Blog Syn #003A - Secret Ingredient

(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.)

It's been a wild month since our post concerning IBX-promoted benzylic oxidation. This piece provoked energetic discussion, evidenced by >200 comments (and counting!) between Blog Syn, two Pipeline posts, and Rich Apodaca's insightful discussion at Depth First. 

Before we wrap up this topic, we at Blog Syn first wish to thank Prof. Phil Baran, Dr. Tamsyn Montagnon, and Dr. Yong-Li Zhong (the original authors) for engaging us honestly and professionally, and helping uncover some of the hidden factors that make this reaction work.

I think we now know the most important one: water.

After reading Tamsyn and Phil's submissions to #003, we were puzzled: what was so different about our reaction conditions? Everyone was following the same procedure  [Santagostino, J. Org. Chem. 1999, 64(12), 4537] to make their IBX...right?

Well, not really. No one's published the actual NMR spectrum for IBX in quite some time. Neither this paper, nor Kirsch OL 2006, nor JOC 1999[1], nor Tet. Lett. 1994 (which the JOC refers back to) do much more than provide a list of peaks. This next image shows the NMR spectra provided by Phil, Tamsyn, and by an anonymous commenter online at Blog Syn. Note the rather large water peak at 3.4 ppm (possibly from some pre-opened d6-DMSO?)

Next, I made some fresh IBX strictly following the JOC 1999 paper, which includes two acetone washes to dry the IBX. The small bump at 8.4 ppm, which we had believed to be an impurity, might actually be the OH proton of non-solvated IBX. Note that, as I titrate in additional H₂O  the bump disappears, the aromatics shift and coalesce, and the 'signature' water peak grows in at 3.4 ppm! 

After discussion with the Blog Syn crew and the authors, we propose "hydrated IBX" may be the active species for the oxidation:

                         

Co-author Yong-Li suggested some ¹⁸O-labeled experiments to determine water's role in the reaction. Sadly, we're not equipped for this type of chemistry, but if any readers are, please feel free to report your findings!

Rxn, 20 h, w/H2O

Now the fun part: "hydrated IBX" performs the oxidation! 

Here's a (straight-baseline) TLC; runs "A" and "B" have varying [H₂O] in the solvent, which does seem to accelerate the reaction (right). Prof. Nicolaou had remarked on this trend in the Details of ACIEE 2002, 993 (see p. 996) noting that enone dehydrogenation yields decreased when solvent was pre-dried over 4A sieves.

Using "wet" DMSO and fluorobenzene (5:1), and heating to 95 deg C in a foil-coated, fully-submerged screwtop vial, I'm now able to convert 2-methylnaphthalene to naphthaldehyde in 52% yield (brsm). My colleagues have also observed increased conversion of toluene and 4-bromotoluene, but neither go to completion by the published time points.

So, what should we recommend? It seems clear that several critical details are missing from the original Supporting Info. How much have we deviated from the initial conditions?

Based on the information above, and the results in our hands over multiple runs, we will change our recommendation to Reproducible with optimization. 

We look forward to future communication with all authors involved, and hope that this interchange inspires chemists to have another look at IBX-promoted oxidation reactions...just add water!

[1] We should point out that JOC 1999 does include KF titration values, but the low water % detected does not rule out sufficient hydration of some IBX. Note also that the elemental analysis values deviate enough to include trace water.

Blog Syn #002: Pd-Catalyzed C-3 Selective C-H Olefination of Pyridines

(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.)

Updated: 2/20/13 - Added Yu rxn pictures

Ref: Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964-6967. doi: 10.1021/ja2021075.

Experimenters: Two - See Arr Oh (Somewhere, U.S.A.), Organometallica (IL)

Recommendation: Pending Blog Syn repeat
Initial - Moderately reproducible - yields/conversion lower than reported; reactivity / regioselectivity mostly consistent with literature. May require optimization.

General scheme:

Context: This reaction comes from a 2011 paper (dx.doi.org/10.1021/ja2021075) by Jin-Quan Yu's group at the Scripps Research Institute titled "Ligand-Promoted C-3 Selective C- H Olefination of Pyridines with Pd Catalysts." See Arr Oh proposed this reaction, noting its potential to be "operationally simple...with few variables to goof up, and wide substrate availability." Synthetically, C-H activation appeals to synthetic chemists due to its high atom efficiency (less waste) and simplicity (no need to pre-functionalize a reaction center).

The procedure employs a Pd catalyst to 'activate' the pyridyl C-3 carbon-hydrogen bond. A bidentate pyridyl ligand, phenanthroline (phen), presumably enhances ligand exchange via the trans-effect (to counteract the strong coordination of the pyridine substrate to the metal center). The reaction is run with a Ag(I) co-catalyst under air, which serves as the terminal oxidant.

The authors highlight the important of 3-alkenyl pyridine derivatives in chemistry, citing numerous natural products and pharmaceuticals exhibiting this motif. They claim the first instance of C-3 selective pyridine olefination (a number of examples with more limited substrate scope and different site selectivity are given). Just how C-3 selective? Yu and coworkers report C-3/C-2/C-4 site selectivity ranging from 7/1/1 to 30/1/1. 

According to Web of Science, the article has been cited 45 times as of February 2013 (including 4 reviews). A cursory SciFinder search didn't find any examples with direct usage of this chemistry; an extension to arylation is found in a 2011 synthesis of preclamol by Yu's group.
Update(2-17): A related reaction for C-2 olefination of pyridines was reported in Adv. Synth. Cat. 2012, 354, 2135. We apologize for this omission.

Experimental

Trial 1 - See Arr Oh

Scale: 0.5 mmol (same as researchers)
Entry: Compound 3a, Table 2 from JACS 2011, 6964.

Reaction in 75 mL
sealed pressure tube.

Reagents: ACROS Ethyl acrylate [140-88-5], 99.5%; Alfa silver carbonate [534-16-7], 99.5%; ALD anhydrous pyridine [110-86-1], 99.8%; STREM Pd(OAc)₂ [3375-31-3], 99%; ALD 1,10-phen [66-71-7], Aldrich DMF, anh. 99.8%

Glassware: Pressure tube (75 mL, Teflon bushing) oven-dried o/n. All dry reagents weighed out in air.

Observations: First 5 mins: yellow pasty suspension. At temp (141.3 deg, sand bath) - deep orange-brown. After 16 h - deep brown, almost homogeneous, silvery Ag(0) / Pd(0) sheen around top of flask. Diluted with EtOAc, filtered over 1/2" Celite plug (2 x 5mL wash), then column chromatography (3 x 1 cm, silica, 1:4 - 1:1 EA / Hept).

Pale yellow oil, 7/1/1 meta / ortho / para, 27% yield overall (38 mg isol'd: 24 mg pdt + 14 mg DMF by NMR integration)

Advice: Crude product an orange gum, tough to handle / redissolve. I would re-load onto silica, and incorporate a water wash to eliminate DMF.

Supplementary images (click to enlarge):

¹H NMR spectrum, post-chromatography.

Reaction setup, before heating.

TLC: left, ethyl acrylate
center, co-spot
right, reaction mixture

Filter.

Reagents employed.

Measured reagents.

Trials 2 and 3 - Organometallica

Scale: 0.5 mmol, as per SI conditions.
Entry: Compound 3a, Table 2 from JACS 2011, 6964.

Reagents: Palladium acetate [3375-31-3] (Strem, fresh bottle stored in glovebox), 1,10-phenanthroline [66-71-7] (Sigma-Aldrich, age unknown), Silver Carbonate [534-16-7] (Strem, ~2 mos old, stored in freezer in amber bottle within glovebox), ethyl acrylate [140-88-5] (Sigma, age unknown-purity >99% by NMR), Pyridine [110-86-1] (ACROS 99.8%), and DMF [68-12-2] (from solvent still, source unknown, see Advice for comments on this reagent).

Glassware: Pressure tube (75 mL).

Trial 3; reaction setup.

Observations: NOTE: This reaction was attempted multiple times. In all cases, the reaction was set up on the bench without precautions against preventing air contamination. Reagents were added neat to 75 mL pressure vessel in the order Pd(OAc)₂, 1,10-phenanthroline, Ag₂CO₃, pyridine, ethyl acrylate, followed by DMF, then sealed and heated at 140˚C for 12 hrs.

For Trial 2, DMF used directly from solvent still, for Trial 3, air was bubbled through DMF for 1 hour prior to use. Trial 2: Reaction darkens, remains heterogeneous. Trial 3 (Pictured): Turns pasty yellow, still some solid left in the flask.

Analysis: ¹H NMR: Trial 2: no conversion observed. Trial 3: ~40% conversion.

Advice: When I first ran this reaction (Trial 2), I panicked. There was absolutely no product; nothing by TLC, nothing by NMR, nothing by GC-MS. However, one of my friends who work on Pd-catalyzed C-H activation remarked that reactions run under air are particularly sensitive to solvent O₂ concentration, so much so that he saturates solvents with O₂ before use. Thinking this might be what plagued me, I aerated my solvent (Trial 3), which seemed to kick off the reaction. This may be the first time I've ever had a reaction fail for having my reagents be too clean!

Supplementary images (click to enlarge):

¹H NMR spectrum, full

¹H NMR spectrum, expanded to show
aromatic region

Results and Discussion

Author* response: Corresponding author Jin-Quan Yu (Scripps) was kind enough to respond with some helpful advice (Bold highlights are mine).

1. As what you have observed, the oxygen concentration is very important to this reaction. So the tube volume is also very important. We used the 50-mL tube, which is the total volume of the tube (from the bottom to the cap). For smaller one, the air is not enough. For bigger one, the pyridine will volatilize too much outside the solution. 

2. Heating and stirring is another important thing. Prior to starting experiments, turn on the hot plate and set the oil bath to 140°C first. To make the oil temperature is stable, you can put a paper clip into the oil, which will help to stir the oil. Put the reaction tube in the middle of hot plate to obtain a stable stirring (500 rpm is enough). Don't let the solid adhere to the tube wall. And make sure the surface of reaction solution is lower than oil surface. 

3. Another thing I should mention is that the quality of Ag₂CO₃ and Phen may ruin this reaction. We found that these chemicals from Strem Chemicals are good quality and there is no risk for this reaction.

Roundup: The reaction certainly works, though certain variables essential to its success are under-emphasized in the original paper (see Author response) and were unfortunately omitted from the SI. Notably, conversion depends on the presence of oxygen in solution (see Organometallica's trials). Even solvent aeration produced substantially lower conversion than the authors report (40% vs. 73% isolated yield). See Arr Oh did, however, observe similar regioselectivity (7/1/1 vs. 12/1/1).

Since both yields and observed regioselectivities fall within the low end of those reported, we classify this procedure as moderately reproducible.

Thanks to See Arr Oh and Organometallica for experiments, and thanks to Prof. Yu for providing feedback. Readers: if you have experience with this reaction or suggestions for future investigations, please feel free to comment.

*Addendum (Feb 20, 2013): After an exchange of emails, Prof. Yu felt it best to have a new postdoc (not an original paper author) repeat the experiment, and sent over pictures of the reaction setup, along with a crude NMR.

The ratio I get from these integrations is 12.7 / 1.5 / 1 (m/o/p), which agrees with the original publication.

Update (2/20/13): Prof. Yu indicates that integration of the crude against 0.5 equiv. of CH2Br2 (4.94 ppm, above) gives an NMR yield of meta-olefination product matching the literature (76%).

Of note, the reagents are quite different - he's using a higher grade of both (1,10-phen) and pyridine, but we don't have information on the acrylate used or the Pd source. Also of note, the 50 mL long, cylindrical tube volume clearly benefits the reaction, as alluded to in Prof. Yu's original email.

We thank Prof. Yu for sending along some clarification. Perhaps this signifies a change in the way reactions are reported; if everyone had to send along photo evidence, would there be so many reproducibility issues in the modern literature?

-SAO

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)

**Thanks for reading our initial venture into collaborative "crowdsourced reaction validation." We appreciate any comments or suggestions for the next go-around. Want to get involved? Have an idea for another (cheap!) reaction to try? Talk to us in the Comments section!

Introduction

Nothing like a good stock
photo to kick things off!

Hello, synthetic chemists! Welcome to Blog Syn, a new chemical literature review site.

We don't just discuss the methods, we put them to the test!

Stay tuned to this page as we figure out exactly how to structure this new venture. In the meantime, if this sounds like something you'd like to be involved in, drop us a message in the comments.

Thanks!
-SAO