Amide
In
Common of amides are formamide (H−C(=O)−NH2), acetamide (H3C−C(=O)−NH2), benzamide (C6H5−C(=O)−NH2), and dimethylformamide (H−C(=O)−N(−CH3)2). Some uncommon examples of amides are N-chloroacetamide (H3C−C(=O)−NH−Cl) and chloroformamide (Cl−C(=O)−NH2).
Amides are qualified as primary, secondary, and tertiary according to whether the amine subgroup has the form −NH2, −NHR, or −NRR', where R and R' are groups other than hydrogen.[5]
Nomenclature
The core −C(=O)−(N) 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
Applications
Amides are pervasive in nature and technology. Proteins and important plastics like Nylons, Aramid, 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.[7] Low-molecular-weight amides, such as dimethylformamide, are common solvents.
Structure and bonding
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
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). There is also a hydrogen bond present between the hydrogen and nitrogen atoms in the active groups.[9] Resonance is largely prevented in the very strained quinuclidone.
In their IR spectra, amides exhibit a moderately intense νCO band near 1650 cm−1. The energy of this band is about 60 cm-1 lower than for the νCO of esters and ketones. This difference reflects the contribution of the zwitterionic resonance structure.
Basicity
Compared to
The proton of a primary or secondary amide does not dissociate readily; its pKa is usually well above 15. Conversely, under extremely acidic conditions, the carbonyl oxygen can become protonated with a pKa 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
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 undergo many chemical reactions, although they are less reactive than
Reaction name | Product | Comment |
---|---|---|
Dehydration | Nitrile | Reagent: |
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) | POCl3, aromatic substrate, formamide |
Bischler–Napieralski reaction | Cyclic aryl imine | POCl3, SOCl2, etc. |
Tautomeric chlorination | Imidoyl chloride |
Synthesis
Amides are usually prepared by coupling a carboxylic acid with an amine. The direct reaction generally requires high temperatures to drive off the water:
- RCO2H + R'2NH → RCO−2 + R'2NH+2
- RCO−2 + R'2NH2 → RC(O)NR'2 + H2O
Esters are far superior substrates relative to carboxylic acids.[12][13][14]
Further "activating" both
- RCO2R" + R'2NH → RC(O)NR'2 + R"OH
- RCOCl + 2R'2NH → RC(O)NR'2 + R'2NH+2Cl−
- (RCO)2O + R'2NH → RC(O)NR'2 + RCO2H
Peptide synthesis use coupling agents such as HATU, HOBt, or PyBOP.[15]
From nitriles
The hydrolysis of nitriles is conducted on an industrial scale to produce fatty amides.[16] Laboratory procedures are also available.[17]
Specialty routes
Many specialized methods also yield amides.[18] A variety of reagents, e.g. tris(2,2,2-trifluoroethyl) borate have been developed for specialized applications.[19][20]
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[21][22] | Carboxylic acid, Grignard reagent with an aniline derivative ArNHR' | |
Aryl imino ether
|
For N,N-diaryl amides. The reaction mechanism is based on a nucleophilic aromatic substitution.[25] | |
Leuckart amide synthesis[26] | Isocyanate | Reaction of arene with isocyanate catalysed by aluminium trichloride , formation of aromatic amide.
|
Ritter reaction[27] | 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. |
olefins[28]
|
Terminal alkenes | A free radical homologation reaction between a terminal alkene and formamide.
|
Dehydrogenative coupling[29] | alcohol, amine | requires ruthenium dehydrogenation catalyst
|
Transamidation[30][31] | amide | typically slow |
Amine α-oxidation[32] | alkyl amine | requires gold catalysts |
See also
- Amidogen
- Amino radical
- Amidicity
- Imidic acid
- Metal amides
References
- ^ "Amide definition and meaning - Collins English Dictionary". www.collinsdictionary.com. Retrieved 15 April 2018.
- ^ "amide". The American Heritage Dictionary of the English Language (5th ed.). HarperCollins.
- ^ "amide - Definition of amide in English by Oxford Dictionaries". Oxford Dictionaries – English. Archived from the original on 2 April 2015. Retrieved 15 April 2018.
- ^ ISBN 9780841201910.
- ^ IUPAC, Chemical Nomenclature and Structure Representation Division (27 October 2004). "Draft Rule P-66.1". Nomenclature of Organic Chemistry (Provisional Recommendations). IUPAC. Full text (PDF) of Draft Rule P-66: Amides, Imides, Hydrazides, Nitriles, Aldehydes, Their Chalcogen Analogues, and Derivatives
- (PDF) from the original on 9 October 2022.
- .
- PMID 17295481.
- ISBN 978-0-471-72091-1
- ^ U.S. patent 5,935,953
- .
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- ISBN 978-3527306732.
- .
- PMID 27673596.
- ^ "Tris(2,2,2-trifluoroethyl) borate 97% | Sigma-Aldrich". www.sigmaaldrich.com. Retrieved 22 September 2016.
- PMID 28948222.
- ^ Bodroux F. (1905). Bull. Soc. Chim. France. 33: 831.
{{cite journal}}
: CS1 maint: untitled periodical (link) - ^ "Bodroux reaction". Institute of Chemistry, Skopje, Macedonia. Archived from the original on 24 September 2015. Retrieved 23 May 2007.
- ISBN 978-0471264187.
- .
- ISBN 978-0-471-85472-2.
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- ISBN 9780471196150.
- ISBN 978-0124336803. Archived(PDF) from the original on 9 October 2022.
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- PMID 17165798.
- PMID 27199089.
- S2CID 246575960.