US 2937971 A
Description (OCR text may contain errors)
GERMICIDE Leon F. Shackell, 8 Albert Ave., Morristown, NJ.
2 Claims. (Cl. 167-'31) The present invention relates to a method of reducing, inhibiting or tempering the corrosive action of a caustic phenol on tissues of the vertebrates in particular, and to compositions thus obtained, wherein useful characteristics of such a phenol are retained, while its corrosive action is reduced or eliminated.
The present application consists of matters divided out of my original application, Serial No. 536,054, filed May 17, 1944, now abandoned; said application disclosing nitrogenous and non-nitrogenous agents for use in reducing the corrosiveness of caustic phenols. The use of non-nitrogenous agents for that purpose is claimed in my copending divisional application, Serial No. 115,955, filed September 15, 1949, now Patent No. 2,854,375. In the present application the claims are directed to nonelected spcies of nitrogenous agents in said original application. Accordingly, the present specification (exclusive' of claims) is intended to be a substantially exact duplicate of the specification in said orignal application except for the omission herein, so far as seems practicable, of references to non-nitrogenous causticity-reducing agents that are disclosed in said original application. Omissions therefrom are indicated herein by triple asterisks The local corrosive action of a phenol is most marked in the monohydroxyphenols, at least those that are not substantially insoluble in water. Carbolic acid, the isomeric cresols and their halogen derivatives are typical examples of highly caustic phenols. Although the isomeric xylenols and phenylphenols and the dihydroxyphenols-pyrocatechol, resorcinol and hydroquinone possess decidedly lower causticities, they exhibit the same type of response to the causticity-reducing agents herein described as do the highly caustic phenols.
In order to prevent confusion, in the description herein a'fter, between the generic term phenol" and the specific compound, C H OH, the latter will be referred to by its common designation of carbolic acid. In addition to the caustic phenols that I have mentioned in the paragraph next above, I intend to include also in the generic term caustic phenol not only individual phenols of that class-whether pure, technically pure or crudebut also mixtures thereof, as well as commercial preparations containing the same, such as the so-called tar acids, cresylic acid, cresylic creosote, carbolic oil, wood creosote and other wood-tar and coal-tar distillates containing substantial proportions of one or more species of the caustic phenols.
The chief characteristics of the local corrosive action of a caustic phenol on the skin are well known. If, for
example, a drop of tricresol or of liquified carbolic acid --i.e., crystals thereof liquefied by admixture with about a en 2,937,971 Patented May 24, 1960 2 less at this point the phenol is washed olf, preferably with ordinary (ethyl or grain) alcohol, the action of the phenol goes on to cause local necrosis to a variable depth in the skin. This so-called burn is slow to heal; not uncommonly leading .to the formation of white scar tissue.
Although carbolic acid for many years has furnished a yardstick-namely, the phenol coeflicient-for measuring the'bacteriostatic and germicidal activities of a great variety of chemical agents, its caustic, corrosive and escharotic action upon the intact skin and upon other animal tissues has limited greatly its use in the local treatment of common infections and infestations of the skin of man and the lower animals, such as pimples, incipient boils, ringworm, mange, pediculosis and the like. The same disadvantage attaches generally to the other caustic phenols mentioned above.
Apparently as a direct result of the corrosiveness of such phenols, substantially all of the search for improved, phenol-type germicides and disinfectants has been directed to the synthesis of coal-tar derivatives possessing as high phenol coefiicients and as low toxicities-systemic and local-as possible.
A principal object of my invention is to provide a method of reducing the corrosive action of a caustic phenol while at the same time avoiding a proportionate reduction in other characteristic activities of the phenol.
A correlative principal object of my invention is to provide a composition of matter, including a phenol and a causticity-reducing agent therefor, whereby the corrosive activity of the phenol is lowered to an extent that is disproportionately great in comparison to any reduction in other characteristic activities.
Another object of my invention is to provide a method of reducing the corrosiveness of a caustic phenol while avoiding any essential alteration in the molecular structure of the phenol.
Another object is to provide a composition of matter,
including a physical mixture of a caustic phenol and a causticity-reducing agent therefor, whereby the causticity of the phenol is reduced without involvement of any substantial chemical interaction between the phenol and the causticity-reducing agent.
Another object is to provide a composition of matter, including a caustic phenol and a phenol-tempering agent which is adapted to inhibit the causticity of the phenol when present in the mixture in an equal or minor proportion, by weight, relative to the phenol.
Another object is to provide a substantially Water-free composition of matter, including a caustic phenol and a tempering agent therefor, the composition being adapted for local application to the human skin, as well as to the skin of lower animals, whereby without injuring the skin to effect destruction of organisms responsible for various cutaneous disorders.
Another object is to provide a composition of matter, containing a caustic phenol and a causticity-reducing agent therefor, wherein the reduction in causticity of the phenol is disproportionately great in comparison with any reduction in the value of its phenol coefiicient.
Another object is to provide, at lower cost than that of prior art phenolic preparations used for like purposes, a substantially water-free composition adapted for use as a germicide, a fungicide, a disinfectant or an insecticide, composing a physical mixture of a caustic phenol and a causticity-reducing' agent therefor; the relative utilities of the several preparations being correlated with their respective causticities in computing their comparative costs.
Another object is to provide a substantially non-caustic composition containing a chemically unchanged caustic phenol in a concentration lying" within a wide range of percentages; the composition still possessing useful characteristics of the untempered phenol.
Another object is to provide a composition of matter, containing a caustic phenol and a causticity-reducing agent therefor, wherein the reduction in causticity of the phenol is disproportionately great in relation to the degree of dilution of the phenol with the causticity-reducing agent.
Another object is to provide a substantially water-free, safely handleable liquid mixture of a caustic phenol and a causticity-reducing agent therefor, the mixture being adapted to effect sterilization of surgical instruments and like metallic objects immersed therein, but being free from any tendency to cause rusting or other metallic corrosion that may occur in the presence of water.
Other objects and uses of my invention will appear as the description thereof proceeds.
For perhaps fifty years a non-corrosive, liquid mixture of equal parts of carbolic acid crystals and gum camphor has been known under the name of camphor-phenol. In 1933 US. Patent No. 1,924,169 was granted to John E. Stacey for an antiseptic preparation comprising a mixture of camphor and one of the cresols.
That camphor-phenol has been, and still is, considered to be a unique system, is evidenced by the fact that as recently as September 1941, A. W. Francis reported the results of an extended physico-chemical study of camphor-phenol mixtures (Journal of American Pharmaceutical Association, vol, 30, pages 229 to 240). Francis refers therein to the Stacey patent. He concludes that his experimental data point to molecular association between camphor and phenol.
As far as I am aware, only two compounds, other than camphor-namely, glycerol and menthol-have been used to form antiseptic preparations with carbolic acid.
Glycerite phenol-one part liquefied carbolic acid mixed with four parts of glycerolis a long-known preparation,listed formerly in the US. Pharmacopoeia and now in the National Formulary.
I understand that menthol recently has been employed as a substitute for camphor in camphor-phenol.
For a period of some fifteen years prior to my dis-- covery of the principle embodied in my novel method and compositions, I had employed camphor-phenol for aborting boils as Well as for the treatment of other skin disorders. A marked disadvantage, however, of camphor-phenol is the great volatility and ready sublimation of the camphor at ordinary temperatures. The result is rapid evaporation of the camphor-phenol, necessitating repeated applications of the mixture to the part being treated.
In attempting to obviate this disadvantage of camphorphenol, and yet to form a composition comprising a similar physical mixture of a caustic phenol with a causticity-reducing agent, so that the mixture still would exhibit high germicidal activity, I have discovered that a great many materials of wide variety, which are made up of polar molecules in a suitable state of polarizanon-i.e., molecules containing one or more polar radicals of certain types possess the property of inhibiting the corrosive action of the caustic phenol on the skin. Consistent with this discovery I have found out also that so-called nonpolar, hydrocarbon molecules-as exemplified by benzene, p-xylene, cyclohexane, and pineneexhibit no detectable causticity-reducing activity, other than any slight effect of that character attributable to dilution of the caustic phenol.
In extending my studiesalong this line I have tested many hundreds of compounds to determine broadly what types of substances will, and what will not, effect a suitable tempering of a caustic phenol without forming a reaction product therewith.
At this point it will sufiice to say that I have found, in general, that polar compounds wherein the polar radicals are anionoid, electron-donating or nucleophilic in character, are particularly effective in reducing the corrosiveness of a caustic phenol. Later herein is a considerable list of such radicals. The term polar radical," as used herein, comprehends not only a polar group comprising a plurality of atoms, but also a single atom, where the latter contributes to the state of polarization or polarizability of a polar material.
Polar compounds, on the other hand, wherein the polar radicalsare solely or preponderantly cationoid, electron-accepting or electrophilic in character, exhibit little, if any, capacity to temper a caustic phenol. Typical examples of such cationoid radicals are halogeno and nitro. I have found, for instance, that the following cationoid compounds are unsuited for use as polar materials in the practice of my invention: Amylene dichloride; chlorobenzene; o-dichlorobenzene; nitrobenzene; l-nitropropane; 2-nitropropane; s-tetrachlorethane; tetrachlorethylene.
I have found, however, that polar compounds, which contain both anionoid and cationoid radicals, may be effective causticity-reducing agents, provided, that their state of molecular polarization or polarizability is preponderantly anionoid in character. That a large enough number of unsaturated carbon atoms in a compound may sufiice to overcome the elfects of a cationoid radical is evidenced by that fact that o-nitrodiphenyl and l-nitronaphthalene are fairly elfective causticity-reducing agents, whereas nitrobenzene is not.
Unless otherwise indicated by the context, I intend my use herein of the term "polar material to denote a compound (or mixture of compounds) the molecular structure'whereof includes one or more anionoid polar radicals which impart to the compound (or mixture of compounds) the property of physically affecting the molecules of a caustic phenol in such a manner that the causticity of the phenol is reduced or inhibited; other characteristics of the phenol, however, remaining substantially unaflected.
As I shall point out hereinafter, in discussing my theory of the mechanism involved, I ascribe the reduction in causticity to orientation polarization of the phenol molecules induced by the molecules of an effective polar material.
As subgeneric to the term polar material I shall use synonymously herein the terms causticity-reducing agent, phenol-tempering agent and phenol-polarizing agent. I preferably employ the last of these terms for areason that will appear later herein.
The general characteristics that a polar material should possess in order to render it suitable for use in the practice of my invention are (a) that it shall be chemically compatible with one or more caustic phenols, i.e., that it shall undergo no substantial chemical reaction (in the conventional sense) with the caustic phenol, or phenols, at atmospheric pressure, at temperatures below C., and in the absence of a condensing agent or other catalyst; (b) that it shall be capable of forming a substantially homogeneous physical system or mixture with an equal or greater weight of the caustic phenol, and (c) that its state of polarization shall be such as to enable it to reduce the causticity of the phenol below the causticity of the same phenol in a control mixture wherein the polar material is substituted by a substantially nonpolar liquid hydrocarbon functioning as a solvent or misicible diluent for the phenol.
Wherever I use the term of the character described with reference to a polar material or phenol-polarizing agent,.I intend the term just quoted to comprehend char- I contemplate as embodying my invention, ordinarily will be liquids at or about room temperatures. Occasionally,
however, I have formed operative embodiments'ofmy invention which appear, respectively, as solids, as p'astes, and as creams.
The character of a composition, embodying my invention, as a physical system or mixture, may be demon-' trated by suitable tests known to the art; for example, by the ready separation from the composition of the more volatile ingredient thereof-whether it be the caustic phenol or the phenol-polarizing agent-either as the result of spontaneous evaporation or of distillation. For instance, a number of mixtures that I have prepared have begun to exhibit caustic efiects only after spontaneous evaporation of a large part of the phenol-polarizing agent, which happened to be more volatile than the phenol. As examples thereof I may mention 1:1 mixtures of carbolic acid with each of the following compounds: Amyl borate, butyl alcohol, heptaldehyde, butyl acetate, ethyl carbonate, butyl ether, diethyl ketone and capronitrile.
Conversely, I have found that certain of my novel compositions-wherein the respective phenol-polarizing agents were substantially nonvolatile solids-could be left in contact with the skin, without eliciting any sign of caustic effect, until the caustic phenol had disappeared therefrom, leaving a finely granular residue of the polar material. As an example thereof I may mention a liquid composition consisting of a mixture of 2 parts of carbolic acid crystals and one part of p-acetophenetide.
I have found that the etiectiveness of a given polar material in reducing the escharotic action of a caustic phenoli.e., its tissue-necrosing or most corrosive type of actionmay be tested accurately and with substantial rapidity on the human subject, while yet avoiding the danger of causing a phenol burn or any permanent disfigurement. The test may be either quantitative or qualitative or a combination of the two.
The quantitative test comprises a determination of the extent to which the polar material is able to delay the onset of initial or early caustic effect of the phenol, as exemplified by a burning sensation, or loss of sensibility to skin pain, or whitening of the skin.
The qualitative test involves observation of the degree to which any one or more of these early caustic efiects is checked or inhibited, or even completely abolished. For example, a mixture of a caustic phenol and a particular polar material may induce some loss of sensibility to skin pain, and yet elicit no sensation of burning. Again, as I have indicated previously, I have made up many compositions embodying my invention, wherein the causticity of the phenol apparently had been inhibited completely, as evidenced by entire absence of any indicia of causticity during a test period which ended with the disappearance of the phenol from the test sample.
My preferred method of testing the efiicacy of a given polar material as a causticity reducing or tempering agent involves primarily the measurement of sensibility to skin pain as afiected by the composition, embodying my invention, which is being tested. Before I describe my preferred method of test, however, I shall discuss briefly the term sensibility to skin pain.
In the technique of a neurologic examination it is a standard medical procedure to test for sensibility to skin pain by light exploratory pricks with the point of a needle or pin. In the case of a normal, intact skin a light pin prick, which is quite insufiicient to puncture the skin, will elicit a fleeting subjective sensation of sharpness, or skin pain. Cessation of function in the sensory nerve supply to a patch of skinas by mechanical injury, disease, or the action of a local anesthetic-results in the loss of sensibility to a pin prick; a condition for which the desigplete analgesia, may exist. Such a diminution commonlyis termed hypalgesia.
In testing the capacity of a given polar material to reduce the causticity 'of a-phenol, I preferably employ the iollowing'metho'dz I say, of the forearm or of the anterior surface of the thigh, when disposed horizontally. The time is noted. Then the subject observes whether or not the mixture causes any sensation of burning. If a sensation of sharp burning occurs within one or two minutes, the test is terminated immediately; that is, the mixture is brushed or scraped off if solid, or is blotted with soft paper tissue, if liquid; and the afiected area of skin is sponged off atleast three times with alcohol. Rubbing alcohol is suitable. a
Where a burning sensation rapidly follows upon the application of the mixture to the skin, its disappearance after washing otf of the mixture ordinarily is succeeded by a transient erythema and hypalgesia. I
If no burning is felt, nor whitening of the skin is observed, within the first two minutes of the test, then the subject (or an observer) pricks the skin lightly two or three times with the point of a needle or pin; passing the point through the mixture. If the pricks elicit no sensory response (analgesia), or if there is a definite blunting of sensation (advanced hypalgesia or incomplete analgesia)-best determined by testing the adjacent, untreated skin in a similar mannerthe test ordinarily is terminated in the manner above described.
If, however, the first pricking trials indicate no definite diminution of sensibility to skin pain, they are repeated at intervals of two or three minutes until either analgesian (or at least advanced hypalgesia) is demonstrable, or until the test has continued for 15 minutes without any perceptible diminution of pain sensibility.
Where 15-minute trials" have elicited negative results,-
I have carried out more rigorous tests with each of numerous compositions embodying my invention; each composition containing at least 50 percent of (originally) caustic phenol. I have permitted each such composition to remain in contact with the skin until disappearance of the phenol, either by volatilization or absorption, leaving behind in some instances a relatively nonvolatile residue of the phenol-polarizing agent. I already have given examples of the formation of such nonvolatile residues in connection with my previous discussion of the physical character of mixtures embodying my invention.
None of the more rigorous tests just referred tosome lasting for more than an hourresulted in anything approaching a phenol burn; and in most instances the sole observable result was a transient erythema. It
was very seldom, in fact, that one of my novel compo-- initely irritant action on rather prolonged contact with the skin, I consider that an erythema, without more, re-' sulting from a 15-minute causticity test of one of my novel compositions, does not warrant any conclusion other than that the composition so tested was devoid of caustic activity, at least for the period of test.
On the basis of many hundreds of tests that I have carried out, I consider that a polar'material is adapted to reduce the corrosiveness of a caustic phenol if a substantially homogeneous physical system, consisting of one part of the polar material in admixture with one part or more of the phenol, when tested on the human.
skin in the manner described, either elicits no burning sensation or exhibits a delay in the timeof onset ofcaustic effect-whether measured subjectively by'a burning' sensation, by hypalgesia, or by analgesia, or objec-f tively by whitening of the skin-in comparison with the time of onset of the caustic elfect of a control mixture consisting of a like proportion of the same phenol and a substantially nonpolar liquid hydrocarbon adapted as a solvent or a miscible diluent therefor.
The hydrocarbon used in making up a control mixture should be capable of forming a homogeneous mixture with at least an equal weight of the caustic phenol. In general, the aliphatic hydrocarbons, because of their limited miscibility with the caustic phenols, are not suitable diluents for forming control mixtures. I have tested the following hydrocarbons, however, and have found them to be satisfactory in this respect: Cyclohexane; pinene; p-xylene; xylenes (mixed). The last was a technically pure grade of xylene, consisting of a mixture of the m-, and p-isomers.
With all control mitxtures that were tested the onset of caustic action was detected by a burning sensation. When this sensation became well defined or sharpwhich occurred in a few seconds after it was first observed-the control mixture was washed away in the manner described above. 1
V In Example 1 beloware given representative results of tests with control mixtures, each made up of equal weights of the caustic phenol and the hydrocarbon solvent or diluent.
All quantities, parts, proportions or ratios of ingre dients given herein are in terms of weight. Furthermore, having reference to the composition of one of my novel mixtures, and unless otherwise indicated, the first member of each numerical ratio stated herein-say 1:1 or l:3-denotes the parts by weight of polar material, and the second member denotes the parts by weight of caustic phenol.
Example 1.-Control mixtures (1:1) of caustic phenols with substantially nonpolar hydrocarbons;
Onset of burning, seconds Phenol Hydrocarbon diluent Oyclohexane Pinene Oarbolic acid Do p-Xylcne Xylenes (mixed) Pinen e Xylenes (mixed)- Pinene Xylenes (mixed) o 2,4-Dichlorophenol. Do
I ordinarily consider that a polar material meets characteristic (0), stated above, if, in a ratio to a caustic beyond the time of onset thereof, as observed in the case of a control mixture-similar to those illustrated in Example lcontaining the same caustic phenol.
My preferred practice of the method which embodies my invention varies, depending upon whether the caustic phenol, as well as the selected causticity-reducing agent, is a solid or liquid at ordinary temperatures. The majority of such phenols, when substantially pure, occur as crystalline solids. The latter melt, however, at temperatures Well below 100 C., and, for the most part, below 50 C. In the presence of small amounts of impurities--for example in the so-called practical or technical grades-the caustic phenols commonly exist as liquids. The latter also is true of some mixtures of isomeric phenols, as exemplified by commercial tricresol, which is a mixture of o-, mand p-cresol.
In reducing the causticity of a phenol which is solid at room temperature I prefer to melt a known weight thereof by any suitable method which does not raise the temperature of any part of the phenol above about 95 C. A water-jacketed kettle which is not attacked by the phenol, nor by the causticity-reducing agent to be incorporated therewith, is convenient. The container should be provided with means for heating the water in the jacket and with suitable mechanism for stirring the contents of the kettle. To the molten phenol in the kettle is added a predetermined quantity of the selected causticity-reducing agent, irrespective whether the latter is in solid or in liquid form. If, upon stirring, the mixture does not readily form a homogeneous liquid, the temperature of the water in the jacket is raised to a point not substantially higher than is required to effect formation of a homogeneous liquid; and in no event higher than about C. The resulting physical mixture may then be drawn off into bottles or other suitable containers provided with closures.
With the great majority of physical mixtures thus formed, the weight ratio of phenol to causticity-reducing agent is shown to have been kept within a suitable range, if, upon standing for a few days in a closed container at room temperature the mixture remains liquid and shows no separation of ingredients in solid form. If the causticity-reducing agent is naturally a liquid, and a crystalline phenol was employed in making the mixture any solid phase subsequently separating therein most probably will be an excess of phenol, which will call for a suitable additional weight of the causticity-reducing agent; for the separated phenol will exhibit substantially the same degree of causticity as untempered phenol.
If, on the other hand, the causticity-reducing agent originally was a solid, and some of the latter separates as a solid phase from its mixture with the phenol, then the liquid mixture may be separated from the polar mate rial by decantation or filtration; or the excess of the phenol-polarizing agent may be liquefied by incorporating therewith a suitable proportion of the phenol, with the aid of a proper degree of heat, as previously described. 1
An alternative method of preparing compositions embodying my invention, when both the phenol and the polar material are solids at ordinary temperatures, is to grind together suitable quantities of the respective ingredients in a triturating device, such as a ball mill or colloid mill.
When the phenol and the polar material are liquids at ordinary temperatures, the forming of a physical mixture thereof may suitably be effected by stirring together, without the aid of heat, predetermined quantities of the respective ingredients.
In order to utilize the benefits attaching to the high concentrations of caustic phenols, which I preferably employ in my novel compositions, I ordinarily do not incorporate therewith any inert, or otherwise compatible, diluent. Nevertheless, where deemed desirable, I may dilute a composition embodying my invention with any suitable nonpolar or polar material. For example, I may dilute the composition with any suitable liquid hydrocarbon, or I may use as a diluent an additional quantity of the same polar material that I have employed as a phenol-polarizing agent in making in the composition. I may employ also as a diluent any one of numerous liquid cationoid compounds which alone are not suitable as phenol-polarizing agents; for example, halogenated hydrocarbons, nitroparaflins, phenyl ether, and the like.
Again, I may, if desired, make a cream, an unguent, a paste or a friable powder out of a liquid embodiment of my invention by suitable incorporation therewith of one or more compatible materials, known to the pharmaceutical art, such as an animal or vegetable fat, starch, talc, bentonite, kieselguhr, wood flour, and the like.
Many of the novel compositions embodying my invention contain preferably 50 percent or more of caustic phenol. Where, however, dilution of such a composition seems desirable for a particular use, the dilution may be integrated with'the method of forming the composition, as follows: The caustic phenol and the selected phenolpolarizing agent, in suitably proportioned quantities, are dissolved, or incorporated, either separately or together, in a quantity of a compatible solvent, or miscible diluent sufficient to yield a final composition having the desired phenol concentration. This variant of my novel method may be employed to advantage when the caustic phenol and the phenol-polarizing agent are both solids at room temperature. The solvent, or miscible diluent, may be non-polar or polar. In fact, if the selected phenolpolarizing agent is liquid at room temperature, it may, if desired, be employed in a dual capacity both as a causticity reducer and as a diluent.
In so far as the individual members of a particular class or generic group of polar materials possess characteristics (a), (b) and (c) that I have described hereinabove, I have found the following generic classes of compounds to be among those capable of accomplishing broadly the objects of my invention; including in partic ular a reduction in the corrosive action of a caustic phenol without a proportionate reduction in other characteristic activities of the phenol: amides; esters; nitriles; oximes;
I have found, additionally, that derivatives or substitution products of the foregoing are capable of effecting a reduction in the corrosiveness of a caustic phenol without causing any substantial change in other characteristics thereof; and thus of accomplishing the general object of my invention (a) when the substituent comprises an anionoid radical; (b) when the substituent corn? prises a cationoid radical-such as halogeno or nitroprovided, that the state of polarization or polarizibility of the derivative is preponderantly anionoid; and when the substituent comprises sulfur. Compounds illustrative of the foregoing group (b) of preponderantly anionoid phenol-tempering agents occur in various examples given below, more particularly in Example 12. In my use of the term sulfuretted polar material I intend to include therein substances containing a mercapto, a sulfonyl, a thiazolyl, a thio, a thiocarbonyl, a thiocyano or a thiophospho radical.
My use of certain generic designations in the second preceding paragraph, as well as in my claims, is intended to comprehend compounds which, unless specifically exceptedsuch as ethers containing the phenoxy radicalcome within ordinary and usual chemical definitions of the respective classes, together with similar, related or analogous compounds, for example:
Amides include acid amides, anilides and ureas.
Esters include ammonium salts of organic acids; esters of mineral acids; esters containing one or more anionoid radicals other than, or in addition to, carbonyldioxy; acidulated amines-primary, secondary and tertiary; acidulated alcoholaminesprimary, secondary and tertiary;
Ethers include I In the subjoined list-along with their conventional chemical formulas or symbolsare examples of polar radicals, anionoid in character which are present in substances coming within one or another of the classes, genera or groups of polar materials set forth above, which I have found to be capable of accomplishing the general objects of my invention. In the su'bjoined list, as well as in Examples 2 to 15, inclusive, ordinary chemical symbols are used in the formulas for the polar radicals. In the formulas R denotes a hydrocarbon residue.
EFFECTIVE PHENOL-POLARIZING RADICALS cyano (CN), diacyl (OCRCO), epoxy (O.-), furyl i6 (C H O), hydroxyl (OI-I), imino .(NI-I), isonitroso (NOH), keto (0:), mercapto (SH), nitrilo (N), nitrilocarbonyl (NCO), nitroso (NO), oxalyl (OCCO), oxamyl (H NCOCO), phospho (P0 silico (SiO sulfonyl (S0 tetrahydrofuryl (0 1-1 0), thiazolyl (C H NS), thio (S), thiocarbonyl (CS), thiocyano (NCS), thiophospho (PS ureido (HNCONH ureylene (HNCONH), unsaturated carbon.
One of the aforenarned phenol-polarizing radicals may be a component of a larger radical; for example, carbonyl is a component of acyl, of acyloxy, of aldo, of carbonyldioxy, and of other polar radicals. Nevertheless, for the purposeof this invention, each of the aforelisted effective. phenol-polarizing radicals is to be considered in its entirety and as a different kind of radical from each of the others. A polar compound, which is an effective phenol-tempering agent, may contain unsaturated carbon in its molecular structure. Such unsaturated carbon is embraced within the general terms polar radical and anionoid radical; audit may contribute somewhat to the phenol-tempering capacity of a compound which additionally contains another and different kind of polar radical. Standing alone in a hydrocarbon, however-as illustrated by pinene and the xylenes in Example 1 above-unsaturated carbon exerts an anionoid action which is insufiicient to render the hydrocarbon suitable for use as a .sole. phenol-tempering agent in the practice of my invention. Consequently, I have employed one or more control mixtures of caustic phenols and substantially nonpolar hydrocarbons, similar to those illustrated in Example 1, as criteria for determining the phenoltempering capacity of a polar material under test,'when formedinto a substantially homogeneous physical mixture with a given caustic phenol-where the latter, and its proportion in the test mixture, where the same as in the control mixture or mixtures.
In Examples 2 to 15, inclusive, are set out illustrative results taken from many hundreds of skin reaction tests that 'I have made on as many different compositions comprising a caustic phenol and a phenol-polarizing agent. In order to present these data as concisely as possible I shall use code symbols as follows: 7
Representative caustic phenols that I have tested are carbolic acid (I), tricresol (II), o-chlorophenol (III), pchlorophenol (IV), and 2,4-dichlorophenol (V). In the examples below the phenol (or phenols) tested with a stated polar material appears'under its symbol in Roman numerals in parentheses following the name of the polar material. It will be observed that in many instances more than one species of caustic phenol was tested with the same phenol-polarizing agent. Unless indicated otherwise, the ratio of polar material to caustic phenol was 1:1; that is, the mixture, as originally made up, consisted of 50 percent of the phenol and 50 percent of the polar material. In certain instances, however, shown by the notation sat, some of the polar material separated from a liquid mixture which was in equilibrium therewith. In such a case the skin test was made with the liquid; the phenol, consequently, comprising a major fraction of the liquid.
For convenience of comparison, the various polar materials have been put into one or another of four cate-v gories-namely, A, B, C, and Drepresenting diminishing grades of effectiveness as phenol-polarizing agents. The mixtures classed in group A evidenced. no caustic action on a fifteen minute contact with the skin. The mixture in group B elicited a moderate grade of caustic reaction--i.e., beginning burning or incomplete analgesia-in 11 to 15 minutes; those in group- C a like grade of reaction in 6 to 10 minutes, and those ingroup D a similar reaction in 2 to 5 minutes.
In a few instances, as already has been pointed out, no caustic efiect was observed until a major portion of the polar material had volatilized. Those cases are indicated by thexnotationfevap. 1
At the head of each of Examples 2 to 15, inclusive, there is a parenthetic note listing the polarradicalsto be foundtin one or another of the specific polar compounds tcsted-which have rendered the compounds suitable as phenol-tempering agents. Unless otherwise indicated, such polar radicals are anionoid in character. Those skilled in the calling will recognize which one or more of the polar radicals thus parenthesized is present in a given polar material.
Example 2.Alcohols (monohydric)* Example 3.-Alcohols (dihydric)* Example 4.-Aldehydes* I Example 5.Amides, includingacid amides, anilides and ureas. (Polar radicals: Acyl, acylamino acyIiminO, carbamyl, oarbonylimino, nitrilocarbonyl, ureido, and ureylene.)
A. Acetamide (I); acetanilide (I-sat.); acetoacetanilide (I, II, IV); p-acetophenetide (I-sat.; II-sat.; III-sat); benzamide (I-solid); N-butylauramide (I, HI); butyl urea (I); caproamide (I); caproanilide (I-sat.; V-sat.); dibutyl cyanamide (I); N,N-di-n-butyllauramide (IV); N,N-diethylacetamide (I); N,N'-diethyl-N,N'-diphenylurea (I); heptamide (I-sat; V-sat.); phenylacetamide (I- sat.); Z-phenylbutyramide (I, II); o-toluamide (I-sat.; Ii-sat.; V-paste); urea (III-solid) B. Benzamide (IV-sat); N,N-di-n-butyllauramide (I).
C. p-Toluamide (I-soft mass).
D. Octadecanamide (I-paste); palmitamide (I-solid).
-Exa'mple 6.Esters, including esters of mineral acids, ammonium salts of organic acids, esters containing one or more anionoid radicals other than carbonyldioxy, acidulated amines-primary, secondary and tertiaryand acidulated alcoholaminesprimary, secondary and tertiary. (Polar radicals: Acyl, amino, carbamyl, carbonyl, carbonyldioxy, cyano, diacyl, furyl, hydroxyl, imino, nitrilo, oxalyl, oxamyl, phospho, *,unsaturated carbon.)
Represenative examples of polar materials which I have found to be suitable for the practice of my invention and which I term esters, are set forth, together with the results of causticity-reduction tests, in subdivisions 6a, 6b, and 6c of the present example. In subdivision 6a are included examples of esters other than examples of acidulated amines and acidulated alcohol amines; the latter two groups being listed, respectively, under subdivisions 6b and 60.
A. ammonium acetate (1); isoamyl carbamate (I, V); diacetylethylenediamine (I- sat.; II-sat.; V-sat.); ethyl carbamate (I, H, III); ethyl cyanoacetate (I); ethyl oxanilate (I, II); i ii l lib-Acidulated amines Amines and alcoholamines constitute polar materials which, by reason of their basicity, form reaction products with caustic phenols. Such basic substances consequently are not suitable, per se, for the practice of my invention. Salts of amines and of alcoholamines, however, which are substantially neutral, or even somewhat acid in reaction, are adapted in general to form with caustic phenols physical mixtures which constitute typical embodiments of my invention.
In the next succeeding five paragraphs hereof I shall use the term amine (or amines") to include the alcoholamines.
The salts of amines which are adapted for the practice of my invention I preferably prepare by reacting a quantity of a given amine with an amount of a selected acid sufficient to yield a substantially neutral product. In
order, however, to prevent any appreciable chemical reaction between any free amine and the later added caustic phenol, 'I prefer to carry the neutralization of the amine slightly to the acid side of neutrality, i.e., to form a product which is acid to litmus paper; the reaction being tested on a solution of a trace of the product in a few drops of distilled water.
7 In the case of an aliphatic or an alicyclic amine a suitable degree of neutralization ordinarily may be effected by reacting equivalent weights of the amine and of the acid. Nevertheless, as I have said, I prefer to carry the acidification to a slight acidity. In some of the mixtures set forth in the present subdivision, as well as in subdivision 6c of the present example, it will be observed that the amine salt has been formed with an excess of acid. In consequence, I prefer to employ the terms acidulated amine and acidulated alcoholaminc instead of amine sal and alcoholamine salt; respectively. Because of the low basicity, however, of aromatic amines in comparison with aliphatic and alicyclic amines, I prefer, in the case of an aromatic amine, to react therewith a quantity of selected acid not substantially greater than is necessary to form a product that is faintly acid to litmus paper. This comes within my term substantially neutral."
Since my preferred criterion of suitable acidification of an amine is based upon the reaction of the product toward an indicator rather than upon the use of equivalent weights of the reactants, I prefer to employ the term acidulated amine rather than amine salt.
I include also, in my use of the terms acidulated amines and acidulated alcoholamines," nitrogenous compounds, of originally basic character, which have been acylated to an extent that renders them substantially neutral in reaction. An example of such an acylated base is diacetylethylenediamine. For present purposes, however, this compound has been included in group 6a.
In forming an acidulated amine, I preferably employ a lower fatty acid such as acetic acid or propionic acid. Nevertheless, I have found that any acid is suitable therefor when the resulting product is capable of forming'a substantially homogeneous physical mixture with an equal or major quantity--preferably not more than five times its weightof a caustic phenol. Examples of acids, other than acetic and propionic acids, that I have used to form salts of amines and of alcoholamines, are: Adipic; benzilic; benzoic; cinnamic; cyclohexanecarboxylic; digly colic; ethylphosphoric; furoic; glycolic; heptylic; hydrocinnamic; lauric; levulinic; malonic; myristic; naphthenic acids (practical grade); oleic; oxalic; phenylacetic; salicylic; sebacic; stearic; d-tartaric; and undecylenic.
All of the substantially neutral, or somewhat acid, salts of amine and/or of alcoholamines, that I have formed with the foregoing acids, I have found to be efiective as causticity-reducing agents for caustic phenols.
In forming an acidulated amine or alcoholamine I may employ an acid anhydride instead of an acid. Examples of acid anhydrides that I have employed to form salts of amines and/ or of alcoholamines are: Benzoic; Z-furoic; heptylic; phthalic; propionic; and succinic.
All of the acidulated amines and alcoholamines that I have formed with the foregoing acid anhydrides, I have found to be effective as causticity-reducing agents for caustic phenols.
The following representative instances under the present subdivision b of Example 6 (Esters) serve to illustrate (1) the formation of acidulated amines and the subsequent formation of physical mixtures of caustic phenols therewith; and (2) the results of tests showing the general suitability of such acidulated amines for use in the practice of my invention.
.In subdivision c of the present Example 6 are set out, in similar fashion, data on representative examples of acidulated alcoholamines and of physical mixtures thereof with caustic phenols.
13 The code letters, A, B, C, and D, employed inearlier examples to indicate the relative effectiveness of a given polar material as a causticity-reducing agent, will be used with like significance in subdivisions 6b and 6c. The code letter, however, will be placed at the end of the formula for a given mixture.
6b.-Acidula'ted amines SERIES 1.AMINES ACIDULATED \VITH PROPIONIC ACID 1.2 parts 4-amino-l,3-dimethylbenzene plus 0.8 part propionic acid; plus 2.0 parts tricresol; A.
(b) 1.4 parts o-aminodiphenyl plus 0.7 part propionic acid; plus 2.1 parts tricresol; D.
(c) 1.4 parts p-aminodiphenyl plus 0.7 part propionic acid; plus 2.1 parts tricresol; C.
(d) 1.1 parts mouoamyla-mine plus 1.0 part propionic acid; plus 2.1 parts tricresol; A.
(e) 1.2 parts o-anisidine plus 0.8 part propionic acid;
plus 2.0 parts tricresol; B.
(i) 1.5 parts benzoyl-l-naphthylamine plus 0.5 part propionic acid; plus 2.0 parts tricresol; D.
(g) 1.5 parts benzylamine plus 1.0 part propionic acid;
plus 2.5 parts carbolic acid; A.
(h) 1.4 parts benzyl-o-toluidine plus 0.6 part propionic acid; plus 2.0 parts tricresol; C.
(i) 1.8 parts N-(mono-n-) butylaniline plus 0.3 palt propionic acid; plus 2.1 parts carbolic acid; C.
(,1) 1.0 part cyclohexylamine plus 1.3 parts propionic acid; plus 2.3 parts carbolic acid; A.
(k) 1.0 part 2,4-diaminotoluene plus 1.2 parts propionic acid; plus 2.2 parts tricresol; A.
(l) 1.0 part diamylamine plus 1.0 part propionic acid;
plus 2.0 parts carbolic acid; A.
(m) 2.3 parts dibenzylamine plus 1.2 parts propionic acid; plus 3.5 parts carbolic acid; A.
(n) 1.8 parts N,N-di-n-butylaniline plus 0.2 part propionic acid; plus 2.0 parts carbolic acid; B.
(o) 2.5 parts dicyclohexylamine plus 1.0 part propionic acid; plus 3.5 parts carbolic acid; A.
(p) 1.1 parts N,N-diethylcyclohexylamine plus 1.4 parts propionic acid; plus 2.5 parts carbolic acid; A.
(q) 1.0 part diethylenetriamine plus 1.5 parts propionic acid; plus 2.5 parts carbolic acid; A.
(r) 1.4 parts diethyl-o-toluidine plus 0.7 part propionic acid; plus 2.1 parts tricresol; A.
(s) 2.0 parts dimethylaniline plus 0.3 part propionic acid; plus 2.3 parts carbolic acid; A.
(t) 0.6 part ethylenediamine plus 1.7 parts propionic acid; plus 2.3 parts carbolic acid; A.
(u) 1.0 part heptylamine plus 1.5 parts propionic acid;
plus 2.5 parts carbolic acid; A.
(v) 0.65 part hydrobenzamide plus 0.35 part propionic acid; plus 1.0 part tricresol; A.
(w) 1.2 parts methylaniline plus 0.9 part propionic acid;
plus 2.1 parts tricresol; B.
(x) 1.0 part morpholine plus 1.0 part propionic acid;
plus 2.0 parts carbolic acid; A.
(y) 1.3 parts l-naphthylamine plus 0.8 part propionic acid; plus 2.1 parts tricresol; C.
(z) 1.3 parts p-phenetidine plus 0.9 part propionic acid;
plus 2.2 parts tricresol; A.
(an) 1.0 part p-phenylenediamine plus 1.5 parts propionic acid; plus 2.5 parts tricresol; C.
(bb) 1.6 parts phenethylamine plus 1.0 part propionic acid; plus 2.6 parts carbolic acid; A.
(cc) 1.3 parts propylenediamine plus 3.5 parts propionic acid; plus 4.8 parts carbolic acid; A.
(dd) 1.2 parts pseudocumidine plus 0.8 part propionic acid; plus 2.0 parts tricresol; B.
(ca) 1.2 parts o-tolidine plus 0.9 part propionic acid;
plus 2.1 parts tricresol; B.
(ff) 1.2 parts o-toluidine plus 0.9 part propionic acid;
plus 2.1 parts tricresol; B.
plus 2.1 parts tricresol; B.
(izh) 2.0 parts tributylamine plus 1.5 parts propionic acid; plus 3.5 parts carbolic acid; A.
(ii) 1.0 part triethylenetetramine plus 1.5 parts propicnic acid; plus 2.5 parts carbolic acid; A.
SERIES 2.-AMINES ACIDULATED WITH ACIDS OTHER THAN PROPIONIC ACID (a) 0.55 part o-aminodiphenyl plus 0.45 part cyclohexanecarboxylic acid; plus 1.0 part 2,4-dichlorophenol; C.
(b) 0.55 part monoamylamine plus 0.45 part oxalic acid;
plus 1.0 part 2,4-dichlorophenol; D.
(c) 0.28 part aniline plus 0.72 part myristic acid; plus 1.0 part o-chlorophenol; D.
(d) 0.55 part benzylamine plus 0.45 part glycolic acid;
plus 1.0 part p-chlorophenol; B.
(e) 0.44 part cyclohexylamine plus 0.56 part benzoic acid; plus 1.0 part o-chlorophenol; B.
( 1.0 part cyclohexylamine plus 1.5 parts ethylphosphoric acid; plus 2.5 parts carbolic acid; A.
(g) 1 .0 part cyclohexylarnine plus 1.5 parts levulinic acid;
plus 2.5 parts carbolic acid; A.
(h) 1.0 part cyclohexylamine plus 2.3 parts naphthenic acids (practical grade); plus 3.3 parts carbolic acid; A.
(i) 2.0 parts cyclohexylamine plus 9.5 parts oleic acid;
plus 11.5 parts carbolic acid; C.
(i) 1.2 parts diamylamine plus 0.8 part benzilic acid; plus 2.0 parts tricresol; A.
(k) 1.1 parts diamylamine plus 0.9 part benzoic acid;
plus 2.0 parts tricresol; A.
(l) 1.0 part diamylamine plus 1.1 parts cinnamic acid;
(0) 1.2 parts diamylamine plus 0.9 part furoic acid;
plus 2.1 parts tricresol; A.
(p) 1.3 parts diamylamine plus 1.2 parts of glycolic acid;
plus 2.5 parts tricresol; A.
(q) 1.0 part diamylamine plus 1.0 part hydrocinnamic acid; plus 2.0 parts tricresol; A.
(r) 1.5 parts diamylamine plus 0.9 part malonic acid;
plus 2.4 parts tricresol; A.
(s) 0.5 part diamylarnine plus 1.5 parts myristic acid;
plus 2.0 parts tricresol; C.
(t) 1.0 part diamylamine plus 3.5 parts oleic acid; plus 4.5 parts carbolic acid; C.
(u) 1.4 parts diamylamine plus 0.6 part oxalic acid;
plus 2.0 parts tricresol; A.
(v) 1.0 part diamylamine plus 1.0 part phenylacetic acid;
plus 2.0 parts tricresol; A.
(w) 0.6 part diamylamine plus 0.4 part sebacic acid;
plus 1.0 part o-chlorophenol; A.
(x) 1.0 part diamylamine plus 1.0 part d-tartaric acid;
plus 2.0 parts tricresol; A.
(y) 0.6 part dibenzylamine plus 0.4 part furoic acid;
plus 1.0 part 2,4-dichlorophenol (sat); A.
(z) 0.44 part dicyclohexylamine plus 0.56 part benzilic acid; plus 1.0 part p-chlorophenol; B.
(aa) 0.5 part N,N-diethylcyclohexylamine plus 0.7 part salicylic acid; plus 1.2 parts 2,4-dichl0rophenol; A. (bb) 0.4 part N,N-diethylcyclohexylamine plus 0.6 part salicylic acid; plus 1.0 part tricresol; A.
(00) 0.58 part diphenylamine plus 0.42 par-t levulinic 38) 0.7 part l-naphthylamine plus 0.3 part ethylpho si phoric acid; plus 1.0 part p-chlorophenol; C.
(hi1) 0.25 part m-phenylcnediamine plus 0.75 part-cinnamic acid; plus 1.0 part tricrc-sol (sat.); E.
(ii) 0.26 part p-plicnylcncdiamiuc plus 0.74 part oleic acid; plus 1.0 part 2,4-dichlorcphenol (sat.); B.
(ii) 0.42 part o-toluidinc plus 058 part phenylacetic acid; plus 1.0 part 2,4-dichlorophcnol; A.
(klc) 0.7 part tributylamine plus 0.3 part adipic acid;
plus 1.0 part p-chlorophenol; A.
(mm) 1.0 part tributylamine plus 2.0 parts olcic acid;
plus 3.0 parts carbolic acid; B. Y 7
SERIES 3.AMINES ACIDULATED WITH ACID ANHYDRIDES (a) 1.1 parts diamylaminc plus 0.9 part benzoic anhy- 6c.-Acidulated alcoholamines spams 1.--ALCOHOLAMINES ACIDULATED WITH PROPIONIC ACID (u) 0.45 part l-aminoethanol plus 0.55 part propionic acid; plus 1.0 part c-chlorophcnol; A.
(b) 1.2 parts Z-aminc-Z-methyl-l,3-prcpanediol plus 0.9
part propionic acid; plus 2.1 parts tricrcsol; A.
(c) 1.0 part 2-amino-2-methyl-l-propanol plus 1.0 part propion-ic acid; plus 2.0 parts carbolic acid; A.
(d) 1.4 parts butyldictiianolaminc plus 0.9 part prcpionic acid; plus 2.3 pans tricresol; A.
(e) 1.2 parts hutylmonoethanolarninc plus 0.8 part propionic acid; plus 2.0 parts tricresol; A. (f) 1.0 part diethanolaminc plus 1.0 part propionic acid;
plus 2.0 parts carbolic acid; A. r (g) 1.0 part 2-diethylaminocthanol plus 1.0 part propionic acid; plus 2.0 parts carbolic acid; A.
(h) 1.0 part di-iso-propanolamine plus 0.5 part propionic acid; plus 1.5 parts carbolic acid; A.
(i) 0.6 part cthyldicthanolamine plus 0.4 part propionic acid; plus 1.0 part tricresol; A.
(j) 4.7 parts 2-hydroxycthylaniline plus 0.5 part propionic acid; plus 5.2 parts carbolic acid; B.
(k) 1.2 parts hydroxyethylethylcnediaminc plus 1.7 parts propionic acid; plus 2.9 parts carbolic acid; A. (l) 1.3 parts 2-hydroxyethyl-p-t0luidine plus 0.7 part propionic acid; plus 2.0 parts tricresol; D. (m) 1.6 parts tni-iso-propanolam-ine plus 1.0 part propicnic acid; plus 2.6 parts carbolic acid; A.
SERIES 2.--ALCOHOLAMINES ACIDULATED WITH ACIDS OTHER THAN PROPIONIC ACID (a) 1.3 parts 2-aminc-2-methyl-l-propanol plus 2.5 parts ethyl-phosphoric acid; plus 3.8 parts carbolic acid; A.
(b) 1.0 pait 2-amino-2-methyl-l-propanol plus 6.0 parts naphthenic acids (practical grade); plus 7.0 parts carbolic acid; C.
(c) 1.0 part 2-amino 2-mcthyl-l-propanol plus 5.0 parts oleic acid; plus 6.0 parts carbolic acid; B.
(d) 0.5 part butyldiethanolamine plus 0.5 part hydrocinnamic acid; plus 1.0 part o-chlorophenol; A.
(e) 0.65 part butylmouoethanolamine plus 0.35 part malonic acid; plus l.0 part p-chlorophenol; A.
(f) 2.0 parts diethanolarnine plus 3.7 parts ethylphosphoric acid; plus 5.7 parts carbolic acid; A.
(g) 2.0 parts dicthanolamine plus 3.3 parts levulinic acid;
plus 5.3 parts carbolic acid; A.
(h) 0.63 pait 'dicthanolaminc plus 0.37 part maleic acid;
plus 1.0 part 2,4-dichlorophenol; A.
(i) 1.0 part dicthanolaminc plus- 3.5 parts naphthenic acids (practical grade); plus 4.5 parts carbolic acid; A.
(i) 1.0 part dicthanolaminc plus 5.0 parts cleic acid;
plus 6.0 parts cai'bolic acid; C.
(k) 0.42 part 2-dicthylamin0ethanol plus 0.58 part cinnamic acid; plus 1.0 part 2,4-dichlorophenol; A.
(l) 1.0 part tricthanolamine plus 2.2 parts benzilic acid;
plus 3.2 parts tricresol; A.
(m) 1.0 part triethanolamine plus 1.3 parts benzoic acid;
plus 2.3 parts tricresol; A.
(n) 1.0 part triethanolaminc plus 1.7 parts cinnamic acid;
plus 2.7 parts tricresol; A.
(0) 0.8 part triethanolaminc plus 1.2 parts cyclohexanc carboxylic acid; plus 2.0 parts tricresol; A.
(p) 1.0 part triethanolamine plus 1.0 part diglycolic acid; plus 2.0 parts tricresol; A.
(q) 0.68 pal: triethanolamine plus 0.32 part diglycolic acid; plus 1.0 part o-cl1lorophenol; A.
(r) 0.7 part triethanolamine plus 1.4 parts furoic acid;
plus 2.1 parts tricrcsol; A.
(s) 1.0 part triethauolamine plus 1.0 part glycolic acid;
plus 2.0 parts tricrcsol; A.
(t) 0.5 part tricthanolamine plus 1.7 part heptylic acid;
plus 2.2 parts tricresol; A.
(u) 0.7 part triethanolamine plus 1.3 parts hydrocin' namic acid; plus 2.0 parts tricresol; A.
(v) 0.5 part triethanolamine plus 1.5 parts lauric acid;
plus 2.0 parts tricrescl; A.
(w) 1.5 parts tricthanolamine plus 1.0 part malonic acid;
plus 2.5 parts tricresol; A.
(x) 2.0 parts tricthanolamine plus 4.3 parts naphthenic acids (practical grade); plus 6.3 parts carbolic acid; A.
(y) 1.0 part triethanolamine plus 1.0 part oxalic acid;
plus 2.0 parts tricresol; C.
(Z) 1.0 part triethanolamine plus 1.3 parts pheuylacctic acid; plus 2.3 parts tricresol; A.
(ca) 0.5 part triethanolamine plus 2.0 parts stearic acid;
plus 2.5 parts tricrcsol (paste); C.
(bb) 1.0 part triethanolamine plus 1.0 part d-tartaric acid; plus 2.0 parts tricresol; A.
(cc) 1.0 part triethanolamine plus 4.0 parts undecylenic acid; plus 5.0 parts tricresol; A.
SERIES 3.ALCOHOLAMINES ACIDULATED WITH ACID ANHYDRIDES (a) 0.42 part Z-diethylaminoethanol plus 0.58 part phthalic anhydride; plus 1.0 part 2,4-dichlorophenol; A.
(b) 0.9 part triethanolamine plus 1.2 parts benzoic anhydride; plus 2.1 parts tricresol; A.
(c) 0.55 part triethanolamine plus 0.45 part benzoic anhydride; plus 1.0 part o-chlorophen'ol; A.
(d) 1.0 part triethanolaminc plus 2.4 parts 2-furcic anhydride; plus 3.4 parts tricresol; A.
(e) 0.6 part triethanolamine plus 1.5 parts heptylic anhydride; plus 2.1 parts tricrescl; A.
(f) 1.0 part triethanolamine plus 1.0 part phthalic anhydridc; plus 2.0 parts tricresol; A.
(g) 1.0 part triethanolamine plus 1.0 part propionic anhydridc; plus 2.0 parts tricresol; A.
(h) 1.2 partstricthanolamine plus 0.8 part succinic anhydride; plus 2.0 parts tricresol; A.
17 nitrogen linkage. (Polar radicals: Azoxy, isonitroso, nitroso.)
A. Acetone oxime (I, II); ethyl-N-nitroso-N-methylctltlrbamate (I, II); heptaldoxime (HI); nitrosobenzene B. Cyclohexanone oxime (I, IV).
C. Azoxybenzene (I); nitrosobenzene (I); isonitrosomethyl hexyl ketone (I, IV).
D. Isonitrosomethyl hexyl ketone (II).
Example 12.Polar compounds containing both anionoid and cation-oid radicals. (Polar radicals-anionoid: acyl, acylimino, carbonyl, carbonyldioxy, hydroxyl, sulfonyl, unsaturated carbon; cationoid: halogeno, nitro.)
A. Acetoacet-2,5-dichloranilide (I); o-chloroacetanilide (I); 2-nitro-2-ethyl-1,3-propanediol (I, H); 2-nitro-2- methyl-l-propanol (II).
B. o-Chloroacetanilide (III); l-nitronaphthalene (II).
C. o-nitro-diphenyl (I, III); 2-nitro-2-ethyl-1,3- propanediol (III); 2-nitro-2-methyl-1-propanol (I, IV).
D. 2-nitro 1 butanol (I, II, V); 2-nitro-2- methy1-1,3-propanedio1 (I-sat.; II-sat.); 1-nitronaphthalene (I).
Example 13.Sulfuretted polar compounds. (Polar radicals: Mercapto, (thiazolyl, thiocyano, a 1: j
A. Benzothiazole (I, V); zothiazole (I, H);
C. Benzylthiocyanate (I);
Example 14.-Organic acid anhydrides* Example 15.Acids-* In the foregoing illustrative Examples 2 to 15, inclusive, each composition contained a polar material which either completely inhibited the corrosive action of a typically caustic phenol, or which delayed the onset of caustic efiect for a period of time which was upwards of twice the time of onset of a like efiect elicited by a control mixture of the same phenol in a substantially nonpolar hydrocarbon solvent or diluent of the type illustrated in Example 1.
Moreover, each of the polar materials set out in Examples 2 to 15, inclusive, possesses characteristics (a), (b) and (c) which, as already stated, are requisites of a phenol-polarizing agent suitable for use in the practice of my invention; each of said polar materials thus constituting a representative species of phenol-polarizing agent coming within one or another of the generic classes of polar materials defined by the respective captions that identify Examples 2 to 15, inclusive. As I already have stated hereinabove, all members of these generic classes of polar materials come within the scope of my invention in so far as any member thereof possesses characteristics (a), (b) and (c) and is not otherwise excluded by reason of any specific limitation that I may have set forth herein.
Example 16.-Tests of mixtures of carbolic acid with two compatible polar materials belonging to difierent classes of compounds.
Thirty-six mixtures were made up, each containing 50 percent of carbolic acid; the remainder of each mixture, respectively, being divided equally between two difierent compounds selected seriatim from the following representative classes of polar materials: Acid amides, acidulated alcoholarnines, aldehydes, anilides, esters, ethers, ketones, nitriles and sulfones. The specific representatives of these classes were, respectively: Acetamide; triethanolamine-1.3 parts, neutralized to litmus with propionic acid-0.7 part; aldol; acetoacetanilide; methyl phthalate; amyl ether; mesityl oxide; octadecanenitrile and sulfonal.
The 36 mixtures were made up so that in no two thereof was the combination of polar radicals the same. The polar radicals were: Acyl; acylamino; aldo; alkoxy; carbonyl; carbonyldioxy; carbonylimino; cyano; hydroxyl; nitrilo and sultonyl.
. 2-methylmercaptoben- None of the 36 mixtures--each, as aforesaid, containing 50 percent of carbolic acid--exhibited any caustic activity when tested on the skin for 15 minutes. That is, all of the mixtures were classifiable in group A, as that category has been employed in preceding examples.
In order to conform to the requisite characteristic (0) of a polar material for use in the practice of my invention,- the minimal eiiective ratio of a suitable polar material to a caustic phenol may not be higher than 1:1 I have found many phenol-polarizing agents, however, each of which is adapted to temper two or more times its: weight of a caustic phenol.
In the course of determining the minimal operative ratios of representative species of the more highly effective phenol-polarizing agents-more particularly those classed as A in Examples 2 to 13, inclusiveI have found that in many instances this minimal operative ratio, as determined by the skin reaction test above described, substantially coincides with that ratio which just, suflices to prevent the segregation, within the mixture, of any appreciable proportion of the phenol as a separate phase. There are various tests known to the art for detecting such a segregation. Since the majority of caustic phenols, that come within the scope of my invention, crystallize, when pure, at temperatures higher than ordinary room temperatures, I have found it a time-saving and convenient procedure to determine, first, by trial, that ratio of a polar material to a caustic phenol which just sufiices to prevent any crystallization of the phenol from its mixture with the polar material when the mixture either is allowed to stand for some time at room temperature in a closed container; or, preferably, is seeded with a crystal of the phenol. In effect, a mixture thus formed comprises a polar material which is substantially saturated with the phenol. The'causticity-reducing capacity of the polar material in such a mixture I may then determine by the skin reaction test above described.
In Example 17 are set forth the results of skin reaction tests made on compositions embodying my invention; each consisting of a representative phenol-polarizing agent in admixture with two or more times its weight of crystalline carbolic acid, most of the compositions being substantially saturated therewith. Carbolic acid was chosen for this series of compositions because it is the most sharply corrosive of the caustic phenols.
In Example 17 the second member of each ratio denotes the number of parts of carbolic acid in admixture with unit part of each phenol-polarizing agent listed after a given ratio; while the percentage figures in parentheses denote the proportions of phenol-polarizing agents that are present. The parenthetic B, C or D following each listed polar material carries with it the same connotation that is attached to it in Examples 2 to 15, inclusive.
1:9 (10%)Acetamide (D) 1:5 (16.7%) *;-benzothiazole (D);
1:4 (20%)-p-Acetophenetide (D); diacetylethylenediamine (B); 7
1:3 (2S%)Acetoacetanilide (D); triethanolamine, acidulated as in Example 16 (D).
1:2 (33.3%)- octadecanenitiile (D);
Having reference to the call in my claims for a mixture of a polar material and a caustic phenol, and more particularly for an amount of the polar material sufficient to reduce the causticity of the phenol, I intend the phrase just quoted to mean that the ratio of polar material to the caustic phenol shall be at or above the minimum that just sutlices to effect a distinct reduction in the corrosiveness of the phenol, as evidenced by the results-either qualitative or quantitative or both-obtained in comparative skin reaction tests of the aforementioned mixture and of a homogeneous control mixture consisting of a like proportion of the same phenol a 19 and a substantially nonpolar hydrocarbon which is liquid at ordinary temperatures and is of the character illustrated in Example 1.
I have tested representative compositions embodying my invention, each composition containing at least 50 percent of a. caustic phenol, ordinarily carbolic acid; and I have found such compositions to be highly effective as insecticidal sprays, as general disinfectants and as germicidal, fungicidal and insecticidal agents in such infections and infestations of the skin as pimples, incipient boils, ringworm, mange and pediculosis. a
My conception of the mechanism of reduction in corrosiveness of a caustic phenol by a suitable polar material stems from the recent extension of electron theory into the field of organic chemistry. In stating my conception I desire to set forth what appears to me to be a rational scientific explanation of my broad discovery. I do not confine myself, however, to that explanation, nor do I intend thereby to limit in any manner or degree the scope of the invention herein described and claimed.
It now is recognized that a chemical reaction-in the conventional sense of the formation of one or more products difiering in molecular structure from the reactants-involves the operation of valence forces leading to exchange of electrons and the formation of chemical bonds between electron-seeking and electron-donating centers or zones within the molecules of the respective reactants. The formation of distinct reaction products, however, may be conditioned upon one or more circumstances such as the special chemical characters of the reactants, the development of an adequate electron density at the sites of reaction in electron-donating molecules, and environmental factors such as favorable solvent media, auxiliary activating agencies such as heat and pressure, catalysts, et cetera.
There are, however, attraction forces, operative between unlike molecules, which are not as strong as the valence forces aforementioned, namely, intermolecular forces insufiicient, per se, to lead to electron exchanges and the formation of reaction products, but sufficient to result in the formation of loose physical complexes. Thus, polar molecules of unlike species may orient each other in much the same manner as two freely movable small bar magnets when brought within their mutual spheres of influence. The result is the formation of loose physical complexes which do not obey the laws of combining proportions and of multiple proportions. In such orientation complexes unlike molecules are held together by electrostatic attraction between positive poles of one molecular species and negative poles of another. The degree of electroaffinity between the unlike molecules making up such physical complexes depends principally upon two independent variables, namely, (1) the the same phenol when mixed in like proportion with'a substantially nonpolar hydrocarbon solvent.
In order to explain the germicidal and fungicidal character of orientation complexes embodying my inven: tion, I assume that suchcomplexes break up or dissociate in contact with highly polar free or solvent; water molecules leaving the phenol molecules in a state wherein they are conditioned for their typical toxic and disinfectant action by a favorable solvent medium, namely water. ,Incidentally, it is because water is one of the polar materials which, other than by any effect as a diluent, does not reduce the corrosiveness of a caustic phenol, that compositions embodying my invention preferably are substantially water-free.
states of polarization of the unlike molecules and (2) their respective polarizabilities.
The-foregoing alfords, I believe, the basis for a working theory of the mechanism of the tempering of a caustic phenol by a suitable polar material in the practice of my invention. I postulate the formation of physical complexes of caustic phenols and phenol-tempering agents through the mechanism of orientation polarization that I have just described. On this postulate is based my preferred use of the term phenol-polarizing agent. Since-as is shown by the many examples that I have given-phenol-tempering capacity is a function of anionoid radicals, and since the phenyl group is electronattracting in character, I assume that in an orientation complex of a caustic phenol and aphenol-polarizing agent, the phenyl radical or residue in the phenol and the anionoid portion of the phenol-polarizing molecule constitute the zones of electrostatic attraction and of closest proximity therebetween. According to my theory, then, the phenol in an orientation complex with a phenol polarizing agent exhibits less afinity for water than does In a composition embodying my invention the apparently. paradoxical combination of high germicidal and fungicidal activity toward microorganisms on or in the skin, with the absence of caustic effect upon the skin itself, may be explained in part by the r'elativelylow content of unbound water in the outermost layer of the epidermis; whereas microorganisms which may be invading the skin have a high solvent water content character-' istic of living protoplasm. A very important circumstance, moreover, is the great surface extension, relative to their individual masses, in microorganisms. Further more, my preferred compositions are those which com' prise fifty percent or'more of a caustic phenol; so that the concentration gradient of the phenol between such a composition and a group of microorganisms is very high, and the destruction of the latter correspondingly p l Having reference to all of the examples set forth hereinabove, I desire it to be understood that they-as well as all specific compounds, substances, or materials, and all quantities, parts, proportions or ratios given therein-are intended to be illustrative only and in no sense limitative of'my invention other than as the same is defined in the accompanying claims.
l. A substantially water-free, phenolic, gcrmicidal composition that is adapted as such for direct local application, said composition comprising a highly caustic phenol in substantially homogeneous physical admixture with a nitrogenous polar material whose molecular structure is rendered preponderantly anionoid in character by the presence therein of an effective number of electron-donating polar groups; said polar material being further characterized (a) by being chemically compatible with the caustic phenol, and (b) by being capable of forming a substantially homogeneous physical system with more than its weight of the caustic phenol; the polar material in said physical system--when said system, so formed, is applied to a substantially dry, cutaneous surfacecausing the phenol therein to exhibit a delay in the time of onset of its caustic effect of at least percent beyond the time of onset of caustic eifect of a control mixture containing the same phenol in the same proportion by weight as in said physical system, but with said polar material being substituted in the control mixture by a substantially nonpolar hydrocarbon of the class consisting of cyclohexane, pinene, p-xylene and a mixture of isomeric xylenes; said polar material being an acidulated amine; said composition containing the caustic phenol in an effective germicidal concentration; and said acidulated amine being present in the composition in an amount sufficient to reduce the causticity of the phenol without proportionately reducing its germicidal power.
2. A substantially water-free, phenolic, germicidal composition that is adapted as such for direct local application, said composition comprising a highly caustic phenol in substantially homogeneous physical admixture with a nitrogenous polar material whose molecular structure is rendered preponderantly anionoid in character by the presence therein of an effective number of electrondonat ing polar groups; said polar material. being further char- 21 acterized (a) by being chemically compatible with the caustic phenol, and (b) by being capable of forming a substantially homogeneous physical system with more than its weight of the caustic phenol; the polar material in said physical system-when said system, so formed, is applied to a substantially dry, cutaneous surfacecausing the phenol therein to exhibit a delay in the time of onset of its caustic efiect of at least 100 percent beyond the time of onset of caustic effect of a control mixture containing the same phenol in the same proportion by weight as in said physical system, but with said polar material being substituted in the control mixture by a substantially nonpolar hydrocarbon of the class consisting of cyclohexane, pinene, p-xylene and a mixture of isomeric xylenes; said polar material being an acidulated alcoholamine; said composition containing the caustic phenol in an efiective germicidal concentration; and said acidulated alcoholamine being present in the composition in an amount 2,347,983 Backoif May 2, 1944 FOREIGN PATENTS 609,164 Germany Feb. 8, 1935 OTHER REFERENCES Bramley: J. Chem. Soc. (London), vol. 109 (1916), pp. 10-45.
Merck Index, 1896, 2nd ed., p. 185.
McNair: Arch. of Dermatology and Syphilology, June 1921, vol. III, pp. 802-808 (Reprint 7 pp., p. 2 of reprint pert).