Anslyn pp. 421 – 488

p. 421  nucleofuge, nucleofugality — what incredibly ugly words ! 

p. 422 — “To a good approximation, the potential energy of the system does not change with substitution of one isotope for another.”  Why?

p. 422 — “For a bond breaking event, the stretching vibration (italics) of that bond is defined (bold) as the reaction coordinate”  — not the distance between the atoms making up the bond.  A vibration isn’t a length.  I think length is what is meant.

p. 423 — while the reduced mass of C-D is > 1, and that of C – H is < 1, the discussion assumes the force constant for a C-D bond is the same as the C-H bond — is this true?  It seems reasonable enough, as the strength of the bond should be related to the electron distribution between the atoms, which should be the same in this case.  Does anyone know?  p. 432 — again — it would be nice to know the actual force constants for C-D and C-H actually are.   In the answer to problem #2 at the chapter end it was stated that the force constant for C-D and C-H is the same — this should be in the text (and right here).

p. 424 — fascinating discussion of the isotope effect — I’ve still got Lars Melander’s book of 1960 (being a pack rat) and the zero point energies are all there — but the graphics aren’t nearly as good.  

pp. 425 – 426 — “We must also identify the vibrational mode that is the reaction coordinate, because ths vibration will not contribute to the isotope effect at the transition state.  This is because the reaction coordinate is not a vibration present in the transistion state, but instead defines the reaction.”   Don’t understand this.  Later it is said that “the A-H stretching mode in the reactant is changing because this bond is breaking”  — if this isn’t a vibration mode, what is? 

Also the notion of a a potential well being perpendicular to the reaction coordinate works only if the potential is a 3 dimensional surface, for the same reason that the cross product doesn’t work in dimensions higher than 3 — there is no unique perpendicular in this case.  Most true potential surfaces (assuming they can be calculated) have a dimension much higher than 3. 

p. 426 — “Bending modes have significantly lower force constants than  stretches”  — why? 

p. 430 — because C-D bonds have lower energy — due to their greater reduced mass — their vibrational excursion is less making them smalller.  A neat example is given in Eq 8.6.  The van der Waals radius of hydrogen is given as 1.20 Angstroms — I can’t seem to find it for Deuterium.  Does anyone know what it is?

p. 432 — Isotopic perturbation of equilibrium — extremely clever — not in Melander because NMR was just coming in back when he wrote the book. 

p. 432 -3 — One infers from the discussion on 432 and Figure 8.8  that the narrower the potential energy well, the higher the force constant.  Is this in fact true?  It doesn’t seem to be explicitly stated anywhere.  Actually it is stated in the Connections on p. 439 — but this should be introduced in the discussion of zero point energies back on p. 422 –> 

p. 441 – “The difference in frequency of bonds with different isotopes arises from differences in the reduced masses.”  Presumably this is because the force constant of the bonds is identical — but I don’t think this was explicitly stated.  One could infer this because the vibrations of H and D  are plotted in the same potential well, when zero point energy of isotopes is discussed (p. 423).    In the answer to problem #2 at the end it was stated that the force constant for C-D and C-H is the same — this should be in the text. 

p. 440 — Proton inventories — having seen how tricky it is to get a straight line when trying to find a reaction rate, I’m somewhat suspicious of the ability to tell a quadratic dependence from a linear one, and even more suspicious of the ability to distinguish a cubic dependence (3 protons) from a quatdaratic one. 

p. 442 — “Thus substituent effects (e.g. effects of various groups — methoxy, nitro, halogen — are almost always discussed in terms of our hybrid valence bond theory/molecular orbital theory approach, wherein localized bonding effects and isolated bonds between atoms are considered.”

      Well, as I read through this section it became apparent how little  the molecular orbital approach was used.  This is classic organic chemistry where substituents were viewed as isolated entities affecting distant sites of the molecule — and nearly always through atom-atom bonding.  Molecular orbitals are nowhere to be found (nor are group orbitals).

     p. 453 — Not many comments — the stuff is pretty straight forward, although the models used for finding resonance, inductive, steric effects are clever (and clearly have been markedly extended in the last 50 years).  However the Taft Topsom idea of breaking substituent constants into four parameters seems like overkill.  von Neumann is reputed to have said something like “give me five parameters and I can fit an elephant on a curve, give me 6 and I can make it dance”.  Also don’t forget that these values are logarithmic plots — which tend to flatten everything.  This is probably OK as rates are linear in the log of the activation energy.

      p. 457 — Good to see my undergrad advisor (Schleyer) getting his name attached to something.  He was heavily involved in the norbornane system in the late 50s along with grad student Don Klinefelter.  He used to refer to Winstein as ‘solvolysis Sol’.  Schleyer had a commanding physical presence (including possible dueling scars) and at our 50th reunion, a fellow undergraduate advisee (Pete Reilly) told me his mother asked him why he was working for a German U-Boat captain.  

p. 462 — Connections:  Fascinating to see how nucleophilicity parameters can tell you the extent of bonding of attacker and leaver to the central carbon in an Sn2 reaction.  Very slick.

p. 469 — a very nice explanation of enthalpy entropy compensation — which drives drug chemists nuts.  The tighter the binding of a ligand to a drug target, the more negative deltaH is, but the tighter the binding the less freedom of motion the ligand has (making deltaS less positive).  Since what we really care about is how negative deltaG is and deltaG = deltaH – T*deltaS, the two effects cancel.   This sort of thing shows the extremely intuitive way that chemists understand thermodynamics. 

p. 469 “The number of these scales and their uses quickly become confusing”.  It goes back to von Neumann — each of the scales is basically a set of fitted parameters, but which one do you use?  It seems to be like second opinions in medicine — which one(s) do you choose to believe?

p. 479 — Horlogerie — not what it sounds like, French of course.  A totally new idea — undreamed of 50 years ago.  “Seven orders of magnitude can be spanned by choosing the correct clocks”.  From the 12 examples given it looks like 10 orders of magnitude can be spanned. 

Great chapter.  I had the (now faint) hope of finishing the book by year’s end. So to get there, I’ve decided to skip doing the many excellent problems at the end of the chapter.  There’s never enough time (even for a retiree).  A cousin’s husband told me ‘retirement is hell, you never get a day off’.

One of my many goals is to have a solid enough background in organic chemistry, physical organic chemistry, statistical mechanics and plain of PChem to really understand what is going on in the various molecular dynamic models of protein folding, structure and chemistry, something the various chemistries should allow us to understand.  We’re far from it.  If we really knew what’s going on we’d have a small molecule inhibitor to prevent hemoglobin S from sickling.   See

As if further proof were needed the first page of the next chapter (p.489) has the following quote.  “The general manner in which enzymes catalyze reactions is still a matter of debate, and so we present several theories.”  If we really understood protein structure and function it wouldn’t be a matter of debate.
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  • Ben T.  On October 17, 2011 at 6:17 pm

    In the reaction coordinate diagrams on e.g. pg. 427, you’re drawing in other vibrational modes right at the transition state as their own little orthogonal potential energy wells. One thing A+D do poorly here is not making it clear in the diagrams that those wells “on top of” the reaction coordinate are orthogonal. On those orthogonal wells, you put in the H and D zero point energies. The reaction coordinate, then, is exactly the same: it is indeed a vibrational mode, that happens to be the one that leads to products. You factor it in to the kinetic isotope effect calculations only in so far as you look at the differences in ZPEs between reactants and transition state vibrations. I’m not sure if that helps, but there it is.

    I think this is because a stretch lengthens and shortens a covalent bond, so you’re messing with the optimal overlap of electrons and the two nuclei; bending doesn’t do this much (at worst you get some steric clashes).

    • luysii  On October 17, 2011 at 9:20 pm

      Ben T. Thanks for trying. I’m still not sure I understand p. 427, but your second paragraph was quite helpful.

      I stayed away from kinetics except as a heuristic device. Woodward never talked about them much. Westheimer would ask a question or two to some wretched grad student kineticist, suggest an experiment or three and it would be back to the lab for another few months of drudgery. I wanted no part of it, but that’s not to say kinetics is unimportant.

  • MJ  On October 17, 2011 at 8:50 pm

    My impression was that once you survived undergraduate p.chem. lab, the days of trying to fit kinetic data to a straight line were over, as any reasonable research laboratory had software to do nonlinear regression (outside of experiments deliberately intended to give you straight lines like pseudo-first order ones). Although most of my data points on that count are biochemistry/biophysics labs – perhaps others have not quite made the software leap.

    I am curious to see what is exactly is meant by “general manner” in relation to enzyme function. I worry that it might be the chemical version of the physicist’s “well, let’s just presume a spherical cow and take the first two terms of the series expansion” approach. Heh.

  • luysii  On October 17, 2011 at 9:13 pm

    MJ: In ’60 – ’62 there was NO software. I’m only a few pages away from their discussion of Enzymatic Catalysis (pp. 523 – 530) and will comment on it shortly.

  • Bryan  On October 21, 2011 at 11:55 am

    Regarding the connection between force constants and the narrowness of the potential well, it’s worth remembering that the force required to move an object out of a potential well is related to the steepness of the potential energy function (F = -dU/dx). If the kinetic energy of the object increases greatly as one moves only a small distance from the equilibrium position, displacing the object from equilibrium must require a greater force. Therefore, narrower potential wells result in larger force constants.

    • Bryan  On October 21, 2011 at 11:57 am

      Correction: If the _potential_ energy of the object increases greatly as one moves only a small distance from the equilibrium position, displacing the object from equilibrium must require a greater force.

  • luysii  On October 21, 2011 at 1:39 pm

    Bryan — of course — I’ve totally forgotten my Freshman physics. My face is red! Force is the negative gradient of potential.

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