The structure of the anti-aging agent J147 used for treating Alzheimer's disease

The mol­ecular structure of the anti-aging agent J147 [systematic name: (E)-N-(2,4-di­methyl­phen­yl)-2,2,2-tri­fluoro-N′-(3-meth­oxy­benzyl­idene)acetohydra­zide], C₁₈H₁₇F₃N₂O₂, has been determined at 150 K. The crystal structure corresponds to the minimum-energy conformation in the gas phase calculated by density functional theory (DFT). 15 other conformations have been calculated and compared with the minimum, denoted 1111. NMR spectroscopic data have been obtained and compared with those from Gauge Independent Atomic Orbital (GIAO) calculations. DFT calculations allow the reduction of the 16 possible rotamers to the four most stable (i.e. 1111, 1112, 1121 and 1222); in addition, the calculated barriers connecting these minima are low enough to permit their inter­conversion. Comparison of the NMR spectroscopic results, both experimental and calculated, point to the 1121 isomer being present in chloro­form solution.

Computing details

Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

(E)-N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N'-(3-methoxybenzylidene)acetohydrazide

Crystal data

C18H17F3N2O2	F(000) = 728
Mr = 350.33	Dx = 1.376 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54184 Å
a = 15.0494 (3) Å	Cell parameters from 8396 reflections
b = 14.2369 (3) Å	θ = 6.4–73.4°
c = 7.9898 (2) Å	µ = 0.97 mm^−1
β = 99.025 (2)°	T = 150 K
V = 1690.68 (7) Å^3	Block, colourless
Z = 4	0.2 × 0.08 × 0.02 mm

Data collection

Rigaku Oxford Diffraction SuperNova diffractometer with a dual source (Cu at zero) equipped with an AtlasS2 CCD area detector	5945 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Cu) X-ray Source	4685 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.037
Detector resolution: 5.3046 pixels mm^-1	θmax = 73.5°, θmin = 3.0°
ω scans	h = −18→18
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2018)	k = −17→17
Tmin = 0.792, Tmax = 1.000	l = −9→9
5945 measured reflections

Refinement

Refinement on F^2	Primary atom site location: iterative
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.035	H-atom parameters constrained
wR(F^2) = 0.096	w = 1/[σ^2(Fo^2) + (0.0644P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.99	(Δ/σ)max < 0.001
5945 reflections	Δρmax = 0.21 e Å^−3
230 parameters	Δρmin = −0.23 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. Refined as a 2-component twin.

The twin ratio is 75:25. The twin components are related by a rotation = 179.9993 deg around the following vectors: Reciprocal space (hkl): 0.9591 -0.0004 -0.2832 Direct space (uvw) : 1.0000 -0.0000 -0.0000

More twin information from Crysalis Pro is shown below HKLF 5 merged

RINT ANALYSIS FOR ALL HKLF5 REFLECTIONS Components measured unique redundancy F2/sig(F2) Rint Rsigma ——————————————————————– 1,2 40817 6202 6.58 13.10 0.037 0.049

RINT ANALYSIS FOR OVERLAPPED REFLECTIONS Components measured unique redundancy F2/sig(F2) Rint Rsigma ——————————————————————– 1,2 15535 2329 6.67 16.27 0.034 0.042

RINT ANALYSIS FOR ISOLATED REFLECTIONS Component measured unique redundancy F2/sig(F2) Rint Rsigma ——————————————————————– 1 12639 1940 6.51 15.24 0.035 0.042 2 12643 1933 6.54 7.05 0.061 0.103

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

	x	y	z	Uiso*/Ueq
C1	0.79743 (10)	0.55247 (11)	0.5015 (2)	0.0310 (3)
F1A	0.80312 (7)	0.52484 (8)	0.66192 (12)	0.0429 (2)
F1B	0.86916 (6)	0.52092 (7)	0.44165 (14)	0.0426 (3)
F1C	0.80174 (6)	0.64552 (7)	0.50186 (15)	0.0465 (3)
C2	0.70649 (9)	0.52283 (11)	0.39492 (18)	0.0269 (3)
O2	0.65540 (7)	0.58383 (8)	0.33280 (15)	0.0346 (3)
N3	0.68799 (8)	0.42978 (9)	0.38228 (16)	0.0274 (3)
N4	0.75575 (8)	0.36869 (9)	0.45448 (16)	0.0275 (3)
C5	0.74210 (9)	0.28083 (11)	0.43262 (19)	0.0292 (3)
H5	0.687429	0.258876	0.368883	0.035*
C6	0.81146 (9)	0.21384 (10)	0.50661 (19)	0.0279 (3)
C7	0.88960 (10)	0.24511 (11)	0.61040 (18)	0.0291 (3)
H7	0.898622	0.310195	0.633233	0.035*
C8	0.95351 (10)	0.18023 (11)	0.6793 (2)	0.0325 (3)
O8	1.03238 (8)	0.20262 (9)	0.77993 (18)	0.0448 (3)
C9	0.94022 (11)	0.08438 (12)	0.6455 (2)	0.0369 (4)
H9	0.984103	0.040119	0.693868	0.044*
C10	0.86373 (11)	0.05411 (12)	0.5422 (2)	0.0371 (4)
H10	0.855136	−0.010989	0.519015	0.045*
C11	0.79887 (10)	0.11852 (11)	0.4717 (2)	0.0328 (3)
H11	0.746236	0.097521	0.399995	0.039*
C12	0.59850 (9)	0.40011 (10)	0.30719 (19)	0.0261 (3)
C13	0.53748 (9)	0.37550 (10)	0.41401 (19)	0.0268 (3)
C13A	0.56160 (11)	0.37566 (12)	0.6041 (2)	0.0350 (3)
H13A	0.600629	0.321894	0.640011	0.052*
H13B	0.506618	0.371151	0.655018	0.052*
H13C	0.593278	0.434026	0.640896	0.052*
C14	0.45046 (9)	0.35210 (11)	0.3373 (2)	0.0286 (3)
H14	0.407817	0.333806	0.407057	0.034*
C15	0.42381 (9)	0.35456 (10)	0.1622 (2)	0.0283 (3)
C15A	0.32796 (10)	0.33260 (12)	0.0862 (2)	0.0371 (4)
H15A	0.311125	0.271072	0.126430	0.056*
H15C	0.322498	0.331594	−0.037665	0.056*
H15B	0.287938	0.380841	0.120305	0.056*
C16	0.48731 (10)	0.37919 (11)	0.0605 (2)	0.0309 (3)
H16	0.470708	0.380628	−0.059150	0.037*
C17	0.57474 (10)	0.40166 (11)	0.1329 (2)	0.0303 (3)
H17	0.617961	0.417993	0.063091	0.036*
C18	1.05443 (11)	0.29985 (13)	0.7989 (3)	0.0445 (4)
H18A	1.052627	0.328445	0.686869	0.067*
H18B	1.114964	0.306629	0.863909	0.067*
H18C	1.010847	0.331309	0.859057	0.067*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0286 (7)	0.0266 (8)	0.0363 (8)	−0.0010 (6)	0.0004 (6)	0.0005 (6)
F1A	0.0474 (5)	0.0470 (6)	0.0305 (5)	−0.0026 (4)	−0.0060 (4)	0.0000 (4)
F1B	0.0270 (4)	0.0430 (6)	0.0587 (6)	−0.0025 (4)	0.0091 (4)	−0.0025 (5)
F1C	0.0396 (5)	0.0269 (5)	0.0667 (7)	−0.0045 (4)	−0.0115 (5)	−0.0011 (5)
C2	0.0259 (6)	0.0274 (7)	0.0269 (7)	−0.0006 (5)	0.0027 (5)	0.0003 (6)
O2	0.0336 (5)	0.0257 (6)	0.0411 (6)	0.0028 (4)	−0.0044 (5)	0.0037 (5)
N3	0.0234 (5)	0.0240 (6)	0.0326 (7)	0.0016 (4)	−0.0020 (5)	0.0027 (5)
N4	0.0237 (5)	0.0266 (7)	0.0311 (6)	0.0039 (5)	0.0005 (5)	0.0027 (5)
C5	0.0274 (6)	0.0283 (8)	0.0305 (8)	0.0017 (5)	0.0001 (5)	−0.0008 (6)
C6	0.0287 (7)	0.0263 (7)	0.0289 (7)	0.0024 (5)	0.0051 (5)	0.0002 (6)
C7	0.0292 (7)	0.0235 (8)	0.0345 (7)	0.0016 (5)	0.0042 (5)	−0.0001 (7)
C8	0.0272 (7)	0.0309 (8)	0.0382 (8)	0.0014 (6)	0.0016 (6)	0.0025 (6)
O8	0.0332 (6)	0.0319 (7)	0.0627 (9)	0.0019 (5)	−0.0129 (5)	0.0040 (6)
C9	0.0361 (8)	0.0273 (8)	0.0465 (10)	0.0080 (6)	0.0036 (7)	0.0063 (7)
C10	0.0409 (8)	0.0245 (8)	0.0449 (9)	0.0020 (6)	0.0035 (7)	0.0000 (7)
C11	0.0333 (7)	0.0284 (8)	0.0355 (8)	0.0001 (6)	0.0019 (6)	−0.0023 (6)
C12	0.0247 (6)	0.0218 (7)	0.0302 (8)	0.0017 (5)	−0.0006 (5)	0.0007 (5)
C13	0.0293 (7)	0.0218 (7)	0.0281 (7)	0.0025 (5)	0.0009 (5)	0.0017 (6)
C13A	0.0350 (7)	0.0391 (9)	0.0294 (8)	−0.0005 (6)	0.0005 (6)	0.0035 (7)
C14	0.0273 (6)	0.0249 (7)	0.0333 (8)	−0.0005 (5)	0.0037 (6)	0.0028 (6)
C15	0.0277 (7)	0.0209 (7)	0.0346 (8)	0.0015 (5)	−0.0003 (6)	−0.0014 (6)
C15A	0.0293 (7)	0.0371 (9)	0.0422 (9)	−0.0019 (6)	−0.0030 (6)	−0.0052 (7)
C16	0.0326 (7)	0.0314 (8)	0.0269 (7)	0.0011 (6)	−0.0010 (6)	−0.0005 (6)
C17	0.0296 (7)	0.0310 (8)	0.0300 (8)	0.0003 (6)	0.0036 (6)	0.0027 (6)
C18	0.0346 (8)	0.0351 (10)	0.0592 (12)	−0.0045 (7)	−0.0067 (8)	0.0017 (8)

Geometric parameters (Å, º)

C1—F1A	1.3303 (19)	C11—H11	0.9500
C1—F1B	1.3260 (18)	C12—C13	1.393 (2)
C1—F1C	1.3262 (18)	C12—C17	1.382 (2)
C1—C2	1.5527 (19)	C13—C13A	1.505 (2)
C2—O2	1.2133 (18)	C13—C14	1.396 (2)
C2—N3	1.354 (2)	C13A—H13A	0.9800
N3—N4	1.3944 (16)	C13A—H13B	0.9800
N3—C12	1.4487 (17)	C13A—H13C	0.9800
N4—C5	1.275 (2)	C14—H14	0.9500
C5—H5	0.9500	C14—C15	1.394 (2)
C5—C6	1.468 (2)	C15—C15A	1.5076 (19)
C6—C7	1.401 (2)	C15—C16	1.393 (2)
C6—C11	1.392 (2)	C15A—H15A	0.9800
C7—H7	0.9500	C15A—H15C	0.9800
C7—C8	1.384 (2)	C15A—H15B	0.9800
C8—O8	1.3629 (19)	C16—H16	0.9500
C8—C9	1.399 (2)	C16—C17	1.389 (2)
O8—C18	1.426 (2)	C17—H17	0.9500
C9—H9	0.9500	C18—H18A	0.9800
C9—C10	1.376 (2)	C18—H18B	0.9800
C10—H10	0.9500	C18—H18C	0.9800
C10—C11	1.393 (2)
F1A—C1—C2	111.48 (12)	C17—C12—N3	119.30 (13)
F1B—C1—F1A	108.32 (12)	C17—C12—C13	122.00 (13)
F1B—C1—F1C	107.26 (12)	C12—C13—C13A	122.68 (13)
F1B—C1—C2	114.04 (13)	C12—C13—C14	117.01 (13)
F1C—C1—F1A	107.32 (13)	C14—C13—C13A	120.30 (14)
F1C—C1—C2	108.13 (12)	C13—C13A—H13A	109.5
O2—C2—C1	118.51 (13)	C13—C13A—H13B	109.5
O2—C2—N3	124.06 (13)	C13—C13A—H13C	109.5
N3—C2—C1	117.39 (12)	H13A—C13A—H13B	109.5
C2—N3—N4	116.80 (11)	H13A—C13A—H13C	109.5
C2—N3—C12	118.88 (11)	H13B—C13A—H13C	109.5
N4—N3—C12	124.16 (12)	C13—C14—H14	118.8
C5—N4—N3	117.62 (12)	C15—C14—C13	122.48 (13)
N4—C5—H5	120.2	C15—C14—H14	118.8
N4—C5—C6	119.54 (13)	C14—C15—C15A	120.39 (14)
C6—C5—H5	120.2	C16—C15—C14	118.42 (13)
C7—C6—C5	120.64 (13)	C16—C15—C15A	121.18 (14)
C11—C6—C5	119.12 (13)	C15—C15A—H15A	109.5
C11—C6—C7	120.24 (14)	C15—C15A—H15C	109.5
C6—C7—H7	120.3	C15—C15A—H15B	109.5
C8—C7—C6	119.33 (14)	H15A—C15A—H15C	109.5
C8—C7—H7	120.3	H15A—C15A—H15B	109.5
C7—C8—C9	120.31 (14)	H15C—C15A—H15B	109.5
O8—C8—C7	124.41 (15)	C15—C16—H16	119.8
O8—C8—C9	115.27 (14)	C17—C16—C15	120.46 (14)
C8—O8—C18	117.16 (13)	C17—C16—H16	119.8
C8—C9—H9	119.9	C12—C17—C16	119.62 (14)
C10—C9—C8	120.13 (14)	C12—C17—H17	120.2
C10—C9—H9	119.9	C16—C17—H17	120.2
C9—C10—H10	119.9	O8—C18—H18A	109.5
C9—C10—C11	120.25 (15)	O8—C18—H18B	109.5
C11—C10—H10	119.9	O8—C18—H18C	109.5
C6—C11—C10	119.74 (14)	H18A—C18—H18B	109.5
C6—C11—H11	120.1	H18A—C18—H18C	109.5
C10—C11—H11	120.1	H18B—C18—H18C	109.5
C13—C12—N3	118.62 (13)