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 SN 1
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, aldehydes and ketones will readily react with strong reducing agents like LiAlH 4 —
but this can be prevented by first reacting the 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