Structural and medium effects on the reactions of the cumyloxyl radical with intramolecular hydrogen bonded phenols. the interplay between hydrogen-bonding and acid-base interactions on the hydrogen atom transfer reactivity and selectivity

Article abstract of DOI:10.1021/jo5009367

A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO^?) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO^? and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO ₄)₂, protonation or Mg²⁺ complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO^? exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Br?nsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems.

Full text of DOI:10.1021/jo5009367

Article
pubs.acs.org/joc
Structural and Medium Effects on the Reactions of the Cumyloxyl
Radical with Intramolecular Hydrogen Bonded Phenols. The
Interplay Between Hydrogen-Bonding and Acid-Base Interactions on
the Hydrogen Atom Transfer Reactivity and Selectivity
Michela Salamone,*,† Riccardo Amorati,‡ Stefano Menichetti,§ Caterina Viglianisi,§ and Massimo Bietti*,†
†Dipartimento di Scienze e Tecnologie Chimiche, Universita
̀
“Tor Vergata”, Via della Ricerca Scientifica, 1, I-00133 Rome, Italy
di Bologna, Via San Giacomo, 11, I-40126 Bologna, Italy
̀
di Firenze, Via della Lastruccia, 3-13, I-50019 Sesto Fiorentino, Italy
‡Dipartimento di Chimica “G. Ciamician”, Universita
̀
§Dipartimento di Chimica “U. Schiff”, Universita
S
* Supporting Information
ABSTRACT: A time-resolved kinetic study on the reactions of the
cumyloxyl radical (CumO•) with intramolecularly hydrogen bonded 2-(1-
piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)-
phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has
been carried out. In acetonitrile, intramolecular hydrogen bonding protects
the phenolic O−H of 1 and 2 from attack by CumO• and hydrogen atom
transfer (HAT) exclusively occurs from the C−H bonds that are α to the
piperidine nitrogen (α-C−H bonds). With 3 HAT from both the phenolic
O−H and the α-C−H bonds is observed. In the presence of TFA or
Mg(ClO4)2, protonation or Mg2+ complexation of the piperidine nitrogen
removes the intramolecular hydrogen bond in 1 and 2 and strongly
deactivates the α-C−H bonds of the three substrates. Under these
conditions, HAT to CumO• exclusively occurs from the phenolic O−H
group of 1−3. These results clearly show that in these systems the interplay
between intramolecular hydrogen bonding and Brønsted and Lewis acid−base interactions can drastically influence both the
HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role
played by tyrosyl radicals in biological systems.
X• + S−H → X−H + S•
INTRODUCTION
(1)
■
Proton-coupled electron transfer (PCET) reactions, broadly
described as reactions in which both electrons and protons are
transferred, are attracting increasing interest, as they are
involved in a variety of important chemical and biological
processes.1,2 Relevant examples include the electron transfer
activation of small molecules (O2, H2O, CO2), nitrogen
fixation, hydrocarbon oxidation, and enzymatic reactions such
as those catalyzed by photosystem II (PSII), class I
ribonucleotide reductase, DNA photolyase, and other systems.
PCET reactions where proton and electron transfers involve
different sites and occur in a single kinetic step have been
named separated concerted proton−electron transfer (CPET)
or, alternatively, multiple site electron−proton transfer (MS-
EPT) reactions,1 as opposed to reactions that occur through
sequential electron−proton transfer (ET-PT) and proton−
electron transfer (PT-ET) pathways. Hydrogen atom transfer
(HAT) is instead described as a PCET reaction where the
proton and electron are transferred from one site to another in
a single kinetic step,1,3 typical examples being represented by
the reactions of free radicals (X•) with hydrogen atom donor
substrates S−H (eq 1).
In keeping with the role played by hydrogen-bonded tyrosine
residues in CPET reactions occurring in redox enzymes such as
PSII,4 where photo-oxidation of these residues has been shown
to be coupled to the transfer of their phenolic protons to the
hydrogen bond accepting histidine residues, and in order to
provide a fundamental understanding of the key parameters
that govern these processes, a variety of intramolecularly
hydrogen bonded phenols have been employed as mechanistic
probes and their reactivity toward one-electron oxidants has
been thoroughly investigated.5−8 Very limited information is
instead available on the HAT reactivity of intramolecularly
hydrogen bonded phenols.
Recently, in order to obtain information in this respect, some
of us have carried out a kinetic study of the reactions of
alkylperoxyl (ROO•) and 2,2-diphenyl-1-picrylhydrazyl
(dpph•) radicals with phenols bearing pendant piperidine
bases in the ortho and meta positions (see structures 2 and 3 in
Received: April 28, 2014
Published: June 3, 2014
© 2014 American Chemical Society
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Chart 1).9 Different reactivity patterns have been observed with
the two radicals. With ROO• the kinetic data have been
explained on the basis of a HAT mechanism, showing in
particular that, when the phenolic O−H group is involved in an
intramolecular hydrogen bond with the piperidine nitrogen,
greater than 2 orders of magnitude decreases in the HAT rate
constant have been measured. With dpph• a solvent-dependent
competition between HAT and ET (PT-ET or MS-EPT)
pathways has been observed instead, a behavior that has been
explained on the basis of the higher oxidizing power of dpph• in
comparison to alkylperoxyl radicals.
in order to understand if, in the reactions with CumO•, acid−
base interactions can influence both the HAT reactivity and
selectivity. For this purpose the effects of trifluoroacetic acid
(TFA) on the reactions of CumO• with phenols 1−3 and N-
benzylpiperidine and of Mg(ClO4)2 on the reactions of CumO•
with phenols 2 and 3 and N-benzylpiperidine have been also
investigated.
RESULTS AND DISCUSSION
■
CumO• has been generated by 355 nm laser flash photolysis
(LFP) of argon or oxygen-saturated acetonitrile solutions (T =
25 °C) containing 1.0 M dicumyl peroxide, as described in eq 2.
As has been pointed out in this study, the observation that
peroxyl radicals are ineffective in HAT from intramolecularly
hydrogen bonded phenols can be of great importance in
biological systems, as it implies that hydrogen bonding between
the phenolic O−H group of tyrosines and basic residues in
proteins may protect this group from hydrogen abstraction by
reactive oxygen species formed during oxidative stress.
Following this indication, it seemed particularly interesting to
study the reactions of these substrates with a genuine HAT
reagent such as the cumyloxyl radical (PhC(CH3)2O•,
CumO•). In comparison to peroxyl radicals, for which kinetic
information is generally obtained through indirect studies,
alkoxyl radicals are known to display a significantly higher HAT
reactivity,10,11 and CumO• is characterized by an absorption
band in the visible region of the spectrum that makes possible
the direct measurement of its reactivity by time-resolved
techniques.12,13 In addition, this radical can be easily generated
from the parent dicumyl peroxide by UV photolysis and is
characterized by a relatively low redox potential.14 Taken
together, these features make CumO• a convenient probe for
the study of the HAT reactivity of intramolecularly hydrogen
bonded phenols. Along this line, we have carried out a detailed
time-resolved spectroscopic and kinetic study of the reactions
of CumO• with phenols 1 and 2, characterized by the presence
of a pendant piperidine base in the ortho position, whose
structures are displayed in Chart 1. As a matter of comparison,
the reactions of CumO• with phenol 3, N-benzylpiperidine, and
4-methoxyphenol have been also investigated.
Under these conditions CumO• is characterized by an
absorption band centered at 485 nm12,13 and, in the absence of
hydrogen atom donor substrates, undergoes C−CH3 β-scission
as the main pathway.12,18
Reactions in Acetonitrile. The reactions of CumO• with
the compounds depicted in Chart 1 have been studied by LFP.
The time-resolved spectra observed after reaction of CumO•
with 2-(1-piperidinylmethyl)phenol (1) in an argon-saturated
acetonitrile solution are displayed in Figure 1.
Chart 1
Figure 1. Time-resolved absorption spectra observed after 355 nm
LFP of an argon-saturated MeCN solution (T = 25 °C) containing
dicumyl peroxide (1.0 M) and 2-(1-piperidinylmethyl) phenol (1; 35
mM) at 128 ns (black circles), 384 ns (white circles), 1.0 μs (gray
circles), 2.6 μs (black squares), and 8.0 μs (white squares) after the 8
ns, 10 mJ laser pulse. Insets: (a) decay of the cumyloxyl radical
monitored at 490 nm; (b) buildup and consequent decay of
absorption monitored at 350 nm; (c) decay of absorption monitored
at 430 nm.
HAT from both phenolic O−H groups11b and the α-C−H
bonds of alkylamines15 to CumO• is well established, and
accordingly the study of its reactions with phenols 1−3 can
provide, in addition to information on the possible protection
of the O−H group through intramolecular O−H- - -N
hydrogen bonding mentioned above, useful information on
the effect of this interaction on the α-C−H reactivity. The
presence of the piperidine basic center also allows us to probe
the effect of Brønsted and Lewis acids on these processes,16,17
The spectrum recorded 128 ns after the laser pulse is
characterized by a broad absorption band centered around 490
nm that, in agreement with literature data,12,13 is assigned to
CumO•. The decay of this band (Figure 1, inset a), which is
accelerated by the presence of 1, is accompanied by a buildup
of absorption between 330 and 420 nm and by a residual
absorption between 430 and 500 nm (insets b and c, showing
the ΔA vs time profiles monitored at 350 and 430 nm,
respectively). An isosbestic point can be identified at 425 nm.
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Figure 1 also shows different time evolutions for the UV
absorption band centered at 350 nm and the visible absorption
band comprised between 390 and 500 nm (insets b and c)
where, on the microsecond time scale, a decay of absorption is
observed only for the former band, indicating that different
species contribute to these absorptions.
for a carbon-centered radical.20 Under these conditions, the
decay of the CumO• visible absorption band (Figure S3, inset
a) is accompanied by the delayed buildup of an absorption
band centered at 430 nm and comprised between 350 and 500
nm (Figure S3, insets b and c, showing the ΔA vs time profiles
monitored at 430 and 450 nm, respectively). This band is
assigned to the peroxyl radicals formed after reaction of radicals
I and II (Scheme 1; X = H) with oxygen, in line with the recent
observation that α-aminoalkylperoxyl radicals derived from
tertiary amines are characterized by absorption bands centered
around 400 nm.21
Very importantly, under both argon and oxygen, no evidence
for the formation of a phenoxyl or a 4-methoxyphenoxyl radical,
characterized by two intense absorption bands around 385 and
400 nm and around 340 and 410 nm,22,23 respectively, has been
obtained (see below), in agreement with the involvement of the
phenolic O−H group in an intramolecular hydrogen bond with
the piperidine nitrogen. This observation clearly indicates that
also with CumO• hydrogen bonding protects the O−H group
from hydrogen abstraction, despite the significantly higher
HAT reactivity displayed by alkoxyl radicals in comparison to
peroxyl radicals,10,11 supporting the hypothesis that in these
intramolecular hydrogen-bonded phenols HAT exclusively
occurs from the α-C−H bonds.
A similar behavior has been observed after reaction of
CumO• with 4-methoxy-2-(1-piperidinylmethyl)phenol (2),
the spectra for which are displayed in the Supporting
Information as Figure S1. The decay of CumO• is accompanied
by a residual absorption between 390 and 560 nm and by a
buildup of absorption between 330 and 370 nm.
The bands observed following decay of CumO• in the
reactions of both 1 and 2 are assigned to the superimposition of
the absorptions of the carbon-centered radicals formed after
HAT from the piperidine α-CH2 and benzylic CH2 groups (α-
C−H bonds thereafter) to CumO• as described in Scheme 1
Scheme 1
The time-resolved spectra observed after reaction of CumO•
with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) in an
argon-saturated acetonitrile solution are displayed in Figure
2A. The decay of CumO• (inset a) is accompanied by the
formation of a transient species (1.0 μs, gray circles)
characterized by two intense absorption bands at 415 and
≤330 nm (insets b and c). An isosbestic point can be identified
at 430 nm. These bands are assigned to the 4-methoxy-3-(1-
piperidinylmethyl)phenoxyl radical III, formed following HAT
from the phenolic O−H of 3 to CumO• (Scheme 2), on the
basis of the comparison with the time-resolved spectrum of the
4-methoxyphenoxyl radical observed after reaction of CumO•
with 4-methoxyphenol (Figure 2B), characterized by two
intense absorption bands at 410 and 340 nm.
(radicals I and II, respectively; X = H, OCH3), on the basis of a
comparison with the time-resolved spectra observed after
reaction of CumO• with N-benzylpiperidine (Figure S2 in the
Supporting Information) and with literature data.19
Support for this assignment is also provided by the time-
resolved spectra obtained after reaction of CumO• with 1 in an
oxygen-saturated acetonitrile solution (Figure S3 in the
Supporting Information). In comparison to the corresponding
experiment carried out in argon, a significantly weaker
absorption at 350 nm is observed, indicating that the species
responsible for this absorption reacts with oxygen, as expected
Figure 2. Time-resolved absorption spectra observed after 355 nm LFP of an argon-saturated MeCN solution (T = 25 °C) containing dicumyl
peroxide (1.0 M) and (A) 4-methoxy-3-(1-piperidinylmethyl)phenol (3; 10 mM) or (B) 4-methoxyphenol (12.1 mM). (A) Spectra recorded at 96
ns (black circles), 224 ns (white circles), 1.0 μs (gray circles), 4.0 μs (black squares) and 12 μs (white squares) after the 8 ns, 10 mJ laser pulse.
Insets: (a) decay of the cumyloxyl radical monitored at 490 nm; (b) buildup and consequent decay of absorption monitored at 415 nm; (c) buildup
and consequent decay of absorption monitored at 340 nm. (B) Spectra recorded at 96 ns (black circles), 288 ns (white circles), 576 ns (gray circles),
and 1.3 μs (black squares) after the 8 ns, 10 mJ laser pulse. Insets: (a) decay of the cumyloxyl radical monitored at 490 nm; (b) Buildup and
consequent decay of absorption monitored at 410 nm; (c) buildup and consequent decay of absorption monitored at 340 nm.
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Scheme 2
With phenol 3 the pendant piperidine moiety cannot engage
in hydrogen bonding with the O−H group that is free and thus
susceptible to attack by CumO•. Unfortunately, due to the
strong absorption displayed by phenoxyl radical III, from the
analysis of Figure 2A no conclusion can be drawn on the
possible concomitant formation of radicals IV and V following
HAT from the α-C−H bonds of 3 to CumO•. However,
information in this respect is provided by the results of time-
resolved kinetic studies on the reaction of CumO• with phenol
3 discussed below.
explained on the basis of the slightly higher hydrogen bond
donor (HBD) ability of phenol in comparison to 4-
H
methoxyphenol (as measured by Abraham’s α2 parameters:
0.60 and 0.57, respectively)24 that results in a decrease in the
strength of the intramolecular hydrogen bond on going from 1
to 2.
The role of intermolecular hydrogen bond interactions on
HAT reactions from tertiary alkylamines has been recently
investigated, showing that in the reaction of CumO• with
triethylamine kH decreases with increasing solvent HBD ability.
An almost 6-fold decrease in kH has been measured on going
from acetonitrile to MeOH (for which kH = 2.19 × 108 and 3.8
× 107 M−1 s−1, respectively).25 This behavior has been
explained on the basis of the decrease in the degree of overlap
between the α-C−H bond and the amine lone pair determined
by solvent hydrogen bonding. When HBD solvents engage in
hydrogen bonding with the nitrogen center, this interaction
decreases the degree of hyperconjugative overlap between the
α-C−H σ* orbital and the lone pair, leading to an increase in
the strength of this bond and to a destabilization of the HAT
transition state and of the carbon-centered radical formed after
abstraction, thus determining a certain extent of deactivation of
the α-C−H bonds toward HAT.
On the basis of this picture, a similar explanation can be put
forward to account for the decrease in kH observed on going
from N-benzylpiperidine to 1 (and 2) where intramolecular
hydrogen bonding between the phenolic O−H and the
piperidine nitrogen leads to a comparable α-C−H deactivation.
In the reaction of CumO• with phenol 3 a value kH = 2.4 ×
108 M−1 s−1 has been obtained. This value is almost three times
higher than the value measured for HAT from 4-methox-
yphenol to CumO• (kH = 8.3 × 107 M−1 s−1) despite the almost
identical O−H BDEs available for these two compounds (81.5
and 81.4 kcal mol−1 for 3 and 4-methoxyphenol,9 respectively).
On the basis of this observation the kH value measured for
reaction between CumO• and 3 reasonably reflects the
contribution of HAT from both the O−H and α-C−H bonds
to give phenoxyl radical III and carbon-centered radicals IV and
V, as described in Scheme 2. Support for this hypothesis is also
provided by the observation that this value (kH = 2.4 × 108 M−1
s−1) is very close to the sum of the kH values measured under
identical experimental conditions for HAT from N-benzylpi-
peridine and 4-methoxyphenol to CumO• (2.13 × 108 M−1
s−1).
Time-resolved kinetic studies of the reactions of CumO•
with phenols 1−3, N-benzylpiperidine, and 4-methoxyphenol
have been carried out by LFP in acetonitrile at T = 25 °C,
following the decay of the CumO• visible absorption band at
490 nm (540 nm in the reactions with 1 and 2, in order to limit
the contribution of the residual absorption due to radicals I and
II) as a function of the concentration of substrate. From plots
of the observed rate constants (kobs) against substrate
concentration, excellent linear relationships have been obtained
and the second-order rate constant for HAT from these
substrates to CumO• (kH) have been derived from the slope of
these plots. The kobs vs [substrate] plots for the reactions of
CumO• with phenols 1−3, N-benzylpiperidine, and 4-
methoxyphenol are displayed in the Supporting Information
as Figures S4−S8, respectively. All the kinetic data thus
obtained are collected in Table 1, together with indications of
the hydrogen atom abstraction site (α-C−H and/or O−H) for
the different substrates.
Table 1. Second-Order Rate Constants (kH) for HAT from
Different Substrates to the Cumyloxyl Radical (CumO•),
Measured in Acetonitrile at T = 25 °C
a
substrate
kH/M−1 s−1
abstraction site
1
2
3
1.7 × 107
3.4 × 107
2.4 × 108
1.3 × 108
8.3 × 107
α-C−H
α-C−H
α-C−H and O−H
α-C−H
O−H
N-benzylpiperidine
4-methoxyphenol
a
Measured in argon-saturated solution employing 355 nm LFP:
[dicumyl peroxide] = 1.0 M. kH values have been determined from the
slope of the kobs vs [substrate] plots, where in turn kobs values have
been measured following the decay of the CumO• visible absorption
band at 490−540 nm. Error ≤10%.
It is also very interesting to compare the rate constants
obtained in this study for reaction of CumO• with phenols 2
and 3 with those measured previously for the corresponding
reactions of these substrates with alkylperoxyl (ROO•) and 2,2-
diphenyl-1-picrylhydrazyl (dpph•) radicals.9 The reactions of
ROO• and CumO• can be rationalized on the basis of the HAT
mechanism described in Schemes 1 and 2, where however with
both substrates a 4-order of magnitude increase in kH is
observed on going from the former to the latter radical, in line
with the significantly higher HAT reactivity displayed by alkoxyl
radicals in comparison to peroxyl radicals.10,11 Along this line,
The following kH values have been measured for the
reactions of 1 and 2 with CumO•: kH = 1.7 × 107 and 3.4 ×
107 M−1 s−1, respectively. On the basis of the discussion
outlined above, these values refer to HAT from the α-C−H
bonds as described in Scheme 1. Comparison between the
value measured for 1 and the kH value measured analogously for
HAT from N-benzylpiperidine to CumO• (kH = 1.3 × 108 M−1
s−1) shows that intramolecular hydrogen bonding leads to an
almost 8-fold decrease in kH. Along this line, the 2-fold increase
in kH observed on going from 1 to 2 can be reasonably
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Figure 3. Time-resolved absorption spectra observed after 355 nm LFP of argon-saturated MeCN solutions (T = 25 °C) containing trifluoroacetic
acid (TFA), dicumyl peroxide (1.0 M,) and (A) 2-(1-piperidinylmethyl)phenol (1) or (B) 4-methoxy-2-(1-piperidinylmethyl)phenol (2). A: [1] =
100 mM, [TFA] = 112 mM, spectra recorded at 128 ns (black circles), 448 ns (white circles), 1.4 μs (gray circles), 4.0 μs (black squares), and 14 μs
(white squares) after the 8 ns, 10 mJ laser pulse. Insets: (a) decay of the cumyloxyl radical monitored at 490 nm; (b) buildup and consequent decay
of absorption monitored at 405 nm; (c) buildup and consequent decay of absorption monitored at 385 nm. B: [2] = 10.8 mM, [TFA] = 12 mM,
spectra recorded at 96 ns (black circles), 320 ns (white circles), 800 ns (gray circles), 2.3 μs (black squares), and 10 μs (white squares) after the 8 ns,
10 mJ laser pulse. Insets: (a) decay of the cumyloxyl radical monitored at 490 nm; (b) buildup and consequent decay of absorption monitored at 415
nm; (c) buildup and consequent decay of absorption monitored at 355 nm.
the low rate constant measured for the reaction of ROO• with
Scheme 3
the intramolecularly hydrogen bonded phenol 2 in acetonitrile
solution (kH = 2.0 × 103 M−1 s−1) reasonably reflects HAT
from the α-C−H bonds. On the other hand, the PT-ET and
MS-EPT pathways described previously for the reactions of
dpph• with 2 and 3 are clearly not accessible to CumO• due to
the lower oxidizing power of this radical in comparison to
dpph• (E° = −0.19 and 0.23 V/SCE for CumO• and
dpph•,9,26,27 respectively).
protonation,16 where the formation of an ammonium ion
prevents overlap between the α-C−H bonds and the nitrogen
lone pair and leads to greater than 4 orders of magnitude
decreases in HAT reactivity. Most importantly, these findings
clearly show that in intramolecularly hydrogen bonded phenols
such as 1 and 2 the HAT selectivity can be drastically changed
through acid−base interactions. Protonation of the piperidine
nitrogen removes the hydrogen bond interaction strongly
deactivating the α-C−H bonds and changing the abstraction
site from these bonds (Scheme 1) to the phenolic O−H group
(Scheme 3).
A very similar behavior has been observed when the reaction
of CumO• with phenol 2 has been studied in the presence of
Mg(ClO4)2. The time-resolved spectra thus obtained in an
argon-saturated acetonitrile solution containing 10.5 mM 2 and
11.2 mM Mg(ClO4)2 are displayed in the Supporting
Information as Figure S9. Also under these conditions the
decay of CumO• is accompanied by the formation of a transient
species characterized by two intense absorption bands at 415
and 355 nm that is assigned to the 4-methoxyphenoxyl radical
having the piperidine nitrogen atom coordinated to the
magnesium ion. On the basis of these results it clearly appears
that, in addition to protonation, also Mg2+ complexation with a
Lewis basic center involved in intramolecular hydrogen
bonding with the phenolic O−H can be successfully exploited
as a tool to control the HAT selectivity. Also, this observation is
in full agreement with the recently described strong
deactivation toward abstraction from the α-C−H bonds of
alkylamines determined by coordination of the nitrogen center
to Mg2+.17
Reactions in Acetonitrile Containing TFA or Mg-
(ClO4)2. The effect of TFA and Mg(ClO4)2 has been then
investigated. The time-resolved spectra observed after reaction
of CumO• with phenols 1 and 2 in argon-saturated acetonitrile
solutions containing TFA (at [substrate] < [TFA]) are
displayed in parts A and B of Figure 3, respectively. With
both substrates the decay of CumO• is accompanied by the
formation of a transient species characterized by two absorption
bands at 405 and 385 nm (Figure 3A, gray circles and insets b
and c) and 415 and 355 nm (Figure 3B, gray circles and insets
b and c). Isosbestic points can be identified between 405 and
410 nm (Figure 3A) and between 430 and 435 nm (Figure 3B).
These bands are very similar to those observed previously for
the phenoxyl and 4-methoxyphenoxyl radicals, the former
characterized by absorption bands centered at 400 and 385 nm
with a shoulder at 360 nm22 and the latter by absorption bands
centered at 410 and 340 nm (Figure 2B), and accordingly are
assigned to the distonic phenoxyl radical cations VI. Formation
of VI can be explained on the basis of HAT from the free
phenolic O−H group of protonated 1 and 2 (1-H+ and 2-H+)
that in turn are formed by TFA protonation of the piperidine
nitrogen as described in Scheme 3 (X = H, OCH3).
Figure 3 also shows that as compared to the spectra recorded
in acetonitrile (Figure 1 and Figure S1 (Supporting
Information)) after addition of TFA the spectrum assigned to
the carbon-centered radicals I and II (Scheme 1) is replaced by
the absorption spectra of the distonic phenoxyl radical cation
VI. This observation is in full agreement with the recently
described α-C−H bond deactivation of alkylamines by
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Scheme 4
Table 2. Second-Order Rate Constants (kH) for HAT from Different Substrates to the Cumyloxyl Radical (CumO•), Measured
at T = 25 °C
a
Measured in argon-saturated acetonitrile solution employing 355 nm LFP: [dicumyl peroxide] = 1.0 M. kH values have been determined from the
slope of the kobs vs [substrate] plots, where in turn kobs values have been measured following the decay of the CumO• visible absorption band at
490−540 nm. Error ≤10%.
The time-resolved spectra observed after reaction of CumO•
with phenol 3 (9.8 mM) in an argon-saturated acetonitrile
solution containing 12 mM TFA is displayed in the Supporting
Information as Figure S10. The decay of CumO• is
accompanied by the formation of two intense absorption
bands at 410 and 350 nm that are assigned to the distonic 4-
methoxyphenoxyl radical cation VII formed following HAT
from the phenolic O−H group of protonated 3 (3-H+) to
CumO•, as described in Scheme 4. In comparison to the
spectrum recorded in acetonitrile (Figure 2), a ≥20 nm red
shift of the phenoxyl radical UV band is observed following
nitrogen protonation. Under these conditions, nitrogen
protonation strongly deactivates the α-C−H bonds and HAT
from the phenolic O−H now represents the exclusive reaction
pathway.
time-resolved kinetic studies have been also carried out. The kH
values thus obtained are collected in Table 2 together with the
indication of the hydrogen atom abstraction site (α-C−H and/
or O−H) for the different substrates under the experimental
conditions employed. For comparison, also included in this
table are the kH values shown in Table 1 for the reactions of
CumO• with phenols 1−3, N-benzylpiperidine, and 4-
methoxyphenol in MeCN.
When HAT from 1 to CumO• has been studied in an argon-
saturated acetonitrile solution containing 105 mM TFA, kobs
has been observed to increase linearly with increasing [1] up to
[1] = [TFA], leading to a rate constant for HAT kH1 = 3.0 ×
106 M−1 s−1 (Figure 4, black circles).
A linear increase in kobs, but with a different slope, has been
then observed for [1] > [TFA], from which, in the 105−150
mM [1] range, a value kH2 = 1.2 × 107 M−1 s−1 has been
obtained (Figure 4, white circles).
In order to obtain quantitative information on the
deactivating effect of TFA and Mg(ClO4)2 on the reactions
of CumO• with phenols 1−3 and with N-benzylpiperidine,
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hypothesis is also provided by the comparison of the latter
kH values with the kH1 and kH2 values measured for the
corresponding reactions of 1 and 2 in the presence of TFA. For
[substrate] ≤ [TFA] a 1 order of magnitude increase in kH1 has
been observed on going from 1-H+ to 2-H+ (kH1 = 3.0 × 106
and 3.0 × 107 M−1 s−1, respectively), in full agreement with the
activating effect exerted by a methoxy ring substituent on HAT
from the phenolic O−H. For [substrate] > [TFA], similar kH2
values and almost identical kH2/kH ratios (0.71 and 0.74, for 1
and 2, respectively) have been obtained instead.
For 3, the measured kH2 value at [3] > [TFA] (1.9 × 108 M−1
s−1) is very similar to the value measured for the corresponding
reaction with CumO• in acetonitrile in the absence of TFA (kH
= 2.4 × 108 M−1 s−1), indicating that under these conditions kH2
reflects HAT from the α-C−H and O−H bonds of 3 as
described in Scheme 2.
Figure 4. Plots of the observed rate constant (kobs) against
concentration of 2-(1-piperidinylmethyl)phenol (1) for reaction of
the cumyloxyl radical (CumO•) measured at T = 25 °C in an argon-
saturated MeCN solution containing 105 mM trifluoroacetic acid
(TFA), by following the decay of CumO• at 490 nm. From the linear
Support for the reactivity patterns observed in the reactions
of phenols 1−3 after addition of TFA is provided by the results
of time-resolved kinetic studies on the reaction between
CumO• and N-benzylpiperidine carried out in the presence
of TFA, the plots for which are displayed in the Supporting
Information as Figure S13. In the presence of 10 mM TFA, no
increase in kobs has been observed up to [N-benzylpiperidine] =
[TFA], providing an upper limit to the rate constant for HAT
from N-benzylpiperidine to CumO• as kH < 1 × 106 M−1 s−1.
An identical behavior, indicative of stoichiometric protonation
of the amine by TFA and of strong α-C−H deactivation, has
been described previously for the reactions between CumO•
and other tertiary alkylamines, where, as mentioned above,
greater than 4 orders of magnitude decreases in HAT reactivity
have been observed after addition of TFA.16 For [N-
benzylpiperidine] > [TFA], a linear increase in kobs with
increasing [N-benzylpiperidine] has been observed and a rate
constant for HAT has been obtained from the slope of this plot
as kH = 1.4 × 108 M−1 s−1. This value is very close to the value
measured previously for the reaction of CumO• with N-
benzylpiperidine in acetonitrile, in the absence of TFA (kH =
1.3 × 108 M−1 s−1, see above and Figure S7 (Supporting
Information)), indicating that the measured rate constant now
reflects HAT from the α-C−H bonds of the nonprotonated
amine.
regression analysis: in the 0−105 mM [1] range (black circles) kH1
=
3.00 × 106 M−1 s−1, r2 = 0.9964; in the 105−150 mM [1] range (white
circles) kH2 = 1.19 × 107 M−1 s−1, r2 = 0.9897. The dashed line
indicates the point where [1] = [TFA] = 105 mM.
In the reaction of CumO• with 2 in an argon-saturated
acetonitrile solution containing 20 mM TFA, the plot for which
is displayed in the Supporting Information as Figure S11, values
of kH1 = 3.0 × 107 M−1 s−1 and kH2 = 2.5 × 107 M−1 s−1 have
been obtained for [2] ≤ [TFA] and [2] > [TFA] (in the 20−
38 mM [2] range), respectively.
The kobs vs [3] plots obtained after reaction with CumO• in
an argon-saturated acetonitrile solution containing 19.6 mM
TFA are displayed in the Supporting Information as Figure S12.
Values of kH1 = 3.5 × 107 M−1 s−1 and kH2 = 1.9 × 108 M−1 s−1
have been obtained for [3] ≤ [TFA] and [3] > [TFA] (in the
20−30 mM [3] range), respectively.
On the basis of the discussion outlined above, at [substrate]
≤ [TFA] phenols 1−3 only exist in the protonated form (1-
H+−3-H+), and accordingly the kH1 values reflect HAT from
the free phenolic O−H groups of these species to CumO• as
described in Schemes 3 and 4. Comparison between the kH1
values thus obtained (kH1 = 3.0 × 106, 3.0 × 107, and 3.5 × 107
M−1 s−1 for 1-H+−3-H+, respectively) and the kH values
measured in acetonitrile under analogous experimental
conditions for HAT from phenol and 4-methoxyphenol to
The effect of Mg(ClO4)2 on the reactions of CumO• with N-
benzylpiperidine and with phenols 2 and 3 has been also
investigated. The kobs vs [substrate] plots thus obtained are
displayed in the Supporting Information as Figures S14−S16.
When the reaction between CumO• and N-benzylpiperidine
was studied in the presence of 10 mM Mg(ClO4)2 (Figure
S14), no increase in kobs was observed up to [N-
benzylpiperidine] = 3/2[Mg(ClO4)2],29 indicative of the
formation of a Lewis acid−base complex between Mg2+ and
the nitrogen center that strongly deactivates the α-C−H bonds
toward abstraction, in line with the very large decreases in HAT
reactivity that have been observed for the reactions between
CumO• and other tertiary alkylamines, after addition of
Mg(ClO4)2.17 In this context, it is important to point out
that a very recent computational study has shown that the
interaction between Mg2+ and the nitrogen lone pair of
triethylamine leads to a 5.1 kcal mol−1 increase in the α-C−H
BDE and to a greater than 4 order of magnitude decrease in
kH.30 For [N-benzylpiperidine] > 3/2[Mg(ClO4)2], a linear
increase in kobs with increasing [N-benzylpiperidine] has been
observed and the rate constant for HAT has been obtained
from the slope of this plot as kH = 1.1 × 108 M−1 s−1, a value
22
CumO• (kH = 1.1 × 107 M−1 s−1 and 8.3 × 107 M−1 s−1,
respectively) shows that the introduction of a protonated 1-
piperidinylmethyl ring substituent determines an up to 4-fold
decrease in the rate constant for HAT from the phenolic O−H
group. This behavior can be reasonably explained on the basis
of the electron-withdrawing effect exerted by the ammonium
group, as it is well-known that the introduction of EWG ring
substituents in phenols leads to an increase in the O−H bond
dissociation enthalpy (BDE) and to a corresponding decrease
in kH.11b,28
At [substrate] > [TFA] the kH2 values measured with 1 and 2
(1.2 × 107 and 2.5 × 107 M−1 s−1, respectively) reflect instead
HAT from the α-C−H bonds of intramolecularly hydrogen
bonded 1 and 2 (Scheme 1), as confirmed by the observation
that these values are in both cases very close to the values
measured previously for reaction of CumO• with 1 and 2 in
acetonitrile, in the absence of TFA (kH = 1.7 × 107 and 3.4 ×
107 M−1 s−1, respectively; see above). Support for this
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that is again very close to the value measured previously for the
reaction of CumO• with N-benzylpiperidine in acetonitrile, in
the absence of Mg(ClO4)2 (kH = 1.3 × 108 M−1 s−1; see above
and Figure S7 (Supporting Information)), indicating that under
these conditions the measured rate constant reflects HAT from
the α-C−H bonds of the noncomplexed amine.
radicals has been evidenced in enzymatic redox reactions
occurring in systems such as PSII, ribonucleotide reductase,
prostaglandin H synthase, and galactose, oxidase,1,4,31 as well as
in the nitration of tyrosine residues, an important oxidative
post-translational modification occurring in proteins.32,33 The
understanding and, possibly, the quantification of the role
played by structure and external stimuli in the formation of
phenoxyl radicals can also be extremely useful to aid organic
chemists in the design of simple bioinspired catalysts able to
mimic nature in crucial processes, such as stereo- and
chemoselective oxidations or energy transfer and storage.
By taking into account this strong deactivation of the α-C−H
bonds determined by Mg2+ complexation, the kH values
measured after reaction of CumO• with phenols 2 and 3 in
the presence of Mg(ClO4)2 at [substrate] ≤ [Mg(ClO4)2] (kH
= 8.3 × 107 and 6.4 × 107 M−1 s−1; Figures S15 and S16
(Supporting Information), respectively) are assigned to HAT
from the free phenolic O−H groups. This is in full agreement
with the spectral evidence provided above for the reaction of
CumO• with 2 in the presence of Mg(ClO4)2 (Figure S9
(Supporting Information)), indicative of the formation of a 4-
methoxyphenoxyl radical bound to magnesium through the
piperidine nitrogen. Very interestingly, the kH values measured
under these conditions are very close to the kH value measured
for HAT from 4-methoxyphenol to CumO• (kH = 8.3 × 107
M−1 s−1) and are 2−3 times higher than the corresponding kH
values measured for HAT from the O−H bonds of 2-H+ and 3-
H+ discussed above. By ruling out HAT from the α-C−H
bonds of Mg2+-bound 2 and 3,17 this behavior may be explained
in terms of perchlorate binding to magnesium in the Lewis
acid−base complex with the piperidine nitrogen that results in a
weaker electron withdrawing effect of this group in comparison
to a protonated piperidinylmethyl group.
In conclusion, the results obtained in this study have clearly
shown that in the reactions between CumO• and phenols 1−3
both the HAT reactivity and selectivity can be drastically
influenced by the interplay between intramolecular hydrogen
bonding and acid−base interactions. In acetonitrile intra-
molecular hydrogen bonding with the piperidine nitrogen,
which is operative with phenols 1 and 2, protects the phenolic
O−H group from HAT and leads to a certain extent of
deactivation of the α-C−H bonds, quantified in the almost 1
order of magnitude decrease in kH measured on going from 1 to
N-benzylpiperidine, where the nitrogen atom is not involved in
hydrogen bonding. Under these conditions exclusive HAT from
the α-C−H bonds of 1 and 2 is observed. With the free phenol
3 HAT occurs from the α-C−H and O−H bonds. Addition of
TFA leads to stoichiometric nitrogen protonation that results in
the removal of the intramolecular hydrogen bond interaction in
1-H+ and 2-H+ and in a strong deactivation of the α-C−H
bonds of 1-H+−3-H+. Under these conditions exclusive HAT
from the free phenolic O−H group of these substrates occurs.
An analogous effect has been observed in the reactions of
CumO• with 2 and 3 after addition of Mg(ClO4)2 where the α-
C−H deactivation determined by a Lewis acid−base interaction
between the magnesium ion and the piperidine nitrogen leads
in both cases to exclusive HAT from the phenolic O−H, clearly
showing that, in addition to protonation, also Mg2+ complex-
ation with a Lewis basic center can be successfully exploited as a
tool to control the HAT selectivity. Along these lines, the
results obtained in this study suggest that, in the reaction
between free radicals and phenolic compounds of biological
interest, the interplay between hydrogen bonding and both
Brønsted and Lewis acid−base interactions can be of crucial
importance in modulating the formation of phenoxyl radicals.
In particular, these findings appear to be of great interest in the
framework of the important role played by tyrosyl radicals in a
variety of processes. For example, the intermediacy of tyrosyl
EXPERIMENTAL SECTION
■
Materials. Spectroscopic grade acetonitrile was used in the kinetic
experiments. Dicumyl peroxide, trifluoroacetic acid (TFA), and
magnesium perchlorate (Mg(ClO4)2) were of the highest commercial
quality available and were used as received. Phenols 2 and 3 were
available from a previous work.9 Phenol 1 was prepared by the Betti
reaction of phenol with paraformaldehyde and piperidine, according to
a previously described procedure.34 Paraformaldehyde (319 mg, 10.63
mmol) was dissolved in MeOH (1.5 mL) containing NaOH (2 mg);
to this solution was added piperidine (905 mg, 10.63 mmol) in 0.5 mL
of MeOH at 10 °C in 5 min, and after the mixture was warmed to
room temperature, phenol (1000 mg, 10.63 mmol) was added in
portions. The reaction mixture was heated to reflux with stirring for 17
h and then cooled to room temperature, diluted with EtOAc (100
mL), and washed with saturated NH4Cl (100 mL). The organic phase
was extracted with a HCl 1 M solution (200 mL), and the aqueous
phase was basified with a solution of 10 M NaOH until pH 8 and
extracted with EtOAc (2 × 100 mL). The combined organic phases
were dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum to obtain the desired product as a pale yellow oil (609 mg,
1
30% yield), identified by H and 13C NMR (Supporting Information,
Figures S17 and S18).
N-Benzylpiperidine was prepared by reductive amination of
benzaldehyde with piperidine according to a previously described
procedure.35 In a round-bottomed flask containing benzaldehyde
(0.658 g, 5.9 mmol) in distilled 1,2-dichloroethane (20 mL) was added
piperidine (0.500 g, 5.9 mmol). Then, sodium triacetoxyborohydride
(1.852 g, 8.3 mmol) was added in small portions and the reaction
mixture was stirred at room temperature overnight. After 20 h the
mixture was diluted with 80 mL of dichloromethane, and the organic
phase was washed with a saturated solution of NaHCO3 (3 × 100
mL), dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum. The crude material was purified by washing the organic phase
with a HCl 0.1 M solution (3 × 50 mL); the aqueous layer was basified
to pH 10 with a 1 M solution of NaOH and then extracted with DCM
(3 × 50 mL). The organic phases were recollected, dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain
the desired product as a yellow oil (413 mg, 40% yield), identified by
1H NMR (Supporting Information, Figure S19).
The occurrence of a strong intramolecular O−H- - -N hydrogen
bond in 1 is confirmed by the large downfield shift exhibited by the
phenolic proton in the 1H NMR spectrum (10.4 ppm as compared to
the usual 5−7 ppm value; see the Supporting Information).5a The
intramolecularly hydrogen bonded nature of 2 has been previously
established.9
Laser Flash Photolysis Studies. LFP experiments were carried
out with a laser kinetic spectrometer using the third harmonic (355
nm) of a Q-switched Nd:YAG laser, delivering 8 ns pulses. 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 in all
experiments. Argon- or oxygen-saturated acetonitrile solutions of
dicumyl peroxide (1.0 M) were employed. All of the experiments were
carried out at T = 25 0.5 °C with magnetic stirring. The observed
rate constants (kobs) were obtained by averaging two to five individual
values and were reproducible to within 5%.
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Second-order rate constants for the reactions of the cumyloxyl
radical with the different substrates were obtained from the slopes of
the kobs (measured following the decay of the cumyloxyl radical visible
absorption band at 490−540 nm nm) vs [substrate] plots. In the
experiments carried out in the presence of TFA or Mg(ClO4)2, care
was taken in order to keep the concentration of these compounds
constant throughout the experiment. Fresh solutions were used for
every substrate concentration.
Lam, O. P.; Lockwood, M. A.; Rotter, K.; Mayer, J. M. J. Am. Chem.
Soc. 2006, 128, 6075−6088.
(7) (a) Zhang, M.-T.; Irebo, T.; Johansson, O.; Hammarstrom, L. J.
̈
Am. Chem. Soc. 2011, 133, 13224−13227. (b) Hammarstrom, L.;
̈
Styring, S. Energy Environ. Sci. 2011, 4, 2379−2388. (c) Irebo, T.;
Johansson, O.; Hammarstrom, L. J. Am. Chem. Soc. 2008, 130, 9194−
̈
9195. (d) Sjodin, M.; Irebo, T.; Utas, J. E.; Lind, J.; Meren
́
yi, G.;
̈
Åkermark, B.; Hammarstrom, L. J. Am. Chem. Soc. 2006, 128, 13076−
̈
13083.
ASSOCIATED CONTENT
(8) (a) Bonin, J.; Costentin, C.; Robert, M.; Savea
Acc. Chem. Res. 2012, 45, 372−381. (b) Costentin, C.; Robert, M.;
Saveant, J.-M.; Tard, C. Angew. Chem., Int. Ed. 2010, 49, 3803−3806.
(c) Costentin, C.; Robert, M.; Saveant, J.-M. Phys. Chem. Chem. Phys.
2010, 12, 11179−11190. (d) Costentin, C.; Robert, M.; Saveant, J.-M.
J. Am. Chem. Soc. 2007, 129, 9953−9963. (e) Costentin, C.; Robert,
M.; Savea
́
nt, J.-M.; Tard, C.
■
S
* Supporting Information
́
Figures giving time-resolved spectra and plots of kobs vs
substrate concentration for the reactions of CumO• and NMR
spectra of phenol 1 and of N-benzylpiperidine. This material is
available free of charge via the Internet at http://pubs.acs.org.
́
́
́
nt, J.-M. J. Am. Chem. Soc. 2006, 128, 4552−4553.
(9) Amorati, R.; Menichetti, S.; Viglianisi, C.; Foti, M. C. Chem.
AUTHOR INFORMATION
Commun. 2012, 48, 11904−11906.
■
(10) For a comparison between the reactivity of alkoxyl and peroxyl
radicals in HAT reactions from the α-C−H bonds of alkylamines, see
for example: Griller, D.; Howard, J. A.; Marriott, P. R.; Scaiano, J. C. J.
Am. Chem. Soc. 1981, 103, 619−623.
Corresponding Authors
*E-mail for M.S.: michela.salamone@uniroma2.it.
*E-mail for M.B.: bietti@uniroma2.it.
Notes
(11) For a comparison between the reactivity of alkoxyl and peroxyl
radicals in HAT reactions from the O−H group of phenols see for
example: (a) Jha, M.; Pratt, D. A. Chem. Commun. 2008, 1252−1254.
(b) Snelgrove, D. W.; Lusztyk, J.; Banks, J. T.; Mulder, P.; Ingold, K.
U. J. Am. Chem. Soc. 2001, 123, 469−477.
(12) Baciocchi, E.; Bietti, M.; Salamone, M.; Steenken, S. J. Org.
Chem. 2002, 67, 2266−2270.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministero dell’Istruzione dell’Uni-
versita
̀
e della Ricerca (MIUR), PRIN 2010-2011, project
2010PFLRJR (PROxi) is gratefully acknowledged. We thank
Prof. Lorenzo Stella for the use of LFP equipment and Dr.
Federica Ceccherini for the preparation of N-benzylpiperidine.
(13) Avila, D. V.; Ingold, K. U.; Di Nardo, A. A.; Zerbetto, F.;
Zgierski, M. Z.; Lusztyk, J. J. Am. Chem. Soc. 1995, 117, 2711−2718.
(14) (a) Bietti, M.; DiLabio, G. A.; Lanzalunga, O.; Salamone, M. J.
Org. Chem. 2010, 75, 5875−5881. (b) Donkers, R. L.; Maran, F.;
Wayner, D. D. M.; Workentin, M. S. J. Am. Chem. Soc. 1999, 121,
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