Sciencemadness Discussion Board - Synthesis of dopamine from catechol

you can make protocatechualdehyde from catechol using the reimer tiemann reaction - Reimer and Tiemann, Ber. 9, 1268 (1876); Tiemann and Koppe, ibid. 14, 2015 (1881).
from there,dopamine is 2 steps away

Have you ever done this, or attempted it? I have, it's an enormous mess. It's a free-radical reaction, and the yields will necessarily be very low, after the nightmarish workup.

Okay, I exaggerated a little. But suffice to say the yield certainly wasn't worth the effort of the workup.

Corrosive Joeseph - 22-10-2017 at 09:31

Excellent choice of research.......... A most fascinating compound indeed

And an interesting choice of routes and precursors to boot

/CJ

[Edited on 22-10-2017 by Corrosive Joeseph]

SWIM - 22-10-2017 at 11:02

Have you considered going the natural route?

Extract L-dopa from broad beans and use your considerable experience with decarboxylations to make dopamine.

You could even do this as well as your other synthesis and then you'd be able to confirm their equivalence with a mixed melting point test.

As for the vanillin demethylation Idea there's a high yielding reaction that uses a 10% excess of aluminum chloride suspended in a methylene chloride solution of vanillin which then has pyridine added (4.4 equivalents) under stirring and is refluxed for 48 hrs to give a claimed 87% yield.

Robert G Lange, J. Org, 27, 2037 (1962)

I haven't looked up the journal entry as I'm pretty sure I'd have to pay through the nose for it, but it is summarized in Feiser and Feiser's Topics in Organic Chemistry.

Actually, I suppose L-dopa might be a little more heat sensitive than tryptophan so maybe that 1st Idea is a non-starter unless you protect those OH groups.

Cryolite. - 22-10-2017 at 12:01

Small correction: the Riemer-Tiemann is not a free-radical reaction. It is a simple electrophillic aromatic substitution reaction by an in-situ generated dichlorocarbene species. First, chloroform is deprotonated to the trichloromethylide anion, and this then loses a chloride to become reactive dichlorocarbene. This carbene is very electron-poor, so it will attack the nearest source of electron density it can find, which happens to be the electron-rich ortho and para positions of a phenol. It replaces the proton which lies on the ring, the proton attaches itself to the carbene, and the chlorines are replaced with water to form the final formyl group.

Assured Fish - 22-10-2017 at 14:30

If you really REALLY wanted to go balls to the wall and were still contempt on the catechol route then you could extend the series to also cover the synthesis of catechol from the somewhat OTC naturally occurring salicylic acid.
By converting it to salicylamide and then hoffman degradation to 2-aminophenol and then diazotize the amine and finally hydrolize the diazonium anion in hot copper sulfate solution.
http://www.sciencemadness.org/talk/viewthread.php?tid=63327
I have done this and most of it is close to quantitative except the Hoffman which produced 80% yield if i recall correctly.

Melgar - 22-10-2017 at 15:12

Quote: Originally posted by Cryolite.

And isn't dichlorocarbene a free radical, with two vacancies? I guess another way to say it is that it is very electron poor, but the whole reason for that is that it's a free radical, no?

I wanted to do something that isn't going to require things that most people can only get on rare occasions, when eBay is looking the other way. I like vanillin because of how easy it is to get, although I kind of wanted to start with catechol. I might just explain that catechol is a component of coal tar and creosote, and that because of how bad that is for you, it's hard to get anymore. It's so common in creosote though, that it seems a bit masochistic to go through too much effort to make it.

The vanillin demethylation method that was mentioned earlier seems to be legitimate, although the pyridine part could be a sticking point. I read somewhere else that the bond disassociation energy is lowest for that particular methyl group, meaning that free radical temperatures with reducing conditions could do it too, if conditions were carefully controlled.

What about the Duff reaction though? Anyone have any experience with that?

clearly_not_atara - 23-10-2017 at 00:05

You think you could just alkylate catechol with nitroethylene directly and save a few steps? There are a few systems I know that carry out this rxn, eg:

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201300579/ab...

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201000271/fu...

http://www.sciencedirect.com/science/article/pii/S0021967300...

http://www.sciencedirect.com/science/article/pii/S0040403901...

Although an OTC procedure hasn't popped up I suspect that Bronsted acid catalyst shouldn't be too hard to manage if you pick the right one.

[Edited on 23-10-2017 by clearly_not_atara]

[Edited on 23-10-2017 by clearly_not_atara]

[Edited on 23-10-2017 by clearly_not_atara]

JJay - 23-10-2017 at 01:02

I think making catechol from aspirin looks like fun, but somehow I doubt the yields would be as good as they look on paper. Then again, aspirin is pretty cheap. I really need to finish working up the toxic mess sitting in my fume hood so I can do some other experiments....

chemplayer... - 23-10-2017 at 02:19

Dopamine was on our wish-list of cool things to make (and do an educational video on), so here's a summary of our journey on various paths:

We tried about 10 times with different ways and different conditions to demethylate vanillin, and with limited success and very poor yields. This is not easy! We make AlCl3 home-made from ZnCl2 however so maybe the zinc impurity interferes with the reaction.

We did successfully make piperonal from peppercorns (extraction, hydrolysis, then oxidation). Not great yields, but enough to play with (gram quantities are feasible), so that would open up the nitromethane route.

Another possible route was to prepare the vanillin-related compound first and then try to demethylate. Vanillin nitro-methane adduct we did produce and it's easy to make and purify. We reduced the nitrostyrene to the nitroalkane but didn't go any further. Can't remember why we didn't take this another step - not sure if we had any reducing agent capable of going that final step, or if we just thought it would be too controversial a reaction to do a video on (even though the product is not pharmacologically active).

We also wanted to try to make vanillyl chloride and then nucleophilically react with cyanide (plus a reduction), but vanillyl chloride turned out to be a lot harder than it looks to make (HCl + zinc chloride + vanillin seem to form a purple complex - again, zinc gets in the way)...

CuReUS - 23-10-2017 at 04:57

One thing that I've noticed is that aromatic formylation reactions that are ortho-directing with phenol, seem to be para-directing with catechol.

where have you noticed this ?

Quote: Originally posted by Assured Fish

I have done this and most of it is close to quantitative except the Hoffman which produced 80% yield if i recall correctly.

truly going BTW would be doing a one pot schmidt/diazotisation on aspirin.It would first get converted to acetyl aminophenol,then NaNO₂ could be added which would react with the excess H₂SO₄ and diazotise the amine.Boiling this solution would convert the diazonium to OH and de-acetylate at the same time to give catechol.

And isn't dichlorocarbene a free radical, with two vacancies? I guess another way to say it is that it is very electron poor, but the whole reason for that is that it's a free radical, no?

this is quite interesting actually.Triplet carbenes are considered free radicals but not singlet carbenes.Which of the two is :CCl₂ ?

Quote:

What about the Duff reaction though? Anyone have any experience with that?

I think a duff reaction on catechol would give benzodioxole instead of the desired product.Even if it worked,the formylation would be ortho and there might be double formylation as well

You think you could just alkylate catechol with nitroethylene directly and save a few steps? Although an OTC procedure hasn't popped up I suspect that Bronsted acid catalyst shouldn't be too hard to manage if you pick the right one.

That's pure genius

. Do you think PPA or ZnCl₂ could be used ?

[Edited on 24-10-2017 by CuReUS]

JJay - 23-10-2017 at 05:39

Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?

Chemi Pharma - 23-10-2017 at 14:42

Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?

If you use borohydride with nickel salt, such as nickel chloride you will produce nickel boride that's capable of easy reduct the nitro group and the double bond.

See: http://www.sciencemadness.org/talk/viewthread.php?tid=66278&...

Melgar - 23-10-2017 at 15:01

Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?

It'll reduce it to a nitroalkane. Because the double bond is highly polarized, NaBH4 can actually reduce it, which is a fairly common thing to do, since nitroalkanes reduce easier, and with the double bond reduced, they won't react with each other during the nitro reduction stage.

JJay - 23-10-2017 at 19:12

Hmm... I meant to buy some nickel chloride a while back and never got around to it. That will definitely have to go on the list.

I just read about a borane-THF adduct capable of reducing carboxylic acids to alcohols. There are papers that describe making it with sodium borohydride and iodine in THF.

Chemi Pharma - 24-10-2017 at 01:26

Say, I was doing some reading on borohydride earlier, and Vogel Practical Organic Chemistry 3rd edition says that it won't reduce nitro groups or alkenes... will it reduce a nitrostyrene?

By the way @Melgar, could you explain to me why sodium borohydride alone can reduce phenyl nitropropene with methylamine directly to metamphetamine in a kind of reductive amination?

I read about an experiment like this on this book:

A Laboratory History of Narcotics
Vol. 1: Amphetamines and derivatives
A Laboratory Manual - 2007 - page nº 111
Jared B. Ledgard

But I can't explain why this can go on, since I ever thought borohydrides alone only reduce the double bond of the alkene to an alkane, but not the nitro group.

Could you or someone here explain to me the mechanisms envolved in this reaction below showed on that book? Is it possible?

Nitroalkenes and redutive amination with methylamine and borohydride.JPG - 25kB

Melgar - 24-10-2017 at 02:38

@ChemiPharma Sodium borohydride can only reduce double bonds that are sufficiently polarized by the groups on either side of it. For most alkenes, this isn't the case, but if, say, there's a strongly electron-withdrawing group on one side and not the other, that will be enough for borohydride to be able to align itself right to reduce it. Sodium borohydride can reduce imines for the same reason it can reduce aldehydes and ketones: because nitrogen (like oxygen) is more electronegative than carbon, and sodium borohydride is good at reducing double bonds to carbon when the carbon is double-bonded to something more electronegative than itself.

Sort of a simplified explanation, but it helps to realize that when sodium borohydride reduces double bonds in imines and nitroalkenes, it's really the same mechanism as when it reduces aldehydes and ketones.

Oh, also, you'll have to quote someone more authoritative than that notorious idiot if you want anyone here to believe that the reaction you describe is real.

[Edited on 10/24/17 by Melgar]

myristicinaldehyde - 24-10-2017 at 02:58

This is an interesting alternative to dopamine, via a pummerer rearrangement and subsequent reduction.

https://www.jstage.jst.go.jp/article/cpb1958/37/12/37_12_339...

The only problem might be preparing the needed methylsulfinylacetamide.

JJay - 24-10-2017 at 03:02

The THF-borane adduct will reduce nitro groups, but I think it hydroborates styrenes. So I suppose it could be used for anti-Markovnikov hydration of some styrenes, but I am not exactly sure what would happen here.

Chemi Pharma - 24-10-2017 at 03:08

Oh, also, you'll have to quote someone more authoritative than that notorious idiot if you want anyone here to believe that the reaction you describe is real.

Sorry @Melgar, but I didn't understand the last part.

This reaction was extracted from a published book.

Do You believe that's impossible to occurs? The author is a fraud? yes or not? why?

Here's the complete text at the book I have cited, on pages 111/113:

Procedure C: Preparation of racemic-methamphetamine hydrochloride (ICE)
Materials•

I. 27 grams of benzaldehyde 8. 30 grams of anhydrous sodium sulfate
2. 20 grams ofnitroethane 9. 3.75 grams of sodium borohydride
3. 5 milliliters of cyclohexylamine 10. 200 mi IIi I iters of methylene chloride
4. 300 milliliters of dry hexane 11. 60 grams of dry hydrogen chloride gas
5. 500 milliliters of dry methanol 12. 50 grams of sodium hydroxide
6. 25 grams of methylamine gas 13. 450 milliliters of diethyl ether
7. 55 grams of anhydrous magnesium sulfate

Summary: racemic-Methamphetmaine (ice), is prepared by reacting phenyl -2-nitropropene with methylamine and sodium borohydride in the presence of methanol. The phenyl-2-nitropropene is formed by the condensation of benzaldehyde with nitroethane in the presence of cyclohexylamine. After the reaction of phenyl-2-nitropropene with sodium borohydride and methanol , the reaction mixture is treated with methylene chloride, and this resulting methylene chloride mixture is then treated with hydrogen chloride, and the resulting acidified mixture is then evaporated to remove the bulk of the methylene chloride. After the bulk of the methylene chloride has been removed, the left over remaining concentrate is then filtered to recover the precipitated product. The precipitated product is then treated with sodium hydroxide to liberate the freebase, which is then extracted into ether. The ether extract is then treated with hydrogen chloride to precipitate the ICE, which is then filtered-off and then vacuum dried or air-dried.

Step I: Preparation of phenyl-2-nitropropene

Into a suitable reflux apparatus, place all at once, 27 grams of benzaldehyde, followed by 20 grams of nitroethane, followed by 5 milliliters of cyclohexylamine. Thereafter, reflux the entire mixture at about 100 Celsius for 3 hours. After refluxing for 3 hours, remove the heat source, and allow the two-phase reaction mixture to cool to room temperature. Then pour the entire reaction mixture into a seperatory funnel , and remove the lower (organic) layer. The upper layer can be recycled or discarded if desired as it will contain the cyclohexylamine catalyst. Then place the recovered lower organic layer into a suitable sized beaker, and then add in 25 milliliters of cold water. Immediately thereafter, rapidly stir the mixture using magnetic stirrer, or other means, for about 30 minutes at room temperature. Then remove the upper water layer by decanting it off, and then place the lower organic layer (containing the desired product), into an ice bath and chi ll to about 0 Celsius. Then, add in about 10 milliliters of cold water, and then allow the total mixture to stand at room temperature for several hours to allow the desired product of phenyl-2-nitropropene to crystal! ize. After 2 hours, most of the desired nitro compound should have precipitated and afterwards, filter-off the precipitated crystals, and then vacuum dry or air-dry them. Finally, recrystallize these dried collected crystals from 150 milliliters of dry hexane, and after the recrystallization process, vacuum dry or air-dry the crystals.

Step 2: Preparation of racemic-methamphetamine

Into a suitable beaker, place 250 milliliters of dry methanol, and then bubble into this methanol , 25 grams of methylamine gas. After the addition of the methylamine gas, add to the resulting methylamine/methanol solution, 25 grams of anhydrous magnesium sulfate (to absorb water), and then place this entire mixture into a suitable flask , and then stopper the flask .
Immediately thereafter, stir the entire mixture for about 10 minutes. After I 0 minutes, carefully filter-off the magnesium sulfate, and do it as fast as possible to avoid moisture absorption by the methylamine/methanol mixture. After the filtration,
place the methylamine/methanol mixture into a suitable 3-neck flask (equipped with motorized stirrer, thermometer, and addition funnel), and then place a phenyl-2-nitropropene solution into the addition funnel-this solution being prepared by adding and dissolving 34 grams of phenyl-2-nitropropene (obtained in step I) into 150 milliliters of dry hexane. Note: the 3-neck reaction flask should be equipped with a calcium chloride drying tube to keep moisture from entering the apparatus. Then
place the 3-neck reaction flask into a cold-water bath at about I 0 to 15 Celsius. Then add to the methylamine/methanol mixture, 30 grams of anhydrous sodium sulfate. Note: this sodium sulfate is to absorb any water formed during the reaction. Note: dried silica gel pieces can be used instead of sodium sulfate if desired. Now, slowly add drop-wise, the phenyl-2- nitropropene/hexane solution form the addition funnel , to the methylamine/methanol mixture over a period sufficient to keep the reaction mixture below 25 Celsius at all times. During the addition, moderately stir the reaction mixture with the motorized stirrer. After the addition of the nitropropene/hexane solution, continue to stir the reaction mixture for I hour at a temperature below 25 Celsius. After this additional I hour of mixing, stop stirring, and then quickly filter the reaction mixture to remove the insoluble sodium sulfate. Then place this filtered reaction into a clean flask, and then place this flask into an ice bath, and chill to - I 0 Celsius. Note: while waiting for the reaction mixture to chill, stopper the flask to keep moisture out. When the temperature of the reaction mixture reaches - I 0 Celsius, remove the stopper, and replace it with a standard powder funnel , and then slowly add in, in small portions at a time, 3.75 grams of sodium borohydride, and after each portion, add in 25 milliliters of methanol (ten 375-milligram portions of sodium borohydride and ten 25-milliliter portions of methanol). During the entire addition, rapidly stir the reaction mixture, and maintain its temperature below 20 Celsius at all times. After the addition of the sodium borohydride and methanol portions, continue to stir the entire reaction mixture at a temperature below 20 Celsius for about 3 hours. After 3 hours, pour the entire reaction mixture into a large flask, and then add in 1200 milliliters of water. Shortly thereafter, add in 200 milliliters of methylene chloride, and then rapidly stir the reaction mixture for about 30 minutes at room temperature. Then decant-off (pour-off) the upper aqueous layer, and then place the remaining lower methylene chloride layer into a seperatory funnel , and drain-off the lower methylene chloride layer- as there will be some upper aqueous layer still remaining. Thereafter, place the methylene chloride layer into a beaker, and then add in 15 grams of anhydrous magnesium sulfate (to absorb water) . Then stir the entire mixture for about 10 minutes, and then filter-off the magnesium sulfate. Then, place the entire mixture into a suitable sized beaker, and then bubble into the mixture, 30 grams (excess) of dry hydrogen chloride gas. After the addition of the hydrogen chloride gas, place the entire acidified mixture into a distillation apparatus or rotary evaporator, and distill-off the methylene chloride at 40 Celsius until only 80% of the total volume remains. Once this point is reached, stop the distillation process, and then remove the left over remaining contents (after it has cooled to room temperature), and then filter these contents to recover the precipitated impure product. Then vacuum dry or air-dry the filtered-off crystals. Thereafter, place these crystals into a clean beaker, and then add in a sodium hydroxide solution prepared by adding and dissolving 50 grams of sodium hydroxide into 250 milliliters of water, and after the addition, stir the entire three 150-millilter portions of diethyl ether, and after the extraction, combine all ether portions (if not already done so), and then dry this combined ether portion by adding to it , 15 grams of anhydrous magnesium sulfate. Then stir the entire mixture for mixture for about 30 minutes at room temperature. Note: sodium hydroxide generates much heart when dissolved in water, so allow the solution to cool before using. After stirring the alkaline mixture for about 30 minutes, extract the entire mixture with with three 150-millilter portions of diethyl ether, and after the extraction, combine all ether portions (if not already done so), and then dry this combined ether portion by adding to it , 15 grams of anhydrous magnesium sulfate. Then stir the entire mixture for about 10 minutes, and then filter-off the magnesium sulfate. Finally, place the filtered ether mixture into an ice bath, and chill to 0 Celsius. Thereafter, bubble into the ether mixture, 30 grams of dry hydrogen chloride gas (excess), and after the addition, stir the entire ether mixture for about 30 minutes. Thereafter, filter-off the precipitated crystals, and then vacuum dry or air-dry the crystals.

[Edited on 24-10-2017 by Chemi Pharma]

JJay - 24-10-2017 at 03:40

No yields. Gas measurements don't look very practical. I mean, sure, you could weigh your methylamine and hydrogen chloride cylinders while in use, but you would need a high-capacity scale. And you could also weigh the methanol solution, but that won't work for the hydrogen chloride. I don't think these procedures were tested. Also, the link to dopamine synthesis here is rather sketchy.

CuReUS - 24-10-2017 at 04:03

you could do a fries rearrangement on catechol with chloro acetylchloride to get 3,4-dioxychloracetophenone.then replace the Cl with NH₂ and reduce the ketone to get dopamine
I wonder if glycine could be used directly instead of chloro acetylchloride.

dopamine.bmp - 311kB

JJay - 24-10-2017 at 04:27

This is the first time I have heard of the Fries rearrangement... interesting. Why doesn't the chloro acetylchloride react with pyridine?

Melgar - 24-10-2017 at 06:08

Quote:

Sorry @Melgar, but I didn't understand the last part.

This reaction was extracted from a published book.

Do You believe that's impossible to occurs? The author is a fraud? yes or not? why?

Hey guys, what's the consensus here on Jared Ledgard? I know he publishes a lot of books that are perhaps one step above Uncle Fester in apparent legitimacy, but with the exact same subject matters. I never actually read any of the books myself, but I've heard they're mostly just compiled from information he found online, with a lot of typos.

Oh, and that synthesis or whatever you have is obviously missing a step. There needs to be a Nef reaction or a dissolving metal reduction with strongly acidic conditions (to reduce to the oxime then hydrolyze), if the intent is to perform a reductive amination.

One thing that I've noticed is that aromatic formylation reactions that are ortho-directing with phenol, seem to be para-directing with catechol.

where have you noticed this ?

It's not for every reaction, only certain ones. The Riemer-Tiemann reaction, for one. Like, it para-formylates guaiacol to give vanillin, and the Ladenburg synthesis of piperine also does a Riemer-Tiemann formylation of catechol. I thought this was true of the Gattermann aldehyde synthesis as well, but I think that's probably always para-directed. It could be that ortho/para formylations often give the ortho isomer as the major product with phenol, and the para isomer as the major product with catechol.

The Duff reaction doesn't seem like it'd work. Ah well. And for those of you giving all sorts of not-very-OTC syntheses, here are the revised criteria:

Reagents must be purchasable within the US
If something is sold by a retail store, it must be a chain store with a presence in at least half of the 50 states
If something is available online, it must be sold by at least three different vendors
Sellers on eBay and Amazon are considered "vendors" for this purpose. Note that the same seller (say, CCS) selling products on multiple platforms only counts as one vendor.

Sorry for the list of rules, I just want this to be something that someone could theoretically reproduce without running into sourcing problems.

I've heard that ethylvanillin is easier to dealkylate than vanillin, but the references all seem to refer to some original Q document that I've been unable to find. If it turns out that this is true, then this might be the way to go. Catechol isn't especially easy to source, and is more expensive than ethylvanillin, so I may just discuss catechol for a minute or two and then proceed to do the synthesis with some vanillin-type aldehyde.

JJay - 24-10-2017 at 07:01

His book King's Chemistry says you can do a reaction that closely resembles a Friedel-Crafts on catechol with allyl alcohol in acetone using potassium carbonate as the catalyst instead of a Lewis acid:

Quote:

Page 96

Step 1: Preparation of 4-allyl catechol
Into a suitable reflux apparatus, place 13 grams (0.45 oz.) of catechol, followed by 14 grams (0.49 oz.) of allyl bromide, and then add in 22 milliliters (0.74 fluid oz.) of dry acetone. Then stir the entire mixture to form a uniform mixture. Immediately thereafter, gradually add in 17 grams (0.59 oz.) of finely divided anhydrous potassium carbonate, and stir the mixture while adding this potassium carbonate. After the addition of the potassium carbonate, reflux the entire reaction mixture at 60 Celsius for about 3 hours. Note: fit a calcium chloride drying tube to the top of the reflux condenser to keep moisture out from the apparatus. After refluxing for about 3 hours, quickly remove the reflux condenser, and replace it with a conventional cold water condenser, fitted with a receiver

Page 97

flask, and then distill-off the acetone until no more acetone passes over into the receiver flask. When this point is reached, stop the distillation process, and allow the reaction mixture to cool to room temperature. Thereafter, pour the distilled reaction mixture left over, into a clean beaker, and then add in 25 milliliters (0.84 fluid oz.) of cold water, followed by 100 milliliters (3.4 fluid oz.) of 10% sulfuric acid solution. Then stir the entire acidic reaction mixture for about 10 minutes. Thereafter, extract the entire reaction mixture with one 50-milliliter portion (1.7 fluid oz.) of diethyl ether. After the extraction process, wash the ether portion by adding to it, a sodium hydroxide solution prepared by adding and dissolving 35 grams (1.2 oz.) of sodium hydroxide into 150 milliliters (5 fluid oz.) of water. Note: the addition of sodium hydroxide to water generates much heat, so allow the mixture to cool to room temperature before using. Thereafter, remove the upper ether layer by using a seperatory funnel, or by decantation, and then discard or recycle this upper ether layer (will contain diallyl ether). Now to the lower water layer, add in 100 milliliters (3.4 fluid oz.) of 10% sulfuric acid, and upon the acid addition, some oil should separate. After the addition of the sulfuric acid, extract the entire acidic mixture (including any separated oil) with three 50-milliliter portions (three 1.7 fluid oz. portions) of methylene chloride. Note: after each extraction, the methylene chloride will be the upper layer. After the extraction process, combine all methylene chloride extracts, if not already done so, and then dry this combined methylene chloride mixture by adding to it, 15 grams (0.52 oz.) of anhydrous magnesium sulfate—thereafter, stir the whole mixture for about 10 minutes, and then filter-off the magnesium sulfate. Thereafter, place the filtered methylene chloride mixture into a distillation apparatus or rotary evaporator, and remove the methylene chloride. When no more methylene chloride is collected, recover the left over remaining oil. Now, to this oil, place it into a reflux apparatus, and heat it to 180 Celsius. Note: during the heating process, the oil will self heat raising the temperature to about 260 Celsius. When this temperature change results, stop the heating process, and then place the oil (which will now be red in color) into a vacuum distillation apparatus (after it has cooled, or simply replace the reflux condenser with the appropriate glass adapters and immediately begin the vacuum distillation process), as similar to the one used for the distillation of safrole as listed above, but use only one condenser and receiver rather then two, and distill the oil at 158 celsius under a vacuum of 16 millimeters of mercury. When no more oil is obtained at this temperature and vacuum, stop the distillation process, and then remove the left over remaining residue, and discard it. To the collected fraction, re-vacuum distill it using the same apparatus (after it has been cooled, and cleaned), and re-vacuum distill the oil at 158 Celsius, under a vacuum of 16 millimeters of mercury to obtain a refined 4-allyl catechol product.

Does this actually work? It's questionable but interesting. Perhaps you might substitute vinyl bromide for allyl bromide if your target is dopamine (and what happens if you substitute a Lewis acid for the potassium carbonate?). It's definitely sketchy, but he might have based this on solid research that he neglected to cite.

He also devoted several pages to how to extract various natural products that might be used to make catecholamines. It's not clear whether he's actually tried this himself.

Edit: The first time I read this I skipped reading most of the workup and missed the rearrangement part... the potassium carbonate is a catalyst for forming the phenyl ether and is actually removed prior to the ring alkylation.

[Edited on 25-10-2017 by JJay]

clearly_not_atara - 24-10-2017 at 10:52

It looks like allyl alcohol might be an active FC electrophile:

http://isivast.org.vn:8888/bitstream/123456789/12963/1/1501....

But unfortunately there are no intermolecular rxns using unsubstituted allyl alcohol on phenols. Looking around I did find an aurous-catalyzed formation of chromans from allyl alcohols and phenols which may explain the lack of such rxns.

Melgar: You know how to make nitroethylene, correct? Nitromethane + formaldehyde + H2SO4. I'm not sure if my idea fell into the "not OTC" category. Anyway I did some more searching and just as was the case with allyl alcohol there are loads of FC rxns with nitroethylene but they all use indoles or pyrroles and no phenols. So nitroethylene F-C is probably out.

However, it turns out that organocopper reagents will react with nitroethylene and other nitroalkenes in the desired manner; see:

http://anonym.to/http://www.chem.ntnu.edu.tw/en/files/writin...

The reagents also react with allylic acetates. These zinc organocuprates can be prepared by transmetallation of organozinc reagents with copper (I) salts, usually CuCN*2LiCl for solubility reasons because the only studies on the zinc-copper reagents use organozinc reagents generated in THF from reactive organohalides and activated zinc.

However, arylzinc reagents can also be generated in acetonitrile, which was not known at the time that the original zinc-organocuprate studies were being carried out. Generating arylzinc reagents in MeCN uses a cobalt catalyst:

http://anonym.to/http://pubs.acs.org/doi/abs/10.1021/ja02894...

Because copper (I) salts generally have much better solubility in acetonitrile (vs THF) it stands to reason that the transmetallation of organozinc@acetonitrile to zinc organocuprate@acetonitrile should work just fine; unfortunately, it doesn't seem that anyone has tried to convert these arylzinc reagents to cuprates. However, it seems like a relatively safe bet - as safe as any bets involving organometallic reagents can be anyway. And ordinary copper (I) salts should be fine -- no need for cyanide.

The resulting organocuprate could then add to nitroethylene. It's not clear to me if the phenols need to be protected in order for this rxn to proceed; organozinc and organocopper reagents are generally somewhat resistant to protons unlike their Li and Mg cousins. Also, phenols are very weak acids in acetonitrile. I'm pretty sure the presence of catalytic amounts of cobalt will not interfere with the transmetallation, as long as the arylzinc is generated before the copper salt is added.

The good news is that bromination of benzodioxole is high-yielding and can be achieved using NH4Br/H2O2 avoiding Br2:

http://anonym.to/https://erowid.org/archive/rhodium/chemistr...

And the most non-OTC thing here is CoBr2, which shouldn't be that hard to obtain in small amounts.

Chemi Pharma - 24-10-2017 at 15:02

His book King's Chemistry says you can do a reaction that closely resembles a Friedel-Crafts on catechol with allyl alcohol in acetone using potassium carbonate as the catalyst instead of a Lewis acid:

Does this actually work? It's questionable but interesting.

Hey @JJay, I'm afraid it will not work. I suspect Jared Ledgard books are not so trustworthy as I have thought.

I found the same reaction you described from his book King's Chemistry Survival Guide at another book called Preparation of Organic Intermediates - David Shirley - Wiley - 1952, between a phenol (cathecol in this case), allyl bromide, Potassium carbonate as a catalizer and acetone as a solvent. That is quite the same reagents.

However, the product is an allyl phenyl ether and not an allyl phenol (cathecol in this case). The addition isn't like a friedel-crafts reaction, but instead, a substitution of the phenolic group by an ether.

Take a look on this:

Reaction between a phenol with allyl bromide and K2CO3.JPG - 56kB

EDIT: Ok, I apologize, The allyl phenyl ether will rearrange (Claisen) to allyl phenol (cathecol) at high temperature. I see that now. Jared Ledgard is not so stupid after all.

[Edited on 24-10-2017 by Chemi Pharma]

SWIM - 24-10-2017 at 16:24

Pretty sure I've seen Shulgin pull this same reaction somewhere in PIHKAL for some compound where the ring substitution pattern couldn't be put together by simpler means.

Looked it up: it's the 4-benzoloxy-3,5-dimethoxyamphetamine synthesis.
He does it to get the 5-methoxyeugenole intermediate.

Note: according to him this is a lousy drug that's not worth making anyway.

[Edited on 25-10-2017 by SWIM]

JJay - 24-10-2017 at 17:27

The allyl phenyl ether will rearrange (Claisen) to allyl phenol (cathecol) at high temperature. I see that now. Jared Ledgard is not so stupid after all.

I kind of skimmed the rearrangement procedure thinking it was just part of the workup... looks plausible, actually.

The $50,000 question is whether this will work with PVC monomer instead of allyl bromide.

[Edited on 25-10-2017 by JJay]

SWIM - 24-10-2017 at 18:14

Doesn't the Claisen rearrangement have a cyclic intermediate?

If so, how would a 2-carbon phenol ether even reach?

Edit: for 'intermediate', read 'transition state'

I do know the difference on a good day.

[Edited on 25-10-2017 by SWIM]

JJay - 24-10-2017 at 18:48

Looks like you might as well just do a Friedel-Crafts.

clearly_not_atara - 25-10-2017 at 00:53

Allylation of catechol is not applicable to dopamine whereas it is applicable to another compound we don't discuss, so I've refrained. However, be assured that there is a route to 4-allylcatechol which involves a Claisen rearrangement. When there is a substituent ortho to the phenol, the Claisen rearrangement can proceed to a 6,6-disubstituted cyclohexadienone, which rearranges to a para-substituted aromatic. I will not give conditions, but with one ortho position blocked, the ortho:para ratio is about 1:1.

[Edited on 25-10-2017 by clearly_not_atara]

CuReUS - 25-10-2017 at 05:41

neither of the two compounds is a catechol.In the RTR ,it is a known fact that if the ortho position is occupied(by methoxy,in guaiacol),the formylation will occur para to OH.And in piperine synthesis,he formylates benzodioxole,which is again known to give para products

Doesn't the Claisen rearrangement have a cyclic intermediate?

If so, how would a 2-carbon phenol ether even reach?

good catch ,all the examples I have seen use some form of allyl(or propargyl).Even if you could make the vinyl ether(which would be difficult), it wouldn't rearrange.

My fries idea would give dopamine in 2 steps if glycine could be used

Waffles SS - 25-10-2017 at 08:23

Synthesis of 3,4-dihydroxybenzaldehyde(Protocatechuic aldehyde) from catechol
DE105798
US4165341

by Reimer–Tiemann reaction:

Reihlen; Illig; Wittig
Chemische Berichte, 1925 , vol. 58, p. 18
Reimer; Tiemann
Chemische Berichte, 1876 , vol. 9, p. 1269
Tiemann; Koppe
Chemische Berichte, 1881 , vol. 14, p. 2021

[Edited on 25-10-2017 by Waffles SS]

Melgar - 25-10-2017 at 20:56

Well, I suppose it's possible to formylate in either order, but sources seem to indicate that the formylation came first. That would make sense, since the Riemer-Tiemann reaction is the lower-yielding of the two, by quite a lot:

[img]http://slideplayer.com/slide/10398918/35/images/39/Piperine+was+synthesized+(Ladenburg,+1894)+by+the+reaction+of+the+piperic+acid+chloride+with+p iperidine,+which+confirmed+the+structure+of+the+molecule.+The+synthesis+of+piperic+acid+was+achieved+starting+from+piperonal,+which+was+obtained+from+ catechol+using+Reimer-Tiemann+reaction+followed+by+the+condensation+with+diiodomethane+in+the+presence+of+a+base..jpg[/img]

good catch ,all the examples I have seen use some form of allyl(or propargyl).Even if you could make the vinyl ether(which would be difficult), it wouldn't rearrange.

My fries idea would give dopamine in 2 steps if glycine could be used

Yes, glycine is certainly on the table. I'm sort of looking to use the most versatile reactions as possible for this synthesis, because it's supposed to be educational though. I'm looking into everything though, but so much has been thrown on the table in this thread that it's taking a while.

@not_atara: Seems like a LOT of speculation. Could it work? Maybe. Would I expect it to work? Certainly not with me doing it.

It would be nice if there were easier ways to get chloroform, because I'd need to test the Riemer-Tiemann reaction at least 5 or 6 times before doing it for real, and large excesses of chloroform always seem to be needed. Considering I get about 100 mL from a gallon of 8-10% sodium hypochlorite, that's a lot of bleach to have to deal with.

By the way, what about ethylvanillin dealkylation? I'd like to try at least two routes just so I can verify that I did it correctly somehow.

SWIM - 25-10-2017 at 22:11

good catch ,all the examples I have seen use some form of allyl(or propargyl).Even if you could make the vinyl ether(which would be difficult), it wouldn't rearrange.

My fries idea would give dopamine in 2 steps if glycine could be used

In all fairness, the above quote is CuReUS.
I certainly don't deserve any credit for his Fries /glycine idea.

However I'm not too humble to point out that in the first part of that quote he's agreeing with me about something. :cool:

JJay - 25-10-2017 at 22:52

Glycine is an interesting idea, but it's not going to form a phenyl ester easily, and if you halogenate it or form an anhydride with it, it's going to try to form peptides. Right?

Chemi Pharma - 26-10-2017 at 09:27

And what about protocatechualdehyde via aldimine with catechol, copper cyanide and HCl ? The formylation in this case is para oriented. I thought about this after take a look on the preparation below:

cathecol - protocatechualdehyde (aldimine).JPG - 72kB

Quote: Originally posted by Waffles SS

Synthesis of 3,4-dihydroxybenzaldehyde(Protocatechuic aldehyde) from catechol
DE105798
US4165341

Also, the idea of @Waffles SS, brought through the patent US4165341 sounds brilliant, about sinthesize protocatechualdehyde from cathecol and glioxilic acid with alumina as a catalizer with high yields (Patent in .pdf attached below)

Protocatechualdehyde is for me the best starting point, cause is only two OTC steps away from dopamine (Henry reaction with nitromethane and reduction with sodium borohydride/nickel chloride in methanol).

[Edited on 26-10-2017 by Chemi Pharma]

Attachment: protocatechualdehyde from cathecol formylation with glyoxylic acid.pdf (689kB)
This file has been downloaded 453 times

clearly_not_atara - 26-10-2017 at 10:18

Fries rearrangement? Cool. But with glycine? I think you'd have to use N-protected glycine in order to prevent polymerization.

You could perhaps do the rearrangement with chloroacetic acid, then react the product with hexamine. But dimerization of alpha-ketoamones is an issue.

I'm not sure if you can make N-protected amines by alkylating cyanate anion in an alcoholic solvent, so the formed isocyanate converts to a carbamate in situ. Succinimide or phthalimide would probably be the responsible choice here.

Melgar - 26-10-2017 at 11:38

That's the Gatterman aldehyde synthesis that I mentioned earlier. It's zinc cyanide though, not copper cyanide. Incidentally, this is similar to a FC acylation, but uses HCN as the source of the formyl group. To keep from having to use HCN gas, it's instead introduced as Zn(CN)2, then reacted with HCl gas. This produces both the Lewis acid and the HCN in situ.

Quote:

Yep, this is similar to how vanillin is made. The trouble is getting glyoxylic acid. Supposedly that can be prepared from magnesium and oxalic acid, but the reaction is very low-yielding if it yields anything. Another preparation mentions oxidizing ethanol with nitric acid, which is much more likely to turn into a nitric-acid geyser than it is to give any glyoxylic acid. Electroreduction of oxalic acid might have to be the way to go here, and supposedly this was how it was made industrially until recently.

Quote:

Protocatechualdehyde is for me the best starting point, cause is only two OTC steps away from dopamine (Henry reaction with nitromethane and reduction with sodium borohydride/nickel chloride in methanol).

I'm unsure of how acidic phenols affect the Henry reaction, although I would expect that you would just need more catalyst, or longer reaction times. That wouldn't be my first choice of reduction methods though. First, because NaBH4 isn't easy to get, and second, because the nickel boride reaction isn't as nice as you probably think it'd be. However, reducing with zinc and HCl can give the amine for nitrostyrenes, provided temperatures are kept below 0C, which is probably the reduction method I'd use.

Chemi Pharma - 26-10-2017 at 12:12

@Melgar, I have cited copper cyanide cause is more OTC. At least here, in south america, I can buy it withouth any restrictions applicable to alkaly cyanides for just US$30,00 for 500 grs. I don't know about US restrictions, by the way. To this reaction it can be zinc or copper or even sylver cyanide. I think every transition metal cyanide will work.

Glyoxylic acid 50% solution w/w is so cheap here that I'm ashamed saying the price: US$18,00 a liter. Glyoxylic acid is sold by perfumary, soap and flagrancies stores, cause it's used as an exfoliating agent to the skin and to make facial masks. I guess you can find the 50% solucion w/w in US easy if you find at this places, or at the e-bay, and not at a chemycal store. So, just buy it instead synthesize.

Henry reaction between nitroethane with protocatechualdehyde is extensed covered by many and many experiments you can read at Rhodium pages and at The Hive. Many guys have registered their suscessful experiments on doing that, with no damage to the phenolic radicals. Care must been taken with benzodiaxole ring, cause it's acidity sensibility, but it's not the case here. I think Nitromethane will behave the same way.

About reduction, borohydride here is easy to get (I have almost 500 grs right now), but I agree with you it's not so OTC if you want to make an educacional video. I never trust in Zn + HCl to reduce nitroalkenes to give high yields. I suggest you, then, Tin + HCl or SnCl2 + HCl, that's a classic and proved way to reduce them with razonable yield.

[Edited on 26-10-2017 by Chemi Pharma]

Melgar - 26-10-2017 at 13:53

First of all, zinc isn't a transition metal. Just figured I'd point that out. Also, the only transition metal that I regularly see used as a FC catalyst is iron. Copper, I'd expect to be too prone to oxidizing things, and I'm not sure about its solubility in its anhydrous form. Now that I think about it, I wonder if potassium ferricyanide or ferrocyanide could do this like zinc? Precipitate potassium as KCl, free cyanide as HCN and iron would be FeCl3. That may be too much cyanide though, even if it did work.

Glyoxylic acid 50% solution w/w is so cheap here that I'm ashamed saying the price: US$18,00 a liter. Glyoxylic acid is sold by perfumary, soap and flagrancies stores, cause it's used as an exfoliating agent to the skin and to make facial masks. I guess you can find the 50% solucion w/w in US easy if you find at this places, or at the e-bay, and not at a chemycal store. So, just buy it instead synthesize.

Are you sure you aren't thinking of GLYCOLIC acid? Because that's exactly what you seem to be describing.

Quote:

About reduction, borohydride here is easy to get (I have almost 500 grs right now), but I agree with you it's not so OTC if you want to make an educacional video. I never trust in Zn + HCl to reduce nitroalkenes to give high yields. I suggest you, then, Tin + HCl or SnCl2 + HCl, that's a classic and proved way to reduce them with razonable yield.

Zinc will only give good yields if temperature is kept cold, below 0C. Also, it has to be a nitrostyrene, not a nitropropene.

Chemi Pharma - 26-10-2017 at 14:15

@Melgar,

I'm pretty sure it's Glyoxylic acid and not Glycolic acid.

I apologize, Glyoxylic acid is used for hair straightening and Glycolic acid is used for skin exfoliation. I misundertood the usage of the both. You are right!

I didn't have it yet at my storage lab and I just have bought hours ago at the Net a 500 ml bottle for U$9,28 + mail expense, to do experiments with cathecol like said at the Patent.

Here's the link I bought it in Brazil:

https://lista.mercadolivre.com.br/acido-glioxilico#D[A:acido-glioxilico]

AliBaba has the same 50% solution w/w to sell worldwide below U$10,00 per Kg:

https://www.alibaba.com/trade/search?fsb=y&IndexArea=pro...

[Edited on 26-10-2017 by Chemi Pharma]

JJay - 26-10-2017 at 16:02

Fries rearrangement? Cool. But with glycine? I think you'd have to use N-protected glycine in order to prevent polymerization.

You could perhaps do the rearrangement with chloroacetic acid, then react the product with hexamine. But dimerization of alpha-ketoamones is an issue.

I'm not sure if you can make N-protected amines by alkylating cyanate anion in an alcoholic solvent, so the formed isocyanate converts to a carbamate in situ. Succinimide or phthalimide would probably be the responsible choice here.

Sigma has an absolutely massive selection of amino protecting reagents. I wonder if you could make one with cyanuric acid. Although succinimide can certainly be found....

clearly_not_atara - 26-10-2017 at 16:57

Apparently glyoxylic acid hair straightening is a real thing, see e.g.:

http://onlinelibrary.wiley.com/doi/10.1111/ics.12148/abstrac...

JJay: I think 5,5-dimethylhydantoin is a better choice than cyanuric acid if you want things to be OTC. Only one of the protons on hydantoin is removed at normal pH ranges, which prevents having to deal with polysubstituted things like 1,3,5-triazane-2,4,6-trione-1,3,5-triacetic acid". 5,5-dimethylhydantoin is the reduction product of BCDMH the common source of pool bromine.

JJay - 26-10-2017 at 19:44

I do think it would be easier to find suitable solvents for hydantoins.

It seems to me as though the rules say that the least OTC part should be the catechol. I cleaned out my fume hood yesterday and am tempted to play with some aspirin to see if I can't get some catechol out of it... but I have a lot of other experiments I want to do, and it would be a lot less time consuming to just buy it.

Waffles SS - 27-10-2017 at 01:39

I worked with glyoxylic acid for more than 3 years.i tried many method for synthesis it.(Periodate method , Electroreduction method, Ozone method , Glyoxal oxidation method, ...).

I believe Easier method is Glyoxal oxidation by Nitric acid(industrial method).
Dispose of Nitrogen oxide is problem of this method that i solved it by different trap

Reaxys search attached
Attachment: glyoxylic acid.pdf (1.7MB)
This file has been downloaded 843 times

[Edited on 27-10-2017 by Waffles SS]

CuReUS - 27-10-2017 at 06:12

This is the first time I have heard of the Fries rearrangement... interesting. Why doesn't the chloro acetylchloride react with pyridine ?

because it can react more easily with the exposed,protruding OH rather than try to react with the flat,boxed in N.Also the lone pair of N is in resonance making it less juicy

Glycine is an interesting idea, but it's not going to form a phenyl ester easily

Fries rearrangement? Cool. But with glycine? I think you'd have to use N-protected glycine in order to prevent polymerization.

I found some methods to make the ester
http://orgsyn.org/demo.aspx?prep=cv2p0310 ( see the 1st and 2nd refs given)
http://www.prepchem.com/synthesis-of-glycine-ethyl-ester-hyd...

[Edited on 27-10-2017 by CuReUS]

JJay - 27-10-2017 at 06:51

I found some methods to make the ester
http://orgsyn.org/demo.aspx?prep=cv2p0310 ( see the 1st and 2nd refs given)
http://www.prepchem.com/synthesis-of-glycine-ethyl-ester-hyd...

That looks like it might actually work! Pure genius....

Hexavalent - 27-10-2017 at 11:58

This is the first time I have heard of the Fries rearrangement... interesting. Why doesn't the chloro acetylchloride react with pyridine ?

because it can react more easily with the exposed,protruding OH rather than try to react with the flat,boxed in N.Also the lone pair of N is in resonance making it less juicy

Chloroacetyl chloride will react with pyridine, indeed much faster than with a hydroxyl group. The pyridine is a nucleophilic catalyst. It is both a good nucleophile, increases the electrophilic character of the intermediate (acyl pyridinium salt is positively charged) and a good leaving group (large and uncharged) and so it facilitates the acylation reaction which would otherwise be much more difficult.

Finally, the lone pair on the nitrogen atom in pyridine is most definitely not conjugated to the pi system. The nitrogen has an sp² orbital which completes the aromatic sextet. The lone pair resides in a p orbital orthogonal to the plane of the ring. There is zero overlap between the aromatic system and this orbital and so it cannot be delocalised (the overlap integral is zero).

[Edited on 27-10-2017 by Hexavalent]

SWIM - 27-10-2017 at 14:31

I thought the lone pair occupied the spare sp2 orbital and the Pi orbital completed the aromatic sextet.
Getting a third sp2 bond to contribute to that ring sounds like a stressful situation for the bonds.
The Pi orbitals (I thought) can just flop over either way like the wobbly bits they are.

Hexavalent - 27-10-2017 at 14:56

My apologies, you're absolutely right, I wrote them the wrong way round. The unhybridised p-orbital completes the aromatic sextet, while the lone pair sits in an sp2 orbital orthogonal to this.

I'm not sure what you mean by saying the "pi orbitals can flop over". In short, assuming you mean p-orbitals, this is not possible since they must maintain matching phase/symmetry to the others.

For a better understanding, have a look at a molecular orbital diagram for a benzenoid system; the p-orbitals which constitute the aromatic system indeed appear symmetric but they are seen as having two lobes of opposite phase. The lowest-energy molecular orbital is achieved when all of these phases are aligned, such as to avoid creating nodal planes which interrupt resonance. The next-highest energy configuration contains one nodal plane. There are two ways of arranging this and so there are two degenerate molecular orbitals. These are the HOMOs. Flipping more p-orbitals results in an antibonding MO which is clearly disfavourable.

[Edited on 27-10-2017 by Hexavalent]

SWIM - 27-10-2017 at 19:48

Sorry for confusing Pi with p in my reply.

What I meant by the inexact term flop-over was that they can bond either to one side or the other along the ring and therefore resonate between the two effectively making 1/2 bond in either direction.

I believe this is also sometimes visualized as a de-localized ring of electrons around the aromatic structure.

Your references to opposite phases, nodal planes, HOMOs &etc is, I am afraid, all just clicks and whistles to me as I have no clear Idea what any of them mean.

I am aware that various less favorable resonant forms are contributory to the overall shape in any molecule, but your terminology is not something I have any familiarity with.

I suspect part of the problem is that we are speaking different languages in terms of terminology.

When 2 p orbitals form a Pi bond they do something which I am referring to as 'flopping over' If you can visual these orbitals and the bond they form you perhaps can see what I mean.

When they are part of a cyclic structure satisfying Huckle's rule they do something I am describing as 'flopping over both ways'. Again, this may be some thing you can visualize.

[grousing deleted]

[Edited on 28-10-2017 by SWIM]

[Edited on 28-10-2017 by SWIM]

Hexavalent - 28-10-2017 at 01:58

The p-orbitals do not flop/bend to one side and then alternate. Resonance is not “flipping between two different structures” (the name is unfortunate); the true structure is the superposition of all canonicals, some of which contribute more strongly than others. Your argument about the p-orbitals bending is correct for an isolated alkene (giving the “banana-shaped” MOs) but not for an aromatic system.

Regardless, the main point I was trying to make previously is that the nitrogen lone pair is not delocalised across the pi system in pyridine. This is true for pyrrole, where it completes the aromatic sextet, but not for pyridine. It is localised and therefore allows for reactivity as a base and as a nucleophile.

[Edited on 28-10-2017 by Hexavalent]

CuReUS - 28-10-2017 at 03:55

Quote: Originally posted by Hexavalent

pyridine is a nucleophilic catalyst. It is both a good nucleophile, increases the electrophilic character of the intermediate (acyl pyridinium salt is positively charged) and a good leaving group (large and uncharged) and so it facilitates the acylation reaction which would otherwise be much more difficult.

the only catalyst in an FC reaction is the lewis acid.Pyridine just acts like a base and mops up any HCl formed,pushing the equilibrium to the right
http://www.mhhe.com/physsci/chemistry/carey/student/olc/grap...

BTW,I found an even better reaction than fries - the nencki reaction http://onlinelibrary.wiley.com/doi/10.1002/9780470638859.con... (procedure given for resorcinol)
http://onlinelibrary.wiley.com/doi/10.1002/prac.18810230111/...

[Edited on 28-10-2017 by CuReUS]

Hexavalent - 28-10-2017 at 04:51

The acylation you're talking about is not a Friedel-Crafts reaction since it does not substitute on the ring. It is a pyridine-catalysed O-acylation to give the chloroacylcatechol. Pyridine will indeed also mop up the HCl produced (unless the hydroxyl group on the catechol is first deprotonated by pyridine before attacking the carbonyl).

The Fries rearrangement requires you to have pre-formed the chloroacylcatechol. AlCl₃ is the catalyst for this to re-arrange.

(Side note - AlCl₃ isn't truly catalytic for the Friedel-Crafts acylation anyway since it is sequestered during the reaction (and therefore unable to provide further catalysis) by coordination to the acyl oxygen.)

This article regarding the Nencki reaction on cresols:

https://link.springer.com/content/pdf/10.1007%2FBF03172188.p...

seems to indicate a problem with obtaining para-selectivity and indeed getting good overall yield for any regiochemistry. The ratio of ortho/para substitution depends on the size of the acid used, and given that they had little success with up to butyric acid, I can't see it working well in this case. Additionally, they specifically mention that a Fries rearrangement is superior to the Nencki chemistry they describe in terms of yield/selectivity.

[Edited on 28-10-2017 by Hexavalent]

CuReUS - 28-10-2017 at 06:50

Quote: Originally posted by Hexavalent

The acylation you're talking about is not a Friedel-Crafts reaction, it is a pyridine-catalysed O-acylation to give the chloroacylcatechol.

you got me there

Quote:

This article regarding the Nencki reaction on cresols:
seems to indicate a problem with obtaining para-selectivity and indeed getting good overall yield for any regiochemistry. The ratio of ortho/para substitution depends on the size of the acid used, and given that they had little success with up to butyric acid, I can't see it working well in this case.

in the resorcinol paper I linked,they used propanoic acid and got 73% yield.We are going to use glycine,so I don't see the size problem here

Quote:

Additionally, they specifically mention that a Fries rearrangement is superior to the Nencki chemistry they describe in terms of yield/selectivity.

It might be superior but can it beat the simplicity of the nencki ?
Also melgar mentioned on pg 1 that he didn't like working with pyridine

The vanillin demethylation method that was mentioned earlier seems to be legitimate, although the pyridine part could be a sticking point.

Melgar - 28-10-2017 at 07:58

Pyridine is a sticking point only because it's not OTC. Neither is chloroacetyl chloride, for that matter. I'd rather like to have the opportunity to work with pyridine, actually, but it's unavailable in all but the smallest quantities OTC, and on eBay it seems to cost about $1/gram, which is extortion. However, I've since learned that triethylamine can also be used, and is available at a price that isn't nearly so ridiculous. The yields are a bit lower, but so what? I'm interested in developing a way to make anhydrous AlCl3 OTC anyway, because it seems like it should be possible somehow, and it's also quite useful.

If it were up to me, somebody would answer my question about whether ethylvanillin is easier to dealkylate than regular vanillin, and if so, how, rather than continue to discuss rearrangements that require chloroacetyl chloride, which is MUCH less OTC than pyridine. I don't mind reading this stuff, but the discussion is getting pretty far out into the weeds as far as speculation, and since catechol is somewhat toxic, I think, I might prefer to start with vanillin or ethylvanillin, which are both considerably safer and considerably more OTC.

[Edited on 10/28/17 by Melgar]

JJay - 28-10-2017 at 09:29

YouTube videos demonstrate decarboxylation of niacin to make pyridine with basic copper carbonate or copper chromite catalyst: https://www.youtube.com/watch?v=FNsqYwzm40M

Is there a reason that can't be done in bulk?

Crowfjord - 28-10-2017 at 11:03

I don't see why not. Members here have made pyridine, also. Magpie has a nice writeup in prepublication on the subject.

Corrosive Joeseph - 28-10-2017 at 11:38

What is the general consensus on vanillin demethylation with AlI3.............?

/CJ

clearly_not_atara - 28-10-2017 at 13:13

JJay: the biggest objection I've heard to pyridine is the smell

CJ: waste of iodine, no practical advantage over HBr or AlCl3/pyridine

[Edited on 28-10-2017 by clearly_not_atara]

Corrosive Joeseph - 28-10-2017 at 14:44

waste of iodine, no practical advantage over HBr or AlCl3/pyridine

[Edited on 28-10-2017 by clearly_not_atara]

@ clearly - Thank you. All I know is aluminum and iodine are much more OTC for me than AlCl3........

/CJ

CuReUS - 28-10-2017 at 23:49

Pyridine is a sticking point only because it's not OTC. Neither is chloroacetyl chloride, for that matter.

chloroacetyl chloride isn't directly OTC,but it can be easily made from OTC chemicals like glycolic acid or even glycine.Once you have chloroacetic acid,you don't need to convert it to the acyl chloride since you can esterify it with phenol in the presence of TCT.
But if you do the nencki,there is no need for chloroacetyl chloride.Glycine can be directly used.Coupled that with the ease of making catechol from aspirin via the one pot method I proposed,i feel that would be a much simpler,shorter and higher yielding route.
one pot aspirin to catechol -http://www.sciencemadness.org/talk/viewthread.php?tid=77708#...

JJay: the biggest objection I've heard to pyridine is the smell

amen to that

[Edited on 29-10-2017 by CuReUS]

Melgar - 29-10-2017 at 08:15

I believe dealkylation can occur with lithium iodide, which forms the lithium phenol salt and an alkyl iodide. You pretty much have to make lithium iodide by combining the elements though, and it'll catch fire if you accidentally use too much lithium, which is extremely easy to do.

I tried dealkylating ethylvanillin with hydrobromic acid. It didn't do much, so I heated it. It turned a really vivid pink and purple color. No idea what that's all about.

I have a lot of aluminum that's alloyed with gallium and other metals, and is attacked very easily. I've used it to make aluminum triiodide by adding iodine to a nonpolar solution with this aluminum alloy in it. Is that something I could do with HCl gas, to get anhydrous AlCl3? Only one way to find out, I guess.

[some time later]

Okay, well the only solvent that seemed to work was diethyl ether. Bubbled HCl into that, with a chunk of activated aluminum, and it bubbled quite a lot, then formed a film on the glass, and the index of refraction of the solution went up noticeably. Interesting...

[Edited on 10/29/17 by Melgar]

JJay - 29-10-2017 at 08:19

I'm going to give this a try starting with 325 mg aspirin x 200 and see how far I get.

I have the materials and equipment on hand to make aluminum bromide, but I don't have much vanillin.

The Duff reaction looks like the easiest, least toxic, and most OTC formylation reaction I'm seeing.

Edit: deleted garish aspirin photo

[Edited on 30-10-2017 by JJay]

Melgar - 29-10-2017 at 08:44

I was thinking the Duff reaction looked safest too, but alas, it appears to only ortho-formylate.

JJay - 29-10-2017 at 09:29

I'm certainly no expert on the Duff reaction, but I've read that it para-formylates when the ortho position is occupied. (Like here: http://www.orgsyn.org/demo.aspx?prep=cv4p0866)

I wouldn't expect high yields, but what leads you to believe that the Duff reaction won't result in the desired product?

DJF90 - 29-10-2017 at 12:01

I'm certainly no expert on the Duff reaction, but I've read that it para-formylates when the ortho position is occupied. (Like here: http://www.orgsyn.org/demo.aspx?prep=cv4p0866)

I wouldn't expect high yields, but what leads you to believe that the Duff reaction won't result in the desired product?

What leads you to believe that catechol will behave like the substrate in that OrgSyn paper? You even say that when the ortho-position is occupied then para-formylation occurs. Can you not count the two(!) unoccupied ortho-positions in catechol?

I'll be honest here guys, I'm shocked by some of the nonsense I've seen in this thread.

JJay - 29-10-2017 at 12:43

@DJF90: The mechanism and selectivity of the Duff reaction is a subject of current research, much of which I find nearly incomprehensible since I don't know how to calculate bond angles from first principles.

But here you go: http://pubs.rsc.org/en/Content/ArticleLanding/1932/JR/JR9320...

And actually, I might just skip catechol....

clearly_not_atara - 29-10-2017 at 12:43

Dealkylation with lithium chloride in refluxing DMF has also been reported, actually. The iodide may not be necessary. As with other situations I think the bromide might be a good compromise.

I'm sorry you weren't successful with HBr. Maybe Bronsted acid catalyzed Friedel-Crafts hydroxyalkylation is the culprit?

[Edited on 29-10-2017 by clearly_not_atara]

DJF90 - 29-10-2017 at 13:14

@DJF90: The mechanism and selectivity of the Duff reaction is a subject of current research, much of which I find nearly incomprehensible since I don't know how to calculate bond angles from first principles.

But here you go: http://pubs.rsc.org/en/Content/ArticleLanding/1932/JR/JR9320...

And actually, I might just skip catechol....

I have no idea what your remark about calculating bond angles is about. If thats what is hindering you though, download the MarvinBeans suite (free software) and let it do the calculations on your behalf (thats what any sane organic chemist would do anyway, albeit with whatever software is licensed to them).

As for the paper you link to, it shows that the reaction is low yielding and unselective when using salicylic acid as substrate. What was you trying to illustrate?

As for skipping catechol, thats kind of outside of the scope of this thread (as the title suggests) and even if it were permissible by the OP, that sort of leaves guaiacol, vanillin, isovanillin, bourbonal and veratraldehyde as viable starting materials, each of which have their own problems/difficulties en route to dopamine.

[Edited on 29-10-2017 by DJF90]

JJay - 29-10-2017 at 13:48

@DJF90: The point was that the Duff reaction doesn't only ortho-formylate. I had mentioned that I didn't expect high yields. I'm still not 100% sure that the Duff reaction will formylate in the right position to make dopamine from catechol, but I suspect it will since one of the ortho positions is occupied relative to the starting phenol group in catechol, no matter which phenol group you start with. The OP wanted multiple routes by which to make dopamine in order to verify the composition of the final product, and I think it is actually possible to prepare dopamine from salcylic acid without ever preparing catechol (although it would likely require protecting an aldehyde).

There's current research on methods for getting high yields and high selectivity from the Duff reaction. Comprehending this research seems to require extensive and detailed knowledge on the geometry of intermediates that I'm certainly not going to memorize for this project, but if I could derive it from first principles, I think I could make more sense of it.

Melgar - 30-10-2017 at 05:41

I'd mostly like routes that start from things that I have, and I currently have about a pound of ethylvanillin that I have absolutely no use for. Also, 100 grams of regular vanillin and 100 grams or so of catechol. The Duff reaction does seem like it's low-yielding even when it's used for the reactions it works well with. Formylating catechols doesn't seem to be a reaction it's used for though, and in a paper I read, the authors actually claimed that it wasn't worth doing the workup to figure out what the yield was.

Am I supposed to use anhydrous HBr for dealkylation? I actually found a source of pyridine that isn't outrageous:

https://www.chemsavers.com/p/pyridine-99-2-5l/

2.5 liters for $100. Odd that I haven't thought to look there recently for anything. They're a little on the expensive side for reagents in general, but they have a huge array of chemicals that I doubt I'd find anywhere else. Incidentally, they're the only supplier that sells to the public that I know of, where it's possible to get TMSCI, although they have it listed as "chlorotrimethylsilane":

https://www.chemsavers.com/search.php?search_query=%22chloro...

However, other tertiary amines besides pyridine are also supposed to work, so I'll probably try TEA before I go ordering anything.

SWIM - 30-10-2017 at 07:58

I have a lot of aluminum that's alloyed with gallium and other metals, and is attacked very easily. I've used it to make aluminum triiodide by adding iodine to a nonpolar solution with this aluminum alloy in it. Is that something I could do with HCl gas, to get anhydrous AlCl3? Only one way to find out, I guess.

[some time later]

Okay, well the only solvent that seemed to work was diethyl ether. Bubbled HCl into that, with a chunk of activated aluminum, and it bubbled quite a lot, then formed a film on the glass, and the index of refraction of the solution went up noticeably. Interesting...

[Edited on 10/29/17 by Melgar]

I've seen a lot of AlCl3 manufacturing attempts in other solvents on here, but I haven't found any yet that have worked well. This might be fairly important in and of itself. At least worth posting as its own thread (or on some AlCl3 thread)so it's easy to find.

Would this stuff be reasonably safe to evaporate if the ether used was peroxide free?

I did a little poking around and US3032508A says even the ether/AlCl3 complex itself works in FC reactions if the AlCl3 content is high enough (between 1 and 2 moles AlCl3 per mole of ether).

Maybe the complex would function as AlCl3 in some other reactions too.

Melgar - 30-10-2017 at 09:02

The hard part was finding a solvent that wouldn't react with aluminum metal, but would dissolve significant amounts of AlCl3. It can't be aromatic, of course, because then the FC reaction starts in. Acetone and MEK both reacted with the aluminum, which surprised me a bit. Of course, there would probably be a bunch of HCl dissolved in the ether, and I think that might be a good thing for FC reactions, no? It'd probably help this particular dealkylation procedure, even.

HCl was generated via H2SO4 and MgCl2, so it should be relatively anhydrous. I stop the reaction by adding water, after all.

I'd post something when I have more to post, I suppose. The aluminum was by no means pure, but all the other metals should either be inert or assist with the reaction, I believe.

Doesn't the FC reaction normally occur in ether? That's one of the reasons I thought to use it. There really aren't that many solvents that are inert enough for the reaction's conditions and also will dissolve AlCl3.

[Edited on 10/30/17 by Melgar]

SWIM - 30-10-2017 at 10:50

I've mostly seen FCs done with an excess of the substance to be alkylated as the solvent to suppress over alkylation, but I haven't seen that many, so my experience isn't a good indicator. And they probably tend to shy away from reactions nowadays that call for huge excesses of benzene. I've only done one with ferric chloride (or zinc? I think it was iron, but would rather not quote that particular journal article here...)

The patent I saw was using the complex made from ether and AlCl3 rather than generating it in situ, so I wasn't thinking about the excess HCl in there in your case, But your thoughts on that sound good to me(for what that's worth).

I'm not trying to talk you into trying anything unconventional for your current project; as you said, best to go for stuff you can rely on as known quantities.

Just wanted to point out you might have found something very useful that might not be covered on SM.
The comment about the ether/AlCl3 complex was just a side thought really. Probably easier to evaporate the solution to dryness rather than titrating it for use as is. I just have a bit of a phobia about boiling anything in ether to dryness

chemplayer... - 4-11-2017 at 02:42

Forgot to mention, this was another interesting potential reaction which could give the dopamine / l-dopa side-chain:

https://www.youtube.com/watch?v=ExVoMqHDFxM

BlackDragon2712 - 6-11-2017 at 16:08

I gave it a thought once... came up with this:

Step 1:

Step 2:

Step 3:

Step 4:

Each step has its reference... I was an idiot and didn't save them but I could look them up (Not on these molecules of course but in rather similar ones)... the funny thing about this is that step 3 is a rather easy hydrogenation that can be done at practically normal room conditions, the bad side though is that palladium acetate is quite expensive... you don't need much though and is not very hard to get either.

clearly_not_atara - 6-11-2017 at 20:01

In this paper, vanillin is reductively aminated with a secondary amine and the product reacts with potassium cyanide in DMF at 120 C to give a phenylacetonitrile via an intermediate quinone methide. The phenylacetonitrile is reduced to the phenethylamine and the product 3O-methyldopamine can be demethylated easily.

http://www.sciencedirect.com/science/article/pii/00404020738...

Outer - 7-11-2017 at 11:20

Allylation of catechol is not applicable to dopamine whereas it is applicable to another compound we don't discuss

Allylation of catechol is applicable to dopamine, by the next scheme:
mono-O-Allyl-catechol => 4-Allyl-catechol => (double bond cleavage) => Ar-CH2-CHO => (reductive amination) => Ar-CH2CH2NH2 (=dopamine)

Chemi Pharma - 7-11-2017 at 12:13

Quote: Originally posted by Outer

Allylation of catechol is not applicable to dopamine whereas it is applicable to another compound we don't discuss

Serious? And where did the other carbon goes? Desappeared by magic?

Do you mean Ozonolysis of the allyl group? It's the only way I know to do this kind of cleavage, but it's not OTC at all.

EDIT: Interesting. I found a recipe to cleavage the double bond with KMNO4 in THF from Rhodium pages. May be it's possible do the cleavage of allyl cathecol in 3,4 Hydroxy Phenyl acetaldehyde and formaldehyde like you said:

https://erowid.org/archive/rhodium/chemistry/alkene2aldehyde...

[Edited on 7-11-2017 by Chemi Pharma]

Melgar - 7-11-2017 at 12:50

@BlackDragon2712 For the demethylation, is there some trick or procedure, assuming you have 48% hydrobromic acid? I'm having trouble finding a good descriptive procedure.

@not_atara Wow. That is a very interesting combination of reactions. The alkali cyanide isn't ideal, but I recently read a 19th century chemical engineering text that described "fusing" a mixture of (I think) sodium sulfide with postassium ferricyanide or potassium ferrocyanide, and getting a molten mixture of NaCN and KCN with the FeS precipitating from the melt. I have plenty of KCN, so it wasn't that useful for me, but I'll have to see if I can find that again. The text claimed that this ratio had a lower melting point, and that for applications where either alkali cyanide could be used, that this mixture was especially convenient.

@Outer I feel like I should reply that the Mannich reaction would be a better way to go than allylation and subsequent ozonolysis or whatever, but I guess I'm not familiar enough with the Mannich reaction to say that with 100% certainty.

I'm toying with the idea of using this reaction to illustrate the vast array of options available for certain syntheses, and encourage the sort of lateral thinking that makes for good organic chemists. Also, emphasize the vastness and variation of organic chemistry; it's not "chemistry of only one element" any more than computer programming is "math with only two numbers". This thread has certainly given me plenty of material. After all, if the goal is education, emphasizing the large variety of potentially useful reactions is probably the most educational way of framing it. It'd have to be split up into a bunch of videos, but that's not a problem.

[Edited on 11/7/17 by Melgar]

Chemi Pharma - 7-11-2017 at 13:02

@not_atara Wow. That is a very interesting combination of reactions. The alkali cyanide isn't ideal, but I recently read a 19th century chemical engineering text that described "fusing" a mixture of (I think) sodium sulfide with postassium ferricyanide or potassium ferrocyanide, and getting a molten mixture of NaCN and KCN with the FeS precipitating from the melt. I have plenty of KCN, so it wasn't that useful for me, but I'll have to see if I can find that again. The text claimed that this ratio had a lower melting point, and that for applications where either alkali cyanide could be used, that this mixture was especially convenient.

Here's the link to get the paper Atara said in PDF:

Synthesis of phenethylamines from phenylacetonitriles obtained by alkylation of cyanide ion with mannich bases from phenols and other benzylamines.
J.H.Short, D.A.Dunnigan, C.W.Ours

http://chemistry.mdma.ch/hiveboard/rhodium/pdf/pea.mannich.b...

Melgar - 7-11-2017 at 13:29

@ChemiPharma Yep, I'd gotten it already from sigh'ubb, but good to have the link. Also, the other way to cleave double bonds that way is by converting to the diol, then reacting with periodate. Not saying it's especially practical, but it might be of some interest down the road.

IIRC you can make sodium periodate just by adding enormous amounts of bleach to elemental iodine. Or, if you add iodine to NaOH for the Finkelstein reaction, you could probably just separate out the NaIO3 and oxidize that with bleach. I think it can be made by electrolysis of an alkali iodide salt, but I'm unclear on the details.

Also... "recipe"? You should really know better by now.

[Edited on 11/7/17 by Melgar]

BlackDragon2712 - 7-11-2017 at 19:42

@BlackDragon2712 For the demethylation, is there some trick or procedure, assuming you have 48% hydrobromic acid? I'm having trouble finding a good descriptive procedure.

Well... I'm going to be plain honest here, I lost all references but for step 2 and 3 a long time ago

... though it is by no means conclusive if it works in this case, the cleavage of methoxy group in guaiacol with HBr is described in Org Syn. here:

http://www.orgsyn.org/demo.aspx?prep=CV1P0149

... The double cleavage of a cathecol like ring is described in page 7 of this link:

https://www.thevespiary.org/library/Files_Uploaded_by_Users/...

I would expect HI to be better in cleaving alkoxy groups...

On a side poorly relevant note though, on this book it's mentioned that LiCl apparently can cleave aromatic methoxy groups on refluxing in DMF for 4-72 hours... though vaguely described it does seems interesting...

https://books.google.cl/books?id=B2BEBAAAQBAJ&pg=PA550&a...

BlackDragon2712 - 7-11-2017 at 19:49

Safer hydrogenation protocol:
http://onlinelibrary.wiley.com/doi/10.1002/chem.201001377/ab...

JJay - 7-11-2017 at 21:04

Chem Player did this video on cleaving the double bond in piperinic acid using a combination of permanganate and periodate: https://www.youtube.com/watch?v=6r9elLR2WjI

The workup would be more somewhat complicated for 4-allyl catechol but is probably not outrageously difficult. If I'm understanding the periodate/glycol oxidation mechanism, it would occur on the order of a million times slower on the catechol phenol groups than on a phenyl 1,2-diol.

Melgar - 8-11-2017 at 00:03

I forgot if this has been posted or not, but this paper describes reduction of nitrostyrenes to dopamine analogs with just zinc and hydrochloric acid in methanol:

https://www.researchgate.net/publication/274084261_Chemosele...

BlackDragon2712 - 8-11-2017 at 00:34

I forgot if this has been posted or not, but this paper describes reduction of nitrostyrenes to dopamine analogs with just zinc and hydrochloric acid in methanol:

https://www.researchgate.net/publication/274084261_Chemosele...

Oh god, this may make the vanillin pathway quite easy if it works!! great finding!

CuReUS - 8-11-2017 at 06:49

Do you mean Ozonolysis of the allyl group? It's the only way I know to do this kind of cleavage, but it's not OTC at all.
EDIT: Interesting. I found a recipe to cleavage the double bond with KMNO4 in THF from Rhodium pages. May be it's possible do the cleavage of allyl cathecol in 3,4 Hydroxy Phenyl acetaldehyde and formaldehyde like you said:

@Outer I feel like I should reply that the Mannich reaction would be a better way to go than allylation and subsequent ozonolysis or whatever

the other way to cleave double bonds that way is by converting to the diol, then reacting with periodate.

Chem Player did this video on cleaving the double bond in piperinic acid using a combination of permanganate and periodate.The workup would be more somewhat complicated for 4-allyl catechol but is probably not outrageously difficult. If I'm understanding the periodate/glycol oxidation mechanism, it would occur on the order of a million times slower on the catechol phenol groups than on a phenyl 1,2-diol.

Won't the catechol convert immediately to quinone in the presence of oxidizing agents ?

JJay - 8-11-2017 at 07:19