The crystal structures and Hirshfeld surface analysis of three new bromo-substituted 3-methyl-1-(phenylsulfonyl)-1H-indole derivatives

The crystal structures of three new indole derivative are described. The supramolecular relations in the system were assessed with a Hirshfeld surface analysis and calculation of the interaction energies, which suggest a primary significance of π–π and C—H⋯π interactions involving the indole moieties.


Chemical context
Derivatives of indole exhibit antibacterial (Okabe & Adachi, 1998) and antitumour (Schollmeyer et al., 1995) activities.In particular, 1-(phenylsulfonyl)indoles are applicable to the synthesis of biologically active alkaloids and their analogues, including pyridocarbazoles, such as the anticancer alkaloid ellipticine, carbazoles, furoindoles, pyrroloindoles, indolocarbazoles and other species.Some of the phenylsulfonyl indole compounds have been shown to inhibit the HIV-1 RT enzyme in vitro and HTLVIIIb viral spread in MT-4 human T-lymphoid cells (Williams et al., 1993).In such systems, the phenylsulfonyl moiety may act either as a protecting or an activating group (Jasinski et al., 2009).Since the related halogen-substituted indoles also demonstrate antibacterial and antifungal activity (Piscopo et al., 1990), one can anticipate a range of functional benefits from the halogen derivatization.Thus, substitution by bromine atoms may significantly enhance in vitro blood-brain barrier permeability, providing evidence for improved delivery to the central nervous system (Bouthenet et al., 2011).Bromination on the phenol ring is important for the antimicrobial activity (Gentry et al., 1999).The incorporation of heavy atoms, such as bromine, increases the generation of reactive species during photosensitization (Semenova et al., 2021).In particular, fluorescent Br-substituted dyes are utilized for photodynamic therapy applications (Liu et al., 2021).The fluorescent 4,6dibromoindolenine cyanine revealed excellent properties for optical tumour imaging (Guerrero et al., 2017).Recognizing the importance of such compounds for biochemical applications and drug discovery and our ongoing research into the construction of indole derivatives have prompted us to investigate a series of Br-substituted species.We report herein the crystal structures determination and Hirshfeld surface analysis of three

Figure 2
The molecular structure of compound II, with atom labelling and displacement ellipsoids drawn at the 30% probability level.The dashed line indicates the intramolecular hydrogen bond.

Figure 3
The molecular structure of compound III, with atom labelling and displacement ellipsoids drawn at the 30% probability level.The dashed line indicates the intramolecular hydrogen bond.
119.60 (13) � for III], with a simultaneous decrease in the N1-S1-C9 angles [104.46 (12) � for I, 103.78 (10) � for II and 105.70 (10) � for III] from the ideal tetrahedral value (109.5 � ) are attributed to the Thorpe-Ingold effect (Bassindale, 1984).The widening of the angles may be due to the repulsive interaction between the two short S O bonds.
In all three compounds, the sum of the bond angles around N1 [355.88 (11), 348.62 (17) and 352.89 (12) � for I, II and III, respectively] indicate sp 2 hybridization (Beddoes et al., 1986).At the same time, as a result of the electron-withdrawing character of the phenylsulfonyl groups, the N1-Csp 2 bonds are longer than the standard length value of 1.355 ( 14) A [N1-C1 = 1.419 (3) for I, 1.425 (3) for II and 1.428 (3) A ˚for III and N1-C8 = 1.434 (3) for I, 1.438 (3) for II and 1.437 (3) A ˚for III] (Allen et al., 1987;Cambridge Structural Database (CSD), Version 5.37;Groom et al., 2016).In all the compounds, the certain expansion of the ipso angles at atoms C1, C3 and C4, and the contraction of the apical angles at atoms C2, C5 and C6 are caused by fusion of the smaller pyrrole ring with the six-membered benzene ring and the strain is taken up by the angular distortion rather than by bond-length distortion (Allen, 1981).The geometric parameters of the present compounds agree well with those reported for related structures (Madhan et al., 2022(Madhan et al., , 2023a,b),b).In all three compounds, the molecular conformations are stabilized by weak C2-H2� � �O2 intramolecular interactions with C2� � �O2 = 2.950 (2)-3.057(4) A ˚.

Supramolecular features
With a lack of conventional hydrogen-bond donor functionality, the supramolecular structures of all three compounds are dominated by weaker interactions, namely by weak C-H� � �O, C-H� � �Br and C-H� � �� hydrogen bonds (Tables 1-3) and slipped �-� stacking interactions (Table 4).
In the structure of I, molecules are linked via double bonds involving C2-H2 and C10-H10 donors and O1 i acceptors [C� � �O = 3.306 (4) and 3.503 (4) A ˚; symmetry code: (i) À x + 1, y À 1 2 , À z + 3 2 ] into the chains propagating along the b-axis direction in the crystal (Table 1).The most salient feature of the array is infinite stacking of the indole moieties, which yields columns down the a-axis.Within these columns, pairs of adjacent molecules are held together by �-� interactions or by double CH 3 � � �� bonds, in alternate sequence (Fig. 4).The counterparts of every such pairs are related by inversion [symmetry codes: (iii) À x + 1, À y + 1, À x + 1; (v) À x, À y + 1, À z + 1, respectively.]For the dimer of the first kind, the geometry parameters are consistent with weak slipped �-� interactions.The shortest intercentroid distance is observed between the pyrrole rings (Table 4).However, the centroid of the N1/C1-C8 group (Cg1) is situated almost above the midpoint of the C1 and C6 bridgehead atoms of the neighbouring molecule and therefore both pyrrole-pyrrole [Cg1� � �Cg1 iii = 3.628 (3) A ˚] and pyrrole-benzo [Cg1� � �Cg2 iii = 3.831 (3) A ˚] interactions may be considered.The entire �-� and CH 3 � � �� bonded stack is additionally stabilized by weak hydrogen bonding of the sulfonyl O atoms [C� � �O = 3.302 (5)-3.702(4) A ˚].One can note the functional importance of the methyl group, which is a donor of three highly directional interactions, viz. the C-H� � �O bond and two C-H� � �� bonds (Table 1).
The structure of II inherits the above motif (Fig. 5).In particular, a combination of �-� and CH 3 � � �� interactions assembles the molecules into columns propagating along the a-axis direction in the crystal, in exactly the same manner as observed for compound I.In this case, the interactions are slightly weaker and the corresponding intercentroid distances [Cg1� � �Cg1 v = 3.692 (3) A ˚; symmetry code: (v) À x + 1, À y + 1, À z + 1] are slightly larger compared with II (Table 4).The outer 2-bromo-5-methoxyphenyl rings also contribute to the packing pattern since they afford �-� interactions with the sulfonyl-bound C9-C14 rings, with typical intercentroid separations of 3.836 (2) A ˚and a relatively small slippage angle of 18.1 (2) � (Table 4).This stacking complements the weak C3-H3� � �O2 i hydrogen bonds [C� � �O = 3.448 (3) A ˚; symmetry code: (i) À x + 1, À y + 1, À z], linking the columns of molecules in the c-axis direction (Fig. 5).There are no hydrogen-bonding interactions with the methoxy O3 atoms, which instead are involved in relatively short Br� � �O contacts of 3.3066 (19) A ˚. Very distal contacts of the type C24� � �Cg4 ix distance exceeds 4.4 A ˚.However, the structure retains the double CH 3 � � �� bonding between inversion-related molecules with C23� � �Cg1 v = 3.560 (3) A ˚[Cg1 is the centroid of the pyrrole ring N1/C1/C6-8; symmetry code: (v) À x + 1, À y + 2, À z + 1].Moreover, these methyl groups also establish distal mutual contacts with the C1-C6 rings [C23� � �Cg2 iv = 3.999 (3) A ˚; symmetry code: (iv) À x + 1, À y + 1, À z + 1], which likely represent very weak CH 3 � � �� bonding.These interactions act in synergy with a set of weak C13-H13� � �O1 i and C19-H19� � �Br1 iii bonds (Table 3) to link the molecules into the columns down the b-axis direction (Fig. 6).Therefore, the main features of the patterns seen for I and II are preserved for III with only minor variations.At the same time, beyond the supramolecular columns, which are nearly intact for all three compounds, the bonding features for III are essentially different.Both kinds of the phenyl rings afford a set of �-� interactions with the generation of discrete tetramers (Fig. 6), with the central duo representing a stack of two antiparallel inversion-related bromophenyl groups

Hirshfeld surface analysis
The supramolecular interactions in the title structure were further assessed by Hirshfeld surface analysis.The Hirshfeld surfaces and 2D fingerprint plots were generated using Crys-talExplorer21 software (Spackman et al., 2021).
The two-dimensional fingerprint plots (Parkin et al., 2007) detailing the various interactions for the molecules are shown in Fig. 7.For all three compounds, Hirshfeld surfaces suggest the dominance of contacts with the hydrogen atoms, accounting for over 90% of the contacts.Beyond the largest fractions of H� � �H contacts (38.7-44.7%), the principal

Table 4
Geometry of stacking interactions (A ˚, � ) for I-III.
Cg is a group centroid; plane� � �CgB is the distance between the mean plane of Group A and the centroid of the interacting Group B; ipa is the interplanar angle; sa is the slippage angle, which is the angle of the CgA� � �CgB axis to the Group A mean plane normal.

Compound
Group A Group B Shortest contacts CgA� � �CgB Plane� � �CgB ipa sa 463 (3)  3.836 (3)  3.646 (3)  9.56 ( 16) 18.1 ( 2) 489 (3)  3.691 (2)  3.488 (2)  0  19.1 (2) Symmetry codes for I: contributors are C� � �H/H� � �C (20.4-25.7%),O� � �H/H� � �O (14.6-17.9%)and Br� � �H/H� � �Br (8.2-12.6%)contacts corresponding to the different kinds of C-H� � ��, C-H� � �O or C-H� � �Br bonds.Every type of such bonding is readily identified by the plots representing pairs of diffuse spikes pointing to the lower left.One can note a common trend for suppression of such hydrogen bonding in II and III.For example, the contribution of the O� � �H/H� � �O contacts for I (17.9%) is perceptibly larger than for II (14.6%), which incorporates an additional methoxy O atom.This effect may be attributed to the increasing significance of �-� interactions for the crystal packing in the case of II and III, in line with the increased number of aromatic groups.In addition, a slight reduction in the Br� � �H/H� � �Br contacts (12.6% for I versus 8.2% and 8.6% for II and III, respectively) may be reflective of a weaker acceptor ability of the phenyl-bound Br atoms with respect to the bromomethyl moieties in I.An overlap between nearly parallel aromatic frames, due to the slipped �-� stacking, is clearly indicated by the C� � �C plots for all compounds, in the form of the blue-green area centred at ca d e = d i = 1.85A ˚.The plots suggest a progressive growth of the significance of these interactions, when moving from I to II and III.In line with this, the contributions of the C� � �C contacts to the entire surfaces are 2.5%, 6.3% and 8.2%, respectively.In the case of II, the peculiar short Br� � �O contacts are also readily identified by the fingerprint plots and they contribute as much as 1.6% to the surface area (Fig. 7).
The interaction energy between the molecules is expressed in terms of four components: electrostatic, polarization, dispersion and exchange repulsion.These energies were obtained using monomer wavefunctions calculated at the B3LYP/6-31G(d,p) level.The total interaction energy, which is the sum of scaled components, was calculated for a 3.8 A radius cluster of molecules around the selected molecule.The scale factors used in the CE-B3LYP bench research marked energy model (Mackenzie et al., 2017) are given in Table 5.The principal interaction pathways for I-III are shown in Figs.8-10, respectively.The interaction energies calculated by the energy model reveal that the interactions in the crystal have a significant contribution from dispersion components.It is worth noting that the primary forces for the crystal packing are associated with different stackings of the indole moieties.Either �-� or double CH� � �� interactions of the inversionrelated molecules are equally important and they are particularly prevalent in the case of I. Thus, the highest energy E tot = À 60.8 kJ mol À 1 corresponds to the pairing pattern of type A (Fig. 8), with contributions from slipped �-� interactions and double C-H� � �O hydrogen bonding.In addition, short contacts of the methylene groups C15 and C3-C4 bonds [C15� � �Cg(C3/C4) iii = 3.412 (2) A ˚; symmetry code: (iii) À x + 1, À y + 1, À z + 1] possibly reflect a kind of weak tetrel C� � �� bonding.The energies of other types of indole/indole interactions for II and III are comparable [E tot = À 43.1 to À 55.1 kJ mol À 1 ] and the primary contributor here is London dispersion [up to À 78.4 kJ mol À 1 ], in accordance with the very large interaction areas.The energies of the slipped �-� interactions of the phenyl rings in II and III are very similar and they account for À 28.9 to À 33.9 kJ mol À 1 (Table 4).The significance of these interactions is comparable with weak C-H� � �O hydrogen bonds.The energies of the latter themselves are only medium, for example À 13.1 kJ mol À 1 (Type D) in I and À 15.7 kJ mol À 1 (Type F) in II.However, pairing of the molecules via multiple hydrogen bonding increases the interaction energies up to À 28.9 kJ mol À 1 (Type C in II, Fig. 9).This rich landscape of bonding modes, with a specific hierarchy of interaction energies, could be applicable as a model for supramolecular interactions of phenylsulfonyl-substituted indoles and their targeting of biomedical substrates.Calculated interaction energies (kJ mol À 1 ) for I-III.
Interaction energies were calculated employing the CE-B3LYP/6-31G(d,p) functional/basis set combination.The scale factors used to determine E tot were: k ele = 1.057, k pol = 0.740, k dis = 0.871, and k rep = 0.618 (Mackenzie et al., 2017).For details of the interaction modes, see Figs. 8-10; R is the distance in A ˚between the centroids of interacting molecules.

Synthesis and crystallization
Compound I: To a mixture of N-phenylsulfonyl-3-methylindole (6.00 g, 22.22 mmol) and paraformaldehyde (3.33 g, 111.1 mmol) in 50 ml of dry CCl 4 , a 33 wt % solution HBr in The principal pathways of the intermolecular interactions for II representing �-� and weak hydrogen bonding, with a cut-off limit for calculated energies of 6.0 kJ mol À 1 .[Symmetry codes: The principal pathways of the intermolecular interactions for II representing �-� and weak hydrogen bonding, with a cut-off limit for calculated energies of 12.0 kJ mol À 1 .[Symmetry codes: The principal pathways of the intermolecular interactions for I representing �-� and weak hydrogen bonding, with a cut-off limit for calculated energies of 6.0 kJ mol À 1 .[Symmetry codes: acetic acid (13.46 ml) was added rapidly.The mixture was kept at room temperature for 6 h.After completion of the reaction (monitored by TLC), the mixture was poured into 100 ml of ice-water and then extracted with CCl 4 (2 � 20 ml).The extract was dried with Na 2 SO 4 .Removal of the solvent in vacuo followed by crystallization from methanol (4 ml) afforded compound I as a colourless solid (yield: 6.9 g, 86%).

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.

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.

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.

Table 6
Experimental details.
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