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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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September 1, 2009

Another Iron Reaction Hits The Mat

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Posted by Derek

Beware of iron! That's the lesson that's being hammered home these days in synthetic chemistry. I wrote recently about the discovery that a series of iron-catalyzed couplings were actually being caused by trace amounts of copper compounds. Now there's another re-examination of some similar iron couplings that were reported last year.

If you click on that last link, you'll see that there was already trouble with the original work. The authors themselves appear to have had a hard time repeating it, and earlier this year they retracted the paper. This latest publication (from other workers) details their own attempts to reproduce the original iron-catalyzed work. In most cases, they got nothing at all, but once (and only once) they had a wonderful spot-to-spot reaction take place with para-bromoacetophenone, which must have been just the sort of thing that excited the original researchers.

But it could never be reproduced. The best guess is that this one reaction may have been catalyzed by trace amounts of palladium. That's plausible, because, as it turns out, the coupling can be run at high conversion with one ten-thousandth of a per cent of palladium acetate. Yes, a substrate-to-catalyst ratio of one million to one is sufficient, and that's the kind of activity that makes it very, very hard to assume that trace amounts of palladium salts aren't doing the work.

It also makes you wonder why anyone would use anything else, at least for activated systems like para-Br acetophenone. In the future, anyone trying to come up with a non-palladium coupling protocol had better stick with the tough reactions that don't work well anyway. That will keep this sort of thing from happening again - and those are the kinds of reactions we need help with, anyway. A new catalyst for coupling red-hot electron-poor aryl bromides, on the other hand, will be greeted with yawns, and with suspicion as well.

Comments (24) + TrackBacks (0) | Category: Chemical News


1. HB on September 1, 2009 12:21 PM writes...

"In the future, anyone trying to come up with a non-palladium coupling protocol had better stick with the tough reactions that don't work well anyway."

What would you say the best candidates for that category are?

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2. startup on September 1, 2009 12:24 PM writes...

Why wonder? Iron is a "green" metal, throw in "low-cost", mention (I dare not use quotation marks here) global warming for a good measure and here's your grant money.

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3. Sili on September 1, 2009 1:52 PM writes...

I know this will make me sound like a troll, but I'm weak enough that what I perceive as weaknesses in the people I admire make me uncomfortable:

Since the subject has been brought up, I'd really like to hear your specific scientific beef with global warming? (I trust people here at least understand the word "global" in this context.)

As for the catalysis, 1 ppm is impressive - even I can see that. Short of some sort of enzyme, I doubt that can be beaten. What's the price of pure iron?

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4. cynical1 on September 1, 2009 2:31 PM writes...

Derek - So you wouldn't believe this new one that just came out in in today?

Recyclable Heterogeneous Iron Catalyst for C−N Cross-Coupling under Ligand-Free Conditions

J. Org. Chem., Article ASAP
DOI: 10.1021/jo901095c
Publication Date (Web): September 1, 2009

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5. alig on September 1, 2009 3:16 PM writes...

I love going off-topic. So I'll feed Sili's troll. There are many issues with anthropologic global warming. One of the biggest is that if you looked at the best estimates of global temperatures over the past 500 million years, we are currently below the mean (~12-22C temperature range, mean ~17C, currently ~14C). One would expect temperatures to rise naturally when you are below the mean. To attempt to keep temperatures below the mean would involve the disruption of the natural cycle.

And besides, "global warming" is out of vogue, it's "climate change" these days.

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6. Chem student on September 1, 2009 3:46 PM writes...

cynincal1: The supporting info says the Fe(acac)3 they purchased from Fluka was 97% pure by HPLC. I dunno about you but that raises a huge red flag for me.

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7. Hap on September 1, 2009 3:56 PM writes...

Records of previous increases should give some idea of what to expect from this one (if it is one), and to compare current climate changes (and the CO2 concs. associated with them) to those in the past. How do we know that a periodic cycle for temperature exists over that time scale? How does the current temperature increase fit with that periodic cycle?

I would have figured if global warming cynics had that good a hole card, it would have been played rather than the "climate scientist/UN/liberal conspiracy theory" or the "look, it's gotten cooler in the last ten years" cards (let alone the "shut up and stop talking politics" card). Why talk smack when you have data?

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8. Hap on September 1, 2009 3:59 PM writes...

97% pure? Whoo-ee! Only 3% crap! That's an awful lot of room for ppm metal contaminants.

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9. Hap on September 1, 2009 4:02 PM writes...

97% pure? Whoo-ee! Only 3% crap! That's an awful lot of room for ppm metal contaminants.

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10. Arjun on September 1, 2009 5:26 PM writes...

Not only is 97% not even close to pure enough, but GC is a pretty lousy way to assess the purity of something like Fe(acac)3.

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11. DC on September 1, 2009 7:14 PM writes...

Maybe someone should try that JOC paper, like in Totsyn...

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12. MTK on September 1, 2009 10:50 PM writes...

One possible way to get an idea of what metal is at work is to conduct the experiment at lower and lower catalyst loading levels until the reaction finally fails to work.

Conduct the same series of experiments with Fe, Pd, and Cu and you should be able to get an idea of which metal is responsible. Not definitive certainly, but could be suggestive.

BTW, every catalysis paper should report reaction performance as a function of catalyst loading level. Unfortunately, many do not.

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13. Alig on September 2, 2009 7:19 AM writes...

Just because you refuse to look at the data, doesn't mean it doesn't exist. If you want a quick refresher on global temperature over a reasonable scale, go to wikipedia and search: geologic temperature record.
It's funny to me that you think 10 years of cooling isn't important, when the AGW folks were using the 20 years previous warming and drawing a line out 200 years and saying "if global warming continues at this current pace we will have a disaster." Well, global warming didn't continue at it's previous pace and now if you draw the line using 30 years of data, we will only have 1/10th the warming.

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14. Hap on September 2, 2009 9:31 AM writes...

"Just because you refuse to look at the data, doesn't mean it doesn't exist."

1) You know, that might actually sound reasonable coming from people who hadn't spent a very long time doing precisely that (Iraq, the deficit, the 8th Amendment, etc., etc., etc.) However...MUWAHAHA!

2) Do you have something that didn't come from some dude in his basement? You know, like peer-reviewed stuff?

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15. Tok on September 2, 2009 9:48 AM writes...

Huh, I don't see much in the way of 10 years of cooling on that chart. It looks more like 30 years of warming.

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16. alig on September 2, 2009 2:26 PM writes...

That data is great to explain my point. Why do AGW folk like to use 1979-1999 data for their illustration of the dangers of global warming? Because that gives the maximal slope to the warming trend. Extend the data back 10 years or forward 10 years and you get a much more gradual slope. The 10 years was just in response to Hap, its only been ~4 of actual cooling with the 5 prior being slower warming. That is clear in the data from you link as well as in the more relevant data from hadcrut3:

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17. Hap on September 2, 2009 3:11 PM writes...

The Republican comment was OTT. Sorry.

I still figure that (even if I were ignoring your data), lots of other people would not be. Talking about whether changes in climate are human-induced or not with data to support your contentions would seem to be a more secure strategy to counter AGW than complaining of liberal biases or conspiracies (after all, the NYT and other papers ignoring Monicagate did Clinton no good at all). The NIPCC, for example, seems childish if you have data - unless you're counting on the support of lots of stupid people or on the debate being a data-free zone, why complain about the UN? If you've got data, arguing about other random things is counterproductive. If you don't have data, it's kind of helpful to move the argument away from facts. So why argue like you lack data if you have it?

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18. Tok on September 2, 2009 4:03 PM writes...

#16 alig - If you extend the data back ten years or 100 years you get the same answer. From 1910 to 2008 the temperature has been increasing fairly consistently with a few bumps here and there as would be expected in a natural system. The recent leveling off of temperature increase can be compared to that which occurred in the early 1980's and 1990's, and may even become as big a dip as was seen in the 1950's, but overall from 1910 to 2008 we've seen a very large temperature increase. The HADCRUT3 analysis you linked to still gives the same overall trend with minor differences.

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19. Chemist on September 2, 2009 4:14 PM writes...

I have been told (but not been able to corroborate, not even in Birch's autobiography) that the use of lithium in the early days of the Birch reduction (1940s) was a source of irreproducible results ... and the occasional accusation of fudging. It turns out that a trace of sodium is required to initiate the reduction when using lithium. As old crappy Li got replaced by fresher, higher purity Li, the reactions failed more often. These days, you can buy Li with a fixed amount of Na "impurity".

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20. alig on September 3, 2009 7:39 AM writes...

If you look at the data from 1900-2000, you get ~0.8 C / century increase in temperature. If you look at the data from 1980-2000, you get ~2.5 C / century increase in temperature. To me that is a huge difference. If we are concerned with a 3 C increase in temperature (was that what we agreed to at the climate meeting?), at 0.8 C / century you have >300 years to stop the warming where as at ~2.5 C / century you have only a little more than 100 years.

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21. Tok on September 3, 2009 8:30 AM writes...

#20 alig - Ah, if only we could just throw down some linear extrapolations and call it a day. Just because the rate is 0.8C/100 years from 1900-2000 does not come close to predicting the same rate of increase into the future. Increases in the rate of CO2 production as well as positive feedback loops will cause faster future warming: We're looking at a 1.8-4C increase average globally. My concern is that higher climates will see more of this (since I live in the USA) because of the positive feedback of ice melt. Call me selfish, but I like the bread basket of the US quite a bit and wouldn't like anything to happen to it.

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22. alig on September 3, 2009 2:44 PM writes...

How many of those models predicted the cooling trend of the last few years? If they can't predict a few years in advance, what makes you think they can predict 100 years in advance.

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23. Tok on September 3, 2009 4:21 PM writes...

Predicting the fine resolution (~1-3 years) and predicting long term (10+ yrs) are completely different things. There will be some ups and downs, but the overall trend is very predictable and obvious at this point.

Based on the previous years, I'm sure very few climatologists are surprised that there may be a few year to year cooling trends.

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24. AlchemX on September 4, 2009 3:39 AM writes...

Throw oxidation of benzyl alcohol in with the "easy" substrates. I could do that with my eyes. Talked to a colleague of mine about using easy stuff like electron poor aryl bromides in couplings. Wayyyy to easy.

To anyone publishing methodologies, please take on some more challenging examples.

EASY Substrate list so far:
p-bromoacetophenone (Couplings)
benzylalcohol (Oxidations)
nitroethene (Asymmetric Michael Reactions)
Tamiflu (not very easy, just tired of seeing it)

Please add to list so we can get some real use out of our RSS feeds.

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