I recently spent some time listening to an acquaintance talk about his days as a student at MIT and as a grad student at Harvard in the early 1950’s.  He had Geoff Wilkinson for inorganic chemistry at MIT as an undergrad and later did his PhD with Wilkinson at Harvard.  Curiously, Wilkinson did radiochemistry in the Manhattan Project prior to joining academia. His radiochemistry experience compelled him to work fast and in test tubes, according to my friend.

My friend’s lab mate in Wilkinson’s group was Al Cotton. They started grad school together ca 1952 or so. This was shortly after the sandwich structure of ferrocene was proposed by Wilkinson’s fellow Harvard prof R. B. Woodward. Woodwards basis for this structure was on symmetry and a single IR stretch absorption. Spectroscopically, the original sigma bonding model didn’t fit the data.  Just prior to this, Wilkinson had begun work on a variety of organometallic Cp compounds. As the story goes, when Woodward expressed interest in making more Cp compounds, Wilkinson went to his office and “had words” with Woodward. Afterwards, Woodward moved on to other things.

My friend laughingly recalls the time he was chewed out by his P-Chem prof, the great George Kistiakowski and earlier, by Arthur Cope at MIT. He recalls being summoned to Cope’s office. Cope was wearing pink slacks which contrasted with his red hair. He was displeased about the impertinent back channel invitation my friend pitched to Linus Pauling to speak to the chemistry club. (I haven’t verified the color of Cope’s hair)

My friend recalls having E. J. Corey as a lab assistant while in an undergraduate lab at MIT. He joked that he saw Corey once at the beginning of the term and once at the end. My PhD advisor, Al Meyers, did his post doc with Corey some years later. Small world.

An interesting bit of chemistry was published by Berit Olofsson at Stockholm University in a recent JOC. The Olofsson lab has previously produced a method for the one-pot preparation of diaryliodonium triflates. This latest work provides diaryliodonium tetrafluoroborates (JOC, 2008, 73, 4602-4607). 

The preparation of I(III) compounds usually starts with an Ar-I compound undergoing oxidation followed by an electrophilic addition/substitution to another arene. Regioselectivity is obtained by choosing a donor with a leaving group such as a boronic acid, stannane, or silane.

What is clever about this process is the fact that a BF4 salt is directly produced. Two equivalents of boron trifluoride etherate are used in the reaction which evidently results in some kind of disproportionation producing the BF4 counter-anion. 

It is known that the reactivity of iodonium compounds is somewhat sensitive to the coordinating ability of the counter-anion, so BF4 is less undesirable than other choices (like chloride). Solubility is greatly influenced by the choice of counter-anion as well. This is particularly true in photo-initiator applications where the choice of carrier fluid may be limited.

The recent issue of Journal of Organic Chemistry, (JOC, 2008, 73(12)) has a few articles that are particularly interesting.

The article by Lipkus, et al., entitled Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry, JOC, 2008,73, 4443-4451, is a particularly ambitious bit of work that only CAS could do. This article describes a scaffold survey of more than 24 million organic compounds in the CAS Registry.

The data set was limited to carbon-based structures containing the heteroatoms H, B, Si, N, P, As, O, S, Se, Te, and the halogens.  Moreover, the work was further limited to framework structures containing rings or linked rings. Acyclic compounds were not included owing to the inapplicability of the framework definition in the search algorithm. Multicomponent substances and polymers are ignored as well.

Lipkus and coworkers found that half of the graph frameworks analyzed are described by only 143 framework shapes.  The remaining half are described by 836,565 graphs.

One of the key conclusions is quoted here-

“It is not surprising that some frameworks occur much more frequently than others. However, the extreme unevenness in the way frameworks are distributed among organic compounds is somewhat surprising. This is particularly true at the graph level, where it is found that only 143 framework shapes can describe half of the compounds. The fact that both graph and hetero frameworks have very topheavy distributions tells us that the exploration of organic chemistry space has tended to concentrate on relatively small numbers of structural motifs.”

Lipkus concludes that cost minimization is one of the drivers of this “… shaping the known universe of organic chemistry.” He comes to this conclusion due to the presence of a power law which describes this distribution. The power law he refers to is a linear log-log relationship that is indicative of what they refer to as the “rich-get-richer process”.

If I understand this correctly, a relatively small number of easily made or commercially available early precursors are comprised of ring graphs that, by virtue of modification, propagate into more complex analogs that retain the original graph. This has the effect of multiplying the frequency of a given graph.

The cost minimization aspect comes from the benefits of familiar chemistry and the commercial availability of a fairly limited set of ring graphs. Adding more rings will usually mean adding more molecular weight and adding problematic synthesis and separation issues.

The authors conclude that the lopsided distribution of organic compounds toward only 143 graphs comprises a bottleneck in drug discovery. They further suggest that more exploration in other areas of chemistry space may be worthwhile.