Clayden pp. 547 – 662

OK, boys and girls, get out your copy of Clayden, Greeves, Warren and Wothers.  If you know the answer to any of the questions (asked out of ignorance not snarkiness) put in a comment.  I’m not going to write Clayden until I’ve finished half the book.  But it’s getting close.  Once again, a tremendous book and great fun to go through.

p. 549  — C – C bond length 1.47  — really?  Most have it at 1.54 Angstroms.  There should be an index entry for ring current (there isn’t).  It’s on p. 251 in the present book.


p. 550  – You’ve got Br–Pyridine+ implying the Br-N bond is covalent.  Is it really?   
*** reply from James “550- not unreasonable to think of this bond as covalent considering the similarities in their electronegativities”
         Thanks !  the electronegativity of N is 3.04 Br is 2.96 according to Clayden’s table 

p. 551 — So neat to see the calculated charge distribution on benzene (as shown by chemical shifts on NMR)  — this is what we thought it was 50 years ago.  Is Xray crystallography now good enough to actually show different electron densities on ortho meta and para positions of say nitrobenzene or toluene?

p. 552 — Has anyone seen the nitronium ion (the way C6H7+ was  seen using SbF6- on the previous page)?    Ditto for HSO3+ (and on p. 554 ditto for the acylium ion)?
*** reply from James “552 – quick wiki search tells me that some simple nitronium salts have been isolated: http://en.wikipedia.org/wiki/Nitronium_ion”
         Thanks!  Luysii
Also, why not give the pKa’s of H2SO4 (-3) and HNO3 (-1.4) instead of saying H2SO4 is stronger. 

p. 553 — Wikipedia has the pKa of HCl as -8 (you have it as -7 on p. 188), which makes it stronger than H2SO4.  However you say that sulfonic acids are about as strong as H2OS4 (pKa -3) and STRONGER than HCl — which doesn’t appear to be the case. 
*** Reply from James “553: good point, pH of tosic acid is ~3 (closer to H2SO4) and weaker than HCl.”

p. 558 — In the cyclic transition state between CO2, Na+ and phenoxide, what’s the solvent?  It’s probably not water, as both ions would be solvated and getting them desolvated along with CO2 all at once would be pretty entropically and enthalpically unfavorable. 

p. 558 — If the electron density in aniline is greater at the ortho and para positions than that of phenole, wouldn’t one expect MORE ring current there hence less shielding, rather than more.  This has come up before.  There must be a disjunction between electron density and ring current, but what is the explanation?

p. 559 — It would be nice see the chemical shifts of the aromatic hydrogens of acetyl aniline to compare them with phenol and aniline. 
 
p. 562 — It looks like sigma conjugation is what we used to call hyperconjugation.  This reminds me of what one of my cynical chiefs of neurology use to say — there never is any progress in neurology but every 10 years we rename the diseases. 

p. 565 — What is ‘fuming nitric acid” as opposed to nitric acid — it sounds like something out of Shakespeare. 

p. 574 — “using acid and zinc amalgam”    We’ve seen a lot of oxidations, reductions by this point.  Hopefully there will be a chapter on oxidation/reduction and why the agents work the way they do.  At this point, the choice of oxidant/reductant seems quite arbitrary.  It’s so arbitrary that there will probably be a separate post about it.

**** Reply from James “this frustrated me as an undergraduate as well. Chemistry is empirical – we end up using the reagents that work well and are simple to use. amalgams are easy to prepare and use – just add finely dispersed metal to mercury, heat, and you’re pretty much ready to go. NaBH4 is also a convenient reductant – it’s easy to use, easily stored, and cheap. Same reason you see -78 deg C a lot – it’s the temperature of the easily prepared dry ice/acetone slush bath.
            Luysii —  Clayden explains what  -78 C actually is on p. 740 — he should have done it sooner.


               Do people actually work with carbon monoxide in academic or pharma small scale drug labs, or is its use confined to industry?   E.g. don’t try this at home.   Ditto for HCN on p. 575
**** Reply from James****** I saw a Corey prep were a cooled syringe was used to add liquid HCN.  Ballsy. It is more commonly made in situ. 
p. 573 — Any idea why the compounds formed from direct nucleophilic attack on the NO2 are unstable? 

p. 584 — You note that Michael acceptors are dangerous, because they are carcinogenic.  You might note that alpha beta unsaturated ketones are formed in the body all the time, by the  oxidation of prostaglandins.  The following paper is interesting.        [ Proc. Natl. Acad. Sci. vol. 107 pp. 6835 – 6840 ’10 ]  A protein found in the senile plaque of Alzheimer’s disease and in the Lewy body of Parkinsonism forms a thiol adduct with a prostaglandin derivative, causing it to aggregate. The culprit is cysteine #152.  The other 5 cysteines in the protein do not react this way, showing incredible selectivity and also just how humble organic chemists must be about the subtlety of the chemistry within us.  It makes the next chapter (#24) on chemoselectivity look like a piker.  More about this in the previous post titled “Protecting groups”

p. 584 — “This is one reason why vitamin C is so beneficial — it removes stray oxidizing agents”.  This might have been considered to be true 10 years ago (based more on theory than evidence), but the whole idea that antioxidants are protective, hasn’t been borne out in several studies.  Consult your medical colleagues for the latest.  In retirement I’ve stopped intensively reading the medical literature, but I can supply some older references, if you wish. 

p. 587 — The “simple cyanoimine” does not look simple to me, nor do I see any way I could make it based on what’s been discussed so far.  Why is iitreadily available?

p. 589 — Sn2 on benzene is impossible because of steric hindrance, but there must be other reasons why “SN2 at sp2 C does not occur”.  You should give them. 
**** Reply from James ” SN2 on sp2 is less favored because you would have a partial positive charge on the sp2 carbon, which is less stable than on an sp3 (hyperconjugation)”

pp. 591 – 2 — Why are the intermediates colored? 
**** Reply from James ” great question – color is related to HOMO-LUMO gap. For instance a lot of transition metal complexes. have small HOMO-LUMO gaps, hence it doesn’t take much energy to excite them (figure out wavelength using E=hV). Hence they are often brightly colored. Something very stable like diamond is colorless b/c of tremendous homo/lumo gap – it only absorbs in UV.
-fuming nitric acid is nitric acid containing dissolved NO2. Similarly, fuming sulfuric acid contains dissolved SO3.

p. 592 — Again, a beautiful example of NMR shifts predicing/explaining reactivity (the chemistry was known long before the compounds were made, so this isn’t post hoc propter hoc). 

p. 594 — You have p. 000 in the top aside box.  I think putting in page numbers to all backward references is a good idea.  
“Fluoride does, in fact, slow down the second step (relative to Cl-).  How can you experimentally find this out? 

p. 597 — Does NO+ have a name? 
***** Reply from James “597 – NO+ is nitrosonium. You can actually buy salts of nitrosonium, for example nitrosonium tetrafluoroborate.”  

 


p. 598 — “If R is an aryl the carbocation is much less stable (for reasons we discussed earlier) ….   A pointer to the discussion would be good.  My guess is that the sp2 orbital is lower in energy than a p orbital (because the electrons are closer to the nucleus in an sp2 orbital) making removal of electrons from it, more energetically expensive.   I seem to have gotten this right based on the discussion in the top sidebox on p. 601. 

p. 599 — in the sidebar at the top you have p. 000.   Also the forward pointer in the second sidebar is nice. There should be a lot more of them in the next edition. 

p. 604 — In the top reaction under the leftmost arrrow, you have NH3 (I).  What does the (I) stand for? (probably liquid, but I’ve learned that assuming what abbreviations stand for is dangerous — particularly in medicine, where usage is far from uniform.    **** James’ (extremely helpful) comment 604 – (l) is liquid, ammonia is a gas at RT but condenses around -40.

p. 615 — You might mention that a 100 amino acid protein contains well over 50 functional groups — exclude glycine, alanine, valine, isoleucine, leucine, proline and phenylalanine.   This is why protein chemistry is so hard.  Actually that’s not quite true in the context of protein structure, as the hydrocarbon side chains of the above are crucial to the 3 dimensional packing of the protein, so they are functional structurally, but are relatively unreactive chemically.   See the last post “Protecting groups”

p. 617 — last paragraph.  Very good to say that the mechanism is unclear, rather than to skip it making the reaction black magic and leaving the novice reader to think that the mechanism IS known, but too complicated to explain.

p. 618 — In the mechanisms of ester and amide reduction by LiAlH4 you have a covalent bond between Li and O in the second ester and the third amide structure (at least it’s drawn the way covalent bonds are drawn).  Do you really mean this?  We consider NaCl as having an ionic bond.  The electronegativity you give for Na is .93 and for Cl is 3.16 giving a difference of 2.23.  The electronegativity difference between Li and Oxygen is 3.44 – .98 = 2.46 an even greater difference than NaCl.  
***** Reply from James “618-good point – probably just laziness – drawing out positive/negative charges all the time takes effort.”
Also, you might mention that the electronegativity of Al is lower than B (1.6 vs. 2.0) explaining the relative abilities of BH3 and AlH4 to donate hydride.

p. 625 — You will definitely need to update the section on hydrogenated fats to include the latest dietary hysteria (trans fats are bad for you).  You’d be amazed how skimpy the evidence for this sort of thing is.  Even sketchier is the evidence that normal people should reduce their salt intake.

pp. 625 – 626 — Is there any reason that the 3 metals used in catalytic hydrogenation (Ni, Pt, Pd) all contain 8 electrons in their d orbitals? 
***** Reply from James “625/638 – transition metal chemistry does seem very arbitrary at this point in the course. A good course in inorganic chemistry/organometallics clears it up. Christina White’s course at UCIC is a fantastic resource. Just read the first handout, it will help a lot. http://www.scs.uiuc.edu/white/index.php?p=lectures
The short answer is, reaction of those electron-rich TMs with dihydrogen leads to a reaction called oxidative addition, where the oxidation state increases by two. The metal needs to be competent to bind to H2, first of all, and then be electron-rich enough to stabilize an increase in its oxidation state.


p. 626 — It’s not clear to me just where CeCl3 is acting in the reduction of the alpha, beta unsaturated ketone to the alcohol. 
***** Reply from James “- 626 – the role of the CeCl3 is to coordinate to the carbonyl oxygen (lanthanides are very oxophilic). This activates the carbonyl carbon towards attack (it actually increases positive charge density on the carbonyl carbon, and it is this ionic contribution which leads to higher reactivity of the hydride at the carbonyl vs. the B position).”
****** Luysii — vert helpful, thanks.

p. 629 — “electron donating groups stabilize ortho and meta electron density”  Wouldn’t it be better to say, electron donating groups DEstabilize electron density at the ipso and para positions? 

p. 633 — It isn’t clear (to me) just how the imidazole is acting as a nucleophilic catalyst in the second reaction from the bottom. 

p. 638 — “We start with this, because overoxidation is difficult.”   This should be “We start with this, because preventing overoxidation is difficult.”

p. 638 — You’ve drawn CrO4H- as tetrahedral.  Is it really? 

p. 638 — Will you ever get into the structure of the bonding orbitals of the transition metal oxidants and what they can and can’t do, or is this assumed in a previous course in general chemistry? 
***** Reply from James  “625/638 – transition metal chemistry does seem very arbitrary at this point in the course. A good course in inorganic chemistry/organometallics clears it up. Christina White’s course at UCIC is a fantastic resource. Just read the first handout, it will help a lot. http://www.scs.uiuc.edu/white/index.php?p=lectures
The short answer is, reaction of those electron-rich TMs with dihydrogen leads to a reaction called oxidative addition, where the oxidation state increases by two. The metal needs to be competent to bind to H2, first of all, and then be electron-rich enough to stabilize an increase in its oxidation state.”


p. 639 — the oxidation state of Ruthenium in Ru04- appears to be 7 not 6.  Also the mechanism of NMO oxidation of the alcohol should be discussed (if known).   I found the discussion incoherent.
***** Reply from James “639 – good point. After oxidation, RuO4 goes to the 5 oxidation state, the purpose of the NMO is to oxidize the Ru back to 7 oxidation state. (it attacks the Ru).”


p. 639 — In the formation of the Dess Martin periodinane, what happens to the KBrO3 in the reaction, clearly it is being reduced, but to what ??? 
***** Reply from James “639 – not sure if to KBrO2, KBrO, or Br2. I never had the pleasure of making DMP through this method, although a colleague did, and said it made a tremendous mess.”

p. 640  — Don’t understand the answer to #4.  Is it correct?

p. 641 — Answer to #12, last one: Couldn’t you form the tosylate from the alcohol and then use SH CH2 CH2 NH2 + base.  Seems like less heavy lifting (assuming you can get SH CH2 CH2 NH2.

p. 661 — A great fun chapter to read (as a former Woodward grad student), but at the end you say the next 4 chapters will discuss C – C bond formation, yet I find no mention of metathesis in the index.  Is this an oversight, or don’t you discuss it?  If not, why not?   Web sites are devoted to metathesis.  Sadly, organic synthesis has apparently fallen into disrepute — See the comments on today’s (26 April ’10) post in “In the Pipeline”  — Maitotoxin Revisited. 
**** Reply from James ” 661 – probably just optimizing the depth/breadth conundrum. Methathesis mechanism involves lots of transition metal chemistry. I agree it should be in the book somewhere though.”

Answer to problem #3 p. 660.   Me2NH is what is added to oxirane to get the product not MeNH2
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Comments

  • James  On May 28, 2010 at 2:41 am

    Very thought provoking, especially for someone who has been an organic chemist for a long time and should know the answers to all of these questions. I don’t have a copy of Clayden in front of me, but here goes:
    550- not unreasonable to think of this bond as covalent considering the similarities in their electronegativities
    552 – quick wiki search tells me that some simple nitronium salts have been isolated: http://en.wikipedia.org/wiki/Nitronium_ion
    553: good point, pH of tosic acid is ~3 (closer to H2SO4) and weaker than HCl.
    574-this frustrated me as an undergraduate as well. Chemistry is empirical – we end up using the reagents that work well and are simple to use. amalgams are easy to prepare and use – just add finely dispersed metal to mercury, heat, and you’re pretty much ready to go. NaBH4 is also a convenient reductant – it’s easy to use, easily stored, and cheap. Same reason you see -78 deg C a lot – it’s the temperature of the easily prepared dry ice/acetone slush bath.
    574 – I saw a Corey prep where a cooled syringe was used to add liquid HCN. Ballsy. It is more commonly made in situ.
    589 – SN2 on sp2 is less favored because you would have a partial positive charge on the sp2 carbon, which is less stable than on an sp3 (hyperconjugation)
    591 – great question – color is related to HOMO-LUMO gap. For instance a lot of transition metal complexes. have small HOMO-LUMO gaps, hence it doesn’t take much energy to excite them (figure out wavelength using E=hV). Hence they are often brightly colored. Something very stable like diamond is colorless b/c of tremendous homo/lumo gap – it only absorbs in UV.
    -fuming nitric acid is nitric acid containing dissolved NO2. Similarly, fuming sulfuric acid contains dissolved SO3.
    597 – NO+ is nitrosonium. You can actually buy salts of nitrosonium, for example nitrosonium tetrafluoroborate.
    604 – (l) is liquid, ammonia is a gas at RT but condenses around -40.
    618-good point – probably just laziness – drawing out positive/negative charges all the time takes effort.
    – 626 – the role of the CeCl3 is to coordinate to the carbonyl oxygen (lanthanides are very oxophilic). This activates the carbonyl carbon towards attack (it actually increases positive charge density on the carbonyl carbon, and it is this ionic contribution which leads to higher reactivity of the hydride at the carbonyl vs. the B position).
    625/638 – transition metal chemistry does seem very arbitrary at this point in the course. A good course in inorganic chemistry/organometallics clears it up. Christina White’s course at UCIC is a fantastic resource. Just read the first handout, it will help a lot. http://www.scs.uiuc.edu/white/index.php?p=lectures
    The short answer is, reaction of those electron-rich TMs with dihydrogen leads to a reaction called oxidative addition, where the oxidation state increases by two. The metal needs to be competent to bind to H2, first of all, and then be electron-rich enough to stabilize an increase in its oxidation state.
    639 – good point. After oxidation, RuO4 goes to the 5 oxidation state, the purpose of the NMO is to oxidize the Ru back to 7 oxidation state. (it attacks the Ru).
    639 – not sure if to KBrO2, KBrO, or Br2. I never had the pleasure of making DMP through this method, although a colleague did, and said it made a tremendous mess.
    661 – probably just optimizing the depth/breadth conundrum. Methathesis mechanism involves lots of transition metal chemistry. I agree it should be in the book somewhere though.
    – send me an email if you want – James

  • luysii  On June 13, 2010 at 9:59 pm

    James — thanks for the excellent comments, i’ve put them in the body of the post itself, and will interpolate them in the coming week, possibly with even more questions. Sorry for the delay in getting to them

  • luysii  On July 1, 2010 at 12:32 pm

    James — your excellent comments have been interpolated at last. They were quite helpful. Thanks.

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