Synthesis of an elusive, stable 2-azaallyl radical guided by electrochemical and reactivity studies of 2-azaallyl anions

The super electron donor (SED) ability of 2-azaallyl anions has recently been discovered and applied to diverse reactivity, including transition metal-free cross-coupling and dehydrogenative cross-coupling processes. Surprisingly, the redox properties of 2-azaallyl anions and radicals have been rarely studied. Understanding the chemistry of elusive species is the key to further development. Electrochemical analysis of phenyl substituted 2-azaallyl anions revealed an oxidation wave at E1/2 or Epa = −1.6 V versus Fc/Fc+, which is ∼800 mV less than the reduction potential predicted (Epa = −2.4 V vs. Fc/Fc+) based on reactivity studies. Investigation of the kinetics of electron transfer revealed reorganization energies an order of magnitude lower than commonly employed SEDs. The electrochemical study enabled the synthetic design of the first stable, acyclic 2-azaallyl radical. These results indicate that the reorganization energy should be an important design consideration for the development of more potent organic reductants.


Synthesis of 1:
Using a modified literature procedure. 7 In air, add 7.0 g (38.6 mmol) of benzophenone imine and 100 mL of DCM to a 250 mL round bottom flask with a Teflon-coated stirbar. Add 4.14 g (38.6 mmol) of benzyl amine to this solution. Cap the round bottom flask with a needle pierced septum and stir for 14 h. Remove the solvent via rotary evaporation to yield a light yellow oil. Add 25 mL of hexanes to induce precipitation and place in a freezer. Collect the solid via vacuum filtration and dry at 50° C at 50 mtorr overnight. The compound was stored in a N2 filled glovebox. Yield: 9.85 g (94 %) NMR spectra matched previously reported spectra. 7

Synthesis of 1:
1 was synthesized according to the literature procedure. NMR spectra matched previously reported spectra. 8

Synthesis of 3:
Using a modified literature procedure. 7 In air, add 1.812 g (10 mmol) of benzophenone imine and 1.832 g (10 mmol) of diphenylmethylamine to a 100 mL round bottom containing 50 mL of 1,2-dichloroethane and a Teflon-coated stirbar. Cap the round bottom with a reflux condenser a needle pierced septum and reflux for 48 h. Filter the suspension through a celite plug, collecting the filtrate. Remove the solvent by rotary evaporation, yielding a white crystalline solid. Dry the compound at 50° C at 50 mtorr overnight. Transfer the solid to a medium porosity fritted filter and wash the solid with pentane (3x2 mL) in a N2 filled glovebox and dry under reduced pressure for 1 h. Yield: 2.56 g (74 %) NMR spectra matched previously reported spectra. 9

Synthesis of 3:
Using a modified literature procedure. 8 To a flame dried flask equipped with a stirbar and 1.000 gram of Na2SO4, was added 10 mL of dry DCM, benzaldehyde (0.265 g, 2.5 mmol) and trityl amine (0.648 g, 2.5 mmol). The reaction was stirred overnight, after which time the solution was filtered through a coarse porosity fritted filter and the solvent removed by rotary evaporation. The resulting solid was dried overnight at room temperature, 50 mtorr, yielding 0.712 g (82 %) NMR spectra matched previously reported spectra. 10

Synthesis of 3-Ad:
3-Ad was synthesized according to the literature procedure. NMR spectra matched previously reported spectra. 11
X-ray quality crystals were obtained from layering concentrated solutions of 2-Li in cold DME and layering with diethyl ether in a -30° C freezer (1:1 v/v).

Synthesis of 2-Na:
A 20 mL glass scintillation vial was charged with a Tefloncoated stirbar, 10 mL of dimethoxyethane (DME), and 0.173 g of sodium amide (4.422 mmol, 1.2 equiv). To this stirred slurry 1.00 g (3.69 mmol, 1 equiv) of solid 1 was added portionwise. The vial was sealed and stirred for 24 h. Filter the suspension through a Celite packed coarse porosity fritted filter. The filtrate was evacuated to driness and redissolved in 8 mL of DME and placed in an -30° C for 1 hour to sufficiently cool, after which it was layered with 10 mL of pentane and returned to the freezer. After 24 h, the mixture was filtered using a medium porosity fritted filter and the crystalline solid was washed with 3x2 mL of cold diethyl ether and dried under reduced pressure for 3 h. Yield: 1.57 g (75%) X-ray quality crystals were obtained from layering concentrated solutions of 2-Na in cold DME and layering with pentane in a -30° C freezer (1:1 v/v).

Synthesis of 2-K:
A 20 mL glass scintillation vial was charged with a Teflon-coated stirbar, 10 mL of toluene ,0.500 g (1.84 mmol, 1 equiv) of 1, and 0.487 g (1.84 mmol, 1 equiv) of 18-crown-6. To this mixture was added 0.217 g (1.93 mmol, 1.05 equiv) of KOtBu as a solid. The now red-purple mixture was stirred for 2 hours at room temperature. Volatiles were removed under reduced pressure. 10 mL of fresh toluene were added and the mixture was then heated to dissolve the purple powder. The resulting solution was allowed to slowly cool to room temperature before being moved into a -30° C freezer. After 24 h, the mixture was filtered using a medium porosity fritted filter and the crystalline solid was washed with 3x2 mL of cold diethyl ether and dried under reduced pressure for 3 h. Yield 0.950 g (90%) ). X-ray quality crystals were obtained from recrystallization from hot toluene.

Synthesis of 4:
A 20 mL glass scintillation vial was charged with a Tefloncoated stirbar, 10 mL of DME, and 0.136 g of sodium amide (3.45 mmol, 1.2 equiv). To this stirred slurry 1 g (2.88 mmol, 1 equiv) of solid 3 was added portionwise. The vial was sealed and stirred for 24 h. Filter the suspension through a Celite packed coarse porosity fritted filter. The filtrate was evacuated to driness and redissolved in 8 mL of DME and placed in an -30° C for 1 hour to sufficiently cool, after which it was layered with 10 mL of pentane and returned to the freezer. After 24 h, the mixture was filtered using a medium porosity fritted filter and the crystalline solid was washed with 3x2 mL of cold diethyl ether and dried under reduced pressure for 3 h. Yield: 1.45 g (78%) X-ray quality crystals were obtained from layering concentrated solutions of # in cold DME and layering with pentane in a -30° C freezer (1:1 v/v).

Dimerization of 2-Na yielding 51-1-rac 51-1-meso, and 51-3:
A 20 mL glass scintillation vial was charged with a Teflon coated stirbar, 4 mL of DME and 0.112 g of 2-Na (0.2 mmol, 1 equiv.) resulting in a purple solution. Another 20 mL glass scintillation vial was charged with 4 mL of DME and 0.040 g of AgPF6 (1.56 mmol, 1 equiv.). Both vials were placed in a -25 °C freezer to cool. After 15 minutes the vials were removed and the Ag + solution was slowly added to the solution of azaallyl anion, resulting in a color change upon complete addition to a yellow solution with black particulate. The solution was filtered using a Celite packed coarse porosity fritted filter. Remove volatiles under vacuum. The solid was redissolved in dichloromethane and filtered again through an alumina packed coarse porosity fritted filter, washing with dichloromethane. Again the volatiles were removed under reduced pressure. The primary species present in the solid were confirmed to be 51-1-rac and 51-1-meso in a 2:3 ratio by H 1 NMR in CDCl3.

Synthesis of 6:
A 20 mL glass scintillation vial was charged with a Teflon coated stirbar, 4 mL of DME and 0.100 g of 4-Na (1.56 mmol, 1 equiv.) resulting in a purple solution. Another 20 mL glass scintillation vial was charged with 4 mL of DME and 0.040 g of AgPF6 (1.56 mmol, 1 equiv.). Both vials were placed in a -25 °C freezer to cool. After 15 minutes the vials were removed and the Ag + solution was slowly added to the solution of azaallyl anion, resulting in a color change upon complete addition to a green solution with black particulate. The solution was filtered using a Celite packed coarse porosity fritted filter. Remove volatiles under reduced pressure. The solid was redissolved in pentane and filtered again using a Celite packed coarse porosity fritted filter. Again the volatiles were removed under reduced pressure resulting in a green powder yielding 0.041 g (82%) of 6.
X-ray quality crystals were grown from concentrated solutions of 6 in acetonitrile at −25 C.

Arylation of 2-M:
A 4 ml scintillation vial charged with a teflon coated stirbar, was charged with 0.041 g (0.2 mmol) of phenyl iodide and 1 mL of dimethoxyethane. While stirring, 0.4 mmol of 2-M was added to yield a purple solution. The vial was sealed and stirred for 4 hours. Upon finishing, the vial was exposed to air and 2 drops of water were quickly added, causing a color change from purple to yellow. The solution was passed through 1 mL of silica using 12 mL of EtOAc. The solvent was removed, and to the crude oil mixture was added CDCl3 and 7 μL of dibromomethane were added as an internal standard to determine the yield.

Alkylation of 2-M:
A 4 ml scintillation vial charged with a teflon coated stirbar, was charged with 0.026 g (0.1 mmol) of phenyl iodide and 1 mL of methyl tertbutyl ether. While stirring, 0.2 mmol of 2-M was added to yield a purple solution. The vial was sealed and stirred for 2 hours. Upon finishing, the vial was exposed to air and 2 drops of water were quickly added, causing a color change from purple to yellow. The solution was passed through 1 mL of silica using 12 mL of EtOAc. The solvent was removed, and to the crude oil mixture was added CDCl3 and     Figure S18b: Scan rate dependence of 2-Na (1 mmol*L -1 ) in DME using [ n NPr4][BAr F 4] (100 mmol*L -1 ) as the electrolyte.           Table S1: X-ray collection parameters.

Computational Details and Supplementary Data
Density Functional Theory (DFT) calculations were carried out using the Gaussian '16 suite (revision A.03). 12 The hybrid functional combining Becke's 3-parameter exchange functional combined with the Lee-Yang-Parr correlation functional (B3LYP) was employed. 6-31-G* basis sets as implemented in Gaussian 16 were employed for light atoms (H, C, N). Iodine atoms were treated with a 28-electron small core pseudo-potential associated with the Stuttgart-Bonn variety of natural orbital incorporating quasi-relativistic effects. Structures were optimized without constraints; convergence criteria were kept to their default values. All stationary points were verified to possess 0 (reaction intermediates) by analytical vibrational frequency calculations. Thermochemistry calculations were performed at 298.15 K. Molecular orbitals were rendered using Gaussview software.
Theory (previously reported here 13,14 ): Equation S1: Estimation of the free energy of the transition state of electron transfer (G*) from the reorganization energy () and from the free energy of electron transfer (G*).  S5: Definition of the internal reorganization energy of either the electron donor ( ( )) or the electron acceptor ( ( )) as related to the sum of the differences in the free energies of the starting material in its optimized geometry ( ( )) and the starting material in the geometry of the product ( ( )) and the differences in the free energies of the product in its optimized geometry ( ( )) and the product in the geometry of the starting material ( ( )).
Scheme S1: The reorganization energies and free energies of electron transfer determined by computation. The compounds are divided by color: green for 2-azaallyl compounds, red for compounds previously described by Murphy, and blue for electrophiles. The solvent field used for the calculation is placed underneath the arrow for electron transfer.

Scheme S2:
The calculated change in free energy Grel and the predicted barrier G* of electron transfer between the SEDs and the substrates. These values were calculated using the values in Scheme S# and the equations above. As a general trend the azaallyl anions have both lower Grel and G* of their electron transfer compared to the previously reported SEDs.