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 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.

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  • Curious Wavefunction  On November 6, 2012 at 10:12 pm

    Japanese chemists have been top-notch in total synthesis and organometallics for several years now. It would be interesting to find out if most of them originated from a particular school, although I would guess many of them have a connection to Noyori and Yasumoto since they have been around for a while.

  • Ryan  On November 7, 2012 at 12:09 pm

    Here is a great intro to organometallic chemistry that answers many of your questions.

    • luysii  On November 7, 2012 at 2:31 pm

      Ryan – thanks for the link. Clearly something that will take a fair amount of time to go through. I’m interested to see if it would be a better place to start than Ch. 40 of Clayden. In fairness to the book, they only could allot 32/1200 pages to organometallic chemistry.

  • Ryan  On November 7, 2012 at 3:04 pm

    Actually it is a collection of several short lessons but goes into much more detail as to what is actually happening. With a basic understanding of ochem you could get through it in a couple of hours. Personally I would read it first as it will allow you to understand the details of the basic reactions, ligand effects, coordination number, geometry, etc. that most organic textbooks gloss over. (I have not seen the new Claydon.)

    • luysii  On November 8, 2012 at 11:51 pm

      Well, I’ve looked at one or two of them and they seem pretty good. The main issue at this point, is just how accurate they are, a question which doesn’t arise with an established textbook like Clayden et. al. What’s the word on the street?

  • Ryan  On November 9, 2012 at 10:22 am

    Uhhh… It’s basic undergrad chemistry. I’m not sure what you mean by “accurate”?

    • luysii  On November 9, 2012 at 12:55 pm

      Hopefully true, and hopefully Evans is a solid chemistry grad student, but see

      Also see any of the In the Pipeline posts on reproducibility of various results in the organic literature — the most recent concerned the way yields are reported, but there are many more along this line.

      So once past the authoritative textbook phase, a certain amount of caveat emptor is in order. Even textbooks aren’t perfect. Look at the bottom sidebar on p. 1116 of Clayden, for a revision of what they wrote in the first edition of their book.

      • Ryan  On November 9, 2012 at 3:30 pm

        I don’t see your point. From the nature of your questions I thought a website outlining basic concepts in plain English would be beneficial to you. This isn’t cutting edge stuff here. If you need a textbook to tell you (there a number of good ones available) then why are you asking these questions anyway? My apologies for trying to be helpful.

      • luysii  On November 9, 2012 at 7:02 pm

        No the site looks good. It’s the reliability of the site that I question. You were quite helpful. Perhaps chemistry is different, but there’s a huge amount of trash out there on the net, particularly about medicine and health. Trust me.

        Curious wavefunction has it right (see below)

  • MJ  On November 9, 2012 at 12:31 pm

    “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”

    Instead of attempting to condense this section from Levine’s ‘Quantum Chemistry’ into a reply, here’s the relevant excerpt from the text as an Adobe Acrobat document – If you’d prefer for me to email it, let me know.

    I think the quote about favoring facts over explanation hints at the messy truth – inorganic chemistry is really hard, although tremendously interesting. There is the old joke that an organic chemist’s periodic table would be the first two rows with very few elements from the third row and beyond. Heh.

    • luysii  On November 9, 2012 at 12:56 pm

      MJ thanks — came through just fine.

  • Curious Wavefunction  On November 9, 2012 at 3:45 pm

    Ryan: I think luysii is simply questioning the authenticity of the source. Given that it’s from the internet, is it as reliable as a bonafide textbook written by tenured professors from established universities? luysii, correct me if I am wrong.

    • luysii  On November 9, 2012 at 7:03 pm

      You’re exactly right.

  • lewis robinson  On November 10, 2012 at 9:06 am

    An intriguing use of organometallic chemistry within a protein is reported [ Science vol. 338 pp. 500 – 503 ’12 ] 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 Rhodiumcomplex 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

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