[Johte]

Going at my reaction from a different angle. It mean's handling an azide of molecular weight < 200 g/mol. What extra precautions do you need to take with purifying one this small?

Also how do I answer the question, what is the optimal reactant ratio for a single-substitution of a di-halide?

[wildfyr]

The only answer I know for the azide one is "carefully and cold"

For the dihalide, I would use 1:1, but you add the nucleophile in slowly, dropwise and possibly cold. You want your amount of dihalide to remain high in comparison to the nucleophile so you don't get double substitution. It matters how strong a nucleophile you're working with. If its a formal anion then it can definitely be finicky, and you will definitely get some disubstituted product. We do a reaction with hydroxybenzophenone and dibromohexane in the presence of potassium carbonate, which we add dropwise, but frankly it then stirs for 3 days at RT so that probably isn't even necessary because that phenol is such a crappy nucleophile.

[wildfyr]

I also feel compelled to recommend you check out the C/N dilution rule when dealing with azides. You can also usually rely on the rule of 6: 6 diluting carbon atoms per reactive group in a compound. Some other azide precautions can be found in these documents. http://www.ehs.ucsb.edu/units/labsfty/labrsc/factsheets/Azides_FS26.pdf https://www.stanford.edu/dept/EHS/prod/researchlab/lab/safety_sheets/08-203.pdf. I suggest you bone up on explosive safety in general before working with low MW azides, a number of chemists without fingers or eyes can attest to the danger of these compounds

[408]

If your MW is 200 and the rest is hydrocarbony and you only have that azide and no more explosohoric units, you are fine.  If the azide is on a tetrazole and the rest of the MW is a dichloramine...lol.  If the rest of the molecule is silver...lol...the criteria you gave is not enough at all. 

C/N ratio is a massive oversimplification.  Need to see the structure.  You can have >80% N and have something you can beat off with a hammer all day and it will not explode. 

[discodermolide]

@widlfryr: Where did you get this information from?
You don't need cold when handling azides and what is the C/N dilution? Whatever that is, is it relevant? I don't think so.
I have made organic azides in scales up to 10kMol  with reaction conditions that do not meet your cold criteria.
So I think the OP needs to be a bit more specific in defining his starting materials before we can make an informed judgement.

[wildfyr]

@discodermolide C/N dilution is a general guideline to help you stay on the safe side of azide chemistry. Its described in the links I posted. Obviously people synthesize iffier azides all the time. But if you are making an azide that isn't described in the literature, and its low MW, then you are walking into possibly dangerous territory. You also have the be conscious of the formation of hydrazoic acid even if your azide is pretty safe.

The cold is important because many azides, especially small ones, will degrade at room temperature, giving off nitrogen and heat, which can get out of control under the wrong circumstances. Obviously not all azides are highly heat sensitive, but if he wants to make nitro propyl azide, keep that crap in the fridge. Or better yet, find another route.

I agree though, OP if you want more than general help, you have to describe your molecule/reaction better.

[408]

Aminotetrazole.  CN5H3. 
Not explosive.

Diaminotetrazine C2N6H4.
Not explosive

C/N ratio is almost useless. 


And not heating an azide is silly.  This removes many of the wonders of azide chemistry!  Thermal formation of nitrenes, etc!!

And keeping cold should only be done after DSC studies.  If your s#*$ is explosive and freezes at 5C, you now have a explosive crystalline/liquid slurry, which can be incredibly sensitive, moreso than pure liquid.  Dont subject a small weight azide to shock and you are golden. 

[wildfyr]

Hey you're cheating, those are conjugated and not technically azides. And I'm all about nitrenes, I use sulfonyl azides as a thermal crosslinker. Hopefully OP is trying to cook something that is already in the lit so he won't be operating blindly (and without DSC data already in hand).

[Johte]

@widlfryr: Where did you get this information from?
You don't need cold when handling azides and what is the C/N dilution? Whatever that is, is it relevant? I don't think so.
I have made organic azides in scales up to 10kMol  with reaction conditions that do not meet your cold criteria.
So I think the OP needs to be a bit more specific in defining his starting materials before we can make an informed judgement.

Trying to singly substitute a dibromo alkane of lengths n=4,5,6. Working with 4 first. Tried first with DMF overnight, tried to acid wash the DMF out but that didn't work out too well. Could find product.

Tried again using methanol over night. PMA and I2 TLC showed very little product, a lot of starting material, and some weird impurity above starting material.

The reaction is from the Sharpless lab which reported >80% yield. I know I'm just starting a organic research but I feel I have enough experience where something like this shouldn't be failing so hard.

[discodermolide]

So your source of azide is sodium azide?
Try a two phase reaction and use a phase transfer catalyst. No acid washes anywhere. A simple extractive wrok-up should be sufficient.

[Johte]

Apologies, just finished finals and a little fried. Yes sodium azide is the source. I don't think I've seen others.

Your suggestion is making me realize the azide not being fully dissolved at reaction volume pre heating is my problem. In the case of DMF how would the biphasic system help? Or are we talking a whole change in solvent i.e. DCM/H2O?

Suggestions on any pt-cats besides TBAF?

[discodermolide]

Change to DCM/H₂O or toluene/water may be better as separation and work-up are easier.. Good stirring and use tetra-n-butylammonium bromide. Sodium azide dissolved in water with catalyst keeping the pH around 9 should avoid any HN₃ formation. But I suppose you are not doing large scale reactions, so that may not matter.
Have fun.

[wildfyr]

50:50 acetone water is what I use for one sodium azide reaction with organics, works like a charm. Rotovap off acetone, then extract with ether or DCM.

So the reaction is basically Dibromo butane+sodium azide, and you want 1-azido-6-bromo butane? Im not sure what to do about disubstituted side products (if you're very lucky you can find a solvent system that lets you get it off with just flashing a plug instead of a real column with pain in the ass stained TLCs), but you should be able to distill off the starting material with a gentle distillation (BP 63-65 °C/6 mmHg). Don't bother with the base unless you're above a few grams. If you do, pick a water soluble one like sodium bicarb, not an organic like pyridine.

Mind giving us the reference you tried?

[Johte]

Agnew, Heather D., Rohde, Rosemary D., Millward, Steven W., Nag, A., Yeo, W.-S., Hein, Jason E., Pitram, Suresh M., Tariq, A., Burns, Vanessa M., Krom, Russell J., Fokin, Valery V., Sharpless, K. Barry. and Heath, James R. (2009), Iterative In Situ Click Chemistry Creates Antibody-like Protein-Capture Agents. Angew. Chem. Int. Ed., 48: 4944–4948. doi: 10.1002/anie.200900488

I saw your reply when I came back to ask discodermolide about distallation. In theory it should have worked but when I attempted it nothing seemed to come out. However I was using glassware joints that may have been too large as I was working with limited glassware.

Distilling out the dibromide would be ideal because I could just add my amine right to the reaction mixture.

Edit: I'm ASSUMING the bp difference here, theres no CAS# for 4-azido-butyl-bromide/bromo-butane.

Edit 2: Flashing a plug?

[wildfyr]

Flashing a plug is when you can use just a really short column and  a solvent system where your product goes right through and all the impurities stay stuck in the silica gel. It takes less time and care.

And 6 mTorr is a pretty low pressure for your standard rough pump/shlenk line setup, you need a good setup to distill that. I still don't see why the original reference isnt working for you.

"Trying to singly substitute a dibromo alkane of lengths n=4,5,6. Working with 4 first. Tried first with DMF overnight, tried to acid wash the DMF out but that didn't work out too well. Could find product."

You should NOT acid wash this, youll generate hydrazoic acid, which is quite dangerous, and is not part of the original procedure. You've already tried just the exact procedure of both dibromobutane and sodium azide in DMF, 50C overnight, add ethyl acetate and extract with water/brine and run the pure hexane column?