Chemistry Blog

Dec 16

How to Succeed in Organic Chemistry – Student Response Edition


I just finished teaching my first full semester of organic chemistry as a real Ph.D. yesterday.  The semester overall went well, and I plan on reminiscing and writing out my thoughts over the past semester here sometime soon.

We had the final yesterday.  My bonus question on the final was “If you could go back to August 25th (the first day of class) and give yourself three pieces of advice on How to Succeed in Organic Chemistry, what three pieces of advice would you give yourself?”

Now, I put a whole paragraph on my syllabus (which they got on the first day of class on 25 Aug) titled How to Succeed in Organic Chemistry.  Many of the pieces of advice students mentioned were pieces of advice I put on that very syllabus… but no one listens to the professor I guess…  We also discussed this topic here on the blog several months ago, but with advice from the professor’s side of the lectern.  Again, no one listens to professors, so perhaps advice from the student’s side of the lectern will be heeded?

My favorite response: “Change your major … just kidding”

Anyway, here they all are.  Compiled and organized (with school specific entries removed).  If you’re a student taking organic chemistry, here is advice from fellow students for fellow students on How to Succeed in Organic Chemistry.  If you won’t believe your professor when (s)he tells you these same things, perhaps you’ll believe your peers.

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Dec 11

Separating the lanthanides: physical versus chemical methods?


How do you separate dirt?

Photo credit: Reuters**

There has been much talk about rare earth metals recently. In short, the People’s Republic of China has become the dominant source of rare earth* elements in the world; the PRC government has used that fact to their strategic advantage. I don’t really wish to get into the political debate; suffice it to say that I think there’s more smoke than fire here and that predictions of war are probably overblown.

There are quite a number of articles on the subject, but only one talked about the chemistry. I was struck by a quote in an article on ForeignPolicy.com by Tim Worstall, a trader in scandium and other rare earths (now there’s a job I didn’t know about):

Another possibility is that we find a new and different way to separate rare earths, as we find new and different sources for the ores. The main difficulty is that chemistry is all about the electrons in the outer ring around an atom, and the lanthanides all have the same number of electrons in that outer ring. Thus we can’t use chemistry to separate them. It’s very like the uranium business: Separating the stuff that explodes from the stuff that doesn’t is the difficult and expensive part of building an atomic bomb precisely because we cannot use chemistry to do it — we have to use physics.

It’s quite apparent that Mr. Worstall is referring to the unusual electronic configuration of the lanthanides, where the 4f orbitals are ‘hidden’ behind the 4d and 5d orbitals. This electronic configuration is also responsible for the lanthanide contraction, in which the atomic radii of the lanthanides are smaller than predictable by periodic trends.

However, I’m not quite sure what Mr. Worstall means when he draws a distinction between chemical and physical separation of the elements. Both this article (from Oxford) and the Wikipedia article on the lanthanides suggest that countercurrent exchange methods are used on industrial scale; it appears that separation is performed by means of ionic radii and size. While this certainly doesn’t rely on the reaction chemistry of the lanthanides (because it appears they all act similar), I have a difficult time calling these techniques physics-based.

Readers, can you shed any more light on the issue? Do you agree with Mr. Worstall’s distinction between chemical and physical means of purifying elements?

*It should be noted that the rare earths are, as they say, neither rare or nor earths.
**Photo from this International Business Times article.

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
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