Category Archives: Clayden's Book

Why math is hard (for me) and organic chemistry is easy

I’ve been reading a lot of hard core math lately (I’ll explain why at the end), along with Clayden et al’s new edition of their fabulous Organic Chemistry text.  The level of sophistication takes a quantum jump about 2/3 of the way through (around pp. 796) and is probably near to the graduate level.  The exercise is great fun, but math and orgo require quite distinct ways of thinking.  Intermixing both on a daily basis brought home just how very different they are.

First off, the concepts in organic chemistry are fuzzy.  On p. 796 the graph of the Karplus relationship between J splitting in NMR and the dihedral angle of the hydrogens being split is shown.  It’s a continuous curve as the splitting is maximal at 180, zero at 90 and somewhat less than maximal at 0 degrees.

There is nothing like this in math.  Terms are defined exactly and the logic is that of true, false and the excluded middle (e.g. things are either true or false).   Remember the way that the square root of 2 was proved not to be the ratio of two whole numbers.  It was assumed that it could be done, and than it was shown no matter how you sliced it, a contradiction was reached.   The contradiction then implied that the opposite was true — if the negative of a proposition leads to a contradiction (it’s false) than the proposition must be true.  Math is full of proofs like this.Or if you are trying to prove A implies B, proving the contrapositive ( not B implies not A) will do just as well.  You never see stuff like this in orgo.

There just aren’t that many concepts in organic chemistry, even though the details of each and every reaction are beyond the strongest memory.  The crucial points are to have the orbitals of the various atoms firmly in mind and where they are in space.  This tells you how molecules will or won’t react, or how certain conformations will be stable (see anomeric effect).  Entropy in physics is a very subtle concept, but pretty obvious as used by organic chemists.  Two molecules are better than one etc. etc.  Also you see these concepts over and over.  Everything you study (just about) has carbon in it.  Chair and boat, cis and trans, exo and endo become part of you, without thinking much about them.

Contrast this with math.  I’m currently reading “Introduction to Topological Manifolds” (2nd. Edition) by John M. Lee.  I’ve got about 34 pages of notes on the first 95 pages (25% of the text), and made a list of the definitions I thought worth writing down — there are 170 of them.  Each is quite precise.  A topological embedding is (1) a continuous function (2) a surjective function (3) a homeomorphism.  No more no less.  Remove any one of the 3 (examples are given) and you no longer have an embedding.  The definitions are abstract for the most part, and far from intuitive.  That’s because  the correct definitions were far from obvious even to the mathematicians formulating them.  Hubbard’s excellent book on Vector Calculus says that it took some 200 years for the correct definition of continuity to be thrashed out.  People were arguing about what a function actually was 100 years ago.

As you read you are expected to remember exactly (or look up) the  170 or so defined concepts and use them in a proof.  So when you read a bit of Lee’s book, I’m always stopping and asking myself  ‘did I really understand what I just read’?  Clayden isn’t at all like that — Oh that’s just an intramolecular Sn2, helped because of the Thorpe Ingold effect, which is so obvious it shouldn’t be given a name.

Contrast this with:

After defining topological space, open set, closed set, compact, Hausdorff, continuous, closed map, you are asked to show that a continuous map from a compact topological space to a Hausdorff topological space is a closed map, and that such a map, if surjective as well is an embedding.   To get even close to the proof you must be able to hold all this in your head at once.  You should also remember that you proved that in a Hausdorff space compact sets are closed.

No matter how complicated the organic problem, you can always look at the molecule, and use the fabulous spatial processing capacity your brain gives you.   The interpretation of NMR spectra in terms of conformation certainly requires logical thinking — it’s sort of organic Sudoku.

I imagine a mathematician would have problems with the fuzzy concepts of organic chemistry.  Anslyn and Dougherty take great pains to show you why some reactions fall between Sn1 and Sn2, or E1cb.

So why am I doing this?  Of course there’s the why climb Everest explanation — because it’s there, big and hard, and maybe you can’t do it.  That’s part of it, but not all.  For reasons unknown, I’ve always like math, even though not terribly good at it.  Then there’s the surge for the ego should I be able to go through it all proving that I don’t have Alzheimer’s at 74.5 (at least not yet).  Then there is the solace (yes solace) that math provides.  Topology is far from new to me in 2011.  I started reading Hocking and Young back in ’70 when I was a neurology resident, seeing terrible disease, being unable to help most of those I saw, and ruminating about the unfairness of it all.  Thinking about math took me miles away (and still does), at least temporarily.  When I get that far away look, my wife asks me if I’m thinking about math again.  She’s particularly adamant about not doing this when I’m driving with her (or by myself).

The final reason, is that I went to college with a genius.  I met him at our 50th reunion after reading his bio in our 50th reunion book.  I knew several self-proclaimed geniuses back then, and a lot a physics majors, but he wasn’t one of them.  At any rate, he’s still pumping out papers on relativity with Stephen Hawking, and his entries in the index of the recent biography by Kitty Ferguson take up almost as many entries as Hawking himself.  He’s a very nice guy and agreed to answer questions from time to time.  But to understand the physics you need to really understand the math, and not just mouth it.

In particular, to understand gravity, a la relativity, you have to know how mass bends 4 dimensional space-time. This means you must understand curvature on manifolds, which means you must understand smooth manifolds, which means that you must understand topological manifolds which is why I’m reading Lee’s book.
So perhaps when the smoke clears, I might have something intelligent to say to my classmate.

The New Clayden pp. 825 – 851

I’m reading a lot of math (about which much more in a future post).  It shifts slightly they way I’m reading Clayden.  In math you want to be certain that you understand exactly what you’re reading.  In this chapter particularly, the understanding is the easy part.  I don’t see how anyone with any spatial sense can find stereo electronics hard.  It seems that the explanations are longer and more detailed than they need to be.  Nonetheless the chapter is filled with clever syntheses, none of which appear to use the disconnection approach.

p. 828 — Nice to see something that isn’t known for sure in an introductory textbook (why small nucleophiles PREFER an axial attack). 

p. 833 — Cyclohexane is slightly bent.  How slightly? 

p. 837 — The transition state is the same for both reactions (formation and destruction of an epoxide of an alkene).  Shouldn’t it be said that this true for all reactions?  Or am I wrong?

p. 844 — Formation of the tricyclo (0, 2, 3) system is incredibly clever.

p. 846 — The reactions forming all sorts of extra rings in the cis decalins are very clever, although you need to think about them occuring in space, probably the original thought about them occurred by drawing the rings flat and seeing what would happen when anions would form and what they would attack.  Although clever, these reactions really don’t result from new concepts, just applying them to molecules in space.  Ditto for endo/exo reactions.  One of the attractions of organic chemistry, there really aren’t a high number of different concepts, but the cleverness arises in applying them.  It’s why I find organic far easier than math which will be the subject of a future post. 

p. 848 – 9 — The beautiful synthesis of the C and D rings of the steroid nucleus with the appropriate stereochemistry.  One can regard a synthesis like this as a mathematical proof of a theorem, with the theorem the final product and the steps of the proof, the steps of the synthesis.  

Chapter End — Intriguing how clever it all is, and how little the disconnection approach to synthesis had to say about any of the syntheses.  Clearly they both have their roles. 

The New Clayden pp. 800 – 824

p. 803 — “The C – X bond doesn’t have to be within the ring — for example the nitrogen heterocycle on the left prefers to have the R group axial, so the nitrogen gets and equatorial lone pair.”  However in this example the oxygen atom is within the ring, I think you mean “”The C – X bond doesn’t have to be outside the ring”

p. 804 — A very slick explanation of why CH2Cl2 is so unreactive.

p. 805 — Stereoelectronics explains why esters prefer the cis conformation.  Perhaps that’s why Nature chose proteins to be made from amides rather than esters (aside from their increased resistance to hydrolysis).  There is essentially no steroelectronic effect because the nitrogen doesn’t have a second set of unpaired electrons.  Granted that the amide bond is always cis in the alpha helix, but trans conformations are also found in proteins, and aren’t much different energetically. 

p. 806 — We are told to look at p. 366 for the definition of small (3,4 ), normal (5,6,7), medium (8 – 14) and large ( over 14) rings — it is actually on p. 368

p. 807 — Probably everyone getting as far as organic chemistry knows that there are kinetic ways to measure deltaS* and deltaT* independently, but the point could use some reiteration here. 

p. 810 — I didn’t like Baldwin’s rules whenI read them in first edition and I don’t like them now.  In particular, the chart on p. 814 is ghastly.  The mnemonics are mangled English and hard to remember.  Perhaps the aversion arises because this sort of thing takes me back to med school, where we had to commit a lot of stuff to memory — primarily because there was no particular underlying logic which could explain it (the names of the 8 small bones of the wrist come to mind).  

However, there is an underlying logic to Baldwin’s rules which rather, than being memorized can actually be understood — here’s the quote from p. 813 “Baldwin’s rules work because they are based on whether or not orbital overlap can ber readily achieved in the conformation required at the transition state.”  There you have it.   Forget the rules and think about what is happening. 

p. 814 – 820 — NMR and Ring Size — the level of sophistication jumps up a Notch here.  No new concepts really, but talmudic logic is required to figure out which proton is coupling to what protein and by how much.  Great stuff. 

p. 815 — Cerulenin has a nice structure.  Just to show you how complicated things can get, and how very simple organic chemical structures are relative to what’s inside us, consider this.  Cerulenin, an epoxide produced by fungi, inhibits fatty acid synthetase.  It attacks the ketoacyl synthase domain of the enzyme, forming a covalent bond to the active site cysteine.  

Here’s what fatty acid synthetase actually is —  [ Proc. Natl. Acad. Sci. vol. 86 pp. 3114 -3118 ’89 ] — a single protein containing 7 enzymatic activities — condensing enzyme — transferase — dehydrase — enoyl reductase — ketoreductase — acyl carrier protein — thioesterase.  The enzyme(s) contains 2505 amino acids and a molecular mass of 272 kiloDaltons.

pp. 820 – 824 — I don’t know why they belabor the concepts Homotopic, Diastereotopic and Enantiotopic so much, they seem pretty simple to me, and barely worth naming. 

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://

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). 

The New Clayden pp. 694 – 756

There’s not much new to say about Chapter 28, on retroSynthetic analysis, since the first edition.  Given the general disrespect that monster syntheses seem to engender today,.  Here’s a repeat of  what I wrote about the chapter years ago.

Retrosynthetic analysis and Moliere

Chapter 30 of Clayden, Greeves et. al. concerns retrosynthetic analysis, but what in the world does this have to do with Moliere?  Well, he wrote a play called Le Bourgeois Gentilhomme back in 1670 and played the central character, Monsieur Jourdain, himself in its first performance (before king Louis XIV).  Jean Baptiste Lully, one of the best composers of the time (Bach hadn’t been born yet) wrote the score for it and also played a role.  M. Jourdain was a wealthy bourgeois gentilhomme who wanted to act like those thought better (e.g. the nobility) at the time.  So he hired various teachers to teach him fencing, dancing and philosophy. The assembled notables watching the play thought it was a riot (did not the French invent the term, nouveau riche).  He was taught the difference between poetry and prose, and was astounded to find that he’d been speaking prose all his life.

So it is with retrosynthetic analysis and yours truly. Back in ’60 – ’62 we studied the great syntheses that had been done to learn from the masters (notably Woodward).  Watching him correctly place 5 asymmetric centers in a 6 membered ring of reserpine was truly inspiring.  Even though Corey had just joined the department, the terms retrosynthetic analysis and synthon were nowhere to be found.  The term is almost a tautology, no-one would think of synthesizing something by making an even more complicated molecule and then breaking it down to the target.  So synthetic chemists have been speaking retrosynthetic analysis from day 1 without knowing it.

Probably the reason that things have become so formalized, is that we have many more reactions at our disposal presently.  Silyl enol ethers and lithium enolates were not in evidence back then (as I recall) — although we spent a lot of time with aldols, Diels Alder’s and Claisen’s back then.   One of the things I hope to acquire reading Clayden (and probably others) is the ability to read the syntheses of today and enjoy them, the way I do an unfamiliar string quartet.  Synthesis back then was an art form, and apparently it still is.  People question its utility (I wonder what Woodward would say), but just how do you use a string quartet? Grooving on the entries in etc. is still probably a year (and 700 pages of Clayden) away, if not longer.

So it is with retrosynthetic analysis and yours truly. Back in ’60 – ’62 we studied the great syntheses that had been done to learn from the masters (notably Woodward).  Watching him correctly place 5 asymmetric centers in a 6 membered ring of reserpine was truly inspiring.  Even though Corey had just joined the department, the terms retrosynthetic analysis and synthon were nowhere to be found.
Here are some notes a questions on the first chapter of heterocyclic chemistry.  The chapter explains why they react the way they do to electrophilic and nucleophilic aromatic substitution.  Pretty obvious is you remember about electronegativity, where the orbitals are, and old fashion resonance structures stabilizing positive and negative charges.  Clear as a bell, so there aren’t many notes and questions.

p. 725 — “Pyridine is a weak base with a pKa (for its conjugate acid) of 5.5”  Why not say the pkaH of pyridine is 5.5?

p. 728 — What is Cl-CO2-Et and how do you make it?

p. 731 — How do you make Br3- ??? Pyridine + HBr + Br2 ??

p. 739 – Epibatidine — [ Proc. Natl. Acad. Sci. vol.  100 pp. 11092 – 11097 ’03 ] The frogs don’t make the stuff — it’s from the insects and plants that they eat — then they ship it to their skin.   It’s an even more fantastic explanation than jumping genes or convergent evolution.

p. 744 — The sulfur ylid chemistry converting a ketone to oxirane is found on p. 665.

p. 744 — I always wondered what tetrazoles were doing in so many drugs.  Now I know — they are substituting for COOH, as their pKa is the same (about 5). 

p. 745 — How to make a single carbon atom (while taking your life in your hands) — fantastic.  Kudos to the chemists who did this — presumably they are still intact.   I well remember the terror I had of diazomethane when I worked with it back in the 60s. 

The New Clayden pp. 614 – 693

Standard stuff about aldol and Claisen condensations.  Important because they are a way of making carbon carbon bonds.  Not much to comment on here.  Well written and clear as a bell.  My main concern about reading this, is whether it is relatively obsolete given the importance of transition metal organic chemistry.  I’ll have to wait to chapter 39 which begins 400+ pages later to find out. 


p. 635 — How do you make hexamethyldisilazane?


p. 637 — The animation of the intermolecular aldol condensation is not to be missed.  You can rotate the animation every which way to watch what is going on.  What you cannot do is change the relative orientation of the parts of the molecule to each other — if you did the reaction wouldn’t work. 


p. 644 — Cute rationalization why carbonates are more electrophilic than esters. 


p. 655 — They spend so much time on carbonyls because it is (or was) the way chemists use to form carbon carbon bonds.  I wonder if this is still true now that we have metasthesis and transition metal chemistry.  This doesn’t come up for another 400 pages.  

p. 657 — Very nice to see actual bond strengths for a change.

p. 658 — Interesting that pKa’s are given in some places but not others.  The pKa of R-SH is 9 – 10 (vs. about 15 for R-OH).   All they said here is that thiols are ‘more acidic’ than alcohols.


p. 660 — Nice to see an issue which isn’t resolved (stabilization of carbanions by sulfur) put into an introductory textbook, which by it’s very nature, must present a lot of factual material as given (e.g. cut and dried).   The interesting stuff is always what is NOT understood.

p. 661 — “Ab initio calculations suggest that the C-S bond in -CH2SH is longer than in CH3SH”  — hasn’t anyone looked? 

p. 663 — “There are many more methods for hydrolyzing dithioacetals and their multiplicity should make you suspicious that none is very good.”  This is also (unfortunately) exactly the case in medicine when you see a large number of treatments for a disease.


p. 668 — Why is the Si – Si bond 2/3 the strength of the C – C bond.  This explains why we don’t have a silicon based life-form, but the fact itself could use some explanation (assuming there is one). 


p. 668 — “Bonds to electronegative elements are generally stronger with silicon than with carbon”  — this is because bonds between elements with greater electronegativity differences are stronger, and silicon is less electronegative than carbon.


p. 669 — The polarization of the C – Si with carbon being relatively negative to Si would have been a great time to bring in why tetramethyl silane (TMS) is used as an NMR reference standard — the most shielded carbon nucleus around. 

p. 669 — What is the geometry of the pentacovalent intermediate of Silicon?  Which d orbital does the fluoride go into, or does Si rehybridize in some way?


p. 673 — The claim is made that electrophilic aromatic substitution is ipso to SiMe3 due to the C-Si sigma bond overlaping with the p-orbitals of the aromatic ring.  What about the d orbitals?  Also how are Ar-SiMe3 compounds made?


p. 674 — A very slick mechanism for the retention of E and Z on electrophilic substitution on a vinyl silane.  Again, why are they assuming it’s only the C-Si sigma bond and not the Si d orbitals — I can see a role for them ‘steering’ the Si atom to the correct position. 


p. 674 — There should be a note pointing to methods for making vinyl silanes of the desired stereochemistry (p. 683).

p. 687 — The mechanism given for the Julia reaction on p. 687 can’t possibly work with the example given on p. 686 for the cyclohexyl starting material, as it has no alpha hydrogen.  Perhaps the base picks off the beta hydrogen. 


p. 691 — Aren’t the D orbitals of phosphorus involved in ylids?  They aren’t mentioned.

The New Clayden pp. 562 – 613

p. 564 — “The black proton removed in the third lithiation is more acidic because it is next to an aromatic ring — true enough but there are 4  more such protons in the molecule.   Why aren’t they attacked? 

p. 566 — It’s hard to figure out just how close SO3H is to the hydrogens in naphthalene without knowing naphthalene carbon carbon bond lengths (which I can’t seem to find).  Probably they don’t change much, and all C-H bonds should be the same. 

p. 571 — “to make radicals we need weak symmetric bonds such as O-O, Br-Br, or I-I”.  Why not give the actual bond strengths which are (respectively) 33, 46 and 36 kiloCalories/Mole.  In contrast the C-C bond is 83, the C-H is 96 – 105, the C-0 bond is 84, and the C-N bond is 69 kiloCalories/Mole.  The book seems to be relentlessly nonQuantitative (probably an editorial decision).   Then, a bit later it is noted that the phenylcarboxy radical will homolytically cleave H-Br because a very strong OH bond will be formed — but no number is given — here it is — 110 – 119 kiloCalories/Mole.    I find the numbers helpful, perhaps beginning students wouldn’t. 

p. 572 “As bromine is brown, it absorbs most wavelengths of visible light” — exactly backwards  — the energy levels of Br2 don’t care what color it is, the difference between them is in the energy range of visible light, which is why bromine is colored.  If it absorbed all light in the visible region it would be black. 

p. 574 — Frontier orbitals — the term is used, but as far as I can tell it was never defined when HOMO and LUMO (which is what they are) were introduced on p. 111.

p. 576 — line 2  “regioslectivity’

p. 581 — “As a C=0 pi bond is stronger than a C=C pi bond”  — this ignores the fact that a C – O bond is also  slightly stronger than a C – C bond.  Thermodynamics cares only about the total energy of the final products, and the C = 0 bond takes 172 kiloCalories/mole to dissociate it while the C = C takes 143, a difference of 29 kiloCalories mole.  Since at 298 K (where RT = .6) every 1.36 kiloCalories/mole changes the equilibrium constant by a factor of 10.   The equilibrium constant should be 10^29/1.36 = 10^21, other things being equal (which they aren’t quite when other bond strengths are factored in). 

p. 590 — Halfway through the book — great fun, well written, bravo.  A lot of the irritants of the previous edition have been removed (notably back references to chapters, rather than specific pages).  In a future edition I think there should be actual values for bond lengths, and bond strengths rather than saying stronger or weaker, longer or shorter. 

p.595 — Alkylation of beta-carbonyls — ho hum. Not so !  The field is alive and well with brand new stuff (5 July ’12) coming out.  See Nature vol. 487 pp. 47 – 48, 86 – 89 ’12 — Leighton uses chiral allylsilanes to react with aldehydes and beta diketones to produce beta hydroxy, beta-allyl ketones which are optically active (because the allyl silane is).  The chiral allylsilane is first tethered to the enol adjacent to an aryl group, and then the fun begins.   The reaction doesn’t discriminate between beta diketones with two different alkyl groups.  Hard core organic chemistry.    Starting from a general chemistry background and reading Clayden to p. 595 tells you just about all you need to know to understand hot stuff in the current literature — not bad ! ! !

p. 599 — Hydride is stated to be ‘small’  — clearly bigger than a proton — it should be the smallest anion around (aside from the electron).  But it isn’t — according to Wikipedia — its ionic radius is 1.46 Angstroms, while that of the fluoride anion is 1.33 (more positive charge pulling the electrons toward the nucleus). 

p. 607 — In the second structural reaction sequence from the body, the tBuOK is on the wrong arrow in the leftmost equilibrium shown.

p. 608 –Line 8 —  “neat” is a chemical term of art, which should be defined. Ditto for work-up (line 13).

p. 608 — Sidebar — there’s nothing about Lewis acids on p. 466.

p. 612 — Just saying ‘dopaminergic antagonist’ is likely to leave chemists (and even premeds) mystified.  You might mention that dopamine antagonists were the first useful drugs we had against schizophrenia and other psychoses.  They are still in use today, although clearly they aren’t perfect or curative.

The New Clayden pp. 528 – 561 and some speculation.

The chapter concerns protecting groups, and the same thoughts came to mind that I had when reading the comparable chapter in the first edition.  Why don’t proteins need them?  So here is part of an earlier post for you to think about

I think we’ve gotten far too used to the immense quantity of functional groups that proteins have, and the fact that, as far as we know, in the vast majority of cases, they don’t react with each other.  Out of the 20 amino acids, 3 are alcohols, 2 are carboxylic acids and yet intramolecular lactones haven’t been found, which isn’t to say they aren’t there, but has anyone really looked?  2 more amino acids have amides on their side chain, do they ever react switch places with the protein backbone?  Then there is lysine with its primary amino group dangling off the peptide backbone, just waiting to get into trouble, thanks to a linear chain of 4 methylenes.

Sometimes rather amazing chemistry does happen deep within proteins.  Here is a post I wrote for Nature Chemistry.  Stuart Cantrill told me that since I wrote it, I can use it elsewhere

OCTOBER 30, 2008

Chemiotics: Sherlock Holmes and the Green Fluorescent Protein

Posted on behalf of Retread

Gregory (Scotland Yard): “Is there any other point to which you would wish to draw my attention?”
Holmes: “To the curious incident of the dog in the night-time.”
Gregory: “The dog did nothing in the night-time.”
Holmes: “That was the curious incident.”

The chromophore of green fluorescent protein (GFP) is para-hydroxybenzylidene imidazolinone. It is formed by cyclization of a serine (#65) tyrosine (#66) glycine (#67) sequential tripeptide. It is found in the center of a beta barrel formed by the 238 amino acids of GFP.

What is so curious about this?

Simply put, why don’t things like this happen all the time? Perhaps nothing quite this fancy, but on a more plebeian level consider this: of the twenty amino acids, 2 are carboxylic acids, 2 are amides, 1 is an amine, 3 are alcohols and one is a thiol. One might expect esters, amides, thioesters and sulfides to be formed deep inside proteins. Why deep inside? On the surface of the protein, there is water at 55 molar around to hydrolyze them purely by the law of mass action (releasing about 10 kJ/Avogadro’s number per bond in the process). Some water is present in the X-ray crystallographic structure of proteins, but nothing this concentrated.

The presence of 55 M water bathing the protein surface leads to an even more curious incident, namely why proteins exist at all given that amide hydrolysis is exothermic (as well as entropically favorable). Perhaps this is why proteins contain so many alpha helices and beta sheets — as well as functioning as structural elements they may also serve to hide the amides from water by hydrogen bonding them to each other. Along this line, could this be why the hydrophilic side chains of proteins (arginine, lysine, the acids and the amides) are rather bulky? Perhaps they also function to sterically shield the adjacent amides. After all, why should lysine have 4 methylene groups rather than just one or two?

Now the serine-tyrosine-glycine tripeptide should occur by chance once in every 8000 tripeptides. The SwissProt database of proteins contains 144,041,553 amino acids in 399,749 proteins as of 14 October 2008. Does this tripeptide occur 18,805 times in the database as it should? If it doesn’t, is negative selection preventing it? If it does occur this often, have we missed other chromophores? Are there other tripeptides missing from SwissProt? If there are, does this tell us how to build other chromophores? Or does it tell us something important about protein structure?

I don’t have the skills to properly interrogate SwissProt or the Protein Data Bank, but I imagine that some of the readership does. Go to it. These are curious incidents indeed.

p. 537 — Dissolving Al from an Al/Ni using concentrated NaOH alloy in some way generates H2.  How does this happen?  Do the electrons given up by Al reduce water to H2 and O2?

p. 554 — Nice to have the absolute configuration of the amino acids as they naturally occur in the body (the L-amino acids) — but there should be a statement to this effect.  Otherwise why bother showing the accurate configuration?

The New Clayden pp. 470 – 527

p. 473 — since when is the C – C bond length 1.47 Angstroms?  — I remember 1.54

p. 475 — Great to see actual physical evidence for the charge distribution in protonated benzene using 13C NMR (and on p. 485 for protonated toluene).

p. 479 — The fact that ortho and para positions are brominated in phenol, shows you that the symmetrical ring current in benzene isn’t the whole picture. The electron distribution is asymmetric as shown by the proton shifts in NMR (and elsewhere by the 13C shifts in NMR).  It would be interesting to see the bond lengths between the ring carbons (I couldn’t find it).

p. 481 — How does concentrated nitric acid oxidize phenol (and to what does it oxidize it?).

p. 482 —  Test question:  Assuming all 3 bromination reactions of benzene, anisole, and N,N dimethylanalinine are done at the same temperature and pressure, how much lower is the free energy of activation of the last compound relative to benzene.  I’m embarassed that the answer was NOT at the tip of my tongue.
In general, the book is silent about the absolute (free) energy of activation of any reaction, as is Anslyn.  Relative rates are easy to figure, if done at the same temperature, because everything cancels (RT, the Arrhenius constant etc.).  The answer is basically exp{ – (E_Activation_1/E_activation_2) }.  So for a difference of 10^9 the ratio of activation energies is 16 (exp(16) is 10^9.

p. 488 — What does FeBr3 look like?  In the mechanism FeBr5- is written down (but not drawn out).

p. 489 — Poor overlap of the p orbitals of the halogens with the p orbital of carbon is mimicked in the following table (however these are sigma bonds, but the effect on p orbital overlap should be the same).

          Bond Length    Strength (KiloCalories/Mole)
C – F       1.39            115
C – Cl      1.78              79
C – Br      1.93             67
C – I         2.14             58


p. 490 — The dissection of the conflicting inductive vs. the resonance effects of halogens on benzene reactivity and regioselectivity is positively talmudic.  Premeds had better get ready to do this sort of thing for the rest of their professional lives.  Strong therapies often work better, but carry a higher risk.  Where is the ‘best point’ which maximizes therapeutic effect and minimizes risk (remembering that people differ in the amount of risk they will accept, and also remembering that hard data to guide such a decision is often thin on the ground or nonexistent).
Just to show that figuring out how to direct substituent attachment to benzene isn’t a dead area, the 28 June ’12 Nature has an editorial (pp. 478 – 479) and a paper (518 – 522) on a new way to accomplish this.  The article mentions something called vicarious nucleophilic subsitution which you should wikipedia — probably too specialized for an introductory textbook.  Interesting, nonethless.  The work is elegant and clever, and I think even a neophyte studying Clayden for the first time would be able to understand large parts of it.  It’s another example of why I love organic.  You build molecules to test your ideas and in this case you build a molecular machine to carry out a reaction.

It’s also amusing, on reading the editorial and the paper, how little shrift organic chemists give to the Heisenberg uncertainty principle and quantum mechanics in general.  This work is all about moving atoms and groups around in space, with the only uncertainty being how to make the reaction work.  Ultimately, of course chemistry rests on QM — atoms of an element have the properties they do because their energy levels are fixed, and identical for all.

p. 491 — It would have been quite a digression for the text, but you should look up the structure of P2O5 (formed by burning elemental phosphorus).  It comes in several forms one of which looks like adamantane (P40xygen10) with oxygens where the secondary carbons would be linking the 4 phosphorus atoms  at what would be the 4 tertiary carbons of amantadine.  In addition there are 4 oxygens coming off the 4 phosphorus atoms.

p. 509 — “The litthium cuprates (R2CuLi) that are formed are not stable”  — what happens to them?

p. 512 — The cyanoimine shown in the inset doesn’t look ‘simple’ to me.  How in the world is it made?

p. 513 — Does the alpha effect explain why Br2 is a better nucleophile than Br- (if in fact it is).  Is this true for all halogens?

p. 517 — It is marvellous to have 13C-NMR to confirm the charge distributions we all ‘knew’ about 50 years ago, for the cyclohexadiene anion and cation.

p. 519 — An 80 fold increase in rate is only a 4 fold decrease in activation energy.  See p. 482 in these notes.

p. 523 — The benzyne intermediate and mechanism is fascinating.  50 years ago people talked about it, but the evidence for its existence was thin.  For some of the impressive things benzynes can do, look at the Wikipedia article.

Away for a bit + The New Clayden pp. 427 – 470

We’ll be away for a bit, leaving before I could post anything on 3 or 4 very interesting molecular biology papers from a chemical and medical perspective.  Relax and enjoy the summer.

p. 427 — The ‘reason’ that Br2 has a low energy empty (antibonding) orbital, is because the Br-Br bond is exceptionally weak, and bonding and antibonding orbitals are usually fairly symmetrically disposed about the energy of two isolated atoms (with the antibonding orbital being a bit higher than the bonding orbital is lower).  The actual values are Br-Br 46, C-H 96, C-C 81 kiloCalories/mole (multiply by 4.184 for kiloJoules/mole).

p. 429 — “with Bromine being lower in the periodic table and having more diffuse lone pairs”  — another way of saying that the atom is larger.  The C-Br bond is 1.93 Angstroms (vs. 1.54 for C-C), but bonds don’t emanate from the center of the atom, but from the periphery, likely making the bromonium ion considerably less strained.  The ionium ion should be even more stable as the C-I bond is 2.16 Angstroms. 

p. 431 — There is an apparent conflict between the fact that aliphatic substitutions on a double bond RAISE the energy of the bonding pi orbital (pi) — e.g. the Highest Occipied Molecular Orbital (HOMO) while they lower the total energy of the molecule.  The explanation given on p. 394 is that it allows the sigma electrons of a CH or a CC bond to interact with the nonbonding pi* orbital, spreading them out in space with a concomitant lowering of the energy.  The more you localize an electron the more energy it has (it’s the uncertainty principle in drag).

p. 432 — What is KHSO5? — they don’t even name it. 

The illustrations in the book that I comment on can be reached on the web by substituting the page number I give for xx in the following

p. 442 — It’s worthwhile looking at the animation of dihydroxylation of ethane by OsO4.  While you can rotate the two molecules in space allowing you to really understand the reaction, what you can’t  do is alter the perfact orientation of the two molecules relative to each other allowing the reaction to occur.   Obviously this sort of thing doesn’t happen all the time or even most of it.  How ‘off’ can the orientations be and still allow the reaction to occur.  Perhaps the solvent cage enclosing the two molecules keeps them together until the proper approach is found.  Does anyone out there know if the lifetime of such a solvent cage can be measured? 

p. 444 — Important to know that transition metal cations are soft electrophiles.  Clearly a cation is an electrophile, but it’s probably the large size of the Hg++ ion (diameter 3.48 Angstroms) which makes it soft (e.g. polarizable, as the orbital electrons are so far from the nucleus). 

p. 445 — The large size of Hg++ is probably why it is able to form a cyclopropene derivative (in addition to the Huckel aromaticity of such a molecule). 

” C = 0 bonds are stronger than C = C bonds”  — why not give the numbers?  They are 172 kiloCalories/mole and 143 respectively.

p. 453 — Its definitely worth a look back to p. 150 looking at the HOMO of the allyl anion — there are no orbitals on the middle carbon.  The node was put on the central carbon to maintain orbital symmetry.  

The enolate anion is a great example of a hard nucleophile (the oxygen) and a soft nucleophile (the alpha carbon) in the same (italics) molecule. 

p. 456 — “only about one part in 10^4 – 10^6 is enol for most compounds”.  It’s worth reminding ourselves of the the numbers we casually throw about as chemists, one part in 10^6 still leaves 6 * 10^17 enols floating around in a 1 molar solution of acetone ! ! !

p. 457 — The fact that you see only one NMR peak from dimedone implies that the tautomerism is occurring faster than every milliSecond (see p. 374 — it’s good that the new edition gives page numbers when pointing to previous discussions, rather than just chapters the way the first edition did). 

p. 459 — Why not give the pKa of vitamin C rather than say it is an acid?

GABA (gamma amino butyric acid) is the major inhibitory neurotransmitter in our brains. 

p. 466 — In the reaction of LDA with acetone, turn on the more controls button and in what appears the space fill button.  It’s almost impossible to see what’s going on (as opposed to the ball and stick models where everything is clear).  How do the little molecules know what to do?