Chemistry from the Deep: Geomimicry

Hydrothermal vent
Source: Geotimes.org

Lots of fascinating chemistry occurs in places humans can't routinely visit. Deep-sea hydrothermal vents, super-hot fissures formed from volcanic activity below the ocean floor, produce plumes of minerals and organic compounds. Through "geomimicry," researchers hope to harness similar conditions for use in labs here on dry land.

A team from Arizona State University - a geochemist, a biogeochemist, and a physical chemist  - report in JOC ASAP some interesting oxidation conditions using only copper salts and hot, pressurized water. With cupric chloride as an additive, benzyl alcohol and phenylacetic acid are oxidized to the corresponding benzaldehyde and benzoic acid in water at 250 Celsius and 40 bar (580 psi). The researchers speculate that the copper ions form different chloride species at high T and P, capable of promoting a series of single-electron transfers out of the organic substrates.


The article closes on an intriguing, somewhat humbling note:

"The vast majority of the organic material on Earth does not participate in the familiar, conventional surface carbon cycle because it is located deep within the crust and therefore undergoes chemical reactions under hydrothermal conditions. In contrast to the majority of reactions close to ambient [temperature and pressure], which tend to be controlled by enthalpic and kinetic factors, reactions...under geochemically relevant conditions tend to be controlled by entropic and thermodynamic forces...this suggests that much new useful organic chemistry may be inspired...by geology."

In other words, the reactions and catalysis we tend to study in labs "above ground" are just the tip of the organic chemistry iceberg....err, volcano?

Oxidase Toolkit: C-H Azidation

Do you ever stare at your late-stage molecules, thinking "They're almost perfect, but I really wish I could add an amine right over there." Thanks to a new reaction, you might soon be able to.

Reporting in Nature, John Hartwig and coworkers have cracked the case: a mixture of iron (II), a tridentate nitrogen ligand, and a modified Togni reagent Zhdankin reagent reliably functionalize tertiary C-H bonds with an azide(N₃ group). The selectivity, yield, and mild conditions match pretty well with White's C-H oxidation, which utilized a similar catalytic manifold.

Hartwig's initial targets for this new reaction include two modified steroids and a gibberellic acid derivative. Sadly, precious few heteroatoms exist in these molecules to gum up the ironworks, but I'm certain they'll address that in the full paper. I'd especially like to point readers to Figure 3, in which the group shows subsequent transformations: heterocycle formation, amine reduction, chemical ligation, and capping with fluorescent tags.

These two reactions together, along with a variety of C-H halogenations and sulfidations, seem to support the growing "oxidase phase" approach to total synthesis. One could imagine that, in a few years, a naked carbon scaffold could be suitably decorated with O, N, S, or X at positions of the scientists' choosing. Wow.

New Tricks for Old Reagents: Oxygen Everywhere!

Passed a time, not too long ago, when if you wanted to oxygenate a selected C-C or C-H bond, you had to jump through several hoops: Over-oxidize (read: DESTROY!) then reduce again. Convert it to another functional group first, then use an expensive catalyst. Use toxic heavy metals (Cr, Hg, Pb, anyone?) in their highest oxidation states...and, oh yeah, heat the heck out of it.

The past decade has seen kinder, gentler oxidations emerge in rapid succession. Cobalt. P-450s. Iron. Now, two recent papers bring new wrinkles to the oxygenation of organic molecules in unexpected ways.

The first, from the Concellon / del Amo group in Org. Lett., relates a neat trick performed by Oxone, usually a reagent reserved to make other oxidants.

The researchers deal with their serendipitous discovery with humility and class:

"This work was not originally intended..[but]...was worth studying. [We] remark that Oxone is a crystalline solid oxidant, easy to handle, non-toxic...and, above all, stable and cheap."

All great reasons to run these reactions, which are formally derivatives of the classic Baeyer-Villiger reaction. They blast through a brief substrate table (26 entries, 33-95% yields), and seem pretty excited about investigating the mechanism.

The second reaction, hot off the Nature presses, involves another legacy reagent: phthaloyl peroxide. I suspect the Siegel group was looking for sp3 C-H activation conditions, but instead discovered a serendipitous site-selective arene activation, reliably producing phenols.

The reaction works across a broad functional group palette - azides, silyl groups, boronate esters, primary halogens - that other oxidants would tear apart. They ultimately do about 50 substrates, including 3 natural product-like scaffolds, with yields ranging from 45-95%.

Deciphering the mechanism requires Ken Houk's computational super-powers. The researchers discover a "reverse-rebound" mechanism operates, meaning an oxygen radical from phthaloyl peroxide adds into the ring, the electron bounces around in the pi cloud, and then ejects the ipso hydrogen in a two-step process. Interestingly, other radical oxygen oxidants (di-benzoyl peroxide) led to primarily sp3 oxidation, showing that the structure of the radical precursor plays a big role here.

Turning Wishes into Horses

A fantastic summary crossed my desk today, courtesy of the RSC's Chemistry World. It profiled a new reaction from the Milstein group, just reported in Nat. Chem., that just looked so tempting: oxidation of a primary alcohol, using water as the "O" source, with hydrogen gas as the lone byproduct.*

And thus began what my brain usually does, "Science Wish Syndrome." Not familiar? Here's the stages:

1. Unbridled Enthusiasm - "Holy cow, that reaction looks fantastic! I'm sure it will produce 20 new analogues / help me wrap up my thesis early / solve world hunger. I can't wait to try it!"

2. Skepticism / Doubt - "Well, Blogger X tried it, and couldn't reproduce the yields. And the Supporting Info says it only works with 100 mesh hyper-refined silver powder sourced from Argentina. Still, it's in Nature / Science / JACS / Angew Chem, so it must work, right?"

3. Despair - "I ordered all the reagents, and used my last 0.3 mg of shootmenowicene in the test reaction. I barely got 10%, and it's a mixture of stereoisomers! Who the heck let this into this journal?"

Readers, does this ever happen to you? Modern chemistry publication, with ASAP format, DOI codes, PDB uploads, and overall rush to publish before the guy on the other side of the pond, seems forced somehow, and doesn't always live up to the glowing reviews crowed about in press releases.

Over at Not the Lab, Vinylogous has suggested that we compile a sort of post-hoc online review journal, playfully named "Blog Syn" (after 800-lb-gorilla-in-the-room-for-synthetic-methods Org. Syn.).

Well, how might something like this work? I'd assume that the community would have some sort of mechanism to suggest papers, say, for when too-good-to-be-true chemistry like the NaH 'oxidation' comes 'round. A central aggregation point, perhaps cultivated by an "Editor / Blogger" would then issue requests for duplication. To ensure results were processed in a timely fashion, a deadline would be suggested (2 weeks?) and the "Duplicators" would have to authenticate that they tried to cleave to the original conditions as best they could. A digital "Stamp of Approval" might then follow the reaction through the online world, indicating, much like Org. Syn., that the reaction works in others' hands.

Readers, would anyone like to be part of such an effort? Methinks the #RealTimeChem crowd could get excited about this. Yes, I know everyone's busy, and this isn't the first thing you think of when there are proposals to write, classes to teach, or conferences to attend. But the literature will only be as good (or as bad) as the folks who contribute, and we desperately need more quality control.

*Update - It occurred to me (too late!) that I sound like I'm condemning the Milstein reaction, which I have not tried, and have no reason to suspect won't work as of this writing. I just wanted to use it as a backdrop for seemingly "perfect" reactions that end up not living up to expectations. The reaction, as reported, needs some scope exploration, so only time will tell if it's as widely applicable as I'd hoped.

The Ad's the Thing - Science Draws 'Em In

Regular readers of Chemical & Engineering News might have noticed a rather rare, eye-catching advertisement in the October 17, 2011 issue. Takasago, a Japanese fine chemical supplier, took out two side-by-side full-page ads (p.40-41) to illustrate the catalytic ability of their new RUCY hydrogenation complexes. The layout suggests two pages of a scientific lab notebook, complete with hand-drawn structures, a font resembling personal handwriting, a table of reagents, even a digitized signature! (I hesitate to believe this is this scientist’s real signature; legal repercussions aside, many Japanese and Chinese scientists sign documents with a stylized kanji or ink stamp). 

A synthetic chemist captures the thrust of the ad immediately: high-turnover catalysts with high selectivity translate directly into time and material savings. But you don’t have to look far these days for “real-live” (staged) science at its best, selling everything from soaps to microprocessors.

Billy Mays: Oxidant Superstar
Source: billymaysfacts.com

I’m reminded of the old dishwashing detergent standard, where a model with long rubber gloves dips a soiled plate into each of two basins, one containing the competitor’s soap, and one with New! and Improved! versions of the blue solution on the right. The grime falls reliably off the desired plate, but the scientific take-home message? Surfactants, formulation, perhaps even enzymatic degradation. It may be exaggerated to make a buck, but the pitch subtly makes you aware of the scientific development underlying the product. The same message pushes through with rust cleaners (solubility, transition metal ligation), or home fragrances (aroma chemistry, vapor pressure, sublimation). Billy Mays (RIP) and his OxiClean never made peroxide bleaching seem so efficient . . . or so sexy.

The real Ajay Bhatt....or Arthur Fonzarelli?
Source: The Oregonian

Don’t think that all these ads just shill for chemistry. Intel’s “Science Rock Star” campaign a few years back featured a strutting, smiling Ajay Bhatt (or his doppelganger), the co-developer of USB technology, proverbially fending off female fans and doting admirers while signing laptops and drinking from his Intel mug. Tongue-in-cheek, maybe, but this ad shines a light on the glaring contrast between the public worship of performers, and the relative ignorance of scientific figures. 


Update (12/24/11) - Added RUCY picture from C&EN