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?

Greener Nylon Synth? Just Add UV and Ozone!

"Any sufficiently-developed technology is indistinguishable from magic" - Arthur C. Clarke

Looks like we'll soon have a more straightforward way to make stockings, zip-ties, and tire belts. 

Adipic acid, a six-carbon diacid representing one of the "sixes" in Nylon 6-6, apparently takes quite a bit of industrial "elbow grease" to make. The current process, starting from cyclohexane, requires cobalt, manganese, copper, and vanadate salts, high pressures of oxygen gas, and hot nitric acid. Out the other side, its responsible for 5-8% of the nitrous oxide we humans spew into the atmosphere each year.

From Science 2014, Hwang and Sagadevan

Now, researchers Hwang and Sagadevan (National Tsing Hua University, Taiwan) believe they have a better method. Reporting in this week's Science, the two disclose a method that sounds so much simpler: flush a sample of cyclohexane with ozone and UV light, and, presto! Solid adipic acid at the bottom of your reactor. No metal salts, no nitrous oxide, no high pressures or temperatures.

Wow, that looks a lot simpler.

The researchers note that zapping ozone produces both singlet oxygen, ¹O₂, and a single singlet oxygen atom O(¹D). The highly reactive single singlet (say that three times fast!) can easily insert into C-H bonds, and, since it seems to prefer insertion next to an already-oxidized carbon, the diol, diketone, and finally diacid products are formed preferentially.

Applause, please: Look at this beautiful pictorial SI!
Twice, in two days.

Just for fun, Hwang and Sagadevan crack open some larger hydrocarbons, and check the selectivity of alkyl-functionalized rings and aromatics. There are tantalizing possibilities here that I'm sure, given the ease of this reaction setup, most organic chemists will already be trying: how do complex natural products* react under these conditions? If anyone tries it this weekend, please drop me a line.

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*For that matter, I wonder if this pathway is operative in human tissues under physiological conditions? Sunlight does have some 300 nm band, and we certainly come into contact with ozone out in the wide world. Hmm.

Friday Fun: Sweet Cardamom (Peroxide)

Rice pudding. Ginger snaps. And...malaria?

That's what'll be going through my head next time I cook with cardamom, thanks to Tom Maimone and coworkers (UC-Berkeley) and their under-the-wire JACS ASAP from yesterday afternoon. The title and abstract scratch all the Baran lab alumni itches: 1) biosynthetically inspired, 2) novel mechanisms, 3) scalable, 4) just four steps! And hey, we're making stable endoperoxides, which all the cool kids are into nowadays.



Not their actual abstract graphic...

As Maimone points out, the latent symmetry of the final product offers a really neat assembly strategy. The group McMurrys together two units of (-)-myrtenal, then hits it with singlet oxygen, initially forming a 6-membered endoperoxide they fragment / rearrange with base. A gentle oxidation (DMP) sets them up for the wild step: stitching together a 7-membered endoperoxide using Mn(III)*, a radical source, a silane reducing agent, and even more oxygen. Simple phosphine reduction knocks down the last hydroperoxide into an alcohol, and the whole target (7 stereocenters!) falls out as a single stereoisomer.

Pretty sweet.

P.S. - Since the group's made over half a gram in just this first push, I'd assume an efficacy paper against live Plasmodium parasite hot on the heels of this one...

*We're apparently already calling this the "Shenvi catalyst"...wasn't this only two months ago?

Highly Active, Barely Seen

Bench chemists know it's tough enough to control the multiple variables that go into any one reaction. But what about the ones you never saw coming?

The literature abounds with cautionary tales: Trace nickel (II) in the NHK reaction. Trace phosphate in the GFAJ "arsenic life" saga. "Metal-free" couplings found to rely upon parts-per-billion levels of Pd or Fe contaminants in "pure" sodium carbonate.

In yesterday's post, a volcanic mudpot-dwelling bacterium flourished in lab culture, but only when its growth media was doped with a rare earth element (REE). The authors had quite a bit of trouble eliminating residual metals from the growth media:

"When testing REE dependency (salts > 99% pure), it was observed that standard serum bottles resulted in a highly variable growth. . . Sand is one of the major raw materials of glass and may contain considerable amounts of REE, and Ce may be used as an additive during glass manufacturing. It was concluded that REEs in glass are extractable, at least partly, by the acidic media used."

Whoa! I confess, I've stirred hundreds of acidic solutions in glassware of all shapes and sizes, and never once have I assayed the rare earth content! And the glass wasn't the only cause for concern:

"Contact of the acidic medium with needles used for sampling was minimized as the metal seems to release REE as well. For these experiments, concentrations of trace elements were (in μM): NiCl2, 1; CoCl2, 1; Na2MoO4, 1; ZnSO4, 1; FeSO4, 5; and CuSO4, 10."

For those playing at home, some of these trace metals guest star at the ppm level in this media. Due to the materials used in glass and disposable needle manufacture, I guess there will always be a baseline of (potentially active) metal contaminants in acidic solution.

Want to take bets that one or more play roles in our favorite cross-coupling reactions?

Catching Copper's Ghosts

Copper, copper, everywhere (and much more than you'd think). It's found in coins, wiring, statues, paints, and even as part of a balanced diet. Chemists, in particular, have long loved copper for its ready availability, well-defined redox states, and its wealth of reactions; just last week, Prof. Sherry Chemler (SUNY-Buffalo) recounted nearly 100 years of copper's catalytic successes* in a Science perspective.

Source: Ogle / Bertz group | Angew. Chem.

Though scientists have long studied copper-catalyzed reaction, several short-lived, unstable intermediates
have defied characterization. Now, Profs. Craig Ogle and Steven Bertz (UNC-Charlotte) may have caught one of these ghosts: an elusive C=O copper pi complex. Using rapid-injection techniques at -100 degrees C, the team "freezes out" the complex, which they study by 2D NMR (which shows relative positions of various atoms) and cryoloop X-ray crystallography (shows absolute position in a fixed crystal lattice).

When the team warms the compound much above -10 degrees C, it immediately falls apart.

Isolating otherwise reactive intermediates lets us peer inside** the "black box" of catalysis. In this structure, the lithium atom tugs at the oxygen's lone pair, allowing the copper to slip into pi-coordination in a "side-on" fashion. Though it's tough to see from this picture (left), the authors point out that five atoms (O, C, Cu, Me-a, Me-b) all sit together in one plane, which validates earlier NMR models. Finally, there's some hints of reactive fate here, as the "bottom" methyl group shortens up, preparing to jump off the copper atom and onto the central carbon, while at the same time, the copper atom cozies up to the oxygen. Remarkable stuff.

* And that was just on one class of reactions!
**The deeper we look, the more crazy, head-scratching stuff we find. Ask your local organometallic enthusiast for more info...

Twisted Olefins in "Click" Chem?

Everyone digs the copper-catalyzed "click" reaction between azides and alkynes - its fruits have ripened into applications for protein labeling, drug analogs, and green synthetic approaches.

Science Express just released an intriguing read from the Fokin group, which uses reaction calorimetry (how hot? how fast?) and mass spec isotopic enrichment studies (where'd that atom come from?) to study the copper-catalyzed click. Using calorimetry, Fokin's group determines that two copper atoms must cooperate to form the desired triazole; the uncatalyzed reaction limps along (~7%) in the same amount of time that the catalyzed reaction - which gives off a brief burst of heat - reaches completion (>96%). 

To try and tease out which copper does what, the team synthesized an isotopically-enriched ⁶³Cu catalyst, which they added to a "normal" (⁶³Cu / ⁶⁵Cu) isotope blend of a copper-bound acetylide. Time-of-flight mass spec showed isotopic enrichment of copper in the resulting isolated copper species. How the heck can that happen?!? 

Well, it can't. . . unless, of course, there's an intermediate where the two copper atoms interchange. Enter the crazy, wild world of gem-dimetalation, a concept several groups (Fürstner, Blum,  Gagné) have recently studied for a variety of d¹⁰ metals (Pd, Ag, Au). Even more crazy, the enrichment indicates that an NHC ligand "jumps" between the two copper atoms, hardly usual behavior for such a strong donor ligand. To explain these results, Fokin constructs a modified catalytic cycle, shown below:

Source: Science | Fokin group, Scripps

Check out that prism-shaped intermediate in the lower left. Anything seem strange about it?

Think, for a moment, about axial chirality. What comes to mind? BINAP, certainly, or the M and P descriptors for allene (cumulated double bonds) chemistry. Well, unless I'm missing something, this intermediate may be the first representation of olefinic axial chirality I've seen. To invoke this intermediate, the alkene in question must really be something special, since the azide has to be disposed roughly 90 degrees out-of-plane! 

Usually, alkenes like to sit in sp² -hybridized space - flat, like a sheet of paper. Rotational energy barriers exist to interchange E to Z olefins, but they usually need lots of energy (heat, light) or a charged intermediate. Here, we have an almost-room-temp, neutral, 3D alkene intermediate: a rare duck indeed.

Great Expectations for 'Metal-Free' Reactions

Reading through some recent "metal-free" coupling literature, I came across a fantastic footnote. Check out the lengths chemists Carsten Bolm and Isabelle Thomé have to go to in order to certify their latest reaction:

"(16) Great care was taken to avoid the presence of transition metal impurities. All starting materials were synthesized without using any transition metal...reagent transfers were performed with one-way plastic spatulas, and new glassware and stirbars were used for the cyclization reactions. The starting materials and reagents were analyzed to the detection limit of 4 ppb by atomic absorption spectroscopy (AAS) or inductively coupled mass spectrometry (ICP-MS).

Data [for a representative intermediate] - Cu < 4ppb, Pd <4 ppb; Kcarb - Cu < 4 ppb, Pd < 4 ppb; DMEDA [ligand] - Cu 2.4 ppm, Pd < 4 ppb." [Emphasis mine]

Sand - Probably > 4ppb "active" metals!
Source: 123RF

Wow. 


I'll be honest with you, I've never tested for metals in my starting materials below ~1 ppm (Food for thought: here's an EMA document detailing allowable catalyst residue in human medicines).  I'd wager that 99.9% of workaday bench chemists haven't, either. 


Bolm's group endures this rigor because, well, they literally wrote the book on trace metal catalysis. Quite honestly, I'd bet that they felt a bit uneasy when they measured the DMEDA copper concentration; more than a few of these "metal-free" reactions proceed with vanishingly small amounts of catalyst.

Come On, Allene! The Crabbé Reaction

Readers: This post was written in response to Rachel Pepling’s call for submissions to the IYC2011 Chemistry Carnival over at CENtral Science

Have you ever been in love?

Has a single, chance moment changed your outlook on life?

Did you ever have the burning desire to . . . add one little methylene group to the end of an alkyne?

I’m an organic chemist, and our emotions tend to track directly with the success of our bench work. In my third year of graduate school, I felt down in the dumps.  My methodology project had no traction; heck, I couldn’t even make the (relatively simple) allene substrates I needed in less than five steps! Such was life when, during my group meeting presentation, a voice chimed in from one of the postdocs sitting in the far corner of the room:

“I think there’s a reaction for this.  Haven’t you tried the Crabbé?”

Credit: scenicreflections.com

(At first, I stared agog, since the name made it sound like he was ordering seafood in a fancy French restaurant, so I thought he was joking, but he wasn’t!)

Turned out, there was a “chemical shortcut” to do just what I needed: the Crabbé takes a terminal alkyne under Mannich-like conditions (di-isopropylamine, formaldehyde, dioxane) – with a dash of copper (I) bromide for good measure – and adds a methylene (=CH₂) unit to form an allene (see scheme). Why make allenes, you ask?  The two alkenes in this three-carbon synthon are orthogonal (at a 90^o angle), which twists their pi-electron clouds away from one another. Thus, each olefin can react independently in reactions like metal coordination or electrophile addition.

The reaction mechanism made me scratch my head for a while, just as it did Crabbé’s researchers working at U. Missouri in the early 1980s. These chemists propose that, after the initial Mannich adduct forms, a copper atom wiggles into coordination between the amine and the alkyne. When you crank up the heat, the amine kicks out a hydride (H^-) from an isopropyl group, which then migrates to the copper. This copper hydride spins around, delivers its hydride payload to the alkyne, and kicks out an imine leaving group. 

Credit: Carl Sagan's Dance Party Blog

It’s a fairly chemoselective reaction, meaning you can use it late in the game in a synthesis (assuming your compound can survive heating in dioxane for a few hours with copper!). My favorite part? I enjoy watching the autumnal palette that evolves during the reaction, from birch-tree yellow to maple-leaf red. Different starting materials lend different shades. And, as most organic chemists will tell you, one-pot preps you can set up and forget about are the reactions we love.