1.1.2 Parallels to the Hydrogen Bond
The σ‐hole concept elicits obvious parallels between the halogen bond and the hydrogen bond (Figure 1.1). As such, halogen bond studies, as well as concepts and nomenclature, were undoubtedly inspired by decades of hydrogen bond research. Similarities have prompted frequent comparison between the two, many of which are discussed in the following sections and ensuing chapters. A motivation of these comparative studies has been to discover the limits and unique features of this “new” noncovalent interaction. As such, studies in solution, solid state, and in silico have already demonstrated promising features of the halogen bond compared with its hydrogen analogue.
1.1.3 Notation and Terminology
The vernacular of the halogen bond parallels the hydrogen bond. For example, the hydrogen bond donor references a molecule or group that contains a Lewis acidic hydrogen atom, while the hydrogen bond acceptor is the Lewis basic molecule or group in the interaction. In describing a halogen bond, the donor refers to the molecule with an electrophilic halogen atom (or simply the atom itself, for example, a bromine donor), and the halogen bond acceptor is the Lewis basic site. Therefore, the common notation for denoting a halogen bond is R–X⋯Y, where R is a covalently bound species, X is any halogen with an electrophilic region, Y is the halogen bond acceptor with an electron‐rich region, and ⋯ indicates the attractive noncovalent interaction. Table 1.1 highlights common R–X species and several typical Y species.
1.1.4 Solid‐state Halogen Bond Contacts
Halogen bond interactions in the solid state are typically quantified by their contact distance and angle with a Lewis base and described using the R–X⋯Y notation. Additionally, halogen bond contacts are often reported along with a percentage of their combined van der Waals (vdW) radii or more frequently a ratio. The ratio has been given various names such as the halogen bond interaction ratio, normalized interaction distance, normalized contact, or reduction ratio. The ratio is generally defined as
Table 1.1 Common halogen bond donors and acceptors.
Source: From Desiraju et al. [2]. © IUPAC.
| Common RX species | Dihalogen molecule (e.g. I2, Br2, ICl, ClF)Haloalkane (e.g. CBr4, CHI3, CnF2n+1I)Haloarene or heteroarene (e.g. iodobenzene, halopyridinium, and haloimidazolium cations)1‐Haloalkyne (e.g. diiodoacetylene)Halonium ion (e.g. diphenyliodonium or bromonium derivatives)Haloimide (e.g. N‐bromo‐ or N‐iodosuccinimide) |
| Common Y species | Lone pair possessing atom (e.g. N atom of pyridine or an amine, O atom of a carbonyl group) π‐System (e.g. double or triple bonds, arene moiety) Anion (e.g. halides, oxyanions) |
1.1.5 Halogen Bond Features
Characteristics of the halogen bond have been established through experimental and theoretical means. From these studies several features of the halogen bond can be gleaned that should be considered in experimental and functional designs:
The halogen bond is a highly directional interaction. The R–X⋯Y angle tends to be close to 180°. This is due, in part, to the physical characteristics highlighted in Figures 1.1 and 1.2.
The halogen bond is highly tunable, with energies up to 200 kJ/mol [11].
Halogens are large atoms resulting in RX bonds, which are longer than R–H counterparts (e.g. vdW radii of 1.46, 1.82, 1.86, 2.04, and 1.20 Å for F, Cl, Br, I, and H, respectively [9]).
Halogen atoms are more hydrophobic than hydrogen atoms and the typical heteroatoms attached to them. Hydrophobicity of halogen atoms is a well‐established phenomenon commonly utilized in drug development where the introduction of a halogen atom into a drug will often result in a drug that is more apt to cross lipid bilayers [12].
Halogen atoms are more polarizable than hydrogens, providing the larger halogen bond donors with a suggested hard–soft acid–base complementarity with soft Lewis bases [13].
Despite the structural differences, both hydrogen and halogen bond donor strength can be tuned similarly by directly altering the donors (substituting heteroatoms and halogens, respectively) and by introducing stronger electron‐withdrawing groups on the R group. Nevertheless, halogen bond tunability is achieved in various ways:
By changing the halogen. A more polarizable halogen will result in a greater σ‐hole (e.g. I > Br > Cl > F). This trend is illustrated in Figure 1.2.
By changing the hybridization of the atom bound to the halogen. For example, with carbon, more s character increases the electron‐withdrawing ability, resulting in a larger σ‐hole on the attached halogen (e.g. C(sp) > C(sp2) > C(sp3)).
By altering the atom, the halogen is bound to (e.g. N–I > C–I).
By adjusting the electron‐withdrawing ability of adjacent moieties. Increasing the electron‐withdrawing ability of adjacent groups results in a greater σ‐hole leading to, in most cases, a more potent interaction. The opposite is true as well – an electron‐donating species will often diminish halogen bond strength.
By noncovalent cooperativity. Noncovalent cooperativity is an emerging strategy to enhance the interaction strength of noncovalent forces. The introduction of a hydrogen bond to the electronegative belt of the halogen further polarizes the halogen resulting in a more potent σ‐hole resulting in a hydrogen bond‐enhanced halogen bond [14–16].
1.1.6 Additional Nomenclature
Prior to the IUPAC definition of the halogen bond, a variety of terms were used to describe the attractive interactions with halogens, many of which have been pointed out by Bent [17]. One term used in early halogen bond studies referred to the interaction as a donor–acceptor complex, a consequence of the focus on charge‐transfer studies. Thus, in many early papers, the halogen is referenced as an acceptor, signifying that the halogen was accepting electron density. This terminology has been mostly phased out when discussing halogen bonds. Other nomenclature found in the literature before the official IUPAC definition includes fluorine [18,19], chlorine [20,21], bromine [22], and iodine bonds [23,24]. While this terminology does