Imperial College London

Henry Rzepa

Thalidomide is a chiral molecule, which was sold in the 1960s as a
sedative in its (S,R)-racemic form. The tragedy was that the (S)-isomer
was tetragenic, and only the (R) enantiomer acts as a sedative. What was
not appreciated at the time is that interconversion of the (S)- and (R)
forms takes place quite quickly in aqueous media. Nowadays, quantum
modelling can provide good *in-silico* estimates of the (free) energy
barriers for such processes, which in this case is a simple keto-enol
tautomerism. In a recently published
article\[cite\]10.1002/chem.201202651\[/cite\], just such a simulation
is reported. By involving two explicit water molecules in the transition
state, an (\~enthalpic) barrier of 27.7 kcal/mol was obtained. The
simulation was conducted just with two water molecules acting as
solvent, and without any additional continuum solvation applied. So I
thought I would re-evaluate this result by computing it at the
ωB97XD/6-311G(d,p)/SCRF=water level (a triple-ζ basis set rather than
the double-ζ used before\[cite\]10.1002/chem.201202651\[/cite\]), and
employing a dispersion-corrected DFT method rather than B3LYP.
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/11/thalidomide.svg "thalidomide"){.aligncenter
.size-full .wp-image-8247 decoding="async"}

Keto-enol tautomerisation occupies a unique position in the history of
mechanistic chemistry\[cite\]10.1002/jlac.18892500306\[/cite\]. In 1889,
Beckmann got the whole field rolling by proposing an inferred enol
intermediate (which he did not observe) to explain the isomerism of
menthone to *iso*-menthone in conc. sulfuric acid. In modelling the
enolisation of thalidomide, I have used **both** implicit and explicit
solvents acting in a self-consistent manner. This approach is not yet
much adopted in the wider literature\[cite\]10.1021/jo100920e\[/cite\].
I have deployed it extensively in this blog as an encouragement to
others (selected examples are listed at the bottom of this post). It is
worth noting at the outset that the transition state reported
previously\[cite\]10.1002/chem.201202651\[/cite\] has a computed dipole
moment of \~10D. My experience\[cite\]10.1021/jo100920e\[/cite\]
suggests that any geometry with a dipole moment of this magnitude (or
greater) is likely to relax when placed into a continuum field, and this
relaxation becomes an important perturbation of both the computed
geometry of the transition state and the intrinsic reaction coordinate
profile computed from that starting point.

The [(re)computed
geometry](http://hdl.handle.net/10.6084/m9.figshare.97276){target="_blank"}
of the aqueous transition state for enolisation of thalidomide is shown
below, and for which the entropy-corrected ΔG^†^~298~ is 31.0 kcal/mol
(the barrier for the prototypical enolisation of propanone is
[computed](http://hdl.handle.net/10.6084/m9.figshare.97291){target="_blank"}
as 34.4 kcal/mol). The value in the
literature\[cite\]10.1002/chem.201202651\[/cite\] is given as 27.7
kcal/mol for the zero-point-energy corrected total energy barrier, but
this value notably does **NOT** include any entropic corrections. The
measured literature value for ΔG^†^~298 ~is reported as 24.3 kcal/mol at
pH 8, a value which probably also includes contributions from both the
pure water catalysed route and those from hydroxide anion catalysis (see
below). At this point, I should remind that the free energy of
activation for a bi- or termolecular reaction in solution must be
obtained by correcting the value obtained for a standard state of 1
atmosphere (the state used for the value quoted above). According
to Alvarez-Idaboy and co-workers\[cite\]10.1021/ol060261z\[/cite\], this
amounts to a total correction of -4.5 kcal/mol for a bimolecular
reaction, and -8.73 kcal/mol for a termolecular reaction. Where one of
the components of a termolecular reaction is also the solvent, these
corrections probably need to be themselves reduced. But this does
achieve a reduction in the computed value of 31.0 kcal/mol to something
quite close to the experimental value! 

::: {#attachment_8261 .wp-caption .aligncenter style="width: 257px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/11/thal1.jpg "thal1"){.wp-image-8261
loading="lazy" decoding="async"
aria-describedby="caption-attachment-8261"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/11/thal-2H2O-1064.451078.log;frame 29;connect (atomno=1) (atomno=31) PARTIAL;connect (atomno=7) (atomno=20) PARTIAL;connect (atomno=20) (atomno=34) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors orange; vibration 20;animation mode loop;');"
width="247" height="149"}

Aqueous transition state for enolisation of thalidomide. Click for 3D.
:::

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/11/thalidomide1.gif "thalidomide1"){.aligncenter
.size-full .wp-image-8293 loading="lazy" decoding="async" width="402"
height="272"}

Next, I want to consider the base-catalysed enolisation pathway. As with
the reaction of dichlorobuteneone with tolyl-thiolate about which I
[wrote in another
post](http://www.ch.imperial.ac.uk/rzepa/blog/?p=7100){target="_blank"},
the authors of the thalidomide
study\[cite\]10.1002/chem.201202651\[/cite\] modelled this route by
introducing a solvated hydroxide anion, "**OH^--^·H~2~O**" into the
structure *without any accompanying counter-ion*. In other words, their
total system has an overall negative charge. I argued before, and I
argue again here, that there is no real need to have to do this. Why not
for example introduce **NaOH•H~2~O** instead? One might argue that the
cationic counter-ion so introduced cannot be properly modelled, but the
combination of explicit first-sphere water molecules coupled with a
continuum model actually handles these counter-ions reasonably well. So
may I introduce you to [my
version](http://hdl.handle.net/10.6084/m9.figshare.97289){target="_blank"}
of the base-catalysed reaction, involving a contact-ion-pair:

::: {#attachment_8272 .wp-caption .aligncenter style="width: 259px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/11/thal2.jpg "thal2"){.wp-image-8272
loading="lazy" decoding="async"
aria-describedby="caption-attachment-8272"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/11/thal-NaOH3H2O-1302.692446.log;frame 21;connect (atomno=1) (atomno=31) PARTIAL;connect (atomno=7) (atomno=20) PARTIAL;vectors on;vectors 4;vectors scale 5.0; color vectors purple; vibration 20;animation mode loop;');"
width="249" height="154"}

Base-catalysed (NaOH) enolisation of thalidomide. Click for 3D.
:::

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/11/thal-NaOH.gif "thal-NaOH"){.aligncenter
.wp-image-8295 loading="lazy" decoding="async" width="270" height="227"}

This
has ΔG^†^~298~ [4.7](http://hdl.handle.net/10.6084/m9.figshare.97293){target="_blank"}
kcal/mol, much lower than the neutral water catalysed reaction. This
value is of course for a standard state for \[Na^+^OH^--^\] (1 atm). At
pH 8, \[OH^--^\] is at least six orders of magnitude less, which may
rationalise why the experimental rate is so much slower than this
barrier might imply. The
[IRC](http://hdl.handle.net/10042/21699){target="_blank"} corresponds to
proton transfer.

I would like to end by noting that many mechanisms which would otherwise
involve the development of charge-separation may well borrow a protic
solvent molecule in the manner shown here to reduce the degree of
charge-separation needed.  Further examples of this are listed below.

------------------------------------------------------------------------

1.  [Oxime formation from hydroxylamine and ketone. Part 2:
    Elimination.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=7822 "Permanent Link to Oxime formation from hydroxylamine and ketone. Part 2: Elimination."){rel="bookmark"}
2.  [Oxime formation from hydroxylamine and ketone: a (computational)
    reality check on stage one of the
    mechanism.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=7779 "Permanent Link to Oxime formation from hydroxylamine and ketone: a (computational) reality check on stage one of the mechanism."){rel="bookmark"}
3.  [Transition state models for Baldwin dig(onal) ring
    closures.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6921 "Permanent Link to Transition state models for Baldwin dig(onal) ring closures."){rel="bookmark"}
4.  [Transition state models for Baldwin's rules of ring
    closure.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6874 "Permanent Link to Transition state models for Baldwin’s rules of ring closure."){rel="bookmark"}
5.  [The mechanism (in 4D) of the reaction between thionyl chloride and
    a carboxylic
    acid.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6816 "Permanent Link to The mechanism (in 4D) of the reaction between thionyl chloride and a carboxylic acid."){rel="bookmark"}
6.  [Mechanism of the diazomethane alkylation of a carboxylic
    acid.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6750 "Permanent Link to Mechanism of the diazomethane alkylation of a carboxylic acid."){rel="bookmark"}
7.  [The mechanism of the Baeyer-Villiger
    rearrangement.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6618 "Permanent Link to The mechanism of the Baeyer-Villiger rearrangement."){rel="bookmark"}
8.  [Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular
    Aldol
    Reactions.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6477 "Permanent Link to Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions."){rel="bookmark"}
9.  [Secrets of a university tutor: tetrahedral
    intermediates.](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6044 "Permanent Link to Secrets of a university tutor: tetrahedral intermediates."){rel="bookmark"}

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


Thalidomide is a chiral molecule, which was sold in the 1960s as a sedative in its (S,R)-racemic form. The tragedy was that the (S)-isomer was tetragenic, and only the (R) enantiomer acts as a sedative. What was not appreciated at the time is that interconversion of the (S)- and (R) forms takes place quite quickly in aqueous media.

Messaggi di Rogue Scholar

Thalidomide. The role of water in the mechanism of its aqueous racemisation.