Chemistry:Amide

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Short description: Organic compounds of the form RC(=O)NR′R″
General structure of an amide (specifically, a carboxamide)
Formamide, the simplest amide
Asparagine (zwitterionic form), an amino acid with a side chain (highlighted) containing an amide group

In organic chemistry, an amide,[1][2][3] also known as an organic amide or a carboxamide, is a compound with the general formula R–C(=O)–NR′R″, where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms.[4][5] 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, such as in the amino acids asparagine and glutamine. It can be viewed as a derivative of a carboxylic acid (R–C(=O)–OH) with the 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)–NH
2), acetamide (H
3C–C(=O)–NH
2), benzamide (C
6H
5–C(=O)–NH
2), and dimethylformamide (H–C(=O)–N(–CH
3)
2). Some uncommon examples of amides are N-chloroacetamide (H
3C–C(=O)–NH–Cl) and chloroformamide (Cl–C(=O)–NH
2).

Amides are qualified as primary, secondary, and tertiary according to whether the amine subgroup has the form –NH
2, –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 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.[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

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.[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 resonance between two alternative structures: neutral (A) and zwitterionic (B).

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). There is also a hydrogen bond present between the active groups hydrogen and nitrogen atoms.[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 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 do not have as clearly noticeable acid–base properties 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, 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 are 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

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

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. 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. Amides are also versatile precursors to many other functional groups. Electrophiles react with 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[11]
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) POCl
3, aromatic substrate, formamide
Bischler–Napieralski reaction Cyclic aryl imine POCl
3, SOCl
2, etc.
Iminoether elimination Imidoyl chloride Oxophilic halogenating agents, e.g. COCl2 or SOCl2

Synthesis

From carboxylic acids and related compounds

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

RCO
2H + R'
2NH → RCO−
2 + R'
2NH+
2
RCO−
2 + R'
2NH
2 → RC(O)NR'
2 + H
2O

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

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

RCO
2R" + 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 + RCO
2H

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' Bodroux reaction.svg
Chapman rearrangement[23][24] Aryl imino ether For N,N-diaryl amides. The reaction mechanism is based on a nucleophilic aromatic substitution.[25]
Isocyanate Reaction of arene with isocyanate catalysed by aluminium trichloride, formation of aromatic amide.
Ritter reaction[26] 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[27] Terminal alkenes A free radical homologation reaction between a terminal alkene and formamide.
Dehydrogenative coupling[28] alcohol, amine requires ruthenium dehydrogenation catalyst
Transamidation[29][30] amide typically slow
Amine α-oxidation[31] alkyl amine requires gold catalysts

See also

References

  1. ↑ "Amide definition and meaning - Collins English Dictionary". http://www.collinsdictionary.com/dictionary/english/amide. Retrieved 15 April 2018. 
  2. ↑ "amide". Boston: Houghton Mifflin Harcourt. 2014. https://www.ahdictionary.com/word/search.html?q=amide. 
  3. ↑ "amide - Definition of amide in English by Oxford Dictionaries". http://www.oxforddictionaries.com/us/definition/english/amide. 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. ↑ 5.0 5.1 5.2 Fletcher, John H. (1974). "Chapter 21: Amides and Imides". Nomenclature of Organic Compounds: Principles and Practice. 126. Washington, DC: American Chemical Society. pp. 166–173. doi:10.1021/ba-1974-0126.ch021. ISBN 9780841201910. https://archive.org/details/nomenclatureofor0000flet/page/166. 
  6. ↑ IUPAC, Chemical Nomenclature and Structure Representation Division (27 October 2004). "Draft Rule P-66.1". Nomenclature of Organic Chemistry (Provisional Recommendations). IUPAC. https://old.iupac.org/reports/provisional/abstract04/favre_310305.html.  Full text (PDF) of Draft Rule P-66: Amides, Imides, Hydrazides, Nitriles, Aldehydes, Their Chalcogen Analogues, and Derivatives
  7. ↑ 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". Journal of Ethnopharmacology 142 (3): 563–590. doi:10.1016/j.jep.2012.05.038. PMID 22659196. https://biblio.ugent.be/publication/2133714/file/2140565.pdf. 
  8. ↑ Bats, Jan W.; Haberecht, Monika C.; Wagner, Matthias (2003). "A new refinement of the orthorhombic polymorph of acetamide". Acta Crystallographica Section E 59 (10): o1483–o1485. doi:10.1107/S1600536803019494. 
  9. ↑ 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. 
  10. ↑ 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, https://books.google.com/books?id=JDR-nZpojeEC&printsec=frontcover 
  11. ↑ U.S. Patent 5,935,953
  12. ↑ Corson, B. B.; Scott, R. W.; Vose, C. E. (1941). "Cyanoacetamide". Organic Syntheses 1: 179. doi:10.15227/orgsyn.009.0036. 
  13. ↑ Jacobs, W. A. (1941). "Chloroacetamide". Organic Syntheses 1: 153. doi:10.15227/orgsyn.007.0016. 
  14. ↑ Kleinberg, J.; Audrieth, L. F. (1955). "Lactamide". Organic Syntheses 3: 516. doi:10.15227/orgsyn.021.0071. 
  15. ↑ 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. 
  16. ↑ Eller, Karsten; Henkes, Erhard; Rossbacher, Roland; Höke, Hartmut (2000). "Ullmann's Encyclopedia of Industrial Chemistry". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001.pub2. 
  17. ↑ Wenner, Wilhelm (1952). "Phenylacetamide". Organic Syntheses 32: 92. doi:10.15227/orgsyn.032.0092. 
  18. ↑ De Figueiredo, Renata Marcia; Suppo, Jean-Simon; Campagne, Jean-Marc (2016). "Nonclassical Routes for Amide Bond Formation". Chemical Reviews 116 (19): 12029–12122. doi:10.1021/acs.chemrev.6b00237. PMID 27673596. 
  19. ↑ "Tris(2,2,2-trifluoroethyl) borate 97% | Sigma-Aldrich". http://www.sigmaaldrich.com/catalog/product/aldrich/790877?lang=en&region=GB. 
  20. ↑ 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. PMID 28948222. Bibcode: 2017SciA....3E1028S. 
  21. ↑ Bodroux F. (1905). "none". Bull. Soc. Chim. France 33: 831. 
  22. ↑ "Bodroux reaction". Institute of Chemistry, Skopje, Macedonia. http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/bodroux1.htm. 
  23. ↑ Schulenberg, J. W.; Archer, S. (1965). "The Chapman Rearrangement". Org. React. 14: 1–51. doi:10.1002/0471264180.or014.01. ISBN 978-0471264187. 
  24. ↑ 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. 
  25. ↑ March, Jerry (1966). Advanced organic Chemistry, Reactions, mechanisms and structure (3rd ed.). Wiley. ISBN 978-0-471-85472-2. 
  26. ↑ 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. 
  27. ↑ Monson, Richard (1971). Advanced Organic Synthesis: Methods and Techniques. New York: Academic Press. p. 141. ISBN 978-0124336803. https://nootropicsfrontline.com/wp-content/uploads/2021/07/wiki_Monson-R.S.-Advanced-organic-synthesis.-Methods-and-techniques-ГХИ-1971.pdf. 
  28. ↑ 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. doi:10.1126/science.1145295. PMID 17690291. Bibcode: 2007Sci...317..790G. 
  29. ↑ 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. 
  30. ↑ 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. doi:10.1038/ncomms11554. PMID 27199089. Bibcode: 2016NatCo...711554B. 
  31. ↑ P. Chatterjee; H. Wang; J. S. Manzano; U. Kanbur; A. D. Sadow; I. I. Slowing (2022). "Surface ligands enhance the catalytic activity of supported Au nanoparticles for the aerobic α-oxidation of amines to amides". Catal. Sci. Technol. 12 (6): 1922–1933. doi:10.1039/D1CY02121D. 

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