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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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July 8, 2013

The Norbornyl Cation Structure (Really)

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Posted by Derek

Here it is 2013, and the last shot has just now been fired in the norbornyl cation debate. I'm too young to have lived through that one, although it was still echoing around as I learned chemistry. But now we have a low-temperature crystal structure of the ion itself, and you know what? It's nonclassical. Winstein was right, Olah and Schleyer were right, and H. C. Brown was wrong.

Everyone's been pretty sure of that for a long time now, of course. But that article from Chemistry World has a great quote from J. D. Roberts, who is now an amazing 95 years old and goes back a long, long way in this debate. He's very happy to see this new structure, but says that it still wouldn't have fazed H. C. Brown: "Herb would be Herb no matter what happened", he says, and from everything I've heard about him, that seems accurate.

Comments (28) + TrackBacks (0) | Category: Chemical News


1. samadamsthedog on July 8, 2013 12:14 PM writes...

Back when i was just an undergrad pup learning chemistry, i went to the Midwest Regional Meeting of the ACS in Akron, OH. Must have been about 1968. The highlight of the meeting was a one-on-one debate between Paul Schleyer and H. C. Brown on this very topic. i had the sense of watching two titans wrestling. Neither got the better of the other, on the basis of the experimental results in reaction chemistry which both models seemed equally capable of explaining. Occam's razor shaved mighty close on both cheeks.

The other thing i remember about the meeting is that just a few blocks from the downtown hotel where the meeting was being held, there was a cheap diner where you could go for lunch. It had those old-fashioned juke-box stations at the table and every few seats along the counter. You could still put in your nickel (or was it already a dime by then?) and hear Hank Williams singing the Lovesick Blues, which had been a hit for him in 1949. Now the downtown's all gone, the rubber's all gone, the diner's probably gone, but I suppose the Lovesick Blues, together with non-classical carbonium ions (carbocation? what's that?) remain.

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2. Hap on July 8, 2013 12:33 PM writes...

I would have figured that being immune to data that doesn't fit your hypothesis wasn't a good condition for a scientist - a bug and not a feature.

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3. Curious Wavefunction on July 8, 2013 1:10 PM writes...

I remember Roberts's quote about Brown stepping over the beautiful flowers of chemistry with his big brown boots. It got really personal at one point.

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4. opsomath on July 8, 2013 1:26 PM writes...

I had the immense privilege of doing my REU with Prof. Roberts back over a decade ago. I wouldn't bet against that man on anything. Not even a coin flip.

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5. molecular architect on July 8, 2013 2:50 PM writes...

I did my PhD at Purdue as the final shots were being fired in this feud. Yes, non-classical ions exist AT EXTREMELY LOW TEMPERATURES. Brown's point was that they were being proposed for reactions at normal temperatures and were not necessary to explain the data (Occam's razor in action). It's quite instructive to look at textbooks of the post-WWII era - there were all kinds of non-classical ions proposed that had no correlation with reality.

Both sides were ultimately correct: non-classical ions can be observed under special conditions but have nothing to do with reactions at normal temperatures.

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6. daen on July 8, 2013 3:13 PM writes...

There's a wee typo in the title ('Norboryl' vs 'Norbornyl').

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7. luysii on July 8, 2013 3:18 PM writes...

Good to see that Dr. Schleyer is still putting out papers. He was my undergraduate chemistry advisor from '58 - '60. A formidable presence back then, and probably now. A fellow chemistry major's mother asked him why he chose to work for a German U-Boat Captain. He had what looked like dueling scars. I never asked. Perhaps they were from a lab explosion.

For a bit more chemical detail on the paper pleas see

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8. Nick K on July 8, 2013 4:53 PM writes...

#5: On the contrary, proponents of the classical carbocation would now have to explain why temperature changes the nature of the ion. The simplest and most parsimonious interpretation is that the norbornyl cation is the same whatever the conditions.

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9. student on July 8, 2013 6:16 PM writes...

#5 are you suggesting that the structure that is presumably the global minimum on the potential energy surface for geometries relevant to the carbocation is somehow not relevant at higher temperatures.

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10. carvone on July 9, 2013 1:02 AM writes...

By the way, it turns out that Mensur fencing is still a current thing in Germany, even today, so it certainly could be what got Dr. Schleyer his scars.

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11. Anonymous on July 9, 2013 1:53 AM writes...

#10, Since he obtained his degrees from US universities, it's highly unlikely he ever engaged in Mensur fencing.

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12. molecular architect on July 9, 2013 8:33 AM writes...

#5 & #9 - If temperature is irrelevant to the structure of the ion, please explain why such extraordinary measures were required to observe it in the recent paper.

Although I'm a Purdue alumni (maybe BECAUSE I'm a Purdue alumni), I'm not a huge HCB fan. The man had an enormous ego and a pugnacious, stubborn approach to debates. That being said, I think he did chemistry a favor in this debate. Take a look at textbooks of the era, nonclassical ions were widely invoked to explain almost any type of reaction with no experimental evidence. Read HCB's book on the problem. He presented compelling simple experiments where the simplest explanation of the results was that one of the classical ions reacted much slower than the other. As a result of his stand, most of the wilder, fanciful structures have disappeared from the current literature and textbooks.

#1 - Much of the discussion about this controversy over the years focused on HCB's personality but the other side was just as combative. I attended a session at the ACS meeting in Seattle in the early 80s where Brown, Winstein, Schleyer, Olah and several others debated their findings. Basically, the others ganged up on Brown, it literally became a shouting match at times. It was like watching a pack of wolves attacking a bear - turned out to be a pretty even matchup. In the end, he demonstrated that all the EXPERIMENTAL data for reaction rates could be explained by the well established theory of classical ions. Personally I like the elegance of the calculations and the nonclassical structures but I always have a bias for experimental data over theoretical calculations.

It's been decades since I last read or thought about the nonclassical ion debate and, in my opinion, it has little bearing on the day-to-day chemistry we do in the lab. I'm a synthesis/medicinal chemist, mechanistic minutiae are only useful to me if they can be used to improve the results of a reaction in the real world of my research. Otherwise, such discussions might be of intellectual/academic interest but irrelevant to my research.

Still, it's kind of sad that we don't have any ongoing grand debates in chemistry today. All of the scientists involved in this one were/are titans of the field.

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13. opsomath on July 9, 2013 9:14 AM writes...

#12: Schleyer is a member of UGA's CCC, which is the flagship of "Theoretical calculations that show the experimental result was wrong." While he's not the most hardcore of that group, it makes sense that he was on that side of the fight.

#7: Prof. Schleyer was on my MS committee, and I did several computational things for him. It's funny to me that he was considered intimidating, as I always found him kindly and approachable. Perhaps it was the beard.

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14. molecular architect on July 9, 2013 9:55 AM writes...

#13 - Reminds me of sitting in a Theoretical Organic Chemistry class at Purdue where Bill Jorgenson said "modern theoretical calculations are so good that they are better than the experimental data".

Mind you, this was in 1978. There was lots of eye-rolling and snickering among the assembled graduate students.

All my years of collaborating with molecular modelers haven't altered my bias for experimental vs. theoretical data.

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15. luysii on July 9, 2013 11:11 AM writes...

#14 Formidable presence doesn't mean intimidating. My undergraduate experience with Schleyer was great -- working about 20 feet away in his lab (when not doing spectra elsewhere), going out for pizza after work done in the evening. He had me to dinner in his home. He was incredibly accessible for any and all chemical questions that I had.

He also did a fair amount of industrial consulting, and a chemist of my acquaintance who used him this way 20 years later had the same opinion.

As an example of formidable, he enjoyed playing recordings of Don Giovanni, particularly the scream emitted by the Don when he found he was going to hell. He was clean shaven back then (as was I).

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16. Nick K on July 9, 2013 11:19 AM writes...

#1é: Perhaps it had to be done at very low temperature to prevent scrambling by hydride shifts? Olah could only observe the ion properly by NMR below -60° for this reason.

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17. Nick K on July 9, 2013 11:28 AM writes...

Apologies, the above post was directed at #12 Molecular Architect.

From the abstract of the paper: "Crystals obtained by reacting norbornyl bromide with aluminum tribromide in CH2Br2 undergo a reversible order-disorder phase transition at 86 kelvin due to internal 6,1,2-hydride shifts of the 2-norbornyl cation moiety. Cooling with careful annealing gave a suitably ordered phase. Data collection at 40 kelvin and refinement revealed similar molecular structures of three independent 2-norbornyl cations in the unit cell. All three structures agree very well with quantum chemical calculations at the MP2(FC)/def2-QZVPP level of theory."

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18. molecular architect on July 9, 2013 1:42 PM writes...

#17, Nick - Yes, I read those experimental details as well. I should have phrased my earlier question more clearly.

I'm not questioning whether the nonclassical norbornyl ion exists under the reported conditions nor whether theoretical calculations show it would be the global minimum on the potential energy surface. As any medicinal chemist working with protein/inhibitor models knows, there are often considerable differences in the calculated properties of a structure (often modeled in the gas phase, with no solvent interactions) and the observed experimental values in solvent at various temperatures.

Brown's experiments were run in polar organic solvent (acetone, if memory serves me well) at normal temperature ranges. His conclusion was that solvolysis of the exo isomer was not accelerated by electronic effects (the basis of the nonclassical ion hypothesis) but that the solvolysis of the endo isomer was retarded by steric effects. Based on his data, a compelling conclusion.

Both sides contributed excellent work in this controversy, generating new ideas regarding structure and reactivity, new analytical tools and methods, etc. Schleyer and his allies have confirmed the existence of the nonclassical ion under extreme conditions but, as far as I am aware, no one has disproven Brown's interpretation of his experimental results.

This was an epic clash of some of Organic Chemistries biggest egos and, at times, all of them were guilty of both ungentlmanly conduct and good science.

As I said earlier, I'm satisfied with mechanistic models that allows me to understand, manipulate and optimize reactions. Brown's theories of steric effects do an admirable job in most cases, without the need to invoke nonclassical structures. That's good enough for my pragmatic needs.

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19. student on July 9, 2013 3:33 PM writes...

"Good enough for pragmatic needs" is not the same as correct. Quit moving the goalposts.

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20. molecular architect on July 9, 2013 4:05 PM writes...

#19 - I haven't moved any goalpost. My statement was: good enough for MY pragmatic needs.

To the best of my knowledge - (I don't claim to be an expert in physical organic chemistry and it's quite possible I'm unaware of something published during the past 25 years on the topic), - nobody has proven the involvement of nonclassical ions in the solvolysis reactions under the conditions which Brown studied. This last paper certainly does not prove it, it only proves the existence of nonclassical ions under very specialized, low temperature conditions.

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21. GladToMoveToProcess on July 10, 2013 9:31 AM writes...

It was a privilege to have grown up chemically during much of the debate (late '60s-early '70s). Great fun to read papers, same issue of JACS, from the Winstein and Brown groups, with the same compounds and substantially the same rate (and racemization, isotope scrambling,...) data, with opposite conclusions. When it was pretty clear that the ion was nonclassical, HCB was arguing whether there was delocalization in the transition state, and whether it was necessary to explain the rate data. Fascinating!

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22. Nick K on July 10, 2013 3:46 PM writes...

#20: You're resorting to special pleading again! You STILL haven't explained why you think the ion at low temperatures should be different from the ion under solvolysis condition. If my memory serves me correctly, even Brown accepted that there WAS a discrete carbocation, just that it consisted of rapidly interconverting classical cations rather than the non-classical one.

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23. Hap on July 10, 2013 4:07 PM writes...

Dumb question 1: How could you distinguish a rapidly equilibrating mixture of carbenium ions from a nonclassical carbocation? NMR won't (if they equilibrate fast enough, NMR will only show the average shift), I don't think IR would. Crystal structures should show the presence of multiple species if they're there, but you might just see too much disorder to resolve them, or maybe you would only see one specie (though it ought to be distinct from the nonclassical ion at low temperatures). They do require lots of compute manipulation, which could lead to bad answers, though the data could be analyzed by others and fits compared).

DQ2: Why should temperature make nonclassical ions observable if they aren't the stable species? Low temperatures should slow bond shifts (but not electronics), but they shouldn't make transition states stable (which is what the nonclassical ions would be if discrete ions were the stable species). Gas phase measurements might, but low-T crystal structures are almost the opposite of gas-phase measurements (because the interactions between molecules should be dominant, even at low-T). It seems like equilibrating ions are a less parsimonious explanation for the data of norbornyl cations than nonclassical species (if Q1 is reasonable and not stupid).

There were some funny nonclassical ions proposed, probably because they looked pretty and seemed neat (for examples, see Chemistry: The Name Game, but they were debunked relatively quickly, I thought, since the perpetrators weren't immune to data.

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24. Anon on July 10, 2013 6:52 PM writes...

#12, #20:
As for the classical vs non-classical structure question, this paper and the associated calculations (details in Supporting Information, especially p. 92) answer this pretty clearly. With reference to the structure shown here
let d1 be the distance between C1 and C6, and d2 the distance between C2 and C6. Now let y=d1-d2 be the difference between these distances. The non-classical structure corresponds to y=0. The classical structure(s) correspond to y=+/- something. Consider the potential along y. The classical view is that y=+/- something is a minimum, with a barrier between (at y=0). The non-classical view is that y=0 is a minimum. The calculations show that y=0 is a minimum. There are no minima (even local minima) associated with the classical structure(s). However, the potential along y is quite flat. A distortion to y=0.1 A leads to a potential energy increase of 1 kJ/mol; 0.2 A is 4 kJ/mol. So, my understanding of this is that the structure is non-classical, but somewhat floppy.

What we have so far is a crystal structure and gas-phase calculations. This doesn't prove that classical structures don't exist in solution, in a highly polar solvent. However, in explaining results in solution which could be due to classical or non-classical structures, Occam's razor would favor non-classical structures. Are there any (reproducible) experimental results which can only be explained by the classical structure? Is there any spectroscopic evidence for the classical structure? If the answer is no, you're just grasping at straws.

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25. Anonymous on July 11, 2013 3:22 AM writes...

#23 Hap: Several years ago the ion was studied at 4K by CP-MAS NMR. Even at that temperature, the ion was completely symmetrical. Of course, you could still argue Jesuitically that the ion was classical and equilibrating. At 4k the energy barrier is so low to make the distinction between classical and non-classical carbocations purely theological.DQ2: The authors of the present study use low temperatures to freeze out hydride shifts.

Non-classical carbocations look much less strange if you know some borane chemistry (Wade's Rules etc.)

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26. Hap on July 16, 2013 2:51 PM writes...

No, I understood that there were stability reasons to perform the experiments at low T, but I thought they were to stabilize any cationic species and not to stabilize the nonclassical cation over the classical cation. Is there any reason that temperature would selectively stabilize the nonclassical cation over the classical cations if the nonclassical cation were not the more stable cation?

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27. J. Mark Roberts on December 27, 2013 8:48 AM writes...

I did my Ph.D. with Saul Winstein and am responsible for the Bicyclo[4.3.1]decatrienyl carbocation. I watched this ion remain stable up to +80º C. With this crystallographic evidence my mentor would be pleased, I'm sure.

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28. J. Mark Roberts on December 27, 2013 8:50 AM writes...

I did my Ph.D. with Saul Winstein and am responsible for the Bicyclo[4.3.1]decatrienyl carbocation. I watched this ion remain stable up to +80º C. With this crystallographic evidence my mentor would be pleased, I'm sure.

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