The New Clayden pp. 757 — 800

 

Chapter 30: There’s a lot more use of the disconnection approach in the discussions of the synthesis of heterocylic aromatic compounds than there was in the previous edition.  The analysis of the Viagra synthesis pp. 768 –> is particularly fascinating.

The sophistication of the chapter is much higher than what went on previously.  It’s great !  The writer assumes that you have all the previous reactions well under your belt, as well as disconnection and moves rapidly on from there.  

In a sense it’s like the switch from undergraduate math books where proofs are laid out in detail, to the graduate lectures, where proofs are sketched and you are expected to fill in the dots.  I wonder how a neophyte hitting this chapter for the first time would take it. 

One can take the analogy a bit further.  The target molecule can  be considered the theorem and and the synthesis the proof.  This is exactly why math is harder than organic chemistry.  The target molecule is almost telling you (thanks to the disconnection approach) how to make it.  The examples in this chapter are fairly simple.  Yet most accounts of syntheses focus on one or two most difficult steps and the target is far more complex — for an example see ttp://heterocyclist.com/2012/08/24/synthesis-of-kopsia-lapidilecta-alkaloids-the-rcm-approach-takes-a-hit-retraction/.

In medical school, the importance of taking an accurate history was stressed — “The patient is telling you the diagnosis” was said over and over, just as the structure of a synthetic target is telling you how to make it.  Certainly, with each passing year, the MD finds the history more and more valuable, and the physical exam less.  Medicine has one further wrinkle that math and synthetic organic chemistry do not.  The manner in which  the patient gives the history and answers your questions is incredibly important.  It’s not just the words, it’s the tune.  Is the patient depressed, angry, confused, hyped-up etc. etc.  That’s why I always took the history myself, and never had the patient fill out some checklist, it throws away information you can get in no other way

I don’t know enough math to know if proofs break down this way.  But there is another huge difference between math and orgo.  In math the definitions are incredibly precise.  A collection of subsets of a given set either satisfies 3 extremely specific criteria to make them open sets and the containing set into a topology, or they don’t.  Chemical reactions aren’t like that — Anslyn and Dougherty take you through Sn1 and Sn2 and their variants, and then show you how there are reactions that fall between them, containing aspects of both.   The idea of a Diels Alder reaction, is independent of any particular exemplar — so the concepts in chemistry are inherently fuzzy.  If you’re good at reasoning by analogy, then chemistry is your oyster.  Don’t try this in a mathematical proof.  So the zillion mathematical definitions (first countable, compactness, path connected in its varieties) must be memorized exactly as they are, and used in proofs that way, and that way only.   Medical concepts are even fuzzier.  It takes a very different type of mind to do math well, one which, unfortunately, I don’t posses, even though I love the stuff.

 Back to chemistry

p. 772 The example of the tautomer of the thioamide interacting with an alpha haloketone is a great example of hard/hard nucleophile/electrophile and soft/soft nucleophile/electrophile interactions occuring specifically in the same pair of molecules, while quite near to each other.  It should probably be pointed to in the next edition when  hard/soft nucleophiles and electrophiles are first discussed. 

p. 775 — Interesting that they didn’t call the reaction of an alkyne and an azide ‘click chemistry‘ which is what Sharpless calls it.  It has proved extremely useful in linking together molecules of biologic interest — e.g. seeing where a protein is binding to other proteins or to DNA.  The uses are endless and still being discovered. 

Here are a few examples:

       [ Proc. Natl. Acad. Sci. vol. 98 pp. 4740 - 4745 '01 ] Propargyl choline is a choline derivative which can be used to label choline containing phospholipids using Click chemistry  (forming cycloaddition products with a fluorophore containing an azide.  Total lipid analysis of labeled cells shows strong incorporation of propargyl choline into all classes of choline phospholipids — and the fatty acid composition of these lipids is quite normal. 

        [ Proc. Natl. Acad. Sci. vol. 105 pp. 2415 - 2420 '08 ] It was used to quickly label DNA using 5 ethynyl 2′ deoxy uridine — which can be detected using fluorescence. 

       [ Science vol. 320 pp. 868 - 869 '08 ] It is a modification of the Huisgen reaction — the trick was using Copper Iodide as a catalyst.  Polymer scientists love it.

        Another type of click reaction adds a thiol across an olefin using light. 

 

       [ Proc. Natl. Acad. Sci. vol. 107 pp. 15329 - 15334 '10 ] Oligonucleotides can be produced by automated solid phase phosphoramidite synthesis — chains over 100 (deoxy) nucleotides can be formed.  It’s harder with RNA because of the reactivity of the 2′ OH group which requires selective protection.  So the limit here is 50 nucleotides.  This work describes click ligation as a way to put them together. 

p. 793 — A very useful explanation of the nomenclature of heterocyclic ring compounds (which is actually or logical than it first appears). 

p. 794 — Aziridine is less basic than pyroldine and piperidine, because the hybridization of the nitrogen has more s character. But no mention is made of why this should mean less basicity — it’s because the s orbital experiences the positive charge of the nucleus more intensely than a p orbital (which has a node at the nucleus), lowering its energy and making it less likely to share (like a spoiled child). 

p. 796 – While coupling NMR is through bonds rather than throught space (e.g. more coupling between H’s trans to each other on a double bond, than cis — they never explained why this is so, nor do they here. 

p. 796 — It don’t see why the dihedral angle in the bicyclic compound shown is any different from 60 degrees, the axial equatorial bond separation, unless the ring configuration by compressing the C – C – C angle, expands the H – C – H angle.

p. 797 — Why is the shift of the  hydrogen on the carbon containing the OH groups so different between axial (3.5) and equatorial (4.0)? 

p. 799 — Neurologists are excellent at reading MRI scans of patients (or they should be), these vary in appearance depending on whether they use T1 or T2 relaxation.  But the whole issue of relaxation from a higher energy state to a lower one is rarely discussed.  

The text says “So far we have assumed that the drop back down (to a lower energy state) is spontaneous, just like a rock falling off a cliff.  In fact it isn’t — something needs to ‘help’ the protons to drop back again — a process called relaxation”.  Why is this the case? Is it similar to laser action, where something needs to stimulate the drop down to a lower energy state with the emission of laser light.  Perhaps one of the cognoscenti reading this can explain why help is needed for a transition to a lower energy state.  I don’t understand it.

Being able to admit you don’t know something and publicly asking for help is one of the joys of being a non-academic.  I doubt that I’d be able to do this if I were a chemistry department chair, as at least 3 – 4 of my fellow Harvard graduate students 52 years ago became (one of them is still at it and going strong — also to be noted is that he came out of a State University). 
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Comments

  • MJ  On August 28, 2012 at 9:38 pm

    My feeling is that the description of relaxation is poorly worded. I would think that something along the lines of “A system that is subjected to the NMR experiment is perturbed from its equilibrium state, and its return to equilibrium is governed by ‘relaxation processes.’ The first is spin-lattice (or longitudinal) relaxation – indicated by T1 – where magnetization is dissipated due to interactions with the surroundings. The other is (the misleadingly termed) spin-spin (or transverse) relaxation – indicated by T2 – where magnetization dephases in the transverse plane.”

    If memory serves, you mentioned you have a copy of Levitt’s “Spin Dynamics” text floating around or otherwise available to you. I would *strongly* suggest checking out the discussions in the text about relaxation and motional averaging. While some of it is spread out in the book, the index should direct you to where he does a good job (I think) of presenting the material in a clear and reasonably strong manner.

  • luysii  On August 28, 2012 at 11:13 pm

    Yes I do have a copy, but plead guilty to having put it aside, until I finish the new Clayden (1/3 is left). I am quite familiar with the explanations of T1 and T2, but the idea put forth by Clayden that a high energy quantum state would need something external it to push it to move to a lower energy state seems foreign to me (and rather peculiar).

    Think of how we regard transition state theory — nothing seems to push the molecule away from the transition state, it just falls down the potential energy mountain. However, on further thought, potential energy is the negative derivative of force with respect to position (classically at least), so some sort of force is always lurking in the background (classically). I’m not sure this applies to quantum mechanics.

    Probably time for me to bend Michelle Francl’s ear about this

  • MJ  On August 29, 2012 at 9:57 pm

    There’s the spontaneous emission argument (which I should have remembered) – the probability for spontaneous emission has a strong dependence on the frequency difference between the two states. While spontaneous emission between electronic states can be in the nanosecond regime, NMR is in the centuries to millennia interval with the same calculation. This gets us back to the entire actual quantum mechanical basis for magnetic resonance, which is actually far subtler than most chemists have time to consider, as I think I’ve mentioned here. (I do like the Levitt’s text presentation of QM as relevant to NMR, though. Actually, I find a lot of the standard quantum/computational quantum chemistry texts to be slightly irritating, but that’s a separate gripe.)

    Having said that – I could imagine that the intended message of the text could be the following – “In the absence of a strong coupling or interaction between two states, transitions between the two will require the assistance of an external influence.” Inelegantly phrased, perhaps, but not quite as troubling to my ear.

  • luysii  On August 29, 2012 at 10:17 pm

    MJ, your comments are always helpful. Electronic state differences are of much higher energy (hence frequency) than those of the NMR, so presumably if one cycle of alternating electromagnetic field going by is what is required for ‘spontaneous emission’, NMR should be slower. But centuries to millennia? A year is 10^9 * 60 * 60 * 24 * 365 = 10^9 * 3.1 * 10 ^7 nanoSeconds. A century would imply a 10^19 fold difference in frequency, which I think is rather higher than that implied by the energy difference. Correct me if I’m wrong. How about a pointer to the formula for spontaneous emission — hopefully it’s in Levitt.

  • MJ  On August 30, 2012 at 9:46 am

    The early discussion in this PDF document (end of page 3, top of page 4) describes the transition probability (couldn’t seem to find a mention in Levitt, sorry!) –

    http://palmer.hs.columbia.edu/courses/NMR_relaxation.pdf

    It’s definitely very slow and not suitable for running a complete NMR experiment in an hour or so. Or – even in my case – over a week or two. For an imperfect comparison, plug in the frequency you’d use for a UV/Vis (electronic absorption) experiment – which is on the order of 10^15 Hz – and you’ll get a much greater probability per unit time. Then remember that the transition moment for an electric dipole transition is stronger than the magnetic dipole transition at play in NMR, and that also boosts the probability.

    I did dig up where I remembered that bit of “centuries to millennia” – the Fayer “Elements of Quantum Mechanics” text (Ch. 12, section C, pg. 188). The derived equation to calculate the probability per unit time for spontaneous emission still has an explicit dependence on the transition dipole bracket.

    There’s something else I think I’m about to remember, but I’ll get back to you.

  • luysii  On September 4, 2012 at 7:23 am

    MJ — thanks for the link. Back from Holiday — time to tackle it. Unfortunately Fayer’s book isn’t available at any of the local colleges.

    • luysii  On September 5, 2012 at 9:58 pm

      Took at look at the reference. I still don’t understand physically how a fluctuating magnetic field increases the probability of a transition from a higher energy level to a lower one. Perhaps the wave function of whatever is producing the field mixes in with that of the nucleus in the higher energy state. I’ll need to go through Levitt when I finish Clayden.

      • MJ  On September 6, 2012 at 8:29 pm

        My practical reason for providing that reference was mostly so as to assure you and any readers that I wasn’t just pulling an equation for the transition probability out of thin air. Heh.

        The foundational picture actually has the fluctuating local magnetic field (the static magnetic field plus the variation caused by interaction with other nuclei and electrons as the molecule is tumbling/being rotated) interacting with the nucleus of interest, and that this interaction is eventually enough to bring it back to the equilibrium state. I think about it like this – if the T1 relaxation time for a nucleus is 100 ms, and you’re looking at a proton in a standard NMR spectrometer (proton Larmor frequency anywhere between 200 and 750 MHz, let’s say), that nucleus precesses about the static magnetic field tens of millions of times in one T1 period. Given that it’s not a very strong interaction between the nucleus and fluctuating local magnetic field, it’s not going to effect immediate relaxation, and it doesn’t, given this criterion. To also put the amount of time in perspective – for a smallish globular protein (say under 20 kDa), its rotational correlation time is on the order of nanoseconds. Small organic molecules are even less than that (10’s to 100’s of picoseconds). That means the molecule/protein containing that nucleus tumbles quite a bit (and collides with plenty of other molecules & solvent) in that time period as well.

        Of course, Levitt does this all a bit more properly. It’s probably the best intro out there to NMR above and beyond the standard introduction one sees in the typical undergraduate chemistry sequences, and sets one up for either texts on specialized applications (proteins, solids) or on the more formal NMR texts.

  • Curious Wavefunction  On September 5, 2012 at 1:08 pm

    “However, on further thought, potential energy is the negative derivative of force with respect to position (classically at least), so some sort of force is always lurking in the background (classically). I’m not sure this applies to quantum mechanics.”

    You may want to look up the Hellmann-Feynman theorem:

    http://en.wikipedia.org/wiki/Hellmann–Feynman_theorem

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