Amide Functional Group

Core Concepts

Amides are a common and useful organic functional group consisting of a carbon, oxygen, and nitrogen atom. In this article, the structure, atomic properties, synthesis, reactions, and role in peptide bonding of the amide functional group are explored.

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What is the Amide Functional Group?

Amides are an organic functional group that consist of a carbon, oxygen, and nitrogen atoms. Amide functional groups have a specific layout of atoms, where the nitrogen bonds to the carbonyl carbon. Based on the number of non-hydrogen groups attached to the nitrogen atom, amides are either classified as primary, secondary, tertiary, or even quaternary.

Different Types of Amides: Primary; Secondary; Tertiary, Quaternary
Figure 1: Primary Amide (Left); Secondary Amide (Center Left); Tertiary Amide (Center Right); Quaternary Amide (Right

Note that the quaternary amine carries a positive formal charge, making it useful to form ionic bonds with an anion.

Amides are most structurally similar to carboxylic acids, which have a second oxygen in place of the nitrogen. Amides are also similar to amines, which consist of  only a nitrogen atom bonded to at least one carbon atom.

Carboxylic Acids (Left) and Amines (Center), Compared to Amides (Right)
Figure 2: Carboxylic Acid (Left), Amines (Center), Amides (Right)

Amides typically have a C-N bond length of 132 to 134 picometers, shorter than an amine C-N bond. This discrepancy is caused by the partial delocalization of the carbonyl pi bond to the C-N bond to form an imine.

Isomerization of Amides
Figure 3: Isomerization of Amides

When writing out a molecule linearly, amides are written as CON. However, IUPAC has very specific nomenclature for naming amides. When naming a molecule with an amide functional group, the chain numbering starts at carbonyl carbon and counts away following standard IUPAC chain naming procedures. You should name any substituents attached to the N molecule with the N- prefix. Following IUPAC nomenclature, one should name the rest of the carbon chain appropriately. Finally, the molecule should end with the suffix -amide. To illustrate this, examples of two molecules containing an amide functional group are shown below.

Naming of Amides: Butanamide (Left); N-chloro-5-methoxy-N,2-dimethylhexanamide
Figure 4: Amide Naming

Examples of Molecules with an Amide Functional Group

Amides are a key organic functional group and form important pieces of both synthetic and natural molecules. Amides are the most abundant functional group in medicinal molecules, proteins, and plastics due to their versatility as a ‘linker’ to connect two or more moieties.

Polymers often contain amides for this connective ability. One of the most common plastics, nylon, is replete with secondary amides, combining flexible carbon groups in between giving nylon its flexible characteristic. On the other hand, Kevlar, one of the strongest synthetic materials, also contains many amides. Exploiting the hydrogen bonding ability of amides (and some clever spacing) creates rigid forces between polymer chains that give Kevlar its strength. The below molecules are Nylon (top) and Kevlar (bottom).

Amide Containing Polymers: Nylon (top), Kevlar (bottom)
Figure 5: The polymer structure of nylon (top) with the structure of Kevlar (bottom) with hydrogen bonds shown. Note the many amides connecting the repeating units of each polymer.

Ubiquitously found in medicinal molecules, amides can hydrogen bond with amino acids in the protein target, ensuring a strong and potent bond with the protein. In biologics, amides are ubiquitous in peptide (protein) drugs as they form the backbone of small proteins. This will be explored in the Amides in Proteins paragraph.

Properties of the Amide Functional Group

The amide group is reasonably polar due to the high electronegativities of the oxygen and the nitrogen. This usually makes small molecules containing amides soluble in polar solvents, including water. The amide group has a polar surface area of 29 square angstroms, which is less than the comparable carboxylic acid functional group but more than the amine group. The ability of primary and secondary amides to donate and accept hydrogen bonds with water also contributes to their solubility.

Amides have a pKa of roughly 16, meaning that they do not want to readily donate a hydrogen molecule. This leads to much less acidic behavior than a carboxylic acid (pKa of 4-5) but more acidic than the amine functional group, which typically acts as a base. This moderate acidity makes them ideal candidates for ionized drug molecules, which are typically more soluble that their non-ionized counterparts.

Amides are easily detectable with spectroscopic methods due to the presence of two well understood functional groups. The carbonyl group is easily detectable in IR spectra at roughly 1650 cm-1and the amine is detectable at 3300-3500 cm-1. Hydrogen atoms attached to the nitrogen atom in a primary or secondary amide exhibit a chemical shift in NMR studies from 5.5 to 8.5 ppm.

Synthesis of Amides

Amides are produced through two main families of synthetic routes. The synthesis of amides involves the reaction of a carboxylic acid and an amine (primary) in an organic solvent such as DCM. These two reactants need a coupling agent (such as DCC or HATU) to combine directly in the lab, through a process known as peptide bonding. Also, an acyl chloride (prepared through the reaction of the carboxylic acid and thionyl chloride) can react with an amine to form an amide. This process is an example of nucleophillic acyl substitution.

Artificial Peptide Bonding with DCC as a coupling agent
Figure 6: Artificial Peptide Bonding: A carboxylic acid and an amide are directly reacted with a coupling reagent in basic conditions. The archetypal solvent for this reaction is dichloromethane (DCM).  
Nucleophilic Acyl Substitution Synthesis of Amides
Figure 7: Nucleophilic Acyl Substitution: The carboxylic acid is first converted to an acyl chloride using thionyl chloride, which is then reacted with a primary or secondary amine to afford the desired amide.

The previous family of reactions works well for large molecules or molecules with fragile functional groups. However, chemists typically prefer a cheaper, quicker, and more efficient reaction for smaller and less fragile reactants. By reacting a carboxylic acid directly with an amide to form a carboxylate and ammonium salt, one can achieve these goals. In a final step, amides condense from the ionic mixture upon heating.

Amide Synthesis via Ammonium Salt
Figure 8: Amide Production Via an Ammonium Salt.   

Reactions Involving Amides

Amides are very versatile functional groups and can undergo many different reactions. One common ambition of chemists is to convert primary amides into primary amines. Fortunately, there are two reactions to achieve this. The first is a standard reduction of the amide to form the amine using a reducing agent such as lithium aluminum hydride.

Direct Reduction of Amides to Amines
Figure 9: Direct Reduction of an Amide to Produce an Amine

Exploiting a clever reaction, one can also convert an amide to an amine with one fewer carbon atom. Known as the Hoffman rearrangement, this reaction converts the amide to an isocyanate using aqueous bromine and sodium hydroxide. Hydrolyzing the isocyanate affords the amine with one fewer carbon atom.

Hoffman Rearrangement: Amides are converted to an isocyanate which is hydrolyzed into an amine with one less carbon atom.
Figure 10: Hoffman Rearrangement

Amides two carbon atoms before an aromatic moiety can undergo a very unique and useful reaction. These types of amides are able to react with themselves to form a new ring on the molecule (known as an imine heterocycle). This mechanism, known as the Bischler-Napieralski reaction is very useful in synthesizing medicinal molecules, which often have rings of this type.

Bischler-Napieralski Reaction
Figure 11: Bischler-Napieralski Reaction

Amides in Proteins

Amides are critical to life, in fact, you have about 1022 amides inside of your body right now. This is because amides form a critical backbone to proteins, the machinery of our cells. In our body, these amides provide flexible support to the molecules that carry out tasks within our cells. During translation, a ribosome brings a carboxylic acid of an amino acid sufficiently close to an amine on the next amino acid reacting to build up a protein like a chain.  

Amides As the Backbone of Proteins: 3D structure (top), 2D Structure (Bottom)
Figure 12: Amides Form the Backbone of All Proteins Between Amino Acids


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