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.