Hail and farewell to the New Clayden pp. 1169 – 1181

Finished at last, in just over 6 months.  A magnificent introduction to organic chemistry (for the future chemist, not for the pre-med.  Far too much detail). As noted in some inserts on the last few posts, the book enables you to read organic papers appearing currently in Nature and Science. Hopefully the authors will get whatever they wanted (fame, glory, money?) from the tremendous effort it must have taken to revise the first edition. Bravo and Thank you all ! ! !

1169 Glivec (imatinib) is Gleevec in the USA

1170  Fluouracil doen’t modify uracil. It inhibits one of the enzymes in the thymidine biosynthetic pathway (thymidylate synthase), resulting in a deficiency in one of the 4 nucleosides making up DNA. 

1171 “Blocking HIV protease inhibitors means mimicking the proteins they  slice up.”

What you are trying to block is the (single) HIV protease with an inhibitor.

The sentence should read 

“Blocking the  HIV protease means mimicking the proteins it slices up.”

1172 “This stops the drug being hydrolyzed, but the drug also has to stop the viral protein being hydrolyzed”

The sentence should read

“This stops the drug from being hydrolyzed, but the drug also has to stop the viral polyprotein from being hydrolyzed”  or (if you don’t want to explain what a polyprotein actually is)

“This stops the drug from being hydrolyzed, but the drug also has to stop the target of the viral protease from being hydrolyzed”

1172 There has been a lot of commentary that research into synthetic organic chemistry and the synthesis of large molecules is more an art form than useful science.  The emergency large scale synthesis of indinavir in gram quantities described here puts the lie to that.  No “Manhattan” project to make it in large quantities could have succeeded without a lot of synthetic reactions developed purely for their interest previously.  — Of interest that the last section “The Future of Organic Chemistry”  pp. 1179 –> makes exactly this point (but I hadn’t read it before writing the above). 

1177 The clever synthesis of oseltamivir by Corey (birthdate 1928) in ’06 shows that he hasn’t resting on his laurels.  As a mathematician said about a difficult problem he threw out for all to solve in 1697, which was solved anonymously.  “I recognize the lion by his paw” — the lion was Newton of course. 

1178 — Not clear why the attack of N bromoacetamide in the presence of SnBr4 results in a bromonium ion on the same side as the NHBoc group.

1181 — Nice ending to the book, but it would have been helpful if they actually recommended books they like on “orbitals and chemical reactions, NMR spectroscopy, molecular modeling, physical chemisty, photochemistry, enzyme mechanisms, biosynthesis, organometally chemistry, asymmetric synthesis (assuming there are any), supramolecular chemistry and polymer and materials chemistry.”

So what’s next?  PChem (not physical organic), statistical mechanics (particularly Molecular Driving Forces as recommended by WaveFunction).  Why?  Because so much of what goes on in the cell is determined by the physical interaction (not chemical) of the cells components (proteins, lipids, metabolites).  We wouldn’t be alive without enzymes and chemical transformations, but there’s far more going than that.  One example:  The processes which determine where and when a given protein coding gene is expressed are purely physical, involving binding of proteins to DNA (and each other), and changes in conformation as they do so.  To be sure, RNA polymerase II is a magnificent molecular machine which involves a good deal of chemistry, but the factors determining where and when aren’t chemical.

So there’s a lot of molecular biology I’ve put aside to write about later, and later is now. I’ve got 6 PNAS’s and 1 Cell sitting beneath my desk with tags in them marking very interesting molecular biology.

Here is where teleology raises its head.  As soon as you ask what something is for, chemistry is silent.  It can only tell you how something happens, not why.  It’s the Cartesian dualism all over again — see https://luysii.wordpress.com/2011/05/11/the-limits-of-chemical-reductionism/

Of course I plan to continue reading organic chemistry thanks to the background Clayden has provided.

Then there’s relativity and the mathematics behind it — a very long term project, hopefully not longer than my 74.5 year old brain holds out.  For why see https://luysii.wordpress.com/2012/09/11/why-math-is-hard-for-me-and-organic-chemistry-is-easy/

Happy thanksgiving to all ! ! !  My son says he likes it because it’s probably the most inclusive holiday we have.

The New Clayden pp. 1102 – 1133

 

In general, very good to see referrals to previously discussed material given as page numbers rather than chapter numbers as it was in the previous edition.  Also good to see that the Harvard and Princeton chemistry departments have people who have done very good work (Evans, MacMillan, Jacobsen).  

p. 1108 The top face of cyclopentadiene is shielded by the ethyl groups attached to Al.  In the second example, the Al isn’t attached to anything, presumably something like AlCl3.  

1110 — The trans enolate in the top line  would be less stable regardless of the orientation of the isopropyl group.  Once this is established, the orientation of the isopropyl group gives an incoming electrophile just one way to attack.  Essentially the oxazolidinone gives you a twofer.  A pleasure to see exquisite stereochemistry re-emerge after the previous chapter on organometallic chemistry. 

p. 1111 —  “less than a milligram of a chiral compound can be passed down a narrow column containing silica modified which  a chiral additive.”

1113 — The 3 dimensional visualization tools for sparteine given by the book’s web link is incredibly helpful, particularly since I don’t have a set of molecular models.  I used to use something called Dreiding models which were very good.  Apparently Aldrich still sells them, but I had trouble with their catalog.  Does anyone know if they’re still available?

1115 How is Tosyl 1,2 phenylendiamine (TsDPEN) actually made so that you get one enantiomer.  What is the chiral starting material. Or do they just crystallize it using an enantiomerically pure chiral compound?

1118 — Why does using ruthenium instead of rhodium broaden the number of substrates undergoing asymmetric hydrogenation.

1123 — What is the geometry of the salen complex of Mn shown at the top of the page.

1124 — It isn’t clear just where the Oso4 sits in DHQD2PHAL or DHQ2PHAL.  Perhaps this isn’t known?

1127 — If you use a different diastereomer of the chiral amino alcohol, do you get a different enantiomer of the product of the aldehyde with diethyl zinc? 

Out of order, but there are 3 great papers in the 26 Oct Science (vol. 338 pp. 479 – 480, 500 – 503, 504 – 506 ’12) on selective formation of one diastereomer or enantiomer using an asymmetric organometallic catalyst.  The first is particularly interesting as it puts a transition metal catalyst catalytic site of a protein.  Here’s some more about it

Streptavidin is protein produced by a microorganism (Streptomyces avidini) which binds biotin very tightly (Kd is 10^-15}. The binding pocket for biotin is large, and the authors hooked a Rhodium complex to the biotin via derivatizing a Rhodium pentamethyl cyclopentadiene ligand so it was covalently attached to the biotin. Then they threw a benzamide derivative + acrylamide at the protein metalloenzyme complex. Apparently everything fit within binding site for biotin within the streptavidin so they actually got out a dihydroisoquinolone. They achieved a 100 fold acceleration in rate (compared to the activity of the isolated rhodium complex) and even better the enantiomeric ratio was ‘as high as ’93:7. So this is aromatic C-H activation within the confines of a protein. Slick

The second paper is more general in that it uses a derivatized cyclopentadiene Rhodium L1, L2 system.  The cyclopentadiene is fused to a saturated cyclohexane ring with substituents hanging off it to create a steric environment such that the L1 (large) and L2 (small) are forced to lie in particular directions.  Then the reaction begins.

Very pleasant to realize, that after some 1100 pages of Clayden, I can read and understand very current research literature. 

Again, it’s worthwhile comparing this to what premeds are up against.  See https://luysii.wordpress.com/2012/10/04/carbenes-and-a-defense-of-pre-meds-and-docs/

1128 — Organocatalysis — so that’s what MacMillian did to become chemistry chief at Princeton ! Clever stuff.

1130 — Showing that chiral auxiliaries aren’t just stereochemical navel gazing (although they certainly are elegant and worthy to gaze at), they were used 4 times in the synthesis of discodermolide.

The New Clayden pp. 1069 – 1101

Overview — A fabulous chapter, with more new (and bizarre) chemistry than the rest of the book.  I wonder what percentage of the ‘average’ total synthesis done today uses transition metal chemistry.

Even so the chapter is a disappointment.  While there is stereochemistry of the organic moieties attached to the transition metal, the disposition of the ligands in space isn’t given for the most part.  The exquisite dance of the orbitals to be found in fragmentation reactions (to give one example) is nowhere to be found.  There is one picture of a d-orbital (p. 1073) in the discussion of back bonding.

To be sure they note (p. 1070) that a lot of work has gone into mechanism, but that the results ‘remain speculative’.  So my disappointment may be with the state of our present knowledge rather than the way the chapter is written.

In the suggestions for further reading we find “Most textbooks of organometallic chemistry favor the inorganic approach of facts rather than explanation.”  I’d say that is true of this chapter, where most of the chemistry is explained as sequences of the following 5 basic reactions

l. Oxidative addition

2. Reductive elimination

3. Migratory insertion

4. Beta hydride elimination

5. Cross coupling

The mechanisms of these 5 aren’t gone into (say the way Sn1 and Sn2 are explained in the rest of the book).

Perhaps the situation here is like the early days of quantum mechanics, when things were being calculated, and results obtained, with little introspection of what’s going on under the hood (although Bohr would say that isn’t a scientific question).  Surely somewhere calculations have been done to show why coordination to a metal changes the reactivity of organic compounds so much (making alkenes coordinated to Pd++ electrophilic to take one example).

They do say Hartwig’s book does go into these things, but it’s quite expensive and doesn’t seem to be available in any of the local college libraries.

Can any of the readers out there send a link to a PDF answering some of these questions in a comment?  I’d be grateful.

1070 — Why is the 4s orbital of lower energy than the 3d, the 5s than the 4d, the 6s lower than the 5d.  The explanations I remember have always seemed like hand waving.  Any comments or explanations>

The ‘explanation’ for the stability of 16 electrons in Ni, Pd, Pt is weak.  ‘Adopting a square planar geometry’ — but as opposed to what other geometry?

1073 — ‘dsp’ orbital  “derived from the vacant d, p and s orbitals of the metal”  — why would the s orbital be empty?

In the terms oxidative and reductive, remember its the metal that’s being oxidized or reduced.

“You do not need to understand all the bonding properties of metal complexes”  — OK, but how about a reference to a place where this is explained?   Perhaps the reference to Hartwig at the end of the chapter is what I want.

1074 — I assume that the X in the second reaction sequence is halogen.

How do we know that the methyl iodide addition to the Iridium complex is trans.  It’s nice to have a reference to stereochemistry (however small) in the first 5 pages of the chapter.   Are transition metal complexes with 4 ligands always square planar?   Can they be tetrahedral?

1075 — 4 coordinated Pd is shown to be square in the diagram.  Is this always true?  A statement to that effect would be good.

1076 — Very hard for me to see how the example in the top row of structures with Wilkinson’s catalyst is a migratory insertion (I guess the alkene inserts into the M-H bond — probably because I usually think of hydrogen as the moving atom).   Carbonyation (2nd row) is much clearer.

1076 — In the carbonylation of Fe(CO)x, drawings of the complexes imply that they are trigonal bipyramidal or octagonal, but this is never stated explicitly.

1076– Why are alkyl groups poorer ligands than CO (lack of backbonding perhaps?).

1077  — Having treated severe carbon monoxide poisoning (with neglible results) and having  prevented cases just about every winter when evaluating patients for headaches, I wonder what special precautions must be taken for ‘maintaining a pressure of carbon monoxide above the reaction mixture.’

p. 1078 — Beta hydride elimination contains a semantic trap — although hydride is eliminated from the carbon skeleton, it winds up bound (italics) to the metal.  At last, some stereochemistry “In more complex structures, the metal and the hydride must be syn to each other on the carbon for the elimination to be possible”

1078 — “most syntheses of organic molecules of any complexity will now involve palladium chemistry in one or more key steps.”  Wow ! !  That being the case, what is it doing in the last 9% of the book.

1079 — “The presence of hydrogen at an sp3 carbon in the beta position must be avoided”.  It’s because beta-hydride elimination is quite exothermic

M-C (30 kiloCalories/mole) —> M-H (60 kiloCalories/mole)

C-H (100 kCal/M) —> C=C (148 kCal/M) — so 78 kCal/mole releasef as heat.

Things that release  heat and gas are known as explosives.

p. 1080 — Watch out — the carbometallation step in the Heck cycle shown, encompasses a bunch of steps — see the carbopallidation reaction scheme on p. 1079.

p. 1081 — I found the mechanisms of Pd++ reduction at the top, extremely confusing and hard to follow.

p. 1081 — Some stereochemistry at last — “the C-Pd and C-H bonds have to eclipse one another for the Pd-H bond to form.

p. 1082 — More stereochemistry — Palladium is very sensitive to steric effects — well not the ion itself, but with all the junk hanging off it (triphenyl phosphines etc. etc.) it has to be bulky.

p. 1083 — the palladium couplings are so diverse.  Does anyone use Grignards or silyl enol ethers etc. etc. anymore in synthesis?

*****

I wrote the following to a practicing organic chemist involved in med chem drug development.

I’ve just finished the 32 pages of Ch. 40 of the new edition of Clayden’s textbook of organic chemistry concerning Organometallic chemistry.  The number of new (and unusual) reactions is simply staggering, and this is only a 32 page account.  Hartwig’s book (which I’ve not read or even seen) has some 1160 pages probably has even more novel reactions.   To an old Woodward grad student, these reactions should have revolutionized synthetic organic chemistry.

My questions to you are

l. Is this true

2. If true, how often are they used in synthesis

a. academic type of stuff that’s never been done before

b. industrial and med chem type — e.g. day to day work making new drug candidates

I  got the following back

The workhorse metal-catalyzed reactions are used a great deal, and it’s gone as far as affecting the kinds of molecules that even get made. But some of these reactions have a reputation for being very finicky about their substrates and conditions – they work on the examples in the paper, but can’t be extended so easily, so people are worried (after they’ve been burned) about trying some of them.

****

p. 1084 Coupling an alkyne to an alkene in the Stille reaction is truly magical.

Out of sequence, and rather delayed because of family events, but the hexahydro Diels Alder reation [ Nature vol. 490 pp. 208 – 212 ’12 ] is not to be missed, showing that there’s all sorts of new organic chemistry to be discovered.

p. 1086 — bottom row of reactions.  The lack of steric hindrance in the coupling reaction might be due to the fact that the central Pd atom is large.  The following web site http://www.webelements.com/palladium/atom_sizes.html gives a variety of radii for Pd.  With a coordination number of 3 the single bond covalent radius is 1.2 Angstroms for Pd (almost as much as a whole C-C bond of 1.54 Angstroms, so the molecules bound to Pd have room to fit in.  Because they are held to Pd there by the bonds, they are already in a position to react with each other, even though in solution, such a close approach would be improbable.  The atomic radii of the transition metals are nowhere mentioned in this chapter.

1087 — Sonoshagira adds another Japanese name to an already impressive list of named transition metal chemistry reactions in the chapter — Suzuki, Kumada, Negishi.  Was there one old Japanese master and are these his students?

1093 — there is a missing R on the benzene ring in the fourth benzene in the first reaction sequence at the top of the page.

1096 — At last, an explanation for one of the unusal reactivity patterns of transition metal chemistry — the drawing away of the pi electrons of an olefin toward the metal.  Probably the partial filling of the pi* orbital by back bonding doesn’t hurt either.  Do the cognoscenti have any thoughts on this one?

1096 — “CuCl2 oxidizes Pd(0) to Pd++ and is itself  oxidized back to Cu++ by oxygen.”   The itself should be the Cu(0).

1098 — The synthesis of claviciptic acid by Hegedus is elegance itself.

The New Clayden pp. 1029 – 1068

p. 1034 — “Small amounts of radicals are formed in many reactions in which the products are actually formed by simple ionic processes.”  Interesting — how ‘small’ is small?  

p. 1036 — A very improbable mechanism (but true) given in the last reaction involving breaking benzene aromaticity and forming a cyclopropene ring to boot.  

p. 1043 — Americans should note that gradient (as in Hammett’s rho constant) means slope (or derivative if the plot of substituents vs. sigma for a particular reaction isn’t a straight line).  However we are talking log vs. log plots, and you can fit an elephant onto a log log plot.  It’s worth remembering why logarithms are necessary iin the first place.  Much of interest to chemists (equilibrium constants, reaction rates) are exponential in free energy (of products vs. reactants in the first case, of transition state vs. reactions in the second).

p. 1044 — Optimally I shouldn’t have to remember that a positve rho (for reaction value) means electrons flow toward the aromatic ring in the rate determining step), but should gut it out from the electron withdrawing or pushing effects on the transition state, and how this affects sigma, by remembering what equilibrium constant is over what for sigma, and rho), but this implies a very high working memory capacity (which I don’t have unfortunately).  I think mathematicians do, which is why I’m so slow at it.  They have to keep all sorts of definitions in working memory at once to come up with proofs (and I do to follow them).  

If you don’t know what working memory is, here’s a link — http://en.wikipedia.org/wiki/Working_memory.  

Here are a few literature references 

        [ Proc. Natl. Acad. Sci. vol. 106 pp. 21017 – 21018 ’09 ] This one is particularly interesting to me as it states that differences among people in working memory capacity are thought to reflect a core cognitive ability, because they strongly predict performance in fluid inteliigenece, reading, attentional control etc. etc.  This may explain why you have to have a certain sort of smarts to be a mathematician (the sort that helps you on IQ tests).  

       [ Science vol. 323 pp. 800 – 802 ’09 ] Intensive training on working memory tasks can improve working memory capacity, and reduce cognitively related clinical symptoms.  The improvements have been associated with an increase in brain activity in parietal and frontal regions. 

I think there are some websites which will train working memory (and claim to improve it).  I may give them a shot. 

Unrelated to this chapter, but Science vol. 337 pp. 1648 – 1651 ’12, but worth bringing to the attention of the cognoscenti reading this –as there is some fascinating looking organometallic chemistry in it.  This is a totally new development since the early 60’s and I look forward to reading the next chapter on Organometallic chemistry.   Hopefully orbitals and stereochemistry will be involved there, as they are in this paper.  Fig 1 C has A uranium atom bound to 3 oxygens and 3 nitrogens, and also by dotted bonds to H and C.

p. 1050 — The unspoken assumption about the kinetic isotope effect is that the C-D and C-H bonds have the same strength (since the curve of potential energy vs. atomic separation is the same for both — this is probably true — but why?    Also, there is no explanation of why the maximum kinetic isotope effect is 7.1.  So I thought I’d look and see what the current Bible of physical organic chemistry had to say about it. 

Anslyn and Dougherty (p. 422 –> ) leave the calculation of the maximum isotope effect (at 298 Kelvin) as an exercise.  They also assume that the force constant is the same.  Exercise 1 (p. 482) says one equation used to calculate kinetic isotope effects is given below — you are asked to derive it 

kH/kD = exp [ hc (vbarH – vbarD)/2KT }, and then in problem #2 plug in a stretching frequency for C-H of 3000 cm^-1 to calculate the isotope effect at 298 Kelvin coming up with 6.5

Far from satisfying.  I doubt that the average organic chemist reading Anslyn and Dougherty could solve it.  Perhaps I could have  done it back in ’61 when I had the incredible experience of auditing E. B. Wilson’s course on Statistical Mechanics while waiting to go to med school (yes he’s the Wilson of Pauling and Wilson).   More about him when I start reading Molecular Driving Forces. 

On another level, it’s rather surprising that mass should have such an effect on reaction rates.  Bonds are about the distribution of charge, and the force between charged particles is 10^36 times stronger than that between particles of the same mass. 

p. 1052 — Entropy is a subtle concept (particularly in bulk thermodynamics), but easy enough to measure there.    Organic chemists have a very intuitive concept of it as shown here.

p. 1054 — Very slick explanation of the inverse isotope effect.  

Again out of context — but more chemistry seems to be appearing in Nature and Science these days.   A carbon coordinated to 6 iron atoms ( yes six ! ! ! ) exists in an enzyme essential for life itself — the plant enzyme nitrogenase which reduces N2 to usable ammonia equivalents for formation of amino acids, nucleotides.   No mention seems to be made about just how unusual this is.  See Science vol. 337 pp. 1672 – 1675 ’12. 

p. 1061 — The trapping of the benzyne intermediate by a Diels Alder is clever and exactly what I was trying to do years ago in a failed PhD project — see https://luysii.wordpress.com/2012/10/04/carbenes-and-a-defense-of-pre-meds-and-docs/

p. 1064 — In the mechanism of attack on epichlorohydrin, the reason for the preference of attack on the epoxide isn’t given — it’s probably both steric and kinetic, steric because attack on the ring is less hindered — the H’s are splayed out, and kinetic, because anything opening up a strained ring should have a lower energy transition state. 

The New Clayden pp. 1003 – 1028

p. 1004 — The nitrosoureas are known carcinogens.  They form DNA adducts (not sure exactly what they are) and are used experimentally to produce random mutations.  Could they be forming carbenes in vivo?

Also, how do you make N-Methyl N-nitroso urea?  N-methyl, N-nitroso toluene sulfonic acid?  

p. 1007 — I assume you make tosyl azide from tosyl chloride plus sodium azide

p. 1007 Rh2(OAc)4 — presumably the structure will be given in the next chapter. 

p. 1014 “Spin flipping, which can occur only through collision with another molecule (solvent usually) is relatively slow on the time scale of molecular rotations . . . “  Well how slow?  These numbers are known.  Why not give them.  Also why does a collision have to be involved for spin flipping to occur?  I think this question has been answered before.  Sorry about asking it again. How about another link to it. 

p. 1016 Interesting bunch of natural products containing cyclopropanes.  How does Nature actually manage their synthesis? 

p. 1018 — How do you make N2-CO2Et?  Possibly using the tosyl hydrazone?

p. 1023 — Metathesis at last.  When I type it, I have to stop myself from typing an awful word I’ve had to type (and utter) for years — Metastasis. 

p. 1024 — In the mechanism shown — why doesn’t the ‘carbene’ attached to Rh leave the Ru and form a cyclopropane with the other olefin? 

Also, all stereochemistry has vanished ! ! !

The catalyst goes from having 5 bonds to various things, to 6 with the bonds shown coming off the ruthenium atom like quills from a porcupine.  Surely the disposition of the bonds in space must be known?  Doesn’t it matter?   Ditto for the metathesis catalysts on 1025.  This is the way things were drawn (if they were drawn at all), in my orgo book of 54 years ago — English and Cassidy.

Hopefully the chapter on organometallics will be more enlightening about what is going on in metathesis reactions.  The discussion in this chapter takes me back to med school — this is what happens — remember it — never mind why.  At least in med school it was because no one knew why.  Here, perhaps they do but they aren’t telling.

Carbenes and a defense of Pre-Meds and Docs

Carbenes ! ! ! A whole 25 page chapter in the new Clayden about them ! It wasn’t like this back in the Spring of ’61.  Carbenes were new and exciting. It’s quite different presently in the department, but back then before you could start work on a PhD you had to pass 8 cumulative exams (cumes).  They were given monthly, so once you had 8 under your belt you could start. Until then, you hung around, took courses, went to seminars and made some money as a teaching assistant.  The rumor was that if you passed the first 8 you’d be nominated to be a Junior Fellow (I think Dan Kemp got in this way).  At any rate, I passed 8 of the first 9, and in May ’61 I was ready to begin work. 

The carbene chapter in Clayden is full of all sorts of ways to make carbenes, but back then we weren’t sure if they were involved in ordinary reactions.  I thought they might be involved in the Wolff rearrangement (see p. 1021 of the new edition) and figured out a way to prove it if they were.  Remember this is May ’61.   

Start with cyclopentadiene, do a Diels Alder with acrylic acid (or the acyl chloride, I forget which).   The addition puts the acyl group endo. React the acyl chloride with diazomethane to form the diazoketone.  Photolyze.  Back then we knew that carbenes reacted with olefins to form cyclopropanes.  If so photolysis of this diazoketone should produce a carbene right next to the double bond.  Formation of such a tangled up compound would prove it.

So I took my idea to Woodward, the great man bought it, and let me work on it as my PhD project (rather than one of his ideas).  I never got it to work due to my lousy lab technique, and my fear of blowing my head off with the explosive diazomethane (Tom Lowry had similar fears, but got diazomethane to work on his PhD project with Corey). 

Time for a social note.  When I stop to think of it, the system that got me to Woodward back then was truly remarkable.  I graduated from a 4 year high school of 212 kids which had never sent anyone to the Ivy League.  There were 48 graduates my year of whom half were boys.  None  of the 24 girls went to college and only 6 of the boys.  Yet 4 years later there I was, in a chemistry department which contained 6 nobel future Nobel laureates.

A fellow graduate student back then (now a department chair) grew up on a chicken farm 35 miles away.  A college classmate, the son of an immigrant shoemaker from Italy, later became the editor of PNAS.  Hopefully this country is continuing to do the same for immigrants and the children and grandchildren of immigrants such as ourselves. 

Over the years I’ve read a lot of snarky comments in various chemistry blogs about pre-meds from people attempting to teach them orgo.  Certainly many of them are justified.  Consider what happened when I tried to clean out one rotten apple from such a class —  https://luysii.wordpress.com/2010/08/24/son-of-a-responsibility-you-didnt-know-you-had/.

However, it’s now time for a little pushback.  

As of 5/61 I’d been studying organic chemistry among other things for just over two and a half years.  Yet that’s all it took to get me to the frontier of the field.   Compare that to med school. Starting 9/62 by 5/65 how close was I to knowing enough medicine to take care of a sick person?  Damned far.  Did I find med school harder than grad school?   I certainly did.  No one in our class found it easy, even the future Nobel laureate (although he seemed to spend a lot of his time playing bridge).  Presumably I was just as smart as I was 5/61.

By the summer of ’66 I’d be an intern, with a resident over me and an attending physician over him, to make sure I didn’t screw up.  By the summer of ’67 I’d be a first year resident, with an intern under me, a resident over me andy an attending over him, to make as sure as we could that we didn’t screw up.  By the summer of  ’68 I was in the service, again with an attending.  After finishing that and a residency, by the fall of ’72 I was on my own ready to take care of people with no one checking my work — some 8 years later.

So ease up on the pre-meds (but not academically).  They’ve got a lot longer and harder intellectual road ahead of them than you do.

The New Clayden pp. 970 – 1002

p. 970 — The authors missed a bet in not discussing why  it takes so much more free energy to break HCl into ions (1347 kiloJoules) than into radicals (431 kiloJoules) — charge separation.  Another missed opportunity was not discussing  just how high the energetic penalty really is for charge separation, and the crucial role of solvent in moderating it. 

p. 971 — To be noted is that fact at all bond strengths in the book (and the literature) are for the free energy required to break the bond into neutral elements (e.g. radicals). 

p. 974 — “electron celibataire”  Y’alors, how I love ze French ! ! !   Shades of Dominique Strauss-Kahn.   What do you expect of a language that divides nouns into masculine and feminine?  LGBT is sure to protest. 

p. 983 — “We expect you to be mildly horrified by the inadequacy of the mechanism above.  But, unfortunately, we can’t do much better because no-one really knows quite what is happening.”   Good to have a confession of less than omnipotence.  Whenever I see something with a transition metal involved, I always wonder, why this particular one?  The McMurry reaction uses titanium, why not Vanadium, why not Scandium? 

p. 994 — “The Sn-C bond is relatively weak”  — All sorts of numerical bond strengths have been given in this chaper (good !), why not give this one? 

Again, irrelevant to Clayden, but not to chemistry.  An interesting article in the 14 Sep  Science (vol. 337 pp. 1322 – 1325 ’12) used a ‘fenced’ porphyrin manganese chloro compound to perform selective aliphatic C – H fluorination of a variety of natural products.  Hopefully the chapter on Organometallic chemistry coming up in 80 pages or so will explain all this.  Given the way the orbitals on S, P, Si have been discussed so far,  I doubt it.  Hopefully the organometallic chemistrhy chapter will be up to the level of the exquisite stereochemistry of fragmentation reactions described in the previous chapter.

p. 997 — Although the term frontier molecular orbital is used in the book, it is never explicitly defined.  You are told to look at the definition of LUMO, HOMO in the index — p. 111 — and their various uses, but the term doesn’t appear there. 

Again, although the MO in LUMO, HOMO, SOMO   stands for molecular orbitals, BUT if you really  look at them, these orbitals are essentially localized to just a few atoms (always more than 1 making them molecular rather than atomic).

The New Clayden pp. 931 – 969

p. 935 — I don’t understand why neighboring group participation is less common using 4 membered rings than it is using  3 and 5 membered rings.  It may be entropy and the enthalpy of strain balancing out.  I think they’ve said this elsewhere (or in the previous edition).   Actually — looking at the side bar, they did say exactly that in Ch. 31.  

As we used to say, when scooped in the literature — at least we were thinking well.

p. 935 — “During the 1950’s and 1960’s, this sort of question provoked a prolonged and acrimonious debate”  — you better believe it.  Schleyer worked on norbornane, but I don’t think he got into the dust up.  Sol Winstein (who Schleyer called solvolysis Sol) was one of the participants along with H. C. Brown (HydroBoration Brown).

p. 936 — The elegance of Cram’s work.  Reading math has changed the way I’m reading organic chemistry.  What you want in math is an understanding of what is being said, and subsequently an ability to reconstruct a given proof.  You don’t have to have the proof at the tip of your tongue ready to spew out, but you should be able to reconstruct it given a bit of time.   The hard thing is remembering the definitions of the elements of a proof precisely, because precise they are and quite arbitrary in order to make things work properly.  It’s why I always leave a blank page next to my notes on a proof — to contain the definitions I’ve usually forgotten (or not remembered precisely).

I also find it much easier to remember mathematical definitions if I write them out (as opposed to reading them as sentences) as logical statements.  This means using ==> for implies | for such that, upside down A for ‘for all’, backwards E for ‘there exists, etc. etc. There’s too much linguistic fog in my mind when I read them as English sentences.

       So just knowing some general principles will be enough to reconstruct Cram’s elegant work described here.  There’s no point in trying to remember it exactly (although there used to be for me).   It think this is where beginning students get trapped — at first it seems that you can remember it all.  But then the inundation starts.  What should save them, is understanding and applying the principles, which are relatively few.  Again, this is similar to what happens in medicine — and why passing organic chemistry sets up the premed for this style of thinking. 

p. 938 – In the example of the Payne rearrangement, why doesn’t OH attack the epoxide rather than deprotonating the primary alcohol (which is much less acidic than OH itself).

p. 955 – Although the orbitals in the explanation of why stereochemistry is retained in 1,2 migrations are called  molecular orbitals (e.g. HOMO, LUMO) they look awfully like atomic orbitals just forming localized bonds between two atoms to me.  In fact the whole notion of molecular orbital has disappeared in most of the explanations (except linguistically).  The notions of 50 years ago retain their explanatory power.  

p. 956 — How did Eschenmoser ever think of the reaction bearing his name?  Did he stumble into it by accident? 

p. 956 — The starting material for the synthesis of juvenile hormone looks nothing like it.  I suppose you could say its the disconnection approach writ large, but the authors don’t take the opportunity.   The use of fragmentation to control double bond stereochemistry is extremely clever.   This is really the first stuff in the book that I think I’d have had trouble coming up with.  The fragmentation syntheses at the end of the chapter are elegant and delicious.

On a more philosophical note, the use of stereochemistry and orbitals to make molecules is exactly what I mean by explanatory power.  Anti-syn periplanar is a very general concept, which I doubt was brought into being to explain the stereochemistry of fragmentation reactions (yet it does).  It appears over and over throughout the book in various guises.

The New Clayden pp. 909 – 930

p. 915 — A bit more could be made of the the prenyl group, rather than just showing its structure.  A huge class of natural products (camphor, vitamin A, cholesterol precursors and in fact those of all steroids) can be considered as various ways of linking the 5 carbons of the prenyl group to form the their carbon skeleton.  Note that the aldehyde precursor of citral also has the prenyl backbone. 

p. 918 — So S, and Se have oxidation states of S– (easy) to understand, S -4 and S -6 (why not S – 5 and S – 7?).  This is unfortunately typical of the generally unsatisfying way organic chemistry treats elements below the second row in the periodic table.  Perhaps things will improve when metallo-organic chemistry of the higher rows is discussed.  Contrast this to the excellent and detailed explanation of pericyclic reaction stereochemistry given by the Woodward  Hoffmann rules in examples later in the chapter.

23 Sep ’12 — Irrelevant to the discussion — but Nature for 13 Sep ’12 (vol. 489 pp. 278 – 281) has a new and cute prostaglandin synthesis involving a double aldol reaction which shortens it to 7 steps.  900 pages of the new Clayden are enough to understand almost all of it (which is why I’m going to get through it before reading anything else)   The paper uses the retrosynthetic disconnection analysis described in Clayden, so that isn’t an academic exercise (something I was wondering about).   In the crucial reaction (the double aldol) two catalysts were used (one was S-proline to get more of one diastereomer — they show why in figure 3), and the order of the addition of the two catalysts and the time between the additions was crucial in increasing yield.  Some poor grad student must have run the reaction a zillion times varying the conditions.

p. 919 — Even the elegantly written Clayden has trouble explaining the [1,5] sigmatropic shift.  Here’s what they say — “The figure ‘1’ in the square brackets shows that the same atom is at one end of the new sigma bond as was at one end of the old sigma bond.”  One picture is worth a thousand words. 

p. 920 — The fused ring systems from intramolecular Diels Alder reactions shown here resemble several natural products — is this their biosynthetic route?  It seems to be given the endiandric acid A synthesis given on p. 926.

p. 925 — It might be a good idea when first discussing the Woodward Hoffmann rules initially (p. 933) to point out that they predict obscure stereochemistry, unpredictable by other methods.  Otherwise it seems like a lot of terminology without much point. You do note this on p. 893 — but saying something like the above rather than just  ‘very helpful’ would be better. 

p. 929 — Who would have predicted the formation of a cyclobutene ring by a rearaangement of a fairly unstressed cyclobutane/cyclohexane fused molecule?  Perhaps the exomethylene group on the cyclobutane drove it, as this would make the cyclobutane ring more strained. 

The New Clayden pp. 877 – 908

p. 878 — “The transition state has 6 delocalized pi electrons and thus is aromatic in character”.  Numerically yes, but the transition state isn’t planar, and there is all sorts of work showing how important planarity is to aromaticity. 

p. 881 — It seems to me that the arrow is wrong in the equation at the bottom. Entropy should increase when a Diels Alder product is broken apart, and since deltaG = deltaH  – T * deltaS heating the product should break it apart not cause it to form.  I guess the heat shown is required to increase molecular velocity so that collisions result in reaction.   Enough kinetic energy will blow anything apart (see Higgs particle).

p. 890 — “It is not cheating to use the regioselectivity of chemical reactions to tell us about the coefficients of the orbitals involved.”    I do think that this sort of thing is  cheating when you use the regioselectivity of chemical reactions as an explanation.  They are adding nothing new.  A real explanation predicts new phenomena, the way the anomeric effect does, for example.  You should contemplate the point at which a description of something becomes an explanation (e.g. epistemology).   It’s not the case here, but it was the case for Newton’s laws of gravitation.  Famously he said Hypotheses non dingo (“I frame no hypotheses”).  It appears in the following

I have not as yet been able to discover the reason for these properties of gravity from phenomena, and I do not feign hypotheses.

Yet his laws of gravity were used to predict all sorts of events never before seen, so they are explanatory in some sense.  

This sort of thing is just what a neurologist experiences learning functional neuroanatomy (e.g.  which part of the nervous system has which function).  Initially almost all of it was developed by studying neurologic deficits due to various localized lesions of the brain and spinal cord.  There’s a huge caveat involved — pulling the plug on a radio will stop the sound, but that isn’t how the sound is produced.  People with lesions of the occipital lobe lose the ability to see in certain directions (parts of their visual fields).  Understanding HOW the occipital lobe processes sensory input from the eyes has taken 50 years and is far from over.  

p. 892 — Unfortunately the rationale behind  the Woodward Hoffmann rules isn’t covered, so it appears incredibly convoluted and arbitrary.  Read the book — “The Control of Orbital Symmetry” which they wrote.  Also, unfortunately, the description of the rules uses the term ‘component’ in two ways.  At step two butadiene and the dienophile are each considered a component, as they are in steps 3, 4, and 5, then the two are mushed together into a single component in step 6. 

p. 894 — I haven’t been looking at the animations for a while, but those of the Diels Alder type reactions are incredible, and almost sexual.  You can rotate the two molecules in space and watch them come together and react.

p. 894 –“Remember, the numbers in brackets, [ 4 + 2 ] etc., refer to the numbers of atoms.  The numbers (4q +2)s and (4r)s in The Woodward Hoffman (should be Hoffmann) refer to the numbers of electrons.”  This is so very like math, where nearly identical characters are used to refer to quite different things.  Bold capital X might mean one thing, italic x another, script X still another.  They all sound the same when you mentally read them to yourself.  It makes life confusing. 

p. 894 — The Alder ene reactions — quite unusual.  The worst thing is that I remember nothing about them from years ago.  They must have been around as they were discovered by Alder himself (who died in 1958).  They produce some rather remarkable transformations, the synthesis of menthol from citronellal being one.  I wonder if they are presently used much in synthetic organic chemistry. 

p. 900 — How do you make OCN – SO2Cl, and why is it available commercially?

p. 904 — The synthesis of the sulfur containing 5 membered ring of biotin is a thing of beauty.  It’s extremely non-obvious beginning with a 7 membered ring with no sulfur at all.