One of the more wide-ranging on my “Lowe’s Laws of the Lab” list is this: The secret of success in synthetic chemistry is knowing what you can afford not to worry about.
That’s because you have to have a cutoff somewhere. There are so many potential things that can affect an experiment, and if you have to sweat every one of them out every time, you’re never going to get anything done. So you need to understand enough to know which parts are crucial and which parts aren’t. I think the beginnings of this law came from my days as a teaching assistant, watching undergraduates carefully weigh out a fivefold excess of reagent. Hmm. Did it matter if they were throwing in 4.75 equivalents or 5.25? Well, no, probably not. So why measure it out drop by drop?
Tom Goodwin, the professor responsible for teaching me inmy first organic chemistry course, once advanced his own solution to this problem. Growing weary of the seemingly endless stream of lab students asking him “Dr. Goodwin, I added X by mistake instead of Y. . .will that make a difference?”, he proposed creating “Goodwin’s Book of Tolerances.” I think he envisioned this as a thick volume like one of those old unabridged dictionaries, something that would live on its own special stand down the hall. “That way,” he told me, “when some student comes up and says ‘Dr. Goodwin, I added cheese dip instead of HCl – will that make a difference?’, I can walk over, flip to page thousand-and-whatever, and say ‘No. Cheese dip is fine.’”
According to him, a solid majority of these questions ended with the ritual phrase “Will that make a difference?” And that’s just what a working chemist needs to know: what will, and what won’t. The challenge comes when you’re not sure what the key features of your system are, which is the case in a lot of medicinal chemistry. Then you have to feel your way along, and be prepared to do some things (and make some compounds) that in retrospect will look ridiculous. (As I’ve said before, though, if you’re not willing to look like a fool, you’re probably never going to discover anything interesting at all).
Another challenge is when the parts of the system you thought were secure start to turn on you. We see that all the time in drug discovery projects – that methyl group is just what you need, until you make some change at the other end of the molecule. Suddenly its suboptimal – and you really should run some checks on these things as you go, rather than assuming that all your structure-activity relationships make sense. Most of them don’t, at some point. An extreme example of having a feature that should have been solid turn into a variable would be that business I wrote about the other week, where active substances turned out to be leaching out of plastic labware.
But if you spend all your time wondering if your vials are messing up your reactions, you'll freeze up completely. Everything could cause your reaction to go wrong, and your idea to keel over. Realize it, be ready for it - but find a way not to worry about it until you have to.