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

Abstract

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.

Figure 1.

Electrostatic models for the hydrogen bond (HB) and halogen bond (XB). a. In an OH bond, the more electronegative oxygen (reflected in the Pauling electronegativity scale, χ_r) draws more of the electron pair towards the oxygen, leaving an electropositive hydrogen to serve as the HB donor. This anisotropic distribution of charges is reflected in the electrostatic potential map calculated for water. b. The σ-hole model for an XB posits that in forming a covalent σ-molecular orbital, the pz orbital of the halogen (X) is depleted, resulting in an electropositive crown and slight flattening of the atom at the tip.

Figure 2.

Relationships between HB and XB donors and acceptors. a. Competitive XB and HB for an acceptor atom. b. Simultaneous HB and XB to an acceptor. c. HB to an amphoteric halogen that serves simultaneously as an XB donor. (Adapted from Rowe et al.)

Figure 3:

Schematics of first generation XB receptor (G1XB) and second generation XB and HB receptors (G2XB). Syntheses can be found in the original publications.^,

Figure 4:

Schematics and associated electrostatic potential (ESP) maps of G1XB (a), G2XB (b), G2XB no amine (c) and G2XB no fluorine (d) showing HBeXB enhancement of the electropositive σ-holes. ESP maps drawn at a 0.004 au isodensity.

Figure 5:

Crystal structures of G1XBme with bromide top view (a, top) and planar view (a, bottom) comparing distances with G2XBme and bromide (b). The planar views include the degrees that the pyridnium rings twist out of coplanarity with the benzene (a, bottom) or fluoroaniline (b, bottom) core.

Figure 6.

The T4 lysozyme (T4L) model system for XB studies. a. The hydroxyl of the tyrosine amino acid at position 18 (Y18) forms an HB to the polypeptide backbone of glutamate E11 (dashes). The side chain of tyrosine at Y88, however, is solvent exposed and does not interact with the remainder of the protein. b. Replacing Y18 with a metachlorotyrosine (^mClY18) maintains the essential HB to E11, with the addition of an XB from the Cl to the peptide oxygen of glycine G28. c. Electrostatic potentials of a chlorophenol model of the ^mClY18 side chain. The Cl substituent shows a weak σ-hole when the hydrogen of the OH is rotated away from the halogen (top) but becomes significantly enhanced when rotated to form an HB.

Figure 7.

Quantum mechanics (MP2) calculated energies (E_MP2) of XBs from chlorobenzene to the carbonyl oxygen of N-acetylamide (NMA, a model for a peptide bond), and effects from adjacent hydroxyl groups. The Cl-XB is fairly weak, and addition of a hydroxyl to an adjacent (ortho) carbon weakens the interaction further. Rotation of the OH to form an HB to the Cl, however, significantly increases the stabilizing potential of the Cl-XB (with E_MP2 becoming more negative by ~1.5 kcal/mol). The inset shows the MP2 calculated inductive effects of a hydroxyl (OH) substituent on charges at the carbons of benzene (phenol). The carbons of benzene carry a charge of −0.15e, determined through an MP2 calculation. The charge at the ortho- and para-carbons become more negative, reflecting the electron donating effect, while that of the meta-carbon becomes more positive, indicative of the electron withdrawing effect of the hydroxyl group to these positions. The Hammett constants for hydroxyl substituents are −0.37 for the para- and +0.12 for the meta-positions, consistent with the quantum calculated effects on the carbon charges.

Figure 8.

Results from survey of structures from the Cambridge Structural Database (CSD) for potential HBeXBs. a. Radial distribution of potential HBeXBs. The CSD was surveyed for structures of halogenated aromatic compounds (Cl, Br, or I), with HB donors (OH or NH₂) at the ortho-position, that form complexes with an XB/HB acceptor (O or N). The distance from the halogen to the acceptor atom, normalized to the sum of the respective van der Waals radii (R_X···(O/N) ≤ 1.05) are plotted radially relative to the angle of approach of the acceptor to the C–X bond (θ₁). b. Plot of normalized distances from the acceptor (A) to the halogen (R_X···A) versus the distance to the HB donor (R_(O/N)···A). HB interactions are distinguished from XBs by R_(O/N)···A ≤ 1.25. c. Radial plot of XBs from a, with HBs removed according to the criteria in b.

Figure 9.

Different types of polarization enhanced noncovalent cooperativity. The HBeXB is a subclass of polarization enhanced XBs where HBing directly to the XB donor enhances the XB interaction. EWG is an electron withdrawing group adjacent to a HB or XB donor, while A refers to electron-rich acceptors of HBs or XBs.