Imperial College London

Henry Rzepa

The original strategic objective of my PhD researches in 1972-74 was to
explore how primary kinetic hydrogen isotope effects might be influenced
by the underlying structures of the transition states involved. Earlier
posts dealt with how one can construct [quantum-chemical models of these
transition states that fit the known
properties](http://wavefunction.fieldofscience.com/2012/03/on-michael-dewar-robin-collingwood-and.html){target="_blank"
rel="noopener"} of the reactions. Now, one can reverse the strategy by
computing the expected variation with structure to see if anything
interesting might emerge, and then if it does, open up the prospect of
further exploration by experiment. Here I will use the base-catalysed
enolisation of 1,3-dimethylindolin-2-ones and the decarboxylation of
3-indole carboxylates to explore this aspect.

[![Indole
diazocoupling](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indolinone3.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/indolinone3.svg)
[![Indole
diazocoupling](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indole-carboxylate2.svg){.aligncenter
.size-full .wp-image-14967 decoding="async" style="text-align: justify;"
width="300"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2016/01/indole-carboxylate2.svg)

The systems and results are shown in the table below, summarised by the
points:

### 1,3-dimethyl-indolinones:  {#dimethyl-indolinones}

1.  The free energy barriers are very low, but show an
    overall increase when changing the substituent from nitro to amino,
    with the 6-position being more sensitive than the 5. However, the
    increase is not consistent.
2.  The transition state mode changes regularly, the wavenumber more
    than doubling along the progression.
3.  The basic structure of the proton transfer evolves smoothly, from
    being an early transition state with 6-nitro to being a late one
    with 6-amino.
4.  The primary kinetic isotope effect shows less variation, but the
    trend is to increase as the transition state gets later, even beyond
    the point where the two bond lengths associated with the tranferring
    hydrogen are equal in length.
5.  As [Dan Singleton has
    pointed out](http://www.ch.imperial.ac.uk/rzepa/blog/?p=14327#comment-166700){target="_blank"
    rel="noopener"} on this blog, the observed KIE is a combination of
    effects based purely on the transition state structure and effects
    resulting from the *sharpness of the barrier* inducing **[proton
    tunneling]{style="color: #ff0000;"}** and this is itself related to
    the magnitude of ν~i~. The KIE ratios tabulated below derive purely
    from the former and do not take into account any such tunneling. We
    can see from the variation in ν~i~ that such tunnelling
    contributions are likely to vary substantially across this range of
    substituents. As a result, deconvoluting the KIE due to the symmetry
    of the proton transfer from the contribution due to tunnelling is
    going to be difficult.
6.  There are other computational errors which might contribute, such as
    solvent reorganisations due to specific substituents, only partially
    taken into acount here. In effect the unsubstituted reaction
    geometry was used as the template for the others, followed of course
    by a re-optimisation which might not explore other more favourable
    orientations brought about by the substituents.

### Indole-3-carboxylic acids:  {#indole-3-carboxylic-acids}

7.  The free energy barriers are now much higher than the indolinones,
    but show a consistent decrease along the series from 6-nitro to
    6-amino. This matches with the idea that the indole is a base and
    the basicity is increased by electron donation and decreased by
    electron withdrawal.
8.  The transition state mode again changes regularly, increasing as the
    barrier decreases.
9.  For 5-H, the computed free energy barrier matches that measured
    remarkably well.
10. The calculated KIE increase regularly along the series 6-nitro to
    6-amino.
11. The calculated KIE for 5-H matches that measured very well, but that
    for the 5-chloro does not. One might safely conclude that the
    outlier is probably the experimental value. The KIE are not obtained
    by direct measurement of the rate of reaction, but inferred from
    solving the relatively complex rate equation with inclusion of some
    approximations and assumptions. Perhaps one of these approximations
    is not valid for this substituent, or possibly an experimental error
    has encroached. Were this work to ever be repeated, this entry
    should be prioritised.
12. The overall variation in KIE is in fact quite small, but if the KIE
    can be measured very accurately, then they should be useful for
    comparison with such calculations.
13. We cannot really conclude whether the magnitude of the KIE closely
    reflects the symmetry of the transition state. For all the examples
    below, the C-H bond is always shorter than the H-O bond. More
    extreme and probably multiple substituents on the ring (5,6-dinitro?
    5,6-diamino?) might have to be used to probe a wider variation in
    transition state symmetry. For example, the maximum value for proton
    transfer from a hydronium ion was stated a long time ago to be
    around 3.6, \[cite\]10.1021/ja01085a025\[/cite\] and it would be of
    interest to see if that value is attained when the proton transfer
    becomes fully symmetry.

|                                                             |                                                       |                                                  |                |      |                                                                         |
|-------------------------------------------------------------|-------------------------------------------------------|--------------------------------------------------|----------------|------|-------------------------------------------------------------------------|
| 1,3-dimethylindolin-2-ones\[cite\]10.14469/hpc/208\[/cite\] |                                                       |                                                  |                |      |                                                                         |
| Model                                                       | ΔG^‡^~298~ (ΔH^‡^~298~)                               | k^H^/k^D^ (298K)                                 | r~C-H~, r~H-O~ | ν~i~ | DataDOIs                                                                |
| 6-nitro                                                     | 1.94                                                  | 3.22                                             | 1.256, 1.417   | 611  | \[cite\]10.14469/ch/191802\[/cite\],\[cite\]10.14469/ch/191796\[/cite\] |
| 5-nitro                                                     | 1.82                                                  | 3.65                                             | 1.289, 1.364   | 895  | \[cite\]10.14469/ch/191800\[/cite\],\[cite\]10.14469/ch/191789\[/cite\] |
| H                                                           | 2.48                                                  | 4.40                                             | 1.326, 1.316   | 1130 | \[cite\]10.14469/ch/191787\[/cite\],\[cite\]10.14469/ch/191782\[/cite\] |
| 5-amino                                                     | 6.73                                                  | 3.86                                             | 1.337, 1.304   | 1182 | \[cite\]10.14469/ch/191803\[/cite\],\[cite\]10.14469/ch/191797\[/cite\] |
| 6-amino                                                     | 3.19                                                  | 4.43                                             | 1.349, 1.291   | 1226 | \[cite\]10.14469/ch/191804\[/cite\],\[cite\]10.14469/ch/191799\[/cite\] |
| Indole-3-carboxylic acids\[cite\]10.14469/hpc/220\[/cite\]  |                                                       |                                                  |                |      |                                                                         |
| 6-nitro                                                     | 25.1                                                  | 2.72                                             | 1.279,1.391    | 706  | \[cite\]10.14469/ch/191807\[/cite\],\[cite\]10.14469/ch/191805\[/cite\] |
| 5-chloro                                                    | 23.1                                                  | 2.80 (2.23)                                      | 1.300,1.361    | 873  | \[cite\]10.14469/ch/191822\[/cite\],\[cite\]10.14469/ch/191825\[/cite\] |
| 5-H                                                         | 22.1 (22.0)^*a*^\[cite\]10.1039/P29770000281\[/cite\] | 2.87 (2.72)\[cite\]10.1039/P29770000281\[/cite\] | 1.304,1.354    | 921  | \[cite\]10.14469/ch/191828\[/cite\],\[cite\]10.14469/ch/191790\[/cite\] |
| 6-amino                                                     | 20.5                                                  | 3.04                                             | 1.308,1.348    | 950  | \[cite\]10.14469/ch/191810\[/cite\],\[cite\]10.14469/ch/191806\[/cite\] |

^*a*^[The barrier is higher than [previously
reported](http://www.ch.imperial.ac.uk/rzepa/blog/?p=15395){target="_blank"
rel="noopener"} because a significantly lower isomer of the ionised
reactant was subsequently located.\[cite\]10.14469/ch/191810\[/cite\]
Use of this new isomer also has a modest knock-on effect on the computed
isotope effect for this system, bringing it into line with the other
substituents and also with experiment.]{style="font-size:10px;"}

Overall, this study of variation in kinetic isotope effects for proton
transfer as induced by variation of ring substitution shows the
viability of such computation. The total elapsed time since the start of
this project is about three weeks, very much shorter than the original
time taken to synthesize the molecules and measure their
kinetics. Importantly, these were very much reactions occuring in
aqueous solution, where solvation and general acid or general base
catalysis occurred. Such reactions have long been thought to be very
difficult to model in a non-dynamic discrete sense. The results obtained
here tends towards optimism that such calculations may have a useful
role to play in understanding such mechanisms.

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

I would like to express my enormous gratitude to my Ph.D. supervisor,
Brian Challis, for starting me along this life-long exploration of
reaction mechanisms. I hope the above gives him satisfaction that the
endeavour back in 1972 has borne some more fruits.

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

#### Acknowledgments

This post has been cross-posted in PDF format at
[Authorea](https://doi.org/10.15200/winn.145337.72903){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"}
:::


The original strategic objective of my PhD researches in 1972-74 was to explore how primary kinetic hydrogen isotope effects might be influenced by the underlying structures of the transition states involved. Earlier posts dealt with how one can construct quantum-chemical models of these transition states that fit the known properties of the reactions.

Rogue Scholar Beiträge

Kinetic isotope effect models as a function of ring substituent for indole-3-carboxylic acids and indolin-2-ones.