Org Prep Daily

April 1, 2013

It curdles if you don’t stir it

Filed under: mechanisms — milkshake @ 5:07 pm


Trityl group on sulfur is unstable to LiAlH4 reduction. It falls off as triphenylmethyl anion – that’s where the gorgeous blood-red color is coming from. (Unlike trityl cation, which is canary yellow). I did not know about this S-trityl instability – my Greene book (3rd edition) for example mentions only the electrochemical reduction at highly negative potentials – and so I presume it is not as widely known.

In my hands, sulfur de-tritylation with LAH happens both with primary and secondary thiols protected as trityl thioethers. The rate of trityl loss seems structure-dependent: metal coordinating groups (such as OH, amino) in the vicinity of sulfur accelerate the LAH-promoted de-tritylation to a point that it cannot be avoided even under mild reaction conditions. In such cases all that remains to be done is completing the de-tritylation by overnight reflux and isolating the free-thiol product from the Al basic salt cake after the usual Fieser workup. The thiol actually ends up stuck within the salt cake as a thiolate; the filtrates contain only triphenylmethane.

Trityl-S group seems to be reasonably stable to borane-THF at room temperature.

Update: Trityl-O reductive cleavage to trityl anion is also facile, it takes place at room temperature with potassium naphthalenide solution in THF


October 29, 2012


Filed under: industry life — milkshake @ 6:56 am

I have been making water-soluble polymers with biomedical applications for the last 16 months and it is quite satisfying: Our macromolecules are usually well behaved – they extract into organic phase. They precipitate as a snow-white fluffy crystalline solid, on a kilo scale. They even have beautiful NMR spectra. Unfortunately, such was not the case with the frothy mixture in the picture. I had to isolate the material from a solution in concentrated HCl (0.3L), with extra sludge of inorganic salts and assorted gunk that included gram quantity of dimethyl sulfide.

The usual process would be: dilute, filtrer, dialyze. But dialysis is a slow and rather frustrating business and we don’t even have bags giant enough for removing few mols of salts and HCl. So I was delighted to learn that ultrafiltration is a turbo-alternative to a dialysis – instead of steeping a swollen dialysis sausage bag (that can burst overnight) for days and waiting for the diffusion to run its course, an ultrafiltration setup visibly labors for you: the pump pushes the mixture against a semi-permeable membrane, water and other small molecular weight material leak out, the macromolecular fraction stays in. The purification is done in few hours.

The peristaltic pump in the picture circulates the crude mixture at moderate pressure and high flow rate (20 psi, 1.7 L/min) from the beaker to bottom of the column; the stuff that flows out at the top is fed back into the beaker in a closed loop. The column consist of a bunch of spaghettini-like capillaries that are coated with a semipermeable membrane. The spaghettini are housed in a plastic pipe casing. It is inside these capillaries that the mixture rushes through at high speed over and over again – water and small molecule material that leaks out through the walls of the capillaries collect in the casing and flow into waste (the sidearm and the transparent bottle). One has to keep adding water into the beaker quite often because with a good column + pumping rate/pressure the mixture gets concentrated rather quickly.

The time to end the purification is when chromatography (GPC) can no longer detect small-molecular weight impurities. Of course with a whopping excess of HCl at the beginning, one doesn’t need to run GPC to confirm that all low-molecular weight material is gone – a pH paper will tell you that. (A sniff test for dimethylsulfide presence is also fast … and revolting…)

September 5, 2012

S-tritylthioacetic acid

Filed under: procedures — milkshake @ 6:53 pm

Neat mercaptoacetic acid 24.0g (260 mmol, about 18 mL) was added in one portion to a solution of trityl chloride 58.0g (208.0 mmol) in benzene 200mL (non-anhydrous, ACS grade). The flask was equipped with a gas outlet Drierite tube and the mixture was stirred for 17 hours: The HCl gas evolution ceased at this point and a heavy white material precipitated out from the reaction mixture. The reaction mixture was stirred under mild vacuum (50 Torr) for about 20 minutes to remove dissolved HCl. The solids were collected by filtration, washed with a small volume of benzene (2×10 mL) and with copious amount of hexane, then dried by suction.

The crude product (57.7g) was dissolved at reflux in benzene 250mL (100C oil bath) and the solution was left undisturbed for 1 day at ambient temperature. The supernatants were decanted off and the obtained crystalline mass was suspended in a small volume of benzene. The solids were collected by filtration, washed sequentially with benzene, cyclohexane and hexane and dried by suction, then on highvac. Y= 54.19g (78% based on Trit-Cl) of white coarse chunky crystals.

1H(CDCl3, 400MHz): 9.96(very br s, 1H), 7.32(m, 6H), 7.19(m, 6H), 7.12(m, 3H), 2.93(s, 2H); 13C(CDCl3, 100MHz): 176.1, 144.0(3C), 129.6(6C), 128.2(6C), 127.1(3C), 67.4, 34.6; TLC: CHCl3-MeOH 10:1 detected with UV and CAM, Rf=0.6

Note: The thiol reactant does not need to be present in excess but mercaptoacetic acid is cheap and its odor is quite tolerable – and adding more helps to improve the crude product purity and yield. This base-free thiol tritylation proceeds faster in more polar solvents like dichloromethane or dichloroethane but the reaction is then accompanied by a promptly vigorous HCl evolution and could be difficult to control on large scale. In benzene, the product gradually precipitates from the reaction mixture in a fairly pure form – this makes aqueous workup and evaporation unnecessary.

Benzene as a reaction solvent can be replaced with benzotrifluoride PhCF3 (400mL for a 58g scale experiment. Cooling on ambient water bath, 4 hours at RT) but PhCF3 alone does not work for recrystallization of Ph3CSCH2CO2H because the product is poorly soluble in it. Also, attempts at replacing benzene with toluene for recrystallization provided product of somewhat inferior purity so two recrystallizations from toluene (2 x 0.5L) were required.

Update: 2-mercaptopropionic acid can be tritylated without a base under similar condition but at elevated temperature: PhCF3 as a solvent, R.T. to reflux (distilled off a small volume of solvent until HCl evolution ceased, then at R.T. overnight. The precipitated crude product was collected by filtration, washed with hexane, dried and re-crystallized from PhCF3 to yield a pure product in 85% yield). 1H(CDCl3, 400MHz): 7.47(m, 6H), 7.29(m, 6H), 7.22(m, 3H), 3.05(q, 7.2 Hz, 1H), 1.211(d, 7.2Hz, 3H); 13C(CDCl3, 100MHz): 179.6, 144.3(3C), 129.8(6C), 128.1(6C), 127.1(3C), 68.4, 42.6, 18.6; TLC: CHCl3-MeOH 10:1 detected with UV and CAM, Rf=0.65

August 2, 2012

Shake and pray

Filed under: lab destruction, procedures — milkshake @ 6:16 pm

There is a pop-chem procedure on YouTube that I find astonishing – it beats the Diet Coke and Mentos trick hands down:

A guy loads NaOH dry solid pellets, about 1 inch high, into a plastic bottle, and adds about 2-3 inch thick layer of dry ammonium nitrate granules. Then he fills the bottle with ethyl ether and adds a good chunk of lithium metal foil. He screws the cap on and swirls the mix around. God have mercy.

This man is not building a home-made ANFO for roadside bombing. It is not going to be a Molotov cocktail enhanced with a metal/oxidizer, or perhaps a crude rocket. He is making a batch of meth by the Shake and Bake method. As he ads a pack of ground pseudoephedrine pills, he squirts in a small amount of water, caps the bottle and starts shaking real fast. The water initiates a vigorous and pretty much uncontrollable reaction of the lithium metal with ammonium nitrate. The solids in ether gradually liquify and become a bottom layer sludge – this all is accompanied by evolution of  copious amounts of ammonia and hydrogen. So he shakes this thing by hand and he periodically vents the ammonia by loosening the cap  when the plastic bottle bulges up too much. Eventually the reaction slows down, the majority of lithium metal gets dissolved and the leftover lithium pieces floating on top of ether attain a bronze/copper hue, this marks the completion of the reduction. The ether layer is decanted into a small plastic bag, saturated with HCl gas (evolved from another soda bottle with sulfuric acid and NaCl) and the hydrochloride salt crashes out and is collected on coffee filter and dried. The yield is about 1-2 grams of a hilbilly-grade crank in form of a white powder, from one large pack of pseudoephedrine pills, about 2 hours start to finish. No glassware anywhere.

The method does not scale – attempts at running bigger batches end in self-immolation. A common error is adding too much water at the beginning, which leads to uncontrollable takeoff:  the whole ether/ammonia/NaOH/NH4NO3/Li brew squirts out. One can try and keep the lid on an a bulging soda bottle by a sheer force but as the Li metal floats on top and fast reaction makes the chunks of lithium pretty hot,  they tend to burrow through the plastic wall and an impressive stream of flaming goodness rushes out with them, delivering bright red and yellow-colored ether flames accelerated by ammonium nitrate and lithium metal all over the place. As one skin graft patient observed “I haven’t seen stuff burning this fast before”.

The Shake and Bake meth is a twist on the classic method using Li metal with anhydrous liquid ammonia/ether. The outdoor storage ammonia tanks are now getting watched and additives are introduced into agriculture-grade NH3(l) so as to ruin its usefulness for dissolved metal reduction. Hence the soda bottle modification for ammonia generation in situ. No need to go to fields, now you can cook in the safety of your home…

Note: It would be easy for a manufacturer to add some organic soluble iron compound like Fe(acac)3 or ferrocene to the ether-based starter fluid  and likewise a small pinch of FeSO4 to the ammonium nitrate in cold packs and lye/drain opener. A finely divided iron promptly decomposes Li metal solution in ammonia to lithium amide and so it would make these materials useless for home brewing.

January 30, 2012

Potassium hydride self-ignition

Filed under: lab destruction — milkshake @ 1:40 pm

I had a rather bad fire last Friday. I was washing a large jacketed glass reaction vessel used for polymer scale-ups, after pouring the reaction mixture out, and a tiny particle of potassium hydride (from this poorly quenched reaction) that was adhering to the bottom of the reaction flask ignited just as I was giving the flask a proper acetone rinse. So I had a flaming flask in my hands + burning hands + flaming sink in front + a whole bunch of wash bottles ablaze next to me (plastic wash bottles peeing their burning solvents around…) A colleague promptly put the fire out with a mid-sized CO2 fire extinguisher before the flames spread any further. There was no damage to the lab, my fingers or the reaction mixture but it was a pretty scary situation – considering how fires in organic labs can get out of control so fast.

Potassium hydride pyrophoric nature is well documented in the literature; from my limited experience I would say KH is quite comparable to potassium metal in its tendency to flame up. But there are some aspects that make KH more treacherous than K metal: KH in paraffin or mineral oil is docile and only when the oil or wax is washed off the pyrophoric nature becomes apparent. Also, the KH appearance (a grayish-white powder) is less dramatic than shiny low-melting globules of K metal and one cannot easily guess whether KH is fully consumed or quenched by the sediment appearance if the reaction produces inorganic precipitate of its own. Also, I noticed that some alcohols react with KH in THF surprisingly sluggishly while reaction of other alcohols is prompt – I believe the solubility of the K-alkoxide in THF plays a role and the KH particles may get coated by a poorly soluble material and laze about the bottom – and then at some later point flame up when least expected.

Since K-alkoxides have significant reactivity advantages over Na and Li alkoxides in alkylation reactions[2], and since the easy-to-handle KH formulation in paraffin wax is now commercially available, it is likely that KH will get used increasingly more often in place of NaH. Despite its innocuous appearance KH is less tame than NaH;  having unreacted KH excess present in the reaction mix makes it prone to auto-ignition during the workup if the reaction was not quenched with care.

Note 1: I was impressed how good is CO2 extinguisher for large solvent fires – and it leaves no mess behind. I don’t think a dry powder extinguisher would have worked nearly as well.

Note 2: Taber et. al.: Tet. Letters 51 (2010), 3545-6

January 18, 2012

Replacement process solvents

Filed under: procedures — milkshake @ 1:45 pm

A recent Organic Process R&D editorial (thanks Chemjobber for pointing it out) publicizes Pfizer Process Group green solvent replacement chart that discourages chemists from using solvents that are either known to be toxic, dangerous to use on large scale or are expensive to dispose as waste. OPR&D makes it now a submission policy that if you used a problematic solvent in your work you have to demonstrate in your paper that you tried (and failed) to find more process-friendly alternatives. I think it is a sensible policy for a chemical industry process journal (and it probably makes the editors job of rejecting marginal manuscripts easier).

Also, Innocentive challenge was recently promising an award (up to 8k) to a winning proposal for replacing dipolar aprotic solvents like DMF, DMAc, NMP with less enviro-problematic alternatives.

I have few comments on the recommended solvent replacements in the table:

1) Acetonitrile is a perfectly good replacement of other dipolar aprotic solvents for things that dissolve in it, unfortunately MeCN dissolving power is quite poor. On the other hand, DMSO is famously bio-innocuous and it dissolves almost anything organic, and quite a few inorganic salts as well. But DMSO properties can complicate the workup, and DMSO can participate in quite a few unwanted sidereaction. I think overall DMSO is a pretty good media for alkylations that involve a reactive nucleophile. If the alkylating agent is highly reactive one might end up with S-alkylated DMSO-derived sideproducts although for many reactions this is not really a problem. Boiling DMSO has oxidizing properties and gives off Me2S funk so the reactions run in DMSO should not be heated above 140C. For acylations (where DMSO would interfere badly) an inexpensive eco-friendly solvent to try is 1,2-propylene carbonate, perhaps diluted with MeCN or DCM to cut down on this high-boiling solvent and to lower the viscosity. Propylene carbonate stability is quite remarkable – it tolerates alkali metals – but I would not heat it with alkoxides and reactive amines, the same limitation as with DMF and NMP. Another possibility for acylations is sulfolane-MeCN mixture. Adventurous eco-fanatic types may even go for triethylphosphate, another cheap degradable goo.

2) A suitable alternative for replacing DCM and DCE in many reactions (but not for AlCl3-promoted Friedel-Crafts) is trifluoromethylbenzene, bp. 102C.

3) For pyridine replacement the chart recommends NEt3 but I think N-methylmorpholine would be a closer surrogate/better alternative – NMM it is much less basic than NEt3 thus less prone to cause ketene-related dark impurities and racemizations during acylations, and it is a better solvent also. A strong fishy reek of NMM is a bit put-off though. If one so desires, Grignard reagents can be prepared in NMM.

4) One relatively underused process solvent is di-n-butyl ether. Its odor is annoying, the boiling point is quite high (142 C) and the dissolving power of Bu2O is not great but this solvent is cheap to buy and easy to dry. Room temperature lithiations with BuLi that require an etheral co-solvent might be a good pick for Bu2O (THF gets cleaved with BuLi at room temperature at appreciable rate, MTBE is pretty inefficient for solvating Li)

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