic acid 4-propylhexanoic acid 2-butylpentanoic acid 4-carboxyoctane 5-carboxyoctane 1. 2. 3. 4. 5. pentylpropylnitrile 4-cyanooctane 5-cyanooctane 2-propylhexanenitrile 2-butylpentanenitrile Learning Check: The structure for oleic acid is shown here. What is the IUPAC name of this compound? O OH 1. 2. 3. 4. 5. cis-octadecenoic acid (Z)-octadec-9-enoic acid (Z)-octadecyl-9-en-1-oic acid (Z)-octadecen-9-oic acid (Z)-9-octadecylenoic acid Solution: The structure for oleic acid is shown here. What is the IUPAC name of this compound? O OH 1. 2. 3. 4. 5. cis-octadecenoic acid (Z)-octadec-9-enoic acid (Z)-octadecyl-9-en-1-oic acid (Z)-octadecen-9-oic acid (Z)-9-octadecylenoic acid Learning Check: Why do carboxylic acids boil at higher temperatures than most molecules of the same molecular weight? 1. 2. 3. 4. 5. They have more oxygen atoms than most other molecules. They can participate in hydrogen bonding. They are polar molecules. They have more oxygen atoms than most other molecules; and they can participate in hydrogen bonding. They can participate in hydrogen bonding; and they are polar molecules. Solution: Why do carboxylic acids boil at higher temperatures than most molecules of the same molecular weight? 1. 2. 3. 4. 5. They have more oxygen atoms than most other molecules. They can participate in hydrogen bonding. They are polar molecules. They have more oxygen atoms than most other molecules; and they can participate in hydrogen bonding. They can participate in hydrogen bonding; and they are polar molecules. Learning Check: Rank the following molecules in acidity from least acidic to most acidic. Cl O O OH Cl A OH B 1. 2. 3. 4. 5. A, C, B B, A, C C, B, A B, C, A C, A, B O OH Cl C Solution: Rank the following molecules in acidity from least acidic to most acidic. Cl O O OH Cl A OH B 1. 2. 3. 4. 5. A, C, B B, A, C C, B, A B, C, A C, A, B O OH Cl C Learning Check: Rank the following molecules in acidity from most acidic to least acidic. OH OH O OCH3 HO A B 1. 2. 3. 4. 5. C A, C, B, D C, B, D, A B, C, A, D A, B, C, D C, B, A, D D Solution: Rank the following molecules in acidity from most acidic to least acidic. OH OH O OCH3 HO A B 1. 2. 3. 4. 5. C A, C, B, D C, B, D, A B, C, A, D A, B, C, D C, B, A, D D Learning Check: Chloroacetic acid is a stronger acid than acetic acid. Which is the best explanation? H3C COOH H3C COO H2C COOH Cl H2C COO Cl acetic acid acetate chloroacetic acid chloroacetate 1. More resonance structures can be drawn for chloroacetic acid than for acetic acid. 2. More resonance structures can be drawn for chloroacetate ion than for acetate ion. 3. Because of its high electronegativity, chlorine is able to donate electrons to the chloroacetate ion by the inductive effect, thereby stabilizing this ion. 4. Because of its high electronegativity, chlorine is able to withdraw electrons from the chloroacetate ion by the inductive effect, thereby stabilizing this ion. 5. Chlorine is larger than hydrogen and can better hold a negative charge. Solution: Chloroacetic acid is a stronger acid than acetic acid. Which is the best explanation? H3C COOH H3C COO H2C COOH Cl H2C COO Cl acetic acid acetate chloroacetic acid chloroacetate 1. More resonance structures can be drawn for chloroacetic acid than for acetic acid. 2. More resonance structures can be drawn for chloroacetate ion than for acetate ion. 3. Because of its high electronegativity, chlorine is able to donate electrons to the chloroacetate ion by the inductive effect, thereby stabilizing this ion. 4. Because of its high electronegativity, chlorine is able to withdraw electrons from the chloroacetate ion by the inductive effect, thereby stabilizing this ion. 5. Chlorine is larger than hydrogen and can better hold a negative charge. Learning Check: Which is the stronger acid? O O OH OH Cl p-Chlorobenzoic acid p-methylbenzoic acid Solution: Which is the stronger acid? O O OH OH Cl p-Chlorobenzoic acid p-methylbenzoic acid Learning Check: What sequence of reagents will accomplish the following? O OH 1. 2. H3O+ CO2 Mg HBr Et2O Br2 Mg h Et2O CO2 H3O+ 3. Br2 CO2 H3O+ h 4. HBr 5. CO2 H3O+ Mg Et2O CO2 H3O+ Solution: What sequence of reagents will accomplish the following? O OH 1. 2. H3O+ CO2 Mg HBr Et2O Br2 Mg h Et2O CO2 H3O+ 3. Br2 CO2 H3O+ h 4. HBr 5. CO2 H3O+ Mg Et2O CO2 H3O+ Learning Check: Which of the following cannot be performed with a nitrile? 1. 2. O CN O CN OH NH2 3. CN NH2 4. 5. CN Br CN O Solution: Which of the following cannot be performed with a nitrile? 1. 2. O CN O CN OH NH2 3. CN NH2 4. 5. CN Br CN O Learning Check: Determine the product of the following sequence: Br 1. NaCN H3O+ DMSO heat 3. 2. O OH NH2 NH2 O O 4. 5. O OH OH CN Solution: Determine the product of the following sequence: Br 1. NaCN H3O+ DMSO heat 3. 2. O OH NH2 NH2 O O 4. 5. O OH OH CN Learning Check: Determine the product of the following: O CH3MgBr SOCl2 NH2 1. H3O+ Et2O 2. O O 3. 5. NH2 HO CN 4. NHCH3 Solution: Determine the product of the following: O CH3MgBr SOCl2 NH2 1. H3O+ Et2O 2. O O 3. 5. NH2 HO CN 4. NHCH3