Chemistry Blog

Dec 03

Officials on House Full of Explosives: “Let’s Set It on Fire!” – Updated


WATCH LIVE!

Several local tv outlets will be live streaming (did stream) the controlled burn at 9am pacific time (noon eastern) 11am pacific (2pm eastern).  I’ll be teaching class at that time, so someone let me know if it’s uneventful or, er, eventful.

NBC

CBS

ABC

FOX


On November 19, a gardener for Escondido, CA, resident George Djura Jakubec was walking in the backyard when he stepped on something causing it to detonate.  The explosion caused burns and abrasions up one leg, under one arm, and on his head and eyebrows, and he was hospitalized.

Officers started searching the yard and home… then quickly retreated when they found numerous explosive compounds and explosive-making materials in and around the house.  According to various reports, items found on the property include:

  • 9-12 pounds (4-6 Kg) of homemade HMTD, PETN, and ETN (which authorities claim may be the largest discovery of its type on US soil…)
  • 13 grenades
  • 9 detonators
  • bags of metal pieces and ball bearings
  • semiautomatic weapons
  • several gallons of nitric acid, sulfuric acid, hydrochloric acid
  • 50 pounds (23 Kg) of hexamine
  • books about explosives
  • a tracker hidden in currency during bank robberies

And then they decided to call off the search because the house was too unsafe for offices.  Who knows what else may be in un-searched corners of the house.

Not surprisingly, Jakubec, a naturalized US citizen originally from Serbia, is in jail on $5 million bail and is charged with more than 25 felonies relating to explosives and bank robbery.  He pleaded not guilty.

Officials say there is no safe way to remove all the explosives from the house, so the best way to neutralize the danger is to burn the house to the ground.  They plan to evacuate 200 homes, build temporary fire-safe walls between the house and its neighbors, spray the wall and neighboring houses with fire-retardant foam, pre-heat the house so it ignites quickly, then start a fire.  They plan to wait until a time after morning rush hour when the winds are calm before starting the fire.  They will need to close part of nearby interstate 15 because of the house’s proximity to the highway.  Gov. Schwarzenegger has declared a state of emergency for San Diego County.

Yikes.

Update (12/4): The North County Times is releasing images taken from inside the house.  Very disturbing.   Very disturbing indeed.  It’s like that one episode of CSI where almost the exact same thing happened.  They’re clearing the house, when the one CSI opens a fridge in the garage.  Then he slowly says to the other CSIs in that low, dramatic tone of voice. ‘stop what you’re doing and slowly walk out of the house.’  They ended up doing the same thing to that house, only they detonated the explosives and esploded the house instead of lighting it on fire.  Click the image for all 12 pictures.

News Stories:

  • 11/21 story on initial searches of house
  • 11/23 story on suspect and house searches
  • 11/24 story on family history of suspect
  • 11/30 story on decision to burn down house
  • 11/30 story on execution of search warrant and list of items found in house
  • The search warrant
  • 12/2 story on preparations to community for burning down the house
  • 12/2 story on safety preparations being taken before burning down the house

Dec 01

My Life and Hard Times*


’Twas brillig, and the spiroketals
Did gyre and gimble in the flasks…

A while back, we had some behind-the-scenes talks about narrating some of our research projects here on the blog.  Ken got us started with his delightful tale of his recent publication.  I’ll go next and tell you about one of my grad school projects.  My story will not be as intriguing as Ken’s because a) the project ultimately failed to achieve its objective and b) we didn’t publish the results.  But I’ll tell you about it anyway, as the project made up the bulk of my dissertation.

I will have to leave out a few details, though, because my PI may want to eventually revisit the project, and I may sit down here soon and churn out a short comm manuscript and submit it for publication at some point.

—–

The project centers around the synthesis of spiroketals in a Diversity-Oriented Synthesis project.  DOS is a strategy for making molecular libraries similar to combichem, but perhaps with a bit more purpose and a bit less reliance on random chance/luck.  In our project, we attempted to synthesize a series of 6,6-spiroketals with orthogonally differentiable functional groups in various positions around the spiroketal core.

A quick primer on spiroketals – spiroketals are spirocyclic tetrahydropyran rings where the rings are fused through a ketal carbon atom.  Spiroketals were chosen because the two rings are historically very rigid – the 3-dimensional orientation is governed by the anomeric effect – a topic I’ve blogged about before.

Additionally, as functional groups are rotated to different positions about the spiroketal framework, the vector relationship between the two functional groups changes.  This was the purpose of synthesizing a library of spiroketals.  We wanted to probe the ability of the spiroketal to act as a scaffold upon which we could position a number of functional groups at unique and specific relative orientation.

Back to DOS.  We wanted to synthesize spiroketals through a convergent approach.  We would position simple functional groups in the various positions through this convergent approach to make a small library of purposely designed spiroketals.  These simple functional groups would be orthogonally differentiable, like an aryl bromide and a terminal alkene.  This would allow us to differentiate each spiroketal at each position using reactions that are orthogonal to each other (that is, the Pd-catalyzed cross coupling reaction would likely not interfere with the terminal alkene and the cross metathesis reaction would likely not interfere with the aryl bromide)

Using this approach, we could prepare a library of spiroketals in short order.  Subsequently, each spiroketal could be used as the starting point for a second library by functionalizing the aryl bromide and the terminal alkene.  The same secondary functionality could be introduced in each secondary library, but each secondary library would be different because of the unique vector relationship between the two functional groups.

All mimsy were the aldols,
And the phosphonates outgrabe…

As shown in the following retrosynthesis, we split the spiroketal precursor (the dihydroxyketone) in half through a Horner-Wadsworth-Emmons olefination to lead back to an aldehyde and a β-keto phosphonate.  The chirality in both fragments arises from an enantioselective aldol addition mediated by a thiazolidinethione chiral auxiliary.

The enantioselectivity issue had been worked out in advance and guided our decision to use the thiazolidinethione-mediated aldol addition.  Additionally, the thiazolidinethione is preferred over the more traditional oxazolidinone because the reduction of the chiral auxiliary can be stopped directly at the aldehyde oxidation state – shortening our synthesis by one step.  Another cool feature of the thiazolidine-mediated aldol addition is that three of the four possible aldol diastereomers can be accessed starting with the same thiazolidinethione starting material simply by changing the reaction conditions (click for larger).

The next interesting reaction is the 1,4-conjugate reduction of the α,β-unsaturated enoate in the presence of the aryl halide.  Because of the aryl halide, typical transition metal hydrogenation is an unfavorable reaction.  We accomplished this reduction by treating the enoate with tosylhydrazine and aqueous sodium acetate in refluxing dimethoxyethane.  The aqueous base reacts with tosylhydrazine to form diimide.  Diimide acts as a reducing agent by engaging in a [4 + 2] reaction with the alkene, delivering the elements of hydrogen across the double bond and releasing elemental nitrogen as the byproduct.

A modified Claisen condensation reaction using the ester and lithiated dimethyl methylphosphonate prepared the β-ketophosphonate in high yield (but only if the internal temperature of the reaction is held steady at -78 °C.  The reaction is completed essentially instantaneously, but if the internal temperature is any warmer than -78 °C, the reaction suffers from dramatically lower yields and very messy reaction mixtures.  To ensure the dropwise addition of reagents without warming the internal temperature, I got to use one of my new favorite pieces of glassware – the jacketed addition funnel (product # UI-4980)).  Another aldol/reduction sequence provided the aldehyde necessary for the Horner-Wadsworth-Emmons olefination.

To carry out the Horner-Wadsworth-Emmons reaction, we utilized barium hydroxide as the base.  This allowed us to deprotonate the β-ketophosphonate under relatively mild conditions.  Unfortunately, without vigorous stirring, the reaction mixture turns into a gel.  It then stops stirring and the reaction suffers from disappointingly low yields.  As long as vigorous stirring is maintained, I obtained consistent yields in the 70-88% range.

Again, a 1,4-conjugate reduction was needed, this time of an α,β-unsaturated ketone in the presence of both the aryl halide and a terminal alkene.  A very interesting reaction was utilized which allowed for consistent yields without over reduction.  A catalytic amount of copper(I) iodide is dissolved in THF and an equal amount of methyl lithium is added.  To the mixture we add hexamethylphosphoric triamide and diisobutylaluminum hydride.  The mixture is kept at -50 °C for a while, then the enone is added.  Presumably, some sort of copper hydride species is formed and facilitates the 1,4-addition of hydride to the enone olefin, without interacting with the terminal olefin.

There are two main unfortunate circumstances surrounding this reaction, though.  I have to use HMPA, and the reduced product has the same TLC Rf value as the enone starting material.  Can’t do anything about using HMPA, just gotta be real careful distilling it and syringing it and disposing of it (double glove and wash everything a lot with a lot of bleach).

To work around the TLC issue, we monitor the reaction by NMR.  Nothing fancy involved – an hour into the reduction a few dozen microliters are taken from the reaction and quenched.  The solvent is removed and the residual oil is analyzed by NMR.  The HMPA signal (which is not removed by the quick mini-extraction) is huge and typically drowns out all the other signals.  Fortunately, I’m really only interested in the 6.5-7.0 ppm range.  By blowing that range up I can see the presence or (hopefully) absence of the characteristic enone proton signals.  If they’re gone, the enone has been reduce; if they’re still there, the reaction’s not complete.

“Beware the Jabberwock, my son!
The jaws that bite, the claws that catch!
Beware the diastereomers, and shun
The frumious steric clash!”

Following 1,4-reduction, all that remains is removal of the protecting groups and acidic spiroketal formation.  When triethylsilyl protecting groups are used, we can accomplish these transformations concurrently by (carefully!) using 48% HF(aq).  The spiroketal we’ve been discussing has the substituents in the ‘naturally occuring’ 2- and 8-positions about the spiroketal ring.  This is a useful proof-of-concept spiroketal, but doesn’t actually locate the substituents anywhere they haven’t already been.

So spiroketal #2 was made, now moving the terminal alkene to the 7-position.  The synthesis of the linear protected dihydroxyketone was more or less uneventful, but one aspect is worthy of note.  We desired to make a highly modular synthetic route to these spiroketals.  Since the aryl halide fragment is the same, we didn’t have to remake the β-ketophosphonate fragment.  All I had to do was make a new aldehyde in three steps and we were ready for HWE coupling.

We then proceeded to the cyclization.  First, I deprotected the silyl ethers using TBAF to give the unprotected dihydroxyketone.  Treatment of the dihydroxyketone with catalytic p-toluenesulfonic acid yielded an inseparable mixture of two spiroketals in a 3:1 ratio.  Interestingly, treatment of the bis-protected dihydroxyketone with HF resulted in the same inseparable mixture of spiroketals, but with the selectivity reversed 1:13.

Whaaat? If the doubly anomeric spiroketal should be thermodynamically stable, why would I see two different results by cyclizing under two different conditions?  And how am I going to tell which is which?  We used 2-dimensional NMR (NOESY and COESY were the most helpful, but we also got HMBC, HMQC, 1D proton, 1D carbon, DEPT, and we also asked the NMR tube really, really nicely what the 3-D conformation was).

In the 1:13 sample, we noticed an nOe correlation between protons labeled Hc and the two methyl groups, but not between Ha and Hb (a correlation we would expect to see in the desired spiroketal).  This meant the product we could produce the most of was ultimately the singly anomeric spiroketal – the wrong spiroketal diastereomer.  A positive nOe correlation was noticed between Ha and Hb in the 3:1 sample… meaning we are forming the doubly anomeric spiroketal – the right spiroketal, but not in synthetically useful selectivity.

It’s worth pointing out that the undesired spiroketal is not undesired because the spiroketal isn’t doubly anomeric, but because the vector relationship between the substituents in the undesired spiroketal is now the same as in the ‘naturally occurring’ spiroketals.  This defeats the purpose of putting the functional groups in different positions about the rings.

We thought we could bias the equilibrium toward the desired spiroketal by increasing the bulk of the methyl group.  So we repeated the synthesis with an isopropyl group in that position to make spiroketal #3.  Again, the modular synthesis only necessitated the synthesis of the aldehyde fragment, and we were ready for HWE coupling and cyclization.

We again performed the cyclization both ways to see what happened.  Again, two different spiroketals were formed, but this time as single compounds, not mixtures.  Again, 2-D NMR experiments were crucial in helping determine the 3-D configuration.  Unfortunately, in neither sample was an nOe correlation noted between protons Ha and Hb, meaning neither spiroketal is in the desired conformation.  In the sample where HF was used for cyclization, extensive analysis of the 2-D data led us to believe we did form the right spiroketal diastereomer, but the steric hindrance of the axial allyl group caused one of the 6-membered rings to be oriented in a boat conformation, not a chair conformation.  We still don’t know the absolute configuration of the other sample, but it ultimately is irrelevant, because the two substituents are not in the desired vector relationship.

So while we proved a modular synthesis of spiroketals, the major goals of the project were not met, in that we could not predictable control the vector relationship between the two substituents.  So we ultimately decided to revamp the project and take our modular synthesis and apply it to the total synthesis of a spiroketal-containing natural product.  But perhaps I’ll save that story for another post…

*My Life and Hard Times is the name of James Thurber‘s autobiography.  In high school, I played James Thurber in a play called Jabberwock based on his autobiography.  It chronicles the hapless Thurber’s teens/early adult life and his mishaps and tribulations in a dysfunctional family.  In the middle of the play, when he feels no one gets him and he gets overwhelmed with his comedy-of-errors life, he recites the Lewis Carrol poem Jabberwocky to the girl of his affection.  She doesn’t get it.  This is how I felt during grad school, so that’s why I framed the post this way.

Nov 26

The Wiley Interscience Blues


Hello, everyone!  Since this is my first post on Chemistry Blog, I should introduce myself.  My name is Nick, and I’m a Ph.D. student in organic chemistry at McGill University, in Montreal.  Mitch contacted me via the chemistry subreddit, and I’ll be writing a few articles with what I hope is a unique perspective.  In advance, I would ask that you excuse my Canadian spellings; the letter “u” will pop up a lot more often than you’re used to.

As anyone who regularly reads scientific journals may have noticed, Wiley redesigned some of their website earlier this year.  Mid-way through the summer, they slicked up their Interscience pages to look more “Web 2.0″, and in the process, broke integration with one of my favourite things, which is Zotero.  Zotero was previously mentioned on the site quite some time ago, as one of several reference management programs available to modern researchers.  Given that it’s free, absurdly easy to use, efficient, fast, allows proxies, and acts as a bridge between OpenOffice and Firefox (with downloadable reference formats), I unabashedly support the abandonement of every other reference management system in favour of it.  Zotero makes collecting references and writing papers a breeze, and a whole lot more enjoyable than any other option I’ve tried.

What Wiley did to break Zotero’s flow was very simple.  Instead of having direct links to actual PDF files as part of their abstract pages (as nearly every other online publishing website does), they now direct you to a PDF file within an “iframe”, meaning that Zotero is not able to “see” the PDF as an actual PDF.  This allows them to place a highly annoying “Wiley Interscience” bar at the top, including your institutional logo, and links to citing articles, abstract, and supplementary info, as seen blow.

This would be okay, except that with Zotero absolutely none of those links are necessary.  When you do the one-click save on an abstract it automatically generates a snapshot of the abstract page, including links to all that information.  Normally, it also saves a copy of the PDF, but Wiley has now made this significantly more complicated.  You must now either save the iframe page as a snapshot (including the annoying header and useless links), or download the PDF separately, import into Zotero, then delete the original download to avoid having duplicate copies on your hard drive.  So basically, instead of a one-click save, you now have an option of a four-step non-PDF download (via the “add item” button, seen above at the bottom left), or a five-step (take snapshot, navigate to “pdf”, download, import, delete) rigmarole.

Compare this to ACS Publications, or ScienceDirect, where you click once on the address bar icon, and get all the above done in about 5 seconds (see below), or even ThiemeConnect, where you simply have to add the PDF as a separate item, and Wiley’s “site improvements” actually begin to look like a big step backwards.

I’ve e-mailed Wiley about this twice, and it seems that their support staff have no idea what Zotero is, or why this is important, and don’t seem to care.    Ultimately this isn’t a huge issue, but I would really love to see a return to the old functionality; as it stands right now I cringe every time I see a paper I want hosted by Wiley Interscience.

Nick

Nov 10

Wiley Wants Organic Chemists


Wiley is looking for organic chemists to participate in the usability testing of a new online chemistry content service on the 17th/18th November 2010. If you are interested and meet the criteria below, kindly contact Azia Mughal.

Notice:

We are looking for people with the following criteria:

  • Currently engaged as a research chemist in an organic chemistry lab at the post-doc level or above.
  • Working either in industry or academia
  • UK Participants, in London should ideally able to travel to Holborn. US participants, we can arrange for you to see the updates on the internet via a live link and call you on the phone to gather your feedback about the different elements.

Participants will be paid a fee in return for their time.

Interested candidates should send their name, email, and institution name to the following email address Azia.Mughal@serco.com and they may be contacted for further information.

Mitch
Read the rest of this entry »

Nov 05

The Life Cycle of a North American Research Project


Simply reading a research article doesn’t provide any insight into how a project progresses from inception to fruition/publication. Sometimes projects start as a good idea. Other times they begin from interesting or unexpected results. Every so often, it is an accident.

These auspicious origins are further clouded by the tendency of authors to present their results as if they were intentional from the very beginning, even if they stumbled upon them. To a younger scientist reading these papers it can feel overwhelming to begin research. They may ask “how could I ever possibly get from here to there?”

A project that I started four years ago at the beginning of graduate school was finally published last week. It was by far my favorite project. Not only because of the content but also because of the journey. In response to a question posed by masterm on the chemistry subreddit, I am going to share my experience with the process between inception and publication for this project and hopefully provide some insight for the uninitiated.

My graduate career can be broken down into two categories: 1) research that pays the bills and 2) purely scientific research. In 2005 when I started graduate school my adviser, Mark Thompson, came to me with a not so simple request: “Find a molecule that exhibits efficient (>10%: more than 10 out of every 100 photons that are absorbed are then emitted) phosphorescence between 750 and 900 nm.” This project fell into category 1 because it had specific, short-term, grant dictated goals along with a long term goal of producing a commercially viable product.

Unfortunately/fortunately the number of published molecules that efficiently phosphoresce in that wavelength range is limited. During the years that followed my colleges and I (team IR) became entrenched in the idea of taking known molecules and extending the π-conjugation to red-shift emission. This strategy was based on a common tenet in small molecule photophysics that says if you extend the π-conjugation of a molecule (add more benzene rings) you will lower the energy of absorption/emission (changing from blue/high energy/shorter wavelength towards red/low energy/longer wavelength). It is a ‘particle in the box’ mentality. That is, if you extend the box you will lower the energy of the system. The words “let’s just add some benzene rings to it” became our regular chorus. With this mantra we had a considerable amount of success, adding benzene rings (benzannulating) platinum porphyrins. Attempts at benzannulating other systems were less successful in that they either did not shift the emission or they were unstable.

At the 2006 ACS meeting in San Francisco I presented my results on one of these “failed” pursuits. I also made an effort to go to as many talks and poster secessions as possible hoping that I would come across a new molecule/ligand that might help reach our goal. I kept seeing 1,3-bispyridylisoindole (BPI) ligand in various catalysis presentations. It caught my attention because it has many of the components that we have in our near-infrared emitters: a pyrrole like our iridium dipyrrins (λem = 672 nm) and platinum porphyrins (λem = 650 nm), an isoindole like platinum tetrabenzoporphyrins (λem = 765 nm) and phthalocyanines (λem = ~1000 nm). It is a simple concept in chemistry that, more often than not, if things look similar they will exhibit similar behaviors.

Before we ever go to the bench and synthesize a new molecule we first perform a DFT calculation to get an estimate of its phosphorescence wavelength (Etriplet-Esinglet or EHSOMO(triplet) – EHOMO(singlet)). In my hotel room that night I performed this high yield “reaction” (Titan: B3LYP, LACVP**) and inserted a platinum chloride into BPI and found the calculated emission wavelength was 675 nm. That is way out into the deep red but not quite to the 750-900 nm we were looking for. So what’s next? The chorus comes around again: “BENZANNULATE!” Adding three benzene rings (bottom right) to the parent structure (top middle) resulted in a modest red-shift in the emission wavelength from 675 nm to 697 nm. Needless to say, this was an anticlimactic result. I was disappointed and wanted to understand why there was only a small shift, so I calculated a series of these molecules (above). A clear trend can be observed, benzannulating the pyrrole ring results in a blue shift, benzannulating the pyridyl ring results in a red shift. The calculated blue shift is counter to the common expectation that benzannulation results in red shifted absorption/emission.

Between my advisers interest in the two molecules predicted to emit above 800 nm and his desire to find out if the calculations were correct, he gave me permission to pursue the project. Following published procedures or slightly modified versions of these reactions I was able to produce several similiar molecules. In both absorption and emission, the predicted trends were correct. In fact, even without taking a measurement it was obvious to the naked eye that the absorption and emission were blue shifting upon benzannulation of the pyrrole ring (left).

So now that we knew that the phenomenon was real, the question was “Why the blue shift?” Turning to literature we were able to find several examples of molecules that exhibit this behavior but the explanations given were either incomplete or molecule specific. No generalized explanation could be found.

So we had a mystery on our hands. Between our preliminary calculations, photophysical and electrochemical measurements we were able to conclude that an unchanging HOMO energy (similar oxidation potential) and a destabilized LUMO energy (increasing reduction potential) with each benzannulation was responsible for the observed trend.

Proud of our result and the conclusion we had reached at this point, I was excited to present the results at the Southern California Inorganic Photochemistry Conference (SCIP). I explained the story and results of the discovery and at the end of my talk Professor Jeffery Zink (UCLA) asked a simple but profound question that I was unable to answer: “Why does the LUMO go up?”

Reflecting on the question I experienced a flashback to constructing orbital diagrams in undergraduate chemistry classes. For the sake of people not to familiar with the topic, I will quickly review molecular orbitals. The interaction between two orbitals can be broken down into three categories: bonding, antibonding and nonbonding. In cases where the energies and symmetries of two orbitals are similar they will interact to produce a stabilized bonding and a destabilized antibonding interaction. The shape and energy of these bonding/antibonding orbitals will be dependent on the energies of the two interacting orbitals. In cases where the orbital energies are extremely unequal no interaction will occur. Similarly, if the symmetry of two orbitals are not similar they will not interact (example: px and py are orthogonal and thus will never interact).

Using thus basic principle to construct an orbital diagram of naphthalene from the combination of benzene and butadiene you will find that a HOMObezene-HOMObutadiene bonding/antibonding interaction destabilizes the HOMO (increases the energy) and a LUMObezene-LUMObutadiene bonding/antibonding interaction stabilizes the LUMO (decreases the energy), as shown below.

The HOMO destabilization and LUMO stabilization inevitably leads to a red-shifted absorption (smaller ΔE for the HOMO to LUMO transition) of napthalene relative to benzene. This type of orbital interaction is the reason behind the common expectation that benzannulation will red-shift absorption/emission.

Without an answer to the question (“Why does the LUMO go up?”) I presented these results again at the 2008 ACS meeting in New Orleans. At the meeting I had a chance to catch up with one of my closest friends and a fellow graduate from the St. Cloud State University’s  chemistry department, Luke Roskop (St. Cloud State is a small university in Minnesota that you have probably never heard of unless you enjoy college hockey). It just so happens he was/currently is a graduate student at Iowa State under one of the world’s foremost theoretical chemists, Mark Gordon. After a conversation that night and permission from both of our advisers we decided we were going to combine our expertise and do our best to come up with an answer.

Over the several months that followed and through a combination of time-dependent DFT calculations, photophysical measurements and a bunch of reading we were leaning towards an argument that involved orbital diagrams. However, it was not until holiday break while both of us were back in Minnesota at Luke’s parent’s dinning room table that we had a break through. As a synthetic chemist, I often pigeon-hole myself into only thinking about molecules that can be made. In fact, I sometimes get an uncomfortable feeling when looking at a molecule that “feels” unstable. One of the things that I love about theoreticians is that if it can be dreamed of they can calculate it. Luke’s ability to imagine the “impossible” became infinity useful on that particular day. Utilizing his remote access to Iowa States computing cluster, Luke just started making changes to the BPI motif to figure out the effects of structural changes on the HOMO/LUMO orbitals and energies. After looking at dozens of molecules a tremendous feeling of clarity hit me. It was one of those rare moments that all scientists search for. My internal conflict floated away and for a brief moment I felt as if the universe made sense. I turned to Luke and said “You are going to love this!” What followed was my tentative explanation of the phenomena and then a long discussion between us to iron out the details. By the end of the night we had outlined what as of last week became our publication.

Ignoring the importance of justifying the use of molecular orbitals (beyond the scope of this summary but is discussed in the paper) our rationalization can be reduced down to a simple molecular orbital argument. In the orbital diagram for benzene we find that a LUMO-LUMO interaction leads to destabilization of the LUMO of naphthalene as compared to benzene. In the system described here, the HOMO of (BPI)PtCl (middle) has very little orbital density at the sites of butadiene addition and as a result no mixing occurs and the HOMO energy/orbital remains unchanged.

The LUMO however, is energetically similar to both the HOMO and the LUMO of butadiene thus the type of interaction that occurs is dictated by the symmetry of butadiene addition. The nodal plane of the LUMO at the end of the isoindole ring of (BPI)PtCl is the same symmetry as the HOMO of butadiene (also has a nodal plane) and thus a bonding/antibonding interaction occurs that destabilizes the LUMO. The unchanged HOMO and the destabilized LUMO results in a blue-shifted absorption of the benzannulated product (right) relative to the parent molecule. Alternatively, the lack of a nodal plane on the pyridine ring at the sight of butadiene addition results in the expected LUMO-LUMO interaction resulting in a stabilized LUMO of the isoquinoline derivative (left) and red shifted absorption relative to the parent molecule. Similar arguments hold true for not only for benzannulating the other positions of (BPI)PtCl but also the previously published examples of blue-shifted absorption upon benzannulation.

In short, we found an unexpected but straight forward visual manifestation of molecular orbital theory.

We finished up the paper (an ordeal in itself), submitted it, and it was accepted after revisions.

Take home message from this project:

  1. Go to presentations that are unrelated to your research/expertise.
  2. Pay attention to your unusual results.
  3. Gather knowledge. The more knowledge you have in a subject matter, the more likely you are to recognize something unusual.
  4. Find an adviser that will let you pursue an interesting project (I have no idea how to make this happen other than word of mouth or just get lucky).
  5. Don’t rule out the imaginary molecules. Sometime they are exactly what you need.
  6. Try not burn any bridges in pursuit of your goals; you might need help later.

Oct 18

Nexium’s Dirty Little Secret


This is Prilosec OTC (omeprazole, also marketed as losec, antra, gastroloc, and a number of other names in other countries):

This is Nexium (esomeprazole, also marketed as sompraz, zoleri, lucen, etc):

Did you note the difference?  I’ll give you a second to look again.

Omeprazole was brought to market by (what is now) AstraZenica in 1989.  It is used in treatment of gastroesophageal reflux desease (GERD, commonly known as acid reflux).  It is a proton pump inhibitor which works by blocking the production of gastric acid by parietal cells.  It was a blockbuster drug.  In the year 2000 alone, omeprazole made $6.26 billion.  But in 2001, omeprazole’s patent was set to expire.  AstraZenica needed something to fill their pipeline, so they looked at their data for omeprazole.

Omeprazole is an example of a little-known class of chiral molecules where the stereogenic atom is not carbon.  We  typically think of stereocenters with carbon as the central atom.  But this is an example of a stereogenic sulfur atom (in case you’re wondering where the fourth ‘thing’ bonded to sulfur is, it is a pair of electrons.  See the explanation of chiral sulfoxides for more information.  Ellman’s chiral auxiliary is a good example of chiral sulfoxides in use).  Omeprazole is a racemic mixture: an equal mixture of (R) and (S) enantiomers.

In looking at their data on omeprazole, they noticed that the (S) enantiomer was more potent than the (R) enantiomer (according to this website, 4 times more potent).  So in 2001, AstraZenica prepared and won FDA approval for enantiomerically pure (S) omeprazole, which they called… esomeprazole.  Very creative.

So in 2001 when omeprazole lost patent protection, esomeprazole came to market.  In theory, you should be able to take a smaller dose of esomeprazole to achieve the same efficacy of omeprazole.  Indeed, the top suggested dose of omeprazole is 80 mg, and the top suggested dose of esomeprazole is 40 mg.  The only difference between the two drugs is the optical purity.  Omeprazole is a racemic mixture, and esomeprazole is optically pure (S) enantiomer.

So while I’m no health care professional (and my opinions should not be taken as such), it seems to me that if you’re taking prescription esomeprazole, you should ask your doctor if a higher dose of omeprazole (which would be cheaper if you get the generic version) would work just as well.

What’s also interesting to me (which I did not know until I was reading up for this post), is that omeprazole and esomeprazole are technically prodrugs: the ingested compound is not actually the active molecule.  Under acidic conditions (like in gastric acid), omeprazole is converted to a tetracyclic cation which is then covalently bound to ATPase:

Note that the tetracycle is achiral – it has no stereocenters, sulfur or otherwise.  So whether you take the chiral esomeprazole or the racemic omeprazole, both are converted to the same achiral tetracycle.  Again something to note if you’re taking the optically pure version of the drug.

Also, another interesting piece of trivia:  omeprazole competitively inhibits the CYP2C19 and CYP2C9 enzymes.  Other drugs – like warfarin and diazepam (valium) depend on these enzymes for metabolism.  As a result of the competitive inhibition, these drugs cannot fully metabolize.  The effective concentrations of these drugs is increased.  People taking warfarin or diazepam should be warned if they are planning on taking omeprazole.

So now you know: omeprazole and esomeprazole are effectively the same drug.  I’m not sure why one would take prescription esomeprazole when omeprazole is available (over the counter in most places).  I understand omeprazole sometimes has more side effects than esomeprazole in some patients, so if that’s the case, so I get taking the drug which minimizes side effects.  Make sure you also read this interesting article written in 2002 about the history of omeprazole.

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