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Preparation and Characterization of a Small Library of Thermally-Labile End-Caps for Variable-Temperature Triggering of Self-Immolative Polymers S. Maryamdokht Taimoory, S. Iraj Sadraei, Rose Fayoumi, Sarah Nasri, Matthew Revington, and John F. Trant J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00135 • Publication Date (Web): 28 Mar 2018 Downloaded from http://pubs.acs.org on March 28, 2018
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The Journal of Organic Chemistry
Preparation and Characterization of a Small Library of Thermally-Labile EndCaps for Variable-Temperature Triggering of Self-Immolative Polymers S. Maryamdokht Taimoorya, S. Iraj Sadraeia, Rose Fayoumia, Sarah Nasria, Matthew Revingtona, John F. Tranta,b* a
Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Ave. Windsor, Ontario N9B 3P4 b Canadian Centre for Alternatives to Animal Methods, University of Windsor, 401 Sunset Ave. Windsor, Ontario N9B 3P4
[email protected]; Fax: 1-519-973-7098
Abstract: The reaction between furans and maleimides has become increasingly a target of interest as its reversibility makes it a useful tool for applications ranging from selfhealing materials, to self-immolative polymers, to hydrogels for cell culture and for the preparation of bone repair. However, most of these applications have relied on simple monosubstituted furans and simple maleimides and have not extensively evaluated the potential thermal variability inherent in the process that is achievable through simple substrate modification. A small library of cycloadducts suitable for the above applications was prepared, and the temperature dependence of the retro-Diels-Alder processes was determined through in situ 1H NMR analyses complemented by computational calculations. The practical range of the reported systems ranges from 40 ºC to >110 ºC. The cycloreversion reactions are more complex than would be expected based on simple trends expected based on FMO analyses of the materials. Keywords: Diels-Alder, Self-immolative polymers, hydrogels, furan-maleimide DielsAlder, kinetic analysis, Density Functional Theory
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1. Introduction The Diels-Alder reaction is potentially the most studied, and certainly one of the most used reactions, in synthetic chemistry over the past 90 years.1 It has remained one of the most efficient carbon-carbon bond forming reactions for much of that period. The mechanism of the transformation is well established, as are the pathways that deviate from the ideal pericyclic transformation. The reaction has drawn renewed interest as an example of “Click” Chemistry,2 as it is often highly exergonic through the conversion of 3carbon-carbon π bonds into 2 σ and 1 π bond, is completely atom efficient, and proceeds without the formation of by-products. The maleimide-furan Diels-Alder reaction is of particular interest as it allows for reversibility: the aromatic stabilization of furan nearly balances the favourability of the σbond forming forward reactions.3 The reaction is exergonic, but is reversible at elevated temperatures and higher dilution. This has allowed for a number of innovative applications in materials science and especially in self-healable systems,4 in thermoresponsive polymers,5 and for the generation 3-dimensional hydrogel matrices6 for tissue culture,7 and bone repair.8 Gillies and Trant recently reported the application of the Diels-Alder reaction between furan and maleimide as a thermally-sensitive end-cap for self-immolative polymers (SIPs).9 SIPs are materials that depolymerize in a head-to-tail fashion upon the cleavage of an end-cap. This scission is dependent on the structure of the end-cap, and various stimuli can be applied to initiate polymer degradation. End-caps sensitive to reduction, oxidation, pH, light, and enzymes have all been developed;10 but heat is particularly attractive for biomedical applications.9, 11 Hyperthermal therapy is the use of localized heat to kill cancer cells, especially by using either external radiofrequency for tumours near accessible body cavities to stimulate nanoparticles, or direct heating using intraluminal or interstitial probes for tumours deeper in the body.12 Thermally sensitive end-caps could provide access to an alternative hyperthermic treatment modality by allowing for localized release of drugs from self-immolative nanoparticles. The system studied in this report relies on the natural instability of 2methylsubsituted furan rings (Figure 1).13 This reactivity can be masked while the furan ring is incorporated into the 7-oxanorbornene construct with maleimide. Two simple systems were examined, a benzyl maleimide and a propargyl maleimide that allowed for the introduction of additional functionality, such as poly(ethylene glycol). Both materials were thermally similar, and degraded with similar profiles: 40 hours at 60 ºC provides the plateau for the depolymerization of the polymer;9 as these polymers degrade rapidly at that temperature, the rate limiting step is end-cap removal.14 Ideally, the technology would not be limited to this temperature range. It would be useful to have more and less stable systems able to respond to different temperature signals. This would provide a library of end-caps useable for a variety of different applications.
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The Journal of Organic Chemistry
Figure 1. A) Observed instability of 2-bromomethylfuran 1, and its analogy to a selfimmolative-polymer conjugated methylfuran derivative 3. B) Use of the masked furan 4 as an end-cap for a self-immolative polymer, 5 as reported by Fan, Trant, and Gillies (Reference 8). Following end-capping, the cycloadduct undergoes a retro-Diels Alder when exposed to heat to liberate the unstable furan derivative and the accompanying maleimide. This work focuses on understanding the role of new functional groups introduced on either the furan or maleimide have on the facility of the retro-Diels Alder reaction. Herein, we report our studies into the establishment of a small catalogue of cycloadduct systems as useful tools for our programs developing biocompatible and micro-lithography self-immolative systems, and our studies in developing nextgeneration hydrogel matrix crosslinking moieties for 3-D cell culture and organoid scaffolding. As the normal-demand Diels-Alder reaction is highly sensitive to the energy difference between the frontier molecular orbitals of the diene (HOMO) and dienophile (LUMO), we tuned the reactivity of the systems by introducing electron withdrawing and donating substituents to both the 2-hydroxymethylfuran (4-position) and maleimide (Nalkylation) functionalities. Although the forward reactions proceeded as expected, there is no clear experimental correlation between the FMO gap and the facility of the retro-Diels Alder reactions. Consequently, we have carried out a combined experimental investigation into the reaction kinetics of the cycloreversion reactions and have accompanied it with a detailed computational analysis of the complete reaction pathway to better characterize these complex systems and understand the factors responsible for the differential reactivity.
2. Results and Discussion Synthesis of the end-cap library, and experimental analysis of the Diels-Alder reaction between α-furfuryl alcohol and N-substituted maleimides.
The forward normal demand Diels-Alder reaction is well understood. There is a clear correlation between the energy gap between the HOMO of the diene and LUMO of the dienophile, and the rate of reaction. Electron rich dienes raise the energy of the HOMO, and electron poor dienophiles lower the energy of the LUMO (see Supporting
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Information for the FMOs of the studied systems; Figure S1). However, this picture is complicated by the presence of potential secondary steric interactions that can either stabilize or destabilize a given transition state.15 The ratio of the two potential products, the endo and exo derivatives, is dependent on the precise experimental conditions; there are few general rules regarding this distribution, and the reactions must be studied on an individual basis. Our current research efforts require ready access to a diverse library of cycloadducts. Consequently, we prepared four different 4-substituted α-furfuryl alcohols (the hydroxymethyl group is required for self-immolative activity via conjugation to an SIP) and three maleimides (Table 1). The particular choice of substrates was determined by balancing electronic diversity with simple synthetic access: any viable SIP endcap will require rapid access to multigram scale amounts of the materials. Each diene was treated with each dienophile in turn to yieldtwelve-different potential cycloadducts. Table 1. The results of the Diels-Alder cycloadditions between 4-substituted α-furfuryl alcohols and N-substituted maleimides. Products are numbered by combining the numbers of the two coupling partners for clarity and easy consistency and subscripts are used to define the two possible stereoisomeric cycloadducts: for example, the cycloadduct between α-furfuryl alcohols 1 and N-(p-methoxyphenyl)-maleimide 5 is cycloadduct 15endo. Yields refer to isolated yields of both isomers. Where the isomers were not readily separable, the yield refers to the combined isolated yield, and the individual bracketed percentages refer to the conversion to each isomer based on crude 1 H NMR based on residual furan. Temperature refers to the reaction temperature at which the cycloaddition was conducted and is a surrogate for reaction facility.
40 ºC 15endo 65% 15exo 15% 75 ºC 25endo
