Organic Chemistry I & II
Organic Chemistry I & II

Organic Chemistry I & II

Lead Author(s): Steven Forsey

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

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

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

Wiley

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

In-book Interactivity

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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 25: Carboxylic Acid Derivatives

Tannic acid is found in the bark, cones, and seeds of Sequoia trees, the world's largest species of tree. The molecule acts as a natural defence against decomposition, termites, and wildfire. [1]


Contents


Learning Objectives

  • Be able to identify what is in common between nucleophilic addition to the carbonyl group in aldehydes and ketones and nucleophilic acyl substitution.
  • Understand the role of Lewis acids in activating the carboxylic acid derivative toward nucleophilic acyl substitution.
  • Understand how and why acyl substitution is different from nucleophilic addition to the carbonyl group in aldehydes and ketones.
  • Understand the role of the leaving group in the mechanism of nucleophilic acyl substitution.
  • Be able to compare reactivity of aldehyde, ketones, and carboxylic acid derivatives with nucleophiles.
  • Understand why the product of nucleophilic acyl substitution may react with another equivalent of nucleophile.
  • Identify a carbonic acid derivative in a given structure.
  • Apply the general mechanism of nucleophilic acyl substitution to interconversions of carboxylic acid derivatives, including Fischer esterification, hydrolysis, and trans-esterification.
  • Compare reactivity of different carboxylic acid derivatives based on stabilization of the acyl group and quality of the leaving group.
  • Apply preparation of carbonic acid derivatives from isocyanates, isothiocyanates, and carbodiimides to biolabeling, preparation of amines, industrial polymers, synthesis of peptides, and their use in nanotechnology.
  • Use interconversions of carboxylic acid derivatives in organic synthesis.


25.1 Nucleophilic Acyl Substitution

Carboxylic acid derivatives are compounds that produce carboxylic acids upon acidic hydrolysis. Examples of some of the most common carboxylic acid derivatives are presented in Figure 25.1 and will be discussed further in this chapter.

​Figure 25.1. Examples of carboxylic acid derivatives​

25.1.1 Leaving Group at the Carbonyl: Consequences for the Reaction with Nucleophiles

The general reaction for nucleophilic acyl substitution and nucleophilic addition to an aldehyde or ketone is given in Figure 25.2. Notice the difference between the two reactions. The heteroatom of the carboxylic acid derivative is a part of the leaving group and is replaced by the nucleophile. Aldehydes and ketones do not possess a leaving group because carbanions or hydride are very poor leaving groups.

Figure 25.2. Comparison between nucleophilic acyl substitution and nucleophilic addition to a carbonyl carbon​​


Notice also that the atom bonded to the carbonyl carbon of aldehydes or ketones does not possess an atom with lone pairs of electrons. Placing an atom with at least one lone electron pair next to the carbonyl group makes a profound influence on its chemical behavior. First, conjugation of the lone electron pair with the carbonyl group stabilizes the compound and reduces its reactivity toward reactions where the C-L bond does not break—enolization, deprotonation, and addition to the carbonyl group—as shown in Figure 25.3.

Figure 25.3. Reaction centers arising from the interaction of the carbonyl group and an atom with a lone electron pair​​


Second, the presence of lone electron pairs is characteristic of more electronegative atoms, which are much weaker bases, and therefore much better leaving groups than carbanions. As a consequence, such compounds are likely to undergo substitution reactions as opposed to aldehydes and ketones which undergo addition reaction. In Figure 25.3, LG is the leaving group, and the rest of the molecule is considered an acyl group. Naturally, replacing the leaving group LG at the acyl group with a nucleophile is termed nucleophilic acyl substitution.


Question 25.1 - Level 1

Click on the electrophilic center.


Question 25.2 - Level 1

Click on the nucleophilic center.


Question 25.3 - Level 1

Click on the leaving group.


A special case of L is –O-, whose negative charge is equally distributed between two electronegative oxygens, making a stable carboxylate anion. Thus, unlike carboxylic acid derivatives, carboxylates (salts of carboxylic acids) undergo nucleophilic addition only with very strong nucleophiles such as organolithiums. The reaction does not proceed to the next step of elimination, which would require a doubly charged anion (O2-) to leave and significantly increase electrostatic energy of the system (Figure 25.4).

Figure 25.4. Addition of organolithium to carboxylate

25.1.2 Interconversion of Acid Derivatives by Nucleophilic Acyl Substitution

Now let us take a more general look at the substitution reactions you already know from previous chapters. Any substitution ends up replacing a leaving group at a substrate with an attacking group. There are three logistical ways to achieve that final result:

1. The leaving group leaves first, and then the incoming group takes its place as illustrated by the following video.

An example of this type of substitution is SN1 reaction, where the leaving group leaves first, and the carbocation then captures the incoming nucleophile.  Another example would be ligand exchange around a metal center, such as replacement of water with ammonia around a copper ion.

2. In the second scenario, the leaving group leaves simultaneously with the incoming group taking its place as illustrated by this video.

The SN2 reaction is an excellent illustration of these logistics.

3. Now, what is significantly different about the substitution when the incoming group enters the molecule first and then the leaving group leaves?

The difference is presence of the second chair, which illustrates that this type of substitution requires some extra space at the reaction center. This space can be a C=C bond when the incoming group donates electrons to or withdraws them from the carbon connected to the reaction center by a C=C bond. Electron donation leads to nucleophilic aromatic substitution through the Meisenheimer complex, while electron withdrawal leads to electrophilic aromatic substitution. In the substrate of the nucleophilic acyl substitution, the leaving group is attached to the carbonyl group (Figure 25.5), where the shift of electrons to the atom of oxygen allows the incoming nucleophile to add to the carbonyl first with the formation of the tetrahedral intermediate. In summary, the nucleophilic acyl substitution has two steps:

1) Addition of a nucleophile to the carbonyl group with formation of a tetrahedral intermediate.

2) Elimination of the leaving group with the restoration of the C=O bond driven by its stability.

Figure 25.5 shows the general mechanism of nucleophilic acyl substitution.

Figure 25.5. General mechanism of nucleophilic acyl substitution​

25.1.3 Transesterification

The simplest example of nucleophilic acyl substitution is transesterification under alkaline conditions. The general mechanism is given in Figure 25.6 and a specific example is also shown in the following video:



Figure 25.6. General mechanism for transesterification under basic conditions​​

While transesterification under alkaline conditions is the simplest example of nucleophilic acyl substitution, it’s a good model for looking into specifics of nucleophilic acyl substitution under basic and acidic conditions. Under alkaline conditions, the nucleophile is usually activated by deprotonation since alkoxides are much stronger nucleophiles than alcohols and the reaction usually proceeds in two steps. For transesterification, the nucleophile and the leaving group have similar basicity, so the equilibrium needs to be shifted to the desired product by using excess of the starting alcohol or by removing the product from the reaction mixture.

Under acidic conditions, protonation occurs first followed by nucleophilic attack. By protonating the carbonyl oxygen, the carbonyl carbon is converted to a good electrophile so that the weak nucleophile, alcohol, can easily attack. 

In general, protonation of the carbonyl group increases its potential energy mostly because of a higher electrostatic energy of a charged particle. Moreover, addition of a neutral nucleophile does not change the charge of the system as it proceeds to the tetrahedral intermediate. As a result, protonation of the carbonyl group decreases the activation energy of the addition step (Figure 25.7). The diagram below does not show the activation energy of protonation, but rather the energy levels of the carbonyl compound before and after protonation. The acid-base reactions normally occur in many steps through a series of differently solvated intermediates.


Figure 25.7. Potential energy comparison between basic, neutral, and acidic reaction condition for transesterification​​


The general reaction mechanism for the acid-catalyzed transesterification is given in Figure 25.8. The reaction occurs in two steps: 1) acid-catalyzed addition of the nucleophile and 2) acid-catalyzed elimination of the leaving group.

Figure 25.8. Mechanism of acid-catalyzed transesterification​


The general mechanism and a specific example are also shown in the following video:

Note that there are no negatively charged reactive species shown in the mechanism of acid-catalyzed transesterification because the “spectator” anions such as HSO4- are not directly involved in the mechanism. Try to avoid the common mistake of using an alkoxide ion for the nucleophilic attack or for proton transfer reactions. One cannot have a strong base and acid in the same solution because they would neutralize each other.

Another common mistake is to have a negatively charged alkoxide ion as the leaving group. An alkoxide ion is a poor leaving group. Thus, in an acid-catalyzed reaction, the second proton transfer from the solvent is necessary so that elimination produces a neutral alcohol as the leaving group (Figure 25.9).

Figure 25.9. Leaving group must be neutral in acid-catalyzed transesterification.​


Question 25.4

Question 25.4 - Level 2

Match the process or molecule to the correct terms given below for the acid-catalyzed transesterification reaction.

question description
Premise
Response
1

1)

A

Nucleophile

2

2)

B

Proton transfer

3

3)

C

Nucleophilic addition

4

4)

D

Elimination

5

5)

E

Tetrahedral intermediate

6

6)

F

Leaving group

7

7)

G

Activated carbonyl group


Fischer esterification is the reaction between a carboxylic acid and an alcohol in the presence of a strong acid catalyst. The mechanism of Fischer esterification is similar to the mechanism of acid-catalyzed transesterification, but the alcohol reacts with a carboxylic acid instead of an ester (Figure 25.10).

25.10.png
Figure 25.10. Mechanism of Fischer esterification​​​

The general mechanism and a specific example are also shown in the following video:


Question 25.5

Question 25.5 - Level 1

Match the intermediates and the final product to numbers given in the mechanism.

question description
Premise
Response
1

1)

A

Compound E

2

2)

B

Compound A

3

3)

C

Compound B

4

4)

D

Compound D

5

5)

E

Compound F

6

6)

F

Compound C


Question 25.6

Question 25.6 - Level 3

Are the following statements about Fisher esterification correct or incorrect?

Premise
Response
1

To shift the equilibrium to the products excess alcohol can be used

A

Incorrect

2

To shift the equilibrium to the products water can be removed as it is formed during the reaction

B

Incorrect

3

To shift the equilibrium to the reactants add water

C

Correct

4

In the Fischer esterification reaction a hydroxide ion is the leaving group

D

Correct

5

In the Fischer esterification reaction water is the leaving group

E

Correct

6

In the Fischer esterification reaction an alcohol is the leaving group

F

Incorrect

G

Incorrect

H

Correct


More examples of nucleophilic acyl substitution under acidic and basic conditions will be discussed in the next section.

25.1.4 Hydrolysis of Carboxylic Acid Derivatives

When water or its conjugate base (OH-) acts as a nucleophile, the nucleophilic acyl substitution produces a carboxylic acid or its salt and thus belongs to the class of hydrolysis reactions. Hydrolysis means “to break with water.” Thus, acid-catalyzed hydrolysis of an ester is essentially Fischer esterification going backwards (Figure 25.11).

Figure 25.11. Acid-catalyzed hydrolysis of an ester​


In the alkaline hydrolysis of esters, the highly basic leaving alkoxide anion immediately captures a proton from the carboxylic acid formed from the tetrahedral intermediate. The mechanism for the hydrolysis of an ester in basic conditions is given in Figure 25.12.

Figure 25.12 Alkaline hydrolysis of esters​​

This acid-base reaction is not reversible because the base completely deprotonates the acid produced in the reaction to a carboxylate salt. The carboxylate salt is not electrophilic enough to react with an alcohol or an alkoxide (reactivity discussed in more detail below). However, it can be readily converted to the carboxylic acid by adding a dilute strong acid.

In a basic solution, the hydrolysis of an ester is called saponification. Saponification of fats, which are long-chained esters, produces soap (Figure 25.13).

Figure 25.13. Saponification of fat molecule using sodium hydroxide.​


These examples illustrate that the nucleophilic acyl substitution often occurs as a part of a more complex reaction sequence that may also include protonation, deprotonation, and proton transfers.

In the above examples, an ester was hydrolyzed in an acidic or basic solution to produce a carboxylic acid (acidic conditions) or carboxylate salt (basic conditions). Thus an ester is a carboxylic acid derivative. All carboxylic acid derivatives are compounds with functional groups that can be hydrolyzed to a carboxylic acid under acidic conditions. All of the compounds shown in Figure 25.14 are carboxylic acid derivatives and can be hydrolyzed to carboxylic acids under acidic conditions.

Figure 25.14. Hydrolysis of carboxylic acid derivatives​​

Hydrolysis of all of the carboxylic acid derivatives follows a similar acid and base hydrolysis mechanisms as were discussed for esters. Thus, once you understand one mechanism, you can do the mechanism for the hydrolysis of any carboxylic acid derivative.

Thioesters, imidoesters, and orthoesters are also carboxylic acid derivatives (see Question 25.7 below). The orthoester is similar to a nitrile in that it is first hydrolyzed to another carboxylic acid derivative—an ester in this case—and then further hydrolyzed to a carboxylic acid.


Question 25.7 - Level 2cca

Click on the carbons that become the carbonyl carbon of the carboxylic acid group after hydrolysis.


A carboxylic acid derivative can be identified by the presence of a carbon connected by three bonds to 1-3 atoms with at least one lone electron pair. Those three bonds can come in various sets: three single bonds, as in orthoesters; one double bond and one single bond, as in esters, thioesters, imidoesters, amides, anhydrides, and acid halides; or one triple bond, as in nitriles. They can connect to one or more atoms with a lone electron pair, most commonly oxygen, nitrogen, or sulfur (Figure 25.15). To derive the structure of a carboxylic acid from its derivative, we need to break all those three bonds (shown in green in Figure 25.15), and replace the freed valences of carbon by –OH and =O.

Figure 25.15. Deriving the structure of a carboxylic acid (RCOOH) from its derivative​


The same way of tracing an acid derivative back to the parent acid also applies to inorganic acids and carbonic acid, whose derivatives will be discussed at the end of this chapter. To derive any carboxylic acid from its derivative, we need to break all bonds (shown in green in Figure 25.16) and replace the freed valences of carbon or a heteroatom (shown in red in Figure 25.16) by –OH and =O.

Figure 25.16. Deriving the structure of an acid from its derivative



Summary of nucleophilic acyl substitution

There are two main steps in the mechanism

  1) Nucleophilic addition to the carbonyl carbon to form a tetrahedral intermediate

  2) Elimination of a leaving group from the tetrahedral intermediate to reform the more stable carbonyl double bond

Basic conditions: Basic conditions increase the nucleophilicity of the nucleophile by converting weak nucleophiles (H2O, ROH) into strong nucleophiles (HO-, RO-). The nucleophile is generally more reactive than the leaving group. If the leaving group and nucleophile have similar basicity, the reaction conditions can be changed to push the reaction to products by adding more of one of the reactants or removing a product that is formed. 

Acidic conditions: The carbonyl functional group is activated through protonation by a strong acid. Protonation of the carbonyl group increases its reactivity towards weak nucleophiles (H2O, ROH). If the nucleophile and the leaving group have similar basicity, the equilibrium can be shifted to the product by adding excess of a reagent or by removing a product from the reaction mixture as it is formed.

25.2 Reactivity of Carboxylic Acid Derivatives

Most reactions of carboxylic acid derivatives involve the nucleophilic acyl substitution steps. In order to understand specific reactions of each carboxylic acid derivative, it is essential to discuss how the structure of a carboxylic acid derivative affects its reactivity.

25.2.1 Structure-Reactivity Relationship of Carboxylic Acid Derivatives

The reactivity trend of carboxylic acid derivatives is shown in Figure 25.17.

Figure 25.17. Relative reactivity of carboxylic acid derivatives

The first step in the mechanism is the nucleophilic addition to the carbonyl carbon. This is a bimolecular reaction, so the rate of reaction is dependent on the nucleophilicity of the nucleophile and the electrophilicity of the carboxylic acid derivative. Once the tetrahedral intermediate is formed, elimination can occur to produce the products or go backwards to reform the reactants. Figures 25.18a and 25.18b shows the potential energy diagrams for three nucleophilic acyl substitution reactions. 

Figure 25.18a. General mechanism of the nucleophilic acyl substitution reaction.
Figure 25.18b. Potential energy diagram of nucleophilic acyl substitution reactions.​​

Potential energy diagram 1) in Figure 25.18b depicts a reaction where the products have lower energy than the reactants. Once the tetrahedral intermediate has formed, the expulsion of the leaving group is the easiest pathway and would readily form the more stable products. This situation usually takes place when the nucleophile is a stronger base than the leaving group for two reasons. First is that according to the definition of the strength of basicity, weaker bases tend to have lower energy than stronger bases, which is why they are formed from acids easier. Second is that the lower energy of a weaker base usually lowers the activation energy leading to it, so weaker bases make better leaving groups just like in the reactions you already know (SN1, SN2, E1, E2).

Potential energy diagram 2) in Figure 25.18b shows a reaction where the reactant and products are of equal energy. This could be a transesterification reaction in a basic solution, so the leaving group and the nucleophile are equal in their ability to leave and the rate of forming the products or reactants would be equal because the forward activation energy is equal to the reverse activation energy. To push the equilibrium to products excess nucleophile would have to be added.

Conversely, if the nucleophile is a weaker base than the leaving group, as in potential energy diagram 3), the expulsion of the leaving group would generate less stable products. Also, the activation energy would be larger for the loss of the leaving group compared to the reverse reaction and expulsion of the newly added nucleophile.

In general we can say that a carboxylic acid derivative will undergo an acyl substitution reaction when the nucleophile is more basic or is only slightly less basic than the leaving group. As long as the difference between the energies of the starting reactants and the products is not large, the equilibrium can be significantly shifted to the products through the addition of excess nucleophile or by the removal of one of the products from the reaction mixture as it is formed. This is the reason that the nucleophile can be slightly less basic than the leaving group.

From the potential energy diagrams in Figure 25.18, we see that the overall rate of reaction is dependent on a number of factors, and both steps must be considered when we compare reactivity of different carboxylic acid derivatives. As opposed to the starting and final carboxylic acid derivatives whose energies are determined by the conjugation with the carbonyl group, the tetrahedral intermediate is lacking such conjugation. Therefore, conjugation of the leaving group with the carbonyl group in carboxylic acid derivatives is another important factor affecting their reactivity. The major conjugation in carboxylic acid derivatives takes place between the lone electron pair (n) on the leaving group and the carbonyl group (π*) and is termed n to π* conjugation (Figure 25.19). The notations n and π* refer to the orbitals, the locations in space for electrons, and will be discussed in the advanced section of this chapter.

Figure 25.19. n to π* conjugation in carboxylic acid derivatives​

Usually, for weakly basic leaving groups, the electron density is mostly located on the heteroatom and conjugates with the carbonyl group less efficiently, making the carboxylic acid derivative more reactive to a nucleophile. This reinforces the trend in reactivity. Carboxylic acid derivatives with good leaving groups react faster with weak bases than carboxylic acids with poor leaving groups and strong bases as outlined in Figure 25.20.

The leaving group’s ability to leave is inversely related to its basicity. Remember: the weaker the base, the better the leaving group.

​Figure 25.20. Predicting reactivity of carbonyl carboxylic acid derivatives

This level of consideration is sufficient for students to successfully perform on standardized tests on organic chemistry. Students interested in more advanced discussion of the reactivity of carboxylic acid derivatives are referred to the last section of this chapter.


Question 25.8 - Level 2

Consider the tetrahedral intermediate and the two leaving groups, hydroxide and chloride. Does this reaction favor reactants or products?

question description
A

Products

B

Reactants


Question 25.9 - Level 2

Consider the tetrahedral intermediate and the two leaving groups, methoxide and amide anion. Does this reaction favor reactants or products?

question description
A

Products

B

Reactants


Thioesters and acyl phosphates are very important biological carboxylic acid derivatives and both of the derivatives react faster than esters (Figure 25.21). The phosphate group is a weaker base, the conjugate base of a stronger acid, than either the thiolate ion or alkoxide ion. Weak bases are better leaving groups and better leaving groups increase reactivity in nucleophilic acyl substitution reactions.

Figure 25.21. Reactivity of esters, thioesters, and acyl phosphates​



Question 25.10 - Level 3

Arrange the following compounds in the order of increasing reactivity toward nucleophilic acyl substitution, with least reactive at the top and most reactive at the bottom. (Hint: for carboxylates, think of acid-base chemistry to infer the reactivity).

A

Sodium acetate

B

Acetyl chloride

C

Acetic anhydride

D

Ethyl acetate

E

Acetamide

F

Ethyl thioacetate


Now, we will discuss in detail how the difference in reactivity of carboxylic acid derivatives and the nature of the nucleophiles bring a unique “flavor” to each specific reaction of a carboxylic acid derivative. Keeping an eye on possible acid-base interactions between the nucleophile, leaving group, and tetrahedral intermediate provides an excellent alternative to memorization of all possible reaction conditions.

25.2.2 Acid Chlorides: Preparation and Nucleophilic Acyl Substitution

Carboxylic acid chlorides are prepared by the reaction of carboxylic acids with thionyl chloride, or PCl5, or other chlorides of inorganic acids (Figure 25.22). As discussed, acid chlorides are very reactive carboxylic acid derivatives. However, their reactivity can be enhanced further with the addition of a nucleophilic catalyst. This will be discussed later in the chapter (see Figure 25.29). Acid chlorides can be prepared by the reaction of carboxylic acids with chlorides of inorganic acids.

Figure 25.22. Synthesis of carboxylic acid chlorides

The mechanism for the reaction of a carboxylic acid with thionyl chloride involves the now very familiar substitution reaction that forms an intermediate then eliminates a leaving group to form more stable products. The sulfur of thionyl chloride is very electrophilic because it is bonded to three electronegative atoms: two chlorines and one oxygen. The first step in the mechanism is a nucleophilic attack by the carboxylic acid on the sulfur atom. After elimination and proton transfer reactions, a very unstable intermediate is formed. The carbonyl group now has an excellent leaving group attached to it: addition of chloride followed by elimination generates the acid chloride, and the leaving group decomposes to SO2 gas plus a chloride ion (Figure 25.23).

Figure 25.23. Mechanism of carboxylic acids with thionyl chloride​

The addition of HCl to an acid will not generate an acid chloride because the carboxylic acid is not a strong enough electrophile to react with a chloride ion. Thus it is necessary to have oxygen bonded to sulfur or phosphorus to create a better electrophile and leaving group.

The mechanism for the reaction of a carboxylic acid with PCl5 is given in Figure 25.24.

Figure 25.24. Mechanism of the reaction of carboxylic acids with PCl5

The mechanisms for the reactions of carboxylic acids with SOCl2 and PCl5 are shown slightly differently to represent different reaction pathways that may take place simultaneously for either case. The intermediate mixed anhydride can be attacked by the nucleophile in either its neutral form (SOCl2 case) or protonated form (PCl5 case). In the latter case, elimination of the leaving group from the tetrahedral intermediate and intramolecular proton transfer may occur in one step, proceeding through a six-membered cyclic transition state. In addition, substitution of Cl- from PCl5 may occur in two steps (addition followed by elimination) due to the ability of phosphorous to be hexacoordinated. However, both reactions are usually performed in the presence of a nucleophilic catalyst, and the mechanism will be discussed later.

Acid halides vigorously react with primary and secondary amines producing amides. This reaction also follows the nucleophilic acyl substitution mechanism.

Question 25.11 - Level 3

What is the intermediate produced on the second step—elimination of the leaving group—of the reaction of ethylamine with an acid chloride?

question description
A

1)

B

2)

C

3)

D

4)

E

5)


Question 25.12 - Level 1

Once the protonated amide is formed, it can react with any unreacted amine and deactivate it as a nucleophile. Which acid-base reaction shows the deactivation of the amine?

question description
A

1)

B

2)


Therefore a second equivalence of ethylamine is needed for this reaction, and the overall reaction outcome is shown in Figure 25.25.

Figure 25.25. Reaction of acid chlorides with amines

Thus, due to the much higher basicity of amines than Cl-, the originally formed protonated amide—a strong acid—protonates the starting amine, deactivating it as a nucleophile. Therefore, each molecule of an acid chloride reacts with two molecules of an amine as shown in Figure 25.25.

Therefore, only half of the amine is converted to an amide and another half to an ammonium salt. If the amine is expensive, it is common practice to use a tertiary amine as a base and bring acylation of the target amine to completion (Figure 25.26).

Figure 25.26. Converting one equivalent of an amine to one equivalent of the corresponding amide

Tertiary amines reversibly react with acid halides, producing an acylammonium, which is missing the proton necessary for the final step of the amide formation (Figure 25.27).

Figure 25.27. Reaction of acyl chloride with tertiary amines​

Reactions of acid halides with alcohols and phenols are usually performed in the presence of pyridine that serves as both an acid-scavenging agent and a nucleophilic acid-base catalyst (Figure 25.28).

​Figure 25.28. Reaction of acyl chloride with alcohols and phenols

The figure below shows the reaction mechanism with a nucleophilic catalyst.

Figure 25.29. Nucleophilic catalyst in the formation of an ester​​​



Question 25.13 - Level 3

In the reaction equation given in Figure 25.28, three intermediates are formed. Match the intermediates in the order they are formed in the mechanism. Remember that pyridine is more basic than the alcohol.

question description
Premise
Response
1

1st^{st} tetrahedral intermediate

A

Structure 2

2

Intermediate

B

Structure 3

3

2nd^{nd} tetrahedral intermediate

C

Structure 1

4

Product

D

Structure 4


Note that acyl pyridinium is more reactive than acid chlorides despite significantly higher acidity of HCl (pKa = -7) than PyH+ (pyridinium cation, pKa = 5.2). This is not surprising, because the atom of nitrogen is lacking a lone electron pair conjugated with the carbonyl and bears a formal positive charge, which makes the acylpyridinium salt highly electrophilic. The overall mechanism involves two acyl substitution reactions, and because pyridine is acting as a nucleophile in the first nucleophilic substitution reaction but is not consumed in the reaction, pyridine is called a nucleophilic catalyst (Figure 25.29).

In summary, acylpyridinium salts have a worse leaving group than acyl chlorides, which is why they are formed from acyl chlorides and pyridine, but they are more reactive than acyl chlorides, which is why they react with alcohols better than acyl chlorides. Therefore, acylpyridinium salts are good intermediates in the catalytic cycle of nucleophilic catalysis, which enables pyridine to catalyze nucleophilic acyl substitution.

Acid halides are hydrolyzed under neutral pH in a matter of minutes, which is still significantly slower than the reaction with amines. Therefore, amines—but not alcohols and phenols—can react with acid halides in an aqueous suspension.

Question 25.14 - Level 2

Acetic anhydride can be synthesized by heating acetic acid with a strong dehydration agent through nucleophilic acyl substitution. Why is this method not practical for preparation of acetic benzoic anhydride (a mixed anhydride)?

question description
A

The reaction will produce significant amounts of both acetic anhydride and benzoic anhydride.

B

Reactivity of benzoic acid is not sufficient.

C

Acetic acid will deactivate the intermediate leading to the mixed anhydride.

D

Benzoic acid will deactivate the intermediate leading to the mixed anhydride.


Acylation of carboxylic acid salts with an acid chloride is a convenient method for preparation of mixed anhydrides (Figure 25.30).

Figure 25.30. Preparation of mixed anhydrides from acid chlorides and carboxylates​​

Acylation of carboxylic acids, however, requires a nucleophilic catalyst, such as a tertiary amine (most commonly pyridine) or tertiary amide (most commonly dimethylformamide, DMF). The same catalyst activates the resulting anhydride as well, which makes acylation of acids by acid halides reversible (Figure 25.31). This reaction also takes place for non-carboxylic acids, such as phosphoric acid, sulfonic acids, and sulfurous acid, providing a very useful method for making acid halides. Thus, refluxing with thionyl chloride (SOCl2, sulfurous acid dichloride) in the presence of catalytic amounts of DMF is a common procedure for conversion of carboxylic acids to their chlorides (Figure 25.31). The low stability of sulfurous acid chloride shifts the reaction equilibrium to completion. Acid chlorides of other inorganic acids react in a similar fashion.

25.31.png
Figure 25.31. Detailed mechanism for preparation of acid chlorides​​​


Acid chlorides are more electrophilic than aldehydes and ketones, which means that they can be converted to aldehydes or ketones by appropriate nucleophiles. Acylation of lithium dialkylcuprates by acid chlorides is a powerful tool for building carbon skeletons of ketones (Figure 25.32). 

Reducing agents designed to be not sufficiently active to react with aldehydes, but still able to reduce acid chlorides, are used for conversion of acid chlorides to aldehydes. Most common examples are lithium tri-(tert-butoxy)aluminium hydride, with which activity of lithium aluminium hydride is reduced by steric hindrance, and Pd/pyridine, a partially “poisoned” hydrogenation catalyst. Examples of preparation of aldehydes and ketones from acid chlorides are summarized in Figures 25.32a and 25.32b.


Figure 25.32a. Mechanism of preparation of ketones from acid chlorides using lithium dialkylcuprates.​​​


Figure 25.32b. General mechanism for the reduction of an acid chloride with the mild reducing reagent, lithium tri-tert-butoxyaluminum hydride. Acid chlorides can also be reduced with Pd/C and hydrogen.

Activation of acid chlorides with strong Lewis acids enables them to act as electrophiles toward aromatic compounds, which you already know from the previous chapters. Most important reactions of acid chlorides are summarized in Figure 25.33.

Figure 25.33. Most important reactions of acid chlorides​.​


Chemical Warfare

An important subclass of esters is the phosphinate ester, which contains a phosphorus atom in place of carbon atom. One famous molecule that contains a phosphinate ester is sarin gas, a highly potent chemical warfare agent that targets the nervous system.

How does sarin gas work? The phosphinate ester of sarin gas reacts with the acetylcholinesterase (AChE) enzyme in the body.


This process disables the AChE enzyme, thus preventing the metabolism of acetylcholine in our bodies. This leads to loss of muscle control in breathing, thus leading to asphyxia and ultimately to death.

Sarin gas has been used as a weapon a few times in history. One of the most recent attacks was in Tokyo, Japan on March 20, 1995, where the religious group Aum Shinrikyo simultaneously released the gas in five subway lines during the morning rush hour. Sadly, 12 people died from these attacks and over 1000 were injured. A documentary of the attack called “A” was made in 1998 to commemorate the attacks. 

25.2.3 Nucleophilic Acyl Substitution in Anhydrides

Anhydrides are slightly less reactive than acid chlorides and contain a more basic leaving group (Figure 25.34). 

Figure 25.34. Leaving groups in acid chlorides and anhydrides

As well, chlorine withdraws electrons more strongly through the sigma bond, making the carbonyl carbon highly electrophilic. These factors account for the differences between similar reactions of those types of carboxylic acid derivatives.


Question 25.15 - Level 2