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!

The After Toxic Carnival Party

Reading Twitter and following the posts from last week’s Toxic Carnival last Friday night, it occurred to me that one famous toxic chemical had not been covered, one so ubiquitous that I held a dilute solution of it in my hand while toasting the success of the carnival.

I am of course talking about alcohol. Or to be more precise ethanol.

Various forms of alcoholic beverage have been enjoyed by humankind for millenia – Stone Age jugs have been found that support the notion that fermented drinks were made as early as 10,000 BC. Sura, a beverage brewed from rice meal, wheat, sugar cane, grapes, and other fruits, was made in ancient India (a favorite of Indra), while the first beer was brewed in ancient Egypt. A common thread from many of the ancient civilizations was that consuming alcohol was blessed by the gods but excessive drinking (to the point of drunkenness) was frowned upon. This idea was carried through into medieval times and even the Puritans brought more beer than water with them to the modern world, a fact that rather clashes with our modern view of what being a Puritan meant.

The principal reason for this was that drinking beer or wine was safer than drinking water. To make beer, a wort is made with boiling water, which sanitizes the water and as long as it is sealed up, remains free of infection once turned into beer (with the addition of hops also helping to preserve the beer). Drinking water was not usually boiled as a rule and was obtained from places that mixed with sewage or other potential forms of infection. Thus, drinking water was dangerous, while drinking beer was safe. More than that, Bavarian monks brewed their doppelbock beer to sustain then during the Lent fast.

But ethanol is not just a recreational and medicinal delight. As a wise philosopher once said:

Wine is fine but whiskey’s quicker
Suicide is slow with liquor.

Ethanol is in fact toxic, with an LD50 in rats of around 10g/kg. The toxicity comes principally from the metabolism of the ethanol via oxidation to the aldehyde (acetaldehyde) and then the acid (acetic acid). Interestingly, the chemical neighbors of ethanol (methanol, n-propanol, isopropanol) are all more toxic all due to the same mechanism, with methanol most toxic (and also the least sedative effect, so it doesn’t even make you drunk first!). Contamination by some of these longer chain alcohols can contribute to an increased hangover from some alcoholic beverages.

But ethanol itself has a number of toxic effects. It is a central nervous system depressant, which initially causes effects in the cortex, hippocampus and nucleus accumbens parts of the brain which are responsible for thinking and pleasure. It causes sleep disruption (lack of REM sleep especially). The lowering of inhibitions and critical thinking also can place the person (or surroundings) in danger due to a lack of good judgment. High acute doses of alcohol result in nausea, depressed heart rate and respiration, coma and possibly death by alcohol poisoning.

It also has quite severe long term effects, with its addictive qualities being a major factor. Alcoholism, cardiovascular problems and alcoholic liver disease are just some of the major problems resulting from chronic exposure. Liver disease in particular has been seen as an alcohol problem, with the graph below showing the relative change in the rates of various disease states compared to 1971. Liver disease (primarily due to alcoholic liver disease) is by far the worst.

So enjoy the post Toxic Carnival party, but perhaps enjoy in moderation.

Toxic Carnival: The Dose Makes the Beauty Treatment

As part of the Toxic Carnival started by ScienceGeist, I present my own contribution, as suggested by the Curious Wavefunction. I’m going to talk about Botox.

Botox is an abbreviation of Botulinum toxin, which is a protein produced by the bacteria Clostridium botulinum. That right there tells you is not exactly good for you and in fact it is the most acutely toxin known, with a lethal dose of 1 ng/kg (intravenously) or 3 ng/kg when inhaled. Rather than the small molecule, it is a protein (or really a family of proteins) and causes botulism, a life-threatening paralyzing illness. This can lead to respiratory failure as even the muscles of the lungs are paralyzed.

Despite this extreme toxicity, the toxin has a number of medical uses. Most famously for removing wrinkles, an effect which is not permanent of course but typically lasts for around 8 months, it also has genuine medical uses. It was first used by ophthalmologists to treat a form of crossed eyes (strabismus) and uncontrollable blinking (blepharospasm). Though effective, the treatment also only last a period of months, requiring reinjection 2 or 3 times a year. It might be imagined as a controlled muscle paralysis, so no surprise that it is also useful in treating muscle spasms, though more surprising is that it is used to treat excessive sweating (the first non-muscular application).

The toxin is in fact a series of related proteins, broadly divided in 7 types (A-G) and further divided into subtypes. The structure of two of those are shown here:

Though it is routinely used in medical and cosmetic procedures, it is acutely toxic. The treatment is an antitoxin, as well as ventilation if needed. A tribute to how well the doctors handle it, almost all cases of botulism result from the bacteria in the food supply rather than medical treatments, though there are some side effects, they are mostly minor and treatable. Improperly preserved food and infant botulism are the most common – sadly almost all the deaths from botulism in the US are infants. Infant botulism occurs when the bacteria colonize the intestine of the infant via ingestion of spores, leading to the release of toxin into the bloodstream. Honey has been identified as a major vector for the spores getting into the gut, thus it is strongly advised that no honey is given to any child under 1 year old, as even a taste can introduce the bacteria. Other than that, avoiding the bacteria is by thorough cooking, as the protein is denatured at elevated temperatures, though the spores are not always killed by boiling, meaning it can begin to grow again once conditions are right.

The toxin has also been examined by various groups as a potential bio-weapon. It has been difficult to weaponize, which is perhaps only partly reassuring, especially when you consider that 4 kg of botulinum toxin could, if properly dispersed, kill the entire human population of the planet. Less than a gram is needed to satisfy the annual needs for medical uses. Oh so useful but oh so deadly.

Single Molecule Charge Distribution

I saw this reported on the BBC web site, the first report of the charge distribution around a single molecule.

This has some implications for nanoscale technology development. But for me, it was just awe-inspiring to see at the molecular level things we have previously only ever talked about as theories and hypotheses. Not quite as much as the first picture of a molecule (but that was the same group, so we should keep an eye on these folks at IBM).

Catching up with the CCC

One of the things I have supposed to posted about was the annual conference of the Carolina Cannabinoid Collaborative, which happened at the end of last month. This was my 3rd CCC meeting and with the added advantage that it was in the Triangle, so no need for a hotel or a long drive (though the last two in Asheville and the Shenandoah Valley were both very pleasant). The Doubletree was of note for a couple of reasons for me personally, it was the place I stayed when I first came to North Carolina for an interview and (more pertinent to the meeting) it was less than 10 minutes walk from my house.

Well, it would have been if it wasn’t cold and wet that weekend. So it was an even shorter drive away.

Anyway, this year’s event was held in conjunction with a NIDA symposium on TRP channels. These are the Transient receptor potential channels, they act to give impressions of taste and smell, and certain TRP channels are classically activated by such things as garlic, menthol and capsaicin (in other words, chili peppers). But they are also activated by the components in marijuana and by the endocannabinoids. I hadn’t read much at all about these channels before the symposium so it was interesting stuff. The plenary lecture was by Craig Montell, who was intimately involved in their elucidation.

The CCC is fairly small, there were about 80 people there for this year’s meeting. This is one of the things a lot of the attendees like about it, it is informal and you can see everything and meet a lot of the people. This one felt a bit more crowded that the last two, due to the size of the meeting room, in which we were fairly well packed. I gave a poster on my work at RTI (on ligands for a CB1-Orexin receptor heterodimer) and this was in the lobby outside our meeting room, an unusual location for sure, but handy for catching people walking through.

The dinner featured a talk by Dr. Rao Rapaka of NIDA, talking about how he came to his present role, how he got involved in drug abuse research and many anecdotes of his time. The dinner itself was in a tent behind the hotel. This is permanently there and is likely to be wonderful during most Carolina fall evenings, but this particular one was rather cold and wet, so it was not quite so nice as it might have been.

There was a second day of talks and another poster session (also in the lobby). My colleague gave one of those talks, a lot more medicinal chemistry than most of them, as this is a meeting primarily of pharmacologists. Even my poster didn’t have a synthetic scheme on it (though one brave soul put one up there).

Favorite Reaction

When I read Rachel Pepling’s call for a carnival of favorite reactions, I almost did not respond. Which reaction to choose? So many cool little reactions: rearrangements, cascade cyclizations, exquisitely set up displacements. But when I thought to limit to things I’d actually done, it became a little easier.

Still, I’ve run more than a few reactions over the years. How about one of those that got me into chemistry: something like the Thermite Reaction (anything involving setting light to magnesium ribbon has to be fun) or the volcano? Or the first Grignard formation I ever did, which as I was laughing at my neighbor as their’s climbed out of the top of their condenser, when mine did the same thing (painting the hood ceiling in the process). Strangely that actually encouraged me to continue in this career rather than try something safer.

I like working out mechanisms, particularly when something unexpected turns out to be important in the sequence. It might be old hat to me now, but when I found out the mechanism of the Swern Oxidation involved the oxygen of the dimethylsulfoxide reacting with oxalyl chloride, I was taken aback: I had never considered something like that happening before. I also like running a reaction with several steps – I’m not sure why, it is just more satisfying than throwing everything in the flask and setting the oil bath to 90 ⁰C. So I came up with an alkylation of Cyclosporin A.
Cyclosporin A
The chemistry was discovered by Dieter Seebach. It is involves the formation of an anion, which is then quenched by an electrophile. That in itself does not seem so remarkable, but first consider that Cyclosporin A is a undecapeptide and in order to obtain alkylation at the desired point (the sarcosine residue), a polyanion needs to be formed, to account for the amide NHs and one hydroxyl group as well. In all, 6 equivalents of LDA are required (formed in situ naturally – does anyone really trust the commercially available LDA?), all with careful temperature control. Then the electrophile is added (in my case it was a disulfide), it reacts with just the part of the molecule you want and then you work it up.

And after that, with so much that can go wrong, if you do it right you get your desired product, cleanly and in a highly satisfying yield.

It is one of those reactions that makes chemistry such a joy. The practical science in its essence.

The Brains of Board Gamers

One of my interests outside of chemistry is in board games, so I was struck by this article in Science. Perhaps slightly embarrassingly, I actually came across it as a board game article looking at science rather than the other way around.

The authors used fMRI to look at the brain activity of various people working on shogi problems (shogi being a chess variant widely played in Japan). There was a group of talented amateurs and a group of professionals and the study looked at the differences between the two groups. Some of the results are very interesting.

Firstly, they see that the professional players make greater use of a part of their brain called the caudate head, which is implicated in learning and memory – which makes sense. The study found that as the problems got more difficult, the professional player made a greater use of their caudate and the amateurs used it less. In other words, the professionals used their built up knowledge, the patterns in the game to formulate their answers, but the amateurs tried harder to think deeply about the problem from first principles. In short, the pros make greater use of their intuition and the amateurs less – they don’t trust their intuition to give them the answer.

They saw this from another direction, when asking the participants if they were confident in their answer. When they were less confident, the professionals were seen to use their caudate more – in other words, their intuition. The authors noted that the professionals were much more likely to get the answer right too: about twice as likely. So their gut feeling is serving them well – presumably it has served them well prior to this and they trust it now. which is part of how they got to be professional players rather than decent amateurs.

Although this is a single study and involves just Japanese chess as its area of study, I think this applies to other situations. Even in just games, I have seen in myself, playing a game I do not know well, getting hung up over what move to make. Analysis paralysis, it is often called. You don’t know which move to make so you dither over it. When I am more confident over my mastery of a game, this happens less and even if I am not sure of the best move, my gut feeling tells me which of my options is likely to be the best.

One of the reasons I like board games is the opportunity to analyze different situations (game positions) and figure out the best way to manage resources, engage the game systems and come up with the best strategy to make the best move, either in the long or short term. It is interesting that the best way to approach a problem is not by brute force analysis but by being familiar with the patterns and typical behavior of the system and trusting intuition over logic, even in a game as dominated by logic as shogi.

A Spicy Lunch

We had our departmental annual lunch today, with a trip to the local Brazilian steakhouse. It was quite tasty and good to chat with a few people.

For the dessert, as it were, Jenny Wiley (who joined RTI recently) gave a talk on her work and in particular about the synthetic marijuana products such as Spice, K2 and the like. I knew something about the subject already, partly from the studies at RTI and also from blogs and web articles. It has certainly been a growing problem.

What struck me is quite how savvy the people selling these products are. Analysis of the incense shows several of the JWH series of indoles (from the chemist John Huffman, who made these for his own work at Clemson) and the makers have picked out some of the more active analogs. That they are following the literature is surprising enough, what struck me was the discovery of a JWH compound that they have not published yet. Are the Spice makers doing their own SAR as well?

Aside from the ingenuity they are showing (and also the story of the head of our department going into a local head shop to get some samples for his analysis), the make-up of these products is disturbing. There is a lot of different synthetic marijuana compounds turning up in the analysis and what’s more they are absorbed onto plant matter which in some cases may have its own effect on the central nervous system. The synthetic products are also significantly more potent than the active product in marijuana (delta-THC) and are delivered ‘pure’. The risk of over-dose must be much larger. That these products are rapidly becoming well known to college and high school students is a worrying trend, I will be looking forward to seeing any progress from the pharmacology end (as well as legally) to see that it is brought under some kind of control.

Update to add this article in the Washignton Post about synthetic marijuana use at the Naval Academy.

And the 2010 Nobel Prize for Chemistry Goes To…

…three chemists! *applause*

The Royal Swedish Academy of Sciences announced this year’s Nobel prize in chemistry and the winners were Richard Heck, Ei-ichi Negishi and Akira Suzuki for their work on palladium-catalyzed cross-coupling reactions.

As a lab chemist, this was immensely pleasing, a Nobel for chemistry I have actually used myself (all 3 reactions in fact!). Curiously, I don’t usually have much interest in the Nobels, they always seem to go to work that is only barely related to what I think of as my subject area. I didn’t think it was anything more than a passing interest except for those directly involved, but I saw blog posts talking about who might be the winner – one factor being that it is something that grad students get tested on, so they study it.

There was some great coverage by several of my regular reads (which i’ll add links to later). Some of the background was fascinating. Like that Richard Heck, who’s work was hugely important to the development of the whole field, is currently retired due to lack of funding and living in the Philippines. A contemporary of Heck’s who was also working on similar chemistry (without developing it as much as Heck) died of cancer. And the whole Nobel rule of “only 3 laureates per award” plus only living scientists can receive the award meant that Stille and Kumara are only posthumously remembered and possibly their deaths meant that the field was narrowed enough to highlight the three above, clearly all Nobel-worthy, but it has become a huge field with a wide variety of work. Since the committee specifically mentioned carbon-carbon bond formation, I daresay Hartwig and Buchwald can still hold out hope that their carbon-nitrogen bond formation contributions will still be recognized.

It is quite funny that this year, after thinking that chemistry was not getting its due, that we got this long awaited award for the palladium chemistry and that the physics award went for the discovery of graphene, the single atom thick layer of carbon. Which might have easily be recognized as a chemistry award too.