Anslyn pp. 1 – 50

      p. xxii — “Some would argue that the last century also saw the near death of the field” .  My friend, Tom Lowry (Mechanism and Theory in Organic Chemistry) told me (this century) that he thought the field had died.

      p. xxiii — I’m not even sure the authors would call the following Physical Organic Chemistry because no covalent bonds are broken or formed, but the way proteins do or do not associate with each other (bonding is probably too strong a word) is absolutely crucial for the understanding of what is going inside our cells.  For example  RNA polymerase II is a protein complex of 12 subunits (Rpb1 – 12) with a mass of 500 kiloDaltons, and size 100 – 140 Angstroms.  None of the interactions between the subunits are covalent.  Ditto for the ribosome  which contains 4500 nucleotides over a few chains and 50 proteins (all noncovalently associated) with a molecular mass of 2.5 megaDaltons. 

       Similarly, the huge and unsolved protein folding problem doesn’t involve covalent bond making or breaking.  This is certainly physical chemistry. Whether or not it is physical organic chemistry is unclear.  Hopefully the book will have something to say about these matters.  Certainly proteins are organic molecules, and physical organic chemistry should be able to say something about the way their parts interact.

        p. 4 “This limitation (of quantum mechanical calculations) is even more severe when solvation or solid state issues become critical”.   Back in the 60’s we used to refer to the DeBye Huckel theory as applicable to slightly contaminated distilled water only.  Every year my wife and I have dinner with a friend from that era (currently a chemistry department chair) and he tells me this is still true.  Remember the concentration of salt in our cells is .3 MOLAR (not a misprint). 

        p. 4 “Most of this material should be familiar to you” — not to this boy.  Molecular orbitals were just coming in in 60 – 62.  Lionel Salem was a post-doc (or something) when I was a grad student.

       p. 4 “Each row in the periodic table indicates a different principal quantum number (with the exception of d and f orbitals which are displaced down one row from their respective principal shells”  — Why?  I’ve never understood why this should be — perhaps an explanation will be forthcoming in this section. 

        p. 5  ”the ability of an electron to feel the trajectory of another electron”.  Certainly informal, but do electrons really have feelings? There’s also a strong argument that they don’t even have trajectories — if they did, how would they get past a node (zero probability of finding them there) in a 2 p orbital.

       p. 7 — formal charge.  This makes biologic sense.  Mammalian nerve talks to mammalian muscle using the neurotransmitter acetylcholine which contains a CH2 – N(CH3)3+ group.  There’s no way the nitrogen can get really near the parts of the protein the molecule binds to (which is negatively charged), so having the positive charges distributed over the hydrocarbon part makes sense. 
p. 14 — Electron density of “.002 electrons/A^2”  — the denominator should be A^3,  Density on a surface doesn’t make sense.  

p. 18 — How are dipole moments for molecules determined? Since the dipole moment is the product of a distance and a charge separation.  Increasing the amount of charge separated and decreasing the distance between them will yield the same Dipole moment.  Is there any way to measure the two separately? Anslyn makes the point with CH3Br and CH3F — which have the same dipole moment. 

p. 21 — In the Going Deeper box “The potential energy cannot be infinite . .. ” is wrong — it should be “The kinetic energy cannot be infinite .. ”   Now I have the 2nd printing and they don’t have an errata page (which I think is awful) correcting errors as they are found with each new printing, so this may have been corrected already.

p. 25 — The discussion of polarizabilities is clear, but the units are not.  It’s probably the relative polarizabilities that are important.   The fact that alkanes are so polarizable is never mentioned in discussions of the membrane potential — given that the interior of biologic membranes is mostly hydrocarbon, this should diminish the potential across it. 

      Now I doubt that the average chemist, organic or otherwise, knows the following.  The potential difference across the cell membrane isn’t that large (70 milliVolts), but the field is enormous, because the 70 milliVolts is across a distance of 70 Angstroms (7 nanoMeters).   So that’s an electric field of 

        70 x 10^-3 volts/7 x 10^-9 meters = 10^7 Volts/meter 
enough to fry your socks off. 
I wrote a post on the subject elsewhere on this blog

p. 27 — “Modern calculational methods now provide accurate representations of the molecular orbitals not only of stable molecules, but of reactive intermediates and even transition states.”  — How do you know they are accurate?  Do they predict reaction rates? 

P. 27 — “In contrast to valence bond theory ‘full-blown’ molecular orbital theory (MOT) considers the electrons in molecules to occupy molecular orbitals that are formed by linear combinations of ALL atomic orbitals on ALL the atoms in the structure”.   I assume that the linear combinations allow weighting of the atomic orbitals as they are combined .  True?  (appears to be true by rule #14 of QMOT on p. 28 which talks about the size of the atomic orbital coefficients).  

   p.28 (added 13 June ’11)  — It wasn’t until I arrived at “Orbital effects” on p. 128 that the utility of the molecular orbital approach made it seem worth learning.  My eyes glazed over in the section on Qualitative Molecular Orbital Theory (pp. 28 –> ) the first time I read it.  So I went back and reread it.  

       Looking back, there are several things which threw me.  Chemists use lines between atoms to represent bonds — not so  in figures 1.7, 1.8 and the rest of the book — the lines just represent the positions of the atoms in space.  Only when the color of the orbital on atom #1 is the same as the color of the orbital on atom #2 is there bonding.  If the colors are different there is antibonding.  If there is no colored orbital on atom #2 the line between atoms #1 and #2 remains, but there is no bonding interaction, so the orbital on atom #1 is a nonbonding orbital. The lines between the atoms remain nonetheless, faking me out.  

     Another point (see figure 1.12 p. 37) — This is the mixing diagram of two CH3 groups to form ethane — there is no significance to which side of the energy levels of the mixed orbitals the orbital diagrams are placed.  This is true of all mixing diagrams in the book.

p. 31 — “We will constantly be checking our qualitative reasoning against quantitative calculations to be sure we are getting things right.”  Well, you’re really checking consistency, but how accurate are the calculations?

p. 31 — If you’re reading this chaper from front to back, make a copy of Figure 1.8 as it is referred to again and again.  Also memorize sigma(CH3), pi(CH3) and sigma(out) — the names are far from descriptive in terms of what you already know about sigma and pi bonds.  Also, the rationale for the names is far from convincing (see p. 32). 

p. 34 — I found the handwaving about the CH2 group rather difficult to believe until the mention of the different ionization energies of the  electrons in water’s lone pairs — proving the two ‘lone pair’ orbitals aren’t equivalent.  Can they actually show the different ionization energies leaving H20 as just lacking one electron (e.g. H3O+) and not stripping out a second electron from H3O+ ??

p. 35 — Even more interesting — the approach of another molecule to water (or any other for that matter) lowers the symmetry of the system allowing orbital mixing, giving two sp3-like orbitals.  QMOT might be proven correct by studying isolated molecules in the gas phase, but most chemistry happens when one molecule approaches another — so how useful is the theory described up to now? 

p. 36 — the fact that orbital mixing of filled identical orbitals from two identical atoms produces two molecular orbitals (bonding and antibonding), which when filled is destabilizing isn’t stressed in most introductory organic books.  But why is this so?   I don’t recall seeing an explanation in the QM course I audited.  “Closed shell repulsion” sounds almost like an explanation but it could use some elaboration.  Hopefully Ch. 14 on perturbation theory some 800 pages later will make this clear. 

p. 36 — In the construction of ethane from two methyl groups “We should use the MOs of pyramidal methyl as this is the geometry appropriate to ethane”.  Do you know this from calculations or from chemistry or chemical spectroscopy?  NMR? Crystallography?   I’ve always wondered how atoms come to be placed exactly where they are found with subsequent construction of molecular orbitals.

p. 37. (added 13 June ’11 ) — very important to note that the highest occupied molecular orbital in ethane has an antibonding interaction between the p orbitals of the two carbons, but it still is a bonding molecular orbital, because the overlap of the carbon p orbitals with the s orbitals of the 6 hydrogens results in a net bonding effect — so not every orbital interaction in a bonding molecular orbital must be bonding, some can be antibonding.

  p. 42 — Most books I’ve read don’t talk about the tilting of the antibonding pi orbital away from the region between the two ‘antibonded’ atoms — nice !  p. 46 — Even better this partially explains the rearward attack on R-Cl in an Sn2 reaction — but simple stereochemistry and physics explains it better. 

p. 43 — “We will show experimental evidence in Chapter 14 (pp. 807 –> ) that supports the fact that hybridization does not actually occur in the standard sp3, sp2 and sp manner”  — can’t wait.  It’s 22 April ’11 We’ll see how long it takes me to get there.

p. 50 — The 3 center 2 electron bond of the diboranes and death of Bill Lipscomb this month is an appropriate way to end this post.  A girlfriend got her PhD with him, liked him a lot (as did everyone) and has a publication with him listed in his Wikipedia article.  

        Which brings me to the women in our entering class of grad students back then.  They all did well, one getting her PhD from Bartlett in 3 years (apparently everything she tried worked the first time).  Interestingly one of the women found the atmosphere at Harvard oppressive and switched to MIT (which she didn’t find oppressive at all, contrary to a lot of the press MIT has received) and got her PhD there.

       Apparently, it was a very different time from the present — the 21 Apr ’11 Nature has a bunch of articles about “The future of the PhD” — something we had no worries about back then.  I still wonder if the situation is as grim for the PhD’s coming out of the Harvard chemistry department — no chauvanism intended, just curiosity.

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  • MJ  On April 25, 2011 at 11:51 pm

    Disclaimer – Not an organic chemist, never read Ansyln & Dougherty, not a protein folding person (I only occasionally bother to read the reviews as they come out).

    Re: molecular dipole moments – I vaguely recall an experiment in my undergrad p.chem. lab (10 years ago now) where molecular dipole moments were measured in solution by measuring the dielectric constant of the pure solution (within the given tolerances for purity, of course). There are also ways to do it using spectroscopic methods utilizing the Stark effect.

    Re: protein folding – well, my inner cynic has always felt it was less a “problem” and more “a really great way to ensure continued funding.” The presence of “intrinsically disordered” proteins suggests that some proteins have the temerity to not bother folding until you make them bind another protein (which we presume has done the decent thing and folded). The notion that “the primary sequence contains all the information necessary for the protein to reach its final tertiary structure” always felt like a giant snub to all of those poor maligned metallproteins out there – what’s the three-letter codon for iron again?

    The fact that people term it a “problem” also underscores my other concern – is it really just a singular problem? What happens with a small, well-behaved soluble protein is not going to be necessarily so for a large, temperamental transmembrane protein which is going to need to interact with the lipids in order to adopt its “resting” ensemble.

    I do think, though, that organic chemistry has useful things to contribute to understanding protein folding, although some of that will have to go through its cousin, polymer chemistry, in the end.

  • Ed Holland  On May 20, 2011 at 6:04 am

    p. 27 — “Modern calculational methods now provide accurate representations of the molecular orbitals not only of stable molecules, but of reactive intermediates and even transition states.” – How do you know they are accurate? Do they predict reaction rates?

    Yes, calculations do predict reaction rates, they also predict properties that we can empirically observe using ultra fast spectroscopy! We have lasers capable of doing TR-IR at less than a picosecond!!!

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