As I entered my fourth year of graduate school in the late 1980s, I was definitely looking for the exit. And since my project was the total synthesis of a large antibiotic molecule, the most likely escape route was (naturally enough!) to finish making the thing. But while that thought came to me almost every hour, it was a difficult strategy to execute.
A major hurdle was that the synthesis had now exceeded 25 linear steps. Anyone who has done this kind of chemistry will understand the difficulty: you lose material at every step, because no reaction yield is perfect. If your recovery is 90% each time, by the time you clear 25 stages you’ll only have 7% of your materials – and at 80% each time you’ll be well under 1%. I resorted to the usual way around this and started a new load of material at the start of the sequence. I loaded the largest container I could locate (a bucket) with more starting material than I had ever dared to process in one go.
I stared at rows of multicolored Erlenmeyer flasks with an increasingly desperate expression.
It worked for the first eight or 10 steps, much to my relief. Not all synthetic reactions grow gracefully, but I’ve gotten this far with more intermediates at this point than I’ve ever seen. However, the next step had always been one of the least productive reactions in the entire sequence. A product that also produced a lot of dark reddish brown impurities. I wasn’t looking forward to this reaction (and subsequent purification) but it had to be done, and one afternoon I got ready and put everything in place.
I was back in the lab around 10 p.m. to check things out (it was graduate school, after all), and the reaction seemed to have ended. Processing of the dark crude mixture consisted of diluting it with a solvent and extracting it in the research group’s largest separating funnel, then evaporating the organic layers and running them through a large white column of silica gel . I got to work, as I had never left the raw mix lying around, and now was not the time to find out what might happen if I did.
The evening continued as I extracted the black substance with saturated ammonium chloride, discarded it, and evaporated the organic layers into a thick slurry, which I loaded onto the large column. It got really, really dark – even worse than I expected. I kept pouring in solvent and removing vial after vial of colorless liquid, then yellow, orange, red, then frankly dark brown – all the while growing more and more worried. In the past, my product came out just before the yellow stuff, but checking bottle after bottle, I couldn’t find any. It was bad; very bad. It was now past midnight and I was standing there staring at rows of multicolored Erlenmeyer flasks with an increasingly desperate expression on my face.
It was becoming apparent that I had destroyed the biggest batch of intermediates I had ever made
I thought back to when I had performed this reaction before. I went back to look at my notebook. It was then that I realized that I had never washed the raw reaction with an ammonium chloride solution before. Instead of this acid balance, I had used a slightly basic sodium bicarbonate solution. Why didn’t I remember, or bother to check? It was becoming increasingly clear that I had destroyed the greatest batch of middlemen I had ever made, the batch that would get me out of graduate school. All through my own carelessness! I found myself alone in the lab with this realization. There was only one thing to do.
I went back to bed. Then I woke up the next morning and went straight back to the lab, where (without wasting time) I set up an even bigger run of that first step. Back to the bucket; There was no other way. The only way out was straight ahead. That’s when I realized I was really going to finish my degree and quit graduate school, because the worst had happened and it hadn’t broken me. I wouldn’t stop until I walked through the door for good.