Substituent effects on the antioxidant capacity of monosubstituted diphenylamines: A DFT study

Cite this paper: Vietnam J. Chem., 2020, 58(6), 742-751 Article DOI: 10.1002/vjch.202000065 742 Wiley Online Library © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH Substituent effects on the antioxidant capacity of monosubstituted diphenylamines: a DFT study Pham Thi Thu Thao 1,2 , Nguyen Minh Thong 3* , Quan V. Vo 4 , Mai Van Bay 5 , Duong Tuan Quang 6 , Pham Cam Nam 1* 1 Department of Chemistry, The University of Danang, University of Science and Technology, 54 Nguyen Luong Bang, Hoa Khanh Bac, Lien Chieu, Da Nang City 55000, Viet Nam 2 Department of Chemistry, Hue University of Sciences, Hue University, 77 Nguyen Hue Le Loi, Hue City 53000, Viet Nam 3 The University of Danang, Campus in Kon Tum, 704 Phan Dinh Phung, Kon Tum 58000, Viet Nam 4 The University of Danang, University of Technology and Education, 48 Cao Thang, Da Nang City 55000, Viet Nam 5 Department of Chemistry, The University of Danang, University of Science and Education, 48 Cao Thang, Da Nang City 55000, Viet Nam 6 Department of Chemistry, University of Education, Hue University 34 Le Loi, Hue City 53000, Viet Nam Submitted April 28, 2020; Accepted August 11, 2020 Abstract There are undesirable effects leading to considerable changes in the properties of polymers and plastics since exposing to oxygen undergo oxidative degradation. Therefore, investigation of the bond dissociation enthalpies (BDEs) of NH bond for a series of monosubstituted diphenylamines is great interest. In this study, DFT-based method B3P86/6-311G was employed to perform this task. In comparison with the available experimental data, this method could reproduce the BDE(NH)s values more accuracy. Effects of substituents and substitution positions on the BDE(NH)s were also examined. Moreover, there is a good correlation of BDE(NH)s with the Hammett's substituent constants. Depending on the nature of substituents, electron withdrawing groups increase the BDE(NH)s but electron donating ones reduce the BDE(NH)s. The hydrogen atom transfer processes from NH bond of these diphenylamines to the peroxyl radical (CH3OO  ) were also analyzed via potential energy surfaces and kinetic calculations. Keywords. Antioxidants, diphenylamine derivatives, DFT, substituent effects, Hammett’s constants. 1. INTRODUCTION In modern society, polymers and plastics are playing an increasingly important role and the products made from them are indispensable. However, when being exposed to oxygen undergo oxidative degradation, there are undesirable effects leading to considerable changes in the properties. [1] Hence, preventing and decreasing the degradative changes in the properties are the challenges faced by researchers. One of the solutions to retard the degradative process is to add small amounts of antioxidants into the polymer or plastic products. Antioxidants can be broadly defined as compounds that can prevent or slow damage to cells caused by free radicals. [2] Based on their mechanism of interference, there are able to arrange into two types including: Preventive antioxidants and radical- trapping antioxidants (or chain-breaking antioxidants). To retard or stop the propagation and autoxidation process, radical-trapping antioxidants and preventive antioxidants were added, they react with chain-carrying peroxyl radicals to yield unreactive radicals. [2-4] Diphenylamine (Ar2NH) and its derivatives are used as radical-trapping antioxidants that have the potential of prohibiting oxidation of lubricants, rubber, polymers, and biological materials. [5-13] The antioxidant mechanisms of diphenylamine behave as autoxidation inhibitors relate the hydrogen atom donating ability of the amino group to the peroxyl radicals carrying to yield a non–radical products and Vietnam Journal of Chemistry Nguyen Minh Thong et al. © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 743 aminyl radical (Ar2N  ), and the latter will react with peroxide converted to the nitroxide form (Ar2NO  ). The antioxidant capacity of diphenylamine might be explained by the formation of unreactive radicals (Ar2N  ) that cannot propagate the chain reaction, [6,14,15] or by Denisov reaction cycle. [14,15] Therefore, in this study, the hydrogen atom transfer (HAT) mechanism would be clarified because its antioxidant activity depended on the hydrogen donating ability. Consequently, the N–H bond dissociation enthalpy (BDE) represents one of the essential descriptors in the estimation of their antioxidant action. [6,16-19] In general, the physicochemical properties of molecule change significantly when one atom in the molecule was substituted by another atom or functional group. [20] In the case of diphenylamine, substituent effects on the strength of the N–H bond are vital to predict several chemical and thermochemical properties and are still attracting much research attention. [21] In particular, Pratt et al. showed that the BDE values of aromatic amines, including diphenylamines are affected by different substituents. [22] Later on, Poliak et al. extensively studied the effects of substituent and substituted position on the N–H BDE values in diphenylamine derivatives using (U)B3LYP/6-311++G(d,p) approach. [23] Presently, several experimental methods [16,24-27] and high level computational chemistry approaches [23,28-35] have been used to determine the BDE(N–H). However, there remains a disadvantage because the computations for molecules with over eight heavy atoms spends a lot of time and requires ultrafast processing speed of computer. As mentioned above, the previous study showed that the B3LYP method with unrestricted formalism and need to be further improved. [23] Therefore, the first aim of this work is to answer the question whether the low cost computational methods could predict accurately the NH BDEs of diphenylamines. The B3P86/6-311G level of theory was tested for accurately BDE(NH) by comparing with the real BDE values. Moreover, the effects of various electron donating or electron withdrawing group on the change of the BDE(N–H) of diphenylamine were also systematically studied when substitution occurred at the ortho, meta and para position for only one aromatic ring. The relationships between the calculated BDEs and Hammett’s constant were also taken into account. Obviously, it is well-known that due to the steric effect, the application of Hammett equation to the ortho substitution of the phenolic ring is unsuccessful. [36] Therefore, our investigation was focused on the case when one substituent was placed at the meta and para site of one phenolic ring of diphenylamine. The second major aim of this work is to understand the antioxidant mechanisms of the diphenylamines. The potential energy surfaces (PES) of reactions between the substituted diphenylamines with CH3OO  radical were calculated at M05-2X/6-311++G(d,p) level of theory. Rate constants for hydrogen atom transfer processes at the NH bond were also computed at the same level of theory using the conventional transition state theory (TST). Figure 1: Diphenylamine and its meta and para monosubstituted derivatives 2. COMPUTATIONAL METHODS The BDE(NH)s for a number of diphenylamines were accurately evaluated using the density functional of B3P86 with unrestricted formalism for open shell. The obtained results were then compared with available experimental values. [37,38] The major factors of homolytic BDE used for determining antioxidant capacity are calculated using the equations (1): BDE(NH) = Hf(YC6H4N C6H5) + Hf(H  )  Hf(YC6H4NHC6H5) (1) where Hf’s are the enthalpies at 298.15 K of each species in the equation (1). The energy of hydrogen atom was calculated at the corresponding level of theory for B3P86 because the energy-lowering corrections for the hydrogen atom will considerably underestimate the BDE’s in this case are in much better agreement with the experimental values. This result was consistent with the previous studies. [38,39] The global minima for reactants, pre-reactive complex (RC), product complex (PC) and products are checked with no imaginary vibrational frequency, whereas transition states (TS) were successfully obtained with one imaginary frequency with negative value and vibrational mode of above imaginary frequency should match the action of the reaction paths. To build the potential energy surface then to calculate rate constants, all of species were performed at M05-2X/6-311++G(d,p) level of Vietnam Journal of Chemistry Substituent effects on the antioxidant capacity of © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 744 theory. [40] All rate constants (k) were estimated in the gas phase by using conventional transition state theory (TST) and 1 M standard state as: (2) where kB, T, h, ΔG #, σ and in the equation (2) are the Boltzmann constant, the temperature, Planck constant, the gas constant, the Gibbs free energy of activation, the reaction symmetry number and accounts for tunneling corrections, respectively [41,42] . All computational calculations were carried out using Gaussian 09 suit of program. [43] Rate constants in the gas phase were generated from output files of the Eyringpy program. [44,45] 3. RESULTS AND DISCUSSION 3.1. Performance of the proposed DFT method for predicting bond dissociation enthalpies of a few diphenylamines with available experimental values Among the mono- and di-substituted diphenylamines, the available experimental BDE(NH) values of diphenylamine derivatives were measured and estimated. [46] Therefore a brief comparison should be carried out to evaluate the reliable performance of these proposed methods when applying on these derivatives having the NH bond. In line with the basis set in combination with B3P86 functional, we pre-evaluated the BDE(NH)s for diphenylamine (Ar2NH) using several basis sets then compared with the experimental value of Ar2NH (87.2 kcal/mol). [46] The discrepancy between the calculated BDE(NH) at each basis set and experimental one was shown figure S1 of Supporting Information - SI, indicating that the smallest discrepancy is at the basis set of 6-311G and 6-31G. Whereas, BDE(NH)s are underestimated in the range of 2.0 to 4.2 kcal/mol when adding the polarized and diffuse functions. To further test the performance of B3P86/6-311G method, we calculated the BDE(NH)s for a series of mentioned diphenylamines and the obtained values were given in table 1. Based on the data in table 1, it is clear that B3P86/6-311G method was found to be appropriate for the prediction of BDE(NH)s with the mean of differences is only -0.2 kcal/mol. Thus, the B3P86 functional with a small basis set 6-311G used for predicting BDE(NH) for diphenylamine derivatives seems to be rationalized. Table 1: Benchmark of the calculated BDE(NH)s for a small set of mono- and di-substituted diphenylamines using B3P86/6-311G Compounds * BDE(NH) (kcal/mol) Calculated Expt. [46] Ar2NH 87.2(0.0) 87.2 mF-Ar2NH 88.1(0.3) 88.4 mCH3-Ar2NH 87.6(0.0) 87.6 pCH3-Ar2NH 86.4(0.5) 86.9 pOCH3-Ar2NH 85.0(0.6)[0.1] 85.6[85.1] pNO2-Ar2NH 89.8(0.6)[1.2] 90.4[91.0] pBr-ArNH-Ar- pBr 87.0(0.0) 87.0 pCH3-ArNH-Ar- pCH3 85.6(0.2) 85.4 pCH3O-ArNH-Ar- pOCH3 83.0(0.3) 83.3 pN(CH3)2-ArNH- Ar-pN(CH3)2 79.3(0.2) 79.5 pC(CH3)3-ArNH- Ar-pC(CH3)3 85.9(0.1) 85.8 Data in parentheses (BDE = BDEcalc. – BDEexpt.) *The information of Cartesian optimized geometries and energies of these compounds and the corresponding radicals can be found in table S1, SI. 3.2. BDE(NH) of meta and para- monosubstituted diphenylamines and the effect of substituents The introduction of the substituents with different nature into an aromatic ring gives compounds with unique properties. Concerning to monosubstituted diphenylamines, figure 1 shows that mono- substitution can occur at the sites numbered from 2 to 6 on the benzene ring. As mentioned in the introduction part, for an ortho substituted position, the rule of the substituent effect did not reveal due to the steric effect on the adjacent NH bond. Therefore, in this work we focused mainly on the BDE(NH)s and the substituent effect at meta and para positions. Using B3P86/6-311G method, all calculated BDE(NH)s values in the gas phase for the studied monosubstituted diphenylamines were given in table 2. The change of BDE(NH) values depends on the type of substituents and the position of replacement are shown in figure 2. At meta substitutions (3- and 5-position), the change of BDE(NH) values influenced by substituents is insignificant. Halogens, EDG and EWG induce the NH BDEs change with the amount smaller than 1.6 kcal/mol. However, the substituent effect is considerably observed at the para position. The strong EDGs like NH2 and N(CH3)2 at the para site reduces BDE(NH) value Vietnam Journal of Chemistry Nguyen Minh Thong et al. © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 745 remarkably and the differences compared with the parent diphenylamine are of 4.3 and 4.5 kcal/mol, respectively. In contrast, the EWGs increase of the NH BDE values of para monosubstituted diphenylamines. The stronger EWGs the larger enhancement of the BDE. For instance, CF3, CN and NO2 groups increase the BDE(NH) up the amount of 1.9, 1.4 and 2.6 kcal/mol respectively. Table 2: Calculated BDE(NH) for meta and para monosubstituted diphenylamines using B3P86/6- 311G method (in kcal/mol) Y Substitution position Meta para 3Y 5Y 4Y H 87.2 87.2 87.2 F 87.9 88.1 86.7 Cl 87.7 87.9 87.2 CH3 87.2 87.6 86.4 OCH3 87.7 88.0 85.0 NH2 87.4 87.0 82.9 N(CH3)2 87.4 86.8 82.7 CF3 88.0 88.3 89.1 CN 88.0 88.2 88.2 NO2 88.1 88.8 89.8 Figure 2: Change of the BDE (NH) of monosubstituted diphenylamines by position and nature of substituent Obviously, the variation in the homolytic bond dissociation enthalpies of diphenylamines shown in Figure 2 depends robustly on the position and nature of substituent and needs to be quantified. The change of the BDEs can be explained in terms of ground effect (GE), radical effect (RE) and total effect (TE). These parameters are calculated from the isodesmic reactions between monosubstituted diphenylamines and related species and expressed in figure 3. Figure 3: Exchange reactions for GE, RE and TE Based on the thermodynamic viewpoint, the GE and RE are the enthalpies of the reaction of the first two reactions in Figure 3, one of which is the change in enthalpy of reaction calculated for 298.15K and 1 atm. The TE is derived from the equation of TE = RE – GE. The calculated results using B3P86/6- 311G for GE, and RE were drawn in Figure 4, in which the upper is the data for meta sites (3Y and 5Y) and the lower is for the para site (4Y). (A) (B) Figure 4: Calculated GE and RE of Y-C6H4-NH- C6H5 at meta- (A) and para- (B) positions In the case of meta substitution, the ground effect and radical effect could be hardly observed when substituents were at positions 3 and 5 on the aromatic ring. Figure 4A indicates the change of neutral and radical derivatives in comparison to the diphenylamine and its radical when substituent Y is at 3- and 5-ring sites. Generally, they change inconsiderably the stabilization of the neutral and the radical species. Both EDG and EWG substituents slightly stabilize the parent diphenylamine and the Vietnam Journal of Chemistry Substituent effects on the antioxidant capacity of © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 746 calculated GEs are just smaller than 0.6 kcal/mol. For radical species, EWGs destabilize the radical species but the largest calculated RE values are just within 0.7-1.2 kcal/mol. Generally, it can be stated that with the “O pattern”, the ground and radical effects are insignificant when both EDG and EWG substituents are at the meta position. Consequently, this causes the BDE(NH)s to slightly change only from 0.0 to 1.6 kcal/mol. The effect trend is more striking when substituents are at the para position. Figure 4B shows that all substituents stabilize the corresponding radicals, except for Y = F, Cl and CF3. It should emphasize that a negligible impact was observed for halogen and all EWG substituents but the significant effect for EDG: The stronger donating electron group, the higher stabilization of the radical. However, there is a clearly opposite impact of the EDG and EWG on the stabilization of ground states. EWGs stabilize the ground species, but destabilization is found for EDGs. Based on the data in figure 4, in case of EDG the calculated enthalpies of the ground stabilization were around of +1.0 kcal/mol and -1.7 to -3.1 kcal/mol for EWG. The calculated BDE(NH) values for pCH3, pOCH3, pNH2, pN(CH3)2 are 86.4, 85.0, 82.9 and 82.7 kcal/mol, respectively. The behavior of the EDG and EWG can be explained that nitrogen atom possesses an electron lone pair, diphenylamines belong to the so called the “Class O” category,[47,48] in which a radical is stabilized by the electron donating substituent at the para position and destabilized by the electron withdrawing one. It also means that the 4-EDG diphenylamine derivatives are slightly more active than the parent diphenylamine but their radical forms are more stable than that of diphenylamine. However, strong electron donating groups substituted at the para positions induce, with a sharp decrease of BDE(NH)s, meanwhile these compounds enrich electron density at the phenolic rings and easy react with oxygen to produce hydroperoxides, rendering them pro-oxidants. It is considered as an important remark for design and synthesize of potential antioxidant. 3.3. Correlation of Hammett parameter with BDE(NH) of monosubstituted diphenylamines In this section, we mainly try to answer how good the linear correlations between the Hammett parameter () with the BDE(NH)s can be found when substitution takes place at the para site of the phenol ring in which p + values were taken from the compilations of Hammett parameters by Hansch, Leo and Taft. [49] Plotting fitted values by calculated values at para positions graphically illustrates R- squared values for regression models (figure 5). Based on figure 5, a good correlation is observed between Hammett constants with BDE(NH) values in case of para substitution with the R-squared of 0.9681. The linear equation from straight line fitting of the para monosubstituted diphenylamines is expressed in the equation (3): 4-position: BDE(NH) = 2.8003+p + 87.0776 (3) Figure 5: Correlation between BDE(NH)s vs Hammett constants at para monosubstituted diphenylamines 3.4. The radical scavenging activity of the studied compounds 3.4.1. Mechanism evaluating It is generally observed that the radical scavenging was mainly focused on the HOO  and HO  radicals, however the high reactivity of HO  and H-bond interactions of HOO with antioxidants may affect the results. [50] In the case of the B3P86 functional a paper by Pereira and co-workers showed this functiona