U.S. patent application number 13/752365 was filed with the patent office on 2013-08-01 for methylidene malonate 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 | 20130197264 13/752365 |
Document ID | / |
Family ID | 47714566 |
Filed Date | 2013-08-01 |
United States Patent
Application |
20130197264 |
Kind Code |
A1 |
Gondi; Vijaya Bhasker ; et
al. |
August 1, 2013 |
METHYLIDENE MALONATE PROCESS
Abstract
An improved process for the production of methylidene malonates
is attained by use of select iminium salt reactants.
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.: |
13/752365 |
Filed: |
January 28, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61591884 |
Jan 28, 2012 |
|
|
|
Current U.S.
Class: |
560/203 |
Current CPC
Class: |
C07C 67/317 20130101;
C07C 253/30 20130101; C07C 67/343 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: |
560/203 |
International
Class: |
C07C 67/343 20060101
C07C067/343 |
Claims
1. A method of producing methylidene malonates by reacting esters,
especially diesters, of malonic acid with certain iminium salts
under appropriate conditions and for an appropriate time period to
yield the corresponding methylidene malonate wherein the iminium
salts generally correspond to the formula ##STR00021## 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 H are in a ring
structure; provided that neither of R.sup.6 and R.sup.7 is a
hydrocarbon moiety comprising a tertiary carbon attached to the N
atom and X is an anion.
2. The method of claim 1 wherein R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently H or an alkyl, aryl, alkenyl or
alkynyl.
3. The method of claim 1 wherein X is a halogen, a non-nucleophilic
anion, and/or acidic anion.
4. The method of claim 1 wherein X is a halogen, a carboxylate or a
sulfonate.
5. The method of claim 1 wherein X is selected from 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, acetate, propionate, isobutyrate, pivalate,
sufate, bisulfate, perchlorate, SbCl.sub.6, SbCl.sub.3, and
SnCl.sub.5
6. The method of claim 1 wherein the maloriic acid ester has the
formula ##STR00022## wherein, in the case of the mono-esters, one
of R.sup.1 and R.sup.2 is H and the other a C.sub.1 to C.sub.18
hydrocarbon or heterohydrocarbon group, the latter having one or
more nitrogen, halogen, or oxygen atoms or, in the case of the
diester, both R.sup.1 and R.sup.2, which may be the same or
different, are each independently selected from C.sub.1 to C.sub.18
hydrocarbon or heterohydrocarbon groups, the latter having one or
more nitrogen, halogen, or oxygen atoms.
7. The method of claim 6 wherein R.sup.1 and R.sup.2 are both
hydrocarbon and/or heterohydrocarbon groups and represent a C.sub.1
to C.sub.10 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 or contain an ether, epoxide, halo, ester, cyano,
aldehyde, keto or aryl group.
8. The method of claim 6 wherein both R.sup.1 and R.sup.2 are
hydrocarbon or heterohydrocarbon groups wherein at least one
contains an ester linkage.
9. The method of claim 6 wherein 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 hydrocarbon or heterohydrocarbon group, the latter having
one or more nitrogen, halogen, or oxygen atoms
10. The method of claim 6 wherein the malonic acid ester is a
diester and a least one of R.sup.1 and R.sup.2 is a group is of the
formula: --(CH.sub.2).sub.n--COOR.sup.3 wherein R.sup.3 is
independently a C.sub.1 to C.sub.17 hydrocarbon or
heterohydrocarbon group, the latter having one or more nitrogen,
halogen, or oxygen atoms, and n is an integer of from 1 to 5.
11. The method of claim 10 wherein R.sup.3 is independently a
C.sub.1 to C.sub.6 lower alkyl and n is 1 or 2.
12. The method of claim 1 wherein the equivalent weight of iminium
salt to malonic acid ester is from 1:1 to 10:1.
13. The method of claim 1 wherein the equivalent weight of iminium
salt to malonic acid ester is from 1:1 to 6:1.
14. The method of claim 1 wherein the equivalent weight of iminium
salt to malonic acid ester is from 1:1 to 4:1.
15. The method of claim 1 wherein the iminium salt is formed
in-situ and the malonic acid ester is directly added to the iminium
reaction product.
16. The method of claim 15 wherein the in-situ reaction involves an
excess molar equivalent of the anhydride or acid chloride
activation agent.
17. The method of claim 15 wherein the iminim salt is formed by the
reaction of an acid halide or an acid anhydride with a
1,1-diaminoalkane.
18. The method of claim 1 wherein the reaction is performed in the
presence of a polar solvent.
19. The method of claim 1 wherein the reaction is performed in the
presence of a non-polar solvent and the anion of the iminium salt
is a carboxylate.
20. A method of producing methylidene malonates comprising the
steps of forming an iminium salt generally correspond to the
formula ##STR00023## 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; provided that neither
of R.sup.6 and R.sup.7 is a hydrocarbon moiety comprising a
tertiary carbon attached to the N atom and X is an anion, and
allowing the so formed iminium salt to react with a malonic acid
ester under appropriate conditions and for an appropriate time
period to yield the corresponding methylidene malonate.
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 an improved process for the
production of methylidene malonates as well as the methylidene
malonates produced thereby and the use thereof.
BACKGROUND
[0003] Methylidene malonates are compounds having the general
formula (I):
##STR00001##
wherein R.sup.1 and R.sup.2 may be the same or different and
represent a C.sub.1 to C.sub.18 hydrocarbon group or
heterohydrocarbon group having one or more nitrogen, halogen, or
oxygen atoms. Such compounds have been known for well over half a
century and their use, or potential use, in both organic synthesis
and polymer chemistry is well known. Similarly, the use of these
compounds as is or as a component of adhesives, including skin
bonding adhesive; molding materials; and the like is equally well
known. Yet, despite all the promise, these compounds have found
limited, If any, commercial success owing to the difficulty of
their production; the poor, though improving, yet still erratic,
yields; and the general instability of these compounds.
[0004] Numerous processes have been developed for the production of
methylidene malonates having a formula similar to or falling within
the formula of formula (I) above. Two of the earliest methods for
the production of methylene dialkyl 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. The former
was unsatisfactory due to very low yield and expensive starting
materials. The latter, though periodically giving better yields
than the iodide process, gave relatively poor yields and, more
critically, was widely inconsistent from batch to batch, even under
the same conditions.
[0005] Despite this inconsistency, early efforts continued to focus
on the formaldehyde method. One of the most widely practiced
formaldehyde methods consisted of reacting diethyl malonate with
formaldehyde in glacial acetic acid in the presence of a metal
acetate catalyst to produce the diethyl methylidene malonate. The
latter was subsequently recovered by distillation following removal
of the catalyst by filtration and separating off the solvent. These
efforts continued to frustrate and various modifications and
iterations of this basic process were developed all in an effort to
improve the consistency and yields associated therewith.
[0006] 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. Bachman et
al. indicate that their process is advantageously carried out in
the presence of inhibitors of the polymerization of monomeric vinyl
compounds. Suitable inhibitors are said to include the copper salts
such as copper chloride and, especially, copper salts of carboxylic
acids such as cupric acetate, iron salts such as ferric acetate,
and phenols, such as hydroquinone. These are added to the solution
mix before the addition of the malonate.
[0007] Although Bachman et al. reported yields of up to 72%, the
results presented are conversion rates, not yields. Looking at the
actual yields of the process, Bachman et al.'s best performance was
a yield of 43% with all others being less than 25%. Though Bachman
et al. speak of high purity and the ability to recover pure
material, they never present any details or data as to what those
purities or recoveries were. In any event, Bachman et al. reported
that the isolated product, upon standing, polymerized in a day to
several weeks time depending upon the purity of the isolated
material, which polymer was then heated to facilitate the reversion
of the polymer to the monomer.
[0008] 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 is 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.
[0009] Coover et al. (U.S. Pat. No. 3,221,745 and U.S. Pat. No.
3,523,097) took 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
sub.sub.jected to vacuum distillation at low temperature to
separate an allegedly high purity methylidene malonate, though with
a low yield. According to Coover at 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.
[0010] In discussing the critical need for high purity materials,
Coover at al. draw particular attention to the extreme sensitivity
of their monomers to the presence of even small amounts of acidic
and basic impurities, the former inhibiting polymerization leading
to sluggish and ineffective adhesive activity and the latter
accelerating polymerization leading to unstable and useless
products. They indicate that the amount of such impurities should
not exceed 100 ppm, preferably not more than 10 ppm. Unfortunately,
other than discussing its limitations with respect to the acidic
and basic impurities, and despite its contention of high purity
materials, Coover at al. never provide any data pertaining to the
purity of their materials. Clearly, though, these materials are not
"pure" materials inasmuch as Coover at al., like the others before
them and since, require redistillation of the "pure"
distillate.
[0011] Additionally, although suggesting that their high purity
materials "have reasonably good" stability when stored in bulk,
they recommend the addition of low levels, 0.0001 to 0.01 weight
percent, of a polymerization inhibitor to the monomer materials in
order to increase storage stability. Suitable polymerization
inhibitors are said to include sulfur dioxide, hydroquinone, nitric
oxide, organic acids, boron trifluoride, hydrogen fluoride, stannic
chloride, ferric chloride, and organic anhydrides. To assist with
cure, particularly cure speed. Coover et al. also suggest the
addition of cure accelerators or catalysts to their formulated
adhesives, but cautions against adding them too early as they would
cause premature polymerization.
[0012] Despite the efforts that had been made in advancing the
production of methylidene malonates, still no viable method was
found. Instability, poor yields, low purity, inconsistency in
production, etc. continued to plague this technology. Yet, effort
continued and eventually led to multi-step processes in which
certain unsaturated molecules served as platforms 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. These efforts, despite their gains in yield and/or
purity, still failed to achieve commercial success.
[0013] 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 he 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. The resultant
crude products were then subjected to multiple distillations,
preferably lower temperature distillations under vacuum, to recover
the purified methylidene malonate. Despite the claim to high
yields, their crude yields were generally in the range of 21-71%,
more importantly, nothing is said with respect to the purity of the
material obtained.
[0014] Though the Bru-Magniez technology showed promise,
instability and inconsistency continued to plague their effort to
commercialize these materials. Indeed, owing to the high
instability of the overall production process and final products,
they reported a high failure rate and of those batches that
actually survived through crude distillation, the resultant
products had to be stored in a freezer even after stabilizing with
upwards of 50,000 ppm SO.sub.2 due to their high instability and
spontaneous polymerization,
[0015] Malofsky et al. (WO 2010/129068) solved some of the problems
associated with process instability of the Bru-Magniez
Retro-Diels-Alder adduct process by using select polymerization
inhibitor systems in association with the stripping step and,
preferably, using the same or different select polymerization
inhibitor systems in association with the subsequent isolation and
purification steps. Although the stabilizer systems and
stabilization techniques of Malofsky et. al. markedly improved the
adduct processes, providing greater stability and consistency to
the process as well as the final products thereot these processes
still require harsh conditions, including temperatures up to
180.degree. C.; prolonged isolation and purification processes,
requiring at least two distillations (three if one employs
distillation to remove the crude liquid product from the solids of
the reaction mix) to achieve suitable purity; and high costs: the
anthracene adduct route is comparatively expensive and while high
purities are attained, the repeated purification steps results in
overall loss in yield.
[0016] More recently, 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, protonated imines, 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:
##STR00002##
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. McArdle then employs these iminium salts in the production of
electron deficient olefin monomers by reacting the same with
certain compounds containing a methylene linkage having at least
one electron withdrawing substituent attached thereto where the
electron withdrawing substituent is selected from nitrile,
carboxylic acids, carboxylic esters, sulphonic acids, ketones and
nitro. Employing ethyl cyanoacetate as the certain compound for
from 30 minutes to an hour with PRIMENE iminium methane sulfonate
resulted in yields and purity of 64%, 90% pure with
methanesulfonate anion; 64%, 80% pure with benzenesulfonates anion;
46%, 77% pure with a 1:1 mixture of methanesulfonates and sulfuric
acid anions. Similar results, 61%, 80% purity, were attained when
the ethyl cyanoacetate was replaced with malononitrile after just
20 minutes reaction time. However, replacement of the ethyl
cyanoacetate with dimethyl malonate resulted in yields of only 30%
after an hour, with no indication as to purity. Use of a different
iminium salt, PRIMENE 81-R iminium-MSA, produced better results,
65% yield and 90% purity with malononitrile, but only a 50% yield
of 50% purity when employed with dimethyl malonate.
[0017] Variations and refinements of the iminium process are taught
in McArdle et al. (U.S. Pat. App. Pub. 2010/0210788) and Bigi et
al. (U.S. Pat. No. 7,718,821) where each found generally similar
results with their specific iminium salts. Of particular interest
in Bigi et. al. is the comparative evaluation of their iminium salt
with dimethylmethylideneammonium iodide, also referred to as
Eschenmoser's salt, in a reaction with ethyl cyanoacetate. The
latter salt is said to have resulted in a low yield, though none is
specified, whereas the former gave yields of in excess of 60%:
thus, showing the importance of the select iminium salts.
[0018] 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 can be
difficult to remove. 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.
[0019] In summary, processes for the direct preparation of
methylidene malonates from formaldehyde give low yields and
inconsistent results. Adduct processes improve yields and purity,
but still suffer from instability, inconsistency and high costs.
Processes in which select stabilizer systems are employed improves
on the instability and inconsistency issues but still suffer from
high costs, not just in materials costs and processing time but in
terms of the overall yield and purity perspective, especially in
view of the need for multiple purification steps which improve
purity but lower yield. McArdle and then Bigi provide an
alternative direction which may address some of the issues but
still suffer from high materials and processing costs and
questionable, if not low, yields and purities.
[0020] Thus, despite decades and decades of effort and the plethora
of processes and process variants and improvements developed over
this extended period, 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. There is still a
need for a low cost, efficient and consistent process for the
production of methylidene malonates in order for these materials to
find commercial utility. Specifically, if methylidene malonates are
ever to realize their commercial potential and promise,
particularly in applications other than niche, high value added
applications whose pricing can better offset the losses, costs and
low yields of current processes, improved processes must be
developed, especially processes that provide for more consistent
and predictable yields with high purity and at lower costs.
[0021] In following, there is a need for processes for the
production of methylidene malonates that are not fraught with
process failures, widely varying yields, unstable products, and
unintended polymerizations and other by-products such as glutarates
and/or dimers, trimers, oligomers and/or polymers of the
methylidene malonates. While low levels of the dimers, trimer,
oligomers and/or polymers may be tolerated, depending upon the
end-use application, it is still best to avoid or certainly lessen
their presence in the final products.
[0022] Furthermore, there is a need for a process which is suitable
for the production of many different methylidene malonates, not
just simple dialkyl substituted monomers. In this respect, it is to
be appreciated that the use of starting materials wherein the
diester of malonic acid contains another functional group, which
may be a heteroatom containing functional group, particularly the
ester functional group, can adversely affect the production of the
corresponding methylidene malonates, making it especially difficult
to do so. Similarly, difficulty is encountered where one intends to
add or modify such functionality in-situ in-process. Additionally,
these additional functional groups may promote undesired and
competitive reactions to the formation of the methylidene malonate.
Thus, there is a need for a general process suitable for the
preparation of methylidene malonates from diesters of malonic acid
containing one or more other functional groups, especially one or
more ester groups.
SUMMARY OF THE INVENTION
[0023] The present invention provides for improved processes for
the production of methylidene malonates and for the purification
and isolation thereof as well as for the methylidene malonates
formed thereby. The improvements provide for a process that
produces methylidene malonates quickly and efficiently, in high
yield and purity, and at relatively low cost.
[0024] According to a first aspect of the present teachings there
is provided a method of producing methylidene malonates wherein
esters, especially diesters, of malonic acid are reacted with
certain iminium salts under appropriate conditions and for an
appropriate time period to yield the corresponding methylidene
malonate. The `minium salts generally correspond to the formula
II
##STR00003##
wherein R.sup.4, R.sup.3, 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; provided that neither of R.sup.6 and
R.sup.7 (inclusive of a ring structure comprising one or both) is a
hydrocarbon moiety comprising a tertiary carbon attached to the N
atom. 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 a conjugate base of an acid, most
preferably a halogen, a carboxylate or a sulfonate.
[0025] Preferred iminium salts are those wherein R.sup.4 and Ware
both 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.
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
dialkyl methylidene ammonium carboxylates, particularly the dialkyl
methylidene ammonium acetates and haloacetates.
[0026] According to a second and preferred aspect of the present
teachings, the aforementioned iminium salt is formed in-situ before
being combined with the malonic acid ester or diester. Although one
may purify or isolate, in whole or in part (e.g., to concentrate
the reaction mix by removing solvent it any), the so formed iminium
salt, it is preferable to merely combine the iminium salt reaction
product with the malonic acid ester or diester as is. Processes for
the production of the iminium salts are well known and fairly
simple to prepare. A preferred process involves reacting a
tetraaklyldiaminomethane with a strong acylating reagent,
especially an acid halide or an acid anhydride, at lowered
temperatures. For example, dimethylmethylideneammonium carboxylate
is prepared by the reaction of tetramethyldiaminomethane with a
carboxylic acid anhydride. Similarly, dimethylmethylideneammonium
halide is prepared by the reaction of tetramethyldiaminomethane
with an acid halide, especially an acid chloride, most especially a
carboxylic acid chloride.
[0027] In accordance with the present teachings, the
dialkylalkylideneammonium carboxylate or the
dialkylalkylideneammonium halide can then be combined with and
reacted with a diester of malonic acid, without isolation of the
carboxylate or halide salt, to form the desired methylidene
malonate monomer. The malonic acid diesters may be symmetric, i.e.,
both ester groups may the same, or asymmetric with two different
ester groups, one or both of which may also include or be
substituted with another functional group, especially an ester
group.
DETAILED DESCRIPTION
[0028] In accordance with the present teachings there is provided a
process, generally an improved process as compared to traditional
methods, for the production of methylidene malonates. This process
generally comprises the reaction of malonic acid esters and,
especially, diesters with certain `minium salts. In accordance with
a second aspect of the present teachings, there is provided a
process, generally an improved process as compared to traditional
methods, for the production of methylidene malonates wherein the
iminium salt is formed in-situ, with or without purification and/or
isolation, before combining the same with the malonic acid ester or
diester.
[0029] Malonic acid esters and diesters are generally of the
formula III:
##STR00004##
wherein, in the case of the mono-esters, one of R.sup.1 and R.sup.2
is H and the other 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 or, in the case of the diester, both
R.sup.1 and R.sup.2, which may be the same or different, are each
independently selected from 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 groups, the latter having one or more nitrogen,
halogen, or oxygen atoms. Preferably R.sup.1 and R.sup.2 are 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.5 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 IV:
--(CH.sub.2).sub.n--COOR.sup.3 IV
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 to C.sub.3, lower alkyl and
n is an integer of from 1 to 5, preferably 1 or 2.
[0030] 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
V:
##STR00005##
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.
[0031] The foregoing esters and diesters of malonic acid are
reacted with certain iminium salts to form the desired methylidene
malonates. The iminium salts generally correspond to the formula
II
##STR00006##
wherein R.sup.4, R.sup.3, 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; provided that neither of R.sup.6 and
R.sup.7 (inclusive of a ring structure comprising one or both) is a
hydrocarbon moiety comprising a tertiary carbon attached to the N
atom. Generally speaking, if a hydrocarbon or heterohydrocarbon,
R.sup.4, R.sup.6, 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.6,
R.sup.6 and R.sup.7 are each independently H or an alkyl, alkenyl
or alkynyl, most preferably alkyl. 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.
[0032] Preferred iminium salts are those wherein R.sup.4 and
R.sup.5 are each independently hydrogen H 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.1 to C.sub.6 lower alkyl, and X is a halogen ore
a substituted or unsubstituted carboxylate. Especially preferred
iminium salts are those wherein R.sup.4 and R.sup.5 are hydrogen or
C.sub.1 to C.sub.3 lower alkyl and R.sup.6 and R.sup.7 are both the
same C.sub.1 to C.sub.3 lower alkyl. Most preferred are the dialkyl
alkylideneammonium chlorides and carboxylates, particularly the
dialkyl alkylideneammonium acetates and haloacetates. For purposes
of clarity, "alkyidene" refers to that portion of the iminium
compound comprising:
##STR00007##
Thus, an iminium compound wherein R.sup.4 and R.sup.6 are H and
R.sup.6 and R.sup.7 are methyl would be referred to as a
dimethylmethylidene ammonium compound.
[0033] 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.
7,569,719, all of which are incorporated herein by reference in
their entirety.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] Another route for 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
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.
[0038] Yet another route for preparing the iminium salts is the
direct reaction of certain diamino compounds, such as the
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. An especially
preferred process of this route employs N,N,N',N'-
tetraalkyl-1,1-diaminoaklanes, such as tetramethyldiaminomethane
and tetraethyldiaminemethane, as the starting amine.
[0039] 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.
[0040] Alternatively, and again as noted above, it is also to be
appreciated that the iminium salts may also 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 malonic acid ester
or diester 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
malonic acid ester or diester.
[0041] 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 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, bromide chloride,
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 to
the diamine. For example, the molar ratio (activator:diamine) of
1:1 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.
[0042] 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.
[0043] 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 II
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.
[0044] 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.,
Eschenmose's salt).
[0045] 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 1:1 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 tetraalkyldiamino methane
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 and with cooling. 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.
[0046] 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.
[0047] The methylidene malonate is prepared by combining the
iminium salt or the in-situ formed iminium salt reaction product
with the malonic acid ester or diester, Although either may be
added to the other, it is preferable that the diester is added to
the iminium salt or iminium salt reaction product. 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 a viscosity increase of the formed
methylidene malonate 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.
[0048] 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 malonic acid
ester or diester 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.
[0049] Although not a requirement, it is preferred that the
reaction of the diester of malonic acid with the
dimethylmethylideneammonium carboxylate 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.
[0050] The solvents employed may be polar or non-polar solvents.
Exemplary polar solvents include, but are not limited to, DMF, THF,
acetonitrile, DMSO, IPA, ethanol and the like. Exemplary non-polar
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, non-polar
solvents do not provide as optimal a reaction performance as the
polar solvents, 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 non-polar solvent before performing any steps to
isolate and/or purify or treat the methylidene malonate monomer.
Furthermore, where the 1,1-disubstituted reaction product is heat
sensitive, whereby high temperatures polymerize, dimerize and/or
degrade the 1,1-disubstituted ethylene monomer produced, it is
preferred to use the lower boiling point solvents for those
processes where subsequent work-up involves higher temperatures
needed for distillation, evaporation, etc., so as to avoid the
aforementioned issues.
[0051] Generally speaking the amount of solvent to be used is from
about 5.times. to about 30.times., preferably about 10.times. to
about 20.times., most preferably, on an economic and environmental
basis, about 15.times. to about 20.times., the amount of malonic
acid ester. Thus, for example, 1 gram of malonic acid ester would
be reacted in 20 ml of solvent.
[0052] 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.
[0053] Likewise, though not a requirement, it is preferred that the
reaction of the diester of malonic acid with the
dimethylmethylideneammonium carboxylate 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. The presence of the acid or
anhydride is believed to stabilize the methylidene malonate monomer
product from polymerization. Suitable acids and anhydrides for
preventing the polymerization of methylidene malonate 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.
[0054] Additional stabilization may be imparted to the reaction
mix, especially following or towards the end of the reaction,
and/or in association with any subsequent work-up to isolate and/or
purify the reaction product, 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.
[0055] The methylidene malonates 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 methylidene malonate 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.
[0056] As noted, it may be desirable to isolate the methylidene
malonate 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.
[0057] 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.
[0058] 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 methylidene malonate 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
methylididene malonate 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
methylidene malonate. Preferred or optimal stabilizers or
combinations of stabilizers as well as the amount thereof to use
can be determined by simple experimentation
[0059] 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 preferably80% 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.
[0060] Thus, while there may be, and most likely is, some loss in
overall yield as a result of the purification process, especially
if multiple fractionation processes are employed or the same
process is repeated one or more times, the purity of the product
significantly improves. This is especially important from a
commercial perspective as the purity of the methylidene malonate is
has a significant impact upon and correlates with its utility and
performance. Specifically, as discussed in Coover et al. (U.S. Pat.
No. 3,221,745) and as found by Applicants, even minor amounts of
impurities impair their utility, especially the cure or
polymerization characteristics of these monomers. Concern with the
presence and amount of impurities and byproducts is even more
paramount, if not an absolute use limiting factor, in the case of
methylidene malonates intended for medical applications, especially
skin bonding applications, e.g., skin bonding adhesives, or other
applications that may require its use in the human body.
[0061] Because the methylidene malonates prepared by the improved
process have fewer and different impurities than methylidene
malonates prepared by previously known processes, they are more
suitable for certain applications. Methylidene malonates prepared
in accordance with the present teachings, especially as a result of
the reaction of a diester of malonic acid with a
dimethylmethylideneammonium carboxylate, are found to have a
different impurity profile than those formed from the more
traditional methods described in the Background, especially those
formed by the adduct processes. Initial studies suggest that these
impurities have less of an impact on cure or polymerization and
performance, making the resultant methylidene malonates especially
suitable for commercial applications, including medical
applications.
[0062] Perhaps one of the most significant changes and improvements
noted in the methylidene malonate reaction products of the present
teaching is the absence or at least marked reduction in dimer. The
presence of methylidene malonate dimer is and has been a
significant impediment to commercial success for these
monomers.
[0063] In any event, the methylidene malonates formed by the
improved process of the present invention 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
[0064] 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.
[0065] Iminium Salts
[0066] A plurality of preformed and in-situ formed iminium salts
were employed. The general structures of these salts were as
follows:
[0067] Halogen Based Salts:
##STR00008##
[0068] Carboxylate Salts:
##STR00009##
[0069] Sulfonate Salts:
##STR00010##
[0070] Monomer
[0071] 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:
##STR00011##
[0072] DMDEE Test
[0073] 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:
##STR00012##
[0074] 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, Le., 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)
[0075] 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.
##STR00013##
EXAMPLE 2
Reverse Addition
[0076] 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
[0077] Malonate 2.1.2 dissolved in DMF was slowly added to 3 eq. of
EIS (lminium 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
[0078] 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 1 hr to 46
55 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 hrs 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
The resifurther addition n 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)
[0079] A series of experiments were run to assess both the ability
to use an in-situ formed Eschenmoser's salt, in this case
Eschenmosers 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 Eq of Reaction Percentage of Monomer Run
AcCl Time (hr) Conversion (%) 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
[0080] 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.
[0081] 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
[0082] 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 Time Conversion In-Solution Run
(eq) Chloride (eq) (hr) (%) Yield (%) 1 6 ##STR00014## 18 98 85 2 3
##STR00015## 20 >99 91 3 2 ##STR00016## 20 90.5 82 4 3
##STR00017## 20 98.6 80 5 3 ##STR00018## 20 97.5 89.9 6 3
##STR00019## 20 99 94.4 7 2 ##STR00020## 20 78.5 --
[0083] 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 and Work Up to Remove Ammonium
Salts
[0084] 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.
[0085] 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-solution yield of 80%.
EXAMPLE 9
Polar and Non-Polar Solvents with Acid Anhydride
[0086] A series of experiments were run with polar (acetonitrile)
and non-polar (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 acid 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 com.sub.pletion, generally 15-20 hours.
[0087] 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
Acetonitrile 68 acetic anhydride E In-situ synthesis from Toluene
27 isobutyric anhydride F In-situ synthesis from Toluene 89%
trimethylacetic anhydride (conversion)
EXAMPLE 10
Use of Iminium I
[0088] 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'-tetraethyldiaminomethane 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 67%.
EXAMPLE 11
Use of Iminium J
[0089] 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%.
[0090] 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.
* * * * *