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1. “Anti-electrostatic” halogen bonding in solution

   https://doi.org/10.1039/d1sc01863a  

   Loy, Cody; Holthoff, Jana M.; Weiss, Robert; Huber, Stefan M.; Rosokha, Sergiy V. (June 2021, Chemical Science)

   null (Ed.)

   Halogen-bonded (XB) complexes between halide anions and a cyclopropenylium-based anionic XB donor were characterized in solution for the first time. Spontaneous formation of such complexes confirms that halogen bonding is sufficiently strong to overcome electrostatic repulsion between two anions. The formation constants of such “anti-electrostatic” associations are comparable to those formed by halides with neutral halogenated electrophiles. However, while the latter usually show charge-transfer absorption bands, the UV-Vis spectra of the anion–anion complexes examined herein are determined by the electronic excitations within the XB donor. The identification of XB anion–anion complexes substantially extends the range of the feasible XB systems, and it provides vital information for the discussion of the nature of this interaction. 

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2. Metal–ligand bonding and noncovalent interactions of mutated myoglobin proteins: a quantum mechanical study

   https://doi.org/10.1515/pac-2025-0454  

   Antonio, Juliana J; Kraka, Elfi (August 2025, Pure and Applied Chemistry)

   Abstract Metal–ligand bonding and noncovalent interactions (NCIs), such as hydrogen bonding orπ–πinteractions, play a crucial role in determining the structure, function, and selectivity of both biological and artificial metalloproteins. In this study, we employed a hybrid quantum mechanics/molecular mechanics (QM/MM) approach to investigate the ligation of water or cyanide in a mutated myoglobin system, in which the native heme scaffold was replaced with M-salophen or M-salen Schiff base complexes (M = Cr, Mn, Fe). Using our local vibrational mode analysis, particularly local vibrational mode force constants as intrinsic bond strength parameters, complemented with electron density and natural orbital analyses we explored the role of metal–ligand bonding and NCIs in different environments within the myoglobin pocket. Our analysis revealed that metal–ligand bonding, for both water and cyanide ligands, is strongest in the delta form of distal histidine and favors salophen prosthetic groups, as indicated by an overall increase in metal–ligand bond strength. Hydrogen bonding between the distal histidine and ligand also exhibited greater strength in the delta form; however, this effect was more pronounced with salen prosthetic groups. Additionally, the NCIs within the active pocket of the protein were found to be variable, highlighting the adaptability of local force constants. In summary, our data underscore the potential of computational methodologies in guiding the rational design of artificial metalloproteins for tailored applications, with local vibrational mode analysis serving as a powerful tool for bond strength assessment. 

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3. Relation between Halogen Bond Strength and IR and NMR Spectroscopic Markers

   https://doi.org/10.3390/molecules28227520  

   Amonov, Akhtam; Scheiner, Steve (November 2023, Molecules)

   The relationship between the strength of a halogen bond (XB) and various IR and NMR spectroscopic quantities is assessed through DFT calculations. Three different Lewis acids place a Br or I atom on a phenyl ring; each is paired with a collection of N and O bases of varying electron donor power. The weakest of the XBs display a C–X bond contraction coupled with a blue shift in the associated frequency, whereas the reverse trends occur for the stronger bonds. The best correlations with the XB interaction energy are observed with the NMR shielding of the C atom directly bonded to X and the coupling constants involving the C–X bond and the C–H/F bond that lies ortho to the X substituent, but these correlations are not accurate enough for the quantitative assessment of energy. These correlations tend to improve as the Lewis acid becomes more potent, which makes for a wider range of XB strengths. 

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4. Halogen Bonding versus Nucleophilic Substitution in the Co-Crystallization of Halomethanes and Amines

   https://doi.org/10.3390/cryst14020124  

   Grounds, Olivia; Zeller, Matthias; Rosokha, Sergiy V (February 2024, Crystals)

   Haloalkanes and amines are common halogen-bond (XB) donors and acceptors as well as typical reagents in nucleophilic substitution reactions. Thus, crystal engineering using these molecules requires an understanding of the interchange between these processes. Indeed, we previously reported that the interaction of quinuclidine (QN) with CHI3 in acetonitrile yielded co-crystals showing a XB network of these two constituents. In the current work, the interactions of QN with C2H5I or 1,4-diazabicyclo[2.2.2]octane (DABCO) with CH2I2 led to nucleophilic substitution producing I− anions and quaternary ammonium (QN-CH2CH3 or DABCO-CH2I+) cations. Moreover, the reaction of QN with CHI3 in dichloromethane afforded co-crystals containing XB networks of CHI3 with either Cl− or I− anions and QN-CH2Cl+ counter-ions. A similar reaction in acetone produced XB networks comprising CHI3, I− and QN-CH2COCH3+. These distinctions were rationalized through a computational analysis of XB complexes and the transition-state energies for the nucleophilic substitution. It indicated that the outcome of the reactions was determined mostly by the relative energies of the products. The co-crystals obtained in this work showed bonding between the cationic (DABCO-CH2I+, QN-CH2Cl+) or neutral (CHI3) XB donors and the anionic (I−, Cl−) or neutral (CHI3) acceptors. Their analysis showed comparable electron and energy densities at the XB bond critical points and similar XB energies regardless of the charges of the interacting species. 

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5. Intermolecular binding preferences of haloethynyl halogen-bond donors as a function of molecular electrostatic potentials in a family of N -(pyridin-2-yl)amides

   https://doi.org/10.1039/d1ob01133b  

   Abeysekera, Amila M.; Averkiev, Boris B.; Le Magueres, Pierre; Aakeröy, Christer B. (January 2021, Organic & Biomolecular Chemistry)

   null (Ed.)

   In order to explore how σ-hole potentials, as evaluated by molecular electrostatic potential (MEP) calculations, affect the ability of halogen atoms to engage in structure-directing intermolecular interactions, we synthesized four series of ethynyl halogen-substituted amide containing pyridines (activated targets); ( N -(pyridin-2-yl)benzamides (Bz-act-X), N -(pyridin-2-yl)picolinamides (2act-X), N -(pyridin-2-yl)nicotinamides (3act-X) and N -(pyridin-2-yl) isonicotinamides (4act-X), where X = Cl/Br/I. The molecules are deliberately equipped with three distinctly different halogen-bond acceptor sites, π, N(pyr), and OC, to determine binding site preferences of different halogen-bond donors. Crystallographic data for ten (out of a possible twelve) new compounds were thus analyzed and compared with data for the corresponding unactivated species. The calculated MEPs of all the halogen atoms were higher in the activated targets in comparison to the unactivated targets and were in the order of iodine ≈ chloroethynyl < bromoethynyl < iodoethynyl. This increased positive σ-hole potential led to a subsequent increase in propensity for halogen-bond formation. Two of the four chloroethynyl structures showed halogen bonding, and all three of the structurally characterized bromoethynyl species engaged in halogen bonding. The analogous unactived species showed no halogen bonds. Each chloroethynyl donor selected a π-cloud as acceptor and the bromoethynyl halogen-bond donors opted for either π or N(pyr) sites, whereas all halogen bonds involving an iodoethynyl halogen-bond donor (including both polymorphs of Bz-act-I ) engaged exclusively with a N(pyr) acceptor site. 

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