Corante

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: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
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
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
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
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


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


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
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

« Alkynes and Nitriles | Main | Valeant Versus Genentech: Two Different Worlds »

May 24, 2013

A New Way to Determine Chirality

Email This Entry

Posted by Derek

There's a new paper out today in Nature on a very unusual way to determine the chirality of organic molecules. It uses an exotic effect of microwave spectroscopy, and I will immediately confess that the physics is (as of this morning, anyway) outside my range.

This is going to be one of those posts that comes across as gibberish to the non-chemists in the audience. Chirality seems to be a concept that confuses people pretty rapidly, even though the examples of right and left shoes or gloves (or right and left-handed screw threads) are familiar from everyday objects, and exactly the same principles apply to molecules. But the further you dig into the concept, the trickier it gets, and when you start dragging the physics of it in, you start shedding your audience quickly. Get a dozen chemists together and ask them how, exactly, chiral compounds rotate plane-polarized light and see how that goes. (I wouldn't distinguish myself by the clarity of my explanation, either).

But this paper is something else again. Here, see how you do:

Here we extend this class of approaches by carrying out nonlinear resonant phase-sensitive microwave spectroscopy of gas phase samples in the presence of an adiabatically switched non-resonant orthogonal electric field; we use this technique to map the enantiomer-dependent sign of an electric dipole Rabi frequency onto the phase of emitted microwave radiation.

The best I can do with this is that the two enantiomers have the same dipole moment, but that the electric field interacts with them in a manner that gives different signs. This shows up in the phase of the emitted microwaves, and (as long as the sample is cooled down, to cut back on the possible rotational states), it seems to give a very clear signal. This is a completely different way to determine chirality from the existing polarized-light ones, or the use of anomalous dispersion in X-ray data (although that one can be tricky).

Here's a rundown on this new paper from Chemistry World. My guess is that this is going to be one of those techniques that will be used rarely, but when it comes up it'll be because nothing else will work at all. I also wonder if, possibly, the effect might be noticed on molecules in interstellar space under the right conditions, giving us a read on chirality from a distance?

Comments (12) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Anonymous on May 24, 2013 9:21 AM writes...

This isn't another paper by those witty MIT kids, is it?

Permalink to Comment

2. rhodium on May 24, 2013 12:47 PM writes...

Since this seems to be based on rotational spectroscopy would this work better than normal methods on molecules that are chiral due to isotopic substitution?

Permalink to Comment

3. gippgig on May 24, 2013 1:52 PM writes...

Another item from Nature that may be of interest: Cancer: Drug for an 'undruggable' protein, doi:10.1038/nature12248

Permalink to Comment

4. Capt. Kirk on May 24, 2013 4:31 PM writes...

Mr. Scott: "Captain, the warp drive appears to have an adiabatically switched non-resonant orthogonal electric field affecting the dilithium crystals!"

Permalink to Comment

5. metaphysician on May 25, 2013 5:03 PM writes...

#4-

I have to admit, that was my first thought, too. It doesn't just sound like technobabble in the abstract, it actually sounds like specifically invented technobabble. Or perhaps technobabble created by a random technobabble generator.

Permalink to Comment

6. Ben on May 25, 2013 7:08 PM writes...

As physicist and sometimes even a molecular spectroscopist, I have to say that this is really cool (*rim shot*) work. (Fair disclosure: I personally know two of the authors and have collaborated with them on unrelated projects in the past.)

The basic idea is actually pretty simple. If you have a polar, chiral molecule (and almost any chiral molecule will be at least marginally polar), then the direction of the total dipole moment versus the molecular axes of rotation will be different between the two enantiomers. Since a quasi-static electric field simply tugs on the net dipole moment, all you need to do to tell the enantiomers apart is to start the molecule spinning (i.e. excite a rotational superposition), and then apply an electric field to the dipole moment. The sign of the torque generated by the electric field depends on the sign of the dipole moment, and so the phase of the response -- basically the sign of the precession resulting from the torque! -- tells you which enantiomer you have.

Of course, calculating the expected phase from scratch requires substantial knowledge of the molecule, e.g. rotational constants and dipole moment values, but those are both reasonably easy to measure independently. The beauty of this technique is that, rather than the maybe couple of degrees of optical rotation that you would get from a saturated solution, here you get a 180-degree phase shift between the two enantiomers -- independent of concentration! Concentration only matters in improving the signal-to-noise in the phase measurement. (This is because they are looking at the free-induction response of the material, not a transmitted signal. The free-induction just gets weaker as the concentration goes down, but it doesn't change shape.)

The use of a cryogenic source is almost a sidebar on the result. I think that the authors are correct in saying it probably will work in a supersonic beam, and time was that any physical chemistry group worthy of the name had at least one supersonic beam machine. They're not hard to build, just a pulsed valve and a bunch of big vacuum pumps. But it is a vacuum/gas-phase technique, not a solution one.

@rhodium: Since the dipole moment only changes due to vibronic couplings under an isotopic substitution, the magnitude of the free-induction signal is probably pretty (very!) weak. But the 180-degree phase shift between enantiomers should still exist.

As for interstellar spectroscopy? Right now, this is a pulsed technique, and cosmic pulsed sources with good phase stability are pretty rare. But maybe there's some pulsar system...?

Permalink to Comment

7. leftscienceawhileago on May 26, 2013 5:40 PM writes...

Ben,
That was a great explanation! Let me know if you ever feel like explaining circular dichroism to me.

Permalink to Comment

8. Anne on May 27, 2013 2:55 AM writes...

Ben,

For the most part pulsars have terrible phase stability - each pulse is modulated noise. The Crab does have giant single pulses that are intrinsically less than about a nanosecond long (and bright enough to see on an analog TV if you knew when to look) but the interstellar medium messes that up pretty quickly. So I'm not too hopeful.

That said, if you did somehow find a chiral population floating around out there, would that imply life, or is there some plausible inorganic process that would prefer (say) d sugars?

Incidentally, the business of rotating plane polarized light makes more sense if you think of it as an equal sum of left- and right-handed circularly-polarized light. Then anything that delays one handedness more than the other rotates the plane of the polarization. And refractive indices arise because molecules delay light that they interact with; it makes a certain sense that a chiral molecule should interact more with light whose electric field spirals one way rather than the other. Not that I'm claiming exceptional clarity either.

Permalink to Comment

9. JRnonchemist on May 27, 2013 12:26 PM writes...

@4 My read is that it is saying that the electric field should not be adding much energy to the sample, and that it should be at right angles to the microwave beam. Some of that is guesswork.

I'm also guessing that the microwave source is tunable, and that one wants most of the emission energy to be originally coming from that.

Re: Chirality: perhaps Mass Effect will popularize the concept some.

Permalink to Comment

10. Project Osprey on May 28, 2013 6:16 AM writes...

While this is all beyond my ken, it does remind me off the Cotton effect.

https://en.wikipedia.org/wiki/Cotton_effect

This has been used to distiguish enantiomers by UV-Vis spectroscopy.

Permalink to Comment

11. Chiral-is-Cool on May 28, 2013 2:21 PM writes...

Ben,

Thanks for the explanation! I'm not a physicist but if I understand your explanation - this is somewhat similar to the idea in the US Patent 7,935,906 linked below: where they caused chiral molecules to spin via a rotated electric field. The spinning molecules then acted as propellers, allowing both chiral separation as they move in opposite directions as well as absolute configuration determination based upon their direction of movement.

http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7,935,906.PN.&OS=PN/7,935,906&RS=PN/7,935,906

Permalink to Comment

12. terrapin on May 29, 2013 6:48 AM writes...

For full disclosure: I am one of the authors (DP) of the paper. Thanks everybody for your comments; I am learning a lot as well.

Osprey: This is, a bit, related to the Cotton effect; it could be, I suppose, called the "nonlinear cotton effect". What we are doing is in many ways theoretically simpler than circular dichroism; the reason CD confuses so many people is that it is very hard! CD is forbidden in the electric dipole approximation, and so the "next least forbidden" terms, such as magnetic or electric quadrupole terms, are essential. What we do is electric dipole allowed, so the Hamiltonian is almost the "simplest possible chiral Hamiltonian".

Pulsars: I am afraid I am pessimistic about this; even if the radiation is (miraculously) polarized just right, it is essential that we only probe an area that is "one cubic wavelength"; this wavelength is the LONGEST wavelength in the system, but is still less than a few meters - hopeless to observe in space. Some kind of CD sounds more hopeful to me.

Finally, a theoretically simpler, and experimentally more sensitive, version has now been done: http://arxiv.org/abs/1305.5223

Thanks, Dave

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
The Worst Seminar
Conference in Basel
Messed-Up Clinical Studies: A First-Hand Report
Pharma and Ebola
Lilly Steps In for AstraZeneca's Secretase Inhibitor
Update on Alnylam (And the Direction of Things to Come)
There Must Have Been Multiple Chances to Catch This
Weirdly, Tramadol Is Not a Natural Product After All