Articles by: Quintus

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

When is a Proton not a Proton?

A recent article in Accounts of Chemical research discusses this very topic as well as some other interesting facts revolving around protons, their structure and their generation. What does H+ signify? Well it means different things to different disciplines. If you are a physicist it refers to one of the fundamental elementary particles, if you are a chemist it refers to a hydrogen ion. So what is it exactly? Well it is a very strong acid about 1056 times stronger than 100% sulphuric acid! Its place in chemistry is well documented even although you can only add H+ to a molecule in the gas phase whereas only a solvated proton can be added in less gaseous media. This has great implications for biology especially where proton pumping is an important function, thus the structure H(H2O)+turns out to be a very important structure. This is especially so because the degree of solvation affects the rate of protonation particularly in proton/electron transfer.

According to Professor Reed, the author of this article a self – ionising acid, HA is very unlikely to form a H2A+ cation, the structure is better represented by the following equation:

proton

In the last few years it has emerged that the H+ is a 2-coordinate species, however, even this may extend to multi-coordinate when hydrogen bonding is involved. So what is the structure of H+ in water? This turns out to be a very difficult question to answer, and several instrumental methods have been applied to solve this problem, including IR and x-ray crystallography. These two methods and lots of hours have turned up H13O6+ ions as the structure. The experimental evidence backing up this claim can be found in this paper, which is open access!

Talking about protons leads to the strongest acids known H(CHB11Cl11) or H(CHB11F11), however the latter species is very difficult to obtain due to the ease with which it gives up its proton. These acids can easily protonate benzene or better alkanes! They are very useful in the study of protonation due to the complete inertness of the anions that do not undergo the usual corrosive reactions associated with other types of super acids. The acid H(CHB11F11) protonates butane to give the t-butyl cation at room temperature. Ethyl chloride is also protonated by H(CHB11Cl11) with concomitant loss of HCl to give the diethyl chloronium salts which can be isolated.

Oxatriquinanes are tricyclic analogues of the H3O+ ion. These very strong acids can H-bond to the last lone pair of oxatriquinane, which is a tetravalent oxygen species with a 2+ charge and is an analogue of the H4O2+ ion.

The Oxatriquinane oxonium cation.

ion

 

So if you are searching for a proton source not accompanied by the usual destructive counter ions try one of these carborane acids.

By August 8, 2013 6 comments science news

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

Molecular Mechanics

Synthesising small molecular machines has been somewhat limited to making molecules that can walk or spin round cogwheels. Mind you that is still pretty impressive. Now things are set to change with a recent publication in Science by Dr Leigh from the University of Manchester in the UK.

The Manchester group synthesised a rotaxane (a molecular ring) threaded through an axle that consists of peptides. The rotaxane has a thiolate moiety that removes the amino acids in sequence and transfers them to the site of the new growing peptide chain. There is a wonderful summary in C&E News, with an interesting video of how it all works.

The group used 1018 machines in parallel to generate milligram quantities of a single sequence peptide. This mimics the ribosome in its valuable function in the generation of peptides. The “arm” picks up the amino acid by a transacylation reaction and delivers them to a different place on the ring.

There are still some problems to be solved, for example the rather slow reaction rate as the ring needs about 12 hours to make the amide bonds. Compare this to the 15-20 bonds per second produced by the ribosome itself. There are a few other problems, and no doubt they are being addressed at this moment. However this paper and the technology are impressive and will probably have a great future.

Imagine what several moles of these could do once things become optimised, producing peptides of any sequence one desired, natural or unnatural. This is a fascinating concept and I look forward to seeing lots more appearing on this system.