The past is truly a foreign country.  From the letters to the editor page of Chemistry and Industry, December 19th, 1964 (page 2096):

Ingenuity in the Lab

Ingenuity in the Laboratory

SIR, — In the far-distant days of my youth, I once formed part of a group of young chemists newly recruited to a laboratory in the very early stages of its fitting-out.  The equipment was then so sparse that although well stocked with reagents, the available apparatus lacked those necessities which enter into the brewing of the cup that cheers.  I still remember, oddly enough, that a large weird-looking tripod stand, bearing a rotatable numbered ring, subsequently identified on later arrival of the missing parts as an immersion refractometer, was adapted for use as an exciting roulette and served to mitigate the boredom of our enforced idleness.

The traditional “elevenses” being denied us, youthful ingenuity soon led to the discovery of a satisfactory ersatz assuagement in the form of a mixture of absolute alcohol and ethyl acetate, suitably diluted with a solution of chloroform in water.  Fortunately for us, the arrival of Bunsen burners, flasks, etc. coupled with an official check on the stock of alcohol, soon saved us from premature addiction to the morning cocktail.

Years later, a visit to the U.S.A. during prohibition days gave me the opportunity of vividly recalling the potency and special bouquet of our tipple.

Yours faithfully,

8 Fairgreen Court,

Emphasis mine.  As though breathing solvents isn’t bad enough.


Finding Alkyl Halides in 13C NMR



Hat tip to a recent talk by Chris Braddock.

79/81Bromine and 35/37chlorine are easy to see in a mass spectrum, as their isotopic abundance leads to characteristic M/M+2 molecular ion ratios (1:1 for bromine, 3:1 for chlorine).  Still, it can be tough to determine the exact location of said bromine/chlorine by NMR, especially if the compound contains a mix of halides.

13C functional group shifts. The 0-50ppm region is a little crowded.

13C functional group shifts. The 0-50ppm region is a little crowded.


However, with the varied atomic mass the bromine/chlorine isotopes have slightly different C-X bond lengths.  This means the carbons experience ever so slightly different environments, with a corresponding change in shift [1].   Alkyl chlorides experience a change of about 0.1hz, enough to see peak doubling on modern spectrometers (turn off window functions/apodization).

1-Chloro-3-Iodopropane NMR (close-up)Unfortunately bromine causes less than half the same shift, a difference that’s invisible absent extremely high fields or custom pulse sequences.  Under normal conditions the bromine-induced doublet instead shows up as a single peak, about 50% broader than the other carbons in my survey of 1-bromopentane.



[1] The clearest explanation I’ve heard is that the shorter C-X bond length slightly shields the carbons, by bringing electrons from the halide closer to the carbon’s nucleus.  Potentially an oversimplification.

What To Look For When Joining A Lab

aka The Life Cycle of a PI aka The Five Types of Profs You Might Work For


Labour day is around the corner, and so is the start of the school year. To help those looking to join a research group I’ve put together a list of the major phases in most professors’ career.

First, a couple of qualifiers. The most important thing when looking for a potential supervisor is their personality. If you get along with a person (and love their research) you’ll likely do very well in their lab, all other factors being equal. That said, when looking for supervisors at the graduate and postdoctoral level I only considered labs that fit the following equation:

Number of papers per year / Number of students ≥ 0.75

That is, for every student in the lab the PI should publish at least 0.75 papers per year (preferably >1, maintained over the last 5 years). This is a high bar, but goes a long way to taking the luck out of a scientific career [0]. Publications are the currency of academia, and regardless of the quality of the lab an extended period of no publications will make it difficult for you to get scholarships, fellowships and grants [1, 2] .


1. The New Hire

Often mistaken for postdocs (or grad students), newly minted assistant professors are a high-risk, high-reward option. At least a plurality of the department believes their research ideas are red hot (otherwise someone else would have the job), but a new professor has no proven track record of independent research or lab management, and their chief source of funding is an ever diminishing start-up grant.

This is the one period where the interests of professor and student are perfectly aligned. New profs live or die by the research output of their students, and so they provide excellent one-on-one training. The first few hires in the lab (graduate or undergrad) will be ideally placed to gain many useful skills, and will reap the lion’s share of the early pubilcations. While a letter of reference from a junior faculty member may not carry as much weight as a professor near retirement, they are also much more likely to be effusive in their praise, and (provided the lab is successful), students will have a solid publication record to stand by.

For postdocs the view is less rosy. Close to the New Hire in experience, a postdoc gains far less from their intensive supervision. Recently postdocs themselves, new professors are also weak in many of the skills that postdocs lack (grant writing, lab management), and so can offer little in the way of training. Worse, the junior professor is just starting out in their independent career, and needs to show a strong ability to create original research. They may be less willing to share credit, and have not built up an extensive network of collaborators.

2. Tenure-track

After 4-6 years a prof can no longer be called a new hire, and working in their lab will be an entirely different experience. Startup funding has given way to early career grants, and the PI has a solid reputation for work in their particular field.. At this point official promotion from assistant to associate professor is either a foregone conclusion or has already happened (otherwise stay far, far away).

In the lab, the first hires are in the process of writing and defending their theses (if they are on track for an 8-year PhD that’s another red flag), and those red-hot ideas that got the professor hired are coming to a close.

The most important factor for the success of an incoming student will be the next round of ideas. Outside of the Ivy league, years 5-10 will be a period of growth for the lab, as initial successes lead to increased funding. It’s a good time to arrive, provided that there are some good ideas to soak up all this new funding [3] . Look for vision, and a clear idea of how the initial works are going to advance. A philosophy of “more of the same, but bigger” can lead to diminishing returns, but with steady funding good profs can strike out into more ambitious territory, with a corresponding boost in impact.

3. Stability Sam

By mid-career an academic has survived both the tenure process and at least one bitter departmental feud. Outside of the odd move, labs that reach this point often exist in a stable equilibrium for a decade or more, old students graduating and being replaced by the same people with different faces. The PI is unlikely to take that fateful trip to Stockholm, but they are well respected in their field, with a dense network of collaborations.

The quality of a mid-career lab can usually be determined from the publication to student ratio, normalized over the last five years or so. Provided the lab culture is good, most labs in this phase will be good to join, especially as a graduate student. One caveat: in this period the burden of ingenuity starts shifting to the student, especially in the experimental details. Time away from the fumehood can translate into a dulling of chemical intuition, and it’s during this period that input from the experienced members of the lab (graduate students or postdocs) becomes important.

4. The Bigwig (Chair, Director, VP Research, etc.)

Broadly speaking, two types of people head into administration: those who have lost much of the original fire that drove them to research, and those with so much fire that one lab is not capable of creating all the change they seek [4] .

Regardless of motivation, administration draws much of these academics’ time, and their research often suffers. If their labs remain productive through the administrative term (and even absent oversight momentum will carry a good publication rate for ~3 years), it is likely that there is a strong guiding hand or culture at the lab level, often either from senior graduate students, postdocs, or research associates. As always, talk to peoiple in the lab—and take the pessimistic ones reports with a grain of salt—and get a feel for the lay of the land.

In the event of an absent PI the lab may still be an excellent fit [5], especially for those with prior training and strong, self-directed work ethic. The chair has first pick of departmental resources, and a good letter of recommendation can carry a lot of weight, especially if they have a history of great research.

5. The Greyhair

Not yet emeritus, these form the old guard in many departments. Those still actively involved in research are adept at departmental politics (expect them to have the nicest offices), and have established a nice, productive routine.

In the lab this may translate into an incredible depth of knowledge, a walking treasure trove of reactions and papers stretching back to the ’60’s. This is excellent for problem solving, but can lead to research calcification. After all, what use are new methods or approaches when the old strategies work just as well? (Especially if the lab has previously developed their own solution.)

Success in this environment depends on working at the edge of the lab’s expertise, either on projects with little history or by completely in the wilderness. With subjects the PI is less comfortable in their wealth of understanding can lead to new insights, and the high impact publications that result. This of course forces you to become an expert in something slightly outside the lab’s speciality, which is great for future job prospects but can be demanding and time intensive without a proper background.

[0] Beware large labs especially.  With 20+ people they will ALWAYS be publishing great work, but this is true even if only 30% of the students are productive.

[1] My favourite counterexample is the double-Nobel prizewinner Frederick Sanger. He published at a rate of 2-5 papers per year for his whole career, and did most of the work either himself or with the aid of a handful of technicians. A graduate student in that lab may not publish much, but they’d get incredible training.

[2] Beware a high concentration of papers with a single (student) lead author. It’s great to BE the golden boy/girl, but much less fun to be one of the many in the shadows.

[3] This is not to say that incoming students won’t have ideas of their own, or have nothing to contribute. However, a PI is committed by way of grants and interest to particular topics and projects. Students to greater or lesser degrees control HOW projects evolve, but it will be some years before most can propose an entirely new research focus.

[4] A third type is occasionally seen, and is best typified by the phrase, “Somebody had to do it.” Their research output tends to mimic those who have lost their fire.

[5] Ie. Expect one or two one-on-one meetings per year.

Five Fact Friday

Toluene will azeotropically remove most solvents, except toluene. A good hivac pump is gold.

Potassium t-butoxide can be purified by dissolving in tetrahydrofuran, then filtering off the solid KOH. 25 g of KOtBu will dissolve in 100 mL THF.

The best source of perfectly dry DMSO is usually a fresh bottle or ampoule of D6-DMSO.

That thing in your oil bath is probably a thermocouple, not a thermometre.

You usually don’t have to go through the university library to access a paper off-campus. Most libraries funnel their off-campus traffic through a proxy server, and you can just copy the redirect from your browser’s history. Add the redirect after the .com of the journal site, but before whatever comes after.

eg. http://pubs.acs.org/journal/orlef7 becomes http://pubs.acs.org.login.ezproxy.library.ualberta.ca/journal/orlef7


Getting through the “black tar phase”

Lately I’ve been stuck in synthetic limbo, a single transformation consuming months of work.  With ample time to think I’ve tried to optimize my workflow, and the broad strokes are outlined below.  I’d be (very) interested to hear from anyone who’s found a different way through.

Fail early, fail often

An implicit assumption in this plan is that the bulk of what I do is wasted effort. Almost all of the reactions are going to fail, while the few that succeed may be low yielding or give products that rapidly decompose, even in the reaction vessel. Depending on the compound common analytical techniques like mass spec. and NMR may be unreliable or exceedingly difficult to interpret. In short, it’s going to be a bumpy ride.

Mentally, the key for me has been to dissociate the ego from the chemistry. It’s easy to get excited when something works and sad when it doesn’t, but the only way out involve a lot of bad news.  Since failure can’t be avoided it has little bearing on your skill as a chemist–you aren’t the first to go through a bit of a rough patch and won’t be the last.

From Baran's Welwitindolinone A synthesis.  At least they got cake.

From Baran’s Welwitindolinone A synthesis (link)At least they got cake.

What’s a win, anyway?

Let’s start by defining success.  The goal is compound XXX, but the various reaction vials aren’t going to shout out their contents.  Purifying each and subjecting the contents to full NMR/MS analysis is incredibly time consuming, and if each run requires a column you’re going to have plenty of time to memorize the treaty of Westphalia.

So ideally we’ll look for the compound of interest in the crude, after either the workup or quench. If you’re lucky enough to have a standard of the material you need to make (and it’s stable), TLC is simple, fast, and informative. I have a preference for multi-coloured stains like anisaldehyde or vanillin, which discriminate spots based on structure as well as Rf.

Crude NMR also sits in the “simple, but powerful” bracket. While I generally don’t run crude NMRs during routine synthesis, a quick scan of the proton spectra will reveal the presence or absence of key peaks, again saving you the time and effort of a tedius workup/purification. This works best for reactions that give >5% yield, as otherwise the peaks of interest tend to be buried in the baseline (longer scans will reduce throughput, which may or may not be a concern).

If you don’t already have a sample of your compound of interest, a different approach is required. Mass spectrometry is the easiest way of spotting a single compound of interest among dozens of byproducts, and nearly every lab has access to at least a basic instrument. GC(-MS) and LC(-MS) both go one step further, giving information on the yield and removing contaminants which might otherwise quench the MS signal. The ideal system may be an automated LC-MS, which is more useful than TLC [1].

Measure twice, cut once

Once you can definitely say if a reaction is successful, it’s time to find a few dozen to try. As the project goes on expect to spend significant amounts of time on Scifinder/Reaxys digging up obscure 1970’s protocols, looking for new conditions and reagents. Don’t worry about trying the obscure and implausible, as presumeably you’ve already tried the conditions most likely to work [2].

Once you have 5-20 papers picked out, start setting up reactions. I’m a big fan of vial chemistry at this stage, for the simple fact that multiple round bottomed flasks don’t fit on stir plates very well. Your starting material is likely precious, so restrict quantities to the smallest amount needed for analysis [3].

Take the time to do things properly. Work only with pre-dried glassware, maintain an inert environment, control the temperature, add reagents slowly, and mix well. Every reaction is new, and it’s hard to know in advance which require special care to work properly. The only thing worse than running 100 reactions without success is running 200 because one that should have worked failed due to a temp. fluctuation or math error.

Limit break

Most reagents will fail to react, while the broad remainder will decompose the starting material. Double your reaction load and try to make every reagent do both, by chilling the reactions that decomposed and heating/forcing those that did nothing at all. If you don’t see product under both gentle and forcing conditions, move on. In the absence of a confirmed hit (ie. a good NMR or LC-MS spectra) I haven’t found it useful to try a full suite of conditions for each reagent, but exploring the limits on either end gives information quickly and cleanly.

Learn from your successes

Eventually you’ll move forward, with one or more reagents forming the compound of interest. With several results the next step is clear: take the highest yielding or most accessible reagent and optimize the conditions, varying the temperature, time, solvent, proton source, catalyst equivalents, etc..  Again, yield by NMR or GC/LC/HPLC traces will save time over a full purification.

If the best reaction remains low yielding after optimization, in my limited experience it’s time to get a better understanding of what’s going on in the flask.  Either set up the reaction in an NMR tube, or if that’s not possible quench the reaction at various timepoints and do a set of crude NMRs or GC/LC/HPLC runs. Either approach gives qualitative information on the kinetics of the reaction(s), which can be used to determine if the low yield is due to transformation of the starting material into various side products or simply the result of decomposition of the final product.

Side product formation is probably the more challenging of the two situations, and can occasionally be (further) reduced by adding pathway-specific inhibitors. Modifications to the reagent itself may also be fruitful, but presumabely if this is the first hit in 100 reactions you’ll be relatively limited on that front [4].

With an unstable product the road forward is somewhat simpler. Overoxidation and the like can be partly controlled via slow addition of reagents (syringe pump), or if the expertise/equipment is available flow chemistry. In the worst case the crude NMR can be used to determine yield over time, and a mid-reaction quench can give good yield based on recovered starting material.

None of these are like the others

I’ll close with a quick disclaimer.  No two projects are the same, and the problems you face will likely be unique as well. Above all pick what works and discard the rest.

[1] And far more expensive, outside of the range of most academic labs. One can dream.

[2] Few obscure conditions are fully tested for substrate scope. I once took an alkylation procedure used on a single non-aromatic primary alcohol and adapted it to a system with four protected hydroxyls, four protected amines and one very hindered secondary alcohol. It worked quite well.

[3] Standard solutions are useful here. Dissolve your compound of interest in a low molarity carrier solvent (DCM/ether/pentane/etc.), add via syringe, then remove the solvent under an inert gas stream if necessary.

[4] It may be possible to elaborate on the reagent, for example moving from proline to a more complex proline-based scaffold (ex). However, unless the other reagents are commercially available or you are in pilot plant setting this route will probably take far longer than is practical.

Praise for the Kugelrohr

I don’t always do a small scale distillation, but when I do I use the Kugelrohr.

Kugelrohr Labeled

One of the lab’s kugelrohrs.

Distilling 1 mL or less has a number of complications, mostly due to condensation outside of the receiving flask.  In the standard setup the compound of interest boils from a RBF, liquifies over what is essentially a water jacketed condenser, then drips into the final receiving flask.  At small volumes there just isn’t enough liquid to form drops, and instead a fair bit of the yield is lost as dew on the condenser (which will also evaporate and leave the system via the vacuum line).

The kugelrohr condenses compounds directly in the collection flask, with the shortest practical distillation gap (about 2.5 cm/an inch).  Very little sample is lost, (if any), and the entire process generally takes less than 20 minutes or so.

Using the Kugelrohr

Transfer your sample of interest to a small round bottom flask, then attach at least two kugelrohr bulbs (female ground glass joint on top, male on bottom).

Place all but one bulb in the air furnace and chill the last bulb to at least 0C [1].  Slowly spin the bulbs (about 1 rotation per second) and gradually increase the heat.

Compounds will distill slowly, appearing first as a thin film then as single droplets.  When two or more samples are being distilled there will generally be a noticeable gap when the volume in the collection bulb does not increase.  At this point slide one of the bulbs in the air furnace out, and cool.

Repeat as needed.  If necessary collection bulbs can be swapped out for fresh glassware, and 3+ compounds can be collected.

KR - PipetWhen finished, allow the bulbs to cool.  The easiest way to drain out samples is to use a curved pipette tip (~30 degree angle, made by holding the pipette at an angle over a bunsen burner).  Use a bit of solvent to rinse the walls, then condense to final volume on a rotovap or with an inert gas stream.

Disassemble the kugelrohr.  Store glassware in the kugeldrawer.

Finding a Kugelrohr

There are now a number of commercial kugelrohr kits, but the physical requirements of the process lend themselves well to ad hoc construction.  The best examples are immortalized in the pages of J. Chem. Ed.,  in loving hand-drawn detail.  The hardest part to source is the heat source, though the air furnace can be replaced by upside-down variacs or spare rotovap.  For the discerning chemist I recommend the work of Guida and Gawley, as they “have found that commercially available “toaster-ovens” suite the purpose beautifully.” [2]

KR - Bath[1] The mode of cooling is a major point of departure in the kugelrohr guides I’ve seen.  I use a a 20 mL vial filled with crushed dry ice/acetone (~9:1 mix), which is loosely held above the outer bulb with a 3-prong clamp.  With good glass-glass contact this cools the collection bulb to -15C or so, far below what you can get with a stream of acetone or DCM.

[2] Urban legend has it that the first Alrich Kugelrohrs were the remains of stray coffee pots, combined with stripped down windshield wiper motors (bonus low-rent personal design).

Amphoteros – A Blogging Professor

For the past six months, Professor Andrei Yudin at the University of Toronto has been on sabbatical, gaining experience with protein crystallography at Toronto’s half of the Structural Genomics Consortium.  Like most chemists branching into biology, he’s mostly been thinking about all the chemistry he could be doing [1].  Rather than keeping these thoughts to himself he set up his own blog, and has been writing nearly every day.  The posts range from useful papers/topics to interesting unsolved research problems, with a few travelogues and biological insights thrown in for good measure.

The Yudin lab does some great work, and these posts are a glimpse into the planning behind each project.  I’d highly recommend taking a look through the archives yourself (the whole thing takes about 2 hours to go through), but in case you’re strapped for time here are some of my favourites:

1) Taking risks in chemistry

The best question to ask at the start of any research project is, “Is this worth the time and effort?”, while the most crucial question to ask periodically thereafter is, “Is it time to pull the plug?”  I’ve never had a dearth of projects or ideas, but feature creep and the sunk cost fallacy are always a problem.

2) Show me the numbers

What can we draw from a 30% yield?  Without the proper analysis the answer is generally, “not much.”  This post emphasizes the importance of a examining the crude reaction via a quantitative assay (HPLC, GC-MS, etc.).  The assay results can be used to determine an assay yield [2], which will show if the low experimental yield is the result of poor technique, poor conversion, or poor selectivity.

3) Empowering students with strong synthetic skills

How good is your microscale technique?  The University of Minnesota likes to challenge students with a MCPBA-based partial epoxidation of geraniol, on the 1 mg scale.  My organic labs heavily relied on microscale kits, but even we didn’t go this low.


[1] I kid, I kid.

[2] Assay yield = Selectivity x Conversion.  Selectivity is determined by the amount of product formed, while conversion is 1 minus the amount of starting material remaining.

Fieser and Fieser: A Labful of Tips


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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. [1].  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.

1) Ethylene dibromide/1,2-Dibromoethane is a Grignard Entrainer/Initiator

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 [2], 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.

3) Sodium Azide and Iodine

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.

4) Tetramethylguanidinium Azide

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 [3].  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.

6) Lithium Dimethylcuprate (Gilman’s Reagent)

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 can convert 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.

Zinc Dust9) Formic Acid Cleaves Many Protecting Groups

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.

Chloroforminium PreparationThis 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.

[1] Pre-Elsevier’s purchase, of course.

[2] Or Purification of Laboratory Chemicals, oddly enough.

[3] Fieser suggests chloroform as a solvent for the azide substitution reaction, which isn’t something I would ever recommend.

Edited to add schemes and Vilsmeier link.

Fieser and Fieser: Once Upon a Time in Chemistry


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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 [1], 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 [2].

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 [3].  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 [4]–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.

[1]  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.

[2] 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.

[3] Cfi. The entire field of protein crystallography.

[4] Few of the TLC stains we take for granted seem to be common at this point.  Instead compounds could be tracked on column, provided one worked with specially prepared morin-stained alumina.