Role of Halogen Substituents on Halogen Bonding in 4,5-DiBromohexahydro-3a,6-Epoxyisoindol-1(4 H )-ones

: A series of 4,5-dibromo-2-(4-substituted phenyl)hexahydro-3a,6-epoxyisoindol-1(4 H )-ones were synthesized by reaction of the corresponding 2-(4-substituted phenyl)-2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-1(6 H )-ones with [(Me 2 NCOMe) 2 H]Br 3 in dry chloroform under reﬂux for 3 − 5 h. In contrast to the 4-F and 4-Cl substituents, one of the bromine atoms of the isoindole moiety behaves as a halogen bond donor in the formation of intermolecular halogen bonding in the 4-H, 4-Br and 4-I analogues. Not only intermolecular hydrogen bonds, but also Ha · · · Ha and Ha · · · π types of halogen bonds in the 4-H, 4-Br, and 4-I compounds, contribute to the formation of supramolecular architectures leading to 2D or 3D structures.

In particular, the effect of R on the halogen bonding at R−Ha· · · Nu has been theoretically studied and successfully applied in catalysis, molecular recognition, crystal engineering, etc. [19][20][21][22][23][24][25][26]. In addition, the role/behavior of the attached halogen atom in organic compounds can be classified into the following types: (i) as an electron with-drawing substituent, (ii) as a halogen bond donor center, and (iii) as a noncovalent bond acceptor site.
In this communication, our goal is to study the role of both electron withdrawing character and halogen bond donor ability of halogen atoms on Br· · · Ha (Ha = F, Cl, Br, I) interactions in a series of crystals of 4,5-dibromo-2-(4-substituted phenyl)hexahydro-3a,6epoxyisoindol-1(4H)-ones (3a-e) (Scheme 1). On the other hand, the isoindole synthon is an important structural unit in many natural products and bioactive compounds, as well as a useful building-block for the construction of new N-containing heterocyclic compounds [27−34]. For instance, heterocyclic compounds containing isoindole moieties have demonstrated a promising biological action and pharmacological activity as pathogen antagonists [29]. The isoindole motif can also be involved as a versatile and powerful intermediate for the synthesis of various chiral heterocyclic compounds with unique properties [27−34]. Thus, the functionalization of isoindole moieties with noncovalent bond donor/acceptor sites can improve their photophysical properties [27], bioactivity [32], coordination ability [35,36], etc.

Materials and Instrumentation
All the chemicals were obtained from commercial sources (Acros Organics, Alfa Aesar) and used as received. Elemental analyses (C, H, N) were performed using a Eurovector EA 3000 (CHNS) elemental analyzer and were within ± 0.4% of theoretical values. The infrared spectra (4000-400 cm −1 ) were recorded on an IR-Fourier spectrometer Infralum FT-801 in KBr pellets. The 1 H and 13 C NMR spectra were recorded at room temperature on a Jeol JNM-ECA spectrometer operating at 600.2 and 150.9 MHz for 1 H and 13 C, respectively. The chemical shifts are reported in ppm using residual solvent peaks of chloroform as the internal references. Liquid chromatography mass spectra were taken on Thermo DSQ II-Focus GC (EI ionization, 200 °C source temperature, 70 eV, RTX-5MS column, helium carrier gas). Electrospray mass spectra (ESI-MS) were taken on Shimadzu LCMS-8040, equipped with dual ion source (DUIS) in electrospray positive mode (interface voltage 4.5 kV, nebulizer gas flow 2 L/min, drying gas flow 15 L/min, desolvation line temperature 250 °C, heating block temperature 400 °C).

Materials and Instrumentation
All the chemicals were obtained from commercial sources (Acros Organics, Alfa Aesar) and used as received. Elemental analyses (C, H, N) were performed using a Eurovector EA 3000 (CHNS) elemental analyzer and were within ± 0.4% of theoretical values. The infrared spectra (4000-400 cm −1 ) were recorded on an IR-Fourier spectrometer Infralum FT-801 in KBr pellets. The 1 H and 13 C NMR spectra were recorded at room temperature on a Jeol JNM-ECA spectrometer operating at 600.2 and 150.9 MHz for 1 H and 13 C, respectively. The chemical shifts are reported in ppm using residual solvent peaks of chloroform as the internal references. Liquid chromatography mass spectra were taken on Thermo DSQ II-Focus GC (EI ionization, 200 • C source temperature, 70 eV, RTX-5MS column, helium carrier gas). Electrospray mass spectra (ESI-MS) were taken on Shimadzu LCMS-8040, equipped with dual ion source (DUIS) in electrospray positive mode (interface voltage 4.5 kV, nebulizer gas flow 2 L/min, drying gas flow 15 L/min, desolvation line temperature 250 • C, heating block temperature 400 • C).

X-ray Analysis
X-ray diffraction analyses were performed at the Center for Shared Use of Physical Methods of Investigation at the Frumkin Institute of Physical Chemistry and Electrochemistry, RAS (CKP FMI IPCE RAS). Single crystals of compounds 3a−e (Table 1) for X-ray crystallography were grown by slow recrystallization of samples from EtOAc/hexane mixtures. Suitable single crystals were selected, immersed in an inert oil, mounted on a glass fiber, and attached to a goniometer head.
The X-ray diffraction data were collected on a Bruker Kappa Apex II automatic fourcircle diffractometer equipped with an area detector (Mo-Kα sealed-tube X-ray source, λ = 0.71073 Å, graphite monochromator) at 296 K for all compounds except 3a, measured at 100 K.
The data frames were collected using the program APEX2 and processed using the program SAINT routine within APEX2. The unit cell parameters were refined over the whole dataset [37]. The data were corrected for absorption on the multi-scan technique as implemented in SADABS [38]. The structures were solved by direct method using SHELXS and refined by full-matrix least-squares on F 2 using SHELXL-2018 software [39] in the anisotropic approximation for all non-hydrogen atoms. Hydrogen atoms on carbon were calculated in ideal positions with isotropic displacement parameters set to 1.2 × U eq (C). Atomic
In the 13 C NMR spectra of 3a-e, the carbon atom of C=O was found at 172.1−172.7 ppm (Figures S3-S7). Not only electron-withdrawing properties of para-substituents, but also their noncovalent bond donor or acceptor character leads to the chemical shift of C Ar −Ha in the 13   The crystal structures of 3a-e were determined by single crystal X-ray diffraction and are shown in Figure 1 along with the atomic numbering schemes. In contrast to 3a-c, both compounds 3d and 3e crystallize with two molecules in the asymmetric unit, of which only one is illustrated in Figure 1. An important feature of the compounds is the presence of the 3aS,4R,5R,6S,7aR and 3aR,4S,5S,6R,7aS stereogenic carbon centers in 3a-c and 3d,e, respectively (Figure 1) 3a−e is not clear, because there is no intermolecular halogen bonding in compounds 3b and 3c (see below). Moreover, ESI-MS and elemental analyses also confirm the chemical structures of 3a-e. The crystal structures of 3a-e were determined by single crystal X-ray diffraction and are shown in Figure 1 along with the atomic numbering schemes. In contrast to 3a-c, both compounds 3d and 3e crystallize with two molecules in the asymmetric unit, of which only one is illustrated in Figure 1. An important feature of the compounds is the presence of the 3aS,4R,5R,6S,7aR and 3aR,4S,5S,6R,7aS stereogenic carbon centers in 3a-c and 3d,e, respectively (Figure 1) Although all 3a-e have at least two potential halogen bond donor centers (Br atoms in the isoindole moiety), there is no intermolecular halogen bonding in the compounds 3b and 3c. In the packing of 3a-e, the most noticeable intermolecular features are C−H⋯O, C−H⋯Br, and C-H⋯π hydrogen bonds, which can also cooperate with C−Br⋯Br, C−Br⋯π, and C−I⋯I types of halogen bonds. Although all 3a-e have at least two potential halogen bond donor centers (Br atoms in the isoindole moiety), there is no intermolecular halogen bonding in the compounds 3b and 3c. In the packing of 3a-e, the most noticeable intermolecular features are C−H· · · O, C−H· · · Br, and C-H· · · π hydrogen bonds, which can also cooperate with C−Br· · · Br, C−Br· · · π, and C−I· · · I types of halogen bonds.
In the crystal of 3a, the molecules are interacting through Br⋯Br type II [3,[44][45][46] of halogen bonding to form a 1D supramolecular chain along the b-axis [47], depicted in Figure 2. The Br(1)⋯Br(2) distance (3.638 Å) is shorter than twice the sum of the Bondiʹs van der Waals radii of the interacting atoms (Br + Br = 1.85 + 1.85 = 3.70 Å) [48], and the < C(4)−Br(1)⋯Br(2) angle is 169.68°.  Figure S8). In contrast to 3a, the bromine atom behaves only as the hydrogen bond acceptor in 3b and 3c affording 3D supramolecular architectures (Figures S9 and S10). In 3c, the attached para-Cl also engages in weak intermolecular hydrogen bonding to support the molecules to orient in a headto-tail arrangement in 3D networks ( Figure S10). Not only intermolecular hydrogen bonds, but both Br•••π and Ha•••Ha types of halogen bond in 3d and 3e play an important role in directing the crystal packing and in the formation of 3D structures (Figures S11 and S12). Cooperation of C−H· · · O, C−H· · · Br, and C−H· · · π hydrogen bonds with the Br· · · Br halogen bonding in the crystal packing of 3a leads to 2D sheets ( Figure S8). In contrast to 3a, the bromine atom behaves only as the hydrogen bond acceptor in 3b and 3c affording 3D supramolecular architectures (Figures S9 and S10). In 3c, the attached