10-23-04 16:04
No 537293
A friend of mine told me this interesting story the other night.. Apparently he accidently broke his only condenser while disconnecting one of the hoses. Angered but not defeated he eyed the limited supply of chemicals at his disposal and here is what happenend:
In a round-bottomed flask equipped with magnetic stirring was added 250 mL of H2O, and 45 mL of 25% NaOH. 15 grams of hydroquinone was then added followed by 26mL of dimethyl sulfate. The flask was stirred at room temperature and after 15 minutes it was obviously no longer basic judging from the light color and flakes of hydroquinone floating around. At this point more 25% NaOH soln was added. In fact, he admits that too much base was added at this point which really hurt the yield in this reaction by slowing it down considerably. Anyhow, after another hour white crystals began to form out of the dark mixture and it took on the familiar smell of p-dimethoxybenzene. Stirring was continued for another 6 hrs, after which he became impatient and proceeded to vacuum filter the crystals on a buchner funnel and wash them with H2O. Yield: 11 grams (58%)
A solution of 10 g of potassium bromide in 250mL acetic acid was stirred on a ice/salt bath. When the solution was sufficiently cold, 5mL of 91% sulfuric acid was added slowly and the solution took on a light brown color. Over the course of the next 30 minutes, while maintaining the temperature at 5 degC, 8mL of 35% hydrogen peroxide was slowly added dropwise and subsequently the solution was allowed to stir for another 2 hrs. The soln was extracted w/2x75mL toluene and the extracts were washed w/50mL 5% NaOH, and then 50mL brine. The toluene was then removed in vacuo yielding a brown oil of presumably 1,4-dimethoxy-2-bromobenzene, which was used directly in the following reaction. Yield was not determined but appeared to him to be very good.
To an unknown amount of 1,4-dimethoxy-2-bromobenzene was added a soln. of 5 grams of glyoxylic acid monohydrate and 12 mL H2O. The solution was stirred vigorously on a ice/salt bath until a temperature of 5 degC was obtained and it was maintained at this temp throughout the subsequent reaction. Over the course of the next 30 minutes, 30mL 91% sulfuric acid was added dropwise; at this point the solution took on a dark black. The stirring was continued for the next 6 hours, the solution gradually taking on a light pink color with off-white crystals floating in the mixture. After completion of the reaction, the mixture was so viscous it could hardly be stirred. 100mL of cold water was then added, the mixture stirred for a short time longer and the crystals were vacuum filtered. The crystals were suspended in 100mL water and sufficent 25% aqueous NaOH was added until all of them dissolved into a dark brown solution. The solution was then extracted w/75mL toluene. The aqueous solution was once again cooled in an ice bath and ice-cold conc. HCl was added which cleared the solution and caused the crystals to precipitate back out and they were once again vacuum filtered and washed w/water. Yield: 20g of 4-bromo-2,5-dimethoxymandelic acid (86% from p-dimethoxybenzene)
To a solution of 40mL distilled water, and 20mL of 31.25% HCl was added a suspension of 20 grams of 4-bromo-2,5-dimethoxymandelic acid. The soln was cooled on an ice/salt bath to 5 degC and stirring was commenced. Into an addition funnel was added 4mL 70% nitric acid and 10mL water. The dilute HNO3 was added dropwise over about 15 minutes. The flask was removed from the ice bath and placed into a water bath maintained at 50 degC. It was heated and stirred at this temperature for about 1 hr. The flask was cooled to room temperature and an ice-cold solution of 60mL 25% NaOH was added which caused the unreacted acid to dissolve into the mixture. The remaining crystals were vacuum filtered and recrystallized from methanol. Yield 12.5g (74%).
Overall yield: 12.5g 4-bromo-2,5-dimethoxybenzaldehyde from 15g hydroquinone (37.5%)
The rest of the story I will leave to your imagination since it has been told here many times before, but I will tell you that it involved nitroethane, cyclohexylamine and aluminum foil. In the end, the experience was quite enjoyable for him as he was introduced to a new friend that goes by the name DOB.
- phenethylman -
(Über-Führer die Ironie)
10-23-04 22:38
No 537329
Third step; 1,4-dimethoxy-2-bromobenzene --glyoxylic acid--> 4-bromo-2,5-dimethoxymandelic acid looks really interesting. Do you happen to have a litterature ref. for that step?
(Hive Bee)
10-24-04 09:50
No 537444
Yield: 20g of 4-bromo-2,5-dimethoxymandelic acid (86% from p-dimethoxybenzene)
Any chance you formed 6-bromo-2,5-dimethoxymandelic acid, or a combination of these two?
President of the Iraqi Chemical Weapons of Mass Destruction Development Society
(Hive Bee)
10-24-04 11:13
No 537451
Third step; 1,4-dimethoxy-2-bromobenzene --glyoxylic acid--> 4-bromo-2,5-dimethoxymandelic acid looks really interesting. Do you happen to have a litterature ref. for that step?
Not with that specific substrate, but the procedure was adapted from Patent US4190583.
Any chance you formed 6-bromo-2,5-dimethoxymandelic acid, or a combination of these two?
Yes, based on the reaction mechanism, one would expect that to be a side-product. However, the potency of the final product seems to be consistent with what one would expect, but then again, no scales that accurate were used. Perhaps this isomer was oxidised/decarboxylated to the aldehyde as well, and then was subsequently eliminated during recrystallization of the aldehyde.
I should add that I believe it is the gradual addition of the acid catalyst that is likely to minimize formation of such side-products. Some of the glyoxylic acid condensations out there use a weaker acid as a catalyst and combine the reactants all at once; others use no catalyst and just run the reaction at high temperature. I don't believe such procedures would be advantageous in this case, in fact, an improvement may be to add the acid over 6 hours and stir for a day.
- phenethylman -
(Über-Führer die Ironie)
10-24-04 14:13
No 537460
Yes, now I remember that patent...
If 1,2-methylenedioxybenzene is activating enough to give good yield, p-dimethoxybenzene would bee too i guess, this is a nice route to 2,5-dimeobenzaldehyde from p-dimethoxybenzene...
did you make the glyoxylic acid yourself? good work phenetylman!
(Hive Bee)
10-24-04 14:33
No 537461
If 1,2-methylenedioxybenzene is activating enough to give good yield, p-dimethoxybenzene would bee too i guess, this is a nice route to 2,5-dimeobenzaldehyde from p-dimethoxybenzene...
Actually I believe there was a discussion here a while ago where it was stated p-dimethoxybenzene would not work, maybe prevention of the di-substituted product is impossible? This is the exact reason I chose to brominate first; to deactivate the ring somewhat.
did you make the glyoxylic acid yourself? good work phenetylman!
Nah, it was purchased quite a while ago and was from Acros Organics. However, I don't believe synthesis would be that difficult though; nitric acid oxidation of acetaldehyde to glyoxal and then a further oxidation to glyoxylic acid may be a suitable route. Also procedures from ethylene glycol or from the reduction of oxalic acid are out there.
- phenethylman -
(Official Hive Translator)
10-24-04 15:29
No 537467
I would say the formylation step looks very doubtful to me, considering very different reactivity of 3,4-MD and 1,4-diMeO-2-Br compounds.
(Hive Bee)
10-25-04 00:19
No 537531
I would say the formylation step looks very doubtful to me, considering very different reactivity of 3,4-MD and 1,4-diMeO-2-Br compounds.
What formylation step? It's a condensation w/the aldehyde functional group of glyoxylic acid to form a subst. mandelic acid and then oxidative decarboxylation to the benzaldehyde.. Do you mean the condensation step to form the acid?
It is a general reaction for aromatics; usually only applied to phenolic compounds. However, I assume the second functional group of glyoxylic acid along with protonation by the acid catalyst makes it a strong enough electrophile to condense w/aromatic ethers as well.
I do agree some ortho-substitution could have taken place, thou I have not the resources to confirm or deny this.. then there's also the possiblility of nitration of the ring during the oxidation step.. so there are definitely disadvantages to this approach.
- phenethylman -
(Hive Bee)
10-25-04 09:00
No 537638
I do agree some ortho-substitution could have taken place, thou I have not the resources to confirm or deny this.. then there's also the possiblility of nitration of the ring during the oxidation step.. so there are definitely disadvantages to this approach.
When brominating 2,5-dimethoxybenzaldehyde, you also obtain a mixture of two isomers. You can remove the 6-bromo isomer by "recrystallization" (dilution). Something similar has been described for nitration. Read up on Rh's page.
I would expect both isomers to be present if the reaction would be possible.
President of the Iraqi Chemical Weapons of Mass Destruction Development Society
(Hive Bee)
10-25-04 20:03
No 537733
"then there's also the possiblility of nitration of the ring during the oxidation step.. so there are definitely disadvantages to this approach".
That does not seem to be a problem if you run the decarboxylation at a low enough temperature and do it in a two phase mixture (aqueous/toluene). The aldehyde goes into the toluene as it is formed. This is speaking from personal experience.
Oh, and use a crystal or two of sodium nitrite to kick start the decarboxylation reaction if you need to. There is no need to use any hydrochloric acid as is suggested in one patent on the Hive.
(Hive Bee)
10-25-04 23:56
No 537781
That does not seem to be a problem if you run the decarboxylation at a low enough temperature and do it in a two phase mixture (aqueous/toluene). The aldehyde goes into the toluene as it is formed. This is speaking from personal experience.
Oh, and use a crystal or two of sodium nitrite to kick start the decarboxylation reaction if you need to. There is no need to use any hydrochloric acid as is suggested in one patent on the Hive.
yeah, I noticed one patent used almost 1 mol equiv NaNO2 per mol of substrate but equal yields were obtained in another procedure which didn't utilize any..
the two-phase rxn sounds like a good idea, thou the consensus appears to be that 50 degC is the magic number i.e. as long as the temp doesn't rise above that then only the mandelic acid chain will be attacked..
too bad my friend has no more glyoxylic acid, there's a bunch of 2,5-diMeo-toluene that wants a formyl group real bad. anyone actually tried the oxalic acid al/hg reduction referred to in this Post 427038 (foxy2: "Preparation of Glyoxylic acid", Novel Discourse)? I imagine the post rxn workup is not too friendly..
Maybee will try that modified duff w/TFA, but damn that shit is pricey..
- phenethylman -
(Hive Bee)
10-26-04 01:50
No 537804
well, since this rxn also involves a photo chemical to phenethylamine (THQ->DOM), I will consider it on topic..
A stirred solution of 4mL formalin, 20mL hydrochloric acid, and 80mL acetic acid was saturated w/HCl gas until it would absorb no more (this took about 5-10 min). 7g of 2,5-dimethoxytoluene was then added dropwise at a moderate rate. The rxn was suprisingly exothermic as hell and HCl gas began to evolve out of the soln as it heated up. Once breathing became difficult the addition was accelerated somewhat so SWIM could get the hell out of there. The addition took about 15 minutes and the exotherm ceased about 5 minutes later. At this point the soln was full of a white precipitate and quenching the reaction in 250mL dH2O caused even more precipitation. The solids were quickly filtered and the area quickly evacuated..
I fear it is the disubstituted product but it seems as if all the 2,5-dimethoxytoluene reacted and there wasn't really enough CH2O to react twice so we will see.. coming soon: a melting point test which should tell the rest of the story.. The plan is to react it w/sodium 2-propanenitronate to give the benzaldehyde which has always given 70%+ yields in the past on alkyl-substituted benzyl halides..
- phenethylman -