Scandium Ion-Promoted Electron-Transfer Disproportionation of 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-Oxide (PTIO•) in Acetonitrile and Its Regeneration Induced by Water

2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO•), a persistent nitronyl nitroxide radical, has been used for the detection and trapping of nitric oxide, as a redox mediator for batteries, for the activity estimation of antioxidants, and so on. However, there is no report on the reactivity of PTIO• in the presence of redox-inactive metal ions. In this study, it is demonstrated that the addition of scandium triflate, Sc(OTf)3 (OTf = OSO2CF3), to an acetonitrile (MeCN) solution of PTIO• resulted in an electron-transfer disproportionation to generate the corresponding cation (PTIO+) and anion (PTIO−), the latter of which is suggested to be stabilized by Sc3+ to form [(PTIO)Sc]2+. The decay of the absorption band at 361 nm due to PTIO•, monitored using a stopped-flow technique, obeyed second-order kinetics. The second-order rate constant for the disproportionation, thus determined, increased with increasing the Sc(OTf)3 concentration to reach a constant value. A drastic change in the cyclic voltammogram recorded for PTIO• in deaerated MeCN containing 0.10 M Bu4NClO4 was also observed upon addition of Sc(OTf)3, suggesting that the large positive shift of the one-electron reduction potential of PTIO• (equivalent to the one-electron oxidation potential of PTIO−) in the presence of Sc(OTf)3 may result in the disproportionation. When H2O was added to the PTIO•–Sc(OTf)3 system in deaerated MeCN, PTIO• was completely regenerated. It is suggested that the complex formation of Sc3+ with H2O may weaken the interaction between PTIO− and Sc3+, leading to electron-transfer comproportionation to regenerate PTIO•. The reversible disproportionation of PTIO• was also confirmed by electron paramagnetic resonance (EPR) spectroscopy.


Results and Discussion
When Sc(OTf)3 was added to a deaerated MeCN solution of PTIO • , the absorption bands at 238, 264, and 361 nm and a broad band at around 600 nm due to PTIO • decreased immediately with clear isosbestic points at 277, 334, 381, and 525 nm, as shown in Figure 1 (Video S1 of the Supplementary Materials).The broad absorption band at 450 nm is diagnostic of the one-electron-oxidized PTIO • (PTIO + ) [33].Thus, an electron-transfer disproportionation of PTIO • is suggested to take place upon addition of Sc(OTf)3 to produce PTIO + and the one-electron-reduced PTIO • (PTIO − ), as in the case of DPPH

Results and Discussion
When Sc(OTf) 3 was added to a deaerated MeCN solution of PTIO • , the absorption bands at 238, 264, and 361 nm and a broad band at around 600 nm due to PTIO • decreased immediately with clear isosbestic points at 277, 334, 381, and 525 nm, as shown in Figure 1 (Video S1 of the Supplementary Materials).The broad absorption band at 450 nm is diagnostic of the one-electron-oxidized PTIO • (PTIO + ) [33].Thus, an electron-transfer disproportionation of PTIO • is suggested to take place upon addition of Sc(OTf) 3 to produce PTIO + and the one-electron-reduced PTIO • (PTIO − ), as in the case of DPPH • [23].The spectral titration (inset of Figure 1) shows the Sc(OTf) 3 /PTIO • molar ratio being 1:2.This suggests that one molecule of PTIO − may be stabilized by one Sc 3+ (Scheme 2).When MeCN was replaced by methanol (MeOH) or ethanol (EtOH) as the solvent, such a spectral change was not observed.This suggests that the stronger solvation of Sc 3+ in MeOH or EtOH compared to that in MeCN may preclude the disproportionation from occurring.
spectral titration (inset of Figure 1) shows the Sc(OTf)3/PTIO • molar ratio being 1:2.This suggests that one molecule of PTIO − may be stabilized by one Sc 3+ (Scheme 2).When MeCN was replaced by methanol (MeOH) or ethanol (EtOH) as the solvent, such a spectral change was not observed.This suggests that the stronger solvation of Sc 3+ in MeOH or EtOH compared to that in MeCN may preclude the disproportionation from occurring.Scheme 2. Sc 3+ -promoted electron-transfer disproportionation of PTIO • .The spectral change after the addition of Sc(OTf)3 (7.9 × 10 −3 M) to a deaerated MeCN solution of PTIO • (5.5 × 10 −5 M) monitored by a stopped-flow technique is shown in Figure 2a.The time course change in the absorbance at 361 nm obeyed second-order kinetics (inset of Figure 2a).The observed second-order rate constant (kdisp, disp: disproportionation) was determined by a decrease in absorbance at 361 nm due to PTIO • .The kdisp value increases with increasing concentration of Sc(OTf)3 ([Sc(OTf)3]) to reach a constant value (Figure 2b).The limiting kdisp value (k∞) and the binding constant (K) between PTIO • and Sc 3+ were determined from curve fitting based on Scheme 3 and Equation (1) to be 9.3 × 10 4 M −1 s −1 and 1.0 × 10 3 M −1 , respectively.spectral titration (inset of Figure 1) shows the Sc(OTf)3/PTIO • molar ratio being 1:2.This suggests that one molecule of PTIO − may be stabilized by one Sc 3+ (Scheme 2).When MeCN was replaced by methanol (MeOH) or ethanol (EtOH) as the solvent, such a spectral change was not observed.This suggests that the stronger solvation of Sc 3+ in MeOH or EtOH compared to that in MeCN may preclude the disproportionation from occurring.
Scheme 2. Sc 3+ -promoted electron-transfer disproportionation of PTIO • .The spectral change after the addition of Sc(OTf)3 (7.9 × 10 −3 M) to a deaerated MeCN solution of PTIO • (5.5 × 10 −5 M) monitored by a stopped-flow technique is shown in Figure 2a.The time course change in the absorbance at 361 nm obeyed second-order kinetics (inset of Figure 2a).The observed second-order rate constant (kdisp, disp: disproportionation) was determined by a decrease in absorbance at 361 nm due to PTIO • .The kdisp value increases with increasing concentration of Sc(OTf)3 ([Sc(OTf)3]) to reach a constant value (Figure 2b).The limiting kdisp value (k∞) and the binding constant (K) between PTIO • and Sc 3+ were determined from curve fitting based on Scheme 3 and Equation ( 1) to be 9.3 × 10 4 M −1 s −1 and 1.0 × 10 3 M −1 , respectively.The spectral change after the addition of Sc(OTf) 3 (7.9× 10 −3 M) to a deaerated MeCN solution of PTIO • (5.5 × 10 −5 M) monitored by a stopped-flow technique is shown in Figure 2a.The time course change in the absorbance at 361 nm obeyed second-order kinetics (inset of Figure 2a).The observed second-order rate constant (k disp , disp: disproportionation) was determined by a decrease in absorbance at 361 nm due to PTIO • .The k disp value increases with increasing concentration of Sc(OTf) 3 ([Sc(OTf) 3 ]) to reach a constant value (Figure 2b).The limiting k disp value (k ∞ ) and the binding constant (K) between PTIO • and Sc 3+ were determined from curve fitting based on Scheme 3 and Equation (1) to be 9.3 × 10 4 M −1 s −1 and 1.0 × 10 3 M −1 , respectively.spectral titration (inset of Figure 1) shows the Sc(OTf)3/PTIO • molar ratio being 1:2.This suggests that one molecule of PTIO − may be stabilized by one Sc 3+ (Scheme 2).When MeCN was replaced by methanol (MeOH) or ethanol (EtOH) as the solvent, such a spectral change was not observed.This suggests that the stronger solvation of Sc 3+ in MeOH or EtOH compared to that in MeCN may preclude the disproportionation from occurring.
Cyclic voltammetry measurements were carried out to examine the effect of Sc 3+ on the redox behavior of PTIO • in deaerated MeCN containing 0.10 M Bu4NClO4.Two well- Cyclic voltammetry measurements were carried out to examine the effect of Sc 3+ on the redox behavior of PTIO • in deaerated MeCN containing 0.10 M Bu 4 NClO 4 .Two well-defined reversible redox waves were observed at −0.98 and +0.70 V vs. the saturated calomel electrode (SCE) for the one-electron reduction and oxidation of PTIO • to produce PTIO − and PTIO + , respectively, in the absence of Sc 3+ (Figure 3).Thus, the separation between the one-electron oxidation and reduction potentials obtained in this study (1.68 V) is slightly smaller than the literature value (1.73 V) [35].Upon the addition of 10 equiv. of Sc(OTf) 3 , however, a drastic change was observed in the cyclic voltammogram (Figure 3).The reversible wave for the one-electron reduction of PTIO • and the oxidation wave of PTIO • disappeared, while a new oxidation peak appeared at +1.66 V vs. SCE.This new peak was assigned to the oxidation of [(PTIO)Sc] 2+ , which was generated by the disproportionation of PTIO • upon the addition of Sc 3+ , to produce PTIO • and Sc 3+ (Scheme 4).Then, PTIO • was further oxidized to PTIO + (Scheme 4).Although the reduction peak of PTIO • in the presence of Sc(OTf) 3 could not be observed due to the disproportionation reaction, such a large (ca.2.6 V) positive shift of the one-electron reduction potential of PTIO • (equivalent to the oxidation peak for PTIO − ) upon the addition of Sc(OTf) 3 enables the disproportionation to occur.
Cyclic voltammetry measurements were carried out to examine the effect of Sc 3+ on the redox behavior of PTIO • in deaerated MeCN containing 0.10 M Bu4NClO4.Two welldefined reversible redox waves were observed at −0.98 and +0.70 V vs. the saturated calomel electrode (SCE) for the one-electron reduction and oxidation of PTIO • to produce PTIO − and PTIO + , respectively, in the absence of Sc 3+ (Figure 3).Thus, the separation between the one-electron oxidation and reduction potentials obtained in this study (1.68 V) is slightly smaller than the literature value (1.73 V) [35].Upon the addition of 10 equiv. of Sc(OTf)3, however, a drastic change was observed in the cyclic voltammogram (Figure 3).The reversible wave for the one-electron reduction of PTIO • and the oxidation wave of PTIO • disappeared, while a new oxidation peak appeared at +1.66 V vs. SCE.This new peak was assigned to the oxidation of [(PTIO)Sc] 2+ , which was generated by the disproportionation of PTIO • upon the addition of Sc 3+ , to produce PTIO • and Sc 3+ (Scheme 4).Then, PTIO • was further oxidized to PTIO + (Scheme 4).Although the reduction peak of PTIO • in the presence of Sc(OTf)3 could not be observed due to the disproportionation reaction, such a large (ca.2.6 V) positive shift of the one-electron reduction potential of PTIO • (equivalent to the oxidation peak for PTIO − ) upon the addition of Sc(OTf)3 enables the disproportionation to occur.The reversibility of the disproportionation of PTIO • by the addition of Sc(OTf)3 has also been examined as in the case of DPPH • [24].The addition of H2O to the PTIO • -Sc(OTf)3 system in deaerated MeCN resulted in the increase in the absorption band at 361 nm due to PTIO • (Figure 4) (Video S2 of the Supplementary Materials).This indicates that an electron-transfer comproportionation occurred to regenerate PTIO • .When H2O was replaced by EtOH or MeOH, the regeneration of PTIO • was also observed.However, the amount of the recovery was significantly lower compared to the case of H2O.
The spectral change after the addition of H2O (1.9 M) to a deaerated MeCN solution containing PTIO • (6.9 × 10 −5 M) and Sc(OTf)3 (3.5 × 10 −5 M) monitored by a stopped-flow technique is shown in Figure 5a.The time course change in the absorbance at 361 nm obeyed second-order kinetics (inset of Figure 5a), from which the observed second-order rate constant for the comproportionation (kcomp, comp: comproportionation) was deter- The reversibility of the disproportionation of PTIO • by the addition of Sc(OTf) 3 has also been examined as in the case of DPPH • [24].The addition of H 2 O to the PTIO • -Sc(OTf) 3 system in deaerated MeCN resulted in the increase in the absorption band at 361 nm due to PTIO • (Figure 4) (Video S2 of the Supplementary Materials).This indicates that an electron-transfer comproportionation occurred to regenerate PTIO • .When H 2 O was replaced by EtOH or MeOH, the regeneration of PTIO • was also observed.However, the amount of the recovery was significantly lower compared to the case of H 2 O.
The spectral change after the addition of H 2 O (1.9 M) to a deaerated MeCN solution containing PTIO • (6.9 × 10 −5 M) and Sc(OTf) 3 (3.5 × 10 −5 M) monitored by a stopped-flow technique is shown in Figure 5a.The time course change in the absorbance at 361 nm obeyed second-order kinetics (inset of Figure 5a), from which the observed second-order rate constant for the comproportionation (k comp , comp: comproportionation) was determined to be 1.4 × 10 4 M −1 s −1 .The comproportionation reactions between reduced and oxidized forms of nitroxyl radicals, hydroxyl amines, and oxoammonium cations, respectively, have been extensively studied [58][59][60][61][62][63][64][65][66].Goldstein et al. determined the k comp value between the hydroxylamine and oxoammonium cation derived from TEMPO to be 5.2 × 10 M −1 s −1 in a phosphate-buffered solution, while the deprotonation of the hydroxylamine resulted in a significant increase in the k comp value (3.3 × 10 4 M −1 s −1 ) [59].This suggests that the electron donor to PTIO + in this study is PTIO − , rather than its protonated form (PTIOH).The k comp value linearly increased with the increasing concentration of H 2 O, as shown in Figure 5b.Thus, the H 2 O-induced comproportionation reaction is shown in Scheme 5.It is suggested that the complex formation of Sc 3+ with H 2 O may weaken the interaction between PTIO − and Sc 3+ , leading to the electron-transfer comproportionation regenerating PTIO • .
The reversibility of the disproportionation of PTIO • by the addition of Sc(OTf)3 has also been examined as in the case of DPPH • [24].The addition of H2O to the PTIO • -Sc(OTf)3 system in deaerated MeCN resulted in the increase in the absorption band at 361 nm due to PTIO • (Figure 4) (Video S2 of the Supplementary Materials).This indicates that an electron-transfer comproportionation occurred to regenerate PTIO • .When H2O was replaced by EtOH or MeOH, the regeneration of PTIO • was also observed.However, the amount of the recovery was significantly lower compared to the case of H2O.
The spectral change after the addition of H2O (1.9 M) to a deaerated MeCN solution containing PTIO • (6.9 × 10 −5 M) and Sc(OTf)3 (3.5 × 10 −5 M) monitored by a stopped-flow technique is shown in Figure 5a.The time course change in the absorbance at 361 nm obeyed second-order kinetics (inset of Figure 5a), from which the observed second-order rate constant for the comproportionation (kcomp, comp: comproportionation) was determined to be 1.4 × 10 4 M −1 s −1 .The comproportionation reactions between reduced and oxidized forms of nitroxyl radicals, hydroxyl amines, and oxoammonium cations, respectively, have been extensively studied [58][59][60][61][62][63][64][65][66].Goldstein et al. determined the kcomp value between the hydroxylamine and oxoammonium cation derived from TEMPO to be 5.2 × 10 M −1 s −1 in a phosphate-buffered solution, while the deprotonation of the hydroxylamine resulted in a significant increase in the kcomp value (3.3 × 10 4 M −1 s −1 ) [59].This suggests that the electron donor to PTIO + in this study is PTIO − , rather than its protonated form (PTIOH).The kcomp value linearly increased with the increasing concentration of H2O, as shown in Figure 5b.Thus, the H2O-induced comproportionation reaction is shown in Scheme 5.It is suggested that the complex formation of Sc 3+ with H2O may weaken the interaction between PTIO − and Sc 3+ , leading to the electron-transfer comproportionation regenerating PTIO • .The reversible disproportionation of PTIO • was also confirmed by the electron paramagnetic resonance (EPR) spectroscopy.The well-resolved five lines with a g value of 2.0067 and a hyperfine coupling constant (aN) of 0.75 mT were observed in the EPR spectrum of PTIO • in deaerated MeCN (Figure 6a).After 0.5 equiv. of Sc(OTf)3 was added to the MeCN solution of PTIO • , the signal intensity was significantly decreased, as shown in Figure 6b, although a trace amount of PTIO • was observed.The addition of H2O to this  The reversible disproportionation of PTIO • was also confirmed by the electron paramagnetic resonance (EPR) spectroscopy.The well-resolved five lines with a g value of 2.0067 and a hyperfine coupling constant (aN) of 0.75 mT were observed in the EPR spectrum of PTIO • in deaerated MeCN (Figure 6a).After 0.5 equiv. of Sc(OTf)3 was added to The reversible disproportionation of PTIO • was also confirmed by the electron paramagnetic resonance (EPR) spectroscopy.The well-resolved five lines with a g value of 2.0067 and a hyperfine coupling constant (a N ) of 0.75 mT were observed in the EPR spectrum of PTIO • in deaerated MeCN (Figure 6a).After 0.5 equiv. of Sc(OTf) 3 was added to the MeCN solution of PTIO • , the signal intensity was significantly decreased, as shown in Figure 6b, although a trace amount of PTIO • was observed.The addition of H 2 O to this PTIO • -Sc(OTf) 3 system in deaerated MeCN resulted in the regeneration of PTIO • , which was confirmed by the increase in the EPR signal intensity due to PTIO • (Figure 6c).The reversible disproportionation of PTIO • was also confirmed by the electron paramagnetic resonance (EPR) spectroscopy.The well-resolved five lines with a g value of 2.0067 and a hyperfine coupling constant (aN) of 0.75 mT were observed in the EPR spectrum of PTIO • in deaerated MeCN (Figure 6a).After 0.5 equiv. of Sc(OTf)3 was added to the MeCN solution of PTIO • , the signal intensity was significantly decreased, as shown in Figure 6b, although a trace amount of PTIO • was observed.The addition of H2O to this PTIO • -Sc(OTf)3 system in deaerated MeCN resulted in the regeneration of PTIO • , which was confirmed by the increase in the EPR signal intensity due to PTIO • (Figure 6c).

Spectral and Kinetic Measurements
To avoid the effect of molecular oxygen (O 2 ), the reactions were carried out under strictly deaerated conditions, where a continuous flow of argon (Ar) gas was bubbled through each MeCN solution.Typically, a 10 µL of aliquot of Sc(OTf) 3 (1.3 × 10 −3 M) in deaerated MeCN was added to a quartz cuvette (10 mm i.d.), which contained PTIO • (7.2 × 10 −3 M) in deaerated MeCN.UV-vis spectral changes associated with the reaction were monitored using an Agilent 8453 photodiode array spectrophotometer thermostated with a Peltier temperature control at 298 K (Agilent Technologies, Santa Clara, CA, USA).The reaction rates were followed by monitoring the absorbance at 361 nm due to PTIO • after mixing of PTIO • in deaerated MeCN with a deaerated MeCN solution containing Sc(OTf) 3 at a volumetric ratio of 1:1 using a stopped-flow technique on a UNISOKU RSP-1000-02NM stopped-flow spectrophotometer (UNISOK Co., Ltd., Osaka, Japan), which was thermostated with a Thermo Scientific NESLAB RTE-7 Circulating Bath (Thermo Fisher Scientific, Inc., Waltham, MA, USA) at 298 K.For the regeneration reaction of PTIO • , a deaerated MeCN solution containing H 2 O were mixed with a deaerated MeCN solution of PTIO • (1.4 × 10 −4 M) and Sc(OTf) 3 (7.0 × 10 −5 M) at a volumetric ratio of 1:1 using a stopped-flow technique.The observed second-order rate constants (k disp and k comp ) were obtained by a least-square curve fit using an Apple MacBook Pro personal computer (Apple Inc., Cupertino, CA, USA) or an HP EliteDesk 800 G4 SFF (HP Inc., Palo Alto, CA, USA).The plots of 1/(A − A ∞ ) vs. time (A and A ∞ are the absorbance at the reaction time and the final absorbance, respectively) were linear until three or more half-lives, with a correlation coefficient ρ > 0.999.The k disp and k comp values were calculated by Slope(A 0 − A ∞ )/[PTIO • ] 0 , where Slope is the slope of the linear plot of 1/(A − A ∞ ) vs. time, and A 0 and [PTIO • ] 0 are the initial absorbance at 361 nm and initial concentration of PTIO • , respectively.In each case, it was confirmed that the k disp and k comp values derived from at least three independent measurements agreed within experimental error of ±5%.

Electrochemical Measurements
The cyclic voltammetry measurements were performed on an ALS-630A electrochemical analyzer (BAS Co., Ltd., Tokyo, Japan) in deaerated MeCN containing 0.10 M Bu 4 NClO 4 as a supporting electrolyte.The continuous flow of Ar gas was bubbled through each MeCN solution to avoid the effect of O 2 .The glassy carbon working electrode (3 mm diameter) (BAS Co., Ltd., Tokyo, Japan) was polished with polishing alumina suspension (BAS Co., Ltd., Tokyo, Japan) and an alumina polishing pad (BAS Co., Ltd., Tokyo, Japan) and rinsed with methanol (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan) prior to each measurement.The counter electrode was a platinum wire (BAS Co., Ltd., Tokyo, Japan).The concentration of PTIO • and Sc(OTf) 3 were 1.0 × 10 −3 and 1.0 × 10 −2 M, respectively.The measured potentials were recorded with respect to an Ag/AgNO 3 (0.01 M) reference electrode (BAS Co., Ltd., Tokyo, Japan) with a sweep rate of 100 mV s −1 at 298 K.The potentials were converted to those vs. the saturated calomel electrode (SCE) by adding 0.29 V [67].

Conclusions
The Sc 3+ with a strong Lewis acidity induced the electron-transfer disproportionation of PTIO • in deaerated MeCN.The electrochemical measurements suggested that the significantly large positive shift of the one-electron reduction potential of PTIO • in the presence of Sc 3+ enables the disproportionation to occur.The addition of H 2 O to the PTIO • -Sc(OTf) 3 system in deaerated MeCN resulted in the regeneration of PTIO • because the complex formation of Sc 3+ with H 2 O weakened the interaction between PTIO − and Sc 3+ .The drastic change in the redox reactivity of PTIO • in the presence of Sc 3+ as a strong Lewis acid provides not only valuable and fundamental information about the effects of the reaction environments on the reactivity of radical species but an excellent opportunity to develop radical-based redox flow batteries.

Figure 3 .
Figure 3. Cyclic voltammograms of PTIO • (1.0 × 10 −3 M) before (blue line) and after (orange line) the addition of Sc(OTf)3 (1.0 × 10 −2 M) in deaerated MeCN containing 0.10 M Bu4NClO4 recorded at the scan rate of 100 mV s −1 on a glassy carbon working electrode at 298 K. Arrows denote starting points and the direction of scanning.

Figure 4 .
Figure 4. Spectral change upon the addition of H2O to a deaerated MeCN solution of PTIO • (7.3 × 10 −5 M) and Sc(OTf)3 (3.7 × 10 −5 M) at 298 K. Orange and blue lines are the initial and final spectra, respectively.Arrows denote the direction of absorption changes.

Figure 5 .Figure 5 .
Figure 5. (a) Spectral change (interval: 0.1 s) observed after the addition of H 2 O (1.9 M) to a deaerated MeCN solution of PTIO • (6.9 × 10 −5 M) and Sc(OTf) 3 (3.5 × 10 −5 M) at 298 K. Orange and blue lines are the initial and final spectra, respectively.Arrows denote the direction of absorption changes.Inset: the second-order plot of the absorbance at 361 nm.(b) Plot of k comp vs. [H 2 O].