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Ambident Nucleophilic Substitution: Understanding Non-HSAB Behavior through Activation Strain and Conceptual DFT Analyses.

ABSTRACT: The ability to understand and predict ambident reactivity is key to the rational design of organic syntheses. An approach to understand trends in ambident reactivity is the hard and soft acids and bases (HSAB) principle. The recent controversy over the general validity of this principle prompted us to investigate the competing gas-phase SN 2 reaction channels of archetypal ambident nucleophiles CN- , OCN- , and SCN- with CH3 Cl (SN 2@C) and SiH3 Cl (SN 2@Si), using DFT calculations. Our combined analyses highlight the inability of the HSAB principle to correctly predict the reactivity trends of these simple, model reactions. Instead, we have successfully traced reactivity trends to the canonical orbital-interaction mechanism and the resulting nucleophile-substrate interaction energy. The HOMO-LUMO orbital interactions set the trend in both SN 2@C and SN 2@Si reactions. We provide simple rules for predicting the ambident reactivity of nucleophiles based on our Kohn-Sham molecular orbital analysis.

SUBMITTER: Bettens T

PROVIDER: S-EPMC7154642 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Ambident Nucleophilic Substitution: Understanding Non-HSAB Behavior through Activation Strain and Conceptual DFT Analyses.

Bettens Tom T Alonso Mercedes M De Proft Frank F Hamlin Trevor A TA Bickelhaupt F Matthias FM

Chemistry (Weinheim an der Bergstrasse, Germany) 20200303 17

The ability to understand and predict ambident reactivity is key to the rational design of organic syntheses. An approach to understand trends in ambident reactivity is the hard and soft acids and bases (HSAB) principle. The recent controversy over the general validity of this principle prompted us to investigate the competing gas-phase SN 2 reaction channels of archetypal ambident nucleophiles CN- , OCN- , and SCN- with CH3 Cl (SN</sub ...[more]

PMID: 31957943

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Project description:In search for the cause leading to low reaction yields, each step along the reaction energy profile computed for the assumed oxidative nucleophilic substitution of hydrogen (ONSH) reaction between 2-phenylquinoxaline and lithium phenylacetylide was modelled computationally. Intermolecular and intramolecular interaction energies and their changes between consecutive steps of ONSH were quantified for molecular fragments playing leading roles in driving the reaction to completion. This revealed that the two reactants have a strong affinity for each other, driven by the strong attractive interactions between Li and two N-atoms, leading to four possible reaction pathways (RP-C2, RP-C3, RP-C5, and RP-C10). Four comparable in energy and stabilizing molecular system adducts were formed, each well prepared for the subsequent formation of a C-C bond at either one of the four identified sites. However, as the reaction proceeded through the TS to form the intermediates (5a-d), very high energy barriers were observed for RP-C5 and RP-C10. The data obtained at the nucleophilic addition stage indicated that RP-C3 was both kinetically and thermodynamically favored over RP-C2. However, the energy barriers observed at this stage were very comparable for both RPs, indicating that they both can progress to form intermediates 5a and 5b. Interestingly, the phenyl substituent (Ph1) on the quinoxaline guided the nucleophile towards both RP-C2 and RP-C3, indicating that the preferred RP cannot be attributed to the steric hindrance caused by Ph1. Upon the introduction of H2O to the system, both RPs were nearly spontaneous towards their respective hydrolysis products (8a and 8b), although only 8b can proceed to the final oxidation stage of the ONSH reaction mechanism. The results suggest that RP-C2 competes with RP-C3, which may lead to a possible mixture of their respective products. Furthermore, an alternative, viable, and irreversible reaction path was discovered for the RP-C2 that might lead to substantial waste. Finally, the modified experimental protocol is suggested to increase the yield of the desired product.

Dataset Information

Ambident Nucleophilic Substitution: Understanding Non-HSAB Behavior through Activation Strain and Conceptual DFT Analyses.

Publications

Ambident Nucleophilic Substitution: Understanding Non-HSAB Behavior through Activation Strain and Conceptual DFT Analyses.

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