What's that Crud in My NMR Sample?

Scene:

The reaction finished in 20 minutes by TLC. You grabbed a quick aliquot for LCMS; one peak! Quickly, you quenched, extracted, perhaps pushed through a silica plug for good measure. After concentration, a gorgeous white powder formed, so you pulled high vac for 20 minutes and rushed down to "get your proton on." But, darn it! Still wet with traces of, well, something...

Friends, has this ever happened to you? Trace impurities in otherwise perfect spectra lead to much head-scratching and SI docs labeled "final product_spectrum 5." 

The three papers linked to this post should help.

• Nudelman, Gottlieb, Kotlyar - 1997. The one that started it all.

• Fulmer, Miller, Sherdan, Gottlieb, Nudelman, Stoltz, Bercaw, Goldberg. Updated for 2010, with an organometallics bent. Now includes gases!

• Babij, McCusker, Whiteker, Canturk, Choi, Creemer, DeAmicis, Hewlett, Johnson, Knobelsdorf, Li, Lorsbach, Nugent, Ryan, Smith, Yang, 2016. The new kids on the block: greener solvents for process chemistry and scale-up. *Update (23 Feb) - A kind commenter points out that #3 is free to download under the ACS AuthorChoice program. Sweet!

The new chart offers recommendations (colored arrows) based on Chem21 assessments of environmental impact, safety, and toxicity. Shown above are chemical shift tables (1H) in deuterated chloroform, acetone, and dimethyl sulfoxide.

If I were joining a synthetic lab this year, or starting an internship / work-study, I'd download 'em all and thumbtack liberally to the back of my bench. Guaranteed utility.

Friday Fun: Greening Chromene Synthesis with a Surprise Solvent

Old adage in organic chemistry: "If nothing's happening, keep heating until something does."

A new paper from OPRD takes that advice to heart. The authors, chemists at Merck's Kenilworth discovery site, are attempting to make a difluorochromene as starting material for a gamma-secretase inhibitor. They identify a [3,3] propargyl Claisen reaction as a logical starting point:

Looks simple, right? Well, the original conditions call for heating the alkynyl precursor in N,N-diethylaniline (yuck!) at 195 degrees Celsius (wow!). And all that for a measly 35% yield at scale. From Kong, Meng, and Su:

"There were two challenges for this reaction on large scale: the poor yield and, in particular, substantial amounts of waste produced post reaction. To produce 1 kg of compound 1, we estimated the use of 25 L of N,N-diethylaniline as solvent, 40 L of 4 N HCl to wash away the basic solvent. Combined with the silica gel needed, such a reaction would create roughly 300 kg of solid and liquid waste."

What to do? The authors reason that decomposition of the solvent at such high temperatures might be inducing the starting material to polymerize. Searching for an inert, high-boiling solvent, they land on a run-of-the-mill lab standby: Silicone Oil.

Again, the authors:

"With excellent thermal stability and good heat transfer characteristics, silicone oil has long been used for oil baths in laboratories as well as refrigerants. It is also highly soluble in hydrocarbon solvents such as toluene and xylene as well as chlorinated hydrocarbons, and therefore, it should be a good solvent for nonpolar compounds such as 6 and 1. With the boiling point of 300 °C for silicone oil vs 220 °C for the desired product 1, it should also be possible to obtain compound 1 by distillation, eliminating the workup step and waste production."

Can't argue with any of that reasoning! Sure enough, heating their starting material under nitrogen in Aldrich high-temp silicone oil (14 mL / 1 g) leads to a 64% recovery of 90-95% pure product by distillation. Notably, the same oil can be pushed through a silica gel plug and immediately re-used, with no notable change in yield or color.

Given the sheer number of high-temp cyclizations - ene reactions, Diels-Alder, Cope rearrangements, alkyne trimers, Bergman cyclization - the authors bullishly predict further use of these relatively inert conditions to open up process-scale variants of these banner reactions.

Get your high-temp silicone fast...it's set to fly off the shelves this weekend!

Happy Friday,
See Arr Oh

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.

--

*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.