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1.9: Carboxylic Acid Derivatives- Interconversion

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    Structures of Carboxylic Acid Derivatives

    Last time we completed our study of the reactions of aldehydes and ketones, compounds in which a carbonyl group is bonded either to carbons or hydrogens. The typical reaction pattern for these compounds was addition, with a nucleophile adding to the carbonyl carbon and an electrophile adding to the carbonyl oxygen. Today we'll look at carboxylic acid derivatives. This group of compounds also contains a carbonyl group, but now there is an electronegative atom (oxygen, nitrogen, or a halogen) attached to the carbonyl carbon. This difference in structure leads to a major change in reactivity. Here we find that the reactions of this group of compounds typically involve substitution of the electronegative atom by a nucleophile. Before looking at that reaction in detail, though, let's see what kind of compounds we're talking about.

    Carboxylic acid is found in vinegar and cream of tartar; Esters are found in fats and cell membranes; Amides are found in nylons and proteins; Acyl Chlorides are found in synthesis of carboxyl derivatives; Acid anhydrides are found in the synthesis of carboxyl derivatives.

    Notice that each of these functional groups has either an oxygen, a nitrogen, or a halogen attached to the carbonyl carbon.

    Substitution by Addition-Elimination

    The typical reactions of these compounds are substitutions -- replacing one of these heteroatoms by a another atom. Here's an example:

    Acyl chloride reacts with alkoxide to form an ester and Cl-.

    The chlorine of the acyl chloride has been replaced by the -OCH2CH3, more specifically by the oxygen atom of that group. This type of reaction, in which an atom or group is replaced by another atom or group, is called a substitution reaction.

    We can begin to connect this reaction type with what we have seen earlier by thinking about the mechanism. We notice that the O- end of the group (called an alkoxide) which is doing the substituting is very much like the oxygen in an OH-. Since we've seen the OH- act as a nucleophile when it attacked the electrophilic carbon of a carbonyl group, let's begin by seeing what happens if we use the same approach here.

    The O- of the alkoxide attacks the carbonyl carbon of the acyl chloride as the CO pi bond becomes a sigma bond resulting in O-.

    The first step is familiar from aldehyde and ketone chemistry. The nucleophilic oxygen uses its electrons to make a new bond to the electrophilic carbonyl carbon while the pi bond's electrons move to the carbonyl oxygen. We've made the necessary oxygen-carbon bond. In the next step, the pi bond is reformed, and the carbon-chlorine bond is broken. This is a new type of step, and it happens when breaking this bond is eased by the electron pair being attracted to an electronegative atom such as oxygen, nitrogen or a halogen. This step is called an elimination. The overall substitution process occurs by an addition-elimination mechanism which begins with a nucleophilic addition to the carbonyl group and finishes with the departure of an atom with the bonding pair of electrons. This atom or group is called a "leaving group."

    Here's a general statement of the mechanism:

    Nucleophile attacks the carbonyl carbon as a form of addition and general group "X" is eliminated. "X" is the leaving group.

    As we look at some specific examples, keep this pattern in mind. There will be some elaborations on it, but we will always find an addition step in which the nucleophile attacks and an elimination step in which the leaving group leaves.

    Esters - Preparation and Mechanisms

    The conversion of acyl chlorides to esters is more commonly carried out by using an alcohol rather than an alkoxide (RO-).

    Acyl chloride reacts with alkoxide to form an ester and Cl-. Acyl chloride reacts with alcohol to form an ester and HCl.

    The mechanism of this reaction starts just the same way the earlier one did; the first step is attack of the nucleophile at the carbonyl carbon. In this instance, the nucleophile is an unshared electron pair on a neutral oxygen atom. The intermediate formed in this step rapidly shifts a proton (H+) to the O-. Such transfers of protons between oxygen atoms or nitrogen atoms are fast. (These intermediates are called "tetrahedral intermediates" since carbonyl carbon has been changed to a tetrahedral geometry and an sp3 hybridization.)

    The oxygen of the alcohol attacks the carbonyl carbon of acyl chloride, breaking the CO double bond and forming O- and OH+, the O- reacts with an H to form another hydroxy group. Another alcohol molecule reacts with the new hydroxy group, taking the hydrogen and causing the carbonyl to reform while the chlorine leaves.

    The tetrahedral intermediate loses HCl in a single step, one in which the H+ is transferred to a second molecule of alcohol and the Cl comes off as Cl-. It is important to notice that the neutral alcohol oxygen serves as the nucleophile. The O-H bond is not broken until after the C-O bond is formed. There is never any alkoxide in this reaction. Indeed, an alkoxide ion could not survive in the strongly acidic (HCl) solution. This pattern, neutral nucleophile attacks first, then the proton is removed, is very common for neutral nucleophiles and must be followed.

    This is a practical and useful method for making esters, but it does make the strong acid HCl, which is often troublesome. A more practical variation is to add a weak base such as pyridine to react with the HCl and neutralize it. This gives us a procedure for making esters from acyl chlorides which uses the following reaction statement:

    Acyl chloride reacts with ethanol and pyridine to form CH3-CO-OCH2CH3, protonated pyridine, and Cl-.

    A similar procedure is used to make amides from acyl chlorides and amines (the amine must have at least one hydrogen attached to the nitrogen).

    Acyl chloride reacts with dimethylamine and pyridine to form CH3-CO-N(CH3)2, protonated pyridine, and Cl-.

    Acyl chlorides are the most reactive carboxylic acid derivatives. The electronegative chlorine atom pulls electrons toward it in the C-Cl bond, which makes the carbonyl carbon more electrophilic. This makes nucleophilic attack easier. Also, the Cl- is an excellent leaving group, so that step is also fast. Because of their reactivity, acyl chlorides are easily converted into esters and amides and are thus valuable synthetic intermediates. They are made from carboxylic acids by this reaction (Atkins & Carey, Sec 12:10):

    Carboxylic acid reacts with SOCl2 to form acyl chloride, SOCl2, and HCl.

    In the mechanism we just looked at, the key steps (attack of a nucleophile and departure of a leaving group) were accompanied by steps in which protons moved from one location to another. Such proton transfers are very common in acid catalyzed reactions. Here's the mechanism for the acid catalyzed formation of an ester from a carboxylic acid and an alcohol:

    The oxygen of carboxylic acid attacks H+ forming OH and a carbocation. The oxygen of an alcohol attacks the carbocation combining the molecules and forming an O+ which then loses it's hydrogen as the other hydroxy group gains another H. OH2+ leaves and the remaining hydroxy group forms a carbonyl and the hydrogen leaves. All steps are reversible.

    Notice that the nucleophilic attack is preceded by protonation of the carbonyl oxygen. We've seen this step before in the acid-catalyzed additions of nucleophiles to carbonyl groups. Its purpose is to increase the reactivity of the carbonyl carbon as an electrophile, so that it can be easily attacked by the alcohol oxygen. After nucleophilic attack, there is a proton transfer. Its purpose is to make one of the OH groups (either will do) into a good leaving group, water.

    Think back to the addition of alcohols to aldehydes to produce hemiacetals. The two mechanisms start off identically. Compare them in detail, and work out the reasons for the different outcome.

    Notice that each step in this mechanism is presented as an equilibrium. That means that the whole reaction represents an equilibrium in which significant amounts of carboxylic acid and alcohol co-exist with ester and water.

    Carboxylic acid and alcohol react reversibly with an acid to form an ester and water.

    This allows us to push the reaction one way or the other by controlling concentrations, particularly of water. If we remove water from the reaction mixture, more ester is formed because carboxylic acid and alcohol react to replace the water we have removed. The resulting formation of ester is called Fischer esterification.

    If we add water to the reaction mixture, equilibrium is restored by the production of more carboxylic acid and alcohol. This is called acid catalyzed ester hydrolysis.

    Amides - Preparations

    Esters can also react with amines or ammonia to form amides. This reaction doesn't involve acid catalysis, so the first step is nucleophilic attack at the carbonyl carbon. Proton transfer follows and loss of the alcohol portion of the ester.

    NH3 attacks the carbonyl carbon of an ester resulting in RC(NH3)+(O-)OR'. NH3+ donates a hydrogen to the oxygen of the ester. The products are RCONH2 and HOR'.

    This gives us two ways to make amides, this one from esters and the earlier one from acyl chlorides. Here's a third and very direct way to make amides, by heating carboxylic acids and amines together.

    Carboxylic acid reacts with HN(R')2 with heath to form RCO(NR')2.


    • Kirk McMichael (Washington State University)

    1.9: Carboxylic Acid Derivatives- Interconversion is shared under a All Rights Reserved (used with permission) license and was authored, remixed, and/or curated by LibreTexts.

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