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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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October 6, 2010

A Nobel For Palladium Couplings, At Last

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Posted by Derek

So, a chemistry Nobel that's just pure chemistry from top to bottom. I'll be darned! This is one that most chemists had on the list of "Worth a prize, but who knows if they'll ever get around to it". (If you check my archives, and those of the other chem-bloggers, you'll see palladium couplings mentioned every time).

One of the sticking points has been who to put on the prize, what with the three-name limit and all. Were Stille alive, he might well be on there instead of Negishi, but that just highlights the trickiness of this area. There are plenty of other people, starting, most likely, with Sonogashira, who have made major contributions in this area. I notice that some people are wondering about Buchwald and Hartwig et al., but that (to me) is a separate issue. This is a prize for carbon-carbon bond formation; carbon-nitrogen can wait its turn.

But as a chemistry prize, I think everyone can agree that palladium-catalyzed C-C bond formation is worthy. Such reactions are the single biggest change to the practice of synthesis since my grad school days. In the mid-1980s, palladium reactions were looked on as being a bit weird, and I hardly knew anyone who'd run one. I didn't have occasion to, myself, until something like 1992. By that time these reactions were well on their way to conquering the world. It's gotten to the point now where some industrial drug discovery organizations have jokingly considered banning the things for a period. They're so useful that the sorts of structures that are easy to make through them tend to get over-represented in drug screening files.

For non-chemists, the reason these things are so well used is that carbon-carbon bonds are both the backbone of organic molecules, and a pain in the rear to make and break. They're pretty solid, but not so solid that they can't be worked with under special conditions, which is why they're so useful for both living systems and for synthetic chemists. A carbon framework is like solid steel construction: very durable and hard to destroy, but if you know how to weld or rivet you can make one yourself. These palladium reactions are the equivalent of riveting; using them, we can stick whole carbon units together as if we were using power tools.

So in honor of today's prize, folks, go run yourself a Heck, Suzuki, or Negishi coupling. They'll probably work; they generally do.

Comments (51) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Anon on October 6, 2010 11:28 AM writes...

Gotta give Stille his props. If his life hadn't been cut so tragically short we would argue about who the "deserving fourth" was that was left out. Maybe make a case for Sonogashira, Kumada, etc., but the committee seems to have chosen wisely this time. Plus they chose actual chemists for doing chemistry.

A bigger mystery to me is why the Pd cross-coupling prize lagged by several years behind olefin metathesis. Heck, Negishi, and Suzuki are all quite fossilized at this point, whereas Grubbs et al. have many years ahead of them. Not understating the importance of metathesis, just thought this one would have come sooner. A lot sooner.

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2. J-bone on October 6, 2010 11:33 AM writes...

It's entirely surprising to me that Heck had to quit doing research for lack of funding. Although there is an article in FASEB analyzing funding sources for various Nobel Laureates' research and several of those projects were also unfunded.

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3. labchmst on October 6, 2010 11:45 AM writes...

A well deserved award. I'm curious what any of you think about the fact that neither Heck nor Negishi are members of USA's National Academy of Sciences. Isn't that kind of like winning the Cy Young Award but not making the All Star Team?

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4. jtd7 on October 6, 2010 11:57 AM writes...

I'll bet their palladium was contaminated with palladium.

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5. hi on October 6, 2010 12:08 PM writes...

Go Purdue!

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6. KC Nicolaou on October 6, 2010 12:08 PM writes...

Damn it.

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7. Anonymous on October 6, 2010 12:41 PM writes...

@6 ROFL Maybe publishing maititoxin will finally get you there...

No, seriously, today everyone in our lab walked around cheering in excitement for this good old-fashion chemical nobel in chemistry.

Ribosome, eat my shorts... Come back when you can insert in labile bonds.

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8. BioGuy on October 6, 2010 1:14 PM writes...

'Ribosome, eat my shorts... Come back when you can insert in labile bonds'

Palladium, man up...come back when you can bring together a symphony of two dozen proteins to synthesize others.

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9. InfMP on October 6, 2010 1:17 PM writes...

Heck losing his funding might have to do with wacky ideas.
He routinely mails letters from the Philippines to a certain Prof asking him to try out some of his different ideas. Apparently they are pretty strange (Cobalt etc) and he wouldn't have the time to try all of them even if he wanted to. I think that its really great he still thinks and cares about Chemistry though - I can't wait to hear his speech in Dec. online.

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10. AlchemistOrganique on October 6, 2010 1:21 PM writes...

@3: It's great that NAS membership is not a prerequisite for getting the Nobel Prize. The award should be given solely on the basis of scientific merit, not one's societal status. I do feel bad for Doug Prasher though, the PhD Biochemist turned truck driver who actually sequenced the GFP gene.

On a slightly tangential topic, I wonder if this year's peace prize will be controversial.

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11. Chemjobber on October 6, 2010 1:26 PM writes...

Prasher drives (drove?) a shuttle bus for an auto dealer in Huntington, AL.

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12. AuCuPdRu on October 6, 2010 1:45 PM writes...

for once since a long time, the committee has well chose the recepients ...
maybe the influence of JE Backvall ??
compares to all these nobel runners ... these 3 great researchers are very humble men ...
I am happy that they do not mix this prize with less importants cross couplings as the Trost-Tsuji, Hiyama, Buchwald-Hartwig ...
for CN couplings, I predict Cu catalysts instead of Pd in 10-20 years
Nevertheless, I am so happy and excited to work in the fiel of homogeneous catalysis : 3 nobel prize these last 9 years !!!
PS : KCN has to keep writing review for nobel recipients ... as his 2 reviews in ACIE on metathesis and Pd-cat ... carry on KCN

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13. John on October 6, 2010 1:45 PM writes...

The article from FASEB is really enlightening. Makes one think about the trend towards building new research institutes and filling it with people working only on soft money. If you're a grant away from being able to support your family with 10+ years of education you're gonna write a grant with the goal of getting funded, not with the goal of doing truly innovative and interesting work.

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14. OrgSynPreppie on October 6, 2010 1:54 PM writes...

Just did a Wikipedia on Prasher...what a depressing story! I'm glad that Tsien and the other awardees actually brought Prasher to the ceremony and publicly acknowledged his pivotal efforts. Still, it sucks to read about the funding problems that Prasher and Heck encountered later in their scientific careers while other profs get tons of research grants for turning out clunky total syntheses and devising yet another (gag) variant of the aldol or Diels-Alder...what bullsh*t!!!

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15. Marcus on October 6, 2010 2:41 PM writes...

Glad to see Real Deserving Folks finally get the recognition they deserve. In the words of the fictitious Chuck Nolan, "Time rules over us without mercy. Not caring if we're healthy or ill. Hungry or drunk. Russian, American, beings from Mars. . . we live or we die by the clock".
Now they can actually clock out without being cheated.

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16. Wavefunction on October 6, 2010 2:45 PM writes...

I'm glad that Tsien and the other awardees actually brought Prasher to the ceremony and publicly acknowledged his pivotal efforts

And then he went back to driving the shuttle bus?

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17. Pallas Renatus on October 6, 2010 3:08 PM writes...

'And then he went back to driving the shuttle bus?'

I do hope not. The prize money alone, split 4 ways, would have given him a few years' decent salary. I'd have at least felt the need to give him *something* more than a free ride to the awards.

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18. F. Sonogashira on October 6, 2010 3:10 PM writes...

Bullsh*t!

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19. small but perfectly formed on October 6, 2010 3:26 PM writes...

There is absolutely no doubt at all in my mind that if Stille were still alive he would have won 1/3 of the prize with Heck and Suzuki. Sorry Negishi.

Nothing against Negishi personally, nothing at all, but the Zn couplings just haven't achieved the same results as the other three at all (at least not in my mind).

Stille couplings, although always described as 'dirty' because of the tin residues, are a true workhorse. If I'd been through a thirty step synthesis and needed the Pd step close to the end to work at all costs then I'd go with Stille every time.

Probably just how it's turned out for me in my research career, but I always say to chemists younger than me that if their mortgage is hanging on success of a late step, then go with tin as it will always couple ... (famous last words there I know !!!)

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20. HK on October 6, 2010 3:38 PM writes...

Prof in my department pointed out how much of a pioneer Heck was in this field. Building off the Wacker process, pioneering the Sonogashira reaction (Sonogashira's contribution was to make cuprates), and not getting a lot of attention for it at the time. It's great that he's getting recognition for it now, but his award, especially, was a long time in coming.

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21. Anonymous on October 6, 2010 3:41 PM writes...

F. Sonogashira on October 6, 2010 3:10 PM writes...

Bullsh*t!

I lol'd

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22. @small but perfectly formed on October 6, 2010 3:47 PM writes...

Gotta admit, Negishi's enthusiasm for ZACA(!) is entertaining. Sonicating Rieke zinc is a pain in the ass though, and so is titrating tBuLi. Why no love for Sonogashira?

Permalink to Comment

23. GKA on October 6, 2010 3:51 PM writes...

@19

To think of Negishi's contribution as only being the reaction which carries his name would be unfair. His screening of various organometallics (including comp. with Zr, Zn, B, Sn, Al) predates both the Stille- and Suzuki-coupling. On a more humorous note: Negishi has never failed me. Stille and Suzuki, on the other hand... :-P

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24. AlchemistOrganique on October 6, 2010 3:54 PM writes...

@22: Because Castro and Stephens already laid the groundwork. Dude, Glaser did copper-alkyne coupling in the late 19th century!

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25. David Formerly Known as a Chemist on October 6, 2010 3:55 PM writes...

This is a well deserved prize. These methodologies revolutionized synthetic chemistry, and vastly expanded the universe of readily achievable target molecules. I did my first palladium-catalyzed cross coupling in 1992, and was hooked on it thereafter. After using cross-coupling to prepare hundreds of synthetic analogues at medchem scale, and to scale up APIs to the hundreds of kilograms, I have the utmost respect and gratitude for the worthy chemists that developed these methods. Kudos!

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26. Large and deformed on October 6, 2010 4:08 PM writes...

@19: Exactly what bodily feature is your monicker describing? On a more serious note, I like the Stille rxn but have been losing intermediates to protodestannylation on normal-phase silica. Any recommended quick fixes?

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27. small but perfectly formed on October 6, 2010 4:24 PM writes...

@ 22 : Nothing against Sonagashira either ... but using TWO precious/coinage metals (Pd & Cu) ... not exactly cheating, but then not exactly cricket either ;-)

@23 : Perhaps ... but according to Backvall in the Announcement address video, Negishi was recognised for the Zn work ... and who am I to argue !!!

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28. Tin man on October 6, 2010 4:26 PM writes...

@26: 0.5-1% triethylamine in the eluent or use neutral (or basic) alumina instead of silica. The latter requires some care as older batches of alumina tend to absorb ambient moisture and may change the elution time of your compound (as compared to fresh material).

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29. Large and deformed on October 6, 2010 4:39 PM writes...

@28 Tin Man: Thanks dude! The TEA deactivation has been hit or miss for me, but we definitely have some alumina.

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30. Chemjobber on October 6, 2010 4:55 PM writes...

When the GFP award came out, I remember a thread where people were bemoaning the fate of Prasher; then, on that same thread, a representative of a mid-tier medical school cancer center commented that 1) did anyone have an e-mail for him and 2) they would like to hire him.

I sure hope something came of that.

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31. small but perfectly formed on October 6, 2010 5:11 PM writes...

@26 : Which bodily feature does my name describe ??? Whichever you find most amusing, but it's most DEFINITELY not my beer belly.

No, actually I post under this name because these days I work with fragments.

Some tin tips : If you've a low molecular weight stannane (i.e. often oily and relatively volatile), then believe it or not, a Kugelruhr can often be your best friend. Otherwise flush your column with polar solvent first (this seems to remove a fair bit of the offending water) and then re-flush with plenty of petrol or hexane prior to loading your compound. The amount of 'added' water (i.e. added by the suppliers) in the acidic silica is what usually controls degree of separation (more water = stronger adsorption). You don't exactly need a lot of polarity in your eluent (nor water in your silica) to clean up most stannanes. Not claiming 100% success, but it seems to work for me ... but then of course, as you've already noted, I'm perfectly formed. ;-)

Hope this is of help to you.

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32. Norepi on October 6, 2010 5:29 PM writes...

@ #5 - YES!

I heard Negishi speak on the steps of the Wetherill Building two hours ago and I'm giving a poster at his lecture series on Monday. He's truly a remarkable individual and is well-deserving of the award.

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33. Large and Deformed on October 6, 2010 6:14 PM writes...

@31: Thanks for the purification advice and the relatively wholesome innuendo. I think I'll stick to chromatography in the fume hood. While I like the reactivity profile of organostannanes in cross coupling, my labmates and I aren't so fond of the smell. I like vegetables, so I wouldn't want to develop an aversion to green peppers!

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34. josie on October 6, 2010 6:18 PM writes...

I'm going home, warm some sake on top of the wood stove, and drink to 3 very deserving chemists. Finally! A real chemistry award.

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35. @30 Chemjobber on October 6, 2010 6:25 PM writes...

Google-stalking brings up a LinkedIn profile for Douglas Prasher as a Research Scientist at Streamline Automation in Huntsville, AL. He only has 6 connections! I hope he's not being standoffish. If anything, I would expect him to get tons of invites especially after the greater scientific community became aware of his harrowing story. Well, I'm glad that he didn't end up like Rosalind Franklin.

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36. Anon on October 6, 2010 6:48 PM writes...

Hail, Hail to Old Ei-Chi Negishi!!!

If I would have known I was studying CHEM 117 under a Nobel laureate those years ago, I would have paid more attention during lecture.

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37. Anonymous BMS Researcher on October 6, 2010 7:08 PM writes...

Go Purdue indeed, one of my degrees is from there! This is the third time a Purdue prof got a Nobel.

http://www.purdue.edu/newsroom/research/2010/101006NegishiNobel.html

Permalink to Comment

38. HealthyCynic on October 6, 2010 7:13 PM writes...

I remembered reading this article last year about Prasher:

http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2009_02_13/caredit.a0900021

Two particular passages struck a cord in me:

(Besides heaping immense accolades on a small number of champions, tournament markets share another feature. They constantly discard huge amounts of very high-quality talent, training, and skill. All the aspiring varsity quarterbacks who don't make the NFL, all the young scientists who come very close to tenure, are cast aside. Prasher differs from an unknown--but undoubtedly very large--number of other highly able former researchers not in that he is necessarily vastly more brilliant than they are (or vastly less brilliant than the three GFP laureates) but in the twist of fate that brought his situation into public view. In the mythic version, science rewards effort and ability, so Prasher's predicament must be some inexplicable mistake. In the real world, casting off large numbers of extremely capable people is no anomaly but simply how a tournament market works...

He is currently exploring options for getting back to research and is open to other offers. His extensive accomplishments, however, have not protected him from the prejudices of at least some other scientists. After a "a great interview" with one potential employer who "knew my scientific history," he recalls, "I thought I had the job because he said, 'All I have to do is okay this with management.' But on the way out, he walked me to the door and asked me, 'What have you been doing since you were in science?' And I told him. He gave me this funny look and I think right then he decided, that was it.")

While so many of us complain about our grad school/postdoc/job and are finding ways to leave science, here is a guy who has been ROYALLY and REPEATEDLY screwed over by the scientific community yet has an honest desire to return to research. Cheers to the perseverance of Prasher as well as this year's Chemistry Laureates! May their stories inspire us all, even when the yield and diastereoselectivity are crappy and some jackass screws up the NMR shims!

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39. cliffintokyo on October 6, 2010 7:27 PM writes...

So happy to see a Nobel for real chemistry.
Great boost, both for chemistry research in Japan and the importance of organometallics for C-C bond formation; right up there with Grignards.
Congratulations to the recipients, and sympathy for those left out by the *rule-of-three*

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40. Chemjobber on October 6, 2010 8:15 PM writes...

" Cheers to the perseverance of Prasher as well as this year's Chemistry Laureates! May their stories inspire us all, even when the yield and diastereoselectivity are crappy and some jackass screws up the NMR shims!"

Amen to that.

Permalink to Comment

41. Zak on October 6, 2010 8:35 PM writes...

Here in Japan the news is all over the TV and newspapers that two Japanese chemists have won the Nobel. In countries other than the US, where it's much more common, winning the Nobel is something the entire country beams with pride at. It's kind of cute, actually.

I wonder why Japanese chemists seem to be especially active in this field....

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42. confused on October 6, 2010 8:37 PM writes...

So which of the three winners is the crystallographer?

@26. Why purify? Carry on crude.

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43. cynical1 on October 6, 2010 8:55 PM writes...

Forget Purdue............Go Blue Hens!

I remember talking to Heck about my undergraduate research back in 84-85, which was on homogeneous Pd catalysis under Taber. Little did I know that my advisor had told me to go down the hall and chat with a future Nobel Laureate. I feel pretty sure that Heck knew the converse was not true but he didn't make me feel like it. He seemed like a really decent guy.

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44. Anonymous on October 7, 2010 1:10 AM writes...

@8 Sure, the proteins/ribosome are impressive, but that's nature doing it, and not man. So why give a prize to man? Just for finding out how it looks? You can no longer compare the novelty of DNA-structure 50-60 years ago, with the ribosome structure now.
Than I find this prize more just, as it rewards all the people who came up with and developed this.

Permalink to Comment

45. Aspirin on October 7, 2010 8:41 AM writes...

By that token you can say that palladium already existed in nature, somebody just used it. The ribosome prize is foremost one for perseverance. The importance is obvious, it's really about who gets there first.

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46. Nick K on October 7, 2010 9:44 AM writes...

This year's Nobel is wonderful news for organic chemistry, but when is the great Rolf Huisgen going to get his prize? It's long overdue!

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47. @Nick K on October 7, 2010 10:39 AM writes...

Hopefully before he joins the extra-emeritus faculty category. Too bad that loon Sharpless gets the most current press for 1,3-dipolar cycloadditions.

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48. Anonymous on October 9, 2010 3:21 PM writes...

#11 "Still, it sucks to read about the funding problems that Prasher and Heck encountered later in their scientific careers while other profs get tons of research grants..."

I disagree. The much more common problem is for a young scientist to do brilliant work; start collecting awards, accolades, and promotions; and gradually become useless as an actual scientist, but nonetheless continue to command outsized resources based on reputation, rather than current productivity. You could characterize a large fraction of senior HHMI investigators, recent Nobel/Lasker award winners, etc... in this way. These people consume a huge amount of funding/lab space and suffer minimal accountability, because no one wants to suggest that the Great Man is no long doing real science. I have no idea if this characterization applies to Heck, but I wouldn't assume that his loss of funding is necessarily an injustice. It may be that he deserved to win the Nobel prize, but no longer deserves to run a lab.

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49. Anonymous on October 10, 2010 9:52 PM writes...

lots of back patting here...almost nausiating. Get real people..get out there and find a new reaction. Think outside the friggin box. The box is full. don't think about extending someone else's work...push the envelope. Think about what you want to acheive and then do some paperwork...LOL

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50. Alligator on January 1, 2011 11:41 AM writes...

Negishi is sort of weird. He gave a seminar to our department a few years ago. I was a little late to the seminar and came in with a Dr. Pepper. He stopped his lecture and said that he would not continue on unless I would get him a Dr. Pepper. I did so, but he never drank it.

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51. alligator10076 on January 1, 2011 11:52 AM writes...

I met Prof. Stille while on sabbatical at CSU. The last time I talked to him was in the library where he commented that the graduate students today put in my less time than he did as a graduate student. I reminded him that graduate students today by virtue or NMR, IR, rapid X-rat analysis, etc got much more accomplished in a day than we did in the days of mixed melting point, derivative making, unambiguous synthesis of new compounds.

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