Abnormal solvent effects on hydrogen atom abstractions. 1. The reactions of phenols with 2,2-diphenyl-1-picrylhydrazyl (dpph?) in alcohols

Article abstract of DOI:10.1021/jo026917t

Rate constants, k_ArOH/dpph?,^s, for hydrogen atom abstraction from 13 hindered and nonhindered phenols by the diphenylpicrylhydrazyl radical, dpph?, have been determined in n-heptane and a number of alcoholic and nonalcoholic, hydrogen-bond accepting solvents. Abnormally enhanced values of k_ArOH/dpph?,^s have been observed in alcohols. It is proposed that this is due to partial ionization of the phenols and a very fast electron transfer from phenoxide anion to dpph?. The popular assessment of the antioxidant activities of phenols with dpph? in alcohol solvents will generally lead to an overestimation of their activities.

Full text of DOI:10.1021/jo026917t

Abn or m a l Solven t Effects on Hyd r ogen Atom Abstr a ction s. 1. Th e
Rea ction s of P h en ols w ith 2,2-Dip h en yl-1-p icr ylh yd r a zyl (d p p h •) in
Alcoh ols
Grzegorz Litwinienko*,1 and K. U. Ingold
National Research Council, 100 Sussex Drive, Ottawa, Ontario, Canada, K1A 0R6
grzegorz.litwinienko@nrc.ca
Received December 28, 2002
Rate constants, ksArOH/dpph•, for hydrogen atom abstraction from 13 hindered and nonhindered
phenols by the diphenylpicrylhydrazyl radical, d p p h •, have been determined in n-heptane and a
number of alcoholic and nonalcoholic, hydrogen-bond accepting solvents. Abnormally enhanced
values of ksArOH/dpph have been observed in alcohols. It is proposed that this is due to partial
•
ionization of the phenols and a very fast electron transfer from phenoxide anion to d p p h •. The
popular assessment of the antioxidant activities of phenols with d p p h • in alcohol solvents will
generally lead to an overestimation of their activities.
In tr od u ction
in 1982.5 Systematic studies on the kinetic solvent effects
(KSEs) of d p p h •/phenol reactions began in 1995.6 The
results of these6 and other studies on the solvent effects
on the kinetics of reactions between various radicals, Y•,
and phenols, ArOH, and other substrates capable,7-15 or
not capable16-19 of acting as hydrogen bond donors
(HBDs) have confirmed that the large KSEs observed for
H-atom abstractions from phenols are mainly, or possibly
solely, a consequence of hydrogen bonding to the solvent,
S, when S is a hydrogen bond acceptor (HBA). Intermo-
lecularly hydrogen-bonded ArOH is essentially unreac-
tive to all Y• (due to steric protection of the OH group by
S), with only the “free”, non-hydrogen-bonded ArOH
being reactive6-14 (see Scheme 1, for Y• ) d p p h •). The
In 1958, Blois2 suggested that the decolorization of the
2,2-diphenyl-1-picrylhydrazyl radical, d p p h •,
in ethanol solutions would provide a convenient method
for measuring the total concentration of antioxidants in
biological materials. Because of its speed and simplicity
this method for assaying the total antioxidant content
in foods and plant products has become extremely
popular.3 By and large, these bio-antioxidants are phenols
and it is interesting to note that kinetic studies on d p p h •/
phenol reactions also began in the late 1950s.4 Initially,
rate measurements were carried out in benzene, toluene,
and CCl4, and were only extended to alcoholic solvents
(5) Rao, A. M.; Singh, U. C.; Rao, C. N. R. Biochim. Biophys. Acta
1982, 711, 134-137.
(6) Valgimigli, L.; Banks, J . T.; Ingold, K. U.; Lusztyk, J . J . Am.
Chem. Soc. 1995, 117, 9966-9971.
(7) Avila, D. V.; Ingold, K. U.; Lusztyk, J .; Green, W. H.; Procopio,
D. R. J . Am. Chem. Soc. 1995, 117, 2929-2930.
(8) MacFaul, P. A.; Ingold, K. U.; Lusztyk, J . J . Org. Chem. 1996,
61, 1316-1321.
(9) Valgimigli, L.; Banks, J . T.; Lusztyk, J .; Ingold, K. U. J . Org.
Chem. 1999, 64, 3381-3383.
(10) Franchi, P.; Lucarini, M.; Pedulli, G. F.; Valgimigli, L.; Lunelli,
B. J . Am. Chem. Soc. 1999, 121, 507-514.
(1) Permanent address: Warsaw University, Department of Chem-
istry, Pasteur 1, 02-093 Warsaw, Poland.
(11) Barclay, L. R. C.; Edwards, C. E.; Vinqvist, M. R. J . Am. Chem.
Soc. 1999, 121, 6226-6231.
(2) Blois, M. S. Nature 1958, 181, 1199-1200.
(12) Foti, M.; Ruberto, G. J . Agric. Food Chem. 2001, 49, 342-348.
(13) Snelgrove, D. W.; Lusztyk, J .; Banks, J . T.; Mulder, P.; Ingold,
K. U. J . Am. Chem. Soc. 2001, 123, 469-477.
(14) Astolfi, P.; Greci, L.; Paul, T.; Ingold, K. U. J . Chem. Soc., Perkin
Trans. 2 2001, 1631-1633.
(3) For the period 1999 to 2001-end, Chemical Abstracts (SciFinder)
lists 468 papers with the word pair diphenylpicrylhydrazyl and
antioxidants.
(4) (a) Bickel, A. F.; Kooyman, E. C. J . Chem. Soc. 1957, 2415-
2416. (b) McGowan, J . C.; Powell, T.; Raw, R. J . Chem. Soc. 1959,
3103-3110. (c) Godsay, M. P.; Lohmann, D. H.; Russell, K. E. Chem.
Ind. (London) 1959, 1603-1604. (d) For a comprehensive listing of rate
constants for the reactions of d p p h • with phenols to 1982, see: Ingold,
K. U. In Landolt-Bo¨rnstein, New Series, Group II, Radical Reaction
Rates in Liquids; Fischer, H., Ed.; Springer-Verlag: Berlin, Germany,
1983; Vol. 13, subvolume c. In the next decade no kinetic measurements
on these reactions were reported (!), see: Ingold, K. U.; Walton, J . C.
In Landolt-Bo¨rnstein, New Series, Group II, Radical Reaction Rates
in Liquids; Fischer, H., Ed.; Springer-Verlag: Berlin, Germany, 1994;
Vol. 18, subvolume c.
(15) Foti, M. C.; Barclay, L. R. C.; Ingold, K. U. J . Am. Chem. Soc.
2002, 124, 12881-12888.
(16) Avila, D. V.; Brown, C. E.; Ingold, K. U.; Lusztyk, J . J . Am.
Chem. Soc. 1993, 115, 466-470.
(17) Wayner, D. D. M.; Lusztyk, E.; Page´, D.; Ingold, K. U.; Mulder,
P.; Laarhoven, L. J . J .; Aldrich, H. S. J . Am. Chem. Soc. 1995, 117,
8737-8744.
(18) Valgimigli, L.; Ingold, K. U.; Lusztyk, J . J . Org. Chem. 1996,
61, 7947-7950.
(19) Lucarini, M.; Pedulli, G. F.; Valgimigli, L. J . Org. Chem. 1998,
63, 4497-4499.
10.1021/jo026917t CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/02/2003
J . Org. Chem. 2003, 68, 3433-3438
3433

Litwinienko and Ingold
SCHEME 1
was also found for H-abstraction from R-tocopherol by
peroxyl radicals9 but not for H-abstraction from the same
•
substrate by the neophyl radical,10 PhCMe2CH2 . Some
proposed explanations for the d p p h •/ArOH anomalous
KSEs in tert-butyl alcohol have been ruled out experi-
mentally.18
Kinetic studies of H-atom abstractions by tert-alkoxyl
radicals in alcoholic solvents have been confined to tert-
butyl alcohol (despite its mp of 25 °C and high viscosity)
because most other alcohols are themselves highly reac-
tive H-atom donors to alkoxyl radicals. This restriction
(based on thermodynamic considerations) does not apply
to H-abstractions from phenols by the d p p h • radical:
concentration of free ArOH depends on the total [ArOH]
and on the equilibrium constant, KsArOH/S. The experi-
mentally observed rate constant in solvent, S, kAs rOH/Y
,
•
is given by,
ArOH + d p p h • f ArO• + d p p h -H
(1)
koArOH/Y
1 + KsArOH/S[S]
•
ksArOH/Y
)
(I)
and during a study designed to explore the applicability
of eq II to sterically hindered phenols some highly
anomalous KSEs were encountered in alcoholic solvents.
•
where koArOH/Y• is the rate constant for reaction of Y• with
non-hydrogen-bonded ArOH, i.e., KoArOH/Y is the experi-
Resu lts a n d Discu ssion
•
mental rate constant in a non-HBA solvent (such as an
alkane) at concentrations of ArOH sufficiently low that
there is no ArOH self-association via H-bonding.
The enthalpy of the ArOH- - -S hydrogen bond (and
hence the magnitude of KsArOH/S and ksArOH/Y•) depends on
the HBD ability of ArOH and the HBA ability of S. The
former is most conveniently quantified (on a relative scale
ranging from 0.00 to ca. 1.0) by Abraham et al.’s R2H
values20 and the latter is most conveniently quantified
(again on a relative scale from 0.00 to 1.00) by Abraham
et al.’s âH2 values.21 Kinetic solvent effects on H-atom
abstractions by highly reactive and relatively unreactive
Y• from substrates having a wide range of RH2 values and
solvents having a wide range of âH2 values can be
accurately described (and predicted) by a simple equa-
tion, viz.,13
Steric protection of the OH group in 2,6-di-tert-bu-
tylphenols does not prevent the formation of a hydrogen
bond with suitable HBAs.23 As would be expected, rate
constants for the reactions at room temperature of d p p h •
with five 2,6-di-tert-butylphenols generally declined mono-
tonically as the HBA abilities of the following solvents
increased: heptane < di-n-butyl ether < acetonitrile <
tetrahydrofuran (THF) < dimethyl sulfoxide (DMSO),
see Table 1, which includes the âH2 values for the
solvents. Indeed, plots of log ksArOH/dpph• vs âH for at least
2
some of these 2,6-But -phenols are quite reasonable (see
2
Figure 1a,b). For 2,6-But -4-Me-phenol these kinetic data
2
yield (via eq II) âH2 ) 0.29. Of course, steric hindrance of
hydrogen bond formation by 2,6-But -phenols will depend
2
on the size and shape of the HBA molecule.24 Thus, the
hindered phenols are not expected to have RH2 values
which are universally applicable (as is the case for
unhindered phenols). We were, therefore, pleasantly
surprised by the (admittedly very rough) correlation of
log ksArOH/dpph for 2,6-But -phenol and 2,6-But -4-Me-
log ksArOH/Y• ) log ko
• - 8.3RHâH
(II)
ArOH/Y
2
2
It should be noted that eq II implies that the relative
magnitude of a KSE depends on the âH2 value of S but
does not depend on the reactivity of Y•. This has been
amply confirmed6,9-11,13,19 and eq II has been found to be
remarkably general. However, even in early work,6 an
alcoholic solvent, tert-butyl alcohol, was found to give
anomalous results for H-atom abstraction from phenol
and R-tocopherol by d p p h • but normal (i.e., “expected”;
eq II) results for H-abstraction from these two substrates
by tert-alkoxyl radicals. That is, the H-abstraction rate
constants with the tert-alkoxyl radicals were depressed
(relative to koArOH/RO•) by the amount expected from the
âH2 value of tert-butyl alcohol (0.49)21 and the depression
observed for a dozen or so other HBA solvents with
known â2H values.6-8,13 However, with d p p h • the rate
constants for H-abstraction from both phenol and R-
tocopherol were five times greater than expected in tert-
butyl alcohol.6 A similar rate enhancement (actually, a
less than expected rate reduction) in tert-butyl alcohol
•
2
2
phenol with âH2 for these five solvents (Figure 1, parts a
and b, respectively). To explore this matter further, we
have measured the equilibrium constants for hydrogen
bond formation between 2,6-But -4-Me-phenol and four
2
HBAs (acetonitrile, THF, DMSO, and pyridine) by IR
spectroscopy.25 These four HBAs have been “calibrated”
by Abraham et al.20 and the measured equilibrium
constants therefore can be converted to the RH2 values
which are given in Table 2. This table also contains an
(22) Ionisation constants of organic acids in aqueous solution;
Serjeant, E. P., Dempsey, B., Eds.; IUPAC Chemical Data Series, No.
23; Pergamon Press: Oxford, UK, 1979.
(23) (a) Bellamy, L. J .; Williams, R. L. Proc. R. Soc. (London) A 1960,
254, 119-128. (b) Ingold, K. U.; Taylor, D. R. Can. J . Chem., 1960,
39, 481-487. (c) Litwinienko, G.; Megiel, E.; Wojnicz, M. Org. Lett.
2002, 14, 2425-2428.
(24) In the case of strongly hindered phenols, the shape and size of
the HBA molecule is a very important factor for H-bond formation.
For example, the OH fundamental stretching frequency of 2,6-But
-
2
4-Me-phenol in heptane occurs at 3655 cm-1. A broad, lower frequency
band due to an intermolecular hydrogen bond has been observed for
this phenol in only a few neat solvents for which the HBA atom is
relatively “exposed”, e.g. dioxane (3431 cm-1) and THF (3400 cm-1).
An intermolecular H-bond is not formed in diethyl ether nor in di-n-
butyl ether (ref 23a).
(20) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Duce, P. P.; Morris,
J . J .; Taylor, P. J . J . Chem. Soc., Perkin Trans. 2 1989, 699-711.
(21) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Morris, J . J .;
Taylor, P. J . J . Chem. Soc., Perkin Trans. 2 1990, 521-529.
3434 J . Org. Chem., Vol. 68, No. 9, 2003

Abnormal Solvent Effects on Hydrogen Atom Abstractions
TABLE 1. Bim olecu la r Ra te Con sta n ts (M-1 s-1) for H-a tom Abstr a ction fr om Th ir teen P h en ols by d p p h • Ra d ica ls in
F ive Non a lcoh olic Solven ts a t Am bien t Tem p er a tu r es
phenol
heptane
(0.00)c
n-butyl ether
acetonitrile
(0.44)c
THF
DMSO
(0.78)c
substituentsa (â2H)
pKa
(0.42)c
(0.51)c
b
2,6-But2-4-MeO
2,6-But2-4-Me
12.15
12.23
12.19
11.70
8.70
22.6
1.1
1.0
0.13
0.022
40
4.9
4.5
0.013
240
2.8
6.7
1.5
0.090
0.15
0.013
0.050
0.56
0.086
0.22
0.011
5.0
0.064
0.034
0.019
0.53
0.74
0.27
0.33
0.052
0.025
3.8
0.61
0.41
0.013
4.9
0.033
0.028
0.010
0.23
0.016
0.021
0.025
0.030
0.031
0.039
0.014
0.0021
0.048d
0.023
0.014
0.0076
2,4,6-But
3
2,6-But
2
2,6-But2-4-CN
2,4,6-Me3 (0.37)
2,6-Me2-4-Cl
2,6-Me2
10.9
0.24
0.023
0.031
0.023
0.40
0.0053
0.0047
0.0006
10.60
2,6-Me2-4-CN
4-MeO (0.57)
4-Me (0.57)
4-But (0.56)
none (0.60)
10.24
10.3
10.3
10.0
0.038
0.045
0.004
2.3
0.19e
Reliable values of RH2 are given in parentheses. All values are from ref 20 apart from 2,4,6-Me3 (taken from ref 13). Phenol pKa
a
b
H
values are from ref 22. c â2 values are from ref 21. This value was taken from ref 13, our measurements gave rate constants five times
greater (see Supporting Information, Table S5). e Literature rate constants for phenol + d p p h • in n-octane are 0.19 M-1 s-1 (ref 6) and
0.22 M-1 s-1 in n-heptane (ref 13).
d
F IGURE 1. Logarithms of the rate constants for hydrogen atom abstraction from phenols by the d p p h • radical: (a) 2,6-But -
2
phenol, (b) 2,6-But -4-Me-phenol, (c) 2,4,6-Me3-phenol, and (d) 4-MeO-phenol. Nonalcoholic solvents are given as filled circles:
2
n-heptane (1), di-n-butyl ether (2), acetonitrile (3), THF (4), and DMSO (5). Open circles denote alcoholic solvents: 2,2,2-
trifluoroethanol (6), methanol, (7) and ethanol (8). Acidified (10 mM acetic acid) alcohols are shown as asterisks: methanol (left)
and ethanol (right). Straight lines were constructed by using data for the five nonalcoholic solvents only. (2,2,2-Trifluoroethanol
has a much lower nucleophilicity and âH2 value than other alcohols. It was used as a solvent only with the four phenols shown in
this figure.)
RH2 value estimated for 2,6-But -4-Me-phenol from an
Although the KSEs for the reaction of d p p h • with four
2
of the 2,6-But -phenols are reasonably well behaved in
NMR determination of its equilibrium constant with
acetone.26 For this phenol, the RH2 values calculated
from IR and NMR data range from 0.18 to 0.25, in fair
agreement with the KSE-derived value of 0.29.
2
heptane, butyl ether, acetonitrile, THF, and DMSO, this
is obviously not the case for 2,6-But -4-CN-phenol nor is
2
it the case for any of these hindered phenols in alcohol
J . Org. Chem, Vol. 68, No. 9, 2003 3435

Litwinienko and Ingold
TABLE 2. Equ ilibr iu m Con sta n ts (KsAr OH/S/M-1) for
Hyd r ogen Bon d F or m a tion betw een 2,6-Bu t2-4-Me-p h en ol
a n d F ou r Solven ts Mea su r ed by IR a n d On e Solven t
Mea su r ed by 1H NMR a n d th e Cor r esp on d in g Ca lcu la ted
methanol. These results suggested that traces of basic
materials were carried over with the distillate. That this
was probably the case was indicated by the deliberate
addition of base to the methanol. For example, the
addition of a methanolic solution of sodium methoxide
to unpurified methanol so as to obtain a final [NaOMe]
) 1.7 × 10-4 M gave ArOH/d p p h • rate constants which
were much greater than those in the unpurified metha-
Va lu es of rH2
a
solvent
method
KsArOH/S
R2H
acetonitrile
THF
DMSO
pyridine
acetone
IR
IR
IR
IR
0.45
0.37
2.17
0.98
0.35b
0.24
0.18
0.25
0.23
0.18
nol: viz., phenol, 0.21 vs 0.038 M-1 s-1; 2,6-But -4-Me-
2
phenol, 63 vs 3.7 M-1 s-1; and 2,4,6-Me3-phenol, 780 vs
43 M-1 s-1. Thus, the anomalous ArOH/d p p h • KSEs in
alcoholic solvents would appear to be due to the presence
of traces of phenoxide anions, ArO-. The phenoxide anion
would be expected to react very rapidly in these solvents
with the highly electron-deficient d p p h • radical.
NMR
a
See Supporting Information, Tables S13-S14 and Figures S1-
b
S4, for details. Equilibrium constant taken from ref 26.
solvents, see Table 3. In particular, the rate constants
for 2,6-But -4-Me-phenol, 2,6-But -phenol, and 2,6-But -
2
2
2
4-CN-phenol were larger in methanol (âH2 ) 0.41) than
H+
ArO- + d p p h • f ArO• + d p p h -
(
8 d p p h -H) (2)
in heptane by factors of 3.4, 28, and an astonishing 940,
respectively. Rate constants for the five 2,6-But -phenols
2
This conclusion is consistent with four observations
reported above. First, the alcohol anomaly is greatest for
methanol, the alcohol that best supports ionization.
Second, the methanol/alcohol anomalies are most obvious
were also measured in ethanol, 2-propanol, and tert-
pentanol (2-methylbutan-2-ol, which is a liquid at room
temperature unlike tert-butyl alcohol), see Table 3. In
these alcohols the rate constants for these hindered
phenols were lower than in heptane with the exception
of 2,6-But -phenol in ethanol and 2,6-But -4-CN-phenol
for the 2,6-But -phenols. This is because these phenols
2
have a much poorer ability to act as HBDs than most
phenols (cf. RH2 values given in Tables 1 and 2). For this
reason, the reduction in the rate constants due to
hydrogen bonding with an HBA solvent, e.g., an alcohol,
is relatively small, which allows the rate accelerating
effect due to ArO- formation to show up much more
clearly than is the case for less hindered and unhindered
phenols with their higher RH2 values. However, there is
still a very substantial KSE anomaly (rate enhancement
relative to rate constants expected from equation II) in
methanol for all these unhindered and relatively unhin-
2
2
in all the alcohols except tert-pentanol (Table 3). More-
over, for 2,6-But -4-CN-phenol the rate constants in the
2
four polar, non-hydroxylic solvents (di-n-butyl ether,
acetonitrile, THF, and DMSO) were also higher than
those in heptane (see Table 1).
A survey of four 2,6-Me2-phenols and four sterically
nonhindered phenols revealed slightly higher rate con-
stants in methanol than in heptane for some of the 2,6-
Me2-phenols but rate constants for these phenols were
lower than in heptane in all other alcohols, see Table 3.
For all the nonhindered phenols, rate constants in
methanol and in all other alcohol solvents were lower
than those in heptane. Nevertheless, for all 2,6-Me2-
phenols and all the unhindered phenols, almost all the
rate constants measured in alcohols were larger than
would be predicted by eq II (see Figure 1c,d and Sup-
porting Information).
As has been the case in all our earlier KSE
studies6-9,13-18 we employed the purest solvents com-
mercially available. The methanol anomaly forced us to
reassess this policy and the methanol was therefore
subjected to purification by fractional distillation (center
cut, reflux ratio 10:1). However, this purified methanol
gave essentially identical kinetic results to those obtained
when methanol was used “straight from the bottle”.
Further purification of the methanol was therefore
undertaken and the reason for the anomalous kinetic
results in alcoholic solvents became clear (eventually)
following the use of methanol distilled from calcium
hydride (to remove any last traces of water from the
purchased anhydrous methanol). To our surprise, ArOH/
d p p h • rate constants measured in this CaH2-distilled
solvent were much greater than those in the unpurified
dered phenols (vide infra), it is just not so obvious because
MeOH
ArOH/dpph
k
• is smaller than kheptane •. Third, the only 2,6-
ArOH/dpph
But -substituted phenol for which the rate constants in
2
methanol, ethanol, and 2-propanol are larger than in
heptane is the most acidic of the hindered phenols, and
hence the most prone to anion formation, viz., 2,6-But -
2
4-CN-phenol (see the pKa values given in Table 1).
Fourth, the alcohol anomaly was first observed for the
reactions of phenol and R-tocopherol with d p p h • in tert-
butyl alcohol.6 There was no tert-butyl alcohol anomaly
in the reactions of these two phenols with tert-alkoxyl
radicals,6 nor for H-atom abstraction from tocopherol by
the neophyl radical,10 but this anomaly occurred in the
peroxyl radical/tocopherol reaction.9 With hindsight, it
is clear that anomalously high rates of H-atom abstrac-
tion from phenols in tert-butyl alcohol were due to the
formation of traces of phenoxide anions which were
highly reactive toward radicals derived from parent
molecules having low pKa values (d p p h •/d p p h -H pKa )
8.527 and ROO•/ROOH pKa ) 12.828) but not toward
radicals derived from parent molecules having high pKa
•
values (RO•/ROH pKa ) 15.1-19.229 and PhCMe2CH2 /
PhCMe3 pKa ∼ 5030).
(27) Luca, C.; Ionita, P.; Constantinescu, T. Rev. Roum. Chim. 1994,
39, 1141-1151.
(28) Richardson, W. H. In The chemistry of peroxides; Patai S., Ed.;
Wiley: New York, 1983; Chapter 5, pp 129-160.
(29) The pKa values for RO•/ROH are 15.1 (MeOH), 15.9 (EtOH),
16.1 (n-propanol, n-butanol), 17.1 (2-propanol), and 19.2 (tert-butyl
alcohol, tert-pentanol), see ref 22.
(25) See refs 13-15 for experimental conditions used for IR mea-
surements of this type, the only difference being that we had to use
much higher concentrations of HBAs in CCl4 (up to 70% acetonitrile,
THF, DMSO, and pyridine). See Experimental Section and Supporting
Information for details.
(26) Wawer, I.; Ke¸cki Z. Ber. Bunsen-Ges. 1976, 80, 522-525.
3436 J . Org. Chem., Vol. 68, No. 9, 2003

Abnormal Solvent Effects on Hydrogen Atom Abstractions
TABLE 3. Bim olecu la r Ra te Con sta n ts (M-1 s-1) for H-Atom Abstr a ction fr om 13 P h en ols by d p p h • Ra d ica ls in
n -Hep ta n e, Meth a n ol, Eth a n ol, 2-P r op a n ol, ter t-P en ta n ol (2-Meth ylbu ta n -2-ol), a n d Acid ified Meth a n ol a t Am bien t
Tem p er a tu r es
MeOH/H+b
phenol
heptane
(0.00)a
MeOH
(0.41)a
EtOH
iso-PrOH
tert-C5OH
substituents (âH2 )
(0.44)a
(0.47)a
(0.49)a
10 mM
100 mM
2,6-But2-4-MeO
2,6-But2-4-Me
22.6
1.1
1.0
0.13
0.022
40
4.9
4.5
0.013
240
2.3
3.9
3.7
0.35
3.9
16
43
3.9
6.8
8.8
0.48
0.45
0.053
0.0038
1.6
0.17
0.31
0.0048
1.2
0.012
0.013
0.0066
1.8
0.13
0.11
0.056
0.12
0.52
0.076
0.32
0.0068
1.2
0.019
0.019
0.0046
1.9
0.12
0.12
c
0.86
0.13
0.88
13
8.4
0.092
3.5
0.0061
0.35
0.34
0.050
7.7
0.89
0.11
0.32
0.0073
3.1
2,4,6-But
3
2,6-But
0.044
0.017d
0.50
0.064
0.087
0.0032
0.99
0.017
0.015
0.0037
2
2,6-But2-4-CN
2,4,6-Me3
2,6-Me2-4-Cl
2,6-Me2
e
4.6
2,6-Me2-4-CN
4-MeO
0.014
18
0.74
0.59
0.038
14
4-But
0.57
0.54
0.010
0.19
0.17
0.017
4-Me
none
2.8
0.19
âH2 values were taken from ref 21. Methanol containing acetic acid (10 and 100 mM unless otherwise noted). c A reported ks for this
a
b
reaction in tert-butyl alcohol was 0.41 M-1 s-1 (ref 11). Concentration of acetic acid ) 1.7 M, the rate constants for this reaction at other
d
concentrations of acetic acid are listed in Table 4. e The results obtained for this phenol were irreproducible for reasons we did not explore.
One set of measurements gave a value 0.12 M-1 s-1 and another independent set of measurements gave 4.0 M-1 s-1 (both results are
presented in Table S6 in the Supporting Information).
F IGURE 2. Plots of the logarithm of the bimolecular rate constant for reaction of d p p h • with 2,6-But -4-Me-phenol (a) and
2
2,6-But -4-CN-phenol (b) at ambient temperature in methanol vs added acetic acid concentration. The inset in panel b shows the
2
dependence for the concentration range 0-10 mM.
TABLE 4. Bim olecu la r Ra te Con sta n ts (ksAr OH/d p p h •) a t
Final confirmation that the formation of traces of
Am bien t Tem p er a tu r es for th e Rea ction of
phenoxide anions in alcoholic solvents enhances the
2,6-Bu t2-4-Me-p h en ol a n d 2,6-Bu t2-4-CN-p h en ol w ith d p p h •
in Meth a n ol Con ta in in g Va r iou s Con cen tr a tion s (C) of
Acetic Acid
ROH
ArOH/dpph
apparent magnitude of k
was obtained by sim-
•
ply adding a small amount of acid to the unpurified
methanol.31 We found that 10 mM acetic acid was
sufficient to reduce the rate constant for reaction of
d p p h • with most, but not all, phenols to a limiting value
(meaning that the rate constant was not significantly
reduced further by the addiction of 100 mM acid), see
Table 3. For example, the effects of variable acetic acid
concentrations on ksArOH/dpph for the weak acid 2,6-But -
2,6-But2-4-Me-phenol
2,6-But2-4-CN-phenol
C/mM
ksArOH/dpph•/M-1 s-1
C/mM
ksArOH/dpph•/M-1 s-1
0.0
0.1
6.7
10.0
33.3
166
3.7
0.0
1.5
10.0
440
1710
16
8.4
0.12
0.040
0.017
0.62
0.13
0.12
0.11
0.12
•
2
4-Me-phenol (pKa ) 12.2) show that only a small con-
centration of acid (ca. 7 mM) is required to reduce the
rate constant to a limiting value (see Figure 2a), whereas
for the much more strongly acidic 2,6-But -4-CN-phenol
2
(pKa ) 8.7), the rate constant was only reduced to the
same value as in heptane even with acetic acid concen-
trations as high as 1.7 M (see Table 4 and Figure 2b).
The 10 and 100 mM acetic acid modulated rate constants
are given in the two right-hand columns of Table 3 and
the rate constants measured with 10 mM acetic acid
added to methanol and ethanol are shown as asterisks
(30) Smiths, M. B.; March, J . March’s Advanced Organic Chemistry,
5th ed.; Wiley: New York, 2001.
(31) Addition of mineral acids or formic or acetic acid at a concentra-
tion higher than 2 M causes a slow decolorization of d p p h •.32 However,
under our experimental conditions solutions of d p p h • in alcohols
containing less than 1 M acetic acid gave rate constants for d p p h •
decolorization which were 3 to 4 orders of magnitude smaller than the
rate constants for the d p p h • + phenol reactions. The acid-catalyzed
decomposition of d p p h • can therefore be neglected.
J . Org. Chem, Vol. 68, No. 9, 2003 3437

Litwinienko and Ingold
SCHEME 2
perfectly valid procedure since the stoichiometries of
reactions 1 and 2 will be the same.
Exp er im en ta l Section
In fr a r ed Mea su r em en ts of rH2 . Experiments were done
in CCl4 (distilled over P2O5) with dry THF, acetonitrile,
pyridine, and DMSO as HBAs and with a Midac M FTIR
spectrophotometer 120 series and CaF2 cell with path length
ca. 2.5 mm. The concentration of free 2,6-But -4-Me-phenol was
2
on the plots of log ksArOH/dpph vs â2H in Figure 1. Similar
determined by using a calibration curve (solutions of the
•
phenol in CCl4). Values of Ks
were obtained from the
slopes of straight lines of ([ArOAHrO]0H/[/SArOH]free) vs concentration
of noncomplexed HBA (see Figures S1-S4, Table S13, and
explanations to Table S14.) A more detailed description of
similar IR measurements of RH2 has been given in refs 13-15.
Mea su r em en ts of Ra te Con sta n ts for th e Rea ction of
P h en ols w ith d p p h •. The procedure used to determine ks was
common to all solvents and phenols. Solutions of d p p h • and
the phenol were prepared in nitrogen-purged solvents and
were kept under nitrogen, with additional nitrogen-purging
when necessary, until they were taken-up into the glass
syringes of the stopped-flow apparatus with their gastight
Teflon plungers. The decay of d p p h • in the presence of a
known concentration of phenols was followed at 517 nm on an
Applied Photophysics Stopped-Flow Spectrophotometer, SX 18
MV equipped with a 150 W xenon lamp. All measurements
were carried out at 23 ( 2 °C. The concentration of d p p h • was
(8.5 ( 1.0) × 10-5 M. Phenols were always used in large excess
over [d p p h •]. The concentrations of phenols are given in Tables
S1-S12, from which the [ArOH]0/[d p p h •]0 ratios can be
calculated. The decays of the d p p h • absorbancies were ana-
lyzed as pseudo-first-order processes to yield kex/s-1. Plots of
kex vs phenol concentration were linear and their slopes gave
the second-order rate constants, ks. Kinetic parameters and
mean values ks with estimated errors are collected in Tables
S1-S12.
large effects induced by the addition of acetic acid were
observed in n-propanol, e.g., ksArOH/dpph (M-1 s-1) for
•
n-propanol (n-propanol + H+) are 7.20 (0.77) for 2,4,6-
Me3-phenol, 13 (1.0) for 4-MeO-phenol, and 0.4 (0.2) for
2,6-But -4-Me-phenol, but the effects in tert-pentanol
2
were much smaller, e.g. 1.6 (1.1) for 2,4,6-Me3-phenol,
see Table S15, Supporting Information.
Con clu sion s
Abnormal kinetic solvent effects were first observed
during studies of H-atom abstraction from two phenols
by the d p p h • radical.6 In that work it was discovered that
the rate constants in tert-butyl alcohol were higher than
would be predicted from the H-bond accepting ability
(âH2 value) of this solvent. Enhanced rate constants have
now been shown to be a general feature of phenol/d p p h •
reactions not only in alcohols but also, for phenols with
low pKa values, in non-hydroxylic, polar solvents (cf. rate
constants for the 2,6-But -4-CN-phenol/d p p h • reaction in
2
di-n-butyl ether, acetonitrile, THF and DMSO, Table 1).
These rate enhancements are due to partial (even very
partial) ionization of the phenol (in those solvents which
can support ionization) and a very fast electron transfer
from the phenoxide anion to the d p p h • radical, see
Scheme 2. This “side” reaction that has such profound
kinetic consequences (in the absence of an acid) has no
precedent known to us in any solvent other than water.33
Ack n ow led gm en t. We thank Dr. Dave Carlsson for
the use his FTIR instrument and Shuqiong Lin for
synthesis of 2,6-But -4-CN-phenol. G.L. thanks The
2
Foundation for Polish Science (FNP) for receipt of a
Postdoctoral Fellowship.
It is clear that our results bring into question all
previous kinetic studies of H-atom abstractions from
phenols in alcoholic solvents.34 However, they also imply
that the use of d p p h • in ethanol to “titrate” for total
antioxidants in foods and plant extracts remains a
Su p p or tin g In for m a tion Ava ila ble: Detailed kinetic
data for reactions of the phenols with d p p h • in neat solvents
(Tables S1-10) and acidified methanol (Tables S11 and S12),
infrared data used for calculation of equilibrium constants for
2,6-But -4-Me-phenol H-bond formation with acetonitrile, THF,
2
pyridine, and DMSO (Table S13 and Figures S1-S4) and other
parameters from which RH2 values were calculated (Table
S14), comparison of rate constants for reactions of four phenols
with d p p h • in neutral and acidified n-propanol and ethanol
(Table S15), a typical plot of d p p h • decay after mixing with a
(32) Solomon, D. H.; Swift, J . D. J . Polym. Sci. A 1965, 3, 3107-
3116.
(33) Electron transfer from un-ionized phenols to electrophilic
radicals is occasionally proposed to be the rate-controlling step
(followed by rapid proton loss) as an alternative to direct H-atom
abstraction.
(34) A large fraction of the papers identified in ref 3 involved studies
on d p p h • + antioxidant reactions in alcoholic solvents (generally
methanol or ethanol).
methanolic solution of 2,6-But -4-CN-phenol (Figure S5). This
2
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026917T
3438 J . Org. Chem., Vol. 68, No. 9, 2003