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The CSD studies confirmed geometric trends from large amounts of data, further validating the characteristics of halogen bonds. However, several solid‐state fundamental studies have demonstrated that the halogen bond is a tunable and predicable supramolecular tool. One example comes from Bruce and coworkers, where they systematically evaluated halogen bond distances between 4‐(N,N‐dimethylamino)pyridine (DMAP) and iodobenzenes with different degrees of fluorination [71]. Here it was shown that the I⋯N distance correlates with the degree of fluorination and with calculated pK_a values, signifying that the halogen bond is tunable for the construction of solids (Figure 1.7). The halogen bond angle (CI⋯N) and distance largely correlate within these data; however there are some outliers that highlight the difficulties in constructing systematic solid‐state investigations where many intermolecular interactions are at play.

Another systematic evaluation of halogen bond tunability comes from a collaborative study between Aakeröy, Metrangolo, and Resnatti [72]. These studies sought to rank common halogen bond donors. Initially, ESP maps of six ditopic halogen bond donor systems were computed to determine the V_S,max at the σ‐hole and establish a hierarchy of halogen bond strength (Figure 1.8). The values highlight how the σ‐hole is influenced by the type of halogen, the hybridization of the carbon the halogen is bound to, and the degree of fluorination. More importantly, the V_S,max rankings were correlated to the operating halogen bond donors in cocrystal structures. For example, when the halogen bond donor 1‐(iodoethynyl)‐4‐iodobenzene is cocrystallized with 4‐phenylpyridine, two halogen bond donor sites compete for a single Lewis basic site (only considering the pyridine nitrogen in this instance). The resulting structure shows that the better halogen bond donor (iodoethynyl) interacts with the pyridine nitrogen, while the weaker iodobenzene donor forms a type I halogen–halogen contact with an adjacent molecule (Figure 1.8b).

The above study suggests that the halogen bond can be used for hierarchical supramolecular synthesis. As such, the Aakeröy group began to consider adopting the hydrogen bond “best donor–best acceptor” concept to the halogen bond construction of crystalline solids [73]. pK_a values have been employed to help predict the best donor–best acceptor pairs for hydrogen bond cocrystals [74]; however, pK_a values are not readily adaptable to many halogen bond systems, leading to the use of ESP values. In one example of this concept transfer, ESP values for several multi‐topic N‐heterocyclic halogen bond acceptors were evaluated and cocrystallized with a diverse set of halogen bond donors [75]. The results highlighted that the site of larger negative ESP was the halogen bond acceptor in the crystal structure, paralleling the behavior of the hydrogen bond. By computing ΔE values (ESP difference) between the two Lewis basic acceptor sites, the authors were able to predict the site of halogen bond contacts. The study concluded that if ΔE was greater than 75 kJ/mol, then selectivity (best donor interacting with best acceptor) would occur. If ΔE was less than 35 kJ/mol, then no preference was observed, and often both acceptor sites would be occupied. Intermediate ΔE values were deemed to be unpredictable. ESP values were also adapted to systems that simultaneously use halogen and hydrogen bonds [76]. Here, a Q value was introduced (the Q value being the difference in ESP values of the halogen and hydrogen bond donor) to help predict which interactions would be present in the final structure. The donor molecules contain both halogen and hydrogen donors and were evaluated with a diverse set of acceptors in a series of cocrystals. It was reported that increasingly large Q values showed a tendency for only hydrogen bonding to be present as the main structure directing interaction. In contrast, lower Q values showed a greater chance of having both interactions operating. However, the authors note this is a “rule of thumb,” and more work in this area needs to be conducted.

Figure 1.7 Halogen bond contacts between DMAP halogen bond acceptor nitrogen and iodine halogen bond donors of perfluoroarenes were evaluated. The various halogen bond donors with corresponding labels are shown in the middle bottom. Plot of N⋯I distance versus degree of fluorination (left) and plot of N⋯I distance versus calculated pK_a (right).

Source: From Präsang et al. [71]. © 2009 American Chemical Society.

Figure 1.8 Six halogen bond donors were systematically evaluated computationally, statistically, and experimentally by Aakeröy et al. The reported values are the V_S,max at the σ‐hole region of the respective halogen in kilojoule per mole (kJ/mol), (a). Iodine atom interactions in the cocrystal structure of 1‐(iodoethynyl)‐4‐iodobenzene and 4‐phenylpyridine (b). CCDC ref code: BISBIQ.

Source: From Aakeröy et al. [72]. © 2013 John Wiley & Sons.

The simultaneous application of the halogen and hydrogen bond has also been evaluated so that they can coexist in the solid state. Here, Aakeröy has contributed tactics to avoid “synthon crossover” [77] by establishing supramolecular synthons that do not interfere with each other. Thus, higher‐order cocrystallization may occur with greater frequency (e.g. ternary and quaternary cocrystals). In this light, the halogen bond is a complementary interaction to employ alongside the hydrogen bond. This is because many hydrogen bond synthons are multipoint, whereas halogen bonds are often single point (Figure 1.9, top) [78]. This feature resulted in the successful construction of a number of cocrystals with simultaneous hydrogen and halogen bonds and is highlighted, in conjunction with other crystal engineering concepts, in ternary cocrystals such as those demonstrated by Tothadi and Desiraju in the (2 : 1 : 1) 4‐nitrobenzamide/fumaric acid/1,4‐diiodobenzene crystal structure (Figure 1.9, bottom) [79].

Figure 1.9 Examples of simultaneous halogen and hydrogen bonding in the construction of cocrystals. The top and middle figures highlighs the single‐point halogen bond synthon and the multipoint hydrogen bond synthon. The bottom structure is an example of a ternary cocrystal assembly utilizing hydrogen and halogen bond synthons. Dotted lines represent halogen or hydrogen bonds. CCDC Ref codes: PAMLIA (top).

(Aakeröy et al. [78].)

YIPCIK (middle). PILLIH (bottom).

(Tothadi and Desiraju [79].)

Simultaneous halogen and hydrogen bonding to carbonyl oxygens has also been of interest. A Protein Data Bank (PDB) study revealed geometrical orthogonality (X⋯O⋯H angle of ≈ 90°) between the halogen and hydrogen bonds when simultaneously interacting with a carbonyl oxygen [80]. Computational analysis showed an energetic orthogonality, meaning that the strength of the hydrogen bond interaction was not impacted by the halogen bond. This suggests that the halogen bond can be used as a recognition interaction without disrupting protein structures largely stabilized by hydrogen bonding. Small molecule analogues have also reproduced the geometric orthogonality [81], although Duncan et al. note some of the limitations of this feature [82]. Additionally, the observed geometric orthogonality between the hydrogen and halogen bond appears to be a somewhat general feature of carbonyls. A CSD evaluation highlighted that geometric orthogonality was persistent when two hydrogen bonds or two halogen bonds interacted with a single carbonyl, suggesting the observation is dictated by the carbonyl acceptor [83].