Organic Chemistry I & II
Organic Chemistry I & II

Organic Chemistry I & II

Lead Author(s): Steven Forsey

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Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

Up to 40-60% more affordable

Lifetime access on any device

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

$219

Hardcover print text only

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

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David R. Klein, “Organic Chemistry”, 3rd Edition

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Always up-to-date content, constantly revised by community of professors

Constantly revised and updated by a community of professors with the latest content

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

In-book Interactivity

Includes embedded multi-media files and integrated software to enhance visual presentation of concepts directly in textbook

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

Customizable

Ability to revise, adjust and adapt content to meet needs of course and instructor

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

All-in-one Platform

Access to additional questions, test banks, and slides available within one platform

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

About this textbook

Lead Authors

Dr. Steven Forsey, Ph.D.University of Waterloo

Steven Forsey is currently a Professor at University of Waterloo, teaching a variety of organic chemistry courses to Chemistry, Science, Chemical Engineering, Nanotechnology and distance education students. He received his Ph.D. (2004) for Synthetic Organic Chemistry from University of Waterloo, Ontario. He is a recipient of the Excellence of Science Teaching Award and has acted as the Teaching Fellow for the Department of Chemistry since 2016.

Contributing Authors

Felix NgassaGrand Valley State University

Neil GargUCLA

Jennifer ChaytorSaginaw Valley State University

Greg DomskiAugustana College

Christian E. MaduCollin Community College

Christopher NicholsonUniversity of West Florida

Franklin OwEast Los Angeles College, UCLA

Robert S. PhillipsUniversity of Georgia

Grigoriy SeredaUniversity of South Dakota

Simon E. LopezUniversity of Florida

Brannon McCulloughNorthern Arizona University

Jason JonesKennesaw State University

José BoquinAugustana College

Stephanie BrouetSaginaw Valley State University

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Chapter 24: Carboxylic Acids

Malic acid, one of the most common carboxylic acids, is found in fruits such as granny smith apples. [1] ​


Contents

Learning Objectives

  • Identify carboxylic acid functional groups and draw the structure of different carboxylic acids.
  • Understand the different synthetic routes to carboxylic acids.
  • Understand and explain the reaction mechanism of carboxylic acids via nucleophilic acyl substitution.
  • Be able to predict the product of the reactions of carboxylic acids and derivatives.
  • Understand the synthesis, reaction mechanisms, and uses of acyl chlorides.

24.1 Introduction

This chapter provides an overview of carboxylic acids, their synthesis, and their reactions. Carboxylic acids can be synthesized from many different functional groups using a variety of different reagents. This chapter investigates common methods of synthesizing carboxylic acids.

This chapter also presents reactions with carboxylic acids that will be examined in more detail in Chapter 25. This is to allow students to obtain an overview of the reactions and become comfortable with the various reactions before studying the reaction in mechanistic detail.

Carboxylic acids are a group of organic compounds that contain the carboxyl group (–COOH). The carboxyl group is formed when the hydroxyl group (–OH) is attached to a carbonyl group (C=O).

Figure 24.1. Generic carboxylic acid and carboxyl group​


It will be of interest to know that many natural products and pharmaceutical products contain this carboxylic acid functional group.

Figure 24.2. Example natural products and pharmaceuticals which contain carboxylic acid functional groups


24.1.1 Nomenclature of Carboxylic Acid

In the IUPAC system of naming, if the COOH group (also written as CO2H) is attached to a straight carbon chain, then locate the longest continuous carbon chain (LCC) containing the carboxyl group and name by replacing the “e” ending of the alkane name with the suffix “-oic acid.” However, if the COOH group is directly attached to a ring, then name the ring and add the word carboxylic acid.

Figure 24.3. Examples of carboxylic acid naming for alkyl and cycloalkyl systems

Carboxylic acids with other functional groups are named according to the following rules:

Figure 24.4. Example naming of two carboxylic acid containing molecules: 4-chloro-3-hydroxyhexanoic acid and 5-bromocyclohex-2-enecarboxylic acid​

Organic compounds with two carboxyl groups are called diacids and are named as alkanedioic acid. In this case, the “e” of the alkane ending is not removed; rather, the suffix “dioic acid” is added to the alkane name.

Figure 24.5. IUPAC and common names of some diacid molecules



Q24.1 - Level 1

What is the IUPAC name for the following compound?

question description
A

2,4-dichloro-3-methylheptanedioic acid

B

3,5-dichloro-4-methylheptanedioic acid

C

2,4-dichloro-5-chloroheptanedioic acid

D

3,5-dichloro-4-methylpentanedioic acid

E

3,5-dichloro-4-methylheptanedioyl acid


Q24.2 - Level 1

What is the structure of 2-cycloheptenecarboxylic acid?

question description
A

a

B

b

C

c

D

d

E

e


Q24.3 - Level 1

What is the IUPAC name for the following compound?

question description
A

1,3-dimethylcycloheptane-6-carboxylic acid

B

3,3-dimethylcycloheptanecarboxylic acid

C

3,6-dimethylcycloheptane-6-carboxylic acid

D

3,6-dimethylcycloheptanecarboxylic acid

E

1,4-dimethylcycloheptane-6-carboxylic acid


Q24.4 - Level 2

Match the following structures with their correct name.

question description
Premise
Response
1

1)

A

3-ethylcyclohexanecarboxylic acid

2

2)

B

(ZZ)-5-ethyl-3-methylhept-3-enoic acid

3

3)

C

(3S¸4SS¸4S)-3-hydroxy-4-phenylnonanoic acid

4

4)

D

1-ethylcyclohexane-3-carboxylic acid

E

(3R¸4RR¸4R)-3-hydroxy-4-phenylnonanoic acid

F

(EE)-5-ethyl-3-methylhept-3-enoic acid


24.2 Commercial Sources of Carboxylic Acids

Carboxylic acids are very important commercial compounds and used in different industries. Most of them are produced on a large scale. In this section, we will explore two important commercial carboxylic acids and their commercial synthesis.

Acetic acid is one of the most important commercial carboxylic acids and is produced in large quantities in the United States for use in the food industry and as an industrial solvent. White distilled vinegar is used inside and outside the home for cleaning, laundry, cooking, automotive care, pickling, and canning, to mention a few.

Acetic acid is used in the food industry as vinegar and is produced by the fermentation of sugar or starch to give ethanol, which is further subjected to oxidative fermentation.

Figure 24.6. Production of acetic acid through fermentation of sugars

Another industrial approach for producing acetic acid is from a rhodium-catalyzed reaction of methanol with carbon monoxide.

Figure 24.7​. Production of acetic acid by a rhodium-catalyzed reaction of methanol and carbon monoxide

Acetic acid can also be produced industrially from the catalytic oxidation of ethylene to give acetaldehyde, which in turn is catalytically oxidized to acetic acid.

Figure 24.8. Catalytic oxidation of ethylene to produce acetic acid

Benzoic acid is another commercially important carboxylic acid that is used as a food preservative and as starting material for the synthesis of some drugs like p-aminobenzoic acid (PABA), which is a component of folic acid and B-complex vitamins.

Figure 24.9. Structure of p-aminobenzoic acid

Benzoic acid is produced industrially by using strong oxidants (like HNO3, KMnO4) to oxidize toluene.

Figure 24.10. Oxidation of toluene to produce benzoic acid


24.3 Synthesis of Carboxylic Acids

Some of the methods for the preparation of carboxylic acids have already been discussed in previous chapters. We are going to review some of these methods and then introduce two more synthetic methods.

24.3.1 Oxidation of Aldehydes and Primary Alcohols (Chapter 14.6)

The oxidation of aldehydes and primary alcohols uses strong oxidizing agents (like Na2Cr2O7/H2SO4/H2O or KMnO4/H2O) to give a carboxylic acid.

Figure 24.11​. Oxidation of alcohols and aldehydes to carboxylic acids. [O] represents an oxidizing agent.

These oxidants can convert both 1o alcohols and aldehydes to carboxyl groups and 2o alcohols to ketones but have no effect on 3o alcohols.

Figure 24.12. Examples of oxidation of primary and secondary alcohols​


Aldehydes can also be oxidized with Tollens’ reagent.

Figure 24.13. Oxidation of propanal with Tollen's reagent

24.3.2 Oxidation of Alkynes to Give Carboxylic Acids (Chapter 13.5.6)

This can be accomplished by ozonolysis (O3) or with acidic KMnO4/heat. Oxidative cleavage of an internal alkyne will give two carboxylic acids as product; however, with a terminal alkyne, it will give a carboxylic acid and CO2 as products.

Figure 24.14. Examples of oxidation of alkynes to give carboxylic acids



Q24.5 - Level 1

Predict the missing product in the reaction below.

question description
A

a

B

b

C

c

D

d

E

e



Drawing Question 24.6 - Level 1

Draw the product of the reaction. 

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Q24.7 - Level 2

Predict the product of the reaction.

question description
A

a

B

b

C

c

D

d

E

e


24.3.3 Oxidation of Alkylbenzenes (For a detailed mechanism see Chapter 21.5.2)

The side chains of alkylbenzenes can be oxidized to carboxyl groups using hot KMnO4 or hot chromic acid provided that the benzylic position has at least one hydrogen atom.

Figure 24.15. Oxidation at the benzylic position using either hot potassium permanganate or hot chromic acid


24.3.4 Hydrolysis of Nitriles (For a detailed mechanism see Chapter 25.2.7)

Nitriles are compounds containing a cyano group. Nitriles can be converted to carboxylic acids when heated with aqueous acids.

Figure 24.16. Conversion of nitrile to carboxylic acid using aqueous acid.

This reaction affords the synthesis of carboxylic acids from alkyl halides using a two-step process. The first step proceeds via an SN2 mechanism to give the nitrile, which is subsequently subjected to hydrolysis (the mechanism for the hydrolysis reaction is given in Chapter 25).

Figure 24.17​. Two-step process to convert from alkyl halide to carboxylic acid


24.3.5 Carboxylation of Grignard Reagents or Alkyllithium (Review of Grignard reaction, Chapter 14.5.2)

Grignard reagents (RMgX) and alkyllithium reagents (RLi) are compounds that can produce carbanions (R-). Therefore, carboxylic acids can be synthesized by converting an alkylhalide to a Grignard reagent, which in turn is treated with CO2 followed by aqueous acid. In addition, carboxylation of alkyllithium will give carboxylic acids.

24.18.png
Figure 24.18​. Carboxylation of Grignard reagents or alkyllithium reagents with carbon dioxide

Mechanism of carboxylation of the Grignard reagent:

Figure 24.19. Mechanism of carboxylation of Grignard reagent​

Note that the synthesis of carboxylic acids via hydrolysis of nitriles and carboxylation of Grignard reagent involves the introduction of one extra carbon atom.


Q24.8 - Level 1

What product is formed from the reaction sequence?

question description
A

a

B

b

C

c

D

d

E

e


Q24.9 - Level 1

Predict the product of this reaction.

question description
A

a

B

b

C

c

D

d

E

e


Q24.10 - Level 3

Which of these reagents will not give the transformation below?

question description
A

a

B

b

C

c

D

d

E

e


24.4 Reaction of Carboxylic Acids: Nucleophilic Acyl Substitution (Chapter 25.1)

The aldehydes, ketones, carboxylic acids, and acid derivatives shown below all contain a carbonyl group (acyl group). Hence, one might think that all will undergo the same types of reactions since the only difference is their leaving groups. However, there is a big difference between a carbonyl functional group bonded to a good leaving group or a poor leaving group.

Figure 24.20

As discussed in previous chapters, aldehydes and ketones have bad leaving groups, a hydride ion or a carbanion. Hence, they tend to undergo a different type of reaction, commonly called nucleophilic addition. Nucleophilic addition changes the hybridization of the carbonyl carbon from sp2 to sp3 and, depending on the nucleophile, can either cause a reduction of the carbonyl carbon (e.g. carbon nucleophile) or no change in the oxidation state (e.g. oxygen nucleophile). On the other hand, carboxylic acids and acid derivatives have better leaving groups, and thus, react via nucleophilic acyl substitution mechanism. In nucleophilic acyl substitution,   the oxidation state of the carbonyl carbon is maintained while the LG is replaced with a  nucleophile.

Figure 24.21. Generic nucleophilic acyl substitution reaction.​

Nucleophilic acyl substitution usually takes place either under acidic or basic conditions, depending on the strength of the nucleophile. In this chapter, we will focus on the nucleophilic acyl substitution of carboxylic acids. For a detailed discussion of other leaving groups, see Chapter 25.

Mechanism of nucleophilic acyl substitutions:

The base-catalyzed mechanism involves the use of strong nucleophiles. This mechanism is a two-step reaction. The first step is a nucleophilic attack on the carbonyl carbon (nucleophilic addition) and the second step is the loss of the leaving group (elimination).

Figure 24.22. Mechanism of generic nucleophilic acyl substitution reaction​​


The acid-catalyzed mechanism involves the use of weak nucleophiles. Under the acid-catalyzed condition, the carboxylic acid is first protonated to activate the carbonyl group. The activated acyl group is then attacked by the weak nucleophile (Nuc-H) followed by subsequent deprotonation, loss of the leaving group, and deprotonation to give the acyl substitution product. In the general reaction below, LG is a good leaving group, such as a halogen.

Figure 24.23. Mechanism of acid catalyzed nucleophilic acyl substitution reaction​


Keeping it Real

Carboxylic acids and their derivatives are seen in countless bioactive molecules. They are also important for various biological functions and regulatory processes. Check out a small sampling of these molecules below!



24.4.1 Reactions of Carboxylic Acids

Carboxylic acids, as the name implies, are organic Brønsted–Lowry acids and so can participate in two types of reactions:

Acid–base reactions: Carboxylic acids can easily react with Brønsted–Lowry bases to form a carboxylate ion provided a weaker conjugate acid and base are formed in the reaction. An acid can be deprotonated by a base that has a conjugate acid with a higher pKa value. Hence, strong nucleophiles like the hydroxyl group, NH3, and RNH2 are strong bases that undergo acid–base reactions. As shown in Figure 24.24, the acid-base reaction would be much faster than the nucleophilic acyl substitution reaction since a weaker acid-base pair is formed. 

Figure 24.24. Proton transfer reaction of 2,2-dimethylpropanoic acid with sodium hydroxide​

Nucleophilic acyl substitution: The lone pair electrons on the carbonyl oxygen atom of the carboxylic acid is used in the protonation of the carboxyl group by strong acids. This protonation occurs preferentially on the carbonyl oxygen due to resonance stabilization (see diagram below). This activates the carbonyl carbon, making it more electrophilic and susceptible to nucleophilic attack by weak nucleophiles such as alcohols.

24.25.png
Figure 24.25. Acid catalyzed nucleophilic acyl substitution reaction between a carboxylic acid and an alcohol.​


Q24.11 - Level 1

This reaction, which is typical of carboxylic acids and their derivatives, is called

question description
A

Nucleophilic acyl addition.

B

Nucleophilic non-acyl substitution.

C

Electrophilic acyl addition.

D

Nucleophilic acyl substitution.

E

Electrophilic acyl substitution.


Q24.12 - Level 2

Which would be a reasonable intermediate in the mechanism for this acid-catalyzed hydrolysis?

question description
A

a

B

b

C

c

D

d

E

e


Q24.13 - Level 2

Which intermediate is involved in the mechanism of this base-catalyzed hydrolysis?

question description
A

a

B

b

C

c

D

d

E

e


24.5 Condensation of Carboxylic Acids with Alcohols: Fischer Esterification (Chapter 25.1.3)

When treated with an alcohol under acidic conditions, carboxylic acids are converted to esters. This synthetic approach is called Fischer esterification.

Figure 24.26. Fischer esterification reaction of a carboxlyic acid with an alcohol.​


This reaction occurs under equilibrium conditions; therefore, according to Le Châtelier’s principle, the forward reaction can be favored by using excess alcohol or by removal of the water molecules as they are formed. The reverse reaction can be favored by using excess water or removing the alcohol molecules as they are produced.

The first step in Fischer esterification is the protonation of the carbonyl oxygen, which activates the acyl group. This is followed by addition of the nucleophile (alcohol), and elimination of the leaving group (water), with subsequent deprotonation to give the ester product shown below.

Examples:

Figure 24.27a. Mechanism of Fischer esterification​


Figure 24.27b. Examples of Fischer esterification

When the γ- or δ-hydroxyl carboxylic acids are used, they lead to intramolecular esterification giving a 5- or 6-membered ring lactones, respectively, as shown below.

Figure 24.28. Intramolecular esterification of gamma and delta hydroxycarboxylic acids​


24.6 Esterification using Diazomethane

Diazomethane is a toxic and explosive gas that easily dissolves in ether to give a yellow solution. This ether solution of diazomethane reacts with carboxylic acids to give methyl carboxylate compounds and nitrogen gas. The toxic and explosive nature of diazomethane makes it unsuitable for large-scale synthesis of methyl esters.

Figure 24.29​. Esterification of carbocylic acids with diazomethane

This reaction involves the initial protonation of the diazomethane by the carboxylic acid to give the carboxylate ion and methyl diazonium ion. This step is then followed by a nucleophilic attack of the carboxylate ion on the methyl diazonium ion to displace the nitrogen gas and give the methyl ester.

Mechanism for esterification using diazomethane:

Figure 24.30​a. Mechanism of esterification of a carboxylic acid using diazomethane.


Figure 24.30​b. Mechanism of esterification of a carboxylic acid using diazomethane.



Q24.14 - Level 1

Provide the major organic product of the reaction shown below.

question description
A

a

B

b

C

c

D

d

E

e


Q24.15 - Level 1

Predict the major organic product of the reaction shown.

question description
A

a

B

b

C

c

D

d

E

e


Q24.16 - Level 1

Which of the following conditions will drive the equilibrium of the Fischer esterification towards ester formation?

A

Addition of water

B

Removal of water as it is formed

C

Addition of an inorganic acid as a catalyst

D

Addition of alcohol


Q24.17 - Level 2

The methyl ester of a carboxylic acid can be synthesized directly using _________.

A

SOCl2_2

B

PCl5_5

C

(COCl)2_2

D

CH2_2N2_2

E

Both options B and D are correct.


Q24.18 - Level 1

Predict the major organic product of the reaction shown below:

question description
A

a

B

b

C

c

D

d

E

e


24.7 Condensation of Carboxylic Acid with Amines

The direct synthesis of amides from carboxylic acid and amines is difficult. Since amines and ammonia are Brønsted–Lowry bases they participate in acid–base reactions with carboxylic acid to give ammonium carboxylate salt. The ammonium carboxylate salt at high temperature (above 100oC) dehydrates to give an amide.

Figure 24.31. Synthesis of amides


Q24.19 - Level 1

Choose the correct product of the reaction below.

question description
A

a

B

b

C

c

D

d

E

e



Amide Bond Formation

Ways to efficiently make amides from amino acid building blocks have been highly sought after for decades. The synthesis of peptides and polypeptides, which are chains of amino acids connected by amide linkages, was a notable challenge in the 20th century.

One of the breakthroughs in peptide synthesis comes from UCLA alumnus Robert Bruce Merrifield (BS 1943; Ph.D. 1949) who won the Nobel Prize in Chemistry in 1984, for his work on solid-phase peptide synthesis. Over time, this methodology has seen significant improvements in scope and utility. 

Example of a modern peptide synthesizer. [7]​


There are countless examples of amide bond-forming reactions from carboxylic acids in biology. One of them can be seen in the synthesis of glutathione, an important antioxidant found in plants, animals, and fungi.

Glutathione is synthesized from three amino acids (glutamate, cysteine, and glycine) using two amide bond forming reactions. In both cases, the amide bonds are formed from the coupling of carboxylic acids and amine substrates. 





Keeping it Real Q24.1


Keeping it Real Q24.1

Using the image above, predict the structure of the amide product γ-glutamylcysteine formed after coupling of glutamate and cysteine.

question description
A

a

B

b

C

c

24.8 Reduction of Carboxylic Acids (For a detailed mechanism see Chapter 25.3.2)

Carboxylic acids are generally difficult to reduce. Only a few reducing agents can react with carboxylic acids. To reduce carboxylic acids, you either use a strong reducing agent or activate the carboxylic acid to other reactive derivatives. In this section, we will review the few reducing agents of carboxylic acids.

24.8.1 Lithium Aluminum Hydride Reduction of Carboxylic Acids (For a detailed mechanism see Chapter 25.3.2)

Lithium aluminum hydride (LiAlH4 or LAH) is a strong nonselective reducing agent and a rich source of hydride ion. It reduces carboxylic acids to primary alcohols. Other mild reducing agents are not strong enough to initiate reduction of carboxylic acids.

Example:

Figure 24.32​. Lithium aluminum hydride reduction of carboxylic acids to alcohols

The first step in this reaction is the deprotonation of the carboxylic acid. This is possible since the LiAlH4 is both a strong nucleophile and a very strong base. Hence, deprotonation of the carboxylic acid by LAH will lead to the liberation of hydrogen gas and the formation of carboxylate ion. The rest of the mechanism could proceed via several possible paths. The most likely path is the nucleophilic addition of hydride ion from AlH3 to the carbonyl group of the lithium carboxylate to give an aldehyde.

Figure 24.33​. First part of the reduction of a carboxylic acid with lithium aluminum hydride - formation of an aldehyde

Once the aldehyde is formed, it is further reduced by LiAlH4 to give an alkoxide, which is then protonated by adding water to give a primary alcohol.

Figure 24.34​. Second part of reduction of a carboxylic acid with lithium aluminum hydride - conversion of the aldehyde intermediate to an alcohol


24.8.2 Borane Reduction of Carboxylic Acids

The limitation of using LAH is that it reduces all compounds with a carbonyl group. An alternate approach to reducing carboxylic acids to primary alcohols is to use the borane-tetrahydrofuran complex (BH3-THF).

Figure 24.35. Borane reduction of a generic carboxylic acid to a primary alcohol

Borane is preferred to LiAlH4 due to its selectivity. BH3-THF can selectively reduce carboxylic acid in the presence of both ketones and aldehydes, whereas LiAlH4 non-selectively reduces all carbonyl groups.

Example:

Figure 24