Imperial College London

Henry Rzepa

[Earlier](http://www.ch.imperial.ac.uk/rzepa/blog/?p=15295){target="_blank"
rel="noopener"} I explored models for the heteroaromatic electrophilic
protiodecarboxylation of an 3-substituted indole, focusing on the role
of water as the proton transfer and delivery agent. Next,
came [models](http://www.ch.imperial.ac.uk/rzepa/blog/?p=15415){target="_blank"
rel="noopener"} for both water and the general **base**
catalysed ionization of indolinones. Here I explore general
**acid** catalysis by evaluating the properties of two possible models
for decarboxylation of 3-indole carboxylic acid, one involving proton
transfer (PT) from neutral water in the presence of covalent un-ionized
HCl (**1**) and one with PT from a protonated water resulting
from ionised HCl (**2**).

[![Indole
diazocoupling](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/decarbox2.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/decarbox2.svg)

The original study\[cite\]10.1039/P29770000281\[/cite\] noted that the
rate of decarboxylation fitted well to the kinetic expression: [rate =
{a + b\[L~3~O^+^\]/(1 +
c\[L~3~O^+^\])}\[indole\]]{style="color:#FF0000;"}, where L can be H
or D. Experimentally, \[L~3~O^+^\] is controlled by adding a strong
general acid such as HCl, which when the
[appropriate](http://www.ch.imperial.ac.uk/rzepa/blog/?p=13394){target="_blank"
rel="noopener"} number of water molecules are
added\[cite\]10.1002/chem.201504016\[/cite\] fully ionizes to
H~3~O^+^.OH^--^. Now for B3LYP+D3/Def2-TZVPD/SCRF=water calculations:

- Model **1 **takes the pure water model and adds HCl (blue above) *via*
  hydrogen bonding to the H~2~O that is transferring the proton to the
  indole ring. Three water molecules are hydrogen bonding to the
  carboxylate oxygens to create a bicyclic network in which a ring of
  either 8 or 10 atoms can act as the proton relay structure. The
  question now arises whether the proton relay takes the longer (red)
  route or the slightly shorter green route.
- Isomeric model **2** uses H~3~O^+^ for proton transfer, with an
  adjacent Cl^--^ to complete the ion-pair.

|       |                     |                                                                                                                                                       |                                                                        |
|-------|---------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Model | ΔG^‡^~298~ (0.044M) | DataDOIs                                                                                                                                              | k^H^/k^[D]{style="font-size: 11px;"}^\[cite\]10.14469/hpc/204\[/cite\] |
| 1     | 27.4                | \[cite\]10.14469/ch/191792\[/cite\],^‡^\[cite\]10.14469/ch/191795\[/cite\],^†^\[cite\]10.14469/ch/191794\[/cite\],\[cite\]10.14469/ch/191767\[/cite\] | 5.69                                                                   |
| 2     | 16.8^‡^ (14.8)^†^   | \[cite\]10.14469/ch/191795\[/cite\],\[cite\]10.14469/ch/191790\[/cite\],\[cite\]-\[/cite\]                                                            | 2.45                                                                   |

^‡^[Reactant as a non-ionised covalent HCl.]{style="font-size:10px;"}
^†^[reactant as an isomeric ionized H~3~O^+^.Cl^-- ^ beng 2.0 kcal/mol
higher in energ within this solvation model. [Note added in proof. A
significantly lower form of the reactant has subsequently been located
which increases the free energy barrier to 22.1 kcal (vis 22.0 actually
measured!). Diacussion of this can be seen in the [associated post
here](http://www.ch.imperial.ac.uk/rzepa/blog/?p=15505){target="_blank"
rel="noopener"}.]{style="color:#FF0000;"}]{style="font-size:10px;"}

1.  An IRC for Model 1 shows that the proton relay takes the red path,
    whereas without the HCl the green path is followed.

     

     

     

    [![Indole
    diazocoupling](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/HCL-cova.gif){.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/HCL-cova.gif)

    The transition state free energy however is ..

2.  10.6^‡ ^or 12.6^†^ kcal/mol **higher** than model **2 **(click on
    the image below to load a 3D model). The general acid catalysed
    model is therefore preferred. The difference in free energy between
    the two models corresponds to a rate acceleration of
    \>10^6^,^ ^which is indeed similar to that
    observed\[cite\]10.1039/P29770000281\[/cite\].

![Decarboxylation using a general acid
catalyst](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/Model2.jpg){.aligncenter
.size-full .wp-image-14967 decoding="async"
onclick="jmolInitialize('../Jmol/','JmolAppletSigned.jar');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2016/01/model2.log;frame 3;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;');"
style="text-align: justify;" width="400"}

The clincher comes with calculation\[cite\]10.14469/hpc/204\[/cite\] of
the kinetic isotope effects (KIE). For general acid catalysis, they were
measured as k^H^/k^D^ \~2.5.\[cite\]10.1039/P29770000281\[/cite\]

- For model 1, using an un-ionised reactant and un-ionised transition
  state, the calculated KIE is 5.69 (very similar to that [calculated
  for the water catalysed
  reaction](http://www.ch.imperial.ac.uk/rzepa/blog/?p=15295){target="_blank"
  rel="noopener"}, 5.66) but not a good fit to experiment.
- For model 2, using the same un-ionised reactant but an ionised
  transition state, KIE = 2.04, a much better fit.
- For model 2, using ionised reactant AND transition state, KIE =
  [[**2.45**]{style="color:#FF0000;"}]{style="font-size:14px;"}, an even
  better fit to experiment.

So we now have a model for the general acid catalysed decarboxylation of
a 3-indole carboxylate which agrees with both the kinetic behaviours and
the isotope effects measured for this reaction. Since the barrier is a
relatively large one, proton tunnelling may play a lesser role in this
interpretation, and the stage is set to use this model to *e.g.* explore
how isotope effects are indeed influenced by tuning the reactivity using
ring substitutents, the original purpose of my researches all those
years ago. Perhaps the catch phrase *I've started so I'll start* is now
more apposite.

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

#### Acknowledgments

This post has been cross-posted in PDF format at
[Authorea](https://doi.org/10.15200/winn.145337.72789){rel="noopener"
target="_blank"}.

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


Earlier I explored models for the heteroaromatic electrophilic protiodecarboxylation of an 3-substituted indole, focusing on the role of water as the proton transfer and delivery agent. Next, came models for both water and the general
<strong>
 base
</strong>
catalysed ionization of indolinones.

Messaggi di Rogue Scholar

I’ve started so I’ll finish. Kinetic isotope effect models for a general acid as a catalyst in the protiodecarboxylation of indoles.