The role of the closing lecture in a Faraday Discussion is to summarise the contributions made to the Discussion over the course of the meeting and in so doing capture the main themes that have arisen. This article is based upon my Closing Remarks Lecture at the 203rd Faraday Discussion meeting on Halogen Bonding in Supramolecular and Solid State Chemistry, held in Ottawa, Canada, on 10-12th July, 2017. The Discussion included papers on fundamentals and applications of halogen bonding in the solid state and solution phase. Analogous interactions involving main group elements outside group 17 were also examined. In the closing lecture and in this article these contributions have been grouped into the four themes: (a) fundamentals, (b) beyond the halogen bond, (c) characterisation, and (d) applications. The lecture and paper also include a short reflection on past work that has a bearing on the Discussion.

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Halogen bonding, chalcogen bonding, pnictogen bonding, tetrel bonding: origins, current status and discussion

The halogen bond (XB) has become an important tool for molecular design in all areas of chemistry, including crystal and materials engineering and medicinal chemistry. Its similarity to the hydrogen bond (HB) makes the relationship between these interactions complex, at times competing against and other times orthogonal to each other. Recently, our two laboratories have independently reported and characterized a synergistic relationship, in which the XB is enhanced through direct intramolecular HBing to the electron-rich belt of the halogen. In one study, intramolecular HBing from an amine polarizes the iodopyridinium XB donors of a bidentate anion receptor. The resulting HB enhanced XB (or HBeXB) preorganizes and further augments the XB donors. Consequently, the affinity of the receptor for halogen anions was significantly increased. In a parallel study, a meta-chlorotyrosine was engineered into T4 lysozyme, resulting in a HBeXB that increased the thermal stability and activity of the enzyme at elevated temperatures. The crystal structure showed that the chlorine of the noncanonical amino acid formed a XB to the protein backbone, which augmented the HB of the wild-type enzyme. Calorimetric analysis resulted in an enthalpic contribution of this Cl-XB to the stability of the protein that was an order of magnitude greater than previously determined in biomolecules. Quantum mechanical (QM) calculations showed that rotating the hydroxyl group of the tyrosine to point toward rather than away from the halogen greatly increased its potential to serve as a XB donor, equivalent to what was observed experimentally. In sum, the two systems described here show that the HBeXB concept extends the range of interaction energies and geometries to be significantly greater than that of the XB alone. Additionally, surveys of structural databases indicate that the components for this interaction are already present in many existing molecular systems. The confluence of the independent studies from our two laboratories demonstrates the reach of the HBeXB across both chemistry and biochemistry and that intentional engineering of this enhanced interaction will extend the applications of XBs beyond these two initial examples.

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Hydrogen Bond Enhanced Halogen Bonds: A Synergistic Interaction in Chemistry and Biochemistry.

Due to their electron deficiency, halonium ions act as particularly strong halogen bond donors. By accepting electrons in both lobes of their empty p-orbital, they are capable of simultaneously interacting with two Lewis bases. The interaction presumes the formation of three molecular orbitals and is accordingly typically entitled as a three-center halogen bond. In analogy to the [D-H-D]+ hydrogen bonds, which are at times entitled as short and strong bonds, the [D-X-D]+ halogen bonds of halonium ions show Bondi normalized interatomic distances of 0.6-0.7 and possess both charge transfer and electrostatic characteristics. The three-center halogen bond of halonium ions shows distinct differences in its properties from coordinative bonds of transition metals and is therefore applicable as a complementary synthon in supramolecular chemistry. The three-center halogen bond modulates the reactivity of halonium ions and is hence a useful tool for synthetic organic chemistry. Following the discussion of the nature and properties of halonium ions' halogen bonds, this tutorial review provides an overview of their current applications to stimulate future developments.

https://pubs.rsc.org/en/content/articlepdf/2020/cs/d0cs00034e

Halogen bonds of halonium ions.

Halogen bonds, which provide an intermolecular interaction with moderate strength and high directionality, have emerged as a promising tool in the repertoire of non-covalent interactions. In this review, we provide a survey of the literature where halogen bonding was used for the fabrication of supramolecular networks on solid surfaces. The definitions of, and the distinction between halogen bonding and halogen-halogen interactions are provided. Self-assembled networks formed at the solution/solid interface and at the vacuum-solid interface, stabilized in part by halogen bonding, are discussed. Besides the broad classification based on the interface at which the systems are studied, the systems are categorized further as those sustained by halogen-halogen and halogen-heteroatom contacts.

Halogen Bonding in Two‐Dimensional Crystal Engineering

The construction of more stable proteins is important in biomolecular engineering, particularly in the design of biologics-based therapeutics. We show here that replacing the tyrosine at position 18 (Y18) of T4 lysozyme with the unnatural amino acid m-chlorotyrosine (mClY) increases both the thermal stability (increasing the melting temperature by ∼1 °C and the melting enthalpy by 3 kcal/mol) and the enzymatic activity at elevated temperatures (15% higher than that of the parent enzyme at 40 °C) of this classic enzyme. The chlorine of mClY forms a halogen bond (XB) to the carbonyl oxygen of the peptide bond at glycine 28 (G28) in a tight loop near the active site. In this case, the XB potential of the typically weak XB donor Cl is shown from quantum chemical calculations to be significantly enhanced by polarization via an intramolecular hydrogen bond (HB) from the adjacent hydroxyl substituent of the tyrosyl side chain, resulting in a distinctive synergistic HB-enhanced XB (or HeX-B for short) interaction...

Increasing Enzyme Stability and Activity through Hydrogen Bond-Enhanced Halogen Bonds.

The recent recognition that halogen bonding (XB) plays important roles in the recognition and assembly of biological molecules has led to new approaches in medicinal chemistry and biomolecular engineering. When designing XBs into strategies for rational drug design or into a biomolecule to affect its structure and function, we must consider the relationship between this interaction and the more ubiquitous hydrogen bond (HB). In this review, we explore these relationships by asking whether and how XBs can replace, compete against or behave independently of HBs in various biological systems. The complex relationships between the two interactions inform us of the challenges we face in fully utilizing XBs to control the affinity and recognition of inhibitors against their therapeutic targets, and to control the structure and function of proteins, nucleic acids and other biomolecular scaffolds.

Relationships between hydrogen bonds and halogen bonds in biological systems.

5-Hydroxymethylcytosine (5hmC) is an epigenetic marker that has recently been shown to promote homologous recombination (HR). In this study, we determine the effects of 5hmC on the structure, thermodynamics, and conformational dynamics of the Holliday junction (the four-stranded DNA intermediate associated with HR) in its native stacked-X form. The hydroxymethyl and the control methyl substituents are placed in the context of an amphimorphic GxCC trinucleotide core sequence (where xC is C, 5hmC, or the methylated 5mC), which is part of a sequence also recognized by endonuclease G to promote HR. The hydroxymethyl group of the 5hmC junction adopts two distinct rotational conformations, with an in-base-plane form being dominant over the competing out-of-plane rotamer that has typically been seen in duplex structures. The in-plane rotamer is seen to be stabilized by a more stable intramolecular hydrogen bond to the junction backbone. Stabilizing hydrogen bonds (H-bonds) formed by the hydroxyl substituent in 5hmC or from a bridging water in the 5mC structure provide approximately 1.5-2 kcal/mol per interaction of stability to the junction, which is mostly offset by entropy compensation, thereby leaving the overall stability of the G5hmCC and G5mCC constructs similar to that of the GCC core. Thus, both methyl and hydroxymethyl modifications are accommodated without disrupting the structure or stability of the Holliday junction. Both 5hmC and 5mC are shown to open the structure to make the junction core more accessible. The overall consequences of incorporating 5hmC into a DNA junction are thus discussed in the context of the specificity in protein recognition of the hydroxymethyl substituent through direct and indirect readout mechanisms.

Rhianon K. Rowe

Papers

Hydrogen Bond Enhanced Halogen Bonds: A Synergistic Interaction in Chemistry and Biochemistry.

Increasing Enzyme Stability and Activity through Hydrogen Bond-Enhanced Halogen Bonds.

Relationships between hydrogen bonds and halogen bonds in biological systems.

Effect of Hydroxymethylcytosine on the Structure and Stability of Holliday Junctions.