Preferred Binding of Carboxylates by Chiral Urea Derivatives Containing α-Phenylethyl Group

Article abstract of DOI:10.1002/hlca.201500177

An efficient, simple protocol for the synthesis of a new family of chiral ureas 1 – 4 is described. The binding properties of 1 – 4 toward different anion (acetate, benzoate, fluoride, and chloride) have been studied by¹H-NMR titration and have been observed in the case of 4 is a selective receptor for acetate. The theoretical calculation M06/6-311+G(d,p) helped us explain the binding properties observed. The most interesting observation is that this calculated structure is consistent with expected, based on the concept of allylic 1,3-strain (A^1,3strain). When chiral caboxylates were studied, urea 1 was the best in discriminating between enantiomers.

Full text of DOI:10.1002/hlca.201500177

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Helv. Chim. Acta 2016, 99, 416 – 424
FULL PAPER
Preferred Binding of Carboxylates by Chiral Urea Derivatives Containing
a-Phenylethyl Group
a
by Mayra Cortes-Hernandez ), Susana Rojas-Lima ), Marcos Hernandez-Rodrıguez ), Julian Cruz-Borbolla ), and
a
b
a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
a
Heraclio Lopez-Ruiz* )
ꢀ
a
ꢀ
) Area Academica de Quımica, Universidad Autonoma del Estado de Hidalgo, Carretera Pachuca-Tulancingo Km 4.5,
ꢀ
ꢀ
ꢀ
ꢀ
Ciudad del conocimiento, 42074 Mineral de la Reforma, Mexico (phone: +527717172000X 2208; fax: +527717172000x6502;
e-mail: heraclio@uaeh.edu.mx)
b
ꢀ
ꢀ
ꢀ
ꢀ
) Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Del. Coyoacan,
ꢀ
04510, Mexico D.F., Mexico
ꢀ
An efficient, simple protocol for the synthesis of a new family of chiral ureas 1 – 4 is described. The binding properties of
1 – 4 toward different anion (acetate, benzoate, fluoride, and chloride) have been studied by 1H-NMR titration and have
been observed in the case of 4 is a selective receptor for acetate. The theoretical calculation M06/6-311+G(d,p) helped us
explain the binding properties observed. The most interesting observation is that this calculated structure is consistent with
expected, based on the concept of allylic 1,3-strain (A1,3 strain). When chiral caboxylates were studied, urea 1 was the best in
discriminating between enantiomers.
Keywords: Ab initio calculations, Density functional theory, Hydrogen bonds, Binding constant.
The design of selective receptors for anions is based on
the geometry of the anion, its size, and basicity. Another
Supramolecular chemistry, defined as chemistry beyond feature to take into account is the possible receptor preor-
Introduction
the molecule [1], is intrinsically dynamic in view of the
reversibility of noncovalent interactions which connect
the molecular components into a supramolecular entity.
ganization or its restricted conformation, both of which
will reduce the conformational entropy loss that occurs
upon guest binding. In this regard, 1,3-disubstitued ureas
Selective anion recognition plays a critical role in biologi- display a preference for (Z,Z)-conformation ideal for
cal processes. A variety of receptors and carriers can be
found throughout the natural world, and molecular recog-
nition using synthetic receptors has been extensively stud-
ied. The urea moiety plays an important role in the
recognition of anions [2] due to its ability to donate two
H-bonds to the anion and also because of its pivotal
role in biological, environmental, and industrial applica-
tion [3].
anion binding which is in sharp contrast to the behavior of
thioureas which prefer the (E,Z)-conformation [11]. This
also applies when the receptor has C(3) symmetry [8b][12].
Herein, we would like to report on the binding prop-
erties of the urea receptors 1 – 4 with acetate anion.
Using 1H-NMR experiments in (D6)DMSO, it was
observed that these molecules are capable of selective
anion recognition of carboxylate over halogen ions and
they have been investigated as chiral receptors for amino
Ureas are frequently used in organocatalysis to acti-
vate substrates by H-bonding or to bind anions [2][4]. In carboxylic acids. Also, the interaction between acetate
this regard, urea complexation with carboxylates has been and urea was modeled by theoretical studies.
used in chiral counterion catalysis and in kinetic resolu-
tions [5]. Many artificial carboxylate receptors, such as
Results and Discussion
guanidinium [6], calix[2]arene[2]triazine [7], bis-chrome-
nyl urea [8] among others [9], have been reported. Recog-
Synthesis of Receptors 1 – 4
nition of carboxylate anions and carboxylic acids by
synthetic receptors is of paramount interest due to their Urea receptors 1 – 4 were obtained through Curtius rear-
presence in a variety of biomolecules, such as amino acids
and peptides, which have huge application in pharmaceu-
tical science [10].
rangement of the corresponding acylazide followed by
capture of the isocyanate with (S)-phenylethylamine [13].
Urea 1 was prepared through this methodology in 96%
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Helv. Chim. Acta 2016, 99, 416 – 424
417
yield (phenylisocyanate obtained via addition of sodium
1H-NMR Titration Studies
azide to benzoyl chloride). Receptors 2, 3, and 4 were
obtained from the di- or triacyl chloride in 68%, 57%,
and 62% yield, respectively (Fig. 1). All compounds were
In order to investigate the binding properties of receptors
1 – 4 and to obtain the stoichiometry of their adducts
with acetate ion, Job plots [14] were first performed.
(Fig. 2) Ureas 1, 3, and 4 showed a 1:1 ratio in their
1
characterized by H-NMR, 13C-NMR, and high-resolution
mass spectrometry.
Fig. 1. Ureas 1 – 4 employed in this study.
Fig. 2. The Job0s plot of receptors 1 – 4 with tetrabutylammonium acetate using 1H-NMR.
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Helv. Chim. Acta 2016, 99, 416 – 424
Table 1. Association constants of receptors 1, 2, 3, and 4 with tetrabutylammonium anions in (D6)DMSO from 1H-NMR titration
Receptor + anion
Stoichiometrya)
Ka (Mꢀ1)b)
dend [ppm]
dinitial [ppm]
Dd [ppm]
1 + AcOꢀ
2 + AcOꢀ
1:1
1:2
213 (7%)c)
10.3132
9.6803
8.3715
8.3328
1.9417
1.3475
Ka1 = 262 (3%)
Ka2 = 39 (10%)c)
74 (5%)c)
3 + AcOꢀ
4 + AcOꢀ
4 + Fꢀ
1:1
1:1
1:1
1:1
1:1
10.1986
7.4560
8.7875
8.2181
7.1356
8.1657
6.4265
6.42645
6.4284
6.4270
2.0329
1.0295
2.3610
1.7897
0.7086
138d) (10%)c)
80d) (3%)c)
4 + C6H5COOꢀ
4 + Clꢀ
54d) (7%)c)
27d) (15%)c)
a) Stoichiometry was determined from Job plots, except for chloride and fluoride anions see Fig. 2. b) Association constants were calculated
by the computer program WINEQNMR [15], which requires the concentration of each component and the observed chemical shift of NHB of
c
the urea. ) Estimated error. d) Ka’s were calculated of NHC.
interaction with acetate and urea 2 showed a 2:1 stoi-
chiometry with acetate (Table 1).
probably because the need of the carboxylate to interact
with other hydrogens which are not at optimal distance in
Complexation of ureas 1 – 4 was measured by stan- these receptors. Although more H-bonds are made in
dard H-NMR titration experiments in (D6)DMSO using these cases, these are weaker, and as a result, ureas 3 and
1
constant host concentration (10 mM) and increasing con-
centration of anions (0.2 – 30 equiv.). The chemical shift
data and total concentrations were analyzed by
WINEQNMR2 [15] to obtain the binding constant. The
addition of tetrabutylammoniun acetate to the solution of
receptor 1 in (D6)DMSO resulted in downfield shifts of
1.94 ppm for both NH of the urea (see Fig. 3). This
behavior is indicative of a direct interaction between this
proton and the anion.
4 have less binding toward acetate. Urea 3 showed a 1:1
stoichiometry with acetate, but lower binding was found
(see Fig. 4). When interaction of F and Cl anions with
receptor 4 was investigated, it was found that fluoride,
due to its basic nature was a better guest than chloride,
but still not as strong as acetate.
Computer Modeling
The analysis of binding constants (Table 1) showed Ab initio calculations showed details of the complexation
that urea 1 gave better bonding than ureas 3 and 4, between ureas 1 – 4 and acetate anion. The conformational
Fig. 3. Stack plot of 1H-NMRs of urea 1 on addition of tetrabutylammonium acetate (0.2 – 33 equiv. in (D6)DMSO, 400 MHz).
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Helv. Chim. Acta 2016, 99, 416 – 424
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Fig. 4. Stack plot of 1H-NMRs of urea 3 on addition of tetrabutylammonium acetate (0.2 – 33 equiv. in (D6)DMSO, 400 MHz).
prediction of ureas 1 – 4 was performed using the Born– the geometries were optimized using DMSO medium by
Oppenheimer molecular dynamics with the exchange and PCM method [23]. All calculations, including zero point
correlation functional PBE in combination with the orbital
and auxiliary basis sets DZVP and GEN-A2, respectively,
as implemented in the program deMonk2k [16]. All the tra-
jectories were recorded at 300 K which was controlled by
energy (ZPE) corrections, were also corrected for the
BSSE using the counterpoise scheme of Boys and Ber-
nardi [24]. The electronic energies (ΔE, ΔH, and ΔG) of
monomers and complexes are summarized in Tables S1
the canonical BOMD simulations with a Hoover chain and S2. Only for carboxylate-urea complexes the theoreti-
thermostat. The simulations were started from the equilib- cal calculations of those energies agree, in the case of
rium geometry, with random velocities assigned to the
atoms. All systems were sampled for 10 ps with a 1 fs step
size. This methodology allows us to find the most stable
conformers [17].
halogen-urea complexes these calculated and experimen-
tal values did not match. The structures of anion-urea
complexes shown correspond to the calculated lowest
energy structures. (SI-Coordinates for Optimized Geome-
tries.). The binding energies of gas phase are larger in
The lowest energy conformers found for all ureas
(Fig. 5) show syn-periplanar arrangements between the absolute magnitude compared to those in DMSO as
expected from the shielding effect by solvent.
C–H bond at the a-phenylethyl fragment and the N–C(O)
A1,3
segment, a manifestation of the allylic
strain [18].
When ureas 1 – 4 were binding to acetate, it was
found that not only the NH of the urea participates in the
complexation process but also aromatic C–H of the phe-
The most stable conformers were selected for each
urea and then a local optimization was performed with
three functionals: the Becke’s three-parameter hybrid nylethyl or the aryl ring on the nitrogen. Fig. 6 shows all
functional (B3LYP) [19], the hybrid functional of Truhlar
and Zhao (M06) [20], and the long range-corrected ver-
sion of wPBE (LC-wPBE) [21]; in all cases, we used the
the possible H-bonding interaction between acetate and
ureas 1 – 4 derived from AIM (atoms molecules) theory
[25], and MULTIWFN (version 3.1) [26] was used to
6-311+G(d,p) orbital basis set for all atoms using the study H-bonding interactions.
Gaussian 09 program (Rev. A 02) (other references
related to use of this method see ref. [22]). For all the
systems, after optimizing the geometries, the frequencies
were calculated to identify local minimum energies using
The green dots in Fig. 6 represent bond critical points
(BCPs). Within this theory, the BCP should connect
directly to the pair of atoms (hydrogen and acceptor
atom) along the path defined by the electron density gra-
the number of imaginary frequencies (NIMAG = 0). All dient. This is one of the most important criteria when
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Helv. Chim. Acta 2016, 99, 416 – 424
Fig. 5. Lowest-energy conformers for ureas 1 – 4 optimized by M06/6-311+G(d,p) in kcal/mol.
Fig. 6. Detailed description of H-bonding interactions between receptors 1 – 4 and acetate ion.
examining intermolecular interactions. Using this crite-
rion, the number of possible H-bonding interaction and B an acceptor. By analyzing the optimized structures,
denoted as X–HꢁꢁꢁB, where X–H is a H-bonding donor
between hosts and MeCO2ꢀ were 4, 4, 3, and 4 for recep-
tors 1, 2, 3, and 4, respectively, as indicated by either
it is observed that the X–H bond length in X–HꢁꢁꢁB is lar-
ger than that of corresponding free X–H bond. For exam-
dashed or dotted line in Fig. 6. In Table 2, H-atoms ple, in adduct 1-OAc N–Hs are elongated by HB ~0.023
ꢀ
ꢁ
involved in H-bonding are denoted as HA, HB, HC, and and HC ~0.021 A. In addition, aromatic HAꢁꢁꢁO and
ꢁ
HD. Relevant physical parameters involving host–guest HDꢁꢁꢁO (~2.5- 2.8 A) H-bond interactions are also
interaction are listed in Table 2. H-bonding is mostly
observed [27].
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Helv. Chim. Acta 2016, 99, 416 – 424
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Table 2. Geometries and charges of receptors 1 – 4 and their AcOꢀ complexa)
Host (complex)
1
2
3
4
1 + MeCOOꢀ
2 + MeCOOꢀ
3 + MeCOOꢀ
4 + MeCOOꢀ
Q (H)
HA
HB
0.0449
0.1402
0.1361
0.0421
0.1403
0.1290
0.0437
0.0475
0.1397
0.1349
0.0356
0.0253
0.1448
0.1399
0.0385
0.0251
0.0794
0.0768
0.0274
0.0236
0.0796
0.0772
0.0248
0.0282
0.0789
0.0764
0.0276
0.0120
0.0803
0.0786
0.0270
HC
HD
0.0353
ꢁ
Bond length (X–H) [A]
HA–C
HB–N
HC–N
HD–C
1.0874
1.0865
1.0113
1.0111
1.0879
1.0870
1.0114
1.0108
1.0875
1.0870
1.0114
1.0107
1.0875
1.0872
1.0344
1.0320
1.0884
1.0864
1.0346
1.0322
1.0890
1.0868
1.0343
1.0319
1.0883
1.0814
1.0361
1.0327
1.0885
1.0114
1.0105
1.0875
ꢁ
Distance (HꢁꢁꢁB) [A]
HAꢁꢁꢁO
2.5125
1.8181
1.8440
2.7684
2.5423
1.8156
1.8439
2.5266
2.5297
1.8183
1.8426
2.9092
2.5613
1.7966
1.8407
2.6868
HBꢁꢁꢁO
HCꢁꢁꢁO
HDꢁꢁꢁO
ꢁ
Distance (XꢁꢁꢁB) [A]
C (ring)ꢁꢁꢁO
NBꢁꢁꢁO
3.3824
2.8501
2.8720
3.7681
3.4000
2.8483
2.8706
3.5573
3.3925
2.8503
2.8715
3.8643
3.3930
2.8306
2.8673
3.6811
NCꢁꢁꢁO
C (ring)ꢁꢁꢁO
Angle [deg]
C–HAꢁꢁꢁO
N–HBꢁꢁꢁO
N–HCꢁꢁꢁO
C–HDꢁꢁꢁO
q(b)b)
136.2
175.0
173.6
152.6
135.1
175.6
172.5
157.5
135.6
175.2
174.5
146.5
133.0
175.4
172.2
151.6
HAꢁꢁꢁO
0.0086
0.0348
0.0328
0.0052
0.0082
0.0349
0.0330
0.0079
0.0083
0.0348
0.0329
–
0.0079
0.0364
0.0332
0.0061
HBꢁꢁꢁO
HCꢁꢁꢁO
HDꢁꢁꢁO
∇2q(b)c)
HAꢁꢁꢁO
0.0331
0.1208
0.1147
0.0268
0.0281
0.1156
0.1105
0.0258
0.0286
0.1152
0.1109
–
0.0274
0.1198
0.1109
0.0197
HBꢁꢁꢁO
HCꢁꢁꢁO
HDꢁꢁꢁO
d
EHꢁꢁꢁB
)
HAꢁꢁꢁO
HBꢁꢁꢁO
HCꢁꢁꢁO
HDꢁꢁꢁO
ꢀ1.721
ꢀ8.796
ꢀ8.104
ꢀ0.998
ꢀ1.635
ꢀ8.855
ꢀ8.145
ꢀ1.5127
ꢀ1.656
ꢀ8.800
ꢀ8.122
–
ꢀ1.583
ꢀ9.414
ꢀ8.198
ꢀ1.165
a
ꢁ
) Q is the partial atomic charge derived using Hirshfeld. Distances are in angstroms [A], angles are in degrees [°]. M06/6-311+G** level or
theory. b) q(b) is the electron density at the bond critical point (BCP’s). c) ∇2q(b) is Laplacian electron density at BCP. When two or more
equivalents were obtained, overage values are listed. d) EHꢁꢁꢁB is the H-bond energy expressed in kcal/mol.
Because host structures are rather rigid and interac-
tion elements are not independent of one another, geo-
metric considerations alone would not be sufficient to
determine the relative strengths of H-bonding. Therefore,
we also considered electronic properties. Another com-
mon feature of H-bonding is the depletion of electron
density around the central H-atom. This was found to be
the case for all interactions in Fig. 6.
positive values of ∇2q(b) and q(b). For strong H-bonds,
∇2q(b) is positive and q(b) is negative. For very strong H-
bonds, both these values are negative. According to this
criteria, as listed in Table 2, HBꢁꢁꢁO and HCꢁꢁꢁO are weak
H-bonds for receptors 1, 2, 3, and 4.
The interaction of aromatic C–H with the acetate was
also confirmed experimentally. As shown in Fig. 7, the
beginning and the end of titration of urea 1 with acetate.
It was found that orthohydrogens were shifted to higher
The topological criteria of the existence of a H-bond
were proposed by Koch and Popelier [28]. Rozas et al. chemical shift than the others hydrogens and defined mul-
[29] have classified H-bonds applying QTAIM parame- tiplets were found because of a higher organization due
ters: the Laplacian of the electron density at HꢁꢁꢁO BCP
to the additional H-bonding.
After the binding studies of ureas with acetate, we
and the total electron energy density at this BCP, desig-
nated further in this study as ∇2q(b) and q(b), respec- set out to explore binding with chiral carboxylates were
tively. Weak and medium in strength H-bond show
studied. Therefore, all guest ureas were titrated with salts
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Helv. Chim. Acta 2016, 99, 416 – 424
Fig. 7. Comparison of aromatic CH of urea 1 and urea 1 + acetate adduct.
of both enantiomers of mandelic acid. Results showed a
lower association compared to that of acetate; this can be
explained in terms of a larger steric effect with the substi-
tuted carboxylate. The enantiorecognition with these
Conclusions
In summary, we synthesized a new family of chiral ureas
as anion receptors containing the a-phenylethyl group
ureas was very low with ureas 3 and 4, and urea 1 gave with benzene platforms. 1H-NMR titrations showed that
the best result in the discrimination of mandelate. Further
studies on the association of this urea with other chiral
carboxylates found nearly no discrimination of protected
aminoacids, phenylglycinate, and alaninate but chiral dis-
receptor 4 is a selective receptor for acetate, and ureas 1
and 2 showed strong association constant for acetate in
polar solvent such as DMSO. In DMSO, acetate was com-
plexed by receptors 1, 3, and 4 via four types of H-bond-
crimination was very high towards the (S)-enantiomers of ing involving urea NB–H and NC–H, and aromatic
N-Boc-prolinate and naproxenate (Table 3).
interaction C–HA and C–HB. However, only eight types
Table 3. Binding constantsa) of receptors 1 – 4 with various anions chirals obtained from 1H-NMR titrations in (D6)DMSO with anions added
as TBA salts
Receptor + anion
Ka (Mꢀ1) (%)b)
dend [ppm]
dinitial [ppm]
Dd [ppm]
Selectivity factor
K(S)/K(R)
1 + (S)-Mandelate
1 + (R)-Mandelate
2 + (S)-Mandelate
2 + (R)-Mandelate
3 + (S)-Mandelate
3 + (R)-Mandelate
4 + (S)-Mandelate
4 + (R)-Mandelate
1 + Boc-(S)-Alaninate
1 + Boc-(R)-Alaninate
1 + CBz-(S)-Phenylglycinate
1 + CBz-(R)-Phenylglycinate
1 + Boc-(S)-Prolinate
1 + Boc-(R)-Prolinate
1 + (S)-Naproxenate
1 + (R)-Naproxenate
26 (3)
54 (4)
31 (6)
19 (5)
16 (6)
16 (7)
20 (8)
17 (6)
98 (2)
92 (6)
32 (6)
29 (10)
402 (2)
59 (2)
417 (3)
83 (3)
11.006
8.3667
8.3634
8.3259
8.3114
8.1696
8.1700
8.2875
8.286
2.6393
2.0825
1.3306
1.5181
1.9359
1.8334
0.9155
0.8305
2.218
2.1c)
1.6
10.4459
9.6565
9.8295
10.1055
10.0034
9.2030
1.0
1.2
9.1165
10.5829
10.6060
10.5105
10.9415
11.1835
10.1757
11.1479
10.7599
8.3649
8.3624
8.3758
8.3748
8.3622
8.3614
8.3622
8.3638
1.1
2.2436
2.1347
2.5667
2.8213
1.8143
2.7857
2.3961
1.1
6.8c)
5.0c)
a) Binding constants were calculated by the computer program WINEQNMR, considering a stoichiometric receptor: anion (1:1) using the
c
chemical shift of NHB. b) Selectivity factor K(R)/K(S). ) Estimated error.
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Helv. Chim. Acta 2016, 99, 416 – 424
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of H-bonding were expected for receptor 2. Theoretical that formed was filtered, and in all cases, crude product
calculation let to the identification of an additional H- was purified by recrystallization using AcOEt to afford the
bonding element. When chiral carboxylates were studied, final product.
the simplest urea 1 was the most effective towards bind- Synthesis of 1-Phenyl-3-[(1S)-1-phenylethyl]urea (1). Ben-
ing and discrimination of enantiomers.
zoyl chloride (0.50 ml, 4.31 mmol) and sodium azide
(0.561 g, 8.62 mmol) were allowed to react according to
the General Procedure for 80 min to give the benzoyl
azide. This product was left stirring at 80 °C for 90 min
to obtain the isocyanate. Then (–)-(S)-a-phenylethylamine
(0.6 ml, 4.70 mmol) was added and the reaction mixture
was stirred overnight at 80 °C to afford 0.870 g (84%
We are indebted to CONACyT for financial support
(grant CB-2012-01-182415) and PRODEP-SEP-2015. One
ꢀ
of the authors (Mayra Cortes-Hernandez) is thankful to
CONACyT for scholarship (332517).
ꢀ
yield) of
1 as a white solid (M.p. 149 – 150 °C).
Supporting Information
20
½aꢂD = ꢀ12.0 (c = 1, CHCl3). IR (KBr) 3315, 1554 (N–
H), 1633 (C=O). 1H-NMR (400 MHz, (D6)DMSO): 1.39
(d, 3 H, J = 7.0); 4.83 (m, 1 H); 6.63 (d, 1 H, J = 7.9);
Supporting Information for this article is available on the
www under http://dx.doi.org./10.1002/hlca201500177.
6.88 (tt,
1 H, J = 1.2, 7.3); 7.19 – 7.23 (m, 3 H);
7.33 – 7.35 (m, 4 H); 7.38 (m, 2 H); 8.40 (s, 1 H). 13C-
NMR (100 MHz, (D6)DMSO): 23.1; 48.6; 117.54; 121.08;
125.8; 126.7; 128.4; 128.7; 140.4; 145.2; 154.4. Anal. Calcd.
C15H16N2O (240.30): C 74.97, H 6.71, N 11.66; found C
74.97, H 6.87, N 11.66. These data are similar to those
reported previously by Feng et al. [30].
Experimental Part
General
All reagents for the synthesis were purchased from
Sigma–Aldrich (St. Louis, MO, USA). Organic solvents
€
were dried by standard procedures. M.p.: Buchi Melting
Point B-540 apparatus (Buchi Switzerland); uncorrected.
Synthesis of 1,10-Benzene-1,3-diylbis{3-[(1S)-1-phenylethyl]
urea} (2). Isophthaloyl chloride (0.500 g, 2.46 mmol) and
sodium azide (0.640 g, 9.85 mmol) were allowed to react
according to the General Procedure for 120 min to give
the isophthaloyl azide. This product was left stirring at
80 °C for 2 h to obtain the isocyanate. Then (–)-(S)-a-
phenylethylamine (0.69 ml, 5.42 mmol) was added and the
reaction mixture was stirred overnight at 80 °C to afford
€
Optical rotations were measured at 20 °C on a PerkinEl-
mer 341 Polarimeter (Waltham, MS, USA) at 589 nm (Na
D line) in a 1.0 dm cell with a total volume of 1 ml. IR
Spectra: PerkinElmer FT-IR spectrometer; reported in
terms on frequency of absorption (cmꢀ1). H-NMR Spec-
1
20
tra: Varian VNMR 400 spectrometer (Agilent Technolo-
gies, CA, USA), operating at 400 MHz at 19 °C using
(D6)DMSO as a solvent purchased from Sigma–Aldrich;
all chemical shift values (d) are reported ppm, using the
reference residual solvent signal (2.50) for (D6)DMSO
solns. Elemental analyses: PerkinElmer 2400 Elemental
Analyzer instrument.
0.614 g (62% yield) as a white solid (M.p. > 300 °C). ½aꢂD
= ꢀ44.7 (c = 1, DMSO). IR (KBr) 3300, 1562 (N–H), 1635
(C=O). 1H-NMR (400 MHz, (D6)DMSO): 1.37 (d, 6 H,
J = 7.0); 4.79 (m, 2 H); 6.53 (d, 2 H, J = 7.9); 6.91 – 6.93
(m, 2 H); 7.02 (dd, 1 H, J = 1.6, 7.0); 7.20 – 7.26 (m, 2 H);
7.32 – 7.33 (m, 8 H); 7.44 (t, 1 H, J = 7.9); 8.35 (s, 2 H).
13C-NMR (100 MHz, (D6)DMSO): 23.1; 48.6; 106.7; 110.5;
125.8; 126.7; 128.4; 128.9; 140.7; 145.2; 154.3. Anal. Calcd.
C24H26N4O2 (402.49): C 71.62, H 6.51, N 13.92; found C
71.49, H 6.48, N 13.68.
General Procedure for the Synthesis of Chiral Ureas
(1 – 4)
Synthesis of 1,10-Benzene-1,4-diylbis{3-[(1S)-1-phenylethyl]
urea} (3). Terephthaloyl chloride (0.510 g, 2.51 mmol) and
sodium azide (0.653 g, 10.04 mmol) were allowed to react
according to the General Procedure for 120 min to give
the terephthaloyl azide. This product was left stirring at
80 °C for 2 h to obtain the isocyanate. Then (–)-(S)-a-
phenylethylamine (0.70 ml, 5.53 mmol) was added and
the reaction mixture was stirred overnight at 80 °C to
In a 25 ml round-bottomed flask containing a magnetic
stirring bar was placed 1 equiv. of the corresponding
acyl chloride in 3 ml of dimethylformamide as solvent, fol-
lowed by the addition of 2 – 6 equiv. of sodium azide. The
resulting solution was stirred at r.t. at 1.5 – 2 h. Then the
reaction mixture was diluted with 30 ml AcOEt, washed
with H2O (2 9 30 ml) and brine (2 9 30 ml). The organic
phase was collected, dried (Na2SO4), filtered, and the sol-
vents were vacuum removed (the temperature is main-
tained not over 25 °C ). The acyl azide was used without
further purification and diluted with 15 ml of dry toluene
under nitrogen in a 50 ml round-bottomed flask containing
a magnetic stirring bar. The resulting solution was allowed
to react for 1.5 – 3 h at 80 °C before addition of 1.1 – 3.3
equiv. of (–)-(S)-a-phenylethylamine. The resulting mix-
ture was then stirred at 80 °C overnight. The precipitate
afford 0.506 g (50% yield) as
a white solid (M.p.
20
> 300 °C). ½aꢂD = ꢀ68.6 (c = 1, DMSO). IR (KBr) 3332,
1575 (N–H), 1640 (C=O). 1H-NMR (400 MHz, (D6)
DMSO): 1.37 (d, 6 H, J = 7.0); 4.80 (m, 2 H); 6.54 (d, 2
H, J = 7.9); 7.21 (s, 4 H); 7.23 (t, 1 H, J = 4.3); 7.32 (m, 8
H); 8.22 (s, 2H). 13C-NMR (100 MHz, (D6)DMSO): 23.2;
48.6; 118.3; 125.8; 126.6; 128.4; 134.2; 145.4; 154.6. Anal.
Calcd. C24H26N4O2 (402.49): C 71.62, H 6.51, N 13.92;
found C 71.59, H 6.51, N 13.70.
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
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424
Helv. Chim. Acta 2016, 99, 416 – 424
Synthesis of 1,10,100-Benzene-1,3,5-triyltris{3-[(1S)-1-phenyl-
ethyl]urea} (4). 1,3,5-benzenetricarbonyl trichloride
Chem. 2002, 2, 247; B. Dietrich, T. M. Fyles, J.-M. Lehn, L. G.
Pease, D. L. Fyles, J. Chem. Soc., Chem. Commun. 1978, 934.
[7] A. I. Vicente, J. M. Caio, J. Sardinha, C. Moiteiro, R. Delgado,
(0.300 g, 1.13 mmol) and sodium azide (0.441 g, 6.78 mmol)
were allowed to react according to the General Procedure
for 120 min to give the product corresponding. Then ben-
zene-1,3,5-tricarbonyl azide was left stirring at 80 °C for 3 h
to obtain the isocyanate. Then (–)-(S)-a-phenylethylamine
(0.47 ml, 3.73 mmol) was added and the reaction mixture
was stirred overnight at 80 °C to afford 0.255 g (40% yield)
ꢀ
V. Felix, Tetrahedron 2012, 68, 670.
ꢀ
[8] F. de la Torre, E. G. Campos, S. Gonzalez, J. R. Moran,
C. Caballero, Tetrahedron 2001, 57, 3945.
[9] a) T. Y. Joo, N. Singh, G. W. Lee, D. O. Jang, Tetrahedron
Lett. 2007, 48, 8846; b) V. Simic, L. Bouteiller, M. Jalabert, J.
Am. Chem. Soc. 2003, 125, 13148; c) T. Akita, Y. Matsui, T.
Yamamoto, J. Mol. Struct. 2014, 1060, 138.
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ꢀ
[11] C. Roussel, M. Roman, F. Andreoli, A. Del Rıo, R. Faure, N.
20
as a white solid (M.p. > 300 °C). ½aꢂD = ꢀ39.2 (c = 1,
DMSO). IR (KBr) 3299, 1552 (N–H), 1641 (C=O). 1H-NMR
(400 MHz, (D6)DMSO): 1.36 (d, 9 H, J = 6.9); 4.78 (m, 3
H); 6.43 (d, 3 H, J = 7.8); 7.06 (s, 3 H); 7.20 – 7.24 (m, 3 H);
7.31 – 7.32 (m, 12 H); 8.29 (s, 3 H). 13C-NMR (100 MHz,
(D6)DMSO): 23.5; 48.9; 100.4; 126.2; 127.1; 128.7; 141.2;
145.6; 154.7. Anal. Calcd. C33H36N6O3 (564.68): C 70.19, H
6.43, N 14.88; found C 69.92, H 6.45, N 14.57.
Vanthuyne, Chirality 2006, 18, 762.
€
[12] M. -L. L. Watat, T. Dulcks, D. Kemken, V. A. Azov, Tetrahe-
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Domınguez, R. Flores-Moreno, G. U. Gamboa, A. Goursot, T.
Heine, A. Ipatov, F. Janetzko, J. M. del Campo, J. U. Reveles,
1
General Procedure for H-NMR Titrations
ꢀ~
ꢀ
A. Vela, B. Zuniga-Gutierrez, D. R. Salahub, deMon2k, Ver-
sion 3, The deMon developers, Cinvestav, Mexico City, 2011.
[17] M. Carmona-Picardo, R. L. Camacho-Mendoza, L. A. Zarate
In a NMR tube, 0.005 mmol of the urea was dissolved in
1
0.5 ml of (D6)DMSO. A H-NMR spectrum was acquired
and the signals in the chemical shift of NH accounted as
free urea. The titrations were carried out by the consecu-
tive additions of tetrabutylammonium salts (NBu4+Xꢀ;
Xꢀ=CH3COOꢀ,C6H5COOꢀ, Fꢀ, Clꢀ) stock solution until
the chemical shift of the HB or HC reached steady values
which was accounted as the urea-anion adduct. With the
data of concentration and chemical shifts during the titra-
tion the binding constants with WINEQNMR2 [15] were
obtained. The stock solution of carboxylate of tetrabutyl-
ammonium was prepared with 0.2 mmol of AcOH in 2 ml
of tetrabutylammonium hydroxide (0.1M in iPrOH and
MeOH), this mixture was placed in an ultrasonic bath for
25 min, the solvents were reduced to dryness before addi-
tion of 1 ml of (D6)DMSO.
ꢀ
Hernandez, J. Cruz-Borbolla, C. A. Gonzalez-Ramırez, T. Pan-
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ꢀ
ꢀ
~
Rico, M. A. Pena-Gonzalez, M. Hernandez-Rodrıguez, New. J.
ꢀ
ꢀ
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Chem. 2013, 37, 2610.
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Received July 7, 2015
Accepted April 18, 2016
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€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com