3-Hydroxy-1-(2-hydroxy-3,4-di­methoxy­phenyl)-2-methyl­propanone

The title compound, C₁₂H₁₆O₅, is an important precursor in the synthesis of polyphenolics. The orientation of the 3-hydroxy-2-methyl­propanone group is largely controlled by intramolecular hydrogen bonding, whilst intermolecular hydrogen bonding links the mol­ecules together in pairs.

Key indicators

• Single-crystal X-ray study
• T = 200 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.037
• wR factor = 0.110
• Data-to-parameter ratio = 15.4

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

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S1. Comment

Polyphenolics occur widely in nature and many of their analogues possess a variety of biological activities i.e. antitumor, antiviral, antibiotic and antifungal. Aryl alkyl ketones with a phenolic hydroxy group in the ortho position are starting materials for the synthesis of different classes of biopolyphenolics. The title compound, (I), in addition to being used as a precursor for complex polyphenolics, may also be a suitable substrate for enantioselective acylation studies using lipases. In the present investigation, several aryl alkyl ketones were hydroxymethylated using formaldehyde in aqueous sodium hydroxide (Barlocco et al., 1985) and then subjected to acylation in organic solvents with vinyl acetate and porcine pancreatic lipase (PPL) and Candida rugosa lipase (CRL). The title compound, (I), was reported to be obtained as an oil by Jain et al. (1989), and due to its importance in synthetic chemistry and in biotransformation studies, we have repeated their procedure only to obtain unsatisfactory results; however, compound (I) was obtained in good yields by the hydroxymethylation of 2-hydroxy-3,4-dimethoxypropiophenone (Ahluwalia et al., 1979). This paper reports its X-ray structure in order to ascertain the constitution unambiguously.

The molecular structure of (I) is illustrated in Fig. 1. The bond lengths and angles are largely unexceptional. Of the two methoxy groups, one (at C4') is coplanar with the phenyl ring, whilst the other (at C3') has a C5—O4—C3'—C2' torsion angle of 97.6 (1)°. The orientation of the 3-hydroxy-2-methylpropanone group is largely controlled by intramolecular hydrogen bonding linking the O3 hydroxyl H atom with O1 (see Fig. 2); this results in C2 and O1 being almost coplanar with the phenyl group [e.g. O1—C1—C1'—C2' = -1.9 (2)°]. Bifurcated hydrogen bonding involving the O2 hydroxyl H atom (the sum of the three angles about this atom is 360°, within the precision of the experiment) links the molecules together in pairs.

S2. Experimental

A solution of 2-hydroxy-3,4-dimethoxypropiophenone (1.05 g, 0.005 mol) in sodium hydroxide (0.5 M, 10 ml, 0.005 mol) and formaldehyde (37%, 0.40 ml, 0.005 mol) was stirred at 303 K for 16 h. The mixture was cooled and acidified to pH 4–5 with concentrated hydrochloric acid and the product was extracted with diethyl ether (2 × 25 ml). The organic layer was dried over sodium sulfate and the solvent evaporated. The residue was chromatographed on silica gel to yield 3-hydroxy-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-methylpropanone as white needles (0.72 g, 60% yield, m.p. 343 K).

S3. Refinement

The temperature of the crystal was controlled using an Oxford Cryosystems Cryostream Cooler (Cosier & Glazer, 1986). Data were collected over a hemisphere of reciprocal space, by a combination of three sets of exposures. Each set had a different ϕ angle for the crystal and each exposure of 10 s covered 0.3° in ω. The crystal to detector distance was 5.01 cm. Coverage of the unique set was over 97% complete to at least 28° in θ. Crystal decay was monitored by repeating the initial frames at the end of the data collection and analyzing the duplicate reflections.

The hydroxyl H atoms were located from an electron-density map and freely refined. Other H atoms were added at calculated positions and refined using a riding model. Anisotropic displacement parameters were used for all non-H atoms; H atoms were given isotropic displacement parameters equal to 1.2 (or 1.5 for methyl H atoms) times the equivalent isotropic displacement parameter of their parent atoms.

Computing details

Data collection: SMART (Siemens, 1994a); cell refinement: SAINT (Siemens, 1995); data reduction: SAINT; program(s) used to solve structure: SHELXTL/PC (Siemens, 1994b); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC; software used to prepare material for publication: SHELXTL/PC.

Figures

	Fig. 1. View of the title molecule showing the atomic numbering. Displacement ellipsoids are drawn at the 50% probability level for non-H atoms. H atoms are shown as spheres of arbitrary radii.
	Fig. 2. Representation of the intra- and intermolecular hydrogen bonding.

3-Hydroxy-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-methylpropanone

Crystal data

C12H16O5	Dx = 1.363 Mg m^−3
Mr = 240.25	Melting point: 343 K
Monoclinic, C2/c	Mo Kα radiation, λ = 0.71073 Å
a = 20.9568 (12) Å	Cell parameters from 4598 reflections
b = 10.6129 (6) Å	θ = 2.4–27.0°
c = 14.7853 (9) Å	µ = 0.11 mm^−1
β = 134.586 (3)°	T = 200 K
V = 2342.0 (2) Å^3	Block, colourless
Z = 8	0.5 × 0.4 × 0.4 mm
F(000) = 1024

Data collection

Siemens SMART CCD area-detector diffractometer	2534 independent reflections
Radiation source: normal-focus sealed tube	2008 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.018
Detector resolution: 8.192 pixels mm^-1	θmax = 27.0°, θmin = 2.4°
ω scans	h = −21→26
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	k = −12→13
Tmin = 0.949, Tmax = 0.959	l = −18→11
6539 measured 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)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.110	H atoms treated by a mixture of independent and constrained refinement
S = 1.06	w = 1/[σ^2(Fo^2) + (0.0603P)^2 + 0.4432P] where P = (Fo^2 + 2Fc^2)/3
2534 reflections	(Δ/σ)max < 0.001
165 parameters	Δρmax = 0.20 e Å^−3
0 restraints	Δρmin = −0.18 e Å^−3

Special details

Experimental. The temperature of the crystal was controlled using the Oxford Cryosystem Cryostream Cooler (Cosier & Glazer, 1986). Data were collected over a hemisphere of reciprocal space, by a combination of three sets of exposures. Each set had a different ϕ angle for the crystal and each exposure of 10 s covered 0.3° in ω. The crystal to detector distance was 5.01 cm. Coverage of the unique set was over 979% complete to at least 27° in θ. Crystal decay was monitored by repeating the initial frames at the end of the data collection and analyzing the duplicate reflections. IR(KBr) ν_max: 3517(OH), 1626(C═O), 1450, 1270, 1112, 998 and 808 cm^-1; UV(CH₃OH) λ_max: 218 and 284 nm; ¹H NMR (60 MHz, FT, CDCl₃) δ: 1.16 (d, J=8 Hz, 3H, CH₃), 2.30 (brs, 1H, OH), 3.20–4.00 (9H, 2xOCH₃, C-2H and C-3H), 6.18 (d, J=9.6 Hz, 1H, C-5'H), 7.19 (d, 1H, J=9.6 Hz, C-6'H) and 12.0 (s, 1H, chelated OH); EIMS, m/z (relative intensity): 240 (M⁺, 18), 181 (100), 120 (20) and 95 (12).

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	0.23471 (6)	0.10151 (9)	0.38188 (9)	0.0397 (2)
O2	0.11909 (7)	−0.04825 (11)	0.42363 (10)	0.0491 (3)
H2	0.1717 (16)	−0.009 (2)	0.489 (2)	0.093 (7)*
O3	0.25689 (6)	0.33737 (10)	0.40202 (9)	0.0387 (2)
H3	0.2690 (12)	0.2572 (19)	0.4132 (17)	0.063 (6)*
O4	0.18555 (6)	0.56909 (8)	0.33589 (9)	0.0394 (2)
O5	0.00860 (6)	0.60420 (9)	0.14341 (9)	0.0415 (3)
C1	0.15183 (8)	0.11280 (12)	0.29649 (12)	0.0319 (3)
C2	0.09563 (9)	−0.00657 (12)	0.23933 (12)	0.0362 (3)
H2A	0.0318	0.0158	0.1885	0.043*
C3	0.12836 (10)	−0.09810 (13)	0.34392 (13)	0.0414 (3)
H3A	0.0938	−0.1775	0.3050	0.050*
H3B	0.1922	−0.1181	0.3962	0.050*
C4	0.10196 (12)	−0.06568 (14)	0.15105 (15)	0.0518 (4)
H4A	0.0840	−0.0035	0.0876	0.078*
H4B	0.0622	−0.1390	0.1081	0.078*
H4C	0.1638	−0.0923	0.2011	0.078*
C5	0.20792 (10)	0.62533 (14)	0.27336 (15)	0.0490 (4)
H5A	0.2502	0.6946	0.3253	0.073*
H5B	0.1535	0.6580	0.1905	0.073*
H5C	0.2355	0.5620	0.2614	0.073*
C6	−0.08524 (9)	0.62789 (14)	0.03954 (14)	0.0458 (4)
H6A	−0.0960	0.7190	0.0288	0.069*
H6B	−0.1181	0.5891	0.0571	0.069*
H6C	−0.1059	0.5918	−0.0384	0.069*
C1'	0.11061 (8)	0.23794 (12)	0.25137 (11)	0.0310 (3)
C2'	0.16641 (8)	0.34630 (12)	0.30908 (11)	0.0309 (3)
C3'	0.12957 (8)	0.46679 (12)	0.27187 (11)	0.0326 (3)
C4'	0.03681 (9)	0.48277 (12)	0.17268 (12)	0.0339 (3)
C5'	−0.01932 (8)	0.37699 (13)	0.11258 (12)	0.0353 (3)
H5'A	−0.0823	0.3872	0.0446	0.042*
C6'	0.01772 (8)	0.25802 (12)	0.15302 (12)	0.0337 (3)
H6'A	−0.0210	0.1870	0.1129	0.040*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0294 (5)	0.0374 (5)	0.0429 (5)	0.0009 (4)	0.0219 (4)	−0.0012 (4)
O2	0.0376 (6)	0.0614 (7)	0.0420 (6)	−0.0113 (5)	0.0257 (5)	−0.0058 (5)
O3	0.0264 (5)	0.0369 (6)	0.0410 (5)	−0.0031 (4)	0.0193 (4)	−0.0041 (4)
O4	0.0382 (5)	0.0345 (5)	0.0397 (5)	−0.0092 (4)	0.0253 (4)	−0.0081 (4)
O5	0.0357 (5)	0.0322 (5)	0.0436 (5)	0.0034 (4)	0.0232 (5)	−0.0008 (4)
C1	0.0303 (6)	0.0351 (7)	0.0317 (6)	−0.0010 (5)	0.0223 (6)	−0.0024 (5)
C2	0.0325 (7)	0.0316 (7)	0.0380 (7)	−0.0020 (5)	0.0224 (6)	−0.0026 (5)
C3	0.0389 (7)	0.0352 (7)	0.0424 (7)	−0.0035 (6)	0.0258 (6)	−0.0001 (6)
C4	0.0619 (10)	0.0418 (8)	0.0479 (8)	−0.0082 (7)	0.0372 (8)	−0.0114 (7)
C5	0.0492 (9)	0.0377 (8)	0.0568 (9)	−0.0054 (6)	0.0360 (8)	0.0036 (6)
C6	0.0369 (8)	0.0415 (8)	0.0451 (8)	0.0098 (6)	0.0238 (7)	0.0039 (6)
C1'	0.0301 (6)	0.0328 (6)	0.0302 (6)	−0.0015 (5)	0.0212 (5)	−0.0024 (5)
C2'	0.0268 (6)	0.0364 (7)	0.0279 (6)	−0.0026 (5)	0.0186 (5)	−0.0033 (5)
C3'	0.0315 (7)	0.0335 (7)	0.0318 (6)	−0.0057 (5)	0.0218 (6)	−0.0060 (5)
C4'	0.0346 (7)	0.0340 (7)	0.0330 (6)	0.0028 (5)	0.0236 (6)	−0.0005 (5)
C5'	0.0274 (6)	0.0383 (7)	0.0310 (6)	−0.0003 (5)	0.0172 (5)	−0.0023 (5)
C6'	0.0289 (6)	0.0340 (7)	0.0320 (6)	−0.0045 (5)	0.0191 (5)	−0.0055 (5)

Geometric parameters (Å, º)

O1—C1	1.2436 (15)	C4—H4B	0.980
O2—C3	1.4239 (18)	C4—H4C	0.980
O2—H2	0.91 (2)	C5—H5A	0.980
O3—C2'	1.3545 (15)	C5—H5B	0.980
O3—H3	0.87 (2)	C5—H5C	0.980
O4—C3'	1.3755 (14)	C6—H6A	0.980
O4—C5	1.4280 (18)	C6—H6B	0.980
O5—C4'	1.3558 (16)	C6—H6C	0.980
O5—C6	1.4314 (16)	C1'—C6'	1.4054 (17)
C1—C1'	1.4649 (17)	C1'—C2'	1.4202 (17)
C1—C2	1.5194 (17)	C2'—C3'	1.3919 (18)
C2—C3	1.5219 (19)	C3'—C4'	1.3987 (17)
C2—C4	1.536 (2)	C4'—C5'	1.4022 (18)
C2—H2A	1.000	C5'—C6'	1.3794 (18)
C3—H3A	0.990	C5'—H5'A	0.950
C3—H3B	0.990	C6'—H6'A	0.950
C4—H4A	0.980
C3—O2—H2	106.5 (14)	O4—C5—H5C	109.5
C2'—O3—H3	105.9 (12)	H5A—C5—H5C	109.5
C3'—O4—C5	113.16 (10)	H5B—C5—H5C	109.5
C4'—O5—C6	118.18 (11)	O5—C6—H6A	109.5
O1—C1—C1'	120.43 (11)	O5—C6—H6B	109.5
O1—C1—C2	117.98 (11)	H6A—C6—H6B	109.5
C1'—C1—C2	121.58 (11)	O5—C6—H6C	109.5
C1—C2—C3	110.27 (11)	H6A—C6—H6C	109.5
C1—C2—C4	108.52 (11)	H6B—C6—H6C	109.5
C3—C2—C4	110.90 (12)	C6'—C1'—C2'	117.20 (11)
C1—C2—H2A	109.0	C6'—C1'—C1	123.66 (11)
C3—C2—H2A	109.0	C2'—C1'—C1	119.14 (11)
C4—C2—H2A	109.0	O3—C2'—C3'	117.28 (11)
O2—C3—C2	112.20 (12)	O3—C2'—C1'	121.92 (11)
O2—C3—H3A	109.2	C3'—C2'—C1'	120.81 (11)
C2—C3—H3A	109.2	O4—C3'—C2'	118.99 (11)
O2—C3—H3B	109.2	O4—C3'—C4'	120.80 (11)
C2—C3—H3B	109.2	C2'—C3'—C4'	120.19 (11)
H3A—C3—H3B	107.9	O5—C4'—C3'	115.06 (11)
C2—C4—H4A	109.5	O5—C4'—C5'	125.09 (11)
C2—C4—H4B	109.5	C3'—C4'—C5'	119.84 (12)
H4A—C4—H4B	109.5	C6'—C5'—C4'	119.46 (12)
C2—C4—H4C	109.5	C6'—C5'—H5'A	120.3
H4A—C4—H4C	109.5	C4'—C5'—H5'A	120.3
H4B—C4—H4C	109.5	C5'—C6'—C1'	122.45 (11)
O4—C5—H5A	109.5	C5'—C6'—H6'A	118.8
O4—C5—H5B	109.5	C1'—C6'—H6'A	118.8
H5A—C5—H5B	109.5
O1—C1—C2—C3	46.75 (16)	O3—C2'—C3'—O4	−4.19 (17)
C1'—C1—C2—C3	−134.59 (12)	C1'—C2'—C3'—O4	175.66 (11)
O1—C1—C2—C4	−74.91 (15)	O3—C2'—C3'—C4'	177.24 (11)
C1'—C1—C2—C4	103.75 (14)	C1'—C2'—C3'—C4'	−2.91 (18)
C1—C2—C3—O2	62.71 (14)	C6—O5—C4'—C3'	177.60 (11)
C4—C2—C3—O2	−177.06 (11)	C6—O5—C4'—C5'	−3.00 (19)
O1—C1—C1'—C6'	178.20 (11)	O4—C3'—C4'—O5	2.37 (17)
C2—C1—C1'—C6'	−0.43 (19)	C2'—C3'—C4'—O5	−179.09 (11)
O1—C1—C1'—C2'	−1.92 (18)	O4—C3'—C4'—C5'	−177.07 (11)
C2—C1—C1'—C2'	179.46 (11)	C2'—C3'—C4'—C5'	1.47 (19)
C6'—C1'—C2'—O3	−177.99 (11)	O5—C4'—C5'—C6'	−178.74 (12)
C1—C1'—C2'—O3	2.12 (18)	C3'—C4'—C5'—C6'	0.64 (19)
C6'—C1'—C2'—C3'	2.17 (18)	C4'—C5'—C6'—C1'	−1.4 (2)
C1—C1'—C2'—C3'	−177.72 (11)	C2'—C1'—C6'—C5'	−0.03 (19)
C5—O4—C3'—C2'	97.59 (14)	C1—C1'—C6'—C5'	179.86 (12)
C5—O4—C3'—C4'	−83.85 (15)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O1	0.87 (2)	1.73 (2)	2.5252 (13)	150.8 (18)
O2—H2···O3^i	0.91 (2)	2.19 (3)	3.0004 (15)	149 (2)
O2—H2···O4^i	0.91 (2)	2.28 (2)	3.0025 (14)	137 (2)

Symmetry code: (i) −x+1/2, −y+1/2, −z+1.