Serendipity — RVW #6

July 28th, 2007

The wrap up is on its way. In the meantime, Retread has come to the rescue with the next installment of his Rip Van Winkle series. Enjoy.

I think Jones’ book is terrific. It’s just a leisurely discourse on organic chemistry, with plenty of examples, hints, exhortations, warnings, opinions etc. etc. It’s always friendly and never turgid or pompous. I’ve now (20 July) made it halfway through, doing most of the problems (as suggested by Paul and Excimer).

A series of comments on the first half would be rather disjointed, so I’ll put just one in now and then. Here’s today’s: I wrote my Junior paper on the Grignard reagent, and it seemed obvious that no one knew what was going on back then. From the discussion on p. 236, it seems like not much has changed. Any comments?


There wasn’t much response to the request for examples of chemical serendipity in the last post, so here are two from medicine to get the discussion going.

Interns don’t get much sleep. On a three-month surgery rotation, it was 36 hours on/12 off, but to get a weekend off, call was bunched so that in one 7-day stretch, it was 5 nights on/2 nights off, making 24 of 168 hours off call. Most nights we got 3-4 hours of crummy sleep. According to legend, Mary Walker was one such intern who in 1934, fell asleep during a lecture on myasthenia gravis (a disease characterized by muscle weakness, which can affect the ability to breathe, hence the “gravis”) for which there was no known treatment. She woke up after the lecture, walked up to the great man and asked how to treat myasthenia. The great man, irritated, said — “It’s just like curare poisoning”, so she went off to the library, looked up curare poisoning, found the treatment (physostigmine), administered it to a myasthenic and became famous.

Few of the drugs first used to treat neurological disease were discovered rationally. The first drug for epilepsy (bromide ion) was thought to work by decreasing libido, as epileptics were thought to be sexually overwrought. Things improved in the 30s with the discovery that seizures could be induced by electric shocks administered to the brain. Zillions of hapless rabbits were shocked while pumped full of various drugs. If the drug increased the current required for seizures, it was a potential anticonvulsant. This is exactly how Dilantin was discovered. Cruel, but at least rational.

Science marches on, and it was soon discovered that drugs getting into the brain (which is mostly fat) had to be soluble in lipids (which meant they weren’t too soluble in water). So potential drugs were first put into amphipathic (soluble in water and lipids) solvents, like soap. Soap is basically a bunch of long chain (12-18 carbons) carboxylic acids. One such solvent was 2-propylpentanoic acid (valproic acid).  Many drugs put into it seemed to work pretty well. Fortunately, someone had the brains to do a control, and found that the actual anticonvulsant was valproic acid (and a very useful one it was — although like everything else in medicine, not without side effects). A case of not throwing out the bathwater. Anything similar in chemistry?


Previous Comments

  1. Ψ*Ψ Says:
    July 28th, 2007 at 5:20 am More stories. I demand more stories. :)
  2. excimer Says:
    July 28th, 2007 at 11:19 am I wrote my Junior paper on the Grignard reagent, and it seemed obvious that no one knew what was going on back then. From the discussion on p. 236, it seems like not much has changed.After reading March’s section on Grignards, I have the feeling that we know a lot more about Grignard reactions than a sophomore organic text is willing to divulge. I think details are sparse because organomagnesium chemistry isn’t exactly conducive to an intro o-chem class. But the nature of organomagnesium compounds in solution, as well as their reactivity with organics as well as metals (there’s been a lot of recent work particularly by Fürstner on metal-catalyzed cross-couplings of Grignards and alkyl halides) has been fairly well-studied. Nowadays the new hotness with Grignards is cross-coupling reactions. I have to say though, Jones does a pretty good job explaining the basics of Grignard and organolithium reagents.
  3. Darksyde Says:
    July 28th, 2007 at 2:09 pm The DLS (dirty little secret) of grignards and organolithium compounds is that they make these oligomeric and polymeric complexes, which are often hard to characterize.Organolithium compounds (from what I understand seem to be slightly more well-behaved; they are more likely to form well-defined complexes). Collum was once asked (quite astutely) in a seminar why his experimental protocols involve months-long recrystallizations of butyllithium at -80C, as synthesists never bother. His answer: “to keep the riff-raff out”.
  4. Anonymous Says:
    July 29th, 2007 at 11:05 am Wasn’t there a serendipitous moment while making the Nozaki Hiyama coupling? Like trace amounts of nickel in their chromium gave them optimal yields? Anyone know the full story?
  5. Klug Says:
    July 29th, 2007 at 12:05 pm Dunno the full story, I believe that a partial description is in the JACS paper co-authored by Kishi and the wonderfully-named William J. Christ. It’s an amazing display of the powers of observations. The cans of CrCl2 initially bought were very active in their reaction, the later cans were moderately active and the final cans were not active at all. It was explained to me (and I could be remembering incorrectly) that it was likely that the company generating the CrCl2 was getting better and better at eliminating the NiCl2 impurity.I’ve heard of a case of a prominent chemist publishing work that noted that reaction yields or rates depended on stir plate speed. Has anyone heard that?
  6. milkshake Says:
    July 29th, 2007 at 2:47 pm A true story:In commie Czechoslovakia, a commodity chemical plant was manufacturing various inorganic salts. Sometimes they succeeded in producing a particularly nice batch of copper sulfate pentahydrate – gem-like inch-sided chunky crystals in gorgeously deeper shade of blue. This was designated as export grade. Now, the commie regime was notoriously short of hard currency so the company management was encouraged to export their product. But as hard as they tried, most of the time they produced only the light-colored and small crystals of the stuff that the western customers did not care much for. So they tried to vary the crystallization temperature, concentration – and nothing worked but then they noticed the gorgeous batched formed mostly in the winter months, when the outside temperatures were below 0C. And mostly at night shifts. And only in one crystallization reservoir – the one located in the corner of the hall, behind some other machinery. Then it dawned on the management that the special properties of that crystallization reservoir hat to do with the fact that the bathrooms were located in another building, about 100 yards away and ammonia copper complexes are deep blue and co-crystallize with copper aqua complexes..
  7. Jose Says:
    July 29th, 2007 at 6:59 pm The DLS area is not magneseates or lithiates, but cuprates- a serious, major morass of conflicting data and structures….The story I heard about the Kishi-Nozaki-Hiyama reaction was that single stir bar was the only one that worked; it had picked up Cr elsewhere which was crucial for co-catalysis with Ni. That is the kind of stuff that gives me nightmares….
  8. Darksyde Says:
    July 29th, 2007 at 8:06 pm Jose: Try doing a PhD in biology. It’s nightmare after nightmare. Your shit works once, and usually the first or second time, which is enough to make you chase the apparition of good news and see it never again. It doesn’t help that lazy postdocs are so full of themselves and convinced that everything should work well — but these are the jackasses that tend to chase artifacts and spew bullshit (”overinterpretation”) out their mouths. Serendipity my foot. It’s just as likely it’s fabricated data.The only redeeming quality about Biology is that they tend to design “control”s better than chemists. About half the time, anyway.

    There’s a reason why I’ve crossed over to the “darksyde”.

    Although word has come around to me that postdocs in synthesis labs (geography dependent) often fit the aforementioned description anyway.

  9. Dennis Says:
    July 31st, 2007 at 4:18 pm As I understand it, the Takai reaction works well with trace amounts of lead. The original paper made no mention of this and it was years later that it was discovered that the zinc used had been tainted.
  10. Retread Says:
    July 31st, 2007 at 10:14 pm To excimer — thanks for the tip about the March’s book and the Grignard reagent. Probably just too advanced for an intro book as you say. March’s book impresses me more like a dictionary than a text. Do people actually plow through it, or just look things up?It’s probably not really serendipity, but Dr. Schleyer used to talk about how the old German chemists got things to crystallize that no one else could. He said their rich full beards contained the seeds of most crystals.

    Off to prepare for my father’s 100th next month, then after that a week of chamber music with friends (which one of their kids calls band camp for adults). To quote an old teenybopper song — see you in September. No further posts till then. Since Psi*Psi likes stories and Shrug is an old Rutgers alum I’ll close with one about my Father and what truly amateur athletics were like back then. He never saw tennis until he went off to Rutgers. He came home to the farm after his freshman year, told his 4 brothers about it, and they chopped down some trees, leveled the ground, put up a net, bought some steel rackets and started playing. One took out a book about how to play tennis from library by Tilden. The time it could be out was only 2 weeks, but when one brother would turn it in, another would come along to take it out.

    By the time he graduated, my father was second on the Rutgers tennis team. Can you imagine that happening today? There’s a summer tennis camp at one of the nearby colleges and some of the kids in attendence are not much bigger than their rackets.

    To all — thanks for the comments.

    Future topics
    Is organic chemistry really that hard? (compared to mathematics).
    Does causality have any meaning in cellular biochemistry?

    Take care

  11. Shrug Says:
    July 31st, 2007 at 11:22 pm Wow, that’s a pretty amazing story! I definitely couldn’t see that happening these days, at least not in any of the NCAA-sanctioned sports.
  12. excimer Says:
    July 31st, 2007 at 11:46 pm retread-March is a terrible read-thru book. However, for a class I had to plow through the sections on Grignard reagents. Good reference, awful read.
  13. Ψ*Ψ Says:
    August 1st, 2007 at 3:45 am IMO, anything related to crystal growth is serendipitous to some degree. The guy I work for also told me stories of chemists with beards. I interpreted this to mean that I could use more facial hair (which I am fortunately lacking). Perhaps cat hair would also work? I have scads of that.
  14. Retread Says:
    August 1st, 2007 at 9:54 am Couldn’t resist one more before I head outPsi*Psi — Only if you cat hangs around the lab a lot. Also, what does IMO mean?
  15. Wavefunction Says:
    August 1st, 2007 at 11:18 am March’s book is a masterful example of balanced exposition in my opinion. The first one-third of the book can be read like a textbook, with excellent discussions on acid-base concepts, stereochemistry, bonding and mechanisms. The other part of the book is more of a dictionary or encyclopedia as Retread mentioned. That’s why March’s book has stood the test of time, because of this dual utility.
  16. Anonymous Says:
    August 1st, 2007 at 11:37 am IMO = in my opinion
    IMHO = in my humble opinion
  17. Darksyde Says:
    August 1st, 2007 at 6:08 pm Am I being goaded into a flamewar by Rip Van Winkle? Sorry, mathematics is, hands down, way harder. My ex-girlfriend was chatting with me about what she studies, and it took her 30 minutes just to get to the definition of the item she’s studying. And she couldn’t tell me why it’s interesting, just that she knew that it was.Let’s just put it this way. Mathematics is harder, organic chemistry requires skills.
  18. Nice Says:
    August 1st, 2007 at 6:42 pm With no disrespect to organic chemistry, someone once pithyly said “Organic chemistry is just like mathematics, only easier”. So I sort of concur with Darksyde. In any case, such discussions becomes silly after an extent.
  19. excimer Says:
    August 1st, 2007 at 9:28 pm Oy gevalt. There is something amazingly disingenuous about comparing math and organic chemistry. It’s like comparing apples to oranges with a bunch of people allergic to oranges. Does it really matter what’s harder? Does it really?* Such a comparison is a battle of egos and semantics, not of reason.*the answer is no
  20. KRP Says:
    August 1st, 2007 at 10:17 pm I wish to listen to what Rip Van Winkle has got to share; I am sure there will be split in the opinions but the way he shares his stories, experiences would be added bonus apart from his dissecting skills of the subject. I for one who wants to listen to him …( read his views and I am sure ‘’psi…psi’’ is also fond of his stories). Organic chemistry may be simple (deceivingly so) on paper as for as it is considered on paper….but it does not stop there as mathematics …… has practical and application part to it. So I would go ahead and say with due respect to mathematicians, (Darksyde, Excimer and Nice to as well) that Organic chemistry is much harder; just a computer /calculator can not do organic chemistry as easily as they do mathematics. If you want to argue and prove, you are most welcome to do so. Here is the simple challenge……Devise a practical synthesis for Azadirachtin, execute the same and provide 100 mg of the sample.This is just my view……and it is subjective as is the topic.
  21. bad wolf Says:
    August 2nd, 2007 at 10:05 am One reason I liked chemistry was that, unlike math or physics, there are no child prodigies to be found. No one, not even Woodward, was just ‘born’ knowing chemistry. It seems to be much more egalitarian in that regard.
  22. Wavefunction Says:
    August 2nd, 2007 at 10:17 am It’s interesting that Woodward himself once contemplated a career in math. He chose chemistry over math because he realised that in math (at least pure math) anything you prove on paper is “true” (Kurt Goedel of course showed that there are always propositions that are ‘undecided’, but that’s a different matter) while in chemistry, it always has to be verified by the iron hand of experiment. He also chose chemistry because he was entranced by the sounds, sights, and smells that it offers, a cornucopia of things that are and that would be.
    I think the discussion about what’s “harder” veers off into context-specific technicalities and becomes meaningless after a point. What is harder, synthesizing Vitamin B12 or proving the Goldbach conjecture? Hmmm…
  23. Darksyde Says:
    August 2nd, 2007 at 8:28 pm Right. There’s a gross misconception that mathematics is something that a computer can parse and solve. In fact constructing an original mathematical proof requires almost the same skills as synthetic organic chemistry: you have to plan a route, referencing known precedent, (often) construct model systems, adjust when a promising avenue closes itself, and know when to quit if the problem’s too hard. In both fields there are also no “right answers” (only wrong ones), and upon inspection, a spookily intersubjective consensus on “elegant solutions” versus “ugly solutions”. And both fields have active areas of research where axioms are trimmed and researchers work in “restricted idea space”s, generating interesting new problems with profound philosophical (math) or practical (chemistry) implications.Woodward’s reasons for choosing chemistry over the math are essentially the same as mine (although I’ve since been lured over to evilness). That, and total intimidation at the praeternatural geniuses who ruled the roost in that field. The reason for chemistry being “egalitarian” is quite practical. No one wants their 16-year old kid working around dangerous solvents, carcinogens, etc while their body is still undergoing development and their motor skills haven’t quite been finely tuned yet.

    In any case, I don’t know of too many problems in synthetic chemistry which have been open and unsolved for 250+ years*. Perhaps someone can enlighten me.

    Agreed with wavefunction that the goldbach conjecture is a great example, since you can explain it to a fifth grader. On the other hand, that *is* one which is sort-of almost solved with extensive computer help (it’s a kludgey solution — think maitotoxin).

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