Amide

File:Amide-(tertiary).svg

General structure of an amide (specifically, a carboxamide)

File:Formamide-3D-balls.png

Formamide, the simplest amide

File:Asparagine w functional group highlighted.png

Asparagine (zwitterionic form), an amino acid with a side chain (highlighted) containing an amide group

In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula Template:Chem2, where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a peptide bond when it is part of the main chain of a protein, and an isopeptide bond when it occurs in a side chain, as in asparagine and glutamine. It can be viewed as a derivative of a carboxylic acid (Template:Chem2) with the hydroxyl group (Template:Chem2) replaced by an amino group (Template:Chem2); or, equivalently, an acyl (alkanoyl) group (Template:Chem2) joined to an amino group.

Common amides are formamide (Template:Chem2), acetamide (Template:Chem2), benzamide (Template:Chem2), and dimethylformamide (Template:Chem2).

Amides are qualified as primary, secondary, and tertiary according to the number of acyl groups bounded to the nitrogen atom.

Nomenclature

The core Template:Chem2 of amides is called the amide group (specifically, carboxamide group).

In the usual nomenclature, one adds the term "amide" to the stem of the parent acid's name. For instance, the amide derived from acetic acid is named acetamide (CH₃CONH₂). IUPAC recommends ethanamide, but this and related formal names are rarely encountered. When the amide is derived from a primary or secondary amine, the substituents on nitrogen are indicated first in the name. Thus, the amide formed from dimethylamine and acetic acid is N,N-dimethylacetamide (CH₃CONMe₂, where Me = CH₃). Usually even this name is simplified to dimethylacetamide. Cyclic amides are called lactams; they are necessarily secondary or tertiary amides.

Applications

Amides are pervasive in nature and technology. Proteins and important plastics like nylons, aramids, Twaron, and Kevlar are polymers whose units are connected by amide groups (polyamides); these linkages are easily formed, confer structural rigidity, and resist hydrolysis. Amides include many other important biological compounds, as well as many drugs like paracetamol, penicillin and LSD. Low-molecular-weight amides, such as dimethylformamide, are common solvents.

Structure and bonding

File:CSD CIF ACEMID06.jpg

Structure of acetamide hydrogen-bonded dimer from X-ray crystallography. Selected distances: C-O: 1.243, C-N, 1.325, N---O, 2.925 Å. Color code: red = O, blue = N, gray = C, white = H.

The lone pair of electrons on the nitrogen atom is delocalized into the Carbonyl group, thus forming a partial double bond between nitrogen and carbon. In fact the O, C and N atoms have molecular orbitals occupied by delocalized electrons, forming a conjugated system. Consequently, the three bonds of the nitrogen in amides is not pyramidal (as in the amines) but planar. This planar restriction prevents rotations about the N linkage and thus has important consequences for the mechanical properties of bulk material of such molecules, and also for the configurational properties of macromolecules built by such bonds. The inability to rotate distinguishes amide groups from ester groups which allow rotation and thus create more flexible bulk material.

The C-C(O)NR₂ core of amides is planar. The C=O distance is shorter than the C-N distance by almost 10%. The structure of an amide can be described also as a resonance between two alternative structures: neutral (A) and zwitterionic (B).

File:Amide resonance v2.svg

It is estimated that for acetamide, structure A makes a 62% contribution to the structure, while structure B makes a 28% contribution (these figures do not sum to 100% because there are additional less-important resonance forms that are not depicted above). Resonance is largely prevented in the very strained quinuclidone.

In their IR spectra, amides exhibit a moderately intense ν_CO band near 1650 cm⁻¹. The energy of this band is about 60 cm₋₁ lower than for the ν_CO of esters and ketones. This difference reflects the contribution of the zwitterionic resonance structure.

Basicity

Compared to amines, amides are very weak bases. While the conjugate acid of an amine has a pK_a of about 9.5, the conjugate acid of an amide has a pK_a around −0.5. Therefore, compared to amines, amides do not have acid–base properties that are as noticeable in water. This relative lack of basicity is explained by the withdrawing of electrons from the amine by the carbonyl. On the other hand, amides are much stronger bases than carboxylic acids, esters, aldehydes, and ketones (their conjugate acids' pK_as are between −6 and −10).

The proton of a primary or secondary amide does not dissociate readily; its pK_a is usually well above 15. Conversely, under extremely acidic conditions, the carbonyl oxygen can become protonated with a pK_a of roughly −1. It is not only because of the positive charge on the nitrogen but also because of the negative charge on the oxygen gained through resonance.

Hydrogen bonding and solubility

Because of the greater electronegativity of oxygen than nitrogen, the carbonyl (C=O) is a stronger dipole than the N–C dipole. The presence of a C=O dipole and, to a lesser extent a N–C dipole, allows amides to act as H-bond acceptors. In primary and secondary amides, the presence of N–H dipoles allows amides to function as H-bond donors as well. Thus amides can participate in hydrogen bonding with water and other protic solvents; the oxygen atom can accept hydrogen bonds from water and the N–H hydrogen atoms can donate H-bonds. As a result of interactions such as these, the water solubility of amides is greater than that of corresponding hydrocarbons. These hydrogen bonds also have an important role in the secondary structure of proteins.

The solubilities of amides and esters are roughly comparable. Typically amides are less soluble than comparable amines and carboxylic acids since these compounds can both donate and accept hydrogen bonds. Tertiary amides, with the important exception of N,N-dimethylformamide, exhibit low solubility in water.

Reactions

Amides do not readily participate in nucleophilic substitution reactions. Amides are stable to water, and are roughly 100 times more stable towards hydrolysis than esters. Amides can, however, be hydrolyzed to carboxylic acids in the presence of acid or base. The stability of amide bonds has biological implications, since the amino acids that make up proteins are linked with amide bonds. Amide bonds are resistant enough to hydrolysis to maintain protein structure in aqueous environments but are susceptible to catalyzed hydrolysis.

Primary and secondary amides do not react usefully with carbon nucleophiles. Instead, Grignard reagents and organolithiums deprotonate an amide N-H bond. Tertiary amides do not experience this problem, and react with carbon nucleophiles to give ketones; the amide anion (NR₂⁻) is a very strong base and thus a very poor leaving group, so nucleophilic attack only occurs once. When reacted with carbon nucleophiles, N,N-dimethylformamide (DMF) can be used to introduce a formyl group.

File:Formylation of Benzene using Phenyllithium and DMF.png

Because tertiary amides only react once with organolithiums, they can be used to introduce aldehyde and ketone functionalities. Here, DMF serves as a source of the formyl group in the synthesis of benzaldehyde.

Here, phenyllithium 1 attacks the carbonyl group of DMF 2, giving tetrahedral intermediate 3. Because the dimethylamide anion is a poor leaving group, the intermediate does not collapse and another nucleophilic addition does not occur. Upon acidic workup, the alkoxide is protonated to give 4, then the amine is protonated to give 5. Elimination of a neutral molecule of dimethylamine and loss of a proton give benzaldehyde, 6.

A new class of amide reactions was discovered in 2015, showing that amides can be converted to esters using nickel catalysis. Many other amide cross-couplings were subsequently developed using nickel or palladium catalysis, including Suzuki-Miyaura couplings.

File:Acid-CatAmideHydrolMarch.png

Mechanism for acid-mediated hydrolysis of an amide.

Hydrolysis

Amides hydrolyse in hot alkali as well as in strong acidic conditions. Acidic conditions yield the carboxylic acid and the ammonium ion while basic hydrolysis yield the carboxylate ion and ammonia. The protonation of the initially generated amine under acidic conditions and the deprotonation of the initially generated carboxylic acid under basic conditions render these processes non-catalytic and irreversible. Electrophiles other than protons react with the carbonyl oxygen. This step often precedes hydrolysis, which is catalyzed by both Brønsted acids and Lewis acids. Peptidase enzymes and some synthetic catalysts often operate by attachment of electrophiles to the carbonyl oxygen.

Reaction name	Product	Comment
Dehydration	Nitrile	Reagent: phosphorus pentoxide; benzenesulfonyl chloride; TFAA/py
Hofmann rearrangement	Amine with one fewer carbon atom	Reagents: bromine and sodium hydroxide
Amide reduction	Amines, aldehydes	Reagent: lithium aluminium hydride followed by hydrolysis
Vilsmeier–Haack reaction	Aldehyde (via imine)	[[Phosphoryl chloride|Template:Chem2]], aromatic substrate, formamide
Bischler–Napieralski reaction	Cyclic aryl imine	[[Phosphoryl chloride|Template:Chem2]], [[thionyl chloride|Template:Chem2]], etc.
Tautomeric chlorination	Imidoyl chloride	Oxophilic halogenating agents, e.g. COCl2 or SOCl2

Synthesis

From carboxylic acids and related compounds

Amides are usually prepared by coupling a carboxylic acid with an amine. The direct reaction generally requires high temperatures to drive off the water:

Template:Chem2

Template:Chem2

Esters are far superiorTemplate:Explain substrates relative to carboxylic acids.Template:Better source needed

Further "activating" both acid chlorides (Schotten-Baumann reaction) and anhydrides (Lumière–Barbier method) react with amines to give amides:

Template:Chem2

Template:Chem2

Template:Chem2

Peptide synthesis use coupling agents such as HATU, HOBt, or PyBOP.

From nitriles

The hydrolysis of nitriles is conducted on an industrial scale to produce fatty amides. Laboratory procedures are also available.

Specialty routes

Many specialized methods also yield amides. A variety of reagents, e.g. tris(2,2,2-trifluoroethyl) borate have been developed for specialized applications.

Specialty Routes to Amides

Reaction name	Substrate	Details
Beckmann rearrangement	Cyclic ketone	Reagent: hydroxylamine and acid
Schmidt reaction	Ketones	Reagent: hydrazoic acid
Willgerodt–Kindler reaction	Aryl alkyl ketones	Sulfur and morpholine
Passerini reaction	Carboxylic acid, ketone or aldehyde
Ugi reaction	Isocyanide, carboxylic acid, ketone, primary amine
Bodroux reaction	Carboxylic acid, Grignard reagent with an aniline derivative ArNHR'	File:Bodroux reaction.svg
Chapman rearrangement	Aryl imino ether	For N,N-diaryl amides. The reaction mechanism is based on a nucleophilic aromatic substitution.
Leuckart amide synthesis	Isocyanate	Reaction of arene with isocyanate catalysed by aluminium trichloride, formation of aromatic amide.
Ritter reaction	Alkenes, alcohols, or other carbonium ion sources	Secondary amides via an addition reaction between a nitrile and a carbonium ion in the presence of concentrated acids.
Photolytic addition of formamide to olefins	Terminal alkenes	A free radical homologation reaction between a terminal alkene and formamide.
Dehydrogenative coupling	alcohol, amine	requires ruthenium dehydrogenation catalyst
Transamidation	amide	typically slow

See also

• Amidogen
• Amino radical
• Amidicity
• Imidic acid
• Metal amides

External links

• IUPAC Compendium of Chemical Terminology