3.1.1. Single Crystal Molecular Structure

The asymmetric unit comprises one molecule of theophylline, one molecule of squaric acid, and three molecules of water (See Figure S8). Theophylline exchanges four HBs with two squarate anions via the N11, N21, and C11 atoms (N11··· O12, 2.63 Å; N21··· O32, 2.64 Å; C11··· O22, 3.03 Å; C11··· O42, 3.12 Å). Interestingly, C11 forms a bifurcated HB with two squarate anions. In addition, O11 and O21 of Theophylline act as HB acceptors with respect to two symmetry-related O1W water molecules (O21··· O1W, 2.77 Å; O11··· O1W, 2.92 Å). The two components interact through a HBs connectivity involving two water molecules (O1W and O2W). O1W exchanges three HBs, two as a donor, as already described, and one as acceptor (range 2.74 Å–2.92 Å), O2w exchanges three HBs, two as a donor, and one as acceptor (range 2.53 Å–2.82 Å). O3W forms two HBs as a donor with a symmetry related molecule (3.31 Å) and with O32 of a squarate anion (2.84 Å), respectively, and it accepts HBs from O2W (2.82 Å), Figure 1. On the other hand, O3w is located into a channel like cavity and, according to the long HB distances, it is more loosely bound to the surrounding molecules, Figure S8.

**Figure 1.** Molecular structure of Theophylline squarate trihydrate with thermal ellipsoids plotted at the 30% probability level, highlighting the intermolecular connection (**a**). The water channel hosting the water molecule O3W is showed along the c-axes (**b**) and along a diagonal direction (**c**).

C–O and C–C bond lengths of the C4 ring of the squarate are quite indicative of the resonance condition because of the mono-anion formation, Figure 2.

**Figure 2.** Resonance structure of monodeprotonated squarate anion with bond distance (Å) indicated.

The C42–O42 bond is the longest being the only pure C–O single bond. C22–O22 is the shortest being the only pure double bond. The other two C–O bonds have an intermediate length having a partial double bond character [31]. It follows that C32–C42 and C42–C12 are the shortest covalent bonds associated with a partial double bond.

There are some intrinsic features in the network that the water molecules establish. As previously discussed, O3W is located in a channel that runs parallel to the *c*-axis (see Figure 1b,c). O3W is the most loosely bound to the surroundings and it would be most likely the first molecule leaving the structure upon dehydration. This is also confirmed by the calorimetric analysis as discussed below.
