[Elazur]

Greetings,

I am currently working on N1,N2-substituted aminoguanidines synthesis and I would be really grateful for someone sharing some knowledge on the matter.

From thiosemicarbazide, I carry out a S-alkylation with methyl iodide to form the S-methylisothiouronium hydroiodide. Then, the salt is reacted with primary and secondary amines in refluxing ethanol. Lastly, guanidine formed is condensed with aromatic aldehydes.

1- During aminoguanidine formation, all S-methylisothiosemicarbazide salt is consumed because I see no trace of it in TLC plates. I also note several by-products (like 3-4). Is that normal for this procedure? Should I first condense the S-methylisothiosemicarbazide salt with the aldehyde, and then promote guanylation? 

2- After I removed the solvent from reaction medium, I get a dark browm oily residue. I triturated it with anhydrous diethyl ether, but nothing precipitated. In some instances, the oily residue is soluble in the ether.

3- Tried to make something crystallize with several solvents, but I was unsuccessful. It does not crystallize at all, and forms again the oily residue when low boiling solvents evaporate.

4- I tried a separation by flash chromatography in MeOH/CHCl3 with this oily residue. I managed to separate a fraction that crystallized, but apparently it was still contaminated with amine as I can see from NMR data. I can not get this, because in TLC plates the stain from amines is always the least retained. It should be eluted during the first chromatographic fractions. How come the product that ellutes during last chromatographic fractions is still contaminated?

5- In some papers, authors add triethylamine or potassium carbonate to the reaction media during guanidine formation stage. II can not get this either, because this would cause a decrease in electrophilicity of the S-methylisothiourea. Am I mistaken?

6- One fraction from flash chromatography separation had formed a precipitate. I evaporated the solvent under reduced pressure, washed it, and recovered a light yellow powder. Then, after some days, I noticed that it turned back to a dark brown oily residue. Should I convert the hydroiodide salt in any other salt, like hydrochloride?

I would appreciate some clarifying on the subject. Thanks.

[TheUnassuming]

OK, so lots going on here and its a little unclear what is what at certain points. So... lets give it a go

1: Normal is relative, unless you have done the exact reaction with very similar substrates.  You could try altering the method, but I would suggest first figuring out what is going on in this case. You see multiple new products by TLC, but until you isolate them you don't really know if they are major products or if they just show up well by TLC.  A clean spot to spot reaction is wonderful, but just because its not doesn't mean you don't have a good reaction. 

2-3: Trying to find perfect crystallization conditions on an unknown mixture of compounds is hit/miss at best.  Columns are generally the best way to get your products isolated. 

4: When running columns with amines, get into the habit of adding 1-5% triethylamine to your mobile phase.  Alternatively, if you are using MeOH on your column, you could add 10% ammonium hydroxide to the MeOH and use as you normally would.  If you don't, the amine will smear all down the column and you will see it in every fraction. 

5: If authors doing your reaction sequence are using a given reagent set, you should probably use it as well.  What do you think the TEA or kcarb will be deprotonating?

6: How were you storing it?  Do you know it was your desired product? 

[Enthalpy]

For my personal information...

How dangerous could pimagedine = aminoguanidine be, in one ton quantity? It makes a nice gas generator to rotate the pumps of a rocket engine, but the hydrazine part suggests it's a carcinogen. I haven't found Msds for that.

Thanks!

[Elazur]

Thanks for replying TheUnassuming. I will give the idea of adding ammonium hydroxide to the mobile phase a go.

5 - I guess the base will deprotonate the salt in order to generate the deprotonated S-methyl isothiosemicarbazide.

6 - I left it inside a desiccator and sealed it. I was going to take to NMR laboratory the day after. So I am not sure if it was the desired product.

I appreciate your help.

[408]

Try to isolate these things as a hydrochloride.  Many of these things are air sensitive.  Turning pink or red or darker is common. 

[TheUnassuming]

5: True.  I suppose the important question is does it need to be in the salt form for the reaction to proceed? 

6: Isolating as the salt can help with stability. Desiccators are good for water sensitive compounds.  Your compound might not be particularly air/temp/light stable.  When in doubt store in a freezer under inert atm. 

[Elazur]

5- I do not know if it is necessary, but the charged nitrogen increases reactivity by enhancing eletrophilicity of the adjacent carbon atom. Some similar reactions appears to proceed only when starting products are in salt form.

6- Thanks for the advice. It is going to be part of my routine from now on.

[Enthalpy]

I'd still be interested in the risks of aminoguanidine, please. Especially because guanidine enables on scheme of rocket engines, but is caustic and volatile, while aminoguanidine looks less volatile at least.

Are any N-N compounds as carcinogenic as hydrazine, MMH, UDMH are? Or do you suspect them so?

[408]

Aminoguanidine is pretty non-toxic.  check "aminoguanidine supplement" on google.   It is sold as anti-aging stuff.

[Enthalpy]

Thank you!