Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• and unsymmetrical N,N'-substituted alkyl- and arylindigos with tunable thermal half-lives (follow-up mechanistic studies in 2022) 2018: first report on photochromic monoarylated indigos Synthesis of indigo derivatives Indigo (Ind) is one of the oldest organic molecules, which has been used as a dye

• accelerated in the presence of acid. In 2017 and 2022, Hecht, Jacquemin and co-workers successfully synthesized a range of N,N'-disubstituted indigos, including N,N'-dialkyl derivatives, using novel approaches and investigated their photophysical properties, in particular, the thermal half-lives and the ratio

• , depending on the solvent, the thermal half-lives varied within a wide range from seconds to days. For example, for compound 17e, the half-lives changed from 8 s (in MeOH) to 11 h (in toluene). In addition, the Z-form of compound 17d was unusually stable in 1,4-dioxane, lasting for almost 6 days. The 2021

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• radioisotope for positron emission tomography (PET) in clinical and preclinical research is 18F. Radiopharmaceuticals should be prepared at the late stage of the entire synthetic protocol because of the short half-lives of radioisotopes [26][27][28][29]. In their study, the authors used an aqueous 18F-fluoride

Substituted nitrogen-bridged diazocines

• Pascal Lentes,
• Jeremy Rudtke,
• Thomas Griebenow and
• Rainer Herges

Beilstein J. Org. Chem. 2021, 17, 1503–1508, doi:10.3762/bjoc.17.107

• approach starting from the corresponding aniline precursors. The Z→E photoconversion yields in acetonitrile are 80–85% and the thermal half-lives of the metastable E configurations are 31–74 min. Particularly, the high photoconversion yields (≈70%) of the water-soluble diazocines are noteworthy, which

• , thermal half-lives (t1/2) of the metastable E-isomers of the 3-bromo and 3-iodo N-acetyl diazocines 10a and 10b (≈30 min) are significantly smaller than the half-lives of the corresponding bromo and iodo N-formyl derivatives 11a and 11b (≈50 min). In general, halogenation decreases the half-lives compared

•  3, Table 2). The photoconversion yields (Z→E) of N-formyl diazocine 11c in water and bromo-NAc diazocine 10a are about 70%, which do not differ significantly from unsubstituted NAc diazocine 10c (72%) [15]. It is interesting to note that the half-lives and activation barriers (E→Z) are increasing

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• modified with the 4'-methoxy modification hybridized better to complementary RNA, rather than DNA, due to the N-type conformation of the sugar pucker, as confirmed by NMR [202]. These same oligomers exhibited half-lives of approximately 40 minutes in the presence of phosphodiesterase I [202]. In contrast

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• increase MB half-lives. The microbubbles were prepared by mechanical agitation using a Vialmix shaker and were characterized by optical microscopy immediately after the preparation and over time. The results show that the incorporation of F-lipopeptides 1–3 led to MBs that are somewhat smaller than those

• with a half-life of 1.1 ± 0.2 h, as compared to 0.6 ± 0.2 for DPPC MBs. MBs incorporating the F-lipopeptides 1 and 2 displayed intermediate half-lives. The reduction in size of the MBs incorporating the F-lipopeptides compared to those incorporating the hydrocarbon compound 4 can be explained by the

• ). Optical micrographs and corresponding size distribution of the perfluorohexane-stabilized microbubbles with a shell of a) DPPC, b) DPPC/F-lipopeptide 3, and c) DPPC/hydrocarbon analog 4. Half-lives of microbubbles (25 °C) containing F-lipopeptides 1–3 and hydrocarbon analog 4. a) Schematic representation

Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo

• Alexander Sailer,
• Franziska Ermer,
• Yvonne Kraus,
• Rebekkah Bingham,
• Ferdinand H. Lutter,
• Julia Ahlfeld and
• Oliver Thorn-Seshold

Beilstein J. Org. Chem. 2020, 16, 125–134, doi:10.3762/bjoc.16.14

• photopharmaceutical scaffold than the widely used azobenzene motif. While para-hydroxyazobenzenes feature negligibly short cis-to-trans thermal relaxation half- lives in aqueous media in the range of μs [24][25], probably making them unsuitable for robust photoswitching applications against intracellular targets

Starazo triple switches – synthesis of unsymmetrical 1,3,5-tris(arylazo)benzenes

• Andreas H. Heindl and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2020, 16, 22–31, doi:10.3762/bjoc.16.4

• isomerization can be reversed either by irradiation with visible light (ca. 450 nm) or thermally, upon heating. The thermal back-isomerization rate can be controlled by various factors: Functional group substitutions on the phenyl rings determine the thermal half-lives of (Z)-ABs [1]. For example, o-fluoro

• substitution prolongs the thermal stability up to years [4], while electron-donating groups attached to the different phenyl rings decrease the thermal half-lives below the time scale of seconds. Even subtle interactions, such as London dispersion in alkyl-substituted ABs, can have a significant influence on

• their isomerization properties [3][4]. Also, the incorporation of AB units into cyclic [5] or macrocyclic structures can control the switching, depending, i.a., on symmetry and ring strain [6][7][8][9]. By combining these approaches, half-lives can be tuned from milliseconds to years. The incorporation

Synthesis and characterization of bis(4-amino-2-bromo-6-methoxy)azobenzene derivatives

• David Martínez-López,
• Amirhossein Babalhavaeji,
• Diego Sampedro and
• G. Andrew Woolley

Beilstein J. Org. Chem. 2019, 15, 3000–3008, doi:10.3762/bjoc.15.296

• , which showed half-lives ranging from 50 ms [25] to a few seconds [26][27]. Instead, compounds 4 and 5 exhibited photoswitching properties similar to those reported for tetra-ortho-thiol-substituted azobenzenes [17]. Conclusion Substitution of p-aminoazobenzene with ortho-bromo and ortho-methoxy groups

• periodically scanned (250 to 600 nm for each scan; integration time: 2s; scan speed: 480 nm/min) in 2-minute intervals. Absorbance data vs time were then fitted to a single exponential equation to obtain thermal relaxation half-lives using Equation 1. Computational methods DFT calculations were performed using

A combinatorial approach to improving the performance of azoarene photoswitches

• Joaquin Calbo,
• Aditya R. Thawani,
• Rosina S. L. Gibson,
• Andrew J. P. White and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2019, 15, 2753–2764, doi:10.3762/bjoc.15.266

• in a wide array of light-addressable applications. Results and Discussion The effect of ortho-substitution on half-life We first assessed the theoretical half-lives for a series of compounds with ortho-substitution on the benzene ring of previously reported azopyrazoles 4pzH and 4pzMe (Table 1

• performance: o-F [13][14], o-Cl [8][29][30], o-OMe [10][29][31], or o-Pyr [32]. For the sake of comparison, both mono- and di-ortho-substitutions were considered. Theoretical half-lives (t1/2) were calculated within the density functional theory (DFT) framework, according to the protocol reported in our prior

• (Table 1). In contrast, chloro-substituted analogues present a significant decrease in the computed half-lives: 90 days for 4pzH-Cl1 and 5 days for 4pzH-Cl2. The inclusion of methoxy and pyrrolidine groups in the ortho-position leads to an enhanced Z-isomer thermal stability compared to unsubstituted

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• that, using 360 nm light, a PPS of high percentage of cis-isomer (PPS360) can be reached. Literature evidence [7][29][30] suggests that this scaffold would have sufficiently long half-lives of the PSS state, i.e., the cis-isomer only slowly reverts to trans in the dark, which was confirmed by early

• previously reported by us [7]) leading to its exclusion from further characterization. The PSS360 forms of exemplary compounds 4d, 6e and 6f have thermal half-lives of 55 [7], 28 and 29 [7] days, respectively, at 10 μM in HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer with 1% DMSO at 25 °C

• VUF16216 (6f), which represents the optimum balance and provides a CXCR3 photoswitch with a PDE value of 0.83, i.e., from antagonism to full agonism. Based on the pharmacological properties of these three compounds and the long half-lives of their PSS states, they will be valuable tools for future

Photochromic diarylethene ligands featuring 2-(imidazol-2-yl)pyridine coordination site and their iron(II) complexes

• Andrey G. Lvov,
• Max Mörtel,
• Anton V. Yadykov,
• Frank W. Heinemann,
• Valerii Z. Shirinian and
• Marat M. Khusniyarov

Beilstein J. Org. Chem. 2019, 15, 2428–2437, doi:10.3762/bjoc.15.235

• cyclohexenone bridges show good cycloreversion quantum yields of 0.20–0.32. The thermal stability of closed-ring isomers reveals half-lives of up to 20 days in solution at room temperature. The ligands were used to explore coordination chemistry with iron(II) targeting photoswitchable spin-crossover complexes

Reversible switching of arylazopyrazole within a metal–organic cage

• Anton I. Hanopolskyi,
• Soumen De,
• Michał J. Białek,
• Yael Diskin-Posner,
• Liat Avram,
• Moran Feller and
• Rafal Klajn

Beilstein J. Org. Chem. 2019, 15, 2398–2407, doi:10.3762/bjoc.15.232

• Arylazopyrazoles represent a new family of molecular photoswitches characterized by a near-quantitative conversion between two states and long thermal half-lives of the metastable state. Here, we investigated the behavior of a model arylazopyrazole in the presence of a self-assembled cage based on Pd–imidazole

Fluorinated azobenzenes as supramolecular halogen-bonding building blocks

• Esther Nieland,
• Oliver Weingart and
• Bernd M. Schmidt

Beilstein J. Org. Chem. 2019, 15, 2013–2019, doi:10.3762/bjoc.15.197

• thermal stability of the Z-isomer, now exhibiting thermal half-lives up to two years at room temperature [36]. Most important for application in supramolecular systems, it should be possible to study both states of the system on a laboratory timescale, a key aspect in the design of our halogen bonded

• MeCN at elevated temperature (60 °C), following the works of Hecht and co-workers [45][46]. The data is presented in Table 2. Additionally, we studied A3 in a wide range of temperatures in MeCN. The half-lives decrease from A1 to A3, an effect that correlates with the increase in dipole moment of the

Diazocine-functionalized TATA platforms

• Roland Löw,
• Talina Rusch,
• Fynn Röhricht,
• Olaf Magnussen and
• Rainer Herges

Beilstein J. Org. Chem. 2019, 15, 1485–1490, doi:10.3762/bjoc.15.150

• coupling to a bulk gold surface via a conjugated linker over 11 bonds and 14 Å [11]. Thermal cis→trans isomerizations of azobenzenes are usually slow with half-lives of the trans-isomer within the range of hours to days at room temperature (parent azobenzene: 4–5 d at 25 °C) [12]. Rotation around the N=N

• . The half-lives (298 K) are similar for both systems (2.12 h for 1 and 2.32 h for 2). The lack of conjugation between the azo function and the ethynyl spacer of 2 yields in a slightly higher half-life, which is in agreement with earlier results [11]. STM Measurements The adsorption behavior of the

• -isomers of 1 and 2 isomerize back to the cis-isomer with half-lives of 2.12 h and 2.32 h at 298 K. The trans→cis activation energies with 86.5 kJ mol−1 for 1 and with 84.7 kJ mol−1 for 2 are similar to the structurally related azobenzenes [11]. Both diazocine-TATAs form highly ordered monolayers on Au(111

Coordination chemistry and photoswitching of dinuclear macrocyclic cadmium-, nickel-, and zinc complexes containing azobenzene carboxylato co-ligands

• Jennifer Klose,
• Tobias Severin,
• Peter Hahn,
• Alexander Jeremies,
• Jens Bergmann,
• Daniel Fuhrmann,
• Jan Griebel,
• Bernd Abel and
• Berthold Kersting

Beilstein J. Org. Chem. 2019, 15, 840–851, doi:10.3762/bjoc.15.81

• the meta-stable cis-form relaxes back thermally to the more stable trans from (Figures S50 and S51 in Supporting Information File 1). Thus, the cis–trans isomerization appears to be not constrained by the [Cd2L]2+ fragment, as revealed by the similar half-lives (τ1/2 cis–trans free deprotonated

Azologization of serotonin 5-HT₃ receptor antagonists

• Karin Rustler,
• Galyna Maleeva,
• Piotr Bregestovski and
• Burkhard König

Beilstein J. Org. Chem. 2019, 15, 780–788, doi:10.3762/bjoc.15.74

• thermal half-lives (THL) of the cis-isomers of compounds 5a, 5b, 12a, 16a–d, 23, and 28 was accomplished by monitoring the increase in absorbance which corresponds to the evolution of the trans-isomer after irradiation and exposure to dark. In contrast to the heterocyclic compounds 5a, 5b, 12a, and 16a–d

• ]. Supporting Information Supporting Information File 98: Detailed photochromic characterization (UV–vis absorption spectra, cycle performances, thermal half-lives) and NMR spectra of all synthesized compounds are provided. The file contains crystal structures of compounds 12b and 16a and experimental

Tuning the stability of alkoxyisopropyl protection groups

• Zehong Liang,
• Henna Koivikko,
• Mikko Oivanen and
• Petri Heinonen

Beilstein J. Org. Chem. 2019, 15, 746–751, doi:10.3762/bjoc.15.70

• was shown to be 4 minutes in methanol and 7 minutes in acetonitrile. The polarity of the solvent has a significant effect on the stability. Slower reactions were observed using 3% acetic acid in dioxane, where the half-lives for 4a and 4c were 80 minutes and 5 minutes, respectively. These results

• , d: R = isopropyl, e: R = CH2CF3. Proposed acetal hydrolysis pathways. Half-lives of 5’-acetal (4a–e) and 3’-acetal-protected (7a,c–e) 2’-deoxythymidines, and 2’-deoxy-3’-O-propen-2-ylthymidine (8b) in acetate (pH 4.94), citrate (pH 5.61) and phosphate (pH 6.82) buffers at 25.0 °C. The ionic strength

Synthesis of functionalized diazocines for application as building blocks in photo- and mechanoresponsive materials

• Widukind Moormann,
• Daniel Langbehn and
• Rainer Herges

Beilstein J. Org. Chem. 2019, 15, 727–732, doi:10.3762/bjoc.15.68

• were investigated by NMR and UV–vis spectroscopy and the results are listed in Table 1. Photostationary states (PSS) as well as half-lives (t1/2) were determined in acetonitrile at 300 K and 298.15 K, respectively. The (cis → trans) and (trans → cis) isomerization were achieved by irradiation into the

• . The half-lives (t1/2) for the thermal relaxation (trans → cis) at 298.15 K of diazocines 4–7 in acetonitrile are between 10.2–16.7 h and thus are in the same order of magnitude as the parent system 1 (15.3 h). In comparison, the 3,3’-diaminodiazocine 2 has a much longer half-life (t1/2) of 24.5 h. The

• ; iii) Zn, Ba(OH)2 H2O/EtOH, and CuCl2/O2, NaOH/MeOH; iv) Ti(Cl)4, DCM; v) ADMP, DBU, THF; vi) PPh3, H2O, THF; viii) TsCl, DMAP, TEA, DCM, and t-BuOK, THF. Photostationary states (300 K), absorption maxima and half-lives (298.15 K), determined by 1H NMR and UV–vis spectroscopy in acetonitrile

Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

• Miriam Schehr,
• Daniel Hugenbusch,
• Tobias Moje,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2018, 14, 2799–2804, doi:10.3762/bjoc.14.257

• functionalization such as cross coupling, peptide coupling or further functionalization. The photoswitchable properties of the S-diazocines 1–5 were investigated using UV–vis and NMR spectroscopic methods. The photostationary states (PSS), half-lives (t1/2) and absorption maxima (λmax) were recorded in acetone and

• nπ* absorption maxima are in a range between 508 nm to 516 nm (for UV–vis spectra measured in acetone see Supporting Information File 1). The half-lives vary from 24.8 h to 6.7 d. For the carboxylic acid functionalized S-diazocine 4 the two isomers generated after irradiation with 405 nm could be

• reported methods. All S-diazocines 1–5 are thermodynamically more stable in their cis configuration. Irradiation with violet light (405 nm) converts the cis into the trans isomer with 50–70% yield. Back-reaction with green to red light (500–660 nm) is quantitative. Thermal half-lives of the metastable

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• utility as chemical probes due to their longer half-lives in biological media. These results suggest that this structural motif could be installed to potentially improve the potencies of other lactone-based SdiA agonists and antagonists. Characterization of the efficacies and potencies of SdiA antagonists

London dispersion as important factor for the stabilization of (Z)-azobenzenes in the presence of hydrogen bonding

• Andreas H. Heindl,
• Raffael C. Wende and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2018, 14, 1238–1243, doi:10.3762/bjoc.14.106

• , our group presented a highly strained bisazobenzophane that was found to be stable exclusively in its (Z,Z)-form. Consequently, no isomerization, neither photochemically nor thermally, to its (E,Z)- or (E,E)-state occurred on the observed time scale [18]. The thermal half-lives of acyclic (Z

• )-azobenzenes can be prolonged dramatically by ortho-fluorine substitution, resulting in half-lives of up to two years at room temperature [19]. These highly thermally stable (Z)-ortho-fluoroazobenzenes can be re-isomerized almost instantaneously in an electrocatalytic fashion [20]. Furthermore, (Z)-azobenzenes

• ,-trimethylhexanoylamino)benzyl]azobenzene (4, Table 1, entry 1), expressed in the longest half-lives τ. However, in the highly polar solvent dimethyl sulfoxide (DMSO) all azoamides (4, 5, Table 1, entries 1 and 2) as well as the azocarbamate 6 (Table 1, entry 3) showed very similar isomerization rates. Additionally

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• Table S1 of reference [32]. At the lowest of the temperatures assayed, the half-live times increased to values between 51 h for OAt-UMP and 86 h for OAt-CMP. Methylimidazolides were slower to hydrolyze. The half-lives of hydrolysis for deoxynucleotides were ranging between 19 h and 29 h whereas t1/2

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• . Similarly, in the search for thiophosphate protecting groups with deprotection half-lives in the range of 100–200 h at 37 °C for sustained CpG ODN immunostimulation in animal models, Beaucage et al. have developed a new class of thermosensitive groups that are hydroxy-alkylated phosphoramidate

• ) phosphoramidothioylbutyl groups to TpsT proceeded with respective half-lives of 135 h, 245 h and 265 h at 37 °C. Therefore, these groups are appropriate for thiophosphate protection of the CpG motif of CpG ODN prodrugs, and they are complementary to those identified earlier [60]. It remains to study such thermosensitive

Preparation and isolation of isobenzofuran

• Morten K. Peters and
• Rainer Herges

Beilstein J. Org. Chem. 2017, 13, 2659–2662, doi:10.3762/bjoc.13.263

• reacted in situ, because it rapidly dimerizes or polymerizes in solvents of medium polarity such as chloroform (t1/2 = 2 h). We observed longer half-lives in low polarity solvents (t1/2 = 12 h in toluene-d8, 150 mM, 27 °C). We have been able to purify the compound by chromatography and to isolate it as a

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• mammalian mannose-binding sites are in general flat and solvent exposed, the half-lives of carbohydrate–lectin complexes are rather short since water molecules can easily access and displace the ligand from the binding site. In contrast, the bacterial lectin FimH benefits from a deep mannose-binding site