Org Prep Daily

January 23, 2008

Awful Seminars

Filed under: industry life — milkshake @ 11:18 pm

When sitting through job interview seminars sometimes one gets a speaker who struggles with the language, presents messy slides or his chemistry seems unremarkable. Please be tolerant - it is the speaker in this case who suffers more than his audience. (I still remember the shivers during my own initial presentations. When I came to US nobody could understand a word of what I was saying- except for the “beta sheet” which was causing people to giggle).

The worst speakers are experienced men - It takes plenty stubborn practice and vanity to arrive at your very own terrible presentation style. Famous men are just as susceptible to the PowerPoint bad habits (5 different font sizes in 5 mismatching colors including the “invisible yellow” favorite, with the bullet points, campy clip-art and artful themes) - and they usualy take themself seriously so they invite you to be awed, by re-emphasizing every aspect and detail of their contributions. Some people are naturally uninspiring or disorganised speakers - but the essence of giving truly awful lecture lies in one’s preparedness to be selfish and inconsiderate. When I hear “First let me very briefly outline” a FEAR strikes me because when the speaker is already apologetic at the beginning of the seminar he is most likely going to mumble through twenty introductory slides and read them out verbatim. Then after 50 minutes of incessant dribble he would look at his watch and say: “Since we don’t have much time if there are no questions I will quickly move onto the second part of my talk…”

The most nauseating seminar I have seen was given by a junior chemistry prof at a Ivy League University: His work was nice and logically presented but he tried hard to connect every tiny detail of his presentation to the precedents from his ilustrious colleagues who were about to decide on his tenure  – and who all happened to be in the audience. He would loudly and frequently praise every single one of them and then again all of them collectively - for their sheer brilliancy and fatherly guidance. This level of sycophancy would be perhaps great during award acceptance speech in Pyongyang - but on this chemistry seminar with the student audience interested in the synthesis talk the outright servility was making one cringe. (Yes it worked. He got his tenure).  Another memorable speaker that I remember listening to in despair was La Clair giving his non-hexacyclinol presentation at ACS in San Francisco in 2006.

Credit: Chad Orzel has a post on terrible seminars in physics. For the bad speakers who want to become more terrible the guidelines can be found here.

January 20, 2008

Wrestling with a robot

Filed under: industry life — milkshake @ 1:35 am

resslin.jpg credit: Adolf Born

The Varian NMR autosamplers that I worked with in my previous jobs had an oversized robotic arm grabbing on samples from a rack and then swinging around wildly, loading them into the magnet hole. The system punished users for making errors. A part of the problem was that the acquisition queue allowed the users to run the samples out of sequence and to occupy any arbitrary position in the large and rather poorly numbered rack. Absent-minded people would always enter an incorrect position or leave their sample in a wrong place.

When the robot would try to pick a sample that was missing and could not find any, it would freeze and sound angry alarm - this held up the queue until our NMR man came and re-set the damned bot. Things got worse when a sample was left in the rack position reserved for the preceding sample that was in the magnet – upon return the robotic arm would shatter both samples by smashing them one into another; this created awful mess that had to be cleaned up before the instrument could be re-set. (Also the mishap could damage the arm or ruin the spinners that cost few hundreds apiece). Sometimes I would see the dreadful thing just happening and I would run to deflect the steely arm – but you know, robots are strong and a man is no match…

January 17, 2008

The trailer chemistry

Filed under: Uncategorized — milkshake @ 5:43 am

Methamphetamine illicit production is a serious problem not to be made light of in these times when getting hold of precursors is growing more difficult. We prepare ourselves for the start of promising TV series this Sunday by comparing the merits of four popular methods [1, 2]:

1. Heating pseudoephedrine with red P and iodine. This is a dirty method that needs glassware and some practice. The reflux produces a nasty phosphine smell, in the absence of fume hood the cook would want to use a mask. This is the actual method featured in “Breaking Bad”.

2. Pseudoephedrine treatment with Li metal and anhydrous condensed ammonia mixture in ether. Anhydrous ammonia is a common fertilizer that could be pilfered from outdoor storage tanks. This used to be a hillbilly favorite method – the cooks stir the mix in a bucket while throwing in the Li chunks. This is feasible only in open country as the escaping NH3 stinks up the whole area. The method is quick, the average batch size tends to be smaller. The complicating factor is a benzene ring over-reduction. The agricultural liq NH3 is nowadays frequently denatured with inorganic salt additives to ruin its usefulness in meth production.

3. Hydrogenation of chloromethamphetamine hydrochloride solution over palladium. The chloro intermediate is obtained by mixing the hydrochloride salt of ephedrine or pseudoephedrine with thionyl chloride. This is a clean and high-throughput method favored by Mexican cartels. It is best performed in pressure hydrogenators – which makes it less available to most home cooks. (It may turn home-friendly should hydrogen-powered cars become common).

4. Reductive amination of phenyl acetone in the presence of methyl amine. This method, popularized by the Hells Angels cooks, produces a racemic crank product that has only half potency of the pseudoephedrine-derived meth. With advent of ephedrine/ pseudoephedrine –based method the old phenylacetone route fell into disuse. Variation of the reductive amination method is still commonly employed in the production of Ectasy.

I grew up in a communist country and I remember the moment when the enormously popular codein headache pills became prescription-only (just as the enterprising chemists figured how to convert it into a fairly potent street version of hydrocodone). Meanwhile ephedrine remained plentiful, being manufactured in town Roztoky for the entire Eastern Bloc. The meth problem in Prague was getting serious – one bottle of cheap decongestant drops contained enough material to produce several doses of meth. But I never got close to the dope-related issues when I was growing up – I was reading books and articles about it once the censors allowed the information about such antisocial decadent problem to be revealed.

Soon after arriving in US, I was asked by the Maricopa County attorney office to volunteer for 20 hours of a community service (because of some very fast highway driving). I noticed that most of my fellow food bank coworkers happened to be paroled men serving out the rest of their sentences on drug-related convictions. To pass the time, sometimes they would make a coment about quality and availability of “stuff” one to another as we were unwrapping boxes of a cheap infant formula – but this had an unreal movie-like quality for me, soon I completed the service and left their parallel universe behind.

Only when I moved to the Bay Area I got face-to-face with the problem. My next-door neighbor in the checkered San Mateo neighborhood was a terminal-stage meth user. A former construction worker, he has lost his job and he was clearly unable to contain himself. He would alternate the dope with heavy drinking (probably to quell the clenched jaw and jittery edginess of the meth high). He was completely manic and very, very angry about injustices that happened to him – he would scream obscenities all alone and he carried long arguments all by himself in his apartment. Sometimes at night I would hear the screaming coming from outside – I would look out and there he was, running back and forth wearing only his shoes and undies – I guess he had a hyperthermia episode so he did some bare-chested shouting along the train-tracks next to our tenement. I remember he also brought a boyfriend over to his place once and they were having a vicious argument next morning and he stood there punching the other guy in the face, right there in the hallway as I was leaving for work. One night the police came over, broke through the window of his apartment and took him away. Unfortunately my neighbor soon posted bail and returned, mad as hell and convinced that I ratted him out (I sure complained to the landlord repeatedly but not to the police – in reality it was his failure to appear in court on a preceding possession charge that got him re-arrested that night). Yet he was sure that I was somehow responsible for his troubles, and he wrote “SNITCH ASSHOLE” on my car and he also threw some eggs at my door – at that point I did call the police and then promptly moved out; my meth-head neighbor was almost 7 feet tall and must have been quite muscular before his habit got better of him.

At that time (six years ago) there was plenty of folks with a growing meth problem in the Bay Area: The dope was cheap, provided a long-lasting high and acted as a great add-on for the active party lifestyle (with Viagra compensating for the most annoying side-effect). One could keep at it for quite some time and feel empowered by it, before washing out as a madman.

Note 1: The manufacture-related information discussed here is available to any unmotivated reader
Note 2: Pseudoephedrine has been phased out in OTC medications, ether is becoming permit-only, red phosphorus and iodine are flagged and so is hydroiodic acid, methyl amine, thionyl chloride, acetic anhydride, phenyl acetone and benzyl chloride. Home possession of hydrogenation equipment is illegal in US. The mandated sentences for meth production and conspiracy to manufacture are harsh; and the unauthorized possession of a sep funnel together with a tubing and aqueous HCl suffices as a proof of intent to manufacture in many jurisdictions.
Note 3: For sordid paranoia-rich bust stories, the reader is encouraged to look up what happened to Hobart Huson aka Strike and to Leonard Pickard + Clyde Apperson


January 7, 2008

3′-(2-amino-1,3,4-thiadiazol-5yl)-benzoic acid ethyl ester

Filed under: procedures — milkshake @ 2:08 am


3-Iodobenzoic acid ethyl ester 13.18g (47.7mmol) solution in anh THF (220mL) was cooled to -78C under Ar. After 20 min a 2M solution of isopropylmagnesium chloride in ether 38mL (76mmol) was slowly added along the flask wall over 15 min at -78C. The flask was placed on a -55C bath and stirred at -55C to -40C for 50 min and then at -40C to -34C for 90 min. The reaction mixture was then cooled back to -78C, anhydrous DMF 20mL was slowly added along the flask wall with intense stirring (a slurry formed), the flask was then placed on a -30C bath and the bath was allowed to expire and reach ambient temperature over 2 hours. The reaction was quenched with saturated aq. NH4Cl (250mL), stirred for 45 min, diluted with water 50mL and ether 100mL, shaken, separated. The organic phase was washed with additional sat. NH4Cl  (250mL) and sat. NaCl (200mL). The aqueous phases were re-extracted with ether (250mL). The combined organic extracts were dried with MgSO4 and evaporated (down to 1.5 Torr, at 40C). The residue was dried on highvac overnight. Y=8.84g (104%) of the crude aldehyde as a pale yellow oil, 94% pure by HPLC, 1H-NMR.

1H(d6-DMSO, 400MHz): 10.103(s, 1H), 8.447(dd, 1.7Hz, 1.4Hz, 1H), 8.254(dt, d: 7.8Hz, t: 1.5Hz, 1H), 8.170(dt, d: 7.7Hz, t: 1.5Hz, 1H), 7.764(t, 7.7Hz, 1H), 4.367(q, 7.1Hz, 2H), 1.350(t, 7.1Hz, 3H)

4.110g (approx 22.18mmol) of the crude aldehyde from the previous step was dissolved in a mixture of acetic acid 20mL and water 10mL. Thiosemicarbazide 2.50g was dissolved in a mixture of acetic acid 20mL and water 20mL with heating, the hot solution was added into the stirred solution of aldehyde. A white precipitate formed. The stirred mixture was allowed to cool to RT. After 1 hour, the precipitated thiosemicarbazone was collected by filtration, washed with some additional AcOH+water 1:1 mixture (2x10mL), then with copious quantity of water, dried by suction and on highvac. The obtained crude thiosemicarbazone (white solid, 4.73g) was suspended in anhydrous ethanol 250mL, iron(III)chloride hexahydrate 21.6g (80mmol) was added and the mixture was refluxed on an 85C oil bath for 2 hours. Charcoal 1g was then added, the mixture was cooled to RT, filtered and the filtrates were concentrated to a small volume (about 30mL). Meanwhile, EDTA disodium salt 35g (94mmol) was dissolved in a mixture of water 200mL and 28% ammonia 20mL. The concentrated reaction mixture was poured in a thin stream into the vigorously-stirred solution of EDTA. The flask was washed with additional ethanol (2x10mL) then with water (2x25mL); the washings were also added to the mix. After 15 min stirring, the precipitated crude product was collected by filtration, washed with water until nearly-white, then dried by suction and on highvac. The crude product (4.36g) was dissolved in refluxing acetonitrile 250mL, the solution was quickly filtered while hot, the Buchner funnel was washed with some additional hot acetonitrile (50mL) and the filtrates were evaporated. The residue was suspended in acetonitrile 40mL, the solids were collected by filtration, washed with acetonitrile (2x20mL), dried by suction and on highvac. Y= 3.780g (80.5% from semicarbazone, 68.5% overall) of a cream-colored solid, about 96% pure by HPLC.

1H(d6-DMSO, 400MHz): 8.304(t, 1.6Hz, 1H), 7.986(m, 2H), 7.623(t, 7.8Hz, 1H), 7.513(br s, 2H), 4.355(q, 7.1Hz, 2H), 1.348(t, 7.1Hz, 3H); LC/MS(+ESI): 250 (M+1)

January 1, 2008

Notes on extraction

Filed under: procedures — milkshake @ 7:55 pm


The emulsions

Emulsions are a nasty. When the phases won’t separate add some brine and gently swirl around (no shaking). If this does not help try to add some ethanol and swirl again. If possible, acidify with diluted HCl or sulfuric acid. If nothing else helps, filter the whole damned emulsion through, using a medium-to-fine-porosity large sintered glass Buchner funnel. This takes some time and effort but it usually does the trick of breaking the milkshake. You can also do the filtration through a plug of charcoal for the extra emulsion-busting effect but you may end up losing some material on the charcoal. (Be sure to use fine porosity funnel as to prevent the charcoal from getting through).

In extreme desperation, chemists were using centrifuge to break emulsions.

You have to expect emulsions with greasy acids in basic conditions and greasy amines in acidic condition. Some compounds are natural detergents – phospholipids for example. One can pair up quartenary ammoniums with greasy anions like perfluorobutyrate or tetraphenyl borate to obtain salts that will extract into organic  – and even separate reasonably on silica column - but these classes of compounds are best not purified by aqueous extraction.
What therefore God hath joined together, let not man put asunder.

Highly soluble compounds

Another class of compounds that should not be purified by aqueous workup are the highly water soluble compounds like polyamines, polyols, unprotected peptides etc. If you have to do aqueous workup, use a minimal volume of water and best saturate it with some salt. Ethyl acetate is the usual choice for the polar compound extraction but in desperate cases one can do multiple re-extractions with a solvent like n-butanol or chloroform+methanol 2:1(v/v) mixture. One shoud expect to extract large quantities of water and salts (sodium acetate for example) into the organic phase when using these alcohol-containig solvents.

In the most unfortunate cases people set up continuous extraction apparatus and let it run overnight - though it is not something commonly seen in the organic lab nowadays. There is always some more convenient non-aqueous workup/isolation alternative.

Please be sure to collect all your aqueous washing and save them until the moment when you hold a flask with your crude product that you can weight.  If you are not sure that you extracted all your product from aqueous phases, run HPLC on them (you can take a sample, blow off organics from it by a stream of nitrogen and apply undiluted onto the column; strongly basic solutions must be acidified to protect the column. It is very pleasing to compare an HPLC of your crude product extract – with the HPLC from the combined aqueous washings that contain all the baseline grass of the impurities you just removed).

Small-scale extractions

If you don’t have a miniature sep funnels the polypropylene 20 mL syringes will work fine for the purpose (the all-plastic kind, without a rubber plunger; the slip-tip syringes are preferable over the luer-lock). I like a needle with sawed-off tip that can be stopped by finger – but other people like to use a sharp needle with a rubber or silicone piece as a stopper.  When you are unstopping the needle do it always with the needle pointed up and with slight negative pressure produced by a pull on the plunger. Squeeze out all air void before inverting the syringe needle down as to prevent your mix from squirting out due to the changing vapor pressure

Please note that polypropylene syringes swell in organic solvents: toluene and dichloromethane swell it quite fast but even ethyl acetate will mis-shape the syringes after while. This will cause syringes to leak over time so it is best to discard the syringes after the extraction.

For small volume extraction done in syringe I like chloroform inplace of dichloromethane – it separates a bit faster (its heavier) and it has a lower vapor pressure.

Small extract volumes can be conveniently dried by direct filtration trough a plug of MgSO4 in a small Buchner funnel (14/20 joint).

Order of washing

The recommended order of washing is diluted acid followed by water (or brine) followed by bicarbonate. One can dry extracts after bicarbonate directly, no additional washing with brine is needed  – drying with MgSO4 takes care of the mild residual basicity - but one should re-wash the extract after an acid wash. (For example citric acid is pretty soluble in ethyl acetate.)  Also washing the extract after acid wash directly with bicarbonate will produce effervescence and pressure buildup in the sep funnel so it is best to add one neutral wash inbetween.

Drying agents

MgSO4 is much more powerful drying agent than Na2SO4 and it comes in different grades – use the the powdered grade, the one that has the consistency of confectioner sugar; the lumpy grade is useless. When MgSO4 fails (typically the mixtures that form stable emulsions also provide milky extracts that are difficult to dry) the comercial 4A powdered activated sieves will work; use Celite plug for filtration from sieves since the powdered 4A sieves have rather fine particles.

Another good drying agent is Na3PO4 and Na2CO3; it works better than K2CO3. (I am not a great fan of KOH or NaOH as drying agents). Since Na-triphosphate and  carbonate are strongly alkaline, they are not compatible with ethyl acetate.

You may want to give the drying agent some time to do its work, like 20 min stirring in a round flask. If you are concerned about dropplets of moisture stuck above the level + on the neck of the flask, you can sprinkle some drying agent onto a funnel that was wetted with the solvent and then wash down the drying agent stuck on the funnel with some additional solvent; that takes care of the problem.

Washing away DMF, DMAc

Both ether and ethyl acetate are the recommended solvets for washing away small volumes of DMF, DMAc, DMSO and tetramethyl urea with water and bicarbonate solution. I don’t know the exact reason why they work better than chlorinated solvents (which tend to extract DMF and others into organic phase) but I suspect the relatively high water solubility of ether and ethyl acetate in water helps to improve the partitioning of DMF, DMAc, etc. into the aqueous phase.

Ether and ethyl acetate can cause some precipitation of salts from saturated salt wash solution (sat NaCl, NaHCO3, NH4Cl) – in that case one should want to dilute the mixture with additional water, to bring the inorganics back into the aqueous phase.

More on extractions here

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