MCAT Organic Chemistry Review

Carboxylic Acid Derivatives

9.2 Reactivity Principles

Regardless of the carboxylic acid derivative at hand, there are some rules that govern the reactivity of these molecules.

RELATIVE REACTIVITY OF DERIVATIVES

In a nucleophilic substitution reaction, the reactivity of the carbonyl is determined by its substituents. Anhydrides are most reactive, followed by esters (which are essentially tied with carboxylic acids), and finally amides. This can be explained by the structure of these molecules. Anhydrides, with their resonance stabilization and three electron-withdrawing oxygen atoms, are the most electrophilic. Esters, by comparison, lack one electron-withdrawing carbonyl oxygen and are slightly less reactive. Finally, amides, with an electron-donating amino group, are the least reactive toward nucleophiles.

KEY CONCEPT

When considering the reactivity of carboxylic acid derivatives toward nucleophilic attack, anhydrides are the most reactive, followed by esters and carboxylic acids, and then amides.

STERIC EFFECTS

Steric hindrance is always worth keeping in mind when considering reactivity. Steric hindrance describes when a reaction does not proceed due to the size of the substituents. A good example of this is in SN2 reactions, which will not occur at tertiary carbons. This effect, which might sound detrimental, can be used to our advantage—for example, if we want to push a reaction in an SN1 direction, rather than SN2, we can use a tertiary substrate. Another way that this is used synthetically is in the creation of protecting groups. As we saw in Chapter 6 of MCAT Organic Chemistry Review, carbonyls will readily react with strong reducing agents like LiAlH4—but this can be prevented by first reacting an aldehyde or ketone with two equivalents of alcohol, producing a nonreactive acetal or ketal. After we complete the rest of the desired reactions, we can then regenerate the carbonyl with aqueous acid. In the context of carboxylic acid derivatives, the size and substitution of the leaving group can affect the ability of a nucleophile to access the carbonyl carbon, thus affecting the reactivity of the derivative to nucleophilic acyl substitution.

KEY CONCEPT

Steric hindrance can be used to control where a reaction occurs in a molecule. Protecting groups may make it too hard for a nucleophile, oxidizing agent, or reducing agent to access or react with a part of the molecule.

ELECTRONIC EFFECTS

There are several electronic effects that must be considered in organic chemistry on the MCAT, and all of them come into play when considering carboxylic acid derivatives. Induction refers to the distribution of charge across σ bonds. Electrons are attracted to atoms that are more electronegative, generating a dipole across the σ bond. The less electronegative atom acquires a slightly positive charge, and the more electronegative atom acquires a slightly negative charge. This effect is relatively weak and gets increasingly weaker as one moves further away within the molecule from the more electronegative atom. This effect is responsible for the dipole character of the carbonyl group, as well as the increased dipole character (and therefore susceptibility to nucleophilic attack) of carboxylic acids—which contain an additional oxygen atom in their leaving group. This also explains the overall relative reactivity of anhydrides, esters, and amides toward nucleophilic attack. Anhydrides have two electron-withdrawing groups, which leaves a significant partial positive charge on the electrophilic carbon. This effect is smaller in amides because nitrogen is less electronegative than oxygen, and the dipole is not as strong.

Resonance and conjugation also affect the reactivity of a molecule. Conjugation refers to the presence of alternating single and multiple bonds. This setup implies that all of the atoms involved in these bonds are either sp2- or sp-hybridized—and therefore have unhybridized p-orbitals. When these p-orbitals align, they can delocalize π electrons through resonance, forming clouds of electron density above and below the plane of the molecule. This type of electron sharing is most commonly demonstrated using benzene, as shown in Figure 9.10.

Figure 9.10. Conjugation in Benzene Parallel unhybridized p-orbitals combine to form delocalized electron clouds above and below the plane of the molecule.

In carbonyl-containing compounds, conjugation can be established with the carbonyl group itself. α,β-unsaturated carbonyls or enones are common examples, as shown in Figure 9.11.

Figure 9.11. Conjugation in a Carbonyl-Containing Compound

KEY CONCEPT

Induction is the distribution of charge across σ bonds. Conjugation and resonance are much more powerful effects and occur in systems with alternating single and multiple bonds.

This type of electron sharing makes for very stable compounds because these compounds have multiple resonance structures. This characteristic allows for the stabilization of a positive charge once the nucleophile has bonded, making these compounds more susceptible to nucleophilic attack.

STRAIN IN CYCLIC DERIVATIVES

Lactams and lactones are cyclic amides and esters, respectively. Certain lactams and lactones are more reactive to hydrolysis because they contain more strain. β-lactams, for example, are four-membered cyclic amides and are highly reactive due to significant ring strain; four-membered rings have both torsional strain from eclipsing interactions and angle strain from compressing the normal sp3 angle of 109.5°. These molecules are part of the core structure of several antibiotic families, as shown in Figure 9.12. The ring strain, and therefore the reactivity, is increased by fusion to a second ring. The four-membered structure of a β-lactam also forces a trigonal pyramidal bond geometry on the nitrogen atom, which reduces resonance, making hydrolysis more likely.

Figure 9.12. Penicillin, a β-Lactam-Containing Antibiotic

REAL WORLD

Many antibiotic families contain β-lactams, including the penicillin family, cephalosporins, carbapenems, and monobactams. Many bacteria have developed β-lactamases, which break β-lactam rings, as a resistance mechanism against these antibiotics. Therefore, β-lactams are sometimes given with β-lactamase inhibitors to increase their efficacy.

MCAT Concept Check 9.2:

Before you move on, assess your understanding of the material with these questions.

1.    Rank the following molecules by decreasing reactivity to OH: acetamide, acetic anhydride, and ethyl acetate.

1.     

2.     

3.     

2.    What is responsible for the increased rate of hydrolysis in β-lactams?

3.    What properties account for the differences in reactivity seen between anhydrides, esters, and amides with nucleophiles?