Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Carbondisulfide Derived Zwitterions
BACKGROUND
Field of the Invention
The present invention relates generally to the field of amines and more
particularly to a classes of amino zwitterions.
Description of the Problem Solved by the Invention
Amines are extremely useful compounds in the buffering of biological systems.
Each class of amine has various limitations which require choosing an amine
based
on multiple factors to select the best amine. For example, pH buffering range
is
typically most important, but issues of chelation, pH range stability, and
solubility also
come into play. Typically, a suboptimal buffer will result in yields that are
well below
the potential yield. The present invention improves the yields in fermentation
and
purification, and improves shelf stability of proteins and amino acids.
SUMMARY OF THE INVENTION
The present invention relates to amines and amine derivatives that improve the
buffering range, and/or reduce the chelation and other negative interactions
of the
buffer and the system to be buffered. The reaction of amines or polyamines
with
various molecules to form amine derivatives and polyamines and derivatives
with
differing pKa's extend the buffering range; derivatives that result in
polyamines that
have the same pKa yield a greater buffering capacity. Derivatives that result
in
zwitterionic buffers improve yield by allowing a greater range of stability
and reduced
conductivity.
DESCRIPTION OF THE FIGURES
Attention is now directed to the following figures that describe embodiments
of
the present invention:
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Fig. 1-2 shows the synthesis of zwitterion type buffers from nitroparaffins.
Fig. 3 shows the synthesis of dithicarbamates from a series of biolgically
active amines.
Fig. 4 shows the synthesis of xanthates from nitroparaffins.
Fig. 5 shows the synthesis of derivatives of dithiocarbamates of biologically
active amines.
Fig. 6 shows the synthesis of derivatives of aromatic dithiocarbamates.
Fig. 7 shows the synthesis of a range of derivatives based on dithiocarbmates
of dopamine.
Fig. 8 shows the synthesis of dithiocarbamate dispersants and polyamine
dithiocarbamate derivatives.
Fig. 9 shows dithiocarbamates from multifunctional secondary amines.
Fig. 10 shows the synthesis of pharmacologically interesting
diothiocarbamates.
Fig. 11 shows the synthesis of dithiocarbamates / xanthates hybrids and
xanthates amino compounds from aminoalcohols and amino acid esters.
Fig. 12 shows the dithiocarbamates / xanthates based on the typical 3
ethylene amines.
Fig. 13 shows the synthesis of benzyl functional zwitterionics.
Fig. 14 shows the synthesis of bis dithiocarbamates and bis xanthates
Fig. 15 shows the synthesis of a bis dithiocarbamate based on citric acid
Fig 16 shows alkoxylates of dithiocarbamates
Fig 17 shows the synthesis of alkoxylates of aminopyridines and dopamine as
well as aminoalcohols.
Fig. 18 shows the synthesis of benzyl substituted amines
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Fig. 19 shows the synthesis of bis-dithiocarbamates and amine oxides
Fig. 20 shows the N-sulfonic acids of a range of primarily secondary amines.
Fig. 21 and 22 show the synthesis of a range of therapeutic bioactive
molecules for treating diseases of the nuerosystem.
Fig. 23 and 24 show the synthesis of a series of oil soluble zwitterions and
polyamines.
Fig. 25 shows the synthesis of a series of quaternary ammonium compounds
with a wide range of uses.
Fig. 26 shows the synthesis of surfactants useful as emulsifiers and other
uses where hydrophilic and hydrophobic species need to come into close
contact.
Fig. 27 shows the synthesis of ester amines, ester polyamines
Fig. 28 shows the synthesis of tertiary ester amine quaternaries.
Several drawings and illustrations have been presented to aid in
understanding the invention. The scope of the present invention is not limited
to
what is shown in the figures.
DETAILED DESCRIPTION OF THE INVENTION
The reaction of carbon disulfide with nitroparaffins or nitroalcohols form an
intermediate from which xanthate and primary amine functionality can be
present in
the same molecule through relatively simple, and high yield reactions. Figures
1, 2
and 4 depict the route to nitro xanthates, which have utility as cross linking
agents
and vulcanizing agents and rubber. The nitro functionality improves adhesion
of the
rubber to the cord in steel belted radial tires and fiber reinforced tire
applications as
well as other reinforced rubber applications. The nitroxanthates can be
utilized as
intermediates in the manufacture of primary amine functional xanthates for
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biological systems, agriculture and antimicrobials as well as many other
applications. It should be noted that here, as well as in other embodiments of
the
invention where a reduction takes place when a xanthate or dithiocarbamate
functionality is present, the reduction of the nitro to the amine must be done
under
relatively mild conditions to limit the co-products of reducing the xanthate
functionality. The xanthates and dithiocarbamates have additional
functionality in
agriculture. The traditional uses such as chelants, and dispersants, are
complimented by their use as antifungal, antimicrobial as well as growth
regulators
as promoters as well as phytocides and insecticides. Often the effects are
more
pronounced when produced as metal salts, such as zinc, tin, copper or any
other
transition metal salts.
Figure 3 shows the synthesis of dithiocarbamtes from a range of biologically
interesting amines. The dithiocarbamates of the alaphatic and aminoalcohols
are a
low cost dispersant, cross linker, with uses in agricultural, antimicrobial,
chelant,
mining collector and buffer. While the aromatic amine based dithiocarbamates
are
useful in the above applications, the cost makes them less commercially viable
in
those applications, however, they show great promise as therapies for diseases
of
the nervous system, such as multiple sclerosis, Alzheimer's, and Parkinson's
diseases. The potential exists for these molecules and their derivatives to be
useful
therapies as channel blockers as well, which is believed to be the mechanism
by
which the molecules of the present invention act as an MS therapy.
Additionally,
the dithiocarbamates are anti-oxidants and have potential as nutritional
supplements as well as cancer therapies.
Figures 5, 6 and 7 show the synthesis of several classes of derivatives of the
dithiocarbamates previously discussed. Several of the derivatives,
particularly the
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pyridine containing derivatives, are biologically active and potential
therapies for
mood disorders, multiple sclerosis, Alzheimer's disease, and Parkinson's
disease.
The carboxcylic acid and ester containing derivatives primarily increase the
dispersing capability of the underlying dithiocarbamtes, reduce the chelating,
or
reduce the cost of manufacture. The molecules of figures 6 and 7 that contain
aromatic rings and require reduction, must be done under mild conditions, such
as
iron with turnings or under very mild conditions with sponge metal catalysts
at
ambient temperatures and pressures of less than 400 psi. The molecules of of
Figure 7 are typically simple one-pot syntheses. Figure 8 contains several
dispersants that are more surfactant in nature, with the higher carbon chain
values
of R being foam formers. The di-dithiocarbamates from diamines are strong
chelants that are of the class bidentate, but tend to undergo ring closure if
not kept
under basic aqueous conditions. Figure 9 further expands on these bidentate
chelants by introducing other chelant groups. Thus allowing for a wider range
of
substrates for chelation and dispersion. Figure 10 shows a family of
aminopyridine
derived dithiocarbamates as well as a dopamine diamine derived
dithiocarbamates
all of which are biologically/ pharmacologically interesting. Similar to those
in
Figures 6 and 7, the reduction steps must be undertaken under mild conditions
to
minimize the reduction of the aromatic groups.
Figure 11 shows the synthesis of dithiocarbamate / xanthates. Line i gives
the example of a dithiocarbamates that possesses an alcohol group. Further
exposure to base and CS2 will cause a xanthate to form in place of the
alcohol.
Line ii carries this forward to include the single step synthesis where 1 or
more
alcohol groups are present. The A', D', and E' are where any alcohols, if
present,
have been converted to xanthate groups (-CH2OCS2H), if no alcohol is present
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a specific A, D or E, then the prime of the original variable remains
unchanged and
the original variable. It is understood by one of ordinary skill, that using
less than
the full amount of CS2 that can be reacted (or base / cation) will result in
some
alcohol groups not being converted to xanthate groups. This concept is shown
in
Figure 12. These products are included as part of the invention. This
principle
applies to lines iii through vii as well. The same principle applies to the
third line on
Figure 8. If alcohol groups are present, then they can be converted to
xanthates as
shown in Figure 11. The addition of xanthate groups increases the efficiency
of the
molecule as a dispersant or mining collector, as well as alter its solubility
characteristics. Lines iii through vi produce xanthates of amino acids or
amino acid
esters. The choice of J allows for a range of solubilities for the free
molecule as well
as the bound molecule when acting as a chelant, collector or dispersant. Lines
v
and vi are the result of J being polyethyleneoxide in lines iii and iv. It is
understood
that this is for illustrative purposes, and that polypropyleneoxide or
polybutyleneoxide or other polyalkoxide is part of the invention, as well as
their
copolymers as J. Line vii shows another way of altering the solubility by
substituting
a less polar group as R. Figure 12 shows the dithiocarbamates / xanthates
based
on the typical 3 ethylene amines.
Figure 13 shows the synthesis of benzyl functional zwitterions. The reaction
of the benzyl chloride species generates a free chloride ion that will
deactivate the
amine to further reaction, so much harsher conditions or pH control are
necessary
to have the reaction go to completion. This becomes a problem once the
reaction
reaches half-way. In cases where there are hydroxyls present, the reaction
will
yield a mix of products with some benzyl group addition occurring on the
alcohol
groups as well as the amine. This is shown in the figure with a single alcohol
group
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present, but is not limited to a single addition. In the cases where more
alcohol
groups are present, the potential to add to any of them exists leading to
greater mix
of reaction products. Enough addition of the benzyl chloride containing
species can
even form a quaternary amine group where two benzyl containing groups add at
the
amine group.
Figure 14 shows the synthesis of bis-dithiocarbamates. Bis-dithiocarbamates
are useful pharmacology, the most well known bis-dithiocarbamate is
disulfiram.
Figure 15 shows an expansion of the bis-dithiocarbmates by using citric acid
as the
starting material. Figure 16 shows the alkoxylation of the dithiocarbamates
previously taught. While the Figure focuses primarily on the addition to the
sulfur of
the dithiocarbamates group, more aggressive reaction conditions and additional
alkoxylating agents will lead to a mixture of reaction products that include
alkoxylation and polyalkoxylation at not just the sulfur, but at the secondary
amine
group, and any alcohols present. In the case where glycidol is used as an
alkoxylating agent, condensation with boric acid leads to particularly good
corrosion
inhibitors, anti-wear, and lubrication. The non-boric acid condensed products
are
useful as anti-wear and lubrication additives in their right.
Figure 17 shows the HLB balancing derivatives of buffers based on
aminopyridines and dopamine. These adjustments will adjust the bioavailability
of
these buffers.
Figure 18 shows the synthesis of n-benzyl functional amines. A
monosubstituted can be readily made to 50% yield, but pH control during the
reaction (addition of base as the reaction proceeds to absorb the chloride ion
produced) will allow the reaction to run to completion. N,N disubstituted
amines can
be made similarly. In the case where alcohols are present in the A, D, or E
group,
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the benzyl containing group will also react on the alcohol group as shown in
in the
example. It is understood that additional alcohol groups are also subject to
substitution if present and sufficient benzyl containing halide is present.
Typically a
mixture species with amine and alcohol substitution will be produced when
alcohols
and amines are present. The case of one alcohol and one amine, with 2 moles of
the benzyl containing halide is shown with the dominant product.
Figure 19 shows the synthesis of bis dithiocarbamates from diamines. The
mono dithiocarbamates can be made from a diamine without introducing mineral
salts, such as those of sodium or potassium. The methyl mono and dimethyl
amines can also be made by reacting the primary amines with formaldehyde,
followed by reduction, typically with hydrogen and sponge nickel. Figure 20
shows
the N-sulfonic acids of secondary amines, as well as the reaction of n-methyl
compounds with monochloric acetic acid (MCA), sodium vinyl sulfonate (SVS),
propane sultone. It is understood that higher sultones will react in an
analogous
fashion and are considered part of the invention. Alkoxylation of the n-methyl
amines is also taught. The polyoxyethylene derivatives may be mixtures, for
example the n-methyl amine may be ethoxylated, then propoxylated to form a
block
polymer chain off the nitrogen, these block and heteropolymer derivatives are
within
the scope of the invention. The synthesis of polyamines is taught via the
reaction
of acrylonitrile and the reduction with hydrogen over sponge nickel. While the
diamine is shown, a triamine and higher homologs can be synthesiszed through
successive acrylonitrile reactions on the terminal amine group followed by
reductions. Adding 1 mole of acrylonitrile to a primary amine stepwise leads
to
linear polyamines. Branching can be introduced by adding 2 moles of
acrylonitrile in
any or all acrylonitrile additions. The polyamines, including the diamine, may
be
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alkoxylated with any alkoxylating agent, typically ethylene oxide, propylene
oxide, or
butylene oxide in any combination or amount will lead to polyoxyethylene
derivatives of the polyamines and are part of this invention, including the
stepwise
block polymerization with differing alkoxylating agents including the
repeating of and
alternating of various alkoxylating agents.
Figures 21 and 22 show the synthesis of a range of therapeutic aminopyridine
derivatives and intermediates. The primary areas of application are multiple
sclerosis, Parkinson's, and Alzheimer's and as monamine oxidase inhibitors.
Antimicrobial effects are also observed in the class.
Figures 23 and 24 show the synthesis of a range of derivatives of trialkyl
primary amines. The largest source of which are the Dow Primene amines (from
Dow Chemical). The dithiocarbamates are excellent mining collectors for
sulfide
ores, such as nickel and copper in flotation recovery as well as
antimicrobial,
dispersants and pest control. Several zwitterionic species are shown that find
utility
in surface modification of minerals in floatation mining and in personal care
as
cleaners. The polyamines are very useful anti-strips in asphalt emulsions. The
alkoxylates of both the Primenes and the polyamine derivatives make excellent
power improvers in oil pipelines. The amine oxides are excellent emollients
and
foam builders in personal care, especially shaving cream. While the drawings
of the
alkoxylation shows a secondary amine resulting, anything over 1 mole of
alkoxylating agent will result in a tertiary amine with similar substitutions
on both ¨H
positions of the hydrogen. Figure 25 shows the synthesis of quaternary
ammonium
compounds. The quaternaries are useful in oilfield as clay modifiers,
converting
clay, typically bentonite, into a hydrophobic clay for drilling lubrication
and for chip
removal. The quaternaries are also excellent corrosion inhibitors in oilfield
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pipelines. The trialkyl quaternaries are excellent fabric softeners and anti-
statics.
Additionally, the quats and the dithiocarbamates are antimicrobial and are
useful in
agriculture for fungal and spore control, particularly the ethylbenzyl quats
and the
dithiocarbamates. The quats are shown as chloride salts and as sulfate salts.
This
is for illustrative purposes only, any other anion, such as acetate is part of
the
invention.
Figure 26 further expands on the alkoxylation of the polyamines of Figure 24.
The most commercially important of the group are the primary amines, which are
used primarily as flotation and reverse flotation collectors in iron ore or
potash
concentration processes. The use of the primary amines of Figure 24 can be
used
in the same manner as primary Tallow amine, Commonly known as Crisamine PT,
by Crison Chemistry, or isodecyloxypropylamine, commonly known as Tomamine
PA-14. The diamines in Figure 24 are useful as well and used similarly to
tallow
diamine, commonly known as Crisamine DT, and isodecyloxypropy1-1,3-
diaminopropane, commonly known as Tomamine DA-14. The polyamines of Figure
24 and 26 are excellent anti-strips in emulsion asphalt formulations. The
alkoxylates, are useful as emulsifiers to emulsify the bitumen in emulsion
asphalt
formulations. The most useful of the alkoxylates are diamine with 3 moles of
ethylene oxide, the triamine with 4 moles of ethylene oxide, and the tertamine
with 5
moles of ethylene oxide. Further, the partial or total neutralization with
acetic acid of
the primary amines, polyamines, and their alkoxylates are more water soluble
and
improve their performance and particularly the handling and application
properties.
Figure 26 shows the acetate of the primary amines, the acetates of the
polyamines
are made in the same fashion and are also part of the invention.
In the case of the asphalt emulsion formulations, the acetic acid evaporates,
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leaving a water resistant asphalt. The acetate of the primary amine is helpful
in
mining as a collector in imparting sufficient water solubility for the
collector to come
in adequate contact with the target mineral. Over neutralization leads to a
reduction
in collector performance as the reduced hydrophobicity leads to less
flotation. A
typical neutralization level of between 15 and 50% is most beneficial for the
primary
and diamines as used as collectors in direct ore flotation or reverse
flotation
processes. However any neutralization level can be used.
Figure 26 also shows the synthesis of amido acid surfactants. The amido
acid surfactants are also useful in mining to control hard water ions that
interfere
with the flotation process. In addition, the amido acid surfactants can
function as
collectors as well. The amido acid surfactants also make excellent surfactants
for
personal care products such as shampoo, lotions and facial scrubs where
mildness
is required. The amido acid surfactants also find utility in oil well drilling
for cleaning
out the formation and borehole walls.
Figure 27 shows the synthesis of ester amines. The ester amines may be
monoalky, dialkyl, or trialkyl. To the extent that an alcohol group is present
in the
nitro alcohol, it may be esterified, so long as the nitro has not been reduced
to the
amine. The reduction step needs to take place under milder conditions, where
the
temperature needs to be controlled. Best results were seen where the
temperature
was kept below 40 C. Poor results were seen when the temperature exceeded 120
C. Too harsh conditions leads to breakdown of the ester linkage. Figure 27
also
shows the synthesis of polyamines, either through reacting acrylonitrile with
any
remaining alcohol groups, or through the addition of acrylonitrile to the
amine.
While the di and triamines are shown, higher analogs can made through
subsequent acrylonotrile additions and reductions. Branching can be introduced
by
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adding 2 moles of acrylonitrile per primary amine, or adding sufficient excess
as to
add to a secondary amine, then reducing the nitrile to the amine.
Acrylonitrile based
polyamines are typically most useful when reacted with acrylo Useful asphalt
emulsifiers can be made by alkoxylating or polyalkoxylating the primary or
secondary amine groups, similar to as shown in Figure 26, as well as any of
the
alcohol groups. Most common alkoxylating agents are ethylene oxide, propylene
oxide, and butylene oxide. However, any other alkoxylating agent may be used,
and they are often used in combination to add block copolymer structures to
the
amine or alcohol group. Further, anti-strips for hot and warm mix asphalt can
be
made by making amides or polyamides by reacting the amine groups with fatty
acid
and driving off a mole of water per mole of fatty acid. The ester mono amines
are
useful as collectors in iron ore purification and potash purification, as well
as
emulsifiers in asphalt to speed the setting time. The dialkyl and trialkyl
mono
amines are useful as co-collectors.
Figure 28 shows the synthesis of the analogous tertiary amines, as well as
their analogous methyl quaternaries. A wider range of quaternaries can also be
made by utilizing other quaternizing compounds as shown in Figure 25.
Similarly,
the methyl sulfate quats can be made by utilizing dimethyl sulfate instead of
methyl
chloride.
In the case of the derivatives that are produced as an ionic molecule, the
pure
zwitterion may be obtained through ion exchange as is routinely carried out on
an
industrial scale. While the derivatives also show only one dithiocarbamate
group, in
many cases a second dithiocarbamate group may be obtained as disclosed in the
earlier figures. The analogous disubstituted derivative, or mono-substituted
analogs
are embodiments of the invention. Additionally, where ethylene oxide is shown
as
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a reactant, one skilled in alkoxylations will immediately recognize that
ethylene
oxide could be substituted with propylene oxide, butylene oxide or any other
alkoxylate or any epoxide ring containg compound to generate the analogous
product. All of these analogs are within the scope of the present invention.
For the
derivatives where an amine group results, such as when acrylonitrile is
reacted with
the nitro xanthates or dithiocarbamates, the amine group can further be
derivatized
with monochloroacetic acid, allylic acids, sodium vinyl sulfonate, sultones,
alkoxylated or phosphonated as shown in my previous patent application number
14/079,369. It is further understood by one skilled in the art that higher
sultones
beyond propane sultone may be substituted and result in the analogous product
with additional carbon or carbons between the sulfur and sulfonate group. All
of
these compounds are also part of the present invention.
The xanthates and dithiocarbamates taught here are most stable and most
easily made as salts. The salts are most commonly sodium salts due to the cost
effectiveness and availability of sodium hydroxide. While not shown as salts
in the
figures, it is understood that the salts are within the scope of the invention
taught
here. The free zwitterions or neutral forms are obtainable via ion exchange,
and
are what are typically shown in the figures. This is shown explicitly in
Figure 9, in
the top reaction series. The salts are not generally shown in the figures to
make it
clear that all salts, are included in the invention, not just sodium salts.
Other bases
can be utilized to drive the formation of the xanthates and dithiocarbamates.
The
resulting salts are within the scope of this invention. Of particular note are
the use
of tertiary amines to drive the xanthate or dithiocarbamate formation. Not
only are
small, volatile tertiary amines useful, but so are fatty tertiary amines,
monoalkyl
tertiary amines, such as the ADMA amines by Lonzaõ di- and trialkyl
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tertiaryamines, including tertiary ether amines, such as those produced by Air
Products, formerly Tomah Products. Also useful are the tertiary amines that
result
from alkoxylating primary and secondary amines and ether amines, but care has
to
be taken not to cause addition to the terminal hydroxyl group. This is
controlled by
adding the alkoxylated amines in a way that there is a very slight excess of
carbon
disulfide at all times versus the alkoxylated amine and the amine to be
converted to
the dithiocarbamate. A further embodiment of the invention taught is the use
specifically of tertiary amines containing at least one alkyl branch that is
from 10 to
14 carbons in making any dithiocarbamates or xanthates, not just the novel
dithiocarbamates and xanthates presented here. These amines show antimicrobial
activity that can be taken advantage of to produce dithiocarbamates complexes
that
have synergistic levels of activity. In agriculture, the use of tertiary
amines as
adjuvents is common. In particular, 15 moles of ethylene oxide or greater
added to
tallow amine, such as Akzo Nobel's Armeen T25, or the ethoxylated ether
amines,
such as Tomamine E-17-5 produces dithiocarbamates that are more readily
bioavailable to the target organisms. The use of such amines in the production
of
all dithiocarbamates and xanthates, not just the novel dithiocarbamates and
xanthates taught here, produces dithiocarbamates and xanthate complexes that
are
much more effective and all such complexes are within the scope of the present
invention.
The mineral bases such as lime, calcium hydroxide or potassium hydroxide
and all others enable the production of the molecules taught, but without
sodium.
This is particularly important in agricultural applications. The agricultural
applications also benefit from the fatty tertiary amines in that they help the
dithiocarbamates or xanthates penetrate the target organism that is to be
controlled.
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If desired, the dithiocarbamates can be made with the starting amine as the
counter
ion. In this case, two molar equivalents of the amine needs to be utilized to
one
molar equivalent of carbon disulfide during manufacture.
While much of the benefits of these molecules have been recognized in
biological systems, the zwitterions and derivatives are also known to be
beneficial
as dispersants, chelants, cross-linkers, antimicrobials, preservatives of
organic
systems, and pH buffers in oilfield drilling systems and hydraulic fracturing.
Additionally, the molecules of the present invention find utility as
collectors in mining
and as depressants. Further, in ball milling, the dispersant characteristics
improve
the characteristics of ore pellets. The zwitterionic molecules of the present
invention also find utility in high energy storage systems, such as lithium
ion and
lithium polymer batteries as a means of improving charge transport and as
acting as
a salt bridge in other battery applications. These compounds also find
application
as asphat antistrip.
Several descriptions and illustrations have been presented to enhance
understanding of the present invention. One skilled in the art will know that
numerous
changes and variations are possible without departing from the spirit of the
invention.
Each of these changes and variations are within the scope of the present
invention.
