Honing Halophilicity

Let's say you have a late-stage drug candidate, with an alcohol, an olefin, and a pyridine. Now you toss in one equivalent of a chlorinating reagent.

Which functional group gets halogenated first?

Babak Borhan and colleagues from Michigan State and Dow may have your answer. In a recent JACS full article, they disclose the HalA (halenium affinity) scale, a DFT-calculated delta to describe the relative reactivity of various groups to an incoming halogen source. They back up their calculations with NMR competition studies, showing, for example, that two structurally similar molecules have a rather skewed 7:1 equilibrium, as predicted by a 1.1 kcal / mol difference in HalA:

Borhan et. al., JACS 2014

Using 500 computationally-evaluated functional chlorenium "acceptors" (Lewis bases), Borhan and colleagues create a chart to help answer our initial question: What reacts first?

I'm certain even more detailed versions of this chart are currently underway. I wonder how well it would extend to prediction of methyl or trifluoromethyl group additions?

The Periodic Table of Mugs

Another big thank-you to the ACS for my brand-new set of periodic table mugs!

This is exactly how they came to me, colors and all... Honest!

I realize I'm one of the lucky ones, and that my earlier agitation may have forced someone's hand. But I'm serious here: Keep up the program, ACS! By membership year, I'm deep into "Row 3" of the table, and I'd love to see some beautiful transition metal mugs. Wouldn't you?

The [3,9] - Reach Exceeds Grasp

Fight in the organic octagon long enough, and you're certain to come across boatloads of sigmatropic rearrangements. There's your classic [3,3] - Cope, Claisen, etc - the [2,3] Wittig, and [1,3] hydride shifts. Sometimes, interlopers crop up, like [4,4] and [5,5] shifts. Molecular modeling even lends support for a [7,7]!

But have you ever seen a [3,9]? Can you picture what such a system might look like? Well, Wegner, Kessler, and Neuburger (Basel) would like you to try. As they report in their latest JACS ASAP, they've posited a rather cool [3,9] to explain the products of a tandem IEDDA (inverse-electron-demand Diels-Alder) followed by a cyclopropanation:

Wegner et. al., JACS 2012

Toss out everything you learned in second-semester organic. The authors describe an "...'allowed' supra-antarafacial [3,9]." This means that the oxygen atom of the putative dihydrofuran lets go from the "top" face, while at the same time the cyclopropane forms on the bottom. They've run calculations on the system, and metal-stabilized versions have been shown to react in similar ways. Heady stuff.

Even more interesting? The catalyst is a bidentate diboron Lewis acid. That's right: each boron atom grabs hold of a single nitrogen atom in the diazine to promote the D-A (You don't see that every day!) The authors make a tiny squeak at the end of their paper regarding possible future synthesis of 'unsymmetrical' versions of their catalyst. I bet that that'll be tough, given the proposed transition-state binding model - one ring flat, one sticking straight up at the incoming dienophile.

My guess? They'll likely try to hang a helically-chiral group on one side, or else staple a PHOX or Evans auxiliary on. 

Time will tell.