Studies via X-ray analysis on inter­molecular inter­actions and energy frameworks based on the effects of substituents of three 4-aryl-2-methyl-1H-imidazoles of different electronic nature and their in vitro anti­fungal evaluation

Macías, M.A.; Elejalde, N.-R.; Butassi, E.; Zacchino, S.; Portilla, J.

doi:10.1107/S2053229618014109

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Studies via X-ray analysis on intermolecular interactions and energy frameworks based on the effects of substituents of three 4-aryl-2-methyl-1H-imidazoles of different electronic nature and their in vitro antifungal evaluation

M. A. Macías, N.-R. Elejalde, E. Butassi, S. Zacchino and J. Portilla

The crystal structures of 2-methyl-4-phenyl-1H-imidazole, C₁₀H₁₀N₂, (3a), 4-(4-chlorophenyl)-2-methyl-1H-imidazole hemihydrate, C₁₀H₉ClN₂·0.5H₂O, (3b), and 4-(4-methoxyphenyl)-2-methyl-1H-imidazole, C₁₁H₁₂N₂O, (3c), have been analyzed. It was found that the electron-donating/withdrawing tendency of the substituent groups in the aryl ring influence the acid–base properties of the 2-methylimidazole nucleus, changing the strength of the intermolecular N—H

N interactions. This behaviour not only influences the crystal structure but also seems to have an important effect on the antifungal activity. Considering the substituent groups, that is, H in (3a), Cl in (3b) and OMe in (3c), the formation of strong N—H

N connections has the probability (3a) > (3b) > (3c), while compound (3c) proves to be more active than (3a) and (3b) at all concentrations against C. neoformans.

Keywords: crystal structure; 1H-imidazoles; antifungal activity; energy frameworks; Hirshfeld surface maps; microwave-assisted reaction.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229618014109/cu3134sup1.cif Contains datablocks 3a, 3b, 3c, global
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229618014109/cu31343asup2.hkl Contains datablock 3a
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229618014109/cu31343bsup3.hkl Contains datablock 3b
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229618014109/cu31343csup4.hkl Contains datablock 3c
	Portable Document Format (PDF) file https://doi.org/10.1107/S2053229618014109/cu3134sup5.pdf 2D fingerprint plots for (3a)-(3c)

CCDC references: 1817751; 1817749; 1817748

Computing details top

For all structures, data collection: CrysAlis PRO (Agilent, 2014); cell refinement: CrysAlis PRO (Agilent, 2014); data reduction: CrysAlis PRO (Agilent, 2014); program(s) used to solve structure: Superflip (Palatinus & Chapuis, 2007). Program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015) for (3a); SHELXL2018/3 (Sheldrick, 2015) for (3b), (3c). For all structures, molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: PLATON (Spek, 2015).

2-Methyl-4-phenyl-1H-imidazole (3a) top

Crystal data top

C₁₀H₁₀N₂	D_x = 1.182 Mg m⁻³
M_r = 158.20	Mo Kα radiation, λ = 0.71073 Å
Trigonal, R3:H	Cell parameters from 2749 reflections
a = 29.196 (4) Å	θ = 3.7–23.4°
c = 5.4212 (10) Å	µ = 0.07 mm⁻¹
V = 4002.0 (15) Å³	T = 298 K
Z = 18	Parallelepiped, colorless
F(000) = 1512	0.22 × 0.12 × 0.09 mm

Data collection top

Agilent SuperNova Dual Source diffractometer with an Atlas detector	1684 independent reflections
Radiation source: SuperNova (Mo) X-ray Source	1204 reflections with I > 2σ(I)
Detector resolution: 5.3072 pixels mm^-1	R_int = 0.080
ω scans	θ_max = 25.7°, θ_min = 3.7°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2014)	h = −35→35
T_min = 0.472, T_max = 1.000	k = −35→35
26163 measured reflections	l = −6→6

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.063	H-atom parameters constrained
wR(F²) = 0.201	w = 1/[σ²(F_o²) + (0.0813P)² + 4.7247P] where P = (F_o² + 2F_c²)/3
S = 1.10	(Δ/σ)_max < 0.001
1684 reflections	Δρ_max = 0.19 e Å⁻³
111 parameters	Δρ_min = −0.15 e Å⁻³
0 restraints	Extinction correction: SHELXL-2016/6 (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: iterative	Extinction coefficient: 0.0037 (8)

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
N1	0.37637 (8)	0.52807 (8)	0.2334 (4)	0.0611 (6)
H1	0.342851	0.506392	0.228755	0.073*
C2	0.41220 (9)	0.52466 (9)	0.3885 (5)	0.0574 (7)
C3	0.39702 (9)	0.48283 (9)	0.5727 (4)	0.0575 (7)
C4	0.43513 (12)	0.48439 (12)	0.7313 (5)	0.0791 (9)
H4	0.469997	0.511551	0.715987	0.095*
C5	0.42230 (14)	0.44658 (14)	0.9105 (6)	0.0885 (10)
H5	0.448488	0.448290	1.014161	0.106*
C6	0.37103 (13)	0.40632 (12)	0.9372 (5)	0.0765 (8)
H6	0.362301	0.381106	1.060336	0.092*
C7	0.33288 (11)	0.40354 (11)	0.7814 (5)	0.0722 (8)
H7	0.298198	0.376028	0.797580	0.087*
C8	0.34546 (10)	0.44133 (10)	0.5999 (5)	0.0655 (7)
H8	0.319143	0.438925	0.494990	0.079*
C9	0.45979 (11)	0.56739 (11)	0.3292 (6)	0.0737 (8)
H9	0.491684	0.575792	0.404289	0.088*
N10	0.45442 (9)	0.59640 (9)	0.1440 (5)	0.0783 (8)
C11	0.40323 (11)	0.57134 (10)	0.0910 (5)	0.0682 (8)
C12	0.37762 (15)	0.58749 (14)	−0.0996 (6)	0.0941 (10)
H12A	0.389955	0.584686	−0.259961	0.141*
H12B	0.386383	0.623422	−0.070974	0.141*
H12C	0.339957	0.564820	−0.091209	0.141*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0510 (11)	0.0565 (12)	0.0709 (13)	0.0232 (10)	−0.0003 (9)	0.0030 (10)
C2	0.0476 (13)	0.0526 (14)	0.0672 (15)	0.0216 (11)	−0.0030 (11)	−0.0045 (11)
C3	0.0535 (14)	0.0554 (14)	0.0642 (15)	0.0276 (11)	−0.0038 (11)	−0.0075 (11)
C4	0.0623 (17)	0.0773 (19)	0.085 (2)	0.0257 (14)	−0.0156 (14)	0.0012 (15)
C5	0.089 (2)	0.092 (2)	0.085 (2)	0.0459 (19)	−0.0218 (17)	0.0047 (17)
C6	0.092 (2)	0.0789 (19)	0.0671 (17)	0.0494 (18)	0.0034 (15)	0.0054 (14)
C7	0.0682 (17)	0.0661 (16)	0.0813 (19)	0.0328 (14)	0.0111 (14)	0.0094 (14)
C8	0.0531 (14)	0.0641 (16)	0.0771 (17)	0.0276 (12)	−0.0010 (12)	0.0051 (13)
C9	0.0555 (16)	0.0634 (16)	0.088 (2)	0.0192 (13)	−0.0063 (13)	−0.0008 (14)
N10	0.0671 (15)	0.0582 (14)	0.0940 (18)	0.0196 (11)	0.0074 (12)	0.0077 (12)
C11	0.0723 (18)	0.0572 (15)	0.0709 (17)	0.0292 (14)	0.0063 (13)	0.0052 (12)
C12	0.108 (3)	0.091 (2)	0.087 (2)	0.053 (2)	0.0015 (18)	0.0208 (17)

Geometric parameters (Å, º) top

N1—C11	1.348 (3)	C6—H6	0.9300
N1—C2	1.384 (3)	C7—C8	1.384 (4)
N1—H1	0.8600	C7—H7	0.9300
C2—C9	1.363 (4)	C8—H8	0.9300
C2—C3	1.464 (3)	C9—N10	1.372 (4)
C3—C4	1.389 (4)	C9—H9	0.9300
C3—C8	1.390 (3)	N10—C11	1.326 (4)
C4—C5	1.375 (4)	C11—C12	1.484 (4)
C4—H4	0.9300	C12—H12A	0.9600
C5—C6	1.372 (4)	C12—H12B	0.9600
C5—H5	0.9300	C12—H12C	0.9600
C6—C7	1.368 (4)

C11—N1—C2	108.0 (2)	C6—C7—H7	119.7
C11—N1—H1	126.0	C8—C7—H7	119.7
C2—N1—H1	126.0	C7—C8—C3	120.7 (3)
C9—C2—N1	104.6 (2)	C7—C8—H8	119.7
C9—C2—C3	132.0 (2)	C3—C8—H8	119.7
N1—C2—C3	123.4 (2)	C2—C9—N10	111.0 (2)
C4—C3—C8	117.6 (2)	C2—C9—H9	124.5
C4—C3—C2	119.4 (2)	N10—C9—H9	124.5
C8—C3—C2	122.9 (2)	C11—N10—C9	105.2 (2)
C5—C4—C3	121.3 (3)	N10—C11—N1	111.1 (2)
C5—C4—H4	119.4	N10—C11—C12	125.7 (3)
C3—C4—H4	119.4	N1—C11—C12	123.2 (3)
C6—C5—C4	120.3 (3)	C11—C12—H12A	109.5
C6—C5—H5	119.8	C11—C12—H12B	109.5
C4—C5—H5	119.8	H12A—C12—H12B	109.5
C7—C6—C5	119.5 (3)	C11—C12—H12C	109.5
C7—C6—H6	120.2	H12A—C12—H12C	109.5
C5—C6—H6	120.2	H12B—C12—H12C	109.5
C6—C7—C8	120.5 (3)

C11—N1—C2—C9	0.2 (3)	C6—C7—C8—C3	−0.1 (4)
C11—N1—C2—C3	179.0 (2)	C4—C3—C8—C7	0.9 (4)
C9—C2—C3—C4	2.5 (4)	C2—C3—C8—C7	−178.2 (2)
N1—C2—C3—C4	−175.9 (2)	N1—C2—C9—N10	−0.3 (3)
C9—C2—C3—C8	−178.4 (3)	C3—C2—C9—N10	−179.0 (3)
N1—C2—C3—C8	3.2 (4)	C2—C9—N10—C11	0.3 (3)
C8—C3—C4—C5	−0.6 (4)	C9—N10—C11—N1	−0.1 (3)
C2—C3—C4—C5	178.5 (3)	C9—N10—C11—C12	−179.8 (3)
C3—C4—C5—C6	−0.3 (5)	C2—N1—C11—N10	−0.1 (3)
C4—C5—C6—C7	1.1 (5)	C2—N1—C11—C12	179.6 (3)
C5—C6—C7—C8	−0.9 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N10ⁱ	0.86	2.04	2.877 (3)	163

Symmetry code: (i) y−1/3, −x+y+1/3, −z+1/3.

4-(4-Chlorophenyl)-2-methyl-1H-imidazole hemihydrate (3b) top

Crystal data top

C₁₀H₉ClN₂·0.5H₂O	F(000) = 840
M_r = 403.30	D_x = 1.303 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
a = 10.4027 (15) Å	Cell parameters from 680 reflections
b = 18.093 (2) Å	θ = 3.7–20.5°
c = 11.1496 (16) Å	µ = 0.33 mm⁻¹
β = 101.573 (14)°	T = 298 K
V = 2055.9 (5) Å³	Parallelepiped, colorless
Z = 4	0.24 × 0.15 × 0.12 mm

Data collection top

Agilent SuperNova Dual Source diffractometer with an Atlas detector	4351 independent reflections
Radiation source: SuperNova (Mo) X-ray Source	2801 reflections with I > 2σ(I)
Detector resolution: 5.3072 pixels mm^-1	R_int = 0.081
ω scans	θ_max = 26.7°, θ_min = 3.0°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2014)	h = −13→13
T_min = 0.815, T_max = 1.000	k = −22→22
49415 measured reflections	l = −14→14

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.060	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.183	w = 1/[σ²(F_o²) + (0.080P)² + 0.5486P] where P = (F_o² + 2F_c²)/3
S = 1.09	(Δ/σ)_max = 0.047
4351 reflections	Δρ_max = 0.29 e Å⁻³
241 parameters	Δρ_min = −0.26 e Å⁻³
1 restraint	Extinction correction: SHELXL-2018/3 (Sheldrick 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: iterative	Extinction coefficient: 0.0074 (15)

Special details top

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

	x	y	z	U_iso*/U_eq
Cl1	0.46093 (11)	0.56263 (5)	0.12617 (9)	0.1082 (4)
H1	0.498 (3)	0.232 (3)	0.818 (4)	0.162*
C4A4	0.5247 (3)	0.49453 (14)	0.2303 (2)	0.0637 (4)
H2	0.380 (3)	0.2351 (18)	0.852 (3)	0.095*
C4A3	0.6419 (3)	0.46119 (14)	0.2234 (2)	0.0637 (4)
H4A3	0.686594	0.474668	0.162345	0.076*
C4A2	0.6929 (2)	0.40728 (14)	0.3082 (2)	0.0551 (6)
H4A2	0.772431	0.385054	0.303845	0.066*
C4A1	0.6271 (2)	0.38585 (12)	0.3997 (2)	0.0480 (5)
C4A	0.6814 (2)	0.32980 (13)	0.4909 (2)	0.0509 (6)
N3A	0.7904 (2)	0.28834 (12)	0.48222 (18)	0.0603 (5)
C2A	0.8126 (3)	0.24518 (15)	0.5798 (2)	0.0643 (7)
N1A	0.7237 (2)	0.25668 (12)	0.6499 (2)	0.0659 (6)
H1A	0.720073	0.234281	0.717171	0.079*
C5A	0.6398 (3)	0.31058 (15)	0.5949 (2)	0.0626 (7)
H5A	0.568517	0.330141	0.622896	0.075*
C2A1	0.9228 (4)	0.1912 (2)	0.6116 (3)	0.1055 (13)
H2A1	0.977380	0.204763	0.688418	0.158*
H2A2	0.973881	0.191536	0.548844	0.158*
H2A3	0.887834	0.142559	0.617984	0.158*
C4A6	0.5086 (2)	0.42070 (14)	0.4028 (2)	0.0621 (7)
H4A6	0.462466	0.407235	0.462699	0.075*
C4A5	0.4576 (3)	0.47468 (14)	0.3193 (2)	0.0637 (4)
H4A5	0.378415	0.497399	0.323410	0.076*
Cl2	−0.11724 (10)	0.61973 (5)	0.11934 (11)	0.1117 (4)
C4B4	−0.0263 (3)	0.55076 (16)	0.2065 (3)	0.0722 (8)
C4B3	−0.0220 (3)	0.48107 (17)	0.1592 (3)	0.0725 (8)
H4B3	−0.065026	0.471064	0.079368	0.087*
C4B2	0.0465 (3)	0.42563 (15)	0.2304 (2)	0.0631 (7)
H4B2	0.050583	0.378711	0.197275	0.076*
C4B1	0.1095 (2)	0.43915 (14)	0.3512 (2)	0.0546 (6)
C4B	0.1779 (2)	0.38037 (13)	0.4293 (2)	0.0531 (6)
N3B	0.1972 (2)	0.31050 (11)	0.38539 (18)	0.0576 (5)
C2B	0.2614 (2)	0.27267 (14)	0.4811 (2)	0.0598 (6)
N1B	0.2831 (2)	0.31480 (13)	0.58251 (19)	0.0632 (6)
H1B	0.323020	0.301162	0.654246	0.076*
C5B	0.2309 (2)	0.38277 (15)	0.5517 (2)	0.0625 (7)
H5B	0.231206	0.422968	0.603740	0.075*
C2B1	0.3059 (4)	0.19475 (17)	0.4799 (3)	0.0908 (10)
H2B1	0.394630	0.193524	0.467728	0.136*
H2B2	0.250111	0.168540	0.414678	0.136*
H2B3	0.301703	0.171794	0.556689	0.136*
C4B6	0.1051 (3)	0.51097 (16)	0.3957 (3)	0.0705 (7)
H4B6	0.148030	0.521767	0.475230	0.085*
C4B5	0.0379 (3)	0.56640 (16)	0.3237 (3)	0.0782 (8)
H4B5	0.036147	0.614052	0.354613	0.094*
O1	0.41918 (19)	0.24866 (12)	0.79476 (17)	0.0701 (5)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.1396 (9)	0.0864 (6)	0.1001 (7)	0.0404 (5)	0.0273 (6)	0.0367 (5)
C4A4	0.0684 (9)	0.0600 (9)	0.0624 (10)	0.0025 (7)	0.0128 (7)	0.0040 (7)
C4A3	0.0684 (9)	0.0600 (9)	0.0624 (10)	0.0025 (7)	0.0128 (7)	0.0040 (7)
C4A2	0.0537 (13)	0.0612 (14)	0.0513 (14)	0.0006 (11)	0.0127 (11)	0.0026 (11)
C4A1	0.0503 (12)	0.0508 (12)	0.0423 (12)	−0.0046 (10)	0.0076 (9)	−0.0037 (10)
C4A	0.0528 (13)	0.0544 (13)	0.0462 (13)	−0.0069 (10)	0.0115 (10)	−0.0013 (10)
N3A	0.0675 (13)	0.0664 (13)	0.0479 (12)	0.0093 (10)	0.0135 (10)	0.0060 (10)
C2A	0.0790 (18)	0.0649 (16)	0.0490 (15)	0.0059 (13)	0.0130 (13)	0.0040 (12)
N1A	0.0828 (15)	0.0680 (13)	0.0469 (12)	−0.0045 (11)	0.0128 (11)	0.0106 (10)
C5A	0.0648 (16)	0.0733 (16)	0.0528 (15)	0.0005 (13)	0.0197 (12)	0.0063 (13)
C2A1	0.133 (3)	0.107 (3)	0.078 (2)	0.054 (2)	0.024 (2)	0.0294 (19)
C4A6	0.0605 (15)	0.0699 (16)	0.0589 (15)	−0.0024 (12)	0.0190 (12)	0.0023 (13)
C4A5	0.0684 (9)	0.0600 (9)	0.0624 (10)	0.0025 (7)	0.0128 (7)	0.0040 (7)
Cl2	0.1057 (7)	0.0917 (7)	0.1373 (9)	0.0210 (5)	0.0233 (6)	0.0435 (6)
C4B4	0.0623 (16)	0.0667 (17)	0.090 (2)	−0.0011 (13)	0.0203 (15)	0.0152 (16)
C4B3	0.0760 (18)	0.0781 (19)	0.0618 (17)	−0.0032 (15)	0.0095 (13)	0.0093 (14)
C4B2	0.0711 (16)	0.0629 (15)	0.0540 (15)	0.0004 (12)	0.0096 (13)	0.0001 (12)
C4B1	0.0471 (12)	0.0637 (15)	0.0538 (14)	−0.0020 (10)	0.0117 (10)	−0.0046 (11)
C4B	0.0478 (12)	0.0641 (15)	0.0486 (14)	−0.0031 (10)	0.0125 (10)	−0.0101 (11)
N3B	0.0596 (12)	0.0611 (12)	0.0498 (12)	−0.0023 (9)	0.0057 (9)	−0.0073 (9)
C2B	0.0553 (14)	0.0665 (15)	0.0549 (15)	−0.0049 (12)	0.0044 (11)	−0.0023 (13)
N1B	0.0560 (12)	0.0871 (16)	0.0447 (12)	0.0032 (11)	0.0062 (9)	−0.0017 (11)
C5B	0.0560 (14)	0.0786 (18)	0.0520 (15)	0.0043 (12)	0.0090 (11)	−0.0133 (13)
C2B1	0.103 (2)	0.0710 (19)	0.088 (2)	0.0036 (17)	−0.0063 (19)	0.0024 (16)
C4B6	0.0657 (16)	0.0734 (18)	0.0718 (18)	−0.0022 (14)	0.0126 (13)	−0.0180 (14)
C4B5	0.0710 (18)	0.0608 (16)	0.105 (2)	0.0004 (14)	0.0230 (17)	−0.0051 (16)
O1	0.0699 (12)	0.0889 (14)	0.0525 (11)	0.0067 (10)	0.0145 (9)	0.0132 (9)

Geometric parameters (Å, º) top

Cl1—C4A4	1.731 (3)	C4B4—C4B3	1.371 (4)
C4A4—C4A5	1.371 (4)	C4B4—C4B5	1.372 (4)
C4A4—C4A3	1.377 (4)	C4B3—C4B2	1.385 (4)
C4A3—C4A2	1.387 (3)	C4B3—H4B3	0.9300
C4A3—H4A3	0.9300	C4B2—C4B1	1.396 (4)
C4A2—C4A1	1.393 (3)	C4B2—H4B2	0.9300
C4A2—H4A2	0.9300	C4B1—C4B6	1.395 (4)
C4A1—C4A6	1.391 (3)	C4B1—C4B	1.466 (3)
C4A1—C4A	1.467 (3)	C4B—C5B	1.366 (3)
C4A—C5A	1.362 (3)	C4B—N3B	1.385 (3)
C4A—N3A	1.378 (3)	N3B—C2B	1.329 (3)
N3A—C2A	1.321 (3)	C2B—N1B	1.345 (3)
C2A—N1A	1.342 (3)	C2B—C2B1	1.485 (4)
C2A—C2A1	1.493 (4)	N1B—C5B	1.360 (3)
N1A—C5A	1.369 (3)	N1B—H1B	0.8600
N1A—H1A	0.8600	C5B—H5B	0.9300
C5A—H5A	0.9300	C2B1—H2B1	0.9600
C2A1—H2A1	0.9600	C2B1—H2B2	0.9600
C2A1—H2A2	0.9600	C2B1—H2B3	0.9600
C2A1—H2A3	0.9600	C4B6—C4B5	1.383 (4)
C4A6—C4A5	1.379 (4)	C4B6—H4B6	0.9300
C4A6—H4A6	0.9300	C4B5—H4B5	0.9300
C4A5—H4A5	0.9300	O1—H1	0.86 (3)
Cl2—C4B4	1.740 (3)	O1—H2	0.86 (2)

C4A5—C4A4—C4A3	120.8 (2)	C4B3—C4B4—Cl2	120.0 (3)
C4A5—C4A4—Cl1	119.3 (2)	C4B5—C4B4—Cl2	119.4 (2)
C4A3—C4A4—Cl1	119.9 (2)	C4B4—C4B3—C4B2	119.9 (3)
C4A4—C4A3—C4A2	119.4 (2)	C4B4—C4B3—H4B3	120.1
C4A4—C4A3—H4A3	120.3	C4B2—C4B3—H4B3	120.1
C4A2—C4A3—H4A3	120.3	C4B3—C4B2—C4B1	120.9 (3)
C4A3—C4A2—C4A1	121.2 (2)	C4B3—C4B2—H4B2	119.5
C4A3—C4A2—H4A2	119.4	C4B1—C4B2—H4B2	119.5
C4A1—C4A2—H4A2	119.4	C4B6—C4B1—C4B2	117.7 (2)
C4A6—C4A1—C4A2	117.4 (2)	C4B6—C4B1—C4B	120.7 (2)
C4A6—C4A1—C4A	121.1 (2)	C4B2—C4B1—C4B	121.6 (2)
C4A2—C4A1—C4A	121.5 (2)	C5B—C4B—N3B	108.9 (2)
C5A—C4A—N3A	109.1 (2)	C5B—C4B—C4B1	128.4 (2)
C5A—C4A—C4A1	128.5 (2)	N3B—C4B—C4B1	122.6 (2)
N3A—C4A—C4A1	122.4 (2)	C2B—N3B—C4B	105.7 (2)
C2A—N3A—C4A	105.9 (2)	N3B—C2B—N1B	110.8 (2)
N3A—C2A—N1A	111.2 (2)	N3B—C2B—C2B1	126.1 (3)
N3A—C2A—C2A1	125.6 (3)	N1B—C2B—C2B1	123.0 (2)
N1A—C2A—C2A1	123.3 (3)	C2B—N1B—C5B	108.0 (2)
C2A—N1A—C5A	107.5 (2)	C2B—N1B—H1B	126.0
C2A—N1A—H1A	126.2	C5B—N1B—H1B	126.0
C5A—N1A—H1A	126.2	N1B—C5B—C4B	106.5 (2)
C4A—C5A—N1A	106.3 (2)	N1B—C5B—H5B	126.7
C4A—C5A—H5A	126.9	C4B—C5B—H5B	126.7
N1A—C5A—H5A	126.9	C2B—C2B1—H2B1	109.5
C2A—C2A1—H2A1	109.5	C2B—C2B1—H2B2	109.5
C2A—C2A1—H2A2	109.5	H2B1—C2B1—H2B2	109.5
H2A1—C2A1—H2A2	109.5	C2B—C2B1—H2B3	109.5
C2A—C2A1—H2A3	109.5	H2B1—C2B1—H2B3	109.5
H2A1—C2A1—H2A3	109.5	H2B2—C2B1—H2B3	109.5
H2A2—C2A1—H2A3	109.5	C4B5—C4B6—C4B1	121.2 (3)
C4A5—C4A6—C4A1	121.8 (2)	C4B5—C4B6—H4B6	119.4
C4A5—C4A6—H4A6	119.1	C4B1—C4B6—H4B6	119.4
C4A1—C4A6—H4A6	119.1	C4B4—C4B5—C4B6	119.7 (3)
C4A4—C4A5—C4A6	119.4 (3)	C4B4—C4B5—H4B5	120.1
C4A4—C4A5—H4A5	120.3	C4B6—C4B5—H4B5	120.1
C4A6—C4A5—H4A5	120.3	H1—O1—H2	104 (4)
C4B3—C4B4—C4B5	120.6 (3)

C4A5—C4A4—C4A3—C4A2	−0.5 (4)	C4B5—C4B4—C4B3—C4B2	0.6 (4)
Cl1—C4A4—C4A3—C4A2	179.3 (2)	Cl2—C4B4—C4B3—C4B2	−177.6 (2)
C4A4—C4A3—C4A2—C4A1	0.5 (4)	C4B4—C4B3—C4B2—C4B1	1.3 (4)
C4A3—C4A2—C4A1—C4A6	−0.1 (4)	C4B3—C4B2—C4B1—C4B6	−2.4 (4)
C4A3—C4A2—C4A1—C4A	−179.0 (2)	C4B3—C4B2—C4B1—C4B	177.5 (2)
C4A6—C4A1—C4A—C5A	−9.1 (4)	C4B6—C4B1—C4B—C5B	7.8 (4)
C4A2—C4A1—C4A—C5A	169.7 (2)	C4B2—C4B1—C4B—C5B	−172.0 (3)
C4A6—C4A1—C4A—N3A	172.4 (2)	C4B6—C4B1—C4B—N3B	−172.7 (2)
C4A2—C4A1—C4A—N3A	−8.8 (3)	C4B2—C4B1—C4B—N3B	7.4 (4)
C5A—C4A—N3A—C2A	0.0 (3)	C5B—C4B—N3B—C2B	−0.3 (3)
C4A1—C4A—N3A—C2A	178.8 (2)	C4B1—C4B—N3B—C2B	−179.9 (2)
C4A—N3A—C2A—N1A	0.2 (3)	C4B—N3B—C2B—N1B	0.2 (3)
C4A—N3A—C2A—C2A1	−178.7 (3)	C4B—N3B—C2B—C2B1	−179.3 (3)
N3A—C2A—N1A—C5A	−0.3 (3)	N3B—C2B—N1B—C5B	0.0 (3)
C2A1—C2A—N1A—C5A	178.6 (3)	C2B1—C2B—N1B—C5B	179.6 (3)
N3A—C4A—C5A—N1A	−0.2 (3)	C2B—N1B—C5B—C4B	−0.2 (3)
C4A1—C4A—C5A—N1A	−178.9 (2)	N3B—C4B—C5B—N1B	0.3 (3)
C2A—N1A—C5A—C4A	0.3 (3)	C4B1—C4B—C5B—N1B	179.9 (2)
C4A2—C4A1—C4A6—C4A5	−0.3 (4)	C4B2—C4B1—C4B6—C4B5	1.6 (4)
C4A—C4A1—C4A6—C4A5	178.5 (2)	C4B—C4B1—C4B6—C4B5	−178.3 (2)
C4A3—C4A4—C4A5—C4A6	0.1 (4)	C4B3—C4B4—C4B5—C4B6	−1.4 (5)
Cl1—C4A4—C4A5—C4A6	−179.7 (2)	Cl2—C4B4—C4B5—C4B6	176.8 (2)
C4A1—C4A6—C4A5—C4A4	0.3 (4)	C4B1—C4B6—C4B5—C4B4	0.3 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N3Bⁱ	0.86 (4)	2.20 (4)	3.059 (3)	178 (5)
N1A—H1A···N3Bⁱ	0.86	2.10	2.956 (3)	173
O1—H2···N3Aⁱⁱ	0.86 (3)	1.92 (3)	2.781 (3)	176 (3)
N1B—H1B···O1	0.86	1.93	2.774 (3)	166
C4A6—H4A6···Cg1	0.93	2.83	3.591 (2)	140
C4B4—Cl2···Cg2ⁱⁱⁱ	1.74 (1)	3.67 (1)	5.375 (3)	166 (1)

Symmetry codes: (i) x+1/2, −y+1/2, z+1/2; (ii) x−1/2, −y+1/2, z+1/2; (iii) −x+1/2, y+1/2, −z+1/2.

4-(4-Methoxyphenyl)-2-methyl-1H-imidazole (3c) top

Crystal data top

C₁₁H₁₂N₂O	D_x = 1.090 Mg m⁻³
M_r = 188.23	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P22₁2₁	Cell parameters from 4715 reflections
a = 7.1530 (11) Å	θ = 4.0–23.2°
b = 7.4824 (14) Å	µ = 0.07 mm⁻¹
c = 21.437 (3) Å	T = 298 K
V = 1147.3 (3) Å³	Parallelepiped, colorless
Z = 4	0.21 × 0.16 × 0.09 mm
F(000) = 400

Data collection top

Agilent SuperNova Dual Source diffractometer with an Atlas detector	3018 independent reflections
Radiation source: SuperNova (Mo) X-ray Source	2034 reflections with I > 2σ(I)
Detector resolution: 5.3072 pixels mm^-1	R_int = 0.071
ω scans	θ_max = 29.6°, θ_min = 2.9°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2014)	h = −9→9
T_min = 0.689, T_max = 1.000	k = −10→9
24966 measured reflections	l = −29→28

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.062	w = 1/[σ²(F_o²) + (0.073P)² + 0.3901P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.181	(Δ/σ)_max < 0.001
S = 1.06	Δρ_max = 0.36 e Å⁻³
3018 reflections	Δρ_min = −0.18 e Å⁻³
129 parameters	Absolute structure: Refined as a perfect inversion twin.
0 restraints	Absolute structure parameter: 0.5

Special details top

Refinement. Refined as a 2-component perfect inversion twin.

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

	x	y	z	U_iso*/U_eq
O1	0.4393 (4)	0.2161 (4)	0.15762 (12)	0.0661 (8)
C2	0.3383 (5)	0.2219 (5)	0.21190 (15)	0.0488 (8)
C3	0.1714 (6)	0.1278 (5)	0.21088 (17)	0.0553 (9)
H3	0.134395	0.068823	0.174739	0.066*
C4	0.0603 (5)	0.1214 (5)	0.26327 (17)	0.0541 (9)
H4	−0.050408	0.056294	0.262173	0.065*
C5	0.1101 (4)	0.2104 (5)	0.31794 (15)	0.0463 (7)
C6	−0.0124 (4)	0.2072 (5)	0.37331 (16)	0.0465 (8)
N7	0.0535 (4)	0.2383 (4)	0.43336 (13)	0.0514 (7)
C8	−0.0942 (5)	0.2307 (5)	0.47001 (17)	0.0542 (8)
N9	−0.2487 (4)	0.1972 (5)	0.43776 (15)	0.0606 (9)
H1	−0.359647	0.187192	0.452771	0.073*
C10	−0.1991 (5)	0.1815 (6)	0.37582 (19)	0.0612 (10)
H10	−0.278433	0.157872	0.342454	0.073*
C11	−0.0918 (6)	0.2552 (6)	0.53962 (19)	0.0717 (12)
H11A	−0.021155	0.160354	0.558451	0.108*
H11B	−0.217539	0.252906	0.555245	0.108*
H11C	−0.035121	0.367902	0.549608	0.108*
C12	0.2786 (5)	0.3030 (5)	0.31825 (17)	0.0509 (8)
H12	0.316468	0.361437	0.354402	0.061*
C13	0.3911 (5)	0.3100 (5)	0.26578 (16)	0.0528 (8)
H13	0.502442	0.374120	0.266760	0.063*
C14	0.6131 (6)	0.3076 (7)	0.1564 (2)	0.0769 (13)
H14A	0.694518	0.258303	0.187567	0.115*
H14B	0.592898	0.432146	0.164845	0.115*
H14C	0.669293	0.294323	0.116019	0.115*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0618 (16)	0.0798 (19)	0.0569 (14)	−0.0089 (16)	0.0056 (13)	−0.0037 (13)
C2	0.0468 (17)	0.052 (2)	0.0481 (16)	0.0024 (16)	−0.0016 (14)	0.0032 (15)
C3	0.058 (2)	0.056 (2)	0.0519 (19)	−0.0063 (18)	−0.0094 (17)	−0.0041 (17)
C4	0.0450 (18)	0.058 (2)	0.059 (2)	−0.0100 (16)	−0.0112 (16)	0.0017 (17)
C5	0.0395 (15)	0.0476 (17)	0.0519 (16)	0.0003 (17)	−0.0084 (14)	0.0051 (15)
C6	0.0376 (16)	0.0493 (19)	0.0526 (17)	0.0012 (15)	−0.0038 (14)	0.0049 (17)
N7	0.0399 (13)	0.062 (2)	0.0526 (15)	−0.0042 (13)	0.0013 (12)	−0.0012 (13)
C8	0.0448 (17)	0.055 (2)	0.0623 (19)	0.0001 (17)	0.0045 (16)	0.0053 (16)
N9	0.0380 (14)	0.074 (2)	0.069 (2)	−0.0021 (16)	0.0067 (14)	0.0079 (18)
C10	0.0400 (18)	0.082 (3)	0.062 (2)	−0.0032 (19)	−0.0088 (17)	0.011 (2)
C11	0.065 (2)	0.083 (3)	0.067 (2)	−0.011 (2)	0.016 (2)	−0.007 (2)
C12	0.0444 (18)	0.056 (2)	0.0525 (17)	−0.0060 (17)	−0.0068 (15)	0.0003 (17)
C13	0.0438 (16)	0.058 (2)	0.0566 (18)	−0.0071 (18)	−0.0040 (16)	0.0000 (16)
C14	0.064 (3)	0.092 (3)	0.074 (2)	−0.009 (3)	0.017 (2)	−0.002 (2)

Geometric parameters (Å, º) top

O1—C2	1.370 (4)	C8—C11	1.503 (5)
O1—C14	1.419 (5)	N9—C10	1.379 (5)
C2—C13	1.382 (5)	N9—H1	0.8600
C2—C3	1.386 (5)	C10—H10	0.9300
C3—C4	1.376 (5)	C11—H11A	0.9600
C3—H3	0.9300	C11—H11B	0.9600
C4—C5	1.394 (5)	C11—H11C	0.9600
C4—H4	0.9300	C12—C13	1.384 (5)
C5—C12	1.390 (5)	C12—H12	0.9300
C5—C6	1.475 (5)	C13—H13	0.9300
C6—C10	1.351 (5)	C14—H14A	0.9600
C6—N7	1.390 (4)	C14—H14B	0.9600
N7—C8	1.318 (4)	C14—H14C	0.9600
C8—N9	1.327 (5)

C2—O1—C14	117.5 (3)	C10—N9—H1	126.2
O1—C2—C13	125.5 (3)	C6—C10—N9	106.3 (3)
O1—C2—C3	115.1 (3)	C6—C10—H10	126.9
C13—C2—C3	119.4 (3)	N9—C10—H10	126.9
C4—C3—C2	120.1 (3)	C8—C11—H11A	109.5
C4—C3—H3	119.9	C8—C11—H11B	109.5
C2—C3—H3	119.9	H11A—C11—H11B	109.5
C3—C4—C5	121.4 (3)	C8—C11—H11C	109.5
C3—C4—H4	119.3	H11A—C11—H11C	109.5
C5—C4—H4	119.3	H11B—C11—H11C	109.5
C12—C5—C4	117.6 (3)	C13—C12—C5	121.3 (3)
C12—C5—C6	121.3 (3)	C13—C12—H12	119.4
C4—C5—C6	121.1 (3)	C5—C12—H12	119.4
C10—C6—N7	108.8 (3)	C2—C13—C12	120.1 (3)
C10—C6—C5	128.4 (3)	C2—C13—H13	119.9
N7—C6—C5	122.7 (3)	C12—C13—H13	119.9
C8—N7—C6	105.9 (3)	O1—C14—H14A	109.5
N7—C8—N9	111.4 (3)	O1—C14—H14B	109.5
N7—C8—C11	125.3 (4)	H14A—C14—H14B	109.5
N9—C8—C11	123.3 (4)	O1—C14—H14C	109.5
C8—N9—C10	107.7 (3)	H14A—C14—H14C	109.5
C8—N9—H1	126.2	H14B—C14—H14C	109.5

C14—O1—C2—C13	0.2 (6)	C6—N7—C8—N9	−0.1 (4)
C14—O1—C2—C3	−178.9 (4)	C6—N7—C8—C11	179.6 (4)
O1—C2—C3—C4	178.7 (3)	N7—C8—N9—C10	0.1 (5)
C13—C2—C3—C4	−0.5 (6)	C11—C8—N9—C10	−179.6 (4)
C2—C3—C4—C5	1.0 (6)	N7—C6—C10—N9	0.1 (5)
C3—C4—C5—C12	−1.4 (5)	C5—C6—C10—N9	−177.8 (3)
C3—C4—C5—C6	178.2 (3)	C8—N9—C10—C6	−0.2 (5)
C12—C5—C6—C10	154.7 (4)	C4—C5—C12—C13	1.4 (5)
C4—C5—C6—C10	−24.9 (6)	C6—C5—C12—C13	−178.2 (3)
C12—C5—C6—N7	−22.9 (5)	O1—C2—C13—C12	−178.6 (3)
C4—C5—C6—N7	157.5 (4)	C3—C2—C13—C12	0.4 (6)
C10—C6—N7—C8	−0.1 (5)	C5—C12—C13—C2	−0.9 (6)
C5—C6—N7—C8	178.0 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C11—H11B···O1ⁱ	0.96	2.72	3.553 (5)	146
C11—H11A···Cg1ⁱⁱ	0.96	2.88	3.605 (5)	133
C4—H4···Cg2ⁱⁱⁱ	0.93	2.90	3.706 (4)	146
C14—H14B···Cg2^iv	0.96	2.91	3.679 (5)	138

Symmetry codes: (i) −x, −y+1/2, z+1/2; (ii) x, −y, −z+1; (iii) −x, y−1/2, −z+1/2; (iv) −x+1, y+1/2, −z+1/2.

CE-B3LYP interaction energies (kJ mol^-1) for (3a) top

N is the number of molecules with an R molecular centroid-to-centroid distance (Å). Electron density calculated using B3LYP/6-31G(d,p) model energies.

N	Symop	R	E_ele	E_pol	E_dis	E_rep	E_tot
2	x, y, z	5.42	-2.6	-1.9	-30.8	12.9	-23.1
1	-x, -y, -z	6.09	-3.9	-0.7	-13.7	4.2	-13.9
1	x-y+2/3, x+1/3, -z+1/3	6.71	-57.8	-16.0	-20.3	63.6	-51.4
1	y+2/3, -x+y+1/3, -z+1/3	6.71	-57.8	-16.0	-20.3	63.6	-51.4
1	-y+2/3, x-y+1/3, z+1/3	7.79	-3.5	-0.5	-12.5	7.5	-10.2
1	-x+y+1/3, -x+2/3, z+2/3	7.79	-3.5	-0.5	-12.5	7.5	-10.2

Scale factors used to determine E_tot: E_ele = 1.057; E_pol = 0.740; E_dis = 0.871; E_rep = 0.618

CE-B3LYP interaction energies (kJ mol^-1) for (3b) top

N is the number of molecules with an R molecular centroid-to-centroid distance (Å). Electron density calculated using B3LYP/6-31G(d,p) model energies. Molecule B (reference).

N	Symop	R	E_ele	E_pol	E_dis	E_rep	E_tot
1	Molecule A, C4B4—Cl2···Cg2	8.75	-0.9	-0.7	-8.8	4.2	-6.6
2	x+1/2, -y+1/2, z+1/2	9.65	-3.4	-0.7	-6.8	2.4	-8.5
1	-x, -y, -z	5.03	-14.3	-2.2	-28.9	16.4	-31.8
1	Water, O1—H1···N3B	6.56	-14.3	-2.2	-28.9	16.4	-31.8
1	Molecule A	4.82	-13.8	-2.4	-30.6	18.6	-31.6
1	Molecule A, N1A—H1A···N3B	7.83	-47.0	-12.7	-17.8	47.6	-45.2
1	Molecule A, C4A6—H4A6···Cg1	5.56	1.3	-2.4	-28.8	18.6	-14.0
2	-x+1/2, y+1/2, -z+1/2	9.90	-4.4	-0.5	-5.6	5.7	-6.5

Scale factors used to determine E_tot: E_ele = 1.057; E_pol = 0.740; E_dis = 0.871; E_rep = 0.618

CE-B3LYP interaction energies (kJ mol^-1) for (3c) top

N is the number of molecules with an R molecular centroid-to-centroid distance (Å). Electron density calculated using B3LYP/6-31G(d,p) model energies.

N	Symop	R	E_ele	E_pol	E_dis	E_rep	E_tot
1	x, -y, -z	8.30	0.7	-2.1	-23.7	11.0	-14.7
2	-x, -y+1/2, z+1/2	10.89	-3.4	-0.9	-8.2	5.9	-7.7
2	x, y, z	7.15	-9.4	-1.4	-12.7	5.5	-18.7
2	-x, y+1/2, -z+1/2	7.17	-8.8	-1.8	-25.7	16.3	-22.9

Scale factors used to determine E_tot: E_ele = 1.057; E_pol = 0.740; E_dis = 0.871; E_rep = 0.618

Antifungal activity of 4-aryl-2-methyl-1H-imidazoles (3a)–(3c)^a top

Entry	Fungi	250	125	62.5	31.2	15.6	7.8	3.9	IC₅₀
(3a)	Ca	38.2±1.0	23. 6±1.3	13.7±0.7	8.0±1.5	9.6±0.0	3.7±0.5	3.1±0.1	>250
(3a)	Cn	54.9±1.2	40.7±1.0	33.3±0.3	31.9±0.6	19.8±0.5	15±0.5	7.8±1.2	250
(3b)	Ca	38.9±0.3	16.3±0.0	7±0.8	3.2±0.3	4.5±0.6	4.6±0.9	3±0.5	>250
(3b)	Cn	100	61.8±0.6	47.2±1.4	27.7±0.3	27.2±0.0	26.3±0.7	12.6±0.5	125
(3c)	Ca	100	61.2±0.2	52.2±0.4	51.2±0.8	50.3±0.2	50.1±0.0	14.9±0.0	7.8
(3c)	Cn	100	100	93.1±2.7	92.4±0.6	93.9±0.5	91.6±0.3	54.2±0.8	3.9
AmpB^b	Ca	100	100	100	100	100	100	100	1.5
AmpB^b	Cn	100	100	100	100	100	100	100	1.0
Clotr^c	Ca	100	100	100	100	100	100	100	0.75
Clotr^c	Cn	100	100	100	100	100	100	100	1.0

Notes: (a) Percentages of inhibition of the 1H-imidazoles (3a)–(3c) and against C. albicans ATCC 10231 (Ca) and C. neoformans ATCC 32264 (Cn). Dilutions are at the range 250–3.9 µg ml^-1. IC₅₀ value represents the concentration of each compound that inhibits 50% of fungal growth. (b) AmpB = Amphotericin B. (c) Clotr = Clotrimazole.

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Studies via X-ray analysis on inter­molecular inter­actions and energy frameworks based on the effects of substituents of three 4-aryl-2-methyl-1H-imidazoles of different electronic nature and their in vitro anti­fungal evaluation

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Studies via X-ray analysis on intermolecular interactions and energy frameworks based on the effects of substituents of three 4-aryl-2-methyl-1H-imidazoles of different electronic nature and their in vitro antifungal evaluation