Application of Halogen Bonding to Organocatalysis: A Theoretical Perspective

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.

Keywords: density functional theory (DFT); halogen bond; mechanism; noncovalent interaction; organocatalysis; supramolecular chemistry.

Figure 1

(a) Electrostatic (σ-hole) and (b) molecular orbital models of halogen bond (XB) formation. The formation of an XB complex between CF₃I (XB-donor) and H₂O (XB-acceptor) is used as an illustration.

Scheme 1

Perfluoroidoalkane (5)-catalyzed reduction of quinolines (1) by Hantzsch ester (2).

Figure 2

Calculated transition states for halogen bond-catalyzed (a) Diels–Alder cycloaddition [52], (b) Michael addition of indole to trans-crotonophenone [53], and (c) Nazarov cyclization reaction [54]. XB distances are in Å and A–I···B angles are in degrees. Hydrogen atoms are omitted for clarity.

Scheme 2

Fluoroiodobenzene-catalyzed hydrocyanation of imines.

Figure 3

Schematic reaction profiles of (a) uncatalyzed hydrocyanation of imine in the gas phase (black solid line), in toluene (red dashed line), 9-catalyzed in toluene (blue dotted line), and 12-catalyzed in toluene (purple short dashed line); (b) mechanism of the uncatalyzed reaction; (c) mechanism of the XB-catalyzed reaction.

Figure 4

Calculated reaction barriers for uncatalyzed and XB-catalyzed Diels–Alder reactions.

Figure 5

Optimized transition states, PhI-3-TS-endo and CAT-3-perFPhI-TS-endo, showing the similar halogen bond lengths. Interaction distances are shown in Å. Hydrogen atoms are omitted for clarity.

Figure 6

Uncatalyzed (red solid line) and I₂-calculated (blue dotted line) reaction profiles for intramolecular cyclization of aminochalcone (21).

Figure 7

Calculated reaction profiles of uncatalyzed (black solid line), I₂ (blue dotted line), and HI-catalyzed (red dashed line) intermolecular Michael addition of indole to trans-crotonophenone (25).

Figure 8

NBO population analysis of XB interaction energies for selected reactions.

Figure 9

Calculated reaction profiles for the cyclization step of I₂-catalyzed iso-Nazarov cyclization of conjugated dienals. Interaction distances are given in Å.

Figure 10

Calculated reaction profiles for the C–C bond addition step of the uncatalyzed and dihalogen (X₂)-catalyzed Michael addition reactions, at the M06-2X/def2-TZVP level. Reaction energies are reported in kcal/mol and free energies at 298.15 K and 1 atm are given in parentheses. Overlaid transition state (TS) structures are shown at the bottom and colored as follows: uncatalyzed black, F₂ cyan, Cl₂ green, Br₂ red, and I₂ purple.

Figure 11

Calculated activation barriers for Michael addition reactions catalyzed by dihalogens versus the HOMO_py–LUMO gap Δε, at the M06-2X/def2-TZVP level.

Scheme 3

Zinc acetate-catalyzed iodolactonization reaction of allyl acetic acid (35).

Scheme 4

Reduction of quinoline by Hantzsch ester catalyzed by imidazolinium and imidazolium.

Figure 12

Calculated reaction profiles for the uncatalyzed (red solid line) and halogen bond-catalyzed (blue dotted line) pathways. Distances are in Å and A–I···B angles are in degrees. C–H hydrogen atoms except for the transferring hydride or proton are omitted for clarity.

Figure 13

Calculated pathways for Brønsted acid-catalyzed (black solid line) and XB-catalyzed (blue dotted line) reduction of quinoline by 39. For comparison, the decomposition of 40 to generate Brønsted acid catalyst is shown in red dashed line.

Figure 14

Calculated reaction profiles for uncatalyzed (red solid line) and iodoimidazolinium 47-catalyzed (blue dotted line) conjugate addition of methylthiophene to enone.

Figure 15

Calculated XB and π···π interaction complexes between 48 and 49. Interaction distances are in Å and A–I···B angles are in degrees. Hydrogen atoms are omitted for clarity.

Figure 16

Transition states of [4+2] cycloaddition between indoles. Interaction distances are in Å and A–I···B angles are in degrees. Hydrogen atoms are omitted for clarity.

Figure 17

Calculated reaction profiles for the uncatalyzed and ICl₃-catalyzed ring-opening polymerization of l-lactide. The uncatalyzed concerted pathway is shown as a black solid line, the uncatalyzed stepwise pathway is shown as a red dotted line, the XB-catalyzed concerted pathway is shown as a blue dashed line, and the catalyzed stepwise pathway is shown as a purple dash-dotted line.