Crystal structure of 22,24,25-trimethyl-8,11,14-trioxa-25-aza-tetra-cyclo-[19.3.1.02,7.015,20]penta-cosa-2,4,6,15(20),16,18-hexaen-23-one.

The title compound, C24H29NO4, is the product of a Petrenko-Kritchenko condensation of 1,5-bis-(2-formyl-phen-oxy)-3-oxa-pentane, pentan-3-one and methyl-ammonium acetate in ethanol. The mol-ecule has mirror symmetry. The aza-14-crown-3 ether ring adopts a bowl conformation stabilized by a weak intra-molecular C-H⋯O hydrogen bond. The conformation of the C-O-C-C-O-C-C-O-C polyether chain is t-g+-t-t-g--t (t = trans, 180°; g = gauche, ±60°). The dihedral angle between the benzene rings fused to the aza-14-crown-4-ether moiety is 72.68 (4)°. The piperidinone ring adopts a chair conformation. The nitro-gen atom has a trigonal-pyramidal geometry, the sum of the bond angles being 335.9°. In the crystal, the mol-ecules are linked by weak C-H⋯O inter-actions, forming zigzag chains propagating along the [100] direction.

Chemical context

Macroheterocycles containing both crown ether and aza­heterocyclic moieties are prospective compounds not only as metal-ion receptors (Pedersen, 1988 ▸), but also as membrane ion-transporting vehicles (Gökel & Murillo, 1996 ▸), as active components of environmental chemistry (Bradshaw & Izatt, 1997 ▸), for the design of organic sensors (Costero et al., 2005 ▸), in nanosized on-off switches and other mol­ecular electronic devices (Natali & Giordani, 2012 ▸). Moreover, they can possess anti­bacterial (An et al., 1998 ▸) and anti­cancer properties (Artiemenko et al., 2002 ▸; Le et al., 2014 ▸, 2015 ▸), and other useful biological activity (Anh & Soldatenkov, 2016 ▸; Tran et al., 2016 ▸).

Recently, we have developed effective methods for the synthesis of aza­crown ethers containing γ-piperidone (Levov et al., 2006 ▸, 2008 ▸; Anh et al., 2008 ▸, 2012a ▸,b ▸,c ▸; Hieu et al. (2011 ▸, 2012a ▸,b ▸) or γ-aryl­pyridine (Anh & Soldatenkov, 2016 ▸; Tran et al., 2016 ▸) subunits. This chemistry allowed us to make systematic studies of the fine structural features of a novel series of aza­crown macrocycles using X-ray diffraction. Such data should be of use for the subsequent design of more certain drug-like macroheterocyclic mol­ecules bearing new would-be pharmacophore groups.

In attempts to apply this chemistry for obtaining aza­crown ethers which contain a 1,3,5-trimethyl-substituted γ-piperidine moiety, we studied the condensation of di­ethyl­ketone and 1,5-bis­(2-formyl­phen­oxy)-3-oxa­pentane in the presence of methyl­ammonium acetate taken both as the nitro­gen source and as the template in ethanol/acetic acid solution. The reaction proceeded smoothly to give the expected aza­crown title mol­ecule, (I), with 32% yield.

Structural commentary

The title compound (Fig. 1 ▸), the product of a Petrenko–Kritchenko condensation of 1,5-bis­(2-formyl­phen­oxy)-3-oxa­pentane, pentan-3-one and methyl­ammonium acetate in ethanol, crystallizes in the ortho­rhom­bic space group Pnma and, in the crystal, occupies a special position on a mirror plane. The aza-14-crown-3 ether ring adopts a bowl conformation stabilized by the weak intra­molecular C16—H16B⋯O11 hydrogen bond (Table 1 ▸, Fig. 1 ▸). The distances from the center of the macrocycle cavity (defined as the centroid of atoms O8/O11/O8A/N14) to the O8, O11 and N14 atoms are 2.265 (2), 1.880 (2) and 2.393 (2) Å, respectively [atoms with the suffix A are related by the symmetry operation x,  − y, z.]. The conformation of the C7—O8—C9—C10—O11—C10A—C9A—O8A—C7A polyether chain is t–g+–t–t–g−–t (t = trans, 180°; g = gauche, ±60°). The dihedral angle between the planes of the benzene rings fused to the aza-14-crown-4-ether moiety is 72.68 (4)°. The piperidinone ring adopts a chair conformation. The nitro­gen N14 atom has a trigonal–pyramidal geometry (sum of the bond angles is 335.9°).

Figure 1

The mol­ecular structure of (I). Displacement ellipsoids are shown at the 50% probability level. H atoms are presented as small spheres of arbitrary radius. The dashed line indicates the intra­molecular C—H⋯O hydrogen bond. Atoms with the suffix A are related by the symmetry operation x,  − y, z.

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C10—H10B⋯O12i	0.99	2.58	3.449 (2)	147
C16—H16B⋯O11	0.96	2.57	3.530 (3)	180

Symmetry code: (i) .

The mol­ecule of (I) possesses four asymmetric centers at the C1, C13, C13A and C1A carbon atoms and can have potentially numerous diastereomers. The crystal of (I) is racemic and consists of enanti­omeric pairs with the following relative configuration of the centers: rac-1R*,13S*,13AR*,1AS*.

Supra­molecular features

In the crystal, mol­ecules of (I) form zigzag chains along [100] via weak C—H⋯O inter­actions (Table 1 ▸, Figs. 2 ▸ and 3 ▸). π–π stacking is observed in the crystal, the distance between parallel benzene rings is 3.446 (3) Å and the shortest inter­molecular C5⋯C7i distance is 3.495 (2) Å [symmetry code: (i) 1 − x, 1 − y, −z].

Figure 2

Crystal packing of (I) along the b axis demonstrating the zigzag hydrogen-bonded chains along [100]. Dashed lines indicate the intra- and inter­molecular C—H⋯O hydrogen bonds.

Figure 3

A portion of the crystal packing of (I) indicating the inter­molecular π–π stacking inter­actions. Dashed lines indicate the intra- and inter­molecular C—H⋯O hydrogen bonds.

Synthesis and crystallization

Methyl­ammonium acetate (3.85 g, 50 mmol) was added to a solution of 1,5-bis­(2-formyl­phen­oxy)-3-oxa­pentane (3.14 g, 10.0 mmol) and di­ethyl­ketone (1.41 g, 10.0 mmol) in ethanol/acetic acid (40 mL/1 mL) mixture. The reaction mixture was stirred at 293 K for three days (monitored by TLC until the disappearance of the starting heterocyclic ketone spot). At the end of the reaction, the formed precipitate was filtered off, washed with ethanol and recrystallized from ethanol solution to give 2.1 g of crystals of (I) (yield 32% m.p. 485–487 K). IR (KBr), ν/cm−1: 1702. 1H NMR (CDCl3, 400 MHz, 300 K): δ = 0.89 (d, 6H, CH3, J = 6.7 Hz), 1.86 (c, 3H, NCH3), 3.19 (d, 2H, H1, H21, J = 10.8 Hz), 3.76–4.16 (m, 10H, Hether and H22, H24), 6.78–7.26 (m, 8H, Harom). Analysis calculated for C24H29NO4: C, 67.72; H, 7.31; N, 5.64. Found: C, 67.54; H, 7.42; N, 5.41.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. All hydrogen atoms were placed in calculated positions with C—H = 0.95 Å (aryl-H), 0.96 Å (methyl-H), 0.98 Å (methyl­ene-H) or 1.00 Å (methine-H) and refined using a riding model with fixed isotropic displacement parameters [U iso(H) = 1.5U eq(C) for the methyl groups and 1.2U eq(C) for all other atoms].

Table 2

Experimental details

Crystal data
Chemical formula	C24H29NO4
M r	395.48
Crystal system, space group	Orthorhombic, P n m a
Temperature (K)	120
a, b, c (Å)	8.1468 (5), 20.3402 (11), 12.0155 (7)
V (Å3)	1991.1 (2)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.09
Crystal size (mm)	0.20 × 0.15 × 0.15
Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2003 ▸)
T min, T max	0.970, 0.980
No. of measured, independent and observed [I > 2σ(I)] reflections	25079, 3128, 2469
R int	0.065
(sin θ/λ)max (Å−1)	0.715
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.056, 0.130, 1.02
No. of reflections	3128
No. of parameters	140
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.34, −0.23

Computer programs: APEX2 (Bruker, 2001 ▸) and SAINT (Bruker, 2005 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2015 (Sheldrick, 2015b ▸) and SHELXTL (Sheldrick, 2008 ▸).

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989016020508/xu5896sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989016020508/xu5896Isup2.hkl

CCDC reference: 1524447

Additional supporting information: crystallographic information; 3D view; checkCIF report

C24H29NO4	Dx = 1.319 Mg m−3
Mr = 395.48	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pnma	Cell parameters from 4090 reflections
a = 8.1468 (5) Å	θ = 3.0–29.2°
b = 20.3402 (11) Å	µ = 0.09 mm−1
c = 12.0155 (7) Å	T = 120 K
V = 1991.1 (2) Å3	Prism, colourless
Z = 4	0.20 × 0.15 × 0.15 mm
F(000) = 848

Bruker APEXII CCD diffractometer	2469 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.065
φ and ω scans	θmax = 30.6°, θmin = 2.0°
Absorption correction: multi-scan (SADABS; Bruker, 2003)	h = −11→11
Tmin = 0.970, Tmax = 0.980	k = −29→29
25079 measured reflections	l = −17→16
3128 independent reflections

Refinement on F2	Primary atom site location: difference Fourier map
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.056	Hydrogen site location: mixed
wR(F2) = 0.130	H-atom parameters constrained
S = 1.02	w = 1/[σ2(Fo2) + (0.046P)2 + 1.66P] where P = (Fo2 + 2Fc2)/3
3128 reflections	(Δ/σ)max < 0.001
140 parameters	Δρmax = 0.34 e Å−3
0 restraints	Δρmin = −0.23 e Å−3

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

	x	y	z	Uiso*/Ueq
C1	0.58338 (18)	0.30912 (7)	−0.07447 (12)	0.0151 (3)
H1	0.4639	0.3029	−0.0903	0.018*
C2	0.60218 (18)	0.37109 (7)	−0.00494 (12)	0.0156 (3)
C3	0.75023 (19)	0.40480 (7)	0.00526 (13)	0.0190 (3)
H3	0.8432	0.3900	−0.0354	0.023*
C4	0.7652 (2)	0.45976 (7)	0.07366 (14)	0.0223 (3)
H4	0.8670	0.4822	0.0793	0.027*
C5	0.6301 (2)	0.48134 (7)	0.13342 (13)	0.0223 (3)
H5	0.6398	0.5188	0.1803	0.027*
C6	0.4808 (2)	0.44885 (7)	0.12557 (13)	0.0195 (3)
H6	0.3888	0.4637	0.1672	0.023*
C7	0.46690 (18)	0.39412 (7)	0.05590 (12)	0.0162 (3)
O8	0.32384 (13)	0.35995 (5)	0.04244 (9)	0.0194 (2)
C9	0.19912 (19)	0.36553 (8)	0.12588 (13)	0.0201 (3)
H9A	0.1387	0.4074	0.1172	0.024*
H9B	0.2488	0.3645	0.2011	0.024*
C10	0.08483 (19)	0.30816 (7)	0.11056 (13)	0.0197 (3)
H10A	−0.0119	0.3129	0.1597	0.024*
H10B	0.0462	0.3062	0.0325	0.024*
O11	0.17272 (19)	0.2500	0.13785 (13)	0.0192 (3)
C12	0.6367 (3)	0.2500	−0.24937 (18)	0.0157 (4)
O12	0.5743 (2)	0.2500	−0.34102 (13)	0.0219 (3)
C13	0.67442 (18)	0.31314 (7)	−0.18726 (12)	0.0160 (3)
H13	0.7951	0.3147	−0.1722	0.019*
N14	0.6428 (2)	0.2500	−0.01435 (14)	0.0148 (3)
C15	0.6282 (2)	0.37347 (7)	−0.25565 (13)	0.0192 (3)
H15A	0.6833	0.3715	−0.3281	0.029*
H15B	0.6626	0.4133	−0.2161	0.029*
H15C	0.5091	0.3744	−0.2667	0.029*
C16	0.6033 (3)	0.2500	0.10474 (17)	0.0186 (4)
H16A	0.6489	0.2885	0.1390	0.028*
H16B	0.4864	0.2500	0.1141	0.028*

	U11	U22	U33	U12	U13	U23
C1	0.0192 (7)	0.0111 (6)	0.0151 (6)	0.0006 (5)	0.0007 (5)	−0.0001 (5)
C2	0.0197 (7)	0.0118 (6)	0.0154 (6)	0.0002 (5)	−0.0012 (5)	0.0008 (5)
C3	0.0200 (7)	0.0152 (6)	0.0217 (7)	0.0009 (5)	−0.0016 (6)	0.0010 (5)
C4	0.0240 (8)	0.0169 (7)	0.0259 (8)	−0.0028 (6)	−0.0061 (6)	−0.0005 (6)
C5	0.0317 (8)	0.0133 (6)	0.0219 (7)	0.0005 (6)	−0.0075 (6)	−0.0042 (6)
C6	0.0248 (7)	0.0161 (7)	0.0177 (7)	0.0031 (6)	−0.0015 (6)	−0.0026 (5)
C7	0.0202 (7)	0.0124 (6)	0.0158 (7)	0.0003 (5)	−0.0018 (5)	0.0004 (5)
O8	0.0198 (5)	0.0201 (5)	0.0183 (5)	−0.0026 (4)	0.0035 (4)	−0.0054 (4)
C9	0.0208 (7)	0.0203 (7)	0.0193 (7)	0.0025 (6)	0.0038 (6)	−0.0033 (6)
C10	0.0176 (7)	0.0217 (7)	0.0199 (7)	0.0033 (6)	0.0015 (6)	−0.0008 (6)
O11	0.0177 (7)	0.0183 (7)	0.0216 (8)	0.000	−0.0020 (6)	0.000
C12	0.0152 (9)	0.0157 (9)	0.0162 (9)	0.000	0.0047 (7)	0.000
O12	0.0306 (9)	0.0190 (7)	0.0160 (7)	0.000	−0.0006 (6)	0.000
C13	0.0161 (6)	0.0149 (6)	0.0169 (7)	−0.0019 (5)	0.0014 (5)	−0.0001 (5)
N14	0.0193 (8)	0.0104 (7)	0.0147 (8)	0.000	−0.0017 (6)	0.000
C15	0.0245 (8)	0.0144 (6)	0.0187 (7)	−0.0008 (6)	−0.0002 (6)	0.0028 (5)
C16	0.0271 (11)	0.0154 (9)	0.0134 (9)	0.000	−0.0003 (8)	0.000

C1—N14	1.4840 (17)	C9—H9B	0.9900
C1—C2	1.5197 (19)	C10—O11	1.4211 (17)
C1—C13	1.547 (2)	C10—H10A	0.9900
C1—H1	1.0000	C10—H10B	0.9900
C2—C3	1.393 (2)	O11—C10i	1.4211 (17)
C2—C7	1.403 (2)	C12—O12	1.213 (3)
C3—C4	1.393 (2)	C12—C13i	1.5168 (18)
C3—H3	0.9500	C12—C13	1.5168 (18)
C4—C5	1.385 (2)	C13—C15	1.524 (2)
C4—H4	0.9500	C13—H13	1.0000
C5—C6	1.388 (2)	N14—C16	1.467 (3)
C5—H5	0.9500	N14—C1i	1.4840 (17)
C6—C7	1.397 (2)	C15—H15A	0.9800
C6—H6	0.9500	C15—H15B	0.9800
C7—O8	1.3666 (18)	C15—H15C	0.9800
O8—C9	1.4319 (18)	C16—H16A	0.9595
C9—C10	1.504 (2)	C16—H16B	0.9593
C9—H9A	0.9900
N14—C1—C2	111.82 (12)	H9A—C9—H9B	108.6
N14—C1—C13	108.23 (12)	O11—C10—C9	107.80 (13)
C2—C1—C13	112.92 (12)	O11—C10—H10A	110.1
N14—C1—H1	107.9	C9—C10—H10A	110.1
C2—C1—H1	107.9	O11—C10—H10B	110.1
C13—C1—H1	107.9	C9—C10—H10B	110.1
C3—C2—C7	118.03 (13)	H10A—C10—H10B	108.5
C3—C2—C1	122.95 (13)	C10—O11—C10i	112.69 (16)
C7—C2—C1	118.96 (13)	O12—C12—C13i	122.11 (9)
C2—C3—C4	121.51 (15)	O12—C12—C13	122.11 (9)
C2—C3—H3	119.2	C13i—C12—C13	115.71 (18)
C4—C3—H3	119.2	C12—C13—C15	111.50 (13)
C5—C4—C3	119.40 (15)	C12—C13—C1	106.80 (12)
C5—C4—H4	120.3	C15—C13—C1	113.36 (12)
C3—C4—H4	120.3	C12—C13—H13	108.3
C4—C5—C6	120.68 (14)	C15—C13—H13	108.3
C4—C5—H5	119.7	C1—C13—H13	108.3
C6—C5—H5	119.7	C16—N14—C1i	113.80 (10)
C5—C6—C7	119.40 (14)	C16—N14—C1	113.80 (10)
C5—C6—H6	120.3	C1i—N14—C1	108.27 (15)
C7—C6—H6	120.3	C13—C15—H15A	109.5
O8—C7—C6	123.03 (14)	C13—C15—H15B	109.5
O8—C7—C2	116.00 (12)	H15A—C15—H15B	109.5
C6—C7—C2	120.97 (14)	C13—C15—H15C	109.5
C7—O8—C9	118.82 (11)	H15A—C15—H15C	109.5
O8—C9—C10	106.99 (12)	H15B—C15—H15C	109.5
O8—C9—H9A	110.3	N14—C16—H16A	109.5
C10—C9—H9A	110.3	N14—C16—H16B	109.4
O8—C9—H9B	110.3	H16A—C16—H16B	109.5
C10—C9—H9B	110.3
N14—C1—C2—C3	80.51 (18)	C2—C7—O8—C9	159.44 (13)
C13—C1—C2—C3	−41.84 (19)	C7—O8—C9—C10	−161.82 (12)
N14—C1—C2—C7	−96.59 (16)	O8—C9—C10—O11	67.31 (16)
C13—C1—C2—C7	141.06 (13)	C9—C10—O11—C10i	−171.15 (10)
C7—C2—C3—C4	0.1 (2)	O12—C12—C13—C15	−1.4 (2)
C1—C2—C3—C4	−177.05 (14)	C13i—C12—C13—C15	−178.58 (11)
C2—C3—C4—C5	0.3 (2)	O12—C12—C13—C1	122.9 (2)
C3—C4—C5—C6	−0.1 (2)	C13i—C12—C13—C1	−54.2 (2)
C4—C5—C6—C7	−0.5 (2)	N14—C1—C13—C12	58.80 (16)
C5—C6—C7—O8	−179.15 (14)	C2—C1—C13—C12	−176.87 (13)
C5—C6—C7—C2	0.9 (2)	N14—C1—C13—C15	−178.02 (12)
C3—C2—C7—O8	179.34 (13)	C2—C1—C13—C15	−53.68 (16)
C1—C2—C7—O8	−3.41 (19)	C2—C1—N14—C16	38.57 (19)
C3—C2—C7—C6	−0.7 (2)	C13—C1—N14—C16	163.56 (14)
C1—C2—C7—C6	176.59 (13)	C2—C1—N14—C1i	166.15 (9)
C6—C7—O8—C9	−20.6 (2)	C13—C1—N14—C1i	−68.85 (18)

D—H···A	D—H	H···A	D···A	D—H···A
C10—H10B···O12ii	0.99	2.58	3.449 (2)	147
C16—H16B···O11	0.96	2.57	3.530 (3)	180