Relevant π-hole tetrel bonding interactions in ethyl 2-triazolyl-2-oxoacetate derivatives: Hirshfeld surface analysis and DFT calculations

Muhammad Naeem Ahmed *a, Khawaja Ansar Yasin a, Shahid Aziz b, Saba Urooge Khan c, Muhammad Nawaz Tahir d, Diego Mauricio Gil e and Antonio Frontera *f
aDepartment of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100 Pakistan. E-mail: drnaeem@ajku.edu.pk
bDepartment of Chemistry, Mirpur University of Science and Technology (MUST) Mirpur-10250 (AJK), Pakistan
cDepartment of Polymer Engineering and Technology University of The Punjab Lahore, Pakistan
dDepartment of Physics, University of Sargodha, Sargodha, Pakistan
eINBIOFAL (CONICET – UNT), Instituto de Química Orgánica – Cátedra de Química Orgánica I, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471 (T4000INI), San Miguel de Tucumán – Tucumán, Argentina
fDepartment de Quimica, Universitat de les Illes Balears, Crta. De Valldemossa km 7.5, 07122 Palma de Mallorca Baleares, Spain. E-mail: toni.frontera@uib.es

Received 4th March 2020 , Accepted 17th April 2020

First published on 17th April 2020


This manuscript reports the synthesis, spectroscopic and X-ray characterization of four triazole derivatives that include an α-ketoester functionality and two phenyl substituents. In particular, ethyl 2-(4-(4-chlorophenyl)-1-(4-methylbenzyl)-1H-1,2,3-triazol-5-yl)-2-oxoacetate (1), ethyl 2-(1-(4-methylbenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)-2-oxoacetate (2), ethyl 2-(1-benzyl-4-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)-2-oxoacetate (3) and ethyl 2-(1-benzyl-4-(4-methoxyphenyl-1H-1,2,3-triazol-5-yl))-2-oxoacetate (4) were synthesized in good yields. All the compounds form self-assembled dimers in the solid state establishing two symmetrically equivalent O⋯π-hole tetrel bonding interactions. These interactions have been analyzed using Hirshfeld surface analysis, DFT calculations and Bader's theory of atoms-in-molecules and further rationalized using molecular electrostatic potential (MEP) surface calculations. We have studied how the nucleophilic/electrophilic nature of the –COOEt and –CO– groups is affected by the substituents of the rings and, consequently, influences the interaction energy of the C⋯O tetrel bond.


1. Introduction

In a short period of time, click chemistry has had a dramatic and diverse impact in many areas of modern chemistry. The versatility of click chemistry and particularly Cu(I) catalyzed Huisgen cycloaddition seems endless, yet we are still in the early developmental stages of this concept driven research. With the discovery and invention of new chemical transformations which meet the click status, the future looks bright for click chemistry.1

1,4,5-Trisubstituted 1,2,3-triazoles have been regarded as highly significant nitrogen-containing heterocycles due to their broad spectrum of biological activities and other prominent properties.2 1,2,3-Triazole scaffolds are ubiquitous structural motifs in various bioactive molecules, pharmaceutical agents and functional materials. Therefore, they have been used in several fields ranging from medicinal chemistry to materials science.3 Furthermore, 1,2,3-triazoles have also been investigated as powerful and versatile ligands for metal coordination, exhibiting tremendous application prospects.4

In addition to the ubiquitous H-bond,5–8 σ-hole-based9,10 noncovalent interactions are also relevant in many areas of chemistry, like crystal engineering11–13 and catalysis. The σ-hole can be defined as a region of positive potential in a main group element located opposite to a covalent bond.14,15 Similarly, some molecules also exhibit π-holes which lie usually above and below the plane of the system,16–19 leading to π-hole interactions with Lewis bases.10 In X-ray structures, π-hole interactions were identified by Bürgi and Dunitz in 1975,20 thus revealing the trajectory along which a nucleophile attacks the π-hole of a carbonyl group. Moreover, the relevance of n → π* interactions in proteins from a lone pair of electrons (n) to the antibonding orbital (pi*) of a carbonyl group has been demonstrated.21 In addition, significant π-hole interactions have been described and studied in benzoic acid dimers,22 nitro derivatives,23–27 and acyl carbon containing molecules.28–30 The physical nature and the factors affecting the strength of π-hole interactions are similar to those of σ-hole interactions.30

In continuation of our previous work highlighting the importance of antiparallel π–π interactions,31 here in this manuscript we report the synthesis and X-ray characterization of four 1,4,5-trisubstituted 1,2,3-triazoles (Scheme 1) that include an α-ketoester functionality.32 Interestingly, these compounds form self-assembled dimers in the solid state where two symmetrically equivalent O⋯π-hole interactions are established. These interactions have been analyzed using Hirshfeld surface analysis, DFT calculations and Bader's theory of atoms-in-molecules and rationalized using molecular electrostatic potential (MEP) surface calculations.


image file: d0ce00335b-s1.tif
Scheme 1 1,4,5-Trisubstituted 1,2,3-triazoles (1–4).

2. Experimental and theoretical methods

2.1. Synthesis

Compounds 1–4 were synthesized by following a procedure already published by us32,33 and were mainly characterized by UV, IR (Fig. 1), HRMS and single crystal X-ray crystallography. Melting points were determined on a Yanaco melting point apparatus and are reported as uncorrected. FT-IR spectra were recorded on a SHIMADZU FTIR-8400S spectrophotometer using the KBr disc method. Similarly, UV spectra were scanned on double beam SHIMADZU UV-1601 UV-visible spectrophotometer. 1H-NMR (300 MHz) and 13C-NMR (100 MHz) spectra were measured on a JEOL-ECA instrument in DMSO with TMS as an internal standard.
image file: d0ce00335b-f1.tif
Fig. 1 UV (left) in EtOH and IR (right) spectra of compounds (1–4).
2.1.1. Ethyl 2-(4-(4-chlorophenyl)-1-(4-methylbenzyl)-1H-1,2,3-triazol-5-yl)-2-oxoacetate (1). White crystalline solid, m. p. 100–102 °C, yield = 83%, Rf = 0.5 (n-hexane[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc), λmax = 311.74 nm in EtOH (0.01 g L−1); IR (KBr, cm−1): νmax 3084 (CHarom), 1743 (CO), 1678 (C[double bond, length as m-dash]C), 1480 (CH2 rocking); 1H-NMR δ ppm 7.50–7.14 (m, 8H), 5.83 (s, 2H), 3.84 (q, 2H, J = 7.2 Hz), 2.32 (s, 3H), 1.01 (t, 3H, J = 7.2 Hz); 13C-NMR δ ppm 177.1, 160.8, 151.6, 138.6, 136.0, 131.1, 130.3, 129.5, 128.9, 128.2, 127.1, 63.0, 54.1, 21.1, 13.4. HRMS (ESI-TOF) (m/z):32 calculated for C20H18ClN3O3, [M + H]+ 384.1109; observed 384.1103.
2.1.2. Ethyl 2-(1-(4-methylbenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)-2-oxoacetate (2). White crystalline solid, m. p. 83–85 °C, yield = 92%, Rf = 0.6 (n-hexane[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc), λmax = 303.37 nm in EtOH (0.01 g L−1); IR (KBr, cm−1): νmax 3057 (CHarom), 1739 (CO), 1682 (C[double bond, length as m-dash]C), 1449 (CH2 rocking); 1H-NMR δ ppm 7.51–7.14 (m, 9H), 5.85 (s, 2H), 3.74 (q, 2H, J = 7.2 Hz), 2.32 (s, 3H), 0.93 (t, 3H, J = 7.2 Hz); 13C-NMR δ ppm 177.4, 160.9, 152.9, 138.5, 134.9, 131.3, 129.7, 129.4, 129.0, 128.6, 128.2, 127.1, 62.8, 54.0, 21.1, 13.2. HRMS (ESI-TOF) (m/z):32 calculated for C20H19N3O3, [M + H]+ 350.1499; observed 350.1502.
2.1.3. Ethyl 2-(1-benzyl-4-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)-2-oxoacetate (3). White crystalline solid, m. p. 66–68 °C, yield = 80%, Rf = 0.5 (n-hexane[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc), λmax = 256.52, 313.80 nm in EtOH (0.01 g L−1); IR (KBr, cm−1): νmax 3063 (CHarom), 1739 (CO), 1689 (C[double bond, length as m-dash]C), 1483 (CH2 rocking); 1H-NMR δ ppm 7.46–7.13 (m, 9H), 5.88 (s, 2H), 3.85 (q, 2H, J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz); 13C-NMR δ ppm 177.1, 162.6 (d, JCF = 245.9 Hz), 160.7, 151.4, 134.1, 131.7 (d, JCF = 7.89 Hz), 130.4 (d, JCF = 8.60 Hz), 128.8, 128.7, 128.2, 127.5, 124.9, 116.8 (d, JCF = 20.8 Hz), 115.9 (d, JCF = 22.9 Hz), 63.0, 54.3, 13.3. HRMS (ESI-TOF) (m/z):32 calculated for C19H16FN3O3, [M + H]+ 354.1248; observed 354.1245.
2.1.4. Ethyl 2-(1-benzyl-4-(4-methoxyphenyl-1H-1,2,3-triazol-5-yl))-2-oxoacetate (4). White crystalline solid, m. p. 128–130 °C, yield = 78%, Rf = 0.5 (n-hexane[thin space (1/6-em)]:[thin space (1/6-em)]EtOAc), λmax = 332.58 nm in EtOH (0.01 g L−1); IR (KBr, cm−1): νmax 3066 (CHarom.), 1744 (CO), 1672 (C[double bond, length as m-dash]C), 1450 (CH2 rocking); 1H-NMR δ ppm 7.46–6.97 (m, 9H), 5.88 (s, 2H), 3.79 (q, 2H, J = 7.2 Hz), 2.82 (s, 3H), 0.99 (t, 3H, J = 7.2 Hz); 13C-NMR δ ppm 177.4, 161.1, 160.8, 152.8, 134.3, 130.4, 128.8, 128.5, 128.1, 126.9, 122.0, 114.1, 62.8, 55.3, 54.2, 13.3. HRMS (ESI-TOF) (m/z):32 calculated for C20H19N3O4, [M + H]+ 366.1448; observed 366.1446.

2.2. Crystallization conditions

Some good-quality single crystals of compounds (1–4) suitable for X-ray diffraction analysis were grown from a mixture of EtOH and EtOAc (dissolving 150 mg of each compound in 5 ml of solvent) by slow evaporation over a period of 48 h at room temperature.

2.3. X-ray data collection and structure refinement

Suitable single crystals of compounds 1–4 were selected for X-ray analyses and diffraction data were collected on a Bruker Kappa APEX-II CCD diffractometer with MoKα radiation at 100 K. Using the SADABS program, semi-empirical corrections were applied.34 The SHELX program was also used to solve all structures by direct methods.35 The positions and anisotropic parameters of all non-H atoms were refined on F2 using the full matrix least-squares technique. The H atoms were added at geometrically calculated positions and refined using the riding model.36 The details of crystallographic data and crystal refinement parameters for compounds 1–4 are given in Table 1.
Table 1 Crystallographic data and details of refinements for compounds 1–4
1 2 3 4
Computer programs: APEX2 (Bruker, 2007), SAINT (Bruker, 2007), SHELXS97 (Sheldrick, 2008), SHELXL2018/3 (Sheldrick, 2015), ORTEP-3 for Windows (Farrugia, 1997), WinGX (Farrugia, 1999) and PLATON (Spek, 2009).
CCDC 988864 988860 988859 988858
Chemical formula C20H18ClN3O3 C20H19N3O3 C19H16FN3O3 C20H19N3O4
M r 383.82 349.38 353.35 365.38
Crystal system, space group Triclinic, P[1 with combining macron] Monoclinic, P21/c Monoclinic, C2/c Triclinic, P[1 with combining macron]
Temperature (K) 296 296 296 296
a, b, c (Å) 8.3157(6), 9.5082(8), 13.1245(10) 8.2517(3), 17.9945(9), 12.2748(6) 28.5939(14), 7.5267(4), 19.3890(8) 8.2922(6), 9.4246(7), 12.9343(10)
α, β, γ (°) 68.898(4), 86.538(4), 85.332(4) 99.877(2) 121.964(1) 111.004(2), 99.018(3), 97.623(2)
V3) 964.38(13) 1795.61(14) 3540.2(3) 912.24(12)
Z 2 4 8 2
Radiation type Mo Kα Mo Kα Mo Kα Mo Kα
μ (mm−1) 0.22 0.09 0.10 0.09
Crystal size (mm) 0.38 × 0.32 × 0.30 0.40 × 0.30 × 0.28 0.38 × 0.28 × 0.25 0.36 × 0.30 × 0.25
Diffractometer Bruker Kappa APEXII CCD Bruker Kappa APEXII CCD Bruker Kappa APEXII CCD Bruker Kappa APEXII CCD
Absorption correction Multi-scan (SADABS; Bruker, 2005) Multi-scan (SADABS; Bruker, 2005) Multi-scan (SADABS; Bruker, 2005) Multi-scan (SADABS; Bruker, 2005)
T min, Tmax 0.670, 0.746 0.670, 0.746 0.670, 0.746 0.670, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections 13[thin space (1/6-em)]504, 3701, 2645 16[thin space (1/6-em)]244, 4114, 2801 14[thin space (1/6-em)]823, 3806, 2426 14[thin space (1/6-em)]140, 4016, 3299
R int 0.021 0.025 0.034 0.027
(sin[thin space (1/6-em)]θ/λ)max−1) 0.617 0.649 0.638 0.644
R[F2 > 2σ(F2)], wR(F2), S 0.057, 0.168, 1.06 0.053, 0.167, 1.04 0.052, 0.161, 1.04 0.046, 0.126, 1.05
No. of reflections 3701 4114 3806 4016
No. of parameters 246 237 234 249
H-Atom treatment H-Atom parameters constrained H-Atom parameters constrained H-Atom parameters constrained 4
Δmax, Δmin (e Å−3) 0.44, −0.50 0.26, −0.23 0.26, −0.25 0.26, −0.25


2.4. Computational methods

The calculations of the noncovalent interactions and molecular electrostatic potential (MEP) surfaces were carried out using Gaussian-16 (ref. 37) and the PBE1PBE-D3/def2-TZVP level of theory. The ultrafine grid has been used in the calculations to ensure the accuracy of the results. Grimme's D3 dispersion correction has been used in the calculations.38 The interaction energies are not BSSE corrected because we have evaluated them in the reduced models of compounds 1–4 and the error is <4%. To evaluate the interactions in the solid state, the crystallographic coordinates were used and only the position of the H-bonds has been optimized. This procedure and level of theory have been successfully used to evaluate similar interactions.39 The interaction energies were computed by calculating the difference between the energies of the isolated monomers and their assembly. The QTAIM calculations40 have been performed at the same level of theory by means of the AIMAll program.41

2.5. Hirshfeld surface calculations

The Hirshfeld surface (HS) analysis and the associated two-dimensional fingerprint (FP) plots42–44 were used to identify and quantify the contribution of different intermolecular interactions existing in the crystal structure and to understand the nature of these interactions. The HS and FP plots were generated using CrystalExplorer 3.1.45 The normalized contact distance (dnorm) enables the identification of the regions of particular importance to the intermolecular interactions. In this surface, any close intermolecular contact will be characterized by two identical red regions. The Hirshfeld surfaces of the studied structures were also mapped with the shape index and curvedness properties. The 3D dnorm surfaces were mapped over a fixed color scale of −0.075 a.u. (red) to 0.75 a.u. (blue), the shape index was mapped in the color range of −1.0 a.u. (concave) to 1.0 a.u. (convex) and the curvedness was mapped in the range of −4.0 a.u. (flat) to 4.0 a.u. (singular). A final analysis of the intermolecular interactions and their contribution to the crystal packing was performed by using 2D FP plots. These plots were mapped using the translated 0.6–2.4 Å range including reciprocal contacts.

3. Results and discussion

3.1. Structural description

In ethyl 2-(4-(4-chlorophenyl)-1-(4-methylbenzyl)-1H-1,2,3-triazol-5-yl)-2-oxoacetate (1), the 4,5-dihydro-1H-1,2,3-triazole group A (C5/C6/N1–N3), the 4-chlorophenyl moiety B (C7–C12/Cl1), and the 4-methylbenzyl group C (C13–C20) are planar with a r. m. s. deviation of 0.0039, 0.0123 and 0.0361 Å, respectively. The dihedral angles A/B, A/C and B/C are 42.09(11)°, 83.32(8)° and 67.39(6)°, respectively. The molecules are connected with each other in the form of dimers through C–H⋯O hydrogen bonds (see Fig. 2). In addition, C20–H20B⋯N1 hydrogen bonds are observed. The crystal structure of 1 shows C–H⋯π interactions, with a Cg1 distance of 2.797 Å (Cg1: C14–C19). The crystal packing appears to be controlled by weak π-stacking interactions [d(Cg1⋯Cg1) = 4.402 Å] involving both 4-methylphenyl rings.
image file: d0ce00335b-f2.tif
Fig. 2 The ORTEP plot of 1 (left) showing the atom numbering, with displacement ellipsoids at the 50% probability level; the right image shows that the molecules of 1 are dimerized. The H-atoms not involved in H-bonding are omitted for clarity.

In ethyl 2-(1-(4-methylbenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)-2-oxoacetate (2), the 4,5-dihydro-1H-1,2,3-triazole group A (C5/C6/N1–N3), the phenyl ring B (C7–C12), and the 4-methylbenzyl group C (C13–C20) are planar with a r. m. s. deviation of 0.0048, 0.0023 and 0.0423 Å, respectively. The dihedral angles A/B, A/C and B/C are 47.93(7)°, 74.97(6)° and 27.50(9)°, respectively. The molecules are connected through C–H⋯O hydrogen bonds between the H atom from the 4-methylbenzyl group and the O-atoms from the keto group (Fig. 3). The supramolecular assembly of 2 also includes π⋯π stacking interactions between the phenyl (Cg1: C7–C12) and triazole (Cg2: C5/N3/N2/N1/C6) rings with an inter-centroid distance of 3.809 Å.


image file: d0ce00335b-f3.tif
Fig. 3 The ORTEP plot of 2 (left) showing the atom numbering, with displacement ellipsoids at the 50% probability level; the right image shows the H-bonding packing pattern in 2 showing that the molecules are interconnected through C(11) chains.

In ethyl 2-(1-benzyl-4-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)-2-oxoacetate (3), the benzene ring of the benzyl group is disordered over two sets of sites with an occupancy ratio of 0.54(3)[thin space (1/6-em)]:[thin space (1/6-em)]0.46(3). The 4,5-dihydro-1H-1,2,3-triazole group A (C5/C6/N1–N3), the 3-flourobenzene moiety B (C7–C12/F1), the benzyl group containing a major part of the disordered benzene ring C (C13/C14A–C19A) and the benzyl group containing a minor part of the disordered benzene ring D (C13/C14B–C19B) are planar with a r. m. s. deviation of 0.0056, 0.0055, 0.0132 and 0.0170 Å, respectively. The dihedral angles A/B, A/C, and A/D are 37.34(10)°, 55.19(4)° and 80.59(5)°, respectively. The major part of the disordered benzene ring is twisted at an angle of 24.05(1)° with respect to its minor part. The ethyl 2-oxoacetate group is not planar. In this group, the torsion angles O1–C3–C4–O3 and O2–C3–C4–O3 are −142.0(2)° and 35.7(4)°, respectively. The molecules are connected with each other through C–H⋯O bonding to form R21(5) loops, where the CH belongs to the fluorobenzene moiety and O-atoms are from the keto groups of the ethyl 2-(4,5-dihydro-1H-1,2,3-triazol-5-yl)-2-oxoacetate part of the molecule. The non-carbonyl oxygen atom is linked to the CH attached to the disordered benzene ring through C–H⋯O hydrogen bonds. The CH of the disordered benzene ring is also linked with the carbonyl atom that is closer to the 4,5-dihydro-1H-1,2,3-triazole group as compared to the other carbonyl oxygen through C–H⋯O bonding as given in Table 2 and shown on the right side of Fig. 4. In this way, each molecule is linked with three adjacent molecules (Fig. 4).

Table 2 Hydrogen-bond geometric features with symmetry codes for compounds 1–4
Compound D–H⋯A D–H H⋯A D⋯A D–H⋯A
1 C8–H8⋯O2i; (i) −x, −y + 1, −z + 1 0.93 2.55 3.448(3) 163
2 C20–H20C⋯O3i; (i) x − 1, y, z 0.96 2.48 3.374(4) 155
3 C13–H13A⋯O1i; (i) –x + 1/2, y − 1/2, −z + ½ 0.97 2.52 3.468(3) 164
C18B–H18B⋯O3ii; (ii) x, y − 1, z 0.93 2.39 3.284(10) 161
C12–H12⋯O2iii; (iii) –x + 1/2, −y + 1/2, −z + 1 0.93 2.54 3.414(3) 158
C12–H12⋯O3iii; (iii) –x + 1/2, −y + 1/2, −z + 1 0.93 2.60 3.307(3) 133
4 C14–H14B⋯O3i; (i) –x + 1, −y, −z 0.97 2.58 3.542(2) 173
C8–H8⋯O2ii; (ii) –x + 2, −y, −z 0.93 2.55 3.459(2) 164



image file: d0ce00335b-f4.tif
Fig. 4 The ORTEP plot of 3 (left) showing the atom numbering, with displacement ellipsoids at the 50% probability level; the right image shows the hydrogen bonding pattern in 3. The H-atoms not involved in H-bonding are omitted for clarity.

In ethyl 2-(1-benzyl-4-(4-methoxyphenyl-1H-1,2,3-triazol-5-yl))-2-oxoacetate (4), the ethoxalyl group A (C1/C2) is disordered over two sets of sites with an occupancy ratio of 0.719(11)[thin space (1/6-em)]:[thin space (1/6-em)]0.281(11). The ethoxalyl group B (O1/C1A/C2A) containing a major part of the disordered CH3CH2– moiety and another ethoxalyl group C (O1/C1B/C2B) containing a minor part of the disordered ethane moiety are planar with a dihedral angle B/C of 45.8 (2)°. The propan-2-ol group D (C3–C5/O3) is planar with a r. m. s. deviation of 0.0099 Å with dihedral angles B/D and C/D being 48.18(75)° and 9.48(2)°, respectively. The 4,5-dihydro-1H-1,2,3-triazole group E (C5/C6/N1–N3), the anisole group F (C7–C13/O4) and the toluene group G (C14–C20) are planar with a r. m. s. deviation of 0.0036, 0.0674 and 0.0217 Å, respectively. The dihedral angles D/E, E/F, and F/G are 14.1 (1)°, 44.7(6)° and 66.8 (4)°, respectively. The molecules are connected with each other in the form of dimers through C–H⋯O bonding to form an R22(12) loop, where CH is from the methyl group of toluene and the O-atom is from the 4,5-dihydro-1H-1,2,3-triazole-5-ketoester part of the molecule (Fig. 5). The dimers are interlinked through C–H⋯O hydrogen bonds, and their geometric features are given in Table 2.


image file: d0ce00335b-f5.tif
Fig. 5 The ORTEP plot of 4 (left) showing the atom numbering, with displacement ellipsoids at the 50% probability level without the minor part of the disordered group; the right image shows the hydrogen bonding pattern in 4. The H-atoms not involved in H-bonding are omitted for clarity.

3.2. Hirshfeld surface analysis

HS analysis is a useful visualization tool for the analysis of intermolecular interactions in the crystal packing and FP plots are used herein to quantify the contribution of various intermolecular contacts present in the crystal structures of 1–4. Fig. 6 shows the Hirshfeld surfaces mapped over the dnorm function in two orientations (columns 1 and 2). Contacts with distances equal to the sum of the vdW radii are represented as white regions and contacts with distances shorter than and longer than the vdW radii are represented in red and blue colors, respectively. The full FP plots for compounds 1–4 are displayed in Fig. 7.
image file: d0ce00335b-f6.tif
Fig. 6 Views of the Hirshfeld surfaces of compounds 1–4 (columns 1–2) mapped with dnorm in two orientations: front view and back view (180° rotated around the vertical axis of the plot). The labels are discussed in the text.

image file: d0ce00335b-f7.tif
Fig. 7 Full 2D fingerprint plots for compounds 1–4.

The large regions labelled 1 in Fig. 6 represent H⋯O/O⋯H contacts, which are relevant in the dnorm maps for all the compounds. These contacts are attributed to the C8–H8⋯O3 and C8–H8⋯O2 hydrogen bonds for compound 1 and to C12–H12⋯O3 and C12–H12⋯O2 for compound 3, which can also be seen in the FP plots as a pair of symmetrical spikes at the (de + di) sum of 2.45 Å for the former and at (de + di) ∼2.40 Å for the latter interaction. The H⋯O/O⋯H contacts are dominant in compounds 1 and 2 with 12.8 and 16.8%, respectively, of the total HS area.

The red spot labelled 5 in the dnorm map for compound 1 (Fig. 6, column 2) represents H⋯C/C⋯H contacts with a 17.5% contribution. In the crystal packing of compound 1, C–H⋯π interactions are observed, where the H⋯C/C⋯H contacts appear in the form of pronounced “wings” on the sides of the FP plot, a of C–H⋯π interactions. In addition, the supramolecular assemblies of compounds 1 and 2 also include π⋯π stacking interactions, which are visible in the dnorm surface as a red spot labelled 6 in compound 1. The shape index and curvedness maps (Fig. S1 and S2 for compounds 1 and 2, respectively) are significant indicators for π-stacking interactions. The pairs of complementary red and blue triangles in the shape index maps and large and flat green regions at the side of the molecule in the curvedness maps are indicative of π-stacking interactions.

The red spot labelled 4 in the dnorm surface of compound 1 is attributed to C–H⋯N hydrogen bonds involving the acceptor N1 and one hydrogen atom H20B of the methyl group. The pair of sharp spikes labelled 3 in the FP plots of compound 1 are associated with N⋯H contacts with an 11.1% contribution to the total HS area.

The larger deep-red spots labelled 3 in the dnorm surfaces of compounds 1–4 are attributed to stronger O2⋯C4 interactions with a contribution of 2.0% to the total Hirshfeld surface.

The dnorm surface of compound 2 shows deep red regions labelled 1 and 2, attributed to the C20–H20C⋯O3 and C12–H12⋯O2 hydrogen bonds. Like in the structure of compound 1, the broad spikes at (de + di) ∼3.3 Å in the FP with a 15.1% contribution to the Hirshfeld surface area are associated with C–H⋯π interactions.

In compound 3, the red regions labelled 4 in the dnorm surfaces (Fig. 6) are attributed to C13–H13A⋯O1 involving the O1 of the carboxylic group as an acceptor and the H13A atom of the methylene group linked to the triazole ring. Note that the H13B atom of the methylene group bound to the triazole ring is involved in bifurcated hydrogen bonds C13–H13B⋯N1 and C13–H13B⋯N2 with both N1 and N2 atoms as acceptors. These interactions are observed as spikes labelled 3 in the FP plot (Fig. 7) with a contribution of 9.5% to the total Hirshfeld surface. In addition, the characteristic “wings” at (de + di) ∼3.7 Å indicate weak C–H⋯π interactions involving the H2B atom of the ethyl group and the C18 atom of the phenyl ring. The red spot labelled 6 in the dnorm map shows weak H⋯F/F⋯H contacts attributed to C15–H15A⋯F1 hydrogen bonds, which are viewed as a pair of broad spikes labelled 5 in the FP plot with a notable contribution of 10.4% to the Hirshfeld surface area.

In compound 4, the H⋯O/O⋯H contacts labelled 1 in Fig. 6 are again dominant, appearing as two larger deep red spots around the H14B atom and around the O3 atom attributed to the strongest C14–H14B⋯O3 hydrogen bonds. These interactions form R22(12) ring motifs. The deep-red spot labelled 2 in the dnorm surface is associated with C8–H8⋯O2 hydrogen bonds involving the H8 atom of the aromatic ring and the O2 atom of the carboxylic group. These interactions are observed in the FP plots as symmetric spikes at (de + di) ∼2.5 Å with a contribution of 18.0% to the total Hirshfeld surface area. The tiny red regions labelled 4 in the dnorm map are attributed to weak C12–H12⋯N1 hydrogen bonds forming centre-symmetric dimers, giving R22(10) graph-set motifs. The proportion of H⋯N/N⋯H interactions comprise 12.2% of the total HS and are characterized by spikes at (de + di) ∼2.8 Å in the FP plots. The supramolecular assembly of compound 4 also suggests the existence of C–H⋯π interactions involving the H19 atom of the phenyl ring and the C6 atom of the triazole ring. These interactions are visible in the dnorm surface as red spots labelled 5, with a contribution of 19.2% to the total HS area.

Theoretical DFT analysis

Experimentally, four new triazole derivatives have been synthesized and X-ray characterized (see Fig. 2–5). These compounds present different substitutions in the aromatic rings. Moreover, the triazole group is substituted by an α-ketoester (ethyl-2-oxoacetate) group that is very relevant determining their solid state architecture as it is further commented below.

We have first computed the molecular electrostatic potential (MEP) surfaces of compounds 1–4 in order to know the most electrophilic and nucleophilic parts of the molecules and to rationalize the interactions observed in their crystal packing. As a model compound, we show the MEP surface of compound 1 in Fig. 8 and the energetic values for the rest of the complexes in Table 3. It can be observed that there is the presence of a π-hole (region of positive potential) over the C-atom of the keto group with an associated MEP value of +16.9 kcal mol−1. The most negative values are located at the carbonyl O-atom of the ester group and the O-atom of the keto group. The MEP values are also positive at the aromatic H-atoms, ranging from +14 to +18 kcal mol−1. This analysis evidences that the interaction of the electron rich O-atoms with either the C-atom of the keto group or the aromatic H-atoms is equally favored, from an electrostatic point of view.


image file: d0ce00335b-f8.tif
Fig. 8 MEP surface (0.001 a.u. isosurface) at the PBE1PBE-D3/def2-TZVP level of theory of compound 1. The MEP values at selected points of the surface are indicated in kcal mol−1.
Table 3 MEP values in kcal mol−1 at the C π-hole and at the O-atoms from the keto and carbonyl ester groups for compounds 1–4 at the PBE1PBE/def2-TZVP level of theory
Compound V s,π-hole V s,O(–CO–) V s,O(COOR)
1 +16.9 −32.3 −33.8
2 +12.9 −33.2 −34.5
3 +17.0 −32.6 −33.8
4 +12.5 −35.7 −37.0


Table 3 shows that the MEP values at the O-atoms of the ethyl-2-oxoacetate group are similar in compounds 1–3 and more negative in compound 4 likely due to the electron donating methoxy group. In contrast, compound 4 presents the smallest π-hole value and compound 3 (with the electron withdrawing F-atom) presents the most intense π-hole.

In the solid state, compounds 1–4 form infinite 1D supramolecular chains (see Fig. 9a for the representative compound 1) that propagates by means of π–π interactions that interconnect the self-assembled dimers. Details of a self-assembled dimer are shown in Fig. 9b, where the formed hydrogen bonding network is highlighted using green dashed lines. The H-bonds are established between the aromatic H-atoms and the O-atoms of the ethyl-2-oxoacetate group. Moreover, the formed two symmetrically equivalent O⋯C interactions are also highlighted using blue dashed lines. The most nucleophilic O-atom belonging to the ester group is located exactly above the electrophilic C-atom of the keto group. The O⋯C distance is significantly shorter than the sum of van der Waals radii (3.22 Å), thus evidencing the importance of this non-covalent contact.


image file: d0ce00335b-f9.tif
Fig. 9 (a) 1D infinite chain observed in the solid state of compound 1. (b) Details of the self-assembled dimer. Distances in Å.

We have analyzed the O⋯C(π-hole) tetrel bonding interactions using DFT calculations. We have first computed the dimerization energies of the dimers of compounds 1–4 (see Fig. 10a) and also the dimerization energies of reduced theoretical models (see Fig. 10b) where both phenyl rings have been substituted by H-atoms (see the small arrows in Fig. 10b). In these reduced models, the H-bonds and other van der Waals interactions due to the proximity of the bulk of both molecules are not established, and consequently, only the contribution of the π-hole tetrel bonding interaction is evaluated. The energetic results along with some geometric features of the complexes are given in Fig. 10 (bottom). The energetic results show that the dimerization energies are very large ranging from −16.0 to −23.2 kcal mol−1 due to the contribution of both the H-bonds and π-hole interactions. It is interesting to highlight that the O⋯C π-hole distance is shorter in compound 4 that, conversely, presents the smallest MEP at the π-hole (see Table 3). This fact is compensated by the large and negative value at the O-atom. In fact, this compound presents the largest interaction energy for the reduced model [ΔE(B)] thus confirming that it exhibits the strongest π-hole tetrel bonding interaction. The weakest interaction is observed in compound 2, which presents the longest O⋯C distance and also a small MEP value at the π-hole (see Table 3).


image file: d0ce00335b-f10.tif
Fig. 10 Energetic and geometric features of the self-assembled dimers of compounds 1–4 (a) and the reduced model (b). Energies in kcal mol−1 and distances in Å. The H-bonds are represented using green dashed lines and the O⋯π-hole interaction using blue dashed lines.

Finally, we have characterized the interactions by using Bader's quantum theory of “atoms-in-molecules” (QTAIM) in order to further evidence the existence of the O⋯π-hole and C–H⋯O interactions. The presence of a bond path (lines of maximum density linking neighboring nuclei in a system) and bond critical point connecting two atoms is a universal evidence of interaction.46 The distribution of bond CPs and bond paths in the dimer of compound 1 as a representative complex is given in Fig. 11. The O⋯π-hole interaction is characterized by a bond CP (blue sphere) and bond path interconnecting the O and C atoms and confirming the interaction. Each C–H⋯O interaction (green spheres) is also characterized by a bond CP and bond path which connect the H atom to the O atom of the keto/ester group. The QTAIM analysis also reveals the existence of C–H⋯π interactions that are formed between the aliphatic H-atom and the electron rich aromatic ring which further contribute to the stabilization of the self-assembled dimers. It is worth emphasizing that the value of charge density ρ(r) at the bond CP is a good indicator of the strength of the interaction, as demonstrated in a great deal of interactions.47–50 The values of ρ(r) at the bond CPs that characterize the π-hole interactions in complexes 1–4 are also included in Fig. 11 along with the dimerization energies of the reduced model complexes. They confirm that the π-hole interaction in 4 is stronger than that in compounds 1–3, also in agreement with the O⋯C distances (d4 values in Fig. 10). In fact, we have represented the value of ρ(r) at the bond CP that characterizes the π-hole interaction versus the interaction energies of the model compounds and we have found a very strong linear relationship (R2 = 0.9818), thus confirming that the ρ(r) at the bond CP is a good indicator of the strength of the interaction and also that the reduced model complexes are adequate to analyze the contribution of the π-hole interactions (Fig. 12). Taking into consideration that the ΔE(B) values gathered in Fig. 11 range from −5.8 to −8.6 kcal mol−1, each π-hole interaction is energetically significant and comparable to a H-bond interaction.


image file: d0ce00335b-f11.tif
Fig. 11 Distribution of bond critical points and bond paths in complex 1. Ring and cage CPs have been omitted for clarity. Moreover, the bond CPs and bond paths corresponding to intramolecular interactions have been also omitted.

image file: d0ce00335b-f12.tif
Fig. 12 Regression plot of electron density values [ρ(r)] at the bond CP that characterizes the π-hole interaction versus the interaction energies.

Conclusion

In this work, we have synthesized and X-ray characterized four new triazole derivatives that exhibit a strong tendency, via the α-ketoester group, to establish two simultaneous π-hole donor–acceptor interactions. The interaction is moderately strong as evidenced by DFT calculations. The O⋯π-hole interactions have been characterized by means of Hirshfeld surface analysis, QTAIM and MEP computational tools. The ρ(r) density values at the bond CPs can be used as a measure of the strength of the interaction. The results reported herein are useful empirical principles of π-hole interactions in crystal engineering and supramolecular chemistry, where these interactions are progressively accepted as functionally relevant.

Conflicts of interest

There is no conflict to declare.

Acknowledgements

The authors are thankful to the University of Azad Jammu and Kashmir, Muzaffarabad for financial support. Antonio Frontera acknowledges financial support from AEI for the funding of project CTQ2017-85821-R (MICIU/AEI/FEDER, EU).

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Footnote

Electronic supplementary information (ESI) available. CCDC 988858–988860 and 988864. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0ce00335b

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