Dual-Wavelength Gated oxo-Diels–Alder Photoligation

Abstract

The control of chemical functionalization with orthogonal light stimuli paves the way toward manipulating materials with unprecedented spatiotemporal resolution. To reach this goal, we herein introduce a photochemical reaction system that enables two-color control of covalent ligation via an oxo-Diels–Alder cycloaddition between two separate light-responsive molecular entities: a UV-activated photocaged diene based on ortho-quinodimethanes and a carbonyl dienophile appended to a diarylethene photoswitch, whose reactivity can be modulated upon illumination with UV and visible light.

By enabling chemical functionalization of molecules and materials with high efficiency and spatiotemporal control, photoinduced ligation reactions¹ are finding applications in a variety of fields ranging from polymer network formation² to surface patterning,³ 3D printing,⁴ and bioconjugation.⁵ In most of the cases, these photoreactions are driven by irradiation with a single light source and, therefore, their time and spatial profile evolution is determined by illumination intensity and the reagents’ concentration and properties. A much more precise control of photoinduced reactivity can, however, be achieved by regulating the ligation processes with two independent optical signals, i.e., two different colors of light that serve as “and” gates for the λ-orthogonal activation and deactivation of the desired reaction on demand.^1b,1c Such a strategy can, among other advantages, grant access to novel lithographic processes⁶ and finely controlled postmodification strategies for materials,⁷ which constitute two key concepts for the development of advanced functional structures.⁸

Current methodologies applied to the dual-wavelength control of photoligation chemistry involve time or spatially resolved two-color irradiation of one of the reagents of a bimolecular reaction, which can be either molecules capable of undergoing photocycloaddition and photocycloreversion processes (e.g., anthracenes^7c) or molecular photoswitches whose reactivity can be reversibly toggled upon photoisomerization.^{6b−6e,7a,7b,9} To control light-induced reactivity with finely selected colors of light, we herein pioneer a reaction strategy that ceases photochemical bond formation upon the simultaneous irradiation of two photoreactive entities (Figure 1a): a photocaged reagent, which becomes activated upon irradiation with one color of light (λ₁), and a photoswitch reversibly isomerizing between reactive and nonreactive states under illumination with two different wavelengths (λ₁ and λ₂). As a result, bond formation proceeds at λ₁ and is halted upon the dual impact of λ₁ and λ₂.

Figure 1.

(a) Strategy for dual-wavelength control of photoligation reactions by combining photocaged and photoswitchable reagents. (b) Normal electron demand oxo-Diels–Alder cycloaddition selected as a photoligation reaction (EDG = electron-donating group; EWG = electron-withdrawing group). (c) General structures of the photogenerated o-quinodimethane dienes and the photoswitchable DAE-trifluoromethyl ketone dienophile employed, which should undergo oxo-Diels–Alder cycloaddition selectively for the closed state of DTE1.

To reach this goal, we herein focus our attention on a photoligation process that has been seldomly explored for light-induced chemical functionalization: the oxo-Diels–Alder cycloaddition, a hetero-Diels–Alder reaction between dienes and carbonyl groups (Figure 1b).¹⁰ When driven under normal electron demand, catalyst-free oxo-Diels–Alder cycloadditions are highly favored for electron-rich dienes and electron-poor dienophiles,¹¹ a condition on which we capitalize herein to reach two-color control of photoreactivity at ambient temperature. Specifically, we select o-quinodimethanes (o-QDMs) photochemically generated from o-methyl benzaldehydes (o-MBAs) as electron-rich dienes (Figure 1c),^10,12 which have been widely exploited for other types of photoligation reactions (e.g., homo-Diels–Alder cycloadditions¹³ and self-dimerization¹⁴). As for the electron-poor dienophile, we choose trifluoromethyl ketones,¹⁵ which are tethered to a diaryl-ethene photoswitch (DAE) to reversibly alter their reactivities upon photoisomerization (Figure 1c). DAEs¹⁶ have already been used to photomodulate homo-Diels–Alder cycloadditions by generating and removing reactive diene functionalities when interconverting between their open and closed states;¹⁷ however, it is another property of these systems that we take advantage of: the change in electronic communication between the substituents of the aryl rings upon photoisomerization.^7a,16 For the herein utilized symmetric dithyenylethene DTE1, the carbonyl group electron density of the two electron-withdrawing trifluoromethyl carbonyl side groups should be dramatically decreased in the closed state of the switch, where they are electronically coupled (Figure 1c). Thus, these interdependent entities become more active dienophiles for the photogenerated o-QDM dienes, thereby allowing for photomodulation of the corresponding oxo-Diels–Alder reaction.

To synthesize DTE1, a classic approach for the preparation of trifluoromethyl ketones was employed, which consists of the trifluoroacetylation of organometallic reagents.¹⁸ Thus, when 1,¹⁹ a common intermediate for the preparation of a variety of DAE switches, was sequentially treated with tert-butyllithium and ethyl trifluoroacetate in anhydrous THF, the open isomer of DTE1 (DTE1_open) was readily obtained in 60% yield (Figure 2a). DTE1 preserves the characteristic photochromic behavior of DAEs. First, its colorless open isomer (λ_abs < 400 nm, Figure 2b) rapidly transforms into the closed DTE1_closed state upon irradiation with UV (or even violet) light (Figure S1). In our hands, this light-induced process proceeded with a high quantum yield (Φ_o-c = 0.37 in toluene) and efficiency, as we determined by ¹H NMR that the photostationary state produced at a λ_exc of 365 nm in toluene contained up to 96% of the closed isomer. DTE1_closed was found to be thermally stable in the dark at room temperature, both in solution and in the solid state. As shown in Figure 2b, it strongly absorbs in the visible region (λ_abs,max = 635 nm in toluene) and, when irradiated with green or red light, quantitatively back-photoisomerizes to the open isomer with a modest quantum yield (Φ_c-o = 0.031 in toluene, Figure S1). Finally, DTE1 shows excellent fatigue resistance and can be reversibly interconverted between its open and closed states without apparent photodegradation (Figure 2c).

Figure 2.

(a) Synthesis of DTE1_open. (b) UV–vis absorption spectra of DTE1_open, DTE1_closed, and o-MBA1 (X = SBu, Figure 3a) in toluene. (c) Variation of the molar fraction of DTE1_closed (as determined from UV–vis absorption data) upon consecutive cycles of irradiation of a toluene solution of this compound with UV (λ_exc = 365 nm) and visible (λ_exc = 650 nm) light to trigger photoisomerization between its open and closed states.

According to our molecular design, the trifluoromethyl carbonyl groups in DTE1_closed should efficiently undergo oxo-Diels–Alder cycloaddition with electron-rich dienes. To validate this hypothesis, we explored the reaction between DTE1_closed and methylbenzaldehyde o-MBA1 (Figure 3a), a model photocaged precursor of diene o-QDM1 that was prepared following the methodology previously reported by us (Scheme S1).²⁰o-MBA1 was selected on the basis of the well-documented capacity of o-MBA derivatives to undergo sequential intramolecular H-transfer and isomerization upon photoexcitation, which produces o-QDM dienes that can be trapped in a Diels–Alder reaction with electron-deficient enes (Figure 1c).^6b,20,21 In addition, by introducing an alkylthio group in o-MBA1, its absorption spectrum bathochromically shifts relative to regular nonsulfurated o-MBAs, reaching maximal photoreactivity at λ_exc ∼ 350–390 nm (Figure 2b).^13,20 At such spectral range, DTE1_open also shows high photoconversion into DTE1_closed, thus ensuring efficient light activation of both substrates of the cycloaddition reaction using a single irradiation wavelength.

Figure 3.

(a) oxo-Diels–Alder reaction of DTE1_closed with the diene photogenerated from o-MBA1 under UV illumination (LED λ_max = 365 nm, Figure S2) and ambient temperature. The adduct A1_closed can be converted to its open isomer A1_open upon irradiation with visible light (LED λ_max = 625 nm, Figure S2). (b) ¹⁹F NMR spectra (565 MHz, CD₃CN) of (i) DTE1_open; (ii) DTE1_closed; (iii) a mixture of DTE1_closed and o-MBA1 after UV illumination (LED λ_max = 365 nm, 0.017 mW cm^–2) for 45 min in deuterated acetonitrile; (iv) a mixture of DTE1_closed and o-MBA1 after UV illumination (LED λ_max = 365 nm, 0.017 mW cm^–2) for 90 min in deuterated acetonitrile, which resulted in nearly quantitative transformation into A1_closed; (v) A1_closed upon irradiation with visible light (LED λ_max = 625 nm, 35 mW cm^–2) for 2 min in deuterated acetonitrile, which led to quantitative photoisomerization into A1_open. For clarity, the ¹⁹F NMR resonances in each spectrum arising from DTE1_open (blue ▲), DTE1_closed (pink ▼), A1_closed (red ●), and A1_open (black ■) are indicated with different symbols. The changes in color of the reaction mixture before illumination (ii, DTE1_closed) and after UV (iv, A1_closed) and subsequent visible (v, A1_open) irradiation are shown as insets in (b).

The photoligation reaction between the activated dienophile DTE1_closed and o-MBA1 was tested at ambient temperature in acetonitrile and toluene under UV illumination (LED λ_max = 365 nm, Figures 3a and S2), and equivalent results were obtained in both solvents. A large excess of o-MBA1 was employed (30:1 molar ratio) to favor complete conversion into the cycloaddition products, while minimizing competing UV light absorption by DTE1_closed. This, in combination with the photochromic properties of DTE1, made light-induced transformation of the closed isomer into the open form negligible at our experimental conditions, as proven by the very low intensity registered along the process for the ¹⁹F NMR signal of DTE1_open (δ = −71.73 ppm) (Figure 3b). In addition, photodegradation of DTE1_closed was not observed either under equivalent illumination conditions in the absence of o-MBA1 (Figure S3). Thus, the evolution of new resonances in the ¹⁹F NMR spectrum of the reaction mixture under UV irradiation selectively reported on the products formed by direct photoligation between DTE1_closed and o-MBA1. In practice, a complex set of NMR resonances was obtained after illumination for 90 min (Figure 3b), where (a) the ¹⁹F NMR resonance of DTE1_closed at δ = −71.26 ppm fully vanished, thus indicating a complete reaction with o-MBA1; (b) three slightly downfield shifted signals appeared at δ = −70.81, −70.82, and −70.87 ppm, which could be assigned to the trifluoromethyl carbonyl groups of the photoproducts; (c) four additional intense peaks developed at rather lower chemical shifts (δ = −77.12, −77.74, −78.40, and −78.41 ppm), which is compatible with the CF₃ substituents of the isochroman moiety formed through cycloaddition.²² It must be noted that, though such a diversity of NMR resonances could indicate the occurrence of competitive photoreactions, they could simply originate from the large number of regio- and stereoisomers that can be produced by light-induced oxo-Diels–Alder cycloaddition between DTE1_closed and o-MBA1 (Scheme S2).

Interestingly, the complex ¹⁹F NMR spectrum obtained for the photoreaction mixture of DTE1_closed and o-MBA1 was largely simplified after irradiation with visible light (LED λ_max = 625 nm, Figure S2), where only two sets of different signals attributable to trifluoromethyl carbonyl (δ = −71.57 and −71.60 ppm) and trifluoromethyl isochromanyl (δ = −78.90 and −79.80 ppm) groups were found (Figure 3b). As color bleaching of the sample was concomitantly observed (Figures 3b and S4), we hypothesize that quantitative ring-opening of the DAE structure of the cycloadducts formed by the reaction between DTE1_closed and o-MBA1 (A1_closed) occurred, thereby yielding the corresponding colorless open-ring products with a lower number of stereoisomers (A1_open, Figure 3a and Scheme S2). Actually, this process could be reverted with UV irradiation and, as such, it is reminiscent of DTE1 photochromism (Figure S4).

Due to its reduced complexity, we subsequently focused on further characterizing A1_open from which the structure of A1_closed was derived. In this way, A1_open and A1_closed were proven to consist of inseparable mixtures of two and four diastereoisomeric pairs of enantiomers, respectively, whose general structures are shown in Figure 3a (see Scheme S2 for the exact stereoisomers). Specific experimental data underpin this assignment. First, a single molecular mass was determined for A1_open by ESI-MS, which matches the value expected for the monocycloaddition products of DTE1 with one unreacted trifluoromethyl carbonyl group (Figure S5). This result is corroborated by the NMR spectra registered for A1_open, which also demonstrate selective hemiacetal formation and 1,3,8-trisubstitution of the isochroman moiety generated, i.e., regio-specific cycloaddition between DTE1_closed and o-MBA1 (Scheme S2 and Figure S6), a typical feature of oxo-Diels–Alder reactions.⁹ Finally, all attempts to resolve the diastereoisomeric mixture of A1_open were found to be unsuccessful (e.g., by LC-MS) and, indeed, variation of the stereoisomer relative ratio was observed in time and upon treatment with acidic media (Figure S7). As previously reported for other cycloadducts formed between o-QDMs and trifluoromethyl ketones,¹⁵ this is a clear signature of mutual interconversion between these stereoisomers by hemiacetal epimerization (Figure S7).

Despite the large o-MBA1 excess used in our photoreactivity experiments with DTE1_closed, selective UV-induced formation of the monocycloaddition adduct A1_closed was found, which did not further evolve into the dicycloaddition product B1_closed. In fact, B1_closed could only be detected when exposing the reaction mixture to very long irradiation times (>10 h) that also led to photodegradation (Figure S8). Therefore, this result evidences that the rate of the oxo-Diels–Alder process critically decreases when converting one of the trifluoromethyl carbonyl groups of DTE1_closed into a hemiacetal moiety, i.e., by removing the electron-withdrawing effect imparted on the other reactive trifluoromethyl carbonyl group. To confirm our conclusion, we prepared monotrifluoromethyl ketone 2 (Scheme S3) and tested its light-induced reactivity with o-MBA1 under equivalent conditions as for DTE1_closed (Figure 4a). Clearly, no cycloadduct formation was observed in this case, which further corroborates that fast oxo-Diels–Alder reactivity of trifluoromethyl ketones with o-QDMs at ambient conditions requires activation by effective conjugation to the electron-withdrawing groups (EWGs).

Figure 4.

(a) Formation rate of the adduct produced by oxo-Diels–Alder cycloaddition of the diene photogenerated from o-MBA1 under UV illumination (LED λ_max = 365 nm, 0.017 mW cm^–2) and two trifluoromethyl ketones in toluene: DTE1_closed and model trifluoromethylthienylketone 2 (Scheme S3). (b) Two-color modulation of the formation rate of the oxo-Diels–Alder cycloadduct formed by the reaction between DTE1_open and o-MBA1 in toluene upon simultaneous irradiation with constant UV intensity (LED λ_max = 365 nm, 0.017 mW cm^–2) and variable visible light power density (LED λ_max = 625 nm; 0 to 1300 mW cm^–2).

In the case of DTE1_closed, such an activation effect could just be inhibited by photoisomerization into DTE1_open with visible light, where the two side trifluoromethyl carbonyl groups are no longer electronically connected (Figure 1c). In this way, we could reach visible light-induced control of the UV-triggered oxo-Diels–Alder reaction between DTE1 and o-MBA1. To demonstrate this concept, we monitored the evolution of the cycloaddition process between DTE1_open and o-MBA1 at ambient temperature under simultaneous illumination with UV (LED λ_max = 365 nm) and visible (LED λ_max = 625 nm) light (Figure 4b). In the absence of visible light, full conversion of DTE1_open into adduct products (92:8 A1_closed/A1_open mixture) was observed after 120 min, though with a somewhat slower rate than when o-MBA1 was directly reacted with DTE1_closed. Hence, efficient UV-induced ligation occurred even when starting from the open isomer of DTE1, as it rapidly photoisomerizes into the activated closed state. In contrast, a dramatic reduction in photoreactivity was observed when the reaction mixture was concomitantly irradiated with red light of increasing intensity (LED λ_max = 625 nm). Since none of the initial reagents (DTE1_open and o-MBA1) absorb red light, its effect on the oxo-Diels–Alder reaction is exclusively attributed to the photoactivity of red-absorbing DTE1_closed. In particular, illumination with visible light converts the UV-generated, activated dienophile DTE1_closed back to DTE1_open (Figure S9) and, accordingly, it must decrease the cycloaddition process with the photoinduced o-QMD1 diene. Indeed, the fact that this reaction was virtually suppressed under sufficiently intense red illumination at which DTE1_closed concentration is nearly residual proves that the oxo-Diels–Alder cycloaddition rate for the open isomer is negligible at ambient temperature. Therefore, our results unambiguously demonstrate light-induced modulation of DTE1 reactivity with o-QMDs and, as such, the viability of our dual-wavelength gated photoligation strategy; i.e., whereas UV irradiation triggers the oxo-Diels–Alder reaction by concurrently generating the reactive DTE1_closed and o-QDM1, illumination with visible light halts the process by photoisomerizing DTE1_closed back to inactive DTE1_open.

In summary, we herein introduce a dual-color controlled photoligation process that relies on the oxo-Diels–Alder reaction between two light-responsive compounds. Specifically, λ₁ (365 nm) induces the activation of a photocaged diene, while λ₂ (625 nm) regulates the reactivity of a photoswitchable carbonyl ene. As a result, covalent bond formation can be effectively induced and halted on demand by λ₁ and λ₂. Such dual-color reaction control offers critical advantages to photoligation chemistry that cannot be reached by merely using a single photoactivating excitation source (e.g., turning on and off λ₁). First, it allows true confinement of the photoreaction in time and space using patterned two-color illumination, which inhibits the effects of the λ₁-photoactivated reagent diffusing out of the irradiated region or surviving longer than the photoexcitation time. Second, it may allow the reduction of the spatial resolution of the photoligation process to the nanometer scale by applying advanced lithographic techniques⁶ on the basis of on–off photoswitchable reactions. Therefore, our photochemical system can find direct application in the preparation of multiresponsive photoresists for the development of miniaturized functional structures.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c00015.

• Further details on compound synthesis and characterization and light-controlled oxo-Diels–Alder cycloaddition (PDF)

The authors declare no competing financial interest.