Structural Biochemistry/Organic Chemistry/Organic Functional Group/Carbonyl/Amide

Amides, like esters, are carboxylic acid derivatives. This is the last class of carboxylic derivatives.

Physical and Chemical Properties

Unlike amines, which are decent bases, amides are weak bases. The conjugate acids of amides have pKa values of around -0.5. The reason amides are not as basic is due to the presence of the carbonyl groups. The carbonyl groups are inherently electron withdrawing and thus pull electron density away from the nitrogen group. Furthermore, resonance delocalizes the electron density from the nitrogen. The lone pair on the nitrogen in the amine can form a double bond with the carbon while the carbonyl bond breaks, giving oxygen a negative charge. Because the nitrogen’s lone pair is being shared with oxygen, it’s electron density is less and thus, does not have the electron density to be a good base. However, comparative to other functional groups such as esters, aldehydes, and ketones, amides are decently basic.

Amides can also hydrogen bond because they contain an N-H bond. Thus, amides can be H-bond acceptors. Because of their ability to hydrogen bonds, they can hydrogen bond with water and other polar solvents. Because they are able to interact with other polar solvents, they can – up to a certain extent – be soluble in these solutions. They override the hydrophobic character of the alkyl groups attached to the carbonyl carbon.

Resonance

Amides are the most unreactive of all carboxylic acid derivatives. This is because of its slight double bond characteristic that reduces the leaving group ability of the nitrogen. This resonance form is more prevalent among amides than it is for carboxylic acids, esters, or anhydrides. This is because nitrogen is the least electronegative, which allows this resonance form to occur more often, since the lone pairs are "more free" so to speak. Since the double bond resonance form occurs more often, the amide bond is the least reactive and the most stable of the carboxylic acid derivatives.

Reactions

Amide Hydrolysis: Amide hydrolysis, unlike its other carboxylic acid derivative counterparts, requires strong heating in a concentrated acid or base. The mechanism is the usual nucleophilic addition-elimination with acid or base catalysis. In acid catalysis, the nitrogen attacks a proton, making it have a positive charge making it a better leaving group. Water attacks the carbonyl carbon, and through a tertiary intermediate, the nitrogen leaves as an amine.

Amide Reduction: Amides can be reduced to amines using Lithium Aluminum Hydride, LiAlH₄, or reduced to aldehydes using DIBAL, a less reactive version of LAH.

Hoffman Rearrangement This reaction is particularly important to organic chemistry. Basically this reaction removes the whole carbonyl group of the amide transforming the substrate into an amine with one less carbon. This reaction requires a halogen, NaOH, and water. The Hoffman rearrangement begins with a base deprotonating the nitrogen to form an amidate ion. The amidate ion is monohalogenated, and once again deprotonated by base, creating an N-Haloamidate intermediate. The Halide is then eliminated creating an acyl nitrene. The next step in the mechanism is called the rearrangement mechanism. In this step, the alkyl group "slides" over from the carbonyl carbon to the nitrene nitrogen. During this step, chirality is maintained. This rearrangement step creates an isocyanate, which is then hydrated creating a carbamic acid. The carboxylic acid group leaves as CO₂, leaving the amide with one less carbon behind.

Forming Amides:

The most common way of forming amides is by nucleophilic attack, where amines are the nucleophile. The mechanism is detailed as follows.

Amines react with carboxylic acids as bases and nucleophiles: This mechanism proceeds similar to those mentioned above for forming esters and carboxylic acids. The amines are excellent nucleophiles because the nitrogen contains a pair of lone electrons. When the nitrogen attacks, the double bond between the carbon and oxygen breaks, resulting in a negatively charged oxygen. At this point, the nitrogen bears a positive charge due to the four bonds. In order to relieve the nitrogen of its positive charge, the terminal alcohol groups removes a hydrogen from the amine, thereby forming a neutral molecule of water. This water molecule is now an excellent leaving group. The loan pair on the oxygen comes back down to form the double bond and the water molecule leaves.

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Amide Bond Formation.

Reactions of Amides:

1. Dicarboxylic acids react with amines to gives imides: Dicarboxylic acids are molecules that contain two carboxylic acid groups. Each of these carboxy groups reacts twice with the amine nitrogen of ammonia. This creates imides. 2. Amino acids cyclize to form lactams: Other amines undergo cyclize intramolecularly in order to form lactams. Cyclic amides are known as lactames.