Characterizing Lewis Pairs Using Titration Coupled with In Situ Infrared Spectroscopy

Under anhydrous conditions, Lewis acids can have a range of solubilities. The two examples we have presented are GaCl₃ and FeCl₃ in DCE. GaCl₃ is homogeneous at the onset of the titration, while FeCl₃ is largely insoluble. Beginning with the homogeneous solution of GaCl₃, we completed a titration from 0-4 equiv 1 in 10 μL increments and extracted the IR spectra (Figure 3A). Examination of the transitions that occur over the course of the titrations shows a formation of a single species in the carbonyl region at 1630 cm^-1, which grows from 0-1 equiv 1 (Figure 3B) ^26,27. When greater than 1 equiv 1 is added to the solution, no change in the peak at 1630 cm^-1 occurs and unbound 1 is observed at 1714 cm^-1 (Figure 3C). These results are consistent with the formation of 2. When the same titration is performed with FeCl₃ (Figure 3D), a peak at 1636 cm^-1 forms from 0-1 equiv 1, which is consistent with 3 (Figure 3E). Importantly, the mixture becomes homogenous once 1 equiv 1 is achieved. When the titration proceeds beyond 1 equiv 1, unbound 1 is observed at 1714 cm^-1, 3 decreases in intensity, an isosbestic point resolves at 1648 cm^-1, and a new peak at 1663 cm^-1 forms.

Using the titration IR data, the equivalents of analyte used can be employed to perform Component Analysis of the solution interactions (Figure 4). To account for dilution, we can employ a normalization with respect to volume of the Beer-Lambert equation (eq. 1):

where 1) both absorbance (A) and volume (V) are measurable terms; 2) molar absorptivity (ε) and pathlength (l) are constant, allowing 3) number of moles (n) to be examined. The normalized absorbance can easily be computed in a spreadsheet (Figure 4B,D), and then this term can be plotted against equivalents of analyte. In Figure 4C, we can see that the signal for 2 increases linearly with respect to 1 until 1 equiv, at which point the signal for 1 increases linearly and 2 is unchanged. In Figure 4F, we see a similar linear increase in the signal of 3 to 1 equiv 1, followed by the presence of 1 beyond 1 equiv added. However, we also observe a linear decrease in the intensity of 3, and we observe less 1 than we should, assuming similar behavior to GaCl₃.

Yet more information is available from the IR data for the titration of FeCl₃ with 1. The maximum amount of 3 that can form is defined by the amount of FeCl₃ added (C_MAX = 2 mmol FeCl₃ in the example titration). We know the amount of 1 we add to the flask (C_ADD), and we can measure the amount of unbound 1 we observe at 1714 cm^-1 (C_OBS) and the amount of 3 we observe at 1636 cm^-1 (C_COORD) using Beer-Lambert relationships. Lastly, we know we cannot account for all of the 1 added to the flask as free 1 or 3, indicating that some 1 is not detected (C_ND). We can combine these terms for 1 in the following mass balance (eq. 2):

We can use the titration data to calculate the values of these terms in each IR spectrum generated during the titration (Figure 5B). With these values, we can plot the amount of 1 missing (C_ND) as a function of the amount 3 consumed (C_MAX-C_COORD) to determine if there is a correlation (Figure 5C). This correlation is consistent with 3 equiv 1 consuming 1 equiv 3, which may form a complex similar to 4. We have obtained further support for this number of attached ketones via examination of solution conductivity, which is consistent with one or more of the chlorides being displaced to the outer sphere of Fe(III), and X-ray crystallography of an analogous structure with benzaldehyde¹². However, it is likely that there is a mixture of different types of highly-ligated structures that are formed in solution, as is indicated by our non-whole number slopes in our consumption analysis in Figure 5, and the crystal structure we observe may simply be the one complex that precipitates.

In addition to the interactions between two species, this method can be used to probe competitive interactions (Figure 7). By establishing the formation and spectral properties of 3 (Figure 7A) and 5 (Figure 7B), the competition of carbonyls for access to the Lewis acid can be observed. By preforming 3 in solution, we can examine how 6 displaces 1 (Figure 7C). When we probe this system, we see that as we add 6 auf 3, not all 6 binds to FeCl₃. However, we do observe the consumption of 3 with concomitant presence of 1, as well as the formation of 5.

Using this type of competition experiment, we have been able to simulate the state of FeCl₃ as a catalyst in carbonyl-olefin metathesis (Figure 8). We previously demonstrated that at low turnovers, carbonyl-olefin metathesis operates via the primary cycle in Figure 8B²⁸. Substrate 7 interacts with FeCl₃ to form complex 9 as the resting state of the cycle. Complex 9 then undergoes turnover-limiting [2+2]-cycloaddition to form oxetane complex 10. Retro-[2+2] yields cycloalkene product 8 and 3, which in turn must have the molecule of 1 displaced by a molecule of 7. However, as the [1] increases, 3 is converted to complex 4. Coordinatively saturated 4 then either sequesters FeCl₃ or is catalytically competent, resulting in a parallel cycle via ketone complex 11 and oxetane complex 12.

In conclusion, the utilization of in situ IR to monitor the titration of Lewis acids with carbonyl compounds allows chemists to gain insight into Lewis acid/base solution interactions under synthetically relevant conditions. Not only can this technique be employed to identify discrete structures, but it can be employed to observe the transition of one discrete species into another, as well. Findings from this method have been utilized to propose the mechanism of other metathesis reactions²⁹. We are currently using data gathered via this method to facilitate the reactivity of recalcitrant substrates in carbonyl-olefin metathesis, as well as to develop new forms of metathesis reactions. Lastly, the competitive interactions between substrate carbonyls and product carbonyls likely impact other Lewis acid-catalyzed reactions. We are employing this method to examine these other catalytic regimes.