Chem A225 Notes Page 101 Chapter 21: Carboxylic …chemnerds.com/chem_A225/notes/HO_A225_notes_08_ch21_klein_2017_s...Chapter 21: Carboxylic Acids and Their Derivatives ... Carboxylic

Chem A225 Notes Page 101

Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.

Chapter 21: Carboxylic Acids and Their Derivatives

I. Nomenclature

A. IUPAC Nomenclature of Carboxylic Acids

1) Find the longest carbon chain which contains the carboxylic acid (COOH) carbon.

2) Count the number of carbon in this chain and determine the parent stem name.

3) Add the suffix “-anoic acid”.

4) Number the carbon chain starting from the carboxylic acid (COOH) carbon.

5) Add substituent names, with appropriate numbers, in from of the acid name.

B. Common Names of Carboxylic Acids (MEMORIZE)

C. IUPAC Names of Dicarboxylic Acids

1) Find the longest carbon chain which contains both carboxylic acid (COOH) carbons.

2) Count the number of carbon in this chain and name it as the corresponding alkane.

3) Add the suffix “-dioic acid”.

Chem A225 Notes Ch 21: Carboxylic Acids and Their Derivatives Page 102


D. Common Names of Dicarboxylic Acids (MEMORIZE)

E. Nomenclature of Carboxylate Salts

Carboxylic acids react with bases to form carboxylate salts.

These salts have two ions: the deprotonated carboxylic acid forms a negative ion that is paired up with a positive counter ion (such as sodium, potassium, or ammonium).

To name the deprotonated (carboxylate) form of a carboxylic acid:

1) Name the related carboxylic acid.

2) Replace the “-ic acid” suffix with “-ate”.

Add the name of the positive counter ion in front to complete the name of the carboxylate salt:



II. Synthesis of Carboxylic Acids

A. Oxidation of 1o Alcohols and Aldehydes (review 13-10)

Observed Reactions

B. Oxidative Cleavage of Alkenes (review Chap. 9 Notes)

Observed Reaction

C. Oxidation of Alkylbenzenes (review 18.6)

Observed Reaction

D. Reduction of CO2 with Grignard Reagents

Observed Reaction



Mechanism

E. Hydrolysis of Nitriles (Heteroatom Exchange)

Observed Reaction

Mechanism: Add H2O --> Add H2O --> Remove NH2



Nitriles can be prepared by SN2 reaction of cyanide ion on 1o alkyl halides:

Cyanohydrins are also nitriles:

III.Introduction Carboxylic Acid Derivatives

These functional groups are called derivatives of carboxylic acids because their structures are derived by replacing the OH of the acid with another heteroatom group.

Nitriles are technically not derivatives of carboxylic acids, but they can be converted to carboxylic acids by hydrolysis, so they have been included in this chapter:

Derivatives

acid chloride

carboxylic acid replace OH acid anhydride

ester

amide

R C

O

Cl

R C

O

OH R C

O

O C

O

R

R C

O

OR

R C

O

NR2



IV.Nomenclature of Carboxylic Acid Derivatives

A. Nomenclature of Acid Chlorides


2) Replace the “-ic acid” suffix with “-yl chloride”.

B. Nomenclature of Acid Anhydrides

Acid anhydrides are treated as two carboxylic acids that have been joined by connecting the OH of one acid to the C=O carbon of the other and removing a molecule of water.

To name acid anhydrides:1) Name each carboxylic acid half, then drop the “acid” part of the names.

2) Put the names in alphabetical order, separated by a space.

3) Add the word “anhydride”, separated by a space, following the names.

4) If the two halves are the same, only write the name once.



C. Nomenclature of Esters

Esters are treated as carboxylates that are attached to alkyl groups.

To name esters:1) Name the carboxylate part of the compound.

2) Add the name of the carbon group of the –OR as an alkyl (-yl ending) in front of the carboxylate name, separated by a space.

D. Nomenclature of Amides


2) Replace the “-oic acid” (for IUPAC names) or the “-ic acid” suffix (for common names) with “-amide”.

3) If the are alkyl groups on the nitrogen, put the name of each alkyl group in front with an “N-” prefix (for example: N-ethyl).



E. Nomenclature of Nitriles

1) Count the number of carbons in the longest carbon chain that contains the nitrile (CN) carbon. Include the nitrile carbon in the count.

2) Name the alkane that has the same number of carbons.

3) Add the suffix “-nitrile” to the alkane name, with no space in between.

V. Nucleophilic Acyl Substitution

A. Nucleophilic Acyl Substitution (SNAc) Mechanism

When there is a heteroatom leaving group attached to a C=O carbon, the leaving group can be replaced in a two-step nucleophilic substitution:



B. Reactivity of Carboxylic Acid Derivatives in SNAc Reactions

All of the derivatives of carboxylic acids have leaving groups in place of the OH group.

The derivatives with the better leaving groups are more reactive. What makes a better leaving group? Groups with a lower basicity are better leaving groups. Use the pKa table to compare possible leaving groups.

Derivatives with better leaving groups can be used to prepare derivatives with poorer leaving groups. In other words, a derivative can be prepared from any other derivative that is above it on the table.

Derivative Name Structure Leaving Group

Acid Chloride

Acid Anhydride

Ester

Amide

R C

O

Cl

R C

O

O C

O

R

R C

O

OR

R C

O

NR2



VI.Synthesis and Reactions of Acid Chlorides and Acid Anhydrides

Acid chlorides and acid anhydrides have similar chemistry (acid chlorides are somewhat more reactive). Their reactions follow similar mechanisms (the only difference is the identity of the leaving groups). Therefore, they are grouped together.

A. Synthesis of Acid Chlorides from Carboxylic Acids and SOCl2

Observed Reaction

We will not cover the mechanism.

B. Synthesis of Acid Anhydrides from Acid Chlorides

Observed Reaction

It is difficult to make mixed anhydrides, where each half comes from a different acid. Usually, a mixture of anhydrides with all possible combinations of the acids is formed.

This reaction follows an SNAc mechanism with Cl– as the leaving group:



C. Hydrolysis of Acid Chlorides and Acid Anhydrides

Observed Reaction

(acid chloride: LG = Cl ; acid anhydride: LG = RC(=O)O)

Hydrolysis is a general term for heteroatom exchange reactions where a heteroatom group is cut off of a compound and replaced with water (or an OH derived from water).

Mechanism of acid chloride and acid anhydride hydrolysis (SNAc with H2O nuc.)

Acid Chlorides are not stable in water. They react instantly with water. Even moisture in the air will cause reaction when they are exposed to the atmosphere.

Acid anhydrides are less reactive and can be handled in the atmosphere for brief periods without a large amount of hydrolysis.

D. Reaction of Acid Chlorides with Dialkylcuprates (Cuprate Coupling) (Review)

Observed Reaction



VII. Synthesis and Reactions of Esters

A. Synthesis of Esters from Acid Chlorides and Acid Anhydrides

Observed Reactions

(acid chloride: LG = Cl ; acid anhydride: LG = RC(=O)O)

Pyridine is added to the reactions to absorb H+ (acid) from the weak nucleophile after it attacks the acyl carbon.

These reactions follow the general SNAc mechanism. The only difference is that the neutral alcohol nucleophile must be deprotonated at the end to become stable.

B. Synthesis of Esters from Alcohols and Carboxylic Acids (Fischer Ester Synthesis)

Observed Reaction



Mechanism: Add ROH --> Remove Oxygen (H2O)

The reaction is an equilibrium reaction. Water is formed as a by-product of the reaction. We can use Le Chatelier’s Principle to obtain the desired product.

To obtain a high yield of the ester:

1) use excess alcohol (ROH) or excess carboxylic acid to push the left side of the reaction, and

2) remove water (H2O) to pull on the right side of the equilibrium.



C. Acid-Catalyzed Hydrolysis of Esters

Observed Reaction

Mechanism: The mechanism is the exact reverse of the Fischer Ester Synthesis mechanism. Practice by writing the mechanism of acid-catalyzed hydrolysis in the space below:



D. Base-Promoted Hydrolysis (Saponification)

Observed Reaction

Mechanism:

The reaction is promoted by base because the base increases the rate of reaction but is consumed (unlike a catalyst which is not consumed).

E. Transesterification of Esters

Observed Reactions

Base (Strong Nucleophile) Mechanism:



Acid-Catalyzed (Weak Nucleophile) Mechanism: Add ROH --> Remove OR

F. Hydride Reduction of Esters to Alcohols

Observed Reaction

Mechanism of Hydride Reduction of Esters:



G. Addition of Grignard Reagents to Esters (Reduction with Grignard Reagents)

Observed Reaction

Mechanism (note the similarity to the hydride reduction mechanism):

H. Cyclic Esters (Lactones)

If a carboxylic acid and a hydroxyl group (alcohol) are in the same molecule, then a cyclic ester can be formed by intramolecular reaction:



Cyclic esters are called lactones. They are classified by the carbon to which the hydroxyl group is attached (which affects the ring size):

Most natural lactones are gamma () or delta () lactones, because 5- and 6-membered rings are the most stable. For example, vitamin C is a gamma () lactone:

Lactones react like normal esters in hydrolysis, hydride reduction, and Grignard addition, except that the ring opens during the reactions:



VIII. Synthesis and Reactions of Amides

A. Synthesis of Amides from Acid Chlorides, Acid Anhydrides, and Esters

Observed Reactions

LG = Cl (acid chloride), R'C(=O)O (acid anhydride), or R'O (ester)

Pyridine is added to the reactions to absorb H+ (acid) from the weak nucleophile after it attacks the acyl carbon. Excess amine can be used instead (for example, excess NH3)

Mechanism (follows the SnAc mechanism):

Most amides cannot be made by direct reaction of a carboxylic acid and an amine (in contrast to esters, which can be made directly from the carboxylic acids).

Amines are more basic than alcohols, and they react with the carboxylic acid by acid-base reaction. The resulting ammonium ions do not have lone pairs, and therefore do not act as nucleophiles. This prevents the amine from reacting with the carbonyl (C=O) carbon and forming the amide.



B. Acid-Catalyzed Hydrolysis of Amides

Observed Reaction

Mechanism: Add H2O --> Remove NR2

C. Base-Promoted Hydrolysis of Amides

Observed Reaction

Mechanism [NOTE: VERY DIFFERENT FROM BOOK]:



D. Hydride Reduction of Amides

Observed Reaction:

Use H2O instead of H3O+ so that amine product is not protonated.

E. Cyclic Amides (Lactams)

Cyclic amides are called lactams, and they are classified in the same way as lactones:

Penicillin is a beta () lactam; its mechanism of action involves acylating a nucleophilic atom on an enzyme:



IX.Synthesis and Reactions of Nitriles

A. Synthesis of Nitriles by SN2 Reaction

Observed Reaction:

The R group on the substrate (R–X) must be CH3, 1o, or unhindered 2o (no SN2 reaction on 3o substrates).

Usually polar aprotic solvents (like DMSO) are used to favor SN2 reaction.

Mechanism (Review, SN2 reaction)

B. Acid-Catalyzed Hydrolysis of Nitriles

Observed Reaction:

The mechanism was covered earlier (Notes 21.III.E, p. 99)

The phases are: Add H2O --> Add H2O --> Remove NH2

C. Hydride Reduction of Nitriles

Observed Reaction:

We will not cover the mechanism of this reaction.



X. Carbonic Acid and Its Derivatives

Carbonic acid is unstable in acid. It decomposes to form CO2 and H2O:

Many higher organisms use the CO2/carbonic acid equilibrium to regulate pH:

CO2 is readily available in biological organisms. Mammals use a carbonic acid derivative to dispose of excess NH3 (which often comes from metabolizing proteins/amino acids):

Diesters of carbonic acid are called carbonates:

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