Combining Photodeprotection and Ligation into a Dual‐Color Gated Reaction System

Abstract We report a photochemical reaction system which requires activation by two colors of light. Specifically, a dual wavelength gated system is established by fusing the visible light mediated deprotection of a dithioacetal with the UV light activated Diels–Alder reaction of an o‐methylbenzaldehyde with n‐ethylmaleimide. Critically, both light sources are required to achieve the Diels–Alder adduct, irradiation with visible or UV light alone does not lead to the target product. The introduced dual gated photochemical system is particularly interesting for application in light driven 3D printing, where two color wavelength activated photoresists may become reality.

Abstract: We reportaphotochemical reaction system which requires activation by two colors of light. Specifically,adual wavelength gated system is established by fusing the visible light mediated deprotection of adithioacetal with the UV light activated Diels-Alder reactiono f an o-methylbenzaldehyde with N-ethylmaleimide. Critically,b oth light sources are required to achieve the Diels-Alder adduct, irradiation with visible or UV light alone does not lead to the target product. The introduced dual gated photochemical system is particularly interesting for application in light driven 3D printing, where two color wavelengtha ctivated photoresists may becomereality.
From photosynthesis, to image formation in eyes, and the camouflage of squids, [1,2] light induced processes are complex and fascinating. In general,o ne of the reaction components must absorb an incident photon to induce ap hotochemical reaction. For example, photochemical ligations, such as the [2+ +2]-cycloaddition of styrylpyrene moieties [3] or the light-induced Diels-Alder cycloaddition of o-methylbenzaldehydes (o-MBAs) with electron-deficient dienophiles, [4] require one reaction partner to be activated to an excited state from which the reactionc an proceed. [5] Apart from photochemical ligations, photosensitized reactions such as photoredox catalytic processes, are widely employed if mild reaction conditions at am-bient temperatures are required. [6] Through photocatalysis, a range of synthetically valuable transformations beyonds imple oxidations and reductions are possible, including stereoselective reactions, cycloadditions and CÀCa nd CÀHet bond formations, as well as photocatalyzed coupling reactions, such as the Mizoroki-Heck coupling. [7][8][9][10][11] In order to expand the applicability of photochemical reactions, the combinationo ft wo distinct light sources, each activating different species, enables an advancedlevel of reaction control.
In principle, there are multiple possibilities to trigger reactions with two colors of light. [12] Ar ecent trend focuses on the development of l-orthogonalr eactions in order to gain further reactionc ontrol. l-Orthogonality refers to the control over multiple reactionp athways, independently triggered by disparate wavelengths. Examples of l-orthogonals ystems include one-pot reaction mixtures of o-methylbenzaldehydes, N-ethylmaleimides and styrylpyrene moieties, where the Diels-Alder reactionc an be exclusively induced in the UV region and the dimerization of the styrylpyrene only occurs under visible light irradiation. [13] The major challenge in wavelength dual-gated photochemistry is preventing the activation of the further redshiftedp hotoreactivee ntity when shorter wavelengths are utilized, as most compounds with stronga bsorption in the visible regiona lso exhibit absorbance bands extending into the UV region.
To implement this technology for applications such as advancedm anufacturing, it is essential to ensure that no product is formed with as ingle wavelength, but is exclusively formed in the presence of both wavelengths. Directl aser writing (DLW) is aw ell-established technique to print microscale 3D features onto surfaces while maintainings patial and temporal control. [14] In DLW, al iquid photoresist is cured solelyi nt he focal point of am onochromatic light beam,p rovided it exhibits sufficient photon flux to enable two-photona bsorption for the reaction to proceed. Three-dimensionals tructures are obtained by movingt he photoresist relative to the focal point and removing any excessl iquid photoresist after irradiation is complete. The high-resolution of DLWe nables novel applications of 3D printing, such as studies of cell behaviors, or in the development of electronic andp hotonic devices. [15][16][17] Further development on the chemistry involved in the photoresist fabrication,a sp roposed herein, would eliminate the need for a two-photon absorption in order to obtain af ocal point as the reactivity would be achieved only in the intersection of two laser beams.
Herein, we combine the photo-induced deprotection of dithioacetal-protecteda ldehyde moieties in the visible wavelength region, [18,19] with o-methylbenzaldehyde activation in the UV region. [20][21][22][23] The mechanism of the dithioacetald eprotection, using oxidizing conditions, has been reported previously in the literature. [19] While some systems have been reported for light-mediatedd ual-gated reactions, most rely on the deprotection of two protecting groupso nasinglem olecule or on the combinationo ft wo l-orthogonal photoligations. [12,[24][25][26] To the best of our knowledge,adual-gated system that combines photo-deprotection and photoligation has not yetbeen reported.
Pyryliums alts, such as 2,4,6-tris(4-methoxyphenyl)pyrylium tetrafluoroborate, are metal-free, excited state photooxidants suitable fort he deprotectiono fd ithioacetals (Scheme 1) upon visible light irradiation. [19,27,28] When activated upon UV irradiation, the o-methylbenzaldehyde forms ar eactive o-quinodimethane, generally referred to as "photoenol" (PE, Scheme1). Once formed, the reactive photoenol may either form aD iels-Alder (D-A) adduct via a[ 4 + +2] cycloadditionw ith suitables ubstrates (e.g.,m aleimides) or rearranges back to the ground state o-MBA. Alternative reactionc hannels can lead to the dimerization or cyclization of the photoenol moiety. [25,29] In the following, we demonstrate the dual-gated activation of ao ne-pot reactionm ixture enabling ligatione xclusively in the presence of two wavelengths.T he reaction mixture consists of 2-(2-methoxy-6-methylphenyl)-1,3-dithiane (ProtPE) as the photo caged o-methylbenzaldehyde, N-ethylmaleimide (NEM) as the electron poor dienophile, bicyclo[2.2.1]hept-2-ene as atrapping agent for reactiveb yproducts and 2,4,6-tris(4-methoxyphenyl)pyrylium tetrafluoroborate as the photoredoxc atalyst (PC). One of the key aspects of any dual-gated approach is to match the kinetics of the two disparate reactions teps, that is, the deprotection step and the Diels-Alder cycloaddition. Suitable molarr atios of all reactionp artners, as wella s light parameters such as wavelength and intensity,n eed to be established in order to obtain the maximum formation of the D-A adduct. Thus, the absorption spectraa nd the extinction coefficients of all reaction components ( Figure 1) are an important source of information. Both the o-MBA as well as the Diels-Alder adduct exhibit no absorption of visible light (> 400 nm), thus, an LED source (l 1 = 415-460 nm) was utilized for the activationo ft he photocatalyst, openingt he first gate of the reaction. In order to limit competitive absorption of the UV photonsb yt he photocatalyst, we minimized the catalyst loading to 1mol %a nd utilized am onochromatic light source. Decreasing the catalyst loading further significantly slowed the deprotection step and increasing it did not have as ignificant improvement on the deprotection (refer to the Supporting Information section6). Previous studies have shown that the maximum quantum yield for the Diels-Alder reactiono fo-MBA with N-ethylmaleimide is red-shifted compared to its maximum  www.chemeurj.org 2020 Wiley-VCH GmbH molar absorptivity coefficient. [29] In dichloromethane, o-MBA exhibitsamaximuma bsorption at 318 nm, however we excited at 350 nm to open the second gate of the reaction by forming the photoenol, while minimizingc ompetitive absorption.
Initial attempts to conductt he wavelength dual-gated reaction in the absence of bicyclo[2.2.1]hept-2-ene as at rapping reagentf ailed. Although the fragments from the deprotection step were not identified in the present work, it is likely that a free thiol or ad isulfide is released. [18,19,30,31] The disulfide is unlikely to influence the Diels-Alder reaction, however af ree thiol can react in at hiol-Michael or thiol-ene reaction with NEM or with the reactive PE. Bicyclo[2.2.1]hept-2-enei sk nown to react more rapidly with thiols compared to maleimides (refer to the Supporting Information section 7). [32] Furthermore, bicyclo[2.2.1]hept-2-ene is not ac ompetitive substrate for the Diels-Alder cycloadditiono fPEwith NEM (refer to the Supporting Information section 8). Therefore, five equivalents of bicyclo[2.2.1]hept-2-ene were added to all experiments to trap any free thiols produced during the deprotection step,m inimizing side reactions. [33] Key experimentalp arameters such as the solvent, species concentrations and oxygen content have an important effect on the outcome. The Diels-Alder reaction with PEs is well examined in acetonitrile, [29] while DCM is often as olvento f choice for organic photocatalysis. [34,35] In the current study,t he deprotection step was six times less efficient in acetonitrile compared to DCM (refer to the Supporting Information section 9). The decreased efficiency of the reaction in acetonitrile is hypothesized to originate from the inferior quantum yield of the PC in acetonitrile. Therefore, DCM was selected as the solvent for all experiments. The presents mall molecule study requires sufficiently low concentrations (i.e. 9.2 mmolL À1 of ProtPE) of absorbing componentst oa chieve ah omogeneous irradiation profile. In the presence of oxygen, and at low concentrations, o-MBA can undergo undesired oxidation once activated by UV light. As ar esult, am inimal quantity of oxidative cyclizeds ide-product was observed in the experiments( refer to the SupportingI nformation section10). Deoxygenation of the reaction mixture was not feasible as oxygen is required to recoverthe catalyst by closing the catalytic cycle. [36] Te mperature, reactiont ime and energyo ft he photons reachingt he reactionm ixture further influence the formation of the Diels-Alder adduct. Heat was found to favor ap artial sulfoxide formation over deprotection (refer to the Supporting Information section 11). Therefore, using al ow power LED for the deprotection was important in the current experimental set-up to minimize thermalh eating and afford high conversions. [18,30,33] Evidence for the wavelengthd ual-gated reaction control was obtained by performing kinetice xperiments with characterization via 1 H-NMRs pectroscopy (Figure 2a)w here all species could be quantified relative to each other (Figure 2b). The ProtPEt riplet resonance( III)a t7 .13 ppm and the triplet resonance at 7.41 ppm (I), which originate from the o-MBA, were used as ap robe for the quantification of the respective species. The D-A adduct formation results in ad istinct doublet at 5.86 ppm (VI), corresponding to the a-proton of the hydroxy group. This resonance serves as ap robe for the quantification of the D-A adduct. [29] The oxidative side-products overlapw ith the aromatic triplet of the D-A adduct (II)a t7 .24 ppm, therefore, the side-products content was determined by subtracting the known content of the D-A adduct (VI).
Ad ual-gated system requiresf ormation of the desired product only when both gates are opened. Irradiating the reaction mixture only with the visible light source l 1 ,s olely leads to the generation of o-MBA and no Diels-Alder adduct;a st he forma- Chem.E ur.J.2020, 26,16985 -16989 www.chemeurj.org 2020 Wiley-VCH GmbH tion of photoenol requires wavelengths below 400 nm. [29] To demonstrate this selectivity of our one-pot system,t he ProtPE was deprotected to approximately 80 %w ith l 1 only within 600 minutes,s howing no Diels-Alder adduct formation throughe nergy transfer processes caused by the photocatalyst. Subsequenti rradiation with both light sources( l 1 and l 2 ) rapidly converted the o-MBA to the D-A adduct, leading to approximately 60 %y ield within two hours.
To further confirm the dual-gated nature,t he reaction mixture wasi rradiated with l 2 only (Figure 3a). In this case, despite weak UV absorption no deprotection of the ProtPE occurred after 7.5 hours irradiationt ime, and hence no D-A adduct was formed.T his is to be expected as pyrylium salts such as the photocatalyst used in this study are knownt oc onsist of two independent chromophore moieties:T he 4-arylpyrylium and the 2,6-diarylpyrylium. [37] The 2,6-diarylpyrylium chromophore absorbsi nt he visible range and is responsible for enabling the catalytic process. The 4-arylpyrylium chromophore absorbsU Vl ight but according to literature does not induce the photoredox process.A saresult, only the visible light source activates the deprotection of ProtPE.I nt he absence of light,nod eprotection was detected after 17 hours.
To furthere xplore the robustness of the dual-gated reaction, the reactionm ixture was simultaneously irradiated with both wavelengths (Figure 3b). The conversions obtained by using either simultaneous or subsequent irradiation were found to be similar.I nb oth approaches,s imultaneous ands equential, the D-A adduct plateaus at about 50-60 %y ield. The two experiments highlight once more the requirement for both wavelengths to be present to induce the dual-gated reaction, enablinga dditional control compared to singlew avelength photochemistry.
In summary,w ei ntroduce ap hotochemical reaction system that requires the presence, subsequent or simultaneously,o f two disparate wavelengths of light to form aD iels-Alder adduct. No cross reactivity was observed for the two underlying reaction steps and each of the gates wereo nly opened with the key wavelength. Hence,w edeveloped aw avelength dual-gated system which is of key interest for the development of dual color photoresists.