MCAT Organic Chemistry Review

Analyzing Organic Reactions

4.4 Chemoselectivity

A key skill in recognizing which reactions will occur is recognizing the reactive regions within a molecule. The preferential reaction of one functional group in the presence of other functional groups is termed chemoselectivity.

REACTIVE LOCATIONS

Which site is the reactive site of a molecule depends on the type of chemistry that’s occurring. A redox reagent, as described above, will tend to act on the highest-priority functional group. Thus, in a molecule with an alcohol and a carboxylic acid, a reducing agent is more likely to act on the carboxylic acid than on the alcohol. For a reaction involving nucleophiles and electrophiles, reactions also tend to occur at the highest-priority functional group because it contains the most oxidized carbon. A nucleophile is looking for a good electrophile; the more oxidized the carbon, the more electronegative groups around it, and the larger partial positive charge it will experience. Thus, carboxylic acids and their derivatives are the first to be targeted by a nucleophile, followed by an aldehyde or ketone, followed by an alcohol or amine. Aldehydes are generally more reactive toward nucleophiles than ketones because they have less steric hindrance.

KEY CONCEPT

The more oxidized the functional group, the more reactive it is in both nucleophile–electrophile and oxidation–reduction reactions.

One common reactive site on the MCAT is the carbon of a carbonyl, which can be found in carboxylic acids and their derivatives, aldehydes, and ketones. Within a carbonyl-containing compound, the carbon of the carbonyl acquires a positive polarity due to the electronegativity of the oxygen. Thus, the carbonyl carbon becomes electrophilic and can be a target for nucleophiles. Further, the α-hydrogens are much more acidic than in a regular C–H bond due to the resonance stabilization of the enol form. These can be easily deprotonated with a strong base, forming an enolate, as shown in Figure 4.9. The enolate then becomes a strong nucleophile, and alkylation can result if good electrophiles are available.

Figure 4.9. Enol and Enolate Forms of a Ketone

A second reactive site for consideration is the substrate carbon in substitution reactions. SN1 reactions, which have to overcome the barrier of carbocation stability, prefer tertiary to secondary carbons as reactive sites, and secondary to primary. For SN2 reactions, which have a bigger barrier in steric hindrance, methyl and primary carbons are preferred over secondary, and tertiary carbons won’t react. This is all because of the mechanism of these two reactions.

STERIC PROTECTION

Steric hindrance describes the prevention of reactions at a particular location within a molecule due to the size of substituent groups. For example, SN2 reactions won’t occur with tertiary substrates. This characteristic of steric protection can be a useful tool in the synthesis of desired molecules and the prevention of the formation of alternative products. Effectively, bulky groups make it impossible for the nucleophile to reach the most reactive electrophile, making the nucleophile more likely to attack another region.

Another way that sterics come into play is in the protection of leaving groups. One can temporarily mask a reactive leaving group with a sterically bulky group during synthesis. For example, reduction of a molecule containing both carboxylic acids and aldehydes or ketones can result in reduction of all of the functional groups. To prevent this, the aldehyde or ketone is first converted to a nonreactive acetal or ketal, which serves as the protecting group, and the reaction can proceed. This reaction is shown in Figure 4.10. Another protective reaction is the reversible reduction of alcohols to tert-butyl ethers.

Figure 4.10. Protection of a Ketone by Conversion to an Acetal

BRIDGE

When an aldehyde is mixed with a diol (or two equivalents of alcohol), it forms an acetal. When a ketone is mixed with a diol (or two equivalents of alcohol), it forms a ketal. Acetal and ketal chemistry is discussed in Chapter 6 of MCAT Organic Chemistry Review.

Don’t worry if this seems overwhelming—this is just a preview of what we will see in later chapters, along with a set of rules that will make it easier to understand how chemical reactions will proceed! Feel free to come back to this chapter later to remind yourself of the rules that apply across the board after reading further chapters.

MCAT Concept Check 4.4:

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

1.    What are the two reactive centers of carbonyl-containing compounds?

·         

·         

2.    In which types of compounds are SN1 reactions most likely to occur? Why?

3.    In which types of compounds are SN2 reactions most likely to occur? Why?