Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

Article abstract of DOI:10.3762/bjoc.15.290

A range of chiral hydrogen-bond-donating organocatalysts was tested in the Ireland–Claisen rearrangement of silyl ketene acetals. None of these organocatalysts was able to impart any enantioselectivity on the rearrangements. Furthermore, these organocatalysts slowed down the Ireland–Claisen rearrangement in comparison to an uncatalyzed reaction. The catalyst-free reaction proceeded well in green solvents or without any solvent. DFT calculations showed that the activation barriers are higher for reactions involving hydrogen-donating organocatalysts and kinetic experiments suggest that the catalysts bind stronger to the starting silyl ketene acetals than to transition structures thus leading to inefficient rearrangement reactions.

Full text of DOI:10.3762/bjoc.15.290

Why do thioureas and squaramides slow down the
Ireland–Claisen rearrangement?
Dominika Krištofíková1, Juraj Filo2, Mária Mečiarová*1 and Radovan Šebesta*1
Full Research Paper
Open Access
Address:
Department of Organic Chemistry, Faculty of Natural Sciences,
Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6,
4215 Bratislava, Slovakia and 2Institute of Chemistry, Faculty of
Beilstein J. Org. Chem. 2019, 15, 2948–2957.
doi:10.3762/bjoc.15.290
1
8
Received: 28 May 2019
Natural Sciences, Comenius University in Bratislava, Mlynská dolina,
Ilkovičova 6, 84215 Bratislava, Slovakia
Accepted: 25 November 2019
Published: 10 December 2019
Email:
Associate Editor: M. Rueping
Mária Mečiarová* - maria.meciarova@uniba.sk; Radovan Šebesta* -
radovan.sebesta@uniba.sk
© 2019 Krištofíková et al.; licensee Beilstein-Institut.
License and terms: see end of document.
*
Corresponding author
Keywords:
DFT calculations; green solvents; H-bonding catalysts;
Ireland–Claisen rearrangement; silyl ketene acetals
Abstract
A range of chiral hydrogen-bond-donating organocatalysts was tested in the Ireland–Claisen rearrangement of silyl ketene acetals.
None of these organocatalysts was able to impart any enantioselectivity on the rearrangements. Furthermore, these organocatalysts
slowed down the Ireland–Claisen rearrangement in comparison to an uncatalyzed reaction. The catalyst-free reaction proceeded
well in green solvents or without any solvent. DFT calculations showed that the activation barriers are higher for reactions involv-
ing hydrogen-donating organocatalysts and kinetic experiments suggest that the catalysts bind stronger to the starting silyl ketene
acetals than to transition structures thus leading to inefficient rearrangement reactions.
Introduction
The Ireland–Claisen rearrangement is a reaction converting geometry of enolates as well as its stereospecificity make this
allyl esters to γ,δ-unsaturated carboxylic acids. Its key step is a transformation synthetically appealing [12,13].
[
3,3]-sigmatropic rearrangement of a silyl ketene acetal, which
is generated in situ by deprotonation of an allyl ester using a Allyl esters of various carboxylic acids undergo rearrangement
strong base [1-3]. The products of the Ireland–Claisen rear- as their lithium enolates or silyl ketene acetals and the corre-
rangement, γ,δ-unsaturated acids, are useful precursors of bio- sponding acids were isolated in 75–80% yields. Accordingly,
logically active compounds and natural products [4-11]. The the Ireland–Claisen rearrangement of lithium enolates gener-
ready availability of allylic esters, the ability to control the E/Z ated from allyl fluoroacetates gave the corresponding α-fluoro-
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γ,δ-unsaturated acids [14]. The Ireland–Claisen rearrangement β-carbon with high yields and excellent diastereo- as well as en-
of Et3N-solvated enolates showed higher reactivity as well as antioselectivity [5]. A reductive rearrangement of allyl esters of
diastereoselectivity when compared with analogous reactions in acrylic acid, catalyzed by in situ-generated copper hydride with
THF [15].
diethoxymethylsilane as a reductive agent gave the γ,δ-unsatu-
rated acid with good to excellent diastereoselectivities [27].
The required ester enolates are typically generated using a
strong base, such as LDA or similar amides in combination with Various asymmetric organocatalyzed rearrangements are known
trialkylsilyl chlorides as silylating agents at low temperature [28]. However, the catalysis of sigmatropic rearrangements is
under strictly anhydrous conditions [3,16,17]. An alternative difficult due to their rather nonpolar transition states, which are
method employs tertiary amines as bases in combination with difficult to be addressed by catalysts [29]. Several stereoselec-
more reactive silylating agents, such as trialkylsilyl triflates tive [3,3]-sigmatropic rearrangements are realized with chiral
[
18,19].
Brønsted acids [30-34]. Jacobsen reported guanidinium-cata-
lyzed enantioselective Claisen rearrangements of O-allyl
The rearrangement of ester enolates generated by LDA with β-ketoesters [35-37]. Hiersemann and Strassner studied the
metal ions bearing bulky cyclopentadienyl ligands proceeded Claisen rearrangement with H-bond-donating organocatalysts
well with yields of up to 90%, and diastereomeric ratios by computational methods and concluded that thioureas are not
strongly depended on the ligands used [20]. The presence of efficient in transition-state stabilization [38].
catalytic amounts of Lewis acids improved the diastereoselec-
tivity and the reaction rate of silyl ketene acetals of (E)-allylic Regarding the usefulness of the Ireland–Claisen rearrangement,
esters [21]. Chiral bromoboranes were used to form boranyl we tried to optimize its reaction course under mild conditions
ketene acetals from ester enolates generated from allyl esters using various bases, solvents, and hydrogen-bond-donating
with tertiary amines. The geometry of the enolates depended catalysts. We also present a computational explanation and
strongly on the solvent and the amine’s structure [22,23].
NMR kinetic study for the inefficient Ireland–Claisen rear-
rangement under thiourea and squaramide catalysis.
The decomposition of the enolate is one of the side reactions,
which can be suppressed by chelation. The chelation-stabilized Results and Discussion
enolates are more stable than the corresponding silyl ketene We started our investigation with the rearrangement of tri-
acetals, and they are capable of a direct rearrangement [24]. The methylsilyl ketene acetal (2a) derived from allyl propionate (1a,
chelation-controlled Ireland–Claisen rearrangement of O-pro- Scheme 1). Silyl ketene acetals 2 can be observed by NMR in
tected allylic glycolate esters proceeded with moderate yields the reaction mixture (see Supporting Information File 1 for
and diastereoselectivities of up to 20:1 [25]. An asymmetric NMR spectra of 2c). This reaction afforded the corresponding
ester-enolate-Claisen rearrangement was achieved by using alu- acid 3a in 63% yield at rt (Table 1, entry 1). At a higher temper-
minum-chelate-bridged enolates and proceeded with high yields ature, the product yield decreased (Table 1, entry 2). The reac-
and diastereoselectivities, and ees up to 86% [26]. Rearrange- tion of the related (E)-but-2-en-1-yl propionate (1b) gave acid
ment of allyl esters of glycine derivatives gave under similar 3b under similar conditions with slightly lower yields. The rear-
conditions amino acids with a quaternary stereocenter on the rangement of lithium enolate, as well as trimethylsilyl ketene
Scheme 1: Ireland–Claisen rearrangement of allyl esters 1a–c.
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Table 1: Ireland–Claisen rearrangement of 1a–c with LDA as the base without organocatalysts.
Entry
R
R’3SiX (equiv)
Temperature (°C)
Time (h)
Yield of 2 (%)
dr
1
2
3
4
5
6
7
8
H
H
Me3SiCl (1.1)
Me3SiCl (1.1)
Me3SiCl (1.1)
Me3SiCl (1.1)
Me3SiCl (1.1)
–
rt
66
rt
66
rt
rt
168
3
72
2
20
20
168
168
63
41
42
36
38
30
0
–
–
Me
Me
Me
Me
Ph
Ph
76:24
76:24
77:23
79:21
–
Me3SiCl (1.0)
t-BuMe2SiOTf (1.1)
rt
rt
0
–
acetal 2b generated from 1b, proceeded with similar yields and product 3c with lower yields. Rearrangement in the presence of
diastereoselectivity (Table 1, entries 3–6). However, the N-methylmorpholine, quinine, and N-methylpyrrolidine
Ireland–Claisen rearrangement attempted with cinnamyl pro- afforded only traces of acid 3c and reactions with DBU,
pionate (1c) did not take place when using LDA as a base DABCO and (S)-1-(pyrrolidin-2-ylmethyl)pyrrolidine did not
(
Table 1, entries 7 and 8).
proceed at all. Of note, the bases used in these Ireland–Claisen
rearrangements did not affect the diastereoselectivity and the
Next, we studied the Ireland–Claisen rearrangement of ester 1c syn/anti ratio was approximately 70:30 in all cases.
using various tertiary amines as bases. The ester enolate was
trapped with Me3SiOTf at −60 °C and allowing the reaction to The Ireland–Claisen rearrangement of allyl propionate (1a) with
proceed at room temperature for 24 h. The best yields of acid 3c Et3N and Me3SiOTf afforded 2-methylpent-4-enoic acid (3a) in
were achieved with triethylamine (74%) and N-cyclohexyl-N- 75% yield. However, the yield of product 3a dropped to 22%
methylcyclohexanamine (65%, Scheme 2) whereas reactions when the reaction was performed at 40 °C. The rearrangement
with trihexylamine and diisopropylethylamine provided the of 1a with t-BuMe2SiOTf gave only 40% of acid 3a (Table 2,
Scheme 2: Ireland–Claisen rearrangement of 1c mediated by tertiary amines.
Table 2: Ireland–Claisen rearrangement with Et3N as a base.
Entry
R
R’3SiOTf
T (°C)
t (h)
Yield of 3 (%)
dr
1
2
3
4
5
6
H
H
H
Ph
Ph
Ph
Me3SiOTf
Me3SiOTf
t-BuMe2SiOTf
Me3SiOTf
Me3SiOTf
–
rt
40
rt
rt
5
24
4
24
24
72
24
75
22
40
74
50
0
–
–
–
69:31
71:29
–
rt
2
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entries 1–3). The yield of acid 3c decreased from 74 to 50% cant role in the Ireland–Claisen rearrangement of 1c. Surpris-
when the reaction was performed at 5 °C (Table 2, cf. entries 4 ingly, all catalysts led to a decreased yield of the acid 3c
and 5) and the reaction temperature did not affect the diastereo- (28–62%) in comparison to 74% yield obtained without any
selectivity of the reaction. No product 3c was obtained when the chiral organocatalyst. Further, none of the chiral organocata-
reaction was performed without silyl triflate (Table 2, entry 6).
lysts considerably affected the diastereoselectivity and acid 3c
was obtained in racemic form in the presence of either tested
We assumed that hydrogen-bond-donating organocatalysts chiral organocatalyst. Similar results were obtained with ester
could activate the enolates or the corresponding silyl ketene 1a. The reaction was tested also in the more polar solvent aceto-
acetals or stabilize the corresponding transition states. In addi- nitrile using catalyst C1, but also in this case no enantioselectiv-
tion, chiral organocatalysts could induce diastereo- as well as ity was observed. Sigmatropic rearrangements proceed via
enantioselectivity. Therefore, we examined the Ireland–Claisen isopolar transition states and, therefore solvent effects are rather
rearrangement of ester 1c in the presence of a range of organo- small. For this reason and due to the complete lack of enantio-
catalysts, including chiral squaramides, thioureas, alkaloids and selectivity, at this stage, we did not investigate other solvents
their derivatives, taddols, binol, chiral phosphoric acid, (S)- with the catalysts collected in Figure 1.
proline and its derivatives, amide of tryptophan (Figure 1).
These catalysts feature varying steric properties from sterically In order to gain further insight into the catalyst’s action in the
encumbered, such as C1, C5, C8, or C10, to less demanding rearrangement, we have studied the effect of catalyst loading in
ones, e.g., C6, C9 or C11. In addition, the acidity of the hydro- the reaction of ester 1c with squaramide C1. The reaction with
gen-bond-donating moiety also ranges over a rather large area Et3N as a base and Me3SiOTf without any chiral organocata-
from pKa (H2O) 1 for phosphoric acid C10 to pKa (DMSO) 28 lyst afforded acid 3c with 74% yield. Repeating the reaction in
of diols C7 and C8. However, neither steric factors, nor the the presence of squaramide C1 (5 mol %) lowered the yield
acidity of the H-bond-donor moiety seemed to play a signifi- from 74 to 37%. A similar yield (35%) was achieved with
Figure 1: Organocatalysts used in this study. Conditions: typical procedure: 1. Et3N (4.9 equiv), DCM, −60 °C, 5 min; 2. Me3SiOTf (1.6 equiv), cata-
lyst (10 mol %), −60 °C; 3. rt, 24 h.
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1
0 mol % of C1 (Table 3, entries 1–3) and further increasing vent effects. However, minor improvements in reaction time
the catalyst loading to 20 and 30 mol % diminished the product have been noted in some cases [39]. Therefore, with the aim of
yield even more (26 and 21%, respectively; Table 3, entries 4 improving the reaction course, we evaluated several other sol-
and 5). Ultimately, one equivalent of squaramide C1 complete- vents, emphasizing green solvents, which have not been evalu-
ly stopped the reaction (Table 3, entry 6).
ated in Ireland–Claisen rearrangements before. 2-Methylte-
trahydrofuran (2-MeTHF) is derived from renewable resources
and has a higher boiling point (80 °C) and lower heat of vapor-
ization compared to THF. The Ireland–Claisen rearrangement
proceeded in 2-MeTHF with slightly lower yield and very simi-
lar diastereoselectivity as in DCM (Table 5, entries 1 and 2). A
low tendency to peroxide formation, stability under acidic and
basic conditions, high boiling point, and low heat of vaporiza-
tion are also positive features of cyclopentyl methyl ether
Table 3: Effect of catalyst loading on the Ireland–Claisen rearrange-
ment of 1c.
(
CpOMe) [40]. From the chemical yield point of view,
Entry
C1 (mol %)
Yield of 3c (%)
syn/anti
cyclopentyl methyl ether was the best solvent for the
Ireland–Claisen rearrangement of ester 1c; acid 3c was isolated
in 84% yield. However, even in CpOMe, catalyst C6 decreased
the yield of acid 3c to 73% (Table 5, entries 3 and 4). A less
toxic alternative to dichloromethane is trifluorotoluene and the
rearrangement of 1c in this solvent afforded acid 3c in 76%
1
2
3
4
5
6
0
5
10
20
30
100
74
37
35
26
21
0
69:31
71:29
63:37
74:26
75:25
–
(
Table 5, entry 5). Glymes are environmentally benign aprotic
polar and chemically inert solvents [41]. The desired product 3c
through Ireland–Claisen rearrangement of 1c was isolated in
We also studied the effect of the amount of base on the 58% when the reaction was carried out in dimethyl ethylene
Ireland–Claisen rearrangement of ester 1c in the presence of glycol (Table 5, entry 6). However, Ireland–Claisen rearrange-
sulfanediamine C6 (Table 4). The best yield of acid 3c (74%) ment of ester 1c did not proceed in 2,2,2-trifluoroethanol, ethyl
was recorded with 4.9 equivalents of Et3N without chiral ʟ-lactate or in 2-butanone.
organocatalyst. The yield of acid 3c decreased to 62% in the
presence of 10 mol % of C6. An even higher amount of base Interestingly, the best yield of acid 3c (95%) was obtained when
did not improve the yield of acid 3c (Table 4, entry 3). The the reaction was carried out without any solvent (Table 5, entry
reaction with 2.5 equivalents of Et3N gave 51% of acid 3c. Also 8). Again, catalyst C6 (10 mol %) decreased the yield under
here, both diastereomers were obtained as racemates.
solvent-free conditions from 95 to 73% (Table 5, entries 8 vs 9).
The Ireland–Claisen rearrangement of cinnamyl isobutyrate
(1d) gave under solvent-free conditions only 17% of the acid 3d
and the analogous reaction in CpOMe afforded the acid in 5%
yield. When cinnamyl butyrate (1e) was used as a starting mate-
rial, product 3e was obtained in a yield of 60% (Scheme 3).
Table 4: Effect of the amount of base on the Ireland–Claisen rear-
rangement of 1c in the presence of C6.
To gain further insights into the organocatalysts effect on the
Ireland–Claisen rearrangement, we have performed quantum-
chemical calculations employing long-range corrected hybrid
density ωB97X-D functional [42]. This dispersion-corrected
functional displays very balanced overall performances and has
demonstrated excellent treatment of noncovalent interactions
Entry Et3N (equiv) C6 (mol %) Yield of 3c (%) syn/anti
1
2
3
4
4.9
4.9
10
0
74
62
70
51
69:31
69:31
71:29
64:36
10
10
10
[
43], which are very important in our studied system. For this,
2.5
we have compared the uncatalyzed Ireland–Claisen rearrange-
ment with three hydrogen-bond-catalyzed reactions. As model
H-bonding catalysts, we selected diphenylthiourea, Schreiner
As mentioned above, the Ireland–Claisen rearrangement, as a thiourea, and the corresponding squaramide with bis(trifluoro-
pericyclic reaction, is expected to be rather insensitive to sol- methyl)phenyl groups. We have evaluated both the (E)- and
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Table 5: Green solvents screening for the Ireland–Claisen rearrangement of 1c.
Entry
Solvent
T (°C)
Yield of 3c (%)
syn/antia
1
2
3
4
5
6
7
8
9
DCM
2-Me-THF
CpOMe
CpOMeb
PhCF3
CH3OCH2CH2OCH3
CH3CN
–
−60
−60
−60
−60
−20
−50
−60
−60
−60
74
63
84
73
76
58
11
95
73
69:31
71:29
68:32
70:30
69:31
70:30
n.d.
69:31
70:30
–b
aBoth diastereomers were obtained as a racemic mixture. bReaction carried out in the presence of C6 (10 mol %).
Scheme 3: Solvent-free Ireland–Claisen rearrangement of cinnamyl esters.
(
Z)-silyl ketene acetal 2c derived from 1c as starting material Using the structures optimized at the ωB97X-D/6-31G* level of
for the reaction. The activation barrier for the uncatalyzed reac- theory we calculated interaction energies between catalysts and
tion of (E)-silyl ketene acetal was 98.5 kJ·mol−1, and for (Z)- starting silyl ketene acetals or corresponding transition state
silyl ketene acetal 88.7 kJ·mol−1 (Figure 2). Charges on the structures at the M06-2X/6-311+G** level. For the Schreiner
allylic oxygen in the reaction transition states are only slightly thiourea (C12) as well as diphenylthiourea interaction energies
more negative than in the starting acetal silyl ketenes. It means were higher in the starting silyl ketene acetal–catalyst com-
that transition states have only slightly dipolar character, which plexes than in the corresponding transition states. For the
would be difficult to stabilize through hydrogen bonding and squaramide catalyst, these energies were similar (Table 6).
consequently reaction less prone to catalysis.
These calculations further support the notion that hydrogen-
bonding organocatalysts bind stronger to starting silyl ketene
Interestingly, the reaction comprising Schreiner thiourea (C12) acetals than to the transition structure and thus are not effi-
had higher activation barriers for both isomers (111.9 kJ·mol−1 ciently catalyzing the Ireland–Claisen rearrangement. The
for (E) and 95.6 kJ·mol−1 for (Z)). These results suggest that reason for this difference, however, remains unclear. The expla-
Schreiner thiourea binds stronger to starting silyl ketene acetal nation may be connected to a more compact transition state of
than to the corresponding transition state. Therefore, it stabi- sigmatropic rearrangements than their starting materials, which
lizes more the starting material than the transition state, which is thus less amenable to additional stabilization via hydrogen-
results in the slow-down of the reaction (Figure 3).
bonding catalysts.
Similar trends were observed also for diphenylthiourea and a To get further insight, we have performed a kinetic study of the
squaramide (Figure 4). reaction using 1H NMR spectroscopy. Figure 5a shows a com-
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Figure 2: ωB97X-D/6-31G* calculated uncatalyzed Ireland–Claisen rearrangement of 1c. Charges on allylic oxygen (blue); C–O bond-breaking and
C–C bond-forming distances in TS (black).
Figure 3: ωB97X-D/6-31G* calculated Schreiner thiourea (12)-catalyzed Ireland–Claisen rearrangement of 1c. Charges on allylic oxygen (blue); C–O
bond-breaking and C–C bond-forming distances in TS (black); hydrogen-bond distances (black).
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Figure 4: ωB97X-D/6-31G* calculated Ph-thiourea (top) and squaramide-catalyzed (bottom) Ireland–Claisen rearrangement of 1c. Charges on allylic
oxygen (blue); C–O bond-breaking and C–C bond-forming distances in TS (black); hydrogen-bond distances (black).
Table 6: Comparison of DFT-calculated interaction energies between starting silyl ketene acetal/transition state structure and catalysts.
Structure
ΔE (kJ·mol−1)a
Structure
ΔE (kJ·mol−1)a
(
E)-2c (C12)
TS-(E)-2c (C12)
Z)-2c (C12)
TS-(Z)-2c (C12)
−135.5
−105.0
−112.1
−98.0
(E)-2c (Ph-thiourea)
TS-(E)-2c (Ph-thiourea)
(E)-2c (squaramide)
TS-(E)-2c (squaramide)
−91.7
−61.8
−119.2
−122.7
(
aCalculated at ωB97X-D/6-31G*// M06-2X/6-311+G** level as a difference between electronic energy of 2c–catalyst (or TS-2c–catalyst) complex and
sum of individual components.
Figure 5: a) Rate of product formation; b) reaction profile without catalyst determined by 1H NMR.
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Beilstein J. Org. Chem. 2019, 15, 2948–2957.
parison of product formation in the presence of 0, 10, and with anhydrous MgSO4. The solvent was evaporated under
5
0 mol % of catalyst C12. As can be seen, the catalyst hindered reduced pressure.
product formation and at 50 mol % catalyst loading product 3c
practically does not form. A reaction profile without catalyst is
displayed in Figure 5b. In this case, the formation of a small
amount of an unidentified byproduct was also observed. The
rate constants for the uncatalyzed and catalyzed reaction are
similar. The activation Gibbs energy was determined to be
approximately 90 kJ·mol−1, which agrees well with the DFT
calculated values. These kinetic measurements support the
notion that H-bonding catalysts bind stronger to starting silyl
ketene acetals and thus prevent it from undergoing
Ireland–Claisen rearrangement. For more details, see Support-
ing Information File 1.
Supporting Information
Supporting Information File 1
Experimental procedures and characterization data for all
compounds, copies of NMR spectra, details of DFT
calculations.
[
https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-290-S1.pdf]
Acknowledgements
This publication is the result of the project implementation
262401200025 supported by the Research & Development
Conclusion
Chiral hydrogen-bond-donating organocatalysts such as Operational Program funded by the ERDF. We thank Dr. Marek
thioureas, squaramides, or alcohols failed to catalyze the Cigáň for valuable discussions.
Ireland–Claisen rearrangement of silyl ketene acetals. Compari-
son experiments showed that increasing catalyst loading gradu- ORCID® iDs
ally slowed-down the reaction. DFT calculations using long-
range corrected hybrid density ωB97X-D functional showed
that thioureas and squaramides stabilize the starting ground
Dominika Krištofíková - https://orcid.org/0000-0001-5081-5986
Radovan Šebesta - https://orcid.org/0000-0002-7975-3608
state more than the corresponding transitions states. This fact References
leads to a higher activation barrier and slower reactions in the
presence of hydrogen-bond donating organocatalysts. On the
other hand, catalyst-free Ireland–Claisen rearrangements
proceed well in green solvents such as CpOMe or under sol-
vent-free conditions. NMR kinetic measurements supported the
notion that thiourea and squaramide organocatalysts bind
strongly to the starting silyl ketene acetals and prevent the
Ireland–Claisen rearrangement. Further experiments towards
finding more effective organocatalysts are underway in our lab-
oratory.
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(
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organic solution was washed with water (3 × 12 mL) and dried
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