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Everado E. Dinavo
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[*] posted on 2-9-2009 at 20:17
Isocyanide Synthesis


Hello everyone,

I am trying to prepare an isocyanide without using any expensive or exotic reagents. So far I have searched all over the internet, the forums here, a few articles (which reference other articles that I do not have access to for the procedures) and orgsyn, and I have found the following methods:

1. N-Monosubstituted amide + deydrating reagent. This is out because the amides are not something I could obtain easily, and the dehydrating reagents are things like POCl3.

2. Alkyl halide + silver cyanide. The expense of the silver cyanide would be an issue. Also I am unsure of the toxicity of it, and would not be comfortable working with it since I have never worked with cyanide salts.

3. Primary amine + chloroform + KOH (Hoffman Synthesis). I have read about using this as a test for primary amines, but I can't find anything else about it, such as the mechanism, typical yield, or exact procedure. I know this method is described in a book by Ugi that I cannot find anywhere, and that is selling for at least $80 used. This seems like the best method to me, especially since I have all of the reagents already. But I don't want to just throw things in a flask and see what happens knowing nearly nothing about the reaction. I would probably use aniline for the amine, but I am somewhat concerned about whether phenyl isocyanide smells worse than other isocyanides. I've worked with them before and can deal with the smell, and I have a decent hood, but I've never worked with phenyl isocyanide.

My question is basically whether anyone knows any details about the Hoffman synthesis, or some other method to isonitriles that I haven't read about.

Any help will be greatly appreciated!
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[*] posted on 3-9-2009 at 04:32


In searching the internet for "isocyanides", presumably covalent (mainly organic) ones, did you use "isonitriles" as a search term? This is what organic isocyanides are usually called, containing the configuration R-N(+)[triplebond]C(-), thereby being both a quaternary ammonium salt and a carbanion. Because of their resulting high polarity, they are much less stable and more easily chemically attacked than nitriles, R-C[triplebond]N, and probably much more toxic on account of this.
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Everado E. Dinavo
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[*] posted on 3-9-2009 at 14:21


Yes, I included isonitriles in my search as well.

I came across an excerpt in an old text on google books today which described Hoffman's procedure for producing phenyl isocyanide. Apparently he did not give an exact protocol when he published his findings long ago, and that might explain the lack of information on it. But at least I have a good idea of where to start now.

R-NH2 + CHCl3 + 3Na/KOH --> R-N≡C, use excess 25% alcoholic hydroxide (water hydrolyzes isocyanides to amides), reflux for an hour, and distill.

After reading the procedure, I think I will try using cyclohexylamine instead of aniline, since cyclohexyl isocyanide will be easier to distill out of the reaction mixture than phenyl (bp 57 instead of 167). The only problem is that the reaction needs alcoholic NaOH, and methanol boils at around the same temperature as the isocyanide. This means I would have to use ethanol (bp 78) to get a 20 degree boiling point difference. I'm thinking about using excess cyclohexylamine so that minimal chloroform will remain in there when it's over, and then distilling out the isocyanide, and redistilling it once more to get as much ethanol as I can out of there. Unfortunately I might be stuck with a significant portion of ethanol in the final product since it might form an azeotrope, and any reagent I can think of using to remove the ethanol will destroy the isocyanide...

As far as toxicity goes, most of the isocyanides are not all that toxic. The MSDS for cyclohexyl isocyanide (which is likely to overestimate the danger of handling it) gives a health rating of 0, which means it is pretty harmless. It probably is too reactive towards water to damage the body much. I have worked with it before and it penetrates latex, which is annoying, but I am not too worried about anything other than getting the smell off of the glassware and out of the hood when I'm done.
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Paddywhacker
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[*] posted on 3-9-2009 at 15:53


Please do a milligram-scale experiment before you think of making an isonitrile in bulk. And read the "worst ever smelling chemical" thread.

If you try what you have proposed in anything except an isolated rural environment you will have hundreds of people panicking over "toxic spill" and a general evacuation by FEMA, toxic spill agencies and possibly chemo-terrorism agencies. It will ruin more than just your whole day.

Edit:-
On the other hand, your chemistry looks feasible. As pointed out, isonitriles cannot be stored ... they polymerize and hydrolyze. But your writeup, when you get out of custody, should make an amusing read.

[Edited on 3-9-2009 by Paddywhacker]
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Everado E. Dinavo
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[*] posted on 3-9-2009 at 19:31


I hope you're exaggerating, because now I'm a bit worried. I've used cyclohexyl isocyanide before, and have been around other people using it outside of a fume hood (I knew better, but they didn't know what they were dealing with). I actually read the "worst stench" thread and was disappointed when I got a whiff of the stuff. I've met people with breath worse than that. A few people on the floor complained that it stank a bit but it went away after a few minutes and that was pretty much it. The distillations are what concerns me since it will all be volatilized at that stage. My hood is pretty good, I usually smell nothing whatsoever when working under there. The hood vents onto the roof of the building, about 50 feet above ground level, and few if any people should be around, so I think it is unlikely that bystanders will notice anything. This is purely speculative though.

I was planning to make 5.6 g on a day when no one would be in the building. Is that considered "in bulk?" A lot of this is going to go straight into an Ugi reaction, and if I have anything left I will ampoule it and hope that it doesn't polymerize before I find a use for it. Part of the reason I chose that scale is that I don't know the yield, and if I get 50% I would never have to do this again.

Anyone who has worked with these: what scale did you use? Is this amount likely to cause attention?
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[*] posted on 3-9-2009 at 20:29


The Ugi book that you mention is a good reference for isonitriles, but the section on their preparation is sparse. The vast majority of the prepretory methods revolve around dehydration of N-alkylformamides using phosgene. Other methods are listed but procedures are omitted.





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not_important
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[*] posted on 3-9-2009 at 21:29


hmmm... CaCl2 binds the lower alcohols similar to the way it does with water.

Alternatively perhaps NaOH in ethylene glycol, distill out the water from the hydroxide-alkoxide exchange, cool, and add other reagents. Obviously you'll not be refluxing the glycol, but on the other hand it's not going to distill out much with the other reagents and products.

And then there is this http://pubs.acs.org/doi/abs/10.1021/ja0644374



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[*] posted on 4-9-2009 at 01:15


I'm sure P2O5 could be used to dehydrate the N-alkylformamides, no? these can be easily made by formin g the anion with NaH or t-BuOK, and addin g amethylating agent once deprotonation is complete.. I have already done this with formamides.. You need to let the amide and NaH to stir at least 30-45min at room temp (addition at 0°C though), and even heat up to 40-50 until H2 evolution virtually ceases, and a slurry of the sodium salt is obtained. Be prepared to use large volumes of dry THF. Then add your methylating agent gradually, at 0°C, there will be more salt formation, so good stirring is a must. Reflux for a couple of hours, following the reaction by TLC (after hydrolyzing sample with EtOH), then when you are done, cool to 0°C and neutralize with EtOH/THF, then water. EXtract aqueous, wash with brine, and evaporate to obtain a crud eproduct you can purify by recrystallization.



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[*] posted on 4-9-2009 at 06:21


Quote: Originally posted by Everado E. Dinavo  

cyclohexyl isocyanide will be easier to distill out of the reaction mixture than phenyl (bp 57 instead of 167)

I can´t believe that the boiling point of cyclohexyl isocyanide is 57°C. In vacuum this could be right, but never at normal pressure!
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Everado E. Dinavo
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[*] posted on 4-9-2009 at 06:46


Quote: Originally posted by grind  
Quote: Originally posted by Everado E. Dinavo  

cyclohexyl isocyanide will be easier to distill out of the reaction mixture than phenyl (bp 57 instead of 167)

I can´t believe that the boiling point of cyclohexyl isocyanide is 57°C. In vacuum this could be right, but never at normal pressure!


Yeah, you're right. I went and checked it again and apparently I missed the 11mm when I looked it up the first time. This complicates things quite a bit...I suppose if I changed the conditions to use equal parts cyclohexylamine and chloroform, then I could use methanol as a solvent instead, boil off MeOH and any remaining CHCl3 at atmospheric pressure, then vacuum distill the isocyanide. If I reconfigure my pump lines a bit I should be able to do this and vent the pump exhaust into the hood. This might actually turn out to give me a cleaner product...

I have decided to scale this back to a gram, that way I can see if it works before I make a big mess and stink. I'll also run an NMR to get a rough idea of the purity. If it looks good I'll scale it up to 5g and post a nice writeup.

not_important, that article looks interesting, but I lack all of the reagents to make those compounds. I'm surprised that the ester group is able to hide the isonitrile odor. Definitely something I'd like to look at in the future. Also good idea with the CaCl2 - I hadn't even thought of using that.

Klute - N-cyclohexylformamide actually has an even easier procedure, involving ethyl formate and cyclohexylamine. I wanted to circumvent that for two reasons: it's an extra step, and I can't find any information on the Hoffman method so I wanted to give that a try and see if it had a decent yield. If this doesn't work, I'll try to make the amide and go that way.
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[*] posted on 4-9-2009 at 11:23


The procedure I outlined is for preparing N-methyl alkylformamides, from N-alkylformamides.

Indeed the most simple and efficient procedure for preparing formamides is refluxing the amine freebase in ethyl formate and removing excess reagent/solvent. I always obtained very clean products in good yields with this method. I also used this method to seperate primary and secondary amines, resulting from unselective N-alkylation of primary amines, by refluxing the crude product mixture in ethyl formate, then adding the solution to excess anhydrous oxalic acid in IPA: the unaffected secondary amine precipitates as the oxalate, while the formamide formed from the primary amine stays in solution.




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[*] posted on 4-9-2009 at 11:53


Very simple way to cyclohexyl formamide:
Reflux cyclohexyl amine with formic acid. Add a solvent (I assume DCM or chloroform should work) in which the product is easy soluble. Wash with cold diluted NaOH (removes formic acid excess completely) and then with cold, diluted HCl (removes amine excess completely). Evaporate the solvent ---> nearly pure amide remains.
The CHCl3/amine/base-way gives usually poor yields. So I strongly recommend to work with the formamide and POCl3. Ok, you expend more effort, but the better yield will hopefully compensate that.
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[*] posted on 4-9-2009 at 22:43


Quote: Originally posted by Everado E. Dinavo  
I hope you're exaggerating, ...

My experience is with phenyl isonitrile. I assume other isonitriles are just as bad, but if you already know your product to be innocuous then I'm sorry for alarming you.
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Everado E. Dinavo
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[*] posted on 7-9-2009 at 15:33


Alright, I gave it a try today and things did not go as well as I expected. I dissolved 1.6 g NaOH in 6.5 mL MeOH. Or tried to, at least. About 2/3 of it dissolved and that had already taken about 30 minutes so I just decided to add in everything else. I put in 1.2 mL cyclohexylamine and 0.85 mL CHCl3 and started heating the bath. Nothing appeared to be happening. Once I hit 50 C, the mixture began to bump badly, so I pulled it off the heat. I assume the heating allowed the rest of the NaOH to dissolve, which was exothermic and heated the methanol to boiling. Some white fumes formed in the condenser at this point. After I got it all cooled down. the reaction mixture was thick and milky and I could not tell if the stirring bar was doing anything or not. I put it back on heat again and set the bath to 65 C. I did not heat to reflux because I was afraid the reaction might be vigorous, but I did not observe anything else occur. After 30 minutes the white mixture had become slightly off-white and I removed it from heat. At this point I realized I made a thoroughly retarded mistake by putting that much NaOH into a glass flask. The condenser was stuck on the flask and I could not remove it. I hope the NaOH that boiled up into the condenser didn't permanently fix the flask on there. I had been planning to remove the flask and transfer it to a vacuum still, but now that I couldn't, I decided just to pour all this crap into waste. I reached under the hood to be greeted by a whiff of cyclohexyl isocyanide. I guess it worked, but I panicked at this point because I was afraid that if the smell was strong enough to get out of my hood, people outside might be able to smell it. I hydrolyzed everything with 0.1 M HCl and put it into aqueous waste. The mixture separated into a top pale brown layer, and a bottom layer with a milky precipitate. I have read that the isocyanide ranges from pale brown to clear. I'm wondering if this was another sign (besides the smell) that it worked. Until I stopped the reaction, I never smelled anything, and I even stuck my head in the hood and took a few whiffs, so it seems to contain it well. Hazmat didn't show up either, which is also good.

I don't know if I'm going to give it another try next weekend or not. Depends on whether or not I ruined my flask/condenser...
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[*] posted on 7-9-2009 at 17:49


Always grease joints exposed to bases like NaOH.

Although I've never smelled cyclohexyl, if it didn't make you gag I have my doubts that you had the desired product.

Your mention of hazmat reminded me of some work I did with mercaptans. Neighbors would call the gas company every time we used them. This was in an industrial park, too. We finally decided to outsmart the neighbors and run the reaction at 2:00 AM. Guess what? The guy from the gas company showed up anyway!
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[*] posted on 8-9-2009 at 17:09


Quote:
Always grease joints exposed to bases like NaOH.


It's better to wrap the male ground glass joint with PTFE tape if one doesn't have PTFE sleeves to prevent seizing from exposure to strong bases :cool:




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entropy51
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[*] posted on 8-9-2009 at 17:31


Why is tape better than grease?



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[*] posted on 9-9-2009 at 18:01


As zed noted in:

http://www.sciencemadness.org/talk/viewthread.php?tid=12383

bases can immobilize ground glass joints :P This has happened to many members that used silicone grease, but won't happen if one uses a PTFE sleeve or wraps the male joint with PTFE tape :cool:




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Everado E. Dinavo
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[*] posted on 9-9-2009 at 19:17


The round bottom itself doesn't look like it took any damage, but it's still really stuck. I believe the isocyanide traces are hydrolyzed by atmospheric moisture by now, so I'll take it out of the hood and take a heat gun to it and see if that works.

Interesting thread there, leu. Maybe I'll try submerging it in coke like some people did if that doesn't work...

Stuck glassware happens to me all the time. Sadly I haven't found a better way besides "try harder." Tape will definitely be used if I reattempt this.
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[*] posted on 9-9-2009 at 20:53


Have a look at the deshydratation systems used here: P2O5 is said to work, triphenylphosphine and CCl4 in presence of triethylamine is fairly accesable.. Diphosgene is also anoption.. Triphosgene might be able to substitute..

http://books.google.fr/books?id=PmCGncuR4ZgC&pg=PA721&lpg=PA...

If you use P2O5 you will need to add a tertiary amine of some sort, according to:

http://books.google.fr/books?id=IgiJTVsbeoYC&pg=PA131&lpg=PA...






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[*] posted on 10-9-2009 at 13:39


@Everado E. Dinavo:
For disconnecting your glassware I recommend the following:
Fill the apparatus with diluted HCl and put the whole construction into diluted HCl. So the acid works from the inner and outer side of the glass. Let it undisturbed for 2 weeks. Clean it with water thoroughly and now you can heat the ground glass joints as usual in order to disconnect it.
This procedure always worked for me and was very helpful to save valuable glassware which was stuck by alkaline mixtures.
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[*] posted on 12-1-2011 at 03:47


Are isocyanides toxic like cyanides? Maybe I will prepare some, but I don't want to poison myself.
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[*] posted on 12-1-2011 at 04:01


Quote: Originally posted by Random  
Are isocyanides toxic like cyanides? Maybe I will prepare some, but I don't want to poison myself.


Alkyl and aryl cyanides are not very poisonous compared with potassium cyanide.
I have worked with isonitriles a lot and they smell pretty awful but I never noticed any toxic effects.
If your neighbours get a whiff they will probably put it down to bad drains!
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[*] posted on 12-1-2011 at 09:20


Isocyanides and isocyanates are both bad news. I'd keep the hell away from them in an amateur setting and avoid them if at all possible in a professional laboratory.

Methyl isocyanide is extremely poisonous.




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[*] posted on 12-1-2011 at 09:50


Methyl isocyanate is miles worse than methyl isocyanide.
I spent a couple of years working with isocyanides and made a lot including methyl isocyanide. It smells really disgusting but I never suffered any ill effects from it.
Now, this baby really is toxic;
http://en.wikipedia.org/wiki/Phosphorus_trifluoride
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