Topological analysis of electron density and the electrostatic properties of isoniazid: an experimental and theoretical study

Rajalakshmi, G.; Hathwar, V.R.; Kumaradhas, P.

doi:10.1107/S2052520613033209

Topological analysis of electron density and the electrostatic properties of isoniazid: an experimental and theoretical study

G. Rajalakshmi, V. R. Hathwar and P. Kumaradhas

Isoniazid (isonicotinohydrazide) is an important first-line antitubercular drug that targets the InhA enzyme which synthesizes the critical component of the mycobacterial cell wall. An experimental charge-density analysis of isoniazid has been performed to understand its structural and electronic properties in the solid state. A high-resolution single-crystal X-ray intensity data has been collected at 90 K. An aspherical multipole refinement was carried out to explore the topological and electrostatic properties of the isoniazid molecule. The experimental results were compared with the theoretical charge-density calculations performed using CRYSTAL09 with the B3LYP/6-31G** method. A topological analysis of the electron density reveals that the Laplacian of electron density of the N—N bond is significantly less negative, which indicates that the charges at the b.c.p. (bond-critical point) of the bond are least accumulated, and so the bond is considered to be weak. As expected, a strong negative electrostatic potential region is present in the vicinity of the O1, N1 and N3 atoms, which are the reactive locations of the molecule. The C—H

N, C—H

O and N—H

N types of intermolecular hydrogen-bonding interactions stabilize the crystal structure. The topological analysis of the electron density on hydrogen bonding shows the strength of intermolecular interactions.

Keywords: isoniazid; charge-density analysis; charge-density distribution; electrostatic properties; intermolecular interactions.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2052520613033209/gw5026sup1.cif Contains datablock I
	Structure factor file (CIF format) https://doi.org/10.1107/S2052520613033209/gw5026Isup2.hkl Contains datablock I
	Portable Document Format (PDF) file https://doi.org/10.1107/S2052520613033209/gw5026sup3.pdf Table of geometrical parameters and residual density map

CCDC reference: 929008

Experimental top

Refinement top

Crystal data, data collection and structure refinement details are summarized in Table 1.

Results and discussion top

Computing details top

Data collection: KAPPA APEX BRUKER-AXS; cell refinement: SAINTPLUS (BRUKER-AXS); data reduction: SAINTPLUS (BRUKER-AXS); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008) XD2006 (Koritsanszky et al., 2006); molecular graphics: ORTEP (Farrugia, 1997) PLATON (Spek, 2003) XD2006 (Koritsanszky et al., 2006); software used to prepare material for publication: XD2006 (Koritsanszky et al., 2006).

Figures top

(I) top

Crystal data top

C₆H₇N₃O	D_x = 1.46 Mg m⁻³
M_r = 137.1	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 2536 reflections
Hall symbol: -P 2yn	θ = 3.6–50.1°
a = 3.7601 (1) Å	µ = 0.11 mm⁻¹
b = 11.2911 (3) Å	T = 90 K
c = 14.6877 (4) Å	Block, colourless
V = 623.58 Å³	0.25 × 0.24 × 0.14 mm
Z = 4

Data collection top

Bruker Kappa APEX II CCD detector diffractometer	6442 reflections with > 2.0σ(I)
ϕ and ω scans	R_int = 0.028
Absorption correction: analytical ?	θ_max = 51.4°, θ_min = 2.3°
T_min = 0.978, T_max = 0.984	h = 0→8
83442 measured reflections	k = 0→24
6960 independent reflections	l = −32→32

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.015	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.017	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	Weighting scheme based on measured s.u.'s
6253 reflections	(Δ/σ)_max = 0.0001
344 parameters	Δρ_max = 0.10 e Å⁻³
0 restraints	Δρ_min = −0.10 e Å⁻³

Crystal data top

C₆H₇N₃O	V = 623.58 Å³
M_r = 137.1	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 3.7601 (1) Å	µ = 0.11 mm⁻¹
b = 11.2911 (3) Å	T = 90 K
c = 14.6877 (4) Å	0.25 × 0.24 × 0.14 mm

Data collection top

Bruker Kappa APEX II CCD detector diffractometer	6960 independent reflections
Absorption correction: analytical ?	6442 reflections with > 2.0σ(I)
T_min = 0.978, T_max = 0.984	R_int = 0.028
83442 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.015	0 restraints
wR(F²) = 0.017	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	Δρ_max = 0.10 e Å⁻³
6253 reflections	Δρ_min = −0.10 e Å⁻³
344 parameters

Special details top

Refinement. Reflections were merged with SORTAV (Blessing, 1995)

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

	x	y	z	U_iso*/U_eq	Occ. (<1)
O(1)	0.71301 (8)	0.43989 (2)	0.05073 (1)	0.015
N(1)	1.29931 (7)	0.36177 (2)	−0.25130 (1)	0.015
N(2)	0.89435 (6)	0.62309 (1)	0.00937 (1)	0.011
N(3)	0.72341 (5)	0.67750 (1)	0.08436 (1)	0.011
C(1)	1.08173 (6)	0.33795 (2)	−0.09844 (1)	0.012
C(2)	1.01894 (5)	0.45917 (1)	−0.09120 (1)	0.010
C(3)	1.09717 (7)	0.53085 (2)	−0.16608 (1)	0.014
C(4)	1.23632 (7)	0.47835 (2)	−0.24409 (1)	0.015
C(5)	1.22274 (7)	0.29375 (2)	−0.17907 (1)	0.014
C(6)	0.86396 (5)	0.50551 (1)	−0.00401 (1)	0.010
H(1)	1.02477	0.27507	−0.04470	0.025 (1)
H(2)	1.04249	0.68198	−0.03658	0.024 (2)
H(3)	1.03933	0.62469	−0.16984	0.030 (2)
H(4)	1.29473	0.53257	−0.30305	0.029 (2)
H(5)	1.28284	0.20056	−0.18732	0.029 (2)
H(3A)	0.50497	0.62897	0.09852	0.032 (2)
H(3B)	0.90580	0.67344	0.14275	0.032 (2)
DUM0	0.00000	0.00000	0.00000	0.000	0.0000

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O(1)	0.02281 (9)	0.01037 (5)	0.01303 (6)	−0.00255 (6)	0.00582 (7)	0.00100 (5)
N(1)	0.01623 (7)	0.01726 (6)	0.01082 (5)	0.00058 (6)	0.00140 (6)	−0.00355 (5)
N(2)	0.01560 (7)	0.00852 (4)	0.00984 (4)	−0.00074 (4)	0.00272 (5)	−0.00017 (4)
N(3)	0.01403 (6)	0.01047 (4)	0.00915 (4)	0.00201 (4)	0.00026 (4)	−0.00010 (3)
C(1)	0.01582 (7)	0.01016 (5)	0.01138 (5)	0.00169 (5)	0.00099 (5)	−0.00044 (4)
C(2)	0.01213 (7)	0.00949 (5)	0.00889 (5)	−0.00010 (5)	0.00046 (5)	−0.00049 (4)
C(3)	0.02019 (8)	0.01140 (5)	0.00935 (5)	−0.00128 (6)	0.00194 (5)	−0.00016 (4)
C(4)	0.02053 (9)	0.01609 (6)	0.00953 (5)	−0.00226 (6)	0.00269 (6)	−0.00127 (4)
C(5)	0.01738 (8)	0.01332 (5)	0.01270 (5)	0.00285 (6)	0.00075 (6)	−0.00271 (4)
C(6)	0.01229 (6)	0.00867 (4)	0.00895 (4)	−0.00047 (4)	0.00099 (4)	0.00035 (4)

Geometric parameters (Å, º) top

O(1)—C(6)	1.2319 (2)	C(1)—C(5)	1.3902 (3)
N(1)—C(4)	1.3416 (3)	C(1)—H(1)	1.0830 (2)
N(1)—C(5)	1.3411 (3)	C(2)—C(3)	1.3968 (2)
N(2)—C(6)	1.3469 (2)	C(2)—C(6)	1.5012 (2)
N(2)—H(2)	1.0990 (2)	C(3)—C(4)	1.3922 (3)
N(3)—H(3A)	1.0090 (2)	C(3)—H(3)	1.0830 (2)
N(3)—H(3B)	1.0990 (2)	C(4)—H(4)	1.0830 (2)
C(1)—C(2)	1.3930 (2)	C(5)—H(5)	1.0830 (2)

C(4)—N(1)—C(5)	117.491 (17)	C(4)—C(3)—H(3)	116.747 (16)
C(6)—N(2)—H(2)	123.349 (15)	N(1)—C(4)—C(3)	123.301 (18)
H(3A)—N(3)—H(3B)	108.935 (13)	N(1)—C(4)—H(4)	117.110 (18)
C(2)—C(1)—C(5)	118.838 (17)	C(3)—C(4)—H(4)	119.583 (19)
C(2)—C(1)—H(1)	123.712 (16)	N(1)—C(5)—C(1)	123.382 (18)
C(5)—C(1)—H(1)	117.448 (16)	N(1)—C(5)—H(5)	115.031 (17)
C(1)—C(2)—C(3)	118.272 (16)	C(1)—C(5)—H(5)	121.580 (19)
C(1)—C(2)—C(6)	118.252 (15)	O(1)—C(6)—N(2)	122.456 (17)
C(3)—C(2)—C(6)	123.464 (15)	O(1)—C(6)—C(2)	121.738 (16)
C(2)—C(3)—C(4)	118.712 (17)	N(2)—C(6)—C(2)	115.792 (14)
C(2)—C(3)—H(3)	124.386 (17)

C(4)—N(1)—C(5)—C(1)	0.3 (1)	H(1)—C(1)—C(5)—H(5)	−2.2 (1)
C(5)—N(1)—C(4)—C(3)	0.0 (1)	C(1)—C(2)—C(3)—C(4)	−0.5 (1)
C(5)—N(1)—C(4)—H(4)	−179.0 (1)	C(1)—C(2)—C(3)—H(3)	174.9 (1)
C(4)—N(1)—C(5)—H(5)	−178.8 (1)	C(1)—C(2)—C(6)—O(1)	−18.1 (1)
H(2)—N(2)—C(6)—O(1)	176.0 (1)	C(1)—C(2)—C(6)—N(2)	163.2 (1)
H(2)—N(2)—C(6)—C(2)	−5.3 (1)	C(3)—C(2)—C(6)—O(1)	160.6 (1)
C(2)—C(1)—C(5)—N(1)	−0.7 (1)	C(3)—C(2)—C(6)—N(2)	−18.1 (1)
C(5)—C(1)—C(2)—C(3)	0.7 (1)	C(6)—C(2)—C(3)—C(4)	−179.2 (1)
C(5)—C(1)—C(2)—C(6)	179.5 (1)	C(6)—C(2)—C(3)—H(3)	−3.9 (1)
C(2)—C(1)—C(5)—H(5)	178.3 (1)	C(2)—C(3)—C(4)—N(1)	0.1 (1)
H(1)—C(1)—C(2)—C(3)	−178.7 (1)	C(2)—C(3)—C(4)—H(4)	179.1 (1)
H(1)—C(1)—C(2)—C(6)	0.1 (1)	H(3)—C(3)—C(4)—N(1)	−175.6 (1)
H(1)—C(1)—C(5)—N(1)	178.8 (1)	H(3)—C(3)—C(4)—H(4)	3.4 (1)

Experimental details

Crystal data
Chemical formula	C₆H₇N₃O
M_r	137.1
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	90
a, b, c (Å)	3.7601 (1), 11.2911 (3), 14.6877 (4)
V (Å³)	623.58
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.11
Crystal size (mm)	0.25 × 0.24 × 0.14

Data collection
Diffractometer	Bruker Kappa APEX II CCD detector diffractometer
Absorption correction	Analytical
T_min, T_max	0.978, 0.984
No. of measured, independent and observed [ > 2.0σ(I)] reflections	83442, 6960, 6442
R_int	0.028
(sin θ/λ)_max (Å⁻¹)	1.100

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.015, 0.017, 1.02
No. of reflections	6253
No. of parameters	344
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.10, −0.10

Computer programs: KAPPA APEX BRUKER-AXS, SAINTPLUS (BRUKER-AXS), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008) XD2006 (Koritsanszky et al., 2006), ORTEP (Farrugia, 1997) PLATON (Spek, 2003) XD2006 (Koritsanszky et al., 2006), XD2006 (Koritsanszky et al., 2006).

Selected geometric parameters (Å, º) top

O(1)—C(6)	1.2319 (2)	C(1)—C(5)	1.3902 (3)
N(1)—C(4)	1.3416 (3)	C(1)—H(1)	1.0830 (2)
N(1)—C(5)	1.3411 (3)	C(2)—C(3)	1.3968 (2)
N(2)—C(6)	1.3469 (2)	C(2)—C(6)	1.5012 (2)
N(2)—H(2)	1.0990 (2)	C(3)—C(4)	1.3922 (3)
N(3)—H(3A)	1.0090 (2)	C(3)—H(3)	1.0830 (2)
N(3)—H(3B)	1.0990 (2)	C(4)—H(4)	1.0830 (2)
C(1)—C(2)	1.3930 (2)	C(5)—H(5)	1.0830 (2)

C(4)—N(1)—C(5)	117.491 (17)	C(4)—C(3)—H(3)	116.747 (16)
C(6)—N(2)—H(2)	123.349 (15)	N(1)—C(4)—C(3)	123.301 (18)
H(3A)—N(3)—H(3B)	108.935 (13)	N(1)—C(4)—H(4)	117.110 (18)
C(2)—C(1)—C(5)	118.838 (17)	C(3)—C(4)—H(4)	119.583 (19)
C(2)—C(1)—H(1)	123.712 (16)	N(1)—C(5)—C(1)	123.382 (18)
C(5)—C(1)—H(1)	117.448 (16)	N(1)—C(5)—H(5)	115.031 (17)
C(1)—C(2)—C(3)	118.272 (16)	C(1)—C(5)—H(5)	121.580 (19)
C(1)—C(2)—C(6)	118.252 (15)	O(1)—C(6)—N(2)	122.456 (17)
C(3)—C(2)—C(6)	123.464 (15)	O(1)—C(6)—C(2)	121.738 (16)
C(2)—C(3)—C(4)	118.712 (17)	N(2)—C(6)—C(2)	115.792 (14)
C(2)—C(3)—H(3)	124.386 (17)

C(4)—N(1)—C(5)—C(1)	0.3 (1)	H(1)—C(1)—C(5)—H(5)	−2.2 (1)
C(5)—N(1)—C(4)—C(3)	0.0 (1)	C(1)—C(2)—C(3)—C(4)	−0.5 (1)
C(5)—N(1)—C(4)—H(4)	−179.0 (1)	C(1)—C(2)—C(3)—H(3)	174.9 (1)
C(4)—N(1)—C(5)—H(5)	−178.8 (1)	C(1)—C(2)—C(6)—O(1)	−18.1 (1)
H(2)—N(2)—C(6)—O(1)	176.0 (1)	C(1)—C(2)—C(6)—N(2)	163.2 (1)
H(2)—N(2)—C(6)—C(2)	−5.3 (1)	C(3)—C(2)—C(6)—O(1)	160.6 (1)
C(2)—C(1)—C(5)—N(1)	−0.7 (1)	C(3)—C(2)—C(6)—N(2)	−18.1 (1)
C(5)—C(1)—C(2)—C(3)	0.7 (1)	C(6)—C(2)—C(3)—C(4)	−179.2 (1)
C(5)—C(1)—C(2)—C(6)	179.5 (1)	C(6)—C(2)—C(3)—H(3)	−3.9 (1)
C(2)—C(1)—C(5)—H(5)	178.3 (1)	C(2)—C(3)—C(4)—N(1)	0.1 (1)
H(1)—C(1)—C(2)—C(3)	−178.7 (1)	C(2)—C(3)—C(4)—H(4)	179.1 (1)
H(1)—C(1)—C(2)—C(6)	0.1 (1)	H(3)—C(3)—C(4)—N(1)	−175.6 (1)
H(1)—C(1)—C(5)—N(1)	178.8 (1)	H(3)—C(3)—C(4)—H(4)	3.4 (1)

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