NMR on the X-Files

I was watching the X-Files last night — because bing-watching 1990’s television is how I opt to spend my free time — when the show mentioned a particular analytical technique readers will be well familiar with: NMR.

One of the reasons I love this show so much is because the blatant pseudo-science presented has a glimmer of real science somewhere embedded in it.  Sure it’s fiction; but I’ve never seen them put up a structure containing a Texas carbon (and I’ve been looking!).

In last night’s episode, Special Agent Dana Scully shows her partner, Special Agent Fox Mulder, a “nuclear magnetic resonance spectra [sic].”  This then comes on screen for a couple seconds (click to embiggen):

Screen cap from The X-Files S4E19 “Synchrony”, approximately 14:30 into the episode

A Proton NMR spectrum indeed!  The protagonist explains the analyte in question is a drop of blood from a murder victim; that’s an awfully clean spectrum from such a complex source.  The compound we are looking at is an experimental super toxin which “catalytically” induces freezing — and subsequent death — in it victims.

Obviously, no such catalyst exists, but this is a real NMR spectrum of something.  The solvent appears to be deutero-chloroform spiked with TMS.  There’s an aromatic signal almost directly on top of the chloroform singlet.  It gets complicated in the 6.5-5.5 region with olefins aplenty.  A singlet at ~4.1 could belong to some kind of substituted anisole, or a chloromethyl group?  The doublet at 3.3 has me stumped.  My first guess would be methylene adjacent to NH, but alas, no NH proton visible.  Down around 2-1 ppm we have a mess of methyl groups and what looks like a t-butyl at 1.2 ppm.

I am awarding a bounty of 10 internet points to the commenter who can propose the most plausible structure for this spectrum.  For historical context, the episode was filmed in 1996-97 in Cambridge, MA using MIT for some of the shots.  So it’s a possibility that the spectrum was pulled from an MIT lab.

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Some chemical whimsy: How much helium?

Helium is pretty cool.  For a number of reasons.  As a gas, it’s lighter than air, and incredibly inert, so you can use it to lift stuff (like balloons or blimps).  As a liquid, helium is exceedingly cold.  Clocking in at 4 Kelvin (-452 °F), it’s the coldest refrigerant available.

So much technology would not be possible without helium.  Ever had an MRI taken at the hospital?  Not possible without liquid helium to cool the superconducting magnet inside the MRI.  My NMR spectrometer (which has been talked about, in depth, before) uses liquid helium for the same reason.  Every six weeks or so, the helium supply of the instrument needs to be replenished.  An NMR spectrometer uses considerably more helium than a balloon.

ALL THE HELIUM

60 liters of helium is quite a bit.

That got me thinking…  If you vaporized all the helium inside a 60 L dewar, just how many balloons could you fill up?  Remember, this isn’t the same helium you buy at a party supply store; liquid helium is many, many times more dense than gaseous helium.

One of my undergraduate professors was fond of brain-teasers called Fermi problems named after the Italian physicist Enrico Fermi, who was renowned for his ability to rapidly estimate answers to incredibly complex problems.  This type of problem solving relies on rounding and the use of simple assumptions to reach approximate solutions (often called a “sanity check”).

Let’s assume the following: gaseous helium is an ideal gas (it’s not, really), and a large party balloon has a volume of about 10 liters.

The tare weight printed on the side of the helium dewar tells me there are 17 pounds of helium in the canister.  Let’s call it 20 for simplicity’s sake.  One pound is about half a kilogram, so there are about 10 kg (10000 grams) of helium.  The molar mass of helium is 4.00 g/mol.  Therefore I have 2500 moles of helium (liquid).  As per the ideal gas law, one mole of a gas occupies 22.4 liters of space.  Call it 20 for round numbers.  So vaporizing my 2500 moles of liquid helium gives me 50000 liters of (now gaseous) helium.

At 10 liters per balloon, my original 60 liter dewar can fill 5000 balloons.  That’s a lot of balloons.  Enough to lift a child off the ground, a la Pixar’s “Up.”  However, that’s only 1% of the helium required to fill the Goodyear blimp.

According the manufacturer’s data, the actual number of balloons we could fill would be closer to 4500.  That number accounts for the the fact that helium isn’t really an ideal gas.  And they didn’t round off all their numbers.

The Art (read: science) of Brewing

It’s been a while since I’ve been in the lab.  Months, in fact; we can chalk my weekend foray into beer brewing up to my desire to get back to the bench.  And what better time to cook up a festive ale than the start of the holiday season?  So, let’s talk about beer (brewing).

Beer is truly an incredible social construct which evolved over the last 9000 or so years.  Prehistoric Chinese cultures developed small-scale brewing operations before they even came up with writing.  That’s right; humans were imbibing beverages of choice well before the pyramids were constructed in Egypt, before there was even an Egyptian civilization in which to build pyramids.  An abbreviated history of mankind would read as follows (in order): agriculture, animal domestication, beer, writing, lots of messy wars, moon landing.  Priorities.

To make grain alcohol, you need yeast and sugar; everything else is simply icing on the proverbial cake.  Most likely this was discovered accidentally when the grain store of some prehistoric civilization was infected with wild yeast.

But what is yeast, and why is it so important in brewing?  Yeast is a common name for any of the 1,500 or so species of eukaryotic fungi belonging to the order Saccharomycetales.  That’s taxonomy speak for fungi that break down sugar.  Simply put, yeast cells take sucrose (table sugar), and using an enzyme called invertase, cleave the glycosidic bond between them.  This process results in two monosaccharide sugars, glucose and fructose.

Sucrose inversion

You may notice a similarity between glucose and fructose, namely they have exactly the same number of carbon, oxygen, and hydrogen atoms composing them.  Both molecules can be written using the same molecular formula, C6H12O6 and are called structural isomers.  This is convenient, since both sugars are converted to ethanol and carbon dioxide in the next step of fermentation, allowing us to write a single formula without violating any pesky conservation of mass laws.  A second enzyme in yeast, called zymase, is responsible for converting hexose sugars into alcohol and carbon dioxide.

fermentation formula

So, you’ve got some yeast and you can add some sugar water to it, this will indeed make alcohol.  Unfortunately, it will not make beer.  What makes beer beer is the use of malted barley or wheat as a source of sugar.  Cereal grains impart specific flavors to a beer: oatmeal gives a sweet flavor, barley makes a brew smokey and gives notes of coffee, and wheat will impart honey sweetness.  The next major characteristic of beer is hop content.  Hops are buds of hop plant, and grow in different strains.  Hops impart bitterness to beer.  Ever tasted an India Pale Ale (IPA)?  The first thing you’ll notice is the aggressive hop flavoring and strong bitterness.  Contrast that flavor with the sweetness of an oatmeal stout or most porters, which have limited hop content.

Alas, maybe you’re not interested in the science of beer.  Maybe you came here hoping I’d share a beer brewing 101 tutorial.  Well, I’d hate to disappoint; click here for an excellent first timer brew, with very detailed instructions on how to brew!

And what’s left to do with the spent grain from brewing?  Why, use similar chemistry to make brewer’s bread, of course!

Brewer's Bread

Cheers!

Mitchell

All Bad Things…

Heads up: there are some chemistry terms you may or may not be familiar with in this post.  I’ve tried my best to explain as I go, and make everything as self-explanatory as possible.  If you find yourself lost, head over to the new glossary section, where I have compiled some simple definitions.

Part Three

Up until this point, the synthetic chemistry presented in Breaking Bad has been quite factual.  Conversion of pseudoephedrine to d-methamphetamine using reagents mentioned in the show is a well-known and documented synthesis.  You probably guessed there’s a “but” following the previous statement.  I’ll get to that, but first let’s talk about the synthetic route I propose Walt most likely used.

It is revealed in season one, in the episode “A No-Rough-Stuff-Type Deal,” that their process involves phenyl-2-propanone or phenylacetone, a chemical which Walt and Jesse initially make in a tube furnace.  Phenylacetone is a prochiral compound, meaning that while it is not chiral itself, it can be made chiral after only a single chemical reaction.

Chirality visual

A carbon with four bonds generally takes the shape of a tetrahedron (left) with the carbon in the center, and the four bonded substituents at the peaks of the tetrahedron. Skeletally, this is represented in the middle image. A carbon is said to be chiral if the four substituents it is bonded to are all different (right).

And that chemical reaction involves methylamine, a difficult to acquire chemical that is central to the plot of several episodes in the series.

“We’re going to use reductive amination to yield methamphetamine.  Four Pounds.”           -Walter White

This makes the homework pretty simple.  Walt and Jesse treat phenylacetone with methylamine, a reaction which yields an intermediate called an imine.

synth of imine

Phenylacetone or “P2P” (left) is treated with methylamine (above arrow) to yield an imine intermediate, shown in square brackets.

The process also releases one molecule of water for every imine formed.  You’ll notice the intermediate compound very closely resembles methamphetamine, except for one key detail: the carbon-nitrogen double bond.  With that bond in place, the intermediate is not chiral, and it certainly isn’t methamphetamine.  Luckily, we haven’t yet done the “reductive” part of the reductive amination.  If a mild reducing agent is added to the mixture (usually either gaseous hydrogen or sodium cyanoborohydride), methamphetamine results.

reduction

Reduction of the imine intermediate with hydrogen gas (or a number of other reagents) yields racemic methamphetamine.

Those of you following along since part one may notice a problem here.  We have indeed synthesized methamphetamine; however, we have done so as a racemic mixture.  That is, we have a mixture of dextro and levorotary methamphetamine.  A fifty-fifty mixture, in fact.  Then how is it that Walt claimed to produce 99.1% enantiomerically pure methamphetamine if the reaction cannot possibly do any better than 50%?  The short answer is, we don’t know.  They leave that part out of the methods described in the show.  At one point, Walt sends Jesse to acquire “40 grams of thorium nitrate,” which has catalytic uses, but no documented use in asymmetric synthesis.

From here on out, this discussion is purely speculative.  There is literature available on enantioselective reductive amination processes.  Instead of using either hydrogen gas or sodium cyanoborohydride, as mentioned above, a chiral hydride source could be employed.  However, the highest enantiomeric excess (ee.) found in literature for these products is only slightly better than 70%.  And if Walt could do better than that, so can we.  Certain chiral metal complexes, such as those of rhodium and titanium, have been demonstrated as incredibly expensive ways to achieve 90%+ selectivity.  But those catalysts would cost more than the meth would sell for.

There are some Lewis base catalysts that might do the job: they are relatively inexpensive, but the best yields are only in the 80% range.  After searching exhaustively, I found one procedure that might do the trick, but it’s going to cost you.  Using a catalytic mixture of (get ready for this) 1,1’-Bis{(S)-4,5-dihydro-3H-binaphthol[1,2-c:2’,1’-e]phosphino}ferrocene and Bis(1,5-cyclooctadiene)diiridium(I) dichloride you might be able to break into that ever elusive 99%+ range of purity.

catalysts

If you want to make Walt’s meth with his purity, you’ll need these catalysts, or similar ones. They aren’t cheap.

Therefore, the only possible conclusion is that Walter White is in fact a wizard.

I hope you’ve enjoyed reading about Breaking Bad chemistry; I’ve certainly enjoyed writing about it.  Hopefully, I’ll bring you all some new content early next week.  Thanks for reading!  And if you have any questions, concerns, or suggestions on what I should tackle next, check the about page for my contact info.

Cheers,

Mitchell

Sources:

Angew. Chem. Int. Ed. 2001, 40, 3425

Organometallics 1998, 17, 3308

Angew. Chem. Int. Ed. 1990, 29, 558.3

This is Glass Grade

Part Two

Hello again!  In this installment, we’re going to get down to brass tacks with methamphetamine synthesis.  Season one of Breaking Bad opens with Walt cooking meth in a run-down RV with his partner Jesse.  I had to do a little “research” to refresh my memory about the process they claimed to use.

Research

It’s a tough job, but someone had to do it.

Jesse and Walt began their meth making operation by converting pseudoephedrine to methamphetamine.  Commercially available pseudoephedrine (PSE), often known as Sudafed, is generally sold over-the-counter in boxes of 24, each tablet containing 30 milligrams of the active ingredient.  In recent years, PSE has been phased out, in favor of phenylephedrine phenylephrine, a compound with similar decongestant properties, but one which cannot be easily modified to make methamphetamine.

Phenylephedrine (top left) has recently replaced pseudoephedrine (top right) in OTC decongestants because it cannot be easily converted to methamphetamine (bottom).

Phenylephedrine (top left) has recently replaced pseudoephedrine (top right) in OTC decongestants because it cannot be easily converted to methamphetamine (bottom).

Remember last time when I talked about the two enantiomers of methamphetamine?  When making meth, stereochemistry is important and we only want the dextrorotary enantiomer because the levorotary enantiomer is not as potent of a stimulant.  Pseudoephedrine makes for a convenient starting point because it is already dextrorotary.  You’ll notice pseudo and methamphetamine look very similar.  In fact, the only difference is that -OH group we need to get rid of.  Fortunately (or unfortunately), a simple, one-step process called reduction does just that, yielding enantiomerically pure d­-methamphetamine.  All you need is some red phosphorous, hydroiodic acid, some solvent, and a blatant disregard for your personal safety.

On a small scale, this method was favored because the materials needed are all readily available, and fairly inexpensive.  The difficulty, as Walt and Jesse discussed, was scalability.  Each box of PSE will yield only about 600 milligrams of methamphetamine, but purchasing fifty boxes of Sudafed from your local Walgreens is sure to attract some attention.  To give you an idea about how little that is, consider a heavy meth user may use as much as 1000 milligrams each day.  Not to mention the reaction will generate deadly phosphine gas, and can spontaneously ignite.

pseudoephedrine

You’d need a lot of these.

From that lengthy list of drawbacks, it’s no wonder Walt began to look for an alternative method of making meth.  He later settled on a synthetic route involving phenyl-2-propanone, referred to as “P2P” in illicit drug manufacturing.  So check back next time, when I’ll be discussing the famous P2P cook, producing Walt’s signature blue meth.

My Baby Blue

Prologue

When I started writing this, I planned on it being a single post covering some background about organic chemistry methods discussed in Breaking Bad.  But more importantly, how accurate those methods are.  However, I soon realized covering everything I wanted to would turn this post into an essay.  So I decided the best course of action would be to break it into parts.  Part one will cover the structure and properties of the drug, while parts two and three will discuss its synthesis in regards to the show.

Part One

Welcome back, faithful viewers.  As promised, this time around I will tackle (with no spoilers!) some of the chemistry from the series Breaking Bad.  For those of you living under a rock for the last five years, Breaking Bad chronicles protagonist Walter White’s descent from beloved high school chemistry teacher to methamphetamine-producing drug kingpin “Heisenberg.”  You also may be quite tired of your friends’ raving reviews about the show, and probably wish they’d shut up about it already.  But I digress.

Let’s briefly discuss the structure and properties of meth.  This is methamphetamine:

meth full formula

Or more succinctly (in what chemists call “skeletal formula”):

meth skeletal

You’ll notice the wavy line representing a carbon-carbon bond.  A wavy line exists because there are two possible enantiomers of methamphetamine.  The dash (left) represents a bond going into the screen, while the wedge (right) represents a bond sticking out at you. Remember, organic molecules are three-dimensional, not flat.

enantiomers

We differentiate these two enantiomers with the Latin prefixes dextro and levo, or simply d and l for short.  The structure on the left is levo-methamphetamine.  It’s rather innocuous and there’s a good chance you’ve unknowingly used it before; it goes by the brand name Vick’s VapoInhaler.  The one on the right is dextro-methamphetamine, and that’s the one favored by recreational methamphetamine users.  A seemingly minor difference in structure turns a highly addictive and very destructive drug into a nasal decongestant.

Methamphetamine is a psychostimulant, belonging to the broader class of psychoactive drugs.  It acts on the central nervous system by increasing the amount of dopamine in the body, causing a variety of physical and psychological effects; hyperactivity, alertness, headaches, increased libido and self-confidence, heart palpitations, psychosis, stroke, and paranoia are just a few of the many effects induced by methamphetamine usage.

Recreationally, the drug is introduced to the body virtually any way you could imagine, and in at least one way you probably can’t.  Meth tablets were given to pilots during WWII to help them stay awake on long bombing runs, and it’s currently prescribed to treat attention deficit hyperactivity disorder (ADHD) and as a last-ditch treatment for severe obesity.

Look out for my next post, where I’ll be talking about Walt and Jesse’s first cook in that run-down Winnebago.