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Halogen Bonding in Solution


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groups to elicit stronger halogen bond interactions. However, in many instances, strong CH hydrogen bond donors are also formed, highlighting a need to ensure molecule performance is largely dictated by halogen bonding and not CH hydrogen bonding or other competing interactions. A modern study addressing this concern comes from the Huber lab [50].

Tabular representation of the 1968 solid-state review by Bent.

      Source: From Bent [17]. © 1968 American Chemical Society.

      Contributing to the collection of halogen bonding data during this time were notable theoretical studies. The concept of the “σ‐hole” discussed above was largely driven by the computational works of Politzer and Murray [5,6]. Specifically, they demonstrated the anisotropic charge distribution of halogen atoms forming one covalent bond, the details of which are elaborated on in the computational section.

      While not comprehensive, this section illustrates that the accumulation of data showing the attractive noncovalent behavior of halogens is consistent across the three primary phases of matter and in silico. These seminal studies and others provided the groundwork for the “rediscovery” of the halogen bond in the early 2000s.

      1.2.1 Rediscovery

Chemical structure of the ChemDraw figure highlighting the use of alkyl- and aryl-dihaloperfluorocarbon halogen bond donors to form predictable 1D networks in the solid state.

      Source: From Metrangolo and Resnati [57]. © 2001 John Wiley & Sons.

      1.3.1 CSD Evaluations

      Possibly, the first CSD evaluation of what we now understand to be the halogen bond was in 1979 where the geometry of the C–I⋯O interaction was evaluated [66]. Murray‐Rust and Motherwell noted an anisotropic distribution of contact distances as a function of C–I⋯O angle, where shorter contacts (and less variability) were observed for near linear (C–I⋯O ∠ ≈180°) contacts. The trend, although less pronounced, was also observed with Br and Cl species, which we now attribute to their weaker halogen bond donor ability. This initial study pulling from 20 000 structures was revisited again seven years later where the database had grown to 40 000 structures [4]. Here, Ramasubbu, Parthasarathy, and Murray‐Rust evaluated halocarbons (C–X (X = Cl, Br, I)) and their contacts with metals, Lewis bases (nitrogen and oxygen species), and other halogens. The geometric characteristics of the “electrophile–nucleophile pairing(s)” showed that electrophilic metals favor a “side‐on” approach to halogens, nucleophiles exhibited a “head‐on” approach, and other halogens can participate as either the nucleophile (head‐on) or the electrophile (side‐on). These early CSD studies and others [67-69] reinforced the trends previously observed by Bent and Hassel, but observations from larger data sets provided more convincing conclusions.