external image adrenalinereaction.jpg


To convert adrenaline to DOPAL using acid catalysis. How this fits into the synthesis of anti-malarials is described here.


Taken from Robbins (1965).
A solution of adrenaline (227.74 mg, 1.243mmol) in 85% phosphoric acid (6 mL) was heated in a 12mL vial to 120C for 15 min in a glycerol bath then removed from heat and allowed to cool for 30 seconds. The solution was added to distilled water (36 mL) and then saturated with NaCl. Ether extracts (15 mL, 15 mL, 10mL), were combined and dried over MgSO4 then evaporated to yield 16A (15.6 mg, 1.22 mmol, 6.85 %yield).


Characterization of 16A

  1. TLC of 3:1 methylenechloride methanol with iodine to stain.
  2. HMR(with integration). HMR extension. NMR 8.5-9.7
  3. solubility: good in methanol, poor in methylene chloride
  4. HMR(w/o integration) D2O added making 16B (note: the scale is way off)


A plausible assignment of the major peaks for the HMR of 16A: 9.57(CHO),8.96(phenol), 8.9(phenol), 6.5(aromatic), 6.6(aromatic), 6.7(aromatic), 3.5 (CH2). Peaks at 3.4 and 2.5 are attributed to DMSO-d6. Addition of D2O removes the 2 peaks near 9 ppm, supporting the phenolic assignments.

Li et al in 1998 report the HMR for the target aldehyde (in DMSO-d6) as: 9.67(t, 1H, CHO), 7.27 (dd, 1H, aromatic), 7.2 (d, 1H, aromatic), 6.9 (d, 1H, aromatic), 3.5 (d, 2H, CH2). The peaks in the 6.9-7.3 ppm range are inconsistent with HMR spectra of 4-alkylcatechols, such as 4-methylcatechol, with the three aromatic hydrogens genrally appearing in the 6.5-6.9 ppm range. Since our spectrum is consistent with the majority of other spectra of similar molecules, we suggest that our assignments are correct and that the peaks reported by Li are erroneous. Our assignment is also consistent with another report from Nobuhiro Fusetani et al Tetrahedron 1994


Based mainly on HMR evidence of the crude ether wash, DOPAL can be made and isolated in 5-10% yield as a major product after a brief (15 min) decomposition of adrenaline in 85% phosphoric acid at 100-120 C. This material is not quite pure enough to be used without chromatography.



1. 12:00] Glycerol bath was placed on hot plate (setting 3.5)
2. 12:15] Adrenaline and phosphoric acid solution began to heat in 15mL glass vial in glycerol bath that was initially at 100C. Setup Video
3. 12:30] Solution heated to 120C over 15 minutes while glycerol bath heated to up to 140C. Acid solution was taken off of heat, and cooled for 30 seconds.
4. Acid solution was added to 36mL distilled water and allowed to sit for 1.5 hours.
5. Saturated with NaCl (without filtering).
6. Poured solution without excess NaCl into a separatory funnel. Extracted with 15 mL ethyl ether.
7. Extracted again with 15 mL ethyl ether and then 10mL ethyl ether. Acid portion was saved.
8. Saturated with NaCl, solution poured into 2 mL of 0.05M potassium phosphate monobasic-sodium hydroxide 7.00pH buffer solution.
9. Poured ether into 50mL beaker without excess salt.
10. Added magnesium sulfate to dry and filtered.
11. Vacumed off the solvent in a rotatory vacuum.
12. Vacumed off remaining ether for 2 hours using high vac, resulting in 16A (15.6 mg)
13. Attempted to dissolve a small portion of 16A in methylene chloride but it did not dissolve
14. Added a small portion of 16A to methanol and it dissolved turning a champagne color.
15. TLC of 16A in methylene chloride produced no movement
16. TLC of 16A in methanol produced too much movement, Rf close to 1.
17. TLC of 16A in 3:1 methylene chloride/methanol produced good movement - Rf = 0.8
18. All of 16A was dissolved in DMSO-d6 and HMR was taken


19. HMR was taken of half of 16A with added D2O (16B)


DOPAL InChI=1/C8H8O3/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,4-5,10-11H,3H2