High-throughput crystallization and crystal structure of N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-di­hydro-1H-pyrazol-4-yl)-2-methyl­benzamide: a benzamide bearing the 4-amino­anti­pyrine moiety

A recent communication on Ru-catalyzed C—H bond aryl­ation with 4-amino­anti­pyrine (AP) reported the synthesis of AP benzamides. In order to provide additional support to the published structures of AP benzamides, crystallization by high-throughput (HTP) encapsulated nanodroplet crystallization (ENaCt) was undertaken. This allowed for conclusive structure determination by single-crystal X-ray diffraction analysis (SCXRD). This article describes the crystallization and X-ray crystal structure of N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-di­hydro-1H-pyrazol-4-yl)-2-methyl­benzamide, C₁₉H₁₉N₃O₂, as a benzamide bearing 4-amino­anti­pyrine, providing structural confirmation. X-ray structure analysis reveals inter­molecular hy­dro­gen-bonding inter­actions between the AP benzamide N—H proton and the carbonyl O atom of the AP moiety.

Computing details

N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-methylbenzamide

Crystal data

C19H19N3O2	F(000) = 680
Mr = 321.37	Dx = 1.284 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54184 Å
a = 14.0430 (7) Å	Cell parameters from 8968 reflections
b = 6.0130 (3) Å	θ = 3.2–74.9°
c = 20.3113 (9) Å	µ = 0.69 mm^−1
β = 104.295 (5)°	T = 150 K
V = 1661.99 (14) Å^3	Plate, colourless
Z = 4	0.19 × 0.1 × 0.04 mm

Data collection

Rigaku XtaLAB Synergy diffractometer with a HyPix detector	3320 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Cu) X-ray Source	2724 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.086
Detector resolution: 10.0000 pixels mm^-1	θmax = 77.3°, θmin = 3.3°
ω scans	h = −17→17
Absorption correction: analytical [CrysAlis PRO (Rigaku OD, 2023), based on expressions derived by Clark & Reid (1995)]	k = −5→7
Tmin = 0.894, Tmax = 0.978	l = −24→24
15556 measured reflections

Refinement

Refinement on F^2	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.052	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.156	w = 1/[σ^2(Fo^2) + (0.0936P)^2 + 0.2977P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
3320 reflections	Δρmax = 0.26 e Å^−3
223 parameters	Δρmin = −0.29 e Å^−3
0 restraints

Special details

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.

Refinement. Single-crystal diffraction data for benzamide 1a were collected on a XtaLAB Synergy HyPix-Arc 100 diffractometer using copper radiation (Cu Kα, λ = 1.54184 Å). The crystal was cooled to 150 K using an Oxford Cryosystems CryostreamPlus open-flow N₂ cooling device. Intensities were corrected for absorption using a multifaceted crystal model created by indexing the faces of the crystal for which data were collected (Clark & Reid, 1995). Cell refinement, data collection and data reduction were undertaken via the software CrysAlis PRO (CryAlisPro, 1995). All structures were solved using SHELXT (Sheldrick, 2015a) and refined by SHELXL (Sheldrick, 2015b) using the OLEX2 interface (Dolomanov et al., 2009). All non-H atoms were refined anisotropically and H atoms were positioned with idealized geometry, with the exception of those bound to heteroatoms, the positions of which were located using peaks in the Fourier difference map. The displacement parameters of the H atoms were constrained using a riding model, with H_iso(H) values set to be an appropriate multiple of the U_eq value of the parent atom.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.38179 (7)	0.60042 (17)	0.42718 (5)	0.0352 (3)
O2	0.64090 (9)	0.5229 (2)	0.34069 (5)	0.0453 (3)
N1	0.58145 (9)	0.4227 (2)	0.43045 (7)	0.0351 (3)
H1	0.5868 (13)	0.423 (3)	0.4736 (10)	0.042*
N2	0.37473 (10)	0.1698 (2)	0.31220 (6)	0.0349 (3)
N3	0.32830 (9)	0.3218 (2)	0.34663 (6)	0.0333 (3)
C1	0.49073 (11)	0.3394 (3)	0.39155 (7)	0.0341 (4)
C2	0.47350 (12)	0.1766 (2)	0.34350 (7)	0.0358 (4)
C3	0.39927 (11)	0.4398 (2)	0.39377 (7)	0.0314 (3)
C4	0.23653 (11)	0.4125 (2)	0.31076 (8)	0.0339 (4)
C5	0.21125 (12)	0.4126 (3)	0.23990 (8)	0.0391 (4)
H5	0.253987	0.349381	0.215301	0.047*
C6	0.12232 (13)	0.5069 (3)	0.20601 (9)	0.0474 (4)
H6	0.103769	0.506162	0.157755	0.057*
C7	0.06064 (13)	0.6014 (3)	0.24150 (10)	0.0520 (5)
H7	0.000435	0.667327	0.217807	0.062*
C8	0.08701 (13)	0.5998 (3)	0.31206 (10)	0.0483 (4)
H8	0.044716	0.665848	0.336515	0.058*
C9	0.17431 (12)	0.5030 (3)	0.34715 (9)	0.0397 (4)
H9	0.191323	0.498654	0.395395	0.048*
C10	0.32328 (14)	−0.0454 (3)	0.29669 (8)	0.0415 (4)
H10A	0.326081	−0.125786	0.339086	0.062*
H10B	0.355110	−0.134114	0.267729	0.062*
H10C	0.254513	−0.018877	0.272952	0.062*
C11	0.54203 (14)	0.0204 (3)	0.32250 (9)	0.0486 (5)
H11A	0.528618	−0.131411	0.335284	0.073*
H11B	0.609824	0.060621	0.345154	0.073*
H11C	0.532985	0.028639	0.273147	0.073*
C12	0.64631 (11)	0.5270 (3)	0.40176 (8)	0.0347 (4)
C13	0.72398 (11)	0.6614 (3)	0.44940 (7)	0.0354 (4)
C14	0.82345 (12)	0.6380 (3)	0.44946 (8)	0.0434 (4)
C15	0.89032 (13)	0.7825 (4)	0.49132 (9)	0.0542 (5)
H15	0.958279	0.768532	0.493049	0.065*
C16	0.86065 (15)	0.9438 (4)	0.52999 (10)	0.0570 (5)
H16	0.907959	1.038829	0.557856	0.068*
C17	0.76266 (14)	0.9680 (3)	0.52843 (9)	0.0494 (5)
H17	0.741807	1.081099	0.554378	0.059*
C18	0.69493 (13)	0.8255 (3)	0.48861 (8)	0.0393 (4)
H18	0.627359	0.839894	0.488038	0.047*
C19	0.85746 (14)	0.4649 (4)	0.40751 (10)	0.0565 (5)
H19A	0.831736	0.319332	0.416327	0.085*
H19B	0.929442	0.460215	0.419470	0.085*
H19C	0.833464	0.501673	0.359240	0.085*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0428 (6)	0.0308 (6)	0.0287 (5)	0.0013 (4)	0.0024 (4)	−0.0027 (4)
O2	0.0568 (7)	0.0476 (7)	0.0299 (6)	0.0012 (6)	0.0078 (5)	−0.0015 (5)
N1	0.0392 (7)	0.0366 (7)	0.0255 (6)	0.0015 (5)	0.0004 (5)	−0.0017 (6)
N2	0.0450 (7)	0.0254 (6)	0.0303 (6)	0.0001 (5)	0.0021 (5)	−0.0021 (5)
N3	0.0388 (7)	0.0282 (6)	0.0291 (6)	−0.0002 (5)	0.0013 (5)	−0.0014 (5)
C1	0.0393 (8)	0.0310 (8)	0.0279 (7)	0.0033 (6)	0.0004 (6)	0.0010 (6)
C2	0.0452 (8)	0.0294 (8)	0.0287 (7)	0.0051 (6)	0.0016 (6)	0.0021 (6)
C3	0.0402 (8)	0.0262 (7)	0.0242 (7)	−0.0016 (6)	0.0013 (6)	0.0007 (6)
C4	0.0372 (8)	0.0242 (7)	0.0356 (8)	−0.0040 (6)	0.0001 (6)	0.0019 (6)
C5	0.0442 (8)	0.0320 (8)	0.0361 (8)	−0.0061 (7)	0.0002 (7)	0.0040 (7)
C6	0.0529 (10)	0.0363 (9)	0.0426 (9)	−0.0076 (7)	−0.0078 (8)	0.0060 (7)
C7	0.0456 (9)	0.0354 (9)	0.0621 (12)	0.0007 (7)	−0.0110 (8)	0.0014 (8)
C8	0.0419 (9)	0.0366 (9)	0.0618 (11)	0.0007 (7)	0.0041 (8)	−0.0051 (8)
C9	0.0440 (9)	0.0305 (8)	0.0411 (9)	−0.0043 (6)	0.0040 (7)	−0.0019 (7)
C10	0.0611 (10)	0.0261 (8)	0.0343 (8)	−0.0070 (7)	0.0063 (7)	−0.0003 (6)
C11	0.0563 (10)	0.0405 (9)	0.0427 (9)	0.0139 (8)	0.0004 (8)	−0.0079 (8)
C12	0.0402 (8)	0.0303 (8)	0.0310 (8)	0.0079 (6)	0.0038 (6)	0.0020 (6)
C13	0.0398 (8)	0.0338 (8)	0.0297 (7)	0.0021 (6)	0.0031 (6)	0.0066 (6)
C14	0.0422 (8)	0.0485 (10)	0.0380 (9)	0.0062 (7)	0.0067 (7)	0.0120 (8)
C15	0.0419 (9)	0.0672 (13)	0.0498 (10)	−0.0065 (9)	0.0041 (8)	0.0157 (10)
C16	0.0630 (12)	0.0571 (12)	0.0453 (10)	−0.0220 (10)	0.0028 (9)	0.0019 (9)
C17	0.0667 (12)	0.0393 (9)	0.0399 (9)	−0.0098 (8)	0.0089 (8)	−0.0016 (8)
C18	0.0478 (9)	0.0353 (9)	0.0333 (8)	0.0004 (7)	0.0071 (7)	0.0013 (6)
C19	0.0488 (10)	0.0657 (13)	0.0545 (11)	0.0189 (9)	0.0118 (9)	0.0095 (10)

Geometric parameters (Å, º)

O1—C3	1.2396 (18)	C9—H9	0.9500
O2—C12	1.2242 (19)	C10—H10A	0.9800
N1—H1	0.86 (2)	C10—H10B	0.9800
N1—C1	1.4148 (19)	C10—H10C	0.9800
N1—C12	1.351 (2)	C11—H11A	0.9800
N2—N3	1.4055 (18)	C11—H11B	0.9800
N2—C2	1.376 (2)	C11—H11C	0.9800
N2—C10	1.4773 (19)	C12—C13	1.503 (2)
N3—C3	1.3933 (18)	C13—C14	1.404 (2)
N3—C4	1.4232 (19)	C13—C18	1.391 (2)
C1—C2	1.361 (2)	C14—C15	1.402 (3)
C1—C3	1.430 (2)	C14—C19	1.496 (3)
C2—C11	1.481 (2)	C15—H15	0.9500
C4—C5	1.395 (2)	C15—C16	1.376 (3)
C4—C9	1.387 (2)	C16—H16	0.9500
C5—H5	0.9500	C16—C17	1.376 (3)
C5—C6	1.389 (2)	C17—H17	0.9500
C6—H6	0.9500	C17—C18	1.383 (2)
C6—C7	1.379 (3)	C18—H18	0.9500
C7—H7	0.9500	C19—H19A	0.9800
C7—C8	1.389 (3)	C19—H19B	0.9800
C8—H8	0.9500	C19—H19C	0.9800
C8—C9	1.385 (2)
C1—N1—H1	114.1 (12)	N2—C10—H10C	109.5
C12—N1—H1	122.7 (12)	H10A—C10—H10B	109.5
C12—N1—C1	122.25 (13)	H10A—C10—H10C	109.5
N3—N2—C10	114.41 (13)	H10B—C10—H10C	109.5
C2—N2—N3	106.81 (11)	C2—C11—H11A	109.5
C2—N2—C10	120.57 (13)	C2—C11—H11B	109.5
N2—N3—C4	117.86 (11)	C2—C11—H11C	109.5
C3—N3—N2	109.39 (12)	H11A—C11—H11B	109.5
C3—N3—C4	124.08 (12)	H11A—C11—H11C	109.5
N1—C1—C3	121.64 (13)	H11B—C11—H11C	109.5
C2—C1—N1	129.16 (14)	O2—C12—N1	123.23 (15)
C2—C1—C3	108.92 (13)	O2—C12—C13	121.13 (14)
N2—C2—C11	120.04 (14)	N1—C12—C13	115.56 (13)
C1—C2—N2	109.45 (14)	C14—C13—C12	120.70 (15)
C1—C2—C11	130.51 (15)	C18—C13—C12	118.77 (14)
O1—C3—N3	124.61 (14)	C18—C13—C14	120.21 (15)
O1—C3—C1	130.33 (14)	C13—C14—C19	121.78 (17)
N3—C3—C1	105.02 (12)	C15—C14—C13	117.12 (17)
C5—C4—N3	119.73 (14)	C15—C14—C19	121.09 (17)
C9—C4—N3	119.17 (13)	C14—C15—H15	119.0
C9—C4—C5	121.09 (15)	C16—C15—C14	122.09 (17)
C4—C5—H5	120.7	C16—C15—H15	119.0
C6—C5—C4	118.69 (17)	C15—C16—H16	119.9
C6—C5—H5	120.7	C15—C16—C17	120.22 (17)
C5—C6—H6	119.6	C17—C16—H16	119.9
C7—C6—C5	120.87 (17)	C16—C17—H17	120.4
C7—C6—H6	119.6	C16—C17—C18	119.17 (18)
C6—C7—H7	120.2	C18—C17—H17	120.4
C6—C7—C8	119.65 (16)	C13—C18—H18	119.4
C8—C7—H7	120.2	C17—C18—C13	121.17 (17)
C7—C8—H8	119.7	C17—C18—H18	119.4
C9—C8—C7	120.68 (18)	C14—C19—H19A	109.5
C9—C8—H8	119.7	C14—C19—H19B	109.5
C4—C9—H9	120.5	C14—C19—H19C	109.5
C8—C9—C4	118.99 (16)	H19A—C19—H19B	109.5
C8—C9—H9	120.5	H19A—C19—H19C	109.5
N2—C10—H10A	109.5	H19B—C19—H19C	109.5
N2—C10—H10B	109.5

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1^i	0.86 (2)	1.96 (2)	2.8125 (17)	171.3 (18)

Symmetry code: (i) −x+1, −y+1, −z+1.

Preparation of stock solutions for encapsulated nanodroplet crystallization (ENaCt) experiments

Vial	Solvent	Mass of compound (mg)	Volume of solvent added (µl)	Concentration of substrate (mg ml^-1)
1	DMSO	1	48	20.8
2	DMF	1	48	20.8
3	MeOH	1	48	20.8
4	2,2,2-TFE	1	12	83.3
5	Toluene	1	192	Supernatant
6	1,2-DCE	1	192	Supernatant
7	2-MeTHF	1	192	Supernatant
8	1,4-Dioxane	1	192	Supernatant
9	EtOAc	1	192	Supernatant
10	MeCN	1	192	Supernatant
11	MIBK	1	192	Supernatant
12	NM	1	192	Supernatant