Flame-induced addition of urea to unsaturated carboxylic acids

Article abstract of DOI:10.1246/bcsj.75.855

When a hydrogen-oxygen flame was blown against an aqueous solution of urea and maleic acid, N-carbamoylaspartic acid was generated. This compound seemed to be formed by the addition of an amidinoxyl radical to a C-C double bond of the acid, followed by a thermal rearrangement of an amidinoxy to a ureido group.

Full text of DOI:10.1246/bcsj.75.855

c. Jpn.
Bull. Chem. Soc. Jpn., 75, 855–856 (2002)
855
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Short Articles
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Flame-Induced Addition of Urea to
Unsaturated Carboxylic Acids1
M. Terasaki et al.
Masanori Terasaki, Shinya Nomoto,* Hajime Mita,
and Akira Shimoyama*
02
5
6
Department of Chemistry, University of Tsukuba,
Tsukuba 305-8571
SJA8
09-2673
1039
(Received November 1, 2001)
Fig. 1. Time-course plots for flame-induced reaction of urea
with maleic acid. The yield of the initial product was ten-
tatively estimated by using mol/area ratio of N-carbamoyl-
aspartic acid (CM-Asp) in LC–MS analysis.
01
01
When a hydrogen-oxygen flame was blown against an
aqueous solution of urea and maleic acid, N-carbamoylaspar-
tic acid was generated. This compound seemed to be formed
by the addition of an amidinoxyl radical to a C–C double
bond of the acid, followed by a thermal rearrangement of an
amidinoxy to a ureido group.
through the jacket of the reaction vessel. At 30-min intervals, a
1-mL aliquot of the solution was withdrawn and analyzed by
LC-MS.
Figure 1 shows time-course plots for the flame-induced re-
action. The concentration of urea decreased very slowly, indi-
cating its low reactivity to a hydroxyl radical, while maleic
acid was decomposed almost completely within 3 h, possibly
due to the high radical reactivity of a C–C double bond, which
is known to be oxidatively decomposed by a hydroxyl radical.
The expected product, N-carbamoylaspartic acid (CM-Asp
(5)), was detected, as shown in Fig. 2. Since CM-Asp was not
detected in the aqueous solution of urea and maleic acid after
refluxing for 2 h, this amino acid derivative seemed to be
formed through a radical reaction of the starting materials. On
the other hand, another product, which was proved to have the
We had found that a hydrogen–oxygen flame, when kept in
contact with an aqueous solution, can supply a hydroxyl radi-
cal and a hydrogen atom into the solution.2,3 The flame-in-
duced reaction is unique in view of the fact that radicals gener-
ated in a gas phase react directly with compounds in a water
phase, and, therefore, this technique provides a clean reaction
system without using any radical-generating reagents. Taking
into account the short lifetimes of the radicals, the reaction
zone in a solution must be limited to the vicinity of the solution
surface exposed to the flame. However, the flame supplies rad-
icals continuously into the solution and affords an effective
radical reaction system. Furthermore, the flame-induced reac-
tion has the advantage of permitting suppression of vigorous
oxidation due to a hydroxyl radical by using hydrogen-rich
flames, in contrast to the previously reported methods of gen-
erating radicals in the water phase by means of an electric
discharge4 or an arc plasma.5
In the course of our study on the role played by urea in the
prebiotic formation of biomolecules on the primitive Earth, we
revealed an excellent feature of urea as a nitrogen source in the
nitrogen-incorporating thermal condensation of unsaturated di-
carboxylic acids producing polyaspartic acid.6 Our present in-
terest is aimed at an elucidation of the radical reaction of urea
leading to the formation of amino acids or related compounds
in water solution. We therefore performed a flame-induced re-
action of urea with unsaturated carboxylic acids in this study.
Although N-halogenated amides and urethanes had been re-
vealed to add to olefins with the aid of UV light to afford their
N-(2-haloethyl) derivatives,7,8 no reports had appeared which
discuss radical reactions of urea with olefins.
Fig. 2. [M + 1]+ Mass fragmentograms (m/z = 177) of
flame-induced reaction products from urea and maleic acid
after exposure to H2–O2 flame for 1 h (a) and for 30 min
(b), heating product of 30-min flame-induced reaction mix-
ture (c), and the authentic sample of N-carbamoylaspartic
acid (d). LC column: TSK gel Amide-80 (Tosoh Ltd.), elu-
ent: MeOH–H2O (99:1).
A hydrogen–oxygen flame (3.2 l min−1 of H2, 0.8 l min−1 of
O2) was blown against the surface of an aqueous solution (200
mL) of urea (0.005 M) and maleic acid (0.05 M) by using a
previously reported apparatus.2 The temperature of the reac-
tion mixture was maintained at 60 °C by circulating cold water

856 Bull. Chem. Soc. Jpn., 75, No. 4 (2002)
© 2002 The Chemical Society of Japan
Scheme 1. Asp: aspartic acid.
Scheme 2. β- and γ-Abu: β- and γ-aminobutyric acids.
the heating produced derivatives of these amino acids. α-Ami-
nobutyric acid was not detected in the hydrolyzate, indicating
that migration of the C–C double bond of compound 6 to the 2,
3-position did not occur during the flame-induced reaction.
The predominance of γ-aminobutyric acid in the product
seemed to be reasonable in view of the higher stability of pos-
tulated intermediate radical 7 than that of 8, considering hyper-
conjugation of the radicals. These results are consistent with
the proposed radical mechanism of the reaction of urea with
unsaturated carboxylic acids, including the addition of 2 to a
C–C double bond as well as a thermal rearrangement of an
isourea to a urea compound.
In conclusion, we found a new feature of the reactivity of
urea to olefin. Urea had been probably present on the primitive
Earth,9,10 and unsaturated carboxylic acids have been found in
meteorites11 as well as in the products of electric discharge ex-
periments using methane9 as a carbon source. This study pro-
poses a novel pathway leading to formation of amino acids
from non-amino acid precursors, possibly effected by energy
sources, such as solar wind, UV-light, lightning, and so forth,
on the primitive Earth. The formation of ureidocarboxylic ac-
ids is of another significance, since they are capable of under-
going thermal polymerization,6 resulting in the formation of
polyamino acids.
same molecular weight as that of CM-Asp (Fig. 2a), was de-
tected only at the initial stage of the reaction. Because this
product was rather unstable, we failed to isolate it from the re-
action mixture. Therefore, it was possible to consider that this
compound was the initial product, which was further trans-
formed into CM-Asp by the action of radicals or heat. To con-
firm this, we heated the reaction mixture under reflux for 1 h
after exposure to the flame for 30 min, and observed a decrease
in the initial product, along with an increase of CM-Asp (Figs.
2b and 2c). We further hydrolyzed the reaction mixtures be-
fore and after heating, and analyzed the amino acids in the hy-
drolyzates. An evidently larger amount of aspartic acid was
found in the hydrolyzate after heating.
From these results, we postulated the mechanism of the
flame-induced reaction to be as follows: a hydroxyl radical
from the flame abstracts a hydrogen atom from urea to give a
ureido (1) and an amidinoxyl radical (2) (Scheme 1), and then
radical 2 adds to maleic acid to form an isourea derivative,
whose structure was assumed to be 4 based on its molecular
weight. Compound 4 underwent a rearrangement by the action
of heat, producing CM-Asp (5). An amidinoxy group is
known to be a good leaving group in substitution reaction, as
exemplified by the fact that heating of O-methylisourea hydro-
chloride affords urea and methyl chloride. We also confirmed
a conversion of O-methylisourea into N-methylurea by reflux-
ing an aqueous solution of commercial O-methylisourea sul-
fate for 1 h in the presence of triethylamine. The conversion of
4 into 5 is likely to be an intramolecular reaction, since it pro-
ceeded in a very dilute solution. In a separate experiment, in
which the same starting mixture as that used in this study was
irradiated with 172-nm UV light at 25 °C, only compound 4
was generated, supporting the idea that a direct addition of rad-
ical 1 to 3 does not occur.
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