3,5-Dinitrobenzoic acid (DNBA) is a dual-function supramolecular reagent: its electron-poor aromatic ring acts as a charge-transfer (CT) acceptor that π-stacks with polycyclic aromatic donors, while its carboxylic acid group hydrogen-bonds to pyridine derivatives through the classical R22(8)R_2^2(8) ring. A 2018 structural study of seven DNBA-containing crystals demonstrated that these two interaction classes can coexist in binary and ternary solids, including one ternary molecular salt formed by proton transfer to an aminopyridine; the salt outcome was rationalized only post hoc from literature calculated pKa values. The broader questions that study left implicit remain open: how broadly the combined CT-stacking plus acid⋯pyridine hydrogen-bonding strategy transfers across donors and pyridine derivatives, what quantitative criteria predict whether a DNBA–pyridine pairing yields a neutral co-crystal or an ionic salt, and how the relative strengths of CT stacking and hydrogen bonding determine packing and electronic coupling. Later work has mapped the DNBA structural landscape in the Cambridge Structural Database, extended the ternary strategy within the nitroaromatic-acceptor family, documented that salt and co-crystal outcomes form a polymorph- and pressure-dependent continuum that defeats any simple ΔpKa threshold, and produced machine-learning classifiers of salt versus co-crystal outcomes that outperform the ΔpKa rule. No validated, interpretable design rules specific to DNBA-based assemblies — where proton transfer converts the CT acceptor itself into a carboxylate anion — exist, so the problem of converting the observed motifs into robust predictive design rules remains open.

Background

Crystal engineering seeks to build multi-component molecular crystals — solids containing two or more chemically distinct neutral molecules (co-crystals) or ion pairs (molecular salts) — by choosing components whose non-covalent interactions combine predictably. Two workhorse interaction classes are relevant here. Charge-transfer (CT) interactions arise between an electron-rich aromatic donor and an electron-poor aromatic acceptor; in the crystal they appear as face-to-face π⋯π stacking (parallel overlapping aromatic rings typically 3.3–3.7 Å apart) that gives deeply coloured, potentially semiconducting solids, classically with 1,3,5-trinitrobenzene (TNB) as the acceptor; TNB-based ternary crystals assembled by combining CT stacking with hydrogen bonding were demonstrated by Seaton et al. (2013). Hydrogen bonding supplies the second class: a carboxylic acid group and a pyridine nitrogen form a cyclic O–H⋯N hydrogen-bonded pair described by the graph-set symbol R22(8)R_2^2(8), meaning an eight-atom ring closed by two hydrogen bonds. 3,5-Dinitrobenzoic acid (DNBA) combines both capabilities in one molecule — an electron-poor dinitroaromatic ring and a carboxylic acid — which is why it was called a many-faceted supramolecular reagent.

The central practical uncertainty is whether co-crystallizing an acid with a pyridine gives a neutral co-crystal or an ionic salt (proton transferred from acid to base). The standard heuristic, the ΔpKa rule, compares the aqueous pKapK_a of the acid with that of the protonated base: ΔpKa=pKa(BH+)−pKa(HA)\Delta pK_a = pK_a(\mathrm{BH^+}) - pK_a(\mathrm{HA}) above roughly 3 is said to favour a salt and values below 0 a co-crystal, leaving a wide grey zone. Large-scale studies delimit its reliability. A Cambridge Structural Database (CSD) survey of acid–base crystalline complexes (Cruz-Cabeza, 2012) showed the rule is only a statistical guide with substantial overlap between salt and co-crystal populations. Childs, Stahly and Park (2007) established the salt–co-crystal continuum: the proton's position is influenced by the crystal packing itself, so the same molecular pair can sit anywhere between neutral and fully ion-paired; later work located continuum states by solid-state NMR (Rajput et al., 2017) and X-ray photoelectron spectroscopy (Tothadi et al., 2021), found polymorphic systems whose forms occupy different points of the continuum (Salajee et al., 2022; Kotte et al., 2023), and showed that pressure can overturn the ΔpKa-based expectation (Das et al., 2024). Lattice-energy calculations including both protonation states (Mohamed, Tocher and Price, 2011) similarly find that the preferred proton position depends on the actual packing, not only on the isolated molecules. Against this background, Lemmerer et al. (2015) showed that calculated pKa values do predict outcome ranges for a nine-complex carboxylic-acid/pyridine series — a partial success that motivates, but does not constitute, a general criterion.

Hill, Levendis and Lemmerer (2018) reported seven DNBA-containing crystals: four binary CT co-crystals with polycyclic aromatic donors (fluoranthene, 9-bromoanthracene, 9-methylanthracene, 9-anthroic acid), all showing donor–acceptor π⋯π stacks with ring-centroid separations of 3.5225(3)–3.5405(1) Å; and three ternary solids in which a substituted aminopyridine hydrogen-bonds to the DNBA carboxyl group through an R22(8)R_2^2(8) ring while the CT stack persists. One ternary, with 3-bromo-2-aminopyridine, is a molecular salt (DNBA deprotonated), rationalized post hoc using literature calculated pKa values (ΔpKa≈1.37\Delta pK_a \approx 1.37); the other two are neutral. Interaction patterns were quantified by Hirshfeld surface analysis — a computational mapping of all intermolecular contacts on a molecule's surface, summarized as percentage contributions of contact types such as C···C, which serves as a proxy for π⋯π overlap. The study thus demonstrates the coexistence of the two interaction classes but leaves their combination unpredictable: the number of known DNBA ternaries was small, the salt-versus-co-crystal outcome was rationalized rather than predicted, and the relative weights of CT stacking and hydrogen bonding in determining packing and electronic properties were not established.

Problem Statement

Convert the demonstrated but un-predicted DNBA motifs into robust design rules for DNBA-based multi-component crystals, making the combined use of charge-transfer π⋯π\pi\cdots\pi stacking toward aromatic donors and carboxylic-acid⋯pyridine hydrogen bonding toward pyridine derivatives a predictive supramolecular strategy. The open questions are: how broadly this combined strategy transfers across aromatic donors and substituted pyridines, and the conditions under which the CT stack and the R22(8)R_2^2(8) acid⋯pyridine ring coexist in binary and ternary DNBA crystals; what quantitative criterion — thermodynamic or electronic descriptors, ΔpKa\Delta pK_a-based or beyond — predicts, for a proposed DNBA–pyridine pairing, whether the crystalline product is a neutral co-crystal or an ionic salt, including continuum cases in which the proton position depends on the particular crystal form; and how the relative strengths of the CT stacking and the hydrogen bonding determine the resulting packing and electronic coupling. These three questions are conjunctive requirements of one objective: all three must be addressed together, and none of them alone constitutes a resolution of the problem. Any such rules must capture the coupling distinctive to DNBA: the proton donor is itself the CT acceptor, so proton transfer converts DNBA into a dinitrobenzoate anion and changes the electron-acceptor strength underlying the CT stack. This predictive capability is what Hill, Levendis and Lemmerer (2018) lacked when they could only rationalize their single salt outcome post hoc from literature calculated pKa values.

References

  1. Hill, T. N.; Levendis, D. C.; Lemmerer, A. 'Binary and ternary co-crystals and molecular salts of 3,5-dinitrobenzoic acid: A many-faceted supramolecular reagent', Journal of Molecular Structure 1168 (2018) 28–38, doi:10.1016/j.molstruc.2018.04.066, https://doi.org/10.1016/j.molstruc.2018.04.066
  2. Seaton, C. C.; Blagden, N.; Munshi, T.; Scowen, I. J. 'Creation of Ternary Multicomponent Crystals by Exploitation of Charge-Transfer Interactions', Chemistry – A European Journal 19 (2013) 10663–10671, doi:10.1002/chem.201203578, https://doi.org/10.1002/chem.201203578
  3. Childs, S. L.; Stahly, G. P.; Park, A. 'The Salt−Cocrystal Continuum: The Influence of Crystal Structure on Ionization State', Molecular Pharmaceutics 4 (2007) 323–338, doi:10.1021/mp0601345, https://doi.org/10.1021/mp0601345
  4. Cruz-Cabeza, A. J. 'Acid–base crystalline complexes and the pKa rule', CrystEngComm 14 (2012) 6362, doi:10.1039/c2ce26055g, https://doi.org/10.1039/c2ce26055g
  5. Lemmerer, A.; Govindraju, S.; Johnston, M.; Motloung, X.; Savig, K. L. 'Co-crystals and molecular salts of carboxylic acid/pyridine complexes: can calculated pKa's predict proton transfer? A case study of nine complexes', CrystEngComm 17 (2015) 3591–3595, doi:10.1039/c5ce00102a, https://doi.org/10.1039/c5ce00102a
  6. Mohamed, S.; Tocher, D. A.; Price, S. L. 'Computational prediction of salt and cocrystal structures—Does a proton position matter?', International Journal of Pharmaceutics 418 (2011) 187–198, doi:10.1016/j.ijpharm.2011.03.063, https://doi.org/10.1016/j.ijpharm.2011.03.063
  7. Hill, T.; Erasmus, R.; Levendis, D. C.; Lemmerer, A. 'Combining two distinctive intermolecular forces in designing ternary co-crystals and molecular salts of 1,3,5-trinitrobenzene, 9-anthracenecarboxylic acid and ten substituted pyridines', CrystEngComm 21 (2019) 5206–5210, doi:10.1039/C9CE00093C, https://doi.org/10.1039/C9CE00093C
  8. Mandal, A.; Rissanen, K.; Mal, P. 'Unravelling substitution effects on charge transfer characteristics in cocrystals of pyrene based donors and 3,5-dinitrobenzoic acid', CrystEngComm 21 (2019) 4401–4408, doi:10.1039/c9ce00561g, https://doi.org/10.1039/c9ce00561g
  9. Scheepers, M. C.; Lemmerer, A. 'Exploring the Crystal Structure Landscape of 3,5-Dinitrobenzoic Acid through Various Multicomponent Molecular Complexes', Crystal Growth & Design 21 (2021) 344–356, doi:10.1021/acs.cgd.0c01217, https://doi.org/10.1021/acs.cgd.0c01217
  10. Tothadi, S.; Shaikh, T. R.; Gupta, S.; Dandela, R.; Vinod, C. P.; Nangia, A. K. 'Can We Identify the Salt–Cocrystal Continuum State Using XPS?', Crystal Growth & Design 21 (2021) 735–747, doi:10.1021/acs.cgd.0c00661, https://doi.org/10.1021/acs.cgd.0c00661
  11. Salajee, A.; Morrison, C.; Erasmus, R.; Lemmerer, A. 'Polymorphism and photoluminescence seen in (2-amino-5-chloropyridine)·(9-anthracenecarboxylic acid)·(trinitrobenzene): a further example of the salt-cocrystal continuum observed by virtue of isolating multiple crystal forms', CrystEngComm 24 (2022) 6297–6301, doi:10.1039/D2CE00490A, https://doi.org/10.1039/D2CE00490A
  12. Kotte, L.; Pendota, V.; Sreedhar, B.; Nanubolu, J. B. 'Famciclovir–fumaric acid: an all-in-one multicomponent system with salt, cocrystal and salt–cocrystal continuum', CrystEngComm 25 (2023) 2662–2678, doi:10.1039/d3ce00200d, https://doi.org/10.1039/d3ce00200d
  13. Quintano, M.; Moura, R. T.; Kraka, E. 'The pKa rule in light of local mode force constants', Chemical Physics Letters 826 (2023) 140654, doi:10.1016/j.cplett.2023.140654, https://doi.org/10.1016/j.cplett.2023.140654
  14. Das, S.; Pratik, S. M.; Datta, A. 'Crystals of Organic Acid–Base Complexes Defy the ΔpKa Rule Under Compression', The Journal of Physical Chemistry C 128 (2024) 17175–17183, doi:10.1021/acs.jpcc.4c05301, https://doi.org/10.1021/acs.jpcc.4c05301
  15. Ghanavati, M. A.; Khalili, B.; Alberico, D.; Rohani, S. 'Machine learning-driven discovery of multicomponent pharmaceutical solid forms via DualNet: confidence-aware prediction and ranking of salts and cocrystals', International Journal of Pharmaceutics 684 (2025) 126117, doi:10.1016/j.ijpharm.2025.126117, https://doi.org/10.1016/j.ijpharm.2025.126117
  16. Liu, H.-Y.; Li, Y.-C.; Wang, X.-D. 'Recent advances in organic donor–acceptor cocrystals: design, synthetic approaches, and optical applications', CrystEngComm 25 (2023) 3126–3141, doi:10.1039/d3ce00146f, https://doi.org/10.1039/d3ce00146f
  17. de Vries, T. E.; Vlieg, E.; de Gelder, R. 'A Multilayer Network Approach for Predicting the Cocrystal–Salt Transition', Crystal Growth & Design 26 (2026) 3752–3760, doi:10.1021/acs.cgd.6c00291, https://doi.org/10.1021/acs.cgd.6c00291
  18. Wiscons, R. A.; Coropceanu, V.; Matzger, A. J. 'Quaternary Charge-Transfer Solid Solutions: Electronic Tunability through Stoichiometry', Chemistry of Materials 31 (2019) 6598–6604, doi:10.1021/acs.chemmater.9b00502, https://doi.org/10.1021/acs.chemmater.9b00502
  19. Novak, J. C.; Makala, M.; MacKenzie, E. L.; Coropceanu, V.; Agosto, K.; Moravek, A. A.; Jurchescu, O. D.; Wiscons, R. A. 'Charge Transport in Ternary Charge-Transfer Solid Solution Single Crystals', Advanced Functional Materials 36 (2026), doi:10.1002/adfm.202523425, https://doi.org/10.1002/adfm.202523425
  20. Rajput, L.; Banik, M.; Yarava, J. R.; Joseph, S.; Pandey, M. K.; Nishiyama, Y.; Desiraju, G. R. 'Exploring the salt–cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering', IUCrJ 4 (2017) 466–475, doi:10.1107/s205225251700687x, https://doi.org/10.1107/s205225251700687x