Charge density analysis of metformin chloride, a biguanide anti-hyperglycemic agent

The experimental charge density analysis of the anti-hyperglycemic agent metformin chloride with high-resolution X-ray diffraction data at low temperature (100 K) has been performed and these experimental results were compared with that derived from the corresponding periodic theoretical calculations at the B3LYP/6-31G** level of theory. The experimental and theoretical multipolar charge-density analyses of metformin chloride have been accomplished in order to understand its structural and electronic properties. The C and N atoms of the molecular backbone adopt a near trigonal geometry due to the occurrence of extensive delocalization/resonance of C—N bonds, as confirmed by topological analysis and also found by Natural Resonance Theory calculations performed in the isolated metformin cation. The molecule contains six C—N bonds and the topological bond order analysis shows that four bonds have bond orders close to 4/3 and two bonds can be considered as single. The analysis of numerical parameters of the valence shell charge concentration reports that the N3 atom, which forms two bonds with C atoms, possesses one non-bonding valence-shell charge concentration (VSCC) in the direction of the electron lone pair. Among the intermolecular interactions of the chloride atom with the H—C and H—N atoms, eight have been found to be shorter than the sum of van der Waals radii. The analysis of contacts on the Hirshfeld surface reveals that the H—N...Cl hydrogen bonds are enriched (over-represented) and act as the driving force in the crystal packing formation. The metformin cations form favorable electrostatic interactions with the chloride anions which have globally a stronger energy than the unfavorable cation/cation interactions.

Computing details

Cell refinement: SAINT v8.27A (Bruker, 2012); data reduction: SAINT v8.27A (Bruker, 2012); program(s) used to refine structure: MoPro (J. Appl. Cryst. 2005, 38, 38-54); molecular graphics: Olex2 (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 (Dolomanov et al., 2009).

(I)

Crystal data

C4H12N5·Cl	Z = 4
Mr = 165.62	F(000) = 352
Monoclinic, P21/c	Dx = 1.390 Mg m^−3
Hall symbol: -P 2ybc	Mo Kα radiation, λ = 0.71073 Å
a = 7.9104 (9) Å	Cell parameters from 8957 reflections
b = 13.8794 (1) Å	θ = 52.4–2.9°
c = 7.9310 (1) Å	T = 100 K
β = 114.606 (6)°	Block, colourless
V = 791.69 (10) Å^3	0.16 × 0.10 × 0.10 mm

Data collection

Bruker APEX-II CCD diffractometer	7523 reflections with > 2.0σ(I)
Radiation source: fine-focus sealed tube	θmax = 52.4°, θmin = 2.8°
Graphite monochromator	h = −17→11
φ and ω scans	k = −27→30
52222 measured reflections	l = −17→17
9027 independent reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.023	Only H-atom coordinates refined
wR(F^2) = 0.042	Weighting scheme based on measured s.u.'s
S = 0.91	(Δ/σ)max < 0.001
9027 reflections	Δρmax = 0.33 e Å^−3
368 parameters	Δρmin = −0.33 e Å^−3
216 restraints	Extinction correction: Isotropic Gaussian
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.06144

Special details

Refinement. Refinement of F² against reflections. The threshold expression of F² > 2sigma(F²) is used for calculating R-factors(gt) and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
Cl1_2	0.155718 (9)	0.484527 (4)	0.276219 (9)	0.0124 (5)
C1_1	0.34268 (4)	0.89652 (2)	0.45834 (5)	0.0156 (5)
H1A_1	0.4264 (8)	0.9128 (4)	0.6019 (3)	0.03457
H1B_1	0.1999 (4)	0.9158 (4)	0.4226 (9)	0.03936
H1C_1	0.3939 (8)	0.9338 (4)	0.3701 (7)	0.03663
C2_1	0.19149 (4)	0.75383 (2)	0.27270 (4)	0.0156 (5)
H2A_1	0.2291 (9)	0.6883 (3)	0.2241 (8)	0.03115
H2B_1	0.1477 (9)	0.8054 (3)	0.1610 (6)	0.03641
H2C_1	0.0778 (6)	0.7393 (5)	0.3097 (9)	0.03294
C3_1	0.47988 (4)	0.736387 (18)	0.55289 (4)	0.0101 (5)
C4_1	0.73773 (4)	0.839457 (18)	0.68654 (4)	0.0100 (5)
N1_1	0.34991 (4)	0.793000 (18)	0.43008 (4)	0.0115 (5)
N2_1	0.46112 (4)	0.64055 (2)	0.54206 (4)	0.0139 (5)
N3_1	0.62491 (4)	0.772164 (17)	0.70228 (3)	0.0111 (5)
N4_1	0.83892 (5)	0.89181 (2)	0.83702 (4)	0.0145 (5)
N5_1	0.76291 (4)	0.85454 (2)	0.53171 (4)	0.0129 (5)
H2D_1	0.3489 (6)	0.6078 (4)	0.4437 (8)	0.02320
H2E_1	0.5758 (6)	0.6005 (4)	0.6159 (9)	0.02666
H4A_1	0.8054 (9)	0.8937 (5)	0.9472 (6)	0.02669
H4B_1	0.9373 (8)	0.9373 (4)	0.8325 (10)	0.02448
H5A_1	0.7060 (10)	0.8090 (4)	0.4224 (6)	0.02569
H5B_1	0.8509 (8)	0.9071 (4)	0.5296 (10)	0.02586

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1_2	0.0116 (17)	0.0127 (17)	0.0124 (17)	0.000949 (17)	0.0045 (7)	−0.000303 (16)
C1_1	0.0138 (17)	0.0109 (17)	0.0200 (17)	0.00173 (7)	0.0050 (7)	0.00074 (8)
H1A_1	0.03806	0.02850	0.02819	0.00013	0.00490	−0.00582
H1B_1	0.01940	0.02783	0.06451	0.00500	0.01117	−0.00328
H1C_1	0.04687	0.02548	0.04331	−0.00255	0.02451	0.00657
C2_1	0.0117 (17)	0.0169 (17)	0.0144 (17)	−0.00132 (8)	0.0015 (7)	−0.00002 (8)
H2A_1	0.02898	0.02586	0.03330	0.00532	0.00771	−0.00734
H2B_1	0.03763	0.02871	0.02874	−0.00259	−0.00022	0.01429
H2C_1	0.02266	0.04423	0.03432	−0.00568	0.01424	−0.00355
C3_1	0.0094 (17)	0.0095 (17)	0.0106 (17)	−0.00046 (6)	0.0034 (7)	0.00024 (6)
C4_1	0.0099 (17)	0.0105 (17)	0.0094 (17)	−0.00112 (7)	0.0038 (7)	−0.00064 (6)
N1_1	0.0098 (17)	0.0101 (17)	0.0124 (17)	0.00041 (6)	0.0025 (7)	0.00062 (6)
N2_1	0.0124 (17)	0.0093 (17)	0.0162 (17)	−0.00065 (7)	0.0022 (7)	−0.00009 (7)
N3_1	0.0109 (17)	0.0114 (17)	0.0097 (17)	−0.00213 (6)	0.0031 (7)	0.00037 (6)
N4_1	0.0153 (17)	0.0170 (17)	0.0119 (17)	−0.00590 (9)	0.0062 (7)	−0.00480 (8)
N5_1	0.0143 (17)	0.0148 (17)	0.0105 (17)	−0.00329 (8)	0.0061 (7)	−0.00091 (7)
H2D_1	0.01841	0.02136	0.02275	−0.00181	0.00153	−0.00257
H2E_1	0.01914	0.02167	0.02910	0.00510	0.00004	0.00393
H4A_1	0.03162	0.03382	0.02115	−0.01024	0.01745	−0.00491
H4B_1	0.02581	0.02745	0.02492	−0.01012	0.01526	−0.00355
H5A_1	0.02885	0.02771	0.02149	−0.00867	0.01146	−0.00961
H5B_1	0.02832	0.02788	0.02519	−0.01165	0.01491	−0.00558

Geometric parameters (Å, º)

C1_1—N1_1	1.4590 (4)	C3_1—N2_1	1.3372 (4)
C1_1—H1C_1	1.0761 (18)	C4_1—N3_1	1.3331 (3)
C1_1—H1A_1	1.0764 (17)	C4_1—N5_1	1.3397 (3)
C1_1—H1B_1	1.0775 (17)	C4_1—N4_1	1.3407 (4)
C2_1—N1_1	1.4565 (5)	N2_1—H2D_1	1.0129 (18)
C2_1—H2C_1	1.0750 (18)	N2_1—H2E_1	1.0159 (18)
C2_1—H2A_1	1.0766 (17)	N4_1—H4A_1	1.0132 (18)
C2_1—H2B_1	1.0774 (17)	N4_1—H4B_1	1.0145 (18)
C3_1—N1_1	1.3376 (4)	N5_1—H5B_1	1.0141 (18)
C3_1—N3_1	1.3545 (4)	N5_1—H5A_1	1.0144 (18)
N1_1—C1_1—H1C_1	108.9 (3)	H2A_1—C2_1—H2B_1	107.9 (5)
N1_1—C1_1—H1A_1	108.9 (3)	N1_1—C3_1—N3_1	122.40 (3)
N1_1—C1_1—H1B_1	107.9 (3)	N1_1—C3_1—N2_1	120.43 (2)
H1C_1—C1_1—H1A_1	110.8 (5)	N3_1—C3_1—N2_1	116.86 (2)
H1C_1—C1_1—H1B_1	110.3 (5)	N3_1—C4_1—N5_1	123.79 (2)
H1A_1—C1_1—H1B_1	110.0 (5)	N3_1—C4_1—N4_1	118.11 (2)
N1_1—C2_1—H2C_1	110.8 (3)	N5_1—C4_1—N4_1	118.02 (2)
N1_1—C2_1—H2A_1	110.8 (3)	H2D_1—N2_1—H2E_1	119.0 (5)
N1_1—C2_1—H2B_1	108.9 (3)	H4A_1—N4_1—H4B_1	119.6 (5)
H2C_1—C2_1—H2A_1	109.1 (5)	H5B_1—N5_1—H5A_1	119.8 (5)
H2C_1—C2_1—H2B_1	109.3 (5)
C1_1—N1_1—C3_1—N3_1	−6.99 (4)	C3_1—N3_1—C4_1—N5_1	−23.70 (5)
C1_1—N1_1—C3_1—N2_1	166.42 (4)	C3_1—N3_1—C4_1—N4_1	159.81 (3)
C1_1—N1_1—C2_1—H2C_1	−83.3 (7)	C4_1—N3_1—C3_1—N1_1	−53.77 (4)
C1_1—N1_1—C2_1—H2A_1	155.5 (8)	C4_1—N3_1—C3_1—N2_1	132.60 (6)
C1_1—N1_1—C2_1—H2B_1	36.9 (7)	N1_1—C3_1—N2_1—H2D_1	−1.1 (7)
H1A_1—C1_1—N1_1—C3_1	−16.4 (6)	N1_1—C3_1—N2_1—H2E_1	164.9 (6)
H1A_1—C1_1—N1_1—C2_1	155.3 (8)	N3_1—C4_1—N5_1—H5B_1	179.9 (2)
H1B_1—C1_1—N1_1—C3_1	−135.8 (7)	N3_1—C4_1—N5_1—H5A_1	−7.0 (7)
H1B_1—C1_1—N1_1—C2_1	36.0 (7)	N3_1—C4_1—N4_1—H4A_1	−16.8 (7)
H1C_1—C1_1—N1_1—C3_1	104.4 (7)	N3_1—C4_1—N4_1—H4B_1	172.3 (4)
H1C_1—C1_1—N1_1—C2_1	−83.8 (7)	N3_1—C3_1—N2_1—H2D_1	172.7 (4)
C2_1—N1_1—C3_1—N3_1	−178.204 (14)	N3_1—C3_1—N2_1—H2E_1	−21.3 (8)
C2_1—N1_1—C3_1—N2_1	−4.79 (4)	N4_1—C4_1—N5_1—H5B_1	−3.6 (7)
H2A_1—C2_1—N1_1—C3_1	−32.7 (7)	N4_1—C4_1—N5_1—H5A_1	169.5 (5)
H2B_1—C2_1—N1_1—C3_1	−151.3 (8)	N5_1—C4_1—N4_1—H4A_1	166.5 (6)
H2C_1—C2_1—N1_1—C3_1	88.5 (7)	N5_1—C4_1—N4_1—H4B_1	−4.4 (8)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C1_1—H1A_1···C4_1	1.0764 (17)	2.485 (6)	2.9931 (6)	107.7 (3)
C1_1—H1A_1···N3_1	1.0764 (17)	2.423 (6)	2.8477 (5)	102.0 (3)
N2_1—H2D_1···Cl1_2	1.0129 (18)	2.311 (3)	3.2756 (5)	158.8 (2)
N5_1—H5A_1···N3_1^i	1.0144 (18)	1.948 (2)	2.9556 (4)	171.77 (12)
N5_1—H5B_1···Cl1_2^ii	1.0141 (18)	2.633 (6)	3.3080 (3)	124.0 (3)
N4_1—H4A_1···Cl1_2^iii	1.0132 (18)	2.436 (4)	3.3104 (3)	144.1 (2)
N2_1—H2E_1···Cl1_2^iv	1.0159 (18)	2.263 (3)	3.2619 (5)	167.22 (18)
N4_1—H4B_1···Cl1_2^v	1.0145 (18)	2.237 (2)	3.2350 (4)	167.58 (15)

Symmetry codes: (i) x, −y+3/2, z−1/2; (ii) −x+1, y+1/2, −z+1/2; (iii) −x+1, y+1/2, −z+3/2; (iv) −x+1, −y+1, −z+1; (v) x+1, −y+3/2, z+1/2.