synthetic chemistry

Explosive Solutions

mercury azides

Instead of starting at the beginning of a paper I want to kick off this commentary with a statement from near the end:

Caution! Covalent azides are potentially hazardous and can decompose explosively under various conditions! Especially Hg2(N3)2, α– and β-Hg(N3)2, and [Hg2N]N3 in this work are extremely friction/shock-sensitive and can explode violently upon the slightest provocation. Appropriate safety precautions (safety shields, face shields, leather gloves, protective clothing) should be taken when dealing with large quantities. Hg compounds are highly toxic! Experimental details can be found in the Supporting Information.”

This wonderful statement appears in a recent publication by Professors Schultz and Villinger at the University of Rostock in Germany. They discuss the preparation of mercury azides and the azide of something called Millon’s Base. This compound was new to me and it turns out to be nitridodimercury hydroxide, [Hg2N]OH.2H2O, which Millon1 discovered by the reaction of mercurous oxide and ammonia in the mid 1800s. In a classic example of understatement the authors’ state that as is the case with most transition metal nitrogen compounds the extremely low energy barriers to explosive decomposition result in difficulties in the isolation and manipulation of said species! Curtius, of rearrangement fame, was apparently the first person to isolate mercury azide Hg2(N3)2 from the reaction of hydrogen azide and mercury2. I guess this was after the discovery of his famous rearrangement.

Structural data for this compound is available from x-ray and revealed two modifications, called α and β. Due to its lability the β modification has not been fully characterised. Schultz etal have now rectified this situation and also report the preparation of the azide salt, [Hg2N]N3 of Millon’s base. They prepared α & β-Hg(N3)2, the latter compound by slow diffusion of aqueous sodium azide into a solution of mercury (II) nitrate separated by a layer of aqueous sodium nitrate. In this synthesis one wonders how any yield was obtained because when the needles of β-Hg(N3)2 begin to form in the lower mercury(II) nitrate layer spontaneous explosions occur during crystal growth. If you want large crystals of either modification, usually obtained by slow crystallisation, I would not recommend it as apparently large crystals seem to explode when you look at them the wrong way, even in solution they detonate. Explosive solutions would be a great name for a company! Anyway, in spite of these difficulties an X-ray structure along with a melting point was obtained.

Turning now to the synthesis of the azide of Millon’s base the authors note that the normal method always produced a mixture of the two modifications. Pure α-[Hg2N]N3 was obtained by treatment of α-[Hg2N]Br with concentrated aqueous sodium azide for 300 days, so you need patience when dealing with these compounds, not only because they are explosive but they suffer from long reaction times. However starting with β-[Hg2N]NO3 the reaction was faster, only taking 4 days for the exchange with azide but produced a mixture of modifications. However, they did manage to obtain both modifications.

Elemental analysis could not be carried out due to their explosive nature and both modifications are sensitive towards heat, shock and especially friction. The bigger the crystal the more sensitive it is. However, slow heating in a DSC instrument showed that they are stable up to 283°C for the β form and 313°C for the α. Rapid heating in a closed vessel caused violent heavy detonation accompanied by a bright blue flash.

The paper has some fascinating x-ray pictures of all the molecules discussed and allowed determination of the N-Hg bond lengths. Together with the chemistry and the dangers involved in this chemistry, a great piece of work has evolved into a wonderful very readable paper. Congratulations to all who participated.

 

References:

1      E. Millon, J. Prakt. Chem. 1839, 16, 58.

2      T. Curtius, Chem. Ber. 1890, 23, 3023

Polymers from Elemental Sulfur

This post is contributed by John Spevacek, an industrial polymer chemist and the author of the blog “It’s the Rheo Thing

While organic chemists are familiar with the elements, very seldom do we ever make use of them as a reactant. Sure, we add elemental magnesium to Grignard reactions and we can add halogens/hydrogen across double bonds, but for the most part, the pure elements are oxidized or reduced or ionized or otherwise modified before they take part in our reactions.

The situation is even that much clearer for my field of polymer chemistry. Pure elements of any sort are just not used at all. We certainly don’t use elemental carbon and hydrogen to make polyolefins, and silicon wafers are useless for making silicone polymers. In short, the refined elements have no place in polymer chemistry.

Until now.

A recent paper in Nature Chemistry (pay-per-view/subscription) showed that elemental sulfur can be directly co-polymerized with an organic molecule. What was more surprising yet was that the polymerization occurred without the use of solvents or even initiators.

From my perspective as a polymer chemist, the uses of sulfur are limited and have historically fallen into three categories. First are the polymers that have the sulfur in the backbone, such as polyphenylene sulfide (PPS), polyethersulfone (PES), and all the countless thiol-ene polymers. Another class are the polymers where the sulfur is peripheral to the backbone, usually as a sulfonate group such as in polystyrene sulfate. And lastly, there are the elastomeric materials where sulfur compounds have been used to vulcanize (crosslink) the polymer chains.

What all three of these sulfur-containing polymers have in common, however, is that none of them are prepared from elemental sulfur. They all require either a reduced or an oxidized form of sulfur in order to form the polymers.

As implied above, this new reaction is very simple. The researchers merely melted the sulfur and added 1,3-diisopropenyl benzene (DIB) at ratios from 90/10 to 50/50 w/w. The S8 rings of sulfur opened up and copolymerized with the vinyl groups.

The reaction mechanism is not explicitly detailed, but I imagine it to be similar to what occurs in thiol-ene polymerizations. Since the organic comonomer is difunctional, the resulting product is crosslinked, not through the sulfur atoms, but instead through the organic monomer. The authors (with tongue-in-cheek) call this “inverse vulcanization”. However, despite the existence of this crosslinking, the polymer still flows as a thermoplastic. (Evidently the numerous sulfide bonds are breaking and reforming under the shear). This is fortunate as it allows the plastic to easily be shaped into a final product using conventional equipment.

While this is the only polymerization reaction I know of using a pure element, this discover by itself is interesting although somewhat limited. Working with molten sulfur imposes two big restraints on the choice of comonomers – that they first be soluble in the molten sulfur and more importantly, that they not volatilize upon exposure to the heat (185 C). In other words, this new reaction opens up only a small set of potential polymers.

But what properties this polymer is already showing!

Consider batteries. We are surrounded in our modern lives by lithium-ion batteries. They are in our cellphones and laptops, our cordless power tools, and even the Mars Curiosity Rover. A relative drawback of these batteries is that the anions are metallic and therefore heavy, reducing the energy density. It’s long been known that lithium-sulfur batteries have a high energy density and lower cost, but the degradation of the sulfur electrodes limits their long-term stability.

Preliminary testing of a lithium battery using this new sulfur-based polymer, however, shows that the performance is nearly identical to that of a standard lithium-sulfur battery but without the degradation. When this result is combined with the ease of processing this new polymer, the potential for lithium-sulfur batteries has suddenly become a lot sunnier.

Almost as sunny yellow as the color of elemental sulfur.

Shades of Gray, The Curious History of LCDs

Prof. George Gray

Today is the 40th anniversary of an innovation in chemistry that has had, arguably, a greater impact on our society than any of the Chemistry Nobel Prize winning achievements in the past 40 year. But the man responsible, George Gray, is only known in select chemistry circles (apart from maybe a few travellers boarding a train traveling between London and Hull that bears his name). Yet you are almost certainly reading this blog on a device that owes its existence to Gray. For he and his small team, of just two post-docs, developed the first liquid crystals that were viable in liquid-crystal displays (LCDs). Forty years ago today his work was published, triggering a multi-billion dollar industry and making today’s abundance of flat screen devices possible.

The breakthrough that emerged from Gray’s small group was the synthesis of 4-Cyano-4′-pentylbiphenyl (5CB). It had a nematic liquid crystalline phase between 22C and 35C which made it the first material that could form the bases of viable LCDs.*

4-Cyano-4′-pentylbiphenyl

Just like so many great innovations getting to this point had been far from easy, largely because there was little appetite for funding research on molecules that, at the time, had no clear applications. Turning liquid-crystals from curiosities into the ubiquitous technologies that they are today required both a burning need for new displays and the foresight of one of the more colourful government ministers.

Enter John Stonehouse, Minister of State for Technology under the UK Prime Minister Harold Wilson. Stonehouse wanted a technology capable of producing flat screen colour displays (a good 30 years before LCD TVs became the norm) with the aim of replacing cathode ray tubes that were costing the Ministry of Defence colossal sums (more than the development costs of Concorde) in royalties. So in 1968 he set up a working group consisting of military brass, civil servants and scientists to find a suitable replacement technology. The way the contracts were distributed is a far cry from how things are done today. The story goes that at one of the group’s meetings liquid-crystals were proposed as a candidate. But the key speaker was unable to answer a question about why light from the projector generated such curious patterns as it reflected off the vials of liquid-crystals. There followed an embarrassingly long silence before a voice piped up from the back of the room exclaiming “I wonder if I can help”. That voice was George Gray’s and come the end of the meeting he and his team of chemists at the University of Hull were awarded the contract to deliver room temperature liquid-crystals.  That they did and the results were patented and published by 1973 with the first LCDs in commercial devices the following year. (Cyril Hilsum was chairing the session and he was recently filmed recounting his memory of the  meeting and the development of LCDs. You can watch it here  http://youtu.be/AaB902_ds-g?t=34m3s )  

At one time the molecules that Gray invented accounted for over 90% of all the liquid-crystals in the world’s calculators, digital watches and LCD clocks. So what became of the money that flowed in via the patents? Well the Ministry of Defence owned most of the intellectual property and made a tidy sum which offset the money they were still paying for cathode ray tubes.  Meanwhile the University of Hull, like most UK academic institutions at the time, didn’t think it was its place to own intellectual property, so the remainder of the royalties went to Gray and his team. But Hull wasn’t left completely out of pocket, the MOD continued to invest in LCD research in Hull until the patents ran out in 1992.

As for Stonehouse he may well have been blessed with the foresight to back LCDs, but he wasn’t so hot with his own businesses. Shortly after the first LCD devices were being manufactured his clothes were found piled on a beach in Florida with no sign of his body. He had apparently committed suicide after a series of disastrous business ventures. In reality he had faked his own death and was winging his way to Australia to start a new life with his mistress. The law caught up with him, briefly mistook him for Lord Lucan before sentencing him to several years in gaol. As if that wasn’t enough intrigue for one man he also turned out to be a Czech spy!

References:

1)  Gray, K.J. Harrison, J.A. Nash. New Family of Nematic Liquid Crystals for Displays, Electronic letters. 9:6. pp 130-131, 1973

2)   Hirohisa Kawamoto, The History of Liquid-Crystal Displays. PROCEEDINGS OF THE IEEE, 90: 4. pp 460-500.  2002

Footnote:

* A working range of 22 to 35C was not, of course, anywhere near sufficient for saleable LCD display.  That came about via a series of  mixtures of 5CB with new cyanobiphenyls which eventually settled on a quaternary mixture known as E7.

Composition of E7. From ‘The History of Liquid Crystal Displays’

 

 

Originally posted (as a slightly different version) in the Guardian.

By March 22, 2013 1 comment synthetic chemistry

Has Tamiflu got a cold?

Tamiflu, made by Roche and licensed by them from Gilead and stockpiled in many countries has proved to be a big money maker for Roche. It is one of two neuramidase inhibitors currently available for the treatment of influenza, the other being Zanamivir from Glaxo. Tamiflu is sold as its mono-phosphate salt. During the recent outbreak of avian flu due to the H5N1 virus Tamiflu was the drug treatment of choice for many physicians.

 

Now questions are being asked again about it’s effectiveness and it’s actual performance in clinical trials, the data of which has not been fully published by Roche in spite of promises to release this information. A new web site has been established to achieve the aim of providing doctors and patients’ access to this information. In a hard hitting editorial the editor of the British Medical Journal gives big Pharma a well deserved tongue (or in this case pencil) lashing, criticising the lack of information as to the clinical trial results of not just these two compounds but a number of others. Which she says must be made available to independent scrutiny.

It turns out that an review of the data on the available neuramidase inhibitors, commissioned by the British Government, discovered that around 60% of the data of the phase III trials collected by Roche has never been made available for examination.

Why does Big Pharma have a level of secrecy that would make the CIA look proud? Well I suppose in the first instance it’s about big money. One Tamiflu pill costs about $10, and that’s expensive. The recommended dosing regimen is 75 mg twice a day for 5 days, $100. Multiply that by the huge number of people contracting influenza and it comes to a lot of money. This year the sales are expected to DOUBLE from $350 million to around $750 million. So, I suppose that alone justifies the most of the secrecy concerning the reluctance to produce the complete trial results. Combined with a supply problem keeping the demand high also pushes the price up. I would hope that the deficit in supply is due to capacity problems and nothing else. Secondly; publishing the results of clinical trials give an insight into the companies working practices, which they most certainly don’t want made public. In the third instance if any minor complications turn up in the trials this may lead the company to tone down their significance, if there is any. Fourthly; could there be any bad publicity arising from any side effects of the compounds. No doubt there are perhaps other reasons that I am unaware of.

Moving back to chemistry the optimisation of the synthesis of Tamiflu makes a very interesting read and I recommend it as an excellent source of solutions to scale-up difficulties. It can be found here unfortunately behind a paywall. The synthesis starts off with shikimic acid and delivers Tamiflu in 17-22% yield after 15 steps. It has two azide reactions; the first one opens an epoxide to give a mixture of hydroxy azides 1 & 2 in a 9:1 mixture:

Both isomers form the same aziridine in the next step. The hydroxy azides are thermally labile, the stability being better in solution.

The next crucial step is the one pot sequence consisting of aziridine formation, via a Staudinger type process, using triphenylphosphine, followed by ring opening with sodium azide/sulphuric acid and finally acylation.

This series of reactions circumvents the unfavourable thermal properties of both the aziridine and the amino azide and allows for faster reactions and higher yields while maintaining process safety and quality of the product.

For this superb piece of process chemistry the Roche group received the Sandmeyer prize of the Swiss Chemical Society in 2006.

By February 16, 2013 3 comments science news, synthetic chemistry