3-Hydroxyisonicotinaldehyde

3-Hydroxyisonicotinaldehyde (HINA), also known as 3-hydroxypyridine-4-carboxaldehyde, is a derivative of pyridine, with hydroxyl and aldehyde substituents. It has been studied as a simple analogue of vitamin B6. In 2020, it was reported as having the lowest molecular weight of all dyes which exhibit green fluorescence.[2][3]

3-Hydroxyisonicotinaldehyde
Names
Preferred IUPAC name
3-Hydroxyisonicotinaldehyde
Other names
3-Hydroxy-4-pyridinecarboxaldehyde
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.238.477
EC Number
  • 810-332-5
  • InChI=1S/C6H5NO2/c8-4-5-1-2-7-3-6(5)9/h1-4,9H checkY
    Key: NVLPDIRQWJSXLZ-UHFFFAOYSA-N checkY
  • c1cncc(c1C=O)O
Properties[1]
C6H5NO2
Molar mass 123.111 g·mol−1
Density 1.327 g/cm3
Melting point 126–128 °C (259–262 °F; 399–401 K)
Hazards
GHS labelling:
GHS07: Exclamation mark
Warning
H302, H315, H319, H335
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Preparation

3-Hydroxyisonicotinaldehyde was first prepared in 1958 by oxidation of 3-hydroxy-4-pyridinemethanol with manganese dioxide.[1] Alternative syntheses have also been reported.[4][5]

Spectroscopic properties

The absorption spectrum of HINA has been the subject of studies dating back to the 1950s, owing to its relationship to vitamin B6 and pyridoxal, of which it is a simple analogue.[6][7][8][9] However, its fluorescent properties were not described until 2020. It is noteworthy for having a green-emitting fluorophore with a wavelength of maximum emission (λem,max) at 525 nm in aqueous solution at alkaline pH, making it the compound of lowest molecular weight to display that property.[2] In acidic solutions, the fluorescence is less intense and becomes blue; the compound has isosbestic points at 270 and 341 nm.[3]

The molecular basis of the observed properties is the presence of a push-pull fluorophore, a feature of many fluorescent and luminescent compounds.[10] At pH above 7.1 in aqueous solutions, HINA is in its anionic form, with its absorbance peak at 385 nm and emission peak at 525 nm. The anion contains just 13 atoms, with a molecular mass of 122 Da. The quantum yield for the emission is 15%, with an emission lifetime of 1.0 ns. The observed Stokes shift of 6900 cm−1 is typical of push-pull dyes.[3]

Uses

In mechanistic studies of vitamin B6
Further information: Pyridoxal phosphate § Catalytic mechanism

HINA has been used as an analogue of pyridoxal 5′-phosphate, the active form of the coenzyme vitamin B6. It is an especially good mimic for the enzyme-bound form of that compound, better than the vitamin or pyridoxal.[11] The enzyme mechanism involves imine formation, giving a Schiff's base, and such derivatives of HINA with amino acids have been studied for their reaction kinetics,[7] leading to insights about the enzymes which use pyridoxal 5-phosphate.[1][11][12][13]

As a dyestuff
HINA fluorescence above and below pH 7[3]

Stable dyes of low molecular weight which are water soluble are useful in biological systems.[2][14][15] HINA has been used to detect and quantify the presence of cysteine in aqueous solutions.[3]

References
  1. Heinert, Dietrich; Martell, Arthur E. (1958). "Studies on pyridoxine and pyridoxal analogs—I". Tetrahedron. 3: 49–61. doi:10.1016/S0040-4020(01)82610-7.
  2. Cozens, Tom (2020-12-16). "Fluorescent molecule breaks size record for green-emitting dyes". chemistryworld.com. Retrieved 2021-12-03.
  3. Kang, Rui; Talamini, Laura; d'Este, Elisa; Estevão, Bianca Martins; De Cola, Luisa; Klopper, Wim; Biedermann, Frank (2021). "Discovery of a size-record breaking green-emissive fluorophore: Small, smaller, HINA". Chemical Science. 12 (4): 1392–1397. doi:10.1039/d0sc05557c. PMC 8179180. PMID 34163902.
  4. O'Leary, Marion H.; Payne, James R. (1971). "Vitamin B6 analogs. Improved synthesis of 3-hydroxypyridine-4-carboxaldehyde". Journal of Medicinal Chemistry. 14 (8): 773–774. doi:10.1021/jm00290a026. PMID 5114077.
  5. Prasad, A.R.; Subrahmanyam, M. (1991). "Vapour phase oxidation in the preparation of 3-hydroxypyridine-4-carboxaldehyde: The vitamin B6 analog". Journal of Molecular Catalysis. 65 (3): L25–L27. doi:10.1016/0304-5102(91)85059-B.
  6. Nakamoto, Kazuo; Martell, A. E. (1959). "Pyridoxine and Pyridoxal Analogs. IV. Ultraviolet Spectra and Solution Equilibria of 3-Methoxypyridine-2(and 4-)-aldehydes and of 3-Hydroxypyridine-2 (and 4-)-aldehydes". Journal of the American Chemical Society. 81 (22): 5863–5869. doi:10.1021/ja01531a006.
  7. Dixon, Jack E.; Bruice, Thomas C. (1973). "Comparison of the rate constants for general base catatlyzed prototropy and racemization of the aldimine species formed from 3-hydroxypyridine-4-carboxaldehyde and alanine". Biochemistry. 12 (23): 4762–4766. doi:10.1021/bi00747a031. PMID 4773854.
  8. Harris, C.; Johnson, R.; Metzler, D. (1976). "Band-shape analysis and resolution of electronic spectra of pyridoxal phosphate and other 3-hydroxypyridine-4-aldehydes". Biochimica et Biophysica Acta (BBA) - General Subjects. 421 (2): 181–194. doi:10.1016/0304-4165(76)90284-1. PMID 1252466.
  9. Sanz, Dionisia; Perona, Almudena; Claramunt, Rosa M.; Elguero, José (2005). "Synthesis and spectroscopic properties of Schiff bases derived from 3-hydroxy-4-pyridinecarboxaldehyde". Tetrahedron. 61: 145–154. doi:10.1016/j.tet.2004.10.036.
  10. Wilhelmsson, Marcus; Tor, Yitzhak, eds. (2016-04-16). Fluorescent Analogs of Biomolecular Building Blocks: Design and Applications. Wiley. pp. 257–280. ISBN 978-1118175866.
  11. French, Thayer C.; Auld, David S.; Bruice, Thomas C. (1965). "Catalytic Reactions Involving Azomethines. V. Rates and Equilibria of Imine Formation with 3-Hydroxypyridine-4-aldehyde and Amino Acids". Biochemistry. 4: 77–84. doi:10.1021/bi00877a014. PMID 14285248.
  12. Maley, John R.; Bruice, Thomas C. (1970). "Catalytic reactions involving azomethines. XII. Transamination of 1-methyl-3-hydroxy-4-formylpyridinium chloride". Archives of Biochemistry and Biophysics. 136 (1): 187–192. doi:10.1016/0003-9861(70)90340-1. PMID 5417614.
  13. Eliot, Andrew C.; Kirsch, Jack F. (2004). "Pyridoxal Phosphate Enzymes: Mechanistic, Structural, and Evolutionary Considerations". Annual Review of Biochemistry. 73: 383–415. doi:10.1146/annurev.biochem.73.011303.074021. PMID 15189147.
  14. Pina, Fernando; Melo, Maria J.; Laia, César A. T.; Parola, A. Jorge; Lima, João C. (2012). "Chemistry and applications of flavylium compounds: A handful of colours". Chemical Society Reviews. 41 (2): 869–908. doi:10.1039/C1CS15126F. PMID 21842035.
  15. Lavis, Luke D. (2017). "Teaching Old Dyes New Tricks: Biological Probes Built from Fluoresceins and Rhodamines". Annual Review of Biochemistry. 86: 825–843. doi:10.1146/annurev-biochem-061516-044839. PMID 28399656.
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