Importance of π-stacking interactions in the hydrogen atom transfer reactions from activated phenols to short-lived N-oxyl radicals

Article abstract of DOI:10.1021/jo500789v

A kinetic study of the hydrogen atom transfer from activated phenols (2,6-dimethyl- and 2,6-di-tert-butyl-4-substituted phenols, 2,2,5,7,8- pentamethylchroman-6-ol, caffeic acid, and (+)-cathechin) to a series of N-oxyl radical (4-substituted phthalimide-N-oxyl radicals (4-X-PINO), 6-substituted benzotriazole-N-oxyl radicals (6-Y-BTNO), 3-quinazolin-4-one-N-oxyl radical (QONO), and 3-benzotriazin-4-one-N-oxyl radical (BONO)), was carried out by laser flash photolysis in CH₃CN. A significant effect of the N-oxyl radical structure on the hydrogen transfer rate constants (k_H) was observed with k_H values that monotonically increase with increasing NO-H bond dissociation energy (BDE_NO-H) of the N-hydroxylamines. The analysis of the kinetic data coupled to the results of theoretical calculations indicates that these reactions proceed by a hydrogen atom transfer (HAT) mechanism where the N-oxyl radical and the phenolic aromatic rings adopt a π-stacked arrangement. Theoretical calculations also showed pronounced structural effects of the N-oxyl radicals on the charge transfer occurring in the π-stacked conformation. Comparison of the k_H values measured in this study with those previously reported for hydrogen atom transfer to the cumylperoxyl radical indicates that 6-CH₃-BTNO is the best N-oxyl radical to be used as a model for evaluating the radical scavenging ability of phenolic antioxidants.

Full text of DOI:10.1021/jo500789v

Article
pubs.acs.org/joc
Importance of π‑Stacking Interactions in the Hydrogen Atom
Transfer Reactions from Activated Phenols to Short-Lived N‑Oxyl
Radicals
Marco Mazzonna,† Massimo Bietti,‡ Gino A. DiLabio,*,§,∥ Osvaldo Lanzalunga,*,† and Michela Salamone‡
†Dipartimento di Chimica and Istituto CNR di Metodologie Chimiche (IMC−CNR), Sezione Meccanismi di Reazione, c/o
Dipartimento di Chimica, Sapienza Universita
̀
di Roma, P.le A. Moro, 5, I-00185 Rome, Italy
‡Dipartimento di Scienze e Tecnologie Chimiche, Universita
̀
“Tor Vergata”, Via della Ricerca Scientifica, 1, I-00133 Rome, Italy
§National Institute for Nanotechnology, National Research Council of Canada, 11421 Saskatchewan Drive, Edmonton, Alberta,
Canada T6G 2M9
∥Department of Chemistry, University of British Columbia, Okanagan, 3333 University Way, Kelowna, British Columbia, Canada
V1V 1V7
S
* Supporting Information
ABSTRACT: A kinetic study of the hydrogen atom transfer from activated phenols (2,6-dimethyl- and 2,6-di-tert-butyl-4-
substituted phenols, 2,2,5,7,8-pentamethylchroman-6-ol, caffeic acid, and (+)-cathechin) to a series of N-oxyl radical (4-
substituted phthalimide-N-oxyl radicals (4-X-PINO), 6-substituted benzotriazole-N-oxyl radicals (6-Y-BTNO), 3-quinazolin-4-
one-N-oxyl radical (QONO), and 3-benzotriazin-4-one-N-oxyl radical (BONO)), was carried out by laser flash photolysis in
CH3CN. A significant effect of the N-oxyl radical structure on the hydrogen transfer rate constants (kH) was observed with kH
values that monotonically increase with increasing NO−H bond dissociation energy (BDENO‑H) of the N-hydroxylamines. The
analysis of the kinetic data coupled to the results of theoretical calculations indicates that these reactions proceed by a hydrogen
atom transfer (HAT) mechanism where the N-oxyl radical and the phenolic aromatic rings adopt a π-stacked arrangement.
Theoretical calculations also showed pronounced structural effects of the N-oxyl radicals on the charge transfer occurring in the
π-stacked conformation. Comparison of the kH values measured in this study with those previously reported for hydrogen atom
transfer to the cumylperoxyl radical indicates that 6-CH3-BTNO is the best N-oxyl radical to be used as a model for evaluating
the radical scavenging ability of phenolic antioxidants.
Hydrogen atom transfer from phenolic O−H bonds to PINO
INTRODUCTION
■
(eq 1) has been analyzed in detail.13,14 This reaction is
In recent years the reactivity of short-lived N-oxyl radicals such as
the phthalimide-N-oxyl radical (PINO) and the benzotriazole-N-
oxyl radical (BTNO) in hydrogen atom transfer from C−H and
O−H bonds has been the object of extensive investigation.1−6
The interest in the reactions promoted by N-oxyl radicals is
associated with the key role played by these reactive species in
both metal-catalyzed and transition-metal-free aerobic oxidation
of several classes of organic compounds1,7 and in the oxidative
degradations promoted by the laccase/N-hydroxylamine/O2
system.8 The latter process has found application in the
degradation of lignin9 and of organic pollutants,10 decolorization
of dyes,11 and in synthetically useful procedures.12
particularly interesting since it can occur as part of the oxidative
degradation of the abundant phenolic residues of lignin
promoted by the laccase/O2 system mediated by N-hydroxyph-
thalimide (NHPI).8j In addition, it has been proposed that the
Received: April 8, 2014
Published: May 1, 2014
© 2014 American Chemical Society
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Scheme 1
analysis of the PINO reactivity with phenols may represent a tool
for evaluating the radical scavenging ability of phenolic
antioxidants.13,14 This assessment was based on the similar
bond dissociation energies (BDE) of the NO−H bond of NHPI
formed after hydrogen transfer to PINO (88 kcal/mol)4,6 and
that of the OO−H bonds formed by alkylperoxyl radicals (89
kcal/mol for tBuOO−H).15 However, it was noted that caution
should be taken when comparing the reactivity of these two
classes of oxygen-centered radicals. Accordingly, a significantly
higher reactivity of PINO with respect to alkylperoxyl radicals
was observed in hydrogen abstraction from phenolic O−H
bonds,14,16 rationalized on the basis of a greater contribution of
polar effects in the reactions promoted by PINO.1,3 Moreover
kinetic studies and theoretical calculations for the reaction of
PINO with activated phenols indicated that this process occurs
by a hydrogen atom transfer (HAT) mechanism with a
contribution from charge transfer (CT) deriving from the π-
stacking of the phenolic and PINO aromatic rings.14 This
mechanism is therefore somewhat different from the proton-
coupled electron transfer (PCET) process suggested to be
operative in the reaction of alkylperoxyl radicals with phenolic
antioxidants where the overlap of the inner oxygen peroxyl lone-
pair with the π-orbitals of the ring moiety of the phenol provides
a channel for electron transfer.17
carried out. The structures of activated phenols and N-oxyl
radicals are shown in Scheme 1.
Theoretical calculations were performed in order to estimate
the O−H bond dissociation energies (BDEs) of the N-
hydroxylamines 1H−8H precursors of aminoxyl radicals 1−8.
Density-funcional theory (DFT) with a continuum solvent
model was used to compute rate constants of the reactions of
aminoxyl radicals with one of the most reactive phenols (4-
methoxy-2,6-dimethylphenol (9)) in order to develop a deeper
insight into the energetics and dynamics of the hydrogen transfer
process.
RESULTS
■
Time-Resolved Studies. In the laser flash photolysis (LFP)
experiments, N-oxyl radicals 1−8 were produced by hydrogen
transfer from the corresponding N-hydroxy derivatives 1H−8H:
4-X-N-hydroxyphthalimides (4-X-NHPIs, 1H−3H), 6-Y-N-
hydroxybenzotriazoles (6-Y-HBTs, 4H−6H), 3-hydroxyquina-
zolin-4-one (NHQO, 7H), and 3-hydroxybenzotriazin-4-one
(NHBO, 8H) to the cumyloxyl radical (eq 3 in Scheme 2).19 The
latter species was generated by 355 nm LFP of an acetonitrile
Scheme 2
The work reported here reflects an interest in hydrogen atom
transfer reactions between phenols and short-lived N-oxyl
radicals and on the effects of noncovalent interactions in radical
reactions. To investigate the effects of the structure of the N-oxyl
radicals on the role played by CT interactions on the hydrogen
transfer process, a time-resolved kinetic study in CH3CN of the
reactions of activated phenols including natural phenolic
antioxidants (2,6-dimethyl- and 2,6-di-tert-butyl-4-substituted
phenols (9−15), caffeic acid (16), (+)-cathechin (17), and
2,2,5,7,8-pentamethylchroman-6-ol (PMC, 18)) with a series of
N-oxyl radicals: 4-substituted phthalimide-N-oxyl radicals (4-X-
PINO, 1−3),18 6-substituted benzotriazole-N-oxyl radicals (6-Y-
BTNO, 4−6), 3-quinazolin-4-one-N-oxyl radical (QONO, 7),
and 3-benzotriazin-4-one-N-oxyl radical (BONO, 8) has been
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Table 1. Second-Order Rate Constants kH (M−1 s−1) for the Reactions of 4-Substituted Phthalimide-N-oxyl Radicals (4-X-PINO,
1−3) with Phenols 9−18 Measured at T = 25 °C
a
b
c
d
e
Error 5%. From ref 14. Experimental values in benzene from ref 25. Calculated values in benzene from ref 26. The BDE value for the weaker
f
O−H bond in the 4-position. BDE value for the 3′-O−H catecholic bond in the isomer (−)-epicatechin.
solution containing 1 M dicumyl peroxide (eq 2).20,21 The
Scheme 3
hydrogen transfer from the N-hydroxy derivatives to the
cumyloxyl radical occurs in competition with β-scission of the
latter, which leads to the formation of acetophenone and a
methyl radical (eq 4, kβ ≈ 6.5 × 105 s−1 in CH3CN20).
After 355 nm laser excitation of a solution of dicumyl peroxide
(1 M) and N−OH derivatives (5 mM) in N2 saturated CH3CN
at 25 °C, the time-resolved spectra showed that the cumyloxyl
radical, characterized by an absorption centered at 485 nm,21
undergoes a first-order decay accompanied by a buildup of the
absorption of the N-oxyl radicals. Absorption spectra of N-oxyl
radicals 4-CO2CH3-PINO and 4-OCH3-PINO are reported in
the Supporting Information, Figures S1−S2, while those of
PINO, 6-Y-BTNOs, QONO, and BONO have been reported in
previous studies.2,22,23 The values of the visible absorption
maximum wavelengths (λmax) are given in Tables 1−3.
The N-oxyl radicals 1−8 are stable on the millisecond time
scale. When an excess of phenolic compound (0.05−5 mM) is
added, a fast first-order decay of radicals 1−8 was observed. As
found in the LFP experiments of the hydrogen atom transfer
promoted by PINO,14 with the exception of 2,2,5,7,8-
pentamethylchroman-6-ol (PMC), no transient signals that
could be assigned to phenoxyl radicals at ca. 380−400 nm were
observed.24 Thus, the kH value for the hydrogen transfer from the
phenolic O−H group of compounds 9−18 to the N-oxyl radicals
1−8 (eq 5 in Scheme 3) is significantly lower than the rate of
combination of the phenoxyl radicals with the N-oxyl radicals (eq
6 in Scheme 3).
of phenolic compounds, excellent linear dependencies were
observed. As an example, Figure 1 shows the plots of kobs for the
decay of the BTNO radical measured at 480 nm versus the
concentration of 4-Z-2,6-(CH3)2C6H2OH (Z = OCH3,
NHCOCH3, CH3, H, Br) in CH3CN at T = 25 °C. The kobs vs
[substrate] plots for the reactions of the N-oxyl radicals 1−8 with
phenols 9−18 are reported in the Supporting Information as
Figures S3−S16.
The second-order rate constants for the hydrogen transfer
from the phenolic O−H to N-oxyl radicals (kH) were obtained
from the slopes of these plots using eq 7 for the reactions with
phenols 9−17 (kobs = kH[PMC] for the reaction of 2−8 with
PMC). The kH values are reported in Table 1 for the reactions
promoted by 4-X-PINOs, in Table 2 for the reactions with 6-Y-
BTNOs, and in Table 3 for the reactions with QONO and
BONO.
kobs = 2kH[ArOH]
(7)
When the pseudo-first-order rate constants (kobs) for the decay
of the N-oxyl radicals measured at the maximum absorption
wavelengths (see Table 1) were plotted against the concentration
Theoretical Calculations. Bond Dissociation Enthalpies.
The computed O−H bond dissociation enthalpies (BDENO‑H
)
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(8H) have calculated O−H BDEs that are larger than those of 4-
X-NHPIs and 6-Y-HBTs, presumably owing to the differential
stability of the resulting radicals. That is, radicals QONO and
BONO contain 6-center, 7-electron rings, whereas 4-X-PINOs
and 6-Y-BTNOs contain 5-center, 6-electron rings.
The computed gas-phase BDEs for 4-X-NHPIs and 6-Y-HBTs
are significantly lower than the experimental BDE values
measured in the polar solvents tBuOH and DMSO for NHPIs2c,6
and in acetonitrile for HBTs.29 This finding is consistent with the
previous computational work30−32 and may be attributed to the
formation of hydrogen bonds with these solvents. For example, it
was found that CH3CN solvent can act as a hydrogen bond
acceptor (HBA) forming a strong H-bond (ca. 7 kcal/mol) with
NHPI, but none with PINO. Thus, the NO−H BDE of NHPI is
enhanced by ca. 7 kcal/mol in such H-bonding solvent.31 The
experimental BDE values for NHPI are also 5−7 kcal/mol higher
than those calculated previously in the same solvents.30 It was
suggested that explicit solvent effects, where discrete solvent
molecules are bound to the solute molecule, are required in order
to adequately model the NO−H bond energy.
Figure 1. Dependence of kobs for the decay of the BTNO radical
measured at 480 nm on the concentration of 4-Z-2,6-(CH3)2C6H2OH
(Z = OCH3, NHCOCH3, CH3, H, Br) in CH3CN at T = 25 °C.
Ultimately, confidence in the calculated BDEs for 1H−8H
may, to some extent be derived from excellent correlation with
the measured rate constants for the reactions with 2,6-dimethyl-
4-methoxyphenol (vide infra).
Hydrogen Transfer Reactions. Density-functional theory
(DFT) calculations were performed to model the reactions
between N-oxyl radicals 1−8 and 4-methoxy-2,6-dimethylphenol
(9) in order to analyze the structural effects of the N-oxyl radicals
on the hydrogen transfer from an activated phenolic compound.
The B3LYP/6-31+G(2d,2p)34−37 approach was used. The
effects of noncovalent interactions in the reacting systems were
modeled with the dispersion-correcting potentials (DCPs)
recently described.38 Since DCPs have not yet been developed
for the F atom, DCPs were applied to the H, C, N, and O atoms
for the N-hydroxylamines 1H−8H precursors of aminoxyl
radicals 1−8 were calculated by using the composite CBS-QB3
approach27 as implemented in the Gaussian-09 program
package.28 The CBS-QB3 approach is capable of providing
BDE values in agreement with experimental values to within
about 1 kcal/mol.
The calculated BDENO‑H values for 1H−8H are reported in
Table 4 along with available experimental values. BDEs for 4-X-
NHPIs and 6-Y-HBTs were measured by the EPR or UV−vis
radical equilibration technique.4,6,29 NHQO (7H) and NHBO
Table 2. Second-Order Rate Constants kH (M−1 s−1) for the Reaction of 6-Substituted Benzotriazole-N-oxyl Radicals (6-Y-BTNO,
4−6) with Phenols 9−18 Measured at T = 25 °C
a
Error 5%.
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Table 3. Second-Order Rate Constants kH (M−1 s−1) for the Reaction of 3-Quinazolin-4-one-N-oxyl Radical (QONO, 7) and 3-
Benzotriazin-4-one-N-oxyl Radical (BONO, 8) with Phenols 9−18 Measured at T = 25 °C
a
Error 5%.
activated complex structures. It has previously been shown that
the reaction between PINO and 2,6-dimethyl-4-methoxyphenol
occurs along a path through a stacked, “cisoid” complex and that
the reaction through a nonstacked, “transoid” activated complex
is much higher in energy.14
Estimations of the effects of acetonitrile solvent were obtained
at the B3LYP-DCP/6-31+G(2d,2p) level of theory using a SMD
continuum solvent model40 applied to the gas-phase optimized
structures. Figure 2a and b show the gas-phase optimized cisoid
Table 4. Calculated and Experimental BDENO‑H Values for N-
Hydroxylamines 1H−8H Precursors of N-Oxyl Radicals 1−8
a
BDENO‑H
calculated CBS-QB3
b
BDE
ΔBDE
−4.4
exptl
c
,
d
,
e
f
NHPI (1H)
83.2
87.0
g
89.6
f h
4-CO2CH3-NHPI (2H)
4-CH3O-NHPI (3H)
HBT (4H)
83.4
83.0
78.0
78.6
77.1
89.0
89.1
−4.6
−4.2
+0.8
87.8 ,
i
f h
86.2 ,
j
85.1
j
6-CF3-HBT (5H)
6-CH3-HBT (6H)
NHQO (7H)
+0.2
86.5
j
+1.7
85.3
−10.2
−10.3
nd
nd
NHBO (8H)
a
b
In kcal/mol. Computed as the difference between 2,6-dimethyl-4-
methoxyphenol (9), for which the CBS-QB3 calculated O−H BDE is
c
78.8 kcal/mol, and 1H to 8H. Calculated as 83.0 kcal/mol with the
G3B3 method in vacuum, and 83.6 kcal/mol in acetonitrile; see ref 30.
d
Calculated as 81.2 kcal/mol using a correction of the result of a DFT
e
method to approach G2M computed BDE; see ref 31. Calculated as
80.8 kcal/mol using B3LYP/6-311+G*, see ref 32. In tBuOH, from
ref 6; the value was re-evaluated to be lower by 1.1 kcal/mol on the
f
Figure 2. (a) Cisoid (π-stacked) pre-reaction complex formed by
BTNO and 4-methoxy-2,6-dimethylphenol (9). (b) Cisoid transition
state structure for the hydrogen transfer process. Ring centers are
indicated by the light purple spheres. Some key distances are shown in
angstroms.
basis of the recalculated phenolic O−H BDE of the reference
g
compound 4-methyl-2,6-di-tert-butylphenol (BHT) (ref 33). Calcu-
h
lated by a thermochemical cycle in DMSO, from ref 2c. From ref 4.
i
Calculated as 79.9 kcal/mol using B3LYP/6-311+G*; see ref 32.
From ref 29.
j
pre-reaction and activated complexes for BTNO + 2,6-dimethyl-
4-methoxyphenol (9). The structures shown in Figure 2 are quite
representative of those associated with the pre-reaction and TS
structures for the reaction of all of the N-oxyl radicals with the
phenol. The coordinates for these complexes are reported in the
Supporting Information. As described above, the stacked
structure that is adopted in the activated complex allows for
in systems containing 6-CF3-BTNO. It has been demonstrated
that DCPs offer incremental improvements to the description of
noncovalent interactions as they are applied to each atom type in
a system.39
A single imaginary vibration mode connecting a π-stacked pre-
reaction complex to a π-stacked post-reaction complex verified
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Table 5. Calculated Gas-Phase Binding Energies (ΔE), Gas-Phase/Acetonitrile Solvent-Phase Free Energies, Relative to
Reactants, of the Pre-reaction Complex (ΔG) and Transition State (TS) Complex (ΔG#), Free Energy Variation (ΔBDFE) for the
Reactions of N-Oxyl Radicals 1−8 with 4-Methoxy-2,6-dimethylphenol (9) as Obtained from B3LYP-DCP/6-31+G(2d,2p)
Calculations, Calculated Solvent-Phase Rate Constants (kH calc), Experimental Rate Constants Measured in Acetonitrile (kH expt),
#
and Net Positive Charge on the Phenoxyl Moiety at the TS (qArO
)
a
a
a
ΔG#
a
b
b
10−6 kH calc
10−6 kH expt
qArO
#
reaction
ΔE
ΔG
ΔBDFE
9 + PINO (1)
9 + 4-CO2CH3-PINO (2)
9 + 4-CH3O-PINO (3)
9 + BTNO (4)
−13.3
−14.6
−13.4
−9.9
−11.8
−10.3
−12.7
−12.5
−0.2/4.4
−1.1/3.5
0.4/4.7
2.4/5.1
1.3/4.6
1.8/4.6
0.6/5.6
0.7/4.5
4.1/7.7
2.7/6.9
4.1/7.8
6.8/8.2
5.1/6.6
7.0/8.5
3.3/7.1
3.9/5.8
−4.2
−6.0
−4.1
3.8
15.1
57.3
8.9
5.4
4.2
8.9
1.3
1.2
6.5
15
0.17
0.20
0.15
0.08
0.12
0.07
0.12
0.15
5.7
9 + 6-CF3-BTNO (5)
9 + 6-CH3-BTNO (6)
9 + QONO (7)
−0.1
4.3
88.3
3.8
−10.7
−11.0
38.5
330.6
9 + BONO (8)
14
a
b
In kcal/mol. In M−1 s−1
the orbitals of the nitroxyl and phenol ring moieties to overlap as
the hydrogen atom is transferred between them.
In the series of the ortho-dimethylated phenols 9−13 and di-
tert-butylated phenols 14 and 15, rate constants increase with the
electron-donating ability of the substituent, reflecting both
enthalpic and polar effects. Electron-donating groups reduce the
bond dissociation enthalpy (BDE) of the phenolic O−H bond
(see Table 1) as a result of the stabilization of the phenoxyl
radical and destabilization of the phenol.33,43,44 As for the polar
effects, it has to be considered that the reaction occurs by a HAT
mechanism with a contribution from charge transfer occurring
between the π-stacked phenolic and N-oxyl aromatic rings in a
cisoid activated complex, as indicated by the calculations (see
Figure 2 for the reaction of BTNO with 4-methoxy-2,6-
dimethylphenol). Thus, an increase of the electron-donating
properties of the phenolic substituents leads to an increased
stabilization of the partial positive charge that develops on the
phenolic ring in the activated complex. In accordance with a
charge separation in the activated complex of the hydrogen
transfer process, high and negative ρ values (Table 6) ranging
The free energies associated with the pre-reaction and TS
structures, along with the calculated rate constants for the
reactions of the N-oxyl radicals 1−8 with 4-methoxy-2,6-
dimethylphenol, relative to the separated reactants, are listed in
Table 5. The binding energies, defined as the negative of the
electronic energy difference between the complex and its
infinitely separated constituents, are also provided in Table 5.
The gas-phase binding energies associated with the pre-
reaction complexes are quite large, ranging from 9.9 to 14.6 kcal/
mol depending on the N-oxyl radical.41 The gas-phase binding
free energies are considerably smaller in magnitude, with all of
the complexes except PINO·9 and 4-CO2CH3-PINO·9
predicted to be unbound relative to the separated monomers.
This is consistent with the loss in entropy associated with the
formation of a dimer from two monomers. The inclusion of
solvent effects via a continuum model simulating acetonitrile
makes all of the binding free energies positive. This indicates that
the solvent model predicts the preferential solvation of the
monomers over the complexes. Overall, the calculations predict
equilibrium constants for complexation of the N-oxyl radicals
with 4-methoxy-2,6-dimethylphenol in the range of 2.7 × 10−3 to
7.8 × 10−5 M−1.42
The calculated gas- and solvent-phase free energies of the TS
complexes relative to separated reactants are also presented in
Table 5. These data show that gas-phase reaction free-energy
barriers are between 1.5 and 4.2 kcal/mol lower than the
corresponding solvent-phase values. Bearing in mind that a 1.3
kcal/mol difference in barrier height corresponds to a 1 order of
magnitude change in rate constant, the differences in gas- and
solvent-phase barrier heights are significant. Using the solvent-
phase free-energy barriers to compute the rate constants for the
reactions produces fair to good results, with kcalc/kexpt ranging
from 2 to 24. This agreement between calculated and
experimental rate constants lends support to a reaction
mechanism involving a stacked activated complex structure.
Table 6. ρ Values Calculated from the Hammett Correlation
in the Reactions of N-Oxyl Radicals 1−8 with 4-X-2,6-
Dimethylphenols (9−13) in CH3CN at 25°C
b
N-oxyl radical
ρ
a
PINO (1)
−2.76 (0.993)
−2.93 (0.976)
−2.85 (0.982)
−2.85 (0.987)
−3.21 (0.991)
−2.74 (0.988)
−2.45 (0.996)
−2.78 (0.995)
4-CO2CH3-PINO (2)
4-CH3O-PINO (3)
BTNO (4)
6-CF3-BTNO (5)
6-CH3-BTNO (6)
QONO (7)
BONO (8)
a
b
From ref 14. r2 values are reported in parentheses.
from the least selective QONO (ρ = −2.45) to the most selective
X
6-CF3BTNO (ρ = −3.21) were determined when the log(kH
/
kHH) values for the reactions of N-oxyl radicals 1−8 with phenols
9−13 were plotted versus the substituent constants σ+.
As an example, Figure 3 shows a Hammett plot for the
reactions of 4-Z-2,6-(CH3)2C6H2OH with BTNO. The
Hammett plots for the reactions promoted by N-oxyl radicals
2, 3, and 5−8 are reported in Figures S17−S22 in the Supporting
Information.
DISCUSSION
■
As reported previously for the hydrogen transfer reactions
promoted by PINO,14 a significant variation of the rate constants
is observed by changing the phenolic structure with all the N-oxyl
radicals investigated. The most reactive phenol, 2,2,5,7,8-
pentamethylchroman-6-ol (PMC), is ca. 4 orders of magnitude
more reactive than the least reactive, 4-bromo-2,6-dimethylphe-
nol.
In all cases the ρ values are significantly more negative than
that found in the hydrogen transfer reaction from 4-substituted-
2,6-dimethylphenols to the styrylperoxyl radical (ρ = −1.36),45
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nol a 12-fold difference in kH is observed between the least
reactive 6-CH3-BTNO (kH = 1.2 × 106 M−1 s−1) and the most
reactive QONO (kH = 1.5 × 107 M−1 s−1). A fairly good linear
correlation is obtained by plotting the experimental kH values for
the hydrogen transfer from 4-methoxy-2,6-dimethylphenol to
the N-oxyl radicals 1−8 (ln kH expt) and the free energy variation
calculated for the same process in acetonitrile (ΔBDFE, see
Table 5) (Figure 4).
Figure 3. Hammett plot for the reactions of 4-Z-2,6-(CH3)2C6H2OH
(9−13) with BTNO (4) in CH3CN at 25 °C.
in accordance with the greater development of electron
deficiency in the phenolic ring in the activated complex for
HAT promoted by the N-oxyl radicals with respect to the peroxyl
radical (vide infra).
The importance of polar effects can be also evinced from the
analysis of the reactivity data for the hydrogen trasfer from the
natural catecholic antioxidants (caffeic acid 16 and (+)-cathechin
17) and the simplified model of α-tocopherol, 2,2,5,7,8-
pentamethylchroman-6-ol (PMC, 18). The rate constants for
the three phenolic compounds are in the order kH(18) > kH(17)
> kH(16), as expected on the basis of the calculated BDE values26
reported in Table 1. However, with PMC, kH values are ca. 3
orders of magnitude higher than those observed with the two
cathecolic substrates, a difference that cannot be rationalized on
enthalpic grounds in view of the small difference in the BDE
values (less than 2 kcal/mol). The remarkable difference in
reactivity between PMC and caffeic acid or (+)-cathechin can be
reasonably explained with the operation of polar effects.
Accordingly, for PMC a greater stabilization of the partial
positive charge that develops in the activated complex of the
HAT process has to be expected in view of the much lower
adiabatic ionization potentials (IP) for PMC calculated in
benzene with respect to caffeic acid or (+)-cathechin (136, 152,
and 159 kcal/mol for PMC, (+)-cathechin, and caffeic acid,
respectively).26
The kH values are significantly influenced by steric effects of
the phenolic ortho-substituents as previously observed in the
reactions with the PINO radical.14 As such, the kH values for 4-
methoxy-2,6-dimethylphenol (9) and 2,4,6-trimethylphenol
(11) are always much higher than those measured for 4-
methoxy-2,6-di-tert-butylphenol (14) and 4-methyl-2,6-di-tert-
butylphenol (15) even though the former reactions are 1.4−1.7
kcal mol−1 less exothermic (see Table 1). Steric effects are also
dependent on the structure of the N-oxyl radicals. Accordingly
the decrease of reactivity observed by replacing the ortho
dimethyl with the ortho di-tert-butyl substituents is lower with the
less hindered 6-Y-BTNOs and higher with the 4-X-PINOs.
The analysis of the structural effects of the N-oxyl radical on
hydrogen transfer reactions from the series of activated phenols
represents the main objective of this study. From the kinetic data
reported in Tables 1−3 it can be noted that significant variations
of kH are observed by changing the structure of the N-oxyl radical.
For example in the reaction of the 4-methoxy-2,6-dimethylphe-
Figure 4. Correlation of experimental kH values measured in acetonitrile
(ln kH expt) and the free energy variation calculated for the hydrogen
transfer from 4-methoxy-2,6-dimethylphenol (9) to N-oxyl radicals 1−8
(ΔBDFE).
In the series of the substituted 4-X-PINOs (1−3) and 6-Y-
BTNOs (4−6) it can be noted that substituents exert a
significant effect on the rate constants for hydrogen transfer
from all the phenolic substrates. The reactivity increases by
increasing the electron-withdrawing properties of the aryl
substituent as found in hydrogen abstraction processes from
C−H bonds4,5,7d,8h,29,32,46 in accordance with the influence of
both enthalpic and polar effects. From an enthalpic point of view,
it has to be considered that BDENO‑H values regularly increase
with increasing electron-withdrawing (EW) power of the aryl
substituents.4,29,32 The BDENO‑H values calculated for 1H−8H
are reported in Table 4 together with the calculated values
reported for NHPI and 4-OCH3-NHPI30−32 and the exper-
imental values determined for 4-X-NHPIs and 6-Y-HBTs by the
EPR and UV−vis radical equilibration technique.4,6,29
Substituent effects on the BDENO‑H values have been explained
on the basis of the destabilization provided by EW substituents to
the charge-separated resonance structure of the N-oxyl radical as
shown in Figure 5.4,29
As described above the reactivity of N-oxyl radicals in the
hydrogen atom transfer from activated phenols is determined not
only by the enthalpic requirements of the ArO−H and NO−H
Figure 5. Resonance structures for 4-substituted phthalimide-N-oxyl
radicals (4-X-PINO) and 6-substituted benzotriazole-N-oxyl radicals (6-
Y-BTNO).
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bond dissociation energies but also by the polar effects that may
provide stabilization to the activated complex. Thus, the presence
of electron-withdrawing substituents in the N-oxyl radicals
confers additional stabilization to the activated complex and
assists the development of the partial negative charge on the
abstracting N-oxyl radical as mirrored by the favorable effect,
described above, exerted by ED substituents on the phenolic
nucleus where a partial positive charge develops (see Figure 6).
previously reported for HAT from α-tocopherol by the
cumylperoxyl radical (3.8 × 105 M−1 s−1 in CH3CN).16,47 N-
Oxyl radicals 1−8 are at least 2 orders of magnitude more
reactive than CumOO• in hydrogen atom transfer from O−H
bonds in activated phenols despite the similar bond dissociation
energies of the O−H bonds in N-hydroxylamines and
alkylhydroperoxides.15,48 Comparison of the kH values deter-
mined in this study with those previously reported for hydrogen
atom transfer to an alkylperoxyl radical would suggest that the
least reactive 6-CH3-BTNO may be the best candidate to be used
as a model for evaluating the radical scavenging ability of
phenolic antioxidants.
CONCLUSIONS
■
π-Stacking interactions between the phenolic and N-oxyl
aromatic groups play an important role in the hydrogen atom
transfer reactions from activated phenols, including the natural
phenolic antioxidants caffeic acid and (+)-catechin, to short-lived
N-oxyl radicals. The hydrogen transfer rate constants increase
with the electron-donating strength of the phenolic ring
substituent and with the electron-withdrawing (EW) power of
the N-oxyl aryl substituent reflecting both enthalpic and polar
effects. As for the enthalpic effects theoretical calculations show
that electron-withdrawing groups increase the NO−H BDE in
the N-hydroxylamine precursor of the N-oxyl radicals. For the
polar effects, the analysis of the structural effects of the N-oxyl
radicals on the role played by charge transfer interactions in the
hydrogen transfer reactions from 4-methoxy-2,6-dimethylphenol
showed a regular increase in the development of positive charge
in the phenolic ring and a corresponding negative charge in the
N-oxyl aryl ring by increasing the EW properties of the N-oxyl
radical substituents.
Figure 6. Cisoid (π-stacked) transition state structures for the hydrogen
transfer from phenolic substrates promoted by 4-X-PINOs and 6-Y-
BTNOs.
The results of theoretical calculations for the hydrogen transfer
reactions between N-oxyl radicals 1−8 and 4-methoxy-2,6-
dimethylphenol (9) permits an analysis of the structural effects of
the N-oxyl radical on the charge transfer contribution to the
activated complex. With all the N-oxyl radicals, the hydrogen
transfer follows the same HAT mechanistic pathway described in
the previous study on the reactions promoted by PINO.14
A
cisoid-type pre-reaction complex is formed between the reactants
(Figure 2) with stabilization energies that depend marginally on
the structure of the N-oxyl radical (Table 5). The pre-reaction
complexes formed by 4-X-PINO radicals are characterized by a
higher degree of stabilization relative to separated reactants in the
series of the N-oxyl radicals investigated with gas-phase binding
energies (ΔE) ranging from −13.3 and −14.6 kcal/mol, while
the 6-Y-BTNO radicals form the less stabilized complex (−11.8 <
ΔE < −9.9 kcal/mol).
The contribution from π-stacking interactions may be also
relevant in the hydrogen atom transfer reactions from benzylic
C−H bonds to short-lived N-oxyl radicals. Information in this
respect will be provided by kinetic studies and theoretical
calculations of hydrogen transfer reactions from alkylaromatics,
benzylic alcohols, and benzylamines to short-lived N-oxyl
radicals, which are currently being performed.
From the pre-reaction complex, the reaction proceeds by a
HAT process through a π-stacked cisoid activated complex in
which the phenolic OH group is rotated so that it is pointing
toward the singly occupied oxygen p-orbital of the N-oxyl radical
(see Figure 2 for the reaction with BTNO). The π-stacking in the
activated complex with the bonding π−π overlap involving the
phenol and N-oxyl rings determines a significant degree of charge
transfer (CT) from the phenolic ring to the N-oxyl ring, which is
responsible for the remarkable polar effects observed in the
hydrogen transfer process. To investigate the role of charge
transfer in the hydrogen atom transfer reactions and its
dependence on the structure of the N-oxyl radicals, the
relationship between the rate constants for the hydrogen transfer
process and the partial positive charge on the phenoxyl moiety of
9 in the activated complex (qArO# in Table 5) has been evaluated.
In the series of aryl-substituted 4-X-PINOs and 6-Y-BTNOs, as
expected, there is a regular increase in electron deficiency of the
phenolic groups with increasing EW properties of the N-oxyl
radical substituents. The relatively small positive charge that
develops in the phenolic ring in the activated complex of the
reactions with BONO and QONO can be attributed to the fact
that the reactions are the most exergonic. Thus, the activated
complex is more reactant-like, and the degree of charge transfer is
less pronounced.
EXPERIMENTAL SECTION
■
Materials. CH3CN (spectrophotometric grade), dicumyl peroxide,
1-hydroxybenzotriazole (HBT, 4H), 6-trifluoromethyl-1-hydroxyben-
zotriazole (6-CF3-HBT, 5H), and 6-hydroxybenzotriazin-4-one
(NHBO, 8H) were used as received. 4-Methoxy-N-hydroxyphthalimide
(4-OCH3-NHPI, 3H), 4-methoxycarbonyl-N-hydroxyphthalimide (4-
CO2CH3-NHPI, 2H), 6-methyl-1-hydroxybenzotriazole (6-CH3-HBT,
6H), and 3-hydroxy-quinazolin-4-one (NHQO, 7H) were synthesized
according to the literature.4,22,23 Phenols 11−18 are commercially
available and were further purified by sublimation. 4-Methoxy-2,6-
dimethylphenol (9)49 and N-(3,5-dimethyl-4-hydroxyphenyl)-acet-
amide (10) were synthesized using previously reported procedures.50
Laser Flash Photolysis Experiments. Laser flash photolysis
experiments were carried out with an Applied Photophysics LK-60 laser
kinetic spectrometer providing 8 ns pulses, using the third harmonic
(355 nm) of a Quantel Brilliant-B Q-switched Nd:YAG laser. The laser
energy was adjusted to ≤10 mJ/pulse by the use of the appropriate filter.
A 3.5-mL Suprasil quartz cell (10 mm × 10 mm) was used for all
experiments. N2-saturated CH3CN solutions of dicumyl peroxide (1 M),
N-hydroxylamines 1H−8H (5.0 mM), and phenol 9−18 (0.05−5 mM)
were used. All experiments were carried out at T = 25 0.5 °C under
magnetic stirring. Data were collected at individual wavelengths with an
Agilent Infinium oscilloscope and analyzed with the kinetic package
provided with the instrument. Rate constants were obtained by
monitoring the change of absorbance at the maximum absorption
The important contribution of charge transfer in the reaction
of N-oxyl radicals with activated phenols is highlighted by the
comparison of the rate constants for reaction with 2,2,5,7,8-
pentamethylchroman-6-ol (PMC) (Tables 1−3) with that
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wavelengths of the N-oxyl radicals 2−8 by averaging 3−5 values. Each
kinetic trace exhibited first-order behavior. Second-order rate constants
were obtained from the slopes of plots of the observed rate constants kobs
vs substrate concentration.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Absorption spectra of 4-CO2CH3-PINO and 4-CH3O-PINO.
Dependence of kobs for the decay of the N-oxyl radicals 1−8 on
the concentrations of phenols 9−18. Hammett plots for the
reactions of 4-X-2,6-(CH3)2C6H2OH with N-oxyl radicals 2, 3,
5−8. Optimized Cartesian coordinates of structures associated
with the reactions of N-oxyl radicals 1−8 with 4-methoxy-2,6-
dimethylphenol (9). This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: Gino.DiLabio@ubc.ca.
*E-mail: osvaldo.lanzalunga@uniroma1.it.
■
Notes
C.; Baiocco, P.; Gerini, M. F.; Lanzalunga, O.; Sjogren, B. J. Mol. Catal.
̈
B: Enzym. 2005, 32, 89−96. (i) Branchi, B.; Galli, C.; Gentili, P. Org.
Biomol. Chem. 2005, 3, 2604−2614. (j) Astolfi, P.; Brandi, P.; Galli, C.;
Gentili, P.; Gerini, M. F.; Greci, L.; Lanzalunga, O. New J. Chem. 2005,
29, 1308−1317.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Thanks are due to the Ministero dell’Istruzione, dell’Universita
della Ricerca (MIUR) for financial support, PRIN 2010-2011
(2010PFLRJR) project (PROxi project), and Westgrid for access
to computational resources. We thank Prof. Lorenzo Stella for
the use of LFP equipment.
■
̀
e
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