Amide

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General structure of an amide (specifically, a carboxamide)
Formamide, the simplest amide
zwitterionic form), an amino acid
with a side chain (highlighted) containing an amide group

In

hydroxyl group (−OH) replaced by an amine group (−NR′R″); or, equivalently, an acyl (alkanoyl) group
(R−C(=O)−) joined to an amine group.

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

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.[5][6]

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

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.[8]

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

zwitterionic
(B).

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

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' pKas are between −6 and −10).

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

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

Mechanism for acid-mediated hydrolysis of an amide.[10]

Amides undergo many chemical reactions, although they are less reactive than

peptidases
and artificial catalysts, are known to accelerate the hydrolysis reactions.

Reaction name Product Comment
Dehydration Nitrile Reagent:
TFAA/py[11]
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
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:

RCO2H + R'2NH → RCO2 + R'2NH+2
RCO2 + R'2NH2 → RC(O)NR'2 + H2O

Esters are far superior substrates relative to carboxylic acids.[12][13][14]

Further "activating" both

) react with amines to give amides:

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]

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[21][22] Carboxylic acid, Grignard reagent with an aniline derivative ArNHR'
Chapman rearrangement[23][24]
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

References

  1. ^ "Amide definition and meaning - Collins English Dictionary". www.collinsdictionary.com. Retrieved 15 April 2018.
  2. ^ "amide". The American Heritage Dictionary of the English Language (5th ed.). HarperCollins.
  3. ^ "amide - Definition of amide in English by Oxford Dictionaries". Oxford Dictionaries – English. Archived from the original on 2 April 2015. Retrieved 15 April 2018.
  4. ^ .
  5. ^ 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
  6. (PDF) from the original on 9 October 2022.
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  9. ^ U.S. patent 5,935,953
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  17. ^ "Tris(2,2,2-trifluoroethyl) borate 97% | Sigma-Aldrich". www.sigmaaldrich.com. Retrieved 22 September 2016.
  18. PMID 28948222
    .
  19. ^ Bodroux F. (1905). Bull. Soc. Chim. France. 33: 831.{{cite journal}}: CS1 maint: untitled periodical (link)
  20. ^ "Bodroux reaction". Institute of Chemistry, Skopje, Macedonia. Archived from the original on 24 September 2015. Retrieved 23 May 2007.
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  26. (PDF) from the original on 9 October 2022.
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