Carboxylic Acids and Nitriles

Introduction Carboxylic Acids Carboxylic acids are abundant in nature and in pharmaceuticals

Introduction Carboxylic Acids The US produces over 2.5 million tons of acetic acid per year, which is primarily used to produce vinyl acetate Vinyl acetate is used in paints and adhesives Carboxylic acid derivatives such as vinyl acetate are very common and play a central role in organic chemistry

Structure and Properties of Carboxylic Acids The carbon atom of the carboxylic acid has a trigonal planar geometry. The acid moiety is capable of strong hydrogen bonding including H-bonding between acid pairs As a result, carboxylic acids generally have high boiling points – consider the BPs of acetic acid (118 °C) and isopropanol (82 °C)

Structure and Properties of Carboxylic Acids In water, the equilibrium generally favors the acid pKa values mostly range between 4 and 5.

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

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 The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5)

Structure and Properties of Carboxylic Acids Electron withdrawing substituents have a great effect on acidity (including synergistic effects with multiple substituents) Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic acids are stronger acids than acetic acid

Substituent Effects on Acidity Electronegative substituents promote formation of the carboxylate ion

Aromatic Substituent Effects Electron-withdrawing (EW) groups increase acidity by stabilizing the carboxylate anion. Electron-donating (activating) groups decrease acidity by destabilizing the carboxylate anion We can use relative pKa’s as a calibration for effects on relative free energies of reactions with the same substituents

EW Substituent Effects on Acidity

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 Example problems Henderson-Hasselbalch equation

Preparing Carboxylic Acids Oxidation of a substituted alkylbenzene with KMnO4 or Na2Cr2O7 gives a substituted benzoic acid (see Section 16.9) 1° and 2° alkyl groups can be oxidized, but tertiary groups are not

From Alkenes Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen (see Section 7.9)

Preparation of Carboxylic Acids In earlier chapters, we have already learned some methods to synthesize carboxylic acids

From Alcohols Oxidation of a primary alcohol or an aldehyde with CrO3 in aqueous acid

Hydrolysis of Nitriles Hot acid or base yields carboxylic acids 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  RCO2H) Best with primary halides because elimination reactions occur with secondary or tertiary alkyl halides

Carboxylation of Grignard Reagents Grignard reagents react with 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

Reactions of Carboxylic Acids LiAlH4 is a strong reducing agent that can convert an acid to a primary alcohol The LAH acts as a base first Then, an aldehyde is produced

Reactions of Carboxylic Acids LiAlH4 is a strong reducing agent that can convert an acid to a primary alcohol The aldehyde is further reduced to the alcohol

Reactions of Carboxylic Acids The more mild borane reagent can also be used to promote the reduction Reduction with borane is selective compared to LAH reduction

Reactions of Carboxylic Acids: An Overview CA can transfer a proton to a base (produces good nucleophile). CA can be reduced by LAH. Nucleophile can add to carbonyl carbon of CA. In addition, carboxylic acids undergo other reactions characteristic of neither alcohols nor ketones

Carboxylic Acid Derivatives Carboxylic acids can be modified without changing the oxidation state: CA Derivatives Because it has the same oxidation state, a nitrile is also an acid derivative despite not having a carbonyl group. Nitriles and CA’s are electrophiles.

Carboxylic Acid Derivatives Acid halides and anhydrides are relatively unstable, so they are not common in nature Some naturally occurring esters are known to have pleasant odors Amides are VERY common in nature

Carboxylic Acid Derivatives To name an acid halide, replace “ic acid” with “yl halide”

Carboxylic Acid Derivatives Alternatively, the suffix, “carboxylic acid” can be replaced with “carbonyl halide”

Carboxylic Acid Derivatives Symmetrical acid anhydrides are named by replacing “acid” with “anhydride” Asymmetrical acid anhydrides are named by listing the acids alphabetically and adding the word anhydride

Carboxylic Acid Derivatives Esters are named by naming the alkyl group attached to the oxygen followed by the carboxylic acid’s name with the suffix “ate”

Carboxylic Acid Derivatives Amides are named by replacing the suffix “ic acid” or “oic acid” with “amide”

Carboxylic Acid Derivatives If the nitrogen atom of the amide group bears alkyl substituents, their names are placed at the beginning of the name with N as their locant

Carboxylic Acid Derivatives Nitriles are named by replacing the suffix “ic acid” or “oic acid” with “onitrile”

Reactivity of Carboxylic Acid Derivatives CA derivatives have electrophilic carbonyl carbons Reactivity can be affected by Induction Resonance Sterics Quality of leaving group

Reactivity of Acid Chlorides The electronegative chlorine enhances the electrophilic character of the carbonyl. There are 3 resonance contributors to the acid chloride Chloride affects the sterics of the nucleophilic attack on the carbonyl The chloride is a good leaving group, which also enhances its reactivity

Amides are the least reactive acid derivative Reactivity of Amides Amides are the least reactive acid derivative Examine the factors below to explain amide reactivity Induction Resonance Sterics Quality of leaving group

Reactivity of Aldehydes and Ketones Aldehydes and ketones are also electrophilic, but they do not undergo substitution – H and –R do not qualify as leaving groups.

Reactivity of Carboxylic Acid Derivatives Nucleophilic acyl substitution is a two-step process Because C=O double bonds are quite stable, the “loss of leaving group” step should occur if a leaving group is present A nucleophile that is a weaker leaving group can replace a stronger leaving group.

Reactivity of Carboxylic Acid Derivatives Not an SN2 mechanism Sometimes a proton transfer will be necessary in the mechanism

Reactivity of Carboxylic Acid Derivatives Under acidic conditions, (-) charges rarely form The first step will NOT be nucleophilic attack The electrophile and nucleophile are both low in energy

Reactivity of Carboxylic Acid Derivatives H3O+ is unstable and drives the equilibrium forward by starting the reaction mechanism Now that the electrophile carries a (+) charge, it is much less stable (higher in energy.

Reactivity of Carboxylic Acid Derivatives Under basic conditions, (+) charges rarely form The OH- is the most unstable species in the reaction and drives the equilibrium forward Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Preparation of Esters Fischer esterification combines a carboxylic acid and an alcohol using an acid catalyst, with multiple proton transfers

Preparation of Esters

Ester Reaction Products Relatively Poor Yields

Specific Reactions with Acid Chlorides/Anhydrides Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

Saponification Products Reaction of ester with water to break ester linkage and produce alcohol and carboxylic acid isopropyl propanoate sodium propanoate ethyl benzoate potassium benzoate Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

Amines Form Amides Amides are formed through reaction of primary and secondary amines with acid chlorides and acid anhydrides. Similar to esterification reactions. Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7th Edition, 2011

Reaction of Acid Chlorides Esters and acid chlorides can be attacked by Grignard nucleophiles

Reaction of Acid Chlorides Two equivalents of the Grignard yield a 3° alcohol

Reaction of Acid Chlorides with LAH Acid chlorides can be reduced using LAH To stop the aldehyde from being reduced to the alcohol, a bulky reducing agent can be used

Reactions of Esters Esters can be fully reduced using reagents such as LiAlH4 Two equivalents of reducing agent are required Two alcohols are produced When performed at low temperature, reduction with DIBAH yields an aldehyde.

Reactions of Amides LiAlH4 can reduce an amide to an amine

Reactions of Acid Chlorides

Reactions of Acid Anhydrides Acetic anhydride is often used to acetylate an amine or an alcohol

Reactivity of Carboxylic Acid Derivatives Neutral nucleophiles are generally less reactive, but they can still react if given enough time An intermediate with both (+) and (-) charge forms

Preparation of Nitriles by Dehydration 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)

Mechanism of Dehydration of Amides Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination

Reactions of Nitriles RCºN is strongly polarized and with an electrophilic carbon atom Attacked by nucleophiles to yield sp2-hybridized imine anions

Hydrolysis: Conversion of Nitriles into Carboxylic Acids Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia

Mechanism of Hydrolysis of Nitriles Nucleophilic addition of hydroxide to CN 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

Reduction: Conversion of Nitriles into Amines Reduction of a nitrile with LiAlH4 gives a primary amine Nucleophilic addition of hydride ion to the polar CN bond, yielding an imine anion The C=N bond undergoes a second nucleophilic addition of hydride to give a dianion, which is protonated by water

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

Spectroscopy of Carboxylic Acids and Their Derivatives Recall that C=O stretching is a prominent peak in IR spectra Recall that conjugated carbonyl signals appear at lower wavenumbers (about 40 cm-1 less)

Spectroscopy of Carboxylic Acids and Their Derivatives The O-H stretch of an acid gives a very broad peak (2500-3300 cm-1) The CΞN triple bond stretch appears around 2200 cm-1 Carbonyl 13C peaks appear around 160-185 ppm Nitrile 13C peaks appear around 115-130 ppm The 1H peak for a carboxylic acid proton appears around 12 ppm Practice with conceptual checkpoint 21.38

Spectroscopy of Carboxylic Acids and Their Derivatives Predict the number and chemical shift of all 13C peaks for the molecule below Predict the number, chemical shift, multiplicity, and integration of all 1H peaks for the molecule below