2-Methyl-4-(4-nitro­phen­yl)but-3-yn-2-ol: crystal structure, Hirshfeld surface analysis and computational chemistry study

In the title mol­ecule, di-methyl­hydroxy and 4-nitro­benzene groups cap a central di-substituted acetyl­ene residue. The extended structure features flattened, hexa­meric clusters sustained by hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds.

Abstract

The di-substituted acetyl­ene residue in the title compound, C₁₁H₁₁NO₃, is capped at either end by di-methyl­hydroxy and 4-nitro­benzene groups; the nitro substituent is close to co-planar with the ring to which it is attached [dihedral angle = 9.4 (3)°]. The most prominent feature of the mol­ecular packing is the formation, via hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds, of hexa­meric clusters about a site of symmetry . The aggregates are sustained by 12-membered {⋯OH}₆ synthons and have the shape of a flattened chair. The clusters are connected into a three-dimensional architecture by benzene-C—H⋯O(nitro) inter­actions, involving both nitro-O atoms. The aforementioned inter­actions are readily identified in the calculated Hirshfeld surface. Computational chemistry indicates there is a significant energy, primarily electrostatic in nature, associated with the hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds. Dispersion forces are more important in the other identified but, weaker inter­molecular contacts.

Chemical context  

Protected acetyl­enes represent a highly privileged class of synthetic inter­mediates for the construction of a variety of different organic compounds (Tan et al., 2013 ▸). The preparation of protected aryl­acetyl­enes can be achieved by the palladium-catalysed Sonogashira cross-coupling of mono-protected acetyl­enes, such as tri­methyl­silyl­acetyl­ene (TMSA), triisopropysilyl­acetyl­ene (TIPSA) and 2-methyl-3-butyn-2-ol (MEBYNOL), with aryl halides (Hundertmark et al., 2000 ▸; Erdélyi & Gogoll, 2001 ▸). Despite the relevance of protected acetyl­enes, the release of the protecting group remains a challenge. While tri­alkyl­silyl groups can be readily removed by treatment with bases or fluoride salts under mild reaction conditions, tri­alkyl­silyl­acetyl­enes are rather expensive, in comparison to MEYBNOL, thereby limiting their use to small-scale synthesis. Thus, MEBYNOL can be viewed as one alternative to other acetyl­ene sources. Nevertheless, the reaction conditions for the release of the 2-hy­droxy­isopropyl protecting group usually requires harsh reaction conditions. Hence, several synthetic routes combine the release of the terminal acetyl­ene with a further transformation, without the isolation of the inter­mediate (Li et al., 2015 ▸). It was in the context of such considerations that the title acetyl­ene compound, (I), previously reported (Bleicher et al., 1998 ▸), was isolated and crystallized. Herein, the crystal and mol­ecular structures of (I) are described along with a detailed analysis of the mol­ecular packing by Hirshfeld surface analysis, non-covalent inter­action plots and computational chemistry.

Structural commentary  

The mol­ecular structure of (I), Fig. 1 ▸, features a di-substituted acetyl­ene residue. At one end, the acetyl­ene terminates with a di-methyl­hydroxy substituent and at the other end, with a 4-nitro­benzene group. The nitro group is slightly inclined out of the plane of the benzene ring to which it is connected, with the dihedral angle between the planes being 9.4 (3)°.

Figure 1.

The mol­ecular structure of (I), showing the atom-labelling scheme and displacement ellipsoids at the 35% probability level.

Supra­molecular features  

The spectacular feature of the mol­ecular packing of (I) is the presence of hexa­meric clusters connected by hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds, Table 1 ▸. As seen from Fig. 2 ▸(a), the six-mol­ecule aggregates are sustained by 12-membered {⋯OH}₆ synthons. The aggregates are disposed about a site of symmetry so the rings have the shape of a flattened chair, Fig. 2 ▸(b). The crystal also features weak benzene-C—H⋯O(nitro) inter­actions, involving both nitro-O atoms. In essence, one nitro group of one mol­ecule forms two such inter­actions with two symmetry-related mol­ecules to form a supra­molecular chain along the c-axis direction with helical symmetry (3₁ screw axis), Fig. 3 ▸(a). An end-on view of the chain is shown in Fig. 3 ▸(b). These weak benzene-C—H⋯O(nitro) inter­actions serve to link the six-mol­ecule aggregates into a three-dimensional architecture, Fig. 4 ▸.

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1O⋯O1i	0.82	1.87	2.682 (2)	173
C10—H10⋯O3ii	0.93	2.67	3.548 (3)	157
C11—H11⋯O2iii	0.93	2.68	3.467 (3)	143

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

Figure 2.

Hydrogen bonding in the crystal of (I): (a) an end-on view of the hexa­gon sustained by hy­droxy-O—H⋯O(hy­droxy) hydrogen bonding (shown as orange dashed lines) and (b) a side-on view. Non-participating hydrogen atoms have been removed for reasons of clarity.

Figure 3.

Details of benzene-C—H⋯O(nitro) inter­actions (shown as blue dashed lines) in the crystal of (I): (a) a view of the supra­molecular chain along the c-axis direction and (b) an end-on view of the chain.

Figure 4.

A view of the unit-cell contents of (I) shown in projection down the c axis. The hy­droxy-O—H⋯O(hy­droxy) hydrogen bonding and benzene-C—H⋯O(nitro) inter­actions are shown as orange and blue dashed lines, respectively.

Hirshfeld surface analysis  

The Hirshfeld surface calculations for (I) were performed in accord with protocols described in a recently published paper (Tan et al., 2019 ▸) employing Crystal Explorer 17 (Turner et al., 2017 ▸). On the Hirshfeld surfaces mapped over d _norm in Fig. 5 ▸(a), the donors and acceptors of O—H⋯O hydrogen bond involving the atoms of the hydroxyl group are characterized as bright-red spots. The faint-red spots near the phenyl-H10, H11 and nitro-O2, O3 atoms on the d _norm-mapped Hirshfeld surface in Fig. 5 ▸(b) represent the effect of weak C—H⋯O inter­actions as listed in Table 1 ▸. The Hirshfeld surface mapped over electrostatic potential in Fig. 6 ▸ also illustrates the donors and acceptors of the indicated inter­actions through blue and red regions corresponding to positive and negative electrostatic potentials, respectively. In the view of a surface mapped with the shape-index property, Fig. 7 ▸(a), the C—H⋯π/π⋯H—C contacts listed in Table 2 ▸ are evident as the blue bump and a bright-orange region about the participating atoms. The overlap between benzene (C6–C11) ring of a reference mol­ecule within the Hirshfeld surface mapped over curvedness and the symmetry related ring, Fig. 7 ▸(b) is an indication of the π–π stacking inter­action between them [centroid–centroid distance = 3.7873 (14) Å; symmetry operation: 1 − x, 1 − y, 1 − z].

Figure 5.

Two views of the Hirshfeld surface for (I) mapped over d _norm: (a) in the range −0.202 to +1.400 arbitrary units and (b) in the range −0.102 to +1.400 arbitrary units, highlighting, respectively, inter­molecular O—H⋯O and C—H⋯O inter­actions through black dashed lines.

Figure 6.

A view of the Hirshfeld surface for (I) mapped over the electrostatic potential in the range −0.098 to + 0.180 atomic units. The red and blue regions represent negative and positive electrostatic potentials, respectively, and show the acceptors and donors of inter­molecular inter­actions, respectively.

Figure 7.

(a) A view of the Hirshfeld surface for (I) mapped with the shape-index property, highlighting inter­molecular C—H⋯π/π⋯H—C contacts by blue bumps and bright-orange concave regions, respectively, and (b) a view of the Hirshfeld surface mapped over curvedness, highlighting π—π contacts between symmetry-related (C6-C11) rings.

Table 2. Summary of short inter­atomic contacts (Å) in (I).

The inter­atomic distances are calculated in Crystal Explorer 17 (Turner et al., 2017 ▸) whereby the X—H bond lengths are adjusted to their neutron values.

Contact	Distance	Symmetry operation
O1⋯H3A	2.71	+ y,  − x + y,  − z
O2⋯H2B	2.69	− y,  + x − y, − + z
O3⋯H2A	2.69	1 − x, 1 − y, 1 − z
C1⋯H1O	2.85	+ y,  − x + y,  − z
C5⋯H3C	2.79	+ y,  − x + y,  − z
C7⋯H2C	2.85	+ y,  − x + y,  − z
C8⋯H2C	2.80	+ y,  − x + y,  − z

The overall two-dimensional fingerprint plot for (I), Fig. 8 ▸(a), and those delineated into H⋯H, O⋯H/H⋯O, C⋯H/H⋯C and C⋯C contacts (McKinnon et al., 2007 ▸) are illustrated in Fig. 8 ▸(b)–(e), respectively, and provide more information on the influence of short inter­atomic contacts upon the mol­ecular packing. The percentage contributions from the different inter­atomic contacts to the Hirshfeld surface are summarized in Table 3 ▸. The greatest contribution to the Hirshfeld surface of 38.2% are derived from H⋯H contacts but these exert a negligible influence on the packing, at least in terms of directional inter­actions, as the inter­atomic distances are greater than sum of their van der Waals radii. The pair of long spikes with their tips at d _e + d _i ∼1.8 Å in the fingerprint plot delineated into O⋯H/H⋯O contacts, Fig. 8 ▸(c), are due to the presence of the O—H⋯O hydrogen bond, whereas the points corresponding to comparatively weak inter­molecular C—H⋯O inter­actions, Table 1 ▸, and the short inter­atomic O⋯H/H⋯O contacts are merged within the plot, Table 2 ▸. The presence of the C—H⋯π contact, formed by the methyl-H2C atom and the benzene (C6–C11) ring, results in short inter­atomic C⋯H/H⋯C contacts, Table 2 ▸ and Fig. 7 ▸(a), and by the pair of forceps-like tips at d _e + d _i ∼2.8 Å in Fig. 8 ▸(d). The points corresponding to other such short inter­atomic contacts involving the acetyl­ene-C5 and methyl-C3—H3c atoms at longer separations are merged within the plot. The arrow-shaped distribution of points around d _e + d _i ∼3.6 Å in the fingerprint plot delineated into C⋯C contacts, Fig. 8 ▸(e), indicate π–π overlap between symmetry-related benzene (C6–C11) rings, as illustrated in Fig. 7 ▸(b). The small percentage contributions from the other inter­atomic contacts listed in Table 3 ▸ have negligible influence upon the mol­ecular packing as their separations are greater than the sum of the respective van der Waals radii.

Figure 8.

(a) The full two-dimensional fingerprint plot for (I) and (b)–(e) those delineated into H⋯H, O⋯H/H⋯O, C⋯H/H⋯C and C⋯C contacts, respectively.

Table 3. Percentage contributions of inter­atomic contacts to the Hirshfeld surface for (I).

Contact	Percentage contribution
H⋯H	38.2
O⋯H/H⋯O	32.1
C⋯H/H⋯C	20.0
C⋯C	4.2
N⋯O/O⋯N	1.7
O⋯O	1.6
C⋯N/N⋯C	1.0
N⋯H/H⋯N	0.8
C⋯O/O⋯C	0.4

Inter­action energies  

The pairwise inter­action energies between the mol­ecules within the crystal were calculated by summing up four energy components comprising electrostatic (E _ele), polarization (E _pol), dispersion (E _dis) and exchange-repulsion (E _rep) terms after applying relevant scale factors (Turner et al., 2017 ▸). These energies were obtained by using the wave function calculated at the B3LYP/6-31G(d,p) level. The strength and the nature of inter­molecular inter­actions in terms of their energies are qu­anti­tatively summarized in Table 4 ▸. The energies calculated for the different inter­molecular inter­actions indicate that the electrostatic contribution is dominant in the O—H⋯O hydrogen bond whereas the dispersive component has a significant influence due to the presence of short inter­atomic C⋯H/H⋯C and O⋯H/H⋯O contacts occurring between the same pair of mol­ecules. The C—H⋯O2(nitro) inter­action has almost the same contributions from the electrostatic and dispersive components. This is in contrast to a major contribution only from the dispersive component for the analogous contact involving the nitro-O3 atom. The dispersion energy component makes the major contribution to the relevant pairs of mol­ecules involved in other short inter­atomic contacts, Table 4 ▸, as well as in C—H⋯π and π–π stacking inter­actions. It is also evident from a comparison of the total energies of inter­molecular inter­actions, Table 4 ▸, that the O—H⋯O hydrogen bond and π–π stacking inter­action are stronger than the other inter­actions, and, of these, the inter­molecular C—H⋯O contacts are weaker than the C—H⋯π inter­actions.

Table 4. Summary of inter­action energies (kJ mol⁻¹) calculated for (I).

Contact	R (Å)	E ele	E pol	E dis	E rep	E tot
O1—H1O⋯O1i
H3A⋯O1i	8.80	−52.3	−12.0	−18.8	72.7	−35.7
H1O⋯C1i
C10—H10⋯O3ii	8.28	−3.7	−1.4	−9.2	4.9	−9.8
C11—H11⋯O2iii	9.51	−5.8	−1.7	−5.7	5.0	−9.6
O3⋯H2A iv
(C6–C11)⋯(C6–C11)iv	4.25	−9.4	−1.8	−47.1	28.9	−34.4
H3C⋯C5v
H2C⋯C7v
H2C⋯C8v	5.78	−2.1	−0.7	−28.6	18.2	−16.4
C2—H2C⋯(C6–C11)v

Symmetry codes: (i)  + x − y,  − x,  − z; (ii)  − x + y, 4/3 − x,  + z; (iii) 4/3 − y,  + x − y,  + z; (iv) 1 − x, 1 − y, 1 − z; (v)  + x − y, −  + x,  − z.

The magnitudes of inter­molecular energies are represented graphically by energy frameworks to view the supra­molecular architecture of the crystal through the cylinders joining centroids of mol­ecular pairs by using red, green and blue colour codes for the components E _ele, E _disp and E _tot, respectively, Fig. 9 ▸. The radius of the cylinder is proportional to the magnitude of inter­action energy, which are adjusted to the same scale factor of 30 with a cut-off value of 3 kJ mol⁻¹ within 2 × 2 × 2 unit cells.

Figure 9.

A comparison of the energy frameworks calculated for (I) and viewed down the c axis showing (a) electrostatic potential force, (b) dispersion force and (c) total energy. The energy frameworks were adjusted to the same scale factor of 30 with a cut-off value of 3 kJ mol⁻¹ within 2 × 2 × 2 unit cells.

Non-covalent inter­action plots  

Non-covalent inter­action plot (NCIplot) analyses provide a visual representation of the nature of the contact between specified species in crystals (Johnson et al., 2010 ▸; Contreras-Garcá et al., 2011 ▸). This method is based on the electron density (and derivatives) and was employed in the present study to confirm the nature of some of the specified inter­molecular contacts. The colour-based isosurfaces generated correspond to the values of sign(λ²)ρ(r), where ρ is the electron density and λ² is the second eigenvalue of the Hessian matrix of ρ. Crucially, through a three-colour scheme, a specific inter­action can be identified as being attractive or otherwise. Thus, a green isosurface indicates a weakly attractive inter­action whereas a blue isosurface indicates an attractive inter­action; a repulsive inter­action appears red. The isosurfaces for three identified inter­molecular inter­actions are given in the upper view of Fig. 10 ▸. Thus, in Fig. 10 ▸(a), a green isosurface is apparent for the conventional hy­droxy-O—H⋯O(hy­droxy) hydrogen bond. Similarly, green isosurfaces are seen between the inter­acting atoms involved in the phenyl-C—H⋯O(nitro), Fig. 10 ▸(b), and the methyl-C—H⋯π(C11–C16), Fig. 10 ▸(c), inter­actions.

Figure 10.

Non-covalent inter­action plots for (a) hy­droxy-O—H⋯O(hy­droxy) hydrogen bonding, (b) the phenyl-C—H⋯O(nitro) inter­actions and (c) the methyl-C—H⋯π(C11–C16) inter­actions.

The lower views of Fig. 10 ▸, show the plots of the RDG versus sign(λ²)ρ(r). The non-covalent inter­action peaks appear at density values less than 0.0 atomic units, consistent with their being weakly attractive inter­actions.

Database survey  

There are four literature precedents for (I) with varying substitution patterns in the appended benzene ring. These are the unsubstituted ‘parent’ compound [(II); FESMEV; Singelenberg & van Eijck, 1987 ▸], and the 4-cyano [(III}; HEFDAA; Clegg, 2017 ▸], 4-meth­oxy [(IV); YUQPEG; Eissmann et al., 2010 ▸] and 3-acetyl-4-hy­droxy [(V); UVETAS; Hübscher et al., 2016 ▸] derivatives. Selected geometric parameters for (I)–(IV) are collated in Table 5 ▸. Of particular inter­est in the mode of supra­molecular association in their crystals. As seen from Fig. 11 ▸, four distinct patterns appear. In (V), three independent mol­ecules comprise the asymmetric unit and these associate about a centre of inversion in space group P2₁/c to form a hexa­meric clusters via hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds as seen in (I), Fig. 11 ▸(a); intra­molecular hy­droxy-O—H⋯O(carbon­yl) hydrogen bonds are also apparent. In (III), the two independent mol­ecules comprising the asymmetric unit associate about a centre of inversion in space group P2₁/n into a supra­molecular dimer via pairs of hy­droxy-O—H⋯O(hy­droxy) and hy­droxy-O—H⋯N(cyano) hydrogen bonds as shown in Fig. 11 ▸(b). In this case, one independent hy­droxy-oxygen atom and one cyano-nitro­gen atom do not accept a hydrogen-bonding inter­action. Three crystallographically independent mol­ecules are also found in (II) (space group Pca2₁) and these self-associate to form a supra­molecular chain via hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds with non-crystallographic threefold symmetry, Fig. 11 ▸(c). Finally, zigzag supra­molecular chains sustained by hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds are found in the crystal of (IV), Fig. 11 ▸(d) in space group Pbca.

Table 5. Geometric data (Å, °) for related 2-methyl-4-(ar­yl)but-3-yn-2-ol mol­ecules.

Compound	Z′	Cring—Cacetyl­ene	Cacetyl­ene—Cacetyl­ene	Cacetyl­ene—Cquaternary	Supra­molecular motif	Reference
(I)	1	1.438 (3)	1.189 (3)	1.471 (3)	hexa­mer	This work
(II)	3	1.443 (5)	1.211 (5)	1.454 (5)	chain	Singelenberg & van Eijck (1987 ▸)
		1.437 (6)	1.192 (6)	1.479 (6)
		1.437 (5)	1.189 (5)	1.479 (5)
(III)	2	1.441 (2)	1.193 (2)	1.490 (2)	dimer	Clegg (2017 ▸)
		1.435 (2)	1.1895 (2)	1.480 (2)
(IV)	1	1.4377 (16)	1.2000 (16)	1.4791 (16)	chain	Eissmann et al. (2010 ▸)
(V)	3	1.4418 (18)	1.1951 (19)	1.4764 (19)	hexa­mer	Hübscher et al. (2016 ▸)
		1.444 (2)	1.194 (2)	1.4859 (19)
		1.4402 (19)	1.1904 (19)	1.4723 (18)

Figure 11.

Supra­molecular association via hy­droxy-O—H⋯O(hy­droxy) hydrogen bonds in (II)–(IV): (a) hexa­meric cluster in (V), (b) dimeric aggregate sustained by additional hy­droxy-O—H⋯N(cyano) hydrogen bonds in (III), (c) views of the supra­molecular chain in (II) with non-crystallographic threefold symmetry and (d) views of the zigzag supra­molecular chain in (IV).

Synthesis and crystallization  

The title compound was prepared as per the literature procedure (Bleicher et al., 1998 ▸). Yield: 87%. Yellow solid, m.p. 377–379 K. ¹H NMR (400 MHz, CDCl₃): δ = 8.16 (dt, J = 8.9, 2.2 Hz, 2H), 7.54 (dt, J = 8.9, 2.2 Hz, 2H), 2.24 (s, 1H) and 1.63 (s, 6H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 147.2, 132.5, 129.8, 123.6, 99.2, 80.5, 66.7 and 31.3 ppm. Irregular colourless crystals of (I) for the X-ray study were grown by slow evaporation of its ethyl acetate solution.

Refinement details  

Crystal data, data collection and structure refinement details are summarized in Table 6 ▸. The carbon-bound H atoms were placed in calculated positions (C—H = 0.93–0.96 Å) and were included in the refinement in the riding-model approximation, with U _iso(H) set to 1.2–1.5U _eq(C). The O-bound H atom was refined with a distance restraint of 0.82±0.01 Å, and with U _iso(H) = 1.5U _eq(O).

Table 6. Experimental details.

Crystal data
Chemical formula	C11H11NO3
M r	205.21
Crystal system, space group	Trigonal, R :H
Temperature (K)	296
a, c (Å)	26.3146 (14), 8.1205 (5)
V (Å3)	4869.8 (6)
Z	18
Radiation type	Mo Kα
μ (mm−1)	0.09
Crystal size (mm)	0.34 × 0.28 × 0.16
Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Sheldrick, 1996 ▸)
T min, T max	0.440, 0.745
No. of measured, independent and observed [I > 2σ(I)] reflections	10643, 2230, 1513
R int	0.080
(sin θ/λ)max (Å−1)	0.627
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.053, 0.149, 1.05
No. of reflections	2230
No. of parameters	139
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.16, −0.27

Computer programs: APEX2 and SAINT (Bruker, 2009 ▸), SIR2014 (Burla et al., 2015 ▸), SHELXL2018/3 (Sheldrick, 2015 ▸), ORTEP-3 for Windows (Farrugia, 2012 ▸), DIAMOND (Brandenburg, 2006 ▸), MarvinSketch (ChemAxon, 2010 ▸) and publCIF (Westrip, 2010 ▸).

Supplementary Material

CCDC reference: 1941466

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

supplementary crystallographic information

Crystal data

C11H11NO3	Dx = 1.260 Mg m−3
Mr = 205.21	Mo Kα radiation, λ = 0.71073 Å
Trigonal, R3:H	Cell parameters from 2006 reflections
a = 26.3146 (14) Å	θ = 2.7–23.9°
c = 8.1205 (5) Å	µ = 0.09 mm−1
V = 4869.8 (6) Å3	T = 296 K
Z = 18	Irregular, colourles
F(000) = 1944	0.34 × 0.28 × 0.16 mm

Data collection

Bruker APEXII CCD diffractometer	1513 reflections with I > 2σ(I)
φ and ω scans	Rint = 0.080
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	θmax = 26.4°, θmin = 1.6°
Tmin = 0.440, Tmax = 0.745	h = −32→32
10643 measured reflections	k = −32→32
2230 independent reflections	l = −9→10

Refinement

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)] = 0.053	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.149	H-atom parameters constrained
S = 1.05	w = 1/[σ2(Fo2) + (0.0511P)2 + 3.9317P] where P = (Fo2 + 2Fc2)/3
2230 reflections	(Δ/σ)max < 0.001
139 parameters	Δρmax = 0.16 e Å−3
1 restraint	Δρmin = −0.27 e Å−3

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.56993 (7)	0.33529 (6)	0.78650 (17)	0.0513 (4)
H1O	0.569241	0.305973	0.823659	0.077*
O2	0.54778 (9)	0.61319 (8)	0.0578 (2)	0.0811 (6)
O3	0.62154 (8)	0.66736 (8)	0.2126 (3)	0.0785 (6)
N1	0.58062 (9)	0.61978 (9)	0.1723 (3)	0.0565 (5)
C1	0.53437 (9)	0.31996 (8)	0.6425 (2)	0.0388 (5)
C2	0.47123 (10)	0.27726 (10)	0.6889 (3)	0.0612 (7)
H2A	0.459150	0.293892	0.775102	0.092*
H2B	0.468058	0.241200	0.726620	0.092*
H2C	0.446510	0.269637	0.594458	0.092*
C3	0.55665 (12)	0.29361 (11)	0.5140 (3)	0.0634 (7)
H3A	0.551638	0.257044	0.553954	0.095*
H3B	0.597504	0.320235	0.493279	0.095*
H3C	0.534860	0.286951	0.413769	0.095*
C4	0.54001 (9)	0.37468 (9)	0.5772 (2)	0.0439 (5)
C5	0.54464 (10)	0.41762 (9)	0.5145 (2)	0.0458 (5)
C6	0.55281 (9)	0.46950 (9)	0.4317 (2)	0.0407 (5)
C7	0.51138 (9)	0.46599 (9)	0.3192 (2)	0.0424 (5)
H7	0.477559	0.430184	0.300298	0.051*
C8	0.52018 (9)	0.51543 (9)	0.2351 (2)	0.0441 (5)
H8	0.492523	0.513284	0.159933	0.053*
C9	0.57045 (9)	0.56768 (9)	0.2648 (2)	0.0416 (5)
C10	0.61185 (10)	0.57274 (9)	0.3773 (3)	0.0515 (6)
H10	0.645262	0.608821	0.396842	0.062*
C11	0.60276 (10)	0.52332 (10)	0.4602 (3)	0.0509 (6)
H11	0.630422	0.526000	0.536242	0.061*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.0636 (10)	0.0378 (8)	0.0474 (8)	0.0216 (7)	−0.0238 (7)	−0.0036 (6)
O2	0.0870 (14)	0.0812 (13)	0.0791 (12)	0.0450 (11)	−0.0075 (11)	0.0315 (10)
O3	0.0734 (13)	0.0474 (10)	0.1082 (15)	0.0254 (10)	0.0056 (11)	0.0178 (10)
N1	0.0592 (12)	0.0508 (12)	0.0661 (13)	0.0324 (11)	0.0118 (10)	0.0164 (9)
C1	0.0463 (11)	0.0376 (10)	0.0322 (9)	0.0206 (9)	−0.0083 (8)	−0.0026 (8)
C2	0.0501 (14)	0.0552 (14)	0.0690 (15)	0.0191 (12)	−0.0049 (11)	0.0064 (11)
C3	0.0898 (19)	0.0674 (16)	0.0493 (13)	0.0514 (15)	−0.0007 (12)	−0.0056 (11)
C4	0.0518 (12)	0.0460 (12)	0.0365 (10)	0.0264 (10)	−0.0029 (9)	0.0014 (9)
C5	0.0577 (13)	0.0484 (12)	0.0364 (10)	0.0303 (11)	0.0001 (9)	0.0009 (9)
C6	0.0535 (12)	0.0444 (11)	0.0311 (9)	0.0297 (10)	0.0052 (8)	0.0026 (8)
C7	0.0452 (11)	0.0423 (11)	0.0400 (10)	0.0223 (10)	0.0024 (9)	0.0009 (8)
C8	0.0480 (12)	0.0543 (13)	0.0379 (10)	0.0317 (11)	0.0011 (9)	0.0045 (9)
C9	0.0486 (12)	0.0431 (11)	0.0413 (10)	0.0291 (10)	0.0088 (9)	0.0080 (8)
C10	0.0491 (13)	0.0422 (12)	0.0598 (13)	0.0203 (10)	−0.0055 (10)	−0.0006 (10)
C11	0.0566 (14)	0.0538 (13)	0.0468 (11)	0.0310 (11)	−0.0109 (10)	−0.0005 (10)

Geometric parameters (Å, º)

O1—C1	1.424 (2)	C3—H3C	0.9600
O1—H1O	0.8200	C4—C5	1.189 (3)
O2—N1	1.221 (3)	C5—C6	1.438 (3)
O3—N1	1.219 (2)	C6—C11	1.387 (3)
N1—C9	1.466 (3)	C6—C7	1.390 (3)
C1—C4	1.471 (3)	C7—C8	1.382 (3)
C1—C2	1.516 (3)	C7—H7	0.9300
C1—C3	1.523 (3)	C8—C9	1.371 (3)
C2—H2A	0.9600	C8—H8	0.9300
C2—H2B	0.9600	C9—C10	1.376 (3)
C2—H2C	0.9600	C10—C11	1.375 (3)
C3—H3A	0.9600	C10—H10	0.9300
C3—H3B	0.9600	C11—H11	0.9300
C1—O1—H1O	109.5	H3B—C3—H3C	109.5
O3—N1—O2	123.3 (2)	C5—C4—C1	175.7 (2)
O3—N1—C9	118.5 (2)	C4—C5—C6	176.5 (2)
O2—N1—C9	118.2 (2)	C11—C6—C7	119.25 (18)
O1—C1—C4	106.76 (15)	C11—C6—C5	120.46 (18)
O1—C1—C2	109.11 (16)	C7—C6—C5	120.27 (19)
C4—C1—C2	110.61 (18)	C8—C7—C6	120.36 (19)
O1—C1—C3	110.10 (17)	C8—C7—H7	119.8
C4—C1—C3	108.98 (16)	C6—C7—H7	119.8
C2—C1—C3	111.20 (18)	C9—C8—C7	118.75 (18)
C1—C2—H2A	109.5	C9—C8—H8	120.6
C1—C2—H2B	109.5	C7—C8—H8	120.6
H2A—C2—H2B	109.5	C8—C9—C10	122.25 (18)
C1—C2—H2C	109.5	C8—C9—N1	118.80 (18)
H2A—C2—H2C	109.5	C10—C9—N1	118.95 (19)
H2B—C2—H2C	109.5	C11—C10—C9	118.6 (2)
C1—C3—H3A	109.5	C11—C10—H10	120.7
C1—C3—H3B	109.5	C9—C10—H10	120.7
H3A—C3—H3B	109.5	C10—C11—C6	120.79 (19)
C1—C3—H3C	109.5	C10—C11—H11	119.6
H3A—C3—H3C	109.5	C6—C11—H11	119.6
C11—C6—C7—C8	0.7 (3)	O3—N1—C9—C10	−9.2 (3)
C5—C6—C7—C8	−177.66 (17)	O2—N1—C9—C10	170.3 (2)
C6—C7—C8—C9	0.2 (3)	C8—C9—C10—C11	1.2 (3)
C7—C8—C9—C10	−1.2 (3)	N1—C9—C10—C11	−178.21 (19)
C7—C8—C9—N1	178.28 (17)	C9—C10—C11—C6	−0.3 (3)
O3—N1—C9—C8	171.3 (2)	C7—C6—C11—C10	−0.7 (3)
O2—N1—C9—C8	−9.2 (3)	C5—C6—C11—C10	177.72 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O1i	0.82	1.87	2.682 (2)	173
C10—H10···O3ii	0.93	2.67	3.548 (3)	157
C11—H11···O2iii	0.93	2.68	3.467 (3)	143

Symmetry codes: (i) x−y+1/3, x−1/3, −z+5/3; (ii) −x+y+2/3, −x+4/3, z+1/3; (iii) −y+4/3, x−y+2/3, z+2/3.

Funding Statement

This work was funded by GlaxoSmithKline grant . Conselho Nacional de Desenvolvimento Científico e Tecnológico grants 303207/2017-5 and 308480/2016-3. Fundação de Amparo à Pesquisa do Estado de São Paulo grants 2013/06558-3 and 2014/50249-8. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior grant . Sunway University grant STR-RCTR-RCCM-001-2019.