Thanks to Brandon and Martyn for pointing out these publications. Be warned, this post turned out seriously long and wordy!
Almost since the dawn of microwave chemistry, which began in the 1980s with people simply putting Erlenmeyer flasks full of reactants in domestic microwaves, chemists have reported all kinds of improvements from heating in this fashion. To name a few of the more common ones, I've heard people claim higher yields, shorter reaction times, cleaner reactions, different selectivities, milder conditions and better overall energy efficiency. Microwave chemistry can be a good thing, and many of these effects are real, widely observed phenomena; the problem is that chemists disagree on their origins. However, comparison between microwave and conventionally heated reactions is fraught with difficulties. One obvious factor is that microwave reactions, at least in the organic chemistry labs that I’ve worked in, are inevitably conducted in sealed tubes, which makes direct comparison to the ‘open’ systems that are typically used in conventional reaction set-ups. Heck, even in open systems, superheating of solvents past their boiling points can occur if nucleation sites are lacking – even two reactions apparently refluxing in the same solvent can be at different temperatures! In fact, simply getting the temperature wrong is probably the major reason for the disparate results obtained when conventional reactions are compared to their microwave ‘equivalents’. This isn't helped by the fact that your average lab microwave only reads the reaction temperature by IR measurements of the surface of the reaction vessel; I’ve heard descriptions of this practice ranging from ‘optimistic’ to ‘demonstrably, hopelessly inaccurate’.
I'm reusing this photo of a microwave just to break up the text a bit!
Because of these (and various other) hard-to-pin-down factors, it’s actually pretty hard to compare conventional and microwave heated reactions, and not everyone has the kit required to do so properly. This has led to numerous claims of so called ‘non-thermal’ or ‘specific’ microwave effects in the literature. These generally explain the apparent benefits of microwave heating by claiming that the microwaves don’t just simply heat the reaction medium (hence ‘non-thermal’), but instead excite (or even stabilise!) particular bonds or intermediates directly, in a fashion distinct from simple macroscopic heating of the reaction mixture. Such claims have been debunked for over a decade, and physical chemists will tell you—at least in the liquid phase—that energy is redistributed amongst the molecules in the reaction vessel on a much shorter timescale than the period of the microwaves used to excite them, making specific heating of one species over another unlikely. Certainly, temperature gradients and macroscopic hotspots may well exist (particularly in viscous/high dielectric/inadequately stirred media), and are readily measured with a temperature probe, but I’ve yet to see credible evidence for the molecular-scale thermal aberrations that are continually reported. It seems that, when investigated in detail, with care to eliminate other factors, claims of non-thermal effects have yet to stand up to scrutiny. In fact, I'm a little baffled as to why we see the continued reporting of results predicated on this phenomenon, with few proper control experiments. I'm not saying that they don't exist, and I'll happily accept their existence when sufficient proof is presented, but I think a lot of rubbish is generally talked on the subject.
One of the most prominent chemists to voice their disbelief in so called ‘non-thermal microwave effects’ is Austrian Professor Oliver Kappe, who's been countering such claims in the literature for at least as long as I’ve been a chemist. He periodically publishes smack-downs of claims of chemistry of this type, most recently in an Angewandte Chemie Essay that appeared just before Christmas (that I blogged about at the time). One of the groups whose work he criticised was that of Gregory Dudley at Florida state university, and things escalated this week with the publication of Dudley's reply to Kappe’s attack, followed swiftly by a further rebuttal by Kappe. The last ‘literature boxing match’ of this type that I can recall was the citalopram back-and-forth in OPRD a couple of years back, covered at the time by Derek over at In The Pipeline, and while the claims made by either side here are not in the same league of dubiosity there’s plenty of thinly veiled frustration and strained civility to enjoy!
Update 1900: This was blogged earlier today by Tom Phillips over at A Chemical Education. Whoops!
Update July, 2013: Part two! Because sometimes you just wanna flog that dead horse a bit longer, you know, to be safe.
For a related post on things to check before publishing your controversial results to avoid potential humiliation, see my old piece on 'metal-free' reactions.
From Angew. Chem. Int. Ed. 2012, 51, 2.
It seems to me that people still talk a great deal about so-called 'non-thermal' effects in microwave reactions; i.e. some kind of mysterious rate acceleration that occurs from excitation (or even stabilisation) of particular bonds or intermediates directly, in a fashion distinct from simple macroscopic heating of the reaction mixture. One of the most prominent critics of those who claim to observe these phenomena is Austrian chemist Oliver Kappe, who's been debunking claims of non-thermal effects for at least a decade and he's just written an excellent Essay in Angewandte Chemie on the subject. Now, few people would argue that a lot of reactions work better in the microwave, but this can often be explained by rapid internal heating or increased pressure; that is, by thermal effects, however dramatic. An example from Kappe's essay illustrates the incredible magnitude of rate improvement that's sometimes observed:
From Angew. Chem. Int. Ed. 2012, 51, 2.
Hi all, we* interrupt our* scheduled** programming to bring you an exciting** Chemistry Carnival entry! See Arr Oh recently had the brilliant idea of a Chem Coach Carnival, where people in different chemical careers describe their working lives to give others an idea of what it's like to be in their shoes. Here's my entry, which unfortunately seems to have turned out a bit too long:
What do you do?
As you might have guessed, I'm currently a 'postdoc' or post-doctoral research associate at a UK university. If you're not familiar with the academic hierarchy you can see where this fits in the academic food chain here, thanks to Karl Collins.
What does a typical day involve?
I'm one of three postdocs in a research group of around twenty people engaged in diverse projects across the spectrum of organic chemistry. When I was at school The RSC ran a campaign to tell people that 'not all chemists wear white coats', but I'm proud to do so for 90% of a normal day. At the moment I'm mostly working on a short-ish biomimetic alkaloid synthesis but in addition to my own project(s), I also get to field questions from PhD and MSci students, show people how to do stuff in the lab, write papers, work on my own crazy ideas, manage an MSci student and worry about what I'm doing with my life. I also do some teaching in the form of undergraduate tutorials, which is great fun. My job is essentially to solve an increasingly varied and intricate series of puzzles, and it's good.
How did you get where you are?
It sometimes feels like I've spent my whole life in full time education as I started university straight after school and my PhD a few months after I finished my undergrad. As it happens, I'm currently still at the same institution from which I obtained my PhD a few months back. Staying in one place like this is usually inadvisable, but it's not a bad university, there's a good climbing wall nearby, and my current position is really just a short term filler until I move to the US next year for a 'real' postdoc. Goodness knows what I'll do after that. Fortunately, thanks to the shorter British PhD, I've only just turned 26.
How does chemistry inform what you do?
I really can't know enough chemistry as it pervades everything I do at work. The deeper my knowledge, the better I'll be at my current job, and the greater the chance I'll have of getting another.
Pros and Cons?
It seems that this job combines most of the good bits of being an academic and a PhD student; on the one hand I get almost total freedom to do what I like, I still spend most of my time in the lab, I get to teach and I get to be familiar with all the stuff that other people in the group work on but I don't have to write grant proposals or a thesis, take exams, or attend many meetings. It's pretty much how I think being a chemist should be. The main problems with the job are that it doesn't pay that well; although money is rarely a problem for me, I couldn't start a family or buy a house; the hours are pretty long, and are only going to get worse when I cross the Atlantic; and it isn't a long term career, as doing more than a couple of one or two year postdocs is widely considered a bad idea. It can also be stressful and frustrating.
A funny story?
Reading through what I've just written I guess I come across as pretty keen on chemistry, but it hasn't been a lifelong interest of mine. I wanted to study physics at university but sucked at math so I ended up studying materials science. That turned out to be a little too last-but-one century for me; the amount of time we spent learning about steel and concrete really put me off. After a year I switched to chemistry, but was a mediocre undergrad as I spent most of my time running the university mountaineering club and planned to get a job in the outdoor industry when I graduated. It wasn't until my final year masters project that things changed for me. Although I usually did much better in inorganic chemistry, I chose to join an organic research group that looked interesting on paper, but to my surprise it turned out to consist only of one mostly retired emeritus professor and a young - but extremely talented - postdoc. To hear those two talk about chemistry was amazing; it was like listening to a conversation in another language, and as they swapped stories about this academic or that, discussed the latest Nicolaou paper or just stood around cracking jokes I realised that the world of organic chemistry was much more interesting than I'd ever realised. I loved the history, the in-jokes and the community. I wasn't a great masters student, but I doubt anyone else in my year learned as much as I did during their project. Four years later I'm still a chemist. And I'm not ready to stop learning yet.
** This is not true.
I was saddened and surprised today to read this story on the BBC News website about a young man who died by overdosing on 2,4-dinitrophenol. Huh? Now, perhaps on account of my long hair and somewhat dishevelled appearance, I get offered a lot of drugs, but this isn't something I've ever heard hawked on street corners. It turns out that despite previous uses as a detonator and pesticide it's apparently quite popular among bodybuilders as a weight loss drug, something the FDA found it to be unsafe for back in 1938. Which is really something as 'safe' had a whole different meaning back then; hell, the 1948 the Nobel Prize for Medicine was awarded to Paul Müller for his discovery of 'wonder' pesticide DDT. But how does 2,4-dinitrophenol work? Well, here's a mechanism of action I wouldn't have guessed:
"DNP acts as a protonophore, allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. This makes ATP energy production less efficient. In effect, part of the energy that is normally produced from cellular respiration is wasted as heat. The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and meet energy demands. DNP is probably the best known agent for uncoupling oxidative phosphorylation."
Well, that sounds tempting! So, for a slightly higher basal metabolism you get a permanent fever, sweats and insomnia! Surprisingly, to me at least, mitochondrial uncoupling appears to be considered a valid approach for the development of anti-obesity drugs, despite these unavoidable side effects. The problem with using 2,4-dinitrophenol for this purpose is that the therapeutic index is very small, and overheating is quite easy even using a 'safe' dose, causing all kinds of problems. I read a few accounts of people's experiences with the drug online, and most of them concluded that taking 2,4-DNP was far more unpleasant than good old fashioned dieting. As Samuel Goldwyn once said, "gentlemen, include me out".
On Monday, See Arr Oh over at Just Like Cooking posted on this non-obvious Diels-Alder reaction recently published by the Vanderwal group, suggesting that it'd make good problem session fodder. And I agree:
Fortunately, this tied in perfectly with my plans to run our group problem session next week on a pericyclic theme and so it was duly incorporated. If you're interested in what else featured, I also included a question on the origin of the metastability of Dewar Benzene (which I've blogged about before).
After a few easier questions I finished up by asking people to suggest a mechanism for this interesting sequence published a few years back.
Last Monday I set my MSci student the task of preparing the above compound and sent him off to do some literature searching. He quickly found a mention of it in a J. Med. Chem. paper, although the authors didn't give any detail themselves on its preparation, instead claiming to have used the method of Shulgin and Shulgin, described in reference 17:
That's right: a reference to PIHKHAL in the primary chemical literature! When I got over my initial surprise I did track down a copy (the university library didn't have it) to look up the procedure. Indeed, a very detailed and reasonable sounding synthesis of the compound is described under the chapter on the synthesis of 2C-T-2 (along with an evocative description of just how high you can get on it).
There's lots of detail and the whole thing is done on sufficient scale to produce 10 grams of the desired compound. Perhaps not too surprisingly, the route starts with chlorosulfonation of 1,4-dimethoxybenzene, followed up with reduction (Zn in HCl) to give the thiophenol which is then ethylated. Easy. We're going to try it this week, and I will enjoy seeing PIHKAL referenced in a lab notebook. It's funny, I've been aware of this book for probably ten years or more - heck, I even gave a talk last year entitled 'Quinones I Have Known And Loved' - but I never thought I'd be reading it at work. Steven Weinreb once said of Russell Marker: "There are more stories told about [him] than any other chemist. Although perhaps many of these stories are apocryphal, they are so fascinating that more of us cannot bear to stop repeating them... they are the campfire stories that bind our profession together", but I think that the same could also easily be said of Shulgin. I mean, along with Humphry Osmond the man actually coined the term 'psychedelic'. I learned today that there's even a Shulgin Index, written in the style of the more common Merck index, describing the physical and pharmacological properties of some of the psychedelics he and others prepared over the years. I hope to one day have the chance to read a copy.
1. More in this vein can be enjoyed in the digitised versions of Shulgin's lab notebooks. Although his handwriting, combined with the quality lost from storage and scanning, can make them quite hard to read in places they seem to be quite interesting and frequently amusing and insightful. Although the first entry in the first book describes his experiences of taking 400 mgs of mescaline sulfate and the results (which, including hallucinations experienced with eyes open and shut were 'very pleasant'), there's also some real explorative medicinal chemistry documented there. They're actually much better kept than the lab books of many PhD chemists I have worked with, and it's easy to forget that this work was largely conducted in a shed in California. If it wasn't, you know, for all the drug taking.
2. Chem. Eng. News, 1999, 77, 78; If you don't have access to that the article was also reprinted verbatim in The Journal of The Mexican Society the same year and can be enjoyed for free here.
3. It's interesting to note that this term come from the Greek for 'mind manifesting', which I think speaks of the pair's optimism for the curative power of such compounds. Hopefully I'll do another post on chemical etymology one day.
Perhaps Organic and Biomolecular Chemistry isn't a journal well known for its reviews, however I recently enjoyed reading this rather unusual perspective by Jason Chen on "Gas Extrusion in Natural Products Total Synthesis". All the classics are there: the retro [4 + 1] cycloaddition of sulfolanes to generate dienes (and the related Ramberg–Bäcklund reaction), the Boger-style 1,2,4,5-tetrazine [4 + 2]-retro-[4 + 2] method for the synthesis of aromatic rings and many more unusual ways to lose nitrogen besides. There are also some much rarer reactions, including an example from Padwa's synthesis of stempeliopine where addition of carbon suboxide (O=C=C=C=O) to a thioamide is followed by a cascade that eventually spits out carbonyl sulfide (OCS). I bet that's a synthesis that makes you unpopular in the lab
Probably the winner for the gassiest sequence described is from a Movassaghi paper that I remember from last year. Although the reaction hasn't actually been used to make a natural product yet, it looks like a useful way to access hetero cyclotryptamine natural products, of which there are many. The idea is to synthesise an unsymmetrical sulfamide, where the two amines are connected to the two units to be linked. Oxidation of this with NCS then generated a thiadiaziridine dioxide in some bizarre Aza-Myers-Ramberg-Bäcklund-type reaction. This then lost sulfur dioxide as expected to give a diazene that was decomposed photolytically with loss of nitrogen to give a pair of radicals that recombined quickly. Amazingly this recombination occurred sufficiently to prevent the formation of homodimeric products. Neat reaction - I love the fact that the linker is completely traceless!
Gas extruding reactions are more important that might be imagined at first (especially for the construction of strained systems), and it's nice to see a review dedicated to them.
1. Carbon suboxide apparently smells (surprisingly?) awful . From an early review on its chemistry:
"The physical properties of carbon suboxide are of considerable interest. It is a gas under ordinary conditions, having an unbearable odor like acrolein and mustard oil. In small amounts it acts as a lachrymator; in high concentrations it attacks the eyes, nose and breathing organs, giving a feeling of suffocation."
There are lots of ways to make it, some of which are more appealing than others. Padwa generates it from dibromomalonoyl dichloride and zinc in ether at room temperature, which sounds quite sensible. Unfortunately, the OCS by-product also smells pretty bad. It's a little known fact that pure carbon disulfide has a pleasant smell redolent of diethyl ether (according to the Merck index; I used to have a CS2 still and I never experienced this). The reason it's so unpleasant to work with are traces of OCS (and thiols) from its manufacture. According to Wolf and Amarego these can be removed by washing with aqueous KMnO4 solution, followed by mercury. Or not.
I wrote this post a couple of weeks back, but wasn't happy with how rambling it was. Anyway, it's only getting more out of date, so I'm putting it up now. Someone might learn something.
I’ve always had a soft spot for hypervalent iodine reagents, especially iodine(III). In fact, they were the cornerstone of a methodology project that I worked on last year. You can imagine, then, that the rather usual looking iodosobenzene derivative above, which was published in Org. Lett. a couple of weeks back (DOI: 10.1021/ol301085v), immediately caught my eye. Such compounds tend to be very useful oxidants, and you can check out a few recent applications on the relevant organic-chemistry.com page. Surprisingly, though, this wonderful new reagent wasn’t being touted as an oxidant (although I’m sure it is)… apparently, it’s a great new coupling agent!
Base image from http://mrsec.wisc.edu/Edetc/nanolab/photonic/index.html
Did anyone else see that paper on Thursday in Chem. Comm. titled "Use of Dimethyl Carbonate as a Solvent Greatly Enhances the Biaryl Coupling of Aryl Iodides and Organoboron Reagents without Adding Any Transition Metal Catalysts", and think "here we go again"? I immediately though it kind of appropriate that Chem. Soc. Rev. very recently published a history of transition metal contaminants in catalysis (DOI: 10.1039/C2CS15249E). However, on reading the Chem. Comm. paper, it seems the authors were very careful both to check all their reagents, and not make any grand claims. Not surprising, really, given the numerous examples of misunderstanding of such results in the literature. Even the title is cautious, saying 'without adding any transition metal catalysts', quite a step down from the bold claims of 'transition metal free' reactions seen in the literature of a decade or so ago.
Enantioselective Total Synthesis of (-)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine
This week saw another brilliant synthesis from the still fairly new Reisman group over at Caltech, this time an epidithiodiketopiperazine (ETP), the group's first. These interesting secondary metabolites have so far only been isolated from fungi, and owe their toxicity to their disulfide bridges that generate reactive oxygen species by redox cycling. Although ETPs have been popular targets for the last 40 years, and the field has seen some impressive chemistry from Kishi in the 70s to more recent efforts by Movassaghi, Overman and Nicolaou. More challenging still are the dihydrooxepine containing ETPs such as acetylaranotin, which has stood unconquered since its isolation 1968, and in fact no synthesis of such a compound has been reported, until now.