MCAT Organic Chemistry Review

Carboxylic Acid Derivatives

Conclusion

We’re sure you’ve noticed that this chapter covers only a few reactions happening in a wide variety of contexts. The MCAT testmakers don’t want you to memorize all the possible reactions; they simply want you to truly understand the trends and the underlying reasons for these reactions. Make sure you know the order of reactivity of the derivatives (from anhydrides, the most, to amides, the least). Also, learn the special reactions of esters and amides. Your study of amides will pay off right away as we explore amino acids and other nitrogen- and phosphorus-containing compounds in the next chapter.

Concept Summary

Amides, Esters, and Anhydrides

·        Amides are the condensation products of carboxylic acids and ammonia or amines.

o   Amides are given the suffix –amide. The alkyl groups on a substituted amide are written at the beginning of the name with the prefix N–.

o   Cyclic amides are called lactams. Lactams are named by the Greek letter of the carbon forming the bond with the nitrogen (β-lactam, γ-lactam, and so on).

·        Esters are the condensation products of carboxylic acids with alcohols (Fischer esterification).

o   Esters are given the suffix –oate. The esterifying group is written as a substituent, without a number.

o   Cyclic esters are called lactones. Lactones are named by the number of carbons in the ring and the Greek letter of the carbon forming the bond with the oxygen (α-acetolactone, β-propiolactone, and so on).

o   Triacylglycerols, which are a form of fat storage, include three ester bonds between glycerol and fatty acids. Saponification is the breakdown of fat using a strong base to form soap (salts of long-chain carboxylic acids).

·        Anhydrides are the condensation dimers of carboxylic acids.

o   Symmetric anhydrides are named for the parent carboxylic acid, followed by anhydride. Asymmetric anhydrides are named by listing the parent carboxylic acids alphabetically, followed by anhydride.

o   Some cyclic anhydrides can be synthesized by heating dioic acids. Five- or six-membered rings are generally stable.

Reactivity Principles

·        In nucleophilic substitution reactions, anhydrides are more reactive than esters, which are more reactive than amides.

·        Steric hindrance describes when a reaction cannot proceed (or significantly slows) because of substituents crowding the reactive site. Protecting groups, such as acetals, can be used to increase steric hindrance or otherwise decrease the reactivity of a particular portion of a molecule.

·        Induction refers to uneven distribution of charge across a sigma bond because of differences in electronegativity. The more electronegative groups in a carbonyl-containing compound, the greater its reactivity.

·        Conjugation refers to the presence of alternating single and multiple bonds, which creates delocalized π electron clouds above and below the plane of the molecule. Electrons experience resonance through the unhybridized p-orbitals, increasing stability. Conjugated carbonyl-containing compounds are more reactive because they can stabilize their transition states.

·        Increased strain in a molecule can make it more reactive. β-lactams are prone to hydrolysis because they have significant ring strain. Ring strain is due to torsional strain from eclipsing interactions and angle strain from compressing bond angles below 109.5°.

Nucleophilic Acyl Substitution Reactions

·        All carboxylic acid derivatives can undergo nucleophilic substitution reactions. The rates at which they do so are determined by their relative reactivities.

·        Anhydrides can be cleaved by the addition of a nucleophile.

o   Addition of ammonia or an amine results in an amide and a carboxylic acid.

o   Addition of an alcohol results in an ester and a carboxylic acid.

o   Addition of water results in two carboxylic acids.

·        Transesterification is the exchange of one esterifying group for another on an ester. The attacking nucleophile is an alcohol.

·        Amides can be hydrolyzed to carboxylic acids under strongly acidic or basic conditions. The attacking nucleophile is water or the hydroxide anion.

Answers to Concept Checks

·        9.1

1.     

Carboxylic Acid Derivative

Formed from –COOH by…

Suffix

Cyclic Naming

Amide

Ammonia or an amine

–amide

Lactam

Ester

An alcohol

–oate

Lactone

Anhydride

Another carboxylic acid

anhydride

Anhydride

2.    A condensation reaction is one in which two molecules are joined with the loss of a small molecule. In all of the examples in this section, the small molecule lost was water.

·        9.2

1.    Anhydrides are the most reactive to nucleophiles, followed by esters, and then amides. Therefore, acetic anhydride will be the most reactive, followed by ethyl acetate and finally acetamide.

2.    β-lactams are susceptible to hydrolysis due to the high level of ring strain, which is due to both torsional strain (eclipsing interactions) and angle strain (deviation from 109.5°).

3.    Electronic effects like induction have some effect on the reactivity of the carbonyl in these three functional groups. Differences in resonance also explain the increased reactivity of anhydrides, in particular. Steric effects could also be significant, depending on the specific leaving group present.

·        9.3

1.    Ammonia acts as the nucleophile. One of the carbonyl carbons of the anhydride serves as the electrophile.

2.    Transesterification is the exchange of one esterifying group for another in an ester. This reaction requires an alcohol as a nucleophile.

3.    Strongly acidic conditions catalyze amide hydrolysis by protonating the oxygen in the carbonyl. This increases the electrophilicity of the carbon, making it more susceptible to nucleophilic attack. Strongly basic conditions greatly increase the concentration of OH, which can act as a nucleophile on amide carbonyls.

Shared Concepts

·        Biochemistry Chapter 11

o   Lipid and Amino Acid Metabolism

·        Organic Chemistry Chapter 1

o   Nomenclature

·        Organic Chemistry Chapter 3

o   Bonding

·        Organic Chemistry Chapter 4

o   Analyzing Organic Reactions

·        Organic Chemistry Chapter 6

o   Aldehydes and Ketones I

·        Organic Chemistry Chapter 8

o   Carboxylic Acids