musings on music and life

May 16, 2016

Classics in Organic Chemistry, Part IV

Filed under: Classics in Organic Chemistry — sankirnam @ 12:41 pm

And now for our next topic, Sir D. H. R. Barton’s Gif Chemistry.

Derek Barton was another one of the “rockstars of organic chemistry” along with esteemed individuals such as R. B. Woodward, E. J. Corey, Professor G. A. Olah, Prof. K. B. Sharpless, and others. Like Einstein, Ernst Rutherford, and a few others, Derek Barton was particularly famous because his most famous work was not what he received the Nobel Prize for! Derek Barton contributed to an extremely wide range of research areas, including radical chemistry, hypervalent bismuth and selenium chemistry, fluorine chemistry, and of course, his last work involved the oxidation of saturated hydrocarbons under mild conditions – a class of reactions dubbed “Gif chemistry”.

The name is derived from the place where this type of chemistry was first studied, Gif-sur-Yvette in France. At the time, the functionalization of saturated hydrocarbons (alkanes) was a hot topic in the organic chemistry community; it still is today, although it has taken on the sexier name of “C-H activation”. I initially learned about this class of reactions when I was reading Iron Catalysis in Organic Chemistry: Reactions and Applications during the course of my PhD. Iron catalysis remains a topic of personal interest, as it focuses on one aspect of the question “can we substitute 3d metals for the precious 4d metals (Ru, Rh, Pd) as catalysts in organic synthesis?”.

In any case, the overall premise of the Gif reactions is the oxidation of saturated alkanes (by air or other oxidants) using iron as the catalyst. In all cases, adamantane was chosen as the substrate for “its non-volatility, which would make good mass balances feasible, and its symmetry, which simplifies the problem of product identification. In addition, adamantane is a nice mechanistic probe. It has 12 equivalent secondary C-H bonds and four equivalent tertiary C-H bonds”.


Conceptually, this is not terribly difficult to understand; the terminal oxidant in both reactions above is O2 from the air, and the solvents involved are pyridine, acetic acid, and water (in the GifII reaction). Pyridine is necessary because you need an organic solvent to dissolve something as nonpolar as adamantane (or any alkane), and acetic acid is employed as an anion once the iron is also in solution. The surprising observation is that this alkane oxidation takes place in the presence of hydrogen sulfide, which is much easier to oxidize than any alkane; in fact, it turned out that the presence of a sulfide (or phosphine) was necessary for the oxidation to proceed.

Historically, oxidative chemistry using Fe is well known in the literature, and the earliest example is probably Fenton’s reagent, which is well over 100 years old. That being said, there is still a lot of uncertainty regarding the mechanism of the Gif reactions, and unfortunately interest in these investigations waned with Derek Barton’s demise in 1998. The main question was whether this reaction proceeded via radical intermediates (like the Fenton system), or did it involve the intermediacy of a high-valent Fe(IV) or Fe(V) species? One of the arguments against the involvement of radicals is the observation that the reaction proceeds in the presence of hydrogen sulfide; the S-H bond is known to quench carbon radicals readily by HAT (hydrogen atom transfer). Another is the regioselectivity of the reaction; since tertiary radicals are more stable than secondary radicals, one would expect the tertiary product (1-adamantanol) to dominate if radicals were really involved. But, as one can see from the figure above, the secondary products are obtained in greater yield.

Barton and his coworkers were able to isolate a soluble black crystalline complex from the dissolution of iron powder in acetic acid and pyridine; it was found that when this complex was employed in the reaction instead of iron powder, better yields and selectivities could be obtained. Barton’s theory was that a high-valent Fe(V) or Fe(IV)-oxo or -hydroxo species was responsible for the oxidation, as that would also account for the selectivity to secondary positions based on steric arguments. There is some precedence for this, as it is believed that high-valent Fe(V)/Fe(IV) is involved in biological oxidations using cytochrome P450.Barton_gif_2

This catalyst or cluster would be considered “primitive” by today’s standards, as the synthesis is pretty trivial, and the ligands are extremely simple. And yet, it is able to do some pretty impressive transformations!

Barton had this to say about how the reactions work:

“The only way that we can explain these results is by a hypothesis that the reagent that oxidizes the hydrocarbon is present in a dormant form (Sleeping Beauty) until it collides with the saturated hydrocarbon (the Prince) and reacts with a saturated C-H bond (the kiss) to form the real reagent, which immediately gives the iron-carbon bond […]. So, the hydrocarbon on contact with the iron species activates and reacts with the activated iron species without separation. The hydrocarbon should be inducing in the (formally) FeV=O species a change that makes possible such an unusual reaction. There is evidence in the literature for this sort of agostic interaction between nonactivated carbon-hydrogen bonds and organometallic species”.

Funnily enough, this chemistry has been rediscovered recently by Prof. M. Christina White (UIUC). I remember reading her papers and wondering in confusion why it was being published in top journals when there was a distinct lack of originality…all she was doing is repackaging the work Barton had done with Gif chemistry! For instance, in this paper, she has almost the same complex that Barton has described above, except that the ligands have been tweaked a little. Instead of using simple pyridine, she is using PDP (2-({(S)-2-[(S)-1-(pyridin-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)pyridine). Of course you’re going to improve the selectivity, lifetime, and TOF of the catalyst by making it better defined, but you’re not inventing a new reaction paradigm here. It should be no surprise that the catalyst therefore has an even greater preference for primary or secondary sites over tertiary sites than Barton’s original systems. I would not consider this work Science-worthy by any means, but hey, what do I know?



For those interested, you can read more on these topics in the references below:

  1. “The Selective Functionaliztion of Saturated Hydrocarbons: Gif Chemistry” Barton, D. H. R.; Doller, D. Acc. Chem. Res. 199225, 504
  2. Barton, D. H. R. Tetrahedron 199854, 5805
  3. Barton, D. H. R.; Doller, D. Pure & Appl. Chem. 199163, 1567
  4. Barton, D. H. R.; Boivin, J.; Gastiger, M.; Morzycki, J.; Hay-Motherwell, R. S.; Motherwell, W. B.; Ozbalik, N.; Schwartzentruber, K. M. J. Chem. Soc. Perkin Trans. I 1986, 947
  5. Barton, D. H. R.; Chabot, B. M. Tetrahedron 199753, 487

1 Comment »

  1. Great post! I am a fan of metal clusters and multinuclear metal complexes. Honestly, I did not know about Barton’s chemistry. I will read the first reference you cited. But, like you, I am also puzzled by some of those papers that have been published in “top” journals like Science and Nature.

    Comment by chemdiary — May 18, 2016 @ 6:44 pm

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