Selective Organic Reactions Enabled by Isotope-Controlled Tunneling Reactivity

Selective Organic Reactions Enabled by Isotope-Controlled Tunneling Reactivity

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A large kinetic isotope effect (KIE) is one of the criteria that indicates quantum mechanical tunneling in a chemical reaction. A larger mass lowers zero-point vibrational energy, resulting in broader energy barrier a particle has to penetrate. Besides tunneling probes, this phenomenon could be a useful tool to enable the desired selectivity in organic reactions. In 2017, an example of isotope-controlled selectivity in a chemical reaction was reported where two products can form by two distinct tunneling pathways (Figure 1). The computational studies predicted that carbene 1 would undergo [1,2]H-tunneling to give vinylcyclopropane 2. On the other hand, the ring expansion would proceed to yield 3 when d3-1 is used. Our goal is to realize these reactions that would be the first example of the selective organic synthesis enabled by isotope-controlled selectivity.


The project consists of experimental and computational parts. In the experimental part, we synthesize suitable carbene precursors, one of which is N-aziridinyl imine 4 (Figure 1). Using 4 as an initial test substrate, we conduct matrix isolation experiments to capture and characterize reactive carbene species generated by flash vacuum pyrolysis or UV irradiation. The identification of reactive intermediates captured in a matrix at 3 K is performed by IR spectroscopy. In the computational part, we compute IR spectra of possible (reactive) intermediates at B3LYP/6-31G(d,p). We also perform computations of IR spectra at CCSD(T)/cc-pVTZ for the optimized structures. The computed IR spectra are used for comparison with experimental spectra.


The synthesis of N-aziridinyl imine 4 was performed starting with commercially available (–)-ethyl L-lactate (Scheme 1). Protection of the hydroxyl group with the 2-tetrahydropyranyl (THP) group was followed by the cyclopropanol formation to give 5. The free hydroxyl group was methylated, and the THP group was removed to reveal secondary alcohol, which was oxidized to give ketone 6. The condensation with hydrazine 7 afforded hydrazone 4. Its deuterated variant d3-4 was also prepared following a-deuteration of 6.

Next, we carried out matrix isolation experiments using 4 as a substrate. After deposition of 4 in an argon matrix at 12 K, photochemical decomposition of 4 to carbene 1 via diazoalkane 8 was attempted at 3 K. Irradiation at 313 nm resulted in the formation of 8, which was assigned based on the strong, characteristic C=N=N absorption at 2060 cm–1. However, diazoalkane 8 was unexpectedly stable against UV irradiation and decomposition of 8 to 1 has not been achieved under photochemical conditions.


N-aziridinyl imines (also known as Eschenmoser hydrazones) is known to generate diazoalkanes – common carbene precursors – without the need for an external base. This would be advantageous when one considers the generation of carbenes thermally by flash vacuum pyrolysis or photochemically in a matrix. In fact, N-aziridinyl imines have been utilized by other research groups to study reactivities of carbenes under matrix isolation conditions. Although photochemical conditions failed in our hands, we envision generation of carbene 1 (via 8) by flash vacuum pyrolysis.


We will establish conditions for thermal generation of carbene 1 by examining reaction parameters such as temperature, length and diameter of quartz tube. Once the method is established, we investigate reactivity of 1 (expectedly [1,2]H-tunneling to form vinylcyclopropane 2). At the same time, we also explore reactivity of d3-1 and see if it undergoes ring expansion to give 3 by carbon tunneling.

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  • Last Update: 2022-06-14 20:36

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