Category Archives: Anslyn & Doughterty

Anslyn pp. 537 – 626

I’m beginning to see what Tom Lowry meant when he told me physical organic chemistry was dead in the USA a few years ago. I can see why.  It seems to have done itself in.  This chapter on mechanism of 20 some reaction types is so complete and clever, that there seems to be little else to do with the classic organic reactions we studied and worked with 50 years ago.

Whether or not organometallic chemistry is equally well understood, is unclear to me at this point.  I’ll have to wait until Chapter 12 (pp. 705 –> ) to find out.  There was very little going on in the 50’s and 60’s aside from the Grignard reagent, chromium oxidations and ferrocene.   However on p. 560 we find out that they still don’t really know the structure of the Grignard reagent.  I wrote my junior paper on it in ’58.  Interestingly, there is some evidence for a radical mechanism some of the time. 

p. 538 — Good to see Edwin Gould getting a mention (by his last name only).  His book “Mechanism and Structure In Organic Chemisty” was the Bible for Physical Organic Chemistry in ’60.  He was a good amateur violinist and I had the pleasure of playing with him at a chamber music festival for amateurs at Interlaken, Michigan years ago.  Sad to note that he passed away at age 85 14 October ’11.  It’s even more interesting that he was not an organic chemist when he wrote his book, but rather a hard core physical chemist.  He was still pumping out papers in 2010 some  60 years after getting his PhD in 1950.  RIP Edwin.

pp. 1061 – 1074 — Appendix A.5  — This was suggested reading before plunging further.  It’s incredibly basic arrow pushing, detailed and specific.  Sort of ‘No organic chemist left behind”.

p. 543 — “The acid catalyzed hydration of most carbonyl structures involves alternative C of the reaction cordinates in Figure 9.13”   Why not give the page number for backward references.  The indexing software should accomodate this.  If not get some new indexing software. 

P. 548 — The cleverness involved in teasing out mechanistic details for what used to be a fairly simple reaction (HX addition to an alkene) is impressive.  Termolecular collisions — who’d a thunk it? 

p. 548 — The squalene –> lanosterol conversion, and the enzyme holding the reactant in place so the correct stereochemistry is obtained, while NOT reacting with the carbenium ion intermediates — are all reasons why it seems improbable (to me at least) that this exquisite chemistry arose by chance (or natural selection operating on chance events if you prefer).  The steroid nucleus is very fundamental to membrane fluidity, and individual steroids are intimately involved in metabolism, so the reaction is fairly fundamental for the existence of multicellular organisms. 

p. 552 — Great to see the inverse isotope effect put to some use.  Caution — although .53 isn’t higher than .8, it does represent a more pronounced inverse isotope effect. 

p. 553 — Although I’ve been snarky about kinetics — I never would have suspected that the kinetics of iodination of an alkene could have been third order.  I’d love to see the data points which separated a cubic rate dependence on iodine from a quadratic rate dependence.

p. 555 — Since steric effects are apparently in hydroboration (antiMarkownikoff etc. etc.)  It would be nice to know how big BH3 actually is.  I couldn’t find this anywhere.

p. 560 — They still don’t really know the structure of the Grignard reagent.  I wrote my junior paper on it in ’58.  Interesting, that there is some evidence for a radical mechanism in some cases. 

p. 561 — Why isn’t the Burgi Dunitz angle exactly that of sp3 hybridization (109 45′)? 

p. 573 — Good to see that high level theory explains carbenes — can’t wait to see how this stuff is actually calculated, but it’s several hundred pages away. 

p. 574 — “Diazomethane explodes on contact with ground glass joints”.  I don’t think this was known ’60 – ’62 when I was trying to work with the stuff.  We knew it was explosive, but weren’t sure just why.  Tom Lowry also had to work with it and, as I found out later, was just as frightened of it as I was.

p. 574 — Basic treatment of N-nitroso ureas generates carbenes.  Interesting as nitroso ureas (such as N-ethyl-N-nitrosourea) are used to produce mutations in experimental animals.   [ Cell vol. 89 pp. 487 – 490, 641 – 653, 655 – 667  ’97 ]  

Not many comments over all these pages.  The chemistry is great as is the understanding of mechanism.  But it’s so good, that it makes me wonder if there’s anything significant left to discover.  Is this why physical organic chemistry is said to be dead?

p. 595 — Aconitase — Interesting chemistry.  But the control mechanisms in the cell are tricky.  Because of the iron sulfur cluster, it exists in a different conformation when iron is deficient (e.g. it no longer has the cluster).  In this form it migrates to the nucleus to turn on transcription of genes which increase the cell’s ability to get iron (by stabilizing the messenger RNA for proteins like ferritin which bind iron).  Organic chemists should love subtlety like this. 

p. 597 — Why does attaching an oxygen or a nitrogen to an imine make it more stable (to hydrolysis)?

p. 606 — “If we have a 95% coupling yield, but we have to perform the reation 40 times to make a peptide with 41 amino acids our overall yield will be .95^40  = < .13.”  This is exactly the problem physicians face when ordering chemistry profiles (panels) — a measurement of a number of unrelated blood constituents — say glucose, sodium ion, calcium ion etc. etc.  When the number of constituents is even 20 the chance of them all being normal (e.g. in the range into which 95% of people fall) is only 35%.  It has to be this way if all the 20 constituents are statistically independent of each other — and usually they are and if they have essentially a Gaussian distribution (bell curve) which they largely do.  This is where the 95% comes from — it includes almost exactly two standard deviations on each side of the mean of a bell curve.  Statistical independence explains the choice of particular constituents to study.  Try explaining why you aren’t going to follow up a minor abnormality to a nervous patient using statistics.  

p. 609 — “Sigma complexes can be observed spectroscopically”  — How do you know what you are seeing spectroscopically is actually a sigma complex?  How was the spectroscopic signature of a sigma complex determined?

p. 616 — How do you make a phenyl radical?

Anslyn pp. 489 – 536

p. 490 — “Why do we want to catalyze a reaction” — to speed it up.  That’s the way chemists think of catalysis, but pedagogically A & D really missed the boat.  Why does the body need catalysis?  Raising the temperature speeds up most reactions, but living things require enzymatic catalysis so the organism doesn’t fry in the process of performing the reactions of intermediary metabolism. You can set a cube of glucose on fire by holding a match to it — it burns quite nicely.  They should have said something to this effect. 

p. 493 — “To achieve catalysis, the catalyst must stabilize the transition state more than it stabilizes the ground state”.  The idea that the ground state and product state must also (italics) be stabilized by the catalyst wasn’t emphasized in the books I read years ago (it isn’t even in Voet’s biochemistry).  Otherwise you have essentially preformed transition states wandering around waiting for a catalyst to bind to them.  Physically impossible. Obvious once you think of it. 

p. 494 “Enzymes have evolved to execute their reactions within a specific time period appropriate for the metabolism of life”.   Tautologous at best.  Fortunately they recover when they flesh this out discussing perfect enzymes (p. 529).

p. 494  — The spatial temporal postulate — that catalysts work by getting (and keeping) the reactants together so they react — is so obvious that I’d never thought of it this way 

p. 495 — Eq. 9.3 should be Fig. 9.3

p. 505 — Organocatalysis — Nice to see one reason why MacMillan is the head of the Princeton chemistry department — stereochemical organic catalysis.  Clever ! ! ! !

p. 506 — The lysozyme example is interesting, but a more complete diagram showing how the saccharide fits into the active site would be more convincing.  Something pushing the CH2OH group wouldn’t work unless the bottom of the ring were sitting on something in the protein preventing it from moving.  

p. 507 — Interesting that the specific acid and the specific base differ from each other by TWO protons, unlike conventional acid base chemistry. 

p. 510 — specific acid and base catalysis — slick way to tell if they are actually occurring by plotting the log of the rate vs. pH (also logarithmic).

p. 516 — Well, it had to happen sooner or later, a poorly written and wordy section of Anslyn && Dougherty.  There’s a lot of huffing and puffing for some pretty simple chemistry and math.   Otherwise, the writing in the book is superb. 

p.520 — The libido rule — who would have thought a chemist would use sex to sell books.  It seems trivial and obvious (the rule that is) and unworthy of a name.  Sex is certainly out there on the net.  A post titled “The tail of RNA polymerase II and the limits of chemical explanation” has generated all sorts of pornographic spam.  Guess why.  

p. 523 – 529 —  The discussion of enzymes is quite good, particularly in making explicit all the assumptions of Michaelis Menten kinetics.  It is especially good in discussing what a perfect enzyme is, how selection has optimized the Km of enzymes to match the concentration of their substrates, and why this as efficient as an enzyme can be. 

        Nonetheless the discussion in this section could be improved.  A few points:     

        In their description of the Michaelis Menten model, they don’t mention that it assumes the product (P) leaves enzyme forever, never to get back to substrate.  This simply isn’t true for many enzymes.  This must be the case as enzymes don’t change the free energy of reactant or product.  If the free energies are close all you need is the law of mass action to reverse the effect of the enzyme.  Many physiologic pumps (notably neurotranmitter reuptake proteins) can be run in reverse, depending on the concentrations of substrate inside and outside the cell. 
    
        A&D  totally ignore the fact that physiologic enzyme concentration are are quite low and that it must be  this way.  The molecular mass of glucose 6 phosphatase with its 357 amino acid must be at least 30 kiloDaltons. Carbonic anhydrase, a perfect enzyme discussed in this section, has a molecular mass of 29 – 35 kiloDaltons (depending on which gene product you are talking about).   So that’s a minimum 29 kiloGram molecular mass —  which is physically impossible to dissolve in 1 kiloGram of water to obtain a 1 molar solution.  

       Wikipedia says that cytoplasmic protein concentration is quite high — about 200 milliGrams/milliLiter.  So even if all the protein in the cell were carbonic anhydrase, its concentration would be 200/29,000 = 6 milliMolar.  But of course, that would leave no room for anything else, and the genome is thought to code for 20,000 or so different proteins, so probably the actually cellular concentration of any given enzyme is at most .6 microMolar.  Of course, exceptions do exist — the protein concentration of hemoglobin in a red blood cells — which is essentially a bag of hemoglobin (no DNA with its transcription machinery, no ribosomes, no messenger RNA) — is about the maximum 5 milliMolar.

      p. 524 —  Vmax is k(cat) * [ Eo ] and is easily measured.  This immediately gives the  Michaelis Menten constant (Km) which is Vmax/2 (this is why Vmax is so useful).  They could have put this in instead of saying “there are several ways to measure k(cat) and Km, which we leave to a textbook devoted to biochemisty”.  

      p. 524 — According to Wikipedia  Michaelis Menton should be Michaelis Menten, for Maude Menten one of the first woman MDs in Canada.  Born in 1879, she got her MD in 1911 and her PhD at the University of Chicago.  At the time women were not allowed to do research in Canada  (and you thought Canada was always so enlightened) so she went to Germany where she began to work with Leonor Michaelis getting her PhD in 1916.  Michaelis Mentin is spelled correctly on p. 523.

       It’s a worthwhile exercise in dimensional analysis to figure out why the unit of the Michaelis Menten constant turns out to be the unit of concentration (e.g. Molar).  A first order rate constant is in units of seconds^-1, a second order rate constant is in unit of moles^-1 * seconds^-1.  Quick — is a reaction going to go more slowly or more rapidly with a numerically larger rate constant.  Answer: the larger for the same reason that you ski faster on a steeper hill.  

p. 526 — You’d better know what a ribbon diagram of a protein is before looking at figure 9.15

p. 529 — “Bimolecular diffusion rates in water at conventional temperatures are in the range of 10^8 – 10^9/Mole * second”  A fact worth remembering.  This is the maximum k1 can be in Michaelis Menten kinetics in the real world. 

       The description of a perfect enzyme is excellent and should be remembered.  It does show the utility of thinking and thinking hard about kinetics (despite all my snarky remarks about them throughout these notes).  

p. 530 — Perhaps when the book was written modifying antibodies to produce enzymes hadn’t been done yet.  The reference to the artifical cyclodextrin enzyme is 14 years old.  

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 https://luysii.wordpress.com/2009/11/09/some-humility-is-in-order/

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.

Anslyn pp. 355 – 420 Part II (367 – 420)


       p. 369 — “In that substitution (for the equilibrium constant) a distribution of states for the transition state is indeed assumed, but it is not a Boltzmann distribution”  — Well, what is it? 

      p. 374 —  In the Going Deeper segment  “The momentum of the CH2 group as the hydrocarbon recoils from the expelled N2”  — a recoil would push the CH2 group away from N2 giving ii rather than iii.  

       p. 380 – Connections — trigonal bipyramidal intermediates in cyclic phosphotriesters.  What about something of more biologic interest, the phospho NON cyclic diesters holding the nucleotides of DNA and RNA together.  

       p. 385 — Lifetime — 1/k  — the term is often bandied about, but I never understood exactly how it was defined ’till now.  Only true for a first order reaction obviously, since the lifetime of an entity in a bimolecular reaction with a second order rate constant will be dependent on the other entity.  You can teach an old dog new tricks !  The units of a first order rate constant k is moles/second, so 1/k is seconds/mole.

      p. 390 Steady state kinetics — The equations look very close to Michaelis Menton kinetics which isn’t discussed until pp. 523. 

      p. 399 — nice to know just what the rate of a diffusion limited reaction is — 10^10 Moles/second 

       p. 400  Converting an IR stretch 3000 – 1000 cm^-1 to a time.  Cm^-1 is just the number of wavelengths/centimeter  So to convert cm^-1 to  frequency, multiply by the velocity of light in centimeters/second (e.g. 3 * 10^10 cm/sec) to get a frequency of 3 – 9 * 10^13/second.  So one vibration takes from 10 – 100 picoSeconds (or .01 – .10  femtoSeconds. 

       p. 403 It would be nice to see a derivation of the Marcus equation. 

       p. 406 — In the Connections section ‘steriod’ should be steroid.

       p. 412 — “the shape of the mountain pass (energy of the transition state) is representative of the entropy changes along the reaction coordinate”  — very nice analogy.  
       Not a lot of comments on 50 pages of Anslyn, but kinetics has always left me cold.  Perhaps it won’t after I get to chapter 14, which is a long 400 pages or so away
 

Anslyn pp. 355 – 420 Part I (pp. 355 – 366)

  

Chapter 7:  Truly a monster chapter, with lots of stuff in it that didn’t exist  the early 60’s.  Even though Part 1 concerns only the first 11 pages it contains three questions for the cognoscenti, some calculations to be checked  and plenty of material.   Still waiting to see how potential energy surfaces are actually calculated as opposed to posited — said to be coming up in chapter 14.  

p. 356 — First line of 7.1 “measurments”

p. 356 — What would be an example of a reaction NOT involving an energy barrier needing to be surmounted?  I can’t really think of one.  Supercooled water perhaps?  But that’s a phase change not a reactions.  

p. 357 — It isn’t a far jump mathematically from saddle point (well explained in the book) to homoclinic points and orbits, where chaos was first glimpsed by Poincare. 

p. 357 — Where does 3N – 6 come from? I suppose it arises from the fact that you can fix the position and momentum of one of the atoms (removing 6 degrees of freedom), with the rest dancing around this fixed point.   Also,  degree of freedom should be defined (it is next page), so a note saying so should be placed in the sentence on this page where the term first appears.

p. 358 — “Internal energy can be both potential and kinetic” — true enough for an oscillating spring, but somehow putting something high off the ground, while increasing its potential energy, doesn’t seem very internal to the object itself.  

p. 358 — Mnemonic — exerGonic — Gibbs free energy of product lower than starting material.  exotHermic — Heat given off — enthalpy of product lower than starting material.

p. 359 — “The minimum energy pathway or the  pathway we depict as the weighted average of all the pathways, is called the reaction coordinate.”  OK–but how do you weight the pathways? 

p. 360 — Nice to see Patch clamping mentioned.  It’s taught neuroscientists and clinicians a tremendous amount — particularly how anticonvulsants (drugs against epilepsy) actually work.  Unfortunately Neher is a chemical ignoramus, talking about nanoDomains near the membrane where concentrations of a particular ion are in the microMolar region, but the domain is so small that there are only 8 calcium ions in this domain.

      Calculation for the cognoscenti to criticize.      [ Proc. Natl. Acad. Sci. vol. 100 p. 7341 ’03 ] Entry of calcium through a calcium channel produces a steep concentration gradient (since the overall intracellular calcium concentration is so low).  Levels of over 100 microMolar are obtained (1000 times the normal intracellular concentration) are reached within these nanoDomains — within 500 Angstroms of the channel pore. 

       My calculation: How many calcium ions is this?  1 milliLiter is 1 cm. on a side.  At a 1 molar concentration 1 milliLiter contains 6 x 10^20 ions.  At a 1 milliMolar concentration it contains 6 x 10^17) ions, at a 100 microMolar concentration a milliLiter contains 6 x 10^16 ions.  How many cubes 50 nanoMeters on a side are there in a cube 10 milliMeters on a side? There are twenty 50 nanoMeter lengths in 1 microMeter, 20,000 lengths in a millimeter, and 200,000 of them in 10 milliMeters so there are 8 x 10^15 50 nanoMeter sided cubes in 1 milliLiter which contains 6 x 10^16 ions at a concentration of 100 microMolar.  So the 500 Angstrom (50 nanoMeter) sided  cube with the calcium channel in the middle of one face contains less than 8 calcium ions.

        What is the volume of a hemisphere of radius 50 nanometers?   It is .5 * (4/3) * pi * (50) * 50 * 50 == 261666 cubic nanometers.  There are 10(7) nanometers in a centimeter, so there are 10(21) cubic nanoMeters in a cubic centimer (or milliliter).   Thus there are 10(21)/2.6 x 10(5) such hemispheres in a cc.  There are 4 x 10(15) of them.   Dividing this into the 6 x 10(16) ions in a cc. at 100 microMolar gives 15 ions in this hemisphere.   Is concentration a meaningful concept in such a small area? (bold !)  500 Angstroms is a long distance where proteins are concerned.  

       Question for the cognoscenti #1:  I look forward to understanding ion velocities and mean free path and diffusion constants by the end of this year (2011).  Perhaps 8 – 16 calcium ions in an area this small isn’t meaningless.  Think of a 3 lane freeway carrying heavy traffic.  On any given 100 foot stretch, there probably aren’t more than 8 – 16 cars (but they are all going one way). So if the ions are zinging around fast enough, the average number of the ions in question contained in this volume at any instant might be quite stable, even if the number is only 8 – 16 ions. If any PChem maven has anything to say on this subject, please enlighten me.

p. 362 — “Rigorous methods for creating reaction coordinate diagrams also exist.  High level computational methods such as we present in Chapter 14 can be used”  Can’t wait to see if they are actually able to calculate the details of a potential energy surface.  But Ch. 14 is a long 445 pages away

       p. 363 — Interesting to know that the activated complex has a lifetime no longer than a vibration (period of a vibration).  This is either new, or not emphasized when I studied transition state theory 50 years ago.   On p. 366 this is elaborated.

       Question for the cognoscenti #2The notion of eigenvector as a force is certainly new to me. Is it in fact correct? Quantum states are eigenvectors, but are they forces?  Seems quite strange !  Any cognoscenti out there?  It’s clear that force is the negative first derivative of energy.  Where do matrices come in?  Eigenvalues as a second derivative of energy was never mentioned in the QM course I took.  Some elaboration could be used here.  I can see why the second derivative must be negative at the top of a hill, that’s just calculus 101 after all, but why do the authors call this an eigenvalue?    Hopefully all will be explained in the far distant Chapter 14 (440+ pages away. 

       p. 366 — The terms are enshrined by usage, but cognitively it would be better to have better differentiated symbols for k, K, k†, K†, K†’ and kappa.

       Henry Eyring !  He came to speak to us as undergraduates in the late 50’s.  It was my first exposure to a Western type guy.  Everything was Aw shucks, I jes’ happened to back into this (amazing) result.  In the West, the one unforgivable sin is bragging, followed by telling people what you are ‘really’ like.  Out there, people are so thin on the ground, that they’ll find out what you’re like without you having to tell them.  Of course I went out and bought Eyring Walter and Kimball, even though I was far from having the background to understand it.

      “We invoke statistical mechanics because a transition state does not have a Boltzmann distribution of states (see the next section), because its lifetime is so fleeting.”  If the Boltzmann distribution isn’t statistical mechanics what is?  Question for the cognoscenti #3:  Does this sentence really make sense? 

Anslyn pp. 298 – 354

p. 298 — I always have trouble keeping enantiomer and diastereomer straight.  The mnemonic I use is that mirrorEnantiomer is easier to pronounce than mirrorDiastereomer.

p. 300 — Nice distinction between chiral and optically active — hadn’t thought of it before.

p. 304 —  Ah, the Cahn Ingold Prelog system, a classic example of cognitive dissonance.  For those who don’t know about this, Google the Stroop test, where you are to read aloud words for colors, themselves colored with the wrong color (example — RED written in green etc. etc.).  It’s harder than you think.  Try it.

So in the Cahn Ingold Prelog system you assign the various groups ‘high’ priorities, and give the highest priority the LOWEST integer value (e.g. 1), causing simlar mental flipflops. 

p. 304 — Another mnemonic — Zus (short for zusammen) sounds like cis.

p. 304 — “Thus, it is commonly stated  that all natural amino acids are L, while natural sugars are D”.  It’s ‘commonly stated’ because it’s true ! 

p. 305 — Helical descriptors — I thought I’d find out what left and right handed DNA helices were all about.  The section gives no clue about how this could be applied to DNA. This isn’t trivial as Z-DNA is unwound and forms a left handed helix (A and B DNA have right handed helices). All 3 forms are crucial physiologically. — p. 336 neither does this discussion of DNA helices.

p. 307 — Nice to see what the naturally occurring amino acids (the L-amino acids) turn out to be in the Cahn Ingold Prelog system, and to have a clear explanation of just what allo-isoleucine and allo-threonine really are. 

p. 308 — The chiral shift reagent is poorly described.  I assume Eu is Europium — something we never used 50 years ago.  Does the 2 D 2 Phe EtOH bump off one of the 3 ligands, or occupy a fourth coordination position? 

p. 311 — Sn — improper rotation.  Of course anything having Sn symmetry can’t be chiral — it has a mirror plane of symmetry.  Is Sn really telling you anything new? 

p. 315 – 317 —  A blizzard of terminology.  Hopefully it will turn out to be useful.  My old chief used to say that there was never any progress in neurology, but every ten years they renamed the diseases. 

p. 325 — The proteins known to contain cystine knots ( basically a disulfide bridge formed by cystine forms a ring through which another portion of the amino acid chain passes ! !  )  are a very important bunch.  Nerve growth factor, Vascular endothelial growth factors, and human chorionic gonadotropin (the latter responsible for placental formation).  

       [ Proc. Natl. Acad. Sci. vol. 107 pp. 8189 – 8194 ’10 ] Proteins with knots in them defy popular concepts of protein folding which say that cooperativity, an increasing degree of nativeness and smooth energy landscapes (whatever they are — perhaps chapter 7 will explain this) are needed for rapid and efficient protein folding.  All this implies that proteins should be knot-free. 

       However, trefoil, figure of eight and penta knots with 3, 4 and 5 projected crossings of the polypeptide backbone (respectively) have been found in proteins from all 3 domains of life.  

      p. 325  What’s the fun of commenting on a text if you can’t be petty?  Euclidian isomerism should be Euclidean isomerism.

      p. 326 — I never thought I’d learn some math reading A&&D, but there it is — only two types of nonplanar graphs ! ! !

      pp. 327 – 330 — Great fun

      pp. 331 — “Going Deeper” I did exactly the same calculation a few years ago, but this time for proteins.  Before looking at the link see if you can figure out the following:  Assume the earth is made of C, H, O, N and S in whatever proportions you need.  Then find the value of n for which  20^n (20 to the nth power) times the average mass of an amino acid (100 Daltons) times n gets you to a mass larger than the earth.  Just make one copy of each of the 20^n possibilities.   Here’s the link — https://luysii.wordpress.com/2009/12/20/how-many-proteins-can-be-made-using-the-entire-earth-mass-to-do-so/

     If you haven’t had enough, try your hand at the number of possible RNA molecules you can make (now you need to assume that the earth is made of C, H, O, N, S and P in the proportions you need).  Here’s the link — https://luysii.wordpress.com/2009/12/28/how-many-distinct-rna-polymers-can-be-made-using-the-mass-of-the-earth-to-do-so/

     We live in a very small corner of a very large protein and RNA space.

p. 332 — A pleasure to read about the Zn metallocene catalysts and the cleverness involved in figuring them out.  I’m still far from convinced that statements using the jargon of “chirotopic but non stereogenic” helps you understand what’s going on. 

p. 334 — The discussion of s-cis and s-trans is quite good, particularly as it applies to proline.  I don’t think most people dealing with proteins know this, although it is well recognized that proline causes unusual protein structures (type I and type II polyProline helices).  Just a 4 kCal difference between s-cis and s-trans and the low (19 kCal) activation energy means most proteins (except proline) have a largely (over 1000 times the s-cis) s-trans conformation.

p. 335 — Good to remember the glycogen (animal starch) and plain old starch (from plants) both have alpha 1 –> 4 glycosidic links between the glucoses.  Glycogen has a lot more branching (via 1 –> 6 glycosidic links) than plant starch. 

p. 339 — The problem origin of enantiomeric excess is similar to the problem of the excess of matter over antimatter in our neck of the universe.  People make noises about how it could happen, but no one has a convincing explanation. 

pp. 340 – 344 — What a blizzard of terms.  Nice to have them all in one place, but I’m not sure how helpful they are.  Remember, at least half your cerebral cortex is involved in analyzing visual input, and each optic nerve has about 1,000,000 fibers which can fire ‘up to’ once a milliSecond, so visual information can be flowing into your brain at 2 gigaBits/second.  

     The terms remind me of the Lilliputians trying to tie down Gulliver by tiny threads.  Our perception of space is so complex, that such reductionism has a very long way to go.

Sorry to be skipping the exercises, but the book is so meaty, that I’ll never get through it before year end if I do them.  The ones I’ve done have been great.

Anslyn pp. 259 – 296


p. 259 — Looking forward to seeing how the pKas of the following
Acetylene 25
NH3 33
Di-isopropyl amide 35
Toluene 40
Benzene   43 (50 C1070)
Methane  48
Butane 50

     are actually defined. 

    1 proton in a liter of water from H-A would only have a pKa of only 16 or so. 

p. 260 — I’ve always thought that the terms acid/base conjugate acid/conjugate base was meaningless, and a source of unnecessary confusion .  All 4 are in equilibrium and what you call each of the 4 moieties depends on where (out of equilibrium) you start. 

p. 261 — Note that Ka as defined in equations 5.7 is really a dissociation constant (Kd) as defined in the previous chapter. 

p. 263 — Ah the Henderson Hasselbalch equation — important in med school, if not medicine itself.  The body maintains blood pH in a very narrow range (7.36 – 7.44) because blood is so highly buffered (hopefully A & D will talk about this).  No they don’t. Buffer is not even in the index.  So I will.  

I don’t know if people still do titrations with a beuret, but if you have done one, you know how infinitesmal the amount of acid you have to add to get a color change at the critical point.  To change ph 7.36 to 7.44 to 7.36 takes under 10 microMoles of protons.   Metabolizing glucose (neutral) to CO2 (acid when dissolved in water) happens all the time in the body.  It gets worse when oxygen isn’t around for the final steps, and lactic acid is produced.  This is why anoxic patients are so acidotic.

Anyway, suppose you add 100 milliMoles of an acid whose pKa is around 7 to water.  It then takes 100 milliMoles of acid to change pH by one unit.  That’s what buffers are all about, and the body is full of them. 

p. 266 — “Therefore, now, new acidity scales are needed, giving a measurement of the effective ability of the concentrated solution to donate protons to an organic compound, just as the pH is the ability of a dilute acid solution to donate protons” — should add “to water”.

p. 267 “too weak of a base” — Oh, well, Anslyn teaches in Texas.  They seem to be teaching him. 

p. 273 — Nice to see some actual values for pKa’s inside proteins.  However the reference is 19 years old.  Isn’t there some more recent data?  Describing how the pKas were determined would be interesting.

p. 274 — Gas phase ‘acidities’ seem to be a rather bizarre construct.  They do tell you something about anion stability. 

p. 276 — So that’s how they determine pKa’s over 16 ! !  It reminds me of the distances scales astronomers use, the farther out you go, the more assumptions you must swallow.  Parallax is pretty straightforward, then come Cepheid variables, red shifts and on and on. 

p. 284  “The princple  influence is the hybridization of the carbon.”  Who learned you,  boy ! 

p. 286 — The structures shown for glutamic acid, aspartic acid, lysine and arginine are worthy of my first organic chemistry textbook circa 1957 — English and Cassidy.

p. 287 — Hoogsteen hydrogen bonding between A and C requires that the cytidine be protonated.  As the pH is lowered below 7 (to pH 5 and 6), triple helical DNA formation is enhanced.   Very nice — didn’t know this. HoweverI doubt that this occurs in vivo.  The body keeps pH very tightly controlled.   You’re practically dead when blood pH goes below 7.0.  However some compartments of the body (think gastric acid in the stromach with its pH of 1) have low pH.   The pH of the cytoplasm of cells is between 7.0 and 7.4, that of the nucleus is held to be .3 – .5 pH units higher (http://jcs.biologists.org/content/109/1/257.short) so it’s unlikely that this is relevant physiologically, fascinating though it is. 

p. 288 — Nice discussion of Lewis acid/base, vs. electrophile/nucleophile.  However, Clayden somewhere gave the example of an anion R2N:- which was a great base, but a lousy nucleophile because it was so sterically obstructed.

p. 289 — Good to see the correlation between polarizability and softness of the nucleophile — I don’t think Clayden ever said so. 

p. 291 — second paragraph second to last line ‘nuclephilic’

Anslyn pp. 201 – 258

p. 207 — Molecular recognition — exactly what physical organic chemistry must address if it is to be more than chemical navel-gazing (fascinating though this is to me).  The fact that 7 transmembrane G protein coupled receptors (GPCRs) can distinguish between dopamine and norepinephrine, which differ by a single oxygen atom binding both in the center of the ring of 7 alpha helices, along with the other examples given in the first paragraph shows its importance to molecular biology, biology, medicine and life.  Hopefully physical organic chemistry has something useful to say about this.  

I learned a fair amount I didn’t know about proteins in the previous chapter, even though it concerned itself with solvents and solutes.  Looking forward.

p. 208 — Important to note that the term ‘binding constant’ refers either  to Ka or Kd — not just Ka.  This wasn’t made clear in the text.  The first example is on p. 209 where the term binding constant is used for the association constant. 

p. 208 — Host and guest discussion.  In most examples of biologic and medical interest the host is a protein.  This means that for a polypeptide with an molecular mass of at least 1000 Daltons (only 10 amino acids), a 1 MOLAR solution is physically impossible — you can’t get a mole of the stuff into a liter.  Drop this by at least 2 orders of magnitude, which means that you can’t even get 10 milliMoles of most proteins into a liter.  So the discussions of biologic interest will have [H] and (of necessity) [HG] rather low (usually microMolar or less).  

p. 210 — The discussion of why [ H ] and [ G ] increase more than [ HG ] with dilution is quite good.  Entropy conquers all ! ! ! 

      Also good point about Ka (and pKa) for acids — it’s really a dissociation constant. The nomenclature however is entrenched.

p. 213 — I realize this isn’t physics book, but an explanation of where ln(Tf/Ti) comes from (the integral of 1/T) would be good.  Otherwise it’s just magic. 

p. 215 — In the next edition you might mention a few allosteric effects which will grab the readers attention — such as those of the benzodiazepine class of drugs (librium, valium, xanax, ativan, halcion etc. etc.) which bind to a receptor for the major inhibitory neurotransmitter in the brain (gamma amino butyric acid) in an allosteric fashion, altering its conformation and making it easier for it to bind gamma amino butyric acid.  This is better than “This is commonly found in Nature”.  Interestingly, the barbiturate anticonvulsants (phenobarbital is one) act the same way.

p. 216 — The enthalpy entropy compensation is one of those types of reasoning that chemists are good at (it is obvious once you think of it), but very difficult to put into mathematical form. 

p. 217 — The derivation of 4.24 from 4.2 and [H]o = { HG ] + [H] would be good. 

p. 217 — 222 –Binding isotherms.   This sort of stuff has always left me cold.  It takes a lot work for the hapless graduate student doing it, and there is always some other explanation for the data, which puts the wretch back in tha lab for another 6 months of experiments.  This is particularly true of kinetic work (which is similar but not covered in this section).  I saw Westheimer pull this on a number of people from ’60 – ’62.  Unlike a lot of the clever experiments in the book, (see “Proton Sponges” on p. 179), this sort of work rarely proves anything.

p. 223 — It is crucial when equating deltaH to the heat absorbed, that the system do no work.  In experiments done under atmospheric pressure, this means no PV work as neither P nor V change (usually).  However there are other types of work which as system can do (electrical for one) and these must be excluded as well. 

p. 224 — The crown ether story is fascinating.  Nothing about it in Clayden so it’s new to me.  I do remember some mumbling about it when people were trying to explain why there was so little sodium and so much potassium in cells.  See the comments on activity coefficients https://luysii.wordpress.com/2011/06/29/anslyn-pp-144-200/ p. 156.

Something rather similar occurs in ion channels letting potassium ions through while making it at least 10 times more difficult for the smaller sodium ion to get through.  There is tight coordination of the potassium ion by the carbonyl oxygens (italics) of the protein backbone, meaning that stripping K+ of its waters is energetically neutral.  The smaller sodium ion doesn’t fit as tightly here so there is the energetic cost of a poorly coordinated positive charge with no waters around in the middle of the membrane (with its low dielectric constant).  The coordination of K+ by carbonyls came as a huge shock to those studying ion channels when the first crystal structures became available.   The crown ethers came much earlier (1967) than crystal structures of membrane proteins, but I wonder if the neurophysiologists and crystallographers knew of them — probably they did as it was a great example of differential coordination of ions slightly different in size.  

pp.  225 – 248 — A bunch of fascinating chemistry, most of which was unfamiliar.  Not much to say about it except about cation pi bonds.  

 p. 240.  Rather interesting that Wikipedia calls cation pi bonds, the Dougherty effect, but that Dougherty is too modest to say so in the text.    [ Nature vol. 458 pp. 384, 534 – 537 ’09 ] If nicotine bound as tightly to to the muscle nicotinic receptors as it does to brain receptors, cigarette smoking would cause fatal muscle contractions.  Acetylcholine (AcCh) makes a cation pi interaction when it binds to the brain AcCh receptor (AcChR).  Nicotine (despite its positive charge at physiologic pH — perhaps because the positive charge is fixed in AcCh and reversible in nicotine, or perhaps the water must be stripped) doesn’t make a similar bond with the muscle AcChR.  A single amino acid difference between the brain receptor responsible for nicotine addition (alpha4beta2) and muscle receptors explains the binding difference.  

p. 249 — The biotin streptavidin complex is widely used in biologic research to tag molecules and follow them throughout the cell.  This is due to the very high Ka of 10^15.

p. 251 — Cyclobutadiane at last.  Sacre Bleu ! ! 

Anslyn pp. 144 – 200

p. 147 — The dielectric constant is measured by how much a substance can alter the capacitance of two plates when placed between them.  If you want to see a variety of ways to actually measure capacitance see http://www.pupman.com/listarchives/1998/April/msg00625.html

p. 149 — Connections — Introduction of 6 different parameters of solvent properties is a real yawner (but necessary).  The connections box on this page makes the reader snap to attention, as they show a real use of two of them(alpha and beta).  Very nice.  Another very nice use of the solvent parameters is the connections box on p. 172. 

The 6 solvent parameters remind me of the 6 blind men and the elephant.  They speak to the same truth — a solvent has many distinct aspects, none of which are the whole story.

p. 152  — last paragraph — “fluxuation” — time for the spellchecker to come out.

p. 156 — DeBye Huckel theory — 50 years ago in grad school we snickered that it only describes slightly contaminated distilled water.  Never forget that the activity coefficient is a fudge factor determined by experiment, not predicted a priori.  Every year my wife and I have dinner with a friend from that era (currently a chemistry department chair), I ask him for the status of DBH and he tells me this is still true (as of Oct ’10).  Remember the concentration of salt in our cells is .3 MOLAR (not a misprint).

In 1962 activity coefficients were used to ‘explain’ why sodium outside cells is 140 milliMolar (roughly) while inside it’s around 10, and why potassium levels are 10 times higher inside cells than outside.   Of course, it’s not an explanation at all.  Coming fresh from grad school, I found this amazingly irritating.  A lot of medicine is like that.  Shut up and remember the way things are, since we don’t know why things are the way we are.  Things have improved presently since we know more about ion channel selectivities, and ion pumps, but there’s still plenty we don’t understand — why we need sleep for one.  

p. 158 — “Energy is not force, but driving force gives a good mental image.”  Anslyn and Dougherty really missed the boat here.  Why call the chemical potential a potential at all?  Because in mechanics the derivative of of the potential energy IS a force.  Why isn’t the Gibbs free energy a force?  Think about it.

Well, as they say, energy isn’t a force.  But there is a deeper reason, moreover the reason is chemical.  When a net force acts on an object there is NOTHING to oppose it.  A difference in Gibbs free energy isn’t the same thing as a force — because of activation energy (italics).  If there were no activation energy a free energy of a chemical change would act exactly like a force.

p. 165 — Excellent discussion of salt bridges in proteins.  Every  paper I’ve read discussing the structure of a particular protein, implicitly assumes that salt bridges are stabilizing.  The excellent discussion shows that (1) it depends on where the salt bridge is (on the outside of a protein, or deep inside) (2) the dielectric constant near the salt bridge — only guessed at in most cases (3) stability is always relative to something else, and compared to hydrophobic side chains of comparable size to asp, glu, lys and arg, the salt bridge deep inside a protein is actually less stable.

p. 166 — An explanation of why the potential energy of ion dipole interactions falls off as 1/r^2 while that of a simple coulombic interaction falls off as 1/r  would be nice. 

p. 168 — A great explanation of the Magic Angle used in NMR spectroscopy.  It’s the angle of offset at which two parallel dipoles (by definition in the same plane) feel no force between them.  

       The potential energy of two parallel dipoles is given by

     E  = -mu1 * mu2 (3 cos^2theta -1)/(4 * pi * r^3 epsilon)

       Where mu1 and mu2 are the dipole moments of the two dipoles, theta is the angle of offset of the two dipoles, r the distance between them, and epsilon is the dielectric coefficient.   E = 0 when theta = arccos {(1/sqrt(3)] which turns out to 54.7 degrees.  So the tube with the NMR sample is inclined by the magic angle to the imposed field, and spun rapidly.  This removes dipole/dipole interactions which would extremely complicate NMR spectra.  It doesn’t affect spin/spin splitting.

      I realize this isn’t a physics textbook, but a pointer to where this and other formulas are derived would be nice.  Otherwise the formulas seem like magic themselves. 

p. 168 “for weak to moderate hydrogen bonds”  — what energy range are we talking about? One of the great strengths of physical organic chemistry (and this book) is its quantitative nature.   The answer is given on p. 171 — you should point to it here, or put the values here.

p/ 172 — Connections — The fact that stronger O – H . . . O bonds have a shorter O – O distance shouldn’t be found here, but where hydrogen bonds are first discussed. 

p. 176  — Going Deeper — very nice discussion.  Anything which helps us understand protein structure more deeply is worthwhile.

p. 179 — The proton sponge and the logical thinking of why para methoxy groups don’t help while ortho methoxy groups do — is exactly why I love organic chemistry.  Have an idea?  Then build a molecule to test it.

p. 184 — re pi stacking.  What about the stacking of the nucleotide bases in DNA and RNA (which we know occurs).  Some mention of this should be made.  In the classic B form of the DNA double helix there are 10.3 bases/turn and they are stacked every 3.4 Angstroms.  Isthe 30 degree shift of each base in this form enough to consider it slip stacking?

Also what about the lady at Cal Tech  (Jacqueline Barton) who calls DNA a pi wire.  [ Proc. Natl. Acad. Sci. vol. 96 pp. 8353 – 8358 ’99 ] I’ve always wondered about this.   The bases stack on top of one another and it seems that charge could easily be transfered through the stack — which she calls a pi-way.   Surely a physical organic chemist should be able to weigh in on this.  I don’t see anything about it in the index.   

p. 189  — “The precise physical origin of the hydrophobic effect has been intensely investigated and is still debated” (as of 2006).  Great statement !   Statements in papers tend to be authoritative.  It’s good to see an honest appraisal of where the field stands.

p. 190 — How are the relative amoungs of linear (anti) and curled up (gauche) n-butane in water actually measured ?  

p. 199 — Fabulous — an explanation of molecular dynamics at last (it uses the derivatives of the molecular mechanics force field equations to get the actual forces involved.  Then clockwork Newtonian universe is set in motion, and stopped after a very short time (Femtoseconds), then the energy of the configuration calculated and the universe set in motion again. 

       (added 30 June ’11 ) Why such a short time?  Because “experience has shown” that allowing the system to follow a trajectory longer that 10^-15 seconds will carry a system into unrealistic geometries, because the forces used in molecular dynamics simulations aren’t true forces (because the potentials they are derived from aren’t true potentials).   Why?  For a great example see problem #27 p. 140.  This is what happens at long bond lengths if a cubic term is added to the quadratic form of the harmonic oscillator to make it more “Morse-like”

  The references at the end of the chapter are pretty skimpy.  Dill’s book “Molecular Driving Forces”, which I’m about to start, doesn’t have a molecular dynamics entry in its index.  Does anyone have any good references for a beginner in moleular dynamics simulations.  If so, post a comment please. 

Molecular dynamics didn’t exist in the 60’s as the computational power for it was nowhere to be found. 

All in all a fabulous chapter.

Anslyn pp. 101 – 143

The book keeps getting better and better.  Here are comments, questions, addenda, errors accumulated as I went through the rest of Chapter 2 and the 52 problems at the end.

p. 102 — Nice to see the C3 and C2 endo forms of ribose drawn out at last.  Papers I’ve read use the term, but never show the structures.  Cn endo means that the endo carbon is above the plane of the ring on the same side as the DNA or RNA base.

p. 105 — In the connections box it is stated that deltaG was determined by infrared spectroscopy — hopefully there will be some detail on exactly how IR spectroscopy can do this later in the book. 

p.106 — deltaE * deltaT = pi * sqrt(2) .  This looks like the Heisenberg Uncertainty principle, in a somewhat different garb, but the units are the same.  However the principle says deltaE * deltaT = hBar.  So what gives.  Nonetheless it is a nice explanation of the NMR timescale — if you accept it.

      Clearly the formula is wrong as later they say that 2.22 is pi * sqrt(2)

but 3.14 * 1.414 = 4.44, so 2.22 is pi/sqrt(2).

      Sad — because I’ve always wondered how NMR was used for kinetics, and I thought this would be an explanation.  I wrote Anslyn about it 10 Jun and I’ll put his reply here. 

      I wrote Anslyn who promptly got back, saying that Dougherty wrote this section.  Here is Dougherty’s reply of 16 June.  Pretty quick responses !   

There is indeed a typo on p 106 that has been corrected in later print runs. pi/sqrt(2) = 2.22.
Typically statements of the uncertainty principle have an h on the right side – see the Wikipedia page.  I think this version just is based on a certain set of units and plugging in values for the fundamental constants.  Right now I don’t really remember where it came from.
Glad that you are (mostly) enjoying the book.

Dennis Dougherty

So beware if you bought a used copy trying to save money and have an earlier printing than the current one which I think is #4 as of 6/11.  My edition  is the second printing)– there is no errata page (which there should be).

p. 108 — “A major role of cholesterol is to insert into and thereby stabilize cell membranes.”    Actually exactly the opposite is true — cholesterol fluidizes cellular membranes by preventing the hydrocarbon chains of phospholipids from packing to each other forming a semi-crystallized state as they do in the membrane of a soap bubble.

p. 111 — Amazing that someone has made bicyclo[1,1,1] pentane, pristane and cubane.  They were chemical hallucinations in the early 60s.  

p. 117 — the Trishomocyclopropenium ion looks like benzene missing an electron.  Is it?  Is it C6H6+ ??

p. 118 — What is photoacoustic calorimetry — sounds like laser accupressure.

p. 122 — It wasn’t until I arrived at “Orbital effects” 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 (italics, bold) 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 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.  Also true of all mixing diagrams in the book.

p. 122 — Some values for the equilibrium constants of the different conformations of CH2F NH2 and CH2F-CH2F would be nice. Also, it would be nice to know how were the relative amounts of the conformations are determined (perhaps this will appear later in the book)

p. 128 –> The discussion of the molecular mechanics method was great, particularly all the caveats.  This appears to be the origin of the force fields used in determining protein structures, and it’s good to see where it comes from.  Presumably molecular dynamics simulations come from the same sort of thing.  The last half of the year will (hopefully) be the year of PChem for me (assuming life doesn’t supervene). 

p. 131 — “They do not necessarily reflect any kind of experimental reality” but two sentences before that we have “Apparently, this particular combination (of parameters) gives the best fit to experimental data.”  Which is it?

p. 135  — also great to see the feet of clay of the force field as applied to biopolymers (my primary interest in knowing this stuff). 

p. 136 — Good to see that Dr. Schleyer got adamantane from a simple Diels Alder condensate (after it was hydrogenated !).   Did he calculate it first using molecular mechanics, predicting the synthesis ?  Amusing that I used Symmetrel (1 amino adamantane) as a therapeutic adjunct in Parkinson’s disease treatment (never enough by itself).

PP. 138 – 143 — Problem set.  In general they’re fun and challenging.  Sometimes the page that a table or a figure referred to in a problem is given.  This is helpful since the chapter contains 73 pages of text.  Usually the page isn’t given — it should be.   Also the answers are long and discursive and bring in material by way of explanation and elaboration that isn’t covered in the text.  It took a while to do all 52 problems and plow through their answers (many of which surprised me), but it was well worth it.  I recommend doing this. 

P. 138  Problem #5 — great problem, I doubt that anyone anticipated that the double bond in trans cyclo-octene is slightly shorter than a normal double bond.  Or did they?  This is likely a case of post hoc propter hoc.  Does anyone know?

Problem #7 — the answer is great and almost constitutes a course in various ways to figure out aromaticity.  If this keeps up, the answer book will be required reading, and essentially another textbook. 

Problem #9 — What about the anomeric effect using the pi bond of the olefin as the donor and the sigma* C  – C bond as the (weak acceptor)? 

Problem #13 — Another explanation (mine) is that with gauche conformations, the two rings lie (to some extent) over each other, while with the anti conformation of the hydrogens, they do not.

Problem #14 benezoid?   Probably should be benzene

Problem #16  — Answer.  Again a nice discussion.  If K = B/A  Then B = K/(K+1),  A = 1(k+1)

Problem #17 — Amazing that people have made the two isomers of benzene and calculated their heats of formation.  It’s sort of chemial bonsai.

Problem #24 — I’m not sure what they’re calling anti (the hydrogens?).  All conformations have phenyl groups on carbons 1 and 2 anti.   A diagram would be nice.

Problem #28 — Dipoles calculated from electronegativities of atoms — but electronegativities weren’t part of the discussion of molecular mechanics, unless it snuck in under coulombic forces.  Molecular mechanics presumably gives you geometry assuming you know how to minimize the various force fields.  No discussion of how this is actually done ! 

Problem #29 — The central geometry of the quaternary carbon must have typical sp3 angles of 109.  The bonds in the cyclopropanes are squished to 35 degrees, and molecular mechanics is poor for strained molecules — since molecules with similar distortions aren’t well represented in the parameterization set. 

Problem #34 — Not sure which isomer is s-trans and which is s-cis in this problem.

Problem #38 — Just the opposite of what I would have expected.  The rationale is interesting and makes sense.  I won’t spoil the fun — look at the problem and see which is harder to bend — sp3 or sp2 or sp1.  Now look at the answer.

Answer:  The more p character in the bond the more directional (and the more s character in a bond the less direction).

Problem #40 — The answer is a whole text on transition states of cyclohexane by itself.  

I did the remaining 12 problems, but this post is long enough