About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« One of Those Days | Main | Don't Optimize Your Plasma Protein Binding »

August 19, 2014

Fluorinated Fingerprinting

Email This Entry

Posted by Derek

19F%20cube%20plot.jpgHow many ways do we have to differentiate samples of closely related compounds? There's NMR, of course, and mass spec. But what if two compounds have the same mass, or have unrevealing NMR spectra? Here's a new paper in JACS that proposes another method entirely.

Well, maybe not entirely, because it still relies on NMR. But this one is taking advantage of the sensitivity of 19F NMR shifts to molecular interactions (the same thing that underlies its use as a fragment-screening technique). The authors (Timothy Swager and co-workers at MIT) have prepared several calixarene host molecules which can complex a variety of small organic guests. The host structures feature nonequivalent fluorinated groups, and when another molecule binds, the 19F NMR peaks shift around compared to the unoccupied state. (Shown are a set of their test analytes, plotted by the change in three different 19F shifts).

That's a pretty ingenious idea - anyone who's done 19F NMR work will hear about the concept and immediately say "Oh yeah - that would work, wouldn't it?" But no one else seems to have thought of it. Spectra of their various host molecules show that chemically very similar molecules can be immediately differentiated (such as acetonitrile versus propionitrile), and structural isomers of the same mass are also instantly distinguished. Mixtures of several compounds can also be assigned component by component.

This paper concentrates on nitriles, which all seem to bind in a similar way inside the host molecules. That means that solvents like acetone and ethyl acetate don't interfere at all, but it also means that these particular hosts are far from universal sensors. But no one should expect them to be. The same 19F shift idea can be applied across all sorts of structures. You could imagine working up a "pesticide analysis suite" or a "chemical warfare precursor suite" of well-chosen host structures, sold together as a detection kit.

This idea is going to be competing with LC/MS techniques. Those, when they're up and running, clearly provide more information about a given mixture, but good reproducible methods can take a fair amount of work up front. This method seems to me to be more of a competition for something like ELISA assays, answering questions like "Is there any of compound X in this sample?" or "Here's a sample contaminated with an unknown member of Compound Class Y. Which one is it?" The disadvantage there is that an ELISA doesn't need an NMR (with a fluorine probe) handy.

But it'll be worth seeing what can be made of it. I wonder if there could be host molecules that are particularly good at sensing/complexing particular key functional groups, the way that the current set picks up nitriles? How far into macromolecular/biomolecular space can this idea be extended? If it can be implemented in areas where traditional NMR and LC/MS have problems, it could find plenty of use.

Comments (11) + TrackBacks (0) | Category: Analytical Chemistry


1. Filip on August 19, 2014 9:10 AM writes...

Hi Derek,
thanks for an interesting article. I have just been looking at this paper from ACS nano using 19F for looking at some ubiquitin speciation:
Keep up the great work.

Permalink to Comment

2. The Iron Chemist on August 19, 2014 9:20 AM writes...

It's neat work, but I'll point out that it's not an entirely new idea. When I was a grad student in the late 1990's and early 2000's, Jim Collman was using fluorinated imidazoles to differentiate various metal porphyrin species from each other.

Permalink to Comment

3. annonie on August 19, 2014 9:20 AM writes...

We had a problem just a few years ago that was solved by 19F-NMR. Why is this new? Just have to remember the sensitivity and unique characteristics of 19F.

Permalink to Comment

4. anon on August 19, 2014 1:05 PM writes...

kinda like when people chemically derivitize enantiomers to tell them apart, but with a protein.

Permalink to Comment

5. @3 on August 19, 2014 8:06 PM writes...

Well...Because it's MIT and it has nice colorful figures??

Permalink to Comment

6. sepisp on August 20, 2014 2:23 AM writes...

This is like a single step off a chromatography, and has the same problems as for instance GC: there's no a priori way of predicting what does a particular peak mean. So, you need to calibrate it with known samples anyway, the exact same thing why LC is laborious.

I'm also surprised 19F is so good at this. If you work with heavy-element NMR, you'll quickly learn that a quadropolar nucleus does exactly what it wants. Peaks can easily shift due to factors that don't appear with 1H or 13C, that are impossible to control, and very difficult to predict (ab initio anyone?).

Also, the fact it's NMR is kind of a letdown. Why not just run NOESY or something like that if you already have NMR? So, the crucial question is scale-down. I see from Figure 4 that the peaks are easily distinguishable in 400 MHz, but I don't know enough about 19F NMR to say if this can be scaled down to a 60 MHz tabletop NMR. If so, then it might be of some use in a regular lab. Otherwise, this will join the very long list of NMR method curiosities.

(Disclaimer: Yes, even if our NMR curiosities guy has a beard, I don't have anything against NMR curiosities. They are intellectually and scientifically very interesting. But, the lack of previous literature makes it an all-uphill race, and in absence of specific funding this cannot be pursued.)

Permalink to Comment

7. newnickname on August 20, 2014 9:00 AM writes...

Short on time ... read the title and brief description ... Still and Wigler used fluorine (as one of several) tags to encode and identify combi chem libraries by MS analysis. PNAS, 1993, 90(23), 10922-10926. That technology laid the foundation for the launch of Pharmacopaeia Pharm, RIP.

Those tags provided constitutional info only; not structural, binding or any other info.

Permalink to Comment

8. worldofchemicals on August 21, 2014 4:58 AM writes...

Quite confusing but still the technique make use of NMR

Permalink to Comment

9. Algirdas on August 21, 2014 10:25 AM writes...

Neat idea. Having said that, it is interesting that all the examples in the figure that Derek includes in his post are trivially distinguished by MS or low-res NMR alone. As it stands right now, this 19F fingerprinting seems to be more of a curiosity.

Sepisp: 19F is spin-1/2, not quadrupolar. Gyromagnetic ratio nearly as high as 1H, too. Large chemical shift dispersion makes it useful and nice to work with.

Permalink to Comment

10. meridia on August 27, 2014 9:24 AM writes...

Hey would you mind stating which blog platform
you're working with? I'm loooking to start my own blog in the near
future but I'm having a hard time selecting between BlogEngine/Wordpress/B2evolution and Drupal.
The reason I ask is because yyour design seems difgferent
then most blogs and I'm looking for something unique.
P.S My apologies for getting off-topic but I had to ask!

Permalink to Comment

11. uk furnitures online on August 30, 2015 10:06 AM writes...

The Internal Revenue Service enables you to deduct the interest on fundings that
qualify as residence acquisition financial obligation.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry