B.R.S.M. When all you have is a hammer everything looks like a nail

24Jul/133

US Here I Come!

Hi all,

Somewhat later than planned, I'm off to the US tomorrow to finally start my postdoc! I suspect I'm gonna be pretty busy finding a place to live and settling into my new group for the next couple of weeks, so things could be quite quiet around here for a little while. I hope to resume blogging when I've gotten into a new routine, and I'm looking forward to having lots of new experiences to write about. Thanks for your advice and patience!

Cheers,

BRSM

P.s. Although this is a dedicated organic synthesis blog, lots of people have asked me about my move to the US, so I'll probably attempt to write a series like Nessa's Transatlantic Tales about my experiences and mix that in with the usual content when normal service resumes. What do you think?

Filed under: Ask the audience, Not Chemistry | 15,307 views | 3 comments 3 Comments
16Jul/1316

Woodward Wednesday 7: Steroids

R. B. Woodward et al., J. Am. Chem. Soc., 1952, 74, 4223 [PDF] (Full paper)

For preliminary communications see: JACS, 1951, 73, 3547 [PDF]; JACS, 1951, 73, 3548 [PDF]; JACS, 1951, 73, 4057 [PDF]; JACS, 1951, 73, 2403 [PDF]

Hundreds, if not thousands, of steroids have been characterised to date, isolated from a bewildering variety of organisms from across the animal, plant and fungal kingdoms. Their roles as hormones, drugs, and in cell membranes make them crucial to life as we know it, and are the reason that they’re one of the best studied classes of natural products. People have been interested in making steroids since the earliest days of total synthesis in the 1930s and 40s, and the field of steroid synthesis has made the careers of legendary chemists such as Russell Marker, George Rosenkranz, Arthur Birch and Carl Djerassi, as well as ensnaring and captivating many others. Indeed, some five Nobel Prizes have been awarded for steroid research, and the fruits of these labours have included many important drugs and much useful chemistry.

R. B. Woodward was also heavily involved in steroid chemistry during his early career, perhaps inspired by his PhD studies on ‘A Synthetic Attack on the Oestrone Problem’. As I wrote about in an earlier post, he also famously collaborated with Konrad Bloch to elucidate the details of steroid biosynthesis, work for which Bloch would receive the Nobel Prize in medicine the year before Woodward received his in chemistry. Woodward’s synthetic contributions to the field came in the form of a groundbreaking synthesis of methyl 3-keto-Δ4,9(11),16-etiocholatrienate, which he resolved and converted into a number of known compounds, achieving the formal total synthesis of some of the best known steroids.

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This flexible intermediate contained enough latent functionality (largely in the form of unsaturation in the carbon skeleton) to enable the interception of previously reported compounds that could be converted into cortisone, testosterone, progesterone and cholesterol, the archetypal members of four of the most important steroid families.

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Filed under: Literature, Total Synthesis, Woodward Wednesdays | 34,953 views | 16 comments Continue reading
5Jul/134

Non-Thermal Microwave Effects: Probably Still Bollocks

Thanks to Brandon and Martyn for pointing out these publications. Be warned, this post turned out seriously long and wordy!

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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’.

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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!

Filed under: BRSM Reviews, Current Literature, Serious | 19,707 views | 4 comments Continue reading