A rational design strategy of radical-type mechanophores with thermal tolerance

Radical-type mechanophores (RMs) are attractive molecules that undergo homolytic scission of their central C–C bond to afford radical species upon exposure to heat or mechanical stimuli. However, the lack of a rational design concept limits the development of RMs with pre-determined properties. Herein, we report a rational design strategy of RMs with high thermal tolerance while maintaining mechanoresponsiveness. A combined experimental and theoretical analysis revealed that the high thermal tolerance of these RMs is related to the radical-stabilization energy (RSE) as well as the Hammett and modified Swain–Lupton constants at the para-position (σp). The trend of the RSE values is in good agreement with the experimentally evaluated thermal tolerance of a series of mechanoresponsive RMs based on the bisarylcyanoacetate motif. Furthermore, the singly occupied molecular orbital (SOMO) levels clearly exhibit a negative correlation with σp within a series of RMs that are based on the same skeleton, paving the way toward the development of RMs that can be handled under ambient conditions without peroxidation.


Synthesis of PMMA-BiACA-4-PMMA (Scheme 2 (in main text))
BiACA-4-Int (64 mg, 0.068 mmol) and methyl methacrylate (4.1 g, 4.4 mL, 41 mmol, 600 eq.) were mixed in 7 mL of toluene at room temperature. The mixture was bubbled with N2 for 30 minutes. To the mixture was added copper (I) bromide (25 mg, 0.17 mmol, 2.5 eq.) and 4,4′-Dinonyl-2,2′dipyridyl (70 mg, 0.17 mmol, 2.5 eq.). The mixture was bubbled with N2 for another 30 minutes. The mixture was heated to 60 °C for 2 hours. Then, to the mixture was added tributyltin hydride (240 mg, 41 mmol, 12 eq.), and the resulting mixture was heated for another 30 min. The mixture was cooled down to room temperature and quenched by adding CHCl3. The copper complex was removed by passing the mixture through an active neutral alumina column. The resulting solution was concentrated and poured into methanol.

EPR studies
5 mM anisole solutions of s-dimers (20 mM for BiACA-4 and BiACA-5, for better sensitivities) were charged in a 3 mm glass capillary with more than 43.5 mm height (effective measuring range), which was then sealed after freeze-thaw cycles. In all cases, the g-values of radical signals were determined as 2.003, suggesting the signals observed were carbon-centered radicals. The dissociation constants Kd were calculated, of which the natural logarithms ln Kd were plotted against 1/T, where T was temperature in kelvin. The natural logarithms of Kd (ln Kd) at 100 °C in anisole of each compound were recorded with the computational results of RSE and a-SOMO levels in Table S1.

5-1. Grinding experiment
Grinding experiments were carried out at room temperature with a ball-mill device (Retsch Mixer Mill MM 400) with a frequency of 30 Hz. About 50 mg of PMMA-BiACA-4-PMMA, together with a stainless ball (d = 5 mm) was charged into the grinding jar. The sample was ground for 60 minutes. No change of optical properties was observed, e.g., color change or fluorescence. The ground sample was collected in an EPR 5 mm quartz capillary, and the capillary was sealed after being degassed. The EPR spectra of the ground samples were measured using a microwave power of 0.2 mW and field modulation of 0.2 mT with a time constant of 0.03 s and a sweep rate of 0.0625 mT/s at room temperature. The concentration of the radicals formed from the cleavage of PMMA-BiACA-4-PMMA unit was determined by comparing the area of the observed integral spectrum with a 0.02 mM solution of TEMPOL in benzene under the same experimental conditions. The Mn 2+ signal was used as an auxiliary standard. The grinding experiments and the EPR measurements were conducted 3 times and the average was used for determination. About 0.102 ± 0.006 % of PMMA-BiACA-4-PMMA dissociated.
18 mg of PMMA-BiACA-4-PMMA (Mn = 24 kDa, PDI = 1.18, 0.0008 mmol) was dissolved in 5 mL of anisole at room temperature. The system was bubbled with nitrogen for 30 minutes. Then, the system was sealed and heated to 130 °C for 90 minutes with an oil bath (first heating). After cooling down to room temperature, the resulting solution was sampled for GPC analysis. Then, to the mixture was added BiACA-4-diol (16 mg, 0.0245 mmol, 30 eq.). The mixture was bubbled with nitrogen for 30 minutes. The mixture was sealed and heated to 130 °C for 90 minutes with an oil bath (second heating). After cooling down to room temperature. The resultant was sampled for GPC analysis.      CoGEF calculations were performed following Beyer's method 6 using Gaussian 16 program package. 1 The distance between the two methyl groups was constrained and increased by increments of 0.1 Å at B3LYP/6-31G(d) level. In order to obtain the energy profile at higher calculation level, after done the calculation, the one previous structure before reaching the top of energy profile was extracted, and it was optimized at UB3LYP/6-31++G(d,p) levels with bond freezing of two methyl groups. Further CoGEF calculation were performed with increments of 0.05 Å at UB3LYP/6-31++G(d) level. The energy of obtained structures at each mechanophores were normalized by each calculated levels of initial structure 0 kcal/mol. Fmax values were calculated from the slope by two points structures preceding the abrupt attenuation in energy. Obtained normalized energies (a.u.) were convert to nJ/mol, and the values were divided by the Avogadro constant. Calculated values (nJ) were divided by displacement (Dm) to provided force of nJ/m (nN).
The geometries were given by stick type model (atom color: gray = carbon, red = oxygen, blue = nitrogen, white = hydrogen).

8-1. Geometry optimization
Cartesian coordinates of all optimized structures at each calculated level were attached to ZIP. All structure were checked not only imaginary vibration but also spin contamination <S 2 > under 0.76 at all calculation levels. Geometry optimization were performed with the following options.
Empiricaldispersion=gd3 was added to option as needed.