Why S_N2 Reactions Don’t Work In Water

Like scales in music theory and integrals in calculus, reaction mechanisms lie at the heart of organic chemistry. These mechanisms chart the step-by-step maneuvers of individual chemical species as they jockey for position during a reaction.

Generations of organic chemistry students have pored over subtle details of some of the best-known forms of this chemical choreography, often learning first about the classic displacement reaction mechanism known as S_N2. In these reactions, a chemical species attacks a reactive carbon atom and displaces an atom or functional group that had been bonded to it. Students often learn that S_N2 reactions, which run smoothly in many organic solvents, don’t work well in water.

That characteristic of S_N2 reactions has been known empirically, and now scientists have uncovered the molecular-level origins of that mechanistic inhibition.

For decades researchers have known that S_N2 reactions don’t work well in aqueous solution, where reactants can potentially be surrounded by millions of interfering water molecules, says Sotiris S. Xantheas, a computational scientist and laboratory fellow at Pacific Northwest National Laboratory. “But how many water molecules are needed to shut off the reaction?” Xantheas asks. “Do we need just a few molecules or a few thousand?” Through a combination of experimental and theoretical work, Xantheas and coworkers in Japan have found that just two or three water molecules can shut down S_N2 reactions (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201207697).

Bimolecular nucleophilic substitution, the full name for the S_N2 mechanism, proceeds by way of an attack by a positive-charge-seeking reactant on a reactive carbon center. The process substitutes the attacking nucleophile for a leaving group, which is displaced in the reaction. A key feature of the mechanism is a high-energy transition-state structure that for a fleeting moment couples the nucleophile and leaving group with the reactive carbon center. The energy of the transition-state structure relative to that of reactants and products plays a central role in determining how easily the reaction proceeds.

Earlier studies showed that the rates of S_N2 reactions involving halide ion nucleophiles and leaving groups—for example, X⁻ + CH₃Cl → XCH₃ + Cl⁻—were a few orders of magnitude lower in protic solvents than in aprotic solvents. Researchers generally proposed that the reaction was suppressed by the formation of large solvation shells around the attacking halide ion. Theoretical analysis and molecular beam studies lent support to that explanation, but the molecular-level details of the solvation process remained unknown.

To ferret out those details, especially the effects of neighboring water molecules on reactants, Xantheas, Yoshiya Inokuchi and Takayuki Ebata of Hiroshima University, and coworkers formed gas-phase I⁻(CH₃I)(H₂O) clusters with up to three water molecules. The team probed the behavior of these clusters, which are models for solvated reactants, via infrared photodissociation spectroscopy, and they interpreted the results on the basis of quantum mechanical calculations and simulations.

By dissociating the complexes, the group found that water molecules readily form hydrogen-bonded complexes with I⁻. Then the water-complexed ion and the methyl iodide species begin to interact by forming intermediates. But once the intermediates with just two or three water molecules form, they’re so stable that they get stuck in that state. The energy barrier they need to surmount to adopt the S_N2 transition-state structure is too high, and so the reaction cannot proceed.

Yale University chemistry professor Mark A. Johnson, a specialist in reaction mechanisms, remarks that cluster studies like this one are important because they reveal the microscopic mechanics that dictate the way solvent molecules modify reaction potential energy surfaces and in some cases mediate the energy required to overcome barriers to reaction.

The behavior of water is particularly interesting, Johnson says, because of the highly cooperative way that networks of water molecules flex to accommodate charged and neutral solutes as those solutes engage to form a reactive encounter.

Johnson adds that future work in this area could move beyond the static pictures associated with stable intermediates on potential energy surfaces and follow the dynamics of large complex systems as they evolve to access the transition state.