Chemistry Heartbreak

…With emphasis on the break.

I’ve not posted recently for a variety of reasons. This prompted me to break that silence:


What you see here is the 1 liter erlenmeyer flask that contained my reaction from yesterday, which I was about to pour. Pick up, slip and, it being quite full, crash.

On the plus side, it is the first step and the starting materials are readily available. It is still one of the worst feelings, to see your work smashed on the hood floor.

More Tough Times

It has not been an easy time in the Research Triangle Park area but we got some more bad news this week. I heard a report that High Point chemical synthesis company PharmaCore had let people go last week. I don’t seem to be able to find any confirmation of that anywhere. Then I also heard yesterday that biotech company Grifols (which acquired Talecris in RTP not too long ago) has shed more R&D positions here. Again, a lack of news source, but since I actually know someone involved, I am pretty certain of my facts there.

What with the decline of GSK in the area, plus the relocation of Pamlico last year, the biotech/pharma industry has been hurting in these parts.

Best of luck to all of those involved.

Working a Saturday

At this point in my career, working on the weekend is generally not what is done. But needs must when the devil drives and all that, a compound is needed for a study and it is needed soon. For that to work, sometimes you just have to put in a weekend shift to make it. Plus I figure that if I am having to work on a Saturday, at least I can get a blog post out of it.

There is an occasional Twitter topic called #realtimechem, so I will do something like that in considerably more than 140 characters.

So setting the scene: we have a compound that went into a study. They asked for some more and we took what intermediates we had to try and get the required amount. It looked like we would be short, but then they said they could finish the study with a lesser amount. Here I was guilty of too much optimism for I said that we might make that with what we have and it turned out I was wrong.

But wheels were set in motion and the deadline was set. We had more starting material in hand but in order to make it in time would need dedication, hard work and to not waste the weekend on trivial things like lazing about the house and telling off the kids for playing too loudly.

So Saturday morning dawns. First things first: check on the reaction I set up Friday evening. An alkylation of a phenol, often done with potassium carbonate as the base, here I found that to give me poor yields and cesium carbonate to be more effective. So I run the TLC to check the reaction is complete. I take a small sample out, add it to a mixture of ethyl acetate and water to take my TLC from the organic layer. The solvent is dimethylformamide which tends to mess up the TLC analysis, so I often do a mini work-up of the reaction to clarify matters.

The reaction is complete, so the reaction is cooled and I turn that mini work-up I just did into a maxi work-up in the big separatory funnel. A bit of an emulsion is dealt with by addition of some sodium chloride solution. The solution of my product and assorted impurities is then absorbed on Celite for solid phase loading onto the chromatography apparatus.

Back in the old days, all the purification was done by hand in mind numbing tedium. Nowadays it is all automated with disposable silica cartridges and pumping automatically altering the solvent mixtures for optimal separation. Well, that is the theory anyway. It is considerably less mind-numbing but not always smooth sailing.

Today my column set up well, but when you need it to behave it always wants to be a little mischievous. I set it going and from having done it before I knew when to expect the compound to elute (and you see a nice UV trace on the screen to reassure you of that fact). Well a little peak comes out and it is not at all what I am expecting, for I put a good amount of there and I want a BIG peak. I frown at the screen, concerned. Another peak comes out – perhaps this is the one? But no, again it is but a tiny hillock when I am looking for a mighty mountain.

Then I notice that the test tube fractions collected are coming out half filled. The pump for the polar solvent is misbehaving.

I comfort myself with the fact that the more polar solvent is already at 100%, so the misbehaving pump shouldn’t affect the column from here on out, though it probably made the gradient less steep than was planned, delaying elution. But then a big peak starts coming out and all is right with the world again. Peak shape is a little ugly. But I can live with that. Then as the peak is coming off, another big peak starts to elute.

This was not according to the scheduled program. The TLC had shown no starting material and only faint spots of any other type. What was this monstrosity?

Well, TLC soon told me that the peak shape was so ugly that it had split into a double headed peak. It was all my compound. So just need to strip it down to dryness for a quick NMR analysis before setting up the next step.

There are two possible states for the NMR machine on a Saturday afternoon. The first is that it sits idle and no one has touched it for hours. But because no one much uses it over the weekend, it is a good time for setting up long carbon-13 experiments and once in a while a couple of those will get queued up and black out any possible NMR time until Sunday night. So it is with some trepidation that I take my NMR tube of compound and deuterated chloroform to the room. And a sigh of relief as I find it all sitting idle.

The analysis confirms what I really knew already, as the white solid on the inside of the flask was clearly (by retinal analysis) the purest and best. So into the next step we go.

I keep some back, as this next reaction can be capricious. It is a cyclization reaction and depending on substituents on the parent molecule, gives different yields, but also is variable in the recovery from batch to batch. I’m putting nice material in, so I am giving it the best chance, though one of the substituents is slightly unfavorable.

In true #realtimechem fashion, I was running the TLC as I typed that. And now I have checked it and the reaction is complete.

My Saturday is about done.

How to Make the Perfect Snowball

It is that time of year when the hand of Winter is felt upon the land and we turn our thoughts to such pursuits as skiing, hot chocolate and, of course, making snowballs. But this is an art not to be undertaken lightly, for there are arcane and obscure techniques to be used. I shall reveal one for you here today and you will never add a snowflake, nor even a drop of water to make it.

First, you require a Dewar. Use it for a while as a vacuum trap, with plenty of dry ice and a little isopropanol. Keeping topping it up with dry ice regularly. Do this for a while, until your extensive experience tells you it is time to move to the next phase. A sign that it is ready is when you have trouble getting the trap out of the Dewar when you want to empty it. This is an art that requires great patience.

Next you let the trap thaw and remove the trap, preferably without breaking it (if you can). The dry ice has gone, but a large block of ice is within, ready to form your perfect snowball.

Now you add some acetone, as the snowball won’t come out without some help. I don’t recommend breaking the Dewar. Let that sit for a short while then drain out the acetone (save it for making cold baths later).

If you have done it right, the snowball shall emerge, perfectly smooth and rounded. Is it not both beautiful and awe-inspiring?



More on the Life of a Contractor

Firstly, Happy New Year everyone. I wish everyone the best for 2013.

But now back to blogging and a comment on my 2011 post about Life as a Contractor, which was about my own experience here. That of course is datum – the singular of data. A recent comment on that post came from Marie, who said:

I started a new gig as a contractor, and have seen that it is worse than your experience. Contractors aren’t treated with as much respect, nor do my coworkers really give a crap about me. My boss is based in another state, I am paid below market rate, no one is eager to train me in the company’s proprietary systems, and I’m finding it very difficult to get plugged into what’s going on as I’m not on employee based email lists.

Marie has my sympathies and even in my own situation (which is much more friendly) there are a few things that I don’t get or don’t see. Some of the software we use does not work right for me, which is a little irritating (I have to give my chemical orders to my lab-mate; oddly, regular lab orders work just fine). My suspicion is that most contractors are in a situation more like Marie’s where they are not part of the company culture, just here temporarily (even if temporarily means months or years). So they are maybe not treated as well or given the perks of the employee. If there is downsizing to be done, contractors will get it first and if you are not going to be here in the long-term, the pay-off for training in systems seems to be less, or the manager may see it as less worthwhile at least. It is a rough place to be in. I know I am lucky to be a contractor that does not have most of these problems.

One thing that has changed since my earlier post (that was in 2011) is that I no longer am using the contractor health insurance package (which was very much limited and coverage maxed quickly). Now I have individual coverage with a high deductible but no max so if something Bad happens, I won’t be bankrupted by it. I am actually wondering how the changes to health insurance will affect that policy, but so far it has been fine.

I must admit to being a little in the dark with how things stand now with regard to contractors and permanent employees. Are more permanent folks being taken on now or is it still the more conservative contractor route, with a note of “if things work out we’ll hire you permanently”? My local data is that not much of either hiring is going on, for synthetic chemistry at least (analytical chemistry is another matter and there seems a relative abundance of those in and around RTP). I’d love to hear from anyone around the country to get their take on it.

My impression is that it is still a tough market, that employers can use contractors for short term fixes and then let them go when that project is done. And there is plenty of people willing to take the chance on a possible temp-to-perm hire so they suffer the short term distresses of the contract agreement. And while the recovery is sluggish as it is I don’t really see why that would change.

I started the post with a best wishes for 2013 and by the end of it, I’m thinking we’ll need those good wishes.

Perfect Separation

They don’t just occur in chemistry catalogs, they can be something in real life too (though the :

My Separatory Funnel

My Separatory Funnel

I will contrast this with the same reaction when I first did it, wherein the layers were darker, murkier and had more insoluble muck in them. The reaction conditions have been slightly tweaked, but broadly the chemicals in the flask are the same, so it is as much about the hands that do the chemistry getting better at it as it is the reaction going on in the flask. Though I did learn some things about the accuracy of the thermocouple of my heating/stirring plate at higher temperatures – this reaction was run at a high enough temperature that the cooling from the air in the hood was enough to prevent the oil bath reaching the desired temperature and the oil temperature measured by thermometer was a little lower than the reading on the dial as well.

Anyway, I thought it was a nice shot to share.


So I’m working in the lab and all the rotavaps on my side of the lab are busy so I go to use the one on the other side. The two on my side are both hooked up to a chiller, but the lone one has a dry ice trap. As a result, this is distinctly the third choice and is not used as much. I’m first to use it today and it needed dry ice, but the water in the bath was low too. So I got a big beaker to refill the bath, added some water. It wasn’t quite enough so I head back over to my side of the lab and refill the beaker to add to the water bath, even though there was a sink right next to the water bath I was filling. So why didn’t I use that sink?

In a word, habit.

It got me thinking about habits and our routines and how we do things.

I am, to an extent, a creature of habit. I like my routine. I see it as a mental check list that gets everything done. If I stray from my usual routine, I might forget to turn on the chiller (for example) which delays the first evaporation of the day. We have by an iterative process worked out the most efficient way to do things on a daily basis. The problem with this is when something disrupts the program, so being able to adapt to the unexpected is necessary, but as chemists working with the ever fickle world of organic chemistry, most of us are used to that as well.

But it occurred to me that the habits are helpful in another way, an important way when doing laboratory work. When things go wrong, you are already doing things right. This is where good habits pay major dividends. That goes from wearing your protective equipment even when you aren’t doing anything particularly dangerous and keeping your lab area clear so a spill doesn’t escalate. Of course, this is also when bad habits come back to bite you, those things you’ve always done and got away with. Adding extra hydrogenation catalyst to push a reaction to completion might be something you can do on a small scale, but when you do that on a multi-gram scale, you have a fire. And if you have a ton of solvent sitting around in your hood then suddenly you have a bigger fire. And if you didn’t bother putting your lab coat on to do this quick little thing, suddenly you have a big problem.

Another good habit to get into is putting things on your blog regularly. Opportunity (or just making the time) has been tricky the last few weeks, but as I believe the song goes, a good habit these days is hard to find.

Giving Thanks

It is Thanksgiving Day here in the US, so I will do my own little thanks post.

First, thanks to everyone reading. This time last year, my subscribers and viewers was OK but it has grown steadily and now several hundred people will get to read my occasional utterances. My best ever single day was for a long time the day In the Pipeline added the blog to its blog roll, but that mark was exceeded by my 10 Nitrogens in a Row post. Mental note: include more stuff that blows up.

That brings me to another thank you: everyone and anyone who gave me the seed for a post. A couple of my co-workers in particular are often giving me ideas, including the 10 Nitrogens post and the series on the unidentified white powder. One lab mate will be telling me something and Will add “you should blog about that!” OK I will and thanks for the tip.

Thanks also to those who have commented or forwarded on the link to the blog. Beyond the odd tweet, I don’t really work that hard on drawing attention to it, relying on word of mouth (or tweet) to bring people here. So I really appreciate those who take the time, including Stuart Cantrill, Mr Nature Chemistry himself, as well as the irrepressible ChemJobber who has featured several of my posts on his own blog, all while somehow maintaining an impressive post regime of his own. Thanks, CJ for the links and all your efforts for the chem blogosphere.

Now it looks like it is time for dessert, so I will thank you all once more and hope to see you all tuning in for the foreseeable future.

10 Nitrogens in a Row

I’m sure Derek Lowe’s “Things I Won’t Work With” series is essential reading for most here (and for those that have missed out, take a look – my favorite was FOOF). He put one up a couple of years back on an interesting structure with 8 nitrogens in a row (two triazoles linked by 2 nitrogens). It was surprisingly stable, despite Derek’s title of that post. It also has a cool color effect where it changes color when you shine light on it (photochromism), due to the central double bond changing from trans to cis and back again.

My lab mates were talking about that and one pondered aloud what would happen if you used tetrazole instead? Luckily someone else has found out for us because, believe me, you didn’t want to be the one doing this particular piece of research.

Inevitably, it was Thomas M. Klapotke’s group that made it, published in 2011 in Inorganic Chemistry. Well, it was almost devoid of carbon by this point so why not? The graphical abstract tells the story eloquently: the structure with a back-drop of broken lab equipment. It was made in the exactly analogous fashion to the 8 nitrogen analog, but that is where the similarity ends. When the Klapotke group say this is one of the most sensitive materials they have handled, you better take notice.

Some choice comments from the paper:

The precipitated N10 compound 4 was not dried in the funnel
because attempts to manipulate the dry solid inevitably led to
extremely loud explosions and the destruction of labware.

we experienced several inadvertent explosions
during handling such as allowing the dry powder to slide down
the inside of a Raman tube or slowing down the rotation rate of a
rotary evaporator

Inadvertent explosions is a lovely expression.

They conclude that the formation of this compound leads to speculation that even longer nitrogen linkages might be possible but note that it “may present challenges for isolation”.

No kidding!

Chem Coach Carnival: My turn

The call was made for a post and I did heed it. Missed putting it on Mole Day, but what’s an order of magnitude between friends?

Your current job.

I work at RTI International, a non-profit research institute in the RTP area of North Carolina.

What you do in a standard “work day.”

It starts with a cup of tea (I’m a stereotypical Brit in that regard), but encompasses reading, writing and lab work. I am more in the lab than my supervisor, but he expects a certain amount of work on papers or grant proposals from me as well. My primary responsibility is keeping the project moving forward in terms of compound supply, so getting new data or scale-up so we have material for the next phase of the project. I’ll add we are more a basic research group than a drug discovery group, so tool compounds that pharmacologists can use to study receptors with is more our game than making a highly bioavailable drug. But many of the same skills apply – it needs to be soluble, for example.

What kind of schooling / training / experience helped you get there?

I have a PhD from the University of St. Andrews in Scotland. I post doc’d in the US at Georgia Tech. My original plan was to go back to the U.K. after that but jobs were scarce at the time and lining up one trans-Atlantically proved difficult. So I ended up staying. Got a job at a non-profit, then at a small contract research company here in RTP. As much as my qualifications, knowing people and being bold with contacting people got me here – I got an interview at my last job because they had hired a process chemist I knew, then I made a good contact with the recruiter who was hiring for this position, plus a number of former co-workers had post doc’d at RTI.

How does chemistry inform your work?

I work in the lab doing synthesis most of the time so it is pretty central to my job and that is how I like it.

Finally, a unique, interesting, or funny anecdote about your career

I could note how my PhD was book-ended by building evacuations due to ammonia release from the lab next door. But that isn’t really about me.

When in school, we were working on making a Grignard reagent. I forget the details, but it was magnesium turnings, a bromide of some sort, maybe some iodine to activate things. We were heating it. The guy behind me (doing the same thing) suddenly cried out and I turned around at saw his reaction spouting out of the top of his condenser. I chuckled turned around and mine did the same thing, shooting out of the top with enough force to mark the ceiling with a nice brown spot.

If I were just coming into the field, would I learn something useful from your story?

I hope so. The lesson I take from my own journey is that it is rarely as smooth as you imagine, you have to adapt and be flexible, be ready to take on things that you did not expect. But also it is possible to make your career into something you enjoy and want to do long term.