Functionalization and Coordination Effects on the Structural Chemistry of Pendant Arm Derivatives of 1,4,7-trithia-10-aza-cyclododecane ([12]aneNS₃)

Abstract

The effect of different pendant arms on the structural chemistry of the 1,4,7-trithia-10-aza-cyclododecane ([12]aneNS₃) macrocycle is discussed in relation to the coordination chemistry of all known functionalized derivatives of [12]aneNS₃, which have been structurally characterized.

1. Introduction

1,4,7-Trithia-10-aza-cyclododecane ([12]aneNS₃ (L in Figure 1) is a well-known 12-membered mixed thia-aza macrocycle featuring a NS₃ donor set suitable for coordination to soft metal ions [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. It has been extensively functionalized at the secondary nitrogen atom to afford pendant arm derivatives for different purposes: fluorescent materials and chemosensors for heavy metal ions [3,4,9,10,11], highly selective heteroditopic ionophores for simultaneous binding, extraction and transport of both the cationic and anionic moieties of toxic and/or precious transition metal salts [12,13], crystal engineering in the preparation of coordination polymers [5,8,12], tuning of the coordination environment around soft metal ions [2,6,7,15], and development of new synthetic methods of mixed-donor thiacrown ethers [1,14]. All structurally characterized pendant arm derivatives of [12]aneNS₃ (L) are reported in Figure 1, including both metal-coordinated ligands (drawn in black) and free ligands (drawn in red). Of note, no X-ray crystal structure of L is known, and L7 is the only derivative of [12]aneNS₃ for which the X-ray crystal structure is known together with some of its transition metal coordination compounds. In this paper, we report the X-ray crystal structure of L12 and the synthesis and structural characterization of two new L derivatives, i.e., L20 and L21∙CHCl₃ (Figure 2). The two new derivatives of L were chosen to favor intermolecular interactions involving the functional groups in the pendant arm and the donor atoms from the macrocyclic moiety. In particular, in the case of L20, we wanted to explore the possibility of intermolecular halogen bonds (XBs) formation involving the S donor atoms of the macrocyclic moiety and the effects on its conformation. The three new crystal structures are discussed and compared with those already known in order to identify particular trends in the conformational changes in the macrocyclic moiety upon coordination with metal ions, and the geometrical effects induced by pendant arms bearing additional functionalities.

2. Materials and Methods

2.1. Materials and Methods

1,4,7-Trithia-10-aza-cyclododecane ([12]aneNS₃) [11] and L12 were synthesized according to the procedure reported in the literature [9]. Reagents and solvents were used that were purchased from Aldrich. Elemental analyses were performed with an EA1108 CHNS-O Fisons instrument (T = 1000 °C). The ¹H- and ¹³C-NMR spectra were determined on a Bruker Avance 600 MHz spectrometer. The mass spectra were recorded on a triple quadrupole QqQ Varian 310-MS mass spectrometer by using the atmospheric pressure ESI technique. All sample solutions were infused into the ESI source with a programmable syringe pump (1.50 mL/h constant flow rate). A dwell time of 14 s was used, and the spectra were accumulated for at least 10 min to increase the signal-to-noise ratio. The mass spectra were recorded in the m/z 100−1000 range. The following scan parameters were chosen [16]: needle voltage 3500 V, shield 800 V, source temperature 60 °C, drying gas pressure 20 psi, nebulizing gas pressure 20 psi, detector voltage 1450 V, and drying gas temperature 110 °C. The isotopic patterns of the measured peaks in the mass spectra were analyzed using the mMass 5.5.0 software package [17]. All mass values were indicated as monoisotopic masses, which were computed as the sum of the masses of the primary isotope of each atom in the molecule (note that the monoisotopic mass may differ from the nominal molecular mass).

2.2. X-ray Diffraction Analyses

Only special features are noted here. Crystallographic data are reported in Table S1 in the Supplementary Materials. Single-crystal X-ray diffraction (SC-XRD) data for compound L12 were collected at 150 K on a Bruker SMART 1000 diffractometer using MoKα radiation. The data were indexed and processed using Bruker SAINT and SMART [18,19]. The structure was solved by the SIR92 [20] solution program using direct methods. SC-XRD data for compound L20 were collected at 293 K on an Agilent SuperNova diffractometer equipped with an Eos detector using MoKα radiation. The data were indexed and processed using CrysalisPro [21] and the structure was solved by SHELXT [22] using dual-space methods. SC-XRD data for the compound L21∙CHCl₃ were collected at 293 K on a Bruker APEX II CCD diffractometer using MoKα radiation. The data were indexed and processed using Bruker SAINT [18]. The structure was solved by SIR92 [20] using direct methods. The models were refined with ShelXL [23] using full-matrix least-squares minimization on F². All non-hydrogen atoms were anisotropically refined. Hydrogen atom positions were geometrically calculated and refined using the riding model. Olex2, version 1.5 [24], was used as the graphical interface. For the compound L21∙CHCl₃, the solvent molecule was disordered and modelled over two sites with statistically the same occupancy [0.49(1) and 0.51(1), respectively]. Complete crystallographic data for the structure of compounds L12, L20, and L21∙CHCl₃ were deposited in CIF format at the Cambridge Crystallographic Data Center (CCDC) with deposition numbers 2248158-2248160, respectively.

2.3. Synthesis of L20

A mixture of 1,4,7-trithia-10-aza-cyclododecane (0.178 g, 0.790 mmol), 2-bromobenzyl bromide (0.199 g 0.790 mmol), and K₂CO₃ (0.37 g, 2.6 mmol) in dry MeCN (50 mL) was heated to reflux for 96 h under a dry N₂ atmosphere. The solid was filtered off and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (DCM) and washed with distilled water. The organic phase was dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica) using DCM/MeOH (10:0.3, v/v) as eluent to give a pale-yellow solid (0.187 mg, 0.63 mmol, 80% yield). Elemental analysis, Found (Calcd. for C₁₅H₂₂BrNS₃): C, 45.68 (45.91); H, 5.58 (5.65); N, 3.71 (3.57); S, 24.42 (24.51)%. M.p. 108 °C; ¹H-NMR (CDCl₃, 600 MHz): δ_H (ppm) 2.65–2.69 (m, 4H), 2.78–2.82 (m, 12H), 3.71 (s, 2H, NCH₂Ar), 7.12 (t, J = 7.1 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), and 7.54 (d, J = 7.5 Hz, 2H); ¹³C{¹H}-NMR (CDCl₃, 150 MHz): δ_C (ppm) 25.90, 27.86, 28.49 (CH₂S), 51.86 (CH₂N), 59.55 (NCH₂Ar), 124.38, 127.41, 129.70, 130.69, 132.85, and 137.88 (aromatic carbons); and ESI-MS(+): m/z = 393 [M+H]⁺. The crystals of L20 suitable for an X-ray diffraction analysis were grown from a DCM solution by diffusion of Et₂O vapor.

2.4. Synthesis of L21

A weighted amount of 2-hydroxy-5-nitrobenzyl bromide (0.170 g, 0.740 mmol) was added to a solution of 1,4,7-trithia-10-aza-cyclododecane (0.150 g, 0.670 mmol) and K₂CO₃ (0.460 g, 3.33 mmol) in dry MeCN (20 mL). The reaction mixture was heated under nitrogen at 80 °C for 24 h and then for 24 h at room temperature. The solid was filtered off, and the solvent was removed under reduced pressure to give a yellow solid (0.170 mg, 0.45 mmol, 68% yield). Elemental analysis, Found (Calcd. for C₁₅H₂₂N₂O₃S₃): C, 48.51 (48.10); H, 6.12 (5.92); N, 7.48 (7.48); S, 25.91 (25.68)%. M.p. 175 °C; ¹H-NMR (CDCl₃/CD₃CN, 600 MHz): δ_H (ppm) 2.68 (m, 4H), 2.76 (m, 8H), 2.81 (m, 4H), 3.71 (s, 2H, NCH₂Ar), 6.56 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 3.0 Hz, 1H), and 8.05 (d, J = 2.8 Hz, 1H); ¹³C{¹H}-NMR (CDCl₃/CD₃CN, 150 MHz): δ_C (ppm) 26.5, 29.2, 29.4(CH₂S), 52.5 (CH₂N), 56.1 (NCH₂Ar), 118.7, 126.2, 126.9, 127.4, 136.7, and 172.6 (aromatic carbons); and ESI-MS(+): m/z = 375 [M+H]⁺. The crystals of L21∙CHCl₃ suitable for an X-ray diffraction analysis were grown from a CHCl₃ solution.

3. Results and Discussion

The X-ray crystal structure of L12 is characterized by the formation of dimeric arrangements via N∙∙∙H–O hydrogen bonds involving the –OH group and the aromatic N atom from the pendant arms of two symmetry-related ligand units (Figure 3). π-π Stacking interactions between the quinoline moieties of adjacent slipped dimers (centroid-centroid distance: 3.77 Å) generate a staircase architecture along the b-axis as shown in Figure S1 in the Supplementary Materials.

In L12, the macrocyclic unit adopts a square-shaped conformation with the four donor atoms occupying the corners. A useful convention to describe the different conformations that an aliphatic macrocycle can adopt is that of Dale [25], and it is based on the sequence of torsion angles around the macrocycle ring, which normally are classified as either anti (≅180°) or gauche (≅60°). According to the Dale convention, a generic conformation is determined by the number of bonds between each corner in the macrocycle (a corner is the atom at which two gauche torsion angles intersect). Considering the sequence of the torsion angles in L12 (

Table 1. Torsion angles (°) for the [12]aneNS₃ moieties in L12, L20, and L21∙CHCl₃ with the Dale conformations in bracket squares (gauche torsion angles in red).

	L12 [3333]	L20 [11334]	L21∙CHCl3 [3333]
N1−C2−C3−S4	−172.90(14)	−66.0(3)	172.32(9)
C2−C3−S4−C5	77.12(18)	88.4(3)	−74.74(12)
C3−S4−C5−C6	75.95(19)	74.0(3)	−72.83(12)
S4−C5−C6−S7	−168.74(13)	175.40(17)	170.11(8)
C5−C6−S7−C8	65.4(2)	59.4(3)	−70.10(12)
C6−S7−C8−C9	67.8(2)	63.3(3)	−68.69(12)
S7−C8−C9−S10	−173.99(13)	−166.01(19)	173.80(8)
C8−C9−S10−C11	73.4(2)	68.5(3)	−70.48(12)
C9−S10−C11−C12	75.6(2)	66.8(3)	−75.57(12)
S10−C11−C12−N1	−165.24(17)	−155.5(2)	166.58(10)
C11−C12−N1−C2	64.8(3)	166.2(3)	−67.18(6)
C12−N1−C2−C3	69.1(2)	−73.8(4)	−69.40(5)

), four corners in the [12]aneNS₃ unit are present at the N and S donor atoms. Each pair of corners is separated by one −N−CH₂−CH₂−S− or −S−CH₂−CH₂−S− side-moiety unit featuring an anti-torsion angle at the C−C bond. Therefore, the conformation adopted by the macrocyclic unit in L12 is [3333], according to the Dale convention, with the lone pairs (LPs) of electrons on the donor atoms in exo-dentate positions (i.e., pointing out of the ring cavity).

This type of conformation with exo-dentate donor atoms positioned at the corners is very common in medium and large aliphatic thioether macrocycles, as demonstrated by diffraction studies [26,27,28]: an anti-torsion angle at the C−C bond in the −S−CH₂−CH₂−S− units is preferred as a consequence of the repulsive 1,4-interaction between the sulfur LPs in a gauche arrangement [29]. On the other hand, a gauche torsion angle at the C−S bond in a −CH₂−CH₂−S−CH₂− sequence is not disfavored by the 1,4-interactions of the methylene protons, which lie beyond the sum of the corresponding van der Waals radii [30]. An opposite trend is observed in oxa-macrocycles due to the different C−O bond length and covalent radius of the donor atom [31].

In general, and in the specific case of L12, metal complexation or the involvement of one of the donor atoms of the [12]aneNS₃ unit in interactions with functionalities present in the pendant arms can strongly affect the conformation adopted by the macrocyclic unit in the solid state.

In fact, the X-ray crystal structure of L20 is also characterized by dimeric arrangements via C−Br∙∙∙S halogen bonds (XBs) involving one of the S donors from the macrocyclic unit as an XB acceptor, and the Br atom on the benzylic pendant arm as an XB donor (Figure 4).

Due to this intermolecular interaction, the macrocyclic unit assumes a [11334] conformation as five corners can be identified in the cyclic structure (three consecutive at the atoms C2, C3, and S4, and the other two at S7 and S10, Table 1). Compared to L12, anti-torsion angles in L20 remain at the C−C bonds in the sequencies S4−C5−C6−S7, S7−C8−C9−S10, and S10−C11−C12−N1 (Table 1), while the torsion angles at the C2−C3 and C12−N1 bonds in the sequences N1−C2−C3−S4 and C11−C12−N1−C2 adopt a gauche and an anti-conformation, respectively (vice versa in the case of L12, Table 1). Presumably, the pulling effect of the bromine atom on the sulfur atom S10 in forming the XB causes the torsion angle at one of the C−N to change from a gauche to an anti-conformation, and the torsion angle at the C2−C3 bond to do the exact opposite.

This does not happen in the structure of L21∙CHCl₃, in which it is the N atom from the macrocyclic unit that is involved in a weak intramolecular interaction with a functional group in the pendant arm. In fact, the conformation adopted by the [12]aneNS₃ unit in L21∙CHCl₃ is again square-shaped [3333] with the exo-dentate donor atoms at the corners and −N−CH₂−CH₂−S− or −S−CH₂−CH₂−S− sequences with anti-torsion angles at the C−C bonds at the sides (Table 1). In this compound, an intramolecular HB is formed between the hydroxyl –OH function and the tertiary N donor from the macrocyclic unit (Figure 5a), which keeps the exo-dentate orientation of the LP in the HB interaction. Furthermore, dimeric arrangements are determined by C−H∙∙∙O HBs involving one oxygen atom from the nitro group and one benzylic hydrogen atom (Figure 5b).

A survey in the CSD (accessed on 13 January 2023) reveals a total of 31 X-ray crystal structures of [12]aneNS₃ (L) derivatives bearing functionalized pendant arms being reported either as free ligands or as metal complexes. The comparative analysis of the conformations assumed by the macrocyclic framework in the crystallographically independent 43 units (Table S5 in the Supplementary Materials) in terms of Dale notation shows that all reported free ligands (8 independent units) feature the [3333] conformation with the exo-dentate donor atoms at the corners (black asterisks in Figure 6a) which is in line with what is found in the structures of L12 and L21∙CHCl₃. The only exception is represented by the structure of L20 mentioned above, and by the conformation assumed by the macrocycle in its bromide salt [HL]Br∙2H₂O [1]. In this compound, the macrocycle is protonated at the secondary nitrogen atom and it assumes an unusual [84] (Table S5) conformation with only two corners, both at the carbon atoms, due to the intramolecular N−H∙∙∙S HB involving the sulfur atom in front of the protonated N donor.

Among the remaining structures in which the macrocyclic moiety is involved in metal coordination, 25 independent units still display the macrocyclic moiety in a [3333] conformation with the corners located on carbon atoms and the donor atoms on –CH₂–CH₂–E–CH₂– (red asterisks in Figure 6a) or –CH₂–E–CH₂–CH₂– (green asterisks in Figure 6a, counting clockwise from the first corner to the left of the N atom as shown in Figure 6) side edges of the square-shaped conformation (E = N or S). A small number of compounds feature a conformation of the metal-coordinated macrocyclic unit in which three corners are located on three consecutive atoms including a S atom in the middle (purple, cyan, green, red, and brown asterisks in Figure 6b, see Table S5). Only in the case of L20 does the sequence of three consecutive corners feature a S atom at the end of the three consecutive atoms involved (yellow asterisks in Figure 6b). Interestingly, no conformations with three consecutive corners involving N as one of the three consecutive atoms are known. Finally, only two structures are known in which the macrocyclic framework adopts a [84] conformation featuring only two corners (both at the same carbon atoms, Table S5), namely [HL]Br∙2H₂O [1] and [CuCl(L14)]CuCl₄ [12].

4. Conclusions

The extent to which a macrocyclic ligand must pre-organize its conformation prior to complexation is one of the structural factors that can strongly affect the stability of the resulting metal complexes. For some macrocycles, the most stable conformation in the free state is not the most suitable to bind the metal ion and some changes are necessary to satisfy the stereochemical requirements of the complexation process. Herein, we have analyzed the conformation adopted in the solid state by the [12]aneNS₃ macrocyclic ring in all its functionalized pendant arm derivatives, both as free ligands and as metal complexes. The derivatives of this 12-membered tetradentate NS₃ macrocycle in their free state adopt a [3333] conformation, regardless of the nature of the functional groups in the pendant arms, with all 4 donor atoms at the corners of a square-shaped structure with the lone pairs in exo-dentate positions. This is also confirmed by the X-ray crystal structures of L12 and L21∙CHCl₃ presented herein. Therefore, upon complexation, a drastic conformational change is required to bring the lone pairs on the donor atoms into endo-dentate arrangements to maximize coordination to the metal ion. The most commonly observed conformation of the [12]aneNS₃ moiety bound to metal ions is still of the type [3333], but the donor atoms sacrifice their preferred corner positions and each becomes part of a “side” of the square-shaped structure, with each side made up of a sequence of gauche- anti-gauche torsion angles. In very few reported cases, endo-dentate arrangements of the donor atoms in the [12]aneNS₃ moiety are reached upon coordination by assuming conformations that are different from the [3333]. These conformations of the type [33114] (or related ones by cyclic permutations of the corner positions, see Figure 6 and Figure S2 in the Supplementary Materials) all feature three consecutive corners, i.e., three consecutive atoms at which two gauche torsion angles intersect, of which a S atom is always in the middle. The other three donor atoms (two S and one N) are not in corner positions. A similar conformation of the [12]aneNS₃ moiety, but with a S donor atom being a terminal corner in the sequence of three consecutive ones (Figure 6b), has been observed in the structure of the free ligand L20, and it is determined by an intermolecular C−Br∙∙∙S halogen bond. In L20, the conformation adopted by the macrocyclic unit is [11334] and not [3333] as normally observed; the three S donor atoms are all in corner positions while the N donor atom is not and is characterized by an endo-dentate orientation of its lone pair. We conclude that this is the only case in which the functional group in the pendant arm affects the conformation assumed by the [12]aneNS₃ macrocyclic moiety due to a direct intermolecular interaction with one of the S donor atoms. Our results suggest that in order to have a conformation other than [3333] for the macrocyclic moiety of uncoordinated pendant arm derivatives of L, rather than considering intramolecular HBs involving the N atom and HB donors in the pendant arms (see the structure of L21∙CHCl₃), it is more convenient to look for functionalities that can interact with the S donors of the macrocyclic moiety.