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SuperOxide
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I chat with Benignum outside of SM, so I've had some previews of this as he's shared some pictures and info on his progress. But I had no idea it was
_this_ epic (literally, epic).
Benignum, thanks for sharing such amazing work. Definitely an inspiration! 
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Benignium
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Thank you, both of you! I appreciate your positive feedback like you wouldn't believe.
timescale - This is a good question that I'm afraid I don't have a good answer to. The suspicion is very non-specifically based on
reports I've read online as well as my own experiences working with these compounds and is, for all intents and purposes, just a hunch. Indeed, the
moisture present in DCM, albeit very minor, could play some part in such a phenomenon, much like the impurities accompanying crude substances
themselves are sometimes seen doing.
The thiophenols definitely seem like an attractive angle of approach in the preparation of the 2C-T-x compounds, but currently I'm undecided on the
specifics.
As for the bioassays, I could consider posting thoughts on my subjective experiences here on this thread, though I would prefer to have the
moderators' explicit blessing first. What's more, finding the time for those subjective experiences has proved somewhat challenging so far. Do let me
know any specific questions you might have, however!
[Edited on 18-4-2022 by Benignium]
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xdragon
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Great content as always, Benignium.
I don't know if you remember, but I talked to you earlier outside of SM when I found you "in the wild" about stereo-selectivity
issues/overchlorination of 2C-H which may form 4,6-dichloro-2,5-dimethoxyphenethylamine and was reported in the literature, which lead to some groups
adopting to different synthetic schemes: chlorination and purification of the starting aldehyde and choosing a reduction which does not dehalogenate,
starting from 2C-B, etc.
It would be nice if we knew how much of a problem this overchlorination is with NCS and N-chlorosaccharin. At the other place - the vespiary - a user
lately reported NCS chlorination of 2C-H and had multiple spots both on TLC as well as an instrumental chromatogram (too tired to log back in, but see
for yourself). Sadly, no qualitative analysis of the peaks could be done.
If you see any way of getting qualitative analysis of both your crude and purified 2C-C and DOC done, that would be very interesting to the whole
community and some nice chemistry work.
All the best to your continued efforts at phenethylamine chemistry - or just chemistry in general, we don't always get to be picky 
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Snakeforhire
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@Begnigium :
You sir, deserve the highest praise for such a comprehensive report, and I extend my deepest thanks to you for this tremendous effort. 
[Edited on 10-6-2022 by Snakeforhire]
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Snakeforhire
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I'm new here and have just learned of nitroalkenes reduction with NaBH4 and a metal salt so y'all have to forgive my ignorant ass if this has been
covered already (not in any post that I could find yet though), but I need some experts' advice :
Is there a significant yield difference between such a reduction done with Ni(II) and Cu(II) salts ?
I'm only asking because I might know where to get some 2,5-DMB, but NiCl2 dihydrate salts are kinda hard to find : all I can find is the hexahydrate,
which I'd have to dehydrate myself and this is a major PitA...
It'd be way easier to find copper chloride actually.
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clearly_not_atara
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I think you probably want to reread the report because this reduction was carried out with copper catalyst and nickel is not mentioned anywhere.
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Snakeforhire
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I know, but I've seen in other threads that other people use nickel salts also.
I just wondered if the metal salt used can make a noticeable difference in the yield of amine.
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karlos³
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Yes it does, with a Ni(II) salt, you probably won't get any yield out.
So far, anecdotal reports of a successful NaBH4/NiCl2 reduction of a nitroalkene are very scarce.
And anecdotal reports from people who failed with it are plenty.
With Cu(II) salt, it will be easy and probably will work on the first try.
And so far, actually everyone has got it to work.
I would call that a "noticeable difference in yield"
verrückt und wissenschaftlich
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lithiumion656
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Is there any known way to induce ring closure of phenethylamine to form indole? I know the chemistry doesn't make this likely but that doesn't
discount some obscure paper/person having found a way to do so.
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myr
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Quote: Originally posted by lithiumion656  | | Is there any known way to induce ring closure of phenethylamine to form indole? I know the chemistry doesn't make this likely but that doesn't
discount some obscure paper/person having found a way to do so. |
Not practically: looking at the synthons, the disconnection between the phenyl ring and the nitrogen would need some sort of Pd or Cu coupling between
an aryl-halide, boronic acid etc. and the N, or SnAr (which would first need substantial modification of the aromatic ring)
If you want to go from a phenethylamine-like backbone to an indole, the best way (I think) would be a 2-nitroaryl nitrostyrene intermediate: acid and
a reducing metal (Zn? Sn? Fe?) would give you an indole with OK yield, probably. I believe this is even used by Shulgin for one of the stranger
indolic psychotomimetics, so it should be robust chemistry.
[Edited on 17-6-2022 by myr]
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Snakeforhire
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| Quote: Originally posted by mr_bovinejony | | Dissolve 2ch in a minimum amount of gaa and add an equal weight of nbs! The product will precipitate after some time of stirring. But the 2ch has to
be pretty pure, I've done it a few times myself |
Forgive me for bumping up your (kinda) old post -and for cluttering Begninium's thread - but you wouldn't happen to have noted the yield you got from the NBS bromination, have you ?
I'm very curious as to what the difference between reactions done elemental bromine in GAA and NBS. I can't seem to find any definitive answer
anywhere, not for lack of trying though. 
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clearly_not_atara
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| Quote: Originally posted by lithiumion656 | | Is there any known way to induce ring closure of phenethylamine to form indole? I know the chemistry doesn't make this likely but that doesn't
discount some obscure paper/person having found a way to do so. |
You can, but you can only form 5,6-dihydroxyindole, and the reaction is spontaneous by cyclization of 4-aminoethyl-o-benzoquinone. This is the
preparation of e.g. adrenochrome (which, despite repute, is inactive).
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Benignium
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xdragon - I do indeed remember – what a wild coincidence that was! So far there is no practical way for me to arrange for such
analyses, but I agree with your notion and will act accordingly if an opportunity presents itself. The Sciencemadness user who goes by Ullmann has
suggested that chlorination of the amine gives an impure mixture, and I feel inclined to assume that NCS yields similar results based on the impurity
reported when they used it to chlorinate 4-methoxyphenol.
Snakeforhire - Much appreciated!
Since my last update, I've completed an endeavor comprising well over twenty steps’ worth of synthetic procedures. As the result, three different
commercially available hydroxybenzenes have been modified to form a set of seven unique substituted benzaldehydes. I've placed a neat little
infographic below to give a more detailed summary. In the next phase, my rather artisanal yields permitting, these synthetic products will be
complemented with two additional commercially obtained benzaldehydes as part of an effort to prepare up to 13 amine targets, with emphasis on
trimethoxyamphetamines and the remaining portion of Alexander Shulgin's magical half-dozen. Right now, however, it's time to begin gradually
unburdening my brain and smartphone; there’s already quite a build-up of interesting chemistry to write up, so much so that I feel a bit swamped.
I plan to segment the documentation in such a way that each one of multiple upcoming posts will deal with an uninterrupted sequence of experiments
leading to a discrete goal, starting with the 2,5-dimethoxy-4-methyl motif. Despite profuse overlap between the procedures, this approach should, with
the correct ordering, allow for a decent sense of chronology.
IUPAC forgive me for what I'm about to do.
On a more general note, one of my aspirations in compiling this work is to provide reliable information by avoiding factual errors and by correcting
myself wherever a mistake has been made. If you detect some falsehood or fallacy, I ask that you kindly point it out either by replying here
or via a U2U. Likewise, in matters of uncertainty discussed as such, I wish to eventually reach conclusive levels of understanding that I can share,
and I welcome any assistance to that end. Now let's segue into amending some previous content.
Amendments, 10/2022
Firstly, the experimentals concerning the preparation of 2C-H omit the fact that the nitroalkene was recrystallized once from IPA prior to reduction.
In my notes, I have also neglected to specify whether the reported yield of 94.5% was calculated for the crude or the recrystallized material. Either
seems like a realistic possibility as the particular recrystallization is very efficient, but I'm almost certain that 94.5% is the crude yield.
Further, the mass of obtained product is incorrect, as 142.2 mmol corresponds to 29.74 grams – not 33.7. Moving on to the reduction, where I've
chosen to give the mass of an arbitrary slurry of copper(II) chloride and water, it's worth pointing out that the reported 1.15 g of catalyst was, to
the best of my recollection, calculated/estimated to correspond to 0.1 equivalents or about 0.82 grams of the pure dihydrate.
What I've referred to as the Henry reaction would be more properly called a Knoevenagel condensation. The Henry/nitroaldol condensation is a distinct
reaction employing a dissimilar selection of catalysts to form β-nitro alcohols.[1][2]
Heating (and unnecessarily storing) methoxyl-containing phenethylamines in the presence of excess hydrochloric acid as I've done on many occasions
should be avoided as it can lead to the dreaded acid cleavage of ethers.[3]
Finally (for now, anyway), I'd like to revoke my endorsement of phenethylamine sulfates in situations where there is the need for a water-soluble salt
that won't partition into organic solvent washes. While the elusive phenethylamine hydrogen sulfates [said to form in the presence of excess (>0.5
molar equivalents) sulfuric acid] could potentially serve this purpose, the hemisulfates are oftentimes hydrophobic to the point of precipitating from
even relatively large volumes of aqueous solution, which is reason enough for me to look elsewhere. So far, acetates work well.
[1]: https://www.sciencemadness.org/whisper/viewthread.php?tid=23...
[2]: https://en.wikipedia.org/wiki/Henry_reaction
[3]: https://www.masterorganicchemistry.com/reaction-guide/acidic...
[Edited on 14-10-2022 by Benignium]
[Edited on 2-11-2023 by Texium]
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Romix
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Anyone knows here how David were making 25B_NBOMe from 2CB? And NBOMEs with other halogens made from 2C's.
Never tried NBOME with Florine in it... But seen RC amph look alike with it...
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Romix
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Am I right guys?
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Romix
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It's hard to dose I heard... goes by micrograms... Offering someone a sniff of the hole in the filter of Pall Mall cigarettes will probably kill the
cunt.
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Benignium
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Right, so.
2,5-dimethoxy-4-methylbenzaldehyde
180.20 g/mol
This one is a bit of a train wreck. But bear with me.
[a3] 2,5-dimethoxytoluene
152.19 g/mol
Methylation of phenols is a central issue when it comes to forming the various methyl ether incorporating phenethylamines. The approach I've chosen
deals with dimethyl sulfate, whose cost-effectiveness and dependability come with the trade-off of, from the amateur perspective, rather prohibitive
toxicity. There are several intriguing and, reportedly, worthwhile alternatives, like trimethyl phosphate and dimethyl oxalate,[1] and I
hope to explore these in the future. For now, however, we're going with the partially phased out terror juice. For the purposes of decontamination and
damage control, plenty of 1.33M ammonia solution (prepared by reacting ammonium chloride and sodium hydroxide) was always kept within reach.
The first experiment is a terrific example of how not to go about the methylation. My goal was to try out a solvent free procedure outlined in the
patent US4065504A. Unfortunately, inadequate agitation, exacerbated by the coarse consistency of the reactants, undermined whatever validity this
endeavor may have had. The reaction scale and reaction vessel were also out of proportion.
The solvent free approach was/is revisited later in more favorable circumstances.
The second experiment applies a very different approach from PiHKAL that is evidently much more practical.
[1]: https://www.thevespiary.org/talk/index.php?topic=18672.msg54...
[2]: https://isomerdesign.com/PiHKAL/read.php?domain=pk&id=23
Experiment 1
Toluhydroquinone (49.89 g, 0.40 mol) and potassium carbonate (145.79 g, 1.06 mol) were placed in a 250 mL Erlenmeyer flask filled with argon, and
shaken until mixed. Dimethyl sulfate (133 g, 1.05 mol) was added using a 25 mL pipette, and magnetic stirring was established with manual assistance
using a glass rod. The flask was fitted with a Liebig condenser. Beginning on the 100°C hotplate setting, the temperature of the mixture (measured by
IR) was gradually brought up to 70°C over 134 minutes. By this point the evolution of CO2 had accelerated considerably, and the color of
the mixture had become increasingly red. Not 15 minutes at this temperature had passed before the mixture had thickened such that stirring became
ineffective. Parts of the gelatinous mixture, propelled by pockets of the evolving gas, began advancing menacingly toward the narrow tube of the
condenser. Eruption was prevented by moving the flask to a cool water bath, and the contents were allowed to return to ambient temperature.
Using two 25 mL portions of acetone[1], the cooled reaction mixture was thinned and transferred to a larger 1000 mL Erlenmeyer. Heating (on
the previously used 150°C hotplate setting) and stirring (with the same small stir bar[2]) were continued. As the mixture approached the
boiling point of acetone, it darkened progressively from the heated and stirred center portion outward. Proper mixing by swirling the flask was
performed twice over the next hour, leading to a dark red porridge with relatively few carbonate beads remaining. This was heated overnight and then
allowed to cool.
[1]: In hindsight, simply using more acetone might have gone a long way toward improving the outcome.
[2]: My selection of stir bars at the time was severely limited.
Toluhydroquinone
Dry ingredients, mixed
Reaction mixture following addition of DMS
Stir bar working hard to keep the entire mass of K2CO3 moving
Dark coloration from contact between ammonia solution and reaction mixture on a stick
Reaction mixture cooling down in a water bath
Acetone-thinned horror porridge. Horridge?
Transferred reaction mixture after a while of reacting
What have I done?
Reaction mixture on the following day
Work-up (1)
150 mL of water was carefully added to the thick tarry sludge. The resulting lumpy mixture was warmed for two hours at ~46°C and then brought up to
74°C before heating was discontinued. The pH of the aqueous phase was determined to be 8–9. On removal of the respirator, there was observed a
(freshly sharpened) cedarwood pencil aroma of such potency that it was clearly discerned a meter or two upwind of the opened 24/40
flask.[1] The water extract was poured into a separate container, and the remaining gummy mass was extracted twice more with 100 mL
portions of hot water, followed by rinsing with a third, tepid portion. The combined aqueous phases were gravity fltered through cotton wool and
extracted with three 50 mL portions of ethyl acetate. The organic extracts were, in combination with ~150 mL of fresh EtOAc and mild heating, used to
extract the remaining mass in the reaction flask until only a very small amount of hard, plasticky material was left.[2]
The decantations of ethyl acetate extract from the reaction flask contained an enormous amount of fine solids which were separated by vacuum filtering
the mixture in two portions. The filter cake from each half was rinsed with three 10 mL portions of ethyl acetate to obtain off-white material which
seemed to quite rapidly discolor on air exposure. With stirring, these solids were suspended in 50 mL of water and 5 mL of ~35% sulfuric acid was
added to make the mixture moderately acidic before setting it aside for further processing. Eventually, the solid was assumed to be mostly potassium
sulfate and this mixture was discarded.
The aqueous extracts were similarly acidified using 25 grams of the ~35% sulfuric acid and set aside with the intention of attempting to recover
unreacted starting material at a later date. However, due to constraints of time and glassware, no such attempt was made, and this partition was
eventually discarded as well.
The ethyl acetate extracts were distilled to remove 250–275 mL of solvent before, during a brief absence of supervision, the mixture was
accidentally overheated to ~160°C. It was then cooled back down to 25°C under a gentle flow of argon. The ~72 grams of black, bitumen-like residue
was distilled at a reduced pressure to yield 16.5 g of a distillate that grew darker and more viscous toward the end of its collection, and retained
the incredibly powerful scent of pencil. A further attempt to steam distill the petrochemical abomination was promptly terminated, as the mixture
forcefully expanded like a kernel of flint corn and puked out beads of marginally refined tar that smelled of lightly aged household garbage and
pencil shavings.
A gram of the vacuum distillate was steam distilled to obtain a yellow oil which solidified when placed in the freezer.[3] 13.3 grams of
the vacuum distillate were dissolved in ~30 mL of toluene and washed with four 10 g portions of 10% NaOH. The toluene was then driven off on a 100°C
hotplate, leaving 5.25 grams of a dark red oil which was steam distilled. The distillate was moved to a separatory funnel along with a small portion
of dichloromethane. Work on this extraction was being performed outside when there was an interruption, and the funnel was left unattended for a few
hours. During this time, the ambient temperature declined, causing the insufficiently tightened PTFE stopcock to shrink just enough (proportionally to
the borosilicate) to allow the dense mixture of product and DCM to leak out while retaining the aqueous phase. To add insult to injury, a brief rain
shower then dispersed the leakage further, ensuring that the eventual paper towel extraction would be destined for disposal. A profoundly sombre
conclusion, though nowhere near as profound as the lingering smell of pencil.
[1]: Whatever was responsible for this aroma clearly had the vapor pressure of a pebble and, therefore, an extremely low odor
detection threshold in the range of ppb, if not ppt. Interestingly, I found a close structural relative, called thymoquinone, that matches this
description quite closely. Perhaps some derivative of it was formed?
[2]: This proved exceedingly tough to remove and was discarded.
[3]: The melting point of 2,5-dimethoxytoluene is 19–21°C,[4] so this is a good sign.
[4]: https://www.chemicalbook.com/ChemicalProductProperty_EN_CB41...
Water being added dropwise to reaction mixture
Lumpy mixture following addition of all water
Material left over from hot water extractions
Sample of above material mixed with ethyl acetate and water
Gravity filtration of water extracts
Slightly discolored filter cake from vacuum filtration of EtOAc decantations
Moderately discolored combined filter cakes
Suspended filter cakes being acidified
Bitumen-like residue from EtOAc extracts
Last of the collected vacuum distillate
Vacuum distillate in receiving flask
Aftermath of failed steam distillation
Steam vomitus
Vacuum distilled crude product
Toluene solution being washed with NaOH solution
Washed toluene phase <> Combined alkaline phases
Steam distillation of impure product
Steam distillate
"Is a man not entitled to the sweat of his brow?"
Experiment 2
Into a 1000 mL two-necked round-bottomed flask were placed toluhydroquinone (50 g, 0.40 mol) and 500 mL of water. After some minutes of stirring the
suspension under flowing argon, a 250 mL separatory funnel, pre-loaded with DMS (83 mL, 0.88 mol), was attached to the angled neck, alongside a Liebig
condenser on the vertical neck. Through the condenser was poured a freshly prepared 20% solution of NaOH (40 g, 1.00 mol), and the mixture was stirred
until no more of the remaining particulate seemed to dissolve. Then, at first, a small portion of the ester was carefully added to gauge the vigor of
its reaction. When it was clear that nothing exciting was happening, approximately half was added at once, followed by the other half soon after. The
entire addition was completed in about six minutes. Formation of the permethylated product could be observed as the appearance of immiscible particles
of liquid which, initially, gave the mixture a cloudy appearance before coalescing into larger droplets. The temperature of the mixture was found to
peak at about 40°C. After two hours of stirring, the pH of the mixture was determined to be strongly basic (12–14). Stirring was continued
overnight.
Dimethyl sulfate over suspension of toluhydroquinone in water
Dissolution of toluhydroquinone as its sodium salt in alkaline water
Initial cloudiness following addition of DMS
Agitated reaction mixture ~20 minutes after DMS addition
Still reaction mixture ~140 minutes after DMS addition
Aftermath of evaporated DMS spill
Work-up (2)
The post-reaction mixture was extracted thrice with 50 mL portions of DCM, and the combined extracts were distilled to leave an amber oil. This was
distilled under aspirator vacuum, at a steady temperature of 102–109°C,[1] to yield 47.28 grams (77.1%) of a pale yellow liquid with a
very pleasant aroma.[2]
[1]: Estimation, based on IR readings from outside surfaces.
[2]: Slightly sweet, herbal, woody, earthy, with hints resembling vanilla, toffee and menthol. Definitely similar to the purified
product of the first experiment, but with no pencil whatsoever.
Crude product set up for vacuum distillation
Completion of vacuum distillation
[b4] 2,5-dimethoxy-4-methylbenzaldehyde
180.20 g/mol
300.37 g/mol (bisulfite adduct; potassium salt)
Another prevalent pursuit in building up to phenethylamines is the formylation of substituted benzenes. Here, one might easily argue that the
challenges faced are more nuanced than they are with your average O-alkylation: for example, in a homologous series of three adjacent compounds, the
intermediate might inexplicably give poor, inconsistent results from the very same procedure that consistently works well with the other two. Such is
the case, reportedly, with 2,5-dimethoxy-1-ethylbenzene and the Vilsmeier–Haack formylation.[1] These surprising pitfalls most certainly
do have explanations, but coming up with them is well beyond my current comprehension of the art. Another might argue that comparing O-alkylation to
formylation is like comparing apples to oranges and therefore wrong, but they would be arguing for the sake of arguing which is obviously a bigger
offense than comparing fruit.
Fortunately, the selection of tools with which substrates like the ones being discussed in this thread can be formylated is reasonably accommodating.
A real beacon of amateur-friendliness among these is the Duff reaction, modified to supplement the action of acetic acid as a reactant by
incorporating sulfuric acid as a strong acid catalyst, thus eliminating the need for trifluoroacetic acid. Now, watch me do it dirty by first
displaying its application on the worst-performing of four substances and then moving on to an entirely different formylation.
In all seriousness, the Duff reaction is a valuable asset in the niche field of phenethylamine chemistry, and I genuinely want to believe that its
full potential as such has not been realized just yet. The person working under the pseudonym Ullmann was, to the best of my knowledge, the first to
make a case for the undeniable feasibility of the H2SO4-modified Duff procedure in formylating precursory benzenes with
sufficiently activating substituents.[2] The work in question gives pertinent insight into the features that define the aforementioned
sufficiency of substitution patterns, along with informative and thought-provoking suggestions pertaining to the reaction mechanism in general. Of
particular intrigue are the connections drawn from the final step of the Duff reaction, where a benzylic imine intermediate is hydrolyzed to yield an
aldehyde; to the Sommelet reaction, which proceeds from an imine to a benzaldehyde in a very similar fashion; and to the Delépine reaction as a side
reaction to both (the Duff and the Sommelet) that produces an amine instead. If my interpretation of this triangular relation is correct, the core
concept presented by Ullmann seems to be that, by altering the conditions following hydrolysis, a Sommelet-type conversion of the yield-limiting
benzylamine side product to the desired benzaldehyde can take place to varying degrees.
The first experiment is me going in blind by applying a procedure, outlined long ago by the prominent Hyperlab user miamiechin, on the basis of its
reported yield, which was the highest that I had seen for this particular substrate.[3] As I neglected the prescribed step of overnight
mixing with ethyl acetate, my reproduction wasn't entirely faithful, but the results were comparable.
The second experiment took place almost two months after the first one, and was actually the last one in a sequence of six later Duff formylations.
The reason behind a second attempt was my desire to investigate whether a modified procedure, which unexpectedly lead to a decent yield of the 4-ethyl
homolog, had actual merit. Unfortunately, I failed to make the experiment a valid point of comparison.
[1]: https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
[2]: https://www.sciencemadness.org/whisper/viewthread.php?tid=11...
[3]: https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
Experiment 1
In a 250 mL round-bottomed flask, 2,5-dimethoxytoluene (10.07 g, 66 mmol) and hexamine (20.18 g, 144 mmol) were dissolved in stirred glacial acetic
acid (152 g) with mild heating. On complete dissolution, the heating was discontinued, and concentrated sulfuric acid (15.7 mL, 289 mmol) was added
dropwise from a pipette. Complete addition took about 20 minutes. A colorless precipitate formed, and the suspension was gently heated to its boiling
point over the course of 50 minutes; there was an initial color shift to a vibrant yellow, which quite abruptly developed into a dark red as modest
amounts of gas bubbled out and the solids disappeared. The resulting slightly hazy solution was heated under reflux for 90 minutes, allowed to cool
and stirred at room temperature overnight. The following day, 50 grams of acetic acid was removed by distilling the mixture under reduced pressure.
Water (104 g) was added, and work-up was undertaken immediately.
Initial white precipitate following addition of sulfuric acid
Transient yellow coloration during heating
Reaction mixture after 90 minutes of refluxing
Work-up (1)
The carrot-juice-resembling mixture was extracted three times using ethyl acetate in portions of 50, 40 and 25 grams, respectively. Each extract was
washed with a few grams of water[1] and combined with the others by gravity filtering into a boiling flask through cotton wool. The mixture
was distilled under atmospheric pressure to remove 90 grams of solvent, followed by further concentration under reduced pressure, in a hot water bath.
The slightly viscous, greenish amber residue was placed on a watch glass to evaporate along with a <10 mL portion of methanol used to rinse the
flask.
Because the third organic extraction was observed to leave crystals behind as it evaporated, the post-reaction mixture was extracted again using 45 mL
of DCM. On the next day, residual DCM was observed to have aggregated to the bottom of the separatory funnel with newly formed solids. Shaking the
funnel resulted in two clear layers, of which the lower organic layer was retained and combined with the previous extract for stripping of the
solvent. The initial air-evaporated extracts had evolved into a triphasic slurry of impure crystals and two immiscible liquids (a dense dark oil and a
less viscous orange phase). The residues were combined quantitatively using <20 mL of methanol, and set up for steam distillation. 250 mL of steam
distillate was collected, which contained exactly one gram of mostly colorless[2] crystalline benzaldehyde with a melting point of
82–84°C (lit. 83–84°C[3]). Extraction of the vacuum filtrate using two small portions of DCM gave a further ~100 mg of yellow
material that was added to the remaining impure product.
The remaining impure product was extracted from the water using a single portion of DCM, and stripped of the solvent. Next, it was exhaustively
extracted with several portions of boiling heptanes which were decanted to a 250 mL beaker; the insoluble material was discarded. As the combined
extracts cooled, a significant amount of red oil separated. Removal of the bulk of this oil was effected by treating the hot solution with 1.24 g of
coarsely ground activated charcoal, waiting for most of it to settle, and decanting off the liquid. The decanted portion was then cooled in the
freezer and vacuum filtered to obtain 7.92 grams of a soft, waxy yellow material mixed with specs of impure charcoal. This was (maximally) dissolved
in 27.65 grams of 80% MeOH, and gentle vacuum filtration of the hot mixture followed by freezer-cooling of the filtrate gave, on vacuum filtration,
4.67 g of a beige crystalline material with slight residual stickiness and a melting point of 79–82°C. All of the used charcoal was discarded.
Another recrystallization from 25 grams of boiling heptanes was done, followed by decanting off the solvent at room temperature[4] and
rinsing the crystals with a small portion of fresh solvent. This gave 4.01 grams of crystals melting at 81–83°C.
Additional product (0.78 g) was obtained from combining the residues of evaporated mother liquors with whatever[5] was gained by carrying
out two additional DCM extractions of the post-reaction mixture over the course of five days and recrystallizing twice: first from 5 grams of 80% MeOH
(0.87 g was received), then from a 3.5:1 mixture of heptanes and MeOH (this solvent gave the nicest crystals).
The combined purified yield from the experiment, therefore, was 5.79 g (48.6%).
[1]: This wasn't likely to do much; a combination of brine and bicarbonate solution washings would be more par for the course.
[2]: Some yellow impurity came over toward the end of collection. I suspect that this is due to an increased concentration of either
impurity relative to water, impurity relative to desired product, or a combination of the two. It also seems possible that the culprit is some kind of
volatile degradation product.
[3]: https://isomerdesign.com/PiHKAL/read.php?domain=pk&id=23
[4]: Solubility in heptanes at RT was determined to be around 27 mg/g.
[5]: Next to nothing, most likely.
Concentration of combined ethyl acetate extracts
Crystals forming in evaporating residue
Steam distilled product
Crude product
Heptane-insoluble tar
Charcoal-treated crude product
Impure crystals from 80% MeOH
Fairly pure crystals from heptanes
Experiment 2
In a 100 mL RBF, 2,5-dimethoxytoluene (10.00 g, 66 mmol) and HMTA (18.42 g, 131 mmol) were dissolved in stirred acetic acid (82 g). A solution of 98%
H2SO4 (26.33 g, 263 mmol) in acetic acid (41 g) was added dropwise during 43 minutes. Despite an interruption in stirring that
occurred in the middle of the addition and lasted for several minutes, the overall exotherm exhibited a fairly stable plateau at 35–40°C. When the
addition was complete, the suspension was stirred for 15 more minutes at room temperature before the flask was moved to a heating mantle, fitted with
a Liebig condenser and brought to a boil in ~30 minutes. The dark red solution was refluxed for 150 minutes after which 30 g of 1-butyl acetate and 30
g of water were added. The mixture was then refluxed for a further 120 minutes, allowed to cool back down to room temperature and stirred as such for
20 hours.
Solids forming in reaction mixture toward the end of reflux period
Work-up (2)
A decision to add 25 g (181 mmol) of potassium carbonate was made, and a 50% solution in water was slowly poured in over a period of seven
minutes.[1] The mixture, now brown and thick with solid precipitate, was diluted with 200 mL of water. A layer of undissolved cream-colored
precipitate settled below two clear, immiscible layers of liquid. A bunch of pale, needle-shaped crystals had formed at the liquid-liquid interface
during the time that it took to set up for vacuum filtration, and most of them were isolated by decantation and separate filtration followed by
rinsing with two portions of water. Once dry, the crystals weighed 0.75 g and melted at 83.5–84.9°C.[2] The remaining solids weighed
13.32 grams and consisted mostly of potassium sulfate. Extraction of product from this material was first attempted by decantation and gravity
filtration in boiling methanol, but this approach proved troublesome and was quickly abandoned. The methanolic mixture was diluted with water and
vacuum filtered, and the solid portion was extracted using a total of 22 grams of BuOAc.
More crystals formed in the filtered post-reaction mixture, and a decision was made to distill it in order to remove the organic liquid phase and find
out what would precipitate. Once the produced distillate seemed to merge exclusively with the aqueous phase (i.e. seemed like mostly water), the
mixture was cooled down in a water bath, resulting in an initial mass of pale needles and the more gradual formation of a dark immiscible oil which
eventually solidified. Separation was effected by vacuum filtering the mixture, washing the solids with water and then air-drying them on a watch
glass; documentation for the obtained solids is missing (save for two images), so, unfortunately, there is no mass to report.
Next, the three product-containing liquid partitions (methanolic filtrate, butyl acetate and filtered post-reaction mixture) were combined with the
biphasic distillate and a 10 mL portion of fresh BuOAc—and shaken. The organic layer was retained, washed with two portions (50 g, then 40 g) of 10%
NaHCO3 and a 10 g portion of 25% NaCl. The two solid partitions were added and the resulting solution was dried using 3 grams of anhydrous
magnesium sulfate.
Finally, a bisulfite purification was carried out. To a vigorously stirred solution of potassium metabisulfite (90 g) in water (200 mL), the filtered
organic solution from above was added, followed by 10 mL of methanol.[3] Due to what seems like a remarkable affinity toward butyl acetate
(or something else in it), the formed solid merged with the organic solvent, assuming its liquid characteristics to an uncanny degree without
substantial dissolution. After stirring the mixture overnight, the solids were vacuum filtered out, rinsed with ~10 mL of MeOH and air-dried to a
constant weight of 12.81 g. An additional portion of approximately 400 mg was obtained from stirring the filtrate (incl. methanol rinse) for two more
days and filtering it again.
To decompose the adduct, it was suspended in 175 mL of water with stirring, and aqueous 20% NaOH was added dropwise until, after adding 9.75 g of the
solution, a pH of 10–11 was indicated by universal pH paper. The end point coincided with the sharp evolution of a chlorine green color in the
liquid phase. The mixture was then stirred for 10 minutes and vacuum filtered. The filtered solids were washed with 4–5 portions of water, totaling
100 mL, and air-dried to a constant weight of 6.85 g (54.9%). Melting point 80.9–81.6°C.[4]
[1]: The reason for adding potassium carbonate was to neutralize sulfuric acid, but the approach was poorly thought out; potassium
leads to a bunch of unnecessary sediment, and an incomplete neutralization seems unlikely to do much else.
[2]: Unbeknown to me at the time, the thermocouple I was using was beginning to deteriorate, which seems likely to have caused a
slight distortion here. Nevertheless, I believe that the crystals were quite pure.
[3]: Previous experimental findings imply a high likelihood of this (the addition of a small quantity of MeOH) significantly
accelerating the formation of the adduct. This instance was no exception.
[4]: Measured on the day of posting this update using a digital thermometer meant for cooking; I've had the worst luck with K-type
thermometry of late, and I'm still working on finding equipment that functions properly. The sharpness of this melting point seems indicative of high
purity.
Post-reaction mixture following addition of potassium carbonate
Above mixture following dilution with water
Solids separated from above mixture by filtration
Mostly water depositing on liquid-liquid interface of biphasic distillate
Cooled filtrate after distilling to remove organic liquid phase
Solids separated from above mixture by filtration
Solution of combined crude product drying over magnesium sulfate
Freshly formed bisulfite adduct
Dry bisulfite adduct
End point of adduct decomposition from above
End point of adduct decomposition from side
Purified product
After seeing all of that you may be left wondering "But where's all the thin-layer chromatography?" And, well, the truth is that there is none*; I
weaseled my way out of running a single TLC plate. But the good news is that I did retain samples of almost everything, although I'm having a hard
time deciding on how best to implement them. The idea of finishing these writeups and following them up with some consolidated TLC experimentation
seems most appealing to the master procrastinator in me.
* Whether it counts or not, I did practice the technique last month, and I might as well end with that. The less-than-exemplary result is this
cut-in-half 2.5 x 7.5 cm plate loaded with samples of 2,5-dimethoxybenzaldehyde (A), 2,5-dimethoxy-4-methylbenzaldehyde (B) and
2,5-dimethoxy-4-ethylbenzaldehyde (C), developed using an approximately 3:1 mixture of heptanes:butyl acetate as the eluent, and photographed under
UV-A:
UV-C inverted the fluorescence but revealed no additional information. No staining was performed.
[Edited on 24-10-2022 by Benignium]
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SuperOxide
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Benignium, your work is just pure art (as always). Love it :-)
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Benignium
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Romix - Indeed you are, my prolific friend! 25B-NBOMe is a remarkably receptor-selective and potent psychedelic that can be prepared
from 2C-B by reductive amination of 2-methoxybenzaldehyde. 2C-C and 2C-I can be used in place of 2C-B, respectively yielding 25C-NBOMe and 25I-NBOMe.
The fluorine analog (25F-NBOMe) is more challenging to prepare and likely several orders of magnitude less potent, which would explain the seeming
absence of illicit trade.
The PsychonautWiki is valuable source of information on psychoactive substances from the perspective of harm reduction, provided that one is mindful
of its open collaboration aspect; please check this article on 25B-NBOMe: https://psychonautwiki.org/wiki/25B-NBOMe.
And please try to avoid posting multiple back-to-back replies—it's bad practice! You can edit previous replies to include the same content.
SuperOxide - I'm glad you enjoyed it. Thank you for making me smile!
[Edited on 25-10-2022 by Benignium]
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DocX
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This is extremely impressive. Following your progress, I would probably have given up at least four times during this synthesis thinking I messed it
up and go back to making soap with the kids in a haze of disbelief in my own ability.
You make me want to be a better man.
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arkoma
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It is truly pleasurable (as in almost physical) to read your posts Beningium. Please never leave us!!
"Horridge" LMFAO
"We believe the knowledge and cultural heritage of mankind should be accessible to all people around the world, regardless of their wealth, social
status, nationality, citizenship, etc" z-lib
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SuperOxide
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| Quote: Originally posted by DocX | This is extremely impressive. Following your progress, I would probably have given up at least four times during this synthesis thinking I messed it
up and go back to making soap with the kids in a haze of disbelief in my own ability.
You make me want to be a better man. |
Seriously, right? His work is actually pretty inspiring. lol. I have a lot to learn before I'm on his level, but it's definitely something to aspire
to.
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Benignium
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DocX, arkoma - Thank you for the incredibly nice replies; the positive reception of this thread is rocket fuel for my morale, and
among the highlights of my year!
A small correction to the previous update: the reaction vessel used in b4 E2 was a 500 mL "RBF" (a flat-bottomed
two-necked round boiling flask, to be more precise).
2,5-dimethoxybenzaldehyde
166.18 g/mol
When given the task to prepare 2,5-dimethoxybenzaldehyde from hydroquinone, it would be perfectly understandable if one were to directly set their
sights on dimethylation, followed by formylation of the resulting 1,4-dimethoxybenzene. What I did was set my sights on the search engines of
discussion boards—not because I somehow knew to expect shenanigans, but because frankly I was only beginning to learn about some of the basic
concepts involved. Consequently, I discovered a somewhat novel approach that would prove to be more feasible for me as an amateur and is therefore the
one whose application I'll be describing in this post.
The first phase of this critical deviation from intuition involves the monomethylation of hydroquinone or, more specifically, of 1,4-benzoquinone, via
its reaction with methanol in the presence of a strong acid catalyst to form a hemiketal intermediate that the hydroquinone then reduces, yielding
4-methoxyphenol and more 1,4-benzoquinone.[1][2] Preservation of one of the phenols in this way offers multiple advantages: most
importantly, it creates new opportunities that make introducing a formyl group considerably more manageable later on; precious methylating agent is
conserved; and the inherently insightful process of becoming familiar with an intermediate compound involves, in this instance, a truly pleasurable
scent of subtly phenolic[3] caramel.
Chronologically, if we look at the infographic from earlier, the preparation of 4-methoxyphenol (a1) took place in early May, making it the
very first one of these catalogued steps. As an addition to the premise set by the above paragraph as well as the infographic, this post also kind
of deals with the preparation of the required 1,4-benzoquinone, which took place in April, predating all but religion, March, and Arnold
Schwarzenegger.
[1]: https://worldwide.espacenet.com/patent/search/family/0101884...
[2]: http://www.sciencemadness.org/talk/viewthread.php?tid=9835
[3]: Smoky, but more akin to a fine Islay whisky, as opposed to a campfire.
Quinhydrone (and early attempts to produce 1,4-benzoquinone)
218.21 g/mol (quinhydrone)
108.10 g/mol (1,4-benzoquinone)
Our journey starts with the preparation of 1,4-benzoquinone, accompanied by a profuse bewilderment due to the fact that a seemingly slam dunk method
for the oxidation of hydroquinone[1] did not seem to work very well, producing mostly some strange, dark, crystalline substance whose exact
color seemed impossible to define. Eventually,[2] by using Ctrl+F to search the 27,695 page monstrosity that is Ullmann's Encyclopedia
of Industrial Chemistry for the word "hydroquinone", this Lovecraftian oddity was identified as quinhydrone—a charge transfer complex arising
from the equimolar combination of hydroquinone and 1,4-benzoquinone. This discovery then led to the revelation that the actual benzoquinone
wouldn't be needed, as roughly twice its weight in quinhydrone could be substituted for it, essentially skipping a non-essential but inevitable step
where some of the benzoquinone would react to form quinhydrone anyway. This was simply great, because as I had already learned empirically,
1,4-benzoquinone is quite irritating—not to mention toxic and carcinogenic—in the concentrations of vapor that it lets off at room temperature,
whereas quinhydrone is odorless and in no apparent hurry to get anywhere. And so, I pivoted to preparing enough quinhydrone instead. But trouble was
brewing. Literally.
In my preoccupation with the quinhydrone phenomenon and wondering about how little iodine would be too little, I hardly paid any attention to
the subtle signs of a profound impact that using water as the sole solvent had. In fact, it was only after my second, more successful encounter with
1,4-benzoquinone much later that I would finally learn about what exactly was going on. In essence, the oxidation of hydroquinone by molecular oxygen
in aqueous solutions is prone to producing new substituted species of hydroquinones and benzoquinones that can participate in mixed redox reactions
with the existing compounds, giving rise to yet more new hydroquinones and benzoquinones, semiquinone and superoxide anion radicals, charge-transfer
complexes, and different kinds of condensation products, all with their own physical and chemical characteristics.[3] In other words, an
oxidative degradation which produces tar takes place. Although the rate of this oxidation is dependent on the pH, it apparently does happen at an
appreciable rate when heat is applied, even in the absence of alkali. Catalysts can also accelerate the process, and it's entirely possible that
something as seemingly innocuous as my permanently brown favorite stir bar could have played a part in this sense.[4] What I find
fascinating is that no product was recovered from the attempt to recrystallize the second portion of product during the third workup; this, to me,
seems to imply that pre-existing degradation products alone can effectively consume hydroquinone and 1,4-benzoquinone in proportionally large amounts.
There's a zombie metaphor/simile to be made here.
[1]: https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
[2]: By the time I was working up the second experiment.
[3]: https://inchem.org/documents/ehc/ehc/ehc157.htm#SubSectionNu...
[4]: https://www.eurekalert.org/news-releases/850535#:~:text=Magn...
Experiment 1
A 250 mL two-necked, flat-bottomed round boiling flask was fitted with a thermometer, and in it were placed hydroquinone (10 g, 91 mmol) and ethanol
(30 mL). With mild heating, the mixture was magnetically stirred to obtain a clear, ~35°C solution before iodine (195 mg, 0.8 mmol) was added. With
sufficient heating to maintain the temperature, a dropwise addition of 11.9% hydrogen peroxide (28.63 g, 100 mmol) was performed over a period of
12–22 hours.
[Fig. 1] Ethanolic solution of hydroquinone and iodine
[Fig. 2] Reaction mixture following partial addition of H2O2
Work-up (1)
The reaction mixture was chilled in the refrigerator and vacuum filtered to obtain a mass of black solids with yellow crystals in it. The wet filter
cake was transferred into a 250 mL conical flask with ~150 mL of water, and steam distillation was attempted as a means of extracting the product. As
the mixture was heated, long, yellow needles of the quinone began to form along the short path still head. As the water began to boil, a blockage
began forming in the condenser tube, and the distillation was aborted. Accumulated crystals from the still head were mechanically extracted with the
help of some water and spread onto a watch glass to dry. The amount of distillate collected was meagre, contained only a few crystals of the product,
and was thus discarded. What remained in the flask, if anything, seemed to have decomposed into dark red tar. After air-drying overnight at room
temperature,[1] the obtained product weighed 0.82 grams (8.4%).
[1]: With a vapor pressure of about 0.1 mmHg / 13 Pa at room temperature, the rate of sublimation is going to be significant enough
to warrant avoiding prolonged periods in open air. In this instance, I didn't notice any visually discernible reduction in quantity.
[Fig. 3] Filtered solids added to water
[Fig. 4] Crystals of sublimed 1,4-benzoquinone
Experiment 2
Into a 250 mL Erlenmeyer, there was added hydroquinone (10 g, 91 mmol), followed by water (200 mL). The flask was placed in a cool water
bath[1] and vigorously stirred. Once the solids had dissolved, iodine (45 mg, 0.2 mmol)[2] was added, and the flask was fitted
with a Claisen adapter, an addition funnel, and a thermometer adapter by which a thermometer was suspended so as to measure the mixture below. When
some undissolved I2 still remained after ~80 minutes, the addition of 11.9% H2O2 (28 mL, 101 mmol) was initiated
despite it. During the 55-minute addition, the mixture became somewhat darker and browner, and a modest amount of sparkling black precipitate was
formed. The mixture was stirred for four more hours.[3]
[1]: The goal this time was to more rapidly add the oxidizer while keeping the mixture below 30°C. The exotherm was found to be a
non-issue; the temperature of the mixture never seemed to differ from that of the bath and stayed below 20°C during the entire addition.
[2]: The role of iodine in this reaction is that of a so-called simple catalyst, i.e. it catalyzes the disproportionation of hydrogen
peroxide into water and oxygen. The amount added was therefore viewed as deciding of only the reaction rate and was determined based on the solubility
of iodine in 200 mL of water (which itself was determined as a sufficient amount to dissolve the hydroquinone).
[3]: Oxygen was still being generated after the four hours of stirring.
[Fig. 5] Hydroquinone under water
[Fig. 6] Undissolved iodine floating around in aqueous hydroquinone solution
[Fig. 7] Reaction mixture at the end of peroxide addition
[Fig. 8] One hour after the end of peroxide addition
[Fig. 9] Precipitated quinhydrone settling
Work-up (2)
The mixture was cooled in the freezer for 30 minutes[1] and vacuum filtered. The solids were placed on a watch glass to dry. More crystals
formed in the filtrate, and it was filtered a second time[2] for a total yield of 3.7 g (37.3%) of dry quinhydrone. As a final stab at
producing 1,4-benzoquinone, the filtrate was heated to 50°C and 10 mL of 11.9% H2O2 was added to it in one portion. The mixture
became dark red and then turned brown and opaque over 1–2 hours, after which heating was discontinued. A small amount of nearly black crystalline
sediment was separated by filtration of the cooled mixture and subsequently discarded along with the filtrate.
Recrystallization of the obtained quinhydrone was attempted from water according to literature.[3] 108 mL of stirred water was heated to
66.4°C and quinhydrone was added in small portions until no more would dissolve; 2.28 g was added. Minimal water was then added to afford a clear
saturated solution[4] that was removed from the hotplate and allowed to cool to room temperature.[5] The cooled mixture was
vacuum filtered to obtain 1.81 g (79.4% recovery) of spectacular, long, flat strips that had two large, reflective facets with a golden shine, but
otherwise looked quite black with a subtle green tinge.
[1]: In my particular freezer, this translates to the mixture being cooled to 5–10°C.
[2]: No more than two hours after the first filtration, according to the photos that I took.
[3]: W.L.F. Armarego (2017), Purification of Laboratory Chemicals (8th ed.)
[4]: Solubility in 65°C water was thus determined to be ~2.1 g/100 mL.
[5]: I vaguely recall an undocumented period of cooling in the refrigerator. In any case, cooling below RT is the way to go.
[Fig. 10] Filtered quinhydrone from reaction mixture
[Fig. 11] Second filtration of reaction mixture
[Fig. 12] Recrystallization of quinhydrone from water
[Fig. 13] Alternative lighting
[Fig. 14] Recrystallized product
Experiment 3
Water (150 mL), hydroquinone (30.09 g, 273 mmol) and a solution of I2 (45 mg, 0.2 mmol) in EtOH (1.84 g) were added to a 250 mL Erlenmeyer.
The flask was placed in a 24°C water bath and, with vigorous stirring, H2O2 (95 mL, 343 mmol) was added over a period of two
hours. Stirring was continued for approximately 15 hours.
[Fig. 15] About what you'd expect
Work-up (3)
The reaction mixture was filtered to obtain an unrecorded quantity of quinhydrone. A little over half of the product was dissolved in 750 mL of 65°C
water, and the mixture was cooled to room temperature before vacuum filtering to yield 8.53 g (28.6%) of crystals that had only a dull shine and a
strangely tattered appearance in comparison to the previously recrystallized quinhydrone.[1] Recrystallization of the other half was
attempted from the filtrate of the previous portion, which resulted in the already somewhat murky mixture becoming considerably more brown and opaque.
No crystals formed on cooling; there was observed only a modest amount of brown sediment that clogged the filter when its separation was attempted.
Interestingly, the addition of some hydroquinone to the obtained filtrate resulted in the formation of some quinhydrone-like crystals. On heating,
these too disappeared into the muddy fluid, never to be seen again.
The recrystallized product was combined with the non-recrystallized portion from the previous experiment. The mixture had a melting point of
172–174°C (lit. 173-174°C)[2].
[1]: Despite there being no mention of it in my notes, I distinctly remember adding a calculated amount of the solid material
directly into cool water, and then wondering about the consequences of doing so as the water heated up. Indeed, this would be the most likely
explanation for the malformed crystals.
[2]: https://www.emdmillipore.com/US/en/product/Quinhydrone,MDA_C...
[Fig. 16] Recrystallization of product (macro image)
[Fig. 17] Recrystallized product
[Fig. 18] Crystals from adding hydroquinone to filtered recrystallization liquor
[Fig. 19] Clogged filter paper being bathed in denatured ethanol
Experiment 4
Hydroquinone (20.01 g, 182 mmol), water (60 mL) and a solution of iodine (66 mg, 0.3 mmol) in ethanol (0.92g) were placed in a 250 mL Erlenmeyer. The
flask was placed in a cool water bath, and with the mixture stirred vigorously, 11.9% hydrogen peroxide (26 g, 91 mmol) was added in one portion.
Stirring was continued for several hours[1]
[1]: The documentation is imprecise, but, given the appropriate molar ratio of hydroquinone to H2O2 used, I'd
assume that the liberation of O2 was waited out.
Work-up (4)
The reaction mixture was refrigerated for some hours, and vacuum filtered to yield 15.89 grams (72.8%) of quinhydrone with a melting point of
173–176°C. This was combined with all of the previously obtained product, and the mixture was used without further purification.
[Fig. 20] Filtered quinhydrone from reaction mixture (macro image)
[a1] 4-methoxyphenol
Also called: MeHQ, mequinol
124.14 g/mol
Not much remains to be said about the reaction itself. Regarding the execution, I remain puzzled as to why 1.65 moles of sodium hydroxide would make a
mixture containing 0.84 moles of sulfuric acid as basic as it did; it doesn't seem like sulfuric acid would be consumed to any significant extent, but
judging by the 0.58 moles acetic acid required for neutralization of the excess alkali there seems to be quite a discrepancy. Perhaps the acid reacts
to form sulfonic acid derivatives or hydroquinone sulfate? I have no external reason to believe that there was fault with my measurements. It's worth
pointing out that while proper neutralization of the acid makes the mixture significantly safer to handle, it is entirely optional.
Experiment 1
In a 1000 mL Erlenmeyer flask, hydroquinone (90.09 g, 818 mmol) was dissolved in methanol (464 g) with rapid magnetic stirring, and concentrated
sulfuric acid (45 mL, 844 mmol) was added dropwise in ~10 minutes using a pipette. Quinhydrone (20,02 g, 92 mmol) was then added in small portions,
along with a 20 mL portion of methanol used for flushing it down, and the mixture was heated under reflux for 4 hours and 10 minutes before allowing
it to cool down.
[Fig. 21] Hydroquinone dissolved in methanol
[Fig. 22] Mixture following addition of sulfuric acid
[Fig. 23] Reaction mixture being refluxed
[Fig. 24] Alternative perspective
Work-up
An aqueous 40% solution of sodium hydroxide (66 g, 1.65 mol)[1] was prepared, placed into a pressure-equalizing addition funnel, and added
to the stirred reaction mixture at a rapid dropwise pace. Before half of it had been added, the mixture became too thick to stir magnetically, and
agitation was continued by swirling the flask. The entire solution was added in 30 minutes, during which the temperature of the mixture peaked at
approximately 40–50°C. The flask was stoppered, and the mixture was stored in the dark at room temperature for ~10h, after which its pH was
measured to be strongly basic.[2]. The mixture was distilled in a hot water bath to remove ~280 mL of methanol over a period of about five
hours. It was then diluted by adding 400 mL of water, allowed to cool, and extracted using two 100 mL portions of DCM. The first extraction seemed to
form an emulsion and could only be partially separated, whereas the second portion of DCM was nearly inseparable due to a copious formation of small,
needle-like crystals.[3] The liquids were maximally drained out of the crystal-filled funnel, and the solids were washed with a third 100
mL portion of DCM which was added to, and shaken with, the drained and separated aqueous phase. Following combination of the DCM extracts, the
remaining aqueous phase was made acidic by adding of acetic acid (40 g).[4] This was then extracted with three further 80 mL portions of
DCM.
The funnel contents were emptied into a 250 mL beaker with the help of some water.[5] The solid-containing mixture was then acidified by
adding acetic acid (20 g) and gravity filtered. The solids in the filter were washed with several small portions of water, followed by three 10–15
mL portions of DCM that were separated and combined with all of the previous organic extracts for desiccation by stirring over
CaCl2.[6] After some hours, the pooled extracts were distilled to remove the solvent, leaving ~106 grams of a thick, dark
residue which solidified completely over the next 24 hours.
The waxy residue was distilled under reduced pressure[7] until a yellow hue was observed in the distillate. Among the solidified material
in the collection flask there was a small quantity of clear, slightly viscous liquid which was initially decanted off, but had solidified after some
days in an open beaker and was thus retained separately—this weighed 8.7 grams. Recrystallization of the outright solid portion was attempted
according to literature[8] from water, but too much solvent seemed to be required. Starting with 20 mL (in 100 mL of water), more and more
methanol was added in an iterative sequence of attempts to obtain crystals from a smaller volume of solvent; each time the product would oil out as a
separate layer until, after adding a total of 90-100 grams of methanol, neither oil nor solid was obtained. The mixture was distilled to remove ~70 mL
of methanol[9] and the denser product-containing layer was separated, mixed with toluene (39 g) and distilled to azeotropically remove the
remaining water until only a single liquid phase was observed in the distilled mixture. This was then placed into a freezer. Crystallization ensued,
and the solidified mixture was broken up and vacuum filtered. The filter cake was rinsed with small portions of petroleum ether, which caused more
crystals to form as it mixed with the filtrate. After a second filtration to recover the newly formed crystals, the combined solids were dried to
yield 57.50 grams of off-white mequinol with a peach hue. This, along with an additional 13.96 grams of slightly dimethoxybenzene-smelling
material—obtained from vacuum distilling the previously mentioned 8.7 grams in combination with 9.4 grams of residue from evaporation of the
recrystallization liquor—correspond to a yield of 57.5%.
[1]: Calculated with the intention of neutralizing most of the acid.
[2]: This was both surprising and alarming, as I fully expected to see a pH of <7 and had read beforehand that the phenolic
product would rapidly oxidize in an alkaline environment. It was as much out of resignation as it was out of curiosity that I elected to carry on
without first correcting the pH; I may need to try again, but at least I'd find out more about the extent of the degradation.
[3]: A significant drop in ambient temperature also coincided with the crystal formation and was likely the main cause.
[4]: According to universal pH paper, the solution was neutral after adding ca. 35 grams of AcOH.
[5]: The crystals seemed to generate a soluble discoloration as they came into contact with the fluids that were used to rinse them;
the liquids became quite dark in color while the solids themselves retained a relatively clean appearance.
[6]: It might have been wiser not to include the initial extracts of the basic mixture, and to instead process them separately; I
suspect that they might have contained only 1,4-dimethoxybenzene (a known side product that could be smelled in the extracts) and impurities.
[7]: An aspirator was used, but the pressure of the supplied water was weak and somewhat inconsistent, leading to a rather poor
vacuum and an estimated boiling point of 190–200°C.
[8]: W.L.F. Armarego (2017), Purification of Laboratory Chemicals (8th ed.)
[9]: This seemed to cause a further yellowing of the solution. The methanolic distillate contained some 1,4-dimethoxybenzene which
crystallized as clear, colorless plates following the addition of water; this was discarded.
[Fig. 25] Basified reaction mixture
[Fig. 26] Distillation of post-reaction mixture to remove methanol
[Fig. 27] Ground glass stopper
[Fig. 28] Initial DCM extract drying over calcium chloride
[Fig. 29] Unexpected crystalline precipitate in separatory funnel
[Fig. 30] Isolated portion of above solids; 17.19 grams of mostly Na2SO4
[Fig. 31] Solvent free residue of combined organic extractions
[Fig. 32] Close-up of gradual crystallization
[Fig. 33] Residue after ~24 hours
[Fig. 34] Residue transferred to a beaker
[Fig. 35] Apparatus used to distill crude product
[Fig. 36] Distillation of crude product
[Fig. 37] "Vacuum" distilled product
[Fig. 38] Product crystallized from toluene
[Fig. 39] Distillation to reclaim product from recrystallization liquor
[Fig. 40] Crystals of 1,4-dimethoxybenzene byproduct in diluted methanolic distillate
[Fig. 41] 12.46 g portion of 4-methoxyphenol used in subsequent formylation
[b2] 2-hydroxy-5-methoxybenzaldehyde
Also called: 5-methoxysalicylaldehyde (5-MSA)
152.15 g/mol
272.32 g/mol (bisulfite adduct; potassium salt)
Two particularly popular alternatives exist for the ortho-formylation of 4-methoxyphenol to form 5-methoxysalicylaldehyde: the Reimer-Tiemann, which
employs dichlorocarbene, generated by basic deprotonation of chloroform, as the electrophile; and the more descriptively named magnesium-mediated
ortho-specific formylation of phenols, which proceeds via the formation and predomination of a magnesium bis(phenoxide) complex at a temperature of
95°C, and its subsequent reaction with formaldehyde.[1][2][3][4][5] The former is somewhat
notorious for its tendency to generate an impure product in modest yields, and its practicality is hindered further by the salicylaldehyde product
being quite prone to oxidative degradation, which translates to something of a positive difficulty modifier to the workup; the latter, though less
encouraging to look at on paper, really shines in contrast, being capable of giving excellent yields of material that need not necessarily be purified
past crude isolation.
My replication of the procedure suffers somewhat from a persisting negligence in the handling of phenols, as well as a lack of effort to characterize
the product. Nevertheless, the results indicate that with a bit of practice, a convenient, clean, and reliably high-yielding method is indeed within
the amateur's grasp.
[1]: https://www.sciencemadness.org/whisper/viewthread.php?tid=61...
[2]: https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
[3]: http://www.sciencemadness.org/talk/viewthread.php?tid=10124
[4]: https://doi.org/10.1039/P19940001823
[5]: US6670510
Experiment 1
Magnesium methoxide (6.04 g, 70 mmol) was prepared by placing magnesium ribbon (1.70 g, 70 mmol), methanol (30 mL)[1] and a tiny crystal of
iodine in a 250 mL two-necked, flat-bottomed round boiling flask (equipped with a stopper and a Liebig condenser with a
K2CO3-packed drying tube), and magnetically stirring the mixture overnight on a 100°C hotplate.
The Liebig on the vertical neck was replaced with a water-cooled short path still head fitted with the drying tube, a 25 mL collection flask, and a
dropper bulb used to plug the vacuum port. A solution of air-dried MeHQ (12.46 g, 100 mmol) in dry toluene (87.5 mL)[2] was prepared with
mild heating, and poured into the methoxide-containing flask.[3] The stopper on the angled neck of the flask was replaced with a
thermometer adapter and a mercury thermometer. The dark blue mixture was heated to its initial boiling point at 72°C,[4] and distillate
was collected for 110 minutes until, at 95°C[5], the first of three equal portions of paraformaldehyde (3/9 g, 100/300 mmol) was injected
by temporary replacement of the thermometer assembly with a powder funnel. Following each addition, the mixture was distilled to remove generated
methanol byproduct so as to re-establish the temperature of 95°C.[6] All three portions of PFA were added in 20 minutes, maintaining the
temperature between 93 and 96°C. After the final addition, the temperature temporarily rose to 98.5°C and was brought back down to 95°C within four
minutes. The mixture was maintained as such until an hour had passed from the end of addition, and then allowed to cool down to room
temperature.[7]
[1]: 16 mL was used initially, but solidification of the mixture necessitated the addition of a further 14 mL.
[2]: Dried over 4Å molecular sieves.
[3]: Adding the toluene first and then adding the phenol to the boiling mixture as a solid—or, better yet, as a separately boiled
(i.e. dried and degassed) solution in additional toluene—would likely improve purity and yield.
[4]: The color of the mixture shifted via seaweed green to a swampy brown.
[5]: Ca. 25.6 g of distillate was collected before beginning the addition, at which point the mixture was quite pale and opaque with
precipitate.
[6]: Ca. 9.3 g of distillate was collected during the entire addition.
[7]: Cooling down (and later acidifying) the mixture under a gentle flow of inert gas would likely improve purity and yield.
[Fig. 42] Beginning of magnesium methoxide formation
[Fig. 43] Progression of magnesium methoxide formation
[Fig. 44] Cue to add more methanol
[Fig. 45] Magnesium methoxide <> Solution of mequinol in toluene
[Fig. 46] Mixture of above materials prior to heating
[Fig. 47] Reaction mixture boiling at ≥72°C
[Fig. 48] Apparatus used to perform the experiment
[Fig. 49] Reaction mixture after distilling for 18 minutes
[Fig. 50] Reaction mixture nearing 95°C after distilling for 80 minutes
[Fig. 51] First addition of PFA after distilling for 110 minutes
[Fig. 52] Reaction mixture following third addition
[Fig. 53] Alternative perspective
[Fig. 54] Reaction mixture after maintaining temperature for one hour
[Fig. 55] Reaction mixture at room temperature after cooling down for two hours
Work-up
To the cooled reaction mixture in a cool water bath, there was added ~23% sulfuric acid (30 g) such that the temperature of the mixture was maintained
in the range of 26 to 33°C. There was a transient precipitation of the product as its bright yellow salt form, followed by the emergence of a
biphasic mixture of mostly clear liquids with some debris floating about. The less dense organic layer was separated, and the aqueous phase was
extracted with a further <20 mL portion of fresh toluene. The combined organic solutions were gravity filtered into a 100 mL conical flask where
they were dried over calcium chloride. The drying agent was removed by filtration and rinsed with a bit of fresh toluene. After some initial trouble
with setting up the aspirator vacuum pump, a configuration was achieved which allowed most of the toluene to be distilled off at an approximate
pressure of 47 mmHg,[1] leaving 13.25 grams of a dark reddish-yellow oil that wouldn't crystallize when chilled to -15°C.[2]
11.22 g of this crude material was used in the subsequent methylation.
A gram of the oil was placed onto a watch glass where ~6% of its mass evaporated over 17 hours in open air, after which the smell of toluene was
completely gone and a faint odor resembling methyl salicylate remained. This was steam distilled to obtain a pale-yellow oil which smelled the same
and caused intense, fluorescent staining of the skin. No apparent visual or olfactory changes were observed on storing the sample in open air at 24°C
for several weeks. A fraction of this sample inside a flame-sealed capillary tube did not solidify in the freezer.
By dissolving another gram of the crude material in a solution of potassium metabisulfite (2 g) in aqueous 35% methanol (20 g), decanting the solution
to leave behind some bright red residue that stuck to the glass, and then washing the solution with an arbitrary mixture of toluene and petroleum
ether, there was obtained 0.45 g of a crystalline adduct that formed overnight and was separated by vacuum filtration. A melting point sample was
heated to 300°C; a sharp initial yellowing was observed at ~150°C, followed by a gradual decomposition to leave a tan solid from which a pale-yellow
oil vaporized and collected outside the furnace. Evaporation of the organic washing gave a mostly solid residue with a slight odor of mequinol.
[1]: A 12V diaphgram water pump rated for 17 L/min at 2.8 bar, connected via minimal ø 15 mm tubing to a vertical brass aspirator
with a ~195 mm length of ø 10 mm exhaust tube whose tip (10 mm or so) is immersed in a reservoir of recirculated water. Convenience is greatly
enhanced by a stopcock in the vacuum line and a remote-controlled socket. A major downside with my particular pump is an overheating safeguard which
doesn't allow for lengthy distillations.
[2]: According to Sigma-Aldrich/Wikipedia/Chemicalbook, the melting point of pure 5-MSA is 4°C.
[Fig. 56] Precipitation of product as its magnesium salt
[Fig. 57] Acidified post-reaction mixture
[Fig. 58] Removal of toluene by vacuum distillation
[Fig. 59] Crude product, stripped of most toluene
[Fig. 60] Sample of crude product
[Fig. 61] Front, L to R: bisulfite solution, organic washing, insoluble residue
[Fig. 62] Crystals of adduct in bisulfite solution <> Organic residue
[Fig. 63] Steam distillate
[Fig. 64] Alternative perspective
[c2] 2,5-dimethoxybenzaldehyde
166.18 g/mol
286.35 g/mol (bisulfite adduct; potassium salt)
Finally, the salicylaldehyde intermediate is methylated to give the desired 2,5-dimethoxybenzaldehyde. Dimethyl sulfate comes into its own here, as
the deactivating nature of the benzylic aldehyde moiety can substantially hinder the action of inferior electrophiles (which is not to say that there
aren't safer alternatives). The experimental procedure was based on US3867458.
Experiment 1
In a 100 mL Erlenmeyer, crude 5-methoxysalicylaldehyde (11.22 g, <74 mmol) was dissolved in acetone (38 mL). To the stirred mixture were then added
K2CO3 (12.53 g, 90 mmol) and Me2SO4 (11.5 mL, 121 mmol). The flask was warmed on the 40°C setting of the
hotplate to keep the temperature of the mixture above 25°C as it was stirred for 28 hours. After this time, more acetone (16.5 mL) and
K2CO3 (10 g, 72 mmol) were added,[1] and the mixture was set aside to stand for seven days at ambient outside
temperatures which fluctuated on either side of 20°C. Over the week, the mixture was shaken 3-5 times.
[1]: The point of adding more K2CO3 was to help avoid a situation where carbonate would be depleted, leaving
only bicarbonate which wouldn't deprotonate unreacted phenol. Whether the late addition was beneficial is anyone's guess.
[Fig. 65] Crude 5-MSA, transferred using DCM which is being removed
[Fig. 66] Addition of acetone to crude 5-MSA
[Fig. 67] Reaction mixture following addition of K2CO3 and DMS
[Fig. 68] Stirred reaction mixture at 28 hours
[Fig. 69] Still reaction mixture at 28 hours
Work-up
The reaction mixture was poured in ~500 mL of water and the resulting mixture was stirred prior to extraction with four 50 mL portions of ethyl
acetate.[1] The organic extracts were pooled and distilled in a hot water bath to obtain ~52.6 grams of coffee-colored residue with the
viscosity of water. A solution of K2S2O5 (45 g) in water (100 mL) was added to the strongly stirred residue and,
after a few hours, the resulting thick porridge of crystalline solids was vacuum filtered and the filter cake washed with 33.6 grams of EtOAc to
obtain an off-white solid which wasn't weighed.
The solid was suspended in ~60 mL of water with rapid stirring, and 8.25 g of an aqueous 20% solution of NaOH was added dropwise to bring the pH to
10–11. The alkaline mixture was then kept in the freezer for 16 minutes and vacuum filtered, rinsing the filter cake with water to obtain an
off-white crystalline mass that was dried to a constant weight of 6.31 g. To further purify the product, it was dissolved in 15 g of 70% ethanol,
filtered to remove a small amount of insoluble white solids, and cooled in the freezer obtain a crystalline pudding which was crudely coaxed out of
the flask it was in and vacuum filtered to obtain 5.08 g of needle-like crystals with a melting point of 48.1–48.8°C.[2] Mechanical
losses were gathered using ca. 25 mL of ethanol, and the residue obtained from overnight evaporation was recrystallized from 70% methanol along with
the residue from evaporating the liquor from the previous recrystallization, to yield an additional 0.93 g of nearly colorless crystals melting at
47.9-48.8°C.[2] In total, there was obtained 6.01 grams[3] of purified 2,5-dimethoxybenzaldehyde. Interestingly, there's
practically no odor to it, whereas the commercially obtained counterpart smells quite intensely like some mix of 1,4-dimethoxybenzene and my
grandparents' basement; this implies that the formylation of 1,4-dimethoxybenzene has been deemed more viable commerically/industrially.
[1]: The fourth extract was colorless.
[2]: The readings from this thermocouple were checked against a mercury thermometer; an offset of about -1°C was observed, i.e.
mercury would have given values that more closely correspond to the literature value of 50°C.
[3]: 49.1% based on crude starting aldehyde. 52.2% if accounting for the observed ~6% content of volatile impurity. 36.0% based on
MeHQ.
[Fig. 70] Reaction mixture after a day of stirring and a week of standing
[Fig. 71] RM being poured in water
[Fig. 72] Waxy solid (ostensibly) containing most of the product
[Fig. 73] Dense, immiscible liquid phase
[Fig. 74] Distillation to concentrate pooled ethyl acetate extracts
[Fig. 75] Formation of bisulfite adduct
[Fig. 76] Filtered bisulfite adduct
[Fig. 77] Adduct set up for decomposition
[Fig. 78] End point of adduct decomposition
[Fig. 79] Filtered product
[Fig. 80] Above material after air-drying
The next post (3/5) will focus on the preparation of 2,5-dimethoxy-4-ethylbenzaldehyde!
[Edited on 5-11-2022 by Benignium]
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SuperOxide
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(wisely choosing not to quote your post, otherwise the scroll bar would disappear) I haven't finished reading your post, but the pictures themselves
are absolutely breathtaking. Your photography skills are on par with your organic chemistry skills.
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Benignium
Hazard to Others
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Aptly put! I appreciate you, man!
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