17.1: Nucleophilic Acyl Substitution

Up until now, we have used nucleophiles to add to the carbonyl to generate a tetrahedral intermediate in a process that is reversible if the nucleophile is a good leaving group. Furthermore, the carbonyls that we have used are aldehydes and ketones, which have rather low lying \(π^{*}\)_C-O orbitals (LUMO).

What would happen if we now had electrophilic carbonyls which were not aldehydes/ketones? Would they have the same or different reactivity? Let’s take a look at a generic reaction:

Like before, the nucleophile attacks the \(π^{*}\) orbital, resulting in a tetrahedral intermediate. This intermediate, however, can collapse with loss of a leaving group. This mechanism is known as a nucleophilic acyl substitution and it can occur under both basic and acidic conditions (overall, this process would be reversible if the leaving group (X^–) is a good nucleophile and the nucleophile (Nuc­^–) is a good leaving group).

Basic conditions:

Acidic conditions:

The types of nucleophiles we will be using for nucleophilic acyl substitution are some of the same ones we used for nucleophilic additions to aldehydes/ketones, plus a few others:

H₂O OH^– ROH RO^– RNH₂ LAH R-Mg-Br R-Li NaBH₄

There is, of course, a diversity of electrophiles that can be used in this reaction, too. They can be arranged in order of increasing reactivity (electrophilicity) as shown below:

Several factors control the reactivity of these carbonyl compounds, and in each case, it is the energy level of the LUMO (\(π^{*}\)_C-O) that is impacted. By lowering the LUMO, the reactivity toward nucleophilic attack (ie. nucleophilic acyl substitution) increases. Getting to the tetrahedral intermediate requires good electrophilicity, so the carbonyl carbon should not have a lot of electron density on it. This is controlled by resonance, s-donation, inductive effects, and electronegativity.

1. For carboxylates and amides, lone pair resonance increases electron density on the carbonyl, making the LUMO higher and decreasing reactivity.

2. Esters and carboxylic acids have roughly the same reactivity and, by most accounts, are completely stable/inert. The oxygen does not like having positive charge, so it does not contribute its electrons as much to the carbonyl.

3. Acid anhydrides have lone pairs on oxygen that can delocalize via resonance, but because no single carbonyl is receiving all of this electron density, the carbonyl becomes more electrophilic. In other words, the lone pairs on oxygen are being pulled in both directions (which is different than esters/carboxylic acids).

4. Acid chlorides are most electrophilic because they suffer from orbital mismatch. Chlorine has lone pairs that are capable of delocalizing towards the carbonyl carbon, but because chlorine is in the second row, it is bigger and has poorer \(π\) overlap (resonance) with the carbonyl carbon. As a result, the lone pairs on chlorine contribute less, making the LUMO extremely low (less electron density = more electrophilic).

Let’s now take each of these electrophiles and treat them with a generic nucleophile under basic conditions:

What you might notice about the reactivity series is that electrophilicity also correlates with leaving group ability (pK_a).

We should be able to take each of our nucleophiles and make any of the carboxylic acid derivatives above. Some nucleophiles will be reactive enough (high enough HOMO) to react with all carbonyls, while others will only react with a few (this is known as chemoselectivity). Likewise, many electrophiles will react with all nucleophiles, while others only a few. In other words, by choosing the appropriate nucleophile, you should be able to react a carboxylic acid derivative on the right side of the reactivity series to make a carboxylic acid derivative farther to the left of the reactivity series (but not vice versa). You may use either acidic or basic conditions, but be careful – there are exceptions.

Let’s start with the acid chloride:

exceptions:

1. formation of carboxylic acids must occur under acidic conditions, otherwise the carboxylate will form;

2. acidic conditions are not needed for ester formation (alcohol is nucleophilic enough) or amide formation (acid will just protonate the amine).

Now, the anhydride:

Next, the carboxylic acid:

exceptions:

1. in the formation of amides, reaction of an amine with a carboxylic acid will just protonate the amine and become unreactive (stay tuned for a better way to do this);

2. ester formation must occur under acidic conditions (Fisher estification), otherwise the carboxylate will form

Next, the ester:

exceptions:

1. forming amides from esters is very rare and only occurs in the presence of a catalyst or using NH₃ as the nucleophile.

2. carboxylic acids can be prepared from esters via acidic or basic hydrolysis. This is the rare exception of being able to take an electrophile on the left hand side of the reactivity series and making something farther to the right.

Finally, the amide:

Notice that in this series, only the acid chloride cannot be made from anything else (stay tuned!).