Why Would You Do That?! – Making cyclic peroxides from triketones

Not to steal any thunder from Derek Lowes’ Things I Won’t Work With, I would like to draw attention to a paper that simply made me exclaim, “Why would you do that?!”

Selective Synthesis of Cyclic Peroxides from Triketones and H2O2

And of course the Russians are up to the most bat-sh*t insane things again. Quick primer on why this set off alarm bells: if you’re not aware, the explosive used in the 2001 shoe bomb plot was triacetone triperoxide, also known as TATP. These compounds are why chemists are taught never to wash flasks that recently contained hydrogen peroxide with acetone; the mixture easily and rapidly forms the dimeric and trimeric acetone peroxides shown to the right. Both of these explode with vigor, and should be avoided at all costs because they can literally take down planes. Want to know why you’re limited to specific volumes of liquids on planes? It’s because that’s the volume of acetone and hydrogen peroxide one would need to inflict enough damage on a jumbo jet to take it down. For those who haven’t flown in a while, it’s not much.

Peroxides of acetone. Danger! Crazy explosives!

So why in the heck were these guys making it?

The interest in the synthesis of radical
polymerization initiators and drugs gave impetus to the
development of methods for the synthesis of peroxides with
the use of carbonyl compounds, their derivatives, and H2O2
the starting reagents.

Now, maybe these aren’t so bad. The authors do report refluxing their compounds in ethanol for extended periods of time, so perhaps the extra mass and being tied up in a ring stabilizes them, but if I were a new graduate student being sold this project, I would be cautious. Remember, the authors who published on FOOF reported storing that, but I don’t think I would ever want to make it, let alone store it, so perhaps some reading between the lines is necessary for this paper.

Thoughts? Would you make these? Is it worth risking your precious, precious fingers?

Damn Russians, why do you always have to make us Americans look like wusses?

The Role of Humans in Chemistry

Bruce Gibb brings us a wonderful analysis of the role of non-scientific factors in scientific policy this month in Nature Chemistry. A representative excerpt follows:

But whatever you can reasonably do to try and shift the statistics in your favour, do it. Time the meeting with your boss, time your organic class filled with pre-medical students and time your general exam to just after feeding time. And if you believe in a higher deity, pray that your grant application will be reviewed just after everyone who reviews it is well sated. Going back to the general exam scenario, meta-considerations about the committee’s stomach contents may not help you if you start a flow of electrons in a mechanism you are drawing by depicting an arrow emanating from a proton. And to switch scenarios again, it may not help you if the boss who is hopefully going to okay your plan had one too many the night before because their beloved pet recently passed away. But it can’t hurt.

Everyone always makes the comments along the lines of “Oh, I would have been able to X if I had only not stayed up so late/not skipped lunch/not had that curmudgeonly synthesis professor with the impressive moustache,” and, excusing a certain amount of whining, there’s some truth to it. Whenever anyone asks me for advice about how to go about applying to graduate school, I generally respond that whether or not you will get in is already predetermined by the greater good, but that you had better hope that no one’s in a bad mood when the admissions committee gets your application.

However, I’m interested in the greater ramifications of how these little things add up over the course of one’s career to make them who they are. The classic example, in my opinion, is the chemist responsible for:

-Coining the term “bond”

-Singlehandedly inventing the field of organometallics (organozinc reagents, specifically), coining the term as well

-Developing the idea behind “valency”

-Revolutionizing chemical education in the 1800’s

-Cleaning up the River Thames, preventing an urban pandemic

If you’re thinking, “Man, Kekule did all that?” then you, sir or madam, have fallen victim to the 1800’s German Hype Machine. The chemist that I refer to is Sir Edward Frankland, a chemist with achievements coming out of every orifice, yet his Wikipedia page (above) is shorter than that for I Can Has Cheezburger?

Sir Edward Frankland, ca 1852

How did Eddie fall so far by the wayside? Well, a read through his biography reveals that he began his organic chemistry career as an analyst, made the queer choice of being the only English chemist of the 1800’s to pursue a doctorate in  Germany, and abandoned a postdoctoral position with a prominent chemist several days after joining to take an academic position at a new university that shortly became defunct. Further, once he managed to move to a more prestigious position, he spent less time doing fundamental research and more time acting as a consultant, gave up some responsibilities for his ailing wife, and began working in more applied areas of chemistry later in his career. Meanwhile, his contemporary the German powerhouse Friedrich August Kekulé von Stradonitz began commenting on many of the same topics, many of which we now (incorrectly) attribute to him.

Kekule, whose beard is one of the few subjects in which he legitimately outdid Frankland

And why is that? Part of it is because Frankland was notoriously disliked, but many of the things I describe above have been parodied in modern scenarios. How many of us end up foregoing an academic career for our families? How often do we realize that we need money more than we need prestige and take the more practical path? How many of us change paths later in our careers, only to look back and wonder what would have happened if we had only stayed on the original path? Even having one’s work misattributed happens ever-so-frequently; did MacMillan really invent organocatalysis (answer: no), or was he simply the one most in the spotlight when people started noticing the field? Is Dieter Seebach the modern Edward Frankland (answer: no), or is there more at work?

Going back to Gibb’s points at the beginning of this rant, these decisions plague us on a daily basis, and many of them are foregone conclusions, others are negligible, but can we take all of these things in stride? How many little inconveniences can a person tolerate before they end up veering off the path? How many risks can we take before we end up worse than when we started?

Basically, what I’m saying is that, beyond just the science, there is a distinct human element to the field that can make the greatest scientists lose hope too soon and the less capable able to skyrocket past the competition. We’d all like to think that hard work will get us our due rewards, but perhaps we just need to make sure our bosses have a ready supply of cookies before they write our recommendation letters.

New-ish Frontiers in Allylic Fluorination?

For my inaugural post on Colorblind Chemist, I’d like to talk about allylic fluorination.

Fluorine has captured the interest of medicinal chemists for a while now; the introduction of the wily halogen can modulate all sorts of pharmacokinetic properties, most importantly being the lipophilicity, which generally tracks fairly well with oral bioavailability. Even better, the newest hotness in the field of fluorine chemistry for the past decade or so has been Positron Emission Tomography (PET), which uses radioactive fluorine-18 atoms to track molecules of interest in biological systems with good signal-to-noise. These two desires have shot fluorination to the forefront of a number of methodology groups’ to-do list, including that of my former advisor, Tobias Ritter. In fact, just recently the Ritter group put out a beautiful paper on the facile fluorination of aromatic substrates, which lends itself directly into PET chemistry (there are a number of constraints on what makes a reaction PET-compatible, including fluorine source, reaction time, and byproduct profile, which are discussed in the linked paper for those who are interested).

So then, where does the state of the art lie? If we ignore PET-compatible constraints, there are actually a number of catalytic methods to generate selective fluorinations, where substrates range from aromatic to aliphatic with varying degrees of success. Today I’d like to focus on allylic fluorination, specifically because this strange reaction system was published in Organometallics recently, and I honestly can’t tell if I love it or hate it.

So what’s the big deal here? Well, a priori, we have a palladium-based system that stoichiometrically generates allylic fluorides from allylic bromides. Or does it perform C-F Activation/Arylation? Technically it does both.

So let’s take a step back and think about what we’re working with. This reaction would have been exciting as hell 17-20 years ago when the only reliable manner for generating allylic fluorides was to use molten caesium fluoride as the fluoride source, but in recent years we’ve had all sorts of break-throughs from the Gouverneur labs at Oxford to create linear allylic fluorides from a-b unsaturated esters, and several iterations of a system from the Doyle labs that enantioselectively generates branched allylic fluorides from  allylic chlorides. We don’t even need to consider Nguyen’s trichloroacetamide system to realize that the bar for allylic fluorination is fairly high.

So what about C-F activation? Well, it turns out that is pretty well precedented as well; in fact, it’s the entire focus of the Hughes group at Dartmouth. So really, what has this paper achieved? This is where I draw the line about whether I love or hate this paper; the practical answer is nothing. The products of this method are precedented, even through palladium catalysis, and so in terms of adding access to new molecules, there really isn’t anything novel. Sure, the method can alkylate a perfluoropyridine AND simultaneously fluorinate an allylic bromide, but honestly, if the day comes where I just happen to need those two things at the same general time, I’m not going to pull the obscure phosphine ligand needed for this off the shelf (or rather, synthesize it, as it isn’t commercially available) to do this.

So, what in the hell am I getting at? To be succinct, this paper does exactly one thing well: it accomplishes fluorination with a very non-traditional fluorine source. Who cares? Well, if we think about the current fluorine sources, which are admittedly rather abundant, they tend to have their subtle drawbacks. For instance, use CsF that’s been exposed to air too long, and it’ll hydrate to the point of being practically useless. Expose AgF to air or light for too long, and it will decompose, and don’t even get me started on the cationic fluorine sources. Further, nearly all of these have some issues with organic solubility, which may not be an issue in PET scenarios, but for med chem, it can be a serious issue if your fluorine source doesn’t agree with your choice of solvent. In this paper, we use a card-carrying organic fluorine source, which is by all approximations air stable, and pluck a fluorine off and put it on our substrate. If you’re really enthusiastic, you could even recycle the spent fluoropyridine with the Ritter method and call yourself square.

Is perfluoropyridine the ideal “organic” fluoride source? Of course not. However, for a relatively simple molecule that’s reasonably priced, it’s certainly not horrible, but the big thing is that it’s something different. I believe that fluorination reactions will make up a very important tool kit of reactions for both medicinal chemists and diagnosticians alike, and thinking up alternatives to CsF and DAST are likely what will enable the next generation of catalysts. So, hats off to Braun et al, it’s probably not what you were going for, but you gave me some food for thought.