Anhydrous Cerium(III) chloride + LiBr solution in THF

 

LiBr 24.5g (282 mmol) was dried in a 0.5L RB flask on highvac (0.2 Torr) at 150C for 12h (overnight), then cooled under Ar to RT and anh THF 0.4L was added via cannula. The the mixture was stirred under Ar until complete dissolution (20 min).

Meanwhile, powdered CeCl3.7H2O 47.5g (Aldrich; 127.5 mmol) was combined with re-distilled thionyl chloride 175mL (2.4 mol) in a 0.5L flask equipped with an efficient reflux condenser topped with a gas outlet tube (vented into a large Erlenmeyer flask filled with soda lime pellets). The mixture was placed on a 70C bath and stirred vigorously for 2 hours; at the end  of this period the gas evolution and SOCl2 reflux nearly ceased. The bath temperature was then raised to 110C and the slurry was refluxed for 12 hours (overnight). The condenser was replaced with a short-path distillation head and the unreacted thionyl chloride was recovered by distillation from a 110C bath. The solid residue remaining in the distillation flask was  briefly dried by using a teflon pump at 10 Torr at 110C/15 min and then flushed with Ar. The bath temperature was raised to 200C and a stream of dry Ar was passed into the flask through the septa for 1 hour at 200C. The solid was further dried on highvac (0.2Torr) at 200C for 12 hours. The obtained anhydrous CeCl3 (a fine white heavy powder) was cooled to 0C under Ar, the anh LiBr THF solution was added via cannula with stirring, the cooling bath was removed and the mixture volume in the flask was adjusted with additional anh THF to about 0.5L total volume. The mixture was then stirred at RT to a complete dissolution (6-12 hours), then used as such.

This procedure yields 0.5L of aprox 0.25M CeCl3.2LiBr in THF as a yellow cloudy solution. The trace amount of a very fine insoluble material present in the mixture can be removed by sedimentation but for most applications this seems unnecessary.

Note 1: The used SOCl2 was re-distilled before use because a new bottle of Aldrich’s “Low Fe 99.5% SOCl2″ came brightly colored. (Don’t listen to Aldrich tech support folks telling you that pure SOCl2 is canary-yellow according to ther specification). The used THF was a common Aldrich BHT-stabilised anhydrous Sure-Seal grade.

Note 2: LiBr and CeCl3.7H2O are hygroscopic and must be stored in a tight bottle. (CeCl3.7H2O powders up very nicely with a mortar and pestle but a soggy material is difficult to use in this procedure). Care was taken to avoid contaminating the flask joints when loading up the solids as this could cause the joints to seize or leak.

Bleak chemistry

Last week I run a reaction in molten imidazole without a solvent, at 240C in a pressure vessel. This reminds me - in Prague we would heat quantities of beta naphtol with neat hydrazine hydrate in a “Bombenrohr” in the electrical oven at 150C, and we were taking that alarming thing periodically out and giving it a hard shake while hot. (Bombenrohr is a fancy German word for a pipe bomb, a steel  tube with screws at ends).  The resulting ooziness was then poured and spooned out into vats of boiling water, to extract away the unreacted hydrazine, naphtol and the sideproduct - betanaphtylamine (I know how it smells so I am gonna die) - and the leftover slime was then repeatedly precipitated as HCl salt, to get 1,1′-binaphtyl-2,2′-diamine. We were making 50 g batches of the racemic stuff that way and we were then resolving them with CSA.

The meanest reaction I did was melting binaphtol with 3 equivalents of Ph3PBr2 without solvent, to get binaphtyl dibromide. The procedure called to “dilute the melt with equal volume of dry Celite, cool the mixture to solidification, break the flask and peal off the glass, crush the solidified reaction mixture into half-inch sized chunks and extract them in Soxhlet” - which I managed, except that hammering the mean black 250mL tar-ball into chunks produced lots of corrosive bits flying everywhere while I was choking on the HBr fumes.

There is no moral to this sad story. 

Tetrabutylammonium Permanganate

In a 0.5L beaker, a slurry of tetrabutylammonium hydrogensulfate 34.0g (100 mmol) in ice cold water 50 mL was treated with 1M NaOH 101 mL and the mix was stirred until complete dissolution. (The pH of the solution was about 11-12, on indicator paper strip). While stirring with a large stainless steel spatula,  aqueous 40% sodium permanganate solution 29mL (=39g, 110 mmol, Aldrich) diluted with cold water 50 mL was gradually added to the beaker and the obtained thick sludge was hand-stirred on ice bath for 20 min. During this time the produced blackberry-colored congealed mass became fine-grained and purple supernatants separated. The solids were collected on a large glass Buchner funnel (350mL, medium porosity), the cake was thoroughly compressed on the funnel, washed with ice-cold water (8×20mL) then fluffed up with a spatula again and washed with more ice-cold water (100mL). In the final washing stage, the produced washings were only light-purple. The solids were dried by air suction and then on highvac.
Y=35.78g (99%) of a bright violet powder.

Note 1: Drying this quantity of material on highvac took one full day. The product is best stored in a dark bottle in the fridge.
Note 2: I just put a small heap of the dried product to torch and it burned wickedly fast like gunpowder - with a puff.
Note 3: People inhaling manganese oxide dust or injecting themself with permanganate solution can develop a Parkinson-like irreversible CNS damage.

Nitroacetic acid

 

90% KOH solid 265 g (4.25 mol, flakes) was loaded into a 1-L sized three-necked flask with a large egg-shaped stirbar. Water 180mL was added in one portion and the mixture was stirred without cooling. The flask was equipped with internal thermometer, an efficient reflux condenser and a side-arm septa. When the resulting hot KOH solution temperature dropped to about100C, neat nitromethane 90 g (80 mL, 1.475 mol) was gradually added by syringe through the side arm, with a vigorous stirring. A strongly exothermic reaction commenced, accompanied with ammonia gas evolution, foaming and precipitate formation. The temperature and gas evolution was controlled by the nitromethane addition rate so that the internal temperature remained between 120 and 140C. This addition took about 30 min. [Note 1] The mixture was stirred then for additional 20 min, the  flask was then placed on a 130 C oil bath and stirred at this temperature for 1 hour with a gentle stream of Ar introduced into the flask through the side arm (the septa was replaced with a gas inlet adapter  [Note 2]). The resulting light-colored slurry was cooled and stirred at RT for about 30 min. The flask was then placed into a refrigerator overnight. The precipitated bis-potassium salt of nitroacetic acid was collected by filtration on a large (350mL, medium porosity) glass Buchner funnel, the wet cake was compressed on the frit. The reaction flask and the filter cake were thoroughly rinsed with fridge-chilled methanol , 6×20mL. The solid was then dried by suction. [Note 3]

The obtained bis-potassium salt (84.4g of a cream-colored crystalline solid, 63% th) was gradually added as a solid into a freezer pre-cooled (-20C) stirred mixture of 85% H3PO4 400g with water 300mL and ethyl acetate 500 mL in a 2L Erlenmeyer flask. The mixture was then placed on a ice/water slush bath and stirred at 0C until all solids have dissolved (about 20 min). The phases were separated, the organic layer was washed with chilled sat NaCl 500 mL , the aqueous phases were re-extracted with additional chilled EtOAc 500 mL. The combined organic extracts were dried with MgSO4, filtered and evaporated from a 17-22C bath, to near dryness. [Note 4] The obtained crystalline residue was covered with ethyl acetate 10 mL, the slurry was diluted with chloroform 250mL and allowed to crystallise for 20 min. The precipitate was collected by filtration, washed with chloroform, dried by suction and then on highvac (30 min). Concentrating the supernatant and covering the residue with 10mL of 1:1 ethyl acetate + chloroform mixture and then diluting the slurry with chloroform 80mL provided a second crop of the pure product. 

The combined yield was 44.85 g of a sugar-like white crystalline solid (Y=58% overall).
1H(CD3CN, 400MHz): 9.578 (very br s, 1H), 5.295 (s, 2H); 13C(CDCl3, 100MHz): 164.34, 77.51

Note 1: The nitromethane adition is promptly exothermic but the ammonia evolution and precipitate formation is slightly delayed. This can cause a foam-over accident if the nitromethane is added too rapidly below the optimal temperature. Above 120C the mixture is easier to stir and the foaming is suppressed but an efficient condenser is needed to keep nitromethane from being carried away by the evolving NH3 gas.

Basic impurities sensitise nitromethane - the used nitromethane should be transferred into a temporary storage flask and drawn from there so that the main bottle is not accidentally contaminated with alkali. If the addition funnel is employed, the funnel should be kept under positive pressure of Ar to keep NH3 from entering the funnel.

Note 2: Argon is passed through the flask sidearm to drive out the remaining ammonia. This is not essential but it seems to produce a lighter-colored reaction mix. Due to some evaporation the internal temperature of the mix holds at around 120C when the mix is stirred on a 130C bath.

Note 3: There are contradicting reports about the shock sensitivity of this bis-potassium salt. To stay on the safe side I tried to avoid grinding and pounding the material too vigorously. After the bis-K-salt washing with methanol, it became non-hygroscopic and the compressed cake could be fluffed up with a spatula on the Buchner funnel, to aid the drying by suction and to keep the cake from turning into a brick. Some residual MeOH is no problem in the next neutralisation step.

Note 4: The mono salt is extremely unstable. The acid is reasonably stable as a solid but it decarboxylates slowly at RT in solution, especially in the presence of water. The solutions were kept below +10C during the extraction workup. (The drying with MgSO4 and the evaporation can be done at ambient temperature, without a delay). The used chloroform was an ACS grade stabilised with amylene, free of ethanol and acidic impurities. Nitroacetic acid is stored in a fridge.

Such, such were the joys

When I was fired from Pfizer, we were told that - because we were getting a better severance payment than the absolute minimum required by law - we must sign a gag agreement. The agreement was that we won’t say anything negative about being fired and about the company that fired us. In this gag agreement we also promised that we would never disclose the severance amount and the existence of the gag agreement. 

Since our closed site was quite large, they did not fire us all at once but they divided us into “waves” . I was lucky to get out early so I still got what was promised by Pfizer - but the colleagues fired few weeks afer me were screwed. Someone at Pfizer figured out that they were giving away too generous severance so they cut it. Many of my colleagues ended up suing the company: their class-action dragged on for years but eventually Pfizer coughed up the rest of the promised money to settle.

After Pfizer I went to Celera in South San Francisco. The place was crazy - they drove us extremely hard there because the company was in trouble and we needed to save it or we would lose our jobs. So we were working like nuts “to have a clinical candidate by the end of the year”and the biggest problem was our management: they were very nervous, they made all kinds of unrealistic promises to appease their superiors but wouldn’t spend money on equipment we needed for the candidate scale-ups. The management was setting us for failure - we were short of people but they would always come up with ridiculous new ideas what else we should do for somebody, ontop of our work. So our medicinal chemistry group ended up doing the scale up, the bulk purifications, the process optimisation, and the formulation work also - while trying to find the best candidate. After 10 months I got tired of this baloney (and our boss) and since I got a job offer I prepared to quit. There was plenty of good chemists at Celera and I talked to some friends discreetly - to see if they would like to go with me - but not discreetly enough and our management found out. And so they decided to fire me preventively. The problem was that they did not have an official reason for firing me - and they would have to pay a severance if they fired me.

The way it happened was rather entertaining: our evil boss came and asked me if the rumor was true - that I would be leaving. I said yes but I would want to stay for another 6 weeks or so, before my new job starts. She said they needed to find a replacement for me and they couldn’t advertise my job because they did not have an open position. So as a favour, please would I write an informal note about the timing so that they could start the hiring process? I wrote the e-mail and the next morning I found myself fired on moment notice. I was called into HR office in administrative building and told I cannot go back because my “written resignation was accelerated” by the HR, and my poor boss could do nothing about it “because it was a standard industry practice”. They would box and mail my stuff.

I asked HR whose idea it was - they told me our boss wanted me out. So I explained the HR that this was a manifest scam: the real reason why they fired me was the argument between me and my group leader. I told the HR the boss was going after me for some time because I criticised her management style and the decisions she made which delayed our project and hurt our company. In these difficult circumstances I did what I could to save our company and was working 14 hours a day including the weekends and I was punished for it - while my boss was trying to fabricate any reasons to fire me in order to cover up her mistakes. Now she did it in a sleazy way and she also manipulated the HR in the process. It was a textbook wrongful dismissal.

The HR immediately called my boss and overruled the firing and I went back to work. The victory lived short: the same evening the boss called an emergency management meeting - all the senior staf, with site director, etc - and she went about the terrible danger that I would steal the company’s intellectual property and lure other employees away. I found myself fired the next Monday.

It took several letters to the company director with “wrongful dismissal” prominently in them - and suddenly I got a check in the mail - over $7000 - and it was much more than they owed me for my unused vacation; it was the money that I would make if I stayed for another 2 months.  Incidentally, two months is the minimum severance required by law to be paid to dismissed employees (in California). After the check cleared I got a phone call from Celera headquarters: their HR boss explained that someone has made a clerical error and they overpaid me by mistake but they did not want me to return their money. You see - they could not call it severance “because I resigned voluntarily and they accelerated it” but they decided to pay my lost income to shut me up.

Some time after I left, my colleagues at Celera in South San Francisco were told that there were going to be “some limited job cuts in the future” and they needn’t to worry as the downsizing would affect only few people in some groups but the company was required by law to give a notice of possible job cuts to everybody. What the top management did not tell the employees was that the headquarters already decided to axe the company site no matter what. The top Celera decision was to quit the pharma business altogether - the only problem was that their research projects were unfinished. To get the best value for their research, Celera needed its employees to take the projects to some reasonable stage before they could sell it to other companies. So the harder the people in the labs worked the sooner they would find themselves out of job…

And the notice was a ploy also: the legal minimum severance counts from the moment of the written notification. The employees believed the management promises that their jobs were not in danger (despite the notice) and that they were protected by the company written policies. They were told that those few people who would lose their jobs would get much better severance than the legal minimum. In fact, they did not. One day the Celera employees were invited for all hands meeting in the administrative building and there they were told there that they can’t go back to lab again. Suddenly guards and boxes appeared at the chemistry building and the chemists were given only few minutes to pack their office belonging. They were constantly watched as to not to sabotage anything.  Despite the assurances, they all got just the minimum, which turned out to be less than 1 month salary because the notice was already in effect. (The group bosses were employed few weeks or months longer, in the empty building, in order to wrap up the projects and put the documentation together. I suppose they got a better deal.) 

So as you can see, the industry has various ways of maximising the shareholders’ value. There is probably someone at your company who will get a bonus for firing you and then screwing you out of your severance.

Arnold Salt

Anhydrous DMF 160mL in a 0.5L round flask was cooled on ice bath and neat POCl3 40 mL (436mmol) was added greadually over 10 min period (exothermic). The mixture was warmed up to RT, bromoacetic acid solid 19.00g (136.7 mmol, Aldrich 99%+) was added quickly in one portion (hygroscopic, wear gloves - bromoacetic acid and POCl3 are nasty). The flask was equipped with a reflux condenser and the mixture was stirred under Ar on oil bath at 90C for 9 hours. The mixture turned orange, with a slow CO2 evolution. The mixture was cooled to RT, DMF was distilled out on highvac (RT to 90C at 0.5 Torr) and the obtained thick residue was treated with ice-cold water 100mL on a sonicator bath. An exothermic hydrolysis commenced. When all residue dissolved and the mixture cooled to RT, solid sodium hexafluorophosphate 46.2g (275 mmol) was added in one portion followed by some additional water (50 mL). The mixture was shaken vigorously for 10 min, the precipitated product was collected using a large Buchner funnel. The solid cake was compressed on the frit, washed with ice-cold water (5×20mL), dried by suction and then on highvac.
Y=61.05g (94%) of a yellowish-white solid

1H(d6-DMSO, 400MHz): 8.439(s, 3H), 3.535(s, 9H), 3.376(s, 9H)

Note 1: The formylation is complete in 6 hours at 90C. KPF6 is probably a better source of hexafluorophosphate because unlike the sodium salt it does not hydrolyse readily, does not etch glass and is non-hygroscopic. Aqueous HPF6 can be also used. It is important to remove most DMF from the reaction mixture, this takes some time (I used a rotovap hooked to oil pump).

Note 2:  The product can be re-crystallised to analytical purity from MeCN + some antisolvent (THF) but the crude material is suitable for most purposes.