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Derek Lowe The 2002 Model

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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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May 15, 2008

Copper: A Gentleman's Disagreement

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Posted by Derek

I was running a copper-catalyzed coupling reaction the other day when my summer intern asked me how it worked. I showed her the mechanism that the authors of the paper had proposed, but pointed out that it was mostly hand-waving. The general features are probably more or less right: the copper iodide presumably does form some kind of soluble complex with the amino acid that’s needed in the reaction mix, and that may well form some sort of complex with the aryl halide, which opens up the ring to nucleophilic substitution, etc. If this were an exam, I’d give full points for that one.

But a lot of these couplings are, as I pointed out to her, very hazily worked out. The Ullman reaction, in various forms, has been with us for many decades, and there are more variations on it than you can count. If it always worked reasonably well, or if people had any strong ideas about how it did so, the literature on it wouldn’t be in the shaggy shape it is. Copper chemistry in particular has been (simultaneously) a very useful area for people to discover new reactions, and a horrible trackless swamp for people trying to explain how they work.

All you have to do is look at the vicious exchanges between Bruce Lipschutz and Steve Bertz during the 1990s about whether such as thing as a “higher-order cuprate” exists. I have absolutely no intention of reconstructing this argument; I would have to be paid at a spectacular hourly rate to even attempt it. It's enough to say that the arguments raged, in an increasingly personal manner, about what state the copper metal was in, what ligands coordinated to it, and what the active form of these reagents might be (as opposed to what the bulk of the mixture was at any given time). It culminated in what must be one of the most direct titles for a scientific paper I've ever seen: It's on lithium! An answer to the recent communication which asked the question: 'if the cyano ligand is not on copper, then where is it?'. That's in Chemical Communications 7, 815 (1996), if you're interested (here's the PDF for subscribers). Bertz continued to shell Lipshutz's position past the time when any fire was being returned, as far as I can tell, and continues to work in the area. Lipshutz, for his part, hasn't published on the higher-order cuprates in some time (being no doubt heartily sick of the whole topic), but has kept up a steady stream of work on new reactions involving copper, nickel, and other metals.

So if well-qualified researchers, brimming with grad students, postdocs, and grant money, can argue for years about copper mechanisms, I'm going to stay out of it. As time goes on, I'm increasingly indifferent to reaction mechanisms, anyway. I want to get product out the other end of the reaction. And while there are times when knowing the mechanism can help reach that goal, those times do not occur as frequently as you might hope.

Comments (16) + TrackBacks (0) | Category: Chemical News | Inorganic Chemistry | Life in the Drug Labs


1. Tot. Syn. on May 15, 2008 9:04 AM writes...

I have enough trouble presenting my PhD work, which has Cu(III) as a key intermediate in the most critical reactions... always gets a question!

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2. processchemist on May 15, 2008 9:30 AM writes...

... But some GOOD model is needed. Otherways people will keep trying to perform Cu catalyzed cyanations and aminations on substrates that don't want to react, no matter how much catalyst you load or how much high is the temperature.
Few hints to the interested ones from my humble experience:
1) If you pick up a paper that says that "finely grounded" sodium or copper cyanide is needed (yes, there's at least one that says so, from a very reputable name), forget you found this one and delete it from the list of references for your project.
2) There MUST be, in some step of the catalytic cycle ,a square planar coordination system with Cu inserted between the aryl system and a Bromine or Iodine anion (or something very close to that- higher order cyano or amino cuprates?). This can explain some reactivity trends I observed - If you work with cyanations or aminations, take your consequences from this totally undemonstrated hypothesis and you'll stay away from frustrating quests for the right, magical ligand and so on
3) Consider the simplest option first: NO LIGAND, plain Ulmann, simple Cu(I)I as catalyst. You can spare time and expensive reagents.

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3. milkshake on May 15, 2008 9:40 AM writes...

When there is possibility to use Buchwald-like Pd chemistry for arylation I allways go with Pd instead of the cruel ullman; Pd-catalysed arylations use much lower metal loading, more ligands are available and we have a better understanding what they do, the catalysts work at lower temperature and the reaction mix is most of time cleaner also.

Cu(+) can be pi-coordinating to benzene ring and making the aryl halogen into a better leaving group while bringing in the nucleophile by coordination. I don't suppose there is a direct insertion to Ar-X producing Ar-Cu(L)n species in Ullman although these must exist in Cu(II)-promoted oxidative arylations with arylboronic acids.

Oh, and did I mention I hate copper-arylations?

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4. processchemist on May 15, 2008 10:14 AM writes...

milkshake, aminations with some alpha hindered rigid amines does not work on some ArX systems, no matter if you shift from Cu(I) to Cu(II) and then to Pd.

Ullmann on scale is a nightmare, it's not always easy to get rid of all Cu traces in the product, but sometimes is the only solution.
For sure somewhere in Asia some people charge tens of Kg of CuCN in tons of DMF then heat the whole to 150-160°C in order to obtain 4-cyanophtalide, the key intermediate in the citalopram process...

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5. milkshake on May 15, 2008 11:44 AM writes...

I used to do TMS-CN workup with small-scale copper reactions and EDTA+ammonia for the lage ones, to get all metals out from my aminopyrimidines. Not fun.

One decent (and under-used) copper system is CuCl 10mol% with N-methylimidazole 50 mol% and Cs2CO3 or K2CO3 in diglyme

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6. rhodium on May 15, 2008 11:54 AM writes...

The Bertz/Lipschutz exchanges are interesting in part because of Bertz' academic appointments, or lack thereof. Steve started studying copper chemistry at the old Bell Labs, where about ten percent of the people could do basic research (some of the early NMR of biomolecules was done there, for example by Shulman and Patel). When ATT was broken up, many left but Steve stayed on a bit longer and eventually the company and he parted ways. Steve became what is rare (and as far as I know, unique in the chemical sciences): an independent scholar. You will note that much of the copper work come from the Complexity Study Center, which, I think, is Steve's house. The NMR work was done in collaboration at UNC Charlotte since most homes lack NMR facilities. I don't know of anyone with more of a dedication to scholarship than Bertz. Its a case study of how drive and intelligence can overcome resource limitations.

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7. LNT on May 15, 2008 12:24 PM writes...

I've had a terrible record trying to reproduce copper promoted amidations. (using bisamine/amino acid type ligands) I'll do it on a small scale, and it works great. I'll try some different substrates, and it works OK. Then I'll try to scale up one of the molecules, it fails miserably. Then I'll try to repeat it at the same scale I originally did, and it works, but only gives 10-20% conversion. Adding more reagent/ligand/catalyst has no effect. Has anyone else had these problems?

Bottom line: I use copper chemistry only when I absolutely have no alternative.

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8. Jose on May 16, 2008 12:15 AM writes...

By the by, it's "Lipshutz," and not "Lipschutz."

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9. TNC on May 16, 2008 9:12 AM writes...

I confess to being a little in love with Lipshutz; he's a great speaker and does interesting work. I didn't know about this copper business, though.

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10. Me on May 18, 2008 9:33 PM writes...

I was blown away by the article from Bertz on CuCN in the Encyclopedia of Reagents which totally overlooked its use in anything other than higher order cuprate chemistry. The venerable use as a method of turning Aryl Halides into Aryl Cyanides wasn't there.

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11. chris on May 20, 2008 11:24 AM writes...

ArX to ArCN - von Braun cyanation. I got this question during my defense, "Is that the rocket guy?" Does anyone know?

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12. Derek Lowe on May 20, 2008 1:14 PM writes...

Nope, that's one Julius von Braun, back in the late 1920s and early 1930s. No relation, as far as I can see. . .

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13. SSG on June 4, 2008 11:26 PM writes...

I was working with Bruce (on non-cuprate chemistry) when all these controversies started. The group meetings were "hot"(wayyyyy back in early 1989), but most of us who were not doing the NMR studies on higher order cuprates, beleived its LiCN (wayyyyyyy before Bertz's ChemComm paper). Simple chemical intutions, no egos involved.
But tell ya, the norbornyl controversy took Saul Weinstein away. This cuprate one is nothing in comparison.
Someone said he likes Bruce's lectures. I do too. Absolutely. He can easily sell a refrigerator to the eskimos.

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14. TNT on April 10, 2010 10:50 PM writes...

I assure you Steve Bertz is no gentleman

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15. Ravinderpal on April 5, 2013 5:44 AM writes...

How to separate CuI from the reaction mixture under homogeneous conditions. i have carried out the reaction in DMSO. i have done the procedure of adding ehtylacetate and water, mixture, but at the end i realized that the CuI is insoluble in water. Please suggest the appropriate method

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16. Totgia on September 5, 2013 3:30 AM writes...

My first analytical project was about analysis of leucine. I had lots of difficulties because this compound almost does not absorb UV. Finally i could do it by forming complexation with copper(2+)

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