In the pursuit of hydrophilic model fac-[Re(CO)3]+ complexes for (radio) pharmaceutical applications, six novel [2 + 1] mixed-ligand complexes of the general type fac-[Re(CO)3(bid)P] were synthesized and characterized, where bid is a bidentate ligand bearing either (N, O) or (S, S′) donor atom sets and P is the hydrophilic phosphine 1,3,5-triaza-7-phosphoadamantane (PTA) or its macrocyclic homologue 1,4,7-triaza-9-phosphatricyclo[]tridecane (CAP). The (N, O) ligands used in this study were picolinic and quinaldic acid, while the (S, S′) ligand was diethyldithiocarbamate. The complexes were synthesized in generally high yields and purity and the characterization was performed by spectroscopic methods, IR, NMR, and elemental analysis. Detailed X-ray crystallographic study of molecular packing by using Hirshfeld analysis tools revealed a plethora of intermolecular interactions such as hydrogen bond, ππ, C-H⋯π, and carbonyl-carbonyl interactions. To our knowledge, the CAP complexes reported herein are the first example of [2 + 1] mixed-ligand fac-[Re(CO)3]+ complexes with CAP. The new complexes might have the potential to serve as platforms for the design of target-specific complexes with favorable pharmacokinetics.

1. Introduction

Rhenium has recently attracted renewed attention in medicine due to its increasing potential applications in the anticancer arena. In fact, two isotopes of rhenium are β-emitters (186Re, Emax = 1.1 MeV, t1/2 = 90.6 h; 188Re, Emax = 2.1 MeV, t1/2 = 17 h) and therefore they are suitable candidates for therapeutic applications in radiotherapy [1]. In addition, rhenium shares a very similar chemistry with 99mTc, the most widely used Single Photon Emission Computed Tomography (SPECT) radioisotope in Nuclear Medicine, and therefore any advancements in synthetic methodologies to access rhenium complexes can be usually applied for the development of more efficient 99mTc radiopharmaceuticals [2]. Furthermore, recent research has shown that rhenium complexes possess potent anticancer properties while exhibiting diverse mechanisms of action, which makes them promising chemotherapeutic agents [3]. In view of the above, the exploration of rhenium’s coordination chemistry remains an important aspect for the development of novel (radio) agents with optimal biological performance.

Increased hydrophilicity is often a central feature of pharmaceutical design because such compounds have favorable in vivo characteristics for medical applications [4] (e.g., increased aqueous media solubility and faster clearance of the drug from the body). The organometallic fac-[M(CO)3]+ core (M = natRe, 186/188Re and 99mTc) is undoubtedly the most versatile precursor for the development of complexes of (radio) pharmaceutical interest. However, its increased lipophilicity can negatively influence the pharmacokinetic profile of the corresponding complexes [5]. This problem can be further exacerbated when common phosphines are used as ligands despite them being suitable for stabilizing metals in intermediate to low oxidation states as in the fac-[M(CO)3]+ core, thanks to their π-acceptor and σ-donor properties [6]. The high lipophilicity and molecular weight of common aryl-and alkyl phosphines usually render these ligands incompatible for target-specific (radio) pharmaceutical applications.

Nevertheless, the hydrophilicity of fac-[M(CO)3]+ compounds can be enhanced by utilizing polar pharmacological modifiers, i.e., biologically innocent polar moieties that lessen the overall lipophilicity of the (radio) pharmaceutical compunds [5, 7]. In this respect, hydrophilic ligands could exert the same role with minimal disruption of the complexes’ structural identity. The phosphine 1,3,5-triaza-7-phosphoadamantane (PTA) and its recently synthesized higher homologue 1,4,7-triaza-9-phosphatricyclo[]tridecane (CAP) [8] are excellent hydrophilic components of transition-metal compounds that are widely used in the fields of organometallic catalysis as well as for pharmaceuticals development [9, 10]. Both PTA and CAP are air-stable, resistant to oxidation, easy to synthesize, and especially PTA is highly water soluble. Upon P-coordination, the remaining three nitrogen atoms can participate in acid-base interactions in aqueous solutions, which can further impact their pharmacokinetic behavior (e.g., biodistribution and cell uptake by cancer cells) [11]. In addition, the nitrogen atoms are reactive under specific conditions, enabling its functionalization (e.g., N-alkylation) and thus, it could be used as a starting point for targeted drug design by tethering biologically active molecules. A further feature that makes CAP particularly interesting is its stereoelectronic properties. CAP combines strong electron-donating ability with an extremely reduced steric hindrance (cone angle = 109°) [12] making this phosphine ligand unique compared to more classical tertiary phosphines.

The coordination chemistry of PTA with transition metals has been extensively reported [9, 13, 14]. In relation to their use as medicinal compounds, ruthenium and platinum have attracted the main focus of relevant research since PTA complexes with these metals exhibit potent anticancer action [1517]. However, the chemistry of PTA with rhenium is being increasingly investigated thanks to rhenium’s promising medical and catalytical applications. PTA complexes have been reported with rhenium in almost all oxidation states ranging from (+VII) to (+I) [1826]. Concerning fac-[ReI(CO)3]+ complexes, PTA is coordinated to the metal centre either in combination with other monodentate ligands (e.g., Cl and Br) [27] or as part of the [2 + 1] mixed-ligand approach where three labile aqua ligands on the fac-[M(CO)3(H2O)3]+ synthon are substituted by a bidentate ligand (bid) and PTA [2832]. Still, the donor atom combinations with PTA in rhenium complexes incorporating the fac-[Re(CO)3]+ core remain limited, despite it being the most prominent synthon in radiopharmaceutical and related medicinal chemistry research. As for CAP, its’ coordination chemistry with rhenium remains largely unexplored and only in combination with monodentate ligands [11].

In addition to the exploration of the [2 + 1] strategy for the design of new Re(I) complexes by using the appropriate ligands, there is an increased interest on the study of intermolecular interactions of Re(I) complexes in the solid state [3335] based on diverse types of interactions of rhenium complexes with DNA [36, 37]. Similar systematic crystal structure studies [3840] have revealed the importance of lone pair π and more specifically the role of carbonyl-carbonyl interactions on the supramolecular assembly of Re complexes. In an effort to develop a new platform of hydrophilic model fac-[Re(CO)3]+ complexes for radiopharmaceutical and/or medicinal chemistry applications, we report herein a series of novel [2 + 1] rhenium complexes of the general type fac-[Re(CO)3(bid)P], where P is PTA or CAP used as the polar, hydrophilic modifier and bid is either quinaldic and picolinic acid (representing N, O donor atom set) or diethyldithiocarbamate (representing S, S′ donor atom set). To our knowledge, this is also the first time where [2 + 1] mixed-ligand fac-[Re(CO)3(bid)(X)] complexes are reported with CAP. The syntheses of the corresponding complexes are presented along with their spectroscopic characterization by NMR, IR, and X-ray crystallography. Hirshfeld surface analysis tools were used to elucidate the intermolecular interactions of the synthesized complexes since the type of these interactions can impact the packing of the complexes and their pharmacokinetic behavior.

2. Materials and Methods

2.1. General Information

All reagents and starting materials were purchased from commercial suppliers and used without further purification. CAP [41], and [NEt4]2[ReBr3CO3] [42] were synthesized by following published procedures. All organic solvents were used as supplied (ACS or HPLC grade) unless otherwise noted. IR spectra were recorded on a Nicolet 6700 FT-IR (Thermo Scientific, USA) in the region 4000–500 cm−1. 1H and 13C-NMR spectra were obtained in DMSO-d6 at 25°C on a Bruker Avance DRX 500 or 250 MHz spectrometer. All 31P-NMR spectra were obtained on the 500 MHz spectrometer. The measured chemical shifts are reported in δ (ppm), and the residual signal of the solvent was used as the internal calibration standard (DMSO-d6: 1H = 2.50 ppm, 13C = 39.51 ppm). For the 31P-NMR, H3PO4 was used as internal reference. All 13C-NMR spectra were measured with complete proton decoupling. Data of NMR spectra were recorded as follows: s = singlet, d = doublet, t = triplet, m = multiplet, brs = broad singlet, br = broad signal). The coupling constant J is reported in hertz (Hz). The designations quinH and picH denote the protons on the aromatic rings of quinaldic and picolinic acid, respectively. In analogy, the designations quin and pic demonstrate the carbons on the respective aromatic rings of the (N, O) ligands. Elemental analysis for C, H, and N was conducted on a PerkinElmer 2400 automatic elemental analyzer (PerkinElmer, USA). HPLC analysis was performed on a Waters 600 chromatography system (Waters, USA) coupled to a Waters 2487 Dual λ absorbance detector (Waters, USA). Separations were achieved on a Macherey-Nagel Nucleosil C-18 RP column (250 × 4 mm, 10 μm) eluted with a binary gradient system including water/0.1% TFA (solvent A) and methanol/0.1% TFA as follows: 0-1 minute, 5% B; 1–11 minutes, 5–70% B; 11–26 minutes 70% B; 26-27 minutes 95% B; 27–42 minutes 95% B; 42–45 minutes 95–5% B. Flow rate, 1 ml/minute; UV detection, 254 and 220 nm.

2.2. Synthesis of the Rhenium Complexes
2.2.1. fac-[Re(CO)3(quin) (H2O)], 1

Complex 1 was synthesized according to a published procedure [43]. Briefly, [NEt4]2[ReBr3CO3] (231 mg, 0.30 mmol) and quinaldic acid (quin) (51.9 mg, 0.30 mmol) were dissolved in H2O (15 mL). The reaction mixture was stirred for 1 h at 60°C during which time a yellow precipitate formed. After cooling at room temperature, the yellow precipitate was filtered, washed with cold H2O, and dried under vacuum. NMR data are in agreement with those reported in the literature. Yield: 70% (97 mg). RP-HPLC: tR = 17.0 minutes; IR (cm−1): 2027, 1903, 1877, 1644. Anal. Calc. for C13H8NO6Re: C: 33.91%, H: 1.75%, N: 3.04%. Found: C: 33.85%, H: 1.63%, N: 3.15%.

2.2.2. fac-[Re(CO)3(quin) (PTA)], 1a

Complex 1 (23.0 mg, 0.05 mmol) and PTA (8.0 mg, 0.05 mmol) were dissolved in MeOH (10 mL) and the yellow reaction mixture was refluxed for 2 h. The solvent was removed under reduced pressure to give 1a after recrystallization from DCM/hexane. Yield: 94% (29 mg). RP-HPLC: tR = 16.9 minutes. IR (cm−1): 2018, 1923, 1874, 1650. Anal. Calc. for C19H18N4O5PRe: C: 38.06%, H: 3.03%, N: 9.34%. Found: C: 38.23%, H: 3.15%, N: 9.28%. 1H-NMR (250 MHz, DMSO-d6, ppm): 8.93 (d, J = 7.4 Hz, 1H, quinH), 8.52 (d, J = 7.7 Hz, 1H, quinH), 8.41–8.23 (m, 2H, quinH), 8.23–8.08 (m, 1H, quinH), 8.04–7.83 (m, 1H, quinH), 4.29 (brs, 6H, NCH2N), 3.76 (brs, 6H, PCH2N). 13C-NMR (63 MHz, DMSO-d6, ppm): 194.59 (d, 2JC-P = 8.1 Hz, cis-carbonyl), 194.44 (d, 2JC-P = 8.1 Hz, cis-carbonyl), 189.62 (d, 2JC-P = 70.1 Hz, trans-carbonyl), 172.10 (s, quinCOO), 152.1, 146.57, 142.07, 133.05, 130.54, 129.80, 129.66, 127.77, 122.98 (9 C quinCOO), 71.38 (d, 3JC-P = 7.2 Hz, NCH2N), 48.52 (d, 1JP-C = 14.7 Hz, PCH2N). 31P-NMR (DMSO-d6, ppm): −71.65.

2.2.3. fac-[Re(CO)3(quin) (CAP)], 1b

Complex 1 (46.0 mg, 0.1 mmol) and CAP (21.9 mg, 0.11 mmol) were dissolved in MeOH (10 mL). The orange reaction mixture was refluxed for 2 h and evaporated to dryness under vacuum. Recrystallization from DCM/hexane afforded the product as an orange crystalline solid. Yield: 52% (35.0 mg). RP-HPLC: tR = 17.5 minutes; IR (cm−1): 2019, 1926, 1877, 1646 cm−1. Anal. Calc. for C22H24N4O5PRe: C: 41.18%, H: 3.77%, N: 8.73%. Found: C: 41.06%, H: 3.69%, N: 8.82%. 1H-NMR (500 MHz, DMSO-d6, ppm): 8.91 (d, J = 8.4 Hz, 1H, quinH), 8.60 (d, J = 8.80 Hz, 1H, quinH), 8.32 (d, J = 8.4 Hz, 1H, quinH), 8.28–8.24 (m, 1H, quinH), 8.21–8.16 (m, 1H, quinH), 7.98–7.92 (m, 1H, quinH), 3.15–2.99 (m, 6H, PCH2N), 2.96–2.80 (m, 6H, N(CH2)2N), 2.71–2.59 (m, 6H, N(CH2)2N). 13C-NMR (125.76 MHz, DMSO-d6, ppm): 195.76 (d, 2JC-P = 5.7 Hz, 2 x cis-carbonyls), 190.94 (d, 2JC-P = 58.3 Hz, trans-carbonyl), 172.06 (quinCOO), 152.21, 146.57, 141.84, 133.02, 130.30, 129.70, 129.64, 127.91, 122.79 (9C, quinCOO), 50.88 (N(CH2CH2)N), 50.77 (N(CH2CH2)N), 48.32 (d, 1JP-C = 8.5 Hz, PCH2N), 31P-NMR (DMSO-d6, ppm): 38.66.

2.2.4. fac-[Re(CO)3(pic) (H2O)], 2

Complex 2 was synthesized according to a published procedure [44]. Briefly, [NEt4]2[ReBr3CO3] (231 mg, 0.30 mmol) and picolinic acid (pic) (74 mg, 0.60 mmol) were dissolved in Η2Ο (15 mL) and the reaction mixture was stirred for 3 h at 70°C. After cooling to room temperature, the volume of the solvent was reduced to ∼3 mL and was placed in the fridge overnight. The yellow precipitate that formed was filtered, washed with cold H2O, and dried under vacuum. NMR data are in agreement with that reported in the literature. Yield: 68% (84 mg). RP-HPLC: tR = 14.9 min; IR (cm−1): 2024, 1895, 1874, 164; Anal. Calc. for C9H6NO6Re: C: 26.34%, H: 1.47%, N: 3.41%. Found: C: 26.26%, H: 1.36%, N: 3.38%.

2.2.5. fac-[Re(CO)3(pic) (PTA)], 2a

Complex 2 (30 mg, 0.07 mmol) and PTA (10 mg, 0.07 mmol) were dissolved in MeOH (7 mL) and the yellowish reaction mixture was refluxed for 2 h. The solvent was then removed under reduced pressure and the residue was recrystallized from DCM/hexane to afford 2a. Yield: 76% (32.0 mg). RP-HPLC: tR = 15.2 minutes. IR (cm−1): 2022, 1946, 1878, 1650. Anal. Calc. for C15H16N4O5PRe: C: 32.79%, H: 2.94%, N: 10.20%. Found: C: 32.65%, H: 3.02%, N: 10.16%. 1H-NMR (500 MHz, DMSO-d6, ppm): 8.81 (brs, 1H, picH), 8.34–8.25 (m, 1H, picH), 8.11 (d, J = 7.2 Hz, 1H, picH), 7.89–7.79 (m, 1H, picH), 4.42–4.28 (m, 6H, NCH2N), 3.84 (brs, 6H, PCH2N). 13C-NMR (125.76 MHz, ppm): 194.78 (d, 2JC-P = 7.6 Hz, cis-carbonyl), 193.94 (d, 2JC-P = 7.6 Hz, cis-carbonyl), 190.03 (d, 2JC-P = 70.8 Hz, trans-carbonyl), 170.87 (picCOO), 153.29, 140.80, 129.29, 126.94, 71.49 (d, 3JP-C = 6.7 Hz, NCH2N), 48.19 (d, 1JP-C = 14.4 Hz, PCH2N). 31P-NMR (DMSO-d6, ppm): −73.26.

2.2.6. fac-[Re(CO)3(pic) (CAP)], 2b

Complex 2 (41.0 mg, 0.10 mmol) and CAP (21.9 mg, 0.11 mmol) were dissolved in MeOH (10 mL). The yellow reaction mixture was refluxed for 2 h and the solvent was removed under reduced pressure to give 2b after recrystallization from DCM/hexane. Yield: 97% (59.0 mg). RP-HPLC: tR = 15.9 minutes. IR (cm−1): 2010, 1891, 1869, 1660. Anal. Calc. for C18H22N4O5PRe: C: 36.55%, H: 3.75%, N: 9.47%. Found: C: 36.47%, H: 3.62%, N: 9.53%. 1H-NMR (500 MHz, DMSO-d6, ppm): δ = 8.90 (brs, 1H, picH), 8.31–8.21 (m, 1H, picH), 8.13–8.05 (m, 1H, picH), 7.86–7.77 (m, 1H, picH), 3.22–3.11 (m, 6H, PCH2N), 3.00–2.89 (m, 6H, N(CH2)2N), 2.79–2.66 (br, 6H, N(CH2)2N). 13C-NMR (125.76 MHz, DMSO-d6, ppm): 196.13 (d, 2JC-P = 5.1 Hz, cis-carbonyl), 195.23 (d, 2JC-P = 5.1 Hz, cis-carbonyl), 191.38 (d, 2JC-P = 59.1 Hz, trans-carbonyl), 170.95 (picCOO), 153.57, 149.63, 140.62, 129.11, 126.76 (5C, picCOO), 51.03 (N(CH2CH2)N), 50.74 (N(CH2CH2)N), 47.94 (d, 1JC-P = 8.8 Hz, P(CH2)N). 31P-NMR (DMSO-d6, ppm): 37.21.

2.2.7. fac-[Re(CO)3(Et2SS) (PTA)], 3a

[NEt4]2[ReBr3CO3] (77.0 mg, 0.10 mmol), PTA (15.7 mg, 0.10 mmol), and sodium diethyldithiocarbamate trihydrate (Et2SS) (22.5 mg, 0.10 mmol) were dissolved in MeOH (4 mL). The reaction mixture was refluxed for 2 h and after cooling to room temperature, the solid that formed was filtered off, washed with cold MeOH, and dried under vacuum. Yield: 42% (25.0 mg). RP-HPLC: tR = 18.8 minutes. IR (cm−1): 2008, 1914, 1878. Anal. Calc. for C14H22N4O3PReS2: C: 29.21%, H: 3.85%, N: 9.73%. Found: C: 29.18%, H: 3.72%, N: 9.85%. 1H-NMR (250 MHz, ppm): 4.46 (s, 6H, NCH2N), 4.18 (s, 6H, PCH2N), 3.63 (m, 4H, NCH2CH3), 1.23 (t, 3J = 7.1 Hz, 6H, NCH2CH3). 13C-NMR (63 MHz, DMSO-d6, ppm): δ = 209.37 (d, 3JC-P = 2 Hz, S=C(S)N), 191.83 (d, 2JC-P = 8.2 Hz, 2 x cis-carbonyls), 190.26 (d, 2JC-P = 69.9 Hz, trans-carbonyl), 71.91 (d, 3JP-C = 6.5 Hz, NCH2N), 49.10 (d, 1JP-C = 16.3 Hz, PCH2N), 44.09 (NCH2CH3), 12.11 (NCH2CH3). 31P-NMR (DMSO-d6, ppm): −84.56.

2.2.8. fac-[Re(CO)3(Et2SS) (CAP)], 3b

[NEt4]2[ReBr3CO3] (77.0 mg, 0.10 mmol), CAP (21.9 mg, 0.11 mmol) and Et2SS (22.5 mg, 0.10 mmol) were dissolved in MeOH (4 mL). The reaction mixture was refluxed for 2 h at which time a yellow precipitate formed. The solid was filtered, washed with cold MeOH, and dried under vacuum. Yield: 45% (29 mg). RP-HPLC: tR = 19.9 minutes. IR (cm−1): 1998, 1898, 1858. Anal. Calc. for C17H28N4O3PReS2: C: 33.05%, H: 4.57%, N: 9.07%. Found: C: 33.16%, H: 4.49%, N: 9.16%. 1H-NMR (250 MHz, DMSO-d6, ppm): δ = 3.74–3.47 (m, 10H, NCH2CH3 overlapping with PCH2N), 3.14–2.96 (m, 6H, N(CH2)2N), 2.96–2.75 (m, 6H, N(CH2)2N), 1.20 (t, 3J = 7.1 Hz, 6H, NCH2CH3), 13C-NMR (63 MHz, DMSO-d6, ppm): δ = 209.06 (s, SSCN), 193.16 (d, 2JC-P = 6.7 Hz, 2 x cis-carbonyls), 191.23 (d, 2JC-P = 57.4 Hz, trans-carbonyl), 51.06 (s, N(CH2)2N), 48.88 (d, 1JP-C = 10.6 Hz, PCH2N), 43.94 (s, NCH2CH3), 12.25 (s, NCH2CH3). 31P-NMR (DMSO-d6, ppm): 29.17.

2.3. X-ray Crystal Structure Determination

A crystal of 1b (0.10 × 0.20 × 0.40 mm) and a crystal of 3a (0.08 × 0.18 × 0.41 mm) were mounted in air. A crystal of 2b (0.08 × 0.22 × 0.53 mm) and a crystal of 3b (0.05 × 0.21 × 0.26 mm) were taken from the mother liquor and immediately cooled to −113°C. Diffraction measurements were made on a Rigaku R-AXIS SPIDER Image Plate diffractometer using graphite monochromated Mo Kα radiation. Data collection (ω-scans) and processing (cell refinement, data reduction, and empirical absorption correction) were performed using the CrystalClear program package [45]. Important crystallographic data are listed in Table 1. The structures were solved by direct methods using SHELXS v.2013/1 and refined by full-matrix least-squares techniques on F2 with SHELXL ver.2014/6 [46, 47]. All hydrogen atoms were located either by difference maps and were refined isotropically or were introduced at the calculated positions as riding on bonded atoms. All non-hydrogen atoms were refined anisotropically. Plots of the structure were drawn using the Diamond 3 program package [48]. The CrystalExplorer package V.17.5 [49] was used for the Hirshfeld Surface (HS) analysis studies of 1b, 2b, 3a, and 3b. For the HS studies, the dnorm and shape decorated surfaces were used together with the fingerprint plots. dnorm is a normalized contact distance, defined in terms of de, di and the Van der Waals (VdW) radii of two atoms at a distance de outside from a point on the surface and at a distance di inside the surface correspondingly [50].

3. Results and Discussion

3.1. Synthesis of the Rhenium Complexes

The synthesis of the new complexes is depicted in Scheme 1 [NEt4]2[Re(CO)3Br3] was used as the rhenium starting synthon for all syntheses. Complexes 1a-1b and 2a-2b were synthesized via the mono-aqua complexes 1 and 2, respectively, formed by the reaction of [NEt4]2[Re(CO)3Br3] with the corresponding (N, O) ligand in water. The aqua Re complexes were then reacted with equimolar amounts of PTA or CAP in refluxing methanol to afford the final [2 + 1] complexes. However, complexes 3a-3b were synthesized more efficiently by a one-pot reaction in methanol, using equimolar amounts of the rhenium precursor, diethyldithiocarbamate, and the corresponding phosphine. Pure compounds were obtained in moderate to excellent yields (42% to 97%) and were characterized by elemental analysis, IR, and NMR-spectroscopy. Crystals suitable for X-ray crystallography were obtained by slow evaporation from DCM/hexane.

3.2. IR Characterization

The IR spectra of all rhenium complexes show the typical pattern for the tricarbonyl fac-[Re(CO)3]+ moiety with bands in the range of 2013–1870 cm−1 [51, 52]. The presence of the strong band at ∼1604–1642 cm−1 is attributed to the stretching of the carboxylate carbonyl shifted to a lower frequency compared to that of free quinaldic acid at 1695 cm−1 [53] and picolinic acid at 1720 cm−1.

3.3. NMR Characterization

The 1H, 13C, and 31P-NMR data obtained for the synthesized complexes are consistent with the proposed structures. Upon coordination of the bidentate and PTA/CAP ligands, characteristic shifts are prominent compared to its non-coordinated states. In the (N, O) complexes, downfield shifts of all aromatic protons of the picolinic and quinaldic acid moiety are noted, attributed to the loss of electron density after coordination of the N-aromatic nitrogen. Coordination of the carboxylate moiety is confirmed by the downfield shift of its carbonyl peak (e.g., 172.10 ppm for complex 1a compared to the corresponding peak of free quinaldic acid at 167.25 ppm).

The 1H-NMR peaks are generally broad indicating a degree of conformational mobility in the compounds and as such, no 1H-31P couplings can be seen for the coordinated phosphine ligands. Nevertheless, 13C-31P couplings are present both in the carbonyl peaks and the PTA/CAP carbons of the new complexes. The carbonyl at the trans-position to the phosphine ligands couples strongly with the P atom displaying a large coupling constant (e.g., 2JC-P = 70.1 Hz at 194.44 ppm for 1a) while a much smaller one is observed for the carbonyls at cis-position (e.g., 2JC-P = 8.1 Hz at 194.59 ppm for 1a) (Table 2), a fact that has been previously reported by us in similar systems [54] and others [55]. Interestingly, this 2JC-P coupling is stronger for the PTA complexes compared to the corresponding CAP complexes (e.g., 2JC-P (trans) = 58.3 Hz and 2JC-P (cis) = 5.7 Hz for 1b). In all PTA complexes, the carbons of the phosphine ligand display the expected 13C-31P couplings (1JC-P for PCH2N and 3JC-P for NCH2N) and appear as doublets. For the CAP complexes, 13C-31P couplings are observed only for the PCH2N carbon, while the NCH2CH2N carbons appear as two differentiated singlets in close proximity (for the N, O complexes) or as one singlet (for the S, S complex). This difference between the (N, O), and (S, S) complexes with CAP could be attributed to the larger degree of asymmetry due to the bulkier (N, O) ligand.

Finally, the 31P-NMR data of all PTA complexes (1a-3a) display significant downfield shifts compared to the free phosphine ligand due to loss of electron density from the P atom, providing proof of coordination of the phosphorus ligand to the fac-[Re(CO)3]+ metal centre (Table 2). The large difference between the 31P-NMR chemical shifts of uncoordinated PTA (−104.01 ppm) and CAP (+47.08 ppm) ligands suggest that these sterically similar phosphanes have substantially different electronic structures [10, 56]. This abnormal behavior is also reflected to the CAP derivatives 1b-3b. As shown in Table 2, their 31P resonances are displaced upfield which is unusual among phosphane ligands but is also observed for other CAP complexes [12]. All complexes reported herein show a single 31P peak demonstrating the absence of isomers, as expected.

3.4. Description of the Structures

The molecular structures of 1b and 2b are shown in Figure 1; selected bond distances and angles are listed in Table 3. Both complexes consist of the fac-[ReI(CO)3] moiety bound to one bidentate (N, O) chelate ligand and to the phosphorus atom of one CAP ligand. The (N, O) chelate ligand in 1b is the anion of quinaldic acid and in 2b is the anion of picolinic acid. The coordination geometry around the ReI ion is distorted octahedral in both 1b and 2b. There are two short Re-CO bond distances (∼1.90 Å) in 1b which are in the trans-position with respect to the (N, O) donor atoms of quinaldato ligand and one longer Re-CO distance at ∼1.94 Å which is in the trans-position to the Re-P bond. The Re-(N, O) bond distances are ∼2.24 and ∼2.14 Å, respectively. The Re-P bond distance is the longest in the coordination sphere (∼2.45 Å). The cis-angles in the coordination sphere are in the range ∼75–105° and the trans-angles are 170.84(12), 175.59(9), and 179.34(12)°. The five-membered ring in the coordination sphere, defined by Re-N-C-C-O, is almost planar with the largest deviation ∼0.11 Å for C(4). In 2b, there are two long Re-CO bond distances (∼1.94 Å), trans to the (N, O) donor atoms of picolinato ligand, and one shorter Re-CO distance at ∼1.88 Å which is trans to the Re-P bond. The Re-(N, O) bond distances are ∼2.22 and ∼2.18 Å, respectively, and the Re-P bond distance is the longest in the coordination sphere (∼2.39 Å). The cis-angles in the coordination sphere are in the range ∼73–101° and the trans-angles are 169.93(17), 174.01(18), and 178.77(16)°. The five-membered ring in the coordination sphere, defined by Re-N-C-C-O, is almost planar with the largest deviation ∼0.05 Å for C(4).

The molecular structures of 3a and 3b are shown in Figure 2; selected bond distances and angles are listed in Table 4. Both complexes consist of the fac-[ReI(CO)3] moiety which is bound to the (S, S) chelate bidentate ligand (diethyldithiocarbamate) and the phosphorus atom of one PTA or CAP ligand (3a or 3b). The coordination geometry around the ReI ion is distorted octahedral in both complexes. There are two short Re-CO bonds in both 3a and 3b with bond distances ∼1.91–1.92 Å which are in the trans-position with the two sulfur atoms of the diethyldithiocarbamate ligand. The longer Re-CO bond with length ∼2.44–2.46 Å is in the trans-position to the phosphorous atom of PTA or CAP. The two Re-S bonds are the longest in the coordination sphere ∼2.52 Å in both complexes. The cis-angles in the coordination sphere are in the range ∼69–102o and the trans-angles are in the range 170–179°. The four-membered ring in the coordination sphere, defined by Re-S-C-S atoms, is essentially planar in both complexes with the carbon atom lying ∼0.02 and ∼0.05 Å out of the best mean plane of the four atoms.

Comparing the Re-P bond length between the complexes synthesized, the following trends can be noted: (i) the Re-P bond length between PTA and CAP complexes that carry the same bidentate ligand (3a and 3b) does not differ significantly, i.e., 2.4375 for 3a and 2.4584 for 3b; (ii) the Re-P bond length of the PTA complex 3a is similar to other fac-[Re(CO)3(bid)PTA] complexes reported in the literature [6, 30]; and (iii) the Re-P bond length of all PTA and CAP complexes synthesized herein is consistently shorter compared to other fac-[Re(CO)3(bid)P] reported in the literature where P is a phosphine other than PTA and CAP, e.g., PPh3, P(Cy)3, P(Cy)2Ph [6, 30, 43] which is possibly attributed to the better σ-donating properties of PTA and CAP.

The intermolecular interactions in the structures of 1b, 2b, 3a, and 3b present interesting characteristics and their geometrical characteristics are listed in Table 5 for all structures. These interactions are also studied by using HS analysis tools. Figure 3(a) presents the intermolecular interactions observed in the structure of compound 1b among the complexes. In addition to commonly observed hydrogen bond, C-H⋯π (Figure 3, Table 5), and ππ interactions [the distance between neighboring centrosymmetrically related quinaldic ligands is 3.467(8) Å, symmetry code (v): −x, 1 − y, 1 − z, Figure 3], the lp(O)-π type interactions between carbonyls coordinated to transition metals [39, 57] are also observed. The C3≡O3 carbonyls are involved in antiparallel CO⋯CO interactions [57], C3⋯O3vi distance [=C3vi∙∙∙O3, symmetry code (vi): −x,−y, 1 − z] equals to 3.104(5)Å, which is less than the sum (=3.22 Å) of van der Waals(vdW) of C (=1.7 Å) and O (=1.52) atoms] and M-C∙∙∙CO type with the distance O5⋯C1i and the angle O5-C1i-O1i (symmetry code(i): x, 0.5−y, 0.5 + z) equal to 3.157(4) Å and 70.8(2)° which are close to the usual one [39]. Through these intermolecular interactions, a layer of complexes is formed parallel to the (100) crystallographic plane (Figure S1a). These layers are stacked parallel to [100] crystallographic direction interacting through C-H⋯π interactions (Table 5, Figure S1b). The fingerprint plot calculated from HS of complex 1b is presented in Figure 4(d) where the contribution of each type of intermolecular interactions is indicated. The percentage contribution of the different type of interactions H⋯H, O⋯H/H⋯O, C⋯H/H⋯C, C⋯O/O⋯C, O⋯O, C⋯C, N⋯H/H⋯N are 42.4, 30.3, 12.5, 5.2, 3.7, 2.9, and 2.9%, respectively. All types of interactions discussed above are also clearly seen on the dnorm HS representation (Figures 4(a) and 4(b)). On the Shape decorated HS, the characteristic blue and red triangles of ππ interactions and the complementary red (concave) and blue (convex) areas characteristic of C-H⋯π interactions are present (Figure 4(c)).

In the structure of compound 2b, an extensive network of intermolecular interactions is observed such as hydrogen bond and C-H⋯π type (Table 5, Figure 5). Layers of complexes are formed parallel to the (100) plane through the hydrogen bond C12-H12B⋯O2, C14-H14A⋯O5, C15-H15B⋯O5, C8-H8⋯O4 and C-H⋯π type of interactions, i.e., C13-H13⋯Cg2, C16-H16⋯Cg2 (Figure S2a, Table 5). C-H carbonyl type of interactions is also contributing in the formation of these layers (C8-H8⋯C1, Figure 5, S2a, Table 5). Neighboring layers are stacked along the a crystallographic axis interacting through hydrogen bond C6-H6⋯O5, C9-H9⋯O1 and C-H C-H∙∙∙π type of interactions, i.e., C16-H16∙∙∙Cg2 (Figure S2b, Table 5). The percentage contribution of H⋯H, O⋯H/H⋯O, C⋯H/H⋯C, N⋯H/H⋯N, O⋯O, C⋯O/O⋯C contacts, based on the fingerprint plot analysis (Figure 6(c)) are 32.9, 45.6, 14.0, 2.6, 2.2, and 1.9%, respectively and the contact points of the most characteristic interactions are indicated in dnorm decorated HS in Figure 6(a). C-H∙∙∙π interactions reveal their presence in the characteristic complementary red (concave) and blue (convex) areas on the HS decorated with Shape property (Figure 6(b)).

In the structure of 3a, layers of complexes are formed parallel to the (001) plane through hydrogen bond interactions (Figure S3, Table 5). These layers are stacked along the c crystallographic axis (Figure 7) and complexes belonging to neighboring layers interact through antiparallel CO⋯CO interactions, where the C3≡O3 carbonyls are involved (C3⋯O3 distance is equal to 3.180(4)Å). The percentage contribution of H⋯H, O⋯H/H⋯O, S⋯H/H⋯S, N⋯H/H⋯N, C⋯H/H⋯C, C⋯O/O⋯C, C⋯S/S⋯C, O⋯S/S⋯O contacts derived from fingerprint plot analysis (Figure 8(b)) are 38.0, 31.5, 8.6, 7.8, 7.1, 2.3, 1.4, and 1.0%, respectively. The most intense interactions, i.e., C9-H9A∙∙∙N4, C9-H9AB∙∙N3 and C13-H13A∙∙∙O1 appear on the dnorm decorated HS in Figure 8(a).

In the case of 3b, complexes interacting through the C8-H8A⋯O2 and C5-H5A⋯S2 hydrogen bonds (Table 5) form layers parallel to the plane (010) (Figure S4) and through the C6-H6B⋯N2 interactions of complexes belonging to neighboring layers stacked along the b axis, the 3D architecture of the structure is built (Figure 9). The percentage contribution of H⋯H, O⋯H/H⋯O, C⋯H/H⋯C, S⋯H/H⋯S, N⋯H/H⋯N contacts derived from fingerprint plot analysis (Figure 10(b)) are 49.2, 29.7, 7.7, 7.0, and 2.5, respectively. Each one of C⋯O/O⋯C, C⋯S/S⋯C, O⋯S/S⋯O type of contacts contributes less than 1%. The most intense interactions, i.e., C8-H8A⋯O2, C5-H5A⋯S2 and C6-H6B⋯N2 appear on the dnorm decorated HS in Figure 10(a), and as spikes in the fingerprint plot (Figure 10(b)).

4. Conclusions

In this work, the coordination chemistry of rhenium with the hydrophilic monodentate phosphines PTA and CAP was explored by synthesizing and characterizing a series of novel [2 + 1] mixed-ligand fac-[Re(CO)3(bid) (X)] complexes. Both PTA and CAP serve the role of the polar and hydrophilic modifier aiming to develop a new platform of hydrophilic fac-[Re(CO3] complexes with favorable pharmacokinetics. The detailed crystal structure studies using the Hirshfeld surface analysis tools have revealed that the C-H⋯O type of intermolecular interactions has the largest contribution in the packing of complexes. In the case of 1b, ππ are one type of the characteristic intermolecular interactions that contribute to the packing of complexes and for the rest are the C-H⋯π. In all structures, the PTA and CAP ligands are coordinated through the P atom with Re and the observation of N⋅⋅⋅H type of interactions in all studied structures reveals the potential of these three nitrogen atoms to develop hydrogen bonds with their environment and thus to impact the pharmacokinetic behavior of these compounds. In the case of 1b and 3b, carbonyl-carbonyl intermolecular interactions are observed among the complexes, which is a type of interaction which recently is discussed as a potential path which could impact the biological and physical properties of these compounds.

This system could potentially be applied in (radio) pharmaceutical design to develop complexes with suitable properties for diagnosis (99mTc), radiotherapy (186/188Re), and chemotherapy (185/187Re) by tethering a biologically active molecule either to the bidentate or the phosphine ligand. The transfer of the coordination chemistry at the 99mTc level, the evaluation of the hydrophilicity of the corresponding complexes, and the investigation of its in vivo performance are currently in progress.

Data Availability

Crystallographic data for the structures reported in this manuscript have been deposited with the Cambridge Crystallographic Data Centre under the CCDC numbers: 2152941 (compound 1b), 2152938 (compound 2b), 2152939 (compound 3a), and 2152940 (compound 3b). Copies of these data can be obtained free of charge from https://www.ccdc.cam.ac.uk/data_request/cif.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


This research was cofinanced by Greece and the European Union (European Social Fund-ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning 2014–2020» in the context of the project “Targeting the kynurenine pathway for tumor imaging and characterization by single photon emission computed tomography (SPECT) and positron emission tomography (PET)” (MIS 5047830). The authors thank Dr. Maria Pelecanou for helpful discussions and advice regarding NMR characterization.

Supplementary Materials

Figure S1: Intermolecular interactions in the structure of compound 1b forming (a) layers of complexes parallel to the crystallographic plane (100) and (b) Stacks of layers along the a crystallographic axis. Figure S2: (a) Intermolecular interactions among neighboring clusters forming layers of complexes arranged parallel to the crystallographic plane (100), and (b) stacking of layers along the a crystallographic axis in the structure of compound 2b through hydrogen bond, C-H∙∙∙π type, and carbonyl interactions. Figure S3: Layers of complexes arranged parallel to the crystallographic plane (001) in the structure of compound 3a through hydrogen bond interactions. Figure S4: Layers of complexes arranged parallel to the crystallographic plane (010) in the structure of compound 3b. (Supplementary Materials)