Anion-molecule nucleophilic substitution (SN2) reaction, X‒ + RY → XR + Y‒, is a fundamental reaction in organic chemistry. Understanding how the reaction proceeds dynamically is particularly important for predicting the products or developing new reactions. A well-established mechanism for SN2 reaction is Walden-inversion, in which the nucleophile (X‒) approaches the carbon atom and substitutes the leaving group (Y‒) on the opposite side. With the breaking of old C–Y bond and the formation of new C–X bond, the resulted configuration of the carbon atom is inverted in product XR. This stereospecificity is crucial in synthetic organic chemistry. In past several decades, gas-phase dynamics of SN2 reactions were found to be more complex than expected1. Distinctive mechanisms that break the traditional Walden inversion pattern were reported for the simple X‒ + CH3Y SN2 reactions. However, configuration retention mechanisms, in which the configuration of the central carbon remains unchanged during the reaction, have been rarely discussed in SN2 reactions when bulkier groups are introduced to the reactant RY.

Varying the residue R from methyl to ethyl, propyl, and tert-butyl opens up competing channels, the base-induced elimination (E2) reactions that produce HX + R’C = CH2 + Y‒. This greatly lowers the SN2 product branching ratio. The competition between SN2 and E2 reactions is significant for the synthesis of pure samples in organic chemistry, and can be affected by multiple factors. Fully understanding the atomic-level dynamics of such complicated systems is inherently difficult. In their recent work, Lu et al. report details of the structure change and energy exchange in a paradigmatic reaction between chloride anion Cl‒ and tert-butyl iodide (CH3)3CI2. This work elegantly combines experiment and computational simulations.

Lu et al. use ion-molecule crossed-beam setup equipped with three-dimensional (3D) velocity map imaging technique to provide a detailed analysis of Cl‒ + (CH3)3CI reaction in gas phase. In the experiment, the velocities of the ions and molecules are controlled separately. The ionic products are detected and displayed as images, which provide the energy and angular distributions of the products. The reactions were studied under high collision energies of 1–2 eV, and the resulted angular distribution of product anion I‒ displays forward scattering. This recalls the previous finding by Carrascosa et al. that increasing the size of the residue R from methyl to tert-butyl, the dynamics drastically change from backward to dominant forward scattering of the leaving ion relative to the reactant RY velocity, where three different X–Y combinations (F–Cl, F–I and Cl–I) were involved3. Forward reactive scattering is found to be a fingerprint of direct E2 dynamic3,4. However, both the SN2 and E2 channels generate product anion I‒, making it difficult to distinguish them experimentally.

To uncover the dynamics details that the experiments do not completely reveal, Lu et al. developed a 39-dimensional potential energy surface (PES) by the fundamental invariant neural network approach based on more than 250,000 energy points. The complexity and accuracy of this full-dimensional PES is impressive. This approach has been used previously in simulating the F‒ + (CH3)3CI reaction by the same group4. Accurate quasi-classical trajectory dynamics simulations are in good agreement with experimental results in product energy partitioning and angular distribution. The E2 trajectories mainly generate forward scattering I‒ ions and the majority of energy is partitioned to the internal energy of the products, leaving relatively cold I‒ that moves slowly. Simulations reveal that E2 dominates over SN2 products and E2 becomes even more important at higher collision energies. The SN2 trajectories only take 15%–22%, such low SN2 reactivities were attributed to the high E2 reactivity of the tert-butyl group rather than its steric hinderance towards SN2 products, as in the case of reaction between F‒ and (CH3)3CI5. Compared with Cl‒ + (CH3)3CI studied here, the collision energy dependence of E2/SN2 branching ratio is different in F‒ + C2H5Cl system, where the QCT simulations on a 21-dimensional PES revealed that increasing the collision energy raises the portion of SN2 reaction, albeit the E2 reaction maintains the dominant role6.

Among the SN2 trajectories of the Cl‒ + (CH3)3CI reaction, a new mechanism appears: The Cl‒ approaches the back-side of (CH3)3CI and induces significant elongation of C–I bond, then the (CH3)3C group flips over, followed by the formation of Cl–C bond (Fig. 1). Of particularly interests is that the configuration of the central carbon atom is retained during the process. The transition state of flip-over mechanism lies 0.8 eV above the reactants and roughly 0.6 eV above the transition state of the traditional backside attack mechanism. Nevertheless, the high collision energy provides sufficient energy to cross the barrier. This flip-over mechanism is fast, with the average duration time of 0.3 ps. Flip-over trajectories mainly lead to forward-scattered I‒ ion, a result of large impact parameter collisions. This is because collisions initiated with larger impact parameter enhances a larger momentum of inertia for the tert-butyl group. Minor portion of flip-over trajectories lead to backward scattering involve small impact parameter collisions.

Fig. 1: Flip-over SN2 mechanism.
Fig. 1: Flip-over SN2 mechanism.The alternative text for this image may have been generated using AI.
Full size image

The quasi-classical trajectory simulation on a 39-dimensional potential energy surface reveals a novel direct SN2 mechanism for anion reacting with tert-butyl halide with retention of configuration, as reported by Lu et al.2.

This flip-over mechanism adds a new variant to the family of configuration-retention SN2 mechanisms. Previously identified mechanisms contain the front-side attack7 and the proton-abstraction induced double-inversion mechanisms8 that were initially observed in X‒ + CH3Y SN2 reactions. However, neither were reported in the Cl‒ + (CH3)3CI reaction, likely due to their high barriers. On the other hand, this flip-over mechanism was not found in methyl or ethyl systems, highlighting the special feature of the symmetric bulky tert-butyl group. Nevertheless, the universality of this flip-over mechanism remains a topic for future research.

The flip-over mechanism is collision induced and found to be more important at higher collision energy. It takes up to 7% among the SN2 trajectories at collision energy of about 2 eV. This collision induced feature is similar to the roundabout mechanism that was firstly observed in Cl‒ + CH3I reaction9, where the incoming Cl‒ collides and induces a rotation of CH3I, followed by displacement. In contrast, roundabout mechanism mainly leads to CH3-inverted products, where in rare cases the configuration of CH3 were retained, as observed in the direct dynamic simulations of OH‒ + CH3I reaction10.

The study by Lu et al. illustrates the exceptional insights into details of reaction dynamics that can be obtained with combined ion-molecule crossed-beam experiment and intensive simulations. The accurate high-dimension PES and millions of simulation trajectories make it possible for the capture of the rare flip-over mechanism in ion-molecule reaction that involves bulky residue. This new stereochemistry retention mechanism expands our understanding of a paradigm reaction. The strong interplay between these state-of-the-art experiments and simulations provides a powerful means to illustrate the effects of multiple factors—including nucleophile type, leaving group, substrate residue size, microsolvation, and collision energy—on the competing SN2 and E2 ion-molecule reactions in the gas phase. As more reactions are studied with these methods, more novel characters in reaction dynamics are expected to be discovered.