U.S. patent application number 13/752384 was filed with the patent office on 2013-08-01 for 1,1-disubstituted ethylene process.
This patent application is currently assigned to OptMed, Inc.. The applicant listed for this patent is OptMed, Inc.. Invention is credited to Vijaya Bhasker Gondi, John Gregory Reid.
Application Number | 20130197263 13/752384 |
Document ID | / |
Family ID | 47714566 |
Filed Date | 2013-08-01 |
United States Patent
Application |
20130197263 |
Kind Code |
A1 |
Gondi; Vijaya Bhasker ; et
al. |
August 1, 2013 |
1,1-DISUBSTITUTED ETHYLENE PROCESS
Abstract
New and improved processes for the production of
1,1-disubstituted ethylenes.
Inventors: |
Gondi; Vijaya Bhasker;
(Burlington, MA) ; Reid; John Gregory; (Groton,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OptMed, Inc.; |
New York |
NY |
US |
|
|
Assignee: |
OptMed, Inc.
New York
NY
|
Family ID: |
47714566 |
Appl. No.: |
13/752384 |
Filed: |
January 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61591884 |
Jan 28, 2012 |
|
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Current U.S.
Class: |
560/185 ;
560/190 |
Current CPC
Class: |
C07C 67/317 20130101;
C07C 67/343 20130101; C07C 253/30 20130101; C07C 253/30 20130101;
C07C 255/23 20130101; C07C 253/30 20130101; C07C 255/19 20130101;
C07C 67/343 20130101; C07C 69/593 20130101 |
Class at
Publication: |
560/185 ;
560/190 |
International
Class: |
C07C 67/317 20060101
C07C067/317 |
Claims
1. A method of producing 1,1-disubstituted ethylenes which method
comprises reacting compounds containing a methylene linkage having
attached thereto at least one electron withdrawing group with an
iminium salt in the presence of an acid chloride and/or acid
anhydride under appropriate conditions and for an appropriate time
period to yield the corresponding 1,1-disubstituted ethylene.
2. The method of claim 1 wherein iminium salt corresponds to the
formula ##STR00025## wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7
are each independently H or a hydrocarbon or substituted
hydrocarbon moiety or a hydrocarbon, substituted hydrocarbon or
heterohydrocarbon bridge whereby the nitrogen atom, the carbon, or
both of formula II are in a ring structure and X is an anion.
3. The method of claim 2 herein R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, alkenyl or alkynyl
and X is a halogen, a non-nucleophilic anion, and/or an acidic
anion.
4. The method of claim 2 wherein R.sup.4 and R.sup.5 are hydrogen
(H) and R.sup.6 and R.sup.7 are each independently an alkyl,
alkenyl or alkynyl moiety and X is a halogen, a carboxylate or a
sulfonate.
5. The method of claim 1 wherein the electron withdrawing groups
are selected from selected from nitriles, carboxylic acids,
carboxylic esters, sulphonic acids, ketones or nitro.
6. The method of claim 1 wherein the compounds to be reacted upon
are the esters, especially the diesters, of malonic acid.
7. The method of claim 1 wherein the acid chlorides and acid
anhydrides are selected from the group consisting of acetyl
chloride, propionyl chloride, isobutyryl chloride, trimethylacetyl
chloride, trifluroacetate, acetic anhydride, isobutyric anhydride,
trimethylacetic anhydride, trifluoroacetic anhydride, sulfonic acid
anhydride, benzoyl chloride, chloroacetylchloride.
8. A method of producing 1,1-disubstituted ethylenes which method
comprises reacting an amine with an acid chloride and/or an acid
anhydride and then reacting the reaction product thereof with a
compound containing a methylene linkage having attached thereto at
least one electron withdrawing group under appropriate conditions
and for an appropriate time period to yield the corresponding
1,1-disubstituted ethylene.
9. The method of claim 8 wherein the acid chloride and/or acid
anhydride is present in an equivalent excess relative to the
compound containing the methylene linkage.
10. The method of claim 1 wherein reaction product of the amine and
the acid chloride and/or anhydride comprises a iminium salt
according to the formula ##STR00026## wherein R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 are each independently H or a hydrocarbon or
substituted hydrocarbon moiety or a hydrocarbon, substituted
hydrocarbon or heterohydrocarbon bridge whereby the nitrogen atom,
the carbon, or both of formula II are in a ring structure and X is
chloride anion or a carboxylate anion.
11. The method of claim 10 wherein R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, alkenyl or
alkynyl.
12. The method of claim 10 wherein R.sup.4 and R.sup.5 are hydrogen
(H) and R.sup.6 and R.sup.7 are each independently an alkyl,
alkenyl or alkynyl.
13. The method of claim 8 wherein the electron withdrawing groups
are selected from selected from nitriles, carboxylic acids,
carboxylic esters, sulphonic acids, ketones or nitro.
14. The method of claim 8 wherein the compounds to be reacted upon
are the esters, especially the diesters, of malonic acid.
15. The method of claim 8 wherein the acid chlorides and acid
anhydrides are selected from the group consisting of acetyl
chloride, propionyl chloride, isobutyryl chloride, trimethylacetyl
chloride, trifluroacetate, acetic anhydride, isobutyric anhydride,
trimethylacetic anhydride, trifluoroacetic anhydride, sulfonic acid
anhydride, benzoyl chloride, chloroacetylchloride.
16. A method of producing 1,1-disubstituted ethylenes which method
comprises reacting compounds containing a methylene linkage having
attached thereto at least one electron withdrawing group with an
iminium salt in the presence of a non-polar solvent for a
sufficient time to yield the corresponding 1,1-disubstituted
ethylene wherein the anionic portion of the iminium salt is a
carboxylate anion.
17. The method of claim 16 wherein the iminium salt is preformed or
is formed in-situ and corresponds to the formula: ##STR00027##
wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each
independently H or a hydrocarbon or substituted hydrocarbon moiety
or a hydrocarbon, substituted hydrocarbon or heterohydrocarbon
bridge whereby the nitrogen atom, the carbon, or both of formula II
are in a ring structure and X is a carboxylate anion.
18. The method of claim 17 wherein R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, alkenyl or
alkynyl.
19. The method of claim 17 wherein R.sup.4 and R.sup.5 are hydrogen
(H) and R.sup.6 and R.sup.7 are each independently an alkyl,
alkenyl or alkynyl.
20. The method of claim 16 wherein the non-polar solvent is
selected from toluene, benzene, diethylether, chloroform, hexane,
cyclohexane and carbontetrachioride.
21. An improved method of producing 1,1-disubstituted ethylenes
involving the reaction of compounds containing a methylene linkage
having attached thereto at least one electron withdrawing group
with an iminium salt wherein the improvement comprises treating a
non-polar solvent solution of the 1,1-disubstituted ethylenic
reaction product with a solid phase material having an acidic to
neutral pH an known to adsorb or absorb polar materials.
22. The improved process of claim 21 wherein the solid phase
material has an acidic pH and is selected from ion-exchange resins,
molecular sieves, zeolites and alumina.
23. The improved process of claim 21 wherein the treatment is
conducted until free amine compounds have been removed or
substantially removed.
24. The improved process of claim 21 wherein the 1,1-disubstituted
ethylene is produced in a non-polar solvent.
25. The improved process of claim 21 wherein the 1,1-disubstituted
ethylene is produced in a polar solvent and the polar solvent is
replaced with a non-polar solvent prior to the addition of the
solid phase material.
26. The improved process of claim 21 wherein the solid phase
material is an acidic, activated alumina and the non-polar solvent
is toluene.
Description
RELATED APPLICATION
[0001] This patent application claims the benefit of prior U.S.
Provisional Patent Application No. 61/591,884 filed Jan. 28, 2012,
entitled Improved Methylidene Malonate Process, Gondi et. al., the
contents of which are hereby incorporated herein in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for improving
cure speed and/or providing more consistent, i.e., batch-to-batch,
cure speed in 1,1-disubstituted ethylene monomers and monomer
containing compositions. The present invention also relates to an
improved process for the production of 1,1-disubstituted ethylene
monomers, including methylidene malonates and cyanoacrylates,
especially methylidene malonates, and the use thereof.
BACKGROUND
[0003] 1,1-disubstituted ethylene monomers and compositions
containing the same are well known and for the most part, widely
available. They have utility in a broad array of end-use
applications, most notably those which take advantage of their cure
or polymerizable properties. Specifically, they find broad utility
in coatings, sealants and adhesives, among other applications.
Those 1,1-disub-stituted ethylenes having one or, preferably, two
electron withdrawing substituents at the 1 position have been used
to provide adhesives and sealants with rapid cure rates and high
bond strengths. Most notable among these are the cyanoacrylates
such as ethyl cyanoacrylate and butyl cyanoacrylate. Another class
of 1,1-disubstituted ethylenes that have demonstrated a lot of
promise, but have limited, if any, commercial success are the
methylidene malonates, including diethyl methylidene malonate.
[0004] Commercial success of the 1,1-disubstituted ethylenes is
reliant upon a number of variables and factors including reasonable
cost, high purity, good, especially long, shelf life and rapid cure
rate. In an effort to achieve these goals, much work has been done
to develop new and/or improved processes and synthetic schemes for
their manufacture, purification and isolation.
[0005] For example, .alpha.-cyano acrylates have been prepared
(U.S. Pat. No. 6,245,933) by reacting a cyanoacetate such as ethyl
cyanoacetate with formaldehyde or a formaldehyde synthon such as
paraformaldehyde in a Knoevenagel condensation followed by
transesterification. The product mixture is then cracked and
distilled to produce the .alpha.-cyano acrylate monomer.
[0006] Similarly, extensive efforts have been undertaken over many
decades in an effort to produce, on a commercially viable basis,
methylidene malonates. Two of the earliest methods for the
production of dialkyl methylidene malonates, the simplest of the
methylidene malonates, were the iodide method in which methylene
iodide was reacted with dialkyl malonates and the formaldehyde
method in which formaldehyde was reacted with dialkyl malonates in
the presence of a base, in solution in alcohol solvents. As an
alternative, Bachman et al. (U.S. Pat. No. 2,313,501) taught the
reaction of a C.sub.1-C.sub.5 dialkyl malonate with formaldehyde in
the presence of an alkali metal salt of a carboxylic acid, in
solution in a substantially anhydrous carboxylic acid solvent,
followed by fractional distillation to separate the desired
product. D'Alelio (U.S. Pat. No. 2,330,033), on the other hand,
alleged that such processes were erratic and more often produced
yields that averaged 10 to 12 per cent. D'Alelio espoused an
improved process with yields on the order of 30% and higher by
reacting a malonic acid ester with formaldehyde in a ratio of one
mole of the former to at least one mole of the latter under
alkaline conditions and, in most cases, in the presence of a
polymerization inhibitor such as copper, copper acetate,
hydroquinone, resorcinol, or catechol, to form a methylol
derivative. The methylol derivative was then acidified to a pH
below 7.0 using a suitable organic or inorganic acid in order to
retard further reaction. The acidified mass is then dehydrated to
form the corresponding methylidene malonate which is subsequently
separated by distillation.
[0007] Not satisfied, Coover et al. (U.S. Pat. No. 3,221,745 and
U.S. Pat. No. 3,523,097) took yet another approach to the formation
of the methylidene malonates, electing to begin with a preformed
dialkyl alkoxymethylenemalonate. In accordance with their process,
the olefinic double bond of the latter compound was subjected to
hydrogenation in the presence of a hydrogenation catalyst and the
hydrogenated compound was then subject to pyrolysis in the presence
of a phosphorous pentoxide inhibitor to strip off the alcohol to
produce the methylene malonate. The resultant mass was then
subjected to vacuum distillation at low temperature to separate an
allegedly high purity methylidene malonate, though with a low
yield. According to Coover et al., the use of low temperature
distillation is said to prevent the contamination of the monomer
with pyrolytic products that commonly result from high temperature
distillation. These high purity monomers are said to be especially
important for surgical applications.
[0008] Eventually, such efforts led to multi-step processes in
which certain unsaturated molecules served as a platform for the
formation of intermediate adducts from which the methylidene
malonates were subsequently stripped and recovered. For example,
Hawkins et al. (U.S. Pat. No. 4,049,698) found that certain malonic
diesters could be reacted with formaldehyde and a linear,
conjugated diene in the presence of a primary, secondary or
tertiary amine at about reflux temperature to form an intermediate
adduct that could then be readily pyrolyzed at temperatures in
excess of 600.degree. C. to split off the desired methylidene
malonate. Similarly, Ponticello (U.S. Pat. No. 4,056,543) and
Ponticello et al. (U.S. Pat. No. 4,160,864) developed processes by
which asymmetrical methylene malonates, especially methyl allyl
methylene malonate, were prepared from previously formed norbornene
adducts, the latter having been prepared by the Diels-Alder
reaction of an alkyl acrylate with cyclopentadiene at room
temperature or with heating or use of a Lewis catalyst. The so
formed monoester norbornene adducts were then reacted with an
electrophile material in the presence of an alkyl-substituted
lithium amide complex to form the diester adduct and subsequently
pyrolyzed at a temperature of 400.degree. C. to 800.degree. C. at a
pressure of 1 mm to 760 mm Hg in an inert atmosphere to strip off
the desired methylene malonates.
[0009] Citing numerous disadvantages of the foregoing processes,
which disadvantages were said to make them difficult, if not
impossible, to adapt to industrial scale, Bru-Magniez et al. (U.S.
Pat. No. 4,932,584 and U.S. Pat. No. 5,142,098) developed a process
whereby anthracene adducts were prepared by reacting mono- or
di-malonic acid ester with formaldehyde in the presence of
anthracene, most preferably in a non-aqueous solvent medium in the
presence of select catalysts. According to Bru-Magniez et al., the
anthracene adducts were said to be readily produced in high yields
with the desired methylidene malonates obtained by stripping them
from the anthracene adduct by any of the known methods including
heat treatment, thermolysis, pyrolysis or hydrolysis; preferably
heat treatment in the presence of maleic anhydride.
[0010] Despite all of these efforts, issues remained and commercial
success wanting owing to continued process frustrations,
instability and unpredictability. Malofsky et al. (WO 2010/129068)
solved some of the problems associated with process instability of
the Retro-Diels-Alder adduct process by using polymerization
inhibitors concurrent with or prior to stripping the adduct.
Inhibitors such as trifluoroacetic acid and hydroquinone were used.
In some examples, trifluoroacetic acid was also added to the
distillate. Only limited curing studies were done, but the
resultant malonates were able to be polymerized with
tetrabutylammonium fluoride. Malofsky teaches a variety of
purification processes including double distillation and extracting
the product with an alkane such as n-heptane. Although this is an
improvement over the art, these various purification processes can
be costly and can reduce yield.
[0011] More recently, in an effort to find alternate and better
routes to producing 1,1-disubstituted ethylenes, a focus has been
directed to certain iminium based processes wherein select iminium
salts are reacted with various compounds containing a methylene
linkage having attached thereto at least one electron withdrawing
group selected from nitriles, carboxylic acids, carboxylic esters,
sulphonic acids, ketones or nitro to form electron deficient
olefins. For example, McArdle et al. (WO 2008/050313, U.S. Pat.
App. Pub. 2009/0203934, and U.S. Pat. No. 8,022,251) have taught
the use certain specific iminium salts having a tertiary carbon
atom attached to a nitrogen atom in the production of electron
deficient olefins, most especially cyanoacrylates, however,
methylidene malonates are also mentioned. The preferred process
involved employing the select iminium salts in producing the
2-cyanoacrylates from nitriles such as ethyl cyanoacetate or
malonitrile, When a formaldehyde derivative is used, the McArdle
iminium salt can have the structure I:
##STR00001##
wherein R.sub.3 is H, alkenyl, or alkynyl; R.sub.4 is a hydrocarbon
moiety comprising a tertiary carbon which is attached to the N
atom, where the tertiary carbon atom is attached to or a part of
one or more substituents selected from linear, branched, or cyclic
alkyl or alkenyl, or one or more together form a cyclic structure;
and X is an anion such as a non-nucleophilic and/or an acidic
anion. These imines may be formed by reacting formaldehyde or a
source thereof with a primary amine having a tertiary carbon atom
attached to the nitrogen to form an imine which is subsequently
reacted with an acid under specified conditions to yield an iminium
salt. Variations and refinements of the iminium process are taught
in McArdle et at (U.S. Pat. Nos. 7,659,423 and 7,973,119 and U.S.
Pat. App. Pub. Nos. 2010/0210788 and 2010/0199888) and Bigi et al.
(U.S. Pat. No. 7,718,821); the contents of all of which are hereby
incorporated herein by reference.
[0012] The McArdle et. al. and Bigi et. al. iminium processes are
not without their shortcomings. Both require high temperature
reactions, temperatures which can promote the in-situ
polymerization of the monomer product. Additionally, these
processes require specific amines to form the iminium salts: amines
that are oftentimes expensive and whose reaction byproducts are
found, particularly in the case of methylidene malonates, to
promote unwanted reactions in-situ, including, specifically
dimerization of the monomer. Further, these processes must be
conducted at a very low pH in order to prevent the retro-conversion
of the iminium salt, back to the imine by loss of a proton. From
the perspective of the formation of cyanoacrylate monomers, these
factors are of low concern, if any, as traditional processes for
the production of cyanoacrylates involves the formation of the
polymer which is then cracked, typically at high temperature, to
form the monomer and have other issues that they too must content
with. However, from the perspective of the formation of methylidene
malonates, these factors are of considerable concern, particularly
inasmuch as the yields and purity of the methylidene malonates so
produced, as shown by McArdle et. al., are still low.
[0013] Thus, despite the advances that have been made, there are
still improvements to be made. More importantly, there still
remains a need for a commercially viable process for the production
and isolation of methylidene malonates: a process which balances
simplicity of process with common or at least less costly materials
with high yields and purity and with consistency and
repeatability.
SUMMARY OF THE INVENTION
[0014] The present invention provides for new and/or improved
processes for the production of 1,1-disubstituted ethylenes,
particularly methylidene malonates and cyanoacrylates, most
especially the methylidene malonates, and for the purification and
isolation thereof as well as for the 1,1-disubstituted ethylenes
formed thereby. Each of these processes presents an improvement
over exiting iminium processes and produces 1,1-disubstituted
ethylenes quickly and efficiently in high yield and purity and at
relatively low cost, particularly as compared to non-iminium
processes and even certain known iminium processes.
[0015] According to a first aspect of the present teachings there
is provided a method of producing 1,1-disubstituted ethylenes which
method comprises reacting compounds containing a methylene linkage
having attached thereto at least one electron withdrawing group,
especially those selected from nitriles, carboxylic acids,
carboxylic esters, sulphonic acids, ketones or nitro, most
especially the esters, especially the diesters, of malonic acid,
with an iminium salt in the presence of an acid chloride and/or
acid anhydride under appropriate conditions and for an appropriate
time period to yield the corresponding 1,1-disubstituted ethylene.
The iminium salts may be a pre-formed, isolated and/or purified
iminium salt or it may be an iminium salt that is formed in-situ by
a process that is integrated into the overall reaction process for
the production of the 1,1-disubstituted ethylene. In the latter
case, depending upon the specific iminium salt and its reactants
and reaction products, it is possible to directly combine the
compound containing the methylene linkage with the reaction product
of the iminium reaction process, a product which, it is believed,
inherently contains the iminium salt.
[0016] Suitable iminium salts generally correspond to the formula
II
##STR00002##
wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each
independently H or a hydrocarbon or substituted hydrocarbon moiety
or a hydrocarbon, substituted hydrocarbon or heterohydrocarbon
bridge whereby the nitrogen atom, the carbon, or both of formula II
are in a ring structure, preferably, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, aryl, alkenyl or
alkynyl; and X is an anion, preferably a halogen, a
non-nucleophilic anion, and/or a conjugate base of an acid, most
preferably a halogen, a carboxylate or a sulfonate. This process
may be performed in the presence of a polar or non-polar solvent or
in a solvent-free process.
[0017] Preferred iminium salts are those wherein R.sup.4 and
R.sup.5 are hydrogen (H) and R.sup.6 and R.sup.7 are each
independently a hydrocarbon or substituted hydrocarbon moiety,
especially an alkyl, aryl, alkenyl or alkynyl moiety, most
especially an alkyl moiety, and X is a halogen or a substituted or
unsubstituted carboxylate. In those instances where R.sup.6 and/or
R.sup.7 have a tertiary carbon atom attached to the nitrogen atom
of the iminium salt, it is preferred that such be used in producing
1,1-disubstituted ethylenes other than the methylidene malonates,
particularly the cyanoacrylates: though again, they are suitable
for the methylidene malonates as well. Especially preferred iminium
salts are those wherein R.sup.4 and R.sup.5 are hydrogen or alkyl,
and both R.sup.6 and R.sup.7 are hydrocarbon moieties, especially
alkyl. Most preferred are the dialkylmethylideneammonium halides
and carboxylates, particularly the dialkyl methylideneammonium
chlorides, acetates and haloacetates. For purposes of clarity,
"alkyidene" refers to that portion of the iminium compound
comprising:
##STR00003##
Thus, an iminium compound wherein R.sup.4 and R.sup.5 are H and
R.sup.6 and R.sup.7 are methyl would be referred to as a
dimethylmethylidene ammonium compound.
[0018] According to a second and preferred aspect of the present
teachings there is provided a method of producing 1,1-disubstituted
ethylenes which method comprises reacting an amine with an acid
chloride and/or an acid anhydride, preferably at an equivalent
excess of acid chloride and/or acid anhydride relative to the
methylene containing compound, to form an iminium reaction product,
typically comprising an iminium salt, and then reacting that
reaction product, with or without isolation or purification, with a
compound containing a methylene linkage having attached thereto at
least one electron withdrawing group selected from nitriles,
carboxylic acids, carboxylic esters, sulphonic acids, ketones or
nitro, most especially the esters, especially the diesters, of
malonic acid, under appropriate conditions and for an appropriate
time period to yield the corresponding 1,1-disubstituted ethylene.
This process too may be performed in the presence of a polar or
non-polar solvent or in a solvent-free process.
[0019] According to a third aspect of the present teachings there
is provided a method of producing 1,1-disubstituted ethylenes which
method comprises reacting compounds containing a methylene linkage
having attached thereto at least one electron withdrawing group
selected from nitriles, carboxylic acids, carboxylic esters,
sulphonic acids, ketones or nitro, most especially the esters,
especially the diesters, of malonic acid, with an iminium salt or
an iminium reaction product in the presence of a non-polar solvent
for a sufficient time to yield the corresponding 1,1-disubstituted
ethylene wherein the anionic portion of the iminium compound or
in-situ formed iminium reaction product is or is prepared from a
carboxylate or an anhydride.
[0020] According to a fourth aspect of the present teachings there
is provided an improved method of producing 1,1-disubstituted
ethylenes involving the reaction of compounds containing a
methylene linkage having attached thereto at least one electron
withdrawing group selected from nitriles, carboxylic acids,
carboxylic esters, sulphonic acids, ketones or nitro, most
especially the esters, especially the diesters, of malonic acid,
with an iminium salt or an iminium reaction product wherein the
improvement comprises treating the 1,1-disubstituted ethylenic
reaction product with a solid phase material known to adsorb or
absorb polar materials in the presence of a non-polar solvent
following completion of the reaction. If the reaction process to
form the 1,1-disubstitute ethylene is conducted in the presence of
a polar solvent, one must first remove and replace the polar
solvent with a non-polar solvent. Treatment with the solid phase
material is continued until most, if not substantially all, of the
polar impurities are absorbed or adsorbed, after which the reaction
product is then isolated/separated from the solid phase material,
e.g., by filtration, centrifugation, decanting, distillation, thin
film evaporation, etc. Suitable solid phase materials include
ion-exchange resins, molecular sieves, zeolites, alumina, and the
like, provided that the same are acidic to neutral pH, preferably
acidic.
[0021] According to yet a fifth aspect of the present teachings
there is provided an improved method of producing 1,1-disubstituted
ethylenes involving the reaction of compounds containing a
methylene linkage having attached thereto at least one electron
withdrawing group selected from nitriles, carboxylic acids,
carboxylic esters, sulphonic acids, ketones or nitro, most
especially the esters, especially the diesters, of malonic acid,
with an iminium salt or an iminium reaction product wherein the
improvement comprises treating the isolated and/or purified
1,1-disubstituted ethylene with a slightly acidic to mildly basic
alumina and thereafter separating the alumina from the treated
1,1-disubstituted ethylene.
[0022] Finally, it is also to be appreciated that the present
teachings provide further improvements in relation to the foregoing
methods, whereby the further improvement lies in the practice of
two or more of the aforementioned processes in a single process for
the production of 1,1-disubstituted ethylenes.
DETAILED DESCRIPTION
[0023] In accordance with the present teachings there are provided
new and/or improved processes or methods for the production of
methylidene malonates. All of these processes generally comprise
the reaction of a compound containing a methylene linkage having
attached thereto at least one electron withdrawing group with a
preformed or in-situ formed iminium salt. As will be noted, there
are several various processes and improvements to existing
processes disclosed herein that may be used individually or in
combination, e.g., the improvements to existing methods are also
applicable to improve the new methods taught herein.
[0024] For purposes of convenience and expediency, unless otherwise
obvious from the text, the term "ethylene precursor" shall refer to
the compounds containing the methylene linkage having attached
thereto the one or more electron withdrawing groups. Similarly,
unless context disallows, reference to the "iminium salt" shall
refer to both a preformed iminium salt as well as the in-situ
formed sale, whether in a purified or isolated state or as the
reaction product of the reactants therefore.
[0025] According to a first aspect of the present teachings there
is provided a method of producing 1,1-disubstituted ethylenes which
method comprises reacting ethylene precursors with an iminium salt
in the presence of an acid chloride and/or acid anhydride under
appropriate conditions, and preferably in the presence of a polar
or non-polar solvent, and for an appropriate time period to yield
the corresponding 1,1-disubstituted ethylene.
[0026] According to a second and preferred aspect of the present
teachings there is provided a method of producing 1,1
-disubstituted ethylenes which method comprises reacting an amine
with an acid chloride and/or an acid anhydride, preferably at an
equivalent excess of acid chloride and/or acid anhydride relative
to the methylene containing compound, to form an iminium reaction
product, typically comprising an iminium salt, and then reacting
that reaction product, with or without isolation or purification,
with an ethylene precursor under appropriate conditions and for an
appropriate time period to yield the corresponding
1,1-disubstituted ethylene. Each of the process steps of this
second aspect of the present teachings is preferably conducted in
the presence of a solvent, which may be polar or non-polar.
[0027] According to a third aspect of the present teachings there
is provided a method of producing 1,1-disubstituted ethylenes which
method comprises reacting an ethylene precursor with an iminium
salt or an iminium reaction product in the presence of a non-polar
solvent for a sufficient time to yield the corresponding
1,1-disubstituted ethylene wherein the anionic portion of the
iminium compound or in-situ formed iminium reaction product is or
is prepared from a substituted or unsubstituted carboxylate or
anhydride.
[0028] According to a fourth aspect of the present teachings there
is provided an improved method of producing 1,1-disubstituted
ethylenes involving the reaction of an ethylene precursor with an
iminium salt wherein the improvement comprises treating the
1,1-disubstituted ethylenic reaction product with a solid phase
material known to adsorb or absorb polar materials in the presence
of a non-polar solvent following completion of the reaction. If the
reaction process to form the 1,1-disubstitute ethylene is conducted
in the presence of a polar solvent, one must first remove and
replace the polar solvent with a non-polar solvent. Treatment with
the solid phase material is continued until most, if not
substantially all, of the polar impurities are absorbed or
adsorbed, after which the reaction product is then
isolated/separated from the solid phase material, e.g., by
filtration, centrifugation, decanting, distillation, thin film
evaporation, etc. Suitable solid phase materials include
ion-exchange resins, molecular sieves, zeolites, alumina, and the
like, provided that the same are acidic to neutral pH, preferably
acidic.
[0029] According to yet a fifth aspect of the present teachings
there is provided an improved method of producing 1,1-disubstituted
ethylenes involving the reaction of an ethylene precursor with an
iminium salt wherein the improvement comprises treating the
isolated and/or purified 1,1-disubstituted ethylene with a slightly
acidic to mildly basic alumina and thereafter separating the
alumina from the treated 1,1-disubstituted ethylene.
[0030] In its most broad concept, the present teachings apply to
the production of 1,1-disubstituted ethylenes having at least one
electron withdrawing substituent at the one position with the
preferred electron withdrawing groups being selected from nitriles
(including cyano), nitro, carboxylic acids, carboxylic acid esters,
sulphonic acids and esters, amides, ketones and formyl, especially
cyano and carboxylic acid esters. Such 1,1-disubstituted ethylenes
generally correspond to the general formula III:
##STR00004##
wherein R is H or C.sub.1 to C.sub.6 hydrocarbyl such as methyl,
ethyl, ethenyl, propyl, propenyl, isopropyl, ispropenyl, butyl, or
phenyl and X and Y are independently selected from C.sub.1 to
C.sub.12 preferably C.sub.1 to C.sub.10, most preferably C.sub.2 to
C.sub.8, hydrocarbyl or heterohydrocarbyl groups provided that at
least one of X and Y is a strong electron withdrawing group.
Exemplary strong electron withdrawing groups include, but are not
limited to, cyano, carboxylic acid, carboxylic acid esters, amides,
ketones or formyl and Y is cyano, carboxylic acid, carboxylic acid
esters, amides, ketones, sulfinates, sulfonates, or formyl.
Monomers within the scope of Formula I include
.alpha.-cyanoacrylates, vinylidene cyanides, alkyl homologues of
vinylidene cyanide, methylidene malonates, dialkyl methylene
malonates, acylactylonitriles, vinyl sulfinates, and vinyl
sulfonates.
[0031] Exemplary preferred 1,1-disubstituted ethylene monomers of
formula I include, but are not limited to:
##STR00005##
[0032] Exemplary preferred 1,1-disubstituted ethylene monomers are
those of the formula IV:
##STR00006##
where R.sup.2 is H or --CH.dbd.CH.sub.2, most preferably H; and X
and Y are ea h independently --CN or --COOR.sup.3 wherein R.sup.3
is:
[0033] a hydrocarbyl or substituted hydrocarbyl group:
[0034] a group having the formula
--R.sup.4--O--R.sup.5--O--R.sup.6, wherein R.sup.4 is a
1,2-alkylene group having 2-4 carbon atoms, R.sup.5 is an alkylene
group having 2-4 carbon atoms, and R.sup.6 is an alkyl group having
1-6 carbon atoms or a group having the formula
##STR00007##
wherein R.sup.7 is --(CH.sub.2).sub.n--; --CH(CH.sub.3)--; or
--C(CH.sub.3).sub.2-- wherein n is 1 to 10, preferably 1-5, and
R.sup.6 is H or an organic moiety, preferably a hydrocarbyl or
substituted hydrocarbyl. Suitable hydrocarbyl and substituted
hydrocarbyl groups include, but are not limited to,
C.sub.1-C.sub.16, preferably C.sub.1-C.sub.8, straight chain or
branched chain alkyl groups; C.sub.1-C.sub.16, preferably
C.sub.1-C.sub.8, straight chain or branched chain alkyl groups
substituted with an acyloxy group, a haloalkyl group, an alkoxy
group, a halogen atom, a cyano group, or a haloalkyl group;
C.sub.2-C.sub.16, preferably C.sub.2-C.sub.8, straight chain or
branched chain alkenyl groups; C.sub.2-C.sub.12, preferably
C.sub.2-C.sub.8, straight chain or branched chain alkynyl groups;
and C.sub.3-C.sub.16, preferably C.sub.3-C.sub.8, cycloalkyl
groups; as well as aryl and substituted aryl groups such as phenyl
and substituted phenyl and aralkyl groups such as benzyl,
methylbenzyl, and phenylethyl. Substituted hydrocarbyl groups
include halogen substituted hydrocarbons such as chloro-, fluoro-
and bromo-substituted hydrocarbons and oxy-substituted hydrocarbons
such as alkoxy substituted hydrocarbons.
[0035] Those skilled in the art will readily appreciate the
ethylene precursors, i.e., the compounds containing a methylene
linkage and having attached thereto at least one electron
withdrawing group, necessary to produce the desired
1,1-disubstituted ethylene as described above. Exemplary electron
withdrawing groups include nitriles (including cyano), nitro,
carboxylic acids, carboxylic acid esters, sulphonic acids and
esters, amides, ketones and formyl. Preferred ethylene precursors
are those compounds having two or more electron withdrawing groups,
wherein the electron withdrawing groups may be the same or
different, for example, the ethylene precursor will have both a
nitrile and carboxylic acid ester withdrawing groups in the case of
the production of cyanoacrylate monomers.
[0036] Representative ethylene precursors include the malonitrile,
malonic acid and its esters (including, particularly, its
diesters), cyanoacetic acid and its esters (including, especially,
the alkyl substituted acids and esters, e.g., ethylcyanoacetate,
butylcyanoacetate, octylcyanoacetate, etc.), ethyl nitro acetate,
Meldrum's acid and the like.
[0037] The present teachings are especially applicable to the
reaction of the iminium salts with the cyanoacetates and the
malonic acid esters. The former generally correspond to the formula
V and the latter to the formula VI:
##STR00008##
wherein, R.sup.1 is H in the case of the mono-esters: otherwise
R.sup.1 and R.sup.2 are each independently a C.sub.1 to C.sub.18,
preferably C.sub.1 to C.sub.12, more preferably C.sub.1 to C.sub.6,
hydrocarbon or heterohydrocarbon group, the latter having one or
more nitrogen, halogen, or oxygen atoms.
[0038] Preferably, R.sup.2 is a C.sub.2 to C.sub.8 alkyl group in
the case of the cyanoacetate. However, for many of the other
ethylene precursors, especially the malonate esters, R.sup.1 and
R.sup.2 are, preferably, both hydrocarbon and/or heterohydrocarbon
groups and represent a C.sub.1 to C.sub.10, more preferably a
C.sub.1 to C.sub.6, linear or branched alkyl group; a C.sub.3 to
C.sub.6 alicyclic group; a C.sub.2 to C.sub.6 alkenyl group; or a
C.sub.2 to C.sub.6 alkynyl group, either or both of which may be
substituted with an ether, epoxide, halo, ester, cyano, aldehyde,
keto or aryl group. Most preferably, both R.sup.1 and R.sup.2 are
hydrocarbon or heterohydrocarbon groups wherein at least one
contains an ester linkage. In this regard, especially desirable
diesters of malonic acid are those wherein at least one of the
R.sup.1 and R.sup.2 groups is of the formula:
--(CH.sub.2).sub.n--COOR.sup.3
wherein R.sup.3 is a C.sub.1 to C.sub.17, preferably a C.sub.1 to
C.sub.6 hydrocarbon or heterohydrocarbon group, the latter having
one or more nitrogen, halogen, or oxygen atoms. Preferably, R.sup.3
is a C.sub.1 to C.sub.6, preferably a C.sub.1 to C.sub.3, lower
alkyl and n is an integer of from 1 to 5, preferably 1 or 2.
[0039] Exemplary diesters of malonic acid include dimethyl
malonate, diethylmalonate, di-isopropyl malonate, di-n-propyl
malonate, and ethyl methyl malonate as well as those of the
formula:
##STR00009##
wherein R.sup.1 and R.sup.3 are the same or different and represent
a C.sub.1 to C.sub.3 lower alkyl, especially ethyl.
[0040] The second critical reactant for the production of the
1,1-disubstituted ethylenes is the iminium. As noted above, these
may be a pre-formed and/or isolated and/or purified iminium salts
or it may be present as an iminium salt or iminium salt reaction
mix that is formed in-situ by a process that is integrated into the
overall reaction process for the production of the
1,1-disubstituted ethylene. In the latter case, depending upon the
specific iminium salt and its reactants and reaction products, it
is possible to directly combine the ethylene precursor with the
reaction product of the iminium reaction process, a product which,
it is believed, inherently contains the iminium salt.
[0041] Suitable iminium salts generally correspond to the formula
II
##STR00010##
wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each
independently H or a hydrocarbon or substituted hydrocarbon moiety
or a hydrocarbon, substituted hydrocarbon or heterohydrocarbon
bridge whereby the nitrogen atom, the carbon, or both of formula II
are in a ring structure, preferably, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, aryl, alkenyl or
alkynyl; and X is an anion, preferably a halogen, a
non-nucleophilic anion, and/or the conjugate salt of an acid, most
preferably a halogen, a carboxylate or a sulfonate. Generally
speaking, if a hydrocarbon or heterohydrocarbon moiety, R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 will have from 1 to 10, preferably
from 1 to 6 carbon atoms. Preferably, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, aryl, alkenyl or
alkynyl, most preferably alkyl. X is an anion, preferably a
halogen, a non-nucleophilic anion, and/or the conjugate base of an
acid, most preferably a halogen, a carboxylate or a sulfonate. In
those instances where R.sup.6 and/or R.sup.7 have a tertiary carbon
atom attached to the nitrogen atom of the iminium salt, it is
preferred that such be used in producing 1,1-disubstituted
ethylenes other than the methylidene malonates, particularly the
cyanoacrylates: though again, they are suitable for the methylidene
malonates as well.
[0042] A group of preferred iminium salts are those wherein R.sup.4
and R.sup.5 are both hydrogen H and R.sup.5 and R.sup.7 are both H
or at least one is H and the other a hydrocarbon or substituted
hydrocarbon moiety, especially an alkyl, aryl, alkenyl or alkynyl
moiety, most especially an alkyl moiety, and X is a halogen or a
substituted or unsubstituted carboxylate. Especially preferred
iminium salts are those wherein R.sup.4 and R.sup.5are hydrogen or
alkyl, most preferably H or a C.sub.1 to C.sub.6 lower alkyl, and
R.sup.6 and R.sup.7 are each independently a hydrocarbon or
substituted hydrocarbon moiety, especially an alkyl, aryl alkenyl
or alkynyl moiety, most especially a C.sub.2 to C.sub.6 lower
alkyl, and X is a halogen or a substituted or unsubstituted
carboxylate. Most preferred are the dialkylalkylideneammonium
halides and carboxylates, particularly the
dialkylalkylideneammonium chlorides, acetates and haloacetates. For
purposes of clarity, "alkyidene" refers to that portion of the
iminium compound comprising:
##STR00011##
Thus, an iminium compound wherein R.sup.4 and R.sup.5 are H and
R.sup.6 and R.sup.7 are methyl would be referred to as a
dimethylmethylidene ammonium compound.
[0043] The iminium salts may be formed by a number of alternative
processes, all of which are well known in the art. One general
route by which they may be formed involves the preparation of the
iminium salt from the corresponding imine, which process may
further involve the formation of the imine from select amines. Such
processes are described in, e.g., Abbaspour Tehrani and De Kimpe,
Science of Synthesis, 27, 313 (2004), and references cited therein;
Jahn and Schroth, Tett. Lett., 34(37), 5863 (1993); M. B. Smith,
Organic Synthesis, McGraw Hill International, Chemistry Series,
1302 (1994) and references cited therein; Hin, B., Majer, P.,
Tsukamoto, T., J. Org. Chem., 67, 7365 (2002)] and in Mannich
reactions [Holy et al, Tetrahedron, 35, 613 (1979); Bryson et al,
J. Org Chem., 45, 524 (1980); and McArdle et. al., U.S. Pat. No.
7569 719, all of which are incorporated herein by reference in
their entirety.
[0044] Generally speaking, the iminium salts (also in the past
referred to as immonium salts) may be methanimimium salts, derived
from formaldehyde; ternary iminium salts derived from aldehydes,
e.g., acrolein and quaternary iminium salts derived from ketones.
Their preparations may be conducted with or without added catalyst
provided that when a catalyst is added, the catalyst should be one
that is not solely a basic nucleophile. Thus, an acidic system
would be preferred and a ditropic system may be used, as well.
[0045] Typically the imines from which the iminium salts are formed
are produced through the reaction of a carbonyl compound,
especially an aldehyde, and an amine, such as a primary amine like
aniline, N-methylamine, or N-propylamine, which reaction results in
the removal of water. Desirably, when a primary amine is used, the
primary amine should be one with some degree of steric hindrance,
such as tertiary butyl amine. The reaction of primary amine with
carbonyl compound is well known and can be a facile, high yielding
reaction that may be conducted on a commercial scale e.g., see U.S.
Pat. No. 2,582,128 and U.S. Pat. No. 5,744,642, both of which are
hereby incorporated herein by reference.
[0046] The so-formed imines from primary amines may be converted
into iminium salts by contacting them with an acidic species, such
as trifluoroacetic acid, acetic acid, sulphuric acid, methane
sulfonic acid, or camphor sulfonic acid, and the like.
[0047] Another route to preparing the iminium salts is the use of
secondary amines wherein a secondary amine, such as dimethylamine,
pyrrolidine, morpholine, and the like, are first converted to their
respective salts and then reacted with the carbonyl compound (with
the removal of water) to produce iminium salts. Alternatively, the
iminium salts can be formed by the reaction of chloromethyl ethers
with N-(trimethylsilyl)amines. See e.g. Jahn and Schroth, Tett,
Lett, 34(37), 5863 (1993) and Abbaspour Tehrani and De Kimpe,
Science of Synthesis, 27, 313 (2004), and references cited
therein.
[0048] Yet another route to preparing the iminium salts is the
direct reaction of certain diamino compounds, such as
1,1-diaminoalkanes, especially substituted diaminoalkanes, and the
like with select activating reagents, especially acid chlorides and
acid anhydrides. Such processes are also well known. Especially
preferred process of this route employ
N,N,N',N'-tetraalkyl-1,1-diaminoaklanes, such as
tetramethyldiaminomethane and tetraethyldiaminomethane, as the
starting amine.
[0049] It is also to be appreciated that many of the suitable
iminium salts are available commercially, such as Eschenmoser's
chloride and iodide salts which are available from The Aldrich
Chemical Co.
[0050] Alternatively, and again as noted above, it is to be
appreciated that the iminium salts may be formed in-situ, e.g., as
an initial step or series of steps in the production of the
methylidene malonates. Specifically, rather than using purchased
materials or separately preparing, isolating and purifying the
iminium salt, the process of preparing the iminium salt is
integrated into the overall methylidene malonate production
process. Here the iminium salt is formed (by any of the known
methods, especially those noted above) and the ethylene precursor
added to the iminium salt, or vice-versa. Depending upon the
specific process used to produce the iminium salt, it may be
desirable, if not necessary, to isolate or consolidate the so
formed iminium salt and/or to remove certain components of the
reaction mix, especially catalysts in the case of those processes
that employ the same, prior to combining the iminium salt with the
ethylene precursor.
[0051] Most preferably, it is desired to generate the in-situ
formed iminium salt using those processes wherein the iminium salt
is prepared directly from the reaction of a 1,1-diamine compound
and an activator which contributes the appropriate counter ion,
either a halide or a non-nucleophilic conjugate base of an acid.
Exemplary anion species include, but are not limited to, chloride,
bromide, iodide, AsF.sub.6, SbF.sub.6, PF.sub.6, BF.sub.4,
CH.sub.3SO.sub.3, CF.sub.3SO.sub.3, benzenesulfonate,
para-toluenesulfonate, sulfate, bisulfate, perchlorate, SbCl.sub.6,
SbCl.sub.3, SnCl.sub.5, carboxylate, and substituted carboxylate.
Generally, the amount of diamine to activator to be used in the
reaction process is a molar equivalence, though the amine may be
used at a slight excess relative to the malonate starting material.
Most preferably, though, the activator is employed at a molar
excess as compared with the diamine. For example, the molar ratio
(activator:diamine) of 1.0:1 to 10:1, more preferably from 1.2:1 to
5:1 and most preferably from 1.5:1 to 2:1, may be used. These
reaction processes occur rapidly and, for the most part,
spontaneously: oftentimes requiring cooling to control the
exotherm. These reactions are also preferred as the product iminium
salt can be used as is and does not require isolation and/or
purification. [0050] The preferred iminium salts are the halide
salts and the carboxylate salts: though as noted and demonstrated,
iminium salts of other anionic species are effective as well. It is
also thought that certain benefits may result from the presence of
the soft anion (as classified by Pearson's Principles of Hard and
Soft Acid Base (HSAB)). In following, although not limited thereto,
it is especially preferred that the carboxylate anion is an
acetate, a propionate, a pivalate, a stearate, an isobutyrate, or a
benzoate; most preferably an acetate.
[0052] For purposes of convenience, the present teachings will be
discussed in terms of the dialkylmethylideneammonium carboxylate
salts, especially the dimethylmethylideneammonium carboxylate
salts. However, it is to be appreciated and intended that these
teachings are equally applicable to and reflective of the iminium
carboxylate salts in general as well as the other iminium salts
mentioned above: all of which are suitable for use in the practice
of the present process. While not wanting to be bound by theory, it
is thought that marked benefit in performance noted with the
carboxylate anion, especially in those iminium salts of Formula VI
above where R.sup.4 and R.sup.5 are H and, optionally, though
preferably, neither R.sup.6 nor R.sup.7 contain a tertiary carbon
atom bonded to the N atom, occurs as a result of improved
solubility.
[0053] The dialkylmethylideneammonium carboxylates may be prepared
by a variety of methods. For example, they can be prepared by
reacting the desired trialkylamine N-oxide with the acid anhydride
of the desired carboxylate anion. Alternatively, the desired
dialkylamine can be reacted with formaldehyde or a formaldehyde
synthon such as paraformaldehyde in the presence of the carboxylic
acid. One preferred method is to prepare the
dialkylmethylideneammonium carboxylate by an anion exchange
reaction with another more common and, preferably, cheaper,
dialkylmethylideneammonium salt such as the commercially available
dimethylmethylideneammonium halides, especially the iodide (i.e.,
Eschenmoser's salt).
[0054] More preferably, the dialkylmethylideneammonium carboxylate
is prepared by the reaction of tetraalkyldiaminomethane with a
carboxylic acid anhydride, e.g., dimethylmethylideneammonium
carboxylate is prepared by the reaction of tetramethydiaminomethane
with a carboxylic acid anhydride. When this method is employed, the
molar ratio of tetraalkyldiaminomethane to carboxylic acid
anhydride is preferably from 1.0:1 to 10:1, more preferably from
1.2:1 to 5:1 and most preferably from 1.5:1 to 2:1. This reaction
is preferably conducted in the presence of a solvent such as
acetonitrile or toluene. The process is preferably conducted at
and, because the reaction is typically exothermic, maintained at a
reaction temperature of between 0.degree. C. to 60.degree. C.
Though not critical, it is preferable for reaction control that the
carboxylic acid anhydride is added to the tetraalkyldiaminomethane
as opposed to latter being added to the former. Furthermore,
because the reaction is exothermic, it is preferred to perform the
addition gradually or in portions. Exemplary carboxylic acid
anhydrides include acetic anhydride, propionic anhydride,
isobutyric anhydride, pivalic anhydride, and benzoic anhydride.
Preferably, the carboxylic acid anhydride is acetic anhydride
because it is readily available and because any unreacted acetic
anhydride and any reaction byproducts such as dimethylacetamide are
easily removed. Reaction times vary depending upon the reactants
and conditions; however, most often the formation of the iminium
salt is completed within a few hours, generally within an hour to
an hour and a half. Again, shorter or longer times may be necessary
to bring the reaction to completion.
[0055] As noted above, the dimethylmethylideneammonium carboxylate
may be prepared en-mass or acquired and stored for use. However,
for cost convenience and overall simplicity and consolidation of
process, it is desirable to employ an in-situ formed
dimethylmethylideneammonium carboxylate, with or without isolation
from its reaction mix. Here, for example, the
dimethylmethylideneammonium carboxylate is formed and, without
isolation, combined with a diester of malonic acid and allowed to
react.
[0056] The 1,1-disubstituted ethylene is prepared by combining the
iminium salt or the in-situ formed iminium salt reaction product
with the ethylene precursor. Although either may be added to the
other, it is preferable that the ethylene precursor is added to the
iminium salt. The reaction is typically, and preferably, performed
at a temperature from 0.degree. C. to 60.degree. C., most typically
at room temperature or higher. Higher temperatures can be used and
tolerated, but such higher temperatures can result in
polymerization or partial polymerization and/or viscosity increase
of the formed 1,1-disubstituted ethylene monomer, which results in
decreased yields and purity. Similarly, temperatures lower than
0.degree. C. may be used but are not necessary and add to the
overall production costs associated with the longer reaction times
and the cooling of the reaction system. Furthermore, it is to be
appreciated that the specific iminium salt or iminium salt reaction
product may also influence the temperature at which the reaction
process is carrier out. For example, the presence of excess acid
chlorides resulting from the in-situ formation of the halide salts
is found to slow the reaction somewhat. Accordingly, elevated
temperatures, generally in the range of from 40.degree. C. to
50.degree. C. appear to provide optimal reaction for those salts.
Similarly, the reaction appears slower with certain carboxylate
salts, again suggesting a desire for elevated temperatures. On the
other hand, certain halide salts, such as the Eschenmoser's salts,
perform well at room temperature.
[0057] The amount of reactants to be employed depends, in part,
upon the selected reactants themselves and the impact, if any, of
excess on the resultant product or process. Generally speaking, the
ratio (on an equivalence basis) of iminium salt to ethylene
precursor is from about 1:1 to 10:1, preferably from about 1:1 to
6:1, most preferably, from an economic standpoint, 1:1 to 1:4.
Again, it is to be appreciated that certain combinations of
reactants will require higher or lower ratio to reach completion,
even higher than the stated ranges.
[0058] Although not a requirement, it is preferred that the
reaction of the reaction of the iminium salt and the ethylene
precursor is carried out in the presence of a solvent. Indeed, if
the iminium salt is formed in-situ, it is preferable that the
iminium salt also be prepared in a solvent, most especially the
same solvent as is to be employed for the overall reaction.
Preferable solvents have a boiling point at atmospheric pressure of
between 40.degree. C. and 150.degree. C. Solvents with lower
boiling points can cause difficulty and reaction instability
because the reaction is exothermic, or in some cases too slow and
require heating. Solvents with higher boiling points can be
difficult to remove in subsequent purification steps. Furthermore,
as noted above, where the iminium salt is formed in-situ, it is
preferred that the same solvent is used for both its preparation as
well as in the reaction with the ethylene precursor.
[0059] The solvents employed may be polar or nonpolar solvents.
Exemplary polar solvents include, but are not limited to, DMF, THF,
acetonitrile, DMSO, IPA, ethanol and the like. Exemplary nonpolar
solvents include, but are not limited to, toluene, benzene,
diethylether, hexane, cyclohexane and carbontetrachloride. Polar
solvents appear to be optimal for reaction performance in preparing
the methylidene malonate; however, pose difficulties in the
subsequent work-up to purify and isolate the methylidene malonate.
In this respect, it is more difficult to remove the polar
by-products from the reaction. On the other hand, nonpolar solvents
do not provide optimum reaction performance, but make work-up and
isolation and purification much simpler and more efficient. It is
also to be appreciated that one can conduct the reaction in a polar
solvent and then switch the solvent to a nonpolar solvent before
performing any steps to isolate and/or purify or treat the
methylidene malonate monomer. Furthermore, it is preferred to use
the lower boiling point solvents since the higher temperatures
needed for distillation of reaction mixes with higher boiling point
solvents may lead to polymerization and/or degradation of the
monomer.
[0060] Generally speaking the amount of solvent to be used is from
about 5.times. to about 30.times., preferably about 10.times. to
about 25.times., most preferably, on an economic and environmental
basis, about 15.times. to about 20.times., the amount of malonic
acid ester, on a volumetric basis.
[0061] Reaction times for the production of the methylidene
malonates will also vary depending upon the reactants, reaction
temperature, and the choice of solvent. Reaction times range from
under an hour to many hours, indeed 20 or more hours may be
necessary to attain complete reaction. Typically, a reaction time
of an hour or so up to six hours is suitable and sufficient.
[0062] Likewise, though not a requirement, it is preferred that the
reaction of the ethylene precursor and the iminium salt occurs in
the presence of an acid or its anhydride, preferably an acid having
a pKa less than 6.0, more preferably less than 5.0. This is
especially so for the reaction involving carboxylate ester ethylene
precursors, most especially when the ethylene precursor is a
malonic acid ester or diester. The presence of the acid or
anhydride is believed to stabilize the 1,1-disubstituted ethylene
monomer product from polymerization. Suitable acids and anhydrides
for preventing the polymerization of 1,1 disubstituted ethylene
monomers are well known and discussed at length in Malofsky et. al.
(US WO 2010/129068), which is hereby incorporated herein by
reference in its entirety. Exemplary acids and anhydrides include,
but are not limited to, acetic acid, acetic anhydride,
trifluoroacetic acid, alkyl sulfonic acids such as methanesulfonic
acid or trifluoromethanesulfonic acid, arylsulfonic acids such as
toluenesulfonic acid, and sulfuric acid. When used, the amount of
acid to be added to the reaction mix is preferably from about 100
to about 20,000 ppm, preferably from about 300 to about 10,000 ppm,
most preferably from about 2000 to about 5000 ppm based on the
amount of the diester of malonic acid. Optimum levels of acid to be
added to a given reaction mix can be determined by simple
experimentation.
[0063] Additional stabilization may be imparted to the reaction
mix, especially following or towards the end of the reaction, by
the addition of one or more free radical polymerization inhibitors.
The free radical stabilizer or polymerization inhibitor, as they
are more commonly referred, may be added alone or in combination
with the acid stabilizer, or any anionic polymerization inhibitor,
again as mentioned in Malofsky et. al. Suitable free radical
inhibitors include, but are not limited to, the hydroquinones and
various hindered phenols, especially para-hydroquinone monomethyl
ether, catechol, pyrogallol, benzoquinones, 2-hydroxy
benzoquinones, t-butyl catechol, butylated hydroxy anisole (BHA),
butylated hydroxy toluene (BHT), t-butyl hydroquinones,
2,2''-methylene-bis (6-tert-butyl-4-methylphenol), and mixtures
thereof. The amount of free radical inhibitor to be added to the
system should generally be from about 100 to about 20,000 ppm,
preferably from about 300 to about 10,000 ppm, most preferably from
about 2000 to about 5000 ppm based on the amount of the diester of
malonic acid. As with the acid stabilizer, the optimal amount of
free radical polymerization inhibitor to be used can be determined
by simple experimentation.
[0064] The 1,1-disubstituted ethylenes formed by the reaction of
the ethylene precursors and the iminium salts may be used as-is,
but are preferably subjected to various separation, isolation
and/or purification steps, all of which are well known in the art.
Where the reaction is conducted in a solvent wherein the reaction
product is highly soluble therein, it is preferable to replace the
solvent with another solvent having no or less solubility
properties for the formed 1,1-disubstituted ethylene monomer.
Again, insofar as isolation and purification of the monomer is
concerned, any of the known methods for purification of like
organic molecules can be employed; however, purification is
preferably achieved by distillation, most preferably under reduced
pressure as this allows for lower distillation temperatures. Like
the concern with higher reaction temperatures, higher distillation
temperatures increase the potential for polymerization or partial
polymerization of the methylidene malonate, thereby decreasing the
yield.
[0065] As noted, it may be desirable to isolate the
1,1-disubstituted ethylene monomer material from the reaction mix
prior to purification, and especially prior to use. Isolation helps
remove unreacted reactants and reaction byproducts. Isolation can
be performed by any of the methods known in the art for such
purpose. For example, isolation may be conducted as a low
temperature distillation under reduced pressure. Alternatively,
isolation may be achieved by solvent washing and separation,
exemplary solvents include water. Yet another alternative is the
treatment of the crude reaction product with a solid adsorbent such
as alumina to remove unreacted reactants and reaction byproducts.
Preferably, isolation is achieved by a combination of these
techniques.
[0066] Following the teachings of Malofsky et, al., the isolation
and/or purification steps are preferably conducted in the presence
of one or more stabilizers/polymerization inhibitors, especially
anionic polymerization inhibitors, most especially acid
polymerization inhibitors, and/or free radical polymerization
inhibitors, most preferably both. Suitable polymerization
inhibitors are discussed above and, in more detail, in Malofsky et.
al. which, again, is hereby incorporated hereby by reference in its
entirety. Preferably the anionic stabilizer/polymerization
inhibitor is an acid stabilizer, most preferably an acid having a
pKa less than 2.0. Exemplary acids include trifluoroacetic acid,
alkyl sulfonic acids such as methanesulfonic acid or
trifluoromethanesulfonic acid, arylsulfonic acids such as
toluenesulfonic acid, and sulfuric acid.
[0067] Although the stabilizers may be used in any isolation
process, they are most preferably used in those isolation processes
that involve elevating or elevated temperatures or any other
conditions that are know to promote, accelerate or initiate
polymerization of 1,1-disubstituted ethylene monomer. In any event,
stabilizers should, and preferably are, employed in the
purification steps, with addition thereof to the distillation pot
as well as the collection or receiver vessel. Stabilizers are also
to be added to the final collected materials to inhibit
polymerization during subsequent storage. Generally speaking the
amount of stabilizer (anionic polymerization inhibitor, free
radical polymerization inhibitor or both) to be added to the
1,1-disubstituted ethylene monomer reaction product, crude reaction
product and/or isolated product should be from about 100 to about
20,000 ppm, preferably from about 300 to about 10,000 ppm, most
preferably from about 2000 to about 5000 ppm based on the amount of
the 1,1-disubstituted ethylene monomer. Preferred or optimal
stabilizers or combinations of stabilizers as well as the amount
thereof to use can be determined by simple experimentation.
[0068] Having disclosed the general aspects and reagents to be
employed in the presently taught and claimed process, attention now
is directed to the specific aspects, each of which are new and/or
improvements over the state of the art.
[0069] According to a one aspect of the present teachings, those
processes in which an ethylene precursor is reacted with an iminium
salt to form a 1,1-disubstituted ethylenes is improved by the
addition of an acid halide, especially an acid chloride, and/or an
acid anhydride to the reaction mix and/or product. The addition of
the acid halide and/or acid anhydride has been found to reduce the
formation of dimer. In this regard, it is believed that the
reaction process generates amines, especially secondary amines,
like diethylamine and their salts, which catalyze or promote dimer
formation. The addition of the acid halide and/or acid anhydride
are believed to scavenge these amines, thereby preventing the
formation of the dimers. The acid halide and/or acid anhydride may
be added at any time, though it is especially beneficial to add it
to the reaction mix before or during the reaction. The amount of
acid halide and/or acid anhydride to be added is not so critical
and can be found by simple experimentation for a particular
reaction system. Oftentimes an amount of up to a molar equivalent
based on the amount of iminium salt present is sufficient: though
larger amounts could be used. Generally lesser amounts, e.g., 0.2
to 0.5 eq. will suffice.
[0070] Alternatively, one may achieve the foregoing benefit by
generating the iminium salt is-situ and using an excess of an acid
halide and/or acid anhydride in the iminium salt formation. By this
method, in addition to forming the desired iminium halide or
iminium carboxylate one also adds to the reaction mix sufficient
acid halide and/or acid anhydride to scavenge the amities. In this
instance, the molar ratio of acid halide or acid anhydride is
generally higher than or at the higher end of the ratio of
activator to diamine discussed above. Here, it is preferred that
the molar ratio is from 1.2:1 to 10:1, preferably from 1.5:1 to
7:1, and most preferably from 1.5:1 to 5:1, may be used.
[0071] Acid halides are well known and widely available. These
generally correspond to the formulae R.sup.9C(O)X and
R.sup.9SO.sub.2X where R.sup.9 is an aliphatic or aromatic
hydrocarbon or substituted hydrocarbon, especially a C.sub.1 to
C.sub.18, preferably a C.sub.1 to C.sub.12, more preferably a
C.sub.1 to C.sub.6, hydrocarbon or substituted hydrocarbon, and X
is fluorine, chlorine, bromine or iodine. Preferred acid halides
are those wherein R9 is a C.sub.1 to C.sub.6 hydrocarbon and X is
chlorine. Especially preferred are the acid chlorides, i.e., those
compounds having the foregoing formula wherein X is chlorine,
including the acyl chlorides, the aroyl chlorides and the sulfonyl
chlorides. Exemplary acid chlorides include acetyl chloride,
propionyl chloride, isobutyryl chloride, trimethylacetyl chloride,
benzoyl chloride, and chloroacetylchloride.
[0072] Similarly, acid anhydrides are well known and widely
available. These are organic compounds that has two acyl groups
bound to the same oxygen atom. Most commonly, the acyl groups are
derived from the same carboxylic acid and correspond to the general
formula (R.sup.9C(O)).sub.2O, wherein R.sup.9 is as defined above.
Exemplary acid anhydrides include formic acid anhydride, acetic
anhydride, propionic anhydride, butyric anhydride, valeric
anhydride, caprilic anhydride, trifluroacetate, isobutyric
anhydride, trimethylacetic anhydride, trifluoroacetic anhydride,
and sulfonic acid anhydride.
[0073] Another aspect of the present teachings pertains to the
select use of iminium carboxylates, either preformed or formed
in-situ, in the processes for the production of the
1,1-disubstituted ethylenes. Specifically, it has been found that
the select use of the iminium carboxylates allows one to use
non-polar solvents as the solvent for the iminium preparation
and/or the reaction of the iminium salt and the ethylene precursor.
Although non-polar solvents do not, in many instances, provide for
the optimal conversion of ethylene precursor to 1,1-disubstituted
ethylene, they do allow for more efficient and effective
separation, isolation and/or purification of the formed
1,1-disubstituted ethylene monomer. This benefit manifest in
several respect including better yields as extraction of the
1,1-disubstitute monomer is easier and more complete than from
polar solvents, particularly those monomers that are highly soluble
in polar solvents.
[0074] Another advantage of the use of iminium carboxylates is the
finding that, in many, if not most instances, the reaction to form
the 1,1-disubstituted ethylenes can be conducted at room
temperature or slightly elevated temperatures. This compares with
many of the acid chlorides which have a tendency to slow the
reaction down, oftentimes necessitating elevated temperature
reaction conditions, generally 30.degree. C. to 65.degree. C. and
higher.
[0075] Although it is possible to perform a solvent swap, wherein a
non-polar solvent is substituted for a polar solvent following the
reaction process, such processes are time consuming, require the
use of additional materials, including expensive solvents like
acetonitrile. Thus, it is especially beneficial to be able to use
non-polar solvents from the outset: a practice that is enabled by
the select use of iminium carboxylates.
[0076] Yet another feature of the present teachings is the finding
that one can improve yields and stability by treating the
1,1-disubstituted ethylene reaction product with a solid phase
material known to adsorb or absorb polar materials in the presence
of a non-polar solvent following completion of the reaction. If the
reaction process to form the 1,1-disubstitute ethylene is conducted
in the presence of a polar solvent, one must first remove and
replace the polar solvent with a non-polar solvent. Treatment with
the solid phase material is performed following the reaction itself
and prior to any further efforts to isolate, separate and/or purify
the 1,1-disubstituted ethylene monomer. The treatment is continued
until most, if not substantially all, of the polar impurities are
absorbed or adsorbed, after which the reaction product is then
isolated/separated from the solid phase material, e.g., by
filtration, centrifugation, decanting, distillation, thin film
evaporation, etc. Suitable solid phase materials include
ion-exchange resins, molecular sieves, zeolites, alumina, and the
like, provided that the same are acidic to neutral pH, preferably
acidic. Acidic materials are needed to prevent or guard against
polymerization of the monomer since many of the 1.1-disubstituted
ethylene monomers are base catalyzed or activated.
[0077] This treatment process will typically employ a large amount
of the solid phase material, generally up to 100 wt % or more based
on the monomer to be treated. Typically, the amount is from about
30 wt % to about 80 wt %, preferably from about 40 wt % to about 70
wt %. The high amount is to enable faster scavenging of the
impurities while minimizing exposure, particularly since the solid
phase materials oftentimes adsorb or absorb TFA and other key
stabilizers. Again, because of the high reactivity of the
1,1-disubstituted ethylenes, especially the cyanoacrylate monomer
and the methylidene malonate monomers, it is best to complete the
treatment as quickly as possible, removing the solid phase material
and them up-stabilizing the monomer as necessary. The specific
amount and time of the solid phase material treatment will vary
depending upon the solid phase material itself, the reaction
product being treated, the temperature, etc.
[0078] Finally, another improvement to the method of producing
1,1-disubstituted ethylenes using iminium salts comprises treating
the isolated and/or purified 1,1-disubstituted ethylene with a
slightly acidic to mildly basic alumina and thereafter separating
the alumina from the treated 1,1-disubstituted ethylene. This
method is disclosed at length in co-pending, co-filed US patent
application entitled "Improved 1,1-disubstituted Ethylene Process",
Mc Conville et. al. and pending U.S. Provisional Patent Application
No. 61/591,882, filed 28 Jan. 2012, the contents of which are
hereby incorporated herein in their entirety by reference.
[0079] Generally speaking, this method entails treating the
isolated and/or purified 1,1disubstituted ethylene with an alumina
having a pH, as measured in neutral water, of generally from about
5.0 to about 8.5, preferably from about 5.5 to about 8.5, more
preferably from about 6.0 to about 8.0, most preferably from about
6.5 to about 7.5. Typically, the alumina treatment is conducted at
from about 0.degree. C. to about 150.degree. C., preferably from
about 20.degree. C. to 70.degree. C., for from about 5 minutes to
about 20 hours, preferably from about 10 minutes to 5 hours. The
quantity of alumina employed depends upon many factors, including
the method employed. Generally speaking, especially in batch
processing, the amount of alumina is from about 0.5 to about 20
weight percent, preferably from about 2 to about 10 weight percent,
based on the weight of the monomer. In the case of continuous
processing, the amount of alumina is determined by the retention
time in the treatment container or column. Specifically, one must
ensure proper retention time in order to ensure sufficient
treatment or one may circulate the monomer through the column until
the desired effect is realized.
[0080] By implementing the improved processes as set forth herein,
one realizes more consistent and improved yields. For example, one
may attain crude yields in excess of 50%, preferably in excess of
60%, more preferably in excess of 80%, most preferably in excess of
90%, with purities of, generally, 60% or more, preferably 70% or
more, more preferably 80% or more, most preferably 90% or more.
Owing to the initial high purity of the crude products, subsequent
purification allows for the even higher purity materials with a
modest to minimal effect on yield. For example, purified yields in
excess of 25%, preferably in excess of 30% with purities of,
generally, 90% or more, preferably 95% or more, more preferably 98%
and even 99% or more are readily attainable.
[0081] The 1,1-disubstituted ethylenes resulting from the present
teachings are well known, though not all have yet made it to
commercial success. These monomers may be employed in a number of
organic syntheses and polymer chemistry applications. In
particular, they are especially useful in the preparation of
various adhesive and sealant applications including industrial,
commercial and consumer adhesive and sealant applications as well
as in medical adhesives, most especially skin bonding applications
for human and animal skin bonding. In light of the benefit of the
present invention, it is believed that these compositions are now
commercially viable as cost effective and stable formulations can
now be made.
EXAMPLES
[0082] Having described the invention in general terms, Applicants
now turn to the following examples in which specific combinations
of reactants, solvents and reaction times were evaluated. These
examples are presented as demonstrating the surprising attributes
of the improved processes of the present. These examples are merely
illustrative of the invention and are not to be deemed limiting
thereof. Those skilled in the art will recognize many variations
that are within the spirit of the invention and scope of the
claims.
[0083] Iminium Salts
[0084] A plurality of preformed and in-situ formed iminium salts
were employed. The general structures of these salts were as
follows:
[0085] Halogen Based Salts:
##STR00012##
[0086] Carboxylate Salts:
##STR00013##
[0087] Sulfonate Salts:
##STR00014##
[0088] Monomer
[0089] Similarly, three different monomer substrates containing a
methylene linkage having attached thereto at least one electron
withdrawing group were employed to further demonstrate the breadth
of the present teachings as follows:
##STR00015##
[0090] DMDEE Test
[0091] In order to assess cure performance of the 1,1-disubstituted
ethylene monomers, a standardized test based on dimorpholinodiethyl
ether ("DMDEE") as a cure initiator/activator was developed. This
standardized test allowed direct comparison from treated and
untreated 1,1-disubstituted ethylene monomers as well as between
different types of treatments and variations of the same types of
treatments. Specifically, the cure characteristics of
1,1-disubstituted ethylene monomers were assess by inducing the
polymerization of the monomers in the presence of DMDEE as
follows:
##STR00016##
[0092] To a tared 4 mL glass vial equipped with a magnetic stir
bar, 55 microliters of a 10% by weight solution of DMDEE in
isopropanol is added. The vial is reweighed to determine the weight
of solution added and monomer is added to the DMDEE solution while
stirring to give 1 mL monomer per 42.5 mg DMDEE solution. Stirring
is continued for one minute. The stir bar is removed and replaced
with a thermocouple. Temperature is plotted versus time. The
polymerization induction time is taken as the time in which the
rise in temperature between two successive data points (three point
running average) first exceeds 0.5.degree. C. A short induction
time is indicative of a monomer that is suitably active for
commercial use, i.e., will polymerize in a reasonable period of
time. A long induction time is indicative of a monomer that, most
likely due to the presence of impurities which inhibit
polymerization, that is unsuitable for commercial use owing to the
lack of polymerization or a cure speed that is too slow to be of
commercial utility.
Example 1
Eschenmoser's Iodide Salt (EIS)
[0093] 6 eq. of EIS (Iminium B) and 0.1 eq. of TFA, were added to
Malonate 2.1.2 in 20 volumes of 19:1 DMF:IPA solvent. The mixture
was stirred for 12-24 hours at room temperature and produced an
in-solution yield of .about.30% of Methylidene Malonate 2.1.2.
Analysis of the reaction product showed considerable dimer
formation as well.
##STR00017##
Example 2
Reverse Addition
[0094] Malonate 2.1.2 dissolved in DMF was slowly added to 6 eq. of
EIS (Iminium B) over a period of 2 hours with stirring at room
temperature. A measurement was taken after 22 hours and it was
found that an in-solution yield of Methylidene Malonate 2.1.2 of
45% had been attained. A further 3 eq. of EIS dissolved in DMF was
added after 22 hours and the reaction continued at room temperature
for an additional 18 hours. The reaction product then showed an
in-solution yield of 47%, Analysis of the reaction product
continued to showed considerable dimer formation as well.
Example 3
Acid Chloride Addition
[0095] Malonate 2.1.2 dissolved in DMF was slowly added to 3 eq. of
EIS (Iminium B) over a period of 2 hours with stirring. A
measurement was taken after 4 hours and it was found that an
in-solution yield of Methylidene Malonate 2.1.2 of 26% had been
attained. 0.25 eq. of acetyl chloride was then added to the
reaction mix and the reaction continued for an additional 16 hours.
The reaction product then showed an in-solution yield of 47%;
however, the level of dimer was markedly reduced after the addition
of the acetyl chloride, indeed, even lower than was present before
the addition of the acetyl chloride. It is theorized that the acid
chloride prevents the dimer formation and may actually reverse its
formation, possibly via a retro Michael addition.
Example 4
Acid Chloride Addition and Higher Temperatures
[0096] Having noted that the addition of the acetyl chloride (AcCl)
appeared to slow the reaction process at room temperature, another
experiment was conducted to consider the impact of higher
temperature in combination with the acetyl chloride addition. To
correlate the impact of the acetyl chloride and temperature on the
reaction and reaction products, both percent conversion of the
Malonate 2.1.2 and the percent of Methylidene Malonate 2.1.2 in the
reaction products were assessed: dimer typically accounting for
sizeable portion of the reaction product. The specific steps and
results are presented in Table 1.
TABLE-US-00001 TABLE 1 Percentage of Time Conversion Monomer in
(hr) Comment (%) Products (%) 1 Malonate was added over 46 55 1 hr
to 3 eq EIS 3 Added 0.25 eq of AcCl after 1 hr 33 73 6 Added
additional 3 eq of EIS 38 75 after 3 hrs 7 Started heating to
40.degree. C. 57 73 21 After 14 hr at 40.degree. C. 62 65 23 Added
additional 0.25 eq AcCl 57 72 25 Added additional 3 eq EIS 61 72 41
Heated to 50.degree. C. 85 57
[0097] The results shown in Table 1 clearly demonstrate the marked
improvement in yield of the desired Methylidene Malonate 2.1.2 as a
result of the addition of the acetyl chloride. Higher temperature
appeared to accelerate the conversion; however, elevating the
temperature too high with the further addition of EIS led to a loss
in the benefit of the acetyl chloride. Presumably, the added EIS
led to additional dimer formation and/or degradation of the
Methylidene Malonate 2.1.2. Additionally, it is to be recognized
that acetyl chloride boils at 52-55.degree. C. and, thus, higher
temperatures may lead to a loss in acetyl chloride itself from the
reaction pot.
Example 5
In-Situ Eschenmoser's Chloride Salt (ECS)
[0098] A series of experiments were run to assess both the ability
to use an in-situ formed Eschenmoser's salt, in this case
Eschenmoser's chloride salt (ECS--Iminium A), in the production of
1,1-disubstituted ethylenes as well as the impact of varying the
mole ratio of the salt forming ingredients on the same. In this
specific set of experiments the ECS was formed by the reaction of
varying amounts of acetyl chloride and 6 Eq. of
tetramethyldiaminomethane (TMDAM) in DMF at 0.degree. C. Following
the formation of the ECS, Malonate 2.1.2 dissolved in DMF was
slowly added to the reaction product of the ECS formation and the
mixture heated to 60.degree. C. The specific experiments and the
results attained thereby are presented in Table 2.
TABLE-US-00002 TABLE 2 Reaction Conversion Percentage of Monomer
Run Eq of AcCl Time (hr) (%) in Products (%) 1 6.5 16 98 62 2 6.5
21 99 45 3 7.5 21 99 69* 4 9 25 59 70 5 12 25 22 55 *this
corresponds to an in-solution yield of Methylidene Malonate 2.1.2
of 68% (% conversion times % Monomer in Products)
Example 6
Use of Acetonitrile as Solvent
[0099] Given the relatively high boiling point of DMF, acetonitrile
was evaluated as an alternate polar solvent, as well as to assess
whether other polar solvents were suitable. In this experiment 300
ml of acetonitrile was added to a three neck round bottom flash
containing 6 eq. TMDAM (56.2 g) and the mixture cooled in an ice
bath to 2-3.degree. C. 7.5 eq. acetyl chloride (48.8 ml) was then
added slowly at a rate whereby the temperature of the reaction mix
was maintained 20.degree. C. After the addition was completed, the
mixture was removed from the ice bath and allowed to come to room
temperature while stirring (.about.1 hour). Once at room
temperature, 1 eq. of Malonate 2.1.2 monomer (20 g) dissolved in
acetonitrile (5 ml) was slowly added. Once the addition was
completed, the mixture was stirred for one hour at room temperature
and then the mixture heated to 60.degree. C. and stirred for an
additional 24 hours. This produced a reaction product with a 97%
conversion and an in-solution yield of 80%, as determined by
GC.
[0100] Once the reaction was complete, the crude reaction mix was
cooled to 30.degree. C. and 400 ml of MTBE added to
precipitate/crash out the amine salts. The solids were removed by
filtration (at continued cold temperature to avoid the salts from
going back into solution/melting) and the remaining filtrate was
found to have an in-solution yield of 73%.
Example 7
Use of Different Acid Chlorides
[0101] A further series of experiments were conducted to assess the
suitability of various acid chlorides in the iminium process. The
same process as employed in Example 6 was employed here as well
with the exception of the acid chloride and the mole ratios of the
same and the TMDAM. The specific experiments and the results
attained thereby are presented in Table 3.
TABLE-US-00003 TABLE 3 TMDAM Acid Chloride Time Conversion
In-Solution Run (eq) (eq) (hr) (%) Yield (%) 1 6 ##STR00018## 18 98
85 2 3 ##STR00019## 20 >99 91 3 2 ##STR00020## 20 90.5 82 4 3
##STR00021## 20 98.6 80 5 3 ##STR00022## 20 97.5 89.9 6 3
##STR00023## 20 99 94.4 7 2 ##STR00024## 20 78.5 --
[0102] Substituting the propionyl chloride (Run 1) for the acetyl
chloride (Example 6) while keeping everything else the same
presented an immediate jump in yield of .about.5%. The yield jumped
even higher when the amount of amine was reduced to 3 eq. and the
amount of chloride reduced to 4.5 eq.
Example 8
Procedure Using Acetonitrile with Work Up to Remove Ammonium
Salts
[0103] In this experiment 15 ml of acetonitrile was added to a
three neck round bottom flask containing 3 eq. TMDAM (1.4 g) and
the mixture cooled in an ice bath to 2-3.degree. C. 4.5 eq.
propionyl chloride (1.8 ml) was then added slowly at a rate whereby
the temperature of the reaction mix was maintained below 20.degree.
C. After the addition was completed, the mixture was removed from
the ice bath and allowed to come to room temperature while stirring
(.about.1 hour). Once at room temperature, 1 eq. of Malonate 2.1.2
monomer (1 g) dissolved in acetonitrile (5 ml) was slowly added.
Once the addition was completed, the mixture was stirred for one
hour at room temperature and then the mixture heated to 60.degree.
C. and stirred for an additional 10 hours. This produced a reaction
product with an in-solution yield of 91%, as determined by GC.
[0104] Once the reaction was complete, the crude reaction mix was
concentrated to remove most of the acetonitrile. The remaining
reaction product appeared as a viscous oil to which was added
toluene and the mixture distilled twice. The mixture was then
dissolved in 10 volumes of toluene and an equal amount of MTBE. The
resultant slurry was then filtered to remove the solids leaving a
solution of the methylidene malonate 2.1.2 monomer at an
in-solutions yield of 80%.
Example 9
Polar and Nonpolar Solvents with Acid Anhydride to Prepare iminium
Salts
[0105] A series of experiments were run with polar (acetonitrile)
and nonpolar (toluene) solvents. The general procedure for both
types of solvents is pretty much the same and begins with the
addition of 15 volumes of the selected solvent to 2 eq. of the
diamine in a round bottom flask kept under nitrogen atmosphere. The
reaction mixture is then cooled to 0-5.degree. C. using an ice bath
and 3.5 eq. of the add anhydride is added to the chilled reaction
mix at a rate whereby the internal temperature never exceeds
10.degree. C. After the addition is complete, the mixture is
removed from the ice bath and allowed to warm to room temperature,
generally over a period of 1-1.5 hours. A solution of the malonate
to be converted and 0.1 eq. sulfuric acid or trifluoroacetic avid
(TFA) in 5 volumes of the same solvent is then slowly added to the
reaction mixture at a rate such that the internal temperature never
exceeds 25.degree. C. Thereafter the processes differ with that
process employing the polar solvent continuing to react at room
temperature for a few hours, typically less than 6. That process
using the non-polar solvent, on the other hand, involved heating
the reaction mix to 40.degree. C. and allowing the reaction to
continue to completion, generally 15-20 hours.
[0106] Table 4 presents the results attained with a number of
different acid anhydride derived iminium salts/reaction products in
accordance with the general procedure of the preceding
paragraph.
TABLE-US-00004 TABLE 4 Iminium Conditions In-solution salt (salt
introduction) Solvent yield (%) C In-situ synthesis from acetic
Acetonitrile 68 anhydride E In-situ synthesis from Toluene 27
isobutyric anhydride F In-situ synthesis from Toluene Not measured
- trimethylacetic anhydride (89% conversion)
Example 10
Use of Iminium I for Methylidene Malonate 2.1.2 Preparation
[0107] Iminium I was generated from
N,N,N',N'-tetraethyldiaminomethane in a manner analogous to the in
situ generation of Iminium C (see Example 9). Thus, 2.90 g of
N,N,N', N'-tetraethylcliaminomethane was dissolved in acetonitrile
(30 mL) and the solution was cooled to 0-5.degree. C. in an
ice-water bath. Acetic anhydride (3.28 g) was added, causing the
temperature to rise to .about.10.degree. C. The ice bath was
removed and the mixture was stirred for .about.1 hr. The mixture
was placed back in an ice-water bath and cooled back to
.about.15.degree. C. A solution of Malonate 2.12 (2.00 g) and
trifluoroacetic acid ((0.11 g) in acetonitrile (10 mL) was then
added and the ice-water bath was again removed. After warming to
20-25.degree. C., the mixture was stirred for an additional 2 hr,
at which point the in-solution yield was measured at 67%.
Example 11
Use of Iminium J for Methylidene Malonate 2.1.2 Preparation
[0108] Iminium J was generated from N,N'-dimorpholinomethane in a
manner analogous to the in situ generation of Iminium I (see
Example 10). Thus, 3.42 g of N,N'-dimorpholinomethane was dissolved
in acetonitrile (30 mL) and the solution was cooled to 0-5.degree.
C. in an ice-water bath. Acetic anhydride (3.28 g) was added,
causing the temperature to rise to .about.10.degree. C. The ice
bath was removed and the mixture was stirred for .about.1 hr. The
mixture was placed back in an ice-water bath and cooled back to
.about.15.degree. C. A solution of Malonate 2.1.2 (2.00 g) and
trifluoroacetic acid ((0.11 g) in acetonitrile (10 mL) was then
added and the ice-water bath was again removed. After warming to
20-25.degree. C., the mixture was stirred for an additional 2 hr,
at which point the in-solution yield was measured at 75%.
Example 12-Scavenger
[0109] 320 ml of toluene and 1.1 eq. of TMDAM (13.8 ml) was added
to a round bottom flask and kept under nitrogen atmosphere. The
reaction mixture was then cooled to 0-5.degree. C. using an ice
bath and 2.5 eq. of the acetic anhydride (21.7 ml) was added to the
chilled reaction mix at a rate whereby the internal temperature
never exceeds 10.degree. C. After the addition was complete, the
mixture was removed from the ice bath and allowed to warm to room
temperature, generally over a period of 1-1.5 hours. A solution of
1 eq. Malonate 2.1.2 (20 g) and 0.1 eq. sulfuric acid dissolved in
toluene (80 ml) was then slowly added to the reaction mixture at a
rate such that the internal temperature never exceeds 25.degree. C.
(10-15 minutes). The reaction was sluggish at room temperature but
improved upon heating. On heating at 40.degree. C., a conversion of
.about.90% was attained after 20 hours, with an in-solution yield
of .about.62%.
[0110] The reaction mixture was cooled to room temperature and 0.1
eq. concentrated sulfuric acid (0.49 ml) added. 13.26 g acidic,
activated alumina (66 wt. %) was then added to the reaction mix and
stirred at room temperature for 1.5 hours to remove impurities,
particularly, it is believed amine salt impurities. GC analysis
before and after the acidic alumina treatment confirmed the removal
of impurities. The so formed slurry is filtered and the filtrate
up-stabilized with 0.05 eq. conc. sulfuric acid (0.295 .mu.l)
before being subjected to a rotary evaporator at 20-22.degree. C.
under high vacuum to remove toluene. The crude product was then
transferred to a distillation pot and up-stabilized with an
additional 0.05 eq. sulfuric acid before commencing distillation.
The pot was heated to 50.degree. C. and maintained at that
temperature under vacuum for at least 30-45 minutes. It is believed
that dimethylacetamide is produced as a byproduct and this step
will ensure its removal to avoid decomposition of the product. On
further heating, Methylidene Malonate 2.1.2 was recovered at a pot
temperature of 156.degree. C., a head temperature of 125.degree. C.
and a vacuum of 0.25 mmHg in a collection vessel containing 0.05
eq. sulfuric acid. The isolated monomer product was 89.5% pure by
GC analysis. A second distillation of the isolated product yielded
6 g (28%) of 98.8% pure Methylidene Malonate 2.1.2 monomer.
[0111] Portions of the isolated monomer were treated with neutral
alumina (WN-3, 6.5 pH) at 40.degree. C. for 20 minutes and
induction times tested for the treated and untreated monomer. The
alumina treatment resulted in the DMDEE induction time dropping
from 134 minutes for the untreated monomer to 37 minutes and less
than 5 minutes after treatment with at 6.7 wt % and 20 wt %,
respectively.
Example 13
Scavengers 2
[0112] Similar experiments were conducted using other scavengers
including A molecular sieves and ion-exchange resins such as Dowlex
Amberlyst 15. Results indicated that these too removed some of the
impurities, however the acidic alumina appeared to be more
effective.
Example 14
Malonate 2.2
[0113] Tetramethyldiaminomethane (TMDAM, 1.1 eq.) and acetonitrile
(5 volumes) were added to a round bottom flask and kept under
nitrogen. The reaction mixture was cooled to 0-5.degree. C. using
an ice-bath. Acetic anhydride (2.5 eq.) was added to the chilled
reaction mixture at a rate such that the internal temperature never
exceeded 10.degree. C. After the addition was complete, the
ice-bath was removed and the reaction was allowed to warm up to
20.degree. C. over a period of 1-1.5 hours. A solution of Malonate
2.2 (1 eq) and acid (trifluoroacetic acid) (0.1 eq.) was prepared
in acetonitrile (5 volumes) and was added slowly at a rate such
that the internal temperature never exceeded 25.degree. C. (time of
addition=10-15 minutes). The reaction was complete in two hours at
room temperature and achieve an in-solution conversion of 76%
Example 15
Cyanoacrylate
[0114] Tetramethyldiaminomethane (TMDAM, 1.1 eq.) and acetonitrile
(15 volumes) were added to a round bottom flask and kept under
nitrogen. The reaction mixture was cooled to 0-5.degree. C. using
an ice-bath. Acetic anhydride (2.5 eq.) was added to the chilled
reaction mixture at a rate such that the internal temperature never
exceeded 10.degree. C. After the addition was complete, the
ice-bath was removed and the reaction was allowed to warm up to
20.degree. C. over a period of 1-1.5 hours. A solution of Ethyl
Cyanoacetate (1 eq) and acid (sulfuric acid or trifluoroacetic
acid) (0.1 eq.) was prepared in acetonitrile (5 volumes) and was
added slowly at a rate such that the internal temperature never
exceeded 25.degree. C. (time of addition=10-15 minutes). The
reaction was complete in two hours at room temperature and achieve
an in-solution conversion of 99%.
[0115] Although the present invention has been described with
respect to aforementioned specific embodiments and examples, it
should be appreciated that other embodiments utilizing the concept
of the present invention are possible without departing from the
scope of the invention. The present invention is defined by the
claimed elements and any and all modifications, variations, or
equivalents that fall within the spirit and scope of the underlying
principles embraced or embodied thereby.
* * * * *