Patent Grant
7659423
1. Field of the Invention
This invention relates to a process for producing electron deficient olefins, such as 2-cyanoacrylates, in a polar solvent, such as an ionic liquid.
2. Brief Description of Related Technology
Cyanoacrylate adhesives are known for their fast adhesion and ability to bond a wide variety of substrates. They are marketed as “super glue” type adhesives. They are useful as an all-purpose adhesive since they are a single component adhesive, very economical as only a small amount will do, and generally do not require any equipment to effectuate curing.
Traditionally, cyanoacrylate monomers are produced by way of a Knoevenagel condensation reaction between a formaldehyde precursor, such as paraformaldehyde, and an alkyl cyanoacetate with a basic catalyst. During the reaction, monomer forms and polymerises in situ to a prepolymer that is subsequently thermally cracked or depolymerised into the pure constituent monomer. This approach has remained essentially the same although various improvements and variants have been more recently introduced. See e.g. U.S. Pat. Nos. 6,245,933, 5,624,699, 4,364,876, 2,721,858, 2,763,677 and 2,756,251.
In U.S. Pat. No. 3,142,698, the synthesis of difunctional cyanoacrylates using a Knoevenagel condensation is described. However the ability to thermally depolyerise the resulting, now crosslinked, prepolymer in a reliable and reproducible manner to produce pure difunctional monomers in high yields is questionable [see J. Buck, J. Polym. Sci., Polym. Chem. Ed., 16, 2475-2507 (1978), and U.S. Pat. Nos. 3,975,422, 3,903,055, 4,003,942, 4,012,402, and 4,013,703].
A variety of other processes for producing cyanoacrylate are known, and some of which are described below.
U.S. Pat. No. 5,703,267 defines a process for producing a 2-cyanoacrylic acid which comprises subjecting a 2-cyanoacrylate and an organic acid to a transesterification reaction.
U.S. Pat. No. 5,455,369 defines an improvement in a process for preparing methyl cyanoacrylate, in which methyl cyanoacetate is reacted with formaldehyde to form a polymer that is then depolymerized to the monomeric product, and in which the purity of yield is 96% or better. The improvement of the '369 patent is reported to be conducting the process in a poly(ethyelene glycol) diacetate, dipropionate, or dibutyrate, having a number average molecular weight of 200-400, as the solvent.
U.S. Pat. No. 6,096,848 defines a process for the production of a biscyanoacrylate, which comprises the steps of esterifying a 2-cyanoacrylic acid or transesterifying an alkyl ester thereof to obtain a reaction mixture; and fractionally crystallizing the reaction mixture to obtain the biscyanoacrylate.
U.S. Pat. No. 4,587,059 defines a process for the preparation of monomeric 2-cyanoacrylates comprising the steps of (a) reacting (i) a 2,4-dicyanoglutarate with (ii) formaldehyde, cyclic or linear polymers of formaldehyde, or a mixture thereof, in the presence of between about 0.5 and about 5 mols of water per mol of 2,4-dicyanoglutarate, at an acid pH of about 3 to slightly less than 7, and at a temperature of about 70 to about 140, to form an oligomeric intermediate product, and (b) removing water that is present from step (a) and thermolyzing the oligomeric intermediate product for a period of time sufficient to effect its conversion to monomeric 2-cyanoacrylates.
Commercial production of cyanoacrylate monomers ordinarily relies on the depolymerisation of a prepolymer formed under Knoevenagel reaction conditions. Previous efforts to produce cyanoacrylates explored alternative routes that do not rely on depolymerisation, for instance in the synthesis of difunctional monomers that cannot be reliably accessed by depolymerisation, or for the synthesis of esters not easily accessed by depolymerisation.
Still today the Knoevenagel condensation reaction is believed to remain the most efficient and prevalent commercial method for producing high yields of monofunctional cyanoacrylates. Nevertheless, it would be desirable to not have to resort to thermally induced depolymerisation of a prepolymer produced by the Knoevenagel condensation reaction. This prospect would also enable facile access to highly useful difunctional monomers, such as so-called bis-cyanoacrylates or hybrid materials of cyanoacrylate and other polymerisable or reactive functions.
The Knoevenagel reaction is well known not only for its usefulness in the manufacture of cyanoacrylates, but also (and perhaps more so) for its immense potential generally in the synthesis of electrophilic olefins from active methylene and carbonyl compounds [G. Jones, Organic Reactions, Vol. XV, 204, Wiley, New York (1967)]. A wide range of catalysts have been employed in carrying out this reaction, each affording variable yields of olefins. The reaction is catalysed by weak bases under homogeneous conditions. More recently, heterogeneous catalysts have been use, many of which include inorganic materials such as clays and zeolites [F. Bigi et al., J. Org. Chem., 64, 1033 (1999)]. These materials are environmentally benign and have been used because they are ditopic in nature, some containing both acidic and basic sites, while others are soley acidic or soley basic. Some Lewis acid catalysts have also been employed in the Knoevenagel reaction [B. Green et al., J. Org. Chem., 50, 640 (1985); P. Rao et al., Tett. Lett., 32, 5821 (1991)]. Since bases are generally active nucleophiles and cyanoacrylate monomer is highly susceptible to initiation of polymerisation by active nucleophiles, it is not possible to exploit base catalysed Knoevenagel synthesis of cyanoacrylate monomer without polymerisation occurring. And while acid catalysed Knoevenagel condensation reactions to form cyanopentadienoate monomers (related to cyanoacrylates) are known (see e.g. U.S. Pat. No. 6,291,544), these routes do not lead to the direct synthesis of cyanoacrylate monomers per se.
The Knoevenagel reaction also liberates water during the condensation of aldehydes with reactive methylene compounds, and neutral and basic water is well known to initiate polymerisation of cyanoacrylate monomers.
The efficiency of the Knoevenagel reaction is also known to be highly solvent dependent and that usually dipolar aprotic solvents, like dimethylformamide or dimethylsulfoxide, or especially useful in this condensation, because the second step, a 1,2-elimination has been reported to be inhibited by protic solvents [L. Tietze and U. Beifuss, Comprehensive Organic Synthesis, B. Trost et al., eds., Pergamon Press, Oxford, Vol. 2, Chapter 1.11, 341 (1991)]. The aforementioned solvents are toxic, teratogenic and suspected carcinogens, and can initiate cyanoacrylate polymerisation, thus their usage is disfavoured on a commercial scale.
Notwithstanding the reported inhibition by protic solvents, various authors have found that the Knoevenagel reaction easily occurs in protic media and also in water, even though this reaction remarkably involves a net dehydration [see e.g. F. Bigi et al., J. Org. Chem., 64, 1033 (1999), P. Laszlo, Ac Chem. Res., 19, 121 (1986), K. Kloestra et al., J. Chem. Soc., Chem. Commun., 1005 (1995), P. Lednor et al., J. Chem. Soc., Chem. Commun., 1625 (1991), and F. Bigi et al., Tett. Lett., 40, 3465 (1999)].
Recently there have been reports of the use of polar aprotic and protic solvents, including water, in uncatalysed Knoevenagel reactions leading to excellent yields and selectivities in the formation of products dervied from malononitrile and mainly aromatic aldehydes, although some aliphatic aledhehydes were reported on [F. Bigi et al., Green Chem., 2, 101 (2000)]. The use of water as a solvent in organic chemistry has received increasing attention in the past decade [see e.g. R. Breslow, Ac Chem. Res., 24, 159 (1991) and Li, Chem. Rev., 93, 2023 (1993)], however a large excess of neutral and basic aqueous reaction media would initiate polymerisation in the Knoevenagel synthesis of cyanoacrylate monomers even though this may offer other benefits since water is an environmentally benign, non flammable, and relatively inexpensive solvent. Thus a depolymerisation step is still required to yield pure monomer.
A highly desirable goal would be to find a solvent with some of the characteristics of water that would encourage high yields and selectivities and preferably act as a solvent-catalyst for the Knoevenagel reaction of electron deficient olefins, such as cyanoacrylates, without resort to a depolymerisation step. If necessary, acidic (e.g. Lewis) catalysts may be used in conjunction with such a solvent, as could common dehydrating agents that would react with water liberated from the Knoevenagel reaction proper.
Several publications have shown that replacing organic solvents by ionic liquids can lead to improvements in well known procedures [T. Welton, Chem Rev., 99, 2071 (1999), D. Morrison et al., Tet. Lett., 42, 6053 and 6097 (2001), and M. Smietana et al., Org. Lett., 3, 1037 (2001)]. Indeed, ionic liquids have been used with some success as solvents in Knoevenagel reactions. For example, n-butyl pyridinium nitrate has been used as a solvent to replace conventional organic solvents in the Knoevenagel condensation of various carbonyl substrates with active methylene compounds [Y-Q Li et al., Chinese Chem. Letts., 14, 5, 448 (2003)]. The ionic liquid, 1-butyl-3-methylimidiazolium chloroaluminate, has been used in the synthesis of electrophilic alkenes via the Knoevenagel condensation [J. Harjani et al., Tet. Lett., 43, 1127 (2002)]. Functionalised ionic liquid solvents have also been used in Knoevenagel reactions [X-M Xu et al., J. Org. Chem., 24(10), 1253 (2004)]. The use of ionic liquids as solvents for Knoevenagel condensation in the presence of specific catalysts for this reaction is also known [Su et al., Synthesis, 4, 555 (2003)].
Recently, J. S. Yadav et al., Phosphane-Catalyzed Knoevenagel Condensation: A Facile Synthesis of α-Cyanoacrylates and α-Cyanonitriles”, Eur. J. Org. Chem., 546-551 (2004) reports of the use of triphenylphosphane [sic, triphenylphosphine] as a catalyst for the Knoevenagel condensation of aldehydes with acidic methylene compounds, such as ethyl cyanoacetate and malonitrile, to afford substituted olefins in an efficient manner under mild and solvent-free conditions. Triphenyphosphine is a known initiator for the polymerization of 2-cyanoacrylates.
However, to date, it is not believed that any one has investigated the synthesis of cyanoacrylates or other electron deficient olefins using an ionic liquid as a solvent in the Knoevenagel condensation reaction.
The present invention provides a direct or “crackless” synthesis of electron deficient olefins, such as cyanoacrylate monomers, using polar or aprotic media, such as ionic liquids. The synthesis hereby provided may be catalysed or uncatalysed, and conventionally is called a Knoevenagel condensation reaction.
The present invention provides a process for the preparation of a reactive electron deficient olefin. In one aspect, the invention includes the steps of:
(a) providing as reactants an aldehyde compound having the structure R—CH═O, where R is hydrogen or vinyl and a compound 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, in a solvent comprising an ionic liquid;
(b) reacting the mixture of reactants under appropriate conditions and for a time sufficient to yield a reactive electron deficient olefin; and
(c) separating from the mixture the so formed reactive electron deficient olefin to yield the reactive electron deficient olefin substantially free from reactants.
In another aspect, the invention includes the steps of:
(a) providing as reactants an aldehyde compound having the structure R—CH═O, where R is hydrogen or vinyl and a compound 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, in a solvent comprising a salt whose melting point is less than 100° C., which in its molten form contains only ions;
(b) reacting the mixture of reactants under appropriate conditions and for a time sufficient to yield a reactive electron deficient olefin; and
(c) separating from the mixture the so formed reactive electron deficient olefin to yield the reactive electron deficient olefin substantially free from reactants.
In yet another aspect, the invention provides a process for the preparation of a 2-cyanoacrylate ester. The steps of this process include
(a) providing as reactants an aldehyde compound (or a source of an aldehyde compound) having the structure R—CH═O, where R is hydrogen and a compound containing a methylene linkage having at least one nitrile and at least one carboxylic ester attached thereto, in a polar solvent;
(b) reacting the mixture of reactants under appropriate conditions and for a time sufficient to yield a 2-cyanoacrylate ester; and
(c) separating from the mixture the so-formed 2-cyanoacrylate ester to yield 2-cyanoacrylate ester substantially free from reactants.
In any of these aspects, the process may be conducted with or without added catalyst. When a catalyst is added, desirably the catalyst should be one that is not a soley basic nucleophilic. Thus, acidic system would be preferred and a ditropic system may be used, as well.
As noted above, the present invention provides a process for the preparation of a reactive electron deficient olefin. In one aspect, the invention includes the steps of:
(a) providing as reactants an aldehyde compound having the structure R—CH═O, where R is hydrogen or vinyl and a compound 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, in a solvent comprising an ionic liquid;
(b) reacting the mixture of reactants under appropriate conditions and for a time sufficient to yield a reactive electron deficient olefin; and
(c) separating from the mixture the so formed reactive electron deficient olefin to yield the reactive electron deficient olefin substantially free from reactants.
In another aspect, the invention includes the steps of:
(a) providing as reactants an aldehyde compound having the structure R—CH═O, where R is hydrogen or vinyl and a compound 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, in a solvent comprising a salt whose melting point is less than 100° C., which in its molten form contains only ions;
(b) reacting the mixture of reactants under appropriate conditions and for a time sufficient to yield a reactive electron deficient olefin; and
(c) separating from the mixture the so formed reactive electron deficient olefin to yield the reactive electron deficient olefin substantially free from reactants.
In yet another aspect, the invention provides a process for the preparation of a 2-cyanoacrylate ester. The steps of this process include
(a) providing as reactants an aldehyde compound (or a source of an aldehyde compound) having the structure R—CH═O, where R is hydrogen and a compound containing a methylene linkage having at least one nitrile and at least one carboxylic ester attached thereto, in a polar solvent;
(b) reacting the mixture of reactants under appropriate conditions and for a time sufficient to yield a 2-cyanoacrylate ester; and
(c) separating from the mixture the so-formed 2-cyanoacrylate ester to yield 2-cyanoacrylate ester substantially free from reactants.
In any of these aspects, the process may be conducted with or without added catalyst, as noted above.
Thus, as an initial reactant in the inventive processes are aldehyde compounds having the structure R—CH═O, where R is hydrogen or vinyl. The aldehyde compound may be an aldehyde itself or a source of an aldehyde, such as one that yields an aldehyde like formaldehyde under reaction conditions. The aldehyde compound in a desirable embodiment includes formaldehyde (or a source thereof, such as paraformaldehyde), 1,3,5-trioxane, or vinyl aldehydes such as acrolein.
As a second reactant in the inventive processes are compounds containing a methylene linkage having at least one electron withdrawing substituent attached thereto. In these compounds, the electron withdrawing substituent is selected from nitrile, carboxylic acids, carboxylic esters, sulphonic acids, ketones and nitro. In a desirable embodiment, these compounds have two or more electron withdrawing substituents, which may be the same or different, such as nitrile and carboxylic acid ester.
Representative examples include malononitrile, malonic acid and its esters, ethyl nitroacetate, cyano acetic acid and its esters, 4-cyclopentene-1,3-dione, cyclopentane-1,3-dione, 4-cyclohexene-1,3-dione, cyclohexane-1,3-dione, 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), and tetronic acid, some of which are commercially available for instance from Aldrich Chemical Co. A particularly desirable example is 2-cyanoacetate.
The structures below illustrate the products that would result from a Knoevenagel reaction involving paraformaldehyde and/or acrolein using the above reactants.
Here, when a source of formaldehyde is used n is 0 in structure (I) and X and Y are nitrile, carboxylic acid, carboxylic acid esters, or X is nitro and Y is carboxylic acid ester, or X is nitrile and Y is carboxylic acid ester, the latter combination giving rise to 2-cyanoacrylates using alkyl cyanoacetates as a substrate, for example. When acrolein is used, n is 1 and the same combinations of X and Y can apply in structure (I).
When a source of formaldehyde is used, structures (II) and (III) would result when cyclopentene diones, cyclohexene diones, cyclopentane diones or cyclohexane diones are used. When acrolein is used, the methylene bond would be conjugated to another alkene group (by analogy to structure (I) above).
When a source of formaldehyde is used, structures (IV) and (V) would result when Meldrum's acid and tetronic acid are used. When acrolein is used the methylene bond again would be conjugated to another alkene group (by analogy to structure (I) above).
The initial reactant and the second reactant are placed in a polar solvent in order to conduct the synthesis. The polar solvent ordinarily comprises an ionic liquid; that is a salt whose melting point is less than 100° C., which in its molten form contains only ions. These polar solvents may optional include a minor amount of water, though in most cases they will be substantially anhydrous.
Examples of certain ionic liquids that may be useful in the present invention include the cation allyl (“AMIM”) and/or butyl methylimidiazole (“BMIM”). As an anion associated with the cation, X− may be PF−6, BF−4, SbF6− or other anions described as ‘soft’ due to declocalisation of charge over several atoms. Other examples of ionic liquids include ethylenediammonium diacetate, ethylammonium nitrate, n-butyl pyridinium nitrate.
In addition to the counterions noted above, phosphate counterions, anions derived from triethylborohydride and thioglycolic acid are also contemplated, such as alkyl or BMIM+BEt3−.
The electron deficient olefin so formed by the inventive processes may be a variety of olefins having at least one electron withdrawing group attached thereto. In a desirably embodiment, as noted above with respect to the second reactant, the electron deficient olefin so formed will have two or more electron withdrawing groups attached thereto, which may be the same or different. Particularly desirable products have two electron withdrawing groups attached thereto which are different, such as 2-cyanoacrylate esters.
Representative examples of 2-cyanoacrylate esters so formed by the inventive processes include methyl, ethyl, n-propyl, i-propyl, propargyl, n-butyl, i-butyl, n-pentyl, n-hexyl, 2-ethylhexyl, n-octyl, n-nonyl, oxononyl, n-decyl, n-dodecyl, allyl, ethynyl, 2-butenyl, cyclohexyl, phenyl, phenethyl, tetrahydrofurfuryl, chloroethyl, 2,2,2-trifluoroethyl, hexafluoroisopropyl, methoxymethyl, methoxyethyl, methoxybutyl, ethoxyethyl, propoxyethyl, butoxymethyl, butoxyethyl and dimethyl siloxane esters of 2-cyanoacrylic acid.
The reaction of the present invention may proceed under mild heating conditions, without heat at room temperature or even at sub room temperature and sub zero temperatures, depending of course on the specific reactants and the scale of the reaction. The reaction requires some temperature to decompose the source of formaldehyde, e.g., paraformaldehyde may be gently heated up to 70° C., to liberate formaldehyde in situ in the reaction medium. The temperature may be reached through an external heating element or internally by means of the exotherm that may be generated depending on the identity of the reactants. The temperature of the reaction is controlled to accommodate such exothermic processes and cooling may be applied even to sub-ambient or sub-zero temperatures where the ionic liquid solvent remains liquid, but by-products like water for example solidify and may be separated.
The time of reaction may be monitored by reference to the formation of the desired product. Infrared spectrometer is a particularly useful tool in this regard. The time may be as little as 30 minutes, for instance, or longer or shorter for that matter depending again on the specific reactants, the scale of the reaction and whether heat is added to the reaction conditions.
Once formed, the product of the reaction may be isolated by direct distillation under vacuum out of the reaction mixture or by freezing it in a solid form and separating off the liquid phase. This is particularly so in the case of 2-cyanoacrylates (particularly their lower esters) which are relatively volatile whereas ionic liquid solvents are noted for their lack of volatility.
The electron deficient olefin so formed by the inventive processes may be stabilized during the synthesis and or isolation procedure and also in the isolated product to improve its shelf life. Suitable stabilizes include anionic stabilizers and free radical stabilizers.
For example, free radical stabilizers include hydroquinone, pyrocatechol, resorcinol or derivatives thereof, such as hydroquinone monoethyl ether, or phenols, such as di-t-butylphenol or 2,6-di-t-butyl-p-cresol, 2,2′-methylene-bis-(4-methyl-6-t-butylphenol), bisphenol A, dihydroxydiphenylmethane, and styrenized phenols.
For example, anionic stabilizers include Lewis acids, sulfuric acid, hydrochloric acid, sulfonic acids, such as methane, ethane or higher sulfonic acids, p-toluene sulfonic acid, phosphoric acid or polyphosphoric acids, silyl esters of strong acids, such as trialkyl chlorosilanes, dialkyl dichlorosilanes, alkyl trichlorosilanes, tetrachlorosilane, trialkyl silylsulfonic acids, trialkyl silyl-p-toluene sulfonates, bis-trialkyl silylsulfate and trialkyl silylphosphoric acid esters.
The amount of either stabilizer used to stabilize the electron deficient olefin prepared by the inventive processes is well known to those of ordinary skill in the art, and may be varied depending on the properties of the resulting composition made from the so formed electron deficient olefin.
The following example is used to illustrate but in no way limit the present invention.
A 500 ml, three necked flask is fitted with a stirrer a pressure equalising dropping funnel, a Dean Stark water trap and a reflux condenser.
Previously and carefully dried ionic liquid, 1-butyl-3-methylimidiazolium hexafluorophosphate ([BMIM]PF6), approximately 70 mls and containing some paraformaldehyde (23 g), are added to the flask with stirring. Gentle heating may be introduced to assist in uniformly suspending the paraformaldehyde to give a slightly viscous opaque white suspension. n-Butylcyanoacetate (100 g) is added to the dropping funnel. The cyanoacetate is added to the flask at a constant rate over a 20 minute time interval while heating if necessary for a period of up to 30 minutes. Methane sulphonic acid and/or SO2 as an anionic stabilizer could be added to the reaction mixture to prevent premature polymerisation, or the N-butylcyanoacrylate monomer could be distilled out of the reaction mixture directly once formed onto the anionic stabilizer.
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