Your colleagues can make you age faster

Credit: Adolf Born

Here is couple of things that always help me – to feel less charitable. The things that make me dream of smell of napalm in the morning:

Silicone oil slick in ultrasonic bath
Strange red crystals all over the bench and chunks of hygroscopic stuff melting on the balances
Keyboard and mouse dissolved into a puddle of plastic goo
Fraction collector racks with the fractions sitting in the hood for weeks at time
Fraction collector that collects in between the tubes after somebody changed the defaults and put a wrong rack in
Mysterious yellow gunk off the prep HPLC column, in your fractions
NMR sample depth measuring device that somebody toyed with
Two spinners on top of one another with broken tubes, in the magnet
Five opened bottles of the same solvent in the shared solvent cabinet
An uncapped bottle of anhydrous non-denaturized EtOH on the bench overnight
A shared reagent bottle that has last few crystals left on the bottom but was not re-ordered
Your new bottle of NaOtBu – left outside your desiccator, half-closed and with a nice crusty layer in it
Swern oxidation, and Borane-DMS worked up outside the hood
Indole, p-chlorophenol and DCC dust on the floor
Crappy pop and gangsta rap playing full blast
Your scissor, pliers, screwdriver that never make it back to you again
Drying stuff from ethyl acetate on lyophilizer
Half-liter of aqueous ammonia evaporated into shared oil pump

(I have observed these atrocities over number of years and couple of jobs. So if any of my current colleagues is reading this, please be assured that this complaint is not about you.)

organic solvents are bad for ya

The Coronene blog brought up a familiar subject – the solvent exposure.  I am not a tox expert myself – but I guess that after few years in the lab one can rank the most-commonly used solvents according to the seriousness of their long-term exposure effects. So here it is the list:

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Almost drinkable: EtOH, i-PrOH, acetone, DMSO, 1,2-propylene glycol

Tolerable: MeOH, EtOAc, butanols, THF, TBME, ether, pentane, heptane, cyclohexane, DMAc, AcOH, NMP, tetramethyl urea, sulfolan

Unhealthy:DCM, toluene, hexane, acetonitrile, ethylene glycol, formamide, DMF, nitromethane, 1,2-dimethoxyethane, trifluoroethanol, benzotrifluoride

Just Bad: Dioxane, benzene, chloroform, 1,2-dichloroethane, pyridine, p-xylene, methoxyethanol, ethoxyethanol, TFA, trichloroethylene, tetrachloroethylene, allyl alcohol, chlorobenzene, biphenyl+diphenyl ether (aka Dowtherm), o-DCB

Gangsta Badass: HMPA, CS2, CCl4, nitrobenzene

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Chemists in synthetic labs should probably have their liver tests and blood count done once a year, to pick up any problem signs related to the chronic exposure. Women in early stages of pregnancy have to be particularly careful when working with organic solvents. Lots of factors can influence relative rates of oxidative metabolism and harmfulness of many  solvents (like dioxane, benzene, hexane, glycol, chloroform etc) is due to the products of their oxidative activation. Some individuals are bound to be more sensitive. 

On a side note, it is interesting how solvent toxicity is species-dependent: EtOAc, dichloroethane and cyclohexane are much more toxic to insects than to humans.

[Pd(py)2].(TFA)2

Pd(OAc)2 253mg (1.127mmol) was dissolved in anh. benzene 17mL (10 min stirring with gentle heating) and pyridine 0.180mL (2.226mmol) was added dropwise over 5 min. The mixture color turned light and a precipitate formed. The closed flask was wrapped in aluminum foil and the mixture was stirred overnight (12 hours). The obtained slurry was evaporated to dryness, the flask with the solid residue was flushed with oxygen and neat trifluoroacetic acid 2.1mL (protein-sequencing grade) was added. The obtained yellow solution was diluted with methanol 20mL and the mixture was stirred under cotton-filled drying tube while wrapped in Al foil for 2 hours. The resulting slurry was filtered through a small medium-porosity frit, the precipitate on the frit was dissolved by gradual washing with 1:1 mixture methanol-dichloromethane (10mL). The combined filtrates were slowly evaporated and the residue was dried on highvac. Y=554mg (100%) of a yellow-white heavy powder. 

1H(CDCl3, 400MHz): 8.512(m, 4H), 7.855(app tt, 7.7Hz, 1.5Hz, 2H), 7.405(m, 4H); 13C(CDCl3, 100MHz): 163.09(q, 37.2Hz, 2C), 151.11(4C), 139.83(2C), 125.70(4C), 114.09(q, 289Hz, 2C)

This is a slightly improved, higher-yielding preparation of a catalyst for the oxidative Pd(II)-catalyzed cyclization of phenols, carboxylic acids and alcohols: Stoltz et al, JACS 127 (2005), 17778-88

Setting up a vacuum manifold

This is a pretty familiar subject that everybody in an organic lab has already dealt with. I have few notes on things that worked for me:

Manifold

Dual-bank manifold (5-fold) with bore glass stopcocks from Chemglass (their new version of it) and the same kind of manifold from Aldrich are both very good for the common organic applications.

I really dislike the manifolds with Teflon highvac stopcocks: their teflon fingers wear out quickly and it is easy to break the manifold if you over-tighten them.

For greasing the glass stopcocks Apiezon grease brands are vastly superior to other hydrocarbon-based lubricants. Apiezon M is somewhat less overpriced than other Apiezons (costs about $60/100g) but it still works better than any other grease brand that I tried. Silicon grease and perfluorinated grease are unsuitable for manifold stopcocks – they cause leaks in the joints.

Vacuum meter

Vacuum meter should be hooked up directly to the manifold, before the cold trap. There are digital vacuum meters on the market but the classical Welsh vacuum gauge is affordable ($600) and robust on continuous use. It is even precise enough to be used for highvac distillation. The Fisher catalog # for this vacuum meter is 11278 (“vacuum gauge 115V 60Hz”).

Bubbler gas outlet/valve

It is good to have a mineral-oil bubbler with a ball that plugs it and prevents a back-suction of oil when vacuum is applied during vacuum/gas back flush on a dual bank manifold. I think it is called Firestone valve after the guy who invented it, even better is if the bubbler valve has an additional shut-of stopcock. One should use the more viscous heavy mineral oil for the bubbler and position the bubbler such that an accidentally sucked-in mineral oil wouldn’t make it into the manifold (one can add a small empty trap flask between the bubbler and manifold). It is a nasty mess if one has to take the manifold apart and clean the oil out.

Cold trap

Many people in academia prefer dry ice trap but adding dry ice and frequently emptying the cold trap is a chore. I like the refrigerated cold traps because they run without much attention and need only infrequent cleaning. They make continually-operating vacuum line very easy to set up and operate. Running the oil pump continually is good for the health of the pump also – if one changes the oil on monthly basis. There is couple of refrigerated vapor trap models on the market, for example from FTS and Thermo-Savant. The cheaper -60C two- or four-liter flask models (about $1500 – 1800) are in my opinion sufficient if one is reasonably careful – evaporating large quantities of super volatile stuff like dichloromethane into the highvac system is bad idea with any setup. (Few mL of highly volatile solvent will pump itself out from the system without any harm over a short time period – if the pump is running continuously).

Isopropanol works fine for the cryo bath in refrigerated vapor traps (the recommended super-expensive silicon cooling-transfer liquid is waste of money).

Thermo Savant has disorganized customer service and long delivery times, also the black rubber caps on the glass insert trap tend to rot and crack after a year or so – one should buy a replacement cap with. (Alternatively, Savant also offers an all-glass insert flask that is much better in my opinion than their standard-issue insert with the rubber cap).

FTS Titan trap is exceptionaly good – but also too large and too expensive; FTS now sells smaller and less expensive models also but I dont have any experience with them.

No cold trap will remove HCl gas. HCl is one of the worst metal-corroding acids – getting HCl into pump will predictably cause it to seize over time; the repair is expensive and the pump is never good ever after. Using an additional KOH pellet or soda lime trap is a good idea if one has to vacuum-dry compounds like acyl chlorides.

Oil pump

Manifold pump should be a two-stage oil pump (with ultimate vacuum below 4 mTorr) and should have the pumping speed well above 120 liters per minute. The pumping speed is the most important parameter and it is a common mistake to buy a manifold pump that is too underpowered for the job.

Old-timers prefer belt-driven pumps for continuous use because the belt-driven pumps tend to withstand more abuse. My complaint about belt driven pumps is that they are too big (for a pump with a decent pumping speed) to be placed under the hood and they tend to generate more heat than direct drive pumps (I don’t know if this is the efficiency thing or a ventilation problem – but I remember having a hood surface seriously hot from a big belt pump that was running underneath). In my opinion direct-drive pumps are now sturdy enough to be run continuously as manifold pumps. I particularly like direct drive Welsh-made Fisher Maxima M12C pump – it has a great pumping speed (230L/min) and the price is reasonable ($1600), the pump is quiet, not too hot to run in a narrow cabinet under the hood (if the backside of the cabinet is removed) and it seems quite reliable and resistant to abuse.

(However I wouldn’t recommend a similar but smaller Maxima M8C pump – because of their lousy lifespan. Almost all the M8Cs that we bough from Fisher have died within 2 years, despite frequent service and warranty repairs. Oil that was slowly seeping from underneath the pump (from a loose seal along the shaft) – a recuring problem that we had with almost all our M8Cs – was a particularly annoying problem.)

If you have both belt-driven and direct-drive pumps in the lab please note that these pumps use different oils which are not interchangeable. Direct-drive pumps operate at more than double rpms of the belt-driven pumps so they use less-viscous oil.

After the oil change, the pump with new oil can take an hour or so to warm up and pump itself out, before achieving its best vacuum.

Vacuum tubing

Tygon thick-walled vacuum tubing is expensive but it is very good for connecting the manifold to the trap and pump. The tubing should be as wide as possible and the connection between the cold trap and manifold should be as short as possible. Rubber tubing has high gas permeability and poor chemical stability so it should be avoided. Butyl rubber is an excellent alternative but it is not transparent like Tygon.

Tygon brand and a common brand vinyl tubing is not good for connecting the manifold stopcocks to the flask or apparatus – one always has to watch out for plasticizers leaching out from the tubing due to traces of organic solventsand getting into the reaction flask. I use the highly flexible natural rubber tubing or – for the really highvac connection to apparatus – the butyl rubber tubing.

For disconnecting the hoses, it is preferable to use a new razor blade rather than sizers when cutting the tubing off the manifold. It is generally a bad idea to try prying the tubing off by force – the glass manifold connectors break off easily.

Leaks and performance

When checking for leaks, one has to start at the pump and keep working his way up to the manifold. If one cannot get below 300 mTorr on a closed manifold, something is leaky along the system (a stopcock for example) – or the pump is going bad. With a good pump setup and a tolerable degree of abuse, 50 mTorr is a good idle vacuum in a common organic chemistry 5-fold dual bank manifold setup.

Update: I have been very fond of  M12C direct drive pumps that we bought initially but I must admit that several of these pumps, especially those pumps we received later in 2007 and in 2008 from Welsh developed a serious oil leak problem, one that seems to be related to faulty seal along the main shaft. This is rather annoying bug, and the Welsh engineer was less-than-helpful and tried to blame the problem on users so that he would not have to deal with that many warranty repairs. I got tired of his excuses and flakiness, and taken together with ridiculously long delivery times (some of these pumps were delivered more than half year after the promised date!) I cannot really recommend Welsh direct drive pumps anymore. If you have the money for it, Leybold pumps have much better reputation for reliability.

Update 2: I also got eventually used to the highvac manifold with teflon fingers – I guess this is what one needs to use with diffusion pump (and liquid nitrogen cooled cold traps) for 5 – 15 mTorr vacuum work needed in polymer chemistry. A bit of overkill for medchem though

Trityl azide is lazy

Before the preparation, sodium azide 10.98g (168.9mmol) was powdered with a spatula and dried in a 0.5L round flask on 80C oil bath on highvac (0.25 Torr) for 90 min. The cooled flask was flushed with Ar, trityl chloride 31.19g (111.0mmol) and anhydrous acetonitrile (about 100mL) was added and the mixture was vigorously stirred at 80C for 4 hours. The reaction mixture was cooled to ambient temperature, the salts were removed by filtration and washed thoroughly with toluene. The combined filtrates were evaporated, the residue was dissolved in hexane 100mL and filtered through a pad of silica 50g. The silica pad was washed with additional hexane 100mL and then with 200mL of 1:1 hexane-dichloromethane mixture. The combined filtrates were evaporated, the residue was dissolved in pentane 100mL. The solution was seeded with a sample of crystalline material*, allowed to crystallize at RT for 1 hour and then in a fridge overnight (+4C, 8 hours). The supernatants were quickly decanted, the crystalline mass in the flask (27.051g) was rinsed with chilled pentane (2x10mL) and then dried on highvac. Evaporating the supernatants and re-crystallizing the residue from pentane (20mL, +4C) provided additional 3.701g of a pure product. The combined yield was 30.752g (97%) of large shiny pale yellow crystals.

1H(d6-DMSO, 400MHz): 7.408(m, 9H), 7.255(m, 6H); 13C(d6-DMSO, 100MHz): 142.48(3C), 128.44(6C), 127.88(9C), 76.98(1C)

Hexane works for crystallization as well. *A simple way to obtain seeds for crystallisation is to dry a small sample of the oily product on highvac, then let it sit in an open flask for a day or two. 

The reaction can also be run in toluene if 5mol% of Bu4NBr is added as solid phase transfer and the azide is powdered thoroughly. Toluene may be a better solvent for process scale-up (the reaction mix can be directly filtered through silica pad, the solvents are not mixed, etc)  but the reaction takes longer to complete and evaporating large volumes of toluene is not fun. Running the reaction in acetonitrile is preferable on lab scale.

Mtr-N3 can be made in the same way from p-methoxytrityl chloride, in nearly quantitative yield as a pale yellow oil.

Trityl azide is easy to work with – it forms gorgeous crystals, is not impact-sensitive and its decomposition occurs well above boiling point of toluene (110C). But it is rather unreactive azide – I tried to use it for making trityl triazoles and the Cu(I)-catalyzed cyclizations did not work on monoaryl alkynes.