Synthesis and characterization of three novel nitrogen-containing macrolides

Article abstract of DOI:10.1515/znb-2011-0910

Three novel nitrogen-containing macrolides have been synthesized by esterification. All of them have been characterized by infrared (IR), elemental analysis, mass spectra (MS), and ¹H NMR spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction. The preparation methods and the intermolecular associations based on C-H···O hydrogen bonds and π-π stacking interactions are discussed.

Full text of DOI:10.1515/znb-2011-0910

Synthesis and Characterization of Three Novel Nitrogen-containing
Macrolides
Xin Leng, Bingqin Yang, Yuanyuan Liu, Yi Xie, and Jie Tong
Key Laboratory of Synthetic and Natural Chemistry of the Ministry of Education, College of
Chemistry and Materials Science, NorthWest University of Xi’an, Taibai Bei Avenue 229,
Xi’an 710069, Shaanxi Provice, People’s Republic of China
Reprint requests to Prof. Dr. Bingqin Yang. Fax: +86 029 88302217.
E-mail: organic lengxin@163.com
Z. Naturforsch. 2011, 66b, 930 – 934; received July 23, 2011
Three novel nitrogen-containing macrolides have been synthesized by esterification. All of them
have been characterized by infrared (IR), elemental analysis, mass spectra (MS), and 1H NMR
spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction. The
preparation methods and the intermolecular associations based on C–H···O hydrogen bonds and π-
π stacking interactions are discussed.
Key words: Macrocycles, Macrolides, Synthesis, X-Ray Crystal Structure, Hydrogen Bonds
Introduction
preparation of macrolides by relatively easy and eco-
nomical routes has been described only in a few cases.
In this article, some novel macrolides with different
ring sizes and annelated with a benzene ring have been
synthesized by esterification of acyl chlorides with di-
ols under high-dilution conditions (Scheme 1), and
single-crystal structure studies of them are presented.
Macrocyclic compouds have attracted increasing at-
tention because of their success in medicinal as well as
recognition chemistry and their widespread occurrence
in nature [1 – 9].
Among the great number of macrocycles which
have been described, macrolides are particularly in-
teresting, which are of high significance in areas as
diverse as drug development as well as supramolec-
ular chemistry and application in the perfume indus-
try. Many macrolides are found to be effective as
chemotherapeutic agents in the treatment of human
and animal diseases, e. g., antibiotics or anticancer
agents [9 – 12]. Macrolides are also expected to act as
cation receptors which can be used in selective com-
plexation, providing simple models that allow us the
molecular understanding of biological processes such
as the generation and propagation of the electrical im-
pulse in the nervous system, muscular contraction and
the interactions of enzymes with cations.
Results and Discussion
The starting materials 2,2ꢀ-(phenylimino)diethanol
and 2,2ꢀ-[(4-methoxyphenyl)azanediyl]diethanol were
prepared according to literature procedures [21].
The most popular way of synthesis of macrocyclic
compounds is always under high-dilution condition in
order to prevent polymerization. Although metal ions
are sometimes used as templates in cyclization, it is al-
ways a hard task to remove the ions after the reaction.
Macrolides 1, 2 and 3 were synthesized by conden-
sation reactions in dry dichloromethane under high-
dilution. In this way, we finally obtained colorless sol-
uble solids of compounds 1, 2 and 3. The preparation
is summarized in Scheme 1. All of the products had
Macrolides have been synthesized and studied ex-
extensively in organic chemistry [13 – 20]. So far, the
Scheme 1.
c
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X. Leng et al. · Three Novel Nitrogen-containing Macrolides
931
Table 1. Crystal structure data for 1 – 3.
1
2
3
Formula
Mr
C14 H17 N O4
C18 H17 N O4
C15 H19 N O5
293.31
263.29
311.33
Crystal size, mm3
Crystal system
Space group
0.35×0.29×0.15
0.22×0.20×0.19
0.37×0.28×0.21
orthorhombic
P212121
7.467(1)
8.848(1)
22.383(3)
90
1478.7(4)
4
1.32
monoclinic
orthorhombic
P21/c
7.793(2)
8.954(2)
18.472(4)
91.159(3)
1288.7(5)
4
1.36
Pbca
8.200(1)
8.418(1)
45.418(6)
90
3135.0(7)
8
1.32
˚
a, A
˚
b, A
˚
c, A
β, deg
3
˚
V, A
Z
Dcalcd, g cm−3
µ(MoKα), cm−1
F(000), e
hkl range
1.0
560
0.9
1312
1.0
624
−8 ≤ h ≤ +9, −10 ≤ k ≤ +5,
−9 ≤ h ≤ +9, −10 ≤ k ≤ +9,
−8 ≤ h ≤ +5, −10 ≤ k ≤ +10
−26 ≤ l ≤ +26
293(2)
−21 ≤ l ≤ +22
293(2)
−34 ≤ l ≤ +53
293(2)
Temperature, K
((sinθ)/λ)max, A
−1
˚
0.597
0.597
0.597
Refl. measd / unique / Rint
Param. refined
6138 / 2291 / 0.0262
173
0.0563 / 0.1040
0.043 / 0.1109
–
14500 / 2774 / 0.0450
208
0.0738 / 0.1441
0.083 / 0
7406 / 2630 / 0.0237
192
0.0430 / 0.0913
0.0432 / 0.0941
1.3(12)
1.004
0.142 / −0.099
R1(F) / wR2(F2)a,b (all refl.)
A / B (weighting scheme)b
x(Flack) [24]
–
GoF (F2)c
∆ρfin (max / min), e A
1.082
1.022
0.152 / −0.144
−3
˚
0.193 / −0.139
R1 = ΣꢁFo| − |Fcꢁ/Σ|Fo|; wR2 = [Σw(Fo − Fc2)2/Σw(Fo2)2]1/2, w = [σ2(Fo2) + (AP)2 + BP]−1, where P = (Max(Fo2,0) + 2Fc2)/3;
a
b
2
c
2
GoF = [Σw(Fo −Fc2)2/(nobs −nparam)]1/2
.
Table 2. Selected bond
1
2
3
˚
lengths (A), angles (deg),
O4–C12
O2–C12
O2–C13
O3–C9
O1–C9
O1–C8
1.192(2)
1.338(2)
1.440(2)
1.200(2)
1.339(2)
1.447(2)
O3–C16
1.207(2)
1.332(2)
1.445(2)
1.194(2)
1.339(2)
1.444(2)
O1–C1
O3–C1
O3–C8
O2–C4
O4–C4
O4–C5
1.199(2)
1.334(2)
1.438(2)
1.198(2)
1.336(2)
1.447(2)
and dihedral angles (deg)
for 1, 2, and 3 with esti-
mated standard deviations
in parentheses.
O4–C16
O4–C17
O1–C9
O2–C9
O2–C8
C12–O2–C13
O4–C12–C11
O4–C12–O2
O2–C12–C11
O2–C13–C14
C9–O1–C8
O3–C9–C10
O3–C9–O1
O1–C9–C10
O1–C8–C7
118.28(15)
125.09(19)
123.16(19)
111.75(17)
107.47(15)
117.96(14)
124.13(17)
123.95(17)
111.92(15)
109.25(14)
113.03(17)
C16–O4–C17
O3–C16–C15
O3–C16–O4
O4–C16–C15
O4–C17–C18
C9–O2–C8
O1–C9–C10
O1–C9–O2
O2–C9–C10
O2–C8–C7
117.43(15)
123.71(18)
123.72(19)
123.71(18)
108.31(15)
117.01(14)
124.44(19)
123.93(18)
111.55(16)
112.76(15)
117.38(19)
C1–O3–C8
O1–C1–C2
O1–C1–O3
O3–C1–C2
O3–C8–C7
C4–O4–C5
O2–C4–C3
O2–C4–O4
O4–C4–C3
O4–C5–C6
118.51(17)
123.6(2)
124.1(2)
112.23(18)
108.17(18)
118.63(16)
125.21(18)
123.20(19)
111.59(18)
106.65(15)
121.05(18)
C14–N1–C7–C8
C18–N1–C7–C8
C7–N1–C6–C5
C7–N1–C14–C13 −120.75(17)
C7–N1–C8–C17 −103.8(2)
C6–N1–C7–C8 −108.0(2)
C7–N1–C9–C10 163.85(18)
C7–N1–C9–C14 −16.8(3)
C14–N1–C6–C1
C14–N1–C6–C5
14.2(2)
C18–N1–C6–C5
C18–N1–C6–C1
168.13(17)
177.19(16)
−9.6(2)
elemental analyses, IR, MS and 1H NMR spectra
All of the macrolides 1, 2 and 3 were crystallized
which were in accordance with the proposed struc- from dichloromethane. Macrolide 1 crystallized in the
tures. A view of the molecules 1, 2 and 3 is shown monoclinic crystal system, space group P21/c, with
in Fig. 1. A summary of the crystal data and numbers four molecules in the unit cell, while 2 crystallized
pertinent to data collection and structure refinement are in the orthorhombic crystal system, space group Pbca
summarized in Table 1.
with eight molecules in the unit cell, and macrolide 3 in
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932
X. Leng et al. · Three Novel Nitrogen-containing Macrolides
1
2
3
Fig. 1. The molecular structures of 1, 2 and 3 showing the atom labeling scheme. Displacement ellipsoids are drawn at the
30 % probability level.
˚
Table 3. C–H···O hydrogen bond data for 1, 2 and 3 (A, deg).
D–H···A
D–H
0.97
0.97
0.97
0.93
H···A
2.28
2.56
2.30
2.49
D···A
D–H···A
1
2
C8–H8A···O3
C18–H18B··· O3
C8–H8B··· O1
C11–H11··· O2
2.71 (5)
3.36 (7)
2.71 (2)
3.36 (3)
106
141
105
156
3
the orthorhombic crystal system, space group P212121,
with four molecules in the unit cell. Selected bond
lengths and angles are listed in Table 2.
Macrolide 1 displays offset face-to-face π-π stack-
ing interactions. All three compounds show interesting
hydrogen bond patterns built up by weak C–H···O in-
teractions. Characteristic data are listed in Table 3.
In the solid state, macrolide 1 (Fig. 1) displays one
ester oxygen (O1) pointing inside the ring, and the
other ester oxygen (O2) projecting outwards. Each
macrolide uses the oxygen atom of the ester carbonyl
(O3) as hydrogen bond acceptor, while the proton
H8A acts as the donor. The lattice stabilization is thus
achieved through weak C–H···O hydrogen bonds and
π-π stacking interactions. Two centrosymmetrically
related benzene rings are π-stacked with a shearing in
Fig. 2. π-π Interaction in the crystal structure of 1.
Experimental Section
Solvents and reagents were purified and dried by standard
methods. The melting points were determined on a XT4 mi-
cro melting point apparatus and are uncorrected. IR spectra
were recorded on a EQUINOX-55 spectrometer in a KBr ma-
such a way that the benzene centroid-to-centroid dis- trix. 1H NMR spectra were recorded on a INOVA-400 NMR
˚
spectrometer, using TMS as internal standard and CDCl3
as solvent. Elemental analyses were performed on a Vario
EL III CHNOS analyzer. Electrospray mass spectra were
obtained with a GC 6890-MS 5973 spectrometer (Agilent).
200 – 300 mesh silica gel was used for column chromatogra-
phy.
tance is 3.855 A and the interplanar separation between
˚
stacked benzene rings in this region is 3.610 A (Fig. 2).
In the solid-state structure of 2, each macrolide uses
the oxygen of the ester carbonyl (O3) as hydrogen
bond acceptor, while the hydrogen H18B acts as the
donor. The two benzene rings of the molecule take an
approximate perpendicular juxtaposition in which they
include an angle of 57.11◦.
The major stuctural features of compound 3 are sim-
ilar to that of macrolide 1. The methoxy substituent re-
mains almost co-planar with the benzene ring to which
it is attached. Each molecule uses the oxygen of the
ester carbonyls (O1, O2) as hydrogen bond acceptors,
whereas the hydrogen H8B and the aromatic proton
H11 act as the donors.
2,2ꢀ-(Phenylimino)diethanol and 2,2ꢀ-[(4-methoxyphenyl)-
azanediyl]diethanol
A mixture of 18.6 g (0.2 mol) of aniline or 24.6 g (0.2 mol)
of 4-methoxyaniline, 5 mL of propionic acid and 100 mL of
water was stirred vigorously, and to this mixture 25 mL of
◦
ethylene oxide was added dropwise at 0 C in the course
◦
of 3 h. The temperature rose gradually to 10 C, and stir-
ring was continued for an additional 24 h. The organic layer
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X. Leng et al. · Three Novel Nitrogen-containing Macrolides
933
was separated and washed with an aqueous saturated solution 736, 695 cm−1. – 1H NMR (400 MHz, CDCl3): δ = 7.80 (m,
of sodium carbonate. All volatiles were evaporated under re- 2H, Har), 7.59 (m, 2H, Har), 7.28 (m, 2H, Har), 6.80 (t, 1H,
duced pressure.
Har), 6.62 (d, 2H, Har), 4.56 [t, 4H, 2(O-CH2)], 3.83 [t, 4H,
2,2ꢀ-(Phenylimino)diethanol: Slightly yellow crystals 2(N-CH2)]. – MS (EI, 70 eV): m/z (%) = 311 (100) [M]+. –
(30.8 g, 85 %). M. p. 56 – 57 ◦C (lit.: 55 – 56 ◦C [21]).
2,2ꢀ-[(4-methoxyphenyl)azanediyl]diethanol: Colorless
solid (29.1 g, 69 % ). M. p. 70 – 71 ◦C.
C18H17NO4 (311.33): calcd. C 69.44, H 5.50, N 4.50; found
C 69.41, H 5.49, N 4.52.
◦
3: Yield: 43 %. M. p. 85 – 87 C. – IR(film): ν = 3065,
2925, 1732 (C=O), 1621, 1515, 1457, 1379, 1275, 1187,
1153, 1043, 813 cm−1. – 1H NMR (400 MHz, CDCl3): δ =
6.85 (t, 2H, Har), 6.60 (d, 2H, Har), 4.35 [t, 4H, 2(CH2-O)],
3.76 (s, 3H, OMe), 3.60 [t, 4H, 2(CH2-N)], 2.63 [d, 4H,
2(CH2-CO)]. – MS (EI, 70 eV): m/z (%) = 293 (100) [M]+. –
C15H19NO5 (293.31): calcd. C 61.42, H 6.53, N 4.78; found
C 61.41, H 6.55, N 4.79.
Macrolides 1, 2 and 3
A mixture of 0.006 mol of 2,2ꢀ-(phenylimino)diethanol
or 2,2ꢀ-[(4-methoxyphenyl)azanediyl]diethanol, 1000 mL of
dry dichloromethane, and 1 mL (0.012 mol) of pyridine
was stirred in the dark at r. t. To this solution 0.006 mol of
succinyl chloride or 1,2-benzenedicarbonyl chloride in
dichloromethane was added dropwise over 4 h. The mixture
was stirred overnight at r. t. About 900 mL of the solvent was
removed under atmospheric pressure, and the residual solu-
tion was washed 4 times with 50 mL of water and dried over
CaCl2. The residue was then purified by column chromatog-
raphy on silica gel, eluting with petroleum ether/ethyl acetate
X-Ray structure determination
X-Ray diffraction data were collected on a Bruker
Smart 1000 CCD diffractometer with graphite-
˚
monochromatized MoKα radiation (λ = 0.71073 A) at
r. t. The structures were solved by Direct Methods and
refined by full-matrix least-squares methods on F2 with the
(2 :1 ).
◦
1: Yield: 45 % . M. p. 82 – 83 C. – IR (film): ν = 3098, programs SHELXS-97 [22] and SHELXL-97 [23]. All non-
3032, 1733 (C=O), 1599, 1504, 1259, 1221 755, 694 cm−1. – hydrogen atoms were refined anisotropically. All hydrogen
1H NMR (400 MHz, CDCl3): δ = 7.26 (m, 2H, Har), 6.79 (t, atoms were treated using a riding model. Due to the lack of
1H, Har), 6.62 (d, 2H, Har), 4.39 [t, 4H, 2(O-CH2)], 3.67 [t, heavy atoms, refinement of Flack’s x parameter [24] for 3
4H, 2(N-CH2)], 2.65 [m, 4H, 2(CH2-CO)]. – MS (EI, 70 eV): proved to be inconclusive.
m/z (%) = 263 (100) [M]+. – C14H17NO4 (263.29): calcd.
CCDC 833941 – 833943 contain the supplementary crys-
C 63.87, H 6.51, N 5.32; found C 63.83, H 6.53, N 5.31.
tallograpic data for this paper. These data can be obtained
2: Yield: 38 % . M. p. 137 – 138. – IR (film): ν = 3062, free of charge from The Cambridge Crystallographic Data
3021, 2910, 1712 (C=O), 1598, 1504, 1461, 1290, 1193, 753, Centre via www.ccdc.cam.ac.uk/data request/cif.
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