Is science sometimes in danger of getting tunnel vision? Recently published ebook author, Ian Miller, looks at other possible theories arising from data that we think we understand. Can looking problems in a different light give scientists a different perspective?

A 1960s PhD. Synthesize Or, Er … Fail?

Ever had trouble making something? Yes, I had further problems. Recall, I needed a sequence of substituted trans-2-phenylcyclopropylamines, and I would get the amine through the carboxylic acid. My aim was to tell whether the para nitro substituent would give the sigma constant typical of conjugation, or no conjugation, which meant I needed the para nitro substituent, and I would prefer the meta nitro substituent to "anchor" the Hammett line.
 
The para nitro compound would be a straightforward nitration, or so I thought, of the carboxylic acid. The literature suggested concentrated nitric acid at 30 degrees C, to get an awful yield, so I tried fuming nitric in an ice bath. The product melted at 170 degrees C, not the required 198 degrees, and was shown to be the then unknown dinitrophenyl cyclopropanecarboxylic acid. Nitric acid diluted with acetic acid kept below 5 degrees for five hours gave a 75%  yield of the right stuff. So far, so good.
 
The meta nitro compound was obtainable, in principle, through my standard synthesis, except that after the Friedel Crafts reaction of succininc anhydride with benzene, I nitrated the resultant ketone, and ended up with the meta nitro substituted keto acid. Easy! Then all went well until the cyclization: a zero yield of cyclopropanecarboxylic acid, and a 100 % yield of shog, aka dirty brown rubbish.
 
It was around about now that supervisor went overseas on a 9 month sabbatical. No advice about what to do. Anyway, I thought I had better make the amines, because these wretched styrenes that I had ordered some time ago refused to turn up. Amine conversion went well, until, disaster, the para nitro compound refused to behave. The Curtius reaction went well enough, and I made the hydrochloride of trans-2-p-nitrophenylcyclopropylamine in good yield. If I dumped this into strong alkali, I got the amine (at least I believe so) but under any conditions near neutral pH, where there could be some of both protonated and base forms present, there was an immediate production of a reddish brown condensed product. By definition, the measurement of a dissociation constant requires both to be present. Using it as a nucleophile to carry out a displacement generally permits some of the protonated form to be present, as you cannot carry out kinetics of a nucleophilic displacement with molar NaOH present. Now what?
 
My nearest piece of inspiration was to risk some of my p-bromo substituted acid and try to carry out a nucleophilic substitution with cyanide. In this reaction, the cyclopropyl ring retards the reaction, but it worked. The yield may not have been magic, but it was adequate. Whew! Not so fast! Conversion to the amine was again, troublesome. I was in trouble. I was also on my own; supervisor remained absent, not even mail, and nobody else was offering help.
 
One final piece of amusement, that could have been in the previous blog. As a reward for supervising senior organic undergraduate labs, I was permitted to get some non-critical synthesis done for me, so I got a student to try the Friedel Crafts reaction of succinic anhydride on ethyl benzene. The student worked well (I supervised the first part very closely!) and eventually the student proudly announced he had a good yield of white material. I suggested he do a melting point, so we could see how pure it was. Some time later, he was still measuring the melting point, so I asked him what was taking so long. "It isn't melting," he replied. A quick flame test told me all I needed to know: he had thrown out the product and kept the aluminium oxide. It would take some time to measure the melting point of that!
Posted by Ian Miller on Nov 17, 2012 2:29 AM Europe/London

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