WO2008127423A2 - Microencapsulated catalyst systems - Google Patents

Abstract

The invention is directed to a microcapsule containing a catalyst. The invention also provides a system for making and using these microcapsules. The inventive microcapsules may be hollow and, further, may encapsulate a solution. Moreover, the catalyst may be soluble in the encapsulated solution. The semi-permeable shell of the microcapsule allows reactants to diffuse into the interior of the microcapsule and react with the catalyst to form a product which may diffuse out of the microcapsule. Using such a system, one pot multi-step reactions can be conducted in the presence of incompatible catalysts, incompatible reagents, and/or incompatible microenvironments.

Description

MICROENCAPSULATED CATALYST SYSTEMS

Cross-Reference to Related Applications

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. provisional application, U.S. S.N. 60/858,832, filed November 14, 2006, the entire contents of which are incorporated herein by reference.

Government Support

[0002] This invention was made with United States Government support under grants CR-19024-430980 and W911NF-06-1-0315 awarded by the Army Research Office, and grants CTS-0329899, CCF-0403990, and CTS-0647257 awarded by the National Science Foundation. The United States Government has certain rights in the invention.

Background of the Invention

[0003] One-pot multi-step reactions are effective at reducing the waste and cost of a synthetic route because they decrease the number of work-up and purification steps, as well as the volume of solvent employed. Though a variety of one-pot multi-step syntheses have been reported, these reactions are limited to a relatively small number of systems where the conditions of the individual reactions must be compatible with each other. [0004] For example, in multi-catalyst reactions, the catalysts must be compatible.

Moreover, catalysts are often the most expensive component of a reaction and are frequently difficult to separate from the product upon workup and purification. In order to overcome these limitations, one approach has been to immobilize catalysts on insoluble solid supports. Upon completion of the reaction, the catalysts are separated from the reaction mixture by physical means, for example, by filtration. Catalysts immobilized on insoluble gels, resins, star-polymers, cross-linked polymers, and magnetic particles have been used to facilitate heterogeneous multi-step reactions (see Gelman et ah, J. Am. Chem. Soc. (2000) 122:11999; and Gelman et ah, J. Am. Chem. Soc. (2001) 40:3647). Cross-linked polymers are especially useful solid supports for catalysts because a myriad of synthetic methods are available for covalently attaching the reactive catalytic moiety. However, these immobilized catalytic systems typically display a lower diffusion rate and experience a different solvation environment as compared to the free homogeneous catalyst system, which often renders the catalyst less selective and/or reactive. [0005] Thus, there continues to be a need for an immobilized catalyst system which retains the activity and/or selectivity of a soluble catalyst in a relatively homogeneous reaction mixture and may be used in conjunction with other incompatible reagents in a one- pot multi-step reaction.

Summary of the Invention

[0006] The present invention is directed to an immobilized catalyst system which retains the activity and/or selectivity of a soluble catalyst in a relatively homogeneous reaction mixture. Such a system may be used in conjunction with incompatible reagents in a one-pot multi-step reaction system. Specifically, the present invention is directed to a microcapsule encapsulating (i.e., "trapping" within the confines of the capsule) a catalyst. Further, the invention is directed toward making these microencapsulated catalysts and toward using these microencapsulated catalysts in one-pot multi-step reaction schemes, for example, in the synthesis of small molecules or synthetic libraries. The present invention has been found effective at reducing the waste and cost of a synthetic route because of the decreased number of steps and solvents employed as compared to more conventional multi- step synthetic procedures. The present invention demonstrates the effectiveness of this method in the one-pot multi-step synthesis of the optically-active anticonvulsant drug pregabalin (LYRICA^®, Pfizer).

[0007] In certain embodiments, the invention is directed to a microcapsule comprising a catalyst encapsulated by a polymeric shell, wherein the microcapsule is hollow, and wherein the polymeric shell is semi-permeable, thereby allowing reactants and products to diffuse in and out of the microcapsule. In other embodiments, the encapsulated catalyst is conjugated to a polymer to afford a catalyst-polymer conjugate in a microcapsule. The semi-permeable shell does not typically allow the catalyst to diffuse out of the microcapsule. The inventive microcapsules may be hollow, and, further, may encapsulate a solution. Moreover, the catalyst is preferably soluble in the encapsulated solution. [0008] The present invention is directed to making such a microencapsulated catalyst. The method comprises providing a first solution of a catalyst; providing a second solution of at least one monomer; dispersing the first solution and the second solution to form an emulsion; and polymerizing the monomer at the interface of the first and second solution under suitable reaction conditions to provide a microcapsule, wherein the microcapsule is hollow; and wherein the microcapsule comprises the catalyst encapsulated by a semi- permeable polymeric shell. In certain embodiments, the first solution comprises a polar protic solvent, a polar aprotic solvent, or mixture thereof. In yet other embodiments, the first solution comprises a solvent with a dielectric constant greater than or equal to 25. In certain embodiments, the dielectric constant of the solution is between 25 to 160 (e.g., such as methanol or DMF). In other embodiments, the second solution comprises a non-polar solvent, or a mixture of non-polar solvents. In still other embodiments, the second solution comprises a solvent with a dielectric constant less than or equal to 5 (e.g., such as benzene, toluene or cyclohexane). In certain embodiments, the dielectric constant of the solution is between 0 to 5. The mixture of the first solution and second solution, in certain embodiments, is an "oil-in-oil" mixture (i.e., droplets of an organic solvent in the continuous phase of another organic solvent). In other embodiments, the emulsion is an oil-in-water or a water-in-oil emulsion.

[0009] The present invention is also directed to the method of using such a microcapsule catalyst. The method comprises (i) providing an inventive microcapsule in a first solvent; (ii) dispersing the microcapsule into a second solvent, wherein the second solvent comprises a reactant (e.g., a starting material); and (iii) allowing the reactant to diffuse into the microcapsule and react with the catalyst to afford a first product. A person skilled in the art will realize there may be multiple variations on this given method. The semi-permeable shell of the microcapsule allows reactants to diffuse into the interior of the microcapsule, react with the catalyst, and diffuse out of the microcapsule. In such a system, one pot multi-step reactions can be conducted in the presence of incompatible catalysts (for example, each catalyst encapsulated in its own microcapule), incompatible reagents (for example, reagents present inside and outside the microcapsule), and/or incompatible microenvironments (for example, solvents, pH, salt concentration, and the like).

Brief Description of the Figures

[0010] FIGURE 1. Synthesis of dimethylaminopyridine-modified linear polystyrene (LPSDMAP) polymer and microcapsules encapsulating the LPSDMAP polymer. [0011] FIGURES 2A-2D. SEM images of microcapsules containing

LPSDMAP. Figures 2A-2D are made with 5%, 7%, 13% and 17% poly(methylene[polyphenyl]isocyanate)(PMPPI), respectively. [0012] FIGURE 3. Model of dimethylaminopyridine (DMAP) capsule catalysis. [0013] FIGURE 4. Comparison of rates of dimethylaminopyridine-modifϊed linear polystyrene (LPSDMAP) (2) and dimethylamino pyridine polystyrene-co- divinylbenzene (PSDMAP) (Fluka, 3 mmol/g) to THF-washed capsules made with varied poly(methylene[polyphenyl]isocyanate) (PMPPI) loading (5% to 17%). [0014] FIGURE 5. Synthesis of an encapsulated azide polymer.

[0015] FIGURES 6A-6B. Functionalization of alkyne pre-formed microcapsules using "click" chemistry. Reaction of azide-containing reagents with pendant alkynyl groups on the polymeric backbone to provide a synthetically modified catalyst-polymer conjugate (Figure 6A). Reaction of alkynyl-containing reagents with azide functionalized pendant groups on the polymeric backbone to provide a synthetically modified catalyst-polymer conjugate (Figure 6B).

[0016] FIGURE 7. The site-isolation of two incompatible catalysts enables a tandem reaction. The two catalysts are microencapsulated polyethyleneimine (PEI) (1) and a nickel-based Michael addition catalyst (2).

[0017] FIGURES 8A-8B. Tandem Lewis-acid model (Figure 8A). Single- catalyst dinitro product formation (dashed-line) vs. double-catalyst Michael adduct formation (solid-line) (Figure 8B).

[0018] FIGURE 9. Monitoring the concentration of trans-nitrostyrene (4) in the reaction between benzaldehyde and nitromethane in the presence of microcapsules Cat 1 and Cat 2 (white dot), and in the absence of microcapsules (black dot). Trans-nitrostyrene is removed from the reaction mixture upon reaction with Cat 2 and dimethylmalonate (DMM) to form Michael adduct (6).

[0019] FIGURE 10. In order to quantify how much of the nickel catalyst is being degraded by the microencapsulated-catalyst, UV-VIS absorbance of the nickel catalyst was monitored over time in the presence and absence of the microcapsules (μcaps). Results show that the μcaps degrade nearly 20% of the initial nickel catalyst within 40 hours. On the other hand, the control also shows 10% degradation. Therefore, the microencapsulated-catalyst is responsible for less than 10% degradation of the nickel catalyst during the course of the one- pot reaction.

[0020] FIGURE 11. Uncorrected data from the Michael reaction between trans- nitrostyrene and dimethyl malonate in the presence of acylated polyethyleneimine (PEI) microcapsules (A), in the presence of untreated PEI microcapsules (B), and in the absence of microcapsules (C), in order to determine if the presence of the microcapsules decreases the catalytic activity of the nickel catalyst (2). It can be seen that in both case where mcaps are present (A = acylated mcaps and B = untreated mcaps), there is an initial rate enhancement compared to the control (C). This enhancement is attributed to the urea groups on the surface of the caps, which have been shown to promote Michael addition catalysis. The reaction with acylated mcaps (A) maintains this rate enhancement throughout the entire reaction while the reaction with untreated mcaps levels off after 60% conversion. This is due to trans- nitrostyrene binding irreversivly to the (B) mcaps and being rendered unavailable for conversion to compound (6).

[0021] FIGURE 12. Emulsions are prepared by dispersing a polar phase containing anhydrous polyethyleneimine (PEI) into a non-polar phase (A). A cross-linked polyurea shell forms upon addition of 2,4-tolylene diisocyanate (TDI) to the continuous phase (B).

[0022] FIGURES 13A-13D. Methanol-in-cyclohexane capsules subjected to a range of conditions (scale bar is 100 μm): crenated in hexanes (Figure 13A) and swollen in methanol (Figure 13B). Optical micrograph of swollen capsules in methanol (scale bar = 50 μm) (Figure 13C). Optical micrograph of crenated capsules in hexanes (scale bar = 30 μm)

(Figure 13D).

[0023] FIGURE 14. Presence of polar solvents in cyclohexane detected by ¹H

NMR after 2 minutes of emulsification.

[0024] FIGURE 15. Response surface graph indicating capsule diameter as a function of the two interacting variables (viscosity of the continuous phase and concentration of PEI) when the remaining three variables are held constant.

[0025] FIGURES 16A-16B. Plot of capsule size dependence on viscosity of the continuous phase and the concentration of [PEI] when the volume of the disperse phase and

[TDI] were held constant (Figure 16A). Plot of capsule size dependence on stirring rate and the volume of the disperse phase when [PEI], [TDI], and viscosity of the continuous phase were held constant (Figure 16B) (polyethyleneimine = PEI; 2,4-tolylene diisocyanate =TDI).

[0026] FIGURE 17. Reaction involving the microencapsulated amine-catalyzed transformation of an aldehyde to a nitroalkene, followed by a transition metal-catalyzed

Michael addition in the same reaction vessel.

[0027] FIGURE 18. Application of the microencapsulated catalyst system to prepare biologically active small molecules. [0028] FIGURE 19. Depiction of a tunable microenvironment. "Oil-in-oil" microencapsulated systems are depicted: a hexanes-in-toluene microcapsule (far left); a methanol-in-toluene microcapsule (middle); and a DMF-in-toluene microcapsule (far right).

Formation of the Henry product (reaction of nitromethane with aldehyde) is successful in the methanol-in-toluene system.

[0029] FIGURES 20 and 21. Depictions of a methanol-in-toluene microencapsulated environment. UV-VIS analysis indicates the toluene phase does not diffuse into the microcapsule.

[0030] FIGURES 22A-22C. Optical micrographs of microencapsulated amine- based Henry reaction catalyst. Poly(ethyleneimine) (PEI) was encapsulated by dispersing a methanolic PEI solution into a continuous cyclohexane phase. Upon emulsification, 2,4- tolylene diisocyanate (TDI) was added to initiate cross-linking at the emulsion interface, forming polyurea shells that contain free chains of PEL The microcapsules crenate when dry and swell when placed in such solvents as methanol and DMF, suggesting a hollow capsule rather than a solid sphere. Catalyst loading was determined to be 4.6 mmol/g by acylation of the catalytic amines with trifluoroacetic anhydride followed by fluorine elemental analysis.

Urea content of the microcapsule shells was found to be 4.9 mmol/g by oxygen elemental analysis. Optical micrographs of dry microcapsules (Figure 22A); microcapsules in methanol a swelling solvent (Figure 22B); and microcapsules in toluene, a non-swelling solvent

(Figure 22C). The scale bar is 30 μm.

[0031] FIGURE 23. Conversion of benzaldehyde (4) after 6 hours for the amine- catalyzed reaction between benzaldehyde and nitromethane. Catalysts for the reaction were free polyethyleneimine (PEI) (black bars, 26.1 mol %) and encapsulated PEI (white bars,

13.8 mol %).

[0032] FIGURE 24. Proposed catalytic system of microcapsule-catalyzed nitroalkene formation.

[0033] FIGURE 25. Single-catalyst addition of nitromethane (top) versus double-catalyst addition of dimethyl malonate (DMM) (bottom).

[0034] FIGURE 26. Kinetic studies on the tandem reaction of 3- methylbutyraldehyde, nitromethane, and dimethyl malonate. Changing the catalyst concentration in the reaction between 3-methylbutyraldehyde (8), nitromethane, and dimethyl malonate revealed that the reaction is first-order in nickel catalyst 2, indicating that the Michael addition of dimethyl malonate to the nitroalkene is the rate-determining step. [0035] FIGURES 27A-27B. Microcapsule-accelerated Michael addition between benzaldehyde (4) and dimethyl malonate in the presence of untreated μcaps (Figure

27A) and in the presence of acylated μcaps (Figure 27B).

[0036] FIGURE 28. Order plot for the Michael addition between benzaldehyde

(4) and dimethyl malonate in the presence of acylated μcaps. Rate is plotted as a function of nickel catalyst 2.

[0037] FIGURE 29. Proposed transition state for the one-pot two-step Henry reaction-Michael addition.

[0038] FIGURE 30. Exemplary one-pot multi-step synthesis of pregabalin using a microencapsulated amine catalyst and a nickel(II) catalyst.

[0039] FIGURE 31. Indication that the nickel catalyst does not diffuse into the microcapsule.

[0040] FIGURE 32. Depiction of a multi-step synthesis of pregabalin

(LYRICA^®, Pfizer) developed by Pfizer that does not use microcapsule technology. The E- factor of the one-pot multistep synthesis as depicted in Figure 30 is calculated to be 31. The

E-factor for Pfizer's multi-step synthesis depicted in Figure 32 is calculated to be 178.

Definitions

[0041] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. [0042] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0043] Where an isomer/enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched." Thus, an "optically-enriched" isomer/enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding isomer/enantiomer. "Optically-enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972)..

[0044] It will be appreciated that the inventive compounds, polymers, conjugates, microcapsules, molecules, starting materials, reagents, reactants, products, and the like, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Examples of permissible substituents are defined herein, and include, but are not limited to, aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetereocyclic, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, trialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxylic acid and carboxaldehyde. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0045] As used herein, a "bond" refers to a single, double, or triple bond between two groups.

[0046] The term "acyl" as used herein refers to a group having the general formula -C(=O)R^A, where R^A is aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, alkoxy, hydroxy, thiol, alkylthioxy, amino, alkylamino, dialkylamino, heterocyclic, or heteroaryl. An example of an acyl group is acetyl (R^A = -CH₃).

[0047] The term "acyloxy" or "ester" as used herein refers to a group of the formula -OC(=O)R^B, where R^B may be aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or heteroaryl.

[0048] The term "amide" or "amido" as used herein refers to a group having the general formula -C(=O)N(R^C)(R^C), -N(H)C(=O)(R^C), or -N(R^C)C(=O)(R^C), where each instance of R is, independently, aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or heteroaryl.

[0049] The term "azido" as used herein refers to a group of the formula -N₃.

[0050] The terms "carboxaldehyde" or "carboxyaldehyde" refers to a group of the formula -CHO.

[0051] The term "carboxylate" or "carboxylic acid" refers to a group of the formula -CO₂H.

[0052] The term "cyano" as used herein refers to a group of the formula -CN.

[0053] The term "isocyano" as used herein refers to a group of the formula -NC.

[0054] The term "imide" or "imido" as used herein refers to a group having the general formula -C(=NR^D)R^D, -OC(=NH)R^D, -OC(=NR^D)R^D, -C(=NH)R^D, -

N(H)C(=NH)R^D, -N(H)C(=NR^D)R^D, -N(R^D)C(=NH)R^D, or -N(R^D)C(=NR^D)R^D, where each instance of R^D is, independently, aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or heteroaryl.

[0055] The term "nitro" as used herein refers to a group of the formula -NO₂.

[0056] The term "oxo" as used herein refers to a group of the formula =0

[0057] The term "thiooxo" as used herein refers to a group of the formula =S.

[0058] The term "hydroxy" or "hydroxyl" as used herein refers to a group of the formula -OH. [0059] The term "activated hydroxyl" as used herein refers to a hydroxyl group in which the hydrogen is replaced with an activating (i.e., electron-withdrawing) group.

Exemplary activating groups include sulfmyl, sulfonyl, or acyl groups.

[0060] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-1).

[0061] The term "sulfmyl" as used herein refers to a group of the formula -

S(=O)R^E, where R^E may be aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, alkoxy, hydroxy, thiol, alkylthioxy, amino, alkylamino, dialkylamino, heterocyclic, or heteroaryl.

[0062] The term "sulfonyl" as used herein refers a group of the formula -

S(=O)2R^F, where R^F may be aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, alkoxy, hydroxy, thiol, alkylthioxy, amino, alkylamino, dialkylamino, carbocylic, heterocyclic, or heteroaryl. Exemplary sulfonyl groups include tosyl (toluene sulfonyl, CH₃C₆H₄SO₂-) and mesyl (methyl sulfonyl, CH₃SO₂-).

[0063] The terms "phosphine" or "phosphino" and "phosphane" or "phosphano" as used herein refers to a group of the formula -P(R )₃, wherein each R is independently, hydrogen, aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetereocyclic, arylalkyl, and heteroarylalkyl.

[0064] The terms "phosphinate" or "phosphinato" as used herein refers to a group of the formula -P(=O)OR^H or -OP(=O)R^H, wherein wherein each R^H is independently selected from the group consisting of hydrogen, aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetereocyclic, arylalkyl, and heteroarylalkyl.

[0065] The terms "phosphazine" or "phosphazino," as used herein, refers to a group of the formula -P(=O)(NR^I)₃ wherein each R¹ is independently hydrogen, aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetereocyclic, arylalkyl, and heteroarylalkyl.

[0066] The term "thiohydroxyl" or "thiol" as used herein refers to a group of the formula -SH.

[0067] The term "aliphatic" as used herein includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons. In some embodiments, the aliphatic group employed in the invention contains 1-10 carbon atoms. In another embodiment, the aliphatic group employed contains

1-8 carbon atoms. In still other embodiments, the aliphatic group contains 1-6 carbon atoms.

In yet another embodiments, the aliphatic group contains 1-4 carbons. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl and cyclic (i.e., "carbocyclic") groups such as cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.

[0068] The term "alkyl" as used herein refers to substituted or unsubstituted, saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. In some embodiments, the alkyl group employed in the invention contains 1-10 carbon atoms. In another embodiment, the alkyl group employed contains 1-8 carbon atoms. In still other embodiments, the alkyl group contains 1-6 carbon atoms. In yet another embodiments, the alkyl group contains 1-4 carbons. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec- pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n- decyl, n-undecyl, dodecyl, and the like, which may bear one or more sustitutents. [0069] The term "acyclic alkylene" as used herein refers to a substituted or unsubstituted, saturated and unsaturated, straight- or branched-chained divalent aliphatic group, as defined herein. In some embodiments, the alkylene group employed in the invention contains 1-10 carbon atoms. In another embodiment, the alkylene group employed contains 1-8 carbon atoms. In still other embodiments, the alkylene group contains 1-6 carbon atoms. In yet another embodiments, the alkylene group contains 1-4 carbons. Examples of acyclic alkylene radicals include, but are not limited to, methylene, ethylene, ethylenylene, propylene, propylenylene, butylene and butylenylene.

[0070] The term "cyclic alkylene" as used herein refers to a divalent substituted or unsubstituted carbocyclic group, as defined herein. In some embodiments, the cyclic alkylene group employed in the invention contains 3-10 carbon atoms. In another embodiment, the alkylene group employed contains 5-8 carbon atoms. In still other embodiments, the alkylene group contains 5-6 carbon atoms. Examples of alkylene dradicals include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene and cycloheptenylene. [0071] The term "alkenyl" denotes a substituted or unsubstituted monovalent group derived from a hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. In certain embodiments, the alkenyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkenyl group employed in the invention contains 2-10 carbon atoms. In another embodiment, the alkenyl group employed contains 2-8 carbon atoms. In still other embodiments, the alkenyl group contains 2-6 carbon atoms. In yet another embodiments, the alkenyl group contains 2-4 carbons. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2- buten-1-yl, and the like, which may bear one or more sustitutents.

[0072] The term "alkynyl" as used herein refers to a substituted or unsubstituted monovalent group derived form a hydrocarbon having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. In certain embodiments, the alkynyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkynyl group employed in the invention contains 2-10 carbon atoms. In another embodiment, the alkynyl group employed contains 2-8 carbon atoms. In still other embodiments, the alkynyl group contains 2-6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like, which may bear one or more sustitutents.

[0073] The term "carbocyclic" as used herein refers to a non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted 3- to 10-membered "all carbon" monocyclic or bicyclic ring system. Carbocyclic groups include substituted or unsubstituted C3-10 cycloalkyl, C5-10 cycloalkenyl, and Cβ-io cycloalkynyl moieties.

[0074] The terms "alkylamino" "dialkylamino" and "trialkylamino" as used herein refers to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR^J wherein R^J is an alkyl group, as previously defined. The term dialkylamino refers to a group having the structure -N(R^J)₂, wherein each R^J is independently selected from the same or different alkyl groups. The term trialkylamino refers to a group having the structure -N(R^J)₂, wherein each R^J is independently selected from the same or different alkyl groups. Additionally, two R^J groups may be taken together to form a substituted or unsubstituted 5- to 6-membered ring. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino. [0075] The term "aminoalkyl" as used herein refers to an amino group, as defined herein, attached to the parent molecular moiety through an alkyl group. [0076] The term "hydroxyalkyl" as used herein refers to a hydroxy group, as defined herein, attached to the parent molecular moeity through an alkyl group. [0077] The term "alkoxy" as used herein refers to a saturated (i.e., "alkyloxy" = alkyl-O-) group attached to the parent molecular moiety through an oxygen atom. Examplary alkoxy groups include, but are not limited to, methyloxy, ethyloxy, propyloxy, isopropyloxy, n-butoxy, tert-butoxy, z-butoxy, sec-butoxy, neopentoxy, n-hexyloxy, and the like.

[0078] The terms "alkylthio" and "thioalkoxy" refer to a saturated (i.e.,

"alkylthio" = alkyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examplary alkylthio moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0079] The term "heteroaliphatic" as used herein refers to a substituted or unsubstituted aliphatic group, as defined herein, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms. As will be appreciated by one of ordinary skill in the art, "heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl groups, and cyclic (i.e., heterocyclic) groups such as heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. [0080] The term "acyclic heteroalkylene" as used herein refers to a divalent substituted or unsubstituted heteroaliphatic group, as defined herein.

[0081] The term "heterocyclic," or "heterocyclyl," as used herein, refers to an substituted or unsubstituted non-aromatic, partially unsaturated or fully saturated, 3- to 10- membered ring system, which includes single rings of 3 to 8 atoms in size, and bi- and tricyclic ring systems which may include aromatic five- or six-membered aryl or heteroaryl groups fused to a non-aromatic ring. These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized or substituted. In certain embodiments, the term heterocylic refers to a non-aromatic 5-, 6-, or 7-membered monocyclic ring wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Exemplary heterocyclics include, but are not limited to, azacyclopropanyl, azacyclobutanyl, 1,3-diazatidinyl, pyrrolidinyl, piperidinyl, piperazinyl, thiranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, tetrahydrothiopyranyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, oxathiolanyl, morpholinyl, thiomorpholinyl, thioxanyl, quinuclidinyl, and the like, which may bear one or more sustitutents.

[0082] The term "cyclic heteroalkylene" as used herein refers to a divalent substituted or unsubstituted heterocyclic group, as defined herein. In some embodiments, the cyclic heteroalkylene group employed in the invention contains 3-10 atoms. In another embodiment, the heteroalkylene group employed contains 5-8 atoms. In still other embodiments, the heteroalkylene group contains 5-6 atoms.

[0083] The term "aryl" as used herein referd to a substituted or unsubstituted mono- or polycyclic, aromatic all-carbon (carbocyclic) moiety having 5-14 carbon atoms. In certain embodiments of the present invention, "aryl" refers to a substituted or unsubstituted monocyclic or bicyclic group. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like, which may bear one or more sustitutents.

[0084] The term "arylene" as used herein refers to a divalent substituted or unsubstituted aryl group, as defined herein. An exemplary arylene groups includes, but is not limited to, phenylene, which may bear one or more sustitutents.

[0085] The term "heteroaryl" as used herein refers to a substituted or unsubstituted mono- or polycyclic, aromatic moiety having 5-14 ring atoms of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. Exemplary heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imadazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pryyrolizinyl, indolyl, quinolinyl, isoquinolynyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinazolinyl, phthalazinyl, napthyridinyl, quinoxalinyl, thiophenyl, thiepinyl, furanyl, benzofuranyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and the like, which may bear one or more sustitutents.

[0086] The term "heteroarylene" as used herein refers to a divalent substituted or unsubstituted heteroaryl group, as defined herein.

[0087] The term "heteroatom" as used herein refers to an oxygen, sulfur, nitrogen, phosphorus, or silicon atom.

[0088] As used herein, when two entities are "conjugated" to one another they are linked by a direct or indirect covalent or non-covalent interaction. In certain embodiments, the association is covalent. In other embodiments, the association is non-covalent. Non- covalent interactions include hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetic interactions, electrostatic interactions, etc. An indirect covalent interaction is when two entities are covalently connected through a linker group. [0089] As used herein, the term "small molecule" refers to a non-peptidic, non- oligomeric organic compound either synthesized in the laboratory or found in nature. Small molecules, as used herein, can refer to compounds that are "natural product-like;" however, the term "small molecule" is not limited to "natural-product-like" compounds. Rather, a small molecule is typically characterized in that it contains several carbon-carbon bonds, and has a molecular weight of less than 1500 g/mol, although this characterization is not intended to be limiting for the purposes of the present invention. In certain embodiments, a small molecule has a molecular weight of less than 1000 g/mol. In certain embodiments, a small molecule has a molecular weight of less than 500 g/mol. In certain embodiments, a small molecule has a molecular weight of less than 400 g/mol. In certain embodiments, a small molecule has a molecular weight of less than 300 g/mol.

[0090] As used herein, the term "incompatible" refers to a situation in which two or more substances or reactions cannot be used together in the same solution. The substances may react or otherwise render each other unreactive. For instance, two catalysts may be incompatible if, when present in the same solution, they interact with each other to form inactive, or less reactive, catalysts. In certain embodiments, the reactions are incompatible because the conditions for the reaction are incompatible {e.g., reactants, catalysts, pH, solvent, temperature, concentration, etc.).

[0091] The terms "emulsifϊer" or "surfactant," as used herein is meant a compound with ampiphilic functionality {i.e., lipophilic and hydrophilic properties) which allows for a dispersion of droplets of one phase into another phase by lowering the interfacial tension between the two immicible liquids. The emulsifϊer is present at the interface, giving a film between both phases. The hydrophilic/lipophilic characteristics of emulsifϊers are normally standardized by their "HLB" value (Hydrophilic/Lipophilic Balance). Methods for determining the HLB value of particular surfactants are known in the art (see for example, U.S. Pat. Nos. 5,603,951; 4,933,179 and 4,606,918, each of which is incorporated herein by reference, which describe surfactants having particular HLB values). This value is always a guide when selecting an emulsifier for a given application. In general, emulsifϊers with strong lipophilic character have a low HLB, while the ones with a strong hydrophilic character have a high HLB. A surfactant with an HLB between 12-20 can be use to modify the size and dispersity of certain embodiments of the presently claimed invention. [0092] The term "interfacial modifier," as used herein, is meant an additive which has an affinity for the interface between two immicible solutions, and physically modifies the interface during the polymerization step (for example, modification of the viscosity, surface area, surface tension, or percolation phenomena at the interface of two solutions). Exemplary interfacial modifiers include, but are not limited to, polyisobutylenes, poly(vinyl alcohol)s, polystyrenes, polyethylenes, glycerols, or polysaccharides.

[0093] An "oil-in-oil" emulsion, as used herein, is meant an emulsion formed between two immicible organic solvent phases, such as a polar solvent (e.g., methanol, ethanol, isopropanol, etc.) as the dispersed phase and a non-polar solvent (e.g., cyclohexane, hexanes, pentanes, benzene, toluene) as the continuous phase to form an emulsion (e.g., such as methanol-in-cyclohexane or methanol-in-toluene emulsions). In certain embodiments, the presently claimed invention uses "oil-in-oil" emulsions to form microcapsules. An "oil- in-oil" microencapsulated system, as used herein, is meant a microcapsule swelled with one solvent and placed in a different solvent, wherein the two solvents are immicible, and wherein neither of the two solvents are pure water or solutions of greater than 50% water. [0094] The term "E-Factor," as used herein, is meant a factor used to measure the efficiency of various chemical reactions, in terms of kilograms of waster per kilogram of desired products. Typically, commercially-available bulk chemicals have an E-Factor of less than 1 to 5, compared with 5 to greater than 50 for fine chemicals, and 25 to more than 100 for pharmaceuticals.

[0095] The term "polypeptide," as used herein, is meant a string of at least three amino acids linked together by peptide bonds. The terms "protein" and "peptide" may be used interchangeably. Peptide may refer to an individual peptide or a collection of peptides. Inventive peptides preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a polypeptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. These modifications may include cyclization of the peptide, the incorporation of D-amino acids, etc. [0096] The term "polynucleotide," as used herein, is meant a polymer of nucleotides. Typically, a polynucleotide comprises at least three nucleotides. The polymer may include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxy cytidine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, C5-propynylcytidine, C5-propynyluridine, C5-bromouridine, C5-fluorouridine, C5- iodouridine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8- oxoguanosine, O(6)-methylguanine, and 2-thiocytidine), chemically modified bases, biologically modified bases (e.g., methylated bases), intercalated bases, modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose), or modified phosphate groups (e.g., phosphorothioates and 5' -N-phosphoramidite linkages).

[0097] The term "polysaccharide," as used herein, is meant a polymer made up of more than one monosaccharide joined together by glycosidic linkages. Exemplary monosaccharides include aldotrioses (e.g., glyceraldehyde), ketotrioses (e.g., dihydroxyacetone), aldotetroses (e.g., erythrose, threose), ketotetroses (e.g., erythrulose), aldopentoses (e.g., arabinose, lyxose, ribose, xylose), ketopentoses (e.g., ribulose, xylose), aldohexoses (e.g., allose, altrose, galactose, glucose, gulose, iodose, mannose, talose), ketohexoses (e.g., fructose, psicose, sorbose, tagatose), ketoheptoses (e.g., mannohepulose, sedoheptulose), octoses (e.g, octolose, 2-keto-3-deoxy-manno-octonate), and nonoses (e.g, silose). Exemplary polysaccharides include agar, agarose, alginate, cellulose, starch, amylose, amylopectin, chitin, glycogen, callose, laminarin, xylan, and galactomannan. [0098] The term "polyelectrolyte," as used herein, is meant a polymer whose repeating units bear an electrolyte group. Complexation between two oppositely charged polyelectrolytes (i.e., anion and cation) can lead to coacervate formation (a dense liquid phase) and secondary organization to form a "polyelectrolyte composite." Exemplary polyelectrolytes include, but are not limited to, poly(aminoethyl methacrylate), poly(hydroxyethyl methacrylate), poly(sodium styrene sulfonate) (PSS), poly(acrylic acid) (PAA), polyethyleneimine, poly(4-vinyl pyridine), poly(4-vinyl-N- butylpyridinium)bromide, and tetraalkyl-ammonium-containing-polymers such as poly(vinylbenzyltrimethyl)ammonium hydroxide.

[0099] The term "sol-gel," as used herein, is meant a colloidal suspension of particles that is gelled to form a solid. The sol-gel process involves the transition of a system from a liquid (the colloidal "sol") into a solid (the "gel") phase. The sol-gel process allows the fabrication of materials, such as inorganic membranes and thin films.

[00100] The term "dielectric constant" (ε) is a number relating the ability of a material (e.g., a solvent or a solution of two or more solvents) to carry alternating current to the ability of vacuum to carry alternating current. The dielectric constant of water and several common organic solvents are provided in Table 1.

Table 1.

Detailed Description of Certain Embodiments of the Invention

[00101] The invention is based on the premise that a soluble catalyst entrapped within the confines of a semi-permeable microcapsule should yield higher activities and/or selectivity than more traditional catalysts immobilized on solid support. The invention also provides for the use of incompatible catalysts and/or reagents in a one-pot reaction system. [00102] To this end, the present invention is directed to a microcapsule containing a catalyst. The invention also provides a system for making and using these microcapsules. The inventive microcapsules may be hollow, and, further, may encapsulate a solution. Moreover, the catalyst may be soluble in the encapsulated solution. The semi-permeable shell of the microcapsule allows reactants to diffuse into the interior of the microcapsule and react with an encapsulated catalyst to provide a product which may diffuse out of the microcapsule. In such a system, one pot multi-step reactions can be conducted in the presence of incompatible catalysts, incompatible reagents, and/or incompatible micro environments .

Semi-Permeable Polymeric Shell

[00103] In one embodiment, the microcapsule is hollow, and includes a soluble catalyst encapsulated by a semi-permeable polymeric shell, wherein the shell allows a reactant to diffuse into the microcapsule and react with the catalyst, and optionally, allows the product of the reaction to diffuse out.

[00104] In certain embodiment, the semi-permeable polymeric shell does not allow the catalyst to diffuse out of the microcapsule. In yet another embodiment, the microcapsule also encapsulates a solvent. In still yet another embodiment, the catalyst encapsulated in the microcapsule is soluble in the encapsulated solvent. The encapsulated solvent remains in the microcapsule by solvation effects, for example, by solvating the catalyst within.

[00105] In certain embodiments, the polymeric shell is a polymer, a blend, a composite, a cross-linked polymer, or a co-polymer.

[00106] For example, in one embodiment, the semi-permeable polymeric shell is a polymer. In another embodiment, the polymer is a linear polymer. In another embodiment, the polymer is a branched polymer. In another embodiment, the polymer is a cross-linked polymer. In another embodiment, the semi-permeable polymeric shell is a co-polymer. In yet another embodiment, the semi-permeable polymeric shell is a poly electrolyte composite. [00107] For example, in certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polyesters, polyethers, polyamides, polyimides, polyamines, polysulfones, polycarbonates, polyureas, polycarbamates, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polypropylenes, polystyrenes, polychloromethyl styrenes, polyazidomethyl styrenes, polyvinyl toluenes, polyvinyl acetylenes, polydivinyl benzenes, polyisocyanates, polyvinyl acetates, polyacrylates, polyacrylate esters, polymethacrylates, polymethacrylate esters, polyvinyl chlorides, polyvinyl alcohols, polyacrylonitriles, polybutadienes, polyarylates, polybutylenes, polyisobutylenes, polybutylene terephthalates, polytetrafluoro ethylenes, polychloroprenes, polyamino esters, poly-β-hydroxybutyric acids, polysiloxanes, polysilsequinoxanes, poly(sodium styrene sulfonate)s, tetraalkyl-ammonium-containing- polymers, sol-gels, polyelectrolytes, polypeptides, polysaccharides, or polynucleotides. [00108] In certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of polyisocyantes, polyamines, polyureas, polysaccharides, polyelectrolytes, or a mixture thereof. In certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or copolymers of polyisocyantes, polyamines or polyureas.

[00109] For example, in certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polysaccharides. In certain embodiments, the polymeric shell is a polysaccharides shell. In certain embodiments, the polymeric shell is a co-polymer of one or more polysaccharides. Exemplary polysaccharides include agar, agarose, alginate, cellulose, starch, amylose, amylopectin, chitin, glycogen, callose, laminarin, xylan, and galactomannan. In certain embodiments, the polymeric shell is an alginate polymer.

[00110] In certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polyisocyantes. In certain embodiments, the polymeric shell is a polymer of a polyisocyante. In certain embodiments, the polymeric shell is a co-polymer of one or more polyisocyanates. Exemplary polyisocyanates include, but are not limited to, poly(methylene[polyphenyl]isocyanate) (PMPPI), toluene diisocyanate and 1,6-diisocyanatohexane. However, in certain embodiments, the polymer of poly(methylene[polyphenyl]isocyanate) (PMPPI) is specifically excluded. [00111] In certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polyamines. In certain embodiments, the polymeric shell is a polyamine shell. In certain embodiments, the polymeric shell is a co-polymer of one or more polyamines. In certain embodiments, the polymeric shell is a co-polymer of one or more polyamines and one or more polyureas. In certain embodiments, the polymeric shell is a co-polymer of one or more polyamines and the monomer 2,4-tolylene diisocyanate (TDI). Exemplary polyamines include poly(ethylene imine) (PEI), tetraethylenepentamine (TEPA), and the commerically available JEFF AMINE^® polyetheramines, such as JEFF AMINE^® monoamines (e.g., the M series); JEFF AMINE^® diamines (e.g., the D, ED and EDR series), JEFF AMINE^® triamines (e.g., the T series), and JEFF AMINE^® secondary amines (e.g., the SD and ST series).

[00112] In certain embodiments, the polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polyureas. In certain embodiments, the polymeric shell is a polyurea shell. In certain embodiments, the polymeric shell is a co-polymer of one or more polyureas. In certain embodiments, the polymeric shell is a co-polymer of one or more polyureas and one or more polyamines. In certain embodiments, the polymeric shell is a co-polymer of one or more polyureas and poly(ethylene imine) (PEI), tetraethylenepentaminepolyamine (TEPA) or a JEFF AMINE^® polyetheramine.

[00113] In certain embodiments, the polymeric shell comprises one or more polyelectrolytes. In certain embodiments, the polymeric shell is a polyelectrolyte shell. In certain embodiments, the polymeric shell is a co-polymer of one or more polyelectrolytes. In certain embodiments, the polymeric shell is a co-polymer of one or more acidic polyelectrolytes and one or more basic polyelectrolytes. Exemplary acidic polyeletrolytes include, but are not limited to, poly(styrene sulfonic acid). Exemplary basic polyeletrolytes include, but are not limited to, poly(4-vinyl pyridine), polyquaternium-2 and poly(diallyldimethyammonium chloride).

[00114] In certain embodiments, the polymeric shell is a co-polymer of poly(ethylene imine) (PEI) and the monomer 2,4-tolylene diisocyanate (TDI), such as the polymeric shell depicted in Figures 12 and/or 31. Encapsulated Catalyst

[00115] As is apparent to one skilled in the art, the catalyst encapsulated in the microcapsule may be any reactive moiety, chemical or biological in nature, which can interact with a suitable reactant. For example, the catalyst may be a nucleophile, an electrophile, a base, an acid, a Lewis acid, a Lewis base, a Brønsted acid, a Brønsted base, an oxidant, or a reductant, or the catalyst may include a metal, a transition metal catalyst, an organometallic catalyst, or an organic small molecule. The entrapped catalyst may be a biological agent such as an enzyme. The entrapped catalyst may be covalently conjugated to a polymer to afford a catalyst-polymer conjugate.

[00116] A suitable reactant may be any chemical compound that can diffuse through the semi-permeable polymeric shell of the inventive microcapsule and be able to react with the encapulated catalyst. For example, if the catalyst is a nucleophile or a base, a suitable reactant is an electrophile or an acid. In certain embodiments, the molecular weight of the reactant is less than 100, 200, 300, 400, 500, 1000, or 1500 g/mol. [00117] In one embodiment, the catalyst is a base. In certain embodiments, the catalyst is an amine-containing polymer which behaves as a base {e.g., a polyamine such as poly(ethylene imine) (PEI)). In other embodiments, the catalyst is an organic base. In yet other embodiments, the catalyst is a basic moiety covalently conjugated to a polymer to afford a catalyst-polymer conjugate. Organic bases envisioned by the presently claimed invention include an optionally substituted amino, alkyl amino, dialkyl amino, trialkylamino, arylamino, heterocyclic, or heteroaryl group. In certain embodiments, the organic base includes an optionally substituted pyridinyl (Py), optionally substituted dimethylamino pyridinyl (DMAP), optionally substituted 4-(N-benzyl-N-methyl)-amino pyridinyl, optionally substituted 2,3-dimethyl pyridinyl, optionally substituted 2,4-dimethyl pyridinyl, optionally substituted 3,5-dimethyl pyridinyl, optionally substituted pyrrolidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrrolyl, or an optionally substituted morpholynyl group. In certain embodiments, the organic base is DMAP.

[00118] In another embodiment, the catalyst is an electrophile. In certain other embodiments, the catalyst is an electrophilic moiety covalently conjugated to a polymer to afford a catalyst-polymer conjugate. Electrophilic moieties envisioned by the presently claimed invention include a halogen, an activated hydroxyl, or an acyl, optionally substituted alkenyl, or optionally substituted alkynyl group. [00119] In another embodiment, the catalyst is a nucleophile. In certain other embodiments, the catalyst is an nucleophilic moeity covalently conjugated to a polymer to afford a catalyst-polymer conjugate. Nucleophilic moieties envisioned by the presently claimed invention include phosphino, phosphinato, phosphazino, azido, amino, thio, isocyano, hydroxyl, or an optionally substituted alkenyl or optionally substituted alkynyl group.

[00120] In certain embodiments, the catalyst encapsulated in the inventive microcapsule is covalently conjugated to a polymer to afford a catalyst-polymer conjugate. Any catalyst may be conjugated to any polymer using synthetic methods and chemical reactions known in the art. Various reactions useful in conjugating a catalyst to a polymer include the formation of carbon-carbon bonds, the formation of esters, ethers, amides, disulfides, or the like. In certain embodiments, the catalyst encapsulated in the inventive microcapsule is covalently conjugated to a polymer to afford a catalyst-polymer conjugate, wherein the catalyst component is pendant to the backbone of the polymer. Additionally, linker groups may be used to further extend the catalyst away from the polymer. [00121] Thus, in certain embodiments, the catalyst encapsulated in the inventive microcapsule is covalently conjugated through a linker group to a polymer to afford a catalyst-polymer conjugate, wherein the catalyst component is pendant to the polymer backbone. In one embodiment, the polymer backbone of the catalyst-polymer conjugate is a linear polymer. In another embodiment, the polymer backbone of the catalyst-polymer conjugate is a cross-linked polymer. In yet another embodiment, the polymer backbone of the catalyst-polymer conjugate is a co-polymer. In another embodiment, the polymer backbone of the catalyst-polymer conjugate is a polyelectrolyte composite. [00122] In certain embodiments, the polymer backbone of the catalyst-polymer conjugate includes polymers, blends, composites, cross-linked polymers or co-polymers of polyesters, polyethers, polyamides, polyimides, polyamines, polysulfones, polycarbonates, polyureas, polycarbamates, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polypropylenes, polystyrenes, polychloromethyl styrenes, polyazidomethyl styrenes, polyvinyl toluenes, polyvinyl acetylenes, polydivinyl benzenes, polyisocyanates, polyvinyl acetates, polyacrylates, polyacrylate esters, polymethacrylates, polymethacrylate esters, polyvinyl chlorides, polyvinyl alcohols, polyacrylonitriles, polybutadienes, polyarylates, polybutylenes, polyisobutylenes, polybutylene terephthalates, polytetrafluoro ethylenes, polychloroprenes, polyamino esters, poly-β-hydroxybutyric acids, polysiloxanes, polysilsequinoxanes, poly(sodium styrene sulfonate)s, tetraalkyl-ammonium-containing- polymers, sol-gels, polyelectrolytes, polypeptides, polysaccharides, or polynucleotides. [00123] In yet another embodiment, the polymer backbone of the catalyst-polymer conjugate comprises one or more polysaccharides, polystyrenes, polyisocyantes, polyamines, polyureas, or polyacetylenes.

[00124] For example, in certain embodiments, the polymer backbone of the catalyst-polymer conjugate comprises one or more polysaccharides. Exemplary polysaccharides include agar, agarose, alginate, cellulose, starch, amylose, amylopectin, chitin, glycogen, callose, laminarin, xylan, and galactomannan. In certain embodiments, the polymer of the catalyst-polymer conjugate is an alginate polymer.

[00125] In certain embodiments, the polymer backbone of the catalyst-polymer conjugate comprises optionally substituted polystyrenes. In certain embodiments, the polymer backbone is a co-polymer of one or more optionally substituted polystyrenes. For example, in certain embodiments, the polymer backbone is a co-polymer of styrene and a substituted polystyrene. In certain embodiments, the co-polymer comprises styrene and an optionally subsituted DMAP-modifϊed styrene. Exemplary catalyst-polymer conjugates comprising tethered DMAP are depicted in Figures 1 and 6B.

[00126] However, in certain embodiments, the catalyst-polymer conjugate comprising a co-polymer of styrene and DMAP-modified linear polystyrene (LPSDMAP) is specifically excluded. In certain embodiments, the microencapsulated catalyst comprising a PMPPI semipermeable polymeric shell and the catalyst-polymer conjugate comprising a copolymer of styrene and DMAP-modified linear polystyrene (LPSDMAP) is specifically excluded.

[00127] In certain embodiments, the excluded catalyst-polymer conjugate comprising a co-polymer of styrene and DMAP-modified linear polystyrene (LPSDMAP) is of the formula:

wherein F and G are, independently, hydrogen, hydroxy, amino, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclic group; m is an integer between 1 and 500; and n is an integer between 1 and 100, is specifically excluded. [00128] In certain embodiments, the excluded catalyst-polymer conjugate comprising a co-polymer of styrene and DMAP-modified linear polystyrene (LPSDMAP) of the above formula, wherein F is an optionally substituted aliphatic group and G is hydrogen, is specifically excluded.

[00129] In certain embodiments, the excluded catalyst-polymer conjugate comprising a co-polymer of styrene and DMAP-modified linear polystyrene (LPSDMAP) of the above formula, wherein F is the group:

and G is hydrogen, is specifically excluded. [00130] In certain embodiments, the polymer backbone of the catalyst-polymer conjugate comprises one or more polyamines. In certain embodiments, the polymer backbone of the catalyst-polymer conjugate is optionally substituted poly(ethylene imine) (PEI). For example, in certain embodiments, the catalyst-polymer conjugate is poly(ethylene imine) (PEI) optionally substituted with an aminoalkyl group.

[00131] In certain embodiments, the polymer backbone of the catalyst-polymer conjugate comprises poly(vinylacetylene). In yet another embodiment, the polymer backbone of the catalyst-polymer conjugate is a hydrocarbon chain, such as that provided by poly(vinylacetylene) .

[00132] In yet other embodiments, pendent groups present on the polymer backbone are modified using "click" chemistry to provide the catalyst-polymer conjugate. The term "click chemistry," as used herein, is a term introduced by Professor K. Barry Sharpless (see "Click Chemistry: Diverse Chemical Function from a Few Good Reactions " Hartmuth C. KoIb, M. G. Finn, K. Barry Sharpless, Angewandte Chemie International Edition (2001) 40:2004, incorporated herein by reference), and describes chemical transformations tailored to generate substances quickly and reliably by joining small units together. These chemical transformations typically obey one or more of the following criteria: (1) high chemical yield; (2) readily available starting materials and reagents; (3) easy product isolation; (4) large thermodynamic driving force; and (5) high atom economy. Exemplary "click" chemistry reactions include: (i) cycloaddition reactions (i.e., the Huisgen 1,3-dipolar cycloaddition); (ii) copper (Cu) catalyzed azide-alkyne cycloadditions; (iii) Diels-Alder reactions; (iv) nucleophilic substitution reactions (e.g., such as additions to small strained rings, like epoxides and aziridines); (v) carbonyl-chemistry-like formation of ureas and amides; and (vi) addition reactions to carbon-carbon double or triple bonds (for instance, epoxidation or dihydroxylation).

[00133] In certain embodiments, the polymer backbone is an optionally substituted poly( vinyl acetylene) comprising pendant acetylene groups which are modified using "click" chemistry to provide the catalyst-polymer conjugate. For example, the acetylene groups can be reacted with azide groups to form a 5-membered heterocyclic ring.

[00134] Exemplary catalyst-polymer conjugates of the present invention have the following formulae (I), (I') or (I"):

(I)

(I') (I") wherein each occurrence of A is an optionally substituted cyclic or acyclic alkylene, optionally substituted cyclic or acyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene group; each occurrence of B is either (N) or (CR^q), wherein R^q is hydrogen, hydroxy, thio, halo, nitro, cyano, amino, acyl, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl group;

F and G are, independently, hydrogen, hydroxy, amino, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclic group; each occurrence of X is, independently, a bond, -O-, -S-, -N(R^W), or an optionally substituted cyclic or acyclic alkylene, optionally substituted cyclic or acyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene moiety, wherein each instance of R^w is, independently, hydrogen, hydroxy, acyl, sulfϊnyl, sulfonyl, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted hetereocyclyl group; each occurrence of Y is, independently, hydroxy, thio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxyaldehyde, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, alkylamino, or dialkylamino group; each occurrence of Z is, independently, hydrogen, hydroxy, thio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, amido, imido, acyl, acyloxy, sulfϊnyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxyaldehyde, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, alkylamino, or dialkylamino group; p is an integer between 0 to 100; m is an integer between 1 and 500; and n is an integer between 0 and 100.

[00135] In certain embodiments, p is an integer between 0 to 50, 0 to 25, 0 to 10, 0 to 6, 0 to 3, or 0 to 2. In certain embodiments, p is an integer between 1 to 50, 1 to 25, 1 to 10, 1 to 6, 1 to 3, or 1 to 2. In certain embodiments, p is 0.

[00136] In certain embodiments, m is an integer between 10 to 500, 10 to 400, 10 to 300, 10 to 200, 10 to 100, 10 to 50, 10 to 25, 10 to 15, or m is an integer between 1 to 10, 1 to 5, or 1 to 2.

[00137] In certain embodiments, n is an integer between 0 to 100, 0 to 50, 0 to 25,

0 to 10, 0 to 6, 0 to 3, 0 to 2, or 0 to 1. [00138] In certain embodiments, each occurrence of A is the same. In certain embodiments, each occurrence of A is different.

[00139] In certain embodiments, A is an optionally substiuted acyclic Ci_6 alkylene group. In certain embodiments, A is an optionally substiuted acyclic Ci_₃ alkylene group. In certain embodiments, A is an optionally substiuted Ci_₂ alkylene group. In certain embodiments, A is -C(R^y)₂-, wherein each instance of R^y is, independently, hydrogen, hydroxy, thio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxyaldehyde, or an optionally substituted aliphatic, heteroaliphatic, aryl, heteroaryl, hetereocyclyl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, alkylamino, or dialkylamino group. In certain embodiments, A is -CH₂-.

[00140] In certain embodiments, each occurrence of B is the same. In certain embodiments, each occurrence of B is different.

[00141] In certain embodiments, each occurrence of B is (N).

[00142] In certain embodiments, each occurrence of B is (CR^q), wherein R^q is hydrogen, hydroxy, thio, halo, nitro, cyano, amino, acyl, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl group. In certain embodiments, B is (CH).

[00143] In certain embodiments, F and G are the same. In certain embodiments, F and G are different.

[00144] In certain embodiments, F and G are, independently, hydrogen, hydroxy, amino, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclic group.

[00145] In certain embodiments, F is an optionally substituted aliphatic group. In certain embodiments, F is an optionally substituted alkyl group. In certain embodiments, group F has the structure:

[00146] In certain embodiments, G is an optionally substituted aliphatic group. In certain embodiments, G is an optionally substituted alkyl group. However, in certain embodiments, G is hydrogen.

[00147] In certain embodiments, each occurrence of X is the same. In certain embodiments, each occurrence of X is different.

[00148] In certain embodiments, X is, independently, a single bond, -O-, -S-, -

N(R^W)-, or an optionally substituted cyclic or acyclic alkylene, optionally substituted cyclic or acyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene moiety. In certain embodiments, X is, independently, a single bond, -O-, -S-, -N(R^W)-, -(CH₂)_P-, or optionally substituted arylene, or optionally substituted heteroarylene moiety. In certain embodiments, X is, independently, a single bond, -(CH₂)_P-, an optionally substituted arylene or optionally substituted heteroarylene moiety. In certain embodiments, X is -(CH₂)_P-. In certain embodiments, X is an optionally substituted arylene moiety. [00149] In certain embodiments, at least one X group is an optionally substituted cyclic alkylene, optionally substituted cyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene group of the formula:

wherein: x is 0 to 5; q is 1 to 3;

W is -C-, -CR^f-, -C(R^f)₂-, -N-, -N(R^g)-, -O-, or -S-; wherein each occurrence of R¹ and R^f is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; and each occurance of and R^g is independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, amino, alkylamino, dialkylamino, amido, imido, acyl, sulfinyl, or sulfonyl; and is a single or double bond.

[00150] For example, in certain embodiments, at least one X group of the formula:

includes, but is not limited to, any of the following ring systems (a) to (j):

(a) (b) (C) (d)

.

(e) (0 (h)

(i) 0)

wherein is a single or double bond, and wherein R¹ and x are as defined herein. wherein each occurrence of R¹ and R^f is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfinyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; and each occurance of and R^g is independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, amino, alkylamino, dialkylamino, amido, imido, acyl, sulfmyl, or sulfonyl; and is a single or double bond.

[00151] In certain embodiments, at least one X group is the ring system (b). In certain embodiments, at least one X group is the ring system (e).

[00152] In certain embodiments, R¹ is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclyl group. In certain embodiments, R¹ is hydrogen.

[00153] In certain embodiments, R^f is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclyl group. In certain embodiments, R^f is hydrogen.

[00154] In certain embodiments, each occurrence of Y is the same. In certain embodiments, each occurrence of Y is different.

[00155] In certain embodiments, Y is, independently, hydroxy, hydroxyalkyl, aminoalkyl, amino, phosphino, phosphinato, phosphazino, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, alkylamino or dialkylamino group. In certain embodiments, Y is, independently, aminoalkyl, amino, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, alkylamino or dialkylamino group. In certain embodiments, Y is, independently, amino, alkylamino, dialkylamino, optionally substituted heteroaryl, or optionally substituted hetereocyclyl group. In certain embodiments, Y is, independently, amino or an optionally substituted heteroaryl group.

[00156] However, in certain embodiments, when Y is optionally substituted heteroaryl, the heteroaryl group dimethylaminopyridinyl (DMAP) is specifically excluded.

In certain embodiments, when Y is optionally substituted heteroaryl, the group:

is specifically excluded. [00157] In certain embodiments, each occurrence of Z is the same. In certain embodiments, each occurrence of Z is different.

[00158] In certain embodiments, each occurrence of Z is, independently, hydrogen or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted hetereocyclyl group. In certain embodiments, each occurrence of Z is hydrogen. In certain embodiments, each occurrence of Z is an optionally substituted aliphatic group. In certain embodiments, each occurrence of Z is an optionally substituted alkenyl or alkynyl group. In certain embodiments, each occurrence of Z is an optionally substituted alkynyl group. In certain embodiments, each occurrence of Z is an optionally substituted aryl or optionally substituted heteroaryl group. In certain embodiments, each occurrence of Z is an optionally substituted aryl group.

[00159] Exemplary catalyst-polymer conjugates are described in greater detail below. For example, in a first aspect, the catalyst-polymer conjugate has the formula I-a, wherein X is an alkylene:

(I-a) and wherein A, B, Z, F, G, Y, p, m, and n, are as defined herein.

[00160] In another embodiment, the catalyst-polymer conjugate has the formula I- b, wherein A is -CH₂-:

(I-b) and wherein B, Z, F, G, X, Y, p, m, and n, are as defined herein. [00161] In other embodiments, the catalyst-polymer conjugate has the formula I-c, wherein A is -CH₂- and B is (CH):

(I-c) and wherein X, Z, F, G, Y, p, m, and n, are as defined herein.

[00162] In other embodiments, the catalyst-polymer conjugate has the formula I- d, wherein A is -CH₂- and B is (N):

(I-d) and wherein X, Z, F, G, Y, p, m, and n, are as defined herein.

[00163] In another embodiment, the catalyst-polymer conjugate has the formula I- e, wherein A is -CH₂- and X is an alkylene:

(I-e) and wherein B, Z, F, G, Y, p, m, and n, are as defined herein.

[00164] In other embodiments, the catalyst-polymer conjugate has the formula I-f, wherein A is -CH₂- and B is (CH), and X is an alkylene:

and wherein X, Z, F, G, Y, p, m, and n, are as defined herein. [00165] In yet other embodiments, the catalyst-polymer conjugate has the formula

I-g, wherein A is -CH₂-, B is (N), and X is an alkylene:

(i-g) and wherein Z, F, G, Y, p, m, and n, are as defined herein.

[00166] In yet other embodiments, the catalyst-polymer conjugate has the formula

I-h, wherein A is -CH₂-, B is (N), X is an alkylene, and Z is hydrogen:

(I-h) and wherein F, G, Y, p, m, and n, are as defined herein.

[00167] In yet other embodiments, the catalyst-polymer conjugate has the formula

I-i, wherein A is -CH₂-, B is (N), X is alkylene, Z is hydrogen, and Y is amino:

(I-i) and wherein F, G, p, m, and n, are as defined herein.

[00168] In another aspect, the catalyst-polymer conjugate has the formula II:

(H) wherein R¹, x, A, B, Z, F, G, X, Y, W, q, p, m, and n, are as defined herein. [00169] In certain embodiments, the catalyst-polymer conjugate has the formula

II-a, wherein A is a -CH₂- group:

(II-a) and wherein R¹, x, W, q, B, Z, F, G, X, Y, , p, m, and n, are as defined herein.

[00170] In certain embodiments, the catalyst-polymer conjugate has the formula

II-b, wherein A and B are -CH₂- groups:

(II-b) and wherein R¹, x, W, q, Z, F, G, X, Y, , p, m, and n, are as defined herein.

[00171] In certain embodiments, the catalyst-polymer conjugate has the formula

II-c, wherein A is -CH₂-, and B is (N):

(ii-c) and wherein R¹, x, W, q, Z, F, G, X, Y, ^: , p, m, and n, are as defined herein.

[00172] In certain embodiments, the catalyst-polymer conjugate has the formula

II-d, wherein A and B are -CH₂- groups, and Z is an optionally substituted phenyl ring:

(II-d) wherein each occurrence of R² is, independently, hydrogen or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; y is 0 to 5, and R¹, x, W, q, F, G, X, Y, , p, m, and n, are as defined herein.

[00173] In certain embodiments, the catalyst-polymer conjugate has the formula

II-e, wherein A is -CH₂-, B is (N), and Z is an optionally substituted phenyl ring:

(II-e) and wherein R¹, x, R², y, W, q, F, G, X, Y, , p, m, and n, are as defined herein. [00174] In certain embodiments, the catalyst-polymer conjugate has the formula

II-f, wherein A and B are -CH₂- groups, and Z is an optionally substituted alkynyl group:

(H f) and wherein R¹, x, R², y, W, q, F, G, X, Y, , p, m, and n, are as defined herein.

[00175] In certain embodiments, the catalyst-polymer conjugate has the formula

II-g, wherein A is -CH₂-, B is (N), and Z is an optionally substituted alkynyl group:

(ii-g) and wherein R¹, x, R², y, W, q, F, G, X, Y, ^: , p, m, and n, are as defined herein.

[00176] In certain embodiments, the catalyst-polymer conjugate has the formula

II-h, wherein A and B are -CH₂- groups, and wherein an X group of the ring system (b) is directly attached to the polymer backbone:

(II-h) and wherein R¹, x, F, G, X, Y, p, m, and n, are as defined herein.

[00177] In certain embodiments, the catalyst-polymer conjugate has the formula

II-i, wherein A and B are -CH₂- groups, Z is an optionally substituted phenyl group, and wherein an X group of the ring system (b) is directly attached to the polymer backbone:

(II-i) wherein x is 0 to 4; y is 0 to 5; and R¹, R², F, G, X, Y, p, m, and n, are as defined herein.

[00178] In other embodiments, the catalyst-polymer conjugate has the formula II- j, wherein A and B are -CH₂- groups, Z is an optionally substituted alkynyl group, and wherein an X group of the ring system (b) is directly attached to the polymer backbone:

(ii-j) wherein R¹, x, R², F, G, X, Y, p, m, and n, are as defined herein.

[00179] In yet other embodiments, the catalyst-polymer conjugate has the formula

II-k wherein A and B are -CH₂- groups, and wherein an X group of the ring system (e) is directly attached to the polymer backbone:

wherein F, G, X, Y, p, m, and n, are as defined herein.

[00180] In yet other embodiments, the catalyst-polymer conjugate has the formula

II— 1 wherein A and B are -CH₂- groups, Z is an optionally substituted phenyl group, and wherein an X group of the ring system (e) is directly attached to the polymer backbone:

(II I) wherein y is 0 to 5; and R², F, G, X, Y, p, m, and n, are as defined herein. [00181] In yet other embodiments, the catalyst-polymer conjugate has the formula

II-m wherein A and B are -CH₂- groups, Z is an optionally substituted alkynyl group, and wherein an X group of the ring system (e) is directly attached to the polymer backbone:

(II-m) wherein R², F, G, X, Y, p, m, and n, are as defined herein.

[00182] In yet other embodiments, the catalyst-polymer conjugate has the formula

II-n wherein A and B are -CH₂- groups, Z is an unsubstituted phenyl group, and and wherein an X group of the ring system (b) is para substituted and is directly attached to the polymer backbone:

(II-n) wherein F, G, Y, p, m, and n, are as defined herein.

[00183] In yet other embodiments, the catalyst-polymer conjugate has the formula

II-o wherein A and B are -CH₂- groups, Z is an unsubstituted phenyl group, wherein an X group of the ring system (b) is para substituted and is directly attached to the polymer backbone:

(II-o) wherein F, G, Y, p, m, and n, are as defined herein.

[00184] In certain embodiments, Y is the catalyst moiety, as described above and herein. For example, in certain embodiments, Y is an electrophic moiety. In certain embodiments, Y is an a basic and/or nucleophic moiety. In certain embodiments, Y is a basic moiety. In certain embodiments, Y is -NH₂, -NH(CHs), pyridinyl, dimethylamino pyridinyl, 4-(N-benzyl-N-methyl)-amino pyridinyl, 2,3-dimethyl pyridinyl, 2,4-dimethyl pyridinyl, 3,5-dimethyl pyridinyl, pyrrolidinyl, pyrazinyl, or pyridazinyl.

[00185] However, in certain embodiments, the catalyst-polymer conjugate of formula H-n is specifically excluded. In certain embodiments, the catalyst-polymer conjugate of formula H-n, wherein Y is a dimethylamino pyridine moiety, is specifically excluded. In certain embodiments, the catalyst-polymer conjugate of formula H-n, wherein Y is the moiety:

, is specifically excluded. [00186] In certain embodiments, the catalyst-polymer conjugate of formula II-o is specifically excluded. In certain embodiments, the catalyst-polymer conjugate of formula II-o, wherein Y is a dimethylamino pyridine moiety, is specifically excluded. In certain embodiments, the catalyst-polymer conjugate of formula II-o, wherein Y is the moiety:

, is specifically excluded.

Encapsulated Solution

[00187] The hollow microcapsule may further comprise an encapulated solvent in addition to the catalyst within its semi-permeable polymeric shell, and the catalyst may be soluble in this encapsulated solvent to provide an encapsulated solution. The encapsulated solvent should be compatible with the encapsulated catalyst. In certain embodiments, the encapsulated solution allows for a desired reaction between the encapsulated catalyst and a diffused reagent.

[00188] In certain embodiments, the encapsulated solution comprises one or more polar aprotic solvents, polar protic solvents, non-polar solvents, or comprises a mixture thereof. Exemplary polar aprotic solvents include, but are not limited to, formamide, dimethylformamide, dimethyl acetamide and dimethylsulfoxide. Exemplary polar protic solvents include, but are not limited to, organic alcohols (e.g., methanol, ethanol, n-propanol, isopropanol and n-butanol) and acids (e.g., acetic acid). Exemplary non-polar solvents include, but are not limited to, pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, chlorobenzene, xylenes, chloroform, dichloromethane, dichloroethane, diethyl ether and tetrahydrofuran.

[00189] In certain embodiments, the encapsulated solution comprises a polar aprotic solvent. In certain embodiments, the encapsulated solvent is selected from formamide, dimethylformamide, dimethyl acetamide and dimethylsulfoxide. In certain embodiments, the encapsulated solvent is dimethylsulfoxide. In certain embodiments, the encapsulated solvent is dimethylformamide.

[00190] In certain embodiments, the encapsulated solution comprises a polar protic solvent. In certain embodiments, the encapsulated solvent is selected from methanol, ethanol, n-propanol, isopropanol and n-butanol. In certain embodiments, the encapsulated solvent is methanol.

[00191] In certain embodiments, the encapsulated solution contains less than 50%,

45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% water. In yet other embodiments, the encapsulated solution does not include water. [00192] In certain embodiments of the present invention, the encapsulated solvent has a dielectric constant (ε) greater than or equal to 15. In certain embodiments of the present invention, the encapsulated solvent has a dielectric constant (ε) greater than or equal to 20. In certain embodiments of the present invention, the encapsulated solvent has a dielectric constant (ε) greater than or equal to 25. In other embodiments, the encapsulated solvent has a dielectric constant of between 15 to 160. In other embodiments, the encapsulated solvent has a dielectric constant of between 20 to 160. In other embodiments, the encapsulated solvent has a dielectric constant of between 25 to 160. In other embodiments of the present invention, the encapsulated solvent has a dielectric constant (ε) less than or equal to 5. In yet other embodiments, the encapsulated solvent has a dielectric constant of between 0 to 5.

Method of Making a Microencapsulated Catalyst

[00193] The invention also provides a system of making an inventive microcapsule encapsulating a catalyst. Such a method includes the steps of:

(i) providing a first solution of a catalyst;

(ii) providing a second solution of at least one monomer;

(iii) dispersing the first solution into the second solution to form an emulsion; and

(iv) polymerizing the monomer at the interface of the first solution and the second solution to provide the microcapsule.

[00194] In certain embodiments, the catalyst of step (i) is soluble in the first solution, and wherein the first solution includes a polar aprotic solvent, a polar protic solvent, a non-polar solvent, or a mixture thereof. In other embodiments, the first solution comprises an organic solvent, or a mixture thereof. In yet other embodiments, the first solution comprises an organic alcohol, formamide, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, xylenes, chlorobenzene, chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or a mixture thereof.

[00195] In yet other embodiments, the first solution contains less than 50%, 45%,

40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% water. In yet other embodiments, the first solution does not include water.

[00196] In certain embodiments, the first solution comprises a solvent with a dielectric constant greater than or equal to 15. In certain embodiments, the first solution comprises a solvent with a dielectric constant greater than or equal to 20. In certain embodiments, the first solution comprises a solvent with a dielectric constant greater than or equal to 25. In certain embodiments, the dielectric constant of the solvent is between 15 to 160. In certain embodiments, the dielectric constant of the solvent is between 20 to 160. In certain embodiments, the dielectric constant of the solvent is between 25 to 160. In certain embodiments, the first solution comprises an alcohol, for example methanol, ethanol, n- propanol, isopropanol, or t-butanol. In certain embodiments, the first solution comprises methanol. In certain embodiments, the first solution comprises dimethylformamide. In certain embodiments, the first solution comprises dimethylsulfoxide.

[00197] In certain embodiments, the second solution of step (ii) is immicible in the first solution, and may comprise a polar aprotic solvent, a polar protic solvent, a non-polar solvent, or a mixture thereof. In other embodiments, the second solution comprises an organic solvent, or a mixture thereof. In yet other embodiments, the second solution comprises an organic alcohol, formamide, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, xylenes, chlorobenzene, chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or a mixture thereof.

[00198] In yet other embodiments, the second solution contains less than 50%,

45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% water. In yet other embodiments, the second solution does not include water.

[00199] In certain embodiments, the second solution comprises a solvent with a dielectric constant less than or equal to 5. In certain embodiments, the dielectric constant of the solvent is between 0 to 5. In certain embodiments, the second solution comprises toluene and/or benzene. In certain embodiments, the second solution comprises cyclohexane. [00200] In other embodiments, the second solution of step (ii) further comprises an emulsifier. Exemplary emulsifiers include the soaps of fatty acids, alkyl- or aryl-alkyl sulphonates, the salts of resin acids, PEG-based surfactants, TRITON surfactants, BRIJ surfactants, TWEEN surfactants, SPAN surfactants, monolaureate (e.g., TWEEN 20, TWEEN 21, SPAN 20), monopalmitate (e.g., TWEEN 40, SPAN 40), monostearate (e.g., TWEEN 60, TWEEN 61, SPAN 60), tristearate (e.g., TWEEN 65, SPAN 65), monooleate (e.g., TWEEN 80, TWEEN 81, SPAN 80), and trioleate (e.g., TWEEN 85, SPAN 85) surfactants. In certain embodiments, SPAN 85 is used as the emulsifier. [00201] In yet other embodiments, the second solution of step (ii) further comprises an interfacial modifier. Exemplary interfacial modifiers include, but are not limited to, polyisobutylenes, polyvinyl alcohol)s, polystyrenes, polyethylenes, glycerols, or polysaccharides.

[00202] According to the presently claimed invention, the method of making the inventive microcapsule includes the step of polymerization (step iv). As is known to one skilled in the art, there are many ways of inducing a polymerization reaction. In one embodiment, the polymerization step (iv) may further first include the step of inducing polymerization by adding an initiator to the emulsion of step (iii). Exemplary initiators include, but are not limited to, peroxides, N-oxides, tert-butyl peroxide, benzoyl peroxide, azobisisobutyrylnitrile (AIBN), tetraethylenepentamine (TEPA), a Ziegler-Natta catalyst, an acid, a base, a Lewis acid, a Lewis base, a Brønsted acid, or a Brønsted base. In another embodiment, the polymerization step (iv) is via ring opening metathesis polymerization (ROMP), reversible addition-fragmentation chain transfer (RAFT) polymerization, reversible addition-fragmentation chain transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), light-induced polymerization, or heat-induced polymerization. [00203] The term "monomer" is meant any polymerizable molecule which reacts with an initiator or other polymerizable molecules to form a semi-permeable polymeric shell, as described herein. For example, if the monomer employed in the polymerizing step is styrene, the resulting polymer is a polystyrene. In certain embodiments, the monomer includes, but is not limited to, 2,4-tolylene diisocyanate (TDI), poly(ethylene imine) (PEI), or poly(methylene[polyphenyl]isocyanate) (PMPPI).

[00204] A number of microcapsules are envisioned in the present invention with differing size and shell thicknesses. For example, thicker walled microcapsules may be obtained by increasing the monomer concentration. In certain embodiments, the diameter of the microcapsule ranges from about 1 micron to about 1000 microns, and the thickness of the polymeric shell ranges from about 1 nanometer to about 100 microns. In certain embodiments the diameter of the microcapsule is from about 1 micron to 900 microns, 1 micron to 800 microns, 1 micron to 700 microns, 1 micron to 600 microns, 1 micron to 500 microns, 1 micron to 300 microns, 1 micron to 200 microns, 1 micron to 100 microns, or 1 micron to 50 microns. In other embodiments, the shell thickness ranges from about 1 nanometer to 50 microns, 1 nanometer to 10 microns, 1 nanometer to 1 micron, 1 nanometer to 0.1 microns, or 1 nanometer to 0.01 microns. Method of Using the Microencapsulated Catalyst

[00205] As described herein, the inventive microcapsule is hollow and encapsulates a catalyst, and, optionally, a polar aprotic, polar protic, or non-polar solution, by its semi-permeable polymeric shell, thereby allowing a reactant to diffuse into the microcapsule and react with the catalyst to provide a product.

[00206] In certain embodiments, the product of the aforementioned reaction may react with a second reactant.

[00207] In certain embodiments, the product of the aforementioned reaction may react with the second reactant within the microcapsule.

[00208] In certain embodiments, the product of the aforementioned reaction may diffuse out of the microcapsule and react with a second reactant. In certain embodiments, this second reactant is not able to diffuse into the microcapsule.

[00209] As is apparent to one skilled in the art, the catalyst encapsulated in the microcapsule may be any reactive moiety, chemical or biological in nature, that can interact with a suitable reactant. The encapsulated catalyst may be covalently conjugated to a polymer to afford a catalyst-polymer conjugate. Suitable catalysts are described herein. For example, the catalyst may be a nucleophile, an electrophile, a base, an acid, a Lewis acid, a

Lewis base, a Brønsted acid, a Brønsted base, an oxidant, or a reductant, or the catalyst may include a metal, a transition metal catalyst, an organometallic catalyst, or an organic small molecule. The encapsulated catalyst may be a biological agent such as an enzyme.

[00210] However, in certain embodiments, the catalyst is not an organic small molecule. In certain embodiments, the catalyst is not a biological agent. In certain embodiments, the catalyst is not an enzyme.

[00211] The presently claimed invention includes a method of using a microcapsule comprising the steps of (1) providing a microcapsule M-I, wherein the microcapsule M-I is hollow, and comprises a semi-permeable polymeric shell encapsulating a catalyst C-I and a first solution S-I; (2) dispersing the microcapsule M-I into a second solution S-2, wherein the solution S-2 comprises a starting material R-I; and (3) allowing the starting material R-I to diffuse into the microcapsule M-I and react with the catalyst C-

1 to afford a first product P-I (Scheme 1). Scheme 1 microcapsule

[00212] In one embodiment, the solution S-2 further comprises a reagent R-2, wherein the reagent R-2 diffuses into the microcapsule M-I, the product P-I reacts with the reagent R-2 to afford a second product P-2, and the product P-2 diffuses out of the microcapsule into the solution S-2 (Scheme 2).

Scheme 2

[00213] In a second embodiment, the solution S-2 further comprises reagents R-2 and R-3, wherein the reagent R-2 diffuses into the microcapsule M-I, the product P-I reacts with the reagent R-2 to afford a second product P-2, the product P-2 diffuses out of the microcapsule into the solution S-2 and reacts with reagent R-3 to afford said third product P-3 (Scheme 3). In certain embodiments, R-3 is a catalyst C-2.

Scheme 3

[00214] In a third embodiment, the solution S-2 further comprises reagents R-2,

R-3, and a catalyst C-2, wherein the reagent R-2 diffuses into the microcapsule M-I, the product P-I reacts with the reagent R-2 to afford a second product P-2, the product P-2 diffuses out of the microcapsule into the solution S-2 and reacts with catalyst C-2 and reagent R-3 to afford said third product P-3 (Scheme 4).

Scheme 4

[00215] In yet other embodiments, the second catalyst C-2 is soluble in the solution S-2. In yet other embodiments, a microcapsule M-2 comprising a semi-permeable polymeric shell encapsulates a catalyst C-2 and a third solution S-3 (Scheme 5). In certain embodiments, the encapsulated catalyst C-2 is soluble in the solution S-3. In still other embodiments, the catalysts C-I and C-2 (encapsulated in microcapsule M-2 or present in solution S-2) are incompatible.

Scheme 5

microcapsule

[00216] One skilled in the art will recognize that there are a variety of permutations that may be involved in the use of these inventive microcapsules as depicted above, and that, for instance, product P-I may diffuse out of a microcapsule M-I and react with a reagent R- 2, or that a product P-2 may diffuse into a second microcapsule M-2 and react with a second catalyst C-2. Additionally, there may be 1 to up to 20 different microcapsules used in a given one-pot multistep reaction. The present invention contemplates such variations on the above principles and embodiments herein.

[00217] For example, in certain embodiments, the present invention provides 2 different microcapsules for a given one-pot multistep reaction. In certain embodiments, the present invention provides 3 different microcapsules for a given one-pot multistep reaction. In certain embodiments, the present invention provides 4 different microcapsules for a given one-pot multistep reaction. In certain embodiments, the present invention provides 5 different microcapsules for a given one-pot multistep reaction.

[00218] In certain embodiments, the first solution S-I and the second solution S-2 are different. In certain embodiments, the second solution S-2 and the third solution S-3 are different. The solutions S-I, S-2, and S-3, independently, comprise a polar aprotic solvent, a polar protic solvent, a non-polar solvent, or a mixture thereof. In certain embodiments, the solution is an organic solvent. In yet other embodiments, the solutions S-I, S-2, and S-3 , independently, comprise an organic alcohol, formamide, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, xylenes, chlorobenzene, chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or a mixture thereof.

[00219] In yet other embodiments, the solutions S-I, S-2, and S-3 each contain less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% water. [00220] In certain embodiments, the solutions S-I or S-3 each comprise a solvent with a dielectric constant greater than or equal to 15. In certain embodiments, the solutions S-I or S-3 each comprise a solvent with a dielectric constant greater than or equal to 20. In certain embodiments, the solutions S-I or S-3 each comprise a solvent with a dielectric constant greater than or equal to 25. In certain embodiments, the dielectric constant of the solvent is between 15 to 160. In certain embodiments, the dielectric constant of the solvent is between 20 to 160. In certain embodiments, the dielectric constant of the solvent is between 25 to 160.

[00221] In certain embodiments, the solutions S-I or S-3 comprise an organic alcohol, for example methanol, ethanol, n-propanol, isopropanol, or t-butanol. In certain embodiments, the solutions S-I or S-3 comprise formamide or dimethylformamide. In certain embodiments, the solution S-I comprises methanol. In certain embodiments, the solution S-3 comprises methanol. [00222] In certain embodiments, the solution S-2 comprises a non-polar solvent, for example, pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, xylenes, chlorobenzene, chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or a mixture thereof. In yet other embodiments, the solution S-2 comprises a solvent with a dielectric constant less than or equal to 5. In certain embodiments, the solution S-2 comprises toluene and/or benzene. In certain embodiments, the solution S-2 comprises cyclohexane.

[00223] As is apparent to one skilled in the art, the catalysts C-I and C-2 may be any moiety, chemical or biological in nature, which can interact with a suitable reactant. For example, the catalysts C-I and C-2 may be, independently, a nucleophile, an electrophile, a base, an acid, a Lewis acid, a Lewis base, a Brønsted acid, a Brønsted base, an oxidant, or a reductant, or the catalyst may include a metal, a transition metal catalyst, an organometallic catalyst, or an organic small molecule. Additionally, the catalysts C-I and C-2 may be, independently, a biological agent such as an enzyme.

[00224] However, in certain embodiments, the catalyst C-I is not an organic small molecule. In certain embodiments, the catalyst C-I is not a biological agent. In certain embodiments, the catalyst C-I is not an enzyme. In certain embodiments, the catalyst C-2 is not an organic small molecule. In certain embodiments, the catalyst C-2 is not a biological agent. In certain embodiments, the catalyst C-2 is not an enzyme.

[00225] In one embodiment, the catalysts C-I or C-2 may a base. In certain embodiments, the catalysts C-I or C-2 may be an organic base. Organic bases envisioned by the presently claimed invention include an amino, alkyl amino, dialkyl amino, trialkyl amino, a heterocyclic, or a heteroaryl group. In certain embodiments, the organic base includes a pyridinyl, dimethylamino pyridinyl, 4-(N-benzyl-N-methyl)-amino pyridinyl, 2,3-dimethyl pyridinyl, 2,4-dimethyl pyridinyl, 3,5-dimethyl pyridinyl, quinuclidinyl, piperazinyl, piperadinyl, pyrrolidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or morpholinyl group.

[00226] In another embodiment, the catalysts C-I or C-2 may be an electrophile.

Electrophiles envisioned by the presently claimed invention include a halo, an activated hydroxyl, acyl, an alkenyl or an alkynyl group.

[00227] In another embodiment, the catalysts C-I or C-2 may be a nucleophile.

Nucleophiles envisioned by the presently claimed invention include an phosphino, phosphinato, phosphazino, azido, amino, heteroaryl, heterocyclyl, thio, isocyano, hydroxyl, alkenyl, or an alkynyl group.

[00228] In certain embodiments, the catalyst C-I encapsulated in the microcapsule

M-I, and/or the catalyst C-2 optionally encapsulated in the microcapsule M-2, may be covalently conjugated to a polymer to afford a catalyst-polymer conjugate, as is described herein.

[00229] An exemplary method of modifying the inventive microcapsules is depicted in Scheme 6 below, and comprises the steps of: (1) providing a microcapsule M-I, wherein the microcapsule M-I is hollow, and comprises a semi-permeable polymeric shell encapsulating a catalyst C-I and a first solution S-I; (2) dispersing the microcapsule M-I into a second solution S-2, wherein the solution S-2 comprises a starting material R-I; and (3) allowing the starting material R-I to diffuse into the microcapsule M-I and react with the catalyst C-I to afford a modified catalyst C-I'. In one embodiment of the above method, the reactive moeity of the catalyst C-I is a nucleophile, and the starting material R-I is an electrophile, or vice versa, and the modified catalyst C-I' is a new catalytic moiety encapsulated by the microcapsule M-I. As such, the inventive microcapsule may be fine- tuned to satisfy certain reactivity requirements.

[00230] A person skilled in the art will recognize the simplicity and attractiveness of such a general method; i.e., rather than having to develop new encapsulation conditions for several different catalyst systems, any catalytic system can be readily available by reacting an appropriately functionalized starting material R-I with an appropriately functionalized catalyst C-I encapsulated in a microcapsule M-I. In certain embodiments, the catalyst C-I is a halide and the starting material R-I is an azide (Scheme 6a). In other embodiments, the catalyst C-I is an alkyne and the starting material R-I is an azide (Scheme 6b). In yet other embodiments, the catalyst C-I is an azide, and the starting material R-I is an alkyne (Scheme 6c). The groups R* and R** attached to the azido or alkynyl functionalities, as depicted above in Scheme 6, may embody a reactive moiety of the new catalyst. The new catalyst may be a different nucleophile, electrophile, base, acid, oxidant, reductant, metal, transition metal catalyst, organometallic catalyst, or small molecule. The new catalyst may be a biological agent such as an enzyme. Scheme 6 microcapsule

moiety

(C)

[00231] Additional exemplary methods of using the inventive microcapsules, as depicted in Schemes 1 to 5, are depicted in Schemes 7 to 9 below, and comprise the steps of:

(1) providing a microcapsule M-I, wherein the microcapsule M-I is hollow, and comprises a semi-permeable polymeric shell encapsulating a catalyst C-I and a first solution S-I; (2) dispersing the microcapsule M-I into a second solution S-2, wherein the solution S-2 comprises a starting material R-I and a reagent R-2; (3) allowing the starting material R-I to diffuse into the microcapsule M-I and react with the catalyst C-I to afford a first product P-I; (4) allowing the reagent R-2 to diffuse into the microcapsule M-I to react with the product P-I to afford a second product P-2, wherein the product P-2 diffuses out of the microcapsule M-I into the solvent S-2.

[00232] In one embodiment of the above method, as depicted in the following scheme (Scheme 7):

Scheme 7 microcapsule

JH

the starting material R-I is R² R³;

.θ

the first product P-I is the conjugate base of R-I : R² A. R³, the reagent R-2 is R LG_? and

the second product P-2 is R²^^R³ ; wherein J is -O-, -N(R^N1)-, or -S-, LG is a suitable leaving group which includes a halo, alkoxy, thioalkoxy, sulfonyloxy, sulfmyloxy, and acyloxy; R^N1, R² and R³ are, independently hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, trialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfinyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; and R⁴ is an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfinyl, sulfonyl, phosphino, phosphinato, phosphazino group.

[00233] In a second embodiment of the above method, as depicted in the following scheme (Scheme 8):

Scheme 8 microcapsule

wherein the starting material R-I is D R5. CH₂ ^Q;

, θ the first product P-I is the conjugate base of R-I: R CHQ, the reagent R-2 is R⁶ CHO, and

the second product P-2

; wherein Q is sulfoxyl, sulfonyl, sulfinyl, acyl, carboxaldehyde, amide, imide, azido, nitro, or cyano; and each occurrence of R⁵ and R⁶ are, independently hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfinyl, sulfonyl, phosphino, phosphinato, or phosphazino group.

[00234] In a third embodiment of the above method, as depicted in the following scheme (Scheme 9), the method further comprises the steps of: (4) allowing the reagent R-2 to diffuse into the microcapsule M-I to react with the product P-I to afford a second product P-2, wherein the product P-2 diffuses out of the microcapsule M-I into the solvent S-2 and reacts with a catalyst C-2 and a reagent R-3 to afford a third product P-3,

Scheme 9

wherein the starting material R-I is D R5. CH₂ ^Q; θ the first product P-I is the conjugate base of R-I: R⁵- -CHQ, the reagent R-2 is R⁶ CHO,

the second product

said reagent R-3 is

and said third product P-3 is

wherein each occurrence of R⁷ is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and Q, R⁵, and R⁶ , are as previously defined. [00235] In certain embodiments, the product P-2 is either

[00236] In certain embodiments, the product P-3 is either:

wherein R⁷ is as previously defined.

[00237] In certain embodiments, catalysts C-I and C-2 are, independently, a base, a Lewis base, a Brønsted base, a metal catalyst, a transition metal catalyst, an organometallic catalyst, an organic small molecule, or an enzyme.

[00238] In certain embodiments, the catalyst C-2 is a metal catalyst. In certain embodiments, the catalyst C-2 is an earth metal, a transition metal, or a a main group metal catalyst. In certain embodiments the catalyst C-2 is a Lewis acid catalyst. [00239] In certain embodiments, the catalyst is a nickel catalyst. In certain embodiments the catalyst C-2 is a nickel (II) catalyst. Exemplary nickel (II) catalysts include [Ni(NR₂)₃]^"; [Ni(CN)₄]^2"; Ni(PPh₃)₂Br₂; [NiCl₄]^2"; NiCl₂(PPh₃)₂; [Ni(NH₃)₆]²⁺; and [Ni(bipy)₃]²⁺. In certain embodiments, the catalyst is a chiral nickel (II) catalyst. Exemplary chiral nickel (II) catalysts include [Ni((S,S)-tBu-BOX))](OTf)₂; [Ni((R,R)- PhDBFOX)](ClO₄)² (3H₂O) (Kanesasa et al. J. Am. Chem. Soc. (1998) 120:3074, 3077); [Ni((R,R)-Ph-B0X)](C104)² ; [Ni((R,R)-Ph-Py-B0X)](C10₄)² ; [Ni((S,S)-Ph-Py- BOX)](ClO₄)² ; BINIM-derived Ni(II) catalysts (Suga et al., Chem Lett (2002) 900); BOX- derived Ni(II) catalysts (Evans et al., J. Am. Chem. Soc. (1999) 121 :7559); trialkylsiloxymethyl-Py-Box-derived Ni(II) catalysts (Iwasa et al., Heterocycles (2000) 52: 939; Iwasa et al, Tetrahedron (2002) 58:227); and Ni(II)-binapthyldiimine catalysts (Bull. Chim. Soc. Jpn. (2003) 76:327). [00240] In certain embodiments, the catalyst C-2 is the chiral nickel (II) catalyst:

[00241] In certain embodiments, the product P-3 is the optically enriched product:

wherein R⁵, R⁶, and R⁷ are as previously defined.

[00242] The presently claimed invention also includes a method of preparing a compound of formula X:

wherein R⁴ is selected from the group consisting of:

R⁷ is an optionally substituted Ci_₆ aliphatic; each occurrence of R⁸ is, independently, an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclic, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino; z is 0 to 5; and each occurrence of R⁹ is, independently, hydrogen, or an optionally substituted aliphatic group; the method comprising the steps of:

(1) providing a solution comprising a microcapsule, nitromethane, a nickel catalyst, and compounds of formula XI and XII:

XI XII wherein the microcapsule is hollow and comprises a catalyst-polymer conjugate encapsulated by a semi-permeable polymeric shell, thereby allowing nitromethane and the compound of formula XII to diffuse into the microcapsule but not allowing the catalyst- polymer conjugate to diffuse out; wherein the polymeric shell and the polymer component of the catalyst-polymer conjugate includes poly(ethyleneimine); and wherein the catalyst component of the catalyst-polymer conjugate is an organic base; and

(2) allowing the microcapsule, nitromethane, the nickel catalyst, and the compounds of formula XI and XII to react under suitable conditions to afford said compound of formula X. [00243] In certain embodiments, R⁴ is any of the following groups:

[00244] In certain embodiments, the nickel catalyst C-2 is the chiral nickel (II) catalyst:

[00245] In certain embodiments, the compound of formula X is the isomer:

(X-I) (X-2)

EXEMPLIFICATION

[00246] The present invention will be more specifically illustrated by the following examples. However, it should be understood that the present invention is not limited by these examples in any manner.

EXAMPLE 1 Microencapsulated Linear Polymers: "Soluble" Heterogeneous Catalysts

[00247] The following provides an example of catalysis using encapsulated linear polymer-catalyst conjugates. This new approach not only provides a more active catalyst than that supported on cross-linked-polystyrene, but allows for simpler tuning. The model reaction investigated is a 4-(Λ/,Λf-dimethylamino)-pyridine (DMAP) catalyzed acylation. This Example shows that catalytic microencapsulated polymers can be optimized with minimal synthetic modification.

[00248] The microencapsulated polymer is synthesized in two steps. The DMAP- modified linear polystyrene (LPSDMAP, 2) is formed by a co-polymerization of a DMAP- modified monomer (1) and styrene (Figure 1). LPSDMAP is then dissolved in chloroform along with poly(methylene[polyphenyl] isocyanate) (PMPPI). This organic phase is then dispersed in an aqueous phase containing poly(vinyl alcohol) as a stabilizer. The interfacial polymerization is initiated with tetraethylenepentamine (TEPA). Once washed and dried, the capsules are isolated as a free-flowing solid (Figures 2A-2D, which depict SEM images of microcapsules containing LPSDMAP made with 5%, 7%, 13% and 17% PMPPI, respectively).

[00249] Acylation of sec-phenethyl alcohol with acetic anhydride in tetrahydrofuran (THF) was used as the test reaction. The converion using the capsules was compared to the conversion of the reaction using dimethylaminopyridine (DMAP), (N- benzyl-N-methyl)-aminopyridine (BMAP), dimethylamino pyridine polystyrene-co- divinylbenzene (PSDMAP), and LPSDMAP (2) (Table 2). As shown in Table 2, the rate of acylation is cut in half between DMAP and its benzyl derivatives (BMAP and LPSDMAP). BMAP' s rate is then decreased by another factor of four when attached to an insoluble support (PSDMAP). The initial microcapsule samples gave rates similar to those for PSDMAP (Table 2).

[00250] The exciting feature of microcapsules is that a number of factors can be changed to create capsules with a desired strength, permeability, or size, without changing the interior polymer. In this case, the optimized rate (Table 2) of the encapsulated DMAP catalyst was achieved by varying the wall thickness of the microcapsules. Wall composition was varied by changing PMPPI concentration in the emulsion. As the amount of PMPPI is increased, the walls grow thicker, which causes the walls to collapse differently. Walls that are thin crumple like paper (Figures 2A and 2B) while thicker walls fold less when dried (Figures 2C and 2D). By varying only the encapsulation procedure, a more active catalyst is created. As seen in Figure 4, the catalytic activity of the capsules increases with decreasing PMPPI concentration. The final catalyst was approximately three times faster than PSDMAP. Table 2. Relative rates of acylation of sec-phenethyl alcohol in the presence of 0.5 mol % catalyst.

a. 17% PMPPI, THF wash. b. 5% PMPPI, no THF wash c. 5% PMPPI, THF wash d. Background k_rei=0.007 The reaction rates were measured using the method of initial rates, e. The THF washing may expose amines in the shell that partially hydrolyze the acetic anhydride.

[00251] Recovered capsules were examined by both light and electron microscopy after each reaction to establish that the capsule walls did not rupture under reaction conditions. Since capsule rupture was not evident, the possibility of polymer diffusion through the wall had to be considered. To test whether the catalyst was leaching from the capsules, the microcapsules were extracted with THF using a Soxhlet apparatus. No significant decrease in catalytic activity was observed. Since THF is an excellent solvent for the entrapped polymer, this data indicates that the linear polymers are too large to diffuse through the capsule shell.

[00252] Since the polymer remains within the capsule throughout the reaction and the PMPPI concentration affects the rate of catalysis, we conclude that reagents, substrates, and products must enter and exit the shell faster than the acylation occurs (Figure 3). Therefore, the rate of the reaction will depend on the rate of the diffusion preequilibria as well as the rate of the DMAP acylation step. As the shell becomes thicker, the diffusion of molecules to the interior slows, causing the overall reaction rate to decrease (Figure 2). The data shows that the shell can be used to tune the encapsulated catalyst.

[00253] In conclusion, it has been demonstrated that catalytic polymers can be encapsulated within microcapsules and that the polymers are retained within the capsules throughout a reaction. It has also been shown that by varying shell thickness the reaction rate is tuned and that with thin, strong walls, the capsules' reaction rate nears that of an unencapsulated polymer. High reactivity is important because increase catalyst loadings fill the reaction vessel with resin, limiting reagent diffusion and mixing.

[00254] General Considerations: Solvents were purified by standard procedures. iSec-Phenethyl alcohol (98%, Aldrich) was used without further purification for the acylation reaction. Triethylamine was purified by sequential treatment with benzoyl chloride and CaH₂, followed by distillation. Acetic anhydride (99.5%, Fluka) was used without further purification. All other reagents were used as received, unless otherwise noted. ¹H NMR spectra were recorded in CDCI₃ on Varian Mercury 300MHz, Inova 400 MHz, and Inova 500 MHz spectrometers operating at 299.763 MHz, 399.780 MHz, and 499.920 MHz, respectively, using residual solvent as the reference. ¹⁹F NMR spectra were recorded in CDCI₃ on a Varian Inova 500 MHz spectrometer operating at 470.338 MHz. Elemental analysis was performed by Robertson Micro lit Laboratories, Inc., in Madison, New Jersey. Gas chromatographic (GC) analyses were carried out on a Varian Model 3800 using a CP-SiI regular phase column (30.0 m x 0.25 mm i.d.). Peak areas were measured using the Varian Star 6.2 software package, and response factors of authentic materials versus mesitylene (internal standard) were calculated for determining 10% conversion. Specific viscosity was measured with a Gilmont GV-2200 falling ball viscometer. Light microscopy was carried out using a Leica DM IL. The microcapsules were imaged by a field emission scanning electron microscope (FESEM, Leo 1550) after sputter coating with palladium-gold at an accelerating voltage of 3.0 kV and a working distance of 4 mm. Micrographs were obtained by secondary electron imaging using a 30/70 signal combination from a side-angle Everhart-Thornley detector and an annular in-lens detector.

[00255] General Acylation Reaction Conditions: All reactions were carried out with sec-phenethyl alcohol, acetic anhydride, DMAP catalyst, triethylamine, and mesitylene in THF at concentrations of 0.323 M, 0.348 M, 0.0018 M, and 0.0346 M, respectively. Reactions were initiated with the addition of acetic anhydride to a solution containing all of the other reagents. When heterogeneous catalysts were used, their volume was not taken into account for the final reaction volume. The insoluble catalysts were weighed into individual reaction vials and diluted in the appropriate volume of stock solution containing: alcohol, triethylamine, mesitylene, and THF. Prior to the reaction, they were allowed to soak/swell for at least 60 minutes to ensure maximum swelling. The reactions containing heterogeneous catalysts were rocked in place of stirring. The reactions were monitored by diluting approximately 10 μL of the reaction mixture in 1.5 mL Of CH₂Cl₂ and analyzing by GC. The dilution appears to serve as an adequate reaction quench. Conversions were calculated as the area of product divided by the sum of product and starting material area. [00256] Representative Encapsulation Procedure: To a 100 mL beaker was added an aqueous solution of poly(vinyl alcohol) (50 mL, 0.5 % w/w in DI H₂O, M_w=89,000-98,000, 99+% hydrolyzed). The organic phase, consisting of CHCl₃ (6.5 mL), poly(methylene(polyphenyl) isocyanate) (1 mL, 1 equiv. isocyanate, 30% incorporation) and PS-DMAP (1) (185.8 mg), was dispersed in the aqueous phase using an IKA Ultra-Turrax T25 homogenizer at 6500 rpm for 2 minutes. The homogenizer tip was removed and a 1" stir bar was added. While stirring, a second aqueous phase consisting of tetraethylenepentamine (34 μL, 0.17 equiv.) in DI H₂O (6.5 mL) was added to the emulsion. The emulsion was stirred overnight. The resulting microcapsules were isolated by centrifugation and washed with DI H₂O (2x 100 mL), EtOH (2x 100 mL), THF (2x 100 mL), and Et₂O (Ix 50 mL). The microcapsules were dispersed in Et₂O (100 mL), transferred to a 250 mL round bottom flask, concentrated by rotary evaporation, and dried under vacuum to yield a free-flowing powder. Characterization was performed using light microscopy (Leica DM IL). [00257] The THF washes were added once it became apparent that small molecule and oligomeric materials were remaining that impact the acylation reaction. Batches made prior to this discovery were washed for > 24 hours in THF and then rewashed in ether and dried.

[00258] Synthesis of 4-(N-methyl-N-vinylbenzylamino)pyridine (1): 4-

(Methylamino)-pyridine (3.72 g, 34.4 mmol) was dissolved in THF (80 mL) and added to dry sodium hydride (1.24 g, 51.6 mmol) in a dry 200 mL round-bottom flask under nitrogen at O⁰C. Upon complete addition, the reaction was allowed to warm to room temperature. After gas evolution ceased (3.5 hours), the reaction flask was cooled to O⁰C and 4- vinylbenzyl chloride, 90% (3.91 mL, 25.0 mmol) in THF (30 mL) was added under nitrogen. The reaction was warmed to room temperature and allowed to react 22 hours. The reaction mixture was filtered and solvent was removed by rotary evaporation. The resulting oil was dissolved in CH₂Cl₂ (50 mL) and washed with water (3 x 40 mL). The organic phase was dried over Na₂SO₄, filtered, and the solvent removed by rotary evaporation. Chromatography on silica was carried out in 1 :5 CH₃OH: CH₂Cl₂ (Rf = 0.24). The product was isolated as a tan solid (5.1 g, 91.1%). ¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd, J= 1.56 Hz, 6.63 Hz, 2H), 7.36 (d, J = 8.19 Hz, 2H), 7.11 (d, J = 8.19 Hz, 2H), 6.66 (dd, J = 10.72 Hz, 28.46 Hz, IH), 6.54 (dd, J = 1.56 Hz, 6.63 Hz, 2H), 5.70 (d, J = 18.52 Hz, IH), 5.22 (d, J= 10.72 Hz, IH), 4.57 (s, 2H), 3.07 (s, 3H). ¹³C NMR (500 MHz, CDCl₃) δ 153.88, 149.43, 136.72, 136.58, 136.21, 126.60, 126.59, 113.91, 106.71, 54.71, 37.80.

[00259] Synthesis of N-benzyl-N-methylaminopyridine: 4-(Methylamino)- pyridine (250 mg, 2.31 mmol) was dissolved in THF (2OmL) and added to dry sodium hydride (80 mg, 3.33 mmol) in a dry 5OmL round-bottom flask under nitrogen at O⁰C. Upon complete addition, the reaction was allowed to warm to room temperature. After gas evolution ceased (3.5 hours), the reaction flask was cooled to O⁰C and benzyl chloride (0.213 mL, 1.85 mL) in THF (10 mL) was added under nitrogen. The reaction was warmed to room temperature and allowed to react 22 hours. The reaction mixture was filtered and solvent was removed by rotary evaporation. The resulting oil was dissolved in CH₂Cl₂ (30 mL) and washed with water (3 x 20 mL). The organic phase was dried over Na₂SO₄, filtered, and the solvent removed by rotary evaporation. Chromatography on silica was carried out in 1 :5 CH₃OH: CH₂Cl₂ (Rf= 0.35). The product was isolated as a white solid (210 mg, 63.6%). ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J = 5.55 Hz, 2H), 7.14-7.36 (m, 5H), 6.65 (d, J = 6.43 Hz, 2H), 4.59 (s, 2H), 3.08 (s, 3H). ¹³C NMR (400 MHz, CDCl₃) δ 154.23, 149.44, 137.10, 128.99, 127.54, 126.54, 106.91, 55.17, 38.00.

[00260] Copolymerization of 4-(N-methyl-N-vinylbenzylamino)pyridine and styrene (2): Compound 1 (2.0 g, 8.9 mmol) was dissolved in styrene (2.05 mL, 17.9 mmol) which had been passed through basic alumina to remove inhibitor. AIBN (12.5 mg, 0.0761 mmol) recrystallized from methanol was added, the solution was sparged with nitrogen for 10 min, sealed, and heated to 8O⁰C for 16 hours. Upon cooling to room temperature the glassy solid was dissolved in CHCl₃ (20 mL) and precipitated into petroleum ether (3x, 1.5 L), yielding a white stringy polymer (2.95 g, 74.6%). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (bs, 2H), 6.49-7.02 (m, J = 8.19 Hz, 15.8H), 4.40 (bs, 2H), 2.96 (bs, 3H), 1.37-1.75 (m, 8.6H). M_v = 201,000 g/mol.

[00261] Soxhlet Extraction of Capsules: 50 mg of capsules from ARB-III-42 were extracted using a Soxhlet apparatus for 24 hours with refluxing THF. The capsules were then washed with ether, to aid in the removal of THF, and dried under vacuum. The dried isolated capsules were then analyzed and found to have an average rate equivalent to 96% of the pre-extracted rate. This rate is well within error of the pre-extraction capsules. [00262] Approximation of Polymer Molecular Weights (M_v): Neither gel permeation chromatography nor MALDI yielded molecular weights for either DMAP- containing polymer, so molecular weights were approximated by measuring the specific viscosities of the polymers in chloroform. The specific viscosity, η_sp, of each polymer was determined at four different concentrations (C_B= 0.0, 0.4, 0.6, and 0.8 g/100mL CHCI3) with falling ball viscometry (24⁰C). Once collected, the specific viscosities were plotted using the Huggins equation,

where the intrinsic viscosity, [η], occurs at the y-intercept. Solving the Mark-Houwink- Sakurada equation for viscosity-average molecular weight, M_v, gives

where K and a are constants for unfunctionalized polystyrene in CHCI3 (K = 1.12x10 , a =

0.73).

[00263] Calculation of Capsule DMAP Loading: The linear polymer (2) DMAP loading was determined on a batch-by-batch basis by ¹H NMR analysis. The maximum DMAP loading was calculated by dividing the molar loading of DMAP by the sum of the weights of polymer and isocyanate. The amine (TEPA) was not included as its mass was relatively small (<5% of isocyanate + polymer). mmol DMAP

= theoretical loading g polymer + g PMPPI

[00264] The loadings assume 100% capture efficiency for the polymer, if polymer is lost during the encapsulation procedure, the loadings will only be lowered. These maximal loadings were determined for each batch of capsules individually to keep the loading of DMAP in the reaction mixtures constant. Table 3. Capsule Batch Analysis

a. Method B - 6.5 mL CHCl₃, 50 mL 0.5% polyvinyl alcohol) solution, 34 μL TEPA b. Two additional THF washes were incorporated prior to treating with ether in the capsule workup. c. Capsules were washed after isolation and drying with THF (x2) and ether followed by a second drying period to remove further small molecule impurities. d. Fluorinated DMAP polymer. e. Exact loadings of Fluorine, determined by EA listed.

EXAMPLE 2 A General Approach to "Soluble" Heterogeneous Catalysts

[00265] Encapsulated catalytic linear polymers have been prepared. When the capsules were swollen the polymeric catalysts bound within remained active and in a solution-like environment. This Example demonstrates direct dependence of rate on the capsule wall thickness, as well as the catalyst's superiority over crosslinked polystyrene support. Differences in the molecular weight and functionality of the polymer-bound catalyst change the nature of the polyurea shell.

[00266] This Example provides a general approach to prepare polyurea capsules containing an alkyne- or azide-functionalized linear polystyrene (Figures 5 and 6A-6B), quantification of a Huisgen reaction on each type of support, and the preparation of a 4- (Λ/,Λf-dimethylamino)-pyridine (DMAP) catalyst for comparison to a commercially available catalyst.

[00267] An azide-functionalized polymer was synthesized by reacting sodium azide with linear poly(styrene-co-chloromethylstyrene), resulting in quantitative displacement of the chloride (Figure 5). The azide survived the encapsulation conditions as indicated by ATR-IR. To determine loading, 4-fluorophenylacetylene was reacted with the microcapsules using the Huisgen reaction. Fluorine elemental analysis showed complete introduction of the labeled acetylene (1.2% F) and ATR-IR revealed total loss of azide signal.

[00268] Encapsulated linear polymer with pendant acetylenes have also been made.

This second system allows azide-containing small molecules and catalysts to be conjugated via the Huisgen reaction (Figure 6A). Functionalization with pentafluorobenzyl azide provided complete consumption of the terminal acetylene as indicated by fluorine elemental analysis (11.4% F).

[00269] The DMAP-catalyzed acylation of sec-phenethyl alcohol was used as an exemplary test reaction. A DMAP analog containing a terminal acetylene was synthesized and clicked into the capsules (Figure 6B). The resulting DMAP-functionalized microcapsules showed complete loss of the azide by ATR-IR. Rate of acylation of sec-phenethyl alcohol was examined using the method of initial rates for the catalyst against the background reaction with the azide-functionalized capsules. The DMAP microcapsules were 260 times more active than prefunctionalized capsules. Notably, the DMAP microcapsules showed a greater rate of reaction than commercially available DMAP on Merrifϊeld resin and the analogous catalyst made by clicking the DMAP analog into an azide-functionalized Merrifϊeld resin (k_rel = 2.1, 1.0, and 1.7, respectively). Presumably, greater rates can be achieved for more optimized swelling of the capsules.

[00270] In conclusion, this Example provides a new and general system for preparing site-isolated polymeric catalysts. Rather than having to develop encapsulation conditions for each new polymer-supported catalyst, any azide- or acetylene-functionalized small molecule or catalyst can be readily attached to an already encapsulated soluble polymer and quickly assayed.

[00271] General Procedure: Solvents were purified by standard procedures.

Triethylamine was purified by sequential treatment with benzoyl chloride, drying over CaH₂, and distillation. All other reagents were used as received, unless otherwise noted. IH NMR spectra were recorded in CDCI₃ on Varian Mercury 300MHz, Inova 400 MHz, and Inova 500 MHz spectrometers operating at 299.763 MHz, 399.780 MHz, and 499.920 MHz, respectively, using residual solvent as the reference. GPC analyses were carried out using a Waters instrument (M515 pump, U6K injector) equipped with a Waters UV486 and Waters 2410 differential refractive index detector and four 5 μm PL Gel columns (Polymer Laboratories; 100 A, 500 A, 1000 A, and Mixed C porosities) in series. The GPC columns were eluted with THF at 40⁰C at 1 mLimin and were calibrated using 23 monodisperse polystyrene standards. ATR-IR was performed on a Nicolet Avatar DTGS 370 infrared spectrometer with Avatar OMNI sampler and OMNIC software. Elemental analysis was performed by Robertson Micro lit Laboratories, Inc., in Madison, New Jersey. Gas chromatographic (GC) analyses were carried out on a Varian Model 3800 using a CP-SiI regular phase column (30.0 m x 0.25 mm i.d.). Peak areas were measured using the Varian Star 6.2 software package, and response factors of authentic materials versus mesitylene (internal standard) were calculated for determining 10% conversion.

[00272] General Acylation Reaction Conditions. All reactions for determining rate were carried out with sec-phenethyl alcohol, acetic anhydride, DMAP catalyst, triethylamine, and mesitylene in THF at concentrations of 0.323 M, 0.348 M, 0.0025 M, and 0.0346 M, respectively. Reactions were initiated with the addition of acetic anhydride to a solution containing all of the other reagents. When heterogeneous catalysts were used, their volume was not taken into account for the final reaction volume. The solid catalysts were weighed into individual reaction vials and diluted in the appropriate volume of stock solution containing alcohol, triethylamine, mesitylene, and THF. Prior to addition of acetic anhydride, the solid catalysts were allowed to soak for at least 1 hour to ensure maximum swelling. The reactions were monitored by diluting approximately 10 μL of the reaction mixture in 2 mL of CH2C12 and analyzing by GC. The dilution appears to serve as an adequate reaction quench. Reactions for conversions were carried out at the same concentrations as above, but with 0.474 M acetic anhydride. Conversions were taken at 20 hours and calculated as the area of product divided by the sum of product and starting material area.

[00273] Copolymerization of 4-vinylbenzyl chloride and styrene (1). 4-

Vinylbenzyl chloride (600 μL, 4.26 mmol) was short-path distilled to remove initiator and combined with styrene (700 μL, 6.54 mmol), which had been passed through basic alumina to remove inhibitor. AIBN (5.9 mg, 0.0359 mmol), recrystallized from methanol, was added, the solution was sparged with nitrogen for 10 min, sealed, and heated to 80⁰C for 16 hours. Upon cooling to room temperature the glassy solid was dissolved in chloroform (15 mL) and precipitated into petroleum ether (2x, 1.5L), yielding a white polymer, 47.8% functionalized with chloromethyl groups by IH NMR (890 mg, 70.2%). IH NMR (300 MHz, CDCl₃) 8 7.065 (bs, 4.7 H), 6.529 (bs, 3.83 H), 4.515 (bs, 2.0 H), 1.394-1.750 (m, 6.28 H). M_n = 95,247 g/mol, M_w = 203,980 g/mol, PDI = 2.25.

[00274] Synthesis of Poly(azidomethylstyrene-co-styrene). Polymer (1) (496 mg) was dissolved in dry dimethylsulfoxide (10 mL) with sodium azide (510 mg, 7.84 mmol) and allowed to stir 16 hours. Water (20 mL) was added, and precipitated polymer was collected by vacuum filtration. The polymer was dissolved in CHC13 (20 mL), dried over Na_zS04, filtered, and precipitated into petroleum ether (1 L). A white polymer resulted (358 mg, 70.4%). IH NMR (300 MHz, CDCh) 8 7.025 (bs, 5.02 H), 6.531 (bs, 3.86 H), 4.221 (bs, 2.0 H), 1.398-1.733 (m, 6.23 H).

[00275] Poly(azidomethylstyrene-co-styrene) Encapsulation Procedure. An aqueous solution of polyvinyl alcohol) (50 mL, 0.5 % w/w in DI H2O, M_w=89,000-98,000, 99+% hydro lyzed) was added to a 100 mL beaker. The organic phase, consisting ofCHCB (6.5 mL), poly(methylene (polyphenyl) isocyanate) (0.33 mL, 1 equiv. isocyanate, 30% incorporation) and poly(azidomethylstyrene-co-styrene) (152 mg), was dispersed in the aqueous phase using an IKA Ultra-Turrax T25 homogenizer at 6500 rpm for 2 minutes. The homogenizer tip was removed and a 1 " stir bar was added. While stirring, a second aqueous phase consisting of tetraethylenepentamine (34 μL, 0.17 equiv.) in DI H2O (6.5 mL) was added to the emulsion. The emulsion was stirred overnight. The resulting microcapsules were isolated by centrifugation and washed with DI H2O (2x 200 mL), ethanol (2x 200 mL), tetrahydrofuran (Ix 20OmL), and diethylether (Ix 200 mL). The microcapsules were dispersed in EtzO (50 mL), transferred to a 100 mL recovery flask, concentrated by rotary evaporation, and dried under vacuum to yield a free-flowing powder. Characterization was performed using light microscopy (Leica DM IL). ATRIR shows azide stretch at 2100 cm-¹. [00276] Synthesis of Prop-2-ynyl-3-(methyl(pyridin-4-yl)amino) propanoate

(2). N-methylamino pyridine (500 mg, 4.6 mmol) and prop argyl acrylate (2.0 mL, 18.1 mmol) were heated to 90⁰C for 2 hours. The residual acrylate was removed by vacuum distillation. The product was purified by column chromatography (silica gel, 10:1 CH2C12/MeOH) to afford a tan solid (653 mg, 65%). IH NMR (400 MHz, CDCl₃) 8 8.19 (d, J = 5.55 Hz, 2H), 7.14-7.36 (m, 5H), 6.65 (d, J = 6.43 Hz, 2H), 4.59 (s, 2H), 3.08 (s, 3H). 13CNMR (400 MHz, CDCH) 8 171.05, 153.22, 149.91, 110.00, 106.93, 75.49, 52.54, 47.29, 37.88, 31.82.

[00277] Functionalization of azide-containing microcapsules with DMAP analog (2). Azidecontaining microcapsules (100 mg, 0.9616 mmollg) were added to a solution of DMAP analog (2) (50 mg, 0.23 mmol), diisopropylethylamine (164 μL, 0.95 mmol), and bromotris(triphenylphosphine) copper (I) (17 mg, 0.018 mmol) in tetrahydrofuran (3mL), and heated to 50⁰C overnight. Microcapsules were isolated by filtration and washed successively with THF (Ix), methanol (Ix), water (Ix), IM HCl (2x), sat. sodium bicarbonate (2x), water (2x), methanol (2x), tetrahydrofuran (2x), and diethyl ether (Ix). The microcapsules were then dried under vacuum to yield a tan, free-flowing solid. ATR-IR showed complete loss of azide stretch at 2100 cm-¹.

[00278] Functionalization of azide-containing microcapsules with l-ethynyl-4- flu oro benzene. Reaction was carried out similarly to the DMAP analog (2) case, except with l-ethynyl-4-fluorobenzene. ATR-IR showed complete loss of azide stretch at 2010 cm-¹. Elemental analysis for fluorine. Calculated: 1.1 % F Found: 1.2% F. [00279] Synthesis of DMAP-functionalized Merrifield resin. Preparation was adapted from Arseniyadis et al (Arseniyadis, S.; Wagner, A.; Mioskowski, C. Tetrahedron Letters 2004, 45, (10), 2251-2253). Merrifield's peptide resin (402 mg, 1.97 mmollg, 1 % divinylbenzene crosslinked, 100-200 mesh) was added to a solution of sodium azide (309 mg, 4.8 mmol), and sodium iodide (15 mg, 0.1 mmol) in dimethylsulfoxide (10 mL) and allowed to stir for 16 hours. The resin was isolated by filtration and washed successively with N₅N- dimethylformamide (2x), water (3x), methanol (Ix), acetone (Ix), tetrahydrofuran (2x), and diethyl ether (Ix). Resin was dried under vacuum. ATR-IR showed strong azide stretch at 2100 cm-¹. Resin was functionalized with DMAP analog (2) as above. Again, A TR - IR showed complete loss of azide stretch.

[00280] Poly(azidomethylstyrene-co-styrene) Encapsulation Procedure. Poly( vinylacetylene) was synthesized and characterized according to Helms et al. (Helms, B.; Mynar, 1. L.; Hawker, C. 1.; Frechet, J. M. J. Journal of the American Chemical Society 2004, 126, (46),15020-15021). MW: 275,000 g/mol PDI = 1.5. Polymer was encapsulated and worked up similarly to above procedure.

[00281] Functionalization of Poly(vinylacetylene)-containing microcapsules with Pentafluorobenzylazide. Pentafluorobenzylazide was prepared according to Demko et al. (Demko, Z. P.; Sharpless, K. B. Angewandte Chemie-International Edition 2002, 41, (12),2110-2113). Huisgen reaction was carried out similarly to the DMAP analog (2) Huisgen reaction, except with pentafluorobenzylazide and poly(vinylacetylene)-containing microcapsules. Elemental analysis for fluorine. Calculated: 11.6% F Found: 11.4% F. [00282] Calculation of Capsule Loading. Loading of functional groups on the soluble polymers was determined by IH NMR analysis. The maximum loading was calculated by dividing the molar loading of functional groups by the sum of the weights of polymer and isocyanate. The amine (TEPA) was not included as its mass was relatively small (<5% of isocyanate + polymer). The loadings assume 100% capture efficiency for the polymer, if polymer is lost during the encapsulation procedure, the loadings will only be lowered. These maximum loadings were determined for each batch of capsules individually to keep the loading of functional groups in the reaction mixtures constant.

Table 4. Relative rates of acylation of sec-phenethyl alcohol in the presence of 0.75 mol

% catalyst.

a. Conversion was taken at 20 hours

EXAMPLE 3 Microcapsule Enabled Multi-Catalyst System

[00283] One-pot multi-step reactions are effective at reducing the waste and cost of a synthetic route because they decrease the number of work-ups and purifications, as well as the volume of solvent used. These reactions are especially useful when multiple catalysts are used so that one traps an unstable intermediate formed by the other. This limitation can be overcome by immobilizing incompatible catalysts on solid supports. Though this strategy has since been used to prevent catalyst interactions, it often results in the loss of catalytic activity and in effect lowers efficiency.

[00284] Recently, one-pot multi-catalyst reactions have been facilitated by site- isolated catalysts that diverge from the traditional solid support paradigm. These Examples show how materials such as sol-gels and star-polymers render incompatible catalysts compatible. However, these reactions are relatively simple and yield the same result when run stepwise. In addition, such successful examples are few and not easily generalized for new catalysts. It is therefore desirable to develop other techniques to site-isolate catalysts for use in one-pot multi-catalyst reactions.

[00285] This Example provides a microencapsulated amine catalyst and demonstrate its utility by applying it to a tandem reaction sequence involving an otherwise incompatible Lewis acid catalyst (Figure 7). The complexity of such reactions is increased by using the second catalyst to trap an intermediate from the first, forming a product that cannot be accessed when the reactions are performed sequentially.

[00286] A tandem amine-Lewis acid system was selected as a model because they are incompatible catalysts without site-isolation, and because this two-catalyst system would be synthetically useful (Figure 8A). A brief screen of the literature suggested that the focus be on nitroalkene formation as half of the tandem reaction sequence. This amine-catalyzed reaction often produces a mixture of nitroalkene and dinitro products, the latter being the result of a second addition of nitroalkane. The Lewis acid chosen for this role is the nickel- based Michael catalyst (2) reported to convert nitroalkenes to the corresponding Michael adduct in high yields (Evans et al, J. Am. Chem. Soc. 2005, 127, 9958-9959). [00287] A screening of a variety of commercially available amine-based catalysts for the reaction between benzaldehyde (3) and nitromethane demonstrated that small, soluble amines were found to catalyze the reaction, producing both trans-/?-nitrostyrene (4) and 1 ,3- dinitro-2-phenyl-propane (5), but when used in tandem with the nickel-based Michael catalyst 2 and dimethyl malonate (DMM), the two catalysts complexed and precipitated (Figure 8B). On the other hand, amine catalysts attached to solid supports such as MCM-41 or polystyrene beads showed no activity toward nitroalkene formation under room temperature conditions suitable for catalyst 2 (Cat. 2). Rather, they required elevated temperatures between 60 and 90 ⁰C to achieve nitroalkene formation.

[00288] Encapsulation of the polymeric amine poly(ethyleneimine) (PEI) helped to address the compatibility and activity problems. The encapsulted catalyst was prepared by dispersing a methanolic PEI solution into a non-polar cyclohexane phase with the help of a stabilizer. Upon emulsifϊcation, 2,4-tolylene diisocyanate (TDI) was added to the continuous phase to initiate cross-linking that occurs only at the interface of the emulsion droplets between TDI and PEL After polymerization, microcapsules containing PEI chains were isolated for use in a reaction after drying. [00289] The new encapsulated (μcap) amine (Cat. 1) was tested as a catalyst for nitroalkene formation. In this experiment, the μcaps were swollen with methanol for five minutes before the remaining reagents were added. The reaction was performed at room temperature and reaction progress was monitored by GC. Like the free amines, the μcap catalyst produces both 4 and 5 (Figure 8B). The retention of catalyst's (1) activity as compared to the traditionally solid-supported amines is due to the unique microenvironment that the capsules possess. A second phenomenon we observed is that the PEI-capsule walls capture intermediate 4 in an irreversible Michael-type addition, resulting in lowered reaction yields.

[00290] The two undesired side reactions of 4 described above presented the opportunity to exploit a one-pot multi-step reaction to its fullest potential: by adding a second catalyst to the system, it was hoped that the transient nitroalkene intermediate would be trapped and directed toward the desired Michael adduct. The tandem reaction was carried out by first swelling the encapsulated amine catalyst in methanol for five minutes and then suspended in toluene. The remaining catalyst and reagents were added and reaction progress was monitored by GC. Initial formation of nitroalkene intermediate was followed by its conversion to the desired Michael adduct (6) rather than undesired 5 (Figure 8B). The Michael adduct was formed in 80% yield after 24 hours. It should be noted that 6 is not formed if only one of the catalysts is present or if the reactions are performed sequentially, as it was demonstrated above that the first reaction alone resulted in two unproductive situations. This series of reactions is performed efficiently only when the catalysts are site- isolated and the reactions are run in one pot (Table 5).

Table 5. Conversion of 3 and yield of 6 after 24 hours.

aYields were determined by GC areas. For cases in which the product was isolated, isolated yields agree with GC yields. [00291] As evidence for catalyst site-isolation, it was investigated whether commercially available unencapsulated PEI could replace the encapsulated catalyst. It was found that the two catalysts (PEI and 2) produce the Michael adduct in only 5.4% yield (Table 5). Based on literature precedence, it is suggested that free PEI strongly chelates nickel (Ni), making it inactive. In addition, by monitoring UV- Vis absorbance of 2 in the presence and in the absence of μcaps, it was determined that the poisoning of 2 occurs only to a small extent. Finally, the rate of the Michael addition between 4 and dimethyl malonate by 2 was found to be enhanced rather than diminished by the presence of μcaps. This phenomenon has been attributed to the activation of 4 by urea groups on the surface of the μcaps. Furthermore, the yield of this reaction is the same as that of the control (no μcaps), suggesting that 2 is not degraded by the PEI and therefore that the Ni and the catalytic amines do not interact. It is concluded based on these results that microencapsulation provides effective site-isolation, preventing catalyst fouling.

[00292] This Example demonstrates the potential for and subsequent development of an active, site-isolated amine catalyst. This encapsulation method results in a catalytically active species that remains site-isolated during a one-pot multi-step reaction, allowing it to be used in tandem with an otherwise incompatible catalyst. This Example demonstrates the capabilities of tandem catalysis to trap and direct reaction intermediates efficiently. The Michael adduct formed by this reaction sequence can be used to access pharmaceutical agents such as baclofen, rolipram, and pregabalin, as well as other gamma-amino acid analogs. [00293] Materials and instrumentation. Dimethyl malonate (Acros, 97%), trifluoroacetic anhyhdride (Acros, 99+%), (±)-trans-l,2diaminocyclohexane (Aldrich, 98%), mesitylene (Aldrich, 98%), trans— nitrostyrene (Aldrich, 99%), polyisobutylene (Aldrich, MW 400, 000), tolylene 2,4-diisocyanate (Aldrich, technical grade, 80%), chloroform (1. T. Baker), nitromethane (1. T. Baker, 99%), acetic anhydride (Mallinckrodt), cyclOhexane (Mallinckrodt), methanol (Mallinckrodt), toluene (Mallinckrodt), poly(ethyleneimine) (Polysciences, Inc., 10,000 MW), and Span 85 (Sigma) were used as received. Benzaldehyde (Aldrich, 99.5%) was washed with saturated NaHC03, distilled, and dried over Na₂S04 prior to use.

[00294] Reactions were rocked on a Thermolyne Speci-Mix test tube rocker.

[00295] For ¹⁹F elemental analysis, microcapsulesacylated with trifluoroacetic anhydride were sent to Robertson Microlit Laboratories for analysis (www.robertson- microlit.com). [00296] Gas chromatographic (GC) analyses were performed using a Varian CP-

3800 GC equipped with a Varian CP-8400 autosampler, a flame ionization detector (FID) and a Varian CP-SiI 5CB column (length = 15 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm. The temperature program for GC analysis held the temperature constant at 80⁰C, heated samples from 80 to 200⁰C at 17°C/min, and held at 200⁰C for 2 min. Inlet and detector temperatures were set constant at 220 and 250 ⁰C, respectively. Mesitylene was used as an internal standard to calculate reaction conversion.

[00297] ¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova-400 (400

MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCH at 7.26 ppm). Data are reported as s = singlet, d = doublet, t = triplet, quin = quintet, m = multiplet; coupling constant( s) in Hz.

[00298] Scanning electron microscopy images were obtained on a Leica 440 SEM at the Cornell Center for Materials Research. Capsules were characterized at 25 kV after sputter coating with palladium-gold.

[00299] Synthesis of microencapsulated poly(ethyleneimine) catalyst. The microcapsule catalyst was prepared by interfacial polymerization of oil-in-oil emulsions, in a slightly different manner than what was described by Kobaslija and McQuade (Kobaslija, M.; McQuade, D. T. Macromolecules (2006) 39:6371-6375). To cyclohexane (50 mL, 11 = 9.5 cp) and Span 85 mixture (2% v/v) stirred at 1500 rpm with a magnetic stirrer, the disperse phase (0.15 g/mL PEl in 6.0 mL methanol and 1.5 mL chloroform) was added at once. After 2 minutes of stirring, 2,4-tolylene diisocyanate (TDI, 1.0 mL in 9.0 mL cyclohexane) was added at once and the stirring was reduced to 500 rpm. After 1 minute, polymerization was stopped by the addition of cyclohexane (30 mL). The resulting capsules were left to settle, further washed with hexanes, and left to air-dry overnight.

[00300] Catalyst Loading. Loading of the microcapsule catalyst active sites was determined via labeling with fluorine and a subsequent fluorine elemental analysis. To microcapsule catalyst (100 mg), loaded in a syringe equipped with a frit, methanol (5 mL) was added to swell them. After 5 minutes the excess methanol was removed and the solution containing trifluoroacetic anhydride (1 mL) in methanol (5 mL) was drawn into the syringe. The mixture was rocked at room temperature overnight. Fluorine labeled microcapsule catalysts were extensively washed with methanol, dried under stream of N₂ and sent for fluorine elemental analysis. To ensure that all the active site were acylated, the microcapsules were checked for the activity in nitro-aldol reaction. As expected for fully acylated microcapsules, they have shown no activity. Results of fluorine elemental analysis suggest that the loading of the catalytically active sites is 4.7 mmol/g.

[00301] Synthesis of nickel-based Michael addition catalyst. The catalyst was prepared in accordance with the preparation described by Seidel and Evans using (± )-trans-l

,2-diaminocyclohexane (Evans, D. A.; Seidel, D. J. Am. Chem. Soc. (2005) 127:9958-9959).

[00302] Catalytic studies general procedure: Microencapsulated PEl catalyst 1 was swollen in methanol before use. Catalyst(s), benzaldehyde (101.6 μL, 1 mmol), nitromethane (0.54 mL, 10 mmol), dimethyl malonate (114.3 μL, 1 mmol), methanol (0.5 mL), toluene (1 mL), and mesitylene (13.9 μL) were placed in a 4 mL glass vessel and sealed with a screw cap. The reaction was rocked at room temperature on a rocker. Reaction conversion was monitored by withdrawing aliquots from the reaction at different time intervals, diluting with methylene chloride, and analyzing by GC with reference to mesitylene.

[00303] One-pot Henry-elimination-Michael reaction, tandem catalysis. PEI catalyst (15 mg) and nickel catalyst 2 (60 mg, 7.4 mol %) were used in the reaction described above.

[00304] One-pot Henry-elimination-Michael reaction, PEI catalyst only. PEI catalyst 1 (15 mg) was used in the reaction described above.

[00305] One-pot Henry-elimination-Michael reaction, nickel catalyst 2 only.

Nickel catalyst 2 (60 mg, 7.4 mol %) was used in the reaction described above.

[00306] One-pot Henry-elimination-Michael reaction using free PEl and nickel catalyst 2. PEl (10,000 MW, 25 mg) and nickel catalyst 2 (60 mg, 7.4 mol %) were used in the reaction described above.

[00307] In order to account for the lost material in cases where conversion of benzaldehyde was not quantitative we did a trans-nitrostyrene (4) binding experiment to the microcapsules. Based on literature reports of nitroalkenes reacting in a Michael-type reaction with primary and secondary amines, it was hypothesized that the microcapsules were removing nitro styrene from the reaction mixture in a similar fashion (Bernasconi, et al. J.

Am. Chem. Soc. (1986) 108:4541- 4549; Lough and Currie, Can. J Chem. (1966) 44:1563-

1569; Mouhtaram, et al. Tetrahedron (1993) 49:1391-1400; Worrall, J. Am. Chem. Soc.

(1927) 49:1598-1605). Briefly, microcapsules (30 mg) swollen in methanol (0.1 mL) were dispersed in toluene (0.5 mL) and trans-nitrostyrene, 4 (150 mg, 1 mmol) was added to the mixture followed by mesitylene (13.7 μL, internal standard). Nitrostyrene concentration was followed over time with GC.

[00308] trans-Nitrostyrene (4). The product can be commercially obtained from

Aldrich for comparison purposes. ¹HNMR(400 MHz, CDCh) b 7.90 (d,J= 13.65 Hz, IH), 7.53 (d,J= 13.65 Hz, IH), 7.48-7.35 (m, 5H); 13C NMR (400 MHz, CDCh) b 139.1,137.1,132.2,130.1, 129.4, 129.3.

[00309] l,3-dinitro-2-phenyl-propane (5). The product can be purified by column chromatography (20%EtOAc/hexanes) to give a brown oil. ¹H NMR (400 MHz, CDCh) b 7.36-7.29 (m, 3H), 7.2-7.17 (m, 2H), 4.76-4.65 (m, 4H), 4.3-4.22 (quin, J= 7.21 Hz, IH); 13C NMR (400 MHz, CDCh) b 134.5, 129.7, 129.2, 127.6, 76.9,41.9. [00310] Methyl-2-carboxymethoxy-4-nitro-3-phenyl-butyrate (6). The product can be purified by column chromatography (20% EtOAc/hexanes) to give a white solid. ¹H NMR (400 MHz, CDCh) b 7.33-7.26 (m, 3H), 7.24-7.21 (m, 3H), 4.95-4.84 (m, 2H), 4.24 (dt, J= 5.1 Hz, 9.0 Hz, IH), 3.86 (d, J= 9.16, IH), 3.75 (s, IH), 3.54 (s, IH); ¹³C NMR (400 MHz, CDCh) b 168.1, 167.5,136.4, 129.3, 128.7, 128.1,77.6,54.9,53.3,53.1,43.2. [00311] As it can be seen from the Figure 9, trans-nitrostyrene (4) is removed from the reaction mixture with microcapsules through an unproductive pathway. This is avoided if nitro styrene is promptly directed to the Michael adduct (6) with the second catalyst (2). [00312] Evidence for catalyst site-isolation: UV- Vis studies. In order to quantify how much of the nickel catalyst (2) is being degraded by μcap catalyst (1), UV-Vis absorbance of the nickel catalyst was monitored over time in the presence and in the absence of the microcapsules. To nickel catalyst (2,60 mg), dissolved in toluene (1 mL), μcap catalyst (1, 15 mg) slurry in methanol (0.5 mL) was added. Absorbance at 394 and 656 nm was followed over time. The control experiment consisted of measuring absorbance at the same wavelengths of the nickel catalyst solution without the μcap catalyst present. Percent nickel catalyst was normalized to the relative absorbance at time zero. Percentages were averaged over the two wavelengths. Results, shown in the Figure 10, suggest that the microcapsules degrade nearly 20% of the initial nickel catalyst within 40 hours. On the other hand, the control also shows 10% degradation. Therefore, μcap catalyst is responsible of less than 10% degradation of the nickel catalyst during the course of the one pot reaction. [00313] Qualitative assessment of nickel catalyst interaction with microcapsules and free PEL To nickel catalyst (2,60 mg) dissolved in toluene (1 mL), either microencapsulated catalyst (1,30 mg) or, as a control, free PEl (30 mg) was added. Color change (green to purple) was captured with a digital camera.

[00314] Michael addition in the presence and absence of microencapsulated PEl

(1). The Michael addition between trans-nitrostyrene (4) and dimethyl malonate was performed in the presence and absence of microencapsulated PEI (1) in order to determine if the presence of the microcapsules decreases the catalytic activity of the nickel catalyst (2). In order to prevent the binding of trans-nitrostyrene to the microcapsules, the primary amines of the microcapsules were acylated with acetic anhydride (acylation with acetic anhydride was done in the same manner as with trifluoroacetic anhydride described in the section Catalyst Loading above). The Michael additions were performed as followed: to either a vial containing 30 mg acylated microcapsules swollen in 0.5 mL MeOH, a vial containing 30 mg of untreated microcapsules swollen in 0.5 mL MeOH, or a vial containing 0.5 mL MeOH was added trans-nitrostyrene (4) (149.2 mg, 1 mmol), nickel catalyst 2 (16.2 mg, 2.0 mol%), and toluene (1 mL). The vial was sealed with a screw cap and he reaction was rocked at room temperature on a rocker. Reaction conversion was monitored by withdrawing aliquots from the reaction at different time intervals, diluting with methylene chloride, and analyzing by GC with reference to mesitylene (Figure 11).

[00315] It can be seen that in both case where mcaps are present (A and B), there is an initial rate enhancement compared to the control (C). This enhancement is attributed to the urea groups on the surface of the caps, which have been shown to promote Michael addition catalysis (Hamza, A.; Schubert, G.; Soos, T.; Papai, 1. J. Am. Chem. Soc. (2006) 128:13151-13160). The reaction with acylated mcaps (A) maintains this rate enhancement throughout the entire reaction while the reaction with untreated mcaps levels off after 60% conversion. This is due to (4) binding irreversivly to the mcaps and being rendered unavailable for conversion to 6. This effect can be corrected for by reporting the normalized yeild of 6: (moles of 6)/(moles of 4 + moles of 6).

[00316] When the results for the untreated microcapsules are corrected, it can be seen that acylated (A) and untreated (B) microcapsules demonstrate similar rate enhancement. More importantly, μcap presence does not decrease the overall yield, as all three cases remain stable at 90% yield of 6 past the 10 hour point. If the nickel catalyst were able to interact with the encapsulated PEl, one would expect to see a dramatic decrease in yield of 6, as is observed in the control experiments. Negligible (0-5%) yield of 6 is obtained in control experiments employing microcapsules alone, microcapsules in the presence of PEl, or no catalyst.

EXAMPLE 4 Polyurea Microcapsules From Oil-in-oil Emulsions via Interfacial Polymerization

[00317] Example 4 demonstrates the preparation of polyurea microcapsules templated by oil-in-oil emulsions. Microcapsules prepared via interfacial polymerization are used to encapsulate a variety of materials including adhesives, agrochemicals, live cells, enzymes, flavors, fragrances, drugs, and dyes. Microcapsules are usually templated by either water-in-oil or oil-in-water emulsions. The composition of the emulsion dictates both the type of material that may be encapsulated and the capsule wall properties. Since most emulsions consist of water and a non-polar organic solvent, the material to be entrapped must be either soluble in water or a non-polar solvent. This strict solubility profile limits the types and/or amounts of materials that can be encapsulated. An alternative protocol that enables the encapsulation of materials soluble in polar organics is a desirable advance. The use of oil-in-oil emulsions is an alternative to classical approaches. In this Example, polar protic or polar aprotic solvent-in-cyclohexane emulsions are used to template the formation of polyurea microcapsules and demonstrate control over capsule size.

[00318] The polar organic solvents chosen were those that could both disperse in cyclohexane and dissolve the polyamine monomer (polyethyleneimine, PEI) used to create the polyurea shell. Methanol, Λ/,N-dimethylformamide (DMF), and formamide met both of these criteria. In all of these cases, the polar organic disperse phase contained PEI and the cyclohexane continuous phase contained polyisobutylene as a polymeric stabilizer. These emulsions were short-lived and would break within minutes if left standing, but could be captured via interfacial polymerization upon addition of 2,4-tolylene diisocyanate (TDI) to the continuous phase with constant stirring (Figure 12). The obtained polyurea microcapsules had smooth shells and displayed similar coefficients of variation of 20-30% (Figures 13 A-13B). In addition to smooth shells, the capsules show the ability to undergo shrinking and swelling reversibly depending on the osmotic pressure. Figure 13A (and Figures 13D, expanded view) is an optical micrograph of crenated (shrunken) capsules in hexanes. Figure 13B (and Figure 13C, expanded view) shows the same capsules swollen in methanol. This shrinking and swelling behavior is a common trait of flexible walled microcapsules. [00319] One application of this new interfacial polymerization method is the encapsulation of water-insoluble molecules. As a demonstration, coumarin-1 (C-I) dye was encapsulated. C-I is soluble in methanol, DMF, chloroform, and dimethylsulfoxide (DMSO), but only sparingly soluble in water and non-polar solvents such as cyclohexane. Utilization of classical water-in-oil systems would prohibit high loading due to the solubility limitations. Use of an oil-in-water system (chloroform-in-water) or our oil-in-oil system (methanol-in-cyclohexane) provides a solution for high loading needs. The methanol-in- cyclohexane system provides an excellent alternative to chloroform-in-water, because chlorinated solvents are problematic due to environmental, cost, and safety concerns. Without optimization, C-I was encapsulated in a methanol-in-cyclohexane system with 63.0+1.0% encapsulation efficiency and a dye loading of 18.2+0.3% (w/w) after drying the capsules. These C-I loaded capsules did not show evidence of 'burst' kinetics (initial rapid release of the active molecule) when exposed to water. "Burst" kinetics hamper controlled release systems, especially in cases where the encapsulant is a polar hydrophobic molecule. Successful and efficient encapsulation of C-I suggests that the oil-in-oil approach is very effective relative to classical systems.

[00320] Next was examined the solubility of methanol, DMF, and formamide in cyclohexane, as capsule formation is strongly dependent on the partition coefficient of the disperse and continuous phase. ¹H NMR spectra of the cyclohexane layer after a 2-minute emulsification revealed that methanol and DMF were present in 11% and 8% respectively (+1% based on ¹³C satellites) in cyclohexane (Figure 14). Formamide and water were below the spectrometer detection limit of 1%. These observations may explain why methanol- and DMF-in-cyclohexane templated microcapsules exhibit thicker shells compared to formamide-in-cyclohexane.

[00321] The formation of capsules (hollow microspheres), as evident from confocal and SEM images, supports our hypothesis that the polymerization takes place only at the interface of the emulsion droplets. A mechanism was considered in which diisocyanate diffused fully into the PEI-rich region, rendering the reaction a solution polymerization in one phase. This scenario was dismissed for multiple reasons. Capsules, apparent from microscopy images, would not form in a solution polymerization in one phase; rather, solid spheres would form. The fact that these particles crenate and swell in polar solvent suggests that interfacial polymerization takes place, yielding thin-shelled capsules. Even though TDI can be mixed with methanol for a short time (one minute) before they visibly react to form urethane, the reaction of PEI with TDI is very fast (less than a second). Thus, TDI cannot reach inside of the polyamine-rich emulsion droplet before it reacts with PEI on the periphery of the droplet. These interfacialy formed polyurea cross-links would slow the inward diffusion of TDI further. In addition, the hypothesis was further tested by performing a homogeneous TDI/PEI polymerization in chloroform/methanol mixture under the same stirring conditions as those when cyclohexane is present. When the TDI was added to a stirred PEI solution in chloroform/methanol, it was found that a solid mass of polymer instantly formed. The fact that the homogeneous case provides no capsules and that we can observe an emulsion prior to polymerization in the case of the cyclohexane/methanol system, we feel that the best explanation for the formation of capsules is an interfacial polymerization taking place at the cyclohexane-methanol interface.

[00322] Surprisingly, the size of the capsules in the DMF or methanol-in- cyclohexane emulsions could not be controlled by stirring speed alone, as is the case in classical emulsions and in the formamide-in-cyclohexane system. In order to ascertain the factors that influence the size of microcapsules, the methanol-in-cyclohexane system was studied in more detail.

[00323] It was postulated that factors such as stirring speed, concentration of PEI and TDI monomers, viscosity of the phases, and the volume ratio of the phases would influence capsule size. In order to get a more comprehensive understanding of how these factors influence the capsule diameter, it was decided to use the engineering method known as Design of Experiments (DOE).

[00324] DOE is a systematic optimization technique in which changes of an observable property, such as capsule size, are monitored as a function of the input variables, such as monomer concentration or stirring rate. This statistical technique enables understanding of how the input variables affect the system in a minimum number of experiments. This technique is powerful because both the effect of each individual variable as well as the interactions between the variables are extracted by changing multiple variables during each experiment. This way, optimization of the property of interest can be achieved. "Changing one variable at a time" is not a good method of investigation because the parameters are rarely independent of each other. A five variable (2-level 2^^5~^) fractional factorial DOE was selected and a total of 16 experimental runs were designed with Design- Expert^®, a DOE program, to examine the influence of the selected variables on the capsule diameter. [00325] From the DOE analysis a response surface model was developed that relates capsule diameter to the tested variables (Figure 15). All of the variables chosen were important for controlling capsule size except for the concentration of diisocyanate monomer. It is interesting to note that the concentration of polyamine monomer has a significant effect. It was hypothesize that PEI acts as an emulsifier.

[00326] The DOE analysis also revealed that two sets of variables depend on each other: (1) the viscosity of the continuous phase and concentration of PEI (Figure 16A) and (2) the stirring speed and disperse-phase volume (Figure 16B). A one variable at a time approach would not have revealed to us that these variables are coupled to each other. It was hypothesized that the viscosity of continuous phase and PEI concentration are coupled because the shear forces responsible for droplet break-up are dependent on the ratio of continuous phase viscosity to disperse phase viscosity. In this case PEI concentration is proportional to disperse phase viscosity. Stirring speed/disperse-phase volume interaction can be explained through shear field argument. As the volume increases a low shear region far away from the stir bar increases and droplets overall feel a smaller shear field. It is clear that the DOE approach is powerful not only because provides new information that a one variable at a time approach cannot obtain, but because it also allows one to map out the conditions to achieve a desired capsule size.

[00327] Figure 15 shows a response surface that correlates capsule size with the two interacting variables (viscosity of the continuous phase and concentration of PEI) when the other variables are held constant. To validate the ability of the model to predict capsule diameter, three different conditions were picked that were not run in the DOE trials. The capsule sizes observed experimentally compared well to the capsule sizes predicted by the model (Table 6). These results suggest that the DOE model is a reliable indicator of capsule size dependence on the tested variables.

Table 6. Comparison of capsule size predicted by the DOE model with the actual size of three different formulations.

a Detailed description of the three formulations can be found within experimental details. b Confocal images were used to determine average capsule diameter. [00328] In conclusion, this Example shows that oil-in-oil emulsions serve as effective templates for creating polyurea microcapsules. This encapsulation procedure can be applied to encapsulate materials that are not soluble in classical water-in-oil or oil-in-water emulsions. This Example also demonstrates that a simple DOE effectively not only creates a model to control capsule size, but provides valuable information regarding the variables that effect capsule size. In this case, the DOE was used to model capsule size, but the DOE analysis could be extended to include factors such as wall thickness, porosity, or release characteristics. Encapsulation of various compounds used in the adhesive, agrochemical, flavor, fragrance, drug, and dye industries could utilize a similar rationale in cases where the classical systems are hampered.

[00329] Materials. Unless otherwise specified, materials were obtained from commercial suppliers and used without further purification. DMF was purified using standard procedure. Coumarin-1 dye was a generous gift from Prof. Alan Taylor, New York State Agricultural Experimental Station, Cornell University. Use of Span 85 as an emulsifϊer was based purely on empirical data after many other emulsifϊers were tried. Possible interference from 'surface active impurities' was considered. However, upon making capsules from materials obtained from several different suppliers and not seeing any change in capsule morphology, it was hypothesized that any surface active impurity influence, if present, would be masked by the Span 85 emulsifϊer.

[00330] Equipment, characterization, and methods. A. Viscosities were measured with a Gilmont dropping ball viscometer. B. Scaning electron microscopy images were obtained on a Leica 440 SEM at the Cornell Center for Materials Research. Capsules were characterized at 25kV after sputter coating with palladium-gold. C. Confocal microscopy was performed on a Leica TCS SP2 Spectral Confocal Microscope System at Cornell's Microscopy, Imaging & Fluorimetry Facility. Capsules prepared with fluorescently labeled PEI were swelled and dispersed in methanol and then in water. Water dispersion was applied to the microscope slide and the capsules were analyzed using provided Leica software. D. For non-confocal images, inverted Leica DMIL was used with a mounted Sony DSC-F717 digital camera and ebqlOO UV source. An emulsion of polar solvent-in- cyclohexane with rhodamine as an encapsulant was placed onto the microscope slide. For coumarin-1 burst kinetics assay dry capsules were placed onto the microscope slide and incubated with either water or methanol. The capsules were then examined for burst kinetics. E. Electronic absorption (UV) spectra were recorded on a Cary 50 Bio UV/Vis spectrometer. Capsules loaded with coumarin-1 dye were swollen in methanol for 5 minutes. The methanol supernatant was then examined for coumarin-1 concentration. Absolute loading of dye per gram of dry capsules was then back calculated. Loading efficiency was calculated as the actual loading over theoretical loading in percent. F. DOE analysis was done using Design-Expert 7 software by Stat-Ease. Average capsule size obtained via confocal microscopy was used as the input, and the variables were examined for significance and interaction. The software built a model for capsule size dependence on five tested variables. This model was used to predict capsule size of three different formulations tested. G. Image J software (NIH, http://rsb.info.nih.gov/ij/) was used to measure perimeters (px) of capsules produced in three tested formulations. Using Microsoft Excel^®, perimeters were converted to diameters (μm) and the mean size and standard deviation were calculated. [00331] General procedure for microcapsule preparation from oil-in-oil emulsions. To cyclohexane (15 ml, viscosity modified with polyisobutylene) and Span 85 mixture (2% v/v) stirred with a magnetic stirrer, the disperse phase was added at once. After 2 minutes of stirring, 2,4-tolylene diisocyanate (TDI, in cyclohexane) was added at once and the stirring was reduced to 500 rpm. After 10 minutes, polymerization was stopped by the addition of cyclohexane (30 mL). The resulting capsules were left to settle, further washed with hexanes, and finally vacuum dried.

[00332] Microcapsule preparation from DMF-in-oil emulsion. To cyclohexane

(15 ml, η= 9.5 cp) and Span 85 mixture (2% v/v) stirred at 1500 rpm with a magnetic stirrer, the disperse phase (0.3 g/mL PEI in 3 mL DMF) was added at once. After 2 minutes of stirring, 2,4-tolylene diisocyanate (TDI, 0.1 mL, in 2.9 mL cyclohexane) was added at once and the stirring was reduced to 500 rpm. After 10 minutes, polymerization was stopped by the addition of cyclohexane (30 mL). The resulting capsules were left to settle, further washed with hexanes, and finally vacuum dried.

[00333] Microcapsule preparation from formamide-in-oil emulsion. To cyclohexane (15 ml, η= 9.5 cp) and Span 85 mixture (2% v/v) stirred at 1500 rpm with a magnetic stirrer, the disperse phase (0.3 g/mL PEI in 3 mL formamide) was added at once. After 2 minutes of stirring, 2,4-tolylene diisocyanate (TDI, 0.1 mL, in 2.9 mL cyclohexane) was added at once and the stirring was reduced to 500 rpm. After 10 minutes, polymerization was stopped by the addition of cyclohexane (30 mL). The resulting capsules were left to settle, further washed with hexanes, and finally vacuum dried. [00334] Microcapsule preparation from methanol-in-oil emulsion. To cyclohexane (15 ml, viscosity at low [-1] level and high [+1] level) and Span 85 mixture (2% v/v) stirred (at low [-1] level and high [+1] level) with a magnetic stirrer, the disperse phase (at low [-1] level and high [+1] level for PEI concentration, at low [-1] level and high [+1] level for volume of the disperse phase) was added at once. After 2 minutes of stirring, 2,4- tolylene diisocyanate (at low [-1] level and high [+1] level for TDI concentration in cyclohexane-total volume 3 mL) was added at once and the stirring was reduced to 500 rpm. After 10 minutes polymerization was stopped by addition of cyclohexane (30 mL). The resulting capsules were left to settle, further washed with hexanes, and finally vacuum dried. [00335] PEI labeling with FITC. Polyethyleneimine (PEI, 99%, MW 10000, 53.0 g) was stirred with fluoresceine isothiocyanate isomer I (FITC, 0.132 g, 0.3 mmol) in methanol (400 mL) overnight at room temperature. Methanol was evaporated in vacuo and the residue dissolved in a minimal amount of water (about 10 mL). The solution was dialyzed against deionized water for 2 days while contained within a SnakeSkin^® dialysis bag (Pierce, 34 mm dry flat width, 3.7 mL/cm, MWCO 3500) or until no more color leached out. The remaining residue was lyophilized overnight and used as is.

[00336] PEI labeling with lissamine rhodamine. Polyethyleneimine (PEI, 99%,

MW 10000, 53.0 g) was stirred with lissamine rhodamine B sulfonyl chloride (0.185 g, 0.3 mmol) in methanol (400 mL) overnight at room temperature. Methanol was evaporated in vacuo and the residue dissolved in a minimal amount of water (about 10 mL). The solution was dialyzed against deionized water for 2 days while contained within a SnakeSkin^® dialysis bag (Pierce, 34 mm dry flat width, 3.7 mL/cm, MWCO 3500) or until no more color leached out. The remaining residue was lyophilized overnight and used as is.

[00337] Preparation of viscous cyclohexane solution. Polyisobutylene (52.74 g,

MW 400,000) was added to cyclohexane (850 ml) and stirred overnight to dissolve. Obtained solution had 158.9 cp viscosity. Five-fold dilution resulted in solution with 5.1 cp viscosity.

[00338] Solution polymerization of polyethyleneimine with 2,4-tolylene diisocyanate. To chloroform (15 mL), viscosity modified with polyisobutylene (20% w/v, MW 80, 000) and Span 85 mixture (2% w/v) stirred at 1500 rpm with a magnetic stirrer, the disperse phase (0.167 g/mL PEI in 3 mL methanol) was added at once. After 2 minutes of stirring, 2,4-tolylene diisocyanate (TDI, 1.0 mL, in 2.0 mL chloroform) was added at once and the stirring was reduced to 500 rpm. Polymerization took place instantly and a big lump of polymer that formed stopped stirring. Obtained polymer was washed with chloroform and analyzed.

[00339] Microcapsule preparation from methanol-in-oil emulsion for DOE studies. To cyclohexane (15 ml, viscosity at low [-1] level or high [+1] level) and Span 85 mixture (2% v/v) stirred (at low [-1] level or high [+1] level) with a magnetic stirrer, the disperse phase (at low [-1] level or high [+1] level for PEI concentration, at low [-1] level or high [+1] level for volume of the disperse phase) was added at once. After 2 minutes of stirring, 2,4-tolylene diisocyanate (at low [-1] level or high [+1] level for TDI concentration in cyclohexane-total volume 3 mL) was added at once and the stirring was reduced to 500 rpm. After 10 minutes, polymerization was stopped by the addition of cyclohexane (30 mL).

The resulting capsules were left to settle, further washed with hexanes, and finally vacuum dried.

[00340] Measurements and Analytical Analysis. The diameters of the capsules were measured within one day of their preparation via Leica software provided with the confocal miscroscope set up. For DOE response, diameters of about twenty capsules were averaged. No strict statistical analysis was performed on these measurements. For the three tested formulations fifty capsules were measured with ImageJ software to determine mean capsule size and diameter coefficient of variation. The percent coefficient of variation (CV) is defined as follows: CV = (σ/μ) • 100, where σ is the standard deviation of the diameter

[μm] and μ is the number-average diameter of the diameter.

[00341] Measurement of loading and loading efficiency of coumarin-1 capsules. Loading of coumarin-1 loaded microcapsules was determined via UV/Vis study of the methanol wash. Dry capsules were subjected to methanol wash for 5 minutes. After short centrifugation, the supernatant was isolated and its absorbance at 374 nm was measured. Molar extinction coefficient for coumarin-1 in methanol was determined to be

25975 IVT¹CnT¹.

[00342] Loading (L) was calculated from the following

equation: L = — - 100, where dye(g) is the mass of dye, in grams, determined to be sample(g) present in a tested sample(g).

[00343] Percent encapsulation efficiency (%en) was calculated from the following equation: %en = 100, where actual loading (actual) is defined as: theoretical actual = — - yield(g), and theoretical loading (theoretical) is defined as the mass of sample(g) dye used in the particular formulation. Yield is reported as mass of dry capsule batch in grams.

Table 7: Magnitude of low ([-I]) and high (+[I]) levels for each variable studied in the

DOE.

Table 8: Table of experimental runs generated by the Design-Expert , v.7

Table 9: Values of variables in the three tested formulations

Table 10. DOE predicted relationship (capsule diameter in μm in terms of the variables studied (equ I))

EXAMPLE 5 Mechanism and Application of a Microcapsule Enabled Multicatalyst Reaction

[00344] Catalyst isolation techniques that enable one-pot multistep reactions hold great potential for increasing the efficiency of chemical synthesis. Performing multiple reactions simultaneously in a single reaction vessel offers possibilities for reduced waste and increased safety, as well as the manipulation of equilibrium. However, although site-isolated catalysts have been developed, the focus has been largely based on catalyst recovery rather than on tandem catalysis.

[00345] Previous Examples have described formation of microcapsule enabled multicatalyst systems that produces synthetically useful products. The reaction involves the amine-catalyzed transformation of an aldehyde to a nitroalkene, followed by a transition metal-catalyzed Michael addition in the same reaction vessel (Figure 17). Typically, amine catalysts and nickel complexes are incompatible due to their tendency to chelate and render each other inactive. However, microencapsulation of PEI forms catalyst 1, which can be used in tandem with the nickel-based catalyst 2.

[00346] The transformation of an aldehyde to a nitroalkene and the subsequent

Michael addition of a malonate ester can be performed in tandem through the use of site- isolated catalysts. The two catalysts are microencapsulated PEI (1) and a nickel-based complex (2). Not only do these two reactions both form C-C bonds, but together they create a versatile synthetic building block. For instance, the nitroalkane can be converted into an amine via reduction or a carbonyl via the Nef reaction, while the ester groups can be transformed into a single carboxylate via hydrolysis-decarboxylation or a diol via reduction. Additional synthetic steps can generate pharmaceuticals such as rolipram, baclofen and pregabulin (Figure 18). [00347] Synthesis and Characterization of Microencapsulated Catalyst.

Encapsulation of an amine-based Henry reaction catalyst was achieved via the interfacial polymerization of oil-in-oil emulsions, as described in the previous Examples. Poly(ethyleneimine) (PEI) was encapsulated by dispersing a methanolic PEI solution into a continuous cyclohexane phase. Upon emulsifϊcation, 2,4-tolylene diisocyanate (TDI) was added to initiate cross-linking at the emulsion interface, forming polyurea shells that contain free chains of PEL The microcapsules crenate when dry and swell when placed in such solvents as methanol and DMF, suggesting a hollow capsule rather than a solid sphere (Figures 22A-22C). Catalyst loading was determined to be 4.6 mmol/g by acylation of the catalytic amines with trifluoroacetic anhydride followed by fluorine elemental analysis. Urea content of the microcapsule shells was found to be 4.9 mmol/g by oxygen elemental analysis. [00348] Activity and Mechanism of Microencapsulated Catalyst. To better understand the importance of μcap swelling, the reaction between benzaldehyde (4) and nitromethane was performed in a range of different solvents. Swelling effects were separated from solvent effects by using both free and encapsulated PEI as catalysts for the formation of trα/75-β-nitrostyrene (5) and l,3-dinitro-2-phenyl-propane (6). Figure 23 shows benzaldehyde conversion after 6 hours for each catalyst. The results for the reactions catalyzed by free PEI (black bars) are not affected by swelling or by the kinetic barrier introduced by the microcapsule shell and therefore indicate how effective each solvent is for this reaction. If the differences in conversion for the reactions catalyzed by encapsulated PEI (white bars) were based exclusively on solvent, we would expect the two cases to show the same trends. This is the case for both swelling and partially swelling solvents; for each catalyst, conversions are high for ethanol, moderate for chloroform, and low for acetone. However, this is not true for non-swelling solvents. While the free PEI-catalyzed reactions revealed that toluene, ether, and THF were good, moderate, and poor solvents, respectively, encapsulated PEI did not produce the same results. Despite the high conversion produced by free PEI in toluene, encapsulation resulted in a catalyst with almost no activity in the same solvent. These results suggest that the solvent dependence of this reaction is two-fold; not only must the solvent be favorable for the PEI-catalyzed reaction, but it also must be able to swell the microcapsules. Acetone swells the capsules but is a poor solvent for the reaction while toluene is a good solvent for the reaction but is unable to swell the μcaps. Both of these cases result in poor conversions of benzaldehyde when encapsulated PEI is used as the catalyst. Ethanol is a good solvent for the reaction that is also able to swell the capsules, and is thus able to produce high conversions with both free and encapsulated PEL Furthermore, in some cases catalytic activity is retained for capsules that are swollen in a swelling solvent and then placed in a bulk non-swelling solvent.

[00349] With a better understanding of the conditions required for catalytic activity, the attention was turned to the mechanism of the μcap catalyst. The transformation of an aldehyde to a nitroalkene can occur via two different pathways. The first involves nitroalcohol formation through a traditional Henry reaction, which is then followed by an elimination to form the double bond. The second proceeds through an imine intermediate rather than the nitroalcohol. This latter mechanism has been suggested for cases in which the catalyst contains both primary and tertiary amino groups, as well as for solid supported catalysis. Being that the catalyst exhibits both of these features, it was predicted that μcap- enabled nitroalkene formation goes through an imine intermediate rather than the nitroalcohol. Indeed, when the μcap-catalyzed condensation of benzaldehyde with nitromethane was followed over time, the nitroalcohol was not observed at any point in the reaction. However, the nitroalcohol was found to be present during the course of the one-pot reaction, possibly having been formed by the amine ligands of the nickel catalyst. This evidence precludes the possibility that elimination occurs as soon as the nitroalcohol is formed and suggests that the reaction might follow the latter route. To further support this hypothesis, when the nitroalcohol is placed in the presence of swollen μcaps, no nitroalkene formation is observed. The inability of the μcap catalyst to convert this potential intermediate to the final product provides further evidence against the nitroalcohol-elimination pathway. A proposed mechanism for μcap-catalyzed nitroalkene formation is shown in Figure 24. [00350] One-Pot Reaction. Previous Examples have described the possibility for the nitroalkene intermediate to either form the dinitro product or go through a Michael-type addition with the encapsulated PEI when subjected to the reaction discussed above. However, we have also shown that when the reaction is run in the presence of a second catalyst-reagent pair, this intermediate can be trapped and directed to a different reaction pathway (see Figure 25).

[00351] Furthermore, because μcaps swollen in methanol will retain their catalytic activity when placed in toluene, the reaction can be run in a mixture of two different solvents. This allows both the μcaps and the nickel catalyst to operate in their respective ideal solvents of methanol and toluene. To demonstrate the scope of this one-pot reaction, we performed this reaction with a variety of aromatic and aliphatic aldehydes. The results are shown in Table 11. It is evident that though the system tolerates both aromatic and aliphatic aldehydes, the introduction of electron-withdrawing substituents on the aromatic substrates results in decreased yields. This effect is most pronounced in entries 6 and 7 for which the cyano- and nitro-substituted benzaldehydes yield minimal product formation. It was found that the rate is maximal for unsubstituted benzaldehyde and steadily decreases as the substituents' σ- values diverge in either direction on the Hammett plot. It is possible that 4-cyano- and nitro-benzaldehyde are too electron-withdrawing to allow for any appreciable imine formation.

Table 11. Scope of the One-Pot Reaction

[00352] To gain information about the mechanism of the overall tandem reaction, we carried out kinetic studies to identify the rate-determining step. Changing the catalyst concentration in the reaction between 3-methylbutyraldehyde (8), nitromethane, and dimethyl malonate revealed that the reaction is first-order in nickel catalyst 2 (Figure 26), indicating that the Michael addition of dimethyl malonate to the nitroalkene is the rate- determining step.

[00353] The kinetic data shown in Figure 26 reveals that the rate of the tandem reaction depends on the concentration of nickel catalyst 2 and consequently on the efficiency of site-isolation. It is therefore instructive to determine whether the rate-determining step is at all retarded by interaction between the two catalysts. We began our investigation by comparing the rates of the Michael addition in the absence and presence of the microencapsulated catalyst. One complicating factor, however, is that the catalytic amines within the μcaps irreversibly react with nitroalkenes, decreasing the amount of starting material available for reaction. Using the Michael addition between trα/75-β-nitrostyrene (5) and dimethyl malonate as a model, we approached this problem in two ways. The first approach was to "normalize" the data from the μcap-containing reaction in order to account for the loss of starting material (Figure 27A). Product yields were calculated using the formula (moles of 7a) / (moles of 5 + moles of 7a). It should be noted that these calculations correct only for decreased product formation due to nitroalkene-μcap interaction; any product suppression due to catalyst interaction should still be apparent. Both reactions attain an adjusted yield of 90% after 10 hours, indicating that the presence of the μcaps does not depress the rate of the Michael addition. Indeed, they instead appear to provide rate enhancement, as the μcap-containing reaction reached its final yield after only 4 hours. [00354] To demonstrate that the apparent rate enhancement is not merely an artifact of data correction, we acylated the reactive amines in order to prevent their reaction with 5. The data shown in Figure 27B confirms the rate enhancement in the presence of microcapsules. This result is consistent with previous studies reporting the acceleration of Michael additions by ureas and thioureas. Since the capsule walls are composed of polyurea, it is not surprising that we observe the same phenomenon in our system. Upon further investigation into this rate enhancement, this reaction proved to be first order in the concentration of urea groups (Figure 28). The proposed transition state for the tandem reaction is illustrated in Figure 29. This finding indicates that the presence of the urea- containing μcaps accelerates the Michael addition and ultimately the overall one-pot reaction. In addition, this rate enhancement does not appear to be accompanied by any degradation in yield, suggesting effective site-isolation of the two catalysts.

EXAMPLE 6 A Concise Synthesis of Pregabalin (LYRICA™, Pfizer): Using a Multi-Catalyst System

[00355] The movement toward chemical sustainability is growing, especially in the pharmaceutical industry, which has one of the highest waste-to-product ratios relative to other chemical sectors. Pfizer has recently redesigned the synthesis of sildenafil citrate (VIAGRA™, Pfizer) and sertraline (ZOLOFT™, Pfizer) in order to increase yields and decrease waste; Roche Colorado did the same for the antiviral agent ganciclovir (CYTOVENE™, Roche). Clearly, due to the widespread ambition to become more efficient, innovations that extend to a variety of syntheses would be extremely beneficial. [00356] Pfϊzer's large-scale synthesis of pregabalin begins with the condensation of a malonate ester with 3-methylbutyraldehyde. The remaining four steps are performed non-selectively and a final resolution with (5)-mandelic acid achieves an overall yield of 25%. A streamlined synthesis makes use of an asymmetric catalytic hydrogenation, avoiding the wasteful resolution. However, although the enantioselective step proceeds in 97.7% ee and the synthesis gives an overall yield of 41.5%, it requires 6 individual steps, one of which uses potassium cyanide to install the amine.

[00357] Enantioselective Synthesis of Pregabalin. An attractive feature of our two-step one-pot reaction, as described in Example 5, is that it not only incorporates an innovative technique for site-isolation, but by using an enantioselective version of 2, it also generates synthetically useful products. The Michael adducts that are created are precursors to γ-amino acids, allowing access to γ-amino butyric acid (GABA) analogs. Pregabalin is one such analog that is approved for the treatment of both epilepsy and neuropathic pain. We imagined a synthesis of pregabalin where our two-catalyst system forms the pregabalin backbone efficiently and enantioselective Iy. The desirability of performing these reactions in tandem rather than sequentially is evident when one considers the difficulty of isolating of the nitroalkene intermediate.

Synthesis of Pregabalin (1)

(1) ΩReagents and conditions: (a) nitromethane, dimethyl malonate, toluene, methanol, r.t.,

75%, microencapsulated catalyst; Ni(II) catalyst; 72% ee. (b) Raney Ni, H₂ (45 psi), EtOH. >99% (c) 5M HCl, 100 ⁰C, 95%, 72% ee. [00358] The addition of nitromethane to 3-methylbutanal is catalyzed by the microencapulated catalyst described in Example 5. Subsequent addition of the malonate ester to nitroalkene intermediate by the nickel catalyst produces the desired Michael adduct in 75% yield and 72% ee. It should be noted that this tandem catalysis system efficiently suppresses the yield of the undesired dinitro byproduct to less than 5%. After filtration of the microencapsulated catalyst, removal of the nickel by chelation with PEI, and distillation of the excess solvent, the crude product is transferred into a Parr vessel containing Raney nickel in EtOH. Overnight hydrogenation of gives quantitative conversion of the ring-closed product. The Raney nickel is removed by filtration, and acid hydrolysis and decarboxylation proceeds in 95% yield of the HCl salt of pregabalin (1), which retains an ee of 72%. [00359] It has been reported that enantiomeric enrichment of pregabalin can be achieved by recrystallization for cases in which the ee is at least 85% of the S-enantiomer. Treatment of the 72% ee HCl salt with base followed by a single recrystallization from isopropanol/water afforded a product with 91.5% ee. Our successful enrichment demonstrates the viability of obtaining an enantiomerically pure product without the need for a resolution step, which would bring the overall yield of this synthesis to 74% of enantiomerically pure material.

[00360] This efficient three-step synthesis has not only improved the overall yield of 1 by a factor of 3, but it has also reduced the cost of production. A cost analysis of Pfizer' s original route, the asymmetric hydrogenation route, and our route estimates that the latter is about half as expensive as the original, costing $4.77 per gram as opposed to the $13.53 per gram demanded by Pfϊzer's sythesis. In addtion to reducing costs, our streamlined synthesis achieves a much more attractive E-factor, due in part to the minimal or nonexistent work-up that is required between reactions (Figure 32).

Table 12. Comparison of reaction metrics for three routes to pregabalin

EXAMPLE 7 Preparation of a polyelectrolyte microcapsule

[00361] A lO w/w% solution of poly(sodium styrene sulfonate) in water at a pH =

3.0 was introduced into the continuous phase. A 0.54 M (based on repeat units) solution of poly(4-vinyl pyridine) in chloroform was introduced via a 30G needle as the dispersed phase. The oppositely charge polymers coascervated at the droplet interface, forming solid shells around the droplets of chloroform. These capsules were collected.

Other Embodiments

[00362] The foregoing has been a description of certain non-limiting preferred embodiments of the invention. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

ClaimsWhat is claimed is:

1. A microcapsule comprising a catalyst encapsulated by a polymeric shell, wherein said microcapsule is hollow, and wherein said polymeric shell is semi-permeable, thereby allowing a reactant to diffuse into said microcapsule.

2. A microcapsule comprising a catalyst encapsulated by a polymeric shell, wherein said microcapsule is hollow, and wherein said polymeric shell is semi-permeable, thereby allowing a reactant to diffuse into said microcapsule; with the proviso that said polymeric shell is not a polymer of poly (methylene [polypheny ljisocyanate) encapsulating a catalyst-polymer conjugate of the formula:

wherein F is the group

, G is hydrogen; m is an integer between 1 and 500; and n is an integer between 1 and 100.

3. The microcapsule according to claims 1 or 2, wherein said catalyst comprises a catalyst conjugated to a polymer backbone to afford a catalyst-polymer conjugate.

4. The microcapsule according to claims 1 or 2, wherein said polymeric shell does not allow said catalyst to diffuse out of said microcapsule.

5. The microcapsule according to claims 1 or 2, wherein said polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polyesters, polyethers, polyamides, polyimides, polyamines, polysulfones, polycarbonates, polyureas, polycarbamates, polyurethanes, polyacetylenes, poly ethylenes, polyethyeneimines, polypropylenes, polystyrenes, polychloromethyl styrenes, polyazidomethyl styrenes, polyvinyl toluenes, polyvinyl acetylenes, polydivinyl benzenes, polyisocyanates, polyvinyl acetates, polyacrylates, polyacrylate esters, polymethacrylates, polymethacrylate esters, polyvinyl chlorides, polyvinyl alcohols, poly aery lonitriles, polybutadienes, polyarylates, polybutylenes, polyisobutylenes, polybutylene terephthalates, polytetrafluoro ethylenes, polychloroprenes, polyamino esters, poly-β-hydroxybutyric acids, polysiloxanes, polysilsesquioxanes, sol-gels, polyelectrolytes, polypeptides, polysaccharides or polynucleotides.

6. The microcapsule according to claim 5, wherein said polymeric shell comprises polymers, blends, composites, cross-linked polymers or co-polymers of polyisocyantes, polyamines or polyureas.

7. The microcapsule according to claim 6, wherein said polyisocyanate is poly (methylene [polypheny ljisocyanate) (PMPPI).

8. The microcapsule according to claim 3, wherein said polymer backbone of the catalyst-polymer conjugate comprises polymers, blends, composites, cross-linked polymers or co-polymers of one or more polyesters, polyethers, polyamides, polyimides, polyamines, polysulfones, polycarbonates, polyureas, polycarbamates, polyurethanes, polyacetylenes, poly ethylenes, polyethyeneimines, polypropylenes, polystyrenes, polychloromethyl styrenes, polyazidomethyl styrenes, polyvinyl toluenes, polyvinyl acetylenes, polydivinyl benzenes, polyisocyanates, polyvinyl acetates, polyacrylates, polyacrylate esters, polymethacrylates, polymethacrylate esters, polyvinyl chlorides, polyvinyl alcohols, poly aery lonitriles, polybutadienes, polyarylates, polybutylenes, polyisobutylenes, polybutylene terephthalates, polytetrafluoro ethylenes, polychloroprenes, polyamino esters, poly-β-hydroxybutyric acids, polysiloxanes, polysilsesquioxanes, sol-gels, polyelectrolytes, polypeptides, polysaccharides, polynucleotides.

9. The microcapsule according to claim 8, wherein said polymer backbone of the catalyst-polymer conjugate comprises poly(styrene), poly(chloromethyl styrene), poly(azidomethyl styrene), poly (vinyl acetylene) or polyethyleneimine.

10. The microcapsule according to claims 1 or 2, wherein said microcapsule ranges from about 1 micron to about 1000 microns in diameter.

11. The microcapsule according to claims 1 or 2, wherein said polymeric shell ranges from about 1 nanometer to about 100 microns thick.

12. The microcapsule according to claims 1 or 2, wherein said catalyst is a nucleophile, an electrophile, a base, an acid, a Lewis acid, a Lewis base, a Brønsted acid, a Brønsted base, an organic small molecule, a metal, a transition metal catalyst, an organometallic catalyst, an oxidant, or a reductant.

13. The microcapsule according to claims 1 or 2, wherein said catalyst is an enzyme.

14. The microcapsule according to claim 12, wherein said base comprises amino, alkyl amino, dialkyl amino, trialkyl amino, an optionally substituted heterocyclic, or an optionally substituted heteroaryl group.

15. The microcapsule according to claim 14, wherein said base comprises an optionally substituted pyridinyl, optionally substituted dimethylamino pyridinyl, optionally substituted 4-(N-benzyl-N-methyl)-amino pyridinyl, optionally substituted 2,3-dimethyl pyridinyl, optionally substituted 2,4-dimethyl pyridinyl, optionally substituted 3,5-dimethyl pyridinyl, optionally substituted quinuclidinyl, optionally substituted piperazinyl, optionally substituted piperadinyl, optionally substituted pyrrolidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted morpholinyl group.

16. The microcapsule according to claim 12, wherein said electrophile comprises a halo, an activated hydroxyl, an acyl group, an optionally substituted alkenyl or an optionally substituted alkynyl group.

17. The microcapsule according to claim 12, wherein said nucleophile comprises a phosphino, phosphinato, phosphazino, azido, amino, thio, isocyano, hydroxyl, alkenyl, or an optionally substituted alkynyl group.

18. The microcapsule according to claims 1 or 2, wherein the interior of said microcapsule further comprises a solution.

19. The microcapsule according to claim 18, wherein said catalyst is soluble in said solution.

20. The microcapsule according to claim 19, wherein said solution comprises a polar aprotic solvent, a polar protic solvent, a non-polar solvent, or a mixture thereof.

21. The microcapsule according to claim 19, wherein said solution comprises an organic alcohol, formamide, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, or a mixture thereof.

22. The microcapsule according to claim 21, wherein said organic alcohol is selected from a group consisting of methanol, ethanol, n-propanol, isopropanol, or t-butanol.

23. The microcapsule according to claim 19, wherein said solution comprises pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, xylenes, chlorobenzene, chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or a mixture thereof.

24. The microcapsule according to claims 1 or 2, said catalyst-polymer conjugate having the formula I:

(I) wherein each occurrence of A is an optionally substituted cyclic or acyclic alkylene, optionally substituted cyclic or acyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene group; each occurrence of B is either (N) or (CR^q), wherein R^q is hydrogen, hydroxy, thio, halo, nitro, cyano, amino, acyl, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl group;

F and G are, independently, hydrogen, hydroxy, amino, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclic group; each occurrence of X is, independently, a bond, -O-, -S-, -N(R^W), or an optionally substituted cyclic or acyclic alkylene, optionally substituted cyclic or acyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene moiety, wherein each instance of R^w is, independently, hydrogen, hydroxy, acyl, sulfmyl, sulfonyl, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted hetereocyclyl group; each occurrence of Y is, independently, hydroxy, thio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxyaldehyde, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, alkylamino, or dialkylamino group; each occurrence of Z is, independently, hydrogen, hydroxy, thio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxyaldehyde, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, alkylamino, or dialkylamino group; p is an integer between 0 to 100; m is an integer between 1 and 500; and n is an integer between 0 and 100.

25. The microcapsule according to claim 24, wherein A is an optionally substituted cyclic or acyclic alkylene or optionally substituted cyclic or acyclic heteroalkylene group.

26. The microcapsule according to claim 24, wherein B is (N) or (CH).

27. The microcapsule according to claim 24, wherein Y is a hydroxy, thio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, carboxy aldehyde, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted hetereocyclyl group.

28. The microcapsule according to claim 27, wherein Y is a amino, alkylamino, dialkylamino, optionally substituted heteroaryl or optionally substituted hetereocyclyl group.

29. The microcapsule according to claim 28, wherein said heterocyclyl group is a pyridinyl, dimethylamino pyridinyl, 4-(N-benzyl-N-methyl)-amino pyridinyl, 2,3-dimethyl pyridinyl, 2,4-dimethyl pyridinyl, 3,5-dimethyl pyridinyl, pyrrolidinyl, pyrazinyl, or a pyridazinyl group.

30. The microcapsule according to claim 24, wherein at least one X group is an optionally substituted cyclic alkylene, optionally substituted cyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene group of the formula:

wherein: x is 0 to 5; q is 1 to 3;

W is -C-, -CR^f-, -C(R^f)₂-, -N-, -N(R^g)-, -O-, or -S-; wherein each occurrence of R¹ and R^f is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; and each occurance of and R^g is independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, amino, alkylamino, dialkylamino, amido, imido, acyl, sulfϊnyl, or sulfonyl; and is a single or double bond.

31. The microcapsule according to claim 30, wherein at least one X group is an optionally substituted cyclic or acyclic alkylene, optionally substituted cyclic or acyclic heteroalkylene, optionally substituted arylene, or optionally substituted heteroarylene group of the formulae:

(e) (0 (g) (h)

(i) 0)

32. The microcapsule according to claim 24, wherein X is a single bond, -(CH₂)_P-, an optionally substituted arylene or optionally substituted heteroarylene moiety.

33. The microcapsule according to claim 32, wherein X is -(CH₂)p-.

34. The microcapsule according to claim 24, wherein Z is, independently, hydrogen or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted hetereocyclyl group.

35. The microcapsule according to claim 24, said catalyst-polymer conjugate having the formula (I-g):

(i-g)

36. The microcapsule according to claim 24, said catalyst-polymer conjugate having the formula (II):

(H) wherein: x is 0 to 5; q is 1 to 3;

W is -C-, -CR^f-, -C(R^f)₂-, -N-, -N(R^g)-, -O-, or -S-; wherein each occurrence of R¹ and R^f is, independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfmyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; and each occurance of and R^g is independently, hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, amino, alkylamino, dialkylamino, amido, imido, acyl, sulfϊnyl, or sulfonyl; and is a single or double bond.

37. The microcapsule according to claim 36, said catalyst-polymer conjugate having the formula (II-e):

(H e) wherein each occurrence of R² is, independently, hydrogen or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfϊnyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group; and y is 0 to 5.

38. The microcapsule according to claim 37, said catalyst-polymer conjugate having the formula (II-i):

(II-i)

39. The microcapsule according to claim 38, said catalyst-polymer conjugate having the formula (II-n):

40. The microcapsule according to claim 38, said catalyst-polymer conjugate having the formula (II-o):

(ii-o)

41. The microcapsule according to claim 36, said catalyst-polymer conjugate having the formula (II— f) :

(ii-D wherein each occurrence of R² is, independently, hydrogen or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfϊnyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxaldehyde group.

42. The microcapsule according to claim 41, said catalyst-polymer conjugate having the formula (II-m):

(II-m)

43. A method of making a microcapsule of claims 1 or 2, said method comprising the steps of:

(i) providing a first solution of a catalyst;

(ii) providing a second solution of at least one monomer;

(iii) dispersing said first solution into said second solution to form an emulsion; and

(iv) polymerizing said monomer at the interface of said first solution and said second solution to provide said microcapsule, wherein the microcapsule is hollow; and said microcapsule comprises said catalyst encapsulated by a semi-permeable polymeric shell.

44. The method according to claim 43, wherein said catalyst is a catalyst conjugated to a polymer backbone to afford a catalyst-polymer conjugate.

45. The method according to claim 43, wherein said catalyst is soluble in said first solution.

46. The method according to claim 43, wherein said first solution comprises a polar protic solvent, a polar aprotic solvent, or mixture thereof.

47. The method according to claim 45, wherein said first solution comprises a solvent with a dielectric constant greater than or equal to 25.

48. The method according to claim 47, wherein said solvent comprises an organic alcohol, formamide, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, N-methyl pyrrolidinone, acetonitrile, or a mixture thereof.

49. The method according to claim 48, wherein said organic alcohol comprises methanol, ethanol, n-propanol, isopropanol, or t-butanol.

50. The method according to claim 43, wherein said wherein said second solution comprises a solvent with a dielectric constant less than or equal to 5.

51. The method according to claim 50, wherein said solvent comprises pentanes, hexanes, heptanes, cyclohexane, methylcyclohexane, toluene, benzene, xylenes, chlorobenzene, chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or a mixture thereof.

52. The method according to claim 43, further comprising providing an emulsifier.

53. The method according to claim 52, wherein said emulsifier is a Tween surfactant, a Span surfactant, or Brij surfactant, or a PEG-based surfactant.

54. The method according to claim 43, further comprising providing a interfacial modifier.

55. The method according to claim 54, wherein said interfacial modifier is a polyisobutylene, a poly(vinyl alcohol), a polystyrene, glycerol, or a polysaccharide.

56. The method according to claim 43, wherein the step of polymerizing comprises inducing polymerization by adding an initiator to said emulsion.

57. The method according to claim 56, wherein said initiator comprises a peroxide, an N-oxide, tert-butyl peroxide, benzoyl peroxide, azobisisobutyrylnitrile (AIBN), tetraethylenepentamine (TEPA), a Ziegler-Natta catalyst, an acid, or a base.

58. The method according to claim 43, wherein said polymerization step is ring opening metathesis polymerization (ROMP), reversible addition-fragmentation chain transfer (RAFT) polymerization, reversible addition-fragmentation chain transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), light-induced polymerization, or heat-induced polymerization.

59. The method according to claim 43, wherein said first solution contains less than 50% water.

60. The method according to claim 43, wherein said second solution contains less than 50% water.

61. A method of using a microcapsule of claims 1 or 2, said method comprising the steps of:

(1) providing a microcapsule M-I, wherein said microcapsule M-I is hollow and comprises a semi-permeable polymeric shell encapsulating a catalyst C-I and a first solution S-I;

(2) dispersing said microcapsule M-I into a second solvent S-2, wherein said solution S-2 comprises a starting material R-I; and

(3) allowing said starting material R-I to diffuse into said microcapsule M-I and react with said catalyst C-I to afford a first product P-I.

62. The method according to claim 61, whereby: said solution S-2 further comprises a reagent R-2; said reagent R-2 diffuses into said microcapsule M-I; said product P-I reacts with said reagent R-2 to afford a second product P-2, and said product P-2 diffuses out of said microcapsule into said solution S-2.

63. The method according to claim 62, whereby: said solution S-2 further comprises a reagent R-3; and said product P-2 reacts with reagent R-3 to afford said third product P-3.

64. The method according to claim 63, wherein said solution S-2 further comprises a catalyst C-2, and wherein said catalyst C-2 catalyzes the reaction between said product P-2 and said reagent R-3.

65. The method according to claim 64, wherein said catalysts C-I and C-2 are incompatible.

66. The method according to claim 61, wherein said first solution S-I and said second solution S-2 are different.

67. The method according to claim 61, wherein said catalyst C-I comprises a catalyst conjugated to a polymer to afford a catalyst-polymer conjugate.

68. The method according to claim 61, wherein said first solution S-I is methanol.

69. The method according to claim 61, wherein said second solution S-2 is toluene.

70. The method according to claim 64, said method further providing a second microcapsule M-2, wherein said microcapsule M-2 is hollow, and comprises a semipermeable polymeric shell encapsulating said catalyst C-2 and a third solution S-3.

71. The method according to claim 70, wherein said catalysts C-I and C-2 are incompatible.

72. The method according to claim 62, wherein said starting material R-I is R CH₂ ^Q;

„ θ said first product P-I is the conjugate base of R-I having the formula R CHQ; said reagent R-2 is R⁶ CHO; and

said second product P-2 is R ; wherein

Q is sulfoxyl, sulfonyl, sulfmyl, acyl, carboxaldehyde, amide, imide, azido, nitro, or cyano; and each occurrence of R⁵ and R⁶ is, independently hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, or phosphazino group.

73. The method according to claims 63, wherein said starting material R-I is R CH₂ ^Q;

Θ said first product P-I is the conjugate base of R-I having the formula R⁵- -CHQ; said reagent R-2 is R⁶ CHO;

said second product P-2 is R

and said third product P-3 is wherein Q is sulfoxyl, sulfonyl, sulfmyl, acyl, carboxyaldehyde, amide, imide, azido, nitro, or cyano; each occurrence of R⁵ and R⁶ is, independently hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclyl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfmyl, sulfonyl, phosphino, phosphinato, or phosphazino group. each occurrence of R⁵ and R⁶ are, independently hydrogen, or an aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetereocyclyl, arylalkyl, or heteroarylalkyl, optionally substituted with an aliphatic, heteroaliphatic, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetereocyclyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, trialkylamino, amido, imido, acyl, acyloxy, oxo, thiooxo, sulfϊnyl, sulfonyl, phosphino, phosphinato, phosphazino, or a carboxyaldehyde group; and each occurrence of R⁷ is, independently hydrogen, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

74. The method according to claim 73, wherein said P-2 is:

75. The method according to claim 73, wherein said P-3 is:

76. A method of preparing a compound of formula X:

(X) wherein

R »4 is selected from the group consisting of:

R⁷ is an optionally substituted Ci_6 aliphatic; each occurrence of R⁸ is, independently, an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetereocyclic, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thio, thioalkoxy, arylthio, heteroalkylthio, heteroarylthio, halo, nitro, cyano, isocyano, azido, hydroxyalkyl, aminoalkyl, thioalkyl, amino, alkylamino, dialkylamino, amido, imido, acyl, acyloxy, sulfϊnyl, sulfonyl, phosphino, phosphinato, phosphazino; each occurrence of R⁹ is, independently, hydrogen, or an optionally substituted aliphatic group; and z is 0 to 5; said method comprising:

(1) providing a solution comprising a microcapsule, nitromethane, an nickel catalyst, and compounds of formula XI and XII:

XII wherein said microcapsule is hollow and comprises a catalyst-polymer conjugate encapsulated by a polymeric shell, wherein said polymeric shell is semi-permeable, thereby allowing said nitromethane and said compound of formula XI to diffuse into said microcapsule but not allowing said catalyst-polymer conjugate to diffuse out of said microcapsule; said polymeric shell and said polymer of said catalyst-polymer conjugate comprise a poly(ethylene-imine) polymer; and said catalyst of said catalyst-polymer conjugate comprises an organic base; and

(2) allowing said microcapsule, said nitromethane, said nickel catalyst, and said compounds of formula XI and XII to react under suitable conditions to afford said compound of formula X.