Enter Retread, Stage Right — RVW #1

May 30th, 2007

What’s all this about?  Well it started like this when I posted the following on The Wall:

24 Apr ‘07

Let’s say you were a graduate student in organic chemistry at Harvard ‘60 – ‘62 (I was), and that you passed 8 of the first 9 cumes (I did) and that you talked Woodward into letting you work on you own idea 9 months after you got there because passing 8 cumes was all you needed to start your PhD work (also true) and were remembered by most concerned as arrogant unfortunately true) and that you were god-awful in the lab (true) and left organic chemistry to go back to medicine. Further suppose that organic chemistry always seemed natural and fun, and that you happened to see a squib in the 12 April Nature about the total synthesis of Lyconadin B, Googled it and found the structure and commentary in TotallySynthetic.Com and fell back in love with organic chemistry, and wished to get up to speed so you could enjoy reading about the field again..

How and where would you start? What are the best introductory texts for organic chemistry, physical organic chemistry? Are there still texts, or is everything on the web now? What is the best place to read about NMR and structure determination (just beginning back then), computational chemistry (practically nonexistent back then — they were still sweating H2+). Also is Debye Huckel theory still what we used to think about it — good for slightly impure distilled water, but not much else. Something better is needed for cell water which is 0.3 molar..

I love the irreverance of the chemical blogs. Have at it folks.



I got this back the same day from Excimer:

I’ll bite: my favorite introductory chem text is by Jones- it has pretty widespread use throughout undergraduate classes still, and I like Anslyn and Dougherty’s “Modern Physical Organic Chemistry” for that subject.

and from Paul:

Excimer mentions my two favorite undergraduate organic texts. I would also consider ordering the solutions manual to Jones, then working out some of the problems. There are few things more satisfying than being able to solve problems to convince yourself you understand what’s going on. If you’re super-excited, what about enrolling in an orgo course at a local community college? Taking courses on a subject always gives me extra motivation to learn things, since you have to stick to a schedule.

So I bought the above (the solution manual hasn’t arrived yet) and started working through Jones ‘04.  Anslyn looks like something I should read after Jones.   I was impressed with how different Jones is than how I remembered my first Organic text (English & Cassidy 2nd Ed. ‘56) so I managed to find a copy on the net and it arrived today.  The next post will contrast the two books.

So this series will be sort of “Rip Van Winkle meets Modern Organic Chemistry”.  Why should you bother reading what’s coming?   Just imagine quitting grad school with what you know and spending the next 45 years reading molecular biology and biochemistry with the background you currently have (in your spare time while going to med school and practicing neurology that is).  I guarantee you’d find it primitive and rather simplistic but would have no problem understanding what’s going on.   So there will be tidbits here and there that you’re unlikely to find elsewhere (such as why Jones is wrong about Strychnine poisoning — I saw a case, and how the cell lets potassium inside while excluding the smaller sodium ion — if you don’t know the answer think of how you’d design a protein to do it — MacKinnon won a Nobel for it — if you can’t wait.  I can assure you that no one had a clue until the structure was solved.  There was a lot of handwaving about differential absorption of Na and K to proteins, and that great fudge factor that no one could calculate — the activity coefficient.

Stay tuned,


Previous Comments

  1. provocateur Says:
    May 30th, 2007 at 6:43 am bogers book and i hv converted evans notesprobs as my ever-growing journal…jerry march is my organic bible!
  2. Ψ*Ψ Says:
    May 30th, 2007 at 9:56 am Oh man. I’d probably blow my brains out if I had to spend 45 years even THINKING about mol bio & biochem again. Two years of that and I was bored stupid.
  3. Uncle Al Says:
    May 30th, 2007 at 10:19 am But what kind of organic synthesis? Slogging through tortured natural product scaffoldings decorated with insane functionalities because (fungal!) metabolism is cruel? Bending carbon to your will in eldritch tortured structures at which hybridization gasps in horror? Fomenting tortured engineering structures so photons and electrons can engage in whoopee as God never intended?Or does he want to crap into a pot labeled “Sales and Marketing” and call it pharma? 60 million Baby Boomers want sustained histamine triple response skin (wheal, edema, flare) to make them look unwrinkled and youthful. Make it so.
  4. Paul Says:
    May 30th, 2007 at 12:38 pm I’d call March’s book more of a hymnal than a Bible—I only read it a couple of pages at a time.
  5. Albert Says:
    May 30th, 2007 at 6:32 pm Ψ*Ψ! I can’t believe that is your opinion on molecular biology!I’m going to spend the rest of my life doing molecular biology, hopefully: it’s pure chemistry ruling living beings!
  6. Ψ*Ψ Says:
    May 30th, 2007 at 10:14 pm Believe it. I don’t think I’d run another PCR if my life depended on it.
  7. kiwi Says:
    May 30th, 2007 at 10:43 pm #6 its just not chemistry is it. everytime i get concerned about synthesis being a bunch of hunches and superstitions, i just cast my eye over to the biologists…
  8. milkshake Says:
    May 30th, 2007 at 11:24 pm At least in organic chemistry one does not have to resort to handwaving like “I don’t know why this does not work now, maybe the company XY changed the procedure for making their antibodies.” Or ” I have to have this in my buffer because everybody does it. (On closer examination it turns out that some frightened postdoc in early 80s actually put a bunch of redundant things in his buffer just to be sure, and this arbitrary mix became incorporated into a standard protocol. From then on nobody was brave enough to tinker with the composition of that brew.)
  9. Ψ*Ψ Says:
    May 31st, 2007 at 12:38 am I see I’m not the only one, hmm? It does bring a more…personal element into the superstition behind the science. While I’ve had synthetic projects I could swear were laughing at me the entire time, somehow it seems more plausible that a particular gene sequence wouldn’t amplify because the wasp died a horrible death in a malaise trap and its body became cursed.
    Anyway, it’s much better to work where there’s no need to worry about fungus taking over the fridge. Roundbottoms half-full of shit that will never crystallize, maybe, but definitely nothing living.
  10. Anonymous Says:
    May 31st, 2007 at 9:26 am To Milkshake:Organic chemistry is not handwaving, is it? Do you really think there is such a thing as an orbital? And when you draw your cute little mechanisms from reactant to product, then that is it, case closed?

    There are many biologists that look at their problems at a level of detail that would probably shock you. It is easy for you to be critical about biology, I suspect, because you work with a system that is well-defined from t=0: you take the Wieland-Miescher ketone and start your synthesis with a Michael addition or aldol or whatever. Biologists are typically going the opposite direction: they start with a complex, and poorly defined system, and work backward. They work with the undefined but typically not, as you point out, because they are afraid to understand simple components such as buffers.

    I am not a biologist. However, I find your overwhelmingly chemocentric view of things to be unfortunate at best.

  11. Albert Says:
    May 31st, 2007 at 10:47 am I fear I’ve started a row.
  12. eugene Says:
    May 31st, 2007 at 11:47 am “Roundbottoms half-full of shit that will never crystallize, maybe, but definitely nothing living.”Wait until you do a racemic separation of a diol by adding a modified yeast bought from Aldrich (or whomever) and stored in the fridge. Every organic chemist should have that experience. Why? Because it works most of the time and it’s very satisfying.
  13. Shite-disturber Says:
    May 31st, 2007 at 11:47 am I don’t know why this does not work now, maybe the company XY changed the procedure for making their antibodies.Hmm – I’ve heard similar phrases uttered from synthetic chemists about ‘bad’ batches of a catalyst, etc…

    You could argue that – since most arrow-pushing mechanisms aren’t followed-up with detailed mechanistic experiments – that there’s plenty of “hand-waving” in organic chemistry. Proposed mechanisms are often based on what makes sense chemically/other evidence, but they are rarely borne out with additional experiments that really nail the exact mechanism.

    I’m not trying to start a row with you, but you’ve got to admit that all scientific disciplines suffer from this problem – and I think it’s a total waste of time to play the “chemistry is better than XXX” game…

  14. Hap Says:
    May 31st, 2007 at 2:08 pm There was a discussion of this a long time ago on Derek Lowe’s blog, with similar results. It may be because chemists, biochemists, and biologists all deal with functions on different scales and so by necessity care about different things – for example, synthetic chemists usually don’t care about mechanism, potential energy surfaces, etc., unless they really have to. Even then, lots of people will usually try everything they can think of rather than approach by mechanistic and computational analysis (because they don’t know what the payoff will be of those studies and they’re trying to make their molecule and time spent on side trails is time they can’t spent making their molecule).I don’t think that there’s quite as much voodoo in chemistry though, because the systems are simpler and so easier to manipulate and understand – there isn’t so much need for kits of reagents so people are forced/can understand what goed into their reactions more easily than a biologist can understand what’s in the cell media. If something is voodooish and can’t be done another way (nickel-chromium couplings, palladium-free couplings), someone can usually break it down fairly quickly to find out what is going on.

    There are people who should know more chemistry, though, and don’t care. A well-know structural biologist/crystallographer taught a chemistry class my first year in grad school, and since there weren’t enough classes to take, a large chunk of the organic students in my year took his class. The first day, he begins talking about water, and draws it on the board as a sphere. It propbably wouldn’t have been so bad if he didn’t seem to go out of his way to hose the chemistry students in his course – maybe he didn’t like being reminded of what he ought to have known. At that length scale, the chemistry should be relevant, and hand-waving or being wrong is likely to be a problem (of course, he had gotten somewhere despite it, so…)

  15. Wavefunction Says:
    May 31st, 2007 at 2:36 pm Please please don’t forget Organic Chemistry by Warren, Wothers, Clayden and Greeves, the BEST modern org chem book I have come across.
  16. Ψ*Ψ Says:
    May 31st, 2007 at 2:38 pm Hey, I’m not really out to argue either. People who like molecular biology can do whatever they want with it (provided they keep it far away from me).
  17. Tot. Syn. Says:
    May 31st, 2007 at 6:59 pm Wavefunction:Stuart Warren has just finished his latest book, which I believe is in pre-press (and thus should be published very shortly). It is reputedly more advanced, aimed at grad students. I’m hoping I get a copy before I finish my Ph D…
  18. Hap Says:
    May 31st, 2007 at 7:02 pm TS: It’s out shortly – there is an ad for it in the latest Wiley book pamphlet. It seemed a little expensive ($85 paperback/$120 hardback), but it’s 900 page, so it’s not ridiculous.
  19. RJ Says:
    May 31st, 2007 at 10:22 pm Do you mean “Organic Synthesis: Strategy and Control”? There are a few copies left on amazon, and I believe you can order it directly off of the Wiley website.
  20. Anonymous Says:
    May 31st, 2007 at 11:20 pm I would suggest Organic Synthesis by Smith. It used to be riddled with errors but I think they have been corrected. I would also suggest skipping Carey/Sundberg and Lowry/Richardson. I would classify March along with Larock’s Comprehensive Transformations; useful references but not very interesting to sit down and read.I would recommend Nicolaou’s Classics in Total Synthesis I and II. Also, the Aldrich catalog–it an interesting item to sit down and leaf through. There are compounds hidden in there that even Uncle Al might not be familiar with (unlikely, but possible). I would also suggest buying a copy of the Merck Index (another interesting read and useful reference).

    On the analytical side of organic chemistry I would recommend Crews, Organic Structure Analysis–it is a fine book. Also round it out with a copy of World Records in Chemistry by a man with a double hyphenated name (first AND last); it is a book every chemist should have by their bathtub.

  21. Retread Says:
    June 1st, 2007 at 6:04 pm Stick around Albert — you’ll have to give up the idea of anything truly ruling anything if you go into molecular biology. Nothing in the cell or the organism is allowed to rule unimpeded (at least in a state of health). Our very notion of comprehensible causality in the cell may have to be abandoned, but this will be the subject of a later installment.Hap mentions potential energy surfaces. Can anyone actually calculate the damn things? In the 60s it was two hydrogen atoms approaching each other and a lot of handwaving. You should see what is going on in protein chemistry. A high dimensional potential energy surface ‘funnel’ is postulated, because proteins fold in a finite time. Is this really an explanation or a fancy description of the obvious designed to confuse the laity without any explanatory power (Docs do this all the time — look up idiopathic if you don’t know what it means). Another installment will talk about the Levinthal paradox.

    Hap also talks about water. Hopefully things have improved since the following was writtenl

    [ Proc. Natl. Acad. Sci. vol. 98 pp. 10533 – 10540 ‘01 ] “Despite the construction of hundreds of model force fields for use in simulations, the great advances in computational technology, and the development of powerful ab initio molecular dynamics methods we remain unable to accurately calculate the properties of liquid water (e.g. heat capacity, density, dielectric constant, compressibility) over wide ranges in conditions. We do not yet have a satisfactory molecular description of how a proton moves in the liquid. We do not fully understand the molecular nature of the surfaces of either ice or liquid water. Although it is clear that the hydrogen bond network and its fluctuations and rearrangement dynamics determine the properties of the liquid, no experimental studies are available showing detalied information about this process (without considerable interpretation).”

    Wavefunction — thanks for the tip, but having laid out nearly $250 of the long green for Jones and the answer book, I’ll stick with it. A future installment will talk about book prices then and now, book quality then and now.

    Anonymous — thanks for the advice — After the 1323 pages of Jones ‘04, I’m going to read Anslyn — recommended by Paul and Excimer — it seems more advanced than Jones. Also Lowry/Richardson (Schueller then) were fellow grad students with me. They’ve both retired but remain friends. They tried several times to get various people to take over the book and update it, but were turned down because the job was just too big.

    All of you — thanks for the comments. I hope you’ll find this stuff interesting.

  22. Ψ*Ψ Says:
    June 1st, 2007 at 9:04 pm Retread: You might not want to click this link. It may make you want to smack yourself. I haven’t been to a campus bookstore in YEARS since discovering the wonderful thing that is Ebay (Amazon is also nice and will suffice).
  23. Ron Says:
    July 10th, 2007 at 8:14 pm Retread, I have a couple of questions regarding chemistry and subsequently going into medicine that I’d like to ask you, if you don’t mind. Could you please e-mail me at rmpalpha (at) gmail (dot) com? Thanks!

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