Hydrogen Bonding of N‐Heterocyclic Carbenes in Solution: Mechanisms of Solvent Reorganization

Abstract

The hydrogen-bond dynamics of N-heterocyclic carbenes plays a central role in their proton-transfer reactions, and the effects of hydrogen bonding are also often invoked in corresponding organocatalytic applications. In the present study, the structures and lifetimes of hydrogen bonds have been investigated for several carbenes in alcohol-containing solutions by classical molecular dynamics simulations. The basicity of the carbene was found to be of major importance; while the least basic carbenes are often in their free form in the solvent, by increasing the basicity the simulations show increased hydrogen bonding, often even with two alcohol molecules at a time. In the latter structure the single lone pair of the carbene is in interplay with two hydrogen bond donors. The exchange mechanism is different for carbenes with different basicities, with different substituents, and in different solvents, occurring through the free carbene for the least basic compounds, and through the aforementioned doubly-hydrogen-bonded structure in case of the most basic derivatives. Since this process plays a central role also in H/D exchange reactions, we argue that the pK values calculated from the related measurements have a varying physical meaning for the different carbenes. The lifetimes of the hydrogen bonds are apparently also clearly related to the basicity of the carbene, with gradually increasing lifetimes for the most basic compounds.

The Mechanism of N‐Heterocyclic Carbene Organocatalysis through a Magnifying Glass

“…The high basicity of NHCs makes them also strong hydrogen bond acceptors, a feature that has been suggested first by Wanzlick, and evidenced later by theoretical calculations and experiments . This is also in accordance with the observations that solvent rearrangement—that is, the exchange of a hydrogen bond donor at the basic site of the NHC (Figure )—is the rate limiting step of H/D exchange reactions of azolium cations.…”

“…Through molecular dynamics simulations we have observed that the exchange of a solvent molecule, which is in hydrogen bond with the NHC, does not necessitate the formation of the free NHC in the solution . Instead, the single lone pair can accommodate a second hydrogen bond donor, allowing for an associative exchange, which can facilitate the hydrogen bond dynamics—thus the solvent exchange—of NHCs (Figure ).…”

“…Through molecular dynamics simulations we have observed that the exchange of a solvent molecule, which is in hydrogen bond with the NHC, does not necessitate the formation of the free NHC in the solution . Instead, the single lone pair can accommodate a second hydrogen bond donor, allowing for an associative exchange, which can facilitate the hydrogen bond dynamics—thus the solvent exchange—of NHCs (Figure ). We assumed that if the capacity of NHC lone pairs to serve as multiple interaction sites is a general feature, it may also allow a concerted reaction mechanism for the related organocatalytic reactions, as was suggested (and immediately rejected) earlier …”

N‐Heterocyclic Carbene Organocatalysis: With or Without Carbenes?

“…Thus, in protic (hydrogen bonding) solvents the dissociative mechanism can be rationalized as a substitution of the ammonium cation by the solvent at the hydrogen bond acceptor hypovalent carbon atom, followed by the reaction depicted in Figure . Such exchange of hydrogen bond donors at NHCs has been discussed before, and has been found to depend on steric effects and the hydrogen bond acceptor strength of the NHC in its rate and mechanism . The reaction of the solvent–NHC hydrogen‐bonded complex with the substrate (Figure ) can be considered as a special case of the associative mechanism depicted in Figure .…”

“…However, hydrogen bonding can also have a tremendous effect on the availability of the free NHC. NHCs are highly basic compounds, and hence they can form very strong hydrogen bonds, which can result in a stabilization up to even 10–20 kcal mol −1 . Although the stabilization by hydrogen bonding activates the aldehyde substrate, it may also occupy the NHC lone pair, which is the very site, to which the electrophilic substrate should bind in the reaction.…”