Sciencemadness Discussion Board - Learning to respect NBS the hard way

Learning to respect NBS the hard way

jam640 - 24-11-2007 at 10:43

Oh boy.
I'm still kinda shaking.

I decided to do a reaction I'd wanted to do for a long time today, an alpha-bromination of a ketone using NBS catalyzed by ammonium acetate. I had done this reaction previously on a millimolar scale and decided to scale up as I would need a larger amount of the product. Scaled up to 0.5 moles, approx, which is not huge.

The reaction proceeded as usual. I dissolved the ketone in diethyl ether, added NBS slowly followed by 10mol% ammonium acetate which heated up the reaction mixture to very slow reflux and caused apparent formation of bromine (ie deep red color). The reaction ran as usual for 2-3 hours, occasionally heated just a slight to get it going. Then I decided that I had to stop for the day, even though the reaction wasn't completely finished as it still was deep red. So turned of heating, and left it to cool.

Go to my computer, surf the net and BLAM. Now the reaction mixture is no longer in the flask but in my entire "laboratory". I was scared shitless. The entire room was fuming, and alpha-halogenated ketones aren't exactly pleasing to eyes, head and throat.

It was terrible, to say the least. I had to run in there, shut everything off. Coughed my lungs out, got out and went outside to get some air and think about what to do. The reaction mixture was everywhere, roof, floor, walls. But I in several consecutive "run-ins" with outdoor air inbetween managed to get everything in control. Still reeks and stinks everywhere but it's pretty much managed now. I was seconds from evacuating the premisses and calling the fire department.

Days like these you are glad that you are alive. And this was _definately_ the last last last time I _ever_ did some chemistry outside a correctly equipped laboratory with fume hoods. Man, this stinks. And me who really needed the product.

jam640 - 24-11-2007 at 10:45

The funny thing is that the reaction stampeded after several hours, after I had turned of the heating.
Strange stuff. I had a long reflux condenser attached, and it was really really stampeding as the stopcocks (3 necked RBF) blew right across the room and smashed. Oh boy.

Eclectic - 24-11-2007 at 11:35

Maybe an unstable intermediate builds up at room temp. that normally breaks down as it forms at reflux temp.?

jam640 - 24-11-2007 at 12:09

I'm getting a bit paranoid about the health effects.
I inhaled some, of course.
It was butyrophenone that was brominated.
Does anybody know toxicity of alpha-bromobutyrophenone?
Could not find any MSDS or toxicological data. I feel perfectly fine, almost, but I'm shivering and getting abit paranoid.
Should I worry?

jam640 - 24-11-2007 at 13:11

I would really really appreciate an prompt reply if anyone has knowledge of the compound in question or similar compounds. I'm getting a little freaked out.

Eclectic - 24-11-2007 at 13:22

Probably no problem with acute toxicity, maybe some chemical pneumonitis in a few days. Any medical treatment would just be supportive. I had chemical pneumonitis from chlorine exposure long ago. It was like a bad chest cold for about two weeks.

Drink lots of fluids.

roamingnome - 24-11-2007 at 13:31

since i just found about about the hazerdous reactions of TCCA a few weeks ago
i'll join the disaster club.

if your still alive the toxicity of your inhalation is not going to kill you. why? elemental bromine is toxic but the metabolic breakdown of its ions is really not.

http://www.epa.gov/chemrtk/pubs/summaries/ethanbrm/c14185tp....

this link show that methyl bromide breaks down into methanol and hydrobromic acid
but ethyl bromide breaks down into bromide ions and ethyl alcohol.

so metabolism of your product will ...not kill you

i guess in addtion to water vitamin E will catch possible free radicals

[Edited on 24-11-2007 by roamingnome]

jam640 - 24-11-2007 at 13:41

Thank you, I'm calmer now.

I really appreciate your posts.
You just get so paranoid and panicy when stuff like this happen, so you most likely also get some placebo effects.
My thorat is sore and my eyes still hurt a bit but other than that I feel pretty fine. Thanks again!

DerAlte - 24-11-2007 at 17:58

Your title fascinated me. I was very eager to find out why you respected the NBS, National Bureau of Standards, now metamorphosed into NSIT. But they don't give away freebies like they used to...

And what do I find? Another undefined abbreviation. What the hell was this NBS? it wasn't on my list of "standard" chemical abbreviations. Perhaps it stood for the Nebraskan Bullshitters Society? I turned Wiki loose on the job. Now part of Wiki has been written by the Nebraskan Bullshitters Society, but the rest is around 87.98% reliable. I found

http://en.wikipedia.org/wiki/N-Bromosuccinimide

so I guess that's what you were talking about and where the bromine came from...

Regards, Der Alte

Sauron - 24-11-2007 at 19:47

N-bromosuccinimide usually is used in chlorinated hydrocarbons as solvent, e.g., CCl4, in which it is soluble, but succinic acid is not, so you follow the progress by the floating succinic acid.

What a-bromoketone were you making?

Quite foolish to do so outside of a hood, you know. Had this happened inside of a hood with sash down you would have had little problem. Take a lesson.

I am at a loss to explain the incident. Your mixture did not explode but violently exited flask through reflux condenser?

Did you have stirring going and turned it off when you killed the heating? Any precipitate settle out or was this all one phase?

jam640 - 25-11-2007 at 00:07

It was butyrophenone.
From an reference (I can look it up later) which said diethyl ether worked bested. Ammonium acetate catalyzes the reaction by producing bromine.

And I know that it was quite foolish. I will never do the same again. I am happy if I'll get out of this without any permanent damage. However I never thought that it would react so violently, and I would transfer the solution via canula, i.e never exposing it to the open.

The reaction was in a thre necked flask, with a reflux condenser. It exited through all three necks. Stirring was on, and it had a precipitate (probably succinimide). I hadn't had the heating on the whole time, only from time to time with careful look at the temperature and ready with some ice. I have no idea what caused this. One thought was that bromine built up but did not react with the ketone, until the very end when so much bromine was present that it exploded. I don't know. Obviously a reaction that doesn't scale up well.

But I'm still alive. The night was a nightmare tho. Very hard sleeping with coughing and teary eyes. My "laboratory" is in connection with my living quarters so it stank up the place (and it still smell some). I am still shaking. And yes, I have lerned my lesson. I will never condone any experiment outside a real laboratory again, as I said.

My vision is a bit blurred. Do you guys think that I should seek medical attention? Or will this pass? I guess it is a common "side effect" of tear gas, so I don't know.

Sauron - 25-11-2007 at 00:22

By all means see an opthalmic surgeon as soon as possible.

I do not think NBS bromination of a ketone needs catalysis at all. And bromine is happy to fall off of succinimide, that is why it is useful as a brominating agent.

Where was that reference you found that told you to use ether?

fractional - 25-11-2007 at 04:35

Quote:

Originally posted by roamingnome
since i just found about about the hazerdous reactions of TCCA a few weeks ago
i'll join the disaster club.

@roamingnome
I think I should join the disaster club, too, also because of an experiment using TCCA turning nasty. I was trying to oxidise/chlorinate ethanol with TCCA (to get chloro-acetaldehydes with chloral as the ultimate target) and I now think that I made ethyl hypochlorite instead, which "decomposes in the cold and explodes on exposure to sunlight or heat" . I can vouch for the correctness of this statement!
What was your experiment?

mitesh - 25-11-2007 at 10:35

Dear jam640,

I don't really know where do you belong to but I don't really agree either with the chaos that you have generated around yourself. I am research scholar persuinig Ph.D. in India. I have done lots of Halogenations (I hate them) and like reactions with hezardous chemicals. There has not been a single week during past two years when one of my reactions haven't blown up. Though my ratio of accedents is higher then the total of my fellow researchers (they are 22), I don't ever penic. Chemistry is all about taking risks. I have never consulted any MSDS till date for my reactions. And still I have managed to keep my guide the happiest person in my group with my progress. Don't worry after the things that have happened. Having said that, go to Doctor if you are not at ease, but don't feel foolish. We (and no body else in the world) don't know the chemistry 100%. We are learning and such accidents (which I would say are experiments with unexpected results) do happen when we explore new fields. Don't get me wrong, as i do not endorse irresponsible behavior in lab (which is what i usually do), but if you feel guilty, then think of me, as I must be the biggest looser having done almost 100 accidents. But I am not, neither are you. Instead of worryng about the accident ant peniking, go to docor and finish the matter. Then you will be able to divert your attention more towards exploring new ideas.

Regards,
M.

Magpie - 25-11-2007 at 14:38

I have never used NBS but its use was covered in my organic course lectures and theory texts. So I looked this use up. My notes said it is particularly useful for brominating allylic alpha positions (without touching the double bond) and the benzylic position (without adding to the ring).

Edit: Also said was that its formation of Br2 is slow and steady.

Edit: The reaction must be light catalyzed, or a radical initiator used.

Of course, this is just general information.

[Edited on by Magpie]

[Edited on by Magpie]

Sauron - 25-11-2007 at 19:57

That's a very narrow explication of NBS use.

It is also very useful for making alpha-bromo carboxylic acids, by the bromination of the acyl chloride. Such a-bromoacids are useful intermediates in the preparation of a-aminoacids, by treating the bromo acid with conc NH4OH.

Neither hv nor a radical initiator are required. In fact those conditions would favor ring bromination if your substrate was an aromatic one.

[Edited on 26-11-2007 by Sauron]

Sauron - 25-11-2007 at 20:19

Dear mitesh

Yes, chemistry involves risks, but we manage our risks by taking appropriate and adequate precautions in advance. For example, I bet you do your preps in a fume hood, wear gloves and goggles or a face plate or maybe even a SCBA depending on what you are using. You would not prepare a half molar scale of a known military grade lachrymator's homolog on an open bench, would you?

Skipping MSDS is fine as they are so often full of nonsense, and everything useful in them you ought to know already.

If you have survived 100 "explosions" (which surely were merely deflegrations at worst, as opposed to high order detonations) then I deduce that you WERE prepared, and forearmed with adequate countermeasures.

What happened to the thread author would have been a minor annoyance in a fume hood, don't you agree?

Remember, most of us on this forum are doing our procedures at home in residential neighborhoods. We can't afford to have an "accident" and have the neighbors' kids crying because their eyes are burning. Can't afford to have the fire dept, hazmat teams and cops out. So damned right we MANAGE our risk taking. We had better, or else we'd be in deep trouble.

jam640 - 26-11-2007 at 01:45

Yes, I agree with both.
Accidents and chemistry go hand in hand, although you should always take the necessary precautions and I tend to read MSDS whenever available (and I feel the need to, as with new potential dangerous compounds).

The mistake I did was not to think of a worst case scenario. I knew the product was most likely very nasty, however I thought that it would stay in the reaction flask and that I could transfer the solvent after the reaction was finished using a syringe i.e never exposing it to the open. However as we all know that it not what happened, and I should have anticipated what to do IF what happened happened which would have meant that I would never have done the reaction. I was foolish, as we all are some times. I am just very glad that noone seems to have gotten hurt. If someone I know was in my house and got ill from this I do not know what I would have done. It was very careless of me to do this, and I very much regret it. As said chemistry and accidents tend to go hand in hand, but you should always take necessary precautions and sometimes (like this) it means that you have to have the necessary equipment to do a certain reaction. As Sauron says, if this had been done properly in a fume hood there would not have been much of a problem involved.

My healt is better now. I had very sore eyes yesterday, and somewhat blurred vision. Could not see a doctor as it was a sunday and today my vision is back to normal. My throat is soar tho, and breathing is somewhat heavy. Kinda feels like a tough cold. Hopefully it will pass soon.

My living quarters still stink, so I've moved out to a friends house. I will get some "odor cleaners" later today to see if it works. I am very happy to recieve some tips on removing the smell. It seems that the lachramatory effect is gone, and I recognize the smell mostly as unreacted starting material, i.e butyrophenone.

Sauron: The reference can be found here http://dx.doi.org/10.1002/chin.200423054
There is also another article that uses diethyl ether and UV-radiation here http://dx.doi.org/10.1016/j.tetlet.2006.12.101

I am aware that NBS often is told to work perfectly without catalysis, however when I researched this particular reaction (i.e alpha-bromination of ketones) all references I could ifnd involved some kind of catalysis. And as I had some ammonium acetate lying around I figured to give it a shot. I Still have a hard time figuring out what really happened, but my best guess would be that bromine concentration was building up over the course of hours and then when it finally reached a high enough concentration it all reacted at once.

[Edited on 26-11-2007 by jam640]

Sauron - 26-11-2007 at 02:18

As a hypothesis it's as good as any, if it stands scrutiny. For example, it only makes sense if the supposedly lagged reaction of Br 2 and the ketone + catalyst was exothermic enough to VERY rapidly heat the solvent to the point where it went from very mild reflux (and heat already turned off, so maybe no boiling at all) to violent egress in almost no time at all. Frankly, this does not strike me as likely. Halogenations do not happen that way.

BTW you told us a half molar basis so you had half a mol of the ketone and half a mol NBS and 0.05 mol NH4OAc, but just how much Et2O did you have in there as solvent (for immediate purposes read: "heat sink").

Was the top of the reflux condenser perhaps closed with a dryug tube? Or was it open?

I don't recall what butyrophenone smells like, but if it smells like acetophenone at all, it is not unpleasant. Maybe just opening all the windows and letting some breeze get through there for a day or two will bring the smell down to a dull roar.

Ever have pneumonia? If so then you will know what pulmonary edema feels like. Try to take a deep breath, if it hurts to do so you have fluid in your lungs (pilmonary edema). Your sore (not soar) throat and upper lungs got seared with that bromine and bromoketone and now that the irritant has been removed and vice versa, your body will eventually reabsorb the fluid and the worst you will have is some scar tissue in your lungs and airway. See a nose & throat specialist and have your airway and lungs checked out. And do see an opthamologist in case you have any corneal damage.

I've had pneumonia, and much later chemically induced pulmonary edema (from nitrosyl chloride) so I am speaking from my own experience. Not fun.

jam640 - 26-11-2007 at 02:59

Yes, I don't know. It just strikes me as very odd that the reaction had been going with slight heating for several hours, and then suddenly react so violently. It feels like some intermediate/reactant must have collected up, to react all at once. Also the solution darkened over time, to become very dark red at the end. After the explosion there "reaction mixture" was light yellow. When I turned of the heating and left the lab there was no reflux or boiling at all, but the reaction flask was still warm. The amount of diethyl ether was slightly over 300 mL and it was a 1L RBF. Maybe too little? The reflux condenser was "semi-closed" by a septum with a needle stuck through to relieve pressure.

The smell is not very unpleasant, but it smells "chemically" and it doesn't feel very good staying in it.

A friend was over to check out the situation yesterday and he thought that the smell was reminiscent of some chemical solvent/cleaning agent. All windows are open as we speak to let it out. Hopefully it will be gone in some days. I am also going ot buy some "odour removers" to see if that helps (but I doubt it).

Never had pneumonia, but taking deep breaths hurts (but just slightly) so I think you're right about the pulmonary edema. I feel pretty ok, but it feels very uncomfortable when going up the stairs fast etc. I will probably go see a doctor later this week and see what they have to say. But at the moment I'm more worried about sanitizing my house.

And again, thank you everyone for your replies. They have been much appreciated and helpful!

Sauron - 26-11-2007 at 03:32

Aha.

I think that closing the reflux condenser was a Very Bad Idea. I bet you did pressurize the system enough so that the ether was somewhat superheated, I bet at the end the needle/septum let go (or maybe one of the glass stoppers that you presumably had in the other two necks) and the sudden depressurization and reduced bp resulted in the violent egress of the flask contents.

Also I think 300 ml ether was indeed too little solvent, was that a direct scaleup from the lit ref you cited? I get they operated on a 10 mmol scale or something (typical these days).

For the Br2 to build up like that would imply that the halogenation was not proceeding (hardly) at all. Which does not speak well for the alleged catalyst. Your ref is from Cheminform, I wonder, is that journal peer reviewed? Or is it like Tet.Lett. these days, full of guano?

My remarks assume that you were not using an excess of NBS, which would account for the dark red color even if the reaction was proceeding apace.

NBS is not magic. It is just a convenient easily handled source of Br2, period. This reaction would work without the ammonium acetate and with Br2 itself.

I'd stick to same scale but use 2X-3X solvent, preferably THF instead of Et2O and put this in a 3L or 5 L flask in case of sudden boilup. Do not restrict the reflux condenser, instead connect it to another condenser set for downward distillation and connect the receiving flask to that with a vacuum adapter closed to the air with a mineral oil bubbler. See? Not a closed system but air tight, no way to pressurize, and at worset if you get a vigorous boilup you will catch it all in the receiver (which ought to be large enough.) You may lose some mineral oil but who cares?

trilobite - 26-11-2007 at 04:07

NBS is used in both ionic and free radical brominations. This is most likely of the ionic type, where the point of using NBS is to provide a low concentration of free bromine in the reaction mixture. Because I'm lazy I shall write our substrate having a hydrogen atom to be substituted as (S)-H, thus our product is (S)-Br and to show the nitrogen and bromine atoms we write N-bromosuccinimide as (R)N-Br, then succinimide that is formed in the reaction is (R)N-H. The reaction proceeds as follows:

1. (R)N-Br + HBr --> (R)N-H + Br2
2. Br2 + (S)-H --> (S)-Br + HBr

First NBS reacts with some HBr in the reaction mixture to give free bromine. Where the HBr comes from is not that important, but it may come from impurities in NBS or be a product of a free-radical side reaction. Bromine then reacts with your substrate in a reaction that gives HBr, which liberates more bromine. This way the concentration of Br2/HBr in the reaction mixture stays pretty much the same, which improves selectivity. They say crude NBS still having a bit bromine in it works very well in practice.

The free radical way is similar, but bromine and alkyl readicals are involved in the mechanism. Now I'll use * to mark the lone electron, so bromine radical would be Br*, our substrate alkyl radical (S)*. First the reaction is initiated to give bromine radicals, then the reaction proceeds as follows:

1. Br* + (S)-H --> (S)* + HBr
2. (R)N-Br + HBr --> (R)N-H + Br2
3. (S)* + Br2 --> (S)-Br + Br*

Now let's focus on ketone bromination. In the ionic reaction between a ketone and bromine it is the enol form of the ketone that reacts with bromine, giving the brominate ketone and HBr. Now, the interconversion of the keto and enol tautomers is catalyzed by acids and bases, so the reaction is very slow in neutral conditions. But as the reaction slowly proceeds some HBr is released, which further increases the reaction rate, which is why the reaction is autocatalytic. If you simply mix enough bromine with acetone and wait, you should get a lachrymatory shower after an induction period.

Traditionally you add the halogen slowly, the induction period is lowered by adding some acid to the reaction mixture or irradiating with UV light (free-radical halogenation releases the acid). Further the reaction might be performed in the precense of solid calcium carbonate that neutralizes the acid, so that you don't get a runaway. I'm not completely certain if the calcium carbonate is also used to catalyze the enol formation or if the method relies in a free-radical mechanism.

Anyway, I don't have access to the article so I'm not sure how the reaction is performed there. My guess would be that somehow your NBS decomposed so that bromine accumulated, unreacted NBS keeping the acidity of the reaction mixture low thus hindering the reaction. Then at some point all the NBS had somehow decomposed, acidity began to rise and it was time for runaway bromination. Why do they use ammonium acetate, I do not know. You could argue that it would catalyze enol formation but then again I don't think ammonium acetate dissolves in ether at all. It might also have some other sort of effect, formation of acetyl hypobromite (AcOBr) perhaps? Or should it be used as an aqueous solution, so that you had two phases? Good stirring would be necessary anyway as your reaction mixture would not be homogeous. Anyway, doing this reaction with NBS without free-radical initiation sounds a bit fishy, but I have no experience. Personally I would likely add hydrogen peroxide to a vigorously stirred two-phase mixture of the ketone in DCM and an aqueous solution of HBr or H2SO4/NaBr or whatever. The rate of addition can be judged by the color of the reaction mixture.

By the way, have you read the article? Do you know the theory behind what you are doing, how to perform the reaction and why? Lack of understanding is the foremost reason behind lab accidents, and even though science involves unknown factors, the advice our PhD student is giving sounds alarming. Do not listen to him. Get to know your stuff and then do it well and don't be stupid. A day in the library saves a week in the lab, if not more.

Then about cleaning up the mess. To neutralize halogenated ketones I would try washing with a base, depending on the place you want to clean. Sodium carbonate, ammonia, sodium hydroxide should all react with the haloketone so that you'd get rid of the worst. Maybe use some fabric softener as a PTC in your cleaning mixture.

Edit: I agree with Sauron about the use of septum and a needle here, but there are a few misconceptions that need to be sorted out.
- in the reaction NBS ends up as succinimide, not succinic acid.
- initiation and catalysts depend on mechanism of the reaction that is being performed, NBS is merely a reagent
- free-radical halogenation is not used for ring bromination, which proceeds through electrophilic substitution, an ionic process

Good luck, but do not rely on it alone!

[Edited on 11/26/2007 by trilobite]

jam640 - 26-11-2007 at 04:45

Sauron: No, it was not a direct scale-up of solvents but an apparently somewhat optimistic estimation. The system was constantly pressure relieved by opening one of the necks, and had been so a minute before the explosive reaction took place. But in retrospect it would have been much wiser to use a system such as you explained. I have no idea on the validity of ChemInform but the article was reasonable well written and similar reactions have been reported before.

trilobite: Thank you for the most informative reply. Your theory sounds very plausible. I have read the article numerous times, and studied other similar systems. I have a degree in chemistry (although my mind isn't what it should be these days) and I have performed some halogenations before and am aware of the mechanistic aspects. Sometimes you just don't spend enough time in the "library" as you should tho. The article writers argues that ammonium acetate works by reacting with NBS to form Br2 and N2. Mixing NBS and ammonium acetate in 1:1 ratio apparently gave a complex that liberated N2/Br2 upon dissolving in diethyl ether (and some other solvents, I don't have the ref in front of me currently and I'm a bit stressed at the moment).

Sauron - 26-11-2007 at 05:21

That doi to Cheminform was just a citation of the article. The article is Chemical Communications, 4, 470-471 (2004)

Fortunately I have RSC access.

So abide a few minutes and I will return with the full text.

Here you go. First off what it says was that Et2O was solvent for cyclic ketones while CCl4 was preferred for acyclic ketones such as your butyophenone. Just as I told you. CCl4 at relux. I do not believe you would have had this problem in this solvent. Especially if you have used sufficient solvent.

If you could not get CCl4 or chloroform then DCM would have been prudent. They list about 10 solvents with reaction times. CCl4 and Et2O were 30 minutes so why were you running yours so long?

I quote from p 470: bottom of left column

"Reactions in Et2O required cooling with water to avoid sudden boiling of the solvent."

You were heating a reaction that required cooling in that solvent and you were using the wrong solvent for the type of ketone you were brominating.

What happened was SPECIFICALLY cautioned about.

The authors were quite right.

The case is solved. Chemist error.

Did you rely only on the 1 page graphical citation in Cheminform, and not bother to obtain the two page Chem.Comm. paper?

Cheminform did not include the warning.

[Edited on 26-11-2007 by Sauron]

Attachment: ChemComm4_470.pdf (116kB)
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trilobite - 26-11-2007 at 05:26

You are welcome. I think NBr3 is formed, a dark red explosive substance, it decomposes to Br2 and N2.

6(R)N-Br + 2NH4OAc --> 6(R)N-H + 2NBr3 + 2HOAc --> 6(R)N-H + 3Br2 + N2 + 2HOAc

Maybe it was NBr3 behind all this? I'm not certain. I suppose that the acetic acid would have some effect on the keto-enol kinetics, but it is only a weak acid, so maybe not. Sounds like a method you might not want to scale up.

[Edited on 11/26/2007 by trilobite]

jam640 - 26-11-2007 at 05:32

Sorry Sauron, I didn't have SciFinder access when I looked it up earlier today so I just did hasty Google and that was what I found first.

jam640 - 26-11-2007 at 05:37

I have attached the full article now.
And it actually gives a caution of the reaction between NIS and ammonium acetate which gave an explosion, possibly accounted for by the formation of NI3.

And I think trilobite is right, this reaction should not be done on anything but microscale.

[Edited on 26-11-2007 by jam640]

[Edited on 26-11-2007 by jam640]

Attachment: nbs.pdf (116kB)
This file has been downloaded 2058 times

Sauron - 26-11-2007 at 06:17

Yes I posted this a few minutes ago upthread.

See bottom of paragraph 5, in left column, p 470

REACTIONS IN ET2O REQUIRE COOLING WITH WATER TOAVOID SUDDEN BOILING OF SOLVENT.

Yet you were heating a reaction that required cooling to hold it to 25 C and you were using Et2O when the authors advised CCl4 at 80 C (reflux) for acyclic ketones, like butyrophenone.

End of story. Not a scale problem. Chemist error.

The warning was plain. What happened was exactly what they described, sudden boiling of solvent.

Numerous other solvents were described as suitable, merely requiring longer rxn times. In case you could not get CCl4 you had other options but you went with the ONLY solvent that was prone to sudden boilup.

Bad choice.

The consequences are punishment enough I am sure, and you know better than anyone that things could have been MUCH worse. You could have gotten a facefull of that lachrymatory fountain jetting from the flask. All that ether COULD have ignited and you'd have had a nasty explosion and fire and the cops just LOVE ether explosions and are conditioned to treat them all as drug lab accidents.

You could have been blinded, or killed.

So I hardly need to berate you.

But face it squarely. Don't blame the scale. Don't blame the mechanism or NBr3 bogeyman. You messed up, in two ways. Three IMO if you start from working with ether without a fume hood.

Case closed. Chemist error. Sorry, fella, you upgefucked.

[Edited on 26-11-2007 by Sauron]

trilobite - 26-11-2007 at 10:23

I think the word you are looking for is an exotherm. But as you know, ether itself isn't responsible for exotherms, the reactions are. NBr3 is no bogeyman, it most likely is the intermediate species in this reaction since nitrogen is evolved. Even the authors seem to recognize this but it might be something they wish not to shout out loud. They still do note that the same reaction with the analogous N-iodosuccinimide is an explosive hazard and even make note of the possible formation of NI3 which is notoriously unstable.

Whatever the reason for the runaway, it is a scale problem if there are exotherms that need cooling. The larger your reaction vessel is, the less you have surface area per mass unit and the harder it is to cool. It might very well be that ether isn't the best solvent to conduct this reaction, no denying that. I don't know the reason for it since I haven't tried the reaction, but I already provided two explanations for what happened. You could easily determine which one is it by following the colours and nitrogen evolution during the reaction.

Your frustfration is understood since you don't seem to grasp even the basics that well, but still try very hard. It is easy to dismiss scientific arguments and go ad hominem when something is too difficult to explain. Surely you must realize that the runaway wouldn't have happened if it wasn't a result of the actual reaction mechanism and thermodynamics? Sudden boiling of solvent is the real bogeyman explanation here and there is no need to read the article for that one, it was a runaway after all.

Sauron - 26-11-2007 at 10:44

Trilobite, did you bother to read the paper that the thread author himself said he used as basis for his procedure?

It STATED that this runaway was going to happen just as it DID happen. It INSTRUCTED anyone following this procedure to COOL any reaction mix using ether as solvent in order to maintain a temperature of 25 C. It TAUGHT that ether was best choice for CYCLIC ketones, while CCl4 was better for ketones such as the thread author's substrate. At 80 C not 25 C.

So this hapless fellow did what?

He selected the wrong solvent for his type of ketone.

He selected the ONLY solvent out of a long list that required a warning about the necessity of cooling to 25 C in order to avoid sudden boiling of solvent.

Then he used too little of the wrong solvent

And instead of cooling the reaction as instructed he HRATED it to reflux, say 10 C above the stated reaction temperature.

And he continued heating intermittently for several hours, while the instruction was that this reaction would be completed in this solvent at 25 C in 30 minutes.

So what we have is a chemist who can't seem to follow a simple procedure.

It is no wonder this reaction ran away. BTW if you had bothered to read my posts on previous page you would have seen that I know the word "exotherm" very well.

I say this fellow screwed the pooch and apparently, in every orifice.

I say that this reaction is very likely to be perfectly safe in competent hands at any scale, if the procedure is adhered to, and proper precautions are taken. This chappie did this in a residence, refluxing ether that did not need to be refluxed, heating when he was supposed to be cooling.

He is lucky he is alive.

BTW I have been doing organic chemistry for 45 years. If you knew my name you could find it in JOC and C.A. So keep your snide condescension to yourself. It is uncalled for.

This matter is closed. There is no mystery.

You want to argue thermodynamics, when what happened here was that the thread author skipped, forgot, misunderstood, or ignored avery specific warning that said "Take this step or you will have a runaway with diethyl ether."

He did NOT take the required, step, he did the worst possible thing and heated what should have been cooled.

End of story.

Still want to argue thermodynamics and mechanisms?

How about basic prudent lab practice and familiarity with the pertinent literature he himself cited?

The runaway does not occur with solvents THF, acetonitrile, CCCl4, CHCl3, DCM, etc etc. ONLY with Et2O. Yet he elected to use Et2).

A self inflicted wound!

And he had better face up to his own arrogance or he will learn nothing from this affair. Nothing.

[Edited on 27-11-2007 by Sauron]

mitesh - 26-11-2007 at 11:13

@ Sauron and jam640

Dear Sir(s),

I do get your point and agree fully with the discussions, however, my point was, why should one feel guilty after having done something wrong (which i don't consider wrong as yet) unintensionally. I may have made mistake in gathering the situation, in which case my apologies.

As per the precautions, only precaution accessible in my lab is an ill maintained fume hood (so be it!). By accidents, i mean instances when my reaction flask shattered into pieces, however, as has been pointed out not all of them were explosions, some were mechanical shocks too. But that is not my point u see!

Only thing i would still stress upon is, when i am working with chemistry, it should be only thing to demand my attention. But i may feel so 'coz i'm still a student. I may not stick to it while i'll have to set up my lab in my home!

Regards,
M.

Sauron - 26-11-2007 at 11:24

A thorough reading indicates that as I suspected these reactions were performed by the authors at a 10 mmol level. Even then, they cautioned that the reaction in Et2O needed cooling to hold it to 25 C or sudden boiling of the solvent would occur.

The required amount of solvent in a typical run was 10 ml. A direct scaleup to half a mol would call for 500 ml. The thread author used 300 ml. A contributing factor in the subsequent excursion from the flask.

The best combination of short rxn time and yield was Et2O FOR CYCLIC KETONES. The best solvent for acyclic ketones was CCl4 @ 80 C.

Which is what I advised as solvent for NBS early in this thread. Succinimide floats on CCl4.

Reaction time in both cases was 30 minutes.

I suspect that the unnecessary prolonged heating was a factor. Heating of ANY kind was contraindicated, as cooling was stated as necessary for Et2O solvent.

This is, again, a compounded, exacerbated chemist error.

A man drives up a mountain. The speed limit is 35. There's a dangerous curve up ahead. He accelerates to 90 and drives off the cliff.

Do we need a "scientific discussion" of vectors and classical mechanics?

Or do we say "Sumbitch was speeding at 55 mph over the limit." ?? Is that an ad-hominen attack, or simply an obvious conclusion?

[Edited on 27-11-2007 by Sauron]

jam640 - 27-11-2007 at 02:44

Sauron: Yes, of course it was my fault. First and foremost because I did not take the necessary safety precautions. However I do not necessarily agree with you on the other points.

In my book there is a vast difference between an exothermic reaction heating a low boiling point solvent to reflux (which was there reason why I used a condenser) and a reaction that obviously "sleeps" for several hours and then in a matter of seconds react explosively.

As I stated previously the reaction had been tried out two times earlier on millimolar scale. The first with 50 mmoles in 20 mL of diethyl ether which was stirred at room temperature for 3 hours. There was no apparent heat generation and the solvent did not start to boil. The yield was miniscule.

The second time I used 30 mL of diethyl ether, and after standing at several hours when the reaction had not gone to completion I decided to gently heat the mixture to see if the reaction would proceed (although somewhat violently) which it did and yields were very good.

Hence from my experiments I drew the conclusions that under my ambient conditions the reaction needed external activation and when I performed it on a larger scale I first allowed it to "work it's magic" followed by very gentle heating to reflux for short periods of time (with external cooling always ready).

However, anyone who actually has tried to repeat a literature synthesis knows that even very small variations can alter the outcome greatly. Heck, I've witnessed reactions that didn't proceed at all in December but worked flawlessly in July. Most likely because of a difference in ambient temperature. Chemistry is not black or white.

The article I reffered to does not report bromination of butyrophenone, where the most similar compound is 1-tetralone. A compound which they brominated in diethyl ether.The acyclic ketones bear very little resemblence to butyrophenone. The other article I refered to reports the bromination of several acetophenones in diethyl ether. I do not agree that the choise of solvent was extremely unwise. And as trilobite says exothermic reactions are always risky to scale up.

There is a reason it's called research.

Sauron - 27-11-2007 at 05:53

You maybe want a lecture on the psychology of denial?

You want to maintain that you proceeded prudently and properly and this just happened out of the blue?

Then you haven't learned a thing.

You chose the wrong solvent. Et2O was for cyclic ketones. CCl4 was advised for acyclic ketones.

Et2O was used at 25 C. With CYCLIC ketones. And needed cooling to avoid just the kind of sudden boilup you achieved.

CCl4 was used at reflux. 80 C. That alone ought to have tipped you that acyclic ketones require harsher conditions than cyclic ketones.

You used an inadequate amount of solvent. 40% less than a direct scaleup. That compounded your error.

So, in hindsight, it is PERFECTLY clear that you erred in choosing Et2O, you erred in heating this reaction mix in this solvent, and you erred in using too little solvent.

Take responsibility for your own mistakes. No one wants to excoriate you for being fallible.

By your own account you got very poor results first time round at 5X the lit. scale (but 60% less solvent than advised) at 25 C for 3 hours. Per the lit., reaction ought to have completed in 30 min. At that point, you ought to have reread the paper more carefully, and the proper conclusion would have been to go to CCl4 and 80 C.

You chose to stick with Et2O and got better results but according to your own account, somewhat violent reaction.

Red warning lights and klaxons ought to have been going off.

But instead you charged on and scaled up 10X from there (50X from lit.) and got your runaway.

If you are surprised, well, no one else is, or ought to be.

No, the literature reaction did not exemplify butyrophenone. But it DID acetophenone, the 2-carbon homolog, and did so in CCl4 at 80 C for 30 min and NO sudden boilup, and with a high yield.

BTW I bet this reaction would run just fine in a pressure vessel at 80 C in Et2O. With butyrophenone, acetophenone or propiophenone.

THF works, requiring 60 minutes, but yield is poorer, and no risk of sudden boilup. Not sure what temp they used with THF.

[---------------------------------------------

If I were wanting to prep this monobromoketone, I would select a method that did not involve ammonium acetate catalysis, to avoid all this hassle.

I would, if possible, work in CCl4.

I would use NBS or Br2. NBS is more convenient but if you have septa and syringe then chilled bromine (to reduce fumes) is not too hard to handle.

I think you might investigate the usual catalysts AIBN and dibenzoyl peroxide. Both have their hazards but you do not need much of them.

Or, return to NH4OAc. In CCl4 you will not have any problems. It lacks the fire hazard of ether, there will be no sudden boilup, the higher bp precludes any difficulty with reflux using conventional condenser and cooling water.

I would not skimp on amount of solvent, and you really ought to be done in 30 minutes.

[Edited on 28-11-2007 by Sauron]

Bronstein - 27-11-2007 at 11:44

Just be glad you did this experiment with butyrophenone and not with propiophenone. I have experienced both the alpha-bromoketones, and the one from propiophenone is much much worse. In fact I think alpha-bromobutyrophenone was fairly pleasant to work with. Every time you brominate propiophenone you swear: "Never again!!".

Sauron - 27-11-2007 at 12:29

How does the a-bromopropiophenone compare to the corresponding acetophenone ("phenacyl bromide") which is a military tear gas? Far worse than the chloride (CN, older standard police tear gas prior to the advent of CS).

I think a lab prep of a-bromoacetophenone can be found in Sartori's book. (The War Gases) in forum library.

syntelman - 20-12-2007 at 05:57

As elemental bromine readily halogenates acyclic ketones such as butyrophenone in diethyl ether at either 0C or room temperature (keeping the addition of bromine at a very moderate level) I doubt that the solvent was the major source for concern here. However it is very unwise to heat exothermic reactions, but hey we all made our fair share of mistakes.

I experimented with NBS to brominate various ketones in DEE some years ago, both without any catalyst and catalyzed by HBr and concentrated sulphuric acid. Although all attempts failed, bromine release was very evident and increased over time but halogenation didn't go to completion and the yields were miniscule. I never witnessed any runaways but all attempts were quenched and worked up after a few hours (I do not have my lab notes with me at the moment so no exact numbers).

My guess is as already said that the problem is the keto-enol tautomerism that with bromine is autocatalytic with the release of HBr. I suspect that the freed succinimide interacts with any present acid and what we see is an increase in bromine concentration until all NBS is consumed and all available succinimide is protonated, whereupon any further liberated HBr instead enolizes the ketone and at that moment we have a very high concentration of bromine leading to a violent chain reaction.

If you decide to re-attempt the reaction I would try using AlCl3 as a catalyst and see if it works. Otherwise bromine is not as hard to work with as you might suspect, BUT it should never be used outside a fume hood (as with a-haloketones so...).

Take it safe, and I hope your health has returned to normal!

Reflux_catalyst - 9-2-2015 at 11:17

Quote: Originally posted by mitesh

Dear jam640,

Chemistry is all about taking risks. I have never consulted any MSDS till date for my reactions.
Regards,
M.

Don't ever say this again. You have no business propagating this garbage. You will go blind or die one day, and it will be your fault.

Mailinmypocket - 9-2-2015 at 11:35

Just FYI: The last time mitesh was online was back in 2007.

CuReUS - 10-2-2015 at 21:39

this is an alternative reagent for NBS.maybe this accident can be prevented by using this
http://www.sciencemadness.org/talk/viewthread.php?tid=61512#...

Dennis A - 14-6-2018 at 23:02

I came across this while searching for related material hopefully its of some use to somebody and avoids accidents rather than causes them i have felt pain like the OP from such reactions ... The reaction is carried out on acetophenone but this of coarse can be substituted the above post has nothing to do with alpha brominations

Can someone tell me what role silica gel has in the reaction ?

They appear to use the NBS upto 3 times after the original reaction so thats some saving of reagents

2.1. Typical experimental procedure

The α-bromination reaction was carried out using acetophenone (1200 mg, 10 mmol), N-bromosuccinimide (2136 mg, 12 mmol), 10% (w/w) silica gel (120 mg) in 10 mL of methanol at reflux conditions until the disappearance of the substrate. (Note: 2136 mg of N-bromosuccinimide was added portion wise i.e. 356 mg for each time in six portions). The progress of the reaction was monitored by TLC. The reaction mass was filtered after the completion of the reaction as per TLC and the catalyst was collected for reuse. The filtrate was concentrated under vacuum. Double distilled water was added to the reaction mixture and quenched with aqueous sodium thiosulfate and the product extracted with dichloromethane (Caution: Severe burning sensation of eyes was observed during the work-up process). The layers were separated and the organic layer was collected and washed thrice with distilled water (3 × 50 mL). The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude product was purified by column chromatography over silica gel (60-120 mesh) using n-hexane-EtOAc (99:1 ratio).

With the aim of studying the recycling of the catalyst, the isolated catalyst was washed with ethyl acetate (5 mL) after its filtration from the reaction medium, collected and dried in vacuum at 70 ℃ to a constant weight. Subsequently it was reused for the abromination of acetophenone and achieved 95%, 86% and 83% yields of product (2a) for first, second and third reuse of catalyst respectively. All products gave spectroscopic data in agreement with the literature [15, 21, 27, 28, 29, 30].

The method is also very practical for scale up in process development. We attempted large scale (100 gram scale) synthesis of 2-bromo-1-phenylethanone 2a and obtained fruitful results with isolated yields ranging from 93% to 96%.

2.2. General experimental procedure for large scale (100 g scale) preparation

The α-bromination reaction was carried out using acetophenone (100 g, 0.832 mol), N-bromosuccinimide (213.6 g, 1.2 mol), 10% (w/w) silica gel (10 g) in 1 L of methanol under reflux conditions until the disappearance of the substrate (Note: 213.6 g of N-bromosuccinimide was added portion wise i.e. 35.6 g for each time in six portions). Excess N-bromosuccinimide (+0.1 mol) was added to complete the reaction as per TLC. The reaction mass was filtered, after the completion of the reaction as per TLC and the catalyst was collected for reuse. The solvent was removed and double distilled water was added to the reaction mixture and was quenched with aqueous sodium thiosulfate. The product was extracted with dichloromethane. (Caution: Severe burning sensation of eyes was observed during the work-up process).

The layers were separated and the organic layer was collected and it was washed with distilled water for three times (3 × 1 L). The collected organic layer was dried over anhydrous Na2SO4 and filtered, concentrated and purified by recrystallization using n-hexane (300 mL). The resulting yield of pure α-brominated ketone, i.e. 2- bromo-1-phenylethanone (2a) was 94%. The same experiment was repeated twice and the yields were 93% and 96%, respectively. The reproducibility of the protocol was thus confirmed with the consistent isolated yields of desired product 2-bromo-1-phenylethanone (2a).

http://html.rhhz.net/zghxkb/20140145.htm

Regards

Melgar - 15-6-2018 at 00:55

I did this with elemental bromine at some point. Added it to acetophenone in some solvent or other (acetic acid IIRC, not sure of the concentration). The literature I was following stressed adding it slowly, which I did. The red color slowly disappeared at first, but disappeared almost instantly with later additions. The later additions also heated the mixture considerably. I'm 99% sure that HBr was forming and lowering the pH, which increased the reaction rate. NBS could help here, since it combines with HBr to release Br2, similar to TCCA and HCl, if I'm not mistaken. Still would recommend adding it in portions and keeping an eye on temperature. Also, would mandate an effective fume hood. That shit made me weep into a towel for what seemed like hours, and could have been hours because I couldn't open my eyes enough to check the time.

I don't know why OP used an ammonium salt here, of all things. It just seems to be asking for trouble. Granted, that was 11 years ago, so I hope he's still alive and well.

carbon85 - 15-6-2018 at 01:42

More information on the related topic however this arises questions for me i hope somebody more educated on such topics can elaborate further

I understand the use of acid catalyst,s to help initiate and speed up the reaction P-TsOH/GAA/HBr and many more

Below is a quote from this link >https://www.sciencedirect.com/science/article/pii/S1350417701001080

Substituted acetophenones react with N-bromosuccinimide (NBS) and p-toluenesulfonic acid (p-TsOH) in the presence of ultrasound in methanol at 35±2°C to give α-bromoacetophenones in high yield. In the absence of ultrasound the reaction takes place at the boiling point of methanol (65°C) and takes longer time. The reaction does not take place in the absence of p-TsOH thermally or sonically. However the reaction is possible under photochemical conditions in the absence of p-TsOH. The best solvent for the reaction was found to be methanol

Its stated they could only get a reaction to take place without the aid of photochemical and ultrasound conditions when the reaction was heated to the BP of MeOH not sure how forgiving that would be to certain substituted ketones

I quote " The reaction does not take place in the absence of p-TsOH thermally or sonically "

Yet in my above post they use no acid catalyst with high yield instead using silica gel can anybody enlighten me as to why ?

Which method is more favourable ?

Then onto this > https://www.academia.edu/14523990/Regioselective_%CE%B1-Brom...

Which uses montmorillonite K-10 clay not exactly OTC to my knowledge never the less some good reading for sure

EDIT in response to melgars comment unseen by the time i posted

Thank you for your input i see no role ammonium acetate playes in the reaction either but the OP for sure is a fool he would have been extremely lucky to come out without any permanent damage !! I have suffered deeply from such reactions rubber gloves and swimming goggles defiantly make things alot easier IMO

I dont mean to hate im sorry if i apear that way i would rather make others more aware of dangers and come up with a solution ie a proven reaction than can safely be performed by anyone with some common sense

He chose to carry the reaction out in diethyl ether when many alternatives were available it " specifically " stated cooling was needed when diethyl ether was used yet he was hell bent on using it not only that he left the reaction "unattended" and "wedged" a septum needle in the top of his refulx condenser and paid for it deeply .

I mean what the hell was it so hard to have some tubing even garden hose lead out the window from his condenser or into scrubber ?

I mean when you have many alternatives solvent wise to perform a reaction in and you pick the most volatile out of them for a " exothermic " reaction and then restrict its only means of it releasing its byproducts/gases to what 1ml or less?

At that rate its pretty much a sealed glass bomb full of super heated flammable solvent fumes and irritating halogenated ketone an extremely foolish act what could only be worse was if innocent people were effected by this

Regards

[Edited on 15-6-2018 by carbon85]

[Edited on 15-6-2018 by carbon85]

Loptr - 15-6-2018 at 07:39

After a few small trials some years ago I found bromine source + AcOH/p-TsOH and a catalytic amount of H2SO4 to work quite nicely. The bromine sources that I tried were DBDMH, NBS, and bromine itself.

I have also tried similar reactions in methanol, acetonitrile, and toluene. I believe that I also ended up with benzyl bromide formation--didn't follow up.

I had the most trouble with methanol.

[Edited on 15-6-2018 by Loptr]

carbon85 - 16-6-2018 at 01:10

Please explain why you had the most trouble with methanol as some people swear by it for such reactions having never tried it myself leaves some questions ,

Did you experience uncontrollable reactions ?

What size reactions were you performing ?

What was the concentration of the ketone in methanol ? This has a effect on rate of reaction as i,m sure you know i tend to double the volume of solvent to substrate

DCM has always been favourable without the aid of acid catalysts the reaction is almost instant every time only a few times slight warming with friction was required however bigger reactions wont be so forgiving and will need a kick start so to speak AlCl3 etc

DCM its good because its non flammable easily stripped from the reaction and easily recycled because of its low BP not to mention the low cost of it hell its even OTC in some products depending where you are on this god forsaken planet however it is considered a carcinogen and "frequent" exposure to heated vapour,s shouldn't be taken lightly

DMSO works a treat when using CuBr2(ll) suppose it would work with NBS but i can only speculate

Regards