Computational Prediction of Structure and Catalytic Activity of New Organic Superacids

A Unity through Knowledge Fund project for young researchers and professionals

co-financed by the APO Ltd. Zagreb


During project duration research efforts were oriented in several directions grouped here in the following few scientific topics:

a) Computational design and prediction of new neutral organic superacids

This represents the  essential part of this project. We had concentrated on two different classes of compounds and three different electronic effects promoting the acidity of organic molecules towards superacidic values. These are:


Properly substituted open–chain polyenes could be used in tailoring superacids. This is surprising and contrary to a generally accepted opinion that (poly)cyclic molecules, which undergo aromatization of their ring(s) in deprotonated forms, are the most useful building blocks of superacids. We revealed that unsubstituted polyenes are already appreciably acidic, but a dramatic increase in their acidity is established upon multiple cyanation. Some of the examined systems closely approach the gas–phase hyperacidity threshold of 245 kcal/mol. It is important to emphasize that many of the investigated polycyano compounds have already been synthesized, like molecules 14 below, either in neutral or anionic forms. This lends credence that other predicted polycyano–molecules are probably prone to synthesis.


In line with our previous results, we demonstrated that several polycyclic organic skeletons, when properly substituted, exhibit very high acidity. The same holds, for example, for compounds 57 below. Our results demonstrated that molecule 6 possesses unusually strong π–electron delocalization over the perimeter of the CC bonds, thus forming a quasi–[14]annulene pattern having aromatic character as high as 91.4%. Polycyano derivatives of systems 56 are exceptionally acidic. However, a record holder in acidity and the first neutral organic hyperacid is dodecacyano derivative of molecule 7, having deprotonation enthalpy as low as 242.8 kcal/mol.


A very abundant functional group present in many biologically relevant molecules is an N–oxide moiety. It turned out that this group, found in the vicinity of the deprotonation centre, exhibits a strong acidifying effect, comparable to a substituent effect of one cyano group. This electronic effect could be used in designing new extremely acidic materials. As an illustration, octacyanoquinolizine N–oxide 8 possesses gas–phase deprotonation enthalpy of 254.8 kcal/mol and the pKa value of –20.2 in DMSO. Such acidifying effect of an N–oxide moiety was estimated to be around 9–17 kcal/mol in the gas–phase deprotonation enthalpy and about 5–11 pKa units in DMSO. This is the first systematic study in the literature revealing impact of an N–oxide group on the acidity constants.


This work was done in a close collaboration with Prof. Tomilov. He was able to synthesize molecule 9. Our extensive calculations revealed that this compound is very acidic having the gas-phase deprotonation enthalpy in between that of HNO3 and HI. Prof. Tomilov determined its pKa value of 7.7 in DMSO, which makes it one of the strongest organic C–H acids known in the literature. Synthesis of some of the cyano derivatives of molecule 9 is attempted, and the most likely candidate is heksacyano–methoxycarbonyl derivative 10, which should be around 25 orders of magnitude stronger acid than 9 in the gas-phase.


This study revealed that out of all halogen derivatives of borane, BBr3 enhances the acidity most efficiently. This acidifying effect assumes values between 34.3 and 111.3 kcal/mol for cyanomethanes, 22.7 kcal/mol for pentacyanopropene, 12.8 kcal/mol for pentacyanocyclopentadiene and 7.2 kcal/mol for undecacyanofluoradene. The last case is particularly interesting, since the corresponding ΔHacid value is 240.0 kcal/mol; quite below hyperacidity threshold.

b) Interpretation of underlying electronic effects leading to highly pronounced


By making use of our original triadic analysis, we were able to identify whether initial (neutral acid), final (conjugate base) or intermediate state effects are responsible for the high acidity of investigated molecules. It turned out that in cyanopolyenes the origin of the acidity amplification with the size of the system was identified as the increased stability of the resulting conjugate bases, which is mirrored through Koopmans’ term appearing in the triadic analysis. This is a pure final state effect.

In compounds bearing an N–oxide group, a similar situation takes place. Specifically, acidity enhancement of an N–oxide moiety is identified through triadic analysis to be a consequence of the final state effect of the anion, where compounds having an N–oxide group benefit from the favorable charge–dipole interaction between the excess negative charge and an N–O group.



c) Estimation of acidity constants in condensed phase

Following our previously developed approach, we estimated pKa values of our proposed superacids in DMSO, which represents industrially important liquid environment. It was shown that acidity trends obtained in the gas–phase were almost completely preserved in DMSO solution. For example, it turned out that the acidifying effect of an N–oxide group, directly bonded to the deprotonation centre, assumes values around 5–11 pKa units in DMSO, while it is between 9–17 kcal/mol in the gas–phase.

In addition, in our combined computational/experimental study, which showed that bis–guanidine compound 11 below represents one of the strongest superbase available, we calculated its pKa value in acetonitrile of 28.6, being in excellent agreement with an experimental value determined in the same work.



d) Evaluation of the catalytic activity

Beside highly pronounced thermodynamical acidity of newly proposed neutral organic superacids in the gas–phase or in the condensed media, for these compounds to have practical value and applicability as catalysts in everyday chemical transformations one needs to evaluate their favorable catalytic activity, or their kinetic acidity. In other words, we tried to determine how easy is for our proposed superacids to give away the proton in a chemical reaction. In doing so, we selected chemical reaction of benzene protonation leading to benzenium cation. This reaction is a model reaction for an extremely important class of organic transformations, namely electrophilic aromatic substitution. Our preliminary results showed that the catalytic activity of our superacids is proportional to their acidity, meaning that stronger the acid in question is the better catalysts it makes. This is very encouraging and promising for our research, because not only that we were able to propose the strongest organic acids in the literature, but also these investigations demonstrated that they would provide one of the most efficient catalysts presently available. 



e) Investigation of the possibility for a spontaneous proton–transfer reaction in

the gas–phase

Some new and interesting results were obtained using carefully selected pairs of acids and bases involved in the mutual interaction that could potentially lead to a spontaneous proton transfer reaction (SPTR) from the acid onto the base in question.












Our results revealed that, first of all, the probability of SPTR depends almost exclusively on the difference in the acidity of an acid and the basicity of a base involved in the interaction. Specifically, the closer these two values are to each other the higher the chance of a successful SPTR event. Secondly, we selected these two molecules for our studies because by substituting these interacting systems at para–positions on both molecules (R1 and R2 substituents) we were able to carefully modify their acidities and basicities leading to a whole spectrum of the corresponding acidity/basicity differences. It turned out that there is some kind of a "magic" threshold close to 80 kcal/mol in the acidity/basicity difference, meaning that (a) when this difference is lower than that one observes SPTR, (b) when it is around 80 kcal/mol or slightly higher there is a transition state (kinetic barrier) connecting acid/base hydrogen bonded pair and deprotonated/protonated ion pair, and (c) when it is much higher than the threshold value there is no SPTR at all. Using our original triadic formula, some further work on this problem should shed more light on these observations and help in its interpretation.

Project Abstract

Project Results




Media Coverage

Project Funding