U.S. patent application number 13/632280 was filed with the patent office on 2013-07-25 for functionalized polymers using protected thiols.
The applicant listed for this patent is Ralph L. DAVID, Julia A. KORNFIELD. Invention is credited to Ralph L. DAVID, Julia A. KORNFIELD.
Application Number | 20130190504 13/632280 |
Document ID | / |
Family ID | 40567761 |
Filed Date | 2013-07-25 |
United States Patent
Application |
20130190504 |
Kind Code |
A1 |
DAVID; Ralph L. ; et
al. |
July 25, 2013 |
Functionalized Polymers Using Protected Thiols
Abstract
A process for the preparation of functional molecules using the
thiol-ene coupling reaction and a process for the preparation of
protected functional thiols, specifically thioesters is provided.
The methods may be used to make functional polymers and other
molecules. The method of making a functionalized polymer using a
thiol-ene reaction comprises: providing a functionalized thioester
having the following formula: ##STR00001## wherein R is a
functional group and COR' is a protecting group; cleaving the
functionalized thioester, forming a functional thiol and an acyl
group; providing a polymer having a pendant vinyl group; and
reacting the polymer with the functional thiol whereby a
functionalized polymer is formed, wherein the functional thiol is
not isolated prior to reacting with the polymer.
Inventors: |
DAVID; Ralph L.; (Pasadena,
CA) ; KORNFIELD; Julia A.; (Pasadena, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DAVID; Ralph L.
KORNFIELD; Julia A. |
Pasadena
Pasadena |
CA
CA |
US
US |
|
|
Family ID: |
40567761 |
Appl. No.: |
13/632280 |
Filed: |
October 1, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12961136 |
Dec 6, 2010 |
8283438 |
|
|
13632280 |
|
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12251708 |
Oct 15, 2008 |
7847019 |
|
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12961136 |
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60998980 |
Oct 15, 2007 |
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Current U.S.
Class: |
546/342 ;
558/255 |
Current CPC
Class: |
C07D 209/86 20130101;
C07C 327/32 20130101; C07D 213/32 20130101; C07C 323/12 20130101;
Y02P 20/55 20151101; C07C 319/02 20130101; C07D 213/59 20130101;
C07C 319/02 20130101 |
Class at
Publication: |
546/342 ;
558/255 |
International
Class: |
C07C 327/32 20060101
C07C327/32; C07D 213/59 20060101 C07D213/59 |
Claims
1. A functionalized thioester made by a method of preparing a
functionalized thioester comprising: (a) reacting a nucleophilic
starting material having a desired functional group with a
nonsymmetrical bifunctional linker molecule, forming a
functionalized intermediate; and (b) reacting the functionalized
intermediate with a thiol acid to form a functionalized
thioester.
2. A functionalized thioester having the following formula:
##STR00022## wherein R is a functional group and COR' is a
protecting group that is readily cleaved to provide a functional
thiol that may be used without isolation to perform thiol-ene
coupling.
3. The functionalized thioester of claim 2, wherein the protecting
group is an acetyl or benzoyl group.
4. The functionalized thioester of claim 2, wherein the functional
group is selected from the group consisting of: amino acid,
peptide, polypeptide, nucleic acid, lipid, carbohydrate, carbazole,
benzoate, phenol, pyridine, cyanobiphenyl, perfluorocarbon,
polyethylene oxide (PEO) and polypropyleneoxide (PPO) groups
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
12/961,136, filed Dec. 6, 2010, which is a divisional of
application Ser. No. 12/251,708, filed Oct. 15, 2008, which takes
priority from U.S. provisional application Ser. No. 60/998,980,
filed Oct. 15, 2007, hereby incorporated by reference.
STATEMENT ON FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
BACKGROUND OF THE INVENTION
[0003] This invention relates to functional polymers and functional
protected thiol compounds, methods of preparation and use.
[0004] Functionalization of polymers having pendant vinyl groups
using thiol-ene coupling is a powerful and versatile method to
prepare well-defined polymeric materials with tailored properties.
However, commercially available mercaptans are limited to a select
few functional groups. Methods of preparing polymers having a
variety of functional groups are needed.
SUMMARY OF THE INVENTION
[0005] According to the present invention there is provided a
process for the preparation of functional polymers and other
molecules using the thiol-ene coupling reaction and a process for
the preparation of protected functional thiols, specifically
thioesters.
[0006] Generally the method of making functional polymers comprises
reacting a protected functional thioester with a deprotecting agent
and a polymer having one or more pendant vinyl groups.
[0007] The protected functional thioesters prepared using the
methods of the invention can be stored and used when desired by
deprotecting and reacting with a desired molecule such as a polymer
having one or more pendant vinyl groups.
[0008] More specifically, provided is a method of making a
functionalized polymer using a thiol-ene reaction comprising:
providing a functionalized thioester having the following
formula:
##STR00002##
wherein R is a functional group and COR' is a protecting group;
cleaving the functionalized thioester, forming a functional thiol
and an acyl group; providing a polymer having a pendant vinyl
group; and reacting the polymer with the functional thiol whereby a
functionalized polymer is formed, wherein the functional thiol is
not isolated prior to reacting with the polymer. In an embodiment,
the cleaving step is performed by reacting the functionalized
thioester with a cleaving agent. In an embodiment, the cleaving
agent is hydrazine. In an embodiment, the hydrazine is a hydrazine
salt or solution thereof. In an embodiment, the hydrazine salt is
hydrazine acetate. In an embodiment, the hydrazine acetate is
formed from reaction of hydrazine HCl with NaOAc in DMF. In an
embodiment, the protecting group is an acetyl or benzoyl group. The
protected functional thioester is deprotected insitu in the
reaction and is not isolated as a separate thiol molecule. In an
embodiment, the method of making a functionalized polymer is a
one-pot reaction.
[0009] The methods of the invention can be used to functionalize
other molecules having one or more vinyl groups by one of ordinary
skill in the art without undue experimentation. The methods of the
invention can be used to add a functional group to a molecule
having a single vinyl group available for reaction, for example.
For example, in molecular synthesis of fine chemicals and drugs a
C--S bond is often desired. The methods described here can be used
to conveniently add a functional group in a synthetic pathway.
[0010] The polymer having a pendant vinyl group is a polymer having
one or more vinyl groups available for reaction. In an embodiment,
the polymer is a polybutadiene. In an embodiment, the polymer
comprises a 1,2 polybutadiene unit. In an embodiment, the polymer
comprises a polymer or copolymer of butadiene having
1,2-polybutadiene units. As known in the art, polybutadienes may be
prepared with a wide distribution of molecular weight and density
of double bonds. The use of all such distributions and densities
are intended to be included herein. The number of pendant vinyl
groups and the extent of reaction as determined by reaction
conditions (specifically the concentration of reactants and the
reaction time) determine the final structure obtained after
reaction. These variables are well known in the art. Other useful
polymers include any polymer or copolymer of butadiene, isoprene,
2-n-heptyl-1,3-butadiene, ethylene, isobutylene, 1-butene,
acrylonitrile, methacrylonitrile, crotonitrile, vinyl acetate,
vinyl benzoate, vinyl methyl ether, vinyl n-butyl ether, allyl
propionate, allyl benzoate, allyl methyl ester or
5-vinyl-2-norbornene. In embodiments, useful polymers include:
polymers and copolymers of styrene, vinyl benzyl chloride
(hereinafter (VBC)), VBC/styrene/divinylbenzene (hereinafter DVB),
butadiene/styrene/VBC, VBC/butadiene/acrylonitrile,
acrylonitrile/styrene/VBC and isoprene/VBC. The identified polymers
are not intended to be an exhaustive list of useful polymers. This
disclosure is intended to include other polymers that have a
pendant vinyl group. These polymers are known to one of ordinary
skill in the art.
[0011] The polymer having a pendant vinyl group and the
functionalized thioester are combined in the desired stoichiometric
ratio to allow the desired amount of functionalization of the
polymer to occur. In one embodiment of the invention, the amount of
pendant vinyl group:functionalized thioester ranges from 0.1 to 100
mol/mol ratio. In one embodiment of the invention, the amount of
pendant vinyl group:functionalized thioester ranges from 0.01 to
100 mol/mol ratio. In one embodiment of the invention, the amount
of pendant vinyl group:functionalized thioester ranges from 0.5-1.5
mol/mol ratio. The stoichiometric amount is selected based on the
desired C.dbd.C/SH molar ratio.
[0012] In an embodiment, the reactions described here are carried
out at a suitable temperature as easily determined by one of
ordinary skill in the art without undue experimentation. In an
embodiment, a reaction is carried out at a temperature selected
over the range of 10 degrees Celsius to 150 degrees Celsius. In
embodiments, useful solvents for the methods described herein
include: a dimethoxyethane solvent, an ether, a halogenated
solvent, or an aromatic solvent. In embodiments, useful solvents
for the methods described herein include dimethoxyethane,
tetrahydrofuran, chloroform, toluene, benzene, ethylbenzene,
xylenes, tetrachloroethane, methanol:THF, or methanol:chloroform.
In embodiments, the solvent is 20:80 methanol:THF. In embodiments,
the solvent is 20:80 methanol:chloroform. As known in the art,
mixtures of solvents may be used. Such mixtures are included in the
disclosure herein, and are easily determined by one of ordinary
skill in the art without undue experimentation.
[0013] In an embodiment, the functional group is selected from the
group consisting of: amino acid, peptide, polypeptide, nucleic
acid, lipid, carbohydrate, carbazole, benzoate, phenol, pyridine,
cyanobiphenyl, perfluorocarbon, polyethylene oxide (PEO) and
polypropyleneoxide (PPO) groups. In embodiments, small (i.e. MW 500
to 5000) polyethylene oxide (PEO) or polypropyleneoxide (PPO)
groups are used. The functional groups specifically identified
herein are not intended to be limiting. This disclosure is intended
to include other desired functional groups that can be used in the
methods of the invention without undue experimentation.
[0014] In an embodiment, the reaction of the polymer with the
functional thiol is initiated by a free-radical initiator. Any
suitable initiator/method of initiation may be used, including
thermal activation and light activation (such as using UV light).
When light, particularly UV light, is used for the reaction, a
photoinitiator may be required, as known in the art. Initiators and
their use are known in the art. In embodiments, the initiator is
chosen from 2,2-azobisisobutyronitrile (AIBN), benzoyl peroxide
(BPO), diisopropyl peroxydicarbonate (IPP), t-butylhydroperoxide
(TBPO), heat-activated initiators, and light-activated initiators
such as camphorquinone (Aldrich),
4-(2-hydroxyethoxy)-phenyl-(2-hydroxy-2-methylpropyl)ketone
(Irgacure 2959, Ciba-Geigy) and mixtures thereof. The amount of
initiator used is well known in the art, is chosen for a given
reaction temperature to achieve a target rate of initiation, and is
typically 0.1% to 20% molar equivalent of the reactants involved in
the radical reactions.
[0015] Also provided in an embodiment is a method of preparing a
functionalized thioester comprising: (a) reacting a starting
material having a desired functional group with a nonsymmetrical
bifunctional linker molecule, forming a functionalized intermediate
and (b) reacting the functionalized intermediate with a thiol acid
to form a functionalized thioester. As used herein, "functionalized
thioester" is intended to be a protected thiol. In an embodiment,
the starting material is a nucleophile. In an embodiment, the
starting material is an electrophile.
[0016] In embodiments, the method of preparing a functionalized
thioester can take a variety of forms. Although Applicant does not
wish to be bound by theory, the following nonlimiting examples are
provided. In one embodiment, a nucleophilic substitution reaction
of a nucleophile having a desired functional group with a
nonsymmetrical bifunctional linker molecule having two leaving
groups (such as ClCH.sub.2CH.sub.2OTs) is followed by reaction with
a thiol acid to form the functionalized thioester (i.e., a
protected thiol). "Ts" stands for the tosyl group. In one
embodiment, a nucleophilic substitution reaction of a nucleophile
having a desired functional group with a nonsymmetrical
bifunctional linker molecule having one leaving group (such as a
chloroalcohol, for example H(OCH.sub.2CH.sub.2).sub.nCl, where n is
an integer from 1 to 10, for example) is followed by conversion of
the linker's other functional group into a leaving group (e.g. in
the example of a chloroalcohol as the linker, conversion of the
hydroxyl group into a tosylate or other leaving group), followed by
reaction with a thiol acid to form the functionalized thioester.
This reaction allows the use of harsher conditions for the first
step, and is a convenient way to incorporate linkers of different
lengths. In one embodiment, esterifying a carboxylic acid
nucleophilic starting material with a chloroalcohol nonsymmetrical
bifunctional linker molecule, followed by reaction with a thiol
acid is used to form the functionalized thioester. In one
embodiment, reacting a nucleophilic starting material having a
desired functional group with allyl bromide followed by a radical
reaction with a thioacid is used to form the functionalized
thioester.
[0017] As used herein, a "nonsymmetrical bifunctional linker
molecule" contains two different functional groups: one functional
group binds to the starting material functional group and the other
functional group binds to a thiol group. As used herein, "binds"
generally indicates covalent bonding between two moieties.
[0018] The thiol acid (also referred to as thioacid) used can be
any thiol acid. In embodiments, the thiol acid is thiobenzoic acid
or thioacetic acid. In embodiments, the nucleophilic starting
material is a carboxylic acid, an alcohol, an amine, a phenol, or a
heterocyclic nitrogen compound. In embodiments, the bifunctional
linker molecule is a chloroalcohol or allylbromide. In embodiments,
the bifunctional linker molecule is a Cl CH.sub.2CH.sub.2OTs or
H(OCH.sub.2CH.sub.2).sub.nCl, where n is an integer from 1 to 10,
for example. In embodiments, the bifunctional linker molecule is
any molecule which is capable of linking a nucleophilic starting
material with a thioacid.
[0019] In an embodiment, the protecting group for the thiol moiety
is an acetyl or benzoyl group. The protecting groups listed
specifically are not intended to be limiting, and other suitable
protecting groups may be used.
[0020] In embodiments, the functional group is selected from those
functional groups described above. In embodiments, the solvent for
the first step in the reactions is DMSO, although other solvents
may be used, as known in the art including those suitable solvents
and solvent mixtures described elsewhere herein.
[0021] Also provided is a functionalized thioester made by the
methods described herein. Also provided is a functionalized
polymeric material made by the methods described herein.
[0022] Also provided is a functionalized thioester having the
following formula:
##STR00003##
wherein R is a functional group and COR' is a protecting group that
is readily cleaved to provide a functional thiol that may be used
without isolation to perform thiol-ene coupling. The functional
groups and protecting groups can be selected from those groups
described herein.
[0023] Also provided is a method of making a functionalized
molecule using a thiol-ene reaction comprising:
providing a functionalized thioester having the following
formula:
##STR00004##
[0024] wherein R is a functional group and COR' is a protecting
group; cleaving the functionalized thioester, forming a functional
thiol and an acyl group;
providing a molecule having a pendant vinyl group; reacting the
molecule with the functional thiol whereby a functionalized
molecule is formed, wherein the functional thiol is not isolated
prior to reacting with the molecule. The molecule can be any
molecule having a pendant vinyl group, including small molecules
and fine chemicals.
[0025] All reactions are carried out under suitable reaction
conditions as known in the art. Suitable reaction conditions
include temperature, time, solvent(s) and other aspects of organic
synthesis that one of ordinary skill in the art is easily able to
determine without undue experimentation using the description
provided herein and the knowledge of one of ordinary skill in the
art. For example, the thiol-ene radical reaction temperature is any
suitable temperature, such as between 10.degree. to 150.degree. C.,
depending on the type of initiator used.
[0026] It will be appreciated that the groups specifically
identified in the protected functionalized thioester moiety may be
connected to each other with a suitable linker or other group, as
known in the art. For example, the functional group may be
connected to the thioester group with one or more atoms or groups.
Also the carbon of the thioester group may be connected to the
protecting group with one or more atoms or groups, for example
methylene linkers. For example, optionally substituted alkyl,
benzyl, or aryl groups can be used including linear or branched
alkyl groups, cyclic aromatic or non-aromatic, heterocyclic
aromatic or non-aromatic structures, all of which may be optionally
substituted with one or more of the same or different substituents.
The optional substituents include one or more of electron donating
or electron donating groups, such as heteroatoms in the chain or
attached to the chain, carbonyl, nitrile, sulfoxy, sulfone,
sulfate, halogen, C1-C6 linear or branched alkyl groups, benzyl,
benzyl groups, ketone, ester, amino, nitro, I, Br, Cl, F, and other
groups which are known in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a .sup.1H NMR trace of unfunctionalized polymer 92
kg/mol 1,2-PB.
[0028] FIG. 2 is a .sup.1H NMR trace of functionalized 1,2-PB
polymer 92 kPB-OH (experimental conditions are given in Table
2).
[0029] FIG. 3 is a .sup.1H NMR trace of functionalized 1,2 PB
polymer 92 kPB-DNB (experimental conditions are given in Table
2).
[0030] FIG. 4 is a .sup.1H NMR trace of functionalized 1,2 PB
polymer 820 kPB8 (experimental conditions are given in Table
1).
[0031] FIG. 5 is a .sup.1H NMR trace of functionalized 1,2 PB
polymer 92 kPB6 (experimental conditions are given in Table 1).
[0032] FIG. 6 is a .sup.1H NMR trace of functionalized 1,2 PB
polymer 820 kPB12 (experimental conditions are given in Table
1).
[0033] FIG. 7 is representative .sup.1H NMR spectra of
functionalized 1,2-polybutadiene polymers (92 kPB13, top trace, and
92 kPB3, bottom trace; refer to Table 1). Note that the two protons
of the RCH.sub.2SCH.sub.2-- methylene groups directly attached to
ring structures are not equivalent and hence give separate signals.
In both spectra, visible peaks at .delta. =6.97, 2.27, and 1.43 ppm
belong to 2,6-ditert-butyl-4-methylphenol (BHT), and peaks near
.delta.=1.6 ppm correspond to water.
[0034] FIG. 8 shows representative solid-state .sup.13C NMR
spectrum of functionalized 1,2-polybutadiene polymer (92 kPB3;
refer to Table 1 and to structure at bottom of FIG. 7).
[0035] FIG. 9 shows representative gel permeation chromatography
trace of functionalized 1,2-polybutadiene (1,2-PB) polymer. The
solid line corresponds to 92 kPB3 (refer to Table 1); the dashed
line is 92 kg/mol 1,2-PB polymer.
[0036] FIG. 10 shows the fraction p.sub.1 of species I (Scheme 4)
to proceed to abstract hydrogen from RSH as a function of [RSH]
exhibits a linear increase at low concentration and saturates above
a characteristic concentration that corresponds to
p.sub.1/(p.sub.2+p.sub.3).apprxeq.10.
[0037] FIG. 11 shows crosslinking (left) and chain scission
(right): gel permeation chromatography traces of 1,2-polybutadiene
functionalized by reaction in the presence of dibenzoyl disulfide
(solid line, left, 92 kPB16), and in a one pot synthesis after
deprotection of triphenylmethyl sulfide derivatives (solid line,
right, 820 kPB14). The dashed lines correspond to polymer starting
materials.
DETAILED DESCRIPTION OF THE INVENTION
[0038] Unless defined otherwise, all technical and scientific terms
used herein have the broadest meanings as commonly understood by
one of ordinary skill in the art to which this invention pertains.
In addition, herein, the following definitions apply:
[0039] Alkyl groups include straight-chain, branched and cyclic
alkyl groups. Alkyl groups include those having from 1 to 30 carbon
atoms. Alkyl groups include small alkyl groups having 1 to 3 carbon
atoms. Alkyl groups include medium length alkyl groups having from
4-10 carbon atoms. Alkyl groups include long alkyl groups having
more than 10 carbon atoms, particularly those having 10-30 carbon
atoms. Cyclic alkyl groups include those having one or more rings.
Cyclic alkyl groups include those having a 3-, 4-, 5-, 6-, 7-, 8-,
9- or 10-member carbon ring and particularly those having a 3-, 4-,
5-, 6-, or 7-member ring. The carbon rings in cyclic alkyl groups
can also carry alkyl groups. Cyclic alkyl groups can include
bicyclic and tricyclic alkyl groups. Alkyl groups are optionally
substituted. Substituted alkyl groups include among others those
which are substituted with aryl groups, which in turn can be
optionally substituted. Specific alkyl groups include methyl,
ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, s-butyl,
t-butyl, cyclobutyl, n-pentyl, branched-pentyl, cyclopentyl,
n-hexyl, branched hexyl, and cyclohexyl groups, all of which are
optionally substituted. Substituted alkyl groups include fully
halogenated or semihalogenated alkyl groups, such as alkyl groups
having one or more hydrogens replaced with one or more fluorine
atoms, chlorine atoms, bromine atoms and/or iodine atoms.
Substituted alkyl groups include fully fluorinated or
semifluorinated alkyl groups, such as alkyl groups having one or
more hydrogens replaced with one or more fluorine atoms. An alkoxyl
group is an alkyl group linked to oxygen and can be represented by
the formula R-0.
[0040] Alkenyl groups include straight-chain, branched and cyclic
alkenyl groups. Alkenyl groups include those having 1, 2 or more
double bonds and those in which two or more of the double bonds are
conjugated double bonds. Alkenyl groups include those having from 2
to 20 carbon atoms. Alkenyl groups include small alkenyl groups
having 2 to 3 carbon atoms. Alkenyl groups include medium length
alkenyl groups having from 4-10 carbon atoms. Alkenyl groups
include long alkenyl groups having more than 10 carbon atoms,
particularly those having 10-20 carbon atoms. Cyclic alkenyl groups
include those having one or more rings. Cyclic alkenyl groups
include those in which a double bond is in the ring or in an
alkenyl group attached to a ring. Cyclic alkenyl groups include
those having a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-member carbon ring
and particularly those having a 3-, 4-, 5-, 6- or 7-member ring.
The carbon rings in cyclic alkenyl groups can also carry alkyl
groups. Cyclic alkenyl groups can include bicyclic and tricyclic
alkyl groups. Alkenyl groups are optionally substituted.
Substituted alkenyl groups include among others those which are
substituted with alkyl or aryl groups, which groups in turn can be
optionally substituted. Specific alkenyl groups include ethenyl,
prop-1-enyl, prop-2-enyl, cycloprop-1-enyl, but-1-enyl, but-2-enyl,
cyclobut-1-enyl, cyclobut-2-enyl, pent-1-enyl, pent-2-enyl,
branched pentenyl, cyclopent-1-enyl, hex-1-enyl, branched hexenyl,
cyclohexenyl, all of which are optionally substituted. Substituted
alkenyl groups include fully halogenated or semihalogenated alkenyl
groups, such as alkenyl groups having one or more hydrogens
replaced with one or more fluorine atoms, chlorine atoms, bromine
atoms and/or iodine atoms. Substituted alkenyl groups include fully
fluorinated or semifluorinated alkenyl groups, such as alkenyl
groups having one or more hydrogens replaced with one or more
fluorine atoms.
[0041] Aryl groups include groups having one or more 5- or 6-member
aromatic or heteroaromatic rings. Aryl groups can contain one or
more fused aromatic rings. Heteroaromatic rings can include one or
more N, O, or S atoms in the ring. Heteroaromatic rings can include
those with one, two or three N, those with one or two 0, and those
with one or two S, or combinations of one or two or three N, O or
S. Aryl groups are optionally substituted. Substituted aryl groups
include among others those which are substituted with alkyl or
alkenyl groups, which groups in turn can be optionally substituted.
Specific aryl groups include phenyl groups, biphenyl groups,
pyridinyl groups, and naphthyl groups, all of which are optionally
substituted. Substituted aryl groups include fully halogenated or
semihalogenated aryl groups, such as aryl groups having one or more
hydrogens replaced with one or more fluorine atoms, chlorine atoms,
bromine atoms and/or iodine atoms. Substituted aryl groups include
fully fluorinated or semifluorinated aryl groups, such as aryl
groups having one or more hydrogens replaced with one or more
fluorine atoms.
[0042] Polymers are molecules or nanoparticles comprising multiple
repeating units, including but not limited to synthetic
homopolymers, copolymers and block copolymers; oligopeptides,
polypeptides and proteins; oligonucleotides and polynucleotides;
oligosaccharides and polysaccharides; hyperbranched molecules and
dendrimers; latex particles and organic/inorganic particles and
inorganic particles bearing organic functional groups on their
surfaces. It is understood that the methods of the invention may be
applied to cross linked polymers and to polymers attached to
surfaces or in pores. When applied to immobilized polymers, it is
understood that the methods of the invention can be applied in a
spatially resolved manner by using spatially-resolved generation of
radicals.
[0043] The invention will now be illustrated by way of example only
and with reference to the following non-limiting examples and
experiments.
[0044] There are several known protecting groups for thiols that
can be used in the present invention. For example, see Wuts, P. G.
M., Greene's Protective Groups in Organic Synthesis/Peter G. M.
Wuts and Theodora W. Greene. 4th ed.; Wiley-Interscience: 2007; ch
6; and Kocienski, P. J., Protecting Groups. 3rd ed.; Thieme: 2004;
ch 5.
[0045] The methods described here can be used for grafting various
functionalities in a one-step polymer reaction (as opposed to
hydroboration or epoxidation). Thiol-ene coupling described here
proceeds under mild reaction conditions and is tolerant of a large
number of functional groups. In particular, the chemistry is water
insensitive, which renders it considerably simpler than
hydrosilylation, for instance. The thiol addition described here
also proceeds with minimal cross-linking or chain scission in
comparison to other modification reactions such as
hydroboration/oxidation.sup.13 and hydrosilylation.sup.23,24.
Finally, desired side-groups are incorporated via unobtrusive
thioether linkages, without the introduction of additional
functionalities (in contrast to functionalization by epoxidation or
radical addition of alkyl iodides, which add one molar equivalent
of hydroxyl, chloro, or iodo functionalities per grafted side
group).
[0046] Thiol-ene addition to PB and other polymers having pendant
vinyl groups offers tremendous versatility for molecular design.
The excellent tolerance of thiol-ene coupling to numerous
functional groups combines with the good availability of polymers
of well-defined microstructures (e.g., content of 1,2-adducts in
PB), macromolecular structure (such as chain topology and
incorporation of other polymer blocks), and size (from <10.sup.4
g/mol to >10.sup.6 g/mol). If desired, a polymer having pendant
vinyl groups can be synthesized according to known methods. The
method is well suited to produce a homologous series of model
materials (i.e., having precisely matched degree of polymerization,
but varying in functionality and/or in extents of
functionalization) that elucidate macromolecular physical
phenomena.
[0047] The main drawback to currently available thiol-ene reactions
is the limited range of commercially available mercaptans
(essentially limited to carboxylic acid, alcohol, 1,2-diol, amine,
alkyl, and fluoroalkyl functionalities). Therefore, the rapid,
high-yield synthetic methods to prepare desired functional thiols
described herein are needed to make thiol-ene functionalization
widely useful. Furthermore, technological application requires that
these synthetic methods be amenable to scale up. Indirect
preparation of thiols through thioester intermediates as described
herein presents significant advantages with regard to safety,
yield, and product stability. Facile procedures to deprotect the
thiols and--without isolation--proceed to functionalize 1,2-PB are
described (e.g., Scheme 1). Thus, this invention shows how to
conveniently extend the number of candidate side-groups for
functionalization of polymers by thiol-ene coupling.
##STR00005##
[0048] Exemplified herein are highly efficient synthetic routes to
an array of protected thiols which were chosen both i) because the
featured side-groups are important functionalities in their own
right, and ii) because each is representative of a general pathway
for incorporation of the thiol moiety (e.g., Scheme 2).
Specifically, phenol and pyridine functionalities are described
because of their relevance as hydrogen-bond donor and acceptor;
carbazole and dinitrobenzoate are of interest as electron donor and
acceptor, and relevant to materials with novel electronic
properties; and 4-cyano-4'-hydroxybiphenyl is of interest for its
liquid-crystalline properties. Of paramount practical significance,
the described chemistry involves: i) inexpensive, readily available
reagents of moderate toxicity and reactivity, ii) no elaborate
equipment or procedures, iii) rapid, quantitative conversions of
limiting reagents in all steps without measurable formation of
side-products, and iv) simple purification (enabled by the clean
synthetic routes) using scalable separation processes (principally
liquid-liquid extraction and washes, occasionally
recrystallization, but no column separations).
[0049] The set of protected thiols exemplified here was chosen to
illustrate clean, high-yield synthetic routes to introduce the
thiol moiety onto functional molecules. Molecules were selected for
the importance of their functionalities and for their reactive
groups available for derivatization (Scheme 2). Thus, the synthesis
of protected mercaptans using an accessible phenol or alcohol group
(compounds 3 and 6), a heterocyclic nitrogen atom (compound 8), an
accessible carboxylic acid group (compounds 10 and 12), a terminal
olefin group (compound 10), or an available halide atom (compounds
3, 8, 12, and 13) are provided as examples. Compounds 3 and 6
illustrate convenient methods to control the distance between the
grafted side-group and the polymer backbone after thiol-ene
coupling. Note that an 8 atom spacer (or other size) can be
incorporated by replacing H(OCH.sub.2CH.sub.2).sub.2Cl with
commercially available H(OCH.sub.2CH.sub.2).sub.3Cl or analogs in
the described procedure for the synthesis of 4.
[0050] Reaction conditions for the synthesis of compounds 2-13
demonstrate highly efficient and scalable methods that can be
generalized to the preparation of related compounds (in terms of
the reactive groups available for derivatization). .sup.1H NMR
analysis of crude reaction mixtures showed that all reaction steps
resulted in quantitative conversion to desired product (except
synthesis of 9 and 11, for which conversion was .about.90%). The
clean synthetic steps made it possible to isolate products in
95-100% purity and 90-100% yield by mere use of liquid-liquid
extraction/washes, and evaporation of low-boiling compounds. In
some cases, further purification was achieved by recrystallization
to yield analytically pure product (compounds 3, 7, 8, and 12).
##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010##
[0051] Functionalization of 1,2-PB. Reaction conditions for 1,2-PB
functionalization given in Table 1 incorporate functional
side-groups while preserving the narrow molar mass distribution of
the unfunctionalized polymer material (Table 1, Scheme 3, FIGS.
7-9). Depending on the application, degrees of functionalization
from s.ltoreq.1% to .gtoreq.50% are of interest; here, systematic
control of functionalization (X.sub.funct) from a few % to 40% is
demonstrate d (Table 1). PB chains with very high 1,2-content tend
to form cyclic adducts, which limit functionalization to
.ltoreq.50% unless very high thiol concentrations are
used..sup.18,19 Accounting for the formation of ring structures by
random cyclization of adjacent repeat units during the addition
reaction, the general structure of the functionalized polymer is as
shown in Scheme 3. That structure is solved by considering that
either five- or six-member rings can be formed, and that polycyclic
structures are possible. Note that any cyclic or polycyclic
structure involves at most one five member ring (on either side of
which can be fused any number of six-member rings), and that there
are exactly as many methyl groups in the functionalized polymer as
there are five-member rings. Let X.sub.funct be the fraction of
reacted 1,2-PB repeat units bearing functional groups,
X.sub.unreact be the fraction of unreacted 1,2-PB repeat units, and
X.sub.cycl be the fraction of reacted 1,2-PB repeat units that are
unfunctionalized. Thankfully, analysis of the general structure
(FIG. 7) provides an unambiguous relationship between X.sub.funct,
X.sub.unreact, X.sub.cycl and three quantities that are readily
determined from the .sup.1H NMR spectra: the relative values of the
integrals of RCH.sub.2S-- methylene protons (S.sub.1),
H.sub.2C.dbd.CH-- alkenic protons (S.sub.2), and aliphatic protons
of chemical shifts below 2.2 ppm (S.sub.3). In terms of the indices
defined in FIG. 1, S.sub.1.about.2 (n+m+m') and S.sub.2.about.2 u.
Furthermore, since none of the side-groups R in the present study
display protons with .delta.<2.2 ppm, S.sub.3.about.[5 n+4
(m+m')+6 (p+p'+t)+7 (q+v)+3 u]. Because there are as many
beginnings as ends in both y and z structures (Scheme 3, top), m=q,
and m'=v; therefore, (p+p'+t+q+v)=(2S.sub.3-3 S.sub.2-5
S.sub.1)/12. Thus, X.sub.funct, X.sub.unreact, and X.sub.cycl can
be calculated by the expressions below without any knowledge of the
relative amounts of the repeat units m, m', p, p', q, t, or v in
the functionalized polymer:
X funct = n + m + m ' n + m + m ' + p + p ' + t + q + v + u = 6 S 1
S 1 + 3 S 2 + 2 S 3 ##EQU00001## X unreact = u n + m + m ' + p + p
' + t + q + v + u = 6 S 2 S 1 + 3 S 2 + 2 S 3 ##EQU00001.2## X cycl
= 1 - X funct - X unreact ##EQU00001.3##
[0052] Functional polymer could also be obtained in a two-step
polymer modification procedure, by thiol-ene addition of
.beta.-mercaptoethanol (BME), followed by esterification of the
incorporated hydroxyl groups with a suitable acyl halide (Scheme 4,
Table 2). The narrow polydispersity of well-defined polymer
material could also be preserved throughout this process (Table 2),
so that the procedure offers a useful alternative to direct
coupling of a thiol derivative when an acyl chloride compound
featuring the desired functionality is readily accessible.
##STR00011##
[0053] Molecular Structure of Functionalized 1,2-PB Polymer. The
potential to form cyclic structures follows from the reaction
mechanism. The addition reaction is initiated by abstraction of a
thiol hydrogen by a cyanopropyl free radical. The resultant thiyl
radical (RS.cndot.) adds to a double bond of 1,2-PB in
anti-Markovnikov fashion.sup.16-18, generating a polymeric alkyl
radical (e.g. Structure I in Scheme 3). As shown in the figure,
transfer of hydrogen from another thiol molecule completes the
addition reaction (Structure II) and regenerates a new RS.cndot.
participant; alternatively, intramolecular reactions of I compete
with hydrogen transfer to form Structures III and IV. As evidence
for the formation of ring structures by intramolecular cyclization,
Schlaad.sup.18,19 pointed to incomplete functionalization at full
conversion of double bonds using 1,2-PB-block-poly(ethylene oxide)
as starting material, i.e. typically only 60-80 functional
side-group were found for every 100 reacted 1,2-PB repeat units.
Direct evidence of cyclization is seen in the .sup.1H NMR spectra
in the present study (bottom trace in FIG. 7 and FIG. 1-6): the
broad peaks below 2.2 ppm are not consistent with the structures of
repeat units w and x in Scheme 3, but consistent with cyclohexyl or
cyclopentyl proton signals. Further, the observed multiple peaks
assignable to the RCH.sub.2SCH.sub.2-- protons of the
functionalized polymer (protons 4, 5, 6, FIG. 7) cannot be
explained in the absence of cyclization, but are consistent with a
combination of the repeat units n, m, and m' in Scheme 3.
##STR00012##
[0054] The question now arises whether radical I in Scheme 4
predominantly forms III or IV during cyclization. Based on the
relative thermodynamic stability of secondary versus primary
radical intermediates, Schlaad and coworkers.sup.18 have suggested
that six-member rings (III) should be preferred over their
five-member counterparts (IV); however, experimental results
discussed in the next few paragraphs give instead evidence to the
contrary. First, the data presented here reveals a high content of
five-member rings in reacted polymer. NMR analysis of our product
for highly functionalized chains shows i) a strong peak around 17
ppm in the solid state .sup.13C spectra (FIG. 8), and ii) a strong
signal at 1-0.9 ppm in the .sup.1H NMR spectra (FIG. 7, bottom).
Both these signals are consistent with the methyl group of
structure v in Scheme 5. Since there are exactly as many
five-member rings as methyl groups in the functionalized polymer,
it is deduced that a large number of unfunctionalized, reacted
monomers cyclized into five-member rings.
[0055] Next, literature results.sup.22,30 on the radical addition
of primary alkyl iodides to 1,2-PB and .alpha.,.omega.-alkadienes
provides further evidence. Although the initiation, addition, and
transfer steps for RI versus RSH radical addition involve molecules
of substantially different reactivity, the intermediate radicals
involved in intramolecular cyclization have essentially the same
structure (i.e. replace RS by R in structures I, III, and IV of
Scheme 5). Thus, the relative rates of formation of five- versus
six-member ring structures should be comparable. According to
reports on the radical addition of perfluoroalkyl iodides to
1,2-PB.sup.22 and 1,6 heptadiene.sup.30, intramolecular reaction of
polymer radical I is expected to form primarily five-, instead of
six-, member cyclic intermediates (structure IV rather than
III).
[0056] In order to make further progress, let us now inquire about
the competition between H-abstraction by I (forming II) versus
cyclization of I (to form III or IV). This competition depends both
on thiol concentration and steric hindrance to H-abstraction by I.
Let r.sub.1, r.sub.2, r.sub.3 and p.sub.1, p.sub.2, p.sub.3 be the
reaction rates and transitional probabilities for the pathways I
II, III, or IV, respectively (Scheme 4). At low extents of
conversion, steric hindrance to H-abstraction by I is small, so
that
p.sub.1/(p.sub.2+p.sub.3)=r.sub.1/(r.sub.2+r.sub.3).about.[RSH].
Schlaad's date demonstrated that at sufficiently high [RSH] (on the
order of 10 M), H-abstraction was predominant, and degrees of
functionalization as high as X.sub.funct=85% could be obtained.
Only marginal increases in X.sub.funct could be achieved with
increasing [RSH] above 10 M, but Schlaad observed that cyclization
began to compete noticeably at [RSH].ltoreq.5 M. It is now shown
that these observations indicate that
p.sub.1/(p.sub.2+p.sub.3).about.10 at 5 M RSH. At low extents of
reactions, p.sub.1(p.sub.2+p.sub.3)=p.sub.1/(1-p.sub.1) is
proportional to [RSH]. The proportionality constant pertinent to
low extents of conversion is denoted by k, i.e.
p.sub.1/(p.sub.2+p.sub.3)=k[RSH], giving p.sub.1=k[RSH]/(1+k[RSH]).
At very high thiol concentrations (k[RSH]>>1 in FIG. 10),
p.sub.1=1 and p.sub.2=p.sub.3=0, so that there is no cyclization.
Upon decreasing [RSH], cyclization begins to compete noticeably.
The onset of competition as seen in FIG. 10 occurs at
k[RSH]=p.sub.1/(p.sub.2+p.sub.3).about.10, where
p.sub.1.apprxeq.0.9.
[0057] The above result has important implications for the relative
formation of five-vs. six-member rings. First, the finding that
k.about.O(1 M.sup.-1) leads immediately to the realization that
under the functionalization conditions used in the present study
([RSH].about.O(10.sup.-1 M or less), radical I (FIG. 5) primarily
undergoes intramolecular reaction, i.e.
p.sub.1.apprxeq.p.sub.1/(p.sub.2+p.sub.3).about.O(10.sup.-1 or
less). Second, the fact that very little of radical I proceeds to
abstract H from RSH under these conditions suggests that likewise
very little of radical III would abstract H under the same
conditions (judging reactivity based on structure similarity).
Therefore, if, as Schlaad suggests, intramolecular cyclization of I
led primarily to the six-member rings III, the similarity of I and
III would cause III to propagate a ladder of many six-member cycles
prior to concluding with H-abstraction from RSH. In that case, the
functionalized polymer here would then display i) very high ratios
of cyclization to functionalization,
X.sub.cycl/X.sub.funct>>1, and ii) very few five-member
rings. Both these results are contrary to the observations.
[0058] The data is consistent with the following predominant
pathway: I.fwdarw.IV.fwdarw.V (Scheme 4) for thiol concentrations
on the order of 10.sup.-2-10.sup.-1 M. That is, I cyclizes
predominantly, and five-member rings are more likely, but IV
abstracts hydrogen predominantly. Note that such different relative
reactivity for radicals I and IV are reasonable based on their
structures. Further, this reaction pathway successfully explains
the observed ratios of X.sub.funct/X.sub.cycl in the relatively
narrow range of 0.65-1 (Tables 1 and 2) over the >1 order of
magnitude range of thiol concentration spanned by our experiments.
If the reaction proceeded exclusively from Ito IV to V
(p.sub.1=p.sub.2=p.sub.5=0), then X.sub.funct/X.sub.cycl=1 and the
polymer structure would consist exclusively of unreacted 1,2 units
and functionalized five-member rings. In reality, deviations from
p.sub.2=0 or p.sub.5=0 account for values of X.sub.funct/X.sub.cycl
smaller than 1, and deviation from p.sub.1=0 account for values of
X.sub.funct/X.sub.cycl larger than 1. Increasing [RSH] increases
p.sub.1, leading to a greater number of acyclic functionalized
units. The general predominant polymer structure is therefore the
one given in Scheme 1.
[0059] Direct or Indirect Functionalization? The utility of
indirect functionalization by esterification of
2-hydroxyethylthio-modified PB (Scheme 4) is somewhat limited by
the high reactivity of acyl halides, which renders them
incompatible with a number of important functional groups and
working conditions. Furthermore, our experience with polymers that
are susceptible to cross-linking (such as high MW 1,2-PB) indicates
that best results are typically achieved by minimizing the number
of synthetic steps involving macromolecules. Finally, the time
invested in the synthesis of protected thiols is easily regained in
subsequent tailoring of polymer properties by quicker adjustments
in the number density of grafted side-groups. Thus, in the research
reported here, it is seen that direct polymer functionalization
according to Scheme 1 is preferable in most cases. However,
indirect functionalization according to Scheme 4 becomes useful
when i) a suitable acyl halide is commercially available, and/or
ii) Scheme 1 fails for one reason or another; e.g. due to
unsatisfactory deprotection of a suitable thiol. For instance,
deprotection of compound 10 to give the corresponding mercaptan did
not give acceptable results due to apparent partial reduction of
the nitro groups.
[0060] Choice of Protecting Group. The motivation for using
protected thiols arises from issues of safety, yield, efficiency,
and product stability. Direct preparation of thiols can be achieved
by addition of hydrogen sulfide (H.sub.2S) to alkenes, or by
substitution of alkyl halides with hydrogen sulfide or hydrosulfide
(HS.sup.-). These methods have the following disadvantages: first,
both hydrogen sulfide and hydrosulfide present considerable health
hazards, and second, sulfide byproducts are usually formed in
significant amounts.sup.27,31. Alternatively, the thiol
functionality can be incorporated indirectly using other
sulfur-containing compounds such as thiolcarboxylic acids,
thiourea, or the thiolsulphate ion, followed by bond cleavage via
e.g. hydrolysis of the intermediates to generate the desired
mercaptan.sup.31. The extra step required by any indirect method is
balanced by the advantages of cleaner, less wasteful reactions, and
the use of less toxic reagents. Because thiols are prone to
oxidation (e.g. in air on standing), storage of protected thiols is
also often considered a wiser choice.
[0061] Based on adverse side reactions that occur with the
triphenylmethyl (trityl) group, it was necessary to turn to other
protecting groups. The widespread use of the trityl grouP.sup.32
reflects the ease by which it is first incorporated by substitution
of halides using triphenylmethyl mercaptan, and the ease with which
it is quantitatively removed (<2 hours in DCM at room
temperature in the presence of TFA and triethyl- or
triisopropylsilane.sup.33-36). The current interest in the trityl
sulfide group was generated by the hope that both deprotection of
the sulfide and addition of the resultant thiol to PB could be
successfully carried out in one pot by using chloroform as the
solvent (procedure described below). Unfortunately, experiments
with 9-[2-(triphenylmethyl)thio]ethyl]carbazole (14) showed that
although both deprotection and addition reactions proceeded as
desired, unacceptable degradation of the polymer also occurred
under such conditions (FIG. 11, right). It is also worth noting
that triphenylmethyl mercaptan is a comparatively expensive reagent
for the introduction of the thiol functionality.
##STR00013##
[0062] Thioesters have been used extensively in the past as
protecting groups of the thiol functionality, with more or less
success towards selective deprotection based on the reagents and
method used.sup.37. In saccharide synthesis, thioester groups have
been reported to be removed under mild conditions, i.e. in <2
hours at room temperature hydrazine acetate in DMF.sup.38-40.
Oxygen esters were reported to be resistant to hydrolysis under
these conditions. In this work, it was found that thioacetic acid
and thiobenzoic acid were essentially equivalent in reactivity, but
that thiobenzoic acid offers the advantage of simpler purification
of the thioester product due to differences in both solubility and
melting point between products and impurities. For instance, the
higher molecular weight products obtained with PhCOSH were usually
solid compounds amenable to recrystallization.
[0063] Synthetic Crossroads for the Introduction of the Thioester
Functionality. Thioesters can be generated using thioacetic acid or
thiobenzoic acid either from nucleophilic displacement of a leaving
group or from radical addition to a terminal alkene (Scheme 2).
Reaction of a halide or tosylate is considerably more convenient
than reaction of an alkene, since the nucleophilic displacement i)
does not require oxygen free conditions, and ii) essentially does
not generate any impurities. Indeed, quantitative radical reaction
of alkenes (e.g. synthesis of 10) is accompanied by the formation
of radical termination products (0.05 to 0.3 molar equivalent)
which can greatly complicate the purification process.
[0064] In some cases a leaving group (e.g. synthesis of 13) or
alkene may be directly available, otherwise they can be introduced
in one of the following ways: i) alcohols can be converted into
good leaving groups by tosylation (e.g. synthesis of 5), ii)
carboxylic acids can be reacted by Fisher esterification with e.g.
2-chloroethanol (e.g. synthesis of 11), and iii) nucleophiles can
be alkylated with, for instance, allyl bromide (e.g. synthesis of
9) or 2-chloroethyl-p-toluenesulfonate (compound 1, e.g. synthesis
of 2 or 7). The following considerations affect decision making
regarding alkylation of nucleophiles. On the one hand, allyl
bromide is considerably more reactive and available than 1, and its
reaction with nucleophiles proceeds cleanly (in contrast, care must
be taken in choosing reaction conditions with compound 1 to prevent
bisubstitution and minimize elimination). On the other hand, the
use of allyl bromide suffers in the conversion of the resulting
alkene to the desired protected thiol (e.g., 9 to 10). As noted
earlier, that reaction is air sensitive, and the side-products are
often difficult to separate from the desired one. As a result, the
ease of conversion and purification of thioesters from halides
(e.g., 3 from 2) often justify the additional care required in the
coupling of 1 to the molecule of interest (e.g. 1 to 2).
[0065] Functional precursors bearing nucleophilic atoms also afford
a convenient method to control the spacer length between the
functional group of interest and the polymer backbone. For
instance, 3, 5 and 8 atom spacers can be accessed by alkylation of
a nucleophile with inexpensively available
H(OCH.sub.2CH.sub.2).sub.nCl (n=1,2,3; Wako Chemicals), followed by
conversion to a protected thiol as in the synthesis of 6.
[0066] Deprotection of acetyl- or benzoyl-thioesters. In all cases
(with the exception of compound 10), cleavage of thioesters was
achieved in >95% yields (verified by .sup.1H NMR analysis) in
2-4 hours with hydrazine acetate in DMF at room temperature (Scheme
1, step 1.1). Significantly, it was discovered that hydrazine
acetate could be generated in situ by ion exchange in DMF from
considerably less expensive hydrazine hydrochloride and sodium
acetate, with equally successful results.
[0067] A most compelling advantage of Scheme 1 for
functionalization of PB using acetyl- or benzoyl-thioesters
consists in the direct addition of the deprotected mercaptan to PB
without its isolation as a purified intermediate. Extraction of the
DMF reaction mixture with chloroform or DCM and subsequent washing
of the organic phase (Scheme 1, step 1.2) yields in .about.30 min a
remarkably pure solution of the thiol in which the only impurities
are small amounts of disulfide (due to exposure to air), unreacted
thioester (<5% of initial amount), DMF, and moisture. Radical
addition of the thiol to PB is highly tolerant of these impurities
and proceeds unaffected by their presence (Table 1).
[0068] Effect of Impurities. The radical addition of mercaptans to
alkenes is known to be highly tolerant of a vast array of
functional groups.sup.27. Indeed, it was found that most impurities
(such as disulfides, thioesters, solvents, water, etc.) were
inconsequential during thiol-ene functionalization of PB, with the
following notable exceptions. First, in one-pot reaction procedures
after detritylation of triphenylmethyl sulfides, some unidentified
compound(s) caused chain scission of 1,2-PB (as mentioned earlier,
FIG. 11, right). Second, it was found that the presence of benzoyl
disulfide (PhCOSSOCPh) resulted in significant cross-linking. For
example, use of a sample of thiobenzoic acid
S-[3-(9-carbazolyl)propyl]ester (16) containing .about.0.2 molar
equivalent of benzoyl disulfide caused polydispersity to increase
from PDI=1.07 to 1.34 at 19% functionalization (FIG. 7, left).
[0069] Implications of Extents of Cyclization for 1,2-PB. Depending
on the reason for modifying the polymer, degrees of
functionalization from a few % up to .about.100% are of interest.
Experiments show cyclization to functionalization ratios
X.sub.cycl/X.sub.funct of 1-1.5, meaning that during the course of
the addition reaction nearly as many reacted monomers were
functionalized as were consumed without functionalization by
intramolecular cyclization. It was found to be the case for
reaction conditions spanning more than one order of magnitude in
thiol concentration in the range
10.sup.-2<[RSH]<3.times.10.sup.-1 M. That is, 1,2-PB
functionalization at moderately low to very low thiol
concentrations proceeds without excessive amounts of cyclization
(which would be expected if radical I in Scheme 4 led primarily to
six-member rings, as explained earlier). The implications of this
result are two-fold. First, low target levels of functionalization
can be readily achieved at low or very low [RSH], with minimal
changes in the physical properties of the polymer product resulting
from cyclic/polycyclic structures. This enables good control of the
extent of reaction and minimizes waste of potentially highly
valuable thiol reagent. Second, the result suggests an alternative
synthetic strategy to using extremely high thiol concentration (on
the order of 10 M!) in order to achieve high degrees of
functionalization (say >70%). Taking advantage of the fact that
cyclization to functionalization ratios remain in the narrow range
of 1-1.5 at thiol concentrations of 0.01-0.1 M, the strategy
involves synthesis of thioester compounds featuring two functional
side-groups per molecule. Deprotection and addition to 1,2-PB
according to Scheme 1 using thiol concentrations on the order of
0.1 M will result in incorporation of e.g. 80% side groups at 40%
functionalization. This type of molecule is shown as compound 17 as
shown in Scheme 7.
##STR00014##
TABLE-US-00001 TABLE 1 Reaction Conditions and Results for 1,2-PB
Functionalization Using Protected Thiol PhCOSR [PB] [AIBN] Rxn time
X.sub.funct.sup.c X.sub.cycl.sup.c M.sub.W.sup.d New .sup.1H NMR
peaks above 2.2 ppm for modified PB Entry.sup.a (g/mL)
[Thiol].sup.b (g/mL) (hrs) % % (kg/mol) PDI.sup.d (all peaks are
broad) 92kPB3.sup.e,g 0.004 1.6 0.005 6.2 40 .+-. 2 48 .+-. 3 199
1.07 7.71-7.43 (6H), 7.01-6.88 (2H), 4.22-4.08 (2H), 2.95-2.43 (4H)
92kPB6.sup.f 0.003 0.5 0.002 3.7 22 .+-. 2 34 .+-. 3 194 1.07
7.71-7.58 (4H), 7.54-7.46 (2H), 7.05-6.95 (2H), 4.19-4.12 (2H),
3.90-3.82 (2H), 3.77-3.67 (2H), 2.77-2.39 (4H) 92kPB8 0.004 1.2
0.001 4.4 36 .+-. 2 41 .+-. 3 146 1.06 8.12-7.95 (2H), 7.53-7.12
(6H), 4.53-4.26 (2H), 2.95-2.72 (2H), 2.65-2.2 (2H) 92kPB12 0.009
1.5 0.001 3.6 16 .+-. 1 18 .+-. 2 98 1.02 7.93-7.83 (2H), 7.88-7.80
(2H), 4.43-4.34 (2H), 2.87-2.44 (4H) 92kPB13.sup.e 0.003 1.9 0.001
2.0 4 .+-. 1 6 .+-. 2 122 1.07 8.55-8.46 (2H), 7.70-7.63 (1H),
7.28-7.22 (1H), 3.70-3.62 (2H), 2.82-2.43 (2H) 820kPB3 0.003 0.3
0.001 1.5 4 .+-. 1 4 .+-. 2 1420 1.45.sup.h 7.69-7.56 (4H),
7.56-7.45 (2H), 7.00-6.91 (2H), 4.19-4.10 (2H), 2.92-2.80 (2H),
2.74-2.49 (2H) 820kPB8.sup.f 0.004 1.3 0.002 3.0 27 .+-. 2 36 .+-.
3 1200 1.25 8.11-7.95 (2H), 7.49-7.12 (6H), 4.52-4.28 (2H),
2.94-2.71 (2H), 2.61-2.2 (2H) 820kPB12.sup.f 0.007 0.2 0.002 3.0 7
.+-. 1 11 .+-. 2 579 1.48.sup.h 7.94-7.87 (2H), 6.87-6.79 (2H),
4.45-4.33 (2H), 2.88-2.41 (4H) 820kPB13 0.007 0.2 0.002 2.5 2 .+-.
1 3 .+-. 2 1310 1.26 8.55-8.46 (2H), 7.70-7.64 (1H), 7.28-7.22
(1H), 3.68-3.62 (2H), 2.82-2.43 (2H) .sup.aModified PB polymers
were named so that the prefix corresponds to the molecular weight
of the starting 1,2-PB chain (98% 1,2 content), and the suffix
represents the thioester reagent (Scheme 2) used. .sup.bIn molar
equivalents of 1,2-PB monomer units, estimated from the mass ratio
of the protected thiol PhCOSR and 1,2-PB. .sup.cThe fraction of
reacted 1,2-PB units that bear functional groups (X.sub.funct) and
that are not functionalized (X.sub.cycl); refer to text. The
reported uncertainties were calculated based on the following
uncertainties for the integrals S.sub.1, S.sub.2, and S.sub.3: the
measurement of S.sub.3 is ~3% accurate, and the uncertainties in
S.sub.1 and S.sub.2 are both < 1% of (S.sub.1 + S.sub.2).
.sup.dMeasured as described in Experimental section using the
Waters setup, except for polymer 92kPB12 (measurements obtained by
MALLS). The 1,2-PB polymers had PDI of 1.07 and 1.26 for the 92
kg/mol and 820 kg/mol 1,2-PB chains, respectively. .sup.e.sup.1H
NMR traces are given in FIG. 2. .sup.f.sup.1H NMR traces are given
in the Supplementary Information section. .sup.gGPC trace is given
in FIG. 4. .sup.hA small amount of cross-linking is believed to
have occurred during workup and handling of the polymer
product.
TABLE-US-00002 TABLE 2 Reaction Conditions and Results for 1,2-PB
Functionalization Using 3,5-Dinitrobenzoyl Chloride (DNBC) New H
NMR peaks above [PB] [AIBN] Rxn time X.sub.funct.sup.d
X.sub.cycl.sup.d M.sub.W.sup.e 2.2 ppm for modified PB Entry.sup.a
(g/mL) [BME].sup.b (g/mL) (hrs) % % (kg/mol) PDI.sup.e (all peaks
are broad) 92kPB-OH.sup.f 0.03 0.6 0.002 1.9 20 .+-. 1 28 .+-. 2
151 1.07 3.77-3.65 (2H), 2.76-2.2 (4H) 820kPB-OH 0.02 0.4 0.001 3.0
15 .+-. 1 24 .+-. 2 1170 1.24 3.77-3.66 (2H), 2.76-2.3 (4H) New H
NMR peaks above [PB-OH] Rxn time X.sub.funct.sup.d X.sub.cycl.sup.d
M.sub.W.sup.e 2.2 ppm for modified PB Entry.sup.a (g/mL)
[DNBC].sup.c [Et.sub.3N].sup.c (hrs) % % (kg/mol) PDI.sup.e (all
peaks are broad) 92kPB-DNB.sup.f 0.02 3.3 5.0 4.0 20 .+-. 1 28 .+-.
2 158 1.08 9.24-9.20 (1H), 9.20-9.12 (2H), 4.64-4.51 (2H),
2.97-2.81 (2H), 2.81-2.41 (2H) 820kPB-DNB 0.02 2.5 3.5 3.3 15 .+-.
1 24 .+-. 2 1410 1.28 9.24-9.20 (1H), 9.20-9.12 (2H), 4.65-4.51
(2H), 2.97-2.83 (2H), 2.80-2.42 (2H) .sup.aModified PB polymers
were named so that the prefix corresponds to the molecular weight
of the starting 1,2-PB chain (98% 1,2 content), and the suffix
represents the functional group added. .sup.bIn molar equivalents
of 1,2-PB monomer units. .sup.cIn molar equivalents of
2-hydroxyethylthio- functionalized monomer units. .sup.dThe
fraction of reacted 1,2-PB units that bear functional groups
(X.sub.funct) and that are not functionalized (X.sub.cycl); refer
to text. The reported uncertainties were calculated based on the
following uncertainties for the integrals S.sub.1, S.sub.2, and
S.sub.3: the measurement of S.sub.3 is ~3% accurate, and the
uncertainties in S.sub.1 and S.sub.2 are both < 1% of (S.sub.1 +
S.sub.2). .sup.eMeasured as described in Experimental section using
the Waters setup. The 1,2-PB polymers had PDI of 1.07 and 1.26 for
the 92 kg/mol and 820 kg/mol 1,2-PB chains, respectively.
.sup.f.sup.1H NMR traces are given in the Supplementary Information
section.
EXPERIMENTAL
[0070] Materials and Instrumentation. Except for thiobenzoic acid
(Alfa Aesar, 94%), carbazole (Aldrich, 95%),
4'-hydroxy-4-carbonitrile (TCl, 95%), thioacetic acid (Aldrich,
96%), allyl bromide (Aldrich, 97%), hydrazine monohydrochloride
(Acros Organics, 98%), p-toluenesulfonyl chloride (Alfa Aesar,
98%), and p-toluenesulfonic acid monohydrate (Aldrich, 98.5%), all
reagents were obtained at 99% purity from Aldrich, Alfa Aesar, or
Mallinckrodt Chemicals. 2,2'-Azobis(2-methylpropionitrile) (AIBN)
was recrystallized biweekly in methanol (10 mL solvent per g AIBN)
and stored at 4.degree. C.; all other reagents were used as
received without further purification. Polybutadiene polymer chains
(98% 1,2-content) of size 92.times.10.sup.3 and 820.times.10.sup.3
g/mol and narrow molecular weight distribution (of polydispersity
index 1.07 and 1.26, respectively) were kindly donated by Dr.
Steven Smith of Procter and Gamble Company. .sup.1H and .sup.13C
NMR spectra were obtained using a Varian Mercury 300 spectrometer
(300 MHz for .sup.1H and 74.5 MHz for .sup.13C); all spectra were
recorded in CDCl.sub.3 and referenced to tetramethylsilane. Polymer
molecular weight measurements were obtained by gel permeation
chromatography using one of two systems. Measurements were either
carried out i) in tetrahydrofuran (THF) at 25.degree. C. eluting at
0.9 mL/min through four PLgel 10 .mu.m analytical columns (Polymer
Labs, 10.sup.6 to 10.sup.3A in pore size) connected to a Waters 410
differential refractometer detector (.lamda.=930 nm) or ii) in THF
on two PLgel 5 .mu.m mixed-C columns (Polymer Labs) connected in
series to a DAWN EOS multi-angle laser light scattering (MALLS)
detector (Wyatt Technology, Ar laser, .lamda.=690 nm) and an
Optilab DSP differential refractometer (Wyatt Technology,
.lamda.=690 nm). In the former case, molecular weight measurements
were analyzed based on calibration using polystyrene standards; in
the latter case no calibration standards were used, and do/dc
values were obtained for each injection by assuming 100% mass
elution from the columns.
[0071] Synthesis of Benzoyl- or Acetyl-Protected Thiols (Scheme 2).
All reactions were monitored by .sup.1H NMR spectroscopy. Analysis
of reaction mixtures was generally performed by washing a .about.1
mL aliquot with water and extracting organic reactants and products
into an appropriate solvent, followed by solvent evaporation, and
redissolving in CDCl.sub.3 for NMR analysis. .sup.13C NMR
resonances of compounds 1, 3, 6, 8, 10, 12, and 13 are documented
below.
[0072] 2-Chloroethyl-p-toluenesulfonate (1). p-Toluenesulfonyl
chloride (172 g, 0.884 mol) and pyridine (59 g, 0.75 mol) were
added to 180 mL dichloromethane (DCM) in a 1 L round-bottom flask
(RBF) which was placed in an ice bath for ca. 5 min.
1-Chloroethanol (40.3 g, 0.496 mol) was added slowly, and the RBF
was taken out of the ice bath and left to stir at room temperature
(r.t.) for 15 hrs. The reaction mixture was poured into a 1 L
separatory funnel, washed twice with 300 mL water+50 mL pyridine,
and again with 300 mL water+75 mL 36% wt aq. HCl (discarding the
aqueous phase after each wash). Removal of the solvent at reduced
pressure yielded analytically pure 1 as a faint yellow, thick syrup
(116 g, 0.494 mol, 100% yield). .sup.1H NMR: .delta.=7.81 (d, 2
aromatic H meta to CH.sub.3, J=8.3 Hz), 7.37 (d, 2 aromatic H ortho
to CH.sub.3, J=8.3 Hz), 4.23 (t, OCH.sub.2, J=5.9 Hz), 3.66 (t,
CH.sub.2Cl, J=5.9 Hz), 2.46 (s, CH.sub.3).
[0073] 4'-(2-(Benzoylthio)ethoxy)[1,1'-biphenyl]-4-carbonitrile
(3). 4'-Hydroxy[1,1'-biphenyl]-4-carbonitrile (5.1 g, 0.025 mol),
2-chloroethyl-p-toluenesulfonate (1, 9.2 g, 0.039 mol), and
potassium carbonate (5.3 g, 0.038 mol) were stirred at 57.degree.
C. in 100 mL dimethyl sulfoxide (DMSO) for 22 hrs, resulting in
quantitative conversion to 2 (verified by NMR analysis). Potassium
chloride (2.1 g, 0.028 mol) was added to the reaction mixture,
which was stirred 3 hrs at 85.degree. C. to convert the excess 1
into dichloroethane. The reaction mixture was poured into a 1 L
separatory funnel containing 300 mL water and extracted with 200 mL
of 2-butanone (MEK). The aqueous phase was extracted with another
300 mL MEK, and the organic extracts were combined and washed 3
times with 300 mL water. Finally, solvent and dichloroethane were
evaporated under reduced pressure at 80.degree. C. to give 2 (6.4
g, 0.025 mol, 100% yield) as a brown-orange syrup which solidifies
upon cooling. To the previous product in 100 mL
N,N-dimethylformamide (DMF) in a 250 mL RBF were added thiobenzoic
acid (7.3 g, 0.050 mol) and potassium bicarbonate (6.8 g, 0.068
mol), and the mixture was stirred at r.t. until CO.sub.2
effervescence ceased, then at 45.degree. C. for 4 hrs. The reaction
mixture was transferred to a 1 L separatory funnel containing 250
mL water, extracted with 400 mL ethyl acetate, and the organic
phase was washed twice with 250 mL water before solvent removal
under reduced pressure. The crude product was purified by
dissolving in 300 mL ethanol at 90.degree. C. (under slight
pressure), and allowing to recrystallize by slowly cooling to r.t.,
then by letting stand overnight at 4.degree. C. Filtration of the
crystals and removal of solvent under reduced pressure gave
analytically pure 3 as ultra-fine, pale brown needles (7.9 g, 0.022
mol, 88% overall yield in 2 steps). .sup.1H NMR: .delta.=8.02-7.96
(m, 2 aromatic H ortho to COS), 7.72-7.43 (m, 3 aromatic H meta and
para to COS, 4 aromatic H ortho and meta to CN, and 2 aromatic H
meta to OCH.sub.2), 7.05 (d, 2 aromatic H ortho to OCH.sub.2, J=8.7
Hz), 4.25 (t, OCH.sub.2, J=6.6 Hz), 3.50 (t, SCH.sub.2, J=6.6
Hz).
[0074] 4'-(2-(2-(Benzoylthio)ethoxy)ethoxy)
[1,1'-biphenyl]-4-carbonitrile (6).
4'-Hydroxy[1,1'-biphenyl]-4-carbonitrile (4.9 g, 0.024 mol),
2-(2-chloroethoxy)ethanol (12.7 g, 0.101 mol) and potassium
phosphate tribasic (K.sub.3PO.sub.4.xH.sub.2O, 22 g at .about.25%
wt water, 0.078 mol) were stirred at 110.degree. C. in 150 mL DMSO
for 12 hrs, resulting in quantitative conversion to 4 (verified by
NMR analysis). The reaction mixture was poured into a 1 L
separatory funnel containing 200 mL chloroform and washed 5 times
with 400 mL water to remove all of the chloroalcohol. The resultant
organic phase was dried with MgSO.sub.4, filtered, and the solvent
was removed under reduced pressure at 60.degree. C. to afford
analytically pure 4 (6.5 g, 0.023 mol, 96% yield) as a pale
yellow-orange syrup which solidifies upon cooling. To this product
in 100 mL DCM at 0.degree. C. were added p-toluenesulfonyl chloride
(22.2 g, 0.115 mol) and pyridine (7.2 g, 0.091 mol), after which
the reaction vessel was allowed warm up to and left to stir at r.t.
for 24 hrs. The reaction mixture was transferred to a 500 mL
separatory funnel, washed twice with 150 mL water+25 mL pyridine,
and again with 150 mL water and 40 mL 36% wt aq. HCl (discarding
the aqueous phase after each wash). The organic phase was again
dried with MgSO.sub.4, filtered, and the solvent was removed under
reduced pressure at 40.degree. C. to yield analytically pure 5 (9.5
g, 0.022 mol, 95% yield), which was finally reacted to generate 6
as follows. To 1.96 g (4.5 mmol) of the said product in 40 mL DMF
were added thiobenzoic acid (0.69 g, 4.7 mmol, 1.05 equiv.) and
potassium bicarbonate (1.0 g, 10 mmol), and the mixture was stirred
at r.t. until CO.sub.2 effervescence ceased, then at 40.degree. C.
for 12 hrs. The reaction mixture was transferred to a 500 mL
separatory funnel containing 200 mL water, extracted with 100 mL
ethyl acetate, and the organic phase was washed three additional
times with 200 mL water, dried with MgSO.sub.4, and gravity
filtered before solvent removal at 80.degree. C. under reduced
pressure to give analytically pure 6 as an orange syrup which
crystallizes upon cooling (1.80 g, 4.5 mmol, 91% overall yield in 3
steps). .sup.1H NMR: .delta.=8.00-7.93 (m, 2 aromatic H ortho to
COS), 7.72-7.39 (m, 3 aromatic H meta and para to COS, 4 aromatic H
ortho and meta to CN, and 2 aromatic H meta to OCH.sub.2), 7.02 (d,
2 aromatic H ortho to OCH.sub.2, J=8.7 Hz), 4.19 (t, ArOCH.sub.2,
J=4.8 Hz), 3.90 (t, ArOCH.sub.2CH.sub.2, J=4.8 Hz), 3.79 (t,
SCH.sub.2CH.sub.2, J=6.5 Hz), 3.33 (t, SCH.sub.2CH.sub.2, J=6.5
Hz).
[0075] Thiobenzoic acid S-[2-(9-carbazolyl)ethyl]ester (8).
Carbazole (15.2 g, 0.086 mol), 2-chloroethyl-p-toluenesulfonate (1,
60.2 g, 0.256 mol), and potassium hydroxide (88% wt pellets, 13.7
g, 0.215 mol) were stirred at r.t. in 300 mL DMSO for 18 hrs,
resulting in quantitative conversion to 7 (verified by NMR
analysis). Trichloroacetic acid (TCA, 22 g, 0.135 mol) and
potassium chloride (20 g, 0.268 mol) were added to the reaction
mixture, which was stirred 4 hrs at 100.degree. C. to convert the
excess 1 to dichloroethane. After titration of the excess TCA by
potassium bicarbonate (15.5 g, 0.155 mol), the reaction mixture was
poured into a 1 L separatory funnel containing 180 mL water and
extracted with 300 mL chloroform. The organic phase was washed
twice with 400 mL water, the solvent was evaporated under reduced
pressure, and the crude product was purified by dissolving in 475
mL boiling ethanol and allowing to recrystallize at r.t. overnight,
yielding analytically pure 7 (16.5 g, 0.072 mol, 83% yield) after
filtration and solvent removal. To 6.8 g (0.030 mol) of this
product in 110 mL DMF were added thiobenzoic acid (8.9 g, 0.061
mol) and potassium bicarbonate (8.0 g, 0.080 mol); the mixture was
swirled with gentle heating until CO.sub.2 effervescence ceased,
then allowed to react 4 hrs at 50.degree. C. The reaction mixture
was poured into a 500 mL separatory funnel containing 100 mL water,
extracted with 100 mL chloroform, and the organic phase was washed
twice with 150 mL water before solvent removal under reduced
pressure. The crude product was purified by first dissolving in 35
mL hot chloroform, adding 200 mL boiling ethanol, and allowing to
recrystallize overnight at r.t. Filtration of the crystals and
removal of solvent under reduced pressure gave analytically pure 8
as very fine, orange-pink needles (8.3 g, 0.025 mol, 70% overall
yield in 2 steps). .sup.1H NMR: .delta.=8.10 (d, 2 carbazole H,
J=7.5 Hz), 8.03-7.96 (m, 2 aromatic H ortho to COS), 7.64-7.57 (m,
3 aromatic H meta and para to COS), 7.54-7.43 (m, 4 carbazole H),
7.30-7.21 (m, 2 carbazole H), 4.55 (t, NCH.sub.2, J=7.8 Hz), 3.44
(t, SCH.sub.2, J=7.8 Hz).
[0076] 3,5-Dinitrobenzoic acid 3-(acetylthio)propyl ester (10).
Potassium bicarbonate (7.2 g, 0.072 mol) was added to
3,5-dinitrobenzoic acid (10.0 g, 0.047 mol) in 150 mL DMSO in a 500
mL RBF, and the slurry was swirled with gentle heating until
CO.sub.2 effervescence ceased. Allyl bromide (11.8 g, 0.095 mol)
was added next, and the RBF was placed in an oil bath to stir at
70.degree. C. for 2.5 hrs. The reaction mixture was poured into a 1
L separatory funnel containing 250 mL chloroform and washed twice
with 400 mL water (discarding the aqueous phase after each wash),
yielding 9 (10.7 g, 0.042 mol, 91% yield) in >99% purity after
removal of allyl bromide and solvent at 80.degree. C. under reduced
pressure. To this product in 100 mL toluene was added thioacetic
acid (9.8 g, 0.124 mol), and the reaction was carried out at
85.degree. C. with argon purge via radical mechanism using AIBN as
the initiator (0.70 g, 4.3 mmol, in 0.175 g increments at 1 hr
intervals). After 6 hrs the reaction mixture was poured into a 1 L
separatory funnel containing 16 g sodium bicarbonate (NaHCO.sub.3,
0.19 mol) in 300 mL water, extracted with 100 mL chloroform, and
the organic phase was washed twice with 300 mL water before solvent
removal under reduced pressure. The crude product was purified by
washing four times in 50 mL hexane at 60.degree. C., yielding 10 in
>99% purity as a viscous, dark brown syrup (9.1 g, 0.028 mol,
59% overall yield in 2 steps). .sup.1H NMR: .delta.=9.24 (t, 1
aromatic H para to CO.sub.2, J=2.1 Hz), 9.19 (d, 2 aromatic H ortho
to CO.sub.2, J=2.1 Hz), 4.52 (t, OCH.sub.2, J=6.3 Hz), 3.07 (t,
SCH.sub.2, J=6.9 Hz), 2.37 (s, CH.sub.3), 2.15 (tt,
OCH.sub.2CH.sub.2CH.sub.2S, J=6.9, 6.3 Hz).
[0077] 4-Hydroxybenzoic acid 2-(benzoylthio)ethyl ester (12).
4-Hydroxybenzoic acid (10 g, 0.072 mol) and 1-chloroethanol (60 g,
0.73 mol) were reacted in the bulk at 110.degree. C. for 16 hrs
with p-toluenesulfonic acid monohydrate (2.7 g, 0.014 mol) as
catalyst. The reaction mixture was transferred to a 500 mL
separatory funnel containing 5 g sodium bicarbonate in 125 mL
water, extracted with 150 mL ethyl acetate, and the organic phase
was washed 4 times with 125 mL water before solvent removal under
reduced pressure, yielding 11 in ca. 97% purity (13 g, 0.063 mol,
88% yield). To this product in 100 mL DMF were added thiobenzoic
acid (18 g, 0.12 mol) and potassium bicarbonate (16 g, 0.16 mol),
and the mixture was stirred at r.t. until CO.sub.2 effervescence
ceased, then at 50.degree. C. for 4 hrs. The reaction mixture was
poured into a 500 mL separatory funnel containing 100 mL water,
extracted with 100 mL chloroform, and the organic phase was washed
3 times with 150 mL water before solvent removal at reduced
pressure. The crude product was finally purified by first
dissolving in 50 mL hot chloroform, adding 25 mL boiling hexane,
and allowing to recrystallize overnight in the freezer. Filtration
of the crystals and removal of the solvent under reduced pressure
gave analytically pure 12 as a pink powder (14.5 g, 0.048 mol, 67%
overall yield in 2 steps). .sup.1H NMR: .delta.=8.02-7.93 (m, 2
aromatic H ortho to CO.sub.2 and 2 aromatic H ortho to COS), 7.59
(tt, 1 aromatic H para to COS, J=7.5, 1.2 Hz), 7.51-7.42 (m, 2
aromatic H meta to COS), 6.87 (d, 2 aromatic H meta to CO.sub.2,
J=8.7 Hz), 5.8 (br, ArOH), 4.50 (t, OCH.sub.2, J=6.5 Hz), 3.47 (t,
SCH.sub.2, J=6.5 Hz).
[0078] Thiobenzoic acid S-[3-pyridinylmethyl]ester (13). Potassium
bicarbonate (12.3 g, 0.123 mol) was added to thiobenzoic acid (14.2
g, 0.097) in 200 mL ethanol in a 500 mL RBF, and the slurry was
swirled with gentle heating until CO.sub.2 effervescence ceased.
3-(chloromethyl)pyridine hydrochloride (10.2 g, 0.060 mol) was
added next, and the RBF was placed in an oil bath to stir at
50.degree. C. for 2.5 hrs. The reaction mixture was poured into a 1
L separatory funnel containing 10 g potassium carbonate
(K.sub.2CO.sub.3, 0.072 mol) in 250 mL water, extracted with 150 mL
DCM, and the organic phase was washed twice with 250 mL water,
gravity filtered, and evaporated to dryness under reduced pressure.
The crude product was purified further by washing in 50 mL hot
hexane to give, after removal of leftover solvent under reduced
pressure, 13 as a brown solid in ca. 96% purity (11.4 g, 0.050 mol,
80% yield). .sup.1H NMR: .delta.=8.64 (d, 1 aromatic H ortho to
CH.sub.2 at the second C of the pyridine ring, J=1.8 Hz), 8.50 (dd,
1 aromatic H para to CH.sub.2 at the sixth C of the pyridine ring,
J=4.8, 1.5 Hz), 7.99-7.90 (m, 2 aromatic H ortho to COS), 7.71
(ddd, 1 aromatic H ortho to CH.sub.2 at the fourth C of the
pyridine ring, J=7.8, 1.8, 1.5 Hz), 7.58 (tt, 1 aromatic H para to
COS, J=7.5, 1.2 Hz), 7.49-7.39 (m, 2 aromatic H meta to COS), 7.24
(dd, 1 aromatic H meta to CH.sub.2 at the fifth C of the pyridine
ring, J=7.8, 4.8 Hz), 4.29 (s, CH.sub.2).
[0079] 1,2-Polybutadiene Functionalization using
9-[2-[(Triphenylmethyl)thio]ethyl]carbazole (14)
[0080] Synthesis of 9-(2-Chloroethyl)carbazole (7). The procedure
was outlined in the description of the preparation of 8. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=8.09 (d, 2 carbazole H, J=7.8
Hz), 7.50-7.37 (m, 4 carbazole H), 7.29-7.20 (m, 2 carbazole H),
4.60 (t, NCH.sub.2, J=7.2 Hz), 3.83 (t, CH.sub.2Cl, J=7.2 Hz).
.sup.13C NMR (300 MHz, CDCl.sub.3): .delta.=140.07, 125.91, 123.07,
120.50, 119.50, 108.43, 44.64, 40.99.
[0081] Synthesis of 9-[2-[(Triphenylmethyl)thio]ethyl]carbazole
(14). Potassium carbonate (4.4 g, 32 mmol), triphenylmethyl
mercaptan (Alfa Aesar, 98%, 3.1 g, 11 mmol), and
9-(2-chloroethyl)carbazole (2.1 g, 9.1 mmol) were stirred at r.t.
in 50 mL DMF for 5 hrs, after which the reaction mixture was
transferred to a 500 mL separatory funnel containing 100 mL water
and extracted with 50 mL chloroform. The organic layer was washed
twice with 100 mL water, the solvent was evaporated under reduced
pressure, and the crude product was purified by washing 3 times in
75 mL hot ethanol. Filtration of the solids and removal of
remaining solvent under reduced pressure gave analytically pure 14
as ultra-fine, white needles (3.1 g, 6.6 mmol, 72% yield). .sup.1H
NMR (300 MHz, CDCl3): .delta.=8.03 (d, 2 carbazole H, J=7.8 Hz),
7.43-7.14 (m, 4 carbazole H and 15 phenyl H), 7.00 (d, 2 carbazole
H, J=8.1 Hz), 4.06 (t, NCH.sub.2, J=8.1 Hz), 2.75 (t, SCH.sub.2,
J=8.1 Hz). .sup.13C NMR (300 MHz, CDCl3): .delta.=144.61, 139.76,
129.69, 128.01, 126.86, 125.56, 122.79, 120.27, 119.00, 108.54,
67.39, 42.37, 30.22.
[0082] Functionalization Procedure and Results. To compound 14
(0.25 g, 0.5 mmol) dissolved in 10 mL chloroform in a 100 mL
Schlenk tube were added triethylsilane (Alfa Aesar, 98%, 0.08 g,
0.7 mmol) and trifluoroacetic acid (TFA, 0.5 mL, 5% vol), and the
mixture was stirred 1-2 hrs at r.t. After addition of 1,2-PB (0.2
g, 4 mmol vinyl groups, dissolved in 10 mL chloroform) and AIBN
(0.03 g, 0.2 mmol), the contents of the Schlenk tube were degassed
in 3 freeze-pump-thaw cycles, then allowed to react at 55.degree.
C. for 3 hrs. Following reaction, the polymer solution was
transferred to a 100 mL jar containing a small amount of BHT,
concentrated by evaporation of all but the last 10 mL solvent under
an argon stream, and precipitated in cold methanol. Final
purification of the polymer was achieved by reprecipitation from a
DCM solution with cold methanol (2-3 times), followed by drying to
constant weight under vacuum at r.t. Reaction conditions and
results for a specific example are given in Table A.1 (first
entry).
[0083] 1,2-Polybutadiene Functionalization Using Thiobenzoic acid
S-[3-(9-carbazolyl)propyl]ester (16)
[0084] Synthesis of 9-Allylcarbazole (15). Carbazole (10.1 g, 0.057
mol) and potassium hydroxide (88% wt pellets, crushed, 7.1 g, 0.11
mol) were stirred in 100 mL DMSO at 50.degree. C. for 30 min before
dropwise addition of allyl bromide (14.7 g, 0.118 mol). After 15
min the reaction mixture was poured into a 500 mL separatory funnel
containing 100 mL chloroform and washed 5 times with 200 mL water
to give, after solvent evaporation at 60.degree. C. under reduced
pressure, compound 15 in >99% purity as a dark brown, viscous
syrup which solidified upon cooling (11.9 g, 0.057 mol, 100%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.14-8.06 (m, 2
carbazole H), 7.49-7.32 (m, 4 carbazole H), 7.28-7.19 (m, 2
carbazole H), 6.04-5.90 (m, CH.dbd.CH.sub.2), 5.19-5.10 (m,
Z--HCH.dbd.CH), 5.07-4.97 (m, E-HCH.dbd.CH), 4.92-4.85 (m,
NCH.sub.2). .sup.13C NMR (300 MHz, CDCl.sub.3): .delta.=140.34,
132.27, 125.67, 122.90, 120.33, 119.00, 116.74, 108.74, 45.21.
[0085] Synthesis of Thiobenzoic acid
S-[3-(9-carbazolyl)propyl]ester (16). Thiobenzoic acid (30 g, 0.20
mol) was added to 9-allylcarbazole (11.9 g, 0.057 mol) in 100 mL
toluene, and the reaction was carried out at 90.degree. C. with
argon purge via radical mechanism using AIBN as the initiator (1.8
g, 11 mmol, in 300 mg increments at 1 hr intervals). After 6 hrs
the reaction mixture was poured into a 1 L separatory funnel
containing 20 g sodium bicarbonate (NaHCO.sub.3, 0.24 mol) in 250
mL water, extracted with 100 mL chloroform, and the organic phase
was washed twice with 200 mL water before solvent removal under
reduced pressure. The crude product was subsequently washed in 100
mL hot hexane, 150 mL ethanol, and finally 150 mL of 15:1
ethanol:chloroform. Evaporation of leftover solvent at 80.degree.
C. under reduced pressure yielded compound 16 in ca. 90% purity as
a dark brown, viscous syrup which solidified upon cooling (9.35 g,
0.024 mol, 42% yield, .about.10% wt dibenzoyl disulfide). .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=8.10 (d, 2 carbazole H, J=8.1
Hz), 8.00-7.95 (m, 2 aromatic H ortho to COS), 7.62-7.41 (m, 3
aromatic H meta and para to COS plus 4 carbazole H), 7.27-7.19 (m,
2 carbazole H), 4.43 (t, NCH.sub.2, J=6.9 Hz), 3.06 (t, SCH.sub.2,
J=6.9 Hz), 2.26 (tt, NCH.sub.2CH.sub.2CH.sub.2S, J=6.9, 6.9 Hz).
.sup.13C NMR (300 MHz, CDCl.sub.3): .delta.=191.56, 140.25, 136.88,
133.50, 128.65, 127.23, 125.75, 122.91, 120.41, 119.00, 108.55,
41.65, 28.95, 26.41.
[0086] Functionalization Procedure and Results. Reaction conditions
and results for a specific example are given in Table A.1 (second
entry).
TABLE-US-00003 TABLE A1 Reaction Conditions and Results for 1,2-PB
Functionalization Using Compounds 14 and 16 [PB] [AIBN] Rxn time
X.sub.funct.sup.c M.sub.W.sup.d New H NMR peaks above 2.2 ppm for
modified PB Entry.sup.a (g/mL) [Thiol].sup.b (g/mL) (hrs) %
(kg/mol) PDI.sup.d (all peaks are broad) 820kPB14 0.011 0.1 0.002
2.9 6 945 2.08 8.12-8.04 (2H), 7.52-7.39 (4H, 7.27-7.19 (2H),
4.56-4.43 (2H), 2.97-2.83 (2H) 92kPB16 0.003 1.1 0.003 3.0 19 187
1.34 8.15-8.03 (2H), 7.56-7.37 (4H, 7.28-7.15 (2H), 4.50-4.27(2H),
2.62-2.30 (4H) .sup.aModified PB polymers were named so that the
prefix corresponds to the molecular weight of the starting 1,2-PB
chain, and the suffix represents the reagent used. .sup.bIn molar
equivalents of 1,2-PB monomer units. .sup.cThe fraction of reacted
1,2-PB units that bear functional groups (refer to text).
.sup.dMeasurements as described in Experimental section using the
Waters setup (the 1,2-PB prepolymers had PDI values of 1.07 and
1.26 for the 92 kg/mol and 820 kg/mol chains, respectively.
[0087] General Procedure for 1,2-PB Functionalization Using a
Protected Thiol PhCOSR (Scheme 1). To the thioester PhCOSR (1-4
mmol) dissolved in 25-75 mL DMF in a 250 mL RBF were added
hydrazine monohydrochloride (ca. 4 equiv., 4-16 mmol) and sodium
acetate (ca. 8 equiv., 8-32 mmol). The RBF was purged with argon
for ca. 10 min and left to stir at r.t. for 2-4 hrs, resulting in
95-100% cleavage of the thioester (verified by NMR analysis). The
thiol product was extracted into 30-40 mL chloroform after addition
of 100 mL water; the organic phase was washed 4 times with 150 mL
water, and transferred into a 100 mL Schlenk tube containing 1,2-PB
(0.1-0.2 g, 2-4 mmol, dissolved in 10 mL chloroform) and AIBN
(50-250 mg, 0.3-1.5 mmol). The contents of the Schlenk tube were
degassed in 3 freeze-pump-thaw cycles, and then allowed to react at
55.degree. C. for 2-6 hrs. Following reaction, the polymer solution
was transferred to a 100 mL jar containing a small amount of
2,6-ditert-butyl-4-methylphenol (BHT), concentrated by evaporation
of all but the last 10 mL solvent under an argon stream, and
precipitated with cold methanol. Final purification of the polymer
was achieved by reprecipitation from a DCM or THF solution
(containing ca. 1% wt BHT) with cold methanol (repeated 2-4 times),
followed by drying to constant weight under vacuum at r.t.
[0088] General Procedure for 1,2-PB Functionalization Using an Acyl
Chloride RCOCl (Scheme 3). To 1,2-PB (0.1-0.5 g, 2-9 mmol)
dissolved in 15-30 mL THF in a 100 mL Schlenk tube was added a 10
mL THF solution of 2-mercaptoethanol (BME, 0.5-2 equiv., 1-20 mmol)
and AIBN (15-50 mg, 0.1-0.3 mmol). The contents of the Schlenk tube
were degassed in 3 freeze-pump-thaw cycles, and then allowed to
react at 55.degree. C. for 2-3 hrs. Following reaction, the polymer
solution was transferred to a 100 mL jar containing a small amount
of BHT and precipitated in cold methanol. The polymer was purified
by reprecipitation from a THF solution (containing ca. 1% wt BHT)
with cold methanol (repeated 1-2 times), followed by drying to
constant weight under vacuum at r.t. To the
2-hydroxyethylthio-functionalized 1,2-PB polymer (0.1-0.5 g)
dissolved in 10-25 mL DCM in a 100 mL RBF were added triethylamine
(Et.sub.3N, 3-5 mol. equiv. of functionalized monomer units) and
the acyl chloride RCOCl (2.5-3 mol. equiv. of functionalized
monomer units), and the reaction mixture was stirred 3-4 hrs at
r.t. Following reaction, the polymer solution was transferred to a
100 or 250 mL jar containing a small amount of BHT, washed with
50-100 mL water and again with 50-100 mL aqueous sodium bicarbonate
(discarding the wash each time), concentrated by evaporation of all
but the last 10 mL DCM under an argon stream, and finally
precipitated with cold methanol. Final purification of the polymer
was achieved by reprecipitation from a DCM solution (containing ca.
1% wt BHT) with cold methanol (repeated 2-3 times), followed by
drying to constant weight under vacuum at r.t.
[0089] Alkylation of Nucleophiles to Introduce Primary Halide or
Alcohol Moieties. To generate .omega.-chloroalkyl or
.omega.-bromoalkyl derivatives, alkylation of nucleophiles is
usually done using .alpha.,.omega. dibromo- or dichloro-alkanes,
e.g., reaction of 4'-hydroxy-biphenyl-4-carbonitrile with
1,6-dibromohexane.sup.25 or carbazole with
1,2-dichloroethane.sup.26. Unfortunately, when using these reagents
bisubstitution is always an issue. In addition, in the case of very
basic nucleophiles (e.g. deprotonated carbazole), elimination
competes effectively; hence, yields tend to be low and product
purification usually requires column chromatography. Yields of
>50% were not achieved for the synthesis of 7 according to
published methods.sup.26 using KOH/K.sub.2CO.sub.3 as base in 1,2
dichloroethane with tetrabutylammonium bromide as phase-transfer
catalyst. Chloroethylation of nucleophiles with
2-chloroethyl-p-toluenesulfonate (1) in DMSO at low to moderate
temperatures overcame both problems stated above. First, the use of
p-toluenesulfonate (tosylate) as leaving group and of a polar
aprotic solvent both favor substitution over elimination.sup.27;
second, because tosylate is a significantly better leaving group
than chlorine, quantitative conversion of both carbazole and
4'-hydroxy-biphenyl-4-carbonitrile to the chloroethyl derivatives
(compounds 7, 2) was achieved without measurable formation of
side-products. Excess 1 could be reacted quantitatively to
1,2-dichloroethane with KCl in a few hours, so that product in
quantitative yields and >95% purity could be obtained by mere
liquid-liquid extraction and removal of solvent and dichloroethane
at reduced pressure.
[0090] Alkylation of nucleophiles to generate .omega.-hydroxyalkyl
derivatives is usually done using .omega.-bromo-1-alkanols or
.omega.-chloro-1-alkanols with K.sub.2CO.sub.3 or NaH as base in
DMF, acetone, or ethanol as solvent (for instance, alkylation of
4'-hydroxy-biphenyl-4-carbonitrile with bromodecanol.sup.28 or
chlorohexanol.sup.29). Published yields for such reactions are
usually <85%, and column chromatography is typically necessary
for isolation of the product. Here it was discovered that
alkylation of 4'-hydroxy-biphenyl-4-carbonitrile with commercially
available H(OCH.sub.2CH.sub.2).sub.nCl (n=1-3, inexpensively
available from Wako Chemicals) in DMSO with K.sub.3PO.sub.4 as base
gave quantitative conversion, and that product (compound 4 or
analog) in >99% purity could be obtained by mere washes due to
the good water solubility of the chloride reagent.
[0091] .sup.13C NMR Resonances of Select Compounds
[0092] All .sup.13C NMR spectra were obtained using a Varian
Mercury 300 spectrometer (corresponding to 74.5 MHz for .sup.13C),
recorded in CDCl.sub.3, and referenced to tetramethylsilane.
Information compiled in the Spectral Database for Organic Compounds
(available online at
http://riodb01.ibase.aist.go.jp/sdbs/cgi-bin/direct_frame_top.cgi)
was used in the process of assigning .sup.13C NMR resonances.
[0093] 2-Chloroethyl-p-toluenesulfonate (1). .sup.13C NMR:
.delta.=145.30 (e), 132.44 (b), 130.00 and 127.97 (c and d), 69.02
(f), 40.83 (g), 21.67 (a).
##STR00015##
[0094] 4'-(2-(Benzoylthio)ethoxy)[1,1'-biphenyl]-4-carbonitrile
(3). .sup.13C NMR: .delta.=191.40 (e), 159.00 (j), 145.11 (n),
136.64 (d), 133.69 (a), 132.57 (p), 131.89 (m), 128.70 and 127.30
(b and c), 128.43 (l), 127.13 (o), 119.09 (r), 115.21 (k), 110.14
(q), 66.70 (g), 28.13 (f).
##STR00016##
[0095] 4'-(2-(2-(Benzoylthio)ethoxy)ethoxy)
[1,1'-biphenyl]-4-carbonitrile (6). .sup.13C NMR: .delta.=191.54
(e), 159.35 (j), 145.12 (n), 136.82 (d), 133.48 (a), 132.54 (p),
131.63 (m), 128.61 and 127.23 (b and c), 128.30 (l), 127.07 (o),
119.10 (r), 115.22 (k), 110.06 (q), 70.05 and 69.38 (h and i),
67.50 (g), 28.65 (f).
##STR00017##
[0096] Thiobenzoic acid S-[2-(9-carbazolyl)ethyl]ester (8).
.sup.13C NMR: .delta.=191.73 (e), 140.07 (h), 136.71 (d), 133.73
(a), 128.74 and 127.35 (b and c), 125.91 (j), 122.98 (m), 120.40
(l), 119.26 (k), 108.74 (i), 42.42 (g), 27.28 (f).
##STR00018##
[0097] 3,5-Dinitrobenzoic acid 3-(acetylthio)propyl ester (10).
.sup.13C NMR: .delta.=195.36 (b), 162.49 (f), 148.67 (i), 133.81
(g), 129.52 (h), 122.47 (j), 65.21 (e), 30.64 (a), 28.68 and 25.50
(c and d).
##STR00019##
[0098] 4-Hydroxybenzoic acid 2-(benzoylthio)ethyl ester (12).
.sup.13C NMR: .delta.=191.42 (e), 166.27 (h), 160.24 (l), 136.65
(d), 133.68 (a), 132.09 (j), 128.70 and 127.32 (b and c), 122.13
(i), 115.28 (k), 63.11 (g), 27.86 (f).
##STR00020##
[0099] Thiobenzoic acid S-[3-pyridinylmethyl]ester (13). .sup.13C
NMR: .delta.=190.74 (e), 150.14 (h), 148.62 (i), 136.48 and 136.42
(d and k), 133.70 and 133.65 (a and g), 128.71 and 127.31 (b and
c), 123.46 (j), 30.38 (f).
##STR00021##
[0100] .sup.1H NMR Spectra of Select Functionalized Polymers
[0101] All spectra were taken in CDCl.sub.3, resulting in a solvent
peak in each case at .delta.=7.24 ppm. Peaks near 1.6 ppm
correspond to water, and visible peaks at .delta.=6.97, 2.27, and
1.43 ppm belong to BHT. Representative Spectra are shown in FIGS.
1-6.
Statements Regarding Incorporation By Reference and Variations
[0102] All references throughout this application, for example
patent documents including issued or granted patents or
equivalents; patent application publications; and non-patent
literature documents or other source material; are hereby
incorporated by reference herein in their entireties, as though
individually incorporated by reference, to the extent each
reference is at least partially not inconsistent with the
disclosure in this application (for example, a reference that is
partially inconsistent is incorporated by reference except for the
partially inconsistent portion of the reference).
[0103] When a group of substituents is disclosed herein, it is
understood that all individual members of those groups and all
subgroups, including any isomers and enantiomers of the group
members, and classes of compounds that can be formed using the
substituents are disclosed separately. When a Markush group or
other grouping is used herein, all individual members of the group
and all combinations and subcombinations possible of the group are
intended to be individually included in the disclosure. When a
compound is described herein such that a particular isomer or
enantiomer of the compound is not specified, for example, in a
formula or in a chemical name, that description is intended to
include each isomer and enantiomer of the compound described
individually or in any combination. When an atom is described
herein, including in a composition, any isotope of such atom is
intended to be included. Specific names of compounds are intended
to be exemplary, as it is known that one of ordinary skill in the
art can name the same compounds differently. Every formulation or
combination of components described or exemplified herein can be
used to practice the invention, unless otherwise stated. Whenever a
range is given in the specification, for example, a temperature
range, a time range, or a composition range, all intermediate
ranges and subranges, as well as all individual values included in
the ranges given are intended to be included in the disclosure.
[0104] All patents and publications mentioned in the specification
are indicative of the levels of skill of those skilled in the art
to which the invention pertains. References cited herein are
incorporated by reference herein in their entirety to indicate the
state of the art, in some cases as of their filing date, and it is
intended that this information can be employed herein, if needed,
to exclude (for example, to disclaim) specific embodiments that are
in the prior art. For example, when a compound is claimed, it
should be understood that compounds known in the prior art,
including certain compounds disclosed in the references disclosed
herein (particularly in referenced patent documents), are not
intended to be included in the claim.
[0105] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the invention.
It will be apparent to one of ordinary skill in the art that
methods, devices, device elements, materials, procedures and
techniques other than those specifically described herein can be
applied to the practice of the invention as broadly disclosed
herein without resort to undue experimentation. All art-known
functional equivalents of methods, devices, device elements,
materials, procedures and techniques described herein are intended
to be encompassed by this invention. Whenever a range is disclosed,
all subranges and individual values are intended to be encompassed.
This invention is not to be limited by the embodiments disclosed,
including any shown in the drawings or exemplified in the
specification, which are given by way of example or illustration
and not of limitation.
[0106] The terms and expressions which have been employed herein
are used as terms of description and not of limitation, and there
is no intention in the use of such terms and expressions of
excluding any equivalents of the features shown and described or
portions thereof, but it is recognized that various modifications
are possible within the scope of the invention claimed. Thus, it
should be understood that although the present invention has been
specifically disclosed by preferred embodiments, exemplary
embodiments and optional features, modification and variation of
the concepts herein disclosed may be resorted to by those skilled
in the art, and that such modifications and variations are
considered to be within the scope of this invention as defined by
the appended claims. The specific embodiments provided herein are
examples of useful embodiments of the present invention and it will
be apparent to one skilled in the art that the present invention
may be carried out using a large number of variations of the
devices, device components, methods steps set forth in the present
description. As will be obvious to one of skill in the art, methods
and devices useful for the present methods can include a large
number of optional composition and processing elements and
steps.
[0107] Many of the molecules disclosed herein contain one or more
ionizable groups [groups from which a proton can be removed (e.g.,
--COON) or added (e.g., amines) or which can be quaternized (e.g.,
amines)]. All possible ionic forms of such molecules and salts
thereof are intended to be included individually in the disclosure
herein. With regard to salts of the compounds herein, one of
ordinary skill in the art can select from among a wide variety of
available counterions those that are appropriate for preparation of
salts of this invention for a given application. In specific
applications, the selection of a given anion or cation for
preparation of a salt may result in increased or decreased
solubility of that salt.
[0108] Every formulation or combination of components described or
exemplified herein can be used to practice the invention, unless
otherwise stated.
[0109] Whenever a range is given in the specification, for example,
a temperature range, a time range, or a composition or
concentration range, all intermediate ranges and subranges, as well
as all individual values included in the ranges given are intended
to be included in the disclosure. It will be understood that any
subranges or individual values in a range or subrange that are
included in the description herein can be excluded from the claims
herein.
[0110] All patents and publications mentioned in the specification
are indicative of the levels of skill of those skilled in the art
to which the invention pertains. References cited herein are
incorporated by reference herein in their entirety to indicate the
state of the art as of their publication or filing date and it is
intended that this information can be employed herein, if needed,
to exclude specific embodiments that are in the prior art. For
example, when composition of matter are claimed, it should be
understood that compounds known and available in the art prior to
Applicant's invention, including compounds for which an enabling
disclosure is provided in the references cited herein, are not
intended to be included in the composition of matter claims
herein.
[0111] As used herein, "comprising" is synonymous with "including,"
"containing," or "characterized by," and is inclusive or open-ended
and does not exclude additional, unrecited elements or method
steps. As used herein, "consisting of" excludes any element, step,
or ingredient not specified in the claim element. As used herein,
"consisting essentially of" does not exclude materials or steps
that do not materially affect the basic and novel characteristics
of the claim. In each instance herein any of the terms
"comprising", "consisting essentially of" and "consisting of" may
be replaced with either of the other terms. The invention
illustratively described herein suitably may be practiced in the
absence of any element or elements, limitation or limitations which
is not specifically disclosed herein.
[0112] One of ordinary skill in the art will appreciate that
starting materials, biological materials, reagents, synthetic
methods, purification methods, analytical methods, assay methods,
and biological methods other than those specifically exemplified
can be employed in the practice of the invention without resort to
undue experimentation. All art-known functional equivalents, of any
such materials and methods are intended to be included in this
invention. The terms and expressions which have been employed are
used as terms of description and not of limitation, and there is no
intention that in the use of such terms and expressions of
excluding any equivalents of the features shown and described or
portions thereof, but it is recognized that various modifications
are possible within the scope of the invention claimed. Thus, it
should be understood that although the present invention has been
specifically disclosed by preferred embodiments and optional
features, modification and variation of the concepts herein
disclosed may be resorted to by those skilled in the art, and that
such modifications and variations are considered to be within the
scope of this invention as defined by the appended claims.
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