Tough-to-Swallow Propargylation

As I thumbed through the recent Tet Lett abstracts, I encountered this title:

"Regioselective propargylation of aldehydes using potassium allenyltrifluoroborate promoted by tonsil"

Turns out, the authors were referring to Tonsil (R), an acid-treated calcium bentonite clay, not the fleshy pockets in the back of the throat associated with immune response. I guess BRSM  doesn't have to update his "Desperate Conditions" list quite yet...

So, in summary:

This.

Source: Sud-Chemie

Not This.

A Wordle Challenge

BRSM wrote a fun post today analyzing my blog's content using Wordle, an infotainment app for gauging word frequency (really? Really.)

I thought I'd extend the concept a bit, and turn Wordle loose on some unsuspecting academics. Below, I've shown five graphics culled from the "Publications" page of five well-known synthetic organic chemists - minus a few* common words.

I've removed the main author's name from each, but can you still guess who they are?

Entry 1

Entry 2

Entry 3

Entry 4

Entry 5

Leave a guess in the comments...if you dare!

*Supporting Information, Chem, Author name, pdf

A Poste-docke Limerick

(This post was written as part of the BRSM Blog Party. For more worldly wisdom, check out Jess's entry, Stu's, Vittorio's, and Freda's...)

There once was a chap from the UK,
Who wanted to study in Ussay.
He said "I know what,
I'll get scuttlebutt,
And figure out how to be OK."

His mates on thine Twitter doth proclaim,
That the Yankee chem kids are most profane.
They 'colour' incorrectly,
Forget 'football' and 'high tea,'
Those Yanks just love coffee and ballgames.

Dollars - not pounds - will buy groceries,
Pounds - and not stone - for the weights, please.
In lab, we know grams,
Kilos and drams,
But don't order 'litres' of gas, geez!

Driving's best done on the right,
Try not to run the red lights.
I'd recommend bussing,
But I'm not quite trusting,
No double-deckers in sight.

Remember your relative youth,
You're prob'ly much further in truth.
Our 'Docs' start too late,
Feel put off and irate,
Student loans and long programs are uncouth.

Keep your head down and do good work,
Take on new skills and avoid jerks.
Get a paper or two,
Make some new friends to boot,
And never say no to some pub perks.

Good luck, B.R.S.M. Come see us sometime, we'll buy you a pint.

Escalation: Authors Respond

Regular readers know I sent out an inquiry to the Fe-S authors a few days back:

Dear Prof. Nguyen:

Good afternoon. My name is See Arr Oh (a pseudonym), and I write a chemistry blog called Just Like Cooking. I've posted about one of your recent publications in JACS ASAP:

http://justlikecooking.blogspot.com/2012/12/desert-island-chemistry-simple-as-fe-s.html

http://justlikecooking.blogspot.com/2012/12/call-to-arms.html

Another chemist at Princeton graciously offered to repeat one of your reactions (Table 2, entry 2), and could not duplicate your group's yield or purity. Further discussion can be found in the comments section of the second post. Additionally several other members of the chemistry community have expressed an interest in running it themselves, with the intention of aggregating data under the Twitter hashtag #RealTimeChem.

Please share some more information - do you have any hints or tips for successful duplication? 

Thank you in advance,

See Arr Oh

seearroh@gmail.com

Unfortunately, my spam filter ate the (prompt) response, and thus I'm posting it a few days later than when I received it back on 1/2/13:

Dear See Arr Oh,

Thank you for your mail. First, you should carry out the reaction in the same scale as described, otherwise, sulfur is comsumed by reacting with methylhetarene before combining with iron. Second, a vigorous stirring is necessary to disperse iron powder into the reaction mixture. At this temperature, the reaction mixture is homogeneous except iron powder. Third, the reaction should be carried out under Ar atmosphere because oxygen is not an innocent impurity. Oxygen in the reaction tube is best removed in vacuo (10 mmHg is ok) then the tube is filled with Ar. This cycle is repeated twice. Before running an NMR spectrum of the crude mixture, paramagnetic iron residue should be removed by syringe filtration to avoid any magnetic pertubation. In most cases, the products were formed as black solid. The prduct is fluorescent with UV lamp.

Sincerely

Nguyen

Interesting tidbits: vigorous stirring, as opposed to a debate in the comments over whether we should stir the reaction at all, scalability issues, and recommendations for NMR analysis - Fe junk really does mess that up!

Methinks this advice might come too late* for anyone trying the reaction today; sorry, B.R.S.M.!

*Addendum - That's a lot of "insider info" in that email, and I'd argue a lot of the online discussion we've had on this reaction could have been avoided by a more complete Supporting Information file. None of that info was available either there or in the paper, nearest I can tell. Readers?

One More for the Road

OK, between my last post and that B.R.S.M. post, we've covered soda, wine, beer, carrots, salmon sperm, bone meal, coffee, and whiskey. If you include his comments, we can toss wool, almond meal, clay, and urine into the mix. But a recent J. Med. Chem. abstract may take the cake for me...

Poop.

Yup, here's the abstract, graphic and everything:

Source: J. Med. Chem. 2012, ASAP

What's the cecum, you ask? Great question! It's a "pocket" of large intestine, immediately following the small intestine and just before the colon. Apparently, it's renowned for two things: a high level of gut flora, and an anaerobic environment. When metabolism / fate scientists want to see what happens to an intestinal prodrug, this model comes into play.

Here's the prep, "fresh" from the Supporting Information:

"A solution of phosphate buffer (50 mM, pH 6.8) was prepared and deoxygenated by bubbling nitrogen for ten minutes. Male Sprague-Dawley rats were sacrificed and the cecum was exposed. The cecal contents were removed and used to make a 10% w/v suspension in the oxygen free buffer."

The microbe-rich slurry, after incubation with the compound at 37 degrees C with exclusion of oxygen, reduces down disulfide bonds, azo groups, even nitro aromatics to the parent anilines in "just a few hours."

Dunno about you, but I still think I prefer ol' Zn / AcOH. Probably smells a bit better, anyway.

Chem Coach Carnival, Day Three

Chemists everywhere! It's not too late to play. Send an email along to seearroh_AT_gmail if you still want to take part.

Day 1

Day 2

Pushing ever onwards. Just after posting the round-up last night, a fresh new batch of recruits showed up! (Not that I'm complaining). Apparently, waaay more folks than I ever thought do Raman spectroscopy for a living. Today, we hear from self-acclaimed 'super-villains,' postdocs, IP counsel, Lecturers, a very familiar Fellow, and two in-silico dudes.

21. Dr. Bodwin, Prof. and Dept. Chair, "Mysterious State U. Midwest." Dr. Bodwin blogs at Everything Under the Copper Sun, Science of Cooking (hmmm...), and maintains electronic lab notebooks at Dr. Bodwin's Electronic Notebook. Call him a faculty leader, recruiter, teacher, budget-maker, just don't call him an "administrator." Dr. Bodwin's story of a grad school "mistake" led him to a whole bunch of unexpected papers...and half his thesis. 

22. Chad, physical chemistry graduate student. Chad blogs at The Collapsed Wavefunction. He claims, like many, that there's no "standard day," and his hours seem to run to grad school extremes. Chad, like many, did a two-year stint in industry before returning to grad school. He plays card games while the laser warms up. Chad recommends learning how to pronounce names of famous chemists before you have to speak them aloud at oral presentations (Good advice!).

23. Dr. Rubidium, Evil Genius / Supervillain. Dr. Rb blogs at JAYFK, Thirty-Seven, and maintains a rockin' Twitter feed. I'm fairly certain she has the henchmen claimed in the post, somewhere deep underground. Dr. Rb walks us through the convoluted world of villains: hierarchy, daily routine, and career objectives. Oh yeah, and forensic science appears in there, somehow. BWAHAHAHA!

24. Michael, grad student / blogger. He blogs at The Organometallic Reader and Cheersical Education. Michael's interests lean heavily towards pedagogy, as one can see from his fantastic organometallic lectures (online). For those who want to teach? "Start early; there's a tired old fogey out there waiting for your youth and enthusiasm." He enjoys long walks on the beach, being recognized on campus solely by voice, and anthropomorphizing chemical events.

25. Marcel, Research Prof. / Computational Chemist, University of Girona. Marcel blogs at Trends in Science. He's an "excellent scientist, performing breathtaking research." Marcel inherited a love of numbers from his accountant father, and feels his postdoc(s) taught him a lot concerning project management. Ask him about how chemistry miraculously 'cured' him of mono...

26. Derek, Research Fellow, Vertex. Derek blogs at In the Pipeline - we consider him the "blogfather" for the chemblogosphere. Derek provides a fantastic med-chem primer, touching briefly on the joys of bench work, project management, binding pockets, and what it's like to bounce around multiple companies. Some of his reactions still form sticky maroon tars; not just yours and mine. Some caveats? "Never talk yourself out of an easy experiment," and "never assume your future grad advisor won't call you in the middle of the night." ; )

27. Darren, Patent Attorney, EIP Elements. Darren blogs at The IP Alchemist (catchy!). He shows us bench types a different aspect, namely examining prior art, and how new ideas become patentable. He's fluent in Japanese; a fringe benefit of the trade (and a postdoc spent in Japan!). Darren's frequent travel to fun and exciting locales makes me dream of a career in the IP office.

28. Janet, Science Philosopher, SJSU. Janet blogs at SciAm's Doing Good Science, as well as Scientopia's Adventures in Ethics and Science. She helps people who are "scared of science" learn about where it comes from. Janet's actually a "double Doctor" - chemistry and philosophy - which you certainly don't see every day. Have a peek at her Philo 133 syllabus, quiz her about the importance of lab safety, or ask about rubbing elbows with Nobelists (twice!).

29. Mark, Applications Scientist, Rigaku Raman. Mark's full entry is published below:

Your current job: I’m working as an Applications Scientist for a portable Raman instrument company.  I’ve enjoyed spectroscopy since graduate school and this position is a good fit for my scientific interests. Because my company is a small startup, it will be a great learning opportunity to develop business skills. The company has a unique product offering for their market, and I’m confident that we’ll be successful. 

What you do in a standard work day: My current position is new, so most of my initial activities have involved training on our equipment and software, sharing insight with coworkers into the c-GMP environment, getting to know our sales force, and learning key marketing messages for the product.  I’ve also begun writing an application note and trade publication articles, as well as helping to edit the user manual.  Because I am a field based employee, I participate in a lot of teleconferences.  I’ll also travel to visit customers, help to train the sales force, and work at trade shows. My position will involve product marketing and seeking out business development opportunities.

A position like this requires soft business skills in addition to technical knowledge.  The ability to network and collaborate with project teams, organize work activity, communicate with customers and coworkers, and frequently delegate without authority are all key to succeeding.

What kind of schooling / training / experience helped you get there? I went to graduate school at a small university and earned a terminal Master’s degree in physical chemistry, specializing in FTIR and Raman spectroscopy.  I’ve held a variety of industrial and pharmaceutical R&D positions as an analytical chemist and also have prior experience as an Applications Scientist with a large analytical instrumentation company. My current position will draw upon that experience base.

I’ve learned that networking is critical career development, not only in finding a new position but also building collaborations to accomplish business goals.  Also, participation and volunteering in professional organizations, such as a local American Chemistry Society section provides opportunities to develop soft skills.

How does chemistry inform your work? I use my understanding of chemistry to help customers select the best solution for their problems or processes.

Finally, a unique, interesting, or funny anecdote about your career: I’m part of a dual chem-career couple.  My wife is a PhD chemist and is currently manager of an analytical group at a specialty chemical company.  We’ve found that geography is critical for dual chem-couples; there really needs to be enough industry where you live to support both careers.  Early in our careers, we worked at the same company.  Seeing the “writing on the wall” we found new positions and relocated before facing a dual lay-off situation.  Altogether, we’ve been really lucky with our jobs so far and work to be supportive of each other’s career growth.

30. Nathan, Computational Chemist. Nathan's full entry published below:

Your current job.

For the past 5 years I’ve led the In Silico Medicinal Chemistry research group at the Institute of Cancer Research in London. I started off as a computer scientist in my undergrad days but moved into chemistry (chemoinformatics) when I joined Prof. Peter Willett’s lab in Sheffield. I’ve had a bit of an unorthodox path to where I am today.

What do you do in a standard “work day”.

My job is now very reactive, which has changed since my time before joining the ICR when my day job was mainly programming. I support both my group and oversee support for our therapeutic projects. This involves lots of computational methods, such as: virtual library design; multi-objective prioritization; docking; pharmacophore searching; building and validating predictive models in QSAR approaches. Much of my work involves assessing the vast space of virtual compounds we could make, but we are unable to in resource-limited academia.

We are a post-graduate college of The University of London so a lot of my time is devoted to supporting our PhD students and PostDocs advising them on tools and techniques to apply in their projects. I also spend a lot of time writing papers with my colleagues, from basic computational methods right through to our teamwork on drug discovery programmes. I am also currently editing my second book, Scaffold Hopping in Medicinal Chemistry, following one that was released recently: Bioisosteres in Medicinal Chemistry.

This year we’ve also had quite a few external visitors, which has led to a few TV appearances on British television on BBC Horizon and Newsnight. You can see the programme on ‘Defeating Cancer’ here: http://www.youtube.com/watch?v=7TyB07imDug&t=42m53s

What kind of schooling / training / experience helped you get there?

I have a first degree in computer science, which was followed by a PhD from Prof. Willett’s lab in Sheffield. In my undergrad life I focused on evolutionary algorithms, particularly writing software to simulate adaptive artificial life models. It was this initial interest in ‘writing software that writes itself’ that led me to work with Peter in Sheffield. I followed this with a Marie Curie Fellowship at Avantium Technologies, Amsterdam and Prof. Johnny Gasteiger in Erlangen for two years and a Presidential Fellowship at Novartis in Basel for another three years.

I never really wanted to work in IT but wanted to use computers to answer questions in other disciplines. I think the most useful experiences I’ve had is working with colleagues from other fields. I find these interactions very rewarding, particularly if you’re unafraid to ask questions that might seem silly. An orthogonal viewpoint has put me in good stead.

Throughout my career, my academic mentors have instilled the clear importance of the scientific method. It is so important in computational sciences to ensure that we do not become beholden to our own ideas because a computer will tell you what you want to hear. At least in real chemistry Mother Nature will give you a slap and say, “No!” The computer often says, “Yes!” This can lead to what I term the ‘pretty picture’ syndrome in some computational work. I always advise my students accordingly to clearly state the hypothesis and how they’re going to test it.

How does chemistry inform your work?

I use mathematics a lot to try and explain chemical phenomena. This is not all that different to scientists in the 19th century who used mathematical representations of molecules with the advent of atomistic theory. One of my mentors referred to a chemical reaction as a context-dependent mathematical graph transform, and in the abstract this is true. I like to look back over old papers and not taken common methods for granted. It is always important to understand how different computational algorithms work: with understanding comes control and can only contribute positively to our work.

There is a famous quote from Feynman: "If it disagrees with experiment it is wrong." This should be the mantra of the computational scientist in whatever field. Our models and predictions must be reduced to practice often to both test our hypotheses but also provide a feedback loop into the system. Therefore, chemistry is fundamental to this. If I suggest a compound that does not fulfil my predicted potential, I have wasted substantially more of someone's time in the lab than in my blase prediction. Due to this, I spend a lot of time doing my best to validate my methods as often as possible.

Finally, a unique, interesting, or funny anecdote about your career.

Although I’m an in silico medicinal chemist, I have been tempted into the lab on occasion. A few years ago I spent a day in the lab working on a halogen dance rearrangement. On my way home that evening I came off my bike, breaking my arm and dislocating my shoulder. Irrationally, I blame working in the lab and that was the end of my synthetic organic chemistry career to date. I knew synthesis was dangerous, but didn’t expect this to be the result.

31. Mike, Technical Editor / Webmaster, AATCC. Mike's full entry published below:

I morphed into science writing unexpectedly, and late in my 30+ year career. I have a BS, Chemistry from the University of Virginia and an MS, Chemistry from Colorado State University, and have been an ACS member since 1980.

Someone once told me that chemists can do practically anything. I didn’t believe them then. I do now!

My loves are natural products/synthetic organic chemistry, astronomy, and meteorology. Was a research chemist primarily in health care products industry. Got swept up in the lure of computer-aided chemistry tools, especially molecular modeling. Learned Unix on my own back in the 1990s. Discovered what “gophers” were, and then, hearing about the Web, realized something big was coming. Got out of the lab and became a webmaster contracting with the National Institute of Environmental Health Sciences for two years. I then rode out the internet boom and bust, until landing my current gig as technical editor of scientific articles and webmaster for the American Association of Textile Chemists and Colorists in 2003.

Adaptability is the key to success in today’s world. I would have never guessed ten years ago that I would have enjoyed being an editor and writer. These were “hidden” talents, until the opportunity presented itself. Even more surprising was finding out that I could write for the public! I had long desired to do this, but didn’t think I had the ability. Two mentors at AATCC convinced me otherwise. As a result of their encouragement, I won a Gold Tabbie Award in 2011 for one of my newsletter articles.

I write articles for AATCC News, the association’s newsletter, relating to textile science. This includes chemistry’s intersection with the larger world of textiles: including fashion! Can you imagine: science on the runway! It’s both fun, challenging, and there is so much to learn!

Most recently, I’ve been an active proponent of social media as an engagement tool. Our Association’s LinkedIn site has become a major textile industry resource. I have little time to blog, but love microblogging (Twitter).

My advice: Do what you love, no matter what, but don’t hesitate taking opportunities to test new skills that broaden your experience. If you want to write, start on Twitter. It’s a great place to meet like-minded people and get your feet wet. Finally, be sure to keep a sense of humor about yourself and what you do-it helps when times are tough.

>>>
>>>
>>>
>>>

32. Late Addition, just under the wire: B.R.S.M., postdoc / blogger, UK (and soon to be in the US of A!). Blogs 'eponymously' at BRSM. A true synthetic chemist, he's proud to "wear the white coat" and work at the bench. I'm jealous amazed that he's achieved so much at such a young age; blame credit the shortened British Ph.D. Seriously, though, BRSM enjoys the freedom of not being bound by grants or teaching (for now). He's prepared for a lifetime of learning...and to learn organic "in-jokes" whenever possible.

Superlatives: Kings of Polyene Mountain

(Thanks to BRSM, for unwittingly providing the theme for this post...)

"We can rebuild him...Better, stronger, faster..." - opening to Six Million Dollar Man

Today's society steeps in superlatives. Never content with the ordinary, we want to know who's the richest, fastest, and the best-looking. Our obsession with "most" even extends into our scientific publishing; JACS actively discourages words such as "novel" or "first" from its article titles.

Well, this paper must have slipped into the system unchecked. Behold: longest of the polyenes!

Martinez, Sliwka Org. Lett 2012

(That numbering system means 80 total carbons, and 27 bonds in conjugation. For example, butadiene is C4:2)

Why embark on this synthesis, to chase the olefinic "holy grail?" Three reasons: the pursuit of "lambda ultimate" (how far can we go into the red?), to fix errors in calculated specs (off by 104 nm!), and to create ever-longer molecular wires.

Check out the Supporting Info for an historical polyene primer, from 1899 to the present. Interestingly, the field seems to have run into roadblocks based not just on available synthetic methods, but on the rock-like solubility of many polyaromatics; further frustration stems from the instability of certain cyclic compounds I'm sure would like to Alder all over the place!

My favorite part of this saga? The gorgeous superstructure of the modeled C80:27 polyene.

Martinez, Sliwka Org. Lett 2012

You might expect an all-trans structure to be stiff as a board, but let's think conformationally - each "prenyl" unit has a methyl group bashing up 'A(1,3)-like' against a neighboring hydrogen. To avoid this, it twists and shifts, producing a pleasing undulation in the overall chain.

All kidding aside, the 'longest' title surely won't stand. Now that the authors have improved methods to synthesize soluble, all-trans, long-chain poly-olefins, it's a matter of time before something wild like C220:50 comes out.

Might I suggest "The Longest Polyene...For Now?"

For Your Consideration...

A New, Improved 47-Step Synthesis of Shootmenowicene

Editor: We originally sent a 1600 x 1200
color abstract. Just picture a 15-member
macrolide, densely functionalized with
heterocycles, five stereocenters,
 and chelated iron.

Abstract: Shootmenowicene, a heterocycle-containing polyketide macrolide polyene siderophore, was originally isolated in 0.009% from immature sprouts of the Bungus bungus tree. We report herein a significantly shortened 47-step route to the natural product (down from 48), which we believe will allow for kilo-scale synthesis for future clinical trials.

Synthetic highlights include: extensive use of Yamamoto's "super-silyl" protecting group, a Sezen C-H arylation / macrocyclization, kilo-scale flash-vacuum pyrolysis (FVP), and enantioselective tributyltin hydride reduction. Efforts to adapt "green" chemical considerations have been made - the penultimate oxidation occurs by swirling flask in open air for three days over twenty equivalents iron oxide catalyst.

This streamlined route utilizes seventeen silica gel purifications, four alumina plugs, two resolutions: D(-)-tartaric acid and 1R(-)-10-camphorsulfonic acid (the expensive ones, sorry!), and a one-pot global HF / Hg / chromic acid deprotection protocol. Overall yield was 0.0008%, as a mixture of diastereomers (brsm).

Two medicinally active methylated analogues will be reported in due course.

Thanks to Derek for the initial inspiration, with a gentle nudge courtesy of Chemjobber.

Press Release

(08:00, USA; 13:00, London GMT, For Immediate Release)*

 'Just Like Cooking' to Merge with Nature Publishing Group; New Journal 'Nature Cooking'

Just Like Cooking, a somewhat relevant chemistry blog based in the United States, has agreed in principal to merge with Nature Publishing Group (NPG), London. The union will result in a new publication - Nature Cooking - set to premiere in 2013 with blogger See Arr Oh as Editor.


Said Nature Chemistry Chief Editor, Stuart Cantrill: "We were thinking about ways to grow the brand beyond simple chemistry and biology, and hit upon this idea whilst eating LN2 ice cream at Chin Chin Laboratorists. See Arr Oh brings a wealth of kitchen-based knowledge, and we'll try for a real 'molecular gastronomy' flavour with this journal." Added Associate Editor Neil Withers: "Quite so."


Editorial staff will be selected from the finest food scientists and celebrity chefs (Pépin, Lagasse, and Morimoto have already signed on), and each issue will feature a fold-out pictorial of the Editorial staff dining at fine Michelin restaurants. Initial issues will explore the finer intricacies of British cuisine, including GC headspace analysis of haggis, density checks for Cornish pasty manufacture, and isolation of potent anti-cancer molecules from Christmas puddings.

Potential Nature Cooking dress code

Reaction around the blogosphere has been decidedly mixed. C&EN Associate Editor Carmen Drahl fought back tears, saying "We were about to rename Newscripts to Foodscripts, just to get See Arr Oh to stay." Bloggers Paul Docherty and B.R.S.M. both applauded the move, while Chemjobber lamented the loss: "I'm not happy, as this reduces chemical employment stateside, but if he sends me back some jammie dodgers and a Doctor Who poster, we'll call it even."


*Please see here for more information.