Showing posts with label NMR. Show all posts
Showing posts with label NMR. Show all posts

Sunday, July 17, 2016

Undergrad Tech: Remember When?

Recently, I sat with a friend sipping coffee, watching passers-by hurriedly moving from one tall building to another. Remarks drifted back towards research - as they're wont to do when chatting with chemists - and she said: "Remember how hard it was just to order things?"

I knew exactly what she meant. Lab tech changes quickly, and you may not even notice until you take a step away from the bench. I'm not part of the generation who spent hours sketching molecules by hand from a rubber template pre-ChemDraw, but nor am I a grad student in the era of tablet computers that can access PDB or Aldrich from a free wireless connection in any lecture hall.

Maybe I'll take a quick stroll down memory lane to see how different things really were when I first started undergraduate research...

Planning: Then, as now, most projects kicked off using pen-and-paper or chalkboard sessions; whiteboards were in about 30% of classrooms and gaining ground, but my first experiences with drawing molecules for my coworkers covered my fingers in tacky powder. I can still smell lab chalk: musty, earthy, sometimes tinged with a faint amine odor if stored too near the reagents cabinet.

Courtesy of Dr. Freddy, at Synthetic Remarks, who seems to recall
chalkboards much more fondly than I.

Once you'd had the discussion, you transcribed it into a lab notebook - usually bound with black vinyl, perhaps featuring brown or maroon faux-leather accents and a bookmark string - and signed the page. Then it was time to dive into the literature. First, you staked out some territory at one of the few hulking beige monitors attached to your shared lab computers. Plan for coffee, since reboots and blue-screen crashes could usually be expected to last 10 minutes, with accompanying Windows jingles or goofy Mac cursor wheels.

(Why were operating systems always a generation behind on shared computers?)

Your 10-minute excuse to go grab a coffee.

Beilstein and SciFinder both offered installed systems with single-user seats. This meant you walked down your lab hallway, shouting "Does anyone need anything on SciFinder?" before logging in. The user interfaces were very Internet 1.0 - muted grey windows, inscrutable black text, fuzzy structures. Mostly, you would up transcribing the reference into your notebook alongside the idea. To get the paper, you usually brought a stack of dimes down to the reference library, and spent the next 20 minutes finding and then copying (don't forget to rotate every other page!) the journal article. The still-warm, toner-scented stapled copies were lugged back to your wooden desk to be pored over until evening. My fingers would often be tinged with more than one color of highlighter or colored pen after a night of intense study.

SciFinder Scholar, 1999. Source: ISTL.org

Synthesis: OK, you know what you want to make, so you need some reagents. Maybe first you glanced through the 2,000-row Excel file your lab has as its de facto "inventory" system. I remember some groups also had a dog-eared, yellowing notebook dangling from a rope of masking tape that listed all the chemicals no one needed any longer - hope you enjoy distillation! Failing these approaches, the trusty catalogs are all lined up against the single lab window, effectively blocking out 20% of the available visual real estate. Names of vendors I remember included Fisher, VWR, Aldrich, Sigma, TCI, and Columbia. Each one had different account reps, pricing, and delivery specs; you'd better believe your boss would ask if you looked up pricey, boutique reagents in more than one source. Someone had the lab job of calling these vendors every few days, providing the lab P.O. number or group credit card, and then taking delivery later that week. Collections of cardboard boxes large and small would be piled near the front door, and every week was Christmas (even if it was just your reagent-grade TEA).




The first and last physical Aldrich catalogs I remember ordering from.
Source: Alfred Bader, Sigma-Aldrich
At some point, you'd have everything needed to run your experiment. Hours passed, TLCs ran, and you scribbled long-hand in that same lined lab notebook. I'm fairly certain I spent thousands of hours hunched over, detailing exactly how the workup went, or scrawling single-line corrections (with initials!) for changes and errors.

Analysis: Instruments fell largely into two camps - things you ran and printed out to later affix into 3-ring binders, or numbers on an LED screen you hastily scribbled onto a Post-it note. UV-Vis and optical rotation fell into this latter camp; I still smile whenever I see a forgotten, tucked-away bookmark reading "+8.75 deg."

I worked in lab right at the death knell of chart-recorders - little red pens in threaded holders that traced a curve based on numeric readouts from an IR or GC. NMR, graciously, always emerged on an ink-jet printer in the corner of a sub-level lab. I was a Bruker shim-jockey for quite a while, bragging that I could shim, acquire, FT, pick, and integrate an 8-scan 1H in under 2 minutes. Of course, many academic labs now have robotic cherry-pickers and automatic data transfer, which must save tons of time (unless you're a biophysicist or monitor kinetics; we might as well chain you to the 600MHz).

Source: Cal State LA / Bruker Instruments

Presentation: My first lab group still owned an overhead transparency viewer, and we were encouraged to print or sketch acetate slides each week for discussion. As these smudged easily when warm or done hastily, there were many grumblings and thrown elbows at the photocopier from fellow labmates on group meeting day. PowerPoint was reserved for "big" talks - oral exams, defense seminars, or preparing a poster for ACS meetings. Once saved and laid out the way you wanted, these were burned onto a CD-R or stored on a 100MB USB flash drive your boss might loan you. The walk to FedEx felt tense, because you didn't want to lose this uncomfortable piece of plastic, which contained the only copy of your slides.
Just don't write on the glass itself, or the PI will get really angry. Trust me.
Source: Amazon

I'm sure that I'm missing more fun events from lab life and technology from the late 20th century. Readers, if you have a special memory from back in the day, please feel free to share it in the comments. I'll update the post if I've missed something vital.

Saturday, February 20, 2016

What's that Crud in My NMR Sample?

Scene:

The reaction finished in 20 minutes by TLC. You grabbed a quick aliquot for LCMS; one peak! Quickly, you quenched, extracted, perhaps pushed through a silica plug for good measure. After concentration, a gorgeous white powder formed, so you pulled high vac for 20 minutes and rushed down to "get your proton on." But, darn it! Still wet with traces of, well, something...

Friends, has this ever happened to you? Trace impurities in otherwise perfect spectra lead to much head-scratching and SI docs labeled "final product_spectrum 5." 

The three papers linked to this post should help.

The new chart offers recommendations (colored arrows) based on Chem21 assessments of environmental impact, safety, and toxicity. Shown above are chemical shift tables (1H) in deuterated chloroform, acetone, and dimethyl sulfoxide.

If I were joining a synthetic lab this year, or starting an internship / work-study, I'd download 'em all and thumbtack liberally to the back of my bench. Guaranteed utility.

Monday, January 11, 2016

The NMR Laundromat

Source: OPRD / CNRS
The simplest, most practical solutions* are often the best.

I'm reminded of classic papers for pragmatic lab procedures, like Clark Still's on flash chromatography, or Gottlieb & Nudelman's on detecting trace NMR impurities. Everyone has encountered their lab's version of the Kugelrohr setup - run by an old electric kettle and a windshield-wiper motor!

From the ASAP of Organic Process Research and Development comes this handy one-pager: a how-to on cleaning dozens of NMR tubes simultaneously, using glassware readily available in just about any synth lab.

Seeing this instantly triggered a "Well, duh!" moment for me - the amount of time I've stood before a stoppered 500mL vacuum flask impaled with a cannula, washing single tubes by hand...I'm sure it reaches into hours, if not days.

If you try this, leave a comment; I'm really quite interested to see how it turns out. I'd also wonder if OPRD might be angling for other quick one-offs. Couldn't hurt to try, right?

*Of course, I'd be remiss if I didn't point unfamiliar readers to the treasure trove that is Not Voodoo.

Thursday, February 12, 2015

Beautiful Chemistry: Hoye's HDDA + Napth Trap

Every so often, a reaction behaves so well that you just publish the crude NMR spectrum.
Professor Tom Hoye's HDDA* reaction, first reported in 2012, apparently fits the bill rather well, wouldn't you say?

From Org. Lett. 2015, ASAP.

Amazing - heat up a heavily conjugated triyne for 2 days, and it just does one thing, reproducibly and immaculately. I wonder whether Hoye and his group have any further tricks up their sleeve to try and control the diastereo  enantioselectivity of that sweet new quaternary center...time will tell.

--
*Please allow me touch of professional jealousy - this reaction opened up so many different questions for the Hoye group that they've published 10 manuscripts on it in just the last 3 years. Damn.

**Perhaps I've developed a love affair with barrelenes. Hmm.

Thanks for the catch, Per-Ola!

Monday, September 22, 2014

Honing Halophilicity

Let's say you have a late-stage drug candidate, with an alcohol, an olefin, and a pyridine. Now you toss in one equivalent of a chlorinating reagent.

Which functional group gets halogenated first?

Babak Borhan and colleagues from Michigan State and Dow may have your answer. In a recent JACS full article, they disclose the HalA (halenium affinity) scale, a DFT-calculated delta to describe the relative reactivity of various groups to an incoming halogen source. They back up their calculations with NMR competition studies, showing, for example, that two structurally similar molecules have a rather skewed 7:1 equilibrium, as predicted by a 1.1 kcal / mol difference in HalA:

Borhan et. al., JACS 2014
Using 500 computationally-evaluated functional chlorenium "acceptors" (Lewis bases), Borhan and colleagues create a chart to help answer our initial question: What reacts first?


I'm certain even more detailed versions of this chart are currently underway. I wonder how well it would extend to prediction of methyl or trifluoromethyl group additions?

Monday, February 17, 2014

Tip of the Iceberg: More Organic Letters Corrections

(Thanks to BRSM for the heads up!)
(UpdateSee here for Derek's post and thoughts)

Looks like another author just felt the heat of the Data Analyst's gaze. Hot on the heels of the Fukuyama corrections, we have a slate of scrubbed-up 1H spectra from the Nakada group (Waseda University).*

Today's corrections in Org. Lett. ASAP (1, 2, 3, 4, 5) all read rather similarly:
"The 1H NMR spectrum for compound x . . .was found to have been edited to remove solvents and impurities"
Peer-reviewed expert in
Musicology
Syntheses affected include a Taxol fragment, (+)-Colletoic Acid, and Erinacine B. The authors claim in each correction that the edits "did not affect any of the conclusions" and that "Yield was found to be correct." Years affected: 2006-2013.

Two questions immediately spring to mind:

1. Why have all the corrections exposed thus far been from one country?
2. How far back will we go? Org Lett.'s been around for 15 years...will we soon get corrections like it's 1999?

*Interestingly, Prof. Nakada's group page seems to be suddenly unavailable. Huh.

Thursday, January 2, 2014

A Soapy Situation

Life has funny ways of surprising you. While analyzing my latest batch of a functionalized sugar, I noticed that the NMR sample foamed upon sonication. Fearing surfactant (read: soap) contamination, I found myself back at the instrument facility with a D2O sample of...Contrex, the orange-labeled glassware rinse I've used ever since I started working at the bench.

Source: Decon Labs
Never thought I'd be taking a soapy NMR...
Unsurprisingly, Decon Labs doesn't list its trade-secret formulation on the MSDS or their website. However, this doesn't seem like something I'm going to investigate a la What's In Lemi-Shine? Seems to be to be a typical mono-aromatic tetraalkylammonium salt, probably containing some KOH, phosphate, or bicarb for good measure.

Best part? It's not a contaminant in my material. On to the next project!

Thursday, November 7, 2013

Start-up, Year Two

As my tiny company hovers on the brink of non-existence, I recently passed my second-year employment anniversary. Here's how the numbers shake out for 2013:

(Year One Stats)

Time
"Standard" 40-hour work weeks: 2
45-60 hour weeks: 46
60+ hour weeks: 4
Total hours where I've been the only employee in the facility: >300
Weekends worked: 4
Holiday + vacation + sick days used: 29
Paycheck snafus: 3

Chemistry
Total Reactions Run (2011-2013): >850
Synthesized compounds evaluated in disease models: 10
Total NMR Experiments (2011-2013): >1,150
Total Papers Downloaded (2011-2013): >2,200
Total Inventory Chemicals: 380
Fume Hood Failures: 3
Total boxes of gloves used (2011-2013): 23

People
Turnover (2011-2013): 70%
Company Interviewees: 7
Happy Hours: 1

Biz Dev
Grants Submitted: 12
Teleconferences: 63
Conferences / Events: 14
Slide Decks constructed: 36
Presentations: 5
Total Business Cards Distributed (2011-2013): 400+ 
Total Reimbursed Mileage (2011-2013): 3,100+

Ephemera
Total Purchase Orders (2011-2013): 317
Continuing Ed / Training Classes: 20 hours
Holiday Parties: 0

Sunday, August 11, 2013

JFK Scare: Analytical Chemistry at the Airport

Please see below for updates as I receive further information...

As reported by multiple news outlets (CNN, Daily Mail, The Atlantic), a 'suspicious package' leaked an unknown substance* onto two customs inspectors at JFK International Airport Sunday afternoon. When the workers fell ill, the FBI quarantined two facilities - one customs, one mail sorting - and tested the material.

Initial assays indicated potential organophosphate chemical weapons. Later tests, however, confirmed that the substance was actually phosphoric acid, leaking from a faulty cosmetics package. The two inspectors, after receiving on-scene treatment, declined further medical attention.

A few points about this story (emphasis mine):
  • Most news agencies reported hesitantly, but not the Daily Mail, which declared: "The package from China tentatively tested positive for VX nerve gas, which can be used as a weapon of mass destruction..." (They even included a strangely-rotated space-filling model of VX in the article!)
I'd be quite interested to know how the FBI field tests for organophosphate nerve agents (Sorry, Daily Mail, but VX, due to its high boiling point and viscosity, is actually not a gas but a thick liquid much like phosphoric acid). I'm aware of certain colorimetric pesticide test strips, and certainly blood chemistry assays for exposed individuals would tell the tale.

But could phosphoric acid give a false positive here? Its chemical properties aren't overall very similar to nerve agent. Unlike VX, phosphoric acid has acidic protons, rendering a much different reactivity and solubility profile. VX soaks deep into skin due to its carbon appendages - hence, organophosphate - which wouldn't really occur with the acid. Perhaps JFK sent a sample out for 31P NMR? This analytical technique would show a resonance close to that of VX, which might incite a high-threat response. Perhaps an LC-MS might also ring warning bells: both compounds should show a fragment around 94 m/z.
  • The Atlantic cheerfully summarized: "It turns out what made the two men sick was actually organophosphate, an ingredient in soda pop."
If I ever find organophosphate in my Coke can, I'm suing. That is, if I survive the encounter...

Organophosphates, to which VX, sarin, soman, and several potent insecticides belong, have alkylated (carbon-functionalized) bonds on their oxygen atoms. Once ingested or absorbed, they tend to interfere with acetylcholinesterase, an enzyme involved in neural signaling. The reporter perhaps meant to say "phosphorus compound" or even "acid," but unfortunately chose the wrong word.

One more thing: I completely understand the highly cautious nature of the law enforcement response. Organophosphates can sicken or kill at remarkably low doses, thus their unfortunate appeal as terror weapons. If any of my readers have experience with airport chemical detection, please write in to set me straight on your detection methods of choice.

Update, 8/12/13 - Changed "parent peak" to "fragment"

*Update 2, 8/12/13 - Chemjobber points out, via Twitter, that the NY Post reported ordinary nail polish remover (usually acetone, or ethyl acetate / iPA) as the culprit. Now I'm even more confused as to how this triggered a nerve agent analytical read!

Update 3, 8/12/13 - Commenters on Reddit and JLC (thanks!) remark that airports have at their disposal DART-based benchtop MS, or perhaps Barringer IONTRAP ion mobility spectrometers. Another commenter suggests M8-M9 detection paper. Vibrational spectroscopy (Raman, IR, etc) has been bandied about as well.

Saturday, June 8, 2013

Pyramid Power!

Atop the energy barrier between hardcore synthetic jocks and dyed-in-the-wool physical chemists lives a dedicated group: the molecular architects. A craving for perfect Platonic shapes, combined with the need to push the limits of bond and orbital theory, drive them towards projects like bullvalenes, cubane, or buckyballs. Despite the obvious challenges - bullvalenes shift and change, cubanes feel some strain - the structures' aesthetic appeal keeps us coming back for more.

Well, another class of shapely compounds seems poised to fall. Enter Pyramidanes*:

Source: JACS | Lee, Sekiguchi
Reported a few days back in JACS by a collaboration between Japanese, French, and Russian scientists, the  near-tetrahedral compounds are within shouting distance of an all-carbon version, never synthesized by human hands. I gotta say, they look pretty awesome. Just staring at it brings up so many questions: what's the hybridization of that top atom? How much strain energy? Could you make some schnazzy ligands from it? How labile is that Sn, anyway? Does this thing blow apart in TBAF?

The crew provides an in-depth discussion of frontier MO theory**, bond orders (fractional all around,
from 0.4-0.7), and NMR properties, concluding that there's a decent structural contribution from the ionic resonance form (see below).

The authors even suggest that the "cyclobutadiene" moiety - the pyramid "base" - can be stuck onto other metals; stable pyramidanes might work as strained-ring storage capsules.

Now I'm excited for the all-carbon version, which (theory predicts) has a lone pair at the apex...crazy!
---

*For the absurdly technical or IUPAC-minded, the authors offer alternative names such as tetracyclo-[2.1.0.0.0] pentane, or (my favorite) [3.3.3.3]fenestrane

**N.B. I'm no p-chemist, so someone else can go through the nitty-gritty there...

Thursday, January 10, 2013

Molecular Machine, Unadorned

So, chemists, you've probably seen this article over at Nature News, which reports a "molecular robot" capable of traveling down a track to assemble a small peptide. Pretty awesome, right?

Source: Nature News | Leigh Group, University of Manchester
Now, that's a cute cartoon, but what's behind the scenes? Intrigued, I hustled over to Prof. Leigh's Supporting Information, and found the real gizmo, spectra and all. Take a look!

Source: Science | Prof. David Leigh
(Yes, that's a carbon NMR, for a single compound.)

I will never complain about characterizing small-molecule drugs again!