3,3’-(4,11-Bis(4-(trifluoromethyl)benzyl)-1,4,8,11-Tetraazacyclotetradecane-1,8-diyl)dipropanenitrile

Abstract

The cyclam derivative (NCCH₂CH₂)₂(^4-CF3PhCH₂)₂Cyclam was prepared by the reaction of H₂(^4-CF3PhCH₂)₂Cyclam with acrylonitrile in methanol. The compound was fully characterized by elemental analysis, mass spectrometry as well as IR and NMR spectroscopy. Crystals of (NCCH₂CH₂)₂(^4-CF3PhCH₂)₂Cyclam suitable for single-crystal X-ray diffraction were obtained by the slow evaporation of a chloroform solution of the compound. The establishment of non-classical hydrogen bonds and unusual nitrile–nitrile and π(CN)^…π interactions determined the solid-state supramolecular architecture of (NCCH₂CH₂)₂(^4-CF3PhCH₂)₂Cyclam.

1. Introduction

Cyclams have received considerable attention over the last few years due to their chemical and biological properties. The high kinetic and thermodynamic stability exhibited by metal complexes supported by cyclam derivatives led to their application as catalysts [1,2,3,4,5,6], radiopharmaceuticals [7,8,9,10,11,12,13] and metallodrugs [14,15,16,17,18,19,20]. The modification of the macrocyclic backbone by the attachment of substituents to nitrogen atoms is essential for the optimization of their electronic and stereochemical properties. Despite a large number of tetrasubstituted cyclams of formula R₄Cyclam being described in the literature, derivatives of the type trans,trans-R₂R’₂Cyclam are much less commonly reported [11,12,20,21,22,23,24,25,26,27,28,29].

Aiming to contribute to the continuous development of cyclam-based compounds, we present herein the synthesis and structural characterization of a new tetrasubstituted cyclam derivative of formula (NCCH₂CH₂)₂(^4-CF3PhCH₂)₂Cyclam. By exploring the undiscovered functionalities of this type of compounds, it might be possible to unlock hidden potential applications in fields ranging from medicine to materials science.

2. Results and Discussion

Refluxing a methanolic solution of H₂(^4-CF3PhCH₂)₂Cyclam, 1, with excess of acrylonitrile afforded (NCCH₂CH₂)₂(^4-CF3PhCH₂)₂Cyclam, 2, in a moderated yield, as shown in Scheme 1.

The ¹H NMR spectrum of 2 (see Figure S1) shows five multiples for the methylene protons of the cyclam ring along with a set of resonances corresponding to the protons of the ^4-CF3PhCH₂ and NCCH₂CH₂ pendant arms of the macrocycle. The ¹⁹F NMR spectrum (see Figure S2) shows one singlet at −62.3 ppm attributed to the CF₃ groups of the ^4-CF3PhCH₂ pendant arms of the cyclam ring. The ¹³C{¹H} NMR spectrum (see Figure S3) is in accordance with the pattern observed in the ¹H and ¹⁹F NMR spectra and, thus, confirms the C_2v symmetry of 2 in solution.

The infrared spectrum of compound 2 (see Figure S4) shows bands between 2945 and 2797 cm⁻¹ assigned to the ν_C-H asymmetric/symmetric stretching vibrational modes of the methylene groups. The band at 2249 cm⁻¹ is assigned to the ν_C≡N of the nitrile group of the CH₂CH₂CN pendant arms of the macrocycle. The ν_C-C stretching (in-ring) band observed at 1615 cm⁻¹ is assigned to the aromatic rings. The strong absorption bands between 1319 and 1156 cm⁻¹ are due to the combination of the ν_C-C and ν_C-N stretching vibrational modes of the cyclam ring. The ν_C-F stretching vibrational modes of the CF₃ groups are observed as strong absorption bands ranging from 1115 to 1063 cm⁻¹. The absorption band observed at 830 cm⁻¹ is characteristic of 1,4-disubstituted aromatic rings.

Crystals of 2 suitable for single-crystal X-ray diffraction were obtained from the slow evaporation of a chloroform solution. Crystal data for 2 (M = 622.70 g/mol) were obtained and used in all calculations: monoclinic, space group C2/c (no. 15), a = 25.328(2) Å, b = 5.7081(5) Å, c = 24.491(2) Å, β = 118.384(4)°, V = 3115.1(5) ų, Z = 4, T = 150(2) K, μ(MoKα) = 0.105 mm⁻¹, D_calc = 1.328 g/cm³, 10,078 reflections measured (1.905° ≤ Θ ≤ 27.180°), 3475 unique (R_int = 0.0579, R_sigma = 0.0820). The final R₁ was 0.0642 (I > 2σ(I)) and wR₂ was 0.1729 (all data). The ORTEP diagram of the solid-state molecular structure of 2 is shown in Figure 1. The overall molecular shape of the macrocycle is remarkably flat and disk-like with the four nitrogen atoms coplanar, as observed in other tetrasubstituted cyclams [30]. The N(1)^…N(1#) and N(2)^…N(2#) transannular distances are 5.59 and 4.95 Å, respectively, which correspond to a cavity size smaller than 1.95 Å calculated from the sum [1.5 + 1.5 = 3.0 Å] of the van der Waals radii of two nitrogen atoms [31].

The solid-state molecular structure of 2 reveals the formation of non-classical C-H^…N hydrogen bonds between the C(1)-H(1A), C(11)-H(11) and C(15)-H(15A) moieties and the acceptor nitrogen atom N(3) of neighboring molecules with distances of 2.520, 2.731 and 2.645 Å, respectively (see Table S1 for details). Unconventional antiparallel nitrile–nitrile interactions are observed with centroid-to-centroid distances of 3.563 Å between the π-systems of the nitrile fragments of two neighboring molecules. The corresponding C(15)-C(16)≡N(3) angle of 179.32° attests its linearity. Unusual π-stacking interactions are also observed between the π-electrons of the nitrile group and the aromatic ring of a neighboring molecule having centroid-to-centroid distances of 3.790 Å. A detailed view of the supramolecular interactions in compound 2 is depicted in Figure 2.

Similar C-H^…N interactions can be observed in other cyclam derivatives containing CH₂CH₂CN pendant arms (NUPZII [32], ICALON [33] and ICALON01 [34]). Nevertheless, antiparallel nitrile–nitrile interactions are only observed in 3,3’-(5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)dipropanenitrile (NUPZII) but with longer centroid-to-centroid distances (3.653 Å) [32].

The above-mentioned interactions are responsible for the tridimensional arrangement of 2 at a supramolecular level that reveals tubular chains growing along the b direction (see Figure 3).

3. Materials and Methods

3.1. General Considerations

Compound 1 was prepared according to a previously published procedure [6]. All other reagents and solvents were commercial grade and used without purification. NMR spectra were recorded in a Bruker AVANCE II 300 MHz spectrometer, at 296 K, referenced internally to residual proton-solvent (¹H) or solvent (¹³C) resonances, and reported relative to tetramethylsilane (0 ppm). Two-dimensional NMR experiments such as ¹H-¹³C HSQC and ¹H-¹H COSY were carried out to make all the assignments. The infrared spectrum was acquired using a Bruker ALPHA II ATR spectrometer with an individual diamond in the range of 3400–400 cm⁻¹ at a resolution of 4 cm⁻¹. Elemental analysis was performed at the SSADS-CACTI UVIGO Laboratory, Spain, using a FISONS EA-1108 automatic analyzer instrument. The mass spectrum was performed at the Structural Analysis Lab of the Faculty of Pharmacy of the University of Lisbon, Portugal, using a Acquity^TM triple-quadrupole mass spectrometer (Waters^®, Wexford, Ireland) operating with an electrospray ionization (ESI) source at 120 °C and applying a capillary voltage of 3.0 kV and a sampling-cone voltage of 60 V. Acetonitrile was used as the solvent and nitrogen was used as both the drying and nebulizing gas.

3.2. Synthesis and Characterization

(NCCH₂CH₂)₂(^4-CF3PhCH₂)₂Cyclam, 2: Compound 1 (0.47 g, 0.91 mmol) was dissolved in methanol (15 mL) and acrylonitrile was added (0.30 mL, 4.58 mmol). The reaction mixture was refluxed overnight. The volume of the solution was reduced by the evaporation of the solvent in a rotavapor, and the concentrated solution was placed in the freezer. The product precipitated out of solution as a white solid that was isolated by filtration, washed with diethyl ether, and dried in vacuum. Yield: 58% (0.33 g, 0.53 mmol). ¹H NMR (CDCl₃, 300.1 MHz, 296 K): δ (ppm) 7.58 (d, 4H, ³J_H-H = 8.1 Hz, Ph), 7.47 (d, 4H, ³J_H-H = 7.8 Hz, Ph), 3.58 (s, 4H, CH₂Ph), 2.64–2.56 (overlapping, 16H total, 4H, [C3]CH₂N, 8H, [C2]CH₂N and 4H, α-CH₂), 2.52–2.47 (m, 4H, [C3]CH₂N), 2.35 (t, ³J_H-H = 6.7 Hz, 4H, β-CH₂), 1.74–1.68 (m, 4H, CH₂CH₂CH₂). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz, 296 K): δ (ppm) 144.2 (i-Ph), 129.4 (q, ²J_C-F = 32.5 Hz, p-Ph), 129.2 (o-Ph), 125.3 (q, ³J_C-F = 3.8 Hz, m-Ph), 124.4 (q, ¹J_C-F = 271.8 Hz, CF₃), 119.2 (CN), 59.2 (CH₂Ph), 51.5 (CH₂), 51.4 (CH₂), 51.3 (CH₂), 51.1 (CH₂), 50.0 (CH₂), 24.5 (CH₂CH₂CH₂), 16.4 (β-CH₂). ¹⁹F{¹H} NMR (CDCl₃, 282.2 MHz, 296 K): δ (ppm) -62.3 (CF₃). FT-IR (ATR, cm⁻¹): 2945 (ν_C-H), 2797 (ν_C-H), 2249 (ν_C≡N), 1615 (ν_C=C), 1355 (ν_C-C, ν_C-N), 1319 (ν_C-C, ν_C-N), 1279 (ν_C-C, ν_C-N), 1156 (ν_C-C, ν_C-N), 1115 (ν_C-F), 1102 (ν_C-F), 1063 (ν_C-F), 830 (ν_C=C). ESI-MS (m/z): 623 [C₃₂H₄₁F₆N₆]⁺, 465 [C₂₄H₃₆F₃N₆]⁺. Anal. calcd for C₃₂H₄₀F₆N₆.H₂O: C, 59.99; H, 6.61; N, 13.12. Found: C, 60.29; H, 7.19; N, 13.90.

3.3. General Procedure for Single Crystal X-ray Crystallography

Crystals of compound 2 suitable for single-crystal X-ray diffraction were coated and mounted on a loop with Fomblin^® oil. Data were collected using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) on a Bruker AXS-KAPPA APEX II diffractometer (Bruker AXS Inc., Madison, WI, USA) equipped with an Oxford Cryosystem open-flow nitrogen cryostat at 150(2) K. Data were corrected for Lorentzian polarization and absorption effects using the SAINT [35] and SADABS [36] programs. SIR2004 [37] was used for structure solution and SHELXL-2014/7 [38] was used for full-matrix least-squares refinement on F². These programs are included in the WinGX-Version 2023.1 program package [39]. The hydrogen atoms were inserted in idealized positions and allowed to refine in the parent carbon atom. Crystallographic and experimental details of data collection and crystal structure determinations are available in Table S2. Illustrations of the molecular structures were made with MERCURY 2022.3.0 [40].