Smells Like Chemistry Prose

From the April 2015 issue of Wired magazine, two wonderfully redolent paragraphs regarding the flavor chemistry of yeast metabolites, courtesy of writer William Bostwick:

"The best sourdoughs command the same sort of cultish reverence as the best sour beers and for years were thought to come only from a few places. San Francisco's loaves are so famous, a Lactobacillus species is named after the city: L. sanfranciscensis, known for molecules like fruity isobutanol, butter-sweet acetoin, and grassy 1-hexanol."

If you're more a fan of lambics, perhaps this flavor profile better suits you:

"Pediococcus produces lactic acid, lambic's dominant flavor note, but can also emit funkier flavors such as buttery diacetyl. . . Brettanomyces also makes stuff like caprylic acid (goat smell) and ethyl lactate (horse-blanket smell). They're what make a farmhouse beer taste like a farm."

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*(Title: Apologies to Nirvana).

(Please) Make More Molecules using Light!

Update (6/29) - Commenters chime in with some notables I'd mistakenly left off the list. I'll append their molecules to the end of this post (vide infra)...

I'm officially calling it: Photoredox catalysis = the new "it reaction" for organic chemistry.

Like many before it - iron catalysis, the gold rush, anything palladium, organocatalysis - photoredox catalysis is now appearing in my RSS feed on a near-hourly basis. We're in the early days of an exciting field; I've noticed more methodology papers and mechanistic studies lately. Assuming you start with a suitable aryl halide, diazonium, or carboxylic acid, the synthetic toolkit of single-electron catalysis seems virtually limitless.

Which begs the question . . .where are all the photoredox total syntheses?

Three examples of recent total syntheses that capitalize
on photoredox catalysis (bonds in red)

SciFinder: "photoredox total synthesis?"
7 hits.

How about "light-mediated total synthesis?"
7 more.

One more try: "photoredox natural products?"
7 hits.

Most of these hits actually lead to conference abstracts, not individual manuscripts. Props to the Stephenson group (Michigan), who leads the charge with syntheses of aspidosperma alkaloids and gliocladin C. Based on SciFinder results, I'd include the MacMillan synthesis of Lyrica, and Lei's isoquinoline syntheses from JOC.

Readers, what am I missing? A pivotal review or book? A group whose research is at the forefront of solar-powered natural product production? Perhaps a major non-English journal article? Any examples where a venerable old lion of total synthesis utilized a photoredox reaction alongside their Diels-Alders and aldol reactions?

For such a large-upside field, it sure seems quiet out there.
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Update: Molecules made with photoredox catalysis, as suggested by my beloved commenters:

Overman, (-)-aplyviolene, Ru(bpy)3
MacMillan, fenofibrate (OK, not a np), Ni(II), Ir(III)
MacMillan, (-)-burshernin, Ru(bpy)3
Nicewicz, methylenolactocin and Protolichesterinic Acid, acridinium
Nicewicz, magnosalin + pellucidin A
Yoon, heitziamide A, Ru(bpz)3
Yoon, epiraikovenal, Ir(III)
Chen + Baran, sceptrin, Ir(ppz)3
Chen, nakamuric acid, Ir(ppy)3
Lawrence / Sherburn, endiandric acid A, kingianins A,D,F, kingianic acid E, Ru(bpy)3
Carreira, (+)-Daphmanidin E, Co-diimine (method here)

More?

Friday Fun: Google Scholar Surprises

From Google, a.k.a. the guys with all the data, comes the most recent Google Scholar metrics.

I'm starting to really enjoy the level of specificity Google's learned around academic sub-fields. For instance, in my own sub-field of organic chemistry, who knew that Green Chemistry and Molecules were rising so quickly through the ranks of top-cited publications?

The h5-index Google's using seems like a shot across the bow of the venerable Thomson Reuters Impact Factor. A glance through the top-cited papers across all of chemistry, couched in this 5-year zetigeist, shows some surprising trends in the field: tunable materials, solar conversion, nanoparticles, and genomic medicine win the day - nary a major total synthesis among the top-cited 'scripts of any journal I could find.

If you have a minute, play around - the Google site is clean, easy to navigate, and provides direct links to publications of interest. If you stumble across anything surprising, let me know in the comments!

Happy searching, Happy Friday!
See Arr Oh

How Long are Postdoctoral Fellowships? - Part 2

Following some interesting interactions with readers on Twitter and in the comments, it seems my initial post could have improved with 1) more data, and 2) break-down by gender. So, I spent some time this weekend digging through my last two Bumper Cars posts (2014-2015, 2015-2016) in order to provide a clearer picture.

How did we get here? Read the original post.

2015 - Random Trillium from a recent weekend hike

For starters, raw numbers - as of this writing, there are 194 confirmed new hires between the two lists. Of these, I was able to track down information about postdoctoral appointments for 132 (68%). Unfortunately, there's no consistent format for how candidates track their experience; I found myself cobbling it together from LinkedIn, university websites, ACS member profiles, and digital thesis repositories.

To keep myself honest, I'm pasting my assumptions below* this post, as before.

Now, to the numbers: First, the aggregate statistics - of the 132, here's the new mean/median/mode:

MEAN:	3.49 years
MODE:	3 years
MEDIAN	3 years

MIN:             0 year (no postdoc!)
MAX:            9 years

(n = 132)

So, roughly in line with what I had before. But what about the gender gap? Do men spend significantly less time as postdoctoral scholars?

First, it helps to clarify what the real split looks like: Of 132 candidates, 39 (29.5%) are female. This may be an admittedly small data set, but I see only a slight difference** in overall time: 

3.47 years for men (n = 93), 3.54 years for women (n = 39).

Edit (6/21): A good spot to insert a quote from a 2013 Beth Halford piece in C&EN:

"For one, although there are no hard numbers to point to, some say people are spending more time in postdoctoral positions. In chemistry, one to two years used to be the norm, but that time frame may be creeping up. Some chemists tell C&EN that they are spending five or more years doing postdoctoral studies."

Seems to be the case, at least to me.

Of course, the best way to make this data set relevant is to send in even more new names! Once I can figure out a good mechanism to capture pharma / gov't hires, I'll try to expand the analysis. Who knows? Maybe we'll get a real live database set up...

--

*These postdocs reflect faculty appointments; I'm clearly not counting those who went into government, pharmaceutical, industry, or left chemistry entirely. If someone has a good idea for how to capture that data, I'm all ears.

Counting time: If someone gave a graduation year - "Ph.D. 2009"-  I assumed a postdoctoral stint until their faculty start date. For example, 2015 start = 6 years a postdoc. If, however, they provided a range - "postdoc 2012-2014" - I assumed that they postdoc'd the difference of that time, or 2 years, despite the fact that, depending on start and end dates, that could reasonably be interpreted as any length of time between 13 months (Dec 2012-Jan 2014) and 36 months (Jan 2012-Dec 2014).

Of the 77 new faculty starting in 2015 or 2016 (as of June 2015), I was only able to find bio-sketch information for half. The following people from my list are represented in the above statistics: Li, Engle, Hyster, Matson, Menard, Personick, Thoi, Tsui, Wasa, Blakemore, Browne, Devery, Gahlmann, Kempa, Limmer, Nelson, Sing, Thompson, Bantz, Hubbard, Garcia-Bosch, Huo, Wei Li, Mirica, Rossini, Seiple, Wu, Anand, Boudreau, Genereux, Jiang, Sletten, Theberge, Fu, Ke, Conley, Raston.

**One additional complicating factor? It's tough to tell who's a postdoc anymore. This study only includes candidates who list their experience as "postdoc", "postdoctoral fellow", "research associate", or something of that ilk. Senior researcher? NSF Fellow? Visiting researcher? Lab assistant? Are these postdoctoral positions, or not? Tough to tell, so I excluded them. Thus, I may be artificially shortening certain candidates' timelines.

Additionally, certain candidates had "gaps" of 1-2 years in their experience, and I could find no information for what they did. Took time off? Worked somewhere that didn't pan out? Had a child? I simply don't know.

The Old Days at Org Syn

Thanks to a bevy of used book stores, I'm slowly completing my collection of Profiles, Pathways, and Dreams, the biographical essay series from editor Jeff Seeman. I recently re-read four of these: Cheves Walling, F.G. Stone, Raymond Lemieux, and the indomitable Jack Roberts' colorful collection of biographical anecdotes. Never one to pull a punch, Roberts wistfully recalls his first involvement with Organic Syntheses in the mid-1950s, then led by famous organic chemist Roger Adams:

"The modus operandi of Organic Syntheses is relatively simple. Much of the work is carried on by mail, and the editors meet twice a year for much of a day to assign preparations, work out difficulties, plan for future volumes, choose new editors, and the like, with the current editor-in-chief presiding. Following that meeting, the editors join with the editorial board for cocktails and dinner at one of the best (and most expensive) restaurants in town. In the old days, the dinner would be followed by . . .an Adams report on whatever was on his mind at the time. He often ribbed his colleagues, without malice, but nonetheless, severely. After Adams finished, the meetings often degenerated into the semblance of a stag smoker, with rounds of off-color jokes, the most tasteless of which usually came from the representatives of the publisher . . .Rather prodigious quantities of spirits, wines, and brandies were consumed, and some of organic chemistry's most renowned practitioners had to be helped off the scene. My first encounter with these bacchanalian festivities was in Atlantic City, in the spring of 1956. I made it back to my hotel under my own steam, but I spent the next day in bed, a lesson I did not forget."

This recollection sounds uncomfortably close to how I felt each time someone in my graduate group passed their oral examinations. Some things never change.

Lord of the (Small) Rings

Quick: What small, odd-looking thing carries metal through harsh trials?

Here's hoping you answered the Doyle group's new ligand: "Fro-DO."

I see what you did there.
Credit: Doyle group, JACS 2015

Unlike common sigma donors - NHCs, amines, phosphorous ligands - EDO (electron-deficient olefin) ligands function as pi-acceptors. Instead of dumping electron density into oxidative addition (adding an R-X bond across a metal atom) EDOs speed up* the other side of  catalysis, namely reductive elimination (joining the organic fragments and restoring the metal's electrons). According to the authors, acceleration of reductive elimination helps to decrease the amount of substrate decomposition due to beta-hydride elimination.

Doyle and coworker Dennis Huang report selective ring-opening of aziridines - no mean feat in itself -  and generate a quaternary center in the process, in 31-86% yields. Using a modified camphor-like sultam for their EDO, the group observes 27% ee, sure to be the focus of its own publication in the near future. Curious about related efforts in other groups? I recommend this Jamison mini-review.

Now, back to the name: "Fro-DO" carries the torch for a small-but-growing literature subculture. Chalk up another example to what The Atlantic recently called "Science's Love Affair with LOTR." I spent a few moments with SciFinder, trying to dig up some more chemistry-themed examples; the Atlantic points out many from geology and astronomy, and precious few from our molecular audience. Without further ado:

• Superconducting magnets used in fusion research, controlled by codes nicknamed SARUMAN and GANDALF

• Retrotransposons in a .small flowering plant, dubbed "Gimli," "Gloin," and "Legolas"

• A breast cancer gene marker, called "Frodo"

• MRI pulse sequences, used to eliminate artifacts, also dubbed "FRODO"

• Finally, a docking program for small molecules and RNA, with an apt name: "MORDOR"

Readers, any more chemistry-themed LOTR callbacks? Send 'em along!

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*...or maybe not. An observant commenter on Reddit noticed that Doyle and colleagues see no correlation between 13C shift of the olefinic EDO carbons and reaction rate. They posit, instead, substantial steric congestion around the metal surface as responsible for the rate enhancement.

How Long are Postdoctoral Fellowships?

For a better analysis with more data, click here.

OK, apologies, chemblogosphere: today is apparently write-guest-posts-for-Chemjobber day.

He poses an interesting question in his "Ivory Filter Flask" post from earlier today:

" What is the median length of a postdoc these days, anyways?"

Well, I may have some answers to that question. Looking through the New Hires, I put together a list, and ran some basic statistics*:

MEAN:	3.7 years
MODE:	3 years
MEDIAN	4 years

MIN:             1 year
MAX:            8 years
(n = 38)

It's tough to make general statements about such a small cohort, but I noticed two trends:

1) Disciplines such as chemical biology, nanomaterials, P-chem, and computational chemistry tended to stay in longer postdocs.

2) About 20% of the faculty profiles were in more than one postdoc or other fellowship program prior to their faculty appointment.

Thoughts? Sound right, or wrong? Please let me know in the comments!

--

*Caveats:

These postdocs reflect pending faculty appointments; I'm clearly not counting those who went into government, pharmaceutical, industry, or left chemistry entirely. If someone has a good idea for how to capture that data, I'm all ears.

Counting time: If someone gave a graduation year - "Ph.D. 2009"-  I assumed a postdoctoral stint until their faculty start date. For example, 2015 start = 6 years a postdoc. If, however, they provided a range - "postdoc 2012-2014" - I assumed that they postdoc'd the difference of that time, or 2 years, despite the fact that, depending on start and end dates, that could reasonably be interpreted as any length of time between 13 months (Dec 2012-Jan 2014) and 36 months (Jan 2012-Dec 2014).

Of the 73 new faculty starting in 2015 or 2016 (as of June 2015), I was only able to find bio-sketch information for half. The following people from my list are represented in the above statistics: Li, Engle, Hyster, Matson, Menard, Personick, Thoi, Tsui, Wasa, Blakemore, Browne, Devery, Gahlmann, Kempa, Limmer, Nelson, Sing, Thompson, Bantz, Hubbard, Garcia-Bosch, Huo, Wei Li, Miller, Rossini, Seiple, Wu, Anand, Boudreau, Genereux, Jiang, Sletten, Theberge, Fu, Ke, Conley, Raston.

Scientific Phone Interview 101

Chemjobber has a post today asking for advice to improve success during phone interviews for scientific positions. As someone who's had to dip a toe in the interview stream several times in the past 5 years (and now routinely conducts phone interviews to fill openings in my department), I have some tips to add to CJ's arsenal:

1. (1 week prior) - Prepare.

• As CJ points out, know who you'll be speaking with, and a rough idea of their backgrounds. Any public source is fair game: LinkedIn, SciFinder, Mendeley, etc. Bonus: If the lead interviewer has recently published something germane to the position, download the paper and see if you can piece together what they were trying to do.

• Learn something about the company. Small, large? Private, public? Start-up? About how many people? Where do you fit in?

• Can you prove you're the candidate for the job, sight unseen? Break down the job description into chunks, and match with your skills. This may sound hokey, but literally grab a sheet of paper, divide into two columns "What they want"  |  "What I have" and begin filling them in. Gaps? Be sure to explain how you'll address them.

• If you don't have one, now's a great time to write up a Research Summary. Don't know how? It's easy! Condense each project you've worked on into one (1) synthetic scheme or graphic, with a plain-language description of no more than 2-3 sentences below. What were we trying to achieve? How did we do it? What did we learn?

2. (the night before) - Review.

• Go over the information from Step 1.

• Make sure you know your own CV / resume. Again, this sounds silly, but the recruiter may ask about anything you've listed, including something you don't think matters for the position in question: "Why did you choose that particular school? In Chem 257, did you happen to cover [my favorite reaction]? Tell me more about that volunteer gig from 5 years ago." 

• Eat a good meal, get some sleep. In the morning, get ready as if you were attending an on-site interview. Say some lines to yourself in the mirror: "Hi, I'm Casey Smith, from Big State University. I'm really excited for this opportunity." Practice answering a few standard questions for yourself: Where do you want to be in five years? What do you know about the job or company? How have your skills and coursework prepared you to take this job?

3. (10 minutes before) - Relax.

• Briefly review the Step 1 materials. By this point, they should be condensed into a short crib sheet.

• Print out your CV / resume, so you can write things in the margins and understand what the interview team is looking at during the call.

• Have a glass of water, clear your throat. Walk around or pace if it makes you feel better.

• Be prepared to receive the call from 5 minutes early to 5 minutes late. Phone connections are tricky things, so be prepared in case you cut out (or the interviewer does). If you do not hear from them, be prepared to send an email that apologizes and requests a follow-up in the next 1-2 days.

4. (during) - Present.

• Phone interviews are increasingly conducted "by committee;" don't be surprised if you end up on a conference line with 4 people. It's considered polite for the hiring company to introduce the call by introducing the people in the room and reiterating (briefly) the job description.

• Politeness always. Please and thank you go a long way.

• You should at this point know how to answer 80% of the questions your interviewer will ask, because you've already answered them for yourself. Experience? CV. Where you want to be in 5 years? Gap analysis - see Step 1. What you've done? Research Summary.

• Take shorthand notes off to one side, because at some point, they'll ask if you have any questions. You MUST have at least one question! This shows interest in the position and a willingness to engage the speaker. 

• Unless...your question is about an "HR" issue: pay, vacation, benefits, etc. Don't ask about these; you'll have a chance during the on-site.

• Always send a thank-you email to acknowledge the interviewers' time and preparation, and be prepared for them to ask for further information.

That's it. Good luck!

Friday Fun: Greening Chromene Synthesis with a Surprise Solvent

Old adage in organic chemistry: "If nothing's happening, keep heating until something does."

A new paper from OPRD takes that advice to heart. The authors, chemists at Merck's Kenilworth discovery site, are attempting to make a difluorochromene as starting material for a gamma-secretase inhibitor. They identify a [3,3] propargyl Claisen reaction as a logical starting point:

Looks simple, right? Well, the original conditions call for heating the alkynyl precursor in N,N-diethylaniline (yuck!) at 195 degrees Celsius (wow!). And all that for a measly 35% yield at scale. From Kong, Meng, and Su:

"There were two challenges for this reaction on large scale: the poor yield and, in particular, substantial amounts of waste produced post reaction. To produce 1 kg of compound 1, we estimated the use of 25 L of N,N-diethylaniline as solvent, 40 L of 4 N HCl to wash away the basic solvent. Combined with the silica gel needed, such a reaction would create roughly 300 kg of solid and liquid waste."

What to do? The authors reason that decomposition of the solvent at such high temperatures might be inducing the starting material to polymerize. Searching for an inert, high-boiling solvent, they land on a run-of-the-mill lab standby: Silicone Oil.

Again, the authors:

"With excellent thermal stability and good heat transfer characteristics, silicone oil has long been used for oil baths in laboratories as well as refrigerants. It is also highly soluble in hydrocarbon solvents such as toluene and xylene as well as chlorinated hydrocarbons, and therefore, it should be a good solvent for nonpolar compounds such as 6 and 1. With the boiling point of 300 °C for silicone oil vs 220 °C for the desired product 1, it should also be possible to obtain compound 1 by distillation, eliminating the workup step and waste production."

Can't argue with any of that reasoning! Sure enough, heating their starting material under nitrogen in Aldrich high-temp silicone oil (14 mL / 1 g) leads to a 64% recovery of 90-95% pure product by distillation. Notably, the same oil can be pushed through a silica gel plug and immediately re-used, with no notable change in yield or color.

Given the sheer number of high-temp cyclizations - ene reactions, Diels-Alder, Cope rearrangements, alkyne trimers, Bergman cyclization - the authors bullishly predict further use of these relatively inert conditions to open up process-scale variants of these banner reactions.

Get your high-temp silicone fast...it's set to fly off the shelves this weekend!

Happy Friday,
See Arr Oh

WWWTP? BBC's Sherlock Edition

Chemical degradation by microscope? Incorrectly-scrawled structures? Wikipedia analyses?
Looks like Scotland Yard should send their consulting detective back to University.

I'm referring, of course, to Sherlock, the BBC reboot that re-imagines Detective Sherlock Holmes and his partner Dr. John H. Watson as modern* Londoners, with text messages and nicotine patches in place of telegrams and pipes. Quick reminder: the Sherlock of Sir Arthur Conan Doyle's original books represents the first fictional character ever recognized by the Royal Society of Chemistry for contributions to science.

Sherlock Holmes hacks into a secret British government database and finds...pyridine and phenol!
Credit: Benedict Cumberbatch and BBC-One

In "The Hounds of Baskerville," Holmes and Watson investigate claims of a giant, red-eyed monster lurking outside - wait for it - a secret military research laboratory called Baskerville. Naturally, the dynamic duo break into the lab under false pretenses, questioning a scientist accused of genetically re-engineering a pet bunny to glow green.**

They later return to Baskerville with a hypothesis: a psychoactive drug, perhaps hidden in an innocuous foodstuff. Holmes sets to work using the analytical instrument of choice for modern chemists - the light microscope. Using nothing more than a pipette and glass window that would have made Bob Woodward proud, Sherlock performs some crude chemical degradation studies:

Who needs NMR, kinetic studies, or a mass spectrometer? I have a mallet and a watch-glass.
Credit: BBC-One

(I'm guessing Sherlock wrote "D-Deuterium?" at the top left to remind himself that the evil research agency might have tried improving their mind-control drug's physicochemical properties : )

The silly Hollywood chemistry builds to a peak when Dr. Watson timidly investigates a scary chemical structure on the lab wall. Don't blink; it's only on-screen for about a second:

"Vancomycin" - Close enough for television?
Source: BBC-One

Well, at least the creators got something right - vancomycin certainly ranks as a "chemical weapon," but it's for killing marauding bacteria, not innocent townsfolk. That chlorocyclohexane on the right *should* be fully aromatic, and I'm sure if I had a higher-res image, I'd start to spot some more structural snafus.

I won't spoil any more of the show, but there's a few other chemical flights of fancy, such as Sherlock analyzing multiple components of floor wax using nothing more than some colored test tubes and his nose. Readers, cue up your online streaming service of choice, and have a look at episode 2.2 - let me know if I've missed more molecular mishaps.

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* Spoiler - the goofy hat remains. Not a bad look, if you ask me.

**The show does mention that the green fluorescent protein was isolated from a jellyfish, which might be the most accurate science in the entire episode.