A case of concomitant polymorphism and spontaneous resolution: the tetra­gonal phase of 5-hydroxy­methyl-7,7,N-trimethyl-6-oxabicyclo­[3.2.1]octane-1-carboxamide

The title compound, C₁₂H₂₁NO₃, crystallizes in two polymorphic forms, viz. the tetra­gonal form described here and the monoclinic form described previously [Foces-Foces, López-Rodríguez, Pérez, Martín & Pérez-Hernández (2007). Cryst. Growth Des. 7, 905-911]. The differences in the conformations of the hydroxy­methyl and methylaminocarbonyl substituents have important consequences in the hydrogen-bond inter­action motifs and, therefore, in the packing arrangements. These forms are concomitant polymorphs with melting points differing by 3 K.

S1. Comment

The structures of ten 7,7-dialkyl-5-hydroxymethyl-6-oxabicyclo[3.2.1] octane-1-carboxylic acid amide derivatives, including the monoclinic polymorph (I), have been recently determined (Foces-Foces et al., 2007). All the reported compounds crystallized as racemates, and the conformations of the hydroxymethyl and N-alkylamide groups were found to be closely related to the type of hydrogen interactions in which they were involved. As part of our structural studies on the inclusion of water molecules into the hydrogen-bond pattern of condensed organic materials, new crystallization attempts of N-alkylamide derivatives in saturated aqueous solution of tetrachloride/n-hexane were undertaken. In the case of 7,7-dimethyl-5-hydroxymethyl-6-oxabicyclo [3.2.1]-1-carboxylic acid methylamide, crystals with different habits (plates and needles in a small quantity) were observed in the same batch suggesting the presence of concomitant polymorphs (Bernstein, 2002).

The plates of (I) belong to the centrosymmetric monoclinic P2₁/c group, while the needles crystallize in the noncentrosymmetric tetragonal P4₁ or the enantiomeric P4₃ space group. However, these crystals, which were separated manually, did not show optical activity, suggesting spontaneous resolution (50:50 mixture of pure enantiomers) of the racemic sample. Several new crystallization attempts were performed under similar conditions and only the monoclinic phase was obtained. This behaviour seems to be not uncommon and has been previously (Dunitz & Bernstein, 1995) and recently reported (Lennartsson et al., 2007). In the methylamide derivatives with ethyl as the alkyl group and with propyl instead of methyl substituents, crystals slightly different in shape appear in the same batch, but all of them were confirmed to belong to the form previously described.

Of the two possible enantiomeric space groups P4₁ or P4₃ for the tetragonal form (II), the former, consistent with the 1R,5R enantiomer (negative value for the C1—C2—C3—C4 torsion angle), was selected (Fig. 1) since the absolute structure cannot be determined reliably. In both polymorphic forms, the bicyclic core is rather rigid, and the features distinguishing the forms concern the conformations of the hydroxymethyl and methylamide substituents, which results in a different hydrogen-bonding patterns. In the monoclinic form, having Z' = 2, the hydroxyl group is disordered over two positions (A and B with occupancies of 2:1) adopting, for the same enantiomer (1R,5R), the -gauche/gauche conformations with respect to ether bridge [O1—C1—C2—O2A/B= -61.4 (3)/49.0 (4) and 63.3 (3)/-48.4 (4)° for the two independent molecules]. In the tetragonal form (Table 1 and Fig. 1) the +gauche/-gauche conformation is observed (1R,5R enantiomer), although with significant differences in the amide disposition [C4—C5—C7—O3= -53.2 (2) and 53.2 (2)° versus -68.6 (4)° in (I) and in (II), respectively].

The presence of the two concomitant polymorphs, with a donor/acceptor ratio of less than 1 for OH, –O– and –CONHCH₃ groups, can be attributed to the different hydrogen-bonding possibilities. In the reported N-alkylamide derivatives (Foces-Foces et al., 2007), the following three types of paired hydrogen interactions were related to the conformations of the hydroxy and methylamide substituents: (1) OH···O═C and NH···O_ether; (2) OH···O_ether and NH···O═C; and (3) OH···O═C and NH···OH. In the tetragonal form (II), the N—H···OH bond connects molecules along the fourfold screw axis into one-dimensional frameworks [C(8) graph-set notation (Bernstein et al., 1995); Fig. 2a and Table 2]. The hydroxy group acts as both donor to the carbonyl group and as acceptor of a hydrogen bond from the amide as in type 3, while the ether atom O1 is only involved in a C—H···O interaction (Table 2). These homochiral chains are then assembled along the a and b axes through OH···O═C and C—H···O_ether bonds into a three-dimensional network (Fig. 2b). However, in the monoclinic form (I), type 1 is observed and the amide group is hydrogen bonded to the ether bridge O1, forming heterochiral chains with a C(6) graph-set motif. Despite the disorder of the hydroxy group, the hydrogen-bonding pattern is not affected, since in each conformation the hydroxy group is hydrogen-bonded to the same carbonyl group. The combination of these interactions results in a two-dimensional network (Fig. 3). The differences in the crystal structures of the two polymorphs are reflected in the simulated powder diffraction spectra (Spek, 2003) shown in Fig. 4.

The proposed rule correlating the molecular conformation of the substituents and the pattern of strong hydrogen interactions in the racemic derivatives (Foces-Foces et al., 2007) is fulfilled by this polymorph. However, the presence of only one enantiomer in the structure drastically affects the crystal packing, since the dimer or synthon formed by centrosymmetrically related molecules, common to the most populated type 3, is absent.

Related literature

For related literature, see: Bernstein (2002); Bernstein et al. (1995); Dunitz & Bernstein (1995); Foces-Foces, López-Rodríguez, Pérez, Martín & Pérez-Hernández (2007); Lennartsson et al. (2007); Spek (2003).

S2. Experimental

The synthesis of the title compound has been recently reported (Foces-Foces et al., 2007) and crystals were obtained upon crystallization from a saturated aqueous solution of tetrachloride/n-hexane (50%). Crystals of the two morphologies were obtained in the same batch, viz. plates (monoclinic form with m.p. 451 K, previously reported) and needles in a small quantity (m.p. 454 K) corresponding to the present tetragonal form (II). The needles were separated manually and did no show optical activity in a chloroform solution (Perkin–Elmer 241). No structural phase transition was detected when cooling the sample from room temperature to 170 K.

S3. Refinement

Friedel pairs were merged during the final cycles of refinements due to the absence of significant anomalous dispersion effects. All H atoms were located in difference Fourier maps and subsequently allowed to refine as riding on their respective C, N and O atoms [C—H = 0.98 (CH₃) or 0.99 Å (CH₂), N—H = 0.88 Å and O—H = 0.84 Å, with U_iso(H) = 1.2U_eq(C,N) and 1.5U_eq(O) please check change].

Computing details

Data collection: Collect (Nonius, 2000); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: HKL DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: WinGX (Farrugia, 1999), PLATON (Spek, 2003) and Mercury (Macrae et al., 2006).

Figures

	Fig. 1. The molecular structure of (II), with 30% probability displacement ellipsoids.
	Fig. 2. (a) The homochiral C(8) chain, along the c axis, resulting from the linkage of the molecules via N—H···OH hydrogen bonds (dotted lines). (b) The three-dimensional hydrogen-bonded framework viewed down c and showing the OH···O═C hydrogen bonds responsible for connecting the chains. H atoms not involved in the N—H···OH or O—H···O═C hydrogen interactions have been omitted for clarity. [Symmetry codes: (i) x, y, z; (ii) -y + 1, x, z + 1/4; (iii) -x + 1, -y + 1, z + 1/2; (iv) y, -x + 1, z - 1/4; (v) x - 1, y, z; (vi) -y + 1, x - 1, z + 1/4.]
	Fig. 3. The two-dimensional structure in the monoclinic polymorph (I), formed by three heterochiral C(6) chains along the a axis (NH···Oether contacts) connected by OH···O═C bonds. Only the major component of the disorder of the hydroxyl group has been maintained. H atoms not involved in the hydrogen interactions have been omitted for clarity.
	Fig. 4. Simulated powder diffraction spectra: (I) monoclinic phase and (II) the present tetragonal phase.

5-Hydroxymethyl-7,7,N-trimethyl-6-oxabicyclo[3.2.1]octane-1-carboxamide

Crystal data

C12H21NO3	Dx = 1.263 Mg m^−3
Mr = 227.30	Melting point: 454 K
Tetragonal, P41	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 4w	Cell parameters from 2593 reflections
a = 8.2616 (18) Å	θ = 2.5–27.5°
c = 17.517 (4) Å	µ = 0.09 mm^−1
V = 1195.6 (4) Å^3	T = 170 K
Z = 4	Needle, colourless
F(000) = 496	0.60 × 0.12 × 0.12 mm

Data collection

Nonius KappaCCD area-detector diffractometer	1282 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.032
Horizontally mounted graphite crystal monochromator	θmax = 27.5°, θmin = 2.5°
Detector resolution: 9 pixels mm^-1	h = −10→10
ϕ and ω scans	k = −10→10
2593 measured reflections	l = −22→22
1412 independent reflections

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)] = 0.050	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.142	H-atom parameters constrained
S = 1.00	w = 1/[σ^2(Fo^2) + (0.0887P)^2 + 0.4581P] where P = (Fo^2 + 2Fc^2)/3
1412 reflections	(Δ/σ)max = 0.001
145 parameters	Δρmax = 0.38 e Å^−3
1 restraint	Δρmin = −0.33 e Å^−3

Special details

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.

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 > σ(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
O1	0.7498 (3)	0.4425 (3)	0.23964 (13)	0.0176 (5)
O2	0.4398 (3)	0.3520 (3)	0.30670 (14)	0.0218 (5)
H2	0.3544	0.3525	0.3327	0.033*
O3	1.1590 (3)	0.3494 (3)	0.39400 (14)	0.0261 (6)
N1	0.9553 (3)	0.3761 (4)	0.47812 (16)	0.0193 (6)
H1	0.8563	0.4113	0.4862	0.023*
C1	0.6639 (4)	0.5433 (4)	0.29450 (18)	0.0161 (6)
C2	0.7056 (4)	0.7204 (4)	0.2773 (2)	0.0254 (8)
H2A	0.6631	0.7907	0.3184	0.031*
H2B	0.6544	0.7535	0.2287	0.031*
C3	0.8901 (4)	0.7402 (4)	0.2715 (2)	0.0292 (8)
H3A	0.9174	0.8564	0.2764	0.035*
H3B	0.9259	0.7039	0.2203	0.035*
C4	0.9840 (5)	0.6441 (4)	0.3328 (2)	0.0240 (8)
H4A	1.0976	0.6313	0.3159	0.029*
H4B	0.9848	0.7073	0.3808	0.029*
C5	0.9122 (4)	0.4750 (4)	0.34908 (17)	0.0159 (6)
C6	0.7356 (4)	0.4968 (4)	0.37123 (18)	0.0161 (6)
H6A	0.6881	0.3951	0.3910	0.019*
H6B	0.7217	0.5839	0.4095	0.019*
C7	1.0197 (4)	0.3930 (4)	0.40864 (19)	0.0168 (6)
C8	0.4824 (4)	0.5144 (4)	0.28705 (19)	0.0201 (7)
H8A	0.4239	0.5904	0.3209	0.024*
H8B	0.4485	0.5366	0.2339	0.024*
C9	0.8925 (4)	0.3708 (4)	0.27517 (19)	0.0173 (6)
C10	1.0321 (4)	0.3769 (6)	0.2181 (2)	0.0302 (9)
H10A	1.1292	0.3301	0.2414	0.036*
H10B	1.0534	0.4896	0.2039	0.036*
H10C	1.0031	0.3149	0.1724	0.036*
C11	0.8543 (5)	0.1942 (4)	0.2934 (2)	0.0290 (8)
H11A	0.9485	0.1438	0.3178	0.035*
H11B	0.8287	0.1363	0.2461	0.035*
H11C	0.7614	0.1890	0.3281	0.035*
C12	1.0435 (4)	0.3013 (5)	0.5409 (2)	0.0254 (8)
H12A	0.9753	0.3004	0.5867	0.031*
H12B	1.1423	0.3633	0.5512	0.031*
H12C	1.0723	0.1900	0.5271	0.031*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0161 (11)	0.0202 (12)	0.0165 (10)	0.0035 (9)	−0.0008 (9)	−0.0037 (9)
O2	0.0149 (11)	0.0224 (12)	0.0281 (13)	−0.0019 (9)	0.0038 (9)	−0.0011 (10)
O3	0.0148 (12)	0.0369 (15)	0.0265 (13)	0.0042 (11)	0.0033 (9)	0.0023 (11)
N1	0.0132 (13)	0.0241 (15)	0.0207 (13)	0.0037 (11)	−0.0009 (11)	0.0028 (11)
C1	0.0159 (14)	0.0150 (14)	0.0175 (14)	0.0022 (12)	−0.0009 (12)	−0.0029 (11)
C2	0.0217 (17)	0.0172 (17)	0.037 (2)	0.0010 (13)	−0.0034 (15)	0.0027 (14)
C3	0.0245 (18)	0.0170 (17)	0.046 (2)	−0.0058 (14)	−0.0053 (17)	0.0104 (16)
C4	0.0216 (17)	0.0157 (16)	0.035 (2)	−0.0034 (14)	−0.0036 (14)	0.0019 (13)
C5	0.0148 (15)	0.0150 (15)	0.0178 (14)	−0.0003 (12)	−0.0017 (12)	−0.0008 (11)
C6	0.0135 (15)	0.0171 (15)	0.0177 (14)	0.0020 (12)	−0.0005 (11)	−0.0018 (12)
C7	0.0126 (14)	0.0178 (16)	0.0200 (15)	−0.0005 (12)	−0.0019 (12)	−0.0005 (13)
C8	0.0160 (16)	0.0205 (17)	0.0238 (16)	0.0029 (13)	−0.0027 (13)	−0.0019 (13)
C9	0.0137 (14)	0.0208 (16)	0.0173 (14)	0.0066 (12)	−0.0024 (12)	−0.0022 (12)
C10	0.0197 (18)	0.050 (2)	0.0212 (17)	0.0117 (16)	0.0045 (14)	−0.0047 (16)
C11	0.0318 (19)	0.0172 (17)	0.038 (2)	0.0059 (14)	−0.0094 (16)	−0.0069 (15)
C12	0.0242 (18)	0.0286 (19)	0.0235 (17)	0.0006 (15)	−0.0036 (13)	0.0075 (14)

Geometric parameters (Å, º)

O1—C1	1.456 (4)	C4—H4B	0.9900
O1—C9	1.459 (4)	C5—C6	1.520 (4)
O2—C8	1.429 (4)	C5—C7	1.529 (4)
O2—H2	0.8400	C5—C9	1.564 (4)
O3—C7	1.233 (4)	C6—H6A	0.9900
N1—C7	1.335 (4)	C6—H6B	0.9900
N1—C12	1.457 (4)	C8—H8A	0.9900
N1—H1	0.8800	C8—H8B	0.9900
C1—C6	1.518 (4)	C9—C11	1.527 (5)
C1—C8	1.524 (4)	C9—C10	1.527 (5)
C1—C2	1.533 (5)	C10—H10A	0.9800
C2—C3	1.537 (5)	C10—H10B	0.9800
C2—H2A	0.9900	C10—H10C	0.9800
C2—H2B	0.9900	C11—H11A	0.9800
C3—C4	1.544 (5)	C11—H11B	0.9800
C3—H3A	0.9900	C11—H11C	0.9800
C3—H3B	0.9900	C12—H12A	0.9800
C4—C5	1.544 (5)	C12—H12B	0.9800
C4—H4A	0.9900	C12—H12C	0.9800
C1—O1—C9	110.2 (2)	C5—C6—H6A	111.7
C8—O2—H2	109.5	C1—C6—H6B	111.7
C7—N1—C12	122.2 (3)	C5—C6—H6B	111.7
C7—N1—H1	118.9	H6A—C6—H6B	109.5
C12—N1—H1	118.9	O3—C7—N1	122.1 (3)
O1—C1—C6	104.5 (2)	O3—C7—C5	122.0 (3)
O1—C1—C8	109.5 (2)	N1—C7—C5	115.9 (3)
C6—C1—C8	114.8 (3)	O2—C8—C1	111.6 (3)
O1—C1—C2	107.8 (3)	O2—C8—H8A	109.3
C6—C1—C2	109.1 (3)	C1—C8—H8A	109.3
C8—C1—C2	110.7 (3)	O2—C8—H8B	109.3
C1—C2—C3	109.7 (3)	C1—C8—H8B	109.3
C1—C2—H2A	109.7	H8A—C8—H8B	108.0
C3—C2—H2A	109.7	O1—C9—C11	108.1 (3)
C1—C2—H2B	109.7	O1—C9—C10	108.5 (3)
C3—C2—H2B	109.7	C11—C9—C10	109.0 (3)
H2A—C2—H2B	108.2	O1—C9—C5	102.3 (2)
C2—C3—C4	113.4 (3)	C11—C9—C5	112.0 (3)
C2—C3—H3A	108.9	C10—C9—C5	116.4 (3)
C4—C3—H3A	108.9	C9—C10—H10A	109.5
C2—C3—H3B	108.9	C9—C10—H10B	109.5
C4—C3—H3B	108.9	H10A—C10—H10B	109.5
H3A—C3—H3B	107.7	C9—C10—H10C	109.5
C5—C4—C3	113.7 (3)	H10A—C10—H10C	109.5
C5—C4—H4A	108.8	H10B—C10—H10C	109.5
C3—C4—H4A	108.8	C9—C11—H11A	109.5
C5—C4—H4B	108.8	C9—C11—H11B	109.5
C3—C4—H4B	108.8	H11A—C11—H11B	109.5
H4A—C4—H4B	107.7	C9—C11—H11C	109.5
C6—C5—C7	115.8 (3)	H11A—C11—H11C	109.5
C6—C5—C4	108.0 (3)	H11B—C11—H11C	109.5
C7—C5—C4	107.7 (3)	N1—C12—H12A	109.5
C6—C5—C9	100.2 (2)	N1—C12—H12B	109.5
C7—C5—C9	112.4 (3)	H12A—C12—H12B	109.5
C4—C5—C9	112.7 (3)	N1—C12—H12C	109.5
C1—C6—C5	100.3 (3)	H12A—C12—H12C	109.5
C1—C6—H6A	111.7	H12B—C12—H12C	109.5
C9—O1—C1—C6	−14.1 (3)	C1—C2—C3—C4	−41.3 (4)
C9—O1—C1—C8	−137.6 (3)	O1—C1—C8—O2	64.3 (3)
C9—O1—C1—C2	101.9 (3)	C4—C5—C7—O3	−68.6 (4)
O1—C1—C2—C3	−50.5 (4)	C4—C5—C7—N1	109.3 (3)
C6—C1—C2—C3	62.4 (4)	C12—N1—C7—C5	−179.5 (3)
C8—C1—C2—C3	−170.3 (3)	C9—C5—C7—O3	56.1 (4)
C2—C3—C4—C5	39.5 (5)	C6—C1—C8—O2	−52.8 (4)
C3—C4—C5—C6	−55.9 (4)	C2—C1—C8—O2	−177.0 (3)
C3—C4—C5—C7	178.4 (3)	C1—O1—C9—C11	103.0 (3)
C3—C4—C5—C9	53.8 (4)	C1—O1—C9—C10	−139.0 (3)
O1—C1—C6—C5	38.3 (3)	C1—O1—C9—C5	−15.4 (3)
C8—C1—C6—C5	158.2 (3)	C6—C5—C9—O1	38.5 (3)
C2—C1—C6—C5	−76.9 (3)	C7—C5—C9—O1	162.1 (3)
C7—C5—C6—C1	−167.7 (3)	C4—C5—C9—O1	−76.0 (3)
C4—C5—C6—C1	71.4 (3)	C6—C5—C9—C11	−77.0 (3)
C9—C5—C6—C1	−46.6 (3)	C7—C5—C9—C11	46.5 (4)
C12—N1—C7—O3	−1.6 (5)	C4—C5—C9—C11	168.5 (3)
C6—C5—C7—O3	170.4 (3)	C6—C5—C9—C10	156.7 (3)
C6—C5—C7—N1	−11.7 (4)	C7—C5—C9—C10	−79.8 (4)
C9—C5—C7—N1	−126.0 (3)	C4—C5—C9—C10	42.2 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O3^i	0.84	1.94	2.779 (3)	179
N1—H1···O2^ii	0.88	2.13	2.936 (4)	152
C6—H6B···O1^ii	0.99	2.39	3.292 (4)	152

Symmetry codes: (i) x−1, y, z; (ii) −y+1, x, z+1/4.