Zwitterionic 4-piperidine­carboxyl­ic acid monohydrate

The title compound, 4-piperidinio­carboxyl­ate (isonipecotic acid), crystallizes as a zwitterion and incorporates one water mol­ecule, i.e. C₆H₁₁NO₂·H₂O. The piperidine ring adopts a chair conformation and the α-carboxyl­ate group is oriented in the equatorial position. The combination of the interactions between the α-amino and α-carboxyl­ate groups and the water mol­ecules builds a three-dimensional assembly of hydrogen bonds.

S1. Comment

Compounds with both amino and carboxylic groups in their molecular structure, such as α–aminoacids, can exist as zwitterions in the crystalline state as well as in aqueous solutions. In a zwitterion both charged groups, COO^- and NH₃⁺ (or NH₂⁺ or NH⁺) interact with each other and with the aqueous solvent by means of electrostatic, polarization and hydrogen-bonding interactions. These interactions affect their structural conformation, functionality and biological activity (Price et al., 1998). \sch

In the solid state zwitterions often cocrystallize with solvent molecules. The role played by the solvent molecules is diverse (Görbitz & Hersleth, 2000); they might be directly involved in the formation of hydrogen bonds with themselves and with the zwitterion, or they could just fill void space. Proline, for example, crystallizes forming infinite chains of dimers linked by head-to-tail hydrogen bonds; water molecules act as bridges among chains, stabilizing the three-dimensional structure (Padmanbham et al., 1995, Janczak & Luger, 1997). Other examples of aminoacids with lateral chains strictly hydrophobic, which pack in a similar way to proline, have been reported in the recent literature (Dalhus & Görbitz, 1999a,b).

In the gaseous phase the aminoacid exists in its neutral form; however, in the presence of solvent molecules, generally water, the aminoacid rapidly ionizes forming the zwitterion [Jensen & Gordon, 1995, Tajkhorshid et al., 1998]. The solvation effects in the zwitterion formation have been the subject of much interest and theoretical studies using different approaches have appeared in the recent literature, particularly concerning the simplest α–aminoacids: glycine and alanine (Jensen & Gordon, 1995; Tajkhorshid et al., 1998).

From the theoretical point of view, it is interesting to study the structural isomers: 2-piperidinecarboxylic acid, (I) (pipecolic acid or homoproline), 3-piperidinecarboxylic acid, (II) (nipecotic acid), and 4-piperidinecarboxylic acid (III) (isonipecotic acid). These compounds have a piperidinium ring, which enables the charge separation between the amino and the carboxylic groups, and offer additional degrees of freedom due to the possibility of different conformers, keeping in mind the simplicity of the molecule to avoid costly computational calculations. Preliminary theoretical calculations (Cuervo et al., 2000) at the ab initio and density functional theory levels have shown that in the absence of water the three isomers exist as the favourable neutral form, with isomer (III) being the least stable by about 20 kcal mol^-1. As water is introduced, the zwitterion becomes the stable form and, for instance, zwitterion (I) is stabilized when two water molecules are added to its vicinity.

The crystalline structure of (I), a potent aminoacid antagonist, has been reported (Bhattacharjee & Chacko, 1979). In the solid state this compound is a zwitterion and crystallizes with four water molecules. Compound (II) is also a zwitterion, but it is not a hydrate [Brehm et al., 1976]. Very little is known of 4-piperidinecarboxylic acid, (III). Our study shows this compound is zwitterionic and crystallizes in the space group Pna2₁, incorporating one water molecule as crystallization solvent. Fig. 1 shows the molecular diagram and labeling scheme of (III). The existence of the zwitterionic form of (III) is confirmed by the presence of two H atoms bonded to the N1 atom, as was depicted in the difference Fourier map where the two H atoms were located, and the almost symmetrical α–carboxylate group, with C1–O1 and C1–O2 distances being equal within 2σ (See Table 1). The piperidine ring adopts the stable chair conformation, as in compounds (I) and (II), and in 12 related piperidinium rings not substituted at the amino group found in the Cambridge Structural Database (Allen & Kennard, 1993). The N–C bond lengths are in agreement with the reported value for piperidinium rings (Allen et al., 1987).

The α–carboxylate group at C2 is attached to the ring in the favourable equatorial position. The orientation of the α–carboxylate group is described by the torsion angles O1–C1–C2–C6 - 57.4 (2), O1–C1–C2–C3 + 178.6 (2), O2–C1–C2–C3 - 2.2 (2) and O2–C1–C2–C6 + 121.8 (2)°. O1 is -0.136 (1) Å below and O2 is +0.946 (2) Å above the piperidine mean plane. The asymmetric arrangement of the α–carboxylate is also observed in the solid state CP MAS ¹³C NMR, which shows two peaks at 25.46 p.p.m. and 27.83 p.p.m., corresponding to C3 and C6, respectively. These two peaks overlap at 25.61 p.p.m. in the ¹³C NMR taken in D₂O due to the free rotation about the C1–C2 bond in the liquid state.

The geometric parameters of the hydrogen bonds are given in Table 2. Two sets of head-to-tail N1–H1B···O2 and N1–H1A···O1 interactions form extended chains which run parallel to the c and b axes, respectively. In addition, water molecules interact with aminoacid molecules through OW–H1W···O2 and OW—H2W···O1 hydrogen bonds, thus producing sinuous chains running parallel to the a axis. The combination of these interactions along the principal directions build an intricate three-dimensional assembly of hydrogen bonds. Fig. 2 show a projection of the cystal structure viewed down the c axis.

Related literature

For related literature, see: Allen & Kennard (1993); Allen et al. (1987); Bhattacharjee & Chacko (1979); Brehm et al. (1976); Cuervo et al. (2000); Dalhus & Görbitz (1999a, 1999b); Görbitz & Hersleth (2000); Janczak & Luger (1997); Jensen & Gordon (1995); Price et al. (1998); Tajkhorshid et al. (1998).

S2. Experimental

A crystal suitable for X-ray diffraction analysis was obtained by slow evaporation of a saturated 1:1 water:ethanol solution of isonipecotic acid (Aldrich, I-1,800–8, 97%). CP MAS ¹³C NMR (400 MHz): δ 181.52 (C-1), 45.77 (C-5), 43.53 (C-4), 41.21 (C-2), 27.83 (C-6), 25.46 (C-3). ¹³C NMR (400 MHz, D₂O): δ 182.08 (C-1), 43.74 (C-4, C-5), 41.37 (C-2), 25.61 (C-3, C-6).

S3. Refinement

The H atoms of the NH₂⁺ moiety were located from difference Fourier maps and refined with isotropic displacement parameters. The H atoms from the water molecule were located in the last difference Fourier map, their positions were refined and their isotropic displacement parameters were set to 1.2 times the equivalent displacement parameter of the OW atom. The H atoms of the piperidine ring were placed in geometrically calculated positions and their isotropic displacement parameters were set to 1.2 times the equivalent displacement parameter of their parent atoms.

Computing details

Data collection: SMART (Siemens, 1996); cell refinement: SAINT (Siemens, 1996); data reduction: SHELXTL (Siemens, 1996); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996; Farrugia, 1997); software used to prepare material for publication: PLATON (Spek, 2000).

Figures

	Fig. 1. ORTEPIII (Burnett & Johnson, 1996; Farrugia, 1997) drawing of (III) showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary radii.
	Fig. 2. ORTEPIII (Burnett & Johnson, 1996; Farrugia, 1997) projection diagram of (III) viewed down the c axis. The interaction N1–H1B···O2 is not shown.

4-piperidinecarboxylic acid

Crystal data

C6H11NO2·H2O	F(000) = 320
Mr = 147.17	Dx = 1.290 Mg m^−3
Orthorhombic, Pna21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2c -2n	Cell parameters from 4773 reflections
a = 11.9647 (11) Å	θ = 1.5–25.4°
b = 8.3276 (7) Å	µ = 0.10 mm^−1
c = 7.6054 (7) Å	T = 293 K
V = 757.78 (12) Å^3	Plate, colourless
Z = 4	0.4 × 0.4 × 0.3 mm

Data collection

Siemens CCD area detector diffractometer	734 reflections with I > 2σ(I)
Radiation source: sealed tube	Rint = 0.038
Graphite monochromator	θmax = 25.4°, θmin = 3.0°
ϕ and ω scans	h = −14→14
6524 measured reflections	k = −10→10
754 independent reflections	l = −9→9

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.101	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0654P)^2 + 0.1836P] where P = (Fo^2 + 2Fc^2)/3
754 reflections	(Δ/σ)max = 0.012
105 parameters	Δρmax = 0.29 e Å^−3
1 restraint	Δρmin = −0.19 e Å^−3

Special details

Experimental. Full sphere. 40 kV / 30 mA 2252 frames 10 sec/frame 0.3° omega No decay was observed. Note that full sphere was collected.

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.

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

	x	y	z	Uiso*/Ueq
C1	0.1857 (2)	0.0763 (3)	0.3030 (3)	0.0319 (5)
C2	0.1668 (2)	0.0637 (3)	0.1041 (3)	0.0303 (5)
H2	0.1411	−0.0456	0.0790	0.036*
C3	0.0790 (2)	0.1790 (3)	0.0341 (3)	0.0380 (6)
H3A	0.1000	0.2882	0.0635	0.046*
H3B	0.0077	0.1564	0.0898	0.046*
C4	0.0669 (2)	0.1634 (3)	−0.1647 (4)	0.0453 (7)
H4A	0.0385	0.0575	−0.1935	0.054*
H4B	0.0136	0.2423	−0.2070	0.054*
C5	0.2622 (3)	0.0720 (4)	−0.1905 (4)	0.0453 (7)
H5A	0.3327	0.0929	−0.2494	0.054*
H5B	0.2391	−0.0366	−0.2188	0.054*
C6	0.2772 (2)	0.0885 (3)	0.0064 (4)	0.0404 (6)
H6A	0.3063	0.1945	0.0330	0.048*
H6B	0.3313	0.0099	0.0467	0.048*
N1	0.1760 (2)	0.1883 (3)	−0.2530 (3)	0.0393 (5)
H1A	0.200 (3)	0.285 (4)	−0.220 (5)	0.048 (8)*
H1B	0.166 (3)	0.172 (3)	−0.374 (5)	0.047 (9)*
O1	0.2552 (2)	−0.0179 (2)	0.3692 (3)	0.0476 (5)
O2	0.1331 (2)	0.1781 (3)	0.3884 (3)	0.0544 (6)
OW1	0.4490 (3)	0.1485 (6)	−0.5067 (5)	0.120 (2)
H1W	0.497 (6)	0.192 (8)	−0.58 (1)	0.144*
H2W	0.405 (5)	0.090 (7)	−0.57 (1)	0.144*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0399 (8)	0.0366 (9)	0.0199 (8)	−0.0016 (6)	0.0001 (7)	0.0023 (6)
C2	0.0388 (9)	0.0315 (8)	0.0206 (9)	−0.0025 (6)	−0.0001 (6)	0.0014 (6)
C3	0.0365 (9)	0.052 (1)	0.026 (1)	0.0030 (7)	−0.0006 (7)	0.0054 (8)
C4	0.046 (1)	0.061 (1)	0.029 (1)	−0.0047 (8)	−0.0108 (8)	0.0074 (8)
C5	0.057 (1)	0.054 (1)	0.0265 (9)	0.0048 (9)	0.0112 (8)	0.0017 (9)
C6	0.0403 (9)	0.055 (1)	0.0264 (9)	0.0041 (7)	0.0016 (8)	0.0050 (8)
N1	0.061 (1)	0.0400 (8)	0.0182 (7)	−0.0066 (7)	−0.0008 (7)	0.0016 (6)
O1	0.0660 (8)	0.0462 (8)	0.0302 (7)	0.0141 (6)	−0.0118 (6)	0.0007 (6)
O2	0.0696 (9)	0.0689 (9)	0.0251 (6)	0.0289 (8)	−0.0033 (6)	−0.0068 (6)
OW1	0.100 (2)	0.192 (3)	0.064 (1)	−0.084 (2)	0.014 (1)	−0.026 (2)

Geometric parameters (Å, º)

C1—O2	1.240 (3)	C3—C4	1.525 (3)
C1—O1	1.248 (3)	C4—N1	1.483 (4)
C1—C2	1.534 (3)	C5—N1	1.493 (4)
C2—C3	1.519 (3)	C5—C6	1.514 (4)
C2—C6	1.530 (3)
O2—C1—O1	123.8 (2)	C2—C3—C4	111.0 (2)
O2—C1—C2	119.2 (2)	N1—C4—C3	110.7 (2)
O1—C1—C2	116.9 (2)	N1—C5—C6	109.8 (2)
C3—C2—C6	110.0 (2)	C5—C6—C2	111.5 (2)
C3—C2—C1	113.8 (2)	C4—N1—C5	111.9 (2)
C6—C2—C1	110.0 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1^i	0.89 (4)	1.86 (4)	2.744 (3)	175 (4)
N1—H1B···O2^ii	0.94 (4)	1.85 (4)	2.776 (3)	169 (3)
OW1—H1W···O2^iii	0.87 (8)	1.97 (7)	2.752 (4)	149 (8)
OW1—H2W···O1^ii	0.85 (7)	2.06 (6)	2.862 (4)	157 (7)

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