United States Patent Office 3,389,143 The various oxidizing agents used include, but is not PURIFICATION OF 1,10-PHENANTHROLINES limited to, nitro compounds, arsenic pentoxide, ferric Bert Halpern, Sunnyvale, Calif., and William G. C. Raper, oxide, ferric sulfate, ferric chloride, stannic chloride and Moorabbin, Victoria, Australia, assignors to Morasato the like. Chemical (Australia) Limited, a company of Australia Substituted 1,10-phenanthroline compounds which can No Drawing. Continuation-in-part of application Ser. N9. be purified by the process of this invention are those of 310,934, Sept. 23, 1963. This application Dec. 13, 1966, the formula: Ser. No. 66,338 Claims priority, application Australia, Sept. 27, 1962, R 22,636/62 L-N 5 Claims. (C. 260-288) O R R R ABSTRACT OF THE DISCLOSURE R Purification of substituted 1,10-phenanthrolines by re wherein R is selected from the group consisting of alkyl, acting the phenanthroline with an organic acid having a phenyl, tolyl, xylyl and hydrogen. When the substituent dissociation constant in the approximate range of 1X 10. is alkyl there can be a maximum of six substitute posi to 1 x 10-6, at 25° C.; partially neutralizing this Solution tions, the remaining R's being hydrogen. The total carbon by addition of a base until a slight permanent precipita atoms of the substituents is limited to a maximum of 12 tion appears in the solution; separating the precipitation 20 carbon atoms. When the substituent is phenyl, tolyl or from the solution; adding a base to the filtrate until an xyly: there can be a maximum of two substitute positions alkaline pH is obtained; and separating the purified phe and the remaining R's being hydrogen. nanthroline from the solvent. 1,10-phenanthroline compounds which have been puri Substituted 1,10-phenanthrolines are utilized as analyti fied by this process include, but is not limited to, 1,10 cal reagents for the determination of metais and as Oxida phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 3,6,8- tion-reduction indicators. tri-n-butyl-1,10-phenanthroline, 2,4,7,8-tetramethyl-1, 0 wountricassassroom phenanthroline, 2,4,7,9-tetramethyl-1, 10-phenanthroline, 3,4,7,8-tetramethyl-1,10 - phenanthroline, 3,5,6,8 - tetra This is a continuation-in-part of application Ser. No. methyl-1,10-phenanthroline, 3,8-di-n-butyl-5,6-dimethyl 310,934, filed Sept. 23, 1963, now abandoned. 30 1,10-phenanthroline, 3,4,5,6,7,8-hexamethyl - 1,10 - phe This invention relates to a process for the purification nanthroline, 5-phenyl-1,10 - phenanthroline and 4.7 - di of 1,10-phenanthroline and substituted 1,10-phenanthro phenyi-,10-phenanthroline. lines. More specifically, this invention is concerned with In the preparation of , 10-phenanthroline metal cont the purification of alkyl or aromatic substituted 1,10-phe plexes, either in an analytical procedure, or for use as an nanthrolines from the impurities present in a phenanthro indicator or to combat infection, it is essential that the line preparative reaction mixture. phenanthroline base be in a pure form. Purity of the base Phenanthrolines, and particularly 1,10-phenanthrolines is judged by the melting point and color of the base, the are used as analytical reagents for the determination of melting point being as close as possible to the optimal, metals, and in the form of metal complexes as oxidation and the color as close as possible to the minimal. reduction indicators. Metal complexes of 1,10-phenan 40 Commercially available phenanthrolines are heavily col throlines are also used to combat infection in humans, ored and must be purified prior to formation of the metal animals and plants. complexes. The usual method of purification described in Crude 1,10-phenanthrolines are usually obtained by a the literature is by repeated recrystallization from ben Skraup reaction or a modified or related Skraup reaction, zene. This method, however, is not an efficient or practi which involves heating a primary aromatic amine, having 45 cal procedure since the solubility of many 1, 10-phenan at least one unsubstituted ortho position, with glycerol, throlines in benzene is low and many recrystallizations sulfuric acid and an oxidizing agent. When the aromatic are required to obtain satisfactory melting points. Reduc amine is a monoamine the resultant compound is a quino tion of the color, in benzene, to give a white 1,10-phe line, substituted in the aromatic portion of the quinoline nanthroline is almost impossible. nucleus. The reaction of an aromatic diamine with two 50 It has been found that the color and melting point of moles of glycerol yields 1,10-phenanthroline with the the crude 1,10-phenanthroline base can be materially im substitutions in the 5- and/or 6-position. proved by (1) dissolving the crude phenanthroline base A more efficient method of preparing 1,10-phenanthro in an organic acid solution, having a dissociation constant lines is to first prepare the 8-amino quinoline and then of from about 1 x 10-4 to 1 x 10-6, at 25° C.; (2) par react this under Skraup reaction conditions. 55 tially neutralizing this solution by addition of a base To substitute the quinoline or phenanthroline in the until slight permanent precipitation appears in the solu heterocyclic rings, a modified Skraup reaction is used in tion; (3) separating this precipitate from the solution; (4) which an oz.f3-unsaturated ketone, such as Substituted acro addition of a base to the filtrate until an alkaline pH is leins, vinyl ketones and the like, is used in place of the obtained; and (5) separating the purified phenanthroline, glycerol. In view of the ease by which c,6-unsaturated 60 which precipitated when the filtrate was made alkaline, ketones polymerize under Skraup reaction conditions, it from the solvent. has been found expedient to employ compounds which The organic acids conveniently used in this process produce or,6-unsaturated ketones or aldehydes, in situ, include acetic acid, formic acid, propionic acid, and the under the reaction condition of a Skraup reaction. like, with acetic acid and aqueous acetic acid being the Various modifications of the Skraup reaction, especial 65 preferred acid. ly when an 8-aminoquinoline is the starting product, The base used is an inorganic carbonate or hydroxide, have been used. These modifications include the use of preferably an alkali metal or alkaline earth carbonate or phosphoric acid in place of the sulfuric acid (Yale modi hydroxide, such as sodium hydroxide, or ammonium hy fication); the addition of moderating agents, such as fer droxide. rous sulfate, acetic acid or boric acid; the use of dilute 70 The amount of base that is added to partially neu sulfuric acid; azetropical removal of water during the re tralize the solution is determined by visual observation action; and changes in the order of mixing the reactants. of the mixture. Base is added until a permanent precipi 3,389,143 3. 4. tate appears, that is, a precipitate which does not redis furic acid is in the range of about 1:1 to 1:15. The pre solve on stirring. It has been observed that during this ferred range for arsenic acid/sulfuric acid is about 1:1 partial neutralization procedure the pH of the solution to 1:5, and the preferred range for arsenic acid/phos varies only slightly from about pH 5 to about pH 6 and phoric acid is about 1:5 to 1:15. that more base is required than the calculated amount for Addition of the carbonyl compound to the amine should neutralization of the free weak acid. Following this pro be slow and with efficient stirring to prevent accumula cedure it was observed that most of the impurities, espe tion of the carbonyl compound and any sudden tempera cially the colored impurities are precipitated by this par ture rise thus reducing the possibility of self condensa tial neutralization. tion of the carbonyl compound. Temperature is not critical during either the partial Upon completion of addition of the carbonyl com neutralization or final neutralization steps. Partial neu O pound the reaction mixture is heated at a temperature tralization is usually at a temperature of about 15 to 50 up to about 35 to 140 C. for about one to two hours. C. and the final neutralization is at 60° C. A temperature The desired 8-nitroquinoline is isolated from the reac of 60° C. is preferred for the final neutralization to in tion mixture by quenching the mixture with water, filter crease the crystal size of the product and thus facilitate ing if desired, and making the mixture alkaline to precipi filtration of the product. The product is washed with tate the 8-nitroquinoline. Other known isolation proce water and dried. dures can also be used. Purification is by known recrys The separation of the impurities from solution, after tallization procedures which yields a satisfactory product partial neutralization, can be conveniently performed in most cases. by filtration. Prior to filtration an adsorbent, such as 20 The 8-nitroquinolines thus produced is reduced to the carbon, and/or a filter aid such as "Celite' can be added corresponding 8-aminoquinoline by a reaction with an to the mixture. ammonium, alkali metal or alkaline earth hydrogen sul The phenanthroline base obtained by this process may fide at about pH of 8.0 to 9.5. The reduction is carried be washed or triturated with an aromatic hydrocarbon out in an aliphatic alcohol solvent medium, at reflux or solvent, following the water wash, to remove any oily im 25 near reflux temperature.