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Full text of "Synthesis of 2-methyl-4-selenoquinazolone, 2-phenylbenzoselenazole, and its derivatives"

3ia 



EXCHANGE 




Synthesis of 2-methyl-4-selenoquinazolone, 

2-phenylbenzoselenazole, and Its 

Derivatives. 



DISSERTATION 



SUBMITTED IN PARTIAL FULFILLMENT OF THE RE- 
QUIREMENTS FOR THE DEGREE OF DOCTOR OF 
PHILOSOPHY IN THE FACULTY OF PURE 
SCIENCE OF COLUMBIA UNIVERSITY 



BY 

YU-GWAN CHEN, M. A. 

NEW YORK CITY 
1922 



Synthesis of 2-methyl-4-selenoquinazolone, 

2-phenylbenzoselenazole, and Its 

Derivatives. 



DISSERTATION 



SUBMITTED IN PARTIAL FULFILLMENT OF THE RE- 
QUIREMENTS FOR THE DEGREE OF DOCTOR OF 
PHILOSOPHY IN THE FACULTY OF PURE 
SCIENCE OF COLUMBIA UNIVERSITY 



BY 

YU-GWAN CHEN, M. A. 

NEW YORK CITY 
1922 



A 



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 



3 478711 



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 com- 
pounds 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, 
ha,s been shown to be a more powerful chromophore than thio- 
carbonyl, :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* 
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 

* Not a new compound but prepared by a, different method. 

4 



PURPOSE OF THE RESEARCH 

Since Berzelius published the first resume of the chemistry 
of selenium, in 1818 (*), many articles have appeared in this 
field. Several reviews ( 2 ) of its compounds, including references, 
have been published, besides the resumes in the chemical diction- 
aries. 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 crit- 
ical examination with other analogues and sulphur compounds 
in particular, and to prepare and study some new organic com- 
pounds containing selenium, for the purpose of gaining addi- 
tional 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 compara- 
tively rare element. Few realize that it has been known for 
over a century and that over twenty selenium minerals, contain- 
ing 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 re- 
search 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 com- 
bustions. 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 extinguish- 
ing 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 ( ?- , 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 work- 
ing 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 ex- 
cretion regularly. In other cases satisfactory results were claimed 
and the liver showed some lesions. The histological modifica- 
tions produced by injections into rabbits are most apparent 
in the liver and kidneys. In the distribution of colloidal prep- 
arations 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,- 
(C 6 H 5 ) 3 SbS, has a curative effect in skin diseases, as it liberates 
"nascent" sulphur on 1 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 
selnoquinazolone prepared in the course of this research and de- 
scribed more fully in another section of the paper, has this pros- 
pect. The quinazolone has the following- structure: 




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 re- 
sults 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 selenocyanidc. The red dyestuf? thus prepared 
is stated to be easily soluble in water. Wassermann, Keysser 
and Wassermann (") made experiments with it, chemothera- 
peutically, on animal tumors. When the solution was injected 

8 



into mice tumors the latter turned red, accompanied by the soft- 
ening- of the tumor after the third injection and complete resorp- 
lion 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 carcenoma 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-selenocyanideanthra- 
quinone 



SeCN 





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-diaminoseleno- 
pyronine. 



NH 2 



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 ta get acquainted with the smell of this gas I allowed 
a bubble not larger than a pea to pass into my nostril ; in conse- 
quence of its smell I so completely loss 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 

9 



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 Hartley 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 trans- 
formed into an organic complex of sulphur or selenium, an(l that 
the transference may be more rapid and powerful in the case of 
hydrogen selenide. 

Biological investigations have sufficiently proved that dye- 
stuffs of the phenazine, oxasine, 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 ( 10 ) 
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 com- 
binations, especially of the ease with which they form organic 
complexes with arsenic compounds. 




Formula (I) is known as 1, 3-dinitrobenzoselenazine ( 21 ), which 
was obtained by the action of picryl chloride pn 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 proto- 
zoa and bacteria. 



10 




H0 3 As 




H0 3 As 



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 em- 
ployed commercially for photograph fixing and for removing 
stains from negatives; thiuret, C 6 H' 7 N 3 S 2 , serves as a substitute 
for iodoform'; thiosinamine-ethyliodide, or tiodine, IH 5 C 2 H< 2 - 
NCSNHC 3 H 5 , is used for relief of lesions of the central nervous 
system; allylthiourea or thiosinamine, (NH' 2 )SC.NHCHj 2 CH:- 
CH 2 , for aiding the absorption of connective tissues, for treat- 
ment 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 Hey- 
den ( 24 ), and are prepared by the action of hydrogen selenide 
on a,lkylcyanamides, 

RNH.CHN + H 2 Se = RNH.CSe.NH 2 

They possess pronounced therapeutic value and, serve as inter- 
mediate products in the production of more stable alkyl halide 
additive compounds. Other carbamides ranging from seleno 
urea itself ( 25 ), (III) and a cyclic urea ( 28 ) (IV) are described 
in the literature: 



NH 2 



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



11 



H 2 C NJH 



C:NH 



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, thio- 
phenetetra-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 



CH 



CH N 



5e 

Selenophene 



CH CH 

v 

Selenazole 



Dimethyl selenophene was prepared from acetonyl acetone 
and phosphorous pentaselenide, 



HC C 



X OH 



N CH 



HC=C, 

HC = 



'Se 



CH 



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 phos- 
phorous triselenide, or by conducting ethylselenide through hot 
tubes ( 29 ). 

Some selenazoles find application also in medicine. At pres- 
ent 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). 

12 





HCN 



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, 





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



Se 

Dimethyl-seleno- Diphenyl-seleno- 

diazole diazole 

Sulphides and disulphides have curative power. Dimethyl- 
sulphide is used for internal) treatment, di-o-aminophenyldi- 
sulphide 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 num- 
ber of selenium compounds act as skin irritants : e.g., dichloro- 
diethyl 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 ( 8B ). 

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 anthra- 
quinone and their phenols are recognized remedies ( 36 ). 



13 



TINCTORIAL REVIEW 

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

HC-CH HC-CH 

II H II If 

HC \ o / H H 

Furane, color-lets Thiophene, colorless 

liquid liquid 

HC CH HC CH ? 

H If (I 

HC CH HC CH 

\ / \ / 

NH 5* 

Pyrrol, colorless liq. Selenophene, yellow liq. 

but turns brownish in air after repeated extraction 

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 ), 

C 6 H S 



CH,N CSe 

1 1 



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 (C 2 H 5 ) 2 Se, is a yellowish heavy oil of un- 
pleasant odor. It combines readily with chlorine to form a 
chloride (C 2 H 5 ) 2 SeCl 2 , and the latter is oxidized by nitric acid to 
form an oxide (C 2 H 5 ) 2 SeO, ( 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 ). 

* Note dimethyl selenophene, however, is colorless. 

14 







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 mole- 
cular weight than sulphur, shows a deeper blue. This hypothesis 
meets a difficulty in the case of coumora,ndione, thionaphthene- 
quinone 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. There- 
fore 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. Mtethyl disulphide only becomes yellow 
when it is treated with chlorine, and in such cases (GH :{ ) 2 S 2 CL> 
is formed ( i3 ), in yellow rhombic crystals. Ethyldisulphide is 
colorless; ethyldisulphidedichloride 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 phenyl- 
diselenide dibromide orange red ones. 

While phenyldisulphide is colorless, when an auxochrome 
group is added, such as NH ; , M the compound is colored. This is 
the case with o-diaminodiphenyldisulphide ( 48 ) which is yellow 
both in solution and in crystalline form. In other words, an auxo- 
chrome in addition to the chromophore group transforms a col- 
orless chromoo-en into a colored one. Therefore groups like 
-S.S- and -Se.Se- are chromophores in the same sense as -N:N-. 
This is in agreement with the chromophore ideas of Hugo Kauf- 
mann. The -Se.Se- is a more powerful .chromophore than 
-S.S-. 

This brings one directly to the inquiry as to why 2-phenyl- 
benzoselenazole, which contains a :Se radical, should be color- 
less; and that even 6-nitro-2-phenylselenazole, with the addition 
of a chromophore NO 2 , should be only faintly colored. The 
benzothiazoles, their isomers and derivatives are mostly color- 
less, and similar causes are probably responsible in the case of the 
phenylbenzoselenazole, for its lack of color. But when this 

15 



selenazole is combined with another chromophore, for example 
an azomethine grouping, the result is a more positively colored 
compound (in this case benzalaminoselenazole), the crystals 
being yellow. The corresponding thiazole derivative is light 
colored. 

The tinctorial value of the selenium derivative is further 
evidenced by the ease with which it forms azo dyes and the deep 
colors of the latter. This was observed when 6-amino-2- 
phenylbenzoselenazole was diazotized and coupled with B-naphthol, 
salicylic acid, etc. The corresponding aminothiazole has been con- 
sidered difficult to diazotize, on account of its insolubility in hydro- 
chloric acid, cold or hot, but the aminoselenazole dissolves readily 
and completely, the coupling is almost instantaneous, and the dyes 
obtained a,re mostly red and of metallic lustre. In view of the 
stability of benzoselenazoles toward hot concentrated acids (with 
the exception of nitric, when nitration ensues) and alkalis, these 
dyes may prove of some commercial interest. 

The azole dyes of the benzoselenazole have been exposed to 
light for weeks, and also exposed to acids and alkalis, and have 
been found to be quite fast. 



EXPERIMENTAL 



Preparation of 2-methyl-4-selenoquinazolone 
Busch prepared quinazolines by the action of o-amino or 
o-nitro benzylamine with phosgene, and thioquinazolines with 
carbon disulphide ( 51 ) : 



y CH 2 -NH 

COC1 7 - C,H/ | 

N NH-co 



C5 2 



Accordingly the same reaction was tried with o-nitrobenzyl- 
amine, prepared by the method of Lellmann and S'tickel ( 50 ), 
using carbon diselenide ( 51 ). The reaction seemed to work, but 
the mixture formed was difficult to extract and it appeared that 
other reactions took place at the same time, due to the impurity 
of the carbon diselenide, as the latter has never been prepared 
in the pure state. 

Another method, which is equally attractive because of its 
simplicity, is that of Babriel and Stelzner ( 52 ), 

16 



X CHO NH 2 /CH-N H 2 

C 6 VU + i C b H^ 1 4- 

^NH Z H Z N-CO ^N H-CO NH 3 

Tn accordance with the above reaction o-aminobenzaldehyde 
should work with equal ease with selenocarbamide, but the initial 
materials were not available. 

The reaction which was used successfully was that of 
Bogert, Breneman and Hand ( 53 ), 

NH 



NCS-NH Z \CS-NH 

+ or 

H5 N 



/NHCOfc. SH 

-> C t H/ 

N CN 

The hydrogen selenide used in the reaction was prepared from 
FeSe by the action of hydrochloric acid, or by heating paraffin and 
selenium, in the proportion of four to one respectively, at 335 
to 350C ( 54 ). 

The selenoquinazoline was prepared from anthranilic nitrile 
by the following methods the anthranilic nitrile being prepared 
from o-nitraniline ( 57 ), 

(a) 20 grams of acetyl-anthranilic nitrile was dissolved in 
absolute alcohol, and dry hydrogen selenide and dry ammonia 
passed into the solution for three hours. The quinazoline crystal- 
lized out gradually on cooling was filtered out and recrystajized 
from dilute alcohol. The yield was about ten per cent. 

(b) 10 grams of acetyl-anthranilic nitrile was heated in 
a sealed tube at 110 with alcohol saturated at zero degree with 
dry hydrogen selenide and dry ammonia. After five hours, the 
tube was taken out and the quinazoline crystallized out on cool- 
ing. Yield was about sixteen per cent. 

As hydrogen selenide was somewhat unstable and did not dis- 
solve freely in alcohol, freshly prepared sodium selenide was 
used in the following method and was found to be more satis- 
factory. It was prepared from Sodium hydroxide in absolute 
alcohol by passing dry hydrogen selenide into the solution for 
about three hours. In the beginning and end of the reaction, 
nitrogen was used to exclude the oxyggn of the air. The selenide 
was collected and dried in an atmosphere of nitrogen, and then 
in a vacuum, in presence of phosphorus pentoxide. When thus 
prepared, sodium selenide was colorless, but on exposure to 

17 



air it turns reddish and finally dark colored. The C. P. selenide 
on the market was black and was found to be entirely useless. 

(c) 20 grams of anthranilic nitrile and fifty grams of sodium 
selenide were mixed and heated in a distilling flask in an at- 
mosphere of nitrogen, and forty grams of acetic anhydride drop- 
ped into the flask very slowly. The temperature was kept at 
115 for half an hour and then raised to distill off the acetic acid 
termed in the reaction, as the condensation hardly went to com- 
pletion in the presence of any trace of acetic acid. The whole pro- 
cess took an hour and half. The flask was removed from the oil 
bath and, after cooling, dilute alkali was run in, in successive por- 
tions, to dissolve out the quinazoline. Into the clear alkaline 
extracts carbon dioxide was bubbled for an hour, and common 
salt then added. The precipitrate was recrystallized several times 
from twenty-five per cent, alcohol. The yield was from twenty 
to twenty-five per cent. 

(d) 10 grams of anthranilic nitrile, twenty grams of acetic 
anhydride, and twenty-five grams of sodium selenide were mixed 
in a sealed tube and heated together for three hours and half at 
110-115. The condensation product wa,s crystalline when the 
tube was cooled to room temperature. The contents of the 
tube were extracted with dilute alkali as before, filtered, preci- 
pitated by carbon dioxide, and recrystallized from dilute alcohol. 
The yield was not over twenty per cent. 

(e) An attempt was made to make o-aminobenzselenamicle, 
and from the latter, by treatment with acetic anhydride, to form 
the quinazoline, but the yield of the amide was too small to 
carry the reaction further. 

The substance prepared by the above methods crystallizes 
from dilute alcohol in needles or prisms of dark brown color. 
It melts at 213.5 (corr.). It dissolves readily in hot alcohol but 
on concentration sometimes forms a sticky mass with a peculiar 
but not unpleasant odor. It dissolves readily in alkalies a,nd is 
slightly soluble in hot benzene and chloroform, but insoluble 
in hot water. Crystals purified from (a) were analyzed and 
gave the following results : 

Calculated for Found 

C H 8 N 2 Se I II 

Carbon 48.38% 48.45% 48.62% 

Hydrogen .... 3.61 3.82 3.52 

Nitrogen 12.55 12.51 12.66 

Selenium .... 35.46 35.60 35.42 

The crystals on standing in the presence of air and light de- 
composed with separation of finely divided selenium and methyl 
quinazolone. 

Analysis of Selenium Organic Compounds 

In the quantitative determination of selenium in quinazoline 

18 



the method adapted by Becker and Meyer was found to be quite 
satisfactory ( 56 ). Other methods are listed in the bibliography 

("). 

In the ultimate analysis of carbon and hydrogen, the ordi- 
nary absolute method was followed with the use of copper 
oxide, lead chromate, and lead peroxide in the tube. In the 
determination of nitrogen the ordinary absolute method was 
also followed excepting that a considerable quantity of specially 
prepared lead chromate powder was mixed with the sample in 
a number six porcelain boat. This was found to be desirable 
when the dinitroselezazole was burned. Selenium dioxide, which 
is a solid, seems to be formed in the tube and carried away by the 
current of carbon dioxide with some difficulty. In such a case the 
analysis usually took four hours after the combustion had actually 
started. In the carbon and hydrogen determination selenium dioxide 
was easily absorbed in the presence of oxygen gas. 

Preparation of 2-Phenylbenzoselenazole 

The first method employed was a modification of the method 
described by Fromm and Martin ( 5S ). Method (b) is an adapta- 
tion of the method for preparing benzothiazoles. 

(a) Twenty grams of benzanilide was mixed in a pyrex 
flask with 160 grams of selenium dust and the flask placed in a 
nitrate bath under an air condenser. After heating for an hour 
at 220 C., the temperature was raised to 250 C., and kept at 
250-280C. for sixteen hours. The dark mass was extracted 
with hot concentrated HCl, the acid extracts filtered through glass 
wool using a hot water funnel. The combined extracts were poured 
into a large volume of water when the selenozole precipitated out 
immediately; it was recrystallized from alcohol. In some cases it 
was necessary to dissolve in hot HCl again and to recrystalize. The 
yield was twelve per cent. 

The above method has the disadvantage that water is 
formed in the reaction and this in turn reacts upon benzanilid 
at the higher temperature necessary (as selenium only melts at 
217C), decomposing the benzanilid into aniline and benzoic acid. 



H ^ie 



/NHCOC 6 H S /NH 2 

C b H 4 S / 



Furthermore benzanilid boils at 160 C. and at such high temper 
atures as 250 C. and over some of it is apt to be driven off. 



19 



(b) 106 grams of benaldehyde were heated with 93 grams of 
redistilled aniline at 120C., for two hours or until the solution 
was clear. The clear benzalaniline was then poured into 160 
grams of selenium dust in a pyrex flask on a sand ba,th, the flask 
being connected with an air condenser as before. In order to 
distribute the flame to better advantage over the bath, an air 
space was made between the Meker burner and the bath by 
introducing a wire gauze. Hydrogen selenide was evolved freely. 
Complete reaction took three days. The extraction and recrystal- 
lization were the same as in the former case. The yield was sixty 
per cent. 

The selenazole crystallizes in colorless long needles, melting 
at 117.5C. (corr.) Fromm and Martin ( 58 ) gave the melting- 
point as 117C. It is insoluble in water, and in the following 
solvents it is lightly soluble in the cold, more easily hot: ether, 
methyl alcohol, acetone, acetic acid, acetic anhydride, chloroform, 
and nitrobenzene. It is difficulty soluble in ethyl alcohol, ethyl ace- 
tate, and carbon tetrachioride, in the cold, but easily soluble 
hot. 

Mononitro Derivative 

The mononitro derivative of the selenazole, 6-nitro-2- 
phenylbenzoselenazole, was prepared by nitration with nitric 
ncid at a low temperature: 

Twenty-five grams of the selenazole were dissolved in 150 
grams of concentrated sulphuric acid, keeping the temperature 
below the room temperature until complete solution took place. 
It was then cooled on a freezing mixture and a mixture of sul- 
phuric and nitric acids (previously prepared and cooled by mix- 
ing 9.5 grams of nitric and fifteen grams of sulphuric acids) 
slowly dropped into it in the course of half an hour, using mechani- 
cal stirring for four hours. The solution was then poured into 
two liters of water (ice water), filtered, dried, and recrystallized 
from acetic acid, and alcohol with the help of animal charcoal. 
The yield was 95 per cent. 

This nitro compound crystallizes in flattened needles of a light 
yellow color. It melts at 202.4C. (corr.). It is very insoluble 
in water; but soluble in hot acetic acid, acetic anhydride, nitro- 
benzene, nitrotoluene, toluene, benzene, alcohol, and difficulty 
soluble when cold. The crystals were analyzed and gave the 
following results, 

Calculated for Found 

C.. 3 H 8 N 0,Se I II 

Nitrogen 9.24% 9.36% 9.48% 

Monoamino Derivative 

The conversion of mononitro compound to 6-amino-2- 
phenylbenzoselenazole was accomplished by the action of tin and 
hydrochloric acid as follows : 

20 



30.3 grams of nitro compound were mixed with 42 grams 
of twenty mesh tin in a liter flask, immersing the latter in cold 
water. 175 cc. of cone. HC1 were slowly added to the flask. 
In some cases it was necessary to apply initial heating but when 
once the reaction started it took place rapidly. After the effer- 
vescence had abated, the flask was heated over a free flame, under a 
leturn condenser, for two hours. The solution usually turned 
to a, pasty mass, due to the formation of a tin double salt. The 
mixture was dissolved in a large volume of water and heated 
on a water-bath, the precipitate filtered out, washed, and pre- 
served. The clear filtrate was treated with concentrated alkali, 
in excess, the separated amine collected, washed with water, 
dried and recrystallized from alcohol, using bone-black. The 
precipitate set aside was treated with strong alkali, the insolu- 
ble residue washed, recrystallized, and added to the main 
product. The yield was 75 per cent. 

This amine crystallizes from alcohol in fine yellowish needles, 
melting a,t 201.2202.3C (corr.). It is insoluble in water and 
ether, difficultly soluble in the hot; and fairly soluble in aniline. 
A pure sample was analyzed and gave the following results : 

Calculated for Found 

C 13 H 10 N 2 Se I II 

Nitrogen 10.25% 10.34% 10.42% 

Carbon 57.18 57.17 57.00 . 

Hydrogen .... 3.69 3.79 3.85 

Decomposition of Monoamino Derivative 

Five grams of the monoamino compound were mixed with 
powdered KOfi, heated together until the mixture just melted, and 
maintained in that state for a few minutes. When the latter had 
cooled down to room temperature, cold water was poured over the 
mixture. The filtered solution was acidified until no further 
precipitate was formed. The precipitate was collected and re- 
crystallized from water, m.p. 121 C. 

One gram of this solid was placed in a test tube, provided 
with a cork and a delivery tube, and heated with soda lime; a 
liquid with the smell of benzene was collected in another test 
tube cooled with water. When this liquid was treated with a 
few drops of nitric acid mixture the smell of nitrobenzene was 
given off. A gram of the crystals was heated with concentrated 
sulphuric acid and alcohol when the odor of ethyl benzoate wa,s 
noted. 

Monacetyl Derivative 

Five grams of the monoamino selenazole were heated on a 
water-bath with 10 cc. of acetic anhydride until the solution was 
clear, which took about two hours. 100 cc. of water were poured 
into the mixture, which was then neutralized with dilute am- 

21 



monium hydroxide. The precipitate was filtered, decolorized 
by animal charcoal, and recrystallized from dilute alcohol. 

The acetyl compound, 6-acetamino-2-phenylbenzoselena- 
zole, forms colorless crystals, melting at 188.1-.7C. (corr.). It is 
insoluble in ether, benzene, carbon disulphide; slightly soluble in 
toluene ; soluble in alcohol, ethyl acetate, amyl acetate, acetone, 
and acetic acid. A pure sample was analyzed and gave the 
following result, 

Calculated for Found 

C 15 H 12 N 2 SeO 

Nitrogen 8.88% 8.92% 8.68% 

Mxmobenzylidene Derivative 

Five grams of the monoamino compound were dissolved in 
200 cc. absolute alcohol with the addition of 3 cc. of benzaldehyde 
a,nd the clear solution was boiled on a water-bath, with a return 
condenser, for two hours. After the solution was boneblacked, 
the yellow precipitate was recrystallized from carbon disulphide. 
The yield was 90 per cent. 

It crystallizes in yellow plates, melting at 156.7-157.6C., 
soluble in benzene, ether, ethyl alcohol, carbontetrachloride, ace- 
tone, but difficulty soluble in ligroin. An analysis of the crys- 
tals showed the following- result, 

Calculated for Found 

C 20 H 14 N 2 Se 
Nitrogen 7.75% 7.92% 7.68% 

An Azo Dye 

Five and four tenth grams of the monoamino compound were 
dissolved in hot cone. HiCl, cooled in ice. and diazotized with 
sodium nitrite solution, until starch iodide paper showed excess 
nitrous acid. The diazotization was performed in ice, with 
mechanical stirring, and required about an hour. The diazo solu- 
tion was poured into a solution of 3 grams B-naphthol in 8 ^rams 
of NaOH a,nd 60 cc. of water, while gradually stirring. A very 
deep red solution formed. This was acidified with excess HC1, 
salted out by NaCl, and crystallized from aniline-alcohol mixture. 
In the pure state, it is a deep red powder, with a metallic lustre 
when rubbed, melting at 284.2 C. An analysis showed the fol- 
lowing result, 

Calculated for Found 

C 28 H 15 N 8 OSe 

Nitrogen 9.81% 9.75% 

Dinitro Derivative 

The nitration for the production of dinitro derivative was 
at first carried out under the same conditions as in the preparation 

22 



of mononitro compound and after the latter was formed more nitric 
acid mixture wa,s added, with the addition of heat : 
cone, sulphuric acid, keeping it below room temperature. It was 
then cooled in a freezing mixture and half the volume of a nitric 
acid mixture (prepared and cooled by mixing 19 grams of nitric and 
30 grams of sulphuric acids was introduced very slowly to the 
selenazole solution through a dropping funnel, maintaining at this 
temperature for two hours (using mechanical stirring). The re- 
maining half of the nitric acid mixture was then slowly introduced 
and the flask was heated on a water-bath for two hours. The solu- 
tion was poured into two liters of water, the precipitate filtered off, 
dried and recrystallized several times from acetic acid. The yield 
was 80 per cent. 

This dinitro compound crystallizes in fine yellow needles, 
m. p., 246.8C. (corn), very insoluble in water, but soluble in 
hot acetic acid, acetic anhydride, nitrobenzene, nitrotoluene. 
ethyl alcohol, and difficultly soluble cold. It was analyzed and 
the following results were found, 

Calculated for Found 

C 13 H 7 N,O 4 Se I II 

Nitrogen 12.07% 12.30% 12.12% 



Diamino Derivative 

The conversion of the dinitro to diamino derivative was ac- 
complished in the same manner as the reduction of mononitro 
derivative excepting that twice a,s much tin and HC1 were used. 

This diamino compound crystalizes in yellowish glistening 
needles from alcohol and pyridine; m. p., 269-270.5C. ; was 
analyzed and gave the following results, 

Calculated for Found 

QaHuNsSe I II 

Nitrogen 14.6% 14.4 14.7 



Diacetyl and Dibenzylidene Derivatives 

The diacetyl and dibenzylidene compounds were also pre- 
pared from this diamino derivatives. The former crystalizes in 
cubes from dilute alcohol; m. p., 307C (Corr.) and the latter in 
beautiful yellow plates from carbon disulphide, m. p., 195-196C. 
(Corr.). An analysis of these two compounds showed the follow- 
ing results, 

Calc. for Calc. for Found 

C 17 H 15 N 3 2 Se C 27 H 19 N 3 Se I II 
Nitrogen .... 9.05% 11.21% 9.21% 11.43% 

23 



Dyeing with Azo Dyes 

Both the monoamino and the diamino derivatives form in- 
tensely colored dyes when diazotized and coupled with phenols 
and aromatic amines. The dyes formed are fast to light. In 
the following table silk is given to represent the fabrics used. 
Wool and cotton were dyed similar shades, though with slight 
variation. Each silk sample was dyed in a,cid or alkaline baths as 
indicated and each bath contained 0.01 gram in twenty cc. solution : 



Diazo. 



On 



Diazo. 



On 



Coupler 


1110110- 

amine 


silk 


diamine 


silk 


Phenol 


deep red 


v. light 


(alk) 


yellow 




(alk) 


yellow 


deep red 




Dimethyl- 


orange 


light 


orange-red 


yellow 


aniline 


(acid) 


yellow 


(acid) 




P-nitrani- 


light 




brownish 


grayish 


iine 


brown 




(acid) 


brown 




(acid) 








P-tolui- 


light 




brownish 


brownish 


dine 


brown 




(acid) 






(acid) 









Pyrogal- 


dark 


grayish 


dark 


grayish 


lic acid 


brown 




brown 






(acid) 




(alk) 




Salicylic 


reddish 


light 


red 


brown 


acid 


(alk) 


brown 


(alk) 




B-naph- 


deep red 


pink 


deep red 


red 


thol 


(alk) 




(alk) 




Sulphani- 


light 


brownish 


brown 


brown 


lic acid 


brown 




(alk) 






(alk) 








A-naph- 


light 


brownish 


yellow 


yellow 


thylamine 


brown 




(acid) 






(acid) 








Resor- 


purple 


red 


dark 


deep red 


cinol 


(alk) 




purple 










(alk) 





24 



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25 



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26 



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37 



VITA 

Yii-Gwan Chen was born in Nanking, China, March 8, 1893. 
After graduation from college in 1915, he further studied Chinese 
classics, 1915-16. He entered Case School of Applied Science, 
Cleveland, Ohio, as a special student in the Department of Chemis- 
try, 1916-17. He registered at Columbia University to pursue 
graduate work in chemistry under the Faculty of Pure Science ; and 
was awarded the degree of Master of Arts in 1918. From Septem- 
ber 1919 to June 1922, he has been pursuing research in organic 
chemistry in the research laboratories of Hlavemeyer Hall, Columbia 
University. 



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