Déjà vu, LPU

Remember when I posted about the highly-similar cyclobutane insertion chemistry coming out of the Cramer group? Well, a new contestant has just been published in ACIEE:

Source: Cramer, ACIEE 2014

I jumped down the rabbit-hole of the Supporting Information, and returned with these two "general" procedures - blink, and you'll miss the differences!

Source: Cramer et. al., ACIEE 2014, February

Source: Cramer et. al., ACIEE, 2014, July

Same catalyst precursor. Same ligand (well, different enantiomer). Same solvent. Same time. Similar reaction temps and purification conditions. Now, I'm not saying that the Cramer group shouldn't have published this paper, but in the same journal? With essentially the same substrates?

Does anyone else believe that these could have been published together, in a single high-impact paper?

A Chempubs Hat Trick

Slow down, Guangbin!
(said I, channeling my inner Dr. Freddy...)

Guangbin Dong of the University of Texas-Austin has just published three papers in three different journals with Impact Factors over three. What's more - he did it all in the same week.

Just think of them as buckyballs

The papers in question?

"Regioselective ketone alpha-alkylation with simple olefins by dual activation"
Science, published 4 July 2014; 2013 IF: 31.0

"Cooperative alkylation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4+2] coupling"
Nature Chemistry, published 6 July 2014; 2013 IF: 21.8

"Alkylation of rhodium porphyrins using ammonium and quinolium salts"
Organometallics, published 7 July 2014; 2013 IF: 4.1

I hereby institute the Chempubs Hat Trick - Three papers, Three Journals, IF > 3.0, one week.

Congratulations to Prof. Dong for winning the inaugural award! But, I'm sure I've missed others who've been so deserving. Readers, have you noticed anyone else - present OR past! - who made this many simultaneous "shots on goal"?

Leave awardees' names in the comments!

Rhodium Gets It Done

Interesting, informative intermediates from Rh(I) silylation

In this week's Science, Hartwig and Cheng disclose some pretty swanky C-H activation chemistry. By combining Rh(I) dimer, a really bulky diphosphine ligand, a cheap, bulky hydrosilane, and a hydrogen "acceptor," the pair turn relatively distant aromatic bonds into highly functional silicon handles. In certain cases, tricks like capping a carbazole with a bulky TIPS group direct the silylation para - all the way to the other side of the aromatic ring!

The authors quickly point out that this silylation runs at "low" temps (80 deg C), uses fairly cheap commercially-available reagents, and occurs with almost reversed selectivity to the corresponding direct borylation conditions. But my favorite part comes from a deep dive into the Supporting Information. Far from the discussion of academic over-publishing we've had for the past few days, Hartwig and Cheng really sculpt a great paper here: Stability studies. Reactivity differences (Si vs. B). Cross-couplings. Preliminary mechanistic details.

As always, there's tons more to do. Getting out of the glovebox with a more stable Rh precursor, or translating the reactivity to an earlier metal (a tall order!). Deeper mechanistic studies would certainly show the way. Even more tantalizing? Using single-enantiomer versions of the bulky ligands to incorporate some chiral-at-silicon synthons. I can't wait to see the rest of this story.

Cyclobutanone Déjà vu

Didn't I just see that reaction? [rubs eyes]

From the laboratory of Prof. Nicolai Cramer (EPF Lausanne) comes some really neat examples of cyclobutanone C-C activation. Just mix with ~2 mol% of cationic Rh(I), and presto! Out comes a [3.1.2] bicyclo product reminiscent of several neuroactive natural products.

Oftentimes, a catalytic reaction will go gangbusters, but will stubbornly refuse all attempts at asymmetric induction. Apparently not so here - Cramer reports the asymmetric version in ACIEE about two weeks after the initial Organometallics report!

Angew. Chem. Int. Ed. 2014, ASAP

Organometallics 2014, ASAP

Honestly, I might never have noticed, except the TOC graphics for both are nearly identical: a comic pair of orange scissors "snipping" apart the cyclobutanone ring.

So, readers, what's your take? Can't wait to see this reaction applied to a challenging target? Or, a strange choice of synthetic "least publishable units" (LPUs)?

Cyclophanes Fall Apart for Rhodium

When chemists design syntheses, they usually think in terms of building up, not tearing down. We alkylate, we esterify, we cyclize, adding always more molecular weight, joining synthons together. Occasionally, bonds must be broken. Considering most protecting groups, severing C-N, C-O, and C-X bonds keeps chemists of all stripes pretty busy. What about C-C scission? Not so much.

Sure, there's your decarboxylations, your ozonolyses, your samarium iodide reductions. Long ago, natural enzymes figured out how to push electron density around to slice up substrates: think about gramine fragmentation, Poitier oxidation, or the (now-defunct) Pictet-Spengler spiro mechanism. But you don't often see fully saturated sp3 carbon-carbon bonds falling apart; after all, we'd be dealing biology a mortal blow with such precarious engineering. 

Wouldn't it be cool, though, if we could just add a specific catalyst, a dash of water, and selectively crack a hydrocarbon?

I don't recall seeing this graphic in the SI...but I can hope.

Turns out you can...if the system's just right. Chinese University of Hong Kong chemistry professor Kin Shing Chan, with coworkers Ching Tat To and Kwong Shing Choi, reported just such a reaction in JACS ASAP yesterday. The scientists mix some Rh(III) porphyrin, some base, and a 100-fold excess of water, heating everything in the dark for 2-3 days. Out pops the "bibenzyl" compound (83%), which initially causes a bit of head-scratching: why don't they see C-H activation products? And where's the hydrogen coming from? 

(**SPOILERS BELOW**)

There's quite a bit of C-H activation, actually - it just doesn't go anywhere under the conditions. Swapping in deuterium oxide leads, unsurprisingly, to "D" incorporation on all the methylene groups and at the two newly-formed methyl groups. So the water indeed provides hydrogen, but not the way we'd usually think about it. No water splitting, no hydride formation, no "M-H." Instead, it's simply a radical quench: each metal-carbon bond, formed from C-C bond homolysis, grabs an "H-dot" from a neighboring water, and the remaining OH radicals shuffle away to produce hydrogen peroxide. And the rate looks pretty screwy, with second-order kinetics in metal, which the authors think means that two separate Rh(II) radical species - from Rh(III) reduction in situ - cooperate to cleave each side of the C-C bond simultaneously.

Source: Chan et. al., JACS ASAP 2012

Well, enough hype: only a few substrates (cyclooctane, cyclophane, strained substrates) have been shown to reliably react with these rhodium porphyrins, and the conditions (200 degrees Celsius, 3-4 days, in the dark?!?) aren't winning any immediate med chem converts. Hey, these things take a little time to become practical, so maybe one day you'll reach for your C-C "knife" of choice, and dial-in your molecular dissection. 

Keith Fagnou - Eternal Authorship

If you died tomorrow, would someone continue your work?
...even up to publication?

Prof. Keith Fagnou
Credit: U. of Ottawa

This thought gave me pause yesterday, as I browsed through journal contents and realized that Prof. Keith Fagnou, formerly of the University of Ottawa, was still publishing well into 2012.


For those unaware: Fagnou passed away unexpectedly in November 2009 after a short bout with H1N1 flu, only 38 years old. His research group, dubbed "The Fagnou Factory," kept coming to work, and kept publishing.


Between 2010-2012, despite Fagnou's death, he authored nearly 20 publications (and counting!). And these aren't retrospectives or reviews, but deep mechanistic and methodological studies, which landed in high-end places like Org. Syn., JACS, and Angewandte Chemie. 


So what's the secret to Fagnou's seemingly eternal success?


First, it pays to work in a "hot" scientific area. In the mid 2000's, C-H activation chemistry was booming, and KF was among the vanguard. From direct Pd-catalyzed arylations of pyridine N-oxides and alkylations of perfluoroaromatics, to Rh(III) cyclizations and explorations into -OPiv metal coordination, Fagnou's research had just begun to take off.


Second, his beloved "Factory" really seemed to love him back. Over his seven-year career at Ottawa, Fagnou mentored 4 postdocs, 24 graduate students, and 22 undergrads, many of whom would later stay on with him to pursue their doctoral degrees. After Keith's death, his group members organized a symposium in his honor, and even assembled a "Chuck Norris legends"-type tribute to him, in a mock JACS template.


I briefly met with Keith after a seminar, and he told us stories of his time as a schoolteacher and hilarious blooper-reel recaps of his time in the Canadian Navy. Everyone at the table felt his enthusiasm for chemistry (and life in general) really got him out of bed in the morning, and inspired others to do the same.


Here's to continued Keith's continued success; if I see an abstract in 2020, I'll hardly be surprised.


Update (2/15/12, 7:30) - Almost forgot this mini-review, published over at Chemistry Blog about a year ago. Derek's post on Keith generated an overwhelmingly supportive row of comments.