organic compounds
2-(4-Acetamidophenoxy)-2-methylpropanoic acid
aFacultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col., Chamilapa, CP 62100, Cuernavaca Mor., Mexico, bCentro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001 Col., Chamilpa, CP 62100, Cuernavaca Mor., Mexico, and cCentro de Investigaciones Químicas, Universidad A. del Estado de Hidalgo, Carr. Pachuca-Tulancingo Km. 4.5, Mineral de la reforma, CP 42184, Hidalgo, Mexico
*Correspondence e-mail: tlahuext@ciq.uaem.mx
In the title compound, C12H15NO4, the dihedral angle between the acetamide group and the ring is 29.6 (2)(su?)°. In the crystal molecules are linked through N—H⋯O and O—H⋯O hydrogen bonds, thereby forming corrugated sheets propagating in the ac plane. These sheets are composed of R44(28) graph-set motifs.
Related literature
For related literature on analogous structures with analgesic and antidyslipidemic activities, see: Kis et al. (2005); Navarrete-Vázquez et al. (2008, 2011); Thorp & Waring (1962); Miller & Spence (1998); Forcheron et al. (2002). For information on hydrogen bonding, see: Bernstein et al. (1995); Jeffrey (1997); Desiraju (1996).
Experimental
Crystal data
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Refinement
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Data collection: CrysAlis PRO (Agilent, 2011); cell CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: PLATON (Spek, 2009) and DIAMOND (Crystal Impact, 2006).
Supporting information
10.1107/S1600536813004856/gw2131sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: 10.1107/S1600536813004856/gw2131Isup2.hkl
Supporting information file. DOI: 10.1107/S1600536813004856/gw2131Isup3.cml
Paracetamol (1 g, 0.0066 mol) and potassium carbonate (2 g, 0.014 mol) were dissolved in the minimum amount of dimethyl sulfoxide and were heated at 40 °C. After 20 minutes, the ethyl 2-bromo-2-methylpropionate (1.45 ml, 0.0099 mol) was added dropwise and the reaction mixture was heated to reflux (80 °C) and monitored by TLC. After the reaction completion (15 h), the reaction mixture was filtered and solid residue was washed off with acetone (10 ml). The total mother liquors were concentrated under reduced pressure and then poured into water and extracted with ethyl acetate (3 x 15 ml). The organic layer was dried over anhydrous Na2SO4 and partially evaporated under reduced pressure.
The resulting solid was treated with a mixture of THF/MeOH/H2O (3:2:1,v/v/v, 6 ml/mmol), and LiOH was added (3 equiv). The mixture stirred at room temperature for 3 h. Then, HCl solution (10% v/v) was added, and most of the organic solvents removed in vacuo. The partly solid residue was extracted with CH2Cl2 (3 x 10 ml), dried with Na2SO4, filtered, and concentrated in vacuo to give a white solid (m.p. 438 K). Single crystals were obtained from methanol. 1H NMR data (200 MHz; DMSO-d6; Me4Si) δ: 1.46 (6H, s, H-9 and H-10), 2.10 (3H, s, CH3CO), 6.78 (2H, d, J = 8.7, H-2 and H-6), 7.44 (2H, d, J = 8.7, H-3 and H-5), 9.83 (1H, bs, N—H). 13C NMR (50 MHz, DMSO-d6) δ: 23.8 (CH3CO), 25.1 (gem-di CH3), 78.7 (C-7), 119.5 (C-2, C-6), 120.2 (C-3, C-5), 133.9 (C-4), 161.8 (C-1), 167.9 (CONH), 175.2 (COOH). EI—MS: m/z (rel. int.) 237 (M+, 25%).
H atoms were positioned geometrically and constrained using the riding-model approximation [C—Haryl = 0.93 Å, Uiso(Haryl)= 1.2 Ueq(C); C—Hmethyl = 0.96 Å, Uiso(Hmethyl)= 1.5 Ueq(C); O—Hhydroxyl = 0.82 Å, Uiso(Hhydroxyl) = 1.5 Ueq(O) = 1.5]. The hydrogen atom bonded to N1 was located by difference Fourier map. Its coordinates were refined with a distance restraint: N—H = 0.86 Å and [Uiso(H) = 1.2 Ueq(N)].
Data collection: CrysAlis PRO (Agilent, 2011); cell
CrysAlis PRO (Agilent, 2011); data reduction: CrysAlis PRO (Agilent, 2011); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: PLATON (Spek, 2009) and DIAMOND (Crystal Impact, 2006).C12H15NO4 | Dx = 1.272 Mg m−3 |
Mr = 237.25 | Melting point: 438 K |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
a = 8.3184 (4) Å | Cell parameters from 9500 reflections |
b = 13.1554 (6) Å | θ = 3.0–29.3° |
c = 12.0452 (5) Å | µ = 0.10 mm−1 |
β = 109.959 (5)° | T = 293 K |
V = 1238.96 (10) Å3 | Prism, colourless |
Z = 4 | 0.19 × 0.14 × 0.13 mm |
F(000) = 504 |
Agilent Xcalibur Atlas Gemini diffractometer | 2179 independent reflections |
Radiation source: (Mo) X-ray Source | 1738 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.045 |
Detector resolution: 10.3659 pixels mm-1 | θmax = 25.0°, θmin = 3.0° |
ω scans | h = −9→9 |
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011) | k = −15→15 |
Tmin = 0.982, Tmax = 0.988 | l = −14→14 |
34747 measured reflections |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.037 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.098 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.04 | w = 1/[σ2(Fo2) + (0.0477P)2 + 0.3201P] where P = (Fo2 + 2Fc2)/3 |
2179 reflections | (Δ/σ)max < 0.001 |
161 parameters | Δρmax = 0.20 e Å−3 |
1 restraint | Δρmin = −0.18 e Å−3 |
C12H15NO4 | V = 1238.96 (10) Å3 |
Mr = 237.25 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 8.3184 (4) Å | µ = 0.10 mm−1 |
b = 13.1554 (6) Å | T = 293 K |
c = 12.0452 (5) Å | 0.19 × 0.14 × 0.13 mm |
β = 109.959 (5)° |
Agilent Xcalibur Atlas Gemini diffractometer | 2179 independent reflections |
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011) | 1738 reflections with I > 2σ(I) |
Tmin = 0.982, Tmax = 0.988 | Rint = 0.045 |
34747 measured reflections |
R[F2 > 2σ(F2)] = 0.037 | 1 restraint |
wR(F2) = 0.098 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.04 | Δρmax = 0.20 e Å−3 |
2179 reflections | Δρmin = −0.18 e Å−3 |
161 parameters |
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. |
x | y | z | Uiso*/Ueq | ||
C1 | 0.57142 (18) | 0.98467 (12) | 0.81385 (13) | 0.0332 (3) | |
C2 | 0.67842 (19) | 0.96019 (12) | 0.92728 (13) | 0.0350 (4) | |
H2A | 0.6433 | 0.9739 | 0.9912 | 0.042* | |
C3 | 0.83553 (19) | 0.91600 (12) | 0.94636 (13) | 0.0355 (4) | |
H3 | 0.9059 | 0.9006 | 1.0229 | 0.043* | |
C4 | 0.88934 (18) | 0.89431 (11) | 0.85144 (13) | 0.0320 (3) | |
C5 | 0.7820 (2) | 0.91711 (13) | 0.73829 (13) | 0.0397 (4) | |
H5 | 0.8165 | 0.9023 | 0.6744 | 0.048* | |
C6 | 0.6234 (2) | 0.96183 (13) | 0.71873 (13) | 0.0419 (4) | |
H6 | 0.5523 | 0.9764 | 0.6422 | 0.050* | |
C7 | 0.29399 (19) | 1.06405 (12) | 0.69952 (13) | 0.0347 (4) | |
C8 | 0.3597 (3) | 1.15075 (14) | 0.64257 (18) | 0.0578 (5) | |
H8A | 0.4046 | 1.2038 | 0.6995 | 0.087* | |
H8B | 0.2675 | 1.1771 | 0.5768 | 0.087* | |
H8C | 0.4484 | 1.1259 | 0.6155 | 0.087* | |
C9 | 0.1450 (2) | 1.10112 (13) | 0.73554 (14) | 0.0421 (4) | |
H9A | 0.1112 | 1.0482 | 0.7779 | 0.063* | |
H9B | 0.0504 | 1.1185 | 0.6662 | 0.063* | |
H9C | 0.1798 | 1.1599 | 0.7852 | 0.063* | |
C10 | 0.23247 (19) | 0.97382 (12) | 0.61524 (12) | 0.0349 (4) | |
C11 | 1.1489 (2) | 0.79383 (12) | 0.95558 (14) | 0.0400 (4) | |
C12 | 1.3223 (2) | 0.76481 (17) | 0.95380 (19) | 0.0633 (6) | |
H12A | 1.4078 | 0.7842 | 1.0271 | 0.095* | |
H12B | 1.3434 | 0.7990 | 0.8897 | 0.095* | |
H12C | 1.3267 | 0.6926 | 0.9434 | 0.095* | |
H1 | 1.099 (3) | 0.8691 (17) | 0.8137 (17) | 0.076* | |
N1 | 1.05465 (16) | 0.85358 (10) | 0.86741 (11) | 0.0362 (3) | |
O1 | 0.41935 (13) | 1.03044 (9) | 0.80935 (8) | 0.0390 (3) | |
O2 | 0.20332 (16) | 0.89154 (9) | 0.66919 (9) | 0.0454 (3) | |
H2 | 0.1674 | 0.8458 | 0.6208 | 0.068* | |
O3 | 0.20982 (17) | 0.97740 (11) | 0.51131 (9) | 0.0566 (4) | |
O4 | 1.09585 (17) | 0.76373 (10) | 1.03443 (11) | 0.0555 (4) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.0302 (8) | 0.0358 (8) | 0.0335 (8) | −0.0015 (6) | 0.0109 (6) | −0.0033 (6) |
C2 | 0.0367 (8) | 0.0422 (9) | 0.0286 (7) | 0.0008 (7) | 0.0145 (6) | −0.0035 (7) |
C3 | 0.0374 (8) | 0.0405 (9) | 0.0279 (7) | 0.0021 (7) | 0.0101 (6) | −0.0001 (7) |
C4 | 0.0341 (8) | 0.0301 (8) | 0.0351 (8) | −0.0017 (6) | 0.0161 (6) | 0.0002 (6) |
C5 | 0.0417 (9) | 0.0518 (10) | 0.0307 (8) | 0.0021 (8) | 0.0190 (7) | 0.0000 (7) |
C6 | 0.0401 (9) | 0.0567 (11) | 0.0282 (8) | 0.0039 (8) | 0.0106 (7) | 0.0009 (7) |
C7 | 0.0328 (8) | 0.0373 (9) | 0.0325 (8) | 0.0009 (7) | 0.0092 (6) | 0.0047 (7) |
C8 | 0.0660 (13) | 0.0443 (11) | 0.0709 (13) | −0.0051 (9) | 0.0333 (10) | 0.0093 (9) |
C9 | 0.0390 (9) | 0.0435 (9) | 0.0423 (9) | 0.0073 (7) | 0.0121 (7) | 0.0020 (7) |
C10 | 0.0314 (8) | 0.0453 (9) | 0.0281 (8) | 0.0011 (7) | 0.0105 (6) | 0.0036 (7) |
C11 | 0.0423 (9) | 0.0361 (9) | 0.0462 (9) | 0.0052 (7) | 0.0210 (8) | 0.0040 (7) |
C12 | 0.0519 (11) | 0.0667 (13) | 0.0807 (14) | 0.0208 (10) | 0.0346 (11) | 0.0217 (11) |
N1 | 0.0377 (7) | 0.0386 (7) | 0.0385 (7) | 0.0047 (6) | 0.0211 (6) | 0.0056 (6) |
O1 | 0.0312 (6) | 0.0541 (7) | 0.0295 (5) | 0.0068 (5) | 0.0073 (4) | −0.0041 (5) |
O2 | 0.0633 (8) | 0.0415 (7) | 0.0362 (6) | −0.0136 (6) | 0.0231 (6) | −0.0078 (5) |
O3 | 0.0713 (9) | 0.0697 (9) | 0.0273 (6) | −0.0061 (7) | 0.0149 (6) | 0.0010 (6) |
O4 | 0.0630 (8) | 0.0584 (8) | 0.0571 (7) | 0.0249 (6) | 0.0362 (7) | 0.0247 (6) |
C1—O1 | 1.3852 (18) | C8—H8A | 0.9600 |
C1—C6 | 1.389 (2) | C8—H8B | 0.9600 |
C1—C2 | 1.390 (2) | C8—H8C | 0.9600 |
C2—C3 | 1.376 (2) | C9—H9A | 0.9600 |
C2—H2A | 0.9300 | C9—H9B | 0.9600 |
C3—C4 | 1.392 (2) | C9—H9C | 0.9600 |
C3—H3 | 0.9300 | C10—O3 | 1.2015 (17) |
C4—C5 | 1.383 (2) | C10—O2 | 1.3268 (19) |
C4—N1 | 1.4264 (19) | C11—O4 | 1.2410 (18) |
C5—C6 | 1.389 (2) | C11—N1 | 1.339 (2) |
C5—H5 | 0.9300 | C11—C12 | 1.499 (2) |
C6—H6 | 0.9300 | C12—H12A | 0.9600 |
C7—O1 | 1.4461 (18) | C12—H12B | 0.9600 |
C7—C8 | 1.525 (2) | C12—H12C | 0.9600 |
C7—C9 | 1.526 (2) | N1—H1 | 0.86 (2) |
C7—C10 | 1.532 (2) | O2—H2 | 0.8200 |
O1—C1—C6 | 126.82 (13) | C7—C8—H8C | 109.5 |
O1—C1—C2 | 114.14 (12) | H8A—C8—H8C | 109.5 |
C6—C1—C2 | 119.04 (14) | H8B—C8—H8C | 109.5 |
C3—C2—C1 | 120.99 (13) | C7—C9—H9A | 109.5 |
C3—C2—H2A | 119.5 | C7—C9—H9B | 109.5 |
C1—C2—H2A | 119.5 | H9A—C9—H9B | 109.5 |
C2—C3—C4 | 120.18 (14) | C7—C9—H9C | 109.5 |
C2—C3—H3 | 119.9 | H9A—C9—H9C | 109.5 |
C4—C3—H3 | 119.9 | H9B—C9—H9C | 109.5 |
C5—C4—C3 | 118.96 (14) | O3—C10—O2 | 123.53 (15) |
C5—C4—N1 | 118.86 (13) | O3—C10—C7 | 123.93 (14) |
C3—C4—N1 | 122.12 (13) | O2—C10—C7 | 112.52 (12) |
C4—C5—C6 | 121.01 (14) | O4—C11—N1 | 121.96 (14) |
C4—C5—H5 | 119.5 | O4—C11—C12 | 121.67 (15) |
C6—C5—H5 | 119.5 | N1—C11—C12 | 116.36 (14) |
C1—C6—C5 | 119.80 (14) | C11—C12—H12A | 109.5 |
C1—C6—H6 | 120.1 | C11—C12—H12B | 109.5 |
C5—C6—H6 | 120.1 | H12A—C12—H12B | 109.5 |
O1—C7—C8 | 112.51 (14) | C11—C12—H12C | 109.5 |
O1—C7—C9 | 103.87 (11) | H12A—C12—H12C | 109.5 |
C8—C7—C9 | 109.84 (14) | H12B—C12—H12C | 109.5 |
O1—C7—C10 | 110.04 (12) | C11—N1—C4 | 127.18 (12) |
C8—C7—C10 | 111.79 (13) | C11—N1—H1 | 116.3 (15) |
C9—C7—C10 | 108.42 (12) | C4—N1—H1 | 116.5 (15) |
C7—C8—H8A | 109.5 | C1—O1—C7 | 122.17 (11) |
C7—C8—H8B | 109.5 | C10—O2—H2 | 109.5 |
H8A—C8—H8B | 109.5 | ||
O1—C1—C2—C3 | −178.80 (14) | O1—C7—C10—O2 | 43.10 (16) |
C6—C1—C2—C3 | 1.4 (2) | C8—C7—C10—O2 | 168.89 (14) |
C1—C2—C3—C4 | −0.5 (2) | C9—C7—C10—O2 | −69.88 (16) |
C2—C3—C4—C5 | −0.5 (2) | O4—C11—N1—C4 | 2.6 (3) |
C2—C3—C4—N1 | 176.59 (14) | C12—C11—N1—C4 | −177.66 (16) |
C3—C4—C5—C6 | 0.6 (2) | C5—C4—N1—C11 | −153.32 (16) |
N1—C4—C5—C6 | −176.60 (15) | C3—C4—N1—C11 | 29.6 (2) |
O1—C1—C6—C5 | 178.93 (15) | C6—C1—O1—C7 | −2.1 (2) |
C2—C1—C6—C5 | −1.3 (2) | C2—C1—O1—C7 | 178.16 (13) |
C4—C5—C6—C1 | 0.3 (3) | C8—C7—O1—C1 | −65.53 (19) |
O1—C7—C10—O3 | −138.24 (15) | C9—C7—O1—C1 | 175.74 (13) |
C8—C7—C10—O3 | −12.4 (2) | C10—C7—O1—C1 | 59.85 (17) |
C9—C7—C10—O3 | 108.79 (17) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O2i | 0.87 (2) | 2.21 (2) | 3.081 (2) | 174 (2) |
O2—H2···O4ii | 0.82 | 1.76 | 2.572 (2) | 172 |
C3—H3···O4 | 0.93 | 2.37 | 2.874 (2) | 114 |
C2—H2A···O1iii | 0.93 | 2.63 | 3.536 | 166 |
C5—H5···O3iv | 0.93 | 2.69 | 3.333 | 127 |
Symmetry codes: (i) x+1, y, z; (ii) x−1, −y+3/2, z−1/2; (iii) −x+1, −y+2, −z+2; (iv) −x+1, −y+2, −z+1. |
Experimental details
Crystal data | |
Chemical formula | C12H15NO4 |
Mr | 237.25 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 293 |
a, b, c (Å) | 8.3184 (4), 13.1554 (6), 12.0452 (5) |
β (°) | 109.959 (5) |
V (Å3) | 1238.96 (10) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.10 |
Crystal size (mm) | 0.19 × 0.14 × 0.13 |
Data collection | |
Diffractometer | Agilent Xcalibur Atlas Gemini diffractometer |
Absorption correction | Multi-scan (CrysAlis PRO; Agilent, 2011) |
Tmin, Tmax | 0.982, 0.988 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 34747, 2179, 1738 |
Rint | 0.045 |
(sin θ/λ)max (Å−1) | 0.595 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.037, 0.098, 1.04 |
No. of reflections | 2179 |
No. of parameters | 161 |
No. of restraints | 1 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.20, −0.18 |
Computer programs: CrysAlis PRO (Agilent, 2011), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008), PLATON (Spek, 2009) and DIAMOND (Crystal Impact, 2006).
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O2i | 0.87 (2) | 2.21 (2) | 3.081 (2) | 174 (2) |
O2—H2···O4ii | 0.82 | 1.76 | 2.572 (2) | 172 |
C3—H3···O4 | 0.93 | 2.37 | 2.874 (2) | 114 |
C2—H2A···O1iii | 0.93 | 2.627 | 3.536 | 166 |
C5—H5···O3iv | 0.93 | 2.687 | 3.333 | 127 |
Symmetry codes: (i) x+1, y, z; (ii) x−1, −y+3/2, z−1/2; (iii) −x+1, −y+2, −z+2; (iv) −x+1, −y+2, −z+1. |
Acknowledgements
This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT) under grant No. 100608.
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Fibrates, such as bezafibrate, clofibrate and fenofibrate, which are ligands for the nuclear receptor PPAR α (Peroxisome Proliferator-Activated Receptor), are used as therapeutic agents in the treatment of dyslipidemia, heart disease and diabetic complications in humans (Forcheron et al.,2002). The fibrate pharmacophore has been of interest to medicinal chemists, and it is a widely used class of lipid-modifying agents that decrease plasma triglycerides (Thorp & Waring, 1962; Miller & Spence, 1998). On the other hand, paracetamol is broadly used as over-the-counter analgesic and antipyretic agent (Kis et al., 2005). In order to assist our knowledge about the stereo electronic requirements from these kinds of molecules to shown antihyperlipidemic activity, we have synthesized and determined the crystal structure of a closed-related nitrofibrate analogue (Navarrete-Vázquez et al., 2008), as well as the compound ethyl 2-[4-(acetylamino)phenoxy]-2-methylpropanoate, which is a bioisoster of clofibrate, with an acetamide group instead of chlorine atom (Navarrete-Vázquez et al.,2011). The last structure resembles to paracetamol, a well known analgesic and antipyretic agent. In this case, the hydrolysis product was obtained in order to find a new biologically active chemical entity.
In (I), all bond lengths and angles show normal values.
In the crystal structure, neighboring molecules are linked through N—H···O, O—H···O hydrogen bonds (Jeffrey, 1997) and weak C—H···O hydrogen bonds (Desiraju, 1996) forming a three dimensional network, Table 1. In the hydrogen-bond pattern, the N—H···O and O—H···O hydrogen bonds are forming corrugated sheets. These sheets are composed of R44(28) graph set motifs (Bernstein, et al., 1995), (Fig. 2, Table 1). Neighboring sheets are further linked by weak C—H···O hydrogen bonds, generating the three dimensional network.