3.4 Global reactivity descriptors:
The frontier orbitals, HOMO and LUMO are the most important in a molecule. These orbitals determine the way how the molecule interacts with other species and gives information about reactivity or stability of specific regions of the molecule. The energy of HOMO characterizes electron donating ability of a molecule while LUMO energy determines the ability to accept an electron. Therefore, higher values of EHOMO indicate a better tendency towards the donation of an electron. As can be seen in Table 4 and Table 5, the molecules CME, CMS, RCS & A2 have high LUMO energies, hence they can accept electrons while molecules DC, DCS, LCC & A3 have the highest HOMO energies that allow them to be the best electron donors. Frontier molecular orbitals (FMOs), HOMO and LUMO plot for all the modifications were shown in Figure 5. The values of the calculated quantum chemical parameters such as the energy of highest occupied molecular orbital (EHOMO), the energy of the lowest unoccupied molecular orbital (ELUMO), energy gap (ΔEGap), ionization potential (I), electron affinity (A), global hardness (η), global softness (S), chemical potential (μ), and electrophilicity index (ω) were presented in Table 4 and Table 5.
The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are very popular quantum chemical parameters. The similar kind of quantum calculations and reactivity descriptor derivation approach has been used by several groups for different kinds of molecules like nucleobases, small chemical compounds and their derivatives65-68. We have used this strategy for studying antisense modifications at the monomer level. The FMOs are important in determining molecular reactivity and the ability of a molecule to absorb light. The vicinal orbitals of HOMO and LUMO play the same role as electron donor and electron acceptor respectively. The energies of HOMO and LUMO and their neighboring orbitals were all negative, which indicates that the corresponding molecule is stable. The HOMO-LUMO energy gap (ΔEGap) is an important stability index. The HOMO-LUMO energy gap of any molecule reflects the chemical stability of the molecule. Through Koopman’s theorem, the HOMO and LUMO energy values are related to the ionization potential ((I= -EHOMO) and electron affinities (A= -ELUMO). (I) and (A) is calculated as the negative of energy Eigenvalues of HOMO and LUMO respectively.
The energies of the HOMO and LUMO as well as the energy gap separating those are useful descriptors for the reactivity of nucleotide bases and base pairs. Due to the delocalization of the mobile electrons, these energies provide information on the stabilization of the molecules. The HOMO-LUMO energy gap is very important in determining the chemical reactivity of the molecule. The high value of the energy gap indicates that the molecule shows high chemical stability, while a small HOMO-LUMO gap means small excitation energies and hence easily reactive. Higher values of the HOMO-LUMO gap were observed in RCS, RC, CMS, and A2 modifications. Ionization potential (I), which is defined as the amount of energy needed to remove an electron from a molecule. High ionization energy indicates high stability and chemical inertness and small ionization energy indicates high reactivity of the atoms and molecules. Modifications DC, DCS, LCC, and A3 were showing lower ionization potential values, which indicate better electron donors. The electronic affinity (A) is defined as the energy released when an electron is added to a neutral molecule. A molecule with high electron affinity (A) values tends to take electrons easily. From Table 4 and Table 5, RCS, CME, CMS and A2 have been the reactive modifications.
This kind of information may be contained within the orbital energies of the HOMO and LUMO but, instead, it may be more useful to study the global reactivity descriptors. The global chemical reactivity descriptors, chemical potential (μ), absolute electronegativity (χ) and chemical hardness (η), global softness (S) and electrophilicity (ω) which were calculated from HOMO and LUMO energies obtained at the level of theory B3LYP/6-31G(d,p) for gas phase as given in Table 4 and B3LYP/6-311G(d,p) for solvent phase as given in Table 5. According to these parameters, the chemical reactivity varies with the structural configuration of molecules. The chemical potential μ (eV) measures the escaping tendency of an electron and it can be associated with the molecular electronegativity then, as μ becomes more negative, it is more difficult to lose an electron but easier to gain one. As shown in Figure 6, Tables 4 and 5, modifications DC, DCS, LCC, LCS, and A3 have the least stability and more reactivity among all the modifications. Electronegativity (χ), representing the ability of molecules to attract electrons and is the negative of the chemical potential (μ) in Mulliken sense. The (χ) values displayed in Tables 4 and 5 show that modifications RCS and A2 have higher electronegativity values compared to other modifications. The global hardness (η) and softness (S) are useful concepts for understanding the behaviour of the chemical system. Softness (S) is a property of molecules that measures the extent of chemical reactivity; it is the reciprocal of hardness. A hard molecule has a large energy gap and a soft molecule has a small energy gap. Therefore, soft molecules will be more polarizable than hard molecules. Theoretical calculations established that the modifications RCS and A5 have the highest hardness values, which indicates the hardest molecules. The modifications LCS and A3 have the highest softness values or can be stated as chemically more reactive molecules. Parr defined the electrophilicity index (ω), as a numerical value which is related to the stabilization of energy when the system acquires an electronic charge and serves as an indicator of the reactivity of a system towards nucleophiles. Electrophilicity gives an idea of the stabilization energy when the system gets saturated by electrons, which come from the external environment. This reactivity information shows if a molecule is capable of donating electrons. The lower values of (ω) indicate the presence of the nucleophilic character, while higher values indicate the presence of a good electrophilic character. Our results indicate that modifications DC, DCS, LCC, and A5 have lower values of (ω) so that these are good nucleophiles. However, the modifications RCS, CMS, and A2 are good electrophiles.