[asdfTT123]

Hi guys,

I'm trying to synthesize an azide compound: 5-Azidonicotinic acid ethyl ester from my starting material, 5-Aminonicotinic acid ethyl ester.  Starting product:

I will be following a protocol from a publication (taken from Walseth et al; J Med Chem. 2010 November 11; 53(21): 7599–7612. doi:10.1021/jm1007209), which basically converts the amine to a diazonium cation followed by nucleophilic substitution with sodium azide to form the azide.  Protocol is as follows:

5-Aminonicotinic acid ethyl ester (10) (3.0 g, 18.05 mmol) was stirred with concentrated HCl (100 mL) in a 0 °C bath. A solution of NaNO2 (1.38 g, 19.86 mmol) in ice water (8 mL) was added dropwise to the stirred slurry of the hydrochloride salt, resulting in a clear solution. This solution was then added to stirred slurry of NaN3 (1.77 g, 27.09 mmole) and sodium acetate (3.9 g) in ice water (3.5 mL). After a few minutes of stirring, a red oil separated from the mixture. The mixture was made basic by the addition of concentrated ammonium hydroxide solution after 10 min and the product was extracted into EtOAc. The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc in hexanes) to give 11 as golden oil34 (1.66 g, 48 %): TLC Rf 0.48 in EtOAc: hexanes (1:5)

I've never done conducted diazotization and azide chemistry before so a few questions:
1. Any safety concerns and precautions I need to take for this reaction?  I understand sodium azide is very toxic but on top of use of fume hood + lab coat + nitrile gloves + goggles, is there anything I need?  Any part of this reaction that may be explosive?
2. What is the purpose of the sodium acetate in the azide formation?
3. Can I use sodium hydroxide in substitute of ammonium hydroxide?  What advantage does using ammonium hydroxide have over NaOH?
4. Do I transfer the diazonium hydrochloride salt solution into another round bottom flask containing the sodium azide, sodium acetate, and water mixture for the second reaction?
5. What are the potential side products/impurities that would require me to run a column?
6. How light sensitive is the azide compound?  Would I have to store the compound in the dark or run the reaction in the dark?
7. Do I need to be careful in handling the final azido compound formed (i.e. can I expect it to be similar toxicity as sodium azide)?

Many thanks for your help.  I can't locate a similar protocol to this anywhere else and I don't have a lab advisor or any other researchers with organic chem experience here.

[opsomath]

This is not too bad of a reaction. Diazos and azides can be dangerous if the ratio of C/N is very small, but you do not have that problem. Just make sure "Dropwise means dropwise" ie don't dump anything into anything suddenly. Honestly the biggest concern here is to make sure you don't dispose of or handle azide inappropriately, be sure to use a teflon spatula or other plastic device to weigh it out, and look up a protocol for quenching it if you have to dispose of any.

1. See above.
2. Acetate scavenges acid, so you don't make HN3. HN3 will blow your s#*$ up.
3. I think so, but it's not that hard to find some ammonium hydroxide. The ammonium is a weaker base.
4. Yes, transfer it dropwise. If I had to do this, I'd keep the diazo salt on ice and transfer with a pipet.
5. Diazos decompose all kinds of weird ways, make sure the pH stays low but you'll still have some tar and dimerization products in all likelihood. Still shouldn't be enough to change your major product.
6. Aromatic azides decompose with light, wrap your vial with foil and store it in the fridge or freezer.
7. This is not the PC answer, but no. It's not very toxic, any more that organic nitriles are as toxic as sodium cyanide.

This is the sort of reaction where it helps to have an experienced person look over your shoulder. I don't suppose you're in South Carolina? Anyway, just be careful and you should be fine. These are energetic reagents, but there's a nice big carbon skeleton and the dilution is pretty reasonable. Maybe scale it down 10x the first time.

[discodermolide]

1) I think you should be OK with that equipment
2) I think the sodium acetate keeps the mixture buffered and reduces the chance of HN₃ formation.
3) Using NaOH may hydrolyse your ester so stick to ammonia.
4) You add your diazonium salt solution to a flask containing the NaN₃ and acetate
5) Side products could be the nicotinic acid ethyl ester may be the acid but that's less likely.
6) Should not be too light sensitive towards normal room lighting.
7) Always be careful when handling chemicals. Regard them all as toxic.

[Borek]

Makes me think of http://www.chemicalforums.com/index.php?topic=38151.0

[Dan]

I would be very careful with this - before the mixture is basified there will be HN₃ present,* which can be extremely dangerous.

*You start with ~1.2 mol of HCl (100 mL c.HCl). Looking at the stoichiometry (20 mmol SM, 30 mmol NaNO₂ and 40 mmol acetate), you are still going to have a >10 fold excess of HCl even with the acetate present. Are you sure it's 100 mL c.HCl and not 10 mL?

[asdfTT123]

Thank you for your help everyone, very thankful to have you guys around!

Regarding the formation of HN3, yes, the protocol definitely says 100 mL of HCl.  Would you recommend lowering the amount of HCl used in the diazotization step?  Or perhaps I could use more dilute HCl (I'm not sure if diluting the HCl with more water would have adverse effects on my yield)?  Also, if I just keep the round bottom flask in the hood, shouldn't I be okay?  Also, should I keep the second reaction (azide formation) on ice as well and immediately neutralize with ammonium hydroxide after?

Regarding the dangers of hydrazoic acid, I heard it is explosive at room temperature...what exactly does this mean?  Does this mean the reaction needs to be kept on ice?  If not, what could happen?

I'm assuming if I use 100 mL of HCl, I would need a lot of ammonium hydroxide to neutralize the reaction...

[opsomath]

It's pretty typical to use a large excess of acid for a diazotization, but Dan has a good point about adding azide to that. This is an unusually large excess, but even this prep from Org. Syn. (which uses less HCl) warns about the formation of HN3:

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0074

[Dan]

I'd follow the literature prep - if you modify it, it may not work well.

HN₃ should be O.K. in solution at low temp in terms of explosive reactions. Nevertheless, I would set up a blast shield for this (however small the explosion risk may be). I would run this on ice throughout - it looks as though this reaction is cold throughout in the prep you posted.

Conc ammonium hydroxide (35%) is around 18 M, so you're probably going to need somewhere in the region of 60 mL. This will get hot fast so definitely cool during the neutralisation. I would monitor the internal temperture of the vessel.

[asdfTT123]

Just wondering, how would I set up a blast shield?

Also, in regards to stirring, I understand that HN₃ is susceptible to shock.  Should I still have a stir bar active in the reaction vessel?

[Dan]

Just wondering, how would I set up a blast shield?

They look like this:



All organic chemistry labs should have one. You just put it between you and the reaction vessel.

[asdfTT123]

I will be attempting this reaction for the first time tomorrow.  Any last minute tips for handling the hydrazoic acid or any other general safety considerations?  I read here that concentrations of hydrazoic acid below 10% should be safe to handle:

http://pubs.acs.org/doi/abs/10.1021/op7000645

Can I assume that the concentration of hydrazoic formed from my reaction would be <10%?  I figure most of the sodium azide would react with my starting reagent and that would only leave a small amount that could potentially form hydrazoic acid.

I just plan on doing everything slowly (dropwise) while keeping everything on ice with light stirring.

[opsomath]

I just plan on doing everything slowly (dropwise) while keeping everything on ice with light stirring.

This is what I have done in all similar reactions. You should be fine. Do it in the hood.

Also, consider scaling down for your first time.

[asdfTT123]

Alright, so I ran the reaction today and followed protocol almost exact (but with everything scaled down by half).  I dont know if my questions are too premature because I haven't finished the work-up, but none of the observations of the reaction matched the protocol.

For example, the starting compound, 5-aminonicotinic acid ethyl ester dissolved perfectly well in the concentrated HCl (protocol said it was a slurry), and upon addition of the sodium nitrite/water solution, it turned bright yellow and a yellow-ish white precipitate came out (protocol said that upon addition of sodium nitrite, the solution became clear).  What gives?

Anyways, I continued along and after I added everything dropwise to the NaN3/sodium acetate mixture, I never saw a red oil precipitate out.  Instead the solution stayed yellow-ish with a yellow-white precipitate.

After neutralization with ammonium hydroxide to basic pH, the solution was creamy white with a very obvious white precipitate in there.  At this point I thought the reaction had failed but I went ahead and extracted it with EtOAc (3x 50 mL) anyways and resulted in a yellow EtOAc fraction.  I ran TLC in 1:5 EtOAc:hexanes and saw a major yellow spot around Rf ~ 0.6 and a very faint spot at the starting point of the TLC.  This is somewhat close to their reports of the desired compound being at Rf ~ 0.48 in the same solvent system.

Any idea what could have possibly went wrong (if anything)?  Anyways, I'll be concentrating it tomorrow, but from the TLC, I don't really see a need to run a column though there is a tiny bit of impurity on the TLC.

I'm just completely puzzled why the descriptions of the reaction along the way didn't match up to the protocol at all.

Thanks again for the help.

[DrCMS]

I would have thought doing the reaction the way you describe (adding the sodium nitrite dropwise to the amine in HCl) would give the diazonium salt but that it would react with the starting material to form an azo dye, most of which are yellowish.

I would add the amine dropwise to nitrous acid (sodium nitrite in HCl) keeping the whole lot at ~0°C and then react it with the sodium azide/acetate.

[opsomath]

I have done it both ways, but with a single amine group on the aryl ring there's no need to worry about order of addition. That's what the large excess of strong acid is for, to make sure that there will be very little free aryl amine.

Adding the nitrite solution to the amine is typical and you see it a lot:

http://www.orgsyn.org/orgsyn/pdfs/V79p0052.pdf

http://www.orgsyn.org/orgsyn/pdfs/CV7P0508.pdf

(If you're a baller, you do it on a 1 mol scale like that last one)