CA2574581A1 - Anti-oxidant macromonomers and polymers and methods of making and using the same - Google Patents

Abstract

Methods of preparing an antioxidant polymer are described comprising polymerizing macromonomers that comprise an antioxidant. By having the antioxidant as part of the macromonomer, a polymer with a higher density of antioxidants is prepared more efficiently than coordinating antioxidants to an already formed polymer. The methods of polymerization also encompass copolymerization wherein different macromonomers comprising different antioxidants may be used. Alternatively, the other macromonomer, or monomer, may not include an antioxidant depending on the intended use of the copolymer and desired properties. The macromonomer comprising a antioxidant may comprise more than one antioxidant which may be the same or different. In one embodiment, the macromonomer is benzene or olefin based, wherein the benzene or olefin is substituted with an antioxidant.

Description

ti/<a,u./t 11\ 1 lVlrlVl\VlV10NOMERS AND POLYMERS AND
METHODS OF MAKING AND USING THE SAME
RELATED APPLICATIONS
This application claims the benefit of U.S. Application No. 60/590,575, filed on July 23, 2004 and U.S. Application No. 60/590,646, filed on July 23, 2004. The entire teachings of the above applications are incorporated herein by reference.

Background of the Invention Most organic materials such as plastics, foods, elastomers, fuels, oils, gasoline and lubricants, fibers are susceptible to degradation due to thermal oxidative processes. Harinful, reactive and unstable free radicals are formed during the oxidation process and attack the nearby stable molecules (polymer chains or small molecules) of the materials, "stealing" their electron.
The 'attacked' molecule loses its electron, resulting itself a free reactive radical to initiate a cascade of chain reactions. Deterioration of their molecular structures as a result of oxidation processes would affect their shelf life, physical and chemical properties.
These oxidative reactions are further enhanced at elevated temperatures. The antioxidant molecules are normally added to protect materials against such destructive effects of harmful and reactive free radicals.
These antioxidants neutralize these reactive free radicals by donating one of their electrons to stabilize "reactive" free radicals thus stopping the electron 'stealing' mechanism.

In many of today's commercial and industrial applications it is desirable to have antioxidants that possess (a) enhanced antioxidant properties, and (b) active and thermally stable at elevated temperatures. Designing of new antioxidants possessing these two desired properties is essential today for the following reasons: The amount of synthetic antioxidant added to some materials, especially in processed food products, is restricted and need to follow Food and Drug Administration (FDA) regulations (for example, 21 CFR 110,115,185,515 and 615, 182.1660, 3169 and 3173, and 21 CFR 184.1660). In most cases the usage is limited to 0.02%
by weight in fat or oil portion of food because some antioxidants such as BHA
(butylated hydroxy anisole) and BHT (butylated hydroxy toluene) are suspected to be carcinogenic beyond certain concentration. It is desirable to design new antioxidants possessing enhanced antioxidant activities so that the materials are protected with lower amount of synthetic antioxidants. In the case of other applications, thermally stable antioxidants are required to protect the materials at high temperatures. For instance, many polyolefins and thermoplastics are processed at elevated temperatures. At these elevated temperatures, some of the antioxidants used today are themselves prone to degradation at these elevated temperatures.
There is a need for antioxidants that are stable and active at elevated temperatures so that the new antioxidants could be used in high temperature material applications.

Brief Description of the Drawings Figure 1 depicts a) the 'H NMR spectrum of 4-acetoxy benzoic acid, b) the 1H
NMR
spectrum of 3,5-di-tert-butyl-4-hydroxy benzyl alcohol, c) the 'H 1VMR
spectrum of the macromonomer formed from 4-acetoxy benzoic acid and 3,5-di-tert-butyl-4-hydroxy benzyl alcohol (compound 1), d) the 'H NMR spectrum of the macromonomer formed from deacetylation of acetylated monomer (compound 1), and e) the 'H NMR spectrum of macromonomer 6.

Figure 2 depicts a) the 'H NMR spectrum of poly(macromonomer compound 1) formed from deacetylation of acetylated monomer (compound 1) and b) the 1H NMR
spectrum of poly(macromonomer compound 6).

Figure 3 depicts the comparison of oxidative induction time (OIT) (min) of polypropylene samples containing 200 ppm of polymeric macromonomer antioxidant (polymer 1) (trace two) and Irganox 1010 (trace one).

Summary of the Invention The present invention relates to methods of preparing an antioxidant polymer comprising polymerizing macromonomers that comprise an antioxidant. By having the antioxidant as part of the macromonomer, a polymer with a higher density of antioxidants is prepared more efficiently than coordinating antioxidants to an already formed polymer. The methods of polymerization of the present invention also encompass methods of copolymerization wherein different macromonomers comprising different antioxidants may be used. Alternatively, the other macromonomer, or monomer, may not include an antioxidant depending on the intended use of the copolymer and desired properties. The macromonomer comprising an antioxidant may comprise more than one antioxidant which may be the same or different.
Polymerization may be carried out with a variety of catalysts known to one of ordinary skill in the art. The catalyst selected will depend, in part, upon the nature of the macromonomer polymerized. In one embodiment, the macromonomer is benzene or olefin based, wherein the benzene or olefin is substituted with an antioxidant.

These embodiments of the present invention, other embodiments, and their features and characteristics, will be apparent from the description, drawings and claims that follow.
Detailed Description of the Iaveyztion De nitions For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

The terms "comprise" and "comprising" are used in the inclusive, open sense, meaning that additional elements may be included.

The term "including" is used herein to mean "including but not limited to".
"Including"
and "including but not limited to" are used interchangeably.

The term "antioxidant" is art-recognized and refers to any of various compounds that are added to substances in order to reduce the effect of oxidation and the accompanying degradation of properties. Non-limiting examples of substances that utilize antioxidants include paints, plastics, gasoline, rubber, and food products.

The term "oxidation" is art-recognized and refers to any reaction in which one or more electrons are removed from a species, thus increasing its valence (oxidation state).

The term "radical" is art-recognized and refers to an electrically neutral or ionic group having one or more unpaired electrons.

The term "substance" is used herein to mean any physical entity, commonly homogeneous, that occurs in macroscopic amounts.

The term "polymer" is art-recognized and refers to a macromolecule comprising a repeating monomeric unit.

The term "monomer" is art-recognized and refers to a compound that is able to combine in long chains with other like or unlike molecules to produce polymers. The terms "macromonomer" and "monomer" are considered functionally the sasne.

The term "homopolyer" is art-recognized and refers to a polymer derived by a single repeating monomer.

The term "copolymer" is azt-recognized and refers to a polymer that is composed of polymer chains made up of two or more chemically different repeating units that can be in different sequences.

The phrase "bulky alkyl group" is used herein to mean an alkyl group branched alpha or beta to a group, such as a benzene ring. The bulky alkyl group may be branched twice alpha to a benzene ring (i.e., to form an alpha-tertiary carbon), such as in a t-butyl group. Other non-limiting examples of a bulky alkyl group include isopropyl, 2-butyl, 3-pentyl, 1,1-dimethlypropyl, 1-ethyl-l-methylpropyl, and 1, 1 -diethylpropyl.

The term "enzyme" is art-recognized and refers to a protein that catalyzes reactions without itself being permanently altered or destroyed.

The term "enzyme mimetic" is art-recognized and refers to any substance that mimics the activity of an enzyme.

The term "catalyst" is art-recognized and refers to any substance that affects the rate of a chemical reaction without itself being consumed ore essentially altered.

The term "synthetic" is art-recognized and refers to production by in vitro chemical or enzymatic synthesis.

The term "instructional material" or "instructions" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of a subject composition described herein for a method of treatment or a method of making or using a subject composition. The instructional material may, for example, be affixed to a container which contains the composition or be shipped together with a container which contains the composition or be contained in a kit with the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.

The terms "number average molecular weight", or "Mll", "weight average molecular weight", "Z-average molecular weight" and "viscosity average molecular weight"
are art-recognized. When the term "molecular weight" or an exemplary molecular weight is described herein, the measure of molecular weight will be clear from the context and/or will include all applicable measures.

"Small molecule" is an art-recognized term. In certain embodiments, this term refers to a molecule which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.

The term "aliphatic" is an art-recognized term and includes linear, branched, and cyclic alkanes, alkenes, or alkynes. In certain embodiments, aliphatic groups in the present invention are linear or branched and have from 1 to about 20 carbon atoms.

The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., Cl-C3o for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer.
Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure. The tertn "alkyl"
is also defined to include halosubstituted alkyls.

The term "aralkyl" is art-recognized, and includes alkyl groups substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms "alkenyl" and "alkynyl" are art-recognized, and include unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

The term "heteroatom" is art-recognized, and includes an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

The term "aryl" is art-recognized, and includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" "heteroaryls," or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings maybe cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names l,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms "heterocyclyl" and "heterocyclic group" are art-recognized, and include 3- to about 1 0-membered ring structures, such as 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles.
Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The terms "polycyclyl" and "polycyclic group" are art-recognized, and include structures with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms, e.g., three or more atoms are common to both rings, are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The term "carbocycle" is art recognized and includes an aromatic or non-aromatic ring in which each atom of the ring is carbon. The flowing art-recognized terms have the following meanings: "nitro" means -NO2; the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl"
means -SOa .

The terms "amine" and "amino" are art-recognized and include both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

~R50 I
+

R51 Iwherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

The term "acylamino" is art-recognized and includes a moiety that may be represented by the general formula:

O

wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m R61, where m and R61 are as defined above.

The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:

0.

N =

wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable. ~ ~~-"-" - W-- The term "alkylthio" is art recognized and includes an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.

The term "carbonyl" is art recognized and includes such moieties as may be represented by the general formulas:

O O
. R55 wherein X50 is a bond or represents an oxygen or a sulfur, and R55 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester' .
Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the fonnula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a"thiocarbonyl"
group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thioester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiocarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a"thioformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above foxxnula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group.

The terms "alkoxyl" or "alkoxy" are art recognized and include an alkyl group, as defmed above, having an oxygen radical attached thereto. Representative alkoxyl groiups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -0-alkenyl, -0-alkynyl, -0-(CH2)m R61, where m and R61 are described above.

The term "sulfonate" is art recognized and includes a moiety that may be represented by the general formula:

fl O
in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term "sulfate" is art recognized and includes a moiety that may be represented by the general fonnula:

I I
O
in which R57 is as defined above.

The term "sulfonarnido" is art recognized and includes a moiety that may be represented by the general formula:

I !I

in which R50 and R56 are as defined above.

The term "sulfamoyl" is art-recognized and includes a moiety that may be represented by the general formula:

N
(I \

in which R50 and R51 are as defined above.

The term "sulfonyl" is art recognized and includes a moiety that may be represented by the general formula:

~I

Ii in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloallkyl, heterocyclyl, aryl or heteroaryl.

The term "sulfoxido" is art recognized and includes a moiety that may be represented by the general formula:

S

in which R5 8 is defined above.

The term "phosphoramidite" is art recognized and includes moieties represented by the general fonnulas:

II I) Q51-p O Q51-p-OR59 wherein Q51, R50, R51 and R59 are as defined above.

The term "phosphonamidite" is art recognized and includes moieties represented by the general formulas:

I
~N~

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.

Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure unless otherwise indicated expressly or by the context.

The term "selenoalkyl" is art recognized and includes an alkyl group having a substituted seleno group attached thereto. Exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH2)m R61, m and R61 being defined above.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms are art recognized and represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.

Certain monomeric subunits of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers and other compositions of the present invention may also be optically active. The present invention contemplates all such compounds, including cis-and trans-isomers, R- and S-enantiomers, 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.

If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

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, 67th Ed., 1986-87, inside cover. The term "hydrocarbon" is art recognized and includes all permissible compounds having at least one hydrogen and one carbon atom. For example, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.

The phrase "protecting group" is art recognized and includes temporary substituents that protect a potentially reactive functional group from undesired chemical transformations.
Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed. Greene et al., Protective Groups in Organic Synthesis 2na ed., Wiley, New York, (1991).

The phrase "hydroxyl-protecting group" is art recognized and includes those groups intended to protect a hydroxyl group against undesirable reactions during synthetic procedures and includes, for example, benzyl or other suitable esters or ethers groups known in the art.

The term "electron-withdrawing group" is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron-withdrawing capability is given by the Hammett sigma (6) constant. This well known' constant is described in many references, for instance, March, Advanced Organic Chemistry 251-59, McGraw Hill Book Company, New York, (1977). The Hammett constant values are generally negative for electron donating groups (a (P) = - 0.66 for NH2) and positive for electron withdrawing groups (a (P) = 0.78 for a nitro group), 6(P) indicating para substitution.
Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like. Exemplary electron-donating groups include amino, methoxy, and the like.

Contemplated equivalents of the polymers, subunits and other compositions described above include such materials which otherwise correspond thereto, and which have the same general properties thereof (e.g., biocompatible), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of such molecule to achieve its intended purpose. In general, the methods of the present invention may be methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.

Method of Polymerization Polymerization of the macromonomers can be catalyzed by a natural or synthetic enzyme or an enzyme mimetic capable of polymerizing a substituted benzene compound in the presence of hydrogen peroxide, where the enzyme or enzyme mimetic typically has a heme or related group at the active site. One general class of enzymes capable of catalyzing this reaction is commonly referred to as the peroxidases. Horseradish peroxidase, soybean peroxidase, Coprinus cinereus peroxidase, and Arthromyces ramosus peroxidase are readily available peroxidases.
Other enzymes capable of catalyzing the reaction include laccase, tyrosinase, and lipase.
Suitable enzymes are able to catalyze the formation of a carbon-carbon bond and/or a carbon-oxygen-carbon bond between two aryl (e.g., phenol) groups when a peroxide (e.g., hydrogen peroxide or an organic peroxide) is present. A subunit or other portion of a peroxidase is acceptable, provided that the active site of the enzyme is still functional.

Enzyme mimetics typically correspond to a part of an enzyme, so that they can carry out the same reaction as the parent enzyme but are generally smaller than the parent enzyme. Also, enzyrne mimetics can be designed to be more robust than the parent'enzyme, such as to be functional under a wider variety of conditions (e.g., different pH range and/or aqueous, partially aqueous and non-aqueous solvents) and are generally less subject to degradation or inactivation.
Suitable enzyme mimetics include hematin, tyro sinase-model complexes and metal-salen (e.g., iron-salen) complexes. Hematin, in particular, can be functionalized to allow it to be soluble under a wider variety of conditions is disclosed in U.S. Application No.
09/994,998, filed November 27, 2001, the contents of which are incorporated herein by reference.

The enzymes and enzyme mimetics described above can be immobilized on a solid.
In addition, the enzymes and enzyme mimetics can be dispersed in a solution or suspension.

The macromonomers described herein can also be polymerized by non-enzymatic chemical methods. For example, polymerization can be catalyzed by metal compounds such as iron chloride or a metallocene. Also, polymerization can be catalyzed by cationic, anionic or free radical initiators such as N,N-azobisisobutyromtrile (AIBN), acetylacetone and peroxides (e.g., tert-butyl hydroxide, benzyl peroxide). Polymerizations of the present invention can be carried out under a wide variety of conditions. The pH is often between about pH 1.0 and about pH 12.0, typically between about pH 6.0 and about pH 11Ø The temperature is generally above about O*C, such as between about 0 C and about 450C or between about 150C and about 30 C
(e.g., room temperature). The solvent can be aqueous (preferably buffered), organic, or a combination thereof. Organic solvents are typically polar solvents such as ethanol, methanol, isopropanol, dimethylfonnamide (DMF), dioxane, acetonitrile, dimethylsulfoxide (DMSO) and tetrahydrofuran (T.HF). The concentration of macromonomer or comacromonomers is typically 0.001 M or greater. Also, the concentration of buffer is typically 0.001 M or greater.

Preferably, the enzyme or enzyme mimetic is added to the solution after addition of the antioxidant macromonomer or comacromonomers. A peroxide is then added incrementally to the reaction mixture, such as not to de-activate the enzyme or enzyme mimetic, until an amount approximately stoichiometric with the amount of antioxidant marcromonomer or cocacromonomers has been added.

Although the enzyme or enzyme mimetic or the chemical initiator is responsible for formation of phenol-based free radicals needed for chain propagation, the coupling of radicals to form a polymer chain is controlled by the phenoxy radical and solvent chemistries. Further details regarding the coupling of phenoxy radicals can be found in "Enzymatic catalysis in monophasic organic solvents," Dordick, J.S., Enzyme Micy=ob. Technol. 11:194-211 (1989), the contents of which are incorporated herein by reference. Coupling between substituted benzene monomers typically occurs ortho and/or para to a hydroxyl group.
Coupling rarely occurs meta to a hydroxyl group.

Polymerization preferably results in the formation of C-C bonds between substituted benzene repeat units (i.e., the benzene rings are directly attached. to each other in a chain).
Preferred polymers will contain at least about 99% C-C bonds, at least about 98% C-C bonds, at least about 95% C-C bonds, at least about 90% C-C bonds, at least about 80% C-C bonds, at least about 70% C-C bonds, at least about 60% C-C bonds or at least about 50%
C-C bonds.
Especially preferred polymers contain about 100% C-C bonds.

In part, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer comprising an antioxidant moiety. In a further embodiment, polymerization is carried out with a catalyst selected from the group consisting of a peroxidase, laccase, tyosinase, lipase, hematin, metal-salen complex, metallocene, a cationic initiator, an anionic initiator, a radical initiator, or metal halide. In a further embodirnent, the catalyst is horse radish peroxidase (HRP). In a further embodiment, the catalyst is a Fe-salen complex. In a further embodiment, the catalyst is AIBN.

In part, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer comprising an antioxidant moiety, wherein the macromonomer comprises a benzene ring substituted with an antioxidant moiety.
In another embodiment, the macromonomer is an alkene substituted with an antioxidant moiety.

In part, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer comprising an antioxidant moiety, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring. In a fiu-ther embodiment, the benzene ring is substituted with at least one bulky alkyl group. In a further embodiment, the bulky alkyl group is a t-butyl group. In a further embodiment, the t-butyl group is adjacent to the hydroxy group. In a further embodiment, the benzene ring is substituted with 2 t-butyl groups adjacent to the hydroxy group.

In part, the present invention relates to a method of preparing an antioxidant polymer comprising reacting a catalyst with a macromonomer having formula I:

M
(CH2)n Z

(CH2)m R R
R R
OH
I

wherein, independently for each occurrence, n and m are integers from 0 to 18, inclusive;

Z is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NH-, -CH=N-, -N=CH-, -C(O)-, -0-, -S-, -S-S-, -S=N-, -N=S-, -C(S)0-, -OC(S)-, -OP(O)(0R4)O-, -OP(OR4)O-, -C(O)OC(O)-, or a bond;
Rl Rl -Z-(CH2)n 0 OH
R is H, C1_6 alkyl, -OH, -NHa, -SH, aryl, ester, or R, , R, , wherein at least one R adjacent to the -OH group is a bulky alkyl group;

Rl is H, C1_6 alkyl, aryl, aralkyl, -OH, -NH2, -SH, or ester wherein at least one Rl adjacent to the -OH group is a bulky alkyl group;

R4 is H, C1_6 alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and R2 ~ R2 R3" \Y R3 M is ~ or ~I
wherein RI Ri ~ -Z-(CH2)n 0 OH
R2 is H, Cl_6 alkyl, -OH, -NH2, -SH, aryl, ester, or R, R, , wherein at least one R2 is -OH; and R3 is H, C1_6 alkyl, aryl, aralkyl, -OH, -NH2, -SH, or ester.

In a further embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising reacting a catalyst with a macromonomer of formula I and the attendant definitions, wherein the catalyst is selected from the group consisting of a peroxidase, laccase, tyosinase, lipase, hematin, metal-salen complex, metallocene, a cationic initiator, an anionic initiator, a radical initiator, or metal halide. In another embodiment, the catalyst is horse radish peroxidase (HRP). In another embodiment, the catalyst is a Fe-salen complex. In a another embodiment, the catalyst is AIBN.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein Z is -OC(O)-. In another embodiment, Z is -C(O)O-. In another embodiment, Z is -C(O)NH-. In another embodiment, Z is -NHC(O)-. In another embodiment, Z is -NH-. In another embodiment, Z is -CH=N-. In another embodiment, Z is -N=CH-. In another embodiment, Z is -C(O)-. In another embodiment, Z is -0-. In another embodiment, Z
is -C(O)OC(O)-. In another embodiment, Z is -S-. In another embodiment, Z is -S-S-. In another embodiment, Z is -N=S-. In another embodiment, Z is -S=N-. In another embodiment, Z is -C(S)O-. In another embodiment, Z is -OC(S). In another embodiment, Z is -OP(O)(OR~)O-. In another embodiment, Z is -OP(OR4)O-. In another embodiment, Z
is a bond.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein both R groups adjacent to -OH are bulky alkyl groups. In a further embodiment, both R groups are t-butyl.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant R2 I ~ R2 definitions, wherein M is Vl\.O

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant R3~ R3 definitions, wherein M is LAJ

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant Rl -Z-(CH2)n O OH
definitions, wherein at least one R is Rl In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein m is 1.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0 and m is 1.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0, m is 1, and Z is -C(O)O-.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0, m is 1, Z is -C(O)O-, and the two R groups adjacent to the OH are t-butyl.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0, m is 1, Z is -C(O)O-, the two R groups adjacent to the OH are t-butyl, R2' R2 R2 ~ R2 andMis VIV

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0, m is 1, Z is -C(O)O-, the two R groups adjacent to the OH are t-butyl, R2 ( R2 R2 ~ R2 M is %-r%J , and the R2 in the para position is OH.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0, m is 1, Z is -C(O)O-, the two R groups adjacent to the OH are t-butyl, M is ulv , the R2 in the para position is OH, and an adjacent R2 is OH.

In another embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant definitions, wherein n is 0, m is 1, Z is -C(O)O-, the two R groups adjacent to the OH are t-butyl, M is ~n= , the R2 in the para position is OH, and the two adjacent R2's are OH.

In a further embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polymerizing a macromonomer of formula I and the attendant defmitions, wherein n is 0, m is 1, Z is -C(O)O-, the two R groups adjacent to the OH are t-butyl, R34;r R3 andMis V~V

In a further embodiment, the present invention relates to a method of preparing an antioxidant polymer comprising polynlerizing a macromonomer of formula I and the attendant defmitions, wherein n is 0, m is 1, Z is -C(O)O-, the two R groups adjacent to the OH are t-butyl, R3'~- R3 M is and R3 is H.

Polymerization of antioxidant macromonomers described above were enzymatically synthesized using either 1) horse radish peroxidase (HR.P) as a biocatalyst or biomimetic type catalysts like 2) Hematin or Fe-Salen.

1) Enzymatic Polymerization of Macromonomer Antioxidants Using HRP

The typical scheme for enzymatic, polymerization is presented in Scheme 1.

Scheme 1. HRP enzymatic polymerization of macromonomer antioxidants.

OH OH
I \ \
HRP, H2O2 n =0 C=O
p MeOH,pH7 t-Bu t-Bu t-Bu t-Bu OH
OH
Polymer 1 In the case of macromonomers containing substituted hindered phenols, the enzymatically synthesized polymer chain may contain both C-C and C-O-C
couplings in the backbone. There is a possibility that these polymeric materials may differ in color from that of starting monomeric antioxidants as a result of partial delocalization of electrons through C-C
bonds between the phenolic repeating units. If the color of the polymeric antioxidant is due to its inherent nature arising from the C-C couplings and delocalization of electrons, it is possible to circunivent such color problem by using acrylate functionalized phenolic macromonomers in the formation of polymeric antioxidants.
Macromonomer antioxidant compound 6 was polymerized using an initiator, a,a'-azobis(isobtyronitrile) (AIBN) to obtain polymeric macromonomer antioxidants.
Polymerization reaction was performed in THF solution. The structure of the polymer was confirmed by high resolution NMR (Figure 2b). The disappearance of the signals corresponding to olefinic protons indicated the polymerization reaction.

2) Biomimetic Polymerization ofMacromonomer Antioxidants Using Fe-Salen The typical scheme for bionAmetic polymerization is presented in Scheme 2.

Scheme 2. Biomimetic polymerization of macromonomer antioxidants.

OH OH
I \ \
Fe-Salen, H202 C=O C=O
TBF I

t-Bu t-Bu t-Bu t-Bu OH OH
Polymer 1 PeffoYmance ofPolymeric .1Vlacromonomer Antioxidants in Polyolefins The ASTM D3895 method was used to evaluate the performance of antioxidants in polyolefins. This is an accelerated ageing test at elevated temperatures under oxygen atmosphere. In the ASTM D3895 and DIN EN 728 method, a differential scanning calorimetry (DSC) instrument is used to detect the degradation by exothermic behavior of the polymeric materials containing antioxidants. The typical experimental conditions were as follows: the sample was heated at 20 C/min to reach 200 C in the nitrogen atmosphere. At this temperature, -the sample was held at constant 200 C for 3 minutes in nitrogen atmosphere.
At the end of this 3 minutes period, gas was changed to oxygeri (20.ml/min flow rate). The sample was continued to hold at 200 C till the sample starts degrading. This is indicated by sudden increase in the exothermic heat.flow as presented in the DSC curve (See Figure 3).

The isothermal oxidative induction time (OIT) is used to compare the performance polymeric antioxidants in polyolefins. The polypropylene samples were extruded into small pellets by mixing with 200 ppm by weight of antioxidants. Figure 3 shows the OIT plots for these materials. The performance of polymeric macromonomer antioxidant is ca.
385 % better compared to Irgonox 1010.

The performances of these antioxidants were also tested by comparing OIT
values for polypropylene samples containing 0.5% level of antioxidants. The OIT values for PP containing polymeric macromonomer antioxidant and Irganox 1010 are 8.0 min and 33.2 minutes, respectively. These results are summarized in Table 1.

Table 1. Comparison of polymeric macromonomer antioxidants with monomeric antioxidants (ASTM D3895 method).

Concentration of Antioxidant OIT in Minutes for Polypropylene Samples with Irganox Polymer AO
200 ppm 0.7 min 2.5 min 5,000 ppm 8.0 min 33.0 min Physical Properties of the Polymeric Macromonomer Antioxidants In certain embodiments, the polymeric macromonomer antioxidant of the subject compositions, e.g., which include repetitive.elements shown in any of the macromonomer formulas, have molecular weights ranging from about 2000 or less to about 1,000,000 or more daltons, or alternatively about 10,000, 20,000, 30,000, 40,000, or 50,000 daltons, more particularly at least about 100,000 daltons, and even more specifically at least about 250,000 daltons or even at least 500,000 daltons. Number-average molecular weight (Mn) may also vary widely, but generally fall in the range of about 1,000 to about 200,000 daltons, or even from about 1,000 to about 100,000 daltons or even from about.1,000 to about 50,000 daltons. In one embodiment, Mn varies between about 8,000 and 45,000 daltons. Within a given sample of a subject polymer, a wide range of molecular weights may be present. For example, molecules within the sample may have molecular weights which differ by a factor of 2, 5, 10, 20, 50, 100, or more, or which differ from the average molecular weight by a factor of 2, 5, 10, 20, 50, 100, or more. For food or edible products (e.g., products fit for human consumption), the molecular weight is advantageously selected to be large enough so that an antioxidant polymer cannot be absorbed by the gastrointestinal tract, such as greater than 1000 amu. For antioxidant polymers blended with a polymeric material, the molecule weight is advantageously selected such that the rate of diffusion of the antioxidant polymer through the polymeric material is slow relative to the expected lifetime of the polymeric material.

One method to determine molecular weight is by gel permeation chromatography ("GPC"), e.g., mixed bed columns, CHZC12 solvent, light scattering detector, and off-line dn/dc.
Other methods are known in the art.

In certain embodiments, the intrinsic viscosities of the polymers generally vary from about 0.01 to about 2.0 dL/g in chloroform at 40 C, alternatively from about 0.01 to about 1.0 dL/g and, occasionally, from about 0.01 to about 0.5 dL/g.

The glass transition temperature (Tg) of the subject polymers may vary widely, and depend on a variety of factors, such as the degree of branching in the polymer components, and the like. When the polymeric macromonomer antioxidant of the invention is a rigid solid, the Tg is often within the range of from about -10 C to about 80 C, particularly between about 0 and 50 C and, even more particularly between about 25 C to about 35 C. In other embodiments, the Tg is low enough to keep the composition of the invention flowable at ambient temperatures.
Then, the glass transition temperature of the polymeric macromonomer antioxidant used in the invention is usually about 0 to about 37 C, or alternatively from about 0 to about 25 C.

Antioxidant polymers of the present invention can be either homopolymers or copolymers. A copolymer preferably contains two or more or three or more different repeating monomer units, each of which has varying or identical antioxidant properties (including monomers having no antioxidant activity). The identity of the repeat units in a copolymer can be chosen to modify the antioxidant properties of the polymer as a whole, thereby giving a polymer with tunable properties. The second, third and/or further repeat units in a copolymer can be either a synthetic or natural antioxidant. In one example, a composition of the invention includes one or more homopolymers and one or more copolymers (e.g., in a blend).
Preferably, both homopolymers and copolymers include two or more substituted benzene repeat units that are directly connected by a C-C or C-O-C bond. Preferably, at least 50%, such as at least 70%, for example, at least 80%, but preferably about 100% of the repeat units in a copolymer are substituted benzene repeat units directly connected by a C-C or C-O-C bond.

Antioxidant polymers of the present invention are typically insoluble in aqueous media.
The solubility of the antioxidant polymers in non-aqueous media (e.g., oils) depends upon the molecular weight of the polymer, such that high molecular weight polymers are typically sparingly soluble in non-aqueous media. When an antioxidant polymer of the invention is insoluble in a particular medium or substrate, it is preferably well-mixed with that medium or substrate.

Antioxidant polymers of the present invention can be branched or linear, but are preferably linear.

Synthesis of Maeromonomer Antioxidants The macromonomer antioxidants of the present invention may be prepared by several different methods and starting materials. The following are synthetic routes to formation of the macromonomer antioxidants: 1) esterification, 2) amidification, 3) ketone formation, 4) alkylation, and 5) anhydride formation.

1) Esterifieation In this approach, two molecules or more possessing antioxidant properties are used to form a macromolecular antioxidant molecule through an esterification process.
Suitable antioxidant-acid type molecule and/or antioxidant-alcohol type molecule are coupled to form an ester linkage by one of the following methods: a) chemical routes b) enzymatic routes, and c) chemoenzymatic routes.
a) Chemical routes Scheme 3 depicts the chemical coupling of acid chloride with antioxidant-alcohol in the presence of base like triethyl amine followed by deacetylation to fortn a macromonomer of the present invention.
Scheme 3. Chemical coupling synthesis of a macromonomer.
OH OAc OAc OH
t-Bu t-BU I \ triethyl amine 2%HCI-MeOH
-~-~ deprotection CH2OH COCI C=0 C=0 O O
I I

I I
t-Bu t-Bu t-Bu t-Bu OH OH
Compound 1 1H NMR characterization is depicted in Figures 1 a-1 c. Formation of an ester linkage is clearly evident from the shift of benzylic protons from 4.6 ppm in alcohol to 5.35 ppm in the acetylated ester product and disappearance of acidic proton of 4-acetoxy benzoic acid at 10 ppm in the product (Figure 1 a). The disappearance of acetoxy peaks at 2.3 ppm in Figure lb is the indication of deacetylation of the final product.

Alternatively, macromonomer compound 1 and analogs thereof could be prepared by refluxing the mixture of 4-hydroxy benzoic acid and 3, 5 di-tert-butyl-4-hydroxy-benzyl alcohol in toluene in presence of anhydrous para-toluene sulponic acid. Journal of Natural Products, 2003, Vol. 66, No. 5.

Another possible chemical synthetic approach for the formation of compound 1 and analogs thereof is the esterification of 4-hydroxy- benzoic acid with 3, 5 di-tert-butyl-4-hydroxy-toulene (BHT) using sodium bromate and sodium hydrogen sulphite at ambient temperature under a two phase systems as depicted in Scheme 4. Tetrahedron (2003), 59, 5549-5554.
Scheme 4. Sodium bromate and sodium hydrogen sulphite coupling.

OH OH OH
t-Bu t-Bu sodium bromate sodium hydrogen sulphite CH3 COOH i =O
O
I

t-Bu t-Bu OH

Compound 1 Analogs of compound 1 can be prepared by the above methods starting with 3,4-dihydroxy benzoic acid and 3, 4, 5-trihydroxybenzoic acid (Gallic acid) and are depicted below as compounds 2 and 3, respectively, or by coupling 4-hydroxy-benzyl alcohol and 3,5-di-tert-butyl-4-hydroxy-propionyl chloride to yield compound 4.

OH
OH OH
HO HO OH

C=0 C=0 ~
~
O O C=0 H2C H2C (CH2)2 f f f t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu OH OH OH
Compound 2 Compound 3 Compound 4 b) Enzymatic routes The general scheme for the synthesis of macromonomer antioxidant molecules either in bulk or solvent medium using lipase as a biocatalyst is presented in Scheme 5.

Scheme 5. Enzymatic routes to macromonomer antioxidants.

OH
OH OH
t-Bu t-Bu + Lipase (! H2)n / C=0 I
(CH2n (CH2)n O
I (CH2)n R R

R= OH, COOH, COOAIkyl f-Bu t-Bu n=0,1,2,3....... k OH

The following scheme shows the synthesis of 4-hydroxy phenyl acetic acid -3, 5-di-tert butyl 4-hydroxybenzyl alcohol ester via the enzymatic route.

Scheme 6. Synthesis of 4-hydroxy phenyl acetic acid -3, 5-di-tert butyl 4-hydroxybenzyl alcohol ester.

OH OH OH
t-Bu t-Bu ~
lipase, toulene ~ /.
molecular seives CH2COOH CH2OH C=0 O

t-Bu t-Bu OH
Compound 5 This procedure was also repeated in which toluene solvent was replaced by dimethoxy polyethylene glycol.

A transesterification approach is also possible via the enzymatic route as depicted in Scheme 7.

Scheme 7. Enzymatic synthesis involving transesterification.

OH OH
OH
t-Bu t-Bu + lipase, toulene molecular seives CH2OH C=0 CH2COOMe u t-Bu OH
Compound 5 The macromonomer antioxidants of the present invention may also comprise an acrylate moiety as depicted in Scheme 8.

Scheme 8. Enzymatic route to methacrylic macromonomer antioxidants.

O
Novozyxne 435 + ~
O"~ O
t-Bu t-Bu 40 OC, toluene, 8h O ( /
OH t-Bu t-Bu OH
Compound 6 c) Chemoenzymatic routes Scheme 9 represents a chemoenzymatic route for the formation of macromonomer antioxidant compound 1.

Scheme 9. Chemoenzymatic preparation of compound 1.

OH
OH OH OH
t-Bu t-Bu CF CH OH lipase HZ o + C-0 O

t-Bu t-Bu OH
Compound 1 Similarly vinyl ester promotes the coupling effectively by shifting the reaction towards product.

2) Amidification The general scheme for the macromonomer antioxidant synthesis via amidification method is presented in Scheme 10 for the chemical route and Scheme 11 for the enzymatic route.

Scheme 10. Macromonomer antioxidant synthesis via chemical amidification.

OH
OH OH

t-Bu \ t-Bu tfiethylamine I ~ + (CH2)n NH
(CH2)n ( C H2)n C=0 R R (CH2)n R = COCl, NH2 n=1,2,3,....k t-Bu t-Bu OH
Compound 7 Scheme 11. Macromonomer antioxidant synthesis via enzymatic amidification.
OH
OH OH

t-Bu t-Bu lipase ( + I-12)n ~
C=0 (CH2)n (CH2)n NH
R R (CH2)n R NH2, COOH, COOalkyl I
n=1, 2, 3, ....k t-Bu t-Bu OH
Compound 9 3) Ketone Formation Under this synthetic route, Friedel-Craft acylation reactions are used to synthesize antioxidant macromonomers.

For example, 2,6-di-tert butyl phenol can be acylated with 4-hydroxy-benzoyl chloride in presence of Lewis acids like aluminum trichloride, boron trifluoride, or zinc chloride, etc. to produce Compound 10 as depicted in Scheme 12.

Scheme 12. Friedel-Craft acylation.

OH
OH OH
t-Bu t-Bu + 0=C
COCI
t-Bu t-Bu OH

Compound 10 This reaction is equally applicable to 3, 4 dihydroxy benzoyl chloride and 3,4,5 trihydroxy benzoyl chloride as acylating agents.

Resorcinol can be acylated with 3,5-di-tert-butyl-4-hydroxy-propionyl chloride, 3,5-di-tert-butyl-4-hydroxy acetyl chloride, or 3, 5 di-tert-butyl-4-hydroxy-benzoyl chloride etc. in the presence of a Lewis acid like aluminum trichloride, boron trifluoride, zinc chloride etc. to form antioxidant macromonomers (Compound 11) as depicted in Scheme 13.

Scheme 13. Acylation of resorcinol.

HO OH
OH I /
HO OH t-Bu t-Bu ( ~ + I / ZnCl7 CH O
/ ~ 2 t-Bu t-Bu OH
Compound 11 In a similar way, pyragallol can also be acylated with 3,5-di-tert-butyl-4-hydroxy-propionyl chloride, 3,5-di-tert-butyl-4-hydroxy acetyl chloride, or 3,5-di-tert-butyl-4-hydroxy-benzoyl chloride etc. in the presence of a Lewis acid like aluminum trichloride, boron trifluoride, zinc chloride, etc. to produce antioxidant monomers (Compound 12) as depicted in Scheme 14.
Scheme 14. Acylation of pyragallol.

OH
HO OH
OH OH I . /
HO OH + t-Bu t-Bu ZnCI, CH O

(;H2CH2COCI CH2 I
t-Bu t-Bu OH
Compound 12 4) Alkylatiofa It is possible to reduce the carbonyl group in compounds 10, 11, and 12 to form a new set of macromonomer antioxidants shown below as compounds 13, 14, and 15, respectively, using a wide range of reducing agents including lithium aluminum hydride (LiAlH4)and sodium borohydride (NaBH4).

OH
HO OH HO " OH
OH

\ I \ I
t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu OH OH OH
Compound 13 Compound 14 Compound 15 5) Anlaydride Formation The general scheme for this process is shown in Scheme 15 using triethylamine as a base in the formation of anhydride macromonomer structures.

Scheme 15. Anhydride synthetic route to macromonomer antioxidants.
OH
OH OH

t-Bu t-Bu (CH2)n + I
C=0 (CH2)n (CH2)n C=O
R R (CH2)n R = COOH, COCl n = 0,1,2,3.......k t-Bu t-Bu OH
Applications The antioxidant polymers of the present invention can be used in a variety of applications. Antioxidant polymers of the present invention can be present in a wide variety of compositions where free radical mediated oxidation leads to deterioration of the quality of the composition, including edible products. such as oils, foods (e.g., meat products, dairy products, cereals, beverages, crackers, potato flakes, bakery products and mixes, dessert mixes, nuts, candies, etc.), and other products containing fats or other compounds subject to oxidation (e.g., chewing gum, flavorings, yeast, etc.).

Antioxidant polymers can also be present in plastics and other polymers, elastomers (e.g., natural or synthetic rubber), petroleum products (e.g., mineral oil, fossil fuels such as gasoline, kerosene, diesel oil, heating oil, propane, jet fuel), adhesives, lubricants, paints, pigments or other colored items, soaps and cosmetics (e.g., creams, lotions, hair products). Soaps and cosmetics, in particular, benefit from the addition of a large proportion of one or more antioxidant polymers of the invention. Soaps and cosmetics can contain, for example, about 1%
to about 20% (e.g., about 5% to about 15%) by weight of antioxidant polymer.

The antioxidant polymers can be used to coat a metal as a rust and corrosion inhibitor.
Antioxidant polymers additionally can protect antioxidant vitamins (Vitamin A, Vitamin C, Vitasnin. E) and pharmaceutical products (i.e., those containing a pharmaceutically active agent) from degradation. The addition of antioxidant polymers is particularly advantageous when the vitamin or pharmaceutically active agent is present in a liquid composition, although the antioxidant polymers is expected also to have a benefit in solid compositions.

In food products, the antioxidant polymers will prevent rancidity. In plastics, the antioxidant polymers will prevent the plastic from becoming brittle and cracking.

Antioxidant polymers of the present invention can be added to oils to prolong their shelf life and properties. These oils can be formulated as vegetable shortening or margarine. Oils generally come from plant sources and include cottonseed oil, linseed oil, olive oil, palm oil, corn oil, peanut oil, soybean oil, castor oil, coconut oil, safflower oil, sunflower oil, canola (rapeseed) oil and sesame oil. These oils contain one or more unsaturated fatty acids such as caproleic acid, palmitoleic acid, oleic acid, vaccenic acid, elaidic acid, brassidic acid, erucic acid, nervomc acid, linoleic acid, eleosteric acid, alpha-linolenic acid, gamma-linolenic acid, and arachidonic acid, or partially hydrogenated or trans-hydrogenated variants thereof. Antioxidant polymers of the present invention are also advantageously added to food or other consumable products containing one or more of these fatty acids.

The shelf life of many materials and substances contained within the materials, such as packaging materials, are enhanced by the presence of an antioxidant polymer of the present invention. The addition of an antioxidant polymer to a packaging material is believed to provide additional protection to the product contained inside the package. In addition, the properties of many packaging materials themselves, particularly polymers, are enhanced by the presence of an antioxidant regardless of the application (i.e., not limited to use in packaging). Common examples of packaging materials include paper, cardboard and various plastics and polymers. A
packaging material can be coated with an antioxidant polymer (e.g., by spraying the antioxidant polymer or by applying as a thin film coating), blended with or mixed with an antioxidant polymer (particularly for polymers), or otherwise have an antioxidant polymer present within it.
In one example, a thermoplastic polymer such as polyethylene, polypropylene or polystyrene is melted in the presence of an antioxidant polymer in order to minimize its degradation during the polymer processing. An antioxidant polymer can also be co-extruded with a polymeric material.

One example of a packaging material included in the present invention is commonly referred to as "smart packaging". Smart packaging is designed, for example, such that it controls gas exchange through the packaging. Examples of smart packaging are described in U.S. Patent Nos. 5,911,937, 5,320,889 and 4,977,004, the contents of which are incorporated herein in their entirety. One conventional type of smart packaging involves a layer of an oxygen barrier such as nylon or poly(ethylene-co-vinyl alcohol) that is typically sandwiched between one or more layers of a moisture-resistant polymer or polymer blend such as polyethylene terephthalate, poly(vinylidene chloride), poly(vinyl chloride), poly(ethylene) or poly(propylene). The layers of moisture-resistant polymer can be either the same or different. In the present invention, one or more of the antioxidant polymers described herein can be added as an additional layer or can be blended with a layer of the packaging material.

One example of a composition that is particularly suitable as a packaging material includes polyethylene and polymer 1, typically where the two polymers are blended together.
The proportion of polymer 1 in the composition is typically about 1 ppm to about 1,000 ppm, such as about 10 ppm to about 100 ppm. The composition can be, for example, in the form of a film or a pellet. The composition can also include a macromonomeric antioxidant, such as compounds 1-15. When the macromonomeric antioxidant is present, the concentration is typically about 1 ppm to about 1,000 ppm.

The concept of having a mixture of an antioxidant polymer and another antioxidant or polymer can generally be applied to combinations of one or more antioxidant polymers described herein and one or more synthetic and/or natural monomeric and/or oligomeric antioxidants and/or preservatives. Such compositions are expected to have both short-term and long-term antioxidant activity. The ratio of polymer to macromonomer and/or oligomer in a composition can be selected so that the composition has the desired set of properties. For example, the ratio of polymer to macromonomer and/or oligomer can be about 1:100 to about 100: 1, such as about 1:10 to about 10:1. Typically, the absolute concentration of antioxidant polymers in such compositions ranges from about 0.1 ppm to about 10,000 ppm.

Exemplification Example 1 Chemical coupling of acid chloride and antioxidant-alcohol. Thionyl chloride was added drop wise to the suspension of 4-acetoxy benzoic acid in chloroform and the reaction mixture was refluxed. After refluxing the reaction mixture for 4 hours; chloroform and excess thionyl chloride were distilled out under vacuum. The white colored acid chloride product was dried under vacuum for 2 hours and then dissolved in dry dichloromethane. The solution of triethylamine and 3, 5 di-tert-butyl-4-hydroxy-benzyl alcohol in dry dichloromethane was added drop wise to it to obtain a yellow colored clear solution and the reaction mixture was stirred for additional 5 hours at room temperature in nitrogen atmosphere. The saturated aqueous sodium bicarbonate solution was then added and the reaction mixture was stirred for additiona130 minutes. The organic layer was separated and triethylamine-hydrochloride was washed off with water, and the product was dried and evaporated under vacuum and subjected later to column chromatography (ethyl acetate-petroleum ether) to obtain the desired ester.

The above ester product was then dissolved in 2% HCl-MeOH solution and stirred at room temperature for deacetylation to occur. After 5 hours, the reaction mixture was poured into large amount of ice-cold water and the solution was extracted with ethyl acetate, and the product was evaporated and then dried. The 'H NMR spectra of starting materials 4-acetoxy benzoic acid and 3,5-di-tert butyl 4-hydroxy benzyl alcohol and coupled product are depicted in Figures 1 a-1 c, respectively.

Example 2 Enzymatic synthesis of antioxidant macromonomer, 4-hydroxy phenyl acetic acid -3, 5-di-tert butyl 4-hydroxybenzyl alcohol ester. To the suspension of 3, 5 di-tert-butyl-4-hydroxy-benzyl alcohol and 4-hydroxy-phenyl-acetic acid in toluene in the presence of molecular sieves was added Candida Antarctica LipaseB (novozyme 435).. The reaction mixture was stirred at 60 C for 20 hours. After the completion of reaction; macromonomer (Compound 5) was purified using column chromatography (ethyl acetate petroleum ether). The molecular structure of this compound was confirmed to Structure VII by high resolution proton NMR.

Example 3 Enzymatic synthesis of antioxidant macromonomer, 4-hydroxy phenyl acetic acid -3, 5-di-tert butyl 4-hydroxybenzyl alcohol ester involving transesterification. To the suspension of 3, 5 di-tert-butyl-4-hydroxy-benzyl alcohol and 4-hyroxy-phenyl-acetic acid methyl ester in toluene was added Candida Antarctica Lipase B(novozyme 435). The molecular sieves were added to trap methanol that was produced as a result of transesterification.
The reaction mixture was stirred at 60 C for 20 hours. Macromonomer compound (Compound 5) was separated using column chromatography. The formation of the compound was confirmed by high resolution proton NMR.

Example 4 Acrylate based antioxidant vinyl macromonomers. Macromonomer antioxidant was prepared using lipase (Novozyme 435) to couple 3,5-di-tert-butyl-4-hydroxybenzyl alcohol to the vinyl ester monomer of methacrylic acid. The enzymatic reaction was carried out at 40 C
for 8 hours in toluene. The reaction product was separated and the structure of the macromonomer product was confirmed by high resolution proton NMR.
Example 5 Chemoenzymatic coupling. 4-hydroxy 2, 2, 2 -trifluoro ethyl benzoate was synthesized by adding a trace amount of sulfuric acid to the mixture of trifluoro ethanol and 4-hydroxy-benzoic acid. Trifluoro-ester promotes the coupling effectively by shifting the reaction towards product the ester. The lipase catalyzed transesterification of this compound with 3, 5 di-tert-butyl-4-hydroxy-benzyl alcohol gives the compound in Structure II(K. Faber, Biotransformations in Organic Synthesis, Springer, New York, 2000, page 347).

Example 6 HRP enzymatic polymerization of macromonomer antioxidant. Macromonomer (compound 1, 0.5 mmole) was dissolved in MeOH: pH=7 (10m1) phosphate buffer and 5 mg of HRP enzyme was added to it. To the reaction mixture 5% hydrogen peroxide solution was added incrementally over the period of 3' hours. After completion of addition, the reaction mixture was stirred for additiona124 hours. After completion of reaction methanol and water were removed, and the product was washed with water and dried. The polymer was characterized using high resolution proton NMR and the molecular weight was estimated to be 3500 using gel permeation chromatography (GPC) with reference polystyrene standards.

Example 7 Fe-salen biomimetic polymerization of macromonomer antioxidant. Compound 1 (4g) was dissolved in THF (20m1) and 80 mg of Fe-Salen was added to it. To the reaction mixture 25%
hydrogen peroxide solution was added incrementally over the period of 1 hour.
After completion of addition, the reaction mixture was stirred for additiona124 hours. After completion of reaction THF was removed, product washed with water and dried.

Incorporation by Reference All of the patents and publications cited herein are hereby incorporated by reference.
Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (63)

1. A method of preparing an antioxidant polymer comprising polymerizing a macromonomer comprising an antioxidant moiety.

2. The method of claim 1, wherein polymerization is carried out with a catalyst selected from the group consisting of a peroxidase, laccase, tyosinase, lipase, hematin, metal-salen complex, metallocene, a cationic initiator, an anionic initiator, a radical initiator, or a metal halide.

3. The method of claim 2, wherein the catalyst is horse radish peroxidase (HRP).

4. The method of claim 2, wherein the catalyst is a Fe-salen complex.

5. The method of claim 2, wherein the catalyst is AIBN.

6. The method of claim 1, wherein the macromonomer comprises a benzene ring substituted with an antioxidant moiety.

7. The method of claim 1, wherein the macromonomer comprises a benzene ring substituted with an antioxidant moiety, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring.

8. The method of claim 1, wherein the macromonomer is an alkene substituted with an antioxidant moiety.

9. The method of claim 1, wherein the macromonomer is an alkene substituted with an antoxidant moiety, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring.

10. The method of claim 1, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring.

11. The method of claim 1, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring wherein the benzene ring is further substituted with at least one bulky alkyl group.

12. The method of claim 1, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring wherein the benzene ring is further substituted with at least one t-butyl group.

13. The method of claim 1, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring wherein the benzene ring is further substituted with at least one t-butyl group adjacent to the hydroxy group.

14. The method of claim 1, wherein the antioxidant moiety comprises a hydroxy substituted benzene ring wherein the benzene ring is further substituted with 2 t-butyl groups adjacent to the hydroxy group.

15. A method of preparing an antioxidant polymer comprising polymerizing a macromonomer having formula I:

wherein, independently for each occurrence, n and m are integers from 0 to 18, inclusive;

Z is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NH-, -CH=N-, -N=CH-, -C(O)-, -O-, -S-, -S-S-, -S=N-, -N=S-, -C(S)O-, -OC(S)-, -OP(O)(OR4)O-, -OP(OR4)O-, -C(O)OC(O)-, or a bond;
R is H, C1-6 alkyl, -OH, -NH2, -SH, aryl, ester, or wherein at least one R adjacent to the -OH group is a bulky alkyl group;

R1 is H, C1-6 alkyl, aryl, aralkyl, -OH, -NH2, -SH, or ester wherein at least one R1 adjacent to the -OH group is a bulky alkyl group;

R4 is H, C1-6 alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and M is wherein R2 is H, C1-6 alkyl, -OH, -NH2, -SH, aryl, ester, or wherein at least one R2 is -OH; and R3 is H, C1-6 alkyl, aryl, aralkyl, -OH, -NH2, -SH, or ester.

16. The method of claim 15, wherein polymerization is carried out with a catalyst selected from the group consisting of a peroxidase, laccase, tyosinase, lipase, hematin, metal-salen complex, metallocene, a cationic initiator, an anionic initiator, a radical initiator, and metal halide.

17. The method of claim 16, wherein the catalyst is horse radish peroxidase (HRP).

18. The method of claim 16, wherein the catalyst is a Fe-salen complex.

19. The method of claim 16, wherein the catalyst is AIBN.

20. The method of claim 15, wherein Z is -OC(O)-.

21. The method of claim 15, wherein Z is -C(O)O-.

22. The method of claim 15, wherein Z is -C(O)NH-.

23. The method of claim 15, wherein Z is -NHC(O)-.

24. The method of claim 15, wherein Z is -NH-.

25. The method of claim 15, wherein Z is -CH=N-.

26. The method of claim 15, wherein Z is -N=CH-

27. The method of claim 15, wherein Z is -C(O)-.

28. The method of claim 15, wherein Z is -O-.

29. The method of claim 15, wherein Z is -C(O)OC(O)-.

30. The method of claim 15, wherein Z is -S-.

31. The method of claim 15, wherein Z is -S-S-.

32. The method of claim 15, wherein Z is -S=N-.

33. The method of claim 15, wherein Z is -N=S-.

34. The method of claim 15, wherein Z is -C(S)O-.

35. The method of claim 15, wherein Z is -OC(S)-.

36. The method of claim 15, wherein Z is -OP(O)(OR4)O-.

37. The method of claim 15, wherein Z is -OP(OR4)O-.

38. The method of claim 15, wherein Z is a bond.

39. The method of claim 15, wherein both R groups adjacent to -OH are bulky alkyl groups.

40. The method of claim 15, wherein both R groups adjacent to -OH are t-butyl.

41. The method of claim 15, wherein M is

42. The method of claim 15, wherein M is

43. The method of claim 15, wherein at least one R is

44. The method of claim 15, wherein n is 0.

45. The method of claim 15, wherein m is 1.

46. The method of claim 15, wherein n is 0 and m is 1.

47. The method of claim 15, wherein n is 0, m is 1, and Z is -C(O)O-.

48. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, and the two R groups adjacent to the OH are t-butyl.

49. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, the two R
groups adjacent to the OH are t-butyl, and M is

50. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, the two R
groups adjacent to the OH are t-butyl, M is and the R2 in the para position is OH.

51. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, the two R
groups adjacent to the OH are t-butyl, M is the R2 in the para position is OH, and an adjacent R2 is OH.

52. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, the two R
groups adjacent to the OH are t-butyl, M is R2 in the para position is OH, and the two adjacent R2's to the para OH are OH.

53. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, the two R
groups adjacent to the OH are t-butyl, and M is

54. The method of claim 15, wherein n is 0, m is 1, Z is -C(O)O-, the two R
groups adjacent to the OH are t-butyl, M is and R3 is H.

55. A method of preparing an antioxidant polymer comprising polymerizing a macromonomer having formula I and at least one other different monomer:

wherein, independently for each occurrence, n and m are integers from 0 to 18, inclusive;

Z is -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NH-, -CH=N-, -N=CH-, -C(O)-, -O-, -S-, -S-S-, -S=N-, -N=S-, -C(S)O-, -OC(S)-, -OP(O)(OR4)O-, -OP(OR4)O-, -C(O)OC(O)-, or a bond;
R is H, C1-6 alkyl, -OH, -NH2, -SH, aryl, ester, or wherein at least one R adjacent to the -OH group is a bulky alkyl group;

R1 is H, C1-6 alkyl, aryl, aralkyl, -OH, -NH2, -SH, or ester wherein at least one R1 adjacent to the -OH group is a bulky alkyl group;

R4 is H, C1-6 alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and M is wherein R2 is H, C1-6 alkyl, -OH, -NH2, -SH, aryl, ester, or wherein at least one R2 is -OH; and R3 is H, C1-6 alkyl, aryl, aralkyl, -OH, -NH2, -SH, or ester.

56. The method of claim 55, wherein polymerization is carried out with a catalyst selected from the group consisting of a peroxidase, laccase, tyosinase, lipase, hematin, metal-salen complex, metallocene, a cationic initiator, an anionic initiator, a radical initiator, and metal halide.

57. The method of claim 55, wherein the catalyst is horse radish peroxidase (HRP).

58. The method of claim 55, wherein the catalyst is a Fe-salen complex.

59. The method of claim 55, wherein the catalyst is AIBN.

60. The method of claim 55, wherein the at least one other different monomer comprises an antioxidant moiety.

61. The method of claim 55, wherein the antioxidant polymer is a random copolymer.

62. The method of claim 55, wherein the antioxidant polymer is block copolymer.

63. The method of claim 55, wherein the antioxidant polymer has bulk antioxidative properties greater than an equivalent amount of antioxidant monomers as measured by ppm by at least 100, 150, 200, 250, 300, 350, 385, or 400%.