Imperial College London

Henry Rzepa

This is the third and final study deriving from my
Ph.D.\[cite\]10.1039/P29750001822\[/cite\]. The first two topics dealt
with the mechanism of heteroaromatic electrophilic attack using either a
diazonium cation or a proton as electrophile, followed by either proton
abstraction or carbon dioxide loss from the resulting Wheland
intermediate. This final study inverts this sequence by starting with
the proton abstraction from an indolinone by a base to create/aromatize
to a indole-2-enolate intermediate, which only then is followed by
electrophilic attack (by iodine).  Here I explore what light quantum
chemical modelling might cast on the mechanism.

[![Indole
diazocoupling](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone.svg){.aligncenter
.size-full .wp-image-14967 decoding="async" style="text-align: justify;"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone.svg)

The concentration of **I~3~**^**--**^ is used to follow the
reaction, given by the expression: [ \[I~3~^--^\] =
k~1~\[B\]\[indolinone\]*t
--* k~-1~/k~2[^\*^]{style="font-size:14px;"}~ln\[**I~3~^--^**\] +
const, ]{style="color:#FF0000;"}where
[ k~2~[\*]{style="font-size:14px;"} = k~2~/715\[**I^--^**\] + k~2~\'
]{style="color:#FF0000;"}, the latter being the rate coefficient for the
reaction between the enolate intermediate and I~3~^--^. With appropriate
least squares analysis of this rate equation,^‡^ a value for k~1~ using
either ^1^H or ^2^H (≡ D) isotopes can be extracted and this gives an
isotope effect k~1~^H^/k~1~^D^ of 6.3 ± 0.6. Note that this value
does NOT depend on \[B\]. Here, I am going to try to see if I can
construct a quantum mechanical model which reproduces this value.

[![Indole
diazocoupling](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone1.svg){.aligncenter
.size-full .wp-image-14967 decoding="async" style="text-align: justify;"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone1.svg)

1.  Model **1** uses just three water molecules as a proton relay
    (B3LYP+D3/Def2-TZVP/SCRF=water).
2.  Model **2** uses 2H~2~O.NaOH solvated by two extra passive water
    molecules. Since under these conditions, the NaOH is largely ionic,
    \[B\] ≡ \[OH^--^\]

|       |                         |                  |                                                                                                             |
|-------|-------------------------|------------------|-------------------------------------------------------------------------------------------------------------|
| Model | ΔG^‡^~298~ (ΔH^‡^~298~) | k^H^/k^D^ (298K) | DataDOIs                                                                                                    |
| 1     | 28.0 (22.9)             | 10.3             | \[cite\]10.14469/ch/191786\[/cite\],\[cite\]10.14469/ch/191765\[/cite\],\[cite\]10.14469/ch/191784\[/cite\] |
| 2     | 2.5 (2.8)               | 4.4              | \[cite\]10.14469/ch/191787\[/cite\],\[cite\]10.14469/ch/191782\[/cite\],\[cite\]10.14469/ch/191785\[/cite\] |

The plot of rate vs \[B\] shows\[cite\]10.1039/P29750001822\[/cite\]
that the uncatalysed (water) rate is very slow (intercept passes more or
less through zero) and the calculated free energy barrier (28.0
kcal/mol) confirms a slow rate at ambient temperatures. Note in the
final (aromatized) product, there is a noticeable hydrogen bond between
the 3-carbon and a water molecule (2.14Å). The calculated kinetic
isotope effect\[cite\]10.14469/hpc/202\[/cite\] is substantially larger
than observed experimentally for the base catalysed contribution.

![Indolineone ionization using 3 water
molecules](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone-water1.gif){.aligncenter
.size-full .wp-image-14967 decoding="async"
onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2016/01/indolinone-ts-747.132069.log;frame 25;');"
style="text-align: justify;" width="400"}

In the presence of NaOH (standard state = 1 atm = 0.044M), the
enthalpy barrier drops very substantially to 2.8 kcal/mol and the free
energy to 2.5 kcal/mol. Similar behaviour was noted previously on this
blog for the [hydrolysis of
thalidomide](http://www.ch.imperial.ac.uk/rzepa/blog/?p=8246){target="_blank"
rel="noopener"}. Although the magnitude of the reduction in barrier in
fact implies an extremely fast reaction, recollect that
\[B\]=\[OH^--^\] appears in the rate equation  and since its value is
very much less than 0.044M, the observed rate is relatively slow.

![Indolineone ionization using 3 water molecules +
NaOH](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone-NaOHa.gif){.aligncenter
.size-full .wp-image-14967 decoding="async"
onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2016/01/indolinone-NaOH-TS-1061.885986.log;frame 69;');"
style="text-align: justify;" width="410"}

The calculated KIE for the hydroxide catalysed mechanism is much smaller
that for the water route, but also smaller than is observed. This is a
value uncorrected for tunnelling, which given the small barrier might be
significant. 

These calculations show how a model for ionization of indolinone can be
constructed, and used to *e.g.* probe the sensitivity of KIE to
perturbations induced by ring substituents, which may form the basis of
a future post.

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

^‡^This is a non-linear equation with kinetics that straddle zero and
first order behaviour. In 1972, it was not easily possible to graph such
functions in a manner where the slope of a linear plot would yield the
rate constant. It was only computers and languages such as Fortran which
allowed such non-linear least squares analysis of the rate. In the
event, it turned out that the presence of 50% methanol in the mixed
aqueous solutions was the cause; in other solvents the kinetics
approximated zero order behavour very well.

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

#### Acknowledgments

This post has been cross-posted in PDF format at
[Authorea](https://doi.org/10.15200/winn.145337.72680){rel="noopener"
target="_blank"}.

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This is the third and final study deriving from my Ph.D.[cite]10.1039/P29750001822[/cite]. The first two topics dealt with the mechanism of heteroaromatic electrophilic attack using either a diazonium cation or a proton as electrophile, followed by either proton abstraction or carbon dioxide loss from the resulting Wheland intermediate.

Rogue Scholar Beiträge

I’ve started so I’ll finish. The ionisation mechanism and kinetic isotope effects for 1,3-dimethylindolin-2 one