As Pure As the Driven Snow (A Random Musing on the Color of a Chemical Compound)

Yesterday I ran a reaction that behaved beautifully. It's a reaction where I've optimized the conditions to make the process nicely efficient, and now that that groundwork has been laid, all that I have to do is plug various electrophiles and nucleophiles in and it tends to work without a hitch.

I conduct the reaction under microwave irradiation, and the process is similar to how you cook or heat food at home. The microwaves excite molecules that are polar in nature (have a significant dielectric constant), causing them to gain kinetic energy and excite neighboring molecules. This manifests itself as heating your food, and in my case, heating my reaction mixture. Just as it takes a fraction of the time to cook/heat food by microwave compared to, say convectional heating, the same is true for chemical reactions in many cases.

That little bit aside, I could tell that my reaction had worked well by a quick LC-MS of the crude reaction mixture. It was clean enough that all that was necessary was to add the proper solvent (in this case I found acetone to work), which preferentially dissolved the impurities and not the product, and then filter the solid.

What I got was a satisfyingly white powder. Organic compounds typically tend to be some shade of white, so this isn't an uncommon occurrence. And sure, color isn't the best indicator of compound purity. But on some levels it might be the most satisfying (especially when you realize you don't have to run column chromatography).

A little chemistry tangent: inorganic molecules often take on more vibrant colors due to the ease with which electrons within those molecules can be excited or promoted to a higher energy level by light. Light (or a photon) is absorbed by the molecule to excite the electron, and the energy of the photon must match the energy the electron needs to reach that excited state. As you might know, the color of light is determined by its wavelength and is correlated with its energy. Thus, a molecule that absorbs red photons (λ=700 nm, lower energy light) will appear green, and a molecule that absorbs violet photons (λ=400 nm, higher energy light) will appear yellow. It's no surprise that if you look at a color wheel, you'll notice a trend. Organic molecules tend to be white because they don't absorb light in the visible region. The lowest unoccupied molecular orbitals (LUMOs) for organic molecules tend to be of higher energy and require ultraviolet light for promotion of electrons--thus their white color (all colors of the rainbow reflected).

Now, of course, afterwards I use the requisite analytical techniques to truly verify purity; namely, liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance (1H-NMR). But when one sees the off-white heterogeneous crude reaction mixture become a nice, white powder in the filter funnel, one honestly has a good idea what they're going to see when the full and proper analytical workup is given.

Grant writing

Greetings fellow science enthusiasts and Organic Matter followers. Just wanted to write a quick note to apologize for not posting a new entry this week. I've researched and written part of it, but had to put it on hold to finish up some grant writing that's at the top of my priority list for the week. It's an R01 grant and I've got responsibility for the chemistry section. I have some really nice ideas for chemistry to use, so a lot of my writing opportunities are being taken up by that right now. I promise to finish up and post the next entry very soon! Enjoy the Memorial day weekend everyone!

:-)

(±)-Thujopsene

For my inaugural blog post, I thought I'd take a look at an oldie, but a goodie–a (semi?) total synthesis from the groovy 1960s, that of racemic thujopsene. This one comes to you courtesy of the now-deceased Prof. William G. Dauben (a fellow original Ohioan like myself) and crew from the University of California at Berkeley. I like to look back at classic synthesis papers not because I'm old (I'm 32, I'm not that old yet!), but because they often contain instructional chemistry that's no longer utilized but still very useful. Thujopsene is a sesquiterpene that really has little bioactivity to speak of. Being one of the essential oils of some conifer trees, it does have a nice scent, though.

I put the semi part in there because it's not clear what the origin of their octalin starting material 1 is. Either way, their first reported step provides a nice contrast between reaction kinetics and thermodynamics. Enolate formation* from 1 with tert-butoxide and addition of iodomethane to 2 provides the less thermodynamically stable alkene in dimethylated 3 (the alkene conjugated with the ketone takes that title). Dimethylation at the a-position leads to the kinetic product. A little redox manipulation followed; Wolff-Kishner reduction (a reaction analagous to the Shapiro reaction) of ketone 3 followed by allylic oxidation to the ketone 5 with Cr(VI). The mechanism of allylic oxidation with chromium is said to proceed via allylic hydride abstraction, followed by trapping of the allylic cation by the reduced chromium reagent.

The powerful reducing agent lithium aluminum hydride was utilized to accomplish a diastereoselective 1,2-reduction of the enone 5 from the convex face to give allylic alcohol 6 in a 95:5 d.r. The authors also attempted Meerwein-Ponndorf reduction of the enone using Al(Oi-Pr)₃. However, nearly a 1:1 ratio of stereoisomers was obtained in this case (58:42). Honestly, given the choice of reducing agent, it's surprising the molecule wasn't completely reduced, alkene and ketone. Nowadays, the Luche reduction is commonly employed when one wants to selectively 1,2-reduce an enone, and this method makes use of the much less reactive sodium borohydride.

The next step was essentially the crux of the paper, as they mentioned in the opening paragraphs their recent studies on cyclopropanation of allylic alcohols (JACS, 1963, 86, 468). Specifically, they found that cis-selectivity was observed, a fact that is crucial to the stereochemistry obtained in the conversion of 6 to cyclopropyl-containing 7. Thus, usage of the Simmons-Smith organozinc reagent gave 7 as a single isomer, but in relatively low yield. A look at the experimental section shows that quite a bit of work was necessary to get the fully purified material, including a spinning band column distillation, recrystallization and flash chromatography over alumina.

Jones oxidation of the hydroxyl group in 7 gave 8 in expectedly high yield, and addition of MeMgBr followed by a workup with ammonium chloride resulted in facile dehydration to alkene 9, with intermediate alcohol 8 not being isolated. The authors mention that a characteristic reaction of thujopsene (9) is its rearrangement to the ring-expanded widdrol (10), and that was accomplished by treatment with oxalic acid in wet ethanol as a final proof of synthesis.

Overall it’s a nice synthesis. Typically when an organic chemist sees a decalin ring structure with a distal alkene, they immediately think of employing a Diels-Alder reaction. However, the presence of the cyclopropyl group necessitates a slightly different synthetic plan. The cyclopropanation reaction wasn’t quite as efficient as in their less complicated model systems, but still delivered the product stereospecifically. Perhaps some of the newer cyclopropanation reagents (rhodium carbenoids, newer organozincs) could give better yields.

*For a half-page review of stereoselectivity in the reductive alkylation of bicyclic enones, see this half-page review I made back in my grad school days.

Original article: Dauben, W. G.; Ashcraft, A. C J. Am. Chem. Soc. 1963, 85, 3673. http://dx.doi.org/10.1021/ja00905a032