3,4-DIHYDROXY-6-NITROBENZALDEHYDE Chemical Properties

Melting point:

202-205°C

Boiling point:

417.0±45.0 °C(Predicted)

Density 

1.667±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

solubility 

DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)

form 

Solid

pka

6.01±0.24(Predicted)

color 

Dark Yellow to Very Dark Brown

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38-43

Safety Statements 

26-36-36/37

Hazard Note 

Irritant

3,4-DIHYDROXY-6-NITROBENZALDEHYDE Usage And Synthesis

Uses

4,5-Dihydroxy-2-nitrobenzaldehyde is used as a reagent in the synthesis of 5,6-diacetoxyindole which is a stable eumelanin precursor. 4,5-Dihydroxy-2-nitrobenzaldehyde is also used in the preparation of 6-aminoisoproterenol which is an impurity of the non-selective beta-adrenergic agonist, Isoproterenol (I874200, HCl).

Synthesis

An aluminum chloride solution was prepared by dissolving pure aluminum chloride (11 g, 82.4 mmol) in anhydrous 1,2-dichloroethane (25 mL) under argon protection and cooling to -5°C. Subsequently, Compound 1 (5 g, 25.6 mmol) was dissolved in anhydrous 1,2-dichloroethane (20 mL) and slowly added dropwise to the above aluminum chloride solution, keeping the temperature between -5°C and 5°C. The reaction was stirred continuously for 2 hours until the complete disappearance of compound 1 was confirmed by TLC detection. Upon completion of the reaction, the mixture was poured into 48% hydrobromic acid (60 mL) and stirred for 48 hours at room temperature (~20°C) until the intermediate chloromethyl ether disappeared (TLC monitoring). The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL), the organic phases were combined and dried with magnesium sulfate. After evaporation of the solvent, the residue was treated with hot hexane. The crude product was further treated with hot dichloromethane (50 mL) to afford 4,5-dihydroxy-2-nitrobenzaldehyde (4.3 g, 90% yield). The product was recrystallized by water (100 mL) to afford chromatographically pure yellow crystals (1.79 g) with a melting point of 202-203 °C and an Rf value of 0.25 (acetone-hexane, 1:2).1H NMR (CDCl3) data: δ 7.21 (s, 1H, C6-H), 7.50 (s, 1H, C3-H), 10.14 (s, 1H, CHO) , 10.85 (s, 2H, 2×OH). 4,5-Dihydroxy-2-nitrobenzaldehyde (0.5 g, 2.7 mmol) was dissolved in DMF and anhydrous finely powdered potassium carbonate (0.94 g, 6.8 mmol) and n-bromobutane (1.1 g, 8.1 mmol) were added. The mixture was stirred under argon protection and protected from light, and the mixture was heated at 60 °C for 15 hours. After completion of the reaction, it was diluted with water and extracted with ether (3 x 50 mL). The organic phases were combined, dried with magnesium sulfate and the solvent was evaporated. The residue was recrystallized by ether to give chromatographically pure compound 5 (0.66 g, 83% yield) as a crystalline powder with a melting point of 80-85 °C and an Rf value of 0.62 (acetone-hexane, 1:2). Elemental analysis measured values (%): C, 61.04; H, 7.20; N, 5.71. molecular formula C15H21NO5 calculated values (%): C, 61.00; H, 7.17; N, 4.74. 1H NMR (CDCl3) data: δ 0.98-1.03 (m, 6H, 2 × CH3), 1.47-1.58 (m, 4H, 2 × CH2), 1.82-1.91 (m, 4H, 2 × CH2), 4.13-4.16 (m, 4H, 2 × CH2), 7.38 (s, 1H, C6-H), 7.58 (s, 1H, C3-H), 10.43 (s, 1H, CHO).

References

[1] Journal of Organic Chemistry, 1980, vol. 45, # 14, p. 2750 - 2753
[2] Synthetic Communications, 1985, vol. 15, # 4, p. 321 - 330
[3] Journal of Organic Chemistry, 1985, vol. 50, # 26, p. 5873 - 5875
[4] Patent: US4595765, 1986, A
[5] Russian Chemical Bulletin, 2016, vol. 65, # 2, p. 507 - 512