Org Prep Daily

February 19, 2007

Ethanolamine can save your skin

Filed under: procedures — milkshake @ 12:37 am

skin2.jpg

I did many terrible things in the lab over the years. One of the earliest mishaps involved a beaker filled with thionyl chloride – about 250mL of it – that I spilled on myself. My advisor was standing next to me as this was happening – and in one instant motion he grabbed a 1 liter bottle of ethanolamine and poured it on me. A cloud of white smoke rose up, I ripped my clothes off and run for the shower. I suffered no burns from the incident.

From that time on, a friendly ethanolamine bottle has been sitting on the shelf in my lab. I later worked at a combichem company and accidental TFA splashes were a frequent occurrence there. Ethanolamine proved to be enormously useful in preventing TFA burns. 

There are many corosive liquids that soak into skin and cause painful burns: acyl chlorides, alkylating agents, bromine, strong acids like HCl in dioxane. The problem is that water, bicarbonate and acetone washing has limited utility if the agent is allowed to soak in – the burn develops from within. But if one applies ethanolamine onto the affected area the amine soaks into skin and neutralizes the corrosive agent there without causing much additional damage. Unlike many amines, ethanolamine is non toxic – it is actually a building block of some phospholipids within cell membranes.

Ethanolamine is applied on the skin in undiluted form for about half a minute and is washed off with water. Afterwards it helps to put a lotion or ointment on the affected area because skin tends to get de-greased and reddened from ethanolamine. A sterile bandage is probably a good idea. Ethanolamine must not be used in or around the eyes.  For HF burns, calcium gluconate in glycerin is more efficient since Ca(2+) can neutralise the toxic effects of fluoride. 

February 10, 2007

Ethanolamine-O-phosphate and N-palmitoylethanolamine-O-phosphate

Filed under: procedures — milkshake @ 7:21 am

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In a 1L round flask, 95g of 85% H3PO4 (808 mmol) plus ice (100g) mixture was combined with ethanolamine 50g (819 mmol) with stirring (exothermic). The resulting solution was concentrated on rotavap from a hot water bath, the obtained oily residue was heated on oil bath at 185C under water-aspirator vacuum (20 Torr). After 3 hours – when the foaming ceased – the flask was cooled. 1 mL of water was added along the flask wall and the crystallization was induced by scratching the flask wall with a spatula. The mixture was left to crystallize at +5C in a fridge for 6 hours. The precipitated solid was collected by filtration using a large coarse-porosity fritted Buchner funnel. The obtained crude solid product was dissolved in water 150mL. Two small spoons of charcoal were added, the mix was gently refluxed for 10 min, cooled, filtered. The obtained pale yellow filtrates were diluted with hot ethanol to the point of cloudiness. The mixture was allowed to crystallize in a fridge overnight. The crystallized product was collected by filtration, dried by suction and on highvac. Y=57.6g (50.5%) of a pale-yellow crystalline solid, m.p. 230-234C(dec.)

A solution of ethanolamine-O-phosphate 10.0g (71mmol) and NaOH 10.0g (250mmol) in water 150mL was cooled to +5C. With vigorous stirring a solution of palmitoyl chloride 16.5g (60mmol) in anh. THF 20mL was added dropwise over 15 minutes. The stirring was continued at 5C  for additional 45 min, then at ambient temperature for 45min. The obtained heterogennous foamy reaction mixture was heated to 70C. After 10 minutes, a solution of BaCl2.2H2O 24.4g (100mmol) in hot water 150mL was added and the mixture was stirred for 15 min. The precipitated crude Ba salt was collected by filtration, washed with methanol, dried by suction and on highvac. Y=30.9g (100%) of a white solid. The material contained some Ba-palmitate impurity. (The crude Ba salt can be re-crystallized to analytical purity from hot AcOH  but the crude salt is suitable for the next step).

2.50g of the crude Ba-salt from the previous step was dissolved in neat acetic acid 25mL at 95C. The solution was placed at 70C hot bath and a solution of 70%  HClO4 1.45g in 5mL of AcOH was added dropwise over 5 min. The mixture was allowed to cool to ambient temperature, then inoculated mechanicaly and allowed to crystallize in refrigerator (+8C) overnight. The crystallized product (1.4g) was collected by filtration and re-crystallized from AcOH 10mL (at RT overnight). Y=1.1g (60%) of beautiful outcrops of white crystals, m.p. 111-115C.

1H(DMSO, 60C, 200MHz): 3.798(app quartet, 2H), 3.248(app t, 2H), 2.055(t, 2H), 1.463(app quintet, 2H), 1.32-1.18(br m, 24H), 0.843(t, 3H)
The spectra was acquired on a ho-hum instrument very long time ago – so don’t trust it too much. DMSO at 60C was used because of the poor product solubility.

Palmitoylethanolamine-O-phosphate is a detergent; it is quite impossible to extract it from an aqueous reaction mixture as a free acid (the reaction mixture should be stirred, not shaked). Hence the isolation through the insoluble Ba salt was used. The problem was then to find a solvent/acid combination that would allow decomposition of the isolated Ba salt.  

HClO4 in AcOH is explosive – it will produce a loud bang if grossly overheated. It is important to control the temperature. Large-scale  preparations with perchloric acid are not recommended. (TfOH would be probably a safer alternative but I did not have it in Prague, 20 years ago.)

October 1, 2006

(S,S) and (S,R)-9-Aza-2-Oxa-[4,3,0]-Bicyclononane-3-Carbonitrile

Filed under: procedures — milkshake @ 11:16 pm

 

2-Chloroacrylonitrile 3.474g (39.7mmol) was added dropwise into a solution of L-prolinol 4.216g (41.7mmol, 1.05eq.) in anh. THF 40mL at 0C over 5 min. The cooling bath was removed and the mixture was stitrred at 0C to RT for one hour and then at RT overnight (11 hours). The reaction mixture was cooled to 0C, a solution of potassium tert-butoxide 4.904g (43.7 mmol, 1.1eq.) in THF 40mL was added dropwise over 10 min, stirred at 0C for 30 min and the reaction was completed at RT (ambient water bath) for 30 min. The reaction was quenched by adding water 1mL, followed by anh. MgSO4 powder. The mixture was stirred for 15 min, filtered (the salts were washed with additional THF) and the filtrates were evaporated. The residue was purified on a column of silica (150g) in a mix dichloromethane-ethyl acetate 5:1 (3L total). Two pure products were obtained (with complete separation):

A: Faster isomer, axial CN, Y=2.006g (33%) of a white crystalline solid

1H(CDCl3, 400MHz): 4.709(dd, 3.5Hz, 0.8Hz, 1H), 3.968(dd, 10.9Hz, 3.1Hz, 1H), 3.649(app t, 10.1Hz, 1H), 3.150(m, 2H), 2.523(dd, 11.7Hz, 3.5Hz, 1H), 2.178(ddABX, 17.5Hz, 9.0Hz, 1H), 2.075(m, 1H), 1.806 (m, 3H), 1.415(m, 1H); 13C(CDCl3, 100MHz): 117.82, 69.50, 63.41, 61.55, 54.48, 53.53, 26.31, 20.82 

B: Slower isomer, equatorial CN, Y=2.776g (46%) of a pale-yellow cryst solid

1H(CDCl3, 400MHz): 4.356(dd, 10.5Hz, 2.7Hz, 1H), 4.049(dd, 10.9Hz, 3.1Hz, 1H), 3.291(dd, 10.5Hz, 9.7Hz, 1H), 3.222(dd, 11.3Hz, 2.7Hz, 1H), 3.089(m, 1H), 2.530(t, 10.5Hz, 1H), 2.253(ddABX, 17.7Hz, 9.0Hz, 1H), 2.152(m, 1H), 1.774(m, 3H), 1.315(m,1H); 13C(CDCl3, 100MHz): 116.94, 71.93, 63.74, 60.86, 55.23, 25.87, 21.06 (All signals in proton spectra of the two stereoisomers were asigned based on COSY data)

(It was a pleasant surprise that the two nitrile diastereomers were quite far apart on silica. I don’t have a clear explanation why this is so but I think the axial cyano isomer may have reduced basicity, for stereoelectronical reasons.) 

Using the same procedure, D-prolinol produced  2.110g (35%) of the axial nitrile and 2.716g (45%) of the equatorial nitrile. This cyclization procedure is quite general for secondary aminoalcohols. For example, N-Me-ethanolamine produced racemic 4-Me-morpholine-2-carbonitrile and diethanolamine produced racemic 4-(-2′-hydroxyethyl)-morpholine-2-carbonitrile, in good yelds. 

The morpholine-2-carbonitriles are not very stable, they should be stored in a freezer – or better yet, used right away for the next step. For the preparation of the corresponding aminomethyl morpholines, LAH reduction works equally well as DIBAL (but it is easier to work up) and the LAH reduction results in no detectable epimerisation if the LAH addition is done at -78C and the reaction mixture is then allowed to gradualy warm up to 0C. (For racemic nitriles, hydrogenation over Adams catalyst on Parr shaker at 50 psi can be also used – but the LAH reduction gave better yields.)

One should be very careful with chloroacrylonitrile – acrylonitriles are nasty irritants and suspected carcinogens.

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