藉由天然鍵結軌域（natural bond orbital，NBO）方法提供以鍵結軌域（bond orbital，BO）空間所展開形成之分子軌域（molecular Orbital，MO）的組成分析，可顯示出以熟悉的路易斯結構所表達的化學訊息。因此，透過實驗化學家獲得取代基對MO能量變化是很容易被接受。經由NBO計算所獲得在BO上電子密度，透露了所有化學鍵上的電子分佈，並提供了由路易斯結構描述電子不定域化的模式。
對於CF3官能基，經由NBO方法已經發現了由σ*CF BO產生對MO的穩定效應和由lp（F）BO引起對MO的不穩定效應。由於這兩個競爭的pi效應幾乎被抵消，由COOP(crystal orbital overlap populations)的值幾乎為零所表明的那樣，因此藉由使用拉電子基團的觀念來降低MO能量，這種化學取代策略發現可有效地解釋將Ir（III）配位錯合物的磷光衍生物顏色調整為藍色區域。
使用對稱二取代二苯二硫（diphenyl disulfide，DPDS）的衍生物進行抗HIV活性研究和雙硫鍵還原性裂解的共同特徵明顯指向DPDS的最低的未佔用電子MO（lowest unoccupied molecular orbital，LUMO）之性質。在抗HIV活性研究中考慮了LUMO能量，而LUMO的組成對於雙硫鍵還原性裂解有關的逐步機轉中σ型自由基陰離子的方法為基礎，已經合理化的解釋:對稱的2,2'-二取代的DPDS衍生物對HIV-1核衣殼蛋白p7鋅指(zinc fingers)的親電子反應速率分布於廣泛範圍。從NBO的角度來看，LUMO的氫鍵穩定主要由σ*SS BO的分子內氫鍵穩定來掌控。在DPDS的LUMO組成中，σ*SS BO比苯基的 π*CC BOs有較大的組成，為形成σ-型自由基陰離子奠定了基礎，此結果是透過使用4,4’-取代DPDS衍生物雙硫鍵進行還原性裂解的研究被發現的。 DPDS及其衍生物中雙硫鍵的減弱歸因於經由負超共軛作用在σ*SS BO上使電子密度增加。

Analysis of compositions of a molecular orbital (MO) expanded in the bond orbital (BO) space provided by the natural bond orbital (NBO) method exhibits information based on the familiar Lewis structure. It is therefore straightforward to explain observations, through chemical substitution on MO energies, obtained by experimental chemists. The electron densities on BOs obtained by NBO calculations reveal the electron distributions on all chemical bonds and supply electron delocalization patterns described in the Lewis structure.
For a CF3 group, both stabilization of the MO exerted by σ*CF BO and destabilization of MO by lp(F) BO have been found by the NBO method. Since these two competing pi-effects are nearly counterbalanced as indicated by the vanishing values of crystal orbital overlap population, the chemical substitution strategy originated from lowering of MOs by using electron-withdrawing group has been found effective in color-tuning to blue region. Those orbital-based rationalizations give insight of color-tuning results observed for phosphorescent derivatives of Ir(III)-complexes.
The common feature involved in the anti-HIV activity study and the reductive cleavage of the disulfide bond, performed on symmetrical disubstituted derivatives diphenyl disulfide (DPDS), is apparently pointed to the lowest unoccupied MO (LUMO) properties of DPDS. The LUMO energy is considered in the anti-HIV activity study, while the LUMO compositions are critical concerning the formation of the σ-type radical anion in the stepwise mechanism associated with the reductive cleavage of the disulfide bond. The symmetrical 2,2’-disubstituted DPDS-derivatives showing widely spanning rates of electrophilic attack of the HIV-1 nucleocapsid protein p7 zinc fingers have been rationalized, based on the LUMO-lowering approach, by the substituents’ π-effects and the hydrogen bond (HB) stabilization effects. In the NBO viewpoint, hydrogen bond stabilization of the LUMO is primarily governed by intramolecular HB-stabilization of the σ*SS BO. The larger composition of σ*SS BO, compared to π*CC BOs of phenyl groups, to the LUMO of DPDS lays the foundation for the formation of σ-type radical anion, found by studies of reductive cleavage of disulfide bond performed on 4,4’-disubstitued DPDS-derivatives. The weakening of disulfide bond in DPDS and its derivatives is attributed to the increasing electron density on σ*SS BO through negative hyperconjugation.

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