3.5 Local reactivity descriptors:
In a chemical reaction, a change in the number of electrons involves the addition or subtraction of at least one electron in the frontier orbitals. Local reactivity descriptors are used to decide the relative reactivity of different atoms in the molecule. It is established that molecules tend to react where the value of descriptor is largest when attacked by soft reagent and where the value is smaller when attacked by the hard reagent. The use of descriptors for the site selectivity of the molecule for the nucleophilic and electrophilic attack has been made. Calculating Fukui functions (FF) helps us determine the active sites of a molecule, based on the electronic density changes experienced by it during a reaction. The Fukui function provides information on the local site reactivity within the molecule and as such it provides a system for the understanding of chemical reactions. These values correspond to the qualitative descriptors of reactivity of different atoms in the molecule. Fukui functions for electrophilic and nucleophilic attacks have been made with the B3LYP/6-311G (d,p) level of theory. With the help of Mulliken atomic charges of cationic and anionic states, local Fukui function (f k+, f k-), local softness values (sk+, sk-), and local electrophilicity indices (ωk+, ωk-) have been calculated.
Based on the Fukui function calculations at the DFT level, the most susceptible sites for nucleophilic, electrophilic and free radical attack for all the modifications are shown in Figure 7. Fukui functions, local softness values and local electrophilicity indices for selected atomic sites in different antisense modifications have been listed in Supplementary Table S4. The Supplementary Table S4 shows that at the DFT level the most susceptible site to a nucleophilic, electrophilic and free radical attack for modification DC is the same and located on C1’. For modification of DCS, the more susceptible site to nucleophilic attack is O4’, while C1’ is the most susceptible site for electrophilic and free radical attacks. The most susceptible site to a nucleophilic, electrophilic, and free radical attack for modification RC is the same and located on C1’ (Supplementary Table S5). For modification of RCS, the more susceptible site to nucleophilic attack is C2’, while C1’ is the most susceptible site for electrophilic and free radical attacks. Modifications LCC and LCS (Supplementary Table S6) show that the most susceptible site to the nucleophilic, electrophilic, and free radical attacks. The Supplementary Table S7 shows that the most susceptible active sites to a nucleophilic and free radical attack for CME modification are located on C1’ while C2’ is the most susceptible site for electrophilic attack. For the modification CMS, the more susceptible site to nucleophilic attack is O21 (Oxygen of methoxyethyl group attached at 2’-O), while C2’ is the most susceptible site for electrophilic and free radical attacks. The proposed novel modifications A1, A2, A4, and A5 (Supplementary Tables S8, S9, S10) show that the most susceptible site to nucleophilic, electrophilic and free radical attacks is C1’. Whereas for the A3 modification the more susceptible site to nucleophilic attack is C1’, while C18 (Carbon of methyl bridge that connects 2’-O and C4’) is the most susceptible site for electrophilic and free radical attacks. It has been observed from the Fukui function results that the modifications DC, RC, LCC, LCS, A1, A2, A4, and A5 are showing single susceptible site C1’ for all the three (nucleophilic, electrophilic and free radical) kinds of attacks. The modifications DCS, RCS, CMS, and A3 are showing single susceptible sites (C1’, C1’, C2’, C18 respectively) for electrophilic and free radical attacks. Whereas CME modification showed a single susceptible site C1’ for the nucleophilic and free radical attack.