Tuesday, 30 April 2013

#ChemClub Reloaded

#chemclub has been running successfully for a couple of months now. This is all down to the people who take time to contribute regularly, so thank you! I hope it's proven interesting and useful.

I've been thinking about ways to expand #chemclub. The first step is blogs - there are plenty of great writers out there covering individual papers in depth. There's been some discussion about the best way to do this, such as starting a separate hashtag. However, I like simplicity and I don't think the #chemclub feed is so crowded that it can't handle more links, so here's the plan.

If you write or find a blog post discussing a specific chemistry paper, old or new, post it to #chemclub and I'll include it in the regular round-up.

I'm especially looking for context: writers who critically discuss why the work matters and put it into context for those who aren't specialists in that area.

I have a few other ideas fermenting too. If you'd like to get involved, get in touch with me on Twitter or leave a comment below.

Sunday, 28 April 2013

#chemclub Roundup #RealTimeChem edition

It's the end of #RealTimeChem week and it's been great fun. Kudos to Dr. Jay and everyone else behind it! In addition to the regular round-up of #chemclub highlights, I'm going to pick out some of the best of #RealTimeChem week.

My favourite thing about this week was the chance to speak to a lot of new people and find new blogs. You might notice that the blogroll (over to your right) has been greatly expanded... For my part, I contributed with by writing about five 'chemistry classics', which you can find links to here. This was also a very exciting week for me as my post about chemophobia was featured at Grand CENtral and Scientific American!

There's been a lot of great chemistry writing this week: Dr. Jess has provided regular round-ups (1 2 3 4 5) at The Organic Solution. The final few posts from the "Chemistry at the Movies" carnival have also trickled in, and are indexed at Just Like Cooking.

A few of my favourite posts from this week:
Open Source Catalysis featured Kat's lab book most days this week. These posts are a beautiful walkthrough of a week in the life of a chemist. (Also, her TLC baselines are nice and straight. Pay attention, SeeArrOh ;) )
Taking Care of Bismuth - love the punny title! - features Trent doing a titration in his kitchen. I never thought I'd find titrations interesting again, but Trent pulls it off. Great read.
At the Interface posted a nice example of how science happens: serendipity, collaboration, and solid knowledge coming together to give an elegant result.
Labsolutely shows how to turn a column into a musical instrument. If you've not seen Vittorio's videos before, you're in for a treat. I reckon his "Chemistry: An Extreme Sport" video should be the trailer for the next Otto lab open day...

Onto the peer-reviewed stuff. Here's some highlights from #chemclub the last couple of weeks:

Friday, 26 April 2013

Chemistry Classics: Foundation of Organic Chemistry


Day five of #RealTimeChem week, and the final post in my series about classic chemistry papers. These quick reads have covered topics varying from chromatography to crystallography, focusing on ubiquitous techniques and revolutionary discoveries.

Today I want to discuss a truly foundational paper which describes a single-step synthesis. The original paper is in German, so I am using the English translation at John Park's ChemTeam website.


Friedrich Wöhler, "On the artificial production of urea", Annalen der Physik und Chemie, 1828, 88, 253-256.


This paper hardly needs introducing; pretty much every undergraduate is told that this paper represents the death of vitalism and the birth of organic chemistry. The usual account runs thus: in the early 19th century, compounds were classified as organic and inorganic based on whether they were found in living or inanimate sources respectively. It was thought that organic matter held some sort of élan vital which was absent from inorganic matter, and was therefore fundamentally different. Under this scheme, transforming inorganic to organic matter would be impossible.


Here, Wöhler synthesised urea - a component of urine and hence an organic compound - from inorganic reagents, thus disproving the notion of vitalism once and for all. Every chemist worldwide read this paper and, good logical positivists they were, immediately abandoned vitalism and thus science was born.


That's not quite how it happened. I've provided some links to relevant historical material below if you want a more accurate picture.


What does Wöhler's paper actually say? It's wonderfully brief, and he gets to the point in the first paragraph: in his previous synthesis of oxalic acid he obtained an unidentified white solid, which turns out to be urea, "a fact that is noteworthy since it furnishes an example of the artificial production of an organic, indeed a so-called animal substance, from inorganic materials". This is the only reference to vitalism in the paper.


His synthesis is simple: decomposition of lead cyanate with liquid ammonia (if you're thinking of trying this, BRSM has some chemtips for you). "It was precipitated in colourless, transparent crystals, often more than an inch long". No fancy purification for Herr Wöhler, oh no.



Pb(CNO)2 + NH3 + H2 Pb(OH)2 + NH4CNO
NH4 ⇌ NH3 + HNCO ⇌ (NH2)2CO

Identification is by comparison of reactivity with authentic samples of urea, and known properties of other possible products such as cyanates. His description of these experiments is poetic in places, quite unlike a modern SI!

He concludes with discussion of the fact that the empirical formulae of urea and hydrated ammonium cyanate are the same, pointing to the existence of isomerism - which is, perhaps, far more important to chemists than the distinction between vitalism and reductionism!


Perhaps the title of this post is inaccurate, as would any attempt to pin the beginnings of organic chemistry to a single moment. Regardless, this experiment remains crucial to the development of organic synthesis and theory.

I hope you've enjoyed this short series of chemistry classics. If you have, you can subscribe to the RSS feed using the button at the top-right of the page, or follow me on twitter.


Some links:

A procedure for repeating this synthesis.
Did the urea synthesis destroy vitalism? 1, 2.
ChemistryWorld podcast about urea

Thursday, 25 April 2013

Chemistry Classics: X-Ray Diffraction

#RealTimeChem week has passed the halfway point, and we've reached the penutlimate post in my series of five classic chemistry papers. These are meant to be quick coffee-break reads covering classic papers from across chemistry; we've covered flash chromatography, NMR spectroscopy, and prebiotic synthesis.

2013 is a significant year indeed. This year we may well have seen history in the making, as Fujita and co-workers published a method of obtaining x-ray structures without the need for crystals. Appropriately enough, this year is also the 100th anniversary of the publication of Bragg's law, an equation which is at the foundation of this technique and won the Nobel Prize a mere two years after publication! Unfortunately, I can't find a copy of Bragg's original paper, "The Diffraction of Short Electromagnetic Waves by a Crystal", anywhere.

And so we turn to a classic application of crystallography, for today is another anniversary: the 60th anniversary of the publication of the crystal structure of DNA.

James D. Watson and Francis H. C. Crick, "Molecular Structure Of Nucleic Acids: A Structure For Deoxyribose Nucleic Acid", Nature, 1953, 171, 737-738.

The story of this discovery is well-known to most people. The centrality of DNA to inheritance had been realised, but its structure and the mechanism of information transmission were both unknown. Using data provided by Rosalind Franklin (who died before the Nobel was awarded, and only relatively recently has started to receive due credit) they determined that DNA has the famous double-helical structure. Another stroke of luck came from a visit of Chargaff to Cambridge; one version of this story goes that, over a formal dinner, he gave Watson and Crick a lesson in tautomerism of nucleobases, prompting them both to rush in their gowns from the table to build models of the now-famous Watson-Crick base pairing.

This classic paper is written in a wonderful, understated fashion.It is brief and contains only two figures. It opens by informing us that their proposed structure "has novel features which are of considerable biological interest", before giving us an overview of the other structures that had been proposed. Notably, the triple-helix proposed by chemistry legends E. J. Corey and Linus Pauling is mentioned. This structure put the hydrophilic backbone at the axis of the helix, and the relatively hydrophobic residues on the outside, protruding into the solution. Their discussion is quietly withering; another triple helix proposed by Fraser is dismissed as "rather ill-defined".

Following this is the now-textbook description of their model of DNA, complete with inter-residue distances, turn angles, and strand diameter. What makes this structure "radically different" is their key innovation of base-pairing, which is described succinctly in three short paragraphs. They then come to their evidence: stereochemical arguments; Chargaff's rule, supporting the necessary ratios of nucleobases; and their new crystallographic data.

Despite hedging somewhat - "it must be regarded as unproved until it has been checked against more exact results" - they scatter tantalising hints of things to come throughout the paper. They predict that RNA will not adopt this structure due to its extra hydroxyl group; that dehydrated DNA will adopt more compact structures (A-DNA); and most famously, they state that "it has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material".



Wednesday, 24 April 2013

Chemistry Classics: Prebiotic Chemistry


#RealTimeChem week rolls on to day three, and part three of 'chemistry classics' is here. This series of five posts is intended to give you a quick dip into the history of chemistry with a look at classic papers. The first two posts covered purification and analysis techniques; today, we're looking at some synthesis!

In honour of Nature Chemistry's focus on prebiotic chemistry this month, and given my own love of the subject, I thought I'd cover a classic paper about the origins of life. Not just a classic paper, but the classic paper: the famous Miller-Urey experiment.

Stanley L. Miller, "A Production Of Amino Acids Under Possible Primitive Earth Conditions", Science, 1953, 117, 528-529.

This paper is doubtlessly the most famous experiment in prebiotic chemistry, and surely is one of the chemistry papers that is most widely-known amongst the general public. The gist of the paper, as you probably know, is this: take a bunch of simple, high-energy molecules that look like they might have been around on the early earth, zap them with a wee spark, and hey presto! you get amino acids and all kinds of biological-looking stuff out.

But what did Miller actually do?

The concept behind Miller's experiment was simple. Based on Oparin's work in the 30s, it was believed that the early earth's atmosphere was a strongly reducing environment composed largely of methane, ammonia, and hydrogen gases, as well as water (both liquid and gaseous). To test this, a specialised piece of glassware which simulated a spatially-separated 'ocean' of water and 'atmosphere' of CH4, NH3, and H2 was built. The gas mixture had a pair of electrodes poking into it to allow for an electrical discharge, meant to simulate lightning and other high energy sources.

The water was boiled, allowing steam to mix with the gases. The design of the glassware prevents backflow: steam rises through the high, inverted U-bend, mixes with the gases, and then any products condense below the gas chamber and settle back into the water chamber. Contrary to popular imagination, the experiment didn't involve a single dramatic spark, but a continuous discharge for a week, during which products accumulated in the refluxing water.

According to Miller, within a day a pink colour developed in the water bath, and after a week it was "deep red and turbid", apparently largely due to the accumulation of the organic products onto colloidal silica produced from the glassware itself. A second collection of yellow, largely insoluble compounds - one of those notorious "intractable mixtures" - also accumulated, but was not analysed here.

The work-up and isolation aren't appealing from a modern perspective. HgCl2 was added to kill anything living in there (just in case!); Ba(OH)2 was added and amines were distilled off; for the acids, H2SO4 was added and again the products were distilled off; and finally, the mixture was neutralised with more Ba(OH)2 and the solution was concentrated to the remaining products.

The analytic method of choice was paper chromatography (if you've been following, you'll know that flash chromatography is a child of the 70s) and the cunning use of stains. The eluent was a mixture of n-butanol, acetic acid, and water, followed by wet phenol. Lovely. Staining with ninhydrin and comparing the products with samples of various amino acids allowed for the identification of products. Doesn't sound too much fun, but it's probably nicer than running a column in phenol!

As you can see, Miller identified milligram quantities of a handful of amino acids: glycine, α- and β-alanine, aspartic acid, and α-amino-butanoic acid. Later work by Miller and others has identified many, many more compounds from this reaction, including dozens of amino acids, sugars (produced by the formose reaction), and other biologically-significant molecules.

It's notable that Urey, Miller's supervisor, appears on the paper only as an acknowledgement. Urey won the 1934 Nobel Prize in Chemistry (for his work on isotopes), and apparently didn't want to receive credit for Miller's pet project, which he had rather gently opposed.

The actual prebiotic relevance of this particular experiment is debatable (and debated!), but it's indisputable that it helped kick-start the field of prebiotic synthesis, and remains practically synonymous with it in the popular imagination.

If you enjoyed this and want more classic synthesis, I can't recommend enough BRSM's 'Woodward Wednesday' series. If you have know any other blogs doing this kind of thing, leave links in the comments below!

Tuesday, 23 April 2013

Chemistry Classics: NMR Spectroscopy


Day two of #RealTimeChem week, and here's post two of five in my series about classic chemistry papers. This is meant to be a quick read to give you an idea of where the techniques organic chemists use every day originated.

Today: James T. Arnold, Srinivas S. Dharmatti, and Martin E. Packard, "Chemical Effects On Nuclear Induction Signals From Organic Compounds", J. Phys. Chem. 1951, 19, 507.

NMR spectroscopy hardly needs introducing. It's a routine technique for probing chemical structure, most commonly using 1H and 13C nuclei. The theory of NMR developed over several decades, and picking one point as the "first NMR paper" is somewhat misleading. Not that I'd let that stop me, of course! For a bit of context on the development of NMR, I recommend this short piece by Stuart Cantrill.

The paper I've picked is not the first NMR spectrum to be published, nor the first observation of chemical shift. I think it represents a turning point, though: the first time NMR was used to characterise the structure of a typical organic molecule, pointing the way to the powerful tool we now have at our disposal.



In less than one page, Arnold et al. report the 1H spectra of the first five alkyl alcohols: methanol, ethanol, n-propanol, n-butanol and n-pentanol. The only spectrum that is printed is that of ethanol (typical chemists...). The authors integrated the peaks (relative to the -OH peak) and showed that they are proportional to the number of protons in the signal. In addition to reporting the spectra of these compounds, the authors allude to measurements of secondary and tertiary isomers, as well as carboxylic acids.

Their final comment is prescient: "It seems to us that there may be certain chemical problems besides analysis, such as the study of chemical reactions and equilibria, which can be investigated by this method."

Within a couple of years, significantly improved spectra of the oh-so-important ethyl alcohol had appeared, allowing chemists to see the fine structure in each peak, and within a couple of decades NMR had been commercialised and widely adopted.


If you're interested, here are a few good articles about the development of NMR which provide context for this paper.
Stuart Cantrill: NMR for chemical analysis, 1950-1951
James N. Shoolery: NMR spectroscopy in the beginning
David Ellard: history of MRI

Monday, 22 April 2013

Chemistry Classics: Flash Chromatography


It's #RealTimeChem week! I'm contributing a series of five posts about classic, foundational papers in organic chemistry. #chemclub classics, if you will.

Each day this week I'll post a quick read about a paper which has profoundly affected the work of organic chemists. I'm just going to give a quick outline for historical interest - something you can read while you post your tweets to #RealTimeChem, and hopefully come away with a renewed appreciation for the powerful tools we have at our disposal.

First up: W. Clark Still, Michael Kahn, and Abhijit Mitra, "Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution", J. Org. Chem. 1978, 43, 2923-2925.



This is the paper which gave the world flash column chromatography, the go-to purification technique for the typical organic chemist. It contains only one reference, but has itself been cited over 8,000 times - a modest number for such an important technique! There's a trend towards avoiding chromatography these days, in order to save on solvents and silica and achieve 'smarter' purification. These are grand ambitions, but don't undermine the crucial importance that flash chromatography has held for the past 35 years.

Column chromatography pre-dates the development of flash chromatography. The key innovation is something we perhaps take for granted: by applying pressure to the top of the column, the speed of elution can be greatly increased, allowing the column to be run in 15 minutes rather than several hours! This comes at the cost of decreased resolution compared to the slower techniques.

Flash chromatography was optimised on benzyl alcohol apparently, and the authors used a UV detector to analyse the separation precisely, rather than relying on TLC as we typically do in the lab. Various factors influencing resolution were identified - the kind of silica, rate of elution, presence of polar impurities, sample size (up to 10 g), and column size. Contrary to the lab lore I've been handed, the method of packing (slurry vs. dry) was found to have minimal influence on resolution.

To demonstrate the power of this technique, the authors separated two isomeric alcohols. Perhaps that's not so impressive from our perspective, but I wonder how impressive it looked to be able to do this quickly and cheaply on a gram scale at the time.



The paper is well-written and logical, and actually a great field guide to column chromatography.

If you're prone to chronocentrism, here are some more recent field guides from around the web:
Brandon Findlay's column week
Atoms and Numbers: overcoming separation anxiety
Chemistry Views: Sarah Millar's tips and tricks
(If you've written one I've missed, let me know and I'll add it.)

I hope you enjoyed this quick dip into some chemical history; more to come tomorrow!

Saturday, 20 April 2013

Points of Authority: BlogSyn and Peer Review

Over at The Collapsed Wavefunction, Chad Jones is talking about a paper in the Journal of Chemical Information and Modeling (admittedly not one that's on my regular reading list...) which includes a straight-faced endorsement of traditional Chinese medicine. His discussion of the paper and issues associated with it is good and definitely worth a read if you're into bad science.

The crux of the problem is one of authority. Peer review is often peddled as a gold standard of authority when debating purveyors of pseudoscience. For example, any debate around creationism (or 'intelligent design') inevitably involves defenders of biology pointing out that few, if any, peer-reviewed papers arguing for design have been published. Conversely, proponents of creationism wave a handful of peer-reviewed papers around as if they refute the much vaster literature of evolutionary biology.

Peer review conveys authority. I suspect that Chad is, in part, frustrated that the hard-earned authority of his field has been lent to something as flaky as TCM. A proponent of TCM could quite plausibly cite this paper as an example of Science™ taking their woo seriously, which not only lends false credibility to TCM, but undermines the authority of the journal that published it.

Reading Chad's post reminded me of the debates about BlogSyn earlier this year. For those who don't know, BlogSyn is an effort by several chemistry bloggers to assess the reproducibility of methods from the chemical (specifically organic synthesis) literature, and achieved notoriety after failing to reproduce some results from the justly-famous Baran lab. No impropriety on the part of Baran et al. was implied by the authors of BlogSyn; the source of the problem was eventually identified, and they all blogged happily ever after.

Following the initial post, discussion at a number of blogs (particularly In the Pipeline) often focused on the perceived lack of authority or legitimacy of the authors of BlogSyn. A relatively common point was that work of this nature ought to be peer-reviewed to ensure the competence and identity of the critics. The fact that SeeArrOh and colleagues are pseudonymous was a point of much contention; Rich Apodaca offered a nice discussion of this. One counter-argument is that they are young scientists early in their careers, and criticising the work of senior researchers could harm their prospects.

In principle, peer review ought to solve some of these problems. In peer review, critics are anonymous and fear no reprisals from those being criticised, but despite their anonymity they are vouched for by the editor of the journal. This allows both the author being reviewed and those reading the journal to assume the work is sound and hence authoritative. From this perspective, critics of BlogSyn seem to be on to something.

These two cases highlight the strengths and weaknesses of peer review. The inclusion of TCM in a chemistry paper is startling because it's the exception; peer review is generally good at ensuring that published work is logically coherent, informed by the literature, and supported by evidence to back up its claims. On the other hand, BlogSyn highlights that peer-review in chemistry routinely fails to assess the key element of science: reproducibility.

There are good reasons that peer review does not assess reproducibility in organic synthesis. Reviewing is time-consuming, and adding more time to that to prepare reagents, fiddle with conditions to get them to work, and so on, would cost the reviewer time and money and delay publication. It seems unlikely that we'll be seeing routine replication in chemistry any time soon.

BlogSyn represents one approach to solving this problem. If pre-publication review is impractical, perhaps open, online, post-publication review of work that has had an impact is a solution.

The question, then, is can we trust BlogSyn? Is it authoritative? How should we assess it relative to a journal?

I suggest that we can trust BlogSyn more than the average peer-reviewed paper, provided we assume honesty on the part of the authors.

While there are exceptions, most peer-reviewed synthesis papers include relatively sparse experimental details due to constraints of space and the need to be easily legible. BlogSyn, on the other hand, takes an open-notebook format in which one can see every TLC plate, every NMR, and multiple repeats of the same reaction by different authors. This allows for a much more direct assessment of the competence of the chemists, the chance to pick up minor mistakes that aren't evident from a written summary, and a direct demonstration of reproducibility. Hence, if we trust the authors, I consider BlogSyn to be a more authoritative account of an experiment than a typical peer-reviewed paper.

Ought we to trust the authors? This brings us back to the problem of pseudonymity. Personally, I know several of the authors of BlogSyn to be people of integrity, and to have persistent identities online. Not every reader of BlogSyn has this knowledge, and they are probably justified in being skeptical. How can BlogSyn achieve a degree of authority which is acceptable to the average chemist, who may not be part of the online community?

No easy or ideal solutions are forthcoming, and it's likely that no solution would satisfy everyone. However, until BlogSyn can gain some legitimacy in the broader community it's hard to see how the project can flourish.

Two solutions spring to mind, and I welcome your criticism and suggestions. The first is to slog it out and establish credibility the hard way: continue to critique work from the literature, build up reputation by engaging with authors and marketing the project, and hopefully gain some acceptance. Alternatively, if an established chemist with a good reputation in the community is willing to verify the identity of, and vouch for the integrity of, the authors of BlogSyn, this may serve to lend legitimacy to the project by association. This third party would be fulfilling a role analogous to that of the journal in traditional peer review.

What other ways might BlogSyn gain credibility? Are there practical ways to solve issues of reproducibility pre-publication? Leave your thoughts below...

Thursday, 18 April 2013

Chemistry at the Movies

This post is part of the Chemistry at the Movies blog carnival started by SeeArrOh of Just Like Cooking. Head over there for a list of other posts.

A while back, a friend and I grabbed a few drinks and settled in to watch the classic movie G.I. Joe: the Rise of COBRA. For those of you who somehow missed this historic motion picture event, it's an adaptation of the eponymous range of toys (called Action Man in the UK). The film is geared at selling more toys: the villains are cartoonish, the action sequences involve all kinds of fancy vehicles, and the only real attempt at acting is probably Christopher Ecclestone's dire version of a Scottish accent. Leave it to Tennant, Chris.

There's a fair amount of sci-fi in this movie, and for the most part it'd be silly to look at its plausibility. City-eating nanobots? Basically magic. However, one scene bears a second look. Preferably a slack-jawed look, with eyes opened wide in horror at the dumb. This movie contains an error so fundamental it makes you wonder what the writers have spent their lives doing.

(Yes, I am going to pick holes in G.I. Joe. No, I have no shame.)

Towards the end our intrepid heroes escape from COBRA's base, which sits on the ocean floor beneath the Arctic ice. Creatively, the villains activate the base's self-destruct sequence and detonate explosive charges in the ice above. The heroes have to escape in cool-looking submarines, weaving in and out of the enormous blocks of ice that are plunging through the water around them.


If you find yourself staring wordlessly at your screen at this point, fear not: you are not alone.

If you're not sure what the problem is, it's time for a home chemistry experiment. Get yourself a drink and drop an ice cube in it. Spoiler: ice does not sink in water.

Water is a weird substance in many ways, but it's so ubiquitous that we overlook its strange behaviour. It's probably the liquid most people handle most often, so we might assume its properties are 'normal'. I remember arguing with my high school science teacher that no, liquids expand when they freeze - after all, pipes burst in winter, right?

Ice is something like 8-9% less dense than liquid water, and hence water expands when it freezes - unlike the majority or other liquids. The most common explanation I've come across is to do with organisation of hydrogen bonds: in the solid, the bonds are quite literally frozen into place, and adopt a stable and roughly constant length. In the liquid, the bonds are constantly breaking and re-forming as molecules tumble around each other, and on average are shorter than in the solid. 


We can exploit this to freak out first-year students and lab visitors. Water's isotopic cousin, D2O, is about 10% denser than the vanilla flavour. This is in part due to the heavier mass of D vs. H - more mass in the same volume gives a denser substance - but also because the hydrogen bonds between D2O molecules are slightly stronger and hence shorter.

The upshot of this is that you can make ice sink... if you enrich it with deuterium. 



I couldn't find a figure for annual production of D2O, but given that the volume of arctic ice is something like 2-3 million km3 I'm not sure this is a viable option for Cobra Commander.

If you enjoyed this be sure to visit Just Like Cooking and read the other posts in the Chemistry at the Movies collection.

Monday, 8 April 2013

#chemclub Roundup: week 6

Double edition! I spent last weekend drinking unhealthy amounts of coffee with old friends, and hence skipped the weekly round-up. On the plus side that means a bumper pack of #chemclub highlights from the last two weeks!

If you've no idea what #chemclub is, read this.