Steric effect in the formation of hydrogen bonded complexes of isopropylamine with alicyclic ethers by ultrasonic and DFT approach
Graphical abstract
Introduction
Organic solvents are widely used at any step of the synthetic route of an active drug intermediate or excipients. They are also employed in pharmaceutical formulation process. Major role of solvent in the synthesis of drug is homogenization of reactants within the reaction medium and also to enhance the rate of the reaction as well as the yield of the product [1]. The choice of solvents in the manufacture of drugs is critical for various reasons. Toxicity, mutagenicity and environmental impact of solvents are to be considered in the choice of solvent in pharmaceutical industry. Aqueous, non-aqueous or mixed solvents are generally employed in the drug industry depending on the requirements of the synthesis. The alicyclic ethers have been found to be potential solvents in pharmaceutical industry [2,3]. Catalyst free one pot protocol sonication method has been developed for the synthesis of biologically important rhodanine derivatives in aqueous and non-aqueous media like THF [4]. THF is also employed as effective solvent in the preparation of an intermediate compound in the manufacture of the antimalarial drug hydroxychloroquine [5]. 1,4-Dioxane is a six membered heterocyclic ether widely used in the preparation of polymers which exists in different conformers and the proportions of its conformers in the liquid phase is not yet established [[6], [7], [8], [9], [10], [11], [12], [13]]. The nature and strength of molecular interactions depends on varied structures of components in the solutions which can be identified by the non- ideal behavior of multicomponent liquid systems [14,15]. The intermolecular interactions drastically modify the physical properties of solutions. Further, the study of molecular complexes of amines and ethers is significant due to their biological importance [16,17]. There are several reports on the molecular interaction between components of primary, secondary, tertiary and cyclic amines with aromatic hydrocarbon, non-electrolyte solvents and cyclic ethers [[18], [19], [20], [21], [22], [23], [24], [25]]. However, there is only scanty data on isopropyl amine – alicyclic ether binary systems and there is a need for further investigation. Ultrasonic studies of hydrogen bonded complexes of anisole with aromatic primary and secondary amines in n-hexane solvent were investigated and theoretical studies were also applied to confirm the conclusions drawn from ultrasonic studies of molecular interactions [[26], [27], [28]]. Hydrogen bond plays vital role in determining the structures and functions of molecular complexes through various H-bonding pattern in molecular assemblies in solutions, solid state as well as in liquid crystalline (LC) state. The importance of H-bonding in liquid crystalline systems was well established and this property in supra-molecular assembly has been used as a tool for design of new LC materials [[29], [30], [31]].
In our earlier papers we reported investigation on the molecular interactions of alicyclic ethers with benzyl amine and n-propyl amine [28,32]. The most favoured amine donor used in transaminase catalyzed enzyme reactions is IPA since it is cheap and achiral [33]. It is also widely used in the synthesis and formulation of insecticides and herbicides [34,35]. The present work is aimed at unraveling the molecular interactions of the two alicyclic ethers [THF and DIOX] with iso-propylamine in n – hexane medium by ultrasonic and DFT studies. Molecular electrostatic potential (MEP) is very useful tool in analyzing the strength of interactions [[36], [37], [38], [39]]. The present study considers computational (MEP contour) as well as experimental techniques to characterize the molecular level interactions in ternary systems of IPA with two alicyclic ethers (THF, DIOX) in n-hexane medium. In recent years, the reduced density gradient (RDG) has been found to be a more useful tool to analyze non-covalent interactions. Both strong and weak non-covalent interactions can be identified through RDG, although applications of RDG to stronger interactions are limited [40]. Plots of reduced density gradient (RDG) versus the electron density multiplied by the sign of the second Hessian eigenvalue (λ2) for the two investigated systems were obtained by reported method [41]. The presence of different types of interactions in the two ternary systems is also established from non-covalent interaction (NCI) plots and reduced density gradient (RDG) plots.
Section snippets
Ultrasonic study
The source of organic compounds used in the work, purity, further purification, their boiling points and purity check method are summarized in Table 1. All measurements were made for freshly prepared solutions by mixing accurate masses of pure liquids in the solvent (n-hexane) to obtain the required range of concentrations from 0.02 M to 0.2 M. The measuring instrument was standardized using triple distilled water and the measurement was in good agreement with reported values in the literature.
Ultrasonic study
The measured values of ultrasonic velocity, density and dynamic viscosity are listed in Table 3 for the two ternary systems at 303.15 K. The computed thermo-acoustical properties of the two systems are presented in Table 4 while Table 5 contains the excess properties. The plots of ultrasonic velocity (u), adiabatic compressibility (κ) and internal pressure (πi) as a function of concentration are shown in Fig. 1(a)–(c). The changes in excess velocity (uE), excess free length (LfE) and excess
Conclusion
The trend for the thermo-acoustical properties and excess properties with concentration of the two ternary systems IPA-THF and IPA-DIOX in n-hexane at room temperature establishes the formation of H-bonded complexes between IPA and the two cyclic ethers. Stability constants (K) determined by ultrasonic method and interaction energies computed by DFT procedure showed that IPA-DIOX complex is more stable than IPA-THF complex. Optimized geometries of the two complexes in n-hexane contained N-H…O
Declaration of competing interest
There is no conflict of interest in publishing the manuscript in the Journal of Molecular liquids. The authors also informed that this manuscript is not funded by any agency.
Acknowledgements
The authors thank the Management of The New College, for the facilities provided and the encouragements shown towards this work. The authors also thank the e – learning centre of The New College, funded by DST e FIST (C.Dy.No.2644/IFD/2015-2016 dt. 21.08.2015).
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