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Niklas
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Synthesis of cubane and cubane related compounds / derivatives
Greetings everyone,
As a disclaimer straight up, I have not yet made this product, but it’s a project I’m currently working on and in a somewhat crudely executed run
I previously managed to successfully prepare, as confirmed by NMR, some of the intermediate bisketone (around 20 g) in a total yield of 33,4% starting
from commercial cyclopentanone. Now my interested has shifted from just making cubane for the sake of it though, and over the last year I came up with
multiple theoretical synthesis leading towards potentially pharmacologically active cubane biosteres of some psychedelics, this aspect will be further
explained below, I wanna explore in practice. Therefore I‘ve decided to scale this whole synthesis up, now using 400 ml of additional
cyclopentanone, and this process and, as far as I’m successful, the following synthesis of some derivatives, I will be documenting in this thread.
As far as you are working of this type of synthesis yourself, be it completely unrelated to my personal goal, I would appreciate you adding your input
and labnotes / procedures as well though, so you can just treat this as a general thread for cubane related stuff.
Introduction
Cubane really is an interesting compound, seemingly defying the previously believed to be quite rigid rules of molecular geometry. While it could be
determined by extensive calculations that cubane would likely be a compound stable enough to be isolated, this could only be fully confirmed in 1964
with its first synthesis by Eaton starting from cyclopentene, taking 15 steps to result in the unsubstituted form of this Platonic hydrocarbon [1].
Fig.1: The first synthesis of the cubane system by Eaton
This was eventually shortened to 10 steps by Tsanaktsidis in 1997 [2], and till this day this path, with some minor modification of the reaction
conditions, remains the general approach to cubane and its derivatives, most notably its 1,4-dicarboxylic acid, which has gained legitimate practical
interest as will be described below. With this yields of 32% are achievable for the dimethyl-1,4-dicarboxylate starting from cyclopentanone, as has
been described by Bartonek from Klapötke’s group in 2023 [3].
Fig.2: Improved synthesis of cubane by Tsanaktsidis
Looking at this synthesis it very much has an appeal to amateur chemistry, for the most part using fairly accessible reagents and leading to a
structurally and energetically, this point will be further explained when talking about real world applications, product. By simply exceeding the path
to include the barium hydroxide catalyzed decarboxylative cyclisation of adipic acid to the starting cyclopentanone, which can be achieved in yields
of 75-80% according to Thorpe [4], one can easily prepare the only considerably hard to get precursor from a widely available chemical. This process
has long been documented on YouTube by Tom‘s lab [5], and has been improved accessibility wise by Tom from Extractions&Ire to use sodium
carbonate as the catalyst with only a minor loss in yield [6].
So, in August of 2020, Tom from Extractions&Ire embarked on attempting this journey of a project, with many other YouTubers soon following
[7][8][9][10][11][12][13], and myself as well, starting a “cubane race“ which ended up being won by Sam from the channel Chemiolis with the
synthesis of dimethyl cubane-1,4-dicarboxylate in Mai of 2023 and the synthesis of unsubstituted cubane in June of the same year [14][15]. While most
of the above mentioned YouTubers never ended up finishing this journey (it is worth noting that Lumiray still seems to be going and that Saffron
Ravenspear has made cubane at this point but simply hasn’t uploaded a video on it yet), Tom did end up successfully preparing a tiny
quantity of the dimethylester in December of 2023 only using hardware store materials, therefore seemingly concluding this short but exciting chapter
of chemistry on YouTube [16].
But due to the previously rather disappointing quantity, in late December of last year, Tom decided to revisit this whole synthesis on a significantly
larger scale, with the eventual goal of preparing energetic derivatives of cubane, and it will be exciting to see how this will turn out [17].
Now that we are already talking about energetic derivatives of cubane, this unsurprisingly is the most obvious and famous real world application of
this compound. With cubane‘s very unfavorable bond angles there is a lot of internal energy in this molecule, with even the simple dicarboxylic acid
having been reported to detonate on attempted kugelrohr distillation [18], making it a great basis for different energetic compounds of great
potential, most famous one being octanitrocubane, which has first been prepared in 1999 by Eaton and Zhang [19]. Most interestingly this compound,
while being tremendously powerful, is actually quite insensitive, giving it great practical potential, if we ignore the unachievably long synthesis.
Some other examples in that regard also include cubane‘s nitrocarbamate esters and their salts which have only recently been first prepared and
evaluated by Bartonek [3][20].
Fig.3: Two energetic derivatives of cubane
Even more interesting is cubane’s potential as a pharmaceutical building block though, as the use of 1,4-disubstituted cubanes instead of
para-substituted benzenes in pharmacologically active compounds like benzocaine has been shown to oftentimes give improved effects and, ironically,
increase metabolic stability [21]. This is, at least for the most part, due to the geometry of cubane shown in the figure below, while lacking double
bonds which may be attacked by undesired oxidative processes in the human body.
Fig.4: Cubane‘s geometry leading to its biosteric properties
While all named applications so far are exclusively research work not yet commercialized due to the high production cost of the cubane system, we will
hopefully see this change eventually, both for the given practical benefits, and the excitement of what feels like a new yet to explore branch of
organic chemistry.
Sources:
[1] Eaton, P. E. Cole, T. W. (1964). The Cubane System. J. Am. Chem. Soc., 86/5, 962–964
[2] Tsanaktsidis, J. Bliese, M. (1997). Dimethyl Cubane-1,4-dicarboxylate: A Practical Laboratory Scale Synthesis.
Aust. J. Chem., 50/3, 189-192
[3] Bartonek, A. et al. (2023). Sensitive 1,4-Disubstituted Nitro-Containing Cubanes: Structures and Properties. J. Org. Chem., 88/18, 12884–12890
[4] Thorpe, J. F. Kon, G. A. R. (1925). Cyclopentanone. Org. Synth., 5/37
[5] https://youtu.be/AyFKsOUNA9I?si=YUAToTJ2QU5YLhG6 ; last accessed: 04.05.2025
[6] https://youtu.be/wepageDzQhw?si=M87BMsrUwph8SiIF ; last accessed: 04.05.2025
[7] https://youtu.be/yNqj-j2Nb7Q?si=MxQJHnphbiaaEib6 ; last accessed: 04.05.2025
[8] https://youtu.be/FKsGdWkeKZs?si=vas_Bh3KAGstlNkF ; last accessed: 04.05.2025
[9] https://youtu.be/9eWgirvNrYg?si=P5DtbLzUTnT6IUjs ; last accessed: 04.05.2025
[10] https://youtu.be/U0chHMCubF8?si=Ntgjd_UaVZEaVCM1 ; last accessed: 04.05.2025
[11] https://youtu.be/5MK4Xpb0Bjc?si=bBQKYc9DOVQT_JFt ; last accessed: 04.05.2025
[12] https://youtu.be/TmwU1NNc-EI?si=5w0K0NCF5nIPz3XA; last accessed: 04.05.2025
[13] https://youtu.be/lLayBaF2xMI?si=w5GycoiDljdGYNGA ; last accessed: 04.05.2025
[14] https://youtu.be/zjp1aR6dSh4?si=B-ihF9xDbPtMd1Yz ; last accessed: 04.05.2025
[15] https://youtu.be/v6jqlL5ZT3M?si=wOUNfbBm9Uf6AsK7 ; last accessed: 04.05.2025
[16] https://youtu.be/BmzCsJUH2m8?si=7xRc8d9TG5xq5vjT ; last accessed: 04.05.2025
[17] https://youtu.be/BXeEew6gDug?si=x135zJK_sXgjclBM ; last accessed: 04.05.2025
[18] Fluorochem Inc. (1989). CUBANE DERIVATIVES FOR PROPELLANT APPLICATIONS. AD-A210 368
[19] Eaton, P. E. Zhang, M. X. Gilardi, R. (2000). Hepta- und Octanitrocubane. Angew. Chem., 112/2, 422-426
[20] Bartonek, A. et al. (2024). Energetic Salts of Cubane-1,4-Dimethylnitrocarbamate. Inorg. Chem., 63/43, 20870–20877
[21] Benjamin, A. et al. (2016). Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere. Angew. Chem., 55/11, 3580-3585
[Edited on 4-5-2025 by Niklas]
[Edited on 4-5-2025 by Niklas]
[Edited on 5-5-2025 by Niklas]
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Niklas
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Synthesis of Cyclopentanone ethylene ketal (1,4-dioxaspiro[4.4]nonane)
A 2 l round bottom flask, set in a glycerol bath on a magnetic stirrer, was charged with 400 ml cyclopentanone (4,52 mol) and 800 ml cyclohexane as
the solvent. The mixture was stirred to result in a clear solution, 640 ml of ethylene glycol (11,48 mol) added forming a separate layer, followed by
5 g of strongly acidic cation exchange resin as the catalyst (Note 1). A Dean-Stark apparatus utilizing a Dimroth condenser was set up, and the
mixture heated to a reflux by warming the glycerol bath to 120 °C until the water generation had largely subsided, in total collecting 310 g of
distillate (Note 2).
After cooling the now light yellow cyclohexane layer was decanted from the small amount of unreacted glycol and the cation exchange resin, the dark
yellow glycol layer extracted twice more using 50 ml cyclohexane each, and the combined extracts dried over anhydrous sodium sulfate. The drying agent
was removed by filtration through a piece of glass wool, the cyclohexane removed by rotary evaporation, and the remaining clear yellow solution, which
has a strong characteristic smell, transferred to a 1 l three-neck round bottom flask set up for fractionated vacuum distillation through a 20 cm
Vigreux column, utilizing an Anschütz-Thiele adapter to allow to take fractions. The crude product was then distilled under vacuum (Note 3), first
collecting around 150 ml of distillate at 36-39 °C likely consisting of residual cyclohexane (Note 4), and then, after increasing the vacuum, finally
the product at 102-105 °C while simultaneously increasing the glycerol bath temperature from 120 to 150 °C to allow for a constant distillation
rate. From this 496,6 g (87,5%) of a clear colorless liquid having a strong characteristic smell (Note 5) were collected. n20D:
1.448 ; 1.448 (/ 1.469) lit.
Note 1: The cation exchange resin used was purchased from Merck KGaA. Alternatively para-toluenesulfonic acid may be used as a catalyst and toluene as
the solvent, initially resulting in a much darker reaction mixture, but still ending up in an acceptable 80% yield. In this case one has to neutralize
the acid by washing with sodium carbonate solution before the distillation though.
Note 2: As excess glycol is used, which forms more water on cyclizing to 1,4-dioxane, the quantity of water collected is not a good indicator for the
end point of the reaction (the theoretical maximum would have been around 81,5 g). To avoid excessive refluxing one can track the progress of the
reaction by TLC (4:1 hexane / ethylacetate) using a vanillin stain.
Note 3: One has to keep the vacuum somewhat low initially as the mixture tends to foam really strongly, at the time I didn’t have my vacuum gauge
connected, but based on the boiling point of the presumably cyclohexane fraction I would assume pressure of around 220 mbar. One may also just remove
the cyclohexane at atmospheric pressure to get around the issue of foaming entirely.
Note 4: Even though this fraction had a clear ketal smell redistillation did not yield any notable quantity of additional product.
Note 5: I find it really hard to describe its smell and even after discussing with other people having handled it we did not manage to come up with a
good description. In literature its smell is oftentimes described as “minty“, but to me that seems completely off.
Pictures:
Fig.1 The apparatus used for the reaction
 
 
Fig.2-5 Performing the reaction
Fig.6 Removal of the cyclohexane by rotary evaporation
Fig.7 Vacuum distillation of the product
Fig.8 The final cyclopentanone ethylene ketal
[Edited on 5-5-2025 by Niklas]
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Niklas
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Badly executed small scale synthesis of the bisketone and what may be improved
Below my above mentioned previous synthesis of around 20 g of bisketone starting from 40 g cyclopentanone ethylene ketal will be described.
In this case the bromination and Dields-Alder reaction were combined in a one-pot sequence according to [1], due to the large volume of the mixture I
will likely be isolating the tribromide on my large scale run though as I‘m limited to using a 4 liter flask at maximum.
endo-2,4-Dibromodicyclopentadiene-1,8-dione diethylene ketal (“Bisketal“):
A 500 ml three neck round bottom flask, equipped with a 250 ml pressure equalizing addition funnel, a gas adapter leading to an argon line, and a
calcium chloride filled drying tube connected to a piece of hosing leading into the shaft of the fumehood, was charged with a 40 g cyclopentanone
ethylene ketal (312 mmol) and 250 ml absolute 1,4-dioxane (Note 1) resulting in a clear colorless solution. The addition funnel was charged with 50 ml
of bromine (976 mmol) (Note 2), the air removed by quickly running argon through the system, and the gas adapter switched out for a jointed
thermometer. The flask was then submerged in an ice bath, and the bromine slowly added with strong magnetic stirring at a rate so that the temperature
stays in the range of 10-20 °C (Note 3). Initially the bromine instantly discolors on addition resulting in a yellow solution, only shifting to a
wine red towards the end, after which stirring was continued at room temperature for two days.
The now cherry red solution of the tribromide was then transferred to a 1 l three neck round bottom flask (Note 4) set in a heating mantle, equipped
with a 250 ml pressure equalizing addition funnel, a mantled Dimroth-condenser set up for reflux and the gas inlet of a fritted gas-washing bottle,
and a majority of the dissolved HBr removed by bubbling argon through the mixture for a couple of minutes (Note 5). The gas inlet was again switched
out for a jointed thermometer, and, with strong magnetic stirring, a solution of 86,7 g sodium hydroxide (2,17 mol) in 435 ml methanol added through
the addition funnel first dropwise and later in a constant stream so that the temperature remains between 30 and 40 °C, causing the mixture to first
turn a cloudy orange from sodium bromide precipitating, and suddenly a blackish-brown. After the addition was completed the mixture was refluxed for
20 h to bring the reaction to completion, during which time it further darkened, and the still warm suspension poured into 1,1 l of distilled water.
After standing in the fridge over night the solids were removed by vacuum filtration through a Büchner funnel, the filter cake throughly washed with
water and twice with a small quantity of -20 °C methanol each removing most of the color, and dried on the air till constant weight (Note 6). From
this 29,77 g (47%; 88% lit.) of the bisketal intermediate were collected as a slightly beige powder that was used as such in the deprotection without
further purification.
Note 1: Commercial dioxane was absolutized using sodium / benzophenone and stored under argon over 3Å molecular sieves.
Note 2: The bromine was prepared by the oxidation of sodium bromide with sodium persulfate and and used as such after shaking with sulfuric acid to
dry.
Note 3: Initially there is a significant exotherm but towards the end of the addition this had largely subsided.
Note 4: One could have performed the synthesis in a 1 l flask straight up, I just originally underestimated the volume resulting from doing the
process one-pot.
Note 5: This step isn’t exactly necessary but it strongly reduces the exotherm on addition of the sodium hydroxide solution.
Note 6: By evaporating the mother liquors to a volume of 500 ml some further product could be isolated as a sticky brown solid crystallizing as beige
crystals on recrystallisation from ethanol / water with some activated charcoal added, this ended up being lost because of an accident though.
Fig.1 The apparatus used for the bromination
  
Fig.2-4 The progress of the bromination
Fig.5 The apparatus used for the Diels-Alder reaction
   
Fig.6-9 The progress of the Diels-Alder reaction
Fig.10 The (slightly wet) bisketal
endo-2,4-Dibromodicyclopentadiene-1,8-dione (“Bisketone“):
While stirring magnetically, to a 250 ml round bottom flask charged with 90 ml of 96% sulfuric acid, was added all the previous product (73,3 mmol) in
portions resulting in a dark brown solution, the flask capped with a stopper, and the mixture stirred for 36 h at room temperature (as it was
currently around 10 °C in the lab the flask was submerged into a water bath warmed to 25 °C). During this time the solution further darkened to
almost a black color, and the product was precipitated by carefully pouring into 500 ml dest. water. After cooling the solid was removed by vacuum
filtration through a Büchner funnel and washed acid free using dest. water, from what, after drying under vacuum, 20,69 g (88,9%; 84% lit.) of a
beige solid resulting melting at 162-164 °C (164-165 °C lit.) (Note 1).
For further purification things were recrystallized from ethylacetate (around 120 ml required) with a spatula of activated charcoal added to remove
colored impurities. On cooling to -20 °C 13,86 g of a slightly off-white crystalline solid were collected as the first crop, and on evaporating to a
volume of around 20 ml under vacuum and once again cooling in the freezer 2,85 g (71,8% total; 88,9% lit.) further product, being ever so slightly
darker, could be collected (Note 2). This product appears to have quite a reasonable purity according to 1H-NMR analysis (DMSO-d6).
Note 1: As the following [2+2]-cycloaddition tends to quickly darken anyway this product may likely already be sufficiently pure to be processed
further.
Note 2: Another small crop could be isolated by concentrating down to a volume of around 5 ml I have not yet gotten to filtering.
  
Fig.11-13 The progress of the deprotection
 
Fig.14-15 The crude (left) and recrystallized (right) bisketone
Fig.16 The NMR spectrum of the final bisketone product
A couple notes on what may be improved in the future especially in the bromination Diels-Alder sequence. First of all I‘ll definitely be further
purifying my bromine, as I mentioned I simply dried by shaking with concentrated sulfuric acid this time, but it’s questionable whether that’s
really sufficient for such a rather sensitive reaction so I‘ll definitely be redistilling over phosphorus pentoxide next time. And on the second
note, which isn’t really of relevance to me anymore as I’d be running things separately in the future, it apparently, according to experimentation
done by Saffron Ravenspear, is advisable to only add hydroxide solution until the dark brown color start appearing, yielding a much purer product even
without performing the lossy methanol washes described above, in an overall better yield.
Sources
[1] Collin, D. E. et al. (2020). Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry. Synth., 53/7, 1307-1314
[Edited on 5-5-2025 by Niklas]
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Niklas
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Got the exact lamp Bartonek has reported using for the UV step, only cost around 70 bucks so that’s convenient.
Planning on doing a test run of the [2+2] on a small scale this weekend.
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BromicAcid
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Very cool endeavor. I'm in your boat, make it just because it's cool. Like when I first heard about fenestranes. Wishing you all the luck in the
world on this one, thanks for the updates!
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Niklas
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Thank you! Yeah fenestranes really are a cool class of compounds as well. Been thinking to attempt Kuck‘s [5.5.5.5] fenestrane synthesis for a while
now too, made a bunch of DBA for that years ago, but eventually just set it aside and never got to continuing, mostly because I kept failing with
preparing the indane-1,3-dione. Once I‘ll be working on the synthesis of centrohexaindane I will be revisiting that Claisen though, and once I have
successfully done that the Fenestrane should be fairly straightforward as well.
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Dr.Bob
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Very nice work. I wish some of the my students in organic labs had done anywhere near that quality of work back when I TA'ed labs.
I used to do more interesting work like that, but now mostly do scale up of contracted stuff, which is not nearly as much fun. But I still enjoy the
joy of making something new or unique when I can.
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Niklas
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Quote: Originally posted by Niklas  | | Note 1: The cation exchange resin used was purchased from Merck KGaA. Alternatively para-toluenesulfonic acid may be used as a catalyst and toluene as
the solvent, initially resulting in a much darker reaction mixture, but still ending up in an acceptable 80% yield. In this case one has to neutralize
the acid by washing with sodium carbonate solution before the distillation though. [Edited on 5-5-2025 by Niklas] |
A further note on this, after some discussion with Saffron Ravenspear I deem it likely that when using TSA the distillation rate has a large impact on
the rate of darkening / tar formation, with fast reflux rate being preferable, as with a slow rate the water can stay around in the reaction mixture,
likely allowing some TSA to turn back into sulfuric acid, which then causes the formation of colored aldol type products (both from the cyclopentanone
and acetaldehyde which likely forms from the excess glycol).
When I did things I refluxed things rather mildly so I can feel safe running things over night, while Saffron vigorously refluxed in a 250-300 °C
heating mantle, and for me as I mentioned things resulted in a really dark red mixture, while for Saffron it ended up being a light yellow. It is
worth mentioning though that the color, as far as there isn’t actual solid tar, isn’t a good indicator for the end result as my yield of 80% still
ended up being more than satisfactory and actually exceeds Saffron‘s yield, probably as I ran it for fives day straight rather than “just“ three
days, or because I used a larger excess of glycol which seems to help with the yield quite a bit, or both, who knows.
 
Also on the UV step, I ended up dropping the lamp and breaking it (whoops), but luckily the company was kind enough to give me a refund as there
appeared to be a malfunction anyway so in the end it’s just delaying things slightly.
And when I‘m already at it, I recently managed to cheaply get a 2 l reactor with a NS45 central joint (30€ including a few more pieces of
glassware), and I‘m planning on using that on scaling up the UV step. I just gotta get a fitting internal tube, but that should be cheap to just get
custom made. For cooling I‘ll just put reactor in a bucket and let a stream of cold water from my thermostat chiller run over it.
 
[Edited on 15-5-2025 by Niklas]
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chempyre235
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Masterful work, as always! Every time I see pictures of your lab, I get a little bit jealous. It looks nice.
I was recently reading about a theoretical derivative called "hypercubane" which would resemble the 4-dimensional cuboid, called a tesseract or
hypercube. I wondered if it could be possible to synthesize this from cubane. So, I did a bit more reading.
I was thinking, monohalogenated cubane could undergo dehydrohalogenation to cubene, which is unstable, but easily partakes in Diels-Alder-type
reactions. By applying the Hunsdiecker or comparable reaction to the dicarboxyl cubane, you should get the dibromo derivative, which can be used to
get the cubene. This can be combined with butadiene to get the 3-cyclohexene-cubene fused ring product. This could continue until all four parallel
bonds are occupied by cyclohexenes. Then, the rings would have to get ethylene bridges somehow...
What are your thoughts?
https://en.wikipedia.org/wiki/Hypercubane
https://www.ch.ic.ac.uk/local/projects/b_muir/Cubane/Cubanep...
https://en.wikipedia.org/wiki/Cubane
 
[Edited on 5/15/2025 by chempyre235]
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Niklas
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Thank you!
Hypercubane really is an interesting compound indeed, first read about I believe two years ago, and honestly put way too much thought into it since
then, without ever coming up with anything good or practical. It doesn’t seem that hard to come up with a synthesis that would make it, but making
that synthesis have a higher yield than 0.001% and short enough to actually be doable, well that’s the hard part.
Same I reckon unfortunately applies for the path you suggested, while it seems like a logical idea, this would only insert two of the cyclohexene
rings with bad control of the regioselectivity (if we imagine using a dihalide accessed from the dicarboxylic acid), and that likely in a fairly bad
yield as this is more of a capturing reaction than a synthetically viable one (milder elimination approaches of course make things more usable, but as
those are based on AB-eliminations you‘d spend a whole lot more effort to still only end up installing two rings). And while I‘m sure there would
be ways going from this, this would simply be unbelievably much effort with a lot of uncertainty connected.. Cubane and the typical derivatives just
don’t feel like good starting points due to the inherent difficulty of late substitution and reactions on cubane, what most of my previous
approaches had been based on is to create a top plane in some way, dimerize a corresponding cyclobutadiene derivative, and then connect the remaining
four double bonds between the planes, but I ended up discarding most of that because of the quite impossible geometry of the required cyclobutadienes.
My latest idea I‘m taking in consideration is to use octa-cycopropylcubane or a similar derivative as a starting point, as this is available in two
steps from dicyclopropylacetylene (https://onlinelibrary.wiley.com/doi/10.1002/anie.200605150), and already has the “octamethylcubane“ structure with the possibility of further
substitution in place. But that was just a random thought I haven’t yet tried going from further. If I manage to come up with something I‘ll
definitely mention it here though.
Anyway, new UV lamp is here, finally running as it should, this time being a little more careful with things.
Directly set up a small test run of the [2+2] using 1,4 g of bisketone, following Bartoneks procedure, details will be given once I‘ll put together
an actual writeup of that run like I did for the previous steps.
   
[Edited on 16-5-2025 by Niklas]
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Niklas
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Small scale synthesis of crude cubane-1,4-dicarboxylic acid
The below [2+2]-cycloaddition was performed using a Philips UV-B PL-L 36W/01/4p 2G11 as described by Bartonek in [1]. The following Quasi-Faworskii
was also performed according to this procedure.
Cubane-1,4-dicarboxylic acid (crude):
In a 50 ml double walled two neck reaction flask (Note 1), equipped with a gas inlet tube on the side neck, 1,4 g of the Bisketone (4,4 mmol) were
suspended in a mixture of 45 ml methanol and 8 ml dest. water. 75 μl of concentrated sulfuric acid (1,4 mmol) were added with the help of an
Eppendorf pipette (Note 2), and the mixture magnetically stirred until all the solids eventually fully dissolved resulting in a yellowish solution,
which was then sparged with argon for approximately 15 minutes and the flask capped. The mixture was irradiated with a 36W UV-B narrowband lamp for 24
h while passing water through the mantle of the flask to cool (Note 3), after which the mixture had turned notably more yellow and no more bisketone
could be detected on analysis with TLC (3:1 hexane / ethylacetate; cerium(IV)-sulfate / polymolybdic acid stain). Bisketone rf=0,45; Cage intermediate
rf=0,09 (Note 4)
The product solution was transferred to a 100 ml round bottom flask, the reaction vessel washed out with more methanol, and the methanol then removed
by rotary evaporation, resulting in a yellow aqueous residue which was diluted with 10 more ml of dest. water and heated in a heating block warmed to
110 ° C for 2 h (Note 5). After cooling a solution of 4,05 g sodium hydroxide (101 mmol) in 15 ml dest. water was added at once to the now orangish
solution, causing things to instantly turn brown, and the resulting mixture heated under reflux for 5,5 h in a heating block warmed to 120 °C with an
Allihin condenser attached. After cooling somewhat 10 ml of fuming hydrochloric acid were carefully added to acidify, and after cooling in the fridge
the precipitated solid was collected by gravity filtration, washed with a little dest. water, and dried under vacuum till constant weight. From this
303 mg (35,8%; 68% lit.) of a light brown powder was collected which was used in the esterification without further purification.
Note 1: While borosilicate isn’t fully transparent at the required wavelength of around 315 nm a borosilicate reaction vessel will do just fine. As
far as a narrowband lamp isn’t used it’s actually less preferable to use quartz as the borosilicate acts as a filter from the lower wavelengths
which cause undesired side reactions to occur.
Note 2: The exact amount of sulfuric acid used doesn’t strictly matter. Therefore, in case a microliter pipette isn’t available, one may just add
1-2 drops of the acid.
Note 3: The lamp itself doesn’t require any cooling as its temperature doesn’t exceed approximately 60°C even on running for multiple hours.
Note 4: It is worth noting that the cage compound shown in figure 1 of the introductory post is almost fully present as the dihydrate to release ring
strain, therefore explaining the high polarity and low rf.
Note 5: This step presumably serves the purpose of hydrolizing any dimethylketal that may have formed during the UV-reaction.
The yield honestly is kind of disappointing, but for a first run it’s acceptable I guess, besides that I still have some mother liquors to
potentially concentrate and get more product out of.
Pictures:
   
Fig.1-4 The [2+2]-cycloaddition
Fig.5 TLC of the reaction mixture
Fig.6 Removal of the methanol
 
Fig.7-8 Hydrolysis of potential Dimethylketal byproducts
  
Fig.9-11 The Quasi-Faworskii reaction
Fig.12 The crude diacid
Sources:
[1] Bartonek, A. et al. (2023). Sensitive 1,4-Disubstituted Nitro-Containing Cubanes: Structures and Properties. J. Org. Chem., 88/18, 12884–12890
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Niklas
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Now that it seems like I have the basic idea of the synthesis figured out and only have to scale things, still have to do the esterification of course
which I just set up, it’s time for me to start thinking about the synthesis of some derivatives.
There is quite a few things to try, but one obvious one which was partly my original motivation to make some cubane back when I started in 2022 is to
make some energetic derivatives, most notably the classic nitrocubanes.
The simplest one to access from the diacid would unsurprisingly be the 1,4-dinitro derivative, and the typical synthesis consists of converting the
diacid to the diacid chloride, react that with a source of azide, convert to the diamine by a Curtius, and oxidize using DMDO. There is one notable
downside to this, and that is the Curtius rearrangement being rather sketchy to perform on such a substrate, having two acyl azides on an already
strained structure really isn’t ideal.
So what I came up with, with some suggestions from Saffron, is a modified Lossen rearrangement which may allow direct access from the dimethylester to
the diamine.
This would be based on first generating free hydroxylamine from the hydrochloride with the potassium carbonate, which could then substitute the ester
forming an acyl hydroxylamine intermediate, which could then rearrange itself to the diisocyanate from the carbonate (https://www.sciencedirect.com/science/article/abs/pii/S00404...), which could of course be hydrolized to the diamine as it‘s also the case when
performing the Curtius.
This will probably be the first experiment I will try with my cubane, so if you have further suggestions on that I would like to hear.
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Lionel Spanner
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That's a good idea, putting the UV lamp inside the vessel - it saves you having to buy quartz flasks, and as a bonus, borosilicate glass blocks the
majority of the UVC on the way out. Having the lamp outside the vessel always struck me as being very inefficient.
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Niklas
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Having a type of immersion well reactor is by far the most efficient way to perform the UV step yeah. For small scale an external lamp is fine, not
that you even really have an option in this case as the reaction vessel is much smaller than the lamp (what Saffron has been doing is to run the
reaction in a Schlenk tube and have a cold finger inside for cooling of the mixture, thought that was quite a nice idea that doesn’t require as
specialized glassware as I used), but on scaling like I’m planning in my 2 l reactor outside irradiation becomes really inefficient.
Talking of that, the glassblower sent me a picture of the tube, will only get it in two weeks but I‘m definitely excited (let’s really hope the
lamp fits xd).
Now getting back to my idea of preparing cubane derivatives, as I very briefly mentioned in the introduction my eventual goal is to prepare some
cubane-biosteres of some psychdelic phenylethylamines. Originally I had a plan of preparing “cubane 2C-B“ simply because 2C-B is probably the most
classic psychedelic of that substance class and because decarboxylative halogenation on cubane is well documented, and had proposed a seemingly pretty
reasonable path, but as I learned recently cubanols have a strong tendency to fragment, and at least one intermediate would be such a compound, and
therefore the path didn’t seem as ideal.
So, ideally one would just install the two methoxy groups by substitution of an intermediate such as the bisketal before even reaching a particularly
strained intermediate, most easily done on the non-bridged cyclopentane ring. Unfortunately though, when trying to make the classic 2C-B biostere this
way, one of the methoxy groups would strictly have to be located on one of the bridgehead carbon atoms, which would be extremely annoying to install
to say the least. However, as Shulgin determined in his early research of trying different mescaline isomers, 2,5-diMeO-4-R isn’t the only active
substitution pattern, ignoring the rather inactive 3,5-diMeO-4-R mescaline pattern, and 2,6-diMeO-4-R, called the Ψ-2Cs, are almost as active /
potent generally. Those have barely been explored in the aryl world due to the considerable difficulty to prepare such a meta substituted system
especially considering the particular simplicity of the normal 2C pattern, but in the cubane world they may actually be the easier targets.
So I came up with the above path, installing the first methoxy group by conjugated addition on the monoketal followed by Saegusa-Ito oxidation to
replenish the double bond. The second methoxy group would be installed by Hassner-Rubottom oxidation followed by simple methylation, and the cubane
system then constructed and substituted by classical means.
Some notes should be made for the installation of the cubylethylamine unit, as this isn’t as simple of a process as it is for the aryl equivalents
where you have the simple option of performing a Henry followed by reduction. Even if one would have an intermediary cubyl carbaldehyde to use for a
potential Henry approach, as there wouldn’t be any aromatic stabilization on the nitroalkene I would guess the “nitrostyrene“ to be really
unstable lowering the yield significantly. Because of this, together with the added inaccessibility of those aldehyde precursors, I proposed to first
perform a modified Claisen condensation alkylating the cubyl carboxyl chloride with the nitroenolate of nitromethane (or nitroethane if the
“amphetamine“ is targeted), followed by reduction of both the nitro group and ketone by the action of LAH and aluminumtrichloride.
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wildfyr
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For UV reactions like this, use a photosensitizer to improve your yield.
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chempyre235
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Using cubanes as isosteres is an interesting concept. I'd imagine there are a few properties about it that change the effects and toxicity somewhat.
For instance, benzenes (and several other aromatic hydrocarbons) are strongly carcinogenic for their ability to oxidize and become intercalated
between nucleotides on the DNA strand, resulting in transcription errors. I can't imagine cubanes would be able to fit the same way, and their
relative inertness would prevent oxidation in the first place.
As for cubane itself, is there some kind of aromatic behavior, is aromaticity possible? Some carbon clusters like adamantane (2+) and
buckminsterfullerene (10+) display spherical aromaticity when protonated.
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Niklas
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@wildfyr The conversion of the UV cyclisation itself should be basically quantitative, as the lamp is already in the right range there would be no
purpose in adding a sensitizer. There is of course the UV-A mediated approach Tom and Sam used that does use benzophenone as a sensitizer, but
honestly it sucks, yield is quite a bit worse, it‘s much less clean (the reaction mixture goes completely brown as compared to using UV-B straight
up where the color only slightly darkens to a yellow), and the benzophenone ends up being kind of more annoying to remove than it is described in the
corresponding paper (https://pubs.rsc.org/en/content/articlelanding/2023/ob/d3ob0...). While it is obviously more accessible, considering the lamp Bartonek is using
still just costs 70€ + maybe 15€ for a ballast, there is not much of a purpose in employing the photosensitized cycloaddition.
Gotta mention that there is an improved version of the benzophenone approach that recently got published that uses xanthone instead which seems to be
quite a bit more suited (https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.20...), but quantitative conversion remains quantitative conversion, so I still don’t
see much of a benefit compared to using UV-B as one would first have to prepare the xanthone which in this case is unnecessary additional effort.
@chempyre235 Have been thinking about there being no potential for undesired aromatic oxidation by something like P450 as well, potentially lowering
the toxicity in some aspects (kinda ironic that something as strained as cubane ends up being more resistant towards enzyme processes than
“stable“ aromatic compounds). And I‘m pretty sure I did read that this is indeed the case, but I can’t recall where.
I would not know about there being a possibility to make cubane display aromaticity, one first glance couldn’t find anything in literature either.
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Niklas
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Small scale synthesis of Dimethyl cubane-1,4-dicarboxylate
The most typical catalyst used for this esterification by far is hydrochloric acid, as has been described in countless papers [1][2][3], and also by
Chemiolis and Extractions&Ire in their YouTube videos regarding that topic [4][5]. In a more recent paper, which is kind of interesting overall as
it’s an improved version of the 385 nm benzophenone sensitized approach using xanthone as I mentioned earlier, cation exchange resin is used instead
appearing to improve yields somewhat (78% vs. 65% looking at Kalpötke‘s yield using HCl), what is obviously a fairly big deal this far down a
multistep synthesis so I decided to go for that. I did however follow the purification described by Klapötke [1], as this conveniently consists of a
simple Soxhlet extraction with hexane which is undoubtedly far superior to both column chromatography and vacuum sublimation.
Dimethyl cubane-1,4-decarboxylate:
All the crude cubane-1,4-dicarboxylic acid from the previous step (303 mg; 1,58 mmol assuming 100% purity) was placed in a 25 ml round bottom flask
containing a stirbar and suspended in 2,6 ml of dried Methanol (Note 1). 36 mg of strongly acidic ion exchange resin (Note 2) were added, the flask
flushed with argon, and the mixture refluxed with an Allihin condenser attached for 16 h using a hot sand bath. During the heating period all the
carboxylic acid dissolved resulting in a dark brown solution, and on cooling a crystalline solid precipitated which was redissolved by addition of 10
ml dichloromethane. The resin was removed by filtration through a piece of glass wool, and the solvent removed by rotary evaporation leaving behind an
amorphous brown solid. This was transferred to a Soxhlet thimble, wiping down the flask with some paper towel to ensure quantitative transferring,
extracted for 26 h using hexanes (Note 3), and the solvent of the yellowish extracts again removed by rotary evaporation. After drying under vacuum
318 mg (91,6%; 79% lit.) of some light yellow slightly waxy flakes were collected. Structural confirmation using NMR will soon follow.
Note 1: The methanol was dried using 3Å molecular sieves. As the reaction can also be performed with aqueous hydrochloric acid as the catalyst I
doubt it really matters too much though.
Note 2: The cation exchange resin used stems from a Merck sample part of the Ph. Eur. reagent kits supposed to be used by pharmacies. It’s the same
catalyst that was used in the cyclopentanone ethylene ketal synthesis described above).
Note 3: The time needed is of course dependent on the reflux rate, I just ran it for this long because I wouldn’t have the time to work up before
that anyway. When following this procedure you should decide yourself when things are done, ideally by taking small samples of the solvent currently
in the Soxhlet and evaporating on a watchglass.
This yield is pretty damn impressive (surprised that I can say that for once in this synthesis lol), and I honestly don’t know of a reported
literature yield higher than that. Of course the product is still quite yellow, but in many sources it is described as an off-white to yellowish solid
even though appearing pure in the NMR, so I am quite hopeful that this isn’t full of some undesired junk either.
Pictures:
 
Fig.1-3 The esterification
 
Fig.4-5 The crude product and purification by Soxhlet extraction using hexanes
Fig.6 The final product
Sources
[1] Bartonek, A. et al. (2023). Sensitive 1,4-Disubstituted Nitro-Containing Cubanes: Structures and Properties. J. Org. Chem., 88/18, 12884–12890
[2] Collin, D. E. et al. (2020). Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry. Synth., 53/7, 1307-1314
[3] Tsanaktsidis, J. Bliese, M. (1997). Dimethyl Cubane-1,4-dicarboxylate: A Practical Laboratory Scale Synthesis.
Aust. J. Chem., 50/3, 189-192
[4] https://youtu.be/zjp1aR6dSh4?si=mOQjCf5wZlBJ6qfa ; last accessed: 20.05.2025
[5] https://youtu.be/FYLkrnFVGCA?si=FgIDOFS93SsScMaR ; last accessed: 20.05.2025
[6] Yan, B. et al. (2024). Synthesis of Bishomocubanone Derivatives via Visible-Light-Induced Intramolecular [2+2] Cycloaddition Reaction. Adv. Synth.
Catal., 367/7
Acknowledgements:
I guess as this is the first “final goal“ of this long projects it’s worth acknowledging some of the people that helped on the way. A big thanks
goes out to Saffron Ravenspear and Andreas Bartonek for giving theoretical advice from their own experiences with this synthesis, without which things
likely would have ended up being a lot more of a pain and at times a lot more discouraging.
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Niklas
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The total yield of that small scale run would be a kinda disappointing 8,9% (80%, 47%, 71,8%, 35,8%, 91,6%) by the way, but as I highlighted
previously it was at times somewhat badly executed and especially on the 47% bromination Dield-Alder sequence there is lots of room for improvement
(and from that also the deprotection yield of 71,8%, as with a more properly executed previous step the lossy purification would become unnecessary).
Also for the [2+2] Faworskii sequence there is still mother liquors to concentrate which do actually already have some more solid precipitating, so
maybe I can manage to still at least reach a two digit yield.
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Niklas
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So, first of all, by concentrating the mother liquors of the diacid to a volume of 10 ml, filtering off the solid, extracting with methanol (to
separate from the sodium chloride that started precipitating at that point), and removing the solvent by rotary evaporation 130 further mg of a brown
solid could be collected, adding 15,4% to the percentage corresponding to a total of 51,2% (68% lit.). Still not perfect, but if the esterification of
this sample works just as well as for the first crop the total yield from bisketone to diester would at least be pretty close (46,9%; 53,7% lit.).
And on another note, another theoretical cubane synthesis I came up with and would like to hear your thoughts on, this time for 9-azahomocubane (which
I would make the lysergamide of for fun as far as it works, but that’s a different story lol). It‘s based on the synthesis of basketene, where COT
and maleic anhydride are reacted in a Diels-Alder reaction followed by [2+2]-cycloaddition and removal of the two carboxylates by a Trost-Chen type of
reaction, and I‘m sure one could also make the azahomocubane from that by typical techniques, but this would barely be more, if not less practical
than what’s currently reported for azahomocubane.
So instead of doing a [4+2] Diels-Alder I wondered whether maybe a [4+1]-cycloaddition with a nitrene would work (it may not be a direct [4+1] but
proceed via an aziridine which would rearrange by a [1,3]-sigmatropic rearrangement, but that’s irrelevant), and after checking literature those
appear to actually be a thing (https://pubmed.ncbi.nlm.nih.gov/21887836/) so this is what I came up with (using and acyl azide as an exemplary nitrene source, I‘m sure there
are better and especially safer options).
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chempyre235
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Not to change the subject, but I was thinking back to hypercubane. If one were to start with di-t-butyl acetylene, which would undergo [2+2]
cycloaddition to tetra-t-butyl cyclobutadiene. The diene could then be made to undergo addition in a manner similar to the tetra-aryl
derivative. All of the carbons would be there and in the correct locations (roughly), and the cubane core would be protected, but a way to bridge the
methyl groups still eludes me.
Also, do you know what kind of yields you'd be looking at for additions versus the conventional synthesis? I'd imagine they'd much better yields, but
I don't know.
On another note, the aromaticity of adamantane is actually a dication of didehydroadamantane, which forms a tetrahedral aromatic bond at the four
tertiary carbons. Since cubes also have tetrahedral symmetry, I wonder if cubane might be able to work similarly.
Lastly, barrelenes (which can be made from catechol and acetylenes) seem like they might also be viable routes to cubanes.
| Quote: |
Epoxidation of barrelene with oxone gives the trioxatrishomobarrelene, which on rearrangement with boron trifluoride (driving force: relief of strain
energy), converts into the trioxatrishomocubane.
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It can also form cyclooctatetraene photolytically. Perhaps a well-placed sterically hindered leaving group could force isomerization to cubane
instead.
https://onlinelibrary.wiley.com/doi/10.1002/anie.198707611
https://en.wikipedia.org/wiki/Four-center_two-electron_bond
https://en.wikipedia.org/wiki/Spherical_aromaticity
https://en.wikipedia.org/wiki/Barrelene
[Edited on 5/23/2025 by chempyre235]
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Niklas
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Had some thought on hypercubane as well lately, didn’t get anywhere with the idea I once mentioned above, but today I came up with this rough
“unpolished“ path.
It is based on some of Gleiter‘s work, particularly his work on dimerizing cyclobutadiene by fixing the two rings with four 1,3-propylene groups.
 
For this cubane synthesis in particular there ends up being a photoequilibrium created that only contains the product in a ratio of 1:14, but for my
proposed application it would likely be fixed into its position even further and as we know from the tetramerization of something like
dicyclopropylacetylene the dimerization of cyclobutadiene can work in synthetically viable yields at times.
The dienediyne synthesis is unfortunately really low yielding (like 5% at maximum), but not like anyone will be attempting this whole scheme anytime
soon anyway so whatever.
A lot is still just kind of open questions and guesswork, but that’s just how it is sometimes, I will try my best further improving my ideas on
hypercubane‘s synthesis though.
Trihomocubane is a lot less strained than actual cubane so I have my doubts whether barrelenes are really that great of a potential cubane precursor.
But maybe it would be of use somewhere, so neat nonetheless.
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Niklas
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| Quote: Originally posted by Niklas | | So, first of all, by concentrating the mother liquors of the diacid to a volume of 10 ml, filtering off the solid, extracting with methanol (to
separate from the sodium chloride that started precipitating at that point), and removing the solvent by rotary evaporation 130 further mg of a brown
solid could be collected, adding 15,4% to the percentage corresponding to a total of 51,2% (68% lit.). Still not perfect, but if the esterification of
this sample works just as well as for the first crop the total yield from bisketone to diester would at least be pretty close (46,9%; 53,7% lit.).
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It appears that the dark brown residue didn’t contain much actual cubane dicarboxylic acid, as esterification and purification by same means as
described above only yielded 56 further mg (38,6%) of a yellowish solid.
This means in total 374 mg of dimethyl cubane-1,4-dicarboxylate were collected as a yellowish solid / yellowish flakes, corresponding to a total yield
of 38,6% (53,7% lit.) starting from 1,4 g bisketone.
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Niklas
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(Improved) small scale synthesis of dimethyl cubane-1,4-decarboxylate from the bisketone
So I redid the whole synthesis starting from my bisketone at the same scale (4,4 mmol), and even though I did barely any changes to the procedure,
things somehow yielded quite a bit more product in comparison so that’s odd, but I definitely won’t complain. So here is the (a bit more brief, as
it’s the same for the most part) notes of this run.
Cubane-1,4-dicarboxylic acid (crude):
The [2+2]-cycloaddition was carried out in the exact same manner as before using 1,4 g of the bisketone (4,4 mmol), with full conversion being
detected after the 23rd hour on analysis with TLC (3:1 hexane / ethylacetate; cerium(IV)-sulfate / polymolybdic acid stain), again resulting in a
yellow solution. The methanol was removed by rotary evaporation, the yellow aqueous residue diluted with 7 further ml of dest. water, and the mixture
refluxed for 3 h by heating in a sand bath with a Dimroth condenser attached. To the slightly darkened, still hot mixture the sodium hydroxide
solution is quickly added, and the reflux continued for 16 h. On cooling to room temperature the resulting dark brown solution is brought to a pH of
1-2 by addition of 8 ml fuming hydrochloric acid, and after cooling in the fridge the crude diacid is collected by gravity filtration and dried under
vacuum. From this 726 mg (81,6%; 68% lit.) of a glittering brown powder were collected, which was again processed as such without further
purification. Further diacid may potentially be isolated from the mother liquors in the same manner as described for the previous run.
Dimethyl cubane-1,4-dicarboxylate:
All the intermediate diacid (726 mg, 3,8 mmol assuming 100% purity) was transferred to a 50 ml round bottom flask and taken up in 6,3 ml of dry
methanol. To this 86 mg of strongly acidic cation exchange resin were added, the flask flushed out with argon, and the mixture refluxed for 14 h by
heating in a sand bath with an Allihin condenser attached. After working up in the same manner as described above 592 mg (71,2%; 79% lit.) of a light
yellow solid were collected.
In total this corresponds to a yield of 61% (53,7% lit.) over three steps from bisketone to diester.
I‘m currently working on figuring out an approach for purification to remove this yellow impurity without much product loss, will hopefully find
something viable in the nextweek or two. Will also revisit the bromination soon (not with the full 500 ml of ketal but on a maybe 40 ml test scale as
this is currently the only other unsatisfactory aspect of this whole procedure.
Pictures:
Fig.1 The [2+2]-cycloaddition
Fig.2 The crude diacid
Fig.3 The Faworskii reaction
 
Fig.4-5 The crude and purified dimethylester
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Niklas
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Some analysis of the dimethylesters
Finally got around to doing some analysis of the final products, and things appear to have indeed been successful 
For the melting points, the visibly more yellow product from the first less successful run melts at 157-160 °C while the sample of the last run melts
at 161-165 °C (161-165 °C lit.).
For this first sample I also did some further instrumental analysis, and the NMR spectra (done in CDCl3), 13C and 1H,
are shown below.
 
Overall they more or less look as they should, of course not being completely pure, but considering the melting point difference I expected worse.
Based on all this I would guess that when executed properly like in the last run that had a yield of 61% from bisketone to diester further
purification after the Soxhlet extraction isn’t required.
Also ran a GCMS of this less pure product, and the data is shown below.
 
This one is interesting as we can see two Major peaks of similar retention time in the GC which have the same parent peak and overall many same weight
fragments in the MS. Based on this and the NMR data this is likely from the cubane system partly rearranging itself in the gas chromatograph to
something like the cuneane.
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