In-Situ Synthesis of Maleimides leading to Polymaleimides without isolating the Monomers and subsequent reduction. By: Robert B. Login Goals:An inexpensive method of producing polymaleimides that are of value by themselves or can be employed as substrates for controlled reduction to copolymers containing succinimide, pyrrolidone and pyrrolidinefunctionality.Although the reduction of polyimides in general have not been extensively studied, reduction of polymaleimides can lead to general procedures for their controlled reduction.

A)-Reaction of Primary Amines with Maleate half esters to prepare Polymaleimides In-Situ without Isolating the corresponding Monomers.

Abstract:The reaction of primary amines with methyl maleate half ester results in a maleamide monomer that can be polymerized in-situ to polymers containing significant amounts of polymaleimides. The evidence for this conclusion is based on the deep red color of neutralized polymaleimides repeatedly mentioned in the polymaleimide literature and also observed with these polymers. I ascribed the red color to either decarboxylation leading to conjugated unsaturation or the formation of furan-pyrol derivatives. This claim is supported by the indication of significant unsaturation and aromaticity exhibited by complicated H-NMR spectrums.

Background: Aspartic acid can be readily polymerized by simply heating the powdery

aspatic acid to temperatures above 180C at atmospheric. The polymerization can be catalyzed by phosphoric acid and the resulting polymers can have significant MW usually in the 20K range while the uncatalyzed is usually in the 5K range. The literature concerning polyasapartic acid is quite extensive and has been reviewed several times(1 ).

The polymerization produces polysuccinic acid which can be hydrolyzed to the corresponding polyaspartic acid. Even maleic acid and ammonium hydroxide will polymerized to the same polysuccinic acid. This suggests that however the ammonia initially adds to maleic acid to form aspartic acid or maleiamide or imide, as the temperature rises eventually only polysuccinic acid is formed.

Fig. 1 Proposed structure of polysuccinimides accounting for all H-NMR protons.

Could this polymerization be applied to primary amines and maleic anhydride or maleic anhydride derivatives so as to increase the variety of polymers produced in a similar manner as the polysuccinimides?

Although polyaspartic acid is a useful polymer, it's structure is fixed. Only the MW can be varied. Post polymerization reactions of the precursor polysuccinimide that opens the imide have been reported; however, this route to derivatives, although useful, is random and cannot be controlled. If related imide monomers could be synthesized, then control of the morphology of subsequent polymers would be possible. Random, blocks or alternating polymers would be possible. This then was the goal of what follows.

Monomers:The Michael reaction of primary amines with maleates, (or starting with N-alkyl aspartic acids), under the same conditions as used to polymerized aspartic acid have been less studied. The usual synthetic methods for preparing N-alkyl amino acids employs the Michael reaction with maleate diesters or maleate methyl half ester in the presence of tertiary amines such as triethylamine(3). However, not using tertiary amines should result not in the Michael reaction but neutralization of the maleate half ester. Condensing this neutralized half ester, at high temperatures, leads to the corresponding polymaleimide. The reason for using lower alkyl maleate half esters is that removal of the methyl or ethyl alcohol is more facile than water, resulting in higher conversion to maleimide that is observed by the fact that unlike the polysuccinimides of aspartic acid, this in-situ polymerization takes place at 150C or less(and vacuum) while the later requires temperatures above 180C. It is also easier to handle maleic anhydride as a solution in methanol as the half ester as it results in the desired maleamide as the process proceeds to polymer.

Bifunctional ethanolamine would be expected to produce even more complicated polymers. Reacting it with the half methyl ester of maleic anhydride and heating to 140-150C and high vacuum with or without phosphoric acid catalysis, results in a brittle red polymer in nearly quantitative yield. Interestingly, this polymer catalyzed by H2PO4 is insoluble in water but gels DMSO, while the uncatalized polymer is soluble. Both are soluble in dilute caustic, where they form a bright red solution that when acidified with HCl becomes colorless(or various shades of pale orange) below pH 8. This cycle can be repeated several times but eventually the red color does not return as if a chemical change had occurred? Even the

polysuccinimdes I have prepared from aspartic acid briefly form this red solution at high pH but the extensive polyaspartic acid literature does not mention this red color!

The same reaction of butyl amine with maleate half esters, resulted in a polymer that was insoluble in water and 1N NaOH where the insoluble polymer turned red. Dissolving this polymer in DMF then adding 1N NaOH resulted in a deep red solution that lost the red color when acidified. This suggests the same chromaphore is in this polymer as that prepared from ethanolamine.

Coleman et. al. (JOC, Jan 1959, p135) found that when they tried to prepare maleimides from primary amines and maleic anhydride in toluene at 90C they obtained excellent yields of the maleiamide but when closure to imide is conducted in xylene at 170-180C poor yields resulted with the major product being an undefined polymer. Similarly, USP 2,306,918 found that the polymer formed in-situ, had the same IR as that prepared from the monomer by FR polymerization. Although no further reports were found, this patent suggests that my premise is reasonable, that the optimization of the in-situ polymerization is a route to a commercial process.

Chromophore:A problem with the polymerization of ethanolamine or N- butyl amine and maleate half esters is to explain the pH color change of the subsequent polymer? Some of the examples prepared are bright red to begin with and when the pH is raised, even the lightly yellowish examples become soluble and bright red. Lowering the pH as mentioned previously, sharply turns the solution relatively colorless much like phenothalein. Examples of related polymers, containing polymaleimides(prepared by FR or anionic polymerization), show similar red color after polymerization and/or at high pH(5). These polymers are said to contain unsaturation linked to an acidic functionality that cause the red color when this acidic functionality is neutralized. This color change can be repeated several times but in some of samples the red color with time will eventually discharge to a light yellow neutral color as if some type of hydrolysis or reaction had occurred ? The

polyaspartic literature contains no specific references to the red color phenomenon. The polyaspartic acids(polysuccinimides) samples I have prepared show some red color initially that discharges very quickly and must not have been much of an issue to those studying this chemistry. Polymaleimides prepared by FR or anionic polymerization have significant and numerous mentions of the red color(5). Several theories of what causes the red color have been put forward by H. C. Haas et. al.(5).

Other possibilities that I think might make sense are based on the decarboxylation of any succinamide segments along the polymer chain, followed by isomerization. This type of decarboxylation is observed when maleic anhydride is polymerized anionically. The succinimides next to the conjugated unsaturation have removable acidic protons resulting in an anionic charge at high pH that is reversible in acidic solutions:

Since the succinimides are next to each other and the alpha protons are acidic, the following might be possible? Whatever causes the color is immaterial to my argument that the red color is the hallmark of the polymaleimides.

CO2H CO2H

R R

R R

n

n

N

H

O N

H

ON

H

O N

H

O

Fig. 6 My ideas for the chromophores.

I prefer the second idea of a cascade reaction in the presence of base. Are the succinimides in an orientation to actually react. Oishi et. al. Claim that based on their optical rotation activity that the threo-diisotactic structure is correct. This structure looks like it would readily react, the driving force being aromaticity. As an aside, these authors mention that their anionic polymerized polymers are red.

-

OH-

H+

H+

OH-

OH-

H+

O

N

NO

O

O

N

O

NO

O

H

O

N

O

NO

O

N

NO

O

O

OH

et. cetera

ON

ON N

OO

I believe the aromatic structures are basic and acid interrupts the conjugation only to be reversed upon neutralization. Eventually hydrolysis disrupts any of the proposed chromaphores.

Since the polymers prepared from methyl maleate half esters form deep red solutions sharply above pH 9-10, strongly suggests that this polymer is really based on a maleimide monomer. This then is a commercial method of inexpensively preparing polymaleimides. Although no FR initiator is employed, homolytic cleavage to form free radicals would not be unexpected at 150C, in addition unreacted amines can polymerize N-alkyl maleimides. Anionic polymerization however seems the better choice. Either way it is very difficult to prevent polymerization.

Example Preparation:Sample 4009: To a 250ml Erlenmeyer equipped with a reflux condenser and magnetic stirrer was charged with 100ml of methanol and 36 g maleic anhydride. After refluxing for ½ hour at which time, 22g of ethanolamine is added drop wise keeping the temperature between 60-65c. Then most of the methanol is evaporated off which results in a viscous golden colored mush.

This intermediate was placed in a suitable container in a heated vacuum desiccator, which was evacuated to -28inches of Hg and slowly heated to 150C. After 2hrs at 140-150C, the product was removed to reveal52.3g of a red plastic. A gram sample of which took 2.1ml 1N NaOH to go from a straw colored solution to a red aqueous solution. If only one carboxylic acid is neutralized then the apparent MW is 476 Daltons. This seems unlikely and therefore the MW is some multiple of this.

The same reaction with a 50/50 mole % mixture of Ethanolamine and Butyl Amine results in a 98.5% yield of a brittle red plastic. The polymer is not soluble in water but dissolves in dilute caustic to afford a bright red foamy solution.

The IR of sample 4009 shows significant carboxylic acid, this is the result of the polymerization of maleamides which do not homopolymerize but readily copolymerize. As maleimides form in the reaction mixture, maleamides are copolymerized with them. Maleamides are readily synthesized in nearly quantitative yields by simply mixing maleic anhydride with primary amines. They can be formed from mixed amines resulting in unique copolymers or added during polymerization to copolymerize with the maleimides as they form in the reaction mixture resulting in block polymer structures. Copolymerization with ethanolamine like the 4009 process example, where small amounts of long chain amines results in surface active polymers with significant utility in a variety of applications such as personal care, cosmetics, drug delivery. In addition, large polymeric molecules are notably non-toxic.

Attempts to polymerize butyl amine by generating the butyl maleimide in toluene with catalytic PTSA and subsequent azeotropic water removal, repeated under various times and temperatures never resulted in yields higher than 70% at best. This result illustrates the remarkable yields obtained by the maleate half ester route as described above.

Attached are H-NMR's of an example of the polymer prepared from methyl maleic half ester and ethanolamine.

This IR is from a polymer prepared from the methyl half ester of maleic anhydride and ethanolamine. This sample of polymer 4009 was cast from DMSO evaporated on a hot plate. The other trace is the NaOH neutralized 4009 cast from methanol.

This IR shows significant carboxylic acids either in the polymer to begin with or formed by hydrolysis. Secondary amide can be seen at 1620 and 1550cm-1Coleman et. al.(6) found that maleamides will not homopolymerize but would copolymerize. The maleamides can be incorporated in the polymaleimide accounting for the carboxylic acid groups.

The following are H-NMR's of the same polymer 4009 and its neutralized version. 4009 was dissolved in water and ppt with methanol. The neutralized

sample was also dissolved in water and ppt with isopropanol. Both samples were vacuum dried at 60-80C.

The NMR's show significant unsaturation and possibly aromatic resonances. Even when neutralized these resonances persist in D2O. In the literature, red chromophores occur when the compound posses polyunsaturastion and/or aromatic structures and significant conjugation such as found in Fulgimides.

B)-In-Situ Polymerization of Amines with Maleic Anhydride to generate Polymaleimides and subsequent reduction to Pyrrolidone Copolymers.

Abstract:The in- situ preparation and polymerization of N-alkylmaleamides results in polymers containing significant amounts of polymaleimides. The evidence for this conclusion is based on the deep red color of polymaleimides repeatedly mentioned in the polymaleimide literature and also observed with these polymers. The red color is ascribed to conjugated unsaturation or aromaticity. This claim is supported by significant unsaturation exhibited in the H-NMR spectrums. Subsequent reduction with LiAlH4 or BH4 or catalytic hydrogenation results in copolymers containing pyrrolidone and pyrrolidine functionality.

L. E. Coleman et. al. (JOC 24, 185, 1959)(6) trying to obtain high yields of the ring closure of N-alkyl maleamides to form the corresponding N-alkyl maleimides, found very low yields with the primary product being a polymer.The yield of their maleimides ranged in the 15-25% range. Careful removal of the solvent xylene under vacuum at low temperature increases the yield to 50%. Since this publication numerous examples have appeared showing how to increase the yield of the desired maleimide. Yields of the maleimide monomer, even in the 90% plus range have been claimed by utilization of acidic catalysts and azeotropic removal of the water of condensation.(7)

The multiple steps required to eventually prepare the desired polymaleimide, leaves much to be desired in a commercial product because of significant expense. No one has investigated the nature of the undesired polymer reported by Coleman. I have found that this polymer is mostly polymaleimide. This polymaleimide is very useful by itself or as a substrate

for partial reduction to pyrrolidone(8) containing copolymers. The goal therefore is to optimize this “undesired” polymerization to form high yields of polymaleamides in-situ without isolating the corresponding maleimide monomers. Polymerization of ethanolamine with methyl maleate half ester is nearly quantitative; however, the same reaction with primary alkyl amines is also possible and results in unexpected high yields of quality polymers. Low yields around 50%-70% can be obtained by employing the altrnative reaction of primary amines with maleic anhydride in aromatic solvents. The maleate half ester route to quality high yield polymers is therefore a superior process and was not obvious or expected.

Reduction of said polymer's pendant succinimides has the potential to result in pyrrolidine and 5-hydroxypyrrolidone along with pyrrolidone repeat units. Control of the reduction to afford the structures that are desired is also a goal of this inventive idea. Reduction of succinimides to pyrrolidone with hydrogenation is well known (USP 6,603,021 and the numerous references therein) and a similar reaction can be accomplished with the polymaleimides.

Reduction of polyimides to polypyrrolidone containing copolymers of various structures is also a feature of this inventive idea. The polyimides are a large diversified group of important useful polymers. Combining their structure with pyrrolidone functionality would result in several interesting and useful properties including the ability to complex pharmaceutically active compounds, increased hydrophylicity, increased dye ability, decreased toxicity, amongst others. With experimentation, not only can reduction result in pyrrolidone functionality, it can also result in pyrrolidine functionality; therefore, a large variety of useful terpolymers can be visualized.Claims:

1. A process for preparing essentially polymaleimides without isolating the corresponding monomers comprising preparing lower alkyl maleate

Reductionm

R R R

nnn

NO

NO ON

O O

half esters and neutralizing them with primary amines followed by removal of methanol and heating said mixture under vacuum to temperatures around 150C.

2. A process where polymers of claims one are reduced with various hydrides, or hydrogenation, or other reductive proceedures to terpolymers containing in addition to succinimide structures, pyrrolidone and pyrrolidine functionality.

3. The process of claim 3 wherein polyimides are reduced to said derivatives.References:

1. T. Nakato et. al. Macromolecules 1998, 31, 2107.2. L. Aurelio et. al. Chem. Rev. 2004, 104, 58233. C. Lee et. al. Bull. Korean Chem Soc., V8, No6, 1987

C. Abshire and L. Berlinguet, Can. J. Chem., 40, 163(1962).K. Harada and K. Matsumoto, JOC Sept. 1966, 2985.A. Zilka and M. Bachi, JOC 24, 1959, 1096.P. Piispanen et. al. Tetrahedron Lett. 46(2005), 2751.M. Boros et. al. Amino Acids(2007) 33, 709.

4. F. Rypacek et. al. Chap. 16, Biopolymers, ACS Symposium Series, 2001.

5. P. Tawney et. al. JOC 1961 p16.K. Onimura et. al. Macromolecules V31, No18, 1998.P. Agarwal et. al. Ind. Eng. Chem. Rev. 2003, 42, 2881.H. Haas and R. MacDonald, J. Polymer Sci.,V11, No. 2, 327, 1973.H. Haas and R. Moreau, Ditto, V13, 2327, 1975.

6. L. E. Coleman JR and J. A. Conrady; J. Poly. Sci.,38,241(1959)7. P. Y. Reddy et. al. JOC 1997, 62, 2652

N. B. Mehta et. al. JOC 1960, 25, 1012.8. S.A. Miller and R. Chamberlin, JOC 1989, 54, 2502.

A.D. Cuiper et. al. JOC 1999, 64, 2567.K.C. Schreiber and V. P. Fernandez, JOC 1961, 26, 1744.H. L. Cohen and L. M. Minsk JOC 1959, 24, 1404.L. M. Rice et. al. JOC 1954, 19, 884.