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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 13, 2007

Underperforming Triple Bonds

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Posted by Derek

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.

Comments (15) + TrackBacks (0) | Category: Life in the Drug Labs


1. milkshake on December 13, 2007 2:04 PM writes...

best CN replacement I have seen so far is Cl and Br

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2. Jason Rush on December 13, 2007 2:16 PM writes...

This article reminded me of a drug with more triple bonds than you can shake a stick at: sodium nitroprusside.

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3. milkshake on December 13, 2007 5:50 PM writes...

Also if you are the more adventurous type you can try azide - it is bent at 120 degree at first N but long and linear. Alkyl azides are fairly stable. Azide in the molecule will make all process chemists totally delighted :)

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4. Course 5 UROP on December 13, 2007 7:08 PM writes...

Unfortunately, linearity may be unique to first row elements in the main group as well. If you look at alkyne congeners (Si-Si, Ge-Ge, etc. triple bonds), funky stuff starts to happen as you go down the period, resulting in 90º R-Pb-Pb angles for "plumbynes." Basically, the lone-pair effect comes into play, and instead of having 2 pi bonds + 1 sigma bond, the formally triple bond consists of 2 polar-dative bonds + 1 sigma bond. The only exception I can think of is phosphaalkynes (C-P triple bonds). Really awesome main group chemistry...if you want more info see Power's review on the subject (Chem. Rev. 1999, 99, 3463).

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5. MattY on December 13, 2007 9:25 PM writes...

Derek, you forgot about my favorite the allene! Two orthoganol double bonds, linear like triple bonds, and are derived from triple bonds. Plus they are chiral. Never seen them in any drugs.

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6. ppp on December 14, 2007 7:54 AM writes...

Are we sure we are not biased against nitriles? The recent HIV clinical candidate UK-453061 has not just one but two CN: they substituted chlorines in the unoptimized lead lowering MW and improving in vivo PK..but we may also be biased against Pfizer..

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7. As You Lean on December 14, 2007 8:04 AM writes...

Good point, Milkshake. If nitroglycerin can make it in the drug market, so can azides.

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8. novice on December 14, 2007 9:13 AM writes...

General question for the medchem audience: has anyone ever considered using an isonitrile as a nitrile replacement? Isonitriles always come to my mind when I'm thinking of different types of triple-bonded funtionality, but I don't have a good handle on their stability. My guess is that their stability is probably pretty terrible, but I'd like to hear other people's opinions.

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9. processchemist on December 14, 2007 12:22 PM writes...

process chemists are used to azides these days (one of the possible intermediates for topiramate, for exemple, is an azide) and people are starting to publish safety data for reactions with hydrazoic acid as possible byproduct or intermediate (in the last OPRD, f.e.)

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10. milkshake on December 14, 2007 1:59 PM writes...

and there is good old AZT. I think the aryl azides are more troublesome because of low decomposition onset and potential phototoxicity.

Isonitriles are pretty toxic and quite reactive (not mentioning the smell). Oh, and they ligate transition metals.

Nitrile is in Celexa (citalopram), the Forrests short-acting SSRI. The idea is to for the drug to clear by the end of the day so that the patients can sleep. Unfortunately a short-acting SSRI creates ups and downs that can be particularly bad if the citalopram is given to a misdiagnosed bipolar patient.

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11. Jonadab the Unsightly One on December 15, 2007 10:33 PM writes...

Has anybody managed to synthesize diazidoacetylene (N=N=N-C≡C-N=N=N)?

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12. Joseph Hertzlinger on December 16, 2007 3:14 AM writes...

What do carbon--boron bonds look like?

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13. Thomas Winwood on February 10, 2009 12:30 PM writes...

Disclaimer: I'm not a practicing chemist, and my experience is limited to A-level chemistry. I also have relatively limited access to scientific literature, so I'd appreciate anyone helping out or providing additional material.

Jonadab the Unsightly One intrigued me; my initial thought was "no way is that going to be stable" so I looked up bond energies and worked out enthalpies of formation. The result I came up with was that my predicted decomposition route (to cyanogen and nitrogen gas) was actually no more or less thermodynamically stable than the diazidoacetylene. However, I made the assumption that the covalently-bonded azide group contains normal nitrogen-nitrogen double bonds, which could easily be (and probably is) false; I have been unable to find any material on the bond energies in this functional group.

The only reference to diazidoacetylene that I have been able to find outside of this blog entry is in this paper which discusses the decomposition of hexaazapentalene to cyanogen and nitrogen gas; a footnote points out isomerisation to diazidoacetylene is unlikely, which implies this compound is a plausible one.

Could anyone suggest further routes of investigation, or point out things I've missed or gotten wrong?

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14. Donnell Tepp on August 18, 2012 10:06 AM writes...

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15. Lachelle Mulhern on March 29, 2014 1:15 PM writes...

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