Blog Syn #001 - Iron / Sulfur Catalysis

(Disclaimer: The following experiments do not constitute rigorous peer review, but rather illustrate typical yields obtained and observations gleaned by trained synthetic chemists attempting to reproduce literature procedures. We've taken efforts to stay close to the original procedure, using similar glassware, equipment, and reagents wherever possible. Images have been cropped and scaled to fit in the allotted space, but have not been digitally altered otherwise.)

Ref: Nguyen, T.B.; Ermolenko, L.; Al-Mourabit, A. J. Am. Chem. Soc. 2013, 135(1), 118-121.
Previous Analysis: Just Like Cooking: Post 1, Post 2, author response
Experimenters: Three - Matt Katcher (NJ), Organometallica (IL), B.R.S.M. (United Kingdom)

Recommendation: Moderately reproducible - yields much lower than anticipated

Trial 1 - Matt

Scale: 1 mmol
Reaction (table, #): Table 2, entry 2

Reagents: Fe was an old Fisher bottle (40 mesh)

Observations: Tried to keep reaction air-free by setting up with a septum over a pressure tube, but I was not extremely rigorous. Fe stuck to stir bar at end of reaction

Purification: Not attempted

Yield - Published: 83%

Actual: <5% by crude NMR

Advice: I still think the reaction might work, but it may not be a simple "dump and stir". If I did it again, I would run it in a Schlenk tube to minimize exposure to air.

Spectra / Photos:

Reaction setup

LC/MS - Target ion: 246 m/z

TLC

Crude NMR

Trial 2 - B.R.S.M.

Scale: 5 mmol
Reaction (table, #): Table 2, entry 1
Reagents: 2-Nitroaniline (Aldrich 98%; of indeterminate age, because I borrowed it), sulfur (Fisher 'lab reagent' grade, fine powder, age unknown), iron (Fisher '97% reduced by hydrogen grade' [no mesh given]), 4-picoline (10 mmol; Aldrich 98%; 1 year old)

Observations: Used 10-mL Schlenk tube that had been dried under vacuum using a heat-gun. The flask was evacuated and back-filled with argon three times. Dark-coloured suspension, agitated at maximum speed by magnetic stir bar.

Purification: Silica gel. Elution with 100:0 - 95:5 CH2Cl2:MeOH gave the product as a beige foam, still containing some impurities (Rf 0.45 in 96:4). Second attempt: Recrystallisation from toluene-hexane (ca 3:1) gave small yellow-golden brown crystals that were dried overnight in vacuo.
Yield - Published: 90%
Actual: before recryst 366 mg (37%); after 241 mg (24%).

Advice: A crude sample of reaction mixture removed at 24 h indicated around 5:1 aniline:product, but this was probably not reliable due to the low solubility of the product in chloroform. The reaction was quite messy, the product streaky and the column non-trivial. 
Spectra / Photos:

400 MHz NMR, after rexstal

Final product

Trial 3 - Organometallica

Scale: 5 mmol
Reaction (table, #): Table 2, entry 3
Reagents: Fe (Aldrich, >99% powder, fine), S (Aldrich, >99.998%, recrystallized)
Observations: Reaction run in inert-atmosphere glovebox in Schlenk bomb. Noted "internet accounts" (trials 1 & 2) before beginning this reaction.

Purification: Pushed through silica pad with DCM, 10%MeOH / DCM. Distilled on bulb-to-bulb apparatus to remove excess picoline.
Yield - Published: 75%
Actual: 35%

Advice: No residual product in picoline distillate or remaining on silica plug. Flask / reaction capable of withstanding increased pressure. Deep brown crude mixture, final product a green powder.
Spectra / Photos:

NMR, post-distillation

TLC, from notebook

Roundup: First, a hearty thanks to all three experimenters for taking time out of their busy schedules to run these reactions. Second, I believe we'd all agree that the reaction works, but in practice we obtain far less material than the original authors. Oxygen contamination plays a major role - note lower yield in Trial 1 - as (we suspect) does mesh size and age of iron and sulfur powders.

Author Response: (When this post goes live, I'll send the link to the corresponding author. Any response will be published in due course)

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