JP4688418B2 - Nanofilm and membrane composition - Google Patents

Description

(Cross-reference to related applications)
This application claims the benefit of US Provisional Patent Application No. 60 / 383,236 (filed on May 22, 2002) and is a part of US Application No. 10 / 226,400 (filed on August 23, 2002). This is a continuation-in-part application, which is a continuation-in-part of US application Ser. No. 10 / 071,377 (filed Feb. 7, 2002), which is incorporated herein by reference in its entirety.

(Field of Invention)
The present invention relates to combined oriented amphiphilic macrocycle modules, nanofilms with specific permeation properties, and various thin layer compositions of nanofilms for filtration and separation. Thin layer nanofilms can be applied to various selective permeation processes.

(Background of the Invention)
Nanotechnology includes the ability to design new structures at the atomic and molecular levels. One nanotechnology field involves the development of chemical substructures, from which hierarchical molecules of the expected characteristics can be assembled. The approach to creating chemical substructures or nanostructures starts at the atomic and molecular level by designing and synthesizing starting materials with high tuning properties. Accurate control at the atomic level is the basis for the development of rationally tailored synthetic structural property relationships, which can provide materials with unique structures and predictable properties. This approach to nanotechnology is inspired by nature. For example, biological mechanisms are based on a structural level hierarchy: atoms are formed in organelles, cells, and finally biological molecules that are placed into organisms. These substructure capabilities are unprecedented in conventional materials and methods (eg, polymerization to produce a statistical mixture, or reactant limitations to enhance specific reaction pathways). For example, the common amino acids 20 found in the native protein, 10 ⁵ or more stable and unique protein is produced.

  One area that benefits from nanotechnology is filtration through membranes. Conventional membranes used in various separation processes can be made selectively permeable to various molecular species. In general, the permeability characteristics of conventional membranes depend on the transport pathway of the species through the membrane structure. Although diffusion paths in conventional permselective materials can be serpentine to control permeation, porosity is not well defined or controlled in conventional methods. The ability to assemble a regular or unique pore structure of the membrane is one of the long-term goals of separation technology.

  The resistance of the species flow through the membrane can depend on the length of the flow path. The resistance can be greatly reduced by using a very thin film as the membrane at the expense of the reduced mechanical strength of the membrane material. Conventional membranes can have a barrier thickness of at least 100-200 nanometers, often in the millimeter range. In general, a thin film of membrane barrier material can be deposited on a thicker porous substrate to restore material strength.

  Membrane separation processes are used to separate components from fluids and may separate atomic or molecular components that are less than a particular “cut-off” size from larger components. Normally, species that are smaller than the cut-off size will pass through the membrane. The cut-off size can be approximately an empirical value, which reflects the phenomenon that the transport rate of components smaller than the cut-off size is simply faster than the transport rate of large components. In conventional pressure-driven membrane separation processes, the major factors that affect component separation are the size, charge, and diffusivity of the components in the membrane structure. In dialysis, the driving force for separation is a concentration gradient, while in electrodialysis, an electromotive force is applied to the ion selective membrane.

  In all these methods, what is needed is a selective permeable membrane barrier for the components of the liquid to be separated.

(Summary of Invention)
In one aspect, the present invention relates to a nanofilm comprising bound oriented amphiphilic macrocyclic modules. The nanofilm module can be attached through the reactive functional group of the module or can be attached through a linker molecule. This coupling can be initiated by chemical, thermal, photochemical, electrochemical or radiation methods.

In some variations, the nanofilm thickness is less than about 30 nanometers, in some cases less than about 4 nanometers, and in some cases about 1 nanometer.
The nanofilm can have a filtration function that can be used to describe the species that pass through the nanofilm. Nanofilms can be permeable only to certain species in certain fluids and species that are smaller than certain species. Nanofilms can have a molecular weight cutoff.
Certain nanofilms can be highly permeable to certain species in certain solvents. Nanofilms can have low permeability to certain species in certain solvents. Nanofilms can be highly permeable to specific species in a particular solvent and have low permeability to other species in a particular solvent.
The nanofilm barrier can be made from a layer of nanofilm. A spacing layer can be used between any two nanofilm layers. Spacing layers can include polymer layers, gel layers, and other substrate layers.
The nanofilm can be deposited on a substrate, which can be porous or non-porous. The nanofilm can have surface binding groups and can be covalently bonded to the substrate through the surface binding groups or can be bonded to the substrate by ionic interaction.
In another variation, the invention relates to a filtration method that includes using a nanofilm to separate components or species from a fluid or solution.
In some cases, the nanofilm is composed of oriented macrocyclic modules deposited on a substrate using a Langmuir trough. In other variations, nanofilms can be made from bound oriented amphiphilic molecules and oriented amphiphilic macrocyclic modules.
In one variation, the nanofilm is composed of oriented amphiphilic molecules joined through hydrophilic groups.

(Detailed description of the invention)
(Macrocyclic module and nanofilm composition)
In one aspect, the invention relates to nanotechnology in the preparation of porous structures and materials with pores of atomic to molecular size. These materials may have a unique structure that is repeated at regular intervals to provide a grid of holes having a substantially uniform size. The unique structure can have a variety of shapes and sizes, thus providing holes of various shapes and sizes. Since unique structures can be formed with monolayers of molecular thickness, the pores defined by the unique structure can include cavities, gaps, or chamber-like structures of molecular size. In general, the pores of atoms to the molecular size defined by these unique structures can be used for selective permeation or molecular sieving functions. Some aspects of nanotechnology are described in Nanostructured Materials, J. MoI. Ying, Academic Press, San Diego, 2001.
The invention further includes the rational design of molecules that can be assembled as building blocks for further assembly into larger species. Standardized molecular subunits or modules can be used from which hierarchical molecules of the expected properties can be assembled. Coupling reactions can be used to join or connect modules in an oriented synthesis.
Nanotechnology involves the assembly of molecular structures to form intermediate sized hierarchical molecules with built-in orientation. Ideally, nanoassemblies begin with a set of synthons that can be assembled to create a module. A synthon is an individual molecule that is the primary starting material. This module may have a set of “arms” destined to interconnect with other modules. A module is a combination of covalently linked synthons. Modules can be used as building blocks for larger molecular species, including uniquely structured species and compositions. A wide range of real-world applications (eg, membranes or porous materials) can be derived from nanochemical means, compositions, and processes.
Molecular modules can be prepared from cyclic organic synthons. The synthons can be bonded together or bonded together to form a module. For example, macrocyclic modules can be prepared with cyclic organic synthons R, R-1,2-transdiaminocyclohexane and 4-substituted 2,6-diformylphenol. These synthons can be combined to form a hexameric macrocyclic module having the following configuration:

Each R group can be different.
This hexamer module and other modules are useful as building blocks to provide structures with specific control and predictable properties. Macrocyclic modules and amphiphilic macrocyclic modules prepared from cyclic organic synthons are described in US patent application Ser. Nos. 10 / 071,377 and 10 / 226,400 and are entitled “Macrocyclic module compositions”. PCT application (filed February 7, 2003) (incorporated herein by reference). Examples of synthons, macrocycle modules and amphiphilic macrocycle modules, and their composites are further described herein below.
Examples of modules useful as building blocks are shown in Table 1:

By providing functional groups to the module that give it an amphiphilic character, the macrocyclic module can be oriented on the surface. For example, if the module is deposited on a hydrophilic surface, the module can rearrange on the surface by hydrophobic substituents or hydrophobic tails attached to the module so that the hydrophobic substituents can be Orient away (leave more hydrophilic facets of the module oriented with respect to this surface). Examples of hydrophobic groups are lower alkyl groups, alkyl groups containing 7, 8, 9, 10, 11, 12 or more carbon atoms (14-30, or 30 or more Including alkyl groups having carbon atoms), substituted alkyl groups, aryl groups, substituted aryls, saturated or unsaturated cyclic hydrocarbons, heteroaryls, heteroarylalkyls, heterocycles, and corresponding substituents. As long as the hydrophobic character of the group is not exceeded, the hydrophobic group may contain several hydrophilic groups or hydrophilic substituents. In further variations, the hydrophobic group can include substituted silicon atoms and can include fluorine atoms.
In other cases, hydrophilic groups may be included in the module that cause the orientation of the module on the surface. Examples of hydrophilic groups include hydroxyl, methoxy, phenol, carboxylic acids and their salts, methyl, ethyl, and vinyl esters of carboxylic acids, amides, amino, cyano, ammonium salts, sulfonium salts, phosphonium salts, polyethylene glycol, epoxy groups, acrylate, sulfonamides, _{nitro, -OP (O) (OCH 2} CH 2 N + RR'R '') O -, guanidinium, aminated, acrylamide, pyridinium, piperidine, and combinations thereof (here , R, R ′, and R ″ are each independently selected from H or alkyl).
The conformation of a surface molecule can depend on the loading, density, or state of the phase or layer that the molecule is on the surface. Surfaces that can be used to orient the module include interfaces (eg, gas-liquid, air-water, immiscible liquid-liquid, liquid-solid, or gas-liquid interface). The thickness of the oriented layer can be substantially a monolayer thickness.
Nanofilms are thin films and can be prepared from macrocyclic modules. Nanofilms can also be prepared from macrocyclic modules in combination with other non-module molecules. In some cases, nanofilms can be prepared from non-modular molecules. The module forming the nanofilm can be deposited on the surface. In some cases, nanofilms are prepared from bonded modules.
Nanofilm compositions can be prepared by orienting amphiphilic macrocycle modules on the surface. A surface-oriented macrocyclic module disposed in a nanofilm layer can provide a unique composition. Nanofilm compositions prepared from surface-oriented macrocyclic modules can be solids, gels, or liquids. The nanofilm module can be in an expanded state, a liquid state, or a liquid expanded state. The state of the nanofilm module can be condensed (collapsed), or it can be in solid phase or in close packing. Nanofilm modules can interact with each other with weak suction. Nanofilm modules prepared from surface-oriented macrocyclic modules do not need to be connected by any strong interaction or coupling. Alternatively, the nanofilm modules can be linked, for example, via covalent bonds or ionic interactions.

As used herein, the term “coupling” for a molecular moiety or species, molecule, and module refers to a linkage or association with another molecular moiety or species, molecule, module (this linkage or The association is specific or non-specific, reversible or irreversible, the result of a chemical reaction, or the result of a direct or indirect physical interaction, weak interaction, or hydrophobic / hydrophilic interaction or , Regardless of whether it is the result of magnetic interaction, electrostatic interaction or electromagnetic interaction). Coupling can be specific or non-specific, and the bond formed by the coupling reaction is often a covalent bond, polar covalent bond, or mixed ionic covalent bond, sometimes hydrogen bond, van der Waals It can be force, London force, ionic force or ionic interaction, electrostatic force or electrostatic interaction, dipole-dipole or dispersive, or other type of coupling.
Modules oriented on the surface can be combined to form a thin layer composition or nanofilm. The surface orientation modules can be combined in a two-dimensional array to form a substantially monolayer nanofilm. A two-dimensional array is generally a single molecular thickness that passes through a thin layer composition and can vary locally due to physical and chemical forces. Module coupling may be performed to form a substantially two-dimensional thin film by orienting the module on the surface before or during the coupling process.
Macrocyclic modules can be prepared to possess reactive functional groups that allow coupling of the module. The natural product formed by the coupling module depends in one variation on the relative orientation of the reactive functional groups with respect to the module structure, and in other cases is covalent, non-covalent or Depends on the arrangement of complementary functional groups in different modules that can form other binding attachments.
In one variation, the module includes reactive functional groups (directly linked to complementary reactive functional groups of other modules to form a link between the modules). The reactive functional group can contribute to the amphiphilic character of the module before or after binding and can be covalently or non-covalently attached to the module. The reactive functional group can be attached to the module before, during or after orientation of the module on the surface.
Examples of reactive functional groups of the module and bonds formed with the coupling module include those shown in Table 2. Each module may have 1 to 30 or more reactive functional groups often selected to bind to another module.
In making a nanofilm from a macrocyclic module and other components, one or more coupling bonds can be formed between the macrocyclic module and the coupling is between the macrocyclic module and the other components. Can occur between. The bond formed between the macrocycle modules can be the product of the coupling of one functional group from each macrocycle module. For example, the hydroxyl group of the first macrocyclic module can be bonded to the acid group or acid halide group of the second macrocyclic module to form an ester bond between the two macrocyclic modules. Another example is an imine bond (—CH═N—) resulting from the reaction of an aldehyde (—CH═O) on one macrocyclic module with an amine (—NH ₂ ) on another macrocyclic module. . Examples of coupling between macrocyclic modules are shown in Table 2.

In Table 2, R and R 'represent hydrogen or an alkyl group, and X is a halogen or other suitable leaving group.

These functional groups can be separated from the module by spacer groups. Examples of spacer groups are alkylene, aryl, acylalkoxy, saturated or unsaturated cyclic hydrocarbons, heteroaryl, heteroarylalkyl, or heterocyclic groups, and the corresponding substituents. Additional examples of spacer groups include polymer, copolymer, or oligomer chains (eg, polyethylene oxide, polypropylene oxide, polysaccharides, polylysine, polypeptides, poly (amino acids), polyvinyl pyrrolidone, polyesters, polyacrylates, polyamines, polyimines, polystyrenes, poly (Vinyl acetate), polytetrafluoroethylene, polyisoprene, neopropene, polycarbonate, polyvinyl chloride, polyvinylidene fluoride, polyvinyl alcohol, polyurethane, polyamide, polyimide, polysulfone, polyethersulfone, polysulfonamide, polysulfoxide, and their Examples of polymer chain spacer structures include linear, branched, comb polymers as well as dendritic polymers, random copolymers. And block copolymers, homopolymers and heteropolymers, flexible chains and rigid chains, spacers can be any group that does not interfere with bond formation, the spacer group being a reactive functional group to which it is attached. It may be substantially longer or shorter.
Coupling of the surface orientation modules to each other can occur via coupling of the reactive functional group of the module and a linker molecule. The reactive functional groups involved can be those exemplified in Table 2. A module can be coupled to at least one other module via a linker molecule. A linker molecule is a separate molecular species used to couple at least two modules. Each module can have 1 to 30 or more reactive functional groups that can be coupled to a linker molecule. The linker molecule can have 1 to 20 or more reactive functional groups that can be coupled to the module.
In some cases, the linker molecule has at least two reactive functional groups, and each reactive functional group can be coupled to the module. In these variations, the linker molecule can include various reactive functional groups for the coupling module. Examples of reactive functional groups and linker molecules of the module are illustrated in Table 3.

In Table 3, n = 1 to 6, m = 1 to 10, R = CH ₃ or H, R ′ = — (CH ₂ ) _n — or phenyl, R ″ = — (CH ₂ ) —, polyethylene glycol ( PEG) or polypropylene glycol (PPG), and X consists of Br, Cl, I or other good leaving groups (carbon, oxygen, nitrogen, halogen, silicon, phosphorus, sulfur and hydrogen atoms only, and 1-20 Organic group having carbon atoms). The module may have various reactive functional group combinations exemplified in Table 3.
Methods for initiating coupling of the module to the linker molecule include chemical methods, thermal methods, photochemical methods, electrochemical methods, and radiation methods.
In one variation illustrated in FIG. 1, a hexameric 1dh module is coupled to a second module via a diethylmalon imidate linker.
Coupling together with one or more members of the module collection, possibly with other bulky or flexible components, to form a thin layer nanofilm material or thin layer nanofilm composition Can produce a nanofilm comprising connected modules. Module coupling may be complete or incomplete and provides various structural variations useful as nanofilm membranes. Nanofilms can have a unique molecular structure. Nanofilm composite structures made from orientation modules and coupling modules can include unique molecular structures with other component structures. The structure of the nanofilm can be a substantially crystalline structure with the exact order of modules coupled over a long distance compared to the size of the module. Nanofilms having a glass structure can also be prepared. Other nanofilms have a module order that is not too long and are amorphous in molecular form. In some variations, the nanofilm is an elastomeric composition of the coupled module. In other cases, the nanofilm is a brittle thin film. Certain nanofilms can be found to have regions with more than one of these structural variations.
Nanofilms made from surface oriented molecular species or modules are very small, often less than about 30 nanometers, sometimes less than about 20 nanometers, and sometimes about 15, 14, 13, 12 , 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or less. The thickness of the nanofilm depends in part on the structure on the module and the nature of the group that gives the module an amphiphilic character. The thickness can depend on the temperature and the presence of a solvent on the surface, or the presence of a solvent located within the nanofilm. Thickness if the group on the module that gives the module an amphiphilic character is removed or modified after the module is coupled, or at other times during or after the nanofilm preparation process Can be modified. The thickness of the nanofilm can also depend on the structure and properties of the surface binding groups on the module. If surface binding groups on the module are removed or modified after the module is coupled, or at other times during or after the nanofilm preparation process, the thickness can be modified. The thickness of the nanofilm made from surface oriented molecular species or modules can be about 300, 200, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 mm. Can be less.
In some cases, the nanofilm can be derivatized to provide biocompatibility or to reduce fouling of the nanofilm due to biomolecule binding or adsorption.
The nanofilm composition may include regions that are uniquely structured (modules connected). The coupling of the module provides a nanofilm where a unique structure can be formed. The structure of the nanofilm defines pores through which atoms, molecules, or particles up to a certain size and composition can pass. One variation of the nanofilm structure faces the fluid medium, either liquid or gas, and provides pores or openings through which atoms, ions, small molecules, biomolecules, or other species can pass. A region of possible nanofilm. The pore dimensions defined by the nanofilm structure can be exemplified by quantum mechanical calculations and evaluations, as well as physical tests.
The pore size defined by the nanofilm structure is explained by the atomic and chemical structure features of the actual nanofilm. The approximate straight dimension of the holes formed in the structure of the nanofilm is about 1-150 inches or more. In certain embodiments, the pore size is about 1-10 mm, about 3-15 mm, about 10-15 mm, about 15-20 mm, about 20-30 mm, about 30-40 mm, about 40-50 mm, about 50-75 mm, It is about 75-100cm, about 100-125cm, about 125-150cm, about 150-300cm, about 300-600cm, about 600-1000cm. The approximate size of the pores formed in the structure of the nanofilm is useful for understanding the porosity of the nanofilm. On the other hand, the porosity of conventional membranes is usually quantified by experimental results such as molecular weight cut-off, which reflects complex diffusivity and other transport properties.
In one variation, the nanofilm structure can be an array of coupled modules that provides an array of substantially uniform sized holes. Uniformly sized holes can be defined by the individual modules themselves. Each module defines a specific size hole, depending on the higher order structure and condition of the module. For example, the higher order structure of the nanofilm linked module may be different from the nascent pure macrocyclic module in the solvent, and both are higher than the higher order structure of the surface direction amphiphilic module prior to coupling. Can be different. A nanofilm structure comprising an array of couplings in a coupled module can provide a matrix or lattice of substantially uniform dimensions based on the structure and higher order structure of the coupled module.
Modules of various compositions and structures that define different sized pores can be prepared. Nanofilms prepared from coupled modules can be made from any one of a variety of modules. Thus, depending on the particular module used to prepare the nanofilm, nanofilms having various dimensions are provided.
In other cases, the nanofilm structure defines pores in the matrix of connected modules. The pores defined by the nanofilm structure can have a wide range of dimensions (eg, dimensions that can selectively prevent the passage of small or macromolecules). A nanofilm structure can be formed from the coupling of two or more modules, where the interstitial pores are defined by the coupling structure of the connected modules. Nanofilms can have an expanded matrix of pores with various dimensions and characteristics. The interstitial pores are, for example, less than about 5 mm, less than about 10 mm, about 3-15 mm, about 10-15 mm, about 15-20 mm, about 20-30 mm, about 30-40 mm, about 40-50 mm, about 50-75 mm. About 75-100 inches, about 100-125 inches, about 125-150 inches, about 150-300 inches, about 300-600 inches, about 600-1000 inches.
The coupling process can yield nanofilms where the area of the nanofilm is not exactly a monolayer. Various types of local structures are possible that do not prevent the use of nanofilms in various applications. Local structural features may include amphiphilic modules that are flipped over or bent in a different direction relative to adjacent modules, with hydrophobic and hydrophilic surfaces oriented differently from adjacent modules. Have. In addition, local structural features include module overlap (the nanofilm is the thickness of two or more molecular layers), local regions (the molecular coupling is not perfect, so some coupling of the module Group may not be coupled to other modules), or may include local regions in the absence of modules. In one variation, due to the layering of the nanofilm structure, the nanofilm has a thickness of up to 30 nanometers.
As used herein, a nanofilm comprising a “directional macrocycle” is a localized structural feature as indicated above, although the macrocycle is oriented substantially uniformly within the film. It can be included that Local structural features are, for example, greater than about 30%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3% of the surface area of the nanofilm. Less than about 1%. Similarly, nanofilms containing “directional amphiphilic molecules” have a region of localized structural features, as indicated above, although the amphiphilic molecules are oriented substantially uniformly within the film. Indicates that it can be included. Local structural features are, for example, greater than about 30%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3% of the surface area of the nanofilm. Less than about 1%.
Nanofilms can also be prepared with a mixture of different modules or with a mixture of macrocyclic modules and other amphiphilic molecules. These nanofilms are an array of coupled modules and other amphiphilic molecules (random order of modules and other amphiphilic molecules, or one type of species is dominant) May not be random in certain regions). Also, nanofilms made from a mixture of different modules, or nanofilms having a mixture of macrocyclic modules and other amphiphilic molecules can disperse an array of pores of various sizes.
In the Langmuir film method, a monolayer of directional amphiphilic species is formed on the surface of the liquid lower phase. Typically, movable plates or barriers are used to compress a monolayer and reduce its surface area to form a thicker monolayer. At different degrees of compression with corresponding surface pressures, the monolayer can reach different condensed states. In some cases, the film reaches a collapse point where a single condensed layer occurs with reduced surface pressure.
The isotherm of surface pressure versus film area is obtained by the Wilhelmy balance method to monitor the film condition. Extrapolation of the isotherm to zero surface pressure reveals the average surface area per module before the modules are coupled. When the hydrophobic group used to orient the molecules of the Langmuir film monolayer is a fatty acid group, the collapse typically occurs at a molecular surface area of about 20 ² / molecule. Thus, the isotherm gives an empirical indication of the state of the thin film.
The nanofilm of oriented chemical species can be deposited on the substrate by various methods to provide a porous film. For example, descriptions of Langmuir films and substrates are described in U.S. Patent Nos. 6,036,778, 4,722,856, 4,554,076, and 5,102,798, and R.A. A. Hendel et al., 119, J. Am. Am. Chem. Soc. 6909-18 (1997). A description of the film on the substrate is given in Munier Cheryan, Ultrafiltration and Microfiltration Handbook (1998).
The substrate can be any surface of any material. The substrate can be porous and non-porous. Examples of porous substrates are polymers, track-etch polycarbonate, track-etch polyester, polyethersulfone, polysulfone, gel, hydrogel, cellulose acetate, polyamide, PVDF, ceramic, anodic alumina, laser cut polyimide And UV etched polyacrylates. Examples of non-porous substrates are silicon, metal, gold, glass, silicates, aluminosilicates, non-porous polymers and mica.
In forming nanofilms using the Lagmuir film method, linker molecules, if present, can be added to the solution containing the module that is deposited on the surface of the Langmuir lower phase. Alternatively, linker molecules can be added to the lower phase of the Langmuir trough and subsequently transferred to the module layer phase for coupling with the module. In some cases, the modules can be added to the lower phase of the Langmuir trough and subsequently transferred to the phase of the module layer for coupling with other modules.
Amphiphilic molecules can be oriented on the surface (eg, air-water interface) in the Langmuir trough. Surface oriented amphiphilic molecules can be compressed to form a Langmuir film. The Langmuir film amphiphilic molecules can be coupled to each other or linked to form a substantially monolayer thin film material. The polar groups of the amphiphilic molecules of the Langmuir film can be coupled together by a coupling reaction to form a thin film material. The hydrophobic tail length of the amphiphilic molecule can be about 8 to 28 carbon atoms. Examples of the hydrophobic tail of an amphiphilic molecule include a hydrophobic group that can be attached to a macrocyclic module to give the module an amphiphilic character.
Examples of polar groups of amphiphilic molecules include amide, amino, ester, -SH, acrylate, acrylamide, epoxy and hydrophilic groups as defined above. The polar groups of the amphiphilic molecule can be directly linked to each other. For example, sulfhydryl groups can be coupled to form disulfide couplings between amphiphilic molecules of Langmuir film. Examples of polar groups include —OH, —OCH ₃ , —NH ₂ , —C≡N, —NO ₂ , — ⁺ NRR′R ″, —SO ₃ ^— , —OPO ₂ ²⁻ , —OC (O ) CH═CH ₂ , —SO ₂ NH ₂ , SO ₂ NRR ′, —OP (O) (OCH ₂ CH ₂ N ⁺ RR′R ″) O ⁻ , —C (O) OH, —C (O) O ⁻ , guanidinium, aminonate, pyridinium, —C (O) OCH ₃ , —C (O) OCH ₂ CH ₃ ,

(Where w is a _{1~6), - C (O)} OCH = CH 2, -O (CH 2) x C (O) NH 2 ( where x is 1 to 6), - _{O (CH 2) y C (} O) NHR ( where y is 1 to 6 a is) (wherein, z is 1 to 6) and _{-O (CH 2 CH 2 O)} z R include It is done.
Coupling can couple two amphiphilic molecules by disulfide coupling, for example, as illustrated in FIG. Coupling can bind more than two amphiphilic molecules, for example, by extended amide coupling. Some of the amphiphilic molecules of the nanofilm can be coupled, but the residue is not bound. Nanofilm amphiphilic molecules (both coupled and uncoupled) can also be via weak non-coupling or coupling interactions (eg hydrogen coupling and other interactions). Can interact.
Pore and barrier properties are found in the structure of nanofilms made by coupling amphiphilic molecules. Pore and barrier properties can be modified by the degree or degree of coupling interaction of amphiphilic molecules and, for example, by linker molecule length.
Polar groups with ester groups and amino groups can be coupled to attach amphiphilic molecules via amide coupling, as illustrated in FIG.
The polar groups of amphiphilic molecules can be linked together with a linker molecule. For example, the amino group of an amphiphilic molecule of a Langmuir film can be coupled with formaldehyde by a Mannich reaction, as illustrated in FIG. The Langmuir film of amphiphile is illustrated on the left side of FIG. 4, and the connection structure formed in the nanofilm when coupling the amphiphile is illustrated on the right side of FIG. Film materials formed by coupling amphiphilic molecules of Langmuir film can have barrier properties useful for filtration.
Nanofilms can be prepared from amphiphilic macrocyclic modules oriented on the surface (eg, air-lower phase interface in a Langmuir trough) without coupling the modules. Amphiphilic modules can be prepared with linking groups that interact with the surface causing the module's orientation. A substantially uniform oriented amphiphilic module monolayer (eg, Langmuir film) can be formed on a hydrophilic surface. A surface-oriented macrocycle module is a nanofilm layer (which can be in an expanded state, a liquid state or a liquid-expanded state, or can be agglomerated, disintegrated, or a solid phase or a dense state) that provides a uniform composition Can be arranged. Nanofilms of oriented amphiphilic macrocyclic modules can be deposited on a substrate by a variety of methods to provide a porous membrane.
Nanofilms can be prepared by orienting amphiphilic macrocycle modules and coupling the modules. The modules can be coupled directly or via a linker molecule. The module can be dissolved in a solvent and deposited at the air-lower phase interface in the Langmuir trough. Amphiphilic modules can be oriented at this interface and compressed into agglomerated films.
The linker molecule can be added to the lower phase or solvent containing the module deposited in the lower phase.
Module coupling can be initiated by chemical methods, thermal methods, photochemical methods, electrochemical methods, and radiation methods.
Coupling of modules in a nanofilm can couple two or more modules by bonding. A coupling may couple two or more modules, for example, with an array of each coupling formed between the two modules. Each module may form more than one bond to another module, and each module may form several types of couplings, including those illustrated in Table 2 and Table 3. . The module may have a direct coupling, a coupling through a linker molecule, and a coupling including a spacer in any combination. Coupling may connect any part of a module to any part of another module. An array of couplings and an array of modules can be described in relation to Bravais lattice theory and symmetry theory.
Some of the nanofilm modules can be coupled, while the rest are not. Nanofilm modules (both coupled and uncoupled) can also have weak non-coupling or coupling interactions (eg hydrogen coupling, van der Waals forces and other interactions) Can interact through. The array of couplings formed in the nanofilm can be represented by a symmetric type or can be substantially unordered.
Functional groups that are added to the module to impart amphiphilic characteristics to the module can be removed after nanofilm formation. The removal method depends on the functional group. For example, lipophilic groups or lipophilic tails attached to the module can be selectively removed. Groups attached to the module that provide amphiphilic characteristics to the module can include reactive functional groups that can be used to remove groups during the nanofilm formation process or at some point thereafter. . Acid hydrolysis or base hydrolysis can be used to remove groups attached to the module by carboxylic acid bonds or amide bonds. Unsaturated groups located in functional groups that give the module amphiphilic character can be oxidized and cleaved by hydrolysis. Also, photolytic cleavage of functional groups that impart amphiphilic character to the module can be performed. Examples of cleavable functional groups include

(Where n is 0-4, which is cleaved by photoactivity), and

(Where n is 0 to 4 and m is 7 to 27, which is cleaved by acid-catalyzed hydrolysis or base-catalyzed hydrolysis).

  Examples of functional groups added to the module that give the module an amphiphilic character include 8C-28C alkyl groups, -O (8C-28C) alkyl, -NH (8C-28C) alkyl, -OC (O). -(8C-28C) alkyl, -C (O) O- (8C-28C) alkyl, -NHC (O)-(8C-28C) alkyl, -C (O) NH- (8C-28C) alkyl,- The carbon atom of CH = CH- (8C-28C) alkyl, and -C≡C- (8C-28C) alkyl ((8C-28C) alkyl group has one or more -S-, double coupling, triple Can be interrupted by a coupling or —SiR′R ″ group, substituted with one or more fluorine atoms or any combination thereof, and R ′ and R ″ are independently (1C-18C) alkyl. Including a), and the like.

(Membrane and filtration)
For example, a membrane that separates chemical species or components from a fluid or solution for filtration purposes is a medium that is contacted with the fluid or solution. Usually, the membrane is a substance that allows the restriction or control of the passage of other chemical species, but acts as a barrier to prevent the passage of some chemical species. In general, the permeants can penetrate the membrane if they have a molecular weight that is smaller than the cut-off size or smaller than the so-called cut-off molecular weight. The membrane may be said to be impermeable to species that are larger than the cutoff molecular weight. Cut-off size or cut-off molecular weight is a characteristic property of the membrane. Selective permeation is the ability of the membrane to cut off, limit or regulate the passage of some species while allowing smaller species to pass through. Thus, selective permeation of the membrane can be functionally described with respect to the largest species that can pass through the membrane under given conditions. Also, the size or molecular weight of the various chemical species can depend on the conditions of the liquid to be separated (which can be determined by the formation of the chemical species). For example, the chemical species may have a range of hydration or solvation in the fluid, and the size of these chemical species associated with the application of the membrane may or may not include hydration water or solvent molecules. Also good. Thus, if a chemical species can permeate the membrane in this form (usually it is found in the fluid), the membrane is permeable to the fluid chemical species. Permeation and permeability can be affected by the interaction between the fluid species and the membrane itself. Although various theories can explain these interactions, experimental measurement of pass / no pass information associated with nanofilms, membranes, or modules is a useful tool for describing transmission properties. If the chemical species cannot pass through the membrane, the membrane is impermeable to the chemical species.
Nanofilms can be, for example, above about 15 kDa, above about 10 kDa, above about 5 kDa, above about 1 kDa, above about 800 Da, above about 600 Da, above about 400 Da, above about 200 Da, above about 100 Da. , Greater than about 50 Da, greater than about 20 Da, less than about 15 kDa, less than about 10 kDa, less than about 5 kDa, less than about 1 kDa, less than about 800 Da, less than about 600 Da, less than about 400 Da, less than about 200 Da, less than about 100 Da, less than about 50 Da , Less than about 20 Da, about 13 kDa, about 190 Da, about 100 Da, about 45 Da, about 20 Da molecular weight species cutoffs.
“High permeability” indicates, for example, a clearance of about 70% or more, about 80 or more, about 90 or more of the solute. “Medium permeability” refers to clearance of, for example, less than about 50%, less than about 60%, less than about 70% of the solute. “Low permeability” indicates, for example, a clearance of less than about 10%, less than about 20%, less than about 30% of the solute. A membrane that has a very low clearance for a chemical species (eg, less than about 5%, less than about 3%) or has a very high elimination reaction for a chemical species (eg, about 95% or more, about 98% or more). Is impermeable to chemical species. The passage or exclusion of the solute is measured by its clearance (which reflects the portion of the solute that actually passes through the membrane). For example, the absence of a pass symbol in Tables 13-14 is that the solute is partly due to the module (sometimes less than 90% exclusion reaction, often at least 90% exclusion reaction, sometimes at least 98% exclusion reaction). Indicates to be excluded. The pass symbol indicates that the solute is partially cleared by the module (sometimes less than 90% clearance, often at least 90% clearance, sometimes at least 98% clearance).
The nanofilm can be deposited on a substrate. Deposition can result in non-covalent or weak adhesion of the film to the substrate via physical interactions and weak chemical forces (eg, van der Waals forces, weak hydrogen bond formation). The membrane can be bound to the substrate by ionic interaction, covalent interaction, or other coupling. The nanofilm deposited on the substrate can function as a membrane. Any number of nanofilm layers can also be deposited on the substrate to form a film.
A single layer or a plurality of layers of various spacing materials can be deposited or attached between the nanofilm layers, and the spacing layer can be attached to the substrate and the first nanolayer. It can be used between the deposited layers of the film. Examples of the composition of the spacing layer include polymer compositions, hydrogels (acrylates, polyvinyl alcohol, polyurethane, silicone), thermoplastic polymers (polyolefins, polyacetals, polycarbonates, polyesters, cellulose esters), polymer foams, heat Biodegradable polymers such as curable polymers, hyperbranched polymers, polylactides, liquid crystalline polymers, polymers made by atom transport group polymerization (ATRP), polymers made by ring-opening metathesis polymerization (ROMP), poly Examples include isobutylene-based and polyisobutylene-based star polymers, and amphiphilic polymers (eg, poly (octadecene maleic anhydride)). Examples of amphiphilic molecules include amphoteric substances containing polymerized groups such as diynes, enes, or aminoesters. The spacing layer can serve to modify the barrier properties of the nanofilm, or can serve to modify transport, flow, or the flow properties of the membrane or nanofilm. Spacing layers can help to modify the functional properties (eg, strength, module or other properties) of the membrane or nanofilm.
Nanofilm deposition on a substrate can be performed by Langmuir-Schaefer, Langmuir-Blodgett or other methods used with Langmuir systems. In one variation, the nanofilm is deposited on the substrate in the Langmuir tank by the position of the substrate in the lower phase below the air-water interface, and the lower phase level until the nanofilm is gradually positioned on the substrate. Is deposited by lowering, thereby depositing.
The nanofilm deposited on the substrate can be cured or annealed by radiation, heat treatment, or drying methods during or after deposition of the substrate.
The nanofilm can be attached to the substrate surface with covalent or non-covalent chemical bonds. To attach the membrane to the substrate, a surface attachment group can be provided on the macrocyclic module that can be used to bond to the substrate. In order to attach the nanofilm to the substrate, several couplings can be performed instead of all surface attachment groups. Examples of reactive functional group modules that can be used as surface attachment groups to bind nanofilms to substrates include amines, carboxylic acids, carboxyl esters, alcohols, glycols, vinyls, styrenes, epoxides, thiols, magnesium halos or Grignard, acrylate, acrylamide, diene, aldehyde and mixtures thereof. Table 4 illustrates the nanofilm surface and complementary functional groups on the substrate surface used to attach the nanofilm to the substrate.

In Table 4, X is a halogen group or a leaving group of another group, and R and R ′ represent hydrogen or an alkyl group. It is understood that the functional groups listed in Table 4 can be inverted (eg, the substrate —NH ₂ can be bound to the nanofilm —C (O) H to form —N═CH— bonds). . Further, it is understood that the functional groups listed in Table 4 can be used to bond with the module, and the functional groups listed in Table 2 can be used to bond the nanofilm and the substrate. Is done.
As illustrated in FIG. 5, the substrate may have reactive functional groups that bind the reactive functional groups of the module to attach the membrane to the substrate. The functional group of the substrate can be a surface group or a bonding group bonded to the substrate, and can be formed by a reaction that bonds the surface group or bonding group to the substrate. The surface groups can also be created on the substrate by various treatments (eg, low temperature plasma treatment, surface etching, solid erosion or chemical treatment). Several methods of plasma treatment are shown in Inagaki, Plasma Surface Modification and Plasma Polymerization, Technological, Lancaster, Pennsylvania, 1996. In one variation, photoreactive groups (eg, benzophenone groups) are bound to the surface or substrate. The photoreactive group can be activated with light (eg, ultraviolet light) to provide a reactive species that binds to the macrocyclic module.
The reactive functional groups on the module and the surface can be blocked with protecting groups until needed. After formation of the bonded module nanofilm layer, the reactive functional group protecting groups that would be used to attach the module membrane layer to the substrate surface may be removed, resulting in subsequent attachment steps. enable.
Spacer groups can be used to link the reactive functional groups of the nanofilm to the substrate. The spacer group for the surface attachment group can be a polymer chain. Examples of polymer chains are polyethylene, oxide, polypropylene oxide, polysaccharide, polylysine, polypeptide, poly (amino acid), polyvinylpyrrolidone, polyester, polyvinyl chloride, polyvinylidene fluoride, polyvinyl alcohol, polyurethane, polyamide, polyimide, Polysulfone, polyethersulfone, polysulfonamide, and polysulfoxide are mentioned. Examples of polymer chain spacer structures include linear, branched, comb polymers and dendritic polymers, random copolymers and block copolymers, homopolymers and heteropolymers, flexible chains and rigid chains. It may also include bifunctional linker groups or heterobifunctional linker groups used to attach biomolecular species and chemical species.

Methods for initiating coupling between the module and the substrate include chemical methods, thermal methods, photochemical methods, electrochemical methods, and radiation methods.
In some cases, the photoreactive group is substrate bound. The photoreactive group can be activated with light (eg, ultraviolet light) to provide a reactive species that binds to the nanofilm. The photoreactive species can be bound to the group of the hydrophobic portion of the atom or nanofilm amphoteric material, or can be bound to the hydrophilic portion of the nanofilm amphoteric material. The photoreactive species can be bound to a nanofilm binding group or other atom or group (an amphoteric substance from the prepared nanofilm or the first part of the module).
Also, surface attachment of modules can be achieved via ligand-receptor mediated interactions (eg, biotin-streptavidin). For example, the substrate can be coated with streptavidin and biotin can be attached via a module, eg, a linker group (eg, PEG or alkyl group).
Examples of processes where nanofilms may be useful include processes involving liquids or gases as a continuous fluid phase, filtration, clarification, fractionation, pervaporation, reverse permeation, dialysis, hemodialysis, affinity separation, oxygen Processing and other processes. Filtration applications include ion separation, desalting, gas separation, small molecule separation, ultrafiltration, microfiltration, ultrafiltration, water purification, sewage treatment, toxin removal, bacterial virus species (eg bacteria, viruses or fungi) Includes removal.

(Synton and macro ring module)
As used herein, the term “alkyl group” refers to a branched or unbranched monovalent hydrocarbon group. “N-mC alkyl” or “(nC-mC) alkyl” means any alkyl group containing from n to m carbon atoms. For example, 1-4C alkyl is referred to as a methyl group, an ethyl group, a propyl group, or a butyl group. Also included are all possible isomers of the indicated alkyl groups. Thus, propyl includes isopropyl, butyl includes n-butyl, isobutyl, t-butyl and the like. An alkyl group of 1 to 6 carbon atoms is referred to as “lower alkyl”. The term alkyl includes substituted alkyl. As used herein, the term “substituted alkyl” refers to an alkyl group having one or more groups appended to any carbon of the alkyl group. The added group is, for example, alkyl, lower alkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, saturated and unsaturated bicyclic It may contain one or more functional groups such as hydrocarbons, heterocycles, and others.

  As used herein, the term “alkenyl” refers to any structure or moiety having an unsaturated C═C. As used herein, the term “alkynyl” refers to any structure or moiety having an unsaturated C≡C.

  As used herein, the terms “R”, “R ′”, “R ″” and “R ′ ″” in chemical formulas are hydrogen or functional groups (each independently selected unless otherwise specified). Say).

  As used herein, the term “aryl” refers to a single aromatic ring or multiple aromatics fused together, covalently bonded, or bonded to a general group such as methylene, ethylene or carbonyl. Refers to a ring and includes polynuclear ring structures. In particular, aromatic rings include substituted or unsubstituted phenyl, naphthyl, biphenyl, diphenylmethyl, and benzophenone groups. The term “aryl” includes substituted aryl.

  As used herein, the term “substituted aryl” refers to an aryl group having one or more groups appended to any carbon of the aryl group. Added groups include, for example, lower alkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, thioether, heterocycle, saturated and unsaturated. It may contain one or more functional groups such as cyclic hydrocarbons (fused to an aromatic ring, covalently bonded, or methylene group, ethylene group or carbonyl linking group (eg carbonyl phenyl ketone)), and others.

  As used herein, the term “heteroaryl” refers to an aromatic ring in which one or more carbon atoms of the aromatic ring are replaced with a heteroatom such as nitrogen, oxygen, or sulfur. Heteroaryl refers to a structure that may include a single aromatic ring, multiple aromatic rings, or one or more aromatic rings combined with one or more non-aromatic rings. It is a structure having multiple rings, fused or non-fused, covalently linked, or linked to a general group such as a methylene or ethylene group, or linked to a carbonyl group such as phenylpyridyl ketone including. As used herein, the term “heteroaryl” includes rings such as, for example, thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, or benzofused analogs of these rings.

  As used herein, the term “acyl” refers to a carbonyl substituent (—C (O) R), where R is alkyl or substituted alkyl, aryl or substituted aryl, where R Can be referred to as alkanoyl substitution).

  As used herein, the term “amino” refers to the group —NRR ′, where R and R ′ are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl or acyl. possible.

As used herein, the term “alkoxy” refers to the group —OR, where R is alkyl, substituted lower alkyl, aryl, substituted aryl. Alkoxyl groups include, for example, methoxy, ethoxy, phenoxy, substituted phenoxy, benzyloxy, phenethyloxy, t-butoxy, and others.
As used herein, the term “thioether” refers to the general structure R—S—R ′, where R and R ′ are the same or different and are alkyl, aryl, or heterocyclic. Can be a group. The SH group can also be referred to as “sulfhydryl” or “thiol” or “mercapto”.

  As used herein, the term “saturated cyclic hydrocarbon” refers to a ring structure such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and the like, containing a substituent. Substituents on saturated cyclic hydrocarbons include substituting one or more carbon atoms of the ring with a heteroatom such as, for example, nitrogen, oxygen, or sulfur. Saturated cyclic hydrocarbons include, for example, bicyclic structures such as bicycloheptane and bicyclooctane, and polycyclic structures.

  As used herein, the term “unsaturated cyclic hydrocarbon” refers to a monovalent non-aromatic having at least one double bond, such as cyclopentene, cyclohexene, etc., containing a substituent. Substituents for unsaturated cyclic hydrocarbons include substituting one or more carbon atoms of the ring with a heteroatom such as, for example, nitrogen, oxygen, or sulfur. As used herein, the term “cyclic hydrocarbon” includes substituted and unsubstituted, saturated and unsaturated cyclic hydrocarbons, and polycyclic structures. Unsaturated cyclic hydrocarbons include, for example, bicyclic structures such as bicycloheptane and bicyclooctane, and polycyclic structures.

  As used herein, the term “heteroarylalkyl” refers to an alkyl group to which a heteroalkyl group is added via an alkyl group.

  As used herein, the term “heterocycle” refers to from 1 to 12 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, trivalent phosphorus, sulfur or oxygen in the ring. A monovalent saturated or unsaturated non-aromatic group having a single condensed ring or a plurality of condensed rings. Examples of heterocycles include tetrahydrofuran, morpholine, piperidine, pyrrolidine and others.

  As used herein, each chemical term explicitly recited above includes a corresponding substituent. For example, the term “heterocyclic” includes substituted heterocyclic groups.

  As used herein, the term “amphiphile” or “amphiphilic” refers to a chemical species that exhibits both hydrophilic and lipophilic properties. In general, the amphiphile includes a lipophilic portion and a hydrophilic portion. The amphiphile can form a Langmuir film.

Examples of hydrophilic moieties include hydroxyl groups, methoxy groups, phenols, carboxylic acids and salts thereof, methyl and ethyl esters of carboxylic acids, amides, amino groups, cyano groups, ammonium salts, amino groups substituted with monoalkyl groups, Amino group substituted with a dialkyl group, —NRR ′, —N≡C, —NHR, sulfonium salt, phosphonium salt, polyethylene glycol, polypropylene glycol, epoxy group, acrylate, sulfonamide, nitro group, —OP (O ) (OCH ₂ CH ₂ N ⁺ RR′R ″) O ⁻ , guanidinium, amino acid salts, acrylamide, and pyridinium, but are not limited to. Such hydrophilic moieties are, for example, polyethylene glycols or, for example, alcohols, carboxylates, acrylates, methacrylates, or

(Wherein y is 1-6) includes groups such as polymethylene chains substituted. In addition, the hydrophilic moiety is an alkyl chain having an internal amino or a substituted amino group (for example, —NH—, —NC (O) R—, or —NC (O) CH═CH ₂ — group). May be included. In addition, the hydrophilic portion includes polycaprolactone, polycaprolactone diol, poly (acetic acid), poly (vinyl acetate), poly (2-vinylpyridine), cellulose ester, cellulose hydroxyl ether, poly (L-lysine hydrobromide), poly (Itaconic acid), poly (maleic acid), poly (styrene sulfonic acid), poly (aniline), or poly (vinyl phosphonic acid).

Examples of lipophilic moieties include, but are not limited to, straight or branched chain alkyls including 1 to 28C hydrocarbons. Examples of groups that can be attached to synthons or macrocyclic modules as lipophilic groups include alkyl groups, —CH═CH—R, —C≡C—R, —OC (O) —R, —C (O). O-R, -NHC (O) -R, -C (O) NH-R, and -O-R (wherein R is a 4-18C alkyl group). Each chain may separately include, but is not limited to, alkenyl groups, alkynyl groups, saturated and unsaturated cyclic hydrocarbons, or aromatic groups. Each chain may also contain one or more silicon atoms that are dispersed between the carbons of the chain and are substituted with alkyl groups, alkenyl groups, alkynyl groups, saturated and unsaturated cyclic hydrocarbons, or aryl groups. . Each chain carbon atom may be substituted with one or more fluorine atoms. The carbon atom of the alkyl group is, for example, —S—, a double bond, a triple bond, or a —SiR′R ″ — group, where R′R ″ is independently H or an alkyl group. Any one of them can be substituted with one or more fluorine atoms, and any combination of these substituents can be used.
As used herein, the term “functional group” includes a chemical group, an organic group, an inorganic group, an organometallic group, an aryl group, a heteroaryl group, a cyclic hydrocarbon group, an amino group (—NH ₂ ), and a hydroxyl group. (—OH), cyano group (—C≡N), nitro group (NO ₂ ), carboxyl group (—COOH), formyl group (—CHO), keto group (—CH ₂ C (O) CH ₂ —), Including but not limited to alkenyl groups (—C═C—), alkynyl groups (—C≡C—), and halo groups (F, Cl, Br and I).

As used herein, the term “active acid” refers to a —C (O) X moiety, where X is a leaving group, and the X group is —C (O) — and the parent nucleus. It is easily replaced by nucleophilicity to form a covalent bond between the sexes. Examples of active acids include acid chlorides, acid fluorides, para-nitrophenyl esters, pentafluorophenyl esters, and N-hydroxysuccinimide esters.
As used herein, the term “amino acid residue” refers to an atom of a synthon that contains at least one amino (—NH ₂ ) and at least one carboxyl group (—C (O) O—). Alternatively, it refers to the product formed when the functional group is coupled through either an amino group or a carboxyl group. Neither amino nor carboxyl groups are included in the coupling which can be blocked with removable protecting groups.
(Synton)
As used herein, the term “synton” refers to a molecule used to create a macrocyclic module. A synthon can be substantially in one isomer configuration, eg, a single optical isomer. The synthon is used to attach the synthon to other single or multiple synthons and can be substituted with a functional group that is part of the synthon. The synthon can be replaced with an atom or group of atoms used to impart a hydrophilic, lipophilic or amphiphilic character to the synthon or a chemical species made from the synthon. The synthon can be replaced with an atom or group of atoms that form one or more functional groups on the synthon that can be used to couple the synthon to other single or multiple synthons. Synthons before substitution with functional groups or groups used to impart hydrophilic, lipophilic or amphiphilic characteristics can be referred to as core synthons. As used herein, the term “syntone” refers to a core synthon and also refers to a synthon substituted with a functional group or group used to impart hydrophilic, lipophilic or amphiphilic characteristics. .
As used herein, the term “cyclic synthon” refers to a synthon having one or more cyclic structures. Examples of cyclic structures include aryl groups, heteroaryl groups, and cyclic hydrocarbon structures including bicyclic and polycyclic ring structures. Examples of core cyclic synthons include benzene, cyclohexadiene, cyclopentadiene, naphthalene, anthracene, phenylene, phenanthracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridine, cyclohexane, cyclohexene, decalin, piperidine, Pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine, tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran, pyrrole, cyclopentane, cyclopentene, triptycene, adamantane, bicyclo [2,2,1] heptane, bicyclo [2,2,1] Heptene, bicyclo [2,2,2] octane, bicyclo [2,2,2] octene, bicyclo [3,3,0] octane, bicycl [3,3,0] octene, bicyclo [3,3,1] nonane, bicyclo [3,3,1] nonene, bicyclo [3,2,2] nonane, bicyclo [3,2,2] nonene, bicyclo [4,2,2] decane, 7-azabicyclo [2,2,1] heptane, 1,3-diazabicyclo [2,2,1] heptane, and spiro [4,4] nonane. Not specified. Core synthons include all isomers, or arrangements of coupling of core synthons to other synthons. For example, core synthon benzenes include synthons such as 1,2- and 1,3-substituted benzenes, and the bonds between synthons are formed at the 1,2- and 1,3-positions of the benzene ring, respectively. Is done. For example, core synthon benzene is

(Wherein L is a bond between synthons, and the 2, 4, 5, and 6 positions of the benzene ring may also have a substituent). Condensation bonds between synthons include direct coupling between the ring atoms of one cyclic synthon to the ring atoms of another cyclic synthon, for example, synthons MX and MX are connected to MM. Bind to form (where M is a cyclic synthon and X is a halogen); for example, when M is a phenyl group, a condensed bond;

As a result.

(Macro-ring module)
A macrocyclic module is a closed ring of coupled synthons. To make a macrocyclic module, the synthon can be substituted with a functional group and the synthon can be coupled to form the macrocyclic module. The synthons can also be substituted with functional groups that remain in the structure of the macrocyclic module. Functional groups remaining in the macrocyclic module can be used to couple the macrocyclic module to other macrocyclic modules.

  The macrocyclic module may include 3 to about 24 annular synthons. In the closed ring of the macrocyclic module, the first annular synthon can be coupled with the second annular synthon, the second annular synthon can be coupled with the third annular synthon, and four annular synthons can be combined. When present in the macrocyclic module, the third annular synthon may be coupled with the fourth annular synthon, the fourth with the fifth, etc., and the nth annular synthon with the previous one. And the nth annular synthon can be coupled with the first annular synthon to form a closed ring of the annular synthon. As one variation, a closed ring of a macrocyclic module can be formed with a linker molecule.

  A macrocyclic module can be an amphiphilic macrocyclic module if hydrophilic and lipophilic functional groups are present in the structure. The amphiphilic character of the macrocyclic module can result from atoms in the synthon or atoms in the bond between synthons, or atoms in the functional group that are coupled during the synthon or bond.

  In some variations, one or more synthons of the macrocyclic module can be replaced with one or more lipophilic moieties, while one or more synthons can be replaced with one or more hydrophilic moieties; Can form amphiphilic macrocyclic modules. The lipophilic portion and the hydrophilic portion can be coupled to the same synthon or bond of the amphiphilic macrocycle module. The lipophilic and hydrophilic portions can be coupled to the macrocyclic module before or after formation of the closed ring of the macrocyclic module. For example, a lipophilic moiety or a hydrophilic moiety can be added to a macrocyclic module by synthon or bond replacement after formation of a closed ring.

  The amphiphilicity of the macrocyclic module can be characterized in part by its ability to form a stable Langmuir film. Langmuir film is measured on the Langmuir trough in millinewtons per meter (mN / m) where a specific barrier speed is measured in millimeters per minute (mm / min) It can be formed at a specific surface pressure and the isobaric creep or change in the film area at a constant surface pressure can be measured to characterize the stability of the film. For example, a stable Langmuir film of a macrocyclic module under aqueous phase can have an isobaric creep of 5-15 mN / m, so that most of the film area is in a period of about 1 hour. Can be maintained. An example of a stable Langmuir film of a macrocyclic module under aqueous phase may have an isobaric creep of 5-15 mN / m, so that about 70% film area is maintained for a period of about 30 minutes, At some times, about 70% film area is maintained for a period of about 40 minutes, and at other times about 70% film area is maintained for a period of about 60 minutes, and at other times, about 70% film The area can be maintained for a period of about 120 minutes. Another example of a stable Langmuir film of a macrocyclic module under aqueous phase may have an isobaric creep of 5-15 mN / m so that about 80% film area is maintained for a period of about 30 minutes At some times, about 85% film area is maintained for a period of about 30 minutes, and at other times about 90% film area is maintained for a period of about 30 minutes, and at other times, about 95% film The area is maintained for a period of about 30 minutes, and at some times about 98% of the film area can be maintained for a period of about 30 minutes.

  In one aspect, individual macrocyclic modules can include holes in their structure. Each macrocyclic module may define a specific size hole depending on the arrangement and condition of the module. Various macroannular modules that define different sized holes can be prepared.

  The macroannular module may include flexibility in its structure. Flexibility allows a macrocyclic module to more easily form a bond with other macrocyclic modules through a coupling reaction. The flexibility of the macrocyclic module can also play a role in regulating the path of chemical species through the pores of the macrocyclic module. For example, since various arrangements are available for the structure, flexibility can affect the pore size of the individual macrocyclic module. For example, if a substituent is not in the pore, the macrocyclic module can have a particular pore size in one conformation, and one or more substituents of the macrocyclic module are located in the pore. In that case, the same macrocyclic module may have different pore sizes in different conformations. Similarly, a macrocyclic module may have a particular pore size in one arrangement when one group of substituents is located in the hole, and a different group of substituents is located in the hole. In some cases, it may have different pore sizes in different arrangements. For example, “one group” of the substituents located in the pore is three alkoxy groups arranged in one regioisomer, and “different groups” of the substituents are the other one There may be two alkoxy groups arranged in regioisomers. The effect of “one group” of substituents located in the pores and “different groups” of substituents located in the pores, together with other regulators, can regulate transport and filtration Is to provide.

  In the production of macrocyclic modules from synthons, synthons can be used as substantially pure single isomers, eg, pure single optical isomers.

In making a macrocyclic module from a synthon, one or more coupling bonds are formed between adjacent synthons. The bond formed between the synthons can be the coupling product of one functional group on one synthon to a complementary functional group on the second synthon. For example, the hydroxyl group of the first synthon can be coupled to the acid group or acid halide group of the second synthon to form an ester bond between the two synthons. Another example is an imine bond (—CH═N—), —CH═O resulting from the reaction of an aldehyde, one synthon with an amine (—NH ₂ ), another synthon. Examples of binding between complementary functional groups and synthons are shown in Table 5.

  In Table 5, R and R 'represent hydrogen or a functional group, and X is a halogen or other preferred leaving group.

  In another variation, the macrocyclic module may have a functional group for coupling with other macrocyclic modules coupled to the macrocyclic module after the initial preparation of the closed ring. For example, the imine bond of a macrocyclic module can be substituted with one of a variety of substituents to produce an additional macrocyclic module. Examples of bonds between synthons having functional groups for coupling macrocyclic modules are shown in Table 6.

In Table 6, X is halogen and Q ₁ and Q ₂ are independently selected synthons that are part of the module.

The synthon functional groups used to form bonds between synthons or other macrocyclic modules can be separated from the synthons by spacers. The spacer can be any atom or group that couples the functional group to the synthon and does not interfere with the bond formation reaction. The spacer is part of the functional group and becomes part of the bond between synthons. An example of the spacer is a methylene group (—CH ₂ —). The spacer can be said to extend the bond between the synthons. For example, if one methylene spacer is inserted into an imine bond (—CH═N—), the resulting imine bond can be —CH ₂ CH═N—.

The bond between synthons can also include one or more atoms provided by external moieties other than the two functional groups of the synthon. The external moiety is an intermediate (eg, coupled with a functional group on another synthon to form a bond between synthons to form a closed ring of synthons from a series of coupled synthons) Can be a linker molecule that can be coupled with a functional group of one synthon. An example of a linker molecule is formaldehyde. For example, an amino group on two synthons can undergo a Mannich reaction in the presence of formaldehyde as a linker molecule to generate a bond —NHCH ₂ NH—.

  The composition of the macrocyclic module can include, for example, from 3 to about 24 cyclic synthons coupled to form a closed ring; the closed ring is a complementary function of at least two other closed rings. At least two functional groups for coupling to the group; wherein each functional group as well as each complementary functional group is C, H, N, O, Si, P, S, B, Al, halogen, and alkali Containing functional groups containing atoms selected from the group consisting of metals and metals from alkaline earth metals. In certain embodiments, the macrocyclic module can include at least two closed rings that are coupled via the aforementioned functional groups. In another embodiment, the macrocyclic module comprises at least three closed rings that are coupled via the aforementioned functional groups.

In another embodiment, the macrocyclic module may comprise from 3 to about 24 cyclic synthons coupled to form a closed ring defining the pore; the second group of substituents is located in the pore A closed ring having a first conformation first pore size when the first group of substituents is disposed in the second conformation pore size and the second pore size;
Here, each substituent of each group was selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogen, and metals from alkali metals and alkaline earth metals. Contains functional groups containing atoms.

In another example, the macrocyclic module is: (a) 3 to about 24 annular synthons coupled to form a closed ring defining a hole; (b) coupled to the closed ring in the hole. , At least one functional group selected to transport a selected chemical species through the pore, wherein the at least one functional group is C, H, N, O, Si, P, Comprising a functional group comprising an atom selected from the group consisting of S, B, A1, halogen, and metals from alkali metals and alkaline earth metals; (c) selected species to be transported through the pores . In some embodiments, the selected species is from the group of ovalbumin, glucose, creatinine, H ₂ PO ₄ ⁻ , HPO ₄ ⁻² , HCO ₃ ⁻ , urea, Na ⁺ , Li ⁺ , and K ⁺ . Selected.

  In some embodiments, the composition of the macrocyclic module is selected from the group of Wang resin, hydrogel, alumina, metal, ceramic, polymer, silica gel, sepharose, sephadex, agarose, inorganic solid, semiconductor, and silicon wafer The solid support is coupled. In other embodiments, the macrocyclic module composition maintains a film area of at least 85% after 30 minutes with a 5-15 mN / m Langmuir trough. In other embodiments, the macrocyclic module composition maintains a film area of at least 95% after 30 minutes with a 5-15 mN / m Langmuir trough. In another embodiment, the macrocyclic module maintains a film area of at least 98% after 30 minutes with a 5-15 mN / m Langmuir trough.

  In some embodiments, the cyclic synthon is benzene, cyclohexadiene, cyclohexene, cyclohexane, cyclopentadiene, cyclopentene, cyclopentane, cycloheptane, cycloheptene, cycloheptadiene, cycloheptatriene, cyclooctane, cyclooctene, cyclooctadiene. , Cyclooctatriene, cyclooctatetraene, naphthalene, anthracene, phenylene, phenanthracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl, decalin, piperidine, pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine, Tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran, pyrrole, triptych , Adamantane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] heptene, bicyclo [2.2.2] octane, bicyclo [2.2.2] octene, bicyclo [3.3.0 ] Octane, bicyclo [3.3.0] octene, bicyclo [3.3.1] nonane, bicyclo [3.3.1] nonene, bicyclo [3.2.2] nonane, bicyclo [3.2.2 ] Nonene, bicyclo [4.2.2] decane, 7-azabicyclo [2.2.1] heptane, 1,3-diazabicyclo [2.2.1] heptane, and spiro [4.4] nonane. Are independently selected.

In other embodiments, each coupled cyclic synthon is (a) a fused bond, and (b) a bond selected from the group consisting of: —NRC (O) —, —OC (O) —, — O—, —S—S—, —S—, —NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O) O—, —C≡. C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) O—, —NHCH ₂ NH—, —NHCH ₂ CH (OH) CH ₂ NH—, —N═CH (CH ₂ ) _p CH═N—, —CH ₂ CH (OH) CH ₂ —, —N═CH (CH ₂ ) _h CH═N— (here H is 1 to 4), —CH═N—NH—, —OC (O) O—, —OP (O) (OH) O—, —CH (OH) CH ₂ NH—, —CH _{(OH) CH 2 -, -} CH (OH) C (CH 3) 2 C (O) O-,

Wherein p is 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; wherein, when the two conformations are different structures, a bond Are independently constructed with respect to synthons that are coupled together in either of two possible conformations (forward and reverse); where Q is one of the synthons joined by a bond Is coupled independently to two adjacent synthons.

  In other embodiments, the closed ring composition may be composed of the following chemical formula:

. Where: J is 2-23; Q ¹ is a synthon, each (a) a phenyl synthon coupled to a bond L at the 1,2-phenyl position, (b) 1,3-phenyl (C) aryl synthons other than phenyl synthons, (d) heteroaryl synthons other than pyridinium synthons, (e) saturated cyclic hydrocarbon synthons, and (f) unsaturated cyclic carbonizations. Independently from the group consisting of hydrogen synthons, (g) saturated bicyclic hydrocarbon synthons, (h) unsaturated bicyclic hydrocarbon synthons, (i) saturated polycyclic hydrogen synthons, and (j) unsaturated polycyclic hydrocarbon synthons and are selected; wherein the position of the rings of each for ^{Q 1} that is not coupled to the coupling L, hydrogen or C,, H, N, O , Si, P, S, B, a It is substituted with a functional group containing a halogen, and an alkali metal and a metal selected atom from the group of the alkaline earth metal; Q ² is a bond L and the coupling at the position of (a) 2,7-naphthyl Aryl synthons other than phenyl synthons and naphthalene synthons, (b) heteroaryl synthons other than pyridine synthons coupled to the bond L at the 2,6-pyridino position, (c) bound at the 1,2-cyclohexyl position (C) a saturated cyclic hydrocarbon synthon other than cyclohexane synthon coupled to L; (d) an unsaturated cyclic hydrocarbon synthon other than pyrrole synthon coupled to the bond L at the position of 2,5-pyrrole; Cyclic hydrocarbon synthon, (f) unsaturated bicyclic hydrocarbon synthon, (g) saturated polycyclic hydrocarbon synthon, Beauty (h) unsaturated polycyclic hydrocarbon synthon, independently from the group is a synthon that is selected consisting of: The position of the ring Q ² 'which is not coupled to L is hydrogen or,, C, H, Substituted with a functional group containing an atom selected from the group consisting of N, O, Si, P, S, B, Al, halogen, and metals from alkali metals and alkaline earth metals; L is a bond between synthons And (b) a bond selected from the group consisting of: —NRC (O) —, —OC (O) —, —O—, —S—S—, —S—. , —NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O) O—, —C≡C—, —C≡C—C≡C— , -CH (OH) -, - HC = CH -, - NHC (O) NH -, - NHC (O) O -, - NHCH 2 NH- _{-NHCH 2 CH (OH) CH 2} NH -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH (CH 2) h CH = N- (Where h is 1 to 4), —CH═N—NH—, —OC (O) O—, —OP (O) (OH) O—, —CH (OH) CH ₂ NH—, _{-CH (OH) CH 2 -,} - CH (OH) C (CH 3) 2 C (O) O-,

Wherein p is 1 to 6; where R and R ′ are each independently selected from the group of hydrogen and alkyl; wherein, when the two conformations are different structures, a bond L is independently configured with respect to synthons that are coupled together in either of two possible conformations (forward and reverse); where y is 1 or 2, and Q ^y is Each independently selected from the group consisting of one of the Q ¹ synthons or Q ² synthons joined by a bond.

In some embodiments, the functional group is hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C (O) OCH ₃ , —C (O) Cl. , —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O) OCH ₃ , —NH-alkyl-C ( _{O) CH 2 CH (NH 2} ) CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl _{aryl, -C (O) CH = CH} 2, -NHC (O _{) CH = CH 2, -C (} O) CH = CH (C 6 H 5),

, P (O) (OH) (OX), —P (═O) (O ″) O (CH ₂ ) _s NR ₃ ^+, each independently selected; where R is hydrogen And each independently selected from the group consisting of 1-6C alkyl; X is selected from the group consisting of Cl, Br and I; r is 1-50; and s is 1-4 .

  In another example, a closed ring composition comprises the following chemical formula:

Where: J is 2-23; Q ¹ is (a) phenyl synthon coupled to bond L at the 1,2-phenyl position, (b) bond L at the 1,3-phenyl position. A synthon independently selected from the group consisting of: a phenyl synthon to be coupled to and a cyclohexane synthon coupled to the bond L at the position of (c) 1,2-cyclohexyl; The position of each uncoupled Q ¹ ring is from hydrogen or a group of metals from C, H, N, O, Si, P, S, B, Al, halogen, and alkali metals and alkaline earth metals. is substituted with a functional group containing a selected atomic; Q ² is a cyclohexane synthon to be coupled to the coupling L at position 1,2 cyclohexyl; wherein the coupling loop to the L Is not the position of the ring Q ² comprise C, H, N, O, Si, P, S, B, Al, halogen, and the alkali metal and alkaline earth been atoms selected from the group consisting of metals from metal Substituted with a functional group; L is a bond between synthons, (a) a condensed bond, and (b) a bond selected from the group: -NRC (O)-, -OC (O)-,- O—, —S—S—, —S—, —NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O) O—, —C≡. C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) O—, —NHCH ₂ NH—, —NHCH _{2 CH (OH) CH 2 NH} -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH (CH 2 _h CH = N- (where, h is 1~4), - CH = N- NH -, - OC (O) O -, - OP (O) (OH) O -, - CH (OH) _{CH 2 NH -, - CH (} OH) CH 2 -, - CH (OH) C (CH 3) 2 C (O) O-,

Wherein p is 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; wherein, when the two conformations are different structures, a bond L is each independently configured for a synthon that is coupled together in either of two possible conformations (forward and reverse); where y is 1 or 2, and Q ^y is Each independently selected from the group consisting of one of Q ¹ synthons or Q ² synthons linked by a bond.

In some cases, the functional group is hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C (O) OCH ₃ , —C (O) Cl, —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O) OCH ₃ , —NH-alkyl-C (O _{) CH 2 CH (NH 2)} CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl _{aryl, -C (O) CH = CH} 2, -NHC (O) _{CH = CH 2, -C (O} ) CH = CH (C 6 H 5),

, —P (O) (OH) (OX), —P (═O) (O ″) O (CH ₂ ) _s NR ₃ ⁺ ; wherein R is from the group consisting of hydrogen and 1-6C alkyl, respectively Independently selected; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4, each independently Selected.

  In another embodiment, the following chemical formula is a closed ring composition:

Where: J is 2-23; Q ¹ is (a) a phenyl synthon coupled to the bond L at the 1,4-phenyl position, (b) an aryl synthon other than phenylcytosine, (c) Heteroaryl synthon, (d) saturated cyclic hydrocarbon synthon, (e) unsaturated cyclic hydrocarbon synthon, (f) saturated bicyclic hydrocarbon synthon, (g) unsaturated bicyclic hydrocarbon synthon, (h) saturated polycyclic Each independently selected from the group consisting of a hydrocarbon synthon and (i) an unsaturated polycyclic hydrocarbon synthon; wherein at least one of Q ¹ is coupled to the bond L at the 1,4-phenyl position phenyl synthon is a ring, and the position of the ring of the ^{Q 1} that is not coupled to the coupling L will, C, H, N, O , Si, P, S, B, Al, halogen, and alkali metal And it is substituted with a functional group containing a metal atom selected from the group of alkaline earth metals; Q ² is, (a) phenyl synthon and naphthalene to be coupled to the coupling L at the position of the 2,7-naphthyl Aryl synthons other than synthons, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon synthons other than cyclohexane synthons coupled to bond L at the 1,2-cyclohexyl position, (d) unsaturated cyclic hydrocarbon synthons (E) a saturated bicyclic hydrocarbon synthon, (f) an unsaturated bicyclic hydrocarbon synthon, (g) a saturated polycyclic hydrocarbon synthon, and (h) an unsaturated polycyclic hydrocarbon synthon. Where the ring position of Q ² that is not coupled to L is hydrogen or C, H, N, O, S substituted with a functional group containing an atom selected from the group consisting of i, P, S, B, Al, halogen, and metals from alkali metals and alkaline earth metals; L is a bond between synthons; a) a condensed bond, and (b) a bond selected from the group consisting of: —NRC (O) —, —OC (O) —, —O—, —S—S—, —S—, —NR—. , — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O) O—, —C≡C—, —C≡C—C≡C—, —CH ( OH) -, - HC = CH -, - NHC (O) NH -, - NHC (O) O -, - NHCH 2 NH -, - NHCH 2 CH (OH) CH 2 NH -, - N = CH (CH _{2) p CH = N -,} - CH 2 CH (OH) CH 2 -, - N = CH (CH 2) h CH = N- ( where, h is 1-4 der ), - CH = N-NH -, - OC (O) O -, - OP (O) (OH) O -, - CH (OH) CH 2 NH -, - CH (OH) CH 2 -, - CH _{(OH) C (CH 3)} 2 C (O) O-,

Wherein p is 1 to 6; where R and R ′ are each independently selected from the group of hydrogen and alkyl; where the two conformations are structurally different L is each independently configured for a synthon linked together in either of two possible conformations (forward and reverse); where y is 1 or 2 and Q ^y Are each independently selected from the group consisting of one of the Q ¹ synthons or Q ² synthons joined by a bond.

  In other embodiments, the composition of the closed ring of the formula is:

, J is 1 to 22, and n is 1 to 24; X and ^{R n} is, C, H, N, O , Si, P, S, B, Al, halogen, and alkali metal and alkaline earth Each independently selected from the group of groups consisting of functional groups containing atoms selected from the group consisting of metals from similar metals; Z is each independently hydrogen or a lipophilic group; L is a bond between synthons Each synthon is (a) a fused bond, and (b) a bond selected from the group consisting of: -N = CR-, -NRC (O)-, -OC (O)-, -O -, - S-S -, - S -, - NR-, - (CRR ') p -, - CH 2 NH -, - C (O) S -, - C (O) O -, - C≡C -, -C≡C-C≡C-, -CH (OH)-, -HC = CH-, -NHC (O) NH-, -NHC (O) O-, -NHCH _{2 NH -, - NHCH 2 CH} (OH) CH 2 NH -, - N = CHCH 2 CH = N -, - N = CH (CH 2) h CH = N-, where, h is 1 to 4 , —CH═N—NH—, —OC (O) O—, —P (O) (OH) ₂ O—, —CH (OH) CH ₂ NH—, —CH (OH) CH ₂ —, —CH _{(OH) C (CH 3)} 2 C (O) O-,

Wherein p is 1 to 6; wherein R and R ′ are each independently selected from the hydrogen and alkyl groups; where the bond L is With respect to the synthon that each independently binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).

In one embodiment, X and R ⁿ are hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C (O) OCH ₃ , —C (O) Cl, — NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O) OCH ₃ , —NH-alkyl-C (O) _{CH 2 CH (NH 2) CO} 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl _{aryl, -C (O) CH = CH} 2, -NHC (O) CH _{= CH 2, -C (O)} CH = CH (C 6 H 5),

, -P (O) (OH) (OX), - P (= O) (O -) O (CH 2) s NR 3 + each independently from the group consisting of selected; wherein, R represents a hydrogen And each independently selected from the group consisting of 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4 .

  In another embodiment, the composition of the closed ring of the formula is:

, J is 1-22, n is 1-48; X and R ⁿ are C, H, N, O, Si, P, S, B, Al, halogen, and alkali metals and alkaline earths Each independently selected from the group consisting of functional groups containing atoms selected from the group consisting of metals from the group of metals; Z is each independently hydrogen or a lipophilic group; L is a bond between synthons (B) a bond selected from the group consisting of: -NRC (O)-, -OC (O)-, -O-, -S-S-, -S-,- NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O) O—, —C≡C—, —C≡C—C≡C—, — CH (OH) -, - HC = CH -, - NHC (O) NH -, - NHC (O) O -, - NHCH 2 NH -, - NHCH 2 CH (OH) CH ₂ NH—, —N═CH (CH ₂ ) _p CH═N—, —CH ₂ CH (OH) CH ₂ —, —N═CH (CH ₂ ) _h CH═N—, where h is 1 to a 4, -CH = N-NH - , - OC (O) O -, - OP (O) (OH) O -, - CH (OH) CH 2 NH -, - CH (OH) CH 2 -, _{-CH (OH) C (CH 3} ) 2 C (O) O-,

Wherein p is from 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; where the bond L is , Each independently of the synthon that binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).
In another embodiment, X and R ⁿ are hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C (O) OCH ₃ , —C (O) Cl, —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O) OCH ₃ , —NH-alkyl-C (O _{) CH 2 CH (NH 2)} CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl _{aryl, -C (O) CH = CH} 2, -NHC (O) _{CH = CH 2, -C (O} ) CH = CH (C 6 H 5),

, -P (O) (OH) (OX), - P (= O) (O -) O (CH 2) s NR 3 + each independently selected from the group consisting of; wherein, R represents a hydrogen And each independently selected from the group consisting of 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4 .

  In another embodiment, the closed ring composition may have the following formula:

, J is 1 to 11 and n is 1 to 12; X and R ⁿ are hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C ( O) OCH ₃ , —C (O) Cl, —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O ) _OCH 3, -NH- alkyl _{-C (O) CH 2 CH (} NH 2) CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl aryl, -C ( _{O) CH = CH 2, -NHC} (O) CH = CH 2, -C (O) CH = CH (C 6 H 5),

, —P (O) (OH) (OX), —P (═O) (O ⁻ ) O (CH ₂ ) _s NR ₃ ^+, each selected from the group consisting of Each independently selected from the group consisting of 6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4; Z is Each independently hydrogen or a lipophilic group; L is a bond between synthons, (a) a condensed bond, and (b) a bond selected from the group consisting of: -NRC (O)-,- OC (O) —, —O—, —S—S—, —S—, —NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O ) O—, —C≡C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) O—, — NH _{CH 2 NH -, - NHCH 2} CH (OH) CH 2 NH -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH (CH 2) _h CH═N—, where h is 1 to 4, —CH═N—NH—, —OC (O) O—, —OP (O) (OH) O—, —CH (OH) CH ₂ NH—, —CH (OH) CH ₂ —, —CH (OH) C (CH ₃ ) ₂ C (O) O—,

Wherein p is from 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; where the bond L is , Each independently of the synthon that binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).

  In another embodiment, the closed ring composition may have the following formula:

, J is 1 to 11 and n is 1 to 12; X and R ⁿ are hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C (O ) OCH ₃ , —C (O) Cl, —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O) OCH _3, -NH- alkyl _{-C (O) CH 2 CH (} NH 2) CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl aryl, -C (O ) CH═CH ₂ , —NHC (O) CH═CH ₂ , —C (O) CH═CH (C ₆ H ₅ ),

, —P (O) (OH) (OX), —P (═O) (O ⁻ ) O (CH ₂ ) _s NR ₃ ⁺ , each of which is selected from the group consisting of hydrogen and 1 Each independently selected from the group consisting of -6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4; Z Are each independently hydrogen or a lipophilic group; L is a bond between synthons, (a) a condensed bond, and (b) a bond selected from the group consisting of: -NRC (O)-, —OC (O) —, —O—, —S—S—, —S—, —NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C ( O) O—, —C≡C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) O—, − _{HCH 2 NH -, - NHCH 2} CH (OH) CH 2 NH -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH (CH 2) _h CH═N—, where h is 1 to 4, —CH═N—NH—, —OC (O) O—, —OP (O) (OH) O—, —CH (OH) CH ₂ NH—, —CH (OH) CH ₂ —, —CH (OH) C (CH ₃ ) ₂ C (O) O—,

Wherein p is from 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; where the bond L is , Each independently of the synthon that binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).

  In another embodiment, the closed ring composition may have the following formula:

, J is 1 to 11 and n is 1 to 12; X is —NX ¹ — or —CX ² X ³ , where X ¹ is an amino acid residue, —CH ₂ C ( _{O) CH 2 CH (NH 2} ) CO 2 - alkyl, and -C (O) is selected from the group consisting of CH = CH ^{_2; X} ₂ and ^{X 3} are hydrogen, _-OH, -NH 2, -SH, Each independently selected from the group consisting of — (CH ₂ ) _t OH, — (CH ₂ ) _t NH ₂ and — (CH ₂ ) _t SH, wherein t is 1-4 and X ² And X ³ are not both hydrogen; R ⁿ is hydrogen, activated acid, —OH, —C (O) OH, —C (O) H, —C (O) OCH ₃ , —C (O) Cl, ^{-NRR, -NRRR +, -MgX, -Li} , -OLi, -OK, -ONa, -SH, -C (O) (CH 2) C _(O) OCH 3, -NH- alkyl _{-C (O) CH 2 CH (} NH 2) CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl aryl, _{-C (O) CH = CH 2} , -NHC (O) CH = CH 2, -C (O) CH = CH (C 6 H 5),

, —P (O) (OH) (OX), —P (═O) (O ⁻ ) O (CH ₂ ) _s NR ₃ ⁺ , each of which is selected from the group consisting of hydrogen and 1 Each independently selected from the group consisting of -6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4; Z is each independently hydrogen or a lipophilic group; L is a bond between synthons, (a) a condensed bond, and (b) a bond selected from the group consisting of: —NRC (O) — , —OC (O) —, —O—, —S—S—, —S—, —NR—, — (CRR ′) _p —, —CH ₂ NH—, —C (O) S—, —C (O) O—, —C≡C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) O— , _{NHCH 2 NH -, - NHCH 2} CH (OH) CH 2 NH -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH (CH 2) _h CH═N—, where h is 1 to 4, —CH═N—NH—, —OC (O) O—, —OP (O) (OH) O—, —CH (OH) CH ₂ NH—, —CH (OH) CH ₂ —, —CH (OH) C (CH ₃ ) ₂ C (O) O—,

Wherein p is from 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; where the bond L is , Each independently of the synthon that binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).

  In another embodiment, the closed ring structure may have the following formula:

, J is 1 to 11, and n is 1 to 12; X and ^{R n} is hydrogen, activated acid, -OH, -C (O) OH , -C (O) H, -C ( O) OCH ₃ , —C (O) Cl, —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O ) _OCH 3, -NH- alkyl _{-C (O) CH 2 CH (} NH 2) CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl aryl, -C ( _{O) CH = CH 2, -NHC} (O) CH = CH 2, -C (O) CH = CH (C 6 H 5),

, —P (O) (OH) (OX), —P (═O) (O ⁻ ) O (CH ₂ ) _s NR ₃ ⁺ , each of which is selected from the group consisting of hydrogen and 1 Each independently selected from the group consisting of -6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4; Z And Y are each independently hydrogen or a lipophilic group; L is a bond between synthons, (a) a condensed bond, and (b) a bond selected from the group consisting of: —NRC (O) -, - OC (O) - , - O -, - S-S -, - S -, - NR -, - (CRR ') p -, - CH 2 NH -, - C (O) S -, - C (O) O—, —C≡C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) _{-, - NHCH 2 NH -,} - NHCH 2 CH (OH) CH 2 NH -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH ( CH _{2) h} CH = N-, where, h is the 1~4, -CH = N-NH - , - OC (O) O -, - OP (O) (OH) O -, - CH ( _{OH) CH 2 NH -, -} CH (OH) CH 2 -, - CH (OH) C (CH 3) 2 C (O) O-,

Wherein p is from 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; where the bond L is , Each independently of the synthon that binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).

  In another embodiment, the closed ring structure may have the following formula:

, J is 1 to 11, and n is 1 to 12; X and ^{R n} is hydrogen, activated acid, -OH, -C (O) OH , -C (O) H, -C ( O) OCH ₃ , —C (O) Cl, —NRR, —NRRR ⁺ , —MgX, —Li, —OLi, —OK, —ONa, —SH, —C (O) (CH ₂ ) ₂ C (O ) _OCH 3, -NH- alkyl _{-C (O) CH 2 CH (} NH 2) CO 2 - _{alkyl, -CH = CH 2, -CH =} CHR, -CH = CR 2, 4- vinyl aryl, -C ( _{O) CH = CH 2, -NHC} (O) CH = CH 2, -C (O) CH = CH (C 6 H 5),

, —P (O) (OH) (OX), —P (═O) (O ⁻ ) O (CH ₂ ) _s NR ₃ ⁺ , each of which is selected from the group consisting of hydrogen and 1 Each independently selected from the group consisting of -6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4; Z And Y are each independently hydrogen or a lipophilic group; L is a bond between synthons, (a) a condensed bond, and (b) a bond selected from the group consisting of: —NRC (O) -, - OC (O) - , - O -, - S-S -, - S -, - NR -, - (CRR ') p -, - CH 2 NH -, - C (O) S -, - C (O) O—, —C≡C—, —C≡C—C≡C—, —CH (OH) —, —HC═CH—, —NHC (O) NH—, —NHC (O) _{-, - NHCH 2 NH -,} - NHCH 2 CH (OH) CH 2 NH -, - N = CH (CH 2) p CH = N -, - CH 2 CH (OH) CH 2 -, - N = CH ( CH _{2) h} CH = N-, where, h is the 1~4, -CH = N-NH - , - OC (O) O -, - OP (O) (OH) O -, - CH ( _{OH) CH 2 NH -, -} CH (OH) CH 2 -, - CH (OH) C (CH 3) 2 C (O) O-,

Wherein p is from 1 to 6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl; where the bond L is , Each independently of the synthon that binds together, where the two conformations are different structures, it is in the form of either of the two possible conformations (forward and reverse).

  In one variation, the macrocyclic module can be a closed ring composition of the following formula:

Where: this closed ring contains a total of 3-24 synthons Q; J is 2-23; Q ¹ is (a) an aryl synthon, (b) a heteroaryl synthon, (c) a saturated cyclic hydrocarbon Synthons, (d) unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated polycyclic hydrocarbon synthons, and (h) unsaturated poly Each independently selected from the group consisting of cyclic hydrocarbon synthons; wherein the position of each Q ¹ ring not bound to bond L is hydrogen or C, H, N, O, Si, P, S, B Substituted with a functional group containing an atom selected from the group consisting of Al, halogen, and metals from alkali metals and alkaline earth metals; Q ² is a synthon, (a) an aryl synthon, (b) a heteroaryl Sint (C) saturated cyclic hydrocarbon synthon, (d) unsaturated cyclic hydrocarbon synthon, (e) saturated bicyclic hydrocarbon synthon, (f) unsaturated bicyclic hydrocarbon synthon, (g) saturated polycyclic hydrocarbon synthon And (h) an unsaturated polycyclic hydrocarbon synthon; wherein the position of the ring of Q ² that is not bound to bond L is hydrogen or C, H, N, O, Si, P , S, B, Al, halogen, and substituted with a functional group containing an atom selected from the group consisting of metals from alkali metals and alkaline earth metals; L is a bond between synthons; NRC (O) -, - OC (O) -, - O -, - S-S -, - S -, - NR -, - (CRR ') p -, - CH 2 NH -, - C (O) S-, -C (O) O-, -C≡C-, -C≡C-C≡C , -CH (OH) -, - HC = CH -, - NHC (O) NH -, - NHC (O) O -, - NHCH 2 NH -, - NHCH 2 CH (OH) CH 2 NH -, - N _{= CH (CH 2) p CH} = N -, - CH 2 CH (OH) CH 2 -, - N = CH (CH 2) h CH = N- ( where, h is 1 to 4), - CH = N—NH—, —OC (O) O—, —OP (O) (OH) O—, —CH (OH) CH ₂ NH—, —CH (OH) CH ₂ —, —CH (OH) _{C (CH 3) 2 C (} O) O-,

Each independently selected from the group consisting of: wherein p is 1-6; wherein R and R ′ are each independently selected from the group of hydrogen and alkyl groups; L is arranged independently for each of the Q ¹ and Q ² synthons, and each L is its two possible forms for the synthon it binds together (the bond to the immediate neighboring synthon to which it binds) Of the Q ¹ _a -NHC (O) -Q ¹ _b and Q ¹ _a -C (O) NH-Q ¹ _b Have one. If independently selected, the synthon Q ¹ can be any cyclic synthon, as described, so that J's synthon Q ¹ can be found in a closed ring in any order. (E.g., cyclohexyl-l, 2-phenyl-piperidinyl-l, 2-phenyl-l, 2-phenyl-cyclohexyl), and the bond L of J is also independently selected and closed ring Can be placed inside. The macrocycle module represented by and included in the above formula includes all stereoisomers of the synthon involved, so that a wide range of stereoisomers of the macrocycle module are in the composition of each closed ring of the synthon Is included.
Methods for making a macrocyclic module composition include, for example: (a) providing a plurality of first annular synthons; (b) contacting a plurality of second annular synthons with the first annular synthon; c) isolating the macrocyclic module composition. In some embodiments, the method can further comprise contacting the linker molecule with the mixture in (a) or (b).
Another method of preparing a composition for transporting a selected species by the above composition includes the following steps: selecting a first cyclic synthon, wherein the first cyclic synthon is C, H, Substituted with at least one functional group comprising a functional group comprising an atom selected from the group consisting of N, O, Si, P, S, B, Al, halogen, and metals from alkali metals and alkaline earth metals. Selecting from 2 to about 23 additional cyclic synthons; incorporating the first cyclic synthon and the additional cyclic synthons into a macrocyclic module composition: wherein the composition comprises 3 to about 24 cyclic synthons; Bonding to form a closed ring defining a pore; wherein at least one functional group of the first cyclic synthon is located in the pore of the macrocyclic module composition and the pore It is selected to transport more selections.
Another method of making a macrocyclic module composition is: (a) providing a plurality of first annular synthons; (b) contacting a plurality of second annular synthons with the first annular synthon; c) contacting the plurality of first cyclic synthons with the mixture from (b).
Another method of making a macrocyclic module composition is: (a) providing a plurality of first annular synthons; (b) contacting a plurality of second annular synthons with the first annular synthon; c) contacting the plurality of third cyclic synthons with the mixture from (b).

  In some embodiments, the method can further comprise the step of supporting the cyclic synthon (s) bound on the solid phase.

  Another method of making a macrocyclic module composition includes the following steps: (a) contacting a plurality of cyclic synthons with a metal complex template; (b) isolating the macrocyclic module composition.

  The macrocyclic module can include functional groups for attaching the macrocyclic module to a solid surface, substrate, or support. Examples of macrocyclic module functional groups that can be used to attach to a substrate or surface include amines, carboxylic acids, carboxylic esters, benzophenones and other photoactivated crosslinkers, alcohols, glycols, vinyls, styryls. Olefin styryl, epoxide, thiol, magnesium halo or Grignard, acrylate, acrylamide, diene, aldehyde, and mixtures thereof. These functional groups bind to the closed ring of the macrocyclic module and can be attached by spacer groups as needed. Examples of solid surfaces include metal surfaces, ceramic surfaces, polymer surfaces, semiconductor surfaces, silicon wafer surfaces, alumina surfaces, and the like. Examples of macrocyclic module functional groups that can be used to bond to a substrate or surface further include those listed in the left column of Tables 5 and 6. Methods for initiating bonding of the module to the substrate include chemical methods, thermal methods, photochemical methods, electrochemical methods, and radiation methods.

  Examples of spacer groups include polyethylene oxide, propylene oxide, polysaccharide, polylysine, polypeptide, poly (amino acid), polyvinyl pyrrolidone, polyester, polyvinyl chloride, polyvinylidene fluoride, polyvinyl alcohol, polyurethane, polyamide, polyimide, polysulfone, Examples include polyethersulfone, polysulfonamide, and polysulfoxide.

(Macro ring module hole)
Individual macrocyclic modules may include holes in their structure. The size of the pores can determine the size of molecules or other chemical species that can pass through the macrocyclic module. The size of the pores of the macrocyclic module is the structure of the synthon used to make the macrocyclic module, the linkage between synthons, the number of synthons in the module, the structure of any linker molecule used to make the macrocyclic module, and the macrocycle It may depend on other structural features of the macrocyclic module, whether inherent in the preparation of the module or added in a later step or modification. The stereoisomerism of the macrocycle module can also be used to adjust the pore size of the macrocycle module by changing the stereoisomer of each synthon used to prepare the closed ring of the macrocycle module.

  The hole size of the macrocyclic module can be varied by changing the combination of synthons used to form the macrocyclic module, or by changing the number of synthons in the closed ring. The pore size can also vary with substituents on the synthon or bond. Thus, by making the pores sufficiently large or small, an effect on the transport of chemical species through the pores can be achieved. Chemical species that can be transported through the pores of the macrocyclic module include atoms, molecules, biomolecules, ions, charged particles, and photons.

The size of the chemical species may not be the only determinant of whether it can pass through the pores of the macrocyclic module. Groups or portions located in or near the pore structure of the macrocyclic module can regulate or influence the transport of chemical species through the pore by various mechanisms. For example, the transport of a chemical species through a pore can be influenced by groups of macrocyclic modules that interact with the chemical species, by other interactions such as ionic or chelating groups, or by complexation of chemical species. Can be done. For example, charged groups such as carboxylate anions or ammonium groups can couple with oppositely charged species and affect their transport. Synthon substituents in the macrocycle module can affect the passage of chemical species through the pores of the macrocycle module. Groups that make the pores of the macrocyclic module somewhat hydrophilic or lipophilic can affect the transport of chemical species through the pores. Atoms or groups can be placed in or near the hole to sterically slow or block the passage of chemical species through the hole. For example, a hydroxyl group or alkoxy group can be coupled to a cyclic synthon and placed in a hole in a macrocyclic module structure, or can be coupled to a bond between synthons and placed in a hole. A wide range of functional groups can be used to sterically slow or block the passage of chemical species through the pores, including C, H, N, O, Si, P, S, B, Al, halogens And functional groups containing atoms selected from the group consisting of alkali metals and alkaline earth metals. Blocking and slowing the passage of chemical species through the pores reduces the size of the pores by steric blocks and slows the passage of the chemical species by creating a path through the non-linear pores. Can be included to slow down transport. The stereochemical structure of the portion of the macrocyclic module that defines the pores and their interior can also affect transport. Any group or moiety that affects the transport of chemical species through the pores of the macrocyclic module can be introduced as part of the synthon used in the preparation of the macrocyclic module or can be added later by various means. For example, S7-1 can react with ClC (O) (CH ₂ ) ₂ C (O) OCH ₂ CH ₃ to convert a phenol group to a succinyl ester group. In addition, the molecular dynamics of synthons and bonds in partially flexible macrocyclic modules can affect the transport of chemical species through the pores of the module. Since the presence of chemical species to be transported through the hole affects the flexibility, conformation, and dynamic behavior of the macrocyclic module, the transport behavior is only explained by the structure of the macrocyclic module itself. May not be. In general, the solvent can also affect the transport of solutes through the pores.

  Macrocyclic modules and arrays of macrocyclic modules are among other applications size exclusion separations, ion separations, gas separations, enantiomeric separations, small molecule separations, water purification, bacterial, fungal or viral filtration, Can be useful for sewage treatment and toxin removal.

  The following examples further describe and implement variations that are within the scope of the present invention. All examples described herein, both in the foregoing description and in the following examples, are provided for purposes of illustration only and are not to be construed as limiting the invention. While exemplary variations of the invention have been described, those skilled in the art will recognize that changes or modifications can be made without departing from the spirit and scope of the invention. It is intended to cover all these changes, modifications, and equivalents that are within the true scope of the invention as set forth in the appended claims.

  All references (including patent applications, patent citations, publications, articles, books, and articles) referenced herein are specifically incorporated by reference herein in their entirety.

Reagents were obtained from Aldrich Chemical Company and VWR Scientific Products. The reaction was carried out under a nitrogen atmosphere or an argon atmosphere unless otherwise specified. The aqueous solvent extract was dried over anhydrous Na ₂ SO ₄ . The solution was concentrated under reduced pressure using a rotary evaporator.

Example 1
(Derivatization of silicon substrate using (3-aminopropyl) triethoxysilane (APTES))
First, the SiO ₂ substrate was sonicated in a piranha solution (3: 1 ratio of H ₂ SO ₄ : 30% H ₂ O ₂ ) for 15 minutes. Thereafter, it was sonicated in Milli-Q water (> 18 MΩ-cm) for 15 minutes. The derivatization step was performed in a glove bag under N ₂ atmosphere. 0.05 mL APTES and 0.05 mL pyridine were added to 9 mL toluene. Immediately after mixing, the newly cleaned SiO ₂ substrate was immersed in the APTES solution for 10 minutes. The substrate was washed with copious amounts of toluene, and then dried with N _2. The deposited APTES film exhibited thickness values in the range of 0.8 to 1.3 nm.

(Example 2)
Amphiphilic module hexamer 1a was dissolved in HPLC grade chloroform at a concentration of about 1 mg / ml. The chloroform solution was applied to the water (Millipore Milli-Q) surface in an LB trough (KSV, Helsinki). Chloroform was evaporated, its hydrophilic groups were immersed in water and its lipophilic groups were present in the air. The amphiphilic module was left on the water surface. The temperature in the system was controlled (approximately ± 0.2 ° C.). The LB trough barrier was slowly compressed (1-10 mm / min). During film compression, the surface pressure was monitored using the Wilhelmy procedure. The shape of the isotherm confirmed that the module formed a Langmuir film on the water surface.

(Example 3)
(Hexamer 1dh with DEM (Langmuir-Blodgett deposition))
The scheme for this preparation is illustrated in FIG. 25 μl of a 1 mg / ml solution of hexamer 1dh in chloroform was dispersed on 2 mg / ml diethyl malonimidate (DEM) in a subphase (pH 8.8, T = 22 ° C.). After waiting 19 minutes to allow diffusion of solvent evaporation, the monolayer was compressed and held at 5 mN / m. The lower phase was then heated to 40 ° C. and held for approximately 60 minutes. A cured solid nanofilm was formed on the surface of this lower phase. This was uniform and uniform in the Brewster Angle microscope image. When touched with the probe, the film cracked, as shown in a Brewster Angle microscope image (shown in FIG. 6A) that captured the film directly above the surface of the lower phase. This indicates that the nanofilm is highly crosslinked. The mass spectral analysis of the cured nanofilm could not be performed because the solid nanofilm blocked the device inlet.

Other monolayers prepared as described above were made hydrophilic by Langmuir-Blodgett deposition by treatment with a piranha solution of H ₂ SO ₄ /30% H ₂ O _{2 in} a ratio of 3: 1 for 10 minutes. ). The substrate was transferred through the air-water interface at a rate of 0.3 mm / min. Image ellipsometry (shown in FIG. 6B) showed a crushed solid film mass on the silicon substrate, the height including the nanofilm and the APTES coating on the substrate was approximately 35 mm.

  The isobaric creep of the solid nanofilm is shown in FIG. In concentrated state, Langmuir film with individual molecules directed on the surface but not coupled between the molecules will diffuse or depressurize when the compressive force is released. In comparison, the coupled module solid nanofilm maintained its shape and film strength over time, even in the presence of solvent, as shown in FIG. The upper line shows the isobaric creep of the nanofilm prepared in the presence of the DEM crosslinker, and the lower line shows the isobaric creep of the nanofilm prepared without the crosslinker.

Example 4
(Hexamer 1dh with DEM (Langmuir-Blodgett deposition))
The presence of module linkage was detected by Fourier transform infrared spectroscopy (FTIR). The FTIR spectrum of the nanofilm of Example 3 is shown in FIG. In FIG. 8A FTIR spectra of nanofilm and hexamer 1dh are shown. In FIG. 8B, the FTIR spectrum of the DEM and DEM in the lower phase after 24 hours is shown. Changes in FTIR indicate the presence of coupling between hexamer 1dh and DEM.

(Example 5)
(Hexamer 1dh with DEM (Langmuir-Schaefer deposition))
25 μl of a 1 mg / ml solution of hexamer 1dh in chloroform was spread over the lower phase of 2 mg / ml diethyl malonimidate (pH 8.8, T = 22 ° C.). After waiting for 15 minutes to allow diffusion of solvent evaporation, the monolayer was compressed and held at 5 mN / m. This monolayer was transferred to a Si wafer (treated with piranha solution for 10 minutes to make it hydrophilic) by Langmuir-Schaefer deposition. Image ellipsometry showed a complete film on a silicon substrate, as shown in FIG. 9, which shows a single piece of nanofilm, and its height was approximately 21 cm.

(Example 6)
(Mannic reaction using octadecylamine)
35 μl of a 1 mg / ml solution of octadecylamine in chloroform was spread on the lower phase of 1% formaldehyde (pH 3, T = 22 ° C.). After waiting for 15 minutes to allow diffusion of solvent evaporation, the monolayer was compressed and held at 20 mN / m. At this surface pressure, the film showed a constant loss of area for approximately 80 minutes, after which the film area increased. After a total of 130 minutes, the film was extracted by manual Langmuir-Blodgett deposition at the air-water interface. Briefly, after immersing the Si wafer through the air-water interface, the wafer was shaken in chloroform to remove the deposited material and the process was repeated. Thereafter, mass spectrometry (ESI mode) was performed on the chloroform solution. The bond structure formed in the nanofilm upon coupling of the amphiphile as detected in the mass spectrum is shown on the right side of FIG.

(Example 7)
(Surface adhesion using reactive ester groups)
First, the silicon substrate modified with APTES was lowered to an aqueous phase of pH 7 at 22 ° C. 160 mL methyl heptadecanoate (MHD) (1 mg / mL CHCl ₃ solution) was dispersed at the air / water interface. After 10 minutes, the film was compressed to 38 mN / m at a speed of 3 mm / min. When reaching 38 mN / m, the substrate was pulled from this lower phase (while maintaining a surface pressure of 38 mN / m) at a rate of 1 mm / min, resulting in a single layer of MHD being deposited. After deposition, some samples were heated at 70 ° C. for 3.5 hours to induce a reaction between surface amine groups (APTES) and MHD ester groups, forming amide bonds. After heat curing, the sample was sonicated with CHCl ₃ to determine the degree of surface adhesion. If the film did not react with the surface, this treatment resulted in the film being removed.

An elliptically polarized image of the substrate is shown in FIG. FIG. 10A shows the substrate after film deposition. FIG. 10B shows the substrate after film deposition and heating at 70 ° C. FIG. 10B shows that some dewetting occurred during heating and the nanofilm remained on the substrate. FIG. 10C shows the substrate after film deposition, heating at 70 ° C., and CHCl ₃ treatment. This also indicates that the nanofilm remained on the substrate.

(Example 8)
(Surface adhesion using reactive acrylic groups)
First, the SiO ₂ substrate was derivatized with a layer of methylacryloxymethyltrimethoxysilane (MAOMTMOS) using the same procedure as described in derivatization with APTES (Example 6). The substrate was then lowered into an aqueous phase at pH 5 at 22 ° C. 170 mL of N-octadecylacrylamide (ODAA) (1 mg / mL CHCl ₃ solution) was dispersed at the air / water interface. After 10 minutes, the film was compressed to 35 mN / m at a speed of 2 mm / min. When reaching 35 mN / m, the substrate was pulled up from the lower phase at a rate of 2 mm / min, resulting in the deposition of one layer of ODAA. After deposition, some samples were irradiated (254 nm) for 40 or 220 minutes to induce coupling between surface acrylic groups (MAOMTMOS) and ODAA acrylic groups. After UV curing, the sample was sonicated in CHCl ₃ to determine the degree of surface adhesion. If the film did not react with the surface, this treatment resulted in the film being removed.

An elliptically polarized image of this substrate is shown in FIG. FIG. 11A shows the substrate after film deposition and exposure to 254 nm UV irradiation for 40 minutes. FIG. 11B shows the substrate after film deposition, irradiation, and CHCl ₃ treatment. FIG. 11B shows that there was a monolayer coupled to the substrate.

Example 9
The unique structure of the hexamer 1dh nanofilm of Example 3 is shown in FIG. 12, where the linkage is made by modular amide bonds via cyclohexyl synthons. The approximate size of the module and structure gap holes are 14 ² , 25 ² , and 40 ² . A sufficiently minimized structure was obtained by MM + molecular mechanics.

(Example 10)
Octamer 5jh-aspartic acid is formed in a concentrated Langmuir film and heated to a temperature sufficient to initiate coupling of the module via an amide bond to form a nanofilm. The unique structure of the octamer 5jh-aspartic acid nanofilm is shown in FIG. 13, where the binding is made by modular aspartic acid amide linkages via piperidine synthons. The approximate size of the pores in the structure is 119 ^{2 to} 200 ² . A sufficiently minimized structure was obtained by MM + molecular mechanics.

(Example 11)
First, two SiO ₂ substrates were derivatized with a layer of acryloxypropyltrimethoxysilane (AOPTMOS) using the same procedure as described in derivatization with APTES (see Example 1). . These substrates and the unmodified SiO ₂ substrate were then lowered to the lower phase of H ₂ O maintained at 22 ° C. Thereafter, hexamer 1jh-AC (1 mg / mL CHCl ₃ solution) was dispersed at the air / water interface. After 10 minutes, the film was compressed to 30 mN / m at a speed of 4 mm / min. When the surface pressure of 30 mN / m was reached, the Langmuir film was irradiated with 254 nm light from a distance of 1.5 inches (1350 μW / cm ² at a distance of 3 inches) for 30 minutes. Thereafter, the substrate was pulled up from the lower phase at a speed of 1 mm / min. As a result, a single layer of crosslinked hexamer 1jh-AC was deposited. After deposition, the sample deposited on the AOPTMOS substrate was irradiated (254 nm) for 30 minutes to induce coupling between the surface acrylic groups (AOPTMOS) and the hexamer 1jh-AC acrylic groups. All samples were then tested by ellipsometry to determine film thickness values. Finally, all samples were sonicated in CHCl ₃ to determine the degree of surface adhesion. If the film did not react with the surface, this treatment resulted in the film being removed. Corresponding Langmuir trough area versus time (during irradiation) graphs and elliptically polarized images of the deposited film are shown in FIGS. 14 and 15, respectively. An elliptically polarized image of a film deposited on a substrate modified with MAOMMTMOS clearly shows that the film is still present after CHCl ₃ sonication, thus indicating that surface deposition has occurred. Conversely, if no UV light was used after deposition on a substrate modified with MAOMMTMOS, or if the film was deposited on silicon, an elliptically polarized image indicates that surface adhesion did not occur.

  Furthermore, the FTIR data shows the disappearance of the vinyl group band upon UV exposure of hexamer 1jh-AC (FIG. 16), which indicates cross-linking between hexamer 1jh-AC and AOPTMOS derivatized substrate. To express.

(Example 12)
The filtration function of the membrane can be explained from its solute exclusion profile. The filtration functions of several nanofilm membranes are illustrated in Tables 7-8.

  (Example of G membrane filtration function)

  (Example of T membrane filtration function)

  The passage or exclusion of the solute is measured by its clearance. It reflects the portion of the solute that actually passes through the membrane. The NP symbol in Tables 7-8 indicates that the solute is partially excluded by the nanofilm, the exclusion sometimes being less than 90%, often at least 90% and sometimes at least 98%. The P symbol indicates that the solute is partially removed by the nanofilm, and its clearance is sometimes less than 90%, often at least 90%, and sometimes at least 98%.

  Have very low clearance of species (eg, less than about 5%, less than about 3%) or very high exclusion of species (eg, greater than about 95%, greater than about 98%) If so, the membrane is impermeable to the chemical species.

(Example 13)
The pore size of the module can be measured by the conductance of a voltage-clamped lipid bilayer test. The module is dissolved in the phosphatidylcholine-phosphatidylethanolamine lipid bilayer. A solution containing the cationic species to be tested is placed on one side of the bilayer. On the other side, a solution containing a cationic species known to be able to pass through the holes in the module is placed. The anions necessary for electrical neutrality are selected so that they do not pass through the pores of the module. If a positive voltage is applied to the solution on the side of the lipid bilayer containing the test species, no current will be detected if the test cation is of a size that cannot pass through the pores of the module. The voltage is then reversed and a positive voltage is applied to the side of the lipid bilayer having a solution containing a cationic species known to be able to pass through the pores. Observation of the predicted current confirms the integrity of the lipid bilayer and the availability of the module's pores as a cation transporter of less than a known size.

  As shown in Table 9, the selective permeability of the macrocyclic module was tested using the voltage clamped double layer method. The “+” sign represents solute permeation and the “−” sign represents solute exclusion. Permeation and exclusion are indicators of clearance. The fixed voltage was 50 mV.

(Example 14)
Solute selective filtration and relative clearance are illustrated in Table 10. In Table 10, the heading “High Permeability” represents more than about 70% to 90% clearance of the solute. The heading “medium permeability” represents a clearance of less than about 50% to 70% of the solute. The heading “low permeability” represents less than about 10% to 30% clearance of the solute.

(Example 15)
Table 11 shows the approximate diameters of the various species that should be considered in the filtration process.

(Synthon and macrocycle module synthesis method)
All chemical structures illustrated and described herein, both in the foregoing description and in the following examples and drawings, are intended to be illustrative unless the illustration, description, or drawings are explicitly limited to any particular isomer. , Including and encompassing all foreseeable variations and isomers of the structure, including all stereoisomers and structural or configurational isomers.

(Method for preparing cyclic synthon)
The synthons of the present invention avoid the need to separate a single configurational isomer or enantiomer from a complex mixture resulting from a non-specific reaction, a stereospecific coupling reaction or at least a stereoselective coupling reaction. Can be employed in the preparation of The following are examples of several classes of synthetic schemes of synthons required for the preparation of the macrocyclic module of the present invention. In general, core synthons are illustrated and do not show lipophilic moieties in their structure, but all the synthetic schemes below are for additional lipophilic moieties or hydrophilics used in the preparation of amphiphilic macrocycle modules and other modified macrocycle modules. It is understood that a sex moiety can be included. The chemical species are numbered with respect to the scheme in which they appear (eg, “S1-1” means structure 1 of Scheme 1).

  The approach for preparing the 1,3-diaminocyclohex-5-ene synthon is shown in Scheme 1.

Enzymatically pure S1-2 is obtained using enzyme-assisted partial hydrolysis of the symmetric diester S1-1. S1-2 is Curtis reacted and then quenched with benzyl alcohol to give protected amino acid S1-3. After iodolactonization of carboxylic acid S1-4, unsaturated lactone S1-6 is obtained by dehydrohalogenation. Opening of the lactone ring with sodium methoxide gave alcohol S1-7, which was mesylated, SN ₂ substituted with azide, reduced, and di-tert-butyl dicarbonate of the resulting amine In a one-pot reaction involving protection at, the configuration is reversed and converted to S1-8. Epimerization of S1-8 to a more stable diequatorial configuration followed by saponification yields the carboxylic acid S1-10. S1-10 is subjected to Curtius reaction. The mixed anhydride is prepared by reaction with ethyl chloroformate followed by aqueous NaN ₃ to give acyl azide, which is thermally rearranged to the isocyanate in refluxing benzene. The isocyanate is quenched with 2-trimethylsilylethanol to give the individually protected tricarbamate S1-11. The 1,3-diamino group is selectively deprotected by reaction with trifluoroacetic acid (TFA) to give the desired synthon S1-12.

  As another variation, an approach to prepare a 1,3-diaminocyclohexane synthon is shown in Scheme 1a.

  Some features of these preparations are described in Suami et al. Org. Chem. 1975, 40, 456 and Kavadias et al., Can. J. et al. Chem. 1978, 56, 404.

  As another variation, an approach to prepare 1,3-substituted cyclohexane synthons is shown in Scheme 1b.

  This synthon remains “Z-protected” until the macrocyclic module is cyclized. A hydrogenation protocol is then performed to deprotect and produce a macrocyclic module with amine functionality.

Norbonane (bicycloheptane) can be used to prepare the synthons of the present invention to achieve stereochemically controlled norbonane polyfunctionalization. For example, Diels-Alder cycloaddition can be used to form norbonanes incorporating various functional groups with specific predictable stereochemistry. Obtaining products with enhanced optical isomerization using appropriate reagents can limit the need for chiral separations.
The approach for preparing 2-diaminonorbornane synthons is shown in Scheme 2.

5- (benzyloxy-methyl) -1,3-cyclopentadiene (S2-13) is reacted with a diethylaluminum chloride / Lewis acid complex of di- (l) -menthyl fumarate (S2-14) at a low temperature, Diastereomerically pure norbornene S2-15 is obtained. Saponification with potassium hydroxide in aqueous ethanol yielded the diacid S2-16, the diacid S2-16 was reacted with diphenylphosphoryl azide (DPPA) in a two-stage Curtius reaction, and the reaction product was treated with 2-trimethylsilylethanol Quench to obtain biscarbamate S2-17. Deprotection with TFA gives diamine S2-18.

  An overview of another approach to this synthon class is shown in Scheme 3.

Ring opening of the anhydride S3-19 with methanol in the presence of quinidine gives the enantiomerically pure ester acid S3-20. Epimerization of the ester group with sodium methoxide (NaOMe) provides S3-21. The carbamate S3-22 is obtained by Curtius reaction with DPPA followed by quenching with trimethylsilylethanol. Saponification with NaOH gives acid S3-23, which is reacted with Curtius and then quenched with benzyl alcohol to give individually protected biscarbamate S3-24. Compound S3-24 can be completely deprotected to give a diamine, or either carbamate can be selectively deprotected.
An approach to prepare endo, endo-1,3-diaminonorbornane synthons is shown in Scheme 4.

5-trimethylsilyl-1,3-cyclopentadiene (S4-25) is reacted with diethylaluminum chloride Lewis acid complex of di- (l) -menthyl fumarate at low temperature to produce almost diastereomerically pure norbornene S4 -26 is obtained. Crystallization of S4-26 from alcohol gives a single diastereomeric recovery of greater than 99%. Bromolactonization followed by rearrangement via silver gives the mixed diester S4-28 with an alcohol moiety in the 7-position. Protection of the alcohol with benzyl bromide and selective deprotection of the methyl ester provides the free carboxylic acid S4-30. Norbornene S4-31 trimethylsilylethylcarbamate is obtained by the Curtius reaction. Biscarbonylation of the olefin in methanol followed by one-step deprotection and dehydration gives the mono-anhydride S4-33. Quinidine-mediated ring opening of anhydride with methanol provides S4-34. Biscarbamate S4-35 is obtained by Curtius conversion of S4-34, and diamine S4-36 is obtained by deprotection of biscarbamate S4-35 with TFA or tetrabutylammonium fluoride (TBAF).

  A summary of one other approach to this class of synthons is shown in Scheme 5.

Benzyl alcohol ring opening of S3-19 in the presence of quinidine yields S5-37 which is enantiomerized in large excess. Iodolactonization to obtain a lactone S5-39 reduction with subsequent NaBH _4. Treatment with NaOMe liberates the methyl ester and free alcohol to produce S5-40. Conversion of alcohol S5-40 to amine S5-41 protected with t-butyl inverted carbamate protected with azide substitution of mesylate S5-40 followed by di-tert-butyl dicarbonate Achieved in a one-pot reaction by reduction to the oxidized amine. Hydrogenolysis of the benzyl ester and epimerization of the methyl ester to the exo configuration, followed by protection of the free acid with benzyl bromide provides S5-44. Saponification of the methyl ester followed by Curtius reaction quenched with trimethylsilylethanol gives the biscarbamate S5-46, which is cleaved with TFA to give the desired diamine S5-47.
An approach for preparing exo, endo-1,3-diaminonorbornane synthons is shown in Scheme 6.

Ring-opening of norbornene anhydride S3-19 in the presence of quinidine with p-methoxybenzyl alcohol gives the monoester S6-48 in a large excess. The free acid Curtius reaction yields the protected total endomonoacid-monoamine S6-49. Biscarbonylation and anhydride formation give exo-mono anhydride S6-51. S6-52 is obtained by selective metallolysis in the presence of quinine. Biscarbamate S5-53 is obtained by Curtius reaction quenched with trimethylsilylethanol. Epimerization of the two esters yields more sterically stable S6-54. Synthon S6-55 is obtained by cleavage of the carbamic acid group.

(Method for preparing macrocyclic module)
Synthons can be coupled together to form a macrocyclic module. As one variation, synthon coupling may be achieved by a concerted scheme. Preparation of macrocyclic modules by concerted pathways can be performed, for example, using at least two types of synthons, each type having at least two functional groups for coupling to other synthons. The functional group can be selected such that the functional group of one type of synthon can only be coupled to the functional group of another type of synthon. When two types of synthons are used, a macrocyclic module having different types of alternating synthons can be formed. Scheme 7 shows the synthesis of concert modules.

  Referring to Scheme 7, 1,2-diaminocyclohexane S7-1 is a synthon having two amino functional groups for coupling to other synthons and 2,6-diformyl-4-dodec-1-y Nylphenol S7-2 is a synthon with two formyl functional groups for coupling to other synthons. An amino group can couple with a formyl group to form an imine bond. Scheme 7 shows a concert product, a hexameric macrocyclic module.

  As one variation, a mixture of tetrameric, hexameric, and octameric macrocyclic modules can be formed in a concerted scheme. The yield of these macrocycle modules can be varied, among other factors, by changing the concentration of various synthons in the reagent mixture or by changing the solvent, temperature, and reaction time.

  The imine group of S7-3 is reduced with, for example, sodium borohydride to obtain an amine bond. When the reaction is carried out using 2,6-di (chlorocarbonyl) -4-dodec-1-ynylphenol instead of 2,6-diformyl-4-dodec-1-ynylphenol, the resulting module is , Will contain an amide bond. Similarly, when 1,2-dihydroxycyclohexane is reacted with 2,6-di (chlorocarbonyl) -4-dodec-1-ynylphenol, the resulting module will contain an ester linkage.

  In some variations, synthon coupling may be achieved by a step-wise scheme. As an example of the stepwise preparation of a macrocyclic module, a first type of synthon is replaced with one protected functional group and one unprotected functional group. The second type of synthon is replaced with an unprotected functional group that couples with the unprotected functional group of the first synthon. The product of reacting the first type of synthon with the second type of synthon can be a dimer (consisting of two coupled synthons). The second synthon can also be substituted with one other functional group, which is protected or does not couple with the first synthon when forming a dimer. The dimer can be isolated and purified, or the preparation can proceed as a one-pot reaction. A dimer can be reacted with a third synthon having two functional groups, only one of the functional groups being coupled with the remaining functional groups of the first or second synthon to form a trimer ( Of three coupled synthons). Such synthon stepwise coupling can be repeated to form macrocyclic modules of various ring sizes. To cyclize, i.e. cyclize, the macrocycle module, the nth synthon coupled to the product is replaced with this second functional group, and this second functional group is replaced with that of the already coupled synthon. , And can be coupled to the second non-coupled functional group, which can be deprotected for that step. The stepwise method is performed with synthons on a solid support. Scheme 8 shows the stepwise preparation of module SC8-1.

  Compound S8-2 is protected with S8-3, where the phenol is protected as a benzyl ether and the nitrogen is protected with a “P” group (which can be any of a number of protecting groups well known in the art). In the presence of methanesulfonyl chloride (Endo, K .; Takahashi, H., Heterocycles, 1999, 51, 337) to obtain S8-4. Removal of the N-protecting group yields the free amine S8-5, which is coupled with synthon S8-6 using any of the standard peptide coupling reactions such as BOP / HOBt. To obtain S8-7. Deprotection / coupling is repeated while alternating synthons S8-3 and S8-6 until a linear structure with 8 residues is obtained. Remove the remaining acid and amine protecting groups on the octamer, cyclize the oligomer (eg, Caba, JM, et al., J. Org. Chem., 2001, 66: 7568 (PyAOP cyclization)) Tarver, JE et al., J. Org. Chem., 2001, 66: 7575 (active ester cyclization)). The R group is an alkyl group bonded to the benzene ring via H or a functional group, and X is N, O, or S. Examples of solid supports include Wang resin, hydrogel, silica gel, Sepharose, Sephadex, agarose, and inorganic solids. The use of a solid support can simplify the procedure as it prevents purification of intermediate intermediates. The final cyclization can be performed in the form of a solid phase. Using the “safety catch linker” approach (Bourne, GT, et al., J. Org. Chem., 2001, 66: 7706), cyclization and resin cleavage can be performed in a single operation.

  As another variation, the concert method involves the reaction of two or more different synthons and linker molecules, as shown in Scheme 9, where R can be an alkyl group or other lipophilic group.

  As another variation, the stepwise linear method includes various synthons and solid supports, as shown in Scheme 10.

  As another variation, the stepwise convergence method includes a synthon trimer and a solid support, as shown in Scheme 11. This method can also be performed with the trimer in solution, without the use of a solid support.

As another variation, the template method includes synthons collected by the template, as shown in Scheme 12. Some features of this approach (and Mg ²⁺ template) are described in Dutta et al., Inorg. Chem. 1998, 37, 5029.

  As another variation, the linker molecule method involves synthon cyclization in solution, as shown in Scheme 13.

Reagents for the following examples were obtained from Aldrich Chemical Company and VWR Scientific Products. All reactions were performed under a nitrogen or argon atmosphere unless otherwise stated. Solvent extraction of the aqueous solution was dried over anhydrous Na ₂ SO ₄ . The solution was concentrated under reduced pressure using a rotary evaporator. Thin layer chromatography (TLC) was performed on Analtech Silica gel GF (0.25 mm) plates or on the Macery-Nagel Algram Sil G / UV (0.20 mm) plates. Chromatograms were visualized using either ultraviolet light, phosphomolybdic acid, or KMnO ₄ . All reported compounds were homogeneous by TLC unless otherwise stated. HPLC was performed on a Hewlett Packard 1100 system using a reverse phase C-18 silica column. Enantiomeric excess was determined by HPLC using a reverse phase (l) -leucine silica column from Regis Technologies. All ¹ [H] and ¹³ [C] NMR spectra were collected at 400 MHz on a Varian Mercury system. Electrospray mass spectra were obtained from Synpep Corp. From or on a Thermo Finnigan LC-MS system.
(Example 16)
(2,6-diformyl-4-bromophenol)
Hexamethylenetetraamine (73.84 g, 526 mmol) was added to TFA (240 mL) with stirring. 4-Bromophenol (22.74 g, 131 mmol) was added in one portion and the solution was heated to 120 ° C. in an oil bath and stirred for 48 h under argon. The reaction mixture was then lowered to room temperature. Water (160 mL) and 50% aqueous H ₂ SO ₄ (80 mL) were added and the solution was stirred for an additional 2 hours. The reaction mixture was poured into water (1600 mL) and the resulting precipitate was collected on a Buchner funnel. The precipitate was dissolved in ethyl acetate (EtOAc) and the solution was dried over MgSO ₄ . The solution was filtered and the solvent was removed on a rotary evaporator. The product was isolated as a yellow solid (18.0 g, 60%) by purification by column chromatography on silica gel (400 g) using a gradient of 15-40% ethyl acetate in hexane.

(Example 17)
(2,6-diformyl-4- (dodecin-1-yl) phenol)
2,6-diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecine (2.00 g, 12.0 mmol), CuI (65 mg, 0.33 mmol), and bis (triphenylphosphine dichloride) ) Palladium (II) was suspended in degassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). The yellow suspension was sparged with argon for 30 minutes and degassed Et ₃ N (1 mL) was added. The resulting brown suspension was sealed in a pressure bottle, warmed to 80 ° C. and left for 12 hours. The mixture was then partitioned between EtOAc and KHSO ₄ solution. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% Et ₂ O in hexane) to give 1.56 g (46%) of the title compound.

(Example 18)
(2,6-diformyl-4- (dodecen-1-yl) phenol)
2,6-diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene (4.8 mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol), 0. 50 g NaHCO ₃ (5.95 mmol), 1.00 g LiCl (23.6 mmol) and 0.100 g palladium diacetate (Pd (OAc) ₂ ) (0.45 mmol) were added to 30 mL degassed anhydrous dimethylformamide. Combined in (DMF). The mixture was sparged with argon for 10 minutes and then sealed in a pressure vial that was warmed to 82 ° C. and left for 40 hours. The crude reaction mixture was partitioned between CH ₂ Cl ₂ and 0.1M HCl solution. The organic layer was washed with 0.1 M HCl (2 ×), brine (2 ×), and saturated aqueous NaHCO ₃ (2 ×), dried over MgSO ₄ and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% hexane in Et ₂ O) to give 0.700 g (51%) of the title compound as the predominantly Z isomer.

(Example 19)
((1R, 6S) -6-methoxycarbonyl-3-cyclohexene-1-carboxylic acid (S1-2))
S1-1 (15.0 g, 75.7 mmol) was suspended in a pH 7 phosphate buffer (950 mL). Porcine liver esterase (2909 units) was added and the mixture was stirred at ambient temperature for 72 hours while maintaining the pH at 7 by the addition of 2M NaOH. The reaction mixture was washed with ethyl acetate (200 mL), acidified to pH 2 with 2M HCl and extracted with ethyl acetate (3 × 200 mL). These extracts were combined, dried and evaporated to give 13.8 g (99%) of S1-2.

(Example 20)
(Methyl (1S, 6R) -6-benzyloxycarbonylaminocyclohex-3-enecarboxylate (S1-3))
S1-2 (10.0g, 54.3mmol) was dissolved in benzene (100 mL) under _{N 2.} Triethylamine (13.2 g, 18.2 mL, 130.3 mmol) was added followed by DPPA (14.9 g, 11.7 mL, 54.3 mmol). The solution was refluxed for 20 hours. Benzyl alcohol (5.9 g, 5.6 mL, 54.3 mmol) was added and refluxing was continued for 20 hours. The solution was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO ₃ (2 × 50 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried and evaporated to 13.7 g (87%). S1-3 was obtained.

(Example 21)
((1S, 6R) -6-Benzyloxycarbonylaminocyclohex-3-enecarboxylic acid (S1-4))
S1-3 (23.5 g, 81.3 mmol) was dissolved in MeOH (150 mL) and the solution was cooled to 0 ° C. 2M NaOH (204 mL, 0.41 mol) was added and the mixture was allowed to reach room temperature and then stirred for 48 hours. The reaction mixture was diluted with water (300 mL), acidified with 2M HCl, extracted with dichloromethane (250 mL), dried and evaporated. The residue was recrystallized with diethyl ether to give 21.7 (97%) of S1-4.

(Example 22)
((1S, 2R, 4R, 5R) -2-benzyloxycarbonylamino-4-iodo-7-oxo-6-oxabicyclo [3.2.1] octane (S1-5))
S1-4 (13.9 g, 50.5 mmol) was dissolved in dichloromethane (100 mL) under N ₂ and 0.5 M NaHCO ₃ (300 mL), KI (50.3 g, 303.3 mmol), and iodine (25. 6 g, 101 mmol) was added and the mixture was stirred at ambient temperature for 72 hours. The mixture was diluted with dichloromethane (50 mL) and the organic phase was separated. The organic phase was washed with saturated aqueous Na ₂ S ₂ O ₃ (2 × 50 mL), water (30 mL), and saturated aqueous NaCl (20 mL), dried and evaporated to 16.3 g (80%) of S1- 5 was obtained.

(Example 23)
((1S, 2R, 5R) -2-Benzyloxycarbonylamino-7-oxo-6-oxabicyclo [3.2.1] oct-3-ene (S1-6))
S1-5 (4.0g, 10mmol) was dissolved in benzene (50 mL) under _{N 2.} 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (1.8 g, 12 mmol) was added and the solution was refluxed for 16 hours. The precipitate was filtered and the filtrate was diluted with EtOAc (200 mL). The filtrate was washed with 1M HCl (20 mL), saturated aqueous Na ₂ S ₂ O ₃ (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried and evaporated to 2.2 g (81%). S1-6 was obtained.

(Example 24)
(Methyl (1S, 2R, 5R) -2-benzyloxycarbonylamino-5-hydroxycyclohex-3-enecarboxylate (S1-7))
S1-6 (9.0 g, 33 mmol) was suspended in MeOH (90 mL) and cooled to 0 ° C. NaOMe (2.8 g, 52.7 mmol) was added and the mixture was stirred for 3 hours, during which time a solution gradually formed. The solution was neutralized with 2M HCl, diluted with saturated aqueous NaCl (200 mL) and extracted with dichloromethane (2 × 100 mL). The extracts were combined, washed with water (20 mL) and saturated aqueous NaCl (20 mL), dried and evaporated. Flash chromatography of the residue (silica gel (250 g), 50:50 hexane / EtOAc) gave 8.5 g (85%) of S1-7.

(Example 25)
(Methyl (1S, 2R, 5S) -2-benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate (S1-8))
S1-7 (7.9 g, 25.9 mmol) was dissolved in dichloromethane (150 mL) and cooled to 0 ° C. under N ₂ . Triethylamine (6.3 g, 8.7 mL, 62.1 mmol) and methanesulfonyl chloride (7.1 g, 62.1 mmol) were added and the mixture was stirred at 0 ° C. for 2 hours. (N-Bu) ₄ NN ₃ (14.7 g, 51.7 mmol) in dichloromethane (50 mL) was added and stirring was continued at 0 ° C. for 3 hours and then at ambient temperature for 15 hours. The mixture was cooled to 0 ° C., P (n-Bu) ₃ (15.7 g, 19.3 mL, 77.7 mmol) and water (1 mL) were added and the mixture was stirred at ambient temperature for 24 hours. Di-tert-butyl dicarbonate (17.0 g, 77.7 mmol) was added and stirring was continued for 24 hours. The solvent was removed, the residue was dissolved in 2: 1 hexane / EtOAc (100 mL), the solution was filtered and evaporated. Flash chromatography of the residue (silica gel (240 g), 67:33 hexane / EtOAc) gave 5.9 g (56%) of S1-8.

(Example 26)
(Methyl (1R, 2R, 5S) -2-benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate (S1-9))
S1-8 (1.1 g, 2.7 mmol) was suspended in MeOH (50 mL). NaOMe (0.73 g, 13.6 mmol) was added and the mixture was refluxed for 18 hours, after which 0.5M NH ₄ Cl (50 mL) was added and the resulting precipitate was collected. The filtrate was evaporated and the residue was triturated with water (25 mL). The insoluble part was collected and combined with the original precipitate to give 0.85 g (77%) of S1-9.

(Example 27)
((1R, 2R, 5S) -2-benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylic acid (S1-10))
S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50 MeOH / dichloromethane (5 mL) and cooled to 0 ° C. under N ₂ before adding 2M NaOH (2.0 mL). The mixture was stirred at ambient temperature for 16 hours. The mixture was acidified with 2M HCl, when a white precipitate was formed. The precipitate was collected, washed with water and hexane and dried to give 0.74 g (90%) of S1-10.

(Example 28)
((1R, 2R, 5S) -2-benzyloxycarbonylamino-5-t-butoxycarbonylamino-1- (2-trimethylsilyl) ethoxycarbonylaminocyclohex-3-ene (S1-11))
S1-10 (3.1 g, 7.9 mmol) was dissolved in THF (30 mL) under N ₂ and cooled to 0 ° C. Triethylamine (1.6 g, 2.2 mL, 15.9 mmol) was added followed by ethyl chloroformate (1.3 g, 1.5 mL, 11.8 mmol). The mixture was stirred at 0 ° C. for 1 hour. A solution of NaN ₃ (1.3 g, 19.7 mmol) in water (10 mL) was added and stirring was continued at 0 ° C. for 2 hours. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was separated, dried and evaporated. The residue was dissolved in benzene (50 mL) and refluxed for 2 hours. 2-Trimethylsilylethanol (1.0 g, 1.2 mL, 8.7 mmol) was added and refluxing was continued for 3 hours. The reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO ₃ (50 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried and evaporated. Flash chromatography of the residue (silica gel (100 g), 67:33 hexane / EtOAc) gave 3.1 g (77%) of S1-11.

(Example 29)
((1R, 2R, 5S) -2-benzyloxycarbonylamino-1,5-diaminocyclohex-3-ene (S1-12))
S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the solution was stirred at ambient temperature for 16 hours, after which the solution was evaporated. The residue was dissolved in water (20 mL), basified to pH 14 with KOH and extracted with dichloromethane (3 × 50 mL). The extracts were combined, washed with water (20 mL), dried and evaporated to give 1.1 g (85%) of S1-12.

(Example 30)
The following procedure was used to achieve isolation of S1b-2: 5.57 g (10.0 mmol) of the methyl ester compound S1b-1 was dissolved in 250 mL of THF using the technique of Schlenk. In a separate flask, LiOH (1.21 g, 50.5 mmol) was dissolved in 50 mL water and degassed by bubbling N ₂ through the solution using a syringe needle for 20 minutes. The reaction was initiated by transferring the basic solution to the flask containing S1b-1 over 1 minute with rapid stirring. The mixture was stirred at room temperature and when the starting material S1b-1 was completely consumed, work-up was started (66% EtOAc / 33% hexane solvent system was used and the phosphomolybdate reagent (Aldrich # 31, 927-9), the starting material S1b-1 has an Rf value of 0.88 and the product is streaked with an Rf value of approximately 0.34 to 0.64. This reaction usually takes 2 days. Work-up: THF was removed under reduced pressure until approximately the same volume of water added to the reaction (50 mL in this case) remained. During this time, the reaction solution forms a white mass that adheres to a stir bar surrounded by a clear yellow solution. When the THF was removed, a separatory funnel with a funnel for pouring into the reaction solution was installed and the Erlenmeyer flask was positioned under this separatory funnel. Some anhydrous Na ₂ SO ₄ was added to the Erlenmeyer flask. This device should be installed before acidification begins. (Installing a separatory funnel, an Erlenmeyer flask, etc., once the solution pH is close to 1 and prior to acidification of the reaction solution that allows phase separation and extraction of the product from the acid) If the separation is not performed immediately, the Boc functionality will be hydrolyzed and will significantly reduce the yield.) Once the volatiles have been sufficiently removed, CH ₂ Cl ₂ (125 mL) and Water (65 mL) was added and the reaction flask was cooled in an ice bath. The solution was stirred rapidly, a 5 mL aliquot of 1N HCl was added with a syringe, and the reaction solution was tested with pH test paper. Acid is added (the solution to be tested is CH ₂ Cl ₂ ) until the dropping point on the pH test paper is achieved showing a red (not orange) around the edge indicating that the pH is 1-2. And as a result, the pH paper will show an accurate measurement at the edge rather than in the middle of the dropping point.), Phase separate by pouring the solution immediately into a separatory funnel. Upon phase separation, twist the stopcock, discharge the CH ₂ Cl ₂ phase (lower phase) into the Erlenmeyer flask, stir the flask, and allow the desiccant to absorb the water in the solution (for this procedure scale, 80 mL of 1N HCl was used). Immediately after phase separation, the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 100 mL), dried over anhydrous Na ₂ SO ₄ , volatiles were removed, 5.37 g / 9.91 mmol beautiful white microcrystals. Which reflects a 99.1% yield. This product cannot be purified by chromatography. This is because the process also hydrolyzes the Boc functionality on the column.

(Example 31)
(Bicyclo [2.2.1] hept-5-ene-7-anti- (trimethylsilyl) -2-endo-3-exo-dicarboxylic acid di- (l) -menthyl (S4-26))
To a solution of S4-25 (6.09 g, 0.0155 mol) in toluene (100 mL) was added diethylaluminum chloride (8.6 mL of 1.8 M toluene solution) at −78 ° C. under N ₂ and this mixture was added to 1 Stir for hours. To the resulting orange solution, S2-14 (7.00 g, 0.0466 mol) was added dropwise as a −78 ° C. solution in toluene (10 mL). The solution was left at −78 ° C. for 2 hours and then slowly warmed to room temperature overnight. The aluminum reagent was quenched with saturated ammonium chloride solution (50 mL). The aqueous layer was separated and extracted with methylene chloride (100 mL), which was then dried over magnesium sulfate. Evaporation of the solvent left a yellow solid that was purified by column chromatography (10% ethyl acetate / hexane) to give S4-26 as a white solid (7.19 g, 0.0136 mol, 87% yield). It was.

(Example 32)
(5-exo-Bromo-3-exo- (l) -menthylcarboxybicyclo [2.2.1] heptane-7-anti- (trimethylsilyl) -2,6-carbolactone (S4-27))
A solution of bromine (3.61 g, 0.0226 mol) in methylene chloride (20 mL) was added to a stirred solution of S4-26 (4.00 g, 0.00754 mol) in methylene chloride (80 mL). Stirring was continued overnight at room temperature. The solution was treated with 5% sodium thiosulfate (150 mL) and the organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (5% ethyl acetate / hexane) to give S4-27 as a white solid (3.53 g, 0.00754 mol, 99% yield). .

(Example 33)
(Bicyclo [2.2.1] hept-5-ene-7-syn- (hydroxy) -2-exo-methyl-3-endo- (l) -menthyl dicarboxylate (S4-28))
S4-27 (3.00 g, 0.00638 mol) was dissolved in anhydrous methanol (150 mL), silver nitrate (5.40 g, 0.0318 mol) was added, and the suspension was refluxed for 3 days. The mixture was cooled, filtered through celite and the solvent was evaporated to give an oily residue. Purification by column chromatography gave S4-28 as a pale yellow oil (1.72 g, 0.00491 mol, 77% yield).

(Example 34)
(2-exo-Methyl-3-endo- (l) -menthylbicyclo [2.2.1] hept-5-ene-7-syn- (benzyloxy) dicarboxylate (S4-29))
Benzyl bromide (1.20 g, 0.0070 mol) and silver oxide (1.62 g, 0.0070 mol) were added to a stirred solution of S4-28 (0.490 g, 0.00140 mol) in DMF (25 mL). . The suspension was stirred overnight and then diluted with ethyl acetate (100 mL). The solution was washed repeatedly with water and then with 1N lithium chloride. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel to give S4-29 as an oil (0.220 g, 0.000500 mol, 36% yield).

(Example 35)
(Bicyclo [2.2.1] hept-5-ene-7-syn- (benzyloxy) -2-exo-carboxy-3-endo- (l) -menthyl carboxylate (S4-30))
S4-29 (0.220 g, 0.00050 mol) was added to a mixture of tetrahydrofuran (1.5 mL), water (0.5 mL) and methanol (0.5 mL). Potassium hydroxide (0.036 g, 0.00065 mol) was added and the solution was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (10% ethyl acetate / hexane) to give S4-30 (0.050 g, 0.00012 mol, 23% yield).

(Example 36)
(Bicyclo [2.2.1] hept-5-ene-7-syn- (benzyloxy) -2-exo- (trimethylsilylethoxycarbonyl) -amino-3-endo- (l) -menthyl carboxylate (S4- 31))
Triethylamine and diphenylphosphoryl azide are added to a solution of S4-30 in benzene. The solution is refluxed for 24 hours and then brought to room temperature. Trimethylsilylethanol is added and the solution is refluxed for a further 48 hours. The benzene solution is partitioned between ethyl acetate and 1M sodium bicarbonate. The organic layers are combined, washed with 1M sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give the crude Curtius reaction product.

(Example 37)
(Bicyclo [2.2.1] heptane-7-syn- (benzyloxy) -2-exo- (trimethylsilylethoxycarbonyl) -amino-3-endo- (l) -menthyl-5-exo-methyl-6- exo-methyltricarboxylate (S4-32))
S4-31, dry copper (II) chloride, 10% Pd / C, and dry methanol are added to the flask with vigorous stirring. After degassing, the flask is filled with carbon monoxide to a pressure slightly above 1 atm and maintained for 72 hours. The solid is filtered and the residue is worked up in the usual manner to give the biscarbonylated product.

(Example 38)
(Anhydrobicyclo [2.2.1] heptane-7-syn- (benzyloxy) -2-exo- (trimethylsilylethoxycarbonyl) -amino-3-endo- (l) -menthylcarboxy-5-exo-6- exo-dicarboxylic acid (S4-33))
A mixture of S4-32, formic acid and a catalytic amount of p-toluenesulfonic acid is stirred at 90 ° C. overnight. Acetic anhydride is added and the reaction mixture is refluxed for 6 hours. Removal of the solvent and washing with ether gives the desired anhydride.

(Example 39)
(Bicyclo [2.2.1] heptane-7-syn- (benzyloxy) -2-exo- (trimethylsilylethoxycarbonyl) -amino-3-endo- (l) -menthyl-6-exo-carboxy-5- exo-methyldicarboxylate (S4-33))
Add quinidine to a solution of S4-32 in an equal volume of toluene and carbon tetrachloride. The suspension is cooled to −65 ° C. and stirred for 1 hour. 3 equivalents of methanol are slowly added over 30 minutes. The suspension is stirred at −65 ° C. for 4 days, after which the solvent is removed under reduced pressure. The resulting white solid is partitioned between ethyl acetate and 2M HCl. Quinine is recovered from the acid layer, and S4-33 is obtained from the organic layer.

(Example 40)
(Bicyclo [2.2.1] heptane-7-syn- (benzyloxy) -2-exo- (trimethylsilylethoxycarbonyl) -amino-3-endo- (l) -menthyl-6-exo- (trimethylsilylethoxycarbonyl) Amino-5-exo-methyldicarboxylate (S4-35))
Triethylamine and diphenylphosphoryl azide are added to a solution of S4-34 in benzene. The solution is refluxed for 24 hours. After the temperature is lowered to room temperature, 2-trimethylsilylethanol is added and the solution is refluxed for 48 hours. Partition the benzene solution between ethyl acetate and 1M sodium bicarbonate. The organic layers are combined, washed with 1M sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give the crude Curtius reaction product.

(Example 41)
(Endo-bicyclo [2.2.1] hept-5-ene-2-benzylcarboxylate-3-carboxylic acid (S5-37))
Compound S3-19 (4.00 g, 0.0244 mol) and quinidine (8.63 g, 0.0266 mol) were suspended in equal amounts of toluene (50 mL) and carbon tetrachloride (50 mL). The suspension was cooled to −55 ° C., after which benzyl alcohol (7.90 g, 0.0732 mol) was added over 15 minutes. After 3 hours, the reaction mixture became homogeneous and was stirred at −55 ° C. for an additional 96 hours. After removal of the solvent, the residue was partitioned between ethyl acetate (300 mL) and 2M hydrochloric acid (100 mL). The organic layer was washed with water (2 × 50 mL) and saturated aqueous sodium chloride solution (1 × 50 mL). Drying over magnesium sulfate and evaporation of the solvent gave S5-37 (4.17 g, 0.0153 mol, 63% yield).

(Example 42)
(2-endo-benzylcarboxy-6-exo-iodobicyclo [2.2.1] heptane-3,5-carbolactone (S5-38))
S5-37 (4.10 g, 0.0151 mol) was dissolved in 0.5 M sodium bicarbonate solution (120 mL) and cooled to 0 ° C. Potassium iodide (15.0 g, 0.090 mol) and iodine (7.66 g, 0.030 mol) were added followed by methylene chloride (40 mL). The solution was stirred overnight at room temperature. After dilution with methylene chloride (100 mL), sodium thiosulfate was added to quench excess iodine. The organic layer was separated and washed with water (100 mL) and sodium chloride solution (100 mL). Drying over magnesium sulfate and evaporation of the solvent gave S5-38 (5.44 g, 0.0137 mol, 91% yield).

(Example 43)
(2-endo-benzylcarboxy-bicyclo [2.2.1] heptane-3,5-carbolactone (S5-39))
S5-38 (0.30 g, 0.75 mmol) was placed in DMSO under N ₂ , NaBH ₄ (85 mg, 2.25 mmol) was added and the solution was stirred at 85 ° C. for 2 hours. The mixture was cooled, diluted with water (50 mL) and extracted with dichloromethane (3 × 20 mL). The extracts were combined, washed with water (4 × 15 mL) and saturated aqueous NaCl (10 mL), dried and evaporated to give 0.14 g (68%) of S5-39.

(Example 44)
(5-endo-hydroxybicyclo [2.2.1] heptane-2-endo-benzyl-3-endo-methyldicarboxylate (S5-40))
Compound S5-39 is dissolved in methanol and sodium methoxide is added with stirring. Removal of solvent gives S5-40.

(Example 45)
(Bicyclo [2.2.1] heptane-2-endo-benzyl-3-endo-methyl-5-exo- (t-butoxycarbonyl) -aminodicarboxylate (S5-41))
In a one-pot reaction, S5-40 is converted to the corresponding mesylate salt with methanesulfonyl chloride, sodium azide is added to replace the mesylate salt to obtain the exo-azide, which is then released by reduction with tributylphosphine. An amine is obtained, which is protected as a t-Boc derivative to give S5-41.

(Example 46)
(Bicyclo [2.2.1] heptane-2-endo-carboxy-3-exo-methyl-5-exo- (t-butoxycarbonyl) -aminocarboxylate (S5-42))
The benzyl ether protecting group is removed by catalytic hydrogenolysis of S5-41 with 10% Pd / C in methanol at room temperature for 6 hours. Filtration of the catalyst and removal of the solvent gives crude S5-42.

(Example 47)
(Bicyclo [2.2.1] heptane-2-endo-carboxy-3-exo-methyl-5-exo- (t-butoxycarbonyl) -aminocarboxylate (S5-43))
Sodium is dissolved in methanol to produce sodium methoxide. S5-42 is added and the mixture is stirred at 62 ° C. for 16 hours. The mixture is allowed to cool and acetic acid is added while cooling to neutralize excess sodium methoxide. The mixture is diluted with water and extracted with ethyl acetate. The extract is dried and evaporated to give S5-43.

(Example 48)
(Bicyclo [2.2.1] heptane-2-endo-benzyl-3-exo-methyl-5-exo- (t-butoxycarbonyl) aminodicarboxylate (S5-44))
Compound S5-43 is reacted with benzyl bromide and cesium carbonate in tetrahydrofuran at room temperature to give benzyl ester S5-44, which is isolated by acid workup of the crude reaction mixture.

(Example 49)
(Bicyclo [2.2.1] heptane-2-endo-benzyl-3-exo-carboxy-5-exo- (t-butoxycarbonyl) -aminocarboxylate (S5-45))
Compound S5-44 is dissolved in methanol and cooled to 0 ° C. under N ₂ . 2M NaOH (2 eq) is added dropwise and the mixture is allowed to reach room temperature and stirred for 5 hours. The solution is diluted with water, acidified with 2M HCl and extracted with ethyl acetate. The extract is washed with water and saturated aqueous NaCl, dried and evaporated to give S5-45.

(Example 50)
(Bicyclo [2.2.1] heptane-2-endo-benzyl-3-exo- (trimethylsilylethoxycarbonyl) amino-5-exo- (t-butoxycarbonyl) aminocarboxylate (S5-46))
Triethylamine and diphenylphosphoryl azide are added to a solution of S5-45 in benzene. The solution is refluxed for 24 hours and then cooled to room temperature. Trimethylsilylethanol is added and the solution is refluxed for 48 hours. The solution is partitioned between ethyl acetate and 1M sodium bicarbonate. The organic layer is washed with 1M sodium bicarbonate and dried over sodium sulfate. The solution is evaporated under reduced pressure to give the crude Curtius product S5-46.

(Example 51)
(Endo-bicyclo [2.2.1] hept-5-ene-2- (4-methoxy) benzylcarboxylate-3-carboxylic acid (S6-48))
Compound S3-19 and quinidine are suspended in an equal volume of toluene and carbon tetrachloride and cooled to -55 ° C. p-Methoxybenzyl alcohol is added over 15 minutes and the solution is stirred at −55 ° C. for 96 hours. After removal of the solvent, the residue is partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer is washed with water and saturated aqueous sodium chloride solution. Dry over magnesium sulfate and remove the solvent to give S6-48.

(Example 52)
(Endo-bicyclo [2.2.1] hept-5-ene-2- (4-methoxy) benzyl-3- (trimethylsilylethoxycarbonyl) aminocarboxylate (S6-49))
Triethylamine and diphenylphosphoryl azide are added to a solution of S6-48 in benzene. The solution is refluxed for 24 hours, cooled to room temperature, trimethylsilylethanol is added and the solution is refluxed for a further 48 hours. Partition the benzene solution between ethyl acetate and 1M sodium bicarbonate. The organic layers are combined, washed with 1M sodium bicarbonate and dried over sodium sulfate. The solution is evaporated under reduced pressure to give the crude Curtius product S6-49.

(Example 53)
(Bicyclo [2.2.1] heptane-2-endo- (4-methoxy) benzyl-3-endo- (trimethylsilylethoxycarbonyl) amino-5-exo-methyl-6-exo-methyltricarboxylate (S6- 50))
S6-49, copper (II) chloride, 10% Pd / C, and dry methanol are added to the flask with vigorous stirring. After degassing the suspension, the flask is filled with carbon monoxide to a pressure slightly higher than 1 atm. The carbon monoxide pressure is maintained for 72 hours. The solid is filtered and the crude reaction mixture is worked up in the usual manner to give S6-50.

(Example 54)
(Bicyclo [2.2.1] heptane-2-endo- (4-methoxy) benzyl-3-endo- (trimethylsilylethoxycarbonyl) amino-5-exo-6-exo-dicarboxylic acid (S6-51))
S6-50, formic acid, and a catalytic amount of p-toluenesulfonic acid are heated at 90 ° C. overnight. Acetic anhydride is added to the reaction mixture and it is refluxed for an additional 6 hours. Removal of solvent and washing with ether gives S6-51.

(Example 55)
(Bicyclo [2.2.1] heptane-2-endo- (4-methoxy) benzyl-3-endo- (trimethylsilylethoxycarbonyl) amino-5-exo-carboxy-6-exo-methyldicarboxylate (S6- 52))
Quinine is added to a solution of S6-51 in an equal volume of toluene and carbon tetrachloride. The suspension is cooled to −65 ° C. and stirred for 1 hour. 3 equivalents of methanol are slowly added over 30 minutes. The suspension is stirred at −65 ° C. for 4 days, after which the solvent is removed. The resulting white solid is partitioned between ethyl acetate and 2M HCl and S6-52 is worked up from the organic layer.

(Example 56)
(Bicyclo [2.2.1] heptane-2-endo- (4-methoxy) benzyl-3-endo- (trimethylsilylethoxycarbonyl) amino-5-exo- (trimethylsilylethoxycarbonyl) amino-6-exo-methyldi Carboxylate (S6-53))
Triethylamine and diphenylphosphoryl azide are added to a solution of S6-52 in benzene. The solution is refluxed for 24 hours and then lowered to room temperature. 2-Trimethylsilylethanol is added and the solution is refluxed for a further 48 hours. Partition the benzene solution between ethyl acetate and 1M sodium bicarbonate. The organic layers are combined, washed with 1M sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give S6-53.

(Example 57)
(Bicyclo [2.2.1] heptane-2-exo- (4-methoxy) benzyl-3-endo- (trimethylsilylethoxycarbonyl) amino-5-exo- (trimethylsilylethoxycarbonyl) amino-6-endo-methyldi Carboxylate (S6-54))
Potassium tert-butoxide was carefully added to a solution of S6-53 in tetrahydrofuran. The basic solution is refluxed for 24 hours, after which acetic acid is added. Standard extraction methods yield the doubly epimerized product S6-54.

(Example 58)
Preparation of the following hexamer:

0 ℃ in the 0.300g of _CH 2 Cl ₂ 5mL (1R, 2R) - ( -) - a trans-1,2-diaminocyclohexane (2.63 mmol), 0.600 g in 5 mL _CH 2 Cl ₂ 2,6-Diformyl-4-bromophenol (2.62 mmol) was added. The yellow solution was warmed to room temperature and stirred for 48 hours. The reaction solution was decanted and added to 150 mL of methanol. After 30 minutes, the yellow precipitate was collected, washed with methanol and air dried (0.580 g, 72% yield).

(Example 59)
Preparation of the following hexamer:

0 ℃ in the 0.300g of _CH 2 Cl ₂ 6mL (1R, 2R) - ( -) - a trans-1,2-diaminocyclohexane (2.63 mmol), 0 in _CH 2 Cl ₂ in 6 mL. 826 g of 2,6-diformyl-4- (1-dodec-1-yne) phenol (2.63 mmol) was added. The orange solution was stirred at 0 ° C. for 1 hour and then allowed to warm to room temperature, after which stirring was continued for 16 hours. The reaction solution was decanted and added to 150 mL of methanol. After decanting the methanol solution, a sticky yellow solid was obtained. Purification of the residue by chromatography gave a yellow powder.

(Example 60)
Preparation of the following hexamer:

0.240 g of 2,6-diformyl-4- (1-dodecene) phenol (0.76 mmol) in 10 mL of benzene was added to (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (0. 087 g, 0.76 mmol) in 10 mL benzene was added. The solution was shielded from external light and stirred at room temperature for 48 hours. The orange solution was dried and chromatographed (silica, 50/50 acetone / Et ₂ O) to give a yellow sticky solid (33% yield).

(Example 61)
Preparation of the following tetramer:

  Preparation of the following hexamer:

Triethylamine (0.50 mL, 3.59 mmol) and (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (0.190 g, 1.66 mmol) were combined in 150 mL EtOAc and 5 with N ₂ . Purged for minutes. To this solution 0.331 g isophthalolyl chloride (1.66 mmol) dissolved in 100 mL EtOAc was added dropwise over 6 hours. The solution was filtered and the filtrate was dried. TLC (5% methanol / CH ₂ Cl ₂ ) shows that the product mixture consists mainly of two macrocyclic compositions. Chromatographic separation (silica, 5% methanol / CH ₂ Cl ₂ ) gave the above tetramer (0.020 g, 5% yield) and hexamer (about 10%).

(Example 62)
Preparation of macrocyclic modules from benzene and cyclohexane cyclic synthons:

To a 5 mL dichloromethane solution of 4-dodecyl-2,6-diformylanisole (24 mg, 0.072 mmol) was added (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (8.5 mg, 0.074 mmol). ) In 5 mL dichloromethane was added. This solution was stirred at room temperature for 16 hours and then added to the top of a short silica column. 22 mg of an off-white solid was isolated by elution with diethyl ether followed by removal of the solvent. Cation electrospray mass spectra were obtained for tetramer (m / z 822, MH ⁺ ), hexamer (m / z 1232, MH ⁺ ), and octamer (m / z 1643, MH ⁺ ) in an off-white solid. Showed existence. Calculated molecular weight is as follows: 4-mer _{+ H (C 54 H 85 N} 4 O 2, 821.67); 6 -mer _{+ H (C 81 H 127 N} 6 O 3, 1232.00); octamer _{+ H (C 108 H 169 N} 8 O 4, 1643.33).

(Example 63)
While not intending to be bound by any one particular theory, one method for estimating the size of the macrocyclic module's pores is the quantum mechanical (QM) and molecular mechanical (MM) calculation methods. In this example, using a macrocyclic module with two types of synthons, “A” and “B”, it was assumed that all bonds between synthons were identical. For the purpose of QM and MM calculation methods, the root mean square deviation in pore area was calculated with a dynamic run.

  In QM, each module was first optimized using the MM + force field approach of Allinger (JACS, 1977, 99: 8127) and Burkert et al. (Molecular Mechanicals, ACS Monograph 177, 1982). Then, using AM1 Hamiltonian (Dewar et al., JACS, 1985, 107: 3903, Dewar et al., JACS, 1986, 108: 8075, Stewart, J. Comp. Aided Mol. Design, 1990, 4: 1) Optimized again. In order to verify the properties of the potential energy surface near the optimized structure, the associated Hessian matrix was calculated using numerical double-difference.

  For MM, the OPLS-AA force field approach (Jorgensen et al., JACS, 1996, 118: 11225) was used. For imine bonds, the dihedral angle was limited to 180 ° ± 10 °. The structure was minimized and equilibrated to 1 picosecond using a 0.5 femtosecond time step. A 5 nanosecond dynamic run was then performed with 1.5 femtosecond time steps. The structure was saved every picosecond. The results are shown in Tables 12 and 13.

  Table 12 shows the pore area of the macrocyclic module derived from QM and MM calculations for various coupling and macrocyclic module pore sizes. In Table 12, the macrocyclic module has alternating synthons “A” and “B”. The synthon “A” is a benzene synthon coupled to the bond L at the 1,3-phenyl position, and the synthon “B” is shown in the left column of the table.

  In addition, Table 13 shows the hole area of the macrocyclic module derived from QM and MM calculations for various coupling and macrocyclic module hole sizes. In Table 13, the macrocyclic module has alternating synthons “A” and “B”. In Table 13, the synthon “A” is a naphthalene synthon that couples to the bond L at the 2,7-naphthyl position, and the synthon “B” is shown in the left column of the table.

Examples of energy minimized configurations of several hexameric macrocyclic modules with substituents are shown in FIGS. 17A and 17B. Referring to FIG. 17A, hexamer 1-h- (OH) ₃ with an —OH substituent is shown. Referring to FIG. 17B, hexamer 1-h- (OEt) ₃ with the —OEt substituent is shown. Differences in pore structure and area between these two cases are evident and they also reflect configurational and flexibility differences. This macrocyclic module yields a composition that can be used to adjust the pores. The selection of the ethoxy synthon substituent of this hexamer composition relative to the hydroxy synthon substituent is a method that can be used to transport selected species.

  The pore size of the macrocyclic module was determined experimentally using a voltage-clamped bilayer procedure. A large amount of macrocyclic module was inserted into the lipid bilayer formed by phosphatidylcholine and phosphatidylethanolamine. A solution containing the cationic species to be tested was placed on one side of the bilayer. On the other side, a solution containing a reference cationic species known to be able to pass through the pores of the macrocyclic module was placed. The anion required for charge balance was selected so that it cannot pass through the pores of the macrocyclic module. When a positive voltage was applied to the solution on the side of the lipid bilayer containing the test species, current was detected if the test species passed through the pores of the macrocyclic module. The voltage is then reversed and a current is detected due to the movement of the reference species through the hole, confirming that the double layer is a barrier to transport and that the macrocyclic module's holes provide transport of the species did.

  Using the above technique, hexamer having 1R, 2R-(-)-trans diaminocyclohexane and 2,6-diformal-4- (1-dodec-1-ynyl) phenol synthon and having an imine group as a bond The macrocyclic module (first module in Table 1) was tested for transport of various ionic species. The results are shown in Table 14.

The results in Table 14 indicate that the cut-off of the selected module's hole passage is a van der Waals radius between 2.0 and 2.6 mm. In Table 12, the hole size calculated by QM and MM is given as the area. Using the circle area formula, A = πr ² , the calculated area of the hole in the first module of Table 12, 14.3 ² gives an r value of 2.13 Å. Ions with van der Waals radii smaller than 2.13 予 期 are expected to pass through the holes and not larger radii, which is what was observed. CH ₃ NH ₃ ⁺ having a radius of 2.0 mm passed through the hole, but CH ₃ CH ₂ NH ₃ ⁺ having a radius of 2.6 mm did not pass. Without sticking to a specific theory, and understanding that several factors affect pore transport, the observed function of dehydrating ions through pores is due to partial dehydration of species entering the pores, During transport, it may depend on the transport of water molecules and ions that pass separately through the pores or with reduced interaction, and on the rearrangement of water molecules and ions after transport. Details of pore structure, composition, and chemistry, flexibility of the macrocyclic module, and other interactions can influence the transport process.

(Example 64)
The pore properties of 1,2-imine-linked and 1,2-amine-linked hexameric macrocyclic modules are illustrated in Table 15. Referring to Table 15, the fixed double layer data shows that certain passages and exclusions through the module holes correlate with the calculated size of the holes. Furthermore, these surprising data show that slight changes in the arrangement of atomic and / or structural properties can discontinuously change in transport properties, and among other factors, transport through pores due to synthon and bond changes. It shows that it is possible to adjust.

(Example 65)
The Langmuir and isobaric levels of hexamer 1a-Me are shown in FIGS. 18A and 18B, respectively.

  The relative stability of the hexameric 1a-Me Langmuir film is illustrated by the leveling data for the isobaric lines shown in FIG. 18B. After about 30 minutes of 5 mN / m surface pressure, the film area decreased by about 30%. The Langmuir isobaric lines and the leveling of the isobaric lines for hexamer 1a-C15 are shown in FIGS. 19A and 19B, respectively. The relative stability of the hexameric 1a-C15 Langmuir film is illustrated by the isobaric leveling data shown in FIG. 19B. After about 30 minutes of 10 mN / m surface pressure, the film area decreased by about 1-2% and after about 60 minutes it decreased by about 2%. The collapse pressure was about 18 mN / m for hexamer 1a-C15.

  Example 66

Templated imine octamer. Amphiphilic dialdehydephenol 1 (500 mg, 1.16 mmol) was added to a 100 mL 3-neck round bottom flask equipped with a stir bar equipped with a condenser and addition funnel under argon. Next, Mg (NO ₃ ) ₂ .6H ₂ O (148 mg, 0.58 mmol) 2 and Mg (OAc) ₂ .4H ₂ O (124 mg, 0.58 mmol) were added in succession. The flask was placed under reduced pressure and filled with argon 3 ×. Anhydrous methanol was transferred to the flask with a syringe under argon and the resulting suspension was stirred. The mixture was then refluxed for 10 minutes to obtain a homogeneous solution. The reaction was cooled to room temperature under a positive pressure of argon. (1R, 2R)-(−)-trans-1,2-diaminocyclohexane 4 was added to the addition funnel followed by cannula transfer of anhydrous MeOH (11.6 mL) under argon. The diamine / MeOH solution was added dropwise to the stirred homogeneous metal template / dialdehyde solution over 1 hour to give an orange oil. The addition funnel was replaced with a glass stopper and the mixture was refluxed for 3 days. The solvent was removed under reduced pressure to give a yellow crystalline solid that was used without further purification.

Amine octamer. To a 50 mL schlenk flask equipped with a stir bar was added imine octamer (314 mg, 0.14 mmol) under argon. Then anhydrous THF (15 mL) and MeOH (6.4 mL) were added via syringe under argon and the suspension was stirred at room temperature. To the homogeneous solution was partially added NaBH ₄ (136 mg, 3.6 mmol) and the mixture was stirred at room temperature for 12 hours. The solution was filtered and then 19.9 mL of water was added. The pH was adjusted to about 2 by addition of 4M HCl, then 6.8 mL of ethylenediaminetetraacetic acid disodium salt dihydrate (0.13M in H ₂ O) was added and the mixture was stirred for 5 minutes. 2.0% ammonium hydroxide was added to the solution and stirring was continued for another 5 minutes. The solution was extracted with ethyl acetate (3 × 100 mL), the organic layer was separated, dried over Na ₂ SO ₄ and the solvent was removed by rotoevaporation to give a pale yellow solid. An amine octamer was obtained by recrystallization from chloroform and hexane. The molecular weight was confirmed by ESIMS M + H = experiment = 2058.7 m / z, calculation = 2058.7 m / z.

  (Example 67)

Hexamer 1j. Two substrates, (−)-R, R-1,2-trans-diaminocyclohexane (0.462 mmol, 0.053 g) and 2,6-diformyl-4-hexadecylbenzylphenol carboxylate (0.462 mmol, 0 200 g) was added to a 10 mL vial equipped with a magnetic stir bar, followed by 2 mL of CH ₂ Cl ₂ . The yellow solution was stirred at room temperature. After 24 hours, the reaction solution was plugged through silica gel with diethyl ether and the solvent was removed by roto-evaporation (232 mg, 98% yield).

Hexamer 1jh. The hexamer 1j (0.387 mmol, 0.594 g) was added under argon to a 100 mL pear flask equipped with a magnetic stir bar and dissolved in THF: MeOH (7: 3, 28:12 mL, respectively). NaBH ₄ (2.32 mmol, 0.088 g) was then slowly and partially added over 6.5 hours at room temperature. The solvent was removed by rotoevaporation and the residue was dissolved in 125 mL ethyl acetate and washed with 3 × 50 mL water. The organic layer was separated, dried over Na ₂ SO _4, the solvent Lot - excluding collected by evaporation. Recrystallization of the resulting residue from CH ₂ Cl ₂ and MeOH gave a white solid (0.440 g, 74% yield).

  (Example 68)

  Hexamer 1A-Me. A solution of 2-hydroxy-5-methyl-1,3-benzenedicarboxaldehyde (53 mg, 0.32 mmol) in dichloromethane (0.6 mL) was added to (1R, 2R)-(−)-1,2-diamino. To a solution of cyclohexane (37 mg, 0.32 mmol) in dichloromethane (0.5 mL). The mixture was stirred at ambient temperature for 16 hours, added dropwise to methanol (75 mL) and cooled (4 ° C.) for 4 hours. The precipitate was collected to give 71 mg (92%) of hexamer 1A-Me.

  (Example 69)

32.7 mg of hexamer 1jh (number of recrystallizations) was added to 30 mL of dry THF. Subsequently, 100 μL triethylamine and 100 μL acryloyl chloride (freshly distilled) were added to the THF mixture using the Schlenk technique. The solution was stirred in an acetone / dry ice bath for 18 hours. A white precipitate remained after removal of the solvent. The precipitate was redissolved in CH ₂ Cl ₂ and filtered through a fritted funnel. The CH ₂ Cl ₂ solution was added to the separatory funnel and washed once with water and then twice with brine (NaCl). The CH ₂ Cl ₂ solution was dried over MgSO ₄ and then filtered to remove MgSO ₄ . A yellow precipitate remained after removal of the solvent.

FIG. 1 illustrates an example scheme for the preparation of hexameric 1dh nanofilms. FIG. 2 illustrates an exemplary scheme for the preparation of nanofilms of amphiphilic alkylthiol molecules. FIG. 3 illustrates an example scheme for the preparation of nanofilms of amphiphilic methyl 2-amino (alkane) oate molecules. FIG. 4 illustrates an example scheme for the preparation of nanofilms of amphiphilic alkylamine molecules. FIG. 5 illustrates an example scheme for nanofilm attachment to a substrate, showing examples of surface binding groups. FIGS. 6A and 6B illustrate examples of ellipsometry images of hexamer 1dh nanofilm preparation. FIG. 7 illustrates an example of isobaric creep of a hexameric 1dh nanofilm. FIG. 8A illustrates an example of an FTIR spectrum for the preparation of a hexameric 1dh nanofilm. FIG. 8B illustrates an example of an FTIR spectrum for the preparation of a hexameric 1dh nanofilm. FIG. 9 illustrates an example of an ellipsometric image of the preparation of a hexameric 1dh nanofilm. FIGS. 10A, 10B and 10C illustrate examples of ellipsometric images of the preparation of methylheptadecanoate nanofilm bonded to a substrate. FIGS. 11A and 11B illustrate examples of ellipsometric images of the preparation of N-octadecylacrylamide nanofilms bonded to a substrate. FIG. 12 illustrates a depiction of the structure of a hexameric 1dh nanofilm. FIG. 13 illustrates a depiction of the structure of the octameric 5jh-asparagine nanofilm. FIG. 14 illustrates the Langmuir trough region versus time for a nanofilm prepared from hexamer 1jh-AC. FIG. 15 illustrates an example of an ellipsometric image of a nanofilm prepared from hexamer 1jh-AC. FIG. 16 illustrates an example of an FTIR spectrum for the preparation of hexameric 1jh-AC nanofilm. 17A and 17B show a depiction of an example structure of an embodiment of a hexameric macrocyclic module. FIG. 2A shows an example of a Langmuir isotherm of an embodiment of a hexameric macrocyclic module. FIG. 2B shows an example of isobaric creep of an embodiment of a hexameric macrocyclic module. FIG. 3A shows an example of a Langmuir isotherm of an embodiment of a hexameric macrocyclic module. FIG. 3B shows an example of isobaric creep of an embodiment of a hexameric macrocyclic module.

Claims (45)

Comprising a coupling macrocyclic module, a nano film, wherein the module, following hexamer 1a, hexamer 1Dh, hexamer 3j- amine, hexamer 1Jh, hexameric Selected from the group consisting of 1jh-AC, hexamer 2j-amine / ester, hexamer 1dh-acryl, octamer 5jh-aspartic acid, octamer 4jh-acryl, and mixtures thereof:

Wherein the module is coupled via a reactive functional group of the module . The nanofilm of claim 1, wherein the module is a hexamer 1dh. 2. The nanofilm of claim 1, wherein the module is coupled to at least one linker molecule. 4. The nanofilm of claim 3 , wherein the at least one linker molecule is

And a mixture thereof, wherein m = 1-10, n = 1-6, R is H or CH ₃ and R ′ is — (CH ₂ ) _n — or Phenyl, R ″ is — (CH ₂ ) _n —, polyethylene glycol (PEG), or polypropylene glycol (PPG), and X is Br, Cl, I, or a carbon atom, oxygen atom, A nanofilm which is a leaving group consisting of a nitrogen atom, a halogen atom, a silicon atom, a phosphorus atom, a sulfur atom, and a hydrogen atom and having 1 to 20 carbon atoms. 2. The nanofilm of claim 1, wherein the nanofilm is coupled by a chemical method, a thermal method, a photochemical method, an electrochemical method, or a radiation method. The nanofilm of claim 1, wherein the nanofilm has a thickness of less than 30 nanometers. The nanofilm of claim 1, wherein the nanofilm has a thickness of less than 4 nanometers. The nanofilm of claim 1, wherein the nanofilm has a thickness of less than 1 nanometer. The nanofilm of claim 1, wherein the nanofilm is

A nanofilm having a filtration function. The nanofilm of claim 1, wherein the nanofilm is

A nanofilm having a filtration function. 2. The nanofilm of claim 1, wherein the nanofilm is impermeable to viruses and larger species. The nanofilm of claim 1, wherein the nanofilm is impermeable to immunoglobulin G and larger species. 2. The nanofilm of claim 1, wherein the nanofilm is impermeable to albumin and larger species. The nanofilm of claim 1, wherein the nanofilm is impermeable to β ₂ -microglobulin and larger species. 2. The nanofilm of claim 1, wherein the nanofilm is permeable only to water and smaller species. The nanofilm of claim 1, wherein the nanofilm has a cutoff molecular weight of 13 kDa. 2. The nanofilm of claim 1, wherein the nanofilm has a cut-off molecular weight of 190 Da. The nanofilm of claim 1, wherein the nanofilm has a cutoff molecular weight of 100 Da. 2. The nanofilm of claim 1, wherein the nanofilm has a cut-off molecular weight of 45 Da. The nanofilm of claim 1, wherein the nanofilm has a cutoff molecular weight of 20 Da. The nanofilm of claim 1, wherein the nanofilm has high permeability to water molecules and Na ⁺ , K ⁺ , and Cs ⁺ in water. A nano film of claim 2 1, wherein the nano-film having a low permeability to glucose and urea, nano film. The nanofilm of claim 1, wherein the nanofilm has high permeability to water molecules and Cl ⁻ in water. The nanofilm of claim 1, wherein the nanofilm has high permeability to water molecules and K ⁺ in water, and low permeability to Na ⁺ in water. 2. The nanofilm of claim 1, wherein the nanofilm has a high permeability to water molecules and Na ⁺ in water, and a low permeability to K ⁺ in water. The nanofilm of claim 1, wherein the nanofilm has low permeability to urea, creatinine, Li ⁺ , Ca ²⁺ , and Mg ²⁺ in water. 27. The nanofilm of claim 26 , wherein the nanofilm is highly permeable to Na ⁺ , K ⁺ , HPO ₄ ²⁻ , and H ₂ PO ₄ ⁻ in water. 27. The nanofilm of claim 26 , wherein the nanofilm is highly permeable to Na ⁺ , K ⁺ , and glucose in water. The nanofilm of claim 1, wherein the nanofilm has low permeability to myoglobin, ovalbumin, and albumin in water. 2. The nanofilm of claim 1, wherein the nanofilm has a high permeability to organic compounds and a low permeability to water. The nanofilm of claim 1, wherein the nanofilm has a low permeability to water molecules and a high permeability to helium gas and hydrogen gas. A nanofilm barrier comprising at least two layers of the nanofilm of claim 1. A nano film barrier according to claim 3 2, wherein the nano-film barrier further comprises at least one gap layer is any two between the nano film layer, nano film barrier. A nano film barrier of claim 3 3, wherein the gap layer comprises a polymer layer or a gel layer, nano film barrier. The nanofilm of claim 1, wherein the nanofilm is deposited on a substrate. A nano film according to claim 35, wherein the substrate is porous, nano film. A nano film according to claim 35, wherein the substrate is non-porous, nano film. The nanofilm of claim 1, wherein the nanofilm has a surface attachment group. A nano film of claim 38, wherein the surface attachment group, an amino, hydroxyl, halo, thiol, alkynyl, magnesium halo, _{aldehyde, -CH = C (CH 3)} 2, vinyl, - (C = C) - _{CH = CH 2, -OC (O} ) CH (CH 3) 2, -OC (O) CH = CH 2, -NC (O) CH = CH 2, carboxy Kishireto, isocyanurate sulfonates, epoxides, streptavidin, and their A nanofilm selected from the group consisting of: The nanofilm of claim 1, wherein the nanofilm is covalently bonded to the substrate via a surface attachment group. 2. The nanofilm of claim 1, wherein the nanofilm is bonded to the substrate through ionic interactions. 2. The nanofilm of claim 1, wherein the nanofilm further comprises a substrate; the nanofilm is coupled to the substrate via a biotin-streptavidin coupling. A method for filtration comprising the step of separating components from a fluid using the nanofilm of claim 1. The nanofilm of claim 1 comprising an oriented macrocyclic module deposited on a substrate using a Langmuir trough. 2. The nanofilm of claim 1 comprising a coupled oriented macrocyclic module comprising: (a) providing the nanofilm of claim 1 comprising a coupled oriented macrocyclic module; And wherein the coupled oriented macrocycle module comprises a hydrophobic region that is cleavable by chemical, thermal, photochemical, electrochemical, or radiological methods; and (B) A nanofilm produced by a process comprising the step of cutting the hydrophobic region.

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