Nucleophilic Fluorination Catalyzed by a Cyclometallated Rhodium Complex

Quantitative catalytic nucleophilic fluorination of a range of acyl chlorides to acyl fluorides was promoted by a cyclometallated rhodium complex [(η5,κ2C-C5Me4CH2C6F5CH2NC3H2NMe)- RhCl] (1). 1 can be prepared in high yields from commercially available starting materials using a one-pot method. The catalyst could be separated, regenerated, and reused. Rapid quantitative fluorination generated the fluoride analogue of the active pharmaceutical ingredient probenecid. Infrared in situ monitoring verified the clean conversion of the substrates to products. VTNA graphical kinetic analysis and DFT calculations lead to a postulated reaction mechanism involving a nucleophilic Rh–F bond.


Instrumentation
NMR spectral analysis was carried out using a Bruker Ascend 400 spectrometer (400 MHz) and Bruker Ascend 500 spectrometer (500 MHz) at room temperature (» 300 K). 1 H and 13 C NMR spectra were calibrated to the corresponding solvent signals (CDCl3: 7.26 ppm for 1 H, 77.16 ppm for 13 C;). The chemical shifts are reported in ppm and coupling constants are given in Hz. A 60s delay was used for quantitative 19 F NMR integration. NMR data was processed using MestReNova software. Multiplicity assignments in NMR spectra are labelled as follows: "s" = singlet, "d"= doublet, "t"= triplet, "q" = quartet, "p" = pentet, "m" = multiplet. Electrospray mass spectra were recorded on a Brucker

Fluorination of benzoyl chloride
Benzoyl fluoride was formed using the general method (Section 1.

Fluorination of toluoyl chloride
Toluoyl fluoride was formed using the general method (Section 1.3.3). Toluoyl chloride (1.0 mmol) was added to a Schlenk tube containing 1 (27 mg, 0.05 mmol) and AgF (190 mg, 1.5 eq.) in dry DCM (5 mL), which had previously been stirred for 10 minutes. The reaction was stirred at 20 °C for 170 minutes, until all of the starting material had been consumed, followed by work-up via filtration through celite, removal of solvent and transfer to a NMR tube, alongside deuterated chloroform (0.5 mL) and α,α,αtrifluorotoluene (20 µL). 19
The reaction was stirred at 20 °C for four hours, followed by work-up via filtration through celite, removal of solvent and transfer to a NMR tube, alongside deuterated chloroform (0.5 mL) and α,α,αtrifluorotoluene (20 µL). 19

Fluorination of probenecid chloride
The probenecid fluoride product was formed using the general method (Section 1.

Fluorination of benzoic anhydride
Benzoyl fluoride was formed using the general method (Section 1.3.3), substituting the acid chloride for the anhydride. Benzoic anhydride (1.0 mmol) was added to a Schlenk tube containing 1 (27 mg, 0.05 mmol) and AgF (190 mg, 1.5 eq.) in dry DCM (5 mL), which had previously been stirred for 10 minutes. The reaction was stirred at 20 °C for 42 hours, until all of the starting material had been consumed, followed by work-up via filtration through celite, removal of solvent and transfer to a NMR tube, alongside deuterated chloroform (0.5 mL) and α,α,α-trifluorotoluene (20 µL Figure S1a shows a time normalised concentration profile, where the concentration of the benzoyl chloride reagent has been reduced ( Figure S1a, green). The lower concentration of starting material has undergone time normalisation and been shifted to overlay at [benzoyl chloride]1/2. As can be seen in Figure S1a, the time normalised concentration profiles for both 1 mmol and 0.5 mmol starting concentration of benzoyl chloride overlay closely. This indicated that over the time course of the reaction at the sampled concentrations no product inhibition or catalyst deactivation is occurring.

VTN analysis
Next, the effect of catalyst activation was investigated. Under normal conditions, the catalyst and silver fluoride are stirred for 10 minutes prior to addition of the acyl chloride reagent. This was conducted to generate the active catalytic species from the pre-catalyst, 1. The effect of catalyst activation was probed, by following the start of the fluorination of benzoyl chloride, upon immediate addition of the substrate and addition of the substrate after 10 minutes equilibration. It can be observed in Figure S1b that the initial rate of reaction between these two systems do not overlay, with an increased rate observed when time was allowed for catalyst pre-activation ( Figure S1b; orange) compared to under non-standard conditions, where catalyst pre-activation was not allowed to occur prior to addition of the acyl chloride substrate ( Figure S1b; blue). After this period of increased initial rate at the beginning of the reaction post catalyst activation the rate of fluorination runs parallel to the non-preactivated reaction. Where excess silver fluoride was used, it was also possible to see the effect of catalyst activation in real time ( Figure S1c). Addition of a second aliquot of benzoyl chloride following consumption of the first aliquot of substrate, in which no catalyst pre-activation occurred, led to a faster initial rate of reaction than the addition of the first aliquot.

Rate order calculation from VTNA analysis
Rate order determination by visual time normalized kinetic analysis was developed by Bures and coworkers. 13 To elucidate the order of the different components within the reaction the effects of the concentration of these components were examined. The reaction profile for the catalytic fluorination of benzoyl chloride, generated through in-situ FTIR analysis, at different concentrations of the substrate were compared. Table S1 presents  Concentration / mmol Time / mins S20 substrate resulted in an overlay between the concentration-time normalised plot at rate order 1 ( Figure S2).
To determine the rate order with respect to catalyst, two reactions with identical initial concentration of benzoyl chloride, but different initial concentration of catalyst were compared. The normalized concentration-time profile was used as described above, where the effect on the change in [cat.], tcat, on the [benzoyl chloride] was examined (Table S2). An assumption of constant concentration of active catalyst in solution is applied. Tcat is given by the following equation; Applying a rate order in catalyst of 1, was observed to give the closest overlay between the concentration-time normalized profiles ( Figure S3), however precise overlay was not observed, signifying added complexity within the system.  Figure S3. Rate order calculation with respect to catalyst, taken from concentration-time normalized data in Table . Closest overlay was observed upon defining rate order with respect to catalyst as 1.

Initial rate calculations
The initial reaction rates for the fluorination of the acyl chloride substrates were calculated by comparing the change in the concentration of the acyl chloride substrate, determined from the concentration normalized reaction profile taken from ReactIR analysis, over the initial 20 minutes of the reaction, following substrate addition. The acyl chloride substrate was added after catalyst preactivation of stirring 1 with AgF for 10 minutes. This initial rate of reaction (mmolh -1 ) was then compared against the carbonyl stretching frequency (cm -1 ) of the acyl chloride substrates (Table S3).

Calibration curve
Off-line 19 Figure S5. Computed free energies (kcal/mol) and labelling scheme for stationary points for the reactions of 11 with toluyl chloride. Inset shows the much higher alternative transitions states for attack via the C-F2 and C-F3 bonds. Crude 1 H and 19 F NMR spectra, including internal standard trifluorotoluene and catalyst.