This is a write-up of a succesfully performed two-step rxn from vanillin to 5-hydroxy-vanillin. It doesn't provide real new stuff, but it does provide a report of a
real performed and several times applied procedure to arrive at a valuable precursor namely the 5-hydroxy-vanillin starting with vanillin. Everything, except the soxhlet apparatus is OTC and easily acquired.
5-Bromo-vanillin from vanillin 60 grms vanillin (0.4 mol) are dissolved with stirring in 300ml GAA. 96grms KBr (0.8 mol) are dissolved in another flask in 150ml dH2O. When all solids are dissolved and both solutions have reached room temperature they are mixed together forming a still water clear solution. In parallel 22ml H2SO4 are diluted with 40ml GAA carefully. The H2SO4/GAA mix is added to the KBr/Vanillin solution from which now solid KBR may precipitate [1]. This still stirrable mixture is put into a 1000ml beaker sitting in a water bath at room temperature. Under moderate mag-stirring 44ml 32% H2O2 (0.8 mol) are added during 60-80 minutes. When the first 30% of the H2O2 has been added, ice cubes are put into the water bath to keep the whole rxn temp at about 20DegC [2]. The 5-Bromo-vanillin appears as a yellow precipitate when approx. 40% of the H2O2 has been added. After finishing the addition of the H2O2, the rxn is stirred further for 1.5hrs in the ice water bath keeping the rxn temp between 15 and 20DegC to complete the rxn. The yellow mix is now put into a 2l beaker containing 1200ml HO with ice cubes and stirred for another 20mins. The 5-Bromo-vanillin is vac filtered and washed with ice water several times. It is not worth to keep the mother liquors since overnight a dark crust is building up at the bottom of the beaker. Total yield of crude 5-bromo-vanillin about 80grsm (approx 90%) with a mp of 160-162 DegC. The crude product is used for the next step. Pure 5-Bromo-vanillin has a mp of 165DegC and forms white! crystals [3].
Notes 1: The separation of solid KBr after the addition of the H2SO4/GAA mix doesn't cause a problem as long as at the beginning of the H2O2 addition the rxn temp is about 20DegC. Later the rxn should be cooled, the KBr dissolves and the 5-Bromo-vanillin precipitates.
2: The bromation of vanillin can be done without elemental bromine using the above described in-situ bromine generation. At no time any smell or vapor of bromine appears and Uemura can't frighten any bees (Thanks to Rhodium).
3: This rxn has been performed several times, it always gives high yields between 85% and 92%. It is however important to keep the temp less than 25DegC (say) to avoid di-bromation of the vanillin. Warming up the rxn does not improve but decrease yields and provides dark colored impure products.
References See
https://www.thevespiary.org/rhodium/Rhodium/chemistry/mmda.mescaline.html
,
Post 266929
(Rhodium: "Re: Alkali metal alkoxides: finally, OTC!", Novel Discourse),
Post 27874 (missing)
(Osmium: "Re: 2CB for the LAH impaired", Methods Discourse) 5-Hydroxyvanillin from 5-Bromo-vanillin 70grms NaOH (1.75 mol) are dissolved in 375ml H2O in a 2 (better 3) neck 1l RB flask equipped with a condensor together with a gas-inlet for inert gas (e.g. argon), inside a magnetic stirr bar. Into this freshly prepared NaOH solution 2grm CuSO4 dissolved in 30ml H2O are added droppwise at 50DegC under stirring. A deep blue solution builds up. The flask is warmed up by means of an heating mantel to 70DegC+, the inert gas stream is activated before 45grsm of bromo-vanillin (0.2 mol) are added slowly under stirring. After each addition of a spatula complete solution of the bromo-vanillin should occur before adding the next amount. Temperature is continuously increased to keep the Na-salt of the bromo-vanillin in solution.
When all bromo-vanillin has been added, the mixture is refluxed under stirring for 20hrs. The inert gas stream should be continued when sufficient inert gas is available
to avoid oxidation. After the reflux time has elapsed, the brown-green rxn mixture is cooled down to 10DegC [3]. It is then made acidic to ph 3-4 by slowly addition of conc. muriatic acid (about 160ml needed) keeping the temperature less than 25DegC.
A gray precipitate forms which is vac filtered off when the mix has been cooled down to 10DegC again. The precipitate is dried in an evacuated excicator to constant weight (35 grms). Instead of a standard solvent extraction or as indicated in some references, applying a continuous solvent extraction over 20hrs! it was found easier to evaporate all water under reduced pressure and apply a Soxhlet extraction on the dried mix of inorganic salts and the hydroxy-vanillin [2]. Therefore the filtered and slightly acidic solution of cooper/sodium salts and hydroxyvanillin was vacuum de stilled at 50-100mbar until the solution starts to bump heavily due to the separation of solids. The solids consisting of Na-salt crystals and organic material are again vac filtered and weighted 98 grms after drying. The remaining almost black oily filtrate was left in a petri dish until all water has evaporated. The black solid left weighted 20 grms.
DCM was found to be a proper solvent choice for the soxleth extraction. It doesn't dissolve any inorganic salts and the hydroxy-vanillin -which is not very good soluble in DCM - crystallizes already during reflux as a coffee cream crust in the flask. Soxhlet extraction was stopped, when the DCM extract became water clear without any yellow touch. The flask was cooled down in the freezer to -20DegC to complete crystallization. The crude hydroxy-vanillin was filtered and dried. A total amount of 26 grms crude product with a mp of 124-127 DegC has been yielded (approx 80%).
Notes 1: Yields are less than reported in the literature. Uemura however did not apply inert gas protection all the time and some parts of the product may have been oxidised further. His work-up strategy is perhaps not optimal, but has some advantages, like minimal amount of solvents and use of standard equipment.
2: Attempts to do classic extraction with e.g. ethyl acetate ended in painful emulsions with the final result of a broken piece of an expensive separation funnel. The hydroxy vanillin seems further to be not very soluble in organic solvent, water seems to bee the preferred solvent!
3: It should be worth to consider direct processing of the still alkaline rxn mix for methylation with DMS (say) to the 3,4,5 trimethoxybenzaldehyde to avoid the picky work-up. The 3,4,5 trimethoxybenzaldehyde may be easier to purify than the 5-Hydroxyvanillin.
References See
Post 287645
(foxy2: "3,4-Dihydroxy-5-methoxybenzaldehyde", Chemistry Discourse),
Post 287652
(uemura: "'3,4-Dihydroxy-5-methoxybenzaldehyde'", Chemistry Discourse) and last not least the big failure via the syringaldehyde route, see
Post 275171
(uemura: "Re: Vanillin", Chemistry Discourse)
Carpe Diem