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Halogen Bonding: Insights from Computational Tools

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: closed (15 February 2020) | Viewed by 43121

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Dr. Paulo Jorge Costa

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Guest Editor

University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal
Interests: computational chemistry; molecular modeling and simulation; halogen bonds; molecular recognition; reaction mechanisms

Special Issue Information

Dear Colleagues,

The distinctive features of halogen bonds have prompted their widespread application in many areas such as supramolecular chemistry, crystal engineering, catalysis, medicinal chemistry, and chemical biology, among others. Given their relevance, computational and molecular modeling methods are extremely helpful in the quest for further understanding the phenomenon or to guide new experimental work. Indeed, theoretical studies are in the frontline of quarrels concerning the nature of the halogen bond, and the study of solvent and substituent effects.

This Special Issue aims to highlight the role of computational methodologies in the study of halogen bonds, ranging from the most common quantum mechanics calculations to force field-based methods. Therefore, original manuscripts reporting the application of computational tools in the study of halogen-bonded systems are encouraged. In addition, perspectives and reviews are also welcome.

Dr. Paulo Jorge Costa
Guest Editor

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Keywords

Halogen bonding
Computational studies
Molecular simulation
Sigma-hole interactions
Noncovalent interactions

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Published Papers (10 papers)

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19 pages, 1965 KiB

Open AccessArticle

An Interacting Quantum Atoms (IQA) and Relative Energy Gradient (REG) Study of the Halogen Bond with Explicit Analysis of Electron Correlation

by Ibon Alkorta, Arnaldo F. Silva and Paul L. A. Popelier

Molecules 2020, 25(11), 2674; https://doi.org/10.3390/molecules25112674 - 9 Jun 2020

Cited by 13 | Viewed by 3229

Abstract

Energy profiles of seven halogen-bonded complexes were analysed with the topological energy partitioning called Interacting Quantum Atoms (IQA) at MP4(SDQ)/6–31 + G(2d,2p) level of theory. Explicit interatomic electron correlation energies are included in the analysis. Four complexes combine X₂ (X = Cl or F) with HCN or NH₃, while the remaining three combine ClF with HCN, NH₃ or N₂. Each complex was systematically deformed by translating the constituent molecules along its central axis linking X and N, and reoptimising its remaining geometry. The Relative Energy Gradient (REG) method (Theor. Chem. Acc. 2017, 136, 86) then computes which IQA energies most correlate with the total energy during the process of complex formation and further compression beyond the respective equilibrium geometries. It turns out that the covalent energy (i.e., exchange) of the halogen bond, X…N, itself drives the complex formation. When the complexes are compressed from their equilibrium to shorter X…N distance then the intra-atomic energy of N is in charge. When the REG analysis is restricted to electron correlation then the interatomic correlation energy between X and N again drives the complex formation, and the complex compression is best described by the destabilisation of the through-space correlation energy between N and the “outer” halogen. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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18 pages, 5385 KiB

Open AccessArticle

Visible Light-Induced Homolytic Cleavage of Perfluoroalkyl Iodides Mediated by Phosphines

by Mario Bracker, Lucas Helmecke, Martin Kleinschmidt, Constantin Czekelius and Christel M. Marian

Molecules 2020, 25(7), 1606; https://doi.org/10.3390/molecules25071606 - 1 Apr 2020

Cited by 24 | Viewed by 4757

Abstract

In an effort to explain the experimentally observed variation of the photocatalytic activity of

^{t}

_{3}

^{n}

_{3}

P and (MeO)

_{3}

P in the blue-light regime [Helmecke et al., Org. Lett. 21 (2019) 7823], we have explored the absorption [...] Read more.

In an effort to explain the experimentally observed variation of the photocatalytic activity of

^{t}

_{3}

^{n}

_{3}

P and (MeO)

_{3}

P in the blue-light regime [Helmecke et al., Org. Lett. 21 (2019) 7823], we have explored the absorption characteristics of several phosphine– and phosphite–IC

_{4}

_{9}

adducts by means of relativistic density functional theory and multireference configuration interaction methods. Based on the results of these computational and complementary experimental studies, we offer an explanation for the broad tailing of the absorption of

^{t}

_{3}

P-IC

_{4}

_{9}

and (MeO)

_{3}

P-IC

_{4}

_{9}

into the visible-light region. Larger coordinate displacements of the ground and excited singlet potential energy wells in

^{n}

_{3}

P-IC

_{4}

_{9}

, in particular with regard to the P–I–C bending angle, reduce the Franck–Condon factors and thus the absorption probability compared to

^{t}

_{3}

P-IC

_{4}

_{9}

. Spectroscopic and computational evaluation of conformationally flexible and locked phosphites suggests that the reactivity of (MeO)

_{3}

P may be the result of oxygen lone-pair participation and concomitant broadening of absorption. The proposed mechanism for the phosphine-catalyzed homolytic C–I cleavage of perfluorobutane iodide involves S₁ ← S₀ absorption of the adduct followed by intersystem crossing to the photochemically active T

_{1}

state. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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22 pages, 4759 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

In Situ Assessment of Intrinsic Strength of X-I⋯OA-Type Halogen Bonds in Molecular Crystals with Periodic Local Vibrational Mode Theory

by Yunwen Tao, Yue Qiu, Wenli Zou, Sadisha Nanayakkara, Seth Yannacone and Elfi Kraka

Molecules 2020, 25(7), 1589; https://doi.org/10.3390/molecules25071589 - 30 Mar 2020

Cited by 26 | Viewed by 4565

Abstract

Periodic local vibrational modes were calculated with the rev-vdW-DF2 density functional to quantify the intrinsic strength of the X-I⋯OA-type halogen bonding (X = I or Cl; OA: carbonyl, ether and N-oxide groups) in 32 model systems originating from 20 molecular crystals. We found that the halogen bonding between the donor dihalogen X-I and the wide collection of acceptor molecules OA features considerable variations of the local stretching force constants (0.1–0.8 mdyn/Å) for I⋯O halogen bonds, demonstrating its powerful tunability in bond strength. Strong correlations between bond length and local stretching force constant were observed in crystals for both the donor X-I bonds and I⋯O halogen bonds, extending for the first time the generalized Badger’s rule to crystals. It is demonstrated that the halogen atom X controlling the electrostatic attraction between the

σ

-hole on atom I and the acceptor atom O dominates the intrinsic strength of I⋯O halogen bonds. Different oxygen-containing acceptor molecules OA and even subtle changes induced by substituents can tweak the

n \to σ^{*}

(X-I) charge transfer character, which is the second important factor determining the I⋯O bond strength. In addition, the presence of the second halogen bond with atom X of the donor X-I bond in crystals can substantially weaken the target I⋯O halogen bond. In summary, this study performing the in situ measurement of halogen bonding strength in crystalline structures demonstrates the vast potential of the periodic local vibrational mode theory for characterizing and understanding non-covalent interactions in materials. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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12 pages, 2816 KiB

Open AccessArticle

Anion Recognition by Neutral and Cationic Iodotriazole Halogen Bonding Scaffolds

by Iñigo Iribarren, Goar Sánchez-Sanz and Cristina Trujillo

Molecules 2020, 25(4), 798; https://doi.org/10.3390/molecules25040798 - 12 Feb 2020

Cited by 3 | Viewed by 3037

Abstract

A computational study of the iodide discrimination by different neutral and cationic iodotriazole halogen bonding hosts was carried out by means of Density Functional Theory. The importance of the size of the scaffold was highlighted and its impact observed in the binding energies and intermolecular X⋯I distances. Larger scaffolds were found to reduce the electronic repulsion and increase the overlap between the halide electron lone pair and the corresponding I-C antibonding orbital, increasing the halogen bonding interactions. Additionally, the planarity plays an important role within the interaction, and can be tuned using hydroxyl to perform intramolecular hydrogen bonds (IMHB) between the scaffold and the halogen atoms. Structures with IMHB exhibit stronger halogen bond interactions, as evidenced by the shorter intramolecular distances, larger electron density values at the bond critical point and more negative binding energies. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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14 pages, 2127 KiB

Open AccessArticle

Theoretical Description of R–X⋯NH₃ Halogen Bond Complexes: Effect of the R Group on the Complex Stability and Sigma-Hole Electron Depletion

by Juan Zurita, Vladimir Rodriguez, Cesar Zambrano, Jose Ramón Mora, Luis Rincón and F. Javier Torres

Molecules 2020, 25(3), 530; https://doi.org/10.3390/molecules25030530 - 25 Jan 2020

Cited by 5 | Viewed by 3775

Abstract

In the present work, a number of R–X⋯NH₃ (X = Cl, Br, and I) halogen bonded systems were theoretical studied by means of DFT calculations performed at the ωB97XD/6-31+G(d,p) level of theory in order to get insights on the effect of the electron-donating or electron-withdrawing character of the different R substituent groups (R = halogen, methyl, partially fluorinated methyl, perfluoro-methyl, ethyl, vinyl, and acetyl) on the stability of the halogen bond. The results indicate that the relative stability of the halogen bond follows the Cl < Br < I trend considering the same R substituent whereas the more electron-withdrawing character of the R substituent the more stable the halogen bond. Refinement of the latter results, performed at the MP2/6-31+G(d,p) level showed that the DFT and the MP2 binding energies correlate remarkably well, suggesting that the Grimme’s type dispersion-corrected functional produces reasonable structural and energetic features of halogen bond systems. DFT results were also observed to agree with more refined calculations performed at the CCSD(T) level. In a further stage, a more thorough analysis of the R–Br⋯NH₃ complexes was performed by means of a novel electron localization/delocalization tool, defined in terms of an Information Theory, IT, based quantity obtained from the conditional pair density. For the latter, our in-house developed C++/CUDA program, called KLD (acronym of Kullback–Leibler divergence), was employed. KLD results mapped onto the one-electron density plotted at a 0.04 a.u. isovalue, showed that (i) as expected, the localized electron depletion of the Br sigma-hole is largely affected by the electron-withdrawing character of the R substituent group and (ii) the R–X bond is significantly polarized due to the presence of the NH₃ molecule in the complexes. The afore-mentioned constitutes a clear indication of the dominant character of electrostatics on the stabilization of halogen bonds in agreement with a number of studies reported in the main literature. Finally, the cooperative effects on the [Br—CN]_n system (n = 1–8) was evaluated at the MP2/6-31+G(d,p) level, where it was observed that an increase of about ~14.2% on the complex stability is obtained when going from n = 2 to n = 8. The latter results were corroborated by the analysis of the changes on the Fermi-hole localization pattern on the halogen bond zones, which suggests an also important contribution of the electron correlation in the stabilization of these systems. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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15 pages, 2044 KiB

Open AccessArticle

Relativistic Effects on NMR Parameters of Halogen-Bonded Complexes

by Ibon Alkorta, José Elguero, Manuel Yáñez, Otilia Mó and M. Merced Montero-Campillo

Molecules 2019, 24(23), 4399; https://doi.org/10.3390/molecules24234399 - 2 Dec 2019

Cited by 10 | Viewed by 3282

Abstract

Relativistic effects are found to be important for the estimation of NMR parameters in halogen-bonded complexes, mainly when they involve the heavier elements, iodine and astatine. A detailed study of 60 binary complexes formed between dihalogen molecules (XY with X, Y = F, Cl, Br, I and At) and four Lewis bases (NH₃, H₂O, PH₃ and SH₂) was carried out at the MP2/aug-cc-pVTZ/aug-cc-pVTZ-PP computational level to show the extent of these effects. The NMR parameters (shielding and nuclear quadrupolar coupling constants) were computed using the relativistic Hamiltonian ZORA and compared to the values obtained with a non-relativistic Hamiltonian. The results show a mixture of the importance of the relativistic corrections as both the size of the halogen atom and the proximity of this atom to the basic site of the Lewis base increase. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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12 pages, 2877 KiB

Open AccessArticle

Halogen and Hydrogen Bonding in Halogenabenzene/NH₃ Complexes Compared Using Next-Generation QTAIM

by Shuman Li, Tianlv Xu, Tanja van Mourik, Herbert Früchtl, Steven R. Kirk and Samantha Jenkins

Molecules 2019, 24(16), 2875; https://doi.org/10.3390/molecules24162875 - 8 Aug 2019

Cited by 7 | Viewed by 3559

Abstract

Next-generation quantum theory of atoms in molecules (QTAIM) was used to investigate the competition between hydrogen bonding and halogen bonding for the recently proposed (Y = Br, I, At)/halogenabenzene/NH₃ complex. Differences between using the SR-ZORA Hamiltonian and effective core potentials (ECPs) to account for relativistic effects with increased atomic mass demonstrated that next-generation QTAIM is a much more responsive tool than conventional QTAIM. Subtle details of the competition between halogen bonding and hydrogen bonding were observed, indicating a mixed chemical character shown in the 3-D paths constructed from the bond-path framework set B. In addition, the use of SR-ZORA reduced or entirely removed spurious features of B on the site of the halogen atoms. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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18 pages, 5404 KiB

Open AccessArticle

Relationships between Interaction Energy and Electron Density Properties for Homo Halogen Bonds of the [(A)_nY–X···X–Z(B)_m] Type (X = Cl, Br, I)

by Maxim L. Kuznetsov

Molecules 2019, 24(15), 2733; https://doi.org/10.3390/molecules24152733 - 27 Jul 2019

Cited by 32 | Viewed by 3693

Abstract

Relationships between interaction energy (E_int) and electron density properties at the X···X bond critical point or the d(X···X) distance were established for the large set of structures [(A)_nY–X···X–Z(B)_m] bearing the halogen bonds Cl···Cl, Br···Br, and I···I (640 structures in total). The best estimator of E_int is the kinetic energy density (G_b), which reasonably approximates the whole set of the structures as −E_int = 0.128G_b² − 0.82G_b + 1.66 (R² = 0.91, mean absolute deviation 0.39 kcal/mol) and demonstrates low dispersion. The potential and kinetic energy densities, electron density, and the d(X···X) distance behave similarly as estimators of E_int for the individual series Cl···Cl, Br···Br, and I···I. A number of the E_int(property) correlations are recommended for the practical application in the express estimates of the strength of the homo-halogen bonds. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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Review

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16 pages, 4503 KiB

Open AccessReview

A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity

by Eric S. Marsan and Craig A. Bayse

Molecules 2020, 25(6), 1328; https://doi.org/10.3390/molecules25061328 - 14 Mar 2020

Cited by 22 | Viewed by 5469

Abstract

Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe⁻) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. THs have the lowest energy C–X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C–X bond. The higher energy C–Br* and C–Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C–X bond. Comparison of the I···Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I···Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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25 pages, 9072 KiB

Open AccessReview

Application of Halogen Bonding to Organocatalysis: A Theoretical Perspective

by Hui Yang and Ming Wah Wong

Molecules 2020, 25(5), 1045; https://doi.org/10.3390/molecules25051045 - 26 Feb 2020

Cited by 51 | Viewed by 6845

Abstract

The strong, specific, and directional halogen bond (XB) is an ideal supramolecular synthon in crystal engineering, as well as rational catalyst and drug design. These attributes attracted strong growing interest in halogen bonding in the past decade and led to a wide range of applications in materials, biological, and catalysis applications. Recently, various research groups exploited the XB mode of activation in designing halogen-based Lewis acids in effecting organic transformation, and there is continual growth in this promising area. In addition to the rapid advancements in methodology development, computational investigations are well suited for mechanistic understanding, rational XB catalyst design, and the study of intermediates that are unstable when observed experimentally. In this review, we highlight recent computational studies of XB organocatalytic reactions, which provide valuable insights into the XB mode of activation, competing reaction pathways, effects of solvent and counterions, and design of novel XB catalysts. Full article

(This article belongs to the Special Issue Halogen Bonding: Insights from Computational Tools)

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