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. 2023 Jan 30;62(6):2680–2693. doi: 10.1021/acs.inorgchem.2c03737

Chiral Co3Y Propeller-Shaped Chemosensory Platforms Based on 19F-NMR

Gabrielle Audsley †, Harry Carpenter †, Nsikak B Essien †, James Lai-Morrice †, Youssra Al-Hilaly ‡,⊥, Louise C Serpell ‡, Geoffrey R Akien §, Graham J Tizzard ∥, Simon J Coles ∥, Cristina Pubill Ulldemolins †,*, George E Kostakis †,*
PMCID: PMC9930122  PMID: 36716401

Abstract

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Two propeller-shaped chiral CoIII3YIII complexes built from fluorinated ligands are synthesized and characterized by single-crystal X-ray diffraction (SXRD), IR, UV–vis, circular dichroism (CD), elemental analysis, thermogravimetric analysis (TGA), electron spray ionization mass spectroscopy (ESI-MS), and NMR (1H, 13C, and 19F). This work explores the sensing and discrimination abilities of these complexes, thus providing an innovative sensing method using a 19F NMR chemosensory system and opening new directions in 3d/4f chemistry. Control experiments and theoretical studies shed light on the sensing mechanism, while the scope and limitations of this method are discussed and presented.

Short abstract

This work explores the sensing and discrimination abilities of propeller-shaped chiral CoIII3YIII complexes built from fluorinated ligands, thus providing an innovative sensing method using a 19F NMR chemosensory system and opening new directions in 3d/4f chemistry. Control experiments and theoretical studies shed light on the sensing mechanism, while the scope and limitations of this method are discussed and presented.

Introduction

The detection and differentiation of chiral enantiomers are important in synthetic and pharmaceutical chemistry, but they can prove challenging.1−6 Two enantiomers may possess different chemical and physical properties; thus, misidentifying their configuration can jeopardize biological and pharmacological activities. For example, the stereochemistry of drugs can significantly affect their activity due to the inherent chirality found in the environments of biological systems. New biologically active chiral compounds are ever-increasing, where approximately 60% of all pharmaceutical drugs are chiral. Developments into asymmetric synthesis routes have stemmed from this increase in the production of chiral compounds; however, a complete stereochemical analysis including the absolute configuration, enantiomeric excess (ee), and total concentration has limited the discovery process.

Conventional high-performance liquid chromatography (HPLC) separates the enantiomers, which are subsequently stereochemically analyzed. The HPLC technique involves a chiral column packed with a chiral stationary phase where enantiomers can be separated. Chiral additives can also be added to the mobile phase to separate enantiomers or form diastereomers beforehand; however, the extensive cost of these chiral columns is a limiting factor for scientific developments. Therefore, the discovery of other ease methods is in need.

The stereochemical discrimination can occur using spectroscopic methods, including circular dichroism (CD) and fluorescence,7−12 by monitoring absorbance intensity change and NMR, presenting chemically shifted signals for different chiral molecules or complexes.13−16 For the latter, a host–guest complex consisting of a chiral substrate sample interacts with a chiral detector molecule, transferring chiral information and inducing a change in the chiral environment, observed as split signals of precise chemical shifts in the corresponding NMR spectrum. NMR chemosensors for chiral discrimination are typically limited to aromatic-based compounds, facilitating signal splitting by inducing a significant shielding effect. 1H NMR dominates the differentiation of organic or biologically relevant molecules, but an increase in the size of these molecules and structural complexity leads to overlapping resonances on an already narrow spectral range, thus making discrimination impossible. Known 1H NMR analytical methods for chiral determination include the addition of chiral solvating agents (CSAs),17−19 chiral lanthanide shift reagents (CLSRs),20 and chiral derivatizing agents (CDAs).21 For example, Pirkle’s alcohol22 determines the absolute configuration and enantiomeric purity of chiral molecules. Although Pirkle’s alcohol is still regularly used to analyze chiral molecules, issues have arisen related to the inaccurate determination of ee due to resonance overlap present in the 1H NMR spectra—a result of a narrow spectral width accompanied by the complicated spectra that arise with large organic compounds.

Hence, the development of heteronuclear-based sensors represents a reasonable alternative to overcome these hindrances. Methods incorporating molecules that bear phosphorous atoms are developed to monitor changes with 31P{1H} NMR due to observable splitting of signals and a broad spectral range compared to 1H NMR spectra.15,23 Moreover, the 19F nucleus of spin quantum number 1/2 has 83% the sensitivity of the 1H nucleus and is found in 100% natural abundance; with great receptivity, it yields strong signals on an NMR spectrum.24−3119F can also be easily incorporated into organic compounds as it mimics the 1H nucleus in many environments and benefits from a lack of background interference due to its low natural occurrence;32,33 thus, it can be used to probe the structure and dynamics of many large and complex biomolecules such as proteins.34 The broad detection window of 19F NMR is conducive to easily distinguishable split signals and narrow overlapping resonances, increasing spectral resolution and providing the simpler deconvolution of complicated spectra. In 2015, Zhao and Swager35 presented a 19F chemosensory method to detect multiple chiral amines. The sensing strategy consisted of a palladium complex built from a chiral pincer ligand, of which the scaffold is facile in preparation alongside having well-known coordination chemistry (Scheme 1, upper).36,37 When varying the substituent R groups of the ligand, the authors envisioned an optimized design by moving the fluorine atoms closer to the analyte, confining the chiral pocket. This change successfully demonstrated more pronounced differences in the chemical shifts of the analytes, allowing for more time-efficient detection with improved resolution. In addition to the assignment of absolute configuration, integrating these 19F NMR spectra gave values in agreement with the actual enantiopurities of the chosen analytes. Following Zhao and Swager’s work, Song et al. designed a chiral sensor based on octahedral rhodium complexes containing fluorine (Scheme 1, middle).38 The advantage of this complex is its two-coordinating site, which permits the sensing of monoamines, diamines, and amino acids. The scaffold was previously used as a successful chiral catalyst in asymmetric catalytic reactions.39,40 Screening tests identified DMSO-d6 as the optimum solvent, presenting a broader chemical shift difference of 0.21 ppm..

Scheme 1. Previous and Current Complexes Used for Amine Sensing with 19F NMR.

Scheme 1

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Complexes formed from organic ligands, transition metal (3d) ions, and/or lanthanide (4f) ions constitute a large class of materials esteemed for their wide range of properties, including luminescence,41−43 magnetism,44−47 and catalysis.48−55 Synthetic-wise, in 3d–4f chemistry, the 3d or 4f metal ions can be targeted and selectively substituted by 3d or 4f ions with similar coordination properties, often without altering the topology of the core. This synthetic alteration has been found in numerous 4f–4f ion and 3d–3d ion substitutions56−60 but is proven difficult for the 4f–4f ion exchange due to the lanthanide contraction. The simultaneous presence of 3d and 4f elements in a single molecule represents an elegant advantage for studying mechanisms and rationalizing experimental data. For example, YIII can be included in this category because it has a size and Lewis acidity similar to HoIII and its diamagnetic character permits monitoring with NMR (1H, 13C, 15N, 19F, or 89Y). It may also be possible to exchange 3d ions in the same oxidation state without distorting the core topology and permitting monitoring with UV–vis, EPR, or NMR. Similarly, the 4f entity may be replaced with GdIII (8S7/2 ground state) so that electron paramagnetic resonance can identify changes in the coordination environment within the complex; this is a process that we have successfully demonstrated in the past.48,51

Recently, we identified the Lewis acidic catalytic efficacy of two chiral propeller-shaped [CoIII3YIIIL6] complexes built from a known Schiff base ligand; other groups investigated the magnetic properties of these components.61−67 These two compounds retain their structure and chirality in solvent media for a prolonged period, over 6 months. The Y metal sits in the center with the CoIII centers and associated pairs of organic ligands forming the propeller wings. Each CoIII center sits in the center of an almost perfect octahedron, while the central YIII center bonds to six O atoms in a trigonal antiprismatic geometry. Given (a) the high ionic radii of 4f ions, thus being difficult to control their ligand exchange with solvent substrates, (b) that amines are known to coordinate to lanthanide metal centers in organic media,68,69 (c) that the coordination geometry of the Co centers is fulfilled, and (d) that the 4f ion is captured in a trigonal antiprism, which limits access to solvent-substrate molecules only via axial sites, thus replicating the coordination sphere of the non-labile Pd and Rh examples,35,38 we envisioned these propeller-shaped molecules as an ideal platform for limited ligand exchange with the solvent-lattice systems. Moreover, the development of 19F-NMR chemosensors relies on modifying already well-understood species; thus, we embarked on a project modifying the ligand used in our previous studies67 by adding a fluorine antenna on the organic scaffold to assemble a 3d–4f entity that can serve as a chiral 19F-NMR chemosensory platform. 19F NMR can then be used to monitor the sensing ability of the system, boasting a broad spectral range and avoidance of complicated and overlapping resonances, the key to efficiency, simplicity, and rapidity with a chiral detection method. The scope and limitations of our approach are discussed herein.

Results and Discussion

Ligand and Complex Synthesis

The ligands (H2LR, H2LS and its racemic version H2L, see Table S1) can be synthesized in one high-yielding condensation reaction from commercial fluorinated salicylaldehyde and the corresponding amino alcohol (see the ESI). These ligands have never been used in coordination chemistry to our knowledge. Following our synthetic protocol, the assembly of the ligands with nitrate or chloride CoII/YIII salts in CH3CN or EtOH solvent media and the presence of triethylamine would harvest the tetranuclear propeller-shaped entity; however, screening tests (Table S1) were carried out to optimize the synthetic procedure and obtain the targeted complexes in high purity. Both protic and aprotic, polar, and non-polar solvents were screened as the ligand can form a hydrogen bond, and it was unclear whether or not this would benefit or disadvantage the crystallization process. X-ray-quality crystals were only grown in EtOH, MeOH, and MeCN. Preliminary crystallographic characterization studies (see the ESI) identified that EtOH was not to be the solvent of choice; an additional non-coordinating ligand can be found in the lattice along with the expected tetranuclear targeted species{[CoIII3YIIIL6][H2L]·x(EtOH)}. MeOH and MeCN produced single crystals of [CoIII3YIIIL6]·x(MeOH) and [CoIII3YIIIL6]·x(MeCN), respectively, but comparatively, MeCN produced a higher yield and higher-purity crystals and additionally presented the same crystal product for both S and R enantiomers when using the chloride salts of both yttrium and cobalt sources. Then, the synthesis was repeated with nitrate salts of yttrium and cobalt instead of the chloride, and these reactions gave the highest yields. Last but not least, reactions at higher concentrations proved to be less efficient.

Single X-ray Diffraction Characterization

Both compounds CR and CS crystallized from acetonitrile were characterized at the NCS UK facility. Both crystals diffract poorly at higher angles; therefore, an exact allocation of the lattice solvent molecules proves challenging, but a co-crystallized ligand, as was the case in the EtOH samples, cannot be identified. Both compounds are isostructural and possess a general formula [CoIII3YIIIL6]·x(MeCN), but the lattice acetonitrile molecules slightly deviate (x is 5.5 for R (CR) and 5.25 for S (CS), respectively). The relevant crystallographic tables, including crystal data, structure refinement, and bond lengths, are found in the Supplementary Material. Both compounds provide the targeted propeller-shaped structure in which the YIII center sits in the middle of a trigonal antiprism (Figure 1). The propeller itself is chiral, and this motif has been seen in other tetranuclear complexes and molecular compounds.66,70−78 Notably, in both compounds, the Flack parameter, an indication of chirality retention,79,80 deviates from the typical values. This notion indicates that the racemization process may occur during crystallization (13 and 21% for CR and CS, respectively), as the crystals are formed and collected after 1 week. This racemization process may be an outcome of the ligands or the propeller shape,73 reversing their chirality. We collected better-quality data for the CR derivative using a Cu source to validate this notion further (Table S3). The analysis provides a Flack parameter of 7%, which is very close to 5% of the enantiomerically pure Fe4 compound,75 indicating that the enantiomeric purity of both CR and CS is of good levels. Given that in both cases (CR and CS), racemization is unavoidable under the current synthetic circumstances and the results presented in the following sections, we did not attempt to validate the Flack parameter of CS.

Figure 1.

Figure 1

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X-ray structures of CR (upper) and CS (lower). Lattice (CH3CN) molecules and H atoms are omitted for clarity. Color code: Y (light blue), Co (pink), C (gray), N (blue), O (red), F (green).

NMR Characterization

As CS and CR are diamagnetic, retrieving 1H NMR without complications was possible. Comparing the 1H NMR spectra of both S- and R-derivatives of H2L and C, there is a clear upfield shift of the imine protons on the transformation of ligand to complex (Figure S2), consistent with a lesser deshielding effect present from the nitrogen now coordinating to cobalt with electronegativity drawn further away from the imine carbon. The C–H proton on the adjacent C to the N has shifted downfield, indicating an increase in shielding due to cobalt coordination. Additionally, the OH peak is lost due to ligand-to-metal coordination.7

The 19F NMR spectra (Figure S3) of both S- and R-derivatives of H2L and C also demonstrated a change in the chemical shift of the resultant resonance, confirming the formation of a new species. Notably, both the 1H and 19F NMR spectra of each pair of derivatives overlay, thus demonstrating an identical chemical shift pattern.

CD

CD is a light absorption spectroscopy that “quantifies” chirality by measuring the differential absorption of optically active molecules in left- and right-handed circularly polarized light; thus, it is possible to investigate the structural features of optically active chiral molecules. CD measurements of enantiomers should be inequivalent but opposite. The spectra of both pairs of H2L and C in solution, acetonitrile 1 mM, confirmed active optical species, demonstrating opposite rotation (Figure 2). However, minor differences in the spectra (i.e., minima and maxima at 285, 310, 410 nm for CS) may be attributed to the racemization process of the propeller or the ligands, evidenced by the Flack parameter (see above).

Figure 2.

Figure 2

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Circular dichroism spectra of H2LS versus H2LR (upper); CS versus CR (lower).

Thermogravimetric Analysis

We conducted a thermogravimetric analysis (under a N2 atmosphere) of both compounds. Both complexes are thermally stable up to 220 °C (Figure S4). The initial weight loss (∼8%, 100 °C) corresponds to lattice CH3CN and possibly absorbed H2O molecules. Above 220 °C, a three-step decomposition is taking place. Taking into account the molecular formula of the crystal structure {CS 5.33 (CH3CN)} and that the anticipated theoretical value of [CoIII3YIIIO6] is 18.72%, we envisage that decomposition completes possibly beyond 1000 °C.

Titration Studies

The exploration of new 19F NMR chemosensory systems relies on repurposing already known systems;35,38 thus, our initial aim was to introduce a broad scope of chiral analytes used in previously known sensing procedures35,38 and assess the sensing ability of CS and CR. To reiterate how the 19F NMR chemosensor works, introducing an analyte to the sensing system induces a change in the environment of the complex, forming a new complex {CS + A}, which will be subsequently recognized as a new, second signal in the 19F NMR spectra. The type of sensor–analyte interaction, covalent bond, hydrogen bond, or aromatic interactions is unclear until further evidence is obtained. From previous works, amines are known to coordinate to lanthanide metal centers68 as well as the recent chiral sensing studies.15,35,38 It is suggestive that the amines will coordinate with the YIII center; however, due to the nature of the ligand with O and NH moieties, hydrogen bonding interactions between the complex and the analyte cannot be excluded.

We used a range of chiral and non-chiral analytes. Preliminary titration tests were performed to standardize the process. Stock solutions of both enantiomers of the analytes were prepared in the following concentrations: 1, 2, 10, and 20 mM, following known protocols.35,38 Each concentration was trialed to decipher optimum reacting conditions—looking for intensity of signals and the chemical shift difference between enantiomeric pairs in the corresponding 19F NMR spectra. 1 mM stock solutions of both CS and CR were prepared in 10 mL CDCl3, and 350 μL of A1 with each complex derivative (in all possible combinations) was then added directly to an NMR tube and recorded instantaneously.

Preliminary testing began with investigating the stability of CS and CR in both CDCl3 and CD3OD, looking for any degradation or change in the spectrum over some time (Tables S5 and S6). Both solvents had been favored in previous works35,38 with their use dependent on the dissolving analyte—whether they required a protic or an aprotic environment. As demonstrated in Tables S5 and S6, there was no change in the 19F NMR spectra of either complex; however, a slight shift of the principal peak −130.06 ppm (CDCl3) over −131.22 ppm (CD3OD) is observed. Notably, 19F NMR spectra recorded after 1 week or month proved complex stability, representing a significant advantage to this sensing method; thus, stock solutions can be prepared and stored. In CD3OD, a coordinating solvent, an additional peak was found at approximately −139 ppm, which may correspond to {C-(CD3OD)x}, where x = 1 or 2 species.

We then used CS to detect A1 in 64 scans, which requires approximately 2 min of running time in CDCl3 and at 30 °C (Table 1). Initial efforts of 1:1 and 1:2 ratios, as seen to be most successful in previous studies,35,38 did not present a split signal; therefore, increasing the amine loading was necessary. In fact, this was found to be an advantage as an analyte signal was achievable using less complex. Both the 1:10 and 1:20 ratios demonstrated amine peaks, but the chemical shift difference between enantiomeric pairs for 1:20 was broader, allowing for more direct discrimination and boasting the advantage of requiring less complex. Therefore, we chose to use the ratio 1:20 for further experimental studies. Then, we examined if additional scans (128 vs 64) shall improve the sensing performance and incorporate compound CR (Table S6). A 20 mM concentration of A1 (in all possible combinations) in CDCl3 at 30 °C with CS and CR was run for 128 scans (Table S7). CS allowed for better chiral discrimination with a broader enantiomeric difference in chemical shift compared to CR. However, as the chemical shift differences were not too dissimilar, 64 scans were deemed more efficient at half the running time. Repeats were then undertaken using A1, but changing the solvent system from CDCl3 to CD3OD; however, no analyte response can be detected at T = 0 (Table S8). An analyte peak appeared at T = 96 h, suggesting that CD3OD can be used for the detection studies but not with an immediate effect.

Table 1. 19F NMR Spectra Using a Different Sensor (1 mM, CDCl3): Amine Ratios (1:1, 1:2, 1:10, 1:20, CDCl3) (T = 303 K).

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After discovering that the sensor can work at large amine-to-complex ratios, the ratio was increased from 1:20 to 1:50 to explore how far this factor may be extended (Table S9). The resulting 19F NMR spectra confirmed the sensing of the A1 analyte. However, the signals were slightly less prominent than with the 1:20 ratio; the chemical shift differences improved by approximately 0.1 ppm in comparison. These enantiomeric differences were better than or comparable to previous works of chiral sensing using 19F sensors,35,38 thus making this complex a competitor against current well-defined metal complex sensors. This notion may suggest that a sensor:amine ratio of 1:50 allows for more rapid discrimination of further analytes.

Analyte Scope and Limitations

After achieving successful results for the sensing of A1, further analytes were introduced (Scheme 2). No additional analyte peak was present for compounds A2, A3 (monoamines), and A4 (diol). Then, we incorporated other amino alcohols (A5–A8) and amino acids (A9–A12) with the same 1,2-amino alcohol backbone compared to A1. For the amino acids, we used CD3OD instead of CDCl3 and NaOMe for dissolving purposes, as demonstrated in previous studies.38 Amino alcohols A5–A7 were successfully sensed but required different ratios (1:100, 1:50, and 1:20, respectively, Table 2), as in some instances, the amine signal was not intense enough to account for a resolved signal.

Scheme 2. The Type of Analytes Tested in This Work.

Scheme 2

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Table 2. 19F NMR Spectra of Complex (1 mM, CDCl3) and different Amino Alcohols (xx mM, CDCl3, T = 303 K)a.

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complex analyte ratio time (h) complex peak complex + analyte peak difference
CS A5 1:100 0 –129.98 –132.22  
CR A5 1:100 0 –129.98 –132.06  
CS A6S 1:50 0 –129.98 –132.72 0.10
CS A6R 1:50 0 –129.98 –132.62
CR A6S 1:50 0 –129.98 –132.65 0.09
CR A6R 1:50 0 –129.98 –132.56
CS A7 1:20 0 –129.98 –132.70  
CR A7 1:20 0 –129.98 –132.72  
CR A8 1:20 0 –129.98 no peak  
CS A8 1:20 0 –129.98 no peak  
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a

The corresponding 19F NMR spectra are given in the order of the table. Data for A8 are omitted for clarity.

All amino acids (A9–A12, Table 3) were sensed successfully using a 1:50 ratio. Both complexes at 0 h are stable when an excess of amino acid is added. The sensed amino alcohol and amino acid analytes (19F NMR spectra found in Tables S10 and S11) were both chiral and non-chiral species. While the chiral species demonstrated how C can successfully sense and discriminate between the S- and R-configurations of each analyte by a chemical shift difference, the non-chiral species (A5 and A12) were introduced to assess the sensing ability of this complex concerning molecular recognition. A split signal correspondent of a non-chiral species introduces a further use for these complexes and chiral discrimination, which is the sensing of species that do not require chiral discrimination by their configurational derivative or induce changes in the chiral environment. For example, this can be developed to detect and recognize specific organic or biological molecules. A8 was not sensed, implying that the five-membered ring holding the 1,2-amino alcohol motif sterically hinders the ability of the motif to approach, and thus interact with, the sensor. To overcome this obstacle, we attempted to obtain the corresponding propeller-shaped structure (Scheme 3), replacing the bulky phenyl ring with a methyl group. Large red block-shaped crystals were instantaneously formed, almost quantitively; however, preliminary and sole single X-ray diffraction characterization (Figure S6) identified the formation of the neutral CoIII species, as shown in Scheme 3. Future efforts will optimize the reaction conditions to obtain the targeted propeller-based structure.

Table 3. 19F NMR Spectra of Complex (1 mM, CD3OD) and Different Amino Acids (50 mM, CD3OD)a.

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complex amine ratio solvent complex peak complex + analyte peak complex + solvent upfield peak enantiomer difference
CS     CD3OD –131.23   –138.99  
CR     CD3OD –131.23   –138.99  
CS A9D 1:50 CD3OD –131.23   –139.28  
CS A9L 1:50 CD3OD –131.23   –139.28  
CS A9D/L 1:50 CD3OD –131.23   –139.28  
CR A9D 1:50 CD3OD –131.23 –134.69 –139.28 0.03
CR A9L 1:50 CD3OD –131.23 –134.66 –139.28
CR A9D/L 1:50 CD3OD –131.23 –134.62 –139.28  
CS A10D 1:50 CD3OD –131.23 –135.13 –138.99 0.03
CS A10L 1:50 CD3OD –131.23 –135.16 –138.99
CS A10D/L 1:50 CD3OD –131.23 –135.07 –138.99  
CR A10D 1:50 CD3OD –131.23 –135.09 –138.99 0.22
CR A10L 1:50 CD3OD –131.23 –135.31 –138.99
CR A10D/L 1:50 CD3OD –131.23 –135.09 –138.99  
CS A11D 1:50 CD3OD –131.23 –135.29 –138.99 0.00
CS A11L 1:50 CD3OD –131.23 –135.29 –138.99
CS A11D/L 1:50 CD3OD –131.23 –135.24 –138.99  
CR A11D 1:50 CD3OD –131.23 –135.29 –138.99 0.00
CR A11L 1:50 CD3OD –131.23 –135.29 –138.99
CR A11D/L 1:50 CD3OD –131.23 –135.27 –138.99  
CS A12 1:50 CD3OD –131.23 –135.31 –138.99  
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a

The corresponding 19F NMR spectra are given in the order of the table (T = 303 K).

Scheme 3. The Anticipated and Obtained Species Following the Synthetic Recipe Described in This Work.

Scheme 3

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Plausible Sensing Mechanisms

Recognition of chiral and non-chiral analytes makes the mechanism for this complex–analyte interaction interesting. The 1,2-amino alcohol motif must be present on the analyte for sensing to occur. Further, it is unclear whether the split signal is representative of an induced change in the chiral environment affecting the inherent chirality of the [CoIII3YIIIL6] by coordination to the central YIII or instead supports the notion that a ligand exchange interaction facilitates this additional peak or a weak H-bonding interaction occurs, as shown in Scheme 4. In the first case (A, Scheme 4), the resultant mono-adduct holds a capped trigonal antiprism geometry and would correspond to a split signal in the 19F NMR spectrum, differentiating from the original peak. As YIII tends to favor a coordination number of 7 or 8, coordination of a further analyte to the YIII metal center from the remaining plane cannot be excluded and would correspond to a bis-adduct. Here, the geometry becomes bicapped trigonal antiprismatic and would correspond to an additional signal in the 19F NMR spectrum. It is relevant to reiterate the additional signal that accompanied the C peak in CD3OD (see Table 3 and S6) at approximately −139 ppm. Coordination of CD3OD to the YIII metal center can form {CoIII3YIIIL6(CD3OD)x} (x = 1 or 2) and, with the further introduction of an analyte, would observe three individual peaks corresponding to {CoIII3YIIIL6}, {CoIII3YIIIL6(analyte)}, and {CoIII3YIIIL6 (CD3OD)x}, similar to Table 4. In the second and third scenarios (B and C, Scheme 4), given that all analytes bear the same 1,2-amino alcohol motif, the additional signal found in the 19F NMR spectrum can be the result of a partial (B) or full (C) ligand exchange process that yields the formation of a new compound {CoIII3YIIIL5L′}, as this has been proposed in a previous work.38 Last but not least, numerous weak hydrogen bonding interactions between the complex and the analyte can occur in the solutions (a representative example, D, is drawn), which may cause the appearance of a second peak in the 19F NMR spectrum.

Scheme 4. Plausible Sensing Mechanisms.

Scheme 4

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Table 4. Computed 19F NMR Chemical Shifts for the Resulting {CoIII3YIIIL6(Analyte)x} Complexes According to the Mechanisms in Scheme 4 and Comparison to the Reported Experimental NMR Values in This Work.

  complex with analyte mechanism solvent experimental 19F NMR shift (ppm) computed 19F NMR shift (ppm)a,b agreement (%)
1 complex only (Co3YL6) none MeOD –131.23 –130.30 99.3%
2 complex onlyc (Co3YL6) none MeOD –131.23 –133.32 98.4%
3 A1R partial ligand exchange CDCl3 –132.05 –129.99 >99.9%
4 A1S partial ligand exchange CDCl3 –132.12 –130.43 98.7%
5 A1Sc partial ligand exchange CDCl3 –132.12 –127.81 96.7%
6 A6R partial ligand exchange CDCl3 –132.72 –130.45 98.4%
7 A6S partial ligand exchange CDCl3 –132.62 –130.64 98.4%
8 A6Sc partial ligand exchange CDCl3 –132.62 –127.92 97.6%
9 A9R partial ligand exchange MeOD –134.66 –129.29 96%
10 A9S partial ligand exchange MeOD –134.69 –129.64 96.2%
11 A1R 6× partial ligand exchanged CDCl3 –132.05 –129.11 99.3%
12 A1S 6× partial ligand exchange CDCl3 –132.12 –130.43 98.7%
13 A6R 6× partial ligand exchange CDCl3 –132.72 –130.64 98.5%
14 A6S 6× partial ligand exchange CDCl3 –132.62 –131.64 99.2%
15 A1R ligand substitution CDCl3 –132.05 –131.25 99.1%
16 A1S ligand substitution CDCl3 –132.12 –131.11 99.2%
17 A6R ligand substitution CDCl3 –132.72 –131.38 99.1%
18 A6S ligand substitution CDCl3 –132.62 –131.30 98.9%
19 A9R ligand substitution MeOD –134.66 –129.21 96%
20 A9S ligand substitution MeOD –134.69 –129.36 92/9%
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a

Calculations were performed at the B3LYP/SDD level of theory with the polarizable continuum model (PCM) as the implicit solvent model.

b

Fluorobenzene (C6H5F) was used as the 19F NMR reference calculated at the same level of theory.

c

This calculation was performed at the M06/Def2-TZVP level.

d

Saturated system with six ligands partially exchanged.

Control Experiments and Theoretical Studies

We performed computational calculations; recorded 1H, 89Y, and additional 19F NMR data; and used other analytes to probe the mechanistic path.

Initially, we performed 1H-decoupled 19F NMR experiments to validate the shape and nature of the observed peaks (Figure 3A). The data were recorded with the same number of scans, and the samples had the same concentration. In the decoupled spectrum, the multiplet peak of the complex appears as single with the same intensity; however, the “analyte+complex” peak retains its broad character, indicative of a chemical exchange and several types of interactions. Using the chiral analytes containing the N–N motif such as SS or RR diphenylethylenediamine in the 1:20 ratio (Figure 3B) provided a second peak at −139.08 ppm. These data were recorded with the inevitable use of coordinating d6-DMSO solvent for solubility purposes. Comparing the data in Table 4, this peak can be attributed to the {CoIII3YIIIL6(DMSO)x} (x = 1 or 2) species; therefore, sensing of analytes with the NN pocket proves challenging. Then, we recorded a sample in CDCl3 (Figure 3C) containing CR, (R)-(−)-2-phenylglycinol, and (S)-(+)-2-amino-1-propanol in a 1:100:100 ratio at 1 mM concentration. The samples of CR with (R)-(−)-2-phenylglycinol and (S)-(+)-2-amino-1-propanol in a 1:100 ratio were also recorded and shown for convenience. These data indicate that CR cannot be used to discriminate between two analytes with similar pocket sizes since only one, possibly average, peak at −132.15 ppm is observed. Next, our studies concentrated on increasing the temperature to facilitate ligand exchange, if any, or alter the H-bonding interactions, thus providing better spectral resolution and improved chemical shift differences (Figure 3D). These data indicate that a full ligand (mechanism C, Scheme 4) exchange process takes place since two new peaks appear; one corresponds to the free ligand (−126 ppm) and the second (∼163 ppm) to an unknown species. Then, we recorded 1H–89Y data for the complex and the complex with an excess of phenylglycinol (Figure S7). The data of the complex show an interaction of the YIII center with the methylenic protons of the ligand (Figure S7 up), which is retained when an excess of phenylglycinol is present (Figure S7 down); however, no other peak that would suggest the presence of a {CoIII3YIIIL6(analyte)x}, since the analyte is in excess, is observed. Last, we recorded the data of the same sample (complex + analyte ratio 1:20) after 4 and 10 days, and three peaks can be identified (Figure 3E). These three peaks can be attributed to the free ligand (H2L), the complex (C), and the complex + analyte. After 10 days, the intensity of the complex peak significantly drops, whereas the intensity of the peak that corresponds to the free ligand significantly increases, signifying that a dynamic ligand substitution is responsible for the sensing process. We then performed theoretical calculations, trialed B3LYP/SDD and M06/Def2-TZVP levels in the recently reported Rh system,38 for the first time, to evaluate their efficacy (Figure S8, Tables S10 and S11, respectively), and identified optimum performance with the M06/Def2-TZVP level (Table S10). Encouraged by the excellent agreement of the computed 19F NMR chemical shifts, we computed the 19F NMR chemical shifts for the four plausible mechanisms shown in Scheme 4. As depicted in Table 4, there is an excellent agreement between the computed 19F NMR chemical shifts of the {CoIII3YIIIL6} complex alone in MeOD for both levels of theory employed (entries 1 and 2) but slightly better for the B3LYP/SDD system (entry 1).

Figure 3.

Figure 3

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(A) A comparison of the 1H-decoupled 19F NMR of the CR complex with phenylglycinol. (B) The 19F NMR spectra of the CR complex with SS or RR diphenylethylenediamine in a 1:20 ratio in the CDCl3:DMSO 9:1 ratio. (C) The 19F NMR of the CR complex with different amino alcohols in the 1:100 ratio at 1 mM concentration. (D) Variable-temperature 19F NMR data indicating that the increase in the temperature facilitates the ligand exchange. (E) 19F NMR data of complex (1 mM, CDCl3) + analyte (1 mM, CDCl3) samples left undisturbed after 4 and 10 days, and other compounds for comparison at T = 303 K.

Our attempts to compute the complex with the mono- and bis-adduct, which means {CoIII3YIIIL6 + (analyte)x, where x = 1 or 2, and analyte (A1, A6, and A9) (Scheme 4, mechanism A) suggest that complex {CoIII3YIIIL6} is very stable in all cases (Figure S9, Table S12). The computed 19F NMR chemical shifts for the resulting complex analytes from the partial ligand exchange mechanism (Scheme 4, mechanism B) are in very good agreement with the experimental values (Table 4, entries 3–10). A slightly better agreement was observed for the computed NMR values for the {CoIII3YIIIL6} complexes when a complete (six times) ligand exchange takes place (Table 4, entries 11–14). Under the experimental evidence gathered in this work, we can argue that the best agreement can be met with the resulting {CoIII3YIIIL5A} species from the ligand substitution mechanism (C, Scheme 4, Table 4, entries 15 to 20). Bearing all these in mind, and considering that complex C is incapable of sensing diols and diamines, the latter due to solubility issues, our chemical intuition inclines mechanism C, Scheme 4, as the most probable.

Comparison with Previous Methods

Referring to the previous work of Zhao and Swager,35 utilizing a Pd-pincer complex and 19F NMR for the sensing of chiral amines, it is vital to explore the differences in their chiral chemosensory system as opposed to our system. First, the Pd sensor is unsuitable for amino acids; it allows discrimination of amino alcohols using 1:1 and 1:2 ratios of sensor:analyte with chemical shift differences of enantiomeric pairs ranging from 0.1 to 1 ppm. Comparatively, the discrimination of amino alcohol enantiomeric pairs using these CoIII3YIII complexes presented a range of 0.02–0.18 ppm, with the higher results of a sensor:amine ratio 1:50. In addition to the advantages—the need to use less amount of the sensor to detect and discriminate between the analytes and boasting broader chemical shift differences—the window for detection, which is the shift difference between the original sensor peak and analyte peak, is broader. For the Pd sensor, the maximum window is 2.5 ppm, whereas using the CS or CR, this difference increases to 8 ppm. This increased difference benefits from a more straightforward interpretation of the resultant spectra and differentiation between existing complex and new analyte signals. Limitations arise with the complex where it cannot sense monoamines, as they lack the significant 1,2-amino alcohol motif present in both amino alcohol and amino acid analogues—the discrimination of monoamines is possible using the Pd complex; however, it again requires a more extensive complex loading with a ratio of 1:1 or 1:2. Moreover, ee determination is possible using the palladium sensor but not doable for CS or CR.

Song et al.38 used fluorinated Rh complex and discriminated chiral enantiomers of monoamines, diamines, and amino acids, thus outperforming CS or CR with enantiomeric differences of up to 0.21 ppm. The ratio of the sensor to the analyte is 1:1. They also found that changing the solvent from CDCl3 to DMSO-d6 increases the chemical shift difference between the two signals of an enantiomeric pair reproduced in other literature using 19F chemosensing systems.16 However, examining the subsequent 19F NMR spectra for both amino alcohols and amino acids in this Rh system, a pair of fluorine resonances can be found per analyte, as on coordination of the analyte to the Rh sensor, the sensor becomes asymmetric with each fluorine inequivalent. Consequently, it is unclear which signal of each pair of signals should be used to compare the enantiomer difference in chemical shift. We only observe an additional fluorine resonance representing the analyte alongside the original peak and providing more facile discrimination using uncomplicated spectra for any amino alcohol and the amino acid analyte in question. To follow, taking even the farthest signal distance of each enantiomeric pair, a maximum of 1 ppm is found for both amino acids and amino alcohols, which again is less than the most significant values for our complexes—0.22 ppm for amino acids and 0.18 ppm for amino alcohols (both in the 1:50 ratio). Interestingly, when optimizing sensing conditions, Song et al. found that increasing the equivalence of the sensor and extending the reaction time to 2 h with a reading taken at 50 °C showed more precise fluorine signals, which is therefore indicative of equilibrium favoring the coordinated analyte complex product. A more general comparison of Zhao and Swager and Song et al.’s complexes35,38 versus ours highlights the incorporation of abundant, low-cost, and non-toxic metals and the use of commercially available ligands for the synthesis of CS and CR.

Conclusions

We present the first example of a 3d/4f 19F-NMR chemosensory system and identify the scope and limitations of this method. These air-stable and easy-to-make complexes are built from non-toxic and inexpensive metals and retain their structure in the solution for a prolonged period; however, the crystallization solvent may impact a needless racemization process or improvise unnecessary impurities. Complexes CS and CR are applicable to sense a specific type of analytes bearing an NH2CX-CHX-OH pocket via a dynamic ligand exchange mechanism (C, Scheme 4). Despite the limited analyte library, our method imposes an extreme sensor:analyte ratio (1:20 or 1:50) and a broad sensing window (8 ppm over 0.8 ppm, as seen in other studies), which are advantageous over other techniques and thus can be used to detect and recognize organic or biological molecules bearing this specific motif at millimolar concentrations. Future work will focus on modifying the existing propeller-shaped motif by (a) replacing the central YIII unit of the propeller-shaped structure with GdIII or EuIII/TbIII ions to allow sensing investigations of the related species with EPR or fluorescence, (b) modifying the organic ligand to enhance the F signal or remove aromatic interactions, and (c) overcoming the racemization effect during crystallization, which will become prone to investigate the chemosensing amine abilities of this 3d/4f system with CD spectroscopy.

Acknowledgments

G.E.K. thanks the EPSRC UK National Crystallography Service at the University of Southampton for collecting the crystallographic data for CS and CR,81 as well as Prof. Annie K. Powell for CHN analysis data. N.B.E. thanks the TETFUND for financial support. We thank Dr. Ramon Gonzalez-Mendez, University of Sussex, for the ESI-MS data.

Data Availability Statement

CCDC deposition numbers 2195856–2195858 contain the supplementary crystallographic data for this paper.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.2c03737.

  • Copies of ESI-MS data, 1H and 19F NMR, TGA, UV–vis, and coordinates for theoretical calculations (PDF)

Author Present Address

# Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Nutrition, INSA-University of Barcelona, Barcelona

Author Contributions

G.A. performed the synthesis and characterization of CS and CR and performed sensing studies. H.C. and N.B.E. expanded the synthetic and sensing aspects. J.L.-M. and C.P.U. performed theoretical calculations. Y.A-.H. and L.C.S. provided the equipment and performed CD studies. G.R.A. performed VT 19F NMR, and 89Y NMR studies. G.E.K., G.J.T., and S.J.C. performed crystallographic analysis. G.E.K. conceptualization. All authors contributed to writing this article.

The authors declare no competing financial interest.

Supplementary Material

ic2c03737_si_001.pdf (4.3MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ic2c03737_si_001.pdf (4.3MB, pdf)

Data Availability Statement

CCDC deposition numbers 2195856–2195858 contain the supplementary crystallographic data for this paper.

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