On the live webcast visible on the Nobelprize website, the Prize announcement was followed by a live phone interview with Prof. Negishi. He let the audience know he was awaken at 5 in the morning by the phone call announcing him the good news, and that he just had time for a coffee before the interview took place. I imagine this was but the beginning of a very long day for him! Quite amusing was when a journalist asked Negishi about the impact of his discoveries for the human beings. At that, Negishi responded something like ‘Do you have any knowledge of Grignard chemistry?’ The journalist laughed before admitting that he had no clue about it, and Negishi explained the impact of carbon cross couplings in much simpler terms.

* Andre Geim is probably the first researcher to detain a Nobel Prize together with a Ig Nobel Prize, obtained in 2000 for levitating a frog with magnets.

He started his presentation by showing his first molecular square, originally prepared nearly 20 years ago [1]. This tetrameric molecule, self-assembled from Pd(II) ‘angles’ and bipyridine linkers, was the starting point of an amazing field of research. In 1995, the 2-dimensional square became a 3-d cage [2]. Again the synthesis was astonishingly simple, allowing to obtain in a high yield a nanocontainer which was found to be able to accomodate simple guests (adamantane derivatives) in its cavity. It important to realize that a ‘classical’ synthesis approach requires many more steps and complications than the simple self-assembly process devised by Fujita.

Octahedral nanocage. The vertices are palladium atoms, and four faces are occupied by tris-pyridyl ligands. Source: http://www.nature.com/materials/news/newsandviews/030522/423394a_f1.html

Interesting features of this cage are that it is water soluble (the Pd centres are charged) and its cavity can accomodate hydrophobic molecules that are not water-soluble. By varying the organic ligand, several differently shaped and sized structures were obtained by self-assembly (such as cages, bowls, boxes, tubes, catenanes, and spheres) [3].

Well it is already good to have nice-looking architectures, but then? What do you answer when your non-scientific friends asks you “So what? What is this useful for?” … Looks like people in Fujita’s group decided to tackle this question very seriously (so that they don’t have to answer ‘er well, at the moment, we don’t have practical applications but potentially it could perhaps one day blah-blah-blah…’) and thus started to investigate what their hollow macromolecules were able to do.

A striking example of application was published in 2006. The cage of the figure above was used to perform a Diels-Alder reaction between two highly hydrophobic reagents in water [4]. The first step is the inclusion of the reagents inside the cage. They are then appropriately oriented to undergo a Diels-Alder reaction, affording the final product, as indicated in the figure below. Remarkably, only one isomer is isolated (the reaction is regioselective), and it is not the isomer one obtains when the reaction is performed without the cage. Furthermore, if a bowl-shaped macromolecule is used intead of the cage to perform the same reaction, it was observed that 1) a different isomer was produced, 2) a catalytic amount of the ‘bowl’ is enough to ensure a high yield, and 3) the Diels-Alder adduct is released from the bowl after formation. This is a typically enzyme-like behaviour: once formed, the reaction product is no longer compatible with the host, and is therefore released, preventing catalyst inhibition.

Diels-Alder reactions performed inside the cage and bowl-shaped molecules.

Other impressive achievements shown during this talk included crystal engineering (a porous coordination network which is able to adapt its size and shape upon guest absorption or removal [4]) and encapsulation of biological molecules (small nucleotides duplexes formed in the hydrophobic pocket of a water-soluble cage [5]).

References:
[1] J. Am. Chem. Soc. 1990, 112, 5645. DOI: 10.1021/ja00170a042
[2] Nature 1995, 378, 469. DOI:10.1038/378469a0
[3] Acc. Chem. Rev. 2005 38 369. DOI: 10.1021/ar040153h
[4] Science 2006, 312, 251. DOI:10.1126/science.1124985
[5] Nature Chemistry 2009, 1, 53 doi:10.1038/nchem.100

Mechanistic investigations have shown the importance of the Cu(I) and of the carboxylate anion for the cross-coupling to work efficiently. These two species are therefore clearly involved in the catalytic mechanism, which is shown below. The thiol ester undergoes complexation to the copper(I) carboxylate, followed by oxydative addition of the bound thiol ester to the Pd(0) catalyst (1). A copper-mediated transmetallation then allows to form the organopalladium compound (2) and eliminates the copper thiolate and boron derivative byproducts. The final ketone (3) is obtained by a reductive elimination that also regenerates the palladium catalyst.

The reaction described above uses a stoechiometric amount of the copper(I) carboxylate. To make it catalytic, it is necessary to regenerate the Cu(I) oxygenate from the eliminated Cu-SR. This was achieved by performing the reaction with an excess of boronic acid, and under air. The Cu-SR bond is broken to form a thioether with the excess boronic acid, and a copper oxygenate is made available to the system. A particular thiol ester was necessary to make the reaction work:

Ref: L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 11260;
J. M. Villalobos, J. Srogl, L. S. Liebeskind, J. Am. Chem. Soc. 2007, 129, 15734.