US 3576873 A
Description (OCR text may contain errors)
United States Patent Ofice 3,576,873 Patented Apr. 27, 1971 ABSTRACT OF THE DISCLOSURE Germicidal, fungicidal, and algicidal N-fl-hydroxyphenethyl quaternary ammonium compounds are obtained by reacting tertiary amines bearing at least one high molecular weight alkyl or alkenyl group with an acid and (epoxyethyl)benzene.
This invention relates to novel germicidal, fungicidal and algicidal quaternary ammonium compounds and to methods for their preparation.
In its product aspect, my invention resides in quaternary ammonium compounds having the structural for- FORMULA I wherein R is alkyl having 1 to 22 carbon atoms, alkenyl having 3 to 22 carbon atoms or phenyl-lower-alkyl; R is lower-alkyl, lower-alkenyl or pheny'l-lower-alkyl; R" is higher-alkyl having 8 to 22 carbon atoms or higheralkenyl having 8 to 22 carbon atoms; An is an anion; v is the valence of An; and n is an integer equal to said valence.
When R is alkyl having 1 to 22 carbon atoms, there are included, for example, methyl, ethyl, n-butyl, n-heptyl, isooctyl, decyl, tridecyl, octadecyl, eicosyl and docosyl. When R is alkenyl having 3 to 22 carbon atoms, there are included, for example, allyl, methallyl, hexenyl, nnenyl, dodecenyl, hexadecenyl, nonadecenyl and eicosenyl.
The term phenyl-lower-alkyl as used herein means a monovalent hydrocarbon radical consisting of phenyl bonded to one of the valences of a divalent lower-alkylene radical having one to four carbon atoms as exemplified by, but not limited to methylene, l,l-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, and the like. Thus, solely for illustration and without limitation, examples of phenyl-lower-alkyl are benzyl, 1 phenylethyl, 2-phenylethyl, 3-phenylpropyl, and the like.
As used in each of the preceding definitions and throughout this disclosure the term lower means groups having at most seven carbon atoms. In contrast, the term higher means groups having from eight to twenty-two carbon atoms. Thus for purpose of illustration and without limitation thereto, lower-alkyl includes, for example; methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, and n-heptyl; lower-alkenyl includes, for example, allyl, methallyl, 2-butenyl, l-hexenyl, and Z-heptenyl; higher-alkyl includes, for example, octyl, nonyl, tridecyl, hexadecyl, eicosyl, and docosyl; higher-alkenyl includes, for example, l-octenyl, l-hexadecenyl, 9-octadecenyl and l-docosenyl.
The term anion, as used herein, means the anion of any salt-forming inorganic or organic acid. The choice of an anion is not critical to the operation of the processes of my invention. Accordingly, by way of illustration and without limitation thereto, anions that may be employed in the invention are, for example, bromide, chloride, i0- dide, fluoride, nitrate, sulfate, phosphate, acetate, formate, p-toluenesulfonate, phenoxyacetate, and the like. The choice of any particular anion will be dependent upon the particular use to be made of the quaternary ammonium salt. For example, in the case of the quaternary ammonium salts of my invention that are to be employed in internal preparations for human or animal use, the anion is chosen from a pharmaceutically-acceptable saltforming inorganic or organic acid. Thus, such an acid is one whose anions are non-toxic and innocuous to the animal organism in elfective concentrations of the quaternary ammonium salts so that beneficial properties inherent in the common structural entity are not vitiated by side-effects ascribable to the anion. Moreover, since one of the objects of this invention is to provide tasteless quaternary ammonium antiseptics for oral use, I prefer to use salt-forming acids whose anions in combination with the quaternary ammonium compounds of my invention are tasteless. I have found that for this purpose, chloride and sulfate are the preferred anions.
In its process aspect, my invention resides in the process for preparing compounds of Formula I which comprises interacting a compound of the formula FORMULA II wherein R, A and R" have the same meanings indicated hereinabove, with a stoichiometric amount of a salt-forming acid, H An" wherein n and v have the meanings hereinbefore given, and approximately one molecular equivalent of (epoxyethyl)-benzene. The reaction is preferably carried out at a temperature between 50 and C. in water or a lower-alkanol having one to three carbon atoms.
Although if desired, the tertiary amine of Formula II can be employed in the form of a previously isolated addition salt of the strong acid, in a preferred mode I interact the amine and the strong acid in situ in such a way that initially approximately 50 percent of the theoretical quantity of the acid is reacted with the amine. Then approximately half of the total amount of the (epoxyethyl)benzene to be employed is added to the mixture followed by the remainder of the acid and finally by the remainder of the (epoxyethyl)benzene.
Another method suitable for preparing the new compounds of Formula I comprises alkylating a tertiary amine of Formula II hereinabove with a beta-hydroxyphenethyl halide.
Quaternary ammonium salts heretofore used as germicidal and fungicidal agents have suffered from inherent drawbacks. One of these drawbacks is that such compounds are usually waxy solids or viscous liquids which tend to readily absorb moisture from the atmosphere. This renders the compounds difiicult to handle and makes it virtually impossible to supply the consumer with a form of the compound that can conveniently be dispensed in measured quantity. Another drawback found in those germicidal and fungicidal quaternary ammonium compounds that have heretofore been used in preparations for oral hygiene, for example, mouthwashes, toothpastes, antiseptic lozenges, and the like, is their unpleasant taste.
In a more particular :product aspect of the present invention, a preferred group of my biocidal N-fl-hydroxyphenethyl quaternary ammonium compounds are represented by the formula FORMULA III wherein R", An, n, and v have the meanings given hereinbefore. These compounds of Formula III are devoid of 3 the above-mentioned drawbacks. For example, when N,N- dimethyl N fi hydroxyphenethyl N myristylammonium chloride is incorporated in biocidally effective amount in a composition for oral hygiene, the composition is devoid of unpleasant taste, tingling sensation, and after-taste. Furthermore N,N-dimethyl-N-fi-hydroxyphenethyl-N-myristylammonium chloride is a free-flowing, white powder which does not tend to absorb moisture from the air. These properties together with its relatively high melting point (97.899.8 C.) make the compound particularly adaptable to incorporation into tablets by conventional pressing techniques.
The organic tertiary amines used as starting materials for the preparation of the compounds of the present invention are either generally known in the art or are prepared by conventional alkylation processes, for example, the alkylation of the appropriate primary or secondary amine.
Exemplary tertiary amines useable in and within the purview of this invention which may be made by such processes are:
2-ethyl-N,N-dimethylhexylamine N,2,2'-triethyldihexylamine N,N-diallylnonylamine N,N-diethyldodecyl amine N,N-dimethyltetradecylamine N-methyl-N-benzylhexadecyl amine N-methyldio ctadecylamine N-isobutyl-N-dodecyl-9-octadecenylamine N- 3 -phenylpropyl) N-( l-methylheptyl) decyl amine N-do decyl-N- 3 -nitrobenzyl octylamine N- 2-b utenyl) -N-( l-methylheptyl) tridecylamine N- 4-methoxybenzyl) -N-propylheptadecylamine N,N-dimethylnonadecylamine N,N-Z-trimethyleicosylamine N,N-dimethyldocosylamine N-hexyl-N-undecyltetradecylamine Nphenethyl N-benzylpent adecylamine N-nonyl-N-pentyll-tetr adecenyl amine N- (4-chlorophenethyl didodecylamine N- (2-methylbenzyl -N-pentadecylhexadecyl amine In another particular product aspect, my invention resides in a mixture of quaternary ammonium compounds wherein R" in Formula I is YCH(CH in which Y is alkyl having 8 to 18 carbon atoms, the average number of carbon atoms being 10.5-11.5.
For the preparation of these compounds the tertiary amine reactant is a mixture represented by the formula N,N-di (lower alkyl -N- [CH (CH Y] Formula IV wherein Y has the same significance indicated above. Such mixtures of amines are described in the copending U.S. patent application of Crounse, Bonta and Ploss, Ser. No. 500,341, filed Oct. 21, 1965 (now U.S. Pat. 3,352,750 issued Oct. 6, 1970), and are prepared by the following process:
A mixture consisting of alpha-olefins having from 8 to 20 carbon atoms is catalytically hydrochlorinated by adding hydrogen chloride to the double bond in the absence of actinic light or peroxides. The resulting 2-chloroalkane is caused to interact with a di-(lower-alkyl)amine to give Z-[di-(lower-alkyl)amino]alkane, which, when caused to interact with (epoxyethyl)benzene gives corresponding mixtures of the desired quaternary ammonium compounds. In practice, the hydrochlorination step has been found to proceed readily at reduced temperatures (040 C.) in the presence of a Lewis acid. The preferred Lewis acid is stannic chloride, but other Lewis acids, for example, aluminum chloride, ferric chloride, zinc chloride and the like are satisfactory.
The reaction of the mixed 2-chloroalkanes with a di (1ower-alkyl)amine is conveniently carried out in aqueous 4 solution, at a pressure of 5 00-1000 pounds per square inch and a temperature of about ZOO-250 C. The use of an excess of the amine reduces the formation of unwanted quaternaries at this stage of the process.
Quaternization of the mixed 2-di-(lower alkyl)aminoalkane with (epoxyethyl)benzene, is readily accomplished by the process previously described hereinabove.
The substitution of simple moieties in the benzene rings of the starting materials used in the processes above described, i.e. (epoxyethyl)benzene (also designated as styrene oxide) and the aromatic amines of Formula II, for example, halo (i.e. chloro, bromo, iodo, and fiuoro), lower alkoxy, lower alkylsulfonyl, lower alkylsulfinyl, nitro, and trifluoromethyl, does not interfere with the operability of the process, and the resulting quaternary ammonium compounds correspondingly substituted in the benzene ring thereof have the same utility as, and are the full equivalents of, the compounds herein claimed.
The structure of the compounds of the invention is established by the mode of synthesis, by chemical analysis and by appropriate spectral properties.
The following examples will further illustrate specific embodiments of the invention without the latter being limited thereto.
EXAMPLE 1 A stirred solution of 192 g. (0.795 mole) of freshlydistilled N,N-dimethylmyristylamine in 40 g. of anhydrous isopropyl alcohol was cooled to 20 C. During a period of thirty minutes at a temperature between 20 and 25 C., there was added dropwise 39.2 g. (0.397 mole) of 37% aqueous hydrochloric acid solution. The mixture was then heated to C. during a period of thirty minutes. At a temperature between 80 and C. there was added over a 1.5 hour period 49.6 g. (0.415 mole) of (epoxyethyl) benzene. The temperature of the mixture was maintained at 80-85" C. for one hour longer and was then cooled to 25 C. A second amount of 39.2 g. (0.397 mole) of 37% aqueous hydrochloric acid was added to the reaction mixture at a temperature between 25 and 30 C. over a period of thirty minutes. After the mixture was stirred for five minutes the pH of the mixture was determined using bromphenol blue indicator and the pH was adjusted to 3.0 to 4.0 by the addition of 2.0 g. portions of N,N- dimethylmyristylamine. The mixture was again heated to 80 C. during a period of thirty minutes and during a period of 1.5 hours 49.6 g. (0.415 mole) of (epoxyethyl) benzene was added at a temperature between 80 and 85 C. Stirring and heating at 80-85 C. were continued for two hours and the pH of the now alkaline solution was adjusted to 7.0 by the addition of 16.08% aqueous hydrochloric acid solution. An additional 5.0 g. (0.042 mole) f (epoxyethyl)benzene was added and the reaction heated for one hour longer at 80-85 C. The pH was then adjusted to and held at 7.0 to 8.0 by the addition of 15 percent aqueous sodium carbonate solution while the mixture was subjected to steam distillation for a period of three hours for the purpose of removing steam-volatile impurities. The mixture was cooled to a temperature between 55 and 60 C. and poured into a mixture Of 1300 g. of ice water. The resultant suspension was stirred at 03 C. for fifteen minutes and then filtered. The collected solid was washed with water at 0-3 C. and dried to constant weight in vacuo at 60-65" C., thus yielding N,N-dimethyl-N-[3- hydroxyphenethyl-N-myristylammonium chloride as a colorless, flee-flowing solid, melting at 97.899.8 C.
Phenol coefficients obtained for this product by standard biological testing procedure are- Organism: Phenol coefficient at 20 C. Staph. aureus 637 Sal. typhosa 667 Association of Official Agricultural Chemists, tenth edition, pages 87-439, Association of Oflicial Agricultural Chemists, Washington, DC, 1965. For example, a solution of 200 parts per million of N,N-dimethyl-N-B-hydroxyphenethyl- N-myristylammoniumchloride in water containing 600 parts per million of dissolved calcium and magnesium salts at 25 C., was found to kill in thirty seconds 99.999 percent or more of the viable cells of Escherichia coli at a concentration of 1X10 cells per milliliter.
N,N-dimethyl-N-fl-hydroxyphenethyl-N myristylammonium chloride was substantially tasteless and when incorporated into a mouthwash composed of a 112000 aqueous solution, the resulting product had neither the bitter taste nor the metallic aftertaste usually found in such germicidal mouthwashes containing quaternary ammoniurn compounds. I
EXAMPLE 2 Using rapid stirring, 120.7 g. (0.5 mole) of freshlydistilled N,N-dimethylmyristylamine was treated at an initial temperature of 25 C. with 95.4 g. (0.25 mole) of 25.69% aqueous solution of sulfuric acid. The mixture became nearly solid and the temperature rose to about 40 C. Fifty ml. of distilled water was added and the mixture was heated to 70 C. To the mixture there was then added during a thirty minute period 62.0 g. (0.515 mole) of (epoxyethyl)benzene. During a period of ten minutes the mixture was heated to 100 C. and heating at 100 to 101 C. was continued for a total of three hours. The pH at he end of the heating period was between 7.0 and 7.1. The mixture was cooled to a temperature between 55 and 60 C. and 136 g. of acetone was added. The resultant solution was then cooled to C., and 408 g. of acetone was added. On standing at 0 C., N,N-dimethyl-N-B-hydroxyphenethyl-N-myristylammonium sulfate separated, from solution. This solid was collected, washed with fresh acetone at 0 to C. and recrystallized from boiling acetone with the aid of decolorizing charcoal. The product was obtained as a colorless free-flowing solid, melting at 73.5 to 177 C.
Phenol coefficients obtained for this product by standard biological testing procedure are- Organism: Phenol coefficient at 20 C. Staph. aureus 687 Sal. typhosa 667 This product was effective as a germicidal agent in hard water as determined by the Chambers test method (100. cit.). For example, a solution of 200 parts per million of N,N-dimethyl-N-fi-hydroxyphenethyl N myristylammonium sulfate in water containing 400 parts per million of I dissolved calcium and magnesium salts at 25 C., was found to kill in thirty seconds 99.999 percent or more of the viable cells of Escherichia coli at a concentration of 1X cells per milliliter.
EXAMPLE 3 Following the procedure of Example 1 hereinabove but substituing N,N-diallyl-n-nonylamine and 4-(epoxyethyl) toluene for the N,N-dimethylmyristylamine and (epoxyethyl)benzene respectively used in that example, there is obtained N,N-diallyl-N-Z-hydroxy 2 (4 methylphenyl) ethyl-N-n-nonylammonium chloride.
EXAMPLE 4 Following the procedure of Example 2 hereinabove but substituting N-methyl N benzylhexadecylamine for the N,N dimethylmyristylamine and substituting 1 (epoxyethyl)-4-chlorobenzene for the (epoxyethyl)benzene used in that example, there is obtained N-benzyl-N-Z-hydroxy- 2 (4 chlorophenyl)-ethyl N methyl-N-hexadecylammonium sulfate.
EXAMPLE 5 Following the procedure of Example 1 hereinabove but substituting N isobutyl N dodecyl-9-octadecenylamine 6 and l- (epoxyethyl)-4-nitrobenzene for the N,N-dimethyl myristylamine and (epoxyethyl)benzene respectively, used in that example, there is obtained N-isobutyl-N-Z-hydroxy 2 (4 nitrophenyl)ethyl N-n-dodecyl-N-9-octadecenylammonium chloride.
EXAMPLE 6 Following the procedure of Example 2 hereinabove but substitution N (4 methoxybenzyl)-N-propylheptadecylamine for the N,N-dimethylmyristylamine and l-(epoxyethyl)-3,5-dimethoxybenzene for the (epoxyethyl)benzene used in that example, there is obtained N-n-propyl-N-2- hydroxy 2 (3,5 dimethoxyphenyl)ethyl-N-4-methoxybenzyl-N-n-heptadecylammonium sulfate.
EXAMPLE 7 Following the procedure of Example 1 hereinabove but substituting N- (4-chlorophenethyl di-n-dodecylamine and l-(epoxyethyl)-4-methylsulfonylbenzene for the N,N-dimethylmyristylamine and the epoxyethylbenezene respectively used in that example, there is obtained N-2-hydroxy- 2-(4-methylsulfonylphenyl)ethyl N 4-ch1orophenethyl- N,N-di-n-dodecylammonium chloride.
Additional compounds prepared by following the procedure of Example 1 or of Example 2 in interacting the appropriate tertiary amine, (epoxyethyl)benzene, and salt-forming acid are:
N-methyl-N-Z-hydroxy-Z- 2,4-dinitrophenyl) ethyl-N- ethyl-N-n-tridecylammonium chloride; N,N,-dimethyl-N- Z-hydroxy- 2- (3 ,4-dimethylphenyl) ethyl- N-Z-ethylhexylammonium sulfate; N-ethyl-N-fi-hydroxyphenethyl-N,N-di (Z-ethylhexyl) ammonium chloride; N,N-diethyl-N-Z-hydroxy-2- (Z-methylphenyl ethyl-N-ndodecylammonium sulfate; N,N-dimethyl-N-Z-hydroxy-2- 3 ,4-dimethylphenyl ethyl- N-tetradecylammonium chloride; N-methyl-N-Z-hydroxy-Z- (Z-methylsulfinylphenyl) ethyl- N,N-di-n-octadecylammonium sulfate; N-1-methylheptyl-N-p-hydroxyphenethyl-N-3-phenylpropyl-N-n-decylammonium chloride; N-octyl-N-2-hydroxy-2- (4-methoxyphenyl) ethyl-N-3 nitrobenzyl-N-n-dodecylammonium sulfate; N-Z-butenyl-N-2-hydroxy-2- 3-chlorophenyl) ethyl-N- 1- methylheptyl-N-n-tridecylammonium chloride; N-n-hexyl-N-Z-hydroxy- 2- Z-methylsulfinylphenyl ethyl- N-n-undecyl-N-n-tetradecylammonium sulfate; N-benzyl-N-B-hydroxyphenethyl-N-phenethyl-N-pentadecylammonium chloride; N,N-dimethyl-N-B-hydroxyphenethyl-N-n-nonadecylammonium chloride; N,N-dimethyl-N-B-hydroxyphenethyl-N-2-methyleicosylammonium chloride; N,N-dimethyl-N-/3-hydroxyphenethyl-N-docosylammonium chloride; N-n-pentyl-N-Z-hydroxy-Z- (3 S-dimethoxyphenyl ethyl- N-n-nonyl-N-l-tetradecenylammonium sulfate; and N-Z-methylbenzyl-N-fl-hydroxyphenethyl-N-n-pentadecyl- N-n-hexadecylammonium chloride.
EXAMPLE 8 (A) Three moles of alpha-olefin (Y-CH=CH wherein Y is alkyl having 9 to 13 carbon atoms) having an average molecular weight of approximately 180, ob-
tained from California Chemical 'Co., and having the following approximate analysis.
Olefin: Percent C 1 C 14 C 23 c 23 C14 C 14 C 1 were caused to react in the absence of a solvent with hydrogen chloride at 15 C. in the presence of 5 percent of stannic chloride as a catalyst. The reaction was complete in about eight hours. The catalyst was removed by extraction of the reaction mixture with dilute hydrochloric acid, water, and dilute sodium bicarbonate solution, and the product Was dried over anhydrous magnesium sulfate. The resulting 2-chloroalkanes were obtained in a yield of 97.5 percent as a crude mixture, n =1.4438, which assayed at 100 percent chloroalkane.
(B) An autoclave was charged with a mixture containing 1 mole of crude 2-chloroalkane (above), 1 mole of sodium hydroxide as a 50 percent aqueous solution, and 1.5 moles of dimethylamine as a 30 percent aqueous solution. The autoclave temperature was raised to 240 C. over a period of three hours and was maintained at 240 C.- L-2 C. for twenty-four hours. The autoclave pressure was 760 pounds per square inch. After cooling, the reaction mixture was separated, and the organic layer washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The Z-dimethylaminoalkane mixture was then distilled. A crude yield of 91.4 percent of theory was obtained.
(C) Following the procedure of Example 1 hereinabove but substituting the mixture of the 2-dimethylaminoalkanes obtained from Example 8B, for the N,N-dimethylmyristylamine used in Example 1 there is obtained a mixture of N,N-dimethyl-N-fi-hydroxyphenethyl-N-lmethylalkylammonium chlorides having a chain length of C C in the l-methylalkyl group.
EMMPLE 9 EXAMPLE 11 Following the procedure given in Example 80, a mixture of N,N-dimethyl-2-hydroxy-2-(4-bromophenyl)ethyl- N-l-methylalkylammonium chlorides having an alkyl chain length of C -C is prepared from 1-(epoxyethyl)- 4abromobenzene and the mixture of the 2-dimethylamino alkanes described in Example 8B.
As further illustration of the present invention, the following compositions can also be prepared from the mixture of Z-dimethylaminoalkanes and the indicated (epoxyethyDbenzene according to the procedure given in Example 80:
Product N, N-dimethyl-N-Z-hydroxy-2-(4- methylphenyl) ethyl-N-l-methyl alkylammonium chlorides.
5-dimethoxyphenyl) ethyl-N-lmethylalkyl ammonium chlor- Epoxy compound 1-(epoxyethyl)-2-methy1benzene.
1-(epoxyethyD-3, E-dimethoxybenzene ides. l-(epoxyethyl)-4-nitrobenzene N, N-dimethyl-N-2-hydroxy 2-(4- nitrophenyl) ethyl-N-l-methylalkyl-ammonium chlorides. l-(epoxyethyl)-2-methylsulfonylbenzene N, N-dimethyl-N-2-hydroxy-2-(2- methylsultonyl)-ethyl-N-1-methylalkylammonium chlorides.
' physical means, for example, fractional distillation or preferably vapor-phase chromatographic separation, to give the individual alpha-olefins, 2-chloroalkanes, or 2- di(lower alkyl)aminoalkane in essentially pure form. From these intermediates, the individual quaternary ammonium compounds can be prepared in essentially pure form by the methods disclosed herein. However, since all of the final products thus obtained are germicidal agents, for many purposes there is no particular advantage in separating them and the mixtures of the quaternary ammonium salts obtained as described above can be used as such without purification.
EXAMPLE 12 A 1:2000 solution of N,N-dimethyl-N18-hydroxyphenethyl-N-myristylammonium chloride in water was prepared. Then a 35.0 ml. portion of the solution was held in the mouth for one minute and then spat out. The solution had a flat taste with no bitterness. The mouth was then rinsed with one 35.0 ml. portion of water. No metallic after-taste or tingling sensation was detected.
The above-described procedure was repeated using a 1:2000 solution of cetyl pyridinium chloride. After one minute a tingling sensation was experienced and after five minutes a metallic taste was still noticeable.
1. A compound of the formula R OH 11 wherein R is alkyl having 1 to 22 carbon atoms, alkenyl having 3 to 22 carbon atoms, or phenyl lower-alkyl;
R is lower-alkyl, lower-alkenyl or phenyl lower-alkyl;
R is higher-alkyl having 8 to 22 carbon atoms or higheralkenyl having 8 to 22 carbon atoms; An is a pharmaceutically-acceptable anion, v is the valence of An; and n is an integer equal to said valence.
2. A compound, according to claim 1 wherein R is alkyl having 1 to 22 carbon atoms, R is lower-alkyl, and R" is higher-alkyl having 8 to 22 carbon atoms.
3. N,N-dimethyl-N-B-hydroxyphenethyl N higheralkyl-ammonium salt, according to claim 1 wherein R and R are each methyl, and R is higher-alkyl having 8 to 22. carbon atoms.
4. A compound according to claim 3 wherein R" is myristyl.
5. A compound according to claim 4 which is N,N- dimethyl-N-fl-hydroxyphenethyl N myristylammonium chloride or sulfate.
6. An aqueous biocidal composition which contains as an essential biocidal ingredient N,N-dimethyl-N-fi-h droxyphenethyl-N-myristylammonium chloride or sulfate according to claim 5.
References Cited Chemical Abstracts, vol. 23, p. 4269 (1929). Quaternary Ammonium Compounds. In Encyclopedia of Chemical Technology, ed. R. E. Kirk & D. F. Othmer. N.Y. Interscience Encyclopedia, vol. 11, p. 379 (1953).
LEON ZITVER, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US. Cl. X.R.
Rig IHHTED STATES PATENT OFFKHB CERTHHCATE HCORRECTMHQ 5, 576, 873 Dated April 27, 1311 Patent No.
Inventor() Crounse It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
T Column 2, line 26, A should read R Column line 8, "substitution" should read substituting Colum in the formula,
R R [R should read R'-' R R" Signed and sealed this 30th day of May 1972.
mDwARn M.FLETcHER,JR. ROBERT GOTTSCHALK Attestlng Officer Commissioner of Patents