CrystEngComm PAPER Cite this: CrystEngComm, 2014, 16, 5917 Received 24th January 2014, Accepted 14th May 2014 DOI: 10.1039/c4ce00191e www.rsc.org/crystengcomm Functional hybrid co-crystals of humic substances: a growth forecast† Giuseppe M. Lombardo, Antonio Rescifina and Francesco Punzo* Basing our reasoning on the only known and available crystalline structure of a hybrid co-crystal of caffeic acid, we extended our study to the analysis of the behaviour of another humic substance, the protocatechuic acid. The abilities and tendencies of both these compounds to give rise to stable hybrid co-crystals with the elements of group I were studied by predicting, via molecular dynamics simulations, their crystalline setups on the basis of a detailed energetic analysis, which allows the detection of the most stable possible structures and their layouts. Without claiming to have performed an ab initio crystal structure prediction, we tried instead to determine the tendencies of a specific set of humic substances to give rise to a particular type of hybrid co-crystals. Introduction Humic substances are characterized by the concomitant presence of carboxylic and phenolic groups which lend them the typical behaviour of polyprotic acids. They play a key role in many biodegradation processes and easily form complexes with ions widely diffused in the environment. 1–5 For this reason this class of compounds is interesting for potential environmental chemistry applications, concerning the complexation of heavy metals via a natural route. 6,7 Our attention was dedicated to protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) as well as to caffeic acid [trans 3-(3,4-dihydroxyphenyl)prop-2-enoic acid, CA], two phenolic phytochemicals widely present in nature. 8–15 Their structures are reported in Fig. 1 which evidences the close similarities between the two molecules which differ by the presence of an ethylenic fragment on the side chain of CA. The latter enables in the CA more than in the PCA an extended delocalization of the aromatic charge. CA is reported to be an active hepatocarcinoma inhibitor 16 as well as a strong in vitro antioxidant, mainly against hyperoxoradicals. 17–19 Its derivatives are used as components of antimitogenic, anti-inflammatory, and immunomodulatory drugs. 20,21 Most of the known studies concerning the attempts to characterize its structural features are based on pure computational approaches 12–16,22 or confined to efforts to characterize its structure in solution. 9,12,15,23,24 All these studies were performed without the extended periodic condi- tions of the crystalline state and therefore do not provide the necessary conditions to perform a direct comparison with real crystal structures. However they all agree in considering the competition between the catecholic and carboxy moieties as the key to interpret the resulting structures, both in the gas phase and in solution. Each of the two moieties seems to be more relevant depending on which group – I, II or III – the element they coordinate belongs to. As expected, all of the authors agree on the pivotal role played by the pH. Our model, on the other hand, is based on the first crystal structure of a hybrid co-crystal of caffeic acid and its potassium salt. PCA has a well-known antimicrobial, anticancer and anti- proliferative activity. 25–27 It acts as a potent antiallergic com- pound 28 as well as a GABA-A receptor modulator. 29 We are interested in the possibility of obtaining good quality hybrid co-crystals of the two above mentioned com- pounds in order to tune, accordingly to different needs, their different properties. The reported structure of CA with the K + ion 30 was considered as a hybrid co-crystal and not a “straight” co-crystal as we evidenced in this structure, in a 1 : 1 ratio, a fully protonated CA moiety together with a CrystEngComm, 2014, 16, 5917–5923 | 5917 This journal is © The Royal Society of Chemistry 2014 Dipartimento di Scienze del Farmaco, Sezione Chimica, Università degli Studi di Catania, Viale Andrea Doria 6, 95125, Catania, Italy. E-mail: fpunzo@unict.it † Electronic supplementary information (ESI) available: Force field validation and principal structural features of the computed structures, as well as the sketches of their crystal packing and their relative computed cif files. See DOI: 10.1039/c4ce00191e Fig. 1 Chemical sketches of 3,4-dihydroxybenzoic acid (PCA) and trans 3-(3,4-dihydroxyphenyl)prop-2-enoic acid (CA).