Selective control of donor-acceptor Stenhouse adduct populations with non-selective stimuli

Abstract

•Thermal isomerization pathways of donor-acceptor Stenhouse adducts are tuned by polarity•Non-selective stimuli produce selective responses in the DASA mixture Natural systems such as cells or organisms consist of thousands of stimulus-responsive and adaptive molecules and assemblies in enzymes and proteins. To achieve a multitude of responses and selectivity despite a limited set of available stimuli, nature relies on highly controlled and shallow multi-step energy landscapes. The development of small molecules with multi-step and multi-responsive reaction pathways provides an opportunity to achieve selectivity and multiple outcomes through the same stimuli. Such properties promise more complex and even life-like adaptive and responsive materials. This work showcases how the complex energy pathway of donor-acceptor Stenhouse adducts (DASAs) can be utilized to program a mixture of DASA derivatives with similar architectures to respond differently to the same change in their energy landscape through non-selective stimuli. Multifaceted material responses upon exposure to stimuli are key for developing life-like materials. Developing such synthetic systems, though not trivial, typically relies on orthogonal stimuli to enable control of molecular systems that enable multi-responsive behavior. Access to complex tunable reaction mechanisms with diverse energy landscapes offers an alternative strategy for controlling out-of-equilibrium processes without requiring orthogonal stimuli for each responsive unit. Donor-acceptor Stenhouse adducts (DASAs) are a class of photoswitches that have complex, tunable, and environmentally sensitive reaction pathways. We present the control of donor-acceptor Stenhouse adduct equilibrium and photoswitching kinetics through changes in the polarity of their environment. Polarity and light can be used to selectively control the pathway outcomes of three DASA derivatives where the orthogonal response comes from changes in the energy landscape and is not driven by their orthogonal response to the given stimuli. This work paves the way to designing multi-responsive and self-regulating life-like materials. Multifaceted material responses upon exposure to stimuli are key for developing life-like materials. Developing such synthetic systems, though not trivial, typically relies on orthogonal stimuli to enable control of molecular systems that enable multi-responsive behavior. Access to complex tunable reaction mechanisms with diverse energy landscapes offers an alternative strategy for controlling out-of-equilibrium processes without requiring orthogonal stimuli for each responsive unit. Donor-acceptor Stenhouse adducts (DASAs) are a class of photoswitches that have complex, tunable, and environmentally sensitive reaction pathways. We present the control of donor-acceptor Stenhouse adduct equilibrium and photoswitching kinetics through changes in the polarity of their environment. Polarity and light can be used to selectively control the pathway outcomes of three DASA derivatives where the orthogonal response comes from changes in the energy landscape and is not driven by their orthogonal response to the given stimuli. This work paves the way to designing multi-responsive and self-regulating life-like materials. The ability to adapt to environmental stimuli and chemical signals is fundamental to biological processes. Numerous naturally occurring molecular systems, such as the activation of proteins and signal cascades,1Wu H. 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Synthetic systems have been designed to respond to both physical (e.g., light, electricity, temperature, and pressure) and chemical (e.g., solvent vapor, chemical analyte, and change in pH) stimuli.2Nie H. Self J.L. Kuenstler A.S. Hayward R.C. Read de Alaniz J. Multiaddressable photochromic architectures: from molecules to materials.Adv. Optical Mater. 2019; 7: 1900224https://doi.org/10.1002/adom.201900224Crossref Scopus (58) Google Scholar,3Andréasson J. Pischel U. Light-stimulated molecular and supramolecular systems for information processing and beyond.Coord. Chem. Rev. 2021; 429: 213695https://doi.org/10.1016/j.ccr.2020.213695Crossref Scopus (24) Google Scholar,4Zarzar L.D. Aizenberg J. Stimuli-responsive chemomechanical actuation: a hybrid materials approach.Acc. Chem. Res. 2014; 47: 530-539https://doi.org/10.1021/ar4001923Crossref PubMed Scopus (71) Google Scholar,5Cruz L. Basílio N. Mateus N. de Freitas V. Pina F. 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Among the various types of stimulus-responsive molecules, photochromic compounds (which undergo a reversible transformation between at least two forms) have multiple, enabling the following advantages: (1) the photochromic molecules can impart reversible, dynamic control over the material properties upon light irradiation; (2) light is often orthogonal to other stimuli, enabling the design and fabrication of more sophisticated systems; (3) the properties of light, including wavelength, mode, and polarization, can be independently controlled to allow for multiplexing with spatiotemporal control; and (4) light is a traceless reagent and does not produce waste products. This realization has led to efforts to go beyond the expected two states that arise from “on/off” or binary “0/1” information afforded by a single photochrome. For example, integrating more than one photochromic unit within a single compound has been uniquely coupled with various signaling agents (i.e., chemical, pH, redox, thermal, or photo) to increase system complexity. However, these methods require a delicate balance to obtain emergent properties without disabling the intrinsic switching properties of the individual components. Because these methods control the logic at the level of a molecular photoswitch, the introduction of photochromes that are activated at different wavelengths is critical. Recent work showed that at least eight distinguishable isomers can be obtained from molecules with combinations of pH- and light-sensitive moieties with the use of a mixture of pH changes and irradiation at different wavelengths.6Szalóki G. Sevez G. Berthet J. Pozzo J.L. Delbaere S.A. A simple molecule-based octastate switch.J. Am. Chem. Soc. 2014; 136: 13510-13513https://doi.org/10.1021/ja506320jCrossref Scopus (72) Google Scholar,7Guerrin C. 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By selectively targeting a specific protein, for example, in a complex mixture of proteins, nature is able to use a set of common stimuli to control a remarkably diverse set of functions. A strategy that is less explored yet more closely mimics nature’s approach is to design synthetic systems that control the out-of-equilibrium pathways that govern the collective response of systems relying on multiple controllable states. This is in part because most traditional responsive molecules lack multi-step processes where small changes in the energy landscape due to chemical cues can result in differing pathway outcomes, regardless of the light irradiation used to drive the reaction out of equilibrium. Donor-acceptor Stenhouse adducts (DASAs) have a multi-step mechanism that offers multiple addressable levers within a single-photochromic system.9Helmy S. Leibfarth F.A. Oh S. Poelma J.E. Hawker C.J. Read de Alaniz J. 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Specifically, we recognized that different classes of DASA derivatives exhibit overall orthogonal responses to the same environmental signal, presenting an opportunity to tune the kinetics and thermodynamics of DASA derivatives with different architectures by using small changes in polarity. Recent work by the Huang group took advantage of the environmental sensitivity of various DASA derivatives to design sequential logic encryption materials, showcasing the power of using DASAs as multi-stimulus-responsive moieties.32Dong Y. Ling Y. Wang D. Liu Y. Chen X. Zheng S. Wu X. Shen J. Feng S. Zhang J. et al.Harnessing molecular isomerization in polymer gels for sequential logic encryption and anticounterfeiting.Sci. Adv. 2022; 8: eadd1980https://doi.org/10.1126/sciadv.add1980Crossref Scopus (2) Google Scholar We envisioned that understanding the effect of polarity on the energy landscape of DASA derivatives would allow for independent control of populations of a mixture of DASAs with non-selective stimuli. The complex mechanism of DASAs includes various isomers and barriers that are close in energy. Because of the nature of this mechanism, small environmental changes, which influence steps along the isomerization pathway, should generate different responses by driving the molecules to separate parts of the energy landscape. To investigate this hypothesis, we chose to study the effect of solvent polarity on three commonly used DASA derivatives (DASA-1, DASA-2, and DASA-3). These three derivatives have differences in the electronic properties of the donors and acceptors, resulting in different ground-state charge separation, i.e., as measured through the solvatochromic slope of the λmax in ten different solvents, where a more negative solvatochromic slope indicates a higher charge separation.29Sroda M.M. Stricker F. Peterson J.A. Bernal A. Read de Alaniz J. Donor–acceptor Stenhouse adducts: exploring the effects of ionic character.Chem. Eur. J. 2021; 27: 4183-4190https://doi.org/10.1002/chem.202005110Crossref Scopus (24) Google Scholar Previous work by Lerch et al. showed that the quantum yield of activation from the A to B of three DASA derivatives is largely independent of solvent and that the difference in kinetics is largely due to the ground-state energy surface.30Lerch M.M. Di Donato M. Laurent A.D. Medved M. Iagatti A. Bussotti L. Lapini A. Buma W.J. Foggi P. Szymański W. Feringa B.L. Solvent effects on the actinic step of donor–acceptor Stenhouse adduct photoswitching.Angew. Chem. Int. Ed. 2018; 57: 8063-8068https://doi.org/10.1002/anie.201803058Crossref Scopus (61) Google Scholar We used the solvation model based on density (SMD) in chloroform with increasing dielectric constant to model the influence on increasing polarity on the energy surface of DASA-1, DASA-2, and DASA-3. Structures were optimized with M06-2X/6-31+G(d,p), which has previously been shown to give reasonable results for DASAs.19Zulfikri H. Koenis M.A.J. Lerch M.M. Di Donato M. Szymański W. Filippi C. Feringa B.L. Buma W.J. Di M. Szyma W. et al.Taming the complexity of donor–acceptor Stenhouse adducts: infrared motion pictures of the complete switching pathway.J. Am. Chem. Soc. 2019; 141: 7376-7384https://doi.org/10.1021/jacs.9b00341Crossref PubMed Scopus (48) Google Scholar Single points were calculated with M06-2X/def2-QZVP. All calculations were done with Gaussian 16.33Frisch M.J. Trucks G.W. Schlegel H.B. Scuseria G.E. Robb M. Cheeseman J.R. Scalmani G. Barone V. Petersson G. Nakatsuji H. et al.Gaussian 16, revision C.01. Gaussian, 2016https://gaussian.com/citation/Google Scholar The method was chosen for its inexpensive cost and reasonable performance compared with those of previously benchmarked methods (see supplemental information section 4.1 for more details). The double-bond character along the triene is directly related to each of the transition-state barriers, both forward (B-Bʹ-Cenol) and backward (Cenol-Bʹ-B-A) (Figures 2A and 2B). A key principle here is that the barrier between A and B behaves opposite to the barriers between B-Bʹ and Bʹ-Cenol upon a change in polarity as a result of the bond alternation along the triene (Figures 2A, 2B, and S4–S27). Upon an increase in polarity, the double-bond character of C3–C4 decreases, leading to a decrease in the energy barrier for the corresponding bond rotation (A to B) (Figures 2 and S7–S27). The same effect leads to an increase in the double-bond character around the C2–C3 bond, leading to an increase in the energy barrier of the corresponding bond rotation (B to B′) (Figures S7–S27). The subsequent 4π-electrocyclization and proton transfer are influenced by the distance between C5 and C1, which is farther in increasingly polar solvents, most likely because of single vs. double bonds along the triene (Figures 2, S5, and S6). These overall trends are similar for all DASAs investigated here (DASA-1, DASA-2, and DASA-3; Figures 3A, S5, and S6).Figure 3Difference in energy landscape for the investigated DASA structuresShow full caption(A) DASA structures of investigated compounds and their respective solvatochromic slope.(B) Calculated energy landscape for the three compounds with M06-2X/def2-QZVP in SMD(chloroform). Energy barriers are shown for each step. Values show the highest barrier after the reactions from B and the recovery from C: the rate-determining steps for the forward and back reactions, respectively.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) DASA structures of investigated compounds and their respective solvatochromic slope. (B) Calculated energy landscape for the three compounds with M06-2X/def2-QZVP in SMD(chloroform). Energy barriers are shown for each step. Values show the highest barrier after the reactions from B and the recovery from C: the rate-determining steps for the forward and back reactions, respectively. Although increasing the dielectric constant of DASA derivatives appears to influence each of the steps of the isomerization in a similar fashion, the DASA derivatives have experimentally different equilibrium and kinetic properties.9Helmy S. Leibfarth F.A. Oh S. Poelma J.E. Hawker C.J. Read de Alaniz J. Photoswitching using visible light: a new class of organic photochromic molecules.J. Am. Chem. Soc. 2014; 136: 8169-8172https://doi.org/10.1021/ja503016bCrossref PubMed Scopus (336) Google Scholar,17Lerch M.M. Wezenberg S.J. Szymanski W. Feringa B.L. Unraveling the photoswitching mechanism in donor–acceptor Stenhouse adducts.J. Am. Chem. Soc. 2016; 138: 6344-6347https://doi.org/10.1021/jacs.6b01722Crossref Scopus (120) Google Scholar To determine the source of the differing behavior, we compared the initial energy landscapes of the three DASA derivatives in chloroform. DASA-1 consists of a dialkylamine donor with strong electron-donating properties combined with a weakly withdrawing acceptor in N,N′-dimethyl barbituric acid, resulting in a solvatochromic slope of −44 nm.27Stricker F. Sanchez D.M. Raucci U. Dolinski N.D. Zayas M.S. Meisner J. Hawker C.J. Martínez T.J. Read de Alaniz J. A multi-stage single photochrome system for controlled photoswitching responses.Nat. Chem. 2022; 14: 942-948https://doi.org/10.1038/s41557-022-00947-8Crossref Scopus (2) Google Scholar DASA-2 retains the weakly withdrawing acceptor but replaces the donor with a weakly donating 2-methylindoline, resulting in a less charge-separated ground state with a solvatochromic slope of -5 nm. DASA-3 consists of a weak donor (2-methylindoline) with a strongly withdrawing CF3-pyrazolone carbon acid as the acceptor. DASA-3 has the most charge-separated ground state with a solvatochromic slope of −60 nm (Figure 3A).29Sroda M.M. Stricker F. Peterson J.A. Bernal A. Read de Alaniz J. Donor–acceptor Stenhouse adducts: exploring the effects of ionic character.Chem. Eur. J. 2021; 27: 4183-4190https://doi.org/10.1002/chem.202005110Crossref Scopus (24) Google Scholar The first important difference in the three DASA derivatives is in the barrier from B to A such that less charge separation results in a higher barrier (Figure 3B). The second key difference is the stability of the first closed isomer, Cenol, in comparison with that of A (Figure 3B). Cenol is the most stabilized for DASA-3 (presumably because of a gain in stability from the aromatic character of the pyrazalone in the closed form) and the least stabilized for DASA-1 (Figure 3B). DASA-1 might have a relatively destabilized Cenol isomer because of increased stabilization of A, which is lost upon cyclization. These differences result in faster ring closure for DASA-3 as a result of a lower barrier for cyclization as well as a faster recovery of A due to having a stabilized Cenol isomer form and therefore a higher concentration of Cenol present before the rate-determining step of the recovery. Similarly, DASA-3 has two steps with similar energy barriers in the recovery (B to A and Cenol to B′), enabling a different rate-determining step and therefore kinetic regime in different environments. In contrast, DASA-1 and DASA-2 have a less stabilized Cenol isomer and are therefore driven to other more favored ring-closed isomers, such as Czwit or Cketo, which might have higher barriers for isomerization back to the open form (Figure 3B). These results highlight how changes in the electronics between DASA derivatives lead to vastly different inherent switching properties as a result of subtle changes in their initial energy landscapes. To investigate how these trends in the energy landscape translate into changes in both kinetics and thermodynamics, we utilized time-dependent UV-visible (UV-vis) spectroscopy and 1H-NMR (Figure 4). DASA-1 can be irradiated with 530 nm light in dichloromethane (DCM) (ε = 8.9), resulting in a 10% loss of absorbance at a λmax of 564 nm in 100 s as a result of the transformation to the closed form. If acetonitrile (ACN, more polar than DCM; ε = 37.5) is added, the forward switching of the DASA slows down, resulting in an overall smaller loss of absorbance in the same amount of time. In contrast, adding diethyl ether (Et2O, ε=4.3), which is less polar than DCM, results in a slight increase in the amount of DASA forming the ring-closed isomer (Figure 4B). The recovery slows down as the amounts of ACN increase, whereas Et2O does not appear to significantly influence the kback (Table S4). These data are in line with the expectation that the increasing barrier from B to B′, combined with a decrease in the back reaction barrier from B to A, should lead to a decreased rate of forward isomerization based on the thermal interconversion steps. We confirmed this by observing the B population through pump-probe spectroscopy. Here, adding ACN led to a decrease in the population of B, whereas adding Et2O slightly increased the population of B under irradiation (Figure S37). Meanwhile, we observed a slowdown in recovery rates upon the addition of ACN, suggesting that the rate-determining step is either Bʹ to B or a different barrier for isomerization between the closed forms that we did not calculate. Irradiation of DASA-2 in DCM with a 617 nm LED led to a full loss of absorbance (Figure 4C). In the dark, we observed recovery to initial absorbance with a two-magnitude slower kback (Table S5) than DASA-1. The forward switching of DASA-2 did not change significantly with a small addition of ACN or Et2O. The rate of recovery, however, increased as the addition of ACN increased and decreased as the addition of Et2O increased. This seems to be reflective of the fact that the high barrier from B to A is solely responsible for the changes in recovery kinetics. Monitoring the population of B via pump-probe spectroscopy showed a similar trend between DASA-2 and DASA-1 with a drop in the population of B and less C-isomer population generated over a set irradiation time with increasing polarity via the addition of ACN (Figure S38). We observed the opposite when we decreased the polarity by adding Et2O, reflecting the increase in B to A and decrease in B to Bʹ barriers (Figure 4C). DASA-3 reached a 33% loss in absorbance when it was irradiated with a 617 nm LED in DCM (Figure 4D). Interestingly, increasing amounts of both ACN and Et2O led a higher percentage of DASA-3 to close upon irradiation in conjunction with a decrease in the rate of recovery from the closed form to the open form in the dark (Table S6). Although we were not able to detect the population of B through our pump-probe methods, we did observe a trend similar to that in DASA-1 and DASA-2 regarding the generation of C-isomers. Increasing the polarity by adding ACN resulted in a decrease in the amount of C-isomers generated in a short irradiation time, whereas the addition of Et2O led to an increase in the generation of C (Figure S39). This suggests that the back reaction from B to A also increases for DASA-3 as polarity increases, although the total amount of C-isomers generated over longer periods of time increases as a result of a simultaneous decrease in the rate of recovery of the closed form (Figure 4D). These results are promising to us because even though polarity influences the barriers of these three DASA derivatives in similar ways, the resulting overall switching behaviors are different. As polarity increases, the forward switching of DASA-1 shuts down, the rate of recovery of DASA-2 increases, and the total switching of DASA-3 increases, whereas the rate of recovery decreases. Furthermore, a similar influence can be observed through stabilizers in solvents (Figure S40) or can be used to reversibly control the photoswitching process through other additives (Figures S41 and S42). To more deeply understand the effect of polarity on the open- vs. closed-from of DASA equilibria, we monitored the 1H-NMR spectroscopy after storing each DASA in the dark for 24 h with and without the addition of dueterated ethaonol (EtOD). DASAs have been shown to exhibit different closed-form isomers; for example, DASA-1 and DASA-3 form the zwitterionic closed form Czwit, whereas DASA-2 forms Cketo (Figure 2).11Hemmer J.R. Page Z.A. Clark K.D. Stricker F. Dolinski N.D. Hawker C.J. Read de Alaniz J. Controlling dark equilibria and enhancing donor-acceptor Stenhouse adduct photoswitching properties through carbon acid design.J. Am. Chem. Soc. 2018; 140: 10425-10429https://doi.org/10.1021/jacs.8b06067Crossref Scopus (98) Google Scholar,12Mallo N. Foley E.D. Iranmanesh H. Kennedy A.D.W. Luis E.T. Ho J. Harper J.B. Beves J.E. Structure-function relationships of donor-acceptor Stenhouse adduct photochromic switches.Chem. Sci. 2018; 9: 8242-8252https://doi.org/10.1039/c8sc03218aCrossref Scopus (73) Google Scholar,22Hemmer J.R. Poelma S.O. Treat N. Page Z.A. Dolinski N.D. Diaz Y.J. Tomlinson W. Clark K.D. Hooper J.P. Hawker C. et al.Tunable visible and near infrared photoswitches.J. Am. Chem. Soc. 2016; 138: 13960-13966https://doi.org/10.1021/jacs.6b07434Crossref Scopus (170) Google Scholar Upon the addition of 10% EtOD, the equilibrium for DASA-1 shifted from 74% to 35% open (Figures 4F and S50). DASA-2, on the other hand, saw a slight increase in the equilibrium from 38% to 46% open (Figures 4G and S51). DASA-3, similar to DASA-1, saw a drop in equilibrium from 100% to 43% open upon the addition of 10% EtOD (Figures 4H and S52). This was most likely due to the fact that the preferred respective closed forms of DASA-1 and DASA-3 (Czwit) are stabilized by polarity, whereas the preferred closed form of DASA-2 (Cketo) is destabilized by polar media.10Lerch M.M. Szymański W. Feringa B.L. The (photo)chemistry of Stenhouse photoswitches: guiding principles and system design.Chem. Soc. Rev. 2018; 47: 1910-1937https://doi.org/10.1039/c7cs00772hCrossref PubMed Scopus (168) Google Scholar,13Stricker F. Seshadri S. Read de Alaniz J. Donor–acceptor Stenhouse adducts.in: Pianowski Z.L. Molecular Photoswitches. Wiley, 2022: 303-324https://doi.org/10.1002/9783527827626.ch14Crossref Google Scholar,19Zulfikri H. Koenis M.A.J. Lerch M.M. Di Donato M. Szymański W. Filippi C. Feringa B.L. Buma W.J. Di M. Szyma W. et al.Taming the complexity of donor–acceptor Stenhouse adducts: infrared motion pictures of the complete switching pathway.J. Am. Chem. 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J. 2021; 27: 4183-4190https://doi.org/10.1002/chem.202005110Crossref Scopus (24) Google Scholar These trends held true with the addition of deuterated dimethyl sulfoxide (DMSO-d6) and ACN as well, although the effect seemed more influenced by hydrogen bonding given that ACN showed less of an effect than dimethyl sulfoxide and ethanol, which had stronger hydrogen-bonding abilities and a larger influence on the equilibrium (Table S1; supplemental information section 11). Interestingly, DMSO-d6 showed an outsized effect on the equilibrium of DASA-3 presumably because of its hydrogen-bond acceptor character. DASAs experience the same de facto change in their energy landscape, but as a result of different starting energy and hybridization, the overall observed response is drastically different. Each of the DASAs favors different parts of the mechanism upon the addition of polarity, allowing for pathway selectivity and control of the accessed state through a secondary stimulus controlling the ground-state chemistry. To showcase this opportunity, we investigated a mixture of DASA-1, DASA-2, and DASA-3 (Figures 5A–5C and S60–S64) in toluene. We chose toluene because its overall slower kinetics lead DASA-2 to close upon irradiation and the subsequent recovery is minimal over extended periods of time (Figures 5B, 5C, and S61), whereas DASA-1 and DASA-3 demonstrate good switching (with slower recovery than in DCM; Figures 5A–5C, S60, and S62). Although toluene is less polar than DCM and the energy surface would start in a more nonpolar environment, increasing the polarity should result in the same effects on the energy surface and therefore similar overall effects on the switching kinetics, as shown in DCM. We chose dimethyl sulfoxide as an additive because of its large effect on the equilibrium of DASA-3 (Table S1 and Figure S55). As predicted, when 15 vol % of DMSO was added to toluene, each DASA had a distinct change in switching properties (Figures 5A–5C and S60–S62). The addition of 15 vol % DMSO caused DASA-3 to quickly thermally isomerize to the closed form (Figures 5A–5C and S62) now that it was thermodynamically trapped in the C-isomers. DASA-1 reset to a new thermal equilibrium with a higher percentage of closed form while suppressing the response to irradiation (Figures 5A and S60). DASA-1 thermally isomerized slower than DASA-3 because of a higher barrier for isomerization, and the light-induced isomerization was shut down by the now lower barrier from B to A than to B′. The addition of DMSO caused DASA-2 to recover from the closed form to the open form and allowed for reversible photoswitching (Figures 5A–5C and S61). The fact that each of these DASAs reacted differently to the same environmental change enables the addition of a single stimulus to change the overall behavior of a complex system of similar molecules. When DASA-1, DASA-2, and DASA-3 were mixed, three overlapping absorbances with distinctive peaks were present (Figures 5A, 5C, and S63). Upon irradiation with white light, all three DASA derivatives (for details on how each population is followed, see supplemental information section 13.3) converted to the closed form (Figure 5C). After irradiation, DASA-1 and DASA-3 recovered, whereas DASA-2 remained trapped in the closed form. This change can be observed in Figure 5A, where only two absorbance peaks are visible upon recovery after the first irradiation. DASA-1 and DASA-3 could then be switched repeatedly with white light, whereas DASA-2 continued to be trapped in the closed form over extended periods of time as a result of a combination of slow thermal recovery and the photochemical reaction from the UV-vis measurement beam (recovery can be observed in 1H-NMR; Figures S74–S77). When 15 vol % of DMSO was added to the solution (Figure 5C), the absorbance of DASA-3 decreased in the dark to 6% of the initial value. The absorbance of DASA-1 also decreased over time to a new equilibrium. Conversely, we observed an increase in the absorbance of DASA-2. In this more polar environment, DASA-1 and DASA-2 were partially in the open form, whereas DASA-3 was closed (Figure 5A). Upon irradiation, DASA-2 switched reversibly, whereas DASA-1 was kinetically trapped in the open form, and DASA-3 was thermodynamically trapped in the closed form (Figure 5C). Through the addition of one stimulus, each DASA reacted differently to light, demonstrating an ability to control a complex system by using multi-stimulus-responsive DASA materials (for a full list of states, see Figure S73). To highlight the generality of this behavior, we repeated the experiment with DASAs similar in electronics to DASA-1 and DASA-2 and observed the same trends (supplemental information section 13.2). Our results highlight the potential of multi-step processes to be used to selectively distinguish between compounds and states without requiring selective stimuli. We believe that using a pathway-discrimination approach to control multi-responsive systems will lead to the design of new complex life-like systems. Here, we investigated the impact of solvent polarity on DASA photoswitches by using a combined computational and experimental approach. Solvent polarity influences key points on the potential energy surface of DASA derivatives that govern the kinetics and thermodynamics of switching. Although polarity has a similar impact on the potential energy surface of each DASA investigated, their overall response varies as a result of their initial energy landscapes. These different responses allow for the use of two non-selective stimuli to selectively control the populations of three DASA derivatives in a mixture. This approach highlights the potential to use non-selective stimuli to control small molecules with complex multi-stimulus-responsive, multi-step potential energy surfaces. The development of such complex systems that can be independently controlled with non-selective stimuli is key to designing systems that mimic the complexity found in nature.