In acid-aminopyrimidine continuum: experimental and computational studies of furan tetracarboxylate-2-aminopyrimidinium salt.

Utsav Garg,Mahboob Alam,Yasser Azim

doi:10.1039/d1ra01714d

Abstract

Salts and cocrystals are the two important solid forms when a carboxylic acid crystallizes with an aminopyrimidine base such that the extent of proton transfer distinguishes between them. The ΔpKa value (pKa(base) − pKa(acid)) predicts whether the proton transfer will occur or not. However, the ΔpKa range, 0 < ΔpKa < 3, is elusive where the formation of cocrystal or salt cannot be predicted. The current study has been done to obtain a generalization in this elusive range with the Cambridge Structural Database (CSD). Based on the generalization, a novel salt (FTCA)−(2-AP)+ of furantetracarboxylic acid (FTCA) with 2-aminopyrimidine (2-AP) is obtained. The structural confirmation was done by single-crystal X-ray diffraction (SCXRD). Density functional theory (DFT) calculations were performed at the IEF-PCM-B3LYP-D3/6-311G(d,p) level to optimize the geometrical coordinates of salt for frontier molecular orbitals (FMOs) and molecular electrostatic potential (MESP). The geometrical parameters of most of the atoms of the optimized salt structure were comparable with SCXRD data. Additionally, results of other computational methods such as ab initio (Hartree–Fock; HF and second-order-Møller–Plesset perturbation; MP2) and semi-empirical were also compared with experimental results of the salt. Quantum theory of atoms in molecules (QTAIM), reduced density gradient (RDG), and natural bond orbital (NBO) analyses were done to calculate the strength and nature of non-covalent interactions present in the salt. Furthermore, Hirshfeld surface analysis, interaction energy calculations, and total energy frameworks were performed for qualitative and quantitative estimations of strong and weak intermolecular interactions.

Highlights

Crystal engineering (CE) is an emerging research area encompassing various domains of physics, chemistry, biology, engineering, materials science, and pharmaceuticals.[1]
The storing and retrieving of crystallographic data in Cambridge Structural Database (CSD) worked as a driving force in understanding intermolecular interactions in terms of robustness of supramolecular synthons that led to the design of new solids having opulent importance both in academia and aDepartment of Applied Chemistry, Zakir Husain College of Engineering & Technology, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India
Scheme 1 General structures of (a) HT synthon (b) popular Linear HeteroTetramer (LHT) synthon via N–H/N interaction (c) proton transferred LHT synthon (CHLHT) via C–H/N interaction found in present case

Summary

Introduction

Pyrimidine and aminopyrimidine bases are the essential components of different nucleic acids (including DNA/RNA) that interact through hydrogen bonding for genetic information transfer.[7,8,9] Likewise, many biologically important compounds, namely drugs, nucleic acids, plant hormones, etc., consist of carboxyl groups in their chain.[10,11,12,13] It is well known that the carboxyl group of proteins interacts with pyrimidine moiety of nucleic acids causing protein–nucleic acid recognition.[14,15,16,17,18] This recognition has been extensively utilized to design salts and cocrystals for Active Pharmaceutical Ingredients (API) and model compounds. Two robust synthons, Linear HeteroTetramer (LHT) and HeteroTrimer (HT),[19,20] are generally found in salt/cocrystal of aminopyrimidine and carboxylic acid.[21,22,23,24,25] The. Paper distinction between salt and cocrystal is an important aspect from a regulatory and legal perspective. The plausibility for the robustness of LHT over HT synthon was reasoned, but the elusive DpKa range (0 < DpKa < 3) was still ambiguous.[33,34] In continuum to the previous work and to resolve the ambiguity of DpKa for a generalization, different computational studies and CSD data have been extensively utilized in the current study. 123 different crystal structures encompassing carboxylic acid-aminopyrimidine synthon have been reported and are available in CSD.[35] Seventy of them 2.4. pKa calculations ChemAxon so ware was used to calculate pKa values for different carboxylic acids and 2-AP.[36]

Materials

Computational studies

Results and discussions

Computational methods

Conclusions