Efficient Non-Catalytic Carboxylation of Diamines to Cyclic Ureas Using 2-Pyrrolidone as a Solvent and a Promoter

Article abstract of DOI:10.1002/adsc.201800945

Carboxylation reactions of diamines were found to proceed rapidly and non-catalytically, producing corresponding cyclic ureas in excellent yields and selectivities when 2-pyrrolidone (2-PY) was used as a solvent. A similar promoting effect with 2-PY was also observed for the carboxylation of monoamines by carbon dioxide (CO₂). Most notably, the carboxylation reactions of mono- and diamines conducted in 2-PY afforded 2–4 times higher yields of corresponding dialkyl ureas and cyclic ureas compared with those in N-methyl-2-pyrrolidone (NMP). Such a dramatic promoting effect using 2-PY is believed to be associated with the multiple hydrogen bonding interactions between 2-PY and the CO₂-containing species of amines. Due to such favorable interactions, carboxylation reactions seem to be more facilitated in 2-PY than in NMP. (Figure presented.).

Full text of DOI:10.1002/adsc.201800945

Title: Highly Efficient Non-Catalytic Carboxylation of Diamines to Cyclic
Ureas Using 2-Pyrrolidone as a Solvent and a Promoter
Authors: Junhyeok Hwang, Donggu Han, Jin Joo Oh, Minserk Cheong,
Hyun-Joo Koo, Je Seung Lee, and Hoon Sik Kim
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800945
Link to VoR: http://dx.doi.org/10.1002/adsc.201800945

Advanced Synthesis & Catalysis
10.1002/adsc.201800945
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Highly Efficient Non-Catalytic Carboxylation of Diamines to
Cyclic Ureas Using 2-Pyrrolidone as a Solvent and a Promoter
1
1
Junhyeok Hwang, Donggu Han, Jin Joo Oh, Minserk Cheong, Hyun-Joo Koo, Je
Seung Lee* and Hoon Sik Kim*
Department of Chemistry and Research Institute of Basic Sciences, Kyung Hee University, 26 Kyungheedaero,
Dongdaemun-gu, Seoul 02447, Republic of Korea
Tel: (+82)-2-961-0432; (+82)-2-961-0458
Fax: (+82)-2-959-6443; (+82)-2-961-0443
E-mail: khs2004@khu.ac.kr; leejs70@khu.ac.kr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201XXXXXX
Abstract: Carboxylation reactions of diamines were found to proceed rapidly and non-catalytically, producing
corresponding cyclic ureas in excellent yields and selectivities when 2-pyrrolidone (2-PY) was used as a solvent. A
similar promoting effect with 2-PY was also observed for the carboxylation of monoamines by carbon dioxide (CO ).
2
Most notably, the carboxylation reactions of mono- and diamines conducted in 2-PY afforded 2-4 times higher yields of
corresponding dialkyl ureas and cyclic ureas compared with those in N-methyl-2-pyrrolidone (NMP). Such a dramatic
promoting effect using 2-PY is believed to be associated with the multiple hydrogen bonding interactions between 2-PY
and the CO
2
-containing species of amines. Due to such favorable interactions, carboxylation reactions seem to be more
facilitated in 2-PY than in NMP.
2
Keywords: Cyclic ureas; CO utilization; Diamines; Carboxylation; Tautomerization
NH
.[7] However, the urea processes possess several
3
Introduction
drawbacks such as the formation of large amounts of
water-insoluble by-products and the equipment
corrosion arising from the handling of aqueous
The direct carboxylation of diamines to cyclic ureas
is considered to be one of the most promising routes
for the transformation of carbon dioxide into valuable
chemicals.[ Of various cyclic ureas, ethylene urea
[8]
ammonia solutions. Nonetheless, the urea process
should not be disregarded because the process could
be more competitive to other processes in terms of
material cost and energy consumption.
1]
(
imidazolidin-2-one) finds uses as an organic
[2]
intermediate in various chemical industries. In
particular, dimethylol ethylene urea, a condensation
product of ethylene urea and formaldehyde, is used as
an effective cross-linking agent for the treatment of
cellulose-based fabrics and papers to inhibit wrinkle
formation.[ Ethylene urea is also used as a
scavenging agent to reduce the free formaldehyde
content in phenolic, melamine, glyoxal and urea
formaldehyde resin systems for coatings, construction
Catalytic carboxylation processes employing CO
as a carbonyl source have also been investigated
2
[1a,9]
intensively.
As a result, numerous homogeneous
and heterogeneous catalysts and catalytic systems
have been developed, including triphenylantimony
3]
oxide/phosphorous pentasulfide (Ph
3
SbO/P S10),
4
tetramethylphenylguanidine/diphenylphosphoryl
azide
(PhTMG/DPPA), tungsten-based
(TBA [WO ]), potassium
polyoxometalates
2
4
[4]
and textile industries. Ethylene urea finds additional
applications in the pharmaceutical industry; as an
intermediate in the synthesis of a variety of new
antibiotics, such as mezlocillin acid and azlocillin
acid,[ as an intermediate in anti-schistosomiasis
drugs and as a basic material for the synthesis of
hydroxide/polyethylene glycol (MW = 1000), and
activated CeO
[1a,9b,9d-9f]
2
.
However, most of the
catalysts reported so far need further improvement
with regard to the activity, stability and/or
recyclability for their practical applications. Non-
catalytic carboxylation processes have also been
attempted, but they often require harsh reaction
conditions to obtain reasonable cyclic urea yields,
5]
[6]
third-generation penicillin derivatives.
Cyclic ureas have been industrially manufactured
by reacting diamines with urea under harsh
o
including high temperature of around 250 C as well
o
[2b,10]
conditions at around 250 C, followed by quenching
as high pressures.
the resulting melt with water to give aqueous
solutions containing the desired cyclic urea and
Recently, we have reported that alkali metal
carbonates and alkali metal bicarbonates are also
effective catalysts for the synthesis of cyclic ureas
1
These authors equally contributed.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
from the carboxylation of diamines in N-methyl-2-
pyrrolidone (NMP), and the yields of cyclic ureas can
be greatly enhanced by the addition of small amounts
of ethylene urea as a promoter. Computational
calculations suggest that catalyst-assisted keto-enol
tautomerization of the ethylene urea is responsible for
the increase of the cyclic urea yields.[11]
can be seen in Table 1, the carboxylation of EDA in
2-PY proceeded almost quantitatively in the presence
of K
2
CO
3
or Cs
2
CO , affording ethylene urea in
3
yields of 98.1 and 99.0%, respectively (entries 9 and
10).
Carboxylation of different amines
Being motivated by this result, we have
investigated the effects of various tautomerizable
compounds on the carboxylation of diamines. In this
work, we report that cyclic ureas can be obtained in
high yields and selectivities from the non-catalytic
carboxylation of diamines using 2-pyrrolidone (2-PY)
as a solvent.
The carboxylation reactions of two propanediamine
(PDA) isomers, 1,2-propanediamine (1,2-PDA) and
1,3-propanediamine (1,3-PDA), were also conducted
o
in NMP and 2-PY at 200 C for 2 h. As with EDA,
the promoting effect of 2-PY was also observed in the
carboxylation of 1,2-PDA and 1,3-PDA, yielding 4-
methylimidazolidin-2-one and 1,3-diazinan-2-one,
respectively. As shown in Table 1, the yields of 4-
methylimidazolidin-2-one and 1,3-diazinan-2-one
were found to increase from 33.5 and 34.1% to 93.3
and 95.1%, respectively when NMP was replaced by
Results and Discussion
Synthesis of cyclic ureas
2
-PY (entries 4, 5 and 11, 12).
The non-catalytic carboxylations of ethylene diamine
The promoting effect of 2-PY was further
(
2
EDA) by CO
2
were conducted in various solvents at
demonstrated in the carboxylation of monoamines.
o
00 C and 5 MPa for 2 h. As shown in Table 1, the
The carboxylation reactions of n-butylamine (n-BA)
o
carboxylation of EDA in NMP produced ethylene
urea in a yield of 21.1%. Surprisingly, the yield of
ethylene urea increased dramatically by about 4 times
from 21.1 to 83.0% when 2-PY was used as the
solvent instead of NMP. The ethylene urea yield of
and cyclohexylamine (CHA) in NMP at 170 C
produced the corresponding dialkylureas, 1,3-
dibutylurea and 1,3-dicyclohexylurea, in low yields
of 8.8 and 2.5%, respectively (entries 6 and 7). In
contrast, the yields of 1,3-dibutylurea and 1,3-
dicyclohexylurea increased to 37.0 and 16.0%,
respectively (entries 13 and 14) in 2-PY, confirming
the beneficial role of 2-PY in the carboxylation of
amines.
8
3.0% is even 9.6% higher than the yield achieved
from the catalytic carboxylation reaction conducted
in NMP using Cs CO , one of the most active
2
3
carboxylation catalysts currently known (Table 1,
entry 3). The yield of ethylene urea was further
increased when the carboxylation of EDA was
conducted in 2-PY with a catalyst. For instance, as
Spectroscopic investigation
To understand the excellent promoting effect of 2-PY
Table 1. Effect of solvent on the carboxylation reaction of
on the carboxylation of diamines, the CO absorption
2
[a]
mono- and diamines by CO
2
.
behavior of a diamines in 2-PY and NMP was
investigated. To this end, 1,2-PDA is chosen as the
Entry Solvent Amine
Catalyst
-
Cyclic urea
yield (%)
21.1
48.2
73.4
33.5
34.1
8.8
diamine because its CO adduct (I) is highly soluble
2
1
2
3
4
5
6
7
8
9
NMP
2-PY
EDA
EDA
EDA
1,2-PDA
1,3-PDA
n-BA
CHA
EDA
EDA
EDA
1,2-PDA
1,3-PDA
[
[
b]
b]
2 3
K CO
Cs
2
CO
3
-
-
-
-
-
[
c]
[
c]
2.5
83.0
98.1
99.0
93.3
95.1
37.0
16.0
5.8
[
[
b]
K
2 3
CO
b]
1
0
1
2
3
4
5
6
Cs
2
CO
3
1
1
1
1
1
1
-
-
-
-
[
c]
n-BA
CHA
EDA
1,2-PDA
[
c]
[
b]
CH
3
OH
K
K
2
CO
CO
3
[
b]
2
3
6.7
[
a]
Reaction condition: amine (100 mmol), PCO2 = 5 MPa,
o
reaction temperature = 200 C, reaction time = 2 h.
Molar ratio of diamine/catalyst was set at 100.
Reaction temperature = 170 C, reaction time = 4 h.
[
[
b]
c]
Figure 1. CO
and at 30 kPa CO
2
absorption capacities of 1,2-PDA at 313 K
in NMP (-●-), and 2-PY (-○-).
o
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
1 x
Figure 2. GC-Mass spectra of (a) 2-PY, (b) 2-PY-d , (c) EDA, and (d) EDA-d .
in 2-PY although its solubility in NMP is rather poor.
As can be seen in Figure 1, the CO absorption rate in
a solution of 20wt.% 1,2-PDA in 2-PY was much
faster than that observed in NMP. The CO
absorption capacity of the 1,2-PDA solution in 2-PY
was also higher than that in NMP. Notably, the 1,2-
PDA solution in 2-PY was transformed into a
homogeneous, viscous solution upon absorption of
(I), possibly through a hydrogen bonding network.
The plot of 1/[1,2-PDA] (where, [1,2-PDA] is the
molarity of 1,2-PDA) versus time gives a straight line,
2
2
indicating that the reaction of CO with 1,2-PDA in
2
2-PY is a second order process with respect to [1,2-
PDA] (see Figure S43 in SI). The rate constant for
each absorption was obtained from the slope of the
corresponding straight line, and deuterium kinetic
CO
2
, whereas the NMP solution of 1,2-PDA became
, generating
isotope effect (k
calculated as 1.61.
H
/k
D
) for CO
2
absorption was
turbid soon after contact with CO
2
insoluble gels (see Figure S1 in Supporting
Information, SI). The only structural difference
between 2-PY and NMP is that 2-PY has a protic
hydrogen atom bonded to the nitrogen atom, whereas
NMP possesses a methyl group bound to the nitrogen
atom. Therefore, we infer that the N-H hydrogen
The proton mobility of the N-H hydrogen atom of
2-PY was investigated by gas chromatography-mass
spectrometry (GC-Mass). For this purpose, deuterated
2-PY (2-PY-d
1
) and deuterated EDA (EDA-d
x
, x = 1
~ 4) were synthesized by allowing D
2
O to interact
with 2-PY and EDA for 2 h, respectively. As shown
in Figure 2, deuterium incorporation into EDA was
atom of 2-PY is responsible for the higher CO
2
absorption rate and capacity in 2-PY than observed in
NMP.
clearly observed after 2-PY-d
Such H-D exchange was also found to take place for
the interaction between EDA-d and 2-PY (see Figure
1
interacted with EDA.
To gain a profound understanding of the role of 2-
x
PY during the CO
/k
As expected, the CO
2
absorption, kinetic isotope effect
2). H-D exchange studies with deuterated 2-PY and
EDA using mass spectrometry demonstrate that 2-PY
is capable of forming a hydrogen bond network
through its peptide group, which could be beneficial
to the carboxylation reaction of EDA. As expected,
(
k
H
D
) was studied. (see Figure S42 and S43 in SI).
absorption rate in a 1,2-PDA
2
solution in deuterated 2-PY was significantly slower
than that in un-deuterated 2-PY. It is likely that the
N-H hydrogen atom of 2-PY contributes to the
formation and stabilization of the carbonation species
deuterium incorporation was not observed when D
2
O
was allowed to interact with NMP, which does not
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
Figure 3. FT-IR spectra of (a) I, (b) 2-PY, (c) 20wt% I in 2-PY, (d) NMP, and (e) 20wt% I mixed with NMP.
possess a protic hydrogen atom. The GC-Mass results the carboxylation of diamines and leading to cyclic
again support that the presence of the protic N-H ureas.
hydrogen atom of 2-PY contributes to the acceleration
The hydrogen bonding interaction of 2-PY with
of the carboxylation of amines. However, the yield of the carbonation species (I) was further investigated by
ethylene urea in a protic solvent, methanol was found FT-IR spectroscopy. Figures 3(a) - (e) are the IR
to be extremely low below 7% even in the presence of spectra revealing interactions of I with 2-PY and
-1
a catalyst (Table 1, entries 15 and 16). These results NMP. The absorption peaks at 1560 cm in Figure
-1
strongly suggest that the presence of a labile proton in 3(a) and 1675 cm in Figure 3(b) can be assigned to
a solvent molecule is necessary, but not sufficient to the carbonyl stretching frequencies of I and 2-PY,
be a good solvent for the carboxylation of respectively. Upon dissolution of 20wt% I in 2-PY,
diamines.[ Comparison of the reactivity of EDA in the carbonyl peak of I shifted by 35 cm to a higher
11]
-1
-1
methanol, NMP, and 2-PY reveals that the solvent of frequency at 1595 cm . The carbonyl peak of 2-PY
-1
choice for carboxylation should be the one which also moved by 12 cm to a higher frequency at 1687
-
1
possesses both proton donating and a proton cm , demonstrating strong interactions between I and
accepting functional groups. In this context, cyclic 2-PY.
amides bearing a peptide group could be regarded as
A similar phenomenon was also observed for the
effective solvents because they are able to function as N-H absorption peaks of I and 2-PY. As shown in
proton shuttles through tautomerization. Among Figure 3, the peaks associated with the N-H stretching
-1
various cyclic amides, 2-PY is of particular interest frequencies of I at 3296 cm was found to shift to a
-1
because it is an inexpensive and thermally stable higher frequency of 3307 cm . These results indicate
liquid. It has been reported that 2-PY can exist as a that there are multiple hydrogen bonding interactions
tautomer although the equilibrium constant for the between the ammonium group of I and the carbonyl
keto to enol transformation is extremely low at room group of 2-PY as well as between the carbonyl groups
temperature (vide infra). Nevertheless, such a keto to of I and the N-H group of 2-PY. This might suggest
enol transformation would be highly beneficial for the that the presence of a CO adduct of a diamine like I
2
carboxylation of diamines, especially when 2-PY is could assist the migration of a H atom from the N-H
present in large quantities at high temperatures to the carbonyl group of 2-PY. In other words, keto to
o
(
around 200 C) because the enol form of 2-PY can enol transformation of 2-PY may proceed via
function as a better proton donor than the keto form. interaction with I. Interestingly, the peak associated
The promoting effect of 2-PY would be more with the N-H stretching frequency of I was found to
pronounced if the enol form is stabilized by a shift to a higher frequency with increasing
carbonation species like I. It is worth mentioning here temperature, implying that the degree of hydrogen
that the carboxylation of EDA to ethylene urea bonding interaction between the ammonium group of
proceeds through [
a
series of protonation- I and the carbonyl group of 2-PY increases with
11,12]
deprotonation steps.
Therefore, the stabilization increasing temperature (see Figure S3 in SI).
of the enol form would enhance the proton donating
ability of 2-PY to a certain extent, thereby facilitating frequency at 1567 cm upon dissolution of I in NMP
The carbonyl peak of I also shifted to a higher
-1
as shown in Figure 3(e). However, as predicted from
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
functioning as a proton shuttle.[11,14] In this context,
alkali metal salts with a multivalent anion such as
carbonate, bicarbonate, or phosphate anion can be
regarded as the catalysts of choice because they can
simultaneously accept and donate a proton from the
carbonation species like I and II. However, for non-
catalytic carboxylation reactions to take place
smoothly, a solvent must play a role in assisting the
proton transfer. The importance of a proton transfer in
the carboxylation of amines is well described in the
[11,15]
literature.
Figure 4. ORTEP drawing of the crystal structure of the cyclic molecule, can be considered one of the most
:1 CO
adduct of EDA (II) displayed with thermal appropriate solvents because 2-PYcontains a peptide
In this context, 2-PY, a five membered
1
2
ellipsoids at 50% probability levels.
moiety (HN-C=O) comprising an acidic N-H proton
and a basic C=O group, that can act as a proton donor
and an acceptor, respectively. Therefore, 2-PY is
capable of functioning as a proton shuttle. The proton
transfer effect of 2-PY would be more pronounced if
it could exist in an enol form. 2-PY is known to exist
as a keto-enol tautomer through the migration of a
labile N-H hydrogen atom from the ring nitrogen or
oxygen atom as shown in Scheme 1, however, the
equilibrium constant toward the enol form is
-7
[16]
calculated to be as low as 1.45  10 at 300 K.
Nonetheless, the equilibrium constant is expected to
be greatly increased if the enol form of 2-PY is
stabilized by a carbonation species like I or II.
Scheme 1. Keto-enol tautomerization of 2-PY.
the significantly lower yield of cyclic ureas in NMP
If the presence of a N-H hydrogen atom is
compared with that obtained in 2-PY, the extent of the responsible for the outstanding performance of 2-PY
-1
as a promoter, the replacement of the N-H hydrogen
atom by a deuterium atom is expected to decelerate
the carboxylation rate of EDA at the early stage of the
reaction. In this context, kinetic isotope effect was
measured for the carboxylation of EDA using
peak shift was only 7 cm , which is about one fifth
of the value observed upon interaction with 2-PY.
Mechanistic consideration
EDA is known to react rapidly with CO
, forming the deuterated and un-deuterated 2-PY. The amount of
2
zwitterionic carbamate species (II).[11] We have also
confirmed the formation of II by X-ray
ethylene urea (EU) produced in deuterated 2-PY was
smaller than that in un-deuterated 2-PY during the
period of reaction time up to 7 min, but became closer
13
crystallography and C NMR spectroscopy. The
crystal structure of II is shown in Figure 4 (see also thereafter (see Figure S44 in SI). As shown in Figure
1
3
Figure S4 and Tables S1-S3 in SI). The C NMR S45 in SI, the plot of ln([EU]) versus time (s) gives
spectrum of the crystals shows a characteristic peak at straight lines. The rate constants for the carboxylation
were obtained from the slopes of the straight lines.
The deuterium kinetic isotope effect (k /k ) was
calculated as 0.89, demonstrating the involvement of
1
64.5 ppm assignable to carbamate species (see
Figure S15 in SI).
H
D
Two possible mechanisms can be proposed for the
formation of cyclic urea from II: (A) nucleophilic N-H hydrogen atom in the carboxylation of EDA to
attack of the amino group on the carbamate carbonyl ethylene urea at least to some extent. Although the
[
12]
carbon atom followed by the loss of water and (B) kinetic isotope effect is not strong, the effect is still
considered significant for a solvent. Such a small
kinetic isotope effect is often observed for the
the formation of an isocyanate intermediate from the
carbamate by elimination of water followed by a
nucleophilic attack of the amino group on the
[17]
reaction proceeded by a S 2 mechanism.
N
[13]
carbonyl carbon of the isocyanate intermediate.
For the intramolecular nucleophilic attack of the Computational calculations
second amine on the carbamate, II needs to be
To develop a better understanding of the promoting
role of 2-PY, the synthesis of ethylene urea from the
non-catalytic carboxylation of EDA in the presence of
transformed into a neutral carbamic acid form (III)
via a proton transfer from the ammonium cation (-
+
-
NH
3
) to the carboxylate anion (-CO ), thereby
2
enabling the nucleophilic attack of the amino group 2-PY was investigated by computational methods
on the carbonyl group. However, the intramolecular (Figure 5). As mentioned above, 2-PY could exist as a
proton transfer from ammonium to carbamate is not tautomer, but the equilibrium shift toward the enol
[
16b,16c]
form is negligible under normal conditions.
an easy process .
Such proton transfer can be facilitated in the
presence of a base catalyst, which is capable of
Therefore, calculation was more focused on the
possible formation and stabilization of the enolate
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
Figure 5. Optimized structures showing the interactions of
-
1
2
EDA with CO and 2-PY: (a) starting (ΔG = 0 kcal mol ),
-
1
Figure 6. Optimized structures of intermediates, transition
states and product involved in pathway A. The numbers in
parenthesis are the Gibbs free energy of formation (G)
(
+
b) II + 2-PY (keto form, ΔG = -6.8 kcal mol ), and (c) II
2-PY + EDA (enolate species, ΔG = 10.3 kcal mol ).
-
1
‡
and transition state energy (G ) are relative values with
respect to that of the reactant complex (energies are in kcal
species of 2-PY through the interaction with II and
EDA. The enol form of 2-PY is highly unstable and
thus it is reasonable to assume that the enol form
would transform into ammonium enolate species as
soon as it forms by reacting with free amine like EDA.
As shown in Figure 5(b), the peptide functional group
-
1
mol ).
of 2-PY in its keto form is found to interact strongly
+
with both the ammonium (-NH
3
) and carbamate (-
-
CO
2
) groups of II via multi hydrogen bonding
interactions.
The Gibbs free energy of formation (G) for the
interaction of the keto form of 2-PY with II to
generate an intermediate species, I1K was calculated
-1
as -6.8 kcal mol . Interestingly, as shown in Figure
(c), the intermediate species, I1K can be transformed
5
into an enolate species, I1E upon interaction with
another molecule of EDA. The Gibbs free energy of
formation (G) for the generation of the enolate
-
1
species (I1E) was calculated as 10.3 kcal mol . It has
been reported that the equilibrium constant for the
tautomerization of 2-PY is increased by 287 times
-7
-5
from 1.45  10 to 4.16  10 when the temperature
is raised from 27 to 187 C.
o
[16c]
Therefore, it is
-1
Figure 7. Optimized structures of intermediates, transition
states and product involved in pathway B. The numbers in
parenthesis are the Gibbs free energy of formation (G)
expected that a G of 17.1 kcal mol for
transformation of 2-PY from keto to enolate species
could easily be overcome at an elevated reaction
‡
o
and transition state energy (G ) are relative values with
temperature around 200 C. Once the enolate species,
respect to that of the reactant complex (energies are in kcal
I
1E is generated, proton transfer can take place more
-
1
mol ).
effectively, thereby facilitating the nucleophilic attack
and water removal processes.
As mentioned above, two pathways, A and B were
considered in the calculations for the synthesis of
ethylene urea from the carboxylation in 2-PY. The
optimized structures of the intermediates and
transition states for pathways A and B are shown in
Figures 6 and 7, respectively. The energy profiles for
both pathways are depicted in Figure 8. For both
pathways, the formation of the enolate intermediate
species, I1E is likely to be the first step.
For the formation of ethylene urea via the pathway
A, the intramolecular nucleophilic attack of the amino
group on the carbamate carbonyl carbon atom should
take place to generate a five membered ring
intermediate species (I2A) where 2-PY exists as a keto
form (Figure 6). The driving force for the nucleophilic
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
Figure 8. Reaction profiles of pathways A and B. The numbers in parenthesis are the Gibbs free energy of formation (G)
‡
-1
and transition state energy (G ) are relative values with respect to that of the reactant complex (energies are in kcal mol ).
attack would be the proton transfer from the subtracting the N-H hydrogen atom bonded to the
ammonium moiety of II to the nitrogen atom of the carbonyl group. The Gibbs free energies of the
enolate species of 2-PY as well as the interaction of transition state (TS2B) and the intermediate species
+
-1
the ammonium cation of [EDAH] with the carbamate (I2B) were calculated as 19.1 and 16.2 kcal mol ,
anion via the transformation of 2-PY from the keto respectively. Further proton transfer from the
form to enolate species. Through such multi hydrogen ammonium cation followed by the loss of water
bonding interactions, the electron density on the would produce isocyanate intermediate species along
carbamate anion of II can be greatly reduced and the with the generation of keto form of 2-PY and EDA.
the nucleophilic attack of the amino group can be The Gibbs free energies of the transition state (TS3B
)
substantialized. The Gibbs free energies of the and the intermediate species (I3B) were calculated as
-
1
transition state (TS2A) and intermediate species (I2A
)
34.5 and 15.6 kcal mol , respectively. Subsequent
for this step were calculated as 42.7 and 34.8 kcal intramolecular nucleophilic attack of the amino group
-1
mol , respectively. Further proton transfer from the on the carbonyl carbon of the isocyanate group
ammonium cation to the ring moiety followed by the followed by loss of water and proton transfers would
loss of water would produce the product along with generate the same product shown in pathway A. The
the generation of EDA. The Gibbs free energies of the Gibbs free energies of the transition state (TS4B and
transition state (TS3A) and the product were calculated TS5B) and the intermediate species (I4B) involved for
-1
-
as 36.7 and -4.3 kcal mol , respectively. Based on the these steps were calculated as 18.7 and 19.6 kcal mol
1
-1
calculated energies, nucleophilic attack can be
for the transition states and 13.0 kcal mol for the
considered the rate determining step for the pathway intermediate species, respectively. The rate
-1
A. However, the activation energy of 42.7 kcal mol
determining step is the formation of isocyanate
for TS2A seems to be rather high for the nucleophilic intermediate species. Like in the pathway A, the
attack to take place. Nonetheless, pathway A should driving force seems to be the reversible
not be ruled out because the reaction temperature at transformation of 2-PY from the keto form into
o
around 200 C is sufficiently high to overcome the enolate species.
activation barrier.
Comparison of the energy profiles shown in Figure
Figure 7 shows the optimized structures of 8 for the pathways A and B strongly suggests that the
transition states and intermediates involved in the pathway B involving the formation of an isocyanate
formation of ethylene urea via the pathway B. Unlike intermediate species is more favorable than pathway
the pathway A, the nucleophilic attack on the anionic A. For instance, Gibbs free energies for the third
carbamate is not necessary, and thus the primary role transition state (TS3B) for the rate determining step of
-1
of the enolate species is to assist the intramolecular the pathway B is calculated as 8.2 kcal mol lower
proton transfer from the ammonium moiety to the than that of TS2A for the pathway A.
carbamate carbonyl carbon of II while simultaneously
7
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
Table 2. Effects of reaction temperature and pressure on N-H hydrogen atom is responsible for the drastic
[
a]
2
the carboxylation of EDA by CO .
increase of the yield of cyclic ureas in 2-PY.
Computational calculations also suggest that 2-PY
plays a pivotal role in the carboxylation of amines
through a reversible transformation from the keto
form into enolate species.
In summary, the carboxylation of mono- and
diamines to produce corresponding dialkylureas and
cyclic ureas can be greatly accelerated even in the
absence of a catalyst by using a solvent possessing a
peptide functional group, which is capable of
functioning as both a proton donor and a proton
acceptor.
o
CO2 (MPa) Yield (%)[b]
Entry Temperature ( C)
P
1
2
3
4
5
6
7
8
9
150
160
170
180
190
200
200
200
200
210
220
5
5
5
5
5
2
5
7
2.8
9.5
22.0
48.1
73.6
80.4
83.0
83.8
84.3
79.7
77.4
10
5
1
0
1
1
5
[
[
a]
b]
Reaction condition: EDA (100 mmol), solvent (2-Py, 20
mL), reaction time = 2 h.
Experimental Section
Chemicals
Yield of ethylene urea.
NMP, 2-PY, and diamines including EDA, 1,2-PDA,
Effects of reaction temperature and CO pressure
2
1
,3-PDA were purchased from Aldrich Chemical Co.,
and used as received. Carbon dioxide (purity >
9.9%) was obtained from Sin Yang Gas Co. and
used without further purification.
Table 2 shows the effect of reaction temperature on
the synthesis of ethylene urea via the carboxylation of
EDA conducted in 2-PY for 2 h in the temperature
9
o
range of 150 – 220 C. The yield of ethylene urea
Absorption of CO
2
increased rapidly with the temperature rise up to 200
o
C, and slightly decreased thereafter. No sign of side
CO absorption experiments were conducted inside a
2
product formation was observed by GC or GC-Mass
o
chamber maintained at 313 K using a 90 mL glass
pressure reaction vessel (Fischer-Porter bottle)
equipped with an inlet and outlet valves, a pressure
gauge, and a thermocouple (Figure S1 in SI). In a
typical experiment, the glass vessel was loaded with
analysis up to 220 C. This is in contrast to the
reaction in NMP, which shows the formation of small
o
[1 1 ]
amounts of side products above 200 C.
In contrast to the temperature effect, the yield of
ethylene urea did not vary substantially with pressure
change. As can be seen in Table 2, the yield of
ethylene urea was found to increase by only 3.9%
from 80.4 to 84.3% when the pressure was increased
from 2 to 10 MPa.
1
8 g of 20wt% 1,2-PDA solution in 2-PY or NMP.
CO was then introduced into the vessel at 30 kPa
from a 150 mL CO reservoir cylinder equipped with
2
2
a pressure regulator and a transducer. The reservoir
cylinder was located inside the chamber, and the
initial temperature and pressure in the cylinder were
set at 313 K and 3.4 MPa, respectively. The change of
the pressure inside the cylinder with the progress of
Conclusion
the CO
2
absorption was monitored, and the weight
was measured at
The non-catalytic carboxylation of mono- and
diamines was greatly facilitated when 2-PY was used
as a solvent. In general, the carboxylation of mono-
and diamines produced 3-8 times higher yields of
corresponding dialkylureas and cyclic ureas than
those obtained in NMP.
H-D exchange studies with 2-PY and EDA using
mass spectrometry clearly demonstrate that 2-PY is
capable of playing roles as a proton donor as well as a
proton acceptor. 1,2-PDA was found to interact with
change upon absorption of CO
2
certain intervals using a balance (OHAUS, EP613C)
with an accuracy of 0.001 g. A blank test was also
conducted with 18 mL water to precisely determine
the amount of CO
NMP or 2-PY. The interactions of I (CO
,2-PDA) with 2-PY and NMP were studied using
2
in a 20wt% 1,2-PDA solution of
2
adduct of
1
FT-IR spectrometer (Nicolet iS10). H-D exchange
studies with deuterated and undeuterated 2-PY and
EDA were investigated by GC-Mass spectrometer
CO
2
much more rapidly in 2-PY than in NMP,
adduct of 1,2-PDA (1,2-PDA-CO
(
Agilent 6890-5973, HP-MS capillary column).
forming a 1:1 CO
2
2
,
I). The carbonation species I was completely soluble
in 2-PY, forming a homogeneous solution. In contrast,
the species I was only slightly soluble in NMP,
implying that the species I interacts much more
strongly with 2-PY than with NMP, possibly via multi
hydrogen bonding interactions.
Kinetic studies with deuterated 2-PY clearly
demonstrates that the proton transfer proceeds
involving the N-H hydrogen atom of 2-PY, and the
Carboxylation of Diamines
All the carboxylation experiments were conducted in
a 100 mL stainless steel bomb reactor equipped with a
thermocouple and an electrical heater. The reactor
was loaded with an amine (100 mmol) and a solvent
(
20 mL), and flushed three times with CO . The
2
reactor was then heated to a desired temperature
8
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Advanced Synthesis & Catalysis
10.1002/adsc.201800945
under pressure of 1.0 MPa CO
2
. At a specified space group Pna2(1), Z = 4, 3713 reflections
temperature, CO
2
pressure was further increased to measured, 1232 independent reflections (Rint
=
5
.0 MPa and maintained throughout the reaction by 0.0406). The final R
1
values were 0.0406 (I > 2σ(I)).
2
means of a CO
2
reservoir equipped with a high The final wR(F ) values were 0.0804 (I > 2σ(I)). The
pressure regulator and a pressure transducer. final R values were 0.0322 (all data). The final
Reactions were carried out for various periods of time, wR(F ) values were 0.0742 (all data). The goodness
after which the reactor was cooled to room of fit on F was 1.065.
temperature and then depressurized. The product
1
2
2
CCDC-1851007 contains the supplementary
mixture was analyzed by NMR spectrometer (400 crystallographic data for this paper. These data can be
MHz, Bruker) and the yields of cyclic ureas were obtained free of charge from The Cambridge
quantified using 1,4-dioxane as an internal standard.
Crystallographic Data Center via www.ccdc.cam.ac.
uk/data_request/cif.
Kinetic isotope effect
Quantum mechanical calculations
The kinetic isotope effect for the carboxylation of
EDA was measured using deuterated 2-PY. To this Computations were made on the interaction of 2-PY
end, the carboxylation reaction of EDA was with the CO
2
adduct of EDA, II using Gaussian 09
[20]
performed in a specially designed 10 mL tube reactor software. All the geometries were optimized with
o
at 200 C and 5 MPa of CO
2
in 2-PY and deuterated the hybrid Becke, three-parameter, Lee–Yang–Parr
2
-PY, respectively (Figure S2 in SI). The tube reactor (B3LYP) exchange–correlation functional with the 6-
was charged with 2.4 g of EDA and 5 mL of 31+G* basis set for C, H, N, and O, Optimized
deuterated or un-deuterated 2-PY, and pressurized geometries were subjected to full frequency analyses
with 5 MPa of CO . The reactor was then immersed at the same level of theory to verify the nature of the
2
o
in an oil bath maintained at 200 C and stayed for a stationary points. Equilibrium geometries were
specified period of time. The product mixture was characterized by the absence of imaginary frequencies.
analyzed by NMR and GC-mass spectrometer.
B3LYP enthalpy and entropy corrections were used
for all thermodynamic corrections. The effect of bulk
solvent was taken into account in the single point
calculations through the self-consistent reaction field
Crystallographic Data and Packing Diagrams
A 90 mL glass pressure bottle (Fisher-Porter vessel) theory (SCRF) based on the Polarizable Continuum
was loaded with 6 g of EDA solution in 20 mL of 2- Model (IEFPCM-UFF) implemented in the Gaussian
pyrroridone and pressurized with 0.3 MPa CO with a 09 program. Since 2-PY and NMP are not available in
2
gentle stirring to afford zwitterionic carbamate the program package, N,N-dimethylacetamide
compound (II) as white solid precipitates. The (DMAc) was used instead in the calculation.
precipitates were collected by filtration, washed with
methanol, and dried at room temperature under
vacuum. Single crystals suitable for X-ray Acknowledgements
crystallography were grown by diffusing methanol
into an aqueous solution of II. Single crystal X-ray This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
diffraction data for zwitterionic carbamate species (II)
funded
by
the
Ministry
of
Education
(NRF-
were collected on a Bruker SMART APEXII
diffractometer equipped with a CCD area detector
using graphite monochromated MoK radiation ( =
2
017R1D1A1B03029207) and (NRF-2017R1D1A1B03029624).
0
.71073 Å). Preliminary orientation matrix and cell
References
parameters were determined from three sets of 
scans at different starting angles. Data frames were
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10.1002/adsc.201800945
FULL PAPER
Highly Efficient Non-Catalytic Carboxylation of
Diamines to Cyclic Ureas Using 2-Pyrrolidone as a
Solvent and a Promoter
Adv. Synth. Catal. Year, Volume, Page – Page
Junhyeok Hwang, Donggu Han, Jin Joo Oh,
Minserk Cheong, Hyun-Joo Koo, Je Seung Lee*
and Hoon Sik Kim*
1
1
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