Exploring intermolecular contacts in multi-substituted benzaldehyde derivatives: X-ray, Hirshfeld surface and lattice energy analyses

Crystal structures of six benzaldehyde derivatives (1–6) have been determined and their supramolecular networks were established by an X-ray crystallographic study. The study has shown that the compounds are linked by various intermolecular interactions such as weak C–H⋯O hydrogen bonding, and C–H⋯π, π–π and halogen bonding interactions which consolidate and strengthen the formation of these molecular assemblies. The carbonyl group generates diverse synthons in 1–6via intermolecular C–H⋯O hydrogen bonds. An interplay of C–H⋯O hydrogen bonds, and C–H⋯π and π–π stacking interactions facilitates the formation of multi-dimensional supramolecular networks. Crystal packings in 4 and 5 are further generated by type I halogen⋯halogen bonding interactions. The differences in crystal packing are represented by variation of substitution positions in the compounds. Structure 3 is isomorphous with 4 but there are subtle differences in their crystal packing. The nature of intermolecular contacts in the structures has been studied through the Hirshfeld surfaces and two-dimensional fingerprint plots which serve as a comparison in constructing different supramolecular networks. The intermolecular interaction energies are quantified utilizing theorectical calculations for the title compounds and various analogous structures retrieved from the Cambridge Structural Database (CSD). Also intermolecular interactions for the molecular pairs are exctrated from respective crystal structures. Essentially, there are some invariant and variable intermolecular contacts realized between different groups in all six structures. The ab initio DFT total lattice energy (ETot) calculations showed a direct correlation with thermal strengths of the title compounds.


Introduction
Crystal engineering of supramolecular networks linked via intermolecular contacts continues to be a dynamic topic in the solid-state studies of self-assembly. 1 Hydrogen bonds are recognized for their contribution in self-assembly when extended structures are constructed from synthons with aromatic moieties. 2 Electronegative atoms such as O and N are recognized to form strong hydrogen bonds D-H/A (D ¼ donor, A ¼ acceptor) with an estimated interaction energy between 16-50 kJ mol À1 . 2 Intermolecular contacts or weak interactions (#15 kJ mol À1 ) such as C-H/p, hydrogen/halogen bonds and p-p stacking are well-known to signicantly inuence the molecular assembly in organic compounds. 3 Numerous synthons that incorporate intermolecular contacts such hydrogen/ halogen bonds, C-H/p, lone pair-p and p-p stacking interactions signicantly affect robustness to produce molecular solids with promising properties. 4 Halogen bonding interactions established in many halogen-containing organic crystals are believed to enhance crystal stability. 5 Essentially, these intermolecular contacts are said to be independently weaker and geometrically less well-dened, but their combined effect can be equally important as strong interactions. 6 It is useful to study the diversity of hydrogen-bonding systems in molecules that contain a rigid benzyloxy core with different positions of substituents, and to explore their structural features including interplay of intermolecular contacts in building the possible supramolecular networks. 7 It is of interest to explore the role of these intermolecular contacts in the molecular assembly of halogen-substituted (benzyloxy)benzaldehydes. An additional interest in the (benzyloxy)benzaldehyde moiety lies in its anticancer activity against HL-60 cells 8 and also serves as important precursors in the design of new inhibitors of HIV-1 integrase. 9 A search of the Cambridge Structural Database (version 5.40, November CSD 2018 release) 10 for benzyloxybenzene derivatives (search + restricted to the aldehyde class) among the organic compounds returned 71 hits (excluding duplicate structures). Further restriction to (benzyloxy)benzaldehyde/(benzyloxy) benzoic acid derivatives (excluding solvates and cocrystals), only 15 structures 11 with refcodes COBNUC, CUNMAZ, DUTRIU, DUTRIU01, DUTRIU02, EROHUP, KERDUH, IPEXEH, LELQUQ, LELRAX, MEQLIE, POMLUA, VOQFIS, XEVROF and XIMPAL are found. Compound 1 crystallizes in a new crystal form in space group P2 1 2 1 2 1 which is different from the orthorhombic Pna2 1 space group reported previously (DUTRIU, DUTRIU01 and DUTRIU02). Sze et al., 2011 reported a similar structure to 6 (refcode: IPEXEH with space group P 1) with different unit cell dimensions. Self-assembly mediated by weak interactions has been established as a convenient and prevailing protocol for the construction of geometrically well-dened structures. A suitable approach to deal with crystal structure prediction is represented by Hirshfeld surface 12 based tool and this method provides a simplistic way of managing valuable statistics on trends in crystal packing. The variations in Hirshfeld surface and the analysis of the resultant 2D ngerprint plot 12 offer a powerful means of quantifying the interactions within the crystal structures, drawing attention to signicant similarity and differences between structures by individuating the packing motifs. In this paper, we report the synthesis of a series of multi-substituted benzaldehyde derivatives. Their structures were conrmed by spectroscopic methods and X-ray crystallography. Essentially, Xray crystallographic analysis of the structures demonstrates the presence of multiple weak and non-covalent C-H/O hydrogen bonding, C-H/p, p-p stacking and halogen/halogen bonding interactions are likely to play an important role in the supramolecular ensembles of these non-planar layered benzaldehyde derivatives in the solid state. To investigate the effect of substituent positions on the resulting compounds as well as the molecular packing, we have examined six benzaldehydes (1-6) with different substituent positions in the aldehyde skeleton. In this paper, we have demonstrated that weak intermolecular contacts are stronger for benzyloxybenzaldehydes than their analogous structures reported by Chattopadhyay. 4 Also, we have shown that there are subtle differences in crystal packing between these structures. In addition, a study of close intermolecular contacts in the title derivatives by Hirshfeld surface and lattice energy analyses is presented.

Materials
All commercially available chemicals and reagents were purchased from Sigma-Aldrich (Pty) Ltd and Merck (Pty) Ltd, and were used without further purication unless stated otherwise. Fourier-transform infrared (FT-IR) spectra were collected on PerkinElmer Spectrum 100 spectrometer with an ATR attachment. Mid-infrared (4000-650 cm À1 ) spectra were obtained by placing samples on a ZnSe crystal plate. The 1 H and 13 C NMR spectra were recorded on either a Bruker Fourier 300 or a 400 MHz spectrometer. Spectra were recorded in deuterated solvent CDCl 3 . All chemical shi values are reported in parts per million (ppm) referenced to residual solvent resonances (CDCl 3 d H 7.26, d C 77.2).

2.
3.1 Hirshfeld surface analysis. The Hirshfeld surfaces are mapped with d norm , and 2D ngerprint plots presented in this work were generated using CrystalExplorer 2.1. 12 The 2D plots were shaped by binning (d i , d e ) pairs in intervals of 0.01Å and colouring each bin of the resulting 2D histogram as a function of the fraction of surface points in that bin, ranging from blue through green to red. Graphical plots of the molecular Hirshfeld surfaces were mapped with d norm using a red-white-blue colour scheme, where red highlights shorter contacts, white is used for contacts around the vdW separation, and blue is for longer contacts.
2.3.2 Quantum chemical calculations Molecular geometry. All calculations done using Gaussian 09D. 17 All geometry was calculated with the B3LYP 18 functional, using the 6-311g(d,p) 19 basis set and an Ultrane grid. The energy for B3LYP was taken from the same calculation. The M06HF energy was calculated at the same basis set from the B3LYP geometry.
Crystal geometry. The structures were optimised using a constrained PBC geometry calculation (with the translation vectors obtained from the CIF les). Energy was calculated for both the B3LYP and M06HF 20 functionals with the 6-311g(d,p) basis set. The dispersion effects were accounted for using Grimme's type 3 dispersion (DFT-D3) 21 and the Basis Set Superposition Error (BSSE) was calculated using Gaussian 09's counterpoint method.
2.3.3 Lattice energy calculations. Crystal lattice energies (kJ mol À1 ) were calculated from single-crystal X-ray diffraction data using the atom-atom force eld with subdivision of the interaction energies into coulombic, polarization, London dispersion, and Pauli repulsion components (AA-CLP method implemented in the CLP-PIXEL computer program package, ver. 3.0; available from http://www.angelogavezzotti.it). 22 Default settings were used, and hydrogen atom positions were assigned by the soware.
2.3.4 Single-crystal X-ray diffraction. All datasets were collected at 200 K using a Bruker APEX-II CCD diffractometer equipped with graphite monochromated Mo Ka radiation (l ¼ 0.71073Å). Flack parameters for the non-centrosymmetric structures 1 and 5 are À0.01 (15) and 0.015(11), respectively. Data reduction was carried out using the Bruker program SAINT. 23 A numerical absorption correction SADABS 24 was applied. The structures of the title compounds were solved using a dual-space algorithm and rened by the full-matrix least-square technique on F2 with anisotropic thermal parameters to describe the thermal motions of all non-hydrogen atoms using the programs SHELXT-2018/2 (ref. 25) and SHELXL-2018/3 (ref. 26) respectively. The hydrogen atoms of the methyl groups were allowed to rotate with a xed angle around the C-C bonds to best t the experimental electron density while all other hydrogen atoms were placed at geometrically idealized positions. The methyl hydrogen atoms were assigned isotropic temperature factors equal to 1.5 times the equivalent temperature factor of the parent atom whereas the displacement parameters for the other hydrogen atoms were taken as U iso (H) ¼ 1.2U eq. (C). Programs: PLATON, 27 Mercury 28 and X-Seed. 29 For structural data and renement parameters for the title compounds, refer to Table 1.

Results and discussion
2.4.1 Structural analysis. X-ray crystallography X-ray crystallography analyses reveal that 1 and 4 crystallize in orthorhombic with space groups Pna2 1 and P2 1 2 1 2 1 , respectively while 2 crystallizes in monoclinic P2 1 /c; 3 and 5 both crystallize in monoclinic P2 1 /n space group and 6 crystallizes in triclinic with P 1 space group. ORTEP diagrams of compounds 1-6 drawn with 50% ellipsoid probability are depicted in Fig. 1. The overall molecular conformation in 1-5 can be described by the relative orientation of two phenyl rings (A: C11-C16 atoms, B: C21-C26 atoms) of the benzyloxybenzene core. The structures 2-5 match the position of benzyloxy substituent in the A ring (at the 2position), while 1 has the benzyloxy substituent at the 4-position. Compound 6 differs from the rest of the structures with the benzyloxy substituent missing. Compound 2 and 6 differ in respect to the ethoxy substituent in the B ring (at 3-and 2-positions, respectively). The molecule of 1 is essentially planar with r.m.s. deviation of 0.0608Å. In the crystal structures of the compounds, the O/O distances range from 2.686(8)-6.380(2) A. The shortest O/O distances is found in 1 while 2 has the longest. The bond-lengths of the A ring in 1-6 lie between 1.374(4) to 1.405(3)Å, the former being at the aromatic carbon anking the ethoxy substituent in 2, and the latter at the point of substitution of the propargyl (2-propynyl) group in 6 and IPEXEH. The internal bond-lengths in the B ring of the compounds (1-5) range from 1.334(6) to 1.429(5)Å (the bondlengths reside in C23-C24 and C25-C26 of 2, respectively).
The bond-angles generally agree well with those featuring in analogous structures.  10 The dihedral angle between the A ring and linear propargyloxy group in 6 is the largest angle equal to 68.37 which is vastly different from 61.77 of IPEXEH. The dihedral angle between the A and B rings vary signicantly with 1 having the smallest angle equal to 5.40 (while for DUTRIU, DUTRIU01 and DUTRIU02 the A/B dihedral angle is 5.23 ,5.86 and 4.97 respectively). In all the compounds with the exception of compound 5; the carbonyl, methoxy and ethoxy groups as well as the halogens lie in the same plane of the A ring. In 5, the A ring is slightly distorted and consequently the two substituted Br1 and Br2 atoms both lie just outside the plane of the ring.

D-H/A d(D-H) d(H/A) d(D/A) L(D-H/A) L
(ii) 1/2 + x, 1/2 À y, z; (iii) 1 À x, À1/2 À y, 1/2 À z; (iv) x, 1/2 À y, 1/2 + z; (v) 3/2 À x, À1/2 + y, Àz; (vi) À1/2 + x, 1/2 À y, À1/2 + z; (vii) À1/2 + x, 1/2 À y, 1/2 + z; (viii) À1/2 + x, 3/2 À y, 1 À z; (ix) 1/2 À x, 1 À y, À1/2 + z; (x) Àx, 1 À y, 2 À z; (xi) Àx, 1 À y, 1 À z.  Table 3 lists the lattice energies obtained from AA-CLP 20 and ab initio DFT calculations. Quantitative comparison between the AA-CLP, B3LYP and M06HF methods was made possible to explore how similar, or different, are the models. However, the comparison is limited to energies for small numbers of molecular pairs. A simple regression analysis reveals that overall E Tot (AA-CLP) ¼ 2.380 E Tot (B3LYP) and E Tot (AA-CLP) ¼ 2.232 E Tot (M06HF), although differences between the two can be as large as +1.1 and +1.2 kJ mol À1 for B3LYP and M06HF (POMLUA) respectively. This means that the lattice energy calculated by AA-CLP (À44.8 kJ mol À1 ) coincide with both B3LYP (À45.7 kJ mol À1 ) and M06HF (À45.8 kJ mol À1 ) methods only for POMLUA. The DFT total energy (E Tot ) calculations showed a direct relationship with thermal strengths of the title compounds (Table S1 and Fig. S1 †). The molecular pair interaction energies for the title compounds are shown in Table S3. † Molecular pairs of 1 (1-5) extracted from crystal structure along with their respective interaction energies are shown in Fig. 8. The maximum stabilization to the crystal structure comes from C-H/O intermolecular interaction involving H23 with O1. The stabilization energy of the pair is À7.0 kJ mol À1 (motif 1) obtained using crystalexplorer v17.5. Another molecular pair (motif 2) has interaction energy of À13.4 kJ mol À1 also involves C-H/O intermolecular interaction involving H25 with O2. Motif 3 involves H2B and O1 with stabilization energy being À26.6 kJ mol À1 . The next stabilized pair (motif 4) show C-H/p intermolecular interaction between H26 and C15 atoms with stabilization energy of À37.0 kJ mol À1 . Last molecular pair 5 involves the interaction of H12 with O1. This pair also involves the interaction of H2A with O1 having interaction energy contributing towards the stability of crystal packing. The interaction for motif (1-5) in 1 is primarily dispersive in nature (Table S3 †). The most stabilized molecular pairs (1-5) of 2 along with their stabilization energies are shown in Fig. 9. The most stabilized molecular pair (motif 1) in 2 shows the presence of C-H/p involving H3A with C12, C13 (of the A ring), O2 and O3 and provides stabilization of À46.7 kJ mol À1 . The next stabilized pair (motif 2) shows H/H (involving H15 interacting with H15 atom) resulting in a stabilization energy of À7.3 kJ mol À1 . The stabilized pair (motif 3) involves C-H/p hydrogen bonding (involving H14 with C23) having an interaction energy of À11.4 kJ mol À1 . The second most stabilized pair is motif 4 which shows the presence of C-H/O (involving O1 interacting with H1, H2A and H22) and lone pair/lone pair (between C1 and O1) forming dimer having an interaction energy of À23.7 kJ mol À1 . Molecular pair 5 shows the presence of C-H/p (involving H23 with C15) having an interaction energy of À8.9 kJ mol À1 that contributes towards the stability of crystal packing. The interaction for motif (1-5) in 2 is similar to 1 and it is primarily dispersive in nature. The extracted    Fig. 11. The interaction for motif (1-5) in 4 is primarily repulsive in nature. The minimum stabilization to the crystal involves molecular stacking to generate dimers and a bifurcated acceptor atom involved in C-H/Cl halogen bonding (involving Cl1 interacting with    with Br2 resulting in interaction energy of À8.9 kJ mol À1 whereas motif 5 shows the presence of bifurcated interaction (involving O1 interacting with both C2 and H2A) forming dimer having an interaction energy of À27.2 kJ mol À1 . Last stabilized pair involves C-H/Br halogen bonding (involving H23 with Br1 and H24 with Br2) interaction forming a dimer having interaction energy of À10.8 kJ mol À1 . Molecular pairs (1-7) providing signicant contribution towards the stabilization along with their interaction energies for 6 are shown in Fig. 13. The molecular pair with maximum energy stabilization (motif 1) shows the presence of two C-H/p hydrogen bonds (H14 interacting with C4) resulting in interaction energy of À40.4 kJ mol À1 . The next stabilized pair (motif 2) shows the presence of lone pair-p interaction (involving C1 with O1 of the carbonyl) and also C-H/O (involving H4 with O1) having interaction energy of À22.6 kJ mol À1 and is dispersive in nature. Motif 3 shows the presence of a lone pair-p interaction between O1 (carbonyl oxygen) and C2 with interaction energy of À13.0 kJ mol À1 . Motif 4 shows the presence of bifurcated donor atom (involving H5C with both O2 and O3) to generate a molecular pair having an interaction energy of À21.0 kJ mol À1 . Another molecular pair (motif 5) in 6 shows the presence of C-H/O hydrogen bonding (involving H2A with O2) forming a dimer with interaction energy of À13.9 kJ mol À1 . Molecular pair 6 having an interaction energy of À25.4 kJ mol À1 shows C-H/O (involved in O1 with H5C) to contribute towards  the stability of crystal packing. Molecular pair 7 involves two H1 interactions with O1 to give the least stabilization energy of À7.1 kJ mol À1 .

Conclusions
In summary, in our effort to explore the role played by these intermolecular contacts in the self-assembly of crystal structures we have studied six related benzaldehyde derivatives by single crystal X-ray diffraction. It is observed that the carbonyl group generates hydrogen bonded motifs in all compounds studied here and their analogous structures (DUTRIU, DUTRIU01, DUTRIU02 and IPEXEH, shown in Fig. S8 †). These crystalline solid materials demonstrate how self-regulating the various weak interactions such as C-H/O hydrogen bonding, p-p and lone pair-p stacking, and type I halogen-halogen interactions which complement each other in crystal packing. Furthermore, hydrogen bonding and p-p intermolecular interactions engineered or manoeuvred themselves abruptly but in a cooperative fashion to inuence the out of plane molecular stacking. The differences in crystal packing are represented by variation of substitution positions in the compounds. Interestingly, compounds 3 and 4 are isomorphous but their crystal packing is vastly different. Considering self-organization systems of this manner, the study in the eld of photo-induced dimerization and crystal engineering in general looks promising. The crystal packing of all the compounds has been analysed using both Hirshfeld surface and theoretical methods. The total energy showed a direct relationship with thermal strengths ("melts") of the title compounds. The structures studied in this work assisted us to appreciate the inuence of intermolecular contacts in constructing supramolecular systems in the solid state.

Conflicts of interest
There are no conicts to declare.  16872 | RSC Adv., 2020, 10, 16861-16874 This journal is © The Royal Society of Chemistry 2020