*3.2. Intermolecular Level*

The guanine ring system was one of the substructures identified via *IsoStar*, illustrated in Figure 4a, with nitrogen and oxygen atoms acting as probes. The distribution of the data points is very close to what was expected, with the majority concentrated around polar contributors. Most of the structures have bifurcated hydrogen bonds, each forming a contact with both O1 and N3. However, the presence of very few turquoise data points indicates that only a minority of hits seems to be at a close distance to the guanine rings (see frequency distribution plot in Supplementary Materials). This observation was unexpected due to the high electronegative character of both nitrogen and oxygen atoms, which in general enables their involvement in relatively strong contacts.

**Figure 4.** *IsoStar* contour plot with guanine as the central group having (**a**) nitrogen and oxygen as the contact groups (internal scaling: level 25—dark blue, level 50—lighter blue, level 75—turquoise) and (**b**) only carbon as the contact group (internal scaling: Level 10—Yellow, Level 25—Blue, Level 50—Green, Level 75—Red).

The contour plot in Figure 4b highlights the ability of carbon to act as a hydrogen bond donor, as well as the dominant presence of possible C–H ... π interactions or π ... π stacking, created due to the delocalized electron density in the aromatic guanine ring system. Other contour plots were constructed using an aliphatic ether as hydrogen bond acceptor and hydroxyl group as the central group. The distributions of the resultant hits of both plots were as expected (Please refer to Supplementary Materials).

Full interaction maps are sensitive to the specific conformation, meaning that each of the forms will have a different map [25]. Comparison of the maps (Figure 5) reveals that the maps associated with form I have a larger area and higher intensity than those pertaining to form II, indicating that the conformation of form I is more accessible for hydrogen bonding. The fully extended conformation of form I enables it to form more hydrogen bonds, which ultimately might be a major contributor to its thermodynamic stability at ambient conditions. Such stability is also evidenced through the fact that form III (hydrate form) converts to form I at temperatures above 180 ◦C, an exothermal transition which proves the monotropic relationship between the two forms [18]. The lack of accessibility in relation to the ether oxygen in form II, due to the proximity of the hydroxyl group, was earlier highlighted by the orientation of the torsion angle in *Mogul* results, which clearly demonstrated a degree of folding.

**Figure 5.** Full interaction map of (**a**) form I and (**b**) form II, with uncharged NH nitrogen (blue), RNH3 nitrogen (light blue), alcohol oxygen (light red) and carbonyl oxygen (red), at level 6.0. The hydrogen bonds predicted by *Mercury* are also shown (intermolecular, red, intramolecular, turquoise).

The geometric features of the hydrogen bonds of both forms were compared with those in the literature, and all results were compatible except those involving a C–H donor, which to the best of our knowledge were not included in any published list (Please refer to Supplementary Materials) [17]. The full interaction maps could not predict the involvement of the carbon donors for form I unless the distance levels were significantly increased. Even though the geometric parameters of the contacts with C–H donors are associated with characteristics of weaker interactions, they have a collective effect on the crystal packing and physicochemical properties of form I [33,34]. The addition of methyl carbon and aromatic carbon as separate probes did not alter maps significantly, suggesting that the C–H ... π contacts and π ... π stacking are less influential in form I, as opposed to in form II (Please refer to Supplementary Materials).
