Posts Tagged ‘United Kingdom’

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What can chemistry learn from photos?

Sunday, June 2nd, 2013

A few years ago, we published an article which drew a formal analogy between chemistry and iTunes (sic)[1]. iTunes was the first really large commercial digital music library, and a feature under-the-skin was the use of meta-data to aid discoverability of any of the 10 million (26M in 2013) or so individual items in the store.‡ The analogy to digital chemistry and discoverability of the 70 or so million known molecules is, we argued, a good one.

Well, the digital photography revolution is very similar; I just checked my personal digital photo library to find it contains almost 14,000 photos dating back ten years now. It is not easy to find a particular photograph! Well, the reason I am posting here is to bring to your attention the first 6 minutes or so of an item in the BBC collection.† It is a very nice accessible explanation of the importance of meta-data for photography, and some of the innovative things that are being done for both acquiring and for manipulating this data. As I listened to this, I felt that for photograph, think molecule! And think of all the innovative things that could be done there as well.

Actually, you might reasonably ask how/whether molecular metadata is deployed here in this blog. It certainly is on Steve Bachrach’s site (see for example this recent post where you will find InChI keys for every molecule displayed; thus InChIKey=GOOHAUXETOMSMM-GSVOUGTGSA-N). I don’t do that on this blog (perhaps I should), but instead I provide URL links to a digital repository where they are displayed: thus follow http://dx.doi.org/10.6084/m9.figshare.706756 and you will find InChIKey=USGIFUSOUDIDJL-UHFFFAOYSA-N where it can be used as a search term to find any other instances of the same molecule at the site.

‡ Historical note: In 1997, we produced a CD-ROM containing the proceedings of the Electronic Conference on Trends in Heterocyclic Chemistry (ECHET96), H. S. Rzepa, J. Snyder and C. Leach, (Eds), ISBN 0-85404-894-4. Because it was entirely digital, we were able to include an “app” which created a visual navigation point derived from analysing the meta-data present (the entire contents had been expressed in HTML and so it was relatively easy to gather this meta-data). The software we used was called Hotsauce and was based on MCF (meta content framework) as developed by Apple engineer Ramanathan V. Guha for an internal experiment (we sometimes forget that in those days Apple was the Google of its day!). Guha left Apple, joined Netscape and MCF became RDF. The rest, as they say, is history. But you can see an early deployment on the CD-ROM I refer to above (these are NOT yet collectors items. Hint!). 

† This being the BBC iPlayer collection, it is quite possible that it is not accessible outside the  UK, or indeed even within the UK it may only be available for 8 days after broadcast.  Which would be a shame.

 

References

  1. O. Casher, and H.S. Rzepa, "SemanticEye:  A Semantic Web Application to Rationalize and Enhance Chemical Electronic Publishing", Journal of Chemical Information and Modeling, vol. 46, pp. 2396-2411, 2006. https://doi.org/10.1021/ci060139e

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Digital repositories. An update.

Saturday, July 21st, 2012

I blogged about this two years ago and thought a brief update might be in order now. To support the discussions here, I often perform calculations, and most of these are then deposited into a DSpace digital repository, along with metadata. Anyone wishing to have the full details of any calculation can retrieve these from the repository. Now in 2012, such repositories are more important than ever. 

In the UK, the main funding organisations are increasingly requiring researchers to deposit their primary data in such open archives, and some disciplines are better than others at this (chemistry does not rank very highly in general however in terms of deposition of data). Our DSpace server is a local one running at Imperial College, but a few months back I became aware of Figshare, which aspires to operate on a much wider and more general scale.  So I have injected one of the calculations reported in another post (the IRC for the sodium tolyl thiolate reaction with dichlorobutenone) into Figshare, making use of the API which has recently been developed for this purpose and implemented by  Matt Harvey. As with DSspace, it issues a DOI, which can be then quoted wherever appropriate (and particularly in scientific articles). This particular deposition is 10.6084/m9.figshare.93096

This repository is still undergoing a lot of development, but already one can see many interesting features, such as export to Endnote or Mendeley, and a QR barcode for devices with cameras. I would encourage anyone who regularly generates e.g. computational chemistry data, or knows a group that does, to encourage them to make use of such facilities.

Postscript: If you have a look at this deposition in Figshare you may already notice some of the developments I note above.  Matt Harvey (who, with Mark Hahnel of Figshare, developed our publish script) has added to the entry:

* A data descriptor document URL

* Wikipedia and pubchem links (automatically resolved from Inchi/Key searches)

* Links to chemspider searches

* Links to all other objects in the  Spectra DSpace repository with a common Inchi/Key

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Shared space (in science).

Friday, January 6th, 2012

I thought I would launch the 2012 edition of this blog by writing about shared space. If you have not come across it before, it is (to quote Wikipedia), “an urban design concept aimed at integrated use of public spaces.” The BBC here in the UK ran a feature on it recently, and prominent in examples of shared space in the UK was Exhibition Road. I note this here on the blog since it is about 100m from my office.

Shared space is the Mornington Crescent of urban design, where you have to work out the rules of the game by in effective participating in it. Thus the new “rules” of travelling down Exhibition Road (by either foot, car, bike, bus or indeed motorbike as I do each day) are not declared, and each participant works them out on the fly. This is supposed to lead to fewer misunderstandings, although the practice does seem rather different (at least at the moment). But where is the chemistry? Well, these thoughts were triggered by two colleagues independently asking me about how chemists use metaphors, and how chemists use representations. I have in fact touched upon both of these previously, and it struck me that this last example, of arrow pushing in organic chemistry, was in fact a nice example of a shared space in chemistry. The rules of arrow pushing are not formally set out (in an IUPAC rule book or similar) but are worked out on the hoof so to speak. Except that the space is shared only by organic chemists. I have observed over the years that e.g. physical or inorganic chemists will mostly not dare venture into that shared space; they often give a rather good impression of not understanding the rules. I also know from experience that mathematicians and physicists regard arrow pushing as anything other than a shared (scientific) space.

Yet the modern scope and ethos of science is that we should all venture into shared spaces (whether they are in or out of our comfort zones). Perhaps, in science, the problem is that so much of what we do has what I refer to as “implicit semantics” (its part of our DNA of e.g. being a chemist). Take for example the diagram below (which I used previously) which sets out four possible sets of rules for this particular shared space. Even so, without further explanation, you might be struggling to infer what message is carried by this diagram. That is because so much of it contains implicit semantics, and unless you recognise the missing features, how can you go about finding out what is invisible?

Curly arrow pushing

My concluding thought would be that shared space is what the semantic web is surely striving for. And if Exhibition Road is anything to go by, it is clearly quite a challenge. But if I (and particularly the pedestrians I encounter there each day) end up surviving 2012, perhaps the Semantic Web may one day come about as well!

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The dawn of organic reaction mechanism: the prequel.

Sunday, November 13th, 2011

Following on from Armstrong’s almost electronic theory of chemistry in 1887-1890, and Beckmann’s radical idea around the same time that molecules undergoing transformations might do so via a reaction mechanism involving unseen intermediates (in his case, a transient enol of a ketone) I here describe how these concepts underwent further evolution in the early 1920s. My focus is on Edith Hilda Usherwood, who was then a PhD student at Imperial College working under the supervision of Martha Whitely.1

The doctoral degree itself had only been introduced into British universities in 1919,1 and so Usherwood was very much a forerunner of the modern system of training.The academic staff and students at Imperial totalled 30, making it one of the largest research schools in UK chemistry at the time. Usherwood’s project was on tautomers, or isomers of molecules which differ only in the position of a labile hydrogen atom. The then quite novel electron-pair symbolism introduced by G. N. Lewis’ in 1916 was adopted to represent two tautomeric equilibria (the supposed mobile or tautomeric hydrogens being enclosed in […])2

  1. [H]C:::N ⇔ C::N[H]
  2. [H]C:::CH ⇔ C::CH[H]

or in our more modern representation (in which lines replace colons, and charges are used to ensure the octet rule is adhered to when possible):

  1. H-C≡N ⇔ –C≡N+-H
  2. HC≡CH ⇔ :C=CH2

Modern structural techniques such as electron diffraction or microwave spectroscopies not yet existing, the problem was tackled using specific heat measurements as a function of temperature. This method suggested to Usherwood that for e.g. equilibrium 2, the concentration of iso-acetylene (we now call this vinylidene) was insignificant at ordinary temperatures, but it became appreciable between 200-300°C. Further evidence was claimed for the formation of the “unseen” vinylidene by observing ketene as a by-product of the oxidation of acetylene. This article very much set the trend of (an almost mandatory) speculation on the outcome of (nowadays much more complex) reactions by the need to formulate a reaction mechanism in which various (otherwise undetected but) plausible intermediates are involved.

Moving on some 90 years, and how might one approach such a problem nowadays? Well, I have oft argued on this blog that a good place to obtain an immediate reality check on a proposed mechanism is a calculation. It will come as no surprise that a very accurate calculation can be done on the systems shown above. For example, CCSD(T)/cc-pVTZ will yield a free energy for the equilibria with a pretty small error (< 1 kcal/mol). We use ΔG = -RT Ln K to inter-convert free energies and equilibrium constants. If we are generous and state that in order to observe an appreciable concentration of a minor species, the equilibrium constant can be no smaller than 10-3, its energy cannot be greater than 4 kcal/mol above the more abundant isomer. Our reality check will be to see if the free energy of vinylidene is indeed no more than 4 kcal/mol greater than acetylene. Well, CCSD(T)/cc-pVTZ predicts vinylidene is 41.3 kcal/mol higher @298K, reduced to 33.8 @2000K (and before you ask, these results took a total of perhaps 30 minutes to obtain).

In 1924, the concept of calculating the relative energies of two species using first principles was not even a glimmer on the horizon. The nature of mechanisms was slowly and often painfully established by recourse to experiments alone. And many of the unseen intermediates often remained just such, their existence only inferred indirectly from the models one constructed (of specify heats in Usherwood’s case). It is perhaps no great surprise that these models do not always stand the test of time. In this case, within a year of Usherwood’s publication, Partington was suggesting that the model for the specific heats of acetylene should have included allowance for polymer formation.3 The modern take, armed with the calculation I note above, might in fact side with Partington after all. As for the formation of ketene by oxidation, it is indeed known that (peracid) oxidation of an alkyne will produce ketene, but the modern mechanism (an interesting exercise in arrow pushing for a student) does not involve vinylidene intermediates.

I will add at this point that Hilda Usherwood was married to Christopher Ingold, and the pair of them subsequently published many of the seminal articles in what became known as physical organic chemistry. That legacy continues to this day with (as I noted above) the almost mandatory speculation about the mechanism of any new reaction. But it is only in the last five years or so that these speculations have started to be increasingly tested against reliably accurate computation. A new era is underway.

1 My post was inspired by reading W. H. Brock, “The case of the Poisonous Socks”, chapter 28, RSC Publishing, 2011, 978-1-84973-324-3.

2 These representations are taken from ref 1, p 225 (and including a correction of replacing C:C as drawn there by C::C). The original article apparently appeared in the proceedings of the British Association of 1924, which is not yet available online.

3 Brock, in ref 1, p226, suggests that Usherwood stood her ground on this one, and won her case by showing that Partington’s evidence for polymerization was valid for only a small part of the temperature range she had investigated. I have not managed to track down the original sources for this exchange.

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Historical detective stories: colourful crystals.

Friday, October 21st, 2011

Organic chemists have been making (more or less pure) molecules for the best part of 180 years. Occasionally, these ancient samples are unearthed in cupboards, and then the hunt for their origin starts. I have previously described tracking down the structure of a 120 year-old sample of a naphthalene derivative. But I visited a colleague’s office today, and recollected having seen a well-made wooden display cabinet there on a previous visit. Today I took a photo of one of the samples:

One of the "Hofmann" collection.

No date, no name, but a structure! As I noted before, when it comes to structures, you have to research the conventions (and numbering) used at the time. Thus note the apparent cyclohexane rings, the N(Me)2 group and the lack of stereochemistry around the alkenes. The former dates the sample to before 1950, whilst the use of Me to mean methyl puts it in the 20th century. Which is shame, since it had been known as the “Hofmann” collection, meaning some sort association with August von Hofmann, the first professor of organic chemistry in the UK, who occupied that position from 1845-1864. Samples that old are very rare. The one above by the way is very deep green (the photo does not do it justice), and very crystalline! Tracing the history of where the display cabinet might have been did indeed reveal that it probably started its life at the same institute as Hofmann was working in (and where I now work), but little more than this was known about it.

A search of the Beilstein database (nowadays known as Reaxys) revealed a collection of samples corresponding to the above structure (with benzenes of course, not cyclohexanes), but co-crystallised with different molecules, and dating from 1921. These were known as the Heilbron collection, and this was encouraging, since Heilbron was indeed a successor to Hofmann, being active in the 1920s. During his career, he and his students probably made 100s, if not 1000s of compounds, so why did they go to the considerable expense of having beautiful wooden cases built to house these particular samples? Probably because the basic colour varied from yellow to black (perhaps 400nm difference in λmax) and for which they had no explanation! So, much like some people are cryofrozen in the hope an advanced civilisation might bring them back to life in the future, these samples were mounted in a display cabinet in the hope that someone would find out the origins of their variable colour.

Well, in 1984 (some 63 years after the event) researchers in the Technion-lsrael Institute of Technology, Haifa, came upon the 1921 article (but not the samples; if they read this they might be amazed that these still exist!), repeated (most of the) syntheses, and determined the crystal structure of three of the molecules (but conspicuously not the one above). One 3D structure is shown below. The colours were ascribed to charge-transfer interactions between the components of the molecules.

DADZIR. Click for 3D

As I noted previously, it is well worth preserving chemical samples for future generations (and sometimes that generation is 120 years in the future!). Sadly, health and safety aspects (real or imagined) mean that such collections are being lost to posterity at an every increasing rate. Soon, there may be no collections of old chemicals left. That would be indeed a loss to science. So if you know of a lovingly preserved case of old chemicals, go take a look at it. And if it’s in danger of being put in the skip, then rescue it. There is no telling what may be scientifically interesting about it.

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Steve Jobs and chemistry: a personal recollection.

Sunday, October 9th, 2011

Steve Jobs death on October 5th 2011 was followed by a remarkable number of tributes and reflections on the impact the company he founded has had on the world. Many of these tributes summarise the effect as a visionary disruption. Here I describe from my own perspective some of the disruptions to chemistry I experienced (for another commentary, see here).

Chemical diagram, circa 1983.

The diagram above originates in 1983 just before the impact of Jobs’ vision burst upon chemistry. It was published in one of the new-generation of camera-ready journal, the objective being to reduce publication times from a typical 12-24 months down to around around three months. Camera-ready meant that the authors had to prepare a photo-ready manuscript; the role of these journals was to photograph, print and publish. The diagram above was prepared using stencils and Rotring technical pens together with Letraset lettering. The snippet above would probably take an hour or two to draft; the diagrams for an entire article were probably about 1 weeks work. Imagine how much time would be needed for a 200 page PhD thesis (some of this time was occupied by rushing out to a purchase more Letraset sheets because one had run out of say the letter r needed to represent the bromine in the above!). The diagram below was publishedin the same camera-ready journal in 1987.

Chemical diagram, circa 1987.

It was produced using Chemdraw on an Apple Macintosh computer introduced in 1984 (and which reached UK chemistry departments in 1985) and printed on an Apple laser printer. It would have taken perhaps 5 minutes to produce. More significantly, by copying and pasting (terms which need little explanation nowadays), one could re-use the diagram repeatedly as a template in a more complex scheme for little extra effort. You might argue that these two diagrams do not actually differ in quality that much (actually, the Apple-derived diagrams are of much higher quality than implied above, and the loss of quality is because the article has subsequently been scanned by the journal). But in fact the impact of Jobs’ Macintosh computer was far greater than just being able to produce nice chemical diagrams. Because it also introduced chemists to disruptive new concepts, the consequences of which are still impacting today.

The first is the idea of the re-use of digital data, as mentioned above. Once one had a diagram drawn, one could use it to almost instantly derive other properties of the molecule. For example, the molecular weight or an atom connection table. This in turn could be used to start an online search. And it was the Macintosh that really bump-started the idea of online activities.

Although chemistry had started going online around 1980 (I remember a single terminal station enabling STN express online access to chemical abstracts being introduced then, and in fact computational chemists were already online around 1974), the idea of an entire department of researchers ALL being online in their lab or office was very much the result of introducing the Macintosh in 1985. It came with a network connector at no extra cost. This in turn allowed all owners of such a computer to connect online to the (then very expensive) laser printer, and as a by-product almost, to the rest of the world! I have described some of the disruption this introduced elsewhere. By around 1987, most of our Mac users were happily going online (it has to be said that owners of IBM PCs were rarely doing so at this time). That is one of the true legacies that Jobs’ disruptive technologies introduced to us chemists.

I am going to quote Samuel Butler now, writing in 1863: “I venture to suggest that … the general development of the human race to be well and effectually completed when all men, in all places, without any loss of time, at a low rate of charge, are cognizant through their senses, of all that they desire to be cognizant of in all other places. … This is the grand annihilation of time and place which we are all striving for, and which in one small part we have been permitted to see actually realised“.

Steve Jobs made a big contribution to that general development of the human race!

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Computers 1967-2011: a personal perspective. Part 3. 1990-1994.

Tuesday, July 12th, 2011

In 1986 or so, molecular modelling came of age. Richard Counts, who ran an organisation called QCPE (here I had already submitted several of the program codes I had worked on) had a few years before contacted me to ask for my help with his Roadshow. He had started these in the USA as a means of promoting QCPE, which was the then main repository of chemistry codes, and as a means of showing people how to use the codes. My task was to organise a speakers list, the venue being in Oxford in a delightful house owned by the university computing services. Access to VAX computers was provided, via VT100 terminals. Amazingly, these terminals could do very primitive molecular graphics (using delightfully named escape codes, which I learnt to manipulate).

An expert on the use of such codes was George Purvis, who hailed from the quantum theory project at the University of Florida at Gainesville. He had developed QUIPU for VAX/VT100 and together we had much fun setting things up for the participants at these QCPE workshops (which ran 1986-1990). During one session, George asked me whether I thought a properly implemented and reasonably cheap graphical user interface might have commercial potential in chemistry. Remember, the VAX/Evans&Sutherland PS390 system we had acquired in 1987 was NOT cheap. I must have encouraged him, since in 1990 George (now part of the CACHE, or computer assisted chemistry, group at the Tektronix corporation in Beaverton) had brought to market a “shrink-wrapped” system which did just that. This was, in many ways, well ahead of its time. It was based on a then state-of-the-art Macintosh computer, with a co-processor that could crunch floating point numbers quite fast (this was then very rare in so called personal computers, being reserved for supercomputers). It had a unique spherical trackball (almost a haptic device) for rotating molecules, and a liquid crystal polarized screen running at 120Hz (60Hz for the left eye, 60Hz for the right eye). Wearing polarized (passive) glasses, the stereo 3D effect via the 19″ screen (big for its day) was awe inspiring. What is more, two people could sit at it and both see molecules in stereo.

We managed to get a grant to purchase such a system, and I well remember taking it to the 1990 Oxford workshop (I had now taken over from Richard for the UK workshops) in the back of my car. This involved driving to my office on a Saturday, and heaving the thing out. A security guard saw me doing this and arrested me. After much ado, I was forced to take the CACHE to my office and told not to try that again. I waited 30 minutes, and took it out the back door (which nowadays has a black security camera watching it, but in those days was not guarded) and on to Oxford (checking for police sirens all the way). I think I made the trip to Oxford with this thing in the back of the car one more time, where I used it to give a poster at a conference, handing out the 3D glasses to anyone who expressed an interest (and reclaiming them rapidly if they posed no interesting question). I still fancy this was almost unique in the history of posters (which tend, even nowadays, to be printed on paper). Reflecting on this, I realise that my total aversion to Powerpoint probably dates from that time.

At this stage, I will tell you about some of the science we did with the remarkable stereographical 3D CACHE system. The first is our realisation that the Pirkle reagent exhibits a π-facial hydrogen bond from the OH group (DOI: 10.1039/C39910000765). Indeed, I notice that four of the posts here relate to this topic! Once you know what you are looking for, its trivial to spot. But I recollect that the crystallographers who did the structure for us had failed to identify this unusual hydrogen bond; it took the CACHE, and its 3D glasses, for us to notice it.

But the really important breakthrough using CACHE was a different molecule, halofantrine (X=Y=Cl, DOI: 10.1039/C39940001135) an antimalarial pharmaceutical molecule.

Halofantrine.

At this stage, pharmaceutical companies were assiduously resolving chiral compounds into their enantiomers and testing each separately for biological activity. It had been noticed that whereas X=H, Y=Cl could NOT be resolved on a chiral column, replacing X=H by X=Cl suddenly made it possible to do so. But why? Well, in order to inspect this with the CACHE system, we asked for the crystal structure to be done. Back it came and Mike Webb and I sat inspecting the coordinates in full stereoscopic glory, as I recollect for about an hour, twiddling the viewpoint here and there. Each of us would take over the haptic trackball for 10-15 minutes, and we would then discuss what we saw. In one of those magical moments (I can assure you that shivers do run down one’s back at moments like this) we spotted that X=H had a strong hydrogen bond to the OH of another molecule, whereas X=Cl did not. Suppressing that C-H…O interaction forces the molecule to π-π stack instead, and this mode now enables it to better interact with the chiral column and hence resolve.

Halofantrine. Click for 3D.

Some of that magic is recreated above. If you click on the image, the coordinates will be loaded. Now that the relevant interaction is highlighted, it is so easy to spot you might wonder how anyone would have ever missed it!. At any rate, shortly after writing this article, I sat down to write another on a new phenomenon called the World-Wide-Web. And to illustrate why the Web might become important, we highlighted halofantrine, and how the Web could carry such immediately visual information to its readers. This blog, in effect, is a direct descendent of that article (which, by the way, is still available in HTML form here). So, 3D graphics led to the (chemical) Web. What a tangled web indeed.

And to end with 3D. I live in hope that shortly, stereoscopic tablets will make an appearance. Given that the CACHE system noted above was heavy (it was a major struggle moving the monitor into the car, as described above), it will be an amazing evolution to see (almost) pocket sized devices being carried around for the same purpose.

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