synthetic chemistry

Great Research is Dull

This post is contributed by Brandon Findlay, and the author of the blog “Chemtips

The best talks, the ones that I go to conferences hoping to see, are the least exciting.  They aren’t sleep inducing, far from it.  But the best talks don’t usually have a lot of flair.  There’s no brilliance at play, and nothing indicates that what I’m hearing will one day change the world.  Instead, I think, “Why doesn’t everyone do things like that?”

Strange as it may sound, such moments are (for me) what make great research stand out.  Great research is the end product of an idea so simple and straightforward that doing things any other way is nonsensical.  If you’re curious about understanding the interplay between drugs and antibiotic resistance, of course you should go isolate millennia old permafrost bacteria.  If you want to discover new reactions, semi-randomly mixing reagents is the way to go.  And if you want to make macrocycles, just dream up a reaction that holds the two ends together with electrostatic charge.  After the fact each idea makes perfect sense, and I wind up feeling an amnesiac; remembering things I didn’t even know I’d forgotten.

Good research (and a lot of flawed work), draws more press, and generally leads to a faint sense of awe.  Almost all of the upper tier total synthesis work is good research, as every sufficiently complicated structure stands out like an Everest on the horizon [1].  “Conquering” each structure grabs the headlines and extends the limits of what’s possible, usually leading to a new technique or two along the way.  But at the end of the day, what have we learned?   Dozens of small discoveries are made while climbing, but they are rarely broadly applicable.  From the top the climbers can see far, but their only concern is even greater mountains on the horizon.  The only follow-up to their work is to reach the same summit again, better [2].

It’s easy for a field to fall into a groove, using the same approach again and again, until every mountain—no matter how small—has at least one flag waving at the top.  Great research shifts your perspective, revealing new worlds and new peaks.  Once the blinders have been removed it’s hard not to look back and think, “Why didn’t I think of that?”

[1] Why climb Everest?  “Because it’s there.

[2] Higher yield, fewer steps, green, single pot, atom economy, protecting group free.  All different ways of seeking out some synthetic Platonic ideal [3].

[3] Disclaimer: Total synthesis requires dedication, intelligence, and perhaps a touch of madness.  I have nothing but respect for those who do it so well.

Sandwiches, Gluttons and Picky Eaters

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

Quintus guest-blogged recently on that iconic sandwich molecule, ferrocene, an iron atom sandwiched between two cyclopentadiene rings. Ferrocene is the first discovered and best known of a broader class of molecules called metallocenes, molecules in which a metal atom is sandwiched between two aromatic ligands (not necessarily cyclopentadienes). The applications of ferrocene at present are rather limited, but that is not the case with metallocenes. I thought I would expand on this subject by showing the particular usefulness of these molecules – the metallocenes – to polymer chemistry. Most people, including chemists, have little idea how important these molecules are to their everyday life. The molecules themselves are not polymerized, but instead are catalysts for the polymerization of olefins such as ethylene and propylene.

 Before we can get into the reaction details, I first need to explain for the stereochemistry of polymers and why it is import. In a isotactic polymer, all the monomers have been added to the chain in the same orientation:

while in an atactic polymer, the orientation is random:

This stereochemistry is critical to the mechanical properties of a polymer. Atactic propylene is easy to make, but is a pile of goo that you can use as a pretty bad adhesive and not much else. The isotactic version however, can crystallize and that then builds the strength of the material. Crystalline polypropylene is a good strong material that we use every day in food packaging, dishwasher safe food containers, carpeting, nonwoven fabrics, ropes and hundreds of other uses.

Read more ›

The Organic Chemists Dream

Now here is something, the simultaneous formation of 96 bonds in a one-pot reaction!! Yes, 96 bonds at one go.

This feat was recently reported in Angewandte Chemie DOI: 10.1002/anie.201202050 , entitled Integrative Self-Sorting Synthesis of a Fe8Pt6L24 Cubic Cage, but I do not profess to understand it.

This would be great for organic chemists. Imagine throwing together carbon, hydrogen, nitrogen, oxygen and a bit of sulphur and a few other trace elements and shaking (not stirring) and out pops a blockbuster drug or a new life form!

Here is what they produced.

 

Sandwiches and other tasty things.

Sandwiches have a long and colourful tradition, said to have been invented by the Earl of Sandwich in the 18th century who apparently ordered his servant to bring him some meat tucked between two pieces of bread. So thus the delicacy was born. I can vouch for the town of Sandwich, in Kent, England, which is a beautiful place, full of old buildings and more importantly pubs selling good beer and guess what? Sandwiches.

Pfizer had a facility there, but in their infinite wisdom they recently closed it. Just up the road was a fireworks factory, lots of little huts dispersed about a rather large field, presumable to avoid explosion of rotten sandwiches. Even further up the road there used to be a hovercraft terminal, which, for a  large fee would transport you and your car over the English Channel to France. That was in the days before the channel tunnel.

To a chemist the word sandwich has another connotation, sandwich compounds in which a metal atom sits between two rings, usually cyclopentadienes. Recently a review appeared describing the discovery, structural elucidation and uses of these interesting compounds (1). I was amazed to read that R.B. Woodward also had his fingers in the pie, or rather sandwich, which I suppose is not too surprising.

Some 60 years ago reports appeared, in Nature and the Journal of the Chemical Society (2,3), describing attempts to prepare fulvalene by oxidising cyclopentadienylmagnesium bromide with FeCl3. They obtained yellow crystals, always nice to see, but they turned out not to be the correct compound, elemental analysis gave the formula FeC10H10 . This compound was soluble in conc. H2SO4 , without decomposition. You can’t say that about modern day sandwiches, except for the ones the railways serve on their roving buffet wagons.

As is the case, and there many examples of it, another group isolated the same compound from an unrelated series of experiments.So what was the structure of this new compound? The big names became involved in solving the puzzle, proposals came from Ernst Otto Fischer (right hand structure), R.B. Woodward, G, Wilkinson (left hand structure).

Their proposals were finally vindicated by X-ray crystallography.

Woodward published his thoughts (4, 5) and proposed the name “Ferrocene” which became generally accepted. Thus compounds of the type M(C5H5)2  became known as metallocenes. Wilkinson and others coined the name “Sandwich compounds”, which also became universally accepted. As an interesting aside; apparently the JACS editor who had the job of refereeing the Woodward communication wrote to him and Wilkinson suggesting that they may have been imbibing in some illegal substances!

The research into these compounds proceeded at a furious pace between 1952 and 1954 and it was observed that the “all’s fair in love and war” policy was strictly adhered to by both the Fisher and the Wilkinson groups. Nevertheless this work produced a plethora of remarkable compounds and I will leave it to the reader to investigate the original literature so well documented in this Angewandte Chemie essay (1).
In 1973 Fischer and Wilkinson were awarded the Nobel Prize for their sandwich work and it’s refinement. Not surprisingly there were those not quite so thrilled with this decision, even going as far as to suggest that a “grave injustice” had been committed. The Nobel Committee reacted appropriately to this correspondence.
Sandwiches have even made their way into the realms of medicinal chemistry. Very recently Salmon etal (6) described Metallocene-Based Inhibitors of Cancer-Associated Carbonic Anhydrase Enzymes IX and XII in the Journal of Medicinal Chemistry. They investigated 20 different sandwiches “comprising of extensive structural diversity” and evaluated their efficacy an inhibitors of carbonic anhydrase. The most potent compound, a sulfonamide, is reproduced here.                                                                                                                          

Derek Lowe at “In the Pipeline” commented on this paper and his contributors added more and the reader is recommended to peek in there (7)!

I myself dabbled in this chemistry, well I cheated and bought my ferrocene derivative. But all the chemistry planned worked and I even obtained an x-ray structure, which I think looks wonderful!

 

 

Well there it is, my first contribution of, I hope, many to Chemistry Blog. I hope you all enjoyed it. Any comments are welcome, except negative ones which will get a mouldy sandwich thrown at them. I recommend everyone to have a read at reference 1, if you can, it’s behind a paywall, as to be expected. We need open access journals.

References

  1. Helmut Werner, Angewandte Cheme International Edition English, 9th May, 2012, DOI: 10.1002/anie.201201598.
  2. T. J. Kealy, P. L. Pauson, Nature 1951, 168, 1039 – 1040.
  3. S. A. Miller, J. A. Tebboth, J. F. Tremaine, J. Chem. Soc. 1952, 632 – 635.
  4. G. Wilkinson, M. Rosenblum, M. C. Whiting, R. B. Woodward, J. Am. Chem. Soc. 1952, 74,2125 – 2126.
  5. R. B. Woodward, M. Rosenblum, M. C. Whiting, J. Am. Chem. Soc. 1952, 74, 3458 – 3459.
  6. Adam J. Salmon, Michael L. Williams, Quoc K. Wu, Julia Morizzi, Daniel Gregg, Susan A.Charman, Daniela Vullo, Claudiu T. Supuran, and Sally-Ann Poulsen; J. Med. Chem.,Publication Date (Web): April 27, 2012 (Article) DOI: 10.1021/jm300427m
  7. http://pipeline.corante.com/archives/2012/05/23/how_come.php
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