A new amidrazone derivative with anti­mycobacterial activity

Of a series of pyridine-2-carboxamidrazone derivatives with activity against mycobacteria, the N¹-[4-(1,1-di­methyl­propyl)­benzyl­idene] derivative reported here, C₁₈H₂₂N₄, is one of the most active. The predicted E isomer about the C11=N12 double bond is confirmed and intramolecular hydrogen bonding involving both amino H atoms helps to keep the mol­ecule flat. The same donor and acceptor atoms also form intermolecular hydrogen bonds.

S1. Comment

Benzylidenepyridylcarboxamidrazones with hydrophobic groups attached to the benzylidene moiety have attracted interest for their antimycobacterial activity (Billington et al., 1998). The title compound, (I), with its 1,1-dimethylpropyl substituent, is particularly active. Its minimum inhibitory concentation of 8–10 µg ml⁻¹ against Mycobacterium fortuitum approaches the 3 µg ml⁻¹ of the established drug isoniazid, (II).

We sought confirmation of the structure of (I), in particular, the configuration about the C11═N12 double bond. The reaction used for the synthesis allows both Z and E isomers, but proton NMR spectrometry and steric considerations suggested the E form, which is now verified. Other structural features, which appear to be similar in further members of this class of compounds currently under investigation, involve torsion angles in the chain joining the two rings (Table 1). Small twists about successive bonds, especially about formally single bonds, create an angle of 12.7 (2)° between least-squares planes through the two ring systems. The inclination of the rings must limit the π-electron overlap achievable. Compared to the average Csp²—C_ar bond length of 1.483 (15) Å (Allen et al., 1987), the C1—C11 bond is considerably shorter [1.446 (4) Å], while the C1P—C14 bond at the opposite end is not [1.473 (4) Å]. A degree of double-bond character in the former is perhaps substantiated by its greater planarity: torsion angles C2—-C1–C11—N12 and N13—C14—C1P—N2P are 178.1 (3) and 172.4 (3)°, respectively.

The amino group is expected to be a hydrogen-bond donor. Its C14—N141 distance of 1.337 (4) Å suggests considerable double-bond character consistent with sp² hybridization at N. Thus, electron density could migrate to the adjacent N13 atom, facilitating resonance-assisted intermolecular N—H···N hydrogen bonding. However, N2P not N13 is the hydrogen acceptor, and N12 makes a distant contact to the other amino H atom. In addition, intramolecular N—H···N interactions to N12 in the chain and N2P in the heterocycle, though kinked, fulfil the criteria used by Taylor et al. (1984) for three-centre hydrogen bonds (Table 2). Preventing an even closer intramolecular approach of N141 to N12, angle N13—C14—N141 is 8–10° larger than the other angles at C14.

The main problem encountered with the structure was disorder in the dimethylpropyl group. Although this should not affect the major structural features described so far, it almost certainly had an effect on what was a difficult refinement leading to a fairly high wR.

S2. Refinement

H atoms were treated as riding with N—H = 0.86 Å and C—H = 0.93–0.97 Å. Two separate positions were refined for each terminal methyl C atom using PART.

Computing details

Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Foftware; data reduction: CADABS (Gould & Smith, 1986); program(s) used to solve structure: SHELXS86 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97.

N'-(4-(1,1-dimethylpropyl)-benzylidene)-2-pyridinecarboxamidrazone

Crystal data

C18H22N4	Dx = 1.154 Mg m^−3
Mr = 294.40	Melting point: 86.3 - 88.4° corrected K
Orthorhombic, Pbca	Cu Kα radiation, λ = 1.54180 Å
a = 21.957 (4) Å	Cell parameters from 25 reflections
b = 20.518 (2) Å	θ = 8.6–25.8°
c = 7.522 (1) Å	µ = 0.55 mm^−1
V = 3388.8 (8) Å^3	T = 293 K
Z = 8	Plate, yellow
F(000) = 1264	0.65 × 0.33 × 0.15 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	1635 reflections with I > 2σ(I)
Radiation source: normal-focus sealed tube	Rint = 0.072
Graphite monochromator	θmax = 72.1°, θmin = 4.0°
ω/2θ scans	h = 0→27
Absorption correction: ψ scan (CADABS; Gould & Smith, 1986)	k = −25→0
Tmin = 0.469, Tmax = 0.921	l = −9→9
6157 measured reflections	3 standard reflections every 120 min
3316 independent reflections	intensity decay: 3.1%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.072	H-atom parameters constrained
wR(F^2) = 0.231	w = 1/[σ^2(Fo^2) + (0.1267P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max < 0.001
3316 reflections	Δρmax = 0.37 e Å^−3
204 parameters	Δρmin = −0.25 e Å^−3
7 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0011 (3)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. 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	Occ. (<1)
C1	0.83084 (14)	0.86269 (14)	0.8422 (4)	0.0530 (8)
C2	0.83927 (15)	0.81339 (16)	0.9658 (5)	0.0632 (9)
H2	0.8174	0.7748	0.9543	0.076*
C3	0.87930 (15)	0.82041 (17)	1.1052 (5)	0.0683 (9)
H3	0.8836	0.7863	1.1858	0.082*
C4	0.91333 (16)	0.87617 (16)	1.1296 (5)	0.0650 (9)
C5	0.90318 (17)	0.92599 (17)	1.0086 (5)	0.0726 (10)
H5	0.9237	0.9652	1.0235	0.087*
C6	0.86411 (15)	0.91955 (17)	0.8684 (5)	0.0643 (9)
H6	0.8597	0.9539	0.7888	0.077*
C11	0.79085 (14)	0.85122 (15)	0.6927 (4)	0.0567 (8)
H11	0.7729	0.8103	0.6827	0.068*
N12	0.77841 (12)	0.89370 (12)	0.5727 (4)	0.0566 (7)
N13	0.74264 (12)	0.86728 (12)	0.4377 (4)	0.0576 (7)
C14	0.73423 (13)	0.90759 (14)	0.3061 (4)	0.0492 (7)
N141	0.75509 (13)	0.96872 (12)	0.2965 (4)	0.0641 (8)
H141	0.7762	0.9846	0.3825	0.077*
H142	0.7474	0.9921	0.2044	0.077*
C1P	0.69906 (12)	0.88248 (13)	0.1540 (4)	0.0478 (7)
N2P	0.68382 (12)	0.92546 (12)	0.0268 (3)	0.0567 (7)
C3P	0.65236 (16)	0.90296 (18)	−0.1108 (5)	0.0693 (10)
H3P	0.6421	0.9321	−0.2006	0.083*
C4P	0.63403 (17)	0.8394 (2)	−0.1288 (5)	0.0757 (11)
H4P	0.6112	0.8260	−0.2264	0.091*
C5P	0.65041 (19)	0.79634 (19)	0.0010 (5)	0.0792 (11)
H5P	0.6391	0.7528	−0.0076	0.095*
C6P	0.68324 (15)	0.81746 (15)	0.1427 (5)	0.0622 (9)
H6P	0.6950	0.7884	0.2313	0.075*
C41	0.95916 (17)	0.8845 (2)	1.2811 (5)	0.0805 (11)
C411	0.9368 (3)	0.9445 (4)	1.4028 (9)	0.092 (3)*	0.703 (14)
H41A	0.9398	0.9843	1.3363	0.137*	0.703 (14)
H41B	0.9620	0.9473	1.5067	0.137*	0.703 (14)
H41C	0.8953	0.9375	1.4379	0.137*	0.703 (14)
C412	0.9332 (9)	0.8960 (13)	1.451 (2)	0.124 (9)*	0.297 (14)
H41D	0.9047	0.9314	1.4435	0.186*	0.297 (14)
H41E	0.9648	0.9069	1.5341	0.186*	0.297 (14)
H41F	0.9124	0.8575	1.4908	0.186*	0.297 (14)
C413	0.9566 (4)	0.8314 (4)	1.4198 (12)	0.087 (3)*	0.578 (17)
H41G	0.9157	0.8273	1.4633	0.130*	0.578 (17)
H41H	0.9833	0.8423	1.5165	0.130*	0.578 (17)
H41I	0.9693	0.7909	1.3678	0.130*	0.578 (17)
C414	0.9846 (8)	0.8132 (6)	1.338 (3)	0.130 (6)*	0.422 (17)
H41J	0.9521	0.7880	1.3886	0.195*	0.422 (17)
H41K	1.0167	0.8181	1.4235	0.195*	0.422 (17)
H41L	1.0001	0.7912	1.2345	0.195*	0.422 (17)
C42	1.01975 (18)	0.9067 (3)	1.2154 (6)	0.0992 (14)
H42A	1.0477	0.9143	1.3131	0.119*	0.542 (19)
H42B	1.0161	0.9463	1.1456	0.119*	0.542 (19)
H42C	1.0473	0.9012	1.3150	0.119*	0.458 (19)
H42D	1.0157	0.9534	1.1982	0.119*	0.458 (19)
C431	1.0414 (5)	0.8479 (8)	1.0970 (17)	0.117 (4)*	0.542 (19)
H43A	1.0812	0.8570	1.0501	0.175*	0.542 (19)
H43B	1.0133	0.8417	1.0007	0.175*	0.542 (19)
H43C	1.0430	0.8090	1.1679	0.175*	0.542 (19)
C432	1.0542 (4)	0.8827 (7)	1.0561 (13)	0.083 (4)*	0.458 (19)
H43D	1.0919	0.9061	1.0460	0.125*	0.458 (19)
H43E	1.0302	0.8896	0.9510	0.125*	0.458 (19)
H43F	1.0624	0.8370	1.0695	0.125*	0.458 (19)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0575 (17)	0.0500 (16)	0.0515 (18)	0.0060 (13)	0.0030 (14)	0.0056 (13)
C2	0.0685 (19)	0.0601 (19)	0.061 (2)	0.0002 (16)	−0.0023 (17)	0.0113 (16)
C3	0.069 (2)	0.072 (2)	0.064 (2)	−0.0013 (17)	−0.0070 (18)	0.0205 (18)
C4	0.066 (2)	0.072 (2)	0.056 (2)	−0.0019 (17)	−0.0030 (16)	0.0112 (17)
C5	0.081 (2)	0.0617 (19)	0.075 (3)	−0.0121 (18)	−0.013 (2)	0.0087 (18)
C6	0.071 (2)	0.0591 (19)	0.063 (2)	−0.0014 (15)	−0.0048 (17)	0.0130 (16)
C11	0.0626 (18)	0.0508 (16)	0.057 (2)	0.0025 (14)	0.0032 (15)	0.0023 (14)
N12	0.0629 (15)	0.0551 (15)	0.0519 (16)	−0.0023 (11)	−0.0067 (13)	0.0037 (13)
N13	0.0650 (16)	0.0571 (15)	0.0507 (15)	−0.0063 (12)	−0.0071 (13)	0.0043 (12)
C14	0.0536 (16)	0.0470 (15)	0.0471 (17)	0.0005 (12)	0.0041 (13)	−0.0018 (13)
N141	0.0873 (19)	0.0520 (14)	0.0529 (16)	−0.0136 (13)	−0.0146 (15)	0.0044 (12)
C1P	0.0496 (15)	0.0485 (15)	0.0453 (16)	−0.0008 (12)	0.0061 (13)	−0.0025 (13)
N2P	0.0669 (15)	0.0534 (14)	0.0498 (15)	−0.0001 (12)	−0.0041 (13)	−0.0018 (12)
C3P	0.085 (2)	0.071 (2)	0.052 (2)	0.0012 (18)	−0.0078 (19)	−0.0037 (16)
C4P	0.082 (2)	0.087 (3)	0.057 (2)	−0.016 (2)	−0.0069 (18)	−0.018 (2)
C5P	0.105 (3)	0.065 (2)	0.067 (2)	−0.027 (2)	0.006 (2)	−0.0132 (19)
C6P	0.080 (2)	0.0504 (17)	0.056 (2)	−0.0070 (16)	0.0042 (17)	−0.0025 (15)
C41	0.077 (2)	0.100 (3)	0.064 (2)	−0.011 (2)	−0.008 (2)	0.015 (2)
C42	0.078 (3)	0.143 (4)	0.077 (3)	0.004 (3)	−0.008 (2)	−0.001 (3)

Geometric parameters (Å, º)

C1—C2	1.387 (4)	C1P—N2P	1.344 (4)
C1—C6	1.391 (4)	C1P—C6P	1.381 (4)
C1—C11	1.446 (4)	N2P—C3P	1.327 (4)
C2—C3	1.376 (5)	C3P—C4P	1.372 (5)
C3—C4	1.379 (5)	C4P—C5P	1.365 (5)
C4—C5	1.387 (5)	C5P—C6P	1.358 (5)
C4—C41	1.530 (5)	C41—C412	1.421 (15)
C5—C6	1.366 (5)	C41—C42	1.491 (5)
C11—N12	1.284 (4)	C41—C413	1.510 (8)
N12—N13	1.393 (4)	C41—C411	1.610 (7)
N13—C14	1.303 (4)	C41—C414	1.624 (12)
C14—N141	1.337 (4)	C42—C432	1.500 (9)
C14—C1P	1.473 (4)	C42—C431	1.574 (10)
C2—C1—C6	116.5 (3)	C5P—C4P—C3P	117.9 (4)
C2—C1—C11	119.0 (3)	C6P—C5P—C4P	119.7 (3)
C6—C1—C11	124.5 (3)	C5P—C6P—C1P	119.3 (3)
C3—C2—C1	121.3 (3)	C412—C41—C42	127.3 (10)
C2—C3—C4	122.3 (3)	C412—C41—C413	58.9 (12)
C3—C4—C5	115.9 (3)	C42—C41—C413	118.9 (5)
C3—C4—C41	123.2 (3)	C412—C41—C4	115.2 (9)
C5—C4—C41	120.8 (3)	C42—C41—C4	112.0 (3)
C6—C5—C4	122.4 (3)	C413—C41—C4	114.2 (4)
C5—C6—C1	121.4 (3)	C412—C41—C411	40.4 (10)
N12—C11—C1	124.4 (3)	C42—C41—C411	103.1 (4)
C11—N12—N13	111.6 (3)	C413—C41—C411	98.5 (5)
C14—N13—N12	112.7 (2)	C4—C41—C411	108.0 (4)
N13—C14—N141	126.0 (3)	C412—C41—C414	93.0 (14)
N13—C14—C1P	116.2 (3)	C42—C41—C414	93.2 (8)
N141—C14—C1P	117.8 (3)	C413—C41—C414	35.0 (6)
N2P—C1P—C6P	121.8 (3)	C4—C41—C414	108.7 (6)
N2P—C1P—C14	117.0 (3)	C411—C41—C414	130.1 (9)
C6P—C1P—C14	121.2 (3)	C41—C42—C432	127.9 (6)
C3P—N2P—C1P	117.2 (3)	C41—C42—C431	102.9 (7)
N2P—C3P—C4P	124.1 (3)	C432—C42—C431	31.1 (5)
C6—C1—C2—C3	−1.0 (5)	C3P—C4P—C5P—C6P	0.7 (6)
C11—C1—C2—C3	176.4 (3)	C4P—C5P—C6P—C1P	0.6 (6)
C1—C2—C3—C4	−0.3 (6)	N2P—C1P—C6P—C5P	−1.2 (5)
C2—C3—C4—C5	2.3 (6)	C14—C1P—C6P—C5P	179.5 (3)
C2—C3—C4—C41	−178.6 (3)	C3—C4—C41—C412	−75.2 (13)
C3—C4—C5—C6	−3.0 (6)	C5—C4—C41—C412	103.9 (13)
C41—C4—C5—C6	177.8 (3)	C3—C4—C41—C42	129.0 (4)
C4—C5—C6—C1	1.8 (6)	C5—C4—C41—C42	−51.9 (5)
C2—C1—C6—C5	0.3 (5)	C3—C4—C41—C413	−9.8 (7)
C11—C1—C6—C5	−177.0 (3)	C5—C4—C41—C413	169.3 (6)
C2—C1—C11—N12	178.1 (3)	C3—C4—C41—C411	−118.2 (5)
C6—C1—C11—N12	−4.6 (5)	C5—C4—C41—C411	60.9 (5)
C1—C11—N12—N13	175.1 (3)	C3—C4—C41—C414	27.5 (9)
C11—N12—N13—C14	−173.9 (3)	C5—C4—C41—C414	−153.4 (9)
N12—N13—C14—N141	−1.7 (4)	C412—C41—C42—C432	164.2 (15)
N12—N13—C14—C1P	177.4 (2)	C413—C41—C42—C432	93.0 (9)
N13—C14—C1P—N2P	172.4 (3)	C4—C41—C42—C432	−43.6 (8)
N141—C14—C1P—N2P	−8.3 (4)	C411—C41—C42—C432	−159.4 (8)
N13—C14—C1P—C6P	−8.3 (4)	C414—C41—C42—C432	68.0 (10)
N141—C14—C1P—C6P	170.9 (3)	C412—C41—C42—C431	143.5 (15)
C6P—C1P—N2P—C3P	0.4 (5)	C413—C41—C42—C431	72.3 (8)
C14—C1P—N2P—C3P	179.7 (3)	C4—C41—C42—C431	−64.3 (6)
C1P—N2P—C3P—C4P	1.0 (5)	C411—C41—C42—C431	179.9 (6)
N2P—C3P—C4P—C5P	−1.6 (6)	C414—C41—C42—C431	47.3 (9)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N141—H141···N12	0.86	2.35	2.636 (4)	100
N141—H142···N2P	0.86	2.37	2.712 (4)	104
N141—H141···N2P^i	0.86	2.31	3.085 (4)	149
N141—H142···N12^ii	0.86	2.61	3.368 (4)	148

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