Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Nucleophilic Substitution Reactions at Acyl Carbons
16.3 Substitution Reactions Involving Acid Chlorides
As we have seen above, alkanoyl chlorides (also known as acid chlorides) are one of the most reactive acyl compounds, and as a result, we will start our discussion of substitution reactions by looking at the substitution reactions of acid chlorides with various nucleophiles. Acid chlorides are very reactive molecules owing to the presence of a very good leaving group, the chloride anion (Cl−). Acid chlorides react readily with nucleophiles to form various products, including carboxylic acids, esters, and amides. The general mechanism for the reaction of an acid chloride with a nucleophile is shown in Reaction (16-5).
(16-5)
The first step of the reaction mechanism is an addition reaction and the second step is an elimination reaction of the leaving group. The various nucleophiles that will be examined in this section include: H2O, NH3, ROH, ROOH, LiAlH4 (hydride ion) and organometallic reagents. The products of the reaction of these nucleophiles with acid chlorides give molecules that have different functionalities.
16.3.1 Substitution Reactions Involving Acid Chlorides and Water
Acid chlorides are very reactive and react readily with water. Owing to the moisture on our bodies, acid chlorides will cause severe irritation when exposed to these compounds. Special precautions must be taken when working with acid chlorides in the laboratory. Acid chlorides, if left open in the lab, will react with moisture in the atmosphere to form the corresponding carboxylic acid. An example of the reaction of ethanoyl chloride and water is shown in Reaction (16-6), these reactions are also referred to as hydrolysis reactions of acid chlorides.
(16-6)
As we have pointed out earlier, the size of the alkyl group bonded to the carbonyl carbon will dictate the reactivity of the acid chloride, and acid chlorides that have large groups react slower than those with smaller groups. Large groups destabilize the tetrahedral intermediate compared to smaller groups. Also, electronegative groups bonded to the carbonyl carbon will increase the reactivity of these types of compounds. The mechanism for the hydrolysis of ethanoyl chloride is shown in Reaction (16-7).
(16-7)
Problem 16.3
i. Give the products of the following reactions.
ii. Give the structure of the acid chloride reactant needed to complete the following reactions.
iii. Arrange the following acid chlorides in order of their reactivity (consider carefully the size of the alkyl groups).
16.3.2 Substitution Reactions Involving Acid Chlorides and Alcohols
The reaction of ethanoyl chloride and methanol is shown in Reaction (16-8). Note that in this case, the product is not a carboxylic as we saw in the reaction with water, but a different functional group, an ester.
(16-8)
The hydrochloric acid that is liberated is usually scavenged by a mild base, which produces a salt that is precipitated out from the reaction solution and helps drive the reaction to the product. Pyridine is typically used as the base for these reactions. As you can imagine, the mechanism for these reactions is similar to that of hydrolysis of acid chlorides, except these reactions involve alcohols. In the first step of the mechanism, the alcohol attacks the carbonyl carbon to form the tetrahedral intermediate. Pyridine, being a base, abstracts the proton from the protonated alcohol to form protonated pyridine, as shown in Reaction (16-9)
(16-9)
In the final step of the mechanism, the oxygen—carbon double bond forms while the chloride anion leaves, as shown in Reaction (16-10).
(16-10)
Problem 16.4
i. Give the major organic products of the following reactions.
ii. Give a reasonable mechanism for the following reaction.
As expected, acid chlorides that have bulky R groups are less reactive than acid chlorides with less bulky R groups toward the reaction with alcohols, and acid chlorides that have electronegative groups bonded to the carbonyl carbon are more reactive, compared to acid chlorides that have less electronegative groups bonded to the carbonyl carbon.
16.3.3 Substitution Reactions Involving Acid Chlorides and Ammonia and Amines
Amines and ammonia are Lewis bases and also nucleophilic, and they react with acid chlorides to form amides. The type of amide produced as products depends on the type of amine used as reactant. The products of the reaction of ammonia and acid chlorides are primary amides; primary amines react with acid chlorides to form secondary amides; secondary amines react with acid chlorides to form tertiary amides. Examples of these reactions are shown in Reactions (16-11) through (16-13). The HCl that is produced in the reaction reacts with excess amines or ammonia to form the corresponding ammonium chlorides.
(16-11)
(16-12)
(16-13)
The amide is a very important functional group, especially in biology. The amide bond as we will see in Chapter 20 bonds amino acids to form peptides, which are the building blocks of protein.
Problem 16.5
i. Give the organic products for the reactions shown below.
ii. Provide an appropriate acid chloride and amine reactant molecules to complete the following reactions.
16.3.4 Substitution Reactions Involving Acid Chlorides and Carboxylate Salts
The conjugate bases of carboxylic acids are carboxylic acid salts and they are nucleophilic, even though they are not very good nucleophiles, but they react with acid chlorides to form the new functional group, anhydride. The general reaction is given in Reaction (16-14).
(16-14)
If the R group of the acid chloride is the same as that of the nucleophile, then the result as shown above is a symmetrical anhydride. A specific reaction is shown in the example given Reaction (16-15).
(16-15)
If, on the other hand, the R groups are different, nonsymmetrical anhydrides are the products. As we will see when we look at the applications of these compounds at the end of the chapter, these compounds are most useful if they are symmetrical.
Problem 16.6
Give the major organic product for each of the following reactions.
16.3.5 Substitution Reactions Involving Acid Chlorides and Soft Organometallic Reagents
The reaction of soft organometallic reagents, such as an organocuprate, results in a ketone, as shown in the example in Reaction (16-16).
(16-16)
Problem 16.7
i. Give the major organic product for each of the following reactions.
ii. For the target ketone molecules shown below, there are two different acid chlorides and two different organocuprates that can be used in separate syntheses to give the desired product. Give the structures of the acid chloride and organocuprate reactants that could be used to synthesize these target molecules.
16.3.6 Substitution Reactions of Acid Chlorides with Hard Organometallic Reagents
On the other hand, in the reaction of acid chlorides with much harder nucleophiles, in this case, also known as very strong reducing agents, the reaction will first give the acyl substitution reaction to give the corresponding ketone, as shown in Reaction (16-17).
(16-17)
You will recall from Chapter 11, in which we examined reduction of carbonyl compounds, that ketones readily react with Grignard reagents to give an alcohol salt as shown in Reaction (16-18).
(16-18)
The salts are readily hydrolyzed in the presence of an acidic medium to give alcohols. In this case, tertiary alcohols result since two alkyl groups from the Grignard reagent are added to the carbon that contains the alcohol functional group, as shown in Reaction (16-19).
(16-19)
An example of the overall reaction is shown in Reaction (16-20).
(16-20)
Problem 16.8
Give the major organic products of the following reactions.
16.3.7 Substitution Reactions of Acid Chlorides with Soft Metal Hydrides Reagents
The reaction of acid chlorides with soft metal hydrides results in aldehydes. It is possible to deliver just one mole of a hydride ion if a soft bulky reducing agent is used, such as lithium tri-tert-butoxyaluminum hydride, an example in which this reagent is used is given in Reaction (16-21).
(16-21)
16.3.8 Substitution Reactions of Acid Chlorides with Hard Metal Hydrides Reagents
On the other hand, in the reaction of acid chlorides with much harder nucleophiles, in this case also known as a very strong metal hydride reducing agents, the reaction will first give an addition of the hydride anion to the acyl carbon, followed by elimination of the chloride anion to give the corresponding aldehyde, as shown in Reaction (16-22).
(16-22)
In the presence of the strong reducing agent, lithium aluminum hydride (LiAlH4), the initial aldehyde that is produced readily reacts with more LiAlH4 agent to give an alcohol salt as shown in Reaction (16-23).
(16-23)
As you can imagine, the salts are readily hydrolyzed in the presence of an acidic medium to give alcohols. In this case, primary alcohols result since two hydrogen atoms are added to the carbon that contains the alcohol functional group, as shown in Reaction (16-24).
(16-24)
An example of the overall reaction is shown in Reaction (16-25).
(16-25)
More examples are shown in Reactions (16-26) and (16-27).
(16-26)
(16-27)
Problem 16.9
Give the major organic products of the following reactions.
Since acid chlorides can be transformed to a wide range of other functional groups, acid chlorides are very important starting compounds in the synthesis of many organic compounds. A summary of some of the major reactions that acid chlorides undergo is shown in Figure 16.1.