Influence of an aromatic system on a substitent

Modifying the reactivity of aromatic compounds in certain positions by the introduction substituents is a standard strategy in organic chemistry. Depending on their effect on the electron density substituents favour the outcome of a reaction towards specific products, empowering chemists to perform complicated many-step reactions.

Figure 1 | Out of the two possible conformations of 5-methoxyindole only the anti-conformer (left) is observed in molecular beam experiments. The numbers of the indole chromophore indicate where the methoxy group (OCH3) is attached.

However, the interplay between the aromatic system and the substituent is not only one-sided: The chromophore can also influence the functional group. Often this influence remains unnoticed, but sometimes you observe a clear effect. An example is the molecule 5-methoxyindole, a derivative of the aromatic amino acid tryptophan. When you take this molecule and cool it in an expansion to internal temperatures of a few Kelvin, you only observe the so-called anti-conformer. In principle, the molecule might also adopt another conformation, syn-5-methoxyindole, but this has never been detected in expansion-based experiments.

Interestingly, changing the position of the methoxy group from carbon atom number 5 to 6 makes all the difference. Now, you can observe both conformations in the experiment and their signal is even comparable in intensity. So, what happens?

In principle, there are many ways to explain the absence of specific conformations from a spectrum. If you use the emission of fluorescence light after electronic excitation to detect the molecules, they might react to the excitation differently. For instance, one conformer might couple to another electronic state, leading to an effective non-radiative de-excitation pathway. This way the molecule would not emit light, remain “dark” and you wouldn’t see any signal at the detector. Also, the geometry of the molecule might change during the excitation in such an unfavourable way that electronic excitation or de-excitation is very weak.

Another explanation is that there are simply no molecules present in that specific conformation. This is also most likely the case for the molecules studied here.  The reason for this is that the two conformations are separated by a barrier and do not have the same energy. If the barrier is high, molecules will be trapped in a specific conformation. On the other hand, if the barrier is low, they might overcome the barrier during the cooling process.

An elegant way to determine these barriers experimentally is to “pump” the molecule to the electronically excited state and then “dump” most of the energy by stimulated emission, as done in the group of Zwier [1, 2]. Depending on whether the energy that remains in the molecule leads to a conformational change, barriers can be determined. However, this procedure has to happen close to the nozzle as the conformers have to be cooled afterwards in order to identify them. Hence, it cannot be applied to conformers which are separated by very low barriers as the subsequent cooling shovels all the population back to the more stable conformer. This is also the case in the present study.

Figure 2 | Pathway for the interconversion of the syn into the anti-conformer and vice versa. ΔE is the minimum energy barrier that has to be overcome for isomerization to occur. At the transition state, the methoxy group is rotated out of the aromatic plane.

The barrier for interconversion ΔE from anti to syn amounts to 860 cm-1 for 6-methoxyindole shown in Figure 2. This is too high to be surmounted during the expansion and we observe both conformers in the experiment. For 5-methoxyindole, where we observe only one conformer, the barrier height is computed to be 680 cm-1. Thus, a relatively small change in barrier height of 190 cm-1 is enough to either populate both conformers or only one. For 4-methoxyindole the barrier is further reduced to 155 cm-1.

In summary, we observe that the puzzle of the missing conformers for methoxyindoles can be explained by the relative stability of the individual conformers and the barriers separating them.

This study was published in the Journal of Molecular Spectroscopy.


[1] B. C. Dian, J. R Clarkson, and T. S. Zwier “Direct Measurement of Energy Thresholds to Conformational Isomerization in TryptamineScience 303, 1169 (2004)

[2] T. S. Zwier, “Laser Probes of Conformational Isomerization in Flexible Molecules and Complexes“, J. Phys. Chem. A 110, 4133 (2006)