Reactivity of phthalimide N-oxyl radical (PINO) toward the phenolic O-H bond. A kinetic study

Article abstract of DOI:10.1021/jo048656o

The reactivity of the phthalimide N-oxyl radical (PINO) toward the OH bond of a series of substituted phenols was kinetically investigated in CH ₃CN. The reaction selectivity and the deuterium kinetic isotope effect were determined. Information on the kinetic solvent effect was also obtained with phenol as the substrate.

Full text of DOI:10.1021/jo048656o

bonds, which leads to the formation of phenoxyl radicals
(reaction 1), as recently shown by the ESR study of
Reactivity of Phthalimide N-Oxyl Radical
(PINO) toward the Phenolic O-H Bond.
A Kinetic Study
Enrico Baciocchi,* Maria Francesca Gerini, and
Osvaldo Lanzalunga*
Dipartimento di Chimica, Universita` degli Studi di Roma
“La Sapienza” and Istituto CNR di Metodologie Chimiche
(IMC-CNR), Sezione Meccanismi di Reazione, P.le A. Moro,
5 I-00185 Rome, Italy
enrico.baciocchi@uniroma1.it;
osvaldo.lanzalunga@uniroma1.it
Pedulli and his associates.11 This information would
instead be of great interest not only to extend our
knowledge on the reactivity of the important class of the
N-oxyl radicals but also considering the fact that reaction
1 can play an important role in the NHPI-mediated
oxidative degradation of lignin promoted by the laccase/
O2 system,14 a process that has a potential application
in the pulp and paper industry.15 Thus, we have consid-
ered it of interest to carry out a kinetic investigation of
the reaction of PINO with a number of substituted
phenols. Most of the reactions were studied in CH3CN,
but some information on the solvent effect was also
obtained. The results of this study are presented here-
with.
PINO has been generated by reaction of NHPI with
Pb(OAc)4 in CH3CN containing 1% AcOH as reported in
the literature.10,16 In this solvent, the spectrum of PINO
was the same as that found by Masui (λmax ) 380 nm8).
As in AcOH, the spontaneous decay of PINO in CH3CN
followed second-order kinetics in line with a dimerization
process. The rate constant was 0.4 M-1 s-1, very close to
that observed in AcOH.10 The slow decay of PINO,
followed spectrophotometrically at its λmax, was strongly
accelerated in the presence of phenol, in line with the
occurrence of reaction 1. This is also clearly shown by
the fact that the decay is extremely slower when the
phenol is replaced by anisole. Furthermore a decrease
(more than 3 times) of the decay rate of PINO was found
when AcOH was replaced by CD3COOD, to convert C6H5-
OH in C6H5OD, indicating a substantial kinetic isotope
effect.
Received August 4, 2004
Abstract: The reactivity of the phthalimide N-oxyl radical
(PINO) toward the OH bond of a series of substituted
phenols was kinetically investigated in CH3CN. The reaction
selectivity and the deuterium kinetic isotope effect were
determined. Information on the kinetic solvent effect was
also obtained with phenol as the substrate.
The phthalimide-N-oxyl radical (PINO) is attracting
continuous attention due to its role in the aerobic
oxidation of the C-H bond in a wide variety of organic
substrates1 (aliphatic hydrocarbons,2 alkylbenzenes,3 al-
cohols,4 benzylamines,5 and N-alkylamides6) induced by
N-hydroxyphthalimide (NHPI) and O2 in the presence of
a metal salt cocatalyst (Ishii reaction). Thus, a relevant
number of studies aimed at assessing the reactivity of
PINO toward the C-H bond are presently available.7-13
In contrast, there is very little quantitative information
with respect to the reaction of PINO with phenolic OH
* To whom correspondence should be addressed. Tel: +39-06-
49913711. Fax: +39-06-490421.
(1) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama,
T.; Nishiyama, Y. J. Org. Chem. 1995, 60, 3934-3935. Ishii, Y.;
Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343, 393-427.
(2) Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama,
Y. J. Org. Chem. 1996, 61, 4520-4526.
(3) Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
J. Org. Chem. 1997, 62, 6810-6813. Wentzel, B. B.; Donners, M. P.
J.; Alsters, P. L.; Feiters, M. C.; Nolte, R. J. M. Tetrahedron 2000, 56,
7797-7803.
(4) Iwahama, T.; Yoshima, Y.; Keitoku, T.; Sakaguchi, S.; Ishii, Y.
J. Org. Chem. 2000, 65, 6502-6507. Minisci, F.; Punta, C.; Recupero,
F.; Fontana, F.; Pedulli, G. F. Chem. Commun. 2002, 688-689.
(5) Cecchetto, A.; Minisci, F.; Recupero, F.; Fontana, F.; Pedulli, G.
F. Tetrahedron Lett. 2002, 43, 3605-3607.
We also made an attempt to obtain some information
on the products of reaction 1 using a substituted phenol
(2-tert-butyl-4-methylphenol) as substrate in order to
simplify the analysis of the reaction mixture. It was found
that the major product (1) was that coming from the
cross-coupling of PINO and the phenoxyl radical (see
Supporting Information).
(6) Minisci, F.; Punta, C.; Recupero, F.; Fontana, F.; Pedulli, G. F.
J. Org. Chem. 2002, 67, 2671-2676.
(7) Minisci, F.; Recupero, F.; Pedulli, G. F.; Lucarini, M. J. Mol.
Catal. A 2003, 204-205, 63-90.
(8) Ueda, C.; Noyama, M.; Ohmori, H.; Masui, M. Chem. Pharm.
Bull. 1987, 35, 1372-1377.
(9) Koshino, N.; Cai, Y.; Espenson, J. H. J. Phys. Chem. A 2003,
107, 4262-4267.
(10) Koshino, N.; Saha, B.; Espenson, J. H. J. Org. Chem. 2003, 68,
9364-9370.
(11) Amorati, R.; Lucarini, M.; Mugnaini, V.; Pedulli, G. F.; Minisci,
F.; Recupero, F.; Fontana, F.; Astolfi, P.; Greci, L. J. Org. Chem. 2003,
68, 1747-1754.
(12) Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta,
C.; Faletti, R.; Paganelli, R.; Pedulli, G. F. Eur. J. Org. Chem. 2004,
109-119.
(13) Annunziatini, C.; Gerini, M. F.; Lanzalunga, O.; Lucarini, M.
J. Org. Chem. 2004, 69, 3431-3438.
10.1021/jo048656o CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
J. Org. Chem. 2004, 69, 8963-8966
8963

FIGURE 2. Hammett plot for the reaction of substituted
phenols with PINO in CH3CN at 25 °C.
FIGURE 1. Dependence of kobs on the concentrations of C6H5-
OH or C6H5OD in CH3CN at 25 °C.
TABLE 1. Second-Order Rate Constants (M-1 s-1) for
the Reaction of the PINO Radical with 4-X-Substituted
Phenols in CH3CN at 25 °C
The data reported in Table 1 also show that the rate
constants regularly increase by increasing the electron-
X
donating properties of the substituent. When the log(kH
/
a
b
kHH) values were plotted against the substituent con-
stants σ+, a good Hammett correlation was obtained (r2
) 0.978) (Figure 2) with a F value of -3.1.
X
kH
kD
1.6
kH/kD
CN
6.0
6.4
23.0
248
298
328
3.7
CF3
COOCH2CH3
This relatively high and negative F value and the fact
that the kinetic data correlate much better with σ+ than
with σ values (r2 ) 0.957) suggest a transition state (TS)
where a partial electron transfer (ET) from the phenolic
ring to the PINO has occurred.21
Br
Cl
H
102
910
3.2
3.1
C6H5
CH3
2680
2850
a Reactions run in CH3CN containing 1% CH3COOH. b Reac-
tions run in CH3CN containing 1% CD3COOD.
It can be of interest to attempt a more detailed
mechanistic discussion by following the recent suggestion
by Mayer and his associates that a reaction between an
oxyl radical and phenol can be better seen as proton
coupled electron transfer (PCET) rather than as classical
hydrogen atom transfer (HAT).24 In a PCET reaction a
hydrogen-bonded complex is first formed between the
reactants, and the electron and the proton are transferred
through different orbitals. Thus, for reaction 1, the O-H
hydrogen should be transferred (as a proton) to a σ-lone
pair on the PINO oxygen, whereas the electron is
transferred from a 2p-π orbital on the phenol to the 2p
singly occupied orbital on the PINO oxygen. However,
very likely, at the transition state the electron jump takes
place when the proton transfer is not yet complete,
leading to a charge unbalance whereby a partial positive
charge resides in the phenol moiety and a partial nega-
tive charge on the PINO oxygen, thus nicely accounting
Using an excess of phenol, the decay of PINO was
found to follow clean first-order kinetics. From the
observed first-order rate constants (kobs) plotted against
the phenol concentration (see Figure 1 for the reaction
of C6H5OH and C6H5OD), the second-order rate constants
for the reaction of 4-X-C6H4OH or 4-X-C6H4OD with
PINO have been determined. The values are listed in
Table 1.17
From the data reported in Table 1, it can be noted that
the kinetic deuterium isotope effects (KDIEs), determined
for phenol, 4-cyanophenol, and 4-methylphenol, are not
very high and are in the range 3.1-3.7. These values are
much lower than the theoretical maximum of kH/kD = 10,
which can be calculated for a thermoneutral hydrogen
atom transfer between two oxygen-centered radicals in
a linear and symmetrical transition state.18 Thus, our
results indicate a nonsymmetrical transition state for the
reaction of PINO with phenols even though the process
is almost thermoneutral.19
(19) O-H bond dissociation energy (BDE) of NHPI is 88.1 kcal
mol-1 11 only 0.5 kcal mol-1 higher than that of phenol (87.6 kcal
,
mol-1).20 HAT from 4-methylphenol to PINO is exothermic for ca. 2.2
kcal mol-1 20
whereas HAT from 4-cyanophenol to PINO is slightly
endothermic for ca. 0.9 kcal mol-1 20
,
.
(14) Sealey, B. J.; Ragauskas, A. J.; Elder, T. J. Holzforschung 1999,
53, 498-502.
(15) Argyropoulos, D. S.; Menachem, S. B. Biotechnology in the Pulp
and Paper Industry; Eriksson, K. E. L., Ed., Springer-Verlag: Berlin,
Heidelberg, 1997; pp 127-158.
(20) Brigati, G.; Lucarini, M.; Mugnaini, V.; Pedulli, G. F. J. Org.
Chem. 2002, 67, 4828-4832.
(21) A full-fledged electron transfer is unlikely being strongly
endergonic; the reduction potential of PINO in CH3CN is 1.07 V vs
NHE,22 whereas the oxidation potential of the phenols investigated
are in the range 1.7-2.4 V vs NHE in CH3CN.23
(22) Gorgy, K.; Lepretre, J.-C.; Saint-Aman, E.; Einhorn, C.; Ein-
horn, J.; Marcadal C.; Pierre, J.-L. Electrochim. Acta 1998, 44, 385-
393.
(16) 1% AcOH was added to increase the solubility of Pb(OAc)4.
(17) Second-order kinetics are observed since the rate of the initial
hydrogen atom transfer from the phenol to the PINO is much slower
than the rate of recombination of the phenoxyl radical with the PINO.10
The second-order rate constants reported in Table
experimentally determined and were not divided by 2.
1
are those
(23) Bordwell, F. G.; Cheng, J.-P. J. Am. Chem. Soc. 1991, 113,
1736-1743.
(24) Mayer, J. M.; Hrovat, D. A.; Thomas, J. L.; Borden, W. T J.
Am. Chem. Soc. 2002, 124, 11142-11147. Mayer, J. M. Annu. Rev.
Phys. Chem. 2004, 55, 363-390.
(18) Simonyi, M.; Fitos, I.; Kardos, J.; Lukovits, I. J. Chem. Soc.,
Chem. Commun. 1975, 252. Melander, L.; Saunders, W. H. In Reaction
Rates of Isotopic Molecules; John Wiley and Sons: New York, 1980.
8964 J. Org. Chem., Vol. 69, No. 25, 2004

as measured by Abraham’s R2 values.29 In particular,
H
H
decay rates are very close in HFP (R2 ) 0.77) and in
H
CH3CN (R2 ) 0.09).
Thus, the reactivity of PINO seems little influenced
by hydrogen bond formation at the radical center. This
behavior contrasts with the observation by Lucarini et
al. that the lifetime of phenoxyl radicals is significantly
increased in the presence of HFP as a consequence of
hydrogen bonding.30 A tentative explanation is that in
phenoxyl radicals the resonance structure involving
charge separation (like structure A) plays a significant
role, which can be further increased by hydrogen bonding.
This possibility is probably lacking for PINO as the
resonance structure B with charge separation should be
of little importance because of the strong electron-
withdrawing effect of the carbonyl groups.
FIGURE 3. Limit transition state structure for the reaction
of PINO with phenols.
TABLE 2. Rate Constants (M-1 s-1) for the
Self-Decomposition of PINO (kd) and for Reaction of
PINO with Phenol in Various Solvents at 25 °C
H
solvent (â2
)
kd
k (PhOH)
HFPa (0.03)
0.9
4.0
0.6b
0.4
>3 × 103
>3 × 103
550
CCl4a (0.05)
CH3COOH (0.42)
CH3CNa (0.44)
328
a In the presence of 1% CH3COOH. b Reference 10.
for the high and negative F value observed.25 This
situation is depicted in Figure 3, where a limit structure
of the transition state is reported.26 Plausibly, the entity
of this charge balance should depend on the electrophilic
character of the oxyl radical, increasing as the radical
becomes more electrophilic. Thus, it is reasonable that a
significantly lower negative F value (-1.02) was deter-
mined in the HAT from substituted phenols to the tert-
butoxy radical (a much less electrophilic radical than
PINO12) in CH3CN.27
A charge unbalanced TS with a limited transfer of the
proton from the phenol to PINO can also explain the
relatively small KDIE values that have been observed,
as well as the decrease in kH/kD values when we move
from 4-cyanophenol (kH/kD ) 3.7) to 4-methylphenol (kH/
kD ) 3.1). Accordingly, on going from electron-withdraw-
ing (CN) to electron-donating (Me) substituents, the
charge unbalance at the transition state should increase
(the electron jump becomes easier), and this should imply
a less extent of proton transfer at the transition state
with consequent lowering of the KDIE.
To investigate the solvent effect upon the reaction of
PINO with phenol, kinetics were also carried out in
AcOH, 1,1,1,3,3,3-hexafluoro-2-propanol (HFP), and CCl4.28
First of all, it was observed that in HFP and CCl4 the
decay of PINO is a second-order reaction, as already
found in AcOH10 and CH3CN. The decay rate constants
are reported in Table 2, and it is interesting to note that
the PINO decay occurs at a similar rate in solvents that
strongly differ in their ability as hydrogen bond donors,
The rate constants for the reaction of PINO with
phenol in the various solvents, also displayed in Table
2, show that PINO reacts at a very similar rate in CH3-
CN and AcOH, whereas the reactivity in CCl4 and HFP
is much higher (only a lower limit value of ∼3 × 103 M-1
s-1 can be given). These findings are in agreement with
the hypothesis by Ingold and his associates that for a
reaction of the type XH + Y• (XH ) phenols, hydroper-
oxides, and anilines)31,32 the reactivity should almost
exclusively depend on the hydrogen-accepting ability of
the solvent, as measured by the Abraham â2 values.33
H
H
The lower is the â2 value, the higher is the reactivity.
Accordingly, the results reported in Table 2 can be
perfectly rationalized on this basis as CH3CN and AcOH
H
have similar â2 values (0.44 and 0.42, respectively),
whereas â2H is much lower for CCl4 (0.05) and HFP (0.03).
As mentioned before, PINO is the reacting intermedi-
ate in the degradation of lignin induced by the laccase/
NHPI/O2 system. Since in lignin the most probable
reaction centers are phenolic O-H and R-hydroxy-
substituted C-H bonds,34 we felt it of interest to acquire
information on the relative reactivity of PINO toward
these two types of bonds.36 To this purpose we have
compared the reactivity of PINO with 4-hydroxybenzyl
alcohol and 4-methoxybenzyl alcohol. The measured rate
(29) 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.
(30) Lucarini, M.; Mugnaini, V.; Pedulli, G. F.; Guerra, M. J. Am.
Chem. Soc. 2003, 125, 8318-8329.
(25) Calculations by Mayer and co-workers24 have shown that in
the transition state of the phenoxyl/phenol exchange more positive
charge is present in the phenol moiety with respect to the starting
phenol.
(26) Figure 3 represents a limit structure of the transition state that
serves only to visualize the consequence of the electron shift occurring
when the proton is only partially transferred (PCET). Of course, it must
be considered that the positive charge in the ring is partially neutral-
ized by the negative charge developing on oxygen, and thus in the
transition state there actually is only a partial positive charge in the
phenyl ring, in line with calculations.25
(27) Determined at 130 °C: Kim, S. S.; Lim, S. Y.; Ryou, S. S.; Lee,
C. S.; Yoo, K. H. J. Org. Chem. 1993, 58, 192-196.
(28) It was possible to examine only a few solvents, since in many
cases there were problems related to the solubility of the PINO
generating system or to a fast reaction of PINO with the solvent.
(31) Avila, D. V.; Ingold, K. U.; Lusztyk, J.; Green, W. H.; Procopio,
D. R. J. Am. Chem. Soc. 1995, 117, 2929-2930.
(32) Snelgrove, D. W.; Lusztyk, J.; Banks, J. T.; Mulder, P.; Ingold,
K. U. J. Am. Chem. Soc. 2001, 123, 469-477.
(33) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Morris, J. J.;
Taylor, P. J. J. Chem. Soc., Perkin Trans. 2 1990, 521-529.
(34) Lignin is a tridimensional polymer built from phenolic and
nonphenolic phenylpropane units linked together by different bonds.35
A large number of phenolic ArOH groups and benzylic ArCH(OH)R
groups are present.
(35) Sarkanen, K. V. Lignins: Occurrence, Formation, Structure and
Reactions; Sarkanen, K. V., Ludwig, C. H., Eds., Wiley-Interscience:
New York, 1971; pp 95-195.
J. Org. Chem, Vol. 69, No. 25, 2004 8965

constants were 936 M-1 s-1 for 4-hydroxybenzyl alcohol
and 100 M-1 s-1 for 4-methoxybenzyl alcohol. Thus, with
PINO, the phenolic O-H bond is more reactive (about
10 times) than the C-H bond of the benzylic CH2OH,
which suggests that initial hydrogen transfer from the
phenolic OH might be the key process in the degradation
of lignin by laccase/NHPI/O2. In this respect, further work
is planned to study the reactivity of PINO toward
phenolic lignin model compounds.
Finally, it can also be remarked that the above result
contrasts with the fact that the BDE of the phenolic O-H
bond is significantly higher (as much as 5.3 kcal mol-1
according to theoretical calculations)37 than that of the
R-hydroxy-substituted benzylic C-H bond.38 Thus, PINO,
an N-oxyl radical, conforms to the general behavior that
the reactions of RO• with the phenolic O-H are intrinsi-
cally favored from the kinetic point of view with respect
to the corresponding reactions with the benzylic C-H.
Zavitsas and Chatgillialoglu have attributed this behav-
ior to the fact that in the transition state the antibonding
interactions are smaller for O‚‚‚H‚‚‚O than for O‚‚‚H‚‚‚C
systems.40 However, it should also be considered that
hydrogen atom abstraction from a phenolic O-H and a
benzylic C-H might take place by different mecha-
nisms: PCET in the former case, classical HAT in the
second.
In conclusion, the results reported in this work provide
significant information with respect to the reaction of
phthalimide-N-oxyl radical with phenolic OH bonds. The
high selectivity and the relatively low deuterium kinetic
isotope effects suggest a nonsymmetrical transition state,
and it seems possible to describe the process as proton-
coupled electron transfer (PCET) rather than as a clas-
sical hydrogen atom transfer (HAT). The rate constant
for the reaction of PINO with phenol increases as the
solvent becomes a weaker hydrogen bond acceptor, in
accordance with the predictions by Ingold and his as-
sociates concerning the kinetic solvent effects for reac-
tions of phenols with hydrogen atom abstracting species.
Finally, the reactivity of PINO is about 10 times higher
toward phenolic O-H bonds than toward R-hydroxy-
substituted benzylic C-H bonds. This result may have
a bearing with respect to the mechanism of the NHPI-
mediated oxidative degradation of lignin promoted by the
laccase/O2 system.
(36) Hydrogen atom transfer from benzylic C-H bonds to PINO, in
the oxidation of nonphenolic lignin model compounds by the laccase/
NHPI/O2 system, has been reported in the literature; see: D’Acunzo,
F.; Baiocco, P.; Fabbrini, M.; Galli, C.; Gentili, P. New J. Chem. 2002,
26, 1791-1794. Baiocco, P.; Barreca, A. M.; Fabbrini, M.; Galli, C.;
Gentili, P. Org. Biomol. Chem. 2003, 1, 191-197.
Acknowledgment. Thanks are due to the Ministero
dell’Istruzione, dell’Universita` e della Ricerca (MIUR),
and the Consiglio Nazionale delle Ricerche (CNR) for
financial support. The authors thank also to Dr. Peter
Mulder for helpful discussions concerning the deuterium
kinetic isotope effect.
(37) Reynisson, J.; Steenken, S. Org. Biomol. Chem. 2004, 2, 578-
584.
(38) It should also be considered that the reactivity of the C-H bond
is enhanced by the presence of the para O-H group (σ+ ) -0.92) more
than the reactivity of the O-H group is enhanced by the presence of
the para CH2OH group (σ+ ) -0.04),39 even though the F value for
the reaction of PINO with benzyl alcohols in CH3CN (-0.68)12,13 is less
negative than the F of the reaction with phenols.
(39) Girault, J. P.; Dana, G. J. Chem. Soc., Perkin Trans. 2 1977,
993-994.
(40) Zavitsas, A. A.; Chatgilialoglu, C. J. Am. Chem. Soc. 1995, 117,
10645-10654.
Supporting Information Available: Instrumentation,
materials, kinetic measurements, reaction of PINO with 2-tert-
1
butyl-4-methylphenol, and H NMR and 13C NMR spectra of
the cross-coupling product 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO048656O
8966 J. Org. Chem., Vol. 69, No. 25, 2004