Clayden pp. 663 – 748

Halfway through Clayden. Hosanna !    A great book.  I am getting a bit tired of the carbonyl group, but there is yet another chapter on the subject to come.  It’s sort of like the blues, the chord pattern is always the same (e.g. the C = O bond), but what you do with it that separates the men from the boys.  Clearly, a lot has been done in the past 50 years.

Time to write the great man himself, and see what he thinks about all this.  Thanks to all the commenters — I’ll get to them shortly, but I just had to get past the halfway point.

p. 663 — “We develop the chemistry of Chapter 21 with a discussion of enols and enolates attacking to alkylating agents . .. ”   Probably a misprint or something added or left out.  The sentence as it stands makes no sense.

p. 666  — You give the pKa of CH3NO2, why not  give the pKa of CH2(CN)2 ?  Along these lines what’s the pKa of R-CH2-CN ??

p. 668  — (grey box on top) LDA is described on p. 540 not p. 538 

p. 668  — You are showing the Li-N bond as covalent.  Is it really?

p. 668 — The transition state shown in the bottom reaction (if that’s what it is, and not just electronic bookeeping) can’t be right.  3 of the 6 atoms in the hexagon must be planar (the enolate), attack on the MeI must be out of this plane (if it’s to be an Sn2 reaction).  The leaving I group must be even farther out of the enolate plane, and to catch it (as shown in the diagram) the lithium must also be out of the enolate plane, making the beautiful, symmetric hexagon shown quite unlikely. 

p. 669 — In the top reaction why isn’t the proton ‘para’ to the ketone also formed?  The charge would be delocalized quite well. 

p. 680 — The compound at the right in the bottom row is missing a phenyl group. 

p. 681 — “the Si-O bond is so strong that even neutral enols react .. ”   Well, just how strong is it? 

p. 689 — You might mention that our body uses the aldol condensation to make glucose out of two 3 carbon fragments.  

p. 690 — “Proton transfers to and from carbon atoms can be slow”   Is this because the electronegativities of C and H are so close together than the bond is quite covalent, as opposed to the more polarized H – N, H – O and H – X bonds which already have more charge polarization (greater dipole moment with the hydrogen more H+ like )?? 

p. 691 — The gray sidebar pointing back to a specific page for the E1cB mechanism is a good idea and this sort of thing should probably be done for subjects brought up over 150 pages back and not subsequently mentioned extensively. 

p. 694 — “ketones are less reactive than aldehydes (Chapter 6)”  — yes but WHERE in chapter six? I didn’t find anything obvious.  Is it due to the small hydrogen?  the less electronegative hydrogen? 

p. 698 — A pointer to how hard it is to make and work with lithium enolates, LDA etc. etc. (e,g, to the discussion in the sidebar on p. 720) might be useful here.  Probably people reading the book will have this in their subconscious having been around labs, in my case being away for 48+ years it came as a shock.  

p. 698 — minus 78 C appears many places in this book.  It isn’t until later in the chapter that you say it is the temperature of acetone with dry ice added.  This should be noted the first time -78 C appears.

pp. 709, 711 — It’s nice that you’re starting to give the names of chemists who’ve developed the chemistry, even if the reactions aren’t named for them.  Somehow named reactions (like named diseases) are easier to remember.  Also just the fact that they were named, makes them seem more important.


p. 721  Answer to #7 — The problem has R2NH under the first arrow.  This is replaced by NMe2 in the Mannich product. 

p. 724 — While you introduce the Claisen condensation with the classic example, because both the two partners are the same, it isn’t clear who is doing what to whom.  On p. 730 you say “Claisen condensations always involve esters as the electrophilic partner.”  Putting that sentence here would make the subsequent discussion much more clear, along with something like “the enols of other carbonyl compounds can sometimes be used”.

p. 726 — The pKa of EtOH is 16, Phi3CH is stated to be a stronger base — how much stronger in terms of pKa? 

p. 728 — you mention sigma conjugation in the side box.  A pointer to this discussion would be nice.  When looking it up in the index, I found that it is also called hyperconjugation.  I wondered about this when I first read p. 562, and the next edition should contain this in the text.  I actually wondered about this when I hit this page (see “Clayden pp. 547 – 662” )
. 
p. 728 — The formic acid carbonyl is electrophilic.  Why?  (1) lack of steric hindrance (2) lack of sigma conjucation.  But NOT from an electronegativity effect as that of H is 2.2 (compared to carbon’s 2.5) which should make the carbonyl of formic acid LESS electrophilic.  Again, this balancing of conflicting data and choosing what actually happens is quite similar to what MDs (should) do for their patients.  Exactly why pre-meds should take and pass organic chemistry.   

The page contains another example of this sort of intellectual balancing act, in the next paragraph, where it is explained by esters are less electrophilic than ketones (electro negativity of the oxygen making them MORE electrophilic, but the resonance electron donating effect of the oxygen lone pair making them LESS electrophilic, with the latter winning out). 

This is followed on the next page by a similar discussion about the carbonyl in the carbonate diester.  

p. 736 — “The magnesium atom bonds strongly to both oxygens lessening their effective negative charge”  Since the enolate anion has a negative charge of – 1 and the magnesium atom has a charge of +2, doesn’t the Mg do more than this?

p. 744 — the structure of coenzyme A is found on 1389 not 1386.

p. 744 — it might be worth while to point that humans have an enzyme called fatty acid synthetase which accomplishes all the reactions of adding the two carbon unit reducing the beta ketone to an alcohol, dehydrating it to an alpha beta unsaturated thioester, and reducing the double bond one after the other by passing each intermediate from one active site to another exactly like an assembly line.  As you might suspect the enzyme is huge.  It has 2505 amino acids and a molecular mass of 272 kiloDaltons (making what organic chemists do look like very small potatoes).  

p. 745 — Answer to #5.  There is no solution for the second compound in this problem.  I used an intramolecular condenstion.  

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