Redetermination of para-amino­pyridine (fampridine, EL-970) at 150 K

Anderson, F.P.; Gallagher, J.F.; Kenny, P.T.M.; Lough, A.J.

doi:10.1107/S1600536805010433

organic compounds

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ISSN: 2056-9890

Volume 61| Part 5| May 2005| Pages o1350-o1353

https://doi.org/10.1107/S1600536805010433

Redetermination of para-aminopyridine (fampridine, EL-970) at 150 K

Frankie P. Anderson,^a John F. Gallagher,^a ^* Peter T.M. Kenny ^a and Alan J. Lough ^b ^*

^aSchool of Chemical Sciences, National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland, and ^bDepartment of Chemistry, 80 St George Street, University of Toronto, Ontario, Canada M5S 3H6
^*Correspondence e-mail: john.gallagher@dcu.ie, alough@chem.utoronto.ca

(Received 16 March 2005; accepted 4 April 2005; online 16 April 2005)

The structure of fampridine (EL-970) or 4-aminopyridine, C₅H₆N₂, has been redetermined at 150 K. The room-temperature structure has been reported previously [Chao & Schempp (1977 ). Acta Cryst. B33, 1557–1564]. Pyramidalization at the amine N atom occurs in fampridine, with the N atom 0.133 (11) Å from the plane of the three C/H/H atoms to which it is bonded; the interplanar angle between the pyridyl ring and NH₂ group is 21 (2)°. Aggregation in the solid state occurs by N—H⋯N and N—H⋯π(pyridine) interactions with N⋯N and N⋯π(centroid) distances of 2.9829 (18) and 3.3954 (15) Å, respectively; a C—H⋯π(pyridine) contact completes the intermolecular interactions [C⋯π(centroid) = 3.6360 (16) Å].

Comment

4-Aminopyridine (fampridine) is used in the treatment of neurological ailments, such as multiple sclerosis (MS), with tests showing that fampridine improves motor function in MS patients (Schwid et al., 1997 ). Related studies have utilized this small molecule on episodic ataxia type 2 (EA2), as it functions as a potassium channel blocker (Strupp et al., 2004 ). Our interest in para-aminopyridine is to react it with aromatic carboxylic acids and acyl chlorides to generate new series of amide-based aromatic systems.

The structures of 2-, 3- and 4-aminopyridine, NC₅H₄NH₂, (I)–(III), have been reported previously using data collected at room temperature on a Nonius CAD-4 diffractometer with Cu Kα radiation (Chao et al., 1975a ,b ; Chao & Schempp, 1977), with corresponding Cambridge Structural Database (CSD; Version V6.26, February 2005 release; Allen, 2002 ) refcodes of AMPYRD, AMIPYR and AMPYRE. In the present study, we report the crystal structure of 4-aminopyridine (fampridine), (IV), at 150 K with greater precision than reported previously for (III) and comment on the intermolecular hydrogen bonding for comparison with the related structures (I)–(III).

In (I)–(III/IV), the primary donor (D) and acceptor (A) are the two NH₂ donor H atoms and the pyridine N atom acceptor. Herein lies a mismatch in the number of strong donor and acceptors groups, although the aromatic CH groups (D) and the π-pyridyl system (A) can redress this imbalance and participate as weaker donor and acceptor groups in the hydrogen-bonding process.

In (I) (Chao et al., 1975a), the primary hydrogen bonding consists of pairs of molecules forming N—H⋯N_pyridine hydrogen bonds in a cyclic array about inversion centres, with graph set R₂²(8) (Bernstein et al., 1995 ) (H⋯N = 2.20 (3) Å, N⋯N = 3.071 (7) Å and N—H⋯N 171 (2)°]. Dimers stack into columns along the b axis direction, although there are no π–π stacking interactions of note. Further association of the dimers occurs via the second N—H donor as N—H⋯N_pyridine interactions (about a twofold screw axis), forming a herringbone-type packing pattern in the [011] direction (interplanar angle 58.9°), with H⋯N = 2.63 (3) Å, N⋯N = 3.416 (7) Å and N—H⋯N = 149 (2)°, and augmented by two C—H⋯π(arene) contacts per N—H⋯N interaction. There are no other interactions of note apart from normal van der Waals contacts.

In (II) (Chao et al., 1975b), N—H⋯N_pyridine interactions link molecules along the a-axis direction in a head-to-tail fashion, thus generating infinite one-dimensional chains [H⋯N = 2.22 (3) Å, N⋯N = 3.123 (4) Å and N—H⋯N = 168 (2)°]. The second NH donor forms an interaction with the amine N atom (lone pair of electrons), with H⋯N = 2.46 (3) Å, N⋯N = 3.336 (4) Å and N—H⋯N = 162 (2)°, thus linking the chains into a three-dimensional herringbone pattern, where each chain is surrounded by six others, and this process is augmented by two C—H⋯π(arene) interactions per molecule of (II), e.g. H⋯C 2.81 and 2.87 Å, only one of which is depicted in the second scheme.

In (III) (Chao & Schempp, 1977), N—H⋯N_pyridine interactions link molecules in a head-to-tail manner, forming zigzag chains along the c-axis direction, with H⋯N = 2.14 Å, N⋯N = 3.007 Å and N—H⋯N = 159°. The second NH donor atom forms an N—H⋯π(pyridyl) interaction with a symmetry-related chain, stacked antiparallel along the b-axis direction, with shortest H⋯C = 2.66 Å and N—H⋯C = 173°. The N—H⋯π(pyridyl) interaction links each chain with two neighbouring chains, each consecutive NH donor alternately donating to either of the two π(pyridyl) groups. Thus, each chain is linked and effectively surrounded by four chains as the π(pyridyl) is also an acceptor of N—H interactions from two extra chains. Of note is that pyramidalization occurs at the amine N atom.

Thus, in structures (I)–(III), an N_amine—H⋯N_pyridine hydrogen bond forms and the remaining amine H-atom donor interacts in the crystal structure in one of three different ways, either via herringbone-type N—H⋯N_pyridine interactions in (I), by N—H⋯N_amine interactions in (II) or as N—H⋯π(pyridyl) interactions in (III), as depicted in the second scheme above. It is pertinent to note that in the original reports the primary hydrogen bonding involving N_amine—H⋯N_pyridine was comprehensively discussed. However, only in (II) was the remaining (second) amine NH donor implicated in an interaction and with the lone pair of electrons on the amine N atom. The authors further qualify this with the statement `although these distances are too long to be recognized as hydrogen bonds'.

In the present study of (IV), the low-temperature structure of (III), the corresponding data are detailed in Tables 1 and 2. Bond lengths and angles are similar but are determined to a higher degree of precision than reported for (III). In (IV), amine atom N1 lies 0.133 (11) Å from the plane of atoms C1, H1A and H1B; this pyramidalization can also be observed by the three angles about N1 summing to 355.3°. The amine N1/H1A/H1B and the pyridyl NC₅ group are twisted from coplanarity by 21 (2)°, while atom N1 is coplanar with the pyridine ring system; the H1A/H1B atoms lie 0.12 (2) and 0.22 (2) Å from this aromatic plane. The hydrogen-bonding distances in (IV) (Table 2) [values for (III) in brackets] are N⋯N 2.9829 (18) Å [3.007 Å], N⋯π(pyridyl) 3.3954 (15) Å [3.460 Å], and a contact between atom C3 and a neighbouring π(pyridyl) of 3.6360 (16) Å [3.704 Å].

In the isoelectronic compound aniline, C₆H₅NH₂, (aminobenzene), studied at 252 K (CSD refcode BAZGOY), two strong donor groups and no strong acceptors are present (Fukuyo et al., 1982 ). Aggregation in the solid state utilizes both NH donor groups as N—H⋯N_amine [N⋯N = 3.180 (6) and 3.373 (5) Å] and N—H⋯π(phenyl) interactions [N⋯Cg = 3.41 and 3.49 Å, H⋯N = 2.70 and 2.64 Å, and N—H⋯π(Cg) = 154 and 150°, where Cg represents the aromatic ring centroids]. The former two N—H⋯N_amine interactions are similar to that observed in (II) above: the latter two are described as having H atoms that are `free from hydrogen bonding' (Fukuyo et al., 1982). Such N—H⋯π(aromatic) interactions have received considerable attention in recent years both in chemistry and in biology (Desiraju & Steiner, 1999 ). The distances and angles associated with these type of interactions in (III) and (IV) are typical of the values reported in the literature.

Figure 1
A view of (IV)

, with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.. H atom sphere radii are arbitrary.

Figure 2
A view of the two primary interactions in (IV)

. Atoms labelled with the suffixes # and * are at the symmetry-related positions (− $[{1\over 2}]$ + x, $[{1\over 2}]$ − y, 1 − z) and ( $[{1\over 2}]$ − x, 1 − y, $[{1\over 2}]$ + z), respectively.

Figure 3
A view of the hydrogen-bonded chain generated by N—H⋯N hydrogen bonds and N—H⋯π(arene) interactions with a neighbouring chain.

Experimental

4-Aminopyridine was purchased from Aldrich Chemical Company Ltd and recrystallized from CH₂Cl₂ prior to analysis.

Crystal data

C₅H₆N₂
M_r = 94.12
Orthorhombic, P 2₁ 2₁ 2₁
a = 5.5138 (4) Å
b = 7.1866 (5) Å
c = 12.0459 (4) Å
V = 477.32 (5) Å³
Z = 4
D_x = 1.310 Mg m⁻³
Mo Kα radiation
Cell parameters from 2026 reflections
θ = 2.6–27.5°
μ = 0.08 mm⁻¹
T = 150 (1) K
Block, colourless
0.25 × 0.20 × 0.15 mm

Data collection

Nonius KappaCCD diffractometer
φ scan and ω scans with κ offsets
Absorption correction: multi-scan(SORTAV; Blessing, 1995 )T_min = 0.979, T_max = 0.988
3217 measured reflections
662 independent reflections
591 reflections with I > 2σ(I)
R_int = 0.030
θ_max = 27.5°
h = −6 → 7
k = −9 → 9
l = −15 → 15

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.031
wR(F²) = 0.086
S = 1.10
662 reflections
89 parameters
All H-atom parameters refined
w = 1/[σ²(F_o²) + (0.0587P)² + 0.0044P] where P = (F_o² + 2F_c²)/3
(Δ/σ)_max < 0.001
Δρ_max = 0.17 e Å⁻³
Δρ_min = −0.13 e Å⁻³
Extinction correction: SHELXL97
Extinction coefficient: 0.13 (4)

Table 1
Selected geometric parameters (Å, °)

N1—C1	1.3597 (18)
C1—C2	1.409 (2)
C1—C6	1.403 (2)
C2—C3	1.378 (2)
C3—N4	1.345 (2)
N4—C5	1.346 (2)
C5—C6	1.375 (2)
N1—H1A	0.95 (2)
N1—H1B	0.94 (2)

N1—C1—C2	122.41 (13)
N1—C1—C6	121.33 (13)
C2—C1—C6	116.25 (13)
C1—C2—C3	119.37 (14)
N4—C3—C2	124.77 (15)
C3—N4—C5	115.25 (13)
N4—C5—C6	124.74 (14)
C5—C6—C1	119.61 (13)

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1B⋯N4ⁱ	0.94 (2)	2.06 (2)	2.9829 (18)	167 (2)
N1—H1A⋯Cg1ⁱⁱ	0.95 (2)	2.61 (2)	3.3954 (15)	141 (2)
C3—H3⋯Cg1ⁱⁱⁱ	1.03 (2)	2.76 (2)	3.6360 (16)	143 (2)
Symmetry codes: (i) $[-x+{\script{1\over 2}}, -y+1, z+{\script{1\over 2}}]$ ; (ii) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]$ ; (iii) $[-x, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

All six H atoms bound to C and N were refined with isotropic displacement parameters with the four C—H bond lengths in the range 0.971 (19) to 1.028 (18) Å. Examination of the structure with PLATON (Spek, 2003 ) showed that there were no solvent-accessible voids in the crystal structure. In the absence of significant anomalous scattering, Friedel pairs were merged prior to the final refinement cycles.

Data collection: KappaCCD Server Software (Nonius, 1997 ); cell refinement: DENZO–SMN (Otwinowski & Minor, 1997 ); data reduction: DENZO–SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996 ) and PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97, ORTEX (McArdle, 1995 ) and PREP8 (Ferguson, 1998 ).

Supporting information

Crystal structure: contains datablocks global, IV. DOI: https://doi.org/10.1107/S1600536805010433/bt6634sup1.cif

Structure factors: contains datablock IV. DOI: https://doi.org/10.1107/S1600536805010433/bt6634IVsup2.hkl

Computing details top

Data collection: KappaCCD Server Software (Nonius, 1997); cell refinement: DENZO–SMN (Otwinowski & Minor, 1997); data reduction: DENZO–SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEX (Burnett & Johnson, 1996) and PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97, ORTEX (McArdle, 1995) and PREP8 (Ferguson, 1998).

4-aminopyridine top

Crystal data top

C₅H₆N₂	? #Insert any comments here.
M_r = 94.12	D_x = 1.310 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 2026 reflections
a = 5.5138 (4) Å	θ = 2.6–27.5°
b = 7.1866 (5) Å	µ = 0.08 mm⁻¹
c = 12.0459 (4) Å	T = 150 K
V = 477.32 (5) Å³	Block, colourless
Z = 4	0.25 × 0.20 × 0.15 mm
F(000) = 200

Data collection top

Nonius KappaCCD diffractometer	662 independent reflections
Radiation source: fine-focus sealed X-ray tube	591 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.030
φ scan and ω scans with κ offsets	θ_max = 27.5°, θ_min = 3.3°
Absorption correction: multi-scan (SORTAV; Blessing, 1995)	h = −6→7
T_min = 0.979, T_max = 0.988	k = −9→9
3217 measured reflections	l = −15→15

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)] = 0.031	All H-atom parameters refined
wR(F²) = 0.086	w = 1/[σ²(F_o²) + (0.0587P)² + 0.0044P] where P = (F_o² + 2F_c²)/3
S = 1.10	(Δ/σ)_max < 0.001
662 reflections	Δρ_max = 0.17 e Å⁻³
89 parameters	Δρ_min = −0.13 e Å⁻³
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.13 (4)

Special details top

Experimental. ? #Insert any special details here.

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.

Planes data ###########

Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane)

-2.7639(0.0029)x + 5.8598(0.0027)y - 3.4889(0.0068)z = 0.9722(0.0035)

* -0.0048 (0.0010) C1 * 0.0023 (0.0011) C2 * 0.0036 (0.0010) C3 * -0.0072 (0.0010) N4 * 0.0047 (0.0011) C5 * 0.0013 (0.0010) C6 0.0000 (0.0021) N1 - 0.1285 (0.0181) H1A -0.2253 (0.0231) H1B

Rms deviation of fitted atoms = 0.0044

-3.3817(0.0787)x + 5.6625(0.0835)y + 0.6624(0.3484)z = 3.2778(0.1869)

Angle to previous plane (with approximate e.s.d.) = 20.9(1.6)

* 0.0000 (0.0000) N1 * 0.0000 (0.0000) H1A * 0.0000 (0.0000) H1B

Rms deviation of fitted atoms = 0.0000

- 2.7837(0.0740)x + 6.0631(0.0710)y - 2.1990(0.1424)z = 1.6604(0.0959)

Angle to previous plane (with approximate e.s.d.) = 15.3(2.1)

* 0.0000 (0.0000) C1 * 0.0000 (0.0000) H1A * 0.0000 (0.0000) H1B 0.1331 (0.0106) N1 - 0.2686 (0.0221) N4

Rms deviation of fitted atoms = 0.0000

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

	x	y	z	U_iso*/U_eq
N1	−0.0935 (2)	0.45712 (19)	0.56319 (10)	0.0302 (4)
C1	0.0307 (3)	0.4568 (2)	0.46567 (11)	0.0244 (4)
C2	−0.0533 (3)	0.3619 (2)	0.37080 (11)	0.0259 (4)
C3	0.0811 (3)	0.3682 (2)	0.27448 (13)	0.0285 (4)
N4	0.2927 (2)	0.4593 (2)	0.26288 (10)	0.0295 (4)
C5	0.3692 (3)	0.5515 (2)	0.35369 (12)	0.0284 (4)
C6	0.2497 (3)	0.5542 (2)	0.45390 (12)	0.0274 (4)
H1A	−0.228 (3)	0.376 (3)	0.5703 (14)	0.034 (5)*
H1B	−0.020 (4)	0.493 (3)	0.6301 (18)	0.054 (6)*
H2	−0.204 (3)	0.292 (3)	0.3720 (12)	0.030 (4)*
H3	0.026 (3)	0.295 (3)	0.2055 (15)	0.036 (5)*
H5	0.523 (3)	0.617 (3)	0.3440 (14)	0.031 (4)*
H6	0.309 (4)	0.626 (3)	0.5168 (15)	0.037 (5)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0328 (7)	0.0322 (7)	0.0257 (7)	−0.0054 (7)	0.0031 (5)	−0.0009 (6)
C1	0.0269 (7)	0.0217 (7)	0.0246 (7)	0.0022 (7)	−0.0016 (5)	0.0025 (6)
C2	0.0257 (7)	0.0253 (7)	0.0268 (7)	−0.0019 (7)	−0.0041 (6)	0.0005 (6)
C3	0.0332 (8)	0.0269 (7)	0.0254 (7)	0.0015 (8)	−0.0042 (6)	0.0012 (6)
N4	0.0309 (7)	0.0310 (7)	0.0267 (6)	0.0009 (6)	0.0010 (5)	0.0031 (5)
C5	0.0266 (7)	0.0274 (7)	0.0313 (8)	−0.0013 (7)	−0.0001 (6)	0.0035 (6)
C6	0.0297 (8)	0.0255 (7)	0.0270 (7)	−0.0013 (8)	−0.0044 (6)	0.0005 (6)

Geometric parameters (Å, º) top

N1—C1	1.3597 (18)	N1—H1A	0.95 (2)
C1—C2	1.409 (2)	N1—H1B	0.94 (2)
C1—C6	1.403 (2)	C2—H2	0.971 (19)
C2—C3	1.378 (2)	C3—H3	1.028 (18)
C3—N4	1.345 (2)	C5—H5	0.978 (19)
N4—C5	1.346 (2)	C6—H6	0.973 (19)
C5—C6	1.375 (2)

N1—C1—C2	122.41 (13)	C1—N1—H1B	121.7 (14)
N1—C1—C6	121.33 (13)	C1—C2—H2	121.3 (9)
C2—C1—C6	116.25 (13)	C3—C2—H2	119.4 (9)
C1—C2—C3	119.37 (14)	C2—C3—H3	120.4 (10)
N4—C3—C2	124.77 (15)	N4—C3—H3	114.8 (10)
C3—N4—C5	115.25 (13)	N4—C5—H5	114.4 (10)
N4—C5—C6	124.74 (14)	C6—C5—H5	120.9 (10)
C5—C6—C1	119.61 (13)	C1—C6—H6	118.4 (11)
H1A—N1—H1B	115.5 (16)	C5—C6—H6	121.9 (11)
C1—N1—H1A	118.1 (10)

N1—C1—C2—C3	179.68 (13)	C3—N4—C5—C6	1.3 (2)
C6—C1—C2—C3	0.5 (2)	N4—C5—C6—C1	−0.5 (2)
C1—C2—C3—N4	0.3 (2)	N1—C1—C6—C5	−179.59 (14)
C2—C3—N4—C5	−1.2 (2)	C2—C1—C6—C5	−0.4 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1B···N4ⁱ	0.94 (2)	2.06 (2)	2.9829 (18)	167 (2)
N1—H1A···Cg1ⁱⁱ	0.95 (2)	2.61 (2)	3.3954 (15)	141.1 (15)
C3—H3···Cg1ⁱⁱⁱ	1.028 (18)	2.76 (2)	3.6360 (16)	143.3 (15)

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

Acknowledgements

JFG thanks Ms Joyce McMahon for recrystallizing compound (IV). FPA, JFG and PTMK thank Dublin City University and the Department of Education, Ireland, for funding the National Institute for Cellular Biotechnology (PRTLI program, round #3, 2001–2008). AJL thanks the University of Toronto and NSERC Canada for funding.

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