Synthesis of CD3

PhotoChemist · Jul 13, 2018

Edit: I missed out a step where you brominate the alcohol and use ammonia before you stick on that sulfone like group.

There doesn't appear to be any total synthesis of this in any literature, found a couple of 2 or 3 step routes that used starting materials you'll never find. The near impossibility to find CD3 in the UK and Europe paired with a bit of boredom had me wonder if synthesis is feasible. I got out a pad of paper and this is what I came up with, CD4 is almost doable but the lithium aluminium hydride, can't imagine that being easy to obtain, there's other ways to do this step but not many ways that will prevent over reaction without finding some difficult to obtain chemicals. This was my best attempt at devising a synthetic route with home synthesis in mind, there are nicer ways to do this but the issue is getting the chemicals, which would be even harder than finding CD3 itself.

So I suppose this is for fun/education only and makes it clear just how this isn't something you're going to do at home, this wouldn't be particularly safe without a fume cupboard, step 4 with mesyl chloride is where things fall apart, it's pretty nasty and I don't think you'd have much chance buying it. May have missed some workup details and haven't covered any purification steps, but I think it would be redundant to bother with it at this point. And like I said it was just for a bit of fun.

Anon Ymous · Jul 14, 2018

Apart from the difficulty of finding the ingredients for every step, the lab apparatus needed, the hazards of dealing with some of the ingredients and (by)products, one also has to deal with yields lower than 100% and these quickly add up in a process with so many steps. Certainly nothing you would dare to make at home. I've synthesized some rather easy to make compounds, considered and attempted to make a rather complex one, but this is far beyond what I'd even entertain as a thought. Still an interesting bit of information.

For the record, CD3 is fairly easily obtainable in Europe and I know of at least 3 sources.

GLS · Jul 14, 2018

I see numerous pitfalls (and some errors) with your proposed synthesis.

The methyl bromoacetate in the first box is commercially available (and cheap), as are all the intermediates of its synthesis as shown, so there would be little point in carrying out that synthesis other than as a technical exercise, or if you wanted to produce kilos of the stuff. Your proposed bromination at the end would also possibly produce a mixture of compounds (i.e. over-brominated products), which would then need to be separated (probably by distillation).

Your first two steps in the second box would also very likely fail, for a couple of reasons. Firstly, alkylation of primary amines with alkyl halides is almost impossible to control, as the product you form (a secondary amine) is more reactive (nucleophilic) than the starting material, so you get mixtures with over-alkylation products (i.e. the tertiary amine or even the quaternary ammonium salt). Secondly, anilines are poor nucleophiles, so the reaction would probably require generous heating to proceed, which would only exacerbate the previous problem. A much better choice would be to use reductive amination with the corresponding aldehydes (rather than bromides) for both of these steps. The (missing) proposed amination of your bromide with ammonia two steps after that would have a similar problem; you could however do it from the bromide with a Gabriel synthesis (i.e. with succinimide/base, then hydrolyse the product with hydrazine).

The Friedel-Crafts methylation you then propose is also a terminal problem for the synthesis, in that you would not get that regioisomeric product. The nitrogen in anilines is electron donating into the ring, and would therefore direct the methylation ortho and/or para, not meta as you have drawn it. The nitration as you have drawn it is fine, but again you would probably get mixtures of regioisomers (i.e. not just the 4-nitro, but the 2- and possibly even the 6-nitro compounds too).

Also I agree that this synthesis is definitely not something you could safely attempt at home. LiAlH4 in particular is very dangerous to use without the proper precautions and experience, and tin reagents are also very toxic (you could easily do that reduction with iron & acetic acid instead).

PhotoChemist · Jul 14, 2018

I was a bit tired when i put this together, yea that +M nitrogen would direct to the 2 or 6 position, but it doesn't matter no one is going to synthesise it, when I first scribbled things down I did make that part first, you'd probably face there issue there of though of having to isolate the right isomer. But this just all points to the fact account for the worst case as far as getting reagents, and assuming things worked its not really practical. I agree it would be a messy synthesis.

You can indeed use aniline as a nucleophile, its done in the synthesis of fentanyl although it is a slow reaction, then they follow up with an acid chloride for the final step, I'm guessing they just rely on kinetic control once the secondary amine is made.

I didn't reckon it would be the best means but there's a that limitation of getting decent materials, something being commercially available and cheap doesn't forgo the need to synthesise something, members of the public can't just buy things like this. If we were going to just go by readily available materials you could probably make this molecule in 3 steps. I just chose bromide as they are easily made from materials almost anyone can buy but the need of reducing agents and of course mesyl chloride, make this all a big no.

And yea over reaction for the step I missed out.

PhotoChemist · Jul 14, 2018

Anon Ymous said:
Apart from the difficulty of finding the ingredients for every step, the lab apparatus needed, the hazards of dealing with some of the ingredients and (by)products, one also has to deal with yields lower than 100% and these quickly add up in a process with so many steps. Certainly nothing you would dare to make at home. I've synthesized some rather easy to make compounds, considered and attempted to make a rather complex one, but this is far beyond what I'd even entertain as a thought. Still an interesting bit of information.

For the record, CD3 is fairly easily obtainable in Europe and I know of at least 3 sources.

Can you tell me where?

Anon Ymous · Jul 14, 2018

PhotoChemist said:
Can you tell me where?

Yes, of course.

1) Keten from Poland. Their web server seems to have some problems at the moment. They stock a wide variety of chemicals, many of them photo related. Their email address is office(at)keten.com.pl . Cheap source, although not always the purest chemicals around. Their shipping charges are cheap too. I've used them and never had a problem. Bank transfer is the only payment option.
2) Saban Suvatlar from Germany. He sells a wide variety of photo chemicals (pricelist). The only source for Potassium Hydroquinone Monosulfonate that I know of, useful if you're interested in E6. A bit on the expensive side, but his chemicals are pure and his service is fine. Fluent in english too and you can contact him at fotosuvatlar(at)live.de . You can pay with paypal.
3) Axelcolor from Italy. Their core business seems to be chemicals for minilabs, but they do sell small quantities of chemicals to amateurs. They have an ebay store and you can contact them through ebay. Don't be put off by the €100 shipping charge, it's just wrong. Ask them for a shipping quote instead. Actually, you can also contact them at this email address, where they are more likely to respond quickly: elisa(at)axelcolor.com. They support paypal. I've bought CD4 from them and everything was fine.

Best regards

PhotoChemist · Jul 14, 2018

Edit: There's no Potassium Hydroquinone Monosulfonate in E6, at least not acording to the ekatachrome processing moldule, unless their E6 process differs from Fuji stuff, but surely by now E6 is E6

Anon Ymous, thanks for that. I was thinking about E6,

And GLS, just out of interest are you in industry or academia?

GLS · Jul 14, 2018

PhotoChemist said:
And GLS, just out of interest are you in industry or academia?

Industry. After completing my PhD and postdoc it was very clear academia wasn't for me.

Anon Ymous · Jul 14, 2018

PhotoChemist said:
Edit: There's no Potassium Hydroquinone Monosulfonate in E6, at least not acording to the ekatachrome processing moldule, unless their E6 process differs from Fuji stuff, but surely by now E6 is E6

Anon Ymous, thanks for that. I was thinking about E6,

I'm sure E6 FD uses HQMS-K. It's mentioned in this MSDS by Kodak, as well as patents by both Kodak and Fuji. VNF-1 first developer on the other hand used HQ. There was a thread here several years ago where both HQ and HQMS-K first developers were used. The one using HQ was clearly inferior.

flavio81 · Jul 14, 2018

So we have now a Photo Chemist and a Photo Engineer on the forum? Wowwww!! Great!

PhotoChemist · Jul 14, 2018

flavio81 said:
So we have now a Photo Chemist and a Photo Engineer on the forum? Wowwww!! Great!

My name is a bit deceptive, I thought it would be fun, although not untrue I've done a bit of photochemistry I certainly know a bit about it, it gets complicated pretty quickly thanks to quantum mechanics. These days photochemistry has very little to do with film, there's not much about it in literature although there's lots of good info in patents. Developing couplers and such to increase spectral sensitivity requires a good understanding of photochemistry. Trying to grasp the content of the technology of the photographic technique book I'd say requires a good basis in photochemistry and some wider chemistry. Couplers in film are all about facilitating forbidden (unprobable) electronic transitions, putting it simply allowing electrons to to jump to places they otherwise wouldn't in silver bromide (othochromatice vs panchromatic) and facilitates a transfer to give you that latent image which acts as a seed for development. Then there's all the materials chemistry involved in actually developing an emulsion.

I will say though photochemistry is a very interesting field of chemistry although I'm now tending towards liquid crystals.

PhotoChemist · Jul 14, 2018

Anon Ymous said:
I'm sure E6 FD uses HQMS-K. It's mentioned in this MSDS by Kodak, as well as patents by both Kodak and Fuji. VNF-1 first developer on the other hand used HQ. There was a thread here several years ago where both HQ and HQMS-K first developers were used. The one using HQ was clearly inferior.

So the VNF-1 is old news? I suppose it's telling by the fact it calls for formaldehyde, interesting though that they have published VNF-1 but not the more recent formulation, I wonder what the purpose of this is.

Actually looks like this was updated 2005.

https://www.kodak.com/uploadedfiles/motion/h24_11.pdf

And yea, the MSDS for the chemicals they sell are drastically different.

Anon Ymous · Jul 14, 2018

E6 still uses formaldehyde in the form of formaldehyde - bisulfite adduct in the pre-bleach solution, it is still needed. An amateur will likely use formaldehyde in the final rinse.

The VNF-1 formulae were published, just like the ECN2 ones. They're both motion picture processes after all.

Photo Engineer · Jul 14, 2018

E6 FD uses HQMS-K! Any substitution can yield superficially acceptable results but not with some degradation of the image and some variation across film types.

E6 and VNF-1 are totally different film types.

Being a PhotoChemist implies one studies the chemical reactions caused by light. A Photographic Chemist or a Photographic Process Chemist implies that one works with processes and associated chemicals. I did this for a number of years before moving into product design and then into emulsion work. So, I am an overall engineer I guess.

The synthesis of any CD is fraught with problems associated with aerial oxidation and low yields unless you use the proper equipment. I suggest works by Arnold Weissberger (his huge series of books on Org Syn are a monument to Org Chem), and works by Paul Vittum, both of EK.

PE

Martin Rickards · Jul 14, 2018

What would be even more interesting would be a possible synthesis for 2(beta-hydroxyethyl) aminophenol sulphate so we could have the original Promicrol again. It was what I used for learning how to develop film

dE fENDER · Jul 14, 2018

Martin Rickards said:
What would be even more interesting would be a possible synthesis for 2(beta-hydroxyethyl) aminophenol sulphate so we could have the original Promicrol again. It was what I used for learning how to develop film

This synthesis easy and one step, but deadly in inadequate or amateur conditions.
https://worldwide.espacenet.com/pub...KC=C&FT=D&ND=4&date=19291207&DB=&locale=en_EP

Martin Rickards · Jul 15, 2018

The 30% caustic soda and the benzene are considered "nasty" today, but no worse than trying to understand the German

GLS · Jul 15, 2018

In nearly all cases benzene can be substituted with toluene, or another less toxic solvent.

Martin Rickards · Jul 15, 2018

GLS said:
In nearly all cases benzene can be substituted with toluene, or another less toxic solvent.

In my first job as a lab rat about 50 years ago, benzene was quite normal.with no special safety measures.

GLS · Jul 15, 2018

Martin Rickards said:
In my first job as a lab rat about 50 years ago, benzene was quite normal.with no special safety measures.

Yes safety measures in the past were woeful, to say the least. I remember reading that way back when, in order to get rid of residual powder from their skin/hair, latex factory workers used to take showers laced with benzene at the end of their shifts!

dE fENDER · Jul 15, 2018

Martin Rickards said:
The 30% caustic soda and the benzene are considered "nasty" today, but no worse than trying to understand the German

About 13 ml cloroethanol occasionally evaporated in small closed room would kill human in 2 hours, some less concentrations will cause deep damage to the nervous system. You can consider benzene as a vitamin, compared to this compound.

GLS · Jul 15, 2018

There are many other ways it could be made. Stewing 2-aminophenol up with ethylene oxide in a sealed vessel would probably work, and wouldn't require any other reagents.

dE fENDER · Jul 15, 2018

GLS said:
There are many other ways it could be made. Stewing 2-aminophenol up with ethylene oxide in a sealed vessel would probably work, and wouldn't require any other reagents.

Oxirane is the compound of the same danger level. Of course, all these synthesises are safe in lab conditions with normal working fume hood.

GLS · Jul 15, 2018

dE fENDER said:
Oxirane is the compound of the same danger level. Of course, all these synthesises are safe in lab conditions with normal working fume hood.

True, it's still nasty. Another option would be to use monoethyl oxalylchloride, then reduce the product down with LiAlH4 (but this would be problematic on scale). There are also approaches to make it using palladium catalysed cross-couplings.

It goes without saying that any serious wet chemistry should never be performed without PPE and a fume hood.

PhotoChemist · Jul 15, 2018

Just for the sake of completeness for myself, obviously completely impossible without a sigma aldrich account and a proper fume cupboard. I was a bit drunk actually when I came up with the attempted home brew version hence all the silly mistakes.

Synthesis of CD3

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