TY - JOUR
T1 - An Insight into Non-Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold
AU - Grover, Nitika
AU - Flanagan, Keith J.
AU - Trujillo, Cristina
AU - Kingsbury, Christopher J.
AU - Senge, Mathias O.
N1 - Funding Information:
This work was supported by grants from Science Foundation Ireland (SFI, IvP 13/IA/1894 and (SFI 18/SIRG/5517), and the European Union's Horizon 2020 research and innovation program under the FET Open grant agreement No. 828779. The manuscript was prepared with the support of the Technical University of Munich – Institute for Advanced Study through a Hans Fischer Senior Fellowship. Open access funding enabled and organized by Projekt DEAL.
Funding Information:
This work was supported by grants from Science Foundation Ireland (SFI, IvP 13/IA/1894 and (SFI 18/SIRG/5517), and the European Union's Horizon 2020 research and innovation program under the FET Open grant agreement No. 828779. The manuscript was prepared with the support of the Technical University of Munich ? Institute for Advanced Study through a Hans Fischer Senior Fellowship. Open access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2020 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH
PY - 2021/2/19
Y1 - 2021/2/19
N2 - 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.
AB - 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.
KW - Bicyclo[1.1.1]pentane
KW - Bioisosteres
KW - Halogen bonding
KW - Hydrogen bonding
KW - Noncovalent interactions
UR - http://www.scopus.com/inward/record.url?scp=85097912295&partnerID=8YFLogxK
U2 - 10.1002/ejoc.202001564
DO - 10.1002/ejoc.202001564
M3 - Article
AN - SCOPUS:85097912295
SN - 1434-193X
VL - 2021
SP - 1113
EP - 1122
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
IS - 7
ER -