2-Pyridone

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2-Pyridone
IUPAC name 2-Pyridone
Other names 2(1H)-Pyridinone,
2(1H)-Pyridone,
1-H-Pyridine-2-one,
1,2 Dihydro-2-oxopyridine,
1H-2-Pyridone, 2-Oxopyridone,
2-Pyridinol, 2-Hydroxypyridine
Identifiers
3D model (JSmol)
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RTECS number UV1144050
Properties
C5H5NO
Molar mass 95.10 g/mol
Appearance Colourless crystalline solid
Density 1.39 g/cm³, solid
Melting point
Boiling point
Solubility in other solvents Soluble in water,
methanol, acetone
Acidity (pKa) 11.65
λmax 293 nm (ε 5900, H2O soln)
Structure
Crystal structure orthorhombic
Molecular shape planar
Dipole moment 4.26 D
Hazards
Main hazards irritating
R-phrases R36 R37 R38
S-phrases S26 S37/39
Flash point {{{value}}}
Related compounds
Other anions {{{value}}}
Other cations {{{value}}}
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)

Infobox disclaimer and references

2-Pyridone is the chemical compound with the formula C5H4NH(O). This colourless crystalline solid is used in peptide synthesis. It is well known to form hydrogen bonded structures somewhat related to the base-pairing mechanism found in RNA and DNA. It is also a classic case of a molecule that exists as tautomers.

Structure

The most prominent feature of the 2-pyridone is the amide group, a nitrogen with a hydrogen bound to it and a keto group next to it. In peptides, amino acids are linked by this pattern.

This pattern is responsible for some remarkable physical and chemical properties.

The hydrogen bound to the nitrogen is suitable to form strong hydrogen bonds to other nitrogen- and oxygen-containing species.

Tautomerism

The hydrogen bond to the nitrogen is also suitable to move to the oxygen. Through hydrogen and electron shift the second tautomer form of the substance is formed. 2-hydroxypyridine is the name for this tautomer. This lactam lactim tautomerism can also be found in other molecules with a similar structure.[1]

Tautomerism in Solid State

The predominant form in solid state is the 2-pyridone. This fact has been clarified by X-ray crystallography which shows that the hydrogen in solid state is closer to the nitrogen than to the oxygen (because of the low electron density at the hydrogen the exact positioning is difficult) and IR-spectroscopy in which the C=O longitudinal frequency is present and the O-H frequencies are absent.[2][3][4][5]

Tautomerism in Solution

To determine which of the two tautomeric forms is present in solution has been the subject of many publications. The energy difference seems to be very small and depending on the polarity of the solvent. Nonpolar solvents favour the 2-hydroxypyridine whereas in polar solvents like alcohols and water the 2-pyridone is favoured.[6][7][8][9][10][11][12][13][14]

The energy difference for the two tautomers in the gas phase was measured by IR-spectroscopy to be 2.43 to 3.3 kJ/mol for the solid state and 8.95 kJ/mol and 8.83 kJ/mol for the liquid state.[15][16][17]

Tautomerisation Mechanism A

The single molecular tautomerisation has a forbidden 1-3 suprafacial transition state and therefore has a high energy barrier for this tautomerisation, which was calculated with theoretical methods to be 125 or 210 kJ/mol. The direct tautomerisation is energetically not favoured. There are other possible mechanisms for this tautomerisation.[16]

Dimerisation

dimer

The 2-pyridone and the 2-hydroxypyridine can form dimers with two hydrogen bonds[18].

Aggregation in Solid-state

In solid state the dimeric form is not present; the 2-pyridones form a helical structure over hydrogen bonds. Some substituted 2-pyridones form the dimer in solid state, for example the 5-methyl-3-carbonitrile-2-pyridone. The determination of all these structures was done by X-ray crystallography. In solid state the hydrogen is located closer to the oxygen so it could be considered to be right to call the colourless crystals in the flask 2-pyridone.[1-5]

Aggregation in Solution

In solution the dimeric form is present; the ratio of dimerisation is strongly dependent on the polarity of the solvent. Polar and protic solvents interact with the hydrogen bonds and more monomer is formed. hydrophobic effects in unpolar solvents lead to a predominance of the dimere. Also the ratio of the tautomeric forms is dependent on the solvent. All possible tautomers and dimmers can be present and form an equilibrium. The exact measurement of all the equilibrium constants in the system are extremely difficult.[17-27]

(NMR-spectroscopy is a slow method, high resolution IR-spectroscopy in solvent is difficult, the broad absorption in UV-spectroscopy makes it hard to discriminate 3 and more very similar molecules).

Some publications only focus one of the two possible patterns, and neglect the influence of the other. For example to calculate the energy difference of the two tautomeres in nonpolar solution, leads too a wrong results if a large quantity of the substance is on the side of the dimer in an equilibrium.

Tautomerisation Mechanism B

The direct tautomerisation is energetically not favoured, but a dimerisation followed by a double proton transfer and a dissociation of the dimer is a self catalytic way from one tautomer to the other. In solution, the tautomerisation can be done over the dimer. Protic solvents also mediate the proton transfer during the tautomerisation. Like the deprotonation and reprotonation during autoprotolyse can leads to both tautomers.

Synthesis

Syntheisis from 2-Pyran

2-Pyrane can be obtained by a cyclisation reaction. 2-Pyridone is formed by an exchange reaction with Ammonia from this 2-pyrane.

Syntheisis from Pyridine-N-oxide

Pyridine forms an N-oxide with some oxidation agents for example hydrogen peroxide. This pyridine-N-oxide undergoes a rearrangement reaction to the 2-Pyridone in acetic anhydride.

In the Guareschi-Thorpe condensation cyanoacetamide reacts with a 1,3-diketone to a 2-pyridone[19][20].

Main Research Interests

Catalytic Activity

After the discovering that 2-Pyridone catalyses the mutarotation of sugars and that 2-pyridone has a large effect on the reaction from activated esters with amines in nonpolar solvent. Acid or base catalysed reactions should depend in first order on pKa value, but as relative weak acid or base enhances the reaction far more than expected. 4-Pyridone shows no such effect, this leads to the conclusion that the special structure and tautomerisation is the cause for this catalysis.

Neither sugar mutarotation nor ester aminolysis in nonpolar solvent have big impact in synthesis. Because sugar mutarotation takes place even without catalysis and ester aminolysis as source for peptide bonds was seldom used and with activated esters the reaction itself is fast. Polar solvents enhance the reaction more than the use of 2-pyridone. The normal synthesis for peptides with DCCI or DMAP give good yields and the previous synthesis of phenyl or nitro-phenyl esters can be avoided. Because of this a direct use of 2-pyridone in ester aminolysis was never the goal of the research. But understanding the simple proton transfer catalysis would be a big step in understanding the principle which is also present in enzyme catalysed reaction. Most of the research was done to understand the activation of the transition state by the 2-pyridone. Isotope labelling, kinetics and quantum chemical methods were used on the mechanism to determine the rate determining step in the reaction.[21][22]

The cyclisation of a macrocycle was catalysed with 2-pyridone. A synthesis trick for unwilling substrates is to use molten 2-pyridone as solvent.

Relation to Base Pairs

2-pyridone dimer compared with base pair

These structures are closely related to the base pairs present in the DNA or RNA. These dimers are sometimes used as simple models for base pairs (in experimental and theoretical studies). The strength of the hydrogen bonds is important for the two strands in DNA and RNA sticking to each other. For the 2-pyridone dimer there are direct measurements of the dimerisation constant and the dimerisation energy which are compared to the calculated ones. Because of the multiple possible base pair combinations, measurements with the natural base pairs are difficult. If the results of the simple 2-pyridone model give good agreement, these theoretical methods are also suitable for base pairs.

Coordination Chemistry

2-Pyridone and some derivatives where used as ligands in coordination chemistry. The main point of this chemistry was that 2-pyridone functions as a 1,3-bridged ligand like carboxylate. There is a large number of dimeric complexes. A review with a literature overview can be found at Rawson and Winpenny.[23]

Analytical Data

NMR spectroscopy

NMR data of 2-Pyridone

1H-NMR

1H-NMR (400 MHz, CD3OD): /ρ = 8.07 (dd,3J = 2.5 Hz,4J = 1.1 Hz, 1H, C-6), 7.98 (dd,3J = 4.0 Hz,3J = 2.0 Hz, 1H, C-3), 7.23 (dd,3J = 2.5 Hz,3J = 2.0 Hz, 1H, C-5), 7.21 (dd,3J = 4.0 Hz,4J = 1.0 Hz, 1H, C-4).

13C-NMR

(100.57 MHz, CD3OD): ρ = 155.9 (C-2), 140.8 (C-4), 138.3 (C-6), 125.8 (C-3), 124.4 (C-5)

UV/Vis spectroscopy

(MeOH):νmax (lg ε) = 226.2 (0.44), 297.6 (0.30).

IR spectroscopy

(KBr): ν = 3440 cm-1–1 (br, m), 3119 (m), 3072 (m), 2986 (m), 1682 (s), 1649 (vs), 1609 (vs), 1578 (vs), 1540 (s), 1456 (m), 1433 (m), 1364 (w), 1243 (m), 1156 (m), 1098 (m), 983 (m), 926 (w), 781 (s), 730 (w), 612 (w), 560 (w), 554 (w), 526 (m), 476 (m), 451 (w).

Mass-spectroscopy

EI-MS (70 eV): m/z (%) = 95 (100) [M+], 67 (35) [M+ - CO], 51 (4)[C4H3+].

References

  1. Forlani L, Cristoni G, Boga C, Todesco PE, Del Vecchio E, Selva S, Monari M, (2002). "Reinvestigation of tautomerism of some substituted 2-hydroxypyridines". ARKIVOC. XI: 198–215.
  2. Yang H. W., Craven B. M. (1998). "Charge Density of 2-Pyridone". Acta Crystallogr. Ser. B54: 912–920. doi:10.1107/S0108768198006545.
  3. Penfold B. R. (1953). "The Electron Distribution in Crystalline Alpha-Pyridone". Acta Crystallogr. 6: 591–600. doi:10.1107/S0365110X5300168X.
  4. Ohms U., Guth H., Heller E., Dannöhl H., Schweig A. (1984). "Comparison of Observed and Calculated Electron-Density 2-Pyridone, C5H5NO, Crystal-Structure Refinements at 295K and 120K, Experimental and Theoretical Deformation Density Studies". Z. Kristallogr. 169: 185–200.
  5. Almlöf J., Kvick A., Olovsson I. (1971). "Hydrogen Bond Studies Crystal Structure of Intermolecular Complex 2-Pyridone-6-Chloro-2-Hdroxypyridine". Acta Crystallogr. Ser. B27: 1201–1208. doi:10.1107/S0567740871003753.
  6. Forlani L., Cristoni G., Boga C., Todesco P. E., Del Vecchio E., Selva S., Monari M. (2002). "Reinvestigation of tautomerism of some substituted 2-hydroxypyridines". ARKIVOC. XI: 198–215.
  7. Vögeli U., von Philipsborn W. (1973). "C-13 and H-1 NMR Spectroscopie Studies on Structure of N-Methyle-3-Pyridone and 3-Hydroypyridine". Org Magn Reson: 551–559.
  8. Specker H., Gawrosch H. (1942). "Ultraviolet absorption of benztriaxole, pryridone and its salts". Chem. Ber. (75): 1338–1348.
  9. Leis D. G., Curran B. C. (1945). "Electric Moments of Some Gamma-Substituted Pyridines". Journal of the American Chemical Society (67): 79–81. doi:10.1021/ja01217a028.
  10. Albert A., Phillips J. N. (1956). "Ionisation Constants of Heterocyclic Substances Hydroxy-Derivates of Nitrogenous Six-Membered Ring-Compounds". J. Chem. Soc.: 1294–1304.
  11. Cox R. H., Bothner-By A. A (1969). "Proton Magnetic Resonance Spectra of Tautomeric Substituted Pyridines and Their Conjugated Acides". J. Phys. Chem. (73): 2465–2468. doi:10.1021/j100842a001.
  12. Aksnes DW, Kryvi (1972). "Substituent and Solvent Effects in Proton Magnetic -Resonance (PMR) Spectra of 6 2-Substituted Pyridines". Acta. Chem. Scand. (26): 2255–2266.
  13. Aue DH, Betowski LD, Davidson WR, Bower MT, Beak P (1979). "Gas-Phase Basicities of Amides and Imidates - Estimation of Protomeric Equilibrium-Constantes by the Basicity methode in the Gas-Phase". Journal of the American Chemical Society (101): 1361–1368. doi:10.1021/ja00500a001.
  14. Frank J., Katritzky A. R. (1976). "Tautomeric pyridines. XV. Pyridone-hydroxypyridine equilibria in solvents of different polarity". J Chem Soc Perkin Trans 2: 1428–1431.
  15. Brown R. S., Tse A., Vederas J. C. (1980). "Photoelectro-Determined Core Binding Energies and Predicted Gas-Phase Basicities for the 2-Hydroxypyridine 2-Pyridone System". Journal of the American Chemical Society (102): 1174–1176. doi:10.1021/ja00523a050.
  16. Beak P. (1977). "Energies and Alkylation of Tautomeric Heterocyclic-Compounds - Old Problems New Answers". Acc. Chem. Res. (10): 186–192. doi:10.1021/ar50113a006.
  17. Abdulla H. I., El-Bermani M. F. (2001). "Infrared studies of tautomerism in 2-hydroxypyridine 2-thiopyridine and 2-aminopyridine". Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (57): 2659–2671. doi:10.1016/S1386-1425(01)00455-3.
  18. Hammes GG, Lillford PJ (1970). "A Kinetic and Equilibrium Study of Hydrogen Bond Dimerization of 2-Pyridone in Hydrogen Bonding Solvent". J. Am. Chem. Soc. (92): 7578–7585.
  19. Gilchrist, T.L. (1997). Heterocyclic Chemistry ISBN 0470204818
  20. Rybakov V. R., Bush A. A., Babaev E. B., Aslanov L. A. (2004). "3-Cyano-4,6-dimethyl-2-pyridone (Guareschi Pyridone)". Acta Crystallogr E. 6: o160–o161. doi:10.1107/S1600536803029295.
  21. Fischer C. B., Steininger H., Stephenson D. S., Zipse H. (2005). "Catalysis of Aminolysis of 4-Nitrophenyl Acetate by 2-Pyridone". Journal for Physical Organic Chemistry. 18 (9): 901–907. doi:10.1002/poc.914.
  22. Fischer C. B., Polborn K., Steininger H., Zipse H. (2004). "Synthesis and Solid-State Structures of Alkyl-Substituted 3-Cyano-2-pyridones" (PDF). Zeitschrift für Naturforschung (59b): 1121–1131.
  23. Rawson J. M., Winpenny R. E. P. (1995). "The coordination chemistry of 2-pyridones and its derivatives". Coordination Chemistry Reviews (139): 313–374. doi:10.1016/0010-8545(94)01117-T.

General references

  1. Engdahl K., Ahlberg P. (1977). Journal Chemical Research (12): 340–341. Missing or empty |title= (help)
  2. Bensaude O, Chevrier M, Dubois J (1978). "Lactim-Lactam Tautomeric Equilibrium of 2-Hydroxypyridines. 1.Cation Binding, Dimerization and Interconversion Mechanism in Aprotic Solvents. A Spectroscopic and Temperature-Jump Kinetic Study". J. Am. Chem. Soc. (100): 7055–7066.
  3. Bensaude O, Dreyfus G, Dodin G, Dubois J (1977). "Intramolecular Nondissociative Proton Transfer in Aqueous Solutions of Tautomeric Heterocycles: a Temperature-Jump Kinetic Study". J. Am. Chem. Soc. (99): 4438–4446.
  4. Bensaude O, Chevrier M, Dubois J (1978). "Influence of Hydration upon Tautomeric Equilibrium". Tetrahedron Lett. (25): 2221–2224.
  5. Hammes GG, Park AC (1969). "Kinetic and Thermodynamic Studies of Hydrogen Bonding". J. Am. Chem. Soc. (91): 956–961.
  6. Hammes GG, Spivey HO (1966). "A Kinetic Study of the Hydrogen-Bond Dimerization of 2-Pyridone". J. Am. Chem. Soc. (88): 1621–1625.
  7. Beak P, Covington JB, Smith SG (1976). "Structural Studies of Tautomeric Systems: the Importance of Association for 2-Hydroxypyridine-2-Pyridone and 2-Mercaptopyridine-2-Thiopyridone". J. Am. Chem. Soc. (98): 8284–8286.
  8. Beak P, Covington JB, White JM (1980). "Quantitave Model of Solvent Effects on Hydroxypyridine-Pyridone and Mercaptopyridine-Thiopyridone Equilibria: Correlation with Reaction-Field and Hydrogen-Bond Effects". J. Org. Chem. (45): 1347–1353.
  9. Beak P, Covington JB, Smith SG, White JM, Zeigler JM (1980). "Displacement of Protomeric Equilibria by Self-Association: Hydroxypyridine-Pyridone and Mercaptopyridine-Thiopyridone Isomer Pairs". J. Org. Chem. (45): 1354–1362. doi:10.1021/jo01296a002.



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