The Role of Water in Lanthanide-Catalyzed Carbon–Carbon Bond Formation

Luminescence-decay measurements in combination with high-performance liquid chromatography analyses were used to study the relationship between rates of catalysis and water-coordination numbers of europium-based precatalysts in the aqueous Mukaiyama aldol reaction. A correlation between reactivity and water-coordination number was observed and is reported here.


or Eu(NO 3 ) 3 H 2 O/tetrahydrofuran
We hypothesized that the water-coordination numbers of lanthanide-based precatalysts influenced the reaction rate and final yield of this reaction. In aqueous solution, lanthanide(III) ions have relatively fast inner-sphere water-exchange rates (~10 8 s -1 ) [17], and each site of exchanging water represents a potential site for benzaldehyde coordination. We hypothesized that a larger water-coordination number would result in greater probability for aldehyde coordination and, consequently, a faster reaction rate because bound aldehyde, 2, is activated for nucleophilic attack by enol ether, 1 ( Figure 1).
We have previously reported the use of luminescence-decay measurements to monitor the average water-coordination number of Eu(OTf) 3 in mixtures of water with organic co-solvents in the presence and absence of substrates [18,19]. In this article, we contribute to the mechanistic understanding of the aqueous lanthanide-catalyzed Mukaiyama aldol reaction by correlating the water-coordination numbers of europium-based precatalysts with steady state reaction rates. Further, we describe the influence of europium counteranions on reaction yields and steady state reaction rates.

Results and Discussion
Water-coordination numbers were determined using measured luminescence-decay rates with Equation 1, where and represent the measured decay rates in H 2 O and D 2 O, respectively; q represents the average water-coordination number; and α accounts for the influence of non-coordinated molecules on luminescence decay [19]. We found the average water-coordination numbers of the studied europium salts in H 2 O/THF mixtures ranging from 1 to 40% H 2 O in THF (v/v) to be between 3.2 and 8.6 water molecules ( Figure 2, Table 1).
These values are in agreement with previous lanthanide-coordination studies which show a maximum coordination number between 8 and 9 [18][19][20].
We hypothesized that Eu(NO 3 ) 3 should have lower catalytic activity than Eu(OTf) 3 , an effective Lewis acid precatalyst, because of its lower water-coordination numbers. By studying Eu(OTf) 3 and Eu(NO 3 ) 3 , we were able to assess the effects of counteranions on the catalytic activity of europium. We chose to use these precatalysts because the water-coordination numbers of europium ions in aqueous solutions are influenced by the composition of the solvent and the identity of the counteranions ( Figure 2). Due to the limited water solubility of 1, we were unable to study 1 at water percentages of less than 40% H 2 O in THF (v/v). To test our hypothesis that water-coordination numbers influence the steady state reaction rate and final yield of this reaction, the yields of Eu(OTf) 3 -and Eu(NO 3 ) 3 -catalyzed Mukaiyama aldol reactions were measured after 48 h in solvent mixtures ranging from 1 to 40% H 2 O in THF (v/v) ( Figure 3). Yields were measured after 48 h because Eu(NO 3 ) 3 -catalyzed reactions in 1, 5, and 10% H 2 O in THF (v/v) required longer than 24 h to reach completion. As shown in Figure 3, Eu(OTf) 3 -and Eu(NO 3 ) 3 -catalyzed Mukaiyama aldol reactions afforded the highest yields at 5 and 15% H 2 O in THF (v/v), respectively. Interestingly, 5 and 15% H 2 O in THF (v/v) roughly correspond to the solvent composition at which increasing the H 2 O concentration has the least effect on the water-coordination number for both Eu(OTf) 3 and Eu(NO 3 ) 3 ( Figure 2).  [19]. Error bars represent the standard error of the mean of between three and nine independent measurements. Table 1. Mean water-coordination numbers (q) of (a) Eu(OTf) 3 and (b) Eu(NO 3 ) 3 in mixtures of H 2 O/THF. Error represents standard error of the mean of between 3 and 9 measurements.  We also investigated the relationship between the water-coordination numbers of europium precatalysts and the steady state reaction rates of the Mukaiyama aldol reaction shown in Figure 1. For these studies, Eu(OTf) 3 or Eu(NO 3 ) 3 was used in solvent mixtures ranging from 1 to 40% H 2 O in THF (v/v) and Eu(OTf) 3 in THF. These europium-containing precatalysts and solvent mixtures were used because of the wide range of water-coordination numbers (3.2 to 8.6) accessible under these conditions ( Figure 2). We expected that this range of water-coordination numbers would allow us to observe changes in reactivity to test our hypothesis regarding the relationship between steady state reaction rate and water-coordination number. To determine the steady state reaction rates of Eu(NO 3 ) 3 -and Eu(OTf) 3 -catalyzed Mukaiyama aldol reactions, we monitored the concentration of product, 3, at 2, 18, 34, 50, and 66 min using HPLC (Figure 4). From these HPLC traces and a calibration curve for 3 produced using the same conditions, the area under the peaks was used to determine concentration. An example of the resulting data is plotted in Figure 5, which exemplifies the linear increase of product concentration as a function of time for the conditions studied between 18 and 66 min. By monitoring the linear increase in product, 3, concentration as a function of time we were able to calculate the steady state reaction rates as the slope of the best fit line in Figure 5 [21]. Table 2 contains a complete list of steady state reaction rates.
From the data in Figure 5 and data from similar experiments using Eu(OTf) 3 or Eu(NO 3 ) 3 in a range of solvents [0-40% H 2 O in THF (v/v)], a relationship was observed between the steady state reaction rates of europium-catalyzed Mukaiyama aldol reactions and solvent composition ( Figure 6). Reactions catalyzed by Eu(OTf) 3 had faster steady state reaction rates than reactions catalyzed by Eu(NO 3 ) 3 in every solvent composition studied. This observation can be rationalized based upon relative binding affinities of the anions for Eu 3+ , which affect the water-coordination numbers of the precatalysts: triflate has a lower binding affinity for lanthanide(III) ions than nitrate [22].  This difference in europium binding affinities between triflate and nitrate results in higher watercoordination numbers for Eu(OTf) 3 compared to Eu(NO 3 ) 3 and, ultimately, corresponds to higher europium accessibility because each water molecule coordinated to Eu 3+ represents a potential site for benzaldehyde coordination and activation for reaction. In general, increasing water percentages resulted in faster steady state reaction rates, but the steady state reaction rates of Eu(OTf) 3 -catalyzed reactions reached a maximum and remained constant at solvent mixtures containing greater than 10% H 2 O in THF (v/v) ( Figure 6).  (Figure 2). The increase of steady state reaction rates of Eu(NO 3 ) 3 -catalyzed reactions over the entire range of solvents in this study can be attributed to the water-coordination number of Eu(NO 3 ) 3 that increases without reaching a maximum with increasing H 2 O in THF from 1 to 40%. An alternative explanation for our observations with Eu(NO 3 ) 3 is the determination of rate by a dynamic involvement of NO 3 in the inner-sphere of the lanthanide ion. However, the slower steady state reaction rates of Eu(NO 3 ) 3 -catalyzed Mukaiyama aldol reactions relative to Eu(OTf) 3 -catalyzed reactions support our hypothesis that larger water-coordination numbers and less strongly binding counteranions enable faster reaction rates.

General
Unless otherwise noted, purchased chemicals were used as supplied. Tetrahydrofuran (THF) was purified using a solvent purification system (Vacuum Atmospheres Company), and water was purified using a PURELAB Ultra Mk2 (ELGA) water purification system. 2-(Hydroxyphenylmethyl)cyclohexanone (3), was synthesized according to a published procedure [1]. Flash chromatography was performed using silica gel 60, 230-400 mesh (EMD Chemicals). Thin layer chromatography (TLC) was performed on silica gel 60 coated ASTM TLC plates F 254 (250 μm thickness). TLC visualization was accomplished using a hand-held UV lamp followed by staining with potassium permanganate (2 g KMnO 4 , 20 g K 2 CO 3 , 5 mL 5% w/v aqueous NaOH, 300 mL H 2 O). High-performance liquid chromatography (HPLC) analyses were performed on a Shimadzu HPLC system equipped with a C18 column (Zorbax Eclipse XDB-C18, 3.5 μm, 4.6 × 150 mm). Detection of eluent was carried out with a photodiode array detector at 210 nm. HPLC analyses used a binary gradient method (pump A: water, pump B: acetonitrile; 40-90% B over 15 min; flow rate: 1 mL/min). Europium concentrations were verified using xylenol orange according to a published procedure [23].

Luminescence-Decay Measurements
Water-coordination numbers were determined by acquiring luminescence-decay measurements using a HORIBA Jobin Yvon Fluoromax-4 spectrofluorometer in decay-by-delay scan mode using the phosphorescence lifetime setting. Experimental details and data analyses were performed according to previously described methods [19].

Conclusions
We have reported the dynamic luminescence-decay measurements of Eu(NO 3 ) 3 and Eu(OTf) 3 in binary solvent mixtures. In addition to monitoring the water-coordination numbers of these europium-containing precatalysts, we measured the yields and steady state reaction rates of the Mukaiyama aldol reaction catalyzed by these salts in solvent mixtures from 1 to 40% H 2 O in THF (v/v), and the steady state rate of the Eu(OTf) 3 -catalyzed Mukaiyama aldol in THF. From these measurements, we found a correlation between steady state reaction rate and water-coordination number as well as between yield and solvent composition. The use of luminescence-decay measurements to probe the coordination environment of europium-based precatalysts in solution enabled the study of the influence of precatalyst coordination-environment on steady state reaction rate. These results are useful in the design of new precatalysts to be used for aqueous, enantioselective, lanthanide-catalyzed bond forming reactions because they suggest that faster rates of catalysis will require lower ligand coordination numbers. Further, the methodology described here can be applied to other lanthanide-catalyzed bond-forming reactions in aqueous media to gain a better understanding of the influence of water on the structure-activity relationship between precatalysts and rates of catalysis.