Cocrystallization of Chiral N7,N16-bis (S-1-Phenylethyl)-1,4,10,13-Tetraoxo-7,16-Diazacyclooctadecane-7,16-Dicarboxamide with Hydrochlorides of Methyl Ethers of Leucine and Valine Enantiomers

Article abstract of DOI:10.1134/S0022476619010207

An attempt to co-crystallize N7,N16-bis(S-1-phenylethyl)-1,4,10,13-tetraoxo-7,16-diazacyclooctadecane-7,16-dicarboxamide (1) with hydrochlorides of methyl ethers (HCMEs) of L- and D-valine and also L- and D-leucine results in separate crystallization of diazacrown-ether 1 (or its monohydrate 1·H₂O) and HCMEs of respective α-amino acids. Crystal structures of D-leucine 1·H₂O (1) and HCME (2) compounds, which were not described previously, are solved by single crystal X-ray diffraction.

Full text of DOI:10.1134/S0022476619010207

Journal of Structural Chemistry. Vol. 60, No. 1, pp. 143-150, 2019.
Russian Text © 2019 M. S. Fonari, S. M. Pluzhnik-Gladyr, G. L. Kamalov, V. Kh. Kravtsov.
COCRYSTALLIZATION OF CHIRAL N7,N16-bis
(S-1-PHENYLETHYL)-1,4,10,13-TETRAOXO-7,16-
DIAZACYCLOOCTADECANE-7,16-DICARBOXAMIDE
WITH HYDROCHLORIDES OF METHYL ETHERS
OF LEUCINE AND VALINE ENANTIOMERS
1 2
M. S. Fonari , S. M. Pluzhnik-Gladyr ,
2
G. L. Kamalov , and V. Kh. Kravtsov
1
An attempt to co-crystallize N7,N16-bis(S-1-phenylethyl)-1,4,10,13-tetraoxo-7,16-diazacyclooctadecane-
7,16-dicarboxamide (1) with hydrochlorides of methyl ethers (HCMEs) of L- and D-valine and also L- and
D-leucine results in separate crystallization of diazacrown-ether 1 (or its monohydrate 1⋅H O) and HCMEs
2
of respective α-amino acids. Crystal structures of D-leucine 1⋅H O (1) and HCME (2) compounds, which
2
were not described previously, are solved by single crystal X-ray diffraction.
DOI: 10.1134/S0022476619010207
Keywords: co-crystallization, crystal structure, enantiomer, crown-ether, amino acid, conformation,
hydrogen bond.
A search for the ways of effective separation of enantiomers is one of the most important problems of
supramolecular chemistry [1]. Examples of the successful recognition of chiral amines and their salts by chiral
macroheterocycles (in particular, derivatives of 18-crown-6 and diaza-18-crown-6) are given in reviews [2, 3]. One of the
approaches to the solution of the problem being discussed is the use of solutions of chiral crown-ethers (CEs) as a liquid
membrane in transporting α-amino acid racemates through it [4].
We have previously reported [5] the preparation of a series of substituted crown-ureas, including optically active
threo-N7,N16-bis(R-1-phenylethyl)-1,4,10,13-tetraoxo-7,16-diazacyclooctadecane-7,16-dicarboxamide, by the counter
synthesis.
In this work, we present data on the synthesis and structure of optically active threo-N7,N16-bis(S-1-phenylethyl)-
1,4,10,13-tetraoxo-7,16-diazacyclooctadecane-7,16-dicarboxamideа (1) which we managed to obtain by the interaction of S-
α-phenylethylisocyanate with 1,10-diaza-18-crown-6 (Scheme).
An attempt was made to consider the possibility of forming complexes of the host–guest type in the interaction (co-
crystallization) of CE 1 with hydrochlorides of methyl ethers (HCMEs) of valine and leucine R- and S-enantiomers. To grow
crystals suitable for the single crystal X-ray diffraction (XRD) analysis we applied a well-proven procedure (see, e.g., [6]) of
diffusion of a replacing solvent carefully deposited on a solution of potential host and guest in the respective solvent.
1
2
Institute of Applied Physics, Chisinau, Republic of Moldova; fonari.xray@phys.asm.md. Bogatsky
Physicochemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine; sergey_pluzhnik@ukr.net. Translated
from Zhurnal Strukturnoi Khimii, Vol. 60, No. 1, pp. 150-157, January, 2019. Original article submitted July 18, 2018;
revised July 18, 2018; accepted September 07, 2018.
0022-4766/19/6001-0143 © 2019 by Pleiades Publishing, Ltd.
143

Scheme.
EXPERIMENTAL
1 13
The melting point was measured in an open capillary. H and C NMR spectra were recorded on a Bruker Advance
1
13
DRX 500 spectrometer (499.95 MHz for H and 125.74 MHz for C); chemical shifts δ are given in ppm relative to TMS as
the internal standard. SSI constants are given in Hz. Mass spectra (electron impact ionization) were measured on a MX 1321
apparatus using the direct sample input, ionization voltage 70 V, ionization chamber temperature 200 °C. The elemental
analysis was carried out on a EuroVector EA3000 CHNS instrument. The optical rotation angle was measured on a Perkin-
Elmer mc 241 polarimeter, 1 dm cuvette. Organic solvents were distilled before the use. Chloroform was dehydrated by
distillation over phosphorus anhydride and diethyl ether was distilled over a sodium wire.
S-α-phenylethylisocyanate was obtained by the modified procedure [7]. 40 g (147.38 mmol) of L-α-
phenylethylamine tartrate (S-isomer) (TU 6-09-05-119-74) were treated with 60 ml of a 50% aqueous solution of potassium
hydroxide. The released free base was extracted by toluene (40 ml×5); combined extracts were dried for 24 h with solid
potassium hydroxide. At 0 °C the obtained solution was stirred for 15 min and treated with an intense flow of dry gaseous
HCl. Then for 5 min an intense phosgene flow was passed through. Phosgene was obtained according to [8]. The reaction
mixture was heated to boiling and treated with a phosgene flow for 3 h until the complete dissolution of the precipitate. The
solvent was removed under reduced pressure (a water jet vacuum pump) and the residue was distilled. We obtained 11.77 g
20
of S-α-phenylethylisocyanate (54.2%). B. p. 72-80 °C (5-10 mm), [α] + 2.24° (with 5.7 C H ), –29.4° (with 2.5 n-C H ),
6 6 7 16
D
PMR δ, ppm in C D , 0.95 (MeC), 3.9 (CH), JMeCH = 6.5 Hz.
6 6
Compound 1. To a solution of 2.54 g (9.68 mmol) 1,10-diaza-18-crown-6 (Pilot Plant, Physicochemical Institute,
Academy of Sciences of Ukraine) in 30 ml of anhydrous chlorophorm at 0 °C a solution of 2.85 g (19.4 mmol) of S-α-
phenylethylisocyanate in 20 ml of dry diethyl ether (DEE) cooled to 0 °C was added. In 24 h the solvent was distilled to
dryness. The residue was washed with DEE (15 ml×3) and crystallized from a 1:5 ethanol–DEE mixture. Yield 4.79 g (89%);
mp 126-127 °C. After the second crystallization from isopropanol m. p. was 133 °C (at a point).
1
H NMR. CDCl . 1.42-1.43, d, J = 6.59, 6H (Me); 3.41-3.64, m, 24H (CE); 4.88, q, J = 6.59, 2H (CH); 6.23-6.24, d,
3
J = 5.76, 2H (NH); 7.19, t, J = 6.86, 2H (п-Ph) 7.30, m, 8H (o-, m-Ph).
13
C NMR. CDCl 23.24, 2C; 50.21, 2C; 50.38, 4C; 70.71, 4C; 71.48, 4C; 126.07, 4C; 126.76, 2C; 128.39, 4C;
3
145.17, 2C; 158.74, 2C.
+
Mass: m/z (%): 556 ([M] , 2); 437([M–MePhCHN] , 3); 409 ([M–MePhCHNHCO] , 12); 263
+
+
+
([HN(C H OC H OC H ) NH ] , 19); 132 ([(C H O) ] , 100); 120 ([MePhCHNH] , 18); 105 ([MePhCH] 26), 77 ([Ph] , 8).
+
+
+
+
2
4
2
4
2
4 2
2
2
4
3
Calculated for C H N O (%): C 64.73, H 7.97, N 10.06.
30 44 4 6
20
Found C 64.69, H 8.01, N 10.04; [α] = +18.952 (with 2.1 CHCl ).
3
D
144

HCMEs of D- and L-leucine and -valine were obtained similarly [9], by placing a portion of amino acid (8-
12 mmol) at room temperature for 24 h in 90 ml of saturated methanol solution of chlorohydrogen. Then the solvent was
removed to dryness on a rotary evaporator, the residue was washed with DEE (15 ml×3), and leucine HCME was crystallized
from a 1:5 methanol–diisopropyl ether mixture (and valine from acetone) and dried in a vacuum desiccator over dry sodium
hydroxide. HCME: L-leucine, yield 86%, m. p. 146 °C; D-leucine, yield 84%, m. p. 145-146 °C; L-valine, yield 81%, m. p.
167-168 °C; D-valine, yield 77%, m. p. 165-167 °C.
Co-crystallization of CE 1 with HCMEs of D- and L-leucine and -valine. A glass tube with an inner diameter of
8 mm constricted in the middle to an inner diameter of 1 mm was filled to the middle of the narrow part (by means of
a pipette with a long capillary end) with a solution of an equimolar mixture of CE 1 and HCME of respective amino acid in
isopropanol. n-Hexane was carefully deposited from above and the system was placed in a hermetic glass container. As
hexane diffused into the solution of components, the crystal growth was observed.
X-ray crystallography. Structural data on the prepared compounds were obtained at room temperature in
an Xcalibur ССD Oxford Diffraction diffractometer (MoK radiation, λ = 0.71073 Å, graphite monochromator, ω-scanning).
α
Unit cell parameters were refined over the entire set of experimental data. Crystal structures were solved by a direct method
and refined by the least squares technique in the anisotropic full-matrix variant for non-hydrogen atoms. Positions of
hydrogen atoms of a water molecule in hydrate 1⋅H O were found from the Fourier difference maps. Positions of the other
2
hydrogen atoms were calculated geometrically and refined isotropically in the rigid body model. All calculations were
2
performed in the SHELX-2014 program package [10]. The refinement was carried out using a set of F values of the
structural data.
In a molecule of CE 1 two fragments of oxyethylene chains are disordered over two positions and refined with
occupancy multiplicities of 0.67(1) and 0.33(1) for the С3–O3–C4–C5–O4 fragment and 0.712(8) and 0.288(8) for the
С9–О5 fragment. Crystallographic data and characteristics of the experiment for compounds 1, 1⋅H O, and 2 are summarized
2
in Table 1; the parameters of hydrogen bonds are listed in Table 2; some torsion angles of a molecule of CE 1 are given in
Table 3; geometric parameters for compound 2 are gathered in Table 4. Crystallographic data for compounds 1, 1⋅H O, and 2
2
have been deposited with the Cambridge Crystallographic Data Center (CCDC No CIF files CCDC No 1856189-1856191,
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
RESULTS AND DISCUSSION
Four experiments on co-crystallization of CE 1 with HCME of R-enantiomer (A) and S-enantiomer (B) of valine and
also with HCME of S-enantiomer (C) and R-enantiomer (D) of leucine were performed. For A two groups of crystals were
successively isolated: monohydrate with the composition 1⋅H O and initial HCME of D-valine whose parameters correspond
2
to those deposited with CCDC (Refcode HABXAK [11], stereoisomer RAJKUK [12]). For B transparent crystals
corresponding to CE 1 proved to be suitable for the measurement. In experiment C a mixture of crystals forms: blocks
corresponding to CE 1 and thin needles (seems to be a guest) whose structure was not solved. Finally, for D also two types of
crystals were found: bulk transparent crystals corresponding to CE 1 and needle-like crystals of better quality than those in
sample С, identified as HCME of D-leucine. Data on the structure of the latter are absent in CCDC.
CE 1 crystallizes in the orthorhombic space group P2 2 2 (Table 1). Ordered fragments of the molecule are
1 1 1
characterized by interatomic distances and bond angles similar to those of substituted diaza-CEs [13]. The molecule takes
a general position in the cell and has an S-like shape (Fig. 1а). The macroheterocycle is elongated towards substituents, which
is indicated by substantially different trans-annular distances between heteroatoms, namely, an increased distance
N(3)…N(4) = 7.549(5) Å as compared to distances О(4)…О(6) = 6.40(2) Å and О(3)…О(5) = 4.11(2) Å.
Phenylcarbamide moieties of the CE 1 molecule are located on both sides of the middle plane of the 18-membered
heterocycle and are differently oriented relative to it: the phenyl ring [С(15)–…–С(20)] is almost orthogonal to the
145

TABLE 1. Crystallographic Data and Characteristics of the Experiment for Compounds 1, 1⋅H О, and 2
2
Value
Parameter
1
2
1⋅H О
2
CCDC number
1856189
1856191
1856190
Chemical formula
C H N O
30 44 4
C H N O
30 46 4
C H ClNO
7 16 2
6
7
М
Crystal symmetry
Space group
а, Å
556.69
Orthorhombic
P2 2 2
574.71
181.66
Monoclinic
Orthorhombic
P2 2 2
P2
1
1
1
1
1 1 1
8.8073(6)
16.8364(8)
20.6508(11)
90
9.9593(5)
10.1522(5)
15.6925(10)
99.618(5)
1564.35(15); 2
1.220
5.3194(5)
9.2599(8)
21.3073(18)
90
b, Å
с, Å
β, deg
3
V, Å ; Z
3062.2(3); 4
1.208
1049.53(16); 4
1.150
3
ρ(calc.), g/cm
–1
0.084
0.087
0.325
μ, mm
F(000)
1200
620
392
3.122-25.250
3.068-25.047
3.615-25.038
θ range, deg
Ranges of reflection indices
–7 ≤ h ≤ 10,
–18 ≤ k ≤ 19,
–24 ≤ l ≤12
7003 / 4870
–11 ≤ h ≤ 10,
–10 ≤ k ≤12,
–9 ≤ l ≤ 18
–4 ≤ h ≤6,
–5 ≤ k ≤11,
–16 ≤ l ≤25
2464 / 1733
Number of meas. / indep. reflections (R )
int
5314 / 4272
(R = 0.0264)
int
(R = 0.0200)
int
(R = 0.0314)
int
2972
419
2964
378
1080
112
Number of reflections with I > 2σ(I)
Number of refined parameters
GOOF
1.019
0.998
0.983
0.0611, 0.1170
0.1128, 0.1416
0.149, –0.171
0.0489, 0.0937
0.0792, 0.1058
0.127, –0.160
0.0550, 0.0719
0.0965, 0.0824
0.254, –0.149
R , wR (I > 2σ(I))
1 2
R , wR (entire set)
1 2
3
Δρ , Δρ , e/Å
max min
TABLE 2. Hydrogen Bonds in Compounds 1, 1⋅H O, and 2
2
Donor–H…Acceptor
d(H…A), Å
d(D…A), Å
Symmetry transformation for the acceptor
∠(DHA), deg
1
N(2)–H(2)…O(1)
N(1)–H(1)…O(2)
2.21
2.25
3.043(5)
3.066(5)
162.9
158.2
x+1/2, 1/2–y, 2–z
2–x, y+1/2, 3/2–z
1⋅H O
2
N(1)–H(1)…O(1W)
N(2)–H(2)…O(4)
2.35
2.22
3.189(6)
2.891(4)
2.907(5)
2.735(5)
165.2
x, y, z
x, y, z
x, y, z
x, y, z
135
O(1W)–H(1W)…O(6)
O(1W)–H(2W)…O(2)
2.12(3)
1.87(3)
151(6)
170(6)
2
N(1)–H(1N)…Cl(1)
N(1)–H(2N)…Cl(1)
N(1)–H(3N)…Cl(1)
C(5)–H(5)…O(2)
2.13(2)
2.12(2)
2.16(2)
2.48
3.153(4)
3.121(5)
3.166(5)
3.453(6)
178(3)
169(4)
172(3)
170
x+1/2, 3/2–y, 2–z
x+1, y+1, z
x, y+1, z
x+1, y, z
146

TABLE 3. Torsion Angles in the Heterocyclic Core of Macrocycle 1
1, deg
Parameter
1⋅H O, deg
2
N3–C2–C3–O3
C2–C3–O3–C4
C3–O3–C4–C5
O3–C4–C5–O4
C4–C5–O4–C6
C5–O4–C6–C7
O4–C6–C7–N4
C6–C7–N4–C8
C7–N4–C8–C9
N4–C8–C9–O5
–178.3(9)
–178(2)
178(2)
–79(4)
178(2)
–154(3)
–51(1)
71.0(6)
75(1)
–61.8(4)
–179.6(4)
–177.5(4)
72.5(5)
–168.0(4)
–177.6(5)
–71.4(6)
–99.1(5)
77.7(6)
–169(1)
59.8(7)
C8–C9–O5–C10
C9–O5–C10–C11
O5–C10–C11–O6
C10–C11–O6–C12
C11–O6–C12–C13
O6–C12–C13–N3
C12–C13–N3–C2
C13–N3–C2–C3
–160(1)
171(1)
150.7(4)
167.0(4)
62.5(5)
85.0(7)
–169.9(5)
89.6(5)
–138.7(4)
76.1(5)
73.5(5)
168.7(3)
98.2(4)
–81.1(6)
–86.5(5)
88.3(5)
TABLE 4. Interatomic Distances and Bond Angles in Compound 2
Parameter
d, Å
Parameter
ω, deg
O(1)–C(6)
O(1)–C(7)
O(2)–C(6)
N(1)–C(5)
C(1)–C(3)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
1.332(6)
1.473(5)
1.187(6)
1.490(5)
1.523(6)
1.519(6)
1.521(6)
1.525(5)
1.526(6)
C(6)–O(1)–C(7)
C(2)–C(3)–C(1)
C(2)–C(3)–C(4)
C(1)–C(3)–C(4)
C(3)–C(4)–C(5)
N(1)–C(5)–C(6)
N(1)–C(5)–C(4)
C(6)–C(5)–C(4)
O(2)–C(6)–O(1)
O(2)–C(6)–C(5)
O(1)–C(6)–C(5)
114.9(5)
111.5(5)
113.3(5)
109.3(4)
117.1(4)
106.7(4)
108.5(4)
112.6(4)
127.1(6)
124.1(6)
108.8(5)
macrocycle, which is evidenced by a dihedral angle of 83.12° whereas the phenyl ring [С(24)–…–C(29)] is practically
parallel to the middle plane of the heterocycle, which is evidenced by a dihedral angle of 5°. In the crystal of CE 1 each
molecule is engaged in four hydrogen bonds NH…O through both amide moieties (Table 2) with four nearest molecules,
generating a three-dimensional hydrogen-bonded motif (Fig. 1b).
Monohydrate 1⋅H O crystallizes in the monoclinic space group P2 (Table 1, Fig. 2). In the complex the CE
2 1
molecule takes a form completely different from that of 1, which has an appreciably changed conformation of the heterocycle
and the arrangement of substituents. This changes occurs due to the penetration of a water molecule involved in three
intermolecular H bonds: by both hydrogen atoms into two ОН…О bonds and one lone pair of the oxygen atom into the
NH…O bond (Table 2). The second amide group is engaged into the intramolecular H bond N(2)…O(4) = 2.891(4) Å.
Heteroatoms of the macrocycle are essentially non-coplanar; nitrogen atoms deviate to one side from the plane drawn through
four oxygen atoms by 1.38 Å and 1.46 Å, and the heterocycle takes a saddle shape. Here the range of trans-annular O…O
147

Fig. 1. ORTEP diagram of compound 1 with atom numbering (thermal ellipsoids are drawn at a 30% probability
level; the second position for disordered fragments is not shown) (а); fragment of packing with showing atoms
involved in hydrogen bonds (hydrogen atoms bonded to carbon atoms are omitted) (b).
and N…N distances narrows from 5.019(5) Å to 5.974(4) Å as compared with CE 1, which indicates their equidistance. The
macrocycle conformation is described by a sequence of torsion angles listed in Table 3.
In adduct 1⋅H O both phenyl substituents are located on one side of the macrocyclic cavity and are turned to
2
opposite sides, forming a dihedral angle between the planes of aromatic rings of 82.62°. Only van der Waals interactions
exist between bulky molecular complexes 1⋅H O in the crystal.
2
A comparison of the structures of CE 1 and its monohydrate 1⋅H O gives evidence of a significant conformational
2
rearrangement of the macrocycle molecule in the latter (which also follows from the comparison of the respective torsion
angles (Table 3) in the macrocyclic fragment of 1) It is accompanied by blocking active (for complexation with guests)
centers of the molecule.
In conclusion, note that compound 2 (HCME of D-leucine) crystallizes in the orthorhombic space group Р2 2 2
1 1 1
(Table 1, Fig. 3) and the C(5) atom reflects the R-absolute configuration. The molecular geometry of the cation is
summarized in Table 4 and coincides with the data given in the recent publication for the cation coordinated to niobium
–
pentachloride [14]. The tripod ammonia center is involved in three almost identical NH…Cl hydrogen bonds; the distances
2
N…Сl = 3.121(5)-3.166(5) Å (Table 2). These H bonds in the form of two alternating supramolecular synthons R (8) [15]
4
and a short interaction C(5)Н…O(2) organize the components into helical chains along the а axis in the crystal (Fig. 3b).
Only van der Waals interactions occur between the chains.
148

Fig. 2. ORTEP diagram of monohydrate 1⋅H O with atom numbering (thermal ellipsoids are drawn at a 30%
2
probability level) (а); conformation of the macrocycle in supramolecular complex 1⋅H O, view of the heterocycle
2
plane (hydrogen atoms bonded to carbon atoms are omitted) (b).
Fig. 3. ORTEP diagram of compound 2 with atom numbering (thermal ellipsoids are drawn at a 30% probability
level) (а); hydrogen-bonded chain in the crystal structure of compound 2 (b).
It seems to us that the results presented can be useful for predicting the formation of host–guest complexes in the
separation of enantiomers by chiral macrocyclic complexones such as CE 1.
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