Amide

From Wikipedia, the free encyclopedia

Not to be confused with Imide.

Structures of three kinds of amides: an organic amide, a sulfonamide, and a phosphoramide.

An amide (/ˈæmaɪd/ or /ˈæmɪd/ or /ˈeɪmaɪd/),[1][2][3] also known as an acid amide, is a

compound with the functional group RnE(O)xNR′2 (R and R′ refer to H or organic groups).
Most common are carboxamides (organic amides) (n = 1, E = C, x = 1), but many other
important types of amides are known, including phosphoramides (n = 2, E = P, x = 1 and
many related formulas) and sulfonamides (E = S, x = 2).[4] The term amide refers both to
classes of compounds and to the functional group (RnE(O)xNR′2) within those compounds.

Amide can also refer to the conjugate base of ammonia (the anion H2N−) or of an organic
amine (an anion R2N−). For discussion of these "anionic amides", see Alkali metal amides.

The remainder of this article is about the carbonyl–nitrogen sense of amide.

Contents
 1 Structure and bonding
 2 Nomenclature
o 2.1 Pronunciation
 3 Properties
o 3.1 Basicity
o 3.2 Solubility
 4 Characterization
 5 Applications and occurrence
 6 Amide synthesis
o 6.1 Other methods
 7 Amide reactions
 8 See also
 9 References
 10 External links

Structure and bonding

The simplest amides are derivatives of ammonia wherein one hydrogen atom has been
replaced by an acyl group. The ensemble is generally represented as RC(O)NH2 and is
described as a primary amide. Closely related and even more numerous are secondary amides
which can be derived from primary amines (R′NH2) and have the formula RC(O)NHR′.
Tertiary amides are commonly derived from secondary amines (R′R″NH) and have the
general structure RC(O)NR′R″. Amides are usually regarded as derivatives of carboxylic
acids in which the hydroxyl group has been replaced by an amine or ammonia.

The lone pair of electrons on the nitrogen is delocalized into the carbonyl, thus forming a
partial double bond between N and the carbonyl carbon. Consequently, the nitrogen in
amides is not pyramidal. It is estimated that acetamide is described by resonance structure A
for 62% and by B for 28% (which does not sum to 100% because there are additional
resonance forms that are not depicted in the above Figure).[5]

Amides possess a conjugated system spread over the O, C and N atoms, consisting of
molecular orbitals occupied by delocalized electrons. One of the π molecular orbitals in
formamide is shown above.

Nomenclature
Main article: IUPAC nomenclature of organic chemistry § Amines and amides

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. Functional groups consisting of –P(O)NR2 and –SO2NR2 are
phosphonamides and sulfonamides, respectively.[6]

Pronunciation

Some chemists make a pronunciation distinction between the two, saying /əˈmiːd/ for the
carbonyl–nitrogen compound and /ˈeɪmaɪd/ ( listen)[contradictory] for the anion. Others replace
one of these with /ˈæmɪd/, while still others pronounce both /ˈæmɪd/, making them
homonyms.

Properties
Basicity

Compared to amines, amides are very weak bases. While the conjugate acid of an amine has a
pKa of about 9.5, the conjugate acid of an amide has a pKa around −0.5. Therefore, amides
don't have as clearly noticeable acid–base properties in water. This relative lack of basicity is
explained by the electron-withdrawing nature of the carbonyl group where the lone pair of
electrons on the nitrogen is delocalized by resonance. 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). It is estimated in silico that acetamide is represented by
resonance structure A for 62% and by B for 28%.[5] Resonance is largely prevented in the
very strained quinuclidone.

Because of the greater electronegativity of oxygen, 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.

The proton of a primary or secondary amide does not dissociate readily under normal
conditions; its pKa is usually well above 15. Conversely, under extremely acidic conditions,
the carbonyl oxygen can become protonated with a pKa of roughly −1.

Solubility

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.

Characterization
The presence of the functional group is generally easily established, at least in small
molecules. They are the most common non-basic functional group. They can be distinguished
from nitro and cyano groups by their IR spectra. Amides exhibit a moderately intense νCO
band near 1650 cm−1. By 1H NMR spectroscopy, CONHR signals occur at low fields. In X-
ray crystallography, the C(O)N center together with the three immediately adjacent atoms
characteristically define a plane.

Applications and occurrence

Amides are pervasive in nature and technology as structural materials. The amide linkage is
easily formed, confers structural rigidity, and resists hydrolysis. Nylons are polyamides, as
are the very resilient materials Aramid, Twaron, and Kevlar. Amide linkages constitute a
defining molecular feature of proteins, the secondary structure of which is due in part to the
hydrogen bonding abilities of amides. Amide linkages in a biochemical context are called
peptide bonds when they occur in the main chain of a protein and isopeptide bonds when they
occur to a side-chain of the protein. Proteins can have structural roles, such as in hair or
spider silk, but also nearly all enzymes are proteins. Low molecular weight amides, such as
dimethylformamide (HC(O)N(CH3)2), are common solvents. Many drugs are amides,
including paracetamol, penicillin and LSD. Moreover, plant N-alkylamides have a wide range
of biological functionalities.[7]

Amide synthesis
Many methods exist in amide synthesis.[8] On paper, the simplest method for making amides
is by coupling a carboxylic acid with an amine. In general this reaction is thermodynamically
favorable, however it suffers from a high activation energy, largely due to the amine first
deprotonating the carboxylic acid, which reduces its reactivity. As such the direct reaction
often requires high temperatures.

RCO2H + R′R″NH ⇌ RCO−

2 + R′R″NH+
2 ⇌ RC(O)NR′R″ + H2O

Many methods are known for driving the equilibrium to the right. For the most part these
reactions involve "activating" the carboxylic acid by first converting it to a better
electrophile; such as esters, acid chlorides (Schotten-Baumann reaction) or anhydrides
(Lumière–Barbier method). Conventional methods in peptide synthesis use coupling agents
such as HATU, HOBt, or PyBOP.[9] In recent years there has also been a surge in the
development of Boron reagents for amide bond formation, including catalytic use of 2-
IodoPhenylBoronic acid[10] or MIBA,[11] and Tris(2,2,2-trifluoroethyl) borate.[12][13]

Reaction name Substrate Details

Beckmann Cyclic
Reagent: hydroxylamine and acid
rearrangement ketone
Schmidt reaction Ketones Reagent: hydrazoic acid
Nitrile Nitrile
Reagent: water; acid catalyst
hydrolysis[14]
Willgerodt– Aryl alkyl
Sulfur and morpholine
Kindler reaction ketones
Carboxyli
c acid,
Passerini reaction
ketone or
aldehyde
Isocyanide
,
Ugi reaction
carboxylic
acid,
 Reaction name Substrate Details
ketone,
primary
amine
Carboxyli
c acid,
Grignard
Bodroux reagent
[15][16]
reaction with an
aniline
derivative
ArNHR′
For N,N-diaryl amides. The reaction mechanism is based
on a nucleophilic aromatic substitution.[19]
Chapman Aryl
[17][1
rearrangement imino
8]
ether

Leuckart amide Reaction of arene with isocyanate catalysed by aluminium

Isocyanate
synthesis[20] trichloride, formation of aromatic amide.
Alkenes,
alcohols,
or other Secondary amides via an addition reaction between a nitrile
Ritter reaction[21]
carbonium and a carbonium ion in the presence of concentrated acids.
ion
sources
Photolytic addition
Terminal A free radical homologation reaction between a terminal
of formamide to
alkenes alkene and formamide.
olefins[22]
Ester
Base catalyzed reaction of esters with various amines to
aminolysis[23][24][25 Esters
] form alcohols and amides.

Other methods

The seemingly simple direct reaction between an alcohol and an amine to an amide was not
tried until 2007 when a special ruthenium-based catalyst was reported to be effective in a so-
called dehydrogenative acylation:[26]
The generation of hydrogen gas compensates for unfavorable thermodynamics. The reaction
is believed to proceed by one dehydrogenation of the alcohol to the aldehyde followed by
formation of a hemiaminal and the after a second dehydrogenation to the amide. Elimination
of water in the hemiaminal to the imine is not observed.

A direct generation of amide from aryl (heteroaryl) alkyl ketones has been accomplished via
copper(II) catalyzed C-C bond cleavage in the presence of diisopropylamine at moderate
temperature. The transformation steps for amide formation comprise catalytic generation of
α-bromo carbonyl species followed by nucleophilic displacement of bromide with sodium
azide in the presence of diisopropylamine. The final step involves the formation of imine by
heating in situ followed by hydrolysis to give the related amide.[27]

Amide reactions

Mechanism for acid-catalyzed hydrolysis of an amide.[28]

Amides undergo many chemical reactions, although they are less reactive than esters. 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. Amides are also versatile precursors to many other functional groups.Electrophiles
attack the carbonyl oxygen. This step often precedes hydrolysis, which is catalyzed by both
Bronsted acids and Lewis acids. Enzymes, e.g. peptidases and artificial catalysts, are known
to accelerate the hydrolysis reactions.

Reaction name Product Comment

Dehydration Nitrile Reagent: phosphorus pentoxide;
benzenesulfonyl chloride; TFAA/py[29]
 Reaction name Product Comment
Hofmann Amine with one fewer
Reagents: bromine and sodium hydroxide
rearrangement carbon atom
Amide reduction Amine Reagent: lithium aluminium hydride
followed by hydrolysis
Vilsmeier–Haack
Aldehyde (via imine) POCl3, aromatic substrate, formamide
reaction
Bischler–Napieralski
Cyclic imine POCl3, SOCl2, etc.
reaction

See also
 Amidicity
 Metal amides

References
1.

 http://www.collinsdictionary.com/dictionary/english/amide
  "amide". The American Heritage Dictionary of the English Language (5th ed.). Boston:
Houghton Mifflin Harcourt. 2014.
  http://www.oxforddictionaries.com/us/definition/english/amide
  IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997).
Online corrected version: (2006–) "amides".
  Kemnitz, Carl R.; Loewen, Mark J. (2007). ""Amide Resonance" Correlates with a
Breadth of C−N Rotation Barriers". Journal of the American Chemical Society. 129 (9):
2521–8. doi:10.1021/ja0663024. PMID 17295481.
  Organic Chemistry IUPAC Nomenclature. Rules C-821. Amides
http://www.acdlabs.com/iupac/nomenclature/79/r79_540.htm
  Boonen, Jente; Bronselaer, Antoon; Nielandt, Joachim; Veryser, Lieselotte; De Tré,
Guy; De Spiegeleer, Bart (2012). "Alkamid database: Chemistry, occurrence and
functionality of plant N-alkylamides" (PDF). Journal of Ethnopharmacology. 142 (3): 563–90.
doi:10.1016/j.jep.2012.05.038. hdl:1854/LU-2133714. PMID 22659196.
  Montalbetti, Christian A. G. N.; Falque, Virginie (14 November 2005). "Amide bond
formation and peptide coupling". Tetrahedron. 61 (46): 10827–10852.
doi:10.1016/j.tet.2005.08.031.
  Valeur, Eric; Bradley, Mark (2009). "Amide bond formation: beyond the myth of
coupling reagents". Chem. Soc. Rev. 38: 606–631. doi:10.1039/B701677H.
  "Greener Methods: Catalytic Amide Bond Formation". Retrieved 2016-09-22.
  "MIBA 96% | Sigma-Aldrich". www.sigmaaldrich.com. Retrieved 2016-09-22.
  "Tris(2,2,2-trifluoroethyl) borate 97% | Sigma-Aldrich". www.sigmaaldrich.com.
Retrieved 2016-09-22.
  Sabatini, Marco T.; Boulton, Lee T.; Sheppard, Tom D. (2017-09-01). "Borate esters:
Simple catalysts for the sustainable synthesis of complex amides". Science Advances. 3 (9):
e1701028. doi:10.1126/sciadv.1701028. ISSN 2375-2548. PMC 5609808  .
  Wenner, Wilhelm (1952). "Phenylacetamide". Organic Syntheses. 32: 92.
doi:10.15227/orgsyn.032.0092.
  Bodroux F. (1905). Bull. Soc. Chim. France. 33: 831.
  "Bodroux reaction". Institute of Chemistry, Skopje, Macedonia.
  Schulenberg, J. W.; Archer, S. (1965). "The Chapman Rearrangement". Org. React. 14.
doi:10.1002/0471264180.or014.01.
  Chapman, Arthur William (1925). "CCLXIX.—Imino-aryl ethers. Part III. The
molecular rearrangement of N-phenylbenziminophenyl ether". Journal of the Chemical
Society, Transactions. 127: 1992. doi:10.1039/CT9252701992.
  March, Jerry. Advanced organic Chemistry, Reactions, mechanisms and structure (3rd
ed.). ISBN 0-471-85472-7.
  Leuckart, R. (1885). "Ueber einige Reaktionen der aromatischen Cyanate". Berichte der
deutschen chemischen Gesellschaft. 18: 873–877. doi:10.1002/cber.188501801182.
  Adams, Rodger; Krimen, L.I.; Cota, Donald J. (1969). Organic Reaction Volume 17.
London: John Wiley & Sons, Inc. pp. 213–326. doi:10.1002/0471264180.
ISBN 9780471196150.
  Monson, Richard (1971). Advanced Organic Synthesis: Methods and Techniques (PDF).
Newyork: Academic Press. p. 141. ISBN 978-0124336803.
  Corson, B. B.; Scott, R. W.; Vose, C. E. (1941). "Cyanoacetamide". Organic Syntheses.
1: 179. doi:10.15227/orgsyn.009.0036.
  Jacobs, W. A. (1941). "Chloroacetamide". Organic Syntheses. 1: 153.
doi:10.15227/orgsyn.007.0016.
  Kleinberg, J.; Audrieth, L. F. (1955). "Lactamide". Organic Syntheses. 3: 516.
doi:10.15227/orgsyn.021.0071.
  Gunanathan, C.; Ben-David, Y.; Milstein, D. (2007). "Direct Synthesis of Amides from
Alcohols and Amines with Liberation of H2". Science. 317 (5839): 790–2.
Bibcode:2007Sci...317..790G. doi:10.1126/science.1145295. PMID 17690291.
  A novel copper-catalyzed C-C bond cleavage of aryl (heteroaryl) alkyl ketones for C-N
bond formation, EJPMR, 2017,4(2), 126-151,
http://www.ejpmr.com/admin/assets/article_issue/1486098724.pdf
  Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 0-471-72091-7

29.  U.S. Patent 5,935,953

External links