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.

The NMR Laundromat

Source: OPRD / CNRS

The simplest, most practical solutions* are often the best.

I'm reminded of classic papers for pragmatic lab procedures, like Clark Still's on flash chromatography, or Gottlieb & Nudelman's on detecting trace NMR impurities. Everyone has encountered their lab's version of the Kugelrohr setup - run by an old electric kettle and a windshield-wiper motor!

From the ASAP of Organic Process Research and Development comes this handy one-pager: a how-to on cleaning dozens of NMR tubes simultaneously, using glassware readily available in just about any synth lab.

Seeing this instantly triggered a "Well, duh!" moment for me - the amount of time I've stood before a stoppered 500mL vacuum flask impaled with a cannula, washing single tubes by hand...I'm sure it reaches into hours, if not days.

If you try this, leave a comment; I'm really quite interested to see how it turns out. I'd also wonder if OPRD might be angling for other quick one-offs. Couldn't hurt to try, right?

*Of course, I'd be remiss if I didn't point unfamiliar readers to the treasure trove that is Not Voodoo.

Friday Fun: Backhanded Compliment

From a recent correction in OPRD, an odd bit of recognition.

In a 2014 paper, Burgard and Turconi, two Sanofi process chemists, laid out their vision for a high-yielding, industrial-scale semisynthesis of artemisinin. Somewhere along the way, a reference to another semisynthesis (Tetrahedron, 2013) got missed. Here's how the overlooked authors find themselves incorporated (emphasis mine):

"Bearing major breakthroughs in synthetic methodology, we are confident that this hybrid approach is far superior to a total synthesis and none of the many total syntheses published [insert ref here] appears to even approach providing a basis for a commercially viable process."

 Ouch. Them's fightin' words.

Happy Friday,
SAO

*One wonders if the first word should be "barring," as in, the authors allow that synthesis might one day catch up. As written, it's much more of a boast.

CPME? New to Me!

While reading through the latest Org. Lett. ASAPs, I came across a slick cross-coupling reported by the Walsh group (UPenn). The reaction unites acetamides and aryl chlorides, helped along by a "hybrid" Buchwald-Kwong pre-catalyst. Neat stuff.

Source: Org. Lett. | Walsh group

A certain passage caught my eye, midway down the second page (emphasis mine):

 "...four common solvents [toluene, cyclopentyl methyl ether (CPME), dioxane, and dimethoxyethane (DME)] were screened..."

All 'common' solvents, even CPME? I don't recall seeing that solvent in Trevor Laird's OPRD piece. Or on several solvent boiling point charts. In fact, I don't think I've ever used it...and I'm doing cross-couplings all day!

A quick literature dig on CPME turned up this OPRD, perhaps its grand introduction to the process scene. Looks like it exhibits several advantages over diethyl ether (higher boiling, lower peroxide formation), and improved safety metrics over dioxane or THF.

Readers: Am I just late to the game? Are process folks everywhere charging liters of CPME into reactors 24/7? Please clue me in.