Patent Application
20230390751
The present disclosure concerns catalytic systems for stereo-selective enrichment, more specifically enantio-selective templated catalytic units that are used for selective enrichment of stereoisomers, in particular enantiomers, in a mixture.
References considered to be relevant as background to the presently disclosed subject matter are listed below:
Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.
Chirality is an unusual aspect of chemistry, a seemingly minor detail with surprisingly far-reaching consequences in physical, chemical, and biological systems. Despite their great similarity, oppositely handed enantiomers of pharmaceutical compounds are known to exhibit wildly different interactions with biological systems, which are themselves inherently chiral. Proteins and peptides are typically chiral structures, encoded in chiral DNA strands that are responsible for their biosynthesis. This gives rise to highly spatially selective interactions between these constructs and molecular substrates, as notoriously demonstrated by the thalidomide catastrophe. This drug, prescribed to pregnant women throughout the 1950s, exhibits strong antiemetic and sedative properties for its (+) enantiomer, while its (−) enantiomer has significant teratogenic effects, which culminated in tens of thousands of children being born with birth defects due to prenatal exposure.
Approximately 50% of drugs on the market today contain at least one chiral center. Many of these compounds exhibit pharmacological asymmetry, having one pharmaceutically useful enantiomer (known as a eutomer) and one or more enantiomers that are nonbeneficial or possibly harmful (distomers). Despite the documented pharmacological asymmetry, some of these compounds are still sold as racemates, even as research shows significant benefits of enantiopure formulations. Chiral compounds are also of importance in other fields, such as agriculture and optics.
To some extent, spontaneous racemization of the active compounds in drugs (i.e. spontaneous transformation of a relatively pure enantiomeric sample to a racemic mixture) is responsible for shortening their shelf-life. Most chemical processes produce both types of enantiomers (a racemic mixture). The various types of enantiomers have the same physical properties, making their separation very difficult and costly.
The challenge is, thus, obtaining chirally pure compounds, as both enantiomers respond to most chemical and physical separation processes identically. This is often obtained by either separation of racemic or scalemic mixtures of enantiomers, or, alternatively, by directly synthesizing the desired enantiomers using asymmetric synthesis methods.
Asymmetric synthesis (i.e. synthesis conditions that are tailored to predominantly produce a selected enantiomer), although highly efficient in terms of feedstock, requires the tailoring of complex, multistep, stereoselective reactions. These can be relatively expensive and may also require additional purification steps to reach sufficient optical purity.
Separation methods, based on the spatial differences between the enantiomers, successive recrystallization, and/or use of enantio-specific absorbing grafted polymers, require extensive development and optimization: namely, selecting an appropriate separation technique for a specific compound and optimizing its parameters, such as elution order and resolution or crystallization phase. As a general rule, the optimized parameters are hard to predict.
Another way to obtain enantiomeric separation is chiral molecular imprinting, i.e. the inclusion of an enantiomerically pure template into a separating matrix to achieve chiral recognition. Chiral imprinting in organic polymers was proposed as an alternative approach to the common chiral chromatography columns, as well as to retention-based separation techniques (e.g. membrane-based techniques). Nevertheless, imprinted polymers tend to lack structural stability, especially at elevated temperatures, significantly limiting their application in industry.
Imprinted oxides have been shown to induce spatial resolution for adsorptive, catalytic and electronic applications [1,2]. A third group of processes, which can be employed either pre- or post-synthesis, is called kinetic resolution. This group includes many different reactions which selectively favor one enantiomer over the other, for either the production of the target molecule or its further reaction into easily separable products [3,4].
The use of photocatalysts, especially anatase-phase titanium dioxide, for the degradation of organic compounds has been documented, particularly in environmental sciences and water treatment technologies. It relies on the light-dependent generation of electron-hole pairs that participate in complex redox reactions, usually mediated via radical species. Molecular imprinting in photocatalytic matrices has been shown to induce selectivity for the degradation of specific species over homologous alternatives, but alas, to date, no chiral-selectivity applications have been shown to be successful [5-6]. It has been shown that coating with ultrathin layers may have an effect on the properties of photocatalysts by altering the number of carriers arriving at the surface as well as by controlling the adsorption of reactants and the desorption of products [7-9].
Current solutions to obtain desired and specific types of enantiomers are expensive, time consuming, have poor throughput, and are not generic, hence require developing new methods and specific sets of conditions for each compound insentiently of similar methods developed for another compound. In many cases the market price of each separated enantiomer is more than 10-20 times higher than the price per mass of the racemic mixture. Therefore, there is a need for methods and catalytic systems that enable effective separation of a favorite enantiomer from a racemic mixture in a cost effective and simple manner.
The present disclosure provides kinetic resolution methods and catalytic systems for obtaining enantiomeric enrichment in a mixture of stereoisomers, in particular mixtures of. The catalytic systems and kinetic resolution methods described herein are based on imprinting a surface of a photocatalyst to form chirally pure templates and minimizing or preventing adsorption of the enantiomers onto a non-templated surface of the photocatalyst. In other words, the catalytic system disclosed herein is based on forming chiral-specific active molecular sites onto the surface of the catalyst that are tailored to interact with a specific enantiomer, while preventing interaction in other areas of the catalyst's surface. While the templating (to be interchangeably also referred to herein as imprinting) is carried out by utilizing the specific enantiomer to be eliminated from the mixture, the catalytic systems and methods of this disclosure are generic in the sense that these are not limited by the specific compound or enantiomer as the templating molecule, and the systems and methods can be easily modified and implemented on any desired enantiomer.
Thus, by one of its aspects, the present disclosure provides a photocatalytic unit for increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a mixture comprising said first and second stereoisomers. The photocatalytic unit has a photocatalytic substrate comprising at least one photocatalyst, and at least one non-photocatalytic coating layer substantially coating said photocatalytic substrate, and a plurality of spaced-apart open molecular cavities defined at an external surface of the photocatalytic unit, the cavities being sized and shaped to correspond to a size and shape of said second stereoisomer, each of the cavities having at least a base portion thereof constituted by said photocatalytic substrate.
The term stereoisomer as used herein is meant to encompass an isomer that possess identical constitution as a corresponding stereoisomer, but which differs in the spatial arrangement of its atoms from the corresponding stereoisomer. In other words, two stereoisomers have the same molecular formula and sequence of bonded atoms, however differing one from the other in the spatial orientations of their atoms. Thus, while stereoisomers are identical to one another in their constitution, stereoisomers typically differ one from the other by their size and shape. By some embodiments, the stereoisomers may be enantiomers, diastereomers and/or cis-trans (E/Z) isomers.
According to some embodiments, the first and second stereoisomers are first and second enantiomers, respectively, of the compound.
Enantiomers are stereoisomers molecules having at least one chiral center, and which are non-superimposable mirror-images of one another.
The mixture of stereoisomers (e.g. a mixture of enantiomers) can, by some embodiments, comprise said at least one first stereoisomer and at least one second stereoisomer at any ratio, e.g. a racemic mixture, a non-racemic mixture, a mixture of more than two stereoisomers, etc.
In the photocatalytic unit of this disclosure, plurality of molecular cavities are defined at an external surface of the unit, and are sized and shaped to correspond to a size and shape of the second (undesired) stereoisomer. As stereoisomers (e.g. enantiomers) typically differ from each other in their size and shape, such that appropriately sized and shaped cavities permit for selective absorption of the second (undesired) stereoisomer into the cavity, while the first (desired) stereoisomer is prevented from such absorption and left in the mixture. Hence, the cavities permit both size and shape inclusion, resulting in effective separation between the first and second stereoisomers.
The cavities are voids formed at the external surface of the unit, and are open ended (i.e. open cavities), as to permit access of the second stereoisomer thereinto. Each cavity has a base, at least a portion thereof being constituted by the photocatalytic substrate. Thus, once a second stereoisomer (e.g. enantiomer) is adsorbed into the cavity, due to the matching of size and shape, it is forced to come into contact with the photocatalytic substrate to permit its decomposition, as will be described hereinbelow.
Each of the cavities has sidewalls that extend from the base portion of the cavity towards an opening of the cavity (i.e. towards the open end of the cavity), and together with the base, form a 3-dimensional void in the shape and size of the second stereoisomer. Thus, the cavities are typically in the shape and size of a single molecule of the second stereoisomer, the molecule being, by some embodiments, an enantiomer.
According to some embodiments, the sidewalls have a bottom portion formed in said photocatalytic substrate and a top portion formed in said non-photocatalytic coating layer. In such an arrangement, the base of the cavity and a bottom portion of its sidewalls are constituted by the photocatalytic substrate, effectively resulting in larger available surface for contacting the molecule of the second stereoisomer adsorbed into the cavity.
According to other embodiments, the sidewalls are substantially defined within said non-photocatalytic coating layer. In other words, in this embodiment, the base of the cavity is constituted by the photocatalytic substrate while the walls of the cavity are constituted by the non-photocatalytic coating.
By some embodiments, the photocatalytic unit comprises two or more types of cavities, each shaped and sized to adsorb and capture a different molecular entity.
In some embodiments, at least a portion of a surface of the cavity is associated with one or more binding increasing moieties. Such binding increasing moieties can, for example, be complexation moieties, and can function to increase or promote adsorption of the second stereoisomer, thereby capturing it within the cavity.
By some embodiments, the cavities are configured for adsorbing and degrading molecules containing one or more organometallic bonds, organic enantiomers, enantiomers of long polymeric chains, enantiomers of peptides or proteins (in a folded, misfolded or unfolded states), or of enantiomers of molecules based on an element other than carbon, such as phosphorus or silicon.
According to other embodiments, the cavities are configured for adsorbing and degrading of at least one alcohol, ether, ester, ketone, aldehyde, hydroxylic acid, aromatic rings, amine, amide, sulfide, disulfide, thiol, sulfenic acid, sulfinic acid, sulfonic acid, sulfonate ester, halide, siloxane, silanol, siloxide, silyl, silene, silole, phosphate, phosphonate, phosphinate, phosphine, phosphonium or mixtures thereof.
The photocatalytic substrate, as noted, comprises at least one photocatalyst. A photocatalyst is a material (compound or composition of matter) that is capable of initiating chemical reactions by absorbing electromagnetic waves, usually in the UV or visible part of the spectrum, thus forming charge carriers (electrons and holes) that arrive at the surface and participate in redox reactions that take place on the surface or in its vicinity. Hence, the photocatalytic units of this disclosure are used for photocatalysis of the second (undesired) stereoisomer (i.e. decomposition upon irradiation), hence reducing the concentration of the second stereoisomer in the mixture to effectively enrich the mixture with the first (desired) stereoisomer.
By some embodiments, the photocatalyst is in planar form, for example a plate, a film, a coating (continuous or non-continuous) layer over a non-reactive substrate, etc.
By some other embodiments, the photocatalyst substrate is in particulate form. When in particulate form, the photocatalyst substrate (and hence the photocatalytic unit) can be of a single type (with all of the particles substantially having the same geometrical form, size, and/or composition) or can be a mixture of two or more different types. The various populations of particles may differ in size, size distribution, shape, chemical composition, spectroscopic property, topology, and/or other physical or chemical characteristics. The particles can be selected amongst isotropic and anisotropic shaped particles. The particles may display any branched and net structures. Without being limited thereto, the particles may be symmetrical or unsymmetrical, may be elongated having a rod-like shape, round (spherical), elliptical, pyramidal, disk-like, branch, network or any irregular shape.
By some embodiments, the photocatalytic substrate particles (and hence also the units) are substantially spherical.
As used herein, the term spherical, or any lingual variation thereof, refers generally to a substantially (nearly) round-ball geometry. The term generally reflects on the spherical non-elongated shape of a particle, which need not be perfectly round in shape. The size of the spherical particle is typically the average diameter thereof.
According to some embodiments, the average particle size of the photocatalytic substrate particles is between about 4 nanometers (nm) and 20 micrometers (μm). By other embodiments, the average particle size of the photocatalytic substrate particles is between about 20 nm and 10 μm, between about 20 nm and 5 μm, or even between about 50 nm and 5 μm.
The term average particle size refers to the arithmetic mean of measured diameters of the particles. When the particle is non-spherical, the term means to denote the average particle size based on the equivalent diameter of the particle (based on its longest dimension).
According to some embodiments, the photocatalytic substrate is in the form of a porous or non-porous homogenous solid body, i.e. the entire solid body is made of one or more photocatalysts.
By a further embodiment, the photocatalytic substrate comprises a core coated by a layer of said at least one photocatalyst. The core is, by some embodiments, a non-photocatalytic core, a photocatalytic core (e.g. made of a different photocatalyst or comprising a different photocatalytic composition), or a co-catalyst.
The co-catalyst can, by way of example, be a noble metal (such as platinum, gold or palladium), an organic compound (e.g. activated carbon, fullerene, carbon nanotubes, graphene oxide and reduced graphene oxide), an oxide or a hydroxide such as silicon oxide, magnesium oxide, zirconium oxide, or another photocatalyst.
In embodiments where the photocatalyst is in the form of a layer coating a reactive or non-reactive carrier substrate (e.g. in a coated plate or core-shell configuration), the photocatalyst can be attached to the carrier substrate by a binder. The binder may be an inorganic binder, e.g. an oxide or a hydroxide, or an organic binder.
In some embodiments, the carrier substrate onto which the photocatalyst is attached is opaque to the wavelengths of radiation being used to activate the photocatalyst. In such embodiments, the irradiation of the photocatalytic unit can be carried out from the side of the photocatalyst (front illumination). Alternatively, the carrier substrate can be transparent or semi-transparent, and in such a case irradiation can be carried out from the carrier substrate side (back illumination), photocatalyst side, or both sides.
In order to increase quantum efficiency of the photocatalytic layer, the photocatalytic units of this disclosure can comprise, by some embodiments, an electrically conducting layer disposed between the photocatalyst layer and the carrier substrate, facilitating the application of voltage, thus increasing quantum efficiency by virtue of enhanced charge separation. Preferably, when the carrier substrate is transparent and illumination is from the back, this electrically conducting layer is made of a transparent material, for example of indium tin oxide.
By some embodiments, the photocatalytic unit can comprise one or more sensitizer compounds or compositions, different from said at least one photocatalyst or c-catalyst, functioning to increase the spectral range of photocatalysis operation of the unit.
According to some embodiments, the photocatalytic substrate comprises two or more photocatalysts.
By other embodiments, the at least one photocatalyst is doped by metals or non-metals to increase light absorption at specific wavelengths. The dopant can reside in the bulk of the photocatalyst or on the surface of the photocatalyst.
The photocatalyst, by some embodiments, absorbs light in the UV part of the spectrum, in the visible part of the spectrum, or both.
According to some embodiments, the photocatalyst is selected from oxides containing one element apart from oxygen (such as TiO2, ZnO, Fe2O3, Bi2O3, WO3, Ta2O5); oxides having corner-shared octahedral units (such as NbO6, TaO6, TiO6); binary oxides (such as SrTiO3, BaTa2O6, LaInO3); oxides having a formula of A2B2O7, where A is a trivalent metal (such as Bi) and B is a four valent metal (such as Y2Ti2O7, Gd2Ti2O7, La2Ti2O7); oxides having the general formula of A2, B*, B**O7, where A is a trivalent metal, B* is a trivalent metal and B** is a pentavalent metal (such as La3TaO7, La3NbO7, Bi2SbVO7); oxides having the general formula of AB**O4, where A is a trivalent metal, and B** is a pentavalent metal (such as InNbO4, InTaO4, BiNbO4); oxyhalides (such as BiOCl, BiOI, BiOBr, BiOF) and mixtures of such oxyhalides (such as BiOClxBr1-x); nitrides (such as Ta3Ns, graphitic carbon nitride); oxynitrides (such as TaON, LaTaO2N); oxysulfates (such as Sm2Ti2O5S2); metal organic frameworks such as MIL177; polyoxometalites (POMs); and any mixture or combination thereof.
According to some embodiments, the photocatalyst comprises oxides, sulfates, sulfides, oxyhalides, nitrides, oxynitrides, selenides, carbides, phosphates, polyoxometalites, and/or metalorganic complexes, that comprise at least one of cadmium, cerium, gallium, iron, tungsten, thallium, lanthanum, yttrium, indium, vanadium, silver, molybdenum, tin, silicon, strontium, lead, astatine, chromium, antimony, selenium, or any mixture or alloy thereof, doped or undoped by at least one dopant.
According to some embodiments, the photocatalyst is selected from TiO2, Bi2O3, WO3, ZnO, NbO6, TiO6, TaO6, InNbO4, InTaO4, BiNbO4, BiTaO4, Ga2BiTaO7, Bi2FeNbO7, Gd3TaO7, Bi2AlNbO7, Bi2GaNbO7, Bi2InNbO7, Y3TaO7, Yb3NbO7, La3NbO7, La3TaO7, CaTiO3, SrTiO3, Sr3Ti2O7, Sr4Ti3O10, K2La2Ti3O10, Rb2La2Ti3O10, Cs2La2Ti3O10, CsLa2Ti2NbO10, La2TiO5, La2Ti3O9, La2Ti2O7, La2Ti2O7:Ba, La4CaTi5O17, KTiNbO5, Na2TiO13, BaTi4O9, Gd2Ti2O7, Y2Ti2O7, α-Fe2O3, K4Nb6O17, Rb4Nb6O17, Ca2Nb2O7, Sr2Nb2O7, Ba5Nb4O15, NaCa2Nb3O10, ZnNb2O6, Cs2Nb4O11, La3NbO7, Ta2O5, K2PrTaO15, K3Ta3Si2O13, K3Ta3B2O12, LiTaO3, NaTaO3, KTaO3, AgTaO3, KTaO3:Zr, NaTaO3:La, NaTaO2:Sr, Na2Ta2O6, K2Ta2O6, CaTa2O6, SrTa2O6, BaTa2O6, NiTa2O6, Rb4Ta6O17, Ca2Ta2O7, Sr2Ta2O7, K2SrTa2O7, RbNdTa2O7, H2La2/3Ta2O7, K2Sr1.5Ta3O10, LiCa2Ta3O10, KNa2Ta3O10, Sr5Ta4O15, Ba5Ta4O15, H1.8Sr0.81Bi0.19Ta2O7, Mg—Ta oxide, LaTaO4, La3TaO7, PbWO4, RbWNbO6, RbWTaO6, CeO2:Sr, BaCeO3, NaInO2, CaIn2O4, SrIn2O4, LaInO3, YxIn2-xO3 (0<x<2), NaSbO3, CaSb2O6, Ca2Sb2O7, Sr2Sb2O7, Sr2SnO4, ZnGa2O4, Zn2GeO4, LiInGeO4, Ga2O3, Ga2O3:Zn, LaTiO2N, Ca0.25La0.75TiO2.25N0.75, TaON, Ta3N5, CaNbO2N, CaTaO2N, SrTaO2N, BaTaO2N, LaTaO2N, Y2Ta2O5N2, Sm2Ti2O5S2, La—In oxysulfide, La3NbO7, Bi2SbVO7, BiOCl, BiOI, BiOBr, BiOF, BiOClxBr1-x (0<x<1), graphitic carbon nitride, and any mixture or combination thereof.
By some embodiments, the photocatalyst is an oxide. By such embodiments, the oxide is selected from titanium dioxide, zinc oxide, strontium titanate, bismuth oxide, bismuth oxihalide, tungsten oxide, and mixtures thereof.
By other embodiments, the photocatalyst is a metal salt. By such embodiments, the salt is selected from zinc sulfide, cadmium sulfide, molybdenum sulfide, antimony sulfide, indium sulfide, silver indium sulfide, gallium phosphate, and mixtures thereof.
By some other embodiments, the photocatalyst is a ceramic material. According to some embodiments, the photocatalyst is selected from carbon nitride, graphitic carbon nitride, boron carbon nitride, zinc selenide, cadmium selenide, and mixtures thereof.
By some other embodiments, the photocatalyst is selected from titanium dioxide, a binary or ternary oxide of bismuth, a binary or ternary oxide of zinc, and graphitic carbon nitride, and mixtures thereof.
As noted, the photocatalytic substrate is substantially coated by one or more non-photocatalytic coating layers.
By some embodiments, the layer of non-photocatalytic coating is an ultrathin layer, i.e. having a thickness of between about 1 and 70 atomic layers, e.g. between about 1 and 50 atomic layers, between about 1 and 30 atomic layers, between about 1 and 25 atomic layers, or even between about 1 and 20 atomic layers. According to some embodiments, the thickness of the non-photocatalytic coating layer is between about 1 and 12 atomic layers.
By some embodiments, the thickness of the non-photocatalytic coating layer is less than about 4 nanometers (nm). According to some embodiments, the thickness of the non-photocatalytic layer is less than about 3 nm, less than about 2 nm, less than about 1 nm, less than about 0.5 nm, or even less than about 0.2 nm.
The non-photocatalytic material (i.e. compound or composition of matter) from which the non-photocatalytic coating layer is made is typically selected to form chemical bonds (covalent, polar covalent, ionic, electrostatic or hydrogen bonds) with the photocatalyst. By some embodiments, the non-photocatalytic coating layer comprises at least one oxide or a hydroxide, for example aluminum oxide, silicon oxide, tin oxide, cerium oxide, zirconium oxide, hafnium oxide, lanthanum oxide and yttrium oxide, and mixtures thereof. By some other embodiments, the non-photocatalytic coating layer comprises at least one metal salt selected from halides, nitrates, nitrates, nitrides, sulfates, sulfides, phosphates, acetates, lactates, citrates, carbonates, and ascorbate salts, and any combination thereof.
By some embodiments, the non-photocatalytic layer comprises a salt selected from zinc sulfide, barium sulfide, strontium sulfide, silicon nitride, cerium carbonate, and mixtures thereof. By some further embodiments, the non-photocatalytic layer is a metal.
The layers of the non-photocatalytic coating may be made of the same or different non-photocatalytic material. In such embodiments, the non-photocatalytic coating layer can comprise two or more types of layers, differing in their composition, each of which has a thickness of at least one atomic layer. By way of example, the first layer is made of silicon dioxide of a O—Si—O—Si layer, on top of which a thicker layer of aluminum oxide is deposited.
According to other embodiments, the non-photocatalytic coating layer comprises one or more oligomers or polymers (e.g. linear, block, graft, random, alternating, branched polymers, or copolymers and polymeric blends).
According to some embodiments, the non-photocatalytic coating layer comprises at least one non-photocatalytic material selected from Al2O3, SiO2, ZrO2, HfO2, La2O3, Y2O3, CeO2, SnO2, SnO, SrS, BaS, and Ce2(CO3)3, and any mixture thereof.
By some embodiments, the photocatalyst is selected from titanium dioxide, a binary or ternary oxide of bismuth, a binary or ternary oxide of zinc, and graphitic carbon nitride, and mixtures thereof, and the non-photocatalytic coating layer comprises at least one non-photocatalytic material selected from Al2O3, SiO2, ZrO2, HfO2, La2O3, Y2O3, CeO2, SnO2, SnO and mixtures thereof.
According to some embodiments, the photocatalytic units comprise an adsorption-suppression layer that is selectively deposited over the non-photocatalytic coating layer. The adsorption-suppression layer may be organic or inorganic, and functions to further reduce and at times substantially eliminate the adsorption of the second stereoisomer onto the surface of the non-photocatalytic coating layer.
By another aspect, the present disclosure provides a photocatalytic unit for increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a mixture comprising said first and second stereoisomers, the unit having a photocatalytic substrate comprising at least one photocatalyst, at least one non-photocatalytic coating layer substantially coating said photocatalytic substrate, and a plurality of spaced-apart open molecular cavities defined at an external surface of the unit, the cavities being sized and shaped to correspond to a size and shape of said second stereoisomer, each of the cavities having a base portion and sidewalls extending from the base portion towards an opening of the cavity, such that at least a base portion and a bottom portion of said side walls are constituted by said photocatalytic substrate and a top portion formed in said non-photocatalytic coating layer.
By a further aspect, the present disclosure provides a photocatalytic unit for increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a mixture comprising said first and second stereoisomers, the unit having a photocatalytic substrate comprising at least one photocatalyst, at least one non-photocatalytic coating layer substantially coating said photocatalytic substrate, and a plurality of spaced-apart open molecular cavities defined at an external surface of the unit, the cavities being sized and shaped to correspond to a size and shape of said second stereoisomer, each of the cavities having a base portion and sidewalls extending from the base portion towards an opening of the cavity, such that the base portion and the sidewalls are substantially defined within said non-photocatalytic coating layer.
By another aspect, the present disclosure provides a photocatalytic unit for increasing the relative amount of at least one first enantiomer of a compound with respect to at least one second enantiomer of the compound in a mixture comprising said first and second enantiomers, the unit having a photocatalytic substrate comprising at least one photocatalyst, at least one non-photocatalytic coating layer substantially coating said photocatalytic substrate, and a plurality of spaced-apart open molecular cavities defined at an external surface of the unit, the cavities being sized and shaped to correspond to a size and shape of said second enantiomer, each of the cavities having a base portion and sidewalls extending from the base portion towards an opening of the cavity, such that at least a base portion and a bottom portion of said side walls are constituted by said photocatalytic substrate and a top portion formed in said non-photocatalytic coating layer.
By a further aspect, the present disclosure provides a photocatalytic unit for increasing the relative amount of at least one first enantiomer of a compound with respect to at least one second enantiomer of the compound in a mixture comprising said first and second enantiomers, the unit having a photocatalytic substrate comprising at least one photocatalyst, at least one non-photocatalytic coating layer substantially coating said photocatalytic substrate, and a plurality of spaced-apart open molecular cavities defined at an external surface of the unit, the cavities being sized and shaped to correspond to a size and shape of said second enantiomer, each of the cavities having a base portion and sidewalls extending from the base portion towards an opening of the cavity, such that the base portion and the sidewalls are substantially defined within said non-photocatalytic coating layer.
By another one of its aspects, the disclosure provides a process of preparing a photocatalytic unit for increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a mixture comprising said first and second stereoisomers, the process comprises:
By another aspect, there is provided a process of preparing a photocatalytic unit for increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a mixture comprising said first and second stereoisomers, said process comprising:
By some embodiments, the stereoisomers are enantiomers.
According to some embodiments, step (a′) comprises mixing said second stereoisomer (also interchangeably referred to herein as a template molecule) with a precursor of the photocatalyst.
By some embodiments, step (a′) is carried out in a solution, that comprises one or more solvents, said template molecules and said precursors. Possible solvents can be any liquid that dissolve both the precursor and the template molecule. By way of example, these solvents are often aqueous or organic solvents, in particular alcohols. In some embodiments, the solution further comprises chelating agents that form complexes with the precursor.
By some other embodiments, step (a′) is carried out in an emulsion, a micro-emulsion, mini-emulsion, nano-emulsion, a double emulsion, liposomal system, lyotropic liquid crystals, organogels or any combination thereof or any other type of micro- or nanostructured liquid. The emulsion may include, but not be limited to, the forms O/W, W/O, W/O/W, O/W/O, W/O1/O2, W/O2/O1, O1/W/O2, O1/O2/W, O2/O1/W, O2/W/O1 and combinations of these forms with bi-continuous phases.
In some embodiments, said precursor is an organometallic complex, which may, for example, comprise a metal ion having alkoxide ligands. In other embodiments, the precursor is a non-organic complex, for example a metal ion chemically associated to nitrate groups, halogen ligands, sulfate groups, and/or hydroxide ligands. In further embodiments, the precursor can comprise a metal ion chelated by a chelating agent, e.g. acetylacetone and carboxylic acids.
When preparing the units starting from step (a′), the ratio between the amount of second stereoisomer (i.e. template molecule) and precursor is calibrated to assure that the photocatalyst preserves its functional properties, and yet the surface concentration of the template molecule is sufficient to obtain a desired number of cavities on the surface of the unit. According to some embodiments, the ratio between the number of atoms in the photocatalyst to that of the second stereoisomer is 50-10,000,000. It should be understood that the optimal ratio can be changed and tailored according to the type of photocatalyst and the type of templating molecule.
When preparing units starting from step (a), by some embodiments, step (a) is preceded by a step (a0) of preparing said photocatalytic substrate. Step (a0) can, by some embodiments, be carried out by any one of sol-gel process, precipitation, electrospinning, atomic layer deposition (ALD), chemical vapor deposition (CVD), plasma-assisted deposition, solid-state reaction, deposition from gas phase or aerosol, or any other suitable method.
According to some embodiments of step (a), the second stereoisomer (i.e. the template molecules) is associated with the surface of the photocatalytic substrate by introducing the photocatalytic substrate into a solution that contains the template molecules. In some embodiments, step (a) is carried out at a temperature of below about 200° C. to promote adsorption of the template molecule onto the surface of the photocatalytic substrate. According to some embodiments, step (a) is carried out at a temperature of between about −50° C. and 200° C., between about −50° C. and 100° C., or even between −50° C. and 50° C. According to other embodiments, step (a) is carried out at a temperature of between about −20° C. and 150° C., between about −10° C. and 120° C., or even between about 0° C. and 100° C.
By some embodiments, step (a) is carried out in gas phase, or a precursor of the photocatalytic material is provided as an aerosol.
In some embodiments, the surface coverage by the template molecules is between about 0.05 and 50%, e.g. between about 0.1% and 30%, between about 1 and 20%, or even between about 3% and 10%.
According to some embodiments, small molecules or ions are added to the solution at steps (a) or (a′) to prevent coagulation of the template molecules at high concentrations. By way of example, charging the template molecules by altering the pH of the solution may prevent the formation of clusters.
In steps (b) and (b′) the surface of the photocatalytic substrate that comprises the template molecules is coated by a layer of non-photocatalytic coating. Typically, the coating is carried out in a selective manner, as to dispose ultrathin layers of the non-photocatalytic material onto the surface, without overcoating the template molecules residing at the surface of the photocatalyst (to enable their degradation or release from the surface at the next stages of preparation). According to some embodiments, selective coating is carried out by atomic layer deposition (ALD), molecular layer deposition (MLD), or by self-assembly of monolayers—techniques which allow for accurate selective coating with ultrathin layers, controlled at an atomic level thickness. By choosing the proper material to be used as non-photocatalytic coating layer by ALD or MLD it is possible to overcoat the photocatalyst in a coating that adheres strongly to the underlying photocatalyst without adhering to the template molecules residing on the surface of the photocatalyst. In self-assembly of monolayers, consecutive building and gradual stacking of monolayers is obtained. The control over the thickness of the non-photocatalytic layer is required for the efficient operation of the photocatalytic unit in its use in stereoisomeric enrichment processes, as the non-photocatalytic coating layer restrains the photocatalytic activity to areas that are not covered by the coating layer, i.e. to the cavities.
Selective coating is typically carried out at a temperature that does not harm or alter the shape of the second stereoisomer and does not cause desorption of these molecules from the photocatalyst's surface. In some embodiments, selective coating by said non-photocatalytic material is carried out at a temperature lower than about 400° C., e.g. lower than about 250° C., lower than about 100° C., lower than about 70° C., or even lower than about 35° C. According to some embodiments, selective coating is carried out at a temperature of between about 2° C. and 250° C. According to some embodiments, selective coating is carried out at a temperature of between about −10° C. and 100° C. According to some other embodiments, selective coating is carried out at a temperature range of between about 0° C. and 80° C. or even between about 20° C. and 60° C.
According to some embodiments, the selective coating is carried out by simultaneously introducing more than one ALD precursor, thus forming a layer that contains several types of non-photocatalytic molecules.
In steps (c) and (c′), following the growth of the coating layer, the template molecules are removed, thus leaving behind empty molecular cavities specifically shaped and sized to accommodate molecules identical to the template molecules. Such removal is carried out by applying conditions onto the coated photocatalytic substrate to degrade the molecules of second stereoisomer (i.e. the template molecules).
According to some embodiments, the removal conditions are exposing the photocatalyst to light, having a wavelength or wavelength band that induces its activation. By way of example, such light may be in the visible range of the spectrum, UV range of the spectrum or even in ranges of shorter wavelength, depending on the type of photocatalyst utilized.
According to other embodiments, the removal conditions are exposure to light at a wavelength or wavelength band that destroys/degrades/decomposes the template molecules. For example, such wavelength or wavelength band can be in spectral ranges of short UV (UV-C), deep UV, X-rays, gamma rays, or any combinations of photons belonging to different ranges.
According to some other embodiments, the removal conditions are obtained by chemical degradation of the template molecules. For example, oxidation by oxidative agents such as ozone, chlorine, fluorine, potassium permanganate, atomic oxygen and the like. Other examples include, but not limited to, reduction by reductive agents such as ammonium hydroxide, immersing in bases such as ammonia, and/or immersion in acids.
By some embodiments, the processes can comprise a step (d) or (d′), following steps (c) and (c′), accordingly, for processing the units into a free-standing film form or into a carrier-supported film. According to such embodiments, steps (d) or (d′) comprises preparing a film from said units. According to some embodiments, the film is porous to facilitate easy mass transport to the cavities.
According to some embodiments, binding of the units to form the film is carried out under elevated temperatures, e.g. between about 25° C. and 1400° C. By some embodiments, the temperature in which binding is carried out is between about 25° C. and 600° C., preferably between about 25° C. and 250° C.
By some other embodiments, binding of the units can be facilitated by utilizing one or more binding materials.
As noted, according to some embodiments, the photocatalytic units may comprise an adsorption-suppression layer is selectively deposited over the non-photocatalytic coating layer. The adsorption-suppression layer can be deposited onto the surface of the non-photocatalytic coating layer before or after steps (c) or (c′)—i.e. before removal of the template molecule or thereafter.
The preparation processes described herein can be applied to any desired templating molecule, and hence, are generic and can be adapted for enrichment of any desired stereoisomer is a mixture of stereoisomers. According to some embodiments, the template molecules (i.e. the second stereoisomer) comprise functional groups that form interactions with the photocatalyst or with its precursor, preferably functional groups capable of forming hydrogen bonds with the photocatalyst or with its precursors. Examples include, but are not limited to, alcohols, esters, ethers, carboxylic acids, amines and amides. In other embodiments, the template molecules are able to form π-π interactions with the photocatalyst or with its precursor, for example aromatic groups with graphitic carbon nitride, aromatic groups with graphene oxide or with carbon nanotubes. In some other embodiments, the interactions are between non-polar groups in the template molecules and non-polar moieties in the photocatalyst or its precursor. In some further embodiments, the interactions are between electrically charged functional groups in the template molecule and electrically charged sites in the photocatalyst or in its precursor.
According to some embodiments, the template molecules are at least partially associated with the non-photocatalytic coating layer. By some other embodiments, the template molecules are associated with both the photocatalyst and the non-photocatalytic coating layer.
In some embodiments, the template molecule is an organic molecule, containing one or more of the following functional groups: alcohol, ether, ester, ketone, aldehyde, hydroxylic acid, aromatic rings, amine, amide, sulfide, disulfide, thiol, sulfenic acid, sulfinic acid, sulfonic acid, sulfonate ester, halide, siloxane, silanol, siloxide, silyl, silene, silole, phosphate, phosphonate, phosphinate, phosphine, and phosphonium.
In other embodiments, the template molecule is a molecule containing one or more organometallic bonds, an organic molecule, a long polymeric chain, a peptide or a protein (in a folded, misfolded or unfolded state) and/or a molecule is based on an element other than carbon and exhibiting chiral chemistry, such as phosphorus or silicon.
According to some embodiments, the templating molecules have one or more chiral centers. Examples of suitable template molecules are leucyl-glycine, bupivacaine, ofloxacin, naproxen, ibuprofen, α-pinene, tramadol, oseltamivir, vancomycin and any other molecule having one or more chiral centers.
By another one of its aspects, the present disclosure provides a method for increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a first mixture comprising said first and second stereoisomers. The method comprises contacting at least one photocatalytic unit as described herein with said first mixture, under conditions permitting adsorption of molecules of said second stereoisomer into said cavities; and irradiating said first mixture in a wavelength or wavelength band to activate the photocatalyst to decompose said molecules of said second stereoisomer within the cavities, thereby obtaining a second mixture enriched by said first stereoisomer.
The first and second stereoisomers are, by some embodiments, first and second enantiomers, respectively, of said compound.
In some embodiments, the first mixture is in liquid form, for example a solution or a suspension in at least one of an aqueous medium, organic medium or a gas at supercritical conditions. By other embodiments, the first mixture is in gas form.
In some other embodiments, the first mixture is deposited on the photocatalyst surface and dried before irradiation.
According to some embodiments, introduction of the photocatalytic units into the first mixture can be carried out prior to removal of the template molecules from the cavities, such that irradiation causes removal of the template molecules from the cavities to free them for adsorption of said second stereoisomer from the first mixture.
By some embodiments, irradiation of the first mixture is at wavelengths (discrete wavelengths or wavelength band) in the ultraviolet range of the spectrum, visible part of the spectrum, deep UV part of the spectrum, X-ray part of the spectrum, infra-red part of the spectrum, or in a distinct pattern of alternating wavelengths.
The photon flux during irradiation can, by some embodiments, be between about 0.001 mW/cm2 and 5 W/cm2. By such embodiments, the photon flux can be between about 0.001 mW/cm2 and 1 W/cm2, between about 0.001 mW/cm2 and 300 mW/cm2, between about 0.1 mW/cm2 and 0.5 W/cm2, between about 0.01 mW/cm2 and 20 mW/cm2, preferably not lower than 0.1 mW/cm2 and not higher than 20 mW/cm2.
In some embodiments, irradiation is carried out concomitantly with cooling of the first mixture, e.g. in cases where relatively high flux of irradiation is utilized.
According to some embodiments, the amount of photocatalyst in the photocatalytic unit, when used as a powder in an aqueous medium, is between 0.001 grams per liter and 50 grams per liter, preferably up to 5 gram per liter, e.g. between 0.001 and 1 grams, between about 0.001 and 0.5 grams, or even between about 0.001 and 0.1 grams per liter.
In some embodiments, the units are used in conjunction with an external power source to supply positive or negative voltage bias to achieve favorable decomposition conditions within the cavities. Thus, by some embodiments, the process further comprises introducing a counter-electrode into the medium to facilitate introduction of energy into the system to assist in degradation of the target molecule. The counter-electrode is typically in contact with the non-photocatalytic coating layer. In some embodiments, the process further comprises application of an electric potential between the two electrodes. The potential can be between about −5V and 5V, e.g. between about −1V and 1V, between about −0.5 V and 0.5 V, between about −0.3 V and 0.3 V, or even between about −0.1 V and 0.1 V.
According to some embodiments, the process results in a second mixture that is substantially enantiomeric-pure.
By yet another aspect, there is provided a photocatalytic unit described herein, for use in a method of increasing the relative amount of at least one first stereoisomer of a compound with respect to at least one second stereoisomer of the compound in a first mixture comprising said first and second stereoisomers, said method comprising: contacting said photocatalytic unit with said first mixture, under conditions permitting absorption of molecules of said second stereoisomer into said cavities; and irradiating said first mixture in a wavelength or wavelength band to activate the photocatalyst to decompose said molecules of said second stereoisomer within the cavities, thereby obtaining a second mixture enriched by said first stereoisomer.
As used herein, the singular form a, an and the include plural references unless the context clearly dictates otherwise. For example, the term “a photocatalyst” or “at least one photocatalyst” may independently include a plurality of photocatalysts, including mixtures thereof.
As used herein, the term about is meant to encompass deviation of 20% from the specifically mentioned value of a parameter, such as temperature, pressure, concentration, etc.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases ranging ranges between a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. It should be noted that where various embodiments are described by using a given range, the range is given as such merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.
It is appreciated that certain features of this disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
Processes of the present disclosure involve numerous process steps which may or may not be associated with other common physical-chemical processes so as to achieve the desired form and/or purity of each of the synthesized components. Unless otherwise indicated, such process steps, if present, may be set in different sequences without affecting the workability of the process and its efficacy in achieving the desired end result.
As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
As used herein, the terms association and surface-association or any lingual variation thereof, refers to the chemical or physical force which holds the two entities together. Such force may be any type of chemical or physical bonding interaction known to a person skilled in the art. Non-limiting examples of such association interactions are ionic bonding, covalent bonding, coordination bonding, complexation, hydrogen bonding, van der Waals bonding, hydrophobicity-hydrophilicity interactions, etc.
In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
Turning first to
In
In
Another configuration of the photocatalytic units of this disclosure is shown in
Shown in
It is of note that although in these schematic representations the photocatalytic units are shown to have a particulate, spherical shape, a person of skill would appreciate that the particles can assume any other suitable shape and size or that the photocatalytic unit can be of a planar configuration. Further, it is noted that the photocatalytic units in particulate form may be processed, by applying suitable means, into free-standing or carrier-supported photocatalytic films.
Glass slides, onto which films of TiO2 were deposited, served as the starting catalytic substrates. LeuGly, a small dipeptide, was chosen as the model molecule due to its single chiral center, the variety of functional groups it has, allowing for several possible interactions with the matrix, and its commercial availability as an enantiopure compound. Al2O3 was chosen as the non-photocatalytic (i.e. activity-dampening) coating layer due to its significantly larger band gap relative to that of TiO2, its favorable band locations, the relatively small lattice mismatch with that of anatase-phase titania, and its suitability for low-temperature, thermal Atomic Layer Deposition (ALD) growth with mild oxidizing reagents such as water.
Testing the passivation capabilities of ALD-grown Al2O3 thin films on TiO2 was performed by forming thin layers (˜60 nm) of anatase-phase titania on silica plates using spin-coating sol-gel method. Part of the plates were overcoated with Al2O3 by thermal ALD, using a MVD100E apparatus (SPTS Ltd.).
The ALD procedure comprised of the following stages: introducing the slides into the reaction chamber, pumping down to less than 1 mTorr, introducing nitrogen to obtain a working pressure of 20 mTorr, introducing 1 Torr of trimethylaluminum (TMA) for 1 sec, purging 5 times with nitrogen, pumping down to the working pressure, introducing 1 Torr of H2O for 1 sec, purging 10 times with nitrogen, and pumping down to the working pressure, thus ending the deposition of a one-cycle overcoating layer. This process was repeated according to the predesigned number of layers.
The default temperature during the process was 50° C. Various thicknesses were tested, controlled by altering the number of overcoating cycles (0, 4, 6, 8, 12). In addition, an eight-layer sample was grown at 60° C. in order to gain insight with regard to the effect of surface temperature. To test the activity suppression capabilities of the overcoating layer, the degradation kinetics of stearic acid were tested: a 5 mg/mL stearic acid solution in methanol was deposited and spun twice at 2500 rpm for 2 min. All plates were then individually placed at a distance of 15 cm under a Blak-Ray® 100 W, 365 nm UV lamp for 40 min, with measurements taken every 10 min. The kinetics were deduced by monitoring changes in the IR absorption CH2(a) peak at 2916 cm−1.
This example demonstrates how ultrathin layers of an oxide (alumina) in the thickness between 4-12 atomic layers act to reduce the photoactivity of titanium dioxide films. The example further demonstrates how altering the temperature during the overcoating process affects the properties of the overcoating, in a manner that influences its ability to prevent photocatalytic reaction at the surface.
Photocatalytic units (to be also referred to hereinbelow as PEDs) comprised of thick TiO2 films on 25 mm×12.5 mm glass slides, overcoated with Al2O3, were prepared by the following procedure. Glass microscope slides (Marienfield) were cleaned by washing in chloroform, ethanol, and deionized water. A mixture of 9.2 g of P25 titania powder (Degussa) and 0.6 g of X-500 titania suspension (TiPE Ltd.) in 12 ml of deionized water was thoroughly (15 min) sonicated (MRC, DC80H) and applied on the glass substrates using the doctor blade method. The deposited thick films (15 μm) were then calcined at 450° C. for 5.5 h to improve adhesion. Next, 300 μl of a 0.25 mg/ml solution of either L-LeuGly (Sigma-Aldrich) or D-LeuGly (Santa Cruz Biotechnology) in deionized water was administered on each of the imprinting-designated slides and spun at 4000 rpm for 80 sec. Part of the TiO2-coated slides, termed as (−,−), were left aside without LeuGly. All of the LeuGly-containing plates and half of the (−,−) slides were overcoated with 10 cycles of Al2O3 ALD, according to the procedure described above. Here, the deposition temperature for all PEDs was 50° C. Finally, the alumina-overcoated plates were UV-ozone cleaned for 15 min (UVOCS® Ltd.) to remove the templating molecules prior to reaction.
The prepared PEDs were divided into four groups: non-overcoated non-templated plates denoted as (−,−), overcoated non-templated plates denoted as (+,−), overcoated L-templated plates (+,L) and overcoated D-templated plates (+,D). The photocatalytic thick film and overcoating aluminum oxide layers were analyzed using XRD (Rigaku, MiniFlex II), XPS (Thermo VG Scientific, Sigma Probe), and SEM+EDS (Zeiss, Ultra-Plus HRSEM).
Additional ultrahigh-resolution AFM measurements were carried out on PEDs prepared using the same sol-gel procedure used in Activity Suppression. Here, the same templating procedure described above for the P25-containing slides (spin-coating with the templating molecules followed by 10 ALD cycles of Al2O3) was performed. One additional sample was made with a templating solution containing 0.5 mg/mL of L-LeuGly rather than the 0.25 mg/mL used elsewhere. This type of PED was chosen, as its corrugation is significantly lower than that of the P25-based PEDs. During the AFM measurements of these samples, the plates were first cleaned for 5 min with oxygen plasma and their surface was wetted with a 0.1 M NaCl solution to remove air pockets. This was followed by a quasi-static 4 h stage approach to minimize signal drift, in an ultrahigh-resolution AFM setup.
The XRD pattern was typical for P25 TiO2 (i.e. a mixture of anatase and rutile), as the alumina layers were too thin to have any diffraction effect (not shown). The SEM-EDS images (
Table 2 presents the atomic concentration (%), as measured by XPS, of PEDs that had been prepared using imprinting solutions of different concentrations of LeuGly (0, 0.1, 0.5, and 1 mg/mL). In all samples the overcoating layer was prepared by 10 ALD cycles of alumina. All measurements were performed prior to stripping the templating LeuGly.
The concentration of oxygen was found to be 56±3%. On a free-carbon basis, the atomic concentration of oxygen was 71%. The atomic concentration of carbon was found to be 18±1% for samples prepared with a low concentration of imprinting molecules. Without wishing to be bound by theory, the high atomic concentration of carbon measured in samples prepared with a high concentration of LeuGly suggests that the templating molecules tend to be deposited as aggregates under this condition during preparation. These aggregates may act to ease the further adsorption of organic contaminants. The conclusion regarding the presence of aggregates in samples prepared with the highest concentration of LeuGly is further supported by the low atomic concentration of Ti found in such samples.
Ultrahigh-resolution AFM measurements were performed on PEDs and on nonimprinted titania films overcoated with alumina (10 ALD cycles), in order to verify the presence of molecular cavities in the PEDs. A plot of the distribution (ρ) of heights (z) relative to the minimum of each frame, as shown in
The photocatalytic degradation kinetics of each enantiomer was performed in a reaction vessel comprised of a perforated-bottom 50 mL beaker in which one photocatalytic plate was placed in each experiment. The perforated beaker was introduced into a larger beaker containing a stirring bar, allowing continuous mixing of the solution during the reaction. A glass cover was used to minimize evaporation.
All tests were conducted with 100 mL of an aqueous solution (0.5 mg/mL) of enantiomerically pure (L or D) LeuGly. The photocatalytic plate was placed 15 cm below a Black-Ray® 100 W 365 nm lamp, following adsorption in the dark for 20 h. Each plate was used twice: first with one enantiomer and then with the second. The concentration of the peptide in solution was determined using a previously developed fluorometric assay with the fluorescent taggant molecule fluorescamine, a method that is enantiomerically blind. The results were fit to an apparent first-order mechanism.
As an initial test of the PEDs, the photocatalytic degradation kinetics of the L-enantiomer of LeuGly was compared with that of the D-enantiomer in an enantiopure solution. This was done both with PEDs and with nonimprinted, non-coated TiO2 films. All PEDs reported in this and in the following sections of this Example were overcoated with a 10-cycle ALD layer. This thickness was found to yield higher selectivity in comparison to that obtained with imprinted PEDs having thinner layers. As shown in
To quantify this apparent selectivity effect, the kinetics were fit to a first-order rate law (Table 3). As portrayed in Table 3, in the absence of imprinted cavities, the rate constant for the degradation of the L-enantiomer was almost identical with the rate constant measured for the D-enantiomer. This was not the case with the coated, imprinted PEDs. The rate constant of the L-enantiomer was significantly higher than that of the D-enantiomer upon using L-imprinted PEDs. The opposite was observed upon degrading LeuGly in the presence of D-imprinted PEDs.
The ratios between the rate constants in the degradation of L-enantiomer to those of the D-enantiomer for the three cases are presented in
A set of reactions with racemic mixtures as reactants was carried out in a Radleys 12-vial parallel reaction system modified with 12 intensity-tuned, voltage-controlled 365 nm LEDs, allowing direct illumination of the vertical plates without interfering with stirring. This system is denoted as “the carousel system”. All vials were simultaneously illuminated following an adsorption equilibrium and were monitored in parallel. Some tests were also performed in the same reactor used for the single-enantiomer kinetics studies. To quantify the concentration of each enantiomer, a chiral-resolving method was developed for an Agilent 1100 HPLC instrument. An Astec Chirobiotic T (4.6 mm×15 cm) chiral column, with an isocratic mobile phase of 70% (by volume) methanol and 30% 50 mM triethylamine acetate (TEAA) in water at a pH of approximately 6.75, was used. The flow rate was 0.4 mL/min, and the temperature was set to 20° C. The run time was 10 min, during which the L-enantiomer was the first to elute at 7 min, while the D-enantiomer eluted 30 sec later. For all measurements the resolution factors were larger than 2.
After assessing the kinetic differences between the enantiomers in separate reactions, we conducted the ultimate selectivity test—enriching an initially racemic solution by preferential degradation of the templating enantiomer.
The preferential adsorption and photocatalytic degradation kinetics are best represented in the form of enrichment curves (
From a practical point of view, successful implementation may require time scales significantly shorter than the typical reaction times reported above. In this context, it should be noted that the use of photocatalytic PEDs in the form of powders is expected to dramatically increase the rates, thus shortening the required reaction time. When a surface area of 50 m2g−1 for the powder is taken into account, a conservative calculation gives an estimated rate increase of at least 1 order of magnitude.
5.87 ml (0.0075 mol) of titanyl sulfate (15% wt in H2SO4) and 1.3 ml HCl (37% wt in H2O) were added to 243 ml of deionized water in a 500 ml round flask. The solution was stirred for 1 hour at room temperatures. 5 ml of NH4OH (25% wt in H2O) were then added to the mixture to stabilize the pH at ˜1.3. The flask was connected to a reflux condenser and heated to 60° C. for 24 h in a silicon oil bath. After 20 h of reflux, 35.5 mg of L-Leucyl-glycine (L-LG) were added. The obtained white colloidal solution was vacuum-filtered and washed with ˜100 ml deionized water. The solids were dried in a drying rack at 60° C. for 50 hrs. The dried off-white powder (total weight 733 mg) was crushed and stored.
A 5.5″ diameter, 15 Ohm loudspeaker was fit with a triggering system set to operate at a frequency of ˜15 Hz upon activation of an attached electrical timer, at a set time. The circuit was operated using four AA batteries, and an additional 3V battery for the timer. A containment device was made using a screw-top polypropylene wafer jar with five round 1 cm holes bored in the top, and fitted with 10 μm pore PTFE frits. 254 mg of the titanium dioxide powder obtained in step A was placed inside the containment device, and placed on top of the speaker membrane. This setup was placed in an MVD100E molecular vapor deposition system operating to grow the overcoating layer by Atomic Layer Deposition (ALD). The timer was set to the planned time of operation, and the system was vacuumed for 16 hrs, to a pressure below 1 mTorr. Upon starting of operation, the system was heated to 60° C., and a cycle was started consisting of 1 Torr of trimethylaluminum (TMA) gas followed by vacuuming to 20 mTorr, followed by 5 purge cycles of 99.9999% nitrogen gas and vacuuming to 20 mTorr, followed by 1 Torr water vapor, followed by vacuuming to 20 mTorr, followed by 10 purge cycles of 99.9999% nitrogen gas and vacuuming to 20 mTorr. This complete cycle was repeated 16 times. The chamber was vented and the setup was removed. The result was about 50 mg of powder, which was stored.
The powder was exposed to UV-ozone in a commercial system (UVOCS®) for 10 min, mixed, and re-exposed for another 10 min.
D. Introduction of Photocatalyst into an Enantiomeric Mixture
A solution containing 50 mg of L-LG and 50 mg of a second enantiomer, D-LG, was prepared in 50 ml deionized water, inside a 200 ml beaker covered with a glass petri dish. In this solution, 50 mg of the catalyst powder were suspended and stirred in the dark for 24 h.
A pair of Osram Eversun L40W/79K, 40W, max emission at 355 nm were located 15 cm from the vessel containing the solution prepared in part D. 0.9 ml samples were taken periodically throughout the reaction, centrifuged at 10000 RPM for 10 min, with the supernatant liquid split into two samples, one 0.025 ml sample diluted by a factor of using 0.475 ml deionized water, and the other diluted by a factor of 2 in 0.2M, pH 7 phosphate buffer solution in deionized water.
The sample diluted by the factor of 20 was then mixed with 1 ml of 0.2 M, pH 7 phosphate buffer solution in deionized water and 0.5 ml of a 0.15 mg/ml solution of fluorescamine in acetone, and each sample was placed in four separate wells in a black 96-well fluorescence reading plate. The fluorescence reading was measured in a Tecan plate reader, with excitation at 390 nm and emission measured at 470 nm, gain at 95%, and the total LG concentration, of both enantiomers, was calculated using a premade calibration curve, using the average value of the four readings. The sample diluted by a factor of 2 was taken as is and measured using circular dichroism in a PiStar circular dichroism spectrophotometer, where initially a phosphate buffer's spectrum was measured between 300 nm and 190 nm as a baseline, and these values were subtracted from all other measurements. A calibration curve was made using different ratios of the L- and D-LG enantiomers at total concentrations similar to those measured using the fluorimetry method described above. The samples were then measured, and their enantiomeric ratio assessed, each measured three times and averaged.
This example shows a clear trend of increasing the enantiopurity (defined herein as D/(D+L)) with increasing reaction time. Hence, exemplifies the ability of an embodiment made of imprinted titanium dioxide particles, where each particle is overcoated with 16 atomic layers of alumina to enrich the relative concentration of the enantiomer that had not been imprinted upon exposing the said particles to UV light.
The efficacy of the adsorption of a specific enantiomer on the surface of a photocatalyst film, following by overcoating the photocatalyst around the adsorbed molecules, thus forming enantiomeric cavities in the inert layer, where the cavities were formed within the photocatalyst, is demonstrated in this example.
9.2 g of a commercially available TiO2 powder (Degussa P25) and 0.6 ml of X-500 suspension were mixed with 12 ml deionized water, and sonicated for 30 min in an ultrasonic bath. Glass microscope slides were cut into 1″×0.75″ pieces, and cleaned with ethanol, then chloroform. These were fixed on two parallel sides to a clean working surface using sticky tape, leaving a total unobstructed area of 0.75″×0.75″. On this area, the P25 mixture was applied in a uniform layer of a thickness on the scale of the piece of tape (approximately 15 micrometer). The coated plates were then calcined for 5.5 h in air at 450° C. in a tubular furnace, the heating rate being 25°/min.
Two solutions, one of 1 mg/ml L-LG in ethanol and the other of 1 mg/ml D-LG in ethanol, were made, and further used to make two 0.25 mg/ml solutions, one of each enantiomer, through dilution with ethanol by a factor of 4. 0.3 ml of the solution of the lower concentration of L-LG were deposited separately on 4 plates and spin-coated for 80 sec at 4000 RPM. Similarly, 0.3 ml of the low concentration solution of D-LG were deposited on 4 different plates and spin-coated for 80 sec at 4000 RPM. The plates were retrieved completely dry, and stored. 4 more plates were stored without adsorption of LG molecules.
The imprinted and non-imprinted plates were overcoated with 8 cycles of TMA and water in the MVD100E system as described in Example 1. Other samples, prepared in the same manner described in stage (a), but without adsorbing the imprinting molecules, were also coated in the same manner. These samples were used as reference samples, to verify the effect of imprinting.
The plates placed with the imprinted and overcoated side facing upwards. Then they were exposed to UV-ozone in a commercial apparatus (UVOCS®) for 15 min.
E. Introduction of Photocatalyst into an Enantiomeric Mixture
Each tested plate was placed in a different beaker. A solution of 50 mg L-LG and 50 mg D-LG in 100 ml deionized water was prepared for each sample. Then, both beakers were covered with a glass petridish and stirred in the dark for 48 hrs.
Both beakers were exposed to a Black-Ray® 100W, 365 nm UV light source located 15 cm from the solution. 0.3 ml samples were taken periodically and refrigerated until analysis. The same procedure was performed with the reference samples.
The samples were placed in HPLC vials, and tested in an Agilent 1100 HPLC, fit with a quaternary pump and an Astec Chirobiotic-T 10 cm×4.2 mm chiral stationary phase column. The analysis was carried out isocratically, with the following parameters: 70% methanol and 30% of 50 mM triethylammonium acetate buffer in water with pH in the range of 6.5-7.0, column temperature at 20° C., injection volume of 5 μl, flow rate of 0.4 ml/min, with the chromatograms obtained at 254 nm (control), 210 nm (working wavelength) and 206 nm (additional control). The total running time of the program was 10 min, with the L-LG peak appearing at 7 min and the D-LG appearing at 7.5 min. After each run, a cleaning sequence was initiated, consisting of 70% methanol and 30% 50 mM triethylammonium acetate buffer in water with pH in the range of 6.5-7.0, column temperature at 20° C., injection volume of 5 μl of pure methanol, flow rate of 1 ml/min, for a total of 7 min. Each time a new buffer was made, a new calibration curve was made for the two different enantiomers.
This example demonstrates the efficacy of an embodiment based on the absorption of a specific enantiomer on the surface of a photocatalyst film, following by overcoating the photocatalyst around the adsorbed molecules, thus forming enantiomeric cavities in the inert layer. This is shown in a complementary manner, i.e. for both cases: upon imprinting D-type and upon imprinting L-type. Hence, example 3 demonstrates the efficacy of several different embodiments described in the detailed description above: Imprinting on a film rather than on particles, imprinting in the inert layer rather than in the photocatalyst and the effect of two different imprinting species.
A suspension of 239 g/L of Degussa P25 particles was made in deionized water. Additionally, a suspension of 30.19 ml of triethyl orthosilicate (TEOS), 46.24 ml of LUDOX silicon dioxide suspension, 0.714 ml of HCl (37% wt in H2O) and 136 ml of isopropanol was made. Then, 3.04 ml of the P25 suspension, 4.9 ml of the TEOS-LUDOX suspension and 2 ml of n-propanol were stirred for 10 min and then sonicated for 10 min. Glass microscope slides were cut into 0.75″×0.5″ pieces, and cleaned with ethanol, then chloroform. On these, 0.15 ml of the TiO2/SiO2 mixture was spin-coated at 4000 RPM for 30 sec, followed by annealing for 30 min in a furnace that was pre-heated to 150° C. Then, a second layer was formed by spin-coating 0.12 ml of the TiO2/SiO2 mixture at 2000 RPM for 30 sec and annealing at 150° C. for 30 min. A new TiO2/SiO2 suspension was made, this time with 3.04 ml of the P25 suspension, 4.9 ml of the TEOS-LUDOX mixture and 1.5 ml of n-propanol, stirred for 10 min and then sonicated for 10 min. From this suspension, 0.1 ml was spin-coated on each plate at 1500 RPM for 30 sec, followed by annealing at 150° C. for 30 min, thus forming a third layer. Then, a fourth layer, made by spin coating another 0.1 ml of the suspension on each plate at 1500 RPM for 30 sec, following by annealing at 150° C. for 30 min was grown.
Two solutions, one of 0.25 mg/L of L-LG in DIW and the other of 0.25 mg/L D-LG in deionized water, were prepared. 0.2 ml of the L-LG solution was spin coated on 6 of the prepared plates at 4000 RPM for 90 sec. Then, 0.2 ml of the D-LG solution was spin coated at 4000 RPM for 90 sec on another 6 of the prepared plates. 10 more plates were left without templating.
Two plates coated with L-LG, two plates coated with D-LG and two plates with no adsorbed molecules were overcoated with 6 cycles of TMA and water as described in example 1. Similarly, two plates of each described type were coated with 10 and 14 cycles of TMA and water. 4 plates were left without overcoating.
This example shows the characterization of the thickness of the ALD-grown overcoating layer after 10 cycles, as ALD growth models usually describe significantly thicker layers.
A silicon wafer was cut into pieces, UVOCS® cleaned, and deposited with 600 μl of an 0.25 mg/ml L-LeuGly solution via spin-coating at 1000 RPM for 2 min, followed by 10 cycles of ALD as described in previous examples. The wafer was then coated with 30 nm of graphite by thermal evaporation followed by 100 nm of chrome by sputtering in order to protect the structure from radiation damage, and was cut into a lamella using FIB. The lamella was imaged using HR-STEM coupled to EDS elemental analysis.
A Bi+3 stock solution was made by dissolving Bi(NO3)3·5H2O in ethylene glycol (48.52 gr/lit), and Cl− stock solution was made by dissolving KCl in deionized water (DIW) (7.441 gr/lit). Both were stirred overnight at room temperature to obtain homogenous solutions. For each batch, 150 ml the Bi+3 solution was placed under stirring in an Erlenmeyer, followed by the slow addition of 150 ml of the KCl solution under stirring to obtain a milky suspension. To samples where matrix-imprinting was performed, either L-LeuGly or D-LeuGly were added in a 1:20 LeuGly:Bi molar ratio (˜145 mg in 300 ml). Reaction commenced for 24 hrs, after which the sample was filtered, washed and dried at 60° C.
B. Preparation of Photocatalyst Films Made from Matrix-Imprinted BiOCl in a Silica Binder
The dried powders were suspended in deionized water at a concentration of 240 mg/ml, sonicated for 5 min, followed by overnight stirring. For better adhesion to the silica substrates, an SiO2 binder suspension was made by sequentially mixing, in a dropwise manner, TEOS, LUDOX colloidal suspension, 37% HCl and isopropanol in a 1.42:2.17:0.034:6.38 volumetric ratio. This suspension was also stirred overnight. The BiOCl suspension was mixed into the TEOS suspension, followed by the addition of n-propanol in a 1:1.612:0.493 volumetric ratio, and thoroughly sonicated for 5 min. This suspension was then deposited using spin-coating on precut 1″×0.5″ fused silica plates, precleaned with ethanol, acetone and water followed by 5 min UVOCS cleaning. 150 μl was deposited on each plate, and spun for 30 sec at 2000 RPM, followed by overnight drying at 60° C. An additional layer was deposited in a similar fashion, for a total of two layers.
Some of these plates were then sent for 10 cycles of Al2O3 ALD overcoating using the same procedure described in previous examples.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2021/051248 | 10/21/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63105360 | Oct 2020 | US |
