Halogen Bonding

Some of you may be familiar with the term “halogen bonding”. In analogy to hydrogen bonding, this weak interaction occurs between an electron donor, such as nitrogen, and a halogen (Cl, Br, I). The halogen acts as an electrophile.

Halogen Bond N...Br

This is possible because the halogen has a region of positive partial charge at its tip, the so-called sigma-hole, as shown by calculations (doi:10.1007/s00894-006-0130-2). The group of Resnati and Metrangolo in Milan have used this interaction to construct a variety of polymeric chains and networks for crystal engineering. As they discuss in their current Science paper (doi:10.1126/science.1162215), it also plays an important role for drug design, which I am particularly interested in. Many drugs on the market are halogenated aromatics. The exact role of the halogen for binding is not always known, since often it was introduced in order to tune the hydrophobicity of the compound. I suspect that in many instances, halogen bonding to a backbone carbonyl oxygen could be of importance.

Clearly, more work is required to further investigate halogen bonding in a biological context. If people want to incorporate this kind of interaction into rational drug design or crystal engineering, good quantitative models will be needed.


  1. I’ve always thought people calling these types of electrostatic interactions a bond is a bit of a misnomer. As chemists, where should we draw the line for what constitutes a bond?

    • It’s a misnomer now, but it didn’t seem to be when the term was coined a hundred years ago. Now it’s so deeply ingrained into the lexicon that it’ll be difficult to root out. A halogen “bond” is only called such because it’s analogous to the H-bond. Other interactions understood much later, like pi-stacking and cation-pi interactions, aren’t called bonds because of their dissimilarity to covalent bonds. Sorry mitch, history is getting in the way of your quest for accurate terminology.

      So is a dative bond a bond, too? Is the only real bond a covalent bond? I’m not an emeritus professor yet, so the semantics don’t really seem relevant to progress in the field.

    • “We shall say that there is a chemical
      bond between two atoms or two groups of atoms in case that
      the forces acting between them are such as to lead to the
      formation of an aggregate with sufficient stability to make it
      convenient for the chemist to consider it as an independent
      chemical species.” ref.: L. Pauling, The Nature of the Chemical Bond, 2. Aufl., Cornell University Press, Ithaca, 1939, chap. 1

  2. Perhaps this is a little too semantic and not enough chemistry, but my understanding of a chemical bond is that it is a combination of orientation (alignment) and distance (too close to be anything but bonded).

    I could be wrong, but it often appears that halogen bonding focuses more on orientation than distance.

  3. This is a very interesting topic.

    Do copper metal centers possess this “sigma hole” but in the reverse sense (i.e. where nitrogen is nucleophilic)?

    • I wouldn’t apply the term “sigma-hole” to a metal because a copper ion is a lewis-acid and thus a non-directional electron acceptor. The sigma-hole of halogens has a very strong directionality.

  4. Phil, what is the typical bonding energy range for these kind of interactions? How much smaller than hydrogen bonds?

    Mitch, to me a bond is a atom-atom interaction where the interaction has an energetic minimum resulting from repulsive forces at shorter distances, and attractive forces at larger distances (likewise, angles).

    • But how shallow a potential minimum are you willing to accept?

    • I can only give you data from calculations. Lommerse et al. (JACS 1996, 118, 3108) have done ab initio calculations with chloro-cyanoacetylene and found a bonding energy of about 10 kJ/mol (2.4 kcal/mol). However, this is not a “typical” system.

      Typical hydrogen bonds (gas phase) are in the range of 3-7 kcal/mol. Ionic H-bonds are much stronger. Still, in an aqueous (i.e. biological) system, halogen bonding can win a competition with hydrogen bonding because water can form H-bonds, too.

  5. I’ll try to give a short answer to some of the issues raised. Yes, it’s true, the definition of chemical bond, having a combination of orientation (alignment) and distance, applies also to halogen bonding since this causes interpenetration of VdW volumes of the interacting atoms by around 20% and occurs on the extension of the C-X bond where the sigma-hole is located (angle 160-180°).
    Halogen bonds are comparable with hydrogen bonds, and span the energy range 1kcal-40kcal/mol (ionic X-bond). Halogen atoms bound to metal centers are not electrophilic (and then do not give XB) but behave as H- and X-bond acceptors (i.e. Lewis bases).
    All these arguments can be found in the papers suggested in my web-site: http://nfmlab.chem.polimi.it

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