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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: derekb.lowe@gmail.com Twitter: Dereklowe

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November 30, 2011

Finding Even More New Reactions By Looking For them

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Posted by Derek

How do you find new reactions? I blogged here in September about a very direct way of doing it, from John Hartwig's lab: set up a bunch of things and see what happens. I liked it very much, but opinions in the comments were mixed. Some people found this approach refreshing, while others found it more simplistic than simple.

Well, get ready for some more, courtesy of the MacMillan group at Princeton. This paper has just come out in Science on reaction discovery, and it takes a very similar approach to "accelerated serendipity". They were looking at photoredox catalysts, which have been used for some interesting studies in the past few years. You mostly see iridium and ruthenium catalysts, with variations of tris-bipyridyl ligands on them, but the variety of reactions that they can initiate is extraordinary.

Clearly, there must be a lot of reactions in this area that haven't even been found, and that's what this latest paper sets out to do:

Assuming that serendipity is governed by probability (and thereafter manageable by statistics), performing a large number of random chemical reactions must increase the chances of realizing a serendipitous outcome. However, the volume of reactions required to achieve serendipity in a repetitive fashion is likely unsuitable for traditional laboratory protocols that use singular experiments. Indeed, several combinatorial strategies have previously been used to identify singular chemical reactions (2–11); however, the use of substrate-tagging methods or large collections of substrate mixtures does not emulate the representative constituents of a traditional chemical reaction. On this basis, we posited that an automated, high-throughput method of reaction setup and execution, along with a rapid gas chromatography–mass spectrometry (GC-MS) assay using National Institute of Standards and Technology (NIST) mass spectral library software, might allow about 1000 random transformations to be performed and analyzed on a daily basis (by one experimentalist). Although we recognized that it is presently impossible to calculate the minimum number of experiments that must be performed to achieve “chance discoveries” on a regular basis, we presumed that 1000 daily experiments would be a substantial starting point.

That it would, and by combining a broad selection of interesting starting materials with several plausible photoredox catalysts, and then basically just letting things rip, they found one. Dicyanobenzene, as it turns out, does a radical coupling with tertiary amines, giving you a direct C-C bond formation route that arylates next to the nitrogen. It's a perfectly believable reaction, but there are a lot of perfectly believable reactions that you could draw in this area that don't actually work.

Looking over the paper, it appears that the more time-consuming parts of the experimental setup were avoiding known chemistry in the starting combinations, and looking over the results to see what was worth following up on in more detail. Those are both human-brainpower intensive tasks; the rest was automated as far as possible. Interestingly, it appears that MacMillan had earlier been trying a very similar approach to that Hartwig paper I blogged about in September, doing reaction discovery with transition metals. But they then switched to photochemistry, thinking that this might be a more wide-open field.

It's not like the reaction dropped out of the robotics fully formed. They saw a new product form with an iridium catalyst, dicyanobenzene, and N,N-dimethylaniline, but further optimization gave better (and more general) conditions. That's as it should be; there's no way (yet) to run enough experiments to both find new reactions and the best ways to run them in one shot. But just getting a whiff of something new and useful is enough, and I don't see any reason not to engage in automated searches for such things.

But from the reaction in the comments here to that Hartwig paper, I gather that not everyone agrees. As far as I can tell, one objection is that famous talented organic chemistry professors shouldn't have to engage in such brute-force exercises. The more elegant way to come up with these things, by this opinion, is to use more brainpower up front, rather than just mixing up a bunch of stuff to see what works. I suppose - not being a famous talented organic chemistry professor, myself - that I'm not so proud. But then, John Hartwig and Dave MacMillan are FTOCPs, and they seem to have swallowed their pride enough to find something new. And good for them!

Comments (45) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Morten G on November 30, 2011 9:15 AM writes...

Pretty much like macromolecular crystallography. Serendipity with a sprinkle of canniness and a lot of optimization (sometimes very little though).

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2. Colm on November 30, 2011 9:43 AM writes...

What is the safety profile of experimentation like this? Granted I am not a chemist in any form, but it seems to me that the sentence:

Assuming that serendipity is governed by probability (and thereafter manageable by statistics), performing a large number of random chemical reactions must increase the chances of realizing a serendipitous outcome.

Could just as easily end 'or an explosion.'

Or are they confining these types of studies to exploring generalized reaction types unlikely to react violently?

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3. Nick K on November 30, 2011 9:56 AM writes...

Colm: The likelihood of an explosion is governed by the difference in enthalpy (delta H) between the products and the reactants. The greater the difference the more exothermic the reaction, and hence the more likely there will be an explosion. The reactions explored in this work probably have small or even negative delta H's, and are thus very unlikely to be explosive.

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4. Curious Wavefunction on November 30, 2011 10:02 AM writes...

Brute force and serendipity are fine. Supramolecular and solid-state chemists have been taking advantage of this approach for a long time - no painstaking bond-by-bond design, just mix in a bunch of chemicals and see what happens. It's time the synthetic chemists learnt from their solid-state brethren.

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5. will on November 30, 2011 10:03 AM writes...

I'm sure that one of the original FTOCPs Sir Robert Robinson would have scoffed at using spectroscopy and crystallization to determine an NP structure in less than a year, when careful degradation studies performed over a decade+ could yield similar information with much greater ~intellectual~ effort

Obviously that's tongue in cheek, but we should remember that the reason we (taxpayers) fund FTOCP is to actually discover stuff, and not simply engage in exercises that make themselves appear intelligent.

Plus, I would imagine this technique would serve a a leaping off point, or lead indentification. I'm sure there's plenty of opportunity to optimize the cyanobenzene catalyst using "conventional" brainpower

I imagine explosions are not much of an issue if the amounts of reagents are kept small (MS-GC analysis requires only a tiny amount of material) and proper shielding/safety precautions are employed

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6. Nick K on November 30, 2011 10:16 AM writes...

Correction to my previous post: exothermic reactions have NEGATIVE delta H's (i.e. they emit heat), so please disregard the the part which says "or even negative delta H's". Apologies.

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7. simpl on November 30, 2011 10:17 AM writes...

Reminds me of the 4-colour theorem. For a purist it is disappointing that a solution took 50 pages and computer grunt insead of elegance. The printer, though, is happy to know that he only need order four inks.
Now, who has a list of reactions waiting for a solution?

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8. Curious Wavefunction on November 30, 2011 10:31 AM writes...

4-color theorem: It's worth noting that two nineteenth century English mathematicians published "elegant" proofs of the theorem that eventually turned out to be wrong. In chemistry as in math, elegance is no guarantee of "truth" (which in chemistry would really correspond to "utility")

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9. luysii on November 30, 2011 10:34 AM writes...

Having plowed through 3/4 of Anslyn and Dougherty, and about to start the chapter on calculational organic chemistry (COC), this sort of experimental work gives me the creeps (about COC). Is it just being used to justify what we already know (post hoc propter hoc), or can it actually predict things? Shouldn't COC have figured out all these newly found reactions?

I have similar misgivings about protein structure prediction -- see http://luysii.wordpress.com/2009/11/29/time-for-the-glass-eye-test-to-be-inserted-into-casp/.

Hopefully all will be revealed before the end of the year. Anslyn and Dougherty have been great so far (except for one chapter)

Pleased to see that MacMillan and Hartwig both have ties to the PU chemistry department.

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10. Folger on November 30, 2011 10:40 AM writes...

One has to wonder how junk like this gets published in any journal much less Science.

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11. old man on November 30, 2011 10:56 AM writes...

This should be viewed as an admission of defeat. Just turn the brain off and let the equipment do the work. This is just like combichem in the pharma industry 10 years ago, and we know how well that worked out.

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12. J.S. Boc on November 30, 2011 11:09 AM writes...

I think part of being an FTOCP is recognizing problems that don't have good and general solutions and coming up with them, elegant or not. I don't see how "accelerated serendipity" can replace that. Nevertheless, I can see its use for discovering some interesting chemistry.

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13. Will on November 30, 2011 11:30 AM writes...

Y Kishi is a FTOCP, but the Ni-Cr coupling was a surrepticious discovery. Much of the apparent low hanging fruit in organic chemistry has been plucked, and nowadays you find groups dedicated to modifying ligands to trivially increase yields of archetypical reactions

If the combi-reaction scheme identifies new trees from which to pluck fruit, I say great. Who cares it didn't come from a dream or whiskey soaked inspiration?

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14. Paul on November 30, 2011 11:50 AM writes...

"Civilization advances by extending the number of important operations which we can perform without thinking about them." -- Alfred North Whitehead

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15. Mr. Fixit on November 30, 2011 12:03 PM writes...

If we step back, this approach is not that different than screening catalysts/ ligands to find out what works for a reaction. Groups have been doing that for years. I am wrong to think this is not that creative an idea?

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16. CMCguy on November 30, 2011 12:07 PM writes...

May be I am taking too literal but always believed Serendipity was more accidental/unexpected observations that provide novel results. Therefore not sure agree is a matter of simply probability and statistics and as others mention this is same trap combichem fell into for drug discovery. On the other hand this does fit well with Louis Pasteur's "Chance favors an open mind" so this would suggest a valid scientific approach. If work produces useful knowledge or better yet new transformation than can do things current chemistries can't or with improvements then may be of value.

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17. Phil on November 30, 2011 12:13 PM writes...

@16: You're absolutely right that this is nothing new. In fact, this kind of high-throughput experimentation (HTE) is already being used at Merck Process and other industrial labs to optimize reactions.

The cool part is the 1000 reactions per day. Hence, the "accelerated" part. Of course, as Derek points out (and what I know from my own experience), running the experiments is no longer the slow step. Analyzing the data becomes rate-limiting, which is fine. Get a computer to analyze the data for you and you go even faster.

Does this paper belong in Science (or Hartwig's for that matter)? I don't think so. The transformation in question isn't paradigm shifting, and the method of HTE is old news. Just because academics started investing money in it doesn't make it the new hotness.

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18. barry on November 30, 2011 12:51 PM writes...

there are more dangers than explosions in such an open-format experimentation. Back in Pittsburgh thirty-odd years ago professor Danishefsky nearly "lost" a grad student who had unwittingly synthesized a potent nerve gas.

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19. Anonymous on November 30, 2011 12:54 PM writes...

This would be Nobel material if the "computer/automation" could establish a new reaction product and optimize the yield without human intervention. Even better if CADD could also be enlisted in the predetermination of the substrate(s)/catalyst(s) process to narrow the field of possible reactions.
Let's see if the old way of optimization via numerous screening reactions by an exploited grad student will become obsolete in the future. I have always believed that it is a matter of time before the experimental organic chemist will become a relic as well!

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20. Curious Wavefunction on November 30, 2011 1:05 PM writes...

Anon: It's going to be a long time before CADD can measurably contribute to accurate prediction in this kind of situation. If you consider the myriad starting materials, products, metals, catalysts and solvent interactions, it basically translates to a many-body problem in which differences of a tenth of a kcal/mol or a hundredth of an angstrom in bond length can tip the scales. We are still far from being able to model the accurate solvation even of a simple arbitrary molecule in water. CADD could start contributing significantly at some point but for now, trial and error combined with semi-rational optimization is probably going to be more efficient than any computing power you throw at the problem.

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21. cynical1 on November 30, 2011 1:25 PM writes...

I think a better title for this post would have been "Even a blind squirrel finds a nut once in a while".

I'll think about this research the next time I see someone using their welfare check to buy lottery tickets.

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22. Bored with this on November 30, 2011 1:54 PM writes...

As with the Hartwig paper, the difficult step in these reactions is not the reaction itself, but the deconvalution process necessary to determine if an interesting/relevant process had occurred. It is truly dissappointing that chemistry has moved towards the kitchen sink approach. One hopes that we will start to use our brain again to actually "invent" interesting and novel reactions that truly benefit the field. This paper demonstrates that anything can be published in Science.

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23. Anonymous on November 30, 2011 2:06 PM writes...

Reminds me of the 4-colour theorem. For a purist it is disappointing that a solution took 50 pages and computer grunt insead of elegance. The printer, though, is happy to know that he only need order four inks.

I doubt printers care. :)

The evolution of the proof of the 4CT in the decades since its was discovered is interesting. It's been simplified substantially. Also, while it's still computer generated, it's now been done in a way that generates a computer-verifiable proof. The verifier for this proof is an entirely separate piece of software. This gives great confidence that the proof actually is correct, even if it's large and difficult for a person to verify.

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24. MoMo on November 30, 2011 2:41 PM writes...

Reminds of a bear we once trapped in VT, except it wasn't a bear-it was a St.Bernard!

Molecules are the same way, drawn in 2-D by mere humans. Only the molecule knows what it is and how it will react.

We darted the dog anyway and sent him home with a radio-collar! LOL

Silly chemists! Molecules are smarter than you!

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25. Paul on November 30, 2011 4:00 PM writes...

There is an interesting parallel to this topic in software engineering, specifically in software testing. The books on software testing will emphasize methodical, rationally designed construction of suites of test cases. But in practice, simple techniques that just bombard a program with huge numbers of randomly generated inputs can be unreasonably effective at finding bugs.

This is important, because this kind of "fuzz testing" is used by hackers to find security holes in commercial software.

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26. tyr on November 30, 2011 4:51 PM writes...

Shame on Science for publishing this garbage. There are plenty of great papers that really push the field forward and solve real problems (often they are in JACS and Angew). This isn't one of them.

Someone should investigate Jake Yeston (chemistry editor according to the website) and the other goons at Science that keep letting papers like this in.

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27. Nick K on November 30, 2011 5:26 PM writes...

One very FTOCP who actually DID invent new reactions was the late DHR Barton. The reactions he invented (quite rationally and non-serendipitously) include the double-extrusion synthesis of hindered alkenes, remote functionalisation, radical deoxygenation and so on. These are valuable and important reactions, and not one of them could possibly have been discovered by this combinatorial method.

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28. SCM on November 30, 2011 5:44 PM writes...

Interesting approach, I haven't read Hartwig & Robbins' paper yet, it will be interesting how the two compare.

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29. Hap on November 30, 2011 6:07 PM writes...

If these reactions were so damn obvious, why didn't anyone find them before? It seems that if we knew enough to generate new reactions consistently out of our knowledge, we'd be doing better than we do.

I don't think it's reasonable to throw away our chemical knowledge, but if combinatorial reaction discovery gets you reactions you didn't find rationally, that seems both notable and useful. The assumption that we know everything and so should just start creating reactions out of that knowledge seems at massive odds with what chemists have actually done. Maybe (this is a shocker) we don't know everything yet.

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30. exGlaxoid on November 30, 2011 6:18 PM writes...

I don't see how the brute force, screening approach for chemical reactions is any different than the natural products screenings that yielded many of our antibiotics, anti-cancer drugs, and countless other medicines.

People like to criticize using serendipity to find knowledge as a lazy practice, but I think using what tools you have to solve your problems the most efficient way is always good.

I hear people complain about combinatorial chemistry, which was certainly oversold and misused in many companies, but it is appropriate for some problems. It also helped to bring about solid-supported reagents, parallel synthesis tools, DOE for chemical development, and better chemical structure/reaction databases in the areas I worked. I think any approach can be useful if the person applying it is aware of multiple approaches and can apply the best one.

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31. Anonymous on November 30, 2011 8:35 PM writes...

The more you admit that you really don't know what you are doing, the more you learn and discover.

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32. tired of hype on November 30, 2011 8:52 PM writes...

29-31 are completely missing the point. No one is arguing that random screening doesn't have its place. These papers are exercises in how far over sales pitches can go. What other obvious things can be renamed and repackaged? Is there anyone that can really say they learned something new?

The question is how this set of obvious papers gets into a journal like Science. the chemistry community should be outraged. Is THIS the best our field can do? Does this represent it?

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33. anonymous on November 30, 2011 9:43 PM writes...

Being a famous prof in the first place helps enormously to get this type of paper published in Science. An assistant prof would never get this accepted unless one of the reviewers was...his/her famous prof graduate or post doc advisor and wants to champion the protege's fledgling career. Better yet -- both famous prof mentors as reviewers.

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34. Iridium on December 1, 2011 2:14 AM writes...

Reaction is new and interesting.
The optimization is well done.
It deserve a very good publication.

It is also fine to screen "random" reactants.
People claiming that it is wrong has never been in a chemistry lab where new reactions are developed. Half of the students mix impossible reagent hoping that a miracles happens.

HOWEVER...
The "concept" accelerated serendipity is just a publicity stunt to get cited more. Authors oversell it.
Many people done it before (David Liu from harvard is another one just a couple of years back). Many people will do it again. To use a machine is not a revolution. Just a very smart application of known technologies.

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35. Eric Robert Jablow on December 1, 2011 7:34 AM writes...

Simpl,

The 4 in "4-color theorem" is not the 4 in "4 printer inks". Color printers need 4 inks because humans perceive colors in a way that demands it. The 4-color theorem is a matter of graph theory and topology, and there is no connection with any particular colors at all.

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36. ProteinChemist on December 1, 2011 10:01 AM writes...

It seems to me that this is a modern application of early organic chemistry. The dye syntheses started out as a basic compound modified ad infinitum to see what happened. They had no idea what the end product would be, and the modifications were developed on the fly with guesswork. Since that approach led to modern drug chemistry, I would think that a way to modernize it would be welcome.

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37. Molecule on December 1, 2011 10:18 AM writes...

I have no objection to any one finding new things this way but is it worth a publication in Science? IMHO its not!! Also, when coworkers are getting cheaply available, one can increase the probability of serendipitous discoveries! Go ahead and good luck!!BUT Science and Nature, at least keep your reputation intact!!

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38. Anonymous on December 1, 2011 10:30 AM writes...

Iridium has this spot oon. it's nice chemistry but the "acceerated serendipity" thing is just a pitch to get it into Science or Nature rather than JACS or Angew.

Kind of sad in a way that organic chemists have to resort to such pitches but that's the way it is.

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39. EC on December 1, 2011 5:30 PM writes...

My two cents on this.

1. This paper (or "accelerated serendipity", as a fancy name for what really amounts to "combinatorial approach to reaction discovery") hasn't solved any important problem in organic chemistry. Nor does it look like it ever will. Rather, it MAY allow one to find some reactions which nobody would have cared to look for. I'd be curious to see just how much money was already poured into this project in order to find out what is published in this manuscript.

2. If 200 years of Organic Chemistry have served to come up with this idea as a "state-of-the-art" methodology in synthesis, then I have to say that these are strange times indeed.

3. The approach itself is anything but novel. Industry has been doing this for YEARS now. But just not calling it "accelerated serendipity".

4. The reaction itself is another example of "exceptional" peer-review. A transformation which uses 3 EQUIVALENTS of the amine component (despite being marketed as a nice method for late-stage derivatisation of drugs or natural products). The limiting reagent is actually the aryl cyanide. I guess none of the reviewers cared to read the Supporting Info (since the manuscript itself seems to ommit this fact from every single scheme). Bummer.

5. As #26 suggested, there is something interesting about such a paper being accepted for publication nearly 1 month after submission. Talk about fast turnaround times for a journal which is typically much, much slower. Sounds to me like Science is after manuscripts that can generate nice headlines in news outlets rather than scientifically original and innovative work.

6. If one day some funding agency decides that it's time to shut down funding for classical methodology development in organic chemistry, I guess that they can cite this paper as a perfectly sound argument. After all, we organic chemists are telling the world that you can discover reactions much faster (a 1000 reactions a day! and serendipitous moments essentially every week) and apparently come up with transformations that are way more exciting, if we just stop doing reactions the good old way and give our compounds to robots. And it got published in the prime scientific journal of our time.

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40. Paul on December 1, 2011 8:06 PM writes...

As #26 suggested, there is something interesting about such a paper being accepted for publication nearly 1 month after submission. Talk about fast turnaround times for a journal which is typically much, much slower.

What you do is write 1000 papers, and submit them in parallel...

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41. Aspirin on December 1, 2011 9:10 PM writes...

It's also interesting to see how the number of methodology and total synthesis (basically, hard core organic synthesis) papers published in Nature and Science has gone up in the last few years. While most of them were decent studies, very few of them deserved to be in Nature or Science. This is another one.

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42. Kaleberg on December 3, 2011 11:40 AM writes...

I read the article in Science and it was only remarkable in giving a vision of how chemistry could be done in the future, that is, a view of how things might be done. Why explore reactions one at a time? Why not just perform a raft of them and see where it takes one?

This approach has revolutionized mathematics. Exploratory computations are often used to develop and guide the development of insight, rather than "pure reason".

It has revolutionized biology. No one thinks twice about applying some biological stress and doing 3,000 protein activity assays on the results.

There is no reason it cannot revolutionize chemistry. I can imagine chemists using systems like this to explore reaction spaces much more broadly and efficiently than any one at a time reaction approach.

In many ways it is not a big change, but it relies on increased computer power and the development of supporting laboratory equipment. Anyone who worked in a biology lab 30 years ago, can't help but notice the changes in available equipment and approaches. Now, they are building entire reaction sequencing systems to reduce the ratio of scut work to brain work in the field. I'd be surprised if we don't see similar changes in chemistry labs over the next few decades.

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43. EC on December 5, 2011 5:02 AM writes...

#42
I see nothing wrong in using combinatorial approaches to optimising and developing reactions. There's a bunch of tools available to do that and Scott Denmark actually pioneers their use.

What I find funny is using the machine as *a replacement* for your creative mind. Can't come up with any ideas for research projects? Then just spend a few million bucks on a system that will randomly mix compounds for you and look at what you get.

The future intro to NIH, NSF and other grant proposals will now sound more like:

"Having figured out, by pure combinatorial mathematics, that mixing compounds A and B in solvent C actually gives product D, we decided to explore this unexpected, unprecedented reaction that nobody cares about"
hilarious!

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44. Re: Kaleberg on December 5, 2011 5:02 AM writes...

Screening 3000 protein activity and finding one hit (even extraordinary) will not put your results on Science and Nature pages. Its not about this way of finding reactions, that is fine, but is that upto the standards of Science and Nature?

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45. Tyrosine on December 11, 2011 4:11 AM writes...

I attended a lecture by Barry Trost (a FTOCP for sure) last week and he was scathing about this type of "research" in academia. His opinion was that screening is generally appropriate for industry looking for a solution, as in drug discovery or processing optimization, but that to do so in academic organic chemistry was intellectually lazy. Also a poor example for students to be involved in discovery by essentially thoughtless brute force. Trost didn't mention Hartwig or MacMillan by name, but then he didn't have to.

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