Intermediates for the Preparation of Poly(Cyanoacrylates) and Applications of the Poly(Cyanoacrylates) so Prepared

.(21) International Application Numberi WORLD INTELLECTUAL PROPERTY ORGANIZATION P Intemational Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 6 : W0 95/26371 cosr 2 2 C09 4/00 co7c 253/30 255/20, 22,g5}19, cJo7F 9740, 9/54, C07C 5 °°‘°ber 1995 323/so . (11) International Publication Number: (43) International Publication Date: PCT/IE94J00O18 (81) Designated States: AU, BG, BR, CA, CZ, FI, GE, HU, JP, KR, NO, NZ, PL, RO, RU, US, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE). (22) International Filing Date: 28 March 1994 (28.03.94) (71) Applicant (for all designated States except US): PATRIQUE LIMITED [IFJIE]; Molyneux House, Bride Street, Dublin 8 Published (IE). With international search report. ‘ With amended claims. (72) Inventors; and (75) Inventors/Applicants (for US only): DYATLOV, Valery Alexandrovich [RU/RU]; Malyl Levshinskyl per, 12-6, Moscow, 119034 (RU). MALEEV, Viktor [RU/RU]; Apartment 66, Street B. Serpuchovskaya, 70, Moscow, 113093 (RU). (74) Agent: ANNE RYAN & CO.; 60 Northumberland Road, Ballsbridge, Dublin 4 (IE). (54) Title: INTERMEDIATES FOR THE PREPARATION OF POLY(CYANOACRYLATES) AND APPLICATIONS OF THE POLY(CYANOACRYLATES) SO PREPARED (57) Abstract A process is provided for the reversible coupling of weak nucleophiles to the carbon-carbon double bond of 2-cyanoacrylic acid or an ester thereof so as to reversibly protect the bond. Examples of weak nucleophiles include alcohols (including diols and polyols), phenols, sulfur nucleophiles such as thiols and thio acids, phosphorus nucleophiles such as dialkyl or diarylphosphites and phosphines, and carbon nucleophiles such as active methylene compounds. The process involves reacting 2-cyanoacrylic acid or an ester thereof with the weak nucleophile in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic catalyst. The compounds produced can be used as intermediates for the preparation of po1y(cyanoacrylates), following elimination of the nucleophile added to give a 2-cyanoacrylate monomer which then polymerizes. The po1y(cyanoacrylates) thereby produced have many applications, for example, in the preparation of films such as single— or multi-layer Langmuir-Blodgett films. AT AU BB BE BF BG BJ BR BY CA CF CG CH CI CM CN CS CZ DE FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States_party to the PCT on the front pages of pamphlets publishing international applications under the PCT. Austria Australia Barbados Belgium Burkina Faso Bulgaria Benin Brazil Belarus Canada Central African Republic Congo Switzerland Cote d'Ivoire Cameroon China Czechoslovakia Czech Republic Germany Denmark Spain Finland France Gabon United Kingdom Georgia Guinea Greece Hung“? Ireland Italy Japan Kenya Kyrgystan Democratic People’s Republic of Korea Republic of Korea Kazakhstan Liechtenstein Sri Lanka Luxembourg Latvia Monaco Republic of Moldova Madagascar Mali Mongolia Mauritania Malawi Niger Netherlands Norway New Zealand Poland Portugal Romania Russian Federation Sudan Sweden Slovenia Slovakia Senegal Chad Togo Tajikistan Trinidad and Tobago Ulaaine United States of America Uzbekistan Viet Nam 10 15 20 25 WO 95/26371 PCT/D394/00018 Description Intermediates for the preparation of polygcyanoacrylatesz and applications of the polygcyanoacrylatesz so prepared Technical Field This invention relates to the reversible coupling of a weak nucleophile to the carbon—carbon double bond of 2—cyanoacry1ic acid or an ester thereof, so as to reversibly protect said bond. Background Art Esters of 2-cyanoacrylic acid having the general formula: CN H2C= / \ CO2R are widely used as monomers for the preparation of polymers and copolymers. The ability of 2—cyanoacry1ic acid esters to polymerise rapidly under the influence of moisture or nucleophilic substances has led to their exploitation as instantaneous adhesives. Thus, cyanoacrylate esters are the main constituents of the rapid-bonding adhesives commonly known as "superg1ues". Bonding results from the conversion of a low—viscosity monomer into a solid polymer by anionic polymerisation. Esters of 2-cyanoacrylic acid are also used for the preparation of po1y(alky1 2—cyanoacrylate) nanoparticles and nanocapsules which may be employed as carrier or delivery systems for drugs or other active agents. Furthermore, esters of 2- cyanoacrylic acid can be used to prepare Langmuir-Blodgett type thin films which may be applied as coatings for components used in the electronics industry. The inherent ability of 2-cyanoacrylic acid esters to undergo rapid anionic polymerisation causes complications as regards their 10 15 20 25 30 WO 95/26371 PCT/IE94/00018 synthesis, chemical modification, and storage. It is necessary to be able. to control the rate of polymerisation of cyanoacrylate monomers in order to permit their successful manipulation prior to carrying out the bonding process. Additionally, there is a need to be able to control the surface—active properties of cyanoacrylate monomers which are to be utilised in Langmuir—Blodgett film applications. ‘ The principal method known for the regulation of the chemical and physical properties of 2-cyanoacrylate monomers and polymers is by variation of the structure of the ester moiety. However, ‘ opportunities for the chemical modification of simple cyanoacrylate esters in order to prepare new monomers are limited due to the high chemical reactivity of the carbon—carbon double bond. Methods for the synthesis of 2-cyanoacrylic acid ester monomers are few in number. An important commercial route to these compounds is the Knoevenagel Condensation Method (H. Lee (Ed.) (1981), "Cyanoacrylic Resins - The Instant Adhesives", Pasadena Technology Press, Pasadena, U.S.A.). According to the Knoevenagel method a cyanoacetic acid ester and formaldehyde are reacted together in the presence of an amine to give alkyl cyanoacrylate oligomers. The free cyanoacrylate ester monomer is then generated by thermally cracking the oligomer and vacuum distilling the monomer on to an acidic stabiliser. The Knoevenagel method is limited to the preparation of alkyl 2—cyanoacrylates which have an alkyl moiety of no more than ten carbon atoms. Above this limit, the monomers cease to be distillable at temperatures which are below their respective thermal destruction temperatures. In fact, n-octyl 2-cyanoacrylate is the monomer with the greatest number of carbon atoms in the ester function that has been reported to have been prepared by the Knoevenagel method (Kublin, K.S. and Miguel, F.M., (1970), J. Amer. Vet. Ass., Vol. 156, No. 3, 313-318; Alco, J.J. and DeRenzis, F.A., (1971), J. Pharmacol. Ther. Dent., Vol. 1, No. 3, 129-132). Short chain (less than ten carbon atoms) alkyl 2—cyanoacrylates with polar groups such as hydroxyl, carboxyl and ester groups, and 10 15 20 25 30 W0 95/2637 1 PCT/IE94/00018 aryl cyanoacrylates cannot generally be prepared by the Knoevenagel _ “ Condensation Method because of their high boiling points. Another method for the preparation of alkyl 2-cyanoacrylic acid esters is based on the transesterification reaction (Voitekunas, J ., Polyakova, A.M., Mager, K.A., Kokhanov, Yu. V. and Voitkov, A.I., U.S.S.R. Patent No. 726,086). This single—stage method involves the transesterification of methyl or ethyl 2—cyanoacrylate with a higher alcohol under acid-catalysed conditions. Because of the relatively low efficiency of the process it is necessary to separate residual methyl or ethyl 2—cyanoacrylate from the product ester by vacuum distillation. A method for the synthesis of 2-cyanoacrylic acid esters involving prior protection of the carbon—carbon double bond of a simple cyanoacrylate derivative is described in U.S. Patent No. 3,903,055. The method can involve three or five steps. In the five- step process, ethyl or isobutyl 2—cyanoacrylate is reacted with anthracene to form its stable Diels-Alder anthracene adduct. Basic hydrolysis of the ester function in the adduct gives the corresponding carboxylic acid salt from which the free acid is obtained upon acidification. The carboxylic acid is next converted into its acid chloride with thionyl chloride, and this is reacted with an alcohol to give a new ester. A displacement reaction involving the stronger dienophile maleic anhydride is then carried out to give the product cyanoacrylate ester together with the anthracene-maleic anhydride Diels-Alder adduct from which it must be separated. The cyanoacrylate ester formed can then be used as a monomer for the - preparation of poly(alkyl 2—cyanoacrylates). It should be noted that this route to alkyl 2—cyanoacrylates is purely a laboratory method, and that it has not proved practicable on a larger scale. Patent Publication JP 91 065340 describes a route to the cyanohydrins of pyruvic acid and its esters which can be used as intermediates for the preparation of 2—cyanoacrylate esters. 10 15 20 25 WO 95/26371 PCT/IE94/000 18 Patent Publication JP 91 075538 describes l—acetoxy-l- cyanopropionic acid esters which can be converted into 2—cyanoacrylate esters by thermal elimination of a molecule of acetic acid. As mentioned supra, some of the physical properties of alkyl 2- cyanoacrylate monomers can be regulated by the preparation of monomers wherein the chemical structure of the ester moiety has been modified. Modification of the ester moiety has been used as a means of controlling the surface-active properties, hydrophobicities, and solubilities of cyanoacrylate esters (Leonard, F., Collins, J .A. and Porter, H.J., (1966), J. Appl. Polym. Sci., Vol. 10, No. 11, 1617- 1623). Long-chain 2—cyanoacrylate esters have been used for the formation of Langmuir-Blodgett films (Matveeva, N.K., Pasekov, V.F. and Save1'eva, L.V., (1991), Mikroelectronika (Akad. Nauk S.S.S.R.), Vol. 20, No. 5, 501-503). The solubility of cyanoacrylate esters in aqueous media is a function of the esterifying radical. A decrease in solubility is achieved by lengthening the alkyl chain. Some control over the properties of alkyl 2-cyanoacrylates can thus be achieved by varying the nature of the esterifying group. However, these changes may lead to polymers which do not have desirable characteristics. Thus, for example, use of butyl 2- cyanoacrylate in an adhesive composition instead of methyl 2- cyanoacrylate may lead to a more manageable rate of polymerisation but will cause a significant decrease in the strength of the bond which is formed. It will be appreciated, therefore, that control of the properties of a 2—cyanoacrylate monomer by variation of the nature of the 10 15 20 25 30 WO 95/26371 PCT/IE94/00018 A esterifying group without at the same time influencing the properties of - the derived polymer is not possible at present. Accordingly, for the above reasons, a method for the modification of the physical and chemical properties of conventional and other alkyl 2-cyanoacrylate monomers which does not affect the properties of the polymers obtained therefrom is highly desirable. The synthesis of ethyl 3-methoxy-2-cyanopropionate via reaction of the sodium salt of ethyl cyanoacetate with chloromethyl methyl ether has been described (Foldi, Z., v. Fodor, G., Demjen, I., Szekeres, H. and Halmos, I, Berichte, 1942, Vol.75, No. 7, 755-763). The same ethyl 3—methoxy—2-cyanopropionate was prepared by an almost identical method in U.S. Patent No. 2,467,926 but was not isolated or characterised. No other 3-alkoxy-2-cyanopropionic acid derivatives have been reported, and this is not surprising since the chloromethyl alkyl ethers required for their synthesis as described supra are usually hazardous and unpleasant materials. Some products resulting from the addition of nucleophiles to the carbon—carbon double bondof 2—cyanoacry1ates have been described. Organosilanes have been added to 2—cyanoacrylic acid and esters thereof with formation of the corresponding saturated products (Kolomnikova, G.D., Prihodchenko, Yu. D. and Gololobov, Yu. G., Izv. R. Akad. Nauk, Ser. Khim., 1992, No. 7, 1655-1657). Thiols and thioacetic acid can be added to ethyl 2-cyanoacrylate to yield ethyl 2-cyano-3-thioalkylpropionates and ethyl 2-cyano-3- acetylthiopropionatc, respectively (Kandror, I.I., Bragina, 1.0., Galkina, M.A. and Gololobov, Yu. G., Izv. Akad. Naul S.S.S.R., Ser. Khim., 1990, No. 12, 2798-2801: ibid., 15th International Symposium on the organic Chemistry of Sulfur, Caen, France, 1992). Thiourea has been added to ethyl 2-cyanoacrylate in the presence of trifluoroacetic acid to give the corresponding saturated 10 15 20 25 W0 95/26371 PCT/IE94/00018 . ‘S-alkylthiouronium trifluoroacetate (Kolorrmikova, Yu.-D., Krilova, T.O., Chernoglasova, I.V., Petrovsky, P.V. and Gololobov, Yu. G., Izv. Russ. Akad. Nauk, Ser. Khim., (1993), No. 7, 1245). Dialkyl and diaryl phosphites have been added to 2-cyanoacrylic acid and its ethyl ester to give dialkyl and diaryl phosphonates (Kolomnikova, G.D., Prihodchenko, Yu. D., Petrovsky, P.V. and Gololobov, Yu. G., Izv. R. Akad. Nauk, Ser. Khim., 1992, No. 8, 1913). Triethyl phosphite has been added to 2—cyanoacrylic acid to yield the derived 3-(diethylphosphono)propionic acid (Kandror, 1.1., Lavrykhin, B.D., Bragina, I.O., Galkina, M.A. and Gololobov, Yu. G., J. Obsch. Khim., (1990), Vol. 6, No. 9, 2160-2168), and to ethyl 2- cyanoacrylate to give ethyl 2-cyano-3-(diethylphosphono)propionate (Kandror, I.I., er al. (1990) supra). Diethyl chlorophosphite and chlorodiphenylphosphine react with ethyl 2-cyanoacrylate in the presence of trifluoroacetic acid to give, respectively, ethyl 2-cyano-3-(diethylphosphono)propionate and ethyl 2-cyano—3-(diphenylphosphinoxy)propionate (Kolomnikova, Yu. D. et al. (1993) supra). Catechyl chlorophosphite reacts similarly with ethyl 2-cyanoacrylate to give the derived catechylphosphonate derivative (Kolomnikova, Yu. D. et al. (1993) supra). Triphenylphosphine reacts with ethyl 2-cyanoacrylate under trifluoroacetic acid catalysis to give ethyl 2-cyano-3- (triphenylphosphonium)propionate trifluoroacetate (Kolomnikova, Yu. D. et al. (1993) supra). Phosphorus-sulfenyl chlorides have been added to 2- cyanoacrylates with formation of the corresponding thiophosphonates (Kolomnikova, G.D., Krilova, T.O. and Gololobov, Yu. G., J. Obsch. Khim., 1993, Vol. 63, No. 3, 716). 10 15 20 25 WO 95/26371 PCT/IE94/000 18 Carbon nucleophiles derived from active methylene compounds- V such as methyl nitroacetate, diethyl malonate and ethyl cyanoacetate have been reacted with ethyl 2-cyanoacrylate to give the expected Michael adducts (Kandror, l.I., Bragina, 1.0., Galkina, M.A.,~Be1okon, Yu. N., Lavrykhin, B.D. and Gololobov, Yu. N., Izv. Russ. Akad. Nauk, Ser. Khim., (1992) No. 10, 2449-2453). None of the compounds mentioned supra have been used for the reversible protection of the carbon—carbon double bond of 2- cyanoacrylates, and conditions for effecting the reverse Michael reactions needed for their conversion into monomeric 2-cyanoacrylates or into poly(2—cyanoacrylates) have not been described. Disclosure of Invention ' The invention provides in a first aspect a process for the reversible coupling of a weak nucleophile to the carbon—carbon double bond of 2-cyanoacrylic acid or an ester thereof, so as to reversibly protect said bond, which comprises reacting 2-cyanoacrylic acid or an ester thereof with said weak nucleophile in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic catalyst. The weak nucleophile can be an alcohol or a phenol. The term alcohol as used herein includes diols and polyols. The weak nucleophilecan also be selected from: i) a thiol, thiophenol, a thioamide, a thio or dithio acid or other thionucleophile; ii) a dialkyl or diarylphosphite, a dialkyl or diarylthiophosphite, a phosphine, phosphorus sulfenyl halide or other phosphorus nucleophile; and 10 15 20 WO 95/26371 PCT/IE94/00018 iii) a carbon acid as hereinafter described. This first aspect of the invention thus provides a method for the reversible protection of the chemically reactive carbon-carbon double bond of polymerisable alkyl or aryl 2—cyanoacry1ates whereby a weak nucleophile added across the double bond can be eliminated under the conditions of base—initiated anionic polymerisation to yield poly(alky1 or aryl 2—cyanoacry1ates) together with the relevant weak nucleophile. The acidic catalyst is suitably a non-volatile acid such as an aliphatic sulfonic acid or an aromatic sulfonic acid. Accordingly, the non-volatile acid is suitably methane sulfonic acid or p-toluenesulfonic acid. Alternatively, the acid catalyst can be a carboxylic acid. An essential feature of the acid catalyst is that it does not react with the alcohol or phenol or other weak nucleophile being used. Preferably, the process is carried out under conditions which inhibit anionic polymerisation. Further, preferably, the process is carried out in the presence of a weak acid. Suitably the weak acid is sulfur dioxide. Preferably, when the weak acid is sulfur dioxide, gaseous sulfur dioxide is bubbled into the reaction mixture as a continuous stream. The anionic polymerisation inhibitor can be an aliphatic sulfonic acid, an aromatic sulfonic acid or carbon dioxide. 10 15 20 25 W0 95/2637 1 PCT/IE94/000 18 Further, preferably, the process according to the invention is carried out in the presence of a free radical polymerisation inhibitor. Suitably the free radical polymerisation inhibitor is benzoquinone, hydroquinone, methylhydroquinone or naphthoquinone. Preferably the inert solvent is benzene, toluene, xylene, hexane or a chlorinated hydrocarbon. The process according to the invention is suitably carried out at a temperature in the range 20—200°C, more especially in the range 80- 100°C. When secondary alcohols or phenols are being reacted in accordance with the invention, irrespective of whether 2—cyanoacrylic acid or an ester thereof is used, preferably the reaction is carried out in the presence of sulfur dioxide to optimize conditions, because of the tendency of cyanoacrylate monomers to polymerise under the reaction conditions. When 2—cyanoacrylic acid is used as a starting compound in accordance with the invention to prepare a 3—alkoxy-2-cyanopropionic acid ester, the water produced is continually removed by azeotropic distillation. Preferably, the total volume of the reaction solvent is kept constant. Further, preferably, when an alcohol or phenol is used as the weak nucleophile, said alcohol or phenol is added gradually to the reaction mixture. According to a second aspect of the invention there is provided a process for the preparation of a compound of the general formula (I): WO 95/26371 PCT/IE94/000 1 8 10 . CN I / < (1) R10 C0218 wherein R1 is: i) C1 or higher saturated, optionally mono- or 10 and R2 is: 15 20 polysubstituted, linear or branched alkyl; ii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); iii) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; or v) a phenyl or optionally mono- or polysubstituted phenyl group, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or 10 15 W0 95/26371 PCT/IE94/000 18 ll vii) a mono— or polysubstituted biphenyl, naphthyl or. other cyclic or polycyclic aromatic or heteroaromatic group. which comprises reacting 2—cyanoacrylic acid or an ester thereof with an alcohol or phenol in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic catalyst. The following scheme depicts the reactions involved in the process according to the second aspect of the invention -hereinabove described: (a) .= < + . 1 I < 2 COZRZ R O COZR CN CN \/ (b) =< + ROH —————> COZH RO CO2H CN CN 2 CN (c) = < + R1QH —-—-> ("'1 L0}; f?‘ co2H R10 co2H RIO C0218 wherein R1 and R2 are as hereinabove defined. In accordance with the second aspect of the invention, there is produced 3—a1koxy- and 3—aryloxy—2-cyanopropionic acids and esters thereof which may be employed as precursors to useful polymerisable 2—cyanoacrylic acid esters, said precursors having desirable chemical and physical properties. WO 95/26371 PCT/IE94/00018 12 Thus, the. invention ‘provides a compound of the general formula (Ia): CN / < . (Ia) R10 CO2R2 wherein R1 is: i) a methyl group; 5 - ii) C2 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or po1y(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, 10 linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; or vi) a phenyl or optionally mono- or polysubstituted phenyl group, 15 and R2 is: i) a hydrogen atom; ii) C1, optionally mono-substituted, alkyl; iii) C2 saturated alkyl except when R1 is methyl; iv) C2 saturated, mono- or polysubstituted alkyl; V) C3 or higher saturated, optionally mono- or 20 polysubstituted, linear or branched alkyl; 10 15 20 25 WO 95/26371 PCT/IE94/00018 1 3 vi) C5 or higher saturated, optionally mono—._o'r... .- polysubstituted cycloalkyl or poly(cycloalkyl)§ vii) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; viii) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; ix) a phenyl or optionally mono- or polysubstituted phenyl group; or X) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group. Functional groups which are representative of those which would normally be used to substitute an R1 or R2 group as hereinabove defined include but are not limited to halogen, carboxyl, nitrile, acylamino and heteroelement-containing groups. In accordance with a third aspect of the invention the weak nucleophile can be a sulfhydryl group as found, for example, in a thiol, a thio acid or a dithio acid. This provides a further method for the reversible protection of the chemically reactive carbon-carbon double bond of polymerisable alkyl or aryl 2-cyanoacrylates whereby a thio compound added across the double bond can be eliminated under the conditions of base—catalysed anionic polymerisation to yield po1y(alkyl or aryl 2-cyanoacrylates) together with the relevant thio compound. The process according to the third aspect of the invention can be used for the preparation of a compound of the general formula (II) and its subsequent conversion into a 2-cyanoacrylate polymer WO 95/26371 wherein R3 is: i) 10 and R4 is: 15 20 PCT/IE94/00018 14 CN / < (11) R38 CO;,_R4 C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl or cycloalkyl; ii) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl or alkynyl; iii) a phenyl or optionally mono- or polysubstituted phenyl group; iv) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group; y) an acyl or thioacyl group; vi) a dialkyl- or diarylphosphonyl group; or vii) a dialkyl- or diarylthiophosphonyl group, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl; WO 95/26371 PCT/IE94/00018 15 v) C3 or higher, optionally ‘mono— or polysubstituted linear or branched alkynyl; vi) a phenyl or optionally mono— or polysubstituted ' phenyl group; or 5 I vii) a mono— or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group, which comprises reacting 2-cyanoacrylic acid or an ester thereof with a sulfhydryl compound in the presence of an inert solvent under 10 polymerisation inhibiting conditions and in the presence of an acidic catalyst under the conditions hereinabove defined followed by elimination of the sulfhydryl addend to give a 2—cyanoacrylate monomer which then polymerises. Alternatively, the sulfliydryl compound itself can act as the acidic l5 catalyst. The following scheme depicts the reactions involved in the process according to the third aspect of the invention: /CN CN = \ 4 + R3SH ——> H 2» CO2R R35 CO2R4 CN CN m’ n COZR4 CO2R4 20 wherein R3 and R4 are as hereinabove defined. W0 95/26371 PCT/IE94/00018 16 V In this third aspect of the invention there is provided . ~. . 3-thioalkyl—, 3-thioa1yl—, 3-thioacyl—, 3-dithioacyl—, 3-thiophosphoryl- and 3-dithiophosphoryl—2-cyanopropionic acids and esters thereof which may be employed as precursors to useful polymerisable 2- 5 cyanoacrylic acid esters. Thus the invention provides a compound of the general formula (Ila): CN / < (Ila) R38 CO2R4 wherein R3 is: i) C1 optionally monosubstituted alkyl wherein the 10 substituent is not a free carboxyl group whenever R4 is an ethyl group; ii) C2 optionally mono- or polysubstituted saturated alkyl wherein the or each substituent is not a primary amino group or a hydroxyl group whenever R4 is an 15 ethyl group, or wherein the substituents do not include a primary amino group and a free carboxy group attached to the same carbon atom whenever R4 is an ethyl group, or wherein the [3—substituent is not another sulfur atom bearing a 2'-carboxy-2'-cyanoethyl 20 function as the free carboxylic acid or as its ethyl or allyl ester whenever the substituent R4 is, respectively, a hydrogen atom, an ethyl group or an allyl group; iii) C3 linear or branched, optionally mono- or polysubstituted saturated alkyl; 25 iv) C4 linear or branched, optionally mono- or polysubstituted saturated alkyl wherein the mono- W0 95/26371 10 15 20 and including PCT/IE94/00018 17 substituent is not a hydrogen atom whenever R4 is an ' ethyl group; v) C5 or higher linear or branched, optionally mono- or polysubstituted saturated alkyl or cycloalkyl; vi) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl; vii) C3 or higher, optionally mono- or polysubstituted linear or branched alkynyl, viii) an unsubstituted phenyl group whenever R4 is not an ethyl group; ix) a mono- or polysubstituted phenyl group; x) a mono- or polysubstituted biphenyl, naphthyl or other polycyclic aromatic or heteroaromatic group, xi) an acyl group other than acetyl except when R4 is other than an ethyl group when R3 may then be any acyl group; xii) a thioacyl group; xiii) a dialkyl or diaryl phosphonyl group excluding diethyl phosphonyl whenever R4 is an ethyl group; xiv) a dialkyl or diaryl thiophosphonyl group excluding diethyl thiophosphonyl when R4 is an ethyl group, sulfoxides and sulfones derived from any of i) - x) above, WO 95/26371 and R4 is: 10 PCT/IE94/00018 18 , i) _ a hydrogen. atom; ii) C1 or higher, linear or branched optionally mono- or polysubstituted saturated alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cyc1oalkyl); iv) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl; V) C3 or higher, optionally mono- or polysubstituted linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group. 15 In accordance with a fourth aspect of the invention the weak nucleophile can be a dialkyl or diaryl phosphite, a dialkyl or diaryl thiophosphite, a phosphine or other phosphorus nucleophile. This aspect of the invention provides another method for the reversible protection of the chemically reactive carbon-carbon double bond of 20 polymerisable alkyl or aryl 2-cyanoacrylates as outlined supra. The process according to the fourth aspect invention can be used for the preparation of a compound of the general formula (III) and its subsequent conversion into a 2—cyanoacrylate polymer: W0 95/26371 PCT/IE94/00018 19 _ 5 Ix’ RO\ / < (111) 6 L P\ C0212 \\_R5O/ wherein R5 is: i) C1 or higher linear or branched saturated alkyl; ii) C5 or higher cycloalkyl; or iii) a phenyl or optionally mono- or polysubstituted 5 phenyl group, and R6 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or 10 polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl; V) C3 or higher, optionally mono- or polysubstituted linear or branched alkynyl; 15 vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono-or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic g1'O11p, 20 and X is: i) an oxygen atom; or W0 95/2637] 10 PCT/IE94/000 18 20 ii) V a sulfur atom; which comprises reacting 2-cyanoacrylic acid or an ester thereof with a phosphite or thiophosphite in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic catalyst under the conditions outlined .hereinabove defined followed by elimination of the addend to give a 2-cyanoacrylate monomer which then polymerises. Alternatively, the phosphite or thiophosphite itself can act as the acidic catalyst. The following scheme depicts the reactions involved in the process according to this aspect of the invention: CN 0 O H /CN 5 ll (R50) pHA+ -= ——-> (RO)2P 6—-> 2 CN CN :> n CN S S n ,CN 5 II (R50) PH+ = 6 -—>(R0)2P CORs-* COZR 2 CN CN —-> n W0 95/26371 10 15 20 PCT/IE94/00018 21 -wherein R.5 and R5 are as hereinabove defined. A In this fourth aspect of the invention there is provided 2-cyano- 3-(dialkylphosphono)-, 2-cyano-3-(diarylphosphono)-, 2-cyano-3- (dia1ky1thiophosphono)- and 2-cyano-3-(diarylthiophosphono)- propionic acids and esters thereof which may be employed as precursors to useful polymerisable 2-cyanoacrylic acid esters. Thus the invention provides a compound of the general formula (IIIa): CN /‘R50 / < (IIIa) , \ 6 I‘ P\ COZR \\\ _ / \ X wherein R5 is: ' i) a methyl group; ii) an ethyl group except when R6 is an ethyl group or a hydrogen atom; iii), a propyl group or substituted propyl group; iv) an isopropyl group except when R6 is an ethyl group or a hydrogen atom and when X is an oxygen atom; V) C4 or higher saturated, optionally mono- or polysubstituted linear or branched alkyl; vi) a cyclohexyl group; vii) an unsubstituted phenyl group except when R6 is an ethyl group or a hydrogen atom and when X is an oxygen atom; wo 95/25371 5 i and R6 is:' 10 15 and X is: 20 PCT/IE94/000 18 22 viii) a mono- or polysubstituted phenyl group; or ix) a phenyl group attached simultaneously and ortho to both oxygen atoms except when R6 is an ethyl group and when X is an oxygen atom, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic gl'O11p, i) an oxygen atom; or ii) a sulfur atom. According to a fifth aspect of the invention there is provided a process for the preparation of a compound of the general formula (IV) and its subsequent conversion into a 2-cyanoacrylate polymer: WO 95/26371 PCT/IE94/00018 23 CN C ,——< (IV) Y'} R73P+ co2R8 wherein R7 is: i) C4 or higher saturated alkyl or cycloalkyl; ii) phenyl except when R8 is an ethyl group; or iii) a mono- or polysubstituted phenyl group, 5 and R3 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cyc1oalky1); 10 iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted 15 phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group, and Y is: a negatively charged ion, 20 which comprises reacting 2—cyanoacrylic acid or an ester thereof with a phosphine in the presence of an inert solvent under polymerisation 10 15 WO 95/26371 PCT/IE94/000 18 24 inhibiting conditions and in the presence of anacidic catalyst undertheg " conditions hereinabove defined followed by elimination of the phosphine to give a 2-cyanoacrylate monomer which then polymerises. Suitable negatively charged ions as values for Y include but are not limited to a chloride or other halide ion, a trifluoroacetate ion or a perchlorate ion. Preferably the acidic catalyst has as its counterion the desired negatively charged ion Y of formula (IV). The following scheme depicts the reaction involved in the process according to the fifth aspect of the invention: CN 7 /CN HY Y" R71-3l-/ I - —> C0212 CN CN TD» n _ 8 wherein R7, R3 and Y are as hereinabove defined. In this fifth aspect of the invention there are provided salts of 2- cyano—3-(trialkylphosphonium)- and 2-cyano—3—(triarylphosphonium) propionic acid and esters thereof which may be employed as precursors to useful polymerisable 2—cyanoacrylic acid esters. Thus, the invention provides a compound of the general formula (IVa): W0 95/26371 wherein R7 is: i) 5 and R3 is: 10 15 and Yis: PCT/IE94/0001 8 25 CN Y '} R73P+/ : ( Va) COZR8 C4 or higher saturated alkyl or cycloalkyl; ii) phenyl except when R8 is an ethyl group; or iii) a mono- or polysubstituted phenyl group, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalky1); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; V) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group, a negatively charged ion. 10 15 20 WO 95/26371 PCT/IE94/00018 26 Suitable negatively charged ions as values for Y include but -are "not limited to a chloride or other halide ion, a trifluoroacetate ion or a perchlorate ion. In a sixth aspect of the invention the weak nucleophile can be a carbon acid. This provides a further ‘method for the reversible protection of the carbon-carbon double bond of polymerisable 2- cyanoacrylic acid esters. The process according to the sixth aspect of the invention can be used for the preparation of a compound of the general formula (V) and its subsequent conversion into a 2-cyanoacrylate polymer: CN (V) 9 11 R R10 wherein R9 is: i) ahydrogen-atom; ii) an electron-withdrawing organic functional group including but not limited to groups such as nitro, carboalkoxy, cyano, acyl, sulfonyl and phosphonyl groups; and R10 is: an electron-withdrawing organic functional group including but not limited to groups such as nitro, carboalkoxy cyano, acyl, sulfonyl and phosphonyl groups, and R11 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; W0 95/26371 PCT/IE94/00018 27 iii) C5» or higher saturated, optionally mono- or . polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; 5 i v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or 10 " other cyclic or polycyclic aromatic or heteroaromatic gI‘O11p, _ which comprises reacting 2-cyanoacrylic acid or an ester thereof with a singly or doubly activated carbon acid in an inert solvent under polymerisation-inhibiting conditions and in the presence of an acidic 15 catalyst under the conditions hereinabove defined followed by elimination of the addend to give a 2—cyanoacrylate monomer which then polymerises. The following scheme depicts the reaction involved in the process according to the sixth aspect of the invention: R9 CN \ ,cN CH2 + =\ 11 R10 / co2R“ R9 C02R 20 R10 wherein R9, R10 and R11 are as hereinabove defined. Thus the invention provides compounds of the general formula (Va): WO 95/26371 PCT/IE94/00018 28 (Va) R9 co2R“ R10 wherein R9 is: i) a hydrogen atom except when R10 is a nitro group 5 10 15 R10is: and R11is: 20 and R11 is an ethyl group; ii) a carboxymethyl group except when R10 is a nitro group and R11 is an ethyl group; iii) a carboxyethyl group except when R10 is a carboxyethyl group or an acetyl group or a cyano group when R11 is an ethyl group; iv) a carboxyalkyl group wherein the alkyl radical is C3 or higher saturated, linear or branched; ' v) an acyl or aroyl group; vi) any other compatible electron-withdrawing organic functional group including but not limited to nitro, cyano, sulfonyl and phosphonyl groups, any compatible electron-withdrawing organic functional group including but not limited to groups such as nitro, carboalkoxy, cyano, acyl, aroyl, sulfonyl and phosphonyl groups, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; 10 15 20 25 W0 95/26371 PCT/IE94/00018 29 iii) C5 or higher saturated, optionally mono— or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono— or polysubstituted, linear or branched alkenyl; V) C3 or higher, optionally mono— or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono— or polysubstituted phenyl group; or vii) a mono— or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group. The processes according to the invention can be carried out in a simple, rapid, facile one—step manner with attendant advantages. Thus, the process according to the invention is a "one-step" process in contrast with the prior art methods described supra with their inherent limitations. The reversible protection afforded by the invention can be used to protect the carbon—carbon double bond of a wide range of 2- cyanoacrylate monomers including substituted or unsubstituted long- chain alkyl cyanoacrylates and multi-functional cyanoacrylates including bis—cyanoacrylates. The invention also provides a composition comprising a compound of any of the formulae (1), (II), (III), (IV) or (V) as hereinbefore defined. Such compositions can include excipients such as a thinner. The compounds of the formulae (1), (II), (III), (IV) and (V) hereinbefore defined can be used in adhesive compositions. 5 10 15 20 25 WO 95/26371 PC T/IE94/000 18 30 The invention also provides poly(cyanoacrylate) materials formed from a compound of any one of the formulae (1), (11), (III), (IV) and (V) hereinbefore defined. A further use of the compounds of any one of the formulae (1), (H), (III), (IV) and (V) hereinbefore defined is in the formation of poly(cyanoacrylate) films. Such films include single or multi-layer Langmuir-Blodgett films. The compounds of the formulae (1), (II), (III), (IV) and (V) hereinbefore defined can also be used in the preparation of poly(cyanoacrylate) nanocapsules. The compounds of the formula (I) are especially suitable for the preparation of such poly(cyanoacrylate) nanocapsules. Poly(cyanoacrylate) nanocapsules prepared in accordance with the invention suitably contain an active agent such as a drug. Compounds of any one of the general formulae (1), (II), (III), (IV) and (V) wherein the esterifying group R2, R4, R5, R8 or R11, as appropriate is a terminal alkyne could be precursors to useful 2- cyanoacrylate monomers and polymers which could be further modified by cross—linking via the well-known Glaser oxidative coupling reaction. Compounds of any one of the general formulae (1), (11), (HI), (IV) and (V) wherein the esterifying group R2, R4, R6, R3 or R11, as appropriate incorporates di- or poly-yne functionality may be valuable for the formation of thin films having useful non—1inear optical properties. The compounds according to the invention are expected to be capable of broad application, particularly where thin-film technology is involved and especially where Langmuir-Blodgett type films are desirable. 10 15 20 25 30 W0 95/26371 PCT/IE94/00018 31 Poly(alkyl 2—cyanoacrylate) films are used as semiconductor , . coating materials wherein they are applied to act as rnicrolithographic photoresists due to their sensitivity to electron beams and to X-rays as described, for example, in U.S. Patent No. 4,279,984, and in Matveeva, N.K., (1990), Biol. Membr., Vol. 7, No. 11, 1200-1204. Such films are usually deposited by application of a solution of an alkyl 2- cyanoacrylate polymer, or its monomer followed by its subsequent polymerisation. Even solutions of cyanoacrylate polymers tend to be unstable over time as indicated in Patent Publications JP 9262588 and JP 0462558, and vapour-deposition techniques have been devised in an attempt to overcome this disadvantage (Woods, J ., Guthrie, J ., Rooney, J ., Kelly, L., Doyle, A. and Noonan, E., (1989), Polymer, Vol. 30, No. 6, 1091-1098). This requires special apparatus, however. The compounds according to the invention offer an alternative method of depositing such films since they are stable as solutions in inert solvents and can be converted into poly(alkyl 2—cyanoacrylates) under anionic conditions. Furthermore, when films laid down in this way are Langmuir-Blodgett or other very thin films then the necessary period of exposure to electron beams or to X-rays should be beneficially reduced. Also such thin films can be expected to greatly modify the capacitance effect and the relative permittivity effect thereby improving dynamic memory capability of the microchip. Accordingly, it is expected that these thin films will find application in the manufacture of low power microchips. Another benefit resulting from the application of thinner films is -increased transconductance with accompanying improved efficiency in terms of speed and memory capacity of thus formed devices. Reduced voltages employing such devices result in reduced power dissipation. Additionally, tighter control over threshold voltage means that such devices may find use in lower power applications with sub-threshold operation in VLSI (very large-scale integration) required, for example, in hearing aids and implants. 10 15 20 25 30 W0 95/26371 PCT/IE94/000 18 32 Thinner film thickness also means improved resolution and reduced feature sizes on microchips, such as, for example, the important interconnection feature between two adjacent "gates" resulting in improved overall performance. When the alkyl ester part of the alkoxycyanopropionic ester molecule contains a metal such as iron (for example, in a ferrocenyl function) and the alkyl of the alkoxy part of the molecule is a long- chain alkyl group, the resulting ordered Langmuir-Blodgett poly(alkyl cyanoacrylate) film laid down on a substrate such as a silicon chip may then be etched with a laser. Such treated areas of film would give rise to low-coke iron or iron oxide indented regions depending on whether the ablation is carried out under an inert atmosphere such as nitrogen or in the oxidising atmosphere of the air, respectively. Also, when sulfur is additionally contained in the alkyl ester radical of such a long- chain alkoxycyanopropionic acid ester, a well-ordered Langmuir- Blodgett poly(alkyl cyanoacrylate) layer would be expected. to give semiconductor FeS regions when etched with a laser. More easily programmable EPROMS may also result from application of this technology. The prospect of achieving ultra-thin films as described herein opens up a wide range of possible applications in the manufacture of future generations of integrated circuits. Many of the key factors which must be present for the specifications of future semiconductor devices as predicted in the literature (see for example Chenming, Hu (1993) Proceedings of the IEEC, Vol. 81, No. 5, p. 682-689), such as, for example, decreased feature size to less than O.lum, improved feature definition, higher speeds, greater density, increased reliability and thinner oxides, are facilitated by the present invention. Thin, tightly controlled, low impurity films offer many advances in semiconductor device fabrication. Depolymerisation by means of laser (or other high-energy beam) etching has potential applications for accurately controlled volumetric geometries. Areas of surface can be 10 15 20 25 30 WO 95/26371 PCT/IE94/00018 33 selectively insulated. The engineering of regions, interconnects, ' channels and layers could be accomplished largely through a chemical route using available production equipment. By laying multiple layers of poly(cyanoacrylate) film where the alkyl ester contains a metal, a semiconductor or an oxide (or where the oxide is produced by carrying out ablation in an oxidising atmosphere), laser etching can produce the features hereinabove mentioned. Furthermore, device trimming, essential in analogue integrated circuits, is also more readily achievable to improved accuracies. The application of the present invention to semiconductor technology may provide digital devices with very low gate delays operating at lower voltages (l.5V), thereby offering greater circuit speeds while maintaining low chip power levels. The reduced feature size, junction depth, and effective channel length could offer SRAM densities up to 4G. While operating voltage can be reduced, as mentioned, the technology could offer tighter control over threshold voltages by ensuring very low impurity levels. Linear devices could benefit from the improved control in manufacturing and region/feature definition, low power and higher levels of integration. MOS and bipolar technologies are equally amenable to the processes. Treatment of thin poly(cyanoacrylate) films with laser or high energy plasma gives coke-free clean holes. Solvent removable (linear poly(cyanoacrylate) films may be laid down on silicon wafers from the monofunctional 2—cyanopropionate derivatives described herein and then masked. Subsequent treatment with laser followed by treatment with hydrofluoric acid (HF) and subsequent removal of remaining polymer using common organic solvents such as benzene, chloroform or acetone would be expected to give clean, well defined holes on the silicon surface. 10 15 20 25 30 WO 95/26371 PCT/IE94/00018 34 Cross-linked and insoluble poly(cyanoacrylate) films may also be _ .~ . ‘ laid down on a silicon surface from multifunctional 2—cyanopropionate derivatives described herein and again be masked and treated in the manner hereinabove described with laser followed by HF. A further poly(cyanoacrylate) layer could then be deposited on the stable solvent- resistant cross-linked poly(cyanoacrylate) film from an appropriate 2- cyanopropionate derivative. When the ester portion of this derivative contains a metal such as iron, for example, in a ferrocenyl radical, ablation of exposed regions of resulting poly(cyanoacrylate) film in an inert atmosphere would give a layer of metal - in this case iron - on the surface. Such a layer would, of course, be conducting in nature. A further layer of silicon dioxide could be laid down, where required, by initial deposition of a poly(cyanoacrylate) film from a silicon-containing (ester portion of molecule) 2—cyanopropionate derivative followed by treatment with laser or high energy plasma in an oxygen—rich atmosphere. Such a layer could also be directly laid down on the silicon surface. In this way, silicon chips containing insulating, conducting and semiconductor multilayers may be fabricated. Also phosphorus—containing poly(cyanoacrylate) films could be laid down from equivalent cyanopropionate derivatives directly onto silicon. Ablation of unmasked regions of film with laser in an inert atmosphere should give phosphorus—doped silicon semi-conductor region used in pnp transmission. Sulfur-containing cyanopropionate derivatives would in the same way as above give sulfur doped semiconductor regions on the silicon surface following treatment of polymer with laser. Such sulfur-doped areas would be expected to improve adhesion of subsequently formed metal films from ablation of metal-containing poly(cyanoacrylate) prepared from a metal-containing (in the ester portion of the molecule) 2—cyanopropionate derivative. 10 15 20 25 30 WO 95/26371 PCT/IE94/0001 8 35 Diacety_lene functional 2.-cyanopropionate derivatives (ester . _ portion of molecule) would give poly(cyanoacrylate) films which could be further modified. For example, some regions could be exposed to high energy ultra-violet light to give, by a free-radical polymerisation process, serni-conducting poly(acety1ene) regions - masked or remaining polymer 1-ayer would be an insulating region. Doping of the semi—conducting poly(acetylene) region by, for example, iodine would give conductive zones. Hence three types of region (insulating, semiconducting, conducting) could be designed into the same poly(cyanoacrylate) monolayer. Such techniques would be useful for the fabrication of molecular electronic devices for super-thin pnp transmission with dramatic component size reduction (down to 10-50 A). A wide variety of poly(cyanoacrylate) films could be prepared from the cyanopropionate derivatives according to the invention for use in photosensitive, non—linear optical and liquid crystal applications. Non-linear optical 2—cyanopropionates would possess asymmetric radicals in the alkyl portion of the molecule. In the same way liquid crystal 2—cyanopropionates would possess cholesterol or methoxy/cyanobiphenyl functionality in the alkyl portion of the molecule. Patent Publication EP 146,505 describes the use of thin (10 um) poly(alkyl 2-cyanoacrylate) films in a process for image formation. The ability to lay down Langmuir—Blodgett, multi-layer or other very thin films utilising compounds of the invention which are precursors to alkyl 2-cyanoacrylate esters and thus to poly(alkyl 2-cyanoacrylates) should permit further useful developments in this area. Conversion of the monomers produced in accordance with the invention into polymer may be carried out by prior application of a V base such as an amine or tetraalkylammonium hydroxide to the surface to be coated or application of base from above as vapour, for example once a film of the compound has been laid down on the untreated surface. In addition the compounds prepared in accordance with the 10 15 20 25 30 35 W0 95/26371 PCT/IE94/00018 36 _ invention could be vapour depositedfollowing the method of Woods J ., » ' et al. supra. Priming of surfaces to be bonded by a suitable base means that the compounds in accordance with the invention may be used as adhesives as indicated above. The cyanoacrylate monomer produced in situ between the two surfaces would be expected to polymerise rapidly in the presence of base forming a solid polymer and hence an adhesive bond. The presence’ of an alcohol or phenol co-product may not be disadvantageous since in fact alcohols have been used as physical additives with cyanoacrylate adhesives to impart porous bonding ability to same as described in Patent Publications JP 55012166 and JP 88039627. Long chain or fluorine containing alkoxycyanopropionic esters would be expected to wet previously difficult to bond surfaces such as polyolefins or poly(tetrafluoroethy1ene) (PTFE) and provide adhesive bonds between previously appropriately base-primed substrates. However, even peeled poly(cyanoacrylate) films have found use in a transfer printing process in Patent Publication JP 8251487. Similarly long chain alkoxcyanopropionic esters instead of aligning themselves onto surfaces as Langmuir—Blodgett films may form micelles in aqueous solution and be used as a means to encapsulate active agents such as drugs upon subsequent polymerisation by addition of a base to the medium to form nanocapsules. This technique of rnicelle polymerisation has previously been employed starting with alkyl cyanoacrylate monomer to give pilocarpine-containing poly(alkyl cyanoacrylate) nanoparticles (Harmia-Pulkkenes, T, Tuomi, A., and Kristoffersson, E. in J . Microencapsulation 1989, Vol. 6, No. l p. 87). As indicated above, the use of poly(alkyl cyanoacrylates) is not limited to the encapsulation of drugs. Thus poly(alkyl cyanoacrylates) can be used to encapsulate other active agents. They have been used for example in an electrostatic suspension developer (Patent Publication DE—A 35 14 867). Cyanoacrylate monomer itself has been rnicroencapsulated together with colour-former in a heat—developable, photo- and pressure—sensitive composition in Patent Publication JP 92278953. In the same way, alkoxycyanopropionic acid esters should be able to be rnicroencapsulated by poly(alkyl cyanoacrylate) to give an 10 15 20 25 WO 95/26371 PCT/IE94/00018 37 adhesive composition when used inconjunction with appropriate basic . primer. Other potential applications for the compounds prepared in accordance with the invention include use as transparent fixation agents of plant tissues (the portions to be fixed should be treated with appropriate base) which may offer advantages over the more reactive and less ‘discriminate’ cyanoacrylate monomer described in Patent Publication JP 63255201. Two recently reported applications of poly(alkyl -cyanoacrylates) is their use as passivating layers on the lithium anode of lithium-thionyl chloride cells (Hsing Yaw H., Hsien Wen K., J. Power Sources 1989 Vol. 26 No. 3-4 p. 419) and Langmuir-Blodgett poly(cyanoacrylate) films as coatings for indium antimonide capacitors (Matveeva, N.K., Pasekov, V.F., and Sa Vel'eva, L.V. (Mikroelektronika Akad. Nauk. SSSR 1991, Vol 20, No. 5 pp. 501-503)). The compounds prepared in accordance with the invention could be used to lay down such layers in photo-resist fabrication. Brief Description of Figures Fig. l is a Langmuir isotherm for the Langmuir-Blodgett film formed in Example 7; Fig. 2 is a Langmuir isotherm for the Langmuir-iBlodgett film formed in Example 8; Fig. 3 is a Langmuir isotherm for the Langmuir—B1odgett film formed in Example 9; and Fig. 4 is a graph of area at constant pressure versus time before and after transferring a Langmuir-Blodgett film formed as described in Example 9 to a silicon [100] surface. 10 15 20 25 30 WO 95/26371 PCT/[E94/00018 38 Modes for Carrying Out the Invention The invention will be further illustrated by the following Examples. Example 1 Synthesis of 2-cyano-3-hexadecyloxypropionic acid 2-Cyanoacrylic acid (0.98 g), p—toluenesulfonic acid (0.17 g) and hydroquinone (0.05 g) were dissolved in dry benzene (250 ml) contained in a 500 ml flask which had previously been washed with 10% sulfuric acid and dried using acetone, and which was fitted with a stirrer, a thermometer, sulfur dioxide and argon inlet adaptors, a dosing funnel and a Liebig condenser arranged for distillation. The solution was sparged with sulfur dioxide and 50 ml of water—benzene azeotrope was distilled off in order to ensure anhydrous conditions. The condenser was then arranged for reflux and a solution of n- hexadecyl alcohol (2.42 g) in dry benzene (50 ml) was added dropwise to the boiling contents of the flask with stirring and continuous sparging with dry sulfur dioxide. Following addition of the alcohol, the solution was heated under reflux during two hours. After this time, sparging with sulfur dioxide was substituted by sparging with argon and the volume of the mixture was reduced to 50 ml by distillation of solvent. The residue was extracted using boiling heptane (100 ml), and heptane and remaining benzene were removed in vacuum to give an oil which crystallised. The solid was recrystallised from hexane to give 2- cyano-3-hexadecyloxypropionic acid (1.37 g; 40%), m.p. 63—65°C, calculated for C2()H37NO3: C 70.8, H 10.1, N 4.1%; found C 69.15, H 10.07, N 4.65%, 1H NMR (C5D6) 0.81 (3H, t, J = 5.7 Hz, —CH3), 1.18 (28H, m, -CH2—), 2.87 (1H, ABX dd, JXA = 5.28 Hz, JXB = 4.43 Hz, -CH(CN)CO2H), 3.07 (2H, t, J = 6.44 Hz, -OCHZCHZ-), 3.18 (1H, ABX m, J AB = 9.30 Hz, -OCL-I_2CH(CN)CO2H), 3.31 (1H, ABX m, -OCfl2CH(CN)CO2H) and 7.13 (1H, s, -CO2H) p.p.m. 10 15 20 25 30 WO 95/26371 PCT/IE94/000 18 39 Example 2 Synthesis of ethyl 2-cyano-3-hexadecyloxypropionate Ethyl 2-cyanoacrylate (1.25 g), 2—cyanoacry1ic acid (0.05 g) and hydroquinone (0.05 g) were dissolved in a mixture of dry benzene (200 ml) and dry toluene (50 ml) contained in a 500 ml flask which had previously been washed with 10% sulfuric acid and then dried using acetone, and which was fitted with a stirrer, a thermometer, sulfur dioxide and argon inlet adaptors, a dosing funnel and a Liebig condenser arranged for distillation. The solution was sparged with sulfur dioxide while water-benzene azeotrope (50 ml) was distilled off in order to ensure anhydrous conditions. The condenser was then arranged for reflux and a solution of n-hexadecyl alcohol (2.7 g) in dry benzene (50 ml) was added to the boiling contents of the flask with stirring and continuous sparging with dry sulfur dioxide. Following addition of the alcohol the mixture was continuously sparged with sulfur dioxide and heated in such a manner that slow distillation of solvent continued during two and one-half hours. After this time, sparging with sulfur dioxide was substituted by sparging with argon and the volume of the reaction mixture was reduced to 50 ml by _ distillation. The remaining solution was cooled, a solid residue which formed was removed by filtration, and remaining solvent was removed by distillation in vacuum to give a solid product (3.4 g). This was recrystallised from hexane to give ethyl 2-cyano—3-hexadecyloxy propionate (2.37 g; 61%), m.p. 44-46°C, g for C22H41NO3: C 71.93, H 11.17, N 3.81%; £Q1.1L1 C 72.17, H 11.68, N 3.56%,1H NMR (C6D6) 0.847 (3H, m,‘-(CH2)nCfl3), 0.913 (3H, t, J = 7.16 Hz, -OCH2C_I:1.3), 1.42 (28H, m, —CH2-), 3.01 (1H, ABX dd, JXA = 5.21 Hz, JXB = 5.23 Hz, —CH(CN)CO2Et), 3.23 (2H, t, J = 6.32 Hz, -CH2OCH2CH-), 3.42 (1H, ABX m, J AB = 9.35 Hz, -OCL-I_2CH(CN) CO2Et), 3.53 (1H, ABX m, —OCfl2CH(CN)CO2Et) and 3.88 (2H, q, J = 7.16 Hz, -CO2CH2CH3) p.p.m. 10 15 20 25 30 WO 95/26371 PCT/IE94/00018 40 _ Example 3 ‘ Synthesis of hexadecyl 2-cyano-3-hexadecyloxypropionate 2-Cyanoacrylic acid (0.96 g, 0.01 mol), p—toluenesulfonic acid (0.17 g) and hydroquinone (0.05 g) were dissolved in dry benzene (250 ml) contained in a 500 flask which had previously been washed with 10% sulfuric acid and then dried using acetone, and which was fitted with a stirrer, a thermometer, sulfur dioxide and argon inlet adaptors, a dosing funnel and a Liebig condenser arranged for distillation. The solution was sparged using dry argon while water-benzene azeotrope (50 ml) was distilled off in order to ensure anhydrous conditions. The condenser was then arranged for reflux and a solution of n—hexadecyl alcohol (2.42 g 0.01 mol) in dry benzene (100 ml) was added to the boiling contents of the flask with stirring and continuous sparging with dry sulfur dioxide. Following addition of the alcohol, the mixture was refluxed during two hours. After this time, the sulfur dioxide sparging was substituted by argon sparging and the condenser was arranged for distillation. A solution of n—hexadecyl alcohol (2.6 g, 0.0108 mol) in dry benzene (100 ml) was added dropwise with constant removal of solvent by distillation. Following this addition, dry benzene (200 ml) was added and the mixture was distilled with stirring and constant sparging using argon until the volume had been reduced to 50 ml. The residue was extracted using boiling hexane (100 ml), and hexane and remaining benzene were removed in vacuum after prior cooling and filtration to give a solid residue (3.95 g). This was recrystallised from hexane to give the hexadecyl ester of 2-cyano—3-hexadecyloxypropionic acid (3.4 g; 60%) m.p. 42-43°C, _caQ1_l_z1t_ecl for C35H69NO3: C 76.73, H 10.48, N 2.48%; mm C 75.57, H 11.09, N 2.59%, 1H NMR (C5D5) 0.85 (6H, 1, J — 6.2 Hz, 2 @ —CH2CH3), 1.12 (4H, m, 2 @ -CH2C_H_3), 1.33 (52H, m, -CH2-), 2.94 (1H, ABX dd, JXA = 5.42 Hz, JXB = 5.10 Hz, -CH2Cfl(CN)CO2-), 3.10 (2H, 1, J = 6.3 Hz, —cH2oCH2cH(CN)—), 3.29 (1H, ABX m, JBA = 9.33 Hz, —OCH_2CH(CN)-), 3.42 (1H, ABX m, -OC_H2CH(CN)-) and 3.86 (2H, 1, J = 6.43 Hz, -CO2C_H2CH2-) p.p.m. 10 15 20 25 30 WO 95/26371 PCT/IE94/00018 41 Example 4 Preparation of polygethyl 2-cyanoacrylate from ethyl 2-cyano-3- hexadecyloxypropionate Ethyl 2-cyano-3-hexadecyloxypropionate (0.36 g) was dissolved in ethanol (5 ml) and water (1 ml) and the mixture was stirred during 24 hours to give an amorphous colourless solid. This solid was separated by centrifugation and dried in vacuum to give 0.35 g of an equimolar mixture of hexadecyl alcohol and poly(ethyl 2- cyanoacrylate, calculated C 71.93, H 11.17, H 3.81, found C 70.03, H 10.94, N 3.35%. The mixture was washed with alcohol and with acetone, and the solid residue was dissolved in chloroform. It was then precipitated with hexane, filtered and dried in vacuum to give 0.1 g of poly(ethyl 2-cyanoacrylate), Ql_c:_11Lc1t£c1 for C6H7NO2: C 57.6, H 5.6, N 11.2; fmljnd C 58.31, H 6.11, N 10.43%, 1H NMR (CDCI3) 0.77 (m, - OCHQCH3), 2.20-2.55 (m, -CH2-) and 4.23 (m, -OCHQCH3) p.p.m. Example 5 Preparation of poly: ethyl 2-cyanoacrylate from triphenyl((2-cyano—2- ethoxycarbonyl )ethyl )phosphonium trifluoroacetate To a solution of 1.6 g (2 ml, 12.5 mmol) of ethyl 2- cyanoacrylate and 2.6 ml (18 .mmol) of trifluoroacetic acid in 2 ml of dry chloroform was added dropwise with stirring and sparging with sulfur dioxide a solution of 3.28 g (12.5 mmol) of triphenylphosphine in 4 ml of dry chloroform. The mixture was stirred at room temperature during 20 minutes and solvents were then evaporated in vacuum. The residual oil contained triphenyl((2-cyano-2- ethoxycarbonyl)et.hyl)phosphonium trifluoroacetate, 31P NMR 21.82 p.p.m., 1H NMR (CDCI3) 1.06 (3H, t, —OCH2C_I:I_3), 3.72 (1H, m, - Cfl(CN)CO2Et), 4.00 (2H, m, -OCHZCH3), and 4.18 and 4.45 (each 1H, m, Ph3P-C_I;I_2—) p.p.m. A solution of 3 g of the above compound in 5 ml of acetone was added dropwise to 30 ml of water and the mixture was stirred during 24 hours to give an amorphous colourless solid. 10 15 20 25 WO 95/26371 PCT/IE94/00018 42 This solid was separated by centrifugation, washed sequentially with. _ water, alcohol and acetone, and dried in vacuum. It was then dissolved in chloroform, precipitated using hexane, filtered and dried in vacuum to give 0.72g (96%) of poly(ethyl 2-cyanoacrylate), calculated for C5H7NO2: C 57.6, H 5.6, N 11.2; mm C 58.01, H 5.86, N 10.83%, 1H NMR (CDCI3) 0.77 (3H, -OCH2Cfi3), 2.20-2.55 (2H, m, -CH2-) and 4.23 (2H, -OCLI_2CH3) p.p.m. Example 6 Preparation of poly(ethyl 2-cyanoacrylate) from ethyl 2-cyano-4- thiaoctanoate To a solution of 1.68 g (2 In], 18.7 mmol) of n-butylmercaptan in 2 ml of dry chloroform was added dropwise with stirring to a solution of 1.6 g (2 ml, 12.5 mmol) of ethyl 2-cyanoacrylate in 2 ml of dry chloroform. The mixture was stirred at 20°C during 24 hours when solvent was evaporated in vacuum to give a colourless transparent oil. This oil was distilled in vacuum to give 1.88 g (70%) of ethyl 2- cyano-4-thiaoctanoate, b.p. 110°C at 0.5 mm Hg, 1H NMR (CDCl3) 0.90 (3H, t, J 6 Hz, Cfl3CH2CH2-), 1.32 (3H, t, J 6.5 Hz, -OCH2Cfl3), 1.4 (2H, m, CH3CLI_2CH2-), 2.64 (2H, t, -CH2C_I-128-), 2.99 and 3.09 (each 1H, ABX, -SCHZCH-), 3.70 (1H, m, -CH2Cfl(CN)CO2Et) and 4.28 (2H, q, J 6.5 Hz, ~OCH2CH3) p.p.m. The above compound (1 g) was added dropwise to 30 ml of water and the mixture was stirred during 48 hours to give an amorphous colourless solid. This solid was separated by centrifugation, washed with water, dried in vacuum, - dissolved in chloroform, precipitated using hexane, filtered and dried in vacuum to give 0.53 g (92%) of poly(ethyl 2-cyanoacrylate), calculated for C6H7NO2: C 57.6, H 5.6, N 11.2; found C 57.23, H. 5.45, N. 11.62%, 1H NMR (CDCI3) 0.77 (m, -OCH2C_I;I_3), 2.20-2.55 (m, -CH2-) and 4.23 (m, -OC_I-12CH3) p.p.m. 10 15 20 25 W0 95/26371 PCT/H994/00018 43 Example 7 Formation of a Langmuir—Blodgett film using 2—cyano-3- hexadecyloxypropionic acid The title compound was dissolved in pure, dry chloroform to give a solution containing 1 g/L. A measured volume (8 x 1O'5 L) of this solution was applied to the surface of pure water of pH 7.13 contained in a Langmuir trough fitted with a movable barrier connected to a torsion balance and a data handling system. After allowing time for the chloroform to evaporate, the surface of the trough was swept by the barrier at a speed of 1.2 cm2/s'1 and the isotherm of surface tension in mN/m versus surface area of the film in cm2 was recorded. A classical Langmuir isotherm showing gas, liquid and solid phases was obtained and is reproduced in Fig. 1. Example 8 Formation of a Langmuir—Blodgett film using ethyl 2-cyano-3- hexadecyloxypropionate This experiment was carried out exactly as described for Example 7 supra except that the amount of chloroform solution of the title compound which was applied to the surface of the water in the trough was 6 x 105 L. The Langmuir isotherm obtained is reproduced in Fig. 2. Example 9 Formation of a Langmuir—Blodgett film using hexadecyl 2-cyano-3- hexadecyloxypropionate This experiment was carried out exactly as described for Example 7 supra. The Langmuir isotherm obtained is reproduced in Fig. 3. W0 95/26371 PCT/IE94/00018 44 Example 10 Formation of a Langmuir—Blodgett film using hexadecyl 2—cyano-3- hexadecyloxypropionate, and its transfer to a silicon |100| surface This experiment was initially carried out in the same way as 5 Example 9 supra. A stable, constant area Langmuir—Blodgett film was obtained and maintained at a surface pressure of 35mN/m. At t = 54s (Fig. 4) a portion of the film was transferred by dipping to a silicon [100] surface of known area, giving a fi1m—transfer ratio of 0.8:1.0. After dipping at t = 843 a stable Langmuir—Blodgett film of reduced 10 constant area was obtained. l0 15 20 25 W0 95/26371 PCT/IE94/00018 45 Claims: - 1. A process for the reversible coupling of a weak nucleophile to the carbon-carbon double bond of 2-cyanoacrylic acid or an ester thereof, so as to reversibly protect said bond, which comprises reacting 2-cyanoacrylic acid or an ester thereof with said weak nucleophile in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic catalyst. 2. A process according to Claim 1, wherein the weak nucleophile is an alcohol. 3. A process according to Claim 1, wherein the weak nucleophile is a phenol. 4. A process according to Claim 1, wherein the weak ' nucleophile is a thiol, a thiophenol, a thioamide or a thio or_dithio acid. 5. A process according to Claim 1, wherein the weak nucleophile is a dialkyl or diaiylphosphite, a dialkyl or diarylthiophosphite, a phosphine, or a phosphorus sulfenyl halide. 6. A process according to Claim 1, wherein the weak nucleophile is a carbon acid. 7. A process according to any preceding claim, wherein the acidic catalyst is a non—volatile acid. 8. A process according to Claim 7, wherein the non—volatile acid is an aliphatic sulfonic acid or an aromatic sulfonic acid. 9. A process according to Claim 8, wherein the acid catalyst is methanesulfonic acid or p-toluenesulfonic acid. 10. A process according to any one of Claims 1-6, wherein the acid catalyst is a carboxylic acid. 10 15 20 25 WO 95/26371 PCT/IE94/000 18 46 11. .A_ process according to any one of Claims 1-10, which is V _ carried out under conditions which inhibit anionic polymerisation. 12. A process according to Claim 11, which is carried out in the presence of a weak acid. 13. A process according to Claim 12, wherein the weak acid is sulfur dioxide. 14. A process according to Claim 13, wherein gaseous sulfur dioxide is bubbled into the reaction mixture as a continuous stream. 15. A process according to any one of Claims 1-11, wherein the anionic polymerisation inhibitor is an aliphatic sulfonic acid, an aromatic sulfonic acid or carbon dioxide. 16. A process according to any one of Claims 1-15, which is carried out in the presence of a free radical polymerisation inhibitor. 17. A process according to Claim 16, wherein the free radical polymerisation inhibitor is benzoquinone, hydroquinone, methylhydroquinone or naphthoquinone. 18. A process according to any one of Claims 1-17, wherein the inert solvent is benzene, toluene, xylene, hexane or a chlorinated hydrocarbon. 19. A process according to any one of Claims 1-18, which is carried out at a temperature in the range 20—200°C. 20. A process according to any one of Claims 1-19, wherein the total volume of the reaction solvent is kept constant. 21. A process according to any one of Claims 1-20, wherein when 2-cyanoacrylic acid is used as a starting compound to prepare a WO 95/26371 PCT/IE94/00018 47 3—alkoxy-2-cyanopropionicvacid ester, the water produced is continually removed by azeotropic distillation. 22. A process according to any one of Claims 1-21, wherein when the weak nucleophile is an alcohol or phenol, the alcohol or 5 phenol is added gradually to the reaction mixture. 23. A process according to any one of Claims 1-3 and 7-22 for the preparation of a compound of the general formula (1): CN / < (1) R10 co2R2 wherein R1 is: i) C1 or higher saturated, optionally mono— or 10 polysubstituted, linear or branched alkyl; ii) C5 or higher saturated, optionally mono— or polysubstituted cycloalkyl or poly(cycloalkyl); iii) C3 or higher, optionally mono— or polysubstituted, linear or branched alkenyl; 15 iv) C3 or higher, optionally mono— or polysubstituted, linear or branched alkynyl; or V) a phenyl or optionally mono— or polysubstituted phenyl group, and R2 is: i) a hydrogen atom; 20 ii) C1 or higher saturated, optionally mono— or polysubstituted, linear or branched alkyl; wo 95/26371 PCT/[E94/00018 48 iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; 5 v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or 10 ” other cyclic or polycyclic aromatic or heteroaromatic group. _ which comprises reacting 2—cyanoacry1ic acid or an ester thereof with an alcohol or phenol in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic 15 catalyst. 24. A process according to any one of Claims 1, 4 and 7-20 for the preparation of a compound of the general formula (II) and its subsequent conversion into a 2-cyanoacrylate polymer: CN / < (H) R3S C0211“ 20 wherein R3 is: i) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl or cycloalkyl; ii) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl or alkynyl; WO 95/26371 and R4 is: 10 15 20 PCT/IE94/000 18 49 iii) a phenyl or optionally mono- -or polysubstituted. phenyl group; iv) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group; v) an acyl or thioacyl group; vi) a dialkyl- or diarylphosphonyl group; or vii) a dialkyl- or diarylthiophosphonyl group, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cyc1oalkyl); iv) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic gfO11p, which comprises reacting 2-cyanoacrylic acid or an ester thereof with a sulfliydryl compound in the presence of an inert solvent under wo 95/25371 PCT/IE94/00018 50 polymerisation inhibiting conditions and in the presence of an acidic . catalyst, followed by later elimination of the sulfhydryl addend to give a 2-cyanoacrylate monomer which then polymerises. 25. A process according to any one of Claims 1, 5 and 7-20 ' 5 for the preparation of a compound of the general formula (III) and its subsequent conversion into a 2-cyanoacrylate polymer: CN __ 5 I," RO\ / < (111) 6 I, P\ C0212 R5O/ \X wherein R5 is: i) C1 or higher linear or branched saturated alkyl; ii) C5 or higher cycloalkyl; or 10 iii) a phenyl or optionally mono— or polysubstituted phenyl group, and R6 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono— or polysubstituted, linear or branched alkyl; 15 iii) C5 or higher saturated, optionally mono— or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono— or polysubstituted linear or branched alkenyl; v) C3 or higher, optionally mono— or polysubstituted 20 linear or branched alkynyl; 10 15 ‘20 WO 95/26371 PCT/IE94/00018 51 vi) a phenyl or optionally mono- or polysubstituted ‘phenyl group; or ' vii) a mono-or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic g1'O11p , and X is: i) an oxygen atom; or ii) a sulfur atom; which comprises reacting 2—cyanoacry1ic acid or an ester thereof with a phosphite or thiophosphite in the presence of an inert solvent under polymerisation inhibiting conditions and in the presence of an acidic catalyst, followed by elimination of the addend to give a 2- cyanoacrylate monomer which then polymerises. _ 26. A process according to any one of Claims 1, Sand 7-20 for the preparation of a compound of the general formula (IV) and its subsequent conversion into a 2-cyanoacrylate polymer: CN r—< (IV) Y '} R73P+ co2R3 wherein R7 is: i) C4 or higher saturated alkyl or cycloalkyl; ii) phenyl except when R3 is an ethyl group; or iii) a mono- or polysubstituted phenyl group, and R3 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; WO 95/26371 PCT/IE94/00018 52 iii) C5 or higher saturated, optionally mono— or , _ polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono— or polysubstituted, linear or branched alkenyl; 5 v) C3 or higher, optionally mono— or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono— or polysubstituted phenyl group; or vii) a mono— or polysubstituted biphenyl, naphthyl or 10 ' other cyclic or polycyclic aromatic or heteroaromatic g1'Ol1p, and Y is: a negatively charged ion, which comprises reacting 2—cyanoacrylic acid or an ester thereof with a phosphine in the presence of an inert solvent under polymerisation 15 inhibiting conditions and in the presence of an acidic catalyst, followed by elimination of the phosphine to give a 2—cyanoacrylate monomer which then polymerises. 27. A process according to Claim 26, wherein Y is but is not limited to a halide ion, a trifluoroacetate ion or a perchlorate ion. 20 - 28. A process according to any one of Claims 1, 6 and 7-20 for the preparation of a compound of the general formula (V) and its subsequent conversion into a 2—cyanoacrylate polymer: CN (V) R9 R10 CO2R“ WO 95/26371 PCT/IE94/00018 53 wherein R9 is:_ i) a hydrogen, atom;- ii) an electron-withdrawing organic functional group selected from nitro, carboalkoxy, cyano, acyl,.sulfonyl and phosphonyl groups; 5 A and R10 is: an electron—withdrawing organic functional group selected from nitro, carboalkoxy cyano, acyl, sulfonyl and phosphonyl groups, and R11 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or 10 polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalky1); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; 15 v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or‘ 20 other cyclic or polycyclic ‘aromatic or heteroaromatic g1‘O11p, which comprises reacting 2—cyanoacrylic acid or an ester thereof with a singly or doubly activated carbon acid in an inert solvent under polymerisation-inhibiting conditions and in the presence of an acidic 25 catalyst followed by elimination of the addend to give a 2-cyanoacrylate monomer which then polymerises. WO 95/26371 PCT/IE94/00018 54 29. A compound of the general formula (Ia): CN / < (Ia) R10 COZR2 wherein R1 is: i) a methyl group; ii) C2 or higher saturated, optionally mono- or 5 polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or po1y(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; 10 V) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; or vi) a phenyl or optionally mono- or polysubstituted phenyl group, and R2 is: i) a hydrogen atom; 15 ii) C1, optionally mono—substituted, alkyl; iii) C2 saturated alkyl except when R1 is methyl; iv) C2 saturated, mono- or polysubstituted alkyl; v) C3 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; WO 95/2637] 10 30. PCT/IE94/00018 55 vi) C5» or higher saturated, optionally mono— or . polysubstituted cycloalkyl or po1y(cycloalkyl); vii) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; viii) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; ix) a phenyl or optionally mono- or polysubstituted phenyl group; or x) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group. A compound of the general formula (Ha): CN / < (IIa) R35 CO2R4 wherein R3 is: i) C1 optionally monosubstituted alkyl wherein the 15 20 25 substituent is not a free carboxyl group whenever R4 is an ethyl group; ii) C2 optionally mono- or polysubstituted saturated alkyl wherein the or each substituent is not a primary amino group or a hydroxyl group whenever R4 is an ethyl group, or wherein the substituents do not include a primary amino group and a free carboxy group attached to the same carbon atom whenever R4 is an ethyl group, or wherein the B-substituent is not another sulfur atom bearing a 2'-carboxy—2'-cyanoethyl function as the free carboxylic acid or as its ethyl or W0 95/2637] 10 15 20 25 PCT/IE94/00018 56 4 allyl ester whenever the substituent R4 is, respectively, _ a hydrogenatom, an ethyl group or an allyl group; iii) C3 linear or branched, optionally mono— or polysubstituted saturated alkyl; iv) C4 linear or branched, optionally mono— or polysubstituted saturated alkyl wherein the mono- substituent is not a hydrogen atom whenever R4 is an ethyl group; v) C5 or higher linear or branched, optionally mono— or polysubstituted saturated alkyl or cycloalkylg vi) C3 or higher, optionally mono— or polysubstituted linear or branched alkenyl; vii) C3 or higher, optionally mono— or polysubstituted linear or branched alkynyl, viii) an unsubstituted phenyl group whenever R4 is not an ethyl group; ix) a mono— or polysubstituted phenyl group; x) a mono— or polysubstituted biphenyl, naphthyl or other polycyclic aromatic or heteroaromatic group, xi) an acyl group other than acetyl except when R4 is other than an ethyl group when R3 may then be any acyl group; xii) a thioacyl group; xiii) a dialkyl or diaryl phosphonyl group excluding diethyl phosphonyl whenever R4 is an ethyl group; WO 95/26371 PCT/IE94/00018 57 xiv) a dialkyl or diaryl thiophosphonyl group , excluding diethyl thiophosphonyl when R4 is an ethyl group, and including sulfoxides and sulfones derived from any of i) - X) 5 V above, and R4 is: i) a hydrogen atom; ii) C1 or higher, linear or branched optionally mono- or polysubstituted saturated alkyl; iii) C5 or higher saturated, optionally mono- or 10 polysubstituted cycloalkyl or poly(cycloa1kyl); iv) C3 or higher, optionally mono- or polysubstituted linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted linear or branched alkynyl; 15 vi) a phenyl or optionally mono- or polysubstituted phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group. 20 31. A compound of the general formula (HIa): CN /‘R50 / < (IIIa) . \ 6 I‘ P COZR \ ‘~—R5o/ \X W0 95/2637 1 wherein R5 is: i)_ 10 15 and R6 is: 20 PCT/IE94/000 1 8 58 a methyl group; ii) an ethyl group except when R6 is an ethyl group or a hydrogen atom; iii) a propyl group or substituted propyl group; iv) an isopropyl group except when R6 is an ethyl group or a hydrogen atom and when X is an oxygen atom; V) C4 or higher saturated, optionally mono- or polysubstituted linear or branched alkyl; vi) a cyclohexyl group; vii) an unsubstituted phenyl group except when R6 is an ethyl group or a hydrogen atom and when X is an oxygen atom; viii) a mono- or polysubstituted phenyl group; or ix) a phenyl group attached simultaneously and ortho to both oxygen atoms except when R6 is an ethyl group and when X is an oxygen atom, i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; WO 95/26371 PCT/IE94/00018 59 v) C3 or higher, optionally mono— or polysubstituted,‘ linear or branched alkynyl; vi) a phenyl or optionally mono— or polysubstituted phenyl group; or 5 C vii) a mono— or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group, and X is: i) an oxygen atom; or ii) a sulfur atom. 10 32. A compound of the general formula (IV a): , CN . — 7 + (IVa) Y R 3P 8 . COZR wherein R7 is: i) C4 or higher saturated alkyl or cycloalkyl; ii) ‘ phenyl except when R3 is an ethyl group; or iii) a mono— or polysubstituted phenyl group, 15 - and R3 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono— or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono— or polysubstituted cycloalkyl or poly(cycloalkyl; W0 95/26371 PCT/IE94/00018 60 iv) C3 or higher,'optiona11y mono— or polysubstituted,._ - _ linear or branched alkenyl; V) C3 or higher, optionally mono— or polysubstituted, linear or branched alkynyl; 5 vi) a phenyl or optionally mono— or polysubstituted phenyl group; or vii) a mono— or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic gI'O1lp, l0 and Y is: a negatively charged ion. 33. A compound according to Claim 32, wherein Y is but is not limited to a halide ion, a trifluoroacetate_ion or a perchlorate ion. 34. A compound of the general formula (Va): CN (Va) R9 Rm CO2R“ 15 wherein R9 is: i) a hydrogen atom except when R10 is a nitro group and R11 is an ethyl group; ii) a carboxymethyl group except when R10 is a nitro group and R11 is an ethyl group; iii) a carboxyethyl group except when R10 is a 20 carboxyethyl group or an acetyl group or a cyano group when R11 is an ethyl group; W0 95/26371 PCT/IE94/00018 61 iv) a carboxyalkyl group wherein the alkyl radical is C3 or higher saturated, linear or branched; V) an acyl or aroyl group; _ Vi) a compatible electron-_withdrawing organic 5 functional group selected from nitro, cyano, sulfonyl and phosphonyl groups, R10 is: a compatible electron-withdrawing organic functional group selected from nitro, carboalkoxy, cyano, acyl, aroyl, sulfonyl and phosphonyl groups, 10 and R11 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cycloalkyl); 15 iv) C3 or higher, optionally mono- or polysubstituted, linear or branched alkenyl; v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; vi) a phenyl or optionally mono- or polysubstituted 20 phenyl group; or vii) a mono- or polysubstituted biphenyl, naphthyl or other cyclic or polycyclic aromatic or heteroaromatic group. 35. A composition comprising a compound of the general 25 formula (1) given and defined in Claim 23. W0 95/26371 10 15 20 PCT/IE94l00018 62 36. A composition comprising a compound of the general‘ formula (II) given and defined in Claim 24. 37. A composition comprising a compound of the general formula (III) given and defined in Claim 25. 38. A composition comprising a compound of the general formula (IV) given and defined in Claim 26. 39. A composition comprising a compound of the general formula (V) given and defined in Claim 28. 40. A compound of the general formula (1) given and defined in Claim 23, for use in an adhesive composition. 41. A compound of the general formula (H) given and defined in Claim 24, for use in an adhesive composition. 42. A compound of the general formula (III) given and defined in Claim 25, for use in an adhesive composition. 43. A compound of the general formula (IV) given and defined in Claim 26, for use in an adhesive composition. 44. A compound of the general formula (V) given and defined in Claim 28, for use in an adhesive composition. 45. A poly(cyanoacrylate) material formed from a compound of the general formula (I) given and defined in Claim 23. 46. A poly(cyanoacrylate) material formed from a compound of the general formula (II) given and defined in Claim 24. 47. A poly(cyanoacrylate) material formed from a compound of the general formula (III) given and defined in Claim 25 . 10 15 20 WO 95/26371 PCT/IE94/00018 63 _ 48. . poly(cyanoacrylate) material formed from a compound. of the general formula (IV) given and defined in Claim 26. 49. A poly(cyanoacrylate) material formed from a compound of the general formula (V) given and defined in Claim 28. 50. A poly(cyanoacrylate) film formed from a compound of the general formula (1) given and defined in Claim 23. 51. A poly(cyanoacrylate) film formed from a compound of the general formula (II) given and defined in Claim 24. 52. A poly(cyanoacrylate) film formed from a compound of the general formula (III) given and defined in Claim 25. 53. A poly(cyanoacrylate) film formed from a compound of the general formula (IV) given and defined in Claim 26. 54. A poly(cyanoacrylate) film formed from a compound of the general formula (V) given and defined in Claim 28. 55. A poly(cyanoacrylate) film according to any one of Claims 50-54, which is a single or multi-layer Langmuir-Blodgett film. 56. Poly(cyanoacrylate) nanocapsules formed from a compound of the general formula (1) given and defined in Claim 23. 57. Poly(cyanoacrylate) nanocapsules formed from a compound of the general formula (H) given and defined in Claim 24. 58. Poly(cyanoacrylate) nanocapsules formed from a compound of the general formula (IH) given and defined in Claim 25. 59. Poly(cyanoacrylate) nanocapsules formed from a compound of the general formula (IV) given and defined in Claim 26. WO 95/26371 PCT/IE94/00018 64 _ 60. Poly(cyanoacrylate) nanocapsules formed from.a- - I ’ compound of the general formula (V) given and defined in Claim 28. 61. Poly(cyanoacrylate) nanocapsules according to any one of Claims 56-60 containing an active agent. 62. Poly(cyanoacrylate) nanocapsnles according to Claim 61, wherein the active agent is a drug. WO 95/26371 65 PCT/IE94/00018 AMENDED CLAIMS [received by the International Bureau on 23 January 1995 (23.01.95); original claims 29 and 31 amended; remaining claims unchanged (2 pages)] 29. A compound. of the general‘ formula (Ia): CN / < (18) l 2 . R o CO2R wherein R1 is: i) a methyl group; ii) C2 or higher saturated, optionally mono- or 5 ’ polysubstituted, linear or branched alkyl except 2- ethylhexyl when R2 is methyl; iii) C5 or higher saturated, optionally mono- or polysubstituted cycloalkyl or poly(cyc1oa1ky1); iv) C3 or higher, optionally mono- or polysubstituted, 10 linear or branched alkenyl; ' v) C3 or higher, optionally mono- or polysubstituted, linear or branched alkynyl; or vi) a phenyl or optionally mono- or polysubstituted phenyl group, 15 and R2 is: i) a hydrogen atom; ii) C1, optionally mono-substituted, alkyl; iii) C2 saturated alkyl except when R1 is methyl or ethyl; iv) C2 saturated, mono- or polysubstituted alkyl; 20 v) C3 or higher saturated, optionally mono- or polysubstituted, linear or branched alkyl; AMENDED SHEET (ARTICLE 19) WO 95/2637] 66 PCTIIE94/00018 wherein R5 is: ,i) a methyl group except where R6 is «an ethyl group 1 and X is an oxygen atom; ii) an ethyl group except when R6 is an ethyl group or a hydrogen atom or when R5 is a methyl, isopropyl 5 or butyl group and X is an oxygen atom; iii) a propyl group or substituted propyl group except that R5 is not a propyl group when R6 is a propyl group and X is an oxygen atom; iv) an isopropyl group except when R6 is an ethyl group 10 or a hydrogen atom and when X is an oxygen atom; v) C4 or higher saturated, optionally mono— or polysubstituted linear or branched alkyl except that R5 is not a butyl group when R6 is a butyl group and X is an oxygen atom; 15 - vi) acyclohexyl group; vii) an unsubstituted phenyl group except when R6 is an ethyl group or a hydrogen atom and when X is an oxygen atom; viii) a mono— or polysubstituted phenyl group; or 20 ix) a phenyl group attached simultaneously and 021120 to both oxygen atoms except when R5 is an ethyl group and when X is an oxygen atom, and R6 is: i) a hydrogen atom; ii) C1 or higher saturated, optionally mono— or 25 polysubstituted, linear or branched alkyl; iii) C5 or higher saturated, optionally mono— or polysubstituted cycloalkyl or poly(cycloalkyl); iv) C3 or higher, optionally mono— or polysubstituted, linear or branched alkenyl; AMENDED SHEET (ARTICLE 19) W0 95/26371 60.00 50.00 40.00 30.00 20.00 Surface Pressure I mNm" |0.00 0.000 I00 200 1/4 (8 x 105L) 300 400 Area I cm’ Fig. 1 PCT/[E94/00018 500 600 W0 95/26371 PCT/IE94/00018 2/4 (6 X 10'5L) 80.00 70.00 ‘E 60.00 g E 50.00- 3.’. = 5; 40.00 P.’ m u 30.00 U ‘-5.5 3, 20.00 10.00 0.000 100 200 300 400 500 600 Area I cm‘ Fig. 2 Surface Pressure/mNm‘1 W0 95/26371 80.00 70.00 60.00 50.00 40.(X) 30.00 20.00 I 0.00 0.000 I00 200 3/4 (8 x 1O‘5L) 300 Area/cmz 400 Fig. 3 PCT/IE94/00018 600 W0 95/26371 PCT/IE94/00018 4/4 403-0 _ ' Dipped area Area/cm3 -# C G\ C 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 time/s Fig. 4 SSIFICATION OF SUBJECI‘ MATTER 6 C08F22/32 C09J4/00 C07F9/40 C07F9/54 INTERNATIONAL SEARCH REPORT Internet" ‘ Application No PCT/IE 94/00018 CO7C253/30 C07C255/20 C07C255/19 C07C323/60 According to lntemational Patent Classification (IPC) or to both national cla.m'ficat:'on and [PC Minimum ‘documentation searched (classification system followed by classification symbols) IPC 6 C08F C09J C07C CO7F Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical. search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant pasages Relevant to claim No. FR,A,2 333 853 (LUBRIZOL) 24 June 1980 see page 10, compound J, claims TETRAHEDRON LETTERS, Vol.35, no.11, 14 March 1994, OXFORD GB pages 1751 - 4 Y. G. GOLOLOBOV ET. AL. ‘Unusual Transformations of Ethyl 2-Cyanoacrylate in Reactions with Trivalent Phosphorus Compounds‘ see whole document _/__ E Further documents are listed in the continuation of box C. E Patent family members are listed in annex. ' Special categories of cited documents : ‘A’ document defining the general state of the art which is not considered to be of particular relevance ‘E’ earlier document but published on or alter the international filing date ‘L’ document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or other special reason (as specified) '0' document referring to an oral disclosure. use, exhibition or other means ‘P’ document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search 11 November 1994 Name and mailing address of the ISA European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040. '13:. 3| 651 epo nl, Fazc (+ 31-70) 340-3016 Form PCT/ISA/210 (second sheet) (July I992) ‘T’ later document published alter the international filing date or priority date and not in conflict with die application but cited to understand the principle or theory underlying the invention ‘X’ document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone ‘Y’ document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is combined with one or more other such docu- 1_'n€tl"l‘IS, such combination being obvious to a person skilled in e art. '&' document member of the same patent family Date of mailing of the international search report 30. 11. 94 Authorized officer Helps, I name 1 of 3 INTERNATIONAL SEARCH REPORT Internet‘ Application No PCT/IE 94/00018 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant pasages LIEBIGS ANNALEN DER CHEMIE, vol.1990, no.7, July 1990, WEINHEIM_DE - pages 697 - 9 . V. J. RAM ET. AL. ‘Unusual Amination by Cleavage of an Exocyclic C-N Linkage with Formamide' see page 697, column 2, line 4 BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, vol.1971, no.5, May 1971, PARIS FR pages 1800 - 3 B. S. KIRKIACHARIAN 'Radicaux libres thermiques: étude d'esters maloniques et cyanoacétiques.' see page 1801; table II CHEMISCHE BERICHTE, vol.118, no.10, October 1985, WEINHEIM DE pages 4131 - 43 G. PENZ ET. AL. 'Synthese der (3-Oxo-2-tos yloxy-1-alkenyl)phosphonsaure-dialkylester . Synthone zur Gewinnung von (Hetarylmethyl)-phosphonsaureestern und 2-substituierten 3-Oxophosphonsaureestern.' see page 4133, compound no. 5e CHEMICAL ABSTRACTS, vol. 109, no. 3, 18 July 1988, Columbus, Ohio, US; abstract no. 21687p, K. SHIRAI ET. AL. ‘Reduction of alpha-beta- unsaturated carbonyl compounds with Clostridium thermosaccharolyticum for optically active carbonyl compound preparation.‘ page 506 ;column 1 ; see abstract & JP5A,63 003 794 (IDEMITSU KOSAN CO. LTD. & 12TH COLLECTIVE INDEX page 72699CS see column 1, line 10 - line 13 CHEMICAL ABSTRACTS, vol. 118, no. 11, 15 March 1993, Columbus, Ohio, US; abstract no. 102094f, G. KOLOMNIKOVA ET. AL. 'Ineraction of alpha-cyanoacrylic acid and alpha-cyanoacrylates with dialkyl and diaryl phosphites' page 866 ;column 2 ; see abstract & IZV. AKAD. NAUK, SER. KHIM., vol.1992, no.8 pages 1913 - 5 Form PCT/ISA/110 (mnlinunion of second sheet) (July 1992) page 2 of 3 IPWNERJLATTCHVAJ.SEAJRCPIIEPCHT Internal’ 1 Application No PCT/IE 94/00018 C.(Conu'nuau‘on) DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document. with indication, where appropriate, of the relevant pasages Relevant to claim No. CHEMICAL ABSTRACTS, vol. 116, no. 13, 30 March 1992, Columbus, Ohio, US; abstract no. 128146h,- ‘ I. I. KANDROR ET. AL. ‘Reaction of alpha-cyanoacrylates with functionally substituted thiols, ethanedithiol and hydrogen sulfide.‘ page 814 ;column 1 ; see abstract & IZV. AKAD. NAUK. SSSR, SER. KHIM.,,: vol.1991, no.12 pages 2816 - 20 CHEMICAL ABSTRACTS, vol. 114, no. 21, 27 May 1991, Columbus, Ohio, US; abstract no. 206538n, I. I. KANDROR ET. AL. ‘the addition of thiols and thio acids to ethyl alpha-cyanoacrylate.' page 760 ;column 2 ; see abstract & IZV. AKAD. NAUK. SSSR, SER. KHIM.,, vol.1990, no.12 pages 2798 - 501 . CHEMICAL ABSTRACTS, vol. 71, no. 5, 4 August 1969, Columbus, Ohio, US; abstract no. 22156y, B. E. IVANOV ET. AL. 'Phosphonomethylation of malonic and cyanoacetic esters.‘ page 335 ;column 1 ; see abstract & IZV. AKAD. NAUK. SSSR, SER. KHIM.,, vol.1969, no.4 pages 889 - 93 US,A,2 765 332 (COOVER ET. AL.) 2 October 1956 see whole document US,A,3 557 185 (ITO ET. AL.) 19 January 1971 see whole document US,A,2 768 109 (COOVER ET. AL.) 23 October 1956 see whole document EP,A,0 007 895 (COUVREUR ET. AL.) 6 February 1980 see claims; examples US,A,3 903 055 (BUCK) 2 September 1975 cited in the application see whole document Form PCT/ISA/210 (continuation of second sheet) (July 1992) Ix. .1-iational application No. INTERNATIONAL SEARCH REPORT PCT/IE 94/ 00018 Box I ' Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article'1'/;(2)(a) for the following reasons: 1.. Claims N os.:. [1 because they relate to subject matter not required to be searched by this Authority, namely: 2. D Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful intemational search can be carried out, specifically: Claim 1 has been searched incompletely. The definition "weak nucleophile" is not clear. 3. Cl Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This lntemational Searching Authority found multiple inventions in this intemational application, as follows: 1. D As all required additional search fees were fimely paid by the applicant. this intemational search report covers all searchable claims. 2. El As all searchable claims could be searches without effort justifying an additional fee. this Authority did not invite payment of any additional fee. As only some of the required additional search fees were timely paid" by the applicant, this intemational search report covers only those claims for which fees were paid, specifically claims Non: No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: D The additional search fees were accompanied by the applicant's protest. E’ No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet (1)) (July 1992) INTERNATIONAL SEARCH REPORT Imormation on patcnt family members Patent document Publication cited in search report date FR-A-2333853 01-07-77 lntx:rna' 1 Application No PCT/IE 94/00018 member(s) date US-A- 4058469 15-11-77 CA-A- 1073441 11-03-80 DE-A,C- 2654412 23-06-77 GB-A- 1538889 24-01-79 JP-A- 52096989 15-08-77 US-A- 4209408 24-06-80 869107 19-01-79 AT-B- 370427 ' 25-03-83 CA-A- 1132069 21-09-82 US-A- ’ 4329332 11-05-82 4489055 18-12-84 818176 27-01-75 DE-A- 2413406 16-10-75 FR-A,B 2264820 17-10-75 GB-A- 1442498 14-07-76 7405836 Form PCT/ISA/210 (patent family nnnax) (July 1992)