Chapter 20 Carboxylic Acids and Nitriles Based on

Chapter 20: Carboxylic Acids and Nitriles Based on Mc. Murry’s Organic Chemistry, 6 th edition © 2003 Ronald Kluger Department of Chemistry University of Toronto Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003

The Importance of Carboxylic Acids (RCO 2 H) n Starting materials for acyl derivatives (esters, amides, and acid chlorides) n Abundant in nature from oxidation of aldehydes and alcohols in metabolism n Acetic acid, CH 3 CO 2 H, - vinegar n Butanoic acid, CH 3 CH 2 CO 2 H (rancid butter) n Long-chain aliphatic acids from the breakdown of fats Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 2

20. 1 Naming Carboxylic Acids and Nitriles n Carboxylic Acids, RCO 2 H n If derived from open-chain alkanes, replace the terminal -e of the alkane name with -oic acid n The carboxyl carbon atom is C 1 Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 3

Alternative Names n Compounds with CO 2 H bonded to a ring are named using the suffix -carboxylic acid n The CO 2 H carbon is not itself numbered in this system n Use common names formic acid (HCOOH) and acetic acid (CH 3 COOH) – see Table 20. 1 Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 4

Nitriles, RC N n Closely related to carboxylic acids named by adding - nitrile as a suffix to the alkane name, with the nitrile carbon numbered C 1 n Complex nitriles are named as derivatives of carboxylic acids. n Replace -ic acid or -oic acid ending with -onitrile Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 5

20. 2 Structure and Physical Properties of Carboxylic Acids n Carboxyl carbon sp 2 hybridized: carboxylic acid groups are planar with C–C=O and O=C–O bond angles of approximately 120° n Carboxylic acids form hydrogen bonds, existing as cyclic dimers held together by two hydrogen bonds n Strong hydrogen bonding causes much higher boiling points than the corresponding alcohols Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 6

20. 3 Dissociation of Carboxylic Acids n Carboxylic acids are proton donors toward weak and strong bases, producing metal carboxylate salts, RCO 2 +M n Carboxylic acids with more than six carbons are only slightly soluble in water, but their conjugate base salts are water-soluble Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 7

Acidity Constant and p. Ka n Carboxylic acids transfer a proton to water to give H 3 O+ and carboxylate anions, RCO 2 , but H 3 O+ is a much stronger acid n The acidity constant, Ka, , is about 10 -5 for a typical carboxylic acid (p. Ka ~ 5) Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 8

Acidity Compared to Alcohols n Carboxylic acids are better proton donors than are alcohols (The p. Ka of ethanol is ~16, compared to ~5 for acetic acid) n In an alkoxide ion, the negative charge is localized on oxygen while in a carboxylate ion the negative charge is delocalized over two equivalent oxygen atoms, giving resonance stabilization Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 9

20. 4 Substituent Effects on Acidity n Electronegative substituents promote formation of the carboxylate

Substituent Effects n An electronegative group will drive the ionization equilibrium toward dissociation, increasing acidity n An electron-donating group destabilizes the carboxylate anion and decreases acidity Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 11

Examples of Inductive Effects on Acidity n Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic acids are stronger acids than acetic acid n Multiple electronegative substituents have synergistic effects on acidity Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 12

20. 5 Substituent Effects in Substituted Benzoic Acids Based on Mc. Murry, Organic Chemistry,

Aromatic Substituent Effects n An electron-withdrawing group (-NO 2) increases acidity by stabilizing the carboxylate anion, and an electron-donating (activating) group (OCH 3) decreases acidity by destabilizing the carboxylate anion n We can use relative p. Ka’s as a calibration for effects on relative free energies of reactions with the same substituents Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 14

20. 6 Preparation of Carboxylic Acids n Oxidation of a substituted alkylbenzene with KMn. O 4 or Na 2 Cr 2 O 7 gives a substituted benzoic acid (see Section 16. 10) n 1° and 2° alkyl groups can be oxidized, but tertiary groups are not Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 15

From Alkenes n Oxidative cleavage of an alkene with KMn. O 4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen (see Section 7. 8) Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 16

From Alcohols n Oxidation of a primary alcohol or an aldehyde with Cr. O

Hydrolysis of Nitriles n Hot acid or base yields carboxylic acids n Conversion of an alkyl halide to a nitrile (with cyanide ion) followed by hydrolysis produces a carboxylic acid with one more carbon (RBr RC N RCO 2 H) n Best with primary halides because elimination reactions occur with secondary or tertiary alkyl halides Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 18

Carboxylation of Grignard Reagents n Grignard reagents react with dry CO 2 to yield a metal carboxylate n Limited to alkyl halides that can form Grignard reagents (see 17. 6) Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 19

Mechanism of Grignard Carboxylation n The organomagnesium halide adds to C=O of carbon dioxide n Protonation by addition of aqueous HCl in a separate step gives the free carboxylic acid Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 20

20. 7 Reactions of Carboxylic Acids: An Overview n Carboxylic acids transfer a proton to a base to give anions, which are good nucleophiles in SN 2 reactions n Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl group n In addition, carboxylic acids undergo other reactions characteristic of neither alcohols nor ketones Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 21

20. 8 Reduction of Carboxylic Acids n Reduced by Li. Al. H 4 to yield primary alcohols n The reaction is difficult and often requires heating in tetrahydrofuran solvent to go to completion Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 22

Reduction with Borane n Borane in tetrahydrofuran (BH 3/THF) converts carboxylic acids to primary alcohols selectively n Preferable to Li. Al. H 4 because of its relative ease, safety, and specificity n Borane reacts faster with COOH than it does with NO 2 Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 23

20. 9 Chemistry of Nitriles n Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and both contain a bond n Both both are electrophiles Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 24

Preparation of Nitriles by Dehydration n Reaction of primary amides RCONH 2 with SOCl 2 or POCl 3 (or other dehydrating agents) n Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with Na. CN) Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 25

Mechanism of Dehydration of Amides n Nucleophilic amide oxygen atom attacks SOCl 2 followed by deprotonation and elimination Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 26

Reactions of Nitriles n RC N is strongly polarized and with an electrophilic carbon atom n Attacked by nucleophiles to yield sp 2 -hybridized imine anions Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 27

Hydrolysis: Conversion of Nitriles into Carboxylic Acids n Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia or an amine Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 28

Mechanism of Hydrolysis of Nitriles n Nucleophilic addition of hydroxide to C N bond n Protonation gives a hydroxy imine, which tautomerizes to an amide n A second hydroxide adds to the amide carbonyl group and loss of a proton gives a dianion n Expulsion of NH 2 gives the carboxylate Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 29

Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 30

Reduction: Conversion of Nitriles into Amines n Reduction of a nitrile with Li. Al.

Mechanism of Reduction of RC≡N n Nucleophilic addition of hydride ion to the polar C N bond, yieldis an imine anion n The C=N bond undergoes a second nucleophilic addition of hydride to give a dianion, which is protonated by water Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 32

Reaction of Nitriles with Organometallic Reagents n Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 33

20. 10 Spectroscopy of Carboxylic Acids and Nitriles. Infrared Spectroscopy n O–H bond of the carboxyl group gives a very broad absorption 2500 to 3300 cm 1 n C=O bond absorbs sharply between 1710 and 1760 cm 1 n Free carboxyl groups absorb at 1760 cm 1 n Commonly encountered dimeric carboxyl groups absorb in a broad band centered around 1710 cm 1 Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 34

IR of Nitriles n Nitriles show an intense C N bond absorption near 2250 cm 1 for saturated compounds and 2230 cm 1 for aromatic and conjugated molecules n This is highly diagnostic for nitriles Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 35

Nuclear Magnetic Resonance Spectroscopy signals are at 165 to 185 n Aromatic and , b-unsaturated acids are near 165 and saturated aliphatic acids are near 185 n 13 C N signal 115 to 130 n Carboxyl 13 COOH Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 36

Proton NMR n The acidic CO 2 H proton is a singlet near 12 n When D 2 O is added to the sample the CO 2 H proton is replaced by D causing the absorption to disappear from the NMR spectrum n Note that the carboxyl proton absorption occurs at 12. 0 Based on Mc. Murry, Organic Chemistry, Chapter 20, 6 th edition, (c) 2003 37