An Insight into Non‐Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold

Abstract

Bicyclo[1.1.1]pentane (BCP) is studied extensively as a bioisosteric component of drugs. Not found in nature, this molecular unit approximates the distance of a para‐disubstituted benzene which is replaced in medicines as a method of improving treatments. Predicting interactions of these drugs with specific active sites requires knowledge of the non‐covalent interactions engaged by this subunit. Structure determinations and computational analysis (Hirshfeld analysis, 2D fingerprint plots, DFT) of seven BCP derivatives chosen to probe specific and directional interactions. X‐ray analysis revealed the presence of various non‐covalent interactions including I ⋅⋅⋅ I, I ⋅⋅⋅ N, N−H ⋅⋅⋅ O, C−H ⋅⋅⋅ O, and H−C ⋅⋅⋅ H−C contacts. The preference of halogen bonding (I ⋅⋅⋅ I or I ⋅⋅⋅ N) in BCP 1–4 strictly depends upon the electronic nature and angle between bridgehead substituents. The transannular distance in co‐crystals 2 and 4 was longer as compared to monomers 1 and 3. Stronger N−H ⋅⋅⋅ O and weaker C−H ⋅⋅⋅ O contacts were observed for BCP 5 while the O ⋅⋅⋅ H interaction was a prominent contact for BCP 6. The presence of 3D BCP units prevented the π ⋅⋅⋅ π stacking between phenyl rings in 3, 4, and 7. The BCP skeleton was often rotationally averaged, indicating fewer interactions compared to bridgehead functional groups. Using DFT analysis, geometries were optimized and molecular electrostatic potentials were calculated on the BCP surfaces. These interaction profiles may be useful for designing BCP analogs of drugs.

Carbon-atom hybridization tunes the halogen-bond strength in the series of DABCO·C2H2n I2 (n = 0–2) cocrystals

“…3). However, these doubts contrast with the recent reports on an NÁ Á ÁI HaB-assisted cocrystal of DABCO with CHI 3 (Adeniyi et al, 2022), 1,3-diiodobicyclo[1.1.1]pentane and 1,3-bis(4-iodophenyl)bicyclo[1.1.1]pentane (Grover et al, 2021), iodobenzene with quinuclidine (Otte et al, 2021), and dipyridyl-naphthalenediimide with 1,4-diiodobenzene and 4,4 0 -diiododiphenyl (Mazzeo et al, 2021).…”

On‐Surface Synthesis of Polyphenylene Wires Comprising Rigid Aliphatic Bicyclo[1.1.1]Pentane Isolator Units

“…As shown in Figure 1a, the 1,3‐bis(4‐iodophenyl) substituted BCP compound is a linear species with an extended carbon backbone [8, 16c] . The DFT optimized structure reveals a single species with a 14.69 Å iodine–iodine distance along the molecular axis.…”

Self-Organization of Porphyrin–POM Dyads: Nonplanar Diacids and Oxoanions in Low-Dimensional H-Bonding Networks

“…This acid excess resulted in a densely interconnected net with the bicyclo[1.1.1]pentane-1,3-dicarboxylate counter-anion structure; the inclusion of additional protonated BCP diacid species formed a tangled hydrogen bonded network, in which each porphyrin is linked to six others. As we have previously discussed, the three-fold symmetry of the bicyclo[1.1.1]pentane unit over a high symmetry site can result in near-complete rotational disorder of the methylene bridges [ 44 ]; this is shown in Figure 10 , with the simple hydrogen-bonded chain of porphyrin with bicyclo[1.1.1]pentane-1,3-dicarboxylic acid inset within the larger hydrogen-bonded network in Figure 11 .…”