Complexes with different aromatic molecules

When different aromatic molecules are combined with guanidinium cation to create the complexes, the number of possible structures grows quickly. In order to make the discussion simpler, several prototypical structures have been selected among the minima located. It is worth noting that, as commented before, especially in the case of

Alba Campo Cacharrón

120

phenol-containing complexes, these prototypical structures are not always found, so only the closest among the minima found were considered. In most cases, T-shaped structures containing phenol coordinated to guanidinium cation show a O-H···π hydrogen bond, whereas purely stacked structures are not found. All these preventions in mind, in the following sections the results for these mixed complexes will be discussed. Five different structures have been considered for mixed complexes of guanidinium, benzene and phenol, as shown in Figure 5.4: two parallel ones and two T- shaped ones, whereas for the doubly T-shaped structure there is only one since Bz-Ph and Ph-Bz are equivalent.

Table 5.2 lists the values obtained for the complexation energies at the M06-2X/6- 31+G* and SCS-MP2/CBS levels of calculation. Considering the values in Table 5.2 for Bz- Ph complexes, it can be appreciated that the doubly T-shaped minimum Bz-Ph-DT reaches a complexation energy of around -28.2 kcal/mol, which is an intermediate value between the results obtained for complexes containing only phenol or benzene. This is as expected since in doubly T-shaped minima the two aromatic molecules do not interact significantly between them, so the interaction depends entirely on the guanidinium···π interaction. As for stacked minima, both show a similar stability around - 19 kcal/mol, which is slightly larger than that observed in benzene complexes (no stacked minima were found for phenol complexes). Finally, T-shaped minima show results which are more difficult to rationalize. Bz-Ph-T is more stable than Ph-Bz-T by 2.5 kcal/mol, but this is a consequence of the contact of guanidinium cation with the hydroxyl oxygen in the former structure. On the other hand Ph-Bz-T shows a O-H···π hydrogen bond which makes it more stable than the corresponding Bz-Bz structure, but less stable than complexes with only phenol, where O-H···O hydrogen bonds are formed. In the case of complexes formed by guanidinium, benzene and indole (Figure 5.5) the behavior is simpler since the minima correspond closely with the prototypical arrangements considered. It is clearly observed that for stacked structures it is more favorable for the indole molecule (In-Bz-P) to be coordinated to guanidinium, with a stability gain of around -4 kcal/mol with respect to coordination to benzene (Bz-In-P). Since the interaction between indole and benzene must be similar in both cases, this difference is related to the stronger interaction of guanidinium with indole. Again, an intermediate behavior between Bz-Bz and In-In complexes is observed. In T-shaped minima coordination to indole is also preferred by about -4 kcal/mol, but this could be also related to the formation of a N-H···π hydrogen bond in the In-Bz-T minimum. Doubly T-shaped structures show a similar behavior with stability midway between indole and benzene complexes.

5. Guanidinium aromatic trimers

Alba Campo Cacharrón

122

Figure 5.4. Selected minima for complexes formed by guanidinium, benzene and phenol as obtained at the M06-2X/6-31+G* level. Selected Distances in Å.

Bz-Ph-DT

Ph-Bz-P

Bz-Ph-P

Bz-Ph-T

Ph-Bz-T

5. Guanidinium aromatic trimers

123

Figure 5.5. Selected minima for complexes formed by guanidinium, benzene and indole as obtained at the M06-2X/6-31+G* level. Selected Distances in Å.

Bz-In-DT

In-Bz-P

Bz-In-P

Bz-In-T

In-Bz-T

Alba Campo Cacharrón

124

Figure 5.6. Selected minima for complexes formed by guanidinium, phenol and indole as obtained at the M06-2X/6-31+G* level. Selected Distances in Å.

1.962 2.698 2.408 1.956 2.207 _2.205 2.252 _1.849 2.239 2.436 2.285 2.230 2.306 2.405 2.314 2.292

Ph-In-P

Ph-In-P

Ph-In-T

Ph-In-T

Ph-In-DT

5. Guanidinium aromatic trimers

125

Finally, for complexes containing the cation plus indole and phenol (Figure 5.6) the behavior is similar overall. For the doubly T-shaped minimum the complexation energy is halfway between those of complexes with only one kind of aromatic molecule. However, it can be observed that phenol coordination is preferred over indole for stacked and T-shaped structures. This is because in the presence of phenol, In-Ph structures correspond to our prototypes, but for Ph-In complexes there are clear deviations. Therefore whereas In-Ph-P is a typical stacked structure with a complexation energy of -27 kcal/mol, Ph-In-P minimum is not stacked, and guanidinium interacts with both aromatic units leading to a complexation energy of -31.7 kcal/mol. In fact this minimum corresponds more closely to a guanidinium coordinated to the hydroxyl group which establishes a O-H···π hydrogen bond to the pyrrol ring of indole. T-shaped minima both present hydrogen bonds. Ph-In-T forms a O-H···π hydrogen bond to the pyrrol ring of indole, whereas a N-H···π hydrogen bond is observed in In-Ph-T, this latter structure being disfavored by about 2 kcal/mol.

So, these mixed complexes behave halfway the complexes formed with only one kind of aromatic molecule. This is especially evident in the case of doubly T-shaped structures, which always show complexation energies almost midway the complexes with only one kind of aromatic molecule. These doubly T-shaped structures are always the most stable found among the clusters studied. A similar behavior is observed in stacked clusters of benzene and indole, but the presence of phenol and the tendency of its hydroxyl group to form hydrogen bonds introduce other possibilities for the interaction. In the absence of extra interactions with the guanidinium cation or hydrogen bonds, stacked structures are the least stable. T-shaped minima are usually the second most stable, but again in phenol complexes the formation of hydrogen bonds can alter the order of stability, favoring coordination of phenol by the guanidinium cation. In the absence of these effects guanidinium coordinates preferentially to indole over phenol and over benzene.

A question arises about whether the kind of structures already discussed is present in proteins. It is known that stacking interactions between aromatic side chains are frequent, as it is the case with the cation···aromatic interactions.[4, 11] It is expected, however that the motifs considered in this work, simultaneously involving three different side chains will be less frequent. However, searching into the Protein Data Bank Europe it is possible to find the kind of structures considered in this work.[52] As example, searching for a pattern formed by a nitrogen atom of guanidinium in arginine contacting with indole ring in tryptophan, which in turn is stacked to phenyl group of phenylalanine (like in In-Bz-P) results in more than forty coincidences. Among these structures there are several of them that resemble the patterns shown in the manuscript. Of course there are geometrical differences that are mainly associated to the more complex environment in the protein, and to the rest of the side chains hindering the free orientation of the aromatic rings and the cationic fragment to interact

Alba Campo Cacharrón

126

in an optimal way. In any case, many of the structures found resemble the minima considered in this work, so it can be expected that their characteristics would be helpful in order to understand these kind of contact in proteins. Also, gas phase results would help to isolate other factors like solvent effects of other groups nearby which can alter the mutual arrangement of aromatic and cationic side chains.