The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool

Article Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool To Shift Reaction Networks Out-of-Equilibrium Using Light Energy Martin Herder and Jean-Marie Lehn* Institut de Science et d’Ingénierie Supramoléculaires, Université de Strasbourg, 8 allée Gaspard Monge, 67000 Strasbourg, France S Supporting Information *

ABSTRACT: We implement sensitized alkoxyamines as “photodynamic covalent bonds”bonds that, while being stable in the dark at ambient temperatures, upon photoexcitation efficiently dissociate and recombine to the bound state in a fast thermal reaction. This type of bond allows for the photochemically induced exchange of molecular building blocks and resulting constitutional variation within dynamic reaction networks. To this end, alkoxyamines are coupled to a xanthone unit as triplet sensitizer enabling their reversible photodissociation into two radical species. By studying the photochemical properties of three generations of sensitized alkoxyamines it became clear that the nature and efficiency of triplet energy transfer from the sensitizer to the alkoxyamine bond as well as the reversibility of photodissociation crucially depends on the structure of the nitroxide terminus. By employing the thus designed photodynamic covalent bonding motif, we demonstrate how to use light energy to shift a dynamic covalent reaction network away from its thermodynamic minimum into a photostationary state. The network could be repeatedly switched between its minimum and kinetically trapped out-of-equilibrium state by thermal scrambling and selective photoactivation of sensitized alkoxyamines, respectively.

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INTRODUCTION Molecular self-assembly and self-organization processes mediated by supramolecular or dynamic covalent interactions generally approach a thermodynamic equilibrium with a stable composition of (supra)molecular entities. Thereby, under given surrounding conditions (e.g., temperature, pH, or the presence of a binder) the “fittest” among all possible species is selectively amplified. Due to its inherent constitutional dynamicity the system is able to adapt in response to changes of the surrounding conditions by the expression of other species and population of new energetic minima.1 However, in living organisms, many self-organized systems reside in an out-ofequilibrium state, i.e., they are accessed and held up by consuming energy, which gives them unique properties that are inaccessible within the thermodynamic minimum. Thus, for the synthetic chemist, designing self-organized systems that can be driven into out-of-equilibrium states is an attractive challenge in order to increase the complexity of attainable structures and functions.2 While this can be achieved using chemical fuels3 as is usually the case in biological processesa particularly advantageous energy source is light due to its noninvasive character and its high spatial, temporal, and energetic resolution. Indeed, a single photoexcited molecule is inherently in a dissipative out-of-equilibrium state and shows properties very different from that of the ground state, e.g., regarding its acidity or redox potentials. Furthermore, photochromic switches and motors4 allow for the controlled access of metastable ground © XXXX American Chemical Society

states after photoexcitation. Consequently, it is a straightforward strategy to couple molecular switches to dynamic selfassembly and self-organization processes and take advantage of their ability by populating their photostationary state to shift the whole system out-of-equilibrium using light energy.5 In a number of beautiful examples this has been achieved by employing changes of the molecular geometry of the switching unit to modulate the outcome of self-organization,6 using the switch as an auxiliary group modulating electronic properties and thus the kinetics of formation and exchange of a binding motif,7 or by using the switch as a catalyst allowing for the spatiotemporal control over the self-organization process.8 Here we present an unprecedented concept to photoinduce out-of-equilibrium states within a dynamic covalent reaction network utilizing “photodynamic covalent bonds” instead of photoswitches. After excitation, these bonds directly undergo dissociation into reactive building blocks, which in a fast thermal back reaction recombine forming (new) molecular entities (Scheme 1a). While there exist many examples for the photocleavage of covalent bonds, only a few systems are available that undergo reversible light-induced dissociation, i.e., that are able to recombine to the bound state. This principle applies for light induced bond formation and scission based on [2 + 2] or [4 + 4] cycloadditions/reversions between coumarin, thymine, cinnamate, and anthracene derivatives, which have Received: April 4, 2018

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DOI: 10.1021/jacs.8b03633 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

equilibrium state using light energy (Scheme 2): When mixing an AOA possessing sensitizers on both the alkyl and nitroxide

Scheme 1. (a) Concept of a Photodynamic Covalent Bond; (b) Heat Induced Reversible Dissociation of AOAs; (c) Literature Examples of Sensitized AOAs Utilized for the Photoinitiation of NMP19f,k,l

Scheme 2. Switchable Dynamic Covalent Reaction Network Consisting of a Sensitized (SS) and a Nonsensitized (RR) AOAa

a

While heat induces formation of the mixed derivatives (RS and SR) and thus equilibration of the network towards the thermodynamic minimum, selective activation of sensitized AOAs SS, RS, and SR with light and the resulting enrichment of the nonsensitized analogue RR drives it back to the initial out-of-equilibrium state.

termini (SS) with a nonsensitized analogue (RR), thermal activation and exchange of the AOAs will lead to an equilibrium situation with the homosubstituted (RR, SS) and mixed (RS, SR) derivatives being present in equal amounts. However, upon irradiation of the equilibrium mixture with light only AOAs carrying a sensitizer on either terminus (SS, RS, SR) are activated by intramolecular energy transfer and thus undergo exchange, while the nonsensitized derivative RR stays inactive. Thus, RR and at the same time due to stoichiometric reasons its agonist SS accumulate simultaneously in the mixture driving the overall reaction back to the initial out-of-equilibrium state. In the present work we develop photodynamic AOAs using xanthone as the sensitizing unit. Thereby, three generations of AOAs (Scheme 3) differing in the molecular architecture of the nitroxide terminus are synthesized and their exchange behavior is investigated in depth before finally realizing the photodynamic reaction network that can be reversibly switched between an equilibrium and a kinetically trapped out-ofequilibrium state by means of thermal and photochemical activation, respectively.

been utilized in the context of dynamic covalent chemistry.9 Nevertheless, in these systems, the unbound state is in general thermodynamically more stable and unselective deep-UV light is needed to induce photodissociation due to the decreased πconjugation of the cycloaddition products. Photocleavable disulfides and diselenides10 as well as hexaarylbiimidazoles11 represent true photodynamic covalent bonds. However, while the former efficiently respond only to deep-UV irradiation, the recombination of the latter is rather slow.12 Besides, the leuco form of triarylmethane dyes13 and specific metal−ligand interactions14 are able to photodissociate reversibly. We presumed that photocleavable alkoxyamines (AOAs) could be a highly interesting alternative: AOAs possess a C-ON group that is stable at room temperature while it dissociates into a transient alkyl radical and a persistent nitroxide radical at elevated temperatures (Scheme 1b).15 Due to the Persistent Radical Effect16 the homolytic dissociation is reversible in the absence of oxygen and therefore AOAs could successfully be applied in numerous thermally operated dynamic covalent systems.17 In addition, in the context of photoinitiation of Nitroxide Mediated Polymerizations (NMP)18 it has recently been shown that by inter- or intramolecular sensitization by a chromophore, which after excitation undergoes intersystem crossing to the triplet state, cleavage of the AOA bond may also be induced photochemically at room temperature19 (see for example NMP photoinitiators in Scheme 1c). Thereby, the possibility to use near-UV light for the homolytic cleavage and the rapid recombination reaction of the radicals are highly advantageous. When utilized in a dynamic covalent reaction network, photosensitization of AOA dissociation enables the selective addressing and activation of individual constituents of the network in dependence of the presence of the sensitizer within the molecule. Conceptually, this allows for the construction of reaction networks that can be repeatedly driven into an out-of-

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RESULTS AND DISCUSSION Choosing the Sensitizer. In order to photoinduce AOA dissociation certain requirements have to be fulfilled by the sensitizer: (i) its selective excitation should be possible in the presence of AOAs or nitroxides to avoid direct photoexcitation of these molecules and potential resulting side reactions, (ii) it should undergo efficient intersystem crossing and its triplet lifetime should be long enough, and (iii) its triplet energy has to be sufficiently high to allow for triplet energy transfer to the AOA bond. Inspection of the UV spectra of a model AOA PhEt-TEMPOPh as well as the corresponding free nitroxide TEMPOPh (Figure 1a) reveals that there is a window between 300−400 nm where selective excitation of a sensitizer is possible. Though the molar absorptivity of nitroxides at wavelengths >400 nm is very low, still their photoexcitation should be avoided as they tend to easily undergo proton abstraction even from very inert molecules in the excited state.20 Thus, in this work a lamp-filter setup was used to ensure

B


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Journal of the American Chemical Society Scheme 3. Structures of all AOAs Synthesized and Investigated in This Study

exchange of the nitroxide moiety of the model AOA PhEtTEMPO with another nitroxide TEMPOPh. First Generation AOAs. On the basis of a one-step synthesis of AOAs starting from benzyl bromide and tertbutylnitrone,24 a very fast access to a bis-xanthone substituted AOA XEt-TXENO was given (Figure 2a). The brominated xanthone precursor XEtBr was obtained from 2-ethylxanthone using a mild visible light mediated bromination protocol25 avoiding otherwise predominant elimination and overbromination reactions (see the SI for all synthetic details). The architecture of the resulting nitroxide building block TXENO (tert-butyl-(1-xanthon-2-ylethyl)nitroxide) is closely related to the well-known TIPNO motif (tert-butyl-(1-isopropyl-1phenylmethyl)nitroxide), which is heavily used for NMP26 and thus promises outstanding properties. Furthermore, in XEt-TXENO the distance between the central C-ON bond and both xanthone units is minimized in order to ensure optimal intramolecular triplet energy transfer.19h Note that due to its two stereogenic centers, XEt-TXENO was obtained as a 1:1 mixture of diastereomers and in the following was used as such. To realize the reaction network that can be light-driven into the out-of-equilibrium state (Scheme 2) XEt-TXENO was combined with an equimolar amount of its nonsensitized, phenyl substituted analogue PhEt-TPENO and subjected to heating to 110 °C in a closed tube under oxygen free conditions to induce thermal scrambling of the AOAs, i.e., to go to the thermodynamic minimum. The reaction was followed by UHPLC as due to the presence of diastereomers and rotational isomers for all involved species and generally rather broad peaks, 1H NMR spectra could not be interpreted. The chromatograms (Figure 2b) show that after 24 h of heating as expected ca. 50% of exchange products with mixed xanthone and phenyl substitution were formed. Unfortunately, no precise quantification could be performed due to poor peak separation even under most optimized UHPLC conditions. Upon subsequent irradiation of the mixture with UV light the relative amount of the exchange products compared to XEt-TXENO clearly decreases. However, in an absolute sense there is only a slight increase of the peak areas corresponding to XEt-TXENO observed before all peak areas slowly decrease with prolonged

irradiation of the samples only with UV light between 310−400 nm. In an intermolecular sensitization experiment, it has been demonstrated19m that the sensitizer’s triplet energy must exceed a value of around 260 kJ/mol in order to efficiently be quenched by an AOA and xanthone (λmax = 336 nm, ΦISC = 1, ET = 310 kJ mol−1)21 was found to be suited. To reproduce this finding under the experimental conditions employed in the present work and to test other potentially suited sensitizers, a simple screening experiment consisting of intermolecular sensitization of the model AOA PhEt-TEMPO in the presence of air was set up. When air is present during AOA dissociation the process becomes irreversible22 as the transient benzyl radical reacts with molecular oxygen to form the corresponding ketone, benzyl alcohol, and benzylhydroperoxide while the nitroxide radical is liberated (Figure 1b). The rate of decomposition of the parent AOA and the emergence of oxidation products was followed using 1H NMR spectroscopy. This and all following experiments were conducted in benzene as preliminary tests on AOA sensitization showed that in other solvents such as dioxane, methanol, methylene chloride, or acetonitrile small amounts of undesired byproducts due to reactions with the solvent are formed. Indeed, during the screening it turned out that xanthone is by far the most efficient sensitizer among the molecules tested giving 45% AOA decomposition after 4 h of irradiation. Notably, benzophenone, which was utilized before to photoinitiate NMP,19 gave only 7% decomposition whereas 3-acetylcoumarin performed slightly better with 10% decomposition.23 Consequently, in the following xanthone is used as the sensitizing unit. The incorporation into different AOA and nitroxide structures only marginally altered its absorption properties (see UV spectra in Figures S1 and S2). In order to prove its ability to sensitize not only AOA decomposition but also exchange reactions an intermolecular sensitization experiment under oxygen free conditions was followed using UHPLC (Figure S3). Thereby it could be demonstrated that 2ethylxanthone as well as methyl xanthone-2-carboxylate, both mimicking those xanthone motifs used later on within AOA structures (compare Scheme 3), are able to sensitize the C


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Figure 2. (a) One-step synthesis of first generation AOAs. (b) UHPLC traces (diode array detector at 336 nm) of samples taken from an equimolar mixture of XEt-TXENO and PhEt-TPENO in benzene (10 mM, nitrogen atmosphere) during heating (110 °C) and subsequent irradiation with UV light (rt). While the two diastereomers ds1 and ds2 of XEt-TXENO show up as two well separated peaks, diastereomers of the exchange products, being indistinguishable due to their identical m/z ratio and UV spectra, show up as two nonbaseline resolved peaks and a third peak fully overlapping with that of the starting material. Note the doubled molar absorptivity of XEt-TXENO at the detection wavelength as compared to the other xanthone containing compounds.

Figure 1. (a) UV−vis spectra of prototype AOA PhEt-TEMPOPh, nitroxide TEMPOPh, and xanthone in acetonitrile (25 °C). The dashed line represents a 100-fold magnification of the spectrum of TEMPOPh. The dotted line shows the transmission spectrum of the filter combination used together with a 125 W high-pressure mercury lamp for irradiation experiments. (b) Intermolecular sensitization of photochemical AOA decomposition using different sensitizers: Normalized peak areas corresponding to the AOA’s benzylic CH proton (filled symbols) and the CH3 group of the formed ketone (open symbols) as obtained from 1H NMR spectra of an equimolar mixture of PhEt-TEMPO and a sensitizer in aerated C6D6 (c = 20 mM) during irradiation with UV light. Peak areas are normalized to the initial value of the benzylic CH proton and to the number of corresponding protons. The blank sample was irradiated without adding any sensitizer.

bly, free TXENO radical was detected only as a minimum trace in all chromatograms recorded during the decomposition reaction. This stands in stark contrast to other photodecomposition experiments on AOAs (vide infra) where generally the liberated nitroxide radical is stable and can be detected by UHPLC. As TIPNO as well as its methyl substituted analogue TPENO are expected to be thermally stable at room temperature27 this finding hints to a pronounced photochemical decomposition of the TXENO moiety that prevents the realization of the desired network. Consequently, a redesign of the system is necessary, which also should avoid the formation of diastereomers in order to simplify the analysis of the reaction networks. Second Generation AOAs. To ensure maximum stability of the nitroxide building blocks an AOA design based on the well-known TEMPO (2,2,6,6-tetramethylpiperidinenitroxide) moiety was chosen. The synthesis of second generation AOAs is accomplished by generating benzylic radicals in the presence of a free TEMPO nitroxide.28 Thereby, 4-hydroxy-TEMPO serves as a building block that is easily prefunctionalized with the xanthone sensitizer by esterification. Note that despite the relatively large spatial separation between the AOA bond and

irradiation time. This is due to the formation of a number of by products containing the xanthone chromophore upon UV irradiation, whose peaks arise at tR < 1 min. Thus, overall photodegradation of the system prevents reestablishing the initial out-of-equilibrium state by light irradiation. In order to gain more insight into the reason for photodegradation XEt-TXENO was also subjected to photochemical decomposition in the presence of air (Figure S4). After 30 min of irradiation the starting material was completely decomposed and the corresponding ketone (2-acetylxanthone) was identified as the main reaction product besides smaller amounts of the benzyl alcohol (1-xanthon-2-ylethanol) as well as the amine N-tert-butyl-N-(1-xanthon-2-yl)ethylamine. NotaD


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synthesized allowing for a detailed investigation of the photochemical behavior of second generation AOAs in dependence of the position of the sensitizer. Both compounds were subjected to photodecomposition to the ketone and nitroxide in the presence of air (Figure S6). It becomes immediately evident that the photodecomposition of XEtTEMPO is much faster than the reaction of PhEt-TEMPOX. For the former an effective quantum yield29 of 0.68 was determined, demonstrating the high efficiency of the photocleavage process when the sensitizer is situated on the alkyl terminus.19a At a constant photon flux the time needed to reach complete photodecomposition of XEt-TEMPO shortens when reducing the concentration while for PhEt-TEMPOX there is no significant change. The latter indicates that the rate of the decomposition reaction after excitation of PhEt-TEMPOX decreases when lowering its concentrations. Another indication for a fundamentally different photochemical behavior of the two compounds is obtained when performing the photodecomposition in the presence of excess naphthalene, an efficient quencher of the triplet state of xanthone.30 While for XEt-TEMPO there is no significant influence on the decomposition rate, in the case of PhEt-TEMPOX the reaction is almost completely inhibited. Taken together these findings indicate that while the former undergoes the expected efficient intramolecular triplet energy transfer after excitation of the sensitizer, in the latter case dissociation of the AOA bond is only achieved via a bimolecular process, i.e., intermolecular energy transfer. To confirm this assumption, initial reaction rates were measured for the photodecomposition of both compounds at varying concentrations. This was done by monitoring the disappearance of the AOA’s characteristic CH−ON signal (Figure 4) and the emergence of a signal for the resulting ketone’s CH3 group (Figure S13) using 1H NMR spectroscopy under precisely controlled irradiation conditions (for photodecomposition NMR spectra and further details of the measurement see Figures S9−S12 in the SI). It becomes evident that for XEt-TEMPO the initial rate of the reaction is

the sensitizer attached to the TEMPO building block for very similar AOA-sensitizer architectures reported before (Scheme 1c), the emergence of an intramolecular triplet energy transfer after photoexcitation was postulated.19d,h,k,l To test for the ability of second generation AOAs to undergo the desired thermal and photochemical exchange reactions, the bis-functionalized derivative XEt-TEMPOX was mixed with an excess (3 equiv) of its nonsensitized analogue PhEt-TEMPO and heated to 100 °C in the absence of oxygen (Figure 3). After

Figure 3. Attempted switching of the reaction network consisting of second generation sensitized AOAs: UHPLC traces (diode array detector at 336 nm) of samples taken from a mixture of XEtTEMPOX (10 mM) and PhEt-TEMPO (30 mM) in benzene after heating (100 °C) and subsequent irradiation with UV light (rt) under oxygen free conditions.

26 h of heating exchange to the mixed derivatives XEt-TEMPO and PhEt-TEMPOX was observed by UHPLC with a conversion of 61%. Importantly, no other byproducts were detected. At this point heating was stopped and the mixture was subjected to UV irradiation with the expectation to reverse the direction of the exchange reaction (vide supra). Surprisingly, the reaction went on into the forward direction, i.e., the mixed exchange products XEt-TEMPO and PhEt-TEMPOX continued to form, until the reaction leveled off at a conversion of approximately 85% after 130 min of irradiation. Notably, when performing the same irradiation experiment on the mixture of XEt-TEMPOX and PhEt-TEMPO without the initial heating step, again the clean formation of the exchange products is observed with a conversion of 87% after 120 min of irradiation (Figure S5). This finding strongly suggests that there is an indirect pathway to photocleave the nonsensitized AOA PhEtTEMPO, which does not absorb the employed UV light, as otherwise a solely photochemically induced exchange could not proceed. As a consequence, it is not possible to reverse the direction of the exchange reaction as PhEt-TEMPO cannot be accumulated. To explain this finding the two mixed AOAs XEt-TEMPO and PhEt-TEMPOX, each possessing only one xanthone group at the alkyl or the nitroxide terminus, respectively, were

Figure 4. Initial reaction rates for the photodecomposition of model AOAs of the second and third generation as a function of AOA concentration in aerated C6D6 as determined by 1H NMR spectroscopy. Monitoring signals (XEt-TEMPO: CHarom at δ = 7.46 ppm, PhEt-TEMPOX: PhEt-CH3 at δ = 1.46 ppm, PhEt-TMIOX: TMIOXCH3 at δ = 1.40 ppm) were selected to avoid overlap with other signals of the AOA or photoproducts. Initial rates for PhEt-TEMPOX were multiplied with a factor of 60 for the sake of clarity. E


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possessing the xanthone moiety at the alkyl radical terminus readily cleave at room temperature under photoirradiation. Thus, by combining these different types of AOAs and by choosing the appropriate conditions the order in which the individual AOAs undergo exchange can be precisely controlled and thus a dynamic reaction network can adapt multiple different states on the way toward the global thermodynamic minimum. To demonstrate this, a mixture of Cum-TEMPO and XEt-TEMPO with an excess (3 equiv) of another free nitroxide TEMPOPh(OMe) was first heated to 110 °C and afterward subjected to UV irradiation (Figure 5, left). Upon

independent of the concentration and thus it follows a unimolecular reaction scheme including intramolecular triplet energy transfer from the sensitizer to the AOA bond (see section 9 of the SI for a detailed analysis of rate equations). In contrast, for PhEt-TEMPOX a linear dependence of the initial reaction rate with the concentration is observed, which proves that the energy transfer between the excited sensitizer and the AOA bond is a bimolecular process. Thus, it can be concluded that the distance between the sensitizer and the AOA bond is too large to allow for an intramolecular energy transfer. As a consequence, upon mixing PhEt-TEMPOX with a nonsensitized AOA Cum-TEMPOPh under oxygen free conditions and applying UV irradiation, an exchange reaction occurs (Figure S7b), as due to its intermolecular nature, there is a similar probability that after excitation of the sensitizer the energy is transferred to another molecule PhEt-TEMPOX or Cum-TEMPOPh. In contrast, when using XEt-TEMPO instead of PhEt-TEMPOX only small traces of the exchange product are observed (Figure S7a) as the intramolecular energy transfer within XEt-TEMPO is much faster than any intermolecular process. A similar behavior is expected for the bis-sensitizer substituted compound XEt-TEMPOX (Scheme 4) used in the reaction network. Due to the fact that the Scheme 4. Energy Transfer Pathways in Second Generation Sensitized AOAs

TEMPOX unit transfers its triplet energy after excitation in an intermolecular fashion also activating the fully nonsensitized constituent of the reaction network its accumulation and thus the light-driven population of the out-of-equilibrium state is prevented. Interestingly, the finding that the sensitizer substituted to the TEMPO moiety undergoes exclusively intermolecular energy transfer to the AOA bond stands in contrast to assumptions made in the literature. In particular, Goto et al.19k reported unimolecular photodissociation kinetics of the related compound PhEt-TEMPOQ (see Scheme 1c) sensitized by a quinoline unit in acetonitrile. To verify our results, we also subjected PhEt-TEMPOQ to the photodecomposition reaction and monitored its concentration dependence (Figure S8). It is clear that with the conditions used in this work (benzene as the solvent; for the influence of acetonitrile vide infra) the photodissociation behavior of PhEt-TEMPOQ is very similar to that of PhEt-TEMPOX undergoing intermolecular energy transfer with bimolecular reaction kinetics. Though second generation AOAs do not allow for the reversible light-induced population of an out-of-equilibrium state in a dynamic reaction network, they still possess the interesting property that their photochemical and thermal dissociation reactions are highly orthogonal:31 ethylbenzene derived AOAs like PhEt-TEMPO and XEt-TEMPO undergo thermal exchange reactions only at high temperatures (>100 °C) whereas cumene derived AOAs like Cum-TEMPO already cleave at moderate heating (>60 °C) and finally AOAs

Figure 5. Orthogonal exchange of second generation AOAs as followed by 1H NMR spectroscopy: Consecutive heating (60 °C, 9 h) and UV irradiation (rt, 30 min) steps of a mixture of XEt-TEMPO and Cum-TEMPO in C6D6 (5 mM, oxygen-free conditions) in the presence of three equivalents of nitroxide TEMPOPh(OMe). Peak areas are normalized to their initial values. Lines are drawn as guide for the eye.

thermal treatment only the cumene derived AOA undergoes exchange of its nitroxide moiety forming Cum-TEMPOPh(OMe) until reaching the expected equilibrium situation. Thereby the other exchange product XEt-TEMPOPh(OMe) was not observed at all. During subsequent UV irradiation now exclusively XEt-TEMPO undergoes exchange, while the amount of Cum-TEMPO and Cum-TEMPOPh(OMe) remains unchanged. The order of the activation stimuli may be reversed (Figure 5, right) with the same selectivity observed. The initial photoactivation seems to be slightly less selective as a small amount of the nondesired exchange product CumTEMPOPh(OMe) is formed (7%). This hints to a partial involvement of intermolecular sensitization processes either as F


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a sealed NMR tube under oxygen free conditions. By careful deconvolution of the NMR spectra all species involved in the reaction could be identified and their relative quantities determined (Figure 6b and 6d, for full 1H NMR spectra see

side reaction of XEt-TEMPO or by traces of xanthone containing decomposition products formed (vide infra). Third Generation AOAs. As it became clear that the distance between the C-ON bond and the sensitizer on the nitroxide terminus has to be reduced to allow for an intramolecular energy transfer, a new nitroxide motif, as stable as the TEMPO moiety, was needed. The nitroxide TMIO32 (1,1,3,3-tetramethylisoindolineoxide) is reported to possess similar electronic and steric properties compared to TEMPO, shows excellent stability,33 and contains an aromatic benzene ring that could be extended to the desired xanthone moiety in close proximity to the N−O bond. Thus, to access the desired structure, TMIO was iodinated twice34 in order to apply a Pdcatalyzed xanthone formation protocol, originally reported on 1,2-dibromobenzene as substrate,35 forming the xanthone containing nitroxide TMIOX (Scheme 5). Generation of Scheme 5. Synthesis of the Xanthone Derived Nitroxide TMIOX and Third Generation Sensitized AOA XEt-TMIOX

benzylic radicals in the presence of TMIOX gave the bisxanthone functionalized third generation AOA XEt-TMIOX as well as the single-substituted compound PhEt-TMIOX. The ability of the TMIOX motif to intramolecularly transfer the triplet energy after excitation was tested as before by investigating the kinetics of photodecomposition of PhEtTMIOX in the presence of air. Following the reaction by UHPLC as well as 1H NMR spectroscopy (Figures S14 and S15) gives a very similar picture to the behavior of XEtTEMPO. In particular, initial reaction rates are independent of the concentration (Figure 4) clearly speaking for a predominantly intramolecular triplet energy transfer from the TMIOX moiety to the AOA bond. Yet, it can be deduced that the reaction is considerably slower by a factor of 2 as compared to XEt-TEMPO. Interestingly, and in contrast to XEt-TEMPO, upon addition of naphthalene the photodissociation is quenched to a certain extent (Figure S14). This indicates that due to the slightly larger distance between sensitizer and AOA bond within the TMIOX moiety the rate of triplet energy transfer is somewhat smaller compared to the sensitizer located on the alkyl terminus. This is also reflected in the lower effective quantum yield for the photocleavage of PhEt-TMIOX of 0.37. Nevertheless, the compound can still be selectively photoaddressed in the presence of other AOAs as demonstrated by irradiating a mixture with Cum-TEMPOPh in the absence of oxygen (Figure S16). Only small amounts (5%) of the exchange product are formed. Taking advantage of these promising properties of the TMIOX building block, the desired reaction network could eventually be realized: equimolar amounts of XEt-TMIOX and nonsensitized PhEt-TMIO were mixed and heated to 110 °C in

Figure 6. Realization of the photodynamic reaction network using third generation sensitized AOAs: Sealed NMR tubes containing degassed solutions of equimolar amounts of XEt-TMIOX and PhEtTMIO in C6D6 (5 mM) were heated (110 °C, 44 h) or irradiated with UV light (rt, 330 min), as indicated. (a) Reaction scheme. (b) Evolution of the network during consecutive long-time heating and irradiation. Relative peak areas of the starting material and reaction product obtained by deconvolution of 1H NMR spectra as well as the normalized overall integral of the overlapping signals for the benzylic CH protons are shown. (c) Evolution of the network upon irradiation only. (d) Selected spectral regions utilized for the quantification by deconvolution (for full NMR spectra see SI).

Figure S17, for a plot of absolute quantities see Figure S18). As expected, upon heating smooth exchange to XEt-TMIO and PhEt-TMIOX occurs until reaching the thermodynamic minimum at a 1:1 mixture of starting materials and exchange products. Thereby, a longer reaction time of 44 h was necessary due to the slightly higher thermal barrier for the dissociation of G


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order to increase the dynamic range of the switching process, the amount of nonsensitized AOA was increased to three equivalents (Figure S20). As expected from the stoichiometry, thermal scrambling of the mixture gives a ratio of XEt-TMIOX: XEt-TMIO of 28:72 while the UV induced back reaction levels off at a 79:21 mixture. Limits of the Reaction Network. To get further insight we investigated the emergence of byproducts under thermal and photochemical activation depending on the position of the sensitizer and the substitution pattern using model AOAs. The principal findings are summarized in Scheme 6 (see Section 8

TMIO AOAs in comparison to previous experiments using TEMPO.33 Markedly, upon subsequent UV irradiation fast regeneration of XEt-TMIOX and PhEt-TMIO at the expense of the mixed AOAs is observed. Upon extending the UV irradiation up to 330 min a photostationary state consisting of a 91:9 mixture of starting materials and mixed compounds evolves. From that point on no further shift of the equilibrium is observed and photodecomposition of the involved species (vide infra) becomes the major process. Notably, when starting with the same system and subjecting it to UV irradiation only, a similar photostationary state of 93:7 starting materials to exchange products is formed (Figure 6c). Obviously, a quantitative back reaction to the initial state cannot be obtained due to partial intermolecular activation of the nonsensitized AOA within the reaction network. This may be caused by a partial intermolecular energy transfer of the TMIOX motif (vide supra) and the presence of small amounts of decomposition products possessing a xanthone unit. Indeed, monitoring of the overall signal for the benzylic CH protons reveals a slow decrease of the total amount of AOAs present in the sample during switching the network between the two states. As major side products two styrenes and two ketones, both stemming from the PhEt or XEt building blocks, respectively, were identified in the NMR spectra (Figure S19) as well as in UHPLC analysis of the mixture at the end of the reaction. UHPLC also proved the presence of free TMIOX nitroxide as well as the corresponding reduced hydroxylamine. Notably, both styrenes evolve during the thermal activation step, while the ketones start to form upon UV irradiation of the sample. During the UV step the amount of styrene1, stemming from the PhEt moiety, does not change anymore, while styrene2, stemming from the XEt moiety continues to form. Despite the slow decomposition of the sample, several cycles of switching of the reaction network between the equilibrium and out-of-equilibrium state could be performed (Figure 7). For this experiment heating and irradiation times were restricted to 24 h and 60 min, respectively, to minimize degradation. After four switching cycles, during which the relative amounts of starting material and exchange products were fully reproduced in the two states of the reaction network, still 81% of the initial total amount of AOAs was present. In

Scheme 6. Thermal and Photochemical Side Reactions of Sensitized AOAs

of the SI for detailed data). Notably, upon thermal activation of PhEt-TEMPO and PhEt-TMIO styrene and the corresponding hydroxylamines were detected as sole and quantitatively formed decomposition products (Scheme 6a, Figure S21). Thereby the disproportionation reaction of PhEt-TMIO is significantly slower than that of PhEt-TEMPO. It is known for TEMPO based AOAs that substitution of the ethylbenzene fragment at the alkyl chain can diminish disproportionation.36 Thus, PhEt(OBz)-TEMPO was synthesized and tested. Though during its thermal activation the corresponding styrene (as both E and Z isomer) was still observed, the disproportionation reaction was much slower than for PhEt-TEMPO (Figure S21). To check if this strategy could increase the fatigue resistance of the reaction network during thermal activation, the benzoyloxy substituted third generation AOA XEt(OBz)TMIOX was synthesized. Indeed, upon thermal equilibration of its mixture with nonsensitized PhEt(OBz)-TEMPO the according exchange products formed quantitatively and no styrene was detected at all (Figure S22). Unfortunately, upon

Figure 7. Repeated switching of the reaction network shown in Figure 6 (C6D6, 5 mM, oxygen free conditions) using shorter heating (Δ, 24 h) and irradiation (UV, 60 min) steps. Relative peak areas as obtained by deconvolution of specific spectral regions and the overall benzylic CH signal area are shown. Lines are drawn as guide for the eye. H


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We demonstrated that, using photochemical and thermal stimuli, such photodynamic covalent reaction network can be reversibly switched (multiple times) between its initial out-ofequilibrium state and the thermally equilibrated thermodynamic state. In the present state, the driving force for the network to react toward the thermodynamic minimum consists mainly in the entropy of mixing, i.e., the depths of the potential wells on the left and the right side of the equilibrium are approximately the same (Figure 8). This results from the fact that all constituents

subsequent photoactivation of the reaction network as well as irradiation of XEt(OBz)-TMIOX alone fast decomposition of the AOAs occurred. Investigation of decompositions products (Figures S23−S24) hints to a photoinduced beta cleavage facilitated by the OBz group as the major decomposition pathway (Scheme S5). Gratifyingly XEt-TEMPO and PhEt-TMIOX are much more resistant toward photodegradation. However, their stability under continuous irradiation in the absence of oxygen, i.e., while constantly undergoing reversible photocleavage, is highly dependent on the position of the sensitizing group within the AOA architecture. For XEt-TEMPO photodegradation is limited to slow radical disproportionation (Scheme 6b) resulting in a loss of 10% of the starting material after 4 h of irradiation (Figure S25a). In contrast, for PhEt-TMIOX photodegradation is significantly faster with a loss of 30% after the same irradiation time (Figure S25b). Thereby, acetophenone was formed quantitatively and a secondary amine stemming from reduction of the TMIOX moiety was detected by UHPLC analysis of the reaction mixture. This strongly indicates that during photoactivation of PhEt-TMIOX the desired cleavage of the C-ON bond competes with the cleavage of the CO-N bond leading to stoichiometric formation of the ketone and amine (Scheme 6c). The latter reaction is a typical side-reaction of AOAs,37 in particular with photosensitizers placed on the nitroxide terminus.38 In case of PhEtTMIOX we estimated relative rates of 100:1 for the two reaction pathways by comparing its photodecomposition in presence and absence of oxygen. Photoirradiation of model AOAs was also carried out using acetonitrile39 as solvent. Thereby, XEt-TEMPO and PhEtTMIOX did not show any significant difference to pure benzene regarding their photostability and photodegradation in absence and presence of oxygen, respectively (Figure S26). In contrast, PhEt-TEMPOX decomposed much faster in acetonitrile than in benzene and the rate was independent of the presence of oxygen (Figure S27a). The formation of N-(1phenylethyl)acetamide as reaction product (Figure S27b) indicates a change of the photosensitization mechanism from triplet energy transfer to photoelectron transfer when going from benzene to acetonitrile.20a This leads to the release of a benzyl cation,40 which reacts with acetonitrile in a Ritter type reaction41 to yield the acetamide product (Scheme S6). The differing sensitization mechanisms in benzene and acetonitrile presumably also explain the contrary photokinetics of PhEtTEMPOQ observed by Goto et al.19k and us.

Figure 8. Thermodynamic picture of the photodynamic reaction network showing the generation of an out-of-equilibrium state under irradiation (bottom). Black arrows indicate the probability of thermal dissociation and recombination reactions while red arrows indicate the probability of photoexcitation from either side of the equilibrium. As photoexcitation is selective for constituents possessing a sensitizer (depicted in red) the amount of nonsensitized building blocks reaching the intermediate high energy region depletes over time leading to a higher probability for the formation of homosubstituted constituents and thus a net flow of material from the right to the left side of the equilibrium under irradiation.

of the reaction network possess the same AOA linkage with similar steric and electronic properties. Upon heating the relatively large barrier between the potential wells can be overcome, i.e., radical species are formed as high energy intermediates, and the reaction toward exchange products proceeds until the net-flow of material from both potential wells is equal, representing the thermodynamic minimum state. This state is frozen at room temperature. However, photochemical activation of sensitized AOAs allows population of the high-energy intermediate region via the triplet excited state of the molecules. While the radical intermediates recombine statistically to form the reaction products of either side of the equilibrium, due to the fact that only AOAs possessing a sensitizer can undergo photoexcitation the amount of nonsensitized building blocks that reach the intermediate region depletes over time. This results in a net flow of material from the right to the left side of the equilibrium until a photostationary state has been reached, i.e., the (re)generation of the kinetically trapped out-of-equilibrium state. The selectivity for specific constituents of the network, i.e., the dependency of photoactivation on the “information” if a sensitizer is present in the molecule, allows for its shifting out-

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CONCLUSION By utilizing photosensitized reversible dissociation of AOAs into their alkyl radical and nitroxide building blocks we were able to develop a “photodynamic covalent bond” that is stable in the absence of light and can only be activated at elevated temperatures, while undergoing efficient and controlled dissociation upon UV irradiation at room temperature, thus inducing the exchange of building blocks and the formation of new constituents within a dynamic covalent reaction network. When AOAs are sensitized in a solely intramolecular fashion, which has been achieved in this work by the structural optimization of the nitroxide terminus and detailed analysis of photodissociation kinetics, specific constituents of the network can be selectively addressed by irradiation, while nonsensitized analogues accumulate. This results in a light-driven population of states different from the overall thermodynamic minimum. I



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of-equilibrium without an intermediate change of the relative ground state energies of the two states. This is reminiscent to Leigh’s molecular information ratchet.42 Thereby, the detour over the excited state and subsequent relaxation is necessary to allow for the reduction of the entropy of the system during this process. With the presented network it is not possible to selectively access the right side of the equilibrium as both states are equally populated in the thermodynamic minimum. However, a larger driving force for the formation of exchange products can be implemented by increasing the difference in free Gibbs energy between the two states, e.g., by reducing the steric congestion of the exchange products or by incorporating the homosubstituted AOA linkages within the main chain of oligomeric or polymeric structures and thus increasing the entropic cost for the population of the left side of the equilibrium. In particular the latter case is highly interesting from the point of view of dynamic materials: one could design a network consisting of monomeric species in the thermodynamic minimum while their oligo- and polymerization would be driven by light on going to the out-of-equilibrium state. Moreover, in photodynamic covalent bonds the photoexcitation and energy transfer steps are directly linked to bond cleavage and exchange. Thus, photodynamic covalent libraries could be constructed and selection of specific constituents could be installed not on the basis of binding to a target molecule, as it is classically done in dynamic combinatorial chemistry, but based on the photochemical and photophysical properties of the individual constituents, such as the efficiency of energy transfer. Furthermore, whereas the present AOA system allows for access to a kinetically trapped out-of-equilibrium state with a rather high thermal barrier toward the energetic minimum, it could in principle be turned into a dissipative system by implementing AOAs, which undergo thermal exchange at or slightly above room temperature. Research in these directions is currently ongoing in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b03633.

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Article

Details on instrumental methods, synthesis and characterization of all compounds, UV−vis spectra, and further photochemical studies (PDF)

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Jean-Marie Lehn: 0000-0001-8981-4593 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.H. thanks the Alexander von Humboldt Foundation for granting a postdoctoral fellowship. We thank the ERC (Advanced Research Grant SUPRADAPT 290585) for financial support. J


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The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool

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