Org Prep Daily

April 6, 2019

Sodium Tetrachloro Bis-(1H-Indazole)-Ruthenate(III) dihydrate

Filed under: procedures — milkshake @ 9:30 am



Sodium sulfate 213.0 g (anhydrous, 3.0 mol of Na) was gradually added into a stirred slurry of Al2(SO4)3 .18H2O 1000g (3.0 mol of Al) in D.I. water 2L and the mixture was stirred to complete dissolution (about 30 min). The total volume was adjusted by addition of D.I. water to 2.7L and the solution was filtered through a fine porosity filter. The obtained 1.1M solution of NaAl(SO4)2 was combined with 226.9g of the Cs salt (350 mmol) in a large 4L beaker. Solid CsCl 6g was added to the stirred mixture, to seed the formation of cesium alum CsAl(SO4)2.12H2O crystals. The mixture was stirred in open Erlenmeyer flask at ambient temperature for 30 hours. During this time, the red-brown slurry of the cesium salt turned into coffee-brown black slurry of the sodium salt intermixed with fine white salt-like crystals of cesium alum. The solids were collected by filtration, rinsed thoroughly with saturated (=1.5M) aqueous sodium sulfate solution (in three portions 3 x 0.5L until the filtrates were colorless) and the obtained filter cake wet with sodium sulfate solution was dried by suction, and then in vacuo for 1 day, until completely dry free-flowing material was obtained. The solids were transferred into a 2L wide-mouth Erlenmeyer flask, 700mL of acetonitrile was added and the mixture was stirred mechanically for 15 min [Note 1]. The resulting deep orange slurry was filtered on a medium porosity Buchner funnel, the cake of insoluble sulfate salts was rinsed with additional acetonitrile (3x100mL until colorless) and was discarded. The combined orange filtrates in a 5L round flask were diluted with MTBE 4L (added in four 1L portions with gentle stirring), the flask was then set aside for 30 min to complete the precipitation. The precipitated crude sodium salt was collected by filtration, rinsed thoroughlt with MTBE (2×0.5L) and dried by suction and then in vacuo.

The crude product, 190.4g of a fluffy brown solid (retaining solvent residues and Cs, about 2500-4000 ppm Cs) was transferred into a dry 10L round flask. 191 g of powdered activated molecular sieves 4A [Aldrich 688363, sodium aluminosilicate, SYLOSIV A4 manufactured by Grace Davidson] was added to the flask followed by methyl ethyl ketone 4.2L. With stirring on high speed (800rpm), methanol 600mL was gradually added into the slurry over a 5 min period. The stirring was continued for 30 min, at this time nearly all dark brown lumps of the material dissolved. The resulting orange slurry was filtered through a fine porosity 3L large Buchner funnel [Note 1]. The spent molecular sieves were thorougly rinsed with additional MEK (2x200mL) and discarded. The combined filtrates were precipitated by a gradual addition of MTBE 10L with mechanical sitrring. After complete MTBE addition, the stirring was turned off and the material was allowed to precipitate for additional 30min. The solids were collected by filtration and rinsed thoroughly with MTBE (2×0.5L) and dried by suction. The purified product 184g, containing solvate-bound MTBE, was combined with 3.3L of wet MTBE (prepared by shaking 4L of MTBE with water 50mL in a closed flask, for 30min, and decanting water-saturated MTBE from the water droplets).  The mixture was stirred in open 5L wide mouth Erlenmenyer for 40 min. The brown solids were collected by filtration, rinsed with wet MTBE, dried by suction [Note 2] and then then in vacuo overnight (15h). The yield was 176.1g of a heavy dark brown granular solid (93.5% of theory), with HPLC purity 98.7% and a matching elemental analysis. The Cs content was below 100 ppm. There was no MTBE residual odor.

Note 1: The solvolysis with acetonitrile and also with methanol leads to a formation of detectable decomposition products on the timescale of hours. The filtration and precipitation needs to be performed immediately as the material is rather unstable in solution.

Note 2: The product has a tendency to retain organic solvent residues. A re-slurry with wet MTBE transforms the solvates into a more stable dihydrate. There is a second, metastable orange-red dihydrate polymorph that forms temporarily from MTBE-solvated product upon exposure to moist air. A sudden appearance of orange-red particles within the brown-black filter cake of the product during the final filtration is an indication that the material was not fully hydrated and retains still some MTBE solvate. The problem is fixed by repeating the re-slurry in wet MTBE.


April 5, 2019

Cesium Tetrachloro bis-(1H-indazole)-Ruthenate(III)

Filed under: procedures — milkshake @ 3:26 am



RuCl3.xH2O 100.0g (x~3, 382mmol) was combined with conc. HCl 0.6L and non-denatured ethanol 0.6 L. The mixture was stirred and distilled under air at normal pressure until the total volume of the mixture was below 400 mL. The distillates were discarded. The obtained dark brown solution remaining in the distillation flask was cooled, filtered through a medium porosity glass Buchner funnel and the filtrates were adjusted with conc. HCl to total volume about 0.5L.

In the meantime, indazole 300g (2.54 mol; 6.64eq.) was dissolved in a mixture of water 800 mL and conc. HCl 4.0 L (with 20 min stirring), the solution was filtered through a medium porosity glass Buchner funnel. This indazole solution was charged into a 15L glass-and-teflon jacketed reactor equipped with an efficient paddle-shaped stirrer, 0.5L addition funnel, a thermoprobe and air-cooled reflux condenser topped with a gas outlet tube for HCl gas release. An additional volume of conc. HCl 4.0L was then charged to the  reactor, the circulator-heating was set to 90C. The temperature in the reactor was let to stabilize for at least 30 min and then carefully maintained at 90 C throughout. The solution of ruthenium trichloride in HCl was added dropwise, at about 250rpm stirring, over a period of 5 hours, using an addition funnel with a stem extended with a piece of polyethylene tubing (to limit splashing). The addition funnel was washed down with a small volume of HCl (2x50mL). The obtained brownish slurry was then stirred at 90C for additional 10 hours. The reaction mixture was cooled down to 25C, with stirring, the slurry of the precipitated product was drained from the reactor through bottom valve into a 15L polyethylene bucket. The solids were collected by filtration on a large (3L) medium porosity glass Buchner funnel, the reactor was washed down with 2M aqueous HCl and the washings were added to the Buchner funnel. The product was rinsed with additional 2M HCl, about 2L, and partially dried by suction overnight. This provided a wet cake (moist with the residual 2M HCl) of the indazolium salt, 598g,  as a brown sticky solid. [Note 1]

The moist indazolium salt was transferred into a 10L wide-mouth flask equipped with an efficient mechanical stirrer with a teflon paddle. CsCl 180g (1.07mol, 2.8 eq., powdered briefly with a spatula to break any lumps) was added to the flask, followed by methyl ethyl ketone 2.0L and non-denatured ethanol (99%) 1.8L The mixture was stirred at 200 rpm for 5 min, the stirring was then turned to high speed and continued for 2 hours at 700 rpm at ambient temperature (22 C). The resulting bright orange slurry was collected by filtration (3 L medium porosity Buchner funnel), the solids were rinsed thoroughly with 99% non-denatured ethanol and partially dried by suction, for about 1 hour. The obtained bright orange cesium salt in the form of MEK-solvate intermixed with residual CsCl was transferred into a large 4 L beaker. 1 L of a 2:1 (v/v) ethanol-water mixture was added and the slurry was stirred in open beaker for 15 min at about 350 rpm. During this time the bright orange color of the MEK-solvated cesium salt slurry faded into cinnamon red-brown color of the hydrate. The solids were collected by filtration (using the same Buchner funnel),  washed thoroughly with 99% ethanol, about 1L. The material was dried by suction overnight  (14 h). The yield was 226.9 g (91.5% theory) of a red-brown heavy solid. The product is approximately monohydrate (it forms initially as dihydrate but loses a part of the solvated water upon drying). The material is bench stable.

HPLC purity 98.5-99% by HPLC (SB Zorbax C18, 3 micron, 4.6x150mm,  a 12 min 10% to 90% linear gradient of MeCN(+0.1%TFA) in water(+0.1%TFA) at 1.0mL/min), the product composition was confirmed by elemental analysis and X-ray crystallography

Note 1: The indazolium salt is a potent contact irritant. Indazole and ruthenium trichloride are caustic to skin. HCl is very corrosive. A full face shield and a protective apron are recommended when loading the reactor with large volumes of conc. HCl. The reactor needs to be completely disassembled and cleaned after the preparation, to prevent damage to seals and metal parts, and decontaminated from Ru residues (rinse with acetone, followed by methanol with added conc. ammonia, about 20:1 by volume, followed by water and acetone rinse)

Note 2: Since Ru(III) salts are paramagnetic, NMR is not helpful for purity determination. HPLC is useful but the resolution of the impurities is very specific to the particular type of reverse-phase HPLC column (SB-C18 Zorbax 3 micron). It is best to use single injections and prepare the individual HPLC samples just before the analysis because the material gradually decomposes in solution.


March 31, 2019

Pearlman’s catalyst

Filed under: procedures — milkshake @ 9:00 pm

TL 1967(17), 1663-4

Pd hydroxide on charcoal, contains 20% Pd by weight

PdCl2 2.0g (11.3 mmol) and activated carbon 4.8g (HCl-washed grade) was combined with DI water 40mL in a 250mL round flask with a large egg-shaped stirbar. The slurry was stirred on a 80C oil bath under air-cooled condenser for 20 minutes. A solution of LiOH.H2O 1.0g in DI water 8 mL was then added in one portion with vigorous stirring, the heating was turned off and the mixture was stirred overnight (16 hours). The solids were collected by filtration, rinsed with DI water, then with a solution of acetic acid 0.2mL in water 40mL and then with DI water again. The filter cake was compressed with a spatula, the product was dried by suction and then on highvac overnight.

Y=5.74g of a black powder

December 23, 2018


Filed under: procedures — milkshake @ 8:31 am



Inorganic Syntheses Vol 35, p. 148

4.20g of RuCl3.xH2O (x~3) and 99% EtOH 100mL (non-denatured) was refluxed gently on a 95C oil bath under air-cooled condenser opened to air, for 3 hours. The obtained dark greenish solution was filtered through a medium porosity fritted funnel, to remove some insoluble particles, the filtrates were evaporated on rotovap in a 300mL flask. The dark honey-like residue was combined with DMSO 16mL. The mixture was stirred on a 150C oil bath under air-cooled condenser opened to air, for 2 hours. During this time the reaction mixture color changed to orange-red and then yellow precipitate formed. After 2 hours, the reaction mixture was allowed to cool to room temperature, the obtained slurry was gradually diluted with acetone 120mL and the mixture was allowed to crystallize overnight (14 hours). The precipitated yellow heavy crystalline solid was collected by filtration, rinsed thoroughly with acetone, dried by suction and then on highvac.

Y=6.58g (85% th) of a yellow crystalline solid.

1H(D2O, 400 MHz, a 10 minute-old sample): 3.46(s,6H), 3.44(s, 6H), 3.35(s, 6H), 2.69(s, 6H)

Note 1: This preparation works best when performed under air. Common Alihn reflux condenser unconnected to water source was used for the purpose.

Note 2: The oxygen-bound axial DMSO ligand solvolyzes readily, the D2O-NMR spectra  actually belongs to the aqua complex and free 1 equiv of DMSO formed in situ. The NMR sample in D2O is not stable, some new peaks start appearing after 20 minutes.



June 10, 2015

The power of blunder – based optimization

Filed under: industry life, procedures — milkshake @ 8:46 pm

I have been trying to optimize a difficult reaction; I thought a presence of zinc chloride might help so I gave this a try and there was an improvement: The results were getting better, week after week.

Some time later – by now with improved product purity and filtrability – I begun to wonder if the zinc chloride effect was real, or maybe something else was going on, so I finally got around to run a control. And sure enough, the reaction worked even better without zinc chloride. So, after many tries with quantities of reagents and additives, I arrived at optimized procedure which looked almost exactly like the one that I started with, except few minor details – the little changes that were incidentally co-introduced because of the ZnCl2 addition – few small changes that make a difference… I would have never tried these changes without it. And I would have given up if I had run the control experiments earlier and found out it does nothing.

It is delightful to read methodology papers, the observations and explanations arranged neatly, flowing like a good detective story, with a chain of clear logical reasoning based on the experimental evidence. But I suspect it is mostly fictional (There is no good place in a process paper to explain that after very slow reagent addition because of a clogged valve that no-one cared to inspect before the pilot run, the impurity profile improved and the troublesome sideproduct from the second step no longer buggers up the recrystallization). I worry that reading published accounts of process research can give the management a very unrealistic impression what a normal project should look like.

May 22, 2014

A kilo-scale hydrogenation reactor?

Filed under: procedures — milkshake @ 8:22 pm

I have been running some hydrogenations of our polymers on kilo scale, at atmospheric pressure under balloons, and it is a bit of a chore. It would be nice to have something akin to a beer keg-sized Parr shaker and run the hydrogenation under few bars of H2, to reduce the catalyst loading and shorten the reaction time.

I wanted to ask the readers from process groups if they worked with a low-pressure batch stirred hydrogenation reactor that they liked and could recommend – for us to buy. Specifically,  we would need a hydrogenator that can accommodate 8-10 liters of a reaction mixture that has tendency to initially foam under reduced pressure (this means that the total available volume should be about 15-20 liters). Maximum operating pressure 3 bar would be enough, no heating or cooling is required and the typical solvent is water. I am not really interested in flow hydrogenation systems because they would be unsuitable to our particular case. A glass vessel or at least a glass window on the top would be nice to have, because of the foaming problem during evacuation.  Thank you for your suggestions!


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