I've written before about some elements and functional groups that don’t exist, but which I want anyway. Today I write in praise of triple bonds, and with the forlorn hope that they could do more. The thing about triple bonds is that they’re straight, the steel spacer bars of the chemist’s building set. Every type of bond has its characteristic angle, and for this one it’s 180 degrees. There’s nothing else like it.
Let’s take on the CN case first. I need something like a nitrile that’s not metabolically labile. There’s nothing like CN – it’s polarized because of the nitrogen, and the triple bond just sort of pokes that charge out there. No other functional group is an exact mimic. But the weakness of the triple bond is that it’s a bit precarious, energetically. Piling up those bonds buys you less and less stability as you go, so there’s quite a bit of energy to be sprung. (That’s why the simplest CC alkyne, acetylene, is such an energetic fuel). In the case of the nitrile, it can be torn up by the liver. Although it sometimes escapes, it’s always under suspicion.
And there’s another problem: its electron-withdrawing means that if you put it on an alkyl carbon it generally makes any hydrogens next to it too labile, so most of the ones you do see are on aromatic rings. And there’s another minor problem with the alkyl cases: if you put a CN anywhere that it can act as a leaving group, you run the risk of giving off the nitrile’s evil twin, negatively charged cyanide ion. Yep, a rock-solid, nonreactive nitrile group would be a big hit. Note to self: get cracking on that one.
While I’m at it, I want to tighten up those alkynes. C-C triple bonds show up sometimes in drugs, but they’re show up a lot more if we weren’t worried about them getting metabolized. You can get some interesting molecular shapes by putting in an alkyne, but the liver loves to oxidize them, especially if they're sitting out there on the end of the molecule. With one stroke of an enzyme it can turn a small, all-carbon terminal alkyne into a nice, soluble carboxylic acid that’ll probably send the whole structure sluicing right out the kidneys. The liver lives for that stuff, and it drives us medicinal chemists crazy.
If I’m going to be in triple-bond wishing mode, I might as well go all the way: I mean, C-C and C-N are basically the only stable triple bonds that we can use. How fair is that? The other possibilities (with oxygen, sulfur, and so on) are all charged up and reactive, and can hardly even be bottled up or even observed, much less dosed as a drug. (Well, there’s carbon monoxide, the simplest CO case, but although it appears to be a neurotransmitter, most weirdly, it has some problems as a drug candidate). A whole new world of new molecules would open up to us – new shapes, new polarity, stuff that no drug target has ever tried to deal with before – if it weren’t for the laws of physics. Note to self: tell someone else to get cracking on that.