SNi (Substitution Nucleophilic Internal)

I only familiar with SN1 and SN2, I never know there is another version of substitution nucleophilic. It is substitution nucleophilic internal that I am going to talk more here. 

Cowdrey was introducing the name in 1937 which occur with retention of configuration. Do you remember that what makes SN1 differ with SN2 is that SN1 occurs with retention, while SN2 occurs with inversion? So, what is the difference between SNi and SN1? Here is the difference, in SNi the ion pair is not completely dissociated so the carbocation is not really formed, while as we know the rate-limiting step of SN1 is the formation of carbocation. The example of the reaction is a reaction between alcohol with thionyl chloride. 

Now, imagine you have a reaction, and you want to confirm that it occurs with SNi. So, how do you do it?

This paper, written by Tanaka et al in 2018, explained how they confirmed their reaction that occurs with SNi by using KIE and DFT. KIE stands for Kinetic Isotope Effect, the change in the reaction rate of a chemical reaction when one of the atom in the reactions is replaced by one of its isotopes. Let me explain about DFT later, focus on KIE first.

There are two type of KIE, primary and secondary KIE. Primary KIE occurs when the bond where the isotope connected is being broken or formed. Meanwhile, secondary KIE occurs when the bond is being broken between a carbon and an atom, not between the carbon and the isotope, the isotope just positioned in the same carbon where the bond is broken.

In primary KIE for deuterium, as it is heavier than H, when the bond is being broken (dissociation), the ratio of reaction rate between C-H and C-D became more than 1, as deuterium makes the reaction rate slower. However, if it is an association, the condition becomes different, so it is called as inverse, the reaction rate of the deuterium becomes faster, so the ratio of the reaction rate less than 1. 

So, how to determine the mechanism reaction using KIE? Tanaka et al used a comparison from another paper that stated 13C KIE for SN1 reaction are 0.995-1.01, while 13C KIE for SN2 is >1.07. Their experiments obtained 13C KIE at the anomeric carbon to be 0.9986 and 0.9999 which is in the range of SN1 reaction. While a paper they referred for the 2H KIE, it stated that 2H KIE for SN 1.08 and 1.05, while for SN2 1.02. From their experiment, they got 1.055 which also in the range of SN1. From 13C and 2H KIE, we could see, both corresponded to SN1. However, if the case is SN1, there is also a possibility to be SNi as the stereochemical preference is the same, which is retention. In order to confirm it, they did further calculation with DFT.

DFT is the abbreviation for Density Functional Theory which has become the most prevalent and efficient tool in studying organic reaction mechanisms (Zhang et al., 2019). From the DFT calculation, they calculated the 13C and 2H KIE by QUIVER, then comparing the results with the experiment data. They found out that the 13C KIE (1.009) to be close with data experimental (0.9986 and 0.9999). While for the 2H KIE (1.072), after being optimized, it was found to be close with data experimental (1.055). The most important part is after the IRC scan (Intrinsic Reaction Coordinate: the path of a chemical reaction after being traced from the transition state to the products and/or reactants using IRC method), the transition structure indicated that the glycosylation mechanism of the 1,2-anhydro donor and glycosyl-acceptor-derived boronic ester was a concerted SNi mechanism. 

[Picture Source: Tanaka et al, 2018]

[Picture Source, Tanaka et al, 2018)

The detail of the mechanism was then investigated by Mayer natural bond order or the reaction coordinate, from the shadowed part, it showed that a glycosidic linkage began to form before the bond breakage between the anomeric carbon and epoxy oxygen, indicating that this reaction mechanism is a concerted SNi mechanism. 

[Picture Source: Tanaka et al, 2018]

If it is SN1, absolutely, the bond must be broken first before the formation of the glycosidic linkage. Hence, it was proved from KIE experimental data and DFT calculated data, both agreed to the SNi reaction mechanism, not SN1. 

That's all from me. If there are some mistakes during the explanation. I apologize. I hope this is useful to you. Thank you for visiting.


Reference:

Tanaka, M., Nakagawa, A., Nishi, N., Iijima, K., Sawa, R., Takahashi, D., & Toshima, K. (2018). Boronic-Acid-Catalyzed Regioselective and 1,2- cis -Stereoselective Glycosylation of Unprotected Sugar Acceptors via S. https://doi.org/10.1021/jacs.7b12108

Zhang, H., Bai, H., Guo, Y., Wei, D., & Zhu, Y. (2019). A density functional theory study on mechanism and substituent effects of a base-free and catalyst-free synthesis of functionalized dihydrobenzoxazoles, 1(September 2018), 1–8. https://doi.org/10.1002/qua.25836