Hydrogels are often synthesized through photoinitiated step-, chain-, and mixed-mode polymerizations, generating diverse network topologies and resultant material properties that depend on the underlying network connectivity. While many photocrosslinking reactions are available, few afford controllable connectivity of the hydrogel network. Herein, a versatile photochemical strategy is introduced for tuning the structure of poly(ethylene glycol) (PEG) hydrogels using macromolecular monomers functionalized with maleimide and styrene moieties. Hydrogels are prepared along a gradient of topologies by varying the ratio of step-growth (maleimide dimerization) to chain-growth (maleimide-styrene alternating copolymerization) network-forming reactions. The initial PEG content and final network physical properties (e.g., modulus, swelling, diffusivity) are tailored in an independent manner, highlighting configurable gel mechanics and reactivity. These photochemical reactions allow high-fidelity photopatterning and 3D printing and are compatible with 2D and 3D cell culture. Ultimately, this photopolymer chemistry allows facile control over network connectivity to achieve adjustable material properties for broad applications.

Dynamic covalent chemistry was employed to improve the holographic grating performance by facilitating diffusion of monomers and network rearrangement in a holographic photopolymer system. Because of the high degree of spatiotemporal control afforded by the radical-mediated addition???fragmentation chain transfer reaction between allyl sulfide (AS) moieties and thiols, this chemistry proved well -suited for the formation of high-quality holographic photopolymers. Through exchange with a monofunctional thiol, polymer chains incorporating AS along the backbone exhibited a decrease of molecular weight of more than 80% upon the light exposure. The dramatic molecular weight reduction resulted in a corresponding viscosity drop of the whole resin system up to 1 order of magnitude. To take advantage of the covalent bond exchange, the polymers with AS (termed AS polymers) functional groups were utilized as ???dynamic binders??? in thiol???ene based holographic photopolymers designed to delay and reduce the viscosity increase of recording media during the holographic exposures. Such light-regulated viscosity reduction was found to greatly improve the recording formulations with limited diffusion of monomer during the recording. The systems utilizing AS polymer demonstrated a notable improvement of the refractive index modulation as large as 70% compared with the nondynamic analogue. Additionally, the haze in these dynamic systems was almost unchanged compared to control groups where no exchange occurred.

In the present study, the photo-initiated copper-catalyzed azide-alkyne cycloaddition (CuAAC) polymerization was utilized to form structurally diverse glassy polymer networks. Systematic alterations in the monomer backbone rigidity (e.g., cyclic or aliphatic groups with a different length of backbone) and the reactive functional group density (e.g., tetra-, tri-, di-, and mono-functional azide and alkyne monomers) were used to provide readily tailorable network structures with crosslink densities (estimated from the rubbery modulus) varying by a factor of over 20. All eight of the resultant networks exhibited glass transition temperatures (Tg) between 50 and 80 °C with tensile toughness ranging from 28 to 61 MJ m-3. A nearly linear dependence of yield stress and elongation at break (broadly defined as strength and ductility, respectively) on the Tg and rubbery modulus was established in these triazole networks. When a flexible di-alkyne monomer (5 carbon spacing between alkynes) was incorporated in a network composed of a tri-alkyne and di-azide monomer, the elongation at break was improved from 166 to 300 %, while the yield stress was reduced from 36 to 23 MPa. Additionally, the polymer ductility was also varied by incorporating mono-functional azides as chain ends in the network - replacing a sterically hindered stiff mono-azide with a more flexible mono-azide increased the elongation at break from 24 to 185 % and the tensile toughness from 6 to 28 MJ m-3.

Thiol-ene networks based on polar and nonpolar monomers at various crosslinking densities were subjected to swelling in organic solvents to measure the Flory-Huggins interaction parameter. To the best of our knowledge, this is the first example of Flory-Huggins measurements for thiol-ene networks in organic media. Experimentally determined values were compared to those predicted using the Hansen solubility parameter approach with the assistance of the HSPiP software, which is used industrially to determine the miscibility. It was shown that the polymer suite in this software does not adequately account for thioether bonds by underpredicting the dispersive Hansen parameter by roughly 5 MPa0.5 when corrected to experimental thiol-ene swelling data. Even with corrections for thioether bonds, HSPiP and Hansen solubility parameters, in general, lack the ability to account for structural factors that impact polymer-solvent interaction parameters, especially for crosslinked polymer networks.

This article describes an efficient enamine organocatalyzed thiol-Michael click reaction and its broad application in cross-linking polymerizations. A series of enamines was shown to catalyze the thiol-Michael reaction via a nucleophilic pathway. By varying the amines as well as the ring size of the ketones, enamines were designed with broad ranges of nucleophilic character ranging from 11 to 17 on the Mayr nucleophilicity scale. Upon evaluating the enamines' organocatalytic effect on the kinetics of reactions involving a thiol and Michael acceptor, wherein butyl 3-mercaptopropionate and 1-hexyl acrylate were used as model reactants, enamines were shown to outperform their base analogs. The efficiency and overall reaction yields, ranging from 11 to 92% based on the thiol conversion, were highly dependent upon the nucleophilicity of the enamines employed. Interestingly, in situ formation of an enamine via photo-deprotection of an amine in the presence of cyclic ketones facilitated the thiol-Michael reaction efficiently while simultaneously enabling higher functional group conversion. This efficiency in the reaction kinetics and conversion was extended to multifunctional derivatives, which resulted in the formation of highly cross-linked polymers.

At its basic conceptualization, photoclick chemistry embodies a collection of click reactions that are performed via the application of light. The emergence of this concept has had diverse impact over a broad range of chemical and biological research due to the spatiotemporal control, high selectivity, and excellent product yields afforded by the combination of light and click chemistry. While the reactions designated as "photoclick" have many important features in common, each has its own particular combination of advantages and shortcomings. A more extensive realization of the potential of this chemistry requires a broader understanding of the physical and chemical characteristics of the specific reactions. This review discusses the features of the most frequently employed photoclick reactions reported in the literature: photomediated azide-alkyne cycloadditions, other 1,3-dipolarcycloadditions, Diels-Alder and inverse electron demand Diels-Alder additions, radical alternating addition chain transfer additions, and nucleophilic additions. Applications of these reactions in a variety of chemical syntheses, materials chemistry, and biological contexts are surveyed, with particular attention paid to the respective strengths and limitations of each reaction and how that reaction benefits from its combination with light. Finally, challenges to broader employment of these reactions are discussed, along with strategies and opportunities to mitigate such obstacles.

A combined experimental and computational study of the reactivities of seven commonly used Michael acceptors paired with two thiols within the framework of photobase-catalyzed thiol-Michael reactions is reported. The rate coefficients of the propagation (kP), reverse propagation (k-P), chain-transfer (kCT), and overall reaction (koverall) were experimentally determined and compared with the well-accepted electrophilicity parameters of Mayr and Parr, and DFT-calculated energetics. Both Mayr's and Parr's electrophilicity parameters predict the reactivities of these structurally varying vinyl functional groups well, covering a range of overall reaction rate coefficients from 0.5 to 6.2 s-1. To gain insight into the individual steps, the relative energies have been calculated using DFT for each of the stationary points along this step-growth reaction between ethanethiol and the seven alkenes. The free energies of the individual steps reveal the underlying factors that control the reaction barriers for propagation and chain transfer. Both the propagation and chain transfer steps are under kinetic control. These results serve as a useful guide for Michael acceptor selection to design and predict thiol-Michael-based materials with appropriate kinetic and material properties.

Conversion plateaus rapidly in radical photopolymerizations (RPPs) following discontinuation of irradiation due to rapid termination of reactive radicals, which restricts the wider use of RPPs in applications that involve nonuniform light access including those with attenuated light transmission or irregular surfaces. Based on our recent report of a radical dark-curing photoinitiator (DCPI) that continues polymerization beyond the cessation of irradiation by enabling latent redox initiation with photo-released amine in the presence of a suitable oxidant, we developed a new DCPI with an absorption spectrum that extends well into the visible range. Our design process involved a series of computational investigations of candidate molecules, including a systematic study of substituents and their position-dependent effects on absorption characteristics, electronic transitions, and the photochemical mechanism and its associated energetics. Our quantum chemical computations identified the target compound 5,7-dimethoxy-6-bromo-3-aroylcoumarin-DMPT/BPh4 and predicted that it would facilitate the dark-curing mechanism by concurrent photo-radical generation and photo-induced release of an efficient redox reductant under visible irradiation. This reductant-tethered chromophore was then synthesized and optically characterized with UV-vis spectroscopy that revealed its strong visible-light absorption with a molar absorptivity of 5710 M-1 cm-1 at 405 nm and 50 M-1 cm-1 at 455 nm. We then demonstrated extensive dark-curing of >35% additional conversion over 25 min following brief activation of the shelf-stable one-part system by irradiation with a 455 nm LED that was ceased at 20% conversion. In contrast, shuttering irradiation of the control formulation at that same point resulted in immediate cessation of conversion, which plateaued at 20%. We determined a remarkable initiator efficiency of 2.82 that results from the additional redox-generated radicals with a 77% photo-reductant generation quantum yield. The combination of superior photo- and dark-curing efficiencies of this new visible DCPI is expected to open new application opportunities in RPP, especially those involving resins that are highly light attenuating, surfaces that possess irregular features that produce uneven irradiance, and production lines where continued dark-curing downstream of the light activation step enhances line efficiencies.

A scalable synthesis of high refractive index, optically transparent photopolymers from a family of low-viscosity multifunctional thiol and alkyne monomers via thiol-yne "click" is described herein. The monomers designed to incorporate high refractive index cores consisting of aryl and sulfide groups with high intrinsic molar refraction were synthesized starting from commercially available low-cost raw materials. The low-viscosity (<500 cP) thiol-yne resins formulated with these new multifunctional monomers and a phosphine oxide photoinitiator underwent efficient thiol-yne polymerizations upon exposure to 405 nm light at 30 mW/cm2. In contrast to the previously reported thiol-ene systems, the kinetic profile of these photopolymerizations showed significant dependence on the nature of the thiol and alkyne monomers. However, the ability of the thiol-yne reaction to introduce a large number of sulfide linkages compared to that of thiol-ene systems yielded cross-linked high optical quality photopolymers with a polymer refractive index that exceeds 1.68 (nD/20 °C). Interestingly, the photopolymer formed from the least sterically hindered alkynyl thioether monomer 2b with flexible thioether core and the dithiol 1a exhibited unprecedented difference in the polymer refractive index as compared to that of the resin with polymerization-induced changes reaching up to 0.08. Furthermore, the implementation of these low-viscosity thiol-yne resins was demonstrated by preparing two-stage photopolymeric holographic materials with a dynamic range of ∼0.02 and haze < 1.5% in two-dimensional high refractive index structures.

AbstractThe reaction of thiols and anhydrides to form ring opened thioester/acids is shown to be highly reversible and it is accordingly employed in the fabrication of covalent adaptable networks (CANs) that possess tunable dynamic covalent chemistry. Maleic, succinic, and phthalic anhydride derivatives were used as bifunctional reactants in systems with varied stoichiometries, catalyst, and loadings. Dynamic characteristics such as temperature‐dependent stress relaxation, direct reprocessing and recycling abilities of a range of thiol–anhydride elastomers, glasses, composites and photopolymers are discussed. Depending on the catalyst strength, 100 % of externally imposed stresses were relaxed in the order of minutes to 2 hours at mild temperatures (80–120 °C). Pristine properties of the original materials were recovered following up to five cycles of a hot‐press reprocessing technique (1 h/100 °C).

In the present work, the photocatalytic activity was investigated toward a thiol-Michael reaction of different combinations of 9-fluorenylmethyl carbamate (Fmoc) derivatives and photocaged amines (PCA) as base amplifiers and the catalytic base, respectively. This phototriggering approach was systematically studied for evaluating its effect on kinetics between thiol and Michael acceptors like acrylate or sulfone wherein, butyl 3-mercaptopropionate (BMP), 1-hexyl acrylate (HA), and ethyl vinyl sulfone (EVS) were used as model reactants. Interestingly, PCAs exhibited low quantum yields by themselves; NPPOC-Hex (2.5 mol %) which when used with BMP and HA, resulted in only 25% thiol conversion; however, when used along with Fmoc-Hex or Fmoc-TMG (2.5 or 5 mol %), it resulted in a higher thiol conversion of 50–60%. Furthermore, use of NPPOC-DEA (5 mol %) with 1 mol % Fmoc-TMG resulted in >70% thiol conversion for the same system. Upon using BMP and EVS nearly complete conversion of functional groups with 5 mol % NPPOC-DEA and 5 mol % Fmoc-DEA was obtained. This enhancement in reaction kinetics and conversion upon addition of an Fmoc derivative to a monofunctional thiol-Michael system was extended to multifunctional derivatives for polymerizing cross-linked polymer networks. Moreover, the kinetic study on model reactants also demonstrated efficient dark curing, resulting in 50–75% thiol conversion with only 30 s irradiation time, leading to validation of the efficacy of Fmoc derivatives and PCAs as photocatalysts for dark cure. Upon precise characterization in cross-linked systems using Raman spectroscopy for TMPTA/PETMP in the presence of 20 mol % NPPOC-DEA and 1 mol % Fmoc-TMG, the extent of dark cure was evaluated for a distance of 16.5 mm, which was observed to undergo maximum conversion and high dark cure propagation upon heating to 70 °C. Therefore, Fmoc-PCA catalysis is a practically useful approach for improving the photoinitiated efficiency of the thiol-Michael reaction and enabling photopolymerization in the dark with a marked improvement in photosensitivity.

Enrichment of mRNA is a key step in a number of molecular biology techniques, particularly in the rapidly growing field of transcriptomics. Currently, mRNA is isolated using oligo(thymine) DNA (oligo(dT)) immobilized on solid supports, which binds to the poly(A) tail of mRNA to pull the mRNA out of solution through the use of magnets or centrifugal filters. Here, a simple method to isolate mRNA by complexing it with synthetic click nucleic acids (CNAs) is described. Oligo(T) CNA bound efficiently to mRNA, and because of the insolubility of CNA in water, >90% of mRNA was readily removed from solution using this method. Simple washing, buffer exchange, and heating steps enabled mRNA's enrichment from total RNA, with a yield of 3.1 ± 1.5% of the input total RNA by mass, comparable to the yield from commercially available mRNA enrichment beads. Further, the integrity and activity of mRNA after CNA-facilitated pulldown and release was evaluated through two assays. In vitro translation of EGFP mRNA confirmed the translatability of mRNA into functional protein and RT-qPCR was used to amplify enriched mRNA from total RNA extracts and compare gene expression to results obtained using commercially available products.

Click nucleic acids (CNAs) are a new, low-cost class of xeno nucleic acid (XNA) oligonucleotides synthesized by an efficient and scalable thiol-ene polymerization. In this work, a thorough characterization of oligo(thymine) CNA-oligo(adenine) DNA ((dA)(20)) hybridization was performed to guide the future implementation of CNAs in applications that rely on sequence-specific interactions. Microscale thermophoresis provided a convenient platform to rapidly and systematically investigate the effects of several factors (i.e., sequence, length, and salt concentration) on the CNA-DNA dissociation constant (K-app). Because CNAs have limited water solubility, all studies were performed in aqueous-DMSO mixtures. CNA-DNA hybrids between oligo(thymine) CNA (average length of 16 bases) and (dA)(20) DNA have good stability despite the high organic content, a favorable attribute for many emerging applications of XNAs. In particular, the K-app of CNA-DNA hybrids in 65 vol % DMSO with 10 mM sodium chloride (NaCl) was 0.74 +/- 0.1 mu M, whereas the K-app for (dT)(20)-(dA)(20) DNA-DNA was found to be 45 +/- 2 mu M in a buffer without DMSO but at the same NaCl concentration. CNA hybridized with DNA following Watson-Crick base pairing with excellent sequence specificity, discriminating even a single-base-pair mismatch, with K-app values of 0.74 +/- 0.1 and 3.7 +/- 0.6 mu M for complementary and single-base-pair mismatch sequences, respectively. As with dsDNA, increasing CNA length led to more stable hybrids as a result of increased base pairing, where K-app decreased from 5.6 +/- 0.8 to 0.27 +/- 0.1 mu M as the CNA average length increased from 7 to 21 bases. However, unlike DNA-DNA duplexes, which are largely unstable at low salt concentrations, the CNA-DNA stability does not depend on salt concentration, with K-app remaining consistent between 1.0 and1.9 mu M over a NaCl concentration range of 1.25-30 mM.

Efficient intracellular delivery of biomacromolecules such as proteins continues to remain a challenge despite its potential for medicine. In this work, we show that mScarlet, a non cytotoxic red fluorescent protein (RFP) conjugated to Click Nucleic Acid (CNA), a synthetic analog of DNA, undergo cell uptake significantly more than either native proteins or proteins conjugated with similar amounts of DNA in MDA-MB-468 cells. We further demonstrate that the process of cell uptake is metabolically driven and that scavenger receptors and caveolae mediated endocytosis play a significant role. Co-localization studies using anti-scavenger receptor antibodies suggest that scavenger receptors are implicated in the mechanism of uptake of CNA modified proteins.

The authors of this Communication regret that there was an error in the grant number of the original funding information. The correct funding source was National Science Foundation (CHE 1808484).

A high-performance holographic recording medium was developed based on a unique combination of photoinitiated thiol-ene click chemistry and functional, linear polymers used as binders. Allyl reactive sites were incorporated along the backbone of the linear polymer binder to enable facile film casting and to facilitate cross-linking by photopolymerization of the thiol-ene monomers that also serve as the writing monomers in this distinctive approach to holographic materials. The allyl content and the ratio of the linear polymer to the writing monomers were varied to maximize and control the refractive index contrast. A blade-coating-based film preparation method was developed to form films from the mixture of linear polymer and the thiol-ene monomers. This approach results in a holographic material with a peak to mean index contrast (Δn) that reaches 0.04. The refractive index contrast was stable for at least two weeks. Haze in holograms with a high writing monomer loading was significantly reduced when a higher allyl content was incorporated into the binder, resulting in the lowest haze around 0.2%. Finally, the media exhibit high resolution as demonstrated by the ability to record reflection holograms with 140 nm pitch and diffraction efficiency in excess of 90%.

Radical photopolymerization (RPP) has grown into a multibillion-dollar technology for reduced energy consumption and waste with increased productivity. However, radical-mediated polymerization ceases almost immediately following discontinuation of irradiation because of rapid termination of reactive centers. This restricts the wider use of RPP in applications that involve light attenuation or irregular surfaces because uniform polymerization is not guaranteed for these challenging exposure conditions and the resultant undercuring leads to compromised material properties and harmful leachable monomers. Herein, we developed a unique radical dark-curing photoinitiator (DCPI) that continues its polymerization beyond the cessation of irradiation. The DCPI achieved a remarkable 25-60% additional conversion over a 1 h period, when light was shuttered at 20% conversion, compared to the 1-3% additional conversion achieved by a Norrish type II control photoinitiator. We elucidated the origin of the high photon efficiency using computational studies and experiments, which suggest that the DCPI may be the most-photon-efficient photoinitiator to date. We also demonstrated that the mechanical properties of dark-cured polymer are similar to and even exceed those of the corresponding polymer obtained by extended photocuring. In particular, the initial 0.1 MPa storage modulus continuously developed to 4.3 MPa without further irradiation, while also exhibiting similar to 30% less shrinkage stress than the full exposure control. With its superior photo- and dark-polymerization efficiency, the DCPI enhances the performance of many existing RPP processes while extending RPP to heretofore unattainable applications. The DCPI accomplishes such a performance through an inherent automatic rectification of initially undercured regions and defies the RPP paradigm that light dosage directly correlates to conversion.

Through thiol-ene photopolymerization of presynthesized oligomers, advanced clickable nucleic acids (CNA-2G) are synthesized with sequence-controlled repeating units. As examples, poly(thymine-adenine) (polyTA) CNA-2G and poly(thymine-thymine-cytosine) CNA-2G are synthesized by polymerizing thiol-ene heterofunctional dimers with pendant thymine-adenine nucleobases and trimer with pendant thymine-thymine-cytosine nucleobases. Based on size exclusion chromatography (SEC) analysis, polyTA and polyTTC have number average molecular weights of 2000 and 1800, respectively, which contain 7-8 pendant nucleobases. Based on the different behavior of the CNA-2G monomers and CNA-2G oligomers with two or more pendant nucleobases in photopolymerization, an unusual thiol-ene chain-growth propagation mechanism is observed for the former and a common thiol-ene step-growth propagation mechanism for the latter. The uncommon thiol-ene chain-growth propagation is hypothesized to rely on a six-membered ring mediated intramolecular hydrogen atom transfer process.