2,6-Dibromo-3,4,5-trimethoxybenzoic acid

The previously unknown crystal structure of 2,6-dibromo-3,4,5-trimethoxybenzoic acid was determined employing state-of-the-art Hirshfeld atom refinement and the crystal packing was analysed using Hirshfeld surface analysis.


Chemical context
Organobromine compounds are valuable precursors in organic and pharmaceutical synthesis.Their participation in homo-and cross-coupling reactions is undisputed and even preferred over the other halogen-containing compounds.In practice, many brominating agents are used for their synthesis, though few of them appear to be safe both for the user-chemist and environment.Therefore, in the present work, we present a new environmentally friendly method for the synthesis of 2,6dibromo-3,4,5-trimethoxybenzoic acid.Its structure is closely related to those of mono-and diiodo-3,4,5-trimethoxybenzoic acids ITMBA and DITMBA (Kolev et al., 2021(Kolev et al., , 2023)).

Structural commentary
DBrTMBA (Fig. 1) crystallizes in the monoclinic space group P2 1 /n with one acid molecule in the asymmetric unit (Z = 4).The carboxylic acid (O1/C7/O2) group is almost perpendicular to the geometrical C 6 mean plane and at an angle of 86.7 (2) � .This derivation is exactly in the middle of the reported geometries of the catemeric DITMBA, which is closer to 90 � and the reported dimeric DITMBA•toluene, which deviates more from 90 � (Kolev et al., 2023).

Supramolecular features
Different to the also related structures of mono-and diiodo-3,4,5-trimethoxybenzoic acids ITMBA and DITMBA•toluene (Kolev et al., 2021(Kolev et al., , 2023)), the title compound exhibits no dimeric structure in the solid state (Fig. 2).Instead, a hydrogen-bonded chain along the crystallographic b-axis direction between neighbouring acids is observed.Molecules of DBrTMBA are arranged in a catemeric fashion along this chain of carboxylic hydrogen interaction.The structure is thus very similar to that of solvent-free DITMBA (Kolev et al., 2023).The O1-O2 distance of the DBrTMBA intermolecular hydrogen-bonding interaction is 2.617 (5) A ˚(Table 1, Fig. 3).
Another interesting structural feature in this syndiotactic arrangement can be described as a carbonyl O2 lone pair(lp)-� (C 6 ) contact with a distance from O2 to the center of geometry of the benzene ring of 3.030 (4) A ˚(Fig. 2).This contact presumably contributes to the deviation from the dimeric structure as observed in ITMBA and DITMBA• toluene (Kolev et al., 2021(Kolev et al., , 2023)).In the latter, the toluene solvent molecule seems to shield the C 6 � system from this kind of interaction, giving rise to a preferred dimeric structure in this solvate.
To understand the crystal packing of DBrTMBA and the contribution of these closest interaction contacts, the software program CrystalExplorer was used for a Hirshfeld surface and interaction analysis (Spackman et al., 2021).Fig. 4b-d show the closest contacts of the hydroxylic acid group as donor/acceptor in hydrogen bonding, as well as the O(lp)-� (C 6 ) interaction in Fig. 4f.The hydrogen donor/acceptor properties of the carboxylic group are visualized in the mapping of the electrostatic potential at the Hirshfeld surface (Fig. 4e).
Table 2 shows the interaction energies of DBrTMBA with the closest neighbor molecules in the crystal packing (colors in Fig. 4g).As expected, the strongest intermolecular interaction      et al., 2016).The structure of the parent compound, which crystallizes in space group Pc, has been reported twice (Qadeer et al., 2007, Bolte, 2011).Three other structures contain TMBA co-crystallized with other organic molecules (Thomas et al., 2019;Chen et al., 2018;Zhang et al., 2021).All of them reveal co-planar arrangements of the benzene rings and hydrogen-bonding interactions.Furthermore, we recently reported on the previously discussed mono-and diiodo-3,4,5trimethoxybenzoic acids ITMBA and DITMBA (Kolev et al., 2021(Kolev et al., , 2023)).

Synthesis and crystallization
The title compound was synthesized according to the following experimental procedure: A solution of 2-iodo-3,4,5trimethoxybenzoic acid (0.36 mmol) in 0.2 M NaOH (0.5 mL) was added dropwise to a magnetically stirred aqueous sulfuric acid solution (3.2 M, 0.6 mL) of KBrO 3 (0.72 mmol).The temperature of the reaction mixture was then raised gradually

Table 2
Interaction Energies (kJ mol À 1 ) for the symmetry-generated neighbors of a molecule of DBrTMBA.
Color code Symmetry operation Figure 5 Fingerprint plots of the Hirshfeld surface of DBrTMBA.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3.An Hirshfeld Atom Refinement (HAR) using NoSpherA2 in Olex2 was performed to obtain non-spherical atomic form factors as well as anisotropic hydrogen atomic displacement parameters (Hirshfeld, 1977, Kleemiss et al., 2021).Orca5 (Neese et al., 2020) was used for the single-point calculations for the HAR procedure at def2-TZVP/M062X level of theory.The H-X distances were fixed to neutron distances from Allen & Bruno (2010) and refined anisotropically with displacement parameter restraints.The choice to fix the H-X distances to neutron distances was made because, even after several attempts at data collection, the data from DBrTMBA did not allow for the refinement of unrestrained hydrogen distances, but did allow for the refinement of softly restrained hydrogen atom anisotropic displacement parameters at these fixed distances.(Sheldrick, 2015), OLEX2.refine(Bourhis et al., 2015), NoSpherA2 (Kleemiss et al., 2021), OLEX2 (Dolomanov et al., 2009) and publCIF (Westrip, 2010).

Figure 1
Figure 1Labelling scheme and structure of DBrTMBA.Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
Figure 2Packing of DBrTMBA along the crystallographic b-axis direction.

Figure 3
Figure 3 Syndiotactic arrangement of DBrTMBA in the crystallographic b-axis direction with O(H)-O and O-center of gravity C 6 and distances in A ˚. Atoms that are not part of the carboxylic group are shown in stick representation for clarity.

Figure 4
Figure 4 Chemical scheme (a) and three different orientations (b)-(d) of the d norm Hirshfeld surface of DBrTMBA.The closest contacts and the eleoctrostatic potential [À 0.077, 0.252, (e)] at the Hirshfeld surface as well as the curvature of the Hirshfeld surface (f) and overview of the nearest neighbors accompanying Table 2 (g) are depicted.

Table 3
Experimental details.