Varying degrees of homostructurality in a series of cocrystals of anti­malarial drug 11-aza­artemisinin with salicylic acids

Roy, M.; Li, K.; Nisar, M.; Wong, L.W.-Y.; Sung, H.H.-Y.; Haynes, R.K.; Williams, I.D.

doi:10.1107/S2053229621004460

Varying degrees of homostructurality in a series of cocrystals of antimalarial drug 11-azaartemisinin with salicylic acids

M. Roy, K. Li, M. Nisar, L. W.-Y. Wong, H. H.-Y. Sung, R. K. Haynes and I. D. Williams

The X-ray structures of three new 1:1 pharmaceutical cocrystals of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0^4,13.0^8,13]hexadecan-10-one, C₁₅H₂₃NO₄) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C₇H₅BrO₃), 4-bromo- (4-BrSalA, C₇H₅BrO₃) and 3,5-dibromosalicylic acid (3,5-Br₂SalA, C₇H₄Br₂O₃)] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P2₁) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br₂SalA cocrystals retain the highly preserved 2₁ stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br₂SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O—H

O=C hydrogen bonds of 2.54 Å in the cocrystals.

Keywords: 11-azaartemisinin; bromosalicylic acid; cocrystal; antimalarial; polymorph; isostructural; homostructural; crystal structure; hetero-seeding.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229621004460/dv3004sup1.cif Contains datablocks mona16cult, mona22cult, mona23cult, global
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229621004460/dv3004mona16cultsup2.hkl Contains datablock mona16cult
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229621004460/dv3004mona23cultsup3.hkl Contains datablock mona23cult
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229621004460/dv3004mona22cultsup4.hkl Contains datablock mona22cult
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229621004460/dv3004mona16cultsup5.cml Supplementary material
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229621004460/dv3004mona23cultsup6.cml Supplementary material
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229621004460/dv3004mona22cultsup7.cml Supplementary material
	Text file https://doi.org/10.1107/S2053229621004460/dv3004sup8.txt CIF data for a struture in Table 2
	Text file https://doi.org/10.1107/S2053229621004460/dv3004sup9.txt CIF data for a struture in Table 2
	Text file https://doi.org/10.1107/S2053229621004460/dv3004sup10.txt CIF data for a struture in Table 2
	Portable Document Format (PDF) file https://doi.org/10.1107/S2053229621004460/dv3004sup11.pdf PXRD patterns

CCDC references: 2080188; 2080187; 2080186

Computing details top

For all structures, data collection: CrysAlis PRO (Rigaku OD, 2020); cell refinement: CrysAlis PRO (Rigaku OD, 2020); data reduction: CrysAlis PRO (Rigaku OD, 2020). Program(s) used to solve structure: SHELXS (Sheldrick, 2008) for mona16cult; SHELXS1986 (Sheldrick, 2008) for mona22cult, mona23cult. For all structures, program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

1,5,9-Trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0^4,13.0^8,13]hexadecan-10-one; 5-bromosalicylic acid (mona16cult) top

Crystal data top

C₁₅H₂₃NO₄·C₇H₅BrO₃	F(000) = 516
M_r = 498.36	D_x = 1.494 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54184 Å
a = 9.9325 (4) Å	Cell parameters from 2387 reflections
b = 9.0196 (3) Å	θ = 3.6–71.7°
c = 12.3942 (4) Å	µ = 2.91 mm⁻¹
β = 93.844 (3)°	T = 100 K
V = 1107.88 (6) Å³	Needle, colourless
Z = 2	0.1 × 0.02 × 0.02 mm

Data collection top

Rigaku OD SuperNova Dual source diffractometer with an Atlas detector	3193 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Cu) X-ray Source	2929 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.048
Detector resolution: 5.1788 pixels mm^-1	θ_max = 72.5°, θ_min = 3.6°
ω scans	h = −12→11
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2020)	k = −11→7
T_min = 0.961, T_max = 1.000	l = −15→15
6416 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.034	w = 1/[σ²(F_o²) + (0.0101P)²] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.061	(Δ/σ)_max < 0.001
S = 1.02	Δρ_max = 0.24 e Å⁻³
3193 reflections	Δρ_min = −0.39 e Å⁻³
295 parameters	Absolute structure: Flack x determined using 735 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: −0.04 (2)
Primary atom site location: structure-invariant direct methods

Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.5532 (3)	0.7034 (3)	0.6656 (3)	0.0225 (7)
C1	0.6030 (5)	0.5514 (5)	0.6640 (4)	0.0207 (9)
O2	0.4123 (3)	0.7154 (3)	0.6221 (3)	0.0251 (7)
C2	0.5065 (4)	0.4579 (4)	0.5911 (3)	0.0220 (9)
H2	0.5368	0.3524	0.5979	0.026*
O3	0.3709 (3)	0.4638 (3)	0.6190 (2)	0.0242 (7)
C3	0.3374 (5)	0.6016 (5)	0.6686 (4)	0.0263 (10)
C4	0.3658 (5)	0.5943 (5)	0.7913 (4)	0.0318 (11)
H4A	0.2810	0.5692	0.8247	0.038*
H4B	0.3946	0.6936	0.8178	0.038*
C5	0.4744 (5)	0.4809 (5)	0.8291 (4)	0.0315 (11)
H5A	0.4883	0.4879	0.9088	0.038*
H5B	0.4389	0.3805	0.8119	0.038*
C6	0.6914 (6)	0.3490 (5)	0.7945 (4)	0.0302 (12)
H6	0.6372	0.2711	0.7539	0.036*
C7	0.8260 (5)	0.3602 (5)	0.7435 (4)	0.0374 (13)
H7A	0.8709	0.2622	0.7474	0.045*
H7B	0.8846	0.4311	0.7858	0.045*
C8	0.8120 (5)	0.4107 (5)	0.6261 (4)	0.0322 (11)
H8A	0.7597	0.3363	0.5821	0.039*
H8B	0.9026	0.4188	0.5977	0.039*
C9	0.7269 (4)	0.6305 (5)	0.5031 (3)	0.0230 (9)
H9	0.7032	0.7368	0.5144	0.028*
O10	0.6069 (3)	0.5879 (3)	0.3318 (3)	0.0252 (7)
C10	0.6114 (4)	0.5677 (4)	0.4321 (4)	0.0213 (9)
N11	0.5111 (4)	0.5003 (4)	0.4782 (3)	0.0224 (8)
C11	0.6121 (5)	0.4957 (5)	0.7815 (4)	0.0251 (10)
H11A	0.6641	0.5718	0.8257	0.030*
C12	0.7402 (4)	0.5617 (5)	0.6168 (4)	0.0248 (10)
H12	0.7954	0.6323	0.6637	0.030*
C13	0.1918 (4)	0.6341 (7)	0.6320 (4)	0.0355 (11)
H13A	0.1639	0.7271	0.6647	0.053*
H13B	0.1343	0.5531	0.6547	0.053*
H13C	0.1830	0.6431	0.5531	0.053*
C14	0.7080 (6)	0.2995 (6)	0.9124 (4)	0.0448 (14)
H14A	0.7521	0.3783	0.9562	0.067*
H14B	0.7634	0.2096	0.9180	0.067*
H14C	0.6191	0.2788	0.9388	0.067*
C15	0.8586 (4)	0.6337 (7)	0.4457 (4)	0.0371 (12)
H15A	0.8808	0.5331	0.4228	0.056*
H15B	0.9315	0.6716	0.4954	0.056*
H15C	0.8477	0.6984	0.3822	0.056*
Br5	0.22969 (5)	0.15227 (6)	−0.14014 (4)	0.03746 (12)
O20	0.4365 (3)	0.4767 (3)	0.1926 (3)	0.0240 (7)
C20	0.3164 (5)	0.4549 (5)	0.2282 (4)	0.0239 (11)
O21	0.2833 (3)	0.4988 (3)	0.3169 (2)	0.0251 (7)
C21	0.2209 (4)	0.3721 (5)	0.1535 (3)	0.0217 (9)
O22	0.0447 (3)	0.3911 (4)	0.2787 (3)	0.0312 (8)
C22	0.0901 (5)	0.3426 (5)	0.1846 (4)	0.0253 (9)
C23	0.0023 (5)	0.2573 (5)	0.1164 (4)	0.0331 (12)
H23	−0.0871	0.2388	0.1358	0.040*
C24	0.0445 (5)	0.2005 (6)	0.0221 (4)	0.0341 (12)
H24	−0.0146	0.1401	−0.0224	0.041*
C25	0.1741 (5)	0.2309 (5)	−0.0087 (4)	0.0279 (10)
C26	0.2608 (5)	0.3163 (5)	0.0553 (3)	0.0245 (9)
H26	0.3483	0.3377	0.0330	0.029*
H11	0.454 (6)	0.466 (7)	0.427 (5)	0.06 (2)*
H22	0.107 (5)	0.430 (5)	0.314 (4)	0.024 (14)*
H20	0.495 (7)	0.516 (8)	0.240 (6)	0.09 (3)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0228 (16)	0.0180 (15)	0.0268 (17)	0.0030 (11)	0.0017 (13)	−0.0012 (11)
C1	0.019 (2)	0.016 (2)	0.026 (2)	0.0005 (17)	−0.0001 (18)	−0.0018 (16)
O2	0.0228 (16)	0.0244 (15)	0.0283 (17)	0.0018 (13)	0.0033 (13)	0.0059 (12)
C2	0.022 (2)	0.020 (2)	0.023 (2)	0.0036 (17)	0.0007 (18)	−0.0014 (16)
O3	0.0230 (16)	0.0231 (16)	0.0265 (16)	−0.0041 (12)	0.0020 (13)	0.0034 (12)
C3	0.028 (2)	0.025 (2)	0.027 (2)	0.0052 (17)	0.009 (2)	0.0037 (17)
C4	0.035 (3)	0.035 (2)	0.026 (2)	0.000 (2)	0.009 (2)	0.0026 (18)
C5	0.040 (3)	0.030 (3)	0.024 (2)	−0.002 (2)	0.001 (2)	0.008 (2)
C6	0.036 (3)	0.021 (2)	0.032 (3)	0.001 (2)	−0.007 (2)	0.001 (2)
C7	0.031 (3)	0.026 (2)	0.053 (3)	0.006 (2)	−0.014 (2)	0.002 (2)
C8	0.020 (2)	0.029 (2)	0.047 (3)	0.0039 (19)	−0.006 (2)	−0.008 (2)
C9	0.021 (2)	0.025 (3)	0.0229 (18)	−0.0023 (19)	0.0010 (15)	−0.0085 (19)
O10	0.0250 (17)	0.0283 (15)	0.0220 (16)	−0.0060 (13)	0.0004 (13)	−0.0024 (12)
C10	0.021 (2)	0.015 (2)	0.027 (2)	0.0004 (17)	0.0030 (19)	−0.0068 (17)
N11	0.023 (2)	0.0190 (17)	0.025 (2)	−0.0028 (15)	0.0007 (16)	−0.0021 (15)
C11	0.031 (3)	0.019 (2)	0.024 (2)	−0.0005 (19)	−0.0068 (19)	−0.0006 (17)
C12	0.024 (2)	0.021 (2)	0.029 (3)	0.0012 (18)	−0.0041 (19)	−0.0041 (17)
C13	0.023 (2)	0.045 (3)	0.039 (2)	0.006 (3)	0.0087 (19)	0.013 (3)
C14	0.059 (4)	0.033 (3)	0.039 (3)	0.002 (3)	−0.020 (3)	0.009 (2)
C15	0.022 (2)	0.056 (3)	0.034 (2)	−0.009 (3)	0.0030 (18)	−0.004 (3)
Br5	0.0368 (3)	0.0506 (3)	0.0255 (2)	−0.0097 (3)	0.00600 (18)	−0.0104 (3)
O20	0.0220 (17)	0.0262 (16)	0.0239 (16)	−0.0061 (13)	0.0030 (13)	0.0032 (13)
C20	0.025 (3)	0.018 (2)	0.027 (3)	−0.0008 (19)	−0.004 (2)	0.0069 (18)
O21	0.0244 (17)	0.0279 (16)	0.0230 (16)	0.0007 (13)	0.0025 (13)	−0.0025 (13)
C21	0.020 (2)	0.024 (2)	0.021 (2)	0.0010 (17)	0.0010 (17)	0.0052 (16)
O22	0.0233 (19)	0.043 (2)	0.0277 (18)	0.0010 (16)	0.0033 (15)	−0.0028 (15)
C22	0.021 (2)	0.031 (2)	0.024 (2)	0.0036 (18)	0.0016 (18)	0.0040 (18)
C23	0.022 (3)	0.046 (3)	0.032 (3)	−0.006 (2)	0.006 (2)	0.000 (2)
C24	0.023 (2)	0.051 (3)	0.027 (2)	−0.012 (2)	−0.002 (2)	−0.003 (2)
C25	0.030 (3)	0.034 (2)	0.020 (2)	−0.001 (2)	0.001 (2)	−0.0020 (19)
C26	0.022 (2)	0.029 (2)	0.023 (2)	−0.0019 (18)	0.0041 (18)	0.0037 (18)

Geometric parameters (Å, º) top

O1—C1	1.458 (5)	C8—C12	1.539 (6)
O1—O2	1.469 (4)	C9—C10	1.509 (5)
C1—C2	1.526 (6)	C9—C12	1.537 (6)
C1—C11	1.538 (6)	C9—C15	1.530 (6)
C1—C12	1.522 (6)	O10—C10	1.254 (5)
O2—C3	1.413 (5)	C10—N11	1.329 (6)
C2—O3	1.413 (5)	Br5—C25	1.892 (5)
C2—N11	1.454 (6)	O20—C20	1.313 (6)
O3—C3	1.435 (5)	C20—O21	1.233 (6)
C3—C4	1.530 (6)	C20—C21	1.482 (6)
C3—C13	1.515 (6)	C21—C22	1.405 (6)
C4—C5	1.536 (6)	C21—C26	1.398 (6)
C5—C11	1.531 (7)	O22—C22	1.351 (5)
C6—C7	1.521 (8)	C22—C23	1.404 (7)
C6—C11	1.543 (6)	C23—C24	1.367 (7)
C6—C14	1.526 (7)	C24—C25	1.395 (6)
C7—C8	1.522 (7)	C25—C26	1.369 (6)

C1—O1—O2	112.3 (3)	C15—C9—C12	114.2 (4)
O1—C1—C2	109.1 (3)	O10—C10—C9	119.9 (4)
O1—C1—C11	107.0 (4)	O10—C10—N11	121.0 (4)
O1—C1—C12	105.1 (4)	N11—C10—C9	118.9 (4)
C2—C1—C11	112.0 (4)	C10—N11—C2	127.4 (4)
C12—C1—C2	110.5 (4)	C1—C11—C6	112.1 (4)
C12—C1—C11	112.8 (4)	C5—C11—C1	113.4 (4)
C3—O2—O1	108.2 (3)	C5—C11—C6	110.4 (4)
O3—C2—C1	113.9 (4)	C1—C12—C8	109.9 (4)
O3—C2—N11	108.5 (3)	C1—C12—C9	110.7 (4)
N11—C2—C1	111.4 (4)	C9—C12—C8	115.9 (4)
C2—O3—C3	113.0 (3)	O20—C20—C21	115.0 (4)
O2—C3—O3	108.1 (3)	O21—C20—O20	123.6 (5)
O2—C3—C4	111.7 (4)	O21—C20—C21	121.4 (5)
O2—C3—C13	104.8 (4)	C22—C21—C20	119.2 (4)
O3—C3—C4	110.8 (3)	C26—C21—C20	121.2 (4)
O3—C3—C13	106.5 (4)	C26—C21—C22	119.5 (4)
C13—C3—C4	114.5 (4)	O22—C22—C21	123.0 (4)
C3—C4—C5	114.3 (4)	O22—C22—C23	117.9 (4)
C11—C5—C4	116.8 (4)	C23—C22—C21	119.1 (4)
C7—C6—C11	110.9 (4)	C24—C23—C22	120.5 (4)
C7—C6—C14	112.1 (5)	C23—C24—C25	120.2 (4)
C14—C6—C11	111.9 (5)	C24—C25—Br5	119.4 (4)
C6—C7—C8	113.0 (4)	C26—C25—Br5	120.1 (4)
C7—C8—C12	110.4 (4)	C26—C25—C24	120.5 (4)
C10—C9—C12	113.5 (4)	C25—C26—C21	120.3 (4)
C10—C9—C15	112.1 (3)

O1—C1—C2—O3	−54.5 (5)	N11—C2—O3—C3	−95.5 (4)
O1—C1—C2—N11	68.6 (5)	C11—C1—C2—O3	63.8 (5)
O1—C1—C11—C5	66.4 (5)	C11—C1—C2—N11	−173.1 (3)
O1—C1—C11—C6	−167.9 (4)	C11—C1—C12—C8	55.7 (5)
O1—C1—C12—C8	171.9 (4)	C11—C1—C12—C9	−175.1 (3)
O1—C1—C12—C9	−58.9 (5)	C11—C6—C7—C8	−53.7 (6)
O1—O2—C3—O3	−74.2 (4)	C12—C1—C2—O3	−169.6 (3)
O1—O2—C3—C4	48.0 (4)	C12—C1—C2—N11	−46.5 (5)
O1—O2—C3—C13	172.5 (3)	C12—C1—C11—C5	−178.5 (4)
C1—O1—O2—C3	46.3 (4)	C12—C1—C11—C6	−52.8 (5)
C1—C2—O3—C3	29.2 (5)	C12—C9—C10—O10	−163.9 (4)
C1—C2—N11—C10	23.4 (6)	C12—C9—C10—N11	20.7 (6)
O2—O1—C1—C2	14.6 (5)	C13—C3—C4—C5	145.8 (4)
O2—O1—C1—C11	−106.7 (4)	C14—C6—C7—C8	−179.5 (4)
O2—O1—C1—C12	133.1 (3)	C14—C6—C11—C1	176.3 (4)
O2—C3—C4—C5	−95.3 (4)	C14—C6—C11—C5	−56.3 (6)
C2—C1—C11—C5	−53.2 (5)	C15—C9—C10—O10	−32.6 (6)
C2—C1—C11—C6	72.6 (5)	C15—C9—C10—N11	151.9 (4)
C2—C1—C12—C8	−70.5 (5)	C15—C9—C12—C1	−175.3 (4)
C2—C1—C12—C9	58.7 (5)	C15—C9—C12—C8	−49.4 (6)
C2—O3—C3—O2	33.5 (5)	Br5—C25—C26—C21	−178.7 (3)
C2—O3—C3—C4	−89.2 (4)	O20—C20—C21—C22	179.7 (4)
C2—O3—C3—C13	145.7 (4)	O20—C20—C21—C26	3.0 (6)
O3—C2—N11—C10	149.5 (4)	C20—C21—C22—O22	2.4 (6)
O3—C3—C4—C5	25.3 (6)	C20—C21—C22—C23	−176.6 (4)
C3—C4—C5—C11	55.3 (6)	C20—C21—C26—C25	175.2 (4)
C4—C5—C11—C1	−33.8 (6)	O21—C20—C21—C22	−0.2 (6)
C4—C5—C11—C6	−160.5 (4)	O21—C20—C21—C26	−176.8 (4)
C6—C7—C8—C12	57.6 (5)	C21—C22—C23—C24	1.6 (7)
C7—C6—C11—C1	50.4 (5)	O22—C22—C23—C24	−177.4 (4)
C7—C6—C11—C5	177.7 (4)	C22—C21—C26—C25	−1.5 (6)
C7—C8—C12—C1	−57.2 (5)	C22—C23—C24—C25	−2.0 (8)
C7—C8—C12—C9	176.4 (4)	C23—C24—C25—Br5	−179.5 (4)
C9—C10—N11—C2	−10.2 (6)	C23—C24—C25—C26	0.7 (8)
O10—C10—N11—C2	174.4 (4)	C24—C25—C26—C21	1.0 (7)
C10—C9—C12—C1	−45.1 (5)	C26—C21—C22—O22	179.1 (4)
C10—C9—C12—C8	80.8 (5)	C26—C21—C22—C23	0.2 (6)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N11—H11···O21	0.88 (6)	2.12 (6)	2.917 (5)	150 (5)
O22—H22···O21	0.81 (5)	1.85 (5)	2.575 (4)	147 (5)
O20—H20···O10	0.88 (7)	1.66 (7)	2.541 (4)	179 (8)

1,5,9-Trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0^4,13.0^8,13]hexadecan-10-one; 3,5-dibromosalicylic acid (mona22cult) top

Crystal data top

C₁₅H₂₃NO₄·C₇H₄Br₂O₃	F(000) = 584
M_r = 577.26	D_x = 1.642 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54184 Å
a = 9.52200 (19) Å	Cell parameters from 3893 reflections
b = 9.3214 (2) Å	θ = 3.3–72.4°
c = 13.3453 (3) Å	µ = 4.78 mm⁻¹
β = 99.6446 (19)°	T = 100 K
V = 1167.76 (4) Å³	Block, colourless
Z = 2	0.05 × 0.05 × 0.04 mm

Data collection top

Rigaku OD SuperNova Dual source diffractometer with an Atlas detector	4060 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Cu) X-ray Source	3811 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.028
Detector resolution: 5.1788 pixels mm^-1	θ_max = 72.3°, θ_min = 3.4°
ω scans	h = −11→7
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2020)	k = −11→10
T_min = 0.977, T_max = 1.000	l = −16→15
6899 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.030	w = 1/[σ²(F_o²) + (0.0219P)² + 0.1825P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.067	(Δ/σ)_max < 0.001
S = 1.03	Δρ_max = 0.27 e Å⁻³
4060 reflections	Δρ_min = −0.44 e Å⁻³
304 parameters	Absolute structure: Flack x determined using 1437 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
2 restraints	Absolute structure parameter: −0.034 (19)
Primary atom site location: structure-invariant direct methods

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.6727 (3)	0.3538 (3)	0.6057 (2)	0.0174 (6)
C1	0.6336 (4)	0.5012 (4)	0.6270 (3)	0.0157 (8)
O2	0.6895 (3)	0.3363 (3)	0.4986 (2)	0.0183 (6)
C2	0.5850 (4)	0.5833 (5)	0.5291 (3)	0.0161 (8)
H2	0.5750	0.6863	0.5477	0.019*
O3	0.6836 (3)	0.5777 (3)	0.4602 (2)	0.0180 (6)
C3	0.7726 (4)	0.4533 (5)	0.4731 (3)	0.0202 (8)
C4	0.9049 (4)	0.4783 (5)	0.5542 (3)	0.0226 (9)
H4A	0.9296	0.3874	0.5913	0.027*
H4B	0.9857	0.5043	0.5198	0.027*
C5	0.8865 (4)	0.5948 (5)	0.6304 (4)	0.0223 (9)
H5A	0.8695	0.6869	0.5934	0.027*
H5B	0.9771	0.6043	0.6786	0.027*
C6	0.7273 (5)	0.7121 (5)	0.7421 (3)	0.0210 (9)
H6	0.7006	0.7845	0.6869	0.025*
C7	0.6002 (5)	0.6935 (5)	0.7974 (4)	0.0223 (9)
H7A	0.5734	0.7882	0.8218	0.027*
H7B	0.6286	0.6313	0.8575	0.027*
C8	0.4707 (5)	0.6274 (5)	0.7296 (3)	0.0210 (9)
H8A	0.3931	0.6135	0.7696	0.025*
H8B	0.4360	0.6937	0.6729	0.025*
C9	0.3858 (4)	0.4046 (5)	0.6214 (3)	0.0173 (8)
H9	0.4228	0.3065	0.6104	0.021*
O10	0.2232 (3)	0.4532 (4)	0.4665 (2)	0.0193 (6)
C10	0.3452 (4)	0.4691 (5)	0.5164 (3)	0.0156 (7)
N11	0.4472 (4)	0.5360 (4)	0.4758 (3)	0.0181 (7)
C11	0.7645 (4)	0.5712 (5)	0.6925 (3)	0.0191 (8)
H11A	0.8005	0.5027	0.7486	0.023*
H11	0.423 (8)	0.567 (10)	0.415 (7)	0.08 (3)*
C12	0.5093 (4)	0.4838 (4)	0.6871 (3)	0.0161 (8)
H12	0.5443	0.4205	0.7466	0.019*
C13	0.8082 (5)	0.4155 (6)	0.3693 (3)	0.0258 (10)
H13A	0.8706	0.3312	0.3755	0.039*
H13B	0.8568	0.4967	0.3434	0.039*
H13C	0.7202	0.3943	0.3222	0.039*
C14	0.8551 (5)	0.7700 (6)	0.8149 (4)	0.0286 (11)
H14A	0.8914	0.6957	0.8644	0.043*
H14B	0.8261	0.8541	0.8505	0.043*
H14C	0.9300	0.7976	0.7764	0.043*
C15	0.2569 (4)	0.3815 (5)	0.6734 (3)	0.0233 (9)
H15A	0.2139	0.4744	0.6845	0.035*
H15B	0.2870	0.3339	0.7389	0.035*
H15C	0.1870	0.3214	0.6303	0.035*
Br3	0.33108 (6)	0.93495 (7)	−0.06310 (4)	0.04324 (17)
Br5	−0.20630 (5)	0.96457 (6)	0.06056 (4)	0.03468 (14)
O20	0.1227 (3)	0.5988 (4)	0.3098 (2)	0.0214 (6)
C20	0.2127 (5)	0.6300 (5)	0.2494 (3)	0.0190 (9)
H20	0.157 (7)	0.538 (8)	0.357 (6)	0.05 (2)*
O21	0.3362 (3)	0.5814 (4)	0.2614 (2)	0.0217 (6)
C21	0.1605 (5)	0.7287 (5)	0.1647 (3)	0.0192 (8)
O22	0.3880 (3)	0.7220 (4)	0.1071 (3)	0.0274 (7)
C22	0.2539 (5)	0.7720 (5)	0.0994 (3)	0.0216 (9)
H22	0.395 (10)	0.661 (8)	0.154 (5)	0.09 (3)*
C23	0.2057 (5)	0.8733 (6)	0.0241 (3)	0.0264 (10)
C24	0.0714 (5)	0.9305 (5)	0.0127 (3)	0.0253 (10)
H24	0.0414	1.0000	−0.0385	0.030*
C25	−0.0206 (5)	0.8849 (5)	0.0778 (3)	0.0232 (9)
C26	0.0220 (5)	0.7856 (5)	0.1532 (3)	0.0207 (9)
H26	−0.0416	0.7558	0.1969	0.025*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0197 (15)	0.0152 (15)	0.0177 (14)	0.0032 (11)	0.0042 (12)	0.0010 (12)
C1	0.0155 (18)	0.014 (2)	0.017 (2)	0.0015 (14)	0.0008 (15)	−0.0002 (15)
O2	0.0189 (15)	0.0195 (16)	0.0177 (15)	−0.0005 (12)	0.0062 (12)	−0.0017 (12)
C2	0.0123 (18)	0.020 (2)	0.017 (2)	0.0000 (15)	0.0028 (15)	0.0014 (16)
O3	0.0163 (14)	0.0213 (15)	0.0173 (15)	0.0000 (12)	0.0056 (12)	0.0012 (12)
C3	0.0189 (17)	0.019 (2)	0.025 (2)	0.0010 (19)	0.0098 (15)	0.0005 (19)
C4	0.0125 (17)	0.025 (2)	0.031 (2)	0.0003 (18)	0.0045 (15)	0.000 (2)
C5	0.0125 (19)	0.024 (2)	0.029 (2)	−0.0020 (17)	−0.0007 (17)	0.0000 (18)
C6	0.023 (2)	0.021 (2)	0.017 (2)	0.0006 (18)	−0.0027 (17)	0.0010 (17)
C7	0.025 (2)	0.024 (2)	0.017 (2)	0.0038 (18)	0.0010 (17)	−0.0035 (17)
C8	0.023 (2)	0.022 (2)	0.018 (2)	0.0044 (17)	0.0053 (17)	−0.0009 (17)
C9	0.0156 (18)	0.020 (2)	0.017 (2)	0.0012 (15)	0.0055 (15)	0.0022 (16)
O10	0.0120 (12)	0.0259 (16)	0.0195 (13)	−0.0010 (13)	0.0006 (10)	0.0018 (15)
C10	0.0129 (16)	0.0166 (19)	0.0175 (17)	0.0038 (17)	0.0035 (14)	−0.0008 (17)
N11	0.0142 (17)	0.0228 (19)	0.0170 (18)	−0.0013 (14)	0.0021 (14)	0.0015 (15)
C11	0.0140 (19)	0.021 (2)	0.021 (2)	0.0014 (16)	−0.0020 (16)	0.0006 (17)
C12	0.0155 (17)	0.019 (2)	0.0144 (17)	0.0021 (16)	0.0037 (14)	0.0028 (16)
C13	0.022 (2)	0.030 (3)	0.029 (2)	−0.0010 (19)	0.0130 (17)	−0.004 (2)
C14	0.031 (3)	0.029 (3)	0.023 (2)	−0.002 (2)	−0.004 (2)	−0.0003 (19)
C15	0.018 (2)	0.036 (3)	0.016 (2)	−0.0004 (18)	0.0043 (16)	0.0010 (18)
Br3	0.0427 (3)	0.0631 (4)	0.0272 (3)	−0.0045 (3)	0.0155 (2)	0.0110 (3)
Br5	0.0343 (2)	0.0472 (3)	0.0227 (2)	0.0173 (2)	0.00495 (17)	0.0120 (2)
O20	0.0159 (14)	0.0252 (17)	0.0221 (16)	−0.0018 (12)	0.0006 (12)	0.0034 (13)
C20	0.019 (2)	0.019 (2)	0.017 (2)	−0.0039 (16)	−0.0008 (16)	−0.0063 (16)
O21	0.0185 (15)	0.0252 (16)	0.0203 (15)	0.0025 (13)	−0.0004 (12)	−0.0030 (13)
C21	0.021 (2)	0.020 (2)	0.016 (2)	−0.0011 (17)	0.0016 (16)	−0.0034 (17)
O22	0.0217 (15)	0.036 (2)	0.0248 (18)	−0.0004 (14)	0.0058 (13)	−0.0025 (15)
C22	0.020 (2)	0.026 (2)	0.017 (2)	−0.0066 (18)	−0.0001 (17)	−0.0072 (17)
C23	0.028 (2)	0.037 (3)	0.015 (2)	−0.005 (2)	0.0054 (17)	−0.0036 (18)
C24	0.034 (2)	0.026 (3)	0.015 (2)	−0.002 (2)	0.0017 (16)	0.002 (2)
C25	0.026 (2)	0.025 (2)	0.017 (2)	0.0005 (18)	−0.0006 (17)	0.0006 (17)
C26	0.022 (2)	0.025 (2)	0.014 (2)	−0.0004 (18)	−0.0001 (16)	−0.0009 (17)

Geometric parameters (Å, º) top

O1—C1	1.463 (5)	C9—C10	1.514 (5)
O1—O2	1.474 (4)	C9—C12	1.534 (5)
C1—C2	1.519 (6)	C9—C15	1.523 (5)
C1—C11	1.542 (6)	O10—C10	1.247 (4)
C1—C12	1.545 (5)	C10—N11	1.342 (5)
O2—C3	1.421 (5)	Br3—C23	1.891 (5)
C2—O3	1.421 (5)	Br5—C25	1.896 (5)
C2—N11	1.452 (5)	O20—C20	1.304 (6)
O3—C3	1.430 (6)	C20—O21	1.245 (5)
C3—C4	1.534 (5)	C20—C21	1.477 (6)
C3—C13	1.522 (6)	C21—C22	1.405 (6)
C4—C5	1.518 (6)	C21—C26	1.406 (6)
C5—C11	1.552 (6)	O22—C22	1.347 (6)
C6—C7	1.529 (6)	C22—C23	1.399 (7)
C6—C11	1.538 (6)	C23—C24	1.370 (7)
C6—C14	1.523 (6)	C24—C25	1.399 (6)
C7—C8	1.531 (6)	C25—C26	1.378 (6)
C8—C12	1.523 (6)

C1—O1—O2	111.4 (3)	O10—C10—C9	121.1 (4)
O1—C1—C2	110.9 (3)	O10—C10—N11	120.8 (4)
O1—C1—C11	107.4 (3)	N11—C10—C9	117.9 (3)
O1—C1—C12	104.1 (3)	C10—N11—C2	126.8 (4)
C2—C1—C11	112.0 (3)	C1—C11—C5	111.4 (4)
C2—C1—C12	110.5 (3)	C6—C11—C1	112.5 (3)
C11—C1—C12	111.5 (3)	C6—C11—C5	110.8 (4)
C3—O2—O1	107.6 (3)	C8—C12—C1	110.8 (3)
O3—C2—C1	113.5 (3)	C8—C12—C9	115.2 (3)
O3—C2—N11	108.2 (3)	C9—C12—C1	109.5 (3)
N11—C2—C1	112.9 (3)	O20—C20—C21	116.1 (4)
C2—O3—C3	113.2 (3)	O21—C20—O20	122.9 (4)
O2—C3—O3	108.0 (3)	O21—C20—C21	120.9 (4)
O2—C3—C4	111.9 (4)	C22—C21—C20	119.2 (4)
O2—C3—C13	105.0 (4)	C22—C21—C26	120.2 (4)
O3—C3—C4	111.2 (4)	C26—C21—C20	120.5 (4)
O3—C3—C13	107.2 (4)	O22—C22—C21	122.9 (4)
C13—C3—C4	113.3 (3)	O22—C22—C23	118.8 (4)
C5—C4—C3	114.1 (4)	C23—C22—C21	118.3 (4)
C4—C5—C11	115.9 (4)	C22—C23—Br3	118.8 (4)
C7—C6—C11	111.6 (4)	C24—C23—Br3	119.2 (4)
C14—C6—C7	110.2 (4)	C24—C23—C22	122.0 (4)
C14—C6—C11	111.1 (4)	C23—C24—C25	118.9 (4)
C6—C7—C8	112.6 (4)	C24—C25—Br5	118.3 (3)
C12—C8—C7	110.6 (3)	C26—C25—Br5	120.4 (4)
C10—C9—C12	113.0 (3)	C26—C25—C24	121.2 (4)
C10—C9—C15	112.2 (3)	C25—C26—C21	119.3 (4)
C15—C9—C12	114.0 (3)

O1—C1—C2—O3	−52.6 (4)	C11—C1—C2—N11	−169.0 (3)
O1—C1—C2—N11	71.0 (4)	C11—C1—C12—C8	55.7 (4)
O1—C1—C11—C5	69.1 (4)	C11—C1—C12—C9	−176.2 (3)
O1—C1—C11—C6	−165.8 (3)	C11—C6—C7—C8	−52.8 (5)
O1—C1—C12—C8	171.2 (3)	C12—C1—C2—O3	−167.6 (3)
O1—C1—C12—C9	−60.6 (4)	C12—C1—C2—N11	−43.9 (5)
O1—O2—C3—O3	−75.7 (4)	C12—C1—C11—C5	−177.4 (3)
O1—O2—C3—C4	47.0 (4)	C12—C1—C11—C6	−52.3 (5)
O1—O2—C3—C13	170.2 (3)	C12—C9—C10—O10	−155.5 (4)
C1—O1—O2—C3	46.2 (4)	C12—C9—C10—N11	28.7 (5)
C1—C2—O3—C3	25.7 (5)	C13—C3—C4—C5	144.5 (4)
C1—C2—N11—C10	23.3 (6)	C14—C6—C7—C8	−176.8 (4)
O2—O1—C1—C2	14.5 (4)	C14—C6—C11—C1	174.0 (4)
O2—O1—C1—C11	−108.2 (3)	C14—C6—C11—C5	−60.6 (5)
O2—O1—C1—C12	133.3 (3)	C15—C9—C10—O10	−25.0 (6)
O2—C3—C4—C5	−97.1 (5)	C15—C9—C10—N11	159.3 (4)
C2—C1—C11—C5	−53.0 (5)	C15—C9—C12—C1	−180.0 (3)
C2—C1—C11—C6	72.2 (5)	C15—C9—C12—C8	−54.3 (5)
C2—C1—C12—C8	−69.6 (4)	Br3—C23—C24—C25	−179.7 (4)
C2—C1—C12—C9	58.5 (4)	Br5—C25—C26—C21	−179.6 (3)
C2—O3—C3—O2	36.5 (4)	O20—C20—C21—C22	177.1 (4)
C2—O3—C3—C4	−86.6 (4)	O20—C20—C21—C26	1.0 (6)
C2—O3—C3—C13	149.1 (3)	C20—C21—C22—O22	3.4 (6)
O3—C2—N11—C10	149.9 (4)	C20—C21—C22—C23	−175.5 (4)
O3—C3—C4—C5	23.7 (5)	C20—C21—C26—C25	175.6 (4)
C3—C4—C5—C11	59.0 (5)	O21—C20—C21—C22	−2.4 (6)
C4—C5—C11—C1	−37.0 (5)	O21—C20—C21—C26	−178.5 (4)
C4—C5—C11—C6	−163.1 (4)	C21—C22—C23—Br3	179.0 (3)
C6—C7—C8—C12	56.6 (5)	C21—C22—C23—C24	0.0 (7)
C7—C6—C11—C1	50.5 (5)	O22—C22—C23—Br3	0.0 (6)
C7—C6—C11—C5	175.9 (3)	O22—C22—C23—C24	−179.0 (4)
C7—C8—C12—C1	−57.4 (5)	C22—C21—C26—C25	−0.5 (7)
C7—C8—C12—C9	177.6 (3)	C22—C23—C24—C25	−0.7 (7)
C9—C10—N11—C2	−15.3 (6)	C23—C24—C25—Br5	−179.7 (4)
O10—C10—N11—C2	169.0 (4)	C23—C24—C25—C26	0.8 (7)
C10—C9—C12—C1	−50.3 (4)	C24—C25—C26—C21	−0.2 (7)
C10—C9—C12—C8	75.3 (4)	C26—C21—C22—O22	179.6 (4)
N11—C2—O3—C3	−100.4 (4)	C26—C21—C22—C23	0.6 (6)
C11—C1—C2—O3	67.4 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N11—H11···O21	0.86 (9)	2.08 (9)	2.910 (5)	163 (9)
O20—H20···O10	0.87 (8)	1.68 (8)	2.542 (4)	167 (7)
O22—H22···O21	0.84 (3)	1.79 (5)	2.558 (5)	152 (9)

1,5,9-Trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0^4,13.0^8,13]hexadecan-10-one; 4-bromosalicylic acid (mona23cult) top

Crystal data top

C₁₅H₂₃NO₄·C₇H₅BrO₃	F(000) = 516
M_r = 498.36	D_x = 1.461 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54184 Å
a = 11.0814 (2) Å	Cell parameters from 3985 reflections
b = 9.28293 (18) Å	θ = 4.0–72.3°
c = 11.1404 (2) Å	µ = 2.84 mm⁻¹
β = 98.638 (2)°	T = 100 K
V = 1132.99 (4) Å³	Block, colourless
Z = 2	0.06 × 0.04 × 0.03 mm

Data collection top

Rigaku OD SuperNova Dual source diffractometer with an Atlas detector	3833 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Cu) X-ray Source	3611 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.032
Detector resolution: 5.1788 pixels mm^-1	θ_max = 72.5°, θ_min = 4.0°
ω scans	h = −12→13
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2020)	k = −11→10
T_min = 0.889, T_max = 1.000	l = −10→13
6749 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.029	w = 1/[σ²(F_o²) + (0.0222P)² + 0.0574P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.068	(Δ/σ)_max = 0.001
S = 1.04	Δρ_max = 0.32 e Å⁻³
3833 reflections	Δρ_min = −0.57 e Å⁻³
295 parameters	Absolute structure: Flack x determined using 1284 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: −0.020 (15)
Primary atom site location: structure-invariant direct methods

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.5838 (2)	0.3279 (3)	0.3424 (2)	0.0178 (5)
C1	0.6268 (3)	0.4741 (3)	0.3744 (3)	0.0155 (7)
O2	0.4522 (2)	0.3118 (3)	0.3446 (2)	0.0208 (5)
C2	0.5307 (3)	0.5568 (4)	0.4319 (3)	0.0173 (7)
H2	0.5574	0.6596	0.4400	0.021*
O3	0.4133 (2)	0.5542 (3)	0.3608 (2)	0.0191 (6)
C3	0.3931 (3)	0.4310 (4)	0.2818 (3)	0.0209 (7)
C4	0.4383 (4)	0.4588 (4)	0.1612 (3)	0.0228 (8)
H4A	0.3681	0.4881	0.1005	0.027*
H4B	0.4706	0.3675	0.1328	0.027*
C5	0.5375 (4)	0.5742 (4)	0.1662 (3)	0.0219 (8)
H5A	0.5023	0.6673	0.1868	0.026*
H5B	0.5606	0.5839	0.0841	0.026*
C6	0.7283 (4)	0.6861 (4)	0.2824 (4)	0.0235 (8)
H6	0.6749	0.7590	0.3148	0.028*
C7	0.8404 (4)	0.6626 (5)	0.3782 (4)	0.0297 (9)
H7A	0.8811	0.7563	0.3983	0.036*
H7B	0.8987	0.5993	0.3442	0.036*
C8	0.8085 (4)	0.5947 (5)	0.4944 (4)	0.0269 (8)
H8A	0.8841	0.5785	0.5524	0.032*
H8B	0.7557	0.6613	0.5327	0.032*
C9	0.7127 (3)	0.3693 (4)	0.5778 (3)	0.0193 (7)
H9	0.6861	0.2710	0.5481	0.023*
O10	0.5944 (2)	0.4163 (3)	0.7382 (2)	0.0229 (6)
C10	0.6058 (3)	0.4341 (4)	0.6289 (3)	0.0175 (7)
N11	0.5211 (2)	0.5039 (4)	0.5528 (2)	0.0176 (5)
C11	0.6542 (3)	0.5467 (4)	0.2570 (3)	0.0183 (7)
H11A	0.7056	0.4781	0.2174	0.022*
H11	0.460 (4)	0.527 (5)	0.579 (4)	0.020 (11)*
C12	0.7425 (3)	0.4519 (4)	0.4665 (3)	0.0192 (7)
H12	0.7981	0.3891	0.4265	0.023*
C13	0.2582 (4)	0.3959 (5)	0.2692 (4)	0.0311 (9)
H13A	0.2379	0.3664	0.3482	0.047*
H13B	0.2392	0.3172	0.2108	0.047*
H13C	0.2104	0.4812	0.2405	0.047*
C14	0.7670 (4)	0.7477 (6)	0.1660 (4)	0.0326 (8)
H14A	0.8198	0.8315	0.1864	0.049*
H14B	0.6943	0.7768	0.1100	0.049*
H14C	0.8116	0.6739	0.1275	0.049*
C15	0.8233 (4)	0.3468 (5)	0.6759 (4)	0.0309 (9)
H15A	0.8482	0.4394	0.7141	0.046*
H15B	0.8909	0.3066	0.6390	0.046*
H15C	0.8018	0.2800	0.7374	0.046*
Br4	0.00338 (4)	0.99999 (6)	1.00460 (4)	0.02935 (11)
O20	0.4469 (3)	0.5614 (3)	0.8454 (2)	0.0224 (6)
C20	0.3400 (3)	0.5854 (4)	0.7813 (3)	0.0172 (7)
H20	0.489 (4)	0.505 (8)	0.807 (4)	0.038 (12)*
O21	0.3082 (2)	0.5340 (3)	0.6785 (2)	0.0202 (5)
C21	0.2576 (3)	0.6798 (4)	0.8389 (3)	0.0172 (7)
O22	0.0968 (3)	0.6524 (3)	0.6671 (3)	0.0268 (6)
C22	0.1403 (3)	0.7102 (4)	0.7765 (3)	0.0195 (8)
H22	0.156 (5)	0.605 (7)	0.652 (5)	0.050 (17)*
C23	0.0647 (3)	0.8052 (4)	0.8268 (4)	0.0219 (8)
H23	−0.0150	0.8259	0.7861	0.026*
C24	0.1077 (3)	0.8693 (4)	0.9377 (3)	0.0211 (8)
C25	0.2221 (4)	0.8425 (4)	1.0010 (3)	0.0209 (7)
H25	0.2492	0.8875	1.0768	0.025*
C26	0.2962 (3)	0.7474 (5)	0.9497 (3)	0.0184 (6)
H26	0.3758	0.7277	0.9914	0.022*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0178 (12)	0.0124 (12)	0.0225 (12)	−0.0014 (10)	0.0007 (10)	−0.0015 (9)
C1	0.0196 (16)	0.0098 (18)	0.0173 (15)	−0.0019 (12)	0.0032 (12)	−0.0014 (12)
O2	0.0158 (12)	0.0183 (12)	0.0269 (14)	−0.0022 (10)	−0.0016 (10)	0.0051 (10)
C2	0.0178 (17)	0.0165 (16)	0.0173 (16)	0.0018 (13)	0.0017 (13)	0.0016 (12)
O3	0.0152 (13)	0.0187 (13)	0.0228 (13)	0.0036 (9)	0.0010 (10)	0.0015 (10)
C3	0.0212 (19)	0.0192 (18)	0.0203 (18)	0.0002 (15)	−0.0034 (14)	0.0039 (14)
C4	0.0270 (19)	0.022 (2)	0.0176 (16)	0.0000 (14)	−0.0015 (14)	0.0002 (12)
C5	0.025 (2)	0.0193 (18)	0.0211 (18)	0.0028 (15)	0.0028 (14)	0.0041 (14)
C6	0.0245 (19)	0.0148 (16)	0.034 (2)	−0.0015 (15)	0.0133 (16)	−0.0013 (15)
C7	0.0218 (19)	0.029 (2)	0.040 (2)	−0.0082 (17)	0.0110 (17)	−0.0032 (17)
C8	0.0211 (19)	0.028 (2)	0.031 (2)	−0.0051 (16)	0.0015 (16)	−0.0065 (16)
C9	0.0192 (17)	0.0215 (19)	0.0175 (17)	0.0060 (14)	0.0031 (14)	−0.0016 (13)
O10	0.0243 (14)	0.0263 (14)	0.0184 (13)	0.0081 (11)	0.0041 (10)	0.0020 (11)
C10	0.0183 (18)	0.0170 (16)	0.0165 (16)	0.0006 (14)	0.0003 (13)	−0.0044 (13)
N11	0.0169 (13)	0.0176 (13)	0.0193 (12)	0.0048 (15)	0.0063 (10)	−0.0007 (15)
C11	0.0197 (17)	0.0156 (16)	0.0211 (17)	0.0021 (13)	0.0076 (14)	0.0003 (12)
C12	0.0153 (17)	0.0191 (17)	0.0232 (17)	0.0029 (13)	0.0032 (13)	−0.0029 (12)
C13	0.019 (2)	0.034 (2)	0.038 (2)	−0.0047 (16)	−0.0029 (16)	0.0067 (17)
C14	0.040 (2)	0.0242 (18)	0.039 (2)	0.000 (2)	0.0229 (17)	0.002 (2)
C15	0.023 (2)	0.047 (3)	0.0227 (19)	0.0116 (19)	0.0023 (15)	0.0002 (18)
Br4	0.02513 (18)	0.03240 (19)	0.03221 (19)	0.00913 (18)	0.00980 (13)	−0.00367 (18)
O20	0.0232 (14)	0.0245 (13)	0.0200 (13)	0.0088 (11)	0.0046 (10)	0.0016 (10)
C20	0.0197 (17)	0.0124 (16)	0.0199 (17)	−0.0001 (13)	0.0039 (13)	0.0043 (13)
O21	0.0213 (12)	0.0172 (14)	0.0230 (12)	−0.0018 (10)	0.0065 (10)	−0.0013 (9)
C21	0.0171 (17)	0.0150 (16)	0.0198 (17)	−0.0001 (14)	0.0038 (13)	0.0030 (13)
O22	0.0193 (13)	0.0320 (15)	0.0281 (15)	−0.0009 (12)	0.0007 (11)	−0.0092 (12)
C22	0.0158 (17)	0.0215 (19)	0.0211 (17)	−0.0043 (13)	0.0027 (14)	−0.0006 (12)
C23	0.0140 (17)	0.0239 (18)	0.0270 (19)	0.0002 (14)	0.0005 (14)	0.0013 (14)
C24	0.0188 (18)	0.0199 (18)	0.0269 (19)	0.0025 (14)	0.0110 (15)	0.0021 (14)
C25	0.0243 (18)	0.0224 (18)	0.0166 (17)	0.0021 (15)	0.0049 (14)	0.0022 (14)
C26	0.0187 (15)	0.0176 (14)	0.0192 (15)	0.0009 (18)	0.0037 (12)	0.0024 (16)

Geometric parameters (Å, º) top

O1—C1	1.465 (4)	C8—C12	1.524 (5)
O1—O2	1.470 (3)	C9—C10	1.514 (5)
C1—C2	1.529 (5)	C9—C12	1.535 (5)
C1—C11	1.542 (5)	C9—C15	1.529 (5)
C1—C12	1.531 (5)	O10—C10	1.254 (5)
O2—C3	1.416 (4)	C10—N11	1.334 (5)
C2—O3	1.418 (4)	Br4—C24	1.903 (4)
C2—N11	1.453 (5)	O20—C20	1.307 (4)
O3—C3	1.440 (5)	C20—O21	1.242 (4)
C3—C4	1.526 (5)	C20—C21	1.479 (5)
C3—C13	1.515 (5)	C21—C22	1.408 (5)
C4—C5	1.529 (5)	C21—C26	1.394 (5)
C5—C11	1.538 (5)	O22—C22	1.352 (5)
C6—C7	1.527 (6)	C22—C23	1.391 (5)
C6—C11	1.536 (5)	C23—C24	1.389 (6)
C6—C14	1.536 (5)	C24—C25	1.378 (5)
C7—C8	1.528 (6)	C25—C26	1.386 (5)

C1—O1—O2	112.1 (2)	C15—C9—C12	113.5 (3)
O1—C1—C2	110.2 (3)	O10—C10—C9	120.8 (3)
O1—C1—C11	107.3 (3)	O10—C10—N11	121.1 (3)
O1—C1—C12	104.3 (3)	N11—C10—C9	118.0 (3)
C2—C1—C11	112.0 (3)	C10—N11—C2	127.7 (3)
C2—C1—C12	110.7 (3)	C5—C11—C1	112.1 (3)
C12—C1—C11	112.0 (3)	C6—C11—C1	112.3 (3)
C3—O2—O1	107.4 (2)	C6—C11—C5	110.8 (3)
O3—C2—C1	113.3 (3)	C1—C12—C9	110.4 (3)
O3—C2—N11	108.9 (3)	C8—C12—C1	110.3 (3)
N11—C2—C1	111.8 (3)	C8—C12—C9	115.1 (3)
C2—O3—C3	113.6 (3)	O20—C20—C21	115.6 (3)
O2—C3—O3	107.5 (3)	O21—C20—O20	123.1 (3)
O2—C3—C4	112.2 (3)	O21—C20—C21	121.3 (3)
O2—C3—C13	104.7 (3)	C22—C21—C20	119.3 (3)
O3—C3—C4	111.3 (3)	C26—C21—C20	121.6 (3)
O3—C3—C13	106.8 (3)	C26—C21—C22	119.0 (3)
C13—C3—C4	113.9 (3)	O22—C22—C21	122.9 (3)
C3—C4—C5	114.5 (3)	O22—C22—C23	117.4 (3)
C4—C5—C11	115.9 (3)	C23—C22—C21	119.7 (3)
C7—C6—C11	111.4 (3)	C24—C23—C22	118.9 (3)
C7—C6—C14	110.0 (3)	C23—C24—Br4	118.3 (3)
C11—C6—C14	111.5 (3)	C25—C24—Br4	118.7 (3)
C6—C7—C8	112.5 (3)	C25—C24—C23	123.0 (3)
C12—C8—C7	110.5 (3)	C24—C25—C26	117.4 (3)
C10—C9—C12	112.4 (3)	C25—C26—C21	122.0 (3)
C10—C9—C15	112.0 (3)

O1—C1—C2—O3	−52.4 (4)	N11—C2—O3—C3	−99.5 (3)
O1—C1—C2—N11	71.1 (4)	C11—C1—C2—O3	66.9 (4)
O1—C1—C11—C5	68.2 (3)	C11—C1—C2—N11	−169.6 (3)
O1—C1—C11—C6	−166.3 (3)	C11—C1—C12—C8	55.9 (4)
O1—C1—C12—C8	171.6 (3)	C11—C1—C12—C9	−175.7 (3)
O1—C1—C12—C9	−60.1 (3)	C11—C6—C7—C8	−53.1 (4)
O1—O2—C3—O3	−75.8 (3)	C12—C1—C2—O3	−167.3 (3)
O1—O2—C3—C4	46.9 (4)	C12—C1—C2—N11	−43.7 (4)
O1—O2—C3—C13	170.9 (3)	C12—C1—C11—C5	−177.9 (3)
C1—O1—O2—C3	46.6 (3)	C12—C1—C11—C6	−52.4 (4)
C1—C2—O3—C3	25.6 (4)	C12—C9—C10—O10	−155.1 (3)
C1—C2—N11—C10	23.8 (6)	C12—C9—C10—N11	28.3 (5)
O2—O1—C1—C2	14.4 (3)	C13—C3—C4—C5	144.7 (4)
O2—O1—C1—C11	−107.7 (3)	C14—C6—C7—C8	−177.3 (4)
O2—O1—C1—C12	133.3 (3)	C14—C6—C11—C1	173.6 (3)
O2—C3—C4—C5	−96.5 (4)	C14—C6—C11—C5	−60.2 (4)
C2—C1—C11—C5	−52.9 (4)	C15—C9—C10—O10	−25.9 (5)
C2—C1—C11—C6	72.7 (4)	C15—C9—C10—N11	157.5 (4)
C2—C1—C12—C8	−69.9 (4)	C15—C9—C12—C1	−178.2 (3)
C2—C1—C12—C9	58.5 (4)	C15—C9—C12—C8	−52.6 (4)
C2—O3—C3—O2	36.7 (4)	Br4—C24—C25—C26	−179.7 (3)
C2—O3—C3—C4	−86.5 (4)	O20—C20—C21—C22	−179.5 (3)
C2—O3—C3—C13	148.6 (3)	O20—C20—C21—C26	5.0 (5)
O3—C2—N11—C10	149.8 (4)	C20—C21—C22—O22	2.5 (5)
O3—C3—C4—C5	24.0 (4)	C20—C21—C22—C23	−176.5 (3)
C3—C4—C5—C11	58.0 (4)	C20—C21—C26—C25	176.2 (3)
C4—C5—C11—C1	−36.3 (4)	O21—C20—C21—C22	1.0 (5)
C4—C5—C11—C6	−162.7 (3)	O21—C20—C21—C26	−174.6 (3)
C6—C7—C8—C12	57.3 (4)	C21—C22—C23—C24	0.6 (5)
C7—C6—C11—C1	50.3 (4)	O22—C22—C23—C24	−178.4 (3)
C7—C6—C11—C5	176.5 (3)	C22—C21—C26—C25	0.7 (6)
C7—C8—C12—C1	−57.8 (4)	C22—C23—C24—Br4	179.6 (3)
C7—C8—C12—C9	176.5 (3)	C22—C23—C24—C25	−0.4 (6)
C9—C10—N11—C2	−16.0 (6)	C23—C24—C25—C26	0.2 (6)
O10—C10—N11—C2	167.4 (4)	C24—C25—C26—C21	−0.4 (6)
C10—C9—C12—C1	−49.9 (4)	C26—C21—C22—O22	178.2 (3)
C10—C9—C12—C8	75.8 (4)	C26—C21—C22—C23	−0.8 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N11—H11···O21	0.81 (4)	2.15 (4)	2.931 (4)	163 (4)
O20—H20···O10	0.86 (6)	1.70 (6)	2.550 (4)	169 (6)
O22—H22···O21	0.83 (6)	1.79 (6)	2.574 (4)	156 (6)

Unit cells for coformers and cocrystals 1–4 all at 100 K top

Compound	a	b	c	α	β	γ	V	Z	Mol. volume	Reference
11-Aza	11.71759 (15)	11.71759 (15)	9.48728 (13)	90	90	120	1128.10 (3)	3	376.0	Nisar et al. (2018a)
SalA	4.8857 (5)	11.2103 (7)	11.2525 (11)	90	92.581 (9)	90	615.68 (9)	4	153.7	Nisar et al. (2018a)
5-BrSalA	6.9581 (7)	7.1413 (8)	8.0284 (9)	81.959 (10)	73.812 (10)	71.352 (10)	362.43 (8)	2	181.2	This work
4-BrSalA	3.8053 (2)	14.6610 (8)	12.9396 (7)	90	97.320 (6)	90	716.02 (7)	4	179.0	This work
3,5-Br₂SalA	10.3703 (4)	10.9444 (4)	14.8108 (6)	90	103.350 (4)	90	1635.55 (10)	8	204.4	This work
1 11-Aza:SalA	9.79451 (14)	9.30687 (13)	11.51291 (16)	90	92.3070 (12)	90	1048.62 (3)	2	524.3	Nisar et al. (2018a)
2 11-Aza: 5-BrSalA	9.9325 (4)	9.0196 (3)	12.3942 (4)	90	93.844 (3)	90	1107.88 (6)	2	554.0	This work
3 11-Aza₂: 4-BrSalA	11.0814 (2)	9.28293 (18)	11.1404 (2)	90	98.638 (2)	90	1132.99 (4)	2	566.5	This work
4 11-Aza₂: 35-Br₂SalA	9.52200 (19)	9.3214 (2)	13.3453 (3)	90	99.6446 (19)	90	1167.76 (4)	2	583.9	This work

Geometry (Å, °) of lactam–acid R₂²(8) heterosynthons in 1–4 top

Cocrystal	O10···O20	N11···O21	C10═O10···O20—C20
1	2.549 (2)	2.911 (2)	41.6
2	2.541 (4)	2.917 (5)	31.7
3	2.550 (4)	2.931 (4)	40.8
4	2.542 (4)	2.910 (5)	37.6

Close contacts (Å) within and between 21 stacks for 1–4 top

	1	2	3	4	Contact
Intra-stack
O1—H11	2.780	2.631	2.987	2.826	11Aza-11Aza
O2—H2/8a	2.666/2.777	3.066/3.152	2.801/3.174	2.856/2.742	11Aza-11Aza
O3—H9	2.432	2.703	2.574	2.478	11Aza-11Aza
O10—H5a/6	2.808/2.922	3.199/3.065	2.731/3.296	2.710/2.773	11Aza-11Aza
O20—H4a	2.947	3.063	3.169	3.071	SalA–11Aza
O21—H6/14b	2.825/2.900	2.742/3.482	2.560/2.908	2.885/2.885	SalA–11Aza
O22—H12	2.913	2.883	2.763	2.689	SalA–11Aza

Inter-stack
O22—H24/	2.888	3.885	/Br4 4.223	4.536	SalA–SalA
O20—H5a	2.820	3.593	2.774	5.629	11Aza–SalA
O22—H13b	2.636	2.677	4.424	5.437	11Aza–SalA
H5a—H26	2.445	2.535	2.531	3.653	11Aza–SalA
O10—H25/	2.520	/Br5 3.022	2.500	/H4b 2.527	SalA–11Aza
O22—H8a	3.970	4.294	2.599	4.384	11Aza–SalA
H8a—H15b	2.811	3.045	4.104	5.955	11Aza-11Aza
O20—H13c	–	8.594	5.459	2.810	11Aza–SalA
O22—Br5	–	3.911	–	3.530	SalA–SalA

Hydrogen-bond comparison (Å) in coformers and cocrystals top

Cocrystal	11-Aza N—H···O	Cocrystal N—H···O	Acid O—H···.O	Cocrystal O—H···O
1 11-Aza:SalA	3.033 (2)	2.911 (2)	2.651 (1)	2.549 (2)
2 11-Aza:5-Br-SalA	–	2.917 (5)	2.645 (3)	2.541 (4)
3 11-Aza₂:4-Br-SalA	–	2.931 (4)	2.665 (5)	2.550 (4)
4 11-Aza₂:3,5-Br₂-SalA	–	2.910 (5)	2.666 (3)	2.542 (4)

Data for cocrystal 1 and 11-Aza are taken from Nisar et al. (2018a) and acids and cocrystals 2–4 are from this work.

Specific volumes (Å³) for cocrystals 1–4 at 100 K top

Cocrystal	Acid volume^a	Combined volume^b	Cocrystal volume^c	Difference in specific volume ΔV
1 11-Aza:SalA	153.7	529.7	524.3	-5.4 (-1.1%)
2 11-Aza:5-Br-SalA	181.2	557.2	554.0	-3.2 (-0.6%)
3 11-Aza₂:4-Br-SalA	179.0	555.0	566.5	+11.5 (+2.1%)
4 11-Aza₂:3,5-Br₂-SalA	204.4	580.4	583.9	+3.5 (+0.6%)

Notes: (a) acid volumes from unit cells measured at 100 K (see Table 3); (b) specific volume of 376.0 Å for 11-azaartemisinin at 100 K (Nisar et al., 2018a); (c) corresponding combined volume from cocrystal structures 1–4.

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Format		BIBTeX
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Varying degrees of homostructurality in a series of cocrystals of anti­malarial drug 11-aza­artemisinin with salicylic acids

Supporting information

Varying degrees of homostructurality in a series of cocrystals of antimalarial drug 11-azaartemisinin with salicylic acids