Contaminated Columns

Good day and welcome to the latest installment of my research ramblings. No conferences or high profile visits this week. Just long hours, little sleep and not enough caffeine to power me through.
As I said last week I had spent my weekend setting up a total of 76 reactions. 40 were on small molecules as a proof of concept and to generate some quick data. Peptide work takes 3x as long as I stated last week. The remaining 36 reactions were on peptides and obviously it all went tits up and I’ll go into that in just a moment. I then spent the remainder of my time being pulled away from my beloved fume hood for colossal time wasting meetings on “data management” and “writing reports”.  The only time I was pulled away and it was acceptable was my group meeting where I went through 3 different papers and learnt a lot about Bredts rule. I do feel I spend too much time being quiet in these meetings and should get more involved in discussion. It is difficult to do this when you are constantly in fear of looking like a monumental retard and saying something ridiculous in front of everyone.
Of my 40 small molecule reactions half could not be analysed (will explain with my peptides) and of the remaining 20, only 5 could be ran on LCMS to see if anything had happened with the remaining molecules too small a mass to try. All 40 were monitored via TLC and thankfully the only ones that appeared to show any reaction were the few that could be ran. Mercilessly, LCMS showed some product actually formed. My boss was very positive, overly happy with these results, encouraging and enthusiastic about the future of this line of research. Sadly, I don’t share his optimism. Perhaps I am just too pessimistic a person, perhaps I’m just too tired and perhaps I am thinking too much like a classical organic chemist focusing too heavily on yields and conversion. Perhaps a mixture of all 3. Currently I feel like there’s a long way to go yet in terms of optimisation but the power of positivity from my boss is relentless and unyielding. A trait I think I’m going to appreciate truly during the difficult times ahead.
And of my peptide modifications… Naturally, I ruined everybody’s day.
I set up all of my reactions without incident and was very proud of the work I had put in. I was using my brand new catalyst which had been liberated from a neighbouring lab and quite excited about what it may do to my reactions. Maybe it would do nothing like all the other things I’ve tried. Maybe it would do something glorious… Going by a generic name I overlooked (stupidly) that it contained triphenylphosphine (TPP)… A grave mistake. LCMS columns are not happy when you put the notoriously difficult to remove triphenylphsophine oxide down them, a common product formed when TPP is being used. They stick to the column (C18), irreversibly contaminate it, and generally spoils everyone else’s data for all eternity. These C18 columns can be very expensive and cannot be readily replaced. I was not popular to say the least. Thankfully a final year PhD in my group was able to save the day and, through a series of washes and reverse flow washes, was able to clean the column. This obviously meant that half of my other 40 reactions were also out of the question as these also contained the C18 column contaminating compound.
At least I’ve learned what catalysts do not work?
Going forward I’ve obviously had to let go of this particular catalysts and move on to greener pastures. This weekend has seen me set up only 12 reactions going back to my initial catalyst and accepting that poor yields are probably guaranteed. I’ve also switched up my starting material to probe the effects of electronics in my system and if electron rich/deficient systems are preferred. Watch this space.
I also had an “ace” idea which in reality will probably be a “crap” idea and I look forward and welcome its future unsuccessfulness. I synthesised the precursor, in a lovely inert addition, which took 2 rounds of columning to purify…2!

Outside of my research, this week chemists were able to form the most tightly braided molecular knot (a pointless endeavour), the moon was found to be older than initially thought (ground-breaking stuff) and turmeric found not to be an ideal drug (who’d have guessed).
Due to constant lab work and not a single day away from the office, my mood is poor and my patience thin. I’m sure the above efforts by scientists is noble but my relative interest is zero.
What isn’t zero is my efforts for this week’s #ReactionRecap where we will go over the McMurry reaction, named after John McMurry Professor Emeritus at Cornell University.
In this reaction, titanium is used as a metal source of electrons in the pinacol reaction and, provided the reaction is kept cold and not left for too long, diols can be isolated from the reaction. However, unlike magnesium or aluminium, titanium reacts further with these diol products to give alkenes.
Titanium (0), which is the source of electrons in the reaction, is produced during the reaction by reacting a Ti (III) salt, usually TiCl3, with a reducing agent such as LiAlH4 or Zn/Cu. The reaction does not work with powdered titanium metal. The McMurry reaction is believed to be a two-stage process involving firstly a pinacol radical–radical coupling. Evidence for this is that the pinacol products (diols) can be isolated from the reaction under certain conditions (observed during the synthesis of Taxol).

The Ti (0) then proceeds to deoxygenate the diol by a mechanism not fully understood, but thought to involve binding of the diol to the surface of the Ti (0) particles produced in the reduction of TiCl3.

Obviously the mechanism above is absolutely dog shite to say the least. But, unfortunately, we can’t do much better because no-one really knows quite what is happening. The McMurry reaction is very useful for making tetrasubstituted double bonds—there are few other really effective ways of doing this. However, the double bonds really need to be symmetrical (in other words, have the same substituents at each end) because McMurry reactions between two different ketones are seldom successful.

McMurry reactions also work very well intramolecularly, and turn out to be quite an efficient way of making cyclic alkenes, especially when the ring involved is medium or large (over about eight members). For example, the natural product flexibilene, with a 15-membered ring, can be made by cyclizing a 15-keto-aldehyde.


That’s me done for this week folks and I’ll catch you down the road.
Reach me @LewisMGooch for all discussions chemistry and beyond. Time to get myself to the shops ASAP before things start to close because obviously it’s Sunday and how dare a shop be open ’till late on a Sunday…


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