Archive for the 'Disciplines' Category

The Chemmy Award for Organic Achievement of the Year goes to:

Melanie Sanford (Michigan) for establishing that Pd(IV) intermediates are important in at least one class of catalytic C–H bond activation reactions

I had decided on the recipient of this Chemmy a long time ago but procrastinated on writing the citation. This weekend, commenter “tuna fish” mentioned that Dr. Sanford might be moving to Yale or Caltech, and while I have no idea if this is true, the comment reminded me of my fondness for her work and that now is as good a time as any to write about it.

First off, trying to “contain” the Chemmy achievement awards in the various chemical disciplines to one year (here: 2006) is going to be difficult, because cool discoveries often take time to develop and get noticed. In this case, Sanford’s C–H activation work can be traced back to 2004. It was only last year, however, that the picture became clear (at least, clear to me).

When I learned organometallic chemistry—way back in 2002—we were essentially taught never to invoke Pd(IV) intermediates in our mechanisms.  Pd(IV) was simply too energetically-inaccessible to be relevant in most cases. Along these lines, I witnessed the merciless ridicule of more than one student by the teaching staff for using Pd(IV). Instead, good boys and girls used the Pd(0)/Pd(II) couple in their mechanisms.

In 2004, Sanford came along and published a simple case of catalytic, chelate-directed C–H bond oxidation:

Instead of outlining a mechanism that shuttled back and forth between Pd(0) and Pd(II), Sanford proposed a mechanism involving Pd(IV):

Naughty!  Or so I thought.  A subsequent study essentially extinguished all doubt that the Pd(IV) mechanism was correct. In this 2005 JACS comm., the Sanford crew hypothesized they could change the system to stabilize the Pd(IV) intermediate, found they could actually isolate it, got a crystal structure showing that it was indeed a Pd(IV) species, and then showed that heating it gave the same types of products that they saw in reactions where the intermediate could not be isolated. Crystal structures are the closest thing we can get to having incontrovertible photographic evidence of what molecules are actually doing, so you can’t really argue this one.  Score one for Pd(IV).

I know a lot of the hardcore synthesis crowd isn’t enamored with this sort of C–H activation chemistry because it is chelate-directed, which limits the scope of the reaction. That’s true, but what makes this batch of work so interesting is not the synthetic utility as much as the scientific value. We gained a new appreciation for the mechanism at play in these reactions and had to reassess a long-held notion of what isn’t reasonable.

So, congratulations to Dr. Sanford and coworkers. Enjoy your Chemmy and keep the good work coming.  And if any of you donkeys out there thinks there was someone else more deserving of this award, feel free to register chemmeow.com and start your own damn blog. 

Princeton University took home the Chemmy for Outstanding Department of 2006, and it looks like they’re going to make a run at defending the title in 2007. Valued sources recently told the ChemBark News Network that the Ivy League school has made generous offers to a number of outstanding young organic chemists who are already tenured in top-five departments. Fresh on the heels of adding Sorensen and MacMillan, Princeton is looking to firmly establish itself as a hotbed of organic chemistry for years to come.

Raiding other schools’ faculties has long been a strategy for building departmental strength. Where the Yankees and Red Sox are the baseball teams most willing to reach deep into their pockets for big-name talent, Harvard is the school most famous for doing so in chemistry. Most of the department’s big guns were hired as tenured professors from other schools: Corey and Jacobsen from Illinois, Whitesides from MIT, Evans and Myers from Caltech, Lieber from Columbia, Schreiber from Yale, and Kahne from Princeton. On the flip side, assistant professors have had a miserable record of gaining tenure in the department (until recently).

While pursuing the free agent market at the expense of decimating your farm system is generally a poor idea in baseball, it is a viable strategy in the world of chemistry. Granting someone tenure equates to giving them a contract for life, something unheard of in the sports world. Unfortunately for universities, it often takes more than seven years to get a handle on the quality of an assistant professor. Hiring a proven forty-year-old is a much safer bet. And unlike in sports, there are no salary caps or luxury taxes in academia, so there are no limits to the amount of money you can spend.

Of course, the strategy of buying talent is contingent on being rich—the more money a school has, the better it can play the game. Schools with less funding not only have a harder time reeling in heavy hitters, they have a harder time retaining members of their faculty who’ve attracted the interest of other schools. Money doesn’t just factor into salary, but also into expanding lab space and improving instrumentation. Ambitious professors want to improve the efficiency of their research and have the flexibility to expand their labs and their programs.

There are some factors that money can’t help.  Geographic location is often important, as it influences features such as the local culture and the employment market for professors’ significant others. And as with anything related to academia, politics can play a big role. If the deans at a school get on an interdisciplinary kick, there many be money available for a nanobiophysical chemist but not for a synthetic one. An aspect that is particularly intriguing about the Princeton move is that it is geared towards pure chemistry instead of the interdisciplinary flavor of the month. That’s rare nowadays.

Of course, this story is still developing and nothing has been set in stone, but things are looking mighty exciting if you’re an organic chemist at Princeton.

The carboxylic acid (500 mg, 1.59 mmol) was dissolved in 15 mL of dry DMF with stirring. O-(7-Azabenzotriazole-1-yl)-N,N,N,N’-tetramethyluronium hexafluorophosphate (HATU, 665 mg, 1.75 mmol) was added as a solid and the resulting clear solution was stirred for 10 min at room temperature. N-Boc-ethylenediamine (0.5 mL, 3.2 mmol) was injected and the resulting yellow solution was stirred for 20 min before 0.8 mL (4.6 mmol) of diisopropylethylamine (DIEA) was added by syringe. The mixture was stirred for 16 h at room temperature, at which point 150 mL of a saturated solution of NaCl was added. The mixture was cooled to 4 °C and the white precipitate was isolated by vacuum filtration over sintered glass and washed with 100 mL of deionized water. Yield 695 mg (1.5 mmol, 96%). White powder. 1H NMR (400 MHz, DMSO-d6): 8.44 (t, J = 6.0, 1H), 7.83 (t, J = 4.9, 1H), 7.74 (d, J = 8.0, 2H), 7.38 (d, J = 8.0, 2H), 7.30 (s, 2H), 6.79 (t, J = 5.3, 1H), 4.28 (d, J = 5.9, 2H), 3.02 (m, 2H), 2.93 (m, 2H), 2.12 (t, J = 6.6, 2H), 2.03 (t, J = 6.6, 2H), 1.46 (m, 4H), 1.35 (s, 9H). 13C NMR(101 MHz, DMSO-d6): 172.84, 172.79, 156.29, 144.55, 143.22, 128.12, 126.35, 78.31, 42.32, 40.78, 39.33, 35.84, 35.78, 28.92, 25.62 (the signals from the two central adipoyl methylene carbons appear to be accidentally equivalent). High Resolution ESI-MS: 457.2118. Calculated for C20H33N4O6S+ [M+H+]: 457.2115.

Notes: Ordinarily, I hesitate to use HATU because it is so freaking expensive. That said, the stuff is magical. I tried this reaction a number of times with EDC HCl and got miserable yields. The first shot with HATU gave 96%—my best yield ever for amide formation.

The above methyl ester (2.5 g, 7.6 mmol) was suspended in 140 mL of THF in a 500-mL round-bottomed flask. In a separate flask, 2.5 g of lithium hydroxide was dissolved in 140 mL of deionized water. Both mixtures were chilled to 4 °C and combined to form a turbid white mixture. After 1 h of stirring, the mixture had become homogeneous. After 24 h, 50 mL of 3 M HCl was added, and the mixture was allowed to warm to room temperature. Following the addition of a 100-mL portion of saturated aqueous NaCl solution, the mixture was extracted four times with 100-mL portions of EtOAc, and the combined organic layers were evaporated. Yield 2.28 g (7.25 mmol, 95%). White powder. 1H NMR (400 MHz, DMSO-d6): 11.99 (s, 1H), 8.39 (t, J = 5.9 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.28 (s, 2H), 4.29 (d, J = 6.0 Hz, 2H), 2.20 (t, J = 6.9 Hz, 2H), 2.14 (t, J = 7.0 Hz, 2H), 1.49 (m, 4H). 13C NMR (126 MHz, DMSO-d6): 175.09, 172.76, 144.55, 143.22, 128.11, 126.36, 42.32, 35.68, 34.07, 25.47, 24.84. High Resolution ESI-MS: 315.1005. Calculated for C13H19N2O5S+ [M+H+]: 315.1009.

In a three-necked, 1000-mL round-bottomed flask were placed 4-nitrobenzaldehyde (1.51 g, 10 mmol), 3,5-di-tert-butylbenzaldehyde (6.66 g, 31 mmol), and tetraphenylphosphonium chloride (75 mg, 0.2 mmol). The solids were dissolved in 400 mL of still-dried methylene chloride and the flask was sealed with rubber septa. Argon was bubbled through the solution for five minutes and pyrrole (3.0 mL, 43 mmol) was injected by syringe. The flask was covered with foil and boron trifluoride-diethyl etherate (0.6 mL, 5 mmol) was injected to begin the reaction. After 1 hour, DDQ (8 g, 35 mmol) was added as a solid to the dark brown-purple solution and the mixture was stirred overnight. The porphyrin products were isolated by flash chromatography on silica gel with 1:1 hexanes:methylene chloride as the eluant. The fast-running porphyrins were separated from each other on a second silica gel column with 80:50:1 hexanes:methylene chloride:triethylamine as the eluant. Unsubstituted tetra-3,5-di-tert-butylphenylporphyrin (R_f=0.57, 0.431 g, 0.4 mmol, 4 %) and the desired monosubstituted porphyrin product (R_f=0.13, 1.51 g, 1.5 mmol, 15 %) were produced in reasonable yields.

Note: I can’t find the exact reference at the moment, but it was almost certainly based on a procedure by J.S. Lindsey. I think it was a Tet. Lett. paper on how the yields for this reaction improve when salts are added (hence the addition of tetraphenylphosphonium chloride).

As part of the ChemBark 2.0 Initiative (set to launch in mid-2018), I want to transfer most of the chemistry-related posts from the old blog on to this one.  Since A Synthetic Environment has been firing off a bunch of top 5 lists, this seems like a good time for a blast from the past: my list of the top 10 organic chemists ever…

Here’s my list of the top 10 organic chemists of all-time, without regard to nationality or sub-specialty. I’m sure that the list is biased towards academic chemists, because their triumphs tend to be more heralded, but I’m sure most of them took plenty of money from industry, too.

10. George Olah

Olah was a giant in the field of physical-organic chemistry and the study of reactive intermediates. With his development of superacids, he was able to study carbocations and essentially end the debate about the existence of nonclassical ions. He has also been celebrated for his work in organofluorine chemistry and organic synthesis.

9. Carl Djerassi

The “Father of the Pill,” Djerassi’s synthesis of the progestagen norethindrone had huge medical and societal consequences–people of the ’60s and ’70s should thank him for all of the uninhibited sex they enjoyed. He is also one of the poster boys (along with Marker and Julian) for using plants as sources of steroidal starting materials needed for industrial syntheses.  Because Djerassi’s pill work can be viewed as a nice, tight package with a profound practical application, I think he’s still got a good shot at picking up a Nobel Prize someday.

8. Paul D. Bartlett

The Bartlett Lab was a physical organic powerhouse, and Frank Westheimer said Bartlett “dominated that field for perhaps four decades.” Bartlett hammered home the concept of using kinetic and stereochemical studies to determine mechanisms, and he elucidated the two-step mechanism of electrophilic additions to olefins and the free radical mechanism of certain polymerizations. He also made important contributions to the study of carbocation stabilization (he synthesized 1-bromonorbornane), hydride transfer, and kinetic vs. thermodynamic control of reactions. Perhaps most importantly, Bartlett is credited with changing the way organic chemistry is taught by introducing the mechanistic perspective that we use today.

7. Sir Robert Robinson

The man made the field of natural product synthesis popular. While he might be condemned for this today, for the latter half of the 20th century, the field drove the discovery and development of new reactions in organic chemistry. His one-step synthesis of tropinone is legendary, and he made fundamental contributions to the structural elucidation and synthesis of steroids, alkaloids, and dyes. He is also credited with inventing the arrow formalism (electron pushing) approach to drawing reaction mechanisms.

6. Jack Roberts

Roberts made numberous contributions to the field of physical-organic chemistry, including his studies of cyclopropylcarbinyl systems and molecular rearrangements. Roberts played a major role in popularizing the use of MO theory among organic chemists and he coined the terms “nonclassical carbocation” and “benzyne.” More importantly, the man essentially brought NMR to organic chemistry. In addition to showing chemists how to use the method to elucidate structure, he pioneered the use of isotopic labels to monitor reaction mechanisms. Despite the fact that NMR is still the single most useful method for the characterization of organic compounds, he hasn’t yet been rewarded with a Nobel Prize. I ask you, where is the justice?

5. H.C. Brown

Sure he won the Nobel Prize for his work with hydroborations, but his contributions to physical-organic chemistry were just as important as those to synthesis. His epic battles with Saul Winstein over the nature of carbocations (classical vs. nonclassical) forced chemists at the time to think critically about how to disprove a mechanism and the existence of a particular reactive intermediate. Of course, Brown’s position on nonclassical ions proved to be wrong, but he made the field better nevertheless.

4. Adolf Johann Friedrich Wilhelm Ritter von Baeyer

Trained by Bunsen and Kekule, Baeyer would go on to win the Nobel Prize in 1905 for his work on aromatic compounds and dyes, which were important at the time for the chemical industry. He is especially famous for his work with indigo. He also synthesized phenolphthalein, fluorescein, and barbituric acid. He studied lactams, terpenes, purines, and polyacetylenes, and conducted seminal work on ring (Baeyer) strain. He also introduced the concept of tautomerization. Baeyer did it all, including training three future Nobel laureates (Fischer, Buchner, and Willstatter) and numerous other famous chemists.

3. Emil Fischer

The German chemist is responsible for developing a number of fundamental synthetic methods, including the Fischer indole synthesis, the Fischer oxazole synthesis, and Fischer esterification. Fischer laid the basis for the entire field of carbohydrate chemistry. His proof of the structure of glucose was a tour de force and don’t forget about his Fischer projections (and his lucky guess). He essentially gave his life to chemistry, as the compounds he worked with literally drove him insane.

2. E.J. Corey

The man is a machine, churning out countless total syntheses, new reaction methods, and well-trained chemists with frightening efficiency. In 2002, he was dubbed “the most cited author in chemistry” by the ACS. His progeny populate both the upper levels of academia and the pharmaceutical industry, and at 77, he’s still going strong.

1. R. B. Woodward

The man is a legend–he revolutionized the fields of structural determination, organic synthesis, and physical-organic chemistry. The Nobel Committee essentially bestowed a lifetime achievement award on him with the ‘65 Prize for “outstanding achievements in the art of organic synthesis,” and he would have won a second in ‘81 for orbital symmetry had he not died in 1979. Some, including Woodward himself, thought that he deserved to share in the ‘73 Prize for the “chemistry of organometallic compounds.” On top of all this, he could drink any other chemist under the table. Salud.

Others meriting consideration (in no particular order): Gilbert Stork, Sir Christopher Ingold, George Hammond, Linus Pauling, Donald Cram, Jean-Marie Lehn, Justus von Liebig, Sir Derek Barton, William von Eggers (the “Bull”) Doering, August Wilhelm von Hofmann

Commenter suggestions: Percy Julian, Grignard, Pasteur, Winstein, Sharpless, Dervan

Move over, Bingel cyclopropanation… I’ve got a new favorite reaction.

While thumbing through a review article on the chemistry of some “extraordinary Maillard flavor compounds,” I came upon this little diddy:

Magnificent! While I don’t want to make a habit of encroaching on Milo’s territory of posting organic reaction mechanisms, you’ll find one after the jump. See if you can figure it out before peeking…

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