Pyrimethaminium nicotinate mono­hydrate

In the title compound, C₁₂H₁₄ClN₄⁺·C₆H₄NO₂⁻·H₂O, the pyrimethamine mol­ecule is protonated at one of the pyrimidine N atoms. The protonated N atom and 2-amino group of the cation inter­act with an adjacent nicotinate anion through a pair of N—H...O hydrogen bonds [graph set R₂²(8)]. The cation, anion and water mol­ecule form a hydrogen-bonded ring motif with graph-set notation R₄²(8). The crystal structure is further stabilized by N—H...O and O—H...O hydrogen bonds and π–π inter­actions [centroid–centroid distance = 3.637 (6) Å].

Key indicators

• Single-crystal X-ray study
• T = 120 K
• Mean [sigma](C-C) = 0.018 Å
• R factor = 0.056
• wR factor = 0.056
• Data-to-parameter ratio = 7.4

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT026_ALERT_3_B Ratio Observed / Unique Reflections too Low ....         34 Perc.
PLAT340_ALERT_3_B Low Bond Precision on C-C Bonds (x 1000) Ang ...         18

Alert level C
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical .          ?
PLAT089_ALERT_3_C Poor Data / Parameter Ratio (Zmax .LT. 18) .....       7.38
PLAT152_ALERT_1_C Supplied and Calc Volume s.u. Inconsistent .....          ?
PLAT244_ALERT_4_C Low   'Solvent' Ueq as Compared to Neighbors for        C16
PLAT369_ALERT_2_C Long   C(sp2)-C(sp2) Bond  C16    -   C20    ...       1.53 Ang.

Alert level G
REFLT03_ALERT_4_G  WARNING: Large fraction of Friedel related reflns may
                     be needed to determine absolute structure
           From the CIF: _diffrn_reflns_theta_max           25.00
           From the CIF: _reflns_number_total               1807
           Count of symmetry unique reflns         1809
           Completeness (_total/calc)             99.89%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present        yes
PLAT860_ALERT_3_G Note: Number of Least-Squares Restraints .......          4

   0 ALERT level A = In general: serious problem
   2 ALERT level B = Potentially serious problem
   5 ALERT level C = Check and explain
   2 ALERT level G = General alerts; check

   2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   4 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Pyrimethamine [2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine] is an antifolate drug used in anti-malarial chemotherapy (Olliaro, 2001). The crystal structure of pyrimethamine (PMN) has been reported from our laboratory (Sethuraman & Muthiah, 2002) as have the structures of various protonated PMN salts (e.g. Devi et al., 2007). As part of these ongoing studies, the synthesis and structure of the title compound, (I), is now described.

The asymmetric unit of (I) contains a protonated pyrimethaminium (PMN) cation, nicotinate anion and a water molecule (Fig. 1). The PMN is protonated at N1 as it is evident from the enhancement of the C—N—C from 116.3 (2)° in neutral PMN molecule A and 116.09 (18)° in molecule B (Sethuraman & Muthiah, 2002) to 119.9 (10)° in (I). The dihedral angle between the 2,4-diamino pyrimidine and p-chlorophenyl rings is 70.3 (6)°. The torsion angle C5—C6—C7—C8, which represents the deviation of the ethyl group from the pyrimidine ring is 77.6 (16)°. The values are close to the results of modeling studies of DHFR-PMN complexes (Sansom et al., 1989). The C5—C9 bond length connecting the pyrimidine and phenyl ring in (I) is 1.472 (2) Å, in agreement with related structutres (De et al., 1989). The protonated N1 cation interacts with the carboxylate group of the nicotinate ion via N—H···O hydrogen bonds forming cyclic hydrogen bonded ring motif represented by graph-set notation R₂²(8) (Bernstein et al., 1995). The oxygen atom of the nicotinate anion bridges the 2-amino, 4-amino group of the PMN cation and water molecule forming a hydrogen bonded ring motif with graph-set notation R₄²(8). The frequently occurring R₂²(8) motif and R₄²(8) motif combine to form another motif, namely a DDA array (Fig. 2). Furthermore, the nicotinate anion and water molecule form a one dimensional supramolecular chain involving N—H···O and O—H···N hydrogen bonds (Fig. 3). π-π interactions between the aromatic rings are observed. The pyrimidine ring of PMN stacks with the nicotinate ring with a perpendicular separation of 3.551 Å, centroid-to-centroid distance of 3.637 (6) Å and a slip angle (the angle between the centroid-to-centroid vector and the normal to the plane) 19.05°.

Related literature

For related literature, see: Bernstein et al. (1995); De et al. (1989); Devi et al. (2007); Olliaro (2001); Sansom et al. (1989); Sethuraman & Muthiah (2002).

S2. Experimental

Hot methanolic solutions of pyrimethamine (62 mg) and nicotinic acid (31 mg) were mixed in a 1:1 ratio. The resultant mixture was warmed over a water bath for 15 minutes and kept at room temperature for crystallization. After a few days colourless blocks of (I) were obtained.

S3. Refinement

The C– and N-bound hydrogen atoms were fixed geometrically (C—H = 0.93–0.96 Å, N—H = 0.86 Å) and refined as riding with U_iso(H) = 1.2U_eq(carrier). The water hydrogen atoms were located from a difference map and were refined with isotropic thermal parameters.

Computing details

Data collection: PW1100 Software (Philips, 1978); cell refinement: PW1100 Software (Philips, 1978); data reduction: PW1100 Software (Philips, 1978); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: PLATON (Spek, 2003).

Figures

	Fig. 1. View of the molecular structure of (I) with 10% probability displacement ellipsoids for the non-hydrogen atoms.
	Fig. 2. A view of the hydrogen bonding network in (I). Symmetry code: (i) -x + 1, y + 1/2, -z + 1.
	Fig. 3. One dimensional chain in (I) observed between the water molecules and nicotinate ion. Symmetry code: (ii) x - 1, y, z.

Pyrimethaminium nicotinate monohydrate

Crystal data

C12H14ClN4^+·C6H4NO2^−·H2O	F(000) = 408
Mr = 389.84	Dx = 1.312 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71069 Å
Hall symbol: P 2yb	Cell parameters from 25 reflections
a = 6.570 (2) Å	θ = 3.1–25.0°
b = 16.055 (3) Å	µ = 0.22 mm^−1
c = 9.480 (2) Å	T = 120 K
β = 99.19 (3)°	Block, colourless
V = 987.1 (6) Å^3	0.23 × 0.20 × 0.18 mm
Z = 2

Data collection

Philips PW1100 diffractometer	617 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.059
Graphite monochromator	θmax = 25.0°, θmin = 3.1°
ω scans	h = −7→7
Absorption correction: ψ scan (North et al., 1968)	k = 0→19
Tmin = 0.951, Tmax = 0.961	l = 0→11
1909 measured reflections	1 standard reflections every 100 reflections
1807 independent reflections	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difmap and geom
R[F^2 > 2σ(F^2)] = 0.056	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.056	w = 1/[σ^2(Fo^2) + (0.0004P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.85	(Δ/σ)max < 0.001
1807 reflections	Δρmax = 0.20 e Å^−3
245 parameters	Δρmin = −0.25 e Å^−3
4 restraints	Absolute structure: Flack (1983), no Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.12 (14)

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All e.s.d.'s are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

Refinement. Refinement on F² for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The observed criterion of F² > σ(F²) is used only for calculating -R-factor-obs 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
Cl1	1.3820 (6)	1.1235 (3)	1.0788 (4)	0.0826 (17)
N1	0.8723 (16)	0.7185 (6)	0.6563 (11)	0.045 (4)
N2	0.5768 (16)	0.6658 (6)	0.5248 (12)	0.068 (5)
N3	0.5978 (15)	0.8085 (6)	0.5670 (11)	0.048 (4)
N4	0.6373 (14)	0.9479 (6)	0.5999 (10)	0.043 (4)
C2	0.680 (2)	0.7323 (8)	0.5826 (14)	0.046 (5)
C4	0.7123 (18)	0.8716 (7)	0.6251 (12)	0.034 (5)
C5	0.9066 (17)	0.8607 (7)	0.7163 (12)	0.033 (4)
C6	0.9795 (18)	0.7822 (8)	0.7277 (12)	0.039 (5)
C7	1.181 (2)	0.7542 (8)	0.8174 (13)	0.059 (5)
C8	1.160 (2)	0.7484 (10)	0.9758 (14)	0.080 (6)
C9	1.0165 (17)	0.9297 (7)	0.7977 (13)	0.036 (4)
C10	1.2012 (18)	0.9616 (7)	0.7664 (13)	0.044 (5)
C11	1.309 (2)	1.0223 (8)	0.8517 (15)	0.058 (6)
C12	1.232 (2)	1.0511 (8)	0.9668 (16)	0.051 (5)
C13	1.052 (2)	1.0240 (8)	0.9967 (14)	0.055 (6)
C14	0.944 (2)	0.9633 (7)	0.9141 (13)	0.048 (5)
O1	0.7388 (16)	0.4955 (5)	0.5855 (10)	0.064 (4)
O2	1.0354 (14)	0.5657 (6)	0.6448 (10)	0.062 (4)
N5	1.042 (2)	0.2718 (7)	0.6972 (13)	0.069 (5)
C15	0.949 (2)	0.3422 (8)	0.6563 (14)	0.050 (5)
C16	1.0447 (18)	0.4212 (8)	0.6779 (11)	0.033 (4)
C17	1.252 (2)	0.4217 (9)	0.7387 (12)	0.051 (5)
C18	1.346 (2)	0.3473 (11)	0.7809 (14)	0.067 (6)
C19	1.235 (3)	0.2749 (9)	0.7587 (17)	0.071 (7)
C20	0.925 (2)	0.5006 (9)	0.6307 (14)	0.052 (6)
O1W	0.1720 (14)	0.6202 (7)	0.3881 (12)	0.068 (4)
H1	0.92590	0.66960	0.65760	0.0540*
H2A	0.45520	0.67150	0.47650	0.0810*
H2B	0.63200	0.61720	0.53600	0.0810*
H4A	0.51890	0.95490	0.54770	0.0510*
H4B	0.70710	0.99030	0.63570	0.0510*
H7A	1.28910	0.79350	0.80580	0.0710*
H7B	1.21960	0.70030	0.78420	0.0710*
H8A	1.05210	0.71010	0.98730	0.1190*
H8B	1.12810	0.80240	1.00990	0.1190*
H8C	1.28800	0.72920	1.02950	0.1190*
H10	1.25300	0.94190	0.68690	0.0520*
H11	1.43330	1.04290	0.83030	0.0690*
H13	0.99860	1.04630	1.07380	0.0660*
H14	0.81950	0.94450	0.93710	0.0570*
H15	0.81240	0.34010	0.61080	0.0600*
H17	1.32490	0.47140	0.75080	0.0620*
H18	1.48340	0.34620	0.82400	0.0810*
H19	1.30090	0.22520	0.78890	0.0850*
H11W	0.116 (17)	0.672 (5)	0.346 (13)	0.08 (5)*
H12W	0.086 (15)	0.604 (7)	0.456 (10)	0.09 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.086 (3)	0.073 (3)	0.080 (3)	−0.026 (3)	−0.014 (2)	−0.018 (3)
N1	0.052 (7)	0.025 (6)	0.053 (7)	0.011 (6)	−0.004 (6)	−0.003 (6)
N2	0.059 (8)	0.034 (7)	0.098 (10)	0.000 (6)	−0.024 (7)	−0.004 (7)
N3	0.049 (7)	0.031 (7)	0.061 (7)	−0.004 (6)	−0.002 (6)	0.002 (6)
N4	0.034 (6)	0.036 (6)	0.053 (7)	0.002 (5)	−0.008 (5)	−0.001 (5)
C2	0.056 (10)	0.032 (8)	0.047 (8)	−0.007 (7)	−0.005 (7)	0.008 (7)
C4	0.041 (8)	0.030 (8)	0.034 (8)	0.002 (6)	0.014 (6)	0.011 (6)
C5	0.035 (7)	0.019 (7)	0.044 (8)	−0.008 (6)	0.003 (6)	0.008 (6)
C6	0.041 (8)	0.043 (8)	0.033 (8)	−0.003 (7)	0.003 (6)	0.008 (7)
C7	0.069 (10)	0.053 (9)	0.051 (9)	0.002 (8)	−0.004 (7)	−0.001 (8)
C8	0.080 (11)	0.082 (11)	0.063 (10)	0.017 (9)	−0.031 (8)	−0.009 (9)
C9	0.030 (7)	0.033 (7)	0.043 (8)	0.004 (6)	0.003 (6)	0.009 (7)
C10	0.040 (8)	0.038 (8)	0.056 (9)	−0.003 (6)	0.017 (7)	−0.014 (7)
C11	0.043 (9)	0.058 (10)	0.077 (11)	−0.034 (7)	0.024 (8)	−0.018 (9)
C12	0.036 (9)	0.053 (9)	0.058 (10)	0.004 (7)	−0.013 (7)	−0.013 (8)
C13	0.059 (11)	0.066 (10)	0.038 (8)	0.008 (8)	0.006 (8)	−0.001 (8)
C14	0.059 (9)	0.037 (8)	0.050 (9)	−0.015 (7)	0.017 (7)	−0.009 (7)
O1	0.062 (7)	0.039 (6)	0.084 (7)	0.004 (5)	−0.011 (5)	−0.004 (6)
O2	0.061 (7)	0.036 (5)	0.083 (8)	−0.007 (5)	−0.004 (5)	−0.003 (6)
N5	0.082 (10)	0.048 (9)	0.073 (9)	−0.009 (8)	0.003 (7)	−0.002 (7)
C15	0.066 (9)	0.022 (7)	0.063 (9)	0.006 (7)	0.010 (7)	0.007 (8)
C16	0.044 (8)	0.031 (7)	0.027 (6)	0.006 (7)	0.017 (6)	0.006 (6)
C17	0.049 (9)	0.046 (9)	0.055 (9)	−0.003 (8)	−0.005 (7)	−0.001 (8)
C18	0.052 (9)	0.075 (11)	0.069 (10)	0.027 (10)	−0.005 (7)	−0.001 (10)
C19	0.104 (15)	0.036 (9)	0.076 (12)	0.010 (10)	0.025 (11)	0.007 (9)
C20	0.060 (11)	0.049 (9)	0.044 (9)	0.008 (9)	−0.004 (8)	−0.004 (8)
O1W	0.056 (6)	0.044 (6)	0.104 (9)	−0.005 (6)	0.013 (6)	0.000 (7)

Geometric parameters (Å, º)

Cl1—C12	1.765 (14)	C9—C14	1.380 (17)
O1—C20	1.233 (17)	C10—C11	1.386 (18)
O2—C20	1.267 (17)	C11—C12	1.36 (2)
O1W—H11W	0.97 (9)	C12—C13	1.332 (19)
O1W—H12W	0.96 (10)	C13—C14	1.374 (18)
N1—C6	1.359 (16)	C7—H7A	0.9693
N1—C2	1.361 (17)	C7—H7B	0.9684
N2—C2	1.335 (16)	C8—H8A	0.9577
N3—C4	1.328 (15)	C8—H8B	0.9601
N3—C2	1.336 (16)	C8—H8C	0.9616
N4—C4	1.328 (15)	C10—H10	0.9305
N1—H1	0.8597	C11—H11	0.9329
N2—H2B	0.8598	C13—H13	0.9313
N2—H2A	0.8599	C14—H14	0.9299
N4—H4A	0.8600	C15—C16	1.416 (18)
N4—H4B	0.8597	C16—C17	1.392 (17)
N5—C15	1.314 (17)	C16—C20	1.527 (19)
N5—C19	1.31 (2)	C17—C18	1.37 (2)
C4—C5	1.434 (16)	C18—C19	1.37 (2)
C5—C9	1.472 (16)	C15—H15	0.9322
C5—C6	1.346 (17)	C17—H17	0.9283
C6—C7	1.523 (18)	C18—H18	0.9297
C7—C8	1.533 (18)	C19—H19	0.9309
C9—C10	1.392 (16)
H11W—O1W—H12W	106 (10)	C8—C7—H7B	109.47
C2—N1—C6	119.9 (10)	C6—C7—H7B	109.38
C2—N3—C4	117.4 (11)	H7A—C7—H7B	108.07
C2—N1—H1	120.04	C6—C7—H7A	109.39
C6—N1—H1	120.09	C7—C8—H8B	109.49
C2—N2—H2A	120.09	H8A—C8—H8B	109.64
C2—N2—H2B	119.91	H8A—C8—H8C	109.55
H2A—N2—H2B	120.00	H8B—C8—H8C	109.31
H4A—N4—H4B	120.00	C7—C8—H8A	109.55
C4—N4—H4B	120.02	C7—C8—H8C	109.28
C4—N4—H4A	119.98	C9—C10—H10	119.45
C15—N5—C19	118.1 (12)	C11—C10—H10	119.50
N2—C2—N3	121.1 (12)	C12—C11—H11	120.42
N1—C2—N3	122.1 (11)	C10—C11—H11	120.38
N1—C2—N2	116.7 (11)	C12—C13—H13	119.99
N3—C4—N4	117.4 (10)	C14—C13—H13	119.66
N4—C4—C5	119.4 (10)	C13—C14—H14	119.34
N3—C4—C5	123.2 (10)	C9—C14—H14	119.32
C4—C5—C9	122.6 (10)	N5—C15—C16	123.6 (12)
C4—C5—C6	115.7 (10)	C15—C16—C17	116.6 (12)
C6—C5—C9	121.6 (10)	C15—C16—C20	120.6 (11)
N1—C6—C7	113.0 (11)	C17—C16—C20	122.7 (12)
C5—C6—C7	126.0 (11)	C16—C17—C18	118.7 (13)
N1—C6—C5	121.0 (11)	C17—C18—C19	119.3 (13)
C6—C7—C8	111.0 (10)	N5—C19—C18	123.7 (14)
C5—C9—C14	120.7 (10)	O1—C20—O2	127.7 (13)
C5—C9—C10	122.4 (11)	O2—C20—C16	113.5 (11)
C10—C9—C14	116.8 (11)	O1—C20—C16	118.9 (12)
C9—C10—C11	121.0 (11)	N5—C15—H15	118.26
C10—C11—C12	119.2 (12)	C16—C15—H15	118.15
Cl1—C12—C11	117.7 (10)	C18—C17—H17	120.80
C11—C12—C13	121.2 (13)	C16—C17—H17	120.51
Cl1—C12—C13	121.1 (11)	C17—C18—H18	120.27
C12—C13—C14	120.4 (13)	C19—C18—H18	120.46
C9—C14—C13	121.3 (12)	N5—C19—H19	118.31
C8—C7—H7A	109.45	C18—C19—H19	118.02
C6—N1—C2—N2	−174.7 (11)	N1—C6—C7—C8	−102.2 (13)
C6—N1—C2—N3	6.0 (19)	C5—C6—C7—C8	77.6 (16)
C2—N1—C6—C5	−6.1 (17)	C5—C9—C14—C13	175.7 (11)
C2—N1—C6—C7	173.7 (11)	C5—C9—C10—C11	−175.1 (11)
C4—N3—C2—N1	0.8 (18)	C10—C9—C14—C13	−1.4 (18)
C2—N3—C4—C5	−7.5 (17)	C14—C9—C10—C11	2.0 (18)
C2—N3—C4—N4	174.7 (11)	C9—C10—C11—C12	−0.4 (19)
C4—N3—C2—N2	−178.5 (11)	C10—C11—C12—Cl1	176.1 (10)
C15—N5—C19—C18	−1 (2)	C10—C11—C12—C13	−2 (2)
C19—N5—C15—C16	−1 (2)	C11—C12—C13—C14	3 (2)
N3—C4—C5—C6	7.2 (17)	Cl1—C12—C13—C14	−175.4 (10)
N4—C4—C5—C9	7.5 (17)	C12—C13—C14—C9	−1 (2)
N3—C4—C5—C9	−170.2 (11)	N5—C15—C16—C20	−178.5 (12)
N4—C4—C5—C6	−175.1 (11)	N5—C15—C16—C17	3.8 (18)
C4—C5—C9—C10	−111.4 (13)	C15—C16—C17—C18	−3.7 (17)
C4—C5—C9—C14	71.6 (16)	C15—C16—C20—O2	−173.8 (11)
C9—C5—C6—C7	−2.4 (19)	C17—C16—C20—O1	−175.8 (11)
C6—C5—C9—C10	71.3 (16)	C17—C16—C20—O2	3.8 (17)
C6—C5—C9—C14	−105.7 (14)	C20—C16—C17—C18	178.6 (11)
C4—C5—C6—C7	−179.9 (11)	C15—C16—C20—O1	6.6 (18)
C9—C5—C6—N1	177.3 (11)	C16—C17—C18—C19	1.7 (19)
C4—C5—C6—N1	−0.1 (17)	C17—C18—C19—N5	1 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2	0.86	1.83	2.686 (14)	175
N2—H2A···O1W	0.86	2.08	2.861 (15)	150
N2—H2B···O1	0.86	2.10	2.957 (13)	172
N4—H4A···O1^i	0.86	2.05	2.897 (14)	168
N4—H4B···O1W^i	0.86	2.26	3.031 (15)	150
O1W—H11W···N5^i	0.97 (9)	1.92 (9)	2.862 (16)	164 (10)
O1W—H12W···O2^ii	0.96 (10)	1.97 (10)	2.862 (14)	154 (9)

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