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Author: Subject: A foray into phenethylamines of the Shulgin kind
xdragon
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[*] posted on 8-11-2022 at 03:54


I don't have the exact protocol anymore, but benzoquinone can be fairly easily synthesised by the oxidation of hydroquinone dissolved in IPA by 1 eq. Oxone in aq. solution, catalysed by 10 mol % NaBr and if needed a bit of heating. KBr will likely not work. This may be interesting for people who do not have access to iodine or useful H2O2 concentrations. Completion of reaction is fairly easily judged by disappearance of the ugly dark colour from the quinhydrone complex.

Some literature on which those findings were based:
(1) Yakura, T.; Ozono, A.; Morimoto, K. An Efficient Catalytic Oxidation of P-Alkoxypenols to p-Quinones Using Tetrabutylammonium Bromide and Oxone. Chem. Pharm. Bull. 2011, 59 (1), 132–134. https://doi.org/10.1248/cpb.59.132.

Also, thanks for your quality write-ups and pictures, Benignium. I'm getting excited for the 4-Et-2,5-DMBA, I got some of the acetophenon but haven't had the time to deal with it yet.


[Edited on 8-11-2022 by xdragon]

[Edited on 8-11-2022 by xdragon]
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Benignium
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[*] posted on 8-11-2022 at 21:46


You're most welcome, xdragon! :)
Great contribution! I've also wondered about the utility of persulfates in this regard, but unfortunately, I haven't looked into it yet.



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[*] posted on 24-11-2022 at 19:33


I'd like to formally welcome everyone to what could become the longest page on Sciencemadness! Not particularly desirable, but then again, neither are the world's longest fingernails, and yet someone has to have them.


2,5-dimethoxy-4-ethylbenzaldehyde
194.23 g/mol




This process of forming 2,5-dimethoxy-4-ethylbenzaldehyde,[1] while reasonably established and straightforward, involves some elements that I found quite intimidating to plan for: in between the more familiar steps of methylation and formylation, there were two classical manipulations that, aside from being efficient in forming the desired alkyl substituent, coincidentally displayed tendencies to demethylate the neighboring methoxyl on the side. Fortunately, ventures outside PiHKAL to browse the usual discussion boards revealed that improved results could be obtained via simple modifications to make the reaction conditions milder.
Moreover, reports of unpredictability and poor yields, from those who had performed the final conversion to an aldehyde, had left me anticipating more of an eventual impediment. However, I was delighted to find out that my impression was substantially inaccurate.

[1]: PiHKAL: #24 2C-E. https://isomerdesign.com/PiHKAL/read.php?domain=pk&id=24


[b1] 1,4-dimethoxybenzene
138.16 g/mol

The methylation of 4-methoxyphenol seems to be about as pleasant as methylations get: the phenol is readily converted, and not terribly fussy when it comes to oxidation, allowing for good yields of a remarkably fragrant[1] product, and doubtlessly the most satisfying substance that I've steam distilled to date.

[1]: The odor is quite unique, but there's something very familiar about it. I suspect that much of this familiarity stems from its resemblance to some species of clover that was (or were) abundantly present in my childhood.


Experiment 1
In a 250 mL round-bottomed flask, 4-methoxyphenol (20.16 g, 162 mmol) was dissolved in acetone (46 mL). Potassium carbonate (27.50 g, 199 mmol) was added to the resultant solution, and the mixture was stirred for 50 minutes prior to adding dimethyl sulfate (20.2 mL, 213 mmol). The mixture was then heated to reflux and shortly allowed to cool back down.[1] Stirring was continued for 20 hours,[2] after which there was a four-hour period of further refluxing. The mixture was allowed to stand for a further 42 hours[2] before the caked solids were broken up by adding, roughly 30 minutes apart, two 10 mL portions of water and an aqueous 10% solution of sodium hydroxide (4.1 g, 103 mmol).

[1]: My intention was to keep refluxing the mixture, but my mantle didn't register the low power setting that I tried to use, and heating was thus discontinued by accident.
[2]: At ambient outside temperatures, fluctuating on either side of 20°C.


[Fig. 1] Solution of MeHQ in acetone being stirred over K2CO3


[Fig. 2] Above mixture after 26 minutes of stirring


[Fig. 3] Reaction mixture following addition of DMS


[Fig. 4] Above mixture after 23 hours, during fourth and final hour of reflux


[Fig. 5] Caked reaction mixture following addition of 10 mL of water




Work-up (1)
After the solid mass in the reaction vessel had been broken up, and the suspension had been stirred for a while, the mixture was vacuum filtered. The filtered solids were washed with a few small portions of acetone. Acetone was then removed from the filtrate by boiling/evaporation under vacuum — initially without heating, until the temperature of the filtrate had reached ~0°C, and then on a 100°C hotplate until it reached 10°C. The mixture was vacuum filtered and the filter cake was dried overnight in open air to yield 19.40 grams (86.5%) of the crude product as brown platelets.

The brown material was mostly dissolved in 25 g of 36–40°C heptanes, leaving 0.53 grams of an insoluble tar in the flask. The flask was rinsed with 5 grams of fresh solvent that was gravity filtered through cotton wool along with the previous portion. The mixture was allowed to stand in a beaker, under a perforated piece of cling film, until it had lost ~11 grams of its mass. This was then cooled to somewhere below 0°C in the freezer, and vacuum filtered to obtain 17.45 g (77.8%) of cream-colored crystals.

Finally, steam distillation of the product from 350 mL of water was attempted. Initially, the short path still head that was used had cool water running through the condenser, which rapidly caused it to become clogged. Using 46°C condenser water (which gradually warmed up to 54°C on its own) allowed the steam distilled product to remain fluid until it was deposited, but necessitated the use of a jointed collection flask as some vaporized product also came over. Once the impure mixture had been depleted of product, the collected distillate was warmed to melt the solidified product, and pitched into a beaker. Filtration of the solidified product gave, after 18 hours of air-drying, 14.25 g (64.1%)[1] of 1,4-dimethoxybenzene as colorless, crystalline chunks.

[1]: A significant portion of the obtained product was lost to evaporation.


[Fig. 6] Post-reaction mixture after breaking up of caked solids


[Fig. 7] Solid product precipitating from vacuum filtrate as acetone boils off


[Fig. 8] Impure crystals of 1,4-dimethoxybenzene


[Fig. 9] 1,4-DMB crystallizing from heptanes <> Heptane-insoluble tar


[Fig. 10] Steam distillation of impure product


[Fig. 11] Premature freezing of steam distilled 1,4-DMB


[Fig. 12] Deposition of gaseous product in receiving flask


[Fig. 13] Purified 1,4-dimethoxybenzene




Experiment 2
In a 1000 mL two-necked RBF, there was placed water (395 mL) and NaOH (18.40 g, 460 mmol). To the stirred, degassed[1] alkaline solution, a separately prepared solution of mequinol (38.15 g, 307 mmol) in acetone (50 mL) was added. Lots of white solid precipitated, and remained undissolved until the addition of a further 50 mL of acetone (somewhat surprisingly) redissolved most of it. Me2SO4 (38 mL, 400 mmol) was then added from a separating funnel at a rapid dropwise pace; the mixture became opaque with precipitate, and the stopcock was fully opened to allow a more exothermic reaction to prevent any solid from negatively affecting the weak magnetic stirring of the heating mantle. A less dense, immiscible liquid phase formed, and the mixture was stirred for a further 4 hours until the formed product had crystallized.

[1]: Degassing was performed by pulling an aspirator vacuum over the stirred mixture twice, each time maintaining it for 5 minutes before normalizing the pressure using argon.


[Fig. 14] Appearance of poorly soluble 4-methoxyphenolate


[Fig. 15] Dissolution of phenolate due to additional acetone


[Fig. 16] Reaction mixture following addition of DMS


[Fig. 17] Crystalline product in alkaline post-reaction mixture




Work-up (2)
NaHCO3 (5 g, 60 mmol) was added to neutralize excess hydroxide, and a direct steam distillation of product from the reaction mixture was attempted. 60 mL of the initial distillate was collected (until two immiscible liquid phases were observed in the condensing vapor) and moved aside.[1] Once distillate was being collected at 90°C, the condenser water was heated up to 50°C, and the distillation was continued until (after collecting ~400 mL) no more product was observed in the distillate.

The steam distillate (collected directly into a separatory funnel) was extracted with dichloromethane — using just enough to dissolve all of the solid product, followed by a second portion of just a few milliliters. Most of the solvent was then atmospherically distilled off in a warm water bath prior to continuing its removal for a moment under reduced pressure. On cooling, the mixture crystallized partially, and it was poured into a recrystallization dish where it was stirred around by hand, under a steady flow of air, until there was obtained a crunchy solid that seemed perfectly dry. The dish was covered with a sheet of paper towel and kept as such for a few hours to afford 38.08 grams (89.7%) of a colorless, crystalline product melting at 54.3–56.6°C (lit. 54–56°C).

[1]: I believe that I discarded this head portion, but there are no records of its fate.


[Fig. 18] 1,4-dimethoxybenzene crystallizing from saturated DCM




[c1] 2,5-dimethoxyacetophenone
180.20 g/mol

Next, the 1,4-dimethoxybenzene is subjected to a classic Friedel-Crafts acylation — acetyl chloride is treated with aluminium chloride to form a strongly electrophilic acylium carbocation that gets attacked by the aromatic ring, yielding an arenium carbocation that then gives up a proton, thus re-establishing aromaticity, generating hydrogen chloride, and regenerating aluminium chloride.

The presence of HCl and AlCl3 makes for a harsh environment that is capable of methoxyl cleavage, giving rise to a 2-hydroxy-5-methoxyacetophenone side product. The reported yield of 2,5-dimethoxyacetophenone in PiHKAL is 77.8%, which is far from terrible, but seems possible to improve upon by taking more time to perform the reaction at lower, more controlled temperatures; a report by the Hyperlab user Pine_tar[1] seemed to suggest that a dropwise addition during active cooling in an ice bath, followed by maintaining the reaction mixture at 4°C for a further six hours, would produce next to no phenol. My intention was to find out, but my quest for evidence had its fair share of flaws.

My first experiment appeared to have been quite successful, up until a rather farcical vacuum distillation which compromised the yield as well as its purity. Luckily, I still had a bunch of mequinol, whose methylation to provide for a second experiment was no issue.

As an unwelcome surprise, I found my sample of aluminium chloride to be quite contaminated, from having completely eroded the material that was serving as the cap liner of the storage (and retail) bottle. With no real options to remedy the situation at hand, I ended up using the (crudely mechanically cleaned) contaminated material. Fortunately, it turned out to be viable, and I eventually decided to use it for the second experiment as well.

[1]: https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...


Experiment 1
In a 250 mL round-bottomed flask, in an ice bath, acetyl chloride (10 g, 127 mmol) was pipetted as a slow stream to a stirred suspension of aluminium chloride (17.63 g, 131 mmol) in DCM (50 mL). A separately prepared solution of 1,4-dimethoxybenzene (13.71 g, 99 mmol) in DCM (33.5 mL) was then pipetted in dropwise over ~15 minutes.[1] The mixture was stirred for a further 126 minutes, until all of the ice in the bath had melted,[2] before being stored for 4 hours in the refrigerator, followed by 20 hours in the freezer, below -20°C.

[1]: Both additions were quite exothermic, producing plooms of vapor as solvent boiled off. For the addition of the benzene in particular, the use of an addition funnel would have been ideal.
[2]: The temperature of the reaction mixture at the time of its removal from the bath was ~6°C.


[Fig. 19] Aluminium chloride of questionable integrity


[Fig. 20] Above aluminium chloride under dichloromethane


[Fig. 21] Reaction mixture following addition of acetyl chloride


[Fig. 22] Reaction mixture after adding ~20% of all 1,4-DMB


[Fig. 23] Reaction mixture after adding all 1,4-DMB




Work-up (1)
The chilled reaction mixture was quenched by pouring it into a 250 mL separatory funnel containing 125 mL of cool water; there was an exothermic reaction, and some DCM boiled off. Once the exotherm had subsided, the biphasic mixture was shaken, and the organic layer was harvested. Two more extractions were performed using 10–15 mL portions of DCM, and the combined DCM partitions were washed with three 20 mL volumes of 5% aqueous NaOH.

The organic extract was concentrated by distillation from a warm water bath to afford 28.63 grams of a clear, brown liquid that was distilled under aspirator vacuum. An initial 1.49 g of a low-boiling, low-viscosity fraction with a uniquely sweet and hydrocarbonesque smell was collected (and allowed to evaporate). Following the largely unsuccessful vacuum distillation and a subsequent remedial steam distillation,[1] there was obtained, by extraction using DCM, 14.93 g (≤83.5%) of a discolored liquid with a faint, agreeable aroma.[2]

Acidification and DCM extraction of the pooled alkaline washes gave, on evaporation, ~70 milligrams of an oily, yellow residue with a pleasant odor which resembled a mixture of carrot and root beer. This was discarded.

[1]: The vacuum line was leaking, which led to some visible scorching of the crude product. The leak was located and wrestled shut by hand, which caused an improperly tightened connection on the water pump to loosen and eventually become disconnected near the end of the distillation, spraying water in my face and allowing a backflow of water into the distillation apparatus. Some of the collected distillate was sucked back into the distillation flask with water, and some (<20%) was ejected through the vacuum line as that water then flash boiled. Fortunately, the water was pure, and none of the glassware broke. The dark red oil in the distillation flask was steam distilled to reclaim some of the sucked back product.
[2]: Bearing resemblance to unsubstituted acetophenone as well as 2,5-dimethoxytoluene, with a definite presence of some unreacted 1,4-dimethoxybenzene.


[Fig. 24] Reaction mixture, fresh out of the freezer


[Fig. 25] Pooled DCM phases


[Fig. 26] L to R: Alkaline washes, DCM-extracted aq. mixture, DCM extract


[Fig. 27] Concentrated DCM extract prior to vacuum distillation


[Fig. 28] Aftermath of blundered vacuum distillation




Experiment 2
A 500 mL two-necked round boiling flask was set up in an ice bath,[1] and a powerfully stirred suspension of AlCl3 (38.69 g, 290 mmol) in DCM (109.6 mL) was materialized inside it. Using a pipette, AcCl (16.8 mL, 236 mmol) was added dropwise over 10 minutes, and the mixture was then allowed to stir for a further two minutes or so before commencing the dropwise addition of a solution of 1,4-DMB (30.06 g, 218 mmol) in DCM (71.5 mL) from a 250 mL addition funnel. After 20 minutes, the addition was paused; the reaction mixture was allowed to cool for 5 minutes, and an additional portion of AcCl (3.1 mL, 44 mmol) was pipetted into the mixture.[2] The addition was then resumed for 75 minutes before pausing again to re-establish the magnetic stirring that had failed up to 10 minutes prior.[3] After about an hour had passed, with the stirring enabled once more, the remaining ~3 mL of solution was added from the funnel over a period of 9 minutes. Two hours after completing the addition, the cooling bath temperature was measured to be 6.5°C, and more ice was added. Stirring was then continued for 40 minutes.

[1]: Water was recirculated down the sides of the flask from below crushed ice using a submersible 12V water pump.
[2]: This portion of acetyl chloride was to be included in the initial addition, but there was a miscalculation. Whatever impact this late addition had doesn't seem to have been terribly detracting.
[3]: A DIY stirrer (elaborated on below) was used to agitate the mixture. Its distance from the ice bath was minimized by using an opportunely proportioned Donald Duck pocketbook as a spacer underneath it. An unforeseen consequence of this was the swelling that took place as the comic absorbed droplets of condensation falling from the underside of the bath, eventually jamming the stirrer. This meant that, for ≤10 overlooked minutes, the benzene was added to a stationary mixture. Not great, but as it turned out, not terrible, either.


Work-up (2)
The reaction mixture was poured in 300 grams of crushed ice, and the resulting biphasic mixture was stirred for 15 minutes. The dense organic phase was collected, and the aqueous phase was extracted twice more with 30 mL portions of DCM. After combination, basic washing with aqueous 5% NaOH (3x40 mL), and distillation of the extracts to remove the solvent, a residual amber liquid was obtained from the organic extract. This was then distilled under reduced pressure at ~170°C to yield 30.45 g (77.8%) of a yellow oil with a measured density of ~1.14 g/cm3 at 20°C,[1] and a familiar, faint aroma which implied a total absence of the starting material. This product was used in the subsequent synthetic step.[2] 5.13 g of a dark brown oil was retained from the distillation flask, but not processed further.

Acidification and organic extraction of the pooled alkaline washes gave a little over 1.5 grams of a yellow solid that had the previously encountered odor of root beer and carrots, a tendency to fuse with polystyrene, and a wide melting point range of 37–45°C; this was the crude 2-hydroxy-5-methoxyacetophenone side product.[3]

[1]: Fisher Scientific: Literature value of 1.1300 g/cm3. https://www.fishersci.com/shop/products/2-5-dimethoxyacetoph...
[2]: The subsequent reduction took place (starting) 49 hours after this vacuum distillate was photographed (fig. 35) and stored in a 100 mL amber glass bottle. Strangely, when I proceeded to pipette it into the reduction mixture, I saw that it had become quite dark and brown in color. The remaining portion darkened further as time progressed, and was combined with the visually unchanged product from the first experiment pending a second distillation.
[3]: The sample whose melting point I report had been stored in a polystyrene cup for a month, crudely scraped off of the maimed plastic, stored in a cling-film-covered 25 mL beaker for two months, filtered as a solution in minimal MeOH, and obtained as a waxy residue on a watch glass (fig. 34) following the evaporation of said MeOH.


[Fig. 29] Reaction mixture next to crushed ice


[Fig. 30] Reaction mixture being poured in crushed ice


[Fig. 31] Quenching mixture being stirred


[Fig. 32] Merged organic partitions <> Aqueous partition


[Fig. 33] Combined alkaline washes being acidified


[Fig. 34] Crude phenolic side product


[Fig. 35] Freshly vacuum distilled 2,5-dimethoxyacetophenone




[d1] 2,5-dimethoxy-1-ethylbenzene
166.22 g/mol

Reduction of the acetyl moiety to obtain the desired ethyl substituent is commonly performed in one of two ways: via the Clemmensen reduction, which employs amalgamated zinc and hydrochloric acid; or by using the Wolff-Kishner reduction where, in strongly basic conditions, a deprotonated hydrazine condenses with the carbonyl carbon, eliminating water to form a hydrazone intermediate whose diimide tautomer collapses on deprotonation, liberating N2 and affording a carbanion that is then rapidly protonated. Both methods share the tendency to cleave methoxyls. Although I chose the latter, I would at some point like to attempt using the Clemmensen on the surplus of produced acetophenone, to find out if the mercury can be omitted for results that are comparable, or perhaps replaced by another alloy, such as one that contains zinc and gallium.

In PiHKAL, the described procedure takes place in triethylene glycol, and the reaction mixture is refluxed at 210°C for 3 hours. This has been criticized as too harsh for 2,5-dimethoxyacetophenone, and cited as the primary reason for the meager reported yield of ≤22.0 g (≤23.9%) of 2,5-dimethoxyethylbenzene from 100 g (555 mmol) of the starting material, with an additional 28 g (30.4%) recovered via isolation and remethylation of the 2-ethyl-4-methoxyphenol side product. As I had no reason to dispute these claims, I decided to plan and execute accordingly.

For my experiment, I opted to go with monoethylene glycol, as that was what I had on hand, having neglected to acquire beforehand the diethylene glycol which others seemed to have preferred. I surmised that with its boiling point of 197°C, the monomer would prove advantageous in helping to ensure that the mixture doesn't get too hot when it boils, and, after seeing the results, I believe that I was largely correct. It turned out that my issues lay elsewhere.

The very first issue encountered was the poor solubility of alkali in MEG. NaOH was chosen over the similarly soluble KOH due to its lower molecular weight and higher apparent purity,[1] and a a small quantity of water, extrapolated from documented instances of the use of hydrazine hydrate, was incorporated with the goal of achieving a consistency that wouldn't overwhelm the modest torque and magnetic power of my heating mantle.[2]

The second issue has to do with a problematic foaming, which, by some divine intervention, persisted on the cusp of ruining things, yet never escalated. The foam appeared to consist of bubbles that were, for the most part, remarkably small, and as someone who enjoys Guinness enough to occasionally purchase it in cans,[3] my immediate thought was that perhaps I was witnessing the evolution of nitrogen — and this would seem to make some sense timing-wise. As to the extent to which nitrogen causes or exacerbates the foaming, I can only guess; it's also possible that the foaming was more or less specific to the use of MEG, or that my particular MEG, obtained via the fractional distillation of an engine coolant, contained culpable contaminants (this could also explain the pronounced yellowing on dissolution of NaOH, which struck me as odd). In any case, I'd like to learn how to prevent the foaming, since it clearly prolongs the contact of glassware with the highly caustic (wet) reaction mixture.

[1]: My new (i.e. old, but unopened) sample of KOH turned out to be quite green for some unknown reason. The moisture content of KOH also tends to be higher.
[2]: Normally, I would have resorted to using my trusty Corning hotplate, but, unfortunately, we developed a prohibitive fault during the summer. The hotplate remains in disrepair to this day, but the void in its place has inspired some nifty solutions, namely the incorporation of PC-fan-based DIY magnetic stirrers in conjunction with accurately adjustable hot water baths utilizing a sous vide immersion circulator.
[3]: Guinness is a beer that is known for its fine, creamy effervescence. To achieve this, the cans are pressurized by the inclusion of liquid nitrogen inside a "floating widget" — a cryptic sphere which inspired my curiosity. Shout-out to Google.


Experiment 1
Monoethylene glycol (126 mL) was situated in a 250 mL two-necked round boiling flask, and to it, in an ice bath and with magnetic stirring, NaOH (29.95 g, 749 mmol) was added in portions, along with some water (7.35 g in total) to aid its dissolution. A sufficiently stirrable mixture was pursued for nearly five hours: not everything dissolved, and the subsequent addition of hydrazine sulfate (32.86 g, 253 mmol) had no perceivable effect on the high difficulty of agitating the mixture; a desireable thinning was achieved by immersing the flask in a 60°C water bath, and once the bath temperature had been brought up to 80°C, 2,5-dimethoxyacetophenone (14.64 g, 81 mmol) was added via pipette. The flask, fitted with a Liebig condenser, was then moved into a 1000 mL heating mantle where it was immediately heated toward reflux with magnetic stirring. After refluxing the mixture for 30 minutes, the heating was discontinued for two hours[1] prior to replacement of the Liebig with a water-cooled short path still head and the initiation of a delicate distillation to remove water: on boiling, a ~120°C foam appeared, and promptly climbed into the fractionating portion of the still head, despite attempts to suppress it by adding more MEG (20 mL was added in total) from a separatory funnel, as well as adjusting insulation and the application of heat.[2] Fortunately, the foaming readily equilibriated such that it never reached the condenser, and after observing no erratic behavior for three hours, the distillation was left to run unattended for two consecutive three-hour periods.[3]

After the six-hour period, the mixture was no longer foaming or boiling; the collection flask was emptied,[4] and heating was increased to raise the temperature of the mixture to 140–150°C, resuming the collection of distillate. After an hour, with the mixture now at ~170°C, only intermittent condensation of 140°C vapor took place in the still head, and the condenser was emptied of most water before incrementing the heat. Soon, the collection of distillate picked up again (to a rate of approximately one drop every two seconds), and a coolant tube was repurposed to observe gas exiting the system at a leisurely pace[5] as the collection temperature climbed past 180°C, eventually reaching 197°C before the reoccurrence of foaming made the short-lived distillation of glycol unsustainable. Combating the foam by adding fresh MEG (10 mL) proved futile once again, and the heating was stepped down, maintaining the mixture at ~190°C until 90 minutes had passed since distillate was first collected at >180°C. At last, the heating was discontinued, and, after concerted cooling of the reaction mixture in air and in water: the workup.

[0]: The temperature of the reaction mixture was exclusively monitored by measuring the outside surface of the flask using an IR thermometer. Hence, the reported values are crude approximations.
[1]: The duration of an external activity.
[2]: Adding an anti-foaming product containing emulsified silicone (for distilling spirits) crossed my mind since I had it on hand, but I refrained as I wasn't absolutely certain of its compatibility; such a strategy seems worth exploring in the future, if need be.
[3]: The foaming was still taking place three hours into this period of six hours, but had completely subsided during the second half.
[4]: 23.27 grams of distillate had been collected overnight/in total.
[5]: The escaping gas was most likely nitrogen. Dozens of bubbles were observed until its evolution appeared to cease, long before the heating did. Volumetric measurement of this gas should provide some worthwhile insight relating to the overall progression of the reaction.


[Fig. 36] Initial portion of NaOH being stirred under MEG


[Fig. 37] Later state of the above mixture after adding more NaOH


[Fig. 38] Mixture following addition of 2,5-dimethoxyacetophenone


[Fig. 39] Reaction mixture after 15 minutes in heating mantle


[Fig. 40] After 30 minutes in heating mantle; beginning of reflux


[Fig. 41] Reaction mixture after refluxing for ~15 minutes


[Fig. 42] Threat of foaming over just as the 30-minute reflux is up


[Fig. 43] Reaction mixture cooling down


[Fig. 44] Equilibriation of foaming


[Fig. 45] Overnight distillate


[Fig. 46] Reoccurrence of foaming


[Fig. 47] Ostensible nitrogen exiting the apparatus


[Fig. 48] Post-reaction mixture cooling down




Work-up
600 mL of cold tap water was placed in a 1000 mL beaker, and the remaining cooled reaction mixture was poured in, followed by the pooled distillates (50 mL). The resulting mixture was stirred for a while and suction filtered into a separatory funnel through cotton wool. The filter was rinsed with several small portions of C7H16 (totaling 50 mL). After shaking the funnel and isolating the organic layer of rinses, two more 50 mL portions of heptane were used to extract the aqueous mixture, and the combined organic extracts were washed with a single 25 mL portion of water, which was deposited in the aqueous partition. The heptane was removed via distillation at a reduced pressure, leaving 11.69 grams of a yellow liquid with the viscosity of water and a strong, remarkably natural[1] carrot aroma with a hint of menthol. An exhaustive steam distillation (which took about three hours) gave 11.31 g (83.8%) of a slightly volatile,[2] perfectly colorless, dense and immiscible liquid phase via organic extraction of the distillate (140–150 mL) using three portions of DCM (10, 5 and 5 mL).

The aqueous partition was made acidic by addition of 33% HCl (45 g)[3] and extracted using three portions of DCM (30, 20, and 20 grams). The pooled extracts were treated with saturated aqueous NaHCO3 (20 g of ~10% soln.) prior to distilling off most of the solvent. After further evaporation on a watch glass, 2.20 g of an amber residue was obtained, which had the viscosity of sulfuric acid and a pleasant, sweet and phenolic carrot aroma. This was stored on the watch glass, at 24°C, for 22 days, during which time it had darkened further and lost ~8% of its mass (down to 2.02 g), before steam distilling it to collect 0.85 grams of a nearly colorless material, with properties[4] as before, floating on ~65 mL of distillate.

[1]: A clean and distinctive raw carrot profile, accompanied by the earthy, moldy character that I associate with some carrot farmers' cellar-like storage conditions. Interestingly, there's a clear resemblance between this and the comparatively subtle earthiness of the methyl homolog, 2,5-dimethoxytoluene.
[2]: The material appears to evaporate; the rate of evaporation seems slower than that of 1,4-dimethoxybenzene or 1,4-benzoquinone, but still significant.
[3]: After adding 40 g of the acid, a pH of 8–9 was measured.
[4]: Viscosity, odor, and gradual darkening on air exposure.


[Fig. 49] Pooled distillate and diluted post-reaction mixture


[Fig. 50] Crude phenolic side product <> Crude neutral main product


[Fig. 51] Steam distillation of desired product


[Fig. 52] Purified 2,5-dimethoxyethylbenzene


[Fig. 53] Steam distillation of phenolic side product




[e1] 2,5-dimethoxy-4-ethylbenzaldehyde
194.23 g/mol
314.40 g/mol (bisulfite adduct; potassium salt)

To formylate the finished benzene, I decided to attempt the Duff reaction, despite anecdotal evidence of impracticality,[1] as an interesting way to gain some initial material to experiment with; the achievement of a worthwhile conversion seemed to require more specialized methods. However, my expectations for the Duff were pleasantly exceeded, and, instead of attempting something different, I believe that a repeat experiment is appropriate, somewhere down the road.

[1]: (Hyperlab) Pine_tar: Purified yield of 40.5%. https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...


Experiment 1
To a magnetically stirred solution of 2,5-dimethoxyethylbenzene (5.00 g, 30 mmol) and hexamine (8.46 g, 60 mmol) in acetic acid (39.08 g), in a 100 mL round boiling flask, there was added dropwise (in 40 minutes) a solution of 98% sulfuric acid (12.08 g, 121 mmol) in acetic acid (28.1 g) via a 250 mL addition funnel. The resulting suspension of white precipitate was stirred for a further 10 minutes, after which the flask was placed into a 1000 mL heating mantle, furnished with a Liebig condenser, and, with stirring, heated under reflux for 120 minutes. Next, the heating was discontinued, and the mixture was allowed to cool below its boiling point before replacing the condenser with a short path still head that was used to remove acetic acid (~33 g) by distilling the mixture for about 30 minutes. The Liebig was then reattached for the revival of reflux, and through it was added 1-butyl acetate (17.34 g), followed by a careful addition[1] of water (20 g) some five minutes later. The mixture was refluxed for a further 100 minutes[2], allowed to cool, and stirred at room temperature for 15 more hours.

[1]: Water and 1-butyl acetate form a low-boiling azeotrope which can boil quite violently.
[2]: During this time, the color of the mixture shifted from a rather dark brownish red (fig. 58) to a considerably lighter shade of reddish amber (fig. 59).


[Fig. 54] Solution of 2,5-dimethoxyethylbenzene and HMTA in AcOH


[Fig. 55] Above mixture following addition of sulfuric acid in AcOH


[Fig. 56] Beginning of reflux


[Fig. 57] Reaction mixture following addition of butyl acetate


[Fig. 58] Reaction mixture following addition of water


[Fig. 59] End of refluxing




Work-up
A small quantity of a pale, needle-like precipitate had formed in the mixture, and was redissolved by adding 10 g of water. The mixture was set aside for about three hours before it was poured into a separatory funnel, rinsing the flask with some water and butyl acetate. The organic phase was separated and combined with two 15-gram portions of BuOAc that had been used to further extract the aqueous mixture. The organic mixture was treated with aqueous solutions of 25% NaCl (9 g), 10% NaHCO3 (9x10 g), and 25% NaCl again (5.5 g), followed by drying over 0.98 g of MgSO4.

0.10 grams of the desiccated extract was placed on a watch glass to evaporate, leaving approximately 10 milligrams of a clear, yellow oil that wouldn't crystallize spontaneously, even after tenacious rubbing with a glass rod. Interestingly, an immediate solidification to a waxy consistency was observed when the oil came in contact with liquid water. A sample of this semisolid material was fought into a capillary tube with the help of a second, thinner capillary tube, and a melting point range of 35.0–42.7°C was determined.

The remaining extract was concentrated by distilling off ~25 g of solvent and cooled back down to room temperature. A freshly prepared solution of potassium metabisulfite (45.25 g) in water (100 g) was added to the vigorously stirred solution of the crude product. After about 20 minutes, the mixture began rapidly thickening with the appearance of a solid adduct. The resulting porridge was stirred overnight (ca. 12 hours) and vacuum filtered. The filter cake was rinsed with some butyl acetate and air-dried on a watch glass to yield 7.33 g of a nearly white solid.

The dried adduct was suspended in 155 mL of stirred water in a 250 mL beaker, and the mixture was basified to a pH of 10–11 by dropwise addition of an aqueous 20% solution of NaOH (5 grams of the solution was used); the end point coincided with the evolution of a green hue. The suspension of benzaldehyde was stirred for five minutes or so, and instead of vacuum filtering it, butyl acetate was added dropwise: 20.58 grams was added, with the initial 2–3 grams being sufficient to dissolve everything, forming immiscible, milky droplets. The biphasic mixture was shaken in a separatory funnel and left to stand for 26 minutes before collecting the organic layer and extracting the alkaline mixture with two more portions of the ester (13 g, then 11 g). The combined organic extracts were washed with water (2.7 g) and 25% NaCl (10 g), followed by drying over 1.02 g of MgSO4 until, after 30 minutes, the solution was clear.[1] The extract was gravity filtered through cotton into a 100 mL round boiling flask along with a small portion of BuOAc used to rinse the flask and the desiccant, and most of the solvent was removed by distillation at standard pressure.[2] The remaining solution was transferred onto a watch glass where the complete evaporation of volatiles gave 4.13 grams (70.6%) of crunchy, unevenly discolored chunks of a glassy solid with a delightful odor of an obscure fruitiness coupled with the generic character of freezer burn on a dairy-based ice cream; this had a melting point of 45.5–47.9°C (lit. 47–48°C). Recrystallization from an unrecorded excess of isopropanol gave 3.45 g (59.0%) of a cleaner but still slightly yellow material which retained the aroma and melted at 46.5–47.6°C.[3]

[1]: The yellow discoloration that was present in the organic solution of the purified product seemed to be adsorbed (or otherwise migrate) to the chunks of magnesium sulfate.
[2]: Something in the mixture seemed to exhibit an adverse reaction to the heating, producing a yellow discoloration. Possible explanations include transformation of the benzaldehyde product as well as that of some impurity, stemming from the chemical extraction of the adduct decomposition mixture. There will be further evidence to support this in the next update, but I'm going to state it right now: I think that mechanical separation of the aldehyde following adduct decomposition is the way to go (where applicable).
[3]: Measured using a different thermocouple.


[Fig. 60] Organic solution of crude product <> Extracted RM and washings


[Fig. 61] Solidification of crude product following contact with water


[Fig. 62] Preliminary sample collected for melting point determination


[Fig. 63] Addition of bisulfite solution to crude aldehyde


[Fig. 64] Initial adduct formation


[Fig. 65] Above mixture prior to filtration


[Fig. 66] Isolated bisulfite adduct


[Fig. 67] Decomposition of adduct


[Fig. 68] Dissolution of purified benzaldehyde in minimal butyl acetate


[Fig. 69] Partitioning of decomposition mixture


[Fig. 70] Solution of purified product in BuOAc drying over MgSO4


[Fig. 71] Product obtained by distillation and evaporation of above solution


[Fig. 72] Recrystallized 2,5-dimethoxy-4-ethylbenzaldehyde



The next installment (4/5) will cover all of the sulfur chemistry, leaving the 2,4,6-trimethoxy motif for last. I aim to complete both before the year is out, but it seems about as likely that I won't quite make it.
Either way, thank you for checking out this one!


[Edited on 26-11-2022 by Benignium]
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[*] posted on 25-11-2022 at 05:47


Quote:
Either way, thank you for checking out this one!


I thank YOU for posting the details of an obvious labor of love fueled by some kinda passion!!!

This was an epic thread when you started it Benignium, and now I fear I may run out of superlatives!!!




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[*] posted on 26-11-2022 at 08:48


I'm stunned, again, by your work, Benignium.

A lot of effort went into these synths (and obviously a lot of amateurish silliness too), but in the end you still have the results!
(Results, that most of us are probably a bit "positively envious" about. :) )

Keep up the hard work and keep us informed (and entertained) with the rest of the remaining preparations too! I swallowed your last post slowly, bit by bit, during a several hours period, as if it was a small glass of the best beverage an amateur organic chemist could enjoy.

Your work is not only encouraging and entertaining but visually pleasing too!

[Edited on 26-11-2022 by Pumukli]
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[*] posted on 26-11-2022 at 15:01


For the acylation of p-dimethoxybenzene, I think you could probably use Ac2O with a Brønsted acid catalyst, e.g.:

https://www.sciencedirect.com/science/article/pii/S138111690...

Heteropolyacids are a lot of work but I think you can achieve similar results with H2SO4 or TsOH or something. Yields are already pretty good so won't get much better, but a cleaner reaction and no noxious AcCl would be nice.

Your Duff results are consistent with my understanding that the Duff on p-dimethoxybenzene is not so great but when there is an activating 4-substitution, even alkyl, the yield is significantly improved.

Overall, really great work, and nice pictures.




[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 5-12-2022 at 04:44


arkoma - The thought of you, out there, supporting me with such vigor is an enduring source of improvement to my self-worth and morale. :)

Pumukli - Your feedback is oozing a palpable sincerity — it is truly incredible. Thank you!

clearly_not_atara - Thank you for your support and the astute intellectual contributions that come with it!



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[*] posted on 12-12-2022 at 20:32


Quote:

The methylation of 4-methoxyphenol seems to be about as pleasant as methylations get: the phenol is readily converted, and not terribly fussy when it comes to oxidation, allowing for good yields of a remarkably fragrant[1] product, and doubtlessly the most satisfying substance that I've steam distilled to date.

[1]: The odor is quite unique, but there's something very familiar about it. I suspect that much of this familiarity stems from its resemblance to some species of clover that was (or were) abundantly present in my childhood.


The steam distillation of 1,4-dimethoxybenzene is incredibly satisfying, isn't it? I ran a few rounds of synthesis on this compound two or so years ago, starting from hydroquinone and dimethylcarbonate. The product also tended to freeze in the condenser. I ended up having to stop the water pump a few times to let the steam melt the mass which was threatening to clog up. And the smell? Beautifully pungent, definitely filled the working space and then some... After smelling it in this context, I started to notice notes of it in cosmetics and perfumes.

Thanks for the incredible thread here, and all of your other fantastic contributions. It's really been a joy to read.
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[*] posted on 16-12-2022 at 12:55


Oh yes — I wasn't quick enough (or my mantle wasn't hot enough) to avert the blockage by stalling the coolant, but the fix was thankfully still simple enough to not devalue the experience.
Beautifully pungent is a great way of putting it; I wonder if there are those who genuinely dislike the scent. Overall, I've found the phenols and their methyl ethers thus far to exhibit perfume-worthy fragrances with an astonishing frequency — all the while offering fascinating insight into the relations of molecular structure and our olfactory perception.

I'd love to read more on your experiences with dimethyl carbonate!


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[*] posted on 5-1-2023 at 07:21


Maximum effort.


The 2,5-dimethoxy-4-(alkylthio)benzaldehydes
212.27 g/mol (R = methyl)
226.30 g/mol (R = ethyl)
240.32 g/mol (R = 1-propyl)




Historically, the formation of the 4-alkylthio substituent has been regarded as a pick-and-mix of excessively difficult, prohibitively hazardous, and/or atrociously malodorous procedures by the amateur chemist, leaving most with no other option than to give up the chase. At the same time, however, the technology to overcome these barriers has been out there, waiting to be commonly accepted and adopted through experimental rediscovery. ‏‏‎ [1][2] Such an initiative was eventually taken by the Sciencemadness user Ullmann, whose absolute treasure chest of a thread ‏‏‎ [3] I would have initially overlooked, were it not for a chance encounter with a more recent thread ‏‏‎ [4] in which another Sciencemadness user, turd, has done an outstanding job in presenting the core issues, and the ways in which Alexander Shulgin, Ullmann, and later they themselves tackled them. Without these contributions, my own efforts in this area would exist only in my dreams. 
  This post comprises my darnedest efforts to compile the entire diverging, 11-step sulfur chemistry portion of the overall endeavor into a concise narrative whose progression remains faithful to the staged approach, according to which the actual events unfolded and interconnected observations were made: in brief, a thiophenolic precursor was prepared, and divided into three portions (excluding an analytical sample), two of which were selectively alkylated at the sulfur prior to stages of jugate permethylation and formylation with the third portion. 
  Even though some of the materials did sport a foul odor — mostly when impure — none were anywhere near as bad in terms of volatility or detection threshold, or even in the qualitative sense, as the simple thiols (encountered in alternative approaches) are purported to be. Honorable mentions should, however, be given out to a very impure sample of 2,5-dimethoxy-4-(methylthio)benzaldehyde, as well as a supposedly microbial smell which haunted the immediate vicinity of the sink where glassware was cleaned; shortly after trace amounts of several of the organosulfur materials were flushed down the drain, the exact same malodor would appear, and linger for a few days. Previously unknown, I would describe the aroma as being reminiscent of decaying organic matter, and decidedly sewer-like. Interestingly, although the phenomenon certainly seemed to coincide with the handling of everything from the thiophenol all the way to the methoxybenzenes (at least), disposal of several milligrams of the five-month-old thiophenol down the same (interveningly inactive) sink caused no odors whatsoever. 
  Finally, this sequence of syntheses spans the breakage of a K-type thermometer and two thermocouples, which (along with some strange values) is why, in December, I redetermined several of the melting point values — while also determining a few missing ones. This was done in one session, using a thermocouple whose readings are reliable, albeit depressed by ~1°C (depending on the temperature range). Although the materials had been stored for about 4–5 months (in airtight containers, at room temperature, and mostly protected from UV), they didn't appear to have degraded significantly: only some rather superficial darkening was observed on the sample of propylthiohydroquinone. The verified values are given in parentheses after the original values (not to be confused with literature values), and may be narrower due to a slower incrementation of temperature.

[1]: Lau & Kestner: Synthesis of 5-hydroxy-1,3-benzoxathiol-2-ones. https://doi.org/10.1021/jo01276a025
[2]: PiHKAL: #167 4T-MMDA-2. http://isomerdesign.com/PiHKAL/read.php?id=167
[3]: (Sciencemadness) Thread by Ullmann. https://www.sciencemadness.org/whisper/viewthread.php?tid=11...
[4]: (Sciencemadness) Thread by turd. https://www.sciencemadness.org/whisper/viewthread.php?tid=62...



Chapter I

THIOPHENOL

[a2] 1,4-benzoquinone
108.10 g/mol

Since the springtime experiments, I felt that I had unearthed sufficient evidence against water to revert back to using an alcoholic solvent. Because I was able to conclude that my rather dilute hydrogen peroxide was definitely capable of producing benzoquinone, I prioritized improving the other parameters over obtaining a higher concentration or seeking a different oxidizer altogether. Eventually, a striking experimental report by the Sciencemadness user homeslice ‏‏‎ [1] convinced me to trial the profound modification of bringing the complete reaction mixture to a boil for just 2–3 minutes. Even though this approach seemed to contradict my previous experimental findings somewhat, it did prove exceedingly efficient.

[1]: (Sciencemadness) homeslice: Experimental report. https://www.sciencemadness.org/whisper/viewthread.php?tid=14...


Experiment 3 (-ish)
In a 1000 mL Erlenmeyer, hydroquinone (40.30 g, 366 mmol) and iodine (0.65 g, 2.6 mmol) were dissolved in isopropyl alcohol (150 mL) with mild heating and magnetic stirring. There was then added, in one portion, 11.9% hydrogen peroxide (140 g, 489 mmol), after which the mixture was promptly heated to its boiling point, maintaining reflux for two minutes under a 200 mm Liebig condenser [1] before cessation of the heating. The mixture was stirred for another 10 minutes on the synchronously cooling hotplate prior to measuring its temperature at ~71°C (using IR); observing no more liberation of oxygen; and moving the flask onto a lab jack, where it was allowed to cool to 50°C over 20 minutes. Further cooling was effected by placing the flask in a cold water bath, where an abundant crystal formation was observed after 30 minutes.

[1]: The condenser was fitted with a U-bend (made up of adapters), whose purpose was to direct any spillage into an empty 500 mL flask in the event of a runaway reaction. No boil-over occurred, but the vigorous evolution of oxygen did enable approximately a gram of quinone-containing solvent vapor to make it past the condenser.


[Fig. 1] Iodine and hydroquinone under isopropanol


[Fig. 2] Complete reaction mixture on the verge of boiling


[Fig. 3] Above mixture about one minute later


[Fig. 4] Post-reaction mixture cooling down




Work-up
The crystal-laden flask was kept in the freezer for 90 minutes prior to vacuum filtering the mixture and rinsing the obtained solids with 5 g of i-PrOH. Then, once the filter cake had been compressed and suctioned free of most of the alcohol, it was recrystallized from 35 g of i-PrOH. The filtered crystals were placed (outside) in front of a fan in a crystallizing dish, where they were dried (with occasional mixing) over about two hours. These crystals, while considerably cleaner, retained a rather dark overall shade of yellow, with a generous sprinkling of ones that were outright reddish; a melting point of 115.5–117.7°C (lit. 115–116°C) was determined. [1] The material was placed in a brass mortar where it was triturated somewhat crudely under 35 g of i-PrOH. Filtration of the mixture gave a slightly reddish liquor, and a high return [2] of a crystalline powder which still appeared quite dirty. The solid was air-dried as before, and then recrystallized once more from 75 g of i-PrOH to little apparent avail; after cooling the mixture in the refrigerator, vacuum filtering it, and washing the filter cake using 20 g of room-temperature i-PrOH, the twice recrystallized, thrice air-dried yield of adamantly contaminated crystalline 1,4-benzoquinone was 31.14 g (78.7%).

[1]: The melting point test was expedited due to highly irritating fumes emanating from the heated capillary tube, leading to some broadening of the experimental value.
[2]: No more than a gram of the quinone seemed to dissolve in the amount of (room-temperature) i-PrOH used.


[Fig. 5] Crystal formation in cooled post-reaction mixture


[Fig. 6] Vacuum filtration to separate crude product


[Fig. 7] Separated crude product


[Fig. 8] First recrystallization; crystallized splatters of hot solution


[Fig. 9] Recrystallized product


[Fig. 10] Triturated product under fresh isopropanol


[Fig. 11] Second recrystallization


[Fig. 12] Alternative perspective (after about a minute)




[b3] 5-hydroxy-1,3-benzoxathiol-2-one
Also called: This
168.18 g/mol

Here's a very nifty little trick, and a key feature of this approach in terms of amateur-friendliness: when 1,4-benzoquinone is treated with an excess of thiourea in the presence of a strong acid catalyst, a thiouronium salt is formed that can then rapidly cyclize on heating to give an imine intermediate, which in turn hydrolyzes with the loss of ammonia to give the title compound. [1][2][3][4][5][6] Not only is this resulting heterocyclic intermediate valuable due to its convenient and high-yielding formation and subsequent hydrolysis (c3) — it also allows for the independent alkylation of each oxygen, paving the way to the fascinating 2- and 5-monoethylated tweetios, like the 5-ethoxy-4-ethylthio-2-methoxyphenylethylamine. [6] 
  Going forward, it should be kept in mind that the thiophenol is remarkably sensitive to oxidation, and any handling in basic conditions should be performed under an inert atmosphere, with care being taken to deoxygenate solvents beforehand.

[1]: Lau & Kestner: Synthesis of 5-hydroxy-1,3-benzoxathiol-2-ones. https://doi.org/10.1021/jo01276a025
[2]: PiHKAL: #167 4T-MMDA-2. http://isomerdesign.com/PiHKAL/read.php?id=167
[3]: (Sciencemadness) Thread by Ullmann. https://www.sciencemadness.org/whisper/viewthread.php?tid=11...
[4]: (Sciencemadness) Thread by turd. https://www.sciencemadness.org/whisper/viewthread.php?tid=62...
[5]: (Hyperlab) Obtaining mercaptohydroquinone. https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
[6]: (Hyperlab) miamiechin: 2C-T-2-5EtO. https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...


Experiment 1
Onto a jointed 1000 mL Erlenmeyer flask were stacked, in order: a 200 mm Liebig condenser; a vertical vacuum distillation adapter with a length of tubing leading to a dilute NaOH solution (gas scrubber); and a loosely stoppered 250 mL separating funnel. To a stirred solution of thiourea (23.28 g, 306 mmol) in approximately 2.5N hydrochloric acid (~244 mL, 557 mmol) [1] in the flask there was added, at a rapid dropwise pace from the funnel on top, a solution of 1,4-benzoquinone (30.00 g, 278 mmol) in acetic acid (170 mL). The addition was completed in 30 minutes, and it caused the temperature of the mixture to gradually rise to around 40°C. Once 15 minutes had passed since the end of addition, the mixture had cooled to 37°C, and solids began to precipitate. The resultant, thick suspension was stirred for as long as it took to let it cool down to as close to room temperature as it was going to get [2] before adding a further portion of 33% HCl (18.50 g, 167 mmol) and then gently heating the mixture to reflux, where it was maintained until an hour had elapsed since it was heated past 80°C. [3]

[0]: The temperatures were measured from exterior surfaces of the glassware using IR.
[1]: Prepared from 61.56 g of 33% HCl and 192 mL of water. Estimating a normality like this (as opposed to calculating it exactly via titration of molarity) seems about as counter-intuitive as wearing sunglasses to bed, but there you go. In fact, full disclosure: none of my acids and bases are properly titrated (nor have they been thus far), and claims like the above 557 mmol of HCl quite frankly do a much better job at depicting my intentions with what I've been sold than they do the exact number of millimoles employed. That said, I'm not looking to advocate undue laxness; what we have in titration is a fantastic opportunity to improve. First thing tomorrow.
[2]: This is ambiguously expressed as "After 90 minutes [added...]" in my notes, and based on the available documentation, it's hard to tell whether this translates to 90 or 75 minutes following the end of addition. Either way, the mixture was slow to cool, and (IIRC) barely did so past 30°C; I believe that there was some exotherm accompanying the solid formation, and that if frictional heat from the stirring was a thing, it was in addition to a significant heat transfer from the active (i.e. perceivably warm) hotplate beneath.
[3]: The temperature of 80°C, while arbitrarily chosen for timing the reflux, was noteworthy for being roughly the point at which bubbles began evolving on heating; likely signifying that a reaction was taking place.


[Fig. 13] Addition of benzoquinone solution to thiourea in hydrochloric acid


[Fig. 14] Mixture following complete addition


[Fig. 15] Alternative perspective (6500K lighting)


[Fig. 16] Initial formation of solids


[Fig. 17] Suspension of supposed isothiouronium chloride


[Fig. 18] Alternative perspective




Work-up
The post-reaction mixture was set aside to cool at room temperature. Crystals began forming from the solution at >60°C, and an impressive crop was observed after seven more stationary hours. This was stored below 10°C for some hours prior to cooling to a temperature of 0–4°C, at which the mixture was vacuum filtered. The unrinsed filter cake [1] was spread out over a coffee filter, which was placed on several layers of paper towel. Air-dried, the crystals weighed 42.73 g (91.5%), melted at 177.7–179.8°C (lit. 170.5–172.5°C; [2] 175.5–176°C [3] ), and had a rather pleasant, familiar odor with a low detection threshold. [4]

[1]: Not knowing much about the solubility of this product, and deeming it quite pure by appearance, I thought it best to not risk rinsing it. In hindsight, it would have made a lot of sense to at least do a quick rinse with water; the solubility seems negligible, and the obnoxious evaporation of acid fumes could have been mostly avoided.
[2]: PiHKAL: #167 4T-MMDA-2. http://isomerdesign.com/PiHKAL/read.php?id=167
[3]: SpectraBase: 1,3-BENZOXATHIOL-2-ONE, 5-HYDROXY-. https://spectrabase.com/spectrum/EjXXUEBshAz
[4]: Visually undetectable quantities on crudely wiped down surfaces could be smelled clearly. The aroma bears an uncanny similarity to that of an odorous sample of impure crystalline MDMA which I encountered many years ago; whose origin was completely unknown; and whose odor I have come to describe as resembling of root beer (which is entirely debatable). Having said all that, it's a distinct possibility that, just as back then, the odor belongs to an impurity, and that none of it is inherent to the actual product. Interestingly, I later found the odor of the crude 2-hydroxy-5-methoxyacetophenone (the phenolic side product of c1) to exhibit a nearly identical component.


[Fig. 19] Initial crystal formation


[Fig. 20] Above mixture after seven hours at 24°C


[Fig. 21] Obtained 5-hydroxy-1,3-benzoxathiol-2-one (in 6500K lighting)




[c3] 2,5-dihydroxythiophenol
Also called: Mercaptohydroquinone
142.18 g/mol

In this next step, the isolated intermediate is saponified using aqueous alkali to yield the desired thiophenol. While the obtained crude yield appeared to be nearly quantitative, the initial melting point tests indicated a significant degree of impurity. It's possible that the conversion via this described procedure may have been incomplete, as I certainly overestimated the purity of my NaOH. On top of this, there was observed what appears to be a tendency to discolor and degrade on heating, which I suspect to be a characteristic of the product, and thus mostly independent of the initial impurity. Prolonged storage in solution also seems like it could be problematic. All things considered, potential improvements include additional base, thin-layer chromatography and, weirdly enough, not bothering with further purification.

[0]: For references, see the previous step.


Experiment 1
In a two-necked 1000 mL RBF, 5-hydroxy-1,3-benzoxathiol-2-one (40.01 g, 0.24 mol) was added through a 200 mm Liebig to a magnetically stirred, deoxygenated [1] solution of NaOH (38.57 g, 0.96 mol) in water (320 mL), against a gentle overpressure of argon. Maintaining the argon flow throughout, the mixture was heated under reflux for an hour and then moved to a water bath, where it was cooled to ambient temperature prior to a colorful [2] acidification via dropwise addition of 33% hydrochloric acid (137.20 g, 1.24 mol).

[1]: Deoxygenation was performed by pulling an aspirator vacuum over the mixture several times, each time normalizing the pressure using argon: first for a period of 5 minutes, and then three more times for as long as it took to reach the final depth of vacuum.
[2]: Green → gray → red amber (with initial foaming) → green → gray → nearly white with a green tinge, and opaque from precipitation and effervescence.


[Fig. 22] Dissolution of starting ester in aqueous alkali


[Fig. 23] Above mixture after about two minutes


[Fig. 24] "Red amber" stage of post-reaction acidification


[Fig. 25] Acidified mixture




Work-up
The acidified suspension was subjected to three vacuum-argon cycles, each giving rise (and fall) to a transient, pastry-like crust over an abundant liberation of residual (hydrogen sulfide-smelling) gas. The mixture was then vacuum filtered to obtain a portion of solid material with a dirty white color and a melting point of 109–116°C (lit. 118–119°C [1] ). Extraction of the filtrate using ethyl acetate, followed by evaporation to dryness, gave a comparable amount of solid which was visibly cleaner and melted at 118–120°C. The portions were combined (thoughtlessly, before knowing their melting points) for a crude yield of 33.19 g (98.1%).

Recrystallization of the crude product was explored. An unrecorded portion (presumably everything) was dissolved in 60 g of boiling ethyl acetate, and 20 g of heptane was added with the intention of lowering its solubility, but the liquids were immiscible. An initial crop of finer off-white crystals (12.8 g, MP ~114°C) was obtained, followed by a second crop (10.9 g) of larger, more distinct crystals with a green hue from concentration of the filtrate through distillation.

Evaporation of the concentrated mother liquor gave about six grams of a gooey, green, crystalline mass, from whence an extraction of product was attempted with two portions of boiling toluene (25, then 21 g) that were decanted off of a sunken brown oil. The combined extracts were heated together to redissolve everything. On cooling, a light-brown oil separated before the formation of crystals. A gram of n-PrOH was added in an attempt to keep more of the oil in solution; the oil temporarily dissolved, but reappeared at a lower temperature, coinciding with crystal formation and prompting the addition of another gram of n-PrOH. The mixture was heated to redissolve the crystals, and on cooling, the oil initially remained in solution while crystals formed. At 24°C, however, some oil had still separated. The mixture was placed in a freezer and the cold liquor was decanted off. Residual oil and solvent were removed by pressing the solids between layers of paper towel before air-drying them to obtain 2.57 g of cream-colored crystals which melted at about 106°C.

The 10.9 g portion was recrystallized from 32 grams of aqueous 10% methanol to yield 8.09 g of crystals (with a melting point of ~117°C) via vacuum filtration of the refrigerated (<10°C) mixture. The mother liquor was used to dissolve the residue from evaporation of the above toluene, as well as the cream-colored crystals obtained from it, and the solution was allowed to slowly evaporate from a cling-film-covered beaker for about seven weeks; the remaining liquid was then pipetted off, leaving yellow, crystalline solids which initially smelled like renally excreted asparagus metabolites (if you know, you know), until they were completely air-dried and odorless, and weighed 3.11 g. A melting point range of 178–191°C (180–188°C) was determined. [2]

The final yield of a uniformly off-white mixture of recrystallized materials seems to have been 23.58 g (69.7%). [3] Only the much later verified melting point value exists (110–117°C). The fresh material had a very slight green tinge, which seemed to give way to a beige hue with time. I would describe the odor as a faint, sulfury sourness, with some of the root beer of the ester precursor sticking through.

[1]: PiHKAL: #39 2C-T. https://isomerdesign.com/PiHKAL/read.php?id=39
[2]: At ~120°C, the material acquired a waxy appearance, as if moistened by some trace amount of melted mercaptohydroquinone. As the sample melted, there was some simultaneous decomposition (i.e. reddening until orange), and a small amount of pale solid material remained on the bottom. Interestingly, the previously mentioned "root beer" smell was distinctly emitted by the melted sample; this could imply an incomplete saponification.
[3]: 19.22 g of the purified product was used and I still have 4.36 g left. This means that 2.69 g isn't accounted for in the notes, and was most likely obtained from two initial small-scale recrystallization attempts from aqueous methanol, whose details are likewise missing — the material should then originate from either the initial 33.19 g or [an unrecorded deduction that is missing from] the 12.8 g which was obtained from the EtOAc recrystallization.


[Fig. 26] Rise of "pastry-like crust" under reduced pressure


[Fig. 27] Combined fractions of crude product


[Fig. 28] Trial recrystallization from aqueous methanol


[Fig. 29] Combined impure fractions after seven weeks in beaker


[Fig. 30] Crystals from (the bottom of) above mixture


[Fig. 31] Purified material used in subsequent syntheses (surplus)




Chapter II

S-ALKYLATION


Another thoroughly fascinating feature of this approach is the exploitation of the differences between oxygen and sulfur as they relate to the atoms being stuck on a benzene ring. A base, such as KOH, deprotonates a thiophenol in preference to a phenol due to the thiophenol being more acidic. In a similar manner, an electrophile which is not particularly aggressive, like the alkyl bromides employed here, will have an overwhelmingly consequential preference for a thiophenolate, which in turn is more nucleophilic than a deprotonated phenol. Therefore, what ends up happening, in this context, is that even if one were to use more base than what is required to deprotonate the thiophenol — and even if there was a significant excess of the more electrophilic ethyl bromide present — the immediate end result would be similar: a virtually exclusive and exhaustive alkylation of the thiol. [1][2] 
  In light of the above, it is then clear to see that using more of each alkyl bromide (and quite possibly the base as well) would more than likely have improved the outcome of these experiments; unreacted starting material most definitely contaminated both of the products, and the same knowledge which could have been used to largely avoid the resultant issues was used to fix them in a bit of a leap of faith, whereby bicarbonate was used to remove the (presumed) thiophenolic impurity in open air. 
  Briefly, the alkyl bromides used in these reactions were prepared via dropwise addition of sulfuric acid to a cooled mixture of KBr, water and alcohol; refluxing the mixture; distilling the product from a hot water bath; washing the product with water, aqueous bicarbonate and brine; and drying over MgSO4.

[1]: (Sciencemadness) Thread by Ullmann. https://www.sciencemadness.org/whisper/viewthread.php?tid=11...
[2]: (Sciencemadness) Thread by turd. https://www.sciencemadness.org/whisper/viewthread.php?tid=62...



[d4] Propylthiohydroquinone
Also called: Hydroquinonyl n-propyl sulfide (probably)
184.26 g/mol


Experiment 1
In a beaker, potassium hydroxide (3.13 g, 56 mmol) was dissolved in methanol (50 mL) with magnetic stirring, and the resulting rather polluted solution [1] was gravity filtered into a double-necked 250 mL round boiling flask through a tiny swab of cotton wool. With the flask set up in a water bath, [2] a dual-port gas adapter was attached to the side neck, and used to connect both an argon bottle and a water aspirator; the vertical neck was stoppered. The alcoholic base was then brought to a boil by pulling a vacuum which was immediately counteracted with an influx of argon to the point of (with help) lifting the stopper; this was repeated two more times prior to replacing the stopper with a powder funnel and slowly adding 2,5-dihydroxythiophenol (7.11 g, 50 mmol) through the sustained argon outflow. The mixture was allowed a moment of idle stirring before 1-propyl bromide (6.47 g, 53 mmol) was added in four dropperfuls over about two minutes. Finally, the argon was terminated; the vertical neck was stoppered; and the mixture was stirred for 135 minutes.

[1]: The KOH (fig. 32) was green and contained some insoluble debris.
[2]: Both S-alkylations were performed in a ≤24°C water bath due to the unknown extent of potential exotherm. Aside from inhibiting the volatilization of the alkyl bromides somewhat, no apparent benefit was had from doing this.


[Fig. 32] Technical grade potassium hydroxide


[Fig. 33] Methanolic solution of KOH and mercaptohydroquinone


[Fig. 34] Reaction mixture within four minutes of 1-PrBr addition


[Fig. 35] Discoloration, likely caused by lingering atmospheric oxygen


[Fig. 36] Post-reaction mixture




Work-up
The methanol was vacuum-boiled twice as before, and acidified (under argon) by adding a gram of 33% HCl. The walls of the flask were washed down with MeOH using a dropper, [1] and the mixture was vacuum filtered. The filtered, slightly off-white solids were washed using 12.7 g of MeOH and air-dried to obtain 4.67 g of (mostly) KBr which exhibited a slight, uneven darkening on air exposure. The filtrate was distilled under reduced pressure to concentrate it down to a volume of ~40 mL before evaporating the remaining methanol under a PC fan and transferring the residue to a water-containing beaker in order to examine its solubility (or complete lack thereof). The water was removed by pipetting and evaporation, leaving 8.3–8.6 g of a clear, honey-colored oil.

After a fruitless attempt to obtain crystals from dissolving exactly one gram of the crude product in heptanes (10.24 g) with a bit of propan-1-ol (1.5 g) — and subsequently converting it into a tarry mess by adding water, distilling off the organic solvents with a bunch of said water, adding sodium bicarbonate solution to the remainder (and the distillate) to see what would happen, and stirring the mixture in the open flask to see for how long [2] — the remainder was allowed to remain in open air on a watch glass. Not much change was observed after seven days, aside from some strangely isolated discoloration near the borders of the glass, and perhaps a shift to a greener hue which wasn't apparent at the time (fig. 41).

Inspired by the result of the preceding initial bicarbonate treatment of the ethylthio derivative (see d3), the entire quantity of material was transferred to a beaker using 3.6 g of ethyl acetate, and 50 mL of a 5% sodium bicarbonate solution was added. The biphasic mixture was stirred magnetically for 5 minutes and then poured into a 250 mL separatory funnel. More EtOAc was added until, after adding ~12 g with occasional swirling, the entire organic phase had risen on top of the aqueous one. The aqueous layer was drained into a beaker, where it was further extracted by stirring with a 10 g portion of the EtOAc prior to being separated and acidified with 3.5 g of 33% HCl. The combined organic phases were washed with 40 g of 25% NaCl, and acidified with 0.78 g of 33% HCl. The acid-treated organic layer was gravity filtered through cotton and distilled to remove the bulk of the solvent. The concentrated solution was poured into a shallow borosilicate dish where it solidified, affording 7.32 g (79.5%) of a cream-colored, crystalline solid with a melting point of 69–72°C (70.4–71.4°C); this had a faint, fruity odor with hints of rubber and dehydrated onion. Nothing was extracted from the aqueous portion.

[1]: The intention was to minimize discoloration from any residual deprotonated material getting oxidized before assimilating to the acidified portion.
[2]: There was an immediate, progressive darkening which resulted in a nearly black mixture overnight (fig. 39). I don't have an explanation for why this happened; the baking soda was reasonably fresh and appropriately stored, and I'm quite certain that the distilled mixture had completely cooled beforehand.


[Fig. 37] Acidic vacuum filtrate and separated solids


[Fig. 38] Crude product (mostly) under water


[Fig. 39] Oxidative degradation of one-gram sample <> Also distillate


[Fig. 40] Freshly isolated crude product


[Fig. 41] Crude product after six days in open air


[Fig. 42] Above material dissolved in butyl acetate


[Fig. 43] Above solution being stirred with aqueous sodium bicarbonate


[Fig. 44] Purified propylthiohydroquinone




[d3] Ethylthiohydroquinone
Also called: 2-(ethylsulfanyl)benzene-1,4-diol
170.23 g/mol

On its surface, the ethylation appears identical to the previous propylation. However, there are a couple of considerations which were not taken into account in performing this next experiment: firstly, ethyl bromide needs comparatively little provocation to peace out prematurely due to its remarkably high vapor pressure; and lastly, it would then follow that continuously pumping an inert gas through the system which contains ethyl bromide is strictly inadvisable — that is, unless there was an actual need to do so, as well as an excess of the bromide which was sufficient to compensate. Which there wasn't.


Experiment 1
A solution of KOH (3.13 g, 56 mmol) in MeOH (50 mL) was gravity filtered into a two-necked 250 mL reaction flask, which was positioned in a cool water bath and connected to argon and vacuum lines via a dual-port gas adapter on the angled neck. Four cycles of deoxygenation were effected in the same manner as in d4 prior to adding the thiophenol (7.11 g, 50 mmol), followed by EtBr (5.80 g, 53 mmol), and stoppering the vertical neck — this time maintaining a slight, continuous efflux of argon into the aspirator reservoir while the mixture was stirred for two hours.


Work-up
To acidify the mixture, a gram of 33% HCl was added, followed by an additional portion of 10 drops. [1] The mixture was vacuum filtered to separate 3.77 g of KBr with an air-sensitive whiteness, and the bulk of the MeOH in the filtrate was removed under vacuum before an exhaustive evaporation to leave a dark yellow oil.

In a bid to remove any unreacted thiophenol, the crude product was treated with bicarbonate. Using an unrecorded amount of ethyl acetate, the crude product was transferred to a beaker, where it was magnetically stirred with 50 mL of 5% aqueous NaHCO3 for a few minutes. The separated organic solution was washed with 20 g of 25% NaCl, and then acidified using 6 g of 5.5% HCl prior to evaporating the solvent and thus obtaining 6.32 g of a yellow oil. [2] No written descriptions of the odor seem to exist. [3] The bicarbonate partition was acidified using 2.38 g of 33% HCl and extracted using EtOAc to obtain 1.46 g of a crystalline residue which was surprisingly light in color, [4] and practically odorless.

Eventually, after storing the product on a watch glass in open air for 19 days, [5] it was decided that a second bicarbonate washing be carried out. The previously bicarbonate-treated product (6.25 g) was transferred to a beaker in 5.6 g of butyl acetate. The solution was stirred with 50 mL of aqueous 5% NaHCO3 for 12 minutes, after which the mixture was poured into a 250 mL separatory funnel along with 8.4 g of additional BuOAc. Unlike before, the funnel was shaken, and quite a bit of discoloration immediately took place. The aqueous layer was drained, acidified, and later extracted to obtain no residue. The organic layer was washed with 26 g of 25% NaCl, acidified with 1.06 g of 33% HCl, gravity filtered, and dried over 0.33 g of MgSO4. To estimate the amount of product in the solution, 0.33 g (out of 20.5 g) was placed on a watch glass, leaving ~90 mg of residue after the evaporation of volatiles; this indicated ~5.59 g of product (65.7%).

Finally, ~11.7 g of the solvent was distilled off to leave a dark, viscous, reddish-brown oil in the flask. Prior to methylation, the flask was warmed to ~50°C and swirled around while simultaneously purging it with argon to further remove residual volatiles.

[1]: Assuming a total volume of 0.5 mL and a density of 1.16 g/mL, this would be approximately 0.58 g.
[2]: A small sample of the oil was placed on a watch glass. Cooling in the freezer produced no crystals, but hardened the oil such that its viscosity was comparable to something like barely malleable glass. The sample acquired a reddish discoloration on standing in open air (fig. 46); over the same span of time, the main portion remained unchanged.
[3]: I vaguely recall a modest, predominantly rubber-like smell, similar to what could be picked up from propylthiohydroquinone and later its methyl ether — soft and sort of sweet, comparable to rubbers that are used in some worn and household items; footwear and cleaning equipment, perhaps?
[4]: Part of my original assumption concerning the efficacy of a bicarbonate treatment was that any unreacted thiophenolate might rapidly oxidize all the way to a hopeless tar following deprotonation. Moreover, I was quite certain that the tar would then immediately partition into the organic solvent, tainting the hydroquinone. In a fascinating twist, the sort of dramatic oxidation that I was expecting didn't seem to take place (unless the mixture is shaken with air in a funnel, apparently). Initially, I supposed that the presence of ethyl (and later even butyl) acetate had a protective effect which allowed for the atmospheric isolation of 2,5-dihydroxythiophenol. However, when its melting point was finally determined five months later; the isolated material was observed to gradually begin browning at ~120°C; partially melt into a chocolate-colored semisolid lump at ~167°C; and then quite sharply blacken and liquefy completely at ~170°C — while the similarly stored actual thiophenol simply assumed a chlorine-like color as it melted at 110–117°C. That said, I imagine that the impurity could still have been impure thiophenol, at the time.
[5]: On the first (or second) day, two tiny specks of the bicarbonate-extracted solid were placed in contact with the edges of the puddle of crude product on the watch glass, with the intention of seeing whether they'd facilitate further solid formation or something else of the sort. After seven days, pale streaks of ultra-fine particulate appeared to be spreading out from the solids (fig. 48), and at the end of the 19-day period, the entire puddle was observed to have become opaque, with a ring of red discoloration around the edges (fig. 49); this was what prompted the second bicarbonate treatment.


[Fig. 45] Impurity in BuOAc (aq. NaCl in the back) <> Product in BuOAc


[Fig. 46] Discolored sample of product


[Fig. 47] Bicarbonate-extracted impurity


[Fig. 48] Streaks of particulate spreading over crude product


[Fig. 49] Above sample after ~18 days in open air


[Fig. 50] Aftermath of second bicarbonate treatment




Chapter III

PERMETHYLATION


While the process of methylation itself is nothing out of the ordinary, the importance of protecting the hydroquinones from atmospheric oxygen is highlighted, particularly in the first experiment, where the thiophenol is only now alkylated. To that end, I figured that I would try incorporating acetone — which was previously used in the aqueous methylation of 4-methoxyphenol (b1) without issues — the idea being that boiling it under vacuum would drive out most of the dissolved oxygen. It has also been suggested that the presence of acetone can significantly inhibit the saponification of dimethyl sulfate by the aqueous alkali, [1] which, if true (and applicable here), would be a nice perk. Overall, the deoxygenation seemed to work well, but the yields were mediocre; this, along with the nearly identical dark brown coloration that each of the post-reaction mixtures acquired on standing, seems to imply an incomplete conversion. 
  Because the territory felt somewhat more uncharted, the initial workup in particular involves a bunch of, as Cave Johnson from Portal 2 might put it, "throwing science at the wall . . . to see what sticks". Out of the things that were attempted, the obvious organic extraction and its treatment by repeated washing with aqueous alkali appeared to be the most effective, and I would consider these steps the bare minimum in terms of isolation — kind of like I would for any of the other methoxybenzenes.

[1]: (The Hive) GC_MS: Acetone as co-solvent. https://the-hive.archive.erowid.org/forum/showflat/Cat-/Numb...



[d2] 1,4-dimethoxy-2-(methylthio)benzene
Also called: 2,5-dimethoxythioanisole
184.26 g/mol


Experiment 1
In a single-necked, 100 mL round boiling flask, [1] acetone (10 mL) was added to a solution of NaOH (6.40 g, 160 mmol) in water (32 mL), and the magnetically stirred mixture was very briefly boiled three consecutive times by reducing the pressure and immediately replacing the atmosphere with argon, whose continued outflow was then utilized to purge the subsequent addition of mercaptohydroquinone (5.00 g, 35 mmol). The resultant solution was stirred for a couple of minutes, and a 250 mL separating funnel containing Me2SO4 (13.3 mL, 140 mmol) was attached, with simultaneous disconnection of the argon line to leave the apparatus open. The addition of DMS, initiated with a rate of about 10 drops per minute, was completed in exactly one hour, with the reaction temperature hovering right around 37.4°C (per IR). The flask was stoppered, and stirring was resumed for two hours before allowing the mixture to stand for about 52 hours at ambient outside temperatures (13–23°C), pending workup.

[1]: The reaction flask was fitted with a vertical vacuum distillation adapter, which was connected to an argon bottle via its gas port. A stopcocked 180° gas adapter was connected to a water aspirator, and attached to the female joint on the distillation adapter; once the vacuum pump had served its function, the gas adapter was removed, and the starting material was added through the distillation adapter. This configuration was utilized in all three of the methylations.


[Fig. 51] Reaction mixture prior to addition of DMS


[Fig. 52] Reaction mixture after adding most DMS




Work-up
The post-reaction mixture was poured into a 250 mL separatory funnel, diluted with 50 mL of water, and extracted using three portions of DCM (20, 5, then 5 mL). The extracts were pooled and stripped of most solvent via distillation in a hot water bath, leaving approximately 5.8 g of a vibrant, reddish-brown oil that had a fairly repulsive odor, reminiscent of dimethyl sulfide and sewage.

The usefulness of steam distillation was gauged by adding 32.67 grams of water to the crude oil and collecting ~10 mL of a biphasic distillate whose bottom organic layer (<0.5 g) was pipetted onto a watch glass and evaporated along with two tiny portions of DCM used to crudely extract the aqueous layer (for not much apparent gain). After a day of standing in open (24°C) air, the residue had shed most of its unpleasant cabbage-like smell, and weighed ~90 mg. When no solidification was observed in over a week, the residue was placed in the freezer where it crystallized as a pale-yellow mass which appeared to melt upon reaching ~18°C on standing at room temperature (lit. 33-34°C [1] ).

NaOH (0.98 g) was added to the remaining ~25 mL of crude product and water, and the mixture was stirred for 15 minutes or so prior to extraction with three small portions of DCM; some color remained in the aqueous alkali. 20 mL of heptane was then added to the combined extracts in a 50 mL flask, and the mixture was distilled to remove DCM, causing some dark, solid impurity to precipitate. Another 20 mL portion of heptane was added, and distillation was resumed until ~15 mL of the mixture remained. This was then gravity filtered through cotton, rinsing the filter twice with fresh heptane. A heavy, red oil separated as the mixture cooled, but was retained due to it potentially containing dissolved product; an addition of 10 mL of toluene merged everything into a clear, amber solution.

0.57 g of finely ground activated charcoal was suspended in the solution at room temperature, and the mixture was then boiled for five minutes, cooled in a water bath, and stirred for two more hours at room temperature. The charcoal was removed by vacuum filtration through qualitative filter paper, affording a solution which was clearly less colored, but not dramatically so. A ~1% fraction of the solution was evaporated on a watch glass to obtain ~50 mg of an oil which crystallized in the freezer, but would melt at a significantly lower temperature (>0°C) than the previously steam distilled sample.

Three more alkaline washes were performed using 10-gram portions of 10% NaOH; the first two washes assumed shades of yellow, and the third portion remained colorless. A total of 3 g of methanol was then added to the third washing, until it caused some more of the discoloration to partition into the aqueous layer. [2] The bright-orange organic solution was further shaken with a small portion of water containing 0.52 g of 33% HCl, followed by an 11 mL portion of water with 0.51 g of dissolved potassium metabisulfite (both of which came out colorless), before evaporation on a watch glass. The residual oil contained some trapped moisture, dust, and a fruit fly, which were separated: the product wasn't soluble in plain heptane, but dissolved in a mixture containing 10% of toluene; this was then filtered through a ball of cotton. Evaporation to a constant weight afforded 3.99 g of an amber oil with a faint, mildly unpleasant smell (4.08 g in total; ≤69.1%).

[1]: PiHKAL: #39 2C-T. https://isomerdesign.com/PiHKAL/read.php?id=39
[2]: This methanol-spiked washing was evaporated; the yellow, hygroscopic residue didn't seem to contain too much of the desired methoxybenzene, and was discarded. All in all, the incorporation of methanol was not worthwhile.


[Fig. 53] DCM extract <> Aqueous partition


[Fig. 54] Removal of DCM by distillation


[Fig. 55] Activated charcoal <> Solution to be treated


[Fig. 56] Alternative perspective


[Fig. 57] Charcoal-treated solution of product


[Fig. 58] Evaporated and refrigerated sample from above solution


[Fig. 59] Solution of product over dilute HCl


[Fig. 60] Purified product with residual moisture and airborne impurities




[e4] 1,4-dimethoxy-2-(propylthio)benzene
Also called: 1,4-dimethoxy-2-(propylsulfanyl)benzene
212.31 g/mol


Experiment 1
In a 100 mL reaction flask, acetone (16 mL) was added to a stirred solution of NaOH (4.84 g, 121 mmol) in water (35 mL), and — in the same manner as before (d2) — the mixture was deoxygenated prior to adding 1,4-dihydroxy-2-(propylthio)benzene (7.00 g, 38 mmol) and setting up a dropwise addition of dimethyl sulfate (10.3 mL, 109 mmol). The entire addition took 30 minutes, with the reaction temperature remaining at ~36°C (IR) throughout. The mixture was stirred for some time following the addition, [1] after which the flask was stoppered and allowed to stand at ambient outside temperatures (above and below 20°C) for six days.

[1]: The exact time wasn't recorded, but most likely all three of the methylation experiments were stirred for two hours following the end of addition.


[Fig. 61] Reaction mixture prior to addition of DMS


[Fig. 62] Reaction mixture after adding most DMS




Work-up
The mixture was diluted with 50 mL of water and extracted with four portions of DCM (20, 5, 5, and 5 mL). The bulk of the solvent was removed by distillation, and the remaining oil was dissolved in 10 mL of heptanes. The addition of a 10 mL portion of 10% aqueous NaOH generated a small quantity of dark sediment on stirring; the mixture was gravity filtered into a separatory funnel through cotton, and chased with a 10 mL portion of additional heptane. The organic phase was retained, and washed with three more identical portions of alkali, followed by 10 mL of water, before it was drained into a 50 mL flask. The separatory funnel was rinsed with a 10 mL portion of toluene which was also added to the flask. This nonpolar mixture was then distilled atmospherically to the point of more dark sediment appearing, after which the distillation was resumed under vacuum until the precipitate eventually redissolved in the residual oil. 10 mL of fresh heptane was then added, which once again precipitated the supposed impurity. The suspension was refluxed for ~10 minutes with a gram of freshly ground activated charcoal. Vacuum filtration (whereby the glassware and separated charcoal were rinsed with 2 mL of heptane) and evaporation of the filtrate to a constant weight gave 5.90 grams (≤73.2%) of a honey-colored oil with a mellow, curiously zingy odor of sulfury rubber paired with some ambiguous middle ground of yellow onion and garlic.

Two weeks later, a ~0.80 g portion which wasn't used in the formylations was steam distilled. A coarse extraction of the collected slightly discolored oil (from 200–250 mL of distillate) using DCM afforded, on evaporation, 0.69 g of an off-white, crystalline solid melting at 31.1–32.9°C (32.1–33.7°C). The odor was unchanged.


[Fig. 63] Dark impurity resulting from treatment with base


[Fig. 64] Steam distillation of unused product


[Fig. 65] Solid 1,4-dimethoxy-2-(propylthio)benzene




[e3] 1,4-dimethoxy-2-(ethylthio)benzene
Also called: 2,5-dimethoxyphenyl ethyl sulfide
198.29 g/mol

The ethyl sulfide homolog was the last to be methylated. The digital notes on my phone seem to have encountered some deconstructive variation of pocket dialing, whereby, in between the addition of dimethyl sulfate and the recorded yield, there is a section which simply states " 6 ". Whatever was done was definitely very similar to the previous experiments: I recall reproducing the basic washing (also supported by fig. 68, which I couldn't place anywhere else), and noting that the product is insoluble in heptanes; conversely, I'm convinced that I skipped the activated charcoal treatment as well as attempting to steam distill the product.


Experiment 1
In a 100 mL reaction flask, a solution of NaOH (4.84 g, 121 mmol) in water (30 mL) was prepared. Acetone (10 mL) was then added prior to deoxygenation of the mixture and addition of the crude 1,4-dihydroxy-2-(ethylthio)benzene (<6.25 g, <37 mmol) [1] via the established method; similarly, the argon cylinder was disconnected as part of initiating the subsequent dropwise addition of DMS (10 mL, 105 mmol) which took 25 minutes to complete and generated a peak temperature of ~43°C (IR). After some additional stirring, the mixture was moved to the side where it remained — stationary and outdoors — for no more than four days.

[1]: The lowest estimate for the amount of starting material used is 5.59 grams (see d3 for details). Prior to its addition, the viscous, oily material was diluted with a small portion of acetone, which was also used to sparingly rinse the adapter through which said addition was made.


[Fig. 66] Reaction mixture prior to addition of DMS


[Fig. 67] Reaction mixture at the end of addition




Work-up
The post-reaction mixture was diluted and extracted with several portions of DCM; the extract was washed with several portions of 10% NaOH solution, before evaporating it to constant weight on a watch glass to obtain 4.85 g of a honey-colored oil which had a tangy, sickly-sweet fruit drop aroma with a touch of rather off-putting, sulfury sourness. Depending on the actual amount of starting material used, the yield comes out at (≤) 66.6–74.5%.


[Fig. 68] Separation of dark impurity (supposedly on treatment with base)


[Fig. 69] All three dimethyl ethers, as utilized (Me \ Et / Pr)




Chapter IV

FORMYLATION


In recognition of my increasing vulnerability to failure, I began the formylations by dedicating a single gram of the most abundant intermediate to doing a pilot experiment. At this point I had run out of ethyl acetate, and switching to the decidedly more stable butyl acetate elicited the idea of incorporating it into the hydrolysis stage under reflux; this was done, and the crude yield from the pilot experiment ended up persuading me into trying a similar procedure on the 2,5-dimethoxyethylbenzene right away, which reinforced the wishful impression that I just might be onto something. The rest of the organosulfur compounds were then formylated — followed by the second portion of 2,5-dimethoxytoluene — and I have to admit: I still haven't the faintest idea as to where I stand on the issue. 
  Here, the yields really weren't great, which begs the logical question "Why?" as well as perhaps an emotional exclamation mark or two. Having pondered the matter, a slew of possible explanations has come to mind — none of which I can truly dispute, and many of which could have been taking place in tandem. Through furious speculation, I found myself in a bit of a rabbit hole which I've attempted to narrate in the hopes that it is of more interest to the chemist than it is to the psychologist. 
  Firstly, there's the Duff hydrolysis conundrum, elaborated on in the 4-Me post (1/5). Hypothetically, based on a statement by the Hyperlab user miamiechin, [1] I might assume there to have been an initial yield of up to ~80% in each case, minus whatever percentage of impurity was present in the starting material. As an interesting side note, it initially seemed like the crude yield of the propyl homolog from the pilot experiment could, by some metrics, [2] be estimated to contain as little as ~10% of impurity, which would have put the yield at roughly 84%. 
  Building on these arcane assumptions, and the observed discrepancy between the yields of the two propyl experiments, it would appear that a large chunk of each product might have been lost in the bisulfite purification. There's the distinct possibility of the formation and/or precipitation of the bisulfite adduct of each aldehyde having been significantly incomplete, which seems to be supported by the observed decelerating but seemingly everlasting precipitation of solids. Another correlation that stands out is how, instead of the usual dropwise addition of sodium hydroxide, a concentrated sodium carbonate solution was used to decompose the obtained adduct from all but the pilot experiment; indeed, at least one person has claimed that the use of (potassium) carbonate instead of hydroxide leads to lowered yields. [3] However, having tried the liquid–liquid extraction of each decomposition, the logistics for such a phenomenon seem somewhat improbable to me, as I wouldn't expect any such loss to be soluble in the aqueous phase. 
  As my newest piece of conjecture, I now realize that there is one more thing which I have managed to repeatedly disregard as if it kept curing scurvy: the acetic acid. In each experiment, 2.2–2.3 g of AcOH was used for every (supposed) millimole of starting material. Each reaction mixture was then diluted to an arbitrary degree with water before a likewise arbitrary amount of butyl acetate was used to extract it. Beyond this point, some interesting observations could be made: for instance, a mere 1.94 g of BuOAc per mmol (of starting material) was sufficient to extract what amounted to a 69.6% purified yield of the methyl homolog, but subsequently washing the organic solution with aqueous bicarbonate would then cause a significant quantity of the product to precipitate. Thus, it would appear that the amount of organically co-extracted acetic acid was decreased via neutralization as well as partitioning to the aqueous phase, forcing the poorly BuOAc-soluble and clearly very hydrophobic aldehyde out of solution. Similar correlations for the other two compounds aren't as conspicuous, but I believe that they're there. Mostly I'm just concerned that I've insufficiently extracted the two seemingly less hydrophobic aldehydes from the acid-containing reaction mixture, but really the bedrock that I keep unearthing here is that individual solubility of the [precursor/aldehyde/adduct] should be the constant main focus in deciding which variables to adjust. At the end of this post, I've included a table that I drafted for reviewing and comparing the experimental parameters; with some tweaks, I believe that it could be a great tool for planning and improving future Duff experiments as well. 
  Finally, I need to address the subject of melting points, as something strange seems to be going on with the separately S-alkylated derivatives. Assuming that the melting point values given in PiHKAL are indeed correct, it would appear almost as if my ethylated and propylated products had been switched at some point. However, I'm willing to risk the existential crisis of a lifetime in declaring that there is just no way that that could have happened. And even then, the melting points wouldn't quite match — which shouldn't be an impurity issue considering the fairly narrow ranges of 1.2°C and 0.9°C determined for the purest respective samples. Moreover, by (re-)verifying the melting point values in December, I have completely ruled out the possibility of a thermometer malfunction. But if Shulgin didn't mix up his values; and if I didn't mix up my products — what could have happened? Judging by the crude melting point of the pilot experiment, which at first seems to conform but then dramatically shifts as the material is purified, it seems like the anomalous behavior could originate from the bisulfite purification process. But then, why wouldn't something similar happen to the methyl homolog as well? It seems worth bringing up that Shulgin apparently used the Rieche (dichloromethyl methyl ether/Lewis acid) to formylate the methylthio compound, and purified it via the bisulfite adduct; [4] while the ethyl and propyl derivatives were formed through the Vilsmeier, and simply recrystallized from methanol until satisfactory [5][6] — with the latter apparently producing a perfect NMR spectrum. The best I could do is some last-minute TLC, but characterization of any products from subsequent syntheses should in time supplement this nicely.

[1]: (Hyperlab) miamiechin: 70–80% yield. https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
[2]: SRS - Rule-of-thumb: 1% of foreign substance will result in a 0.5°C depression. https://www.thinksrs.com/downloads/pdfs/applicationnotes/MPP...
[3]: (Hyperlab) ramboTT_1: [7] (KOH vs. K2CO3). https://hyperlab.info/inv/index.php?s=&act=ST&f=17&a...
[4]: PiHKAL: #39 2C-T. https://isomerdesign.com/PiHKAL/read.php?id=39
[5]: PiHKAL: #40 2C-T-2. https://isomerdesign.com/PiHKAL/read.php?id=40
[6]: PiHKAL: #43 2C-T-7. https://isomerdesign.com/PiHKAL/read.php?id=43



[f2] 2,5-dimethoxy-4-(propylthio)benzaldehyde
240.32 g/mol
360.49 g/mol (bisulfite adduct; potassium salt)


Experiment 1
In a 25 mL reaction flask, 1,4-dimethoxy-2-(propylthio)benzene (1.00 g, ≤4.7 mmol) and urotropine (1.32 g, 9.4 mmol) were mostly dissolved in magnetically stirred acetic acid (6.20 g). To the mostly clear solution was then added a solution of 98% sulfuric acid (1.88 g, 18.8 mmol) in acetic acid (4.12 g); the addition was performed dropwise, over 19 minutes, using a Pasteur pipette; and the ensuing cream-colored suspension was stirred for five more minutes at room temperature. The flask was then fitted with a condenser, and its contents were brought up to a boil in a 1000 mL heating mantle. After refluxing the mixture for 120 minutes, there was added butyl acetate (4.37 g) which separated a dense, dark oil. Once the heterogenous mixture had been refluxed for another 80 minutes, water (5.03 g) was carefully added, and the heating was kept up for 60 more minutes before allowing the mixture to cool to room temperature, at which it was then stirred for 13 hours.


[Fig. 70] Solution of substituted benzene and HMTA in AcOH


[Fig. 71] Reaction mixture following addition of sulfuric acid


[Fig. 72] Reaction mixture prior to addition of butyl acetate


[Fig. 73] Reaction mixture following addition of butyl acetate


[Fig. 74] Reaction mixture following addition of water




Work-up
The bilayered mixture was poured into a 250 mL separating funnel and shaken with additional water (25 mL) and BuOAc (10 g). Once partitioned, the aqueous phase was extracted with two or three further 10 g portions of the ester, and the organic partitions were combined for treatments with water (10 g), 10% sodium bicarbonate (3x10 g), and finally a second portion of water (10 g). The treated organic solution was gravity filtered into a 50 mL flask through cotton (removing a small amount of dark sediment), and distilled until ~5 g of a yellow solution remained; this was evaporated to a constant weight on a watch glass, yielding 1.06 g (<93.8%) of a waxy, yellow residue with a melting point of 71–77°C (lit. 76–77°C [1] ) and a small amount of (likely inorganic) impurity which didn't melt. Dissolution of the material in 11.8 g of methanol was incomplete, even with a gram of butyl acetate as a co-solvent, but the residual solids dissolved in the plain ester (1.88 g).

A solution of potassium metabisulfite (7.53 g) in water (16.8 g) was prepared. The methanolic solution of crude aldehyde was funneled into the stirred bisulfite through cotton wool, and the mixture promptly thickened with solids that were pale apart from some dark orange bits here and there. The previous 1.88 g portion of BuOAc was then added, which appeared to dissolve the colored impurity. After about 30 minutes, the mixture was vacuum filtered, and the moist filter cake was strenuously rinsed with 8 g of fresh BuOAc before being placed on a watch glass to dry. The filtered mixture continued to develop solids; a second filtration was performed after about an hour, followed by a third one on the next day. The filtrate was retained for further observation.

In a beaker, the accumulated (partially dried) adduct was suspended in 50 mL of water with good stirring, and 2.35 g of a 20% NaOH solution was added to raise the pH to 10–11, followed by 5 g of BuOAc used to dissolve the solid phase. The mixture was then transferred to a separating funnel, using an additional 2.5 g of BuOAc to rinse the beaker. The phases were separated, and a further 0.44 g of the 20% NaOH was added to the aqueous portion [2] prior to extracting it with two more five-gram portions of BuOAc. Once combined, the organic extracts were washed with 10 g of 25% NaCl and a few grams of water. Most of the solvent was then distilled off, and as residual water was removed with it, a small amount of supposed salt precipitated; the residual organic solution was drawn into a pipette through a swab of cotton and deposited onto a watch glass to evaporate. Consequently, there was obtained 0.75 g (66.3%) of an odorless, slightly yellow, crystalline residue with a melting point of 82.9–84.6°C.

[1]: PiHKAL: #43 2C-T-7. https://isomerdesign.com/PiHKAL/read.php?id=43
[2]: The presence of butyl acetate seemed to either buffer the pH down or distort the reaction between the mixture and universal pH paper; a pH of ~9 was indicated, hence the addition.


[Fig. 75] Initial organic extract <> aqueous partition


[Fig. 76] Residue from evaporation of above extract


[Fig. 77] Alternative perspective


[Fig. 78] Formation of bisulfite adduct


[Fig. 79] Wet bisulfite adduct


[Fig. 80] Bisulfite-purified product


[Fig. 81] Additional precipitation from retained bisulfite mixture




Experiment 2
To a well-stirred solution of the benzene (4.04 g, ≤19 mmol) and HMTA (5.36 g, 38.1 mmol) in AcOH (25.55 g) in a 100 mL reaction flask, 98% sulfuric acid (7.63 g, 76.2 mmol) in AcOH (18.13 g) was added dropwise (from a 250 mL addition funnel) over 22 minutes, causing the temperature of the mixture to plateau at 31–32°C. Following completion, the thick suspension was stirred for seven more minutes at room temperature prior to being brought to a reflux for 130 minutes. This was followed by one hour of stirring sans heating, after which there was added water (20.30 g) and BuOAc (14.68 g). Stirring as such was continued for ~30 minutes, and the mixture was refluxed for an additional 40 minutes before allowing it to cool once more.


[Fig. 82] Reaction mixture being heated


[Fig. 83] Above mixture 3 minutes later




Work-up (2)
After some 20 hours at room temperature, [1] the mixture was diluted with 15 g of water, and partitioned. The aqueous portion was extracted twice with BuOAc (12, then 21 g), and the extracts were merged with the organic portion. This was shaken twice with 25 g portions of water in a separatory funnel and then drained into a stirred suspension of NaHCO3 (10 g) in 90 mL of water; an additional three grams of NaHCO3 was required to retain alkalinity in the aqueous phase (one gram followed by four half-gram portions). The organic solution was separated and dried over 1.02 g of MgSO4.

Omitting distillation [2] to remove excess solvent, a solution of potassium metabisulfite (35.52 g) in water (78.63 g) was added to the dried organic solution with strong stirring. Solids began forming after about 10 minutes. After about 12 hours, the mixture was vacuum filtered. The filter cake was rinsed with methanol, [3] which appeared to give rise to further precipitation on mixing with the filtrate. [4] The cake was air-dried to a constant weight of 3.44 g, and a second filtration of the mixture ~18 hours later gave 0.38 g of additional solids for a total of 3.82 g.

The twice harvested bisulfite mixture was partitioned. The organic portion was used to extract the remainder of the reaction mixture (where the two 25 g water washings had also been deposited). Another extraction was done using BuOAc (10 g), and the combined organic extracts were washed with water (10 g), 25% NaCl (10 g), 10% NaHCO3 (8x10 g), and 25% NaCl (10 g) again, before being dried over 1.25 g of MgSO4 for ~20 minutes. Meanwhile, the aqueous bisulfite solution from before was replenished via dissolution of an additional 1.18 g of K2S2O5, and then combined with this new organic extract. The mixture was stirred for ~12 hours and filtered. The solids were rinsed with MeOH (2 mL) and BuOAc (6 g). The air-dried solids (3.03 g) were merged with the previously obtained 3.82 grams.

In an attempt to ensure that all of the available benzaldehyde would be retained, the spent bilayered bisulfite mixture was combined with that of the previous experiment. After 24 hours of standing, there had formed a bunch of additional solid material, which was separated by vacuum filtration and rinsed with 2 mL of MeOH. This, in combination with a later 0.68 g portion of even more solid material (rinsed with BuOAc), weighed 3.85 g.

The two portions of ostensible adduct were processed forth separately, beginning with the latter. The solid was added to a ~26.2% solution of Na2CO3 (17.49 g) in water (49.38 g), and the mixture was stirred for 15 minutes. There was then added 5 mL of butyl acetate, which was noted to dissolve the solid phase sluggishly (in 10–20 seconds). The mixture was left to stand for a little over an hour before the phases were separated and the aqueous portion was extracted with two 5 mL portions of BuOAc. The organic extracts were combined, dried over 0.31 g of MgSO4 and evaporated on a watch glass to yield 0.32 g of a crystalline residue with a melting point of 83.6–84.6°C.

The former 6.85 g portion was similarly decomposed in 80 g of the ~26.2% Na2CO3. The solid phase didn't seem to dissolve too well, with most of it persisting after [probably 5–15 minutes] of being suspended in a stirred emulsion containing 10 mL of butyl acetate. Instead of adding more BuOAc right away, the mixture was vacuum filtered. The filtered solids dissolved partially when rinsed with a 10 mL portion of BuOAc, so an approach was chosen whereby the same biphasic mixture was repeatedly filtered through the solids into a separatory funnel, with BuOAc being added incrementally until, after adding three more portions (10, 10 and 5 mL) for a total of 45 mL, only a few dozen crumbs remained. [5]

The liquid mixture was partitioned, and the organic solution was dried over 0.64 g of MgSO4 for >24 hours. No longer omitting distillation (due to forgetting about [2] ) the dried solution was distilled to remove the bulk of the solvent prior to evaporation of the remainder on a watch glass to yield 2.38 g (52.0%) of a wintry, crystalline residue melting at 82.4–84.6°C.

A recrystallization of the combined product of both experiments (3.45 g) from ~19 mL of isopropanol gave 3.21 g (56.3%) of odorless, cream-colored crystals with a melting point of 84.1–84.9°C (82.9–83.8°C).

[1]: It isn't specified whether the mixture was stirred or just stood there for ~20 hours.
[2]: Caution due to the observed heat-induced discoloration during the preceding workup of the 2,5-dimethoxy-4-ethylbenzaldehyde, as well as a suspicious discoloration of the purified product from the pilot experiment.
[3]: The amount wasn't recorded; it was added in one portion using a 10 mL pipette, and was definitely no less than 2 mL. I seem to recall using 6 mL but am way too uncertain to conclude thus.
[4]: This could mean an improvement to the rate and/or quantity of adduct formation, but it could also just be the precipitation of a dissolved portion of the filter cake and/or some insolubilized undesired material. As mentioned previously, I believe that methanol generally has a beneficial effect on the adduct formation through acting as a phase transfer catalyst (where applicable).
[5]: These crumbs were identified as mostly product by their mixed melting point. However, they were pending characterization long enough to be excluded from the initial yield and its recrystallization, and, by extension, from the purified yield. I seem to have since misplaced the crumbs, but I'd say there was probably no more than 100 mg (fig. 90).


[Fig. 84] Organic extract over aqueous bicarbonate suspension


[Fig. 85] Treated extract being stirred with bisulfite solution


[Fig. 86] Above mixture after 11 hours of stirring


[Fig. 87] 3.85 g portion of adduct being added to aqueous alkali


[Fig. 88] Above mixture after 13 minutes of stirring


[Fig. 89] Above mixture following addition of butyl acetate


[Fig. 90] Extracts from the two individual decompositions drying


[Fig. 91] Undissolved crumbs of product on filter paper


[Fig. 92] Evaporation residue of bisulfite-purified product




[f1] 2,5-dimethoxy-4-(ethylthio)benzaldehyde
226.30 g/mol
346.47 g/mol (bisulfite adduct; potassium salt)


Experiment 1
1,4-dimethoxy-2-(ethylthio)benzene (4.60 g, ≤23.2 mmol) and HMTA (6.50 g, 46.4 mmol) were dissolved in AcOH (30.4 g) in a 100 mL reaction flask. To the stirred solution was then added, dropwise, over 33 minutes, a solution of 98% H2SO4 (9.29 g, 92.7 mmol) in AcOH (22 g). On completion, the mixture was refluxed for 90 minutes after which there was added (through the condenser) BuOAc (19.00 g), followed by a cautious addition of water (10.40 g). After refluxing the reaction for another 70 minutes, it was allowed to cool for 20 minutes prior to adding a second portion of water (10 mL). Stirring was then continued for ~19 hours at 24°C.


[Fig. 93] Addition of HMTA to substituted benzene in acetic acid


[Fig. 94] Reaction mixture prior to heating


[Fig. 95] Reaction mixture approaching reflux


[Fig. 96] Above mixture after 10 minutes


[Fig. 97] Mixture after 50 minutes of refluxing with water present


[Fig. 98] Monophasic post-reaction mixture




Work-up
In a separatory funnel, the monophasic post-reaction mixture was shaken with 53 mL of water and 15 g of BuOAc, and the two layers were separated. The aqueous portion was extracted twice using 10 g portions of BuOAc. Once combined, the organic portions were treated with 10% NaHCO3 (4x20 g, then 2x10 g) until a washing remained alkaline. The amber organic solution was dried overnight over 1.15g MgSO4. A 0.17 g sample was evaporated to dryness in a 10 mL beaker to obtain an unweighed, crystalline melting point sample with an unpleasant odor. [1]

A bisulfite solution (38.7 g of K2S2O5 in 86.2 g of H2O) was added to the stirred, gravity filtered organic solution in a 250 mL flask, along with 10 mL of MeOH. In ~10 minutes, the mixture had turned into an unstirrable porridge. The flask was swirled occasionally over the next 14 hours prior to vacuum filtering the mixture, washing the filter cake with 6 mL of MeOH followed by a total of 20 mL of BuOAc, and air-drying the obtained solids to a constant weight of 6.28 g.

Because the dried adduct had a rather dirty yellow color which wouldn't wash away on the filter, it was magnetically stirred with 20 mL of methanol in a 50 mL flask for about two hours. Filtration and air-drying of the mixture afforded 4.40 g of a significantly less discolored solid. The filtrate was combined with the separated aqueous portion of the previously used bisulfite mixture; [2] powerful stirring of the mixture followed by vacuum filtration, and drying of the separated solids, gave 1.53 g of material which was likewise much less discolored than what was had before.

A dark, crystallizing oily substance was observed to appear on top of the mixture of washings and extracted reaction mixture; a ~40 mL portion of the distilled organic phase from the bisulfite mixture was used to re-extract the mixture. The extract was treated with two portions of 10% NaHCO3 (40 g, 30 g) followed by 10 g of 25% NaCl, and then stirred overnight with the pre-used aqueous bisulfite to receive 3.18 grams of additional precipitate.

The accumulated adduct was added to 83 g of stirred ~26.2% sodium carbonate solution. After waiting 15 minutes, 10 mL of BuOAc was added, and the mixture was stirred for 10 minutes. The solid phase dissolved partially. Two more five-milliliter portions of the ester were needed to obtain a clear mixture; these were added 10 minutes apart. A small quantity of unidentified debris appeared at the liquid–liquid interface of the still mixture, and was gravity filtered out. The organic phase was separated, and the aqueous phase was extracted twice more with 10 mL portions of BuOAc. The combined organic extracts were dried over 0.76 g of MgSO4 for ~24 hours, and concentrated through distillation under reduced pressure. Following evaporation of the residual volatiles, there remained 2.62 g of slightly sticky, yellow crystals melting at 73.6–79.8°C (lit. 87–88°C [3] ). These were recrystallized from ~28 mL of isopropanol, giving 2.38 g (45.3%) of crispy, odorless crystals which were lighter in color and had a melting point of 77.1–78.8°C (76.9–78.1°C).

[1]: For whatever reason, it seems that the melting point was never determined. But there is a picture of the sample (fig. 101).
[2]: In hindsight, it seems likely that much of the dissolved portion consisted of the adduct, and instead of just putting it back (and probably hurting the yield in doing so), it would have been prudent to evaporate the MeOH and examine the residue.
[3]: PiHKAL: #40 2C-T-2. https://isomerdesign.com/PiHKAL/read.php?id=40


[Fig. 99] Aqueous portion of diluted reaction mixture <> Organic extract


[Fig. 100] Washed extract <> Washings and above aqueous portion


[Fig. 101] Underutilized sample of impure product


[Fig. 102] Treated extract being stirred with bisulfite solution


[Fig. 103] Above mixture after 12 minutes of stirring


[Fig. 104] Dried bisulfite adduct


[Fig. 105] Decomposition of adduct


[Fig. 106] Above mixture after adding 20 mL of butyl acetate


[Fig. 107] Evaporation of extract from adduct decomposition


[Fig. 108] Alternative perspective (distorted white balance)




[e2] 2,5-dimethoxy-4-(methylthio)benzaldehyde
212.27 g/mol
332.44 g/mol (bisulfite adduct; potassium salt)


Experiment 1
In a 100 mL reaction flask, there was prepared a solution of 2,5-dimethoxythioanisole (3.99 g, ≤21.7 mmol) and hexamine (6.08 g, 43.4 mmol) in AcOH (29 g). A solution of 98% H2SO4 (8.68 g, 87.0 mmol) in AcOH (19 g) was then added — dropwise, and with strong stirring — in 30 minutes, during which the reaction mostly took place at ~31°C. Following completion, the mixture was stirred for an additional 10 minutes at ambient 24°C prior to being refluxed for two hours. Water (10 g) and BuOAc (10 g) were then added, followed by another portion of water (10 g) after 45 more minutes of refluxing, at which point the heating was discontinued. After six hours of stirring, the mixture was warmed to 70°C (with a short-lived intention of further refluxing) and allowed to cool again. The mixture was stirred for 17 more hours and allowed to stand for another two.


[Fig. 109] Solution of substituted benzene and HMTA in AcOH


[Fig. 110] Reaction mixture following addition of sulfuric acid in AcOH


[Fig. 111] Reaction mixture approaching reflux


[Fig. 112] Reaction mixture after 110 minutes of reflux


[Fig. 113] Reaction mixture prior to second addition of water


[Fig. 114] Monophasic post-reaction mixture




Work-up
The mixture was transferred to a separatory funnel where it was diluted with 50 g of water, causing a great deal of precipitation; the addition of 10 g of BuOAc redissolved the solid phase on shaking. The organic phase was collected and combined with two more ester extractions (12 g, 10 g), and the resulting mixture was treated with two 50-gram portions of 10% NaHCO3; this produced a pale precipitate [1] which required several iterative solvent additions to redissolve: in order, there was added, portionwise, BuOAc (12 mL), DCM (1, then 2 mL), water (20 mL), and DCM (7, 10 and 5 mL). Finally, only a few solid particles remained, and the biphasic mixture was partitioned. Treatment of the product-containing partition was resumed with a further 5 g of the aqueous bicarbonate, followed by 10 g of 25% NaCl. There was then added 0.97 g of MgSO4. [2]

The mixture was distilled to remove DCM, which was then used to further extract the remainder of the reaction mixture, where solids had now formed. [3] The latter extract was concentrated and then evaporated to yield 440 mg of a vibrant, reddish-orange residue with a rather vomit-inducing smell, reminiscent of the truly visionary delicacy known as stockfish; melting point 71–91°C. To the former extract, there was added a bisulfite solution (36.51 g of K2S2O5 in 81.01 g of H2O) and 10 mL of methanol; the mixture almost immediately became unstirrably thick. Vacuum filtration of the mixture was performed a total of three times, as the filtrate would thicken once more before finally producing a ~100 mg portion of additional solid. Thus, in total, there was obtained 8.74 g of dried precipitate.

The obtained adduct was suspended in 85 g of ~26.2% Na2CO3, and the mixture was stirred for 15 minutes before adding 15 mL of BuOAc, which resulted in no discernable dissolution but rather constituted a mesmerizing, doughy vortex with the hydrophobic benzaldehyde. When an additional 15 mL portion of BuOAc (and 10 minutes of stirring on either side of it) made no apparent difference to the quantity of solids, the mixture was vacuum filtered through qualitative filter paper, and the filter cake was rinsed with 100 mL of water to obtain, after air-drying, 3.01 g of a pale, greenish-yellow solid exhibiting a slightly incomplete melting at 97.6–99.6°C (lit. 99–100°C [4] ). The organic portion of the filtrate was washed with the previous 100 mL portion of water, filtered, and dried over 0.39 g of MgSO4; approximately two percent (0.51 g) of the solution was evaporated to obtain ~10 mg of a residue melting at 99.0–99.6°C.

Recrystallization was trialed by first gauging the solubility in 2-propanol: a 0.50 g portion of the solid material was dissolved in ~8 mL of the alcohol, and the boiling mixture was gravity filtered through cotton to remove a small quantity of insolubles; by visually inspecting the crop of crystals from cooling the liquor, the ratio of solvent was deemed apt. The rest of the solids were then dissolved in 32 g of 2-PrOH, gravity filtered, and combined with the two fractions in alcohol and BuOAc. The mixture was distilled to remove alcohol [5] and placed in the freezer. Vacuum filtration of the <0°C mixture gave 3.20 g (69.6%) of nearly colorless but deceivingly fluorescent, odorless crystals with a melting point of 101.0–101.5°C (96.2–96.9°C). [6]

[1]: This (along with the other instances of unexpected precipitation) was most likely the product, whose solubility in butyl acetate seemed to be the lowest of the three homologs (in fact, of all of the benzaldehydes so far). In the notes, I haven't specified whether it was the first or the second bicarbonate washing which caused the precipitation, and it could be that both portions ended up in the funnel at the same time with all of the additional organic solvent, with the third five-gram portion being used to verify complete neutralization of the acid.
[2]: It is unclear if the solution was actually dried (and filtered) prior to the subsequent distillation; DCM is a considerably better solvent for the product than BuOAc, ergo, its (sufficient) removal should precipitate the product — mixing it with the sulfate, if the sulfate was present. In any case, it does seem like I made it to the bisulfite purification with no such incident.
[3]: Another detail was omitted in not noting whether the re-extracted mixture contained the previous bicarbonate washings; as I recall, it did.
[4]: PiHKAL: #39 2C-T. https://isomerdesign.com/PiHKAL/read.php?id=39
[5]: The final volume of solvent was crudely estimated (after the fact) to be ~35 mL.
[6]: The verified value was obtained by placing the sample in the furnace whose temperature was already quite close to the melting point; the abrupt heating seems to have been the cause of the slight depression.


[Fig. 115] Precipitation on rinsing reaction flask with water


[Fig. 116] Precipitation on aqueous dilution of reaction mixture


[Fig. 117] Precipitation on washing extract with aqueous bicarbonate


[Fig. 118] Spoonful of bisulfite adduct from the source


[Fig. 119] Precipitation during secondary extraction of reaction mixture


[Fig. 120] Secondary extract


[Fig. 121] Evaporation residue of above extract


[Fig. 122] Dried bisulfite adduct


[Fig. 123] Decomposition of adduct in aqueous sodium carbonate


[Fig. 124] Water floating on aldehyde floating on water — under BuOAc


[Fig. 125] Above mixture, vigorously stirred


[Fig. 126] Solids from vacuum filtration of above mixture


[Fig. 127] Purified aldehyde under 2700K white LED (corrected WB)


[Fig. 128] Purified aldehyde under UV-A


[Fig. 129] Illumination: Indirect evening sunlight <> UV-A


[Fig. 130] Table for reviewing experimental parameters




Thin-layer chromatography 
To lessen the ambiguity of this post, I decided to squeeze in some TLC; despite some initial perplexity, useful results were obtained. Samples in the approximate range of 3–6 milligrams were placed in test tubes, each containing a gram of isopropanol. Four identical plates (25 x 75 mm) were prepared by applying a spot of each sample, which were labeled as A (Me), B (Et), and C (Pr). Each of the plates was developed using a different mobile phase before being placed in chronological order and photographed under UV-A and UV-C lighting.

Mobile phases, from left to right:
[1] Toluene
[2] Toluene/Propan-2-ol (9:1)
[3] Heptanes/Butyl acetate (10:1)
[4] Heptanes/Butyl acetate (3:1)

Retardation factors (RF), from left to right:
[1] ~0.17
[2] 0.69–0.70
[3] A: 0.15; B: 0.19; C: 0.27
[4] A: 0.32; B: 0.40; C: 0.47


[Fig. 131] Samples being dissolved in isopropanol


[Fig. 132] Developed TLC plates under UV-A


[Fig. 133] Developed TLC plates under UV-C



[Fig. 134] Recrystallized benzaldehydes (Me / Et \ Pr)



So, here we are, with all three of the intended benzaldehydes* in modest quantities. I'd be lying if I said I wasn't thrilled with the result (and having gone through with sharing it to the best of my ability), but I'd also be remiss if I didn't disclose that I am sweating profusely from the mere thought of still needing to get to my ultimate goal of 3–6 amines with what I have. That said, there are other targets in the 4-alkylthio realm that I'm interested in (for instance, the rather spooky 2C-T-21), so, for better or for worse, having another go from scratch isn't entirely unlikely. Or undesired. 
*Assuming that PiHKAL contains a couple of bad melting points. Gulp. 

The final 2,4,6-trimethoxybenzaldehyde post will be somewhat more delayed, as I'll be unable to dedicate quite as much of my time to putting it together. 
But it will come.  
And it will be nice. 


[Edited on 6-1-2023 by Benignium]
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SuperOxide
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[*] posted on 5-1-2023 at 14:37


Bravo, Benignium.

I will read over your latest post in more detail when time permits.

Curious - are you planning on synthesizing every compound in PiHKAL?

[Edited on 5-1-2023 by SuperOxide]
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Benignium
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[*] posted on 6-1-2023 at 06:39


Please do, and let me know what you think!

Although I might enjoy trying my hand at synthesizing every single one, biology makes it so that my plan has to involve a degree of cherry-picking, and not all of the cherries grow on this one tree, either — phenethylamine or otherwise.


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