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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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March 29, 2007

I Want A New Nitro

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Posted by Derek

Quite a while ago (sheesh, five years - this is an old blog, as these things go!), I wrote about a "Chemical Wish List". There are a lot of elements and functional groups that nature has not provided us with, and we could really use them. The earlier post was a request for something the size of fluorine that's electron-donating instead of electron-withdrawing, but today I have another one for the list.

I want a nitro group, or something a lot like it, that's metabolically stable. Nitro's an odd duck, as the structure in its brief Wikipedia entry will show. That drawing is a compromise attempt to represent reality (dotted lines in chemical structures are a giveaway for that). You can draw other resonance structures, all of which approach the truth to greater or (mostly) lesser degrees. Basically, the two oxygens have more electon density on them that usual, and the nitrogen has less. Neither oxygen has a full negative charge on it, but they're closer to it than usual.

And that's what makes nitro interesting. It's quite a polar functional group, and compounds that contain it reflect that. Take a look at the simplest organonitro compound, nitromethane. It dissolves freely in water, and boils at nearly the same temperature, 100 degrees C. Boiling point is a fairly good surrogate for polarity, other things being equal, since it's measuring how well the molecules prefer each other's company in the liquid state, as opposed to flying off on their own in the gas phase. For comparison, methanol (CH3OH) boils at about 65 degrees C, and methylamine is wimpy indeed, fizzing away at about minus 6. Now, there are some molecular weight differences in there which can't be totally ignored, but there's no doubt that nitro is one polar group.

We need polar groups in medicinal chemistry. Those, along with the general shape of the molecule, are the biggest parts of binding energies to our in vivo protein targets. Nitro groups uniquely offer a positive charge right next to a forked arrangement of partial negatives, and I'm sure we could do a lot with that - if the darn things didn't get chewed up in living systems. That nitrogen is nearly as oxidized as it can get (well, there's nitrate anion, true), and there are plenty of systems in the body ready to bring it back down.

That's where the trouble starts. If you go all the way down from nitro, you end up with an amine (NH2). But the intermediates along the way - hydroxylamines, nitrosos, all that kind of thing - are rather reactive and nasty. Those are what give nitro groups their bad reputation in medicinal chemistry - too many of them, especially the ones where the nitro is on an aromatic ring, are experimental (or, gulp, real-world) carcinogens because of those metabolites. The same thing happens to aryl amines, too, because other enzyme systems can oxidize them up to the nasty middle steps. I don't think that they make it all the way up to nitro in vivo, but more perverse things than that happen in biochemistry all the time. For those who don't know this stuff and would like to know more, here's a nice presentation on the basics of drug metabolism - navigate down to #88 in the frame to get to the nitro section.

Now, it's not like there are no nitro-containing drugs. Putting the group on a five-membered heterocyclic ring is often a tolerable move, and there are plenty of examples of that working out. But there's always going to be some suspicion attached to the group, and you're never sure that things are going to work out, since human metabolism can differ from your animal models. Most medicinal chemists opt for caution, and don't put nitro groups on any of their aromatic rings to avoid heartbreak later on. (And of course, there are aliphatic nitros, but those have their own problems).

No, what I want is something that's the size, shape, and polarity of a nitro group, but is rock-solid to metabolism. Sort of a trifluoromethyl group with lots of charge on it. We could certainly have a good time with one of those. . .

Comments (12) + TrackBacks (0) | Category: Life in the Drug Labs


1. Art on March 29, 2007 3:49 PM writes...

This is sort of an unrelated question, but I was wondering if anyone knows of a stronger pi withdrawing group than nitro groups.

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2. milkshake on March 30, 2007 8:32 AM writes...

Derek, I have seen this problem repeatedly: nitro works and nothing else, and there are no really good substitutes for it.

Recently we had good luck replacing niro with nitrile, in other cases it was carboxamide or acetamidomethyl.

There is one reasonably general surrogate that does not get used nearly as much as it should: benzofurazane. If the starting nitroaromatic compound can tolerate a small substituent next to the nitro, then benzofurazane is a good call. Benzofurazanes can be made from o-nitroanilines or o-nitroazides, using a simple chemistry.

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3. Jordan on March 30, 2007 9:40 AM writes...

I know nothing of pharma so forgive the naive question. Has anyone ever looked at phosphonates as electron-withdrawing groups?

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4. Jose on March 30, 2007 12:16 PM writes...

Derek, you wrote, "We need polar groups in medicinal chemistry. Those, along with the general shape of the molecule, are the biggest parts of binding energies to our in vivo protein targets."

I just ran across this: "The lipophilic groups, from which much of the interaction energy between a ligand and a protein is derived, differ from functional groups, which loom large in the psyche of synthetically trained chemists."
"Implications of Protein Flexibility for Drug Discovery" Nature Reviews, Drug Disc. (2003), 527-541.

I had always agreed with your way of thinking, and underlined that quote as it was so contrary. Any thoughts?

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5. TotallyMedicinal on March 30, 2007 12:44 PM writes...

Derek, off the top of my head I was thinking that a pyridine-N-oxide might come close to a arylnitro in terms of elctron withdrawing, physchem and steric properties. Anyone have any experience of that modification?

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6. Bunsen Honeydew on March 30, 2007 4:05 PM writes...

Derek, how do sulfoxides, sulfones, sulfonamides and sulfonates fair in medicinal chemistry?

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7. Tropane on March 31, 2007 8:49 AM writes...

In the dye world, a trifluoromethanesulfonyl group is nearly as good an electron acceptor as a nitro group.

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8. Rufus on April 1, 2007 8:38 PM writes...

I was at the Florida Heterocycle Conference in Gainesville last year, and a talk by Prof. Dolbier discussed some synthetic methodology for preparing aryl pentafluorosulfides (Ar-SF5). I got the impression that these were fairly stable. If so, is the extra molecular weight scaring away medicinal chemists?

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9. milkshake on April 2, 2007 12:23 AM writes...

I think the problem with ArSF5 is that this group is pretty big and quite greasy and often in medchem the tendency is to go in opposite direction. Also people are less familiar with the group and there are not too many good methods for introducing it (it was readical chemistry if I remember correctly) although this is beginnig to change and some of the ArSF5 pieces are now available. If there is one successful drug with SF5 that makes it into clinic then I think others will be more likely to emulate it.

-SF5 is not a good equivalent of nitro though.

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10. NFI on April 5, 2007 2:21 AM writes...

Nitirle is a good bet (as already mentioned). Best thing is not to put nitro in your compounds in the first place and then you don't have to worry about trying to replace it!

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11. mike on April 6, 2007 1:03 AM writes...

if I remember correctly, there are groups that can replace oxygen atoms in mulecules- usually in solfonic acids- very strong electron withdrawing groups and I doubt nature has an enzyme that can do much to them- C(CN)2 is a group that can replace O's in solfonic acids, makes them MUCH stronger acids. also, making a nitro mimic that is structurally similar might make it easier to replace them in drugs.

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12. JFT on July 24, 2015 10:12 PM writes...

There is a journal... ...and it has some real people behind it. Though I've never submitted anything. I think there are interesting negative results, I've certainly had syntheses that ground to a halt in a dead-end corner of a thing that looked like a natural product because the structure is too hindered or the proton won't deprotonate or the damned ketone is invincible to every known reduction. I did manage to get a really awful epoxide to open though.

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