Hydrogen atom abstraction kinetics from intramolecularly hydrogen bonded ubiquinol-0 and other (poly)methoxy phenols

Article abstract of DOI:10.1021/ja9937674

The effect of methoxy substitution on the abstraction of the phenolic hydrogen atom involved in intramolecular hydrogen bonding by tert-butoxyl and cumyloxyl radicals has been investigated by laser flash photolysis. Also transition state calculations for

Full text of DOI:10.1021/ja9937674

J. Am. Chem. Soc. 2000, 122, 2355-2360
2355
Hydrogen Atom Abstraction Kinetics from Intramolecularly Hydrogen
Bonded Ubiquinol-0 and Other (Poly)methoxy Phenols
Martine I. de Heer,† Peter Mulder,*,† Hans-Gert Korth,‡ Keith U. Ingold,*,§ and
Janusz Lusztyk§
Contribution from the Leiden Institute of Chemistry, Leiden UniVersity, P.O. Box 9502,
2300RA Leiden, The Netherlands, Institut fu¨r Organische Chemie, UniVersita¨t-GH Essen,
D-45117 Essen, Germany, and Steacie Institute for Molecular Sciences, National Research
Council of Canada, Ottawa, Ontario, Canada K1A OR6
ReceiVed October 20, 1999. ReVised Manuscript ReceiVed December 16, 1999
Abstract: The effect of methoxy substitution on the abstraction of the phenolic hydrogen atom involved in
intramolecular hydrogen bonding by tert-butoxyl and cumyloxyl radicals has been investigated by laser flash
photolysis. Also transition state calculations for methoxyl radical and 2-methoxyphenol have been carried out
by a density functional theory (DFT) method. Hydrogen atom abstraction is surprisingly easy from
intramolecularly hydrogen bonded methoxyphenols, in contrast to intermolecularly hydrogen bonded molecules.
The kinetic solvent effect, investigated in six solvents with different hydrogen bond accepting properties, on
the hydrogen atom abstraction reaction from o-methoxy phenols was shown to be smaller than for non-hydrogen
bonded phenols, and is independent of further methoxy substitution. The high rate constant for hydrogen atom
abstraction from ubiquinol-0 (2.8 × 109 M-1 s-1 in CCl4) and the small kinetic solvent effect make it a good
antioxidant, even in a polar environment.
Introduction
Many natural antioxidants are alkoxy-substituted phenolic
compounds, which can trap peroxyl radicals by donating a
hydrogen atom. Two phenolic antioxidants, R-tocopherol and
ubiquinol-10, are important in the protection of human low-
density lipoproteins (LDL). In homogeneous solution peroxyl
radicals abstract the phenolic hydrogen from R-tocopherol,
ArOH, and the resulting R-tocopheroxyl radical, ArO•, then
scavenges a second peroxyl radical forming nonradical prod-
ucts.1 However, in LDL an alternative pathway is possible for
the R-tocopheroxyl radical: it can abstract a hydrogen atom
from a lipid molecule, thus creating an oxidative chain reaction
known as tocopherol-mediated peroxidation, TMP.1 This TMP
process is inhibited by ascorbate in the aqueous phase and by
ubiquinol-10, Q10H2, in the lipid of the LDL particle. The Q10H2
is believed to inhibit TMP by donating a phenolic hydrogen
atom to the R-tocopheroxyl radical, reaction 1. The resultant
semiquinone radical or radical anion reacts with dioxygen to
yield the quinone and the water-soluble superoxide radical
not abstracted.2-4 This raises the pertinent question: Are
intramolecularly hydrogen-bonded phenols really reactive to-
ward free radicals? Herein, we show using o-methoxyphenols
that their phenolic hydrogen atoms are abstracted by radicals
surprisingly readily.
The antioxidant activity of substituted phenols can be related
to the bond dissociation enthalpies of the phenolic O-H bonds,
BDE(O-H). In previous studies,5,6 BDE(O-H)s have been
determined by using a photoacoustic calorimetry technique for
R-tocopherol6 and several o-methoxy-substituted phenols, in-
cluding ubiquinol-0, Q0H2, the simplest ubiquinol, which lacks
the 10 isoprenoid units of Q10H2.5 From these studies it can be
inferred that reaction 1 is slightly endothermic. It was found
that 2-methoxyphenol was almost entirely intramolecularly
hydrogen bonded even in strong hydrogen bond accepting
(HBA) solvents.5 Nevertheless, a thermodynamic solvent effect
was observed, suggesting an additional interaction between the
ArO• + Q10H2 f ArOH + Q10H•
(1)
(2)
Q10H• (Q10•-) + O2 f Q10 + O2•- + (H+)
anion which escapes from the LDL particle and thus stops the
TMP. In Q10H2 the phenolic hydrogens are intramolecularly
bonded. Thus, reaction 1 involves the abstraction of an
intramolecularly hydrogen-bonded phenolic hydrogen atom.
More interestingly, it has been firmly established that phenolic
hydrogen atoms involved in intermolecular hydrogen bonds are
(2) Avila, D. V.; Ingold, K. U.; Lusztyk, J.; Green, W. H.; Procopio, D.
R. J. Am. Chem. Soc. 1995, 117, 2929-30.
(3) MacFaul, P. A.; Ingold, K. U.; Lusztyk, J. J. Org. Chem. 1996, 61,
1316-21.
(4) Valgimigli, L.; Banks, J. T.; Ingold, K. U.; Lusztyk, J. J. Am. Chem.
Soc. 1995, 117, 9966-71.
† Leiden University.
(5) de Heer, M. I.; Korth, H. G.; Mulder, P. J. Org. Chem. 1999, 64,
6969-75.
‡ Universita¨t-GH Essen.
§ National Research Council of Canada.
(1) Bowry, V. W.; Ingold, K. U. Acc. Chem. Res. 1999, 32, 27-34.
(6) Wayner, D. D. M.; Lusztyk, E.; Ingold, K. U.; Mulder, P. J. Org.
Chem. 1996, 61, 6430-3.
10.1021/ja9937674 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/26/2000

2356 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
de Heer et al.
Scheme 1
romethane is high and close to the diffusion-controlled limit.
For the o-methoxyphenols on changing the solvent from CCl4
to ethyl acetate the decrease in rate constants is smaller, with
an average of ca. 6 for 2-methoxy-, 2,4-dimethoxy-, and 2,6-
dimethoxyphenol and ubiquinol-0. Thus, the presence of an
intramolecular hydrogen bond attenuates the kinetic solvent
effect arising from intermolecular hydrogen bonding but does
not completely eliminate it.11,13
The two hydroxyl groups of ubiquinol-0 are not equivalent,
the hydroxyl group ortho to the methyl group (OHa) has been
calculated by DFT to have a somewhat lower BDE(O-H) and
to form a slightly stronger intramolecular hydrogen bond than
the hydroxyl group meta to the methyl group (OHb).5,15 The
difference in BDE(O-H) is however quite small (0.9 kcal mol-1
by DFT calculations), so hydrogen atom abstraction from both
hydroxyl groups will be feasible.
intramolecularly bonded hydrogen and a solvent molecule. Thus,
2-methoxyphenol in a HBA solvent can be present in four
different forms, see Scheme 1.
DFT-Calculated Transition States for Hydrogen Atom
Abstraction. Density functional theory calculations on the
B3LYP/6-31G(d,p) level have been performed for the transition
states for hydrogen atom abstraction by the methoxyl radical
(as a computational model for tert-butoxyl and cumyloxyl) from
hydrogen-bonded and non-hydrogen-bonded 2-methoxyphenol
and the structures are given in Figure 1. The O-H-O angle in
both transition state structures is similar, 162.9° in the hydrogen-
bonded form and 162.4° in the non-hydrogen-bonded form.
Intermolecular hydrogen bonding with the solvent prevents
hydrogen atom abstraction, as has been observed for many
different HBA solvents, and the magnitude of the kinetic solvent
effect is independent of the nature of the abstracting radical.2,4
To determine whether hydrogen atom abstraction is possible
from the intramolecularly hydrogen-bonded phenols, rate con-
stants have been measured by laser flash photolysis (LFP) for
the hydrogen atom abstraction by alkoxyl (tert-butoxyl and
cumyloxyl) radicals from various (poly)methoxy phenols in-
cluding Q0H2 in solvents with different HBA properties. In
addition, transition state structures for hydrogen atom abstraction
from free and intramolecularly hydrogen-bonded 2-methoxy-
phenol by the methoxyl radical were calculated by a density
functional theory (DFT) method.
In the ground state structures only a small increase of the
O-H bond length is observed in the hydrogen-bonded form
compared to the non-hydrogen-bonded form of 2-methoxyphe-
nol, see Figure 2. In the transition state, however, the O-H
bond is more elongated and the OH-methoxyl radical distance
is significantly shorter in the hydrogen-bonded form, indicating
a “later” transition state. Intramolecular hydrogen bonding in
the transition state also keeps the phenolic OH group much
closer to the plane of the aromatic ring (dihedral angle 14.6°)
than is the case for the non-hydrogen-bonded form where the
OH group is twisted out of the aromatic ring plane by about
25° in the transition state. The hydrogen atom abstraction from
the hydrogen-bonded form occurs as a synchronous lengthening
Results
Laser Flash Photolysis. The rate constants for hydrogen atom
abstraction from methoxyphenols by alkoxyl radicals were
measured by laser flash photolysis (LFP). tert-Butoxyl or
cumyloxyl radicals were generated from the corresponding
dialkyl peroxides.7 Upon irradiation of a solution of the peroxide
and the phenol under investigation, the peroxide decomposes
“instantaneously” to give two alkoxyl radicals, reaction 3, which
then abstract the hydroxylic hydrogen atom, reaction 4. The
rate constants were measured by monitoring the pseudo-first-
order growth of the phenoxyl radical for 4-methoxyphenol, 2,4-
dimethoxyphenol, and ubiquinol-0. In the case of 2-methoxy-
phenol and 2,6-dimethoxyphenol, the growth of the phenoxyl
radicals could not be monitored directly because of their low
extinction coefficients. Instead, the pseudo-first-order decay of
the cumyloxyl radical was measured.
(8) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Morris, J. J.; Taylor,
P. J. J. Chem. Soc., Perkin Trans. 2 1990, 521-29.
(9) Calculated from the equilibrium constants (Table 3) and the
concentration of the pure solvent. The equilibrium constants in Table 3 are
calculated with eq 5 and the solvent concentration as used in the
experiment: 100 vol % for 2-methoxy- and 2,6-dimethoxyphenol and
70 vol % in the case of 4-methoxyphenol, 2,4-dimethoxyphenol, and
ubiquinol-0; âH2 for di-tert-butyl peroxide is set at zero. If appropriate the
k4 is recalculated by using the equilibrium constants, the concentration of
the pure solvent, and eq 5.
(10) Snelgrove, D. W.; Banks, J. T.; Lusztyk, J.; Mulder, P.; Ingold, K.
U. Manuscript in preparation.
(11) Rate constants for hydrogen atom abstraction by tert-butoxyl radicals
from 4-methoxyphenol and 2-methoxyphenol of 1.6 × 109 and 1.7 × 108
M-1 s-1, respectively, in 1:2 benzene-di-tert-butyl peroxide, have been
reported.12
ROOR f 2RO•
(3)
(4)
(12) Das, P. K.; Encinas, M. V.; Steenken, S.; Scaiano, J. C. J. Am.
Chem. Soc. 1981, 103, 4162-6.
RO• + ArOH f ROH + ArO•
(13) Relative rate constants reported by Bors et al.14 for hydrogen atom
abstraction by alkoxyl radicals from 2-MeO-, 4-MeO-, and 2,6-(MeO)2-
PhOH in aqueous solution (1:2.5:7.5) and for 2-MeO- and (2,6-MeO)2-
PhOH (1:1.3) in n-hexane deviate from the relative rate constants for these
compounds calculated from the absolute rate constants measured in our
study; with CCl4 as the solvent the ratio for 2-MeO-, 4-MeO-, and 2,6-
(MeO)2-PhOH equals 1:31:2.6.
The effects of six solvents with different HBA properties on
the kinetics of reaction 4 are summarized in Table 1.
For 4-methoxyphenol, the only phenol examined with no
possibility of forming an intramolecular hydrogen bond, a large
solvent effect is observed. The rate constant decreases by a factor
of ca. 30 on changing from the poor hydrogen bond-accepting
solvent, tetrachloromethane, to the strong hydrogen bond-
accepting solvent, ethyl acetate. The rate constant in tetrachlo-
(14) Bors, W.; Michel, C.; Saran, M. Biochim. Biophys. Acta 1984, 796,
312-9.
(15) The conformation of the two methoxy groups in Q0H2 is different,
the one ortho to OHb is twisted further out of the phenyl plane, which gives
rise to a longer hydrogen bond length and thus a weaker hydrogen bond.
The higher overall BDE(O-H) of OHb is caused by the effect of the position
of methyl substituent.
(7) The reactivity of both alkoxyl radicals for hydrogen atom abstraction
is essentially the same.4

H-Bonded Ubiquinol-0 and Other (Poly)methoxy Phenols
J. Am. Chem. Soc., Vol. 122, No. 10, 2000 2357
Table 1. Rate Constants, k4, for Hydrogen Atom Abstraction from (Poly)methoxy Phenols by Alkoxyl Radicals
k4 (10-7 M-1 s-1) for (poly)methoxy phenolsa
â2H
2-MeOc
2,6-(MeO)2c
2,4-(MeO)2
ubiquinol-0d
4-MeOd,e
b
d
solvent
pentane
tetrachloromethane
benzene
anisole
acetonitrile
0.00
0.05f
0.14
0.26
0.44
0.45
0.49
11
9.3
8.2
3.7
1.6
1.5
1.3
24
18
10
4.4
4.2
6.7
86
76 (72)
280
220 (200)
300
230 (210)
21 (16)
22 (17)
15 (10)
43 (31)
56 (42)
49 (36)
13 (9.1)
14 (10)
5.9 (4.0)
ethyl acetate
tert-butyl alcohol
a Error in k4 approximately (10%. b Values from ref 8. c LFP at 308 nm, with 0.13 M dicumyl peroxide. d LFP at 337 nm, with 30 vol %
di-tert-butyl peroxide. Values in parentheses are recalculated for the pure solvent.9 â2H for di-tert-butyl peroxide is set at 0. e Similar values are
obtained from competitive kinetic studies, ref 10. f For tetrachloromethane a âH2 of 0.05 is used, instead of 0.0 from ref 8, see ref 10.
Figure 1. B3LYP/6-31G(d,p)-calculated transition state structures for hydrogen abstraction by methoxyl radical from intramolecularly hydrogen-
bonded (top right) and non-hydrogen-bonded 2-methoxyphenol. The C2-C1-O-H torsion angle is 14.6° in the hydrogen-bonded transition state
and 25.1° in the non-hydrogen-bonded situation.
Table 2. B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p)-Calculated
Thermochemical Data for Hydrogen Abstraction from
2-Methoxyphenol by Methoxyl Radicala
transition state
∆Hq ∆Gq
hydrogen abstraction
ground state
∆4H298
∆4G298
298
298
hydrogen bonded
non-hydrogen bonded
-5.1
-7.6
+4.3
+2.5
-16.1
-20.5
-16.2
-20.7
a All values in kcal mol-1
.
the relevant geometrical parameters were close to those expected
for the transition structure). The O-H-O angle was always
around 170°.16
Figure 2. Ground state and transition state structures for the hydrogen
abstraction by methoxyl radical from hydrogen-bonded and non-
hydrogen-bonded 2-methoxyphenol, with relevant bond lengths in
angstroms.
The relative Gibbs free energy change, ∆∆Gq298, for the
hydrogen atom abstraction from the non-hydrogen-bonded
2-methoxyphenol is favored by 1.8 kcal mol-1 (Table 2), which
would cause the rate of hydrogen atom abstraction from the
non-hydrogen-bonded form to be 20 times as great as that from
the hydrogen-bonded form.18 For both transition states, a
negative activation enthalpy and a large negative activation
entropy are predicted. The differences in reaction enthalpy
of the O-H bond and the intramolecular hydrogen bond, and a
shorthening of the newly formed MeO-H bond.
Unfortunately, numerous attempts to calculate the analogous
transition state structure for hydrogen atom abstraction from
4-methoxyphenol by methoxyl radical were unsuccessful. Either
transition structures were obtained which, according to vibra-
tional analysis, corresponded to rotational barriers in 4-meth-
oxyphenol-methoxyl complexes, or the optimization cycles
displayed an irregular “oscillatory” behavior between states of
about 0.4 kcal mol-1 difference in electronic energy (though
(16) Tanaka et al.17 computed transition states for hydrogen atom
abstraction from several para-substituted phenols by hydroperoxyl and
methylperoxyl radicals at the HF/STO-3G level, finding O-H-O angles
of 180°, in contrast to our results for o- and p-methoxyphenol.
(17) Tanaka, K.; Sakai, S.; Tomiyama, S.; Nishiyama, T.; Yamada, F.
Bull. Chem. Soc. Jpn. 1991, 64, 2677-80.

2358 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
de Heer et al.
∆4H298 and reaction free energy change ∆4G298, -4.4 and -4.5
kcal mol-1, respectively, are the energies required to break the
intramolecular hydrogen bond. These are gas-phase values for
isolated molecules.
Discussion
Hydrogen Atom Abstraction from o-Methoxyphenols.
From the previously determined ∆Hintra-HB of -4.3 kcal mol-1
for various o-methoxyphenols,5 it can be calculated that in a
non-HBA solvent such as a saturated hydrocarbon at 298 K
less than 0.1% of the phenol exists in the non-hydrogen-bonded
form.5 A Hammett correlation for hydrogen atom abstraction
by alkoxyl radicals from several para-substituted phenols in CCl4
gave the following correlation: log k4 ) -0.37∑σ+ + 9.12
with r2 ) 0.89,19 the slope of this plot is solvent dependent. By
using the substituent constant for the o-methoxy group, the
expected rate constant for hydrogen atom abstraction from “free”
2-methoxyphenol is estimated to be 2.0 × 109 M-1 s-1 22
. When
Figure 3. Solvent effect on the kinetics of hydrogen abstraction from
(poly)methoxy phenols: (0) 4-methoxyphenol (dashed line), (2)
ubiquinol-0, (b) 2,4-dimethoxyphenol, ([) 2,6-dimethoxyphenol, and
(9) 2-methoxyphenol; (]) 2,6-dimethoxyphenol in tert-butyl alcohol
was not used in the linear fit.
hydrogen atom abstraction is only possible from this form, 0.1%
of “free” 2-methoxyphenol in solution would result in an
observed rate constant of 2.0 × 106 M-1 s-1. The much higher
experimental rate constant in CCl4 of 9.3 × 107 M-1 s-1 can
only be interpreted by a direct hydrogen atom abstraction from
the intramolecularly hydrogen-bonded form. The experimental
rate constant is also a factor of 20 lower than the derived value
for “free” 2-methoxyphenol, which corresponds to a difference
in Gibbs energy of activation of ∆∆Gq298 ) 1.8 kcal mol-1, in
perfect agreement with the DFT result. For the electron-rich
ubiquinol-0, the calculated value of k4 for the hypothetical “free”
para position the difference in rate constants is relatively small.
Substitution at the ortho or para position of 2-methoxyphenol
by methoxy groups causes a relatively larger acceleration of
the reaction rate. A Hammett plot of the rate constants obtained
in CCl4 for the o-methoxyphenols gave the following correla-
tion: log k4 ) -1.39∑σ+ + 7.15 with r2 ) 0.95,24 a much
larger slope F than in the case of the non-hydrogen bonded
phenols with F ) -0.37. Also, the slope is independent of the
solvent, which is a direct consequence of the identical solvent
effect shown by all investigated o-methoxyphenols (see below).
form (present at less than 0.1%) would be 10 × 109 M-1 s-1 22
,
only a factor 4 faster than the experimental value in CCl4 of
2.8 × 109 M-1 s-1. As a result, the contribution of hydrogen
atom abstraction from the non-hydrogen-bonded form, if present,
to the overall rate constant becomes even smaller when more
electron-donating substituents are attached to the aromatic ring.
Apparently the nonlinearity of the intramolecular hydrogen
bond leaves the phenolic hydrogen atom available for abstrac-
tion, in contrast with the situation for linear intermolecularly
hydrogen-bonded phenols.
Solvent Effect on Hydrogen Atom Abstraction from
(MeO)xPhOH. The solute basicity parameter, âH, is a measure
2
of the ability of a compound to accept hydrogen bonds.8 The
âH2 values are based on the equilibrium constant for hydrogen-
bond formation between a donor and an acceptor in dilute
solutions in CCl4, but are applicable also in the pure HBA
solvents because only 1:1 complexes between the phenol and
the solvent molecules are formed. It has been found that for
the abstraction of the hydroxylic hydrogen atom from phenol,
R-tocopherol, and tert-butyl hydroperoxide, plots of log k vs
âH2 are linear.10 The same kind of plots are shown for the
investigated methoxyphenols in Figure 3, where for 4-methoxy-
phenol, 2,4-dimethoxyphenol, and ubiquinol-0 the recalculated
values for the pure solvent are used. The slopes of the straight
lines are a measure of the kinetic solvent effect: a stronger
interaction between the phenol and the solvent leaves less “free”
phenol available for hydrogen atom abstraction, and hence the
measured reaction rate decreases. The fact that intramolecularly
hydrogen-bonded phenols still exhibit kinetic solvent effects
implies that an additional, i.e., intermolecular, hydrogen bond
can be formed between the intramolecularly hydrogen-bonded
molecule and the HBA solvent. Such an entity, in which the
hydrogen atom interacts with three different neighboring atoms,
has in several studies been shown to exist in crystal structures25
That phenolic hydrogen atoms involved in intramolecular
hydrogen bonds can, indeed, be abstracted is further borne out
by the high reactivity of 2,6-dimethoxyphenol toward alkoxyl
radicals (see Table 1) since there can be no non-hydrogen-
bonded form of this phenol.
The substituent effect on the hydrogen atom abstraction for
o-methoxyphenols is more pronounced relative to other (non-
hydrogen bonded) phenols. For the phenols substituted at the
(18) The DFT calculations on 2-methoxyphenol show that on formation
of the intramolecular hydrogen bond the positive (Mulliken) charge on this
hydrogen increases slightly, from 0.315 to 0.331, consequently the rate for
reaction with the electrophilic alkoxyl radical may decrease.
(19) A plot of log(k4/M-1 s-1) vs ∑σ+ with the rate constants (M-1 s-1
)
for phenol (8.6 × 108,4 σ+ ) 0), R-tocopherol (4.2 × 109,4 ∑σ+ ) -1.40),
4-MeO-PhOH (3.0 × 109 (this work), σ+ ) -0.78), 4-CF3-PhOH (7.1 ×
108,10 σ+ ) 0.61), 4-Me3C-PhOH (1.9 × 109,10 σ+ ) -0.26), 4-Cl-PhOH
(1.09 × 109,10 σ+ ) 0.11), and 3,5-Cl2-PhOH (8.8 × 108,10 ∑σ+ ) 0.80)
with CCl4 as the solvent gave the following correlation: log k4 ) -0.37∑σ+
+
+
+ 9.12 with r2 ) 0.89; σp values from ref 20, σm values from ref 21.
(20) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-95.
(21) March J. AdVanced Organic Chemistry: Reactions, Mechanisms,
and Structure; McGraw-Hill Inc.: New York, 1968; p 241
(22) Taking σo+ ) 0.66σp+, a correlation found in several experimental
studies,6, 23 the σo+ for an o-methoxy group would be -0.51, implying that
the rate constant for nonintramolecularly hydrogen-bonded 2-methoxyphenol
would be 2.0 × 109 M-1 s-1. For ubiquinol-0 the same procedure gives
∑σ+ ) -1.58 and k4 for “free” ubiquinol of 5.0 × 109 M-1 s-1. Assuming
that both OH groups are equivalent, the overall rate would be 10 × 109
(23) Jonsson, M.; Lind, J.; Eriksen, T. E.; Mere´nyi, G. J. Chem. Soc.,
Perkin Trans. 2 1993, 1567-8.
(24) A plot of log(k4/M-1 s-1) vs ∑σ+ with the rate constants in CCl4
from Table 1 and ∑σ+ for 2-MeO-PhOH (-0.51), 2,6-(MeO)2-PhOH
(-1.03), 2,4-(MeO)2-PhOH (-1.29,) and ubiquinol-0 (-1.58) gave the
correlation log k4 ) -1.39∑σ+ + 7.15 with r2 ) 0.95; σp+ and σo+ values
M-1 s-1
.
from ref 20, σm values from ref 21.
+

H-Bonded Ubiquinol-0 and Other (Poly)methoxy Phenols
J. Am. Chem. Soc., Vol. 122, No. 10, 2000 2359
Table 3. Equilibrium Constants for Intermolecular Hydrogen Bonding of Methoxy-Substituted Phenols with Various Solventsa
2-MeOb
2-MeOc
2,6-(MeO)2
2,4-(MeO)2
ubiquinol-0c
4-MeOc
c
c
tetrachloromethane
benzene
acetonitrile
ethyl acetate
tert-butyl alcohol
0.02
0.03
0.30
0.61
0.71
0.01
0.25
0.51
0.60
0.03
0.24
0.49
0.27
0.02
0.24
0.40
0.68
0.04
0.41
0.56
0.64
0.03
1.7
2.7
7.0
a Kinter-HB in M-1 (error approximately (15%), calculated with eq 5 with the solvent concentration as used in the LFP experiment: The neat
liquid when dicumyl peroxide was used or 70 vol % when di-tert-butyl peroxide was used. Kinter-HB values derived this way are apparent values
because solvent concentrations are used instead of activities. b Calculated with respect to the rate constant in pentane. c Calculated with respect to
the rate constants in CCl4.
and in solution.26 It seems reasonable to assume that the
abstraction of doubly hydrogen bonded phenolic hydrogen atoms
does not occur.
results in an enthalpy for this hydrogen bond of -2.9 kcal
mol-1 32
As expected, ∆Hinter-HB for the additional hydrogen
.
bond is lower than the value for 4-methoxyphenol and ethyl
acetate of -4.5 kcal mol-1 as measured by photoacoustic
calorimetry.5,33 For the other solvents, ∆Hinter-HB for hydrogen-
bond formation with the o-methoxyphenols becomes ca. 1.0 kcal
mol-1 for benzene (K′inter-HB ca. 0.03 M-1), -2.5 kcal mol-1
for acetonitrile (K′inter-HB ca. 0.3 M-1), and -3.0 kcal mol-1
for tert-butyl alcohol (K′inter-HB ca. 0.7 M-1).
Ubiquinol and r-Tocopherol. Ubiquinol-0 has been shown
to possess the same hydrogen-bonding properties as the other
o-methoxyphenols studied. Exactly the same behavior is ex-
pected for ubiquinol-10, the natural antioxidant present in human
LDL. The two phenolic groups will be hydrogen bonded to their
adjacent methoxy groups, thus preventing the formation of
strong hydrogen bonds with solvent molecules or polar solutes.
In this way, part of the phenolic hydrogen atoms remain
available for hydrogen atom abstraction even in a strong HBA
environment. This is important in the LDL particle where
ubiquinol together with R-tocopherol perform their antioxidant
function. The LDL particle is not homogeneous and consists
of a core of neutral lipids and a coat of polar lipids,1 capable of
accepting hydrogen bonds.
The rate constant for hydrogen atom abstraction from
R-tocopherol by tert-butoxyl radical in tetrachloromethane is
4.2 × 109 M-1 s-1,4 close to our value for ubiquinol-0 of 2.8
× 109 M-1 s-1 in the same solvent. This is in agreement with
the small difference in BDE(O-H) for both compounds,
77.3 kcal mol-1 for R-tocopherol6 and 78.5 kcal mol-1 for
ubiquinol-05 (the latter value includes the enthalpy involved in
breaking the intramolecular hydrogen bond). In HBA solvents,
however, R-tocopherol is not protected against strong solvent
interactions and in ethyl acetate k4 decreases to 2.9 × 108 M-1
s-1,4 a factor of 2 lower than the 5.6 × 108 M-1 s-1 found for
ubiquinol-0 (Table 1).
The same differences in kinetic solvent effects have been
found in antioxidant studies: In a non-HBA environment,
ubiquinol-10 is about 10 times less reactive than R-tocopherol
toward peroxyl radicals.34 In aqueous lipid dispersions, however,
both compounds show equal antioxidant activity.35 In the polar
environment the rate of hydrogen atom abstraction from
The slopes of the log(k4/M-1s-1) vs âH2 lines in Figure 3 for
the three o-methoxyphenols and ubiquinol-0 are equal and,
hence, the fraction of available phenolic compound for hydrogen
atom abstraction is the same (kinetic solvent effect).27 The slope
of ca. -2.0 is significantly smaller than the slope for 4-meth-
oxyphenol (-4.2) and phenol (-5.2),28 which is reasonable since
a hydroxyl group already firmly involved in an intramolecular
hydrogen bond can be only a poor hydrogen bond donor to a
HBA solvent.
Equilibrium Constants for Intermolecular Hydrogen
Bonding. From the rate constants measured in different solvents,
the equilibrium constants for intermolecular hydrogen bonding
with the solvent can be calculated with the aid of eq 5.2,3,29 For
2-methoxyphenol K′inter-HB (see Scheme 1) was calculated with
respect to the rate constant measured in pentane, a non-HBA
solvent. For the other phenols measurements in pentane were
not possible due to low solubility, instead the equilibrium
constants were calculated with respect to the rate constant
measured in the poor HBA solvent CCl4, for comparison the
K′inter-HB values for 2-methoxyphenol were also calculated this
way (Table 3). For the ortho-substituted phenols this is the
equilibrium constant for the formation of the additional hydrogen
bond of the intramolecularly hydrogen-bonded molecule with
the solvent.30
S
S
kC4 Cl ) k4(1 + Kinter-HB[S])
(5)
4
The K′inter-HB values in one solvent are very similar for all
o-methoxyphenols, see Table 3, and will be close to the K′inter-HB
for 2-methoxyphenol calculated with respect to pentane. The
equilibrium constant of around 0.6 M-1 for the intermolecular
hydrogen bonding of o-methoxyphenols with ethyl acetate
(25) (a) Jerslev, B.; Larsen, S. Acta Chem. Scand. 1991, 45, 285-91.
(b) Stomberg, R.; Hauteville, M.; Lundquist, K. Acta Chem. Scand. 1988,
B42, 697-707. (c) Velavan, R.; Sureshkumar, P.; Sivakumar, K.; Natarajan,
S. Acta Crystallogr. 1995, C51, 1131-3.
(26) Bureiko, S. F.; Golubev, N. S.; Pihlaja, K. J. Mol. Struct. 1999,
480-481, 297-301.
(27) The observed rate constant for 2,6-dimethoxyphenol in tert-butyl
alcohol is higher than could be expected from the hydrogen bond accepting
properties of the solvent. This may be caused by steric hindrance to the
formation of the intermolecular hydrogen bond.
(31) Jawed, I. Bull. Chem. Soc. Jpn. 1977, 50, 2602-5.
(32) Using ∆Sinter-HB ) 10.7 cal mol-1 K-1 derived for hydrogen bonding
of 2-methoxyphenol with ethyl acetate.5
(28) Data from refs 3 and 4.
(33) Intermolecularly hydrogen bonded complexes of the two forms of
2-methoxyphenol with formaldehyde (as model for ethyl acetate) were also
calculated by DFT, resulting in ∆Hinter-HB of -4.1 kcal mol-1 for the
intramolecularly hydrogen bonded form and -5.9 kcal mol-1 for the non-
hydrogen bonded form. The difference of 1.8 kcal mol-1 is comparable to
the difference of 1.6 kcal mol-1 for the experimental intermolecular
hydrogen bond enthalpies of 2-methoxyphenol and 4-methoxyphenol with
ethyl acetate.
(34) Barclay, L. R. C.; Vinqvist, M. R.; Mukai, K.; Itoh, S.; Morimoto,
H. J. Org. Chem. 1993, 58, 7416-20.
(35) Ingold, K. U.; Bowry, V. W.; Stocker, R.; Walling, C. Proc. Natl.
Acad. Sci. U.S.A. 1993, 90, 45-9.
(29) Banks, J. T.; Ingold, K. U.; Lusztyk, J. J. Am. Chem. Soc. 1996,
118, 8, 6790-1. Correction: Banks, J. T.; Ingold, K. U.; Lusztyk, J. J.
Am. Chem. Soc. 1996, 118, 12485.
(30) The equilibrium constant derived for 4-methoxyphenol and aceto-
nitrile of 1.7 M-1 is low compared to 3.7 M-1 measured by infrared
spectroscopy.31 This appears to be a general phenomenon: equilibrium
constants derived by kinetic methods have been found to be lower than
those obtained by the IR method.29 Also, from our photoacoustic calorimetric
value for ∆Hinter-HB for 4-methoxyphenol and ethyl acetate of 4.5 kcal
mol-1,5 the equilibrium constant would be 9 M-1, again significantly higher
than the 2.7 M-1 from the kinetic results.

2360 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
de Heer et al.
the applied laser wavelength. The LFP experiments (4 to 8 laser shots)
were performed in 7 mm quartz cuvettes, and solutions were thoroughly
deoxygenated by purging with nitrogen for 5 min prior to photolysis.
Second-order rate constants were calculated by least-squares fitting of
the experimental pseudo-first-order rate constants vs the phenol
concentration, using at least five different concentrations.
4-Methoxyphenol, 2,4-dimethoxyphenol, and ubiquinol-0 kinetics
were measured with di-tert-butyl peroxide, since these phenols have a
strong absorption at 308 nm. The growth of the phenoxyl radical was
monitored directly at 410 (4-methoxyphenol), 408 (2,4-dimethoxyphe-
nol), or 430 nm (ubiquinol-0).
The kinetics for 2-methoxyphenol and 2,6-dimethoxyphenol were
measured using dicumyl peroxide and monitoring the decay of the
cumyloxyl radical at 485 nm.37 For these compounds, the phenoxyl
radicals could not be monitored directly due to their very low extinction
coefficients.
Materials. 2-Methoxyphenol was twice distilled under vacuum,
4-methoxyphenol and 2,6-dimethoxyphenol were sublimed twice,
dicumyl peroxide was recrystallized from methanol, and di-tert-butyl
peroxide was passed over alumina prior to use.
2,4-Dimethoxyphenol and 2,4,6-trimethoxyphenol were synthesized
following a literature procedure38 from the corresponding benzalde-
hydes, and were further purified by sublimation. Ubiquinol-0 was
obtained by reduction of ubiquinone-0 with Na2S2O4.
Solvents were of the highest purity available and were used without
further purification, except for anisole which was purified by extraction
with 2 M NaOH followed by washing with water to remove phenolic
impurities and distillation from chips of sodium metal. When tert-butyl
alcohol was used with dicumyl peroxide, 5% benzene was added to
the solvent.
Computational Procedures. Density functional theory (DFT)
calculations were performed with the Gaussian 94 suite of programs39
on an IBM RS/6000 computer. Geometries of ground and transition
states were fully optimized to stationary points on the (U)B3LYP level
using the 6-31G(d,p) basis set. Frequency calculations were performed
on the same level of theory. Zero-point vibrational energies (ZPVE)
were scaled by a factor of 0.9805.40
R-tocopherol has decreased more, caused by the stronger
hydrogen-bonding interactions, than for ubiquinol-10, which is
protected against these strong interactions.
Conclusions
A phenolic hydrogen can form a linear intermolecular
hydrogen bond with a particular solvent. Hydrogen atom
abstraction from this complex by free radicals does not take
place. Upon increasing the hydrogen-bonding capability of the
solvent, the amount of available phenol diminishes (kinetic
solvent effect). With a hydrogen bond accepting substitutent,
such as methoxy, at the ortho position, the phenolic hydrogen
is almost exclusively involved in nonlinear intramolecular
hydrogen bonding. Hydrogen atom abstraction from this entity
remains feasible. The rate constant is lower relative to the
(hypothetical) non-hydrogen bonded phenol, since the transition
state now pertains to the rupture of a covalent O-H bond and
a hydrogen bond in a synchronized fashion. A smaller kinetic
solvent effect is present for intramolecularly hydrogen-bonded
phenols. Thus, the relative effectiveness in LDL particles of
the antioxidants R-tocopherol and ubiquinol (an intramolecularly
hydrogen-bonded phenol) will depend on the hydrogen-bonding
capability of the microenvironment.
Experimental Section
The laser flash photolysis (LFP) equipment has been described
previously.36 Alkoxyl radicals were generated by photolysis of solutions
containing 30 vol % di-tert-butyl peroxide at 337 nm or 0.13 M dicumyl
peroxide at 308 nm. The optical densities of the solutions were 0.3 at
(36) (a) Scaiano, J. C.; Tanner, M.; Weir, D. J. Am. Chem. Soc. 1985,
107, 4396-4403. (b) Scaiano, J. C. J. Am. Chem. Soc. 1980, 102, 7747-
53.
(37) Avila, D. V.; Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 1992,
114, 4, 6576-7.
(38) Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49,
4740-1.
(39) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, W. P. M.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G.
A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.;
Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, ReVision E.3; Gaussian,
Inc.: Pittsburgh, PA, 1995.
Acknowledgment. We thank the Hochschulrechenzentrum
Essen for generous allotment of computer resources. We also
thank the National Foundation for Cancer Research for financial
support. One of us (M.I.deH.) thanks The Netherlands Orga-
nization for Scientific Research (NWO) for the travel grant and
D.W. Snelgrove for technical assistance and useful discussions.
We thank Prof. Dr. J. Cornelisse for carefully reading the
manuscript.
(40) (a) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-
16513. (b) Korth, H.-G.; Sicking, W. J. Chem. Soc., Perkin Trans. 2 1997,
715-19.
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