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Living Polymerization of 2-Ethylthio-2-oxazoline and Postpolymerization Diversification
- You-Chi Mason WuYou-Chi Mason WuDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesMore by You-Chi Mason Wu
- and
- Timothy M. Swager*Timothy M. Swager*[email protected]Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesMore by Timothy M. Swager
Copyright © 2019 American Chemical Society. This publication is licensed under CC-BY-NC-ND.
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Abstract
The postpolymerization modification of polymers produced by living polymerization is an attractive method to create precision nanomaterials. We describe the living cationic ring-opening polymerization of a 2-alkylthio-2-oxazoline to furnish a polythiocarbamate. The polythiocarbamate is activated toward substitution by N- and S-nucleophiles via oxidation of the S to an SO2. Mild substitution conditions provide broad functional group tolerance, constituting a versatile postpolymerization modification platform with access to a diversity of polyureas and polythiocarbamates. We further demonstrate the utility of this strategy by synthesizing and functionalizing block copolymers.
The ability to tailor chemical functionalities of polymers dictates their practical applications. The development of new functional polymers is often limited by the polymerization reaction, and small changes in monomers can compromise access to controllable compositions and molecular weights. (1,2) Postpolymerization modification (PPM) can address these challenges, wherein functional groups that would be incompatible with a polymerization can be used for the diversification of polymer structures. (1,2) Furthermore, in situ PPM within complex systems can confer stimuli-responsive properties, with implications in sensing, drug delivery, and dynamic materials. (3−6)
PPM platforms ideally utilize modification chemistries that are mild and specific, such as click chemistry or nucleophilic substitution of activated leaving groups. (1,7−10) PPM methods often employ polymers created by radical polymerization, whereas compatibility with cationic polymerizations constrains the available platforms for PPM. (2) Among the most extensively investigated monomers for cationic ring-opening polymerization (CROP) are cyclic imino ethers, such as oxazolines. (11,12) The living character of oxazoline polymerization enables controlled molecular weight and dispersity, as well as access to complex architectures such as block and graft copolymers. (13) Polyoxazolines have wide utility in biomedical and materials applications as a result of their desirable features including robust polymerization, biocompatibility, and chemical versatility. (14−16) Critical to these applications is the incorporation of functional groups that tailor the chemical, biological, thermomechanical, and other properties of the polymers (Figure 1). To this end, polyoxazolines with pendant alkenes and alkynes have been reported, allowing functionalization via click chemistries such as thiol–ene addition and azide–alkyne cycloaddition (Figure 1a). (5,17,18) Direct substitution by nucleophiles is often a more straightforward and versatile PPM method. Methyl ester-containing polyoxazolines undergo amidation with primary amines, but this method has limited scope, and to avoid harsh conditions additional manipulations were undertaken to convert the methyl ester to an activated ester (Figure 1a). (19−22) As such, the development of more general, versatile, and robust PPM strategies warrants further attention.
Figure 1
Figure 1. PPM strategies based on CROP of oxazoline derivatives. (a) Elaboration of polyoxazolines with pendant alkenes and alkynes by click chemistries, or with pendant esters by amidation (refs (17−22)). (b) Polymerization of 2-alkoxy-2-oxazolines (ref (25)). (c) This work: Living CROP of 2-ethylthio-2-oxazoline and postpolymerization functionalization.
Investigations of oxazolines beyond those with C-based substituents at the 2-position are limited. Miyamoto et al. disclosed the polymerization of cyclic amine-substituted oxazolines (i.e., pseudoureas), but the polymerization was hindered by substituents larger than pyrrolidinyl, and living character was not demonstrated. (23,24) The same group investigated the polymerization of 2-alkoxy-2-oxazolines (i.e., cyclic iminocarbonates) and found that pervasive chain transfer occurred as a result of nucleophilic attack of the monomer on the alkoxy group of the active chain end (Figure 1b), unless the monomer contained a bulky neopentoxy group. (25)
We were encouraged to explore the polymerization of novel oxazolines by reports of nucleophilic diversification of carbamates by displacement of the O-substituent. (26−28) Nonetheless, the substitution is particularly challenging for N,N-disubstituted carbamates and requires a highly activated leaving group (e.g., 4-nitrophenolate) or activation by a Lewis acid (e.g., AlMe3). (26,28) In these cases, however, the corresponding cyclic imino ether monomers are synthetically difficult to access and polymerize, and substitution conditions are harsh.
Our approach to create oxazolines for PPM was inspired by biological studies showing that thiocarbamate-based pesticides are oxidized to the sulfinyl or sulfonyl species in cells, upon which they act as potent S-carbamoylating agents. (29−33) As a result, we set out to create similar structures by the CROP of a 2-alkylthio-2-oxazoline (Figure 1c). We hypothesized that the alkylthio side chain would suppress chain transfer processes relative to the alkoxy side chain owing to the diminished driving force of the ensuing C═S vs C═O bond formation. Subsequently, postpolymerization activation of the thiocarbamates by oxidation would enable substitution by moderate nucleophiles. This scheme constitutes a versatile and atom-economical platform to access 2-substituted polyoxazolines—alternatively viewed as N,N-linked polyureas and polythiocarbamates—with broad functional group tolerance (Figure 1c).
The 2-ethylthio-2-oxazoline monomer (1) was synthesized in two steps from ethanolamine (34,35) and purified by distillation from CaH2 under reduced pressure. Monomer 1 was polymerized at 90 °C in PhCN using MeOTs as the initiator to yield polythiocarbamate P1 (Figure 2a). The polymerization was terminated at 8 h using N-phenylpiperazine, and 1H NMR end group analysis supports successful end-capping (Figure S3). We note that, based on the kinetics data in Figure 2e, monomer conversion is near completion (97%) at 8 h; when the terminating agent was added at 16 h instead of 8 h, end groups were not observed by 1H NMR, suggesting that chain-terminating side reactions do occur after prolonged heating at high monomer conversions. The structure of P1 was confirmed by 1H and 13C NMR, FT–IR, and MALDI–TOF MS analyses (Figures S12, S13, and S71 of the Supporting Information and 2b).
Figure 2
Figure 2. (a) CROP of 1 to give P1. (b) MALDI–TOF MS of a low-molecular weight, piperidine-terminated sample of P1. (c) Mn and Đ of P1 at various [M]/[I]. (d) Monitoring of Mn and Đ of P1 at increasing monomer conversion. (e) First-order kinetic analysis of the polymerization of 1. Mn and Đ determined by SEC with polystyrene standards; monomer conversion determined by NMR.
Paralleling the well-known CROP of 2-alkyl-2-oxazolines, the polymerization of 1 is living. To demonstrate this behavior, we polymerized 1 at various monomer-to-initiator ratios ([M]/[I]). The size exclusion chromatography (SEC) traces are monomodal and narrow (Figure S4), and Mn increased linearly with [M]/[I] while Đ remained low (≤1.3) and largely insensitive to Mn (Figure 2c). A single polymerization reaction monitored at various monomer conversion values displayed linear Mn vs conversion (Figure 2d). Additionally, the consumption of the monomer exhibited first-order kinetics (Figure 2e). These observations are consistent with a low incidence of chain transfer, which was anticipated with the alkylthio substituent.
The activation and substitution steps for PPM were developed using a small-molecule analog of polymer P1, wherein we found that the sulfoxide and sulfone are neatly generated with the respective addition of 1 or 2 equiv of m-CPBA (Scheme S1). (31) The substitution step was probed by reacting the sulfone with benzylamine as the nucleophile. Reaction with the sulfone at room temperature gave the corresponding urea in 97% isolated yield, whereas the sulfoxide required mild heating to 35 °C to reach full conversion within the same reaction time (Scheme S2). Notably, we found that the thiocarbamate sulfoxide and sulfone groups are hydrolytically stable, which allowed all reactions to be performed in wet solvents under open flask conditions.
Polythiocarbamate P1 is converted by m-CPBA to sulfonyl polymer P2, which enables substitution by various N- and S-nucleophiles (Scheme 1). We first assessed the substitution with benzylamine, a primary alkylamine, to provide polyurea P3a. 1H NMR spectra of P1, P2, and P3a, shown in Figure 3, confirm the high efficiencies of both the oxidation and substitution reactions. SEC traces of the polymers remained monomodal and narrow and retention times remained mostly unchanged (Figures S6 and S7), which indicates that polymer degradation or cross-linking does not occur.
Scheme 1
Scheme 1. Activation of P1 by Oxidation and Substitution Scope of P2a
aIsolated yields reported. Full conversion observed in all cases.
bMn = 21.2 kDa, Đ = 1.26. See SI for full SEC characterization.
c0.1 mmol scale.
d0.9 g, 5 mmol scale.
eDMF used as solvent.
f2 equiv of DBU added.
gAmine added as HCl salt.
h3 equiv of DIPEA (N(Et)(i-Pr)2) added.
iNH3(aq) (5 equiv), TFE.
jDMF/MeOH used as solvent.
kl-Cysteine methyl ester HCl (3 equiv), Et3N (3 equiv), DMF/MeOH; then LiOH/H2O, 2 h.
l1.5 equiv of each amine was used. Substitution ratio determined by 1H NMR.
Figure 3
Figure 3. 1H NMR spectra of (a) P1, (b) P2, and (c) P3a.
The scope of the explored functionalization is reported in Scheme 1. Substitution proceeded smoothly and selectively with secondary alkylamines (P3b, c) in addition to primary alkylmines, with no observed cross-reactivity with nucleophilic alcohols (P3c), thioethers (P3d), pyridines (P3e), and tertiary amines (P3f). Arylamines were unreactive under these conditions (P3g, n). Electrophilic groups such as alkyl chlorides (P3h) and esters (P3i, m) were tolerated as well. The installation of alkynyl (P3j) and norbornenyl (P3k) groups provides opportunities for further functionalization via azide–alkyne cycloaddition or ring-opening metathesis, respectively. Substitution by ammonia produced an intriguing polyurea (P3l), which is only soluble in fluorinated alcohols (TFE and HFIP). High isolated yields and full conversion of the sulfonyl groups were achieved in all cases, and products were purified by precipitation, dialysis, or preparative SEC, depending on solubility and scale.
Aliphatic (P3m) and aryl (P3n) thiols proved to be competent substitution partners with the addition of an amine base such as DIPEA (Scheme 1). Following this observation, we evaluated the competitive reactivity of thiol vs amine groups. Treatment of P2 with cysteamine resulted in exclusive reactivity at the thiol to give polythiocarbamate P3o, while the amine remained unaffected. The S-selectivity was corroborated by NMR analysis of model compound reactions as well as FT–IR characterization of the polymer (Figures S1 and S2) and is consistent with literature reports in aqueous systems at pH 8. (31) Lastly, substitution by l-cysteine methyl ester, followed by one-pot hydrolysis with the addition of LiOH/H2O, provided zwitterionic poly(amino acid) P3p.
In addition to homopolymers, random copolymers were produced by substitution of P2 with multiple nucleophiles in one pot. A mixture of an electron-rich and an electron-poor benzylamine was used (Scheme 1, P3q). Unsurprisingly, the nucleophilicities of the amines influenced their relative substitution rates and thus the final composition of the copolymer. This heterofunctionalization strategy opens the door to multifunctional polymers with tunable compositions.
Although arylamines were unreactive toward substitution under the aforementioned conditions, we hypothesized that the addition of a strong, hindered base would generate highly nucleophilic anilides by deprotonation. In this case, direct substitution of the relatively inert polythiocarbamate P1 should be possible, obviating the need for the oxidative activation step. Gratifyingly, with the use of LiHDMS as the base in THF, the substitution of P1 proceeded smoothly with arylamines containing an electron-withdrawing chloro substituent (P3r) or an electron-donating methoxy substituent (P3s), as well as with a secondary alkylarylamine (P3t) and a polycyclic arylamine (P3u) (Scheme 2). In addition to expanding the scope to encompass arylamines, these results highlight the range of reactions achievable with this polymer system.
Scheme 2
Scheme 2. Substitution of P1 by Arylaminesa
aIsolated yields reported. Full conversion observed in all cases.
In order to further demonstrate the utility of the living CROP and mild functionalization conditions, we synthesized a block copolymer P5 from monomers 1 and 2-ethyl-2-oxazoline (4) via sequential monomer addition (Figure 4a). Samples taken after the first and second block formation were each analyzed by SEC, which showed a clear shift in retention time after the addition and reaction of 4, while Đ remained low (<1.3) (Figure 4b). The small high-molecular weight shoulder and low-molecular weight tail in the SEC trace of the diblock copolymer (Figure 4b, purple) are likely due to chain coupling and transfer processes known to occur in the polymerization of 2-ethyl-2-oxazoline. (36) Subsequently, the same procedure was employed for the activation of the thiocarbamate groups in the block polymer (P6), followed by substitution with benzylamine (P7, Figure 4a). Using this mild method, the amide groups were unaffected while additional functionalities were installed, as confirmed by NMR (Figures S57–S62).
Figure 4
Figure 4. (a) Polymerization, activation, and substitution of block copolymer. (i) PhCN, 90 °C, 4 h. (ii) 90 °C, 12 h. (iii) Piperidine, 1 h, 74% yield. (iv) m-CPBA, DCM, rt, 5 h. 96% yield. (v) BnNH2, CHCl3, rt, 16 h. 95% yield. (b) SEC traces of block copolymer P5 sampled after step (i) (green) and (iii) (purple).
In conclusion, we have demonstrated an efficient, general procedure to access diverse polyureas and polythiocarbamates via CROP of 2-ethylthio-2-oxazoline. The living polymerization enables the construction of precise, complex polymer architectures. The mild conditions and broad functional group tolerance of postpolymerization substitution provide a platform for the divergent synthesis of functional polymers.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b06009.
Experimental details, model compound studies, and characterization data (PDF)
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Author Information
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- Timothy M. Swager - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;
http://orcid.org/0000-0002-3577-0510;
- You-Chi Mason Wu - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;http://orcid.org/0000-0002-6585-7908
Acknowledgments
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This work was supported by the U.S. Army Research Laboratory (ARL) and the U.S. Army Research Office through the Institute for Soldier Nanotechnologies (ISN), under Cooperative Agreement number W911-NF-18-2-0048.
References
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This article references 36 other publications.
- 1Blasco, E.; Sims, M. B.; Goldmann, A. S.; Sumerlin, B. S.; Barner-Kowollik, C. Macromolecules 2017, 50, 5215– 5252, DOI: 10.1021/acs.macromol.7b00465Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCqsrfF&md5=be1dc3159bb83222f6cc5d84f700303b50th Anniversary Perspective: Polymer FunctionalizationBlasco, Eva; Sims, Michael B.; Goldmann, Anja S.; Sumerlin, Brent S.; Barner-Kowollik, ChristopherMacromolecules (Washington, DC, United States) (2017), 50 (14), 5215-5252CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)A review. The translation of small mol. chemistries into efficient methodologies for polymer functionalization spans several decades, enabling crit. advances in soft matter materials synthesis with tailored and adaptive property profiles. The present Perspective explores-based on selected examples-50 years of innovation in polymer functionalization chemistries. These span a diverse set of chemistries based on activated esters, thiol-ene/yne processes, nucleophilic systems based on isocyanates, reactions driven by the formation of imines and oximes, ring-opening processes, cycloaddns., and-in a recent renaissance-multicomponent reactions. In addn., a wide variety of chain types and architectures were modified based on the above chemistries, often with exquisite chem. control, highlighted by key examples. We conclude our journey through polymer functionalization with the-in our view-most critically required advances that have the potential to move from "science fiction" to "science fact".
- 2Gauthier, M. A.; Gibson, M. I.; Klok, H.-A. Angew. Chem., Int. Ed. 2009, 48, 48– 58, DOI: 10.1002/anie.200801951Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFGhuw%253D%253D&md5=03fb20ea96f3cd5a5cf86bd3cf682066Synthesis of functional polymers by post-polymerization modificationGauthier, Marc A.; Gibson, Matthew I.; Klok, Harm-AntonAngewandte Chemie, International Edition (2009), 48 (1), 48-58CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Post-polymn. modification is based on the direct polymn. or copolymn. of monomers bearing chemoselective handles that are inert towards the polymn. conditions but can be quant. converted in a subsequent step into a broad range of other functional groups. The success of this method is based on the excellent conversions achievable under mild conditions, the excellent functional-group tolerance, and the orthogonality of the post-polymn. modification reactions. This Review surveys different classes of reactive polymer precursors bearing chemoselective handles and discusses issues related to the prepn. of these reactive polymers by direct polymn. of appropriately functionalized monomers as well as the post-polymn. modification of these precursors into functional polymers.
- 3Zeininger, L.; Nagelberg, S.; Harvey, K. S.; Savagatrup, S.; Herbert, M. B.; Yoshinaga, K.; Capobianco, J. A.; Kolle, M.; Swager, T. M. ACS Cent. Sci. 2019, DOI: 10.1021/acscentsci.9b00059 .Google ScholarThere is no corresponding record for this reference.
- 4Yu, J.; Zhang, Y.; Ye, Y.; DiSanto, R.; Sun, W.; Ranson, D.; Ligler, F. S.; Buse, J. B.; Gu, Z. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 8260– 8265, DOI: 10.1073/pnas.1505405112Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOhsbjP&md5=5cb0d879f1ce52df37b20c87e3f1eef8Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin deliveryYu, Jicheng; Zhang, Yuqi; Ye, Yanqi; DiSanto, Rocco; Sun, Wujin; Ranson, Davis; Ligler, Frances S.; Buse, John B.; Gu, ZhenProceedings of the National Academy of Sciences of the United States of America (2015), 112 (27), 8260-8265CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") contg. glucose-responsive vesicles (GRVs; with an av. diam. of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioredn. under hypoxic conditions. The local hypoxic microenvironment caused by the enzymic oxidn. of glucose in the hyperglycemic state promotes the redn. of HS-HA, which rapidly triggers the dissocn. of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chem. induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
- 5Estabrook, D. A.; Ennis, A. F.; Day, R. A.; Sletten, E. M. Chem. Sci. 2019, 10, 3994– 4003, DOI: 10.1039/C8SC05735DGoogle Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjslehurk%253D&md5=aa4a4bda477789256f4b7782bfe50ad7Controlling nanoemulsion surface chemistry with poly(2-oxazoline) amphiphilesEstabrook, Daniel A.; Ennis, Amanda F.; Day, Rachael A.; Sletten, Ellen M.Chemical Science (2019), 10 (14), 3994-4003CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Emulsions are dynamic materials that have been extensively employed within pharmaceutical, food and cosmetic industries. However, their use beyond conventional applications has been hindered by difficulties in surface functionalization, and an inability to selectively control physicochem. properties. Here, we employ custom poly(2-oxazoline) block copolymers to overcome these limitations. We demonstrate that poly(2-oxazoline) copolymers can effectively stabilize nanoscale droplets of hydrocarbon and perfluorocarbon in water. The controlled living polymn. of poly(2-oxazoline)s allows for the incorporation of chem. handles into the surfactants such that covalent modification of the emulsion surface can be performed. Through post-emulsion modification of these new surfactants, we are able to access nanoemulsions with modified surface chemistries, yet consistent sizes. By decoupling size and surface charge, we explore structure-activity relationships involving the cellular uptake of nanoemulsions in both macrophage and non-macrophage cell lines. We conclude that the cellular uptake and cytotoxicity of poly (2-oxazoline) stabilized droplets can be systematically tuned via chem. modification of emulsion surfaces.
- 6Wei, M.; Gao, Y.; Li, X.; Serpe, M. Polym. Chem. 2017, 8, 127– 143, DOI: 10.1039/C6PY01585AGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCnsLfK&md5=91102616a33aec520d7f522ec0dfda2bStimuli-responsive polymers and their applicationsWei, Menglian; Gao, Yongfeng; Li, Xue; Serpe, Michael J.Polymer Chemistry (2017), 8 (1), 127-143CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)A review. Responsive polymer-based materials are capable of altering their chem. and/or phys. properties upon exposure to external stimuli. These materials have been intensively studied over the years for a diverse range of applications, e.g., for on-demand drug delivery, tissue generation/repair, biosensing, smart coatings, and artificial muscles. Here, we review recent advances in the areas of sensing and biosensing, drug delivery, and actuators. Specific examples are given in each of these areas, and we highlight our group's work on poly(N-isopropylacrylamide)-based microgels and assemblies.
- 7Larsen, M. B.; Herzog, S. E.; Quilter, H. C.; Hillmyer, M. A. ACS Macro Lett. 2018, 7, 122– 126, DOI: 10.1021/acsmacrolett.7b00896Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlSiuw%253D%253D&md5=56e49dd1799df6797af5ff724ddbdde6Activated Polyacrylamides as Versatile Substrates for Postpolymerization ModificationLarsen, Michael B.; Herzog, Shannon E.; Quilter, Helena C.; Hillmyer, Marc A.ACS Macro Letters (2018), 7 (1), 122-126CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)The displacement of an activated leaving group in polymeric repeat units is a powerful method of postpolymn. modification. This strategy enables the synthesis of polymers otherwise unobtainable by direct polymn. as well as the prepn. of a diverse array of macromol. structures. We demonstrate that the activation of acrylamide through the introduction of two tert-butyloxycarbonyl (Boc) groups followed by radical polymn. leads to a new class of activated polyacrylamides analogous to well-known activated polyacrylates. Trans-amidation of poly(di(Boc)-acrylamide) utilizing primary amines proceeds to high conversion under mild conditions, and the products can be readily purified. Less nucleophilic secondary amines and alcs. require more forcing conditions. We demonstrate the utility of this approach by prepg. copolymers capable of on-demand gel formation and the synthesis of block polymers using controlled radical polymn.
- 8Larsen, M. B.; Wang, S.-J.; Hillmyer, M. A. J. Am. Chem. Soc. 2018, 140, 11911– 11915, DOI: 10.1021/jacs.8b07542Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslSmtbbP&md5=44ca3ceb90afb3caf269fc09eefd6dd9Poly(allyl alcohol) Homo- and Block Polymers by Postpolymerization Reduction of an Activated PolyacrylamideLarsen, Michael B.; Wang, Shao-Jie; Hillmyer, Marc A.Journal of the American Chemical Society (2018), 140 (38), 11911-11915CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Direct polymn. of allyl alc. generally results in low molar mass oligomers or highly branched or cross-linked structures, and the properties and applications of linear, high molar mass poly(allyl alc.) (PAA) are relatively unexplored. Such macromol. materials that cannot otherwise be obtained directly can be accessed by postpolymn. modification strategies. Herein we describe the synthesis and characterization of linear, high molar mass PAA by borohydride redn. of a new activated polyacrylamide. The facile polymn. and mild redn. conditions enable the prepn. of PAA of targeted molar masses and low dispersity, as well as PAA block polymers via chemoselective redn. of the activated amide moiety.
- 9Kubo, T.; Swartz, J. L.; Scheutz, G. M.; Sumerlin, B. S. Macromol. Rapid Commun. 2019, 40, 1800590, DOI: 10.1002/marc.201800590Google ScholarThere is no corresponding record for this reference.
- 10Agar, S.; Baysak, E.; Hizal, G.; Tunca, U.; Durmaz, H. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1181– 1198, DOI: 10.1002/pola.29004Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsF2ms7Y%253D&md5=6ae9f50bfb1027facded9f5b869c7800An emerging post-polymerization modification technique: The promise of thiol-para-fluoro click reactionAgar, Soykan; Baysak, Elif; Hizal, Gurkan; Tunca, Umit; Durmaz, HakanJournal of Polymer Science, Part A: Polymer Chemistry (2018), 56 (12), 1181-1198CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)A review. Post-polymn. modification (PPM) of polymers is extremely beneficial in terms of designing brand new synthetic pathways toward functional complex polymers. Fortunately, the new developments in the field of org. chem. along with controlled/living radical polymn. (CLRP) techniques have enabled scientists to readily design and synthesize the functionalized-polymers for wide range of applications via the PPM. In this regard, the reactivity of para-fluorine atom in the fluorinated arom. structures toward the nucleophilic substitution reactions has made the polymers possessing this group to become a very strong candidate that can undergo efficient PPM. Besides, it has been proven that the thiol-functionalized compds. react with the para-fluorine atom of the pentafluorophenyl group more rapidly and efficiently than the amine- and the hydroxyl-functionalized compds. Furthermore, the milder exptl. conditions to achieve quant. conversions have led to the reaction between the thiol and the structures possessing pentafluorophenyl groups to be referred to as a click-type reaction. Given this information, this review article aims to present the scientific developments regarding the thiol-para-fluoro "click" (TPF-click) chem., and its impact on PPM to construct novel polymeric structures. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym.Chem. 2018.
- 11Kobayashi, S.; Uyama, H. J. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 192– 209, DOI: 10.1002/pola.10090Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtlansA%253D%253D&md5=3bb1b024b0d09f27d95f91fc9a640bf4Polymerization of cyclic imino ethers: from its discovery to the present state of the artKobayashi, Shiro; Uyama, HiroshiJournal of Polymer Science, Part A: Polymer Chemistry (2001), 40 (2), 192-209CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)A review. Topics concerning the cationic ring-opening polymn. of cyclic imino ethers such as oxazolines and functional material prodn. based on the resulting polymers are reviewed. Cyclic imino ethers are readily subjected to isomerization polymn. via cationic initiators. Mechanistic studies have provided a new concept, electrophilic polymn. Double isomerization polymn. and no-catalyst alternating copolymn. are interesting examples that show characteristics of the ring opening of cyclic imino ethers. The living polymn. of these monomers affords precisely controlled polymeric materials. Through the use of the unique properties of the product polymers, various functional polymeric materials, such as polymeric nonionic surfactants, compatibilizers, hydrogels, stabilizers for dispersion polymn., biocatalyst modifiers, and supramol. assemblies, have been developed.
- 12Bloksma, M. M.; Schubert, U. S.; Hoogenboom, R. Macromol. Rapid Commun. 2011, 32, 1419– 1441, DOI: 10.1002/marc.201100138Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotV2huro%253D&md5=f32e590dd6c3fc10a9044eaed4aa4a7fPoly(cyclic imino ether)s Beyond 2-Substituted-2-oxazolinesBloksma, Meta M.; Schubert, Ulrich S.; Hoogenboom, RichardMacromolecular Rapid Communications (2011), 32 (18), 1419-1441CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. 2-Oxazolines (2-OZO) are 5-membered cyclic imino ethers whose cationic ring-opening polymn. (CROP) mechanism and resulting polymer properties are extensively studied. However, also 6- and 7-membered cyclic imino ethers can be polymd. via CROP. Together with the much less studied 4- and 5-substituted main-chain chiral poly(2-oxazoline)s (P-2-OZO), these compds. are interesting monomers to enhance the versatility of (co)poly(cyclic imino ether)s. To emphasize the potential of such alternative cyclic imino ether monomers, we provide an overview on the polymns. of 2-oxazine (2-OZI) and chiral 4- and 5-substituted 2-OZO and of selected properties of the resulting polymers. In addn., the hydrolysis of these polymers into the corresponding poly(alkylene imine)s will be addressed.
- 13Verbraeken, B.; Monnery, B. D.; Lava, K.; Hoogenboom, R. Eur. Polym. J. 2017, 88, 451– 469, DOI: 10.1016/j.eurpolymj.2016.11.016Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFKjtb3P&md5=cae1b851c4bd443a95813720d5aac69cThe chemistry of poly(2-oxazoline)sVerbraeken, Bart; Monnery, Bryn D.; Lava, Kathleen; Hoogenboom, RichardEuropean Polymer Journal (2017), 88 (), 451-469CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)A review. As we celebrate the 50th birthday of the discovery of poly(2-alkyl/aryl-2-oxazoline)s (PAOx) this year we see a research field that is rapidly expanding after some lesser academic activity in the nineties. This renewed interest in PAOx stems from the fact that this polymer class combines high synthetic versatility with good biocompatibility, opening up the way to highly functional (biocompatible) materials. PAOx are prepd. by living cationic ring-opening polymn. (CROP) of 2-oxazolines, which will be the in-depth focus off this review. The variety of 2-oxazoline monomers that are readily available or can easily be synthesized, allows for tuning of polymer properties and introduction of diverse functionalities and provides access to different polymer architectures. Moreover, thanks to the living nature of the CROP, well-defined polymers with narrow molar mass distribution and high end-group fidelity can be obtained.
- 14Lorson, T.; Lübtow, M. M.; Wegener, E.; Haider, M. S.; Borova, S.; Nahm, D.; Jordan, R.; Sokolski-Papkov, M.; Kabanov, A. V.; Luxenhofer, R. Biomaterials 2018, 178, 204– 280, DOI: 10.1016/j.biomaterials.2018.05.022Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtF2is73K&md5=49238795f04ad2b54db26f1d40fb9c98Poly(2-oxazoline)s based biomaterials: A comprehensive and critical updateLorson, Thomas; Luebtow, Michael M.; Wegener, Erik; Haider, Malik S.; Borova, Solomiia; Nahm, Daniel; Jordan, Rainer; Sokolski-Papkov, Marina; Kabanov, Alexander V.; Luxenhofer, RobertBiomaterials (2018), 178 (), 204-280CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A review. Poly(2-oxazoline)s have been investigated for decades as biomaterials. Pioneering early work suggested that hydrophilic poly(2-oxazoline)s are comparable to poly(ethylene glycol) regarding their potential as biomaterials, but the ready com. availability of the latter has led to its meteoric rise to become the gold std. of hydrophilic synthetic biomaterials. In contrast, poly(2-oxazoline)s almost fell into oblivion. However, in the last decade, this family of polymers has gained much more interest in general and as biomaterials in particular. The rich chem. and comparably straightforward synthesis of poly(2-oxazoline)s gives many opportunities for tailoring the properties of the resulting biomaterials, allowing the chemist to explore new conjugation chem., and to fine-tune the molar mass, hydrophilic-lipophilic balance as well as architecture. Thus, the wide range of demands for various applications of biomaterials can be suitably addressed. This review aims to give a comprehensive and crit. update of the development of poly(2-oxazoline) based biomaterials, focusing on the last 5 years, which have seen an explosive increase of interest. We believe that the research regarding this diverse family of polymers will remain strong and will keep growing, in particular after the promising first-in-human studies of a poly(2-oxazoline) drug conjugate. This review aims at researchers and students new to this polymer family and seasoned poly(2-oxazoline) experts alike and attempts to showcase how the chem. diversity of poly(2-oxazoline)s allows a relatively facile and broad access to biomaterials of all kinds.
- 15Nam, S.; Seo, J.; Woo, S.; Kim, W. H.; Kim, H.; Bradley, D. D. C.; Kim, Y. Nat. Commun. 2015, 6, DOI: 10.1038/ncomms9929 .Google ScholarThere is no corresponding record for this reference.
- 16Glassner, M.; Vergaelen, M.; Hoogenboom, R. Polym. Int. 2018, 67, 32– 45, DOI: 10.1002/pi.5457Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFCksb%252FN&md5=0972fad481324923bcad6b1ee2aa24f7Poly(2-oxazoline)s: A comprehensive overview of polymer structures and their physical propertiesGlassner, Mathias; Vergaelen, Maarten; Hoogenboom, RichardPolymer International (2018), 67 (1), 32-45CODEN: PLYIEI; ISSN:0959-8103. (John Wiley & Sons Ltd.)A review. Poly(2-oxazoline)s (PAOx) are of increasing importance for a wide range of applications, mostly in the biomedical field. This review describes the synthesis of 2-oxazoline monomers and their cationic ring-opening polymn., and gives a comprehensive overview of all reported PAOx homopolymers. In the second part of the review, the polymer properties of these PAOx homopolymers with varying side-chain structures are discussed. Altogether, this review intends to serve as an encyclopedia for poly(2-oxazoline)s enabling the straightforward selection of a polymer structure with the desired properties for a certain application. © 2017 Society of Chem. Industry.
- 17Luxenhofer, R.; Jordan, R. Macromolecules 2006, 39, 3509– 3516, DOI: 10.1021/ma052515mGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjsleksrw%253D&md5=be98fae8cf230d1b1bd245ae17ce4983Click Chemistry with Poly(2-oxazoline)sLuxenhofer, Robert; Jordan, RainerMacromolecules (2006), 39 (10), 3509-3516CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)A new 2-oxazoline with a pendant alkyne moiety, 2-(pent-4-ynyl)-2-oxazoline, 1 (PynOx), was synthesized from com. available compds. Polymn. of PynOx with Me triflate as initiator and copolymn. with 2-methyl- or 2-ethyl-2-oxazoline (MeOx or EtOx) as comonomers results in well-defined water-sol. polymers of narrow molar mass distributions and predefined ds. p. Since the alkyne moiety is compatible with the living cationic polymn., no protection group was needed. The consecutive copper-catalyzed Huisgen 1,3-dipolar cycloaddns. of two different azides with the polymer bound alkynes to the 1,2,3-triazoles were quant.
- 18Gress, A.; Völkel, A.; Schlaad, H. Macromolecules 2007, 40, 7928– 7933, DOI: 10.1021/ma071357rGoogle Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWgur3L&md5=07124bc2496c4fd1d735bb52a6f768c6Thio-Click Modification of Poly[2-(3-butenyl)-2-oxazoline]Gress, Anja; Voelkel, Antje; Schlaad, HelmutMacromolecules (Washington, DC, United States) (2007), 40 (22), 7928-7933CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The radical addn. of mercaptans (RSH) onto poly[2-(3-butenyl)-2-oxazoline], which is available through a living/controlled cationic ring-opening isomerization polymn., can proceed smoothly in the absence of side reactions, exhibiting the characteristics of a click reaction. The "thio-click" reaction can be performed under feasible ([RSH]/[C:C] ∼ 1.2-1.5, no transition metal additives) and mild conditions (generation of radicals with UV light at room temp.) and goes to completion within a day. Hydrophobic fluoropolymers can be prepd. in the same way as water-sol. (co-)polymers or glycopolymers, starting from readily available materials.
- 19Mees, M. A.; Hoogenboom, R. Macromolecules 2015, 48, 3531– 3538, DOI: 10.1021/acs.macromol.5b00290Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosFGrtL8%253D&md5=d3a43f13b98ba485234b4506e6dca3ecFunctional Poly(2-oxazoline)s by Direct Amidation of Methyl Ester Side ChainsMees, Maarten A.; Hoogenboom, RichardMacromolecules (Washington, DC, United States) (2015), 48 (11), 3531-3538CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are biocompatible pseudopolypeptides that have received significant interest for biomedical applications in recent years. The growing popularity of PAOx in recent years is driven by its much higher chem. versatility compared with the gold std. in this field, poly(ethylene glycol) (PEG), while having similar beneficial properties, such as stealth behavior and biocompatibility. We further expand the PAOx chem. toolbox by demonstrating a novel straightforward and highly versatile postpolymn. modification platform for the introduction of side-chain functionalities. PAOx having side chain Me ester functionalities is demonstrated to undergo facile uncatalyzed amidation reactions with a wide range of amines, yielding the corresponding PAOx with side-chain secondary amide groups contg. short aliph. linkers and a range of side-chain functionalities including acid, amine, alc., hydrazide, and propargyl groups. The PAOx with side-chain Me ester groups can be prepd. by either partial hydrolysis of a PAOx followed by the introduction of the Me ester via modification of the secondary amine groups with Me succinyl chloride or by the direct copolymn. of a nonfunctional 2-oxazoline monomer with a 2-methoxycarbonylethyl-2-oxazoline. Thus, this novel synthetic platform enables direct access to a wide range of side-chain functionalities from the same methyl-ester-functionalized poly(2-oxazoline) scaffold.
- 20Vancoillie, G.; Brooks, W. L. A.; Mees, M. A.; Sumerlin, B. S.; Hoogenboom, R. Polym. Chem. 2016, 7, 6725– 6734, DOI: 10.1039/C6PY01437BGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1CgurnL&md5=c0d073569d1e1037aaba45da6d500283Synthesis of novel boronic acid-decorated poly(2-oxazoline)s showing triple-stimuli responsive behaviorVancoillie, Gertjan; Brooks, William L. A.; Mees, Maarten A.; Sumerlin, Brent S.; Hoogenboom, RichardPolymer Chemistry (2016), 7 (44), 6725-6734CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Boronic acid-functionalized (co)polymers have gained increasing attention in the field of responsive polymers and polymeric materials due to their unique characteristics and responsiveness towards both changes in pH and sugar concns. This makes these (co)polymers excellently suited for various applications including responsive membranes, drug delivery applications and sensor materials. Unfortunately, boronic acid-based polymer research is also notorious for its challenging monomer synthesis and polymn. and its overall difficult polymer purifn. and manipulation. In light of this, many research groups have focused their attention on the optimization of various polymn. techniques in order to expand the field of BA-research including previously unexplored monomers and polymn. techniques. In this paper, a new post-polymn. modification methodol. was developed allowing for the synthesis of novel boronic acid-decorated poly(2-alkyl-2-oxazoline) (PAOx) copolymers, utilizing the recently published PAOx Me ester reaction platform. The developed synthetic pathway provides a straightforward method for the introduction of pH- and glucose-responsiveness, adding this to the already wide variety of possible responsive PAOx-based systems. The synthesized BA-decorated PAOx are based on the thermoresponsive poly(2-n-propyl-2-oxazoline) (PnPropOx). This introduces a pH and glucose dependence on both cloud and clearance point temps. of the copolymer in aq. and pH-buffered conditions, yielding a triply-responsive (co)polymer that highlights the wide variety of obtainable properties using this pathway.
- 21Van Guyse, J. F. R.; Mees, M. A.; Vergaelen, M.; Baert, M.; Verbraeken, B.; Martens, P. J.; Hoogenboom, R. Polym. Chem. 2019, 10, 954– 962, DOI: 10.1039/C9PY00014CGoogle Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlWrsL4%253D&md5=1f02c55e14822acab2986fb3b0dbc523Amidation of methyl ester side chain bearing poly(2-oxazoline)s with tyramine: a quest for a selective and quantitative approachVan Guyse, Joachim F. R.; Mees, Maarten A.; Vergaelen, Maarten; Baert, Mathijs; Verbraeken, Bart; Martens, Penny J.; Hoogenboom, RichardPolymer Chemistry (2019), 10 (8), 954-962CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are a class of cytocompatible polymers that have received growing interest over the past decade. This growing interest can mainly be attributed to their greater chem. versatility compared to other cytocompatible polymers, such as poly(ethylene glycol) (PEG), that originate from the diverse set of monomers compatible with the cationic ring-opening polymn. Within this contribution we focus on the modification of Me ester functional PAOx, on which we recently reported the quant. conversion of Me ester side chain bearing PAOx via direct amidation for a no. of amines. While this approach is robust, it can be challenging to introduce certain amines, due to their high cost, poor soly. or addnl. functionalities. Here we evaluated three alternative amidation approaches of Me ester side chain bearing PAOx with tyramine in terms of selectivity and quant. conversion to the resp. secondary amides. The amidation proceeded successfully via DMTMM coupling, PFP-activation and TBD catalysis, although only the latter 2 methods selectively yielded the desired product. In summary, we present valuable alternatives to our earlier reported method, contributing further to the biomedical application potential of PAOx.
- 22Glassner, M.; Verbraeken, B.; Jerca, V. V.; Van Hecke, K.; Tsanaktsidis, J.; Hoogenboom, R. Polym. Chem. 2018, 9, 4840– 4847, DOI: 10.1039/C8PY01037DGoogle Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1eit7rM&md5=e34a1a96728eb9b6a119d3a2a6a22fb7Poly(2-oxazoline)s with pendant cubane groupsGlassner, Mathias; Verbraeken, Bart; Jerca, Valentin Victor; Van Hecke, Kristof; Tsanaktsidis, John; Hoogenboom, RichardPolymer Chemistry (2018), 9 (39), 4840-4847CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)The effect of cubane side chains on polymer properties is rarely explored. Here, the synthesis of a 2-oxazoline monomer having a cubane moiety in the 2-position is reported. Cationic ring-opening polymn. gives the corresponding poly(2-oxazoline). However, homopolymn. only yields oligomeric species that were found to be insol. in a wide range of solvents. Sol. polymers are obtained by copolymn. of the cubane contg. monomer with 2-ethyl-2-oxazoline. The resulting copolymers show thermoresponsive behavior in aq. soln. with a cloud point temp. that varies with copolymer compn. The Me ester functionality of the cubane contg. monomer can be used for side-chain modifications via a direct amidation post-polymn. modification reaction.
- 23Miyamoto, M.; Aoi, K.; Yamaga, S.; Saegusa, T. Macromolecules 1992, 25, 5111– 5114, DOI: 10.1021/ma00045a044Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XlsFWmtr4%253D&md5=7bde0542be0392de9eeb4d8c5af603d2Double isomerization polymerization of 2-amino-2-oxazolines: a novel ring-opening polymerization accompanying isomerization of growing speciesMiyamoto, Masatoshi; Aoi, Keigo; Yamaga, Seiji; Saegusa, TakeoMacromolecules (1992), 25 (19), 5111-14CODEN: MAMOBX; ISSN:0024-9297.2-Oxazolines with cyclic imine substituents at the 2-position are subject to ring-opening isomerization polymn. Poly[(N-carbamoylimino)ethylene] is produced by cationic ring-opening polymn. of these cyclic pseudoureas with Me trifluoromethanesulfonate or Me tosylate. Poly[(1,3-diazolidin-2-one-1,3-diyl)oligomethylene] is produced by cationic ring-opening isomerization polymn. initiated by alkyl halides, MeI, or benzyl chloride or bromide.
- 24Miyamoto, M.; Shimakura, M.; Tsutsui, K.; Hasegawa, K.; Aoi, K.; Yamaga, S.; Saegusa, T. Macromolecules 1993, 26, 7116– 7124, DOI: 10.1021/ma00078a002Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmslWrurs%253D&md5=74671983843bc1f3dbeafd0bea5fab9eDouble isomerization polymerization of 2-amino-2-oxazolines having four- to eight-membered cyclic imino substituentsMiyamoto, Masatoshi; Shimakura, Masakazu; Tsutsui, Koji; Hasegawa, Kiyoshi; Aoi, Keigo; Yamaga, Seiji; Saegusa, TakeoMacromolecules (1993), 26 (26), 7116-24CODEN: MAMOBX; ISSN:0024-9297.The polymn. behaviors of 2-amino-2-oxazolines having 4- to 8-membered cyclic amino rings at their 2-positions, i.e., 2-(1-azetidinyl)-2-oxazoline, 2-(1-pyrrolidinyl)-2-oxazoline, 2-piperidino-2-oxazoline, 2-(1-azepanyl)-2-oxazoline, 2-(1-azocanyl)-2-oxazoline, and 2-morpholino-2-oxazoline, are described. Two quite different polymers were produced by the polymn. of these monomers via cationic mechanisms. One was poly[(N-carbamoylimino)ethylene] produced by the usual cationic ring-opening isomerization polymn. of the monomers with an alkylsulfonate initiator. The other was poly[(1,3-diazolidin-2-one-1,3-diyl)oligomethylene] produced by a new mode of cationic ring-opening isomerization polymn. (double isomerization polymn.) initiated by an alkyl halide, in which the isomerization of propagating species occurred during the propagation. The polymn. mechanisms were studied by the isolation of 1:1 adducts of the monomers with each of the initiators, and it was proved that the nucleophilicity of the counterion derived from the initiator was the main factor which detd. the polymn. pathway. The steric effect of the 2-substituent in the monomers on the polymerizability is also discussed.
- 25Miyamoto, M.; Aoi, K.; Morimoto, M.; Chujo, Y.; Saegusa, T. Macromolecules 1992, 25, 5878– 5885, DOI: 10.1021/ma00048a004Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XlvFagu7k%253D&md5=78c75e7abd97be5e90e26621bf661d21Ring-opening isomerization polymerization of cyclic iminocarbonatesMiyamoto, Masatoshi; Aoi, Keigo; Morimoto, Masao; Chujo, Yoshiki; Saegusa, TakeoMacromolecules (1992), 25 (22), 5878-85CODEN: MAMOBX; ISSN:0024-9297.Five- and 6-membered cyclic iminocarbonates having primary or secondary alkoxy substituents were newly prepd. and their cationic ring-opening polymn. was examd. The polymn. of 2-ethoxy-2-oxazoline (I) with Me trifluoromethanesulfonate proceeded smoothly at 20° and yielded poly[N-(ethoxycarbonyl)imino]ethylene] in a high yield, although the d.p. was ∼10 due to the chain transfer involving the 2-ethoxy substituent of the propagating species. The chain-transfer was suppressed in the polymn. of 2-(neopentyloxy)-2-oxazoline. The reaction of I with a catalytic amt. of alkyl halide yielded no polymeric product, but an isomerized product, 3-ethyl-2-oxazolidone, instead. The mechanisms for polymn., chain-transfer, and isomerization were discussed and the ring-opening polymerizabilities of 2-isopropoxy-2-oxazoline and 2-isopropoxy-5,6-dihydro-4H-1,3-oxazine were compared with those of their 2-Me homologs on the basis of kinetic results.
- 26Bridgeman, E.; Tomkinson, N. C. Synlett 2006, No. 2, 243– 246, DOI: 10.1055/s-2005-923584Google ScholarThere is no corresponding record for this reference.
- 27Gallou, I.; Eriksson, M.; Zeng, X.; Senanayake, C.; Farina, V. J. Org. Chem. 2005, 70, 6960– 6963, DOI: 10.1021/jo0507643Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFWntrY%253D&md5=0db13cbc0dd4e98f34fc777501f5397dPractical Synthesis of Unsymmetrical Ureas from Isopropenyl CarbamatesGallou, Isabelle; Eriksson, Magnus; Zeng, Xingzhong; Senanayake, Chris; Farina, VittorioJournal of Organic Chemistry (2005), 70 (17), 6960-6963CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A very convenient method for the synthesis of unsym. ureas from isopropenyl carbamates is described. The synthetic efficiency of traditional methods for urea formation, such as use of phosgene or alkyl and aryl carbamates, is limited by the formation of sym. urea side products or reaction reversibility. Isopropenyl carbamates react with amines cleanly and irreversibly and give unsym. ureas in high yield and purity. This method is ideal for the rapid synthesis of compd. libraries.
- 28Lee, S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D. Tetrahedron 2004, 60, 3439– 3443, DOI: 10.1016/j.tet.2004.02.034Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisVGntbk%253D&md5=8328167272c773f5e0d2be502bb1f0ddThe direct conversion of carbamates to ureas using aluminum amidesLee, Sang-Hyuep; Matsushita, Hana; Clapham, Bruce; Janda, Kim D.Tetrahedron (2004), 60 (15), 3439-3443CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)The conversion of carbamates, e.g., I, into ureas, e.g., II, using aluminum amide complexes is reported. This reaction was used to prep. di-, tri- and tetra-substituted ureas from carbamate-protected primary or secondary amines by substitution with primary or secondary amines in the presence of stoichiometric quantities of trimethylaluminum. A reactivity trend of the various carbamates was obsd. and Me and benzyl carbamates reacted selectively in the presence of t-Bu carbamates.
- 29Casida, J. E.; Gray, R. A.; Tilles, H. Science 1974, 184, 573– 574, DOI: 10.1126/science.184.4136.573Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXksF2hs78%253D&md5=6c2713a468b00beb1cc8f986658d9c18Thiocarbamate sulfoxides. Potent, selective, and biodegradable herbicidesCasida, John E.; Gray, Reed A.; Tilles, HarryScience (Washington, DC, United States) (1974), 184 (4136), 573-4CODEN: SCIEAS; ISSN:0036-8075.Treatment of benthiocarb [28249-77-6], butylate [2008-41-5], cycloate [1134-23-2], EPTC [759-94-4], molinate [2212-67-1], pebulate [1114-71-2], and vernolate [1929-77-7] with m-chloroperoxybenzoic acid [937-14-4] yielded corresponding thiocarbamate sulfoxides which were more toxic to broadleaf weeds, and less toxic to corn, than were the parent compds. The thiocarbamate sulfoxides showed hydrolytic instability in aq. alk. medium, and low thermal stability. The sulfoxides were rapidly metabolized by mice; they may be intermediates in the mammalian metab. of thiocarbamate herbicides.
- 30Zimmerman, L. J.; Valentine, H. L.; Valentine, W. M. Chem. Res. Toxicol. 2004, 17, 258– 267, DOI: 10.1021/tx034209cGoogle Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXls1Sqtg%253D%253D&md5=99ad68a2ef115d3e136099556e1a2ceaCharacterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the RatZimmerman, Lisa J.; Valentine, Holly L.; Valentine, William M.Chemical Research in Toxicology (2004), 17 (2), 258-267CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Thiocarbamates are a major class of herbicides used extensively in the agricultural industry. It has been shown that thiocarbamates can form reactive sulfoxide and sulfone intermediates, which may be involved in the toxicity of thiocarbamates through covalent modification of cysteine and serine active sites of enzymes. Molinate has been shown to generate an S-hexahydro-1H-azepine-1-carbonyl adduct on the Cys 125 residue of the β2- and β3-chains of rat globin analogous to that reported for disulfiram and to inhibit aldehyde dehydrogenase and nonspecific esterase activity. The present study examd. whether other thiocarbamate herbicides produce similar covalent protein modifications and enzyme inhibition to that reported for molinate and whether S-(N,N-dialkylaminocarbonyl)cysteine adduct levels are correlated to enzyme inhibition or the structure of thiocarbamate herbicides. Addnl., the potential of molinate to act as a peripheral demyelinating agent similar to disulfiram was evaluated. To address these aims, rats were exposed i.p. to molinate, vernolate, ethiolate, EPTC, or butylate for 5 days after which Hb was isolated and analyzed for protein adducts using HPLC and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. In addn., brain, liver, and testes mitochondrial and microsomal fractions were assayed for nonspecific esterase, low Km ALDH, or total ALDH activities, and S-(N,N-dialkylaminocarbonyl)cysteine adducts were measured by LC/MS/MS. For the neurotoxicity assessments, rats were administered molinate parenterally for subchronic periods and morphol. evaluations performed on peripheral nerves. All of the thiocarbamates except butylate produced S-(N,N-dialkylaminocarbonyl)cysteine adducts on globin and the quantity of adducts detected decreased with increasing size of the nitrogen substituents. In contrast, a clear relationship between cysteine modification in mitochondrial and microsomal samples to nitrogen substituents was not evident, and although molinate produced relatively high levels of adducts and esterase inhibition and butylate low levels of adducts and esterase inhibition for most samples, in general, the level of S-(N,N-dialkylaminocarbonyl)cysteine adducts did not appear to be related to enzyme inhibition. Molinate did not produce segmental demyelination in peripheral nerve, suggesting that molinate and possibly other thiocarbamates do not share the neurotoxic potential of dithiocarbamates.
- 31Erve, J. C. L.; Jensen, O. N.; Valentine, H. S.; Amarnath, V.; Valentine, W. M. Chem. Res. Toxicol. 2000, 13, 237– 244, DOI: 10.1021/tx990191nGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhslSrsL4%253D&md5=69472a3ccfa33e712c739bcc1b009e18Disulfiram Generates a Stable N,N-Diethylcarbamoyl Adduct on Cys-125 of Rat Hemoglobin β-Chains in VivoErve, John C. L.; Jensen, Ole N.; Valentine, Holly S.; Amarnath, Venkataraman; Valentine, William M.Chemical Research in Toxicology (2000), 13 (4), 237-244CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Disulfiram (DSF) is a drug used in aversion therapy to treat alcoholics and acts by inhibiting mitochondrial low-Km aldehyde dehydrogenase. Investigations into the mechanisms for in vivo inactivation suggest that the DSF metabolite S-methyl-N,N-diethylthiocarbamate sulfoxide reacts irreversibly with an active site Cys. This work aimed to det. if DSF generates monothiocarbamate adducts on cysteine residues in vivo by examg. Hb. Sprague-Dawley rats were treated with DSF po for 2, 4, and 6 wk. Rats have four different globin β-chains, of which three (β-1-3) contain two cysteine residues each. MALDI-TOF MS anal. of two new globin species from DSF-treated rats collected by HPLC revealed increments of 99 Da above the mass of the unmodified chains (β-2 and β-3). In a sep. expt., the globin mixt. was digested for 2 h with Glu-C and reanalyzed by MALDI-TOF MS. Results showed a peptide at m/z 2716.3 having a mass 99 Da higher than a known Cys-contg. peptide. Subsequently, the Glu-C digest was analyzed using Q-TOF tandem MS, enabling observation of the +4 charge state of the peptide with m/z 2716.3. This peptide was fragmented to produce y-sequence ions that located the modification to Cys-125 (present on both β-2 and β-3). Cys-125 is the most reactive of two cysteine residues on these β-chains. To confirm the structure of the modification, globin was hydrolyzed with 6 N HCl at 110° for 18 h. The adduct survived these conditions so that S-(N,N-diethylcarbamoyl)cysteine was detected in the hydrolyzates of treated rats on the basis of comparison with the tandem MS spectrum of a std. These results extend the findings of others obtained using glutathione conjugates and demonstrate the ability of DSF to covalently modify Cys residues of proteins in a manner consistent with the prodn. of S-methyl-N,N-diethylthiocarbamate sulfoxide, or sulfone, intermediates.
- 32Melnyk, O.; Ollivier, N.; Besret, S.; Melnyk, P. Bioconjugate Chem. 2014, 25, 629– 639, DOI: 10.1021/bc500052rGoogle Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXktl2iurw%253D&md5=1174c70fb11da46092c6c6cc40f8c710Phenylthiocarbamate or N-Carbothiophenyl Group Chemistry in Peptide Synthesis and BioconjugationMelnyk, Oleg; Ollivier, Nathalie; Besret, Soizic; Melnyk, PatriciaBioconjugate Chemistry (2014), 25 (4), 629-639CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)A review. The design of novel chemoselective and site-specific ligation methods provides new tools for obtaining complex scaffolds, peptidomimetics, and peptide conjugates. The chem. of the N-phenylthiocarbonyl group has led to several developments in peptide ligation chem. and peptide bioconjugation during the last 10 years. The aim of this review is to provide an overview of this emerging field.
- 33Hwang, Y.; Thompson, P. R.; Wang, L.; Jiang, L.; Kelleher, N. L.; Cole, P. A. Angew. Chem., Int. Ed. 2007, 46, 7621– 7624, DOI: 10.1002/anie.200702485Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtF2rs73P&md5=b22b8895a712334168bd1351ae674dc3A selective chemical probe for coenzyme A-requiring enzymesHwang, Yousang; Thompson, Paul R.; Wang, Ling; Jiang, Lihua; Kelleher, Neil L.; Cole, Philip A.Angewandte Chemie, International Edition (2007), 46 (40), 7621-7624CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A CoA-based affinity probe with a sulfoxycarbamate functionality can selectively identify several acetyltransferases relative to other enzymes and proteins. It leaves behind a desthiobiotin tag that can be used for western blotting and mass spectrometric characterization.
- 34Long, L.; Clapp, R. C.; Bissett, F. H.; Hasselstrom, T. J. Org. Chem. 1961, 26, 85– 88, DOI: 10.1021/jo01060a020Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXpvFCitQ%253D%253D&md5=b0b1fa3b7e94c0b5608ffa2a143f9c74Isothiuronium, alkylthio.ovrddot.oxazolinium, and alkylthiothiazolinium picratesLong, Louis, Jr.; Clapp, Richard C.; Bissett, Frank H.; Hasselstrom, TorstenJournal of Organic Chemistry (1961), 26 (), 85-8CODEN: JOCEAH; ISSN:0022-3263.N-Substituted S-alkylisothiuronium picrates, RSC(:NH)NHR'.HOC6H3N3O6 (I), were shown to be useful derivs. for identification of SC(NH2)NHR' (II) obtained from naturally occurring isothiocyanates. II (0.01 mole) and 0.011 mole alkyl iodide, RX, in 10 ml. alc. refluxed 10 min., treated with 0.01 mole picric acid in 15-20 ml. hot alc., H2O added slowly, and the ppt. on cooling purified by recrystn. from alc., H2O, or dil. alc. gave the I (R, R', and m.p. given): Me, Me, 183-4.5°; Et, Me, 161-2.5°; Me, Et, 163-4°; Et, Et, 126-7°; Me, Pr, 153-4°; Et, Pr, 119-20°; Me, iso-Pr, 167-8°; Et, iso-Pr, 154-5°; Me, H2C:CHCH2, 148-9°; Et, H2C:CHCH2, 124.5-5°; Me, Bu, 154-5°; Et, Bu, 122-3°; Me, EtMeCH, 112.5-14°; Me, Me2CHCH2, 163.5-4.5°; Et, Me2CHCH2, 151-2°; Me, H2C:CHCH2CH2, 135.5-6.5°; Et, H2C:CHCH2CH2, 129-30°; Me, MeS(CH2)3, 112.5-13.5°; Et, MeS(CH2)3, 103-4°; Me, Ph, 176-7.5°; Et, Ph, 198.5-9.5°; Me, PhCH2, 173-4°; Et, PhCH2, 143.5-4.5°. Major and characteristic infrared absorption bands for I (R = Et) were tabulated. All I showed strong characteristic max. at 6.13-6.16 and 6.28-6.30 μ due to NH2 deformation mode and to the NCN system. Formation of well defined x-ray diffraction patterns favored the use of I in the isolation and identification of micro quantities. The prepn. of a deriv. to assist in the identification of (-)-5-vinyl-2-thio.ovrddot.oxazolidone, O.CS.NH.CH2.CRR' (III, R = CH:CH2, R' = H) (IV) (goitrin), was investigated. Model expts. with 2-thiothiazolidone (V) and III (R = R' = H) (VI) showed that alkylation could be effected most satisfactorily in abs. alc. in the presence of NaOEt. V refluxed in alc. 45 min. with a slight excess of MeI in the absence or presence of NaOEt and the products isolated as the picrates yielded 51 and 84% yields, resp., of 2-methylthio-2-thiazolinium picrate, m. 150-1°, infrared spectrum given, identical with a sample prepd. by cyclization of Me 2-hydroxyethyldithiocarbamate. Ethylation under alk. conditions gave 2-ethylthio-2-thiazolinium picrate, m. 112.5-14° (dil. Me2CO). Abs. alc. (15 ml.) contg. 0.26 g. Na and 1.17 g. 2-thio.ovrddot.oxazolidone treated portionwise with 1.64 g. MeI in 7 ml. abs. alc., the mixt. kept 1 hr. at 20°, refluxed 45 min., the residue on evapn. extd. with Et2O, the product taken up in 20 ml. alc., and treated with 2.6 g. picric acid in 50 ml. alc. yielded 44% 2-methylthio-2-oxazolinium picrate, O.CH(SMe).NH.CH2CRR.HOC6H3N3O6 (VII, R = R' = H) (VIII), m. 124.5-5.5° (Me2CO), infrared spectrum given. Alkylation in aq. alc. in the presence of NaOH gave 24% VIII, but no alkylated product was recovered as the picrate in the absence of alkali, and the starting material was decompd., probably by the acid formed in the reaction. Alkylation of 0.5 g. dl-5-vinyl-2-thio.ovrddot.oxazolidone with MeI and NaOEt in abs. alc. followed by treatment with picric acid yielded 33% dl-VII (R = HC:CH2, R' = H) (IX), m. 104.5-5.5° (CHCl3-C7H16). Similar treatment of 150 mg. (-)-5-vinyl-2-thio.ovrddot.oxazolidone, isolated from rutabaga seeds, yielded 33% l-IX, [α] -32.8° (c 0.2, MeOH). Methylation of 0.5 g. 5,5-dimethyl-2-thio.ovrddot.oxazolidone in abs. alc. gave 57% VII (R = R' = Me), m. 133-4.5° (CHCl3-C7H16).
- 35Perez, C.; Monserrat, J.-P.; Chen, Y.; Cohen, S. M. Chem. Commun. 2015, 51, 7116– 7119, DOI: 10.1039/C4CC09921DGoogle Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltFWjtrs%253D&md5=47fae789e2adf3691d3a2fc840e76d62Exploring hydrogen peroxide responsive thiazolidinone-based prodrugsPerez, Christian; Monserrat, Jean-Philippe; Chen, Yao; Cohen, Seth M.Chemical Communications (Cambridge, United Kingdom) (2015), 51 (33), 7116-7119CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A novel approach for developing prodrugs based on masked carboxylic acids is described. Rather than using conventional esterase-based activation, thiazolidinone protecting groups have been identified that can reveal carboxylic acid groups upon activation by hydrogen peroxide. This may prove valuable in the continuing development of prodrug strategies that rely on reactive oxygen species as a trigger.
- 36Monnery, B. D.; Jerca, V. V.; Sedlacek, O.; Verbraeken, B.; Cavill, R.; Hoogenboom, R. Angew. Chem., Int. Ed. 2018, 57, 15400– 15404, DOI: 10.1002/anie.201807796Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVGlt7jL&md5=86a79df258188fa4ef6311f001a1d2d1Defined High Molar Mass Poly(2-Oxazoline)sMonnery, Bryn D.; Jerca, Valentin V.; Sedlacek, Ondrej; Verbraeken, Bart; Cavill, Rachel; Hoogenboom, RichardAngewandte Chemie, International Edition (2018), 57 (47), 15400-15404CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Poly(2-alkyl-2-oxazolines) (PAOx) are regaining interest for biomedical applications. However, their full potential is hampered by the inability to synthesize uniform high-molar mass PAOx. In this work, we proposed alternative intrinsic chain transfer mechanisms based on 2-oxazoline and oxazolinium chain-end tautomerization and derived improved polymn. conditions to suppress chain transfer, allowing the synthesis of highly defined poly(2-ethyl-2-oxazoline)s up to ca. 50 kDa (dispersity (ETH) <1.05) and defined polymers up to at least 300 kDa (ETH<1.2). The detn. of the chain transfer consts. for the polymns. hinted towards the tautomerization of the oxazolinium chain end as most plausible cause for chain transfer. Finally, the method was applied for the prepn. of up to 60 kDa molar mass copolymers of 2-ethyl-2-oxazoline and 2-methoxycarbonylethyl-2-oxazoline.
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Abstract
Figure 1
Figure 1. PPM strategies based on CROP of oxazoline derivatives. (a) Elaboration of polyoxazolines with pendant alkenes and alkynes by click chemistries, or with pendant esters by amidation (refs (17−22)). (b) Polymerization of 2-alkoxy-2-oxazolines (ref (25)). (c) This work: Living CROP of 2-ethylthio-2-oxazoline and postpolymerization functionalization.
Figure 2
Figure 2. (a) CROP of 1 to give P1. (b) MALDI–TOF MS of a low-molecular weight, piperidine-terminated sample of P1. (c) Mn and Đ of P1 at various [M]/[I]. (d) Monitoring of Mn and Đ of P1 at increasing monomer conversion. (e) First-order kinetic analysis of the polymerization of 1. Mn and Đ determined by SEC with polystyrene standards; monomer conversion determined by NMR.
Scheme 1
Scheme 1. Activation of P1 by Oxidation and Substitution Scope of P2aaIsolated yields reported. Full conversion observed in all cases.
bMn = 21.2 kDa, Đ = 1.26. See SI for full SEC characterization.
c0.1 mmol scale.
d0.9 g, 5 mmol scale.
eDMF used as solvent.
f2 equiv of DBU added.
gAmine added as HCl salt.
h3 equiv of DIPEA (N(Et)(i-Pr)2) added.
iNH3(aq) (5 equiv), TFE.
jDMF/MeOH used as solvent.
kl-Cysteine methyl ester HCl (3 equiv), Et3N (3 equiv), DMF/MeOH; then LiOH/H2O, 2 h.
l1.5 equiv of each amine was used. Substitution ratio determined by 1H NMR.
Figure 3
Figure 3. 1H NMR spectra of (a) P1, (b) P2, and (c) P3a.
Scheme 2
Scheme 2. Substitution of P1 by ArylaminesaaIsolated yields reported. Full conversion observed in all cases.
Figure 4
Figure 4. (a) Polymerization, activation, and substitution of block copolymer. (i) PhCN, 90 °C, 4 h. (ii) 90 °C, 12 h. (iii) Piperidine, 1 h, 74% yield. (iv) m-CPBA, DCM, rt, 5 h. 96% yield. (v) BnNH2, CHCl3, rt, 16 h. 95% yield. (b) SEC traces of block copolymer P5 sampled after step (i) (green) and (iii) (purple).
References
ARTICLE SECTIONSThis article references 36 other publications.
- 1Blasco, E.; Sims, M. B.; Goldmann, A. S.; Sumerlin, B. S.; Barner-Kowollik, C. Macromolecules 2017, 50, 5215– 5252, DOI: 10.1021/acs.macromol.7b00465Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCqsrfF&md5=be1dc3159bb83222f6cc5d84f700303b50th Anniversary Perspective: Polymer FunctionalizationBlasco, Eva; Sims, Michael B.; Goldmann, Anja S.; Sumerlin, Brent S.; Barner-Kowollik, ChristopherMacromolecules (Washington, DC, United States) (2017), 50 (14), 5215-5252CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)A review. The translation of small mol. chemistries into efficient methodologies for polymer functionalization spans several decades, enabling crit. advances in soft matter materials synthesis with tailored and adaptive property profiles. The present Perspective explores-based on selected examples-50 years of innovation in polymer functionalization chemistries. These span a diverse set of chemistries based on activated esters, thiol-ene/yne processes, nucleophilic systems based on isocyanates, reactions driven by the formation of imines and oximes, ring-opening processes, cycloaddns., and-in a recent renaissance-multicomponent reactions. In addn., a wide variety of chain types and architectures were modified based on the above chemistries, often with exquisite chem. control, highlighted by key examples. We conclude our journey through polymer functionalization with the-in our view-most critically required advances that have the potential to move from "science fiction" to "science fact".
- 2Gauthier, M. A.; Gibson, M. I.; Klok, H.-A. Angew. Chem., Int. Ed. 2009, 48, 48– 58, DOI: 10.1002/anie.200801951Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFGhuw%253D%253D&md5=03fb20ea96f3cd5a5cf86bd3cf682066Synthesis of functional polymers by post-polymerization modificationGauthier, Marc A.; Gibson, Matthew I.; Klok, Harm-AntonAngewandte Chemie, International Edition (2009), 48 (1), 48-58CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Post-polymn. modification is based on the direct polymn. or copolymn. of monomers bearing chemoselective handles that are inert towards the polymn. conditions but can be quant. converted in a subsequent step into a broad range of other functional groups. The success of this method is based on the excellent conversions achievable under mild conditions, the excellent functional-group tolerance, and the orthogonality of the post-polymn. modification reactions. This Review surveys different classes of reactive polymer precursors bearing chemoselective handles and discusses issues related to the prepn. of these reactive polymers by direct polymn. of appropriately functionalized monomers as well as the post-polymn. modification of these precursors into functional polymers.
- 3Zeininger, L.; Nagelberg, S.; Harvey, K. S.; Savagatrup, S.; Herbert, M. B.; Yoshinaga, K.; Capobianco, J. A.; Kolle, M.; Swager, T. M. ACS Cent. Sci. 2019, DOI: 10.1021/acscentsci.9b00059 .Google ScholarThere is no corresponding record for this reference.
- 4Yu, J.; Zhang, Y.; Ye, Y.; DiSanto, R.; Sun, W.; Ranson, D.; Ligler, F. S.; Buse, J. B.; Gu, Z. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 8260– 8265, DOI: 10.1073/pnas.1505405112Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOhsbjP&md5=5cb0d879f1ce52df37b20c87e3f1eef8Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin deliveryYu, Jicheng; Zhang, Yuqi; Ye, Yanqi; DiSanto, Rocco; Sun, Wujin; Ranson, Davis; Ligler, Frances S.; Buse, John B.; Gu, ZhenProceedings of the National Academy of Sciences of the United States of America (2015), 112 (27), 8260-8265CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") contg. glucose-responsive vesicles (GRVs; with an av. diam. of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioredn. under hypoxic conditions. The local hypoxic microenvironment caused by the enzymic oxidn. of glucose in the hyperglycemic state promotes the redn. of HS-HA, which rapidly triggers the dissocn. of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chem. induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
- 5Estabrook, D. A.; Ennis, A. F.; Day, R. A.; Sletten, E. M. Chem. Sci. 2019, 10, 3994– 4003, DOI: 10.1039/C8SC05735DGoogle Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjslehurk%253D&md5=aa4a4bda477789256f4b7782bfe50ad7Controlling nanoemulsion surface chemistry with poly(2-oxazoline) amphiphilesEstabrook, Daniel A.; Ennis, Amanda F.; Day, Rachael A.; Sletten, Ellen M.Chemical Science (2019), 10 (14), 3994-4003CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Emulsions are dynamic materials that have been extensively employed within pharmaceutical, food and cosmetic industries. However, their use beyond conventional applications has been hindered by difficulties in surface functionalization, and an inability to selectively control physicochem. properties. Here, we employ custom poly(2-oxazoline) block copolymers to overcome these limitations. We demonstrate that poly(2-oxazoline) copolymers can effectively stabilize nanoscale droplets of hydrocarbon and perfluorocarbon in water. The controlled living polymn. of poly(2-oxazoline)s allows for the incorporation of chem. handles into the surfactants such that covalent modification of the emulsion surface can be performed. Through post-emulsion modification of these new surfactants, we are able to access nanoemulsions with modified surface chemistries, yet consistent sizes. By decoupling size and surface charge, we explore structure-activity relationships involving the cellular uptake of nanoemulsions in both macrophage and non-macrophage cell lines. We conclude that the cellular uptake and cytotoxicity of poly (2-oxazoline) stabilized droplets can be systematically tuned via chem. modification of emulsion surfaces.
- 6Wei, M.; Gao, Y.; Li, X.; Serpe, M. Polym. Chem. 2017, 8, 127– 143, DOI: 10.1039/C6PY01585AGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCnsLfK&md5=91102616a33aec520d7f522ec0dfda2bStimuli-responsive polymers and their applicationsWei, Menglian; Gao, Yongfeng; Li, Xue; Serpe, Michael J.Polymer Chemistry (2017), 8 (1), 127-143CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)A review. Responsive polymer-based materials are capable of altering their chem. and/or phys. properties upon exposure to external stimuli. These materials have been intensively studied over the years for a diverse range of applications, e.g., for on-demand drug delivery, tissue generation/repair, biosensing, smart coatings, and artificial muscles. Here, we review recent advances in the areas of sensing and biosensing, drug delivery, and actuators. Specific examples are given in each of these areas, and we highlight our group's work on poly(N-isopropylacrylamide)-based microgels and assemblies.
- 7Larsen, M. B.; Herzog, S. E.; Quilter, H. C.; Hillmyer, M. A. ACS Macro Lett. 2018, 7, 122– 126, DOI: 10.1021/acsmacrolett.7b00896Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlSiuw%253D%253D&md5=56e49dd1799df6797af5ff724ddbdde6Activated Polyacrylamides as Versatile Substrates for Postpolymerization ModificationLarsen, Michael B.; Herzog, Shannon E.; Quilter, Helena C.; Hillmyer, Marc A.ACS Macro Letters (2018), 7 (1), 122-126CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)The displacement of an activated leaving group in polymeric repeat units is a powerful method of postpolymn. modification. This strategy enables the synthesis of polymers otherwise unobtainable by direct polymn. as well as the prepn. of a diverse array of macromol. structures. We demonstrate that the activation of acrylamide through the introduction of two tert-butyloxycarbonyl (Boc) groups followed by radical polymn. leads to a new class of activated polyacrylamides analogous to well-known activated polyacrylates. Trans-amidation of poly(di(Boc)-acrylamide) utilizing primary amines proceeds to high conversion under mild conditions, and the products can be readily purified. Less nucleophilic secondary amines and alcs. require more forcing conditions. We demonstrate the utility of this approach by prepg. copolymers capable of on-demand gel formation and the synthesis of block polymers using controlled radical polymn.
- 8Larsen, M. B.; Wang, S.-J.; Hillmyer, M. A. J. Am. Chem. Soc. 2018, 140, 11911– 11915, DOI: 10.1021/jacs.8b07542Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslSmtbbP&md5=44ca3ceb90afb3caf269fc09eefd6dd9Poly(allyl alcohol) Homo- and Block Polymers by Postpolymerization Reduction of an Activated PolyacrylamideLarsen, Michael B.; Wang, Shao-Jie; Hillmyer, Marc A.Journal of the American Chemical Society (2018), 140 (38), 11911-11915CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Direct polymn. of allyl alc. generally results in low molar mass oligomers or highly branched or cross-linked structures, and the properties and applications of linear, high molar mass poly(allyl alc.) (PAA) are relatively unexplored. Such macromol. materials that cannot otherwise be obtained directly can be accessed by postpolymn. modification strategies. Herein we describe the synthesis and characterization of linear, high molar mass PAA by borohydride redn. of a new activated polyacrylamide. The facile polymn. and mild redn. conditions enable the prepn. of PAA of targeted molar masses and low dispersity, as well as PAA block polymers via chemoselective redn. of the activated amide moiety.
- 9Kubo, T.; Swartz, J. L.; Scheutz, G. M.; Sumerlin, B. S. Macromol. Rapid Commun. 2019, 40, 1800590, DOI: 10.1002/marc.201800590Google ScholarThere is no corresponding record for this reference.
- 10Agar, S.; Baysak, E.; Hizal, G.; Tunca, U.; Durmaz, H. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1181– 1198, DOI: 10.1002/pola.29004Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsF2ms7Y%253D&md5=6ae9f50bfb1027facded9f5b869c7800An emerging post-polymerization modification technique: The promise of thiol-para-fluoro click reactionAgar, Soykan; Baysak, Elif; Hizal, Gurkan; Tunca, Umit; Durmaz, HakanJournal of Polymer Science, Part A: Polymer Chemistry (2018), 56 (12), 1181-1198CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)A review. Post-polymn. modification (PPM) of polymers is extremely beneficial in terms of designing brand new synthetic pathways toward functional complex polymers. Fortunately, the new developments in the field of org. chem. along with controlled/living radical polymn. (CLRP) techniques have enabled scientists to readily design and synthesize the functionalized-polymers for wide range of applications via the PPM. In this regard, the reactivity of para-fluorine atom in the fluorinated arom. structures toward the nucleophilic substitution reactions has made the polymers possessing this group to become a very strong candidate that can undergo efficient PPM. Besides, it has been proven that the thiol-functionalized compds. react with the para-fluorine atom of the pentafluorophenyl group more rapidly and efficiently than the amine- and the hydroxyl-functionalized compds. Furthermore, the milder exptl. conditions to achieve quant. conversions have led to the reaction between the thiol and the structures possessing pentafluorophenyl groups to be referred to as a click-type reaction. Given this information, this review article aims to present the scientific developments regarding the thiol-para-fluoro "click" (TPF-click) chem., and its impact on PPM to construct novel polymeric structures. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym.Chem. 2018.
- 11Kobayashi, S.; Uyama, H. J. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 192– 209, DOI: 10.1002/pola.10090Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtlansA%253D%253D&md5=3bb1b024b0d09f27d95f91fc9a640bf4Polymerization of cyclic imino ethers: from its discovery to the present state of the artKobayashi, Shiro; Uyama, HiroshiJournal of Polymer Science, Part A: Polymer Chemistry (2001), 40 (2), 192-209CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)A review. Topics concerning the cationic ring-opening polymn. of cyclic imino ethers such as oxazolines and functional material prodn. based on the resulting polymers are reviewed. Cyclic imino ethers are readily subjected to isomerization polymn. via cationic initiators. Mechanistic studies have provided a new concept, electrophilic polymn. Double isomerization polymn. and no-catalyst alternating copolymn. are interesting examples that show characteristics of the ring opening of cyclic imino ethers. The living polymn. of these monomers affords precisely controlled polymeric materials. Through the use of the unique properties of the product polymers, various functional polymeric materials, such as polymeric nonionic surfactants, compatibilizers, hydrogels, stabilizers for dispersion polymn., biocatalyst modifiers, and supramol. assemblies, have been developed.
- 12Bloksma, M. M.; Schubert, U. S.; Hoogenboom, R. Macromol. Rapid Commun. 2011, 32, 1419– 1441, DOI: 10.1002/marc.201100138Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotV2huro%253D&md5=f32e590dd6c3fc10a9044eaed4aa4a7fPoly(cyclic imino ether)s Beyond 2-Substituted-2-oxazolinesBloksma, Meta M.; Schubert, Ulrich S.; Hoogenboom, RichardMacromolecular Rapid Communications (2011), 32 (18), 1419-1441CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. 2-Oxazolines (2-OZO) are 5-membered cyclic imino ethers whose cationic ring-opening polymn. (CROP) mechanism and resulting polymer properties are extensively studied. However, also 6- and 7-membered cyclic imino ethers can be polymd. via CROP. Together with the much less studied 4- and 5-substituted main-chain chiral poly(2-oxazoline)s (P-2-OZO), these compds. are interesting monomers to enhance the versatility of (co)poly(cyclic imino ether)s. To emphasize the potential of such alternative cyclic imino ether monomers, we provide an overview on the polymns. of 2-oxazine (2-OZI) and chiral 4- and 5-substituted 2-OZO and of selected properties of the resulting polymers. In addn., the hydrolysis of these polymers into the corresponding poly(alkylene imine)s will be addressed.
- 13Verbraeken, B.; Monnery, B. D.; Lava, K.; Hoogenboom, R. Eur. Polym. J. 2017, 88, 451– 469, DOI: 10.1016/j.eurpolymj.2016.11.016Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFKjtb3P&md5=cae1b851c4bd443a95813720d5aac69cThe chemistry of poly(2-oxazoline)sVerbraeken, Bart; Monnery, Bryn D.; Lava, Kathleen; Hoogenboom, RichardEuropean Polymer Journal (2017), 88 (), 451-469CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)A review. As we celebrate the 50th birthday of the discovery of poly(2-alkyl/aryl-2-oxazoline)s (PAOx) this year we see a research field that is rapidly expanding after some lesser academic activity in the nineties. This renewed interest in PAOx stems from the fact that this polymer class combines high synthetic versatility with good biocompatibility, opening up the way to highly functional (biocompatible) materials. PAOx are prepd. by living cationic ring-opening polymn. (CROP) of 2-oxazolines, which will be the in-depth focus off this review. The variety of 2-oxazoline monomers that are readily available or can easily be synthesized, allows for tuning of polymer properties and introduction of diverse functionalities and provides access to different polymer architectures. Moreover, thanks to the living nature of the CROP, well-defined polymers with narrow molar mass distribution and high end-group fidelity can be obtained.
- 14Lorson, T.; Lübtow, M. M.; Wegener, E.; Haider, M. S.; Borova, S.; Nahm, D.; Jordan, R.; Sokolski-Papkov, M.; Kabanov, A. V.; Luxenhofer, R. Biomaterials 2018, 178, 204– 280, DOI: 10.1016/j.biomaterials.2018.05.022Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtF2is73K&md5=49238795f04ad2b54db26f1d40fb9c98Poly(2-oxazoline)s based biomaterials: A comprehensive and critical updateLorson, Thomas; Luebtow, Michael M.; Wegener, Erik; Haider, Malik S.; Borova, Solomiia; Nahm, Daniel; Jordan, Rainer; Sokolski-Papkov, Marina; Kabanov, Alexander V.; Luxenhofer, RobertBiomaterials (2018), 178 (), 204-280CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A review. Poly(2-oxazoline)s have been investigated for decades as biomaterials. Pioneering early work suggested that hydrophilic poly(2-oxazoline)s are comparable to poly(ethylene glycol) regarding their potential as biomaterials, but the ready com. availability of the latter has led to its meteoric rise to become the gold std. of hydrophilic synthetic biomaterials. In contrast, poly(2-oxazoline)s almost fell into oblivion. However, in the last decade, this family of polymers has gained much more interest in general and as biomaterials in particular. The rich chem. and comparably straightforward synthesis of poly(2-oxazoline)s gives many opportunities for tailoring the properties of the resulting biomaterials, allowing the chemist to explore new conjugation chem., and to fine-tune the molar mass, hydrophilic-lipophilic balance as well as architecture. Thus, the wide range of demands for various applications of biomaterials can be suitably addressed. This review aims to give a comprehensive and crit. update of the development of poly(2-oxazoline) based biomaterials, focusing on the last 5 years, which have seen an explosive increase of interest. We believe that the research regarding this diverse family of polymers will remain strong and will keep growing, in particular after the promising first-in-human studies of a poly(2-oxazoline) drug conjugate. This review aims at researchers and students new to this polymer family and seasoned poly(2-oxazoline) experts alike and attempts to showcase how the chem. diversity of poly(2-oxazoline)s allows a relatively facile and broad access to biomaterials of all kinds.
- 15Nam, S.; Seo, J.; Woo, S.; Kim, W. H.; Kim, H.; Bradley, D. D. C.; Kim, Y. Nat. Commun. 2015, 6, DOI: 10.1038/ncomms9929 .Google ScholarThere is no corresponding record for this reference.
- 16Glassner, M.; Vergaelen, M.; Hoogenboom, R. Polym. Int. 2018, 67, 32– 45, DOI: 10.1002/pi.5457Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFCksb%252FN&md5=0972fad481324923bcad6b1ee2aa24f7Poly(2-oxazoline)s: A comprehensive overview of polymer structures and their physical propertiesGlassner, Mathias; Vergaelen, Maarten; Hoogenboom, RichardPolymer International (2018), 67 (1), 32-45CODEN: PLYIEI; ISSN:0959-8103. (John Wiley & Sons Ltd.)A review. Poly(2-oxazoline)s (PAOx) are of increasing importance for a wide range of applications, mostly in the biomedical field. This review describes the synthesis of 2-oxazoline monomers and their cationic ring-opening polymn., and gives a comprehensive overview of all reported PAOx homopolymers. In the second part of the review, the polymer properties of these PAOx homopolymers with varying side-chain structures are discussed. Altogether, this review intends to serve as an encyclopedia for poly(2-oxazoline)s enabling the straightforward selection of a polymer structure with the desired properties for a certain application. © 2017 Society of Chem. Industry.
- 17Luxenhofer, R.; Jordan, R. Macromolecules 2006, 39, 3509– 3516, DOI: 10.1021/ma052515mGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjsleksrw%253D&md5=be98fae8cf230d1b1bd245ae17ce4983Click Chemistry with Poly(2-oxazoline)sLuxenhofer, Robert; Jordan, RainerMacromolecules (2006), 39 (10), 3509-3516CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)A new 2-oxazoline with a pendant alkyne moiety, 2-(pent-4-ynyl)-2-oxazoline, 1 (PynOx), was synthesized from com. available compds. Polymn. of PynOx with Me triflate as initiator and copolymn. with 2-methyl- or 2-ethyl-2-oxazoline (MeOx or EtOx) as comonomers results in well-defined water-sol. polymers of narrow molar mass distributions and predefined ds. p. Since the alkyne moiety is compatible with the living cationic polymn., no protection group was needed. The consecutive copper-catalyzed Huisgen 1,3-dipolar cycloaddns. of two different azides with the polymer bound alkynes to the 1,2,3-triazoles were quant.
- 18Gress, A.; Völkel, A.; Schlaad, H. Macromolecules 2007, 40, 7928– 7933, DOI: 10.1021/ma071357rGoogle Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWgur3L&md5=07124bc2496c4fd1d735bb52a6f768c6Thio-Click Modification of Poly[2-(3-butenyl)-2-oxazoline]Gress, Anja; Voelkel, Antje; Schlaad, HelmutMacromolecules (Washington, DC, United States) (2007), 40 (22), 7928-7933CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)The radical addn. of mercaptans (RSH) onto poly[2-(3-butenyl)-2-oxazoline], which is available through a living/controlled cationic ring-opening isomerization polymn., can proceed smoothly in the absence of side reactions, exhibiting the characteristics of a click reaction. The "thio-click" reaction can be performed under feasible ([RSH]/[C:C] ∼ 1.2-1.5, no transition metal additives) and mild conditions (generation of radicals with UV light at room temp.) and goes to completion within a day. Hydrophobic fluoropolymers can be prepd. in the same way as water-sol. (co-)polymers or glycopolymers, starting from readily available materials.
- 19Mees, M. A.; Hoogenboom, R. Macromolecules 2015, 48, 3531– 3538, DOI: 10.1021/acs.macromol.5b00290Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosFGrtL8%253D&md5=d3a43f13b98ba485234b4506e6dca3ecFunctional Poly(2-oxazoline)s by Direct Amidation of Methyl Ester Side ChainsMees, Maarten A.; Hoogenboom, RichardMacromolecules (Washington, DC, United States) (2015), 48 (11), 3531-3538CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are biocompatible pseudopolypeptides that have received significant interest for biomedical applications in recent years. The growing popularity of PAOx in recent years is driven by its much higher chem. versatility compared with the gold std. in this field, poly(ethylene glycol) (PEG), while having similar beneficial properties, such as stealth behavior and biocompatibility. We further expand the PAOx chem. toolbox by demonstrating a novel straightforward and highly versatile postpolymn. modification platform for the introduction of side-chain functionalities. PAOx having side chain Me ester functionalities is demonstrated to undergo facile uncatalyzed amidation reactions with a wide range of amines, yielding the corresponding PAOx with side-chain secondary amide groups contg. short aliph. linkers and a range of side-chain functionalities including acid, amine, alc., hydrazide, and propargyl groups. The PAOx with side-chain Me ester groups can be prepd. by either partial hydrolysis of a PAOx followed by the introduction of the Me ester via modification of the secondary amine groups with Me succinyl chloride or by the direct copolymn. of a nonfunctional 2-oxazoline monomer with a 2-methoxycarbonylethyl-2-oxazoline. Thus, this novel synthetic platform enables direct access to a wide range of side-chain functionalities from the same methyl-ester-functionalized poly(2-oxazoline) scaffold.
- 20Vancoillie, G.; Brooks, W. L. A.; Mees, M. A.; Sumerlin, B. S.; Hoogenboom, R. Polym. Chem. 2016, 7, 6725– 6734, DOI: 10.1039/C6PY01437BGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1CgurnL&md5=c0d073569d1e1037aaba45da6d500283Synthesis of novel boronic acid-decorated poly(2-oxazoline)s showing triple-stimuli responsive behaviorVancoillie, Gertjan; Brooks, William L. A.; Mees, Maarten A.; Sumerlin, Brent S.; Hoogenboom, RichardPolymer Chemistry (2016), 7 (44), 6725-6734CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Boronic acid-functionalized (co)polymers have gained increasing attention in the field of responsive polymers and polymeric materials due to their unique characteristics and responsiveness towards both changes in pH and sugar concns. This makes these (co)polymers excellently suited for various applications including responsive membranes, drug delivery applications and sensor materials. Unfortunately, boronic acid-based polymer research is also notorious for its challenging monomer synthesis and polymn. and its overall difficult polymer purifn. and manipulation. In light of this, many research groups have focused their attention on the optimization of various polymn. techniques in order to expand the field of BA-research including previously unexplored monomers and polymn. techniques. In this paper, a new post-polymn. modification methodol. was developed allowing for the synthesis of novel boronic acid-decorated poly(2-alkyl-2-oxazoline) (PAOx) copolymers, utilizing the recently published PAOx Me ester reaction platform. The developed synthetic pathway provides a straightforward method for the introduction of pH- and glucose-responsiveness, adding this to the already wide variety of possible responsive PAOx-based systems. The synthesized BA-decorated PAOx are based on the thermoresponsive poly(2-n-propyl-2-oxazoline) (PnPropOx). This introduces a pH and glucose dependence on both cloud and clearance point temps. of the copolymer in aq. and pH-buffered conditions, yielding a triply-responsive (co)polymer that highlights the wide variety of obtainable properties using this pathway.
- 21Van Guyse, J. F. R.; Mees, M. A.; Vergaelen, M.; Baert, M.; Verbraeken, B.; Martens, P. J.; Hoogenboom, R. Polym. Chem. 2019, 10, 954– 962, DOI: 10.1039/C9PY00014CGoogle Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlWrsL4%253D&md5=1f02c55e14822acab2986fb3b0dbc523Amidation of methyl ester side chain bearing poly(2-oxazoline)s with tyramine: a quest for a selective and quantitative approachVan Guyse, Joachim F. R.; Mees, Maarten A.; Vergaelen, Maarten; Baert, Mathijs; Verbraeken, Bart; Martens, Penny J.; Hoogenboom, RichardPolymer Chemistry (2019), 10 (8), 954-962CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are a class of cytocompatible polymers that have received growing interest over the past decade. This growing interest can mainly be attributed to their greater chem. versatility compared to other cytocompatible polymers, such as poly(ethylene glycol) (PEG), that originate from the diverse set of monomers compatible with the cationic ring-opening polymn. Within this contribution we focus on the modification of Me ester functional PAOx, on which we recently reported the quant. conversion of Me ester side chain bearing PAOx via direct amidation for a no. of amines. While this approach is robust, it can be challenging to introduce certain amines, due to their high cost, poor soly. or addnl. functionalities. Here we evaluated three alternative amidation approaches of Me ester side chain bearing PAOx with tyramine in terms of selectivity and quant. conversion to the resp. secondary amides. The amidation proceeded successfully via DMTMM coupling, PFP-activation and TBD catalysis, although only the latter 2 methods selectively yielded the desired product. In summary, we present valuable alternatives to our earlier reported method, contributing further to the biomedical application potential of PAOx.
- 22Glassner, M.; Verbraeken, B.; Jerca, V. V.; Van Hecke, K.; Tsanaktsidis, J.; Hoogenboom, R. Polym. Chem. 2018, 9, 4840– 4847, DOI: 10.1039/C8PY01037DGoogle Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1eit7rM&md5=e34a1a96728eb9b6a119d3a2a6a22fb7Poly(2-oxazoline)s with pendant cubane groupsGlassner, Mathias; Verbraeken, Bart; Jerca, Valentin Victor; Van Hecke, Kristof; Tsanaktsidis, John; Hoogenboom, RichardPolymer Chemistry (2018), 9 (39), 4840-4847CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)The effect of cubane side chains on polymer properties is rarely explored. Here, the synthesis of a 2-oxazoline monomer having a cubane moiety in the 2-position is reported. Cationic ring-opening polymn. gives the corresponding poly(2-oxazoline). However, homopolymn. only yields oligomeric species that were found to be insol. in a wide range of solvents. Sol. polymers are obtained by copolymn. of the cubane contg. monomer with 2-ethyl-2-oxazoline. The resulting copolymers show thermoresponsive behavior in aq. soln. with a cloud point temp. that varies with copolymer compn. The Me ester functionality of the cubane contg. monomer can be used for side-chain modifications via a direct amidation post-polymn. modification reaction.
- 23Miyamoto, M.; Aoi, K.; Yamaga, S.; Saegusa, T. Macromolecules 1992, 25, 5111– 5114, DOI: 10.1021/ma00045a044Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XlsFWmtr4%253D&md5=7bde0542be0392de9eeb4d8c5af603d2Double isomerization polymerization of 2-amino-2-oxazolines: a novel ring-opening polymerization accompanying isomerization of growing speciesMiyamoto, Masatoshi; Aoi, Keigo; Yamaga, Seiji; Saegusa, TakeoMacromolecules (1992), 25 (19), 5111-14CODEN: MAMOBX; ISSN:0024-9297.2-Oxazolines with cyclic imine substituents at the 2-position are subject to ring-opening isomerization polymn. Poly[(N-carbamoylimino)ethylene] is produced by cationic ring-opening polymn. of these cyclic pseudoureas with Me trifluoromethanesulfonate or Me tosylate. Poly[(1,3-diazolidin-2-one-1,3-diyl)oligomethylene] is produced by cationic ring-opening isomerization polymn. initiated by alkyl halides, MeI, or benzyl chloride or bromide.
- 24Miyamoto, M.; Shimakura, M.; Tsutsui, K.; Hasegawa, K.; Aoi, K.; Yamaga, S.; Saegusa, T. Macromolecules 1993, 26, 7116– 7124, DOI: 10.1021/ma00078a002Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmslWrurs%253D&md5=74671983843bc1f3dbeafd0bea5fab9eDouble isomerization polymerization of 2-amino-2-oxazolines having four- to eight-membered cyclic imino substituentsMiyamoto, Masatoshi; Shimakura, Masakazu; Tsutsui, Koji; Hasegawa, Kiyoshi; Aoi, Keigo; Yamaga, Seiji; Saegusa, TakeoMacromolecules (1993), 26 (26), 7116-24CODEN: MAMOBX; ISSN:0024-9297.The polymn. behaviors of 2-amino-2-oxazolines having 4- to 8-membered cyclic amino rings at their 2-positions, i.e., 2-(1-azetidinyl)-2-oxazoline, 2-(1-pyrrolidinyl)-2-oxazoline, 2-piperidino-2-oxazoline, 2-(1-azepanyl)-2-oxazoline, 2-(1-azocanyl)-2-oxazoline, and 2-morpholino-2-oxazoline, are described. Two quite different polymers were produced by the polymn. of these monomers via cationic mechanisms. One was poly[(N-carbamoylimino)ethylene] produced by the usual cationic ring-opening isomerization polymn. of the monomers with an alkylsulfonate initiator. The other was poly[(1,3-diazolidin-2-one-1,3-diyl)oligomethylene] produced by a new mode of cationic ring-opening isomerization polymn. (double isomerization polymn.) initiated by an alkyl halide, in which the isomerization of propagating species occurred during the propagation. The polymn. mechanisms were studied by the isolation of 1:1 adducts of the monomers with each of the initiators, and it was proved that the nucleophilicity of the counterion derived from the initiator was the main factor which detd. the polymn. pathway. The steric effect of the 2-substituent in the monomers on the polymerizability is also discussed.
- 25Miyamoto, M.; Aoi, K.; Morimoto, M.; Chujo, Y.; Saegusa, T. Macromolecules 1992, 25, 5878– 5885, DOI: 10.1021/ma00048a004Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XlvFagu7k%253D&md5=78c75e7abd97be5e90e26621bf661d21Ring-opening isomerization polymerization of cyclic iminocarbonatesMiyamoto, Masatoshi; Aoi, Keigo; Morimoto, Masao; Chujo, Yoshiki; Saegusa, TakeoMacromolecules (1992), 25 (22), 5878-85CODEN: MAMOBX; ISSN:0024-9297.Five- and 6-membered cyclic iminocarbonates having primary or secondary alkoxy substituents were newly prepd. and their cationic ring-opening polymn. was examd. The polymn. of 2-ethoxy-2-oxazoline (I) with Me trifluoromethanesulfonate proceeded smoothly at 20° and yielded poly[N-(ethoxycarbonyl)imino]ethylene] in a high yield, although the d.p. was ∼10 due to the chain transfer involving the 2-ethoxy substituent of the propagating species. The chain-transfer was suppressed in the polymn. of 2-(neopentyloxy)-2-oxazoline. The reaction of I with a catalytic amt. of alkyl halide yielded no polymeric product, but an isomerized product, 3-ethyl-2-oxazolidone, instead. The mechanisms for polymn., chain-transfer, and isomerization were discussed and the ring-opening polymerizabilities of 2-isopropoxy-2-oxazoline and 2-isopropoxy-5,6-dihydro-4H-1,3-oxazine were compared with those of their 2-Me homologs on the basis of kinetic results.
- 26Bridgeman, E.; Tomkinson, N. C. Synlett 2006, No. 2, 243– 246, DOI: 10.1055/s-2005-923584Google ScholarThere is no corresponding record for this reference.
- 27Gallou, I.; Eriksson, M.; Zeng, X.; Senanayake, C.; Farina, V. J. Org. Chem. 2005, 70, 6960– 6963, DOI: 10.1021/jo0507643Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFWntrY%253D&md5=0db13cbc0dd4e98f34fc777501f5397dPractical Synthesis of Unsymmetrical Ureas from Isopropenyl CarbamatesGallou, Isabelle; Eriksson, Magnus; Zeng, Xingzhong; Senanayake, Chris; Farina, VittorioJournal of Organic Chemistry (2005), 70 (17), 6960-6963CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)A very convenient method for the synthesis of unsym. ureas from isopropenyl carbamates is described. The synthetic efficiency of traditional methods for urea formation, such as use of phosgene or alkyl and aryl carbamates, is limited by the formation of sym. urea side products or reaction reversibility. Isopropenyl carbamates react with amines cleanly and irreversibly and give unsym. ureas in high yield and purity. This method is ideal for the rapid synthesis of compd. libraries.
- 28Lee, S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D. Tetrahedron 2004, 60, 3439– 3443, DOI: 10.1016/j.tet.2004.02.034Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisVGntbk%253D&md5=8328167272c773f5e0d2be502bb1f0ddThe direct conversion of carbamates to ureas using aluminum amidesLee, Sang-Hyuep; Matsushita, Hana; Clapham, Bruce; Janda, Kim D.Tetrahedron (2004), 60 (15), 3439-3443CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)The conversion of carbamates, e.g., I, into ureas, e.g., II, using aluminum amide complexes is reported. This reaction was used to prep. di-, tri- and tetra-substituted ureas from carbamate-protected primary or secondary amines by substitution with primary or secondary amines in the presence of stoichiometric quantities of trimethylaluminum. A reactivity trend of the various carbamates was obsd. and Me and benzyl carbamates reacted selectively in the presence of t-Bu carbamates.
- 29Casida, J. E.; Gray, R. A.; Tilles, H. Science 1974, 184, 573– 574, DOI: 10.1126/science.184.4136.573Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXksF2hs78%253D&md5=6c2713a468b00beb1cc8f986658d9c18Thiocarbamate sulfoxides. Potent, selective, and biodegradable herbicidesCasida, John E.; Gray, Reed A.; Tilles, HarryScience (Washington, DC, United States) (1974), 184 (4136), 573-4CODEN: SCIEAS; ISSN:0036-8075.Treatment of benthiocarb [28249-77-6], butylate [2008-41-5], cycloate [1134-23-2], EPTC [759-94-4], molinate [2212-67-1], pebulate [1114-71-2], and vernolate [1929-77-7] with m-chloroperoxybenzoic acid [937-14-4] yielded corresponding thiocarbamate sulfoxides which were more toxic to broadleaf weeds, and less toxic to corn, than were the parent compds. The thiocarbamate sulfoxides showed hydrolytic instability in aq. alk. medium, and low thermal stability. The sulfoxides were rapidly metabolized by mice; they may be intermediates in the mammalian metab. of thiocarbamate herbicides.
- 30Zimmerman, L. J.; Valentine, H. L.; Valentine, W. M. Chem. Res. Toxicol. 2004, 17, 258– 267, DOI: 10.1021/tx034209cGoogle Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXls1Sqtg%253D%253D&md5=99ad68a2ef115d3e136099556e1a2ceaCharacterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the RatZimmerman, Lisa J.; Valentine, Holly L.; Valentine, William M.Chemical Research in Toxicology (2004), 17 (2), 258-267CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Thiocarbamates are a major class of herbicides used extensively in the agricultural industry. It has been shown that thiocarbamates can form reactive sulfoxide and sulfone intermediates, which may be involved in the toxicity of thiocarbamates through covalent modification of cysteine and serine active sites of enzymes. Molinate has been shown to generate an S-hexahydro-1H-azepine-1-carbonyl adduct on the Cys 125 residue of the β2- and β3-chains of rat globin analogous to that reported for disulfiram and to inhibit aldehyde dehydrogenase and nonspecific esterase activity. The present study examd. whether other thiocarbamate herbicides produce similar covalent protein modifications and enzyme inhibition to that reported for molinate and whether S-(N,N-dialkylaminocarbonyl)cysteine adduct levels are correlated to enzyme inhibition or the structure of thiocarbamate herbicides. Addnl., the potential of molinate to act as a peripheral demyelinating agent similar to disulfiram was evaluated. To address these aims, rats were exposed i.p. to molinate, vernolate, ethiolate, EPTC, or butylate for 5 days after which Hb was isolated and analyzed for protein adducts using HPLC and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. In addn., brain, liver, and testes mitochondrial and microsomal fractions were assayed for nonspecific esterase, low Km ALDH, or total ALDH activities, and S-(N,N-dialkylaminocarbonyl)cysteine adducts were measured by LC/MS/MS. For the neurotoxicity assessments, rats were administered molinate parenterally for subchronic periods and morphol. evaluations performed on peripheral nerves. All of the thiocarbamates except butylate produced S-(N,N-dialkylaminocarbonyl)cysteine adducts on globin and the quantity of adducts detected decreased with increasing size of the nitrogen substituents. In contrast, a clear relationship between cysteine modification in mitochondrial and microsomal samples to nitrogen substituents was not evident, and although molinate produced relatively high levels of adducts and esterase inhibition and butylate low levels of adducts and esterase inhibition for most samples, in general, the level of S-(N,N-dialkylaminocarbonyl)cysteine adducts did not appear to be related to enzyme inhibition. Molinate did not produce segmental demyelination in peripheral nerve, suggesting that molinate and possibly other thiocarbamates do not share the neurotoxic potential of dithiocarbamates.
- 31Erve, J. C. L.; Jensen, O. N.; Valentine, H. S.; Amarnath, V.; Valentine, W. M. Chem. Res. Toxicol. 2000, 13, 237– 244, DOI: 10.1021/tx990191nGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhslSrsL4%253D&md5=69472a3ccfa33e712c739bcc1b009e18Disulfiram Generates a Stable N,N-Diethylcarbamoyl Adduct on Cys-125 of Rat Hemoglobin β-Chains in VivoErve, John C. L.; Jensen, Ole N.; Valentine, Holly S.; Amarnath, Venkataraman; Valentine, William M.Chemical Research in Toxicology (2000), 13 (4), 237-244CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Disulfiram (DSF) is a drug used in aversion therapy to treat alcoholics and acts by inhibiting mitochondrial low-Km aldehyde dehydrogenase. Investigations into the mechanisms for in vivo inactivation suggest that the DSF metabolite S-methyl-N,N-diethylthiocarbamate sulfoxide reacts irreversibly with an active site Cys. This work aimed to det. if DSF generates monothiocarbamate adducts on cysteine residues in vivo by examg. Hb. Sprague-Dawley rats were treated with DSF po for 2, 4, and 6 wk. Rats have four different globin β-chains, of which three (β-1-3) contain two cysteine residues each. MALDI-TOF MS anal. of two new globin species from DSF-treated rats collected by HPLC revealed increments of 99 Da above the mass of the unmodified chains (β-2 and β-3). In a sep. expt., the globin mixt. was digested for 2 h with Glu-C and reanalyzed by MALDI-TOF MS. Results showed a peptide at m/z 2716.3 having a mass 99 Da higher than a known Cys-contg. peptide. Subsequently, the Glu-C digest was analyzed using Q-TOF tandem MS, enabling observation of the +4 charge state of the peptide with m/z 2716.3. This peptide was fragmented to produce y-sequence ions that located the modification to Cys-125 (present on both β-2 and β-3). Cys-125 is the most reactive of two cysteine residues on these β-chains. To confirm the structure of the modification, globin was hydrolyzed with 6 N HCl at 110° for 18 h. The adduct survived these conditions so that S-(N,N-diethylcarbamoyl)cysteine was detected in the hydrolyzates of treated rats on the basis of comparison with the tandem MS spectrum of a std. These results extend the findings of others obtained using glutathione conjugates and demonstrate the ability of DSF to covalently modify Cys residues of proteins in a manner consistent with the prodn. of S-methyl-N,N-diethylthiocarbamate sulfoxide, or sulfone, intermediates.
- 32Melnyk, O.; Ollivier, N.; Besret, S.; Melnyk, P. Bioconjugate Chem. 2014, 25, 629– 639, DOI: 10.1021/bc500052rGoogle Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXktl2iurw%253D&md5=1174c70fb11da46092c6c6cc40f8c710Phenylthiocarbamate or N-Carbothiophenyl Group Chemistry in Peptide Synthesis and BioconjugationMelnyk, Oleg; Ollivier, Nathalie; Besret, Soizic; Melnyk, PatriciaBioconjugate Chemistry (2014), 25 (4), 629-639CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)A review. The design of novel chemoselective and site-specific ligation methods provides new tools for obtaining complex scaffolds, peptidomimetics, and peptide conjugates. The chem. of the N-phenylthiocarbonyl group has led to several developments in peptide ligation chem. and peptide bioconjugation during the last 10 years. The aim of this review is to provide an overview of this emerging field.
- 33Hwang, Y.; Thompson, P. R.; Wang, L.; Jiang, L.; Kelleher, N. L.; Cole, P. A. Angew. Chem., Int. Ed. 2007, 46, 7621– 7624, DOI: 10.1002/anie.200702485Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtF2rs73P&md5=b22b8895a712334168bd1351ae674dc3A selective chemical probe for coenzyme A-requiring enzymesHwang, Yousang; Thompson, Paul R.; Wang, Ling; Jiang, Lihua; Kelleher, Neil L.; Cole, Philip A.Angewandte Chemie, International Edition (2007), 46 (40), 7621-7624CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A CoA-based affinity probe with a sulfoxycarbamate functionality can selectively identify several acetyltransferases relative to other enzymes and proteins. It leaves behind a desthiobiotin tag that can be used for western blotting and mass spectrometric characterization.
- 34Long, L.; Clapp, R. C.; Bissett, F. H.; Hasselstrom, T. J. Org. Chem. 1961, 26, 85– 88, DOI: 10.1021/jo01060a020Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3MXpvFCitQ%253D%253D&md5=b0b1fa3b7e94c0b5608ffa2a143f9c74Isothiuronium, alkylthio.ovrddot.oxazolinium, and alkylthiothiazolinium picratesLong, Louis, Jr.; Clapp, Richard C.; Bissett, Frank H.; Hasselstrom, TorstenJournal of Organic Chemistry (1961), 26 (), 85-8CODEN: JOCEAH; ISSN:0022-3263.N-Substituted S-alkylisothiuronium picrates, RSC(:NH)NHR'.HOC6H3N3O6 (I), were shown to be useful derivs. for identification of SC(NH2)NHR' (II) obtained from naturally occurring isothiocyanates. II (0.01 mole) and 0.011 mole alkyl iodide, RX, in 10 ml. alc. refluxed 10 min., treated with 0.01 mole picric acid in 15-20 ml. hot alc., H2O added slowly, and the ppt. on cooling purified by recrystn. from alc., H2O, or dil. alc. gave the I (R, R', and m.p. given): Me, Me, 183-4.5°; Et, Me, 161-2.5°; Me, Et, 163-4°; Et, Et, 126-7°; Me, Pr, 153-4°; Et, Pr, 119-20°; Me, iso-Pr, 167-8°; Et, iso-Pr, 154-5°; Me, H2C:CHCH2, 148-9°; Et, H2C:CHCH2, 124.5-5°; Me, Bu, 154-5°; Et, Bu, 122-3°; Me, EtMeCH, 112.5-14°; Me, Me2CHCH2, 163.5-4.5°; Et, Me2CHCH2, 151-2°; Me, H2C:CHCH2CH2, 135.5-6.5°; Et, H2C:CHCH2CH2, 129-30°; Me, MeS(CH2)3, 112.5-13.5°; Et, MeS(CH2)3, 103-4°; Me, Ph, 176-7.5°; Et, Ph, 198.5-9.5°; Me, PhCH2, 173-4°; Et, PhCH2, 143.5-4.5°. Major and characteristic infrared absorption bands for I (R = Et) were tabulated. All I showed strong characteristic max. at 6.13-6.16 and 6.28-6.30 μ due to NH2 deformation mode and to the NCN system. Formation of well defined x-ray diffraction patterns favored the use of I in the isolation and identification of micro quantities. The prepn. of a deriv. to assist in the identification of (-)-5-vinyl-2-thio.ovrddot.oxazolidone, O.CS.NH.CH2.CRR' (III, R = CH:CH2, R' = H) (IV) (goitrin), was investigated. Model expts. with 2-thiothiazolidone (V) and III (R = R' = H) (VI) showed that alkylation could be effected most satisfactorily in abs. alc. in the presence of NaOEt. V refluxed in alc. 45 min. with a slight excess of MeI in the absence or presence of NaOEt and the products isolated as the picrates yielded 51 and 84% yields, resp., of 2-methylthio-2-thiazolinium picrate, m. 150-1°, infrared spectrum given, identical with a sample prepd. by cyclization of Me 2-hydroxyethyldithiocarbamate. Ethylation under alk. conditions gave 2-ethylthio-2-thiazolinium picrate, m. 112.5-14° (dil. Me2CO). Abs. alc. (15 ml.) contg. 0.26 g. Na and 1.17 g. 2-thio.ovrddot.oxazolidone treated portionwise with 1.64 g. MeI in 7 ml. abs. alc., the mixt. kept 1 hr. at 20°, refluxed 45 min., the residue on evapn. extd. with Et2O, the product taken up in 20 ml. alc., and treated with 2.6 g. picric acid in 50 ml. alc. yielded 44% 2-methylthio-2-oxazolinium picrate, O.CH(SMe).NH.CH2CRR.HOC6H3N3O6 (VII, R = R' = H) (VIII), m. 124.5-5.5° (Me2CO), infrared spectrum given. Alkylation in aq. alc. in the presence of NaOH gave 24% VIII, but no alkylated product was recovered as the picrate in the absence of alkali, and the starting material was decompd., probably by the acid formed in the reaction. Alkylation of 0.5 g. dl-5-vinyl-2-thio.ovrddot.oxazolidone with MeI and NaOEt in abs. alc. followed by treatment with picric acid yielded 33% dl-VII (R = HC:CH2, R' = H) (IX), m. 104.5-5.5° (CHCl3-C7H16). Similar treatment of 150 mg. (-)-5-vinyl-2-thio.ovrddot.oxazolidone, isolated from rutabaga seeds, yielded 33% l-IX, [α] -32.8° (c 0.2, MeOH). Methylation of 0.5 g. 5,5-dimethyl-2-thio.ovrddot.oxazolidone in abs. alc. gave 57% VII (R = R' = Me), m. 133-4.5° (CHCl3-C7H16).
- 35Perez, C.; Monserrat, J.-P.; Chen, Y.; Cohen, S. M. Chem. Commun. 2015, 51, 7116– 7119, DOI: 10.1039/C4CC09921DGoogle Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltFWjtrs%253D&md5=47fae789e2adf3691d3a2fc840e76d62Exploring hydrogen peroxide responsive thiazolidinone-based prodrugsPerez, Christian; Monserrat, Jean-Philippe; Chen, Yao; Cohen, Seth M.Chemical Communications (Cambridge, United Kingdom) (2015), 51 (33), 7116-7119CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A novel approach for developing prodrugs based on masked carboxylic acids is described. Rather than using conventional esterase-based activation, thiazolidinone protecting groups have been identified that can reveal carboxylic acid groups upon activation by hydrogen peroxide. This may prove valuable in the continuing development of prodrug strategies that rely on reactive oxygen species as a trigger.
- 36Monnery, B. D.; Jerca, V. V.; Sedlacek, O.; Verbraeken, B.; Cavill, R.; Hoogenboom, R. Angew. Chem., Int. Ed. 2018, 57, 15400– 15404, DOI: 10.1002/anie.201807796Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVGlt7jL&md5=86a79df258188fa4ef6311f001a1d2d1Defined High Molar Mass Poly(2-Oxazoline)sMonnery, Bryn D.; Jerca, Valentin V.; Sedlacek, Ondrej; Verbraeken, Bart; Cavill, Rachel; Hoogenboom, RichardAngewandte Chemie, International Edition (2018), 57 (47), 15400-15404CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Poly(2-alkyl-2-oxazolines) (PAOx) are regaining interest for biomedical applications. However, their full potential is hampered by the inability to synthesize uniform high-molar mass PAOx. In this work, we proposed alternative intrinsic chain transfer mechanisms based on 2-oxazoline and oxazolinium chain-end tautomerization and derived improved polymn. conditions to suppress chain transfer, allowing the synthesis of highly defined poly(2-ethyl-2-oxazoline)s up to ca. 50 kDa (dispersity (ETH) <1.05) and defined polymers up to at least 300 kDa (ETH<1.2). The detn. of the chain transfer consts. for the polymns. hinted towards the tautomerization of the oxazolinium chain end as most plausible cause for chain transfer. Finally, the method was applied for the prepn. of up to 60 kDa molar mass copolymers of 2-ethyl-2-oxazoline and 2-methoxycarbonylethyl-2-oxazoline.
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