º
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CONDENSATION OF NITROMALONIC ALDEHYDE
WITH º •AMINOPROPIONIC ACID.
A DISSERTATION
SUBMITTED IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF DOCTOR OF
PHILOSOPHY IN THE UNIVERSITY OF MICHIGAN.
By
Edward Mark Homan
1917
For the suggestions and direction given during
the development of this research, the author expresses
his kindlest appreciation to Professor William J. Hale.

CONTENTS.
I. HISTORY.
Alkyl pyrroles.
Early syntheses
Isolation of homopyrrole
Isomers of homopyrrole
Conversion of N alkyl derivatives to
C alkyl compounds
Proof of position of substituents
Mononi tropyrroles .
-nitropyrrole
-nitropyrrole
Mononitro alkyl pyrroles
Oxidations
Diacetyl nitropyrrole
Carbopyrrolic acids
Hydrolysis of Pyro coll
Pyrrole and (NH4)2CO3 in sealed tube
Pyrrole and C014
Oxidation of pyrrole aldehyde
Grignard reactio}
Pyrryl glyoxylic acids,
From acetyl pyrroles
Pyrryl acetic acid
Nitrocarbopyrrolic acids
Denitropyrdcoll
Nitration of carbopyrrolic acid
10
10
10
ll
l2
13
13
14
l4
l4
14
14
lă
16
16
16

Nitromalonic aldehyde and glycine
ester
Constitution
II • THEORY.
Introduction
- Possible condensations
Identity of condensation product
Attempted oxidation
Free acid
3'-nitro- * -methyl pyrrole
6'-nitro- * -pyrryl acetamide
3'-amino- C -pyrryl acetamide
III. EXPERIMENTAL .
B -alanine hydrochloride esters
16
17
19
20
23
23
24
25
25
26
28
6 -nitro-º-pyrryl acetic acid ethyl ester 30
º
3-nitro-ºx - pyrryl acetic acid
3-nitro-º-methyl pyrrole
3-nitro-ºx -pyrryl acetamide
3-amino- -pyrryl aeetamide
Summary -
Bibliography
B -nitro- P -pyrryl acetic acid methyl ester 30
33
33
34
34
3%
zº


I. HISTORICAL PART.
In 1869 Lubavin'” succeeded in synthesizing an alkyl
pyrrole derivative by heating the potassium salt of pyrrole
with ethyl iodide. By distillation a colorless oil was ob-
tained from the mother liquor. The oil which boiled at
155-175°, possessed an odor-like turpentine and upon
standing took on a deep red color. It was immiscible with
water and dissolved in hydrochloric acid forming a pyrrole-
red color. Lubavin was unable to proºve whether or not
this compound was a nitrogen or carbon alkyl substituent.
Analysis showed the compound to have the formula C4H4(C2H5)N.
Bell, (*) some years later, prepared an ethylpyrrole
by dry distillation of the ethylamine of mucic acid. This
product, when pure, boiled at 121°. Bell!”) cites the boil-
ing point even by Lubavin as an error. Later, Bell made
the methylpyrrole by distilling the methylamine of mucic
acid. This product boiled at liz-llä”. In 1878, (+) Bell re-
peated the work of Lubavin by heating the potassium salt of
pyrrole with ethyl iodide. He obtained a product boiling
at 121°C. Bell supposed this substance to be the N-alkyl
derivative. -
C4H4NK tº C2H5I ſº KV t C4H4NC2H5
It should be noted, however, that Bell made no attempt
to verify his statement and, contrary to his original

article, stated that long boiling with hydrochloric acid
resinified the ethyl pyrrole.
In the distillation products of animal tar, volatile
with steam, Wéidel and ciamician") found a fraction boil-
ing constantly at 145-146°. An analysis showed the formula
to be C5H7N, and the name "homo-pyrrole" was given to the
compound. The freshly distilled oil was colorless but, on
standing, changed more rapidly than does pyrrole itself.
Acids did not resinify the oil and mercuric chloride preci-
pitated the white mercurio salt. Pyrrole does not form a
corresponding salt of mercury. The monoacetyl derivative
gave a silver salt, confirming the assumption that the acetyl
group was not attached to the nitrogen of the ring. The
formula of the methylacetylpyrrole was evidently
GAB206HG3)4(GOCH2) NH. The methylpyrrole obtained by Bell!”
differed from the product with which these investigators were
working. Evidently, Bell had prepared the nitrogen substi-
tution product. Later Giamician and Dennstedt") determined
the boiling point of Bell's compound and found it to be
114-115° at 747.5 mm.
In the year 1881. ciamician!") found that by fusing
"homo-pyrrole" (b.p. 145-146°) with molten potassium
hydroxide, he obtained two carbopyrrolic acids • One acid
melted at 191° and had all the characteristic properties of
the acid mentioned by Schwanert.'” The other acid melted
at 161°. Ciamician converted these acids back to their

corresponding methyl pyrroles and found the high melting
acid, ºx-carbopyrrolic acid, gave a methyl pyrrole which
boiled at 147-148°. He called this the " Y-homo-pyrrole".
# Cr-c H #C c +!
—º.
U. ACS” C- « O OVA
3 \\\\
M \, g p
The low melting acid was called " F-homo-pyrrole" and
gave a methyl pyrrole boiling at 142-142°.
# C. c + c tº H C C-C bott
U. —º- U.
14|| Y\\\
By mixing these two isomeric "homo-pyrroles" it was found
that the mixture distilled at 145-146°.
ciamician and silber!”) later prepared the acetyl
derivatives of these two isomeric "homo-pyrroles." The
"homo-pyrrole" distillate boiling at 140-153° gave two
acetylated compounds. One melted at 85-86° and was proved
to be the G-acetyl derivative. The other acetyl-pyrrole was
the nitrogen acetyl product but these authors did not state
whether it was the CX or B "homo-pyrrolet that had been
acetylated. The low melting compound was given the name
methyl-pyrryl-methylketone or pseudo acetyl "homo-pyrrol e."
The nitrogen substituted product was called acetyl "homo-
pyrrole ..."
sonife,” working on the constitution of pyrrole
isolated a crystalline acetyl pyrrole melting at 90°, He.
called the product the N-alkyl derivative C4H4NOC2H30).

Ciamician and Denneteat,”
in repeating Schiff's work,
obtained two acetylated pyrroles. One of the se products
melted at 90° and corresponded to the c-alkyl compound men-
tioned by Schiff. It was found that this compound did not
decompose when heated with potassium, as Schiff had stated,
but it formed a potassium salt when treated with potassium
hydroxide solution. The formation of the silver salt showed
that the alkyl group was not on the nitrogen atom. Later,'”
attempts to oxidize this acetyl compound with alkaline per-
manganate gave the keto-carboxylic acid but the simple
carbopyrrolic acid was not produced.
C4H2(Go GHz) NH C4H2(GO GOOH) NH.
The second acetyl pyrrole, an oil distilling at 177-
178°, was called simply acetyl pyrrole and conformed
to the formula of an N-alkyl derivative. This compound was
insoluble in water; gave a white precipitate with mercuric
chloride; and readily reduced a solution of silver nitrate.
It was easily resinified when treated with hydrochloric acid
and boiling it with potassum hydroxide decomposed it into
pyrrole and acetic acid.
From the foregoing statements, it is easily seen that
there were not a few irregularities in the early prepara-
tions of alkyl pyrroles. It was not clear just which compounds
were "N" substituents and which were "C" substituents or,
perhaps it is better to say that the experimental conditions

necessary for the preparation of one class of compounds, to the
exclusion of the other type, were not well determined.
It remained for Giamician and Magnaghi to clear up this
difficulty. In 1885, Giamician and Silber!” heated acetyl
pyrrole with acetic anhydride in a sealed tube at zoo”c. The
result was the formation of pyrrolen-dimethyldiketone.
# C H CH ch, ce. # Cr-i CH
...U., + chº" º, U.a.
WW Y\\\ -
To afford an explanation for this peculiar change, the authors
suggested that, perhaps, the acetyl pyrrole changed into pyrryl
methyl ketone
tº CT-II c. lt Hct—l CAſ
...U. -> U.
\ to CH2 Y ºf
and that to this compound, the second acetyl group attached itself.
Giamician and Magnashiº verified the preceding sug-
gestion by heating acetyl pyrrole in a sealed tube. When the
temperature was kept at 300° a fundamental decomposition took
place, liberating ammonium salts and free pyrrole. By holding
the temperature at 250-280° it was found that the desired pyrryl-
methyl-ketone could be obtained. This was the first definite
experimental proof to show that the "N" substituents of the
pyrrole ring could be changed into C-alkyl derivatives by heating.
Later, gianasian and zanetti (*) found that by heating potassium
pyrrole salt with alkyl iodides both the "N" and "C" derivatives
were formed and that the higher the tempe rature, the greater the
tendency to form the carbon substituted compounds • Pictet and
(16)
Cripieux prepared the C-phenyl pyrrole by passing N-phenyl
pyrrole through a heated tube.
In the previous discussion we have stated that certain
derivatives were C{ carbon substituted compounds but we have
not given the proof necessary to substantiate such a statement.
It was a long established fact that pyrrole and its derivatives
were converted by halogens, in alkaline solution, into halogen
derivatives of maleinimide. Ciamician and silber!”) found that
many bromine derivatives of pyrrole are oxidized to dibrommaleini-
mide by nitric acid. Such a reaction shows that the bromine is
z
Orl the 3 and º carbon atoms of the pyrrole ring,
- A
G
By treating brominated pyrrol en-dimethyl-diketone with fuming
nitric acid, sp. gr. 1.52, and heating on the water bath dibrom-
maleinimide was obtained as a final product. The formation of
mononitro-acetyl pyrrole was an intermediate step in the reaction.
U. -> II". → "Uſ. "U"
CH*%-co CH-, wo.ºkcock, 7 mSv/kWp, CŞ. JO
W\ M. H. WA Y\\\
This reaction proved definitely that the alkyl substituents are
on the X carbon atom.
The most satisfactory method for the preparation of
C. carbon substituents of pyrrole is oddo's adaptation(*)
of the Grignard Reaction. By the use of acid chlorides or
anhydrides, pyrryl alkyl ketones are prepared. The X -carbo-
pyrrolic acids can also be prepared in the same way.
The preceding paragraphs have dealt with those compounds
of pyrrole whose substituent groups contained carbon. Now we


-10-
come to the second class of substituted pyrroles, those
which do not have carbon in the substituent, e.g. , the
nitropyrroles,
The first nitropyrrole, whose identity can be definite-
ly established, was synthesized by Angeli and Alessandri.”
When an ether solution of pyrrole was boiled several hours
with ethyl nitrate a & -nitropyrrole was isolated, m.p.
63.5°. Hale and Hoytſºo) found that this º -nitropyrrole
readily polymerized to a dimolecular structure which melted
O
at lol "U. M0. —ſ "I — C U. 0.
* a ** º C. WH
Hale and Hoyt heated DK -nitro- OK -carbo pyrrolic acid in a
sealed tube and a yellow oil, which they call & -nitropyrrolà
was produced. Only a few points were given to establish the
identity of this compound. These are the only references in
the literature to what may be called "free" nitropyrroles.
The derivatives of nitropyrrole have been widely discussed.
The first alkyl nitropyrrole was prepared by Ciamician
and silber(*) in 1885. It was found that, at higher
temperatūres, concentrated nitric acid decomposed both acetyl
and pseudo-acetylpyrrole. By cooling the reacting system
to 18° C and then slowly adding the pyrrole methyl ketone
a mononitropyrryl methyl ketone was formed. It melted at
196-197°. oxalic acid was a by-product. Later!” careful
repetition of this work gave four nitration products, i.e. &
mononitropyrryl methyl ketone, di-nitropyrryl methyl ketone,
dinitropyrrole and B -mononitropyrryl methyl ketone. -

•ll-
The 3-mono nitropyrryl methyl ketone
t; G-CH
\Us U.
\\\
was extracted by ether from an alkaline solution. This pro-
duct was soluble in hot water and its solution was neutral
to litmus. Treatment with hydrochloric acid gave no change,
but with fuming sulphuric acid it dissolved readily, being
reprecipitated when water was added. It was soluble in cold
alkalies, and the corresponding salts could be formed by
boiling the alkaline solution.
All attempts to oxidize this C(-mononitropyrryl methyl
ketone to the corresponding glyoxylic or to the nitro-carbo-
pyrrolic acid failed. By treating with acid permanganate or
potassium dichromate in acetic acid solution some of the
material was oxidized to acetic acid but the larger portion
was recovered unchanged. By treating with bromine in
hot water solution, a resinous mass was obtained from
which dibrommaleinimide was extracted.
- The sodium carbonate solution from which the C( -nitro-
pyrryl methyl ketone had been removed, was acidified with
sulphuric acid. This acid solution was extracted with ether.
Evaporation of the ether left a resinous mass which crystal-
lized after standing several days in a desiccator . From
this crystalline mass the º -mononitropyrryl methyl ketone
W3.8 **. Yū; C H
Uſ. Ó Y U.
W H Yū

-l?--
This product was purified by sublimation and melted at
156°. The water solution was acidic in character and the
material could not be extracted from an alkaline solution
with ether. The authors did not mention any attempted
oxidation of this compound to its corresponding glyoxylic
or carbopyrrolic acid. However, it is to be expected that
such efforts would have given the same negative results as
the º mononitro derivative.
In the same year, Giamician and silber(*) treated
pseudo-acetyl pyrrole with fuming sulphur ic acid, sp. gr.
1,88, and obtained a crystalline sulphonate,
º SO2K) NH3
GOCH3
No further work was done on this compoſſind, i.e. oxidation
products as well as the position of the sulphonate group were
not determined.
One year later, Ciamician and silber!”) treated
pyrrolen-dimethyl-dike tone with cold fuming nitric acid and
obtained a mono-nitro derivative which melted at 149°C.
*AC C-Yuo,
U. co (8.
It will be noticed that in the case of 3-nitropyrrolen
dimethyl diketone only one product is possible but with
pyrryl methyl ketone there may be two isomers.
horſ-ſtylda Wº, C tº
U. Ö Y "D.",
M\l MW

Although Ciamician and Silber called this product a
* -nitropyrryl methyl ketone they did not give any reason
why it should not be the Baerivative.
Thus far we have discussed the compounds of pyrrole
which are not free acid derivatives. The first carboxylic
acid of pyrrole was isolated by schwanert!” when he dis-
tilled mucic acid. It melted at 191°. Since the structure
of pyrrole had not been determined at that time, it was im-
possible to show the position of the aarboxyl group . After
Baeyer's formula for pyrrole was accepted, it became evident
that the carboxyl group was on a carbon atom adjacent to
the nitrogen.
tº C c \!
U. CUof
W\\
Bell (*) by heating his methyl pyrrole with alcoholic
potash in a sealed tube at 120-130°, obtained a carbopyrrolic
acid which melted at 135°C. When the water solution of
this acid was heated it decomposed liberating carbon dioxide
and leaving the methyl pyrrole unchanged.
(25) obtained a carbo-
In 1880, Weidel and Ciamician
pyrrolic acid by the hydrolysis of pyrreoll. One year later,
ciamician!” oxidized potassium "homo-pyrrole" with molten
potassium hydroxide and isolated two carbopyrrolic acids.

one asia was identical with that prepared by Schwanert.”

The other acid melted at le1° and was the B -carbopyrrolic
acid. Giamician and Silber!”) affected the first direct
synthesis of ^{-carbopyrrolic and by heating pyrrole and
ammonium carbonate in a sealed tube at 120-130°. This
method is the best, save the one by Oddo to be mentioned
later, for preparing large quantities of the acid. These
Sąjūe investigators” prepared small quantities of the
acid by heating carbon tetrachloride with pyrrole in
alcoholic potassium hydroxide for several hours on the steam
bath. At this time it was also shown that heating the po-
tassium pyrrole salt in a stream of carbon dioxide produced

(29) oxidized pyrrolaldehyde
the acid. Bamberger and Djerdjian
to its acid by alkaline permanganate. The last method of
preparation is that given out by Oddo in 1906(30). By
using the Grignard reagent and carbon dioxide With pyrrole,
oddo was able to prepare large quantities of the OK. -carbo-
pyrrolic acid. The reaction is outlined as follows:
"T." tº U' ºU" —y U.
fl C^*( H Hººk #1C º \\C W CC00 li
W \\\\ \\\\ \\
º
In discussing the more complex carboxylic acids of
pyrrole only two types will be mentioned:
I. Pyrryl glyoxylic acid (keto-carboxylic),
II. Pyrryl fatty acids.
The pyrryl glyoxylic acids are prepared by oxidizing the
corresponding pyrryl methyl ketone (pseudo-acetyl pyrrole) .
(31)

Giamician and Dennistedt obtained the pyrryl C( glyoxylic

-15-
acid by oxidizing with permanganate.
// C CH {{C C H.
Ul cock, U. to 100+
\\\\ W \\
It was not possible to convert this acid into the corres-
poſſiding carbopyrrolic acid.
H C CH !C C}{
> U. c cºſ
H U. coºf H Y\t
\\?\
(32) oxidized the diacetyl pyrrole
Giamician and Silber
{ & X^ diacetyl pyrrole) to the carbopyrrolen glyoxylic acid
by alkaline permanganate and when the keto-carboxylic acid
was fused with alkali the di carbopyrrolic acid was produced.
"U" H * U. º |AC. C+!
ck, co- ` Cº ºt, cºcº *** cº-fº * Co-º-º/
The more complex pyrryl fatty acid derivatives were dis-
covered by Piloty(*) in the decomposition of blood products.
The simplest acid of the series, A-pyrryl acetic acid, was
(34) When pyrrole or N-methyl
synthesized by Piccinini.
pyrrole was boiled with diazo acetic acid, nitrogen was
evolved and an acid melting at 112-133° was isolated.
Ho CH MN H C – C. H.
D. f | cº-ºff ~ ||, | | ||
Włł
#Q_g ch: Coot,
W. H.
-16-
No subsequent reference to this acid could be found.
The first nitro-carbopyrrolic acid was produced by
Weidel and ciamician!” when they nitrated pyro coll and
then hydrolyzed the dini tropyrro coll. From one molecule
of dinitro-pyrocoll, two molecules of a nitro-carbopyrrolic
acid melting at 144-146° were produced. In 1886, Giamician
and silbert%) attempted to nitrate the free acid obtained
by Schwanert". Dini tropyrrole was obtained and carbon
dioxide was evolved. Later, Andrelini (*") showed that if
the ester of carbopyrrolic acid were nitrated instead of the
free acid, the reaction ran smoothly and from the reaction
system, now made alkaline, an acid, melting at 21.7% could
be extracted by ether. When no more acid would be extracted
from this alkaline solution, the system was made acid and
again extracted with ether. This yielded a second nitro-
carbopyrrolic acid melting at 161°.
Although the three possible mononitro-carbopyrrolic
acids were known, it was not until many years later that
Hale and Hoyt (*9) established the spatial relationship
existing between them. By condensing nitromalonic aldehyde
with amino acetic acid ester, glycine ester, these investi-
gators made a nitro-carbopyrrolio acid whose nitro group was

A.
in the º position to the carboxyl group.
ſ
º, , , O C.
Yu () 2. c # 0. H.) Y? **— c."
C rz , , –2 | X }///
H C T C HO Hyo-coºr C - C
- H

-17-
This acid melted at 217° and was the same as the one
Andrelini had extracted from the alkaline solution. Hale
and Hoyt heated the nitro-pyrrolic acid obtained from ni-
trating pyrrooll with naphthalene in a sealed tube. A
compound was isolated whose melting point was 63.5. This
was the same º -nitropyrrole first prepared by Angeli and
Alessandri'”). The acid from which this nºtropyrrole came
was evidently the 6 -nitro-º-carbopyrrolic acid since the
higher melting acid was the 3'-nitro compound, and the
two acids gave the same 3 -nitro-pyrrole.
U., -,
H C L J C - Coq à * * * > *, *,
\\\\
z. C
"II" – Co., ºf -2 U.
lſ c. c 0 H
f
The remaining acid must be then the 0 -nitro- º -carbo-
pyrrolic acids
In a brief summary of the preceding paragraphs we find,
at first, the position of the alkyl substituent on the pyrroße
ring was not definitely determined and all reactions gave a
mixture of N and C derivatives; then it became known that
heating changed the alkyl group from the N to the C atom.
Much work has been done on the action of nitric acid upon
the higher homologues of pyrrole as well as pyrrole itself.
The simple nitro-methyl pyrrole is not mentioned. Sulphonates
of pyrrole are not known. The acetyl pyrroles are oxidized
to give various compounds but no oxidation products of the
nitro-acetyl pyrroles have been prep ared. One N-methyl- -
pyrryl acetic acid has been mentioned but nothing has been

said of nitro- * -pyrryl acetic acid. It is with this
acid and some of its derivatives that we shall deal
presently.





II. THEORETICAL CONSIDERATIONS ,
It has been known for some time that l, 3-dialdehydes
condense with two adjacent methylene groups in juxtaposition
to acetyl or benzoyl groups to form cyclic structures. These
dialdehydes also condense with certain diamino compounds.
Thus nitromalonic aldehyde was found to condense with urea
to form a pyrimidine.
H
o Y\0,-C. C O H.
6. —s
H\ H
With guanidine an amino pyrimidine was obtained.
| - H
* … Bº 2 C – * N
H | —5. *-ºs. ,, … ",
\ "TNA 2 – WN, ſº –
cHGT)-c-Mil, tas,"
In the work of Hale and Brill it was stated that alkyl
or acyl substituted ureas gave only the straight chain
compound, a monoureide; but later work upon certain di-
ketones indicates that the akyl substituted pyrimidines may
be formed in this reaction •
, N - = M_2 > valu:
Y\l, s ºr " , ºff-cº º ce whº, X = \
\\ ~ TV + - \\ ^ Scho __ - \l, Cs wº
c H 0 co-MHCH, - - - C -º
H. CH,
Hale and Hoyt (*9) brought into condensation with l, 3-
dialdehydes a compound which had an amino group adjacent to
a methylene group and this latter, in juxtaposition to a
carboxyl. It was found that the reaction ran smoothly and
that a pyrrole derivative was produced.

-20-
cho ºn / C ~ |
Mºcº , → mo, Q = c – C o O C, H
tº Sc Ho Hºc-coot,\, # = c- • "3-
In the preceding reaction between glycine ester and sodium
nitromalonic aldehyde, it was found that the first product
of the condensation was a straight chain compound which had
involved only the amino group with one aldehyde group. This
product gave a test for a free aldehyde group when this straight
chain compound was treated with alkali, an intramolecular
condensation was found to take place and yielded a nitropyrrole
derivative -º
- - C // - ci *\ -
ºc º *} H c. I d \scº = W ºccº. W)0. 2% Y1
C H, C - cov (, A. \ * c \, → Q
|
C T C-cooc, \, .
H ****
When the constitution of this cyclic condensation pro-
duct, - the B-nitro-3 - carbopyrrolic acid, had been es-
tablished, it was thought desirable to study the condensa-
tion of 1, 3-dialdehydes with a class of compounds containing
an amino group adjacent to a methylene group as above, but
which, in turn, was once removed from a carboxyl group by
a second methylene group. In choosing such a compound, we
found that ſ -aminopropionic acid, B -alanine, answered
our purpose. Here we have the primary amino group on a
chain of two methylenic group S and a carboxyl. From the
work of preceding investigators one might expect five possible
configurations for the condensation product.
I. The first would involve one aldehyde group with
one molecule of acid giving a straight chain compound.
o A M- – C (JOC *
\\\\s 2 C H M (CH), h; wº C H), Cô0 ( , h;
2 T N —º ,-
tl C H (, " cut -
II. Both aldehyde groups would be dondensed, each with
one molecule of acid.
... nºw- H
mo, cºo Hº CH), cort, R, WU, 2 : M (Ct.), Cººt,
~ --- —”
H \cho tº- (c H\cº C. H.; H T \;= n-(CH), Cow C. H.-
III. The two adjacent methylene groups could react
with one molecule of aldehyde and a cyclopentadiene would
result. ------ \t
\, , C Hº º nº. 2 C- ºr "",
*- C - —- 2
H ~ \ c Ho tº-coºl, || N fi 2- C-C coe, t,
IV. The & carbon atom and the amino group of the
acid could condense with one molecule of aldehyde forming
a pyridine compound.
o HMY Y10. H
\,- 2 C HO º, **-ºs,
A “scº "..., " " —c.
* – I Wºº- t", *06 C. H.
W. The 3 carbon a tom of the acid and the amino group
could react giving a derivative of pyrrole.
tº - T Y 03.
\t, 2 c tº H\}, 3 = 2
- | → 1 \ y li
h N C HO tº cºcooch, * Sol, cool,
In a preliminary conden sation between molecular quanti-
ties of sodium nitromalonic aldehyde and B -alanine ethyl
ester hydrochloride, a yellow precipitate appeared in the
aqueous solution. This product analyzed for G8Blowz04, 8.
formula which excluded, at once, all consideration of


-22-
possibilities I and II. Formula one was also excluded
because the substance at hand did not give a test for a
free aldehyde. An examination of the five possible formulae
shows that III, IV and W are the same empirically, GsHlo"20 º
In formula III we might expect a free amino group but this
was proved to be absent by negative tests with the carbylamine
reaction. The presence of a possible 2-amino-cyclopentadiene
is therefore excluded from further consideration.
There remain for discussion the possibilities IV and W.
Formula IV would indicate a 3 -nitro-P -carbopyridinic
acid. Such a compound has not been mentioned in the liter-
ature. However, judging from the general characteristics
of the carboxylic acids of pyridine and also from the nitro-
carbopyrrolic acids, we should expect that, upon heating,
8, compound of this type would liberate carbon dioxide and
give as residue a º -nitropyridine.'”
º \\
2 < \ C
MQ, C \c-coo Hº- mºſ Sea
1.
| | — CO., f 'll
º º
The condensation product failed to give any such result
when heated, Further tests for the presence of a pyridine
ring in the condensation product were negative. Methyl
iodide failed tâ give the expected addition product and the
ferrous sulphate test was negative • -
As a result of the various tests which gave negative

results we were led to adopt formula W - the pyrrole structure -

for the condensation product and with this formula in mind,
we proceeded to study its properties. The first test used
to identify the compound was the pine shaving test. We ob-
tained the characteristic pyrrol red coloration. This indica-
tion, therefore, led us to assume at once the condensation
product had the structure given by formula W and is the ethyl
ester of *-nitro-º-ºrry, acetic acid.
W0s. C — C. *
|| ||
* Cº-C-C tº- ( 00 c. -
Y\\\ ti,
In the study of a compound of the type just mentioned,
it was thought interesting to attempt to oxidize off the chain
substituent and leave in its place the carboxyl residue. In
case such a reaction could be affected, the oxidation product
f A-
would be the º -nitro- * -carbopyrrolic acid mentioned by
Andrelina") and by Hale and Hoyt.(*9)
H. C. c \\
\, g –c H U
| | → H, 0 t c 0, + U ºn
\\ C. c-c\, cooh. \{\
^^\\
ciamician and silber” attempted to oxidize a similar
compound, nitropyrryl méthyl ketones \)
D. a. A U. a "U".
t * “". HC ** “We \\\\ . 3.
but no corresponding glyoxylic or carbopyrrolic acid could
be obtained. We were not at all surprised to find that
our compound resisted all attempts of oxidation, although
with certain reagents, decomposition, not oxidation, took
place. When the condensation product was dissolved in strong

alkali a fundamental change occurred and the odor of an

-24-
isonitrile was ra- In the many attempts that have
been made to oxidize this condensation product, it should
be noted that the strong reagents such as permanganate,
dichromate, persulphate and the like were too drastic, even
in very dilute solution. The less active agents, such as
hydrogen peroxide, ferric axide, ferric chloride, and dilute
nitric acid had no definite effect upon the material. The
action of the mild oxidizing medium, potassum ferrocyanide,
was negligible • Since these attempted oxidations were futile,
we did not continue the work trying to obtain the 3-nitro-
* ecarbopyrrolic acid.
In a study of the condensation product itself, one of
the first difficulties encountered was that this pompound,
an ester could not be saponified readily without a further
decomposition taking place. Even when very dilute weak
alkalies were used the same decomposition occurred before
the system was made acid. The oily residue obtained by ethyl
acetate extraction gave crystals after long standing. These
crystals melted at 188° and liberated carbon dioxide from
a solution of sodium carbonate • All of the brown oil which
was left by the evaporation of the ethyl acetate did not
crystallize. If some of the crystals which did come out of
this residue were melted, carbon dioxide was evolved and
the residue was an oil, in all respects, similar to the
non-crystallizing substance from the ethyl acetate extraction.
We assumed, therefore, that this oil is the methyl nitropyrrole

which would remain after carbon dioxide had been eliminated
from *-nî wo-º-eyrryl acetic acid
cA wº-c-c"
| | – C () + (l || º
\\CºS-CW, too A * | \,8-ch,
\\\\ YA
\\ 1 cº-
Evidently, since the acid is always accompanied by this oil
and when decomposed leaves the oil as a residue, the free
acid is incapable of existing as such in an alkaline solu-
tion and is decomposed.
We did not determine the accurate boiling point of
º -nitro- (-methyl pyrrole. We found that this methyl
derivative, as with the acetic acid derivative mentioned
above, resisted all attempts of oxidation • We had hoped to
oxidize the X-methyl substituent to the carboxyl and thus
f
obtain the B-nitro- %-carbopyrrolic acid discovered by
Andrelini. -
\tic–s" *i-fi."
| "... a svº-c to H
\\ * 3 W. H.
The acid amide of B-nitro-º-pyrryl acetic acid ethyl
ester was prepared by passing dry ammonia gas into an
alcoholic solution of the ester. The introduction of ammonia
turned the solution a deep red, and upon spontaneous evapora-
tion, there appeared a red oil which after many days separated
into red plates melting at 65°. This product gave a Hofman
test for the primary amine.

MU*. c.A.A -> *Aé CH
U..., { ºvcon H,
\\\\ WR

-26-
If the preceding compound is the acid amide then upon boil-
ing with a mineral acid there should be liberated free
/
P-nitro-3-pyrryl acetic acid. Experiments gave us the
/
expected results and we obtained the ſ -nitro-º-pyrryl
acetic acid (m.p. 188°).
ww.c-ch
*T)jº || ||
* H 0} 7 - I - -
\\, we 2. t{- Coot,
w ºc-‘tº, om
^^\\ Yºº
We now attempted the reduction of the nitro group in
order to study the derivatives of *-amino- *-methyl
pyrrole • It was found that reduction was best affected
by hydrogen sulphide in alcoholic ammonia solution, other
reagents being too drastic • The introduction of ammonia
gas into an alcoholic solution of the ester produced the
ańid amide and the subsequent saturation with hydrogen
sulphide brought about the reduction. When hydrogen sulphide
was passed into the red ammonical solution of the acetamide
of nitro-pyrrole, the color changed to a dark brown. This
solution was allowed to stand for several days and then
allowed to evaporate spontaneously. From the gray crystalline
residue extraction by means of carbon tetrachloride gave
yellow plates melting sharply at 123°. This material
did not give a test for nitrogen, however, the gray erystal-
line mass which remained after extraction with carbon
tetrachlori de did give the primary amine test. This gray
product melted sharply at 192°; was practically in-soluble
in all reagents; did not give the fine shaving test for the

pyrrole nucleus and evidently contained sulphur 3. We did

-27 -
not continue the work on the identity of this compound.
From these foregoing statements it will be seen that the
solid, crystalline products which result when ſº-nitro-
* -pyrryl acetic acid is reduced in ammonia solution with
hydrogen sulphide are not the desired amino pyrroles. We
now investigated the mother liquor from which the crystalline
products were obtained. When the alcoholic ammonia solution
was evaporated a red oil similar to that obtained in the -
preparation of the Q-awe-a-wºrry, acetamide was ob-
tained - Evidently all that remained in the solution than
was the unchanged nitro pyrryl acetamide.
The condensation product gave all the characteristic
tests the C-alykl pyrrol derivatives. The possibility
of acyclopentadiene structure drops out, as well as the more
probable pyridine compound. It was hoped that by the use
of B -aminopropionic acid we should be able to prepare the
hither to unknown nitro-carbopyridinic acid by involving
the amino group and the C(-methylene group - Possibly, the
influence of the carbethoxyl group is not sufficient to
cause the methylene group adjacent thereto, to enter the
reaction. It will remain for future work to determine the
activating influence of the carbethoxyl group upon a con-
tiguous CH2 group - Also, it may be that the effect of the
carboxyl grºat those methylene groups not adjacent to
it are more readily involved. But working under the con-
àitions by which the compound just discussed was made, it
is evident that the pyrrole formation is the most favored and
that this derivative is formed to the exclusion of all other
possibilities.
-28-
III. EXPERTMENTAL PART.
The nitromalonic aldehyde used in this work was prepared
according to the method given by Hill and Torrey”.
Furfural was oxidized to mucobromic acid by means of bromine
and the mucobromic acid was then converted into the sodium
salt of nitromalonic aldehyde by the action of sodium nitrite.
In preparing 8-amino propionic acid ester, º -alanine ester,
41
we modified Holm's } adaptation of the Hoogewerf and Van
Dorp method.”
We saw fit to prepare the hydrochloride of B -alanine
esters directly and to save time in isolating the free £-
alanine used the following methods 16 gm. of bromine were
slowly added to 500 cc. of a loſſ solution of sodium were oy
potassum hydroxide at o°. The hypobromite solution was
allowed to stand for 30 minutes in the ice bath and then lo
gm. of succinimide were slowly dissolved in it • The flask
was now removed from the ice and its contents allºwed to rise
to room temperature. The solution was slowly heated up to
50°. At 40° the yellow liquid became colorless. A tempera-
ture between 56° and 60° was maintained for two hours. The
total time required for heating was about three hours.
After the period of warming was over, the solution was
again put in ice, cooled to 0°, and made strongly acid with
concentrated hydrochloric acid. Care should be taken that
the adid is not added too rapidly and the temperature


-29-
should not rise. After acidification, the liquid was
evaporated to dryness on the steam bath; the brown crystal-
line residue washed with dry ether to remove any succinic
acid which may have been present. The § -alanine Was 110 W
extracted with a minimum amount of absolute ethyl alcohol.
A White residue of potassium chloride and bromide remained.
The alcoholic solution of 3-alanine was saturated with dry
hydrogen chloride gas and the inorganic salts, thus pre-
cipätated, were filtered off. The solution was then
evaporated, in absence of water, to a thick syrup. The
inorganic salts were again removed and after the filtrate
was cooled for several hours at -lo”, white needles of
* -aminoproptonio acid ethyl ester hydrochloride appeared.
These crystals must be filtered from a cold solution as
they are exceedingly soluble in the warm mother liquor.
The crystals were very hydroscopic and melted at 65.5°.
The yield was one gram.
The hydrochloride of methyl ester of B-alanine was
prepared in the foregoing manner by using methyl alcohol.
This compound was not as hydroscopic as the ethyl derivative
but it had a tendency to come out with the last precipita-
tion of the metallic chloride and, thus, was lost. The yield
of the methyl derivative was smaller than with the ethyl,
although the former was more easily handled after it was
once obtained a The hydrochloride of the methyl ester melted

at 90-91°.

/
º -NITRO-º-PYRRYL AGETIC ACID ETHYL ESTER, GsHlonzoa.
One gram of sodium nitromalonic aldehyde was dissolved
in 6 cc. of water and to this solution 0.8 gm. of -alanine
ethyl ester hydrochloride were added. The mixture was allowed
to stand at room temperature for 5 hours. A precipitate of
yellow needles appeared. This crude substance weighed 0.5
gm. and, after being purified, melted at 81°. The yield of
pure material was 0.3 gm. The º'-nitro- % -pyrryl acetic
acid ethyl ester was readily soluble in benzene, ligroin,
chloroform, acetone, ethyl acetate, warm water and acetic
acid; fairly soluble in cold alcohol and gold water; slightly
soluble in ether and ligroin. The product was best recrystal-
lized from 95% alcohol. The water solution was neutral to
litmus and did not liberate carbon dioxide from a sodium
carbonate solution.
Analysis.
0.1467 gm. of substance gave 19.5 cc. of moist nitrogen at
23.5° and 729.4 mm.
Calculated bo 08Hloºz84 Found
14.19
W º 14.15
B-mino- C(-PYRRYL AGETIC ACID METHYL ESTER, G7H8N2O4.
.25 gm. of sodium nitromalonic aldehyde were dissolved
in 2 cc. of water and to this solution o.15 sm. of | -amino
propionic acid methyl ester were added. The system was
allowed to stand at loº over night and then the condensation
product in large plates was filtered off. The crude product
melted at 95°. This methyl ester was readily soluble in

-31-
methyl alcohol, water and acetic acid; fairly soluble in
acetone, benzene and ethyl acetate; slightly soluble in
ethyl alcohol and insoluble in ether, chloroform, and ligroin.
(3-nitro- *( -pyrryl acetic acid methyl ester was best
recrystallized from methyl alcohol and the pure product melted
at 112°. A
We sought to oxidize 3-nitro- 0 -pyrryl acetic acid
ethyl ester to its corresponding 3-nitro- * -carbopyrrolic
acids. The first method of oxidation attempted was by alkali
fusion • When the ester was dropped upon the molten potassium
hydroxide, the substance caught fire. The odor of an
isoni trile was detected. Oxidation by sodium peroxide
was unsuccessful although the base, liberated when sodium
periºxide was placed in water, was of sufficient strength to
decompose the ester. Hydrogen peroxide had no effect whatever.
It was found that potassium dichromate in sulphuric acid
and in acetic acid was too strong a reagent for such a re-
action and the ester was changed in such a way that no
crystalline oxidation product could be obtained. When the
dichromate was used in acetic acid solution the color was
changed. This reduction was evidently due to the oxidizing
of some of the acetic acid. If the reaction were stopped
when the first green color appeared, no oxidation product
could be isolated a The unchanged ester could not be re-
covered from this system.
By the use of potassium permanganate we failed to get
any oxidized derivative • Apparently acid permanganate was


too drastic. Hsing a neutral solution there was no color

-32-
change and when the excess acetone, used as a solvent,
was distilled off, nothing could be extracted from the resi-
due • When alkaline permanganate was tried an odor of isoni trile
was noticed. There was no color change in the solution.
When ammonium persulphate was tried the result was
negative • With ferric chloride in acetic acid solution, no
oxidation product could be isolated due to the large amount
of ferric hydroxide that was formed. When the ester was
treated with cold dilute nitric acid no reaction to ok place .
If the ester were heated with nitric acid, sp. gr. 1.5l,
the characteristic isonitrile odor was evolved but no oxida-
tion product could be isolated. The nearest approach made
toward oxidation was with potassium ferriyanide and potassium
hydroxide. Q32 gm. of ester were heated with l gm. of
Kaf (CN)6 and o.5 gm. KOH in 20 cc. for two hours with a
free flame. The solution became yellow and a flocculent pre-
cipitate appeared, The contents of the flask were cooled
and acidified with hydrochloric acid. Hydrogen cyanide was
evolved in large quantities and the solution became deep
blue showing that reduction had taken place • The liquid
was now evaporated to dryness on the steam bath and the
solid remaining was extracted with ethyl acetate. When
the ethyl acetate had been evaporated the solid residue was
washed with ether. The ºther extract gave a dark colored
solid which melted at about 2009. All attempts to repeat
this experiment failed although the conditions were varied

in all possible ways •

-33-
2
§ -NITRo-º-Merity. PyRRYE AGEric acid, C6H6N2O4 •
0.2 gm. of B-nitrºgyrryl acetic acid ethyl ester were
dissolved in 5 cc. of N barium hydroxide and the solution
let stand 2-3 hours. #. solution was now made strongjºy acid
with 1:10 sulphuric acid. The barium sulphate was filter ed
off and the solution extracted with ethyl acetate. The
ethyl acetate was allowed to evaporate spontaneously and
an oil remained. From this heavy yellow oil crystals finally
separated. This product was taken up in water from which
it was easily recrystallized. The pure Gyrystals melted
sharply at 188°. 3-nitro-ºº-wºrn acetic acid is readily
soluble in hot alcohol, acetone and ethyl acetate • It is
fairly soluble water, ether and carbon tetrachloride; in-
soluble in benzene, ligroin and chloroform. This compound
was readily recrystallized from water in yellow flakes. A
water solution liberated carbon dioxide from a sodium carbonate
solution. the silver salt of the acid is soluble in water.
A preliminary analysis, while not accurate enough for publica-
tion, conforms to the formula assigned to the free acid.
6-mirro- % -METHYL PYRROLE, GBH, N202.
This oil appeared along with the free 3-nitro-º-pyrryl
acetic acid and could not be crystallized. It is fairly
miscible with water, and readily miscible with the ordinary
reagents. The boiling point lies above 200° but we could
not determine: it accurately since our oil apparently contained
an impurity which caused decomposition • Gombustibn analyses
did not check sufficiently well to warrant their publication.



ſ
º -NITRO-º-PYRRYL AGETAMIDE, Cºngog.
0.2 gm. of *-nitro- * -pyrryl acetic acid ethyl ester
were dissolved in 5 cc. of 95% alcohol and dry ammonia gas
passed in. The addition of the gas produced a deep red color.
Spåntaneous evaporation of this red solution left a red oil
which crystallizedon long standing. These crystals melted at
65°. The amide was readily soluble in alcohol, acetone, ethyl
acetate and water, slightly soluble in chloroform, and in-
soluble in ether benzene, ligroin and carbon tetra chloride.
It crystallized best from ether and the pure crystals melted
at 65°. It was very difficult to isolate this free body and,
consequently, no analyses were made •
ſ
º –AMINo- + -PYRRYL AGETAMIDE, GsH3N20.
0.2 gm, of -nitro- -pyrryl acetic acid ethyl ester
were dissolved in alcohol and dry ammonia gas passed in until
the solution became dark red. Hydrogen sulphide was now
led into the solution and the color became dark grown. The
flask was now stoppered and let stand a few days and then a
crop of long gray needles appeared. These crystals melted
at about 200°. It was found that this compound was prac-
tically insoluble in all reagents. Boiling with dilute hydro-
chloric acid or with dilute sodium carbonate had no effect
on the compound. However extraction with carbon tetra-
chloride gave a yellow crystalline product which melted at
1239. The insoluble portion melted at 192°. The product
melting at 123° did not contain nitrogen but the higher


-35-
melting fraction gave a carbylamine test and was evidently
an amino compound. It did not give the fine shaving test,
for pyrrole. However, on account of the insolubility of
this material, we did not deem it advisable to continue work
on the identity of compound at this time. Analysis showed
the nitrogen content to be 15-20%.

-36-
SUMMARY.
In this investigation it is shown that nitromalonic
aldehyde can be involved in a condensation with p-amino-
propionic acid ester in such a way that only one compound
is formed. The production of this substance, a P-nitro-ºx
pyrryl acetic acid derivative, shows that only the B-methylene
and amino groups of the acid ester are brought into conden-
sation. It is found that the free 3-nitro-w -pyrryl acetic
acid is somewhat unstable and when heated or decomposed by
alkalies goes over into another new compound, methyl nitro-
pyrrole. The properties of these two classes of substances
are studied. It is shown that the º -alkyl substituent on
8. º -nitropyrrole nucleus is resistant to all oxidizing
reactions •


10
ll
l2
13
14
15
16
17
18
19
2O
21
22
23
24
25
-2'-
BIBLIOGRAPHY,
Iubavin,
Bell
Bell
Bell
Weidel & Ciamician
Ciamician & Dennistedt
Ciamician
Schwanert
Ciamician & Silber
Schiff
Giamician & Dennstedt
Ciamician & Dennistedt
Giamic ian & Silber
Ciamician & Magnaghi
Giamician & Zanetti
Pictet & Cripieux
Ciamician & Silber
Oddo
Angeli & Alessandri
Hale & Hoyt
Ciamician & Silber
Ciamician & Silber
Giamician & Silber
Ciamician & Silber
Weidel & Giamician
Ber. 2, lol (1869).
Ber. 9, 935 (1876).
Ber. 10, 1866 (1877).
Ber, ll, 18ll (1878).
“Ber. 13, 75 (1880).
Ber. 17, 2959 (1884).
Ber. 14, 1056 (1881).
Ann - der. Chem. lló, 274 (1860).
Ber. 19, 1408 (1886).
Ber, 10, 1500 (1877).
Ber. 16, 2348 (1883).
Ber. 17, 2949 (1884).
Ber. 18, 881 (1885).
Ber. 18, 1828 (1885).
Ber. 22, 2518 (1889).
Ber. 28, 1905 (1895).
Ber. 20, 698 (1887).
Ber. 43, l012 (1910).
R.A.L. (5), 20, I, 311 (1911).
J. Am. Chem. Soc. 37, 2538 (1915).
Ber. 18, 413 (1885)
Ber. 18, 1456 (1885).
Ber. 18, 879 (1885).
Ber. 19, 1078 (1886).
M., I 279 (1880).

26
27
28
29
30
3l
32
33
34
35
36
37
38
39
40
4l
42
Ciamician
Giamician & Silber
Giamician & Silber
Bamberger & Djerdjian
Oddo
Ciamician & Dennistedt
Giamician & Silber
Piloty.
Piccinini
Weidel & Ciamician
Ciamician & Silber
Andrelini
Hale & Brill
Fried
Hill & Torrey
Holm
Hoogewerf & Wan Dorp
Ber. 14, 1056 (1881).
Ber. 17, 1150 (1884).
Ber. 17, 1437 (1884).
Ber. 33, 536 (1900) .
Gazz. Chim. 39, I, 649 (1909).
Ber. 17, 2944 (1884).
Ber. 19, 14ll (1886).
Ann. der Chèm. 366, 245,255 (1909).
Gazz. Chim. 29, I, 363 (1899).
Gazz. Chim. l.2, 39 (1882).
Ber. 19, 1080 (1886) .
Gazz. Chim. 19, 20, 330 (1889).
J. Am. Chem. Soc. 34, 82, (1912).
Ber. 45, 428, (1912).
Amer. Chem. J. 22, 25 (1899).
Arch. der Pharm. 242, 590 (1904) .
Rec. d. Trav. de Pays bas. 10,4 (1891)

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