Category Archives: Organic Chemistry

Submerged Reaction Energy Barriers


The energy of your calculated transition state (TS) is lower than that of the reagents. That’s gotta be an error right? Well, maybe not.

Typically, in classical transition state theory, we associate the reaction barrier to the energy difference between the reaction complex and the TS, in other words, we associate the reaction barrier to the relative energy of the TS. However, this isn’t always the case, since the TS isn’t always located at the barrier, which simply may not exist or may be a submerged one, i.e. the TS relative energy is negative with respect to the reaction complex. This leads to negative activation energies, but one must bear in mind that the activation energy is not equal to the relative energy of the TS but rather to the slope of the Arrhenius plot, which in turn comes from the Arrhenius equation given below.

k = Aexp(Ea/RT) 
or in logarithmic form
Lnk = LnA + (Ea/RT)

The Arrhenius plot is then the plot of Lnk vs T-1, with slope Ea

Caution is advised since the apparent presence of such a barrier may be due to a computational artifact rather than to the real kinetics taking place, that’s why an IRC calculation must follow a TS optimization in order to verify the truthfulness of the TS; keep in mind that in classical transition state theory, we’re ‘slicing‘ a multidimensional map along a carefully chosen reaction coordinate but this choice might not entirely be the right one, or even an existing one for that matter. I also recommend to change the level of theory, reconsider the reaction complex structure (because a hidden intermediate or complex may be lurking between reactants and TS, see figure 1) and fully verifying the thermochemistry of all components involved before asserting that any given reaction under study has one of these atypical barriers.

Chemistry Makes the Chemical


The compound shown below in figure 1 is listed by Aldrich as 4,5,6,7-tetrahydroindole, but is it really?

tetrahydroindole

Fig 1. An indole?

To a hardcore organic chemist it is clear that this is not an indole but a pyrrole because  the lack of aromaticity in the fused ring gives this molecule the same reactivity as 2,3-diethyl pyrrole.  If you search the ChemSpider database for ‘tetrahydroindole’ the search returns the following compound with the identical chemical formula C8H11N but with a different hydrogenation pattern: 2,3,3a,4-Tetrahydro-1H-indole

14650657

Fig 2. Also listed as an indole

The real indole, upon an electrophilic attack, behaves as a free enamine yielding the product shown in figure 3 in which the substitution occurs in position 3. This compound cannot undergo an Aromatic Electrophilic Susbstitution since that would imply the formation of a sigma complex which would disrupt the aromaticity.

indole_reaction

On the contrary, the corresponding pyrrole is substituted in position 2

pyrole_reaction

These differences in reactivity towards electrophiles are easily rationalized when we plot their HOMO orbitals (calculated at the M062X/def2TZVP level of theory):

If we calculate the Fukui indexes at the same level of theory we get the highest value for susceptibility towards an electrophilic attack as follows: 0.20 for C(3) in indole and 0.25 for C(2) in pyrrole, consistent with the previous reaction schemes.

So, why is it listed as an indole? why would anyone search for it under that name? Nobody thinks about cyclohexane as 1,3,5-trihydrobenzene. According to my good friend and colleague Dr. Moisés Romero most names for heterocyles are kept even after such dramatic chemical changes due to historical and mnemonic reasons even when the reactivity is entirely different. This is only a nomenclature issue that we have inherited from the times of Hantzsch more than a century ago. We’ve become used to keeping the trivial (or should I say arbitrary) names and further use them as derivations but this could pose an epistemological problem if students cannot recognize which heterocycle presents which reactivity.

So, in a nutshell:

Chemistry makes the chemical and not the structure.

A thing we all know but sometimes is overlooked for the sake of simplicity.

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