Tautomeric polymorphism of the neuroactive inhibitor kynurenic acid

Kynurenic acid (KYN; systematic name: 4-hy­droxy­quinoline-2-carb­oxy­lic acid, C₁₀H₇NO₃) displays a therapeutic effect in the treatment of some neurological diseases and is used as a broad-spectrum neuroprotective agent. However, it is understudied with respect to its solid-state chemistry and only one crystal form (α-KYN·H₂O) has been reported up to now. Therefore, an attempt to synthesize alternative solid-state forms of KYN was undertaken and six new species were obtained: five solvates and one salt. One of them is a new polymorph, β-KYN·H₂O, of the already known KYN monohydrate. All crystal species were further studied by single-crystal and powder X-ray diffraction, thermal and spectroscopic methods. In addition to the above methods, differential scanning calorimetry (DSC), in-situ variable-temperature powder X-ray diffraction and Raman microscopy were applied to characterize the phase behaviour of the new forms. All the compounds display a zwitterionic form of KYN and two different enol–keto tautomers are observed depending on the crystallization solvent used.

Computing details

Data collection: CrysAlis CCD 1.171.38.41 (Rigaku Oxford Diffraction, 2015) for ortho_a; CrysAlis CCD (Rigaku OD, 2015) for kyn_100. Cell refinement: CrysAlis RED 1.171.38.41 (Rigaku Oxford Diffraction, 2015) for ortho_a; CrysAlis RED (Rigaku OD, 2015) for kyn_100. Data reduction: CrysAlis RED 1.171.38.41 (Rigaku Oxford Diffraction, 2015) for ortho_a; CrysAlis RED (Rigaku OD, 2015) for kyn_100. Program(s) used to solve structure: SHELXT (Sheldrick, 2014) for ortho_a; SHELXT (Sheldrick, 2015a) for kyn_100. Program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2014) for ortho_a; SHELXL2014 (Sheldrick, 2015b) for kyn_100. Molecular graphics: Brandenburg & Putz (2006). Diamond 3.0. Crystal and Molecular Structure Visualisation, University of Bonn, Germany for ortho_a; DIAMOND (Brandenburg, 2005) for kyn_100. Software used to prepare material for publication: SHELXL2014/7 (Sheldrick, 2014) for ortho_a; SHELXL2014 (Sheldrick, 2015b) for kyn_100.

(ortho_a)

Crystal data

C10H7NO3·H2O	Dx = 1.553 Mg m^−3
Mr = 207.18	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pccn	Cell parameters from 1562 reflections
a = 13.9295 (7) Å	θ = 2.3–27.0°
b = 17.8065 (9) Å	µ = 0.12 mm^−1
c = 7.1429 (4) Å	T = 100 K
V = 1771.69 (16) Å^3	Parallelepiped, colourless
Z = 8	0.28 × 0.26 × 0.23 mm
F(000) = 864

Data collection

KUMA KM-4 with CCD detector diffractometer	2447 independent reflections
Radiation source: fine-focus sealed X-ray tube	2260 reflections with I > 2σ(I)
Detector resolution: 10.6249 pixels mm^-1	Rint = 0.020
ω–scan	θmax = 30.5°, θmin = 2.3°
Absorption correction: multi-scan CrysAlisPro 1.171.38.43 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	h = −19→19
Tmin = 0.984, Tmax = 1.000	k = −23→23
32133 measured reflections	l = −10→10

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.030	Only H-atom coordinates refined
wR(F^2) = 0.080	w = 1/[σ^2(Fo^2) + (0.0444P)^2 + 0.7162P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max < 0.001
2447 reflections	Δρmax = 0.38 e Å^−3
164 parameters	Δρmin = −0.19 e Å^−3
0 restraints	Extinction correction: SHELXL-2014/7 (Sheldrick 2014, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.017 (2)

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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
N1	0.60814 (5)	0.25460 (4)	0.26030 (10)	0.00951 (15)
H1N	0.6586 (9)	0.2352 (6)	0.2109 (16)	0.011*
C2	0.60012 (5)	0.32951 (4)	0.26966 (11)	0.00928 (16)
C3	0.51748 (5)	0.36310 (4)	0.33814 (11)	0.01005 (16)
H3	0.5129 (8)	0.4163 (6)	0.3451 (16)	0.012*
C4	0.44019 (5)	0.31826 (4)	0.39471 (11)	0.01007 (16)
C5	0.44945 (5)	0.23815 (4)	0.38734 (11)	0.00983 (16)
C6	0.37499 (6)	0.18888 (5)	0.44390 (12)	0.01269 (17)
H6	0.3171 (9)	0.2091 (6)	0.4936 (17)	0.015*
C7	0.38693 (6)	0.11256 (5)	0.42899 (12)	0.01416 (17)
H7	0.3375 (9)	0.0784 (6)	0.4657 (17)	0.017*
C8	0.47348 (6)	0.08246 (4)	0.35792 (12)	0.01295 (17)
H8	0.4794 (8)	0.0285 (7)	0.3493 (16)	0.016*
C9	0.54791 (6)	0.12872 (4)	0.30432 (11)	0.01149 (16)
H9	0.6068 (8)	0.1103 (7)	0.2529 (16)	0.014*
C10	0.53604 (5)	0.20721 (4)	0.31834 (11)	0.00954 (16)
C1	0.68546 (5)	0.37417 (4)	0.19377 (11)	0.00994 (16)
O1	0.68350 (4)	0.44422 (3)	0.21907 (8)	0.01315 (14)
O2	0.74812 (4)	0.33700 (3)	0.11000 (9)	0.01250 (14)
O3	0.35788 (4)	0.34571 (3)	0.45420 (9)	0.01335 (14)
H3O	0.3536 (9)	0.3973 (7)	0.4459 (17)	0.020*
O4	0.34159 (4)	0.48782 (3)	0.44271 (10)	0.01426 (14)
H4A	0.3408 (9)	0.5088 (7)	0.5521 (19)	0.021*
H4B	0.2921 (9)	0.5062 (7)	0.3845 (18)	0.021*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0083 (3)	0.0083 (3)	0.0120 (3)	0.0006 (2)	0.0004 (2)	0.0001 (2)
C2	0.0087 (3)	0.0089 (3)	0.0102 (3)	−0.0005 (3)	−0.0010 (3)	0.0004 (3)
C3	0.0098 (3)	0.0078 (3)	0.0125 (3)	0.0002 (3)	−0.0002 (3)	0.0001 (3)
C4	0.0088 (3)	0.0110 (4)	0.0105 (3)	0.0006 (3)	−0.0005 (3)	−0.0004 (3)
C5	0.0091 (3)	0.0096 (4)	0.0109 (3)	−0.0004 (2)	−0.0014 (3)	−0.0001 (3)
C6	0.0097 (3)	0.0126 (4)	0.0157 (4)	−0.0011 (3)	−0.0001 (3)	0.0004 (3)
C7	0.0128 (4)	0.0124 (4)	0.0173 (4)	−0.0040 (3)	−0.0008 (3)	0.0012 (3)
C8	0.0160 (4)	0.0079 (4)	0.0150 (4)	−0.0009 (3)	−0.0020 (3)	−0.0005 (3)
C9	0.0125 (3)	0.0095 (4)	0.0125 (3)	0.0008 (3)	−0.0009 (3)	−0.0006 (3)
C10	0.0095 (3)	0.0093 (4)	0.0098 (3)	−0.0008 (3)	−0.0012 (3)	0.0003 (3)
C1	0.0085 (3)	0.0102 (4)	0.0111 (3)	−0.0002 (2)	−0.0011 (3)	0.0021 (3)
O1	0.0136 (3)	0.0081 (3)	0.0178 (3)	−0.0009 (2)	0.0020 (2)	0.0004 (2)
O2	0.0100 (3)	0.0113 (3)	0.0163 (3)	0.0018 (2)	0.0021 (2)	0.0016 (2)
O3	0.0088 (3)	0.0100 (3)	0.0213 (3)	0.00129 (19)	0.0032 (2)	−0.0005 (2)
O4	0.0138 (3)	0.0102 (3)	0.0188 (3)	0.0023 (2)	−0.0013 (2)	−0.0011 (2)

Geometric parameters (Å, º)

N1—C2	1.3402 (10)	C6—H6	0.953 (12)
N1—C10	1.3758 (10)	C7—C8	1.4137 (12)
N1—H1N	0.860 (12)	C7—H7	0.956 (12)
C2—C3	1.3865 (10)	C8—C9	1.3784 (11)
C2—C1	1.5295 (10)	C8—H8	0.966 (12)
C3—C4	1.4000 (10)	C9—C10	1.4108 (11)
C3—H3	0.950 (11)	C9—H9	0.957 (12)
C4—O3	1.3169 (9)	C1—O2	1.2481 (10)
C4—C5	1.4333 (10)	C1—O1	1.2607 (10)
C5—C10	1.4146 (10)	O3—H3O	0.922 (13)
C5—C6	1.4172 (11)	O4—H4A	0.866 (14)
C6—C7	1.3732 (11)	O4—H4B	0.869 (13)
C2—N1—C10	122.32 (7)	C6—C7—C8	120.41 (7)
C2—N1—H1N	119.3 (7)	C6—C7—H7	121.5 (7)
C10—N1—H1N	118.3 (7)	C8—C7—H7	118.1 (7)
N1—C2—C3	121.08 (7)	C9—C8—C7	120.97 (7)
N1—C2—C1	115.78 (7)	C9—C8—H8	120.8 (7)
C3—C2—C1	123.10 (7)	C7—C8—H8	118.2 (7)
C2—C3—C4	119.62 (7)	C8—C9—C10	118.95 (7)
C2—C3—H3	120.3 (7)	C8—C9—H9	123.1 (7)
C4—C3—H3	120.1 (7)	C10—C9—H9	117.9 (7)
O3—C4—C3	123.43 (7)	N1—C10—C9	120.04 (7)
O3—C4—C5	117.36 (7)	N1—C10—C5	119.24 (7)
C3—C4—C5	119.21 (7)	C9—C10—C5	120.70 (7)
C10—C5—C6	118.83 (7)	O2—C1—O1	127.49 (7)
C10—C5—C4	118.50 (7)	O2—C1—C2	115.96 (7)
C6—C5—C4	122.67 (7)	O1—C1—C2	116.53 (7)
C7—C6—C5	120.12 (7)	C4—O3—H3O	113.9 (8)
C7—C6—H6	120.4 (7)	H4A—O4—H4B	105.0 (11)
C5—C6—H6	119.5 (7)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O2^i	0.860 (12)	1.964 (12)	2.7968 (9)	162.7 (11)
O3—H3O···O4	0.922 (13)	1.621 (13)	2.5420 (8)	176.3 (12)
O4—H4A···O1^ii	0.866 (14)	1.867 (14)	2.7245 (9)	170.1 (12)
O4—H4B···O1^iii	0.869 (13)	1.901 (13)	2.7657 (8)	172.8 (12)

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

4-Hydroxyquinoline-2-carboxylic acid dimethyl sulfoxide monosolvate (kyn_100)

Crystal data

C10H7NO3·C2H6OS	Dx = 1.449 Mg m^−3
Mr = 267.29	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 4335 reflections
a = 4.9552 (3) Å	θ = 4.0–28.7°
b = 10.8444 (6) Å	µ = 0.27 mm^−1
c = 22.7982 (11) Å	T = 100 K
V = 1225.09 (12) Å^3	Parallelepiped, colourless
Z = 4	0.41 × 0.21 × 0.12 mm
F(000) = 560

Data collection

Kuma KM-4 with CCD detector diffractometer	3044 independent reflections
Radiation source: fine-focus sealed X-ray tube	2756 reflections with I > 2σ(I)
Detector resolution: 10.6249 pixels mm^-1	Rint = 0.043
ω–scan	θmax = 29.5°, θmin = 2.6°
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2015)	h = −6→6
Tmin = 0.923, Tmax = 1.000	k = −14→14
14513 measured reflections	l = −30→30

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.036	Only H-atom coordinates refined
wR(F^2) = 0.085	w = 1/[σ^2(Fo^2) + (0.0461P)^2 + 0.2943P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max = 0.001
3044 reflections	Δρmax = 0.28 e Å^−3
202 parameters	Δρmin = −0.25 e Å^−3
0 restraints	Absolute structure: Flack x determined using 999 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.11 (4)

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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
N1	0.4240 (4)	0.57092 (18)	0.64364 (8)	0.0134 (4)
H1N	0.400 (6)	0.497 (3)	0.6280 (11)	0.016*
C1	0.2551 (4)	0.6078 (2)	0.68693 (9)	0.0133 (5)
C2	0.2626 (4)	0.7243 (2)	0.70933 (10)	0.0142 (5)
H2	0.136 (6)	0.745 (2)	0.7379 (11)	0.017*
C3	0.4488 (5)	0.8131 (2)	0.68733 (10)	0.0143 (4)
C4	0.6293 (4)	0.7717 (2)	0.64121 (9)	0.0128 (4)
C5	0.6112 (4)	0.6500 (2)	0.62013 (10)	0.0129 (5)
C6	0.8211 (5)	0.8519 (2)	0.61598 (10)	0.0152 (4)
H6	0.833 (6)	0.931 (3)	0.6314 (11)	0.018*
C7	0.9875 (5)	0.8112 (2)	0.57177 (10)	0.0174 (5)
H7	1.122 (6)	0.867 (2)	0.5541 (11)	0.021*
C8	0.9707 (5)	0.6890 (2)	0.55168 (10)	0.0169 (5)
H8	1.090 (6)	0.662 (3)	0.5208 (12)	0.020*
C9	0.7862 (5)	0.6084 (2)	0.57544 (9)	0.0157 (5)
H9	0.776 (6)	0.521 (3)	0.5630 (12)	0.019*
C10	0.0594 (5)	0.5112 (2)	0.70766 (10)	0.0147 (5)
O1	0.0523 (3)	0.40961 (15)	0.68567 (7)	0.0198 (4)
O2	−0.0967 (3)	0.55173 (16)	0.74977 (7)	0.0189 (4)
H2O	−0.213 (7)	0.492 (3)	0.7623 (13)	0.028*
O3	0.4615 (3)	0.92330 (15)	0.70606 (8)	0.0192 (4)
S1	0.31948 (12)	0.24150 (5)	0.59155 (3)	0.01884 (15)
O4	0.4115 (4)	0.36511 (15)	0.56837 (7)	0.0225 (4)
C11	0.5227 (6)	0.2125 (3)	0.65437 (12)	0.0232 (5)
H11A	0.706 (7)	0.226 (3)	0.6453 (14)	0.035*
H11B	0.491 (7)	0.128 (3)	0.6659 (13)	0.035*
H11C	0.465 (6)	0.266 (3)	0.6838 (13)	0.035*
C12	0.4662 (8)	0.1296 (3)	0.54349 (13)	0.0317 (6)
H12A	0.374 (7)	0.140 (3)	0.5046 (15)	0.048*
H12B	0.435 (8)	0.049 (3)	0.5597 (15)	0.048*
H12C	0.657 (8)	0.144 (3)	0.5412 (15)	0.048*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0127 (9)	0.0113 (9)	0.0161 (9)	−0.0004 (7)	0.0006 (8)	−0.0021 (8)
C1	0.0090 (10)	0.0160 (11)	0.0147 (10)	0.0004 (8)	−0.0022 (8)	0.0025 (9)
C2	0.0114 (10)	0.0153 (11)	0.0159 (10)	0.0009 (8)	−0.0004 (8)	0.0019 (9)
C3	0.0116 (10)	0.0120 (11)	0.0192 (11)	0.0022 (9)	−0.0018 (9)	−0.0010 (9)
C4	0.0085 (9)	0.0157 (11)	0.0142 (10)	0.0014 (8)	−0.0009 (8)	0.0013 (8)
C5	0.0104 (10)	0.0139 (11)	0.0143 (10)	0.0010 (8)	−0.0011 (8)	0.0027 (8)
C6	0.0123 (10)	0.0150 (11)	0.0184 (11)	0.0016 (10)	−0.0022 (9)	0.0005 (9)
C7	0.0126 (10)	0.0219 (13)	0.0177 (11)	−0.0025 (9)	0.0007 (9)	0.0037 (9)
C8	0.0137 (10)	0.0236 (13)	0.0136 (11)	0.0012 (10)	0.0033 (9)	−0.0012 (9)
C9	0.0150 (10)	0.0146 (11)	0.0177 (11)	0.0008 (9)	−0.0003 (9)	−0.0023 (8)
C10	0.0129 (10)	0.0150 (11)	0.0162 (10)	0.0002 (9)	0.0011 (9)	0.0015 (9)
O1	0.0186 (8)	0.0151 (9)	0.0258 (8)	−0.0026 (7)	0.0046 (7)	−0.0015 (7)
O2	0.0164 (8)	0.0142 (9)	0.0262 (9)	−0.0015 (7)	0.0082 (7)	−0.0002 (7)
O3	0.0155 (8)	0.0123 (8)	0.0299 (9)	−0.0002 (7)	0.0066 (7)	−0.0051 (7)
S1	0.0185 (3)	0.0155 (3)	0.0225 (3)	−0.0032 (2)	−0.0012 (2)	−0.0010 (2)
O4	0.0328 (10)	0.0142 (9)	0.0206 (8)	−0.0021 (7)	0.0000 (8)	0.0000 (7)
C11	0.0239 (13)	0.0219 (14)	0.0238 (12)	−0.0004 (11)	0.0002 (11)	0.0023 (10)
C12	0.0491 (19)	0.0174 (14)	0.0285 (14)	−0.0008 (13)	0.0026 (14)	−0.0042 (11)

Geometric parameters (Å, º)

N1—C1	1.355 (3)	C8—C9	1.376 (3)
N1—C5	1.372 (3)	C8—H8	0.96 (3)
N1—H1N	0.88 (3)	C9—H9	0.99 (3)
C1—C2	1.363 (3)	C10—O1	1.210 (3)
C1—C10	1.504 (3)	C10—O2	1.309 (3)
C2—C3	1.425 (3)	O2—H2O	0.92 (3)
C2—H2	0.93 (3)	S1—O4	1.5112 (18)
C3—O3	1.270 (3)	S1—C11	1.779 (3)
C3—C4	1.452 (3)	S1—C12	1.789 (3)
C4—C5	1.408 (3)	C11—H11A	0.95 (3)
C4—C6	1.411 (3)	C11—H11B	0.97 (3)
C5—C9	1.412 (3)	C11—H11C	0.94 (3)
C6—C7	1.375 (3)	C12—H12A	1.00 (3)
C6—H6	0.93 (3)	C12—H12B	0.96 (4)
C7—C8	1.404 (3)	C12—H12C	0.96 (4)
C7—H7	0.99 (3)
C1—N1—C5	121.2 (2)	C9—C8—H8	120.1 (17)
C1—N1—H1N	118.7 (18)	C7—C8—H8	119.2 (17)
C5—N1—H1N	119.8 (17)	C8—C9—C5	119.3 (2)
N1—C1—C2	122.0 (2)	C8—C9—H9	121.9 (17)
N1—C1—C10	114.9 (2)	C5—C9—H9	118.7 (17)
C2—C1—C10	123.1 (2)	O1—C10—O2	126.3 (2)
C1—C2—C3	120.8 (2)	O1—C10—C1	121.5 (2)
C1—C2—H2	117.8 (17)	O2—C10—C1	112.15 (19)
C3—C2—H2	121.3 (17)	C10—O2—H2O	111.2 (19)
O3—C3—C2	123.3 (2)	O4—S1—C11	105.51 (12)
O3—C3—C4	120.2 (2)	O4—S1—C12	105.35 (14)
C2—C3—C4	116.4 (2)	C11—S1—C12	98.24 (15)
C5—C4—C6	118.8 (2)	S1—C11—H11A	109.9 (19)
C5—C4—C3	119.9 (2)	S1—C11—H11B	107.1 (18)
C6—C4—C3	121.3 (2)	H11A—C11—H11B	111 (3)
N1—C5—C4	119.7 (2)	S1—C11—H11C	107.1 (19)
N1—C5—C9	119.9 (2)	H11A—C11—H11C	111 (3)
C4—C5—C9	120.4 (2)	H11B—C11—H11C	110 (3)
C7—C6—C4	120.3 (2)	S1—C12—H12A	106 (2)
C7—C6—H6	122.4 (18)	S1—C12—H12B	108 (2)
C4—C6—H6	117.2 (17)	H12A—C12—H12B	112 (3)
C6—C7—C8	120.4 (2)	S1—C12—H12C	109 (2)
C6—C7—H7	120.3 (16)	H12A—C12—H12C	112 (3)
C8—C7—H7	119.2 (16)	H12B—C12—H12C	109 (3)
C9—C8—C7	120.7 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O4	0.88 (3)	1.97 (3)	2.816 (3)	159 (2)
O2—H2O···O3^i	0.92 (3)	1.61 (3)	2.494 (2)	162 (3)

Symmetry code: (i) −x, y−1/2, −z+3/2.