Molecular Architecture, Troger’s Base and Balloons

The people who make the science happen…

Kristen Baker and Josh Sgroi (holding Troger's base model) in front of the NMR.

Kristen Baker and Josh Sgroi (holding Troger’s base model) in front of the NMR.

My name is Kristen Baker and I am working alongside of Josh Sgroi in Dr. Jameson’s lab.  We are both rising juniors, I am a chemistry major with a math minor and Josh is a chemistry major with a French minor.  This past semester, Josh and I both took Organic Chemistry with Dr. Jameson, and became interested in the work he is doing.  Day to day in the lab is normally around the same, we run a lot of chromatography columns, NMRs, TLCs, and use the Rotovap constantly. Working in Dr. Jameson’s lab can be quite entertaining as we all tend to talk to our chemicals and yell at them when they are “misbehaving”.  Fridays are by far our favorite day as Dr. Jameson always takes us out for coffee to take a break from the lab and have some life chats.

Living on campus during the summer is definitely different than living here during the academic year, but not in a bad way.  I live in an apartment with 7 other girls and 1 guy.  Since we do not have a meal plan and must make all of our meals, we tend to do a lot of dinners together.  On Tuesdays we make tacos as an apartment family.  We also go to Wings and Yuengs at The Blue and Grey on Wednesday nights and normally take a trip to Mr. G’s right after.  Every morning my apartment encourages each other to go to the gym before work, sometimes it works and other times we just roll over and sleep another hour. On weekends some of us go home since we all live within two hours or so of campus, but whoever is here knows that Scott makes waffles at 11 sharp Sunday morning.  There is also a ton of activities going on that is not just our apartment, such as pick up sports and free Rita’s Italian ice.

I’m Josh Sgroi and my apartment also has its rituals. I am the only guy in an apartment with 4 girls. Every morning Jenn, Leah and myself (Josh), wake up and eat our cereal while watching Match Game ‘76 on GSN. I’ve never really been into game shows, but this show is proof that retro is always better. We then walk over to the Science Center together and talk about life. I often coordinate dinner with Jenn and Leah. So far, we’ve made Swedish meatballs with homemade mashed potatoes, a vegetable and ham sautée over pasta, as well as a lot of Jello. (We even made them using zoo animal Jello molds!) We’ve also gotten pizza a couple of times when we have no idea what to make. On the weekend I drive out to my boyfriend’s for the weekend while Jenn and Leah stay to take care of their projects as they’re in the Biology department and have to watch over rats and such.

 

What is Troger’s base?

We are synthetic organic chemists applying our skill at making molecules to Troger’s base derivatives. Troger’s base is a molecule possessing a rather inflexible 90-degree bend. As such, it is an ideal structural element for the construction of molecules having curved shapes. Thus: molecular architecture.

Here are several renditions of the core of the Troger’s base molecule:

TB1

Notice the one on the left, which clearly shows the atom connectivity, shows nothing of the three-dimensional curvature of the molecule. That is one limitation of depicting three-dimensional objects on the two –dimensional medium of paper (or computer screen). The middle structure hints at some three-dimensionality; the thick bonds are coming out of the page. The last structure gives a good idea of the curvature of the molecule. For most Troger’s base derivatives the aromatic ring planes are oriented within a few degrees of 90. Of course, the best renditions show something of the three-dimensional nature of the molecule:

TB2

The image on the left (above) is looking at the molecule down the edges of the aromatic rings. This shows the curvature of the molecule. The image on the right is looking down from the top of the molecule. The images come from a molecular modeling program which (roughly spealing) shows a calculated most stable structure of a molecule. Finally, below are two slightly different views of a model of Troger’s base that we’ve been carrying around as a show and tell prop when we talk about our research.  The top image clearly shows the 90 degree relation of the aromatic rings and the bottom image shows something of the cleft between the two rings.

  TB3                              TB4

 

Troger’s base is a fascinating molecule. We admit that we obsess over it. It keeps us awake at night thinking of ways to tame it. Don’t take our word for it that it is fascinating. Troger’s base has it’s own chapter in a book titled “Fascinating Molecules in Organic Chemistry”.

Troger’s base is a historically important molecule. It was first reported in 1887 in a paper by Julius Troger, a graduate student at the University of Leipzig (Germany), who isolated a white solid from the reaction of p-toluidine with formaldehyde under the influence of acid. The relatively primitive instruments of the time allowed him to determine a formula for the compound, but gave no clue about the structure. As a result of his inability to determine the structure of the molecule he prepared, he received a mediocre grade for his doctoral thesis. It wasn’t until 1935 (48 years later!) that the structure was correctly determined.

One of the interesting properties of Troger’s base is that it is chiral. What makes this relatively unique is that it is chiral by virtue of possessing four different groups on the amine nitrogen. It turns out that in determining chirality, lone pairs count as groups, so an amine nitrogen with three different groups and a lone pair has four different groups – the classic characteristic for chirality in a tetrahedral carbon atom. Racemic mixtures of molecules which are chiral at carbon can be separated into their enantiomers by a variety of techniques, but chiral amine nitrogen atoms rapidly “flip” between their enantiomers, even at temperatures well below 0 °C. This “umbrella in the wind” mechanism (below)

amine inversion

makes it impossible to resolve most chiral-at-nitrogen amines. Notice that the structures above are non-superimposable mirror images. The structure of Troger’s base, with its nitrogen at a bridgehead position, makes the amine ring flip sterically impossible. Vladimir Prelog recognized this, and in 1944, he and Wieland reported the resolution of Troger’s base into its enantiomers by column chromatography using D-lactose as the stationary phase. The rather large column contained 2.7 kg of specially prepared D-lactose and the separation of 6 grams of racemic Troger’s base resulted in a yield of only 5.5 % of each enantiomer. This achievement was significant for two reasons: 1) it represented the first resolution of a chiral-at-nitrogen amine, and 2) it was almost certainly the first application of chiral chromatography on a preparatively useful scale. And Vladimir Prelog was uniquely positioned to make this discovery: He is the father of organic stereochemistry and his application of the R/S rules (Cahn-Ingold-Prelog priority rules) for stereogenic atoms systematized what had become a confusing concept in organic chemistry. For this important contribution, Prelog shared the 1975 Nobel Prize in Chemistry.

 

Our goals

You will notice in the images above that the groups in the 2- and 8-positions of Troger’s base project at an almost ideal 90 degree angle from the core of the molecule.  This makes these positions crucial for the elaboration of more complex right angle architectures.  Common strategies for appending groups to an aromatic ring are any of a number of palladium catalyzed reactions, such as the Heck, Suzuki, Stille and Sonogashira reactions.  These are just some of the large number of variations on this class of reactions.  These reactions are so important that they were recognized in a Chemistry Nobel Prize shared by Heck, Suzuki and Negishi in 2010.

untitled

Like most reactions at aromatic rings, palladium catalyzed reactions possess some important reactivity trends. Substitution of the aromatic halide is promoted by electron-withdrawing aromatic substituents and hindered by electron-donating substituents.  In order for these reactions to take place with any kind of reasonable rate and yield, we utilize iodine, the most reactive of the halogens in these reactions.

 

What does synthetic organic chemistry look like?

One of the reactions that Kristen is running.  The (Carolina blue) balloon keeps the desired gas over the reaction.  The apparatus to the right is a syringe pump for the very slow addition of reagents.

One of the reactions that Kristen is running. The (Carolina blue) balloon keeps the desired gas over the reaction. The apparatus to the right is a syringe pump for the very slow addition of reagents.

Josh likes to decorate his balloons.  Notice the orange color (not as nice as Kristen's Carolina blue...).  Josh is a fan of the Dutch national football team.

Josh likes to decorate his balloons. Notice the orange color (not as nice as Kristen’s Carolina blue…). Josh is a fan of the Dutch national football team.

Josh sometimes mistakes his hood sash for a lab notebook....  Did I mention that he is a Dutch football fan?

Josh sometimes mistakes his hood sash for a lab notebook…. Did I mention that he is a Dutch football fan?

 

An organic extraction.  A (Dook - boo!!) blue aqueous layer and a yellow organic layer.  Most organic layers are darker than this, so we are happy.

An organic extraction. A (Dook – boo!!) blue aqueous layer and a yellow organic layer. Most organic layers are darker than this, so we are happy.

 

Hopefully we’ll have an update for a post later this summer.

 

 

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