Intercalation of nucleobases by metal dipicolinates
4.3: Intercalation of discrete adeninium or cytosinium cations in layers of polymeric metal quinolinates
triple hydrogen bonds. In that complex, the cytosinium cation form a hydrogen bonded cyclic tetramer in association with the complex anion [36].
(a) (b)
Fig. 4.2.3: (a) ORTEP of 4.5 (drawn with 50% thermal ellipsoids), (b) View showing hydrogen bond interactions of cytosinium cation with Zn(II) dipicolinates and lattice water molecules in 4.5.
4.3: Intercalation of discrete adeninium or cytosinium cations in layers of polymeric
The crystallized water molecules further contribute to the stability of these complexes bridging the oppositely charged species through hydrogen bond.
(a) (b)
Fig. 4.3.1: (a) Hydrogen bond and -stacked adeninium cations in layers of Mn(II) quinolinates, (b) Hydrogen bonded cytosinium cations in layers of Cu(II) quinolinates.
The complex {[1H,3H-cyt]2[CuL2] 6H2O}n (4.7) intercalates 1H,3H-cytosinium cation in polymeric layers of Cu(II) quinolinates by electrostatic and hydrogen bond interactions. The amine group and N3H atom of cytosine interacts with carboxylate group of polymeric complex but no - stacking interactions exist among the nucleobases. The C=O group and N1H atom of cytosinium cation interacts with crystallized water molecules. The rigid polymeric complexes irrespective of metal ions show the intercalation of the stable tautomeric form of the nucleobase in the cationic layers of the complexes.
4.4: Intercalation of cytosinium assemblies in layers of adipic acid, citric acid
Several attempts have been made to synthesize supramolecular complexes in the analogues organic systems, using pyridinedicarboxylic acids and nucleobases, but the crystallization was not successful as these complexes led to microcrystalline solids. However, we succeed to synthesize cytosine complexes with flexible organic molecules such as adipic acid and citric acid. Both the adipic acid and citric acid (Fig. 4.4.1a) are considered as safe excipients and therefore widely used to synthesize multi-component crystals with large number of active pharmaceutical ingredients (API) [39-41]. In this study, the adipic acid-cytosine (1:2) supramolecular complex (4.8) shows partial proton transfer from the acid to the cytosine
base. The partially protonated cytosines form a dimeric or duplex hydrogen bonded assembly via triple hydrogen bonds. The dimeric assembly is intercalated in layers of adipic acid infinite chain (Fig. 4.4.1a-b). The hydrogen bonded interactions of the cytosine duplex assembly have already been discussed in section 4.2. The H-atom attached to N3 atom of cytosinium cation is disordered over two positions. A similar disordered situation of cytosine assembly has been elaborated in the cocrystal with decavanadate anion, Na3[V10O28][cytH]3 [cyt]3·10H2O based on charge density analysis and topological analysis [42]. It has been stated that the H-atom is statistically distributed between the two cytosine molecules at high temperature.
OH HO
O
O
HO OH
O O
HO O HO
Adipic acid (AA) Citric acid (CA) (a)
(b) (c)
(d) (e)
Fig. 4.4.1: (a) Organic host molecules studied, (b) Hydrogen bond interactions of cytosinium assembly with adipic acid viewed along a axis, (c) Close view of duplex assembly of cytosinium, (d) Hydrogen bond interactions of trimeric cytosine-cytosinium assembly in layers of citric acid viewed along b axis, (e) Close view of trimeric cytosine-cytosinium assembly.
In the complex described in this chapter, adipic acid adopts a conformation different from its crystal structure in its unsolvated form. The acidic protons occupy an inversion center leading to a polymeric 1D chain of adipic acid. The interaction of cytosine with adipic acid takes place through amine group and N1H protons. The cytosine assemblies are further stabilized by face to face - interactions (centroid to centroid distance ~ 3.65 Å).
Citric acid-cytosine complex (1:3) (4.9) shows the presence of partially ionized citric acid and protonated and neutral cytosine molecules in the crystal structure. These protonated and neutral cytosine molecules form two different triple hydrogen bonded self-assemblies. These cytosine-cytosinium assemblies are further held together by double N1H···O=C or N4H···O=C hydrogen bonds leading to a planar trimeric motif with a length of 19.44 Å intercalated between layers of citric acid (Fig. 4.4.1c). The crystallized water molecule is encapsulated within the parallel layers of partially ionized citric acid and cytosinium assemblies. They are hydrogen bonded to the N1H proton of cytosine, oxygen atoms of 3- carboxy group and hydroxyl group of two adjacent citric acid molecules. It is to be mentioned that the crystal structures consists of equal numbers of cytosine molecules corresponding to the acid groups irrespective of their neutral or protonated form. Flexible nature of the organic acids allow cytosine molecules not only to interact with the acids but also among themselves to form duplex assemblies via triple hydrogen bond. In a study by Pedireddi and coworkers showed formation of 3D assemblies of molecular adducts of cytosine with benzoic acid, phthalic acid and isophthalic acid [43]. A tetrameric assembly based on cytosine duplex was observed in 1:1 cytosine-benzoic acid adduct, whereas the phthalic acid and isophthalic acid stabilized the infinite cytosine assembles based on similar hydrogen bonded duplex assembly. Thus by correlating the patterns obtained with adipic acid and citric acid in this study with other assemblies available in literature, it appears that cytosine prefer dimeric triple hydrogen bonded assembly in the dicarboxylic acid complexes.
We also anticipated similar intercalation chemistry with other two nucleobases, guanine and thymine but unfortunately, we were not successful. It has been seen that compared to adenine and cytosine, supramolecular complexes with guanine and thymine are less [44-46].
This may be due to insoluble nature of guanine and weak basicity of thymine nucleobase [47]. Attempts to synthesize complexes with guanine, dissolving in dilute hydrochloric acid,
followed by treatment with metal dipicolinate complexes led to crystallize them independently. Thymine also did not bind with the metal containing dicarboxylic acid starting materials. We are interested on other host molecules with different functional moieties that could interact with guanine and thymine as a future prospectus.
4.5: Conclusion
We have demonstrated the intercalation of hydrogen bonded infinite chain of adeninium cations having two non-equivalent 1H,9H and 3H,7H-adeninium cations at alternating positions in layers of Mn(II)/Cu(II) dipicolinates. This is the first solid-state characterized 1H,9H and 3H,7H-adeninium tautomer in relatively rigid dipicolinate frameworks. We have also established the stabilization of adeninium cation in rigid 1D coordination polymer of Mn(II) quinolinates. The other interesting finding of this chapter was the intercalation of different types of hydrogen bonded cytosine assemblies such as discrete, dimeric, trimeric and tetrameric assemblies in layers of various host molecules. The discrete cations of cytosine are stabilized by electrostatic, hydrogen bond and stacking interactions within the polymeric inorganic layers of Cu(II) quinolinates. Intercalations of dimeric and trimeric assemblies were observed in flexible organic host molecules such as adipic acid and citric acid respectively. Intercalation of tetrameric planar 1D ribbon formed by neutral and 1H,3H- cytosinium cation was established in a seven-coordinated Mn(II) dipicolinate complex.
Thus, it appears difficult to understand the nature of assembly formation in a particular metal complex or in an analogues organic system. However, it can be predicted that the assemblies are dependent on the central metal ions and the nature of host molecules.
Further, crystal packing and hydrogen bonding functionality also plays key role in the formation of different types of nucleobase assemblies. This chapter therefore demonstrates generation of different types of nucleobase assemblies with definite dimension and shape in confined environment. It may further contribute to the molecular recognition processes of the cations of adenine or cytosine by these different artificial host molecules.