Fluorescence-based Measurement of the Lewis Acidities of Lanthanide Triflates in Solution
Despite the prominence of rare earth complexes to act as Lewis-acid catalysts in organic synthesis, the comprehensive measure of the Lewis-acid strength of such compounds has yet to be performed due to incompatibilities with existing methods. We report our results in measurement of a sequence of lanthanide triflates via our recently established Fluorescent Lewis adduct (FLA) method. The persistence in solution of these Lewis acids as solvated coordination complexes is accurately measurable by the FLA method. However, several of the RE species exhibit fluorescence quenching, which may potentially inhibit the measurement. Nevertheless, meaningful FLA measurements were still able and the results correspond to both periodic trends and were even consistent with previous correlated reported data.
Introduction<!>Materials and methods<!>Results<!>Non-quenching species<!>Partially quenching species<!>Strongly quenching species<!>Solvent influence<!>Discussion<!>Conclusion
<p>Being simply defined as electron pair acceptors, Lewis acids are key reagents in organic synthesis. Amongst many applications, they have proven particularly useful as catalysts and are known to enable a variety of chemical transformations to occur under very mild conditions and often with unique selectivities. 1 A diverse selection of Lewis acids is available with compositions spanning the whole periodic table, ranging from main group elements to metal salts. Among the latter, rare-earth metal triflates [RE(OTf)3] have been intensively used as catalysts since the beginning of the 1990s as they display numerous advantageous features. 2 Compared to other metal-based Lewis acids, they are stable in water, enabling organic chemical transformations to occur in aqueous medium. Catalytic loadings are usually low, and catalysts can usually be easily recovered and reused with minimal loss of activity.</p><p>However, the exact nature of the rare-earth metal often plays a prominent role in the efficiency of RE(OTf)3 catalysts. For instance, a screening of RE(OTf)3 catalysts for a model aldol reaction gave yields varying between 8% (La) and 91% (Yb). 3 Likewise, yields ranging from 24% (Pr) to 89% (Eu) were observed in a Friedel-Crafts aromatic sulfonylation reaction. 4 This complicates the optimal choice of RE(OTf)3 catalyst for a given chemical transformation. The catalytic efficiency of RE(OTf)3 compounds has usually been rationalized by considering their ionic radii, which decrease steadily along the lanthanide series. High catalytic activity (and thus, high Lewis acidity) is then associated to species with a small ionic radius, such as Sc(III) or Yb(III). 2 Nevertheless, many results do not support this trend, with reaction yields that do not correlate with the ionic radius of the RE(OTf)3 catalyst employed. 5,6 A quantitative evaluation of the Lewis acidity of RE(OTf)3 catalysts would thus be highly desirable to gain proper insight into their reactivities. Surprisingly however, there has only been a single study to this end to date, where Yamaguchi and Imamoto compare the competitive ligand dissociation of Ln(III) compounds using tandem mass spectrometry. 7 However, this set of data did not reflect the behavior of RE(OTf)3 catalysts in solution, which would be better in order to emulate the environment in which these compounds are used.</p><p>We recently reported 8 and refined 9 a new method for evaluating the relative acidity of a vast series of Lewis acids in solution. This method uses a set of luminescent Lewis-basic dithienophosphole oxide probes whose emission is red-shifted upon coordination to Lewis acids via their P=O functional group.</p><p>We found that the chromaticity of the resulting fluorescent Lewis adducts (FLA), assessed by their Commission Internationale de l'Éclairage (CIE) coordinates, correlates very precisely with the strength of the Lewis acids. By using the (x,y) coordinates of the CIE diagram, we were able to attribute a specific Lewis acid unit (LAU) value to more than 50 Lewis acids belonging to very different classes of compounds (neutral boranes, heavy group 13 elements, cationic and metallic species). Unlike other strategies, the FLA method delivers a solution-based measurement of the effective Lewis acidity of a species in a given environment. Consequently, this method seemed particularly well-suited for assessing the Lewis acidity of rare-earth metal triflates. It is worth noting that this represents a challenging task as lanthanides generally display similar physicochemical properties and detectable changes are often minimal. The relevance of this study is also reinforced by the various applications of rare-earth phosphine oxide complexes, especially in catalysis and photoluminescence. 10 The scope and limitations of the FLA method applied to RE(OTf)3 compounds are the subject of this paper.</p><!><p>All solvents were dried with an MBraun Solvent Purification System. Flash column chromatography was performed using a SiliaFlash M60 silica gel (60−120 μm). NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer. Chemical shifts were referenced to residual nondeuterated solvent peaks (7.26 ppm for 1 H and 77.16 ppm for 13 C for CHCl3). Optical spectroscopy was performed on an Agilent Cary 5000 UV−vis spectrophotometer. Fluorescence spectroscopy was performed on an Edinburgh Instruments FS5 spectrofluorometer. Lanthanide triflates Ln(OTf)3 were purchased from Strem, stored in a glovebox and used without further purification. All dithienophosphole oxide probes except 2* were synthesized according to literature procedures. [11][12][13] Probe 2* was synthesized as follows: 2,6-dibromo-dithieno[3,2-b:2',3'-d]phosphole oxide 12 (500 mg, 1.12 mmol, 1.0 eq) and 4-tertbutylphenylboronic acid (399 mg, 2.24 mmol, 2.0 eq) were dissolved in 30 mL toluene. To this solution, 15 mL aqueous 2M Na2CO3 was added, followed by Pd(PPh3)4 (130 mg, 0.11 mmol, 0.1 eq). The mixture was stirred at 100 °C for 15 h then cooled down to rt. Dichloromethane was added, the mixture washed with water (1x), brine (1x), dried over MgSO4, filtered and concentrated. Column chromatography (SiO2, 100% CH2Cl2 to 9/1 CH2Cl2/EtOAc) followed by recrystallization from CHCl3/acetone gave the product (433 mg, 0.78 mmol, 70%) as an orange solid. The samples for the FLA method were prepared and measured as follows: The corresponding Ln(OTf)3 salt (200 or 500 eq) was mixed with a 2.5 10 -5 M solution of a dithienophosphole oxide probe (3 mL).</p><p>The resulting mixture was sonicated for 1 minute to ensure complete dissolution. Its UV-visible spectrum was measured immediately, followed by its fluorescence spectrum (excitation at the maximum wavelength of absorption).</p><!><p>The FLA method utilizes a series of emissive dithieno[3,2-b:3',2'-d]phosphole oxide Lewis-basic probes. 8,9 A single FLA measure of a Lewis acid requires measuring the emission of the corresponding Lewis acid-base adduct. The chromaticity of the emission of each adduct is plotted in CIE space where a parabolic trend can be established. This trend is compared against the chromaticity of the emission of the free phosphole oxide probes in solution. Our original reports 8,9 used toluene as a solvent due to its relatively low reactivity toward strong Lewis acids, however, for measuring the rare earth Lewis acids, tetrahydrofuran (THF) was used. THF was chosen both for its ability to solubilize the majority of the rare earth species tested, as well as its propensity to generate a rare earth complex with a single dithienophosphole ligand in addition to several coordinated THF molecules. To minimize potential error, a new solvent fit function was generated for THF. To generate this function, the chromaticity of the emission of each of a total of 6 probes from our previous studies were measured. As shown in Figure 1A, the plot of the chromaticities of emissions fit very well with a parabolic function, which was then used for THF-based FLA measurements. A new probe, 2*, was also developed. Probe 2* contains the same core phosphole oxide with probe 2, but with a pendant p-tert-butyl group bound to the 2,6-5 substituted phenyl rings. This additional weak donor affords a marginal redshift in the emission spectrum in an attempt to circumvent some of the reabsorption that leads to the emission quenching in these species. The fluorescence spectra of the FLAs formed upon addition of 200 eq of a RE(OTf)3 salt to probes 1, 2 and 8 in THF was then recorded (Figure 2, see SI for the other probes). The LAU values of the RE(OTf)3 salts were then extracted based on the fit (Figure 1B). The results of the measurements were, somewhat expectedly, impacted by the specific lanthanide being measured, due to the ability of some of the RE compounds to quench the fluorescence. 14 Nonetheless, the data could be categorized into three general groups, demonstrated in Figure 2: the RE(OTf)3 salts that are: (1) non-quenching, consisting of Sc, Y, La, Ce, Gd, and Lu; (2) partially quenching, consisting of Tb, Dy, and Yb; and (3) strongly quenching, consisting of Pr, Nd, Sm, Eu, Ho, Er, and Tm.</p><p>The degree to which a fluorescent Lewis adduct was quenched varied by choice of phosphole oxide probe, but in general the property of non-, moderately-, or strongly-quenching was retained. The quenching systems are, unsurprisingly, those that typically exhibited additional absorption events in the UV-vis absorption spectra.</p><!><p>Pleasingly, the FLA method can easily discriminate between elements of group three (Sc, Y and La): in this case, the difference in the fluorescence of the adducts can even be seen by the naked eye. Lewis acid units (LAU) values for Sc 3+ , Y 3+ and La 3+ are 36.82, 31.68 and 26.67, respectively, showing a considerable decrease in terms of Lewis acidity when going down group 3. This is in accordance with the pronounced increase of atomic radii for these elements and the concomitant shielding of the atomic nucleus. The FLA method can also distinguish the neighboring lanthanides La 3+ and Ce 3+ (LAU of 27.18 for the latter). The LAU value of Lu 3+ (32.45) is close to the one found for Y 3+ , which is again in agreement considering the similarity of the ionic radii. With the margin of error for the FLA measurement being 0.25 LAU, 9 this means that Y 3+ and Lu 3+ have a measurable difference in terms of Lewis acid strength. Interestingly, the LAU value of Gd 3+ (27.46) is lower than expected. This may reflect the so-called "gadolinium break" and is in agreement with the fact that Gd(OTf)3 displays a poor catalytic efficiency in some reactions. 4 The LAU value for Sc 3+ in THF (Dimroth-Reichardt ET(30) parameter 37.4 kcal/mol, donor number 20.0 kcal/mol) 15,16 is much higher than the one found in a solvent of similar polarity and donicity like Et2O. This may be attributable to THF generating only mono-coordination complexes with RE species, which does not hinder binding of the Lewis base.</p><!><p>For these three compounds, a noticeable amount of fluorescence quenching can be deduced from the emission spectra of the FLAs. Nevertheless, the corresponding CIE coordinates fit the probe parabola quite well, which indicates that the LAU values are reliable and were found to be 30.40, 28.70 and 30.45 for Tb 3+ , Dy 3+ , and Yb 3+ , respectively. The reliability may be due to the fact that chromaticity is composed of hue, saturation, and intensity, and that the solution quenching may impact intensity or saturation while maintaining hue, i.e., spectral features such as emission maxima are unaffected. This, in addition to the fact that shifts in CIE coordinates are linear combinations of the individual changes in solution, allows us to still determine chromaticity and use it when emission quenching is minor.</p><!><p>The fluorescence of the probe is strongly quenched in the case of the remaining seven lanthanides. This translates to CIE coordinates that start to deviate from the probe parabola. Adduct formation with the Lewis base probes is still observed, due to the clear redshift in emission maxima of the probe, however, the emission intensity is significantly reduced. For this reason, the attribution of a LAU value becomes challenging. This is especially the case for Eu 3+ (LAU = 5.81*) and Pr 3+ (LAU = 23.53*) since their CIE coordinates show the strongest deviation from the probe parabola, meaning that the LAU value cannot be safely extracted from the chromaticity. The other lanthanides, whose CIE coordinated still roughly fit the probe parabola, display reasonable LAU values (28.28, 28.51, 31. 25, 32.58, 29.45   for Nd 3+ , Sm 3+ , Ho 3+ , Er 3+ , and Tm 3+ , respectively) which follow the general upward trend between La 3+ and Lu 3+ .</p><!><p>In hopes of reducing the fluorescence quenching, a set of solvents (acetone, chloroform, dimethylsulfoxide (DMSO), acetonitrile, methanol and toluene) was screened. The absorption and emission spectra of the FLAs with a strong quencher (Eu 3+ ) and with a non-quencher (Gd 3+ ) were recorded (Figure 3). As the solubility of RE(OTf)3 salts was limited in chloroform and toluene, a saturated solution was used instead. Depending on the solvent, different behaviors were observed: acetonitrile showed the same behavior as THF, with Eu 3+ being totally quenched, while Gd 3+ is not. No difference in terms of absorption and emission could be detected when using DMSO and methanol: this was attributed to the strong coordinating ability of these solvents, meaning that the formation of a lanthanide-solvent adduct is preferred and that no FLA is formed. In fact, similar behavior was observed with other Lewis acids for acetonitrile. 17 On the contrary, Eu 3+ exhibited weaker quenching in acetone and particularly in toluene. However, the maxima of the emission spectra of the FLA of Gd 3+ and Eu 3+ are still very different, which leads to unrealistic LAU values for Eu 3+ . Finally, the behavior of Eu 3+ and Gd 3+ was reversed in chloroform, which may be attributed to the very low solubility of the FLAs in this solvent.</p><!><p>As a whole, and despite some shortcomings, the FLA method is able to quantitatively assess the Lewis acidities of RE(OTf)3 compounds. It is thus possible to distinguish between the minute differences of rare-earth compounds by means of Lewis acid strength. Our results also coincide with the investigation of Yamaguchi and Imamoto, suggesting that FLA measurements are fully appropriate and accurate. Indeed, in both cases, a sharp decrease of Lewis acidity between Sc and La, followed by a slow increase between La and Lu was observed (Figure 4). This trend also aligns well with the progression of ionic radii in the periodic table. The main issue here is the strong fluorescence quenching of the probe, which hampers the attribution of a meaningful LAU value for the very strong quenching REs (Eu 3+ and Pr 3+ ). The fluorescence quenching mechanism can be either static or dynamic: in the former case, a non-fluorescent groundstate complex is formed before excitation occurs, whereas in the latter, interaction of the fluorophore in an excited state with the quencher causes radiation-less deactivation to the ground state.</p><p>Examination of the absorption spectra of probe 2 alone and in the presence of 200 eq Eu(OTf)3 (the strongest quencher) revealed a bathochromic shift of 14 nm induced by the addition of Eu 3+ (Figure 6). This strong perturbation of the absorption spectrum points toward a static fluorescence quenching.  The shoulder at 394 nm is attributed to an f-f transition of Eu(OTf)3.</p><p>To assess the quenching quantitatively, probe 1 was titrated in THF with Eu(OTf)3 (Figure 6).</p><p>Fluorescence intensity decreased progressively upon addition of Eu(OTf)3 until the emission nearly disappeared. We applied the Stern-Volmer relationship 19 and obtained a linear I/I0 vs. Q plot (Figure 7). Along with the fact that the absorption spectrum of dithienophosphole oxide probes in strongly modified in the presence of Ln 3+ salts, this supports a static fluorescence quenching mechanism. The Stern-Volmer constant (KSV = 1.66 10 5 L.mol -1 ) for Eu 3+ is very high. Such a strong quenching ability for Eu 3+ was already observed for other fluorophores, especially indole derivatives. The fluorescence quenching of aromatic systems by lanthanide ions is a known phenomenon and has been already studied for indole ring systems, 20-24 coumarins, 25 porphyrins, 26 and fluoresceins. 27 Qualitatively, the emission of the solutions of 500 equivalents of RE(OTf)3 exhibited reduced intensity, and were more difficult to measure an accurate LAU value, however simply reducing the concentration of the lanthanide Lewis acid risks not generating a saturated solution of Lewis adduct. The use of 200 equivalents of RE(OTf)3 appears to be an acceptable balance between intensity and saturation.</p><!><p>Lanthanide triflates were successfully measured with the FLA method, despite the propensity for several of the rare-earth complexes to quench fluorescence. Lanthanides that afforded little to no fluorescence quenching could be measured and even be readily discerned from one another. For the species that afforded more significant fluorescence quenching, an LAU value could still be generated, albeit with far less certainty. Nonetheless, the resulting effective Lewis strengths are consistent with both periodic trends and available literature measures. For the strong quenching species, spectroscopic data point toward a static fluorescence quenching mechanism. These data, and the method in general, may afford a means by which to study the fluorescence quenching of these rare earth species, and alternatively may provide insight into a way the FLA method can handle independently fluorescent species, or fluorescence quenching species, with as high a precision as typical FLA measurements. In addition, the use of CIE, as a linear combination of all changes to the emission in solution, means that the quenching titrations may afford, in a future time, a means by which to separate emission or quenching events from the full emission spectrum.</p>