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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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August 20, 2012

Enzymes, Nanotech, and Picky, Picky Details

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Posted by Derek

The controversy I wrote about last week, about whether (some) enzymes work by using extremely fast movements (rather than by putting things into their place and letting them do their thing) may remind some folks of the supposed medieval arguments about angels dancing on the heads of pins. But it also reminds me a bit of some other arguments in organic chemistry over the years. The horrible prototype is, of course, the norbornyl cation.

There was a time when people would simply leave the room when that topic came up, because they knew that they were in for another round of fruitless wrangling. Was its structure that of two rapidly interconverting standard carbocations, or a single bridged "non-classical" one that broke the previously accepted rules? George Olah and H. C. Brown, Nobel laureates both, were on opposite sides of that one, but every physical organic chemist from about 1950 to about 1980 probably had to take a stand one way or the other. (It is commonly accepted that Olah's side won), but the arguments got pretty esoteric by the end. Update: the battle was first joined by Saul Winstein, who did not live to see his proposal vindicated by Olah's spectroscopic studies).

Another one, which came along a few years later, was the "synchronous / asynchronous" mechanism of the Diels-Alder reaction. Do the new bonds in that one form at the same time, or does one form, and then the other? That one involved the physical organic people again, as well as plenty of computational chemists. I stopped following the debate after a while, but I believe that the final reckoning was that most standard Diels-Alder reactions were synchronous, within the limits of detection, but that messing with the electron density of the two reactants could easily push the reaction into asynchronous (or flat-out stepwise) territory.

So why does this level of detail matter? The problem is, chemistry is all about things like bond formation and bond breaking, and about interactions between individual molecules (and parts of molecules) that change the energies of the systems involved. And those things are nothing but picky details, all the way down. Thermodynamics, which runs chemical reactions and runs the rest of the universe, is the most rigorous branch of accounting there is. Totaling up those energies to see which side of the ledger wins out can easily involve the fate of single water molecules, or even to single protons, and you don't get much pickier than that.

This sort of thing is one argument used against the feasibility of molecular nanotechnology. How are we to harness such fine distinctions, at such levels? But it's worth remembering that we ourselves, and every other living creature, are nanotech machines at heart. Our enzymes are constantly breaking bonds, twisting single molecules, altering reaction rates, and generating specific, defined molecular products. If they weren't, we'd fall right over. We eventually fall over anyway, because none of these machines work perfectly. But they work pretty well, and they make our own chemical efforts look like stone axes and deer-bone hammers.

So we may find getting down to this level of things to be a lot of work, and hard to understand, and frustrating to deal with. But that's where we're going to have to be if we're ever going to do real chemistry, the kind that's that's indistinguishable from magic.

Comments (16) + TrackBacks (0) | Category: Chemical News


1. anchor on August 20, 2012 9:26 AM writes...

Derek: Why repeat paragraphs? To hit the point home twice?

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2. luysii on August 20, 2012 9:33 AM writes...

Ken Houk has a computational article on Diels Alder in the latest PNAS (vol. 109 pp. 12869 12865 '12, 7 August) that I have -- the mails around here being terrible.

Assuming you trust UB3LYP/6-31G(d) to calculate trajectories, bond formation doesn't occur at the same time. However, the time difference between bond formation (femtoSeconds) is shorter than a C - C vibrational period so essentially bond formation is simultaneous.

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3. RB Woodweird on August 20, 2012 9:39 AM writes...

When I was very young I found and began to read an old copy of a Bobbsey Twins "adventure" which had been misprinted so that some chapters were missing and some chapters were repeated, but the chapter numbering was continuous. It was like some absurdist novelization of Memento but with curly-haired chubby children. I was so young that I trusted absolutely that books were inviolate, so that this twisting of time and space must have contained some meaning I was still too young to comprehend.

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4. Will on August 20, 2012 9:50 AM writes...

another one that came along as i was in grad school was the osmium dihydroxylation mech question, pitting another two nobelists, ECJ and K Sharpless against each other

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5. NanoFab on August 20, 2012 10:15 AM writes...

This is an interesting article. Machine-Phase Chemistry mechanosynthetic chemistry is definitely possible as we see it in nature and see no chemical laws that contradict it.

Enzymes as you show are mechanochemical machines as are other devices in biology. Soon we will be able to assemble atoms and molecules industrially in a pre-ordered fashion, using enzyme like devices and molecular assembly. We will make long diamond fibers and atomic precision ceramics, metals and polymers and lots and lots and LOTS of graphene and fullerenes, in any shape we want, from the nano to mega level.

Check out and

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6. Curious Wavefunction on August 20, 2012 10:24 AM writes...

Then there was the controversy between Firestone and Huisgen over whether dipolar cycloadditions are concerted or stepwise.

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7. Curious Wavefunction on August 20, 2012 10:29 AM writes...

Forgot to mention this in the earlier comment; as you no doubt must be aware, H C Brown's principal antagonist in the non-classical ion debate was not Olah but Saul Winstein; Olah "merely" put the nails in the coffin. Some even say that the stress shortened Winstein's life.

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8. anon the II on August 20, 2012 11:10 AM writes...

I always thought it was Martin Saunders, with that 13C perturbation stuff, who put the norbornyl cation to rest. In Winstein's favor, of course.

read here

Wikipedia doesn't mention Saunders contribution.

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9. Chemjobber on August 20, 2012 11:26 AM writes...

Winstein on H.C. Brown: "That man is nothing but a shyster lawyer."

Them's fightin' words!

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10. David Formerly Known as a Chemist on August 20, 2012 11:47 AM writes...

This takes me back to my graduate school days, where me and a few of my nerdy friends would sit around and discuss such fine points over a few pitchers of beer (and we wonder why scientists are often depicted as being slightly askew). Now, 20-some odd years later, these fine points seem somewhat quaint considering I haven't thought about them since, and these sorts of questions never come up when asking "why didn't the drug candidate work in human trials when it was so damned impressive in the animal models", or "why won't those shortsighted VCs fund my idea". This is esoteric subject matter indeed and unfortunately representative of "deep" conversations I had in my idealistic youth, back when I still believed I had a chance to develop a reaction that would be named after me, or that my thesis would actually be read and appreciated by someone! Bringing up such topics at parties is the perfect buzzkill, up there with your nasty hemorrhoid or the weekend you found god.

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11. Nicko on August 20, 2012 5:27 PM writes...

stone axe is kind of harsh... I'd say at least an atlatl

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12. Dave on August 20, 2012 5:30 PM writes...

Is the following link nonsense? It seems to be claiming a holy grail:

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13. Anonymous BMS Researcher on August 20, 2012 9:12 PM writes...

I was at Purdue when HC Brown got his Nobel.

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14. Sisyphus on August 20, 2012 10:16 PM writes...

All that matters now is how many compounds you made last week or how many reaction you ran or how many times you republished the same material during a PhD career. Science is dead. Vorsprung durch Technik.

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15. Myma on August 21, 2012 11:22 AM writes...

Chemistry, when it comes down to it, is all about a small handful of principles: entropy and enthalpy; steric hindrance; orbitals and electron densities.

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16. Tom Kolesar on October 15, 2012 9:31 AM writes...

On and off for some time I have been searching for an article written by H. C. Brown about the non-classical carbonium ion controversy. He wrote an article for one of those free magazines, I believe it was American Laboratory. Although Brown had a definite viewpoint he presented the arguments in what Fox News would now call a “fair and balanced debate.” Finally he summed up the reason for the controversery . (This is how I remember, more or less, the summation.) “George Olah and Saul Winstein live in Los Angeles. When they look up to the heavens to discern the structure of the norbornyl cation, the fog and smog of LA obscures their view. I however live in the mid-West . Here the skies are clear. We can definitely see there are no dotted lines in the structure.”

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