Radical Stabilization Energies Research Articles

Reactivity Prediction of Cu-Catalyzed Halogen Atom Transfer Reactions Using Data-Driven Techniques.

In catalysis, linear free energy relationships (LFERs) are commonly used to identify reaction descriptors that enable the prediction of outcomes and the design of more effective catalysts. Herein, LFERs are established for the reductive cleavage of the C(sp3)-X bond in alkyl halides (RX) by Cu complexes. This reaction represents the activation step in atom transfer radical polymerization and atom transfer radical addition/cyclization. The values of the activation rate constant, kact, for 107 Cu complex/RX couples in 5 different solvents spanning over 13 orders of magnitude were effectively interpolated by the equation: log kact = sC(I + C + S), where I, C, and S are, respectively, the initiator, catalyst, and solvent parameters, and sC is the catalyst-specific sensitivity parameter. Furthermore, each of these parameters was correlated to relevant descriptors, which included the bond dissociation free energy of RX and its Tolman cone angle θ, the electron affinity of X, the radical stabilization energy, the standard reduction potential of the Cu complex, the polarizability parameter π* of the solvent, and the distortion energy of the complex in its transition state. This set of descriptors establishes the fundamental properties of Cu complexes and RX that determine their reactivity and that need to be considered when designing novel systems for atom transfer radical reactions. Finally, a multivariate linear regression (MLR) approach was adopted to develop an objective model that surpassed the predictive capability of the LFER equation. Thus, the MLR model was employed to predict kact values for >2000 Cu complex/RX pairs.

MIDA- and TIDA-Boronates Stabilize α-Radicals Through B-N Hyperconjugation.

Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp3 -rich small molecules. The ability of boron-containing functional groups to modify the reactivity of α-radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p-orbitals have a significant stabilizing effect on α-radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N-methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α-radicals via σB-N hyperconjugation in a manner that allows site-selective C-H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α-radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p-orbitals, but that hyperconjugation of tetrahedral boron-containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α-carbon.

MIDA‐ and TIDA‐Boronates Stabilize α‐Radicals Through B−N Hyperconjugation

AbstractMultifunctional organoboron compounds increasingly enable the simple generation of complex, Csp3‐rich small molecules. The ability of boron‐containing functional groups to modify the reactivity of α‐radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p‐orbitals have a significant stabilizing effect on α‐radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N‐methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α‐radicals via σB‐N hyperconjugation in a manner that allows site‐selective C−H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α‐radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p‐orbitals, but that hyperconjugation of tetrahedral boron‐containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α‐carbon.

A rational design strategy of radical-type mechanophores with thermal tolerance.

Radical-type mechanophores (RMs) are attractive molecules that undergo homolytic scission of their central C-C bond to afford radical species upon exposure to heat or mechanical stimuli. However, the lack of a rational design concept limits the development of RMs with pre-determined properties. Herein, we report a rational design strategy of RMs with high thermal tolerance while maintaining mechanoresponsiveness. A combined experimental and theoretical analysis revealed that the high thermal tolerance of these RMs is related to the radical-stabilization energy (RSE) as well as the Hammett and modified Swain-Lupton constants at the para-position (σp). The trend of the RSE values is in good agreement with the experimentally evaluated thermal tolerance of a series of mechanoresponsive RMs based on the bisarylcyanoacetate motif. Furthermore, the singly occupied molecular orbital (SOMO) levels clearly exhibit a negative correlation with σp within a series of RMs that are based on the same skeleton, paving the way toward the development of RMs that can be handled under ambient conditions without peroxidation.

Stability of Carbocyclic Phosphinyl Radicals: Effect of Ring Size, Delocalization, and Sterics.

In this computational study, we report on the stability of cyclic phosphinyl radicals with an aim for a systematical assessment of stabilization effects. The radical stabilization energies (RSEs) were calculated using isodesmic reactions for a large number of carbocyclic radicals possessing different ring sizes and grades of unsaturation. In general, the RSE values range from −1.2 to −14.0 kcal·mol–1, and they show practically no correlation with the spin populations at the P-centers. The RSE values correlate with the reaction Gibbs free energies calculated for the dimerization of the studied simple radicals. Therefore, the more easily accessible RSE values offer a cost-effective estimation of global stability in a straightforward manner. To explore the effect of unsaturation on the RSE values, delocalization energies were determined using appropriate isodesmic reactions. Introducing unsaturations beside the P-center into the backbone of the rings leads to an additive increase in the magnitude of the delocalization energy (∼10, 20, and 30 kcal·mol–1, respectively, for radicals with one, two, and three C=C bonds in the conjugation). Parallelly, the spin populations at the P-centers also dwindle gradually by ∼0.1 e in the same order, indicating that the lone electron delocalizes over the π-system. Radicals containing exocyclic C=C π-bonds were also investigated, and all of these radicals have rather similar stabilities independently of the ring size, outlining the primary importance of the two exocyclic π-bonds in the conjugation. Among the radicals involved in our study, those with the best electronic stabilization are the unsaturated three-, five-, six-, and seven-membered rings containing the maximum number of conjugated vinyl fragments. The largest delocalization energy of 31.5 kcal·mol–1 and the lowest obtained spin population of 0.665 e were found for the fully unsaturated seven-membered radical (phosphepin derivative). Importantly, the electronic stabilization effects alone are insufficient for stabilizing the radicals in monomeric forms epitomized by the exothermic dimerization energies (−40 to −58 kcal·mol–1). Therefore, it is essential to apply sterically demanding bulky substituents on the α-C-atoms. Tweaking the steric congestion enabled us to propose radicals that are expected to be stable against dimerization and, consequently, may be realistic target species for synthetic investigations. The effects contributing to the stability of radicals having sterically encumbered substituents have also been explored.

Anodic Reactivity of Alkyl S-Glucosides.

A voltammetric study of a series of alkyl and aryl S-glucosides unveiled the reactivity patterns of alkyl S-glucosides toward anodic oxidation and found noteworthy differences with the trends followed by aryl derivatives. The oxidation potential of alkyl S-glucosides, estimated herein from square-wave voltammetry peak potentials (Ep), depends on the steric properties of the aglycone. Glucosides substituted with bulky groups exhibit Ep values at voltages more positive than the values of those carrying small aglycones. This relationship, observed in all analyzed alkyl series, is evidenced by good linear correlations between Ep and Taft's steric parameters (ES) of the respective alkyl substituents. Moreover, the role of the aglycone's steric properties as a primary reactivity modulator is backed by poor correlations between Ep and the radical stabilization energies (RSEs) of the aglycone-derived thiyl radicals (RS•). In contrast, aryl glucosides' Ep values exhibit excellent correlations with the aryl substituents' Hammett parameters (σ+) and the ArS• RSEs, evidencing the inherent stability of the reactive radical intermediate as the primary factor controlling aryl glucoside's electrochemical reactivity. The reactivity differences between alkyl and aryl S-glucosides also extend to the protective group's effect on Ep. Alkyl S-glucosides' reactivity proved to be more sensitive to protective group exchange.

UREMP, RO-REMP, and OO-REMP: Hybrid perturbation theories for open-shell electronic structure calculations.

An accurate description of the electron correlation energy in closed- and open-shell molecules is shown to be obtained by a second-order perturbation theory (PT) termed REMP. REMP is a hybrid of the Retaining the Excitation degree (RE) and the Møller-Plesset (MP) PTs. It performs particularly encouragingly in an orbital-optimized variant (OO-REMP) where the reference wavefunction is given by an unrestricted Slater determinant whose spin orbitals are varied such that the total energy becomes a minimum. While the approach generally behaves less satisfactorily with unrestricted Hartree-Fock references, reasonable performance is observed for restricted Hartree-Fock and restricted open-shell Hartree-Fock references. Inclusion of single excitations to OO-REMP is investigated and found-as in similar investigations-to be dissatisfying as it deteriorates performance. For the non-multireference subset of the accurate W4-11 benchmark set of Karton et al. [Chem. Phys. Lett. 510, 165-178 (2011)], OO-REMP predicts most atomization and reaction energies with chemical accuracy (1 kcalmol-1) if complete-basis-set extrapolation with augmented and core-polarized basis sets is used. For the W4-11 related test-sets, the error estimates obtained with the OO-REMP method approach those of coupled-cluster with singles, doubles and perturbative triples [CCSD(T)] within 20%-35%. The best performance of OO-REMP is found for a mixing ratio of 20%:80% MP:RE, which is essentially independent of whether radical stabilization energies, barrier heights, or reaction energies are investigated. Orbital optimization is shown to improve the REMP approach for both closed and open shell cases and outperforms coupled-cluster theory with singles and doubles (CCSD), spin-component scaled Møller-Plesset theory at second order (SCS-MP2), and density functionals, including double hybrids in all the cases considered.

Thiol‐Ene Polymerization of Natural Monomers: A DFT Study

AbstractThis study investigates the thiol‐ene reaction mechanism of natural monomers using quantum chemical tools. The structure‐reactivity relationship for these monomers is elaborated by the aid of radical stabilization energies (RSEs), intermolecular interactions, the curve‐crossing model, Hammond Postulate, and Evans–Polanyi relationships. Geometry optimizations, frequency, and energy calculations are performed at the M06‐2X/6‐31++G(d,p) level of theory. A crucial parameter for thiol‐ene polymerization, which is the ratio of the propagation reaction (kp) and the chain transfer reaction (kct) rate constants (kp/kct), is calculated in order to elucidate the thiol‐ene reaction mechanism. In light of these energetic and kinetic calculations, it is suggested that linalool, d‐limonene, terpinolene, and γ‐terpinene are considered natural monomer candidates for thiol‐ene polymerization due to their almost equal magnitude of the rate constants (kp/kct≈1). The thiol‐ene polymerization potential of some specific unsaturated fatty acids is another prominent finding in this study.

Effect of Solvent on Antioxidant Activity of Zanthoxylum oxyphyllum Edgew and its DFT Study

Background: Free radicals can easily damage DNA, proteins and lipids within the tissue. Anti-oxidants from natural sources can diminish the actions of free radicals. The current study deals with the chemical composition and antioxidant activity of the leaves of Zanthoxylum oxyphyllum Edgew. Methods: The antioxidant activities for DPPH, FRAP, ABTS radicals, phosphomolybdate assay, reducing power, and chelating power assay were evaluated of ethanol (ET), methanol (ME), chloroform (CH), ethyl acetate (EA), and petroleum ether (PE) extracts of the leaves. The Density Functional Theory (DFT) study was carried out on major identified phytochemicals to evaluate bioactive molecules responsible for the antioxidant activity. Results: It was observed that the ME extract showed the most potent scavenging activity in DPPH, FRAP, ABTS radicals, phosphomolybdate assay, reducing power, and chelating power assay. The phenolic acids and flavonoids like quercetin, gallic acid, sinapic acid, etc. were identified. The DFT study was done for major phytochemicals of ME extract to evaluate the most responsible bioactive molecule for antioxidant activity. The Gallic acid exhibited the lowest bond dissociation energy (BDE) of 314.9 kcal/mol in gas, 309.2 kcal/mol in methanol, respectively, along with the highest value of radical stabilization energy (RSE), 29.5 kcal/mol. Conclusion: Gallic acid was found to be the most responsible antioxidant among the other compounds, and ME the best solvent system for extraction, followed by CH.

Antiaromaticity-Promoted Radical Stability in α-Methyl Heterocyclics.

Aromaticity is a fundamental and important concept in chemistry, and usually, the enhancement of aromaticity brings additional thermodynamic stability to a compound. Moreover, since radicals can act as intermediates in chemical reactions, they have attracted considerable attention from both experimental and theoretical chemists for a long time. However, it remains unclear whether there is a relationship between the thermodynamic stability of cyclic planar radicals and their aromaticity. In this work, using various aromaticity indices including anisotropy of the induced current density analysis and nucleus-independent chemical shifts against the radical stabilization energy, we systematically investigated the relationship between aromaticity and the thermodynamic stability of α-methyl heterocyclics. Density functional theory calculations suggest that the stronger the antiaromaticity of the original form heterocyclics, the higher the thermodynamic stability of the corresponding radicals, which is in sharp contrast to the general knowledge that aromaticity brings compounds' thermodynamic stabilities. The principal interacting spin orbital analysis shows that the stronger the π-bond formed between the heterocyclics and the α-methyl carbon, the more spin density the radicals tend to be distributed on the heterocyclics. Thus, the strong π-bonding is one of the factors for improving the thermodynamic stability of radicals.

Scalable Electron Correlation Methods. 8. Explicitly Correlated Open-Shell Coupled-Cluster with Pair Natural Orbitals PNO-RCCSD(T)-F12 and PNO-UCCSD(T)-F12.

We present explicitly correlated open-shell pair natural orbital local coupled-cluster methods, PNO-RCCSD(T)-F12 and PNO-UCCSD(T)-F12. The methods are extensions of our previously reported PNO-R/UCCSD methods (J. Chem. Theory Comput., 2020, 16, 3135-3151, https://pubs.acs.org/doi/10.1021/acs.jctc.0c00192) with additions of explicit correlation and perturbative triples corrections. The explicit correlation treatment follows the spin-orbital CCSD-F12b theory using Ansatz 3*A, which is found to yield comparable or better basis set convergence than the more rigorous Ansatz 3C in computed ionization potentials and reaction energies using double- to quaduple-ζ basis sets. The perturbative triples correction is adapted from the spin-orbital (T) theory to use triples natural orbitals (TNOs). To address the coupling due to off-diagonal Fock matrix elements, the local triples amplitudes are iteratively solved using small domains of TNOs, and a semicanonical (T0) domain correction with larger domains is applied to reduce the domain errors. The performance of the methods is demonstrated through benchmark calculations on ionization potentials, radical stabilization energies, reaction energies of fragmentations and rearrangements in radical cations, and spin-state energy differences of iron complexes. For a few test sets where canonical calculations are feasible, PNO-RCCSD(T)-F12 results agree with the canonical ones to within 0.4 kcal mol-1, and this maximum error is reduced to below 0.2 kcal mol-1 when large local domains are used. For larger systems, results using different thresholds for the local approximations are compared to demonstrate that 1 kcal mol-1 level of accuracy can be achieved using our default settings. For a couple of difficult cases, it is demonstrated that the errors from individual approximations are only a fraction of 1 kcal mol-1, and the overall accuracy of the method does not rely on error compensations. In contrast to canonical calculations, the use of spin-orbitals does not lead to a significant increase of computational time and memory usage in the most expensive steps of PNO-R/UCCSD(T)-F12 calculations. The only exception is the iterative solution of the (T) amplitudes, which can be avoided without significant errors by using a perturbative treatment of the off-diagonal coupling, known as (T1) approximation. For most systems, even the semicanonical approximation (T0) leads only to small errors in relative energies. Our program is well parallelized and capable of computing accurate correlation energies for molecules with 100-200 atoms using augmented triple-ζ basis sets in less than a day of elapsed time on a small computer cluster.

Reliable radical stabilization energies from diffusion Monte Carlo calculations.

We assess the performance of variational (VMC) and diffusion (DMC) quantum Monte Carlo methods for calculating the radical stabilization energies of a set of 43 carbon-centered radical species. Even using simple single-determinant trial wavefunctions, both methods perform exceptionally well, with mean absolute deviations from reference values well under the chemical accuracy standard of 1 kcal/mol. In addition, the use of DMC results in a highly concentrated spread of errors, with all 43 results within chemical accuracy at the 95% confidence level. These results indicate that DMC is an extremely reliable method for calculating radical stabilization energies and could be used as a benchmark method for larger systems in future.

Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme

While designing the anti-inflammatory agents targeting cyclooxygenase-2 (COX-2), we first identified a water loop around the heme playing critical role in the enzyme catalysis. The results of molecular dynamic studies supported by the strong hydrogen-bonding equilibria of the participating atoms, radical stabilization energies, the pKa of the H-donor/acceptor sites and the cyclooxygenase activity of pertinent muCOX-2 ravelled the working of the water–peptide channel for coordinating the flow of H·/electron between the heme and Y385. Based on the working of H·/electron transfer channel between the 12.5 Å distant radical generation and the radical disposal sites, a series of molecules was designed and synthesized. Among this category of compounds, an appreciably potent anti-inflammatory agent exhibiting IC50 0.06 μM against COX-2 and reversing the formalin induced analgesia and carageenan induced inflammation in mice by 90% was identified. Further it was revealed that, justifying its bidentate design, the compound targets water loop (heme bound site) and the arachidonic acid binding pockets of COX-2.

Sulforaphane: A natural product against reactive oxygen species

Reactions of sulforaphane, the most important component of broccoli, with radicals have been studied using theoretical chemistry. Reliable methods of density functional theory have been used to study mechanisms of reaction of sulforaphane with reactive oxygen species: •OH, •OCH3, •OOH and O2·-. Three mechanisms of radical reactions have been considered: radical adduct formation (RAF), hydrogen atom transfer (HAT) and single electron transfer (SET). All studied reactions have been studied in gas phase, water and n-octanol solutions. Water is used as a model for blood serum and n-octanol mimics the role of lipid environment. In order to design more effective molecules, some derivatives of sulforaphane have been studied in terms of solubility and antioxidant activities. Radical stabilization energies are studied to determine radical scavenging ability of sulforaphane and its derivatives.

An Air-Stable, Neutral Phenothiazinyl Radical with Substantial Radical Stabilization Energy.

The vital effect of radical states on the pharmacological activity of phenothiazine‐based drugs has long been speculated. Whereas cationic radicals of N‐substituted phenothiazines show high stability, the respective neutral radicals of N‐unsubstituted phenothiazines have never been isolated. Herein, the 1,9‐diamino‐3,7‐di‐tert‐butyl‐N 1,N 9‐bis(2,6‐diisopropylphenyl)‐10H‐phenothiazin‐10‐yl radical (SQH2 .) is described as the first air‐stable, neutral phenothiazinyl free radical. The crystalline dark‐blue species is characterized by means of EPR and UV/Vis/near‐IR spectroscopy, as well as cyclic voltammetry, spectro‐electrochemical analysis, single‐crystal XRD, and computational studies. The SQH2 . radical stands out from other aminyl radicals by an impressive radical stabilization energy and its parent amine has one of the weakest N−H bond dissociation energies ever determined. In addition to serving as open‐shell reference in medicinal chemistry, its tridentate binding pocket or hydrogen‐bond‐donor ability might enable manifold uses as a redox‐active ligand or proton‐coupled electron‐transfer reagent.

Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE.

Experimental assessment of catalytic reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates and sensitivity of cofactors such as iron-sulfur clusters. Here, we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical S-adenosylmethione enzyme 7-carboxy-7-deazaguanine synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+, or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semiempirical methods. The impact of intermolecular interactions on RSE was clearly established, and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates as candidates for catalytic turnover by QueE.

Philicity of Acetonyl and Benzoyl Radicals: A Comparative Experimental and Computational Study.

In this work, the reactivities of acetonyl and benzoyl radicals in aromatic substitution and addition reactions have been compared in an experimental and computational study. The results show that acetonyl is more electrophilic than benzoyl, which is rather nucleophilic. A Hammett plot analysis of the addition reactions of the two radicals to substituted styrenes clearly support the nucleophilicity of benzoyl, but in the case of acetonyl, no satisfactory linear correlation with a single substituent-related parameter was found. Computational calculations helped to rationalize this effect, and a good linear correlation was found with a combination of polar parameters (σ+ ) and the radical stabilization energies of the formed intermediates. Based on the calculated philicity indices for benzoyl and acetonyl, a quantitative comparison of these two radicals with many other reported radicals is possible, which may help to predict the reactivities of other aromatic radical substitution reactions.

Performance of the NOF-MP2 method in hydrogen abstraction reactions

The recently proposed natural orbital functional second-order M{\o}ller-Plesset (NOF-MP2) method is capableof achieving both dynamic and static correlation even for those systems with significant multiconfigurational character. We test its reliability to describe the electron correlation in radical formation reactions, namely, in the homolytic X-H bond cleavage of LiH, BH, CH4, NH3, H2O and HF molecules. Our results are compared with CASSCF and CASPT2 wavefunction calculations and the experimental data. For a dataset of 20 organic molecules, the thermodynamics of C-H homolytic bond cleavage, in which the C-H bond is broken in the presence of different chemical environments, is presented. The radical stabilization energies obtained for such general dataset are compared with the experimental data. It is observed that NOF-MP2 is able to give a quantitative agreement for dissociation energies, with a performance comparable to that of the accurate CASPT2 method.

Theoretical investigation of thiol-ene click reactions: A DFT perspective

In this study, a detailed quantum chemical investigation of the contribution of phenyl thiol derivatives in thiol-ene reaction mechanism has been carried out for the first time. DFT calculations have been used to investigate the role of substitution in thiol-ene reactions. It is well known that the reaction mechanism is strongly controlled by the kP/kCT ratio, where kP is the propagation rate constant of the thiyl radical’s addition to the alkene and kCT is the rate constant of chain transfer to a thiol. The electrophilic nature of the phenylthio radicals and the singlet-triplet (S-T) gap of alkenes are mainly responsible for the variation of the activation barriers for the propagation reaction, this demonstrates the importance of the ene functionality on the propagation reaction. A correlation between the radical stabilization energy of the carbon centered radical intermediate and the chain transfer activation energy could not be established. The transition structures of the chain transfer reactions were shown to be stabilized by intramolecular interactions, which have lowered the activation barriers. In this study, we underlie the kP/kCT ratio which is highly dependent not only on the alkene functionality, but also on the thiol functionality. Tailor-made polymers can be obtained by altering the substituents or their positions, and the computational procedure described herein is expected to guide the synthesis.

Deciphering Stability of Five-Membered Heterocyclic Radicals: Balancing Act Between Delocalization and Ring Strain.

Computational studies on five-membered heterocycles with single heteroatom and their isomeric dehydro-borole 1a-1c, cyclopentadiene 2a-2c, pyrrole 3a-3c, furan 4b-4c, phosphole 5a-5c, and thiophene 6b-6c radicals have been carried out. Geometrical aspects through ground state electronic structures and stability aspects using bond dissociation energies (BDE) and radical stabilization energies (RSE) have been envisaged in this regard. Spin densities, electrostatic potentials (ESP), and natural bond orbital (NBO) analysis unveiled the extent of spin delocalization. The estimated nucleus-independent chemical shifts (NICS) values revealed the difference in aromaticity characteristics of radicals. Particularly the heteroatom centered radicals exhibit odd electron π-delocalized systems with a quasi-antiaromatic character. Various factors such as, the relative position of the radical center with respect to heteroatoms, resonance, ring strain and orbital interactions influence the stability that follows the order: heteroatom centered > β-centered > α-centered radicals. Among the influences of various factors, we confirmed the existence of a competition between delocalization and the ring strain, and the interplay of both decides the overall stability order.