The Tools of the Trade

Ever wonder what an organic chemistry lab looks like?  Well, wonder no more!  I put together this virtual tour of sorts for the curious.  I’m going to take you through the facilities and equipment used by those who do what I do.

Tools of the trade: a virtual tour of an organic chemistry lab

The first stop every morning is the same: I boot up my computer and check Twitter.  Twitter has become an immensely useful tool for staying on top of new chemical research and gathering opinions from other scientists.  Other bloggers often discuss new methods from recent publications, and combined with scanning the feeds of major chemistry journals, I can get a rapid grasp on what’s important today.

That, and cracking lame chemistry jokes.

Next, it’s time to head down to my hood, where I spend the majority of my time.  For the uninitiated, a fume hood is a cabinet that pulls in air, creating negative pressure in the area where I’m doing experiments.  The air is then run through the ventilation system, and safely vented outside the building.  This prevents such unpleasant happenings as me getting a face-full of toxic hydrogen fluoride gas, or tripping out on diethyl ether fumes.

Where the magic (read: science) happens

Where the magic (read: science) happens

You’ll also notice a bunch of stuff sitting around my fume hood.  Starting from the top left, we have shelves of reagents and some glassware I use very frequently.  Then there’s the long, glass tube running horizontally across the top of the hood.  That’s called a Schlenk line; one end is hooked up to an inert gas (nitrogen or argon) and the other end to a vacuum pump.  This allows me to remove air and atmospheric water from a reaction flask, and replace it with inert gas.  Some compounds are highly sensitive to air.  Continuing to the right, you’ll see some waste containers, and a number of solvent bottles containing chemicals I use so frequently it makes sense to keep a stock of them in my hood.  Doubling back to the left (foreground) you’ll see a couple of hot plates, which double as magnetic stirrers.  These allow precise control of reaction temperature.

Everything so far is something you’d find in pretty much any organic chemist’s workspace.  However, you may have noticed the large aluminium plate making up the counter of the hood.  Since I work with explosive material, it is critical that the risk of static discharge be eliminated.  Rubbing your feet on carpet and then touching the compounds I work with would be inadvisable, to put it lightly.  So, my entire workspace is electrically grounded, including the floor in front of the hood.

We work with compounds that are SUPPOSED to go boom.  Ideally not mid-experiment though.

We work with compounds that are SUPPOSED to go boom. Ideally not mid-experiment though.

Another component of my workspace somewhat unique to explosive operations is steel armor plating.  The sides and rear of my fume hood are surrounded by ¼” thick steel plates.  In the unfortunate event of an accidental detonation, any fragmentation would be restricted from adjacent labs and hallways.

Rotary Evaporators

Rotary Evaporators

Next to my work area are two rotary evaporators or “RotaVaps.”  These allow chemists to rapidly remove solvent from reaction mixtures, isolating the products of the reaction.  By placing the mixture under a vacuum and providing gentle heating, the solvent boils much more rapidly (and at a lower temperature) than it otherwise would.  A cold trap then cools the gaseous solvent, where it condenses into a liquid in an adjacent flask.  Since these RotaVaps are also used for explosive material, they are also armored, just like my hood.

Now let’s check out the bread and butter of any organic chemist: the most powerful tool in my structural determination arsenal.  I am, of course, talking about nuclear magnetic resonance spectroscopy (NMR).  NMR is used to analyze the number and chemical environment of certain active nuclei.  Most commonly analyzed is hydrogen, followed by carbon; fluorine, nitrogen, and phosphorous are also active, but much less commonly analyzed.  NMR allows chemists to rapidly determine whether or not a reaction has worked as intended, and to verify the structure of compounds.

Our nuclear magnetic resonance spectrometer, AKA my one true love.

Our nuclear magnetic resonance spectrometer, AKA my one true love.

As always, thanks for reading!  Feel free to let me know how you felt about this piece, comments, questions, and suggestions are always welcome!

-Mitch

Safety First!

Safety First!

Advertisements

Winter Chemistry or: Everything You Ever Wanted to Know About Ice, and Then Some

Foreword:

Hello all!  It’s been a busy holiday season full of travel, friends and family, interviews, and surprisingly little chemistry.  As such, this blog got pushed to the backburner so to speak.  But I’m back!

I’ve heard it’s been quite cold in the Northeast this last week.  While I have been rocking a t-shirt in Southern California, temperatures in the Boston area have inched into the sub-zero range, with parts of the Midwest reaching record-breaking lows.  Heavy snowfall has impeded holiday travel in much of the northern parts of the country, and iced-over roads have made driving difficult.

Bummer.
Photo credit: Yoon S. Byun, Boston Globe

 

It’s that ice part we’re going to talk about this time.  We skate on it, put it in our drinks, compress it into balls and throw it at each other, and curse Old Man Winter while we chip it off the windshields of our cars.  It is a ubiquitous formation on our planet, so let’s take a few minutes to learn about its structure and properties.

Ice, Ice, and More Ice

Did you know there 17 different documented forms of ice?  For you Vonnegut fans out there, Ice-Nine actually does exist; however, it (thankfully) won’t destroy all life on earth.  That being said, the vast majority of the ice you encounter is Ice Ih (pronounced “ice one-h”).  In fact, unless you’ve been to one of the poles where temperatures can reach -100⁰ C (-148⁰ F), that’s most likely the only ice you’ve ever seen.  The subscript “h” stands for “hexagonal” and denotes how individual molecules of water bond together in a crystal lattice.  It turns out that ice formation is very sensitive to temperature and pressure.

You may have seen a similar diagram in high-school chemistry. There are a few more phases of water than your teacher told you about.

 

In addition to the typical hexagonal lattice structure, ice can also form cubic, rhombohedral, and tetragonal geometric configurations; ice can even freeze in a completely disordered manner, forming amorphous ice.

 

Hexagonal ice lattice structure.

Hexagonal ice lattice structure.

Why is Ice Slippery?

At face value, this seems like a question a toddler might ask, just after inquiring about “why the sky is blue.”  But if the answer was as simple as “because it is,” I wouldn’t be talking about it here.  Believe it or not, this topic has been the subject of scientific debate since the mid-nineteenth century.  It has long been known that solid water (ice) is less dense than its liquid counterpart.  Indeed, water is one of only half a dozen or so substances known to exhibit this property.  It therefore follows that compressing ice will lower its freezing point, causing it to melt.

The Kelvin brothers (for whom the temperature scale is named) theoretically outlined and experimentally verified that water’s freezing point is dependent on external pressure.  This offers one explanation as to why ice-skating works.  The blade of an ice-skate is very thin, and exerts force on only a small area, resulting in very high pressure.  In 1886, an engineer by the name John Joly worked out that the pressure an ice-skater would exert on the ice would be close to 500 times atmospheric pressure, enough to lower the freezing point of ice from 0⁰ C to -3.5⁰ C.  This would allow regional melting of ice directly under the ice skater’s blade.

You may notice a problem here: how is it possible for people to ice skate in temperatures below -3.5⁰ C?  And never mind ice skating, how is ice slippery when you’re walking on it?  Your shoes certainly don’t generate enough pressure to melt ice.  As it turns out, very, very cold ice isn’t slippery on its own.  If you were to run your hand over it, the texture would be similar to sandpaper.  In fact, there is a fair amount of friction between the bottom of your shoe or the tire on your car, and ice.  This friction generates heat, just like when you rub your hands together for warmth, and the heat can be sufficient to melt a thin layer of ice.

We now have two explanatory models for why ice is slippery, but we remain with one problem.  Ever tried standing on a patch of black ice?  Even though you’re not moving, it’s still slippery.  Since there’s no movement, there isn’t any heat generated by friction.  So there must by a third model to explain this phenomena.  In 2002, scientists at the Lawrence Berkeley National Lab demonstrated that a thin layer of liquid water exists on top of ice.

This layer persists down to temperatures of about -20⁰ C (-4 ⁰ F), at which point water molecules do not have sufficient energy to break out of their crystal lattice structure.  See, water molecules are held together by electrostatic forces, similar to how a balloon will stick to your hair if you rub it against something.  In the case of water, this force is called a hydrogen bond.  When solid ice interacts with air, the molecules in air disrupt the formation of a crystal lattice, resulting in a thin film of liquid-like water.

This layer was measured to be approximately one hundred-millionth of an inch thick, 6 water molecules across.  If the sole of your shoe were scaled to be as large as the tallest building on earth (Burj Khalifa, 2,722 ft) then the water layer would still be ten-thousand times thinner than a penny on the sidewalk.  

Seriously, I did the math.

That penny is a long way down.

So there we have it: seventeen different types of ice, condensed matter physics, pressure, friction, equilibrium, and intermolecular forces.  All that to explain the chemistry of why ice is slippery.  I hope you’ve found this post interesting and informative, and I’ll do my best to keep the chemistry coming.

Cheers,

Mitchell

Sources:

https://archive.org/stream/scientificprocee5188687roya#page/452/mode/2up

http://iopscience.iop.org/0953-8984/14/8/108/pdf/0953-8984_14_8_108.pdf

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.

The Nobel Prize in Chemistry

On October 9, Martin Karplus (Strasbourg), Michael Levitt (Stanford), and Arieh Warshel (USC) were jointly awarded the 2013 Nobel Prize in Chemistry (along with a $1.2 million award!).  Together, these three have been running computational chemistry experiments since the birth of the microprocessor.  Their work has been groundbreaking in computational chemistry, and will continue to develop into powerful tools for chemists.  You can read the official press release here.

Before we talk about why their contributions are important, let’s briefly discuss quantum mechanics.  I know what you’re thinking, “but you promised in the ‘about‘ section that this blog would be easy to understand!”  It will be, I promise.  We’ll keep this completely qualitative.

Atoms and molecules move.  A lot.  And usually, they move really fast.  It works something like this:

molecular DOF

All atoms and molecules can move in the x, y, or z directions, and thus have no less than 3 degrees of freedom (DoF). A diatom (top center) can rotate about two axes of symmetry, in addition to x, y, and z movement, and therefore has 5 DoF’s. The non-linear triatomic molecule (top right) has 3 rotational axes, and it has 3 vibrational modes (shown above, below, and the the right of the molecule).

Additional bonds add additional degrees of freedom, allowing new rotations and vibrations.  You can see how even small molecules, consisting of only a couple dozen atoms can have incredibly complicated molecular dynamics.  If you consider biological molecules, such as proteins, which can contain tens (or even hundreds) of thousands of atoms, molecular movement becomes unfathomably complicated.

Titin, the largest known protein, consists of approximately 33,000 amino acid residues, and has over 1.5 million degrees of freedom.

Since using computational models to predict how molecules will interact with each other must account for all these degrees of freedom, the task is very complex and quite time consuming.  Large super-computers can take hours to model even simple interactions.  Interactions between small molecules and proteins can be exploited to treat diseases; computationally determining these interactions is a key step in drug discovery.

But how do we get from cool computer program to Nobel Laureate?

computer

Previously, quantum mechanical calculations could not be successfully paired with classical mechanics in theoretical chemistry.  Calculations based on classical mechanics are much simpler and take much less time than quantum-based calculations.  Classical mechanics is effective at modeling the large, outer structure of proteins, but breaks down when you attempt to model interactions between proteins and the small molecules (drugs) that bind them.

Karplus, Levitt, and Warshel devised a method by which complex drug-protein binding interactions are handled by quantum-based calculations, while the movement of the larger protein structure is determined independently by classical methods.  This method significantly speeds up calculations, and allows more accurate predictions to be made about drug-protein interactions.  With better models, “wet” chemists can design and synthesize more effective drugs to treat a variety of illnesses.

Stay tuned for next time, when I discuss the chemistry behind Breaking Bad.  Just how good is 99.1% purity?