Amide

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Not to be confused with Imide.
For the amide anion NH−
2, see azanide.

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

Due to the dual use of the word 'amide', there is debate as to how to properly and unambiguously name the derived anions of amides in the first sense (i.e., deprotonated acylated amines), a few of which are commonly used as nonreactive counterions.[5]

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

Structure and bonding[edit]

The simplest amides are derivatives of ammonia wherein one hydrogen atom has been replaced by an acyl group.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 Amides are usually regarded as derivatives of carboxylic acids in which the hydroxyl group has been replaced by an amine or ammonia.

AmideResonance.png

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). One final thing to note when looking at the bonds of an amide is that there is also a hydrogen bond present between the active groups hydrogen and nitrogen atoms.[6]

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[edit]

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.[7]

Pronunciation[edit]

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

Properties[edit]

Basicity[edit]

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%.[6] 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. 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.

Solubility[edit]

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[edit]

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[edit]

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.[8]

Amide synthesis[edit]

Many methods exist in amide synthesis.[9] 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.[10] 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[11] or MIBA,[12] and Tris(2,2,2-trifluoroethyl) borate.[13][14]

Reaction name Substrate Details
Nucleophilic reaction acyl chloride or acid anhydride Reagent: ammonia or amine|-
Beckmann rearrangement Cyclic ketone Reagent: hydroxylamine and acid
Schmidt reaction Ketones Reagent: hydrazoic acid
Nitrile hydrolysis[15] Nitrile Reagent: water; acid catalyst
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[16][17] Carboxylic acid, Grignard reagent with an aniline derivative ArNHR′ Bodroux reaction.svg
Chapman rearrangement[18][19] Aryl imino ether For N,N-diaryl amides. The reaction mechanism is based on a nucleophilic aromatic substitution.[20] Chapman Rearrangement
Leuckart amide synthesis[21] Isocyanate Reaction of arene with isocyanate catalysed by aluminium trichloride, formation of aromatic amide.
Ritter reaction[22] 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[23] Terminal alkenes A free radical homologation reaction between a terminal alkene and formamide.
Ester aminolysis[24][25][26] Esters Base catalyzed reaction of esters with various amines to form alcohols and amides.

Other methods[edit]

Dehydrogenative acylation of amines is catalyzed by organoruthenium complexes:[27]

DehydrogenativeAmidation.svg

The reaction proceed by one dehydrogenation of the alcohol to the aldehyde followed by formation of a hemiaminal, which undergoes a second dehydrogenation to the amide. Elimination of water in the hemiaminal to the imine is not observed.

Transamidation is typically very slow, but it is accelerated with Lewis acid[28] and organometallic catalysts:[29]

RC(O)NR'2 + HNR"2 → RC(O)NR"2 + HNR'2

Primary amides (RC(O)NH2) are more amenable to this reaction.

Amide reactions[edit]

Mechanism for acid-catalyzed hydrolysis of an amide.[30]

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 Brønsted 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[31]
Hofmann rearrangement Amine with one fewer carbon atom Reagents: bromine and sodium hydroxide
Amide reduction Amine Reagent: lithium aluminium hydride followed by hydrolysis
Vilsmeier–Haack reaction Aldehyde (via imine) POCl3, aromatic substrate, formamide
Bischler–Napieralski reaction Cyclic imine POCl3, SOCl2, etc.

See also[edit]

References[edit]

  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.). Boston: Houghton Mifflin Harcourt. 2014.
  3. ^ "amide - Definition of amide in English by Oxford Dictionaries". Oxford Dictionaries - English. Retrieved 15 April 2018.
  4. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "amides". doi:10.1351/goldbook.A00266
  5. ^ "Resolving Ambiguous Naming for an Ionic Liquid Anion". Chemistry International -- Newsmagazine for Iupac. 29 (4). 2007. doi:10.1515/ci.2007.29.4.16.
  6. ^ a b 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.
  7. ^ Organic Chemistry IUPAC Nomenclature. Rules C-821. Amides http://www.acdlabs.com/iupac/nomenclature/79/r79_540.htm Archived 21 January 2011 at the Wayback Machine
  8. ^ 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.
  9. ^ 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.
  10. ^ Valeur, Eric; Bradley, Mark (2009). "Amide bond formation: beyond the myth of coupling reagents". Chem. Soc. Rev. 38 (2): 606–631. doi:10.1039/B701677H. PMID 19169468.
  11. ^ "Greener Methods: Catalytic Amide Bond Formation". Retrieved 22 September 2016.
  12. ^ "MIBA 96% | Sigma-Aldrich". www.sigmaaldrich.com. Retrieved 22 September 2016.
  13. ^ "Tris(2,2,2-trifluoroethyl) borate 97% | Sigma-Aldrich". www.sigmaaldrich.com. Retrieved 22 September 2016.
  14. ^ Sabatini, Marco T.; Boulton, Lee T.; Sheppard, Tom D. (1 September 2017). "Borate esters: Simple catalysts for the sustainable synthesis of complex amides". Science Advances. 3 (9): e1701028. Bibcode:2017SciA....3E1028S. doi:10.1126/sciadv.1701028. PMC 5609808. PMID 28948222.
  15. ^ Wenner, Wilhelm (1952). "Phenylacetamide". Organic Syntheses. 32: 92. doi:10.15227/orgsyn.032.0092.
  16. ^ Bodroux F. (1905). Bull. Soc. Chim. France. 33: 831.CS1 maint: untitled periodical (link)
  17. ^ "Bodroux reaction". Institute of Chemistry, Skopje, Macedonia.
  18. ^ Schulenberg, J. W.; Archer, S. (1965). The Chapman Rearrangement. Org. React. 14. pp. 1–51. doi:10.1002/0471264180.or014.01. ISBN 978-0471264187.
  19. ^ Chapman, Arthur William (1925). "CCLXIX.—Imino-aryl ethers. Part III. The molecular rearrangement of N-phenylbenziminophenyl ether". Journal of the Chemical Society, Transactions. 127: 1992–1998. doi:10.1039/CT9252701992.
  20. ^ March, Jerry (1966). Advanced organic Chemistry, Reactions, mechanisms and structure (3rd ed.). ISBN 978-0-471-85472-2.
  21. ^ Leuckart, R. (1885). "Ueber einige Reaktionen der aromatischen Cyanate". Berichte der deutschen chemischen Gesellschaft. 18: 873–877. doi:10.1002/cber.188501801182.
  22. ^ 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.
  23. ^ Monson, Richard (1971). Advanced Organic Synthesis: Methods and Techniques (PDF). Newyork: Academic Press. p. 141. ISBN 978-0124336803.[permanent dead link]
  24. ^ Corson, B. B.; Scott, R. W.; Vose, C. E. (1941). "Cyanoacetamide". Organic Syntheses. 1: 179. doi:10.15227/orgsyn.009.0036.
  25. ^ Jacobs, W. A. (1941). "Chloroacetamide". Organic Syntheses. 1: 153. doi:10.15227/orgsyn.007.0016.
  26. ^ Kleinberg, J.; Audrieth, L. F. (1955). "Lactamide". Organic Syntheses. 3: 516. doi:10.15227/orgsyn.021.0071.
  27. ^ 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.
  28. ^ T. A. Dineen, M. A. Zajac, A. G. Myers (2006). "Efficient Transamidation of Primary Carboxamides by in situ Activation with N,N-Dialkylformamide Dimethyl Acetals". J. Am. Chem. Soc. 128 (50): 16406–16409. doi:10.1021/ja066728i. PMID 17165798.CS1 maint: uses authors parameter (link)
  29. ^ Emma L. Baker, Michael M. Yamano, Yujing Zhou, Sarah M. Anthony, Neil K. Garg (2016). "A two-step approach to achieve secondary amide transamidation enabled by nickel catalysis". Nature Communications. 7: 11554. Bibcode:2016NatCo...711554B. doi:10.1038/ncomms11554. PMC 4876455. PMID 27199089.CS1 maint: uses authors parameter (link)
  30. ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 978-0-471-72091-1
  31. ^ U.S. Patent 5,935,953

External links[edit]

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