Part 1

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Every effort has been made to replicate this text as faithfully as possible. Some changes have been made. They are listed at the end of the text.

Synthesis of 2-methyl-4-selenoquinazolone, 2-phenylbenzoselenazole, and Its Derivatives.

DISSERTATION

SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE FACULTY OF PURE SCIENCE OF COLUMBIA UNIVERSITY

BY

YÜ-GWAN CHEN, M. A.

NEW YORK CITY

1922

ACKNOWLEDGMENT AND DEDICATION

The following research was undertaken at the suggestion of Professor Marston Taylor Bogert to whose interest and advice this work owes whatever merit it may possess.

Y. G. CHEN.

CONTENTS

Acknowledgment and Dedication 2

Abstract of the Dissertation 4

Purpose of the Research 5

Introduction 7

Pharmacological Review 8

Tinctorial Review 14

Experimental: 16

2-methyl-4-selenoquinazolone Four Methods of Preparation

Analysis of Selenium Organic Compounds

2-phenylbenzoselenazole Mononitro Derivative Monoamino Derivative Monoacetyl Derivative Monobenzylidene Derivative An Azo Dye Dinitro Derivative Diamino Derivative Diacetyl and Dibenzylidene Derivatives

Dyeing with Azo Dyes

Bibliography 25

Vita 28

ABSTRACT OF THE DISSERTATION

1. What was attempted?

Attempt was made to study organic selenium compounds of the heterocyclic series in reference to those properties leading to tinctorial and pharmaceutical possibilities.

2. What were the methods of attack?

(a) Organic selenium compounds were reviewed and their properties examined critically with those of allied compounds.

(b) Some new heterocyclic compounds of selenium were studied and their characteristic properties more closely examined along the desired line.

3. In how far were the attempts successful?

The literature was reviewed and classified with reference to the properties under consideration, and new selenium organic compounds were prepared and studied which it is hoped may throw some additional light upon the problem.

4. What contribution actually new to the science of chemistry has been made?

(a) Compounds newly made have been shown to exhibit a distinct tinctorial value in comparison with their analogues.

(b) They have been shown to be chemically easier to handle than the corresponding sulphur compounds.

(c) Selenium, in the nucleus of cyclic compounds, has been shown to be instrumental for a positive coloration at least equal to the --NH-- or --S-- groupings. The selenocarbonyl, :C:Se, has been shown to be a more powerful chromophore than thiocarbonyl, :C:S, or carbonyl itself, :C:O.

(d) Two series of azo dyes of selenium have been prepared and have been shown to possess a marked tinctorial value.

(e) The following new compounds have been prepared:

2-methyl-4-selenoquinazolone 2-phenylbenzoselenazole[A] 6-nitro-2-phenylbenzoselenazole 6-amino-2-phenylbenzoselenazole 6-acetylamino-2-phenylbenzoselenazole 6-benzylideneamino-2-phenylbenzoselenazole (B-naphthyl)-6-azo-(2-phenylbenzoselenazole) Dinitro-2-phenylbenzoselenazole Diamino-2-phenylbenzoselenazole Diacetyldiamino-2-phenylbenzoselenazole Dibenzylidenediamino-2-phenylbenzoselenazole

PURPOSE OF THE RESEARCH

Since Berzelius published the first resume of the chemistry of selenium, in 1818(1), many articles have appeared in this field. Several reviews(2) of its compounds, including references, have been published, besides the resumes in the chemical dictionaries. These reviews are confined mainly to the inorganic side. No attempt has ever been made to compile a bibliography of selenium organic compounds.

From time to time, articles have appeared, but the field is still a promising one, with many alluring possibilities.

In the perusal of the organic records of the metal, distributed over the span of a century, there are indications of the value of selenium compounds for pharmaceutical and tinctorial uses. An effort has been made to collect these scattered data for critical examination with other analogues and sulphur compounds in particular, and to prepare and study some new organic compounds containing selenium, for the purpose of gaining additional light upon the chemistry of such substances, and in the hope of discovering some which may be of practical service in medicine or elsewhere.

Synthesis of 2-methyl-4-selenoquinalozone, 2-phenylbenzoselenazole and Its Derivatives

INTRODUCTION

The general conception of selenium is that it is a comparatively rare element. Few realize that it has been known for over a century and that over twenty selenium minerals, containing from one to sixty-six per cent. of the metal, are considered by the mining corporations as important. Beside being a by-product of sulphuric acid manufacture, it is separated also in the electrolytic refining of copper. The demand for the metal is so small that there are half a dozen concerns in the United States either willing to supply gratis any reasonable quantity for research work, or to sell it at cost. In a special report of the National Research Council on selenium(3), it is estimated that there could be produced annually, without making any material additions to the present plants, not less than 300,000 pounds.

In fact selenium has, in recent years, gradually been brought more and more to the attention of the general public through its application to military uses and other purposes. In the glass industry, for example, it was used as decolorizer during the War period. It has been found that it imparts a violet red tint to the pyrex tubing after the latter has been used for a few combustions. The coloration is especially noticeable when a broken piece is examined. This may find an important place in the ceramic industry. In turning off the gas light of the city at day break, in controlling the draft of the factory chimneys, and in regulating the rapidity of the manufacture of sulphuric acid, the selenium cell is an important labor saving factor. In a similar way it is used in automatically lighting and extinguishing light buoys. It also finds application in photometry, wireless telephony, military telegraphy, and army signaling as well as for the transmission of signatures, handwritings, finger prints, and images in general(3)(4).

The question of the vulcanization of rubber also should be considered. Some experiments have been published claiming the similarity of the action of selenium and sulphur on rubber(4)(5). The cost need not be prohibitive, since the supply could be easily increased and the price reduced provided there were a demand. In the personal experience of the writer, when working with the hydrogen selenide gas, the rubber connections of the apparatus soon turned red, and after a few hours were so clear a red that visitors to the laboratory imagined that the writer was using the ordinary red rubber connections. The rubber thus changed seems to be softer and more elastic than the original; this observation will be followed up.

In this country the National Research Council has created a special committee of seven to investigate the various possible uses of selenium and tellurium.

PHARMACOLOGICAL REVIEW

Duhamel and Rebiere(6)(7) showed that an injection of a trace of red colloidal selenium into rabbits increased urea excretion regularly. In other cases satisfactory results were claimed and the liver showed some lesions. The histological modifications produced by injections into rabbits are most apparent in the liver and kidneys. In the distribution of colloidal preparations in the animal body by injection, Duhamel and Juillard(8) found that the liver contained the greatest amount. Six years later the former(9) used a similar preparation introduced into the animal intravenously, and selenium was again found in the liver, although in smaller quantity.

Sulphur compounds have similar physiological action. It is known that triphenylstibine sulphide, or sulphoform, (C₆H₅)₃SbS, has a curative effect in skin diseases, as it liberates “nascent” sulphur on the skin. It is equally natural to expect some organic selenium compound which liberates finely divided selenium to exert a remedial influence on animal bodies. The selenoquinazolone prepared in the course of this research and described more fully in another section of the paper, has this prospect. The quinazolone has the following structure:

N /\ / \\ | | C-CH₃ | | | | | NH \/ \ / C Se

Experiments were carried on at L’Institut Pasteur in Paris under the supervision of M. Borel for the treatment of cancer in mice. No human subjects were experimented upon, although results were claimed by using selenides and their oxidized salts.

Selenium dyes were found to be medicinals, although no relation has yet been established between constitution of these organic dyes and their therapeutic value. Wassermann(10) made several eosin preparations, by coupling the sodium derivative with potassium selenocyanide. The red dyestuff thus prepared is stated to be easily soluble in water. Wassermann, Keysser and Wassermann(11) made experiments with it, chemotherapeutically, on animal tumors. When the solution was injected into mice tumors the latter turned red, accompanied by the softening of the tumor after the third injection and complete resorption after ten injections, unless the dose used was too great for the animal. In that case death often occurred. Good results were also reported, in connection with this experiment, on four different strains of mouse carcinoma and one strain of mouse sarcoma. In the latter case, relief was found sooner but the former disappeared more slowly. Another preparation was made later(12) and introduced into mice intravenously and again found to have good results.

The following is the structure of 2-selenocyanideanthraquinone--

O C SeCN /\ / \ /\ / | | | | | | | | \/ \ / \/ C O

which has also been reported to have medicinal uses(13).

P. Ehrlich and Hugo Bauer(14) synthesized from p.p′-diamino-diphenyl- methane the red dye 3,6-diaminoselenopyronine.

CH /\ / \\ /\ | | | | H₂N| | | |NH₂ \/ \ // \/ Se

The dye has been used upon mice and caused pronounced edema. The toxicity of both the selenopyronine and the corresponding sulphur compound was compared under similar conditions in the same experiment, and it was found that the selenium dye was toxic in 1/3000 gram, but the sulphur dye was toxic in 1/2500 gram per twenty gram weight of the animal.

This physiological activity was noted years ago with the inorganic compounds of selenium and Berzelius(15) described the poisonous effect of hydrogen selenide quite impressively; “In order to get acquainted with the smell of this gas I allowed a bubble not larger than a pea to pass into my nostril; in consequence of its smell I so completely lost my sense of smell for several hours that I could not distinguish the odor of strong ammonia even when held under my nose. My sense of smell returned after five or six hours, but severe irritation of the mucous membrane set in and persisted for a fortnight.” The writer has been working on the gas for some time and was also quite seriously affected once, the injury persisting for many days. That it is more poisonous than the hydrogen sulphide is well known.

Bruere(16) showed that when hydrogen sulphide was passed into blood solution sulphemoglobin was produced in considerable quantity, due to the chemical action of sulphur and hematin. He stated further that sulphemoglobin may be found in animal blood when a large amount of the gas has been inhaled. He made selenhemoglobin in the same manner. Sixteen years later, Clarke and Hurtley also proved that selenhemoglobin may be made by passing hydrogen selenide into blood(17). These experiments may be interpreted to mean that the oxy-hemoglobin is transformed into an organic complex of sulphur or selenium, and that the transference may be more rapid and powerful in the case of hydrogen selenide.

Biological investigations have sufficiently proved that dyestuffs of the phenazine, oxazine, thiazine, acridine series show an injurious effect on protozoa, especially those dyes containing substituted amino groupings and of a simple structure(18). In the case of the thiazine dyes of the methylene blue class, the physiological importance has well recognized in their use as feeble antiseptics and analgesics. Ehrlich and Guttmann(19) initiated the use of methylene blue as an antiperiodic and its use in that line has been continued.

In the field of the selenazine dyes, pharmacologists have not yet paid much attention to them, on account of the newness of the discovery, but P. Karrer claims that they are indisputably “vital dyestuffs”(20). The prospect of synthesizing selenazine dyes and their use as drugs seems to be bright, judging from the fact that they are easily prepared and capable of many combinations, especially of the ease with which they form organic complexes with arsenic compounds.

NO₂ NH NO₂ NH NO₂ (I) /\ /\ /\ / \ /\ /\ / \ /\ | |NH₂ Cl| | | | | | | | | | | | | | = | | | | = | | | | | |SeH NC| |NO₂ | |SeH | |NO₂ | | | |NO₂ \/ \/ \/ / \/ \/ \ / \/ O₂N Se

Formula (I) is known, as 1, 3-dinitrobenzoselenazine(21), which was obtained by the action of picryl chloride on the zinc salt of o-aminoselenophenol; the product (picrylaminoselenophenol) being then treated with alkali and thus converted to the dye, which upon experimentation showed marked effects upon protozoa and bacteria.

N /\ / \ /\ N | | | | NH₂ /\ // \ /\ (II) | | | | /\ | | | | \/ \ / \/ + | | = | | | | Se | | \/ \\ / \/ Cl \/ Se HO₃As \ NH /\ | | | | \/ HO₃As

Formula (II), known as 3-(p-phenylarsonic)-aminoselenazine, is red in dilute alkali and green in mineral acid, and is a typical dye in a series from the coupling of selenodiphenylamine with arsenic compounds. All possess similar toxicity as the thiazine dyes(20). Other selenazines are listed in the bibliography(22).

No less than half dozen thioureas are commonly used as drugs. Thiourea itself paralyzes the nerve centers, and is employed commercially for photograph fixing and for removing stains from negatives; thiuret, C₆H₇N₃S₂, serves as a substitute for iodoform; thiosinamine-ethyliodide, or tiodine, IH₅C₂H₂NCSNHC₃H₅, is used for relief of lesions of the central nervous system; allylthiourea or thiosinamine, (NH₂)SC.NHCH₂CH:CH₂, for aiding the absorption of connective tissues, for treatment of burns, keloids, urethral diseases, sclerotic conditions of the ear(23).

Selenocarbamide and a number of its derivatives have been prepared and studied. One class of seleno ureas has been patented as pharmaceutical products by Chem. Fabrik von Heyden(24), and are prepared by the action of hydrogen selenide on alkylcyanamides,

RNH.CHN + H₂Se = RNH.CSe.NH₂

They possess pronounced therapeutic value and, serve as intermediate products in the production of more stable alkyl halide additive compounds. Other carbamides ranging from seleno urea itself(25), (III) and a cyclic urea(26) (IV) are described in the literature:

NH₂ CH₂-Se / | \ Se:C (III) | C:NH (IV) \ | / NH₂ CH₂-NH

The latter, known as ethylene-selenourea, may be classified also in the azole group as 2-iminotetrahydroselenazole (V).

H₂C----NH | | (V) H₂C C:NH \ / Se

The literature for the other normal carbamides is listed in the bibliography(27).

Selenoantipyrines, selenosaccharine, selenoindigoes have also been prepared.

Thiophene and its derivatives are of considerable therapeutic interest. Thiophene itself is found to be useful in lessening the elimination of sulphuric acid in urine, and is employed in the dermatological practice. Sodium thiophene sulphonate, thiophenetetra-bromide, thiophene diiodide, are all medicinals(23).

A number of selenophenes are recorded in the literature. Their relation to the selenazoles may be easily seen from the following formulas:

CH--CH CH--N || || || || CH CH CH CH \ / \ / Se Se

Selenophene Selenazole

Dimethyl selenophene was prepared from acetonyl acetone and phosphorous pentaselenide,

CH₃ CH₃ / / HC=C HC=C | \ | \ | OH + P₂Se₅ = | Se | OH | / | / HC=C HC=C \ \ CH₃ CH₃

The compound thus obtained is stated to have the same odor as thiophene, but no mention is made in regard to its uses(28). Selenophene was prepared from sodium succinate and phosphorous triselenide, or by conducting ethylselenide through hot tubes(29).

Some selenazoles find application also in medicine. At present only the isoazoles are known to have physiological uses. One of them was prepared from anthraquinone selenocyanide, by the action of ammonia under pressure(30).

NH₂H N-Se O || C SeCN C /\ / \ /\ /\ / \ /\ | | | | = | | | | + HCN + H₂O \/ \ / \/ \/ \ / \/ C C O O

Another type of azoles, benzoselendiazole (piaselenol) and five of its derivatives, have been also described as medicinals(31). The diazole itself has the following structure,

N N //\ /|\ //\ / \ | | | Se or | || Se \\/ \|/ \\/ \ / N N

Diazoles of the following structure are also known, but no data were found, regarding their physiological action(32):

N-N N-N / \ // \\ CH₃C CCH₃ C₆H₅C CC₆H₅ \ / \ / Se Se

Dimethyl-seleno-diazole Diphenyl-seleno-diazole

Sulphides and disulphides have curative power. Dimethylsulphide is used for internal treatment, di-o-aminophenyldisulphide is used for intramuscular injections. Diallyl sulphide is also a medicament. Methyl selenide has some effect on the internal parts of the body(33). Hanzlik and Tarr(34) at the American University Experimental Station, showed that a number of selenium compounds act as skin irritants: e.g., dichlorodiethyl selenide, dichlorovinyl selenide, trichlorodiethyl selenide and selenium mustard oil. The first mentioned proved as potent as the sulphide, but the others fell somewhat below in their effects. Diantipyryl selenide is another therapeutical agent(35).

The diselenides occupy an important place of their own. The selenophenols do not remain unchanged in the air, but are always oxidized to the diselenides, which can be again reduced to the selenophenols. So far only the diselenides of anthraquinone and their phenols are recognized remedies(36).

TINCTORIAL REVIEW

Many of the seleno organic compounds are colored, while the corresponding sulphur derivatives are colorless.

HC-CH HC-CH || || || || HC CH HC CH \ / \ / O S

Furane, colorless Thiophene, colorless liquid liquid

HC--CH HC--CH || || || || HC CH HC CH \ / \ / NH Se

Pyrrol, colorless liq. Selenophene, yellow liq. but turns brownish in air after repeated extraction[B]

This brings selenophene more akin to pyrrole than thiophene, but the group -NH- in the molecule of pyrrole is an auxochrome. The selenium atom in a cyclic compound also acts like an auxochrome.

Selenoantipyrine(37),

C₆H₅ N / \ CH₃N CSe | | CH₃C===CH

forms pure yellow crystals from alcohol, while the corresponding compounds of oxygen and sulphur are colorless.

Similarly, the 2-methyl-4-selenoquinazolone is deep brown in color, while the thio compound, prepared by Bogert and Hand(38) is light brown or yellow and the corresponding oxygen compound is colorless or nearly so.

Diethyl selenide (C₂H₅)₂Se, is a yellowish heavy oil of unpleasant odor. It combines readily with chlorine to form a chloride (C₂H₅)₂SeCl₂, and the latter is oxidized by nitric acid to form an oxide (C₂H₅)₂SeO,(39). Diethyl sulphide is a colorless syrupy liquid, as well as diethyl amine and diethyl ether.

The gradation of color is quite pronounced in the case of selenonaphthene quinone(40).

CO CO CO CO /\ / \ /\ / \ /\ / \ /\ / \ | | CO | | CO | | CO | | CO \/ \ / \/ \ / \/ \ / \/ \ / O S NH Se

It would be most natural to conclude that the chromophore :CS is more powerful than :CO, and that :CSe is most powerful of all, as shown in our study of quinazoline compounds. It would equally follow that :S is a more powerful color-forming radical in a cyclic compound than that of :O; and :NH than that of :S; and :Se again most powerful of the whole series.

Lesser and Weiss(41) in their research on selenoindigo stated that the selenium dyestuff, on account of its greater molecular weight than sulphur, shows a deeper blue. This hypothesis meets a difficulty in the case of coumorandione, thionaphthenequinone and isatin series, where the -NH- radical has an atomic weight of 15, and -S- 32, and showed the reversed order of color. This seems to be the case in the selenophene series also. Therefore this theory is not without exceptions.

The diselenides present a very interesting study also. Methyl disulphide is colorless, but methyldiselenide(42) is a reddish yellow liquid. Methyl disulphide only becomes yellow when it is treated with chlorine, and in such cases (CH₃)₂S₂Cl₂ is formed(43), in yellow rhombic crystals. Ethyldisulphide is colorless: ethyl- disulphidedichloride is a faint yellow oil(44). But the corresponding ethyldiselenide is a red liquid(45). Phenyl disulphide is colorless, and phenyldisulphide dibromide is of mother-of-pearl appearance, and practically colorless(46), while phenyl diselenide forms pure yellow needles(47), and phenyldiselenide dibromide orange red ones.