Crystal structure of 3-hy-droxy-2-(4-hy-droxy-3-meth-oxy-phenyl-methyl)-5,5-di-methyl-cyclo-hex-2-enone.

In the title compound, C16H20O4, a new starting compound for the synthesis of various heterocycles, the partially saturated six-membered ring adopts a sofa conformation. An intra-molecular O-H⋯O hydrogen bond is observed in the guaiacol residue. In the crystal, mol-ecules are assembled into a sheet structure parallel to the ab plane via O-H⋯O hydrogen bonds. The hydrogen-bond pattern is described by an R44(28) graph-set motif. The sheets are further linked by C-H⋯O hydrogen bonds into a three-dimensional network.

Chemical context

Cyclic 2-aryl­methyl-1,3-diketones attract inter­est as valuable inter­mediates for organic chemistry. A few of the latest examples of these cyclo­hexa­nedione derivatives have been used as starting compounds for the synthesis of various heterocycles [e.g. tetra­hydro­benzo­furan­ones (Yoshida et al., 2010 ▸) or tetra­hydro-1H-xanthen-1-ones (Sudheendran et al., 2012 ▸)], as well as carbocycles, e.g. analogues of Wieland–Miesher and Hajos–Parrish ketones (Xu et al., 2013 ▸).

Structural commentary

Fig. 1 ▸ shows the mol­ecular structure of the title compound, which exhibits an intra­molecular O—H⋯O hydrogen bond (Table 1 ▸). In crystalline state, the mol­ecules assume the enol tautomeric form, 1a. In the dimedone fragment, the bond distances reflect the effect of conjugation in the flat fragment O1=C3—C4=C5—O2. The double bonds, O1=C3 and C4=C5, are elongated [1.246 (2) and 1.357 (3) Å, respectively], while the single bond C3—C4 is shortened [1.447 (3) Å] as compared with standard double and single bonds (Allen et al., 1987 ▸). The general shape of the mol­ecule is characterized by the torsion angles C3—C4—C7—C8 = −62.8 (2)° and C4—C7—C8—C9 = 152.2 (2)°, thus exhibiting an extended conformation. The partially saturated C1–C6 ring adopts a sofa conformation. The distance of atom C1 from the mean plane formed by atoms C2–C6 is 0.612 (3) Å. The dihedral angle between the mean plane of the C1–C6 ring and the C8–C13 benzene ring is 75.69 (6)°.

Figure 1

The mol­ecular structure of the title compound, with the atom-numbering scheme and 50% probability displacement ellipsoids. The intra­molecular hydrogen bond is shown as a double-dashed line.

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2A⋯O4i	0.97	2.49	3.417 (3)	161
C14—H14C⋯O1ii	0.96	2.49	3.247 (3)	136
O2—H2⋯O1iii	0.88 (3)	1.74 (3)	2.586 (2)	161 (3)
O4—H4⋯O3	0.94 (4)	2.10 (4)	2.638 (2)	115 (3)
O4—H4⋯O2iv	0.94 (4)	2.11 (4)	2.919 (2)	142 (3)

Symmetry codes: (i) ; (ii) ; (iii) ; (iv) .

Supra­molecular features

In the crystal, the mol­ecules are assembled into a sheet structure parallel to the ab plane via O—H⋯O hydrogen bonds (Table 1 ▸). The hydrogen-bonding pattern in the sheet is described by an (28) graph-set motif (Fig. 2 ▸). Furthermore, weak C—H⋯O hydrogen bonds join the sheets into a three-dimensional network (Table 1 ▸).

Figure 2

A packing diagram of the title compound, viewed along the c axis. O—H⋯O hydrogen bonds are shown as dashed lines. For clarity weak C—H⋯O bonds are not depicted.

Database survey

A search of the Cambridge Structural Database (Version 5.39, last update February 2018; Groom et al., 2016 ▸) gave 76 structures of 3-hy­droxy-5,5-di­methyl­cyclo­hex-2-enone derivatives. The closest structures are 2-(naphthalen-1-ylmeth­yl)- and 2-(3-chloro­phen­yl)methyl-substituted dimedones (NIHTEE and NIHTII, respectively; Ramachary & Kishor, 2007 ▸).

Antiradical activity against free radicals

Compound 1 demonstrates notable anti­radical activity against free radicals. Free radical tests were realized according to the procedures described previously (Mierina et al., 2017 ▸). 1,1-Diphenyl-2-picrylhydrazyl test: inhibition, when molar ratio of the compound and free radical is 1:1, was 93.3±2.5%; IC50 was 23.0±0.6 µM (starting concentration of free radical was 100 µM). Galvinoxyl test: inhibition was 82.3±1.0% and IC50 – 20.3±2.0 µM.

Synthesis and crystallization

3-Hy­droxy-2-(4-hy­droxy-3-meth­oxy­phenyl­meth­yl)-5,5-di­methyl­cyclo­hex-2-enone (1a) was synthesized according to the reaction scheme in Fig. 3 ▸. Formic acid (3.6 ml) was added to a solution of dimedone 2 (500 mg, 3.6 mmol) and vanillin 3 (543 mg, 3.6 mmol) in tri­ethyl­amine (5.5 ml) while cooling in an ice-bath. The reaction mixture was then heated at 413 K for 5 h, followed by cooling to room temperature, pouring into ice (700–800 ml) and filtering the formed solid. The solid material was purified by crystallization from chloro­form leading to the target compound 1a (615 mg, 62%) with m.p. 466–468 K. Single crystals were obtained from a methanol solution. IR (KBr) ν, cm−1: 3470, 2935, 2645, 1580, 1515, 1375, 1250, 1230, 1200, 1040.

Figure 3

Reaction scheme for the title compound (1a) and its tautomer (1 b).

The enol form, 1a, was observed exclusively in a DMSO solution. 1H NMR for compound 1a (300 MHz, DMSO-d) δ, ppm: 10.71–10.08 (1H, brs, OH), 8.68–8.37 (1H, brs, OH), 6.68 (1H, s, HAr), 6.59 (1H, d, J = 7.7 Hz, HAr), 6.50 (1H, d, J = 7.7 Hz, HAr), 3.68 (3H, s, OMe), 3.41 (2H, brs, CH2Ar, overlapping with H2O signal), 2.34–2.13 (4H, brs, 2CH2), 0.98 (6H, s, 2Me). 13C NMR for compound 1a (75 MHz, DMSO-d) δ, ppm: 147.1, 144.1, 132.7, 120.2, 115.0, 113.3, 112.5, 55.5, 31.7, 28.0, 26.5. Mixture of keto–enol tautomers (1a and 1b) was observed in a chloro­form solution. The ratio of enol 1a and ketone 1b was 1.35:1 (at room temperature). 1H NMR for compound 1a (300 MHz, CDCl3) δ, ppm: 6.84–6.63 (3H, m, HAr), (2H, brs, 2OH), 3.82 (3H, s, OMe), 3.61 (2H, s, CH2Ar), 2.33–2.29 (4H, brs, 2CH2), 1.07 (6H, s, 2Me). 1H NMR for compound 1b (300 MHz, CDCl3) δ, ppm: 6.84–6.63 (3H, m, HAr), 5.62–5.68 (1H, brs, OH), 3.86 (3H, s, OMe), 3.56 (1H, t, J = 5.4 Hz, CHCH2), 3.11 (2H, d, J = 5.4 Hz, CHCH2), 2.65 (2H, d, J = 13.4 Hz, Ha from CH2), 2.44 (2H, d, J = 13.4 Hz, Hb from CH2), 1.16 (3H, s, Me), 0.82 (3H, s, Me).

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. Hydrogen atoms bonded to O atoms were refined freely. Other H atoms were included in the refinement at geometrically calculated positions with C—H = 0.93–0.97 Å and treated as riding with U iso(H) = 1.2U eq(C) or 1.5U eq(C-meth­yl).

Table 2

Experimental details

Crystal data
Chemical formula	C16H20O4
M r	276.32
Crystal system, space group	Orthorhombic, P b c a
Temperature (K)	190
a, b, c (Å)	9.3504 (3), 13.6265 (4), 22.8790 (9)
V (Å3)	2915.09 (17)
Z	8
Radiation type	Mo Kα
μ (mm−1)	0.09
Crystal size (mm)	0.32 × 0.17 × 0.12
Data collection
Diffractometer	Bruker KappaCCD
No. of measured, independent and observed [I > 2σ(I)] reflections	6082, 3295, 2149
R int	0.057
(sin θ/λ)max (Å−1)	0.649
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.059, 0.131, 1.04
No. of reflections	3295
No. of parameters	192
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.21, −0.19

Computer programs: COLLECT (Bruker, 2001 ▸), SCALEPACK (Otwinowski & Minor, 1997 ▸), DENZO (Otwinowski & Minor, 1997 ▸), SIR2004 (Burla et al., 2005 ▸), SHELXL2017 (Sheldrick, 2015 ▸), ORTEP-3 for Windows (Farrugia, 2012 ▸) and publCIF (Westrip, 2010 ▸).

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989018006941/is5495sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989018006941/is5495Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989018006941/is5495Isup3.cml

CCDC reference: 1841730

Additional supporting information: crystallographic information; 3D view; checkCIF report

C16H20O4	Dx = 1.259 Mg m−3
Mr = 276.32	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbca	Cell parameters from 32401 reflections
a = 9.3504 (3) Å	θ = 1.0–27.5°
b = 13.6265 (4) Å	µ = 0.09 mm−1
c = 22.8790 (9) Å	T = 190 K
V = 2915.09 (17) Å3	Block, colourless
Z = 8	0.32 × 0.17 × 0.12 mm
F(000) = 1184

Bruker KappaCCD diffractometer	Rint = 0.057
CCD scans	θmax = 27.5°, θmin = 2.8°
6082 measured reflections	h = −12→12
3295 independent reflections	k = −17→17
2149 reflections with I > 2σ(I)	l = −29→29

Refinement on F2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.059	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.131	w = 1/[σ2(Fo2) + (0.0489P)2 + 1.0327P] where P = (Fo2 + 2Fc2)/3
S = 1.04	(Δ/σ)max = 0.006
3295 reflections	Δρmax = 0.21 e Å−3
192 parameters	Δρmin = −0.19 e Å−3

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.

	x	y	z	Uiso*/Ueq
O1	0.75371 (16)	0.50507 (9)	0.63597 (7)	0.0331 (4)
O2	0.62541 (15)	0.83466 (10)	0.63025 (7)	0.0287 (4)
O3	0.16966 (16)	0.39470 (10)	0.68561 (7)	0.0367 (4)
O4	0.13650 (15)	0.39579 (10)	0.57111 (7)	0.0319 (4)
C1	0.9683 (2)	0.71070 (12)	0.58699 (9)	0.0224 (4)
C2	0.8992 (2)	0.60988 (13)	0.57748 (9)	0.0256 (5)
H2A	0.864618	0.605845	0.537577	0.031*
H2B	0.971321	0.559458	0.582589	0.031*
C3	0.7777 (2)	0.58996 (13)	0.61829 (9)	0.0230 (5)
C4	0.6838 (2)	0.66925 (13)	0.63552 (9)	0.0213 (4)
C5	0.7173 (2)	0.76168 (13)	0.61827 (9)	0.0216 (4)
C6	0.8495 (2)	0.78837 (13)	0.58489 (9)	0.0243 (5)
H6A	0.886941	0.849470	0.600375	0.029*
H6B	0.823687	0.799694	0.544389	0.029*
C7	0.5558 (2)	0.64569 (13)	0.67303 (10)	0.0277 (5)
H7A	0.508367	0.706600	0.683286	0.033*
H7B	0.589063	0.615710	0.709003	0.033*
C8	0.4470 (2)	0.57763 (13)	0.64472 (9)	0.0232 (5)
C9	0.3616 (2)	0.51732 (13)	0.68030 (9)	0.0258 (5)
H9	0.374309	0.517992	0.720617	0.031*
C10	0.2589 (2)	0.45705 (13)	0.65589 (9)	0.0252 (5)
C11	0.2391 (2)	0.45584 (13)	0.59560 (9)	0.0244 (5)
C12	0.3230 (2)	0.51344 (15)	0.56037 (10)	0.0300 (5)
H12	0.310764	0.512153	0.520037	0.036*
C13	0.4265 (2)	0.57391 (14)	0.58529 (10)	0.0287 (5)
H13	0.483160	0.612663	0.561127	0.034*
C14	0.1966 (3)	0.37943 (17)	0.74571 (11)	0.0469 (7)
H14A	0.293311	0.357396	0.750859	0.070*
H14B	0.131964	0.330679	0.760536	0.070*
H14C	0.182851	0.439830	0.766563	0.070*
C15	1.0448 (2)	0.71292 (14)	0.64588 (10)	0.0317 (5)
H15A	0.977325	0.700158	0.676564	0.048*
H15B	1.087200	0.776352	0.651680	0.048*
H15C	1.118201	0.663631	0.646450	0.048*
C16	1.0760 (2)	0.73067 (15)	0.53816 (10)	0.0345 (5)
H16A	1.115861	0.795077	0.543051	0.052*
H16B	1.028672	0.726735	0.500998	0.052*
H16C	1.151155	0.682745	0.539763	0.052*
H2	0.664 (3)	0.892 (2)	0.6238 (13)	0.079 (10)*
H4	0.085 (4)	0.368 (3)	0.6024 (16)	0.114 (14)*

	U11	U22	U33	U12	U13	U23
O1	0.0372 (8)	0.0110 (6)	0.0510 (10)	−0.0009 (6)	0.0078 (8)	0.0033 (6)
O2	0.0240 (8)	0.0128 (7)	0.0493 (10)	0.0022 (6)	−0.0014 (7)	0.0001 (6)
O3	0.0393 (9)	0.0406 (9)	0.0304 (9)	−0.0196 (7)	0.0011 (7)	0.0042 (7)
O4	0.0283 (8)	0.0362 (8)	0.0312 (9)	−0.0096 (7)	−0.0035 (7)	−0.0033 (7)
C1	0.0241 (10)	0.0168 (9)	0.0262 (11)	−0.0004 (8)	0.0006 (9)	0.0004 (8)
C2	0.0287 (11)	0.0172 (9)	0.0308 (12)	0.0006 (8)	0.0033 (9)	−0.0035 (8)
C3	0.0253 (11)	0.0149 (9)	0.0288 (12)	−0.0019 (8)	−0.0012 (9)	−0.0016 (8)
C4	0.0199 (10)	0.0145 (9)	0.0297 (12)	−0.0023 (8)	−0.0019 (9)	−0.0035 (8)
C5	0.0207 (11)	0.0163 (9)	0.0278 (12)	0.0010 (8)	−0.0047 (8)	−0.0014 (8)
C6	0.0241 (10)	0.0151 (9)	0.0336 (12)	−0.0028 (8)	−0.0038 (9)	0.0029 (8)
C7	0.0306 (12)	0.0160 (9)	0.0366 (14)	−0.0026 (9)	0.0042 (10)	−0.0034 (8)
C8	0.0222 (10)	0.0164 (9)	0.0310 (12)	0.0031 (8)	0.0031 (9)	0.0003 (8)
C9	0.0283 (11)	0.0233 (10)	0.0260 (12)	0.0005 (9)	0.0014 (9)	0.0000 (8)
C10	0.0236 (10)	0.0198 (9)	0.0322 (12)	−0.0023 (9)	0.0060 (9)	0.0024 (8)
C11	0.0207 (10)	0.0197 (9)	0.0328 (12)	0.0011 (8)	−0.0013 (9)	−0.0003 (9)
C12	0.0330 (12)	0.0300 (11)	0.0271 (13)	−0.0028 (10)	−0.0005 (10)	0.0037 (9)
C13	0.0279 (11)	0.0222 (10)	0.0359 (13)	−0.0035 (9)	0.0038 (10)	0.0061 (9)
C14	0.0604 (17)	0.0503 (14)	0.0300 (14)	−0.0262 (13)	0.0077 (12)	0.0032 (11)
C15	0.0263 (11)	0.0273 (11)	0.0414 (14)	0.0024 (9)	−0.0045 (10)	−0.0003 (10)
C16	0.0333 (12)	0.0270 (11)	0.0432 (15)	−0.0024 (10)	0.0077 (10)	0.0000 (10)

O1—C3	1.246 (2)	C7—H7A	0.9700
O2—C5	1.342 (2)	C7—H7B	0.9700
O2—H2	0.88 (3)	C8—C13	1.374 (3)
O3—C10	1.371 (2)	C8—C9	1.406 (3)
O3—C14	1.413 (3)	C9—C10	1.381 (3)
O4—C11	1.380 (2)	C9—H9	0.9300
O4—H4	0.94 (4)	C10—C11	1.392 (3)
C1—C15	1.526 (3)	C11—C12	1.371 (3)
C1—C16	1.529 (3)	C12—C13	1.394 (3)
C1—C2	1.534 (3)	C12—H12	0.9300
C1—C6	1.534 (3)	C13—H13	0.9300
C2—C3	1.495 (3)	C14—H14A	0.9600
C2—H2A	0.9700	C14—H14B	0.9600
C2—H2B	0.9700	C14—H14C	0.9600
C3—C4	1.447 (3)	C15—H15A	0.9600
C4—C5	1.357 (3)	C15—H15B	0.9600
C4—C7	1.507 (3)	C15—H15C	0.9600
C5—C6	1.498 (3)	C16—H16A	0.9600
C6—H6A	0.9700	C16—H16B	0.9600
C6—H6B	0.9700	C16—H16C	0.9600
C7—C8	1.521 (3)
C5—O2—H2	111 (2)	C13—C8—C9	118.18 (18)
C10—O3—C14	117.73 (17)	C13—C8—C7	122.47 (18)
C11—O4—H4	107 (2)	C9—C8—C7	119.33 (19)
C15—C1—C16	109.41 (17)	C10—C9—C8	120.5 (2)
C15—C1—C2	109.91 (16)	C10—C9—H9	119.7
C16—C1—C2	109.48 (16)	C8—C9—H9	119.7
C15—C1—C6	110.69 (16)	O3—C10—C9	126.20 (19)
C16—C1—C6	109.34 (16)	O3—C10—C11	113.78 (17)
C2—C1—C6	107.99 (16)	C9—C10—C11	120.02 (18)
C3—C2—C1	113.20 (15)	C12—C11—O4	119.9 (2)
C3—C2—H2A	108.9	C12—C11—C10	119.98 (19)
C1—C2—H2A	108.9	O4—C11—C10	120.14 (18)
C3—C2—H2B	108.9	C11—C12—C13	119.7 (2)
C1—C2—H2B	108.9	C11—C12—H12	120.2
H2A—C2—H2B	107.8	C13—C12—H12	120.2
O1—C3—C4	119.70 (18)	C8—C13—C12	121.57 (19)
O1—C3—C2	120.54 (17)	C8—C13—H13	119.2
C4—C3—C2	119.71 (16)	C12—C13—H13	119.2
C5—C4—C3	118.27 (18)	O3—C14—H14A	109.5
C5—C4—C7	123.16 (17)	O3—C14—H14B	109.5
C3—C4—C7	118.55 (16)	H14A—C14—H14B	109.5
O2—C5—C4	118.71 (17)	O3—C14—H14C	109.5
O2—C5—C6	116.90 (15)	H14A—C14—H14C	109.5
C4—C5—C6	124.37 (17)	H14B—C14—H14C	109.5
C5—C6—C1	114.44 (15)	C1—C15—H15A	109.5
C5—C6—H6A	108.7	C1—C15—H15B	109.5
C1—C6—H6A	108.7	H15A—C15—H15B	109.5
C5—C6—H6B	108.7	C1—C15—H15C	109.5
C1—C6—H6B	108.7	H15A—C15—H15C	109.5
H6A—C6—H6B	107.6	H15B—C15—H15C	109.5
C4—C7—C8	114.73 (17)	C1—C16—H16A	109.5
C4—C7—H7A	108.6	C1—C16—H16B	109.5
C8—C7—H7A	108.6	H16A—C16—H16B	109.5
C4—C7—H7B	108.6	C1—C16—H16C	109.5
C8—C7—H7B	108.6	H16A—C16—H16C	109.5
H7A—C7—H7B	107.6	H16B—C16—H16C	109.5
C15—C1—C2—C3	67.9 (2)	C3—C4—C7—C8	−62.8 (2)
C16—C1—C2—C3	−171.93 (17)	C4—C7—C8—C13	−29.1 (3)
C6—C1—C2—C3	−53.0 (2)	C4—C7—C8—C9	152.22 (17)
C1—C2—C3—O1	−146.67 (19)	C13—C8—C9—C10	−0.8 (3)
C1—C2—C3—C4	35.9 (3)	C7—C8—C9—C10	177.99 (17)
O1—C3—C4—C5	176.34 (19)	C14—O3—C10—C9	−9.4 (3)
C2—C3—C4—C5	−6.2 (3)	C14—O3—C10—C11	170.34 (19)
O1—C3—C4—C7	−2.0 (3)	C8—C9—C10—O3	179.63 (18)
C2—C3—C4—C7	175.47 (18)	C8—C9—C10—C11	−0.1 (3)
C3—C4—C5—O2	175.08 (17)	O3—C10—C11—C12	−178.86 (17)
C7—C4—C5—O2	−6.6 (3)	C9—C10—C11—C12	0.9 (3)
C3—C4—C5—C6	−3.2 (3)	O3—C10—C11—O4	0.3 (3)
C7—C4—C5—C6	175.11 (19)	C9—C10—C11—O4	−179.93 (16)
O2—C5—C6—C1	163.97 (17)	O4—C11—C12—C13	−179.95 (17)
C4—C5—C6—C1	−17.7 (3)	C10—C11—C12—C13	−0.8 (3)
C15—C1—C6—C5	−76.1 (2)	C9—C8—C13—C12	0.9 (3)
C16—C1—C6—C5	163.26 (17)	C7—C8—C13—C12	−177.81 (18)
C2—C1—C6—C5	44.2 (2)	C11—C12—C13—C8	−0.1 (3)
C5—C4—C7—C8	118.9 (2)

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2A···O4i	0.97	2.49	3.417 (3)	161
C14—H14C···O1ii	0.96	2.49	3.247 (3)	136
O2—H2···O1iii	0.88 (3)	1.74 (3)	2.586 (2)	161 (3)
O4—H4···O3	0.94 (4)	2.10 (4)	2.638 (2)	115 (3)
O4—H4···O2iv	0.94 (4)	2.11 (4)	2.919 (2)	142 (3)