Imperial College London

Henry Rzepa

I mentioned in my [last
post](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6438){target="_blank"
rel="noopener noreferrer"} an unjustly neglected
[paper](http://dx.doi.org/10.1063/1.1700491){target="_blank"
rel="noopener noreferrer"} from that golden age of 1951-1953 by Kirkwood
and co. They had shown that Fischer's [famous
guess](https://webspace.yale.edu/chem125/125/history99/6Stereochemistry/Fischer/FischerGlucosePrf.pdf "Berichte der deutschen chemischen Gesellschaft 24, 1836 (1891)"){target="_blank"
rel="noopener noreferrer"} for the absolute configurations of organic
chiral molecules was correct. The two molecules used to infer this are
shown below.

[![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/04/kirkwood.svg "kirkwood"){.aligncenter
.size-full .wp-image-6456
decoding="async"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/04/kirkwood.svg)  
Using the theory Kirkwood had developed, the prediction for the optical
rotation at the sodium D line for the (R,R) enantiomer of epoxybutene
(Kirkwood did not use this R,R notation, which was still in the future)
was +43°. The measured value was \[α\]D +59°. The (R,R) enantiomer did
indeed correspond to Fischer notation.

QED.

A postscript is that a modern equivalent of Kirkwood's result, using the
ωB97XD/6-311+G(d,p) method gives +67° for the [gas
phase](http://hdl.handle.net/10042/to-13883){target="_blank"
rel="noopener noreferrer"} and +57° for
[solution](http://hdl.handle.net/10042/to-13884){target="_blank"
rel="noopener noreferrer"} (in CCl~4~). The experimental value relates
to the pure liquid. In fact, Kirkwood had been very aware that solvation
can influence the measured value of an optical rotation, and so even
today, a match between experiment and calculation of ± 16 ° is
considered a good fit.

But when it comes to the second molecule, (R)-1,2-dichloropropane, we
are in a different ball park. In fact, most of Kirkwood's article is
devoted to unravelling this second system. This is because it was
realised that it is conformationally flexible. Two conformations (this
term was then often used interchangeably with configuration, which might
confuse a modern audience) called *trans* and *skew* (now called *anti*
and *gauche*) were considered and it was realised that the relative
populations would be influenced by temperature and particularly, the
solvent. I quote here the final conclusion: *We have assigned the
absolute configuration of Fig. 2 to the dextrorotatory isomer of
1,2-dichloropropane. This was done without any experimental data
concerning the optically active forms of the molecule, using only
the calculated dependence of the rotatory power on conformation (Table
II) and the information about the potential of internal conformation
obtained from the electron diffraction and dipole moment measurements*.

Non trivial then! Perhaps this is why these techniques were not
immediately picked up by synthetic chemists to verify the absolute
configuration of their own molecules. But my point is that the use of
such techniques now seems to be growing exponentially, which is why this
post is headed the golden age of computational spectroscopy. So what of
such a modern take on  (R)-1,2-dichloropropane (in heptane, which
corresponds to the measured value of +20 to +30, and -21° for the (S)
enantiomer). Well, there are in fact three viable conformations, not two
as Kirkwood supposed. He did not know that the *gauche* stereoelectronic
effect favoured two of them despite the greater steric encumbrance. The
calculated rotations
are [+53](http://hdl.handle.net/10042/to-13885){target="_blank"
rel="noopener noreferrer"} (*anti*),
[+96](http://hdl.handle.net/10042/to-13886){target="_blank"
rel="noopener noreferrer"} (*gauche*) and
[-182°](http://hdl.handle.net/10042/to-13887){target="_blank"
rel="noopener noreferrer"} (second *gauche* conformer). Such dependence
on conformation is sadly not unusual, and it means you have to know the
Boltzmann population very accurately indeed to infer an observed value.
This might in part explain the rather circuitous argument used by
 Kirkwood for dichloropropane!

Fortunately, nowadays optical rotation (more accurately referred to as
optical rotatory power, or ORP) is just one of a growing armoury of
spectroscopic measurements that can be computed to the accuracy required
to draw firm conclusions. These include ORD (optical rotatory
dispersion, or variation with the frequency of the polarised light
used), ECD (electronic circular dichroism) and VCD (vibrational circular
dichroism). It is still not absolutely routine, but these techniques are
now found in an increasing number of synthetic chemists' toolkits.

And my final reflection is to ponder that the golden age of
pharmaceutical synthesis (lets say  1950 -- 2000, but  I know I may get
dissent), in which certainty about the separate physiological effects of
both enantiomers of chiral drugs became mandatory, would not have been
possible without Kirkwood's pioneering article, along of course with
[Bijvoet's](http://dx.doi.org/10.1038/168271a0){target="_blank"
rel="noopener noreferrer"} independent result.

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


I mentioned in my last post an unjustly neglected paper from that golden age of 1951-1953 by Kirkwood and co. They had shown that Fischer’s famous guess for the absolute configurations of organic chiral molecules was correct. The two molecules used to infer this are shown below.

Publicaciones de Rogue Scholar

A golden age for (computational) spectroscopy.