What Does “Inquiry” Mean?

The phrase “inquiry-based labs” has been buzzing around my department for a while now. If it’s possible to crown a king of buzzwords in the realm of chemistry laboratories, “inquiry” is probably it.

On the surface, the idea of inquiry-based laboratories seems straightforward. The idea is to design and implement experiments that require students to engage in the process of scientific inquiry—exploring questions using the scientific method and making claims based on empirical evidence. To some degree, inquiry-based experiments have to “take the training wheels off” and throw students into a situation whose outcome is unknown. The catch is that the extent to which students should be left to explore on their own is by no means clear. Some great work has been done to clarify the continuum of inquiry labs.

Dirty little secret: these kinds of experiments make professors uncomfortable too! When a student makes a mistake during a prescriptive (procedural) experiment, it’s often easy to point to what they did and say “you made a mistake in step x.” The egregiousness of the mistake is related to how far the student is from the expected outcome. But when the outcome and procedure become uncertain, how can students or faculty know when a mistake is made? Anyone who has engaged in scientific research knows that this is a constant theme: did I make a mistake, or am I really observing something new? (Personal aside: I found this tension soul crushing during my early years in graduate school.)

Eventually, every professional scientist has to look this issue square in the face and become comfortable—on an emotional level—with the difference between sloppy technique and novel results. Much of that comes with experience learning and practicing science professionally. However, there’s a great argument to be made that the affective side to inquiry—the cosmic comfort one develops with uncertainty—can be developed through inquiry-based experiments in college.

So what keeps many faculty from implementing inquiry-based labs? You rarely see the other side of the coin in the chemical education literature, of course. Some have raised the point that students don’t learn as much from open-ended experiments, which could yield problematic results. On a more fundamental level, what students learn changes drastically when they work through inquiry-based labs. I don’t agree with the claim that students learn less from well designed inquiry-based labs, but I will admit that what they learn changes drastically. The focus shifts from verifying existing knowledge to constructing arguments based on data and observations.

I’m excited to get into the business of running inquiry-based experiments at large scale—I’ve always enjoyed shaking things up!

WNPS Solution

The chemistry world can be a very small place. Last semester, for example, I TA’ed for a professor who had my undergrad organic professor as her organic TA in undergrad. What does this have to do with Wednesday’s problem? To put it plainly, I don’t remember ever learning oxymercuration from the aforementioned prof. In all fairness to RBG I spent many hours asleep in that class, having it a mere eight hours after the 12-4am dorm night-desk shift. Still though, before last semester, mercury was basically the element that filled thermometers to me and little else. But Wednesday’s problem demonstrates that under the right conditions, mercury can do magic!

The cornerstone of the problem is the Ritter reaction, in which an isonitrile attacks an electrophile before being attacked by some nucleophile (classically, water) at carbon. The overall transformation leads to substituted amides in the classical case, but with other nucleophiles around, interesting architectures can fall out. In Stevens’s case, mercury-mediated fragmentation of the pinene skeleton generated both the electrophile (a carbocation) and the nucleophile (a double bond) in one fell swoop! The fragmentation can be rationalized by the release of ring strain associated with the starting cyclobutane. Attack by the isonitrile and trapping by the alkene, with loss of mercury to form the exocyclic alkene, leads to the intermediate X, an imine. The imine is then reduced on its top face to form the final product. Stevens makes a big deal of the reduction stereochemistry in the paper, although it makes sense to me considering the “roof-like” bicyclic structure of the imine.

Same time, same place, next week…be there or be square.

Hooray for isocyanides!

WNPS: How I Learned to Stop Worrying and Love Carbocations

Tonight’s problem comes once again from Harvard’s challenging organic problems website.<Nerdy Final Fantasy 7 Reference>

In the early 1980’s, Robert Stevens’s group at UCLA studied nucleophilic additions to and reductions of tetrahydropyridiniums, which could potentially yield alkaloid products. Actually getting to these cyclic imines and iminium ions in the first place can be an interesting exercise in arrow-pushing. It certainly was in the case of makomakine, which the Stevens group made from beta-pinene in only two steps! Barret Valentine would be proud.

Mercuric ion, being a Lewis acid, does interesting things with that double bond to start things off. From there, the arrows get crazy! See if you can draw a mechanism for the transformations below and come up with the intermediate X. One million EXP if you can!

I'll be dipped, this's tougher 'n Ruby Weapon!

WNPS Solution

Wednesday night’s problem featured a variant of the venerable Staudinger reaction, which can be used to reduce azides to amines or generate iminophosphoranes which can participate in aza-Wittig reactions, which form imines rather than alkenes. The reactivity of azides is apparently more subtle than one might think, if this reaction has anything to say about it.

In the presence of base and electrophilic phosphorus, substitution first takes place to generate a phosphite. The phosphite then attacks the “hanging” nitrogen of the azide, which neutralizes the central nitrogen and leaves the phosphorus poised for attack by the negatively charged azide nitrogen, which generates the heterocycle shown (what would the name of this heterocycle be…?). Retro [2+2] cycloaddition from this dihydrotriazaphosphete releases nitrogen gas and gives the “curious intermediate” alluded to, an iminophosphorane. [3,3] sigmatropic rearrangement then generates the product.

The selectivity for the E olefin can be rationalized by a six-membered transition state that places the methyl group equatorial.Staudinger, then [3,3]!

Interesting stuff! Tune in next week for another Wednesday Night Problem Session…

Brownie Points for Harvard, and a New Post Series

Come one come all! I'm absolutely crazy! I'm givin' away chemistry problems for FREE!Welcome to Wednesday night problem session boys and girls! This new series will push your chemical abilities to the limit, and may amuse and amaze your friends! Without further ado, today’s problem comes from Harvard’s Challenging CCB Problems Database, which is pretty much the greatest website ever constructed.

Mapp et al. have described a synthesis of allylic amines from allylic alcohols using the reaction shown below.Interesting!Note the sweet E/Z ratio they obtained. Provide a mechanism for this transformation and an explanation for the observed E selectivity.

Hint: the mechanism involves a rather curious intermediate. Don’t cheat now! Answers coming soon!

Annoying Heterocycles

Nomenclature is one of the most annoying roadblocks encountered while reading the chemical literature, and in no structural class is this more apparent than the heterocycles. Indeed, the problem is only getting worse as molecular structures grow more and more complex and unique. I’ve been known to pass over a paper or two at the sight of some obnoxious heterocycle in the title.

The Hantzsch-Widman system is currently the accepted method for the systematic naming of heterocyclic compounds. Ring size and saturation are specified by a suffix:

Size: (unsaturated), (saturated)
3-membered: -irine, -irane
4-membered: -ete, -etane
5-membered: -ole, -olane
6-membered: -ine, -inane
7-membered: -epine, -epane
8-membered: -ocine, -ocane

Small nitrogen-containing rings are named slightly differently; -iridine, -etidine, and -olidine are used for 3-, 4-, and 5-membered rings respectively. The location of heteroatoms on the ring is specified by prefixes. Oxa-, thia-, selena-, aza-, phospha-, sila-, and bora- are examples, and elements from earlier groups are placed first. So, for example, a four-membered ring with an oxygen atom next to a nitrogen is a 1,2-oxazetidine. Rings that are not fully conjugated are named as hydrogenated derivatives of the fully unsaturated heterocycles.

We can thank history for a plethora of exceptions to the H-W system. The small nitrogen cycles of course come to mind, with names starting in pyrr- or pip-. 1,2-diazole is commonly known as pyrazole, for example. Fused heterocycles are an absolute mess; a picture’s worth a thousand words.

Put your thinking caps on boys and girls!

Note from personal experience: committing the H-W system to mind may help improve your love life. In my case, it was “oxazaborolidine”…but that’s a story for another time.

The Epic Power Outage of Aught-nine, Part I

FAIL.Wow. I am literally speechless. I literally don’t know what to say. I am literally without words.

…OK that’s not really true. Actually I can think of a number of choice words to describe this situation, chief among which is “FUBAR.” At approximately 4 pm this afternoon, as I was gingerly weighing out potassium bis(trimethylsilyl)amide inside our drybox, the power went out. In the entire freakin’ building, and on the entire freakin’ campus. As soon as the lights cut I felt the gloves get limp and the gas circulation stop. Luckily I had managed to get the cap back on the bottle before the building breathed its last breath, although the weighed solid is still sitting on the balance under a flow of argon jerry-rigged to the box’s house vacuum inlet (kudos C-Buts, brilliant solution). And my to-be-deprotonated organic substrate is still sitting under argon in my hood. Of course, the most worrisome aspect of this whole situation is the fact that liters upon liters of chemical samples in freezers and under inert atmospheres are now getting the chance to bathe in oxygen, nitrogen, and water.

Incredibly, Roger Adams Lab doesn’t seem to have any sort of backup power system. Need supplies to hook something up to deal with the power outage? Too bad, the storeroom door is controlled by an electronic card reader! Granted, that building consumes massive amounts of power, and establishing a backup power system for it would be a pain in the butt as a result, but isn’t it worth it to keep the place from turning into a time bomb whenever the power goes?

On the bright side, my Sunday is free again. I’ll report the news as it comes in, but for now I’ve got to figure out what to do with myself…What to do, what to do?