Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• intermolecular hydrogen bonding changes, leading to variations on how hydrated the cryogel is, triggering a volume phase transition [34][35]. Changes in solubility can be described by the upper critical solution temperature (UCST) and lower critical solution temperatures (LCST). The UCST is the temperature at

• which a polymer becomes soluble upon heating, and the LCST is the temperature at which polymers become insoluble upon heating. Any LCST or UCST behaviour can be identified from a polymer/solvent phase diagram, if it has both one-phase and two-phase regions [34][36]. Most commonly, the physical change in

• ][37][38]. Furthermore, a polymer in cryogel form which exhibits LCST behaviour at below the body temperature of ≈37 °C would be suitable to use for medicinal applications in humans, as it would be insoluble at above these temperatures (i.e., normal body environment) and so would retain its structure

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

• underlying structure–property relationships governing the thermoresponse of sterically constrained assemblies, are still poorly understood. Furthermore, the clear majority of publications deals with polymers that exhibit a lower critical solution temperature (LCST) behavior, with PNIPAAM as their main

• physicochemical interplay between the architecture of the polymer assembly and the resulting thermoresponsive switching behavior will be in the foreground of this consideration. Keywords: lower critical solution temperature (LCST); responsive coating; smart material; thermoresponsive polymer; upper critical

• of solvents. In solution, stimuli responsive polymers undergo a conformational, so-called coil-to-globule, transition. Depending on whether the solubility increases below (LCST for lower critical solution temperature [46][47][48][49]) or above (UCST for upper critical solution temperature [50][51][52

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• ). The results obtained were consistent with those reported by O’Reilly using a polymeric backbone with catalytic centres inside the chain [56]. The authors outlined the possibility of recycling the catalyst based on the lower critical solution temperature (LCST) of the catalytic polymer system. The

LCST phase behavior of benzo-21-crown-7 with different alkyl chains

• Yan Deng,
• Xing Li,
• Qiao Zhang,
• Zheng Luo,
• Chengyou Han and
• Shengyi Dong

Beilstein J. Org. Chem. 2019, 15, 437–444, doi:10.3762/bjoc.15.38

• .15.38 Abstract The introduction of hydrophobic units into crown ethers can dramatically decrease the critical transition temperature of LCST and realize macroscopic phase separation at low to moderate temperature and concentration. Minor modifications in the chemical structure of crown ethers (benzo-21

• -crown-7, B21C7s) can effectively control the thermo-responsive properties. Keywords: crown ethers; hydrophobic units; lower critical solution temperature; LCST; thermo-responsiveness; supramolecular chemistry; Introduction The introduction of stimuli-responsiveness into artificial materials is vital

• to design advanced functional materials [1][2][3][4][5][6][7]. An external thermal stimulus is often applied to supramolecular systems to realize reversible control over supramolecular self-assemblies [8][9][10][11][12][13]. In this context, lower critical solution temperature behavior, known as LCST

An amphiphilic pseudo[1]catenane: neutral guest-induced clouding point change

• Tomoki Ogoshi,
• Tomohiro Akutsu and
• Tada-aki Yamagishi

Beilstein J. Org. Chem. 2018, 14, 1937–1943, doi:10.3762/bjoc.14.167

• ; Introduction Thermo-responsive molecules exhibiting a lower critical solution temperature (LCST) are very important for applications such as controlled drug release [1], molecular separation [2], and tissue culture substrates [3]. Poly(N-isopropylacrylamide) (pNIPAAm) is a widely used thermo-responsive polymer

• , which exhibits a clouding point around 32 °C [1][2][3][4]. Recently, thermo-responsive molecules with additional functions have been developed to replace pNIPAAm [5][6][7][8][9][10]. For example, we have developed thermo-responsive macrocyclic molecules which exhibit LCST behavior regulated by host

• in the clouding point. The clouding point of 1 increased upon addition of a cationic guest as the hydrophilic ratio in the molecule increased by formation of the complex with the hydrophilic cationic guest [5]. We also demonstrated photoresponsive LCST behavior by using a photoresponsive host–guest

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• -soluble polymers [109]. For instance, PNIPAM is a thermo-responsive polymer, which has a lower critical solution temperature (LCST) of 32 °C. Above the LCST, individual polymer chains switch from a swollen coil configuration to a collapsed globular one, providing a nano-environment that is suitable for

Spatial effects in polymer chemistry

• Helmut Ritter

Beilstein J. Org. Chem. 2017, 13, 2015–2016, doi:10.3762/bjoc.13.198

• polymer chains. Here, the LCST effects fit into the dynamic, space-spreading strength model. I am convinced that this systematic approach provides the insights to allow a targeted and rapid development of new materials and methods. Findings concerned with spatial effects can be further explored by modern

Block copolymers from ionic liquids for the preparation of thin carbonaceous shells

• Sadaf Hanif,
• Bernd Oschmann,
• Dmitri Spetter,
• Muhammad Nawaz Tahir,
• Wolfgang Tremel and
• Rudolf Zentel

Beilstein J. Org. Chem. 2017, 13, 1693–1701, doi:10.3762/bjoc.13.163

• with unique properties. Alternatively, it is possible to coordinate low molar mass ionic liquids to polymers by complexation of their anions to cyclodextrin side chains. This can have an influence on their lower critical solution temperature (LCST) [10][11]. Beside their use as organic solvent, they

Stimuli-responsive HBPS-g-PDMAEMA and its application as nanocarrier in loading hydrophobic molecules

• Yongsheng Chen,
• Li Wang,
• Haojie Yu,
• Zain-Ul-Abdin,
• Ruoli Sun,
• Guanghui Jing,
• Rongbai Tong and
• Zheng Deng

Beilstein J. Org. Chem. 2016, 12, 939–949, doi:10.3762/bjoc.12.92

• that responds to changes in temperature, pH and ionic strength [13][14]. Among temperature-responsive polymers, PDMAEMA is an important material, as its low critical solution temperature (LCST) is close to the human body temperature. The stimuli-responsive polymers can be prepared by grafting or

• important, because the LCST of PDMAEMA in water is near the human body temperature; a fact that might be exploited in drug delivery systems. We checked the light transmittance of the HBPS-g-PDMAEMA aqueous solution at a wavelength of 500 nm and a concentration of 10 mg/mL by using a UV–vis spectrophotometer

• reached a stable value at 40 °C. The curve of the first derivative showed that the transmittance decreased dramatically at a temperature of about 39 °C, which is the LCST of HBPS-g-PDMAEMA in water at a concentration of 10 mg/mL. Figure 2B shows the phase transition of HBPS-g-PDMAEMA in water. When the

Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

• Lisa Markenstein,
• Antje Appelt-Menzel,
• Marco Metzger and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 3087–3096, doi:10.3762/bjoc.10.325

• temperatures (LCST) at 52.5 °C (DIMEB-HES) and 84.5 °C (RAMEB-HES), respectively. LCST phase separations could be completely avoided by the introduction of a small amount of carboxylate groups at the HES backbone. The methylated CDs conjugated to the HES backbone exhibited significantly lower cytotoxicities

• than the corresponding monomeric CD derivatives. Since the binding potentials of these CD conjugates were very high, they are promising candidates for new oral dosage forms of anaesthetic actives. Keywords: anaesthetics; complexation; cyclodextrin; LCST; lower critical solution temperature; midazolam

• DIMEB 1a. a) Ba(OH)2·8H2O/BaO/Me2SO4 Synthesis of propargylated HES 2. Synthesis of 5a by [2 + 3] cycloadditon, a) CuSO4, ascorbate, 50 °C, 48 h. Structures of a) midazolam and b) sevoflurane. Compositions, yields, and LCST of methylated CD-HES conjugates synthesized by [2 + 3] cycloaddition

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

• Lisa F. Becker,
• Dennis H. Schwarz and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 2920–2927, doi:10.3762/bjoc.10.310

• derivatives 2, 3 and 4 were indeed highly soluble in water at 25 °C but upon heating the clear solutions turned turbid at a certain temperature and the compounds precipitated. The observed phase separation at the so-called lower critical solution temperature (LCST) is typical for uncharged polymeric

• amphiphiles, such as methyl cellulose [47], poly(N-isopropylacrylamide) (pNiPAAm) [48], and also for methylated CDs [49], and CDs completely modified with oligoethylene glycol units [50]. While the LCST transition of the statistical derivative 2b1 was within a rather broad temperature range (30–40 °C), the

• uniform derivative 3b1 showed a sharp transition at 42 °C (Figure 3). The LCST was only scarcely dependent on the ring size of CD but increased with the length of the hydrophilic oligoethylene oxide chain, as listed in Table 1. The LCST should be beyond 40 °C for being applicable for the delivery of drugs

Influence of cyclodextrin on the UCST- and LCST-behavior of poly(2-methacrylamido-caprolactam)-co-(N,N-dimethylacrylamide)

• Alexander Burkhart and
• Helmut Ritter

Beilstein J. Org. Chem. 2014, 10, 1951–1958, doi:10.3762/bjoc.10.203

• (LCST) in water and an upper critical solution temperature (UCST) in ethanol, 1-propanol, and 1-butanol. The solubility properties of the copolymers can be influenced significantly by the addition of randomly methylated β-cyclodextrin (CD). The complexation of the copolymers with CD, was confirmed by

• the use of ROESY-NMR-spectroscopy. Keywords: cyclodextrin; LCST; lysine; 2-methacrylamido-caprolactam; UCST; Introduction Recently, increasing interest has been spent on thermoresponsive polymer solutions, mainly because of their potential application in the field of drug delivery, gene delivery, or

• tissue engineering [1][2][3]. Especially polymers having a lower critical solution temperature (LCST) in water, like poly(N-isopropylacrylamide) or modified poly(N-vinylpyrrolidone) are extensively described in literature [4][5]. Below the critical temperature (TC) these polymers are soluble and they

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards ‘clickable’ biodegradable polylactide

• Quanxuan Zhang,
• Hong Ren and
• Gregory L. Baker

Beilstein J. Org. Chem. 2014, 10, 1365–1371, doi:10.3762/bjoc.10.139

• family of water-soluble and temperature responsive biodegradable PLA material with tunable lower critical solution temperature (LCST) in a range from 25 to 65 °C was obtained after ‘click’ grafting with a mixture of alkyl and PEG azides. Starting from the same precursor 1 [18], Yu and coworkers have

End-group-functionalized poly(N,N-diethylacrylamide) via free-radical chain transfer polymerization: Influence of sulfur oxidation and cyclodextrin on self-organization and cloud points in water

• Sebastian Reinelt,
• Daniel Steinke and
• Helmut Ritter

Beilstein J. Org. Chem. 2014, 10, 680–691, doi:10.3762/bjoc.10.61

• methylated β-cyclodextrin (RAMEB-CD). Additionally, the influence of the oxidation of the incorporated thioether linkages on the cloud point is investigated. The resulting hydrophilic sulfoxides show higher cloud point values for the lower critical solution temperature (LCST). A high degree of

• functionalization is supported by 1H NMR-, SEC-, FTIR- and MALDI–TOF measurements. Keywords: chain-transfer polymerization; cyclodextrins; end-group functionalization; host–guest interaction; lower critical solution temperature (LCST); poly(N,N-diethylacrylamide); Introduction Supramolecular chemistry was first

• temperature are widely investigated [13]. Within this group of materials, thermosensitive water-soluble polymers, possessing a lower critical solution temperature (LCST), have attracted much attention in several studies within the last decades [13][14][15][16][17]. The nature of the end-group of a short chain

Oligomeric epoxide–amine adducts based on 2-amino-N-isopropylacetamide and α-amino-ε-caprolactam: Solubility in presence of cyclodextrin and curing properties

• Julian Fischer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 2803–2811, doi:10.3762/bjoc.9.315

• diglycidyl ether to give novel oligomeric thermoresponsive epoxide–amine adducts. These oligomers exhibit a lower critical solution temperature (LCST) behavior in water. The solubility properties were influenced with randomly methylated β-cyclodextrin (RAMEB-CD) and the curing properties of the amine–epoxide

• mixtures were analyzed by oscillatory rheology and differential scanning calorimetry, whereby significant differences in setting time, viscosity, and stiffness were observed. Keywords: amino acids; curing properties; cyclodextrin; epoxide–amine oligomers; LCST; Introduction Many partially hydrophobic

• polymers exhibit a lower critical solution temperature (LCST) behavior in water [1][2]. Below the critical temperature (Tc) these substances are completely soluble in water, whereas above the Tc they precipitate. Thereby, hydrogen bonds between polymer chains and water molecules in cold water lead to good

Polymeric redox-responsive delivery systems bearing ammonium salts cross-linked via disulfides

• Christian Dollendorf,
• Martin Hetzer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 1652–1662, doi:10.3762/bjoc.9.189

• -dependent solubilities with lower critical solution temperatures (LCST) of 32 and 50 °C, respectively, in neutral media [50][51]. Therefore, the temperature-dependent behavior of poly(DEAAm-co-DMAEMA) and the influence of thiol side-chains on the cloud point temperatures (Tc) was investigated. Samples 3, 4a

• heating and cooling rate of 1 °C·min−1 was used. Sample 3 showed cloud points of 22.6 in pH 10 buffer solution and 23.7 °C with 0.03 M DTT. This is more than 10 °C lower than the LCST of poly(DMAEMA) in pH 10 buffer solution reported in the literature [50]. The cloud points for samples 4a and 4b just

Influence of cyclodextrin on the solubility and the polymerization of (meth)acrylated Triton^® X-100

• Melanie Kemnitz and
• Helmut Ritter

Beilstein J. Org. Chem. 2012, 8, 2176–2183, doi:10.3762/bjoc.8.245

• °C due to a typical LCST effect. By addition of 1 equiv of RAMEB-CD (1a) the cloud point is shifted from 66 to 71 °C. This can be attributed to the increasing hydrophilicity. Figure 2 shows the changes of the transmittance as a function of the temperature. After the addition of a second equiv of

• RAMEB-CD (1b) no LCST behavior could be observed over the whole temperature range from 5 to 95 °C. This was due to the much more hydrophilic character of the complex, which is a result of coverage of the hydrophobic part of 1. Complexation of the (meth)acrylic monomer derived from Triton® (2 and 3) with

• hydrophobicity of the modified monomers 2 and 3 the LCST increases significantly (Table 1). Homopolymerization of the uncomplexed (meth)acrylic monomers 2 and 3 in DMF The macromonomers 2 and 3 respectively were homopolymerized in DMF with 2,2′-azobis(2-methylpropionitrile) (AIBN) as initiator (Scheme 2). The

Cyclodextrin-induced host–guest effects of classically prepared poly(NIPAM) bearing azo-dye end groups

• Gero Maatz,
• Arkadius Maciollek and
• Helmut Ritter

Beilstein J. Org. Chem. 2012, 8, 1929–1935, doi:10.3762/bjoc.8.224

• [4-(4’-aminophenylazo)phenyl]amine. This dye-end-group-labeled polymer showed acidochromic effects, depending on the pH and the presence of randomly methylated β-cyclodextrin (RAMEB-CD). Also higher cloud-point values for the lower critical solution temperature (LCST) in the presence of RAMEB-CD were

• techniques. Water-soluble polymers, which exhibit a lower critical solution temperature (LCST), e.g., many poly(N-alkylacrylamides), have found numerous practical applications in waterborne smart materials such as bioactive surfaces, selective bioseparation, or hyperthermia-induced drug delivery [14

• easily protonated. These results correspond to the work of Toda et al. [19]. Furthermore, the solution properties of polymer 6, depending on the temperature in the presence of RAMEB-CD, were investigated. As expected, 6 is soluble in cold water below the critical solution temperature (LCST). However, due

Supramolecular hydrogels formed from poly(viologen) cross-linked with cyclodextrin dimers and their physical properties

• Yoshinori Takashima,
• Yang Yuting,
• Miyuki Otsubo,
• Hiroyasu Yamaguchi and
• Akira Harada

Beilstein J. Org. Chem. 2012, 8, 1594–1600, doi:10.3762/bjoc.8.182

• reports of supramolecular complexes with cyclodextrin (CD) dimers. A supramolecular hydrogel, which was constructed by the formation of an inclusion complex between the copolymer with an adamantyl group and CD dimer, showed a lower critical solution temperature (LCST) [11]. Another report indicated that

Influence of cyclodextrin on the solubility of a classically prepared 2-vinylcyclopropane macromonomer in aqueous solution

• Helmut Ritter,
• Jia Cheng and
• Monir Tabatabai

Beilstein J. Org. Chem. 2012, 8, 1528–1535, doi:10.3762/bjoc.8.173

• vinylcyclopropane end group and a poly(N-isopropylacrylamide) (poly(NiPAAm)) chain was obtained from amidation of 1-ethoxycarbonyl-2-vinylcyclopropane-1-carboxylic acid (4) with an amino-terminated poly(NiPAAm) 3 as an example. This macromonomer 5 showed an LCST effect after complexation of the vinyl end group with

• DLS was about 4.1 nm. DSC measurement showed the glass-transition temperature (Tg) at about 123.5 °C. Due to the hydrophilicity of the amino end groups of 3 a typical LCST (lower critical solution temperature) was observed close to that of unmodified poly(NiPAAm) at about 33.4 °C (Figure 2). Via

• . Therefore, we came to the conclusion that the Me2-β-CD ring preferably includes the vinylcyclopropane unit instead of the isopropyl unit. The supramolecular complex 7 shows the typical LCST behavior (31.7 °C) of poly(NiPAAm) (Figure 4). After free radical initiated ring-opening polymerization of 5, a

Chiral recognition of ephedrine: Hydrophilic polymers bearing β-cyclodextrin moieties as chiral sensitive host molecules

• Sabrina Gingter and
• Helmut Ritter

Beilstein J. Org. Chem. 2011, 7, 1516–1519, doi:10.3762/bjoc.7.177

• reported recently, the CD containing NIPAAm copolymer 1 exhibits lower critical solution temperature (LCST) behavior in water [23]. As expected, the supramolecular system 2 turned out to be soluble in cold water only below the LCST of 32 °C. However, due to the presence of relatively hydrophilic ephedrine

• in the host–guest system, the LCST rises to 35 °C for polymer 2, which is 3 °C higher than the value for pure poly(NIPAAM). The increase of LCST takes place because the hydrophobic phenyl ring of ephedrine is incorporated into the CD cavity, and the hydrophilic OH and amino groups are located in the

Chiral recognition of macromolecules with cyclodextrins: pH- and thermosensitive copolymers from N-isopropylacrylamide and N-acryloyl-D/L-phenylalanine and their inclusion complexes with cyclodextrins

• Sabrina Gingter,
• Ella Bezdushna and
• Helmut Ritter

Beilstein J. Org. Chem. 2011, 7, 204–209, doi:10.3762/bjoc.7.27

• -isopropylacrylamide (NIPAAm). The resulting copolymers 3D and 3L exhibit a lower critical solution temperature (LCST) of 25 °C. As a further benefit, the presence of a free carboxylic group in the copolymer system gives a high sensitivity to the pH value in respect to the LCST value. The enantioselective recognition

• of the side groups of copolymers 3D and 3L and their solubility behaviour were investigated by dynamic light scattering and 2D NMR spectroscopy, respectively. Keywords: amino acid; chiral recognition; cyclodextrins; LCST; stimuli-responsive polymers; Introduction Chiral recognition has attracted

• conditions (Scheme 1). The molar weight distribution of polymers 3D and 3L were determined by gel permeation chromatography (GPC) after silylation of the free carboxylic groups with trimethylchlorosilane. The resulting copolymer 3D, 3L (1:20) is soluble in water below the critical solution temperature (LCST

Hybrid biofunctional nanostructures as stimuli-responsive catalytic systems

• Gernot U. Marten,
• Thorsten Gelbrich and
• Annette M. Schmidt

Beilstein J. Org. Chem. 2010, 6, 922–931, doi:10.3762/bjoc.6.98

• , biocompatibility, and a tunable lower critical solution temperature (LCST) in water. The phase separation can alternatively be initiated by magnetic heating caused by magnetic losses in ac magnetic fields. The immobilization of porcine pancreas trypsin to the core–shell nanoparticles results in highly active

• , nanoparticulate biocatalysts that can easily be separated magnetically. The enzymatic activity of the obtained biocatalyst system can be influenced by outer stimuli, such as temperature and external magnetic fields, by utilizing the LCST of the copolymer shell. Keywords: biocatalysis; biolabelling; core–shell

• stabilizing shell composed of LCST or upper critical solution temperature (UCST) polymers lead to nanocomposites that show thermally inducible flocculation behavior in the carrier medium [14][15][16][17][18][19][20][21]. The particles agglomerate at a critical temperature resulting in an enhanced magnetic

Novel multi-responsive P2VP-block-PNIPAAm block copolymers via nitroxide-mediated radical polymerization

• Cathrin Corten,
• Katja Kretschmer and
• Dirk Kuckling

Beilstein J. Org. Chem. 2010, 6, 756–765, doi:10.3762/bjoc.6.89

• molecular weight distribution remained moderate. The results of copolymer characterization are summarized in Table 2. DSC measurements revealed two separated Tgs, indicating a microphase separation of the block copolymers in the dry state. Aqueous solutions of these block copolymers showed an LCST behavior

Calix[4]arene-click-cyclodextrin and supramolecular structures with watersoluble NIPAAM-copolymers bearing adamantyl units: “Rings on ring on chain”

• Bernd Garska,
• Monir Tabatabai and
• Helmut Ritter

Beilstein J. Org. Chem. 2010, 6, 784–788, doi:10.3762/bjoc.6.83

• . Adamantyl carboxylate is known to be a more effective guest [15] than the polymer attached adamantane moiety itself. Thus, the inclusion of the low molecular weight adamantyl carboxylate into the cavity of the CD component of 4 leads to a replacement of copolymer 5. pH-Depending and LCST measurements of the

• . Experimental cloud point temperature (LCST) and hydrodynamic diametera depending on the balance of hydrophobic/hydrophilic interactions of calixarene-click-cyclodextrin 4 with copolymer 5 depending on pH.