dabco, dibromoethane, fieser, formic acid, gilman's reagent, grignard, KtOBu, lithium dimethylcuprate, Potassium Butoxide, Sodium Azide, toluenesulfonyl chloride, vilsmeier, vilsmeier-haack, zinc dust
It’s hard to look back and not wonder what we’ve lost. Organic chemistry is not immune to fickle trends and fashion, and more than one darling of yesteryear lies forgotten in the dusty pages of Tet. Lett. . While I’ve no desire to go back to preparing platonic solids, there’s a few tricks I feel happier to have up my sleeves.
Grignard reactions are notoriously finicky, which is why they are a standard feature in second-year organic chemistry labs. The key lies in initiating the reactions. Exposure to oxygen leaves a thin film of magnesium oxide on the surface of the metal, which weak bromides are unable to pierce.
Ethylene bromide is far stronger than your average electrophile, and will rapidly clear the magnesium oxide. The product is ethylene gas, allowing both a clear sign that the grignard is proceeding and ensuring that no new grignard reagents are added to the system.
2) Toluenesulfonyl Chloride Purification (original unavailable)
TsCl is one of those chemicals that no organic lab will ever be without, in large part due to the fact that someone bought 250 g over a decade ago. Unfortunately, by now what’s left in the bottle has at least partially decomposed to TsOH and HCl.
The cost of regenerating TsOH may be greater than a fresh bottle, but all is not lost. Simply dissolve the entire bottle in about 2.5 mL chloroform per gram of material, then dilute five-fold in petroleum ether. Filter off the resulting impurities, remove any fine impurities with activated carbon, and concentrate off the solvent. The resulting “fine white crystals of analytically pure tosyl chloride, m.p. 67.5-68.5 [degC]” can go back in the bottle, while the TsOH collected during the first filtration can be kept elsewhere for future use.
2b) Potassium tert-Butoxide Purification
A reagent of 1001 uses, KOtBu rapidly hydrolyzes in air to form potassium hydroxide and butanol. Unfortunately this process has no effect on the appearance of the off-white powder, and it can be almost impossible to tell if bottle has gone off. While not mentioned in Fieser and Fieser , here’s a neat trick for purifying the mixture:
Dissolve the powder in a small amount of dry tetrahydrofuran. While potassium t-butoxide has magnificent solubility in THF (25 g/100 mL, according to Fieser and Fieser), potassium hydroxide is so inert it can be used as a drying agent. After filtration of the KOH the solvent can be removed under stringent anhydrous conditions (perhaps an Ar stream), or an aliquot can be mixed with water and titrated to determine the effective KOtBu concentration for a stock solution.
Here’s a nice use for an old reagent. Thiols and thioketones catalyze the reaction of sodium azide and iodine, and the liberated nitrogen can be used as a spot test to detect sulfur compounds.
Nucleophilic substitution with sodium azide followed by palladium reduction is a beautiful way to convert alkyl halides to primary amines, but unfortunately sodium azide has very poor solubility in non-polar solvents. The usual solution is to use dimethylformamide and/or water, but this reagent makes for a nice acetonitrile-soluble alternative . The corresponding halide salt is insoluble in diethyl ether, and can be crashed out following completion of the reaction.
5) The DABCO-Bromine Complex
DABCO binds to bromine quite strongly, and the resulting DABCO-Bromine complexes are good oxidizing agents for the conversion of sulfides to sulfones. Interestingly, this seems to have been rediscovered some 40 years later, with a recent publication in Tet. Lett. on alcohol oxidations.
I’m hesitant to call this reagent “forgotten”, but it is less well known than I would expect. Effectively a soft carbanion, lithium alkyl cuprates replace good leaving groups with inversion of stereochemistry, convert acyl chlorides to the corresponding ketones, and add 1-4 to enones. As an added bonus, these organocopper compounds will also reduce disubstituted alkynes to cis-alkenes.
7) Dimethylsulfoxide and Acetic Anhydride
This combination somewhat surprisingly converts secondary alcohols to ketones.
8) Zinc Dust and Dimethylformamide
Zinc causes rapid bromine elimination, converting alkyl bromides to alkenes. This effect is so strong that it will even break aromaticity, converting o-xylene to a (rather unstable) tetraene.
The go-to conditions for cleavage of hindered acid-labile protecting groups is HCl in MeOH, but occasionally that just isn’t strong enough. Pure formic acid has a bit more kick, and will remove carbamates and acetals (and presumably silyl ethers) much more readily.
10) The Vilsmeier Reagent (Dimethylformamide-Thionyl Chloride)
Ever wonder why chlorinating reactions work so well with a little DMF in the flask? Thionyl chloride, oxalyl chloride, phosphorus pentachloride and phosgene all react with dimethylformamide to form a charged chloroforminium species through elimination of SO2.
This compound has been isolated (pdf), and is a (relatively) mild chlorinating reagent, reacting with alcohols and carboxylic acids to give alkyl chlorides and acyl chlorides, respectively. It also formylates electron rich aromatic rings, via the Vilmeier-Haack reaction.
 Pre-Elsevier’s purchase, of course.
 Or Purification of Laboratory Chemicals, oddly enough.
Edited to add schemes and Vilsmeier link.
The past is a foreign country: they do things differently there.
-L. P. Hartley
Imagine a world without flash chromatography, HPLC, high resolution MS or high field NMR, though if you ask nice you may be able to get time on the department’s new 60 MHz NMR (1D proton spectroscopy only, of course).
In this environment, how did chemists ever determine what lay in the bottom of their flasks? IR is an excellent method for determining which functional groups are present, but like elemental analysis it says very little about how the bonds are put together. Closely related compounds and isomers would be nearly impossible to distinguish by these methods, and so changes in physical properties became key.
While presently chief paperweight , tracking physical properties was what role that the CRC handbook was made for. Older versions of the book had even less of the spectroscopic properties we now rely on for compound characterization, instead focusing on tests we may no longer even routinely perform. Chief among these is of course melting point, but density and optical rotation also receive special mention .
Necessity drove innovation in purification techniques as well. Distillation at reduced pressure can do wonders with low molecular weight oils, and with enough time almost any solid can be recrystallized . Recrystallization solves many of the above mentioned structural assignment problems as well, but unfortunately could not be applied to every case. Oils are nearly impossible to recrystallize and analyze (some do solidify at low temperatures), and many solids have enough disorder to highlight the fine crystallographic distinction between “theoretically possible” and “incredibly difficult.” To combat these beasts several classes of recrystallization aids were devised.
Sodium bisulfite is likely the best known crystallization agent, and the most generally applicable. Aldehydes combine with bisulfite to form stable sulfonic acid/alcohol adducts that are at best sparingly soluble in water. Filtration of the resulting precipitate removes water soluble impurities, while alcohol/ether washes draw off the more organic soluble contaminants. A final exposure to weak acid or base regenerates the original aldehyde, which is then collected via simple liquid/liquid extraction.
Somewhat less amenable were reagents like p-phenylazobenzenesulfonyl chlroide and p-phenylazobenzoyl chloride, which react with free amines and alcohols respectively to form brightly coloured azo dyes. These compounds could be readily isolated by paper or silica chromatography–no stains required –and recrystalized to allow for X-ray analysis, but only through destruction of the original material. Carboxylic acids and amine salts which could do the same were highly prized, and there are far too many to list here. One interesting example is dehydroabieyylamine, which selectively recrystallizes various penicillins. Recrystallization aids fell out of favour in the research lab with the advent of flash chromatogrpahy, but these agents are still very useful for resolving mixtures of chiral compounds.
 The CRC handbooks were giants, because in the pre-computer age they had to be to contain all relevant compounds. The 1963 edition was 3600 pages long.
 Augmenting IR and providing more detailed structural information was of course a multitude of functional group tests. In the 1960′s though their sun was setting, so I’ll cover them another time.
 Cfi. The entire field of protein crystallography.
For the past few days I’ve been at the International Chemistry Biology Society‘s annual conference. True to form I blogged about the talks, highlighting the research I found most interesting (with links, as much as possible).
I’m headed to Kyoto this week for the International Chemical Biology Society’s annual meeting. While there I’ll be livetweeting as @Chemtips alongside Maggie Johns, as well as posting highlights of interesting research to the ACS Chemical Biology community.
If you’re going to be at ICBS 2013, come say hi! This will be my first trip to Kyoto, so I’ll be easy to spot–I’m the one frantically flipping through a Japanese phrasebook.
AKA the Good, the Bad, and the Ugly.
Organometallics aside, the greatest advance since the days of Fieser and Fieser isn’t the development of new chemical transformations . Rather, it’s the gradual replacement of hazardous or toxic reagents with more benign variants. We do much the same work as before, but with greater substrate scope and less risk.
That said, it’s no surprise that water reactive workhorses like SOCl2/PCl3/POCl3/PCl5 have extensive write-ups in Fieser and Fieser. We may no longer regularly run reactions in refluxing benzene (never mind the CCl4 recrystallizations), but with proper technique these are perfectly safe and highly effective chlorinating reagents.
That figure up above is from a reference article, and it shows the lengths chemists used to go to for a little PCl5. Chlorine gas from a lecture bottle is bubbled through sulfuric acid to remove any residual water, then reacted with PCl3 dripping down from an addition funnel. Cl2 is no treat to play with, but it’s a common trend in F2 for even relatively benign reagents to require hazardous preparations .
Pertrifluoroacetic acid is a good example. A powerful oxidizing agent with dozens of uses, CF3CO3H readily converts amines and oximes to nitro groups, installs phenols in mildy activated aromatic rings, and is an excellent Baeyer-Villiger reagent. Unfortunately pertrifluoroacetic acid decomposes on standing, and preparation in situ requires 90% HOOH (ie. propellant grade). Reactions using 30% peroxide and higher generally require the use of an explosion proof screen, and I’m not certain how the 90% solution could be safely stored in a lab filled with organic vapours.
Rocket fuel makes for stressful afternoon, but chemists occasionally get a little desperate. There are limits though, and this last would probably force me to hang up my lab coat and take a week of unplanned vacation.
Oxygen difluoride, better behaved cousin of FOOF, is prepared by passing fluorine gas through a 2% solution of sodium hydroxide. The resulting vapor must first be purified to remove the residual F2 and roughly full equivalent of byproduct O2 produced during the reaction. This is done by cooling the mixture in a bath of liquid oxygen, then fractionally distilling out the desired gas . Once pure, OF2 can be stored at room temperature in large glass bulbs, though it will react violently with silica and molecular sieves. It is described as having a peculiar, foul odor.
Once formed the gas is bubbled into trichlorofluoromethane (Freon 11, now banned by the Montreal protocol) at -78 degC, where it will oxidize alkenes and acetylenes to the corresponding mono- and di- alphafluoroketones. Primary (aliphatic) amines are smoothly converted into the corresponding nitrosos (two equivalents of the amine are lost as the fluoride salt). The whole setup from start to finish is an ugly beast, and I’m happy to say to those looking for a nitroso prep that there are better ways.
 Yes, that’s a pretty big aside. It’s been forty-six years.
 Given the plethora of hazardous preparations I was surprised at how cautious Fieser and Fieser are with diazomethane. Five separate preparations are given, listed in order of preference. Bis-(N-methyl-N-nitroso)terephthalamide is their preferred precursor, but this is 25 years before the first report of TMS-CN2.
 To quote the original authors,
Further purification can be accomplished by pumping
on the trap containing the liquid while it is still immersed
in liquid air. A water pump is best, since the gas coming
off (principally oxygen at first) will eventually cause loud,
but not damaging, explosions if it comes in contact with the
oil of an oil-filled pump.
The 1960′s were a heady time. The Varian A-60 made it’s debut early, marking the beginning of routine NMR analysis, while research by Woodward and others demonstrated the power and adaptability of organic chemistry (for which he received the Nobel in 1965). The literature was booming, and the fourth volume of Organic Syntheses was larger than the first three combined.
If structural complexity was limited only by one’s imagination, work in the lab was considerably more challenging. Though founded in the mid-fifties, the rise of Aldrich was still well over a decade away, and fine chemical manufacturing was in it’s infancy . Aside from the few hundred bulk chemicals used in industry, if a reagent was needed for a particular transformation the only recourse was to prepare it in the lab.
Chemists of the period turned to Fieser and Fieser’s “Reagents for Organic Synthesis.” Essentially a chemistry cookbook, the twenty-six volumes of Fieser2 explain the use and preparation of the sort of mid-level reagents we take for granted, like sodium borohydride and acetyl chloride. Volume 1 in particular has a reputation for sound advice and useful tips, even now, and has been on my to-read list for quite a while. Unfortunately there’s far too much information to list everything in a single blog post, so I’ve divided things up into broad categories. Click through for the first post in the series;
Labour Day has come and gone, unofficially marking the end of summer 2013 . At least we have photos.
Natalie of Picture it Chemistry fame then went for a jaunt to the Bristol Botanic Gardens, for a look at natural product chemistry in its native habitat. There’s a nice tie in to the carboniferous forests of the distant past, highlighting how even modern oil-based reagents still ultimately stem from plants/animals/bacteria.
And now it’s back to the lab. If I missed your contribution to the carnival (or you have strong opinions on the difference between a canyon and a gorge), please let me know.
 The number of people on campus has increased by an order of magnitude, and every morning is cooler than the last. According to the calendar autumn starts in three weeks, but this far north I’m calling it early.
*The post is my contribution to the #ChemTravelCarnival. If you’ve written a travelogue (or want to) let me know!*
Geology is applied chemistry, on the million year timescale. The forces we take advantage of in the lab–acidity, Brownian motion, temperature control–work wonders on the ground beneath our feet, slowly shaping the landscape.
Last month I took a trip out to Maligne Canyon (muh-leen) in Jasper National Park . The canyon was one of the highlights of my summer, both because of the beautiful scenery and because walking through the canyon was like looking back through time.
Much of the eastern half of Jasper park is built on limestone, layers of calcium carbonate that formed from crushed seashells millions of years into the past. As the Maligne river flowed over this bedrock, dissolved sulfates and carbon dioxide (as carbonic acid) slowly dissolved the streambed, cutting a series of waterfalls into the ground.
The path of the canyon is set by the flow of water, and the water is often caught in small eddy pools. Over time the constant circular motion erodes the soft rock walls, forming small hollows as the streambed sinks down. Occasionally the river will change course, and a narrow circular shelf is left behind.
At points the canyon is at least 40 metres deep, but only a few metres wide. Moss clings to the walls, living off the spray of water and faint sunlight, while small trees find purchase in the shelves left by eddy currents. Occasionally a larger tree will fall and be caught by the rock face, hanging suspended. More rarely a boulder will do the same, forming a natural bridge from one side of the canyon to the other.
Even without erosion the rock around the canyon is porous, filled with alcoves and tiny caves. In the largest of the alcoves birds nest, though as they are strictly nocturnal none were visible on my trip.
About fifteen kilometres upstream a rockslide buries the majority of the Maligne river, and not all paths back to the surface are the same length. The flow of water increases significantly as we move down the canyon, with dozens of small rivers emerging from the rock .
By the end of the canyon the narrow stream has become a broad river, and all the caves and cliffs are left behind. Eventually the river will join up with the Athabasca river, winding its way north until it drains into the Arctic Ocean.
True to its glacial origins the Maligne river is bright turquoise, heavy with nanometre stones called rock flour. Rock flour has its origins in movement of glaciers scraping deep cuts into bedrock . However, that story belongs to another trip.
 Technically the canyon is a gorge. Yes, that is confusing.
 This underground network of caves between Medicine lake and Maligne canyon is almost certainly the most extensive in Jasper, if not the Canadian Rockies. Unfortunately, all attempts to explore it have met in failure, with even the broadest tunnels quickly ending in cave ins. Water can seep through the cracks, but little else.
 One theory for the formation of Maligne Canyon (shown in the first image above) is that the gorge was originally an underground stream. Movement of glaciers above wore away ground above, until the water was exposed.