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

# 2005 International Union of Crystallography Printed in Great Britain – all rights reserved The structure of fampridine (EL-970) or 4-aminopyridine, C5H6N2, has been redetermined at 150 K. The roomtemperature 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 (pyridine) interactions with N N and N (centroid) distances of 2.9829 (18) and 3.3954 (15) Å, respectively; a C—H (pyridine) contact completes the intermolecular interactions [C (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, NC 5 H 4 NH 2 , (I)-(III), have been reported previously using data collected at room temperature on a Nonius CAD-4 diffractometer with Cu K 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 NH 2 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 -pyridyl system (A) can redress this imbalance and participate as weaker donor and acceptor groups in the hydrogen-bonding process.
In (III) (Chao & Schempp, 1977), N-HÁ Á ÁN pyridine interactions link molecules in a head-to-tail manner, forming zigzag chains along the c-axis direction, with HÁ Á ÁN = 2.14 Å , NÁ Á ÁN = 3.007 Å and N-HÁ Á ÁN = 159 . The second NH donor atom forms an N-HÁ Á Á(pyridyl) interaction with a symmetryrelated chain, stacked antiparallel along the b-axis direction, with shortest HÁ Á ÁC = 2.66 Å and N-HÁ Á ÁC = 173 . The N-HÁ Á Á(pyridyl) interaction links each chain with two neighbouring chains, each consecutive NH donor alternately donating to either of the two (pyridyl) groups. Thus, each chain is linked and effectively surrounded by four chains as the (pyridyl) is also an acceptor of N-H interactions from two extra chains. Of note is that pyramidalization occurs at the amine N atom. A view of the two primary interactions in (IV). Atoms labelled with the suffixes # and * are at the symmetry-related positions (À 1 2 + x, 1 2 À y, 1 À z) and ( 1 2 À x, 1 À y, 1 2 + z), respectively.

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.
Thus, in structures (I)-(III), an N amine -HÁ Á ÁN 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-HÁ Á ÁN pyridine interactions in (I), by N-HÁ Á ÁN amine interactions in (II) or as N-HÁ Á Á(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 -HÁ Á ÁN 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 NC 5 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) ( In the isoelectronic compound aniline, C 6 H 5 NH 2 , (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-HÁ Á ÁN amine [NÁ Á ÁN = 3.180 (6) and 3.373 (5) Å ] and N-HÁ Á Á(phenyl) interactions [NÁ Á ÁCg = 3.41 and 3.49 Å , HÁ Á ÁN = 2.70 and 2.64 Å , and N-HÁ Á Á(Cg) = 154 and 150 , where Cg represents the aromatic ring centroids]. The former two N-HÁ Á ÁN 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-HÁ Á Á(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.

Crystal data
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.