Surface-modified silica materials

Abstract

Disclosed is a method of making surface-modified silica particles, comprising performing a sol-gel condensation of a silica precursor in the presence of a catalyst, a zwitterion-comprising alcohol, and, optionally, an ionic liquid electrolyte porogen.

Description

[0001]TUV-18425 SURFACE-MODIFIED SILICA MATERIALS RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No.: 63 / 654,520, filed May 31, 2024. GOVERNMENT SUPPORT This invention was made with government support under grant no.2209500 awarded by the National Science Foundation. The government has certain rights in the invention. BACKGROUND Silica materials are used in a number of biomedical applications such as biosensing, drug delivery, and diagnostics imaging. These materials are also attractive because they are easily available from commercial sources with a wide particle size range. However, silica particle surfaces possess a high negative charge at physiological pH, leading to rapid nonspecific protein adsorption. Nonspecific protein adsorption, which results in silica particle aggregation and deactivation of the functional sites, is one of the major challenges to the use of silica materials in many biomedical applications. To reduce nonspecific adsorption of biomacromolecules in complex biological systems, several approaches have been employed to modify silica surfaces with anti-fouling materials. Among these anti-fouling materials, poly(ethylene glycol) (PEG) has been widely used because the repeated ethoxy units in the PEG chain can form a compact hydration layer around the silica particle through hydrogen bonding, providing efficient energy and steric barrier to protect protein adsorption. The commercial availability of a variety of PEG derivatives with different functional groups makes it possible to meet the needs of surface modifications. However, recent studies found that PEG suffers from slow degradation in physiological conditions, and immune system may produce PEG-specific antibodies. Accordingly, better anti-fouling modifications of silica materials are needed. - 1 - FoleyHoagUS12885817.4 TUV-18425 SUMMARY OF THE INVENTION In some embodiments, the present disclosure relates to a method of making surface- modified silica particles, comprising: a) combining a silica precursor, a catalyst, a zwitterion-comprising alcohol, and, optionally, an ionic liquid electrolyte (ILE), thereby producing a reaction mixture; b) allowing the reaction mixture to age for a period of time, thereby producing a gelled mixture; and c) drying the gelled mixture, thereby producing the surface-modified silica particles. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is a graph showing thermogravimetric analysis (TGA) of silica samples synthesized with or without L-α-glycerophosphorylcholine (alpha-GPC, or GPC) and in the presence of 50 vol.% ionic liquid electrolyte (ILE). FIG.2 is a graph showing data obtained using energy dispersive X-ray spectroscopy (EDS) in signal counts versus X-ray energy (keV) for silica gels prepared with no ILE and no alpha-GPC. The sample shows a phosphorus (P Kα) to silicon (Si Kα) count ratio of 0.00. FIG.3 is a graph showing data obtained using EDS in signal counts versus X-ray energy (keV) for silica gels prepared with alpha-GPC and no ILE. The sample shows a phosphorus (P Kα) to silicon (Si Kα) count ratio of 0.04. FIG.4 is a graph showing data obtained using EDS in signal counts versus X-ray energy (keV) for silica gels prepared with ILE and no alpha-GPC. The sample shows a phosphorus (P Kα) to silicon (Si Kα) count ratio of 0.00. FIG.5 is a graph demonstrating data obtained using EDS in signal counts versus X-ray energy (keV) for silica gels prepared with alpha-GPC and ILE. The sample shows a phosphorus (P Kα) to silicon (Si Kα) count ratio of 0.04. FIG.6 is a photograph of silica gel samples prepared without ILE. Left vial: gel prepared without alpha-GPC. Right vial: gel prepared with alpha-GPC. - 2 - FoleyHoagUS12885817.4 TUV-18425 FIG.7 shows a scanning electron microscopy (SEM) image of the surface of a silica gel sample containing no ILE and prepared without alpha-GPC. FIG.8 shows an SEM image of the surface of a silica gel sample containing no ILE and prepared with alpha-GPC. FIG.9 shows an SEM image of the surface of a silica gel sample prepared with 50 vol.% ILE and without alpha-GPC. FIG.10 shows an SEM image of the surface of a silica gel sample prepared with 50 vol.% ILE and with alpha-GPC. FIG.11 is a photograph of xerogels obtained using an ILE porogen and different amounts of GPC in the sol−gel reaction mixture. From left to right: GPC:TEOS molar ratios of 0 (control), 1:20, 1:10, and 1:5. FIG.12 is a photograph of ionogels obtained using an ILE porogen and different amounts of GPC in the sol−gel reaction mixture. From left to right: GPC:TEOS molar ratios of 0 (control), 1:20, 1:10, and 1:5. Ionogels were prepared using approximately 50 vol % ILE porogen in the reaction mixture. FIG. 13 shows TGA traces of ionogels prepared using GPC:TEOS molar ratios of 0 (control), 1:20, 1:10, and 1:5. Inset shows the weight percentage remaining immediately after a 15 min isothermal hold at 100 °C. FIG. 14 is a plot showing shear viscosity of ionogels prepared using GPC:TEOS molar ratios of 0 (control), 1:20, 1:10, and 1:5, as well as that of the ILE porogen (1 M LiTFSI in BMP TFSI), versus shear rate. Values were measured while increasing the shear rate from 10−1to 103s−1. FIG. 15 shows SEM micrographs of the silica gel materials. (a−d) Xerogels synthesized using GPC:TEOS molar ratios of 1:5 (a), 1:10 (b), 1:20 (c), and no GPC / control (d). (e−h) Silica within ionogels (ILE porogen removed) synthesized using GPC:TEOS molar ratios of 1:5 (e), 1:10 (f), 1:20 (g), and no GPC / control (h). - 3 - FoleyHoagUS12885817.4 TUV-18425 FIG. 16 shows SEM micrographs of silica within ionogels (ILE porogen removed) at 1000X magnification. Samples synthesized using GPC:TEOS molar ratios of 1:5 (a), 1:10 (b), 1:20 (c), and no GPC / control (d). FIG.17 shows ATR-FTIR spectra for (a) GPC molecule, with characteristic peaks of the zwitterionic portion of GPC annotated; (b) ionogels containing GPC:TEOS molar ratios of 1:5 (blue), 1:10 (orange), 1:20 (green), and no GPC / control (red). FIG.18 is a photograph of a xerogel (left) and an ionogel (right) prepared with L-carnitine, using a 1:10 L-carnitine:TEOS molar ratio. FIG. 19 is a photograph silica gel synthesized using aqueous NH3 as a catalyst (5.88:1 NH3:TEOS): Sample 1A on the left synthesized without GPC additive; Sample 1B on the right synthesized with GPC additive. FIG. 20 is a photograph silica gel synthesized using aqueous NH3 as a catalyst (11.75:1 NH3:TEOS): Sample 2A on the left synthesized without GPC additive; Sample 2B on the right synthesized with GPC additive. FIG. 21 shows SEM micrographs of ‘control’ colloidal silica particles prepared without GPC additive (Example 9); Sample 1A is on the left, and Sample 2A is on the right. DETAILED DESCRIPTION OF THE INVENTION Zwitterionic materials are efficient anti-fouling materials due to the formation of a strong hydration layer through electrostatic interaction. However, use of high molecular weight zwitterionic polymer coatings leads to an increase in the hydrodynamic size of particles, which may negatively impact their biomedical applications. In addition, the difficulty in the synthesis of zwitterionic polymers is challenging their utilization. Zwitterionic silane chemistry is a straightforward strategy to produce zwitterionic-modified surfaces and has been proven to be successful in anti-fouling without significantly increasing the particle size. However, strict anhydrous condition and inert gas protection were required during the silane synthesis, which is challenging the large-scale particle synthesis. - 4 - FoleyHoagUS12885817.4 TUV-18425 In some embodiments, the present disclosure relates to a method for synthesizing porous silica materials that feature zwitterionic functional groups attached to their surface using a one- pot, sol-gel approach. In some embodiments, the present disclosure relates to a method for synthesizing porous silica materials that feature zwitterionic phosphorylcholine (PC) functional groups attached to their surface using a one-pot, sol-gel approach. In some embodiments, the present disclosure relates to a method for synthesizing porous silica materials that feature zwitterionic L-carnitine-derived functional groups attached to their surface using a one-pot, sol- gel approach. In some embodiments, the PC groups are incorporated onto the silica surface through the simple addition of a low-cost molecule which is sold as a nutritional supplement, L- alpha-glycerylphosphorylcholine (alpha-GPC, or GPC), into the one-pot sol-gel reaction mixture. In some embodiments, the addition of alpha-GPC has been observed to dramatically accelerate the sol-gel reaction speed, as measured by sample gelation time (from several hours down to only a few minutes, in some cases). Porous silica materials can be synthesized via sol-gel reaction using a tetraalkoxysilane precursor such as tetraethoxysilane (TEOS), tetramethoxysilane (TMOS), or other similar starting material. Either a base or acid catalyst (such as formic acid, FA, for the latter) can be combined with TEOS or a similar precursor in a reaction vessel and allowed to react. Optionally, a liquid porogen, such as a conventional solvent or an ionic liquid electrolyte (ILE), can be added to the reaction mixture. The porogen may serve either as a nonreactive spectator or it can participate in the reaction. Silica gel materials are created through a series of several reactions that occur, including both hydrolysis and condensation reactions. Following evaporation or removal by other means of any non-solid volatile reaction byproducts, the remaining silica gel can be used for many potential applications. In some embodiments, if a non-volatile ILE is used in the synthesis, the resulting silica / ILE composite can serve as a nonflammable electrolyte for electrochemical devices (such as batteries or supercapacitors). In some embodiments, the disclosed method provides a way to reduce reaction times (and therefore increase throughput) for producing commercial silica materials (coatings, particulates, porous scaffolds, etc.) that are synthesized using a sol-gel approach. In some embodiments, the present disclosure provides a method by which phosphorylcholine (PC) zwitterionic groups, having well-recognized properties of biocompatibility, anti-fouling, anti-thrombogenicity, anti- - 5 - FoleyHoagUS12885817.4 TUV-18425 fogging, anti-icing, improved wettability, hydration capacity, etc. can be covalently attached to a silica material prepared through a one-pot sol-gel reaction. In some embodiments, the disclosed method uses a low cost, commercially available small molecule additive (alpha-GPC) to obtain a PC-modified silica material in a one-pot reaction, and, in some cases, at an accelerated rate. Alpha-GPC is produced by deacylation of cell membrane phospholipids (e.g. phosphatidylcholines, lecithin) through chemical and / or enzymatic means. Alpha-GPC is a natural choline compound found in the brain, and it is currently produced at a commercial scale and sold as a nutritional supplement or nootropic (cognitive enhancer) at low cost. Examples of methods of synthesis of alpha-GPC can be found, for example, in US Patent No.9,617,288, which is incorporated herein in its entirety by reference. In some embodiments, the alpha-GPC additive accelerates the overall sol-gel reaction speed, thereby reducing the time needed to obtain a freestanding gel material. In formulations containing 50-60 wt.% ILE, the gelation time was reduced from > 6 h without the additive down to just a few minutes when alpha-GPC was present. Such acceleration of the reaction rate can reduce processing times for commercial silica materials synthesized using the sol-gel approach. This likely occurs through Si—O bond(s) formed between a silicon atom on the nascent silica solid material and one (or both) of the –OH functional groups present on the alpha-GPC additive. Fabrication of silica materials via sol–gel synthesis is a well-studied, versatile, and industrially relevant technology. Due to their high chemical / thermal stability and bioinert nature, silica materials find applications in biosensing, drug delivery, diagnostic imaging, dental repair, and other biomedical applications. Silica gels that are conventionally dried immediately following sol–gel synthesis result in dense, microporous structures known as xerogels. It is also possible to include a nonvolatile liquid porogen within the sol–gel reaction mixture, which allows one to create microporous silica-supported gels that do not dry out any further after removing volatile reaction byproducts, such as ethanol and water. An important class of nonvolatile liquid porogens is ionic liquids (ILs), which are salts possessing a melting point below 100 °C. ILs are nonflammable, ionically conductive, and have been shown to be able to template the formation of porous silica monoliths without the need for additional surfactants. When the final content of the IL phase in a gel is at least 50% by volume or mass, such materials are termed “ionogels.” Silica-supported ionogels have previously been demonstrated to exhibit excellent thermal stability, tunable mechanical character, and suitability - 6 - FoleyHoagUS12885817.4 TUV-18425 as electrolytes for electrochemical energy storage devices. Furthermore, the dissolution of a lithium salt within an IL can yield a safer electrolyte for lithium-ion batteries, due to the nonflammable nature of these ionic liquid electrolytes (ILEs). Zwitterion (ZI)-decorated surfaces that have covalently bound ZI moieties are recognized as improving fouling resistance, biocompatibility, and antithrombogenicity. ZI- decorated silica gel surfaces can be prepared using several strategies. One approach is to graft on zwitterionic polymer chains. Another is to utilize a silanization reaction using a ZI-modified silane, which is a rapid process, but requires additional synthesis and purification steps. In some embodiments, the present disclosure relates to addition of a ZI molecule possessing accessible hydroxyl groups into the sol–gel reactant mixture, yielding a ZI-decorated silica gel in a straightforward, single step. In some embodiments, L-α-glycerophosphorylcholine (GPC) can be used as such a PC-type ZI to include in the sol–gel process due to its high biocompatibility, natural abundance, and commercial availability. GPC, which corresponds to the hydrolyzed headgroup of natural phospholipids such as lecithin, is an acetylcholine precursor found in the brain. It is also marketed and sold as a dietary supplement for enhancing cognitive ability, and available at a low cost. In some embodiments, the present disclosure relates to the synthesis of PC-type ZI- decorated silica gels via a simple room temperature, one-pot, acid-catalyzed sol–gel reaction. Several molar ratios of the ZI additive (GPC) relative to the silica precursor (tetraethyl orthosilicate, TEOS) were studied, and gels were prepared both with and without a lithium salt- containing ILE porogen. The presence of GPC was observed to dramatically reduce the gelation time compared to control gels prepared without GPC. Samples prepared with ILE porogen (50 vol % of the reaction mixture) resulted in ionogels, while those prepared without a porogen were dried to obtain xerogels. Energy dispersive X-ray spectroscopy (EDS) was used to confirm the covalent attachment of PC-type ZI groups on the silica surfaces of both gel types following a two-step washing procedure. These findings suggest that the one-pot sol–gel approach described here may provide a powerful way to develop additional ZI-decorated silica materials with a variety of ZI chemistries for biomedical and energy storage applications. The generation of silica via sol–gel reaction of a silicon alkoxide precursor such as TEOS occurs through a polycondensation process involving both hydrolysis and condensation steps. Using formic acid (FA) as the catalyst, reaction mechanisms are preceded by rapid protonation - 7 - FoleyHoagUS12885817.4 TUV-18425 of -OR or −OH groups bonded to silicon. FA can also participate in a carboxylation reaction with the TEOS precursor, generating silyl formate groups that can rapidly condense with silanol or other silyl formate groups. a silanol group derived from TEOS during sol–gel silica synthesis. Hydrolysis and condensation processes continue to propagate and form a mesoporous silica gel network, entrapping any liquids present (i.e., a spectator porogen, such as an ILE, and / or byproducts of the sol–gel reaction such as ethanol, ethyl formate, and water) and preventing the reaction mixture from flowing when a gelation point is reached. Subsequent drying and aging provides the final product, which is a xerogel in the case of no added porogen (FIG. 11), or an ionogel in the case of a significant volume fraction of ILE added (FIG. 12). As seen in FIG. 11, the addition of GPC to the sol–gel reaction mixture at a GPC:TEOS molar ratio greater than 1:20 can dramatically impact the final appearance of the resulting xerogel. Increasing the concentration of GPC in the sample formulation increases the opacity of the final silica xerogel, indicating that the resulting microstructure of the silica monolith has likely been altered. Additionally, for xerogels prepared with the two largest concentrations of GPC studied here (GPC:TEOS molar ratios of 1:10 and 1:5), the final xerogel diameter (resulting from reaction mixtures prepared inside of identical 1-dram glass vials, ∼13 mm inner diameter, after drying and shrinking) is notably larger (FIG. 11). Since GPC can only be incorporated onto the surface of growing colloidal silica sols, the presence of a sufficient amount of GPC in the sol–gel reaction mixture may introduce additional Coulombic and / or steric interactions between growing sols that results in a larger average distance between them as they condense into a gel, thereby reducing the effective silica gel density. An increased porosity of the GPC-modified xerogels likely results in the enhanced visible light scattering observed (FIG. 11), enabled by the refractive index contrast between the silica particles and air inside the pores. In contrast, as seen in FIG. 12, ionogels prepared using the same GPC:TEOS molar ratios did not exhibit the same visual opacity differences as the xerogel materials. This is not unexpected, however, since any - 8 - FoleyHoagUS12885817.4 TUV-18425 potential differences in silica gel network structure may not be visible at the macroscopic scale when a large amount of ILE (here, > 90 wt %, see FIG.13) is present in the final ionogels. While the main reason for adding GPC to the sol–gel reaction formulations here was to realize the covalent attachment of PC-type ZI moieties onto the silica gel surface, a rather dramatic and unexpected second effect was observed: a substantial reduction in the time required to reach the nonflowing gel state. As summarized in Table 1, the observed gelation times for samples prepared with GPC were significantly faster than for the corresponding control gels prepared without it. For the xerogel samples, the control formulation (no GPC) reached the gel state after approximately 30 min, whereas xerogels prepared with GPC gelled in under 5 min. Notably, the same reduction in the time required for gelation was observed for all three GPC:TEOS molar ratios examined (1:20, 1:10, and 1:5). Even more dramatic was the gelation time reduction for the ionogel samples prepared using ∼50 vol % ILE porogen in the reaction mixture. While the control formulation (no GPC) did not gel until approximately 5.5 h after mixing, all three of the formulations with GPC gelled in less than 5 min, corresponding to a more than 60-fold decrease in the gelation time. A possible explanation for the spectacular acceleration of the gel formation process due to GPC may be due to its extremely hydrophilic nature. Given its proclivity to form a robust hydration layer of water molecules, it is possible that GPC acts to attract water molecules as they are being generated during the sol–gel process (Scheme 1), thereby driving condensation reactions forward. Sequestration of water around the ZI GPC units may also be expected to increase the apparent local concentration of the FA catalyst. It has previously been shown that increasing the molar ratio of FA:TEOS by adding more FA can substantially reduce gelation times, though not to such a low value (<5 min) as achieved here. - 9 - FoleyHoagUS12885817.4 TUV-18425 Table 1. Gelation times of silica gels prepared without porogen (xerogels) or with ILE porogen (ionogels), varying the molar ratio of GPC:TEOS in the reaction mixture. Thermal to assess the effectiveness of the employed postreaction drying procedure, as well as to determine the mass fraction of silica created within each ionogel formulation. Thermogravimetric analysis (TGA) traces of the control ionogel (no GPC), and of the three ionogels prepared with varying GPC:TEOS molar ratios are shown in FIG.13. All four ionogels experience no significant mass loss below ∼300 °C and the TGA traces reveal a single mass loss event, between approximately 400–500 °C, that is consistent between all samples and indicative of the decomposition of the ILE. The final silica content in all four ionogel formulations was approximately 5–7 wt %, as indicated by the weight percentage remaining above 600 °C. Although no separate mass loss events corresponding to the GPC ZIs were observed, this can be explained either by the relatively low GPC mass concentration in the ionogels (nominally 4, 2, and 1 wt % for GPC:TEOS molar ratios of 1:5, 1:10, and 1:20, respectively) compared to that of the ILE, and / or by the GPC degradation temperature window coinciding with that of the ILE itself and being obscured. The inset to FIG.13 highlights the weight percentage remaining after a 15 min isothermal hold at 100 °C for each ionogel. This hold step was performed to try and remove any loosely bound volatile components (e.g., water, ethanol) that may have remained after the ionogels were rigorously dried under vacuum at room temperature for at least 24 h, followed by additional curing under vacuum at 120 °C for 4 h. As seen in FIG.13 (inset), all four ionogel formulations lost less than 1.5 wt % of volatiles during the isothermal hold step. The trend in the - 10 - FoleyHoagUS12885817.4 TUV-18425 mass percentage of volatiles removed at low temperature was observed to decrease as the GPC content in the ionogel increased: the control ionogel (no GPC) lost approximately 1.4 wt % during the isothermal hold, while losses for the GPC-containing ionogels were approximately 1.2, 0.9, and 0.5 wt % for the 1:20, 1:10, and 1:5 GPC:TEOS molar ratio formulations, respectively. This could be due to the hydrophilic nature of GPC, since a higher ZI content may be expected to be able to sequester more water due to its strong hydration, preventing it from evolving until higher temperatures. Shear viscosity versus shear rate data measured for the four GPC-containing ionogel formulations and the liquid ILE porogen are shown in FIG.14. All of the ionogels exhibited shear thinning behavior across the shear rate range examined. Notably, the three ionogels formulated with GPC exhibited viscosities that were approximately 2–4 times higher than those of the control ionogel at all shear rates. As no significant difference in silica content was determined among the GPC-containing ionogels or the control (FIG.13), the viscosity data suggest that that the silica primary particle size inside the ionogels prepared with GPC is smaller than that within the control ionogel, since smaller solid particles for the same silica content would correspond to a greater solid / liquid interfacial area that should increase ionogel viscosity. However, there was no significant difference in measured viscosity values between the three ionogels formulated with GPC, indicating that the silica particle sizes between these materials are likely comparable. Both of these conclusions are corroborated by SEM imaging of the silica networks upon removal of the ILE phase (see below). For the ionogel samples prepared with GPC, a plateau in shear viscosity values was observed for shear rates between approximately 1–10 s–1, with two separate shear thinning regions at lower and higher shear rates. This phenomenon has been seen previously in other colloidal gel systems and may be caused by changes in monolith structure and aggregate size under applied shear conditions. After the shear rate ramp experiments were completed for each ionogel, the materials were no longer freestanding gels, indicating an irreversible breakup of the silica network. As seen in FIG.14, the liquid ILE porogen exhibited Newtonian behavior below approximately 100 s–1, above which shear thinning behavior appeared. Shear-thinning behavior at high shear rates has been reported previously for ILs, although the critical shear rate for the 1 M LiTFSI / BMP TFSI ILE employed here occurs at a relatively low value. - 11 - FoleyHoagUS12885817.4 TUV-18425 While an increase in electrolyte viscosity typically has a negative impact on its ionic conductivity, it should be noted that the room temperature ionic conductivity values measured for all of the ionogels, approximately 1.0 mS / cm, was essentially unchanged compared to that of the ILE itself (Table 2). Table 2. Room temperature ionic conductivity values measured for ionogels prepared using varying molar ratios of GPC:TEOS, along with that of the neat ILE (1M LiTFSI in BMP TFSI). Errors indicate the standard deviation of 3 replicate measurements. GPC:TEOS Molar Ratio Ionic conductivity (mS cm-1) This level of room temperature ionic conductivity is widely accepted to be sufficient for electrochemical devices such as lithium-ion batteries. While the presence of PC-type ZI moieties has previously been reported to boost ionic conductivity levels within polymer-supported ionogels, the same was not observed for the GPC-containing silica-supported ionogels developed here. One reason for this difference may be a greater extent of local PC moiety aggregation within the present colloidal silica ionogels, since it is unlikely that all of the GPC present was able to participate in condensation reactions and become covalently bound on the growing silica network. Thus, PC groups may likely be located both at the silica particle / ILE interface (covalently bound GPC) as well as within the ILE porogen liquid phase itself (unbound GPC). In order to visualize the morphology of the various silica materials formed, the xerogels and ionogels were washed using water and ethanol sequentially to remove any unreacted GPC, as well as to remove the ILE (in the case of ionogels). SEM was used to image the resulting silica materials, as shown in FIG.15. First, comparing the micrographs of the xerogels, FIG.15, panels a-d, there appears to be a qualitative difference in the smoothness of the silica, where a greater concentration of GPC resulted in rougher surfaces. Higher magnification imaging was attempted to better understand these differences; however, the dense silica xerogel surface impeded this due to surface charging. In contrast, the microporous silica networks formed inside - 12 - FoleyHoagUS12885817.4 TUV-18425 the ionogels were more readily imaged at high magnification, as shown in FIG.15, panels e-h. These images reveal two key findings, namely, that the presence of GPC in the ILE porogen reduces the silica primary particle size (approximately 500–600 nm diameter particles when using GPC vs approximately 1400–1500 nm diameter particles for the control), and that an increasing amount of GPC increases the nanoscale roughness / texturing of these particles (see also FIG.16). Indeed, the smaller silica particles formed within the GPC-containing ionogels (FIG.15, panels e-g) compared to those within the control ionogel synthesized without GPC (FIG.15, panel h) are consistent with the greater shear viscosity values observed when GPC is present in the formulations, as discussed above. These morphological results may also provide insight into the faster gelation times observed for the ionogels containing GPC (Table 1), as the formation of smaller silica particles–but an unchanged total silica content (FIG.13) – would imply a greater number of particles created, which could more readily form a 3D network to support the ILE porogen in a nonflowing gel state. To verify that zwitterionic PC moieties were covalently bonded to the silica surface of all gels where GPC was included in the sol–gel formulation, EDS spectra were collected during SEM characterization. Attention was focused on the elemental signals from silicon and oxygen (mainly from silica), fluorine and sulfur (present in the ILE anion, TFSI–), and phosphorus (present only in GPC). Displayed in Table 3 are the average weight percentage values measured for each of these elements across three locations on each sample. It was observed that the weight percentages of fluorine and sulfur measured on the ionogel silica samples were nonzero, indicating that the water / ethanol washing procedure did not fully remove all of the ILE. This may be due to entrapment of the ILE during the formation of the sol–gel network. Importantly, all of the silica materials prepared with GPC in the reaction mixture (both xerogels and ionogels) showed statistically significant weight percentages of phosphorus, while the control samples (prepared without GPC) showed no detectable amount of phosphorus. Since the gels were washed thoroughly with water and ethanol (both solvents in which GPC is miscible) prior to SEM / EDS characterization, these data provide compelling evidence for GPC participating in condensation reactions with silanol groups during the sol–gel synthesis (Scheme 1). FTIR spectra of the thoroughly washed and dried ionogel silica samples also support the presence of PC moieties on the silica surface (FIG.17). FIG.17 shows ATR-FTIR spectra for GPC (FIG. 17, panel a) and for the thoroughly washed ionogel silicas (FIG.17, panel b). Spectra for the - 13 - FoleyHoagUS12885817.4 TUV-18425 washed xerogels are not shown due to challenges in making adequate sample contact with the FTIR crystal. In FIG.17, panel a, GPC exhibits key absorption bands that can be attributed to the zwitterionic component of the molecule. These bands are located at: 1487 cm-1and 962 cm-1,which correspond to the aliphatic quaternary ammoniumgroup; as well as 1245 cm-1 and 1040cm-1, characteristic of the (P-O-CH2) and (O-P-O-CH2)groups present in the molecule,respectively. In FIG.17, panel b, characteristic peaks for the control silica (red spectrum) include: 1078 cm-1and 799 cm-1, representing silicon dioxide, and 934 cm-1, characteristic of hydrogen bonded silanol groups.4When comparing the control ionogel with ionogels synthesized using GPC, there are two notable band shifts. First, there is a consistent shift in the silanol band at 934 cm-1for the control ionogel to higher wavenumbers with any amount of GPC, indicating the presence of the quaternary ammonium group. Second, there is nominal shift in the silicon dioxide band peak near 1078 cm-1for the control ionogel to lower wavenumbers, particularly for the 1:5 and 1:10 GPC:TEOS molar ratio ionogels. This shift may indicate the presence of the (O-P-O-CH2) vibrations in the sample. These band shifts provide additional evidence of the persistent presence of GPC on the ionogel silica after the samples were thoroughly washed with water, ethanol, and methanol; all three are solvents in which GPC is readily soluble. Notably, the phosphorus weight percentage was not found to increase significantly with increasing GPC content in the reaction mixture. Among the xerogels, the average phosphorus signal increased from 1.9 wt % to 2.8 wt % as the GPC:TEOS molar ratio was increased from 1:20 to 1:5, while the corresponding ionogels showed an increase in phosphorus from only 1.7 wt % to 2.1 wt %. This suggests there may likely be unreacted GPC present in the gels prior to washing them, especially those formulated with higher GPC:TEOS molar ratios. - 14 - FoleyHoagUS12885817.4 TUV-18425 Table 3. EDS Map Sum Spectra of the Washed Silica Gelsa aAverage wt.% values represent averages across three locations per sample (with standard deviations). In some embodiments, the present disclosure relates to a straightforward, one-pot approach to create PC-type ZI-functionalized silica gel materials, including both xerogels and ILE-rich ionogels, using commercially available reagents. Important insights into the roles played by the ZI additive, GPC, during sol–gel silica synthesis at room temperature have been obtained. First, the presence of GPC markedly reduces the time to reach the nonflowing gel state, from on the order of hours to mere minutes, both with / without the presence of a nonvolatile ILE porogen (50 vol % in the reaction mixture). This is consistent with a reduction in the silica primary particle size without altering the total amount of silica formed when GPC is included in the formulations, as confirmed by thermal analysis and SEM imaging. Moreover, the PC- modified silica ionogels exhibited higher shear viscosity values by a factor of approximately 2–4 versus those of the control ionogel prepared without GPC. Second, evidence that supports the successful condensation of GPC hydroxyl groups with hydrolyzed silica precursor (TEOS) to covalently bind zwitterionic PC moieties on the silica surface during sol–gel synthesis was obtained by EDS characterization of thoroughly solvent-washed and dried samples, which indicated the uniform presence of phosphorus. In some embodiments, the present disclosure relates to a method of making ZI-decorated organic / inorganic oxide materials in a one-pot - 15 - FoleyHoagUS12885817.4 TUV-18425 reaction for a variety of potential applications that can leverage the outstanding antifouling and biocompatible nature of many zwitterionic functional groups. In some embodiments, the present disclosure relates to the use of the low-cost nutraceutical molecule, L-carnitine (L-Car), a zwitterionic molecule with a single hydroxyl group, is silica gelation. Use of L-Car impacts the synthesis and morphology of the silica gels participates in covalent silica surface modification, similar to GPC. Images of gels prepared with L-Car are shown in FIG. 18 and respective gelation times are shown in Table 4. L-carnitine (L-Car) Table 4. Gelation times of silica gels prepared with L-carnitine compared to control gels. Gel Type L-Car:TEOS Molar Ratio Gelation Time , d of making surface- modified silica particles, comprising: a) combining a silica precursor, a catalyst, a zwitterion-comprising alcohol, and, optionally, an ionic liquid electrolyte (ILE), thereby producing a reaction mixture; b) aging the reaction mixture for a period of time, thereby producing a gelled mixture; c) drying the gelled mixture, thereby producing the surface-modified silica particles. In some embodiments, the silica precursor comprises a silicon alkoxide, a silane, a polysilicate, or Si(OH)4. In some embodiments, the silica precursor comprises a silicon alkoxide. In some embodiments, silica precursor comprises tetraethoxysilane (TEOS), tetramethoxysilane - 16 - FoleyHoagUS12885817.4 TUV-18425 (TMOS), tetra-n-propoxy silane (TPOS), methyltrimethoxysilane (MTMS), 1,2- bis(triethoxysilyl)ethane, 1,4-bis-(triethoxysilyl)benzene, or a combination thereof. In some embodiments, the silica precursor is TEOS. In some embodiments, the silica precursor is Si(OH)4. In some embodiments, the silica precursor is colloidal silica. In some embodiments, the catalyst comprises an acid. In some embodiments, the acid is selected from the group consisting of formic acid, acetic acid, citric acid, oxalic acid, HCl, HNO3, H2SO4, H3PO4, and HBF4. In some embodiments, the acid is formic acid. In some embodiments, the catalyst comprises a base. In some embodiments, the base is selected from the group consisting of NH4OH, LiOH, NaOH, KOH, Na(OC(O)CH3), NaHCO3, NaHSO4, NaH2PO4, and Na2HPO4. In some embodiments, the base is NH4OH. As used herein, “NH4OH” refers to aqueous solution of ammonia. In some embodiments, the reaction mixture comprises the ILE. In some embodiments, the ILE comprises an ionic liquid. In some embodiments, the ionic liquid comprises a cation selected from the group consisting of N,N’-dialkylimidazolium, N,N-dialkylpyrrolidinium, alkylammonium, alkylphosphonium, and N-alkylpyridinium; and an anion selected from the group consisting of hexafluorophosphate, tetrafluoroborate, tetracyanoborate, tris((trifluoromethyl)sulfonyl)methide, trifluoroacetate, trifluoromethanesulfonate, bis((trifluoromethyl)sulfonyl)imide, bis(fluorosulfonyl)imide, thiocyanate, tosylate, nitrate, and tris(pentafluoroethyl)trifluorophosphate. In some embodiments, the ionic liquid is selected from the group consisting of 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, 1- butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-2,3,4,5-tetramethylimidazolium bromide, 1-butyl- 2,3,4,5-tetramethylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-4-methylpyridinium bis-(trifluoromethylsulfonyl)imide, 1-butylpyridinium bis(trifluoromethylsulfonyl)imide, 1- butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, and 1-butyl-3-methylimidazolium acetate. In some embodiments, the ionic liquid is 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide. In some embodiments, the ILE further comprises a salt. In some embodiments, the salt comprises a cation selected from lithium cation and sodium cation; and an anion selected from the group consisting of hexafluorophosphate, tetrafluoroborate, tetracyanoborate, tris((trifluoromethyl)sulfonyl)methide, trifluoroacetate, trifluoromethanesulfonate, - 17 - FoleyHoagUS12885817.4 TUV-18425 bis((trifluoromethyl)sulfonyl)imide, bis(fluorosulfonyl)imide, thiocyanate, tosylate, nitrate, and tris(pentafluoroethyl)trifluorophosphate. In some embodiments, the salt is lithium bis(trifluoromethylsulfonyl)imide. In some embodiments, the reaction mixture does not comprise a fluoride ion source. In some embodiments, the reaction mixture does not comprise a salt comprising a fluoride anion. In some embodiments, the reaction mixture does not comprise a fluoride anion. In some embodiments, the zwitterion-comprising alcohol comprises a zwitterion- comprising moiety. In some embodiments, the zwitterion-comprising alcohol is a zwitterion- comprising polyol. In some embodiments, the zwitterion-comprising alcohol is a zwitterion- comprising diol. In some embodiments, the zwitterion-comprising alcohol is represented by the following structural formula: , wherein Z is the zwitterion-comprising In some embodiments, zwitterion-comprising moiety comprises an anionic moiety and a cationic moiety, and wherein: the cationic moiety is represented by one of the following structural formulas: , an alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, (cycloalkyl)alkyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, and (heterocycloalkyl)alkyl, and the anionic moiety is represented by one of the following structural formulas: - TUV-18425 In some embodiments, the cationic moiety is represented by the following structural .In some embodiments, each of Ra, Rb, and Rc is independently C1-3 alkyl. Insome each of Ra, Rb, and Rcis methyl. In some embodiments, the anionic moiety is represented by the following structural formula: . the zwitterion-comprising moiety is represented by the following structural formula: . In some embodiments, the alcohol is represented by the following structural formula: . In some embodiments, the particles comprises about 0.1 wt% to about 10 wt% phosphorus. For example, the surface-modified silica particles comprises about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 8 wt%, about 0.1 wt% to about 6 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 2 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 8 wt%, about 1 wt% to about 6 wt%, about 1 wt% to about 5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 2 wt%, about 2 wt% to about 10 wt%, about 2 wt% to about 8 wt%, about 2 wt% to about 6 wt%, about 2 wt% to about 5 wt%, about 2 wt% to about 4 wt%, or about 2 wt% to about 3 wt% phosphorus. In some embodiments, the surface-modified silica particles comprises about 1 wt% to about 5 wt% phosphorus. In some - 19 - FoleyHoagUS12885817.4 TUV-18425 embodiments, the surface-modified silica particles comprises about 1 wt% to about 3 wt% phosphorus. In some embodiments, the anionic moiety is represented by the following structural formula: . the zwitterion-comprising moiety is represented by the following structural formula: . In some embodiments, the alcohol is represented by the following structural formula: . In some embodiments, the catalyst, and the zwitterion- comprising alcohol comprises: i) combining the catalyst and the zwitterion-comprising alcohol, thereby producing a first mixture; and ii) adding the silica precursor to the first mixture, thereby producing the reaction mixture. In some embodiments, combining the silica precursor, the catalyst, the zwitterion- comprising alcohol, and the ILE comprises: i) dissolving the zwitterion-containing alcohol in the ILE, thereby producing a second mixture; ii) adding the catalyst to the second mixture, thereby producing a third mixture; and iii) adding the silica precursor to the third mixture, thereby producing the reaction mixture. In some embodiments, the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 20:1 to about 1:1. For example, the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 20:1 to about 1:1, about 18:1 to about 1:1, about 16:1 to about 1:1, about 14:1 to about 1:1, about 12:1 to about 1:1, about 10:1 to about 1:1, about 8:1 to about 1:1, about 6:1 to - 20 - FoleyHoagUS12885817.4 TUV-18425 about 1:1, about 4:1 to about 1:1, about 2:1 to about 1:1, 20:1 to about 4:1, about 18:1 to about 4:1, about 16:1 to about 4:1, about 14:1 to about 4:1, about 12:1 to about 4:1, about 10:1 to about 4:1, about 8:1 to about 4:1, 20:1 to about 8:1, about 18:1 to about 8:1, about 16:1 to about 8:1, about 14:1 to about 8:1, about 12:1 to about 8:1, about 10:1 to about 8:1, 20:1 to about 10:1, about 18:1 to about 10:1, about 16:1 to about 10:1, about 14:1 to about 10:1, or about 12:1 to about 10:1. In some embodiments, the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 20:1, about 18:1, about 16:1, about 14:1, about 12:1, about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, or about 1:1. In some embodiments, the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 10:1. In some embodiments, the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 5:1. In some embodiments, the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 20:1 to about 1:1. For example, the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 20:1 to about 1:1, about 18:1 to about 1:1, about 16:1 to about 1:1, about 14:1 to about 1:1, about 12:1 to about 1:1, about 10:1 to about 1:1, about 8:1 to about 1:1, about 6:1 to about 1:1, about 4:1 to about 1:1, about 2:1 to about 1:1, 20:1 to about 4:1, about 18:1 to about 4:1, about 16:1 to about 4:1, about 14:1 to about 4:1, about 12:1 to about 4:1, about 10:1 to about 4:1, about 8:1 to about 4:1, 20:1 to about 8:1, about 18:1 to about 8:1, about 16:1 to about 8:1, about 14:1 to about 8:1, about 12:1 to about 8:1, about 10:1 to about 8:1, 20:1 to about 10:1, about 18:1 to about 10:1, about 16:1 to about 10:1, about 14:1 to about 10:1, or about 12:1 to about 10:1. In some embodiments, the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 20:1, about 18:1, about 16:1, about 14:1, about 12:1, about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, or about 1:1. In some embodiments, the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 12:1. In some embodiments, the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 6:1. In some embodiments, the reaction mixture comprises about 20 vol.% to about 80 vol.% ILE. For example, the reaction mixture comprises about 20 vol.% to about 80 vol.% ILE, 20 vol.% to about 70 vol.% ILE, 20 vol.% to about 60 vol.% ILE, 20 vol.% to about 50 vol.% ILE, 20 vol.% to about 40 vol.% ILE, 20 vol.% to about 30 vol.% ILE, 30 vol.% to about 80 vol.% ILE, 30 vol.% to about 70 vol.% ILE, 30 vol.% to about 60 vol.% ILE, 30 vol.% to about 50 - 21 - FoleyHoagUS12885817.4 TUV-18425 vol.% ILE, 30 vol.% to about 40 vol.% ILE, 40 vol.% to about 80 vol.% ILE, 40 vol.% to about 70 vol.% ILE, 40 vol.% to about 60 vol.% ILE, 40 vol.% to about 50 vol.% ILE, 50 vol.% to about 80 vol.% ILE, 50 vol.% to about 70 vol.% ILE, 50 vol.% to about 60 vol.% ILE, 60 vol.% to about 80 vol.% ILE, 60 vol.% to about 70 vol.% ILE, or 70 vol.% to about 80 vol.% ILE. For example, the reaction mixture comprises about 20 vol.%, about 30 vol.%, about 40 vol.%, about 50 vol.%, about 60 vol.%, about 70 vol.%, or about 80 vol.% ILE. In some embodiments, the reaction mixture comprises about 50 vol.% to about 60 vol.% ILE. In some embodiments, the period of time is about 1 hour to about 10 seconds. For example, the period of time is about 1 hour to about 10 seconds, about 50 minutes to about 10 seconds, about 40 minutes to about 10 seconds, about 30 minutes to about 10 seconds, about 25 minutes to about 10 seconds, about 20 minutes to about 10 seconds, about 15 minutes to about 10 seconds, about 10 minutes to about 10 seconds, about 9 minutes to about 10 seconds, about 8 minutes to about 10 seconds, about 6 minutes to about 10 seconds, about 5 minutes to about 10 seconds, about 4 minutes to about 10 seconds, about 3 minutes to about 10 seconds, about 2 minutes to about 10 seconds, about 1 minute to about 10 seconds, about 1 hour to about 10 seconds, about 50 minutes to about 30 seconds, about 40 minutes to about 30 seconds, about 30 minutes to about 30 seconds, about 25 minutes to about 30 seconds, about 20 minutes to about 30 seconds, about 15 minutes to about 30 seconds, about 10 minutes to about 30 seconds, about 9 minutes to about 30 seconds, about 8 minutes to about 30 seconds, about 6 minutes to about 30 seconds, about 5 minutes to about 30 seconds, about 4 minutes to about 30 seconds, about 3 minutes to about 30 seconds, about 2 minutes to about 30 seconds, about 1 minute to about 30 seconds, about 50 minutes to about 1 minute, about 40 minutes to about 1 minute, about 30 minutes to about 1 minute, about 25 minutes to about 1 minute, about 20 minutes to about 1 minute, about 15 minutes to about 1 minute, about 10 minutes to 1 minute, about 9 minutes to about 1 minute, about 8 minutes to about 1 minute, about 6 minutes to about 1 minute, about 5 minutes to about 1 minute, about 4 minutes to about 1 minute, about 3 minutes to about 1 minute, about 2 minutes to about 1 minute, about 50 minutes to about 2 minutes, about 40 minutes to about 2 minutes, about 30 minutes to about 2 minutes, about 25 minutes to about 2 minutes, about 20 minutes to about 2 minutes, about 15 minutes to about 2 minutes, about 10 minutes to 2 minutes, about 9 minutes to about 2 minutes, about 8 minutes to about 2 minutes, about 6 minutes to about 2 minutes, about 5 minutes to about 2 minutes, about 4 minutes to about - 22 - FoleyHoagUS12885817.4 TUV-18425 2 minutes, about 3 minutes to about 2 minutes, about 50 minutes to about 5 minutes, about 40 minutes to about 5 minutes, about 30 minutes to about 5 minutes, about 25 minutes to about 5 minutes, about 20 minutes to about 5 minutes, about 15 minutes to about 5 minutes, about 10 minutes to 5 minutes, about 9 minutes to about 5 minutes, about 8 minutes to about 5 minutes, or about 6 minutes to about 5 minutes. In some embodiments, the period of time is about 30 minutes to about 30 seconds. In some embodiments, the period of time is about 10 minutes to about 1 minute. In some embodiments, the period of time is about 1 hour, about 50 minutes, about 40, about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 9 minutes, about 8 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, about 1 minute, or about 30 seconds. For example, the period of time is about 5 minutes, about 2 minutes, or about 1 minute. Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps. The transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, - 23 - FoleyHoagUS12885817.4 TUV-18425 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive; any species linked by "or" also includes any mixture thereof. Unless specifically stated or obvious from context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural. Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about. As used herein, the term “zwitterion” refers to a molecule or part of a molecule comprising a cation and an anion within its structure. Zwitterions can be electrically neutral if the total cationic charge equals total anionic charge within the molecule. The total charge of a zwitterion can be pH dependent. For example, depending on the pKa values of the anionic functional groups in the zwitterion, the functional groups can exist in a neutral form at lower pH values and as anions at higher pH values. In some embodiments, the cationic functional groups in the zwitterion can exist in a neutral form at higher pH values and as cations at lower pH values. In some embodiments, the total charge of a zwitterion is not pH dependent. As used herein, the term “zwitterion-comprising alcohol” refers to an alcohol, i.e., a compound having one or more C-OH groups, comprising a zwitterion in its molecular structure. As used herein, a zwitterion-comprising alcohol does not have a silicon atom in its structure. As used herein “ionic liquid electrolyte” refers to salt (or a mixture of salts) having a melting point below 100 °C. As used herein, “aging the reaction mixture” refers to allowing the silica precursor in the reaction mixture to undergo conversion to silica gel, as indicated by the reaction mixture reaching a gel point. The gel point is determined by a tilt test, i.e. upon reaching the gel point the mixture does not flow when tilted. Aging the reaction mixture can involve, for example, agitating the reaction mixture, e.g., stirring or shaking, letting the reaction mixture be undisturbed, heating the reaction mixture, or cooling the reaction mixture, or a combination of one or more of these steps. - 24 - FoleyHoagUS12885817.4 TUV-18425 The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur. The term “alkyl” as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and (cycloalkyl)alkyl groups. In certain embodiments, a straight- chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a C1-C10 alkyl group, C1-C9 alkylgroup, C1-C8 alkyl group, C1-C8 alkyl group, C1-C6 alkyl group ̧C1-C5 alkyl group ̧C1-C4 alkylgroup ̧C1-C3 alkyl group, or C1-C2 alkyl group. In certain embodiments, the term “alkyl” refersto a C1-C6 alkyl group, for example a C1-C6 straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C12 branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C8branched-chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The term “cycloalkyl” means mono- or bicyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C3- C7)cycloalkyl, which represents a monocyclic saturated carbocyclic ring, having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2)w-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycloalkyl, a monocyclic heterocycloalkenyl, or a monocyclic heteroaryl. The bridged or - 25 - FoleyHoagUS12885817.4 TUV-18425 fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocycloalkyl, a 5 or 6 membered monocyclic heterocycloalkenyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted. The term “spirocycloalkyl” as used herein refers to a bicyclic cycloalkyl ring system in which the two rings are linked by a common atom, such as a quaternary carbon atom. The spirocycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the spirocycloalkyl ring system. Suitable spirocycloalkyl groups include, but are not limited to, spiro[2.2]pentane, spiro[3.3]heptane, spiro[4.4.]nonane, spiro[2.3]hexane, and spiro[3.4]octane. The term “cycloalkylene” as used herein refers to a divalent cycloalkyl group. In some embodiments, a cycloalkylene may be fused to an arylene or heteroarylene group; i.e., a cycloalkylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the cycloalkylene is saturated at all atoms except the atoms that are fused to the arylene group. The term “(cycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of cycloalkylalkyl is cyclohexylmethyl group. The term “cycloalkenyl” as used herein refers to a cycloalkyl group as defined above that additionally comprises at least one carbon-carbon double bond. In certain embodiments, the cycloalkenyl is a a mono- or bicyclic carbocyclic ring having at least one carbon-carbon double bond and containings from 3 to 12 carbon atoms. For avoidance of doubt, a cycloalkenyl group is not aromatic. The term “cycloalkynyl” as used herein refers to a cycloalkyl group as defined above that additionally comprises at least one carbon-carbon triple bond. In certain embodiments, the cycloalkynyl is a mono- or bicyclic carbocyclic ring having at least one carbon-carbon triple bond and containing from 3 to 12 carbon atoms. For avoidance of doubt, a cycloalkynyl group is not aromatic. - 26 - FoleyHoagUS12885817.4 TUV-18425 The term “cycloalkenylene” as used herein refers to a divalent cycloalkenyl group. In some embodiments, a cycloalkenylene may be fused to an arylene or heteroarylene group; i.e., a cycloalkenylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the cycloalkenylene comprises at least one saturated carbon atom and at least one carbon-carbon double bond in addition to the atoms that are fused to the arylene group. The term “heterocycloalkyl” as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, wherein for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, and 2- azobicyclo[3.1.0]hexane. A heterocycloalkyl group may be optionally substituted by one or more substituents as described below. The term “spiroheterocycloalkyl” as used herein refers to a bicyclic heterocycloalkyl ring system in which the two rings are linked by a common atom, such as a quaternary carbon atom. The spiroheterocycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the spiroheterocycloalkyl ring system. The term “heterocycloalkylene” as used herein refers to a divalent heterocycloalkyl group. In some embodiments, a heterocycloalkylene may be fused to an arylene or heteroarylene group; i.e., a heterocycloalkylene may be bonded at two adjacent positions to an arylene or - 27 - FoleyHoagUS12885817.4 TUV-18425 heteroarylene group. In such embodiments, the heterocycloalkylene is saturated at all atoms except the atoms that are fused to the arylene group. The term “(heterocycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups. The term “heterocycloalkenyl” as used herein refers to a heterocycloalkyl group, as defined above, that additionally comprises at least one carbon-carbon double bond. For avoidance of doubt, a heterocycloalkenyl group is not aromatic. The term “heterocycloalkynyl” as used herein refers to a heterocycloalkyl group, as defined above, that additionally comprises at least one carbon-carbon triple bond. For avoidance of doubt, a heterocycloalkynyl group is not aromatic. The term “heterocycloalkenylene” as used herein refers to a divalent heterocycloalkenyl group. In some embodiments, a heterocycloalkenylene may be fused to an arylene or heteroarylene group; i.e., a heterocycloalkenylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the heterocycloalkenylene comprises at least one carbon-carbon double bond in addition to the atoms that are fused to the arylene group. The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2- heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as those described below. That is, in one embodiment, a “substituted alkyl” is an “alkylene”. - 28 - FoleyHoagUS12885817.4 TUV-18425 The term “amino” is a term of art and as used herein refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: , wherein Ra, Rb, and Rceach -(CH2)x-Rd, -C(O)-alkyl, - C(O)-alkenyl, where the alkyl or may substituted, or optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl,, or Raand Rb, taken together with the N atom to which they are attached form a heterocycle having from 4 to 8 atoms in the ring structure, which may be optionally substituted; Rdrepresents optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain embodiments, only one of Ra or Rb comprises a carbonyl adjacent to the N atom, e.g., Ra, Rb, and the nitrogen together do not form an imide. In other embodiments, Raand Rb(and optionally Rc) each independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or -(CH2)x-Rd. In certain embodiments, the term “amino” refers to –NH2. In certain embodiments, the term “alkylamino” refers to -NH(alkyl). In certain embodiments, the term “dialkylamino” refers to -N(alkyl)2. The term “amido”, as used herein, means -NHC(=O)-, wherein the amido group is bound to the parent molecular moiety through the nitrogen. Examples of amido include alkylamido such as CH3C(=O)N(H)- and CH3CH2C(=O)N(H)-. The term “acyl” is a term of art and as used herein refers to any group or radical of the form RC(O)- where R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl. The term “aminoalkyl” as used herein refers to an alkyl group substituted with one or more one amino groups. In one embodiment, the term “aminoalkyl” refers to an aminomethyl group, i.e., -CH2NH2. The term “aminoacyl” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups. - 29 - FoleyHoagUS12885817.4 TUV-18425 The term “aminothionyl” is a term of art and as used herein refers to any group or radical of the form RC(S)-, wherein R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. The term “aminophosphoryl” as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(O)(OH)NMe2. The term “azide” or “azido”, as used herein, means an –N3 group. The term “carbonyl” as used herein refers to -C(=O)-. The term “thiocarbonyl” as used herein refers to -C(=S)-. The term “alkylphosphoryl” as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O)(OH)Me. The term “alkylthio” as used herein refers to alkyl-S-. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group. The term “carboxy”, as used herein, means a -CO2H group. The term “aryl” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group comprises from 6-10 carbon ring atoms (i.e., (C6-C10)aryl). The aromatic ring may be optionally substituted at one or more ring positions with one or more substituents as described below. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, heterocycloalkyls, heterocycloalkenyls, and / or heterocycloalkynyls. In certain embodiments, the term “aryl” refers to a phenyl group. The term “arylene” as used herein pertains to a diradical obtained by removing two hydrogen atoms of an aryl group, as defined above. Arylene includes, without limitation, 1,2- phenylene, 1,3-phenylene, and 1,4-phenylene, as depicted below: . Arylene groups may be ring positions with one or more substituents, valency permitting, such as the exemplary substituents described below. To - 30 - FoleyHoagUS12885817.4 TUV-18425 provide an exemplary illustration: in certain embodiments of Formula (I), ring may be arylene, e.g., phenylene. In certain such embodiments, the phenylene is ring at two and only two adjacent positions, and the ring phenylene is additionally to –J- and additionally any present occurrences of RB. The arylene at ring could therefore be represented as . The term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, 1,3-dihydro-2H-imidazol-2-one, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The “heteroaryl” may be optionally substituted at one or more ring positions with one or more substituents as described below. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, heterocycloalkyls, heterocycloalkenyls, and / or heterocycloalkynyls. The term “heteroarylene” as used herein pertains to a diradical obtained by removing two hydrogen atoms of a heteroaryl group, as defined above. Heteroarylene includes, without limitation, the divalent heteroarylene groups depicted below: - 31 - FoleyHoagUS12885817.4 TUV-18425 . Heterorylene groups may be ring positions with one or more substituents, valency permitting, such as the exemplary substituents described below. The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group. The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein, wherein the moiety is appended to the parent molecular moiety through the alkyl group. The term “alkoxy” as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, wherein some or all of the hydrogens of the alkyl group are replaced with halogen atoms, as defined herein. Representative examples of haloalkoxy include, but are not limited to, -OCF3. The term “alkoxyalkyl” as used herein refers to an alkyl group, as defined herein, substituted by an alkoxy group as defined herein. The term “alkoxycarbonyl” as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term “alkylcarbonyl”, as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by –C(=O)–, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term “arylcarbonyl”, as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by –C(=O)–, as - 32 - FoleyHoagUS12885817.4 TUV-18425 defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl. The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy. The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propen-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-). The term “aryloxy” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term “carbocyclyl” as used herein means a monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1- cyclohexenyl and 2-cyclopentenylmethyl. The term “cyano” is a term of art and as used herein refers to –CN. The term “halo” is a term of art and as used herein refers to –F, –Cl, –Br, or –I. The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms, as defined herein. Representative examples of haloalkyl include, but are not limited to, trifluoromethyl and fluoroethyl. The term “hydroxy” is a term of art and as used herein refers to –OH. The term “hydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl. - 33 - FoleyHoagUS12885817.4 TUV-18425 Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule comprises a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction. The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. In certain embodiments, the optional substituents contemplated in this invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, - 34 - FoleyHoagUS12885817.4 TUV-18425 cycloalkenyl, cycloalkynyl, (cycloalkyl)alkyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, (heterocycloalkyl)alkyl, hydroxyl, alkoxy, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, carboxylalkyl (e.g., - alkylene-(COOH)), silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl (e.g., -S(O)2alkyl), sulfonamido, Boc (-C(O)-O-C(CH3)3), ketone (e.g., -CO(alkyl)), aldehyde (-C(O)H), ester (e.g., - COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano. As used herein, the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieities that follow are each substituted or unsubstituted. For example, “substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” or “optionally substituted aryl, heteroaryl, and cycloalkyl” means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl. EXAMPLES Materials The ionic liquid, 1-butyl-1-methylpyrrolidinium bis-(trifluoromethylsulfonyl)imide (BMP TFSI, 99%) was purchased from IoLiTech. The lithium salt, lithium bis(trifluoromethylsulfonyl)-imide (LiTFSI, 99.95%), was purchased from Sigma-Aldrich. L-α- glycerophosphorylcholine (GPC, 98%) was purchased from Nootropics Depot. L-carnitine (98%) was purchased from Ambeed. All of these materials were used as received and stored under nitrogen atmosphere inside a glovebox (O2and H2O < 0.1 ppm), with appropriate quantities of each transferred by sealed vials into a chemical fume hood at the time of use. The acid catalyst, formic acid (FA, 88%), silica precursor, tetraethyl orthosilicate (TEOS, 98%), and denatured ethanol (95%), were purchased from Fisher Scientific and used as received. The methanol (99.8%) was purchased from ThermoFisher scientific and used as received. Example 1: Synthesis of silica gels in the presence of ILE The porous silica materials were synthesized using the following ILE: lithium bis(trifluoromethylsulfonyl)imide (LiTFSI, 99.95%) dissolved at a concentration of 1 M in the ionic liquid 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (BMP TFSI, 99%). Each reaction sample contained approximately 0.25 mL of the ILE, to which desired quantities - 35 - FoleyHoagUS12885817.4 TUV-18425 of TEOS (98%) and formic acid (FA, 88 wt. % in H2O) were added such that the ILE represented 50% or 60% of the total reaction mixture by volume (v / v). The molar ratio of FA to TEOS was fixed at 12:1. FA was added to the ILE first, and then TEOS was added to ensure a well-mixed solution prior to reaction, and the final mixture was vortexed and left to rest until a gel point was reached. The gel point was determined by a tilt test, i.e. if the mixture did not flow when tilted, it was considered to have reached the gel point; the sample was subsequently left to finish reacting and dry inside a chemical fume hood. For the samples prepared with alpha-GPC, alpha-GPC was dissolved in the ILE prior to the addition of FA and TEOS. Example 2: Synthesis of silica gels without ILE Silica materials were also synthesized without an ILE. Each reaction sample contained 0.26 mL of FA and 0.115 mL of TEOS, such that the molar ratio of FA to TEOS remained fixed at 12:1. For some samples, 13 mg of alpha-GPC was added to the reaction vessel prior to the addition of FA, and TEOS was added to the sample last, such that the molar ratio of TEOS to alpha-GPC was 10:1. The observed acceleration in the reaction (via gel point time) for representative control samples (synthesized without alpha-GPC) and samples synthesized with alpha-GPC are shown in Table 5. Table 5. Gel Point Measurements of Silica Gel Samples. Sample Observed Gel Point Time Example 3: Characterization of silica gel samples TGA Analysis - 36 - FoleyHoagUS12885817.4 TUV-18425 In order to compare the final silica content of the gels prepared both with and without alpha-GPC, thermogravimetric analysis (TGA) was used to remove the nonvolatile ILE by decomposing it at high temperatures, and measuring the amount of the remaining silica. Samples were placed on a platinum pan and the temperature was ramped at 20 °C / min to 100 °C and held for 15 minutes, then ramped at 20 °C / min to 1000 °C and held for another 15 minutes. The TGA traces in FIG.1 show that there was no significant difference in silica content between gels made with and without alpha-GPC (approximately 6 wt.% silica remaining), indicating that the increased reaction rate in the presence of alpha-GPC did not affect the silica yield. EDS Analysis Evidence that PC functional groups from alpha-GPC were covalently attached to the porous silica surface for samples prepared with alpha-GPC present was obtained via energy dispersive X-ray spectroscopy (EDS). Samples containing either 50% v / v ILE or no porogen, as well as without or with alpha-GPC in the reaction mixture were prepared as described in Examples 1 and 2. After the reaction was completed, samples were extensively washed with ethanol and water to remove any residual reaction byproducts, the ILE porogen, and / or unbound alpha-GPC molecules. Samples were dried under nitrogen for 2 hours, and then further dried under vacuum overnight before they were sputter coated with a thin layer (<10 nm) of elemental gold, and placed into a scanning electron microscope (SEM) for visualization and EDS characterization. The EDS data presented in FIGs.2-5 reveal notable phosphorous counts for the surfaces of silica gels prepared with alpha-GPC present (FIGs.3 and 5), and zero phosphorous counts for control samples prepared without alpha-GPC (FIGs.2 and 4). Since alpha-GPC is the only reactant possessing a phosphorous atom, these data demonstrate the attachment of PC functional groups to the silica surface, indicating that alpha-GPC is participating in the sol-gel reaction process with the hydrolyzed silica precursors. Sample morphology Qualitative differences were observed between the samples prepared with alpha-GPC and control samples prepared without it. FIG.6 shows a photograph of two gels that do not contain any ILE porogen. The control gel prepared without alpha-GPC exhibits a transparent, glass-like - 37 - FoleyHoagUS12885817.4 TUV-18425 appearance (left vial), while the gel prepared with alpha-GPC is visually opaque (right vial). There are also qualitative differences observed in the porous silica microstructures, as revealed by SEM analysis. FIGs.7-10 show surfaces of samples prepared with and without ILE porogen, as well as with and without alpha-GPC. When alpha-GPC is included in the sol-gel reaction (FIGs.8 and 10), there are noticeable surface morphology changes between the silica gels prepared without ILE (i.e. a visibly rougher surface is obtained when alpha-GPC is included), and clear primary silica particle size differences observed between the gels prepared with ILE (approximate particle diameters of 160-200 nm without alpha-GPC and 70-160 nm when alpha- GPC is included). Example 4. Preparation of Ionic Liquid Electrolyte To prepare the ionic liquid electrolyte (ILE), 2.87 g of LiTFSI and 14 g of BMP TFSI were added to a vial and vigorously stirred at 80 °C for 4 h under nitrogen atmosphere inside a glovebox. The resulting lithium concentration in the ILE was approximately 1M. Example 5. Preparation of Xerogels Xerogels were prepared by first adding the appropriate amount of alpha-GPC to a 1-dram glass vial. Next, 260 μL of FA and 115 μL of TEOS were added to the vial, and the mixture was briefly vortexed to dissolve the GPC and combine all reagents. Mixtures were left to react in the vial (uncapped) inside a chemical fume hood for 24 h. Next, samples were dried in a vacuum chamber at room temperature for at least 24 h, then aged under vacuum at 120 °C for 4 h. All resulting xerogels were stored inside of a vacuum chamber at room temperature prior to characterization. Example 6. Preparation of Ionogels Ionogels were prepared by adding the appropriate amount of alpha-GPC to a 1-dram glass vial along with a stir bar. Next, an appropriate amount of ILE was added to the vial, and the mixture was stirred at 80 °C for 1 h or until the mixture was visibly clear. It should be noted that an ILE consisting of 1 M LiTFSI in BMP TFSI was chosen as the porogen in part because alpha- GPC is poorly soluble in neat BMP TFSI. The alpha-GPC content in ILE was varied to achieve targeted alpha-GPC:TEOS molar ratios of 1:5, 1:10, 1:20, and 0 (control). Each sample contained 250 μL of the alpha-GPC in ILE mixture, to which 173 μL of FA and 77 μL of TEOS - 38 - FoleyHoagUS12885817.4 TUV-18425 were added, and then vials were vortexed and left uncapped inside a fume hood for 24 h. Samples were dried under vacuum at room temperature for at least 24 h, followed by aging at 120 °C for 4 h under vacuum. All resulting ionogels were stored inside of a vacuum chamber at room temperature prior to characterization. Example 7. Characterization Methods For all gels, those prepared with or without ILE porogen, the gelation time was determined using a simple vial tilt test. The first tilt test was performed 5 min after mixing all reagents together, then at 15 and 30 min after mixing, and any subsequent tilt tests were performed at 30 min intervals. Thermal characterization was performed using thermogravimetric analysis (TGA) using a TGA Q500 (TA Instruments). TGA traces followed the procedure of a 10 °C / min ramp to 100 °C, then a 15 min isothermal hold at 100 °C, then a 20 °C / min ramp to 1000 °C. Scanning electron microscopy (SEM) with energy dispersive X-ray spectroscopy (EDS) was performed with Zeiss Sigma 300 SEM at three locations for each of the eight samples prepared. ImageJ software was used to adjust contrast levels in the micrographs. Prior to SEM characterization, gels were first immersed in deionized water for 2 h. The water was removed, and the gels were then immersed in denatured ethanol for 2 h. The ethanol was then removed, and gels were dried for 2 h under flowing nitrogen, followed by drying overnight under vacuum at room temperature. Finally, samples were mounted onto aluminum stubs using carbon tape, then sputter coated with carbon (21 nm thick layer for ionogel silica powder, 6 nm thick layer for xerogel fragments) to reduce charge buildup on the silica surfaces. EDS elemental signals for carbon were therefore ignored. Infrared spectroscopy characterization was performed with a PerkinElmer Spectrum 1000 with Spectrum software Fourier-transform infrared (FTIR) spectrometer, equipped with an attenuated total reflectance (ATR) apparatus. Prior to FTIR characterization, gels were first immersed in deionized water for 2 h. The water was removed, and gels were then immersed in denatured ethanol for 2 h. The ethanol was then removed, and gels were then immersed in methanol for 2 h. The methanol was then removed, and gels were dried overnight under vacuum at room temperature. Rheological tests were conducted with an HR10 rheometer (TA Instruments), utilizing a CP40–2 cone–plate configuration (diameter: 40 mm, angle: 2°). For each rheological measurement, approximately 750 μL of ionogel was loaded onto the plate, and slowly compressed to a 50 mm gap, while applying a 1 s–1shear rate to allow - 39 - FoleyHoagUS12885817.4 TUV-18425 uniform application of the gel. A 1 s–1shear rate was maintained for 1 min, then no shear was applied for 2 min to allow the sample to rest prior to the experiment. Varying shear rate sweeps were performed from 0.1–1000 s–1. Ionic conductivity values were measured via electrochemical impedance spectroscopy (EIS). For EIS measurements, approximately 25 μL of electrolyte was sandwiched between indium tin oxide (ITO)-coated glass electrodes using a 1 mm thick PTFE spacer (11 mm outer diameter, 5 mm inner diameter). Impedance spectra were collected using a frequency response analyzer (VersaSTAT 3, Princeton Applied Research) with a 10 mV voltage amplitude over the range of 10 Hz - 500 kHz. Ionic conductivity values were calculated using the high frequency plateau of real impedance value (Z’) as t / (Z’A), where t is the spacing between electrodes (0.1 cm) and A is the electrolyte-filled spacer cross-sectional area (0.2 cm2). Example 8. Synthesis of xerogel and ionogel in the presence of L-carnitine. Xerogels were prepared by first adding the appropriate amount of L-carnitine to a 1-dram glass vial. Next, 260 μL of FA and 115 μL of TEOS were added to the vial, and the mixture was briefly vortexed to dissolve the L-carnitine and combine all reagents. Mixtures were left to react in the vial (uncapped) inside a chemical fume hood for 24 h. Samples were dried under vacuum at room temperature for at least 24 h. Optionally, samples can be aged at 120 °C for 4 h under vacuum. All resulting xerogels were stored inside of a vacuum chamber at room temperature prior to characterization. Ionogels were prepared by adding the appropriate amount of L-carnitine to a 1-dram glass vial along with a stir bar. Next, an appropriate amount of ILE was added to the vial, and the mixture was stirred at 20 °C for 1 h or until the mixture was visibly clear. The L-carnitine content in ILE was chosen to achieve targeted L-carnitine:TEOS molar ratio of 1:10. Each sample contained 250 μL of the L-carnitine in ILE mixture, to which 173 μL of FA and 77 μL of TEOS were added, and then vials were vortexed and left uncapped inside a fume hood for 24 h. Samples were dried under vacuum at room temperature for at least 24 h. Optionally, samples can be aged at 120 °C for 4 h under vacuum. All resulting ionogels were stored inside of a vacuum chamber at room temperature prior to characterization. - 40 - FoleyHoagUS12885817.4 TUV-18425 Example 9. Synthesis of silica gels in the presence of alpha-GPC and a base catalyst. The following general procedure for generating silica particles was used with the amounts of reagents shown in Table 6 below. In a vial an appropriate amount of GPC was measured. Then, required volumes of ethanol, ammonia solution in water, and additional water as needed were added and mixed well. Once these reactants were well-mixed and all of the GPC was fully dissolved, an appropriate amount of tetraethyl orthosilicate (TEOS) was added and mixed at 400 rpm for 24 hours. In the cases where no GPC was added (control samples 1A and 2A) the amounts of all other ingredients were unchanged. Table 6. Ratios of reagents in the base-catalyzed syntheses of silica gels. Sample 1A Amount In reaction mixture Molar ratio with TEOS Ethanol (95%) 3.00 mL 32.8:1 (EtOH:TEOS) Particle size measurements collected using dynamic light scattering (DLS) indicate that silica particles Sample 1A and Sample 2A (i.e. two different ‘control’ recipes, neither containing - 41 - FoleyHoagUS12885817.4 TUV-18425 GPC) exhibited hydrodynamic radii of 155 nm and 239 nm, respectively. For Sample 1B (prepared with GPC), DLS could not determine the radius of the silica formed (too small to measure). Furthermore, for Sample 2B (also prepared with GPC), DLS indicated a hydrodynamic radius of 76 nm, which was around 32% that of Sample 2A. This effect can also be seen visually at the macroscopic level in FIGs.19 and 20, indicating a significant change in silica dispersion turbidity when GPC is included in the reaction mixture. Scanning electron microscopy (SEM) was utilized to visualize Samples 1A and 2A, shown in FIG.21, and these images corroborate the particle sizes measured with DLS. However, the silica in samples prepared with GPC (Samples 1B and 2B) did not sediment effectively and retained too much liquid to be effectively imaged. INCORPORATION BY REFERENCE All US and PCT patent application publications and US patents mentioned herein are hereby incorporated by reference in their entirety as if each individual patent application publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. - 42 - FoleyHoagUS12885817.4

Claims

TUV-18425 CLAIMS We claim:

1. A method of making surface-modified silica particles, comprising: a) combining a silica precursor, a catalyst, a zwitterion-comprising alcohol, and, optionally, an ionic liquid electrolyte (ILE), thereby producing a reaction mixture; b) aging the reaction mixture for a period of time, thereby producing a gelled mixture; c) drying the gelled mixture, thereby producing the surface-modified silica particles.

2. The method of claim 1, wherein the silica precursor comprises a silicon alkoxide, a silane, a polysilicate, or Si(OH)4.

3. The method of claim 1, wherein the silica precursor comprises tetraethoxysilane (TEOS), tetramethoxysilane (TMOS), tetra-n-propoxy silane (TPOS), methyltrimethoxysilane (MTMS), 1,2-bis(triethoxysilyl)ethane, 1,4-bis-(triethoxysilyl)benzene, or a combination thereof.

4. The method of claim 1, wherein the silica precursor is TEOS.

5. The method of any one of claims 1-4, wherein the catalyst comprises an acid.

6. The method of claim 5, wherein the acid is selected from the group consisting of formic acid, acetic acid, citric acid, oxalic acid, HCl, HNO3, H2SO4, H3PO4, and HBF4.

7. The method of claim 5, wherein the acid is formic acid.

8. The method of any one of claims 1-4, wherein the catalyst comprises a base.

9. The method of claim 8, wherein the base is selected from the group consisting of NH4OH, LiOH, NaOH, KOH, Na(OC(O)CH3), NaHCO3, NaHSO4, NaH2PO4, and Na2HPO4.

10. The method of claim 8, wherein the base is NH4OH. - 43 - FoleyHoagUS12885817.4TUV-18425 11. The method of any one of claims 1-10, wherein the reaction mixture comprises the ILE.

12. The method of claim 11, wherein the ILE comprises an ionic liquid.

13. The method of claim 11, wherein the ionic liquid comprises a cation selected from the group consisting of N,N’-dialkylimidazolium, N,N- dialkylpyrrolidinium, alkylammonium, alkylphosphonium, and N-alkylpyridinium; and an anion selected from the group consisting of hexafluorophosphate, tetrafluoroborate, tetracyanoborate, tris((trifluoromethyl)sulfonyl)methide, trifluoroacetate, trifluoromethanesulfonate, bis((trifluoromethyl)sulfonyl)imide, bis(fluorosulfonyl)imide, thiocyanate, tosylate, nitrate, and tris(pentafluoroethyl)trifluorophosphate.

14. The method of claim 12, wherein the ionic liquid is selected from the group consisting of 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-2,3,4,5- tetramethylimidazolium bromide, 1-butyl-2,3,4,5-tetramethylimidazolium bis(trifluoromethylsulfonyl)imide, 1-butyl-4-methylpyridinium bis- (trifluoromethylsulfonyl)imide, 1-butylpyridinium bis(trifluoromethylsulfonyl)imide, 1-butyl-3- methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, and 1- butyl-3-methylimidazolium acetate.

15. The method of claim 13, wherein the ionic liquid is 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide.

16. The method of any one of claims 11-14, wherein the ILE further comprises a salt.

17. The method of claim 16, wherein the salt comprises a cation selected from lithium cation and sodium cation; and an anion selected from the group consisting of hexafluorophosphate, tetrafluoroborate, tetracyanoborate, tris((trifluoromethyl)sulfonyl)methide, trifluoroacetate, - 44 - FoleyHoagUS12885817.4TUV-18425 trifluoromethanesulfonate, bis((trifluoromethyl)sulfonyl)imide, bis(fluorosulfonyl)imide, thiocyanate, tosylate, nitrate, and tris(pentafluoroethyl)trifluorophosphate.

18. The method of claim 16, wherein the salt is lithium bis(trifluoromethylsulfonyl)imide.

19. The method of any one of claims 1-18, wherein the zwitterion-comprising alcohol comprises a zwitterion-comprising moiety.

20. The method of claim 19, wherein the zwitterion-comprising alcohol is a zwitterion- comprising polyol.

21. The method of claim 20, wherein the zwitterion-comprising alcohol is a zwitterion- comprising diol.

22. The method of any one of claims 19-21, wherein the zwitterion-comprising alcohol is represented by the following structural formula: , wherein Z is the zwitterion-comprising23. The method of any one of claims 19-22, wherein the zwitterion-comprising moiety comprises an anionic moiety and a cationic moiety, and wherein: the cationic moiety is represented by one of the following structural formulas: ,an alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, (cycloalkyl)alkyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, and (heterocycloalkyl)alkyl, and - 45 - FoleyHoagUS12885817.4TUV-18425 the anionic moiety is represented by one of the following structural formulas: .

24. cationic moiety is represented by the followingstructural .

25. The method of claim 24, wherein each of Ra, Rb, and Rcis independently C1-3alkyl.

26. The method of claim 25, wherein each of Ra, Rb, and Rcis methyl.

27. The method of any one of claims 23-26, wherein the anionic moiety is represented by the following structural .

28. The method of any one of claims 19-27, wherein the zwitterion-comprising moiety is represented by the following structural formula: .

29. The method of any one of claims 1-28, wherein the zwitterion-comprising alcohol is represented by the following structural formula: - 46 - FoleyHoagUS12885817.4TUV-18425 .

30. The method of any one of claims 1-29, wherein the surface-modified silica particles comprise about 0.1 wt% to about 10 wt% phosphorus.

31. The method of claim 30, wherein the surface-modified silica particles comprise about 1 wt% to about 5 wt% phosphorus.

32. The method of any one of claims 23-26, wherein the anionic moiety is represented by the following structural formula: .

33. The method of any one of claims 18-26, wherein the zwitterion-comprising moiety is represented by the following structural formula: .

34. The method of any one of claims 1-26, wherein the zwitterion-comprising alcohol is represented by the following structural formula: .

35. The method of any one ofcombining the silica precursor, the catalyst, and the zwitterion-comprising alcohol comprises: i) combining the catalyst and the zwitterion-comprising alcohol, thereby producing a first mixture; and ii) adding the silica precursor to the first mixture, thereby producing the reaction mixture. - 47 - FoleyHoagUS12885817.4TUV-18425 36. The method of any one of claims 1-34, wherein combining the silica precursor, the catalyst, the zwitterion-comprising alcohol, and the ILE comprises: i) dissolving the zwitterion-containing alcohol in the ILE, thereby producing a second mixture; ii) adding the catalyst to the second mixture, thereby producing a third mixture; and iii) adding the silica precursor to the third mixture, thereby producing the reaction mixture.

37. The method of any one of claims 1-36, wherein the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 20:1 to about 1:

1.

38. The method of claim 37, wherein the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 10:

1.

39. The method of claim 37, wherein the reaction mixture comprises the silica precursor and the zwitterion-containing alcohol in a molar ratio of about 5:

1.

40. The method of any one of claims 1-39, wherein the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 20:1 to about 1:

1.

41. The method of claim 40, wherein the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 12:

1.

42. The method of claim 40, wherein the reaction mixture comprises the catalyst and the silica precursor in a molar ratio of about 6:

1.

43. The method of any one of claims 1-42, wherein the reaction mixture comprises about 20 vol.% to about 80 vol.% ILE.

44. The method of claim 43, wherein the reaction mixture comprises about 50 vol.% to about 60 vol.% ILE. - 48 - FoleyHoagUS12885817.4TUV-18425 45. The method of any one of claims 1-44, wherein the period of time is about 1 hour to about 10 seconds.

46. The method of claim 45, wherein the period of time is about 30 minutes to about 30 seconds.

47. The method of claim 45, wherein the period of time is about 10 minutes to about 1 minute. - 49 - FoleyHoagUS12885817.4

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