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Active Ester Functionalized Azobenzenes As Versatile Building Blocks

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Active Ester Functionalized Azobenzenes As Versatile Building Blocks molecules Article Active Ester Functionalized Azobenzenes as Versatile Building Blocks Sven Schultzke 1,2,† , Melanie Walther 1,2,† and Anne Staubitz 1,2,* 1 Institute for Analytical and Organic Chemistry, University of Bremen, Leobener Straße 7, D-28359 Bremen, Germany; [email protected] (S.S.); [email protected] (M.W.) 2 MAPEX Center for Materials and Processes, University of Bremen, Bibliothekstraße 1, D-28359 Bremen, Germany * Correspondence: [email protected]; Tel.: +49-421-218-63210 † These authors contributed equally to this work. Abstract: Azobenzenes are important molecular switches that can still be difficult to functionalize selectively. A high yielding Pd-catalyzed cross-coupling method under mild conditions for the intro- duction of NHS esters to azobenzenes and diazocines has been established. Yields were consistently high with very few exceptions. The NHS functionalized azobenzenes react with primary amines quantitatively. These amines are ubiquitous in biological systems and in material science. Keywords: azobenzene; diazocine; molecular switches; palladium-catalyzed carbonylation; photo- switchable NHS ester; N-hydroxysuccinimide; chemical biology 1. Introduction Citation: Schultzke, S.; Walther, M.; Staubitz, A. Active Ester Photoswitchable molecules add photoresponsiveness to diverse materials such as poly- Functionalized Azobenzenes as mers [1–6], dendrimers [7,8] or biomolecules [9–23]. By precise adjustment of the synthetic Versatile Building Blocks. Molecules strategy the switch can be incorporated into the target material and its switching properties 2021, 26, 3916. https://doi.org/ can be utilized. However, in many cases, it is exactly this tailored functionalization of the 10.3390/molecules26133916 photoswitch that is the major challenge and the bottleneck in a successful project. Due to its fast and efficient photoswitching characteristics, as well as its high fatigue- Academic Editors: Estelle Léonard resistance [24], azobenzene is widely used in versatile applications such as molecular ma- and Muriel Billamboz chines [3,25–28], data storage materials [29–32], or photopharmacology [9–23]. Upon irra- diation with UV-light, typical azobenzenes undergo isomerization from the thermodynam- Received: 31 May 2021 ically favored (E)-isomer to the less stable (Z)-isomer (Figure1, left). The re-isomerization Accepted: 23 June 2021 can occur either by irradiation with light or by thermal relaxation [24,33]. The half-lives of Published: 26 June 2021 the latter strongly depend on the azobenzenes’ substitution pattern and are therefore tun- able for the specific application [34]. The isomerization is accompanied by a change of sev- Publisher’s Note: MDPI stays neutral eral physicochemical characteristics: the geometry [35,36], the end-to end-distance [35,36], with regard to jurisdictional claims in and the electronic properties [37] (e.g., absorption and dipole moment). The thermodynam- published maps and institutional affil- ically favored (E)-form is planar [35] and without a dipole moment [37]. The (Z)-isomer on iations. the other hand has a bent geometry where the phenyl rings are twisted ~55◦ out of plane to the azo group [36]. Moreover, the (Z)-isomer shows a dipole moment of 3.0 Debye [37]. The end-to-end distance of the (E)- and (Z)-isomer differs by ~3.5 Å [35,36]. In biological systems, azobenzenes bind typically in an elongated confirmation; its biological activity Copyright: © 2021 by the authors. is controllable via the switching process [9]. The isomerization to the (Z)-isomer occurs Licensee MDPI, Basel, Switzerland. by irradiation with UV-light, which might harm cells and tissues [38–40]. Therefore, a This article is an open access article red-shifting of the absorption wavelength is desirable and in biological applications may distributed under the terms and be even necessary [9]. In addition, a separation of the absorption spectra of both isomers conditions of the Creative Commons is important to avoid mixtures of isomers. Starting from 2009, ortho-substituted azoben- Attribution (CC BY) license (https:// zenes [41–50] and ethylene-bridged azobenzenes, the so-called diazocines [51,52], have creativecommons.org/licenses/by/ 4.0/). been discovered to be promising candidates to overcome the two limitations of a typical Molecules 2021, 26, 3916. https://doi.org/10.3390/molecules26133916 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 14 of both isomers is important to avoid mixtures of isomers. Starting from 2009, ortho-sub- Molecules 2021, 26, 3916 2 of 13 stituted azobenzenes [41–50] and ethylene-bridged azobenzenes, the so-called diazocines [51,52], have been discovered to be promising candidates to overcome the two limitations of a typical azobenzene. Depending on the substituents in ortho-position, not only the ab- azobenzene. Depending on the substituents in ortho-position, not only the absorption sorption is shifted towards longer wavelength but also the thermal half-life may be dras- is shifted towards longer wavelength but also the thermal half-life may be drastically ticallyextended extended due todue steric to steric and electronic and electronic interactions interactions [48]. Diazocines [48]. Diazocines are also a are particularly also a partic- ularlyimportant important class ofclass azobenzenes, of azobenzenes, because because the bent (theZ)-isomer bent ( isZ)-isomer thermodynamically is thermodynamically favored favoreddue to due the ringto the strain ring of strain the eight-membered of the eight-membered ring (Figure1 ring, right). (Figure The isomerization 1, right). The of isomeri- di- zationazocines of diazocines is in both directions is in both possible directions using possible visible light; using the visible isomerization light; the to the isomerization elongated to the( Eelongated)-form occurs (E)-form upon irradiation occurs upon with irradiation light in the rangewith oflight 400 in nm, the the range re-isomerization of 400 nm, to the re- isomerization(Z) with 530 nmto (Z [51) with]. 530 nm [51]. E azobenzeneortho-azobenzene diazocine F N (Z) F (Z) (E) F N N N F N N h 1 kBT(h 2) h 1 kBT(h 2) h 1 kBT(h 2) 365 nm >400 nm >500 nm 410 nm 400 nm 530 nm F F N N N (E) N (E) (Z) F NN F FigureFigure 1. Isomerization 1. Isomerization of azobenzene of azobenzene [24] [24,], tetra-ortho-fluorinated tetra-ortho-fluorinated azobenzene azobenzene [48 [48]] and and diazocine diazocine [51]. [51]. To incorporate such azobenzenes into a larger system, a suitable functional group isTo necessary incorporate that reacts such selectivelyazobenzenes with into the a specific larger targetsystem, position a suitable of the functional material. groupN- is necessaryHydroxysuccinimide that reacts selectively (NHS) esters with react the selectively specific undertarget mild position conditions of the with material. primary N-Hy- droxysuccinimideamines, which can (NHS) be found esters for example react selectively in commercially under available mild polymersconditions but with of course primary amines,also in which all proteins can be and found peptides for example as well as in in commercially nucleic acids. Due available to the ubiquitypolymers of primarybut of course alsoamines, in all proteins NHS esters and are peptides versatile as building well as blocks in nucleic for instance acids. inDue peptide to the synthesis ubiquity [53 of– 55primary], amines,bioconjugate NHS esters chemistry are versatile [56–60] as building well as functionalized blocks for instance materials in peptide and polymers synthesis [61–71 [53–55],]. bioconjugateThe use of NHS chemistry esters for [56–60] the formation as well ofas amidesfunctionalized has several materials advantages: and NHS polymers esters are[61–71]. comparatively easy to prepare. They are the only active esters that can be isolated [72]. The use of NHS esters for the formation of amides has several advantages: NHS esters are In comparison to the coupling reaction of a primary amine with a carboxylic acid using a comparativelycarbodiimide couplingeasy to prepare. agent such They as N,N are0-dicyclohexylcarbodiimide the only active esters that (DCC), can NHSbe isolated esters are [72]. In comparisonless toxic. Theyto the can coupling be used underreaction physiologic of a primary or slightly amine basic with conditions a carboxylic [72]. Moreover, acid using a carbodiimidethe products coupling of their transformations agent such as are N,N easier′-dicyclohexylcarbodiimide to purify as water-soluble NHS (DCC), is released NHS esters areduring less toxic. the amide They formationcan be used [53 ].under physiologic or slightly basic conditions [72]. More- over, theTraditionally, products NHSof their esters transformations are synthesized byare a easier coupling to reactionpurify as of thewater-soluble carboxylic acid NHS is releasedwith NHS during in the the presence amide of formation a carbodiimide [53]. coupling agent [73,74], which is known to have anTraditionally, allergenic potential NHS and esters to form are urea synthesized as byproduct. by Thus,a coupling the product reaction purification of the mightcarboxylic acidbe with challenging NHS in [72 the]. The presence carboxylic of a acid carbodiimide can also be activated coupling by agent using anhydrides[73,74], which and theiris known analogues for example N,N0-disuccinimidyl carbonate (DSC) [75]. More recently, coupling to have an allergenic potential and to form urea as byproduct. Thus, the product purifica- reactions of alcohols [76]
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